Carbon-Nitrogen Bond Formation via Catalytic Alcohol Activation

University of Groningen

Carbon-nitrogen bond formation via catalytic alcohol activationYan, Tao

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Carbon-Nitrogen Bond Formation

via Catalytic Alcohol Activation

Tao Yan

The work described in this thesis was carried out at the Stratingh Institute for

Chemistry, University of Groningen, The Netherlands.

This work was financially supported by University of Groningen.

Cover design by Tao Yan.

Printed by Ipskamp Printing, Enschede, The Netherlands.

ISBN: 978-94-034-0047-1 (printed version)

ISBN: 978-94-034-0046-4 (digital version)

faculty of science and engeneering

stratingh institute for chemistry

Carbon-Nitrogen Bond Formation via Catalytic Alcohol Activation

PhD thesis

to obtain the degree of PhD at the University of Groningen on the authority of the

Rector Magnificus Prof. E. Sterken and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Monday 18 September 2017 at 12.45 hours

by

Tao Yan

born on 27 June 1990 in Anhui, China

Supervisors

Prof. B. L. Feringa

Prof. K. Barta

Assessment Committee

Prof. J. G. de Vries

Prof. B. de Bruin

Prof. M. Beller

Contents

Chapter 1

Borrowing hydrogen meets metal-ligand bifunctional catalysis, an introduction to the thesis

1

Chapter 2

Iron catalyzed direct alkylation of amines with alcohols

21

Chapter 3

Benzylamines via iron catalyzed direct amination of benzyl alcohols

49

Chapter 4

Pyrroles via Iron-Catalyzed N-Heterocyclization from Unsaturated Diols and Primary Amines

75

Chapter 5

Direct N-alkylation of unprotected amino acids with alcohols

93

Chapter 6

Ruthenium catalyzed N-alkylation of amino acid esters with

121

Nederlandse samenvatting 141

English summary 143

Acknowledgements 145

1

Chapter 1

Borrowing hydrogen meets metal-ligand bifunctional catalysis,

an introduction to the thesis

1.1 Introduction

1.1.1 Catalysis: key to a sustainable future

1.1.2 Catalytic carbon-nitrogen bond formation: the focus of this thesis

1.2 Metal-ligand bifunctional catalysis

1.2.1 Background

1.2.2 The Shvo catalyst

1.2.3 The Knölker complex

1.2.4 Recent progress in bifunctional catalysis

1.3 Catalysis based on the borrowing hydrogen strategy

1.3.1 Alkylation of amines with alcohols through borrowing hydrogen

1.3.2 Challenges and recent discoveries

1.4 Conclusion

1.5 Outline of the thesis

Chapter 1

2

1.1 Introduction

1.1.1 Catalysis: the key to a sustainable future

Catalysis is the tool to tune the kinetics of a chemical transformation, that allows

desired reactions to be conducted selectively, under mild reaction conditions.[1]

Catalysis is one of the few areas with a direct influence on our daily life.[2] It

contributes directly and indirectly to 35% of the global GDP.[3]

Currently, a variety of chemical transformations still rely on the use of

stoichiometric reagents and low atom economy processes.[1,2,4] These include the

use of protecting groups or harsh reaction conditions, mainly due to high activation

energy of the desired transformations. During these processes, stoichiometric

amount of side-products are produced and frequently discarded. Also, the

increasing demand for a more environmental benign society and the changing

landscape of accessible chemical feedstocks and energy sources, indicate we are

facing a transition period of energy and chemical production.[5]

Catalysis, beyond accelerating chemical transformations, allows the use of

renewable carbon sources through converting bio-based molecules and CO2 to

more valuable chemicals, as well as accessing alternative energy such as

converting and storing solar energy in chemicals.[5,6] Consequently, the new

advances in catalysis will not only lead to considerable economic benefit, but more

importantly, are key to build a sustainable society.[7]

1.1.2 Catalytic carbon-nitrogen bond formation: the focus of this thesis

This thesis discusses an alternative methodology to construct carbon-nitrogen

bonds[8], using widely abundant alcohols as substrates instead of the traditional

alkyl halides or aldehydes, promoted by metal-ligand bifunctional catalytic systems.

As an introduction to this thesis, this chapter gives background to the field of

ligand-metal bifunctional catalysis which is dramatically changing the face of

chemistry, in particular redox chemistry.[9] The introduction will include catalysis

based on the borrowing hydrogen strategy which will be also extensively involved

in the following chapters. Further, literature background to the Shvo catalyst[10a]

and the Knölker complex[10b] which are important catalysts employed in this thesis

will also be discussed.

1.2 Metal-ligand bifunctional catalysis

1.2.1 Background

Transition metal catalyzed chemical transformations promote the efficient and

environmentally benign synthesis of molecular targets[11]. In conventional

transition metal based catalysis, the coordination and further transformation of the

substrate is performed at the metal center and the role of the ligand is to keep the

metal complex in solution as well as regulate the electronic and steric properties

of the transition metal complex[12]. However, there is a class of catalysts, in that

the coordination and chemical transformation occurs on both the metal center as

well as the ligand. An early example from the Noyori group described the

Introduction to the thesis

3

asymmetric hydrogenation of ketones using a ruthenium diphosphine-diamine

complex.[13] The diamine ligand acts as the proton donor that stabilizes the alkoxy

before forming an alcohol by reduction of a simple ketone (Scheme 1, intermediate

1). It was proposed that the substrate is in the second coordination sphere of the

catalyst complex, not directly coordinated to the metal center[14] (Scheme 1, A).

The original halogen contained BINAP-Ru(II) complexes were only found to be

active for hydrogenation of functionalized ketones with nitrogen, oxygen or

halogen atoms near the carbonyl group (Scheme 1, B)[15]. In the latter case, the

additional heteroatom is required to form a metallacycle (Scheme 1, intermediate

2) to stabilize the alkoxy ligand before protonation. The type of catalysis described

in Scheme 1A was coined as ‘metal-ligand bifunctional catalysis’ by Noyori in

2001.[9a,16]

Scheme 1: A Asymmetric hydrogenation of acetophenone with a ruthenium BINAP

diamine complex; B asymmetric hydrogenation of activated carbonyls with

ruthenium BINAP complex.

1.2.2 The Shvo catalyst

In 1984, it was reported by the Shvo group that the reactivity of transfer

hydrogenation reactions catalyzed by triruthenium dodecacarbonyl was

significantly improved by adding diphenylacetylene (Scheme 2, A).[17] Later on, it

was proven that a ruthenium complex bearing cyclopentadienone was formed and

played an essential role.[18] The structure of the complex was determined by X ray

spectroscopic analysis (Scheme 2, B) by the Shvo group.[10a] The initial synthetic

approach to obtain this complex took 2 steps (Scheme 2, C, a) during which

Ru3(CO)12 (3) and tetraphenylcyclopentadienone (4) were heated to reflux in

benzene, forming [Ph4(4-C4CO)]-Ru(CO)3 (Cat 2)[19]. Subsequently, Cat 2 was

refluxed in isopropanol to give Shvo’s catalyst (Cat 1)[10a]. An alternative synthetic

Chapter 1

4

approach to Cat 1 was reported by Bäckvall and coworkers through sequentially

treating Cat 2 with an aqueous Na2CO3 in acetone, and an aqueous NH4Cl (Scheme

2, C, b)[20]. Finally, a concise, one-step synthesis of Cat 1 was reported by Casey

through heating 3 and 4 in methanol (Scheme 2, C, c)[21].

Scheme 2: A Crystal structure of Cat 1; B approaches of preparation of Cat 1.

Shvo’s catalyst was mainly applied in hydrogen transfer reactions (Scheme 3, A),

for example, oxidative coupling of primary alcohols to esters[22a], oxidation of

alcohols to ketones[22b] or to form imines with amines[22c], and the hydrogenation

of ketones, alkenes[22d] and imines[23]. The complex was also successfully used in

the dynamic kinetic resolution of secondary alcohols through the coupling of

enzyme catalyzed acetylation of one of the alcohol enantiomers and Cat 1

catalyzed racemization of the remaining alcohols[24]. Recently, several hydrogen

auto-transfer reactions were also reported using Shvo’s catalyst, including N-

alkylation of amines with aliphatic amines[25a], C-3-alkylation of indoles[25b] and tri-

alkylation of ammonium salts with alcohols[25c].

Scheme 3: Selected reactions catalyzed by Cat 1.


5

The bench-stable diruthenium complex Cat 1 actually is still a pre-catalyst which

is activated by heat and dissociates into two mono-ruthenium complexes, a 16-

electron species Cat 2-O, and an 18-electron complex Cat 2-H (Scheme 4, A).

Cat 2-H was the first reported well-defined metal-ligand bifunctional catalyst. The

formed Cat 2-O can then participate in, for example, dehydrogenation of

isopropanol to form acetone and Cat 2-H, and subsequent hydrogenation of

acetophenone reforms Cat 2-O through intermediate 3 (Scheme 4, B).

The reactivity and application of this complex has been extensively reviewed in

2005[26a], 2009[26b], 2010[26c] and 2011[26d].

Scheme 4: A Activation of Cat 1; B catalytic properties of Cat 2-H and Cat 2-O.

1.2.3 The Knölker complex

One of the first iron complexes used in organic synthesis was Fe(CO)5.[27] Back in

the 1950s, the reaction of Fe(CO)5 with alkynes was reported to be a [2+2+1]-

cycloaddition[28ab] (Scheme 5, A) resulting in the formation of tricarbonyl(4-

Chapter 1

6

cyclopentadienone)iron complex. The cyclopentadienone ligands obtained through

demetallation of the complexes had drawn considerable interest.[28c] However, the

reactivity of the complexes was not explored.

Scheme 5: A [2+2+1]-cycloaddition between Fe(CO)5 and 2 alkynes; B synthesis

of Cat 3 and Cat 3-H.

Until 1999, Knölker and coworkers reported key reactivity studies of tricarbonyl

cyclopentadienone complexes[10b]. It was observed, that especially when treating

iron complex Cat 3 that bears two trimethylsilane (TMS) substituents, sequentially

with aqueous NaOH in tetrahydrofuran (THF) and H3PO4, the mono-iron hydride

complex Cat 3-H (Knölker complex) can be obtained (Scheme 5, B). Cat 3-H was

fully characterized also by X ray analysis (Scheme 6, A)[10b].

Scheme 6: A Crystal structure of Cat 3-H; B mechanistic illustration of Cat 3-H

catalyzed hydrogenation of acetophenone; C Relative activity for stoichiometric

acetophenone reduction in toluene-d8 at 5 °C.

In 2007, the first catalytic reactivity of the Knölker complex (Cat 3-H) was

discovered by Casey and Guan[29] (Scheme 6, B). It was established, that the iron

hydride complex Cat 3-H, acts as a metal-ligand bifunctional catalyst in the


7

hydrogenation of ketones. In this case, the non-innocent[30] cyclopentadienone

backbone acts as a proton donor, while the metal center bears the hydride. In this

way, selective reduction of polar unsaturated bonds such as C=O and C=N[31]

becomes possible through an appropriate intermediate (such as intermediate 4).

The formed Cat 3-O can be reduced to Cat 3-H with molecular hydrogen (Scheme

6, B). Later, in 2012 Casey and Guan reported that iron hydride complexes Cat 3-

H and Cat 5-H give comparable activity to the ruthenium hydride complex Cat 4-

H in stoichiometric acetophenone reduction. This suggests that these more

economical iron catalysts are attractive alternatives to ruthenium catalysts

(Scheme 6, C)[32]. The dimerization of Cat 3-H or Cat 4-H for providing binuclear

species as Cat 1 has not been detected, suggesting that the bulky TMS groups

prevent such formation of the hydride bridged dimeric complexes.

Scheme 7: Tricarbonyl(4-cyclopentadinenone)iron complexes in catalysis: (A)

hydrogen transfer reactions and (B) dual catalysis.

Chapter 1

8

After Casey and Guan’s initial discovery on the catalytic behaviour of the Knölker

complex, several studies involving this complex have been reported. These

included reductive amination[31], hydrogenation of carbonyl compounds and imines

in water[33], transfer hydrogenation of carbonyl compounds and imines[34],

Oppenauer-type oxidation of alcohols[35] (Scheme 7, A). Furthermore, catalytic

systems involving dual catalysis were described, in which the Knölker complex

catalyzed hydrogen transfer reactions were coupled with organo-catalysis[36] or

enzyme promoted transformations[37] (Scheme 7, B). Moisture and air stable

complex Cat 3 is frequently used as a pre-catalyst. One CO ligand in Cat 3 can be

easily removed by Me3NO, generating Me3N, CO2 and active species Cat 3-O

(Scheme 6A).

Several analogues of the original complex have been reported through steric and

electronic modifications[38] of Cat 3 (Scheme 8). Modifications of the proton donor

site on the non-innocent ligand were reported by Nakazawa[39] and Guan[40], and

chirality was introduced to the metal complex by Wills[41], Berkessel[42] and

Gennari[43]. The field has been reviewed by Knölker[44], Guan[45], as well as

Quintard and Rodriguez[46] recently.

Scheme 8: Analogues of Knölker’s complex.

1.2.4 Recent progress in metal-ligand bifunctional catalysis

Since Noyori’s ruthenium diphosphine-diamine system was reported in 1995,

besides the development of the Shvo and Knölker complexes, considerable

progress has been established in this area[47,59]. For example, Morris and coworkers

reported well-defined iron complexes bearing PNNP ligands (such as Cat 8, shown

in Scheme 9) for the asymmetric transfer hydrogenation of carbonyl compounds

and imines. The reactions were completed within minutes in most cases, and the

ee reached 99% when imines were employed as the substrates[48]. Related to these

excellent results established by the Morris group, Bullock highlighted the potential

of iron-based catalysts to reach reactivity comparable to that obtained with noble

metal catalysts[49] (Scheme 9).


9

Scheme 9: Comparison of bifunctional catalyst systems developed by Noyori and

Morris.

In 2004, Milstein and coworkers reported a new type of ruthenium pincer complex,

that operates via the aromatization-rearomatization of a pyridine based

heteroaromatic ligand. This complex catalyzed the acceptorless dehydrogenation

of alcohols to ketones[50] and esters[51]. Subsequently the acceptorless

dehydrogenation and coupling between alcohols and amines to form amides was

reported[52] (Scheme 10, A). Comparing to classical metal-ligand bifunctional

catalysts that bear N-donors to activate H2 or alcohols and subsequently reducing

polar unsaturated bonds, the Milstein-type pincer complex has a C-donor (Scheme

10, B), and is able to activate a wider variety of bonds, including N-H bonds[53],

CO2[54], nitriles[55] and O2

[56].

Scheme 10: A Milstein pincer complex catalyzed acceptorless dehydrogenative

coupling for the synthesis of esters and amides; B activation of H2 by the Milstein

pincer complex Cat 9.

Recently, a number of new metal-ligand bifunctional catalysts have been

reported[57]. Selected examples are shown in Scheme 11, in which the structures

shown are after dihydrogen activation. In these complexes, the p- or π electron on

the ligand offers a proton acceptor site that is involved in the heterolytic splitting

of dihydrogen which results in the formation of the corresponding metal hydride.

Interestingly, Harman and Peters recently reported a nickel complex featuring a

borane moiety in the supporting ligand scafford (Scheme 11)[57e]. The property of

this complex is more comparable to a heterobimetallic complex (boron mimics a

second metal)[58] instead of a Noyori-type bifunctional complex. The catalytic

Chapter 1

10

applications of metal-ligand bifunctional complexes were reviewed by

Khusnutdinova and Milstein recently[59].

Scheme 11: Metal-ligand bifunctional complexes.

Starting from the reduction of polar unsaturated bonds, through the activation of

diverse bonds, to the recent application in the ‘borrowing hydrogen’ chemistry,

metal-ligand bifunctional complexes that operate based on metal-ligand

cooperation, have opened the gate to more efficient catalysis.

1.3 Catalysis based on borrowing hydrogen strategy

1.3.1 Alkylation of amines with alcohols through borrowing hydrogen

Selective C-N bond formation is a challenging task for synthetic chemists[8]. The

traditional methodologies include reductive amination of carbonyl compounds[60],

or nucleophilic substitution of amines with alkyl halides[61]. These methods,

however, suffer from either unstable and limited accessible substrates or the

formation of stoichiometric amounts of side products as waste. In the chemical

industry, alcohols are preferred reaction partners for alkylation of ammonia or

various amines, they however require harsher reaction conditions[62].

Scheme 12: First examples on transition metal catalyzed alkylation of amines

with alcohols by (A) Grigg and (B) Watanabe.


11

In 1981, Grigg and coworkers reported the first example of alkylation of amines

with alcohols under significantly milder conditions using transition metal

catalysts[63] (Scheme 12, A). They proposed that the reactivity of the alcohol was

improved by the formation of the corresponding carbonyl compound, which

subsequently underwent imine formation with the amine reaction partner.

Reduction of this imine intermediate resulted in the alkylated amine. At around the

same time, Watanabe and coworkers also reported the alkylation of anilines with

various alcohols catalyzed by a ruthenium complex[64] (Scheme 12, B).

Following these studies, during the past 3 decades, various catalytic systems have

been developed for direct alkylation of amines with alcohols, mostly using

ruthenium or iridium based catalysts[65] (Scheme 13). This field has been

extensively reviewed[66].

Scheme 13: Alkylation of amines with alcohols catalyzed by ruthenium or iridium

based catalytic systems.

Chapter 1

12

To characterize these types of reactions, Williams et al. coined the term ‘borrowing

hydrogen’[67] in 2004. During the catalytic cycle, an alcohol is dehydrogenated to

the corresponding carbonyl compound, which reacts with the amine to form an

imine (Scheme 14, A). The hydrogen delivered from the alcohol is temporarily

stored at the metal complex. The imine is reduced in situ to the alkylated amine

by the hydrogen stored on the metal complex. Key features are that the process

is hydrogen neutral, no other reagents are needed and the only stoichiometric by-

product is water. Variations of this reaction have also been reported, for instance,

C-C bond formation through alcohol activation[68,69] (Scheme 14, B) and alkane

metathesis through dehydrogenation of alkane to alkene, alkene metathesis and

hydrogenation of alkene to alkane[70] (Scheme 14, C).

Scheme 14: A Proposed mechanism of alkylation of amines with alcohols through

borrowing hydrogen; B C-C bond formation through alcohol activation; C alkane

metathesis through borrowing hydrogen.

Alkylation of amines with alcohols through borrowing hydrogen has been applied

in the pharmaceutical industry due to its significant economic benefit compared to

traditional methodologies of N-alkylations[66]. For example, Pfizer recently

developed a new pathway for synthetizing a GlyT1 inhibitor (9) (Scheme 15)[65h].

Comparing to conventional pathway, the key optimization was a direct amination

of alcohol 6 with amine 7 to provide the key intermediate 8 through the borrowing

hydrogen strategy. It is a redox-neutral process that avoids the use of

stoichiometric amount of oxidant and reductant.


13

Scheme 15: Conventional and Pfizer’s pathway for the synthesis of a GlyT1

Inhibitor.

1.3.2 Challenges and recent discoveries

The borrowing hydrogen strategy has been recognized as a key concept in catalysis

and sustainable chemistry, as it is a highly atom economic process[71]. Since the

first examples reported by the groups of Grigg[63] and Watanabe[64], and till recent

discoveries[65,66], most reactions were promoted by ruthenium or iridium based

catalytic systems. After three decades of discovery, the scientific community

realized that the main challenge was to developa non-precious metal based

catalyst for promoting this transformation[66d,72]. Iron with its high Earth-

abundance[73a], low cost[73b] and toxicity[73c], has been identified as an attractive

candidate.

In 2014, our group reported the first example of alkylation of amines with alcohols

with the well-defined bifunctional iron complex (Knölker complex)[74] (Scheme 16,

A). Subsequently, Wills and coworkers[75a] reported the same transformation with

an analogue complex Cat 16. Zhao and coworkers[75d] showed that with the

assistance of Lewis acids, the yields of alkylated amines could be significantly

improved when secondary alcohols were employed. The synthesis of allylic

amines[75c] and pyrroles[76], and -alkylation of ketones with alcohols[75d] were

further explored using the same catalytic system. In 2016, Kirchner and

coworkers[77] reported a PNP pincer type iron complex Cat 17 catalyzed alkylation

of amines with alcohols.

Besides iron, cobalt pincer complexes were successfully applied in the same

transformation by the groups of Kempe[78a], Zhang[78b] and Kirchner[78c] (Scheme

16). Also, novel catalytic systems based on manganese pincer complexes were

reported by the groups of Beller[79ab] and Sortais[79c] (Scheme 16, B). Several types

Chapter 1

14

of hetero-aromatics were also synthetized employing Co[80] and Mn[81] based

catalysts.

Scheme 16: (A) Iron, (B) Cobalt and manganese catalyzed alkylation of anilines

with alcohols.

1.4 Conclusion

In the past decades, tremendous progress has been made in the development of

metal-ligand bifunctional catalysis and the borrowing hydrogen strategy, mainly

with noble metal complexes. Recently, there is a clear interest in moving towards

non-precious metals based catalytic systems. In particular, iron based systems are

desired due to their lower toxicity, abundance and lower price as more sustainable

alternatives to noble metal catalysts.[73] Recent literature suggests that iron

catalysis is potentially able to cover the entire range of catalysis for organic

synthesis[44,82]. Carefully designed ligands which are capable of stabilizing as well

as cooperating with the metal center, are key for promoting desired chemical

transformations.


15

1.5 Outline of the thesis

This thesis describes the development of novel catalytic methods for the selective

alkylation of amines with alcohols through the borrowing hydrogen methodology,

using metal-ligand bifunctional complexes, in particular the Knölker complex and

the Shvo catalyst.

In Chapter 2, the discovery of the first well-defined iron complex catalyzed

alkylation of amines with alcohol is described. Chapter 3 describes the application

of the discovered method for transformations involving benzyl alcohols in order to

obtain benzylamines. In Chapter 4, iron catalyzed pyrrole synthesis is described

by N-heterocyclization of amines with unsaturated diols. Chapter 5 describes the

direct N-alkylation of unprotected amino acids with alcohols using the Knölker

complex and the Shvo catalyst with retention of stereochemistry. Chapter 6

describes the use of the Shvo catalyst in alkylation of amino acids esters with

alcohols, without racemization.

Chapter 1

16

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17

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Chapter 1

20

21

Chapter 2

Iron catalyzed direct alkylation of amines with alcohols

The selective conversion of carbon-oxygen bonds into carbon-nitrogen bonds to

form amines is one of the most important chemical transformations for the

production of bulk and fine chemicals and pharma intermediates. An attractive

atom economic way of carrying out such C-N bond formations is the direct N-

alkylation of simple amines with alcohols through the so-called borrowing

hydrogen strategy. Recently, transition metal complexes based on precious noble

metals have emerged as suitable catalysts for this transformation; however, the

crucial change towards highly selective methodologies, which use abundant,

inexpensive and environmentally friendly metals, in particular iron, has not yet

been accomplished. In this chapter, the homogeneous, iron-catalyzed, direct

alkylation of amines with alcohols is described. The scope of this new methodology

includes the selective monoalkylation of anilines and benzyl amines with a wide

range of alcohols as well as the use of diols in the formation of five-, six- and

seven- membered nitrogen heterocycles, which are privileged structures in

numerous pharmaceuticals.

Part of this chapter was published:

T. Yan, B. L. Feringa, K. Barta, Nat. Commun., 2014, 5, 5602.

Chapter 2

22

Introduction

Amines are among the most valuable classes of compounds in chemistry,

omnipresent in natural products, in particular alkaloids[2a], and widely used as

pharmaceuticals, agrochemicals, lubricants and surfactants[1,2,3]. Therefore the

development of efficient catalytic methodologies for C-N bond formation is a

paramount goal in organic chemistry.

The choice of an alcohol[4,5] as substrate for direct C-N bond formation is highly

desirable in order to produce secondary and tertiary amines and N-heterocyclic

compounds (Figure 1).

Figure 1: Catalytic, direct N-alkylation of amines with alcohols. a Conventional conversion

of alcohol into amine via installing a leaving group before nucleophilic substitution with an

amine donor or oxidizing alcohols to carbonyl compounds followed by reductive amination.

b The direct C–N bond formation via coupling of primary alcohols and amines forms

secondary amine products R1–NH–R2. R1–OH is a short- or long-chain aliphatic alcohol and

may contain aromatic functionality. R2–NH2 is an aromatic or aliphatic amine. c Using diols

of various chain lengths the products are 5- (n=1), 6- (n=2) or 7- (n=3) membered N-

heterocycles.

Alcohols are readily available through a variety of industrial processes and are

highly relevant starting materials in view of recent developments in the field of

renewables as they can be obtained via fermentation or catalytic conversion of

lignocellulosic biomass.[6,7] Conventional non-catalytic transformations of an amine

with an alcohol take place via installing a suitable leaving group instead of the

alcohol functionality followed by nucleophilic substitution, or oxidizing alcohols to

carbonyl compounds followed by reductive amination; these multistep pathways

suffer from low atom economy[8] or limited selectivity and the production of

stoichiometric amounts of waste (Figure 1a).[9]

A privileged catalytic methodology for the direct coupling of alcohols with amines

is based on the so-called borrowing hydrogen strategy (Figure 1b, 1c and Figure

2). During the catalytic cycle an alcohol is dehydrogenated to the corresponding

carbonyl compound, which reacts with the amine to form an imine. The imine is in

Alkylation of amines with alcohols

23

situ reduced to the alkylated amine and the metal complex facilitates the required

hydrogen shuttling. In fact the hydrogen delivered by the alcohol is temporarily

stored in the metal complex. Key features are that the process is hydrogen neutral,

no other reagents are needed and the only stoichiometric by-product is water.

A number of transition metal complexes have proven effective in this catalytic C-

N bond formation, in particular those based on ruthenium[10-12] and iridium[13].

These and related methodologies have been extensively reviewed[1,3,4,14-16].

Despite recent progress, the key challenge is the development of catalysts that

rely on the use of widely abundant, inexpensive metals[3,17]. Iron is considered to

be the ultimate, sustainable alternative for ruthenium[18], however, no unequivocal

reductive amination via a borrowing hydrogen mechanism has been reported[19].

Direct N-alkylation of amines with alcohols is limited to iron-halogenides under

rather harsh reaction conditions (160-200 °C), not proceeding via a hydrogen

autotransfer pathway[20].

This work shows that a well-defined homogenous Fe-based catalyst can be

successfully used in this atom-economic process, with a broad substrate scope.

These direct, Fe-catalyzed transformations are highly modular, and provide water,

as the only stoichiometric byproduct. The products are valuable secondary and

tertiary amines or heterocycles, which contain diverse moieties R1 (from the

alcohol substrate) and R2 (from the amine substrate) (Figure 1).

The presented direct waste-free alcohol to amine functional group interconversions

are important toward the development of sustainable iron based catalysis and will

enable the valorization of biomass-derived alcohols in environment-benign

reaction media.

Results and discussion

We reasoned that direct C-N bond formation with an iron catalyst is possible

provided by the catalytic complex which shows high activity both in alcohol

dehydrogenation (Figure 2a, Step 1) and imine hydrogenation (Figure 2a, Step 3).

The realization of this concept for direct alkylation of amines with alcohols using

cyclopentadieneone iron tricarbonyl complex Cat 3, the precurse to form Knölker’s

complex[21] Cat 3-H, is presented here (Figure 2). Iron cyclopentadienone complex

Cat 3 (Figure 2b), has been recently employed in catalysis including hydrogenation

of ketones[22], reductive amination[23], transfer hydrogenation of carbonyl

compounds and imines[24a], Oppenauer-type oxidation of alcohols[24b] as well as

cooperative dual catalysis[25]. Given its unique reactivity, we considered Cat 3 a

promising candidate for the development of the desired iron-catalyzed hydrogen

borrowing methodology. To achieve the direct amination of alcohols, the key

challenge is to match alcohol dehydrogenation and imine hydrogenation steps by

establishing conditions under which the formed Fe-H species (Cat 3-H) from the

initial alcohol dehydrogenation step is able to reduce the imine at a sufficient rate,

not requiring the use of dihydrogen.

Chapter 2

24

Catalytic N-alkylation with alcohols Preliminary experiments using 4-

methoxyaniline (1a) and a simple aliphatic alcohol, 1-pentanol (2a), with 5 mol%

pre-catalyst Cat 3 and 10 mol% Me3NO oxidant (to form active Cat 3-O) at 110 °C

in toluene showed the formation of 4-methoxy-n-pentylaniline (3aa), albeit with

only 30% selectivity at 48% substrate conversion (Table 1, entry 1). Although

promising, the initial results using common organic solvents indicated low

conversion of 1a or low selectivity towards 3aa and analysis of the reaction

mixtures identified insufficient imine reduction as the key problem. We reasoned

that most probably a weakly coordinating ethereal solvent is needed to stabilize

the key iron intermediates Cat 3-O[27]. In addition, imine formation might be

facilitated in solvents, which have limited miscibility with water. The major

breakthrough came when the green solvent cyclopentyl methyl ether (CPME), one

that uniquely combines such properties, was selected as reaction medium. CPME

recently emerged as a low-toxicity, sustainable solvent alternative for

tetrahydrofuran[28].

Figure 2 Individual reaction steps in the iron-catalyzed N-alkylation of amines using iron

cyclopentadienone complexes. a The overall transformation is the direct coupling of an

alcohol (R1–OH) with an amine (R2–NH2) to form the product amine (R1–NH–R2). The

sequence of reaction steps starts with the dehydrogenation of R1–OH to the corresponding

aldehyde with iron complex Cat 3-O (Step 1). Thereby one ‘hydrogen equivalent’ is

temporarily stored at the bifunctional iron complex Cat 3-O, which is converted to its

reduced, hydride form Cat 3-H. In Step 2, the carbonyl intermediate reacts with amine

R2–NH2 to form an imine intermediate and water. In Step 3, the hydrogen equivalent

“borrowed” from alcohol R1–OH are used in the reduction of the imine intermediate to

obtain the desired product R1–NH–R2. The reduction is accompanied by conversion of iron

hydride Cat 3-H to Cat 3-O, thereby a vacant coordination site is regenerated and the

catalytic cycle closed. b Reactivity of Fe cyclopentadienone complexes: Cat 3 is an air- and

moisture-stable iron tricarbonyl precatalyst. The active Cat 3-O complex is in situ

generated from Cat 3 by the addition of Me3NO to remove one CO. Cat 3-O is readily

converted to Cat 3-H by reaction with an alcohol.


25

Table 1: Optimization of reaction conditions for N-alkylation of p-methoxyaniline

(1a) with 1-pentanol (2a).

Entry 2a

[eq.]

Sol. T

[°C]

Conv. 1a

[%]a

Sel. 3aa

[%]a

Sel. 4aa

[%]a

1 1 Toluene 110 48 30 10

2 2 Toluene 110 71 50 20

3 2 DCE 110 75 15 41

4 2 CH3CN 110 10 <2 <2

5 2 DMF 110 18 10 2

6 2 THF 110 42 22 19

7 2 Dioxane 110 50 34 15

8 2 CPME 110 88 74 13

9b 2 CPME 110 77 67 9

10c 2 CPME 110 8 0 0

11 2 CPME 130 97 94 (91) 2

12 1 CPME 130 99 95 <1

13 6 CPME 130 99 90 <1

General reaction conditions: General Procedure A, 110 or 130 °C, 2 ml solvent, 18 h,

isolated yield in parenthesis. aConversion and selectivity were determined by GC-FID; bCat

3b was used without Me3NO; cCat 3 was used, Me3NO was replaced by 10 mol% NaOH.

In CPME at 110 °C, amine 1a is alkylated with pentanol to provide 3aa in 74%

selectivity at 88% conversion of 1a. Full conversion of 1a and an excellent (91%)

isolated yield of 3aa were obtained at slightly higher temperature (130 °C) (Table

1, entry 11). Product formation profiles (Table 2) show that the reaction is highly

selective and essentially complete within 7 h. The concentration of the imine

intermediate stays constantly low, and exclusive mono-N-alkylation to 3aa with

increasing 1a conversion is observed. Although multiple N-alkylation is often a

notorious side reaction[1], it should be noted that the use of 1 equiv of alcohol 2a

is sufficient to form 3aa selectively and even a larger excess (6 equiv) of 2a did

not result in further alkylation of the secondary amine product (Table 1, entry 12

and 13).

Chapter 2

26

Table 2: Product formation profiles for products 3aa, 4aa and substrate 1a.

Entry Time [h] Remain 1a

[%]a

Sel. 3aa

[%]b

Sel. 4aa

[%]b

1 1 92 11 6

2 2 59 31 8

3 3 48 40 8

4 5 21 70 4

5 7 1 92 1

General reaction conditions: General Procedure A, 1a (0.5 mmol), 2a (1 mmol), 130 °C,

CPME (2 ml). Reactions were set up in parallel and runs were stopped at given time. aConversion determined based on GC-FID using octadecane as internal standard. bSelectivity determined based on GC-FID and corresponding conversion.

Next, an in situ NMR study (Figure 3) was conducted, using d-8 toluene at 100 °C

that allowed the detection of all key reaction intermediates (as depicted in Figure

2a), that is, 1-pentanol (2a), 1-pentanal, amine 3aa and the corresponding imine,

in support of the borrowing hydrogen mechanism.

Selective monoalkylation of anilines The general applicability of this method

for the selective monoalkylation of substituted anilines was examined using 1-

pentanol 2a and 17 anilines 1a–1q with diverse electron density and steric

hindrance on the amino group. The isolated yields under optimized conditions are

shown in Table 3.


27

Figure 3: In situ 1H NMR study of the N-alkylation of p-methoxyaniline (1a) with 1-

pentanol (2a) in toluene-d8 at 100 °C. Full ppm range, showing 2 small absorptions at

9.41 and 7.65 ppm, which can be attributed to HA (pentane-1-al)[26a] and HI (imine 4aa)[26b].

Table 3: Selective monoalkylation of anilines with alcohols.

General reaction conditions: General Procedure A, 0.5 mmol 1, 1 mmol 2, 2 ml CPME,

130 °C, 18 h, isolated yields, unless otherwise specified. For details see Table 4 and Table

5. a120 °C; bselectivity determined by GC-FID; c2 mmol 2 was used.

Chapter 2

28

Monoalkylation of various anilines with 1-pentanol The reactivity of

substrates 1a–1q was also compared under standard reaction conditions (reaction

time 18 h) to assess substituent effects (Table 4). Selective monoalkylation was

observed in each case; however, the differences in reactivity were significant.

Para-substituted anilines were more reactive than ortho- or metasubstituted

analogues (Table 4, entry 1-2), wheras the reactivity of toluidines increased in the

order ortho (1c) < meta (1d) < para (1e) probably owing to a combination of

basicity and steric effects (Table 4, entry 4, 6 and 8). It was further more

established that anilines comprising electron-withdrawing substituents were less

reactive and that the reactivity of para-halogenated anilines decreased in the order:

fluoro (1h), chloro (1i) > iodo (1k) (Table 4, entry 13, 15 and 19). Whereas para-

substituted anilines bearing strong withdrawing groups including –COOCH3, -NO2,

-CN do not give desired products (Table 4, entry 20-22).

Table 4: Assessment of reactivity of functionalized anilines (1a-1q) in N-

alkylation with 1-pentanol (2a).

Entry 1 / R T

[h]

Temp.

[°C]

Conv.

1 [%]a

Sel. 3 [%]b

1 1a p-OCH3 18 130 97 3aa 94 (91)

2 1b o-OCH3 18 130 28 3ba 27

3 1b o-OCH3 38 120 63 3ba 51 (42)

4 1c o-CH3 18 130 23 3ca 12

5 1c o-CH3 39 120 83 3ca 71(49)

6 1d m-CH3 18 130 50 3da 40

7 1d m-CH3 62 130 >99 3da >95 (84)

8 1e p-CH3 18 130 88 3ea 75 (63)

9 1e p-CH3 22 130 >99 3ea 90 (91)

10 1f p-OH 18 130 >99 3fa 84 (69)

11 1f p-OH 4 130 96 3fa 92 (94)

12 1g o-F 18 130 25 3ga 13

13 1h p-F 18 130 84 3ha 60

14 1h p-F 42 120 >95 3ha 84(77)

15 1i p-Cl 18 130 73 3ia 54

16 1i p-Cl 63 120 87 3ia 77(76)

17 1j p-Br, m-CH3 18 130 33 3ja 18

18 1j p-Br, m-CH3 39 120 80 3ja 62(58)

19 1k p-I 18 130 16 3ka 8

20 1l p-COOCH3 18 130 <5 3la 0

21 1m p-NO2 18 130 <10 3ma 0

22 1n p-CN 18 130 <5 3na 0

23 1o H 18 130 75 3oa 54

24 1o H 25 130 97 3oa 86(90)

25 1p o-NH2 18 130 85 3pa 52

26 1q p-Me, m-NH2 15 130 92 3qa 60 (58)

General reaction conditions: General Procedure A, 0.5 mmol 1a-q, 1 mmol 2a, 130 °C, 2

ml CPME, isolated yield in parenthesis. aConversion determined by GC-FID; bSelectivity

determined by GC-FID. Main products also see Table 3.


29

Accordingly, the best result was obtained with p-hydroxyaniline, which was

converted to 3fa in excellent 94% isolated yield already after 4 h (Table 4, entry

11). This increased reactivity might be attributed to the enhanced nucleophilicity

of 1f or the presence of the relatively acidic phenol moiety, which likely catalyzes

the imine formation step. p-Methoxyaniline was converted to 3aa within 7 h (Table

2), and para-methylaniline (1e), being less reactive, gave 3ea in 91% isolated

yield after 22h (Table 4, entry 9). Unsubstituted aniline (1o) gave 3oa 90%

isolated yield after 25 h (Table 4, entry 24).

Other substrates required further optimization, which was initially conducted using

one of the least reactive substrates 1b. It was shown that prolonged reaction times

and the addition of molecular sieves (to accelerate the imine formation step) lead

to satisfactory results and products 3ba (Table 4, entry 3), as well as 3ca, 3da,

3ia and 3ja were isolated in moderate-to-high yields (42–84%) (Table 4, entry 5,

7, 16 and 18). Taking advantage of the distinct difference in reactivity between

substituted anilines, the selective monoalkylation of 1-methyl-2,4-diamino-

benzene (1q) resulted in preferential formation of 3qa in 58% isolated yield (Table

4, entry 26).

Table 5: N-alkylation of p-methoxyaniline (1a) with various alcohols (2b-2l).

Entry 2 Time [h] Conv.

1a [%]a

Sel. 3 [%]b Sel. 4 [%]b

1 2b n-Octanol 18 85 3ab 79 (69) 4ab 6

2 2c Ethanol 18 94 3ac 90 (85) 4ac 2

3 2d Methanol 18 8 3ad 0 4ad 0

4c 2e Propane-2-ol 24 42 3ae 12 4ae 24

5c 2f Cyclohexanol 24 50 3af 14 4af 32

6 2g Benzyl-alcohol 18 79 3ag 12 4ag 66

7 2h Phenylethanol 18 93 3ah 87 (75) 4ah 5

8 2i Ethane-1,2-diol 22 82 3ai 70 (74) 4ai 0

9 2k Hexane-1,6-diol 22 83 3ak 65 (43) 4ak 0

10d 2i Ethane-1,2-diol 24 80 3pi 40 4pi 0

11d 2i Ethane-1,2-diol 42 90 3pi 60 (45) 4pi 0

General reaction conditions: General Procedure A, 0.5 mmol 1a, 1 mmol 2a, 130 oC, 2 ml

CPME, isolated yield in parenthesis. aConversion determined by GC-FID; bSelectivity

determined by GC-FID; c2 mmol alcohol 2 was used; d3 mmol 2i was used and 2-

aminoaniline (1p) was used instead of 1a. Main products also see Table 3.

Monoalkylation of p-methoxyaniline with various alcohols Having

established the reactivity pattern of anilines, we found that the selective

monoalkylation of p-methoxyaniline (1a) proceeds with a variety of alcohols (2b-

2l) with excellent results (Table 5). For instance, octanol (2b), ethanol (2c) as

well as 2-phenyl-ethane-1-ol (2h) were readily converted to the corresponding

amines 3ab, 3ac and 3ah in 69–85% isolated yields (Table 5, entry 1, 2 and 7).

Chapter 2

30

Alkylations using methanol were not successful (Table 5, entry 3), probably

because the dehydrogenation of MeOH with employed catalytic system is

unfavored. Interestingly, selective mono-alkylation with ethane-1,2-diol (2i) and

hexane-1,6-diol (2k) delivered valuable amino-alcohols 3ai (74%) and 3ak (43%)

(Table 5, entry 8-9). Notably, 2,3-dihydro-quinoxaline (3pi) containing a

heterocyclic structure could also be constructed directly from inexpensive ethylene

glycol (Table 3; Table 5, entry 10-11).

N-alkylation of aliphatic amines with aliphatic alcohols It is important that

aliphatic amines could also be successfully used as reaction partners with various

alcohols (Figure 4). For instance, pentane-1-amine (5a) was alkylated with

benzylalcohol (2g), providing 6ag in 67% yield. The same monoalkylated amine

was obtained in 62% yield by a reverse route from benzylamine (7a) and 1-

pentanol (2a), showing the flexibility and versatility of the new catalytic

transformation. The reaction of piperidine (5b) with 2-phenylethylamine (2h)

afforded tertiary amine 6bh in 53% isolated yield. Interestingly, furfuryl-amine

(5c), which can be derived from lignocellulosic biomass through furfural, displayed

an interesting reactivity towards bis-N-alkylation. In the reaction of 5c with 3 equiv

of 2a, preferentially the corresponding tertiary amine (6caa) was formed.

Figure 4: N-Alkylation of various aliphatic amines with alcohols. a Modular synthesis with

aliphatic amines and alcohols. Pentyl-1-amine (5a) can be coupled with benzyl-alcohol (2g)

or benzyl amine (7a) is coupled with 1-pentanol (2a) to afford the same amine product. b

The methodology can be extended to secondary amines, piperidine (5b) is alkylated with

2-phenyl-1-ethanol (2h). c The reaction of furfuryl-amine (5c) with 1-pentanol (2a)

results in bis-N-alkylation product 6caa. aMolecular sieves were added.


31

N-alkylation of benzylamines N-alkylated benzyl amines are particularly

important targets, as these moieties are present in a variety of drug molecules[29].

Figure 5: Reactivity of various benzylamines (7) with 1-pentanol (2a) based on

conversion in 6 h. General reaction conditions: General Procedure A, 0.5 mmol 7, 1 mmol

2a, 130 oC, 2 ml CPME, conversion was determined by GC-FID using octadecane as internal

standard.

Again a distinct substituent effect was observed in the benzylamine reaction

partner (Table 6). Para-methyl substituted 7g and unsubstituted 7a showed lower

reactivity than meta-halogen substituted benzylamines (7b–7f), which reacted

much faster with 1-pentanol (2a). This is probably due to the increased rate of

reduction of the corresponding imines.[30] Substituted N-alkylated benzylamines

8ba, 8ca, 8da and 8ea were obtained in excellent, 80–95% isolated yield.

Following the alkylation over 6 h confirmed that the reactivity of benzyl amines

7a–7e, increases in the order 7a<7b<7c<7d<7e, reflecting the increasing

electronegativity of the substituents (Figure 5).

Chapter 2

32

Table 6: N-Alkylation of benzylamines with 1-pentanol and diols.

General reaction conditions: General procedure A, 0.5 mmol 7, 1 mmol 2, 130 oC, 18-50

h, isolated yields after purification. aSelectivity determined by GC-FID.

Heterocycle formation with various benzylamines and diols Building on the

excellent reactivity of benzyl amines 7c–7e, we attempted the formation of

nitrogen-containing heterocycles of various sizes using diols of different chain

lengths (butane-1,4-diol 2m, pentane-1,5-diol 2l or hexane- 1,6-diol 2k) (Table

6). An additional advantage of the use of benzylamines is that the free N-

heterocycles can be readily obtained by common debenzylation procedures.

Despite the fact that a sequential catalytic N,N-dialkylation at the same nitrogen

has to occur involving each of the hydroxyl groups of the diol, we reasoned that

the first intermolecular alkylation is followed by an iminium ion-based alkylation,

likely facilitated by the intramolecular nature of the second alkylation step. To our

delight, pyrrolidine 9cm, containing a key five-membered heterocycle, was

obtained in 60% yield from 7c and butane-1,4-ol (2m). Six-membered piperidine

derivative 9cl was constructed using pentane-1,5 diol (2l) and 7c. As seven-

membered ring formation is generally challenging in organic synthesis, it is a

notable feature of our new Fe-based catalytic procedure that various azepane type

N-heterocyclic compounds were readily obtained using benzyl amines 7b–7e and

hexane-1,6-diol (2k). It is remarkable that in all these reactions, full conversion

and perfect product selectivity was observed. Among all derivatives, the chloro-

substituted 9bk was obtained with the highest isolated yield (85%). In contrast,


33

the reaction of unsubstituted benzylamine 7a with 2k afforded the monoalkylation

product, showing that the second cyclization step was much slower in this case.

These results highlight the value of this methodology in accessing biological

important nitrogen heterocycles, which contain -F and -CF3 substituents. These are

frequently encountered motives in pharmaceutically active compounds (Figure 6).

Synthesis of pharmaceutically relevant molecules To demonstrate the power

of the new C–N bond formation, we applied the Fe-catalyzed direct amine

alkylation as a key connection step in the synthesis of the N-arylpiperazine drug

Piribedil (12) (Figure 6), a dopamine antagonist used in the treatment of

Parkinson’s disease[11,31]. The application of iron-based homogeneous catalyst in

the preparation of pharmaceutically active molecules is highly desired, given the

limited allowed ppm levels of noble metal catalysts in the final products[29].

Commercially available 1-(2-pyrimidyl)-piperazine (10) and 4 equiv of piperonyl

alcohol (11) were used as the substrates, providing Piribedil in 54% isolated yield.

This direct, base free catalytic coupling illustrates several advantages for drug

syntheses: no auxiliary reagents are required, an iron catalyst and the green

solvent CPME are used, and water is the only waste product.

Figure 6: Direct synthesis of Piribedil 12.

Conclusion

We have developed a versatile Fe-based catalytic approach for the direct coupling

of amines and alcohols. Key elements are a single bifunctional Fe-catalyst for

alcohol dehydrogenation and imine hydrogenation, and the use of the green

solvent CPME. The variety of primary amines and alcohols, including those derived

from biomass, which can be coupled, provides an excellent basis for highly flexible

methodology to synthesize a broad array of secondary amines and nitrogen

heterocycles and holds promise for future application in diversity-oriented

synthesis strategies. The first upscaling experiments showed that this direct N-

alkylation can provide up to gram amounts of secondary amines. Mechanistic

investigations are needed to elucidate the role of steric and electronic parameters

in the rate-determining step, which can be both the imine formation as well as the

imine reduction. For example, p-hydroxy aniline was rapidly converted within 4 h,

whereas o-methoxy aniline was much less reactive. Similarly, benzyl-amines

display marked reactivity difference, depending on the nature and position of the

substituents at the aromatic ring. We foresee that control of the reactivity of well-

defined iron catalysts, as shown here successfully for the borrowing hydrogen

strategy in the direct alkylation of amines with alcohols, will enable the discovery

of a range of other new catalyst structures and sustainable transformations, using

abundant iron.

Chapter 2

34

Experimental section

General methods

Chromatography: Merck silica gel type 9385 230-400 mesh or Merck Al2O3 90

active neutral, TLC: Merck silica gel 60, 0.25 mm or Al2O3 60 F254 neutral.

Components were visualized by UV, Ninhydrin or I2 staining. Progress of the

reactions was determined by GC-MS (GC: HP 6890, MS: HP 5973) with an HP012

column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an

AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). Conversions

were determined by GC-FID (GC: HP 6890) with an HP-5 column (Agilent

Technologies, Palo Alto, CA). GC-MS and GC-FID analysis method: 60 °C 5 min,

180 °C 5 min (10 °C/min), 260 oC 5 min (10 °C/min). 1H- and 13C NMR spectra

were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) using

CDCl3 or CD2Cl2 as solvent. In situ 1H NMR spectra were recorded on a Varian Unity

Plus Varian-500 (500 MHz) using toluene-d8 as solvent. Chemical shift values are

reported in ppm with the solvent resonance as the internal standard (CDCl3: 7.26

for 1H, 77.00 for 13C; CD2Cl2: 5.32 for 1H, 53.84 for 13C; toluene-d8: 7.09 for 1H).

Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet,

t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and

integration. All reactions were carried out under an Argon atmosphere using oven

dried glassware and using standard Schlenk techniques. THF and toluene were

collected from a MBRAUN solvent purification system (MB SPS-800). Dioxane

(99.5%, extra dry), dichloroethane (DCE, 99.8%, extra dry), N,N-

dimethylformamide (DMF, 99.8%, extra dry) and acetonitrile (CH3CN, 99.9%,

extra dry) were purchased from Acros without further purification. Aniline, 4-

methylbenzylamine, benzylamine, 3-trifluoromethylbenzylamine were purified by

distillation. 4-Methylaniline was purified by recrystallization. 2-Methoxyaniline was

purified by column chromatography. All other reagents were purchased from

Sigma or Acros in reagent or higher grade and were used without further

purification. Complex Cat 3, Cat 3b was synthetized according to literature

procedures[32].

Preparation of Cat 3 and Cat 3b

1,8-Bis(trimethylsilyl)-1,7-octadiyne To a solution of 1,7-octadiyne (2 mL,

1.56 g, 15 mmol) in THF (20 mL), a solution of n-BuLi (20.6 mL of a 1.6M in

hexane solution, 33 mmol, 2.2 equiv) was added dropwise over 20 min at -78 °C

under N2, in a 100ml Schlenk tube. After stiring for 10 min at -78 °C, and 1 h

under room temperature, trimethylsilyl chloride (8.4 ml, 66 mmol, 4.4 equiv) was

added slowly and the mixture was stirred at room temperature for 16 hours. The

cloudy, white mixture was quenched with saturated aqueous NH4Cl (5 mL) followed

by water until all of the white precipitate dissolved. The organic layer was removed


35

and the aqueous layer was extracted with pentane. The combined organic layers

were dried over anhydrous Na2SO4 and the solvent was evaporated under reduced

pressure to give a yellow oil. Purification of the crude product by Kugelrohr

distillation afforded 3.56 g (95% yield) of a light yellow oil/solid mixture (product

is a low-melting solid). 1H NMR (400 MHz, CDCl3, ppm): δ 2.23–2.28 (m, 4H),

1.60–1.64 (m, 4H), 0.15 (s, 18H). The physical data were identical in all respects

to those previously reported.[32]

Tricarbonyl(1,3-bis(trimethylsilyl)-4,5,6,7-tetrahydro-2H-inden-2-

one)iron (Cat 3) A solution of 1,8-bis(trimethylsilyl)-1,7-octadiyne (1.2 g, 4.8

mmol) and diiron nonacarbonyl (1.74 g, 4.8 mmol, 1 equiv) in toluene (60 mL) in

a 250 ml oven-dried Schlenk tube was heated to 120 °C and stirred for 24 hours

under argon. After cooling, the mixture was filtered over celite. Then the solution

was concentrated and filtered over silica to remove all the iron black. The solution

was evaporated under reduced pressure. The remaining solid residue was washed

with cold pentane and crystalized in heptane affording yellow a crystalline solid,

which is air and moisture stable (1.36g, 68% yield). 1H NMR (400 MHz, CDCl3): δ

2.50–2.62 (m, 4H), 1.77–1.87 (m, 4H), 0.26 (s, 18 H). 13C NMR (100 MHz, CDCl3):

δ 209.04, 181.22, 110.99, 71.74, 24.77, 22.41, –0.28. The physical data were

identical in all respects to those previously reported.[32]

Acetonitrile dicarbonyl(1,3-bis(trimethylsilyl)-4,5,6,7-tetrahydro-2H-

inden-2-one)iron (Cat 3b) An oven-dried 250 ml Schlenk tube was charged with

100 ml dry acetone and 2 ml dry CH3CN and degassed with N2 for 20 min. Then 1

g Cat 3 (2.38 mmol) was added under N2, stirring for 1 min until it fully solubilized.

216 mg Me3NO (1.2eq) was added under N2. A direct color change from yellow to

orange was observed in 5 s. The conversion of Cat 3 can be monitored by TLC

(pentane/ethyl acetate = 1/1, on silica gel, RfCat1a = 0.95, RfCat1b = 0.35). After 1

h, the solvent was removed under a vacuum; Cat 3b was purified through flash

chromatography, and obtained as brown solid (0.91g, 88% yield). 1H NMR (400

MHz, CDCl3): δ 2.05 – 2.48 (m, 4H), 2.21 (s, 3H), 1.38 – 1.73 (m, 4H), 0.22 (s,

18 H). 13C NMR (100 MHz, CDCl3): δ 212.80, 180.12, 126.00, 106.58, 69.91, 24.83,

22.31, 4.43, -0.12. The physical data were identical in all respects to those

previously reported.[32]

Cat 3 and Cat 3b are slightly light sensitive but air stable.

Representative procedures

General procedure A: An oven-dried 20 ml Schlenk tube, equipped with a stirring

bar, was charged with amine (0.500 mmol, 1 equiv), alcohol (given amount), iron

complex Cat 3 (0.025 mmol, 10.5 mg), Me3NO (0.050 mmol, 3.75 mg) and

cyclopentyl methyl ether (solvent, 2 ml). Solid materials were weighed into the

Schlenk tube under air, the Schlenk tube was subsequently connected to an argon

line and vacuum-argon exchange was performed three times. Liquid starting

materials and solvent were charged under an argon stream. The Schlenk tube was

capped and the mixture was rapidly stirred at room temperature for 1 min, then it

was placed in a pre-heated oil bath at the appropriate temperature and stirred for

Chapter 2

36

a given time. The reaction mixture was cooled down to room temperature and the

crude mixture was filtered through celite, eluted with ethyl-acetate, and

concentrated in vacuo. The residue was purified by flash column chromatography

to provide the pure amine product.

General procedure B (With molecular sieves): An oven-dried 20 ml Schlenk tube,

equipped with stirring bar, was charged with amine (0.5 mmol, 1 equiv), alcohol

(given amount), iron complex Cat 3 (0.025 mmol, 10.5 mg), Me3NO (0.05 mmol,

3.75 mg) and cyclopentyl methyl ether (solvent, 2 ml). The solid starting materials

were added into the Schlenk tube under air, the Schlenk tube was subsequently

connected to an argon line and a vacuum-argon exchange was performed three

times. Liquid starting materials and solvent were charged under an argon stream

followed by addition of 35.0–45.0 mg activated molecular sieves 4A. The Schlenk

tube was capped and the mixture was rapidly stirred at room temperature for 1

minute, then was placed into a pre-heated oil bath at the appropriate temperature

and stirred for a given time. The reaction mixture was cooled down to room

temperature and the crude mixture was filtered through celite, eluted with ethyl

acetate, and concentrated in vacuo. The residue was purified by flash column

chromatography to provide the pure amine product.

Upscaling procedure for N-alkylation of p-methoxyaniline An oven-dried

100 ml Schlenk tube, equipped with a stirring bar, was charged with p-

methoxyaniline (7.40 mmol, 0.910 g, 1 equiv), iron complex Cat 3 (0.37 mmol,

155 mg, 0.05 equiv) and Me3NO (0.74 mmol, 55.5 mg, 0.10 equiv) under air and

the Schlenk tube was subsequently connected to an argon line and vacuum-argon

exchange was performed three times. Then 1-pentanol (14.8 mmol, 1.62 ml, 2

equiv), cyclopentylmethylether (solvent, 30 ml), 3Å molecular sieves (800 mg)

were charged under an argon stream. The Schlenk tube was capped and the

mixture was rapidly stirred at room temperature for 3 min, then was placed into a

pre-heated oil bath at 130 °C and stirred for 18 h. After cooling down to room

temperature, the crude mixture was concentrated in vacuo. The residue was

purified by flash column chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5)

to provide 1.085 gram of p-methoxy-N-pentylaniline in 76% isolated yield.

General procedure for in situ 1H NMR study of the N-alkylation of p-

methoxyaniline (1a) with 1-pentanol (2a) in toluene-d8 at 100 °C. 0.12 mmol p-

anisidine (1a), 0.24 mmol 1-pentanol (2a), 0.012 mmol Cat 3, 0.024 mmol Me3NO

and 0.6 ml toluene-d8 were added in a J-Young NMR tube under argon. The tube

was sealed in an argon flow and placed in the pre-heated (100 °C) NMR machine,

shimming was performed at reaction temperature. In the following 8 h, 16 spectra

were recorded.


37

Spectral data of isolated compounds

4-methoxy-N-pentylaniline (3aa): Synthesized according to

General procedure A. p-Anisidine (0.062 g, 0.500 mmol) affords

3aa (0.088 g, 91% yield). Yellow oil obtained after column

chromatography (SiO2, N-pentane/EtOAc 100:0 to 95:5). 1H NMR

(400 MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 8.8 Hz,

2H), 3.75 (s, 3H), 3.06 (t, J = 7.2 Hz, 2H), 1.55 - 1.69 (m, 2H),

1.30 - 1.50 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz,

CDCl3) δ 151.93, 142.79, 114.85, 114.00, 55.78, 44.99, 29.34, 22.50, 14.01. The

physical data were identical in all respects to those previously reported.[33]

2-methoxyl-N-pentylaniline (3ba): Synthesized according to

General procedure B. o-Anisidine (0.056 ml, 0.5 mmol) affords

3ba (0.041 g, 42% yield). Yellow oil obtained after column

chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5). 1H NMR

(400 MHz, CDCl3) δ 6.90 (td, J = 7.6, 1.1 Hz, 1H), 6.79 (d, J =

7.9 Hz, 1H), 6.58 – 6.74 (m ,2H), 4.05 – 4.35 (br.s, 1H), 3.87

(s, 3H), 3.14 (t, J = 7.1 Hz, 2H), 1.61 – 1.75 (m, 2H), 1.32 –

1.50 (m, 4H), 0.95 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 146.68, 138.47,

121.26, 116.02, 109.69, 109.29, 55.33, 43.67, 29.40, 29.23, 22.52, 14.02. HRMS

(APCI+, m/z): calculated for C12H20NO [M+H]+:194.15394; found: 194.15387.[34]

2-methyl-N-pentylaniline (3ca): Synthesized according to

General procedure B. o-Toluidine (0.053 ml, 0.5 mmol) affords 3ca

(0.043 g, 49% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 7.15 (m, J = 7.7 Hz, 1H), 7.07 (d, J = 7.2, 1H),

6.60 – 6.70 (m, 2H), 3.35 – 3.60 (br.s, 1H), 3.17 (t, J = 7.1 Hz,

2H), 2.16 (s, 3H), 1.64 – 1.74 (m, 2H), 1.35 – 1.50 (m, 4H), 0.96

(t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 146.36, 129.96,

127.10, 121.63, 116.58, 109.58, 43.93, 29.41, 29.30, 22.52, 17.42, 14.04. HRMS

(APCI+, m/z): calculated for C12H20N [M+H]+: 178.15903; found: 178.15896.[34]

3-methyl-N-pentylaniline (3da): Synthesized according to

General procedure A. m-Toluidine (0.054 ml, 0.5 mmol) affords

3da (0.074 g, 84% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 7.05 – 7.15 (m, 1H), 6.51 – 6.62 (m, 1H),

6.38 – 6.51 (m, 2H), 3.32 – 3.85 (br.s, 1H), 3.13 (t, J = 7.2 Hz,

2H), 2.32 (s, 3H), 1.57 – 1.72 (m, 2H), 1.32 – 1.52 (m, 4H), 0.96

(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 148.52, 138.89, 129.03, 117.97,

113.42, 109.82, 43.95, 29.32, 29.26, 22.48, 21.59, 14.02. HRMS (APCI+, m/z):

calculated for C12H19N [M+H]+: 178.15903; found: 178.15874.[35]

Chapter 2

38

4-methyl-N-pentylaniline (3ea): Synthesized according to

General procedure A. p-Toluidine (0.054 g, 0.5 mmol) affords 3ea




2H), 3.08 (t, J = 7.1 Hz, 2H), 2.24, (s, 3H), 1.56 – 1.67 (m, 2H),

1.27 – 1.50 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz,

CDCl3) δ 146.26, 129.65, 126.23, 112.87, 44.34, 29.34, 29.30, 22.50, 20.33,

14.02.[33]

4-(pentylamino)phenol (3fa): Synthesized according to General

procedure A. 4-Aminophenol (0.055 g, 0.5 mmol) affords 3fa (0.084

g, 94% yield).Yellow oil obtained after column chromatography

(SiO2, n-pentane/EtOAc 90:10 to 60:40). 1H NMR (400 MHz, CDCl3)

δ 6.68 (d, J = 8.0 Hz, 2H), 6.55 (d, J = 8.2 Hz, 2H), 3.90 – 1.69

(br.s, 2H), 3.05 (t, J = 6.8 Hz, 2H), 1.52 – 1.69 (m, 2H), 1.28 –

1.45 (m, 4H), 0,91 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ

148.12, 142.23, 116.23, 114.83, 45.42, 29.30, 22.47, 13.99. HRMS

(APCI+, m/z): calculated for C11H25N [M+H]+: 180.13829; found: 180.13823.

4-fluoro-N-pentylaniline (3ha): Synthesized according to

General procedure A. 4-fluoroaniline (0.047 ml, 0.5 mmol) affords

3ha (0.070 g, 77% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 6.80 – 6.95 (m, 2H), 6.47 – 6.58 (m, 2H), 3.27

– 3.59 (br.s, 1H), 3.06 (t, J = 7.1 Hz, 2H), 1.55 - 1.67 (m, 2H),

1.31 - 1.44 (m, 4H), 0.88 – 0.99 (m, 3H). 13C NMR (100 MHz,

CDCl3) δ 155.61 (d, J = 234.4 Hz), 144.86, 115.53 (d, J = 22.3 Hz), 113.49 (d, J

= 7.4 Hz), 44.63, 29.30, 29.20, 22.48, 14.00.[36]

4-Chloro-N-pentylaniline (3ia): Synthesized according to

General procedure A. 4-Chloroaniline (0.063 g, 0.5 mmol)

affords 3ia (0.075 g, 76% yield). Yellow oil obtained after column



2H), 3.75 (s, 3H), 3.07 (t, J = 7.2 Hz, 2H), 1.55 - 1.67 (m, 2H),

1.27 - 1.44 (m, 4H), 0.92 (t, J = 6.7 Hz, 3H). 13C NMR (100

MHz, CDCl3) δ 147.02, 128.93, 121.45, 113.63, 44.03, 29.25,

29.08, 22.45, 13.98.[33]

4-bromo-3-methyl-N-pentylaniline (3ja): Synthesized

according to General procedure B. 4-Bromo-3-methylaniline

(0.092 g, 0.5 mmol) affords 3ja (0.074 g, 58% yield). Yellow

oil obtained after column chromatography (SiO2, n-

pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ

7.26 (d, J = 8.6 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 6.31 (dd, J

= 8.6, 2.8 Hz, 1H), 3.35 – 3.80 (br.s, 1H), 3.06 (t, J = 7.1 Hz,

2H), 2.31 (s, 3H), 1.50 – 1.65 (m, 2H), 1.30 – 1.42 (m, 4H), 0.92 (t, J = 6.8 Hz,


39

3H). 13C NMR (100 MHz, CDCl3) δ 147.74, 138.14, 132.56, 114.93, 111.83, 111.32,

43.99, 29.27, 29.12, 23.05, 22.47, 14.01. HRMS (APCI+, m/z): calculated for

C12H19NBr [M+H]+: 258.06954; found: 258.06738.

N-Pentylaniline (3oa): Synthesized according to General

procedure A. Aniline (0.046 ml, 0.5 mmol) affords 3oa (0.073 g,

90% yield). Yellow oil obtained after column chromatography (SiO2,

n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.15

– 7.25 (m, 2H), 6.68 – 6.67 (m, 1H), 6.59 – 6.67 (m, 2H), 3.45 –

3.80 (br.s, 1H), 3.13 (t, J = 7.2 Hz, 2H), 1.57 – 1.71 (m, 2H), 1.32

– 1.48 (m, 4H), 0.95 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 148.45,

129.16, 117.03, 112.65, 43.94, 29.31, 29.22, 22.49, 14.02. The physical data

were identical in all respects to those previously reported.[33]

4-Methyl-N1-pentylbenzene-1,3-diamine (3qa): Synthesized

according to General procedure A. 2,4-Diaminotoluene (0.061 g, 0.5

mmol) affords 3qa (0.056 g, 58% yield). Yellow oil obtained after

column chromatography (SiO2, n-pentane/EtOAc 90:10 to 50:50). 1H

NMR (400 MHz, CDCl3) δ 6.85 (d, J = 8.0, 1H), 6.05 (dd, J = 8.0, 2.2

Hz, 1H), 6.00 (d, J = 2.2 Hz, 1H), 3.25 – 3.65 (br.s, 3H), 3.07 (t, J =

7.2 Hz, 2H), 2.08 (s, 3H), 1.55 – 1.66 (m, 2H), 1.33 – 1.43 (m, 4H),

0.94 (t, J = 7.0, 3H). 13C NMR (100 MHz, CDCl3) δ 147.93, 145.17,

130.91, 111.44, 103.87, 99.64, 44.21, 29.29, 29.27, 22.46, 16.33, 14.00. NOESY-

NMR spectrum see figure 7. HRMS (APCI+, m/z): calculated for C12H21N2 [M+H]+:

193.16993; found: 193.16962.

1,2,3,4-Tetrahydroquinoxaline (3pi): Synthesized according to

General procedure A. o-Phenylenediamine (0.054 g, 0.5 mmol) affords

3pi (0.030 g, 45% yield). Orange solid obtained after column

chromatography (SiO2, n-pentane/EtOAc 90:10 to 50:50). 1H NMR (400

MHz, CDCl3) δ 6.55 – 6.63 (m, 2H), 6.46 – 6.54 (m, 2H), 3.42 (s, 4H), 3.25 –

3.54 (br.s, 2H). 13C NMR (100 MHz, CDCl3) δ 133.57, 118.77, 114.72, 41.34. The


4-Methoxy-N-octylaniline (3ab): Synthesized according

to General procedure A. p-Anisidine (0.062 g, 0.5 mmol)

affords 3ab (0.081 g, 69% yield). Yellow oil obtained after

column chromatography (SiO2, n-pentane/EtOAc 100:0 to

95:5). 1H NMR (400 MHz, CDCl3) δ 6.68 (d, J = 8.7 Hz, 2H),

6.60 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H), 3.06 (t, J = 7.2 Hz,

2H), 1.55 – 1.65 (m, 2H), 1.34 – 1.44 (m, 2H), 1.16 – 1.44

(m, 8H). 13C NMR (100 MHz, CDCl3) δ 151.96, 142.81, 114.88, 114.03, 55.81,

45.05, 31.81, 29.67, 29.42, 29.25, 27.19, 22.64, 14.08. The physical data were


Chapter 2

40

4-Methoxy-N-ethylaniline (3ac): Synthesized according to General

procedure A. p-Anisidine (0.062 g, 0.5 mmol) affords 3ac (0.064 g, 85%

yield). Yellow oil obtained after column chromatography (SiO2, n-

pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 6.79 (d, J =

7.1 Hz, 2H), 6.60 (d, J = 7.3 Hz, 2H), 3.75 (s, 3H), 3.02 – 3.23 (m, 2H),

1.24 (t, J = 6.8, 3H). 13C NMR (100 MHz, CDCl3) δ 152.04, 142.70, 114.86,

114.10, 55.79, 39.44, 14.97. The physical data were identical in all respects to

those previously reported.[39]

4-Methoxy-N-phenethylaniline (3ah): Synthesized according to

General procedure A. p-Anisidine (0.062 g, 0.5 mmol) affords 3ah


chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5).1H NMR

(400 MHz, CDCl3) δ 7.28 - 7.46 (m, 2H), δ 7.12 – 7.28 (m, 3H),

6.79 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 3.75 (s, 3H),

3.37 (t, J = 7.0 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H). 13C NMR (100

MHz, CDCl3) δ 152.15, 142.16, 139.35, 128.73, 128.52, 126.32,

114.88, 114.36, 55.74, 46.01, 35.54. The physical data were identical in all

respects to those previously reported.[40]

2-((4-Methoxyphenyl)amino)ethanol (3ai): Synthesized

according to General procedure A. p-Anisidine (0.062 g, 0.5 mmol)

affords 3ai (0.062 g, 74% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 6.74 – 6.84 (m, 2H), 6.58 – 6.66 (m, 2H), 3.79

(t, J = 5.2 Hz, 2H), 3.75 (s, 3H), 3.23 (t, J = 5.2 Hz, 2H), 2.86 – 3.08

(br.s, 1H). 13C NMR (100 MHz, CDCl3) δ 152.49, 142.14, 114.86,



6-((4-Methoxyphenyl)amino)hexan-1-ol (3ak):

Synthesized according to General procedure A. p-Anisidine

(0.062 g, 0.5 mmol) affords 3ak (0.048 g, 43% yield). Yellow

oil obtained after column chromatography (SiO2, n-


6.72 – 6.82 (m, 2H), 6.52 – 6.62 (m, 2H), 3.74 (s, 3H), 3.63

(t, J = 6.6 Hz, 2H), 3.06 (t, J = 7.1 Hz, 2H), 2.31 – 2.51 (br.s,

2H), 1.51 – 1.68 (m, 4H), 1.31 – 1.43 (m, 4H). 13C NMR (100

MHz, CDCl3) δ 151.99, 142.64, 114.85, 114.10, 62.75, 55.79, 44.94, 32.61, 29.56,

26.92, 25.55. HRMS (APCI+, m/z): calculated for C13H21NO2 [M+H]+: 224.16451;

found: 224.16428.

N,N-Dipentylfurfurylamine (6caa): Synthesized

according to General procedure B. Furfurylamine (0.044 ml,

0.5 mmol) affords 6caa (0.075 g, 63% yield). Yellow oil

obtained after column chromatography (SiO2, n-


7.35 (d, J = 2.0, 1H), 6.30 (dd, J = 2.8, 2.0 Hz, 1H), 6.15 (d, J = 3.0, 1H), 3.64


41

(s, 2H), 2.40 (m, J = 7.6, 2H), 1.40 – 1.62 (m, 4H), 1.15 – 1.40 (m, 8H), 0.88

(t, J = 7.0, 6H). 13C NMR (100 MHz, CDCl3) δ 152.88, 141.66, 109.88, 108.11,


C15H25NO [M+H]+: 238.21666; found: 238.21654.

1-Phenethylpiperidine (6bh): Synthesized according to General

procedure B. Piperidine (0.049 ml, 0.5 mmol) affords 6bh (0.050 g, 52%

yield). Yellow oil obtained after column chromatography (Al3O2, n-

pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CD2Cl2) δ 7.23 –

7.34 (m, 2H), 7.10 – 7.34 (m, 3H), 2.72 – 2.80 (m, 2H), 2.48 – 2.56

(m, 2H), 2.35 – 2.48 (m, 4H), 1.52 – 1.62 (m, 4H), 1.33 – 1.48 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 140.60, 128.66, 128.29, 125.88, 61.43,



N-Pentyl-phenethylamine (6ah or 6da): Synthesized

according to General procedure A. Phenethylamine (0.063 ml,

0.5 mmol) affords 6da (0.031 g, 32% yield). Amylamine (0.058

ml, 0.5 mmol) affords 6ah (0.014 g, 15% yield). Yellow oil

obtained after column chromatography (SiO2, MeOH/EtOAc

0:100 to 5:95). 1H NMR (400 MHz, CD2Cl2) δ 7.24 – 7.33 (m,

2H), 7.12 – 7.24 (m, 3H), 2.79 – 2.91 (m, 2H), 2.68 – 2.79 (m, 2H), 2.58 (t, J =

7.2 Hz), 1.38 – 1.48 (m, 2H), 1.22 – 1.32 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H). 13C

NMR (100 MHz, CD2Cl2) δ 141.03, 129.09, 128.68, 126.29, 51.65, 50.19, 36.83,



N-Pentylbenzylamine (6ag or 8aa): Synthesized according

to General procedure A. Benzylamine (0.055 ml, 0.5 mmol)

affords 8aa (0.055 g, 62% yield). Amylamine (0.058 ml, 0.5

mmol) affords 6ag (0.059 g, 67% yield). Yellow oil obtained

after column chromatography (SiO2, n-pentane/EtOAc 50:50 to

0:100). 1H NMR (400 MHz, CD2Cl2) δ 7.26 – 7.37 (m, 4H), 7.16

– 7.26 (m, 1H), 3.77 (s, 2H), 2.61 (t, J = 7.2 Hz, 2H), 1.57 – 1.80 (br.s, 1H), 1.45

– 1.55 (m, 2H), 1.27 – 1.36 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz,

CD2Cl2) δ 141.46, 128.62, 128.45, 127.07, 54.33, 49.89, 30.24, 30.01, 23.07,

14.27. The physical data were identical in all respects to those previously

reported.[43]

3-Chloro-N-pentylbenzylamine (8ba): Synthesized

according to General procedure A. 3-Chlorobenzylamine (0.061

ml, 0.5 mmol) affords 8ba (0.084 g, 80% yield). Yellow oil

obtained after column chromatography (SiO2, n-pentane/EtOAc

50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.06

– 7.25 (m, 3H), 3.76 (s, 2H), 2.60 (t, J = 7.2 Hz, 2H), 1.59 – 1.70 (br.s, 1H), 1.45

– 1.55 (m, 2H), 1.27 – 1.35 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz,

CDCl3) δ 142.50, 134.17, 129.56, 128.14, 126.98, 126.16, 53.40, 49.37, 29.67,

Chapter 2

42

29.46, 22.56, 14.01. HRMS (APCI+, m/z): calculated for C12H19ClN [M+H]+:

212.12005; found: 212.11983.[44]

3-Fluoro-N-pentylbenzylamine (8ca): Synthesized

according to General procedure A. 3-Fluorobenzylamine (0.057

ml, 0.5 mmol) affords 8ca (0.085 g, 87% yield). Yellow oil

obtained after column chromatography (SiO2, n-pentane/EtOAc

50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.34 (m,

1H), 6.98 – 7.18 (M, 2H), 6.93 (td, J = 8.4, 2.1 Hz, 1H), 3.79

(s, 2H), 2.61 (t, J = 7.3 Hz, 2H), 1.76 – 2.04 (br.s, 1H), 1.45 – 1.61 (m, 2H), 1.22

– 1.37 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.93 (d,

J = 245.5 Hz), 142.96 (d, J = 7.3 Hz), 129.73 (d, J = 8.2 Hz), 129.63 (d, J = 2.8

Hz), 114.86 (d, J = 21.2 Hz), 113.70 (d, J = 21.2 Hz), 53.35, 49.31, 29.62, 29.47,

22.56, 14.00. HRMS (APCI+, m/z): calculated for C12H19FN [M+H]+: 196.14960;

found: 196.14938.[44]

3-Trifluoromethyl-N-pentylbenzylamine (8da):

Synthesized according to General procedure A. 3-

Trifluorobenzylamine (0.072 ml, 0.5 mmol) affords 8da (0.115

g, 94% yield). Yellow oil obtained after column chromatography

(SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz,

CDCl3) δ 7.60 (s, 1H), 7.46 – 7.56 (m, 2H), 7.37 – 7.46 (m,

1H), 3.84 (s, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.06 – 2.21 (br.s, 1H), 1.45 – 1.57 (m,

2H), 1.26 – 1.35 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ

141.31, 131.44, 130.66 (q, J = 32.3 Hz), 128.72, 124.79 (q, J = 3.7 Hz), 124.20

(d, J = 272.2 Hz), 123.73 (q, J = 3.8 Hz), 53.41, 49.39, 29.61, 29.46, 22.55,

13.98. HRMS (APCI+, m/z): calculated for C12H29F3N [M+H]+: 246.14641; found:

246.14594.[44]

3-Fluoro-5-trifluoromethyl-N-pentylbenzylamine

(8ea): Synthesized according to General procedure A. 3-

Fluoro-5-trifluoromethylbenzylamine (0.073 ml, 0.5

mmol) affords 8ea (0.125 g, 95% yield). Yellow oil

obtained after column chromatography (SiO2, n-

pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.28

(d, J = 9.1 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 3.88 – 4.04 (br.s, 1H), 3.48 (s, 2H),

2.61 (t, J = 7.1 Hz, 2H), 1.43 – 1.59 (m, 2H), 1.25 – 1.37 (m, 4H), 0.88 (t, J =

6.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.56 (d, J = 248.5 Hz), 143.59 –

143.81 (m), 132.39 (dd, J = 33.1, 7.8 Hz), 123.30 (dd, J = 272.4, 2.7 Hz), 120.52

– 120.74 (m), 118.50 (d, J = 21.6 Hz), 111.39 (dq, J = 24.5, 3.8 Hz), 52.62,

49.08, 29.35, 29.23, 22.48, 13.92. HRMS (APCI+, m/z): calculated for C13H18F4N

[M+H]+: 264.13699; found: 264.13668.

3-Chloro-4-fluoro-N-pentylbenzylamine (8fa): Synthesized according to

General procedure A. 3-Chloro-4-fluorobenzylamine (0.069 ml, 0.5 mmol) affords

8fa (0.050 g, 43% yield). Yellow oil obtained after column chromatography (SiO2,

n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.43 (m,


43

1H), 7.14 – 7.22 (m, 1H), 7.02 – 7.11 (m, 1H), 3.73 (s,

2H), 2.59 (t, J = 7.5 Hz, 2H), 1.93 – 2.08 (br.s, 1H), 1.43

– 1.58 (m, 2H), 1.25 – 1.37 (m, 4H), 0.83 – 0.93 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 157.07 (d, J = 247.5 Hz),

137.34, 130.15, 127.69 (d, J = 7.0 Hz), 120.69 (d, J = 17.8

Hz), 116.29 (d, J = 20.9 Hz), 52.71, 49.26, 29.56, 29.45,

22.54, 13.99.

1-(3-fluorobenzyl)pyrrolidine (9cm): Synthesized according to

General procedure A. 3-Fluorobenzylamine (0.057 ml, 0.5 mmol)

affords 9cm (0.054 g, 60% yield). Yellow oil obtained after column

chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR

(400 MHz, CD2Cl2) δ 7.21 – 7.32 (m, 1H), 7.02 – 7.15 (m, 2H), 6.93

(td, J = 8.6, 2.2 Hz, 1H), 3.59 (s, 2H), 2.32 – 2.60 (m, 4H), 1.67 –

1.82 (m, 4H). 13C NMR (100 MHz, CD2Cl2) δ 162.87 (d, J = 245.1 Hz), 142.06 (d,

J = 6.2 Hz), 129.56 (d, J = 8.4 Hz), 124.27 (d, J = 2.8 Hz), 115.57 (d, J = 21.4

Hz), 113.70 (d, J = 21.4 Hz), 60.14, 54.14, 23.45. The physical data were identical

in all respects to those previously reported.[45]

1-(3-fluorobenzyl)piperidine (9cl): Synthesized according to


affords 9cl (0.060 g, 62% yield). Yellow oil obtained after column

chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400

MHz, CD2Cl2) δ 7.25 – 7.37 (m, 1H), 7.07 – 7.25 (m, 2H), 6.90 – 7.07

(m, 1H), 3.60 (s, 2H), 2.30 – 2.72 (m, 4H), 1.56 – 1.77 (m, 4H), 1.39

– 1.55 (m, 2H). 13C NMR (100 MHz, CD2Cl2) δ 163.34 (d, J = 244.1 Hz),

142.76 (d, J = 7.0 Hz), 129.87 (d, J = 8.3 Hz), 124.86 (d, J = 2.7 Hz), 115.81 (d,

J = 21.2 Hz), 113.80 (d, J = 21.2 Hz), 63.48 (d, J = 1.9 Hz), 54.93, 53.84, 26.51,


reported.[46]

1-(3-fluorobenzyl)azepane (9ck): Synthesized according to


affords 9ck (0.069 g, 67% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 7.18 – 7.30 (m, 1H), 7.00 – 7.18 (m, 2H), 6.84

– 6.98 (m, 1H), 3.63 (s, 2H), 2.45 – 2.72 (m, 4H), 1.43 – 1.84 (m,

8H). 13C NMR (100 MHz, CDCl3) δ 162.94 (d, J = 244.9 Hz), 143.01 (d, J = 6.0

Hz), 129.40 (d, J = 8.1 Hz), 124.06 (d, J = 2.7 Hz), 115.31 (d, J = 21.2 Hz),

113.49 (d, J = 21.3 Hz), 62.24 (d, J = 1.9 Hz), 55.61, 28.26, 26.97. HRMS (APCI+,

m/z): calculated for C12H19FN [M+H]+: 208.14960; found: 208.14928.

1-(3-chlorobenzyl)azepane (9bk) : Synthesized according to

General procedure A. 3-Chlorobenzylamine (0.061 ml, 0.5 mmol)

affords 9bk (0.095 g, 85% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 7.36 (s, 1H), 7.14 – 7.25 (m, 3H), 3.61 (s, 2H),

2.55 – 2.66 (m, 4H), 1.58 – 1.70 (m, 8H). 13C NMR (100 MHz, CDCl3)

Chapter 2

44

δ 142.36, 134.01, 129.32, 128.66, 126.82, 126.72, 62.15, 55.58, 28.20, 26.98.

HRMS (APCI+, m/z): calculated for C13H19ClN [M+H]+: 224.12005; found:

224.11979.

1-(3-(trifluoromethyl)benzyl)azepane (9dk): Synthesized

according to General procedure A. 3-Trifluoromethylbenzylamine

(0.072 ml, 0.5 mmol) affords 9dk (0.087 g, 68% yield). Yellow oil

obtained after column chromatography (Al2O3, n-pentane/EtOAc

100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.55 (d, J

= 7.5 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.41 (m, 1H), 3.69 (s, 2H),

2.51 – 2.70 (m, 4H), 1.53 – 1.72 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 143.31,

131.91, 130.43 (q, J = 21.7 Hz), 128.48, 125.25 (q, J = 3.8 Hz), 124.33 (d, J =

272.4 Hz), 123.53 (q, J = 3.8 Hz), 62.22, 55.60, 28.27, 26.98. HRMS (APCI+,

m/z): calculated for C14H19F3N [M+H]+: 258.14641; found: 258.14615.

1-(3-fluoro-5-(trifluoromethyl)benzyl)azepane (9ek): Synthesized

according to General procedure A. 3-Fluoro-5-

trifluoromethylbenzylamine (0.073 ml, 0.5 mmol) affords 9ek



(400 MHz, CDCl3) δ 7.40 (s, 1H), 7.32 (d, J = 9.7 Hz, 1H), 7.18 (d,

J = 8.2 Hz, 1H), 3.67 (s, 2H), 2.53 – 2.69 (m, 4H), 1.52 – 1.73

(m, 8H). 13C NMR (100 MHz, CDCl3) δ 162.58 (d, J = 247.7), 144.78 (d, J = 7.1

Hz), 132.08 (dd, J = 33.0, 8.3 Hz), 123.46 (dd, J = 272.5, 3.1 Hz), 120.67 –

120.86 (m), 118.65 (d, J = 21.2 Hz), 111.04 (dq, J = 24.9, 3.8 Hz), 61.90 (d, J =

1.6 Hz), 55.68, 28.36, 26.95. HRMS (APCI+, m/z): calculated for C14H18F4N

[M+H]+: 267.13699; found: 276.13666.

Piribedil (12): Synthesized according to General

procedure B. 1-(2-Pyrimidyl)piperazine (10) (0.082 g,

0.5 mmol) and 4 eq. piperonyl alcohol (11) affords 12


chromatography (Al2O3, n-pentane/EtOAc 90:10 to

50:50). 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 4.7Hz, 2H), 6.88 (s, 1H), 6.75 (s,

2H), 6.45 (t, J = 4.7Hz, 1H), 5.93 (s, 2H), 3.81 (t, J = 4.9 Hz, 4H), 3.44 (s, 2H),

2.47 (t, J = 5.0Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 161.60, 157.62, 147.62,

146.62, 131.74, 122.19, 109.66, 109.45, 107.83, 100.85, 62.80, 52.77, 43.62.

The physical data were identical in all respects to those previously reported.[47,48]


45

Figure 7 NOESY-NMR spectrum of isolated compound 3qa.

Chapter 2

46

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spectrum of imine 4aa, in situ generated from 0.12 mmol p-methoxy-aniline (1a)

and 0.50 mmol pentane-1-al. The compounds were solubilized in 0.6 ml toluene-d8

at room temperature, after 0.5 hour the 1H NMR spectrum was recorded at 100 °C.

The indicative aldehyde proton HA is found at 9.40 ppm. The indicative imine proton

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47

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Chapter 2

48

49

Chapter 3

Benzylamines via iron catalyzed direct amination of benzyl alcohols

Benzylamines play a prominent role in numerous pharmaceutically active

compounds. Thus, the development of novel, sustainable catalytic methodologies

to provide access to these privileged structural motifs is of central importance.

Herein we describe the use of a well-defined homogeneous iron-complex for the

construction of a large variety of benzylamines. The methodology consists of the

direct coupling of readily available benzyl alcohols with simple amines through the

borrowing hydrogen methodology. A variety of substituted secondary and tertiary

benzylamines are obtained in moderate to excellent yields. Furthermore, we

explore the versatility of this methodology in the one-pot synthesis of asymmetric

tertiary amines, sequential functionalization of diols and the synthesis of N-benzyl

piperidines, for the first time with an iron catalyst. In addition, direct conversion

of renewable building block 2,5-furan-dimethanol to pharmaceutically relevant

compounds is achieved.


T. Yan, B. L. Feringa, K. Barta, ACS Catal., 2016, 6, 381−388.

Chapter 3

50

Introduction

Benzylamines are frequently encountered motifs in biological systems, and are

highly valuable targets due to their versatility[1] (Scheme 1). Many

pharmaceuticals contain a benzylamine moiety. Prominent examples include

Rivastigmine[1b], a cholinergic agent for treating dementia due to Parkinson’s

disease; Ezetimibe[1c], a drug that helps reducing plasma cholesterol levels; and

Emend[1d], an aprepitant that blocks the neurokinin 1 (NK1) receptor. Developing

efficient pathways that allow for selective synthesis of benzylamines, especially

starting from readily available substrates using sustainable catalysts based on non-

toxic and inexpensive metals is an important goal[2-4].

Scheme 1: Benzylamine based bio-active compounds.

Methods for the synthesis of benzylamine derivatives are shown in Scheme 2, A

and B. Catalytic hydroamination of alkenes or alkynes is an efficient way to access

1-methyl-benzylamines.[2] Furthermore, benzylation of amines with benzyl-halides

via nucleophilic substitution[3] leads to the formation of stoichiometric amounts of

waste. Reductive amination[4] is a catalytic and atom-economic alternative,

however here the aldehyde reaction partner is usually unstable and frequently

generates side-products.

Among these methods, direct amination of benzyl alcohols is a preferred method

because these substrates are readily available and can even be obtained from

renewable resources[5,6], making this route a highly sustainable alternative.

However, direct nucleophilic substitution of the hydroxyl group of benzyl alcohols

with amines is an energy and cost intensive process[7,8], while, installing a good

leaving group instead of the hydroxyl functionality will suffer from low atom-

efficiency. The desired, catalytic way to perform the direct coupling of benzyl

alcohols with amines involves the borrowing hydrogen[9] strategy (Scheme 2, C).

In this case, a specific sequence of reaction steps will occur: dehydrogenation of

the alcohol to aldehyde (step a), imine formation (step b) reduction of imine (step

c), which maintains high atom-efficiency[10] while requiring much lower activation

Benzylamines

51

energy[9c]. Additionally, this method provides innocuous water as the only side

product.

Scheme 2: Comparison of synthetic pathway to access benzylamine derivatives.

A Hydroamination of styrene with amine. B Comparison of amination of benzyl alcohols,

benzyl halides and benzyl aldehydes. C Catalytic amination of alcohols through borrowing

hydrogen.

Since the first examples of catalytic amination of alcohols through borrowing

hydrogen reported by Grigg[11] and Watanabe[12] in 1981, considerable progress

has been made in this area[13]. However, mostly precious metal catalysts containing

ruthenium[14] or iridium[15] were used. Cheap, low-toxic and abundant transition

metals like iron, have been only scarcely used for this transformation[16,18,19].

In Chapter 2, the first example of direct amination of alcohols catalyzed by a well-

defined iron[17] complex through the borrowing hydrogen strategy is described.[18]

This work focused on the use of diverse aromatic amines and aliphatic alcohols

and diols. Two examples were also included using benzyl alcohol as substrate,

however, these reactions suffered from rather low yields. Very recently, Wills and

coworkers also reported on the iron catalyzed amination of alcohols[19a]. They

observed no product formation when benzylamine was employed as the reaction

partner. Later, Zhao and coworkers reported iron catalyzed amination of secondary

alcohols with assistance of 0.4 equiv AgF[19b]. However, only a limited number of

examples have been reported on the use of benzyl alcohols.

Here, a highly versatile method for the synthesis of a large variety of benzylamines

through direct iron catalyzed amination of benzyl alcohols is presented. In addition

to the impressive scope, important novel aspects are the one-pot synthesis of

asymmetric tertiary amines as well as uncovering the reactivity trends in the

sequential functionalization of benzyl alcohols. Moreover, a fully sustainable, two

Chapter 3

52

step pathways from a cellulosic platform chemical to a pharmaceutically active

compound is described.


Optimization of reaction conditions 4-Methylbenzyl alcohol (1a) and

morpholine (2a) were selected as the starting materials for optimization of the

reaction conditions for direct coupling of benzyl alcohols with secondary amines

(Table 1). Using the previously reported conditions[18] with additional assistance of

molecular sieves, only 39% conversion was obtained (Table 1, entry 1). A solvent

screening showed, that etherate solvents like tetrahydrofuran (THF) and dioxane

gave low conversions (33% and 30%, respectively, Table 1, entry 2-3).

Dichloroethane (DCE) gave full conversion but the desired product (3a) was not

detected presumably due to nucleophilic substitution of the solvent (DCE) with

morpholine (2a) (Table 1, entry 4). More polar solvents like acetonitrile and

dimethylformamide (DMF) gave very poor conversion (Table 1, entry 5-6). In

toluene, 64% conversion was obtained (Table 1, entry 7). When other iron sources

such as FeCl3, Fe2(CO)9, and iron(II) phtalocyanine were applied instead of Cat 3,

the conversions were unsatisfactory (Table 1, entries 8−10). Using Cat 3, the

conversion improved to 87% when the temperature was increased to 135 °C in

toluene, probably due to the acceleration of imine reduction (Table 1, entry 11).

Similar results were obtained in CPME at 135 °C (82%, Table 1, entry 12).

Increasing the loading of 1a to 2 mmol in toluene gave full conversion and an 87%

isolated yield of 3a (Table 1, entry 13).

Table 1: Optimization of reaction conditions for amination of 4-methylbenzyl

alcohol (1a) with morpholine (2a).

Entry 1a [mmol] Solvent T [°C] Conversion [%]

1 1 CPME 130 39

2 1 THF 130 33

3 1 Dioxane 130 30

4 1 DCE 130 >95a

5 1 CH3CN 130 <5

6 1 DMF 130 <5

7 1 Toluene 130 64

8b 1 Toluene 130 <5

9c 1 Toluene 130 <5

10d 1 Toluene 130 <5

11 1 Toluene 135 87

12 1 CPME 135 82 13 2 Toluene 135 >95 (87)

General reaction conditions: General procedure, 0.5 mmol 2a, 1 or 2 mmol 1a, 0.02 mmol

Cat 3, 0.04 mmol Me3NO, 2 ml solvent, 18 h, 130 or 135 °C, 95-105 mg molecular sieves,

unless otherwise specified, isolated yield shown in parenthesis, conversion was determined

by GC-FID using decane as the internal standard; aNo 3a has been observed based on GC-

MS, high conversion of amine probably due to the reaction between amine and solvent; b4

Benzylamines

53

mol% FeCl3 instead of Cat 3 and Me3NO; c2 mol% Fe2(CO)9 instead of Cat 3 and Me3NO; d4 mol% Iron(II) phthalocyanine instead of Cat 3 and Me3NO.

Reactions of benzyl alcohols with secondary amines Next, under optimized

reaction conditions, a variety of secondary amines and benzyl alcohols were tested

(Table 2). Benzyl alcohol 1b with an electron-donating –OCH3 substituent reacted

smoothly with 2a providing full conversion and 88% isolated yield of 3b (Table 2,

entry 1). When less electron-rich substrates 1c and 1d were employed, lower

reactivity was observed; 60% of 3c and 40% of 3d were isolated after 18 and 24

h reaction time, respectively (Table 2, entry 2-3). Interestingly, also for 2-

thiophenemethanol (1e), a high isolated yield (74%) of 3e was obtained (Table 2,

entry 4). For other secondary amines, such as 1-methyl-piperazine (2b),

piperazine (2c) and di-n-butyl-amine (2d), the corresponding products were also

obtained in good to excellent yields (Table 2, entry 5-9). Interestingly, when

piperazine (2c), which has two reactive -NH sides, was tested with 2 mmol (4

equiv) of 1c under the general conditions (Table 2), 35% of mono N-benzylation

and 55% of di-N-benzylation product was obtained. By increasing the amount of

1c to 3 mmol (6 equiv), the di-N-benzylation product (3h) was obtained in 90%

isolated yield (Table 2, entry 7).

Table 2: Amination of benzyl alcohols with secondary amines.

Entry Substrate 1 Product 3 Yield [%]

1 1b

3b

88

2 1c

3c

60

3a 1d

3d

40

4a 1e

3e

74

5b 1a

3f

78

6 1f

3g

69

7cde 1c

3h

90

8cde 1e

3i

80

9a 1a

3j

65

10 1a

3k

91

Chapter 3

54

11a 1d

3l

63

12a 1g

3m

69

13 1a

3n

89

14a 1e

3o

79

15a 1h

3p

59

General reaction conditions: General procedure, 0.5 mmol 2, 2 mmol 1a, 0.02 mmol Cat

3, 0.04 mmol Me3NO, 2 ml toluene, 18 h, 135 °C, 95-105 mg molecular sieves, isolated

yields are shown; a24 h; b0.03 mmol Cat 3 and 0.06 mmol Me3NO were employed; c3

mmol 1 was employed.

Next, secondary benzylic amines, which are less basic compared to secondary

aliphatic amines[20], were used as the substrate (Table 2). N-methyl benzylamine

(2e) reacted smoothly with 1a, 1d, 1g and the corresponding products were

obtained in good to excellent yields (Table 2, entry 10–12). Similarly the reaction

of 1,2,3,4-tetrahydroisoquinoline (2f) with alcohols 1a, 1e, 1h provided the

corresponding products in high yields (Table 2, entry 13–15). Remarkably, alcohols,

which possess hetero-aromatic moieties such as 1e and 1h, which have the

possibility to act as chelating ligands[21], could also be used as shown in various

entries in Table 2, and products 3e, 3i, 3o and 3p were obtained in good to

excellent yield.

Reactions of benzyl alcohols with primary amines The synthesis of mono-N-

alkylated benzylamines from the corresponding primary benzylamines and

aliphatic alcohols was described in our previous work[18], which is also shown in

chapter 2. Here we demonstrate a new alternative route to the same products,

starting from benzyl alcohols and aliphatic amines (Table 3), which to the best of

our knowledge has not been previously reported with any iron catalyst and allows

great synthetic flexibility for the selection of the substrates and more insight into

the reaction mechanism.

First, n-pentylamine (4a) was selected for the synthesis of a variety of

functionalized benzyl alcohols (Table 3, entry 1–6). Selectivity towards the mono-

alkylation products was sensitive to the amount of alcohol substrate added. For

example, 2 equiv loading of 4-methoxybenzyl alcohol (1b) lead to preferential

formation and 54% isolated yield of 5a (Table 3, entry 1), however further

increasing 1b loading lead to more dialkylation product. On the other hand, only

using 1.5 eq. of 1b, the corresponding imine was detected as the major product.

The same behavior was observed with 4-methylbenzyl alcohol (1a). In addition,

increasing Cat 3 loading to 6 mol% provided 61% isolated yield of 5b (Table 3,

entry 2).

Benzylamines

55

Table 3: Amination of benzyl alcohols with primary amines.

Entry Substrat 1 Product 5 Yield [%]b

1a 1b

5a

54

2a 1a

5b

61

3 1c

5c

59

4 1g

5d

53

5bc 1i

5e

42d

6bc 1j

5f

22e

7 1c

5g

60

8 1c

5h

61

9bc 1f

5i

60

10b 1a

5j

70

11bc 1a

5k

66

12bc 1c

5l

56

General reaction conditions: General procedure, 0.5 mmol 2, 2 mmol 1a, 0.02 mmol Cat

3, 0.04 mmol Me3NO, 2 ml toluene, 18 h, 135 °C, 95-105 mg molecular sieves, isolated

yields are shown. a1 mmol 1 was employed; b0.03 mmol Cat 3 and 0.06 mmol Me3NO

were employed; c24 h; d41% of corresponding was observed based on GC-FID integration; e58% of corresponding was observed based on GC-FID integration.

Interestingly, when less electron-rich substrates such as benzyl alcohol (1c) and

4-fluorobenzyl alcohol (1g) were examined, less di-N-benzylation product was

observed and 59% and 53% of mono-N-benzylation products were isolated,

respectively (Table 3, entry 3-4).

The reaction of 3-chlorobenzyl alcohol (1i) and 3-trifluoromethylbenzyl alcohol (1j)

with n-pentylamine (4a) (Table 3, entry 5-6) was examined as comparison with

our previous approach[18] that used 3-chloro and 3-trifluoromethyl substituted

benzylamines. In the present case, both reactions provided preferentially imine.

Increasing the catalyst loading to 6 mol% and reaction time to 24 h, provided more

amine product 5e, but still low amount of desired amine 5f (Table 3, entry 5-6).

Increasing the reaction temperature to 140 °C in order to facilitate imine reduction

resulted in catalyst decomposition.

Chapter 3

56

Scheme 3: Reactivity difference through different substrates.

In our previous study[18], electron-deficient benzylamines were more reactive

towards mono-alkylation than their electron rich analogues. The results shown

here, however, conclude that N-alkylated benzylamines are more readily obtained

starting from electron-rich benzyl alcohols than from electron poor benzyl alcohols

(Scheme 3). The reason for this reactivity difference can likely be attributed to

differences in the rate of the imine reduction step.[22] It has to be noted that the

imine intermediates formed from benzyl alcohols will possess a double bond in

conjugation with the aromatic system (Scheme 3, Pathway A) and those formed

from benzyl amines will not (Scheme 3, Pathway B). These reactivity differences

under similar conditions, also show that isomerization of the imine double bond is

not likely. The detailed understanding of these mechanistic details and rate limiting

steps will be subject of future in depth studies.

Next, a series of other primary amines were tested as substrates (Table 3, Entry

7-12). Long chain amines like n-nonylamine (4b) and 2-phenylethamine (4c) were

benzylated with benzyl alcohol (1c) providing 5g and 5h in good isolated yields

(Table 3, entry 7-8). Furthermore, primary benzylamines and anilines could be

applied to readily provide 5k and 5l (Table 3, entry 9–12).

Three component synthesis of asymmetric benzylic tertiary amines Taking

advantage of the differences in reactivity between aliphatic and benzyl alcohols,

we have developed a straightforward approach for the direct three component

synthesis of asymmetric benzylic tertiary amines (Table 4). To this end, a method

using benzyl alcohol (1c), n-pentylamine (4a) and n-butanol (8a) was

implemented with 6 mol% Cat 3 loading, at 135 °C (Table 4, entry 1-3).

Gratifyingly, the desired non-symmetric N-n-butyl-N-n-pentylbenzylamine (9a)

was predominant in the reaction mixture that also contained smaller amounts of

the expected di-N-benzyl-n-pentylamine (10a), and di-N-n-butyl-n-pentylamine

(11a). The desired tertiary amine with three distinctly different alkyl moieties 9a

was isolated in 51% yield (Table 4, entry 1). The one-pot procedure was extended

Benzylamines

57

to the synthesis of other non-symmetric tertiary amines 9b and 9c (Table 4, entry

4–6).

Table 4: Three component synthesis of asymmetric benzylic tertiary amines.

Entry 1 / mmol

8a /

mmol

Sel. 9 [%] Sel. 10

[%]

Sel. 11

[%]

1 1c / 2 R = H 1.5 9a 64 (51) 7 21

2 1c / 1.5 R = H 2 9a 56 13 31

3 1c / 2 R = H 1 9a 47 21 12

4 1g / 2 R = 4-F 1.5 9b 49 (40) 4 28

5 1g / 0.75 R = 4-F 2 9b 23 1 51

6a 1b / 1 R = 4-OMe 1 9c 61 (43) 15 20

General reaction conditions: General procedure, 0.5 mmol 4a, 0.75-2 mmol 1, 1 or 1.5

mmol 8a, 0.03 mmol Cat 3, 0.06 mmol Me3NO, 2 ml toluene, 24 h, 135 °C, 195-205 mg

molecular sieves, conversion and selectivity are based on GC-FID integration, isolated

yields in parenthesis, unless specified; an-hexanol was used instead of n-butanol, hexyl-

group was formed instead of butyl- group.

Sequential functionalization of diols to obtain diverse diamines Sequential

functionalization of diols is undoubtedly a valuable synthetic tool to obtain com-

pounds with great diversity. Here we present, for the first time, a selective iron

catalyzed method that allows for the preparation a non-symmetric functionalized

diamines. This reaction sequence was demonstrated on the preparation of

compound 14 whereby diol 12a was selectively mono-alkylated with 2a forming

13a. This was followed by amination of 13a with 2e to provide 14. (Scheme 4)

Scheme 4: Sequential functionalization of diols.a

Condition a: General procedure, 0.5 mmol 2a, 1.5 mmol 12a, 0.02 mmol Cat 3, 0.04

mmol Me3NO, 135 °C, 2 ml toluene, 18 h, 95-105 mg molecular sieves. 63% of 13a was

isolated. Condition b: General procedure, 0.5 mmol 2e, 1 mmol 13a, 0.03 mmol Cat 3,

0.06 mmol Me3NO, 135 °C, 2 ml toluene, 18 h, 95-105 mg molecular sieves. 30% of 14

was isolated.

Chapter 3

58

Diverse approaches to N-benzyl piperidines N-hetercycles are compounds of

major interest due to their prominent role in bio-active compounds e.g.

pharmaceuticals and agrochemicals.[23] In chapter 2, the direct synthesis of

benzyl-protected five, six, and seven membered-heterocycles from benzylamines

and diols has been shown.[18]

Scheme 5: A Retro-synthetic analysis of N-benzyl piperidines; B diverse

approaches for synthesizing N-benzyl piperidines.a

aGeneral reaction conditions: General Procedure, 0.5 mmol 15a or 15b, 2 mmol 1, 0.02

mmol Cat 3, 0.04 mmol Me3NO, 135 °C, 2 ml toluene, 18 h, 95-105 mg molecular sieves,

isolated yield are shown, unless otherwise specified; a24 h; byields were calculated based

on GC-FID using decane as the internal standard; c0.5 mmol 1c’, 1 mmol 15c’ were

employed; d0.03 mmol Cat 3, 0.06 mmol Me3NO were employed.

Benzylamines

59

Here, we have investigated versatile synthesis routes for the preparation of N-

benzyl piperidines as representative example for benzyl protected N-heterocycles,

illustrated in Scheme 5. The same N-benzyl piperidine 16 can be obtained via three

distinct routes, starting from different substrates. For example, 16 can be

synthesized from three sets of substrates through four pathways (Scheme 5, A).

N-benzyl piperidine 16 can be obtained from benzyl alcohol (1) and piperidine

(15a) through the formation of bond a (Scheme 5, A, Pathway 1). Alternatively,

compound 16 can be obtained from alcohol 1 and 5-amino-1-pentanol (15b)

through the sequential formation of bonds a and b (Scheme 5, A, Pathway 2a), or

b and a (Scheme 5, A, Pathway 2b). Also, N-benzyl piperidine 16 can be

synthesized starting from 1,5-pentanediol (15c’) and benzyl amine 1c’ during

which bonds b and c are formed (Scheme 5, A, Pathway 3). These substrate

variations allow for choosing the most suitable pathway[24] taking into account

optimal balance of reactivity, selectivity and substrate abundance. In order to show

the power of this method, N-benzyl piperidines 16a, 16b, 16c and 16d were

synthesized through different pathways, with good to excellent yields (Scheme 5,

B).

Scheme 6: Synthesis of key intermediate to muscarinic agonist, N-[5-([l'-

substituted-acetoxy)methyl]-2-furfurylldialkylamines.

General reaction condition: General Procedure, 0.5 mmol 2e, 2 mmol 12b, 0.02 mmol

Cat 3, 0.04 mmol Me3NO, 135 °C, 2 ml toluene, 24 h, 95-105 mg molecular sieves. 60%

of 13b was isolated.

From cellulose derived platform chemicals to pharmaceutically active

molecules It was reported that furanic compounds of the general structure 18

shown on Scheme 6 are a class of pharmaceutically active compounds possessing

potential antimuscarinic activity. Pharmaceutical studies have especially focused

on systematic modifications on variations in the ester- and amine side chains.[25]

Here we show an efficient and fully sustainable synthetic strategy towards

obtaining key intermediate 13b. This compound can be prepared directly from

benzyl amine derivative 2e and diol 12b using our iron catalyzed methodology.

Diol 12b used in this reaction can be obtained in high yield from 5-

(hydroxymethyl)furfural (HMF, 17), via a sustainable pathway we have recently

reported[26]. In this procedure, HMF, which is one of the most important cellulose

derived platform chemicals undergoes catalytic hydrogenation using robust, CuZn

alloy nanopowder catalysts[26b]. This novel combination of methods allows for the

Chapter 3

60

easy, waste free synthesis of key bioactive intermediate 13b in 60% yield from

renewable resources, using sustainable catalysis.

Conclusion

In conclusion, we have established, for the first time, general methodology for the

catalytic formation of value-added benzylamines through amination of benzyl

alcohols using a well-defined iron catalyst that operates through a hydrogen

borrowing mechanism. Many synthetically challenging routes were systematically

explored, starting from readily accessible substrates that do not require prior

alcohol activation by stoichiometric methods. This included the one-pot synthesis

of asymmetric tertiary amines, the sequential functionalization of diols, and the

synthesis of important synthons, for example, N-benzylpiperidines, through

diverse synthetic pathways. In addition, direct conversion of the renewable

building block 2,5-furan-dimethanol to pharmaceutically relevant compounds was

achieved with unprecedented simplicity.


General methods









180 °C 5 min (10 °C/min), 260 °C 5 min (10 °C/min). 1H- and 13C NMR spectra


CDCl3, CD3OD, or CD2Cl2 as solvent. Chemical shift values are reported in ppm with

the solvent resonance as the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C;

CD3OD: 3.31 for 1H, 49.00 for 13C; CD2Cl2: 5.32 for 1H, 53.84 for 13C). Data are

reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t =

triplet, q = quartet, br. = broad, m = multiplet), coupling constants (Hz), and


(110 °C) dried glassware and using standard Schlenk techniques. THF and toluene

were collected from a MBRAUN solvent purification system (MB SPS-800). Dioxane



extra dry) were purchased from Acros without further purification. Molecular sieves

4A were purchased from Acros, and heated in a Schlenck flask under 180 °C in

vacuo overnight for activation before using. All other reagents were purchased

from Sigma or Acros in reagent or higher grade and were used without further

purification. Complex Cat 3 was synthesized according to literature procedures[27]

with slight modifications. The synthesis of Cat 3 was carried out as described in

Chapter 2.

Benzylamines

61


General procedure An oven-dried 20 ml Schlenk tube, equipped with a stirring


complex Cat 3 (4–6 mol%), Me3NO (8–12 mol%) and toluene (solvent, 2 ml). The

solid starting materials were added into the Schlenk tube under air, the Schlenk

tube was subsequently connected to an argon line and a vacuum-argon exchange

was performed three times. Liquid starting materials and solvent were charged

under an argon stream followed by addition of 95–105 mg activated molecular

sieves 4A. The Schlenk tube was capped and the mixture was rapidly stirred at

room temperature for 1 min, then it was placed into a pre-heated oil bath at the

appropriate temperature and stirred for a given time. The reaction mixture was

cooled down to room temperature and the crude mixture was filtered through celite,

eluted with ethyl acetate, and concentrated in vacuo. The residue was purified by

flash column chromatography to provide the pure amine product.

Reagents and characterization methods Reagents were of commercial grade

and used as received, unless stated otherwise. Chromatography: Merck silica gel

type 9385 230-400 mesh or Merck Al2O3 90 active neutral, TLC: Merck silica gel

60, 0.25 mm or Al2O3 60 F254 neutral. Components were visualized by UV,

Ninhydrin or I2 staining. 1H- and 13C NMR spectra were recorded on a Varian

AMX400 (400 and 100.59 MHz, respectively) using CDCl3, CD3OD, or CD2Cl2 as

solvent. Chemical shift values are reported in ppm with the solvent resonance as

the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C; CD3OD: 3.31 for 1H, 49.00

for 13C; CD2Cl2: 5.32 for 1H, 53.84 for 13C). Data are reported as follows: chemical

shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br. = broad,

m = multiplet), coupling constants (Hz), and integration.

Procedure of amination of 4-methoxybenzyl alcohol (1b) with morpholine

(2a) provides 3b: An oven-dried 20 ml Schlenk tube, equipped with a stirring

bar, was charged with 4-methoxybenzyl alcohol (2 mmol, 0.276 g), iron complex

Cat 3 (4 mol%, 8 mg) and Me3NO (8 mol%, 3 mg) under air. The Schlenk tube

was subsequently connected to an argon line and a vacuum-argon exchange was

performed three times. Morpholine (0.5 mmol, 0.044 g), and toluene (solvent, 2

ml) were charged under an argon stream followed by addition of 95–105 mg

activated molecular sieves 4A. The Schlenk tube was capped and the mixture was

rapidly stirred at room temperature for 1 min, then was placed into a pre-heated

oil bath at 135 °C and stirred for 18 h. The reaction mixture was cooled down to

room temperature and the crude mixture was filtered through celite, eluted with

ethyl acetate, and concentrated in vacuo. The residue was purified by flash column

chromatography (SiO2, CH2Cl2/EtOAc 80:20 to 50:50) to provide the pure amine

product 3b (0.091 g, 88% isolated yield).

Chapter 3

62


4-(4-Methylbenzyl)morpholine (3a): Synthesized according to

General procedure. Morpholine (0.044 g, 0.50 mmol) affords 3a (0.083

g, 87% yield). Light yellow solid obtained after column chromatography

(SiO2, CH2Cl2/EtOAc 80:20 to 50:50). 1H NMR (400 MHz, CDCl3) δ 7.21

(d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 3.70 (t. J = 7.9 Hz, 4H),

3.47 (s, 2H), 2.36 – 2.51 (m, 4H), 2.34 (s, 3H). 13C NMR (100 MHz, CD3OD) δ



4-(4-Methoxybenzyl)morpholine (3b): Synthesized according to

General procedure. Morpholine (0.044 g, 0.50 mmol) affords 3b (0.091

g, 88% yield). Yellow oil obtained after column chromatography (SiO2,

CH2Cl2/EtOAc 80:20 to 50:50). 1H NMR (400 MHz, CDCl3) δ 7.18 – 7.26

(m, 2H), 6.18 – 6.90 (m, 2H), 3.79 (s, 3H), 3.70 (t, J = 4.7 Hz, 4H),

3.44 (s, 2H), 2.42 (t, J = 4.5 Hz, 4H. 13C NMR (100 MHz, CDCl3) δ



4-Benzylmorpholine (3c): Synthesized according to General

procedure. Morpholine (0.044 g, 0.50 mmol) affords 3c (0.053 g, 60%

yield). Yellow oil obtained after column chromatography (SiO2,

CH2Cl2/EtOAc 80:20 to 50:50). 1H NMR (400 MHz, CD2Cl2) δ 7.10 – 7.45

(m, 5H), 3.65 (t, J = 4.7 Hz, 4H), 3.48 (s, 2H), 2.35 – 2.46 (m, 4H). 13C NMR (100 MHz, CD2Cl2) δ 138.57 129.50, 128.53, 127.37, 67.33, 63.68, 54.06.

The physical data were identical in all respects to those previously reported.[29]

4-(4-Chlorobenzyl)morpholine (3d): Synthesized according to

General procedure. Morpholine (0.044 g, 0.50 mmol) affords 3d (0.042


CH2Cl2/EtOAc 80:20 to 50:50). 1H NMR (400 MHz, CD2Cl2) δ 7.21 – 7.37

(m, 4H), 3.57 – 3.74 (m, 4H), 3.45 (s, 2H), 2.26 – 2.51 (m, 4H). 13C

NMR (100 MHz, CDCl3) δ 136.17, 132.89, 130.42, 128.40, 66.89, 62.58,


reported.[29]

4-(Thiophen-2-ylmethyl)morpholine (3e): Synthesized according

to General procedure. Morpholine (0.044 g, 0.50 mmol) affords 3e

(0.068 g, 74% yield). Yellow oil obtained after column chromatography

(SiO2, CH2Cl2/EtOAc 80:20 to 50:50). 1H NMR (400 MHz, CDCl3) δ 7.19

– 7.25 (m, 1H), 6.86 – 7.00 (m, 2H), 3.69 – 3.74 (m, 6H), 2.44 – 2.53 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 141.15, 128.05, 127.53, 126.47, 67.72, 58.07, 54.25.


Benzylamines

63

1-Methyl-4-(4-methylbenzyl)piperazine (3f): Synthesized

according to General procedure. 1-Methylpiperazine (0.050 g, 0.50

mmol) affords 3f (0.081 g, 79% yield).Yellow oil obtained after column

chromatography (SiO2, EtOAc/MeOH 100:0 to 90:10). 1H NMR (400

MHz, CDCl3) δ 7.20 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 3.46

(s, 2H), 2.20 – 2.70 (br.s, 8H), 2.33 (s, 3H), 2.28 (s, 3H). 13C NMR (100 MHz,

CDCl3) δ 136.52, 134.97, 129.11, 128.80, 62.71, 55.05, 52.97, 45.96, 21.05. The

physical data were identical in all respects to those previously reported.[30] HRMS

(APCI+, m/z): calculated for C13H21N2 [M+H]+: 205.16993; found: 205.16999.

1-Methyl-4-piperonyl piperazine (3g): Synthesized according to

General procedure. 1-Methylpiperazine (0.050 g, 0.50 mmol) affords

3g (0.081 g, 69% yield). Yellow oil obtained after column


MHz, CDCl3) δ 6.83 (s, 1H), 6.58 – 6.79 (m, 2H), 5.91 (s, 2H), 3.39

(s, 2H), 2.15 – 2.70 (br.s, 8H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3)

δ 147.51, 146.47, 132.00, 122.14, 107.74, 100.77, 62.64, 55.02, 52.80, 45.91.


1,4-Dibenzylpiperazine (3h): Synthesized according to

General procedure. Piperazine (0.043 g, 0.50 mmol) affords 3h

(0.120 g, 90% yield). Yellow solid obtained after column

chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5). 1H

NMR (400 MHz, CD2Cl2) δ 7.27 – 7.55 (m, 8H), 7.07 – 7.27 (m,

2H), 3.49 (s, 4H), 2.26 – 2.63 (br.s, 8H). 13C NMR (100 MHz, CDCl3) δ 138.02,



1,4-Bis(thiophen-2-ylmethyl)piperazine (3i): Synthesized

according to General procedure. Piperazine (0.043 g, 0.50 mmol)

affords 3i (0.095 g, 68% yield). Brown solid obtained after

column chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.18 - 7.26 (m, 2H), 6.93 – 9.97 (m,

2H), 6.88 – 6.93 (m, 2H), 3.73 (s, 4H), 2.27 – 2.83 (br.s, 8H). 13C NMR (100 MHz,

CDCl3) δ 141.23, 126.38, 126.13, 124.99, 56.94, 52.60. HRMS (APCI+, m/z):

calculated for C14H19N2S2 [M+H]+: 279.09842; found: 279.09850.

Di-N-n-butyl-4-methylbenzylamine (3j): Synthesized according

to General procedure. Di-n-butylamine (0.065 g, 0.50 mmol) affords

3j (0.076 g, 65% yield). Yellow oil obtained after column



2H), 3.53 (s, 2H), 2.41 (t, J = 7.3 Hz, 4H), 2.35 (s, 3H), 1.40 – 1.55

(m, 4H), 1.25 – 1.37 (m, 4H), 0.90 (t, J = 7.3 Hz, 6H). 13C NMR (100

MHz, CDCl3) δ 136.93, 136.03, 128.74, 128.70, 58.16, 53.39, 29.15, 21.07, 20.07,

20.61, 14.09. HRMS (APCI+, m/z): calculated for C16H28N [M+H]+: 234.22163;

found: 234.22173.

Chapter 3

64

N-benzyl-N-methyl-4-methylbenzylamine (3k):

Synthesized according to General procedure. N-

Methylbenzylamine (0.061 g, 0.50 mmol) affords 3k (0.102 g, 91% yield). Yellow

oil obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.44 (m, 4H), 7.23 – 7.28 (m, 3H), 7.08 – 7.17

(m, 2H), 3.52 (s, 2H), 3.51 (s, 2H), 2.34 (s, 3H), 2.19 (s, 3H). 13C NMR (100 MHz,

CDCl3) δ 139.17, 136.50, 135.99, 128.95, 128.91, 128.90, 128.19, 126.91, 61.69,

61.55, 42.11, 21.10. The physical data were identical in all respects to those


N-benzyl-N-methyl-4-chlorobenzylamine (3l):


Methylbenzylamine (0.061 g, 0.50 mmol) affords 3l (0.077 g, 63% yield). Orange

solid obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0 to

95:5). 1H NMR (400 MHz, CDCl3) δ 7.13 – 7.50 (m, 2H), 3.54 (s, 2H), 3.50 (s, 2H),

2.19 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 138.90, 137.73, 132.55, 130.15, 128.86,


C15H17ClN [M+H]+: 246.10440; found: 246.10451.

N-benzyl-N-methyl-4fluorobenzylamine (3m):


Methylbenzylamine (0.061 g, 0.50 mmol) affords 3m (0.079

g, 69% yield). Yellow oil obtained after column chromatography (Al2O3, n-

pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.52 (m, 6H),

7.23 – 7.31 (m, 1H), 6.95 – 7.10 (m, 2H), 3.54 (s, 2H), 3.50 (s, 2H), 2.20 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.88 (d, J = 244.6 Hz), 139.12, 134.96 (d, J = 3.1

Hz), 130.29 (d, J = 7.7 Hz), 128.85, 128.21, 126.96, 114.95 (d, J = 21.1 Hz),



2-(4-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline

(3n): Synthesized according to General procedure. 1,2,3,4-

Tetrahydroisoquinoline (0.067 g, 0.50 mmol) affords 3n (0.106

g, 89% yield). Yellow oil obtained after column chromatography (Al2O3, n-


7.15 – 7.21 (m, 2H), 7.03 – 7.15 (m, 3H), 6.97 – 7.03 (m, 1H), 3.67 (s, 2H), 3.65

(s, 2H), 2.91 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 5.9 Hz, 2H), 2.37 (s, 3H). 13C NMR

(100 MHz, CDCl3) δ 136.68, 135.15, 134.85, 134.35, 129.05, 128.95, 128.65,

126.58, 126.03, 125.51. 62.46, 56.04, 50.51, 29.09, 21.12. The physical data


2-(thiophen-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

(3o): Synthesized according to General procedure. 1,2,3,4-

Tetrahydroisoquinoline (0.067 g, 0.50 mmol) affords 3o (0.090 g, 79% yield).

Yellow oil obtained after column chromatography (Al2O3, n-pentane/EtOAc 100:0

to 95:5).1H NMR (400 MHz, CDCl3) δ 7.24 - 7.32 (m, 1H), δ 7.05 – 7.23 (m, 3H),

6.90 – 7.04 (m, 3H), 3.93 (s, 2H), 3.72 (s, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.81 (t,

J = 5.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 141.78, 134.61, 134.26, 128.65,

Benzylamines

65

126.57, 126.41, 126.08, 125.94, 125.56, 125.03, 56.76, 55.68, 50.22, 29.04. The


2-((5-methylfuran-2-yl)methyl)-1,2,3,4-

tetrahydroisoquinoline (3p): Synthesized according to

General procedure. 1,2,3,4-Tetrahydroisoquinoline (0.067 g, 0.50

mmol) affords 3p (0.067 g, 59% yield). Yellow oil obtained after column

chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3)

δ 7.05 – 7.20 (m, 3H), 6.96 – 7.04 (m, 1H), 6.15 (d, J = 3.0 Hz, 1H), 5.80 – 6.03

(m, 1H), 3.67 (s, 4H), 2.93 (t, J = 6.0 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H), 2.30 (s,

3H). 13C NMR (100 MHz, CDCl3) δ 151.94, 149.72, 134.57, 134.13, 128.55, 126.53,

126.01, 125.48, 109.64, 105.88, 77.32, 76.68, 55.47, 54.62, 50.26, 28.89, 13.68.

HRMS (APCI+, m/z): calculated for C15H18NO [M+H]+: 228.13829; found:

228.13844.

N-n-Pentyl-4-methoxybenzylamine (5a): Synthesized

according to General procedure. n-Pentylamine (0.044 g, 0.50

mmol) affords 5a (0.056 g, 54% yield). Yellow oil obtained after

column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.5 Hz, 2H), 6.86 (d, J =

8.6 Hz, 2H), 3.79 (s, 3H), 3.73 (s, 2H), 2.61 (t, J = 7.3 Hz, 2H), 1.87 – 2.03 (br.s,

1H), 1.44 – 1.61 (m, 2H), 1.17 – 1.39 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR

(100 MHz, CDCl3) δ 158.57, 132.27, 129.30, 113.71, 55.18, 53.31, 49.23, 29.57,



N-n-Pentyl-4-methylbenzylamine (5b): Synthesized according

to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords

5b (0.058 g, 61% yield). Yellow oil obtained after column



2H), 3.76 (s, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.34 (s, 3H), 2.10 – 2.20 (br.s, 1H),

1.46 – 1.60 (m, 2H), 1.24 – 1.38 (m, 4H), 0.90 (t, J = 6.80 Hz, 6H). 13C NMR (100

MHz, CDCl3) δ 136.92, 136.45, 129.00, 128.10, 53.57, 49.21, 29.52, 29.48, 22.54,

21.02, 13.99. The physical data were identical in all respects to those previously

reported.[36]

N-n-Pentyl-benzylamine (5c): Synthesized according to General

procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords 5c (0.052

g, 59% yield). Yellow oil obtained after column chromatography

(SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz,

CD2Cl2) δ 7.26 – 7.37 (m, 4H), 7.16 – 7.26 (m, 1H), 3.77 (s, 2H), 2.61 (t, J = 7.2

Hz, 2H), 1.57 – 1.80 (br.s, 1H), 1.45 – 1.55 (m, 2H), 1.27 – 1.36 (m, 4H), 0.91

(t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CD2Cl2) δ 141.46, 128.62, 128.45, 127.07,

54.33, 49.89, 30.24, 30.01, 23.07, 14.27. The physical data were identical in all


Chapter 3

66

N-n-Pentyl-4-fluorobenzylamine (5d): Synthesized according

to General procedure. n-Pentylamine (0.044 g, 0.50 mmol) affords

5d (0.052 g, 52% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 7.18 – 7.42 (m, 2H), 6.80 – 7.15 (m, 2H), 3.75

(s, 2H) 2.60 (t, J = 7.3 Hz, 2H), 1.53 – 1.65 (br.s, 1H), 1.42 – 1.57 (m, 4H), 1.20

– 1.40 (m, 4H), 0.89 (t, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 161.8 (d, J

= 244.5 Hz) 136.1 (d, J = 3.4 Hz), 129.6 (d, J = 7.9 Hz), 115.1 (d, J = 21.1 Hz),

77.00, 53.26, 49.38, 29.69, 29.51, 22.58, 14.03. HRMS (APCI+, m/z): calculated

for C12H19FN [M+H]+: 196.14960; found: 196.14961.

N-n-Pentyl-3-chloro-benzylamine (5e): Synthesized


mmol) affords 5e (0.044 g, 42% yield). Yellow oil obtained after

column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.06 – 7.25 (m, 3H), 3.76 (s, 2H), 2.60

(t, J = 7.2 Hz, 2H), 1.59 – 1.70 (br.s, 1H), 1.45 – 1.55 (m, 2H), 1.27 – 1.35 (m,

4H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 142.50, 134.17, 129.56,

128.14, 126.98, 126.16, 53.40, 49.37, 29.67, 29.46, 22.56, 14.01. The physical

data were identical in all respects to those previously reported.[18]

N-n-Pentyl-3-trifluoromethylbenzylamine (5f): Synthesized


mmol) affords 5f (0.27 g, 22% yield). Yellow oil obtained after

column chromatography (SiO2, n-pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.46 – 7.56 (m, 2H), 7.37 – 7.46 (m,

1H), 3.84 (s, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.06 – 2.21 (br.s, 1H), 1.45 – 1.57 (m,

2H), 1.26 – 1.35 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ

141.31, 131.44, 130.66 (q, J = 32.3 Hz), 128.72, 124.79 (q, J = 3.7 Hz), 124.20

(d, J = 272.2 Hz), 123.73 (q, J = 3.8 Hz), 53.41, 49.39, 29.61, 29.46, 22.55,


reported.[18]

N-Benzyl-n-nonylamine (5g): Synthesized according to General

procedure. n-Nonylamine (0.072 g, 0.50 mmol) affords 5g (0.070 g,

60% yield). Yellow oil obtained after column chromatography (SiO2, n-

pentane/EtOAc 50:50 to 0:100). 1H NMR (400 MHz, CDCl3) δ 7.29 –

7.43 (m, 4H), 7.22 – 7.28 (m, 1H), 3.81 (s, 2H), 2.63 (t, J = 7.4 Hz, 2H), 2.32 –

2.42 (br.s, 1H), 1.46 – 1.60 (m, 2H), 1.05 – 1.42 (m, 14H), 0.87 (t, J = 6.9 Hz,

3H). 13C NMR (100 MHz, CDCl3) δ 139.72, 128.35, 128.22, 126.97, 53.73, 49.18,

31.83, 29.72, 29.51, 29.49, 29.23, 27.28, 22.62, 14.06. The physical data were


N-Benzyl-2-phenylethamine (5h): Synthesized according to

General procedure. 2-Phenylethamine (0.061 ml, 0.50 mmol)

affords 5h (0.064 g, 61% yield). Yellow oil obtained after column


(400 MHz, CDCl3) δ 7.15 – 7.40 (m, 10H), 3.83 (s, 2H), 2.89 – 2.96 (m, 2H), 2.82

Benzylamines

67

– 2.89 (m, 2H), 2.64 – 2.73 (br.s, 1H). 13C NMR (100 MHz, CDCl3) δ 139.78, 139.62,

128.69, 128.44, 128.38, 128.17, 127.01, 126.15, 77.32, 77.00, 76.68, 53.59,

50.28, 36.05. The physical data were identical in all respects to those previously

reported.[38]

N-Piperonyl-3-trifluoromethylbenzylamine (5i):

Synthesized according to General procedure. 3-

Trifluoromethylbenzylamine (0.088 ml, 0.50 mmol) affords 5i


chromatography (SiO2, n-pentane/EtOAc 90:10 to 50:50). 1H

NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.48 – 7.58 (m, 2H), 7.40 – 7.47 (m, 1H),

6.87 (s, 1H), 6.72 – 6.80 (m, 2H), 5.95 (s, 2H), 3.84 (s, 2H), 3.72 (s, 2H), 1.75

– 1.87 (br.s, 1H). 13C NMR (100 MHz, CDCl3) δ 1.47.77, 146.64, 141.14, 133.76,

131.47 (q, J = 1.3 Hz), 130.69 (q, J = 32.0 Hz), 128.77, 124.83

(q, J = 3.8 Hz), 124.19 (d, J = 272.2 Hz), 123.82 (q, J = 3.9 Hz),

121.28, 108.65, 108.10, 100.92, 52.95, 52.36. HRMS (APCI+,

m/z): calculated for C16H15F3NO2 [M+H]+: 310.10494; found:

310.10516.

N-(4-Methylbenzyl)-4-fluorobenzylamine (5j): Synthesized according to

General procedure. 4-Fluorobenzylamine (0.063 g, 0.50 mmol) affords 5j (0.080

g, 70% yield). Yellow oil obtained after column chromatography (SiO2, n-


7.20 – 7.26 (m, 2H), 7.12 – 7.20 (m, 2H), 6.95 – 7.09 (m, 2H), 3.78 (s, 4H), 2.36

(s, 3H), 1.75 – 1.81 (br.s, 1H). 13C NMR (100 MHz, CDCl3) δ 161.87 (d, J = 244.6

Hz), 137.00, 136.55, 135.95 (d, J = 3.1 Hz), 129.63 (d, J = 8.0 Hz), 129.06,

128.06, 115.08 (d, J = 21.1 Hz), 52.75, 52.23, 21.05. HRMS (APCI+, m/z):

calculated for C14H19N2S2 [M+H]+: 230.13395; found: 230.13404.

N-(4-Methylbenzyl)-4-methoxyaniline (5k): Synthesized

according to General procedure. 4-Methoxyaniline (0.062 g, 0.50

mmol) affords 5k (0.076 g, 67% yield). Yellow oil obtained after

column chromatography (SiO2, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 7.8 Hz, 2H), 7.17 (d, J =

7.8 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 6.63 (d, J = 8.9 Hz, 2H), 4.25 (s, 2H), 3.76

(s, 3H), 2.36(s, 3H). 13C NMR (100 MHz, CDCl3) δ 152.16, 142.38, 136.75, 136.50,

129.22, 127.52, 114.86, 114.13, 55.76, 49.00, 21.06. The physical data were


N-Benzyl-4-methoxyaniline (5l): Synthesized according to General

procedure. 4-Methoxyaniline (0.062 g, 0.50 mmol) affords 5l (0.060


n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.20 –

7.45 (m, 5H), 6.81 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 4.30 (s, 2H),

3.76 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 152.17, 142.32, 139.59, 128.53, 127.51,



Chapter 3

68

N-n-Butyl-N-n-pentylbenzylamine (9a): Synthesized


mmol) affords 9a (0.059 g, 51% yield). Yellow oil obtained after

column chromatography (Al2O3, n-pentane/EtOAc 100:0 to

95:5). 1H NMR (400 MHz, CD2Cl2) δ 7.26 – 7.45 (m, 4H), 7.15 – 7.26 (m,1H), 3.56

(s, 2H), 2.32 – 2.50 (m, 4H), 1.40 – 1.55 (m, 4H), 1.20 – 1.38 (m, 6H), 0.80 –

1.00 (m, 6H). 13C NMR (100 MHz, CD2Cl2) δ 140.42, 128.76, 127.92, 126.48, 58.55,


for C16H28N [M+H]+: 234.22163; found: 234.22160.

N-n-Butyl-N-n-pentyl-4-fluorobenzylamine (9b):

Synthesized according to General procedure. n-Pentylamine

(0.044 g, 0.50 mmol) affords 9b (0.050 g, 40% yield). Yellow

oil obtained after column chromatography (Al2O3, n-


6.85 – 7.10 (m, 2H), 3.51 (s, 2H), 2.29 – 2.51 (m, 4H), 1.37 – 1.57 (m, 4H), 1.15

– 1.37 (m, 6H), 0.77 – 1.01 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 161.25 (d, J =

243.1 Hz), 135.96, 129.75 (d, J = 7.8 Hz), 114.12 (d, J = 21.0 Hz), 57.37, 29.18,


C16H27FN [M+H]+: 252.21220; found: 252.21233.

N-n-Hexyl-N-n-pentyl-4-methoxylbenzylamine

(9c): Synthesized according to General procedure. n-

Pentylamine (0.044 g, 0.50 mmol) affords 9c (0.063 g,

43% yield). Yellow oil obtained after column

chromatography (Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H),

3.80 (s, 2H), 3.51 (s, 3H), 2.30 – 2.48 (m, 4H), 1.39 – 1.55 (m, 4H), 1.15 – 1.38

(m, 10H), 0.80 – 1.00 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 158.46, 130.01,

113.45, 57.76, 55.20, 53.52, 31.77, 29.66, 27.12, 26.74, 26.46, 22.65, 22.60,

14.08, 14.05. HRMS (APCI+, m/z): calculated for C19H34NO [M+H]+: 292.26349;

found: 292.26360.

(3-(morpholinomethyl)phenyl)methanol (13a): Synthesized

according to General procedure. Morpholine (0.044 g, 0.50 mmol)

affords 13a (0.065 g, 63% yield). Yellow solid obtained after

column chromatography (SiO2, EtOAc/MeOH 100:0 to 90:10). 1H

NMR (400 MHz, CD2Cl2) δ 7.15 – 7.45 (m, 4H), 4.65 (s, 2H), 3.65 (t, J = 4.7 Hz,

4H), 3.49 (s, 2H), 2.42 (t, J = 4.7 Hz, 4H), 2.28 – 2.47 (br.s, 1H) 13C NMR (100

MHz, CD2Cl2) δ 141.80, 138.59, 128.68, 128.65, 128.08, 126.04, 67.25, 65.23,


found: 208.13327.

Benzylamines

69

N-Benzyl-N-methyl-5-hydroxymethyl-furfurylamine (13b):

Synthesized according to General procedure. N-Methylbenzylamine

(0.061 g, 0.50 mmol) affords 13b (0.069 g, 60% yield). Yellow solid

obtained after column chromatography (SiO2, EtOAc/MeOH 100:0 to

90:10). 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.47 (m, 4H), 7.20 –

7.28 (m, 1H), 6.00 – 6.33 (m, 2H), 4.55 (s, 2H), 3.45 – 3.64 (m,

4H), 2.90 – 3.08 (br.s, 1H), 2.22 (s, 3H) 13C NMR (100 MHz, CDCl3) δ 153.81,

151.99, 138.07, 129.16, 128.19, 127.06, 109.44, 108.08, 61.12, 57.31, 53.27,

41.88. HRMS (APCI+, m/z): calculated for C14H18NO2 [M+H]+: 232.13321; found:

232.13323.

N-Benzyl-N-methyl-3-morpholinomethyl-benzylamine

(14): Synthesized according to General procedure. N-

Methylbenzylamine (0.061 g, 0.50 mmol) affords 14 (0.047 g,

30% yield). Yellow solid obtained after column chromatography

(Al2O3, n-pentane/EtOAc 90:10 to 80:20). 1H NMR (400 MHz,

CDCl3) δ 7.29 – 7.42 (m, 5H), 7.24 – 7.29 (m, 3H), 7.18 – 7.24

(m, 1H), 3.71 (t, J = 4.7 Hz, 4H), 3.53 (s, 2H), 3.48 – 3.53 (m, 4H), 2.45 (t, J =

4.7 Hz, 4H), 2.20 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 139.18, 139.16, 137.60,

129.74, 128.91, 128.19, 128.12, 127.88, 127.80, 126.94, 66.99, 63.42, 61.78,

61.69, 53.60, 42.25. HRMS (APCI+, m/z): calculated for C20H27N2O [M+H]+:

311.21195; found: 311.21179.

1-Benzylpiperidine (16a): Synthesized according to General

procedure. Piperidine (0.043 g, 0.50 mmol) affords 17a (0.057 g, 65%

yield). Yellow oil obtained after column chromatography (Al2O3, n-

pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.05 – 7.55

(m, 5H), 3.46 (s, 2H), 2.27 – 2.49 (m, 4H), 1.52 – 1.66 (m, 4H), 1.40

– 1.51 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 139.58, 129.45, 128.43, 127.11,



1-(4-Methylbenzyl)piperidine (16b): Synthesized according to

General procedure. Piperidine (0.043 g, 0.50 mmol) affords 17b (0.068

g, 72% yield). Yellow solid obtained after column chromatography (Al2O3,

n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J

= 7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 3.46 (s, 2H), 2.32 – 2.46 (m,

4H), 2.34 (s, 3H), 1.53 – 1.63 (m, 4H), 1.39 – 1.48 (m, 2H). 13C NMR (100 MHz,

CDCl3) δ 136.37, 135.26, 129.22, 128.74, 63.53, 54.36, 25.91, 24.35, 21.06. The


1-(4-Methoxybenzyl)piperidine (16c): Synthesized according to

General procedure. Piperidine (0.043 g, 0.50 mmol) affords 17c (0.080

g, 78% yield). Yellow solid obtained after column chromatography (Al2O3,

n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J

= 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.42 (s, 2H), 2.20

– 2.50 (m, 4H), 1.50 – 1.65 (m, 4H), 1.35 – 1.50 (m, 2H) 13C NMR (100

Chapter 3

70

MHz, CDCl3) δ 158.52, 130.49, 130.34, 113.40, 63.18, 55.16, 54.30, 25.93, 24.38.


1-(thiophen-2-ylmethyl)piperidine (16d): Synthesized according to

General procedure. Piperidine (0.043 g, 0.50 mmol) affords 17d (0.053

g, 58% yield). Yellow solid obtained after column chromatography

(Al2O3, n-pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ

7.18 – 7.25 (m, 1H), 6.92 – 6.98 (m, 1H), 6.86 – 6.92 (m, 1H), 3.70 (s, 2H), 2.34

– 2.51 (m, 4H), 1.54 – 1.63 (m, 4H), 1.36 – 1.47 (m, 2H). 13C NMR (100 MHz,

CDCl3) δ 141.79, 126.31, 125.92, 124.71, 57.74, 54.06, 25.89, 24.24. The


Benzylamines

71

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Chapter 3

74

75

Chapter 4

Pyrroles via Iron-Catalyzed N-Heterocyclization from

Unsaturated Diols and Primary Amines

Pyrroles are prominent scaffolds in pharmaceutically active compounds and play

an important role in medicinal chemistry. Therefore, the development of novel,

atom-economic and sustainable catalytic strategies to obtain these moieties is

highly desired. Recently, direct catalytic pathways have been established that

utilize readily available alcohol substrates. These approaches rely on the use of

noble metals such as ruthenium or iridium. Here we report on the direct synthesis

of pyrroles with a catalyst based on the earth-abundant and inexpensive iron. The

method uses 2-butyne-1,4-diol or 2-butene-1,4-diol, which can be directly coupled

with anilines, benzyl amines and aliphatic amines to obtain a variety of pyrroles in

moderate to very good isolated yields.


T. Yan, K. Barta, ChemSusChem, 2016, 9, 2321–2325.

Chapter 4

76

Introduction

Pyrroles are important building blocks in medicinal chemistry[1] since many

pharmaceutically active compounds contain these moieties. For example,

aloracetam[2] was been previously used in studies for treating Alzheimer’s disease,

isamoltane[3] was shown to exhibit anxiolytic effects on rodents, elopiprazole[4] is

an antipsychotic drug, and Lipitor is a drug for treating cardiovascular disease

(Figure 1).

Figure 1: Bioactive compounds containing pyrrole moieties.

Owing to the importance of pyrroles, many classical synthetic pathways such as

the Hantzsch[5], Knorr[6], and Paal-Knorr[7] synthesis (Scheme 1, A) as well as

related multicomponent reactions[8] have already been established. These

stoichiometric routes however, may suffer from poor substrate accessibility, harsh

reaction conditions and multi-step syntheses that lead to the formation of waste

and low atom economy[9]. Thus the development of novel catalytic methods, to

create the pyrrole scaffold efficiently is subject of intensive research.[10] Several

elegant approaches, broadly related to the borrowing hydrogen strategy,[11] have

been recently reported that rely on the catalytic dehydrogenation of easily

accessible alcohol substrates, (Scheme 1, A). In 2013, Beller[12] and coworkers

reported on the ruthenium-catalyzed three-component pyrrole synthesis where

secondary alcohols, diols and primary amines were coupled in analogy to the

classical Hantzsch synthesis. Michlik and Kempe[13] achieved the direct iridium-

catalyzed coupling of alcohols and amino alcohols to obtain pyrroles, and Milstein[14]

and coworkers presented a similar, ruthenium-catalyzed method. In 2011,

Crabtree et al.[15] described the formation of pyrroles from 1,4-diols and amines.

In the course of these reactions, the alcohol substrates undergo dehydrogenation

to the corresponding carbonyl-compounds, which further react with the amine to

form the desired pyrrole product and the hydrogen equiv borrowed from the

alcohol substrate are concomitantly liberated from the catalyst.[12-15]

In the studies by the groups of Watanabe[16] and Williams[17] it was shown that

pyrroles can also be directly obtained from amines and unsaturated diols, such as

2-butyne-1,4-diol with an appropriate ruthenium catalyst. In this case it was

proposed that the reaction likely proceeds through an internal hydrogen transfer

Pyrroles

77

isomerization to the corresponding saturated dicarbonyl compounds that

subsequently undergoes pyrrole formation with an amine reaction partner.

Our group has previously established the first iron-catalyzed formation of

pyrrolidines[18] from amines and 1,4-butane-diol using Knölker’s complex[19,20]

(Scheme 1, B), which was described in chapter 2. Based our previous results[18,21]

and the reports of Watanabe and Williams, we envisioned the possibility of the iron

catalyzed direct pyrrole formation starting from primary amines and unsaturated

diols. A reactivity similar to the ruthenium-based system was expected, since the

iron-complex is capable of alcohol dehydrogenation.

Scheme 1: A Classic and modern synthetic pathways to access pyrroles; B iron

catalyzed direct synthesis of pyrrolidines and pyrroles from amines and diols.

A

Classic pyrrole synthesis

B

Catalytic pyrrole synthesis

C


We started our investigation using 2-butyne-1,4-diol (2a) and 4-(N,N-

dimethylamino)-aniline (1a) to establish the novel iron-catalyzed methodology

towards pyrroles. Similarly to our previous work[18,21], Cat 3 was selected as the

pre-catalyst, while Me3NO was used to generate the catalytically active iron

complex. A variety of solvents were screened and the reaction temperature varied

between 110-130 °C. The first attempts at 110 °C in solvents tetrahydrofuran

(THF), dioxane, acetonitrile (CH3CN) and dimethylformamide (DMF) resulted in

very similar conversion values of up to 70% and moderate product selectivities

(Table 1, entry 1-4). Conversion of 1a and product selectivity slightly improved in

Chapter 4

78

CPME and toluene at 110 °C (Table 1, entry 5-6). The results could be further

improved to full conversion of 1a and near perfect selectivity of 3a at 130 °C in

toluene and a good 83% isolated yield of 3a was achieved (Table 1, entry 7).

Similarly, full conversion but slightly lower 3a yield (76%) was obtained when the

reaction was conducted at 120 °C (Table 1, entry 8).

Table 1: Optimization of reaction conditions to obtain N-(4-dimethylamino-

phenyl)-pyrrole (3a) from 4-(N,N-dimethylamino)-aniline (1a) and 1,4-diols (2).

Entry 2 Solvent T [oC] Conv. 1a [%]a Sele. 3a [%]a

1 2a THF 110 67 65

2 2a dioxane 110 70 68

3 2a CH3CN 110 68 67

4 2a DMF 110 67 66

5 2a CMPE 110 71 69

6 2a toluene 110 73 71

7 2a toluene 130 >99 98 (83)

8 2a toluene 120 >99 95 (76)

9 2b toluene 110 94 44

10 2b CPME 110 90 25

11 2b toluene 120 >99 63 (59)

General reaction conditions: General Procedure, 0.5 mmol 1a, 1 mmol 2, 0.02 mmol Cat

3, 0.04 mmol Me3NO, 2 ml solvent, 18 h, 110-130 °C, isolated yield in parenthesis. aValues

based on GC-FID selectivity.

After having established that diol 2a can be successfully used as the substrate to

form 3a, we explored the use of cis-2-butene-1,4-diol (2b) as the starting material.

Catalytic runs conducted with 2b in toluene and CPME at 110 °C resulted in 94%

and 90% conversion but only 44 and 25% selectivity for 3a, respectively (Table 1,

entry 9-10). At 120 °C full 1a conversion and a good, 59% isolated yield of 3a

was obtained (Table 1, entry 11) without significant over-reduction to

pyrrolidines.[16] Therefore 2b can be regarded as alternative reaction partner to

2a, despite the slightly lower product yields obtained.

With the optimized reaction conditions in hand, a variety of anilines were tested

(Table 2). Electron-rich 4-methoxy-aniline (1b) reacted smoothly with 2-butyne-

1,4-diol (2a), leading to 80% isolated yield of 3b (Table 2, entry 1). When 4-

methyl-aniline (1c) was used as substrate, much lower conversion and 36%

isolated yield of 3c was obtained. Similar behavior was observed in the reaction of

electron poor 4-fluoro-aniline (1d) with 2-butyne-1,4-diol (2a), that yielded 30%

of 3d at 33% substrate conversion. Interestingly, in both of these cases almost

full conversion and much higher product selectivity were achieved when cis-2-

butene-1,4-diol was employed as coupling partner instead of 1a, providing 59%

Pyrroles

79

and 47% isolated yields of 3c and 3d, respectively (Table 2, entry 2-3). According

to these results, 2b was selected for further reactions with 4-chloro-aniline (1e),

4-bromo-aniline (1f) and 3,4-(methenedioxy)-aniline (1g). In all these cases

excellent substrate conversions and very good product selectivity was observed

and the desired products 3e, 3f and 3g were obtained in 45%, 44% and 37%

isolated yields, respectively (Table 2, entry 4-6). It was also shown that product

selectivity and isolated yields could be improved in the coupling of 1e with 4 equiv

of diol 2b. Ortho-substituted anilines (1h–1j) could also be successfully used

whereby electron-donating substituents gave better product yields (Table 2, entry

7–9).

Table 2: Direct synthesis of N-substituted pyrroles from anilines and 1,4-diols.

Entry 1 2 Product 3 Conv. 1 [%]a Sele. 3 [%]a

1 1b 2a 3b 92 90 (80)

2 1c 2a

3c 42 36

2b >99 90 (59)

3 1d 2a

3d 33 30

2b 91 75 (47)

4 1e 2b

3e 85 63 (45)

2bb 98 72 (54)

5 1f 2b 3f 94 61 (44)

6 1g

2b 3g >99 68 (37)

7 1h

2b 3h 70 42 (36)

8 1i

2b 3i 90 52 (25)

9 1j

2b 3j 56 36 (15)

General reaction conditions: General Procedure, 0.5 mmol 1a, 1 mmol 2a, 0.02 mmol Cat

3, 0.04 mmol Me3NO, 2 ml toluene, 18 h, 130 °C, isolated yield in parenthesis, unless

otherwise specified. aConversion is based on GC-FID selectivity; bThe reaction was operated

in a sealed 20 ml vial with 4 equiv 2b in 22 h.

After aniline derivatives were also converted to N-phenyl-pyrroles successfully,

primary aliphatic amines were explored under standard reaction conditions using

2-butyne-1,4-diol (2a) as reaction partner. Interestingly, a series of benzyl amines

with varying electron density all afforded full substrate conversions, excellent

product selectivity and good isolated yields of the desired N-benzylpyrroles. The

coupling of benzylamine (5a) with 2a leads to the formation of N-benzylpyrrole

(6a) with 61% isolated yield (Table 3, entry 1). Similarly, good results were

obtained with a variety of halogenated benzyl amines, such as 4-chloro-

benzylamine (5b), 4-fluoro-benzylamine (5c), 3-trifluoromethyl-benzylamine (5d)

and 3-fluoro-4-chloro-benzylamine (5e), which afforded the corresponding N-(4-

Chapter 4

80

chlorobenzyl)-pyrrole (6b), N-(4-fluorobenzyl)-pyrrole (6c), N-(3-

trifluoromethylbenzyl)-pyrrole (6d) and N-(3-fluoro-4-chlorobenzyl)-pyrrole (6e)

products in 57%, 52%, 55% and 65% isolated yields, respectively (Table 3, entry

2-5). With electron-rich benzylamines 5f and 5g, the desired N-(4-methylbenzyl)-

pyrrole (5f) and N-piperonyl-pyrrole (5g) were obtained in good, 65% and 60%

isolated yields, respectively (Table 3, entry 6-7). Interestingly, even 3-picolylamine

(5h) reacted smoothly with 2-butyne-1,4-diol (2a) forming N-(3-picolyl)pyrrole in

76% isolated yield, although pyridine is a potential ligand that may coordinate to

iron[22] (Table 3, entry 8). Product N-furfuryl-pyrrole (6i), which has already been

proposed as food additive[23], was obtained in 43% yield from furfurylamine (5i)

(Table 3, entry 9). For other aliphatic amines such as 2-phenylethylamine (5g) and

dodecylamine (5k), the corresponding pyrrole products were obtained in 41% and

42% isolated yield (Table 3, entry 10-11). Cyclohexylamine (5l) reacted with 2a

providing N-cyclohexylpyrrole (6l) in 33% yield (Table 3, entry 12).

Table 3: Direct synthesis of N-substituted pyrroles from anilines and 1,4-diols.

Entry 5 Product 6 Sele. 3 [%]a

1 5a

6a 90 (61)

2 5b

6b 85 (57)

3 5c 6c 73 (52)

4 5d

6d 88 (55)

5 5e

6e 87 (65)

6 5f 6f 87 (65)

7 5g

6g 83 (55)

8 5h 6h 92 (76)

9 5i 6i 71 (43)

10 5j 6j (41)

11 5k 6k 86 (42)

12 5l 6l 85 (33)

General reaction conditions: General Procedure, 0.5 mmol 5, 1 mmol 2a, 0.02 mmol Cat

3, 0.04 mmol Me3NO, 2 ml toluene, 18 h, 130 °C. In all cases, full conversion was obtained. aValues shown are GC-FID selectivity, numbers in brackets are isolated yields.

Scheme 2: GPC analysis of N-benzyl pyrrole formation from benzylamine and 2-

butyne-1,4-diol.

Pyrroles

81

Mn (number-average molar mass): 260 g/mol, Mw (mass-average molar mass): 347 g/mol,

D (polydispersity): 1.336. Molecular weight of the highest intensity of fraction Mw = 100-

200: 160; Mw = 200–300: 215; Mw = 300–5000: 340.

Scheme 3: GPC analysis of control experiment using 2-butyne-1,4-diol as the only

substrate.

Mn (number-average molar mass): 234 g/mol, Mw (mass-average molar mass): 284 g/mol,

D (polydispersity): 1.215; Molecular weight of the highest intensity of fraction. Mw = 100

- 200: 160; Mw = 200 – 300: 214; Mw = 300 – 100: 353.

To summarize the results in Table 1-3 discussed above, generally good to excellent

substrate conversions were seen. Similarly, product selectivity was good to

Chapter 4

82

excellent based on GC-FID and GC-MS measurements, albeit the isolated product

yields were lower. This may be an indication of side reactions involving species not

detectable by these GC measurements. Indeed, gel permeation chromatography

(GPC) measurements of the crude product mixture confirmed the presence of

oligomeric side products for a typical run with 2-butyne-1,4-diol (2a) and

benzylamine (5a) (Scheme 2) in the broad molecular weight (Mw) range of 300–

5000 g/mol.

In addition, when 2a alone was subjected to standard catalytic conditions, full

substrate conversion was observed alongside the formation of a dark brown

unidentified precipitate and no volatiles were detected by GC measurement

(Scheme 3). Furthermore, GPC measurement confirmed the formation of

oligomeric side products. Thus, the most likely source of such competing side

reactions is the isomerization of substrate 2a to the corresponding ,β-unsaturated

aldehyde as shown in Scheme 4.

Scheme 4: Possible pathways for pyrrole formation.

Other reaction pathways such as the formation of secondary or tertiary amines

that may be a result of over-alkylation and imine reduction were not observed,

indicating the preference for intramolecular pyrrole formation. Also, the

corresponding pyrrolidine analogues were only sparingly observed when 2b was

used as substrate. More mechanistic and spectroscopic insights are required to

understand the sequence of reaction steps occurring. This may lead to

improvement of product yields. Future research should also address a broader

substrate scope, especially different substitution patterns on the pyrrole ring.

Conclusion

In conclusion, in this chapter, the first iron-catalyzed direct method for the catalytic

formation of pyrroles by coupling of unsaturated diols with primary amines has

been described. Various derivatives of anilines, and benzyl amines as well as other

aliphatic primary amines were successfully used in the construction of pyrrole

moieties, which are important scaffolds in medicinal chemistry. The desired

product yields range from high to moderate and future studies will address further

mechanistic details of this interesting noble metal free transformation. The

presented catalytic strategy is direct, straightforward, and allows for the use of a

wide range of amines. In addition, this new catalytic method relies on the use of

Pyrroles

83

inexpensive and abundant catalyst for the construction of scaffolds that are very

important in the pharmaceutical industry.


General methods









180 °C 5 min (10 °C/min), 260 °C 5 min (10 °C/min). 1H- and 13C NMR spectra


CDCl3, CD3OD, or CD2Cl2 as solvent. Chemical shift values are reported in ppm with

the solvent resonance as the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C;





(110oC) dried glassware and using standard Schlenk techniques. THF and toluene





4A were purchased from Acros, and heated in Schlenck under 180 °C in vacuo

overnight for activation before using. All other reagents were purchased from

Sigma or Acros in reagent or higher grade and were used without further

purification. Complex Cat 3 was synthesized according to literature procedures[24]

with slightly modification. The synthesis of Cat 3 was carried out as described in

Chapter 2.


General procedure: An oven-dried 20 ml Schlenk tube, equipped with stirring


complex Cat 3 (4 mol%), Me3NO (8 mol%) and Toluene (solvent, 2 ml). The solid

starting materials were added into the Schlenk tube under air, the Schlenk tube

was subsequently connected to an argon line and a vacuum-argon exchange was

performed three times. Liquid starting materials and solvent were charged under

an argon stream. The Schlenk tube was capped and the mixture was rapidly stirred

at room temperature for 1 min, then was placed into a pre-heated oil bath at the


cooled down to room temperature and concentrated in vacuo. The residue was

purified by flash column chromatography to provide the pure amine product.

Chapter 4

84

Procedure of synthetizing N-(4-dimethyl-phenyl)-pyrrole from 4-

dimethylamino aniline and butyn-1,4-diol: An oven-dried 20 ml Schlenk tube,

equipped with stirring bar, was charged with 4-dimethylamino aniline (0.5 mmol,

0.068 g), butyn-1,4-diol (0.5 mmol, 0.086 g), iron complex Cat 3 (4 mol%, 8 mg)

and Me3NO (8 mol%, 3 mg) under air. The Schlenk tube was subsequently

connected to a vacuum/argon Schlenk line and a vacuum-backfill cycle was

performed three times. Toluene (solvent, 2 ml) were charged under an argon

stream. The Schlenk tube was sealed with a screw cap and the mixture was rapidly

stirred at room temperature for 1 min, then was placed into a pre-heated oil bath

at 130 °C and stirred for 18 h. The reaction mixture was cooled down to room

temperature and the crude mixture was filtered through celite, eluted with ethyl

acetate, and concentrated in vacuum. The residue was purified by flash column

chromatography (SiO2, pentane/EtOAc 100:0 to 80:20) to provide the pure

product N-(4-dimethyl-phenyl)-pyrrole (0.077 g, 83% isolated yield).

Pyrroles

85


N-(4-dimethyl-phenyl)-pyrrole (3a): Synthesized according to General

procedure. 4-Dimethylamino aniline (0.068 g, 0.50 mmol) affords 3a

(0.077 g, 83% yield). Brown solid was obtained after column

chromatography (SiO2, pentane/EtOAc 100:0 to 80:20). 1H NMR (400 MHz,

CDCl3) δ 7.27 – 7.31 (m, 2H), 6.99 – 7.05 (m, 2H), 6.77 – 6.81 (m, 2H),

6.30 – 6.38 (m, 2H), 3.00 (s. 6H). 13C NMR (100 MHz, CDCl3) δ 148.86, 131.18,


respects to those previously reported[25].

N-(4-Methoxy-phenyl)-pyrrole (3b): Synthesized according to General

procedure. 4-Methoxy aniline (0.062 g, 0.50 mmol) affords 3b (0.070 g,

80% yield). Light yellow solid was obtained after column chromatography

(SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.29 –

7.37 (m, 2H), 6.99 – 7.06 (m, 2H), 6.91 – 6.99 (m, 2H), 6.30 – 6.38 (m,

2H), 3.84 (s. 3H). 13C NMR (100 MHz, CDCl3) δ 157.60, 134.45, 122.13, 119.64,


previously reported[26].

N-(4-Methyl-phenyl)-pyrrole (3c): Synthesized according to General

procedure. 4-Methyl aniline (0.054 g, 0.50 mmol) affords 3c (0.028 g, 36%

yield with the use of 2a; 0.047 g, 59% yield with the use of 2b). Light yellow

solid was obtained after column chromatography (SiO2, Pentane/EtOAc

100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.37 (m, 2H), 7.19 –

7.29 (m, 2H), 7.04 – 7.14 (m, 2H), 6.32 – 6.42 (m, 2H), 2.41 (s. 3H). 13C NMR

(100 MHz, CDCl3) δ 138.44, 135.30, 129.98, 120.48, 119.33, 110.02, 20.80. The

physical data were identical in all respects to those previously reported[27].

N-(4-Fluoro-phenyl)-pyrrole (3d): Synthesized according to General

procedure. 4-Fluoro aniline (0.056 g, 0.50 mmol) affords 3d (0.024 g, 30%

yield with the use of 2a; 0.038 g, 47% yields with use of 2b). Light yellow

oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc

100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.40 (m, 2H), 7.08 –

7.18 (m, 2H), 6.96 – 7.06 (m, 2H), 6.28 – 6.44 (m, 2H), 2.41 (s. 3H). 13C NMR

(100 MHz, CDCl3) δ 160.61 (d, J = 244.98 Hz), 137.15 (d, J = 2.86 Hz), 122.26

(d, J = 8.39 Hz), 119.60, 116.25 (d, J = 22.77 Hz), 110.42, . The physical data

were identical in all respects to those previously reported[28].

N-(4-Chloro-phenyl)-pyrrole (3e): Synthesized according to General

procedure. 4-Chloro aniline (0.064 g, 0.50 mmol) affords 3e (0.040 g, 45%

yield). Light yellow solid was obtained after column chromatography (SiO2,

Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.44 (m,

2H), 7.30 – 7.36 (m, 2H), 7.00 – 7.11 (m, 2H), 6.30 – 6.42 (m, 2H), 2.41

(s. 3H). 13C NMR (100 MHz, CDCl3) δ 139.28, 131.00, 129.58, 121.57, 119.23,


reported[29].

Chapter 4

86

N-(4-Bromo-phenyl)-pyrrole (3f): Synthesized according to General

procedure. 4-Bromo aniline (0.085 g, 0.50 mmol) affords 3f (0.048 g, 44%

yield). Light yellow solid was obtained after column chromatography (SiO2,

Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.60 (m,

2H), 7.22 – 7.35 (m, 2H), 7.00 – 7.12 (m, 2H), 6.30 – 6.45 (m, 2H), 2.41

(s. 3H). 13C NMR (100 MHz, CDCl3) δ 139.73, 132.54, 121.88, 119.15, 118.65,


reported[30].

N-(3,4-Methylenedioxy-phenyl)-pyrrole (3g): Synthesized according

to General procedure. 3,4-(Methylenedioxy)aniline (0.069 g, 0.50 mmol)

affords 3g (0.035 g, 37% yield). Light yellow solid was obtained after

column chromatography (SiO2, Pentane/EtOAc 90:10 to 70:30). 1H NMR

(400 MHz, CDCl3) δ 6.95 – 7.02 (m, 2H), 6.88 – 6.94 (m, 1H), 6.80 – 6.88

(m, 2H), 6.27 – 6.38 (m, 2H), 6.01 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 148.30,

145.62, 135.68, 119.82, 114.01, 109.93, 108.42, 103.01, 101.57, 77.00. HRMS

(APCI+, m/z): calculated for C11H10NO2 [M+H]+: 188.07061; found: 188.07078.

N-(2-Methoxy-phenyl)-pyrrole: Synthesized according to General

procedure. 2-Methoxy aniline (0.062 g, 0.50 mmol) affords 3c (0.031

g, 36% yield with the use of 2b). Light yellow liquid was obtained after

column chromatography (SiO2, pentane/EtOAc 100:0 to 95:5). 1H NMR

(400 MHz, CDCl3) δ 7.20 – 7.38 (m, 2H), 6.95 – 7.10 (m, 4H), 6.25 – 6.40 (m,




N-(2-Methyl-phenyl)-pyrrole: Synthesized according to General

procedure. 2-Methyl aniline (0.054 g, 0.50 mmol) affords 3c (0.020 g,

25% yield with the use of 2b). Light yellow liquid was obtained after

column chromatography (SiO2, pentane/EtOAc 100:0 to 95:5). 1H NMR

(400 MHz, CDCl3) δ 7.23 – 7.33 (m, 4H), 6.78 – 6.82 (m, 2H), 6.30 – 6.35 (m,




N-(2-fluoro-phenyl)-pyrrole: Synthesized according to General

procedure. 2-fluoro aniline (0.056 g, 0.50 mmol) affords 3c (0.012 g,

15% yield with the use of 2b). Light yellow liquid was obtained after


(400 MHz, CDCl3) δ 7.35 – 7.45 (m, 1H), 7.16 – 7.29 (m, 3H), 7.02 – 7.08 (m,

2H), 6.30 – 6.40 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 154.47 (d, J = 249.3 Hz),

129.0 (d, J = 10.5 Hz), 127.11 (d, J = 7.7 Hz), 124.93 (d, J = 1.5 Hz), 124.73 (d,

J = 3.8 Hz), 121.35 (d, J = 3.6 Hz), 117.03 (d, J = 20.6 Hz), 109.92. The physical

data were identical in all respects to those previously reported[33].

Pyrroles

87

N-benzyl-pyrrole (6a): Synthesized according to General procedure.

Benzylamine (0.054 g, 0.50 mmol) affords 6a (0.048 g, 61% yield).

Light yellow oily liquid was obtained after column chromatography (SiO2,

Pentane/EtOAc 95:5 to 90:10). 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.38

(m, 3H), 7.10 – 7.17 (m, 2H), 6.66 – 6.76 (m, 2H), 6.16 – 6.26 (m, 2H), 5.09 (s.

2H). 13C NMR (100 MHz, CDCl3) δ 138.13, 128.67, 127.58, 126.94, 121.12, 108.45,


reported[34].

N-(4-Chloro-benzyl)-pyrrole (6b): Synthesized according to General

procedure. 4-Chloro benzylamine (0.044 g, 0.50 mmol) affords 6b

(0.055 g, 57% yield). Light yellow oily liquid obtained after column

chromatography (SiO2, Pentane/EtOAc 95:5 to 90:10). 1H NMR (400

MHz, CDCl3) δ 7.27 – 7.40 (m, 3H), 7.10 – 7.13 (m, 2H), 6.64 – 6.78

(m, 2H), 6.16 – 6.30 (m, 2H), 5.05 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 136.65,

133.42, 128.81, 128.24, 121.02, 108.73, 52.57. The physical data were identical

in all respects to those previously reported[35].

N-(4-Fluoro-benzyl)-pyrrole (6c): Synthesized according to General

procedure. 4-Fluoro benzylamine (0.063 g, 0.50 mmol) affords 6c

(0.046 g, 52% yield). Light yellow oily liquid was obtained after column


MHz, CDCl3) δ 7.07 – 7.15 (m, 3H), 6.96 – 7.06 (m, 2H), 6.65 – 6.75

(m, 2H), 6.17 – 6.27 (m, 2H), 5.05 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 162.22

(d, J = 245.87 Hz), 133.88 (d, J = 3.11 Hz), 128.65 (d, J = 8.11 Hz), 120.97,

115.55 (d, J = 21.74 Hz), 108.64, 52.58. The physical data were identical in all


N-(3-Trifluoromethyl-benzyl)-pyrrole (6d): Synthesized according

to General procedure. 3-Trifluoromethyl benzylamine (0.088 g, 0.50

mmol) affords 6d (0.062 g, 55% yield). Light yellow oily liquid obtained

after column chromatography (SiO2, Pentane/EtOAc 95:5 to 90:10). 1H

NMR (400 MHz, CDCl3) δ 7.52 – 7.62 (m, 1H), 7.43 – 7.49 (m, 1H),

7.38 – 7.43 (m, 1H), 7.23 – 7.29 (m, 1H), 6.65 – 6.75 (m, 2H), 6.20 – 6.30 (m,

2H), 5.14 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 139.28, 131.09 (d, J = 22.29 Hz),

130.19 (d, J = 1.41 Hz), 129.30, 124.54 (quat, J = 3.84 Hz), 129.95 (d, J = 272.50

Hz), 123.64 (quat, J = 3.83 Hz), 121.12, 109.04, 52.81. HRMS (APCI+, m/z):

calculated for C12H11F3N [M+H]+: 226.08381; found: 226.08415.

N-(3-Fluoro-4-chloro-benzyl)-pyrrole (6e): Synthesized according

to General procedure. 3-Fluoro-4-chloro benzylamine (0.080 g, 0.50

mmol) affords 6e (0.068 g, 65% yield). Light yellow oily liquid was

obtained after column chromatography (SiO2, Pentane/EtOAc 95:5 to

90:10). 1H NMR (400 MHz, CDCl3) δ 7.13 – 7.21 (m, 1H), 7.05 – 7.13

(m, 1H), 6.93 – 7.02 (m, 1H), 6.63 – 6.73 (m, 2H), 6.18 – 6.28 (m, 2H), 5.03 (s.

2H). 13C NMR (100 MHz, CDCl3) δ 157.49 (d, J = 248.78 Hz), 135.25 (d, J = 3.85

Hz), 129.08, 126.59 (d, J = 7.30 Hz), 121.28 (d, J = 17.87 Hz), 120.96, 116.76

Chapter 4

88

(d, J = 21.31 Hz), 108.99, 52.10. HRMS (APCI+, m/z): calculated for C11H10ClFN

[M+H]+: 210.04803; found: 210.04824.

N-(4-Methyl-benzyl)-pyrrole (6f): Synthesized according to General

procedure. 4-Methyl benzylamine (0.061 g, 0.50 mmol) affords 6f (0.052

g, 60% yield). Light yellow oily liquid was obtained after column


MHz, CDCl3) δ 7.13 – 7.22 (m, 2H), 7.03 – 7.10 (m, 2H), 6.66 – 6.76

(m, 2H), 6.16 – 6.26 (m, 2H), 5.06 (s. 2H), 2.37 (s, 2H). 13C NMR (100 MHz, CDCl3)

δ 137.29, 135.06, 129.32, 127.02, 121.01, 108.34, 53.07, 21.04. The physical


N-Piperonyl-pyrrole (6g): Synthesized according to General

procedure. Piperonylamine (0.076 g, 0.50 mmol) affords 6g (0.056 g,

55% yield). Light yellow oily liquid was obtained after column


MHz, CDCl3) δ 6.74 – 6.79 (m, 1H), 6.66 – 6.72 (m, 2H), 6.63 – 6.66

(m, 1H), 6.60 – 6.63 (m, 1H), 6.16 – 6.22 (m, 2H), 5.94 (s. 2H), 4.97 (s, 2H). 13C

NMR (100 MHz, CDCl3) δ 148.00, 147.09, 131.88, 120.88, 120.48, 108.46, 108.23,


previously reported[35].

N-(3-Picolyl)-pyrrole (6h): Synthesized according to General

procedure. 3-Picolylamine (0.054 g, 0.50 mmol) affords 6h (0.060 g,

76% yield). Light yellow oily liquid was obtained after column


MHz, CDCl3) δ 8.40 – 8.60 (m, 2H), 7.32 – 7.40 (m, 1H), 7.20 -7.29 (m, 1H), 6.62

– 6.74 (m, 2H), 6.15 – 6.25 (m, 2H), 5.09 (s. 2H). 13C NMR (100 MHz, CDCl3) δ

149.05, 148.28, 134.66, 133.68, 123.68, 120.92, 109.02, 50.70. The physical


N-(2-Furfuryl)-pyrrole (6i): Synthesized according to General

procedure. Furfurylamine (0.049 g, 0.50 mmol) affords 6i (0.032 g, 43%

yield). Light yellow oily liquid was obtained after column chromatography

(SiO2, Pentane/EtOAc 80:20 to 40:60). 1H NMR (400 MHz, CDCl3) δ 7.32–

7.42 (m, 1H), 6.68 – 6.76 (m, 2H), 6.30 – 6.38 (m, 1H), 6.22 – 6.30 (m, 1H),

6.15 – 6.22 (m, 2H), 5.03 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 150.74, 142.65,



N-(2-Phenylethyl)-pyrrole (6g): Synthesized according to General

procedure. 2-Phenyl ethylamine (0.061 g, 0.50 mmol) affords 6g (0.035

g, 41% yield). Light yellow oily liquid was obtained after column


MHz, CDCl3) δ 7.29– 7.39 (m, 2H), 7.26 – 7.29 (m, 1H), 7.10 – 7.18 (m, 2H),

6.58 – 6.68 (m, 2H), 6.12 – 6.22 (m, 2H), 4.14 (t, J = 7.65 Hz, 2H), 3.09 (t, J =

7.61 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 138.39, 128.62, 128.50, 126.55,

Pyrroles

89


those previously reported[37].

N-Dodecyl-pyrrole (6k): Synthesized according to General procedure.

Dodecylamine (0.093 g, 0.50 mmol) affords 6k (0.050 g, 42% yield).


Pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CDCl3) δ 6.62– 6.70 (m, 2H),

6.12 – 6.18 (m, 2H), 3.87 (t, J = 7.20 Hz, 2H), 1.70 – 1.83 (m, 2H), 1.18 – 1.38

(m, 18H), 0.90 (t, J = 6.63 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 120.41, 107.71,

49.62, 31.90, 31.57, 29.61, 29.60, 29.55, 29.48, 29.32, 29.20, 26.76, 22.67,


reported[38].

N-Cyclohexyl-pyrrole (6l): Synthesized according to General procedure.

Cyclohexylamine (0.050 g, 0.50 mmol) affords 6l (0.025 g, 33% yield).


Pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CDCl3) δ 6.70– 6.78

(m, 2H), 6.10 – 6.18 (m, 2H), 3.75 – 3.87 (m , 2H), 2.05 – 2.15 (m, 2H), 1.82 –

1.94 (m, 2H), 1.56 – 1.69 (m, 2H), 1.33 – 1.48 (m , 2H), 1.19 – 1.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 118.39, 107.31, 58.65, 34.66, 25.72, 25.49. The

physical data were identical in all respects to those previously reported[39].

Chapter 4

90

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Chapter 4

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93

Chapter 5

Direct N-alkylation of unprotected amino acids with alcohols

-Amino acids are the most abundant chiral amine sources in nature and basic

units of proteins. Their derivatives are widely used in catalysis, fine chemical

synthesis or as building blocks in functional materials. Therefore, developing

efficient ways for the derivatization of -amino acids is highly desired. N-alkylation

of -amino acids is one of the most common ways of derivatization. The traditional

pathways including reductive alkylation with aldehydes and nucleophilic

substitution of alkyl halides face a number of limitations such as the formation of

stoichiometric amount of side products and complex procedures for purification. In

this chapter, an unprecedented methodology for the direct N-alkylation of

unprotected -amino acids with alcohols is described. Notably, this methodology

allows for good retention of the optical purity in the final products. The described

method is direct, catalytic and highly selective, only producing water as by-product

and allows for an extremely simple purification process. The scope includes N-

alkylation of natural -amino acids and simple peptides with simple alcohols, fatty

alcohols and diols. Using fatty alcohols and amino acids as only reaction partners

result in the formation of mono-N-alkyl amino acids using a molecular iron catalyst.

Finally, a fully sustainable catalytic system for the production of renewable

surfactants is presented.

Part of this chapter will be issued as a patent:

N-alkylated amino acids and oligopeptides, uses thereof and methods for providing

them, P114699EP00.

Part of this chapter has been submitted for publication:

T. Yan, B. L. Feringa, K. Barta, submitted.

Chapter 5

94

Introduction

-Amino acids[1] are one of the major classes of organic products produced from

nitrogen fixation[2], a core process for life, and represent a perfectly sustainable

amine alternative to the ones based on fossil carbon sources[3]. N-alkyl amino

acids[4] are an essential class of -amino acid derivatives since they are versatile

building blocks in biological and chemical synthesis, and their inherent chirality

and zwitterion property allows for broad application in various areas (Figure 1, A).

For example, Muraglitazar is a dual peroxisome proliferator-activated receptor

agonist[5]; N-alkylated dipeptides are carriers to transport Cu(II), Zn(II), and Ni(II)

across cell membranes[6], to promote catalytic reactions in cells[7]; a zinc complex

bearing N-isopropyl-L-proline ligand finds use in asymmetric catalysis[8]; and N-

alkyl amino acids can also be used as functional materials such as surfactants[9]

and as monomers for the synthesis of nontoxic, biodegradable polymers[10] as well

as modified proteins[11].

Figure 1: Fields of application of N-Alkyl amino acids

Surprisingly, despite the broad potential of this class of compounds, a highly

selective and atom-economic method for the derivatization of -amino acids has

not yet been developed[12]. The most common stoichiometric methods for the N-

alkylation of -amino acids are reductive alkylation with aldehydes using

borohydrides as reductant[13] and nucleophilic substitution of alkyl halides[14].

These conventional methodologies suffer from limited availability, versatility or

stability of the starting materials, and the formation of stoichiometric amounts of

salts as waste (Figure 2, A). A number of methodologies have been developed,

however these require multiple protection steps or tedious purification

procedures.[4] Therefore, to carry out N-alkylation of -amino acids in an efficient,

selective and atom-economic manner is a major challenge.

A desired approach to carry out such a direct and atom economic transformation

would be the direct N-alkylation of amino acids with alcohols through the borrowing

hydrogen strategy[15] (Figure 2, B). Alcohols are abundant chemical reagents that

can be derived from renewable resources through fermentation, depolymerization

of lignocellulose[16] as well as reduction of fatty acids contained in plants oil.[17] As

such, they have a clear advantage compared to other alkylation reagents. Alcohols

have been already used as reagents to alkylate amines on an industrial scale[18],

however these methods require harsh reaction conditions. With the development

of the hydrogen borrowing strategies for the direct N-alkylation of amines with

alcohols using a variety of transition metal catalysts, this reaction has been

accomplished very efficiently, and a broad variety of alcohols and amines were

N-alkylation of unprotected amino acids

95

used.[15] However, the direct and selective N-alkylation of amino acids with

alcohols has not yet been demonstrated using this method, probably due to the

poor solubility of amino acids in organic solvents and their zwitterionic property,

which makes the substrates sensitive to changes of pH and basic or acidic reagents.

Moreover, racemization under the reaction conditions may be a serious problem,

since most hydrogen borrowing methods require the addition of base.[15]

Figure 2: A Comparison of different methodologies of N-alkylation of -amino acids; B

proposed mechanism of alkylation of amines with alcohols.

To the best of our knowledge, only 2 examples[19ab] of N-alkylation of free amino

acids with alcohols have been reported using heterogeneous catalysts and showing

limited substrate scope (Scheme 1, A). Notably, palladium catalyzed N-allylation

of unprotected amino acids with allylic alcohols was recently reported. A palladium

π-allyl species was involved in the catalytic cycle (Scheme 1, B)[19c]. In Chapter 2,

the first direct N-alkylation of amines with alcohols with a well-defined iron

complex was described[20] (Scheme 1, C). This methodology is efficient and base-

free, thus we envisioned that it would also allow for the direct N-alkylation of

unprotected -amino acids with alcohols, possibly without racemization.


Alkylation with EtOH With the above mentioned goal in mind, the investigation

started using proline (1a) as the substrate, ethanol (2a) as the alkylation reagent

and Knölker’s complex[21a] Cat 3 as the catalyst (Table 1, entry 1). Quantitative

yield of N-ethyl proline (3aa) was obtained with 4 mol% of Cat 3, at 90 °C for 16

h (Table 1, entry 2). However, when leucine (1b) was used as the substrate, at

90 °C for 15 h, 15% conversion of 1b was observed. The dramatic drop of

reactivity of using 1b as the substrate probably due to the low solubility of 1b in

ethanol (Table 1, entry 3). Then the loading of Cat 3 was increased to 10 mol%,

Chapter 5

96

at 110 °C, 70% conversion of 1b was observed (Table 1, entry 4). When CF3CH2OH

was selected as the solvent, at 100 °C for 24 h, Cat 3 and its analogue Cat 3b

were employed and gave 30% and 70% conversion of 1b, respectively. (Table 1,

entry 5 and 6). Using Cat 3b gave higher conversion of leucine (2b) comparing to

using Cat 3, probably because Cat 3b was more efficient in generating the

catalytically active species.[22] Employing 4 mol% Cat 3b as the catalyst,

CF3CH2OH as the solvent, at 110 °C for 42 h, full conversion of 1b and 49% isolated

yield of diethyl leucine (3ba) was obtained.

Next, the ruthenium analogue of Cat 3, the Shvo catalyst[21b] (Cat 1) was also

investigated. Surprisingly, quantitative yields of both 3aa and 3ba from 1a and

1b were observed, respectively (Table 1, entry 8 and 9). Interestingly, the Shvo

catalyst (Cat 1) has mainly been used in hydrogen transfer reactions[21c] and only

very few examples have shown its ability to promote N-alkylation of amines[23].

The conditions described in entry 7 and 9 (Table 1) were taken as starting point

for further investigation.

One crucial requirement for a method designed for the modification of amino acids

is the retention of the chiral information contained in the starting material. Thus,

the enantiomeric excess (ee) of the N-alkylated products was investigated (Table

2). In this case, Cat 3b gave quantitative yield of 3aa with 94% retention of ee,

and 45% yield of 3ba with 80% ee retention (Table 2, entry 2 and 4). In the

meantime, Cat 1 gave both 3aa and 3ba in quantitative yields as described, with

retention of ee of 93% and 99%, respectively (Table 2, entry 1 and 3).

Phenylalanine (1d) was selected to react with 2a, catalyzed by both Cat 3b and

Cat 1 for further comparison. Cat 3b gave 3da in 55% yield with 72% retention

of ee, and Cat 1 gave 3da in quantitative yield with 97% retention of ee (Table 2,

Scheme 1: A N-Methylation of unprotected amino acids with MeOH catalyzed by

heterogeneous catalysts; B palladium catalyzed N-allylation of tryptophan with 2-

methyl-3-buten-2-ol; C base-free iron catalyzed alkylation of amines with alcohols.


97

entry 7 and 8). Based on these preliminary results, Cat 1 was chosen for the

further study of the reaction scope.

Then, other -amino acids including valine (1c), serine (1e) and alanine (1f) were

examined and quantitative yields of the corresponding diethylation products 3ca,

3ea and 3fa were obtained, with ee values of 99, 86 and 84%, respectively (Table

2, entry 6, 9 and 10). The partial racemization in the latter cases was probably

due to the activity of the Shvo catalyst in the dehydrogenation of amines to imines

and rehydrogenation of imines back to amines, which were described previously

by the groups of Beller[23] and Casey[24]. The lower steric hindrance of the

stereogenic center of 3ea and 3fa comparing to 3ca allows for easier racemization.

In order to improve the retention of stereochemistry in 3fa, the temperature was

lowered to 60 °C while prolonging the reaction time. Quantitative yield of 3fa was

obtained, however the ee of the final product was only improved slightly to 86%

(Table 2, entry 11).

The simplest -amino acid glycine (1g) was used and gave a quantitative yield of

N,N-diethyl-glycine (3ga) (Table 2, entry 12). On the other hand, lysine (3h) was

unreactive, whereas N6-acetyl-lysine (3i) gave 74% yield of the corresponding

N2,N2-diethylation product 3ia (Table 2, entry 13-16). The above results clearly

showed that all primary amino acids selectively gave N,N-diethylated products in

excellent yields when reacted with 2a under neat condition.

Table 2: Direct N-ethylation of unprotected amino acid (1) with ethanol (2a).

Table 1: Optimization of reaction conditions for direct N-ethylation of proline (1a)

or leucine (1b) with ethanol (2a).

Entry 1

[mmol]

Cat. [mol%] 2a

[ml]

T.

[h]

Temp.

[oC]

Conv. 1

[%]a

Sel. 3

[%]a

1 1a / 0.5 Cat 3 / 4, Me3NO / 8 2 18 110 >99 >99

2 1a / 0.5 Cat 3 / 4, Me3NO / 8 2 16 90 >99 >99 (99)

3 1b / 0.5 Cat 3 / 4, Me3NO / 8 4 15 90 15 n.d.

4 1b / 0.2 Cat 3 / 10, Me3NO / 20 5 18 110 70 n.d.

5b 1b / 0.5 Cat 3 / 4, Me3NO / 8 4 24 100 30 n.d.

6b 1b / 0.5 Cat 3b / 4 4 24 100 70 n.d.

7b 1b / 0.5 Cat 3b / 4 4 42 110 >95 (49)

8 1a / 0.5 Cat 1 / 0.5 5 18 90 >99 >99 (99)

9 1b / 0.2 Cat 1 / 1 5 18 90 >99 >99 (99)

General reaction conditions: general procedure, 0.2 or 0.5 mmol 1a (or 1b), 2–5 ml 2a,

Cat 3 + Me3NO, Cat 3b, or Cat 1 (given amount), neat, 14-24 h, 90-110 °C , isolated

yields in parenthesis. aConversion and selectivity are based on 1H NMR; b1 ml CF3CH2OH

was added.

Chapter 5

98

Entry 1 / [mmol] T.

[h]

Temp.

[oC]

Conv.

1 [%]a

Sel. 3 [%]a ee

[%]b

1 1a L-Proline / 0.2 18 90 >99 3aa >99 (99) 93

2e 1a L-Proline / 0.5 18 90 >99 3aa >99 (99) 94

3 1b L-Leucine / 0.2 18 90 >99 3ba >99 (99) 99

4de 1b L-Leucine / 0.5 42 110 >95 3ba (49) 80

5 1c L-Valine / 0.2 18 90 >99 3ca 55 n.d.

6 1c L-Valine / 0.2 24 90 >99 3ca >99 99

7 1d L-Phenylalanine / 0.2 18 90 >99 3da >99 97c

8de 1d L-Phenylalanine / 0.5 42 110 >90 3da (55) 72

9 1e L-Serine / 0.2 18 90 >99 3ea >99 86

10 1f L-Alanine / 0.2 18 90 >99 3fa >99 84

11 1f L-Alanine / 0.2 47 60 >99 3fa >99 86

12 1g Glycine / 0.2 18 90 >99 3ga >99 /

13 1h Lysine / 0.2 18 90 <1% 3ha n.d. /

14d 1h Lysine / 0.2 18 100 <1% 3ha n.d. /

15 1i N6-Ac-lysine / 0.2 18 90 >99 3ia <5% /

16d 1i N6-Ac-lysine / 0.2 18 90 >99 3ia (74) n.d.

General reaction conditions: General procedure, 0.2 mmol 1, 5 ml 2a, 1 mol% Cat 1, neat,

18-47 h, 60-110 °C, unless otherwise specified, isolated yields in parenthesis. aConversion

and selectivity are based on 1H NMR; bee was measured through corresponding amino acid

amide using chiral HPLC, unless otherwise specified; cee was measured through

corresponding amino acid methyl ester using chiral HPLC; d1 ml CF3CH2OH was added; e5

mol% Cat 3b was used instead of Cat 1.

Alkylation with iPrOH With the results of N-ethylation of -amino acids with 2a

in hand, the secondary alcohol isopropanol (2b) was also applied to alkylate -

amino acids (Table 3). Under neat conditions, 2a was quantitatively converted to

N-isopropyl-proline (3ab) (Table 3, entry 1). However, when phenylalanine (1d)

was tried, no significant formation of the corresponding N-alkyl amino acid was

observed due to the poor solubility of 1d in isopropanol (2b). This prompted us to

investigate the use of solvents like H2O, MeOH (2c) or CF3CH2OH[25] (2d). While

H2O or 2c gave unsatisfactory improvement, the use of 2d gave quantitative yield

of N-isopropyl-phenylalanine (3db) (Table 3, entry 3-9). Only the mono-alkylation

product was observed in this case, probably due to the steric hindrance created

after the insertion of the first isopropyl-moiety that inhibited the second alkylation

step. Following the same procedure, amino acids leucine (1b), valine (1c), serine

(1e) and alanine (1f) have also been successfully mono-isopropylated, providing

N-isopropylation of amino acids 3bb, 3cb, 3eb and 3fb in quantitative yields,

respectively (Table 3, entry 10-21). This method could be used in the future to

easily obtain mono-N-alkylated amino acids (non-proteinogenic amino acids) for

the synthesis of modified proteins with higher lipophilicity.

Table 3: Direct mono N-isopropylation of amino acid (1) with isopropanol (2b).


99

Entry 1 / [mmol] 2b

[ml]

Sol.

[ml]

T.

[h]

Conv.

1 [%]a

Sel. 3 [%]a

1 1a Proline / 0.2 2 / 18 >99 3ab >99 (99)

2b 1a Proline / 0.5 2 / 16 88 n.d.

3 1d Phenylalanine / 0.2 5 / 18 <5 n.d.

4 1d Phenylalanine / 0.2 4.5 H2O 0.5 45 <1 n.d.

5 1d Phenylalanine / 0.2 4.5 2c 0.5 45 15 n.d.

6 1d Phenylalanine / 0.2 4 2c 1 18 12 n.d.

7d 1d Phenylalanine / 0.2 4 2c 1 18 85 n.d.

8 1d Phenylalanine / 0.2 3 2c 2 18 10 n.d.

9 1d Phenylalanine / 0.2 4 2d 1 24 >99 3db >99 (99)

10 1b Leucine / 0.2 5 / 18 <5 n.d.

11 1b Leucine / 0.2 4 2d 1 24 40 n.d.

12c 1b Leucine / 0.2 4 2d 1 28 >99 3bb >99 (99)

13 1c Valine / 0.2 5 / 18 <5 n.d.

14 1c Valine / 0.2 4 2d 1 24 >99 3cb >99 (99)

15 1e Serine / 0.2 5 / 18 <5 n.d.

16 1e Serine / 0.2 4 2d 1 24 15 n.d.

17c 1e Serine / 0.2 4 2d 1 24 40 n.d.

18d 1e Serine / 0.2 4 2d 1 24 >99 3eb >99 (99)

19 1f Alanine / 0.2 5 / 18 <5 n.d.

20 1f Alanine / 0.2 4 2d 1 24 67 n.d.

21 1f Alanine / 0.2 4 2d 1 28 >99 3fb >99 (99)

General reaction conditions: General procedure, 0.2 or 0.5 mmol 1, 2-5 ml 2b, neat or

with solvent (amount shown in the table), 1 mol% Cat 1, 16-45 h, 90 °C , unless otherwise

specified, isolated yields in parenthesis; aConversion and selectivity are based on 1H NMR; b4 mol% Cat 3b was used instead of Cat 1; c2 mol% Cat 1 was used; d100 °C.

Alkylation with diverse alcohols After exploring the reactivity of various -

amino acids with ethanol (2a) and isopropanol (2b), diverse alcohols were

investigated (Table 4). As previously shown, MeOH (2c) or CF3CH2OH (2d) did not

react with 1a, probably because they were not prone to be dehydrogenated under

the present reaction conditions, which allowed for the possibility of using 2c or 2d

as solvent. The use of other alcohol substrates such as 1-butanol (2e),

cyclopropylmethanol (2f) and 2-chloroethanol (2g), employed in the reaction with

1a, resulted in quantitative yield of 3ea, 55% yield of 3af, and 71% yield of 3ag,

respectively (Table 4, entry 3-5). Also, benzyl alcohol (3h) and 4-chlorobenzyl

alcohol (3i) were successfully applied to benzylate 1a with good yields of 68% and

82%, respectively (Table 4, entry 6 and 7). Here it needs to be pointed out, that

the chloro group on 3ag and 3ai would allow the further functionalization of the

obtained amino acid derivatives. Subsequently, the use of other amino acids such

as phenylalanine (1d) and glycine (1g) were examined. Phenylalanine 1d reacted

with 1-butanol (2e) to give 84% yield of 3de (Table 4, entry 8). The reaction of

1d with 1,5-pentane-diol (2k) gave 35% yield of the di-alkylated 3dk as the major

product (Table 4, entry 10). The introduced two hydroxyl groups on 3dk, could

Chapter 5

100

not only be handles for further functionalization, but also dramatically increase the

hydrophilicity of the product.

Table 4: Direct N-alkylation of unprotected amino acid (1) with various alcohols

(2).

Entry 1 [mmol] 2 Sol.

[ml]

T.

[h]

Conv.

1 [%]a

Yield 3 [%]

1 1a Proline / 0.2 2c MeOH / 2 ml / 18 <1 3ac n.d.

2 1a Proline / 0.2 2d CF3CH2OH / 2

ml

/ 18 <1 3ad n.d.

3 1a Proline / 0.2 2e nBuOH / 2 ml / 24 >99 3ae >99

4 1a Proline / 0.5 2f / 5 ml

/ 18 >99 3af 55

5 1a Proline / 0.2 2g / 2 ml / 18 >99 3ag 71

6 1a Proline / 0.2 2h BnOH / 2 ml / 18 >99 3ah 68

7 1a Proline / 0.5 2i / 2

mmol

2d/tol.

1/4

20 >99 3ai 82

8 1d Phenylalanine /

0.5

2e nBuOH / 4 ml 2d 2 24 >99 3de 84

9 1d Phenylalanine /

0.5

2j 1-nonanol / 1

ml

2d/tol

2/2

24 >99 3dj 75

10b 1d Phenylalanine /

0.2

2k 1,5-

pentanediol /

2 mmol

2d/tol

2/3

18 >99 3dk 35

11 1g Glycine / 0.5 2h BnOH / 2

mmol

2d/tol

2/3

18 n.d. 3gh 52

12 1g Glycine / 0.5 2j 1-nonanol / 2

mmol

2d/tol

2/3

24 >99 3gj 91

13 1g Glycine / 0.2 2l 2-butanol / 4

ml

2d 1 24 >99 3gl >99

14 1g Glycine / 0.5 2m 1-pentanol /

2 mmol

2d/tol

2/3

18 >99 3gm 90

15 1g Glycine / 0.5 2m 1-pentanol /

0.6 mmol

2d/tol

2/3

18 >99 3gm’ 46

3gm 29

16 1g Glycine / 0.5 2n 1-dodecanol /

2 mmol

2d/tol

2/3

18 >99 3gn 92

General reaction conditions: General procedure, 0.2 or 0.5 mmol 1, 0.6–2 mmol or 2-5 ml

2, neat or with solvent (amount shown in the table), 1 mol% Cat 1, 16-24 h, 90 °C,

isolated yields are shown. aConversion is based on 1H NMR; b100 °C.

Next, the functionalization of glycine 1g with various alcohols was further explored.

Upon reaction with benzyl alcohol 2h, the di-benzylation product 3gh was obtained

in 52% yield, while when secondary alcohol 2-butanol (2l) was employed to

alkylate glycine 1g, selective mono-alkylation was observed and the product 3gl

was obtained in quantitative yield (Table 4, entry 11 and 13). After this, the

possibility of mono-alkylation with primary alcohols was also investigated. Using 4


101

eq. of 1-pentanol (1m), glycine 1g was successfully di-alkylated giving 90% of

3gm. When the amount of 1m was decreased to 1.2 eq., 46% mono-alkylated

product 3gm’ and 29% of the di-alkylated product 3gm were obtained (Table 4,

entry 14 and 15).

Scheme 2: N-alkylation of amino acids with various alcohols.

General reaction conditions: General procedure, 0.2 or 0.5 mmol 1, 1-5 ml or 0.6–2 mmol

2, 1 mol% Cat 1, neat when using ethanol (2a), 1 ml CF3CH2OH (2d) was added when

using iPrOH (2b), 18-28 h, 90 °C, isolated yields are shown, ee was measured through

corresponding amino acid amide using chiral HPLC, unless otherwise specified. #neat;

^CF3CH2OH was used as solvent; aee was measured through corresponding amino acid

methyl ester using chiral HPLC; b2 mol% Cat 1 was used; c100 °C. For details see Table

2-4.

The isolated yields of N-alkylated amino acids and their retention of ee under

optimized conditions are shown in Scheme 2.

Alkylation of peptides Encouraged by the promising results regarding the

functionalization of amino acids, we attempted the extension of this novel method

to simple free peptides, which possess similar physical properties and functional

Chapter 5

102

groups as the corresponding amino acids (Table 5). First, the simple dipeptide

glycylalanine (4a) was chosen to react with 2a and gratifyingly, the corresponding

di-ethylated product 5aa was obtained quantitatively (Table 5, entry 1). Based on

this protocol, the hydrophobicity or hydrophylicity of peptides can be modulated

by introducing either longer chain alkyl groups or more polar moieties bearing

hydroxyl groups. Indeed, when 1-dodecanol (2n) was reacted with dipeptide 4a,

the corresponding dialkylated product 5an was obtained in 82% yield. This type

of lipophilic dipeptide has been used for transporting metal ions across

membranes[6] (Table 5, entry 2). On the other hand, the reaction of 1,5-pentane-

diol 2k with 4a, afforded 36% 5ak, bearing additional hydroxyl groups (Table 5,

entry 3).

Table 5: Alkylation of N-terminus of oligo-peptides with alcohols.

Entry 4 [mmol] 2 Sol.

[ml]

T.

[h]

Conv.

4 [%]a

Yield 5 [%]

1 4a

/ 0.2

2a ethanol / 5

ml

/ 24 >95 5aa >95

2 4a

/ 0.5

2n dodecanol

/ 2 mmol

2d/tol

2/3

18 n.d. 5an 82

3 4a

/ 0.5

2k 1,5-

pentanediol

/ 2 mmol

2d/tol

2/3

24 n.d. 5ak 36

4 4b

/ 0.2

2a ethanol / 5

ml

/ 24 n.d. 5ba 50

5 4b

/ 0.5

2a ethanol / 5

ml

2d 2 18 n.d. 5ba 67

General reaction conditions: General procedure, 0.2 or 0.5 mmol 4, 2 mmol or 5 ml 2,

neat or with solvent (amount shown in the table), 1 mol% Cat 1, 18 or 24 h, 90 °C, isolated

yields are shown. aConversion is based on 1H NMR.

Following the successful and diverse functionalization of a dipeptide, a tri-peptide

leucylglycylglycine (4b) was tested in the reaction with 2a, which lead to the

formation of the corresponding di-ethylated product 5ba with 67% isolated yield

(Table 5, entry 4 and 5). The above reactions represent the first example of the

selective di-alkylation of peptide substrates on their N-terminus using simple

alcohols, allowing for good product yields and easy purification[26]. This

methodology can potentially be used for protein N-terminus modification, thereby


103

affecting protein activation, conversion and degradation, allowing further

diversifying of biological functions[27].

Sustainable surfactants Amino acids attract increasing interest in recent years

as starting material for synthetizing bio-based surfactants, among which N-

alkylated amino acids derived surfactants are not well studied because they are

relatively difficult to be synthetized[9]. Envisioning the possibility of easily

synthetizing long-chain N-alkylated amino acids with our methodology, 1-nonanol

(2j) was selected for the N-alkylation of phenylalanine 1d and glycine 1g. Di-

alkylated compounds 3dj and 3gj were selectively obtained with yields of 75%

and 91%, respectively (Scheme 2, Table 4, entry 9 and 12). The reaction also

readily proceeded with 1-dodecanol (2n) and glycine 1g as substrate, obtaining

the corresponding product 3gn in 92% yield (Table 4, entry 16). For all the cases,

selective dialkylated products were obtained.

Realizing that chirality is not an essential property requirement for a surfactant,

here the iron based Cat 3b was employed for the direct synthesis of a surfactant

from natural amino acids and fatty alcohols (Scheme 3). Glycine (1g) and 1-

dodecanol (2n) were reacted under 110 °C for 24 h with 5 mol% Cat 3b.

Surprisingly, 54% mono-N-dodecylglycine (3gn’) and 8% N,N-didodecylglycine

(3gn) were isolated. The use of Cat 3b leads to the preferential formation of

mono-N-alkyl amino acids, which have already shown surfactant properties[9].

After adding KOH and H2O to 3gn’, a rich foam formation was clearly seen

(Scheme 3), indicating its amphiphilic property. Subsequently, various fatty

alcohols that can be potentially derived from biomass, including 1-nonanol (2j),

1-decanol (2o), 1-tetradecanol (2p), 1-hexadecanol (2q) and 1-octadecanol (2n)

were reacted with 1g, and gave 32–69% isolated yields of the corresponding

mono-N-alkyl glycine derivatives 3gj', 3go', 3gp', 3gq' and 3gr' (Scheme 3).

Alanine (1f) and proline (1a) were reacted with 1-dodecanol (2n) and 1-nonanol

(2j), with 5 mol% Cat 3b, 49% of 3fn’ and 52% of 3aj were isolated, respectively

(Scheme 3). Long-chain alcohols can be produced from natural fats and oils[23].

This opens possibilities for the fully sustainable production of long-chain N-alkyl

amino acid based surfactants entirely derived from biomass, with non-precious

iron based catalyst[28].

Chapter 5

104

Scheme 3: Iron catalyzed N-alkylation of amino acids with fatty alcohols.

General reaction conditions: General procedure, 0.5 mmol 1, 1 ml 2, 3 ml CF3CH2OH, 5

mol% Cat 3b, 24 h, 110 °C, isolated yields are shown. aThe products was transformed to

corresponding methyl ester before isolation, 2 mmol 2; bneat.

Conclusion

In conclusion, the first direct N-alkylation of free -amino acids and simple

peptides with a variety of alcohols using 0.5-1 mol% of a homogeneous Ru catalyst

was demonstrated. The presented atom-economic transformations only result in

water as byproduct, thereby significantly simplifying the purification procedure.

The reaction is highly selective, and most products were obtained in quantitative

yield. Reaction temperature as low as 60 °C can be used with several substrates.

Particularly, the use of long chain alcohols and amino acids as only reaction

partners to obtain mono-N-alkyl amino acids, especially with a molecular iron

catalyst was established, which holds great potential for the fully sustainable

production of completely bio-based surfactants.

This work is not only a significant addition to sustainable homogeneous catalysis

related to the atom economic modification of challenging substrates such as amino

acids, but will likely open new possibilities for material science for the production

of surfactant as well as for the easy and selective chemical modification of proteins

or peptides in biochemistry. Future research will focus on exploring the potential

of this intriguing reaction under mild conditions as well as in aqueous solutions.


General methods


active neutral, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by


105

UV, Ninhydrin or I2 staining. Progress of the reactions was determined by NMR.

Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ

Orbitrap XL (ESI+). 1H- and 13C NMR spectra were recorded on a Varian AMX400

(400 and 100.59 MHz, respectively) using CDCl3, CD3OD, D2O or DMSO-d6 as

solvent. Chemical shift values are reported in ppm with the solvent resonance as

the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C; CD3OD: 3.31 for 1H, 49.00

for 13C; D2O: 4.79 for 1H; DMSO-d6: 2.50 for 1H, 39.52 for 13C). Data are reported

as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q =

quartet, br. = broad, m = multiplet), coupling constants (Hz), and integration. All

reactions were carried out under an Argon atmosphere using oven (110 °C) dried

glassware and using standard Schlenk techniques. Toluene were collected from a

MBRAUN solvent purification system (MB SPS-800). CF3CH2OH (>99.0%) was

purchased from TCI without further purification. The synthesis of Cat 3 and Cat

3b was carried out as described in Chapter 2. Cat 1 was purchased from Strem.

All other reagents were purchased from Sigma, TCI or Acros in reagent or higher

grade and were used without further purification.


General procedure: An oven-dried 20 ml Schlenk tube, equipped with stirring

bar, was charged with amino acid (or peptide, given amount), Cat 1 or Cat 3

(given amount) and alcohol (given amount), solvent (or neat). Amino acid (or

peptide) and catalyst were added into the Schlenk tube under air, the Schlenk tube

was subsequently connected to an argon line and a vacuum-backfill cycle was

performed three times. Alcohol and solvent was charged under an argon stream.

The Schlenk tube was sealed with screw cap. The mixture was rapidly stirred at

room temperature for 1 min, then was placed into a pre-heated oil bath at the


cooled down to room temperature and concentrated in vacuum. The residue was

characterized by 1H NMR spectroscopy to determine conversion. Further

purification was conducted through flash column chromatography or crystallization

to provide the pure N-alkyl amino acid (or peptide) product.

Esterification procedure (for preparation of methyl esters of long-chain N-alkyl

amino acids 3gp’, 3gq’ and 3gr’): General procedure was performed and

continued until the stage when the reaction mixture was cooled down to room

temperature. Subsequently, 3 ml benzene was added, and TMSCHN2 (2M in

toluene) was added under stirring. The progress of the reaction can be monitored

by TLC (SiO2, mono-N-alkyl amino acid, Rf = 0.3 in ethylacetate/MeOH = 1/1;

methyl mono-n-alkyl amino acid ester, Rf = 0.3 in Et2O). Then the corresponding

methyl ester was purified by flash chromatography (SiO2, tol/Et2O 50/50 – 0/100).

Procedure of ethylation of proline (1a) with ethanol (2a): An oven-dried 20

ml Schlenk tube, equipped with stirring bar, was charged with proline (0.5 mmol,

58 mg) and Cat 1 (0.0025 mmol, 2.7 mg) under air. The Schlenk tube was

subsequently connected to a vacuum/argon Schlenk line and a vacuum-backfill

cycle was performed three times. Then 5 ml ethanol was charged under an argon

stream. The Schlenk tube was sealed with a screw cap. The mixture was rapidly

Chapter 5

106

stirred at room temperature for 1 min, then was placed into a pre-heated oil bath

at 90 °C and stirred for 18 h. The reaction mixture was cooled down to room

temperature, concentrated and dried in high vacuum for 2 h. The residue was

weighed (72 mg) and characterized by 1H- and 13C NMR spectrospcopy. The NMR

spectrums of the residue show pure ethyl proline (3aa) without detectable

impurity and this indicates that the desired product was obtained in quantitative

yield. Ethyl proline 3aa was transformed to the corresponding amino acid amide

6aa for ee determination (93%) measured by chiral HPLC.

Procedure of iron catalyzed mono-alkylation of glycine (1g) with 1-

decanol (2o): An oven-dried 20 ml Schlenk tube, equipped with stirring bar, was

charged with glycine (0.5 mmol, 38 mg) and Cat 3b (0.025 mmol, 10 mg) under

air. The Schlenk tube was subsequently connected to a vacuum/argon Schlenk line

and a vacuum-backfill cycle was performed three times. Then 1 ml 1-decanol, 3

ml CF3CH2OH were charged under an argon stream. The Schlenk tube was sealed

with a screwed cap. The mixture was rapidly stirred at room temperature for 1

min, then was placed into a pre-heated oil bath at 110 °C and stirred for 24 h. The

reaction mixture was cooled down to room temperature, concentrated in vacuum.

The residue was purified by flash chromatography (SiO2, EtOAc/MeOH 70:30 to

50:50) to provide mono-decyl-glycine (3go’) (74 mg, 69% isolated yield).


107


N-ethyl-proline (3aa): Synthesized according to General

procedure. Quantitative yield of 3aa was obtained after removing

the volatiles of reaction residue by high vacuum. 1H NMR (400 MHz,

D2O) δ 3.83 – 3.96 (m, 1H), 3.64 – 3.78 (m, 1H), 3.15 – 3.33 (m,

2H), 3.05 – 3.15 (m, 1H), 2.35 – 2.52 (m, 1H), 1.99 – 2.16 (m, 2H), 1.85 – 1.99

(m, 1H), 1.27 (t, J = 7.28 Hz, 3H). 13C NMR (100 MHz, MeOD) δ 173.46, 70.13,

55.45, 51.51, 30.32, 24.34, 11.31. HRMS (APCI+, m/z): calculated for C7H14NO2

[M+H]+: 144.10191; found: 144.10181. The physical data are identical to those

previously reported.[19a] The ee (93% when using Cat 1, 94% when using Cat 3b)

were measured through corresponding amino acid amide 6aa using chiral HPLC,

for details see Determination of enantiomeric excesses retention.

N,N-diethyl-leucine (3ba): Synthesized according to General

procedure. Quantitative yield of 3ba was obtained after removing

the volatiles of reaction residue by high vacuum. 1H NMR (400

MHz, D2O) δ 3.58 – 3.67 (m, 1H), 3.08 – 3.30 (m, 4H), 1.67 –

1.78 (m, 1H), 1.51 – 1.67 (m, 2H), 1.26 (t, J = 5.24 Hz, 6H), 0.83

– 1.00 (m, 6H). 13C NMR (100 MHz, D2O) δ 176.34, 68.56, 48.14 (br.s), 38.83,

27.77, 25.52, 23.04, 11.13 (br.s). HRMS (APCI+, m/z): calculated for C10H20NO2

[M-H]-: 186.14886; found: 186.15012. The ee (99% when using Cat 1, 80% when

using Cat 3b) were measured through corresponding amino acid amide 6ba using

chiral HPLC, for details see Determination of enantiomeric excesses retention.

N,N-diethyl-valine (3ca): Synthesized according to General

procedure. Quantitative yield of 3ca was obtained after removing


MHz, D2O) δ 3.45 – 3.52 (m, 1H) 3.05 – 3.35 (m, 4H), 2.22 –

2.40 (m, 1H), 1.15 – 1.40 (m, 6H), 0.99 – 1.10 (m, 3H), 0.86 – 0.99 (m, 3H) 13C

NMR (100 MHz, D2O) δ 174.31, 74.85, 49.85, 45.30, 28.02, 22.22, 18.81, 11.73,


174.14879. The physical data are identical to those previously reported.[29] The ee

(99%) was measured through corresponding amino acid amide 6ca using chiral

HPLC, for details see Determination of enantiomeric excesses retention.

N,N-diethyl-phenylalanine (3da): Synthesized according to

General procedure. Quantitative yield of 3da was obtained after

removing the volatiles of reaction residue by high vacuum. 1H

NMR (400 MHz, D2O) δ 7.12 – 7.43 (m, 5H), 3.80 – 3.93 (m,

1H), 3.08 – 3.40 (m, 4H), 2.98 – 3.31 (m, 2H), 1.17 – 1.33 (m, 6H). 13C NMR

(100 MHz, D2O) δ 172.37, 135.44, 129.06, 128.80, 127.28, 67.81, 45.70 (br.s),

33.44, 8.42 (br.s). HRMS (APCI+, m/z): calculated for C13H18NO2 [M-H]-:

220.13321; found: 220.13433. The ee (97% when using Cat 1, 72% when using

Cat 3b) were measured through corresponding amino acid amide 6da using chiral

HPLC, for details see Determination of enantiomeric excesses retention.

Chapter 5

108

N,N-diethyl-serine (3ea): Synthesized according to General

procedure. Quantitative yield of 3ea was obtained after removing


MHz, D2O) δ 3.98 – 4.18 (m, 2H), 3.79 – 3.91 (m, 1H), 3.37 –

3.52 (m, 1H), 3.18 – 3.37 (m, 3H), 1.18 – 1.40 (m, 6H). 13C NMR

(100 MHz, D2O) δ 173.91, 69.38, 60.55, 50.29, 47.45, 11.81, 10.96. HRMS (APCI+,

m/z): calculated for C7H14NO3 [M-H]-: 160.09682; found: 160.09811. The ee was

measured through corresponding amino acid amide 6ea using chiral HPLC, see

Determination of enantiomeric excesses retention.

N,N-diethyl-alanine (3fa): Synthesized according to General

procedure. Quantitative yield of 3fa was obtained after removing


MHz, D2O) δ 3.77 – 3.92 (m, 1H), 3.19 – 3.39 (m, 2H), 3.00 –

3.20 (m, 2H), 1.38 – 1.52 (m, 3H), 1.17 – 1.37 (m, 6H). 13C NMR (100 MHz, D2O)

δ 174.31, 61.46, 47.04, 44.97, 11.47, 9.29, 8.32. HRMS (APCI+, m/z): calculated

for C7H16NO2 [M+H]+: 146.11756; found: 146.11746. The physical data are

identical to those previously reported.[30] The ee (84% at 90 °C, 86% at 60 °C)

was measured through corresponding amino acid amide 6fa using chiral HPLC, see

Determination of enantiomeric excesses retention.

N,N-diethyl-glycine (3ga): Synthesized according to General

procedure. Quantitative yield of 3ga was obtained after removing


MHz, D2O) δ 3.66 (s, 2H). 3.22 (q. J = 7.31 Hz, 4H), 1.26 (t. J = 7.32 Hz, 6H). 13C

NMR (100 MHz, D2O) δ 173.50, 57.36, 52.14, 52.11, 11.13. HRMS (APCI+, m/z):

calculated for C6H14NO2 [M+H]+: 132.10191; found: 132.10180. The physical data

are identical to those previously reported.[31]

N6-acetyl-N2,N2-di-ethyl-lysine (3ha): Synthesized

according to General procedure. N6-acetyl-lysine (0.094 g,

0.50 mmol) affords 3ha (0.090 g, 75% yield). White solid

was obtained after column chromatography (SiO2,

EtOAc/MeOH 80:20 to 50:50). 1H NMR (400 MHz, D2O) δ

4.02 – 4.13 (m, 1H), 2.96 – 3.08 (m, 4H), 2.82 – 2.96 (m, 2H), 1.97 (s, 3H), 1.70

– 1.84 (m, 1H), 1.51 – 1.70 (m, 3H), 1.25 – 1.38 (m, 2H), 1.07 – 1.24 (m, 6H). 13C NMR (100 MHz, D2O) δ 181.63, 176.06, 57.47, 54.04, 49.59, 33.75, 25.86,

25.15, 24.49, 11.12. HRMS (APCI+, m/z): calculated for C12H25N2O3 [M+H]+:

245.18597; found: 245.18593.

N-isopropyl-proline (3ab): Synthesized according to General

procedure. Quantitative yield of 3ab was obtained after removing


D2O) δ 3.93 – 4.05 (m, 1H), 3.62 – 3.72 (m, 1H), 3.47 – 3.61 (m,

1H), 3.13 – 3.26 (m, 1H), 2.29 – 2.44 (m, 1H), 2.00 – 2.15 (m, 2H), 1.79 – 1.97

(m, 1H), 1.20 – 1.40 (m, 6H). 13C NMR (100 MHz, D2O) δ 174.53, 65.80, 56.99,

52.28, 29.59, 23.59, 17.39, 17.26. HRMS (APCI+, m/z): calculated for C8H16NO2


109

[M+H]+: 158.11756; found: 158.11747. The physical data are identical to those


N-isopropyl-phenylalanine (3db): Synthesized according

to General procedure. Quantitative yield of 3db was obtained

after removing the volatiles of reaction residue by high

vacuum. 1H NMR (400 MHz, D2O) δ 6.87 – 7.24 (m, 5H), 3.24

– 3.34 (m, 1H), 2.71 – 2.80 (m, 1H), 2.45 – 2.65 (m, 2H), 0.74 – 0.93 (m, 6H). 13C NMR (100 MHz, D2O) δ 181.45, 137.84, 129.08, 128.33, 126.40, 62.55, 45.96,

39.09, 22.57, 19.72. HRMS (APCI+, m/z): calculated for C12H18NO2 [M+H]+:

208.13321; found: 208.13312. The physical data are identical to those previously

reported.[32]

N-isopropyl-leucine (3bb): Synthesized according to General

procedure. Quantitative yield of 3bb was obtained after removing


D2O-NaOH) δ 3.08 – 3.21 (m, 1H), 2.52 – 2.66 (m, 1H), 1.37 – 1.54

(m, 1H), 1.16 – 1.35 (m, 2H), 0.86 – 1.05 (m, 6H), 0.68 – 0.86 (m,

6H). 13C NMR (100 MHz, D2O) δ 177.15, 61.65, 53.02, 42.23, 27.09, 24.64, 23.83,


found: 174.14872. The physical data are identical to those previously reported.[33]

N-isopropyl-valine (3cb): Synthesized according to General

procedure. Quantitative yield of 3cb was obtained after removing the

volatiles of reaction residue by high vacuum. 1H NMR (400 MHz, D2O)

δ 3.09 – 3.20 (m, 1H), 2.82 – 2.96 (m, 1H), 1.81 – 2.00 (m, 1H),

0.99 – 1.25 (m, 6H), 0.85 – 0.98 (m, 6H). 13C NMR (100 MHz, D2O) δ 181.45,


for C8H18NO2 [M+H]+: 160.13321; found: 160.13307. The physical data are

identical to those previously reported.[34]

N-isopropyl-serine (3eb): Synthesized according to General

procedure. Quantitative yield of 3eb was obtained after removing


D2O) δ 3.85 – 4.01 (m, 2H), 3.72 – 3.79 (m, 1H), 3.38 – 3.52 (m,

1H), 1.24 – 1.36 (m, 6H). 13C NMR (100 MHz, D2O) δ 174.36, 63.67, 62.42, 53.03,


148.09682; found: 148.09671.

N-isopropyl-alanine (3fb): Synthesized according to General

procedure. Quantitative yield of 3fb was obtained after removing the

volatiles of reaction residue by high vacuum. 1H NMR (400 MHz, D2O)

δ 3.71 – 3.80 (m, 1H), 3.38 – 3.50 (m, 1H), 1.42 – 1.53 (m, 3H),

1.26 – 1.37 (m, 6H). 13C NMR (100 MHz, D2O) δ 177.76, 57.76, 52.17, 21.17,



Chapter 5

110

N-n-butyl-proline (3ae): Synthesized according to General

procedure. Quantitative yield of 3ae was obtained after removing


MeOD) δ 3.78 – 3.90 (m, 1H), 3.65 – 3.78 (m, 1H), 3.15 – 3.27

(m, 1H), 2.95 – 3.15 (m,2H), 2.30 – 2.46 (m, 1H), 1.99 – 2.15

(m, 2H), 1.82 – 1.98 (m, 1H), 1.56 – 1.76 (m, 2H), 1.30 – 1.47 (m, 2H), 0.83 –

1.04 (m, 3H). 13C NMR (100 MHz, MeOD) δ 173.50, 70.60, 56.38, 55.95, 30.30,

28.94, 24.34, 20.88, 13.96. HRMS (APCI+, m/z): calculated for C9H16NO2 [M-H]-:


reported.[36]

N-cyclopropylmethyl-proline (3fb): Synthesized according to

General procedure. Proline (0.058 g, 0.50 mmol) affords 3fb (0.046

g, 55% yield). White solid was obtained after column


MHz, CDCl3) δ 3.83 – 4.01 (m, 1H), 3.67 – 3.83 (m, 1H), 2.98 -

3.14 (m, 1H), 2.70 – 2.95 (m, 2H), 2.22 – 2.38 (m, 1H), 2.05 – 2.22 (m, 1H),

1.86 – 2.05 (m, 2H), 0.95 – 1.09 (m, 1H), 0.49 – 0.70 (m, 2H), 0.18 – 0.40 (m,

2H). 13C NMR (100 MHz, CDCl3) δ 170.64, 68.63, 59.14, 53.96, 29.01, 23.06, 6.63,

4.45, 4.06. HRMS (APCI+, m/z): calculated for C9H14NO2 [M-H]-: 168.10191;

found: 168.10321.

N-(2-chloroethyl)-proline (3ag): Synthesized according to

General procedure. Proline (0.058 g, 0.50 mmol) affords 3ag (0.063

g, 71% yield). White solid was obtained after crystallization in

MeOH/Et2O. 1H NMR (400 MHz, D2O) δ 4.45 – 4.65 (m, 3H), 3.76 –

3.93 (m, 2H), 3.33 – 3.54 (m, 2H), 2.38 – 2.55 (m, 1H), 2.15 – 2.32

(m, 1H), 1.97 – 2.14 (m, 2H). 13C NMR (100 MHz, D2O) δ 169.50, 66.38, 59.35,

46.16, 41.59, 28.06, 23.07. HRMS (APCI+, m/z): calculated for C7H13ClNO2

[M+H]+: 178.06293; found: 178.06289.

N-benzyl-proline (3ah): Synthesized according to General

procedure. Proline (0.019 g, 0.20 mmol) affords 3ah (0.028 g,

68% yield). White solid was obtained after crystallization in Et2O. 1H NMR (400 MHz, CDCl3) δ 9.33 (br.s, 1H), 7.28 – 7.52 (m, 5H),

4.11 – 4.37 (m, 2H), 3.74 – 3.90 (m, 1H), 3.59 – 3.74 (m, 1H),

2.78 – 2.94 (m, 1H), 2.17 – 2.38 (m, 2H), 1.79 – 2.08 (m, 2H). 13C NMR (100

MHz, CDCl3) δ 171.02, 130.73, 130.53, 129.40, 129.04, 67.31, 57.61, 53.31,



N-(4-chloro-benzyl)-proline (3ai): Synthesized according to

General procedure. Proline (0.058 g, 0.50 mmol) affords 3ai

(0.098 g, 82% yield). White solid was obtained after column

chromatography (SiO2, EtOAc/MeOH 90:10 to 50:50). 1H NMR

(400 MHz, D2O) δ 7.28 – 7.48 (m, 4H), 4.12 – 4.34 (m, 2H), 3.75

– 3.88 (m, 1H), 3.41 – 3.54 (m, 1H), 3.03 – 3.18 (m, 1H), 2.31 – 2.48 (m, 1H),

1.80 – 2.09 (m, 3H). 13C NMR (100 MHz, D2O) δ 176.56, 137.60, 134.51, 131.87,


111


C12H15ClNO2 [M+H]+: 240.07858; found: 240.07854. The physical data are

identical to those previously reported.[38]

N,N-(di-n-butyl)-phenylalanine (3de): Synthesized

according to General procedure. Phenylalanine (0.083 g, 0.50

mmol) affords 3de (0.116 g, 84% yield). White solid was

obtained after column chromatography (SiO2, EtOAc/MeOH

90:10 to 80:20). 1H NMR (400 MHz, CDCl3) δ 9.36 (br.s, 1H),

7.10 – 7.35 (m, 5H), 3.83 – 3.94 (m, 1H), 3.42 – 3.56 (m, 1H), 2.88 – 3.07 (m,

3H), 2.70 – 2.85 (m, 2H), 1.52 – 1.67 (m, 2H), 1.36 – 1.52 (m, 2H), 1.05 – 1.27

(m, 4H). 13C NMR (100 MHz, CDCl3) δ 170.49, 137.88, 128.76, 128.55, 126.65,


C17H26NO2 [M-H]-: 276.19581; found: 276.19703.

N,N-(di-n-nonyl)-phenylalanine (3dj): Synthesized

according to General procedure. Phenylalanine (0.083 g, 0.50

mmol) affords 3dj (0.147 g, 75% yield). White solid was

obtained after column chromatography (SiO2, Pentane/EtOAc

50:50 to 0:100, then EtOH/MeOH 90/10). 1H NMR (400 MHz, CDCl3) δ 8.68 (br.s,

1H), 7.13 – 7.31 (m, 5H). 3.84 – 3.93 (m, 1H), 3.50 – 3.58 (m, 1H), 2.88 – 3.05

(m, 3H), 2.67 – 2.79 (m, 2H), 1.53 – 1.67 (m, 2H), 1.38 – 1.52 (m, 2H), 0.98 –

1.35 (m, 24H), 0.75 – 0.89 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 170.49, 138.02,

128.75, 128.59, 126.67, 67.41, 51.76, 33.71, 31.67, 29.30, 29.05, 29.03, 26.70,

25.07, 22.50, 13.94. HRMS (APCI+, m/z): calculated for C27H48NO2 [M-H]-:


reported.[32]

N,N-di-(5-hydroxypentyl)-phenylalanine (3dk):

Synthesized according to General procedure.

Phenylalanine (0.083 g, 0.50 mmol) affords 3dk

(0.059 g, 35% yield). White solid was obtained after

column chromatography (SiO2, EtOAc/MeOH 50:50 to 30:70). 1H NMR (400 MHz,

D2O) δ 7.23 – 7.45 (m, 5H), 3.91 – 4.03 (m, 1H), 3.47 – 3.65 (m, 4H), 3.13 –

3.32 (m, 4H), 2.95 – 3.13 (m, 2H), 1.58 – 1.79 (m, 4H), 1.45 – 1.58 (m, 4H),

1.21 – 1.43 (m, 4H). 13C NMR (100 MHz, D2O) δ 172.40, 135.73, 128.94, 128.85,


for C19H32NO4 [M+H]+: 338.23258; found: 338.23176.

N,N-di-n-nonyl-glycine (3gj): Synthesized according to General

procedure. Glycine (0.038 g, 0.50 mmol) affords 3gj (0.149 g, 91%

yield). White solid was obtained after column chromatography (SiO2,

EtOAc/MeOH 90:10 to 70:30). 1H NMR (400 MHz, CDCl3) δ 8.78 (br.s,

1H), 3.48 (s, 2H), 2.95 – 3.15 (m, 4H), 1.52 – 1.75 (m, 4H), 1.03 – 1.42 (m,

24H), 0.65 – 0.95 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 167.42, 55.99, 53.92,

31.63, 29.26, 29.03, 28.99, 26.66, 23.71, 22.47, 13.90. HRMS (APCI+, m/z):

calculated for C20H44NO2 [M+H]+: 328.32155; found: 328.32095.

Chapter 5

112

N,N-di-benzyl-glycine (3gh): Synthesized according to

General procedure. Glycine (0.038 g, 0.50 mmol) affords 3gh

(0.066 g, 52% yield). White solid was obtained after

precipitation in MeOH/Et2O. 1H NMR (400 MHz, DMSO-d6) δ

7.20 – 7.40 (m, 10H), 3.73 (s, 4H), 3.15 (s, 2H). 13C NMR (100

MHz, DMSO-d6) δ 172.19, 139.00, 128.53, 128.24, 126.98, 56.79, 53.00. HRMS


The physical data are identical to those previously reported.[39]

N-2-butyl-glycine (3gl): Synthesized according to General

procedure. Quantitative yield of 3gl was obtained after removing


MHz, D2O) δ 3.48 – 3.67 (m, 2H), 3.14 – 3.27 (m, 1H), 1.68 – 1.84 (m, 1H), 1.47

– 1.66 (m, 1H), 1.22 – 1.35 (m, 3H). 0.88 – 1.03 (m, 3H). 13C NMR (100 MHz,

D2O) δ 174.11, 58.44, 49.00, 28.27, 17.51, 11.47. HRMS (APCI+, m/z): calculated

for C6H14NO2 [M+H]+: 132.10191; found: 132.10181.

N,N-di-(n-pentyl)-glycine (3gm): Synthesized

according to General procedure. Glycine (0.038 g, 0.50

mmol) affords 3gm (0.097 g, 90% yield). White solid was

obtained after column chromatography (SiO2, EtOAc/MeOH 90:10 to 70:30). 1H

NMR (400 MHz, D2O) δ 3.68 (s, 2H), 3.05 – 3.25 (m, 4H), 1.56 – 1.80 (m, 4H),

1.20 – 1.40 (m, 8H), 0.75 – 1.00 (m, 6H). 13C NMR (100 MHz, D2O) δ 173.36,


C12H26NO2 [M+H]+: 216.19581; found: 216.19574.

N-n-pentyl-glycine (3gm’): Synthesized according to

General procedure. Glycine (0.038 g, 0.50 mmol) affords

3gm’ (0.033 g, 46% yield). White solid was obtained after column

chromatography (SiO2, EtOAc/MeOH 60:40 to 30:70). 1H NMR (400 MHz, D2O) δ

3.57 (s, 2H), 2.91 – 3.13 (m, 2H), 1.54 – 1.80 (m, 2H), 1.20 – 1.46 (m, 4H), 0.75

– 0.99 (m, 3H). 13C NMR (100 MHz, D2O) δ 174.07, 51.74, 50.13, 30.40, 27.75,



N,N-di-n-dodecyl-glycine (3gn): Synthesized according to

General procedure. Glycine (0.038 g, 0.50 mmol) affords 3gn (0.189

g, 92% yield). White solid was obtained after column


MHz, CDCl3) δ 8.36 (br.s, 1H), 3.49 (s, 2H), 2.95 – 3.15 (m, 4H),

1.52 – 1.75 (m, 4H), 1.03 – 1.42 (m, 36H), 0.75 – 0.95 (m, 6H). 13C NMR (100

MHz, CDCl3) δ 167.51, 56.23, 54.01, 31.80, 29.51, 29.42, 29.38, 29.23, 29.11,

26.73, 23.74, 22.57, 13.99. HRMS (APCI+, m/z): calculated for C26H54NO2 [M+H]+:


reported.[31]


113

N-dodecyl-glycine (3gn’): Synthesized according to General

procedure. Glycine (0.038 g, 0.50 mmol) affords 3gn’ (0.066 g,

54% yield). White solid was obtained after column chromatography (SiO2,

EtOAc/MeOH 70:30 to 40:60). 1H NMR (400 MHz, KOH, D2O) δ 3.00 – 3.20 (m,

2H), 2.38 – 2.58 (m, 2H), 1.36 – 1.57 (m, 2H), 1.12 – 1.35 (m, 18H), 0.73 – 0.90

(m, 3H). 13C NMR (100 MHz, KOH, D2O) δ 180.96, 55.23, 51.69, 34.63, 32.69,

32.61, 32.54, 32.40, 32.22, 31.93, 30.15, 25.28, 16.42. HRMS (APCI+, m/z):

calculated for C14H30NO2 [M+H]+: 244.22711; found: 244.22711. The physical

data are identical to those previously reported.[41]

N-nonyl-glycine (3gj’): Synthesized according to General

procedure. Glycine (0.038 g, 0.50 mmol) affords 3gj’ (0.052 g,

51% yield). White solid was obtained after column chromatography (SiO2,

EtOAc/MeOH 70:30 to 40:60). 1H NMR (400 MHz, KOH, D2O) δ 2.90 – 3.18 (m,

2H), 2.30 – 2.56 (m, 2H), 1.28 – 1.55 (m, 2H), 1.02 – 1.38 (m, 12H), 0.65 – 0.91

(m, 3H). 13C NMR (100 MHz, KOH, D2O) δ 181.71, 55.18, 51.50, 34.34, 32.09,


C11H24NO2 [M+H]+: 202.18016; found: 202.18010.

N-decyl-glycine (3go’): Synthesized according to General

procedure. Glycine (0.038 g, 0.50 mmol) affords 3go’ (0.075

g, 69% yield). White solid was purified by column

chromatography (SiO2, EtOAc/MeOH 70:30 to 50:50). 1H NMR (400 MHz, KOH,

D2O) δ 3.00 – 3.15 (m, 2H), 2.36 – 2.58 (m, 2H), 1.36 – 1.54 (m, 2H), 1.05 –

1.35 (m, 14H), 0.73 – 0.90 (m, 3H). 13C NMR (100 MHz, KOH, D2O) δ 181.42,

55.34, 51.67, 34.49, 32.45, 32.30, 32.22, 32.05, 31.99, 30.04, 25.18, 16.35.

HRMS (APCI+, m/z): calculated for C12H26NO2 [M+H]+: 216.19581; found:

216.19589. The physical data are identical to those previously reported.[41]

methyl N-tetradecylglycinate (methyl ester of 3gp’: 3gp’-

Me): Synthesized according to General procedure and

Esterification procedure. Glycine (0.038 g, 0.50 mmol) affords

3gp’-Me (0.046 g, 32% yield). Oily compound 3gp’-Me was purified by column

chromatography (SiO2, tol/Et2O 50/50 – 0/100). 1H NMR (400 MHz, CDCl3) δ 3.72

(s, 3H), 3.41 (s, 2H), 2.52 – 2.64 (m, 2H), 1.42 – 1.54 (m, 2H), 1.15 – 1.36 (m,

22H), 0.83 – 0.91 (m, 3H) 13C NMR (100 MHz, CDCl3) δ 173.02, 51.71, 50.84,

49.67, 31.91, 30.04, 29.68, 29.66, 29.65, 29.64, 29.60, 29.57, 29.51, 29.34,


286.27406; found: 286.27430.

methyl N-hexadecylglycinate (methyl ester of 3gq’: 3gq’-


Esterification procedure. Glycine (0.038 g, 0.50 mmol) affords 3gq’-Me (0.059 g,

38% yield). Oily compound 3gq’-Me was purified by column chromatography

(SiO2, tol/Et2O 50/50 – 0/100). 1H NMR (400 MHz, CDCl3) δ 3.73 (s, 3H), 3.43 (s,

2H), 2.52 – 2.64 (m, 2H), 1.42 – 1.58 (m, 2H), 1.13 – 1.37 (m, 26H), 0.80 – 0.94

(m, 3H) 13C NMR (100 MHz, CDCl3) δ 172.71, 51.78, 50.65, 49.60, 31.92, 29.85,

Chapter 5

114

29.68, 29.67, 29.65, 29.60, 29.57, 29.49, 29.35, 27.19, 22.68, 14.11. HRMS


methyl N-octadecylglycinate (methyl ester of 3gr’: 3gr’-


Esterification procedure. Glycine (0.038 g, 0.50 mmol) affords

3gr’-Me (0.067 g, 39% yield). Oily compound 3gr’-Me was purified by column

chromatography (SiO2, tol/Et2O 50/50 – 0/100). 1H NMR (400 MHz, CDCl3) δ 3.71

(s, 3H), 3.40 (s, 2H), 2.53 – 2.64 (m, 2H), 1.42 – 1.52 (m, 2H), 1.17 – 1.36 (m,

30H), 0.80 – 0.91 (m, 3H) 13C NMR (100 MHz, CDCl3) δ 173.01, 51.68, 50.83,

49.67, 31.90, 30.04, 29.67, 29.66, 29.64, 29.59, 29.57, 29.50, 29.34, 27.21,


found: 342.33681.

N-dodecyl-alanine (3gn’): Synthesized according to General

procedure. Alanine (0.045 g, 0.50 mmol) affords 3gn’ (0.063

g, 49% yield). Compound 3gn’ was purified by column

chromatography (SiO2, EtOAc/MeOH 70:30 to 40:60). 1H NMR (400 MHz, KOH,

D2O) δ 3.00 – 3.20 (m, 2H), 2.38 – 2.58 (m, 2H), 1.36 – 1.57 (m, 2H), 1.12 –

1.35 (m, 18H), 0.73 – 0.90 (m, 3H). 13C NMR (100 MHz, KOH, D2O) δ 180.96,

55.23, 51.69, 34.63, 32.69, 32.61, 32.54, 32.40, 32.22, 31.93, 30.15, 25.28,


258.24302.

N-nonyl-proline (3aj): Synthesized according to

General procedure. Proline (0.053 g, 0.50 mmol) affords

3aj (0.063 g, 52% yield). White solid was obtained after

column chromatography (SiO2, EtOAc/MeOH 90:10 to

50:50). 1H NMR (400 MHz, CDCl3) δ 3.92 – 3.06 (m, 1H), 3.61 – 3.78 (m, 1H),

3.06 – 3.22 (m, 1H), 2.90 – 3.06 (m, 1H), 2.71 – 2.89 (m, 1H), 2.27 – 2.43 (m,

1H), 2.13 – 2.27 (m, 1H), 1.88 – 2.09 (m, 2H), 1.60 – 1.79 (m, 2H), 1.05 – 1.43

(m, 12H), 0.72 – 0.95 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 170.24, 69.66, 55.60,

54.77, 31.68, 29.38, 29.27, 29.05, 26.64, 25.66, 23.48, 22.53, 13.97. HRMS


N,N-diethyl-glycyl-alanine (5aa): Synthesized according

to General procedure. Quantitative yield of 5aa was

obtained after removing the volatiles of reaction residue by

high vacuum. 1H NMR (400 MHz, D2O) δ 4.08 – 4.22 (m,

1H), 3.88 – 4.03 (m, 2H), 3.17 – 3.31 (m, 4H), 1.30 – 1.36 (m, 3H), 1.21 – 1.30

(m, 6H). 13C NMR (100 MHz, D2O) δ 179.44, 164.77, 53.19, 51.17, 49.43, 16.92,

8.30. HRMS (APCI+, m/z): calculated for C9H19N2O3 [M+H]+: 203.13902; found:

203.13895.

N,N-di-(5-hydroxy-pentyl)-glycyl-alanine

(5ak): Synthesized according to General

procedure. Glycyl-alanine (0.073 g, 0.50 mmol)

affords 5ak (0.036 g, 36% yield). White solid was obtained after column


115

chromatography (SiO2, EtOAc/MeOH 60:40 to 30:70). 1H NMR (400 MHz, D2O) δ

4.15 – 4.23 (m, 1H), 3.55 – 3.67 (m, 4H), 3.19 – 3.34 (m, 2H,), 2.52 – 2.71 (m,

4H), 1.47 – 1.66 (m, 8H), 1.28 – 1.44 (m, 7H). 13C NMR (100 MHz, D2O) δ 182.21,

175.12, 64.25, 59.67, 57.15, 53.19, 33.76, 28.20, 25.58, 20.44. HRMS (APCI+,

m/z): calculated for C15H31N2O5 [M+H]+: 319.22275; found: 319.22278.

N,N-di-(n-dodecyl)-glycyl-alanine (5an):

Synthesized according to General procedure. Glycyl-

alanine (0.073 g, 0.50 mmol) affords 5an (0.199 g,

82% yield). White solid was obtained after column

chromatography (SiO2, EtOAc/MeOH 90:10 to 50:50). 1H NMR (400 MHz, CDCl3) δ

8.20 (br.s, 1H), 4.17 – 4.38 (m, 1H), 3.24 – 3.60 (m, 2H), 2.52 – 2.95 (m, 4H),

1.45 – 1.64 (m, 4H), 1.11 – 1.42 (m, 39H), 0.70 – 0.95 (m, 6H). 13C NMR (100

MHz, CDCl3) δ 177.93, 167.98, 56.32, 54.16, 49.95, 31.87, 29.64, 29.61, 29.58,


for C29H59N2O3 [M+H]+: 483.45202; found: 483.45170.

N,N-diethyl-glycyl-alanine (5ba): Synthesized

according to General procedure. Leucyl-glycyl-

glycine (0.123 g, 0.50 mmol) affords 5ba (0.101

g, 67% yield). White solid was obtained after

column chromatography (SiO2, EtOAc/MeOH 60:40

to 30:70). 1H NMR (400 MHz, D2O) δ 3.86 – 4.02 (m, 2H), 3.75 (s, 2H), 3.38 –

3.48 (m, 1H), 2.71 – 2.88 (m, 2H), 2.46 – 2.62 (m, 2H), 1.68 – 1.83 (m, 1H),

1.32 – 1.54 (m, 2H), 0.97 – 1.13 (m, 6H), 0.83 – 0.96 (m, 6H). 13C NMR (100

MHz, D2O) δ 179.02, 177.83, 173.32, 64.90, 46.57, 45.81, 44.84, 40.43, 27.43,

25.57, 23.61, 14.04. HRMS (APCI+, m/z): calculated for C14H28N3O4 [M+H]+:

302.20743; found: 302.20747.

Chapter 5

116

Determination of enantiomeric excesses retention

N-(4-bromophenyl)-1-ethylpyrrolidine-2-

carboxamide (6aa): According to a literature procedure[42],

6aa was prepared from 3aa (28.6 mg, 0.20 mmol), 4-

bromoaniline (38.1 mg, 0.22 mmol), EDC•HCl (46.3 mg,

0.24 mmol), DMAP (29.3 mg, 0.24 mmol), and HOBt•H2O (30.8 mg, 0.20 mmol),

in 3ml CH3CN at room temperature overnight. Then aq. NaHCO3 was added, and

the mixture was extracted 3 times with EtOAc. The organic phase was

concentrated under vacuo and the residue was purified by column chromatography

(SiO2, Pentane/EtOAc 50:50 to 0:100) to afford 6aa as a light yellow solid. 1H NMR

(400 MHz, CDCl3) δ 9.57 (s, 1H), 7.35 – 7.57 (m, 4H), 3.21 – 3.31 (m, 1H), 3.09

– 3.19 (m, 1H), 2.65 – 2.78 (m, 1H), 2.52 – 2.65 (m, 1H), 2.33 – 2.47 (m, 1H),

2.14 – 2.31 (m, 1H), 1.92 – 2.02 (m, 1H), 1.68 – 1.89 (m, 2H), 1.12 (t, J = 7.22

Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.46, 136.84, 131.85, 120.78, 116.35,


C13H16BrN2O [M-H]-: 295.04405; found: 295.04510.

The ee was determined by chiral HPLC analysis. Chiralcel OD-H column,

Phenomenex, Ltd; heptane/isopropanol (99:1); flow rate: 0.5 ml/min; detection:

UV 232 nm; retention times 22.2 min (major) and 26.8 min (minor).

2-(diethylamino)-N-(4-methoxyphenyl)-4-

methylpentanamide (6ba): According to a literature

procedure[42], 6ba was prepared from 3ba (37.4 mg,

0.20 mmol), 4-methoxyaniline (27 mg, 0.22 mmol),

EDC•HCl (46.3 mg, 0.24 mmol), NEt3 (56 ul, 0.4 mmol),

and HOBt•H2O (30.8 mg, 0.20 mmol), in 3 ml CH3CN at

room temperature overnight. Then aq. NaHCO3 was added, and the mixture was

extracted 3 times with EtOAc. The organic phase was concentrated under vacuo

and the residue was purified by column chromatography (SiO2, Pentane/EtOAc

50:50 to 20:80) to afford 6ba as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ

9.44 (s, 1H), 7.42 – 7.52 (m, 2H), 6.79 – 6.91 (m, 2H), 3.78 (s, 3H), 3.30 – 3.43

(m, 1H), 2.38 – 2.75 (m, 4H), 1.73 – 1.98 (m, 2H), 1.28 – 1.37 (m, 1H), 1.06 –

1.15 (m, 6H), 0.95 – 1.01 (m, 3H), 0.90 – 0.95 (m, 3H). 13C NMR (100 MHz, CDCl3)

δ 155.95, 131.42, 125.62, 120.66, 114.12, 55.48, 44.48, 34.47, 26.43, 23.44,

21.98, 13.79. HRMS (APCI+, m/z): calculated for C14H23N2O3 [M+H]+: 293.22235;

found: 293.22245.



UV 250 nm; retention times 20.2 min (minor) and 29.0 min (major).

2-(diethylamino)-N-(4-methoxyphenyl)-3-

methylbutanamide (6ca): Compound 6ca was

prepared from 3ca (35.0 mg, 0.20 mmol), 4-

methoxyaniline (27 mg, 0.22 mmol), COMU[43] (257 mg,

0.60 mmol) and N,N-diisopropylethylamine (70 ul, 0.4

mmol) in 1 ml DMF, at room temperature for 1 h. DMF was removed under vacuo


117

and purified by column chromatography (SiO2, Pentane/EtOAc 50:50 to 20:80) to

afford 6ca as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.58 (br.s, 1H), 7.40

– 7.53 (m, 2H), 6.79 – 6.90 (m, 2H), 3.78 (s, 3H), 2.91 – 3.12 (m, 1H), 2.58 –

2.80 (m, 4H), 2.12 – 2.28 (m, 1H), 1.09 (d, J = 6.9 Hz, 3H), 1.00 – 1.07 (m, 6H),

0.98 (d, J = 6.7 Hz, 3H). HRMS (APCI+, m/z): calculated for C16H27N2O2 [M+H]+:

279.20670; found: 279.20673.




methyl diethylphenylalaninate (6da): According to a

literature procedure[44], 6da was prepared from 3da. To a

stirred solution of the 3da (44.2 mg, 0.2 mmol) in

toluene/MeOH (1/1 ml), TMSCHN2 (0.4 mmol, 2M in toluene)

was added. The mixture was stirred for 1 h at room temperature and concentrated

in vacuo to give 6da as a transparent oily compound. 1H NMR (400 MHz, CDCl3) δ

7.12 – 7.40 (m, 5H), 3.64 – 3.74 (m, 1H), 3.65 (s, 3H), 3.06 – 3.17 (m, 1H), 2.89

– 3.02 (m, 1H), 2.75 – 2.89 (m, 2H), 2.52 – 2.65 (m, 2H), 1.08 (t, J = 7.17 Hz,

6H). 13C NMR (100 MHz, CDCl3) δ 173.06, 138.68, 129.21, 128.18, 126.20, 64.95,



The ee was determined by chiral HPLC analysis. Chiralcel OZ-H column,

Phenomenex, Ltd; heptane/isopropanol (99.7:0.3); flow rate: 0.5 ml/min;

detection: UV 190 nm; retention times 18.1 min (major) and 19.9 min (minor).

2-(diethylamino)-3-hydroxy-N-(4-methoxy-

phenyl)propanamide (6ea): According to a literature

procedure[42], 6ea was prepared from 3ea (32.0 mg,

0.20 mmol), 4-methoxyaniline (27 mg, 0.22 mmol),

EDC•HCl (46.3 mg, 0.24 mmol), NEt3 (56 ul, 0.4 mmol),

and HOBt•H2O (30.8 mg, 0.20 mmol), in 3 ml CH3CN at room temperature

overnight. Then aq. NaHCO3 was added, the mixture was extracted 3 times with

EtOAc. The organic phase was concentrated under vacuo and the residue was

purified by column chromatography (SiO2, Pentane/EtOAc 50:50 to 20:80) to

afford 6ea as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 7.40

– 7.50 (m, 2H), 6.83 – 6.92 (m, 2H), 4.02 – 4.10 (m, 1H), 3.81 – 3.89 (m, 1H),

3.79 (s, 3H), 3.48 – 3.57 (m, 1H), 2.56 – 2.82 (m, 4H), 1.14 (t, J = 7.07 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 156.45, 130.40, 121.15, 114.21, 101.59, 63.98,

58.56, 55.48, 44.87, 14.11. HRMS (APCI+, m/z): calculated for C14H23N2O3

[M+H]+: 267.17032; found: 267.17031.




Chapter 5

118

N-(4-bromophenyl)-2-(diethylamino)propanamide

(6fa): According to a literature procedure[42], 6fa was

prepared from 3fa (29.0 mg, 0.20 mmol), 4-bromoaniline

(38.1 mg, 0.22 mmol), EDC•HCl (46.3 mg, 0.24 mmol),

DMAP (29.3 mg, 0.24 mmol), and HOBt•H2O (30.8 mg, 0.20 mmol), in 3 ml CH3CN

at room temperature overnight. Then aq. NaHCO3 was added, the mixture was

extracted 3 times with EtOAc. The organic phase was concentrated under vacuo

and the residue was purified by column chromatography (SiO2, Pentane/EtOAc

50:50 to 20:80) to afford 6fa as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ

9.65 (s, 1H), 7.35 – 7.57 (m, 4H), 3.39 – 3.58 (m, 1H), 2.35 – 2.74 (m, 4H), 1.22

– 1.31 (m, 3H), 1.04 – 1.15 (m ,6H). HRMS (APCI+, m/z): calculated for

C13H20BrN2O [M+H]+: 299.07535; found: 299.07614.





119

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121

Chapter 6

Ruthenium catalyzed N-alkylation of amino acid esters with

alcohols

-Amino acids are the most abundant chiral amine sources in nature. Selective

functionalization of amino acids and their derivatives is a highly-desired

transformation. In Chapter 5, the direct N-alkylation of unprotected amino acids is

described. As common amino acid derivatives, the functionalization of amino acid

esters holds vast interest, due to their better solubility in organic solvents

compared to their acid analogues. This Chapter describes, for the first time, the

direct N-alkylation of amino acid esters with alcohols, producing water as the only

waste. The scope includes direct N-alkylation of phenylalanine, alanine, valine,

proline esters and prolinamide with 1-pentanol and benzyl alcohols, with good to

excellent yields and stereochemistry retention.

Part of this chapter will be submitted for publication:

T. Yan, B. L. Feringa, K. Barta, to be submitted.

Chapter 6

122

Introduction

N-alkyl amino acid esters are prominent chiral moieties in bio-active compounds

(Figure 1). For example, Cilazapril[1] and Enalapril[2] are angiotensin-converting

enzyme inhibitors; Ximelagatran[3] is an anticoagulant that has been investigated

as a replacement for warfarin.

Figure 1: N-alkyl amino acid ester contained pharmaceutical compounds.

An attractive way to synthesize N-alkyl amino acid esters is the direct alkylation

of amino acid esters with alcohols through the borrowing hydrogen strategy. The

advantage of using alcohols as alkylation reagents has been extensively discussed

in previous chapters (Chapter 2, 3 and 5). In this Chapter we explore the possibility

of the direct alkylation of N-alkyl amino acid esters with alcohols. With the

development of the borrowing hydrogen strategy[4], the direct alkylation of amines

with alcohols has been achieved under relatively mild reaction conditions[5].

However, this method still has not been applied to direct N-alkylation of amino

acid esters bearing acidic α-proton[5g]. Probably this is due to the possibility of

competing transesterification[6] and unsatisfactory ee retention[7], as common

catalyst systems frequently require the addition of a strong base for activation of

the catalyst or substrates[5].

Figure 2: A Alkylation of amines catalyzed by Cat 1 or Cat 3; B generation of active

species Cat-O.

N-alkylation of amino acid esters

123

Based on the work described in Chapter 2, 3 and 5, we envisioned the possibility

of the direct N-alkylation of amino acid esters with alcohols (Figure 2, A). In our

earlier studies we have shown that by using pre-catalysts based on Fe[8] or Ru

(Figure 2, A), a catalytically active species Cat-O, can be generated[9] through

several routes without the need of adding any strong base (Figure 2, B). This is a

key aspect for performing such reactions without any racemization.

To establish our methodology, phenylalanine methyl ester (1a) and pentanol (2a)

were first selected as the substrates, and Cat 3 was employed as the pre-catalyst

(Scheme 1, A). Using toluene as the solvent, at 135 °C for 18 h, the

transesterification products, N-pentyl phenylalanine pentyl ester (3c) and N-

dipentyl phenylalanine pentyl ester (4a) were obtained as the major products.

When phenylalanine ethyl ester (1b) was used, significant amount of

transesterification was still observed, and 3c was obtained in 49% isolated yield.

Unfortunately, a significant racemization occurred with only 19% ee measured in

the obtained product 3c. On the other hand, when 4-methylbenzyl alcohol (2b)

was reacted with phenylalanine esters, the imine side product 5a was observed as

the major product (Scheme 1, B).

Scheme 1: Iron catalyzed N-alkylation of phenylalanine esters with (A) pentanol

and (B) 4-methylbenzyl alcohol.

General reaction conditions: General procedure, 0.5 mmol 1, 3 mmol 2a or 2 mmol 2b,

0.02 mmol Cat 3, 0.04 mmol Me3NO, 1 ml toluene, 18 h, 135 °C, 95-105 mg molecular

sieves, unless otherwise specified, isolated yield in parenthesis. Conversion and selectivity

were determined by GC-FID. aThe ee value of 3c is 19%; b1 mmol 2b was used.

Chapter 6

124

Since unsatisfactory results were obtained with the Fe based Cat 3, next the Ru-

based Shvo catalyst[10] (Cat 1), was investigated (Table 1). Phenylalanine pentyl

ester (1c) and 4-methylbenzyl alcohol (2b) were selected as substrates and

toluene as solvent. The use of only 0.5 mol% Cat 1, at 120 °C for 18 h, gave full

conversion of 1c and 55% selectivity of N-(4-methyl)-benzyl phenylalanine pentyl

ester (3f), although significant transesterification side-products were also

observed (Table 1, entry 1). However, when phenylalanine benzyl ester (1f) was

used as starting material, 69% conversion of 1f and 60% selectivity of N-(4-

methyl)-benzyl phenylalanine benzyl ester (3g) were observed, showing lower

reactivity but higher stability of the benzyl ester compared to the pentyl ester

(Table 1, entry 2). Gratifying, when the reaction temperature was lowered to

100 °C, no significant trans-esterification was observed and 39% conversion of 1c

and 38% selectivity for 3f were obtained (Table 1, entry 3). Next, in order to

improve substrate conversion under milder reaction temperatures, we used 4 mol%

of diphenyl phosphate (A1) based on previous studies by the group of Noyori in

Brønsted acid assisted ruthenium catalyzed hydrogenation of ketones[11]. Indeed,

conversion of 1c was improved to 55%, and 54% selectivity of 3f was achieved

(Table 1, entry 4). While phenylalanine methyl ester (1a) gave 99% conversion

and 69% yield of 3d, phenylalanine ethyl ester (1b) has shown 47% conversion

and 45% selectivity of 3e (Table 1, entry 5-6). The positive results with phosphoric

acid are likely due to the facilitation of the imine formation[12] step. Also, the

formation of ruthenium-hydride-phosphonate complex (Figure 3, C) bearing a

more acidic proton comparing to the original Cat 2-H (Figure 3, A and B),

facilitates the imine reduction step.[11,13]

Figure 3: A Generation of active species Cat 2-H; B reduction of imine intermediate with

Cat 2-H; C reduction of imine intermediate with Cat 2-H cooperated by diphenyl

phosphate.


125

Table 1: Ruthenium catalyzed N-alkylation of phenylalanine ester with 4-

methylbenzyl alcohol.

Entry R1 / 1

0.5 mmol

2b /

mmol

Sol. Addi

.

Temp

[oC]

Conv.

1 [%]a

Sel.

3 [%]a

Sel. 4

[%]a

1 n-pentyl/1c 0.75 Tol. / 120 >99 3f 55 <1

2 Bn/1f 0.75 Tol. / 120 69 3h 60 <1

3 n-pentyl/1c 1 Tol. / 100 39 3f 38 <1

4 n-pentyl/1c 1 Tol. A1 100 55 3f 54 <1

5 Me/1a 1 Tol. A1 100 98 3d 93 (69) <1

6 Et/1b 1 Tol. A1 100 47 3e 45 <1

7 n-pentyl/1c 1 CPME A1 100 26 3f 23 <1

8 n-pentyl/1c 1 THF A1 100 18 3f 10 <1

9 n-pentyl/1c 1 Hept. A1 100 34 3f 32 <1

10 n-pentyl/1c 2 Tol. A1 100 >99 3f 58 4b 32

11 n-pentyl/1c 2 Tol. A2 100 >99 3f 72 4b 20

12 n-pentyl/1c 2 Tol. A3 100 92 3f 85 4b 2

13 n-pentyl/1c 2 Tol. A1 95 >99 3f 93 (86) <1

General reaction conditions: General procedure, 0.5 mmol 1, 0.75-2 mmol 2b, 0.5 mol%

Cat 1, 2 ml toluene, 18 h, 95-120 °C, isolated yield in parentheses, unless otherwise

specified. Conversion and selectivity were determined by GC-FID.

Next, 1c was chosen for further optimization and solvent screening was performed

whereby the use of cyclopentylmethyl ether (CPME), tetrahydrofuran (THF) and

heptane as solvents gave 26%, 18% and 34% conversion of 1c, respectively

(Table 1, entry 7-9). Toluene was chosen for further screening of Brønsted acid

additives. When 4 mol% of A1 and 4 equiv of 2b were used, the desired product,

3f was obtained with 58% selectivity and 32% side product N,N-di-(4-methyl)-

benzyl phenylalanine pentyl ester (4b) was observed (Table 1, entry 10). When

the Brønsted acids p-toluenesulfonic acid (PTSA, A2) and benzoic acid (A3) were

employed instead of A1, comparable results were obtained (Table 1, entry 11-12).

When the temperature was lowered to 95 °C, under standard condition with

addition of 4 mol% A1, 86% isolated yield of 3f with 96% ee retention were

obtained, indicating the best result (Table 1, entry 13) under these optimized

reaction conditions.

Chapter 6

126

Table 2: Ruthenium catalyzed N-alkylation of amino acid ester with various

alcohols. (Struction of the products are shown in Scheme 2)

Entry 1 2 t / h Conv. 1

[%]

Sel. 3 [%] ee [%]

1ab

/1c /2b 23 >99 3f 93 (86) 96

2 /1b /2b

18 >99 3e 95 (85) 94

3 /1c

/2c

24 94 3i 87 (74) 95

4 /1c

/2a 24 82 3c 81 (78) 91

5 /1c /2d

18 91 3j 89 (76) 89

6 /1e /2b

28 >99 3k 98 (64) 83

7 /1e

/2c

30 >99 3l 81 (52) n.d.

8 /1e

/2a 40 80 3m 76 (31) n.d.

9 /1f /2d

18 88 3n 85 (79) 96

10 /1f /2g

14 75 3o 74 (70) 97

11 /1f

/2c

24 76 3p 73 (66) 92

12

/1g

/2a 46 >99 3q 99 (86) 99

13

/1g /2b

16 >99 3r 86 (84) 99

14

/1g /2e

16 >99 3s 90 (87) 99

15

/1g /2c

28 >99 3t 84 (82) >99

16

/1h /2b

18 83 3u 48 (35) 99

General reaction conditions: General procedure, 0.5 mmol 1, 2 mmol 2, 1 mol% Cat 1, 2

ml toluene, 18 h, 100 °C, isolated yield in parentheses, unless otherwise specified.

Conversion and selectivity were determined by GC-FID. a95 °C; b0.5 mol% Cat 1.

With the optimized reaction conditions in hand, the scope of the reaction was

further explored (Table 2). Amino acid ester 3f was obtained in 86% yield and 96%

ee retention from phenylalanine pentyl ester (1c). N-(4-methyl)-benzyl

phenylalanine ethyl ester (3e) was obtained with 69% yield and 94% ee retention

from phenylalanine ethyl ester (1b) (Table 2, entry 1-2). Other alcohols including

4-chlorobenzyl alcohol (2c), pentanol (2a) and 1-phenylethanol (2d) have also


127

been chosen to react with 1c, giving 74% yield and 95% ee of 3i, 78% yield and

91% ee of 3c, and 76% yield and 89% ee of 3j, respectively (Table 2, entry 3-5).

Scheme 2: Ruthenium catalyzed N-alkylation of amino acid ester.

General reaction conditions: General procedure, 0.5 mmol 1, 1-2 mmol 2, 0.5-1 mol% Cat

1, 4 mol% A1, 2 ml toluene, 18 h, 95-100 °C, isolated yields and ee values are shown.

For details see Table 2.

The reactivity of different types of amino acid esters was next explored. When

alanine isopropyl ester (1e) was reacted with alcohols 2b, 2c and 2a, products

3k, 3l and 3m were obtained with 64%, 52% and 31% isolated yields, respectively

(Table 2, entry 6-8). The ee of 3k was measured as 83%, indicating that slight

racemization occurred. Employing the corresponding pentyl ester 1f in the reaction

with alcohols 2d, 2g and 2c, N-benzylated amino esters 3n, 3o and 3p were

obtained as in good yields (79%, 70% and 66%) with excellent ee’s of 96%, 97%

and 92%, respectively (Table 2, entry 9-11). When valine pentyl ester (1g) was

reacted with alcohols 2a, 2b, 2e and 2c, the corresponding products 3q, 3r, 3s

and 3t were obtained in good isolated yields (82-87%), with excellent retention of

ee 99 to >99% (Table 2, entry 12-15). Glutamic acid diethyl ester (1h) reacting

with 2b, gave 35% 2-pyrrolidinone derivative 3u with 99% ee, undergoing

intramolecular amide formation during the reaction (Table 2, entry 16). The

Chapter 6

128

isolated yields and optical purities of the obtained N-alkylated amino acid esters

are described in Table 2 and are illustrated in Scheme 2.

Table 3: Ruthenium catalyzed N-alkylation of proline ester.

Entry t [h] Conv. 1 [%] Sel. 3v [%] ee [%]

1a 24 82 62 (42) 70

2b 15 73 62 71

3c 15 70 51 62

4d 15 53 47 78

General reaction conditions: General procedure, 0.5 mmol 1, 2 mmol 2b, 0.5-1 mol% Cat

1, 2 ml toluene, 18 h, 95-100 °C, isolated yield in parentheses, unless otherwise specified.

Conversion and selectivity were determined by GC-FID. a95 °C; b2 mol% A1; c2 mol% A2

instead of A1; dno A1.

Next, proline pentyl ester (1j), comprising a secondary amine moiety was chosen

as substrate (Table 3). When 1j reacted with 2b, N-(4-methyl)-benzyl proline

pentyl ester (3v) was obtained with 42% yield and 70% ee retention (Table 3,

entry 1). The ee dropped significantly compared to the previously used substrates

that have a primary amine moiety. When decreasing the amount of Brønsted acid

additives A1 and A2 to 2 mol%, 71% and 62% ee for N-benzylated product 3v

were obtained, respectively (Table 3, entry 2-3). Without using any Brønsted acid,

78% ee of 3v and lower conversion of proline pentyl ester 1j were observed (Table

3, entry 4).

Scheme 3: Catalytic N-alkylation of prolinamide with 4-methylbenzyl alcohol.

Further, we explored the possibility of using an amide, prolinamide (6), instead of

the amino acid ester as the substrate, the corresponding product, N-(4-methyl)-

benzyl prolinamide (7) was obtained in 83% yield and ee of 59% (Scheme 3).

Interestingly, when Cat 3 was employed in the reaction between 6 and 2b, only

the corresponding imidazolidin-4-one derivative 8 was obtained, indicating a


129

slower imine reduction step that allowed for an intramolecular addition of the

formed imine with the amide (Scheme 3).

In the present case, with both the proline ester and prolinamide, the corresponding

N-alkylated products were obtained with ee values of 70% and 59%, respectively

(Table 3, entry 1; Scheme 3). However, the direct N-alkylation of the amino acid

itself (L-proline), gave excellent retention of ee (Figure 2, A) as described in

Chapter 5.

Conclusion

In summary, this chapter describes a general method for the direct N-alkylation of

amino acid esters with alcohols through borrowing hydrogen strategy, with good

to excellent yields and retention of ee. Only proline pentyl ester and prolinamide

show significant racemization under the established reaction conditions for N-

alkylation with alcohols. Future work should focus on the development of new

catalytic systems that would allow for even milder reaction conditions, which could

lead to higher ee retention and prevent transesterification. Future efforts should

also focus on extending the scope of the reaction to achieve the selective N-

functionalization of a broad variety of amino acid derivatives.


General methods









180 °C 5 min (10 °C /min), 260 °C 5 min (10 °C/min). 1H- and 13C NMR spectra

were recorded on a Varian AMX400 (400 and 100 MHz, respectively) using CDCl3,

CD3OD, or CD2Cl2 as solvent. Chemical shift values are reported in ppm with the

solvent resonance as the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C;





(110 °C) dried glassware and using standard Schlenk techniques. THF and toluene





4A were purchased from Acros, and heated in a Schlenck under 180 °C in vacuo

overnight for activation before use. The synthesis of Cat 3 was carried out as

described in Chapter 2. Cat 1 was purchased from Strem. All other reagents were

Chapter 6

130

purchased from Sigma, TCI or Acros in reagent or higher grade and were used

without further purification.

Representative procedure

General procedure: An oven-dried 20 ml Schlenk tube was equipped with a

stirring bar. The solid starting materials were added into the Schlenk tube under

air, the Schlenk tube was subsequently connected to a vacuum/argon Schlenk line

and a vacuum-backfill cycle was performed three times. Liquid starting materials

and solvent were charged under an argon stream. The Schlenk tube was sealed

with a screw cap. The mixture was rapidly stirred at room temperature for 1 min,

then it was placed into a pre-heated oil bath at the appropriate temperature and

the mixture was stirred for a given time. The reaction mixture was cooled down to

room temperature and the crude mixture was concentrated in vacuum and purified

by flash column chromatography to provide the product. The enantiomeric excess

(ee) was measured by chiral HPLC.

Procedure of N-alkylation of valine pentyl ester (1g) with 4-methyl benzyl

alcohol (2b): An oven-dried 20 ml Schlenk tube, equipped with a stirring bar,

was charged with 4-methylbenzyl alcohol (2 mmol, 0.244 g) and Cat 1 (1 mol%,

5.4 mg) under air. The Schlenk tube was subsequently connected to a

vacuum/argon Schlenk line and a vacuum-backfill cycle was performed three times.

Then valine pentyl ester (0.5 mmol, 0.094 g) and 2 ml toluene were charged under

an argon stream. The Schlenk tube was sealed with a screw cap. The mixture was

rapidly stirred at room temperature for 1 min, then was placed into a pre-heated

oil bath at 100 °C for 18 h. The reaction mixture was cooled down to room

temperature, concentrated in vacuum. The residue was purified by flash

chromatography (SiO2, pentane/EtOAc 100:0 to 95:5) to provide the product N-

(4-methylbenyl) valine penyl ester 3r (0.124 g, 84% yield) with ee value of 99%

measured by chiral HPLC.


131

Spectral data and ee determination of isolated compounds

N-pentyl-phenylalanine pentyl ester (3c): Synthesized

according to General procedure. Phenylalanine penyl ester (0.118

g, 0.50 mmol) affords 3c (0.119 g, 78% yield). Light yellow oil

compound obtained after column chromatography (SiO2,

Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.14 –

7.32 (m, 5H), 3.94 – 4.08 (m, 2H), 3.47 – 3.52 (m, 2H), 2.94 – 3.02 (m, 1H),

2.86 – 2.94 (m, 1H), 2.52 – 2.62 (m, 1H), 2.42 – 2.52 (m, 1H), 1.38 – 1.55 (m,

4H), 1.16 – 1.32 (m, 8H), 0.80 – 0.92 (m, 6H). 13C NMR (100 MHz, CDCl3) δ

174.80, 137.34, 129.15, 128.34, 126.62, 64.70, 63.20, 48.15, 39.81, 29.71,

29.35, 28.20, 27.96, 22.49, 22.24, 13.99, 13.90. The physical data were identical

in all respects to those previously reported HRMS (APCI+, m/z): calculated for

C19H32NO2 [M+H]+: 306.24276; found: 306.24298.



detection: UV 221 nm; retention times 21.3 min (minor) and 24.1 min (major).

N-(4-methylbenzyl)-phenylalanine methyl ester (3d):

Synthesized according to General procedure. Phenylalanine methyl

ester (0.090 g, 0.50 mmol) affords 3d (0.098 g, 69% yield). Light

yellow oil compound obtained after column chromatography (SiO2,


7.34 (m, 9H), 3.73 – 3.84 (m, 1H), 3.66 (s, 3H), 3.59 – 3.65 (m, 1H), 3.53 – 3.59

(m, 1H), 2.93 – 3.04 (m, 2H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 174.95,

137.25, 136.52, 136.41, 129.15, 128.95, 128.30, 128.03, 126.60, 61.94, 51.65,


previously reported HRMS (APCI+, m/z): calculated for C18H22NO2 [M+H]+:

284.16451; found: 284.16520.

N-(4-methylbenzyl)-phenylalanine ethyl ester (3e):

Synthesized according to General procedure. Phenylalanine ethyl

ester (0.097 g, 0.50 mmol) affords 3e (0.126 g, 85% yield). Light



7.34 (m, 9H), 4.06 – 4.17 (m, 2H), 3.75 – 3.83 (m, 1H), 3.58 – 3.67 (m ,1H),

3.50 – 3.57 (m, 1H), 2.90 – 3.03 (m, 2H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3)

δ 174.54, 137.34, 136.53, 136.51, 129.23, 128.96, 128.26, 128.06, 126.56,

62.01, 60.52, 51.65, 39.73, 21.04, 14.15. The physical data were identical in all

respects to those previously reported HRMS (APCI+, m/z): calculated for

C19H24NO2 [M+H]+: 298.18053; found: 298.18016.




N-(4-methylbenzyl)-phenylalanine pentyl ester (3f): Synthesized according

to General procedure. Phenylalanine pentyl ester (0.118 g, 0.50 mmol) affords 3f

(0.146 g, 86% yield). Light yellow oil compound obtained after column

Chapter 6

132

chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR

(400 MHz, CDCl3) δ 7.05 – 7.34 (m, 9H), 3.97 – 4.10 (m, 2H), 3.73

– 3.84 (m, 1H), 3.58 – 3.66 (m, 1H), 3.50 – 3.57 (m, 1H), 2.90 –

3.03 (m, 2H), 2.33 (s, 3H), 1.48 – 1.60 (m, 2H), 1.17 – 1.37 (m,

4H), 0.82 – 0.96 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 174.69,

137.36, 136.53, 129.22, 128.97, 128.28, 128.07, 126.57, 77.32,

77.00, 76.68, 64.74, 62.07, 51.67, 39.79, 28.22, 27.97, 22.24, 21.05, 13.91. The

physical data were identical in all respects to those previously reported HRMS





N-(4-chlorobenzyl)-phenylalanine pentyl ester (3i):

Synthesized according to General procedure. Phenylalanine pentyl

ester (0.118 g, 0.50 mmol) affords 3i (0.133 g, 74% yield). Light



7.34 (m, 9H), 3.99 – 4.12 (m, 2H), 3.75 – 3.84 (m, 1H), 3.55 –

3.65 (m, 1H), 3.44 – 3.53 (m, 1H), 2.89 – 3.03 (m, 2H), 1.46 – 1.63 (m, 2H),


138.08, 137.22, 132.55, 129.34, 129.17, 128.32, 128.26, 126.59, 64.80, 61.90,


C21H27ClNO2 [M+H]+: 360.17248; found: 360.17287.




N-(1-phenylethyl)-phenylalanine pentyl ester (3j): Synthesi-

zed according to General procedure. Phenylalanine pentyl ester

(0.118 g, 0.50 mmol) affords 3j (0.129 g, 76% yield). Light yellow

oil compound obtained after column chromatography (SiO2,


7.33 (m, 6H), 7.05 – 7.16 (m, 4H), 3.97 – 4.12 (m, 2H), 3.65 – 3.75 (m, 1H),

3.22 – 3.32 (m, 1H), 2.80 – 2.95 (m, 2H), 1.48 – 1.60 (m, 2H), 1.18 – 1.37 (m,


129.28, 128.25, 128.14, 126.84, 126.71, 126.46, 77.00, 64.64, 60.30, 56.52,


C22H30NO2 [M+H]+: 340.22711; found: 340.22739.


133

GC spectrum of crude mixture, contains 2 pair of enantiomeric isomers:

GC spectrum of isolated one pair of enantiomeric isomers:




Chapter 6

134

N-(4-methylbenzyl)-alanine isopropyl ester (3k): Synthesized

according to General procedure. Alanine isopropyl ester (0.066 g, 0.50

mmol) affords 3k (0.075 g, 64% yield). Light yellow oil compound


95:5). 1H NMR (400 MHz, CDCl3) δ 7.12 – 7.32 (m, 4H), 5.03 – 5.19 (m,

1H), 3.74 – 3.86 (m, 1H), 3.60 – 3.73 (m, 1H), 3.30 – 3.42 (m, 1H),

2.37 (s, 3H), 1.23 – 1.38 (m, 9H). 13C NMR (100 MHz, CDCl3) δ 175.19, 136.66,

136.52, 129.00, 128.16, 77.00, 67.95, 55.96, 51.56, 21.84, 21.71, 21.00, 18.98.

HRMS (APCI+, m/z): calculated for C14H22NO2 [M+H]+: 236.16451; found:

236.16467.




N-(4-chlorobenzyl)-alanine isopropyl ester (3l): Synthesized

according to General procedure. Alanine isopropyl ester (0.066 g, 0.50

mmol) affords 3l (0.075 g, 52% yield). Light yellow oil compound


95:5). 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.35 (m, 4H), 4.98 – 5.12

(m, 1H), 3.70 – 3.82 (m, 1H), 3.54 – 3.68 (m, 1H), 3.24 – 3.33 (m,


129.55, 128.47, 68.17, 64.28, 55.99, 51.13, 21.87, 21.73, 19.02. HRMS (APCI+,

m/z): calculated for C13H19ClNO2 [M+H]+: 256.10988; found: 256.11062.

N-pentyl-alanine isopropyl ester (3m): Synthesized according to

General procedure. Alanine isopropyl ester (0.066 g, 0.50 mmol) affords

3m (0.31 g, 31% yield). Light yellow oil compound obtained after column


MHz, CDCl3) δ 4.96 – 5.10 (m, 1H), 3.21 – 3.32 (m, 1H), 2.50 – 2.59

(m, 1H), 2.41 – 2.50 (m, 1H), 1.38 – 1.55 (m, 2H), 1.17 – 1.37 (m, 13H), 0.80 –

0.95 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 175.39, 67.93, 56.86, 47.98, 29.87,

29.44, 22.51, 21.86, 21.73, 19.05, 13.97.

N-(4-methylbenzyl)-alanine pentyl ester (3n): Synthesized

according to General procedure. Alanine pentyl ester (0.080 g, 0.50

mmol) affords 3n (0.104 g, 79% yield). Light yellow oil compound


95:5). 1H NMR (400 MHz, CDCl3) δ 7.17 – 7.25 (m, 2H), 7.07 – 7.16 (m,

2H), 4.07 – 4.17 (m, 2H), 3.72 – 3.82 (m, 1H), 3.57 – 3.67 (m, 1H),

3.32 – 3.42 (m, 1H), 2.33 (s, 3H), 1.58 – 1.73 (m, 2H), 1.26 – 1.42 (m, 7H), 0.84

– 0.98 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 175.82, 136.62, 136.61, 129.05,

128.20, 64.80, 55.89, 51.64, 28.33, 28.03, 22.28, 21.07, 19.14, 13.95. HRMS






135

N-benzyl-alanine pentyl ester (3o): Synthesized according to

General procedure. Alanine pentyl ester (0.080 g, 0.50 mmol) affords

3o (0.087 g, 70% yield). Light yellow oil compound obtained after


(400 MHz, CDCl3) δ 7.05 – 7.55 (m, 5H), 4.03 – 4.18 (m, 2H), 3.75 –

3.85 (m, 1H), 3.61 – 3.71 (m, 1H), 3.31 – 3.42 (m, 1H), 1.57 – 1.72 (m, 2H),


139.69, 128.38, 128.23, 127.04, 77.00, 64.82, 55.98, 51.93, 28.33, 28.03, 22.27,


found: 250.18030.




N-(4-chlorobenzyl)-alanine pentyl ester (3p): Synthesized

according to General procedure. Alanine pentyl ester (0.080 g, 0.50

mmol) affords 3p (0.093 g, 66% yield). Light yellow oil compound


95:5). 1H NMR (400 MHz, CDCl3) δ 7.15 – 7.30 (m, 4H), 4.02 – 4.16

(m, 2H), 3.70 – 3.79 (m, 1H), 3.53 – 3.64 (m, 1H), 3.25 – 3.36 (m,

1H), 1.54 – 1.67 (m, 2H), 1.22 – 1.38 (m, 7H), 0.80 – 0.95 (m, 3H). 13C NMR

(100 MHz, CDCl3) δ 13C NMR (101 MHz, cdcl3) δ 175.68, 138.21, 132.69, 129.51,

128.44, 64.85, 55.88, 51.15, 28.29, 27.99, 22.24, 19.16, 13.93. HRMS (APCI+,

m/z): calculated for C15H23ClNO2 [M+H]+: 284.14118; found: 284.14156.




N-pentyl-valine pentyl ester (3q): Synthesized according to

General procedure. Valine pentyl ester (0.094 g, 0.50 mmol) affords

3q (0.111 g, 86% yield). Light yellow oil compound obtained after


(400 MHz, CDCl3) δ 7.09 – 7.28 (m, 4H), 4.03 – 4.15 (m, 2H), 2.88 –

2.97 (m, 1H), 2.47 – 2.58 (m, 1H), 2.32 – 2.43 (m, 1H), 1.78 – 1.94 (m, 1H),

1.55 – 1.68 (m, 1H), 1.36 – 1.53 (m, 3H), 1.17 – 1.36 (m, 8H), 0.77 – 0.98 (m,

12H). 13C NMR (100 MHz, CDCl3) δ 175.45, 67.56, 64.37, 48.74, 31.64, 29.88,

29.41, 28.37, 28.07, 22.53, 22.23, 19.09, 18.82, 13.99, 13.89. HRMS (APCI+,

m/z): calculated for C15H32NO2 [M+H]+: 258.24276; found: 258.24287. The ee

was determined by chiral HPLC analysis. Chiralcel OZ-H column, Phenomenex, Ltd;

heptane/isopropanol (99.8:0.2); flow rate: 0.5 ml/min; detection: UV 223 nm;

retention times 13.6 min (major) and 15.6 min (minor).

N-(4-methylbenzyl)-valine pentyl ester (3r): Synthesized

according to General procedure. Valine pentyl ester (0.094 g, 0.50

mmol) affords 3r (0.124 g, 84% yield). Light yellow oil compound


95:5). 1H NMR (400 MHz, CDCl3) δ 4.03 – 4.15 (m, 2H), 2.88 – 2.97

Chapter 6

136

(m, 1H), 2.47 – 2.58 (m, 1H), 2.32 – 2.43 (m, 1H), 1.78 – 1.94 (m, 1H), 1.55 –

1.68 (m, 1H), 1.36 – 1.53 (m, 3H), 1.17 – 1.36 (m, 8H), 0.77 – 0.98 (m, 12H). 13C NMR (100 MHz, CDCl3) δ 175.45, 67.56, 64.37, 48.74, 31.64, 29.88, 29.41,

28.37, 28.07, 22.53, 22.23, 19.09, 18.82, 13.99, 13.89. HRMS (APCI+, m/z):

calculated for C18H30NO2 [M+H]+: 292.22711; found: 292.22741.




N-benzyl-valine pentyl ester (3s): Synthesized according to

General procedure. Valine pentyl ester (0.094 g, 0.50 mmol) affords

3s (0.120 g, 87% yield). Light yellow oil compound obtained after


(400 MHz, CDCl3) δ 7.20 – 7.45 (m, 5H), 4.07 – 4.20 (m, 2H), 3.78 –

3.89 (m, 1H), 3.54 – 3.68 (m, 1H), 2.95 – 3.05 (m, 1H), 1.85 – 1.99 (m, 1H),

1.58 – 1.73 (m, 2H), 1.27 – 1.43 (m, 4H), 0.83 – 1.02 (m, 9H). 13C NMR (100

MHz, CDCl3) δ 175.32, 140.13, 128.24, 128.22, 126.91, 66.61, 64.51, 52.52,


for C17H28NO2 [M+H]+: 278.21146; found: 278.21182.




N-(4-chlorobenzyl)-valine pentyl ester (3t): Synthesized

according to General procedure. Valine pentyl ester (0.094 g, 0.50

mmol) affords 3t (0.128 g, 87% yield). Light yellow oil compound


95:5). 1H NMR (400 MHz, CDCl3) δ 7.18 – 7.36 (m, 4H), 4.05 – 4.17

(m, 2H), 3.75 – 3.83 (m, 1H), 3.47 – 3.58 (m, 1H), 2.90 – 2.98 (m,

1H), 1.84 – 1.97 (m, 1H), 1.57 – 1.70 (m, 2H), 1.25 – 1.42 (m, 4H), 0.75 – 1.03

(m, 9H). 13C NMR (100 MHz, CDCl3) δ 175.21, 138.62, 132.56, 129.52, 128.32,

77.32, 77.00, 76.68, 66.44, 64.56, 51.73, 31.65, 28.36, 28.07, 22.24, 19.33,

18.50, 13.92. HRMS (APCI+, m/z): calculated for C17H27ClNO2 [M+H]+: 312.17248;

found: 312.17291.




ethyl N-(4-methylbenzyl)-5-oxopyrrolidine-2-carboxylate (3u):

Synthesized according to General procedure. Glutamic acid diethyl

ester (0.102 g, 0.50 mmol) affords 3u (0.038 g, 35% yield). Light



7.15 (m, 4H), 4.94 – 5.04 (m, 1H), 4.05 – 4.20 (m, 2H), 3.88 – 3.97 (m, 2H),

2.48 – 2.62 (m, 1H), 2.34 – 2.45 (m, 1H), 2.31 (s, 3H), 2.13 – 2.28 (m, 1H), 1.98

– 2.09 (m, 1H), 1.18 – 1.28 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 174.93, 171.74,

137.42, 132.67, 129.31, 128.46, 77.00, 61.36, 58.70, 45.23, 29.57, 22.75, 21.05,


137


262.14421.




N-(4-methylbenzyl)-proline pentyl ester (3v): Synthesized

according to General procedure. Proline pentyl ester (0.093 g, 0.50

mmol) affords 3u (0.061 g, 42% yield). Light yellow oil compound

obtained after column chromatography (Al2O3, Pentane/EtOAc 95:5 to

90:10). 1H NMR (400 MHz, CDCl3) δ 7.03 – 7.28 (m, 4H), 3.98 – 4.18

(m, 2H), 3.83 – 3.94 (m, 1H), 3.45 – 3.58 (m, 1H), 3.17 – 3.31 (m, 1H), 2.96 –

3.08 (m, 1H), 2.30 – 2.44 (m, 1H), 2.32 (s, 3H), 2.04 – 2.18 (m, 1H), 1.83 – 2.01

(m, 2H), 1.70 – 1.81 (m, 1H), 1.55 – 1.69 (m, 2H), 1.21 – 1.43 (m, 4H), 0.78 –

1.02 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 174.17, 136.53, 135.19, 129.12,

128.78, 65.13, 64.61, 58.13, 52.99, 29.27, 28.29, 28.01, 22.85, 22.27, 21.07,


290.21177.




N-(4-methylbenzyl)-prolinamide (7): Synthesized according to

General procedure. Prolinamide (0.057 g, 0.50 mmol) affords 3v

(0.090 g, 83% yield). Light yellow oil compound obtained after column


MHz, CDCl3) δ 7.20 – 7.35 (br.s, 1H), 7.07 – 7.20 (m, 4H), 6.20 – 6.40

(br.s, 1H), 3.84 – 3.97 (m, 1H), 3.35 – 3.50 (m, 1H), 3.09 – 3.23 (m, 1H), 2.94

– 3.04 (m, 1H), 2.26 – 2.40 (m, 1H), 2.33 (s, 3H), 2.14 – 2.25 (m, 1H), 1.85 –

1.97 (m, 1H), 1.64 – 1.82 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 178.30, 136.78,

135.38, 129.02, 128.54, 67.15, 59.31, 53.62, 30.50, 23.93, 21.02. HRMS (APCI+,

m/z): calculated for C13H19NO2 [M+H]+: 219.14919; found: 219.14921.




Chapter 6

138

Representative NMR and HPLC spectrums

1H NMR (400 MHz, CDCl3) and 13C NMR (100 MHz, CDCl3) spectrums of N-(4-

methylbenzyl) valine pentyl ester (3r)


139

HPLC spectrums of racemic and one enantiomer of N-(4-methylbenzyl) valine

pentyl ester (3r) HPLC Conditions: Chiralcel OD-H column, Phenomenex, Ltd; heptane/isopropanol

(99.5:0.5); flow rate: 0.5 ml/min; detection: UV 221 nm; retention times 14.1 min (major) and 20.9 min (minor).

Racemic 3r

Enantiomer 3r

Chapter 6

140

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Castro, A. Previero, Int. J. Peptide Protein Res., 1993, 41, 323-325; c) M. Pugniere,

C. San Juan, A. Previero, Biotechnol. Lett., 1985, 7, 31-36; d) M. Bodanszky, A.

Bodanszky, Chem. Commun., 1967, 591-593.


[9] a) T. Yan, B. L. Feringa, K. Barta, ACS Catal., 2016, 6, 381–388; b) T. Yan, K. Barta,

ChemSusChem, 2016, 9, 2321–2325; c) A. J. Rawlings, L. J. Diorazio, M. Wills, Org.

Lett., 2015, 17, 1086−1089; d) H.-J. Pan, T. W. Ng, Y. Zhao, Chem. Commun.,

2015, 51, 11907-11910.

[10] Selected review and reactivities with Shvo catalyst: a) B. L. Conley, M. K. Pennington-

Boggio, E. Boz, T. J. Williams, Chem. Rev., 2010, 110, 2294–2312; b) D. Hollmann,

S. Bahn, A. Tillack, M. Beller, Angew. Chem. Int. Ed., 2007, 46, 8291–8294; c) S.

Imm, S. Bahn, A. Tillack, K. Mevius, L. Neubert, M. Beller, Chem. Eur. J., 2010, 16,

2705–2709; d) C. Segarra, E. Mas-Marza, J. A. Mata, E. Peris, Adv. Synth. Catal.,

2011, 353, 2078–2084.

[11] The ruthenium hydride-phosphonate interaction was initially reported by M.

Tokunaga, PhD Thesis, Nagoya University, 1995, later on cited in review: R. Noyori,

T. Ohkuma, Angew. Chem. Int. Ed., 2001, 40, 40-73.

[12] One example shows the addition of acid facilitates the formation of an imine

intermediate in the catalytic reductive amination of aldehydes with amines, see: A.

Pagnoux-Ozherelyeva, N. Pannetier, M. D. Mbaye, S. Gaillard, J.-L. Renaud, Angew.

Chem. Int. Ed., 2012, 51, 4976–4980.

[13] Two recent examples of metal-phosphoric acid interaction in catalytic redox

chemistry, see: a) S. Zhou, S. Fleischer, K. Junge, M. Beller, Angew. Chem. Int. Ed.,

2011, 50, 5120–5124; b) Y. Zhang, C.-S. Lim, D. S. B. Sim, H.-J. Pan, Y. Zhao,

Angew. Chem. Int. Ed., 2014, 53, 1399–1403.

Nederlandse samenvatting

141


Dit proefschrift beschrijft de ontwikkeling van nieuwe methodes voor het vormen

van koolstof-stikstof verbindingen via katalytische alcohol activatie met de nadruk

op de directe aminering van alcoholen via een cyclus van het onttrekken en

toevoegen van waterstof.

Alcoholen zijn goedkope, atoxische en gemakkelijk verkrijgbare stoffen. Ze worden

in de organische synthese veel gebruikt als alkylerende. Daarentegen is de directe

aminering van alcoholen bijzonder uitdagend omdat de hydroxylgroep (–OH) een

slecht vertrekkende groep is. Alcoholen worden daarom meestal geactiveerd door

de –OH groep om te zetten in een beter vertrekkende groep zoals een tosylaat (–

OTs), mesylaat (–OMs) of halogenide (–X) groep. Dit is een strategie die

stoichiometrische hoeveelheden potentieel schadelijk afval produceert.

De beschreven katalytische methodologie overkomt de typische beperking van de

klassieke amine synthese die een redox-actieve katalysator gebruikt. De

katalysator dehydrogeneert alcoholen tot de afgeleide carbonyl moleculen die

daarna gekoppeld worden met een amine met vorming van een iminogroep. Het

in de dehydrogenering van het alcohol gevormde waterstofmolecuul wordt

opgeslagen op de katalysator en hergebruikt voor de hydrogenering van de

verkregen iminogroep tot het gewenste aminoproduct. De reactie is direct,

gebruikt geen stoichiometrische reagentia en is relatief atoom-efficiënt met alleen

één molecuul water als bijproduct.

Hoofdstuk 1 is een inleiding op het werk in dit proefschrift. Het begint met een

algemeen overzicht van de rol en het belang van katalyse. Daarna presenteert het

de achtergrond van metaal-ligand bifunctionele complexen inclusief de twee

belangrijkste gebruikte katalysatoren in dit onderzoek: Knölkers complex en

Shvo’s katalysator. Daarna worden de nieuwste ontwikkelingen in de katalyse die

gebruikt maakt van een waterstofcyclus beschreven. Tot slot wordt een conclusie

gepresenteerd gebaseerd op het voorafgaande werk en worden de

onderzoekvragen en aanpak van het onderzoek in dit proefschrift geformuleerd.

Hoofdstuk 2 beschrijft het eerste voorbeeld van een goed-gedefinieerd

ijzercomplex dat geschikt is voor de katalytische alkylering van amines met

alcoholen. Voor de directe katalytische alkylering van amines met alcoholen via

een strategie die gebruikt maakt van een waterstof cyclus werden tot nu toe alleen

edelmetalen gebruikt, zoals op ruthenium en iridium gebaseerde complexen. De

pioniers in dit veld verklaarden dat de volgende uitdaging zou zijn om dit soort

omzettingen te realiseren met goedkope metalen, zoals ijzer. Het onderhavige

werk toont aan dat amines selectief gealkyleerd kunnen worden met alcohol via

een homogene ijzerkatalysator, Knölkers complex, waarbij vergelijkbare

reactiviteit wordt behaald als via edelmetalen. Tot de mogelijkheden van deze

nieuwe methode behoren ook de selectieve mono-alkylering van primaire anilines

en benzylische amines met alcoholen met daarbij de synthese van stikstof-

houdende heterocyclische structuren met 5, 6 en 7 atomen van benzylische amines

en diolen, een soort verbindingen die zeer belangrijk zijn voor de farmaceutische


142

industrie. Zo wordt de één staps-synthese van een anti-Parkinson medicijn vanuit

twee commerciële grondstoffen beschreven. De aldehyde- en imine-houdende

tussenproducten worden aangetoond met in situ 1H NMR.

Hoofdstuk 3 focust op de synthese van benzylische amines via de directe aminering

van benzylische alcoholen. Tijdens het werk gepresenteerd in hoofdstuk 2 bleken

benzylische alcoholen uitdagende substraten te zijn voor de daar gepresenteerde

reactie, omdat de imino groepen in de tussenverbindingen geconjugeerd zijn met

de aromatische ring structuur en dus moeilijk te hydrogeneren zijn met Knölkers

complex. Daarom laat dit hoofdstuk specifieke reactiecondities en

substraatcombinaties zien waarbij benzylische alcoholen efficiënt geamineerd

kunnen worden met een grote verscheidenheid aan amines. Verschillende

synthetisch uitdagende verbindingen zijn hierbij relatief eenvoudig verkregen.

In hoofdstuk 4 wordt de ijzer-gekatalyseerde pyrrool synthese vanuit primaire

amines en onverzadigde diolen beschreven. Hoofdstuk 2 liet zien dat benzylische

amines en 1,4-butaandiol leiden tot pyrrolidines, terwijl dit hoofdstuk laat zien dat

1,4-buteendiol of 1,4-butyndiol resulteren in pyrrolen. Deze reactie vindt

waarschijnlijk plaats via ijzer-gekatalyseerde isomerisatie van de onverzadigde

diolen naar de bijbehorende aldehydes gevolgd door een in situ Paal-Knorr pyrrool

synthese. Met deze methode worden een grote hoeveelheid verschillende primaire

anilines, benzylische amines en alifatische amines succesvol omgezet in pyrrolen

met matige tot goede opbrengsten. Gelpermeatiechromatografie laat zien dat

oligomeren en polymeren, die waarschijnlijk het resultaat zijn van condensatie van

de onstabiele carbonyl-houdende tussenproducten, het belangrijkste bijproduct

zijn van deze reacties.

Selectieve N-alkylering van amines in aminozuren en korte eiwitketens zonder de

noodzaak voor het gebruik van beschermende groepen is een essentiële chemische

omzetting voor de farmaceutische- en materiaalindustrie. Hoofdstuk 5 introduceert

een nieuwe, algemeen toepasbare methode voor de directe N-alkylering van

onbeschermde aminozuren en korte eiwitketens met alcoholen in hoge

opbrengsten en met behoud van de stereochemie onder toepassing van zowel

ijzer- als rutheniumkatalysatoren. In de meeste gevallen kunnen de N-

gealkyleerde aminozuren verkregen worden in kwantitatieve opbrengst na het

afdampen van de vluchtige stoffen van het reactiemengsel. Selectieve di-alkylering

van de N-terminus van di- en tripeptides met alcoholen wordt ook beschreven. Ten

slotte wordt de ijzer gekatalyseerde mono-N-alkylering van aminozuren met

vetalcoholen aangetoond. De verkregen N-gealkyleerde aminozuren met lange

vetketens kunnen gebruikt worden als oppervlakte-actieve stoffen.

English Sumary

143

English Sumary

This thesis describes the development of novel methodologies for carbon-nitrogen

bond formation through catalytic alcohol activation, mainly focusing on the direct

amination of alcohols through borrowing hydrogen strategy.

Alcohols are cheap, low-toxic and abundant chemicals. They are common

alkylation reagents used in organic synthesis. However, the direct amination of

alcohols is highly challenging, as the hydroxyl group (-OH) is a poor leaving group.

Alcohols are conventionally activated through converting the –OH to a better

leaving group, such as a tosylate (-OTs), mesylate (-OMs) or halide (-X), which

produces stoichiometric amounts of potentially toxic salts as waste. An alternative

pathway is oxidizing the alcohols to the corresponding carbonyl compounds,

followed by reductive amination, which requires stoichiometric amount of oxidants

and reductants and also produces large amounts of waste.

The presented catalytic method, avoids the common limitations encountered by

the classical amine formation reactions through employing a redox-active catalyst.

The catalyst dehydrogenates alcohols to the corresponding carbonyl compounds

which undergo imine formation with the amine reaction partner. The hydrogen

“borrowed” from the alcohol is temporarily stored on the metal catalyst and

returned back to the formed imine to obtain the desired amine product. The

reaction is direct, applies no stoichiometric reagents and produces water as the

only byproduct.

Chapter 1 is an introduction to this thesis. It starts with an overview of the role

and importance of catalysis in general. Then, it presents the literature background

of metal-ligand bifunctional complexes including the Knölker complex and the Shvo

catalyst, which are the two main catalysts employed in this thesis. The following

content shows the current state-of-the-art in borrowing hydrogen type catalysis.

The last part of this chapter is a conclusion of the above parts and contains the

outline of this thesis.

Chapter 2 describes the first example of a well-defined iron complex catalyzed

alkylation of amines with alcohols. Direct alkylation of amines with alcohols

through borrowing hydrogen strategy is an area dominated by noble metals, e.g.

ruthenium and iridium based catalytic systems. The pioneers of this field stated

that the next challenge was replacing noble metals with cheap metals, such as iron.

This work shows that amines can be selective alkylated with alcohols using a

homogeneous iron catalyst, the Knölker complex, achieving comparable reactivity

as noble metals did in this transformation. The scope of this novel method includes

the selective mono-alkylation of primary anilines and benzylamines with alcohols

as well as the formation of 5, 6 and 7 membered nitrogen containing heterocycles

from benzylamines and diols – moieties highly relevant for the pharmaceutical

industry. Moreover, anti-Parkinson drug has been synthetized in one step from 2

commercially available substrates in good yield. The aldehyde and imine

intermediates have been observed in an in situ 1H NMR study.

English Sumary

144

Chapter 3 focuses on the direct amination of benzyl alcohols to form benzylamines.

In Chapter 2 it was found that benzyl alcohols are rather challenging substrates

since the corresponding imines that are conjugated to aromatic rings are more

difficult to be reduced using the Knölker complex. Therefore this chapter’s focus is

devoted to finding reaction conditions and substrate combinations which allow for

benzyl alcohols to be aminated efficiently with a large variety of amines. Otherwise

synthetically challenging products were obtained this way.

In chapter 4, iron catalyzed pyrrole formation from primary amines and

unsaturated diols is described. Chapter 2 shows that benzylamines and 1,4-

butandiol provide pyrrolidines, while this chapter shows that primary amines and

1,4-butendiol or 1,4-butyndiol provide pyrroles. The reaction is believed to occur

via iron catalyzed isomerization of unsaturated diols to the corresponding

aldehydes followed by in situ Paal-Knorr pyrrole synthesis. Using this method, a

large variety of primary anilines, benzylamines and aliphatic amines have been

converted to pyrroles in moderate to good yields. Gel permeation chromatography

(GPC) showed that oligomers and polymers, presumably formed via the

condensation of instable carbonyl intermediates, are the main side products during

these transformations.

Selective N-alkylation of amines of amino acids and oligopeptides without the need

for protecting groups is an essential chemical transformation in the pharmaceutical

and materials industry. Chapter 5 demonstrates a novel, general method for the

direct N-alkylation of unprotected amino acids and oligo-peptides with alcohols in

excellent yields and retention of stereochemistry. In this work, both iron and

ruthenium based catalysts are used. For most cases, N-alkyl amino acids can be

obtained in quantitative yields upon removing the volatiles from the reaction

mixture. Selective dialkylation of N-terminus of di- and tripeptides with alcohols

are also presented. Finally, iron catalyzed mono-N-alkylation of amino acids with

fatty alcohols are shown. The formed long-chain N-alkyl amino acids were shown

to act as surfactants.

Chapter 6 presents the ruthenium (Shvo catalyst) catalyzed N-alkylation of amino

acid esters with alcohols. It provides a general method for direct mono-N-

alkylation of amino acid esters with a variety of benzyl alcohols and 1-pentanol in

excellent yields and retention of stereochemistry. When a proline ester or

prolinamide is employed, significant racemization is observed.

To conclude, this thesis demonstrates that metal-ligand bifunctional catalysts are

able to promote N-alkylation of amine with alcohols. The work has addressed

highly challenging goals within this research field; the development of efficient

methods employing iron-based catalytic system as well as functionalizing highly

challenging substrates such as unprotected amino acids. Due to these

achievements that are well in-line with the principles of green-chemistry the

presented methods offer new sustainable catalytic strategies for the

pharmaceutical and chemical industries.

Acknowlegments

145

Acknowlegments

On September 2nd 2013, a rainy early morning, I took a train in northern Germany

and arrived in Groningen in the afternoon. This was the day I started my PhD.

Time flies and now it comes to the end. My six years European journey, at this

time, will also going to the end. Sometimes, when I recalled this period, it was just

like a long movie playing in my head. I am so happy that I made the decision to

explore Europe, another side of the world. I want to thank every people I have

met, who have helped me to grow.

First, I would like to thank Ben and Katalin, for giving me this opportunity to do

my PhD research in Groningen. Thanks for your patient and strong support during

the last four years. I am glad I have worked with both of you. Katalin, I am really

appreciated that you have never lost your patient on me and always want to

encourage me. Ben, if I need to find a role model for my future career, it must be

you. Thanks for your inspiration and support.

I also would like to thank all other Stratingh staff members, thanks for the

discussions during group seminars. Because of you all, we have such a nice

working environment.

Thanks Prof. Beller, Prof. de Bruin and Hans for being the members of my thesis

reading committee. Peter, thank you (and your father) for the translation of this

thesis abstract and summary.

Peter and Giovanni, thanks for being my paranymphs. It was such a great time we

have spent together, especially the fantastic trips to Iceland and California, pizza

Friday, board games weekends (with delicious food from Marzia), etc.

Martin, you are also almost finishing your PhD now, you are always energetic and

brought so much fun to the group. I hope I can manage getting to your wedding.

Zhuohua, you are always quite, but once talking with you, everyone will know you

are a great guy. Anand, how are you doing now, got married? Laurie, I did not

know we have overlapped staying in Rennes. It was really great to meet another

cheerful French girl in Groningen. Anaϊs, sorry I said your home-made sweets were

too sweet, haha. Hopefully you are soon finishing your Bachelor in Brazil and

starting your PhD in Europe. I look forward to meeting you in Brazil or States in

the future. Ciaran, you are a big fan of board game, hopefully we will play it again

soon. Chris, thanks for hosting Peter and me in Santa Barbara, it was a really great

memory for me. Jurjen, it always fun to talk with you, especially when you are

eating your “delicious sandwich”. Marilena, it always happy to talk with you, and

thanks for your pasta. I heard you will start your Master in Amsterdam, so see you

soon in my promotion. Balint, you are a highly motivated guy and always want to

improve yourself. I believe all your dreams will come true. Nastya, a strong

independent Russian girl, I am glad to meet you and sometimes be your mentor.

Acknowlegments

146

I believe you will be more relaxed, and I am afraid probably I cannot manage to

speak Russian. Saravana, we both did Master in Rennes, I was shocked when you

told me you would come to our group for a postdoc when I was still in my last year

of PhD. Ale, welcome to the group, unfortunately I am just going to leave,

otherwise we will have a lot of fun for sure. Walle, probably you cannot read my

writing, but please remember the good days when I was feeding you.

Tilde, you have special power, as every time I talk with you, I just feel happier.

Thanks for inviting me to lots of events. Pablo, you are a cool guy, you always

know how to make parties. One of the greatest things I have done in Groningen

was cycling to Maastricht with you. Ravi, we are always having funny conversion,

I hope you will find a very good position in India. Juan Fer, I cannot believe I am

drinking beer and discussing about politics with a Spanish, haha. I normally do not

drink, but with you guys I have to. And other guys, Mamen, Ciccio, Simone,

Xingchen, Jiafei, it was great time that I hanged out with you.

Jiawei, it was a bit sad when you left Groningen. I really had great time with you;

especially we had Scuba diving together. Depeng, thanks for your all suggestions

during my research. Now, you have started your independent scientific career in

Guangzhou, good luck for you. Jiajia, I “followed” you from Rennes to Groningen,

but now not to Delft, haha. Thanks for all the random talks.

Giulia, you always collect people for Borrel. Now you found a real job, bought a

house and a car, just waiting for getting retired, haha. Boris, you are definitely a

fun guy when you got drunk. Stefano, I enjoyed a lot when we were snowboarding

together, I hope I can be as good as you one day. Diederik, it was a great fun that

we organized workweek together. Massimo, it was always great to talk with you,

thanks for all your suggestions. Annika, probably the first time I talked with you

was in the Dutch class. Although I do not remember what I have learned, I am so

glad to be your friend. Ivana, thanks for your explanation about the defence

process, otherwise I will get delayed. I wish you good luck for your grant proposal

and hopefully see you in the States. Raquel, you are a typical Spanish girl, as you

always give everybody warm greeting. I hope you enjoying happy life with Matt in

Spain.

I would like to thank you all, Michael, Sander, Valentín, Anne, Hugo, Lilianna, Manu,

Cora, Lara, Andreas, Ruben, Ana, Nathalie, Yans, Arjan, Sara, Duenpen, Sandeep,

Juan, Pat, Davide, Francesco, Jonas, Steven, Francesca, Wiktor, Tom, Ani, Marco,

Jana, Kaja, Dusan, Erik, Jinling, Jiawen, Yuchen, Wojtek, Matea, krzysztof, Carlos,

Tati, Wenhao, Varsha, Bert, Shermin, etc. Well, Probably I have not counted

everybody.

Also, I would like to thank the guys I have met and had fun with outside of

Stratingh Institute, from Groningen, Rennes, Rostock and other random spots on

the map where I have travelled in.

Acknowlegments

147

Last, I want to thank my parents for your endless support. (感谢父母多年来的支持)

Now, I am waiting for the visa to States. It will be a new journey. I believe a lot

of fun experiences, interesting people and challenges are waiting for me. Of course,

I am ready for you.

See you guys! Take care!

Sincerely,

Tao

August 9th 2017, Groningen

Carbon-Nitrogen Bond Formation via Catalytic Alcohol Activation

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