“PALLADIUM AND NICKEL-CATALYZED CARBON-CARBON COUPLING …

INAUGURAL DISSERTATION

ZUR ERLANGUNG DES DOKTORGRADES DER NATURWISSENSCHAFTLICHEN FAKULTÄT DER

KARL-FRANZENS UNIVERSITÄT

GRAZ, ÖSTERREICH

ZUM THEMA

“PALLADIUM AND NICKEL-CATALYZED

CARBON-CARBON COUPLING

REACTIONS FOR THE SYNTHESIS OF

QUINOLONE AND BISQUINOLONE

DERIVATIVES”

VORGELEGT VON

MAG. JAMSHED HASHIM

OKTOBER 2008

The work presented in this thesis was conducted at the Institute of Chemistry, Division of Organic and Bioorganic Chemsitry, at the Karl-Franzens University of Graz between November 2004 till October 2008. First of all, thanks to Allah for granting me the courage to fulfil my duties. I would like to thank the Higher Education Commission of Pakistan for a Ph.D. scholarship and the Austrian Exchange Service (ÖAD) for adminstrative help. I am cordially thankful to my supervisor Prof. Dr. C. Oliver Kappe for his encouraging and kind supervision. Special thanks to Prof. Dr. Georg Uray, Prof. Dr. Walter M. F. Fabian and Dr. Anne-Marie Kelterer for fluorescence, computational and enantioseparation studies in Chapter D. Thanks to Dr. Toma N. Glasnov for sharing results during the projects. I would like to thank the Prof. Dr. Wolfgang Stadlbauer for helpful discussions, Prof. Dr. Klaus Zanger and Bernhard Werner for recording numerous NMR Spectra, and Dr. Claudia Reidilinger for LC-MS analysis. My sincere and kind thanks to all my former and current colleagues and friends, especially to Jennifer, Nuzhat, Hana, Doris, Bimbisar, Mitra, Bernadett, Florian for all their support, discussions, help and making these years memorable for me. My parents, my brothers, sister, aunt and his family deserve special thanks for their support all through these years and making the possibility for acquiring the education. Big thank to my wife Nuzhat for her nice company and a son Hadi.

For my beloved parents. (Muhammad Hashim Khan & Firdous Hashim)

Table of Contents

A Introduction 1

1.1. Mechanistic Aspects of C-C Bond Forming Reactions 2

2. Types of Transition-Metal-Catalyzed C-C Coupling 3

Reactions.

2.1. The Suzuki-Miyaura Reaction 3

2.2. The Heck Reaction 4

2.3. The Sonogashira Coupling Reaction 6

2.4. The Stille Reaction 7

2.5. Ullmann-Type Reactions 7

3. Conclusion 9

4. References 10

B Symmetrical Bisquinolones via Metal-Catalyzed Cross- 12

Coupling and Homocoupling Reactions

1. Introduction 13

2. Results and Discussion 14

3. Conclusion 20

4. Experimental Section 20

5. References 28

C Symmetrical Bisquinolones via Nickel(0)-Catalyzed 30

Homocoupling of 4-Chloroquinolones

1. Introduction 31

2. Results and Discussion 33

3. Mechanistic Discussion 40

4. Conclusion 41

5. Experimental Section 41

6. References 47

D Bisquinolones as Chiral Fluorophores – A Combined 50

Experimental and Computational Study of Absorption

and Emission Characteristics

1. Introduction 51

2. Results and Discussion 52

2.1. Fluorescence 52

2.1.1. Computational Results 61

2.2. Separation of Enantiomers 65

3. Conclusion 68

4. Experimental Section 68

5. References 78

Appendix Summary 82

List of Publications

This thesis is based on the following publications:

1. Hashim, J.; Glasnov, T. N.; Kremsner, J. M.; Kappe, C. O.; Symmetrical

Bisquinolones via Metal-Ctalyzed Cross-Coupling and Homocoupling

Reactions. J. Org. Chem. 2006, 71, 1707-1710.

2. Hashim, J.; Kappe, C. O.; Synthesis of Symmetrical Bisquinolones via

Nickel(0)-Catalyzed Homocoupling of 4-Chloroquinolones. Adv. Synth.

Catal. 2007, 349, 2353-2360.

3. Hashim, J.; Kelterer, A.-M., Glasnov, T. N.; Kappe, C. O.; Uray, G.;

Fabian, W. M. F.; Bisquinolones as Chiral Fluorophores – A combined

Experimental and Computational Study of Absorption and Emission

Characteristics. Eur. J. Org. Chem. 2008, submitted for publication

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 1

A Transition-Metal-Catalyzed Carbon-Cabon Coupling

Reactions

1. Introduction

Transition-metal-catalyzed carbon-carbon coupling reactions belong to the most powerful and

flexible transformation known to organic chemists and have caused a real revolution in

organic synthesis in past decades.1 This art allowed cross-coupling of substrate in ways that

would have previously been thought impossible.2 In general, mild reaction conditions, high

functional group tolerance and broad availability of reagents have contributed to the growing

success of these C-C bond formation methods. Most C-C coupling protocols generally involve

the interaction of nucleophilic metallic reagents with electrophilic organohalides (or related

substrate)3 which are catalyzed by different transition-metals (as shown in Scheme 1).4

catalyst[M2] R1 R2R1M1 R2X+

M1 = Li (Murahashi)Mg (Kumada-Tamao, Corriu)B ( Suzuki-Miyaura)Al (Nozaki-Oshima, Negishi)Si (Tamao-Kumada, Hiyama-Hatanaka)Zn (Negishi)Sn (Migita-Kosugi, Stille).....

M2 = Fe, Ni, Cu, Pd, Rh,.......X = I, Br, Cl, OSO2R,......

Scheme 1. Different methodologies of C-C bond forming reactions.

In this context homogenous transition-metal catalysis has gained enormous relevance

in various C-C coupling reactions such as Heck, Stille, Suzuki and Sonagashira reactions.5

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 2 However, these reaction typically need hours or days for completion with traditional heating

under reflux condition.6 Besides the classical thermal activation mode, new methods have

emerged in the recent years. Such as 1) microwave, 2) ultrasound, 3) high pressure, 4)

micellar solutions, 5) microemulsions, 6) electrochemical activation, 7) nanofiltration, 8)

microreactors, 9) ball-milling conditions.4 Fortunately many of transition-metal-catalyzed

transformation can be significantly enhanced by microwave irradiation. Infact homogenous

transition metals catalyzed reactions represent one of the most important and best studied

reaction type in microwave-assisted organic synthesis.6 Further, It is appeared from the recent

literature that microwave irradiation mostly, not only results in a dramatic acceleration of

reaction, but also results in cleaner outcomes and increased yields.7

1.1. Mechanistic Aspects of C-C Bond Forming Reactions

Although carbon-carbon coupling reaction are catalyzed via different metals, e.g. palladium,

nickel, copper, iron (as shown in Scheme 1). However, a major part of the research in this

highly important area has been devoted to palladium catalysis. In general, carbon-carbon

coupling reaction catalyzed by palladium follow the usual reaction mechanism as shown for

coupling of organo metalics with organo halides of triflates in Scheme 2.5

Pd(0)

R1 Pd XR1 Pd R2

R1 R2 R1X

R2 MM X

oxidativeaddition

reductiveelimination

transmetallation

M = B, Sn, Si, Zn, Mg

Scheme 2. Major steps of palladium-catalyzed coupling reaction. (Catalytic cycle found in

textbooks).

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 3 2. Types of Transition-Metal-Catalyzed C-C Coupling

Reactions

Transition-metal-catalyzed reactions can be listed as follows:

1) Suzuki 2) Heck 3) Sonogashira 4) Stille 5) Ullmann

6)Fukuyama 7) Negishi 8) Kumada 9) Hiyama

In this overview some of the microwave-assisted transition-metal catalyzed reactions are

covered:

2.1. The Suzuki-Miyaura Reaction

The Suzuki-Miyaura coupling is basically the reaction of arylboronic acids with aryl halides

and triflates in the presence of palladium catalyst to form biaryl fragments, which are present

in many biologically active molecules. The advantages of employing the Suzuki-Miyaura

coupling include mild reaction conditions, tolerance to a wide range of functional groups, and

the availability of various boronic acids which are, in turn, generally low in toxicity and a

stable starting material.8 The Suzuki reaction is today arguably one of the most versatile tools

for cross-coupling reaction. As it is well-known fact that microwave (MW) heating has

emerged as a powerful technique by which reactions can be brought to completion in shorter

reaction times in a number of cases, so it is not surprising that carrying out high-speed Suzuki

reactions under controlled microwave conditions can be considered almost a routine synthetic

procedure today, given the enormous literature precedent for this transformation.9 The

reaction has also attracted the attention of several chemists involved in high-throughput

chemistry, as a large variety of boronic acids are commercially available.10

The first MW-promoted Suzuki couplings were published in 1996 (Scheme 3), which

is related to the coupling of phenylboronic acid with 4-methylphenyl bromide to give a fair

yield of product after a reaction time of less than 4 min under MW-irradiation. The same

reaction had previously reported with 4 h conventional heating time.11

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 4

Pd(PPh3)4, EtOH, DME, H2O

MW, 55 W, 2.8 min+

55%

Br

MeO (HO)2B MeO

Scheme 3. Suzuki coupling of phenylboronic acid with 4-methylphenyl bromide.

Recently, Hoornaert and co-workers have reported the microwave-assisted one-pot

synthesis of symmetrical highly functionalized 2(1H)-pyrazinones via Suzki-Miyaura-type

reaction (Scheme 4).12

N

N Pd(PPh3)4, K2CO3, dioxane

MW, 100 °C, 15-30 min

R1

Cl

R6

Cl

O

N

N

N

NO O

Cl

R6 R6

Cl

R1 R1

8 examples(49-68%)

OB

O

O

OB

Scheme 4. Suzuki-Miyaura-type homodimerization of 2(1H)-pyrazinones .

2.2. The Heck Reaction

The Heck reaction is broadly defined as Pd(0)-mediated coupling of an aryl or vinyl halide or

sulfonate with an alkene under basic conditions. Since its discovery, this methodology has

been found to be very versatile and applicable to a wide range of aryl species and a diverse

range of olefins.1f,4 This is generally a very mild reaction and does not require strict

anhydrous or inert conditions. Among aryl halide, iodides are very by far the most used, while

few examples of benzenesulfonate derivatives have also been reported.13 Solution-phase Heck

reactions were carried out successfully by microwave-assisted organic synthesis (MAOS) as

early as 1996.

In this context, the Heck arylation in Scheme 5 was the first example of a microwave-

assisted, palladium-catalyzed C-C bond formation. Thereby reducing reaction times from

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 5 several hours under conventional reflux conditions to sometimes less than five minutes.14 The

same high chemo and regioselectivity was found as in classical, oil bath heating (Scheme 5).11

Pd(OAc)2, Et3N, DMF

MW, 60 W, 4.8 min+

63%(oil bath, 100 °C, 17 h, 64%)

I

Br Br

Scheme 5. Chemoselective Heck coupling of 4-bromoiodobenzene and styrene.

A synthetically useful application of an intramolecular microwave-assisted Heck

reaction was described by Gracias et al (Scheme 6).15

Pd(OAc)2, PPh3, Et3N, MeCN

MW, 125 °C, 60 min

98%

I

N O

PhNHCH2Ph

O

MeO2C

PhNHCH2Ph

O

NO

MeO2C

Scheme 6. Intramolecular Heck reaction for the synthesis of seven-membered N-heterocycles.

Recently, Larhed and coworkers developed a general procedure for carrying out

oxidative Heck couplings, that is, the palladium(II)-catalyzed carbon-carbon coupling of

arylboronic acids with alkenes using copper(II) acetate as a reoxidant (Scheme 7),16 which is

another addition in already vast spectrum of MW-assisted heck chemistry.

Pd(OAc)2, Cu(OAc)2,LiOAc, DMF

MW, 100-140 °C, 5-30 min+

17 examples(45-81%)

B(OH)2

R

EWG

EWG

R

Scheme 7. Oxidative Heck-coupling of boronic acids and alkenes.

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 6 2.3. The Sonogashira Coupling Reaction

In this palladium-catalyzed reaction, aryl or vinyl halides or triflates couple to unactivated

terminal alkynes in the presence of a Cu(I) cocatalyst, usually delivered in the form of CuI.

Very mild conditions and tolerance to many other functional groups are among the advantages

of this procedure. Moreover, the triple bond can be converted into various new functionalities,

making this reaction very useful for combinatorial library generation.8

In 2001, Gogoll published the first pivotal work on the effect of directed microwave

activation on the efficiency and productivity in the Sonogashira coupling employing several

different aryl precursors (Scheme 8).17

Pd(PPh3)Cl2, CuI, Et2NH, DMF, LiCl

MW, 60 W, 4.8 min+

80-99%

ArX SiMe3

X = I, Br, Cl, OTfAr = carboaryl or heteroaryl

Ar SiMe3

Scheme 8. Palladium-catalyzed Sonogashira reaction with trimethylsilylacetylene.

Interestingly, new nickel18and copper19 catalyst systems have been introduced, even

“transition metal-free” reactions have been proposed.20 The solvent-free Sonogashira coupling

via Nickel is highly important as shown in Scheme 9. In this reaction sequence addition of

copper enhanced the reaction rate resulting in full conversion after irradiation for only 3

minutes in a domestic oven.

Ni(0), PPh3, CuI, KF, Al2O3

MW, 3 min+

53-75%

Br

BrR1

XR2

R1

R2

R1 = Cl, Br, MeR2 = NO2, COMe, OMe

Scheme 9. Solvent-free nickel-catalyzed Sonogashira reaction.

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 7 2.4. The Stille Reaction

The Stille coupling is a versatile reaction in which a variety of C-C bonds can be obtained by

reaction between stannanes and halides or pseudohalides.10 This base-free reaction is very

reliable, high yielding, and tolerant of many functionalities. The main drawback is the modest

reactivity of the organotin reactants and the formation of stoichiometric tin by-product which

is difficult to separate, but these limitations can be overcome by a judicious choice of

experimental conditions. The Stille reaction was one of the earliest transition metal-catalyzed

reactions to be accelerated with MW-assistance (Scheme 10).21

Pd2dba3, Ph3As, LiCl, NMP

MW, 50 W, 2.8 min+

68%Bu3Sn

OTf

O O

Scheme 10. Stille coupling with 4-acetylphenyl triflate.

One of the many applications reported is the Stille coupling of tin reagents with

fluorinated tags, in which the products and excess of the toxic tin-containing reagents can be

easily separated from the reaction mixture and, in the case of the reagents, be recycled.14 One

example of the tagged organostannanes is presented in Scheme 11.22

Pd(PPh3)2Cl2, LiCl, DMF

MW, 60 W, 2 min

63%

OTf

O

OMe

O

OMe

O(CH2CH2C6F13)3Sn+

O

Scheme 11. Stille-coupling with the tagged furan stannane reagent.

2.5. Ullmann-Type Reactions

The Ullmann-type reaction, that is, homocoupling of aryl or vinyl halides is conventionally

mediated by copper at high temperatures.23 Ullmann first reported this reaction in 1901.24

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 8 Although the coupling conditions that were first reported are still widely used, a host of

modifications have been made to the reaction. Some of these modifications have been made to

the reaction. Some of these modifications include the use of activated and alternative metals,

often resulting in much lower coupling temperatures. Nickel and palladium are the most

utilized source of alternative metals to effect this transformation.7 In recent years, Pd/C-

catalyzed Ullmann type coupling in the presence of reducing agents, such as sodium formate,

hydrogen, zinc, indium, or triethylamine has attracted increasing attention.5

To the best of our knowledge, very rare progress has been done in the use of Cu as a

catalyst for Ullmann reaction via using microwave irradiation. However, first report on the

controlled microwave mediated Ullmann-type N-arylation of N-H containing heteroarenes

with aryl bromide is reported in 2003 (Scheme 12).25

CuI, K2CO3, NMP

MW, 195 °C, 1-3 h

BrNH2

Me

+ NHHet NH2

MeNHet

9 examples(66-96%)

Scheme 12. Cu-catalyzed Ullmann-type N-arylation of N-H heteroarenes.

The introduction of Ni as an agent in the coupling of aryl halides represents a major

advance in the field.26 There have been rapid developments in the use of Ni-catalyzed

coupling reactions17,27 after the Semmelhack and co-workers 1971 report,28 where they used

Ni(cod)2 in DMF as an alternative to copper in the reductive homocoupling of aryl halides

(Scheme 13). Until now, there is very rare work reported on Ullmann-type Ni-catalyzed

homocoupling reaction via using microwave-irradiation.29

Ni(cod)2, DMF

52 °C82%

Br

Scheme 13. Ullmann-type homocoupling reaction via nickel-catalyst.

On the other hand, the relatively few palladium-mediated homocouplings reported to

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 9 date either are not general or, as with the nickel procedures, require inconvenient reaction

conditions to regenerate the active Pd(0) species.30 Few years ago, Lemaire and Rawal groups

published Pd-catalyzed Ullmann-type homocoupling reactions. Importantly Rawal and co-

workers reported a convenient and general protocol for aryl halides homocoupling towards

symmetrical biaryls, however, this procedure is conventional in heating mode (Scheme 14).31

Pd(OAc)2, P(o-tol)3 or As(o-tol)3,hydroquinone, Cs2CO3, DMA

25-100 °C, 1-48 h14 examples

(39-99%)

X

R R

R

Scheme 14. Palladium-catalyzed Ullmann-type reaction.

3. Conclusion

Now-a-days, transition metal-catalyzed carbon-carbon bond forming reactions belong

in the toolbox of synthetic organic chemist and cover an extremely wide range of

modifications and applications since first developed in 1970s. In all the methodologies

different activation modes have been utilized. But carrying out these cross/homo-coupling

reactions under controlled microwave irradiation can be considered today most effective. The

Suzuki-Miyaura and Stille protocols are two of the most versatile and well-investigated

microwave-assisted cross-coupling reactions in modern organic synthesis. It is indicative that

the combined approach of microwave irradiation and homogenous catalysis can offer a nearly

synergistic strategy in the sense that the combination has greater potential than its two

separate parts in isolation. In this Chapter the recent publications4,14,23 on carbon-carbon

coupling reactions were covered.

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 10 5. References

[1] a) Muci A. R.; Buchwald S. L. Top. Curr. Chem. 2002, 219, 131-209; b) Littke A.

F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176-4211; c) Prim, D.; Campagne,

J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041-2075; e) Kotha, S.;

Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633-9695; f) Beletskaya, I. P.;

Cheprakov, A. V. Chem. Rev. 2000, 100, 3009-3066; g) Ley, S. V.; Thomas, A. W.

Angew. Chem. Int. Ed. 2003, 42, 5400-5449.

[2] a) Cross-coupling Reactions; Miyaura, N. A practical Guide; Ed.; Springer: Berlin,

2002; b) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F.,

Eds. 2nd ed.; Wiley-VCH: Weinheim, 2004.

[3] Prokopcova, H.; Kappe, C. O.; Angew. Chem. Int. Ed. 2008, 47, 3674-3676.

[4] Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005, 61, 11771-11835.

[5] Yin, L.; liebscher, J. Chem. Rev. 2007, 107, 133-173.

[6] Kappe, C. O.; Angew. Chem. Int. Ed. 2004, 43, 6250-6284.

[7] Appukkuttan, P.; Van der Eycken, E. Eur. J. Org. Chem. 2008, 7, 1133-1155.

[8] Testero, S. A.; Mata, E. G. J. Comb. Chem. 2008, 10, 487-497.

[9] Homogenous transition-metal-catalysis: a) Larhed, M.; Moberg, C.; Hallberg, A.

Acc. Chem. Res. 2002, 35, 717-727; b) Olofsson, K.; Larhed, M.; In Microwave-

Assisted Organic Synthesis (Eds.: Lidström, P.; Tierney, J. P.), Blackwell, Oxford,

2004, Chap. 2.

[10] Ersmark, K.; Larhed, M.; Wannberg, J. Curr. Opin. Drug Discov. Devel. 2004, 7,

417-427.

[11] Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582-9584.

[12] De Borggraeve, W. M.; Appukkuttan, P.; Azzam, R.; Dehaen, W.; Compernolle, F.;

Van der Eycken, E.; Hoornaert, G.; Synlett 2005, 777-780.

[13] Yu, K.-L.; Deshpande, M. S.; Vyas, D. M. Tetrahedron Lett. 1994, 35, 8919-22.

[14] Kappe, C. O.; Stadler, A. Microwave in Organic and Medicinal Chemistry 2005, vol.

25, Wiley-VCH.

[15] Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 417-420.

[16] Andappan, M. M. S.; Nilsson, P.; Larhed, M. Mol. Diversity 2003, 7, 97-106.

[17] Erdelyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165-4169.

[18] Yan, J.; Wang, Z.; Wang, L. J. Chem. Res.(S) 2004, 1, 71-73.

[19] He, H.; Wu, Y. J. Tetrahedron Lett. 2004, 45, 3237-3239.

Transition-Metal-Catalyzed Carbon-Carbon Coupling Reactions 11 [20] Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Eur. J. Org. Chem. 2003, 24,

4713-4716.

[21] Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron Lett. 1996, 37, 8219-8222.

[22] Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.; Hallberg, A. J. Org. Chem.

1997, 62, 5583-5587.

[23] Loupy, A. Microwaves in Organic Synthesis 2006, vol. 2, Wiley-VCH.

[24] a) Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174-2185; b) Ullmann, F.; Meyer,

G. M.; Loewenthal, O.; Gilli, E. Liebigs Ann. Chem. 1904, 332, 38-81.

[25] Wu, Y.- J.; He, H.; LۥHeureux, A. Tetrahedron Lett. 2003, 44, 4217-4218.

[26] Knight, D. W.; Trost, B. M.; Fleming, I.; Pattenden, G. In Comprehensive Organic

Synthesis; Eds.; Pregamon: Oxford, 1991; vol. 3, p. 481.

[27] Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Bull. Chem. Soc. Jpn. 1990, 63,

80-87.

[28] Semmelhack, M. F.; Helquist, P. M.; Jones, L. D. J. Am. Chem. Soc. 1971, 93, 5908-

5910.

[29] J. Hashim, T. N. Glasnov, J. M. Kremsner, C. O. Kappe, J. Org. Chem. 2006, 71,

1707-1710.

[30] a) Tsuji, J. Palladium Reagents and catalysts; Wiley: New York, 1995; b) Torii, S.;

Tanaka, H.; Morisaki, K. Tetrahedron Lett. 1985, 26, 1655-1658.

[31] Hennings, D. D.; Iwama, T.; Rawal, V. H. Org. Lett. 1999, 1, 1205-1208.

Metal-Catalyzed Cross-Coupling and Homocoupling 12 B Symmetrical Bisquinolones via Metal-Catalyzed Cross-

Coupling and Homocoupling Reactions

Graphical Abstract

NR1

O

Cl

R2R3

R4

N OR1R2

R3

R4

NOR1 R2

R3

R4

Method A:

Method B:

PdCl2(dppf), [B(pin)]2, KOH, BuClMW, 130-145 °C, 35 min

NiCl2, PPh3, Zn, KI, DMFMW, 205 °C, 25 min

Abstract

Functionalized 4,4′-bisquinolones can be efficiently synthesized by microwave-assisted

palladium(0)-catalyzed one-pot borylation/Suzuki cross-coupling reactions, or via nickel(0)-

mediated homocouplings of 4-chloroquinolin-2(1H)-one precursors. Both methods are also

applicable to other types of symmetrical biaryls.

Metal-Catalyzed Cross-Coupling and Homocoupling 13 1. Introduction

Substituted biaryls play an important role in organic chemistry.1,2 Many natural products,

pharmaceuticals, herbicides and fine chemicals contain symmetrical or unsymmetrical biaryl

units. In addition, biaryls are applied as chiral ligands in catalysis, as liquid crystals or organic

conductors.1 Bis-heterocycles are also well-known in the literature and often display similarly

interesting biological and physical properties.2-5 Important structural motifs are, for example,

bipyridines,3 bithiophenes4, and bipyrroles.5

In the context of our ongoing interest in the chemistry of functionalized quinolin-

2(1H)-ones (carbostyrils),6 we became interested in the generation of the corresponding 4,4′-

bisquinolones of type 1. This novel class of bis-heterocycles are of interest both as aza-

analogues of biscoumarin natural products (e.g., 4,4′-biisofraxidin)7 and because of their

anticipated fluorescent properties as push-pull carbostyrils (R3 = R4 = OMe).8

N OR1R2

R3

R4

NOR1 R2

R3

R4

1; R1 = Me, Ph; R2 = H, alkylR3 = R4 = H, OMe

O OOMe

HO

MeO

OO OH

OMe

OMe

4,4'-biisofraxidin

Figure 1. Aza-analogues of biscoumarin natural products.

Here we report two different methods for the synthesis of bisquinolones of type 1 that

are based either on Pd(0)-catalyzed one-pot borylation/Suzuki cross-couplings or Ni(0)-

mediated homocouplings (Ullmann reaction) of 4-chloroquinolin-2(1H)-one precursors. Both

methods rapidly deliver bisquinolones in good to excellent yields employing controlled

microwave irradiation (MW) and are applicable not only toward the preparation of the desired

symmetrical bisquinolones but also as general methods for a symmetrical biaryl synthesis.

Several recently developed protocols for the preparation of symmetrical biaryls from

arylhalides via cross-coupling chemistry involve the use of bis(pinacolato)diboron as a

reagent.9−11 In these Pd(0)-catalyzed one-pot transformations, arylboronic esters are formed

Metal-Catalyzed Cross-Coupling and Homocoupling 14 as intermediates, which are not isolated, and undergo subsequent Suzuki coupling to directly

form the desired biaryls.9−11 The preferred catalyst for this transformation is PdCl2(dppf)

(dppf = diphenylphosphinoferrocene).9,11

2. Results and Discussion

As a starting point for the synthesis of bisquinolones 1, we investigated the one-pot

borylation/Suzuki cross-coupling of readily available 4-chloro-1-methylquinolin-2(1H)-one

2a6 as a model substrate (Table 1). All initial optimization studies were performed on a 0.25

mmol scale using automated sequential microwave processing to allow for shorter reaction

times and higher yields.10-12 An extensive optimization of the reaction parameters included

the amount of bis(pinacolato)diboron reagent, the type and the concentration of the Pd

catalyst, and the required base, solvent, reaction time, and temperature.

An initial attempt to adapt the previously reported protocols where aryl iodides,9

bromides,9,11 triflates,9 and reactive 2-chloroazaheterocycles10 have been employed as

precursors quickly demonstrated that the use of the suggested K2CO3 or KF base was not

successful. Under the published reaction conditions,9-11 only trace amounts of the desired

bisquinolone product 1a were obtained from the chloro precursor 2a, regardless of the

catalyst, solvent system and the reaction temperature. Gratifyingly, we discovered that the use

of the much stronger base KOH (4.5 equiv) in conjunction with PdCl2(dppf) as catalyst (10

mol%) provided excellent conversions (> 90%), depending on the solvent system used

(dioxane, 115 °C, 30 min).13

When several of the commonly used solvents for this type of transformation were

screened, such as DMSO, DMF or toluene, we noticed that, while the starting material was

consumed, the major reaction product with these solvents was the dehalogenated product, 1-

methylquinolin-2(1H)-one. Suitable solvents for the one-pot borylation/Suzuki cross-coupling

that minimized dehalogenation (<10 %) included dioxane, CH2Cl2, and 1,2-dichloroethane.

The best solvent identified in our studies, however, was 1-chlorobutane. Under optimized

reaction conditions (see Table 1, entry 3), full conversion to the bisquinolone 1a was achieved

within a 25 min reaction time, with only 3% of the dehalogenated product formed. It should

be noted that reducing the amount of KOH to, for example, 2.0 equiv also led to an increased

formation of the dehalogenated product.

Metal-Catalyzed Cross-Coupling and Homocoupling 15

Table 1. Catalyst/Ligand Screening for the Pd(0)-Catalyzed Bisquinolone Synthesisa

NMe

O

Cl

OB

O

O

OB

NMe

O

N OMe

2a

1a

[Pd], KOH, n-BuCl

MW, 130 °C, 30 min

entry catalyst

(mol%)

additive

(mol%)

product distribution

(%)b

1 PdCl2(dppf) (5) dppf (7) 22/61/17

2 PdCl2(dppf) (10) - 3/89/8

3 PdCl2(dppf) (10) dppf (7) 0/97/3c

4 Pd(OAc)2 (5) dppf (10) 0/92/8

5 Pd(PPh3)4 (8) - 1/91/8

6 palladacycled (2.5) dppf (10) 0/63/37

7 Pd2(dba)3 (2.5) - 0/60/40

8 Pd2(dba)3 (2.5) dppf (7) 0/84/16

9 Pd2(dba)3 (2.5) t-Bu3PHBF4

(5)

0/86/14

10 Pd2(dba)3 (2.5) PCy3 (5) 0/88/12

a Reaction conditions: 0.25 mmol chloroarene 2a, 4.5 equiv KOH, 0.7 equiv bis (pinacolato) diboron, 1.5 mL n-BuCl, sealed vessel, single mode, microwave irradiation at 130 °C for 30 min.

b Product distribution refers to relative peak area (%) ratios of crude HPLC-UV (215nm) traces: starting material/product/dehalogenated product.

c Product isolation by flash chromatography provided an 85% yield of bisquinolone 1a. d Herrmann’s palladacycle[trans-di(µ-acetato)bis[o-di-o-tolylphosphino)benzyl]dipalla- dium(II) .

Substantial efforts were made to identify the optimum catalyst, reaction temperature,

and time for this reaction (Table 1). After considerable experimentation, it was found that a

130 °C reaction temperature allowed the one-pot bisquinolone coupling to proceed within less

than half an hour. Whereas lower reaction temperatures resulted in longer reaction times,

Metal-Catalyzed Cross-Coupling and Homocoupling 16 higher temperatures produced more side and decomposition products. Among the many

catalysts tested, PdCl2(dppf) proved to be optimal. However, a 10 mol% loading of the

catalyst was required to achieve acceptable conversions. In fact, best results were obtained

upon the addition of a further amount of 7 mol% of free dppf ligand to slow catalyst

decomposition.9 Many other Pd catalyst/ligand systems proved significantly less efficient,

leading to a higher percentage of the dehalogenated product, although the use of

Pd(OAc)2/dppf or Pd(PPh3)4 furnished product yields that were also high (Table 1).

Importantly, the conversions determined by the HPLC monitoring of the crude

reaction mixtures (Table 1) nicely matched isolated product yields. From the experiment

described in entry 3, for example, an 85% yield of bisquinolone 1a was obtained after flash

chromatography. Our optimized one-pot borylation/Suzuki cross-coupling conditions were

applicable to a series of 4-chloroquinolin-2(1H)-one substrates, allowing the preparation of

various functionalized symmetrical bisquinolones (cf. Table 3).

The high costs of the required bis(pinacolato)diboron reagent and the Pd catalyst in the

above-mentioned cross-coupling protocols prompted us to explore an alternative

homocoupling method such as the Ullmann reaction,2 which would not require the use of an

additional cross-coupling partner. Among the many different available protocols for

successful bi(hetero)aryl synthesis via homocoupling methods,2-5 we were particularly

attracted by Ni-mediated reductive homocouplings, where the active Ni(0) complex is

prepared directly from an inexpensive Ni(II) salt and a reducing reagent such as Zn dust in the

presence of triphenylphosphine.2,14

As with the cross-coupling protocol, a careful optimization of the reaction conditions

with respect to the solvent, molar ratios (reagents and additives), time, and temperature was

performed for the homocoupling of chloroquinolone 2a (Table 2). Initial experiments

indicated that the general procedures for aryl halide homocouplings2,14,15 involving dry DMF

as the solvent, NiCl2 as the metal source, PPh3 as the ligand, and Zn dust as the reducing

reagent were also applicable to bisquinolone synthesis under microwave irradiation

conditions. Acceptable product yields of the homocoupled bisquinolone 1a were obtained

within 25 min at about a 205 °C reaction temperature; the only observed byproduct being

again the dehalogenated quinolone. As a result of the unreactive nature of the aryl chloride

precursor, it was necessary to use Ni in stoichiometric amounts (1.3 equiv). Lowering the

amount of Ni led to incomplete conversions. Similarly, we found that the presence of 1.3

equiv of Zn proved optimal for this transformation, with both lower and higher amounts of Zn

resulting in more dehalogenated product. Ligands such as PPh3 are essential in Ni-mediated

Metal-Catalyzed Cross-Coupling and Homocoupling 17 homocoupling reactions to stabilize the in situ generated Ni(0) catalyst and aryl Ni species

during the reaction sequence.15 In the present case, 4.0 equiv of PPh3 provided optimum

product yields.

Table 2. Effect of Iodide Additives on Ni(0)-Mediated Homocouplings of 4-

Chloroquinolonesa

NMe

O

Cl

NMe

O

N OMe

2a

1a

NiCl2, Zn, PPh3, DMFiodide additive

MW, 205 °C, 25 min

entry iodide additive

(equiv)

product distribution

(%)b

1 NaI (1.8) 0/88/12

2 KI (1.8) 1/95/4c

3 - 21/76/3

4 KI (1.0) 19/78/3

5 KI (1.6) 11/85/4

a Reaction conditions: 0.25 mmol chloroarene 2a, 1.3 equiv NiCl2, 1.3 equiv Zn dust, 4.0 equiv PPh3, iodide additive, 1.5 mL dry DMF, sealed vessel, single mode, microwave irraddiation at 205 °C for 25 min.

b Product distribution refers to relative peak area (%) ratios of crude HPLC-UV (215 nm) traces: starting material/product/dehalogenated product.

c Product isolation by flash chromatography provided a 90% yield of bisquinolone 1a.

Nevertheless, by applying the above-mentioned reagent mixtures, it proved difficult to

achieve high conversions in the desired short time frames. It is well-known that halide ions,

especially iodide, enhance the reaction rate of Ni-catalyzed homocoupling reactions.2,15 The

iodide ion is believed to function as a bridging ion between Ni and Zn in the electron transfer

process and/or as a donor ligand for the highly coordinatively unsaturated Ni(0) complex.15

The screening of several iodide sources in our model reaction finally resulted in the use of 1.8

Metal-Catalyzed Cross-Coupling and Homocoupling 18 equiv of KI as an additive (Table 2, entry 2). Under these optimized condition, the formation

of the dehalogenated byproduct could be kept to a minimum (ca. 4%), allowing the desired

bisquinolone homocoupling product 1a to be isolated in 90% yield after flash

chromatography.

Having two different optimized protocols for the efficient generation of symmetrical

bisquinolones from readily available 4-chloroquinolin-2(1H)-one substrates at hand, we next

proceeded to investigate the scope of these coupling procedures for (i) the preparation of a

variety of functionalized bisquinolones and (ii) the use of these methods as general high-

speed symmetrical biaryl coupling methods. Gratifyingly, both methods provided moderate to

excellent isolated product yields for all the quinolone systems, tested (entry 1-6, Table 3). For

the electron-rich mono- or disubstituted methoxy analogs (entry 4-6, Table 3), somewhat

higher reaction temperatures (145 °C) were applied in the cross-coupling protocol (Method A)

to achieve good yields.16 The required 4-chloroquinolone precursors were readily available

from the known 4-hydroxyquinolones by microwave-assisted chlorination using POCl3 as the

chlorinating reagent.6 For the examples displayed in Table 3, the Pd-catalyzed cross-coupling

method (Method A) proved to be somewhat more reliable, furnishing higher isolated product

yields (68-85%) as compared to those of the Ni-mediated homocoupling method (Method B,

39-90%). A clear disadvantage of the Ni method additionally lies in the required extensive

purification process, removing large quantities of the PPh3 ligand by flash chromatography.

We next attempted to synthesize 4,4′-biscoumarin starting from 4-chlorocoumarin using both

coupling methods. Biscoumarins are of considerable interest because of their physiological

properties and their presence as important structural units in a variety of biologically active

natural products (i.e., 4,4′-biisofraxidin).7 The generation of biscoumarins via cross-coupling

chemistry to our knowledge has not been reported in the literature.16,17 By changing to a

toluene/Cs2CO3 solvent/base system in the Pd-catalyzed one-pot borylation/Suzuki cross-

coupling (Method A), we achieved the preparation of 4,4′- biscoumarin in a moderate 67%

yield. The standard reaction conditions employing KOH as base furnished only very small

amounts of the desired product, presumably a result of the hydrolysis/destruction of the

sensitive coumarin heterocycle. When our base-free Ni(0)-mediated homocoupling protocol

was used, a near quantitative 98% yield of 4,4′-biscoumarin was obtained.17, 18

While both our protocols were optimized for the rather specific and comparatively

unreactive 4-chloroquinolin-2(1H)-one precursors (entry 1-6, Table 3), we were interested to

see if these procedures could also be used as general high-speed biaryl coupling methods.

Gratifyingly, we were pleased to find that both microwave-assisted coupling methods were

Metal-Catalyzed Cross-Coupling and Homocoupling 19 Table 3. Synthesis of Biaryls via Microwave-Assisted Cross- and Homocoupling of

(Hetero)aryl Chlorides and Bromides

Method A:PdCl2(dppf), [B(pin)]2, KOH, BuClMW, 130 °C, 35 min

Method B:NiCl2, Zn, PPh3, DMF, KIMW, 205 °C, 25 min

(Het)Ar-X

X = Cl, Br

(Het)Ar-Ar(Het)

entry substrate yield (%)a

Method Ab Method Bc

entry substrate yield (%)a

Method Ab Method Bc

1 NMe

O

Cl

85 90 6 NMe

O

Cl

MeO

MeO

82e 41

2 N O

Cl

68 68 7 O O

Cl

67f 98

3 N O

Cl

83d 39 8 N

Br

91e 94

4 NMe

O

ClMeO

83e 70 9 S

Br

89 65

5 NMe

O

Cl

MeO

70e 74 10 Br

91e 65

a Isolated yields of pure product. b Reaction conditions: 0.30 mmol substrate, 10 mol% PdCl2(dppf), 7 mol% dppf, 0.7 equiv bis(pinacolato)diboron, 4.5

equiv KOH, 2.0 mL n-BuCl, sealed-vessel, single-mode, microwave irradiation at 130 °C for 30 min. c Reaction conditions: 0.25 mmol substrate, 1.3 equiv NiCl2, 4.0 equiv PPh3, 1.3 equiv Zn, 1.8 equiv KI, 1.5 mL DMF,

sealed-vessel, single-mode, microwave irradiation at 205 °C for 25 min. d Reaction conditions: 10 mol% Pd(OAc)2, 20mol% dppf, 1.5 mL dioxane. e Reaction temperature: 145°C. f Reaction conditions: 6 mol% Pd(PPh3)4, 2.5 equiv CsCO3, 1.5 mL toluene.

also applicable to the more commonly used hetero(aryl) bromide substrates, such as 3-

bromoquinoline, 2-bromothiophene, and 1-bromonaphthalene (Table 3). Without any further

optimization, good to excellent yields of the corresponding bis(hetero)aryls were obtained.

Again, the Pd-catalyzed one-pot borylation/Suzuki cross-coupling conditions generally

provided somewhat higher product yields (ca. 90%) compared with those of the Ni-mediated

Ullmann homocoupling procedure.

Metal-Catalyzed Cross-Coupling and Homocoupling 20 3. Conclusion

In summary, we have developed two generally applicable high-speed methods for the

preparation of symmetrical (hetero)biaryls using either Pd(0)-catalyzed cross-coupling or

Ni(0)-mediated homocoupling principles. The procedures are particularly valuable for the

preparation of novel types of bisquinolones, which are presently under investigation as

fluorescent probes. Results from these studies will be published elsewhere. We are currently

investigating alternative catalytic cross- and homocoupling protocols to access

unsymmetrical bisquinolones.

4. Experimental Section

General Methods All cross and homocoupling reactions involving air sensitive reagents were carried out under

an atmosphere of dry argon. Dry-flash chromatography was performed on Merck Silica gel 60

H (< 45 nm particle size). TLC analyses were performed on pre-coated (Merck Silica gel 60

HF254 ) plates. 1H NMR and 13C NMR spectra were recorded on a Bruker AMX360 and 500

instrument in CDCl3 or DMSO-d6 at 360 and at 90 MHz respectively. Melting points were

obtained on a Gallenkamp melting point apparatus, Model MFB-595 in open capillary tubes.

FTIR spectra were recorded on Perkin-Elmer 298 spectrophotometer using KBr pellets. Low

resolution mass spectra were obtained on an Hewlett-Packard LC/MSD Agilent 1100 series

instrument using atmospheric pressure chemical ionization (APCI) in positive or negative

mode. Analytical HPLC analysis was carried out on two different Shimadzu systems. The

Shimadzu LC-10 includes LC10-AT(VP) pumps, an autosampler (S-10AXL), and a dual

wavelength UV detector. The separations were carried out using a C18 reversed phase

analytical column, LiChrospher 100 (E. Merck, 100 x 3 mm, particle size 5 µm) at 25 °C and

a mobile phase from (A) 0.1 % TFA in 90:10 water/MeCN and (B) 0.1 % TFA acid in MeCN

(all solvents were HPLC grade, Acros; TFA was analytical reagent grade, Aldrich). The

following gradient was applied: linear increase from solution 30 % B to 100% B in 7 min,

hold at 100% solution B for 2 min at a flow rate of 0.5-1.0 mL/min. The Shimadzu LC-20

system includes a LC-20AD pump, a SIL-20A autosampler, a diode array detector (SPD-

M20A), a column oven (CTO-20A) and a degasser (DGU-20A5). The separations were

carried out using a Pathfinder®AS100 reversed phase analytical column (150 x 4.6 mm,

Metal-Catalyzed Cross-Coupling and Homocoupling 21 particle size 5 µm) at 25 °C and a mobile phase from (A) 0.1 % TFA in 90:10 water/MeCN

and (B) 0.1 % TFA acid in MeCN (all solvents were HPLC grade, Acros; TFA was analytical

reagent grade, Aldrich). The following gradient was applied: linear increase from solution 20

% B to 100% B in 7 min, hold at 100% solution B for 2 min at a flow rate of 0.5-1.0 mL/min.

The 4-hydroxyquinolin-2-one precursors required for the preparation of

chloroquinolones 1-6 were obtained from Aurora Feinchemie GmbH. Zn-powder (Merck

108789, < 60 μm particle size) was used for the Ni(0)-mediated homocouplings. All

anhydrous solvents (stored over molecular sieves), catalysts and ligands were obtained from

standard commercial vendors and were used without any further purification. Solvents for

column chromatography have been distilled prior to use.

Microwave Irradiation Experiments

Microwave-assisted synthesis was carried out in an Emrys™ Synthesizer or Initiator 8 single-

mode microwave instrument producing controlled irradiation at 2.450 GHz (Biotage AB,

Uppsala), including proprietary Workflow Manager Software (version 2.1). Experiments were

carried out in sealed microwave microwave (2 to 5 mL filling volume) process vials utilizing

the standard absorbance level (300 W maximum power). Reaction times under microwave

conditions refer to hold times at the temperatures indicated, not to total irradiation times. The

temperature was measured with an IR sensor on the outside of the reaction vessel.

General Procedure for the Preparation of 4-Chloroquinolin-2-ones 1-6 and

4-Chlorocoumarin.2 To 1.70 mmol of corresponding 4-hydroxyquinoline-2(1H)-one or 4-hydroxycoumarin,

respectively in a microwave process vial were added 520 mg (3.40 mmol, 320 µL) of POCl3

and 2 mL of anhydrous dioxane. The mixture was stirred for 2 min at room temperature to

allow complete homogenization. The sealed vial was heated by microwave irradiation for 25

min at 120 °C. After cooling to ambient temperature, the mixture was poured onto 20 mL of

ice water. The resulting solution was neutralized with 0.5 M KOH. After stirring for 20 min,

the neutral solution was extracted with 3 x 20 mL of diethyl ether. The organic layers were

combined, washed with 2 x 50 mL of water and dried over anhydrous MgSO4. The solvent

was removed under vacuum to produce the desired 4-chloroquinoline-2(1H)-ones (entry 1-6,

Table 3) and 4-chlorocoumarin, respectively. Samples of analytical purity were obtained by

recrystallization from ethanol. The physical and spectroscopic data of the known

Metal-Catalyzed Cross-Coupling and Homocoupling 22 chloroquinolones 1 (82% yield),6 2 (65% yield),19 3 (94% yield)19 and of 4-chlorocoumarin

(56% yield after flash chromatography)19 were in good agreement with literature data.

NMe

O

ClMeO

C11H10ClNO2

4-Chloro-6-methoxy-1-methylquinolin-2(1H)-one 4.

82% yield, mp 161–163 °C (ethanol); 1H-NMR (360 MHz, CDCl3): δ 3.69 (s, 3H), 3.90 (s,

3H), 6.90 (s, 1H), 7.24 (dd, J = 2.75 and 9.19 MHz, 1H), 7.32 (d, J = 9.20 Hz, 1H), 7.14 (d, J

= 2.73 Hz, 1H); 13C NMR (90 MHz, CDCl3)δ 29.7, 55.7, 107.8, 115.9, 120.0, 120.6, 121.4,

134.3, 143.5, 155.1, 160.5; MS (pos. APCI) m/z 223 (100, M), 188 (54, M – 35). Anal. Calcd.

for C11H10ClNO2: C, 59.07; H, 4.51; N, 6.26. Found: C, 59.04; H, 4.43; N, 6.05.

NMe

O

Cl

C11H10ClNO2MeO

4-Chloro-7-methoxy-1-methylquinolin-2(1H)-one 5.

77% yield, mp 123–125 °C (ethanol); 1H-NMR (360 MHz, CDCl3): δ 3.66 (s, 3H), 3.90 (s,

3H), 6.74 (s, 1H), 6.79 (s, 1H), 6.89 (d, J = 8.90 Hz, 1H), 7.91 (d, J = 8.90 Hz, 1H); 13C NMR

(90 MHz, CDCl3) δ 29.7, 55.7, 98.8, 110.1, 113.4, 117.8, 127.8, 141.4, 144.3, 161.5, 162.7;

MS (pos. APCI) m/z 223 (100, M), 188 (54, M – 35). Anal. Calcd. for C11H10ClNO2: C,

59.07; H, 4.51; N, 6.26. Found: C, 59.03; H, 4.57; N, 6.20.

NMe

O

Cl

C12H12ClNO3MeO

MeO

4-Chloro-6,7-dimethoxy-1-methylquinolin-2(1H)-one 6.

64% yield, mp 219–220 °C (ethanol); 1H-NMR (360 MHz, DMSO-d6): δ 3.63 (s, 3H), 3.85 (s,

3H), 3.96 (s, 3H), 6.74 (s, 1H), 7.03 (s, 1H), 7.27 (s, 1H); 13C NMR (90 MHz, DMSO-d6) δ

30.1, 56.6, 70.1, 99.0, 106.4, 111.5, 117.7, 135.9, 142.7, 145.6, 153.5, 160.2; MS (pos. APCI)

m/z 253 (100, M), 219 (47, M – 34). Anal. Calcd. for C12H12ClNO3: C, 56.82; H, 4.77; N,

Metal-Catalyzed Cross-Coupling and Homocoupling 23 5.52. Found: C, 56.83; H, 4.70; N, 5.41.

General Procedure for the One-Pot Borylation/Suzuki Cross Couling of

Haloarenes (Method A, Table 3). A mixture containing 0.30 mmol of the corresponding haloarene (Table 3), 24.5 mg (0.03

mmol, 10 mol%) of PdCl2(dppf), 11.6 mg (0.021 mmol, 7 mol%) of dppf, 53.3 mg (0.21

mmol, 0.7 equiv) of bis(pinacolato)diboron and 75.7 mg (1.35 mmol, 4.5 equiv) of finely

crushed KOH powder (analytical grade) was suspended in 2.0 mL of anhydrous 1-

chlorobutane under an argon atmosphere in a 5 mL microwave vial (Pyrex) equipped with a

magnetic stirring bar. The vial was sealed, stirred for 4 min at room temperature, and then

heated for 35 min at 130 °C (see Table 3 for deviations). Thereafter, the solvent was removed

under reduced pressure. The product was directly isolated by gradient dry flash

chromatography, using appropriate solvents. For yields, see Table 3.

General Procedure for the Homocoupling of Haloarenes (Method B, Table

3). A mixture containing 0.25 mmol of the corresponding haloarene (Table 3), 42.1 mg (0.325

mmol, 1.3 equiv) of anhydrous NiCl2, 262.3 mg (1 mmol, 4.0 equiv) of PPh3, 21.2 mg (0.324

mmol, 1.3 equiv) of Zn powder (<60 µm particle size), and 74.7 mg (0.45 mmol, 1.8 equiv) of

KI was dissolved in 1.5 mL anhydrous DMF under an argon atmosphere in a 5mL microwave

vial (Pyrex) equipped with a magnetic stirring bar. The vial was sealed, stirred for 4 min at

room temperature, and then heated for 25 min at 205 °C. Thereafter, the solvent was removed

under reduced pressure. The product was isolated by gradient dry flash chromatography,

using appropriate solvents. For yields, see Table 3.

NMe

O

N OMe

C20H16N2O2

4,4´-Bis-(1-methylquinolin-2(1H)-one) (Table 3, entry 1).

Metal-Catalyzed Cross-Coupling and Homocoupling 24 Mp 283-284°C (acetonitrile). IR (KBr) νmax 1648 cm-1; 1H NMR (360 MHz, DMSO-d6) δ

3.71 (s, 6H), 6.67 (s, 2H), 7.11-7.17 (m, 4H), 7.64-7.67 (m , 4H); 13C NMR (90 MHz,

DMSO-d6) δ 29.8, 115.8, 119.6, 121.6, 122.7, 127.3, 131.8, 140.2, 146.1, 160.9; MS (pos.

APCI) m/z 317 (25, M + 1), 316 (100, M). Anal. Calcd for C20H16N2O2: C, 75.93; H, 5.10; N,

8.86. Found: C, 75.95; H, 4.98; N, 8.78.

N O

N O

C24H20N2O2

7,7´-Bis-(2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one) (Table 3, entry 2).

Mp 270°C dec. (acetonitrile); IR (KBr) νmax 1637 cm-1; 1H NMR (360 MHz, DMSO-d6) δ

2.02-2.13 (m, 4H), 2.99 (t, J = 5.8 Hz, 4H), 4.13 (t, J = 5.6 Hz, 4H), 6.62 (s, 2H), 6.96 (d, J =

7.6 Hz, 2H), 7.02 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 6.98 Hz, 2H); 13C NMR (90 MHz, DMSO-

d6) δ 20.6, 27.8, 42.6, 119.7, 121.4, 121.9, 125.3, 125.4, 130.5, 136.8, 146.4, 161.2; MS (pos.

APCI) m/z 368 (100, M).

N O

N O

C30H20N2O2

4,4´-Bis-(1-phenylquinolin-2(1H)-one) (Table 3, entry 3).

Mp > 400°C dec. (CCl4); IR (KBr) νmax 1661 cm-1; 1H NMR (360 MHz, CDCl3) δ 6.81 (d, J

= 8.4 Hz, 2H), 6.91 (s, 2H), 7.14 (t, J = 7.57 Hz, 2H), 7.38-7.45 (m, 8H), 7.60 (t, J = 7.36 Hz,

2H), 7.68 (t, J = 7.62 Hz, 4H); 13C NMR (90 MHz, CDCl3) δ 116.6, 119.4, 122.4, 122.6,

127.0, 128.9, 129.2, 130.4, 130.9, 137.4, 141.2, 147.0, 161.5; MS (pos. APCI) m/z 441 (25, M

+ 1), 440 (100, M).

Metal-Catalyzed Cross-Coupling and Homocoupling 25

NMe

O

N OMe

MeOMeO

C22H20N2O4

4,4´-Bis-(6-methoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 4).

Mp 256-258°C (ethanol); IR (KBr) νmax 1648 cm-1; 1H NMR (360 MHz, DMSO-d6) δ 3.58 (s,

6H), 3.69 (s, 6H), 6.57 (d, J = 2.8 Hz, 2H), 6.66 (s, 2H), 7.34 (dd, J = 9.25 and 2.8 Hz, 2H),

7.62 (d, J = 9.29 Hz, 2H); 13C NMR (90 MHz, DMSO-d6) δ 29.8, 55.8, 110.0, 115.9, 119.4,

120.4, 122.5, 134.7, 145.5, 154.8, 161.1; MS (pos. APCI) m/z 377 (25, M + 1), 376 (100, M).

NMe

O

N OMe

MeO

MeO

C22H20N2O4

4,4´-Bis-(7-methoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 5).

Mp 232-234°C (ethanol); IR (KBr) νmax 1658 cm-1; 1H NMR (360 MHz, DMSO- d6) δ 3.67 (s,

6H), 3.89 (s, 6H), 6.45 (s, 2H), 6.76 (d, J = 8.67 Hz, 2H), 7.04-7.07 (m, 4H); 13C NMR (90

MHz, CDCl3) δ 29.8, 56.2, 99.7, 110.8, 113.5, 117.9, 128.8, 142.0, 146.3, 161.5, 162.3; MS

(pos. APCI) 377 (25, M + 1), 376 (100, M). Anal. Calcd for C22H20N2O4: C, 70.20; H, 5.36;

N, 7.44. Found: C, 70.23; H, 5.26; N, 7.37.

NMe

O

N OMe

MeO

MeO

C24H24N2O6

MeOMeO

4,4´-Bis-(6,7-dimethoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 6).

Mp 276-277 °C dec. (ethanol); IR (KBr) νmax 1642 cm-1; 1H NMR (360 MHz, DMSO-d6) δ

3.45 (s, 6H), 3.74 (s, 6H), 3.96 (s, 6H), 6.46 (s, 2H), 6.57 (s, 2H), 7.09 (s, 2H); 13C NMR (90

Metal-Catalyzed Cross-Coupling and Homocoupling 26 MHz, CDCl3) δ 30.0, 56.2, 56.4, 97.6, 108.2, 112.7, 119.1, 136.1, 145.2, 145.8, 152.8, 162.0;

MS (pos. APCI) m/z 437 (50, M + 1), 436 (100, M).

O O

O O

C18H10O4

4,4´-Bis-(2H-chromen-2-one) (Table 3, entry 7).

Mp 215-216°C (acetonitrile; lit.20 Mp 215 °C); 1H NMR (360 MHz, CDCl3) δ 6.50 (s, 2H),

7.22-7.24 (m, 4H), 7.47 (d, J = 8.42 Hz, 2H), 7.60-7.65 (m, 2H). MS (pos. APCI) m/z 291

(95, M + 1), 290 (45, M), 252 (100, M – 38), 236 (M – 54).

NC18H12N2N

3,3´-Bisquinoline (Table 3, entry 8).

Mp 269-271°C (ethanol) (lit.21 Mp 271 °C); 1H NMR (360 MHz, CDCl3) δ 7.70 (t, J = 7.25

Hz, 2H), 7.85 (t, J = 7.42 Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H), 8.29 (d, J = 8.4 Hz, 2H), 8.57 (s,

2H), 9.33 (s, 2H). MS (pos. APCI) m/z 257 (20, M + 1), 256 (100, M).

C8H6S2S S

2,2´-Bisthiophene (Table 3, entry 9).

Mp 30-32 °C (diethyl ether) (lit.22 Mp 32-34 °C); 1H NMR (360 MHz, CDCl3) δ 7.02 (dd, J =

3.70 and 4.96 Hz, 2H), 7.19-7.24 (m, 4H). MS (pos. APCI) m/z 166 (100, M).

C20H14

1,1´-Bisnaphthalene (Table 3, entry 10).

Mp 158-159 °C (acetone) (lit.23,24 Mp 158.8-159 °C); 1H NMR (360 MHz, CDCl3) δ 7.29-7.32

Metal-Catalyzed Cross-Coupling and Homocoupling 27 (m, 2H), 7.40 (d, J = 8.38 Hz, 2H), 7.47-7.52 (m, 4H), 7.59-7.63 (m, 2H), 7.96 (dd, J = 2.97,

8.13 Hz, 4H).

Metal-Catalyzed Cross-Coupling and Homocoupling 28 5. References

[1] For reviews on biaryls, see: (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.;

Lemaire, M. Chem. Rev. 2002, 102, 1359. (b) Shimizu, H.; Nagasaki, I.; Saito, T.

Tetrahedron 2005, 61, 5405. (c) Bringmann, G.; Price Mortimer, A. J.; Keller, P.

A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005, 44, 5384.

[2] Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265.

[3] (a) Leadbeater, N. E.; Resouly, S. M. Tetrahedron Lett. 1999, 40, 4243. (b) Tiecco,

M.; Tingoli, M.; Testaferri, L.; Bartoli, D.; Chianelli, D. Tetrahedron 1989, 45,

2857.

[4] (a) Colon, I.; Kelsey, D. R. J. Org. Chem. 1986, 51, 2627. (b) Hassan, J.; Lavenot,L.;

Gozzi, Lemaire, M. Tetrahedron Lett. 1999, 40, 857.

[5] Grigg, R.; Johnson, R. W. J. Chem. Soc. 1964, 3315.

[6] Glasnov, T. N.; Stadlbauer, W.; Kappe, C. O. J. Org. Chem. 2005, 70, 3864.

[7] (a) Pharkphoom, P.; Hiroshi, N.; Wanchai, D. E. Planta Med. 1998, 64, 774. (b) Lei,

J.-G.; Lin, G.-Q. Chin. J. Chem. 2002, 20, 1263.

[8] (a) Strohmeier, G.; Fabian, W. M. F.; Uray, G. Helv. Chim. Acta 2004, 87, 215. (b)

Lee, H.-K.; Cao, H.; Rana, T. M. J. Comb. Chem. 2005, 7, 279.

[9] (a) Nising, C. F.; Schmid, U. K.; Nieger, M.; Bräse, S. J. Org. Chem. 2004, 69,6830.

See also: (b) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997, 38, 3841. (c)

Ishiyama, T.; Murata, M.; Miyaura, N.; J. Org. Chem. 1995, 60, 7508. (d) Ishiyama,

T.; Itoh, Y.; Kitano, T.; Miyaura, N.; Tetrahedron Lett. 1997, 38, 3447.

[10] De Borggraeve, W. M.; Appukkuttan, P.; Azzam, R.; Dehaen, W.; Comper- nolle,F.;

Van der Eycken, E.; Hoornaert, G. Synlett 2005, 777.

[11] Melucci, M.; Barbarella, G.; Zambianchi, M.; Di Pietro, P.; Bongini, A. J. Org.

Chem. 2004, 69, 4821.

[12] Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.

[13] The effect of stronger bases such as KOH probably lies in their stronger

nucleophilicity. For a detailed description of the reaction mechanism in these biaryl

formations and the role of the base, see ref. 9.

[14] (a) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.; Montanucci, M. Synthesis

1984, 736. (b) Ford, A.; Sinn, E.; Woodward, S. J. Chem. Soc., Perkin Trans. 1

1997, 927. (c) For a recent report on iron-catalyzed homo- couplings, see: Cahiez,

G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M. Org. Lett. 2005, 7, 1943.

Metal-Catalyzed Cross-Coupling and Homocoupling 29 [15] (a) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995, 60, 176. (b)

Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060.

[16] Beletskaya, I. P.; Ganina, O. G.; Tsvetkov, A. V.; Fedorov, A. Y.; Finet, J.-P. Synlett

2004, 2797.

[17] For Suzuki and related cross-coupling reactions involving 4-sulfonyloxysubstituted

coumarins, see: (a) Boland, G. M.; Donnelly, D. M. X.; Finet, J.-P.; Rea, M. D. J.

Chem. Soc., Perkin Trans. 1 1996, 2591. (b) Donnelly, D. M. X.; Finet, J.-P.; Guiry,

P. J.; Rea, M. D. Synth. Commun. 1999, 29, 2719. (c) Yao, M.-L; Deng, M.-Z.

Heteroat. Chem. 2000, 11, 380. (d) Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001,

66, 3642.

[18] For Ni-catalyzed homocouplings of 4-sulfonyloxy-substituted coumarins, see: Lei,

J.-G.; Xu, M.-H.; Lin, G.-Q. Synlett 2004, 2364.

[19] Stadlbauer, W. Monats. Chem. 1986, 117, 1305.

[20] Deshmukh, R. S. K.; Paradkar, M. V. Synth. Commun. 1988, 18, 589.

[21] (a) Uyeda, K. J. Pharm. Soc. Jpn. 1931, 51, 495. (b) Chem. Abstr. 1931, 25, 5427.

[22] Nishihara, Y.; Ikegashira, K.; Toriyama, F.; Mori, A.; Hiyama, T. Bull. Chem. Soc.

Jpn. 2000, 73, 985.

[23] Ibuki, E.; Ozasa, S.; Fujioka, Y.; Mizutani, H. Bull. Chem. Soc. Jpn. 1982, 55, 845.

[24] Collet, A.; Brienne, M. J.; Jacques, J. Bull. Chem. Soc. Jpn. 1972, 1, 127.

Nickel(0)-Catalyzed Homocoupling Reaction 30 C Symmetrical Bisquinolones via Nickel(0)-Catalyzed

Homocoupling of 4-Chloroquinolones

Graphical Abstract

NR1

O

Cl

N OR1

NOR1

0.25 equivs. NiCl2(PPh3)20.25 equivs. DPEphos

1.3 equivs. Zn, 1.8 equivs. KI

dioxane, MW, 130 °C, 30 min

R4

R3

R2

R2

R3

R4

R4

R3

Abstract

A method for the gram-scale preparation of functionalized 4,4´-bisquinolones using a

microwave-assisted Ullmann-type homocoupling reaction is described. The method is catalytic

in nickel(0) which is generated in situ by reduction from an inexpensive Ni(II) source and

utilizes readily available 4-chloroquinolin-2(1H)-ones as starting materials. In contrast to the

alternative palladium(0)-catalyzed one-pot borylation/Suzuki cross-coupling reaction, the new

method avoids the use of an expensive catalyst and cross-coupling partner such as

bis(pinacolato)diboron.

Nickel(0)-Catalyzed Homocoupling Reaction 31 1. Introduction

The structural sub-unit of symmetrical biaryls plays an important role in organic and medicinal

chemistry, and is found in a wide variety of natural products including alkaloids such as the

anti-HIV alkaloid michellamine B,[1] coumarins (4,4´-biisofraxidin),[2] polyketides[3] and

terpenes (Figure 1).[4] Compounds incorporating symmetrical biaryl moieties also find

applications as conductors for thin film transistor (e.g., 2,2′-bidithieno[3,2-b:2′,3′-d] thio-

phene),[5] as electronic and optoelectronic materials (e.g., indenofluorenes),[6] as chiral ligands

in catalysis (e.g., BINAP)[7] and in chiral or achiral liquid crystals (e.g., paracyclophanes).[8]

The biaryl subunit also constitutes an important structural motif in several pharmaceuticals

(e.g., in the laxative agent 4,4′-biphenol),[9] and in agrochemicals (e.g., in the non-selective

broad-spectrum herbicide Paraquat).[10] Related biaryl heterocycles are also well known in the

literature and often display similarly interesting biological and physical properties.[11]

O

O O

OO

O O

O

O O

S SS

S

S

S

PPh2PPh2

BINAPNH

OH

Me

OMeOH

OHOMe

Me

HN

OHMe

Me

Me OH

MeHO

OHHO N NMe Me

2 Cl

Michellamine B indenofluorenes

2,2´-bidithieno[3,2-b:2 ,́3 -́d]thiophene 4,4 -́biphenol Paraquat

++

_

paracyclophanes

Figure 1. Important symmetrical biaryl products.

In view of the substantial interest and broad application of symmetrical biaryls,[1-11]

considerable efforts have been undertaken to achieve efficient, economical, safe, and

Nickel(0)-Catalyzed Homocoupling Reaction 32 environmentally benign methods for their preparation in many academic and industrial

laboratories.[12] Since the first biaryl couplings performed by Ullmann over a century ago

applying stoichiometric amounts of copper metal,[13] the catalytic use of transition metals,

especially of palladium and nickel, in the formation of symmetrical biaryls is now well

established.[12] In this context we recently reported the first synthesis of 4,4′-bisquinolones of

type 1.[14] These novel, symmetrical bis-heterocycles are of considerable interest as aza-

analogues of biscoumarin natural products (e.g., 4,4′-biisofraxidin),[2] because of their

anticipated fluorescent properties as push–pull carbostyrils (1, R3 = R4= OMe),[15] and as

starting materials for the synthesis of novel aza-BINAP analogs (Figure 2).[16]

N OR1R2

R3

R4

NOR1 R2

R3

R4

O OOMe

OO OH

OMe

OMe

HO

MeO

N OR1

PPh2

N

Ph2P

OR1

4,4'-biisofraxidin1; R1 = Me, Ph; R2 = H, alkylR3 = R4 = H, OMe

"aza-BINAP"

R3

R4

R4

R3

Figure 2. 4,4′-Bisquinolones and 4,4′-biscoumarins.

In our recent publication we have outlined the generation of 4,4′-bisquinolones 1,

employing both a palladium(0)-catalyzed one-pot borylation/Suzuki cross-coupling method,

and a nickel(0)-mediated homocoupling protocol using the corresponding 4-chloroquinolin-

2(1H)-ones 2 as precursors.[14] Both methods did in fact allow the successful, high-yielding

preparation of a variety of bisquinolones of type 1, in addition to 4,4′-biscoumarin and a range

of other symmetrical bi(hetero)aryls. However, both procedures have severe disadvantages

that make them impractical for a larger scale synthesis required for our purposes: most

prominently, the borylation/Suzuki approach relied on the use of the rather expensive

bis(pinacolato)diboron cross-coupling reagent[17] and additionally required 10 mol% of the

costly palladium/ligand source PdCl2(dppf).[17] While the alternative homocoupling method

avoids the use of a cross-coupling partner and therefore appeares to be more favorably from

the standpoint of atom economy,[18] our original nickel-mediated method utilized

stoichiometric amounts of a nickel(II) source (1.3 equivalents of NiCl2) and required 4

Nickel(0)-Catalyzed Homocoupling Reaction 33 equivalents of triphenylphosphine as ligand.[14] The subsequent complex chromatographic

separation of the desired product from triphenylphosphine and its oxide impurity in fact only

allowed the preparation of quantities of bisquinolones 1 on a less than 50-mg scale.[19] We now

report an improved method for the homocoupling of 4-chloroquinolin-2(1H)-one 2 (see Table

1, Table 2 and Table 3) that utilizes a comparatively inexpensive combination of a nickel

catalyst [25 mol% of NiCl2(PPh3)2] and an additional bidentate ligand (25 mol% of

DPEphos).[17] Importantly, using this method good isolated product yields can be obtained

without purification by chromatography, allowing the preparation of bisquinolones 1 in gram-

scale quantities.

2. Results and Discussion

The main problem in the reported cross- and homocouplings involving 4-chloroquinolin-

2(1H)-ones[14] lies in the fact that these heteroaryl chlorides are comparatively unreactive as

coupling partners. It is well known that aryl chlorides, despite the fact that those substrates

would generally be the most useful ones because of their low cost and the wide availability,[20]

are comparatively unreactive as coupling partners in transition metal-catalyzed processes when

compared to aryl bromides and iodides.[20] General and efficient protocols employing aryl

chlorides as starting materials in such transformations have only recently emerged in the

literature.[20-23] The low reactivity of aryl chlorides is usually attributed to the strength of the

C-Cl bond (bond dissociation energies for Ph-X: Cl = 96 kcal mol-1; Br = 81 kcal mol-1; I = 65

kcal mol-1) which leads to a reluctance of aryl chlorides toward oxidative addition to transition

metal centers, a critical step in many transition metal-catalyzed coupling reactions.[20]

In our original nickel-mediated reductive homocoupling, the active nickel(0) complex

was generated from a nickel(II) salt and Zn dust as reducing agent in the presence of

triphenylphosphine as ligand.[14] In order to simplify and possibly to improve this procedure

we have now considered the direct use of a nickel(0) source. The successful use of the

commercially available zerovalent nickel complex Ni(COD)2 (COD = 1,5-cyclooctadiene) in

related homocoupling reactions of aryl bromides or iodides (Scheme 1)[24,25] prompted us to

apply these conditions also to the homocoupling of 4-chloro-1-methylquinolin-2-(1H)-one 2a

as a model substrate (Table 1).[24,25]

Nickel(0)-Catalyzed Homocoupling Reaction 34 Table 1. Reaction optimization for the nickel(0)-mediated reductive homocoupling of 4-

chloroquinolone 2a using Ni(COD)2.[a]

NMe

O

Cl

NMe

O

N OMe

2a

1a

Ni(COD)2, 2,2'-dipyridyl, solvent, KI

MW,120-195 °C, 25-35 min

entry Ni(COD)2

(equiv)

2,2´-dipyridyl

ligand (equiv)

KI additive

(equiv)

time [min] solvent / temp

[°C]

product

distribution

(%)[b]

1 0.50 1.0 - 25 DMF / 195 40/52/8

2 0.75 1.0 - 25 DMF / 195 0/97/3

3 0.75 - - 25 DMF / 195 20/75/5

4 0.75 1.0 - 35 dioxane / 130 10/90/0

5 0.75 1.0 0.5 35 dioxane / 130 0/99/1c

6 0.75 0.5 0.5 35 dioxane / 130 5/94/1

7 0.75 1.0 0.5 35 THF / 120 9/80/11

8 0.75 1.0 0.5 55 DMSO / 160 17/73/10 [a] Reaction conditions: 0.25 mmol chloroquinolone 2a, Ni(COD)2, 2,2´-dipyridyl, KI, 1.5 mL dry solvent, sealed vessel

single mode microwave irradiation. See the Experimental Section for further information. [b] Product distribution refers to relative peak area (%) ratios of crude HPLC-UV (215 nm) traces: starting material 2a

/product 1a/dehalogenated product. [c] Product isolation by filtration through Celite, evaporation, and subsequent recrystallization furnished a 93% yield of

bisquinolone 1a.

All optimization studies were performed on a 0.25 mmol scale using sealed vessel

microwave heating in order to extend the available temperature range above the boiling point

of the individual solvent.[27] An extensive optimization of the reaction parameters included the

amount of the nickel reagent, the type and concentration of additional ligands, the use of other

additives, different solvents, reaction time and temperature. While aryl bromides and iodides

have been shown to undergo this type of coupling of this type with relative ease,[24,25] only one

example of a reductive homocoupling which involves an aryl chloride is known, providing a

mere 14% product yield.[24] In these transformations, the oxidative addition generally is the

rate-limiting step (Scheme 1). Aryl halides which have comparatively small dissociation

energies (e.g., aryl iodides) will undergo faster oxidative addition to the metal center and

Nickel(0)-Catalyzed Homocoupling Reaction 35

L = solvent or COD- 2 L

LnNi(0) + ArX [LnNi ][ArX] Ni(I)X+ Ar

Ni(I)X + ArX ArNi(III)X2

ArNi(III)X2 + ArNi(III)X2 Ar2Ni(III)X + Ni(II)X2

Ar2Ni(III)X Ar-Ar + Ni(I)X

ArX + L4Ni(0) Ni(II)

X

Ar L

Lox. add.

Ni(II)

X

Ar L

L

+ ArX [ArNi(III)XL2] [ArX]chain start

chainpropagation

Scheme 1. Proposed mechanism of Ni(0)-mediated homocouplings of aryl halides using Ni(0)

species.[26]

ultimately will show a higher reactivity in the reductive homocoupling.[24] Since there is no

regeneration mechanism in this homocoupling, (stoichiometric amounts of Ni(COD)2 have

to be employed in order to achieve full conversion. In the case of 4-chloro-1-methylquinolin-

2-(1H)-one 2a the use of 0.75 equivs. of the sensitive Ni(COD)2 reagent (1.5 equivs. per biaryl

product) provided the best results. Lowering the amount of Ni(COD)2 led to incomplete

conversions (Table 1, entry 1), with the only observed by-product being the dehalogenated

quinolone.[14] Nickel(0)-mediated homocoupling reactions routinely rely on additional

ligands,[12,24-26,28] which stabilize the catalyst and the arylnickel species during the reaction

sequence and restrict decomposition. In the present case, 1.0 equivalent of 2,2′-dipyridyl

exhibited an optimum effect on the observed conversion (compare entries 2 and 3). Close to

quantitative conversions were observed by heating the reaction mixture in DMF at 195 °C for

25 min. Under these conditions, only very small amounts of the dehalogenated side-product,

1-methylquinolin-2-(1H)-one, were observed by HPLC monitoring. Ultimately, we found that

optimum results were achieved by switching to anhydrous dioxane as a solvent, which allowed

reduction of the reaction temperature to 130 °C. Further improvements were made by adding

0.5 equivalents of potassium iodide as an additive since it is known that iodide ions enhance

the reaction rate of nickel-catalyzed homocoupling reactions (compare entries 4 and 5).[28]

Under optimized reaction conditions (Table 1, entry 5), full conversion to bisquinolone 1a was

Nickel(0)-Catalyzed Homocoupling Reaction 36 observed within a 35 min reaction time with only 1% of the dehalogenated by-product formed.

Gratifyingly, product isolation in this case did not require chromatography and simply

involved filtration through a Celite pad, evaporation of solvent, and recrystallization of the

crude product from acetonitrile to provide a 93% isolated product yield of the desired

bisquinolone 1a. This protocol could be scaled to 1.0 mmol to provide 1a in ca. 100 mg

quantity. Despite this fact, the high cost and pronounced air sensitivity of the Ni(COD)2

reagent,[17] employed in almost stoichiometric amounts, precluded this method from being

used for the preparation of larger quantities of bisquinolones.

OPPh2 PPh2

PPh2

Ph2PFe

DPEphos dppf

Figure 3. Structures of bidentate ligands DPEphos and dppf.

We therefore turned our attention again to our original reductive homocoupling

protocol starting from a nickel(II) source in the hope to turn the stoichiometric method into a

catalytic version that would require less metal, and therefore also a smaller amount of the

reducing agent and, most importantly, less ligand which would greatly simplify the

purification process and thus make this method scalable. A number of examples involving the

Ni-mediated homocoupling of aryl chlorides to biphenyls have been reported in the

literature.[29,30] In this context, several sources of nickel(II) were evaluated under the originally

reported in situ reductive conditions using zinc dust.[14 In addition, in light of the results

obtained with Ni(COD)2, the solvent system was changed from DMF to dioxane. In our

originally reported protocol requiring stoichiometric amounts of an Ni source using DMF as

solvent,[14] we assume that the reductive elimination step is not favorable, therefore not

allowing the regeneration of the active Ni(0) species. The use of DMF or other coordinating

dipolar aprotic solvents will likely lead to de-coordination of ligands from the Ni(0) complex

and to the formation of undesired side products.[30] Employing dioxane as solvent, most of the

tested nickel(II) salts/complexes such as NiCl2, NiCl2(PPh3)2, NiCl2(dppe), NiCl2(dppf) and

Ni(acac)2 were effective in the desired homocoupling (Table 2). In all cases the only by-

product was the dehalogenated quinolone. By adding an additional amount of a bidentate

Nickel(0)-Catalyzed Homocoupling Reaction 37 Table 2. Catalyst/ligand screening for the nickel(0)-mediated reductive homocoupling of 4-

chloroquinolone using Ni(II) complexes.[a]

NMe

O

Cl

NMe

O

N OMe

2a

1a

Ni-catalyst, ligand, dioxane, Zn, KI

MW, 130 °C, 30 min

[a] Reaction conditions: 0.25 mmol chloroarene 2a, Ni-catalyst, ligand, 1.3 equivs. Zn dust, 1.8 equivs. KI, 1 mL dry dioxane, sealed vessel single mode microwave irradiation at 130 °C for 30 min.

entry catalyst (mol%) additive (mol%) Product

distribution(%)[b]

1 NiCl2(PPh3)2 (10) dppf (20) 0/61/39

2 NiCl2(PPh3)2 (20) dppf (10) 0/87/13

3 NiCl2(PPh3)2 (20) dppf (20) 0/91/9[c]

4 NiCl2(dppe) (20) dppf (20) 0/68/32

5 NiCl2(dppf) (25) dppf (25) 0/71/29

6 Ni(acac)2 (25) dppf (25) 1/65/34

7 NiCl2(PPh3)2 (25) DPEphos (25) 0/91/9[d]

[b] Product distribution refers to relative peak area (%) ratios of crude HPLC-UV (215 nm) traces: starting material 2a /product 1a/ dehalogenated product.

[c] Product isolation by flash chromatography provided a 86% yield of bisquinolone 1a. [d] For an 11-mmol run, product isolation by an extractive work-up and recrystalliza-tion led to 74%

yield of isolated pure product.

ligand (see mechanistic discussion below), such as bis(2-diphenylphosphinophenyl)ether

(DPEphos) or diphenylphosphinoferrocene (dppf) (Figure 3) to the reaction mixture, the

amount of the required nickel(II) complex could be reduced to 20 mol% and the

dehalogenation pathway could be largely suppressed (entries 3 and 7).

One of the best sets of conditions (entry 3) employed 20 mol% of NiCl2(PPh3)2 as

Ni(II) complex and 20 mol% of dppf as ligand employing the traditional reductive

environment (1.3 equivs. Zn dust, 1.8 equivs. KI). Microwave heating of the reaction mixture

at 130 °C for 30 min provided full conversion to the bisquinolone product with less than 10%

of the dehalogenated by-product being formed (86% isolated yield by flash chromatography).

Equally high selectivity and efficiency toward homocoupling was displayed employing

DPEphos as a ligand system, albeit using a 25 mol% catalyst and ligand loading (entry 7).

Nickel(0)-Catalyzed Homocoupling Reaction 38

While both methods required only 0.20-0.25 equivs. of the relatively inexpensive

nickel(II) complex NiCl2(PPh3)2 as catalyt,[17] the true advantage lies in the fact that here

chromatography is not required to separate triphenylphosphine and the additional

dppf/DPEphos ligands from the bisquinolone product. Notably, the use of DPEphos (entry 7)

provides equally high conversions as dppf (entry 3), but is the ligand of choice due to the

significantly lower cost.[17] We have therefore performed a ca. 40-fold scale-up of the

experiment described in entry 7 employing 11 mmol of chloroquinolone 2a as starting

material employing a larger microwave process vial (11-mL reaction volume). Gratifyingly,

monitoring the crude reaction mixture by HPLC demonstrated the full scalability of this

process: again, less then 10% of the unwanted dehalogenated quinolone was observed, with

HPLC traces being nearly indentical to those of the small scale experiment. In the purification

procedure, the dioxane solvent was evaporated under reduced pressure. After addition of

acetonitrile and warming to ca. 80 °C the crude reaction mixture was filtered through a pad of

Celite. Since DPEphos is nearly insoluble under those conditions, most of the ligand material

could be removed. Evaporation of the acetonitrile solvent furnished the crude bisquinolone

product which was subsequently dissolved in dichloromethane and washed three times with

saturated aqueous ammonium chloride solution. Evaporation of dichloromethane and

recrystallization of the crude material from acetonitrile provided bisquinolone 1a in 74% yield

(purity > 99% by HPLC at 215 nm).

In order to evaluate the general applicability of this homocoupling protocol, a number

of different 4-chloroquinolone substrates (in addition to 4-chlorocoumarin)[14] were subjected

to the optimized coupling protocol outlined above (Table 2). Utilizing the optimized catalytic

method detailed in Table 2 (entry 7), all substrates did undergo homocoupling to the respective

biaryl derivatives in >98% conversion and with very high selectivity. The amount of

dehalogenated by-products in most cases was below 5%. In fact, we find that this new protocol

involving catalytic amounts of NiCl2(PPh3)2 in combination with DPEphos as ligand provides

equally high isolated product yields (71-92%) compared to our previously published method

employing stoichiometric amounts of a Ni(II) source.[14] In most cases, the extractive work-

up/purification elaborated above specifically for bisquinolone 1a was also successful for other

biaryl derivatives, although the isolated yields using this non-chromatographic method were

not always as high as when using standard flash chromatography (Table 3).

Nickel(0)-Catalyzed Homocoupling Reaction 39 Table 3. Nickel(0)-mediated reductive homocoupling of 4-chloroquinolone using

NiCl2(PPh3)2 and DPEphos.[a]

NiCl2(PPh3)2, DPEphos, Zn, KIdioxane

MW, 130 °C, 30 min(Het)Ar-Cl (Het)Ar-Ar(Het)

2 1

entry substrate yield [%][b]

1

NMe

O

Cl

85 (69)

2

N O

Cl

92 (39)

3

NMe

O

ClMeO

71 (−)[c]

4

NMe

O

Cl

MeO

79 (45)

5

NMe

O

Cl

MeO

MeO

83 (34)

6

O O

Cl

92 (73)

[a] Reaction conditions: 0.50 mmol chloroarene 2, 25 mol% NiCl2(PPh3)2, 25mol% DPEphos, 1.3 equivs. Zn dust, 1.8 equivs. KI, 0.8 mL dry dioxane, sealed vessel single mode microwave irradiation at 130 °C for 30 min.

[b] Isolated yields of pure product using flash chromatography. In parenthesis, isolated yields obtained by extractive work-up and recrystallization (see Experimental Section).

[c] Due to the insolubility of this material in acetonitrile, the extraction procedure was not successful in this case.

Nickel(0)-Catalyzed Homocoupling Reaction 40 3. Mechanistic Discussion

It is known that bidentate ligands such as dppf (Figure 3) increase the electron density on low-

valent transition metals, making the metal more nucleophilic, thus facilitating the oxidative

additionand reducing the propensity for reductive elimination.[26,31] The use of NiCl2(dppf) in

the presence of an additional amount of dppf (Table 2, entry 5) may lead to the formation of a

rather stable coordinatively saturated Ni(0) ligand complex (Figure 4) with tetrahedral

geometry having large ligand bite angles (dppf = 96°). This reduces the accessibility for

oxidative addition.[32] In contrast, a co-ordinatively unsaturated Ni(0) complex generated from

NiCl2(PPh3)2 and dppf (Figure 4) is more efficient toward oxidative addition and will enhance

the overall efficiency of the catalytic cycle.[32] In the specific homocoupling reaction described

in Table 2, NiCl2(PPh3)2 has proven to be more efficient and selective than the bidentate ligand

catalyst NiCl2(dppf) (compare entries 3 and 5). NiCl2(PPh3)2 is surrounded by monodentate

ligands and is thus more efficient to generate coordinatively reactive Ni(0) in situ in the

presence of an additional dppf ligand.

NiCl

Cl

P

P

Ph

PhPh

Ph

PhPh

(II)

NiCl2(PPh3)2

dppfNiPh3P

PP

co-ordinatively unsaturatedNi(0) complex

faster towardoxidative addition

NiCl

Cl

P

P

PhPh

PhPh(II)

NiCl2(dppf)

dppfNi

PP

co-ordinatively saturatedstable Ni(0) complex

slower towardoxidative addition

(0)

(0)PP

dppf

Fe

Figure 4. Difference in catalytic activity of coordinatively unsaturated and saturated Ni(0)

complexes.

Nickel(0)-Catalyzed Homocoupling Reaction 41 4. Conclusion

In summary, we have developed a Ni(0)-catalyzed reductive homocoupling reaction of easily

accessible 4-chloroquinolin-2(1H)-ones that provides 4,4′-bisquinolones in good yields. In

contrast to our previous protocol,[14] this new method only requires 0.25 equivalents of a

comparatively inexpensive Ni source and does not rely on chromatography for product

isolation. Key to the success was a change of solvent and the combined use of bidentate and

monodentate ligands providing more active Ni(0) catalytic species. The method is therefore

scalable and will allow us to further study the properties of these novel types of

bisheterocylces.

5. Experimental Section

General Methods All homocoupling reactions involving air-sensitive reagents were carried out under an

atmosphere of dry argon. Dry flash chromatography[33] was performed on Merck Silica gel 60

H (< 45 nm particle size). TLC analyses were performed on pre-coated (Merck Silica gel 60

HF254 ) plates. 1H NMR and 13C NMR spectra were recorded on a Bruker AMX360 and 500

instrument in CDCl3 or DMSO-d6 at 360 and at 90 MHz respectively. Melting points were

obtained on a Gallenkamp melting point apparatus, Model MFB-595 in open capillary tubes.

FT-IR spectra were recorded on Perkin-Elmer 298 spectrophotometer using KBr pellets. Low

resolution mass spectra were obtained on an Hewlett-Packard LC/MSD Agilent 1100 series

instrument using atmospheric pressure chemical ionization (APCI) in positive or negative

mode. Analytical HPLC analysis was carried out on two different Shimadzu systems. The

Shimadzu LC-10 includes LC10-AT(VP) pumps, an autosampler (S-10AXL), and a dual

wavelength UV detector. The separations were carried out using a C18 reversed phase

analytical column, LiChrospher 100 (E. Merck, 100 x 3 mm, particle size 5 µm) at 25 °C and a

mobile phase from (A) 0.1 % TFA in 90:10 water/MeCN and (B) 0.1 % TFA acid in MeCN

(all solvents were HPLC grade, Acros; TFA was analytical reagent grade, Aldrich). The

following gradient was applied: linear increase from solution 30 % B to 100% B in 7 min,

hold at 100% solution B for 2 min at a flow rate of 0.5-1.0 mL/min. The Shimadzu LC-20

system includes a LC-20AD pump, a SIL-20A autosampler, a diode array detector (SPD-

M20A), a column oven (CTO-20A) and a degasser (DGU-20A5). The separations were carried

Nickel(0)-Catalyzed Homocoupling Reaction 42 out using a Pathfinder®AS100 reversed phase analytical column (150 x 4.6 mm, particle size 5

µm) at 25 °C and a mobile phase from (A) 0.1 % TFA in 90:10 water/MeCN and (B) 0.1 %

TFA acid in MeCN (all solvents were HPLC grade, Acros; TFA was analytical reagent grade,

Aldrich). The following gradient was applied: linear increase from solution 20 % B to 100%

B in 7 min, hold at 100% solution B for 2 min at a flow rate of 0.5-1.0 mL/min.

The 4-hydroxyquinolin-2-one precursors required for the preparation of

chloroquinolones (Table 3, entry 1-6) were obtained from Aurora Feinchemie GmbH. Zn-

powder (Merck 108789, < 60 μm particle size) was used for the Ni(0)-mediated

homocouplings. All anhydrous solvents (stored over molecular sieves), catalysts and ligands

were obtained from standard commercial vendors and were used without any further

purification. Solvents for column chromatography have been distilled prior to use.

Microwave Irradiation Experiments

Microwave-assisted synthesis was carried out in an Emrys™ Synthesizer or Initiator 8 single-

mode microwave instrument producing controlled irradiation at 2.450 GHz (Biotage AB,

Uppsala), including proprietary Workflow Manager Software (version 2.1). Experiments were

carried out in sealed microwave microwave (2 to 5 mL filling volume) process vials utilizing

the standard absorbance level (300 W maximum power). Reaction times under microwave

conditions refer to hold times at the temperatures indicated, not to total irradiation times. The

temperature was measured with an IR sensor on the outside of the reaction vessel.

Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-one 2a using Bis(1,5-

cyclooctadiene)nickel(0) A mixture containing 48.4 mg (0.25 mmol) of 4-chloro-1-methylquinolin-2(1H)-one (2a),[34]

51.7 mg (0.188 mmol, 0.75 equivs.) of Ni(COD)2, 39.0 mg (0.25 mmol, 1.0 equiv.) of 2,2´-

dipyridyl, and 20.8 mg (0.125 mmol, 0.50 equivs.) of KI was suspended in 1.0 mL of

anhydrous dioxane under an argon atmosphere in a 5-mL Pyrex microwave vial equipped with

a magnetic stirring bar. The vial was sealed, stirred for 4 min at room temperature, and then

heated for 35 min at 130 °C. Thereafter, the solvent was removed under reduced pressure, the

remaining residue dissolved in CH2Cl2 and filtered through a small pad of Celite. Evaporation

of the solvent and recrystallization of the resulting crude material from acetonitrile delivered

pure bisquinolone 1a; yield: 36.8 mg (93%).

The reaction was also performed on a 1.0-mmol scale (130 °C for 55 min) providing

the same product yield.

Nickel(0)-Catalyzed Homocoupling Reaction 43 Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-one 2a using

Bis(triphenylphosphine)nickel(II) Dichloride and Diphenylphosphino-

ferrocene. A mixture containing 48.4 mg (0.25 mmol) of 4-chloro-1-methylquinolin-2(1H)-one (2a),

32.7 mg (0.05 mmol, 20 mol%) of NiCl2(PPh3)2, 27.7 mg (0.05 mmol, 20 mol%) of

diphenylphosphinoferrocene (dppf), 21.2 mg (0.324 mmol, 1.3 equivs.) of Zn powder and 74.7

mg (0.45 mmol, 1.8 equivs.) of KI was suspended in 1.0 mL anhydrous dioxane under an

argon atmosphere in a 5-mL Pyrex microwave process vial equipped with a magnetic stirring

bar. The vial was sealed, the mixture was stirred for 4 min at room temperature, and then

heated by microwave irradiation for 30 min at 130 °C. Thereafter, the solvent was removed

under reduced pressure. The product was isolated by gradient dry flash chromatography using

EtOAc/acetone as solvent mixture to obtain pure bisquinolone 1a; yield: 34.0 mg (86%).

Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-one 2a using

Bis(triphenylphosphine)nickel(II) Dichloride and DPEphos. A mixture containing 2.13 g (11 mmol) of 4-chloro-1-methylquinolin-2(1H)-one (2a), 1.8 g

(2.75 mmol, 25 mol%) of NiCl2(PPh3)2, 1.48 g (2.75 mmol, 25 mol%) of DPEphos, 935 mg

(14.3 mmol, 1.3 equivs.) of Zn powder and 3.29 g (19.82 mmol, 1.8 equivs.) of KI was

suspended in 11mL anhydrous dioxane under an argon atmosphere in a 20-mL Pyrex

microwave vial equipped with a magnetic stirring bar. The vial was sealed, the mixture was

stirred for 4 min at room temperature, and then heated for 30 min at 130 °C. In the purification

procedure, dioxane solvent was evaporated under reduced pressure. After addition of 60 mL of

acetonitrile and warming to ca. 80 °C the crude reaction mixture was filtered through a pad of

Celite to remove insoluble DPEphos ligand in addition to most of the triphenylphosphine

ligand. Evaporation of the acetonitrile solvent furnished the crude bisquinolone product

contaminated with small quantities of triphenylphosphine which was subsequently dissolved

in 400 mL of dichloromethane and washed three times with 150 mL of saturated aqueous

ammonium chloride solution (to remove inorganic potassium iodide). Drying of the organic

phase over anhydrous MgSO4, filtration through a pad of Celite, evaporation of

dichloromethane and subsequent recrystallization (2 times) from acetonitrile provided

bisquinolone 1a; yield: 1.28 g (74%, purity > 99% by HPLC at 215 nm).

Nickel(0)-Catalyzed Homocoupling Reaction 44 Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-one 1-5 using

Bis(triphenylphosphine)nickel(II) Dichloride and DPEphos A mixture containing 0.50 mmol of the corresponding Chloroarene (Table 3, entry 1-5), 81.8

mg (0.125 mmol, 25 mol%) of NiCl2(PPh3)2, 67.3 mg (0.125 mmol, 25 mol%) of DPEphos,

42.5 mg (0.65 mmol, 1.3 equivs.) of Zn powder and 149.4 mg (0.90 mmol, 1.8 equivs.) of KI

was suspended in 0.8 mL anhydrous dioxane under an argon atmosphere in a 5-mL Pyrex

microwave process vial equipped with a magnetic stirring bar. The vial was sealed, the

mixture was stirred for 4 min at room temperature, and then heated by microwave irradiation

for 30 min at 130 °C. Thereafter, the solvent was removed under reduced pressure. The

products were isolated by gradient dry flash chromatography using EtOAc/acetone as solvent

mixture to obtain the pure biaryls (Table 3, entry 1-5); yield: 71-92%.

Alternatively, products were isolated using an extractive work-up/purification

method as described above for compound 1a. Yields for both protocols are given in Table 3.

NMe

O

N OMe

C20H16N2O2

4,4´-Bis-(1-methylquinolin-2(1H)-one) (Table 3, entry 1):

Mp 283-284°C (acetonitrile). IR (KBr) νmax 1648 cm-1; 1H NMR (360 MHz, DMSO-d6) δ 3.71

(s, 6H), 6.67 (s, 2H), 7.11-7.17 (m, 4H), 7.64-7.67 (m , 4H); 13C NMR (90 MHz, DMSO-d6)

δ 29.8, 115.8, 119.6, 121.6, 122.7, 127.3, 131.8, 140.2, 146.1, 160.9; MS (pos. APCI) m/z 317

(25, M + 1), 316 (100, M). Anal. Calcd for C20H16N2O2: C, 75.93; H, 5.10; N, 8.86. Found: C,

75.95; H, 4.98; N, 8.78.

Nickel(0)-Catalyzed Homocoupling Reaction 45

N O

N O

C24H20N2O2

7,7´-Bis-(2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one) (Table 3, entry 2):

Mp 270°C dec. (acetonitrile); IR (KBr) νmax 1637 cm-1; 1H NMR (360 MHz, DMSO-d6) δ

2.02-2.13 (m, 4H), 2.99 (t, J = 5.8 Hz, 4H), 4.13 (t, J = 5.6 Hz, 4H), 6.62 (s, 2H), 6.96 (d, J =

7.6 Hz, 2H), 7.02 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 6.98 Hz, 2H); 13C NMR (90 MHz, DMSO-

d6) δ 20.6, 27.8, 42.6, 119.7, 121.4, 121.9, 125.3, 125.4, 130.5, 136.8, 146.4, 161.2; MS (pos.

APCI) m/z 368 (100, M).

NMe

O

N OMe

MeOMeO

C22H20N2O4

4,4´-Bis-(6-methoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 4):

Mp 256-258°C (ethanol); IR (KBr) νmax 1648 cm-1; 1H NMR (360 MHz, DMSO-d6) δ 3.58 (s,

6H), 3.69 (s, 6H), 6.57 (d, J = 2.8 Hz, 2H), 6.66 (s, 2H), 7.34 (dd, J = 9.25 and 2.8 Hz, 2H),

7.62 (d, J = 9.29 Hz, 2H); 13C NMR (90 MHz, DMSO-d6) δ 29.8, 55.8, 110.0, 115.9, 119.4,

120.4, 122.5, 134.7, 145.5, 154.8, 161.1; MS (pos. APCI) m/z 377 (25, M + 1), 376 (100, M).

NMe

O

N OMe

MeO

MeO

C22H20N2O4

4,4´-Bis-(7-methoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 5):

Mp 232-234°C (ethanol); IR (KBr) νmax 1658 cm-1; 1H NMR (360 MHz, DMSO- d6) δ 3.67 (s,

Nickel(0)-Catalyzed Homocoupling Reaction 46 6H), 3.89 (s, 6H), 6.45 (s, 2H), 6.76 (d, J = 8.67 Hz, 2H), 7.04-7.07 (m, 4H); 13C NMR (90

MHz, CDCl3) δ 29.8, 56.2, 99.7, 110.8, 113.5, 117.9, 128.8, 142.0, 146.3, 161.5, 162.3; MS

(pos. APCI) 377 (25, M + 1), 376 (100, M). Anal. Calcd for C22H20N2O4: C, 70.20; H, 5.36;

N, 7.44. Found: C, 70.23; H, 5.26; N, 7.37.

NMe

O

N OMe

MeO

MeO

MeOC24H24N2O6

MeO

4,4´-Bis-(6,7-dimethoxy-1-methylquinolin-2(1H)-one) (Table 3, entry 6):

Mp 276-277 °C dec. (ethanol); IR (KBr) νmax 1642 cm-1; 1H NMR (360 MHz, DMSO-d6) δ

3.45 (s, 6H), 3.74 (s, 6H), 3.96 (s, 6H), 6.46 (s, 2H), 6.57 (s, 2H), 7.09 (s, 2H); 13C NMR (90

MHz, CDCl3) δ 30.0, 56.2, 56.4, 97.6, 108.2, 112.7, 119.1, 136.1, 145.2, 145.8, 152.8, 162.0;

MS (pos. APCI) m/z 437 (50, M + 1), 436 (100, M).

O O

O O

C18H10O4

4,4´-Bis-(2H-chromen-2-one) (Table 3, entry 7):

Mp 215-216°C (acetonitrile; lit.20 Mp 215 °C); 1H NMR (360 MHz, CDCl3) δ 6.50 (s,

2H), 7.22-7.24 (m, 4H), 7.47 (d, J = 8.42 Hz, 2H), 7.60-7.65 (m, 2H). MS (pos. APCI)

m/z 291 (95, M + 1), 290 (45, M), 252 (100, M – 38), 236 (M – 54).

Nickel(0)-Catalyzed Homocoupling Reaction 47 6. References

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Nickel(0)-Catalyzed Homocoupling Reaction 48

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Absorption and Emission Characteristics of Bisquinolones 50 D Bisquinolones as Chiral Fluorophores – A Combined

Experimental and Computational Study of

Absorption and Emission Characteristics

Graphical Abstract

NR1

O

X

N OR1

NOR1

R3

R2

R2

R3

R3

R2

NR1

O

R3

R2

R4

N

O

OCH3

N OCH3

O

O

O

O

NR1

O

NN

N

R3

R2

N O

R3

R2

R1

X = Cl, BrR1 = H, MeR2 = H, OMeR3 = H, OMe, CF3, OHR4 = H, OMe, CN

Absorption and Emission Characteristics of Bisquinolones 51 Abstract

Biscarbostyrils (4,4’-bisquinolones) can be synthesized from 4-chloro-2-quinolinones using a

Pd-catalyzed one-pot borylation/Suzuki cross-coupling protocol or via Ni(0)-mediated

reductive homocoupling. The electronic spectra of biscarbostyrils 4b-8 exhibit unusual

properties in comparison to the corresponding carbostyrils 1-3. Similar absorption spectra are

accompanied by red-shifted emission maxima up to 520 nm. Unsubstituted biscarbostyril 4b

displays the unusual property of a blueshift in dimethylsulfoxide as compared to water. For a

set of diversely substituted biscarbostyrils and related 4-aryl-2-quinolinones very selective

substitution patterns in order to increase fluorescence quantum yields are observed. In

bisquinolone 7, an additional diphenylphosphinoxide substitution in position 3 and 3´

increased the quantum yield to 0.2 and the epsilon value to 25000. A crown ether linkage

from position 6 to 6´ in biscarbostyrils improved the emission maximum from 470 to 500nm,

but the fluorescence quantum yield only from 0.03 to 0.06. Time-dependent density

functional calculations of absorption and emission spectra of selected derivatives show good

agreement with the corresponding experimental data. Especially, the large Stoke’s shift

observed for biscarbostyrils as well as their rather low fluorescence quantum yields can be

rationalized on the basis of these calculations. Like 1,1´ binaphthalenes the biscarbostyril

structures are axially chiral. Most of the enantiomers were baseline HPLC separated on the

Pirkle type ULMO column, with separation factors of up to 2.5. As expected for this π-acidic

chiral stationary phase electron donating methoxy substituents improve separation behavior.

1. Introduction

In addition to the traditional coumarin-based fluorophores,[1] comparatively few derivatives

of the structurally related quinolin-2(1H)-ones (carbostyrils) have found applications as

fluorescence markers.[2] Today, mainly “carbostyril 124” (7-amino-4-methylquinolin-2(1H)-

one) is known as fluorescent dye, whereas for enzymatic essays N-acylated versions of

“carbostyril 124” are used routinely. Recently, we have shown in a systematic study that

suitable functionalization of carbostyrils leads to derivatives with absorption and emission

characteristics comparable to those of coumarins.[3-5] For example, 4-trifluoromethyl

analogue 3b (Table 1) has an absorption maximum of 370 nm, an emission maximum of 440

nm, and a quantum yield of ca. 0.5,[4,8] which compares favorably with unsubstituted

Absorption and Emission Characteristics of Bisquinolones 52 carbostyril 1 and the 6,7-dimethoxy substituted analogue 2 (λmax(abs) 338 and 351 nm,

λmax(em) 396 and 402 nm, and fluorescence quantum yield 0.02 and 0.11). Carbostyrils are

more resistant towards pH changes (ring opening) and other thermal or chemical (oxidative

damage) bleaching reactions.[6] Moreover, they are easily functionalized, leading to versatile

fluorescent tags for proteins or polysaccharides.[7,8] Their photophysical properties and

chemical stability, thus, makes this class of compounds useful for bioconjugation in aqueous

media. Our group has also published a pH sensor measuring europium luminescence decay

time dependent on the protonation of bromothymol blue with a sol-gel embedded 3-

acylamino-4-trifluoromethyl-6,7-dimethoxycarbostyril europium complex.[9]

In recent years 4,4’-biscarbostyrils of type 4b, aza-analogues of biscoumarin natural

products (e.g., 4,4’-biisofraxidin[10]), have become readily available.[11] In view of the intense

long-wavelength fluorescence of photolabile bisisoquinolinones, e.g. for 6,6'-dimethoxy-2,2'-

diphenyl-2H,2'H-[4,4']biisoquinolinyl-3,3'-dione 4a[12] we wondered whether suitably

modified 4,4’-biscarbostyrils also would exhibit similar bathochromic shifts of their

absorption and emission bands. Furthermore, the anticipated axial chirality of these

derivatives offers the possibility for chiral recognition. Along similar lines, they also might

serve as ligands in asymmetric catalysis. Recently, biscarbostyril-based mono- and

diphosphine ligands of the aza-BINAP type have been reported.[13] Here we present a

combined experimental and computational study on 4,4’-biscarbostyrils 4–9b and compare

their photophysical properties with monomeric carbostyrils 1–3 and the isomeric 6,6'-

dimethoxy-2H,2'H-[4,4']biisoquinolinyl-3,3'-dione 4a. In addition, results for 4-aryl- (10a–

c), 4-heteroaryl- (11a–c), and 4-arylethinylcarbostyrils (12a,b) are presented. Experimental

absorption and fluorescence characteristics are also provided for the crown ether derivative

13 and the diphenyl phosphine- and phosphine oxide analogues as well as their bromine-

containing precursors 14–17c.[13] Since all investigated bisquinolones are axially chiral, a

HPLC study of enantioseparation effects on the Pirkle type chiral stationary phase (CSP)

ULMO is also presented.

2. Results and Discussion

2.1. Fluorescence: The first part in Table 1 shows fluorescence data of previously

investigated carbostyrils 1-3[4,5] compared with 4,4´-bisquinolones 4b-9b.[11] Due to the

synthetic protocol for the biscoupling reactions requiring previous N-methylation,[12] all

Absorption and Emission Characteristics of Bisquinolones 53 Table 1. Electronic spectra of all investigated compounds

Compound Solvent λmax e λmax exc λmax em Φ structure

1 DMSO 331 4250 340 380 0.023

H2O 326 4850 335 373 0.011

2 DMSO 351 5500 355 402 0.092

H2O 338 6000 343 396 0.071

3a DMSO 390 12400 400 436 0.610

H2O 380 11000 385 432 0.500

3b DMSO 370 9700 375 440 0.346

H2O 360 9700 365 430 0.331

4a DMF 505 28000 - 540 - O

N

NH3CO PhH3CO Ph

O

4b DMSO 340 11300 340 425 0.008

H2O 333 10800 330 470 0.016

5 DMSO 366 7800 370 475 0.028

H2O x quench

6 DMSO 350 8500 342 425 0.027

H2O 344 9500 330 458 0.009

7 DMSO 357 10000 360 495 0.039

H2O quench

8 DMSO 355 11900 358 500 0.052

DMSO* 340 8100 345 470 0.013

H2O 346 12200 520 0.006

9a DMSO 352 10500 360 505 0.003

9b

DMSO* 335 340 405 0.002

DMSO 335 9200 340 406 0.002

Absorption and Emission Characteristics of Bisquinolones 54

10a DMSO 355 9800 365 431 0.023

10b

H2O 346 350 431 0.008

DMSO 354 9200 365 428 0.027

10c

H2O 346 350 428 0.009

DMSO 363 9200 374 505 0.008

11a

H2O 360 360 470 0.006

DMSO 345 6200 352 411 0.016

11b DMSO 345 5800 350 415 0.020

11c DMSO 360 6500 365 450 0.185

12a DMSO 355 7700 355 425 0.005

12b DMSO 385 9000 385 460 0.057

13 DMSO 375 7900 380 500 0.060

Absorption and Emission Characteristics of Bisquinolones 55

14a

H2O 359 7500 350 500 0.001

DMSO 362 9700 362 437 0.010

14b DMSO 375 13200 375 438 0.001

15a DMSO 365 23900 365 430 0.002

15b DMSO 380 21000 400 470 0.008

15c

H2O 376 20400 400 490 0.001

DMSO 380 25600 395 470 0.189

16a DMSO 339 9800 340 430 0.002

16c DMSO 355 9300 354 430 0.016

17a

DMSO* 340 8800 340 420 0.005

DMSO 341 14000 341 420 0.003

17c DMSO 358 16600 360 415 0.015

* double maximum

Absorption and Emission Characteristics of Bisquinolones 56 carbostyrils with the exemption of 2 and 12b in the Table were prepared as the N1-

methylated species. Because of this synthetic requirement, they do not allow the formation

of the 2-OH tautomers. We have recently shown,[7,14] that absorption and emission maxima of

the N-alkylated derivatives are very similar to the NH varieties. Independent on the

substituent at N1, all carbostyrils exhibit a slight excitation and emission blue-shift in water

compared with DMSO. The recently published carbostyril 3a, having a cyano group in

position 4, had remarkable properties: it displayed an independence of emission maxima (ca

430 nm) and fluorescence quantum yields (about 0.5) in water, polar and apolar solvents.[8]

Interestingly, unsubstituted biscarbostyril 4b showed an absorption maximum of 340

nm in DMSO and 333 nm in water not much different from the parent carbostyril 1. To our

surprise, however, the (low yielding) emission maximum was 425 nm in DMSO and 470 nm

in water. Compound 1 had emitted at 380 and 373 nm, respectively. In water, 4b was red

shifted even compared with the best push-pull substituted 6,7-dimethoxycarbostyril 3a,

generally emitting at shorter wavelength than in DMSO.

As a consequence, we assumed that biscarbostyrils 5-9b would top all emission data

of simple 6,7-dimethoxycarbostyrils. However, this was only the case in terms of a somewhat

longer wavelength emission and hence larger Stoke´s shifts. Fluorescence quantum yields

were low even in DMSO and to our surprise methoxy substituents quenched emission in

water almost completely. This was not at all the case in the emission spectra of the above

mentioned 4-cyano analogue 3a,[8] and we had observed only an about 15-50% decrease in

300 350 400 450 500 550 600λ (nm)

Int (

au)

4b - exc 4b - em 8 - exc 8 - em 5 - exc 5 - em

Figure 1. Electronic spectra of unsubstituted biscarbostyril 4b, the mixed 6,7-dimethoxy/6,7-

H analogue 8 and the symmetrical 6,6´-dimethoxy-biscarbostyril 5.

Absorption and Emission Characteristics of Bisquinolones 57 the 4-CF3 series.[7] Studies of unsymmetrical biscarbostyril 8 in dichloromethane and in

glycerol at -30°C did not increase fluorescence, hence quenching is not affected by the

polarity or viscosity of the environment.

A remarkable feature of the mixed substitution in 8 and 9a is a fluorescence double

maximum representing both single carbostyril parts. This must be due to the perpendicular

arrangement of the carbostyril subunits and hence both parts behave just as single

chromophores. The symmetrical example 9b exhibits the characteristics of the shorter

wavelength absorbing trifluoromethyl part of 9a. The emission spectra of 8 can not be

completely separated but the mean emission wavelength is lowered to 470 nm if excitation

occurs at 340 nm, the maximum of the unsubstituted species 4b.

In order to investigate the effect of simple phenyl substitution in position 4, we

prepared 4-arlycarbostyril derivatives 10a-c applying standard Suzuki cross-coupling

chemistry.[15] To our disappointment, none of the investigated new compounds had a

fluorescence quantum yield exceeding 0.04. The emission maximum of 4-(p-cyanophenyl)-

carbostyril 10c is blue-shifted in water as in all monocarbostyrils, but contrasts the behavior

of biscarbostyrils 4b, 6 and 8. Interestingly, in DMSO 10c yielded even less fluorescence

compared with 10a and 10b. However, as expected, due to the electronegativity of the 4-

cyano substituent in DMSO a significant red shift to 505 nm was observed, exactly the value

found with mixed bisproduct 9a. We also investigated several 4-triazolo substituted

analogues. Interestingly, the fluorescence of the known[16] analogs 11a and isomer 11b did

not significantly surpass the fluorescence observed for carbostyril 1. We additionally

prepared the 6,7-dimethoxy substituted analogue of 11b, namely the 6,7-dimethoxy-1-

methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)quinolin-2(1H)-one 11c, using standard “Click”

chemistry as shown in Scheme 1.[16] Compound 11c was absorbing at 360 nm, almost at the

same wavelength as the CF3 model compound 3b and was found as an interesting candidate.

Scheme 1. Synthesis of 6,7-dimethoxy-1-methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)quinolin-

2(1H)-one 11c.

Absorption and Emission Characteristics of Bisquinolones 58 It emitted at 430 nm with a fluorescence quantum yield 0.19, that is about 50% of the

quantum yield observed for 3b (fluorescence maximum 440nm).

In the light of these fairly low intensities the question arose if less steric demanding

substituents in position 4 would raise the quantum yield. We thus prepared 4-

phenylacetylene-substituted analogues 12a and 12b having an acetylene bridge between the

4-phenyl substituent and the carbostyril framework. The required 1-methyl-4-

(phenylethynyl)quinolin-2(1H)-one (12a) was prepared by Sonogashira cross-coupling

reaction of the corresponding bromide with phenylacetylene at room temperature (Scheme

2).[16] For the synthesis of 12b, a different synthetic route had to be taken since the synthesis

of the corresponding dimethoxy-derivatized 4-bromocarbostyril proved to be difficult.

Applying the Sonogashira conditions to a suitable bromo quinoline-N-oxide precursor[16] and

phenylacetylene led to the desired C-C coupling, providing the 6,7-dimethoxy-4-

(phenylethynyl)quinoline 1-oxide in good yield. The latter could be further converted into the

desired isomeric quinolone (12b) in a single synthetic step utilizing the known photochemical

rearrangement of quinoline-N-oxides to quinolin-2(1H)-ones (Scheme 2).[16]

Scheme 2. Synthesis of 1-methyl-4-(phenylethynyl)quinolin-2(1H)-one 12a and 6,7-

dimethoxy-4-(phenylethynyl)quinolin-2(1H)-one 12b.

Absorption and Emission Characteristics of Bisquinolones 59 Compared with carbostyril 10b the absorption wavelength maximum was red shifted in 12b

from 365nm to a double maximum at 385 and 410 nm (Stoke’s shift 3010 cm-1) and the

emission wavelength was shifted from 431 to 470 nm (Stoke’s shift e 1925 cm-1). Hence the

electronic spectra were well comparable with any long wavelength absorbing 6,7-dimethoxy-

substituted carbostyril. Disappointing was again the fluorescence quantum yield, although

with 5% somewhat better than all biscarbostyrils.

As a variation of the biscarbostyril series we next prepared macrocycle 13, a crown

ether bridged version of bis-6-methoxy-carbostyril 5. In recent years, crown ethers have

attracted much attention for their interesting binding properties with metal and organic

cations.[17,18] In general, crown ether macrocycles with two-dimensional circular cavities have

been widely studied[19] with respect to their complexation of predominantly alkali and

alkaline earth metals and ammonium salts.[20] In the present work we report the successful

synthesis of a mono cavity crown-ether based quinolone derivative 13.

N

NMe

Me

MeOMeO

O

O

N

NMe

Me

HOHO

O

O

Me

OOOO

N

NMe

O

O

O

O

O O

OTs OTs

5 18 13

BBr3, DCM

r.t., 16 h

K2CO3, DMF

90 °C, 16 h

Scheme 3. Synthesis of biscarbostyril crown ether 13.

The synthesis was achieved from methyl ether 5 by tribromoborane cleavage[21] to form the

6,6´-dihydroxy analogue 18. After reaction with tetraethylene glycol ditosylate[18,21] we

obtained 13 in 71% yield. We hoped not only to get more information about the steric change

conserving the same substitution pattern, but also to get complexation with alkali metal ions

shifting the absorption and emission wavelength by involvement of the lone pair of the 6,7

oxygens. On the one hand we succeeded in shifting the emission wavelength from 475 nm in

5 to 500 nm in crown ether 13. On the other hand, the fluorescence quantum yield was with

6% in DMSO the highest, topping all other bisquinolinones. Quenching in water was again

dominant. Disappointing was also that addition of Li, Na, K, and Cs ions[22,23] did not change

Absorption and Emission Characteristics of Bisquinolones 60 the absorbance and fluorescence values. Studies are ongoing to find response for organic

ammonium ions.

The investigated bisquinolinones display axial chirality and are potential catalysts to

be used as BINAP analogues.[13] Therefore we measured also the fluorescence of the

published diphenyl phosphine- and phosphine oxide analogues as well as of the brominated

precursors 14-17c.[13] Most of the compounds showed extremely weak fluorescence. To our

Table 2. Calculated (TDDFT-B3PW91/TZVP//BP86/SVP) absorption and emission

wavelengths λ (nm) and oscillator strengths in DMSO.

absorption emission

λ / nm f λ / nm f

1a 314 (308) 0.16 (0.16) 348 0.16

2a 339 (332) 0.29 (0.29) 376 0.25

3a 415 0.22 481 0.18

3ba 368 (360) 0.27 (0.27) 413 0.24

4b 332 0.08 399 0.07

5 366 0.01 492 0.03

6 342 0.11 399 0.06

7 379 0.14

8 382 0.02 479 0.02

10a 353 0.26

10b 351 0.29

10c 397 0.10

12b 412 0.23

4ab 437 (469) 0.14 (0.24) 471 (533) 0.03 (0.00)

[a] B3PW91/TZVP//B3LYP/6-31G(d) results in parentheses. [b] results for the second rotamer in parentheses; experimental values in DMF are λabs

= 485 nm and λflu = 530 nm; the calculations refer to the N1H model compound.

Absorption and Emission Characteristics of Bisquinolones 61 surprise, symmetrical diphenyl phosphine oxide 15c had with 0.19 the highest fluorescence

quantum yield of all investigated bisquinolinones. Also, the extinction coefficient 25600 is

2.5 times higher in comparison to parent compound 7. The UV maximum of 380 nm is 20 nm

red shifted and the fluorescence maximum of 470 nm is 20 nm blue shifted compared with 7.

This leads in combination with the fluorescence quantum yield to a total sensitivity and

Stoke´s shift well fitting to the class of substituted mono-coumarins and -carbostyrils.

2.1.1 Computational Results: To rationalize the experimental findings described above,

quantum chemical calculations (time-dependent density functional theory, TDDFT) have

been performed. Selected pertinent results of the TDDFT calculations are given in Table 2.

Also presented there is the computed influence of the solvent (DMSO, H2O) on the

absorption/emission characteristics. The TDDFT procedure has proven as a reliable tool for

the electronic features including absorption and emission characteristics of structurally

related coumarins dyes.[24] In simple carbostyril derivatives, TDDFT calculations using AM1

geometries had given quite good agreement between computed and experimental excitation

energies.[3-5] The situation is less satisfactory for bicarbostyrils. Here, the influence of

substituents on the long-wavelength absorption band is only poorly described when using

AM1 geometries. Apparently, there is little to choose between the two density functionals,

Figure 2. Plot of calculated (B3PW91/TZVP//BP86/SVP) vs. experimental absorption

maxima λabs (nm) in DMSO.

Absorption and Emission Characteristics of Bisquinolones 62 B3PW91 and PBE0, in terms of calculated trends; with respect to basis set, TZVP appears to

be preferable over 6-31G(d). Irrespective of the geometry, basis set and density functional

used, the largest deviations between experimental and calculated λmax–values are obtained for

compounds 7, 8, and 10c. For instance, omitting these three compounds increases the

correlation coefficient for B3PW91/TZVP//BP86/SVP – calculated λmax–values from R2 =

0.87 to R2 = 0.98 (Figure 2). Similarly, the largest discrepancy between experimental

fluorescence maxima and calculated S1 → S0 transition energies result for 7, 8, and 10c, e.g.

for B3PW91/TZVP longest wavelength transitions based on AM1 optimized S1 geometries,

R2 = 0.84, and R2 = 0.93 if 7, 8, and 10c are omitted from the correlation. BP86/SVP S1–

geometries for compounds 1 – 6, 8 result in R2 = 0.95 (PBE0/TZVP) and R2 = 0.96

(B3PW91/TZVP), respectively, to be compared with R2 = 0.90 obtained from AM1 CI=4

geometries (B3PW91/TZVP).

Some of these discrepancies, e.g. longest wavelength absorption of biscarbostyril 8,

can be rationalized on the basis of the nature of the involved electronic transitions.

Consequently, the following discussion of the relevant electronic features is based on

B3PW91/TZVP//BP86/SVP calculations in DMSO as solvent.

Figure 3. Plot of calculated (B3PW91/TZVP//BP86/SVP) vs. experimental Stokes’s shifts

Δν (cm–1) in DMSO (the regression line shown is results by taking into account both values

for 8).

Absorption and Emission Characteristics of Bisquinolones 63

The absorption spectra of biscarbostyrils do not differ significantly from their

monocarbostyril counterparts. In contrast, fluorescence maxima show a substantial

bathochromic shift (see Table 1). In Figure 3, a plot of the observed vs calculated

(B3PW91/TZVP/BP86/SVP) Stoke’s shift in DMSO is presented. With the exception of the

“mixed” derivative 8, the correlation is very good. However, experimental data suggest that

the observed absorption band actually is a superposition of two electronic transitions, see

below. Consequently, considerably better agreement between observed and calculated

Stoke’s shifts results when using the second calculated electronic transition [R2 = 0.61 (8/1)

vs R2 = 0.95 (8/2)].

In carbostyrils 1 – 3 the longest wavelength transition corresponds to the π (HOMO)

→ π* (LUMO) transition. Introduction of the methoxy groups at C6 and C7 preferentially

raises the HOMO and substitution by CF3 at C4 mainly affects the LUMO because of the node

of the HOMO at that position, Figure 4. The combined effects of both substituents, thus, result

in the observed bathochromic shift 1 → 2 → 3. Calculated oscillator strengths for this

transition are reasonably large, f = 0.16 – 0.27, in line with the experimentally found extinction

coefficients of ε = 4000 – 10000, Table 1. In the symmetric bicarbostyrils 4b, 5, and 7 but not

6, all electronic transitions occur pairwise at nearly the same wavelength. In the unsubstituted

4,4’-bicarbostyril 4b both calculated transitions with λ1 = 332 [π (HOMO) → π* (LUMO)]

and λ2 = 330 nm [π (NHOMO) → π* (LUMO)], have small but comparable oscillator

Figure 4. Orbitals involved in the first electronic transition of compound 3 (A) and 4b (B).

Absorption and Emission Characteristics of Bisquinolones 64 strengths f = 0.08 and f = 0.06. Thus, taken together, this explains the relatively large

absorption intensity, ε = 11000. In contrast, fluorescence occurs from the S1 state alone; hence

the very low quantum yields observed for 4,4’-bicarbostyrils. The low intensity of both

transitions can be rationalized in terms of the orbitals involved, Figure 4. Both the HOMO and

the NHOMO are mainly localized within one single carbostyril moiety, whereas the lowest

virtual orbital is of biphenyl-type; the concomitant poor overlap between these two orbitals,

NHOMO or HOMO and LUMO, respectively, leads to the small oscillator strength f. A

similar electronic structure description also holds for 5 and 7. The resulting two transitions, π

(HOMO) → π* (LUMO) and π (NHOMO) → π* (LUMO), at 365 nm are very weak, f = 0.01

and 0.03 and, thus, should be hidden below the much more intense (f = 0.18) π (HOMO) → π*

(NLUMO) absorption calculated at λ = 357 nm.

In contrast to 4, 5, and 7, there is a quite substantial splitting of the first two singlet

states in 7,7’-dimethoxy-4,4’-biscarbosytil 6, with calculated (B3PW91/TZVP//BP86/SVP,

DMSO) absorption maxima at λ1 = 342 [π (HOMO) → π* (LUMO)] and λ2 = 333 nm [π

(NHOMO) → π* (LUMO)]. A third transition, π (HOMO) → π* (NLUMO) results at λ2 =

320 nm. The first and this latter one appear to be quite intense, f = 0.11 and f = 0.28. All

biscarbostyrils show a long wavelength shoulder in their experimental absorption band; in 6

this shoulder is clearly resolved resulting in two well-separated maxima (DMSO) at λ1 = 350

nm and λ2 = 336 nm with ε1 = 8500 and ε2 = 10400. Obviously, this second band has to be

assigned to the third calculated electronic transition.

The calculated (B3PW91/TZVP//BP86/SVP, DMSO) longest wavelength transition

in 8, λ1 = 382 nm, f = 0.02, is a pure charge transfer (CT) π (HOMO) → π* (LUMO)

transition where the HOMO and LUMO are localized at the 6,7-dimethoxy substituted and

the unsubstituted carbostyril moiety. The second transition, λ2 = 346 nm, is governed by the

π (HOMO) → π* (NLUMO) excitation describing a locally excited state within the 6,7-

dimethoxy substituted carbostyril fragment. Hence the quite large calculated intensity f =

0.27. This also explains the large discrepancy between experimental and calculated longest

wavelength absorption of 8: actually it is the second electronic transition which is responsible

for the observed absorption band.

Although the oscillator strength is just one factor contributing to fluorescence

quantum yields, the present calculations reveal the intrinsic low φF-values of the investigated

biscarbostyrils. Thus, as described above, no observable quantum yield effect of temperature,

viscosity or less polar solvent could be observed. In p-quaterphenyl fluorophores where the

Absorption and Emission Characteristics of Bisquinolones 65 dihedral angle τ between the two central rings is constrained by dialkoxy spacers, a clear

correlation between τ and the rate constant for radiationless transitions has been observed.[25]

Here, we do not find a correlation between the torsion of the two carbostyril moieties and the

fluorescence quantum yield. Although 4-aryl derivatives 10a-c show larger calculated

oscillator strengths, these derivatives still have rather low quantum yields. Since radiationless

deactivation by phenyl twisting might be a possible reason, we have separated the phenyl

group from the carbostyril moiety by the steric less demanding acetylene moiety, compound

12b. Compared with the 4-phenyl derivative 10a a bathochromic shift of both absorption and

fluorescence can be observed, Δλexp(abs) = 30 nm and Δλexp(flu) = 29 nm (DMSO).

Somewhat larger effects are predicted by the calculations, Δλcalc(abs) = 50 nm and Δλcalc(flu)

= 83 nm (DMSO) based on AM1 geometries. However, quantum yields are still fairly low, φF

= 0.06. Thus, we have not pursued this type of structural modification any further. In

contrast, according to the calculations, directly connecting the cyano group at C4, compound

3a, should lead to absorption and emission at reasonably long wavelengths, λcalc(abs) = 411

nm and λcalc(flu) = 449 nm (DMSO) with rather large oscillator strengths, Table 2. Indeed,

compound 3a has been found to be highly fluorescent, φF = 0.61 in DMSO,[8] with

experimental absorption and emission maxima in good agreement with the theoretical

predictions.

2.2. Separation of Enantiomers

In order to separate bisquinolone enantiomers we have chosen ULMO as a Pirkle type chiral

stationary phase separating enantiomers of π-electron rich aromatic compounds particularly

well.[26] Also axial chiral binaphthol derivatives have been previously resolved on this chiral

stationary phase (CSP). Results are collected in Table 3 showing chiral recognition of all

investigated axially chiral compounds using the same mobile phase, n-heptane/dioxane 1:1.

Already enantiomers of simple biscarbostyril 4b are separated on the 125 mm column with

almost sufficient resolution (1.43). As expected for this type of CSP, methoxy substituents

increase chiral discrimination. 3,3´-Dibromo derivative 15a is best resolved (5.62) and has

the large separation factor α 2.42. Interestingly, crown ether 13 is better resolved than the

6,6´-dimethoxy analogue 5 (3.81 vs 2.23). Retention of the first eluting enantiomer is equal

but the CSP interaction of the second enantiomer of the crown ether is intensified (Figure 5).

Looking closer at results in Table 3, some interesting trends can be extracted. 6-Alkyloxy

Absorption and Emission Characteristics of Bisquinolones 66 Table 3. HPLC Enantiomer Separation of Bisquinolin-2-ones on an ULMO Chiral Stationary

Phase.

Compound k1 k2 α res Structure

4b 1.70 2.04 1.20 1.43

5 3.26 5.42 1.66 2.23

6 2.32 3.02 1.30 1.95

7 6.66 10.28 1.54 2.05

9a 1.93 2.67 1.38 1.69

9b 0.67 0.72 1.08 0.53

13 3.76 7.02 1.87 3.81

14a 4.21 8.12 1.93 3.63

15a 3.30 7.98 2.42 5.82

16a 0.70 0.73 1.04 0.21

17a 0.64 0.81 1.26 1.13

substituents increase non-specific interactions most, which is reflected in prolonged retention

and hence large k1 values (5, 14a). 3-Bromo substituents decrease k1 hence non-specific

Absorption and Emission Characteristics of Bisquinolones 67 interactions and elute the better retained enantiomer with similar k2 parameters as observed

with 7 and 13. Therefore, bromides 14a-17a are better separated than other analogues in this series.

0 5 t (min) 10

4b

13

Figure 5. Enantiomer separation of compound 4b and crown ether 13 on the ULMO Chiral

Stationary Phase

Resolution of biscarbostyrils containing only electron withdrawing trifluoromethyl

substituents is poor (9b, 16a, 17a). In terms of retention trifluoromethyl substituents in

position 6 inhibit interaction with the CSP and both k values are small leading to small

separation factors. Investigating 9b on the π-basic D-naphthylalanine CSP which should

better interact with electron deficient aromatic rings, however, no chiral recognition at all was

observed (k = 0.50). Also the simple biscarbostyril 4b was not separated (k = 1.20). In short,

chiral recognition on ULMO could be achieved for all investigated biscarbostyrils and the

most promising candidate to get liquid chromatographic separation in a preparative scale was

the 3,3-dibromo compound 15a, which is the potential precursor for an enantiopure diphenyl

phosphine catalyst.[13]

Absorption and Emission Characteristics of Bisquinolones 68 3. Conclusion

Absorption and emission maxima of selected mono- and biscarbostyrils, calculated by time-

dependent density functional theory, show good agreement with the corresponding

experimental data, especially with the B3PW91/TZVP//BP86/SVP procedure. The largest

deviations, irrespective of the geometries, basis set, or density functional used, are found for

compounds 7, 8, and 10c. In compound 8 the experimentally observed absorption/emission

maxima apparently are a superposition of two electronic transitions, hence the discrepancy

with the calculated results. Calculated Stokes’s shifts also nicely correlate with the

experimental ones, again with the exception of 8 for which exact experimental

absorption/emission maxima are difficult to obtain. Furthermore, the S1→S0 transitions in

biscarbostirys are characterized by very low oscillator strengths, responsible for their low

fluorescence quantum yields.

4. Experimental Section

General Methods 1H NMR and 13C NMR spectra were recorded on a 360 MHz instrument at 360 and at 90

MHz respectively. Chemical shifts (δ) are expressed in ppm downfield from TMS as internal

standard. The letters s, d, t, q and m are used to indicate singlet, doublet, triplet, quadruplet

and multiplet. FTIR spectra were recorded using KBr pellets. Low resolution mass spectra

were obtained on a LC/MS instrument using atmospheric pressure chemical ionization

(APCI) in positive or negative mode. Analytical HPLC analysis was carried out on a C18

reversed-phase (RP) analytical column (119 × 3 mm, particle size 5 mm) or a reversed-phase

column (150 × 4.6 mm, particle size 5 µm) at 25 °C using a mobile phase A

(water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA) at a flow rate of

0.5 mL/min. The following gradient was applied: linear increase from solution 30% B to 100

% B in 8 min, hold at 100% solution B for 7 min. The synthesized compounds were purified

on a Biotage SP1 automated flash chromatography system using cartridges packed with KP-

SIL, 60 Å (32-63 µm particle size). Melting points were obtained on a standard melting point

apparatus in open capillary tubes. TLC analyses were performed on pre-coated (silica gel 60

HF254) plates. All anhydrous solvents (stored over molecular sieves), and chemicals were

obtained from standard commercial vendors and were used without any further purification.

Absorption and Emission Characteristics of Bisquinolones 69

Carbostyril 1 is commercially available (Alfa Aesar), whilst

carbostyrils/biscarbostyrils 2,[4] 3a-b,[8] 4-7,[11] 9b,[13] 11a,b[16] and 14-17[13] have been

previously reported from our laboratories.

Microwave Irradiation Experiments

Microwave-assisted synthesis was carried out in an Emrys™ Synthesizer or Initiator 8 single-

mode microwave instrument producing controlled irradiation at 2.450 GHz (Biotage AB,

Uppsala), including proprietary Workflow Manager Software (version 2.1). Experiments were

carried out in sealed microwave microwave (2 to 5 mL filling volume) process vials utilizing

the standard absorbance level (300 W maximum power). Reaction times under microwave

conditions refer to hold times at the temperatures indicated, not to total irradiation times. The

temperature was measured with an IR sensor on the outside of the reaction vessel.

Electronic Spectra 1cm cells were used for all experiments. UV/Vis spectra were recorded using a Shimadzu

UV/Vis scanning spectrophotometer UV-2101 PC; concentration: 10-4 mol/L. Standard

excitation and emission spectra were recorded using a Perkin-Elmer LS50B luminescence

spectrometer at ambient temperature, standard slit width 3 or, if compounds were very

weakly fluorescent, 5 or even 10 nm; concentration was between 0.5 and 1 × 10-6 M,

adjusting for an average absorption value 0.1 at the excitation wavelength. For measurements

in water, a 10-2 M stock solution in DMSO was used. Approximate -30 °C measurements

were done using a freezer and placing the cells into a dry argon atmosphere. Also degassing

with ultrasound/argon did not significantly change emission intensities. Relative fluorescence

quantum yields were calculated from the fluorescence areas using quinine sulfate at pH1 as a

standard (0.560); DMSO values were corrected with the factor (nH2O/nsolvent)2. DMSO was of

purest grade (Sigma Aldrich, Buchs, Switzerland) and checked for intrinsic fluorescence.

Computational Details Electronic transition energies (absorption and emission) were calculated by time-dependent

density functional theory (TDDFT)[27] using various density functionals (B3LYP,[28]

B3PW91,[29] PBE0,[30] and BP86[31]) and basis sets [6-31G(d), [32] SVP,[33] and TZVP[34]).

Geometries were optimized by the semiempirical AM1 method[35] (CI = 4 for S1

optimization) or by density functional theory calculations [BP86/SVP for S0 and S1 states; for

S0 also B3LYP/6-31G(d) was used]. Solvent effects (dimethylsulfoxide, water) were

Absorption and Emission Characteristics of Bisquinolones 70 approximated by the IEF-PCM procedure.[36] To investigate excited states including electron

correlation post-Hartree-Fock methods using multiple Slater determinants can be used.

Coupled Cluster (CC) methods are exact, but time-consuming methods. In order to save

computer time at a low loss of accuracy, the Coupled Cluster Singles Doubles CCSD

equations can be approximated to be correct only through first order, using the singles as

zeroth-order parameter (CC2[37]). Programs used were AMPAC,[38] TURBOMOLE,[39] and

Gaussian 03.[40] Visualization was done by MOLDEN[41] and MOLEKEL.[42]

Chiral Separations Chiral HPLC measurements were performed using a HEWLETT PACKARD series HP1050

instrument consisting of a pumping system, a multiple wavelength detector and an

autosampler and the HPChemstation software. The chiral stationary phases (CSPs) were an

(S,S)-ULMO column (125x4mm) and a covalent D-naphthylalanine column (250x4mm)

from REGIS, Morton Grove, Ill, USA. Mobile phase solvents were of HPLC grade

(MERCK, Darmstadt, Germany). The mobile phase was n-heptane/dioxane 1:1. 5µl of a

sample solution (concentration about 0.05mg/mL) was injected. All runs were performed at

25 °C and wavelength was adjusted according to absorption maxima (Table 1).

6,7-Dimethoxy-1,1'-dimethyl-4,4'-biquinolin-2,2'(1H,1'H)-dione) (8):

A mixture of 76.1 mg (0.30 mmol) of 6,7-dimethoxy-1-methyl-4-chloroquinolin-2(1H)-

one,[11] 58.1 mg (0.30 mmol, 1.0 equiv) of 1-methyl-4-chloroquinolin-2(1H)-one,[11] 49.0 mg

(0.060 mmol, 10.0 mol%) of PdCl2(dppf)2, 23.3 mg (0.042 mmol, 7 mol%) of dppf, 106.6 mg

(0.42 mmol, 0.7 equiv) of bis-(pinacolato)diboron, 151.5 mg (2.7 mmol, 4.5 equiv) of finely

crushed KOH powder (analytical grade), and 2.0 mL of n-BuCl, in a 2 mL Pyrex microwave

vial was equipped with a magnetic stirring bar and sealed. The resulting mixture was stirred

for 5 min at room temperature under Ar and then heated for 30 min at 145 °C via single-

mode microwave irradiation. After cooling to ambient conditions, the solvent was removed

under reduced pressure and the product directly purified by automated flash chromatography

Absorption and Emission Characteristics of Bisquinolones 71 using petroleum ether/EtOAc as eluent to 56.5 mg (50%) of 6,7-dimethoxy-1,1'-dimethyl-

4,4'-biquinolin-2,2'(1H,1'H)-dione) (8) as a colorless solid, mp 155-157 °C (ethanol); IR

(KBr) νmax 3435, 1650, 1258 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.59 (s, 3H), 3.84 (s, 6H),

4.04 (s, 3H), 6.61 (d, J = 7.4 Hz, 2H), 6.75 (s, 1H), 6.88 (s, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.28

(d, J = 7.5 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H); 13C NMR (90 MHz,

CDCl3) δ: 29.7, 29.9, 56.3, 97.5, 108.2, 112.9, 114.7, 119.2, 119.6, 121.7, 122.4, 127.5,

131.4, 136.1, 140.1, 145.2, 145.4, 146.5, 152.7, 161.6; MS (pos. APCI) m/z 376 (100, M),

377 (20, M + 1). The known symmetrical bisquinolones 7[11] and 4[11] were isolated in 17%

and 10% yield, respectively, as by-products.

6,7-Dimethoxy-1,1'-dimethyl-6'-(trifluoromethyl)-4,4'-biquinolin-2,2'(1H,1'H)-dione

(9a):

A mixture of 76.1 mg (0.30 mmol) of 6,7-dimethoxy-1-methyl-4-chloroquinolin-2(1H)-

one,[11] 78.5 mg (0.30 mmol, 1.0 equiv) of 4-chloro-1-methyl-6-(trifluoromethyl)quinolin-

2(1H)-one,[13] 49.0 mg (0.060 mmol, 10.0 mol%) of PdCl2(dppf)2, 23.3 mg (0.042 mmol, 7

mol%) of dppf, 106.6 mg (0.42 mmol, 0.7 equiv) of bis-(pinacolato)diboron, 293.2 mg (0.9

mmol, 4.5 equiv) of finely crushed KOH powder (analytical grade), and 2.0 mL of n-BuCl, in

a 2 mL Pyrex microwave vial was equipped with a magnetic stirring bar and sealed. The

resulting mixture was stirred for 5 min at room temperature under Ar and then heated for 30

min at 145 °C via single-mode microwave irradiation. After cooling to ambient conditions,

the solvent was removed under reduced pressure and the product directly purified by

automated flash chromatography using petroleum ether/EtOAc as eluent to 22.7 mg (17%) of

9a as orange solid, mp 237-239 °C (ethanol); IR (KBr) νmax 3436, 1649, 1309 cm–1; 1H-NMR

(360 MHz, CDCl3) δ: 3.62 (s, 3H), 3.86 (s, 6H), 4.06 (s, 3H), 6.55 (s, 1H), 6.62 (s, 1H), 6.83

(s, 1H), 6.91 (s, 1H), 7.53 (s, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H); 13C

NMR (90 MHz, CDCl3) δ: 29.9, 30.0, 56.3, 97.7, 107.8, 112.4, 115.3, 119.3, 119.4, 123.2,

124.6, 124.9, 125.1, 127.8, 136.3, 142.2, 144.2, 145.4, 146.2, 153.0, 161.3; MS (pos. APCI)

m/z 444 (100, M), 445 (25, M + 1). The known symmetrical bisquinolones 9b[13] and 7[11]

were isolated in 4% and 76% yields, respectively, as by-products.

Absorption and Emission Characteristics of Bisquinolones 72

6,7-Dimethoxy-1-methyl-4-phenylquinolin-2(1H)-one (10a):

A mixture of 76.1 mg (0.30 mmol) of 6,7-dimethoxy-1-methyl-4-chloroquinolin-2(1H)-

one),[11] 36.6 mg (0.30 mmol, 1.0 equiv) of phenylboronic acid, 0.7 mg (0.003 mmol, 1.0

mol%) of Pd(OAc)2, 2.7 mg (0.012 mmol, 4 mol%) of PPh3, 91.1 mg (0.9 mmol, 125 µL, 3.0

equiv) of Et3N, and 2.0 mL of DME/H2O (3:1), in a 2 mL Pyrex microwave vial was

equipped with a magnetic stirring bar and sealed. The resulting mixture was stirred for 5 min

at room temperature and then heated for 30 min at 150 °C via single-mode microwave

irradiation. After cooling to ambient conditions, the solvent was removed under reduced

pressure and the product directly purified by flash chromatography using petroleum

ether/EtOAc as eluent to 82.4 mg (93%) of 10a as a white solid, mp 135-137 °C (ethanol); IR

(KBr) νmax 3435, 1649, 1422, 1257 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.75 (s, 3H), 3.79

(s, 3H), 4.04 (s, 3H), 6.59 (s, 1H), 6.87 (s, 1H), 6.99 (s, 1H), 7.43-7.56 (m, 6H); 13C NMR

(90 MHz, CDCl3) δ: 29.8, 56.2, 97.4, 108.8, 113.6, 118.8, 128.6, 128.7, 128.8, 136.1, 137.6,

144.8, 150.4, 152.1, 162.0; MS (pos. APCI) m/z 295 (100, M), 296 (40, M + 1).

6,7-Dimethoxy-4-(4-methoxyphenyl)-1-methylquinolin-2(1H)-one (10b):

This material was prepared in an analogous fashion as described for 10a above, except that

45.6 mg (0.30 mmol, 1.0 equiv) of 4-methoxyphenylboronic acid is used to produce 83.9 mg

(86%) of 10b as light yellow crystals, mp 178-180 °C (ethanol); IR (KBr) νmax 3436, 1661,

1258, 822 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.77 (s, 3H), 3.79 (s, 3H), 3.89 (s, 3H), 4.04

(s, 3H), 6.56 (s, 1H), 6.85 (s, 1H), 7.03 (d, J = 8.9 Hz, 3H), 7.39 (d, J = 8.6 Hz, 2H); 13C

NMR (90 MHz, CDCl3) δ: 29.8, 55.4, 56.2, 97.4, 108.8, 114.1, 118.6, 128.6, 130.1, 132.0,

136.1, 144.8, 150.1, 151.9, 159.9, 162.1; MS (pos. APCI) m/z 325 (100, M+1).

Absorption and Emission Characteristics of Bisquinolones 73

6,7-Dimethoxy-4-(4-cyanophenyl)-1-methylquinolin-2(1H)-one) (10c):

This material was prepared in an analogous fashion as described for 10a above, except that

44.1 mg (0.30 mmol, 1.0 equiv) of 4-cyanophenyl boronic acid is used to produce 64.4 mg

(67%) 10c as a yellow solid, mp 223-225 °C (ethanol); IR (KBr) νmax 3476, 2227, 1652,

1424, 1260, 840 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.76 (s, 3H), 3.81 (s, 3H), 4.05 (s, 3H),

6.56 (s, 1H), 6.78 (s, 1H), 6.88 (s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H); 13C

NMR (90 MHz, CDCl3) δ: 29.9, 56.2, 97.6, 107.9, 112.6, 112.8, 118.3, 119.1, 129.6, 132.5,

136.3, 142.3, 145.2, 148.3, 152.6, 161.6; MS (pos. APCI) m/z 320 (100, M), 321 (20, M + 1).

6,7-Dimethoxy-1-methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)quinolin-2(1H)-one (11c):

Into a 25 mL round bottom flask, equipped with a magnetic stirring bar, 500 mg (1.97 mmol)

of 6,7-dimethoxy-1-methyl-4-chloroquinolin-2(1H)-one,[11] and 386 mg (3 equiv, 5.94 mmol)

of fresh sodium azide together with 10 mL DMF were added. The reaction mixture was then

heated at 100 °C for 16h. After the reaction was completed the solvent was removed under

reduced pressure and the residue purified by dry-flash chromatography with EtOAc as eluent.

The solvent was removed under reduced pressure to provide 292 mg (57%) of 4-azido-6,7-

dimethoxy-1-methylquinolin-2(1H)-one as a colorless solid, mp 163-164 °C (decomp.)

(ethyl acetate); IR (KBr) νmax 3429, 2120, 1631, 1427, 1259 cm–1; 1H-NMR (360 MHz,

CDCl3) δ: 3.70 (s, 3H), 3.95 (s, 3H), 4.02 (s, 3H), 6.37 (s, 1H), 6.76 (s, 1H), 7.20 (s, 1H); 13C

NMR (90 MHz, CDCl3) δ: 29.6, 56.2, 97.1, 104.1, 104.5, 108.8, 135.9, 145.1, 147.8, 153.1,

162.0; MS (pos. APCI) m/z 260 (100, M), 261 (15, M + 1). Into a 5 mL microwave glass

vial, equipped with a magnetic stirring bar, 312 mg (1.2 mmol) of the above mentioned azide,

30 mg (0.1 equiv, 0.12 mmol) CuSO4.5H2O and 24 mg (0.1 equiv, 0.12 mmol) sodium

Absorption and Emission Characteristics of Bisquinolones 74 ascorbate together with 2 mL of DMF were added, followed by 145 µL (135 mg, 1.1 equiv,

1.32 mmol) of phenylacetylene. The reaction mixture was sealed and stirred for 5 min.

Thereafter, the vial was heated at 110 °C for 20 min in a Biotage Initiator microwave

instrument. After the reaction was completed the resulted mixture was poured onto 100 mL

of ice-water and stirred for an additional 1 h. The formed solids were filtered off on a

Büchner funnel and washed extensively with additional 2 x 500 mL portions of water to give

237 mg (55%) of pure 11c, mp 234-235 °C (ethanol); IR (KBr) νmax 3436, 3132, 1641, 1584,

1462, 1264, 1017 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.79 (s, 3H), 3.84 (s, 3H), 4.05 (s,

3H), 6.71 (s, 1H), 6.87 (s, 1H), 7.30 (s, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.47-7.51 (m, 2H), 7.94

(d, J = 7.2 Hz, 2H), 8.19 (s, 1H); 13C NMR (90 MHz, CDCl3) δ: 30.2, 56.3, 97.4, 106.1,

109.0, 113.3, 121.0, 125.9, 128.9, 129.1, 129.5, 136.8, 142.7, 145.8, 148.1, 153.5, 161.4; MS

(pos. APCI) m/z 362 (100, M), 363 (20, M + 1), 334 (85, M – 28).

1-Methyl-4-(phenylethynyl)quinolin-2(1H)-one (12a):

Into a 10 mL round bottom flask, equipped with a magnetic stirring bar, 200 mg (0.84 mmol)

of 1-methyl-4-bromoquinolin-2(1H)-one,[16] 102 µL (1.1 equiv, 95 mg, 0.93 mmol) of

phenylacetylene, 59 mg (0.084 mmol, 10 mol%) of Pd(PPh3)2Cl2, 16 mg (0.084 mmol, 10

mol%) of CuI, 165 µL (1.1 equiv, 120 mg, 0.93 mmol) of N-ethyldiisopropylamine and 5.0

mL of dioxane were added. The resulting reaction mixture was stirred for 2 hrs at room

temperature. Thereafter, the solvent was removed under reduced pressure and the crude

residue purified by dry-flash chromatography using petroleum ether/EtOAc (1:2) as eluent to

yield 199 mg (91%) of 12a as a colorless solid mp 106-107 °C (ethanol); IR (KBr) νmax 3434,

2923, 2852, 1654, 750 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 3.76 (s, 3H), 6.99 (s, 1H), 7.32-

7.45 (m, 5H), 7.62-7.68 (m, 3H), 8.16 (d, J = 7.9 Hz, 1H); 13C NMR (90 MHz,

CDCl3) δ: 29.5, 84.0, 98.7, 114.3, 120.1, 121.9, 122.3, 124.5, 127.5, 128.6, 129.5, 131.1,

132.0, 132.5, 139.9, 161.5; MS (pos. APCI) m/z 259 (100, M), 260 (20, M + 1).

Absorption and Emission Characteristics of Bisquinolones 75

6,7-Dimethoxy-4-(phenylethynyl)quinolin-2(1H)-one (12b):

Into a 10 mL round bottom flask equipped with a magnetic stirring bar, 500 mg (1.76 mmol)

of 4-bromo-6,7-dimethoxyquinoline 1-oxide,[16] 213 µL (1.1 equiv, 198 mg, 1.94 mmol) of

phenylacetylene, 124 mg (0.18 mmol, 10 mol%) of Pd(PPh3)2Cl2, 34 mg (0.084 mmol, 10

mol%) of CuI, 437 µL (1.5 equiv, 342 mg, 2.64 mmol) of N-ethyldiisopropylamine and 5.0

mL of dioxane were added. The resulting reaction mixture was stirred for 2h at room

temperature. Thereafter, the solvent was removed under reduced pressure and the crude

residue purified by dry-flash chromatography using petroleum ether/EtOAc (1:2) as eluent to

yield 377 mg (70%) of 6,7-dimethoxy-4-(phenylethynyl)quinoline 1-oxide as a colorless

solid, mp 185-186 °C (EtOAc); IR (KBr) νmax 3436, 2784, 2200, 1659, 1513, 1420, 1264,

1145, 855 cm–1; 1H-NMR (360 MHz, CDCl3) δ: 4.06 (s, 3H), 4.07 (s, 3H), 7.32 (d, J = 6.44,

1H), 7.39-7.4 (m, 3H), 7.53 (s, 1H), 7.53-7.59 (m, 2H), 8.04 (s, 1H), 8.33 (d, J = 6.41, 1H); 13C NMR (90 MHz, CDCl3) δ: 56.0, 56.1, 84.8, 98.3, 98.5, 106.7, 111.7, 121.5, 121.9, 129.4,

130.4, 132.2, 132.4, 135.0, 145.6, 152.9, 161.3; MS (pos. APCI) m/z 306 (100, M), 290 (18,

M - 16). A stirred solution of 405 mg (1.33 mmol) of the above quinoline 1-oxide in 25 mL

of MeOH, placed in a crystallization dish, was irradiated with an OSRAM Ultra-Vitalux®

300W lamp for 90 min. The addition of a several 5 mL portions of MeOH is needed to

prevent the reaction mixture from running dry. After the rearrangement is complete, the

reaction mixture is concentrated under vacuum and the residue is poured onto cold water,

stirred for 15 min and filtered to give 363 mg (89%) of 12b as a light yellow solid, mp 269-

271 °C (ethanol); IR (KBr) νmax 3436, 2784, 2200, 1659, 1513, 1420, 1264, 1145 cm–1; 1H-

NMR (360 MHz, CDCl3) δ: 3.85 (s, 3H), 3.88 (s, 3H), 6.62 (s, 1H), 6.92 (s, 1H), 7.34 (s, 1H),

7.52-7.53 (m, 3H), 7.73-7.74 (m, 2H), 11.79 (s, 2H); 13C NMR (90 MHz, CDCl3) δ: 57.3,

85.5, 98.3, 107.0, 112.5, 116.0, 121.5, 129.4, 131.0, 132.2, 133.0, 133.5, 135.0, 146.5, 153.5,

161.2; MS (pos. APCI) m/z 305 (100, M).

Absorption and Emission Characteristics of Bisquinolones 76

NCH3

O

NCH3

O

HOHO

6,6'-Dihydroxy-1,1'-dimethyl-4,4'-biquinolin-2,2'(1H,1'H)-dione (18):

A mixture of 229.6 mg (0.61 mmol) of biscarbostiryl 5[11] in a 10 mL Pyrex microwave vial

was equipped with a magnetic stirring bar and sealed. After purging with Ar for 5 minutes

and the addition of 3.0 mL of DCM, 536.16 mg (2.14 mmol, 206 µL, 3.5 equiv) of BBr3 was

added under ice cooling. The resulting mixture was stirred for 16 h at room temperature. The

resulting mixture was poured onto ice water and after stirring for 20-30 minutes, the required

product is collected by filtration to yield 204 mg (96%) of 18 as a yellowish solid, mp >300

°C (ethanol); IR (KBr) νmax 3432, 3268, 1638, 1565 cm–1; 1H-NMR (360 MHz, DMSO-d6) δ:

3.67 (s, 6H), 6.51 (d, J = 2.6 Hz, 2H), 7.13 (dd, J = 9.1 Hz, 2.7 Hz, 2H), 7.52 (d, J = 9.1 Hz,

2H), 9.45 (s, 2H); 13C NMR (90 MHz, DMSO-d6) δ: 29.7, 111.1, 117.1, 120.4, 120.9, 121.7,

133.7, 145.6, 152.8, 160.3; MS (neg. APCI) m/z 348 (100, M), 349 (20, M + 1), 347 (10, M –

1), 346 (30, M - 2).

6,6'-(Tetraethyleneoxy)-1,1'-dimethyl-4,4'-biquinolin-2,2'(1H,1'H)-dione (13):

A mixture of 52.3 mg (0.15 mmol) of 6,6'-dihydroxy-1,1'-dimethyl-4,4'-biquinolin-

2,2'(1H,1'H)-dione (18) in a 50 mL round bottom flask was equipped with a magnetic stirring

bar and sealed. After purging with Ar for 5 min 5.0 mL of a DMF-K2CO3 (K2CO3, 82.9 mg,

0.60 mmol, 4.0 equiv) suspension was added dropwise at 90 °C under Ar. After an additional

30 min 90.5 mg of tetraethylene glycol ditosylate (0.18 mmol, 72 µL, 1.2 equiv) was added

dropwise. The resulting mixture was stirred for 16 h at 90 °C under Ar. After removal of the

solvent under reduced pressure the crude product was purified on a SP1 automatic flash

chromatography system using DCM/acetone as eluent to yield 53.9 mg (71%) of crown ether

13 as a yellowish solid, mp 262-263 °C (ethanol); IR (KBr) νmax 3436, 2924, 2856, 1654 cm–

Absorption and Emission Characteristics of Bisquinolones 77 1; 1H-NMR (360 MHz, DMSO-d6) δ: 3.39-3.45 (m, 8H),3.52-3.54 (m, 4H), 3.69 (s, 6H),

3.81-3.85 (m, 2H), 4.08-4.12 (m, 2H), 6.56 (d, J = 2.6 Hz, 2H), 6.68 (s, 2H), 7.36 (dd, J = 9.2

Hz, 2.7 Hz, 2H), 7.62 (d, J = 9.3 Hz, 2H); 13C NMR (90 MHz, DMSO-d6) δ: 29.8, 68.0, 68.7,

70.2, 70.4, 111.5, 117.1, 119.2, 120.1, 122.7, 134.6, 145.8, 153.6, 160.6; MS (pos. APCI) m/z

506 (100, M), 507 (45, M + 1).

Absorption and Emission Characteristics of Bisquinolones 78 5. References

[1] a) G. Zheng, Y.-M. Guo, W.-H. Li, J. Am. Chem. Soc. 2007, 129, 10616-10617; b)

E. K. Feuster, T. E. Glass, J. Am. Chem. Soc. 2003, 125, 16174-16175; c) E. P.

Diamandis, Analyst 1992, 117, 1879-1884; d) F. Badalassi, P. Crotti, G. Klein, J.-

L. Reymond, Eur. J. Org. Chem. 2004, 2557-2566; e) S. R. Trenor, A. R. Shultz,

B. J. Love, T. E. Long, Chem. Rev. 2004, 104, 3059-3078; f) M.-S. Schiedel, C. A.

Briehn, P. Bauerle, Angew. Chem. Int. Ed. 2001, 40, 4677-4680; g) M. Kozlov, V.

Bergendahl, R. Burgess, A. Goldfarb, A. Mustaev, Anal. Biochem. 2005, 342, 206-

213.

[2] a) P. Ge, P. R. Selvin, Bioconjugate Chem. 2008, 19, 1105-1111; b) D. J. Williams,

M. Gilmore, L. Steward, M. Verhagen, K. R. Aoki, US Patent 2006, 2006063221;

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Summary 82 Summary

The thesis is divided into 4 chapters which include an overview of transition-metal catalyzed

carbon-carbon cross-coupling and homocoupling reactions based on highly functionalized

novel quinolones. In addition, some recent literature related to C-C coupling reactions is

discussed.

Chapter A is a summary on transition-metal-catalyzed carbon-carbon coupling reactions.

Transition-metal-catalyzed carbon-carbon bond formations have caused a real revolution in

organic syntheses in the past decades. Aryl-aryl bond formation has been known for more

than a century and was one of the first reactions involving a transition metal. This protocol

has been substantially improved and expanded over the past 30 years, providing an

indispensable and simple methodology for preparative organic chemists. Recent

developments in the cross-coupling of substrates are noteworthy and has previously been

thought impossible. Owing to their widespread applications in the organic synthesis a plethora

of literature has been published. The following are the well-known transition-metal-catalyzed

reactions: Suzuki, Heck, Sonogashira, Stille, Ullmann, Fukuyama, Negishi, Kumada, and

Hiyama cross-couplings.

Now-a-days, transition metal-catalyzed carbon-carbon bond forming reactions are

powerful tools in the toolbox of synthetic organic chemist and cover a extremely wide range

of modifications and applications since first developed in 1970s. In all the methodologies

different activation modes have been utilized. Carrying out these cross/homo-coupling

reactions under controlled microwave irradiation can be considered today as a very effective

way. It is indicative that the combined approach of microwave irradiation and homogenous

catalysis can offer a nearly synergistic strategy in the sense that the combination has greater

potential than its two separate parts in isolation.

Chapter B is focused on the efficient synthesis of functionalized 4,4′-bisquinolones by

microwave-assisted palladium(0)-catalyzed one-pot borylation/Suzuki cross-coupling

reactions, or via nickel(0)-mediated homocouplings (Ullmann reaction) of 4-chloroquinolin-

2(1H)-one precursors. Substituted biaryls play an important role in organic chemistry. Many

natural products, pharmaceuticals, herbicides and fine chemicals contain symmetrical or

unsymmetrical biaryl units. Important structural motifs are, for example, bipyridines,

Summary 83 bithiophenes, and bipyrroles. The synthesized novel class of bis-heterocycles are of interest

both as aza-analogues of biscoumarin natural products (e.g., 4,4′-biisofraxidin). Both methods

rapidly deliver bisquinolones in good to excellent yields employing controlled microwave

irradiation (MW) and are applicable not only toward the preparation of the desired

symmetrical bisquinolones but also as general methods for other types of symmetrical biaryl

synthesis. The procedures are particularly valuable for the preparation of novel types of

bisquinolones, which are presently under investigation as fluorescent probes.

In chapter C, a method for the gram-scale preparation of functionalized 4,4´-

bisquinolones using a microwave-assisted Ullmann-type homocoupling reaction is described.

The method is catalytic in nickel(0) which is generated in situ by reduction from an

inexpensive Ni(II) source and utilizes readily available 4-chloroquinolin-2(1H)-ones as starting

materials. In contrast to the alternative palladium(0)-catalyzed one-pot borylation/Suzuki

cross-coupling reaction, the new method avoids the use of an expensive catalyst and cross-

coupling partner such as bis(pinacolato)diboron. The structural sub-unit of symmetrical biaryls

plays an important role in organic and medicinal chemistry, and is found in a wide variety of

natural products including alkaloids such as the anti-HIV alkaloid michellamine B, coumarins,

polyketides and terpenes. Compounds incorporating symmetrical biaryl moieties also find

applications as conductors for thin film transistor applications, as electronic and optoelectronic

materials, as chiral ligands in catalysis (e.g., BINAP) and in chiral or achiral liquid crystals. In

view of the substantial interest and broad application of symmetrical biaryls, considerable

efforts have been undertaken to achieve efficient, economical, safe, and environmentally

benign methods for their preparation in many academic and industrial laboratories. Since the

first biaryl couplings performed by Ullmann over a century ago applying stoichiometric

amounts of copper metal, the catalytic use of transition metals, especially of palladium and

nickel, in the formation of symmetrical biaryls is now well established. We have developed a

Ni(0)-catalyzed reductive homocoupling reaction of easily accessible 4-chloroquinolin-2(1H)-

ones that provides 4,4′-bisquinolones in good yields. In contrast to our previous protocol, this

new method only requires 0.25 equivalents of a comparatively inexpensive Ni source and does

not rely on chromatography for product isolation. Key to the success was a change of solvent

and the combined use of bidentate and monodentate ligands providing more active Ni(0)

catalytic species. The method is therefore scalable and will allow us to further study the

properties of these novel types of bisheterocylces.

Chapter D comprises the fluorescent and computational studies of quinolones and

bisquinolones derivatives. The electronic spectra of biscarbostyrils exhibit unusual properties

Summary 84 in comparison to the corresponding carbostyrils. Similar absorption spectra are accompanied

by red-shifted emission maxima up to 520 nm. Unsubstituted biscarbostyril displays the

unusual property of a blueshift in dimethylsulfoxide as compared to water. For a set of

diversely substituted biscarbostyrils and related 4-aryl-2-quinolinones very selective

substitution patterns in order to increase fluorescence quantum yields are observed. In

addition to the traditional coumarin-based fluorophores, comparatively few derivatives of the

structurally related quinolin-2(1H)-ones (carbostyrils) have found applications as fluorescence

markers. Carbostyrils are more resistant towards pH changes (ring opening) and other thermal

or chemical (oxidative damage) bleaching reactions. Moreover, they are easily functionalized,

leading to versatile fluorescent tags for proteins or polysaccharides. Their photophysical

properties and chemical stability, thus, makes this class of compounds useful for

bioconjugation in aqueous media. In chapter D a combined experimental and computational

study on photophysical properties of 4,4’-biscarbostyrils is presented. In addition, results for

4-aryl-, 4-hetaryl-, and 4-arylethinylcarbostyrils are also discussed. Experimental absorption

and fluorescence characteristics are also provided for the crown ether derivative and the

diphenyl phosphine- and phosphine oxide analogues as well as their bromine-containing

precursors. Since all investigated bisquinolones are axially chiral, a HPLC study of

enantioseparation effects on the Pirkle type chiral stationary phase (CSP) ULMO is also

presented. Absorption and emission maxima of selected mono- and biscarbostyrils, calculated

by time-dependent density functional theory, show good agreement with the corresponding

experimental data, especially with the B3PW91/TZVP//BP86/SVP procedure. Calculated

Stokes’s shifts also nicely correlate with the experimental ones, again with the exception of

only one compound. Furthermore, transitions in biscarbostirys are characterized by very low

oscillator strengths, responsible for their low fluorescence quantum yields.