Method development for the synthesis of organosulfur compounds and their functionalization by C–H activation and reductive borylation Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der RWTH Aachen University zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigte Dissertation vorgelegt von Master of Science (M. Sc.) Carl Albrecht Dannenberg aus Gummersbach, Deutschland Berichter: Universitätsprofessor Dr. rer. nat. Carsten Bolm Universitätsprofessor Dr. rer. nat. Dieter Enders Tag der mündlichen Prüfung: 02.03.2017 Diese Dissertation ist auf den Internetseiten der Universitätsbibliothek online verfügbar.
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Method development for the synthesis of organosulfur
compounds and their functionalization by C–H activation and
reductive borylation
Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der RWTH Aachen
University zur Erlangung des akademischen Grades eines Doktors der
Naturwissenschaften genehmigte Dissertation
vorgelegt von
Master of Science (M. Sc.)
Carl Albrecht Dannenberg
aus Gummersbach, Deutschland
Berichter: Universitätsprofessor Dr. rer. nat. Carsten Bolm
Universitätsprofessor Dr. rer. nat. Dieter Enders
Tag der mündlichen Prüfung: 02.03.2017
Diese Dissertation ist auf den Internetseiten der Universitätsbibliothek online verfügbar.
The work presented in this thesis was carried out from April 2014 until November 2016 at
the Institute of Organic Chemistry, RWTH Aachen University, Aachen (Germany) under the
supervision of Professor Dr. Carsten Bolm.
I would like to thank Professor Dr. Carsten Bolm for the opportunity to work in his group,
the scientific freedom, excellent working conditions and his guidance throughout this thesis.
Parts of this work have already been published:
C. A. Dannenberg, V. Bizet, C. Bolm, Synthesis 2015, 47, 1λ51‒1λ5λ.
C. A. Dannenberg, L. Fritze, F. Krauskopf, C. Bolm, Org. Biomol. Chem. 2017, 15, 1086‒1090.
Für meine Familie
Table of contents 1. Theoretical Background ................................................................................................1
1.1. Introduction to sulfoximines and sulfilimines ...........................................................1
4.1. General methods and chemicals ........................................................................ 107
4.2. Determination of physical data ........................................................................... 108
4.3. Synthesis and analytical data of compounds ...................................................... 110
4.3.1. Synthesis of substrates................................................................................ 110
4.3.2. Synthesis of N-alkylsulfoximines 31 and N-methylsulfoximines 30 .............. 113
4.3.3. Synthesis and characterisation data of N,S-dimethyl-S-phenylsulfiliminium bromide (119a) ...................................................................................................... 128
4.3.4. Synthesis of N-cyanosulfoximines 35 .......................................................... 129
4.3.5. One-pot synthesis of N-cyano-S-methyl-S-phenylsulfoximine (35a)............. 139
4.3.6. Synthesis of enantioenriched starting material and product ......................... 140
4.3.7. Synthesis of boronic acid pinacol esters ...................................................... 141
4.3.8. Isolation of N-methylbenzenesulfinamide (132a) as by-product ................... 143
4.3.9. Synthesis of boronic acid neopentyl ester 113a ........................................... 143
4.3.10. Synthesis of ortho-borylated N-protected sulfoximines 133........................ 144
4.3.11. Isolation of N-methylbenzenesulfinamide (132a) as side product .............. 155
4.3.12. Synthesis of N-methyl-S-methyl-S-((1,1'-biphenyl)-2-yl)sulfoximine (136a) 155
4.3.13. Synthesis of N-acetylsulfilimines ................................................................ 157
4.3.14. Synthesis of N-acetylsulfilimineacrylates ................................................... 167
Two improved iridium-catalyzed borylation processes were published in 2002 by Ishiyama,
Miyaura, Hartwig and co-workers, who used iridium complexes of bipyridines,[132] and by
Introduction
31
Smith III and co-workers, who employed iridium-phosphine complexes.[133] Decisive
advantages of the first process over the second are the higher reactivities of the iridium
complexes and milder reaction conditions (room temperature to 80 °C compared to 100 to
150 °C).[107f, 134] Using this catalytic approach variously substituted arenes 77 could be
borylated in moderate to excellent yields under relatively mild conditions. However, a drastic
excess of the arene 77 was still necessary to allow an efficient conversion and the selectivity
of mono-substituted arenes 77 could not be significantly improved (Scheme 42).[132] In a
subsequent study both the catalyst and the bipyridine ligand were optimized further, thereby
also reducing the necessary amount of arene 77 considerably (from 60 to 2 equivalents
compared to B2pin2). Testing various iridium(I) precursors revealed that the use of
[Ir(COD)(OMe)]2 generated the most active catalyst, which was found to be a 16e- complex
with the general formula [Ir(N–N)(Bpin)3] (complex 86, Scheme 42, where N–N stands for the
used bipyridine ligand). The lack of additional vacant coordination sites of this species for a
directing group, next to the one for the C–H bond of the substrate, can arguably explain the
lack of selectivity of the process towards any directing effects by basic functionalities. Thus,
the regioselectivity of this process is mainly controlled by steric factors. [125a, 134] The
investigation of the bipyridine ligand revealed, that while electron-donating substituents in the
4,4’-position were beneficial for the activity of the catalyst, the opposite trend was observed for
electron-withdrawing groups. Also, methyl groups in 6,6’-position prevented catalysis
completely, likely because the bipyridine ligand cannot bind to the iridium complex.[135]
Scheme 42: Bipyridine-assisted borylation of arenes and catalytically active species 86.
To enable effects of directing groups in these reactions, different strategies have been
developed to allow site-selective borylations. In the following the three main strategies are
shortly described. The first method involves a relay-directed borylation. One example for this
strategy is the use of a silyl-directing group 87 as described by Hartwig and co-workers in
2008. In contrast to standard directing groups, the dialkyl hydrosilyl group 87 used in this
process is not Lewis basic and can replace one of the Bpin ligands by Si–H/Ir–B σ-bond
metathesis (see complex 89, Scheme 43). Employing the previously established system of
iridium catalyst and bipyridine ligand, together with a combination of B2pin2 and HBpin four
Introduction
32
substrates could be borylated in ortho-position (88) in moderate to good yields. While the
directing group is easily removable, the additional steps to introduce and cleave it as well as
loss of product due to diborylated side products and a narrow scope exacerbate the synthetic
value of this protocol (Scheme 43).[136]
Scheme 43: Ortho-borylation using a silyl-directing group.
A second strategy utilizes outer-sphere direction, in which the directing effect of the directing
group stems from an interaction with the ligand of the catalyst. Smith III, Maleczka, Singleton
and co-workers utilized mono-Boc-protected anilines 90 in combination with the standard
iridium-bipyridine catalyst system to control the ortho-selectivity. The acidic NH group of the
aniline 90 can form a bond with the basic oxygen atom of one of the catalyst’s boryl groups
(see complex 92, Scheme 44). For this procedure electron-donating substituents on the
bipyridine ligand proved beneficial, since these increase the basicity of the oxygen atom,
thereby strengthening its interaction with the NH bond (Scheme 44). A drawback of this
strategy is the incomplete ortho-selectivity, as only para-substituted substrates could
exclusively be borylated in ortho-position. Furthermore, the protocol hinges upon a suitable
directing group, since the authors found that even a small change in the directing group, e.g.
using free anilines, could completely prevent the desired reaction.[125a, 137]
Scheme 44: Outer-sphere-directed borylation.
Introduction
33
The third strategy enables selective ortho-borylation through chelate-direction. The key to this
method is the generation of an additional vacant coordination site for the coordination of a
basic directing group in the catalyst-substrate complex through ligand modification.[125a] One
example is the regioselective ortho-borylation of benzoates 93 reported by Ishiyama, Miyaura
and co-workers (Scheme 45). Instead of using a bipyridine-based ligand, the electron-poor
phosphine P[3,5-(CF3)2C6H3]3 in combination with the standard iridium catalyst enables a free
coordination site, which can be exploited for coordination by the oxygen of the benzoates 93
(complex 95, Scheme 45) to afford the ortho-borylated products 94 in high yields and complete
regioselectivity. Disadvantageously, an excess of benzoate 93 (5.0 equivalents) is necessary
to prevent ortho-diborylation.[125a, 138]
Scheme 45: Chelate-directed ortho-borylation.
Another protocol developed by Lassaletta, Fernández and co-workers utilizes hemilabile
N,N-ligands to achieve a nitrogen-directed iridium-catalyzed ortho-borylation. After screening
various hemilabile ligands, picolinaldehyde N,N-dibenzylhydrazone 97 in combination with
[Ir(COD)(OMe)]2 proved to be an efficient system delivering ortho-borylated arylpyridines and
isoquinolines 98 in moderate to good yields under relatively mild conditions. Depending on the
steric hindrance around the biaryl axis of the substrate, different products were observed.
Sterically hindered products exhibited no internal N–B bond interaction, delivering product 98a.
In contrast, if less hindered substrates were used, the more polar, four-coordinate boron
species 98b were generated (Scheme 46).[125a, 139]
Introduction
34
Scheme 46: Ortho-borylation of arylpyridines and isoquinolines.
The authors also proposed a mechanism for this reaction, which is depicted in a general
fashion with an arbitrary directing group and hemilabile N,N-ligand (Scheme 47). In the first
step, the directing group of substrate 99 can coordinate to the catalytically active species 86,
generating iridium complex 100. Due to the hemilability of the N,N-ligand, a vacant coordination
site can be temporarily generated by dissociation of the weaker nitrogen donor forming the
coordinatively unsaturated intermediate 101. From this species, ortho-C–H activation is likely
favored, leading to iridium species 102. Reductive elimination under formation of the desired
ortho-C–B bond leads to species 103, which can recoordinate the hemilabile ligand on the
vacant coordination site (104). In the last step, dissociation of the product 105 and subsequent
reaction with B2pin2 regenerate the catalytically active species 86.[125a, 139]
Introduction
35
Scheme 47: General mechanism for the ortho-borylation using hemilabile N,N-ligands.
In a recent report by Chattopadhyay and co-workers the chelate-directed ortho-borylation was
conducted using 8-aminoquinoline (107) as hemilabile ligand leading to an efficient conversion
of aldehydes 106 into the corresponding borylated products 108. To achieve borylation, the
aldehydes 106 were in situ transformed to the corresponding N-tert-butylimines to allow
coordination to the iridium catalyst. In comparison to other protected imines (e.g. methyl- and
isopropylimine), the tert-butyl group exhibited a fitting amount of steric hindrance to create a
vacant coordination site and direct borylation into the ortho-position (Scheme 48, top).
Interestingly, by using 3,4,7,8-tetramethyl-1,10-phenanthroline (109) instead of
8-aminoquinoline (107) as ligand, meta-borylation (110) proved possible under otherwise
identical reaction conditions. The authors propose a combination of an electrostatic interaction
between the iridium complex and the imine as well as a secondary B–N bond interaction
between the Bpin ligand and the imine as cause for the success of this protocol (Scheme 48,
bottom).[140]
Introduction
36
Scheme 48: Regioselective ortho- and meta-borylation of aldehydes.
While the vast majority of the reported protocols for borylation are catalyzed by iridium
complexes, several reports also exist for the selective ortho-borylation using palladium[141]-,
ruthenium[142]- and rhodium[143]-catalysis as well as under metal-free conditions.[125a, 144]
1.2.3. Reductive borylation
As site-selectivity remains a challenge in directing group-assisted borylation, the transition
metal-catalyzed borylation of aryl halides and sulfonates presents a viable alternative
delivering boronic acids or esters in high yields (Scheme 49).[145]
Scheme 49: General scheme for a catalyzed reductive borylation.
In 1995, a seminal report by Miyaura and co-workers employed PdCl2(dppf) in combination
with B2pin2 to convert aryl bromides and iodides 111 to arylboronic esters 85 in low to excellent
yields. Additionally, KOAc proved to be necessary for high yields and selectivity, since stronger
bases such as K3PO4 and K2CO3 promoted a Suzuki–Miyaura coupling between the generated
arylboronic ester and the starting material (Scheme 50).[146]
Introduction
37
Scheme 50: Palladium-catalyzed borylation of aryl halides (Miyaura borylation).
Mechanistically, this so called Miyaura borylation closely follows the Suzuki–Miyaura coupling,
as it also contains the three key steps of oxidative addition, transmetalation and reductive
elimination (compare Scheme 27).[145a, 146] Only two years later, reports by Masuda and co-
workers highlighted the use of pinacolborane as sole boron source for the borylation reaction,
accessing a different mechanism involving a cationic palladium intermediate (Masuda
borylation).[145a, 147]
Subsequent reports developed the reductive borylation in terms of the catalyst and the possible
starting materials. Not only palladium, but also nickel, copper and zinc catalysts proved to be
applicable. The activity of these catalysts crucially depends on the right choice of ligand and
base. Furthermore, even aryl chlorides and aryl fluorides could be reductively borylated. [145a,
145b, 148]
Recently, the reductive borylation has been further expanded enabling the formation of C–B
bonds from C–C, C–N, C–O and C–S bonds. In 2012, Tobisu, Chatani and co-workers
developed a rhodium-catalyzed synthesis for the borylation of nitriles 112 with bis(neopentyl
glycolato)diboron (B2nep2). The boronic esters 113 could be obtained in moderate to excellent
yields by cleavage of the C–CN bond (Scheme 51). Importantly, this protocol is compatible
with common functional groups such as esters, ethers, chlorides and fluorides. The latter two
allow for an orthogonal functionalization by cross-coupling making this protocol synthetically
attractive.[149]
Scheme 51: Rhodium-catalyzed reductive borylation of nitriles 112.
Introduction
38
Subsequently, Chatani, Tobisu and co-workers also reported on the borylative cleavage of
C–N bonds employing nickel catalysis in 2014.[150] The combination of Ni(COD)2 with an
NHC ligand (IMes•HCl) and B2nep2 as borylating agent proved suitable to convert N-aryl
amides and carbamates 114 in low to moderate yields to the boronic esters 113 (Scheme 52).
Scheme 52: C–N bond cleavage by reductive borylation.
Also, Martin and co-workers demonstrated the C–O fission of aryl ethers 115 by reductive
borylation.[151] Using tricyclohexylphosphine and sodium formate under otherwise similar
conditions to the system utilized by Tobisu, Chatani and co-workers various aryl ethers 115
could be borylated in moderate to good yields (Scheme 53). Concurrently, Tobisu, Chatani and
co-workers revealed that both nickel and rhodium catalysis is suitable to affect the borylative
cleavage of the C(aryl)–O bond of 2-pyridiyl ethers. As these are often used as directing
groups, this protocol showed an effective method to remove and simultaneously valorize the
products after C–H functionalization.[152]
Scheme 53: C–O bond cleavage by reductive borylation.
Only recently, Hosoya and co-workers reported on the borylation of aryl sulfides 1. A catalytic
system consisting of [Rh(OH)(COD)]2 and tricyclohexylphosphine could efficiently catalyze the
reductive borylation of various aryl methyl sulfides 1 under relatively mild reaction conditions.
Importantly, efficient promotion of the catalysis was only achieved when the rhodium catalyst
was preconditioned with the phosphine ligand and the boron source (Scheme 54).[153]
Additionally, albeit in lower yields, the procedure was also applicable to diphenyl sulfide and
methyl phenyl sulfoxide. Coincidentally, the group of Yorimitsu also reported on the borylation
Introduction
39
of aryl sulfides 1 by palladium-NHC catalysis strikingly demonstrating that the catalytic system
has to be tailored for the starting material to achieve catalysis.[154]
Scheme 54: Rhodium-catalyzed reductive borylation of aryl methyl sulfides 1.
40
Results and Discussion
41
2. Results and Discussion
2.1. Synthesis of N-alkylated sulfoximines
2.1.1. Background and aim of the project
N-Alkyl- 31 and N-methylsulfoximines 30 represent a synthetically valuable group of bioactive
compounds in the sulfoximine family. Various pathways are described to obtain N-alkyl- 31
and N-methylsulfoximines 30, albeit most of these require NH-sulfoximines 7 as substrates for
their synthesis (see chapter 1.1.3.). The product scope of the described protocols is rather
limited or only applicable to N-alkylsulfoximines 31, but not to N-methylsulfoximines 30.
Literature procedures that generate the desired sulfoximines directly from sulfides 1 are rare,
as only one report by Schaumann and co-workers is known, which is however limited to
N-methylsulfoximines 30. The protocol uses N-methyl-O-mesitylsulfonyl-hydroxylamine (33)
as imination source and m-CPBA in a subsequent oxidation for the synthesis of the desired
N-methylsulfoximines 30.[82] As the synthesis of these sulfoximines was not their primary
target, the yields and the substrate scope (4 examples) were rather narrow. Thus, we were
interested in developing a straightforward synthesis of N-alkyl- 31 and N-methylsulfoximines
30 using a sequential imination/oxidation procedure (Scheme 55).
Scheme 55: Synthetic strategies towards the synthesis of N-alkyl/N-methylsulfoximines.[155]
Results and Discussion
42
2.1.2. Project realization
2.1.2.1. Previous results
The project was initiated by Dr. Vincent Bizet and his preliminary results are summarized in
the following. In initial attempts primary amines 117 were employed as imination source for the
envisioned process. As an investigation based on mass spectrometry by Cooks and co-
workers showed, treatment of alkyl amines with bromine leads to N-bromoalkylamines 118.[156]
These would in a subsequent step react with thioanisole (1a) to produce alkyl sulfiliminium
bromides 119.[157] Oxidizing alkyl sulfiliminium bromides 119 should then lead to the desired
N-alkylated sulfoximines 31.
In a first experiment, a combination of MeNH2 (117a, 2.8 equivalents) and Br2 (1.4 equivalents)
in methanol was reacted at room temperature. After stirring for 5 min to form
N-bromomethaneamine (118a), thioanisole (1a) was added and the reaction mixture was
stirred for another 10 min. This led to full conversion of thioanisole (1a). Analysis by 1H NMR
spectroscopy revealed the crude mixture as the desired N-methylsulfiliminium bromide (119a)
and sulfoxide 2a formed in a 92:8 ratio (see Table 1, entry 1). Next, the reaction parameters
were varied to minimize or avoid the formation of sulfoxide 2a. Firstly, the reaction was carried
out at 0 °C. However, this resulted in a lower sulfilimine to sulfoxide ratio (85:15, see Table 1,
entry 2). Secondly, the substrate/reagent ratio was varied. Employing 2.0 equivalents of
methylamine and 1.0 equivalent of bromine was detrimental for the formation of the sulfilimine
(Table 1, entry 3). Also, 4.0 equivalents of methylamine and 2.0 equivalents of bromine did not
improve the ratio of sulfilimine to sulfoxide (Table 1, entry 4). Lastly, different solvents were
tested as reaction medium. Both ethanol and H2O were utilized and gave similar sulfilimine to
sulfoxide ratios as methanol (Table 1, entries 5–6). Notably, the use of 2,2,2-trifluoroethanol
as solvent reversed the selectivity of the reaction yielding the sulfoxide as major product (Table
1, entry 7). With DCM as solvent an almost equal formation of sulfilimine and sulfoxide was
observed (Table 1, entry 8), while both products could not be observed using acetone (Table
1, entry 9). The comparatively low ratio in DCM and the absence of products in acetone might
be attributed to their inability to solubilize methylammonium bromide (120a), which was
identified as the precipitate in these reactions. Also iodine was used to replace bromine,
however, no reaction could be observed (Table 1, entry 10).
Results and Discussion
43
Table 1: Screening of reaction parameters.a
Entry Solvent 119a:2a ratiob
1 MeOH 92/8
2c MeOH 85/15
3d MeOH 80/20
4e MeOH 85/15
5 EtOH 90/10
6 water 80/20
7 2,2,2-trifluoroethanol 25/75
8 DCM 54/46
9 acetone n.r.
10f MeOH n.r. a Reaction conditions: Thioanisole (1a, 0.50 mmol), MeNH2 (117a, 1.4 mmol, 2.8 equiv.) and Br2 (0.70 mmol, 1.4 equiv.) in denoted solvent (3.0 mL) at rt for 15 min. b Determined by 1H NMR spectroscopy. c The reaction was carried out at 0 °C. d Use of 2.0 equiv. of MeNH2 (117a) and 1.0 equiv. of Br2.
e Use of 4.0 equiv. of MeNH2 (117a) and 2.0 equiv. of Br2. f Use
of I2 instead of Br2.
Since the best results were obtained with the original conditions in methanol as solvent, it was
chosen as reaction medium for the sulfur imination (Table 1, entry 1). To isolate
N-methylsulfiliminium salt 119a, methanol was removed under vacuum and acetone was
added, thereby yielding a solution of 119a and a precipitate of 120a, which could be readily
removed by filtration. Investigation of the stability of the N-methylsulfiliminium salt 119a
revealed stability for up to five days at 20 °C, but fast decomposition at room temperature.[40b]
2.1.2.2. Continuation of the project
Due to the instability of the N-methylsulfiliminium salt 119a, establishing a subsequent
oxidation step seemed to be crucial to prevent decomposition. The low solubility of
methylammonium bromide (120a) proved beneficial, because it allowed the separation of the
intermediate N-methylsulfiliminium bromide (119a), which could directly be used in the
oxidation process.
To investigate suitable reaction conditions for the oxidation of the sulfilimine salt to
sulfoximine 30, 119a was employed as model substrate (Table 2). Common oxidants were
Results and Discussion
44
tested for the oxidation of sulfilimine salt 119a. Fortunately, with both m-CPBA and KMnO4 as
oxidants, the formation of N-methylsulfoximine 30a could be observed under the tested
reaction conditions by TLC and 1H NMR spectroscopy (Table 2, entries 1–2). In contrast,
sodium hypochlorite and hydrogen peroxide were not active as oxidants for product formation,
presumably due to an insufficient oxidation potential (Table 2, entries 3–4).
Table 2: Oxidation of N-methylsulfiliminium bromide (119a).a
Entry Oxidant (equiv.) Solvent Base (equiv.) Reaction
1b m-CPBA (1.5) EtOH K2CO3 (3.0) +
2 KMnO4 (2.0) acetone - +
3c NaOCl (2.0) EtOAc - -
4d H2O2 (3.0) MeOH K2CO3 (3.0) - a Reaction conditions: N-methylsulfiliminium bromide (119a, 0.50 mmol) under denoted conditions in solvent (3.0 mL) for 2 h at rt. b At 0 °C. c tBu4NI (0.20 mmol, 0.40 equiv.) was added as phase transfer catalyst. d Used as
H2O2 solution in water (50%).
In the next step, the two successful oxidants were tested in a sequential imination/oxidation
procedure to generate N-methylsulfoximine 30a. Fortunately, both m-CPBA and KMnO4
yielded the desired product in moderate to good yields (Table 3, entries 1–2). Due to the
potential hazards of the peroxy acid m-CPBA, we tried to improve the synthesis using KMnO4
as oxidant and were delighted to find that an increase in reaction time to 16 h improved the
yield to 71% (Table 3, entry 3) making KMnO4 the oxidant of choice for this protocol.
Additionally, employing acetone as solvent for the oxidation reaction had the aforementioned
operational advantage of separating the insoluble methylammonium bromide 120a by filtration.
Unfortunately, the yield of 30a could not be further increased, presumably due to instability of
the intermediate sulfiliminium salt 119a. This was also indicated by sulfide 1a, which could in
part be recovered. As a by-product of the reaction, sulfoxide 2a was detected.
Results and Discussion
45
Table 3: Sequential imination/oxidation of thioanisole (1a).a
Entry Oxidant (equiv.) Solvent Yield 30a [%]
1b m-CPBA (1.5) DCM 71
2c KMnO4 (2.0) acetone 64
3c,d KMnO4 (2.0) acetone 71
a Reaction conditions: Thioanisole (1a, 0.50 mmol), MeNH2 (117a, 1.4 mmol) and Br2 (0.70 mmol) at rt for 15 min in methanol (3.0 mL), then oxidation as denoted in solvent (6.0 mL) for 2 h at rt. b At 0 °C. c At rt. d For 16 h.
With the optimized reaction conditions in hand, an array of differently substituted sulfides
1a–s was employed in this sequential imination/oxidation procedure. As mentioned above, the
model substrate 30a could be isolated in a good yield of 71%. The scalability of the process
was proven by performing a reaction on a 10 mmol scale. The desired product could be
isolated in 52% yield, which was considered acceptable for a scaled-up reaction (Table 4, yield
in parentheses). The decrease in yield might be attributed to decomposition of the instable
sulfiliminium salt 119a during rotary evaporation, as evaporation of solvent on this scale was
considerably longer. Substituted aryl methyl sulfides 1b–l with electron-withdrawing and
electron-donating groups on the arene led to the desired products in low to moderate yields
(up to 68%). Seemingly, the strong negative inductive effect of the fluorine atom leads to a
lower yield of the corresponding N-methylsulfoximine 30b compared to the chlorine and
bromine atom (30c and 30d, respectively). Fortunately, employing both meta- and ortho-
substituted bromophenyl methyl sulfides 1e–f, the desired product could be isolated in 52%
and 31%, respectively. In general, ortho-substituted thioanisoles only furnish the N-methylated
sulfoximine in low yields (30f and 30g), presumably due to steric hindrance. Moderate yields
could be obtained using para-methyl, -methoxy and -acyl as phenyl-substituent (30h–j). As an
exception, employing 4-nitrothioanisole (1k) in the procedure only led to 21% of the
N-methylated sulfoximine 30h. This might be attributed both to the strong mesomeric effect as
well as the low solubility of the substrate in methanol. Apparently, a strong negative mesomeric
effect is detrimental to the reaction. Apart from that, methyl-2-naphtyl sulfide was applicable,
yielding the corresponding sulfoximine 30l in 58% yield. Gratifyingly, using the developed
procedure, N-methyl-S-methyl-S-pyridinylsulfoximine (30m) could be obtained in 46% yield,
proving to be superior to existing protocols in both yield, time and required synthetic steps.[82]
The protocol also proved to be applicable to dialkyl-substituted sulfides yielding 30n in a
moderate yield of 44%. In contrast, benzyl methyl sulfide only furnished the product 30o in
Results and Discussion
46
15% yield. Subsequently, the protocol was extended to sulfides with other substituent
combinations. While N-methyl-S-ethyl-S-phenylsulfoximine (30p) was isolated in a moderate
yield of 53%, the desired product containing a cyclopropyl substituent (30q) could only be
obtained in a low yield of 12%. In line with earlier observations, diphenyl sulfide 30r did not
react.[158] Fortunately, also more complex dialkyl-substituted sulfides 30s were applicable in
this protocol yielding the N-methylated product in a moderate yield of 46%. Noteworthy, 30s is
the protected N-methyl analog of methionine sulfoximine (MSO, 41), which potently inhibits an
essential enzyme, -glutamylcysteine synthetase, in the glutathione biosynthesis.[159]
Table 4: Scope of the imination/oxidation procedure.a
a Reaction conditions: sulfide 1 (1.0 mmol), MeNH2 (117a, 2.8 mmol) and Br2 (1.4 mmol) in methanol (6.0 mL) at rt for 15 min, then oxidation with K2CO3 (2.0 mmol), KMnO4 (3.0 mmol) in acetone (10 mL) at rt for 16 h. For 30a in parentheses: result from a reaction on a 10 mmol scale.
Obtaining these results using methylamine as imination source, we wondered if the protocol
could be extended to other amines, allowing the synthesis of various N-substituted
sulfoximines (Table 5). For comparability, thioanisole (1a) was again chosen as model
substrate. While the procedure is applicable to various alkyl amines, yields were unfortunately
low. Using ethylamine, n-butylamine and cyclohexylamine as imination source, the desired
N-alkylated sulfoximines 31a–c could be obtained in low yields (35%, 32% and
19%, respectively). Employing iso-propylamine, only traces of the product were observed by 1H NMR spectroscopy and mass spectrometry. Furthermore, products 31e, 121–123 and 7a
were not accessible with this procedure. This might be attributed to the stereoelectronic effects
of the employed amines (e.g. tert-butyl amine, aniline or methyl carbamate) possibly
exacerbating both the imination and the oxidation step of the procedure. Also, ammonia was
Results and Discussion
47
tested to generate the unprotected NH-sulfoximine 7a, however no reactivity could be
observed.
Table 5: Scope of the N-alkylsulfoximine synthesis.a
a Reaction conditions: Thioanisole (1a, 1.0 mmol), RNH2 (117, 2.8 mmol) and Br2 (1.4 mmol) in methanol (6.0 mL) at rt for 15 min, then oxidation with K2CO3 (2.0 mmol), KMnO4 (3.0 mmol) in acetone (10 mL) at rt for 16 h.
Results and Discussion
48
2.1.3. Summary and outlook
A straightforward synthesis of N-methylsulfoximines 30 and various N-alkylsulfoximines 31
from readily available sulfides through a sequential imination/oxidation procedure has been
developed. The process tolerates various functional groups forming the desired products in
low to good yields (Scheme 56). Furthermore, the presented method does not proceed through
the NH-sulfoximine as an intermediate. Comparing the ease of handling (mild reaction
conditions), the economy of time and the availability of chemicals, this process, despite its low
yields, presents a viable synthetic alternative to existing protocols. In further studies, a stronger
imination source than the in situ generated N-bromoalkylamines 118 might be necessary to
improve the stability of the created sulfilimine intermediates and thereby increase the yield of
the desired products. A second option might be the use of additives to activate the sulfides
making them more readily react with the N-bromoalkylamines 118.
Scheme 56: Synthesis of N-methyl- and N-alkylsulfoximines.
Results and Discussion
49
2.2. Synthesis of N-cyanosulfoximines
2.2.1. Background and aim of the project
To date, a plethora of methods was established to synthesize sulfoximines 3. Most procedures
employ transition metal catalysts to iminate sulfoxides 2. In contrast, only few processes allow
sulfoxide imination by use of transition metal-free procedures. Among these, two methods
have found the broadest application, using either a combination of sodium azide and sulfuric
acid[37] or O-mesitylsulfonylhydroxylamine (MSH) as iminating agent.[160] Both represent highly
toxic and explosive reagents making the search for new protocols desirable. Initially intrigued
by a report by Appel et al., who used HOSA in combination with sodium methanolate for the
imination of aliphatic sulfides 1 (Scheme 57, A), we wondered if HOSA can also be used for
the imination of sulfoxides 2 to generate the free NH-sulfoximine 7.[39a, 39b, 39d] Similarly, Bolm
and co-workers developed a procedure for the synthesis of N-cyanosulfilimines 36 by using a
combination of potassium tert-butoxide, cyanamide and NBS (Scheme 57, B).[24] Instead of
NBS, molecular iodine could be employed delivering the products in slightly lower yield.
Furthermore, Krüger and co-workers recently showed that a combination of sodium hydride,
DBDMH and 2,2,2-trifluoroacetamide could furnish the corresponding
N-trifluoroacetylsulfilimines 22 from sulfides 1 (Scheme 57, C).[49] As these protocols allowed
the transition metal-free access to sulfilimines 4, we envisioned a protocol that employs such
stable reagents under mild conditions to access sulfoximines 3 from the corresponding
sulfoxides 2.
Scheme 57: Selected sulfide iminations and aim of the project.
Results and Discussion
50
2.2.2. Project realization
In initial attempts methyl phenyl sulfoxide (2a) was chosen as model substrate and subjected
to the above mentioned reaction conditions or other common imination sources and oxidants
(see chapter 1.1.2.1. and 1.1.4., Scheme 57 and Table 6). While no reaction was observed in
all cases with HOSA, and 2,2,2-trifluoroacetamide as imination source, N-cyanosulfoximine
35a was detected by TLC and mass spectrometry employing NBS, DBDMH and TCICA as
oxidants and cyanamide as imination source.
Table 6: Synthesis of sulfoximine 3 employing different amines and oxidants.a
Oxidant NBS DBDMH I2 NaOCl TCICA
Imination source
HOSA n.r. n.r. n.r. n.r. n.r.
2,2,2-Trifluoroacetamide n.r. n.r. n.r. n.r. n.r.
Cyanamide 35a 35a n.r. n.r. 35a
a Reaction conditions: sulfoxide 2a (0.20 mmol), KOtBu (0.30 mmol), imination source (0.30 mmol) and oxidant (0.30 mmol) in methanol (1.0 mL) at rt for 4 h.
Encouraged by the product formation, the reaction conditions were optimized in terms of
oxidant, base, solvent, equivalents and temperature. As TCICA also yielded the desired
product, the two chlorine-based oxidants NCS and DCDMH were applied under the reaction
conditions as well (see Table 7). The progress of the reaction was monitored by TLC.
Surprisingly, employing NCS as oxidant gave the best result with 77% of sulfoximine 35a
(Table 7, entry 1). For the complete conversion, 2 h were found to be sufficient. The other two
chlorine-based oxidants, DCDMH and TCICA, also delivered the desired product, albeit in
slightly lower yield with 55% and 40%, respectively (Table 7, entries 2–3). In contrast, both
bromine-based oxidants only led to trace amounts of N-cyanosulfoximine 35a (Table 7, entries
4–5). The difference in activity between chlorine- and bromine-based oxidizing agents might
be explained either by the steric hindrance of the bromine-intermediate or the discrepancy in
oxidizing potential. Interestingly, these observations are in line with earlier reports from Bolm
and co-workers concerning the synthesis of sulfonimidamides[161] and sulfondiimines.[162]
Results and Discussion
51
Table 7: Optimization of the oxidant for the synthesis of N-cyanosulfoximine 35a.a
Entry Oxidant Yield 35a [%]
1 NCS 77
2 DCDMH 55
3 TCICA 40
4 NBS traces
5 DBDMH traces a Reaction conditions: sulfoxide 2a (0.20 mmol), KOtBu (0.40 mmol), cyanamide (0.40 mmol), oxidant (0.80 mmol) in MeOH (1.0 mL) at rt for 2 h.
Subsequently, with NCS as the oxidant for the reaction a screening for the optimization of the
base was carried out. Moreover, the role of base, oxidant and the order of addition were
investigated (Table 8). With a pKa value of 11.38,[163] deprotonation of cyanamide should
require a strong base. Therefore, first attempts with sodium acetate and cesium carbonate,
both rather weak inorganic bases, as well as triethylamine, as weak organic base, did not yield
the desired product (Table 8, entries 1–3). In contrast, with both potassium carbonate and
potassium phosphate, N-cyanosulfoximine 35a could be isolated in moderate yields of 60%
and 56%, respectively (Table 8, entries 4–5). Employing strong inorganic bases such as
sodium methanolate and sodium tert-butoxide delivered the desired product in 34% and 38%,
respectively (Table 8, entries 6–7). Lastly, the imination proceeded with 75% yield using
potassium hydroxide as base (Table 8, entry 8). The results indicate that both the chemical
hardness of the potassium cation as well as the basicity have a decisive impact on the yield of
35a (compare Table 7, entry 1 and Table 8, entry 8 vs entries 6–7). The addition order also
proved pivotal for this transformation. Adding NCS to the sulfoxide before cyanamide and
potassium tert-butoxide results in a distinctly lower yield of 35a (37%) due to a competing side
reaction to the corresponding sulfone, which could also be isolated and identified (Table 8,
entry 9). Therefore, cyanamide needs to be deprotonated in situ before addition of the oxidant
to isolate the product in high yield. Investigation of the role of base and oxidant revealed that
by omission of either, N-cyanosulfoximine 35a could not be observed, proving them essential
for the reaction (Table 8, entries 10–11). If the base is omitted, cyanamide cannot be
deprotonated and can thus not attack the activated sulfoxide, while omission of oxidant
prevents the formation of the activated sulfoxide.
Results and Discussion
52
Table 8: Optimization of base for the synthesis of N-cyanosulfoximine 35a.a
Entry Base Yield 35a [%]
1 NaOAc n.r.
2 Cs2CO3 n.r.
3 TEA n.r.
4 K2CO3 60
5 K3PO4 56
6 NaOMe 34
7 NaOtBu 38
8 KOH 75
9b KOtBu 37
10 - n.r.
11c KOtBu n.r. a Reaction conditions: sulfoxide 2a (0.20 mmol), base (0.40 mmol), cyanamide (0.40 mmol), NCS (0.80 mmol) in MeOH (1.0 mL) at rt for 2 h. b Addition of NCS 10 min before addition of base and cyanamide. c No addition of oxidant.
Next, various solvents were tested for their suitability as reaction medium (Table 9). Toluene,
DCM, DCE, diethyl ether and 2,2,2-trifluoroethanol did not prove suitable as solvent for this
reaction (Table 9, entries 1–5). In contrast, with both ethyl acetate and THF, formation of the
product could be observed. However, in addition to the product several side products as well
as starting material were detected. For this reason, we refrained from determining the yield of
these reactions (Table 9, entries 6–7). The polar solvents acetonitrile, ethanol and methanol
were suitable reaction media for the imination yielding the desired product in 66%, 62% and
77%, respectively (Table 9, entries 8–10). Water as highly polar and protic solvent, proved to
be the solvent of choice for the reaction delivering the protected sulfoximine 35a in a very good
yield of 89% (Table 9, entry 11). Presumably, water can best stabilize an ionic intermediate
that is formed in this reaction and enable the solubility of the employed base.
Results and Discussion
53
Table 9: Screening of solvents.a
Entry Solvent Yield 35a [%]
1 toluene n.r.
2 DCM n.r.
3 DCE n.r.
4 diethyl ether n.r.
5 2,2,2-trifluoroethanol n.r.
6 EtOAc n.d.
7 THF n.d.
8 MeCN 66
9 EtOH 62
10 MeOH 77
11 H2O 89
a Reaction conditions: sulfoxide 2a (0.20 mmol), KOtBu (0.40 mmol), cyanamide (0.40 mmol), NCS (0.80 mmol) in denoted solvent (1.0 mL) at rt for 2 h.
In order to optimize the reaction both in terms of yield and atom economy, the equivalents of
base, amine and oxidant as well as temperature were varied. Lowering the amount of base led
to a significant decrease in yield (Table 10, entry 2). Also lowering base, amine and oxidant to
only 1.5 equivalents gave N-cyanosulfoximine 35a in a slightly lower yield (compare Table 10,
entry 1 and 3). Gratifyingly, an equimolar combination of base, amine and oxidant delivered
the desired product in 93% (Table 10, entry 4). Since KOH gave a very similar result to KOtBu
in the base screen (compare Table 8), it was also employed with the optimized ratio of
equivalents giving 35a in 85% yield. Therefore, KOH represents a viable alternative to KOtBu
for this transformation in view of availability and price (Table 10, entry 5). As a last parameter
for optimization, the reaction was carried out at various temperatures. An increase in
temperature led to a significant decrease in product yield (Table 10, entry 6–7), which could
be attributed to a favoring of the side reaction forming the corresponding sulfone under these
conditions. Lowering the temperature to 0 °C proved beneficial affording N-cyanosulfoximine
35a in an excellent yield (95%, Table 10, entry 8). The substrate scope, however, was
established using room temperature as temperature of choice due to ease of handling and the
negligible improvement in yield.
Results and Discussion
54
Table 10: Screening of equivalents and temperature.a
Entry Equiv. of
base/amine/oxidant Temperature [°C] Yield 35a [%]
1 2.0/2.0/4.0 rt 89
2 1.0/2.0/2.0 rt 39
3 1.5/1.5/1.5 rt 79
4 2.0/2.0/2.0 rt 93
5b 2.0/2.0/2.0 rt 85
6 2.0/2.0/2.0 100 59
7 2.0/2.0/2.0 50 75
8 2.0/2.0/2.0 0 95
a Reaction conditions: sulfoxide 2a (0.20 mmol), KOtBu, cyanamide, NCS as denoted in H2O (1.0 mL) at denoted temperature for 2 h. b KOH as base instead of KOtBu.
With the optimized conditions in hand, the substrate scope of the reaction was investigated.
Firstly, subjecting the model substrate to the reaction conditions on a 50 mmol scale, the
scalability of the developed protocol was proven, yielding N-cyanosulfoximine 35a in 86% yield
(Table 11, yield in parentheses). Both electron-donating and electron-withdrawing aryl methyl
sulfoxides were applicable in the reaction delivering the desired products in low to excellent
yields (Table 11, 35a, c–e, h–k, t–u). As an exception, ortho-bromobenzenemethylsulfoxide
(2f) did not react under the reaction conditions. In contrast, both para- and meta-
bromobenzenemethylsulfoxide (2d) and (2e) were converted to the corresponding
N-cyanosulfoximine 35d and 35e in 85% and 71%, respectively. This series reveals that an
increase in steric hindrance in the vicinity of the sulfinyl moiety impairs reactivity to generate
sulfoximine 35 and in case of the ortho-substituted substrate 2f completely prevents the
reaction. Additionally, ortho-fluorobenzenemethylsulfoxide (2t) also provided the desired
product, albeit in a moderate yield of 54%, again proving steric hindrance to be a decisive
factor for this transformation. In line with earlier observations, this again highlights the
necessity of the chlorine-based oxidant, which at least in part seems to base its activity on its
adequate size for this imination. Fortunately, also 2-(methylsulfinyl)pyridine (2m) could be
converted to the corresponding product 35m in a moderate yield of 69% demonstrating that
the procedure can be extended to heteroaryl-containing sulfoxides. While both N-cyano-S-
cyclopropyl-S-phenylsulfoximine (35q) and N-cyano-S-allyl-S-phenylsulfoximine (35v) could
be obtained in moderate to good yields with 78% and 55%, respectively, displaying further
Results and Discussion
55
variety in the scope, (vinylsulfinyl)benzene (2w) could not be converted to the desired product.
This might be attributed to the reactivity of the vinylic double bond. Diaryl sulfoxides (2r and
2x) only gave low yields of the desired products (17% and 15%, respectively). Full conversion
was observed, in these cases however, the main product was found to be the corresponding
sulfone preventing a higher yield of the desired sulfoximine. The reversed selectivity most likely
arises from the electronic activation of the two aromatic rings as well as their steric hindrance.
Also, these substrates exhibited a lower solubility compared to the previously described alkyl
aryl sulfoxides further hampering the reaction. To our delight, the protocol could also be used
to convert dialkyl sulfoxides (2n, 2y and 2z) yielding dialkylated N-cyanosulfoximines 35 in
moderate to low yields (48%, 50% and 23%), respectively. N-Cyano-S,S-dimethylsulfoximine
(35z) was prepared on a 5.0 mmol scale. The low yields for dialkylated sulfoximines
presumably stem from the high water solubility of the products and their volatility.
Table 11: Substrate scope for the synthesis of N-cyanosulfoximines 35.a
a Reaction conditions: sulfoxide 2 (0.20 mmol), KOtBu (0.40 mmol), cyanamide (0.40 mmol), NCS (0.40 mmol), H2O (1.0 mL), rt, 2 h. The yield of 35a shown in parentheses resulted from a reaction on 50 mmol scale. b Prepared on a 5.0 mmol scale.
Several experiments were carried out to develop a one-pot procedure that would deliver the
desired N-cyanosulfoximines 35 in high yields starting from sulfides 1. Using NCS
(1.0 equivalents) for the oxidation process as well as for the consecutive imination delivered
the desired product in moderate 57% yield over two steps (Table 12, entry 1). To test if the
one-pot procedure proceeds better in another reaction medium, the solvent was changed to
methanol. However, this lowered the yield of 35a to 42% (Table 12, entry 2). Therefore, the
Results and Discussion
56
following experiments with common oxidants for sulfides were carried out in water as reaction
medium. While hydrogen peroxide as oxidant only led to traces of the product, in combination
with acetic acid N-cyanosulfoximine 35a could be isolated in 19% yield (Table 12, entry 3–4).
With K2S2O8 only traces of the product were observed due to over-oxidation to the
corresponding sulfone (Table 12, entry 5). Fortunately, using NaIO4 as oxidant led to the
desired product in 85% yield over two steps (Table 12, entry 6).
Table 12: Development of a one-pot procedure for N-cyanosulfoximines 35.a
Entry Conditions step 1 Yield 35a [%]
1 NCS (1.0 equiv.), H2O, rt, 1 h 57
2 NCS (1.0 equiv.), MeOH, rt, 1 h 42
3 H2O2 (2.0 equiv.), H2O, rt, 16 h traces
4 H2O2 (2.0 equiv.), CH3COOH (1.0 equiv.),
H2O, rt, 16 h 19
5 K2S2O8 (1.1 equiv.), H2O, rt, 2 h traces
6 NaIO4 (1.1 equiv.), H2O, rt, 16 h 85
a Reaction conditions: Thioanisole (1a, 0.20 mmol), for oxidation: conditions as indicated, for imination: KOtBu (0.40 mmol), cyanamide (0.40 mmol), NCS (0.40 mmol) in denoted solvent (1.0 mL) at rt for 2 h.
To investigate the stereoselectivity of the developed procedure, an enantiomerically enriched
mixture of sulfoxide (S)-2a was prepared and subsequently employed. The resulting
N-cyanosulfoximine 35a had to be converted into the free NH-sulfoximine 7a following a
literature procedure due to a lack of adequate conditions for separation of the two enantiomers
of 35a by chiral HPLC.[24] Deprotection proceeds by substitution of the cyano group with a
trifluoroacetyl group from TFAA forming 125a. Methanolysis in a basic medium delivers the
free NH-sulfoximine 7a (Scheme 58).
Scheme 58: Deprotection of N-cyanosulfoximine 35a.
Results and Discussion
57
To investigate the stereoselectivity of the reaction, samples of both enantiomerically enriched
sulfoxide (S)-2a and deprotected NH-sulfoximine 7a resulting from the described procedure
were measured by chiral HPLC and polarimeter. Comparison of the obtained data revealed,
that the developed reaction proceeds under inversion of the configuration at the sulfur atom.
Taking the optimization process, the substrate scope and the investigation of stereochemistry
into account, a mechanism for the developed procedure was postulated (Scheme 59). In the
first step, sulfoxide 2a is activated by oxidative chlorination with NCS at the free electron pair
of the sulfoxide forming intermediate I. Nucleophilic attack of intermediate I in an SN2-type
reaction by the in situ generated deprotonated cyanamide leads to inversion of configuration
and product formation by elimination of HCl.
Scheme 59: Proposed reaction mechanism.
Results and Discussion
58
2.2.3. Summary and outlook
A protocol for the direct transition metal-free imination of a broad variety of sulfoxides 2 was
developed. The desired N-cyanosulfoximines 35 could be obtained in low to excellent yields
under mild reaction conditions. The procedure employed readily available starting materials,
avoided the use of thermally labile compounds, proved to be scalable and proceeded under
inversion of the preexisting stereochemistry (Scheme 60).
Scheme 60: Synthesis of N-cyanosulfoximines 35 by imination.
A one-pot procedure consisting of oxidation with NaIO4 and imination with the developed
protocol afforded access to N-cyanosulfoximine 35a in 85% yield over two steps (Scheme 61).
Thereby, the developed reaction presents a viable alternative complementing existing
procedures.
Scheme 61: One-pot procedure for the synthesis of N-cyanosulfoximine 35a from sulfide 1a.
Further studies should focus on expanding the product scope. Both diaryl and dialkyl sulfoxides
2 only gave low to moderate yields. By use of a stronger chlorinating agent than NCS, these
sulfoxides might deliver the desired N-cyanosulfoximines 35 in high yields. Additionally, the
choice of solvent is crucial for the conversion of diaryl sulfoxides as solubility might be an
important factor for successful conversion in this imination protocol.
Results and Discussion
59
2.3. Reductive borylation of sulfoximines
2.3.1. Background and aim of the project
As the group of Bolm and co-workers recently reported on a radical C–S bond cleavage of
sulfoximines,[164] we wondered if a C–S bond cleavage can also be induced by a nickel-
catalyzed reductive borylation. This method would allow late-stage functionalization of complex
molecules, since the generated arylboronic esters can easily be further modified by
cross-coupling. Literature precedent revealed that both C–N and C–O bond cleavage had been
achieved using this process, making a C–S bond fission also feasible. Tobisu, Chatani and co-
workers successfully employed nickel catalysis for the borylative cleavage of C–N bonds.[150]
The combination of Ni(COD)2 with an NHC ligand (IMes•HCl) and B2nep2 as borylating agent
proved suitable to convert N-aryl amides and carbamates 114 in low to moderate yields
(Scheme 62).
Scheme 62: C–N bond cleavage by reductive borylation.
Also, Martin and co-workers demonstrated the C–O fission of aryl ethers by reductive
borylation.[151] Using tricyclohexylphosphine and sodium formate under similar conditions as
the system utilized by Tobisu, Chatani and co-workers various aryl ethers could be borylated
in moderate to good yields (Scheme 63).
Scheme 63: C–O bond cleavage by reductive borylation.
Results and Discussion
60
2.3.2. Project realization
Initial attempts for a reductive borylation were transferred to sulfoximines by applying reaction
conditions from Tobisu, Chatani and co-workers.[150] For first test reactions
N-methylsulfoximine 30a was subjected to the reported reaction conditions. In further
experiments, the necessity of base and ligand was tested (Table 13).
Table 13: First reactions for the reductive borylation of N-methylsulfoximine 30a.a
Entry Base equiv. Ligand equiv. Yield 85a [%]
1b 0.20 0.20 traces
2 0.20 0.20 14
3 - - n.r.
4c - 0.20 n.r.
5c 0.20 - n.r. a Reaction conditions: sulfoximine 30a (0.50 mmol), NaOtBu and IMes•HCl as denoted, Ni(COD)2 (0.05 mmol), B2pin2 (1.0 mmol) in toluene (1.5 mL) at 80 °C for 20 h. b At 160 °C. c For 16 h.
Fortunately, employing the reported reaction conditions, the reaction mixture showed traces of
the desired product 85a by mass spectrometry (Table 13, entry 1). In an attempt to adapt the
reaction conditions to the sulfoximine substrate, the reaction was carried out at 80 °C (Table
13, entry 2). In this case, phenylboronic ester 85a could be isolated in 14% yield. To potentially
simplify the reaction system and investigate the necessity of both base and ligand, the reaction
was carried out omitting either one of the two or both at the same time (Table 13, entry 3–5).
However, these experiments showed that the combination of base and ligand is required to
generate the desired product 85a. As a subsequent step, the substituent at the nitrogen atom
of the sulfoximine was varied to find the optimal N-substituted sulfoximine for the reductive
borylation (Table 14).
Results and Discussion
61
Table 14: Variation of the N-substituent on the sulfoximine.a
Entry Sulfoximine Yield 85a [%]
1 30a 19
2 126a 10
3 7a 17
4 29a 17
5 125a traces
6 35a traces a Reaction conditions: sulfoximine (0.50 mmol), NaOtBu (0.10 mmol), IMes•HCl (0.10 mmol), Ni(COD)2 (0.05 mmol), B2pin2 (1.0 mmol) in toluene (1.5 mL) at 80 °C for 16 h.
Variation of the N-substituent on the sulfoximine potentially indicated a trend. Electron-
donating groups led to isolation of the phenylboronic ester 85a in low yields (Table 14, entries
1-4). In contrast, strongly electron-withdrawing groups only led to traces of the desired product
(Table 14, entries 5–6). The best yield was obtained using N-methylsulfoximine 30a (19%,
Table 14, entry 1).
Next, various catalysts were tested for their activity in the reductive borylation of sulfoximines.
Mostly Nickel(0) and Nickel(II) catalysts were employed as well as the rhodium- and iridium-
based analogs of Ni(COD)2 (Table 15). Unfortunately, only Ni(COD)2 proved to be catalytically
active for the reductive borylation (Table 15, entry 1). Using a rhodium catalyst only traces of
the desired product could be observed (Table 15, entry 2). However, further investigation of
various rhodium catalysts could presumably be expected to deliver the product in higher yields
as several reports on the rhodium-catalyzed reductive borylation of sulfides indicated.[149, 152a]
Ni(PPh3)2Cl2 did not catalyze the reaction (Table 15, entry 3), while other Ni(0) or Ni(II)
catalysts only delivered traces of the borylated product (Table 15, entries 4–6). Utilizing the
iridiumchloride analog of Ni(COD)2 no reaction could be observed (Table 15, entry 7).
Results and Discussion
62
Table 15: Catalyst screening for the reductive borylation of sulfoximines.a
Entry Catalyst Yield 85a [%]
1 Ni(COD)2 19
2 [RhCl(COD)]2 traces
3 Ni(PPh3)2Cl2 n.r.
4 Ni0 traces
5 Ni(acac)2 traces
6 NiCl2 traces
7b [IrCl(COD)]2 n.r. a Reaction conditions: sulfoximine 30a (0.50 mmol), NaOtBu (0.10 mmol), IMes•HCl (0.10 mmol), catalyst (0.05 mmol), B2pin2 (1.0 mmol) in toluene (1.5 mL) at 80 °C for 16 h. b At 120 °C with sulfoximine 7a.
Due to these results, the investigations were continued using Ni(COD)2 as catalyst.
Furthermore, in the following ligand screening both N-methyl- and NH-sulfoximines were
tested due to the similar results achieved with the two sulfoximines and the availability of
NH-sulfoximines. For the screening of ligands, various NHC ligands with an imidazolium
backbone as well as phosphines were employed (Table 16).
Results and Discussion
63
Table 16: Ligand optimization.a
Entry Substrate Ligand 127 Yield 85a [%]
1 30a 127a 17
2 30a 127b 30
3 30a 127c traces
4 30a 127d traces
5 30a 127e traces
6 30a 127h traces
7 30a 127i traces
8 7a 127a 20
9 7a 127b 18
10 7a 127c c.m.d
Results and Discussion
64
Table 16: continued
11 7a 127d traces
12 7a 127e c.m.d
13 7a 127f n.r.
14 7a 127g n.r.
15 7a 127h traces
16 7a 127i n.r.
17b,c 7a 127e 20
18b,c 7a 127i n.r.
a Reaction conditions: sulfoximine (0.50 mmol), NaOtBu (0.10 mmol), ligand 127 (0.10 mmol), Ni(COD)2 (0.05 mmol), B2pin2 (1.0 mmol) in toluene (1.5 mL) at 80 °C for 16 h. b At 120 °C. c Without use of base. d c.m. – complex mixture.
Of all the investigated ligands, the previously employed 1,3-bis(2,4,6-trimethylphenyl)-
imidazoliumchloride ligand (IMes•HCl, 127a) and its corresponding methyl derivative 127b
delivered the best results with yields from 17% to 30% (Table 16, entries 1, 2 and 8, 9). A
general look at the screened ligands reveals that only arylic imidazole ligands (127a, 127b,
127c, 127e) seem to generate the desired product 85a. Interestingly, ligand 127c could only
deliver the desired product if NH-sulfoximine 7a was utilized (compare Table 16, entries 3 and
10). Yet, the product was not entirely pure and the better synthetic availability of ligand 127a
and 127b over 127c made us prefer those ligands. For both sulfoximine substrates employing
ligand 127d did not lead to the formation of phenylboronic ester 85a (Table 16, entries 4 and
11), demonstrating the necessity of a conjugated aromatic system in the NHC ligand for
conversion. Also, the free carbene 127e was subjected to the reaction conditions (Table 16,
entry 5 and 12). While N-methylsulfoximine 30a only showed traces of product 85a, it was
obtained with NH-sulfoximine 7a. However, the product could not be isolated entirely pure,
which is why results with ligands 127a and 127b were preferred. Alkylated imidazolium ligands
127f and 127g did not react under the applied reaction conditions, presumably because the in
situ generated catalyst is not active enough for conversion (Table 16, entry 13 and 14).
Subsequently, phosphine-based ligands (127h and 127i) were applied in the reaction, since
other reports also indicated the reductive borylation employing these ligands (Table 16, entries
6–7 and 15–16).[150-151, 165] Unfortunately, both triphenylphosphine (127h) and
tricyclohexylphosphine (127i) could at best only deliver traces of the phenylboronic ester 85a.
Additionally, we carried out tests under omission of base, since both the free NHC carbene
127e and phosphine 127i do not need the base for the activation of the ligand. As expected,
the reaction also proceeded without base in case of the carbene yielding the desired product
Results and Discussion
65
in 20% (compare Table 16, entries 12 and 17). In contrast, the phosphine ligand could also not
produce the boronic ester 85a under these conditions (compare Table 16, entries 16 and 18).
In the next step, the reaction temperature was varied to increase the yield (Table 17). Due to
availability, reactions were performed with NH-sulfoximine 7a as substrate and IMes•HCl 127a
as ligand.
Table 17: Variation of temperature.a
Entry Temperature [°C] Yield 85a [%]
1 60 12
2 80 20
3 120 38
4 160 32 a Reaction conditions: sulfoximine 7a (0.50 mmol), NaOtBu (0.10 mmol), IMes•HCl (0.10 mmol), Ni(COD)2 (0.05 mmol), B2pin2 (1.0 mmol) in toluene (1.5 mL) at denoted temperature for 16 h.
A decrease in temperature to 60 °C also led to a decrease in yield of 85a (Table 17, entry 1).
The reaction at 80 °C delivered the product in 20% yield (Table 17, entry 2). An increase in
temperature to 120 °C proved optimal, yielding the phenylboronic ester 85a in 38% yield (Table
17, entry 3), since higher temperatures only led to 32% yield (Table 17, entry 4).
In the following, the solvent for the reaction was optimized (Table 18). Using methanol, the
boronic ester 85a could not be obtained (Table 18, entry 1). Also other highly polar solvents,
such as acetonitrile and DMSO as well as DCE as apolar solvent could not deliver the product
(Table 18, entries 2–4). In contrast, ethereal solvents such as THF and 1,4-dioxane were
suitable for the reaction yielding the product in 35% and 26% yield, respectively (Table 18,
entries 5–6).
Results and Discussion
66
Table 18: Solvent optimization.a
Entry Solvent Yield 85a [%]
1 MeOH n.r.
2 MeCN n.r.
3 DMSO traces
4 DCE n.r.
5 THF 35
6 1,4-dioxane 26 a Reaction conditions: sulfoximine 7a (0.50 mmol), NaOtBu (0.10 mmol), IMes•HCl (0.10 mmol), Ni(COD)2 (0.05 mmol), B2pin2 (1.0 mmol) in denoted solvent (1.5 mL) at 120 °C for 16 h.
With the results in hand, we were intrigued to test the applicability of the protocol on various
other organic sulfur compounds. Different sulfoximines (7l, 7aa, 30r, 128) as well as thioanisole
(1a), sulfoxide 2a, sulfone 129, sulfonylchloride 130 and sulfonamide 131 were subjected to
the reaction conditions (Table 19).
The results reveal, that reactions with sulfoximines containing a bigger aromatic system,
enable the isolation of the corresponding product in low to moderate yields with 44% and 37%,
respectively (Table 19, entries 1–2). Also, the isolation by column chromatography was easier
due to their Rf-values and their visibility under UV light. Furthermore, S-diphenylsulfoximine
30r was utilized (Table 19, entry 3). In this case, the desired product 85a as well as the
corresponding by-product N-methylbenzenesulfinamide 132a could be isolated in a yield of
22% with traces of B2pin2 and clearly identified by NMR spectroscopy and mass spectrometry,
proving the C–S bond fission. A clean isolation was not successful as the sulfinamide
presumably forms an adduct with B2pin2. In analogy to a report by Watson as well as Shi and
co-workers, the N-dimethylated sulfoximine 128 was subjected to the reaction conditions.[165-
166] However, formation of the desired product 85a could not be observed (Table 19, entry 4).
Thioanisole (1a) did not react under these conditions (Table 19, entry 5). Subsequently
published reports revealed the possibility of a reductive borylation of sulfides 1 employing a
rhodium- or palladium-based system.[153-154] Concerning the other sulfur compounds, only
sulfoxide 2a generated the boronic ester 85a in a low yield of 8% (Table 19, entry 6).
Results and Discussion
67
Unfortunately, with sulfone 129, sulfonylchloride 130 and sulfonamide 131 the product could
only be observed in traces (Table 19, entry 8) or not at all (Table 19, entries 7 and 9).
Table 19: Reductive borylation of various organosulfur compounds.a
Entry Substrate Yield 85 [%]
1 7l 44
2 7aa 37
3b 30r 24
4 128 n.r.
5 1a n.r.
6 2a 8
7 129 n.r.
8 130 traces
9 131 n.r. a Reaction conditions: substrate (0.50 mmol), NaOtBu (0.10 mmol), IMes•HCl (0.10 mmol), Ni(COD)2 (0.05 mmol), B2pin2 (1.0 mmol) in toluene (1.5 mL) at 120 °C for 16 h. b At 80 °C.
Since the other sulfur compounds did not prove applicable under these reaction conditions,
sulfoximine 7a was further used as model substrate to optimize the base and base amount of
the reaction (Table 20). The base equivalents were optimized, since they were assumed to be
Results and Discussion
68
of importance for the deprotonation of the employed carbene, thereby delivering the ligand and
thus the active catalyst for the reaction.
A first experiment was performed, using an equimolar amount of base and ligand only leading
to 9% of the desired product (Table 20, entry 1). Employing 0.50 equivalents of sodium
tert-butoxide led to the desired product 85a in 34% yield (Table 20, entry 2). While this is
slightly lower than the previously obtained 38% with 0.20 equivalents (Table 17, entry 3), the
necessity of base for the liberation of the ligand led us to employ 0.5 equivalents of base to
ensure generation of the active catalyst species. A further increase of equivalents led to a
decrease in yield to 28% (Table 20, entry 3–4). With 3.0 equivalents of base the pinacol boronic
ester could not be observed (Table 20, entry 5). Furthermore, it must be mentioned that higher
amounts of base led to a slurry mixture, which is why further toluene was added to ensure
sufficient mixing (Table 20, entries 4–5). Subsequently, various bases were tested. Employing
KOtBu also delivered the product in a similar yield with 31% (Table 20, entry 6). Also, cesium
carbonate and sodium hydride furnished the phenylboronic ester 85a in comparable yields with
30% and 24%, respectively (Table 20, entries 7–8). With weak bases such as K3PO4, KOAc
and NaHCO3 only traces of the desired product 85a could be observed (Table 20, entries 9–
11). An organic base, such as triethylamine could not furnish the boronic ester 85a (Table 20,
entry 12).
Results and Discussion
69
Table 20: Base and base equivalent screening.a
Entry Base (equiv.) Yield 85a [%]
1b NaOtBu (0.10) 9
2 NaOtBu (0.50) 34
3 NaOtBu (1.0) 28
4c NaOtBu (2.0) 28
5c NaOtBu (3.0) n.r.
6 KOtBu (0.50) 31
7 Cs2CO3 (0.50) 30
8 NaH (0.50) 24
9 K3PO4 (0.50) traces
10 KOAc (0.50) traces
11 NaHCO3 (0.50) traces
12 TEA (0.50) n.r. a Reaction conditions: sulfoximine 7a (0.50 mmol), base as denoted, IMes•HCl (0.10 mmol), Ni(COD)2 (0.05 mmol), B2pin2 (1.0 mmol) in toluene (1.5 mL) at 120 °C for 16 h. b With IMes•HCl (0.05 mmol, 0.10 equiv.). c Toluene (4.5 mL).
In the following step, the amount of diborane was varied. Additionally, another diborane source
was tested and COD was added as additional ligand (Table 21).
A reduction of diborane equivalents to one equivalent only furnished the desired product in
25% yield (Table 21, entry 1). In comparison, the previously used two equivalents delivered
the pinacol boronic ester in 38% yield (Table 17, entry 3). Changing the diborane source to
bis(neopentyl glycolato)diboron, the borylated product 113a could only be obtained in 13%
yield (Table 21, entry 2). As a last experiment, cyclooctadiene was added to the reaction
mixture to investigate whether it is beneficial for the formation of the active catalyst species
assuming that it is crucial as ligand in the active species (Table 21, entry 3). With 33% yield of
the product 85a, COD seemingly did not have an influence on the reaction. Subsequently, the
reaction time was optimized (Table 22).
Results and Discussion
70
Table 21: Optimization of borane and additives.a
Entry Diborane (equiv.) Yield 85a or 113a [%]
1 B2pin2 (1.0) 25
2 B2nep2 (2.0) 13
3b B2pin2 (2.0) 33
a Reaction conditions: sulfoximine 7a (0.50 mmol), NaOtBu (0.25 mmol), IMes•HCl (0.10 mmol), Ni(COD)2 (0.05 mmol), B2pin2 (1.0 mmol) in toluene (1.5 mL) at 120 °C for 16 h. b Addition of COD (0.50 mmol, 1.0 equiv.).
Interestingly, only 1 h of reaction time was enough to furnish the borylated product 85a in 30%
yield (Table 22, entry 1). With 8, 16, and 72 h similar yields between 29–38% were obtained
(Table 17, entry 3 and Table 22, entries 2–3). Together, these results hint at catalyst
deactivation, since the product is already formed in the first hour. Longer reaction times do not
increase the yield, therefore the catalyst is not able to promote the reaction anymore. At the
same time, both the sulfoximine 7a as well as the phenylboronic ester 85a are stable under
the reaction conditions. Even after 72 h the product can be isolated in comparable yields and
the remaining starting material can be reisolated.
Table 22: Screening of reaction times.a
Entry Time [h] Yield 85a [%]
1 1 30
2 8 30
3 72 29 a Reaction conditions: sulfoximine 7a (0.50 mmol), NaOtBu (0.25 mmol), IMes•HCl (0.10 mmol), Ni(COD)2 (0.05 mmol), B2pin2 (1.0 mmol) in toluene (1.5 mL) at 120 °C for 16 h.
To investigate the assumed catalyst deactivation, the amount of catalyst, ligand and base was
increased (Table 23). An increase in catalyst loading revealed a significant raise in the yield of
Results and Discussion
71
the boronic ester 85a. Using 30 mol% of catalyst the product could be obtained in 50% yield
(Table 23, entry 1), while a stoichiometric amount of catalyst led to full conversion of the
starting material furnishing the product in 99% yield (Table 23, entry 2). These experiments
proved that catalyst deactivation is responsible for the low yields of the reaction.
Table 23: Tests for catalyst deactivation.a
Entry Mol% Ni(COD)2 Yield 85a [%]
1 30 50
2b 100 99
a Reaction conditions: sulfoximine 7a (0.50 mmol), Ni(COD)2, base and ligand were adjusted to the catalyst loading (base: 0.50 equiv., ligand 0.20 equiv.), B2pin2 (1.0 mmol) in toluene (1.5 mL) at 120 °C for 16 h. b For 2 h.
In subsequent experiments, several reactions were performed to investigate the reason for the
catalyst deactivation. Since it was assumed that the sulfinamide might be responsible for
catalyst deactivation, sulfinamide 132b was added beforehand to the reaction mixture to test
its influence on the reaction (Table 24).
Firstly, sulfinamide 132b was subjected to the reaction conditions, after 1 h of reaction time
the sulfoximine 7a was added and the reaction was continued under the standard reaction
conditions (Table 24, entries 1–2). In both cases, only traces of the product 85b that is
generated from the sulfinamide 132b could be observed. Interestingly, when an equimolar
amount of sulfinamide 132b and catalyst were used, the sulfinamide was completely
converted, however only partially to the desired product (Table 24, entry 2). The same result
could be obtained when the sulfoximine 7a was not added to the reaction mixture, proving that
the borylated product 85b stems from the sulfinamide 132b (Table 24, entry 3). These
experiments clearly prove that the sulfinamide that is generated as by-product is at least in
part responsible for the deactivation of the catalyst. Subsequently, we investigated if the
starting material itself might also be able to deactivate the catalyst. By subjecting the
sulfoximine 7a to the reaction conditions and only adding the reaction partner B2pin2 after 1 h
to the reaction, no product could be observed, possibly demonstrating that the sulfoximine 7a
itself can inhibit catalysis (Table 24, entry 4).
Results and Discussion
72
Table 24: Investigation on the deactivation.a
Entry Substrate (mmol) Added substrate after 1 h (mmol)
Time [h] Product Yield [%]
1 132b (0.50) 7a (0.50) 2 85b traces
2 132b (0.10) 7a (0.50) 2 85b traces
3 132b (0.50) --- 1 85b traces
4 7a (0.50) B2pin2 (1.0) 2 --- n.r.
a Reaction conditions: substrates 7a and 132a as denoted, B2pin2 (1.0 mmol), NaOtBu (0.25 mmol), IMes•HCl (0.10 mmol), Ni(COD)2 (0.05 mmol), in toluene (1.5 mL) at 120 °C for denoted time. After 1 h an additional substrate was added as denoted.
In final experiments, Cu(TC) was added to the reaction mixture to trap the generated
sulfinamide by formation of a copper-sulfinamide complex, as the sulfinamide could be proven
to deactivate the catalyst (Table 25).
Table 25: Trapping experiments.a
Entry Cu(TC) equiv. Yield 85a [%]
1 0.10 n.r.
2 1.0 n.r. a Reaction conditions: sulfoximine 7a (0.50 mmol), NaOtBu (0.10 mmol), IMes•HCl (0.10 mmol), Ni(COD)2 (0.05 mmol), B2pin2 (1.0 mmol) in toluene (1.5 mL) at 120 °C for 16 h.
Reactions with Cu(TC) as additive were not successful, completely preventing product
formation both with 0.10 and 1.0 equivalents (Table 25, entries 1–2).
Results and Discussion
73
2.3.3. Summary and outlook
A catalytic system for the reductive borylation of sulfoximines was investigated. Several
sulfoximines could successfully be employed in this reaction. By screening various
parameters, the yield for the model substrate could be increased from 10% to 38%. However,
after an extensive screening, catalyst deactivation was found to be responsible for the low
yields (Scheme 64). The sulfinamide, which is generated as a by-product in the reaction could
be determined as at least one reason for catalyst deactivation. Unfortunately, experiments to
trap the sulfinamide by the addition of a copper complex completely prevented a reaction. Also,
the reductive borylation was transferred to various other organosulfur compounds
demonstrating that the employed system is only generating the pinacol boronic ester for
sulfoximines and in very low yields for sulfoxides.
Scheme 64: Best conditions for the reductive borylation of sulfoximine 7a.
Further studies should concentrate on a rhodium- or palladium-based catalytic system as these
showed success for sulfides and might not be affected by the catalyst poison
sulfinamide.[153-154] A general study on pathways to prevent the catalyst poisoning by
sulfinamides (and various other organosulfur compounds) should be explored as these are
also the reason for catalyst deactivation in the ortho-borylation of sulfoximines. Here, problems
could also arise in future projects.
Results and Discussion
74
2.4. C–H borylation of sulfoximines and their use in Suzuki–Miyaura couplings
2.4.1. Background and aim of the project
Inspired by the developments in C–B bond formation by C–H activation,[107f, 125a] we wondered
if sulfoximines can be borylated selectively. While the literature on borylation is vast (see
chapter 1.2.2.2.), reports by Hartwig, Ishiyama, Miyaura and co-workers especially caught our
attention.[132, 134-135] In these studies, the borylation of arenes 77 was achieved using a
combination of an iridium catalyst with bipyridine ligands and B2pin2 as borylation source.
Borylation occurred at the C–H bonds para or meta to the substituent of the arene and not at
the sterically hindered ortho-C–H bond. Additionally, a weak electronic effect directs the
reaction to the more electron-poor carbon. By carefully choosing disubstituted arenes, the
regioselectivity of the reaction could be controlled leading to only one monoborylated product
in moderate to excellent yields (Scheme 65).[135]
Scheme 65: Iridium-catalyzed borylation of arenes 77.
As site-selectivity still remained a challenge in these earlier works, various groups continued
to develop protocols for the ortho-borylation of substituted arenes. Recently, Chattopadhyay
and co-workers reported on the ligand-enabled ortho- and meta-borylation of aromatic
aldehydes 106.[140] Site-selectivity was achieved by the choice of ligand. Especially the ortho-
borylation (Scheme 66) intrigued us, as we assumed that the inherent imine function in
sulfoximines 3 might be usable in this C–H activation.
Scheme 66: Ortho-selective borylation of aldehydes 106.
Results and Discussion
75
2.4.2. Project realization
In first attempts to transfer the C–H borylation to sulfoximines, various N-substituted
sulfoximines were subjected to typical conditions for borylation by Hartwig, Ishiyama, Miyaura
and co-workers (Table 26).
Table 26: First borylation attempts.a
Entry Sulfoximine Solvent Temperature [°C] Time [h] Yield 133 [%]
1 30a toluene 1) 25, then 2) 80 1) 16, then 2) 5 traces
2 7a toluene 1) 25, then 2) 80 1) 16, then 2) 5 traces
3 35a toluene 1) 25, then 2) 80 1) 16, then 2) 5 traces
4 30a n-pentane 25 18 traces
5 7a n-pentane 25 18 traces
6 35a n-pentane 25 18 traces
7 30a n-octane 80 16 traces
8 7a n-octane 80 16 traces
a Reaction conditions: sulfoximine (0.25 mmol), [Ir(COD)(OMe)]2 (3.8 mol), dtbpy (7.5 mol), B2pin2 (0.38 mmol) in denoted solvent (1.5 mL), temperature and time.
Employing NH-, NMe- and N-cyanosulfoximines (7a, 30a, 35a), the product could not be
detected by TLC and isolation of the product by column chromatography did not prove
possible, however mass spectrometry showed signals for the borylated product (Table 26,
entries 1–8). Both low product yields and possible decomposition of the borylated product on
silica gel might be the reasons for the difficulties in isolating the desired product.
2.4.2.1. Iridium-catalyzed ortho-borylation of sulfoximines
While initial attempts at a C–H borylation of sulfoximines failed, the report by Chattopadhyay
and co-workers on the borylation of aldehydes by in situ generated imines using
Results and Discussion
76
8-aminoquinoline (8-AQ, 107) as ligand inspired us to transfer these reaction conditions to
sulfoximines (Table 27).[140a]
Table 27: First attempts of ortho-borylation on sulfoximines.a
In analogy to the work by Chattopadhyay, with N-methylsulfoximine 30a the ortho-borylated
product 133a could be isolated for the first time in 23% yield (Table 27, entry 1). In contrast,
free NH-sulfoximine 7a did not react under the reaction conditions (Table 27, entry 2).
N-Cyanosulfoximine 35a could also provide the ortho-borylated sulfoximine 134a in 8% yield
(Table 27, entry 3). With other N-substituted sulfoximines, such as 29a, 125a, and 126a, only
traces of the product could be observed by mass spectrometry and an isolation of the products
remained unsuccessful (Table 27, entry 4–6).
Subsequently, various catalysts were tested for their activity in the ortho-borylation of
sulfoximines (Table 28). Interestingly, even the chloride analog of the employed
[Ir(COD)(OMe)]2 catalyst could not deliver the desired product 133a (compare Table 27, entry
1 and Table 28, entry 1). Also, other iridium catalysts such as [IrCp*Cl2]2 and [Ir(COD)2][BF4]
were not suitable for the promotion of the reaction (Table 28, entry 2–3). Additionally, a
common rhodium and ruthenium catalyst were tested for their activity, albeit no reaction could
be detected (Table 28, entries 4–6). Surprisingly, of the tested catalysts, only [Ir(COD)(OMe)]2
proved to be applicable in this reaction (Table 27, entry 1).
Entry Substrate Yield 133 or 134 [%]
1 30a 23
2 7a n.r.
3 35a 8
4 29a traces
5 125a traces
6 126a traces
a Reaction conditions: sulfoximine (0.50 mmol), [Ir(COD)(OMe)]2 (7.5 mol), 8-AQ (15 mol), B2pin2 (0.35 mmol) and HBpin (25 mol) in THF (1.5 mL) at 90 °C for 16 h.
Results and Discussion
77
Table 28: Catalyst screening.a
In the next step, a solvent and temperature screening was carried out to optimize the yield
(Table 29). Interestingly, switching from THF to 1,4-dioxane as reaction medium the product
yield could be increased from 23% to 45% yield (Table 29, entry 1 vs Table 27, entry 1). Also,
apolar solvents such as DCE and toluene proved to be suitable providing the product 133a in
25% and 33% in comparable yields to THF, respectively (Table 29, entries 2–3). Highly polar
and protic solvents, such as acetonitrile, DMSO and MeOH were not applicable, presumably
due to coordination to the catalyst, inhibiting the generation of the active species in situ (Table
29, entries 4–6). Thereupon, the reaction temperature was investigated regarding its influence
on the reaction. With 40 °C the desired product could not be observed, presumably due to the
lack of activation energy (Table 29, entry 7). An increase to 60 °C led to isolation of the ortho-
borylated sulfoximine 133a in 40% yield (Table 29, entry 8). The best yield could be obtained
using 80 °C as reaction temperature furnishing the product in 57% yield (Table 29, entry 9). A
further increase in temperature from 100 °C to 140 °C led to a decrease in yield from 51% to
20% (Table 29, entries 10–12). Next to the reisolation of starting material, the reason for the
decrease in yield at high temperatures could be attributed to the increasing formation of
N-methylbenzenesulfinamide 132a as a side product. While the yields of the side product even
at high temperatures were still low (0–15%), it was assumed that it might act as catalyst poison,
explaining the low to moderate yields.
Entry Catalyst Solvent Temperature [°C] Yield 133a [%]
1 [Ir(COD)(Cl)]2 THF 90 n.r.
2 [IrCp*Cl2]2 THF 90 n.r.
3 [Ir(COD)2][BF4] THF 90 n.r.
4 [Rh(COD)2][BF4] THF 90 n.r.
5 [Rh(COD)Cl]2 THF 90 n.r.
6 [Ru(p-cymene)Cl2]2 1,4-dioxane 80 n.r.
a Reaction conditions: sulfoximine 30a (0.50 mmol), catalyst (7.5 mol), 8-AQ (15 mol), B2pin2 (0.35 mmol) and HBpin (25 mol) in denoted solvent (1.5 mL), temperature for 16 h.
Results and Discussion
78
Table 29: Solvent and temperature optimization.a
Next, the reaction time and the equivalents of the two boron sources were investigated
(Table 30). With 1 h of reaction time, only 23% of the ortho-borylated sulfoximine 133a could
be isolated (Table 30, entry 1). A reaction time of 4 and 8 h, respectively, led to 34% and 56%
of the desired product (Table 30, entries 2–3). Therefore, the reaction time can effectively be
shortened to 8 h, since a very comparable yield to the previously obtained 57% yield of 133a
with 16 h of reaction time could be achieved (compare Table 29, entry 9 and Table 30, entry
3). A further increase in reaction time to 40 h was not accompanied by an increase in yield
(Table 30, entry 4), potentially indicating that catalyst deactivation already occurs during the
reaction time of 8 h. However, it also demonstrated that the product is stable under the applied
reaction conditions. To ensure complete conversion, the reaction time was kept at 16 h.
Subsequently, the amount of B2pin2 was varied. Both a decrease to 0.50 equivalents as well
as an increase in the amount of B2pin2 (1.0, 1.5, 2.0 equivalents) did not lead to an
improvement in the yield of 133a with yields ranging from 36% to 54% (Table 30, entries 5–8).
While 1.0 and 1.5 equivalents gave comparable yields, 0.50 and 2.0 equivalents of the
diborane proved to be detrimental for the yield of the reaction. Unfortunately, raising the
Entry Solvent Temperature [°C] Yield 133a [%]
1 1,4-dioxane 90 45
2 DCE 90 25
3 toluene 90 33
4 MeCN 90 n.r.
5 DMSO 90 n.r.
6 MeOH 90 n.r.
7 1,4-dioxane 40 n.r.
8 1,4-dioxane 60 40
9 1,4-dioxane 80 57
10 1,4-dioxane 100 51
11 1,4-dioxane 120 28
12 1,4-dioxane 140 20 a Reaction conditions: sulfoximine 30a (0.50 mmol), [Ir(COD)(OMe)]2 (7.5 mol), 8-AQ (15 mol), B2pin2 (0.35 mmol) and HBpin (25 mol), in denoted solvent (1.5 mL) at denoted temperature for 16 h.
Results and Discussion
79
amount of HBpin also could not enhance the yield of the borylated product 133a. With both 10
and 30 mol% of HBpin comparable yields as with 5.0 mol% could be obtained (compare Table
29, entry 9 and Table 30, entry 9–10). A further increase to 1.0 equivalent of HBpin was
seemingly detrimental furnishing only 35% of the boronic ester 133a (Table 30, entry 11).
Table 30: Optimization of time and boron equivalents.a
Entry Time [h] B2pin2 (equiv.) HBpin (mol%) Yield 133a [%]
1 1 0.70 5.0 23
2 4 0.70 5.0 34
3 8 0.70 5.0 56
4 40 0.70 5.0 55
5 16 0.50 5.0 43
6 16 1.0 5.0 54
7 16 1.5 5.0 54
8 16 2.0 5.0 36
9 16 0.70 10 55
10 16 0.70 30 56
11 16 0.70 100 35
a Reaction conditions: sulfoximine 30a (0.50 mmol), [Ir(COD)(OMe)]2 (7.5 mol), 8-AQ (15 mol), B2pin2 and HBpin as denoted in 1,4-dioxane (1.5 mL) at 80 °C for denoted time.
Consequently, various experiments were carried out to investigate the importance of the boron
sources and the ligand. Furthermore, a syringe pump was employed to add the diborane and
the sulfoximine over time to test the importance of the reagent concentration in the reaction
mixture (Table 31).
Results and Discussion
80
Table 31: Optimization studies.a
In a first experiment, HBpin was omitted. Interestingly, the product could be isolated in 20%
yield (Table 31, entry 1). Also, omission of B2pin2 under use of a stoichiometric amount of
HBpin furnished the product in 43% yield (Table 31, entry 2). Still, the best yield that could be
obtained employed a combination of B2pin2 and HBpin, which seems beneficial for the reaction
system. Presumably, HBpin acts as a better catalyst activator than B2pin2 more efficiently
starting the catalytic cycle. Interestingly, upon omission of the ligand, the desired product 133a
could still be isolated, albeit in lower yields (Table 31, entry 3–4), proving the necessity of a
ligand for an efficient ortho-direction. The comparison between the two experiments again
shows the importance of utilizing the two boron sources in combination, since B2pin2 alone
only delivers 18% of the product, while the addition of 5.0 mol% HBpin doubles the yield. Next,
B2pin2 was added over time. A portion-wise addition of B2pin2 could still furnish the ortho-
borylated sulfoximine 133a in 47% yield (Table 31, entry 5). In contrast, both fast and slow
addition via syringe pump only delivered the product in 36% or not at all, demonstrating that a
high reagent concentration of B2pin2 in the reaction mixture is beneficial for the progress of the
reaction (Table 31, entries 6–7). The same experiment was conducted for the addition of
Entry Time [h] B2pin2 (equiv.) HBpin (mol%) Yield 133a [%]
1 16 0.70 --- 20
2 16 --- 100 43
3b 16 0.70 --- 18
4b 16 0.70 5.0 36
5c 24 1.1 5.0 47
6d 24 1.1 5.0 36
7e 24 0.70 5.0 n.r.
8f 16 0.70 5.0 37
9g 24 2 x 0.70 5.0 60
a Reaction conditions: sulfoximine 30a (0.50 mmol), [Ir(COD)(OMe)]2 (7.5 mol), 8-AQ (15 mol), B2pin2 and HBpin as denoted in 1,4-dioxane (1.5 mL) at 80 °C for denoted time. b Reaction without ligand. c Portion-wise addition of B2pin2 (3 times 0.35 equiv. at start, after 4 and 8 h). d Addition by syringe pump over first 15 min. e Addition of B2pin2 by syringe pump over first 4.5 h. f Addition of sulfoximine 30a by syringe pump over first 4.5 h. g Addition of B2pin2 only after 4 h.
Results and Discussion
81
sulfoximine 30a showing similar results with a slightly decreased yield of 37% of 133a
(Table 31, entry 8), highlighting that a high substrate concentration is not detrimental for the
progression of the reaction. As a last experiment, both sulfoximine and B2pin2 were added
again after 8 h of reaction time (Table 31, entry 9). With a yield of 60% of the ortho-borylated
product 133a, however, it seems that the catalyst is not active anymore after 8 h to turnover
further starting material.
Consequently, the amount of catalyst was investigated to prove deactivation of the catalyst.
Additionally, the importance of the amount of solvent was tested (Table 32).
Table 32: Catalyst and solvent optimization.a
Entry Mol% Ir-catalyst Mol% 8-AQ Yield 133a [%]
1 10 20 38
2 5.0 10 47
3 2.5 5.0 49
4 0.50 1.0 51
5 1.5 6.0 34
6b 1.5 3.0 57
7c 1.5 3.0 63
8d 2 x 1.5 2 x 3.0 53
9e 1.5 3.0 n.r.
10f 3.0 6.0 56
a Reaction conditions: sulfoximine 30a (0.50 mmol), [Ir(COD)(OMe)]2 and 8-AQ as denoted, B2pin2 (0.35 mmol) and HBpin (β5 mol) in 1,4-dioxane (1.5 mL) at 80 °C for 16 h. b Reaction with 0.5 mL of solvent. c Reaction with 3.0 mL of solvent. d After 16 h second addition of catalyst and 8-AQ and subsequent reaction for further 20 h. e Reaction on 1.0 mmol scale with tenfold dilution. f Reaction on 2.5 mmol scale with B2pin2 (1.4 equiv.) and HBpin (10 mol%).
First, the catalyst loading was investigated. In these experiments, the amount of ligand was
adjusted to the catalyst loading. Assuming a higher catalyst loading might improve the yield,
10 mol% of catalyst were employed (Table 32, entry 1). In this case, only 38% of the product
could be isolated. Due to this result further catalyst loadings were tested, however, also with
Results and Discussion
82
5.0, 2.5 and 0.50 mol% of the catalyst the yield could not be improved with yields ranging from
47% to 51% yield (Table 32, entries 2–4). Also, we doubled the amount of ligand to check if
additional direction is beneficial to the reaction (Table 32, entry 5), yet with only 34% yield the
additional ligand rather seems to inhibit the reaction. By lowering and increasing the amount
of solvent, the reaction mixture was concentrated and diluted, respectively (Table 32, entries
6–7). Since the obtained results were comparable to the previously best conditions,
concentration does not seem to be a critical factor, which is why the previous conditions were
maintained. Subsequently, both catalyst and ligand were added again after the reaction time
and the reaction continued under the previous conditions (Table 32, entry 8). Interestingly, the
53% yield of 133a indicate catalyst deactivation. While a second addition of catalyst should
lead to higher yields, the reaction mixture seemed to contain sufficient catalyst poison to
sequester the catalyst. Since low catalyst loadings seemed beneficial for the reaction, the
reaction was performed in a tenfold dilution (Table 32, entry 9). Albeit, under these conditions
no reaction to the boronic ester 133a could be observed. By doubling the amount of the boron
sources, the scalability of the reaction could be proven furnishing the product in a comparable
56% yield (Table 32, entry 10).
To gain a better understanding of the reaction, different ligands and substrates were subjected
to the reaction conditions. Moreover, additives such as bases, acids and Cu(TC) were tested
to improve the yield by either improving catalysis through protonation/deprotonation (acid or
base) or trapping of the sulfinamide. Additionally, the necessity of inert and anhydrous
conditions was investigated for the reaction (Table 33). Unfortunately, both picolylamine and
2-aminopyridine proved to be inferior ligands compared to 8-aminoquinoline only delivering the
product in 17% and 28%, respectively (Table 33, entry 1–2). In analogy to the work published
by Chattopadhyay and co-workers, N-tert-butylsulfoximine 31e was prepared and subjected to
the reaction conditions (Table 33, entry 3).[140a] However, while the ortho-directed borylation of
imines proceeded best with N-tert-butylimines for Chattopadhyay and co-workers, in our case
the borylated N-tert-butylsulfoximine could not be observed. Instead, the starting material could
be reisolated. Next, the product 133a was employed in the reaction. Surprisingly, TLC after the
reaction did not show signs of decomposition and only traces of the starting material 30a, yet
only 48% of the product 133a could be reisolated (Table 33, entry 4). While counter-intuitive
at first, it seems that the desired product decomposes readily when subjected to column
chromatography. Presumably, the acidic silica gel decomposes the product. This is in line with
earlier observations showing the product to be stable under the reaction conditions (Table 30,
entry 4). While not stable under column chromatography conditions, storage of the product on
the bench did not lead to decomposition even after one month. Furthermore, methyl phenyl
sulfone (129) was tested as starting material. As no reaction could be observed, the N-methyl
group of the sulfoximine seems crucial as directing group (Table 33, entry 5).
Results and Discussion
83
Table 33: Optimization studies.a
Entry Comment Yield 133a [%]
1 picolylamine as ligand 17
2 2-aminopyridine as ligand 28
3b starting material (see below) n.r.
4c starting material (see below) 48
5d starting material (see below) n.r.
6 NaOtBu (0.50 equiv.) n.r.
7 NaOMe (0.50 equiv.) n.r.
8 NaOMe (0.05 equiv.) 27
9 CH3COOH (0.50 equiv.) n.r.
10 normal 1,4-dioxane n.r.
11 Cu(TC) (0.10 equiv.) traces
12 Cu(TC) (1.0 equiv.) traces
a Reaction conditions: sulfoximine 30a (0.50 mmol), [Ir(COD)(OMe)]2 (7.5 mol), 8-AQ (15 mol), B2pin2 (0.35 mmol) and HBpin (25 mol) in 1,4-dioxane (1.5 mL) at 80 °C for 16 h. b N-tert-butylsulfoximine 31e was used as substrate. c The borylated product 133a was used as starting material. d Methyl phenyl sulfone 129 as starting material, reaction time 4 h.
Adding 0.50 equivalents sodium tert-butoxide, sodium methanolate or acetic acid to the
reaction mixture, the formation of product 133a could not be observed (Table 33, entry 6–7,
9). In contrast, with 0.05 equivalents of sodium methanolate the product could still be isolated
in 27% yield (Table 33, entry 8), however these acidic or alkaline additives in general seem to
considerably inhibit catalyst formation. As last experiments for this part of the optimization, the
stability of the process was investigated by conducting the reaction under an ambient
atmosphere. Employing normal 1,4-dioxane under an atmosphere of air, the product could not
be observed. While traces of water might be responsible for the failure of the reaction, oxygen
at least seems detrimental to the progress of the reaction (Table 33, entry 10). Therefore, an
Results and Discussion
84
inert and anhydrous atmosphere is necessary for the success of the reaction. Lastly, Cu(TC)
was added to trap the generated sulfinamide. Unfortunately, with both 0.10 and 1.0 equivalents
the ortho-borylated product 133a could only be observed in traces (Table 33, entries 11 and
12).
To investigate the formation of the side product, the reaction was performed at high
temperatures with and without addition of the catalyst (Table 34).
Table 34: Formation of the side product.a
Entry Comment Yield 132a [%]c
1 standard reaction 11
2 no catalyst n.r.
3b no boron source, no ligand n.r.
a Reaction conditions: sulfoximine (0.5 mmol), 8-AQ (15 mol), B2pin2 (0.35 mmol) and HBpin (25 mol) in 1,4-dioxane (1.5 mL) at 140 °C for 16 h. b At 80 °C. c Calculated by 1H NMR spectroscopy.
Interestingly, the product could be isolated in 11% yield with traces of B2pin2 under use of the
iridium catalyst and clearly identified by NMR spectroscopy and mass spectrometry (Table 34,
entry 1). A clean isolation was not successful as the sulfinamide presumably forms an adduct
with B2pin2, further strengthening the hypothesis, that it might act as inhibitor or poison in this
reaction. In contrast, the sulfinamide could not be observed if the catalyst was omitted (Table
34, entry 2). Seemingly, the demethylation of N-methylsulfoximine 30a is an iridium-catalyzed
process, occurring parallel to the formation of the product 133a, which makes the inhibition of
this reaction pathway difficult. Also, only employing the catalyst with substrate and solvent, the
formation of the sulfinamide could not be observed, revealing that the process necessitates
the boron source as reducing agent in combination with an iridium species as catalyst (Table
34, entry 3).
As the sulfinamide 132a was assumed to be the reason for catalyst deactivation, several
experiments were carried out using sulfinamide 132c as deliberately added catalyst poison in
the reaction (Table 35).
Results and Discussion
85
Table 35: Deactivation experiments.a
Entry Comment Yield 133a [%]
1 132c to start the reaction, after 1 h addition of 30a and further reaction
for 16 h
n.r.
2 16 h of reaction with 132c and 30a to start the reaction
n.r.
a Reaction conditions: sulfoximine 30a (0.50 mmol), sulfinamide 132c (0.05 mmol) as denoted, [Ir(COD)(OMe)]2 (7.5 mol), 8-AQ (15 mol), B2pin2 (0.35 mmol) and HBpin (25 mol) in 1,4-dioxane (1.5 mL) at 80 °C for denoted times.
In the first experiment, sulfinamide 132c was added at the start of the reaction without
sulfoximine 30a. After 1 h under the standard reaction conditions, the mixture was cooled down
and sulfoximine 30a was added to the mixture. 0.05 equivalents of sulfinamide 132c were
sufficient to suppress the reaction completely (Table 35, entry 1). In a further test, sulfinamide
and sulfoximine were subjected to the reaction conditions at the same time (Table 35, entry
2). Again, no product could be observed. These experiments strongly suggest that deactivation
of the catalyst occurs through the formation of the side product, N-methylbenzenesulfinamide
(132a).
Even though the deactivation of the catalyst could be proven, the scope of the ortho-borylation
was tested with various N-methylsulfoximines 30 (Table 36). While using the standard
substrate 30a led to a moderate yield of 57% of the desired ortho-borylated product, a
substituent on the phenyl ring of the substrate generally led to a low yield or no reaction at all.
Halogen substitutions on the phenyl ring in para-positions with fluorine (133b) and chlorine
(133c) gave low yields of 19% and 7%, respectively. A bromine substituent both in para- and
meta-position of the phenyl ring only led to 9% and 11%, respectively (133d and 133e). In
contrast, with bromine in the ortho-position (133f) no reaction could be observed, presumably
due to steric hindrance of the other ortho-position. With these results a trend for the para-
halogen substitution is not clearly visible. Surprisingly, the fluorine substitution gave the best
result even though it is the most electron-withdrawing substituent. On the other hand, electron-
Results and Discussion
86
donating groups such as para-methyl and para-methoxy could deliver 31% and 18% of the
ortho-borylated product, respectively (133h and 133i). Employing other strongly electron-
withdrawing groups such as para-acetyl and para-nitro did only furnish traces of the product or
did not lead to product formation at all (133j and 133k). Hence, a clear substitution pattern that
is beneficial for the ortho-borylation is not deductible from the obtained results.
Table 36: Scope of the ortho-borylation.a
a Reaction conditions: sulfoximine 30 or 35a (0.50 mmol), [Ir(COD)(OMe)]2 (7.5 mol), 8-AQ (15 mol), B2pin2 (0.35 mmol) and HBpin (25 mol) in 1,4-dioxane (1.5 mL) at 80 °C for 16 h. b c.m. - complex mixture.
Pyridinyl-substituted sulfoximine 30m did not deliver the desired product. In combination with
the result of the para-nitro group it seems that additional nitrogen atoms hinder the reaction.
Furthermore, by employing the cyclohexyl-substituted sulfoximine 30n the reaction should be
expanded to sp3-hybridized carbon atoms. Unfortunately, the product could not be observed,
thus the reaction is only applicable to sp2-hybridized carbon atoms. In a next step, the methyl
substituent on sulfur was varied. Interestingly, when employing an ethyl group the yield could
be increased to 69% (133p). A cyclopropyl substituent gave a slightly lower yield with 39%
(133q). Diphenyl-substituted sulfoximine 30r proved to be the best substrate for the reaction,
yielding the product in 78%. Additionally, the diborylated product could also be observed in
traces. As a last experiment, N-cyanosulfoximine 35a was subjected to the reaction conditions
to prove that other N-substituted sulfoximines can be converted in the described borylation.
While the product could be observed in traces, purification was not possible due to a complex
Results and Discussion
87
reaction mixture. Further improvements in the reaction could make this a viable alternative as
a substrate. Especially, varying the R2 moiety might be beneficial for the reaction, as it hinders
a reductive demethylation to the sulfinamide, thereby preventing the generation of a proven
catalyst deactivator.
Strikingly, all prepared ortho-borylated substrates showed a shift of the boron atom between 9
and 11 ppm in the 11B NMR spectra, which is indicative of a four-coordinate boron species
135a (see Scheme 67). The equilibrium between the two boron species must therefore be
heavily shifted towards the four-coordinate species 135a. In contrast, an uncoordinated pinacol
boron species displays a shift between 29 and 31 ppm (compare products in chapter 4.3.7.).
Unfortunately, attempts to obtain a crystal structure of 133a/135a by X-ray diffraction failed.
Therefore, the structure of the synthesized compounds cannot be verified definitely. Literature
precedent however strongly supports the formation of a four-coordinate boron species.[167]
Scheme 67: Equilibrium between the two boron species.
2.4.2.2. Suzuki–Miyaura couplings of ortho-borylated sulfoximines
To valorize the ortho-borylated substrates, we established conditions for the Suzuki–Miyaura
coupling with aryl bromides. Due to the optimization for the ortho-borylation being carried out
with N,S-dimethyl-S-phenylsulfoximine (30a), the ortho-borylated product 2-(N-methyl-S-
methylsulfonimidoyl)phenylpinacolborane (133a) was chosen as model substrate for the
optimization of the coupling reaction. First reactions were carried out with Pd(PPh3)4 as catalyst
varying the reaction temperature (Table 37). While a reaction at room temperature did not take
place (Table 37, entry 1), the product 136a could be obtained in 10% yield at 40 °C (Table 37,
entry 2). To our delight, raising the temperature further also led to an increase in yield. With
60 °C, 25% of the product 136a could be detected (Table 37, entry 3). The best results however
were obtained with 80 °C and 100 °C yielding the product in 69% and 61%, respectively (Table
37, entries 4–5). In contrast, the product could not be detected at 120 °C (Table 37, entry 6).
The displayed yields in the table were calculated by 1H NMR spectroscopy, because the
obtained products were contaminated with triphenylphosphineoxide. The contamination
(usually not more than 5%) was however only detected after the optimization of the reaction
Results and Discussion
88
temperature, so that the following optimization steps were carried out assuming 100 °C to be
the best temperature for the reaction.
Table 37: Optimization of the temperature.a
Entry Temperature [°C] Yield 136a [%]b
1 rt n.r.
2 40 10
3 60 25
4 80 69
5 100 61
6 120 n.r.
a Reaction conditions: sulfoximine 133a (0.20 mmol), Pd(PPh3)4 (10 mol), bromobenzene (0.24 mmol), aq. deg. K2CO3 (0.60 mmol) in 1,4-dioxane (1.5 mL) at denoted temperature for 16 h. b Yield calculated by 1H NMR spectroscopy.
In a next step, the reaction was performed in different reaction media to find the ideal solvent
for the coupling (Table 38). Using THF as solvent, the coupling product 136a could only be
obtained in 21% drastically lowering the yield that was obtained with 1,4-dioxane (Table 37,
entry 5 vs Table 38, entry 1). Toluene, DCE and acetonitrile furnished the desired product 136a
in moderate yields of 57%, 50% and 60%, respectively (Table 38, entries 2–4). Highly polar
solvents such as MeOH and DMF could only deliver the product in low yields of 32% and 21%,
respectively (Table 38, entries 5–6). To our delight, 1,4-dioxane proved to be the best solvent
for the reaction potentially facilitating a possible one-pot reaction or a sequential execution of
ortho-borylation and coupling reaction.
Results and Discussion
89
Table 38: Solvent optimization.a
Entry Solvent Yield 136a [%]b
1 THF 21
2 toluene 57
3 DCE 50
4 MeCN 60
5 MeOH 32
6 DMF 21
a Reaction conditions: sulfoximine 133a (0.20 mmol, 1.0 equiv.), Pd(PPh3)4 (10 mol), bromobenzene (0.24 mmol), aq. deg. K2CO3 (0.60 mmol) in denoted solvent (1.5 mL) at 100 °C for 16 h. b Yield calculated by 1H NMR spectroscopy.
In the following, the chemical nature of the base needed for an optimal yield was investigated
(Table 39). The base screening showed that similar results as for potassium carbonate could
be obtained using sodium hydrogen carbonate and sodium carbonate giving 62% and 65%
yield, respectively (compare Table 37, entry 5 vs Table 39, entries 1–2). In contrast to the other
carbonate-based bases, cesium carbonate only furnished the coupling product 136a in 38%
yield (Table 39, entry 3). Strong bases did not prove to be beneficial for the yield of 136a, as
NaOMe with 41% of the product, KOtBu only showing traces and KOH with no product
formation, proved (Table 39, entries 4–6). Employing tripotassium phosphate as base only
furnished the product in 24% yield (Table 39, entry 7). Seemingly, a carbonate counter-anion
is beneficial for the coupling reaction. Due to very similar results with carbonate bases,
potassium carbonate was further utilized for the base equivalent screening. While
1.5 equivalents of base only led to 36% of the desired product 136a, with 2.0 equivalents of
potassium carbonate the product could be obtained in 75% yield (Table 39, entries 8–9). An
excess of base with 5.0 equivalents proved detrimental only yielding 24% of the product (Table
39, entry 10).
Results and Discussion
90
Table 39: Investigation of base and base equivalents.a
Entry Base (equiv.) Yield 136a [%]b
1 NaHCO3 (3.0) 62
2 Na2CO3 (3.0) 65
3 Cs2CO3 (3.0) 38
4 NaOMe (3.0) 41
5 KOtBu (3.0) traces
6 KOH (3.0) n.r.
7 K3PO4 (3.0) 24
8 K2CO3 (1.5) 36
9 K2CO3 (2.0) 75
10 K2CO3 (5.0) 24
a Reaction conditions: sulfoximine 133a (0.20 mmol), Pd(PPh3)4 (10 mol), bromobenzene (0.24 mmol), base (aq. deg.) as denoted in 1,4-dioxane (1.5 mL) at 100 °C for 16 h. b Yield calculated by 1H NMR spectroscopy.
In a last step, both reaction time and equivalents of bromobenzene were varied to improve the
yield (Table 40). Before the screening of the reaction time a test reaction was carried out and
the reaction progress was monitored by TLC. Since TLC indicated full conversion after 6 h of
reaction time, both 4 h and 6 h of reaction time were tested (Table 40, entries 1–2). A reaction
time of 4 h proved to be enough yielding the product in 72% yield, while with 6 h a similar yield
could be obtained with 68%. To ensure complete conversion of the starting material, 6 h of
reaction time were chosen as ideal time. Subsequently, the equivalents of bromobenzene were
raised to 1.5 and 2.0 (Table 40, entries 3–4). While with 1.5 equivalents only 61% of the
coupling product 136a could be obtained, 2.0 equivalents furnished the desired product in a
very good yield of 89%.
Results and Discussion
91
Table 40: Optimization of time and bromobenzene equivalents.a
Entry Time [h] Bromobenzene equiv. Yield 136a [%]
1 4 1.2 72
2 6 1.2 68
3 6 1.5 61
4 6 2.0 89
a Reaction conditions: sulfoximine 133a (0.20 mmol), Pd(PPh3)4 (10 mol), aq. deg. K2CO3 (0.40 mmol), bromobenzene as denoted in 1,4-dioxane (1.5 mL) at 100 °C for the denoted time.
As it was assumed that the purification by column chromatography led to a decrease in yield
of the ortho-borylated product 133a as well as to simplify the synthetic work, a sequential
reaction execution was performed with the best reaction conditions at that time (Scheme 68).
Gratifyingly, both reactions proceeded best in 1,4-dioxane, making a purification of the reaction
mixture and solvent change unnecessary.
Scheme 68: Sequential ortho-borylation and Suzuki–Miyaura coupling.
Employing the denoted procedure (Scheme 68), the coupling product 136a could be obtained
in a moderate yield of 61% over two steps. In comparison, if the reaction is carried out in two
separate steps, with 57% for step 1 (Table 29, entry 9) and 68% for step 2 (Table 40, entry 2),
an overall yield of only 39% could be obtained. A sequential reaction execution therefore
enables a distinctively higher yield of the desired product. In line with earlier observations, the
difference of 22% in yield indicates that the ortho-borylated product 133a must partially
decompose during purification by column chromatography with the acidic silica gel.
Results and Discussion
92
2.4.3. Summary and outlook
An iridium-catalyzed synthesis for the ortho-borylation of N-methylsulfoximines 30 was
established. Various sulfoximines could be subjected to the reaction conditions yielding the
desired product 133 in low to good yields (Scheme 69). Unreacted starting material can be
recovered in this process. The low yields could be attributed to a side reaction, namely an
iridium-catalyzed reductive demethylation of the sulfoximine to the corresponding
N-methylsulfinamide, which subsequently acts as catalyst poison. Inert and anhydrous
conditions are required for this reaction. The product can at least partly decompose during
column chromatography also explaining the low yields. Storage of the product on the bench
however, even over a month, did not lead to decomposition.
Scheme 69: Ortho-borylation of sulfoximines 30.
The borylated products were further modified using a Suzuki–Miyaura coupling reaction. After
optimization of the process, a very good yield of the coupling product 136a could be obtained
(Scheme 70).
Scheme 70: Suzuki–Miyaura coupling of sulfoximine 30a.
It could be shown that a sequential reaction execution leads to higher yields. The reason might
be that the borylated product 133a is partially decomposing during column chromatography.
The ortho-borylation of sulfoximines should be further optimized. Above all, hydrogen
acceptors should be used as additives, which might function as sacrificial reductants instead
of the starting material or the product as shown by Ito, Ishiyama and co-workers.[168]
DFT studies concerning the observed side reaction might give insight into the deactivation
pathway, thereby allowing the development of strategies to prevent it. Furthermore, different
Results and Discussion
93
boron sources could be employed facilitating the ortho-borylation.[169] As demonstrated in this
thesis, the work-up procedure can be improved, preferably avoiding the use of slightly acidic
silica gel. In lieu of a work-up procedure however, it might also be advantageous to develop
sequential functionalizations under the use of the obtained reaction mixture as shown in this
thesis. If amenable conditions for the borylation can be found, it would be worthwhile to
investigate conditions for Chan–Evans–Lam couplings or a Petasis reaction.[170] Instead of a
borylation a silylation might also be feasible.[171] In contrast to boron, silicon should not
generate a four-coordinate species, thereby possibly facilitating the work-up procedure.
Results and Discussion
94
2.5. Scope extension of N-acetylsulfilimines and their C–H olefination
2.5.1. Background and aim of the project
As the group of Bolm developed several protocols for the C–H activation of
sulfoximines.[111, 172] we envisioned transferring the C–H olefination as versatile and atom-
economic process to sulfilimines to further valorize these compounds. To achieve this goal,
the rhodium(III)-catalyzed selective ortho-olefination of sulfoximines by C–H activation served
as a starting point for this investigation.[111] In this work, Bolm and co-workers demonstrated
that various N-acetylsulfoximines 29 could be olefinated in ortho-position with both acrylates
and styrenes 60 in low to excellent yields (Scheme 71). The authors also showed that the
generated products 62 could be further functionalized in an intramolecular Michael addition
delivering cyclic sulfoximines.
Scheme 71: Ortho-olefination of sulfoximines 29.
Furthermore, Satoh, Miura and co-workers showed that sulfoxides 2 could also be applied in
this type of reaction (Scheme 72). The olefinated products 64 could be obtained in moderate
to excellent yields.[115] In contrast to the protocol by Bolm and co-workers, however, only a few
sulfoxides were tested. Also the procedure was only shown to be effective for acrylates 63.
Scheme 72: Ortho-olefination of sulfoxides 2.
As Bolm and co-workers only previously established an elegant protocol for the synthesis of
N-acetylsulfilimines 28 (see Table 41),[25] these compounds seemed to be ideal substrates for
the investigation. The protocol employs a ruthenium catalyst to mediate a light-induced nitrene
transfer to the sulfide.
Results and Discussion
95
2.5.2. Project realization
2.5.2.1. Synthesis of starting materials
For the investigation of N-acetylsulfilimines 28 using C–H activation, the substrates were
prepared applying a procedure by Bolm and co-workers (see chapter 1.1.2.2.).[25] The
substrate scope of the reaction was expanded for this project, also proving the generality of
this method (Table 41). The imination of sulfides by this decarboxylative method is especially
effective with S-aryl-S-methyl sulfides 1a–k, leading to the corresponding N-acetylsulfilimines
28a–k in moderate to excellent yields. Both electron-donating (e.g. 28h–i) and electron-
withdrawing (e.g. 28b–f and 28k) substrates are well tolerated under these conditions.
Substrate 28g presents an exception giving only a moderate yield of 48%, presumably due to
steric hindrance or the fact that the ester group can also be activated by light thereby inhibiting
the reactivity of the sulfide. In contrast, employing S-phenyl-S-alkyl/vinyl sulfides, the
corresponding N-acetylsulfilimines could not be observed (in case of 28v) or only be obtained
in low yields (28q, 28w, 28ab). Unfortunately, also S-heteroaryl-S-methyl sulfides only
delivered the desired products in low yields (28m and 28ac).
Table 41: Extension of the substrate scope for N-acetylsulfilimines 28.a
a Reaction conditions: sulfide 1 (2.5 mmol), dioxazol-5-one 27 (2.7 mmol) with Ru(TPP)CO (2.5 mol) in toluene (10 mL) at rt for 8 h under UV irradiation.
Results and Discussion
96
This might be attributed to their electronic properties or the additional possibility of coordination
for the ruthenium catalyst thereby exacerbating the reactivity of the sulfide. Lastly,
N-benzacetylsulfilimine 28ad could be obtained in a moderate yield of 37%.
2.5.2.2. C–H olefination of N-acetylsulfilimines
After establishing the scope for the starting materials, N-acetyl-S-methyl-S-phenylsulfilimine
(28a) was chosen as model substrate for the reaction and subjected to conditions that were
applied to the corresponding N-acetylsulfoximines by Bolm and co-workers and the
corresponding sulfoxides by Satoh, Miura and co-workers.[111, 115] While the desired product
137a could not be observed under the reaction conditions by Bolm and co-workers, the product
could be obtained in 44% yield with the conditions used by Satoh, Miura and co-workers
(Scheme 73). Under these conditions the corresponding sulfide could be observed in small
amounts next to unreacted starting material showing that the starting material is not completely
stable under these reaction conditions. In fact, the thermal instability of sulfilimines is known in
literature.[8]
Scheme 73: First test for the C–H activation of N-acetylsulfilimine 137a.
With this promising result in hand, a screening of solvent and additive was carried out to find
the optimal reaction medium and additive for the reaction (Table 42). Optimization of the
reaction conditions allowed a decrease of the catalyst loading to 2.5 mol%. Also the amount
of N-acetylsulfilimine was reduced to 1.5 equivalents to make the process more economic. To
ensure completion of the reaction the reaction time was extended to 16 h. Highly polar solvents
such as tert-amyl alcohol and DMF were not suitable preventing the reaction to the desired
product 137a (Table 42, entries 1–2). With acetonitrile, a slightly less polar solvent, a yield of
20% for 137a could be obtained (Table 42, entry 3). Chlorobenzene, 1,4-dioxane and diglyme
yielded the olefinated N-acetylsulfilimine 137a in slightly higher yields of 24%, 29% and 29%,
respectively (Table 42, entries 4–6). The best yields were obtained using apolar solvents. DCE
and toluene delivered the desired product in 33% and 40%, respectively, making toluene the
solvent of choice for further optimization (Table 42, entry 7–8). Strikingly, during the solvent
Results and Discussion
97
screening the corresponding sulfides were again observed in small amounts (less than 10%),
thereby also explaining the below average yields. Unfortunately, other oxidants such as
Cu(OAc)2•H2O and AgOAc did not yield the desired product (Table 42, entries 9–10).
Additionally, using sodium acetate as additive instead of the usual oxidant Ag2CO3 revealed
that the oxidant is necessary for the reaction (Table 42, entry 11).
Table 42: Solvent and oxidant screening.a
Entry Solvent Salt additive/oxidant Yield 137a [%]
1 tert-AmOH Ag2CO3 n.r.
2 DMF Ag2CO3 n.r.
3 MeCN Ag2CO3 20
4 PhCl Ag2CO3 24
5 1,4-dioxane Ag2CO3 29
6 diglyme Ag2CO3 29
7 DCE Ag2CO3 33
8 toluene Ag2CO3 40
9 toluene Cu(OAc)2•H2O n.r.
10 toluene AgOAc n.r.
11 toluene NaOAc n.r. a Reaction conditions: N-acetylsulfilimine 28a (0.38 mmol), [RhCp*(MeCN)3][SbF6]2 (6.3 mol), 63a (0.25 mmol) with denoted additive/oxidant (0.25 mmol) and solvent (2.0 mL) for 16 h at 120 °C.
Next, various catalysts were tested for their activity in the reaction (Table 43). The two
employed palladium catalysts as well as the ruthenium-based catalyst were not able to
catalyze the reaction (Table 43, entry 1–3). Interestingly, using [RhCp*Cl2]2 and AgSbF6 to
generate the previously used catalyst in situ only afforded the desired product in 12% yield
(Table 43, entry 4). The tetrafluoroborate analog of the previously employed catalyst was also
tested for its activity yielding the product 137a in 41% (Table 43, entry 5). However, this
reaction was carried out at 100 °C. For comparison, the same reaction was also carried out
with [RhCp*(MeCN)3][SbF6]2, which delivered the product with a moderate yield of 73% (Table
43, entry 6).
Results and Discussion
98
Table 43: Optimization of catalyst.a
Entry Catalyst Yield 137a [%]
1 Pd(OAc)2 n.r.
2 PdCl2(MeCN)2 n.r.
3b [Ru(p-cymene)Cl2]2 n.r.
4b [RhCp*Cl2]2 12
5c [RhCp*(MeCN)3][BF4]2 41
6c [RhCp*(MeCN)3][SbF6]2 73
a Reaction conditions: N-acetylsulfilimine 28a (0.38 mmol), 63a (0.25 mmol), [RhCp*(MeCN)3][SbF6]2 (6.3 mol), Ag2CO3 (0.25 mmol), toluene (2.0 mL), 16 h, 120 °C. b Addition of AgSbF6 (25 mol, 10 mol%). c Reaction at 100 °C.
Subsequently, the reaction temperature and the catalyst loading were investigated to increase
the yield further (Table 44).
Table 44: Screening of temperature and catalyst loading.a
Entry Temperature [°C] Catalyst loading [mol%] Yield 137a [%]
Unfortunately, both lowering and increasing the temperature diminished the yield of olefinated
N-acetylsulfilimine 137a (compare Table 43, entry 6 and Table 44, entries 1–3). While a
Results and Discussion
99
temperature of 80 °C still gave only slightly lower yields (entry 1), the reaction did not proceed
at all at 140 °C (Table 44, entry 3). A decrease of the catalyst loading to 1.0 mol% proved
detrimental only delivering the desired product in 29% yield (Table 44, entry 4). Likewise, an
increase in catalyst loading to 5.0 mol% could not improve the yield (Table 44, entry 5),
revealing 2.5 mol% as optimal catalyst loading for the reaction.
In a last optimization, the ratios of substrates and oxidants as well as the reaction time were
varied (Table 45). Increasing the equivalents of the N-acetylsulfilimine 28a or n-butylacrylate
63a did not improve the yield of the desired olefinated product 137a (Table 45, entries 1–2).
Furthermore, an equimolar ratio of N-acetylsulfilimine 28a, n-butylacrylate 63a and Ag2CO3 led
to 56% of the product (Table 45, entry 3). Also doubling the amount of oxidant did not prove
beneficial for the reaction (compare Table 43, entry 6 and Table 45, entry 4). Shortening the
reaction time to 4 h led to a slight decrease in yield with 63% of the desired product 137a
(Table 45, entry 5).
Table 45: Optimization of ratios and reaction time.a
Entry Equiv. of 28a/63a/Ag2CO3 Time [h] Yield 137a [%]
1 2.0/1.0/1.0 16 66
2 1.0/2.0/1.0 16 48
3 1.0/1.0/1.0 16 56
4 1.5/1.0/2.0 16 59
5 1.5/1.0/1.0 4 63 a Reaction conditions: N-acetylsulfilimine 28a, acrylate 63a, Ag2CO3 as denoted above, [RhCp*(MeCN)3][SbF6]2 (6.γ mol), toluene (2.0 mL), for denoted time at 100 °C. .
With the optimized conditions in hand, the substrate scope of the reaction was investigated
(Table 46). Firstly, various N-acetyl-S-aryl-S-methylsulfilimines 28a–k were subjected to the
reaction conditions. The model substrate could be obtained in 60% yield by performing the
reaction on a 2.0 mmol scale. The product could be obtained with both ortho-fluoro sulfilimine
28b and para-chloro sulfilimine 28c in 43% and 50% yield, respectively. Interestingly, both
para- and meta-bromo-substituted N-acetylsulfilimine delivered the desired product in 43% and
67% yield, whereas the ortho-bromo substrate did not react under the reaction conditions
(28d–f). Steric hindrance in the ortho-position of the sulfilimine therefore seems to be
Results and Discussion
100
detrimental for the reaction. A methyl and a methoxy group in the para-position of the sulfilimine
(28h and 28i) were also tolerated yielding the olefinated product in 36% and 56%.
Unfortunately, with para-acetyl as substituent on the aryl ring only traces of the product could
be isolated (137j). Substrates 28g, 28k, 28q, 28v–w, 28ab were also subjected to the reaction
conditions. In all cases, however, no product could be observed. This might not be surprising
for para-nitro N-acetylsulfilimine 28k which oftentimes does not react due to the nitro group
and ortho-benzoate N-acetylsulfilimine 28g due to the already mentioned steric hindrance. An
additional cyclopropyl (28q), vinyl (28w) or cyano group (28ab) seems to impede the
olefination either yielding only traces of the product or not furnishing it at all. Unfortunately,
both heteroaromatic N-acetylsulfilimines, containing thiophene and pyridine, could not yield
the desired product (137m and 137ac). Subsequently, instead of N-acetylsulfilimine 28a,
N-benzacetylsulfilimine 28ad was subjected to the reaction. The olefinated product 137ad
could not be observed, which might be explained by both the electronic and steric properties
of the phenyl ring exacerbating coordination to the rhodium complex as well as reaction with
the ortho-C–H bond. In the last step, the acrylate was varied. While methyl and ethyl acrylate
only led to trace amounts of the desired products (137ae and 137af), employing phenyl and
p-methoxyphenyl acrylate delivered the olefinated N-acetylsulfilimine in moderate yields of
45% and 54%, respectively (137ag and 137ah). In contrast, presumably due to the strong
negative inductive effect of the nitro group, para-nitrophenyl acrylate did not react under these
conditions (137ai). Further attempts were carried out to generate the olefinated
N-acetylsulfilimine 137a in a sequential reaction process or one-pot procedure. Therefore,
several experiments were set up testing the activity of both the ruthenium and the rhodium
catalyst in the imination and olefination step (Table 47). Employing only the ruthenium catalyst
for both the imination and the olefination process delivered N-acetylsulfilimine 28a in a low
yield of 21% (Table 47, entry 1). As expected, the ruthenium catalyst is able to catalyze the
imination process, albeit in low yields, however it is not able to instigate the C–H activation of
the generated N-acetylsulfilimine 28a. Furthermore, the low yield indicates that the additional
reagents for the C–H activation interfere in the imination process. No product was observed
when the rhodium catalyst was utilized for the sequential imination/olefination procedure
(Table 47, entry 2). Unsurprisingly, rhodium is unable to mediate the imination, making the
C–H activation impossible.
Results and Discussion
101
Table 46: Scope of the Rh(III)-catalyzed ortho-olefination.a
a Reaction conditions: N-acetylsulfilimine 28 (0.38 mmol), acrylate 63 (0.25 mmol), [RhCp*(MeCN)3][SbF6]2 (6.3 mol), Ag2CO3 (0.25 mmol) in toluene (2.0 mL) at 100 °C for 16 h. Yield in parentheses obtained from a reaction performed on 2.0 mmol scale.
Subsequently, both catalysts were employed in combination (Table 47, entry 3). Under these
conditions the desired product 137a could not be observed. Possibly the combination of all
reagents, especially the two catalysts, inhibits the formation of a catalytically active species for
conversion in two distinct steps. However, N-acetylsulfilimine 28a was isolated in 46% yield,
seemingly suggesting a synergistic effect of ruthenium and rhodium, since the ruthenium
catalyst alone only produced 21% of sulfilimine 28a. To prove a synergy between the two
catalysts further experiments would have to be conducted. As a last experiment, a sequential
addition of the reagents was tested. Therefore, the standard procedure for the synthesis of
N-acetylsulfilimine 28a was set up. After the designated reaction time, the missing reagents
for the olefination were added and the mixture subjected to the optimized reaction conditions
(Table 47, entry 4). The desired product 137a could be isolated in 23% yield, while
N-acetylsulfilimine 28a could not be observed. Although the general possibility of a sequential
Results and Discussion
102
reaction could be proven, conducting the synthesis consecutively should be preferred, since
the yield over two steps is significantly higher with 72% (98% for step 1, 73% for step 2).
Table 47: Experiments towards a sequential imination/olefination procedure.a
a Reaction conditions: Thioanisole (1a, 0.38 mmol), 27a (0.39 mmol), catalyst as denoted above, 63a (0.25 mmol), Ag2CO3 (0.25 mmol), for denoted time and conditions in toluene (2.0 mL) in a one-pot procedure. b Sequential addition of reagents for imination and olefination.
Results and Discussion
103
2.5.3. Summary and outlook
The scope of N-acetylsulfilimines 28 was extended using the reported protocol by Bolm and
co-workers.[25] The efficiency of the procedure for the synthesis of N-acetyl-S-aryl-S-
methylsulfilimines (28a–k) could be highlighted. At the same time, limitations of the protocol
were revealed for other N-acetyl-S-phenyl-S-alkylsulfilimines (28q, 28u–w) and heteroaryl-
containing N-acetylsulfilimines (28p and 28x). A protocol for the ortho-olefination of
N-acetylsulfilimines with various acrylates could be established affording the products in low
to good yields (137a–e, 137h–i and 137ag–ah). A combination of [RhCp*(MeCN)3][SbF6]2 as
catalyst and Ag2CO3 as oxidant proved essential for a successful transformation (Scheme 74).
Furthermore, the scalability of this reaction was proven. As the substrate scope was rather
narrow, the stability of both starting materials and products should be further investigated to
adjust the reaction conditions to the substrates. Additionally, N-benzacetylsulfilimine 28ad
should be employed as substrate in a modified procedure to investigate, if ortho-olefination
can be tuned by the reaction conditions to occur on the N-acetyl moiety as well as on the aryl
moiety bound to sulfur. Also, the substrates could be further valorized by subsequent
transformations, e.g. in a Michael addition or an oxidation reaction.
Scheme 74: Ortho-C–H olefination of N-acetylsulfilimines 28.
104
Conclusion
105
3. Conclusion
In this thesis two new methodologies were developed for the synthesis of N-methyl- and N-
cyanosulfoximines (30 and 35). The obtained products as well as NH- and other N-protected
sulfoximines were subsequently employed for the reductive borylation and ortho-C–H
borylation. Furthermore, the scope of N-acetylsulfilimines 28 was expanded and substrates
were olefinated in ortho-position by using C–H activation.
The first project aimed at establishing a procedure for the facile access of
N-methylsulfoximines 30. The instability of the formed N-methylsulfilimine intermediates 119
made a consecutive oxidation to the stable N-methylsulfoximines 30 necessary, but is also the
reason for the low to average yields. Diversely substituted sulfides 1 could be employed as
substrates yielding the desired products 30 in an unprecedented sequential imination/oxidation
procedure in low to moderate yields. Of note, this procedure only uses bromine as toxic reagent
under otherwise mild reaction conditions. Importantly, this step- and time-efficient protocol
generates N-methylsulfoximines 30 without the intermediacy of NH-sulfoximines 7.
In a second project, a straightforward and complementary procedure for the synthesis of
N-cyanosulfoximines 35 from the corresponding sulfoxides 2 was developed. Depending on
the substitution pattern of the sulfoxide 2 low to excellent yields of the desired products 35
could be obtained. While alkyl aryl sulfoxides 2 generally deliver the N-cyanosulfoximines 35
in moderate to excellent yields, both dialkyl and diaryl sulfoxides 2 only furnish the product 35
in low to moderate yields. The synthesis proceeds transition metal-free, utilizes readily
available reagents under very mild reaction conditions and is scalable. Of particular note, the
imination proceeds under inversion of the preexisting stereochemistry. Furthermore, a one-pot
procedure starting from the corresponding sulfides 1 could be established delivering a fast
access to N-cyanosulfoximines 35 in good yields.
The third project aimed at a nickel-catalyzed reductive borylation of sulfoximines 3. In
combination with an NHC ligand the desired boronic ester 85 could be obtained by C–S bond
fission in low to moderate yields. Catalyst deactivation was found to be the reason for the
unsatisfactory yields. Experiments revealed that the sulfinamide by-product, as well as the
starting material acted as catalyst poison. Unfortunately, experiments to trap the catalyst
poison to ensure a catalytic reaction failed. Thus the reductive borylation could only be
accomplished by stoichiometric use of the catalyst Ni(COD)2. Attempts to expand the concept
with the employed catalytic system to other organosulfur compounds demonstrated that only
sulfoxides 2 react similarly under these reaction conditions.
Conclusion
106
The C–H borylation of N-methylsulfoximines 30 was investigated in a fourth project. After
various attempts on the borylation of sulfoximines 3, an iridium-catalyzed ligand-directed
synthesis for the ortho-borylation could be established. Various sulfoximines could be
borylated in ortho-position in low to moderate yields. Catalyst deactivation through
N-methylsulfinamide 132a, which is generated in an iridium-catalyzed side reaction was found
to be responsible for the low yields. Noteworthy, loss of product during work-up revealed the
instability of the ortho-borylated sulfoximines 133 towards slightly acidic silica gel being
another reason for the low yields. Characterization by 11B NMR spectra revealed that the
borylated products exist as four-coordinate boron species 135 in solution. Further modification
by Suzuki–Miyaura coupling generated the ortho-biarylated sulfoximine 136 in an excellent
yield showing the value of the procedure, which is also applicable in a sequential reaction
procedure of ortho-borylation and Suzuki–Miyaura coupling.
In a last project, the scope of N-acetylsulfilimines 28 was expanded and subsequently utilized
to investigate their ortho-C–H olefination. While the ruthenium-catalyzed nitrene transfer
worked especially well for most alkyl aryl sulfides 1, some exceptions were found and
heteroaryl containing sulfides 1 presented themselves as difficult substrates in this reaction
only yielding the desired products in low yields. In the C–H olefination of the synthesized
substrates, [RhCp*(MeCN)3][SbF6]2 as catalyst and Ag2CO3 as oxidant proved to be essential
for conversion. Only few substrates could successfully be ortho-olefinated delivering the
desired products 137 in low to good yields.
Experimental Section
107
4. Experimental Section
4.1. General methods and chemicals
Unless otherwise stated, all commercial reagents and solvents were used without additional
purification. All air- or moisture-sensitive reactions were carried out under argon atmosphere
in dried glassware using standard Schlenk and vacuum line techniques. Air- and
moisture-sensitive chemicals were stored in a glovebox (MBraun labmaster 130) and weighed
into the required glassware inside the glovebox. Temperature-sensitive chemicals were kept
under argon in a refrigerator or freezer. All experiments were performed, if not otherwise
mentioned, using a PTFE-coated magnetic stir bar. Photoreactions were performed in glass
flasks and irradiated by a PHILIPS HPK 125W high pressure mercury vapor lamp (cooled with
water, radiation range from 200 to 600 nm). 4-Methylbenzenesulfinamide (132b) was
graciously provided by Hao Yu. NH-S-Methyl-S-phenylsulfoximine (7a) both in its racemic and
enantiomerically pure form were provided by Susanne Grünebaum. NHC ligand 127c was
provided by Shunxi Dong.
Solvents:
Solvents for column chromatography were distilled before use. Solvents for anhydrous
reactions were either purchased or dried according to standard procedures.
THF distilled over Solvona®
Toluene distilled over Solvona®
Chromatography and TLC:
Flash chromatography was performed on MERCK silica gel 60 (40–63 m) with application of
light pressure (0.1–0.5 bar). Analytical thin layer chromatography (TLC) was carried out on
MERCK precoated silica gel 60 F254 plates. Visualization on TLC plates was achieved by the
use of UV light (254 nm) or treatment with a basic aqueous solution of KMnO4 or an acidic
ninhydrine solution in acetone followed by heating.
Preparative HPLC:
Preparative HPLC was carried out on Varian, Kromasil-RP-18 250 × 30 mm, MeOH–H2O;
12 mL•min-1, 51 bar, 254 nm, SD-1 PumpeProstar 320 UV Detector for compounds
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Acknowledgments
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7. Acknowledgments
First I would like to express my sincere gratitude to Prof. Dr. Carsten Bolm for giving me the
opportunity to conduct my doctoral studies in his group. I enjoyed being part of his team. I
thank you for your constant support and time, discussions, both scientific and secular, the
scientific freedom, an excellent infrastructure and your faith in me.
Also, I thank Prof. Dr. Dieter Enders for being the second examiner of this thesis.
Apart from that, I thank Prof. Guy C. Lloyd-Jones for letting me conduct my interdoc at the
University of Edinburgh. You have expanded my view on science and shown me that the closer
you look the more wonders are waiting to be uncovered.
I am indebted to the DAAD for a short term research scholarship and to the GDCh and the
GSK foundation for a travel grant.
I would like to thank Dr. Ingo Schiffers, Ingrid Voss and Daniela Gorissen for their support in
administrative questions as well as always having time for personal discussions.
I thank Dr. Gunter Geibel, Gertrud Schellenberg, Elisabeth Steins-La Noutelle, Martina
Gösgens and Gabi Peters for their support and advice in the coordination of the trainees. I also
wish to thank all my trainees, especially André Teppler, Riccardo Müller and Darren Rice who
were helping hands in my lab. It has been a tough but unbelievably rewarding job to teach and
supervise you in your education.
I am grateful to the permanent staff of the institute for their help, be it measuring of samples,
repairing lab equipment or acquisition of chemicals/ lab ware.
Thanks to Arno Claßen, Susi Grünebaum and Pierre Winandy for their synthetic contributions
as well as advice on synthesis procedures.
Additionally, I owe thanks to my researchers Marvin Heuschen, Daniel Josef Bell, Felix
Krauskopf and Lars Fritze for their synthetic contributions and scientific as well as secular
discussions.
A special thanks goes to current and former colleagues: Dr. Jakob Mottweiler, Dr. Vincent
Bizet, Dr. Anne-Dorothee Steinkamp, Dr. Hannah Baars, Dr. Arne Philips and Dr. Christa
Lehmann, Magdalene Teh and Ph. D. Paul Alan Cox for their friendship and support. Having
you around made the daily work in the lab and the time outside the lab a lot more entertaining.
Acknowledgments
192
Apart from that I would also like to thank the whole AK Bolm for fruitful discussions and a good
time.
For proofreading this thesis I thank Dr. Bjoern Schulte, Dr. Jakob Mottweiler, Dr. Christa
Lehmann, Dr. Anne-Dorothee Steinkamp, Torsten Rinesch and Dr. Peter Becker.
Also I am grateful to my flat mates Janosch Maghon, Andreas Schmid and Claudia Dähling.
Thank you for most welcome distractions, games, lunches and discussions after a day of work
in the lab.
I feel privileged to have such good friends as Janosch Maghon, Dr. Bjoern Schulte and Oliver
Marco Timpanaro. I know that I can always count on you.
I would also like to thank my sisters Iris Timpanaro, Elfi Schranz, Inga Dittmann and their
families for being in my life and making it worthwhile.
At last I would like to thank my parents, Herbert and Sigrid Dannenberg from the bottom of my
heart for their sacrifices, their love, their advice, their much needed patience with me and their
support until now and in the future. Without you I would not have been able to complete this
thesis so easily. I consider myself extremely lucky and grateful to have you as my parents.
Thank you for never stopping to believe in me and accepting me as I am.
Curriculum Vitae
193
8. Curriculum Vitae
Personal Information
Name Carl Albrecht Dannenberg
Date of Birth 20.03.1989
Place of Birth Gummersbach
Nationality German
Education
Since 04/2014 Doctoral studies in the group of Prof. Bolm, Institute of Organic Chemistry, RWTH Aachen University
05/2016 – 07/2016 Interdoc in the group of Prof. Lloyd-Jones, School of Chemistry, University of Edinburgh (Scotland)
10/2011 – 02/2014 Master of Science (Chemistry), RWTH Aachen University Master thesis: “Aminations and Iodinations of 2-Aryl-1,3,4-oxadiazoles”, in the group of Prof. Bolm
10/2008 – 09/2011 Bachelor of Science (Chemistry), RWTH Aachen University
Bachelor thesis: “Untersuchungen zur organokatalytischen enantioselektiven Reduktion von Ketiminen”, in the group of Prof. Enders