method development for the synthesis of organosulfur

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

1.1.1. Properties ........................................................................................................1

1.1.2. Synthetic pathways to sulfoximines and sulfilimines .........................................2

1.1.2.1. Oxidation of sulfides and sulfilimines .............................................................3

1.1.2.2. Imination of sulfides and sulfoxides ...............................................................4

1.1.3. Synthesis and applications of N-alkyl- and N-methylsulfoximines ...................13

1.1.4. Synthesis and applications of N-cyanosulfoximines .......................................16

1.1.5. Biological relevance of sulfoximines and sulfilimines ......................................19

1.2. Relevant reaction types ........................................................................................21

1.2.1. Suzuki–Miyaura cross-coupling .........................................................................21

1.2.2. Directing group-assisted C–H activation ............................................................23

1.2.2.1. Oxidative C–H olefination ............................................................................25

1.2.2.2. Borylation: From stoichiometric reactions to directed C–H borylation ..........29

1.2.3. Reductive borylation ..........................................................................................36

2. Results and Discussion ...............................................................................................41

2.1. Synthesis of N-alkylated sulfoximines ...................................................................41

2.1.1. Background and aim of the project .................................................................41

2.1.2. Project realization ..........................................................................................42

2.1.2.1. Previous results ..........................................................................................42

2.1.2.2. Continuation of the project ..........................................................................43

2.1.3. Summary and outlook ....................................................................................48

2.2. Synthesis of N-cyanosulfoximines ........................................................................49




2.3. Reductive borylation of sulfoximines .....................................................................59




2.4. C–H borylation of sulfoximines and their use in Suzuki–Miyaura couplings ..........74



2.4.2.1. Iridium-catalyzed ortho-borylation of sulfoximines .......................................75

2.4.2.2. Suzuki–Miyaura couplings of ortho-borylated sulfoximines ......................... 87

2.4.3. Summary and outlook .................................................................................... 92

2.5. Scope extension of N-acetylsulfilimines and their C–H olefination........................ 94

2.5.1. Background and aim of the project ................................................................ 94

2.5.2. Project realization .......................................................................................... 95

2.5.2.1. Synthesis of starting materials .................................................................... 95

2.5.2.2. C–H olefination of N-acetylsulfilimines ........................................................ 96

2.5.3. Summary and outlook .................................................................................. 103

3. Conclusion ............................................................................................................... 105

4. Experimental Section ................................................................................................ 107

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

5. Abbreviations............................................................................................................ 177

6. References ............................................................................................................... 183

7. Acknowledgments .................................................................................................... 191

8. Curriculum Vitae ....................................................................................................... 193

Introduction

1

1. Theoretical Background

1.1. Introduction to sulfoximines and sulfilimines

1.1.1. Properties

Sulfoximines and sulfilimines represent the aza-analogs of sulfones and sulfoxides (Figure 1).

In case of sulfoximines, the formal exchange of an oxygen atom by a nitrogen atom, leads to

a tetracoordinated sulfur compound, which in contrast to sulfones bears a stereogenic center

(if R1 and R2 are not equal). Sulfilimines are tricoordinated sulfur compounds, which are also

generated by replacement of oxygen with nitrogen. Due to their free electron pair, chirality is

existent if different substituents are present.

Figure 1: Relevant sulfur compounds for this thesis.

Sulfoximines are spatially structured as a contorted tetrahedron. Using both X-ray

crystallography and spectroscopic data, sulfoximines could be shown to have a high double

bond character of the S–N bond (Figure 2).[1] The nitrogen atom of NH-sulfoximines is usually

mildly basic and nucleophilic. In contrast, the proton displays weakly acidic properties

(pKa ~ 24 for R1 = Ph, R2 = H, R3 = H) giving the NH group an amphoteric character.[1-2]

Depending on the substituent on the nitrogen atom (R3), the acidity of the α-protons on the

sulfur atom can broadly vary (e.g. in DMSO: pKa = 32 for R1 = Me, R2 = Ph, R3 = Me; pKa ~ 25

for R1 = Me, R2 = Ph, R3 = Ts).[3]

Figure 2: Properties of sulfoximines.

Introduction

2

Along with their chemical stability, tolerating various reaction conditions, these properties lead

to applications as ligands in asymmetric metal catalysis[4] and chiral auxiliaries.[1, 5]

Furthermore, they receive increasing attention in pesticide research[6] and medicinal

chemistry,[7] which will later be elaborated on in more detail (chapter 1.1.5.).

Their non-oxidized structurally related counterparts, either called sulfilimines or sulfimides,

have not been as thoroughly investigated as sulfoximines in terms of their structural and

physical properties. Investigation of several differently substituted sulfilimines by X-ray

crystallography exhibited the sulfur atom as center of a trigonal pyramid. It contains a free

electron pair and is connected to two substituents R1 and R2 as well as to a nitrogen atom

(Figure 3).[8] At ambient temperature single enantiomers are stable, however racemization,

presumably due to pyramidal inversion, is observed at higher temperatures (100 °C).[9] So far

the bond order of the S–N bond in sulfilimines has not been clearly determined. The stability

of the bond is however heavily influenced by the substituent on the nitrogen atom (R3). Stable

sulfilimines are generated by electron-withdrawing substituents, that can withdraw electron

density from the S–N bond creating a zwitterionic structure with a negative charge at the

nitrogen atom and a positive charge at the sulfur atom (Figure 3).[10]

Figure 3: Properties of sulfilimines.

Due to the thermal instability of sulfilimines, their application in organic synthesis has been

limited. They mostly serve as an intermediate to access sulfoximines.[1, 8, 11] However, recent

reports also reveal their biological activity.[12]

1.1.2. Synthetic pathways to sulfoximines and sulfilimines

Sulfoximines 3 are mainly accessed by two pathways, which both employ the corresponding

sulfide 1 as starting material. In the first pathway (Scheme 1, A), oxidation generates

sulfoxide 2, which is subsequently converted to sulfoximine 3 by imination. The second

pathway (Scheme 1, B) employs the inverse process of imination and oxidation to obtain

sulfoximines 3 by generating sulfilimines 4 as intermediate. A plethora of imination and

oxidation methods can be used to form the desired sulfoximines with a broad substrate scope

Introduction

3

under various reaction conditions (see chapter 1.1.2.1. and 1.1.2.2.). Another, albeit lesser

explored option is the conversion of sulfoxides 2 to sulfilimines 4 and subsequent oxidation to

sulfoximines 4 (Scheme 1, C). Various transformations have been developed for this pathway,

but will not be discussed in detail.[13] Other pathways require the synthesis of

sulfonimidoylchlorides 5 or sulfonimidates 6 to obtain sulfoximines 3 by Lewis acid-catalyzed

alkylation or nucleophilic substitution, respectively, and therefore represent rather exotic

examples.[14] In contrast, sulfilimines 4 are only accessible by imination of sulfides or

conversion of sulfoxides (Scheme 1, B and C).

Scheme 1: Prominent pathways for the synthesis of sulfoximines.

1.1.2.1. Oxidation of sulfides and sulfilimines

As seen in Scheme 1, accessing sulfoximines 3 over the two most common pathways requires

an oxidation of either sulfides 1 or sulfilimines 4. Various oxidants can be employed in these

transformations. In case of racemic sulfide oxidation, the most commonly used oxidants are

meta-chloroperoxybenzoic acid (m-CPBA),[15] hydrogen peroxide,[16] magnesium

monoperoxyphthalate (MMPP),[17] Oxone®,[18] sodium periodate,[19] nitric acid,[20] tert-butyl

hypochlorite[21] and (diacetoxy)iodobenzene (PhI(OAc)2, also known as PIDA).[22] A recent

protocol also allows the oxidation with molecular oxygen as oxidant through visible light

photoredox catalysis with TiO2 (Scheme 2, top).[23] Racemic sulfilimine oxidation is mostly

performed with oxidants such as m-CPBA,[24] sodium periodate[25] and potassium

permanganate (KMnO4, Scheme 2, bottom).[26]

Introduction

4

Scheme 2: Oxidation of sulfides 1 and sulfilimines 4.

Sulfoxides 2 can also be prepared in a stereoselective manner. Various metal-catalyzed

procedures have been developed to oxidize the prochiral sulfides 1 to the corresponding

asymmetric sulfoxides 2. Modena[27] as well as Kagan[28] independently developed an

enantioselective oxidation for the synthesis of chiral sulfoxides 2. In these first asymmetric

oxidations, the combination of stoichiometric amounts of titanium(IV)-isopropylate,

(R,R)-diethyltartrate and tert-butyl hydroperoxide led to the formation of various sulfoxides 2 in

both low to excellent yields and enantiomeric excesses being highly dependent on the

substrate. Later reports improved the process using only catalytic amounts of the titanium

complex and cumene hydroperoxide as oxidant.[29] The groups of Jacobsen[30] and Katsuki[31]

employed Mn-salene complexes for the asymmetric oxidation with hydrogen peroxide as mild

oxidant. Further protocols were developed by Bolm and co-workers revealing ligand-

accelerated vanadium[32] and iron[33] catalysis in combination with hydrogen peroxide to be

effective for the synthesis of enantioenriched sulfoxides 2. Apart from procedures that employ

metal catalysts, in 2012, Wang, Tao and co-workers also reported on a metal-free

enantioselective oxidation of sulfides 1 using a chiral phosphoric BrØnsted acid. The desired

asymmetric sulfoxides could be obtained in up to excellent yields and good enantiomeric

excesses with hydrogen peroxide as mild oxidant.[34] Another, albeit less explored method, is

the chiral resolution of racemic sulfoxides 2. Using diastereomerically pure sulfinates in

combination with organometallic reagents enantiomerically enriched sulfoxides 2 could be

obtained.[35]

1.1.2.2. Imination of sulfides and sulfoxides

Imination represents the other transformation that has to be performed along the two prominent

pathways to access sulfoximines 3 from sulfoxides 2 or for generating the sulfilimines 4 from

the corresponding sulfides 1.[11] A strict separation between iminations for sulfides 1 and

sulfoxides 2 cannot be drawn, as some protocols can be applied to both substrate classes,

while others are specifically designed for only one.

Introduction

5

Transition metal-free procedures

Bentley et al. developed the first protocol for sulfoxide imination leading to the discovery of

sulfoximines 3.[36] Using a combination of sodium azide and sulfuric acid led to the in situ

generation of hydrazoic acid (HN3), which represents a powerful iminating agent converting

various alkyl sulfoxides to the corresponding NH-sulfoximines 7 (Scheme 3).[37]

Scheme 3: Sulfoxide imination using in situ generated hydrazoic acid.

Although highly toxic and explosive, the use of hydrazoic acid as iminating agent is still in

practice, since it offers a reliable access to free NH-sulfoximines 7, if the temperature is kept

below 45 °C.[3] Only recently, Kappe, Roberge and co-workers employed TMS-azide in a

superacidic continuous flow imination to obtain the free NH-sulfoximines 7 in moderate yield

demonstrating that the in situ generated hydrazoic acid, can be tamed under the right

conditions. However, it must be mentioned that the stereochemistry could not be retained in

the process due to racemization of the sulfoxide under the strongly acidic conditions. [38]

In 1958, Appel et al. employed hydroxylamine-O-sulfonic acid (HOSA) as mild iminating

reagent. However, HOSA is only applicable for the imination of dialkyl sulfides, while alkyl aryl

sulfides only react in very low yields and sulfoxides 2 do not react at all under these

conditions.[39]

A third transition metal-free procedure utilizes O-mesitylenesulfonylhydroxylamine (MSH, 8)

as iminating reagent.[40] Both sulfides and sulfoxides can undergo imination to the

corresponding S-aminosulfonium 9 and S-aminosulfoxonium 10 salts (Scheme 4). In case of

10, a subsequent deprotonation by base generates the free NH-sulfoximines 7.[40c] An

advantage over iminations with hydrazoic acid is the retention of stereochemistry.[41] However,

due to its thermal instability MSH (8) is also highly explosive, which is why alternative methods

for imination are usually preferred.[42]

Introduction

6

Scheme 4: MSH (8) as iminating reagent for sulfides 1 and sulfoxides 2.

Several more recent protocols use PhI(OAc)2 in combination with an amine or sulfonamide to

generate a reactive iminoiodinane species. These species allow the imination of various

sulfides 1 and sulfoxides 2 (Scheme 5).

Scheme 5: Metal-free imination using PhI(OAc)2.

Using sulfonamides as amine source for imination, various N-sulfonylsulfilimines can be

obtained from alkyl- and aryl-substituted sulfides in moderate yields (47–61%, Scheme 5,

A).[43] Cho and Bolm also developed a protocol for the imination of both sulfides 1 and

sulfoxides 2 to their corresponding iminated products using para-nitrobenzylsulfonamide with

PhI(OAc)2 at elevated temperatures (82 °C, Scheme 5, B).[44] Imination of sulfoxides 2 was

achieved by Yudin and co-workers using N-aminophthalimides (Scheme 5, C). With this

protocol moderate to excellent yields could be obtained (48–94%). The scope of the reaction

appears to be limited, since only four substrates were subjected to these reaction conditions. [45]

Cyanamide can also be used in combination with PhI(OAc)2 to access N-cyanosulfilimines in

good to excellent yields following a procedure by Bolm and co-workers (Scheme 5, D).[46] Only

recently, Bull, Luisi and co-workers reported on the PhI(OAc)2-mediated imination of

sulfoxides 2 with ammonium carbamate. Under mild reaction conditions the protocol delivers

the free NH-sulfoximines 7 in low to excellent yields (9–90% yield) for a broad substrate range

(Scheme 5, E).[47]

Introduction

7

Interestingly, not only PhI(OAc)2, but also tert-butyl hypochlorite, NBS (N-bromosuccinimide)

and iodine can be employed to synthesize N-cyanosulfilimines. In this reaction a

bromosulfonium species is generated as intermediate, instead of an iminoiodinane.

Subsequent attack of the cyanamide salt or the in situ deprotonated cyanamide generates the

desired N-cyanosulfilimines. In case of NBS, the latter could be obtained in moderate to

excellent yields (50–91%). In contrast, conversion with iodine resulted in lower yields.[24, 48]

Along those lines, a similar protocol was developed by Krüger and co-workers. Using a

combination of DBDMH (1,3-dibromo-5,5-dimethylhydantoin) and 2,2,2-trifluoroacetamide

gave access to N-trifluoroacetylsulfilimines in moderate to good yields (71–80%).[49]

In 2010, sulfonylimino- 3-bromane 11 was reported to be an efficient agent for the imination of

both sulfides and sulfoxides by Ochiai, Nakanishi and co-workers.[50] Various

N-triflylsulfilimines 12 and N-triflylsulfoximines 13 could be obtained in up to excellent yields

(Scheme 6). Competition experiments between sulfides and sulfoxides revealed that the more

nucleophilic sulfides are more reactive then their corresponding sulfoxides.

Scheme 6: Metal-free imination reported by Ochiai and co-workers.

Apart from these transition metal-free synthetic approaches, an example by Yudin and co-

workers applies electrochemistry for the synthesis of sulfoximines.[51] In a sequential

imination/deprotection procedure, N-aminophthalimide is electrochemically oxidized to the

corresponding nitrene, which reacts in a nitrene transfer reaction with sulfoxides 2.

Subsequently, the N–N bond of the generated N-phthalimide-protected sulfoximines is cleaved

electrochemically to deliver the free NH-sulfoximines 7 in moderate to good yields. However,

only five substrates were applicable, while various N-phthalimide-protected sulfoximines

decomposed under the reaction conditions for the deprotection.[51]

Transition metal-catalyzed imination

A wide variety of protocols allow the imination of sulfides 1 and sulfoxides 2 using transition

metals. Most of these methods additionally employ either directly an iminoiodinane species or

a hypervalent iodine(III) species, which in situ generates the iminoiodinane in combination with

Introduction

8

an amine. Various copper, silver, iron, manganese and rhodium catalysts are applicable in

these reactions (Scheme 7).

Scheme 7: Iminoiodinane-mediated synthesis of sulfilimines 4 and sulfoximines 3.

N-Toluenesulfonylsulfilimines are generated from sulfides 1 using a combination of CuOTf and

N-(para-toluenesulfonyl)iminophenyliodinane in moderate to good yields (53–83%, Scheme 7,

A). Additionally, employing bisoxazoline ligands enabled the synthesis of enantioenriched

sulfilimines 4 in moderate enantiomeric excesses (up to 71% ee). A drawback of this method

are rather long reaction times (26–48 h).[52] A subsequent report by Malacria and co-workers

demonstrated that Cu(OTf)2 and N-(para-toluenesulfonyl)iminophenyliodinane can be used to

iminate sulfoxides 2 to N-toluenesulfonylsulfoximines in good to excellent yields (72–96%,

Scheme 7, B).[53] In 2005, Bolm and co-workers reported silver nitrate with 4,4 ,4 -tri-tert-butyl-

β,β μ6 ,β -terpyridine (4,4’,4’’-t-Bu3tpy) as suitable catalytic system for the synthesis of both

sulfilimines 4 and sulfoximines 3 (Scheme 7, C).[54] An alternative protocol by Bolm and co-

workers could prove that an iron-catalyzed imination is possible with Fe(OTf)2 and various

sulfonyliminophenyliodinanes. The protocol was applicable for sulfides 1 and sulfoxides 2

under retention of configuration (Scheme 7, D).[55] A subsequent investigation revealed that an

imidative kinetic resolution of racemic sulfoxides 2 can also be achieved by iron catalysis.

Various sulfoxides 2 could be iminated delivering enantiomerically enriched sulfoximines 3 in

low to very good yields and moderate to good enantiomeric excesses (Scheme 7, E).[56] Katsuki

and co-workers could prove that a manganese-salen complex is active in the enantioselective

sulfimidation of sulfides 1 yielding the N-tosylated sulfilimines in up to excellent yields.

However, the enantiomeric excesses were mostly moderate (Scheme 7, F).[57] The most

prominent method for sulfide and sulfoxide imination is based on a rhodium-catalyzed system.

Even though the rhodium catalyst is rather expensive when compared to the previously

Introduction

9

described catalysts, the stability and scope of the protocol as well as the facile deprotection

(especially when using 2,2,2-trifluoroacetamide or tert-butyl carbamate) present significant

advantages, which were already exploited in first industrial processes.[58] Rh2(OAc)4 can either

be set to react with a preformed iminoiodinane (Scheme 7, G) or an in situ formed

iminoiodinane species generated from PhI(OAc)2 and the utilized amine (Scheme 7, H). The

created Rh-nitrenoid species allows a nitrene transfer to sulfide 1 or sulfoxide 2.[59] While the

initial protocol only reported the successful use of 2,2,2-trifluoroacetamide and

4-nitrobenzenesulfonylamide as amine source,[59a] Bull, Luisi and co-workers employed

various carbamates under nearly identical conditions to broaden the substrate scope.[59b] After

the initial report by Bolm and co-workers,[59a] Dauban, Dodd and co-workers developed a

stereoselective rhodium-catalyzed imination of sulfides 1 (Scheme 8).[60] By transferring a

chiral nitrene species generated by combining (S)-N-(p-toluenesulfonyl)-p-

toluenesulfonimidamide 14 with the hypervalent iodine species PhI(OCOtBu)2, various

sulfilimines 15 were produced in a mild chemo- and diastereoselective manner with up to

excellent yields. Oxidation of these substrates into the corresponding sulfoximines 3 could be

performed under preservation of the steric information that was introduced by imination.[60]

Scheme 8: Stereoselective imination using hypervalent iodine compounds.

If hypervalent iodine species are not used to create a reactive intermediate, the nitrogen source

for imination has to be readily reactive by itself. Thus, azides are also commonly used in

combination with metals to affect the nitrene transfer to both sulfides 1 and sulfoxides 2. Bach

and co-workers developed the first FeCl2-catalyzed imination with tert-butyloxycarbonyl azides

generating N-Boc-substituted sulfilimines 16 and sulfoximines 17 in up to excellent yields

(Scheme 9).[61]

Scheme 9: Iron-catalyzed nitrene transfer with azides.

Introduction

10

Further reports by Katsuki and co-workers demonstrated the use of Ru(CO)salen complexes

(for example 18, Scheme 10) as potent nitrene transfer catalysts for the enantioselective

imination of sulfides with tosyl azide.[62] The generated sulfilimines 19 could be obtained in up

to excellent yields and enantiomeric excesses (Scheme 10).[62a] Later studies focused on

examining various N-alkoxycarbonyl azides for their activity in these reactions and 2,2,2-

trichloro-1,1-dimethylethoxycarbonyl azide was found to be the most effective reagent for

sulfide imination.[62b]

Scheme 10: Ru-salen-mediated nitrene transfer to sulfides 1.

In 2014, Arnold and co-workers reported on the first intermolecular nitrene transfer that is

catalyzed by an enzyme. At the core of the enzyme, an iron(III) heme is responsible for the

activity, forming a formal iron(IV) nitrenoid species that can either transfer to the sulfide 1 or

be reduced from the tosyl azide to the sulfonamide. Although the reactivity is strongly

depending on the electronic properties of the sulfide 1 and the reduction of the azide to the

corresponding sulfonamide lowers the efficiency, the protocol demonstrates a promising

approach towards N-tosylsulfilimines 19.[63]

Only recently, Lebel and co-workers established an iron-catalyzed imination of sulfides 1 and

sulfoxides 2 combining flow chemistry and photochemistry. Using UVA light, the flow process

can be accomplished in under 2 h providing access to N-Tces-protected sulfilimines 20 and

sulfoximines 21 in high yields (Scheme 11). NH-Sulfoximines 7 can be readily obtained by

deprotection of the Tces group. Additionally, the process tolerates a chiral reagent which

delivers easily separable diastereomeric sulfilimines 4. Sulfoxide racemization does not occur

in this imination, in contrast to the earlier presented method by Kappe, Roberge and co-

workers.[38] Thereby the steric information of the desired sulfoximines 21 is retained in this

protocol.[64]

Introduction

11

Scheme 11: Synthesis of N-Tces-protected sulfilimines 20 and sulfoximines 21.

Another class of iminating agents for sulfides 1 and sulfoxides 2 are activated amines. One

example was published by Carreira and co-workers, who used

N,O-bis(trifluoroacetyl)hydroxylamine as electrophilic nitrogen source for the synthesis of

sulfilimines 22. With catalytic amounts of Cu(OTf)2, N-trifluoroacetylsulfilimines 22 could be

obtained in moderate to excellent yields. However, the iminating reagent has to be prepared

from trifluoroacetic anhydride and hydroxylamine hydrochloride with subsequent deprotonation

using tert-butyllithium (Scheme 12).[65]

Scheme 12: Sulfide imination by Carreira and co-workers.

Lebel and co-workers reported on the stereoselective imination of sulfides 1 with

mesyloxycarbamates 23. High yields and good diastereomeric ratios of sulfilimines 24 were

obtained with 4-dimethylaminopyridine (DMAP) as ligand, presumably forming a sulfide-

DMAP-Rh(II) complex, which displays a low and irreversible redox potential. The authors

hypothesize that subsequent oxidation with bis(DMAP)DCM (25) forms the catalytically active

Rh(II)-Rh(III) dimer species (Scheme 13).[66]

Introduction

12

Scheme 13: Rhodium-catalyzed imination with mesyloxycarbamates 23.

A recent protocol by Richards, Ge and co-workers utilizes O-(2,4-dinitrophenyl)-hydroxylamine

(DPH, 26) as iminating agent. While the authors did not investigate the mechanism, the

formation of a Rh-nitrenoid species that can iminate the rhodium-coordinated sulfoxide is likely.

An advantage of this protocol is the direct access to NH-sulfoximines 7, which oftentimes have

to be prepared by an additional deprotection step after imination. Except for ortho-substituted

aryl alkyl sulfoxides, which only gave the sulfoximines 7 in low yields, the protocol exhibits a

good functional group tolerance with moderate to excellent yields (Scheme 14).[67]

Scheme 14: Rhodium-catalyzed synthesis of NH-sulfoximines 7.

Another important class of iminating agents are nitrogen-containing heterocycles. These can

be effective nitrene precursors and at the same time represent a more stable source when

compared to azides. The group of Armstrong enabled the sulfide imination using oxaziridines

to produce N-Boc-protected sulfilimines 16 in moderate to excellent yields. However, in this

procedure the employed oxaziridines have to be prepared in a tedious procedure. [68] Also,

Sauer et al. proved that 3-substituted-1,4,2-dioxazol-5-ones 27 can be used for the imination.

Heating these compounds leads to the proliferation of carbon dioxide and an active nitrene

species.[69] Developing this system further, Bolm and co-workers could establish an efficient

imination protocol to access N-acetylsulfilimines 28 and -sulfoximines 29 at room temperature.

Instead of thermally generating the nitrene species, a ruthenium catalyst together with visible

light irradiation can form a rutheno N-acetyl nitrene species, which is readily transferred to

Introduction

13

sulfides 1 and sulfoxides 2 (Scheme 15). The products are obtained in moderate to excellent

yields. Additionally, the produced sulfilimines 28 can conveniently be further oxidized in a one-

pot procedure with NaIO4.[25, 70]

Scheme 15: Imination using 1,4,2-dioxazol-5-ones 27 as nitrene precursor.

1.1.3. Synthesis and applications of N-alkyl- and N-methylsulfoximines

Various methods to synthesize N-alkylated sulfoximines can be utilized. Oftentimes, however,

these methods either only produce N-methylsulfoximines 30 or their longer alkyl chain analogs

31. In this chapter an overview of the existing methods is given.

A two-step protocol by Bolm and co-workers provided N-alkylated sulfoximines 31 by

N-acetylation with acyl halides and subsequent reduction with a borane-solvent adduct or

catecholborane (Scheme 16, A).[71] However, the instability of the reducing agent on a larger

scale limits the applicability of this protocol. Another approach to introduce the alkyl chain can

be achieved by a nucleophilic substitution. Various reports demonstrated that alkyl iodides and

bromides can be utilized in combination with strong bases, such as sodium hydride[72] or

butyllithium[73] to alkylate NH-sulfoximines 7. This protocol can also be combined with phase

transfer catalysis (in DME/mineral oil) under strictly anhydrous conditions (Scheme 16, B).[74]

A more recent protocol by Bolm and co-workers employs alkyl halides in a superbasic system

generated from KOH and DMSO to deliver N-alkylated sulfoximines 31 in moderate to excellent

yields (Scheme 16, C).[75] An iron-catalyzed hetero-cross-dehydrogenative coupling utilizes

di-tert-butyl peroxide (DTBP) and diarylmethanes providing N-diarylmethylsulfoximines 31 in

moderate to good yields (Scheme 16, D).[76] In a similar report, Yu, Cheng and co-workers

synthesized N-alkylated sulfoximines 31 from simple alkanes using a copper-catalyzed

oxidative C(sp3)–H/N–H coupling (Scheme 16, E). The authors assume that a radical process

is operative. The desired products can be obtained in moderate to good yields. Additionally,

the protocol can be extended to amides.[77] A recent report by Yu and co-workers also allows

Introduction

14

the copper-catalyzed N-ethylation by using bis(1,1-dimethylpropyl)peroxide 32 (Scheme 16,

F).[78]

Scheme 16: N-alkylations of NH-sulfoximines 7.

In contrast, the preparation of N-methylsulfoximines 30 often requires the use of strong

methylating agents. Early examples for the N-methylation of NH-sulfoximines 7 with strong

methylating agents were reported by Johnson et al.[79] and Greenwald and co-workers.[80]

Johnson et al. employed trimethyloxonium tetrafluoroborate (Scheme 17, A), while Greenwald

and co-workers used methyl fluorosulfate (“magic methyl”, Scheme 17, B). In a subsequent

report iodomethane was successfully utilized as methylating agent with sodium hydride

(Scheme 17, C). Most commonly however, reductive amidation with a mixture of

p-formaldehyde and formic acid under Eschweiler-Clarke-like reaction conditions is applied to

synthesize N-methylsulfoximines 30 yielding the products in moderate to excellent yields. The

only drawback of this method are the long reaction times under reflux (up to several days and

up to 130 °C, Scheme 17, D).[81] The above mentioned protocol by Yu and co-workers for the

synthesis of N-alkylated sulfoximines 31 additionally allows the copper-catalyzed

N-methylation of NH-sulfoximines 7. Under these reaction conditions, DTBP together with the

copper catalyst generates a methyl radical, which can react with the deprotonated

NH-sulfoximine and deliver the N-methylated product 30 after oxidation with copper in

moderate to good yields and broad functional group tolerance (Scheme 17, E).[78]

Introduction

15

Scheme 17: Synthesis of N-methylsulfoximines 30.

All the aforementioned protocols require the NH-sulfoximine 7 as intermediate. So far only one

protocol was reported allowing a direct access to N-methylsulfoximines 30 from sulfides 1

(Scheme 18).[82] Sulfide imination is accomplished by the use of N-methyl-O-mesitylsulfonyl-

hydroxylamine (33)[83] generating sulfonium arylsulfonates 34, which in a subsequent oxidation

with m-CPBA provide N-methylsulfoximines 30. The described protocol is limited to

2-(alkylthio)pyridines and only furnishes the products in low yields (38% over two steps).[82]

Scheme 18: Direct synthesis of N-methylsulfoximines 30 from sulfides 1.

As the N-alkyl group represents a very stable protecting group, Bolm and co-workers also

devised a protocol to deprotect the alkyl group and deliver the free NH-sulfoximine 7. Following

a Polonovski-type dealkylation using tert-butyl hydroperoxide (TBHP) and FeCl2, the reactive

sulfoximine intermediate can be trapped with a suitable aldehyde or anhydride yielding the

corresponding N-acetyl- and N-aroylsulfoximines. In these reactions 1-hydroxybenzotriazole

(HOBt) was found to be an effective additive reducing both the necessary equivalents of the

anhydride and the peroxide source. A subsequent acid-mediated cleavage allows access to

the free NH-sulfoximine 7 in excellent yields (exemplified for N-acetylsulfoximines 29 in

Scheme 19). The method is applicable to both N-methyl- and N-alkylsulfoximines (30 and 31),

respectively.[81d]

Introduction

16

Scheme 19: Dealkylation of N-methyl- and N-alkylsulfoximines (30 and 31).

1.1.4. Synthesis and applications of N-cyanosulfoximines

As one aim of this thesis is the development of new strategies for the synthesis of

N-cyanosulfoximines 35, the current methods to obtain these compounds will be further

elaborated upon.

The first two protocols for the synthesis of N-cyanosulfoximines 35 were developed by Bolm

and co-workers and their imination procedure was already described in chapter 1.1.2.2. The

generated N-cyanosulfilimines 36 can subsequently be oxidized with m-CPBA or potassium

permanganate to yield the N-cyanosulfoximines 35 in moderate to good yields

(Scheme 20).[24, 46, 84]

Scheme 20: Synthesis of N-cyanosulfoximines 35 from sulfides 1.

Apart from these two procedures, several groups reported on the N-cyanation of

NH-sulfoximines 7. In one of the above mentioned reports, the authors describe the

N-cyanation of NH-sulfoximines 7 with cyanogen bromide and DMAP. Even though cyanogen

bromide is extremely toxic, an advantage of this procedure is the retention of the steric

information of the employed NH-sulfoximine 7 (Scheme 21, A).[46a] Cheng and co-workers

demonstrated an oxidative copper-catalyzed N-cyanation. This procedure was not only

applicable to NH-sulfoximines 7, but also to secondary amines. While the reaction yields the

products in moderate to excellent yields, the scope of the reaction is limited and next to CuBr2

as catalyst, the cyanation source, CuCN, had to be used in excess to allow an efficient

transformation (Scheme 21, B).[85] In a subsequent report they could establish another

Introduction

17

N-cyanation protocol. For this copper-catalyzed process, azobisisobutyronitrile (AIBN) was

used as safe cyanation source under relatively mild reaction conditions. Moderate to excellent

yields could be achieved with this method and the substrate scope could again be expanded

to secondary amines (Scheme 21, C).[86] Another process was developed by Shao and co-

workers, who employed acetonitrile as both solvent and safe cyanation source. A cyano radical

is assumed to be generated by the C–CN bond cleavage through combination of DTBP and

the copper catalyst (Cu2O). The radical can subsequently interact with a Cu(II)-sulfoximine

species and deliver the product under reductive elimination. The desired products 35 can be

obtained in moderate to good yields. However, the employed reaction conditions are relatively

harsh (120 °C, 24 h, Scheme 21, D).[87]

Scheme 21: N-cyanation of NH-sulfoximines 7.

The N-cyano group can be used as a protecting group, but can also be employed for further

modification. To deprotect the N-cyanosulfoximines 35 to the free NH-sulfoximines 7, Bolm

and co-workers established two protocols. The first protocol delivers the

N-trifluoroacetylsulfoximines as intermediates by cleavage of the cyano group with

trifluoroacetic anhydride (TFAA). In the next step methanolysis of these substrates yields the

free NH-sulfoximines 7 (Scheme 22, A).[24] An alternative procedure employs sulfuric acid to

directly synthesize the free NH-sulfoximines 7 under reflux conditions (Scheme 22, B).[88]

Scheme 22: Deprotection of N-cyanosulfoximines 35.

Further modifications can, as presented by Bolm and co-workers, be exploited for the

hydrolysis of the nitrile group to form N-aminoformyl-S-methyl-S-phenylsulfoximine 37a

(Scheme 23).[84]

Introduction

18

Scheme 23: Hydrolysis of N-cyanosulfoximine 35a.

Also the nitrile group provides an ideal reactant for cycloadditions. The group of Bolm

presented a [3+2] cycloaddition of the cyano group with sodium azide providing access to

N-(1H)-tetrazolesulfoximines 38 in moderate to excellent yields. To enable an efficient

transformation a stoichiometric amount of ZnBr2 and harsh reaction conditions were necessary

(120 °C, 24 h, Scheme 24). The tetrazole-substituted sulfoximines 38 could also be further

functionalized at the NH group of the tetrazole and derivatized into the corresponding

1,3,4-oxadiazoles.[46a]

Scheme 24: [3+2] cycloaddition of N-cyanosulfoximines 35.

Another protocol for the functionalization of N-cyanosulfoximines 35 was recently reported by

Lee and co-workers using N-sulfonyl-1,2,3-triazoles 39 in a rhodium-catalyzed

N-imidazolylation. Mechanistically, an interaction of the rhodium catalyst with the triazole is

proposed leading to the formation of a Rh-carbenoid under proliferation of molecular nitrogen.

This species can subsequently react with the sulfoximine to generate

N-imidazolylsulfoximines 40 with a broad functional group tolerance in moderate to excellent

yields (Scheme 25). The authors also developed a one-pot protocol, in which the triazoles 39

are formed in situ through a copper-catalyzed [3+2] cycloaddition of alkynes and azides

delivering the products 40 in a consecutive rhodium-catalyzed process.[89]

Scheme 25: Synthesis of N-imidazolylsulfoximines 40.

Introduction

19

1.1.5. Biological relevance of sulfoximines and sulfilimines

Sulfoximines were discovered in 1949 by Bentley et al., who synthesized methionine

sulfoximine (MSO, 41),[36, 90] which was found to cause canine hysteria and epileptiform fits in

dogs.[91] MSO (41) inhibits the glutathione synthesis resulting in an enhanced effect of cytotoxic

agents.[92] Due to these properties, buthionine sulfoximine (BSO, 42), an analog of 41, was

synthesized for the use in cancer treatment studies, revealing better inhibition of the

glutathione synthesis (Figure 4).[93]

Figure 4: Early examples of bioactive sulfoximines.

So far only one sulfoximine was able to reach the market due to its bioactivity. Sulfoxaflor (43),

an N-cyanosulfoximine also known as Isoclast, represents a potent insecticide developed by

DowAgroScience.[6] However, various other sulfoximines also show promising activities. Both

BAY 1000394 (44, Bayer)[7a, 94] and AZD6738 (45, Astra Zeneca)[58c] demonstrated potent

kinase inhibition and anti-cancer activities. While the sulfoximine 44 inhibits the cyclin-

dependent kinases (CDK), the sulfoximine 45 from Astra Zeneca is an ATR (ataxia

telangiectasia and RAD3-related) inhibitor (Figure 5).

Figure 5: Sulfoxaflor (43) and two kinase-inhibiting sulfoximines (44 and 45).

In a recent work by Walker and co-workers (Pfizer), N-methylsulfoximine (S)-46 proved better

than its sulfone analog due to an equipotent inhibitory activity on proline-rich tyrosine 2 and a

significantly reduced hERG (human Ether-à-go-go-Related Gene) liability (Figure 6, left).[95]

Subsequently, Goldberg and co-workers (Astra Zeneca) could prove that

N-methylsulfoximines possess a higher solubility paired with an equivalent isolipophilicity. By

preparing both the NH- 48 and N-methyl-analog 49 of sulfone 47 and testing their solubility in

Introduction

20

aqueous solutions, they found that NH-sulfoximine 48 is 29 times as soluble as its sulfone

analog and N-methylsulfoximine 49 is more than 200-fold more soluble (Figure 6, right).[96]

Figure 6: N-methylsulfoximines as inhibitors (left) and in solubility studies (right).

In comparison, the literature on the bioactivity of their chemical precursor is scarce. So far,

sulfilimines have not yet been marketed for their bioactivity in medicinal and agrochemistry.

Prosulfalin 50 showed activity as a herbicide,[97] while the two sulfilimine derivatives 51 and 52

exhibited a superior selectivity and activity as insecticide against the oriental armyworm and

the diamondback moth compared to their parent compound flubendiamide (Figure 7).[12a, 12b]

Figure 7: Selection of bioactive sulfilimines.

Introduction

21

1.2. Relevant reaction types

1.2.1. Suzuki–Miyaura cross-coupling

Catalytic cross-coupling reactions have become one of the most important tools for the

formation of C–C bonds in modern synthetic chemistry. They have been intensively

investigated, since they offer an easy access to complex molecules relevant for the

development of new pharmaceuticals, crop protecting agents and conducting polymers. Due

to the large impact of their research, Negishi, Suzuki and Heck have been awarded the Nobel

price in Chemistry for the development of palladium-catalyzed cross-coupling reactions in

organic synthesis in 2010 (Scheme 26). Cross-coupling reactions in which an organic halide

reacts with the desired nucleophilic reagent avoid the low reactivity of common organic

reagents (e.g. saturated hydrocarbons).[98]

Scheme 26: Palladium-catalyzed cross-coupling.

Especially the Suzuki–Miyaura coupling has become a reaction of choice for the formation of

C–C bonds. While organohalides or pseudohalides generally have to be used, organoboron

reagents have several advantages over other organometallic compounds (e.g. tin, zinc). Their

cost and toxicity is generally lower and their availability as well as their preparation and

handling are easier. They also offer a broad functional group tolerance and are environmentally

benign.[99] In the Suzuki–Miyaura coupling, the organohalide 53 adds to the

palladium(0) catalyst in an oxidative addition. Transmetalation occurs with the organoboron

compound 54 and an additive base. Finally, reductive elimination yields the product 55 and

regenerates the palladium(0) catalyst (Scheme 27).[100]

However, the Suzuki–Miyaura reaction with boronic acids also has competing side reactions,

such as protodeboronation, oxidation and palladium-catalyzed homocoupling (Scheme 28).[100]

The protodeboronation is the most frequently observed side reaction in catalytic coupling

reactions that utilize organoboron compounds. It describes the substitution of the boron

functional group by a proton. There are several factors that influence protodeboronation, e.g.

base, water concentration, solvent, reaction temperature, substrate and leaving group.[101]

Introduction

22

Scheme 27: Mechanism of the Suzuki–Miyaura coupling reaction.

Scheme 28: Most common side reactions of arylboronic acids in Suzuki–Miyaura couplings.

To mitigate these side reactions, several organoboron reagents have been developed as the

right choice can be decisive for the success of the cross-coupling reaction. Boronic esters and

especially pinacol boronic esters are commonly used in Suzuki–Miyaura couplings due to their

stability, reactivity, relative cost and facile accessibility. A reduced Lewis acidity, which stems

from the σ-donating ability of the carbon, allowing the oxygen of the boronic ester to conjugate

more readily into the electron deficient boron, leads to them usually being less reactive than

their boronic acid analogs.[99d] Additionally, pinacol boronic esters can be applied in two stage

borylation/Suzuki–Miyaura coupling sequences with otherwise typically unstable 2-heteroaryl

and polyfluorophenyl boronic acids 56 (exemplified for the latter in Scheme 29).[102] The

borylated products 57 can directly be converted to the coupling product 58.

Introduction

23

Scheme 29: Sequential borylation and Suzuki–Miyaura coupling with pinacol boronic esters.

1.2.2. Directing group-assisted C–H activation

The development of new methodologies and the improvement of atom economic processes

for the synthesis of complex molecules represents one of the main goals of a synthetic chemist.

Along those lines the ascendency of C–H activation allowed further improvement of catalytic

coupling reactions. This direct conversion of rather unreactive C–H bonds into C–C or

C–heteroatom bonds circumvents the necessity of prefunctionalization and avoids waste

products, which often entail additional purification steps (Scheme 30).[103]

Scheme 30: Juxtaposition of conventional cross-coupling and the C–H activation approach.

The methodology can profitably be applied to many areas of chemistry, e.g. for late

diversification steps in small molecules or polymers. Moreover, the synthesis of new

compounds by C–H activation enables new discoveries in other scientific areas such as

biology, physics, electrical engineering and material sciences. [103b, 103c] As C–H bonds exhibit

both high dissociation energies and pKa values (ca. 460 kJ•mol-1, ~43 for benzene in water),

suitable transition metal catalysts have to be used, to allow a transformation. [104] To direct the

regioselectivity of the C–H activation to the ortho-position, Lewis basic directing groups, which

bear a lone pair of electrons have been applied.[103b, 103c, 104b, 105] Fundamental studies provided

evidence, that heteroaromatics such as pyridines and pyridine-N-oxides, as well as a plethora

of other functional groups such as acetanilides, esters, carbamates, imines and amides can

Introduction

24

successfully be applied as directing groups.[103c] The directing group can coordinate to the

transition metal due to its lone pair, bringing the metal in proximity to the C–H bond and

facilitating the insertion of the transition metal into the adjacent C–H bond. Thereby, the crucial

step, the formation of an energetically preferred metallacycle is possible (Scheme 31).

Subsequently, the reactive intermediate can interact with the reaction partner to form the

desired product.[104b]

Scheme 31: Directing group-assisted C–H activation.

Directing groups can be differentiated by their strength of coordination and denticity. Nitrogen

containing groups are especially strong directing groups due to their σ-donor abilities. The

strong monodentate coordination enables the formation of thermodynamically stable

metallacycles. Oftentimes, however, these directing groups need additional synthetic steps to

be introduced into the molecule before the reaction and are difficult to cleave after the reaction,

exacerbating the purpose of C–H activation. In contrast, weakly coordinating monodentate

directing groups, can be easily cleaved or further modified, but generate comparatively labile

metallacycles.[104b] Bidentate directing groups combine two functional groups. These can

enable a strong coordination with the transition metal as well as serve as auxiliaries in

subsequent steps in the reaction mechanism.[106] In the last ten years, the research field of

directing group-assisted C–H activation/functionalization by transition metal catalysis has

developed tremendously, enabling a wide range of transformations, e.g. arylation, olefination,

alkynylation, amination, borylation, halogenation to name only a few. These processes mostly

employ second and third row transition metals such as palladium, rhodium, ruthenium and

iridium. However, more and more processes are being developed that also utilize first row

transition metals such as manganese, cobalt, copper and nickel. [104b, 107]

Introduction

25

1.2.2.1. Oxidative C–H olefination

Early works by Fujiwara and Moritani represent the first example of an oxidative C–H

olefination. In these reactions palladium(II) complexes were used to mediate the reaction

between arenes and olefins.[108] Since then, various groups have expanded the scope of this

reaction by using different substrates and catalysts (especially palladium and

rhodium).[104a, 107d, 107e, 109] The successful ortho-olefination of both acetophenones and

benzamides 59 was reported by Glorius and co-workers (Scheme 32). Styrenes as well as

acrylates 60 could efficiently be coupled delivering the desired products 61 (E-olefins, only two

substrates also gave low amounts of the Z-product) in moderate to excellent yields using a

catalyst system consisting of [RhCp*Cl2]2/AgSbF6 and Cu(OAc)2 as oxidant under relatively

harsh reaction conditions (120 °C for 16 h). Under these conditions, no diolefinated product

was observed and C–H activation occurred exclusively at the sterically less hindered site,

offering excellent regioselectivity.[110]

Scheme 32: Ortho-olefination of acetophenones and benzamides.

Subjecting N-acetylsulfoximines 29 to similar reaction conditions, Bolm and co-workers were

able to obtain the ortho-olefinated products 62 with activated olefins such as styrenes and

acrylates 60 in up to excellent yields (Scheme 33).[111]

Scheme 33: Ortho-olefination approach by Bolm and co-workers.

The same catalyst system and oxidant are also applicable for the ortho-olefination of

acetanilides,[112] benzoate esters,[113] aldehydes[113] and phenol carbamates when the reaction

parameters such as temperature, solvent and reaction time are adjusted accordingly.[114]

Introduction

26

A slightly different system was employed by Satoh, Miura and co-workers for the ortho-

olefination of sulfoxides 2 with acrylates 63. Instead of using the precatalyst [RhCp*Cl2]2 to

generate the catalytically active species in situ with the silver salt AgSbF6,

[RhCp*(MeCN)3][SbF6]2 was directly employed. For the efficient conversion an increased

amount of catalyst (8.0 mol%), three equivalents of the sulfoxide 2 (compared to the acrylate

63) and reaction conditions that had to be slightly adjusted for the respective substrate, were

necessary (compare Schemes 32 to 34). Even under these modified conditions, the desired

products 64 could only be obtained in low to good yields with a narrow substrate scope. [115]

Scheme 34: Sulfoxides 2 in ortho-olefination reactions.

A proposed mechanistic pathway for a Rh(III)-catalyzed ortho-olefination begins with the

generation of the catalytically active species 65 from a precursor 66, oftentimes through the

addition of a silver salt. This active Rh(III) species is brought into proximity of the C–H bond by

coordinating to the directing group of substrate 67. A base, either external or bound to the

catalyst, enables the electrophilic ortho-rhodation by consecutive coordination of the

catalytically active species to the directing group of the substrate and ortho-C–H bond

activation under release of a protonated base (BH) to generate an aryl-Rh species 68. Upon

coordination of an olefin 60 to the formed rhodacycle migratory insertion leads to the formation

of an alkyl-Rh(III) complex 69. In a subsequent -hydride elimination the ortho-olefinated

product 70 is formed and the Rh(I) species oxidized to regenerate the catalyst 65

(Scheme 35).[107c] Adversely, these Heck-type couplings are limited to activated olefins such

as acrylates and styrenes.[111, 116]

Introduction

27

Scheme 35: General mechanism for the Rh(III)-catalyzed ortho-C–H olefination.

By slightly changing the reaction conditions, Li and co-workers were able to efficiently

synthesize -lactams 71 from N-aryl benzamides 72 and alkenes 63 in a Rh(III)-catalyzed

sequential oxidative ortho-olefination and Michael reaction. Product formation was observed

in high yield and selectivity for acrylates 63 (Scheme 36).[117] Additionally, the reaction also

proceeded with acrylonitrile and enones such as ethyl vinyl ketone. Steric effects of the

substituents in the benzene ring as well as the donor ability of heteroatoms included in the

aromatic system seem to govern the selectivity of the C–H activation. In case of heterocyclic

carbamides, oxidative olefination occurred with different reactivity and selectivity. Depending

on the stereoelectronic effects of the substrate, only ortho-olefination occurred, while the

sequential Michael-type cyclization did not proceed.[104a, 117]

Scheme 36: Synthesis of -lactams by sequential ortho-olefination and Michael addition.

Introduction

28

The combination of sequential ortho-olefination and Michael addition is now broadly

established as rather difficult to synthesize substrates become accessible through this

procedure. Examples are protocols from Glorius and co-workers to access -butyrolactam

derivatives[110] and Bolm and co-workers to obtain cyclic sulfoximine derivatives.[111]

Ruthenium catalysis is also broadly applicable for the ortho-alkenylation through directing

group-assisted C–H activation.[104b] Ackermann and co-workers demonstrated that a cationic

ruthenium(II) complex, formed by interaction of the precatalyst [RuCl2(p-cymene)]2 with a silver

salt (AgSbF6), promotes the site-selective olefination of aryl carbamates 73 with acrylates 63

yielding the desired products 74 with broad functional group tolerance in moderate to good

yields (Scheme 37). The directing group could be easily removed, allowing access to ortho-

substituted phenols. Noteworthy, by doubling the catalyst and silver additive loading, the

oxidant loading of the copper salt could be drastically reduced (2.0 equivalents to

0.3 equivalents), enabling the use of oxygen as terminal oxidant, still yielding the products in

moderate yields.[118] Further reports by the same group also demonstrated the applicability of

the catalyst system and oxidant under different reaction conditions for the ortho-olefination of

sulfonic acids, sulfonyl chlorides and sulfonamides.[119]

Scheme 37: Ortho-olefination of carbamates 73.

In a subsequent report, Ackermann and co-workers also reported on a sequential oxidative

ortho-alkenylation and aza-Michael addition of amidines 75 and acrylates 63 through

ruthenium(II) catalysis. Under these reaction conditions the substrates undergo

dehydrogenation after the Michael addition to afford 1-iminoisoindolines 76 in low to good

yields (Scheme 38).[120]

Introduction

29

Scheme 38: 1-Iminoisoindoline 76 synthesis.

Recent reports on oxidative Heck-type reactions revealed that these reactions can also be

carried out by employing manganese catalysts,[121] by combining rhodium catalysis with

photoredox catalysis[122] or be performed under mechanochemical and solventless conditions

in a ball-mill.[123]

1.2.2.2. Borylation: From stoichiometric reactions to directed C–H borylation

Converting C–H bonds to C–B bonds by metal-catalyzed C–H bond functionalization is a more

recent field of study and significant progress has been made in the last two decades to develop

borylations from metal-mediated stoichiometric synthetic approaches into efficient metal-

catalyzed and regioselective procedures that are used in material science, fine chemical and

natural product synthesis.[107f] Direct borylation, in contrast to previous methods that rely on

the accessibility of aryl halides, represents a step- and atom-economic access to organoboron

compounds (compare Scheme 30).[107f, 124] It has been used as a complementary method to

the directed ortho metalation (DoM), due to the regioselectivity thus far being mostly governed

by steric factors enabling a different product scope.[125] Key steps in the reaction pathway of

both alkanes and arenes exhibit favorable rates for the conversion of the C–H bond to the

C–B bond in case of boronic esters. Both the strong σ-donor properties of the boryl group as

well as the presence of an unoccupied pZ-orbital on boron in a boryl complex enable accessible

barriers for C–H bond cleavage and C–B bond formation.[107f, 126] In 1995, stoichiometric

amounts of defined metal-boryl complexes were reported to react with both benzene 77a and

pent-1-ene 78 under UV light irradiation to form boronic esters (79a and 80, respectively) in up

to high yields under proliferation of molecular hydrogen (Scheme 39). Not only the displayed

iron complex 81, but also the analog manganese- and rhenium-boryl complexes were

successfully applied in this reaction.[127] Other substituted arenes gave mixtures of variously

ortho-, meta- and para-substituted arylboronic esters, which could also be influenced by the

employed metal-boryl complex.[127-128]

Introduction

30

Scheme 39: Pioneering works in C–B bond formation.

Four years later, Hartwig and co-workers demonstrated the first example of a rhenium-

catalyzed borylation converting alkanes and alkylethers 82 with bis(pinacolato)diboron (B2pin2)

to alkylboronic esters 83 in moderate to excellent yields. High regioselectivity for the

conversion of the primary C–H bond was observed. Alkyl ethers 82 could also be successfully

employed reacting at the sterically least hindered terminal methyl group. The reaction was

again performed under UV irradiation. Additionally, two bar of carbon monoxide were

necessary to stabilize the rhenium catalyst (Scheme 40).[129]

Scheme 40: Rhenium-catalyzed borylation.

Also in 1999, Smith III and co-workers reported on the catalytic activity of

IrCp*(PMe3)(H)(Bpin) 84 in the borylation of benzene 77a with pinacolborane (HBpin).

However, in these procedures the catalyst was only able to undergo ca. three turnovers and

the borylation required relatively harsh reaction conditions to proceed (150 °C, 120 h,

Scheme 41).[130] Subsequent reports revealed that while mono-substituted arenes only

provided a mixture of arylboronic esters with poor selectivity, 1,3-disubstituted arenes

exclusively yielded 3,5-disubstituted arylboronic esters.[131]

Scheme 41: Early iridium-catalyzed borylation.

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.

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]


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).


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


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.


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


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


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.


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.


49

2.2. Synthesis of N-cyanosulfoximines


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.


50


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]


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.


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.


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.


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


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


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.


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.


58


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.


59

2.3. Reductive borylation of sulfoximines


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.


60


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).


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).


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).


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


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


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).


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).


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


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).


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).


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


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).


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).


73


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.


74

2.4. C–H borylation of sulfoximines and their use in Suzuki–Miyaura couplings


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.


75


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



4 30a 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


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.


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.


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.


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).


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.


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


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).


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


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).


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-


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


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


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.


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).


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%.


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.


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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


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.


94

2.5. Scope extension of N-acetylsulfilimines and their C–H olefination


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.


95


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.


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


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).


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 [%]

1 80 2.5 69

2 120 2.5 40

3 140 2.5 n.r.

4 100 1.0 29

5 100 5.0 54 a Reaction conditions: N-acetylsulfilimine 28a (0.38 mmol), 63a (0.25 mmol), [RhCp*(MeCN)3][SbF6]2 as denoted, Ag2CO3 (0.25 mmol), toluene (2.0 mL), 16 h, Δ.

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


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


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.


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


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

Entry Catalyst (mol%) Yield 28a [%] Yield 137a [%]

1 Ru(TPP)CO (1.0) 21 n.r.

2 [RhCp*(MeCN)3][SbF6]2 (2.5) n.r. n.r.

3 Ru(TPP)CO (1.0) and

[RhCp*(MeCN)3][SbF6]2 (2.5) 46 n.r.

4b Ru(TPP)CO (1.0) and

[RhCp*(MeCN)3][SbF6]2 (2.5) 0 23

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.


103


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.

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

methyl 2-(N,S-dimethylsulfonimidoyl)benzoate (30g),


108

N,S-dimethyl-S-(4-nitrophenyl)sulfoximine (30k) and N-methyl-S-cyclopropyl-S-

phenylsulfoximine (30q) after column chromatography.

4.2. Determination of physical data

Melting points:

Melting points were measured with a Büchi Melting Point B-540 apparatus.

HPLC analysis:

HPLC analysis was performed with an Agilent 1200- or an Agilent 1100-series system and

chiral stationary phases from Chiral Technologies Inc or Astec with chiral stationary phases

(Chiralcel OB-H, Chiralpak AD-H) from Chiral Technologies Inc.

Optical rotation:

Optical rotations were determined on a Perkin Elmer P241 instrument and are given in

deg•cm3•g-1•dm-1. Measurements were carried out at room temperature using a wave length

of 589 nm in a cuvette (d = 1 dm), concentration c is given in g•100 mL–1.

NMR spectroscopy:

Nuclear magnetic resonance (NMR) spectra were recorded on an Agilent VNMRs 400

(11B: 128 MHz, 19F: 376 MHz, 1H: 400 MHz, 13C: 101 MHz) or an Agilent VNMRs 600 (11B:

192 MHz, 19F: 564 MHz, 1H: 600 MHz, 13C: 151 MHz) spectrometer. The chemical shifts are

given in parts per million (ppm) relative to the residual solvent peak of the non-deuterated

solvent (1H NMR: CHCl3: = 7.26 ppm, CH3OH: = 3.31 ppm, 13C NMR: CDCl3: = 77.16 ppm,

CD3OD: = 49.00 ppm). For the deuterated solvent the absolute frequency of the lock signal

of the 2H resonance signal was measured to set the chemical shift in the 19F and 11B NMR.

Carbon spectra were recorded decoupled. Quaternary carbon atoms with boron substituent

are not denoted in all cases due to quadrupolar relaxation making a distinction of signals

difficult.

The multiplicity is reported with the following abbreviations: br s = broad singlet, s = singlet,

d = doublet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet,

qt = quartet of triplet, t = triplet, tt = triplet of triplet, m = multiplet, and coupling constants were

given in Hertz (Hz). Note: Signals in the carbon spectra recorded on Agilent VNMRs 600

(around 83 ppm) are artefacts and do not belong to the molecule.


109

IR spectroscopy:

Infrared (IR) spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer with

a diamond/KRS5 ATR unit. Wave numbers are given in reciprocal centimeters (cm-1). All

signals are indicated, irrespective of their transmission intensity. Band shape and intensity is

characterized by the following abbreviations:

vs = very strong (0–20%), s = strong (21–40%), m = middle (41–60%), w = weak (61–80%),

vw = very weak (81–100%).

Mass spectrometry:

Mass spectra were acquired on a Finnigan SSQ7000 or a Finnigan MAT-95 spectrometer.

Peaks are given in m/z and the intensity is given as a percentage of the base peak. High

resolution mass spectra were recorded on a Thermo Scientific LTQ Orbitrap XL spectrometer.

For analysis mass fragments (m/z) above 5% in relation to the basis peak as well as fragments

that were considered to be characteristic fragments of the substance were reported. As the

generated substances in chapter 2.4. were not all stable under EI conditions, CI measurements

were additionally conducted, if necessary. Substances in chapter 2.5. sometimes show mass

signals above the mass peak under EI conditions. These might indicate that the substance

exists as a dimeric species and not necessarily as monomer.

Elemental Analysis:

Elemental analysis (EA) was performed on an Elementar Vario EL instrument. All values are

given as mass percentages. A sample is considered authentic for ΔC,H,N ≤ 0.5%.


110

4.3. Synthesis and analytical data of compounds

4.3.1. Synthesis of substrates

All sulfoxides 2 employed in this thesis were synthesized using literature procedures. [16, 173]

Additionally, the following compounds were synthesized according to literature procedures:

- N-Boc-S-Methyl-S-(4-bromophenyl)sulfoximine (17d)[59b]

- N-Acetyl-S-methyl-S-phenylsulfoximine (29a)[71]

- N-Trifluoroacetyl-S-methyl-S-phenylsulfoximine (125a)[24]

- N-(4-Methylphenyl)-S-methyl-S-phenylsulfoximine (126a)[174]

- NH-S-Methyl-S-(2-naphthyl)sulfoximine (7l)[13f, 24, 59a]

- N,N-(Dimethylamino)-S-methyl-S-phenylsulfoxonium tetrafluoroborate (128)[175]

- N-Methyl-S-diphenylsulfoximine (30r)[81d]

- 1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride (127a)[176]

- 1,3-Dimesityl-4,5-dimethyl-1H-imidazol-3-ium chloride (127b)[176]

- [RhCp*(MeCN)3][SbF6]2[177]

- 3-Methyl-1,4,2-dioxazol-5-one (27a)[25]

- 3-Phenyl-1,4,2-dioxazol-5-one (27b)[25]

- N-Benzoyl-S-methyl-S-phenylsulfilimine (28ad)[25]

Synthesis of NH-S-methyl-S-(4’-methyl-((1,1’biphenyl)-4-yl))sulfoximine (7aa)

N-Tert-butyloxycarbonyl-S-methyl-S-(4’-methyl-((1,1’biphenyl)-4-yl))sulfoximine (17aa)

A dried Schlenk flask was charged with N-Boc-S-methyl-S-(4-bromophenyl)sulfoximine (17d,

1.0 g, 3.0 mmol, 1.0 equiv.), Pd(PPh3)4 (69 mg, 0.06 mmol, 0.02 equiv.), acetonitrile (15 mL)

and p-tolylboronic acid (0.49 g, 3.6 mmol, 1.2 equiv.). Subsequently, a degassed solution of

potassium carbonate (0.62 g, 4.5 mmol, 1.5 equiv.) in H2O (5.0 mL) was added dropwise. The

reaction mixture was refluxed for 16 h. The Boc-protected product was obtained after

evaporation under reduced pressure and column chromatography (eluent: n-pentane/EtOAc

1:1) as a yellow oil in 81% yield.


111

1H NMR (600 MHz, CDCl3): = 8.01 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.52 (d, J =

8.1 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 3.27 (s, 3H), 2.42 (s, 3H), 1.41 (s, 9H) ppm.

13C NMR (151 MHz, CDCl3): = 157.9, 146.8, 139.0, 136.9, 136.2, 130.0, 128.1, 128.0, 127.4,

80.8, 45.0, 28.2, 21.3 ppm.

MS (EI, 70 eV): m/z (%) = 346 ([M]+, 7), 290 (11), 273 (7), 272 (38), 246 (5), 215 (11), 185

(14), 184 (100), 183 (11), 182 (10), 165 (6), 152 (6).

IR (ATR): v = 2978 (w), 2928 (w), 2248 (vw), 1919 (vw), 1659 (vs), 1593 (m), 1523 (vw), 1483

(w), 1391 (w), 1367 (m), 1272 (vs), 1156 (vs), 1035 (vw), 962 (vs), 893 (s), 859 (s), 807 (vs),

764 (s), 730 (s) cm-1.

HRMS (ESI): calc. for C19H24NO3S [M+H]+: 346.1471, found: 346.1473.

NH-S-Methyl-S-(4’-methyl-((1,1’biphenyl)-4-yl))sulfoximine (7aa)

N-Tert-butyloxycarbonyl-S-methyl-S-(4’-methyl-((1,1’biphenyl)-4-yl))sulfoximine (17aa) was

dissolved in DCM (25 mL). After addition of concentrated HCl (5.0 mL), the reaction mixture

was stirred for 2 h at room temperature. The reaction was stopped by addition of NaOH

solution (4 M) until the reaction mixture turned alkaline. The organic phase was separated and

the aqueous phase was washed with DCM (3 x 30 mL). The combined organic phase was

evaporated under reduced pressure. The residue was subjected to column chromatography

(eluent: n-pentane/EtOAc 1:1) to obtain the product as white solid in 71% yield.

M.p.: 168–169 °C


8.1 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 3.15 (s, 3H), 2.69 (br s, 1H), 2.42 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 146.2, 141.7, 138.8, 136.4, 129.9, 128.4, 127.8, 127.3, 46.4,

21.3 ppm.

MS (EI, 70 eV): m/z (%) = 247 (5), 246 (25), 245 ([M]+, 35), 230 (5), 215 (9), 197 (5), 183 (24),

182 (100), 181 (8), 167 (10), 166 (6), 165 (17), 155 (17), 153 (5), 152 (18).


112

IR (ATR): v = 3437 (vw), 3298 (w), 3213 (w), 3064 (vw), 3007 (vw), 2964 (vw), 2921(w), 2857

(vw), 2732 (vw), 2329 (vw), 2180 (vw), 2087 (w), 1996 (vw), 1924 (vw), 1797 (vw), 1679 (vw),

1590 (m), 1521 (vw), 1483 (m), 1390 (m), 1313 (w), 1271 (vw), 1218 (vs), 1132 (s), 1093 (s),

997 (vs), 941 (vs), 843 (w), 806 (vs), 754 (vs), 726 (s) cm-1.

HRMS (ESI): calc. for C14H15NOS [M+Na]+: 268.0767, found: 268.0763.

N-Tert-butyl-S-methyl-S-phenylsulfoximine (31e)

Prepared according to a modified literature procedure.[178]

A round bottom flask was charged with NH-S-methyl-S-phenylsulfoximine (7a, 0.78 g,

5.0 mmol, 1.0 equiv.), tert-butyl 2,2,2-trichloroacetimidate (1.8 mL, 10 mmol, 2.0 equiv.),

copper(II) triflate (90 mg, 0.25 mmol, 0.05 equiv.) and nitromethane (30 mL). The resulting

reaction mixture was stirred at room temperature for 2 h. The product could be obtained after

evaporation of the solvent under reduced pressure and purification by column chromatography

(eluent: n-pentane/EtOAc 2:1) as a yellow oil in 20% yield. 1H NMR (600 MHz, CDCl3): = 7.97–7.91 (m, 2H), 7.54–7.51 (m, 1H), 7.48 (m, 2H), 2.99 (s,

3H), 1.16 (s, 9H) ppm.

13C NMR (151 MHz, CDCl3): = 145.0, 132.2, 129.1, 128.0, 55.2, 48.4, 33.1 ppm.

MS (EI, 70 eV): m/z (%) = 213 (5), 212 ([M]+, 39), 197 (12), 196 (100), 180 (2), 125 (2), 59 (3).

IR (ATR): = 3364 (vw), 3065 (vw), 2966 (s), 2655 (vw), 2294 (vw), 2091 (w), 1990 (vw), 1919

(vw), 1726 (s), 1598 (vw), 1448 (w), 1361 (w), 1315 (vw), 1238 (vs), 1121 (vs), 1077 (m), 968

(s), 832 (m), 739 (s), 692 (s) cm-1.

HRMS (ESI): calc. for C11H18NOS [M+H]+: 212.1104, found: 212.1100.

N,4-Dimethylbenzenesulfinamide (132c)


113

A round-bottom flask was charged with 4-methylbenzenesulfinamide (132b, 0.13 g,

0.85 mmol, 1.0 equiv.) and acetonitrile (7.0 mL). After complete dissolution of the sulfinamide,

the reaction mixture was cooled to 0 °C, sodium hydride (60 wt% in mineral oil, 32 mg,

0.81 mmol, 0.95 equiv.) was added and the reaction mixture was stirred for 5 min. In the next

step, iodomethane (50 l, 0.81 mmol, 0.95 equiv.) was added dropwise and the reaction

mixture was stirred over night. The product could be obtained after evaporation of the solvent

under reduced pressure and purification by column chromatography (eluent:

n-pentane/EtOAc 3:1) as a yellow solid in 42% yield.

M.p.: 47–48 °C

1H NMR (600 MHz, CDCl3): = 7.62–7.51 (m, 2H), 7.28 (d, J = 7.8 Hz, 2H), 4.31–4.18 (br s,

1H), 2.56–2.49 (m, 3H), 2.39 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 141.3, 140.4, 129.6, 126.2, 25.6, 21.4 ppm.

MS (EI, 70 eV): m/z (%) = 169 ([M+], 13), 140 (7), 139 (87), 122 (10), 121 (100), 120 (6), 111

(5), 108 (6), 92 (6), 91 (19), 89 (5), 78 (10), 77 (12), 67 (5), 65 (17), 63 (6).

IR (ATR): = 3477 (vw), 3216 (s), 3044 (vw), 2920 (w), 2323 (w), 2104 (w), 1996 (vw), 1916

(vw), 1649 (vw), 1596 (vw), 1445 (m), 1176 (vw), 1046 (vs), 812 (s), 708 (vw) cm-1.


4.3.2. Synthesis of N-alkylsulfoximines 31 and N-methylsulfoximines 30

General procedure A:

A round-bottom flask, equipped with a magnetic stir bar, was charged with methanol (6.0 mL)

and an alkylamine 11 (2.8 mmol, 2.8 equiv.) for the synthesis of 31 and methylamine (11a,

33% in EtOH, 0.36 mL, 2.8 mmol, 2.8 equiv.) for the synthesis of 30. Subsequently, bromine

(0.08 mL, 1.4 mmol, 1.4 equiv.) was added dropwise. The reaction mixture was stirred

vigorously for 5 min. Afterwards, sulfide 1 (1.0 mmol, 1.0 equiv.) was added and the reaction

mixture was stirred for another 10 min. The reaction progress was monitored by TLC. After full

consumption of 1, the solvent was removed under reduced pressure. The residue was taken

up in acetone (25 mL) and filtered over filter paper. The filtrate was concentrated under


114

reduced pressure to ca. 10 mL. After addition of potassium carbonate (0.28 g, 2.0 mmol,

2.0 equiv.) and potassium permanganate (0.47 g, 3.0 mmol, 3.0 equiv.) the reaction mixture

was stirred for 16 h at room temperature. Then, the solvent was removed under reduced

pressure, the mixture was diluted with DCM (20 mL) and washed with distilled water (30 mL).

The aqueous phase was extracted with DCM (3 x 10 mL). The combined organic phases were

dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified

by column chromatography (eluent: n-pentane/EtOAc, substrate dependent) to yield

N-alkylsulfoximine 31 or N-methylsulfoximine 30.

N-Ethyl-S-methyl-S-phenylsulfoximine (31a)

Prepared from thioanisole (1a) and ethylamine (11b) according to the general procedure A,

the compound was obtained as a colorless oil in 35% yield after column chromatography

(eluent: n-pentane/EtOAc 2:1 to EtOAc).

1H NMR (400 MHz, CDCl3): = 7.87–7.82 (m, 2H), 7.57–7.47 (m, 3H), 3.02 (s, 3H), 2.98–2.90

(m, 1H), 2.81–2.73 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H) ppm.

13C NMR (101 MHz, CDCl3): = 139.6, 132.8, 129.4, 128.7, 45.2, 38.5, 18.3 ppm.

MS (EI, 70 eV): m/z (%) = 184 (6), 183 ([M]+, 11), 170 (5), 169 (9), 168 (100), 142 (7), 141

(78), 140 (7), 126 (10), 125 (24), 124 (13), 97 (11), 92 (6), 91 (5), 78 (9), 77 (24), 65 (5), 63

(6), 51 (16).

IR (ATR): = 3396 (vw), 3061 (vw), 2968 (m), 2925 (w), 2855 (w), 2681 (vw), 2327 (vw), 2103

(vw), 1992 (vw), 1920 (vw), 1737 (vw), 1641 (vw), 1583 (vw), 1475 (vw), 1445 (m), 1408 (vw),

1375 (vw), 1292 (w), 1226 (vs), 1136 (vs), 1088 (s), 988 (s), 865 (vw), 814 (w), 775 (m), 743

(vs), 689 (m) cm-1.


N-Butyl-S-methyl-S-phenylsulfoximine (31b)


115

Prepared from thioanisole (1a) and n-butylamine (11c) according to the general procedure A,

the compound was obtained as a yellow oil in 32% yield after column chromatography (eluent:

n-pentane/EtOAc 2:1 to EtOAc).

1H NMR (600 MHz, CDCl3): = 7.87–7.83 (m, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.4 Hz,

2H), 3.03 (s, 3H), 2.92–2.87 (m, 1H), 2.74–2.69 (m, 1H), 1.51–1.45 (m, 2H), 1.33–1.23 (m,

2H), 0.81 (t, J = 7.4 Hz, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 139.7, 132.8, 129.4, 128.7, 45.2, 43.6, 35.0, 20.4, 13.9 ppm.

MS (EI, 70 eV): m/z (%) = 212 ([M]+, 4), 169 (5), 168 (66), 142 (8), 141 (100), 140 (7), 126

(12), 125 (34), 124 (15), 97 (13), 91 (5), 78 (11), 77 (26), 63 (6), 51 (7).

IR (ATR): = 3821 (vw), 3401 (w), 3064 (vw), 2928 (s), 2863 (s), 2674 (vw), 2323 (w), 2097

(w), 1994 (vw), 1913 (vw), 1658 (w), 1581 (vw), 1531 (vw), 1447 (s), 1411 (w), 1368 (vw), 1311

(w), 1232 (vs), 1132 (vs), 1085 (vs), 976 (vs), 863 (w), 782 (m), 742 (vs), 688 (s) cm-1.


N-Cyclohexyl-S-methyl-S-phenylsulfoximine (31c)

Prepared from thioanisole (1a) and cyclohexylamine (11d) according to the general procedure

A, the compound was obtained as a colorless oil in 19% yield after column chromatography


1H NMR (600 MHz, CDCl3): = 7.92–7.89 (m, 2H), 7.60–7.56 (m, 1H), 7.55–7.51 (m, 2H), 3.03

(s, 3H), 2.86–2.80 (m, 1H), 1.89–1.85 (m, 1H), 1.69–1.61 (m, 3H), 1.49–1.45 (m, 1H), 1.40–1.34 (m, 1H), 1.32–1.26 (m, 1H), 1.16–1.06 (m, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 140.9, 132.8, 129.3, 128.7, 54.3, 45.8, 37.7, 36.5, 25.7, 25.6,

25.4 ppm.

MS (EI, 70 eV): m/z (%) = 240 (6), 239 (18), 238 (100), 237 ([M]+, 43), 236 (20), 195 (7), 194

(57), 141 (5), 125 (3), 97 (3), 91 (2), 77 (3).

IR (ATR): = 3854 (vw), 3400 (w), 3063 (vw), 3011 (vw), 2925 (vs), 2852 (s), 2663 (vw), 2335

(vw), 2088 (vw), 1992 (vw), 1919 (vw), 1735 (vw), 1654 (vw), 1582 (vw), 1532 (vw), 1445 (s),


116

1410 (w), 1366 (w), 1316 (w), 1230 (vs), 1131 (vs), 1083 (s), 1018 (vw), 971 (s), 889 (w), 839

(vw), 787 (m), 742 (vs), 689 (s) cm-1.


N,S-Dimethyl-S-phenylsulfoximine (30a)

Prepared from thioanisole (1a) and methylamine (11a) according to the general procedure A,


(eluent: EtOAc).


(s, 3H), 2.65 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 138.9, 133.0, 129.6, 128.9, 45.1, 29.7 ppm.

MS (EI, 70 eV): m/z (%) = 172 (5), 171 (11), 170 (100), 169 ([M]+, 23), 168 (14), 156 (9), 154

(42), 141 (10), 140 (6), 125 (10), 106 (19), 97 (6), 77 (17), 51 (9).

IR (ATR): = 3882 (vw), 3195 (m), 3062 (s), 2921 (s), 2314 (vw), 2098 (vw), 1999 (vw), 1912

(vw), 1672 (vs), 1446 (s), 1369 (w), 1312 (m), 1236 (vs), 1149 (s), 1093 (m), 967 (m), 847 (w),

751 (vs), 687 (s) cm-1.


N,S-Dimethyl-S-(4-fluorophenyl)sulfoximine (30b)

Prepared from 4-fluorothioanisole (1b) and methylamine (11a) according to the general

procedure A, the compound was obtained as a yellow oil in 38% yield after column

chromatography (eluent: n-pentane/EtOAc 1:1 to EtOAc).

M.p.: 59–60 °C


117

1H NMR (600 MHz, CDCl3): = 7.94–7.89 (m, 2H), 7.29–7.25 (m, 2H), 3.09 (s, 3H), 2.66 (s,

3H) ppm.

13C NMR (151 MHz, CDCl3): = 165.6 (d, J = 254.6 Hz), 134.8 (d, J = 3.1 Hz), 131.6 (d, J =

9.2 Hz), 116.9 (d, J = 22.6 Hz), 45.3, 29.6 ppm.

19F NMR (564 MHz, CDCl3): = 105.5 (m) ppm.

MS (EI, 70 eV): m/z (%) = 188 (18), 187 ([M]+, 49), 173 (6), 172 (38), 159 (17), 158 (9), 144

(7), 143 (32), 142 (9), 127 (6), 125 (8), 124 (100), 123 (8), 115 (13), 112 (6), 110 (17), 109 (7),

97 (9), 96 (12), 95 (34), 83 (13), 75 (23), 69 (5), 64 (9), 54 (6), 50 (5), 49 (7), 48 (5).

IR (ATR): = 3452 (vw), 2914 (w), 2295 (vw), 2093 (vw), 1913 (vw), 1735 (m), 1588 (m), 1468

(m), 1402 (w), 1230 (vs), 1136 (vs), 975 (s), 835 (vs), 765 (s) cm-1.

HRMS (ESI): calc. for C8H11NOSF [M+H]+: 188.0540, found: 188.0533.

S-(4-Chlorophenyl)-N,S-dimethylsulfoximine (30c)

Prepared from 4-chlorothioanisole (1c) and methylamine (11a) according to the general

procedure A, the compound was obtained as a colorless oil in 60% yield after column


1H NMR (600 MHz, CDCl3): = 7.83 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 3.07 (s, 3H),

2.64 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 139.8, 137.5, 130.4, 130.0, 45.2, 29.7 ppm.

MS (EI, 70 eV): m/z (%) = 206 (7), 205 ([M, 37Cl]+, 10), 204 (23), 203 ([M, 35Cl]+, 26), 190 (11),

188 (27), 177 (6), 175 (18), 174 (6), 161 (11), 160 (10), 159 (33), 158 (8), 143 (8), 142 (34),

141 (8), 140 (100), 139 (7), 138 (5), 133 (6), 131 (14), 128 (9), 127 (6), 126 (13), 125 (6), 113

(14), 112 (11), 111 (40), 108 (10), 105 (9), 104 (5), 99 (10), 85 (6), 77 (12), 75 (47), 74 (13),

73 (6), 63 (19), 61 (6), 61 (7), 50 (20), 34 (5).

IR (ATR): = 3561 (vw), 3202 (vw), 3069 (vw), 2916 (w), 2804 (vw), 2296 (vw), 2096 (vw),

1923 (vw), 1670 (s). 1575 (m), 1471 (m), 1393 (w), 1313 (w), 1237 (vs), 1146 (vs), 1086 (vs),

971 (vs), 833 (vs), 768 (vs) cm-1.


118

HRMS (ESI): calc. for C8H11NOSCl [M+H]+: 204.0244, found: 204.0241.

S-(4-Bromophenyl)-N,S-dimethylsulfoximine (30d)

Prepared from 4-bromothioanisole (1d) and methylamine (11a) according to the general

procedure A, the compound was obtained as a white solid in 53% yield after column


M.p.: 59–60 °C


3H) ppm.

13C NMR (101 MHz, CDCl3): = 138.1, 132.9, 130.5, 128.3, 45.2, 29.7 ppm.

MS (EI, 70 eV): m/z (%) = 255 (5), 251 (11), 250 (93), 249 ([M, 81Br]+, 59), 248 (100), 247 ([M,

79Br]+, 51), 246 (13), 236 (6), 235 (7), 234 (66), 233 (6), 232 (57), 221 (10), 220 (6), 219 (11),

218 (7), 205 (18), 204 (10), 203 (18), 202 (6), 187 (8), 186 (80), 185 (10), 184 (79), 172 (6),

157 (10), 155 (10), 105 (7), 76 (6), 75 (7), 63 (5), 50 (6).

IR (ATR): = 3197 (vw), 2915 (m), 2807 (w), 2283 (vw), 2087 (vw), 1922 (vw), 1671 (m), 1569

(m), 1464 (m), 1383 (m), 1314 (w), 1227 (vs), 1145 (vs), 1081 (vs), 968 (vs), 826 (vs), 756 (vs)

cm-1.

HRMS (ESI): calc. for C8H11NOSBr [M+H]+: 247.9743, found: 247.9739.

S-(3-Bromophenyl)-N,S-dimethylsulfoximine (30e)

Prepared from 3-bromothioanisole (1e) and methylamine (11a) according to the general

procedure A, the compound was obtained as a yellow oil in 52% yield after column

chromatography (eluent: n-pentane/EtOAc 1:1).


119

1H NMR (600 MHz, CDCl3): = 8.04–8.02 (m, 1H), 7.82–7.79 (m, 1H), 7.74–7.72 (m, 1H),

7.45–7.42 (m, 1H), 3.07 (s, 3H), 2.63 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 141.1, 136.1, 131.8, 131.1, 127.4, 123.7, 45.1, 29.7 ppm.

MS (EI, 70 eV): m/z (%) = 251 (10), 250 (89), 249 ([M, 81Br]+, 37), 248 (100), 247 249 ([M,

79Br]+, 31), 246 (11), 235 (5), 234 (54), 232 (52), 221 (8), 219 (8), 205 (7), 203 (7), 186 (20),

185 (7), 184 (22), 183 (6), 157 (15), 155 (13), 108 (8), 105 (14), 104 (7), 96 (8), 92 (5), 77 (9),

76 (25), 75 (27), 74 (13), 69 (5), 63 (18), 61 (5), 50 (19).

IR (ATR): = 3408 (vw), 2914 (m), 2809 (w), 2305 (vw), 1737 (m), 1568 (w), 1410 (m), 1238

(vs), 1134 (vs), 973 (vs), 855 (m), 777 (vs) cm-1.


S-(2-Bromophenyl)-N,S-dimethylsulfoximine (30f)

Prepared from 2-bromothioanisole (1f) and methylamine (11a) according to the general

procedure A, the compound was obtained as a white solid in 31% yield after column


M.p.: 78–79 °C

1H NMR (600 MHz, CDCl3): = 8.19 (dd, J = 7.9, 1.7 Hz, 1H), 7.74 (dd, J = 7.9, 1.2 Hz, 1H),

7.50 (td, J = 7.7, 1.2 Hz, 1H), 7.42 (td, J = 7.7, 1.7 Hz, 1H), 3.25 (s, 3H), 2.58 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 137.7, 135.6, 134.1, 133.8, 128.4, 121.0, 42.6, 29.7 ppm.

MS (EI, 70 eV): m/z (%) = 251 (10), 250 (96), 249 ([M, 81Br]+, 36), 248 (100), 247 ([M, 79Br]+,

29), 246 (9), 234 (50), 232 (48), 221 (9), 220 (7), 219 (9), 218 (7), 205 (10), 204 (5), 203 (10),

186 (32), 185 (5), 184 (36), 183 (6), 157 (17), 155 (19), 153 (16), 139 (8), 138 (16), 125 (18),

120 (5), 109 (7), 108 (25), 106 (8), 105 (51), 104 (28), 97 (11), 96 (42), 95 (8), 92 (17), 91 (30),

89 (6), 85 (9), 83 (13), 82 (6), 81 (8), 78 (16), 77 (57), 76 (68), 75 (84), 74 (41), 70 (10), 69

(20), 65 (15), 64 (13), 63 (84), 61 (16), 60 (9), 57 (6), 55 (6), 51 (18), 50 (69), 48 (8), 47 (11),

46 (6), 45 (12).


120

IR (ATR): = 3840 (vw), 3405 (m), 2924 (m), 2662 (vw), 2320 (vw), 2206 (vw), 2104 (vw),

1908 (vw), 1733 (s), 1550 (vs), 1428 (s), 1374 (s), 1240 (vs), 1141 (s), 1094 (vs), 957 (m), 903

(m), 836 (m), 754 (vs), 690 (vs) cm-1.


Methyl 2-(N,S-dimethylsulfonimidoyl)benzoate (30g)

Prepared from methyl-2-(methylthio)benzoate (1g) and methylamine (11a) according to the

general procedure A, the compound was obtained as a colorless oil in 25% yield after column

chromatography (eluent: n-pentane/EtOAc 1:1) and preparative HPLC chromatography.

1H NMR (600 MHz, CDCl3): = 7.97–7.94 (m, 1H), 7.61 (m, 2H), 7.56–7.53 (m, 1H), 3.91 (s,

3H), 3.23 (s, 3H), 2.57 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 168.7, 137.3, 134.7, 132.9, 130.8, 129.1, 53.2, 45.0,

29.6 ppm.

MS (EI, 70 eV): m/z (%) = 228 (20), 227 ([M]+, 13), 212 (17), 200 (5), 199 (39), 198 (29), 196

(18), 184 (8), 183 (86), 169 (5), 168 (10), 167 (100), 166 (6), 165 (6), 164 (6), 153 (18), 152

(54), 148 (10), 137 (6), 136 (7), 135 (10), 133 (11), 132 (50), 125 (10), 121 (13), 120 (15), 119

(5), 118 (6), 109 (11), 108 (9), 106 (6), 105 (55), 104 (48), 97 (8), 96 (19), 95 (6), 92 (45), 91

(13), 79 (8), 78 (11), 77 (55), 76 (42), 75 (11), 74 (12), 70 (5), 69 (6), 65 (7), 64 (10), 63 (31),

59 (7), 51 (9), 50 (22).

IR (ATR): = 3609 (vw), 3379 (vw), 3188 (vw), 3016 (vw), 2950 (w), 2879 (vw), 2806 (vw),

2329 (vw), 2174 (vw), 2095 (vw), 1990 (vw), 1729 (vs), 1663 (w), 1590 (vw), 1567 (vw), 1432

(s), 1288 (vs), 1242 (vs), 1150 (vs), 1111 (vs), 1056 (s), 959 (s), 854 (m), 829 (w), 776 (vs),

747 (vs) cm-1.

HRMS (ESI): calc. for C10H13N1O3SNa [M+Na]+: 250.0508, found: 250.0506.


121

N,S-Dimethyl-S-(4-methylphenyl)sulfoximine (30h)

Prepared from 4-methylthioanisole (1h) and methylamine (11a) according to the general


chromatography (eluent: EtOAc).


2.62 (s, 3H), 2.43 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 143.9, 135.7, 130.3, 128.9, 45.2, 29.6, 21.6 ppm.

MS (EI, 70 eV): m/z (%) = 184 (6), 183 ([M]+, 23), 168 (19), 155 (14), 140 (5), 139 (27), 138

(5), 121 (10), 120 (100), 119 (5), 118 (5), 108 (6), 107 (7), 105 (6), 93 (5), 92 (14), 91 (63), 89

(10), 79 (7), 78 (8), 77 (19), 65 (32), 63 (17), 51 (6).

IR (ATR): = 3399 (vw), 2919 (w), 2804 (vw), 2364 (vw), 2089 (vw), 1925 (vw), 1660 (vw),

1595 (w), 1408 (w), 1313 (w), 1234 (vs), 1142 (vs), 1100 (vs), 971 (vs), 815 (s), 759 (s) cm-1.


N,S-Dimethyl-S-(4-methoxyphenyl)sulfoximine (30i)

Prepared from 4-methoxythioanisole (1i) and methylamine (11a) according to the general




3H), 2.64 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 163.4, 131.0, 130.0, 114.8, 55.8, 45.5, 29.6 ppm.

MS (EI, 70 eV): m/z (%) = 201 (2), 200 (12), 199 ([M]+, 30), 184 (14), 171 (8), 156 (5), 155

(35), 139 (5), 137 (8), 136 (100), 123 (10), 121 (13), 108 (11), 95 (5), 92 (12), 77 (14), 64 (6),

63 (11).


122

IR (ATR): = 3555 (vw), 2925 (w), 2568 (vw), 2299 (vw), 2084 (vw), 1906 (vw), 1737 (w), 1588

(s), 1489 (m), 1309 (m), 1237 (vs), 1139 (vs), 1098 (vs), 1020 (s), 971 (s), 836 (vs), 764 (s)

cm-1.

HRMS (ESI): calc. for C9H14NO2S [M+H]+: 200.0740, found: 200.0736.

S-(4-Acetylphenyl)-N,S-dimethylsulfoximine (30j)

Prepared from 4-(methylthio)acetophenone (1j) and methylamine (11a) according to the

general procedure A, the compound was obtained as a white solid in 68% yield after column


M.p.: 71–72 °C


3H), 2.65 (s, 3H) ppm.

13C NMR (101 MHz, CDCl3): = 197.0, 140.5, 129.4, 129.3, 128.2, 44.9, 29.7, 27.1 ppm.

MS (EI, 70 eV): m/z (%) = 213 (11), 212 (77), 211 ([M]+, 52), 210 (9), 198 (11), 197 (11), 196

(100), 183 (16), 182 (11), 167 (18), 152 (11), 149 (6), 148 (54), 132 (7), 121 (5), 106 (7), 105

(6), 104 (5), 91 (9), 76 (5).

IR (ATR): = 3566 (vw), 3360 (vw), 3281 (vw), 3091 (vw), 3055 (vw), 2996 (w), 2962 (vw),

2914 (w), 2880 (w), 2801 (vw), 2637 (vw), 2298 (vw), 2175 (vw), 2081 (vw), 1945 (vw), 1841

(vw), 1684 (vs), 1573 (w), 1393 (s), 1360 (m), 1319 (vw), 1224 (vs), 1145 (vs), 1096 (s), 962

(vs), 835 (s), 778 (vs), 742 (s) cm-1.

EA: calc. for C10H13NO2S: C 56.85%, H 6.20%, N 6.63%; found: C 56.85%, H 6.15%, N 6.63%.

N,S-Dimethyl-S-(4-nitrophenyl)sulfoximine (30k)


123

Prepared from 4-nitrothioanisole (1k) and methylamine (11a) according to the general

procedure A, the compound was obtained as a yellow solid in 21% yield after column

chromatography (eluent: n-pentane/EtOAc 1:1) and preparative HPLC chromatography.

M.p.: 127–128 °C


3H) ppm.

13C NMR (151 MHz, CDCl3): = 150.6, 145.4, 130.2, 124.8, 44.8, 29.6 ppm.

MS (EI, 70 eV): m/z (%) = 215 (19), 214 ([M]+, 38), 213 (6), 201 (6), 200 (10), 199 (100), 186

(14), 170 (6), 153 (14), 151 (14), 150 (11), 140 (10), 105 (22), 104 (5), 92 (7), 76 (9), 75 (6),

63 (7), 50 (7).

IR (ATR): = 3104 (w), 3055 (vw), 2995 (vw), 2919 (m), 2810 (vw), 2635 (vw), 2450 (vw),

2289 (vw), 2207 (vw), 2164 (vw), 2093 (vw), 2007 (vw), 1945 (vw), 1821 (vw), 1707 (vw), 1604

(w), 1518 (vs), 1468 (m), 1402 (vw), 1345 (vs), 1229 (vs), 1146 (vs), 1081 (vs), 990 (vs), 966

(s), 856 (vs), 770 (vs), 736 (vs), 682 (s) cm-1.

HRMS (ESI): calc. for C8H11N2O3S [M+H]+: 215.0485, found 215.0485.

N,S-Dimethyl-S-(2-naphtyl)sulfoximine (30l)

Prepared from 2-methylthionaphthalene (1l) and methylamine (11a) according to the general



1H NMR (600 MHz, CDCl3): = 8.45 (s, 1H), 7.95 (dd, J = 12.5, 8.4 Hz, 2H), 7.89 (d, J = 8.1

Hz, 1H), 7.80 (dd, J = 8.6, 1.6 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 6.9 Hz, 1H), 3.11

(s, 3H), 2.64 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 135.7, 135.0, 132.7, 130.6, 129.7, 129.2, 128.9, 127.9, 127.5,

123.5, 44.9, 29.6 ppm.


124

MS (EI, 70 eV): m/z (%) = 221 (3), 220 (10), 219 ([M]+, 37), 204 (11), 191 (8), 175 (25), 157

(12), 156 (100), 147 (12), 144 (5), 141 (5), 129 (17), 128 (33), 127 (72), 126 (10), 115 (31),

101 (6), 77 (9), 63 (9).

IR (ATR): = 3863 (vw), 3390 (w), 3014 (w), 2915 (w), 2803 (w), 2311 (w), 2093 (w), 1995

(vw), 1918 (vw), 1713 (vw), 1587 (w), 1501 (vw), 1455 (w), 1409 (w), 1341 (w), 1235 (vs), 1141

(vs), 975 (s), 845 (s), 755 (vs) cm-1.


N,S-Dimethyl-S-(2-pyridinyl)sulfoximine (30m)

Prepared from 2-methylthiopyridine (1m) and methylamine (11a) according to the general



1H NMR (600 MHz, CDCl3): = 8.76 (m, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.94 (td, J = 7.7, 1.2

Hz, 1H), 7.53–7.47 (m, 1H), 3.23 (s, 3H), 2.66 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 157.5, 150.6, 137.9, 126.6, 123.6, 41.1, 29.7 ppm.

MS (EI, 70 eV): m/z (%) = 171 ([M]+, 2), 155 (4), 142 (20), 127 (7), 124 (16), 107 (10), 96 (9),

95 (7), 93 (4), 92 (6), 80 (22), 79 (37), 78 (100), 76 (6), 75 (5), 67 (12), 63 (8), 52 (15), 51 (53),

47 (5).

IR (ATR): = 3847 (vw), 3420 (m), 2916 (m), 2804 (vw), 2694 (vw), 2296 (m), 2092 (m), 1996

(vw), 1916 (w), 1742 (w), 1643 (vw), 1569 (m), 1423 (s), 1315 (vw), 1236 (vs), 1149 (vs), 1103

(vs), 974 (s), 854 (m), 766 (vs), 689 (vw) cm-1.

EA: calc. for C7H10N2OS: C 49.39%, H 5.92%, N 16.46%; found: C 49.24%, H 5.96%,

N 16.32%.


125

N,S-Dimethyl-S-cyclohexylsulfoximine (30n)

Prepared from cyclohexyl methyl sulfide (1n) and methylamine (11a) according to the general



1H NMR (600 MHz, CDCl3): = 2.88 (tt, J = 12.3, 3.4 Hz, 1H), 2.76 (s, 3H), 2.73 (s, 3H), 2.25–

2.16 (m, 2H), 1.88 (d, J = 13.5 Hz, 2H), 1.68 (d, J = 13.0 Hz, 1H), 1.48–1.37 (m, 2H), 1.30–

1.22 (m, 2H), 1.19–1.11 (m, 1H) ppm.

13C NMR (151 MHz, CDCl3): = 62.5, 34.7, 29.2, 26.6, 26.5, 25.6, 25.2 ppm.

MS (EI, 70 eV): m/z (%) = 176 ([M]+, 10), 145 (5), 94 (24), 93 (23), 83 (27), 79 (6), 78 (47), 77

(5), 67 (10), 63 (13), 55 (100), 54 (5), 53 (13), 47 (5).

IR (ATR): = 3530 (w), 2928 (vs), 2865 (s), 2804 (w), 2323 (vw), 2089 (w), 1993 (vw), 1644

(vw), 1450 (m), 1227 (vs), 1131 (vs), 958 (m), 849 (s), 752 (vw), 694 (w) cm-1.


N,S-Dimethyl-S-benzylsulfoximine (30o)

Prepared from benzyl methyl sulfide (1o) and methylamine (11a) according to the general



1H NMR (600 MHz, CDCl3): = 7.41–7.35 (m, 5H), 4.32 (s, 2H), 2.85 (s, 3H), 2.70 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 130.7, 129.8, 129.1, 128.9, 59.5, 38.4, 29.6 ppm.

MS (EI, 70 eV): m/z (%) = 183 ([M]+, 1), 168 (3), 92 (7), 91 (100), 89 (5), 65 (21), 63 (9).

IR (ATR): = 3868 (vw), 3393 (w), 2918 (m), 2806 (w), 2323 (w), 2091 (w), 1896 (w), 1652

(w), 1454 (m), 1413 (m), 1314 (w), 1232 (vs), 1117 (vs), 976 (m), 843 (m), 774 (m), 699 (m)

cm-1.


126

HRMS (ESI): calc. for C9H13NOSNa [M+Na]+: 206.0610, found: 206.0614.

N-Methyl-S-ethyl-S-phenylsulfoximine (30p)

Prepared from ethyl phenyl sulfide (1p) and methylamine (11a) according to the general




3.19–3.09 (m, 2H), 2.66 (s, 3H), 1.21 (t, J = 7.5 Hz, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 137.0, 133.0, 129.7, 129.5, 50.9, 29.6, 7.5 ppm.

MS (EI, 70 eV): m/z (%) = 184 (12), 183 ([M]+, 7), 155 (12), 154 (21), 126 (11), 125 (24), 109

(20), 108 (6), 107 (89), 106 (60), 105 (26), 97 (21), 94 (13), 91 (6), 79 (11), 78 (50), 77 (100),

76 (5), 65 (10), 61 (7), 60 (8), 51 (48).

IR (ATR): = 3827 (vw), 3408 (w), 3062 (vw), 2932 (w), 2878 (w), 2804 (w), 2666 (vw), 2321

(vw), 2099 (w), 2000 (vw), 1920 (vw), 1741 (vw), 1646 (vw), 1580 (vw), 1447 (s), 1233 (vs),

1142 (vs), 981 (vw), 927 (vw), 859 (vs), 771 (s), 728 (vs), 689 (s) cm-1.


N-Methyl-S-cyclopropyl-S-phenylsulfoximine (30q)

Prepared from cyclopropyl phenyl sulfide (1q) and methylamine (11a) according to the general


chromatography (eluent: n-pentane/EtOAc 1:1 to EtOAc) and preparative HPLC

chromatography.


(m, 1H), 1.46–1.38 (m, 1H), 1.08–0.97 (m, 2H), 0.82–0.73 (m, 1H) ppm.


127

13C NMR (151 MHz, CDCl3): = 139.2, 132.7, 129.4, 129.0, 32.9, 29.9, 5.8, 4.9 ppm.

MS (EI, 70 eV): m/z (%) = 197 (6), 196 (38), 195 ([M]+, 44), 194 (22), 167 (8), 166 (5), 154

(13), 147 (10), 126 (8), 125 (51), 118 (6), 117 (19), 116 (11), 115 (13), 109 (15), 107 (29), 106

(100), 105 (13), 104 (5), 97 (33), 94 (8), 91 (6), 87 (5), 85 (34), 83 (49), 79 (13), 78 (23), 77

(81), 76 (5), 65 (9), 61 (6), 53 (5), 51 (40), 50 (15), 49 (5), 48 (10), 47 (15).

IR (ATR): = 3573 (vw), 3394 (vw), 3059 (vw), 3014 (vw), 2915 (w), 2875 (w), 2804 (w), 2663

(vw), 2329 (vw), 2097 (w), 1990 (vw), 1908 (vw), 1733 (vw), 1640 (vw), 1581 (vw),1444 (s),

1305 (w), 1242 (vs), 1186 (m), 1145 (vs), 1109 (s), 1082 (s), 997 (vw), 887 (vs), 857 (vs), 760

(s), 724 (vs), 689 (s) cm-1.


Methyl (2S)-2-(((benzyloxy)carbonyl)amino)-4-(N,S-dimethylsulfonimidoyl)butanoate

(30s)

Prepared from methyl (S)-2-(benzyloxycarbonylamino)-4-methylmercaptobutanoate (1s) and

methylamine (11a) according to the general procedure A, the compound was obtained as a

viscous colorless oil in 46% yield (mixture of two diastereomers) after column chromatography

(eluent: EtOAc).

1H NMR (400 MHz, CDCl3): = 7.45–7.12 (m, 5H), 6.22 (dd, J = 41.1, 7.9 Hz, 1H), 5.05 (s,

2H), 4.40 (s, 1H), 3.69 (s, 3H), 3.19–2.99 (m, 2H), 2.80 (s, 3H), 2.69 (s, 3H), 2.39–2.27 (m,

1H), 2.20–2.07 (m, 1H) ppm.

13C NMR (101 MHz, CDCl3): = 171.7, 171.6, 156.1, 136.0, 128.5, 128.2, 128.1, 67.1, 52.7,

52.6, 52.5, 49.9, 38.6, 38.4, 29.0, 28.9, 26.1, 26.0 ppm.

MS (EI, 70 eV): m/z (%) = 343 (1), 342 ([M]+, 2), 250 (2), 249 (3), 158 (10), 146 (2), 120 (2),

114 (11), 111 (2), 107 (3), 97 (3), 94 (9), 92 (9), 91 (100), 85 (2), 83 (3), 79 (2), 78 (10), 71 (3),

65 (4), 57 (4).

IR (ATR): = 3855 (vw), 3319 (w), 2943 (m), 2807 (vw), 2641 (vw), 2320 (w), 2082 (w), 1717

(vs), 1529 (s), 1446 (m), 1223 (vs), 1148 (vs), 1047 (vs), 853 (m), 744 (m) cm-1.


128

HRMS (ESI): calc. for C15H23N2O5S [M+H]+: 343.1322, found: 343.1328.

4.3.3. Synthesis and characterisation data of N,S-dimethyl-S-phenylsulfiliminium

bromide (119a)

A 100 mL round-bottom flask, equipped with a magnetic stir bar, was charged with methanol

(50 mL) and methylamine (11a, 33% in EtOH, 3.5 mL, 28 mmol, 2.8 equiv.). Subsequently,

bromine (0.72 mL, 14 mmol, 1.4 equiv.) was added dropwise. The reaction mixture was stirred

vigorously for 5 min. Afterwards, thioanisole (1a, 1.2 mL, 10 mmol, 1.0 equiv.) was added and

the reaction was stirred for another 10 min. After full consumption of 1a, the solvent was

removed under reduced pressure. The residue was taken up in acetone (30 mL) and filtered

over filter paper. The filtrate was concentrated under reduced pressure until ca. 10 mL and

was then added dropwise to cold diethyl ether (200 mL) under vigorous stirring to form a milky

solution. After ca. 30 min, the solution became completely clear along with the formation of an

oily off-white precipitate sticking all around the flask. The solvent was carefully removed

keeping the precipitate in the flask. The oily residue was dried under high vacuum to give

N,S-dimethyl-S-phenylsulfiliminium bromide (119a) as a viscous yellow oil in 85% yield which

was used without further purification.

1H NMR (600 MHz, CD3OD): = 8.00–7.99 (m, 2H), 7.84–7.81 (m, 1H), 7.78–7.76 (m, 2H),

4.85 (s, 1H), 3.49 (s, 3H), 2.68 (s, 3H) ppm.

13C NMR (151 MHz, CD3OD): = 135.4, 131.8, 129.8, 129.7, 29.6, 28.0 ppm.

IR (ATR): = 3860 (vw), 3741 (vw), 3428 (m), 3051 (vs), 2912 (m), 2822 (m), 2742 (vw), 2660

(vw), 2549 (vw), 2317 (s), 2110 (m), 1997 (w), 1924 (w), 1772 (vw), 1691 (w), 1580 (w), 1441

(vs), 1320 (m), 1152 (w), 1070 (vs), 974 (vs), 840 (w), 751 (vs), 684 (vs) cm-1.

MS (ESI): m/z (%) = 154 ([M-Br]+, 51), 139 (24), 124 (100), 107 (28).


129

4.3.4. Synthesis of N-cyanosulfoximines 35

General procedure B

A sealed tube, equipped with a magnetic stir bar, was charged with the respective sulfoxide 2

(0.20 mmol, 1.0 equiv.). Distilled water was added (1.0 mL). Then KOtBu (45 mg, 0.40 mmol,

2.0 equiv.) followed by H2NCN (17 mg, 0.40 mmol, 2.0 equiv.) were added and the mixture

was stirred for 10 min. Subsequently, NCS (53 mg, 0.40 mmol, 2.0 equiv.) was added and the

solution was stirred for 2 h at room temperature. The reaction mixture was transferred into a

separating funnel containing DCM (15 mL) and distilled water (5 mL). Then, 1 M NaOH

(25 mL) was added into the separating funnel. The aqueous layer was extracted with DCM

(3 x 10 mL), and the combined organic phase was dried over MgSO4. After evaporation of the

solvent the product 35 was purified by column chromatography (eluent: n-pentane/EtOAc,

substrate dependent).

N-Cyano-S-methyl-S-phenylsulfoximine (35a)

Prepared from (methylsulfinyl)benzene (2a) according to the general procedure B, the

compound was obtained as a colorless solid in 93% yield after column chromatography (eluent:

n-pentane/EtOAc 2:1).


(s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 136.1, 135.6, 130.4, 128.0, 111.9, 44.9 ppm.

The analytical data are in accordance with the literature.[24]


130

N-Cyano-S-methyl-S-(4-chlorophenyl)sulfoximine (35c)

Prepared from 1-chloro-4-(methylsulfinyl)benzene (2c) according to the general procedure B,


(eluent: n-pentane/EtOAc 3:2).

1H NMR (600 MHz, CDCl3): = 7.95–7.90 (m, 2H), 7.67–7.63 (m, 2H), 3.33 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 142.7, 134.5, 130.7, 129.5, 111.6, 44.8 ppm.


N-Cyano-S-methyl-S-(4-bromophenyl)sulfoximine (35d)

Prepared from 1-bromo-4-(methylsulfinyl)benzene (2d) according to the general procedure B,

the compound was obtained as a colorless solid in 85% yield after column chromatography


1H NMR (600 MHz, CDCl3): = 7.87–7.80 (m, 4H), 3.34 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 135.1, 133.8, 131.4, 129.5, 111.6, 44.9 ppm.


N-Cyano-S-methyl-S-(3-bromophenyl)sulfoximine (35e)


131

Prepared from 1-bromo-3-(methylsulfinyl)benzene (2e) according to the general procedure B,



M.p.: 110–111 °C


(s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 138.7, 138.0, 131.8, 130.8, 126.6, 124.3, 111.4, 44.8 ppm.

MS (EI, 70 eV): m/z (%) = 260 ([M, 81Br]+, 15), 259 (73), 258 ([M, 79Br]+, 15), 257 (71), 219 (96),

217 ([M-NCN]+, 96), 209 (10), 205 (86), 202 (87), 182 (10), 180 (33), 176 (20), 174 (22), 173

(10), 171 (11), 156 (40), 154 (63), 142 (8), 141 (14), 140 (14), 139 (64), 124 (9), 121 (7), 119

(15), 111 (22), 108 (24), 96 (46), 95 (29), 93 (17), 92 (12), 90 (7), 79 (12), 75 (100), 77 (14),

76 (81), 75 (93), 74 (66), 69 (21), 67 (23), 64 (11), 63 (69), 52 (14), 51 (46), 50 (99), 47 (12).

IR (ATR): v = 3786 (vw), 3366 (vw), 3063 (m), 2997 (m), 2913 (m), 2306 (vw), 2187 (vs), 1896

(vw), 1733 (w), 1568 (w), 1408 (s), 1325 (w), 1183 (vs), 1092 (vs), 978 (vs), 803 (vs), 732 (s),

668 (w) cm-1.

EA: calc. for C8H7N2OSBr: C 37.08%, H 2.72%, N 10.81%; found: C 37.03%, H 2.90%,

N 10.63%.

N-Cyano-S-methyl-S-(4-methylphenyl)sulfoximine (35h)

Prepared from 1-methyl-4-(methylsulfinyl)benzene (2h) according to the general procedure B,




2.47 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 147.1, 132.9, 130.9, 127.9, 112.1, 44.9, 21.8 ppm.



132

N-Cyano-S-methyl-S-(4-methoxyphenyl)sulfoximine (35i)

Prepared from 1-methoxy-4-(methylsulfinyl)benzene (2i) according to the general procedure

B, the compound was obtained as a colorless solid in 98% yield after column chromatography


M.p.: 103–104 °C


3.29 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 165.2, 130.3, 126.6, 115.6, 112.3, 56.1, 45.2 ppm.

MS (EI, 70 eV): m/z (%) = 209 ([M]+, 22), 169 ([M-NCN]+, 13), 154 (100), 147 (10), 139 (7),

123 (15), 95 (13), 92 (17), 78 (8), 77 (13), 69 (11), 64 (15), 63 (42), 57 (9), 55 (8), 50 (9).

IR (ATR): v = 3373 (vw), 3098 (vw), 2921 (s), 2858 (m), 2584 (vw), 2183 (vw), 1897 (vw), 1737

(vw), 1580 (vs), 1474 (s), 1316 (m), 1240 (vs), 1085 (vs), 976 (vs), 809 (vs) cm-1.


N-Cyano-S-methyl-S-(4-acetylphenyl)sulfoximine (35j)

Prepared from 1-(4-(methylsulfinyl)phenyl)ethan-1-one (2j) according to the general procedure

B, the compound was obtained as a colorless solid in 67% yield after column chromatography


M.p.: 120–121 °C


2.67 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 196.3, 142.3, 139.8, 129.9, 128.5, 111.5, 44.6, 27.1 ppm.


133

MS (EI, 70 eV): m/z (%) = 223 (9), 222 ([M]+, 57), 182 ([M-NCN]+, 34), 169 (10), 167 (100),

152 (27), 145 (5), 139 (12), 124 (9), 104 (8), 76 (9).

IR (ATR): v = 3382 (vw), 3098 (vw), 2982 (w), 2901 (w), 2642 (vw), 2361 (vw), 2190 (vs), 1990

(vw), 1896 (vw), 1686 (s), 1569 (vw), 1488 (vw), 1399 (m), 1363 (w), 1302 (vw), 1245 (vs),

1191 (vs), 1100 (w), 1067 (vw), 970 (vs), 823 (vs), 706 (m) cm-1.

EA: calc. for C10H10N2O2S: C 54.04%, H 4.544%, N 12.60%; found: C 53.82%, H 4.456%,

N 12.52%.

N-Cyano-S-methyl-S-(4-nitrophenyl)sulfoximine (35k)

Prepared from 1-(methylsulfinyl)-4-nitrobenzene (2k) according to the general procedure B,




13C NMR (151 MHz, CDCl3): = 151.9, 142.0, 129.8, 125.5, 110.8, 44.7 ppm.


N-Cyano-S-methyl-S-(pyridin-2-yl)sulfoximine (35m)

Prepared from 2-(methylsulfinyl)pyridine (2m) according to the general procedure B, the

compound was obtained as a yellow oil in 69% yield after column chromatography (eluent:


1H NMR (600 MHz, CDCl3): = 8.79 (d, J = 4.7 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.11–8.06

(m, 1H), 7.70–7.67 (m, 1H), 3.51 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 154.7, 150.9, 139.1, 128.9, 122.5, 111.6, 39.8 ppm.


134

MS (EI, 70 eV): m/z (%) = 265 (12), 263 (16), 181 ([M]+, 24), 166, 141 ([M-NCN]+, 10), 86 (10),

84 (64), 82 (100), 78 (16), 48 (8), 47 (20).

IR (ATR): v = 3485 (vw), 3014 (m), 2922 (m), 2661 (vw), 2339 (vw), 2193 (vs), 1578 (m), 1425

(m), 1244 (vs), 975 (vs), 770 (vs) cm-1.

HRMS (ESI): calc. for C7H7N3OSNa [M+Na]+: 233.0200, found: 233.0202.

N-Cyano-S-cyclohexyl-S-methylsulfoximine (35n)

Prepared from (methylsulfinyl)cyclohexane (2n) according to the general procedure B, the

compound was obtained as a colorless oil in 48% yield after column chromatography (eluent:


1H NMR (600 MHz, CDCl3): = 3.25–3.19 (m, 1H), 3.12 (s, 3H), 2.33–2.26 (m, 2H), 2.04–1.99

(m, 2H), 1.62–1.55 (m, 4H), 1.43–1.33 (m, 2H) ppm.

13C NMR (151 MHz, CDCl3): = 112.2, 64.3, 36.8, 25.5, 24.9, 24.6 ppm.

MS (EI, 70 eV): m/z (%) = 187 ([M]+, 16), 171 (7), 105 (21), 104 (11), 89 (8), 83 (68), 81 (18),

79 (9), 67 (16), 63 (24), 57 (11), 55 (100), 53 (13).

IR (ATR): v = 3881 (vw), 3478 (vw), 2931 (vs), 2864 (m), 2336 (vw), 2189 (vs), 1722 (w), 1638

(w), 1451 (m), 1235 (vs), 967 (s), 820 (vs) cm-1.


N-Cyano-S-cyclopropyl-S-phenylsulfoximine (35q)

Prepared from (cyclopropylsulfinyl)benzene (2q) according to the general procedure B, the




135


2.73–2.67 (m, 1H), 1.70–1.66 (m, 1H), 1.36–1.29 (m, 2H), 1.14–1.10 (m, 1H) ppm.

13C NMR (151 MHz, CDCl3): = 136.3, 135.2, 130.0, 127.8, 112.4, 33.6, 7.1, 5.9 ppm.

MS (EI, 70 eV): m/z (%) = 207 ([M]+, 11), 205 (41), 165 ([M-NCN]+, 15), 124 (100), 97 (26), 78

(8), 77 (35), 65 (6), 51 (25).

IR (ATR): v = 3881 (vw), 3476 (vw), 3039 (w), 2662 (vw), 2330 (vw), 2193 (vs), 2109 (w), 1998

(vw), 1805 (w), 1445 (m), 1244 (vs), 1184 (vs), 1081 (s), 881 (s), 831 (vs), 732 (vs), 686 (s)

cm-1.


N-Cyano-S-diphenylsulfoximine (35r)

Prepared from sulfinyldibenzene (2r) according to the general procedure B, the compound was

obtained as a colorless solid in 15% yield after column chromatography (eluent:


M.p.: 100–101 °C

1H NMR (600 MHz, CDCl3): = 8.02–7.98 (m, 4H), 7.71–7.67 (m, 2H), 7.63–7.58 (m, 4H) ppm.

13C NMR (151 MHz, CDCl3): = 137.5, 134.9, 130.2, 128.1, 112.0 ppm.

MS (EI, 70 eV): m/z (%) = 242 ([M]+, 32), 202 ([M-NCN]+, 32), 185 (6), 174 (16), 173 (14), 155

(9), 154 (73), 152 (9), 141 (11), 125 (18), 109 (91), 97 (57), 93 (19), 92 (18), 78 (12), 77 (40),

69 (12), 65 (52), 57 (10), 51 (100).

IR (ATR): v = 3790 (vw), 3698 (vw), 3375 (vw), 3073 (w), 2924 (m), 2647 (vw), 2288 (vw),

2189 (vs), 2008 (w), 1913 (vw), 1780 (vw), 1581 (vw), 1449 (s), 1180 (vs), 1085 (vs), 1000 (s),

835 (s), 735 (vs), 682 (vs) cm-1.



136

N-Cyano-S-methyl-S-(2-fluorophenyl)sulfoximine (35t)

Prepared from 1-fluoro-2-(methylsulfinyl)benzene (2t) according to the general procedure B,

the compound was obtained as a yellow oil in 53% yield after column chromatography (eluent:


1H NMR (600 MHz, CDCl3): = 8.06–8.02 (m, 1H), 7.83–7.78 (m, 1H), 7.47 (t, J = 7.7 Hz, 1H),

7.37 (t, J = 16.1 Hz, 1H), 3.49 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 159.0 (d, J = 257.5 Hz), 138.3 (d, J = 8.9 Hz), 130.7, 125.8

(d, J = 3.6 Hz), 124.2 (d, J = 13.8 Hz), 118.1 (d, J = 20.9 Hz), 111.2, 43.8 (d, J = 3.6 Hz) ppm.


MS (EI, 70 eV): m/z (%) = 199 (28), 198 ([M]+, 100), 157 ([M-NCN]+, 79), 143 (100), 140 (26),

130 (6), 125 (25), 115 (33), 112 (14), 109 (10), 97 (17), 95 (18), 85 (13), 83 (37), 81 (5), 77

(11), 75 (31), 74 (11), 69 (12), 57 (11), 51 (15), 50 (14), 45 (9).

IR (ATR): v = 3490 (vw), 3020 (w), 2926 (w), 2197 (vs), 1828 (vw), 1718 (vw), 1592 (m), 1470

(m), 1253 (vs), 1195 (vs), 1074 (m), 978 (s), 827 (vs), 766 (vs) cm-1.

HRMS (ESI): calc. for C8H7N2OSFNa [M+Na]+: 221.0192, found: 221.0155.

N-Cyano-S-methyl-S-(4-formylphenyl)sulfoximine (35u)

Prepared from 4-(methylsulfinyl)benzaldehyde (2u) according to the general procedure B, the



1H NMR (600 MHz, CDCl3): = 10.16 (s, 1H), 8.20–8.17 (m, 4H), 3.40 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 190.3, 141.1, 140.8, 131.0, 128.9, 111.3, 44.6 ppm.


137

MS (EI, 70 eV): m/z (%) = 209 (17), 208 ([M]+, 92), 169 (9), 168 ([M-NCN]+, 97), 154 (8), 152

(100), 152 (8), 146 (5), 125 (45), 124 (8), 121 (58), 97 (29), 91 (9), 77 (44), 76 (20), 75 (11),

74 (11), 65 (15), 63 (14), 51 (38), 50 (22).

IR (ATR): v = 3640 (vw), 3386 (vw), 3091 (vw), 3014 (w), 2922 (w), 2853 (w), 2389 (vw), 2195

(vs), 2142 (vw), 1995 (vw), 1945 (vw), 1705 (vs), 1578 (w), 1383 (m), 1324 (vw), 1302 (w),

1247 (vs), 1194 (vs), 1087 (s), 976 (vs), 910 (vw), 817 (vs), 770 (vs), 735 (s), 688 (s) cm-1.


N-Cyano-S-allyl-S-phenylsulfoximine (35v)

Prepared from (allylsulfinyl)benzene (2v) according to the general procedure B, the compound

was obtained as a colorless oil in 55% yield after column chromatography (eluent:



5.77–5.69 (m, 1H), 5.47 (d, J = 10.4 Hz, 1H), 5.27 (d, J = 16.1 Hz, 1H), 4.12–4.08 (m, 2H) ppm.

13C NMR (151 MHz, CDCl3): = 135.6, 133.7, 130.0, 129.1, 127.8, 122.2, 112.0, 61.2 ppm.

MS (EI, 70 eV): m/z (%) = 206 ([M]+, 5), 126 (8), 125 (100), 117 (8), 109 (7), 97 (52), 78 (21),

77 (89), 65 (9), 57 (7), 51 (50), 50 (13).

IR (ATR): v = 3840 (vw), 3456 (vw), 3066 (vw), 2917 (w), 2335 (vw), 2193 (vs), 2116 (w), 1802

(w), 1635 (w), 1444 (m), 1243 (vs), 1186 (vs), 1089 (s), 948 (m), 826 (s), 755 (m) cm-1.


N-Cyano-S-phenyl-S-(2-pyridinyl)sulfoximine (35x)

Prepared from 2-(phenylsulfinyl)pyridine (2x) according to the general procedure B, the



M.p.: 107–108 °C


138


8.06–8.00 (m, 1H), 7.77–7.71 (m, 1H), 7.66–7.60 (m, 2H), 7.59–7.55 (m, 1H) ppm.

13C NMR (101 MHz, CDCl3): = 155.7, 151.2, 138.9, 135.4, 134.4, 129.9, 129.6, 128.2, 123.3,

111.8 ppm.

MS (EI, 70 eV): m/z (%) = 244 (27), 243 ([M]+, 16), 203 ([M-NCN]+, 25), 202 (8), 187 (9), 186

(63), 170 (29), 156 (13), 155 (100), 154 (14), 125 (25), 109 (14), 97 (20), 78 (59), 77 (26), 52

(12), 51 (62), 50 (13).

IR (ATR): v = 3808 (vw), 2959 (m), 2656 (vw), 2194 (s), 1739 (vs), 1573 (w), 1430 (s), 1368

(s), 1215 (vs), 1085 (vs), 808 (vs) cm-1.


N-Cyano-S-tetrahydrothiophenesulfoximine (35y)

Prepared from tetrahydrothiophene 1-oxide (2y) according to the general procedure B, the



1H NMR (600 MHz, CDCl3): = 3.56–3.48 (m, 2H), 3.33–3.25 (m, 2H), 2.43–2.26 (m, 4H) ppm.

13C NMR (151 MHz, CDCl3): = 112.5, 53.0, 23.6 ppm.


N-Cyano-S-dimethylsulfoximine (35z)

Prepared from dimethyl sulfoxide (2z) according to the general procedure B on a 5.0 mmol

scale, the compound was obtained as a colorless solid in 23% yield after column

chromatography (eluent: n-pentane/EtOAc 1:1).

M.p.: 85–86 °C


139

1H NMR (400 MHz, CDCl3): = 3.34 (s, 6H) ppm.

13C NMR (101 MHz, CDCl3): = 111.9, 42.7 ppm.

MS (EI, 70 eV): m/z (%) = 120 (6), 119 (47), 118 ([M]+, 100), 78 (22), 63 (35), 61 (7), 48 (6),

47 (5), 46 (10), 45 (19).

IR (ATR): v = 3953 (vw), 3390 (vw), 3009 (s), 2919 (w), 2644 (vw), 2342 (vw), 2187 (vs), 1929

(vw), 1712 (vw), 1627 (vw), 1508 (vw), 1412 (w), 1333 (w), 1192 (vs), 1029 (s), 942 (s), 809

(vs), 693 (w) cm-1.

EA: calc. for C3H6N2OS: C 30.50%, H 5.12%, N 23.71%; found: C 30.70%, H 5.14%,

N 23.63%.

4.3.5. One-pot synthesis of N-cyano-S-methyl-S-phenylsulfoximine (35a)

A sealed tube was charged with thioanisole (1a, 25 mg, 0.20 mmol, 1.0 equiv.), H2O (1.0 mL)

and NaIO4 (45 mg, 0.21 mmol, 1.1 equiv.) and stirred at room temperature for 16 h. Then

KOtBu (45 mg, 0.40 mmol, 2.0 equiv.) followed by H2NCN (17 mg, 0.40 mmol, 2.0 equiv.) were

added and the mixture was stirred for 10 min. Subsequently, NCS (53 mg, 0.40 mmol, 2.0

equiv.) was added and the solution was stirred for 2 h at room temperature. The reaction

mixture was transferred into a separating funnel containing DCM (15 mLand distilled water

(5 mL). Then, 1 M NaOH (25 mL) was added into the separating funnel. The aqueous layer

was extracted with DCM (3 x 10 mL), and the combined organic phase was dried over MgSO4.

After evaporation of the solvent the product was purified by column chromatography (eluent:

n-pentane/EtOAc 2:1) to yield N-cyano-S-methyl-S-phenylsulfoximine (35a) as a white solid in

85%.

1H NMR (400 MHz, CDCl3): = 7.99 (d, J = 7.3 Hz, 2H), 7.78 (t, J = 7.5 Hz, 1H), 7.68 (t, J =

7.8 Hz, 2H), 3.34 (s, 3H) ppm.

13C NMR (101 MHz, CDCl3): = 136.1, 135.6, 130.4, 128.0, 111.9, 44.9 ppm.



140

4.3.6. Synthesis of enantioenriched starting material and product

(S)-Methyl(sulfinyl)benzene (2a)

To investigate the stereochemistry of the described protocol, an enantiomerically enriched

mixture of (S)-methyl(sulfinyl)benzene (2a) was prepared after a procedure by Kagan and co-

workers.[29a]

HPLC: OB-H, n-heptane/i-PrOH = 70:30, 0.5 mL/min, = 210 nm, 20 °C, tR (major) = 14.2 min,

tR (minor) = 24.0 min; ee = 72%.

Optical rotation: [α]D20 = 103.4° (c = 1.70, acetone).


13C NMR (151 MHz, CDCl3): = 145.5, 130.9, 129.2, 123.3, 43.8 ppm.

The analytical data are in accordance with the literature.[29a, 179]

(R)-NH-S-Methyl-S-phenylsulfoximine (7a)

The prepared sulfoxide (S)-2a was subjected to the general procedure B on a 2.0 mmol scale

to prepare 35a. In the next step 35a was converted to the corresponding NH-sulfoximine 7a

after a procedure by Bolm and co-workers.[24] HPLC and optical activity measurements

revealed inversion of stereochemistry.

HPLC: AD-H, n-heptane/i-PrOH = 80:20, 0.6 mL/min, = 210 nm, tR (major) = 19.1 min, tR

(minor) = 17.4 min; ee = 73%.

Optical rotation: [α]D20 = 25.6° (c = 1.11, acetone).

1H NMR (600 MHz, CDCl3): = 7.96 (m, 2H), 7.59–7.54 (m, 1H), 7.52–7.47 (m, 2H), 3.05 (s,

3H), 2.72 (br s, 1H) ppm.


141

13C NMR (151 MHz, CDCl3): = 143.5, 133.0, 129.2, 127.7, 46.2 ppm.

The analytical data are in accordance with the literature.[24, 180]

4.3.7. Synthesis of boronic acid pinacol esters

General procedure C

A Schlenk tube was charged with NH-sulfoximine 7 (0.50 mmol, 1.0 equiv.). Using a glovebox,

sodium-tert-butanolate (9.6 mg, 0.10 mmol, 0.20 equiv.) and bis(1,5-cyclooctadiene)nickel

(14 mg, 0.05 mmol, 0.10 equiv.) were added. Subsequently, under an atmosphere of argon,

IMes•HCl (34 mg, 0.10 mmol, 0.20 equiv.), B2pin2 (0.25 g, 1.0 mmol, 2.0 equiv.) and toluene

(1.5 mL) were added. The reaction mixture was stirred at 120 °C for 16 h. After cooling to room

temperature, evaporation under reduced pressure and purification by column chromatography

(eluent: n-pentane/EtOAc 30:1) the product 85 could be obtained.

4,4,5,5-Tetramethyl-2-phenyl-1,3,2-dioxaborolane (85a)

Prepared from NH-S-methyl-S-phenylsulfoximine (7a) according to the general procedure C,




1.35 (s, 12H) ppm.

13C NMR (151 MHz, CDCl3): = 134.9, 131.4, 127.8, 83.9, 25.0 (C–B not observed) ppm.


142

11B NMR (128 MHz, CDCl3): = 30.5 ppm.


4,4,5,5-Tetramethyl-2-(naphthalen-2-yl)-1,3,2-dioxaborolane (85l)

Prepared from NH-S-methyl-S-(2-naphtyl)sulfoximine (7l) according to the general procedure

C, the compound was obtained as a colorless solid in 34% yield after column chromatography


1H NMR (600 MHz, CDCl3): = 8.40 (s, 1H), 7.92–7.90 (m, 1H), 7.88–7.84 (m, 3H), 7.53–

7.48 (m, 2H), 1.41 (s, 12H) ppm.

13C NMR (151 MHz, CDCl3): = 136.4, 130.5, 128.8, 127.8, 127.1, 125.9, 84.1, 25.1 (C–B not

observed) ppm.

11B NMR (128 MHz, CDCl3): = 31.1 ppm.


4,4,5,5-Tetramethyl-2-(4'-methyl-(1,1'-biphenyl)-4-yl)-1,3,2-dioxaborolane (85aa)

Prepared from NH-S-methyl-S-(4’-methyl-((1,1’biphenyl)-4-yl))sulfoximine (7aa) according to

the general procedure C, the compound was obtained as a colorless solid in 34% yield after

column chromatography (eluent: n-pentane/EtOAc 30:1).


8.1 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 2.42 (s, 3H), 1.38 (s, 12H) ppm.


143

13C NMR (151 MHz, CDCl3): = 143.9, 138.2, 137.5, 135.4, 129.6, 127.2, 126.4, 83.9, 25.0,

21.3 (C–B not observed) ppm.

11B NMR (128 MHz, CDCl3): = 30.9 ppm.


4.3.8. Isolation of N-methylbenzenesulfinamide (132a) as by-product

Employing sulfoximine 30r in the general procedure C, both the desired product 85a (24%, for

analytical data, see above) and the by-product N-methylbenzenesulfinamide (132a, 22%,

calculated by 1H NMR) with traces of B2pin2 could be isolated after column chromatography

(eluent: n-pentane/EtOAc 30:1 to EtOAc). For the sake of clarity, the signals for B2pin2 are

denoted as well and are marked within the analytical data. Slight shifts of B2pin2 compared to

the analytical data in the literature might be attributed to adduct formation.

1H NMR (600 MHz, CDCl3): = 7.77–7.61 (m, 2H), 7.58–7.38 (m, 3H), 4.25 (br s, 1H), 2.54

(d, J = 5.5 Hz, 3H), 1.27–1.20 (m, 24H, B2pin2 impurity) ppm.

13C NMR (151 MHz, CDCl3)= 143.5, 131.0, 129.0, 126.2, 75.2 (B2pin2 impurity), 25.9, 25.0

(B2pin2 impurity), 24.7 (B2pin2 impurity) ppm.


4.3.9. Synthesis of boronic acid neopentyl ester 113a


144

A Schlenk tube was charged with NH-S-methyl-S-phenylsulfoximine (7a, 0.50 mmol,

1.0 equiv.). Using a glovebox, sodium-tert-butanolate (9.6 mg, 0.10 mmol, 0.20 equiv.) and

bis(1,5-cyclooctadiene)nickel (14 mg, 0.05 mmol, 0.10 equiv.) were added. Subsequently,

under an atmosphere of argon, IMes•HCl (34 mg, 0.10 mmol, 0.20 equiv.), B2nep2 (0.23 g,

1.0 mmol, 2.0 equiv.) and toluene (1.5 mL) were added. The reaction mixture was stirred at

120 °C for 16 h. After cooling to room temperature, evaporation under reduced pressure and

purification by column chromatography (eluent: n-pentane/EtOAc 30:1) the product 113a could

be obtained as a white solid in 13% yield.


3.78 (s, 4H), 1.03 (s, 6H) ppm.

13C NMR (101 MHz, CDCl3): = 134.0, 130.8, 127.7, 72.5, 32.0, 22.1 (C–B not observed)

ppm.

11B NMR (128 MHz, CDCl3): = 26.7 ppm.


4.3.10. Synthesis of ortho-borylated N-protected sulfoximines 133

General procedure D

A Schlenk tube was charged with N-methylsulfoximine 30 (0.50 mmol, 1.0 equiv.). After

introducing the Schlenk tube into a glovebox, it was charged with bis(1,5-cyclooctadiene)di-µ-

methoxydiiridium(I) (5.0 mg, 7.5 mol, 1.5 mol%). Subsequently, under an atmosphere of

argon, 8-aminoquinoline (107, 2.2 mg, 15 mol, 3.0 mol%) and bis(pinacolato)diboron (89 mg,

0.35 mmol, 0.70 equiv.) were added. The reagents were dissolved in dry 1,4-dioxane (1.5 mL).

After addition of pinacolborane (4.0 L, 2.5 mol, 5.0 mol%), the septum was tightly closed

with a layer of parafilm and the Schlenk tube was heated at 80 °C for 16 h. The reaction mixture

was cooled down to room temperature and evaporated under reduced pressure. The product


145

133 could be obtained after purification by column chromatography (eluent: n-pentane/EtOAc,

substrate dependent) and if necessary recrystallization.

2-(N-Methyl-S-methylsulfonimidoyl)phenylpinacolborane (133a)

Prepared from N,S-dimethyl-S-phenylsulfoximine (30a) according to the general procedure D,



M.p.: 105–106 °C


(m, 1H), 7.40–7.34 (m, 1H), 3.24 (s, 3H), 2.92 (s, 3H), 1.29 (s, 6H), 1.27 (s, 6H) ppm.

13C NMR (151 MHz, CDCl3): = 152.5 (br s), 136.8, 134.3, 131.7, 128.3, 122.0, 79.4, 40.7,

27.2, 26.9, 24.9 ppm.

11B NMR (128 MHz, CDCl3): = 9.8 ppm.

MS (EI, 70 eV): m/z (%) = 295 ([M]+, 11), 280 (25), 279 (7), 267 (25), 266 (7), 238 (6), 237

(38), 236 (14), 211 (5), 210 (13), 209 (100), 208 (27), 196 (16), 195 (5), 180 (8), 179 (12), 178

(42), 177 (12), 167 (31), 166 (13), 165 (6), 163 (5), 152 (10), 151 (12), 150 (28), 149 (18), 142

(5), 141 (62), 140 (5), 136 (6), 135 (5), 125 (9), 124 (6), 105 (5), 91 (5), 83 (5), 77 (5), 61 (8),

48 (25), 47 (11).

IR (ATR): = 3442 (w), 2972 (m), 2283 (w), 2218 (w), 2091 (w), 2026 (vw), 1937 (vw), 1650

(vw), 1458 (w), 1373 (w), 1145 (vs), 1012 (vs), 872 (vs), 742 (vs) cm-1.

EA: calc. for C14H22NO3SB: C 56.96%, H 7.51%, N 4.74%; found: C 56.88%, H 7.91%,

N 4.74%.


146

5-Fluoro-2-(N-methyl-S-methylsulfonimidoyl)phenylpinacolborane (133b)

Prepared from N,S-dimethyl-S-(4-fluorophenyl)sulfoximine (30b) according to the general

procedure D, the compound was obtained as a colorless solid in 19% yield after column

chromatography (eluent: n-pentane/EtOAc 1:1 to EtOAc) and recrystallization in n-pentane.

M.p.: 78–79 °C


7.11 (td, J = 8.4, 2.4 Hz, 1H), 3.32 (s, 3H), 2.97 (s, 3H), 1.32 (s, 6H), 1.31 (s, 6H) ppm.

13C NMR (101 MHz, CDCl3): = 167.1 (d, J = 257.4 Hz), 132.2, 124.8 (d, J = 9.7 Hz), 118.4

(d, J = 20.3 Hz), 116.4 (d, J = 25.1 Hz), 79.7, 41.1, 27.3, 27.0, 25.1 (C–B not observed) ppm.

11B NMR (128 MHz, CDCl3): = 9.0 ppm.

19F NMR (376 MHz, CDCl3): = 103.3 (dd, J = 12.3, 8.2 Hz) ppm.

MS (EI, 70 eV): m/z (%) = 255 (7), 228 (18), 227 (46), 226 (8), 214 (7), 199 (5), 198 (8), 197

(13), 196 (56), 195 (15), 185 (36), 184 (19), 183 (10), 182 (6), 181 (10), 170 (19), 169 (23),

168 (50), 167 (24), 166 (5), 161 (5), 160 (9), 159 (100), 158 (11), 155 (6), 154 (20), 153 (12),

152 (6), 150 (10), 149 (6), 143 (29), 142 (15), 141 (7), 140 (6), 136 (5), 127 (8), 126 (9), 125

(7), 124 (7), 123 (12), 122 (6), 115 (5), 112 (5), 111 (5), 109 (20), 108 (6), 107 (6), 106 (8), 105

(6), 97 (7), 96 (6), 95 (10), 85 (34), 84 (6), 83 (45), 77 (11), 75 (5), 73 (5), 71 (7), 69 (12), 63

(6), 59 (72), 58 (7), 57 (30), 56 (8), 55 (17), 51 (5), 48 (5), 47 (11).

MS (CI, methane): m/z (%) = 540 (5), 476 (5), 342 ([M+C2H5]+, 16), 316 (8), 315 (19), 314

([M+H]+, 100), 313 (32), 312 (8), 298 (10), 255 (11), 254 (5), 228 (5), 227 (10), 214 (11).

IR (ATR): = 3392 (w), 2925 (s), 2604 (vw), 2314 (vw), 2101 (w), 1996 (vw), 1910 (vw), 1728

(vs), 1570 (m), 1450 (s), 1374 (vs), 1247 (vs), 1137 (vs), 1021 (s), 964 (vw), 872 (vs), 771 (s)

cm-1.

HRMS (ESI): calc. for C14H22NO3SFB [M+H]+: 314.1392, found: 314.1391.


147

5-Chloro-2-(N-methyl-S-methylsulfonimidoyl)phenylpinacolborane (133c)

Prepared from N,S-dimethyl-S-(4-chlorophenyl)sulfoximine (30c) according to the general

procedure D, the compound was obtained as a yellow oil in 7% yield after column

chromatography (eluent: n-pentane/EtOAc 1:1 to 1:3).

1H NMR (600 MHz, CDCl3): = 7.76 (d, J = 1.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.42 (dd, J =

8.3, 1.9 Hz, 1H), 3.32 (s, 3H), 2.98 (s, 3H), 1.33 (s, 6H), 1.32 (s, 6H) ppm.

13C NMR (151 MHz, CDCl3): = 141.9, 135.1, 132.1, 128.9, 123.5, 79.8, 41.1, 27.4, 27.1,

25.1, 24.7 (C–B not observed) ppm.

11B NMR (128 MHz, CDCl3): = 9.3 ppm.

MS (EI, 70 eV): m/z (%) = 212 (10), 201 (10), 186 (14), 175 (15), 170 (9), 169 (10), 159 (14),

149 (14), 142 (10), 140 (14), 139 (14), 134 (13), 127 (14), 125 (18), 123 (12), 121 (10), 113

(13), 112 (11), 111 (24), 110 (10), 109 (19), 108 (10), 107 (14), 99 (16), 97 (34), 96 (15), 95

(30), 91 (10), 89 (9), 85 (35), 84 (18), 83 (61), 82 (16), 81 (28), 79 (12), 77 (21), 76 (15), 75

(22), 74 (10), 71 (45), 70 (23), 69 (51), 67 (23), 63 (34), 61 (14), 59 (53), 58 (24), 57 (100), 56

(30), 55 (85), 53 (10).

MS (CI, methane): m/z (%) = 330 ([M+H, 35Cl]+, 10), 232 (12), 206 (36), 205 (12), 204 (100),

203 (6), 202 (7), 200 (16), 173 (5), 170 (18), 145 (10).

IR (ATR): = 3448 (m), 2924 (vs), 2585 (vw), 2326 (vw), 2101 (vw), 1915 (vw), 1731 (vs),

1559 (w), 1452 (s), 1373 (vs), 1245 (vs), 1144 (vs), 1083 (vs), 1014 (s), 973 (s), 886 (vs), 818

(vw), 767 (s) cm-1.

HRMS (ESI): calc. for C14H22NO3SClB [M+H]+: 330.1097, found: 330.1094.


148

5-Bromo-2-(N-methyl-S-methylsulfonimidoyl)phenylpinacolborane (133d)

Prepared from N,S-dimethyl-S-(4-bromophenyl)sulfoximine (30d) according to the general



M.p.: 101–102 °C

1H NMR (600 MHz, CDCl3): = 7.93 (s, 1H), 7.60–7.58 (m, 2H), 3.32 (s, 3H), 2.98 (s, 3H),

1.33 (s, 6H), 1.32 (s, 6H) ppm.

13C NMR (151 MHz, CDCl3): = 135.6, 135.1, 131.8, 131.1, 123.6, 79.8, 41.1, 27.4, 27.1, 25.1

(C–B not observed) ppm.

11B NMR (128 MHz, CDCl3): = 9.2 ppm.

MS (EI, 70 eV): m/z (%) = 150 (10), 149 (22), 148 (15), 140 (11), 136 (19), 135 (26), 134 (32),

133 (10), 123 (16), 122 (16), 121 (18), 115 (14), 113 (11), 109 (12), 108 (13), 107 (13), 105

(10), 104 (11), 103 (18), 102 (11), 101 (13), 97 (11), 96 (10), 95 (20), 92 (10), 91 (11), 89 (19),

87 (10), 85 (30), 84 (18), 83 (100), 82 (11), 81 (9), 78 (14), 77 (35), 76 (29), 75 (33), 74 (21),

73 (16), 71 (16), 70 (14), 69 (46), 67 (14), 65 (11), 64 (9), 63 (53), 61 (25), 60 (13), 59 (97), 58

(37), 57 (76), 56 (28), 55 (89), 53 (16), 51 (13), 50 (14), 47 (18), 46 (13).

MS (CI, methane): m/z (%) = 376 ([M+H, 81Br]+,6), 374 ([M+H, 79Br]+, 6), 360 (6), 358 (6), 347

(6), 345 (6), 317 (16), 316 (9), 315 (15), 314 (6), 290 (5), 289 (24), 288 (10), 287 (23), 286

(10), 276 (7), 274 (9), 259 (5), 258 (18), 257 (6), 256 (17), 247 (12), 246 (6), 245 (12), 244 (7),

230 (11), 229 (6), 228 (12), 221 (21), 219 (23), 83 (8), 78 (9), 77 (6), 76 (15), 75 (13), 74 (12),

73 (7), 69 (17), 65 (7), 64 (10), 63 (100), 62 (10), 61 (30), 60 (15).

IR (ATR): = 3406 (m), 3264 (w), 2923 (s), 2324 (vw), 2187 (vw), 2079 (vw), 2005 (vw), 1932

(vw), 1739 (m), 1649 (vw), 1549 (w), 1468 (m), 1371 (m), 1259 (s), 1191 (s), 1138 (vs), 1067

(s), 1012 (vs), 875 (vs), 765 (vs) cm-1.

HRMS (ESI): calc. for C14H22NO3SBrB [M+H]+: 374.0591, found: 374.0593.


149

4-Bromo-2-(N-methyl-S-methylsulfonimidoyl)phenylpinacolborane (133e)

Prepared from N,S-dimethyl-S-(3-bromophenyl)sulfoximine (30e) according to the general



M.p.: 160–161 °C

1H NMR (600 MHz, CDCl3): = 7.86 (d, J = 1.2 Hz, 1H), 7.74–7.71 (m, 1H), 7.71–7.67 (m, 1H),

3.32 (s, 3H), 2.96 (s, 3H), 1.32 (s, 6H), 1.31 (s, 6H) ppm.

13C NMR (151 MHz, CDCl3): = 138.9, 137.5, 133.5, 125.1, 121.9, 79.9, 41.2, 27.3, 27.0, 25.3

(C–B not observed) ppm.

11B NMR (128 MHz, CDCl3): = 10.3 ppm.

MS (EI, 70 eV): m/z (%) = 317 (6), 295 (7), 294 (38), 289 (17), 288 (8), 287 (14), 259 (6), 258

(12), 257 (7), 256 (8), 247 (6), 245 (8), 230 (14), 229 (7), 228 (12), 221 (21), 219 (21), 167

(18), 150 (10), 149 (100), 127 (14), 126 (6), 85 (17), 81 (5), 71 (25), 70 (9), 69 (6), 57 (17).

MS (CI, methane): m/z (%) = 500 (5), 419 (6), 404 (9), 402 (9), 378 (5), 377 (15), 376 ([M+H,

81Br]+, 99), 375 (43), 374 ([M, 79Br]+, 100), 373 (25), 360 (5), 358 (7), 317 (7), 315 (7), 296 (7),

290 (9), 289 (11), 288 (10), 287 (10), 276 (6), 274 (6).

IR (ATR): = 3465 (s), 2923 (s), 2642 (vw), 2317 (vw), 2089 (vw), 1934 (vw), 1737 (m), 1647

(w), 1576 (w), 1456 (s), 1372 (s), 1261 (s), 1198 (s), 1142 (vs), 1067 (w), 1009 (vs), 886 (vs),

824 (vw), 758 (vs), 662 (vw) cm-1.

HRMS (ESI): calc. for C14H22NO3SBrB [M+H]+: 374.0591, found: 374.0591.

5-Methyl-2-(N-methyl-S-methylsulfonimidoyl)phenylpinacolborane (133h)


150

Prepared from N,S-dimethyl-S-(4-methylphenyl)sulfoximine (30h) according to the general


chromatography (eluent: n-pentane/EtOAc 1:2) and recrystallization in n-pentane.

1H NMR (600 MHz, CDCl3): = 7.60–7.56 (m, 2H), 7.22 (d, J = 8.0 Hz, 1H), 3.27 (s, 3H), 2.94

(s, 3H), 2.41 (s, 3H), 1.32 (s, 6H), 1.31 (s, 6H) ppm.

13C NMR (151 MHz, CDCl3): = 145.3, 134.0, 132.3, 129.4, 122.0, 79.6, 41.0, 27.2, 27.0, 25.0,


11B NMR (128 MHz, CDCl3): = 10.0 ppm.

MS (EI, 70 eV): m/z (%) = 223 (12), 210 (6), 192 (16), 181 (12), 180 (9), 179 (6), 177 (6), 166

(12), 165 (12), 164 (18), 163 (16), 162 (6), 156 (6), 155 (36), 154 (10), 150 (11), 149 (22), 148

(8), 147 (6), 146 (12), 145 (6), 140 (10), 139 (55), 138 (11), 137 (8), 135 (6), 133 (7), 131 (6),

123 (11), 122 (18), 121 (23), 119 (17), 118 (12), 117 (22), 116 (8), 115 (8), 113 (6), 111 (11),

110 (6), 109 (9), 108 (10), 107 (10), 105 (41), 104 (18), 103 (14), 99 (6), 97 (17), 96 (7), 95

(12), 93 (7), 92 (14), 91 (63), 90 (17), 89 (29), 88 (5), 84 (12), 83 (23), 82 (6), 81 (13), 79 (17),

78 (27), 77 (45), 76 (19), 75 (6), 74 (5), 71 (27), 79 (17), 69 (39), 68 (5), 67 (20), 66 (9), 65

(31), 64 (9), 63 (43), 62 (6), 61 (19), 60 (11), 59 (100), 58 (35), 57 (82), 56 (28), 55 (78), 54

(5), 53 (19), 52 (6), 51 (12), 47 (10), 46 (7), 45 (40).

MS (CI, methane): m/z (%) = 312 (7), 311 (19), 310 ([M+H]+,100), 309 (30), 184 (14), 101 (8).

IR (ATR): = 3474 (m), 2925 (s), 2305 (vw), 2112 (vw), 1939 (vw), 1738 (vs), 1648 (vw), 1576

(vw), 1451 (m), 1369 (s), 1241 (vs), 1139 (vs), 1080 (s), 1018 (vs), 869 (vs), 765 (vs), 658 (vw)

cm-1.

HRMS (ESI): calc. for C15H25NO3SB [M+H]+: 310.1643, found: 310.1642.

5-Methoxy-2-(N-methyl-S-methylsulfonimidoyl)phenylpinacolborane (133i)

Prepared from N,S-dimethyl-S-(4-methoxyphenyl)sulfoximine (30i) according to the general

procedure D, the compound was obtained as a white solid in 18% yield after column

chromatography (eluent: n-pentane/EtOAc 3:1 to 1:3) and recrystallization in n-pentane.


151

M.p.: 81–82 °C

1H NMR (600 MHz, CDCl3): = 7.65 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 6.93 (dd, J = 8.6, 2.3

Hz, 1H), 3.88 (s, 3H), 3.29 (s, 3H), 2.97 (s, 3H), 1.33 (s, 6H), 1.32 (s, 6H) ppm.

13C NMR (151 MHz, CDCl3): = 164.8, 128.1, 124.0, 115.6, 115.2, 79.5, 55.7, 41.2, 27.4, 27.1,


11B NMR (128 MHz, CDCl3): = 9.1 ppm.

MS (EI, 70 eV): m/z (%) = 239 (19), 238 (5), 208 (13), 197 (11), 196 (7), 193 (5), 182 (8), 181

(8), 180 (18), 179 (7), 172 (7), 171 (59), 170 (31), 167 (5), 166 (6), 165 (14), 164 (5), 162 (8),

157 (5), 156 (10), 155 (100), 154 (6), 152 (5), 151 (6), 149 (5), 135 (5), 134 (5), 123 (10), 122

(5), 121 (13), 83 (8), 77 (9), 69 (6), 63 (8), 59 (7), 57 (69), 55 (10).

MS (CI, methane): m/z (%) = 354 ([M+C2H5]+, 7), 328 (5), 327 (13), 326 ([M+H]+, 70), 325 (19),

324 (5), 267 (5), 239 (5), 228 (14), 202 (6), 200 (100), 199 (11), 198 (11), 171 (8), 155 (5), 136

(9), 101 (18), 85 (19), 83 (30).

IR (ATR): = 3428 (m), 2981 (m), 2925 (m), 2647 (vw), 2315 (vw), 2184 (vw), 2108 (vw), 1998

(vw), 1929 (vw), 1740 (w), 1653 (vw), 1565 (s), 1461 (m), 1420 (m), 1373 (m), 1324 (w), 1240

(vs), 1199 (vs), 1138 (vs), 1084 (s), 1017 (vs), 868 (vs), 810 (w), 768 (vs) cm-1.


2-(N-Methyl-S-ethylsulfonimidoyl)phenylpinacolborane (133p)

Prepared from N-methyl-S-ethyl-S-phenylsulfoximine (30p) according to the general

procedure D, the compound was obtained as an orange oil in 69% yield after column



152

1H NMR (600 MHz, CDCl3): = 7.86 (d, J = 7.4 Hz, 1H), 7.71–7.59 (m, 2H), 7.42 (t, J = 7.6

Hz, 1H), 3.61–3.52 (m, 1H), 3.48–3.40 (m, 1H), 2.95 (s, 3H), 1.34 (s, 6H), 1.32 (s, 6H), 1.26 (t,

J = 7.4 Hz, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 134.7, 134.5, 131.8, 128.3, 122.6, 79.6, 47.9, 27.6, 26.9, 25.1,


11B NMR (128 MHz, CDCl3): = 9.7 ppm.

MS (EI, 70 eV): m/z (%) = 228 (8), 226 (6), 225 (8), 224 (44), 223 (41), 222 (7), 196 (8), 195

(6), 193 (5), 192 (21), 191 (6), 181 (19), 180 (16), 179 (13), 178 (6), 166 (18), 165 (25), 164

(32), 163 (14), 162 (6), 157 (5), 156 (11), 155 (100), 154 (15), 153 (5), 152 (16), 151 (9), 150

(14), 149 (16), 148 (6), 147 (6), 139 (6), 138 (10), 137 (20), 136 (33), 135 (19), 134 (7), 127

(8), 126 (47), 125 (13), 123 (6), 121 (6), 120 (6), 119 (20), 118 (7), 117 (7), 111 (6), 110 (7),

109 (42), 108 (14), 107 (10), 106 (10), 105 (24), 104 (9), 103 (8), 97 (8), 95 (5), 94 (6), 92 (6),

91 (27), 87 (5), 85 (23), 84 (6), 83 (43), 79 (6), 78 (24), 77 (33), 76 (6), 73 (27), 72 (10), 71 (9),

70 (5), 69 (11), 65 (8), 63 (5), 61 (7), 59 (14), 58 (7), 57 (16), 56 (6), 55 (15), 51 (8), 50 (6), 47

(7), 45 (6).

MS (CI, methane): m/z (%) = 533 (9), 532 (5), 338 ([M+C2H5]+, 8), 312 (6), 311 (16), 310

([M+H]+, 71), 309 (24), 308 (8), 294 (5), 281 (6), 254 (5), 251 (12), 250 (5), 239 (6), 238 (34),

237 (9), 233 (6), 226 (7), 225 (15), 224 (100), 223 (37), 222 (5), 210 (7), 200 (14), 196 (6), 195

(5), 184 (10), 170 (5), 155 (10), 85 (13), 83 (21).

IR (ATR): = 3450 (vw), 2968 (s), 2927 (s), 2580 (vw), 2323 (vw), 2193 (vw), 2108 (vw), 1921

(vw), 1733 (vs), 1564 (vw), 1450 (m), 1369 (s), 1241 (vs), 1199 (vs), 1144 (vs), 1077 (w), 1019

(vs), 880 (vs), 739 (vs) cm-1.


2-(N-Methyl-S-cyclopropylsulfonimidoyl)phenylpinacolborane (133q)


153

Prepared from N-methyl-S-cyclopropyl-S-phenylsulfoximine (30q) according to the general

procedure D, the compound was obtained as colorless solid in 32% yield after column


M.p.: 160–161 °C

1H NMR (600 MHz, CDCl3): = 7.83 (d, J = 7.4 Hz, 1H), 7.65–7.58 (m, 2H), 7.39 (t, J = 7.5

Hz, 1H), 2.96 (s, 3H), 2.36–2.28 (m, 1H), 1.68–1.61 (m, 1H), 1.40–1.31 (m, 13H), 1.31–1.25

(m, 1H), 1.16–1.10 (m, 1H) ppm.

13C NMR (151 MHz, CDCl3): = 137.3, 134.3, 131.7, 128.2, 122.5, 79.5, 29.4, 27.4, 27.2, 25.4,


11B NMR (192 MHz, CDCl3): = 9.3 ppm.

MS (EI, 70 eV): m/z (%) = 237 (17), 236 (32), 235 (9), 205 (6), 204 (26), 203 (8), 193 (8), 180

(5), 179 (8), 178 (5), 176 (6), 169 (11), 168 (13), 167 (95), 166 (22), 165 (21), 164 (15), 163

(17), 162 (9), 152 (24), 151 (14), 150 (13), 149 (50), 148 (8), 147 (14), 145 (5), 143 (10), 140

(6), 139 (6), 138 (6), 137 (14), 136 (38), 135 (39), 134 (19), 133 (7), 132 (13), 131 (6), 129 (5),

127 (7), 126 (12), 125 (85), 124 (7), 123 (12), 122 (9), 121 (16), 120 (11), 119 (14), 118 (21),

117 (45), 116 (36), 115 (29), 114 (5), 111 (7), 110 (8), 109 (41), 108 (19), 107 (12), 106 (24),

105 (25), 104 (16), 103 (17), 102 (6), 101 (6), 97 (23), 96 (7), 95 (7), 94 (6), 93 (6), 92 (16), 91

(41), 90 (7), 89 (11), 87 (6), 84 (7), 82 (7), 81 (6), 79 (8), 78 (24), 77 (78), 76 (13), 75 (7), 74

(7), 73 (39), 72 (14), 71 (13), 70 (30), 69 (24), 68 (6), 67 (8), 66 (5), 65 (20), 64 (6), 63 (12), 61

(16), 60 (10), 59 (100), 58 (27), 57 (44), 56 (16), 55 (45), 53 (12), 52 (7), 51 (27), 50 (14), 48

(5), 45 (21).

MS (CI, methane): m/z (%) = 322 ([M+H]+, 12), 321 (6), 320 (7), 306 (18), 293 (7), 263 (27),

262 (11), 237 (5), 236 (15), 235 (100), 234 (26), 233 (13), 222 (6), 205 (6), 204 (39), 203 (9),

193 (8), 169 (6), 168 (7), 167 (60), 166 (7), 165 (7), 149 (23), 125 (24), 117 (11), 83 (5).

IR (ATR): = 3463 (m), 2972 (m), 2325 (vw), 2217 (vw), 2081 (vw), 2010 (vw), 1939 (vw),

1739 (vs), 1641 (vw), 1562 (vw), 1439 (m), 1367 (vs), 1204 (vs), 1151 (vs), 1076 (m), 1018

(vs), 945 (w), 887 (vs), 767 (vs), 673 (w) cm-1.



154

2-(N-Methyl-S-phenylsulfonimidoyl)phenylpinacolborane (133r)

Prepared from N-methyl-S-diphenylsulfoximine (30r) according to the general procedure D,

the compound was obtained as colorless oil in 78% yield after column chromatography (eluent:

n-pentane/EtOAc 3:1 to 2:1) and recrystallization in n-pentane.

1H NMR (600 MHz, CDCl3): = 7.98 (d, J = 7.8 Hz, 2H), 7.86 (d, J = 7.5 Hz, 1H), 7.64 (t, J =

7.4 Hz, 1H), 7.60–7.54 (m, 3H), 7.44 (d, J = 7.9 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 2.81 (s, 3H),

1.39 (s, 6H), 1.38 (s, 6H) ppm.

13C NMR (151 MHz, CDCl3): = 138.2, 135.0, 134.3, 134.2, 131.4, 130.2, 129.8, 128.5, 122.8,

79.7, 27.7, 27.1, 25.4 (C–B not observed) ppm.

11B NMR (128 MHz, CDCl3): = 9.2 ppm.

MS (EI, 70 eV): m/z (%) = 357 ([M]+, 9), 343 (5), 300 (10), 299 (5), 273 (5), 272 (92), 271 (25),

258 (9), 242 (6), 241 (16), 240 (59), 239 (14), 230 (11), 229 (31), 228 (9), 223 (5), 214 (6), 213

(16), 212 (33), 211 (13), 204 (9), 203 (26), 202 (10), 201 (14), 200 (6), 199 (5), 196 (8), 195

(7), 186 (8), 185 (15), 184 (49), 183 (6), 182 (14), 181 (8), 180 (6), 173 (6), 172 (5), 171 (7),

169 (6), 167 (6), 166 (6), 165 (20), 164 (17), 163 (9), 156 (12), 155 (17), 154 (19), 153 (8), 152

(21), 151 (8), 150 (9), 149 (23), 147 (6), 141 (7), 140 (5), 139 (8), 138 (5), 137 (13), 136 (36),

135 (19), 134 (7), 132 (7), 129 (6), 127 (7), 126 (6), 125 (13), 123 (9), 122 (9), 121 (8), 120 (7),

119 (6), 115 (6), 113 (5), 111 (9), 110 (9), 109 (42), 108 (10), 107 (7), 106 (25), 105 (17), 104

(9), 103 (7), 99 (8), 98 (6), 97 (23), 96 (7), 95 (8), 93 (7), 92 (7), 91 (10), 87 (8), 85 (40), 84

(10), 83 (70), 82 (7), 81 (9), 79 (8), 78 (16), 77 (100), 76 (8), 74 (6), 73 (7), 71 (14), 70 (8), 69

(17), 67 (6), 65 (12), 63 (6), 61 (5), 60 (5), 59 (30), 58 (9), 57 (33), 56 (13), 55 (29), 53 (5), 51

(24), 50 (8), 48 (5), 47 (9), 45 (6).

IR (ATR): = 3419 (vw), 3057 (vw), 2925 (s), 2331 (vw), 2077 (vw), 1932 (vw), 1736 (m), 1640

(vw), 1451 (m), 1369 (m), 1258 (s), 1201 (s), 1146 (vs), 1077 (m), 1018 (vs), 946 (vw), 867

(vs), 738 (vs) cm-1.



155

4.3.11. Isolation of N-methylbenzenesulfinamide (132a) as side product

A Schlenk tube was charged with N-methylsulfoximine 30a (85 mg, 0.50 mmol, 1.0 equiv.).

After introducing the Schlenk tube into a glovebox, it was charged with bis(1,5-

cyclooctadiene)di-µ-methoxydiiridium(I) (5.0 mg, 7.5 mol, 1.5 mol%). Subsequently, under an

atmosphere of argon, 8-aminoquinoline (107, 2.2 mg, 15 mol, 3.0 mol%) and

bis(pinacolato)diboron (89 mg, 0.35 mmol, 0.70 equiv.) were added. The reagents were

dissolved in dry 1,4-dioxane (1.5 mL). After addition of pinacolborane (4.0 L, 2.5 mol,

5.0 mol%), the septum was tightly closed with a layer of parafilm and the Schlenk tube was

heated at 140 °C for 16 h. The reaction mixture was cooled down to room temperature and

evaporated under reduced pressure. The product 132a could be obtained with traces of B2pin2

after purification by column chromatography (eluent: n-pentane to n-pentane/EtOAc 1:1) in

11% yield (calculated by 1H NMR spectroscopy). For the sake of clarity, the signals for B2pin2

are denoted as well and are marked within the analytical data. Slight shifts of B2pin2 compared

to the analytical data in the literature might be attributed to adduct formation.

1H NMR (600 MHz, CDCl3)= 7.69 (dd, J = 7.8, 1.4 Hz, 2H), 7.58–7.42 (m, 3H), 4.17 (br s,

1H), 2.55 (d, J = 5.5 Hz, 3H), 1.27–1.20 (m, 24H, B2pin2 impurity) ppm.

13C NMR (151 MHz, CDCl3): = 143.5, 131.0, 129.0, 126.2, 75.2 (B2pin2 impurity), 25.9, 25.0

(B2pin2 impurity), 24.7 (B2pin2 impurity) ppm.


4.3.12. Synthesis of N-methyl-S-methyl-S-((1,1'-biphenyl)-2-yl)sulfoximine (136a)


156

A Schlenk tube was charged with ortho-borylated N-methylsulfoximine 133a (59 mg,

0.20 mmol, 1.0 equiv.) and tetrakis(triphenylphosphine)palladium (12 mg, 10 mol, 5.0 mol%).

The Schlenk tube was evacuated and flooded with argon. The reagents were dissolved in dry

1,4-dioxane (1.5 mL) and bromobenzene (65 L, 0.40 mol, 2.0 equiv.) was added to the

reaction mixture. Subsequently, a degassed solution of distilled water (0.20 mL) with

potassium carbonate (55 mg, 0.40 mmol, 2.0 equiv.) was added. The Schlenk tube was tightly

sealed with parafilm and heated for 6 h at 100 °C. After cooling to room temperature,

evaporation under reduced pressure and purification by column chromatography

(n-pentane/EtOAc 3:1) the product 136a could be obtained as yellow solid in 89% yield.

M.p.: 113–114 °C

1H NMR (600 MHz, CDCl3): = 8.19 (dd, J = 7.9, 1.1 Hz, 1H), 7.59 (td, J = 7.4, 1.3 Hz, 1H),

7.54 (td, J = 7.7, 1.3 Hz, 1H), 7.43–7.38 (m, 3H), 7.37–7.30 (m, 3H), 2.70 (s, 3H), 2.65 (s, 3H)

ppm.

13C NMR (151 MHz, CDCl3): = 141.9, 139.3, 137.6, 133.0, 132.3, 130.6, 129.4, 128.3, 128.0,

127.9, 43.8, 29.8 ppm.

MS (EI, 70 eV): m/z (%) = 246 (11), 245 ([M]+, 42), 244 (47), 217 (11), 215 (5), 201 (12), 200

(6), 199 (13), 198 (6), 197 (6), 185 (18), 184 (35), 183 (11), 182 (7), 181 (17), 180 (14), 171

(6), 169 (10), 168 (19), 167 (42), 166 (20), 165 (7), 154 (12), 153 (27), 152 (100), 151 (27),

150 (10), 149 (5), 141 (5), 139 (11), 128 (6), 127 (11), 126 (10), 115 (10), 96 (8), 92 (8), 91 (8),

83 (8), 77 (12), 76 (9), 75 (7), 69 (8), 64 (5), 63 (15), 57 (15), 55 (8), 51 (9), 45 (6).

IR (ATR): = 3458 (vw), 2922 (vs), 2860 (s), 2324 (vw), 2182 (vw), 2109 (vw), 1985 (vw),

1891 (vw), 1738 (vs), 1572 (vw), 1454 (s), 1369 (s), 1308 (vw), 1235 (vs), 1139 (vs), 1071 (m),

963 (s), 854 (m), 769 (vs), 703 (vs) cm-1.



157

4.3.13. Synthesis of N-acetylsulfilimines

General procedure E[25]

A round bottom flask was charged with sulfide (1, 2.5 mmol, 1.0 equiv.) and methyl-1,4,2-

dioxazol-5-one (27a, 0.27 g, 2.7 mmol, 1.1 equiv.). Subsequently, the flask was frozen in liquid

nitrogen, evacuated and filled with argon. Under an argon flow toluene (10 mL) and

[Ru(TPP)CO] (1.9 mg, 2.5 µmol, 1.0 mol%) were added. The reaction mixture was stirred for

8 h under UV irradiation. Evaporation of solvent under reduced pressure and purification by

column chromatography yielded the product 28.

N-Acetyl-S-methyl-S-phenylsulfilimine (28a)

Prepared from thioanisole (1a) according to the general procedure E, the compound was

obtained as a yellow solid in 93% yield after column chromatography (eluent: EtOAc to

EtOAc/MeOH 100:3).

1H NMR (400 MHz, CDCl3): = 7.75 (dd, J = 7.5, 2.1 Hz, 2H), 7.58–7.48 (m, 3H), 2.81 (s, 3H),

2.13 (s, 3H) ppm.

13C NMR (101 MHz, CDCl3): = 181.9, 135.4, 132.0, 129.7, 126.5, 34.3, 24.0 ppm.



158

N-Acetyl-S-methyl-S-(4-chlorophenyl)sulfilimine (28c)

Prepared from 4-chlorothioanisole (1c) according to the general procedure E, the compound

was obtained as a brown solid in 99% yield after column chromatography (eluent: EtOAc to

EtOAc/MeOH 100:3).

M.p.: 64–65 °C


3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.3, 138.7, 134.2, 130.3, 128.2, 34.5, 24.3 ppm.

MS (EI, 70 eV): m/z (%) = 265 (5), 264 (40), 263 (12), 262 (95), 218 ([M, 37Cl]+, 29), 217 (9),

216 ([M, 35Cl]+, 76), 202 (19), 201 (5), 200 (48), 176 (36), 175 (9), 174 (93), 160 (39), 159 (13),

158 (100), 157 (8), 145 (5), 143 (13), 131 (6), 109 (11), 89 (51), 75 (7).

IR (ATR): = γ8γ4 (vw), γ451 (vw), γ14β (w), γ014 (m), β66γ (vw), βγ07 (vw), β0λ6 (vw),

1915 (vw), 1738 (w), 1560 (vs), 1473 (s), 1359 (vs), 1296 (vs), 1085 (s), 982 (vs), 803 (vs),

736 (vs), 628 (s) cm-1.

HRMS (ESI): calc. for C9H10NOSClNa [M+Na]+: 238.0069, found: 238.0064.

N-Acetyl-S-methyl-S-(4-bromophenyl)sulfilimine (28d)

Prepared from 4-bromothioanisole (1d) according to the general procedure E, the compound


EtOAc/MeOH 100:3).

1H NMR (600 MHz, CDCl3): = 7.74–7.48 (m, 4H), 2.77 (s, 3H), 2.09 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.3, 134.9, 133.3, 128.3, 127.0, 34.4, 24.2 ppm.


159


N-Acetyl-S-methyl-S-(3-bromophenyl)sulfilimine (28e)

Prepared from 3-bromothioanisole (1e) according to the general procedure E, the compound


EtOAc/MeOH 100:3).

M.p.: 55–56 °C

1H NMR (400 MHz, CDCl3): = 7.87 (t, J = 1.8 Hz, 1H), 7.70–7.58 (m, 2H), 7.38 (t, J = 7.9 Hz,

1H), 2.79 (s, 3H), 2.11 (s, 3H) ppm.

13C NMR (101 MHz, CDCl3): = 182.4, 138.0, 135.4, 131.4, 129.4, 125.4, 124.0, 34.6,

24.3 ppm.

MS (EI, 70 eV): m/z (%) = 309 (45), 306 (35), 262 (37), 261 ([M, 81Br]+, 7), 260 (36), 259 ([M, 79Br]+, 2), 247 (8), 246 (80), 245 (6), 244 (74), 222 (5), 221 (9), 220 (100), 219 (15), 218 (99),

217 (5), 205 (8), 204 (86), 203 (14), 202 (85), 201 (6), 171 (9), 169 (8), 165 (5), 139 (6),

123 (13), 122 (12), 108 (15), 88 (70), 76 (6), 75 (6), 50 (5).

IR (ATR): = 3850 (vw), 3426 (w), 3055 (vw), 3004 (w), 2922 (wv), 2856 (vw), 2663 (vw), 2326

(vw), 2107 (vw), 1993 (vw), 1917 (vw), 1670 (vw), 1566 (vs), 1460 (w), 1408 (m), 1359 (s),

1296 (ws), 1164 (vw), 1099 (m), 1067 (w), 982 (s), 935 (w), 878 (vw), 792 (ws), 750 (m), 676

(m) cm-1.

EA: calc. for C9H10NOSBr: C 41.55%, H 3.87%, N 5.38%; found: C 41.49%, H 3.79%, N 5.34%.


160

N-Acetyl-S-methyl-S-(2-bromophenyl)sulfilimine (28f)

Prepared from 2-bromothioanisole (1f) according to the general procedure E, the compound


EtOAc/MeOH 100:3).

M.p.: 138–139 °C


7.51 (td, J = 8.0, 1.1 Hz, 1H), 7.38 (td, J = 7.7, 1.6 Hz, 1H), 2.81 (s, 3H), 2.15 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.2, 135.9, 133.8, 133.2, 129.1, 127.4, 121.8, 33.3,

24.4 ppm.

MS (EI, 70 eV): m/z (%) = 260 ([M]+, 3), 246 (13), 244 (11), 220 (18), 218 (18), 204 (30), 203

(6), 202 (30), 180 (28), 139 (7), 123 (14), 122 (17), 121 (6), 108 (26), 96 (6), 90 (7), 89 (7), 88

(100), 77 (8), 76 (8), 75 (10), 74 (6), 69 (7), 63 (5), 62 (7), 50 (8), 45 (6).

IR (ATR): = 3069 (vw), 3005 (vw), 2923 (w), 2853 (vw), 2706 (vw), 2302 (vw), 2100 (vw),

1932 (vw), 1851 (vw), 1809 (vw), 1731 (vw), 1576 (vs), 1419 (s), 1358 (s), 1288 (vs), 1151

(vw), 1091 (w), 989 (s), 928 (m), 864 (vw), 801 (ws), 749 (vs), 710 (m) cm-1.

EA: calc. for C9H10NOSBr: C 41.55%, H 3.87%, N 5.38%; found: C 42.04%, H 4.03%, N 5.37%.

Methyl-2-(N-acetyl-S-methylsulfinimidoyl)benzoate (28g)

Prepared from methyl-2-(methylthio)benzoate (1g) according to the general procedure E, the

compound was obtained as a brown oil in 48% yield after column chromatography (eluent:

EtOAc to EtOAc/MeOH 100:3).


161


7.73 (td, J = 8.0, 1.3 Hz, 1H), 7.57 (td, J = 7.6, 1.0 Hz, 1H), 3.95 (s, 3H), 2.87 (s, 3H), 2.15 (s,

3H) ppm.

13C NMR (151 MHz, CDCl3): = 181.9, 165.6, 138.9, 134.1, 131.3, 131.0, 128.5, 125.0, 52.8,

34.5, 24.4 ppm.

MS (EI, 70 eV): m/z (%) = 252 (18), 240 ([M]+, 3), 196 (5), 195 (11), 194 (88), 193 (13), 179

(6), 178 (7), 153 (5), 152 (46), 151 (12), 150 (22), 138 (7), 137 (14), 136 (100), 135 (77), 143

(16), 125 (13), 124 (12), 123 (14), 119 (42), 118 (10), 110 (10), 109 (47), 100 (33), 97 (13), 94

(18), 93 (5), 92 (6), 91 (41), 84 (13), 80 (7), 78 (6), 77 (23), 69 (6), 66 (6), 65 (17), 60 (30), 59

(6), 56 (5), 51 (25), 50 (8).

IR (ATR): = γ880 (vw), γγλ7 (w), γ044 (vw), βγβ4 (vw), β0λλ (w), 1λ04 (vw), 1671 (s), 1568

(vs), 1442 (w), 1362 (s), 1293 (vs), 1071 (w), 967 (s), 800 (m), 750 (m), 688 (m) cm-1.

HRMS (ESI): calc. for C11H13NO3SNa [M+Na]+: 262.0514, found: 262.0508.

N-Acetyl-S-methyl-S-(4-methylphenyl)sulfilimine (28h)

Prepared from 4-methylthioanisole (1h) according to the general procedure E, the compound

was obtained as a brown oil in 73% yield after column chromatography (eluent: EtOAc to

EtOAc/MeOH 100:3).


2.41 (s, 3H), 2.11 (s, 3H) ppm.

13C NMR (101 MHz, CDCl3): = 182.2, 143.2, 132.4, 130.8, 126.9, 34.6, 24.4, 21.6 ppm.

MS (EI, 70 eV): m/z (%) = 244 (7), 243 (9), 242 (65), 198 (5), 197 (11), 196 ([M+], 100), 180

(25), 154 (32), 139 (7), 138 (53), 137 (9), 111 (5), 91 (15), 88 (10), 65 (5).

IR (ATR): = γ4β4 (w), γ00γ (w), βλβ4 (w), βγ11 (vw), β0λλ (vw), 1λβ5 (vw), 1565 (vs), 14ββ

(s), 1360 (s), 1291 (vs), 1188 (w), 984 (vs), 801 (vs) cm-1.



162

N-Acetyl-S-methyl-S-(4-methoxyphenyl)sulfilimine (28i)

Prepared from 4-methoxythioanisole (1i) according to the general procedure E, the compound


EtOAc/MeOH 100:3).

1H NMR (400 MHz, CDCl3): = 7.70 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 3.85

(s, 3H), 2.79 (s, 3H), 2.10 (s, 3H) ppm.

13C NMR (101 MHz, CDCl3): = 182.0, 162.9, 129.0, 126.2, 115.6, 55.8, 34.7, 24.4 ppm.


N-Acetyl-S-methyl-S-(4-acetylphenyl)sulfilimine (28j)

Prepared from 4-(methylthio)acetophenone (1j) according to the general procedure E, the

compound was obtained as a white solid in 90% yield after column chromatography (eluent:


M.p.: 132–133 °C


3H), 2.11 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 196.7, 182.4, 140.8, 139.9, 129.6, 126.9, 34.2, 26.9,

24.2 ppm.

MS (EI, 70 eV): m/z (%) = 270 (13), 224 ([M]+, 21), 209 (5), 208 (37), 184 (5), 183 (11), 182

(90), 168 (5), 167 (22), 166 (65), 165 (6), 153 (6), 152 (12), 151 (100), 137 (5), 136 (5), 124

(8), 123 (12), 122 (7), 121 (5), 108 (9), 90 (6), 89 (7), 88 (91), 79 (7), 77 (7), 76 (6).


163

IR (ATR): = γ854 (vw), γ6γβ (vw), γγ5γ (vw), γ007 (m), 2926 (w), 2701 (vw), 2493 (vw),

2293 (w), 2103 (vw), 1985 (vw), 1931 (vw), 1684 (s), 1571 (vs), 1356 (vs), 1285 (vs), 1112

(vw), 983 (s), 809 (vs), 716 (vw) cm-1.


N-Acetyl-S-methyl-S-(4-nitrophenyl)sulfilimine (28k)

Prepared from 4-nitrothioanisole (1k) according to the general procedure E, the compound


EtOAc/MeOH 100:3).


2.15 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.7, 150.1, 143.3, 127.8, 125.1, 34.3, 24.2 ppm.


N-Acetyl-S-methyl-S-(2-pyridinyl)sulfilimine (28m)

Prepared from 2-methylthiopyridine (1m) according to the general procedure E, the compound


EtOAc/MeOH 100:3).

1H NMR (600 MHz, CDCl3): = 8.64 (d, J = 4.3 Hz, 1H), 7.94–7.83 (m, 2H), 7.49–7.36 (m,

1H), 2.96 (s, 3H), 2.16 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.9, 156.2, 150.3, 138.4, 125.7, 122.8, 31.5, 24.5 ppm.


164

MS (EI, 70 eV): m/z (%) = 184 (6), 183 ([M]+, 51), 167 (39), 142 (51), 141 (5), 135 (18), 126

(7), 125 (24), 124 (100), 96 (51), 95 (23), 94 (9), 88 (21), 80 (5), 79 (24), 78 (65), 67 (8), 62

(5), 52 (17), 51 (27), 50 (5), 47 (8), 46 (4).

IR (ATR): = γ4β0 (m), γ005 (vw), βλβ5 (vw), βγβ0 (vw), β10γ (vw), 1λ10 (vw), 167β (vw),

1565 (vs), 1423 (s), 1361 (s), 1298 (vs), 1125 (vw), 983 (s), 783 (vs) cm-1.


N-Acetyl-S-cyclopropyl-S-phenylsulfilimine (28q)

Prepared from cyclopropyl phenyl sulfide (1q) according to the general procedure E, the

compound was obtained as a brown solid in 97% yield after column chromatography (eluent:


M.p.: 101–102 °C


(m, 5H) ppm.

13C NMR (101 MHz, CDCl3): = 182.5, 135.8, 132.1, 129.9, 127.0, 27.8, 24.6, 6.2, 5.2 ppm.

MS (EI, 70 eV): m/z (%) = 415 (5), 280 (21), 210 (6), 209 (14), 208 (100), 207 ([M]+, 5), 192

(13), 166 (24), 150 (5), 149 (6), 125 (6), 124 (15), 123 (6), 117 (6), 114 (8), 109 (25), 97 (11),

80 (5), 77 (7), 73 (23), 65 (6), 51 (7).

IR (ATR): = γβ07 (s), βγββ (vw), β0λ7 (vw), 1λ14 (vw), 165λ (vs), 1560 (vs), 144β (s), 1γ0β

(vs), 1002 (s), 811 (s), 754 (s), 685 (m) cm-1.



165

N-Acetyl-S-methyl-S-(2-fluorophenyl)sulfilimine (28t)

Prepared from 2-fluorothioanisole (2t) according to the general procedure E, the compound


EtOAc/MeOH 100:1).

M.p.: 98–99 °C

1H NMR (600 MHz, CDCl3): = 7.74 (ddd, J = 8.3, 7.0, 1.7 Hz, 1H), 7.54–7.49 (m, 1H), 7.33

(td, J = 7.8, 1.0 Hz, 1H), 7.17 (ddd, J = 9.5, 8.4, 1.0 Hz, 1H), 2.84 (s, 3H), 2.15 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.4, 159.5 (d, J = 249.9 Hz), 133.9 (d, J = 8.1 Hz), 127.4,

125.8 (d, J = 3.3 Hz), 122.7 (d, J = 15.4 Hz), 116.6 (d, J = 20.1 Hz), 33.3, 24.4 ppm.


MS (EI, 70 eV): m/z (%) = 202 (5), 201 (11), 200 ([M]+, 100), 184 (42), 158 (38), 143 (6), 142

(66), 141 (7), 127 (9), 115 (6), 109 (10), 88 (26), 83 (12), 75 (8).

IR (ATR): = γ858 (vw), γγ5β (vw), γ0β0 (w), βλβ8 (vw), ββλ4 (vw), β0λλ (vw), 18ββ (vw),

1729 (vw), 1572 (vs), 1459 (s), 1360 (s), 1292 (vs), 1212 (s), 1125 (w), 976 (s), 927 (s), 765

(vs) cm-1.

EA: calc. for C9H10NOSF: C 54.25%, H 5.06%, N 7.03%; found: C 54.07%, H 4.99%, N 7.06%.

N-Acetyl-S-phenyl-S-vinylsulfilimine (28w)

Prepared from phenyl vinyl sulfide (1w) according to the general procedure E, the compound


EtOAc/MeOH 100:3).

M.p.: 120–121 °C


166

1H NMR (600 MHz, CDCl3): = 7.72–7.40 (m, 5H), 6.46 (dd, J = 16.4, 9.2 Hz, 1H), 6.15 (dd, J

= 16.4, 1.0 Hz, 1H), 5.98 (dd, J = 9.2, 1.0 Hz, 1H), 2.11 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.2, 134.1, 132.6, 132.2, 129.9, 127.7, 126.7, 24.5 ppm.

MS (EI, 70 eV): m/z (%) = 286 (15), 242 (6), 241 (14), 240 (100), 239 (18), 226 (5), 225 (11),

224 (91), 198 (10), 197 (24), 193 ([M]+, 1), 183 (8), 182 (25), 181 (7), 180 (8), 167 (16), 166

(11), 165 (11), 153 (6), 152 (56), 151 (27), 150 (13), 122 (8), 121 (5), 120 (7), 108 (5), 88 (29),

85 (10), 83 (17), 47 (6), 45 (8).

IR (ATR): = 3395 (vw), 3073 (vw), 2943 (w), 2313 (vw), 2097 (vw), 1901 (vw), 1703 (vs),

1572 (vs), 1428 (s), 1363 (m), 1281 (vs), 1182 (w), 1109 (s), 976 (vs), 797 (vs), 755 (vs), 692

(w) cm-1.


N-Acetyl-S-cyanomethyl-S-phenylsulfilimine (28ab)

Prepared from (phenylthio)acetonitrile (1ab) according to the general procedure E, the

compound was obtained as a brown solid in 14% yield after column chromatography (eluent:


1H NMR (600 MHz, CDCl3): = 7.97–7.93 (m, 2H), 7.70 (t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.6 Hz,

2H), 4.15 (d, J = 16.0 Hz, 1H), 3.98 (d, J = 15.9 Hz, 1H), 2.12 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 183.2, 133.8, 130.4, 130.2, 128.0, 110.5, 37.5, 24.2 ppm.

MS (EI, 70 eV): m/z (%) = 209 (5), 208 (12), 207 (100), 206 ([M]+, 6), 191 (5), 167 (9), 166

(34), 165 (50), 164 (6), 151 (40), 149 (5), 148 (6), 126 (5), 125 (25), 124 (74), 123 (5), 113 (5),

110 (5), 109 (23), 97 (38), 80 (16), 77 (16), 65 (13), 51 (14).

IR (ATR): = γ841 (vw), 3073 (vw), 2985 (w), 2932 (w), 2646 (vw), 2253 (vw), 2109 (vw), 1916

(vw), 1819 (vw), 1564 (vs), 1450 (m), 1364 (vs), 1301 (vs), 1159 (w), 1071 (w), 1001 (s), 955

(m), 858 (s), 812 (vs), 760 (vs), 694 (s) cm-1.


167

EA: calc. for C10H10N2OS: C 58.23%, H 4.89%, N 13.58%; found: C 57.85%, H 4.83%, N

13.23%.

N-Acetyl-S-methyl-S-(2-thiophenyl)sulfilimine (28ac)

Prepared from 2-(methylsulfanyl)thiophene (1ac) according to the general procedure E, the

compound was obtained as a brown oil in 13% yield after column chromatography (eluent:



(d, J = 0.9 Hz, 3H), 2.05 (d, J = 1.0 Hz, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.3, 135.2, 132.9, 132.6, 127.6, 36.5, 24.2 ppm.

MS (EI, 70 eV): m/z (%) = 190 (7), 189 (7), 188 (75), 187 ([M]+, 1), 172 (13), 146 (23), 132 (9),

131 (11), 130 (94), 115 (21), 103 (15), 90 (5), 89 (5), 88 (100), 71 (17), 47 (6), 45 (5).

IR (ATR): = 3912 (vw), 3424 (w), 3075 (w), 3004 (vw), 2922 (vw), 2322 (vw), 2098 (vw), 1923

(vw), 1665 (vw), 1565 (vs), 1408 (m), 1359 (s), 1297 (vs), 1087 (vw), 990 (s), 849 (w), 795 (s),

724 (vs) cm-1.

HRMS (ESI): calc. for C7H9NOS2Na [M+Na]+: 210.0023, found: 210.0018.

4.3.14. Synthesis of N-acetylsulfilimineacrylates

General procedure F


168

A sealed tube was charged with N-acetylsulfilimine 28 (0.38 mmol, 1.5 equiv.), acrylate 63

(0.25 mmol, 1.0 equiv.), silver carbonate (69 mg, 0.25 mmol, 1.0 equiv.), the catalyst

[RhCp*(MeCN)3][SbF6]2 (5.2 mg, 6.3 µmol, 2.5 mol%) and dry toluene (2.0 mL). After

degassing the reaction mixture for 5 min, it was stirred at 100 °C for 16 h. After cooling to room

temperature, the solvent was evaporated under reduced pressure and purification by column

chromatography (eluent: EtOAc/MeOH, substrate dependent) yielded the product 137.

Butyl-3-(2-(N-acetyl-S-methylsulfinimidoyl)phenyl)acrylate (137a)

Prepared from N-acetyl-S-methyl-S-phenylsulfilimine (28a) according to the general procedure

F, the compound was obtained as a yellow solid in 73% yield after column chromatography

(eluent: EtOAc to EtOAc/MeOH 100:3).

M.p.: 88–89 °C

1H NMR (600 MHz, CDCl3): = 8.17 (d, J = 15.7 Hz, 1H), 7.96–7.92 (m, 1H), 7.65 (dd, J =

7.5, 1.6 Hz, 1H), 7.61–7.46 (m, 2H), 6.48 (d, J = 15.7 Hz, 1H), 4.22 (td, J = 6.7, 1.5 Hz, 2H),

2.72 (s, 3H), 2.13 (s, 3H), 1.72–1.65 (m, 2H), 1.42 (s, 2H), 0.95 (t, J = 7.4 Hz, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.1, 165.9, 137.8, 135.6, 134.7, 132.2, 131.5, 127.7, 125.8,

123.9, 65.1, 33.8, 30.8, 24.2, 19.3, 13.9 ppm.

MS (EI, 70 eV): m/z (%) = 309 (11), 308 (64), 307 ([M]+, 25), 293 (5), 292 (29), 264 (6), 251

(6), 250 (34), 248 (5), 234 (7), 219 (6), 218 (7), 208 (7), 207 (15), 206 (84), 203 (11), 194 (8),

193 (6), 192 (28), 191 (7), 178 (8), 177 (12), 176 (7), 166 (7), 165 (43), 164 (50), 163 (9), 162

(8), 161 (5), 159 (8), 151 (8), 150 (8), 150 (25), 149 (37), 148 (39), 147 (100), 146 (22), 137

(6), 136 (11), 135 (22), 134 (41), 121 (9), 119 (9), 118 (10), 117 (15), 116 (8), 115 (6), 103 (5),

102 (7), 91 (8), 90 (5), 89 (8), 88 (40), 57 (22).

IR (ATR): = 3837 (vw), 3415 (vw), 3063 (vw), 2955 (s), 2871 (m), 2662 (vw), 2325 (w), 2083

(w), 1991 (vw), 1918 (vw), 1712 (vs), 1634 (m), 1563 (vs), 1466 (s), 1363 (s), 1305 (vs), 1173

(vs), 1064 (w), 1020 (w), 976 (s), 933 (m), 867 (w), 800 (m), 757 (s), 687 (w) cm-1.



169

Butyl-3-(2-(N-acetyl-S-methylsulfinimidoyl)-5-chlorophenyl)acrylate (137c)

Prepared from N-acetyl-S-methyl-S-(4-chlorophenyl)sulfilimine (28c) according to the general

procedure F, the compound was obtained as a yellow solid in 50% yield after column

chromatography (eluent: EtOAc to EtOAc/MeOH 100:3).

M.p.: 120–121 °C

1H NMR (400 MHz, CDCl3): = 8.09 (d, J = 15.7 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.62 (d, J

= 2.1 Hz, 1H), 7.52 (dd, J = 8.6, 2.1 Hz, 1H), 6.48 (d, J = 15.7 Hz, 1H), 4.22 (t, J = 6.7 Hz, 2H),

2.71 (s, 3H), 2.11 (s, 3H), 1.73–1.64 (m, 2H), 1.46–1.37 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H) ppm.

13C NMR (101 MHz, CDCl3): = 182.2, 165.5, 138.8, 136.6, 136.2, 134.2, 131.5, 127.6, 127.4,

125.0, 65.2, 33.7, 30.8, 24.1, 19.3, 13.8 ppm.

MS (EI, 70 eV): m/z (%) = 342 ([M, 35Cl]+, 1), 181 (6), 90 (5), 89 (10), 88 (100), 75 (5), 71 (5),

69 (6), 62 (7), 58 (5), 57 (96), 56 (31), 55 (22), 51 (5), 47 (10), 45 (8).

IR (ATR): = 3836 (vw), 3420 (vw), 3063 (w), 2936 (s), 2710 (vw), 2295 (vw), 2088 (vw), 1908

(vw), 1719 (vs), 1637 (w), 1564 (vs), 1450 (s), 1300 (vs), 1181 (vs), 1096 (vw), 980 (s), 908

(m), 804 (s), 695 (w), 629 (w), 563 (vw) cm-1.

HRMS (ESI): calc. for C16H20NO3SClNa [M+Na]+: 364.0750, found: 364.0745.

Butyl-3-(2-(N-acetyl-S-methylsulfinimidoyl)-5-bromophenyl)acrylate (137d)

Prepared from N-acetyl-S-methyl-S-(4-bromophenyl)sulfilimine (28d) according to the general




170

M.p.: 123–124 °C


1H), 6.48 (d, J = 15.7 Hz, 1H), 4.22 (t, J = 6.7 Hz, 2H), 2.71 (s, 3H), 2.11 (s, 3H), 1.71–1.64

(m, 2H), 1.42 (dt, J = 15.0, 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.2, 165.5, 136.5, 136.3, 134.8, 134.4, 130.6, 127.4, 127.1,

125.1, 65.2, 33.6, 30.7, 24.1, 19.3, 13.8 ppm.

MS (EI, 70 eV): m/z (%) = 386 ([M]+, 2), 286 (9), 272 (6), 270 (5), 245 (5), 243 (6), 229 (5), 228

(12), 227 (30), 226 (12), 225 (28), 224 (5), 214 (8), 212 (7), 205 (14), 199 (5), 197 (6), 180 (9),

176 (5), 163 (10), 149 (6), 148 (19), 147 (11), 134 (11), 133 (10), 115 (5), 90 (6), 89 (14), 88

(100), 75 (6), 57 (54), 56 (6), 55 (6).

IR (ATR): = 3065 (vw), 2928 (m), 2869 (w), 2656 (vw), 2292 (vw), 2185 (vw), 2114 (vw),

1908 (vw), 1718 (s), 1637 (w), 1454 (m), 1406 (w), 1362 (w), 1299 (vs), 1185 (vs), 1072 (w),

978 (s), 932 (m), 876 (m), 804 (s), 743 (w), 686 (m) cm-1.

HRMS (ESI): calc. for C16H20NO3SBrNa [M+Na]+: 408.0245, found: 408.0240.

Butyl-3-(2-(N-acetyl-S-methylsulfinimidoyl)-4-bromophenyl)acrylate (137e)

Prepared from N-acetyl-S-methyl-S-(3-bromophenyl)sulfilimine (28e) according to the general



M.p.: 134–135 °C

1H NMR (600 MHz, CDCl3): = 8.08–8.02 (m, 2H), 7.67–7.63 (m, 1H), 7.51 (d, J = 8.4 Hz,

1H), 6.47 (d, J = 15.7 Hz, 1H), 4.22 (t, J = 6.7 Hz, 2H), 2.71 (s, 3H), 2.13 (s, 3H), 1.71–1.61

(m, 2H), 1.47–1.33 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.3, 165.7, 137.6, 136.7, 135.5, 133.3, 129.0, 128.6, 125.9,

124.2, 65.2, 33.8, 30.8, 24.1, 19.3, 13.8 ppm.


171

MS (EI, 70 eV): m/z (%) = 386 ([M]+, 1), 286 (6), 284 (6), 245 (8), 243 (9), 229 (5), 228 (10),

227 (19), 226 (9), 225 (15), 214 (6), 212 (6), 205 (9), 176 (6), 163 (7), 149 (5), 148 (16), 147

(11), 134 (11), 133 (8), 115 (5), 101 (5), 90 (7), 89 (18), 88 (100), 75 (7), 74 (5), 63 (6), 62 (7),

57 (71), 56 (14), 55 (11), 47 (7).

IR (ATR): = 3412 (vw), 3063 (w), 2950 (s), 2318 (vw), 2173 (vw), 2076 (vw), 1712 (vs), 1571

(vs), 1455 (s), 1300 (vs), 1182 (vs), 1067 (s), 969 (vs), 841 (vs), 790 (vs) cm-1.

HRMS (ESI): calc. for C16H20NO3SBrNa [M+Na]+: 408.0245, found: 408.0240.

Butyl-3-(2-(N-acetyl-S-methylsulfinimidoyl)-5-methylphenyl)acrylate (137h)

Prepared from N-acetyl-S-methyl-S-(4-methylphenyl)sulfilimine (28h) according to the general



M.p.: 115–116 °C

1H NMR (600 MHz, CDCl3): = 8.14 (d, J = 15.7 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.44 (s,

1H), 7.36 (d, J = 8.2 Hz, 1H), 6.45 (d, J = 15.7 Hz, 1H), 4.20 (t, J = 6.7 Hz, 2H), 2.69 (s, 3H),

2.39 (s, 3H), 2.09 (s, 3H), 1.71–1.63 (m, 2H), 1.46–1.36 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 181.9, 165.9, 142.9, 138.0, 134.6, 132.5, 132.4, 128.2, 125.9,

123.5, 65.0, 33.9, 30.8, 24.2, 21.4, 19.3, 13.8 ppm.

MS (EI, 70 eV): m/z (%) = 322 ([M]+, 1), 179 (6), 178 (5), 164 (5), 163 (8), 162 (8), 161 (25),

160 (5), 149 (7), 148 (13), 147 (14), 134 (5), 133 (12), 132 (5), 131 (7), 115 (10), 105 (6), 91

(8), 90 (5), 88 (71), 77 (6), 65 (5), 63 (5), 62 (5), 58 (5), 57 (100), 56 (21), 55 (14), 47 (9), 45

(5).

IR (ATR): = 3839 (vw), 3356 (vw), 2945 (s), 2644 (vw), 2316 (w), 2175 (vw), 2044 (w), 1912

(vw), 1709 (vs), 1636 (m), 1573 (vs), 1460 (m), 1298 (vs), 1176 (vs), 979 (vs), 875 (vw), 803

(vs) cm-1.



172

Butyl-3-(2-(N-acetyl-S-methylsulfinimidoyl)-5-methoxyphenyl)acrylate (137i)

Prepared from N-acetyl-S-methyl-S-(4-methoxyphenyl)sulfilimine (28i) according to the

general procedure F, the compound was obtained as a brown solid in 36% yield after column


M.p.: 129–130 °C


(m, 2H), 6.44 (d, J = 15.7 Hz, 1H), 4.21 (t, J = 6.7 Hz, 2H), 3.85 (s, 3H), 2.70 (s, 3H), 2.08 (s,

3H), 1.73–1.63 (m, 2H), 1.47–1.35 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 181.8, 165.9, 162.6, 138.1, 136.6, 128.1, 126.4, 123.9, 117.6,

112.5, 65.0, 55.8, 34.2, 30.8, 24.2, 19.3, 13.8 ppm.

MS (EI, 70 eV): m/z (%) = 296 (19), 250 (15), 236 (5), 233 (7), 222 (11), 195 (6), 194 (5), 189

(10), 180 (9), 179 (12), 178 (21), 177 (59), 176 (7), 166 (5), 165 (10), 164 (25), 163 (5), 151

(6), 150 (14), 149 (77), 148 (8), 147 (9), 135 (7), 134 (11), 133 (5), 121 (23), 91 (6), 90 (6), 89

(12), 88 (86), 77 (8), 63 (7), 58 (5), 57 (100), 56 (7), 55 (8), 47 (6).

MS (CI, methane): m/z (%) = 366 ([M+C2H5]+, 20), 340 (7), 339 (20), 338 ([M]+, 100), 322 (5),

296 (5), 281 (12), 207 (9).

IR (ATR): = 3388 (vw), 2935 (m), 2312 (vw), 2100 (vw), 1995 (vw), 1921 (vw), 1698 (vs),

1576 (vs), 1467 (s), 1287 (vs), 1234 (vs), 1032 (vs), 975 (vs), 873 (s), 800 (s) cm-1.


Butyl-3-(2-(N-acetyl-S-methylsulfinimidoyl)-3-fluorophenyl)acrylate (137t)


173

Prepared from N-acetyl-S-methyl-S-(2-fluorophenyl)sulfilimine (28t) according to the general

procedure F, the compound was obtained as a white solid in 41% yield after column


M.p.: 118–119 °C

1H NMR (400 MHz, CDCl3): = 8.50 (d, J = 15.9 Hz, 1H), 7.56–7.49 (m, 1H), 7.42 (d, J = 7.8

Hz, 1H), 7.23–7.17 (m, 1H), 6.39 (d, J = 15.8 Hz, 1H), 4.20 (t, J = 6.7 Hz, 2H), 3.07 (s, 3H),

2.04 (s, 3H), 1.73–1.61 (m, 2H), 1.45–1.34 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H) ppm.

13C NMR (101 MHz, CDCl3): = 182.4, 165.8, 162.3 (d, J = 256.8 Hz), 139.3, 138.9 (d, J = 2.2

Hz), 134.4 (d, J = 9.7 Hz), 124.6, 123.9 (d, J = 3.1 Hz), 121.3 (d, J = 13.4 Hz), 118.5 (d, J =

21.9 Hz), 65.0, 30.8, 29.8 (d, J = 5.7 Hz), 23.7, 19.2, 13.8 ppm.

19F NMR (376 MHz, CDCl3): = ‒107.7 (dd, J = 10.2, 5.2 Hz) ppm.

MS (EI, 70 eV): m/z (%) = 372 (8), 328 (8), 327 (22), 326 (100), 325 ([M]+, 18), 310 (22), 284

(5), 282 (6), 268 (23), 252 (6), 225 (12), 224 (68), 221 (5), 212 (5), 210 (15), 195 (5), 183 (24),

182 (27), 168 (14), 167 (24), 166 (21), 165 (50), 164 (8), 154 (6), 153 (8), 152 (19), 136 (6),

135 (10), 88 (18), 57 (7).

IR (ATR): = 3849 (vw), 3633 (vw), 3331 (vw), 3062 (w), 2944 (m), 2699 (vw), 2491 (vw),

2281 (vw), 2095 (vw), 1967 (vw), 1697 (vs), 1641 (m), 1558 (vs), 1467 (m), 1306 (vs), 1243

(vs), 1178 (vs), 974 (vs), 793 (vs) cm-1.

HRMS (ESI): calc. for C16H20NO3SFNa [M+Na]+: 348.1046, found: 348.1040.

Phenyl-3-(2-(N-acetyl-S-methylsulfinimidoyl)phenyl)acrylate (137ag)

Prepared from N-acetyl-S-methyl-S-phenylsulfilimine (28a) according to the general procedure

F, the compound was obtained as a yellow solid in 45% yield after column chromatography

(eluent: EtOAc to EtOAc/MeOH 100:3).

M.p.: 165–166 °C


174


1H), 7.66–7.55 (m, 2H), 7.46–7.37 (m, 2H), 7.32–7.09 (m, 3H), 6.69 (d, J = 15.7 Hz, 1H), 2.76

(s, 3H), 2.13 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.1, 164.2, 150.6, 139.7, 136.2, 134.4, 132.4, 132.0, 129.6,

127.8, 126.1, 126.0, 122.8, 121.6, 33.8, 24.1 ppm.

MS (EI, 70 eV): m/z (%) = 328 ([M]+, 1), 312 (5), 235 (8), 234 (59), 206 (10), 194 (6), 193 (20),

192 (100), 178 (6), 177 (45), 165 (8), 164 (6), 161 (9), 150 (7), 149 (12), 148 (9), 147 (18), 146

(17), 145 (8), 137 (4), 136 (18), 135 (11), 134 (70), 133 (6), 121 (12), 118 (5), 117 (10), 116

(14), 115 (8), 109 (5), 103 (5), 102 (17), 95 (5), 94 (28), 93 (11), 91 (7), 90 (11), 89 (21), 88

(21), 77 (17), 76 (11), 75 (9), 71 (9), 70 (6), 69 (11), 66 (7), 65 (49), 63 (12), 62 (9), 57 (17), 56

(5), 55 (10), 51 (12), 50 (5), 47 (5), 45 (7).

IR (ATR): = 3843 (vw), 3369 (vw), 3062 (w), 2930 (w), 2660 (vw), 2315 (vw), 2108 (vw), 1989

(vw), 1874 (vw), 1736 (s), 1637 (w), 1562 (vs), 1476 (s), 1303 (vs), 1138 (vs), 983 (vs), 794

(vs) cm-1.


4-Methoxyphenyl-3-(2-(N-acetyl-S-methylsulfinimidoyl)phenyl)acrylate (137ah)

Prepared from N-acetyl-S-methyl-S-phenylsulfilimine (28a) according to the general

procedure F, the compound was obtained as a brown oil in 54% yield after column


1H NMR (600 MHz, CDCl3): = 8.36 (d, J = 15.7 Hz, 1H), 7.97 (dd, J = 7.8, 1.3 Hz, 1H), 7.75–

7.69 (m, 1H), 7.64–7.54 (m, 2H), 7.14–7.05 (m, 2H), 6.94–6.87 (m, 2H), 6.66 (d, J = 15.7 Hz,

1H), 3.80 (s, 3H), 2.75 (s, 3H), 2.12 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): = 182.1, 164.6, 157.5, 144.1, 139.5, 136.0, 134.4, 132.3, 131.9,

127.8, 125.9, 122.9, 122.3, 114.6, 55.7, 33.7, 24.1 ppm.


175

MS (EI, 70 eV): m/z (%) = 234 (15), 193 (7), 192 (54), 177 (31), 161 (8), 150 (5), 149 (11), 148

(9), 147 (16), 145 (5), 136 (15), 135 (13), 134 (100), 133 (6), 124 (16), 123 (94), 121 (13), 118

(7), 117 (7), 116 (15), 115 (11), 109 (12), 108 (9), 103 (5), 102 (23), 95 (62), 90 (13), 89 (21),

88 (19), 82 (6), 81 (5), 80 (12), 79 (5), 77 (10), 76 (10), 75 (9), 74 (5), 65 (16), 64 (9), 63 (17),

62 (8), 54 (9), 53 (8), 52 (17), 51 (11), 47 (5).

MS (ESI): m/z (%) = 398 (5), 382 (5), 381 (22), 380 ([M+Na]+, 100), 359 (9), 358 ([M]+, 44).

IR (ATR): = 3834 (vw), 3370 (vw), 2927 (w), 2315 (vw), 2103 (vw), 1858 (vw), 1732 (s), 1575

(vs), 1495 (s), 1302 (s), 1188 (s), 1128 (vs), 976 (vs), 767 (vs) cm-1.


Abbreviations

177

5. Abbreviations

8-AQ 8-aminoquinoline

Ac acetyl

acac acetylacetonate

AcOH acetic acid

AIBN azobisisobutyronitrile

aq. aqueous

Ar aryl

ATR attenuated total reflection or ataxia telangiectasia and RAD3-related

Boc tert-butyloxycarbonyl

BSO buthionine sulfoximine

c.m. complex mixture

ca. circa

cat. catalyst

Cbz carboxybenzyl

CDK cyclin-dependent kinase

CDI 1,1’-carbonyldiimidazole

CI chemical ionization

COD 1,5-cyclooctadiene

Cp* pentamethylcyclopentadiene

Cu(TC) copper(I) thiophene-2-carboxylate

d.r. diastereomeric ratio

DABCO 1,4-diazabicyclo[2.2.2]octane

dba dibenzylideneacetone

DBDMH 1,3-dibromo-5,5-dimethylhydantoin

DCDMH 1,3-dichloro-5,5-dimethylhydantoin

Abbreviations

178

DCE 1,2-dichloroethane

DCM dichloromethane

de diastereomeric excess

deg. degassed

DFT density functional theory

DMAP 4-dimethylaminopyridine

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DoM directed ortho metalation

DPH O-(2,4-dinitrophenyl)-hydroxylamine

dppf 1,1’-bis(diphenylphosphino)ferrocene

DTBP di-tert-butyl peroxide

dtbpy 4,4’-di-tert-butyl-β,β’-dipyridyl

e.r. enantiomeric ratio

EA elemental analysis

ee enantiomeric excess

EI electron ionization

ESI electrospray ionization

esp α,α,α’,α’-tetramethyl-1,3-benzenedipropionic acid

equiv. equivalent(s)

Et ethyl

et al. and others (lat.: et alii, et aliae)

EtOAc ethyl acetate

EtOH ethanol

Abbreviations

179

eV electron volt

GC gas chromatography

GP general procedure

h hour

HBpin pinacolborane

hERG human Ether-à-go-go-Related Gene

HOBt 1-hydroxybenzotriazole

HOSA hydroxylamine-O-sulfonic acid

HPLC high-performance liquid chromatography

HRMS high resolution mass spectrometry

HV high vacuum

Hz Hertz

IMes 1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride

iPrOAc isopropyl acetate

IR infrared spectroscopy

J coupling constant (in Hz)

M.p. melting point

m- meta-

m-CPBA meta-chloroperbenzoic acid

M metal or molar

Me methyl

MeCN acetonitrile

MeOH methanol

min minute(s)

mL milliliter

Abbreviations

180

MMPP magnesium monoperoxyphthalate

MS mass spectrometry or molecular sieve

Ms mesyl

MSO methionine sulfoximine

MSH O-mesitylsulfonylhydroxylamine

MTBE methyl tert-butyl ether

n.d. not determined

n.r. no reaction

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

nep neopentyl glycolato

NHC N-heterocyclic carbene

NMR nuclear magnetic resonance

Ns nosyl

nta (S)-N-1,8-naphthoylalanine

nttl tetrakis(N-1,8-naphthoyl-tert-leucinate)

o- ortho-

OAc acetate

Opiv O-pivalate

p- para-

Ph phenyl

PIDA phenyliodine diacetate, PhI(OAc)2

pin pinacolato

ppm parts per million

PTFE polytetrafluoroethylene

Abbreviations

181

Rf retardation factor

rt room temperature

sat. saturated

SN2 bimolecular nucleophilic substitution

TBHP tert-butyl hydroperoxide

Tces trichloroethoxysulfonyl

TCICA trichloroisocyanuric acid

tert-AmOH tert-amyl alcohol

TEA triethylamine

Tf triflate TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

TLC thin layer chromatography

TM transition metal

TMEDA N,N,N’,N’-tetramethylethane-1,2-diamine

TMS- trimethylsilyl-

Tol tolyl

TPP tetraphenyl porphyrin

Ts tosyl

UV ultraviolet

vs versus

wt% percentage by mass

chemical shift (in ppm)

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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

08/1999 – 06/2008 Abitur, Gymnasium Moltkestraße, Gummersbach

08/1995 – 06/1999 Elementary School, Freie Christliche Bekenntnisschule Gummersbach

Experience

Since 04/2014 Researcher, Institute of Organic Chemistry, RWTH Aachen University

04/2012 – 11/2012 Research assistant, Catalytic Center, Institute for Technical and Macromolecular Chemistry, RWTH Aachen University

Scholarships

12/2016 GDCh and GSK travel grant, ICOS 21, Mumbai, India

05/2016 – 07/2016 DAAD short-term doctoral scholarship, Edinburgh, Scotland

method development for the synthesis of organosulfur

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