Selective Transformations of Sulfondiimines Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der RWTH Aachen University zur Erlangung des akademischen Grades einer Doktorin der Naturwissenschaften genehmigte Dissertation vorgelegt von Master of Science Rebekka Anna Bohmann aus Düsseldorf, Deutschland Berichter: Univ.-Prof. Dr. rer. nat. Carsten Bolm Univ.-Prof. Dr. rer. nat. Dieter Enders Tag der mündlichen Prüfung: 01.03.2017 Diese Dissertation ist auf den Internetseiten der Universitätsbibliothek online verfügbar.
Transcript
Selective Transformations of Sulfondiimines
Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der
RWTH Aachen University zur Erlangung des akademischen Grades einer Doktorin
der Naturwissenschaften genehmigte Dissertation
vorgelegt von
Master of Science
Rebekka Anna Bohmann
aus Düsseldorf, Deutschland
Berichter:
Univ.-Prof. Dr. rer. nat. Carsten Bolm
Univ.-Prof. Dr. rer. nat. Dieter Enders
Tag der mündlichen Prüfung: 01.03.2017
Diese Dissertation ist auf den Internetseiten der Universitätsbibliothek online verfügbar.
The work presented in this thesis was carried out from October 2012 to December 2016 at the
Institute of Organic Chemistry of RWTH Aachen University under the supervision of Professor
Dr. Carsten Bolm. Part of the work presented in chapter 4.2 and 7 was conducted from March
to May 2015 at the Department of Applied Chemistry of the Graduate School of Engineering of
Osaka University under the supervision of Professor Dr. Masahiro Miura.
I would like to express my deepest gratitude to Prof. Dr. Carsten Bolm for the opportunity to
choose and work on challenging and exciting projects under excellent working conditions, and
for his continuous support during my doctoral studies in Aachen. In addition, I thank Prof. Dr.
Masahiro Miura for giving me the opportunity to work in his group on highly interesting topics.
Furthermore, I would like to thank Prof. Dr. Dieter Enders for delivering a second expert opin-
ion. I am grateful to the Deuts he Fors hu gsge ei s haft (international research training
group 1628: Selectivity in Chemo- and Biocatalysis ) for financial support during this doctoral
thesis.
Parts of this work have already been published:
R. A. Bohmann, C. Bolm, Org. Lett. 2013, 15, 4277–4279.
C. M. M. Hendriks, R. A. Bohmann, M. Bohlem, C. Bolm, Adv. Synth. Catal. 2014, 356, 1847–1852.
R. A. Bohmann, Y. Unoh, M. Miura, C. Bolm, Chem. Eur. J. 2016, 22, 6783–6786.
R. A. Bohmann, J.-H. Schöbel, C. Bolm, Synlett 2016, 27, 2201–2204.
Für meine Familie
T a b l e o f C o n t e n t s | I
Table of Contents
I. INTRODUCTION .......................................................................................................... 1
Sulfur (also spelled as sulphur) represents one of the few solid elements existing in nature in its
elemental state, and it is the 16th most abundant element in the earth crust. Often occurring as
brilliant yellow powder, it can be found in pure form in regions with high volcanic activity (Fig-
ure I). From ancient times, sulfur was well-known; medieval alchemists referred to sulfur as any
flammable substance. Already the Roman historian Pliny described the mining of sulfur in Italy
and Sicily, regions with high volcanic activity and its applications in medicine, bleach, matches,
and lamp wicks.[1]
Figure I: Sulfur deposits around steaming sulfur dome on volcanic solfatara vent. Mount Io (Io-zan, 硫黄
山, lit. "Sulfur Mountain"), Kussharo caldera, Akan National Park, Hokkaido, Japan. Copyright 2015,
Rebekka Anna Bohmann.
Sulfur has a highly variable, diverse chemistry of high importa e i toda ’s world. Sulfur com-
pounds are utilized in numerous chemical manufacturing processes, such as the production of
agricultural fertilizers, iron, steel, and paint pigments. Approximately 90% of all sulfur is applied
to the manufacture of sulfuric acid (H2SO4), which is the most abundant industrial chemical in
the world.[2] Various sulfur derivatives exist differing in the oxidation state at the sulfur atom (II,
IV, or VI). Among them are the tetracoordinated sulfur(VI) derivatives.
1 Sulfur (VI) Derivatives
From formal exchanges of the oxygen atoms of sulfones by nitrogens result the aza-analogous
sulfoximines and sulfondiimines, wherein the hexavalent sulfur atom forms two formal double
bonds with oxygen or nitrogen atoms and a single bond to each of the two carbon atoms (Fig-
ure 1-1).[3]
2 | I n t r o d u c t i o n
Figure 1-1: The diaza analogs of sulfones are the objectives of this thesis.
The sulfones represent an intensively investigated compound class (3124370 substance entries
in Scifinder®),[4] well-known for their applications in organic chemistry[3, 5] or as biologically ac-
tive compounds incorporated in drugs and agrochemicals.[6] Despite the potential stereogenic
center and increased structural variability of sulfoximines and sulfondiimines (Figure 1-1), to
date, both compound classes have been less frequently explored compared to sulfones. In di-
rect comparison, sulfoximines are more established than sulfondiimines (substance entries in
Scifinder®: 68069 versus 1343);[4] they have been applied in synthetic organic chemistry as chi-
ral auxiliaries and ligands,[7] in medicine, and in crop protection.[8] Exchanging the oxygen atom
of sulfoximines with a nitrogen atom leads to the structurally related sulfondiimines.[9]
1.1 Sulfondiimine derivatives
Despite the numerous valuable properties sulfondiimines exhibit, they have received only mar-
ginal interest from the scientific community to date, and their syntheses and applications ap-
pear significantly restricted. This chapter represents an introduction into sulfondiimine deriva-
tives with reviews about their syntheses, N-functionalization reactions, and applications.
Classification and nomenclature
In this thesis, several sulfondiimine subclasses will be differentiated, which vary in the substitu-
tion of the nitrogen atoms—N-unsubstituted (NH,N'H-), N-monosubstituted (NH-), and N,N'-
disubstituted sulfondiimines—or the sulfur—S,S-dialkyl, S-alkyl-S-aryl, and S,S-diaryl sul-
fondiimines (Figure 1-2).
Figure 1-2: Nomenclature of sulfondiimine subclasses.
I n t r o d u c t i o n | 3
Properties and reactivity
Sulfondiimines show versatile reactivities comparable to that of sulfoximines, including nucleo-
philic and basic nitrogen atoms and acidic hydrogen atoms at the nitrogen and in -position to
the sulfur atom. In contrast to the well-known structurally related sulfones, sulfoximines and
sulfondiimines possess a potentially stereogenic center at the sulfur atom (Figure 1-3).
Figure 1-3: Properties and reactivity of the sulfondiimine functional group.
Protonations of S,S-dialkyl NH,N'H-sulfondiimines 1 result in the formation of sulfonium salts 2
and their subsequent decompositions by C‒“ o d lea age in highly acidic and polar media
(Scheme 1-1). The pKa values of sulfonium salts 2 have been calculated from potentiometric
titrations and range from 5.26 to 5.93, indicating the weak basicity of the nitrogen atoms of
sulfondiimines 1.[10]
Scheme 1-1: Decomposition of S,S-dialkyl sulfondiimines 1 in acidic and polar media.[10]
Under certain conditions, sulfondiimines readily undergo deiminations (Scheme 1-2). For ex-
ample with elemental sulfur in liquid ammonia, N-unsubstituted and NH-N'-tosylated sul-
fondiimines 8 and 9 were reduced to the corresponding sulfides 10 and the N-tosylated sul-
filimines 11, respectively, at 100 °C after 2 h (path a).[11] Interestingly, different aromatic disul-
fides 12 were obtained by the degradation of S-(4-nitrophenyl) sulfondiimines 8 and 9 at 60 °C
after two to three hours (path b).[12]
4 | I n t r o d u c t i o n
Scheme 1-2: Deiminations of sulfondiimines occurred with elemental sulfur in liquid ammonia.[11-12]
The reduction of different S,S-diaryl or S-aryl-S-alkyl sulfondiimines 13 with tert-butyl nitrite in
chloroform or dichloromethane afforded N-tosylated sulfilimines 14 in almost quantitative
yields (Scheme 1-3).[13]
Scheme 1-3: Reduction of sulfondiimines 13 with tert-butyl nitrite in chloroform.[13]
Structure
The sulfone-analogous structure of sulfondiimines has firstly been proved for N-unsubstituted
S,S-dimethyl sulfondiimine 15 by X-ray crystallography (Figure 1-4)[14] and electron diffraction in
the gas phase.[10, 15]
Figure 1-4: Crystal structure of NH,N'H-S,S-dimethyl sulfondiimine (15).[14]
Both studies revealed a tetrahedral configuration around the sulfur atom (C2v, local symmetry),
hereas a ide ed N‒“‒N o d a gle r stal: ± °; gas: . ± . ° i di ates i tera tio of the nitrogen lone electron pairs. The “‒N dista es represent typical values for double bonds
(crystal: 1.53 ± 0.04 Å, gas: 1.533 ± 0.002 Å).[10, 15] In addition, NH,N'H-sulfondiimine 1 as a polar
functional group has been reported to undergo intermolecular hydrogen bonding in the crystal-
line state and in solution.[10]
I n t r o d u c t i o n | 5
The “‒N o d le gths o ser ed for N-H-N',S,S-triphenyl sulfondiimine [16; S‒N (N-Ph): 1.546 ±
0.001 Å, S‒N (N-H): 1.526 ± 0.002 Å] by YOSHIMURA and coworkers[16] and N-H-N',S-diphenyl-S-
methyl sulfondiimine (17; “‒N : . 88 ± 0.0017 Å, Figure 1-5), subjected to X-ray analysis as
the standard substrate of this thesis (chapter 7.1), are comparable to those observed for 15
(Figure 1-4).[16] In both cases, the “‒N dista e to the phenyl-substituted nitrogen appears
longer than that to the unsubstituted nitrogen, indicating lo er “‒N o d stre gth.
Figure 1-5: The molecular structure of N-H-N',S-diphenyl-S-methyl sulfondiimine (17).
Although the ature of the “‒N bonds in these structures is still under discussion, ranging from
semipolar single bonds to essentially covalent double bonds,[3] the doubly bonded description
will be used in this thesis.
1.1.1 Syntheses
This chapter will summarize the synthetic access to NH,N'H-sulfondiimines 18 and
N-monosubstituted sulfondiimines 19. The success of the particular imination methods strongly
depends on the substitution patterns at the sulfur atoms of the resulting S,S-dialkyl, S-alkyl-S-
aryl, and S,S-diaryl sulfondiimines (Scheme 1-4).
Scheme 1-4: Overview on the synthesis of sulfondiimine derivatives.
Sulfondiimines can be synthesized from different starting materials: sulfides 20, sulfilimines 21
and their derivatives 22|23, and S-fluorothiazynes 24. The particular imination strategies in-
volve different iminating agents.
6 | I n t r o d u c t i o n
Bisimination of sulfides
The first synthetic approach towards sulfondiimines was reported by COGLIANO and BRAUDE in
1964. Accidentally, they obtained S,S-dialkyl sulfondiimines 1 by the chloroamination of com-
mercially available dialkyl sulfides 25 (Scheme 1-5) in 2-propanol, and reported sulfiliminium
salts as the key intermediates of this transformation.[17] Subsequently, the selectivity of the
oxidative bisimination towards sulfondiimines 1 was enhanced by APPEL and coworkers in
1966[18] and LAUGHLIN and YELLIN in 1967.[19] Both groups succeeded in precluding the for-
mation of sulfones and sulfoximines as the major byproducts from moisture and hydroxylic sol-
vents by performing the reactions in dry acetonitrile. From some synthetic procedures, the hy-
drochlorides of the desired sulfondiimines resulted as well. The treatment with aqueous sodi-
um carbonate solutions for deprotonation and extraction with DCM delivered the desired sul-
fondiimines.
Scheme 1-5: Synthesis of NH,N'H-S,S-dialkyl sulfondiimines 1 by the chloroamination of sulfides 25.[17-19]
Disadvantageously, these protocols involved the generation of chloramine from gaseous chlo-
rine and ammonia, whereas the sulfondiimines were usually obtained in unpredictable and low
yields. As improvement, HAAKE and coworkers in 1970 reported the in situ generation of chlo-
ramine (NH2Cl) in dry acetonitrile from tert-butyl hypochlorite and liquid ammonia (Scheme
1-6). While this procedure proved readily applicable to the synthesis of several S,S-dialkyl sul-
fondiimines (12–85% yield),[20] the yields of S-alkyl-S-aryl sulfondiimines were low (14–26%),
and S,S-diaryl derivatives remained inaccessible.[10]
Scheme 1-6: The in situ generation of chloramine for the synthesis of sulfondiimines 18 was developed
by HAAKE and coworkers. [10, 20]
This result coincides with the work of FURUKAWA, OAE and coworkers, who failed to synthesize
S,S-diphenyl sulfondiimine from diphenyl sulfide and a combination of tert-butyl hypochlorite
and ammonia in dichloromethane. In lieu thereof they could identify S,S-diphenylsulfilimino-
S,S-diphenylsulfonium chloride (26) as the unexpected product (Scheme 1-7).[21]
Scheme 1-7: Attempted synthesis of S,S-diphenyl sulfondiimine by FURUKAWA and coworkers.[21]
I n t r o d u c t i o n | 7
Imination of S-fluorothiazynes
As an alternative to the sulfides as substrates, YOSHIMURA and coworkers in 1992 firstly re-
ported the preparation of S,S-diarylated S-fluorothiazynes such as 27 (Scheme 1-8) by the reac-
tion of N-bromo-S,S-diphenylsulfilimines with tetrabutylammonium fluoride (TBAF) at 0 °C in
dry tetrahydrofurane. From reactions of S,S-diphenylated S-fluorothiazyne 27 with excess
amounts of primary aryl- and alkylamines 28 (Scheme 1-8) the corresponding S,S-diaryl NH-
sulfondiimines 29 were accessed in mainly good yields (37–79%). With ammonia as the reagent,
the structurally related sulfoximine represented the major product (66% yield), whereas the
desired N-unsubstituted sulfondiimine 29a was obtained only in a low yield (23%).[22]
Scheme 1-8: S-Fluorothiazyne 27 served as alternative substrate for the synthesis of S,S-diphenyl sul-
fondiimines 29.[16, 22]
As advancement, in 2008 the same group further improved the structural variety and yields of
the products 29 (74–98%) by the use of acid catalysts or base under solvent-free conditions.
Nevertheless, the scope of sulfondiimines obtained from YOSHIMURA’s method remained re-
stricted to S,S-diphenylated products 29 (Scheme 1-8).[16]
Imination of sulfilimines
Sulfilimines and their derivatives, which are accessible from the imination of sulfides with a
range of iminating agents,[23] have been employed as alternative starting materials in the syn-
thesis of sulfondiimines.
In 1971, APPEL and KOHNKE employed S,S-dimethylsulfilimine 30 in a transformation with in
ethyl sulfondiimines (45%) as hydrates in moderate yields.[24]
Scheme 1-9: Syntheses of N-alkylated S,S-dimethyl sulfondiimines 31 from sulfilimine 30.[24]
In addition, OAE and coworkers intensively investigated the oxidative imination of diaryl-
sulfilimines. Inspired by the chemistry of sulfoximines, initial attempts included electrophilic
oxidative iminations of S,S-diphenyl sulfilimine 32 (Scheme 1-10) with hydrazoic acid (path a) or
O-mesitylenesulfonylhydroxylamine (MSH; path b) and nucleophilic oxidative imination with a
combination of MSH and sodium carbonate (path c). However, at no time the desired sul-
fondiimine 29a was observed.[21]
8 | I n t r o d u c t i o n
Scheme 1-10: Initial attempts of OAE and coworkers for the synthesis of S,S-diphenyl sulfondiimine 29a
failed.[21]
In contrast, with sodium N-chloro 4-methylbenzenesulfonamide (chloramine-T) and excess so-
dium tosylamide the oxidative imination of sulfilimines 21 towards N-tosyl-protected sul-
fondiimines 33 proved successful (Scheme 1-11). As initial attempts were performed in metha-
nol, an S,S-diphenyl (54%) and an S,S-cyclohexyl sulfondiimine (33%) were obtained in nonsatis-
fying yields due to the formation of nonseparable sulfoximines byproducts.[25] Similar to the
chloroaminations of sulfides (Scheme 1-5),[18-19] the byproduct formation in the oxidative imina-
tion of sulfilimines was anticipated under strictly anhydrous reaction conditions in
acetonitrile.[26]
Scheme 1-11: Synthesis and deprotection of N-tosyl sulfondiimines 33.[25-26]
While this protocol proved readily applicable to the preparation of S,S-diarylated products in
good yields (31–90% yield), the yields of two S-aryl-S-alkyl sulfondiimines were lower (44–45%),
and no S,S-dialkyl sulfondiimine was reported. Advantageously, cleavage of the tosyl group
readily proceeded under acidic conditions, giving NH,N'H-sulfondiimines 8 in almost quantita-
tive yields (Scheme 1-11).[26]
During these studies, S,S-diphenyl-N-chlorosulfilimine (34) was detected by HPLC, and isolated.
As it readily reacted with nitrogen nucleophiles in dry acetonitrile, affording N-tosyl as well as
NH,N'H- and N-alkyl sulfondiimines 29 (Scheme 1-12), it was suggested as key intermediate of
the oxidative imination process.[21]
Scheme 1-12: Reactivity of N-chlorosulfilimine (34) with different nitrogen nucleophiles towards sul-
fondiimine derivatives 29.[21]
I n t r o d u c t i o n | 9
Under related conditions (Scheme 1-11; R1 = Me, R2 = para-tolyl), CHRISTENSEN and KJÆR re-
ported about the treatment of (R)-S-methyl-S-(para-tolyl)-sulfilimine [(R)-35] with chloramine-T
in liquid ammonia, affording the laevorotatory enantiomer of optically active N-tosyl-S-methyl-
S-(para-tolyl)-sulfondiimine [ ‒ -36]. As the resolution of racemic 36 failed, ‒ -36 was convert-
ed with nitrous acid (HNO2), a process known to proceed with retention of the configuration for
structurally related sulfoximines. As the reaction afforded sulfilimine (S)-35, (S)-configuration of
‒ -36 was proposed.[27] Comparable to OAE and coworkers,[26] YAGUPOL'SKII and coworkers
performed the oxidative imination of S,S-diphenylsulfilimine (32) in dry acetonitrile with sodium
N-chlorotriflamide as the iminating agent, affording sulfondiimine 37 in 85% yield (Scheme
1-13).[28]
Scheme 1-13: Synthesis of N-triflyl-protected sulfondiimine 37 by YAGUPOL'SKII and coworkers.[28]
Imination of sulfiliminium salts
A limiting factor for the scope of sulfondiimines accessible from free sulfilimines 21 and particu-
larly from their N-halo derivatives 22 (Scheme 1-4) is the lability of these substrates; notably,
violent decompositions of both have been reported in the literature.[17-18, 21]
As advancement, HAAKE and GEORG in 1983 reported the possibility of replacing free sul-
filimines 21 by their readily accessible and more stable salts 23 (Scheme 1-14). In the one-step
synthesis of NH,N'H-sulfondiimines with tert-butyl hypochlorite and liquid ammonia in acetoni-
trile, these salts gave comparable yields to the free sulfilimines as substrates. This protocol
proved suitable for the synthesis of S,S-diaryl sulfondiimines (36–57% yield) and two S-aryl-S-
alkyl sulfondiimines (21–60% yield). Noteworthy, the synthesis of S-methyl-S-(para-nitrophenyl)
sulfondiimine and of S,S-diaryl derivatives with electron-withdrawing substituents failed for this
procedure, and no S,S-dialkyl derivative was reported.[29]
Scheme 1-14: One-step synthesis of NH,N'H-sulfondiimines 18 from sulfiliminium salts 23.[29]
In summary, the most efficient synthetic approaches to sulfondiimines existed for
S,S-dialkylated and S,S-diarylated derivatives, whereas the access to S-aryl-S-alkyl sul-
fondiimines remained most challenging. To overcome this limitation, in 2012 BOLM and
coworkers developed a general one-pot oxidative imination protocol for sulfiliminium salts 23
(Scheme 1-15).[30]
10 | I n t r o d u c t i o n
In this process, in situ generated free sulfilimines underwent chlorination–imination sequences
facilitated by N-chlorosuccinimide (NCS) and primary amines. In related computational studies,
an S-chloro-S,S-dialkylnitridosulfane was proposed as the reactive intermediate of this reaction
process.[31] As the method proved generally applicable to different amines 28 and sulfiliminium
salts 23, it provided access to various N-monosubstituted sulfondiimines 19 in moderate to
good yields (27–80%).
Scheme 1-15: A general protocol for the synthesis of NH-sulfondiimines 19 from sulfiliminium salts 23
was developed by BOLM and coworkers.[30]
The significant functional–group tolerance included electron–donating as well as electron–withdrawing substituents. For instance, amines 28 with free hydroxyl or alkynyl moieties could
be applied. While various substituents on the aryl group of a range of synthetically challenging
S-alkyl-S-aryl derivatives were well-tolerated, electron-rich substrates gave the best results. It is
noteworthy that also representative NH,N'H-, S,S-dialkyl, and S,S-diaryl sulfondiimines 19 have
been prepared. In contrast to previous work,[27] a resolution of (rac)-N-phenyl-S-methyl-S-
phenyl sulfondiimine 17 by chiral supercritical-fluid chromatography (SFC) readily afforded
enantiomerically pure sulfondiimines (S)-17 and (R)-17, whose absolute configurations were
determined by the comparison of calculated and measured ECD spectra (Scheme 1-16).[30]
Scheme 1-16: Enantiomerically pure sulfondiimines with the stereogenic center at the sulfur atom.[30]
The N-unsubstituted and N-monosubstituted sulfondiimine derivatives accessible from differ-
ent precursors as illustrated in this chapter represent polyfunctional groups allowing a variety
of transformations. To date, mainly N-functionalization reactions have been investigated.
1.1.2 N-Functionalization reactions
Due to their weakly basic and nucleophilic functionalities, N-unsubstituted and
N-monosubstituted sulfondiimines undergo substitution reactions on the nitrogen atoms with
various electrophiles. Strongly depending on the particular conditions, N-functionalizations to-
wards N-monosubstituted (19) or N,N'-disubstituted (38) sulfondiimines as discussed in this
chapter (Scheme 1-17)[32] or cyclizations (chapter 1.1.3.3) can occur. In particular, NH,N'H-S,S-
dialkyl sulfondiimines 1 were employed as a model substrate for N-functionalization
reactions.[10]
I n t r o d u c t i o n | 11
Scheme 1-17: Overview on the N-functionalization reactions of sulfondiimines.
N-Halogenations
In the context of N-halogenation reactions (Scheme 1-18), the treatment of S,S-dimethyl sub-
strate 15 with halogens X2 afforded N-mono- (39, X = Br)[18] and N,N'-dihalogenated derivatives
40 (X = Cl, Br, I).[33] As they readily exchange halogen atoms with nucleophilic compounds of
various elements E (E = P, As, S, Se, Te), N-halogen sulfondiimines 39 and 40 appear as interest-
ing substrates for the synthesis of different N-substituted sulfondiimines; however, the serious
explosion hazard involved dramatically reduces their applicability.[34]
Scheme 1-18: N-Halogenations of NH,N'H-S,S-dimethyl sulfondiimine (15).[10, 18, 33-34]
N-Metalations
In particular, NH,N'H- and N-silylated sulfondiimines have been N-metallated with different
organometallic reagents (M = Al, Ge, Sn). Generally, the metal-complexing abilities of NH,N'H-
sulfondiimines 1 were reported to parallel those of aliphatic amine oxides for various metals M
(M = V, Cr, Fe, Cu)[19] except for silver and mercury; with both, they form insoluble
precipitates.[10] Of interest for subsequent N-alkylations (Scheme 1-25), with use of strong ba-
ses such as potassium amide in liquid ammonia[35] or sodium hydride in toluene,[10] monoalkali
salts 41 of S,S-dialkyl sulfondiimines 1 have been isolated (Scheme 1-19).
Scheme 1-19: N-Metalations of S,S-dialkyl sulfondiimines 1 afforded monoalkali metal salts 41.[10, 35]
12 | I n t r o d u c t i o n
Formation of N‒E bonds (E = Si, P, B, As, N, S)
Furthermore, especially NH,N'H- (1) and N-halogenated sulfondiimines 39 or 40 have been
combined with different organoelementary (E = Si, P, B, As) reagents, and various applications
of the N-functionalized products in the synthesis of variable sulfur-nitrogen-E-containing het-
erocycles have been reported.[10] In addition, nitrations of N-unsubstituted or N,N'-disilylated
sulfondiimines were reported to proceed with nitronium tetrafluoroborate or dinitrogen pent-
oxide in acetonitrile and to afford N,N'-dinitrated sulfondiimines (E = N).[36]
Of special interest as precursors of N-sulfenylaziridines (Scheme 1-33), N-sulfenyl sul-
fondiimines 42 proved accessible from S,S-diphenyl-N-tosyl sulfondiimine (29b) with arenesul-
fenyl chlorides 43 under basic conditions (Scheme 1-20).[37]
Scheme 1-20: N-Sulfenylations of sulfondiimines 29b by YOSHIMURA and coworkers.[37]
C‒N Bond formations
In close relation to S,S-dialkyl NH,N'H-sulfondiimines 1 applied in heterocyclic chemistry (chap-
ter 1.1.3.3), of special interest for this thesis, sulfondiimines can undergo C‒N bond-forming
reactions with a variety of electrophilic carbon sources.
As such, condensations of substrates 1 with cyanogen chloride[34] (N-cyanations), amino
acids[38] (Scheme 1-34), and acyl anhydrides or halides[39] (N-acylations) have been investigated.
Contextually, N-mono- (44) and N,N'-disubstituted sulfondiimines 45 were obtained in 80 to
100% yield from additions to heterocumulenes 46, whereas synthetic access to asymmetric bis-
adducts 45 was facilitated by the addition of a different isocyanate 47 to NH-sulfondiimine 44
(R3 ≠ R4, N-carbamoylations; Scheme 1-21).[10]
Scheme 1-21: N-Carbamoylations of sulfondiimines with isocyanates.[10]
More recently, an organocatalytic kinetic resolution of NH-sulfondiimine 17 with enal 72 was
reported by BOLM and coworkers. Depending on the catalyst, N-substituted product 38 was
obtained with –75% ee (with catalyst I) or 58% ee (with catalyst II). Disadvantageously, with
both catalysts unreacted substrate 17 was recovered with low ee values (Scheme 1-22).[40]
I n t r o d u c t i o n | 13
Scheme 1-22: Kinetic resolution of a sulfondiimine by BOLM and coworkers.[40]
Furthermore, reactions of sulfondiimines 1 with differently substituted cyanoimidates 48
(Scheme 1-23) have been reported by RIED and JACOBI,[41] and HAAKE and coworkers.[42]
Scheme 1-23: Overview on the N-functionalizations of sulfondiimines 1 with cyanoimidates 48.[41-42]
In the same context, some N-alkenylations of sulfondiimines 1 were reported. As such, N-alk-1-
enyliminosulfur compounds 50-52 were obtained from reactions with dimethyl acetylenedicar-
boxylate (53) in THF[10], ,β-unsaturated ketones 54[43], and nitriles 55
[44] (Scheme 1-24).
Scheme 1-24: N-Alkenylations of sulfondiimines 1 with activated alkyne 53 or alkenes 54|55.[10, 43-44]
14 | I n t r o d u c t i o n
N-Alkylations
Of special interest regarding the biological activity of the products (chapter 1.1.3.1) is the sur-
prisingly unexplored synthetic access towards N-(amino)alkylated sulfondiimines. To improve
the low basicity and nucleophilicity of the sulfondiimine nitrogens, N-alkylations of sul-
fondiimines predominantly started from the corresponding monoalkali metal salts 41 (Scheme
1-19).[10]
One of the scarce N-alkylations of sulfondiimines was reported by APPEL and ROSS in 1969.
While the use of ethyl iodide resulted in low product yields, by employing ethyl bromide for the
alkylation of NH,N'H-S,S-dimethyl-sulfondiimine potassium salt 41, the corresponding alkylated
product 56 was obtained in a high yield (path a, Scheme 1-25).[35a]
Scheme 1-25: N-Alkylations of sulfondiimines metal salts 41 with alkyl halides 57.[35a, 45]
In addition, HAAKE reported the synthesis of N-methyl-N'-H-S-benzyl-S-methyl sul-
fondiimine (58, 82% yield) by methylation of the corresponding N-free sulfondiimine 59 with
trimethyloxonium tetrafluoroborate (Me3O+BF4–) as a strong alkylating agent and subsequent
deprotonation of the resulting tetrafluoroborate salt (58–H+BF4–) in liquid ammonia.[10] As an
advancement, in a more general protocol HAAKE and coworkers presented the N-alkylation of
sulfondiimine sodium salts 41 with aminoalkyl chlorides, affording a range of N-aminoalkylated
S,S-diarylated sulfondiimines 56 in very good yields (path b, Scheme 1-25).[45-46] Disadvanta-
geously, due to the low nucleophilicity of the nitrogens in the substrates, both the metalation
and the N-alkylation step required long reaction times (two to seven days each). Interestingly,
when N-tosyl-activated sulfondiimine 29b was employed in MANNICH-type three-component
reactions with formaldehyde and secondary amines 60, N-aminomethyl-N'-tosyl sulfondiimines
56 could be isolated in good yields (Scheme 1-26).[45]
Scheme 1-26: MANNICH-type N-aminoalkylations of sulfondiimine 29b.[45]
Restricted to a single example, in 2012 BOLM and coworkers reported the one-pot N-alkylation
of NH-sulfondiimine 17 with 3-bromo-prop-1-yne (57n) in THF (Scheme 1-27).[30]
Scheme 1-27: Alkylation of NH-sulfondiimine 17 by BOLM and coworkers.[30]
I n t r o d u c t i o n | 15
N-Arylations
Firstly in 1986, RIED and PAULI reported about different N-(hetero)aromatic sulfondiimine de-
rivatives 61 of improved stability compared to NH,N'H- or N-methyl-N'H-sulfondiimines, acces-
sible through N-arylations of S,S-dialkyl sulfondiimines 1 with nitro-substituted (hetero)aryl
chlorides 62 under different basic conditions (Scheme 1-28).[39]
Scheme 1-28: N-Arylations of N-unsubstituted sulfondiimines 1 by RIED and PAULI.[39]
More recently, C‒N ross–coupling strategies well-established for NH-sulfoximines have been
investigated in connection with the N-arylation of NH-sulfondiimines by BOLM and
coworkers.[30, 47] From an ULLMANN-type cross-coupling of NH-sulfondiimine 17, N-(2-
nitrophenyl)-substituted product 61f was isolated in 50% yield (Scheme 1-29).[30]
Scheme 1-29: First ULLMANN-type cross–coupling of sulfondiimine 17 with an aryl iodide.[30]
As an improvement, a general and effective BUCHWALD–HARTWIG-type procedure for the
N-arylation of N'-monosubstituted sulfondiimines 19 with aryl bromides 64 was developed.
With a combination of tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] and 2-dicyclohexyl-
phosphino-2',6'-diisopropoxybiphenyl (RuPhos) as the catalyst system, access to functionalized
N,N'-disubstituted products 61 was provided in good to high yields (Scheme 1-30), including the
first sulfondiimine-based 2,1-benzothiazine (Scheme 1-45).[47]
Scheme 1-30: BUCHWALD–HARTWIG-type N-arylations of N'H-sulfondiimines 19.[47]
In the context of this work, a protocol for the cleavage of para-methoxyphenyl (PMP) groups in
N-PMP-protected sulfondiimines 61 has been discovered. With excess cerium ammonium ni-
trate (CAN) as the oxidant under basic conditions synthetically useful NH-derivatives 19, diffi-
cult to prepare by other means, have been accessed (Scheme 1-31).[47]
16 | I n t r o d u c t i o n
Scheme 1-31: Oxidative deprotection of N-PMP sulfondiimines 61.[47]
1.1.3 Applications
Presumably due to the limitations in the synthesis of sulfondiimines (chapter 1.1.1), to date, the
applications of this highly underestimated class of compounds appear restricted as well. This
chapter will give an introduction into the reports on biological activities of sulfondiimines and
into their applications in synthetic organic—particularly heterocyclic—chemistry.
1.1.3.1 Biologically active derivatives
This chapter will give an overview on the biological activities reported for sulfondiimine deriva-
tives. Notably, although a number of sulfondiimine derivatives with interesting biological activi-
ties have been patented as pharmaceutical or agricultural agents, no marketed compounds
have appeared to date.
Pharmacologically active sulfondiimines
In the context of pharmacologically active sulfondiimine derivatives, in 1976[46] and 1983,[45]
HAAKE and others reported on the synthesis of N-aminoalkylated examples 56 (Figure 1-6) with
neurotropic and musculotropic spasmolytic activity and on their use as spasmolytic agents. The
best results were obtained with an NH-S,S-diphenyl derivative, whose activity proved compara-
ble to some commercially available antihistamines and anticholinergic agents.
During the investigation of structure-activity relationships a special importance of the R-group
(O >> NH) on the effectivity of the spasmolytic agents was observed, whereas changes in the
S,S-diaryl group or the N'-side chain did not have a significant effect.[45]
Figure 1-6: N-Aminoalkylated aza-sulfone analogs 56 as spasmolytic agents.[45-46]
Furthermore, SCHWARTZ and WART in 1995 claimed the activity of NH,N'H-sulfondiimines 65
(Figure 1-7) as matrix metalloproteinase (MMP) inhibitors and their utility in the modulation of
physiological functions or the treatment of diseases associated with MMP modulation. Contex-
tually, MMPs represented proteinases believed to be responsible for the metabolic turnover of
protein components of the extracellular matrix of humans.[48]
I n t r o d u c t i o n | 17
Figure 1-7: NH,N'H-Sulfondiimines 65 are matrix metalloproteinase (MMP) inhibitors.[48]
More specifically, SCHWARTZ and others focused on sulfondiimine 66 as potent matrixins
(MMPs) inhibitor in 2000.[49] The compound proved potent against MMP-1 (IC50, 180 nM),
MMP-2 (IC50, 63 nM), and MMP-9 (IC50, 44 nM). Upon investigations of its role in human micro-
vascular endothelial cell proliferation, a correlation between the anti-metalloenzyme activity
and the effects of the inhibitor on the growth and invasion of endothelial cells was
suggested.[49a]
Figure 1-8: Sulfondiimine 66 represents a potent MMP inhibitor.[49]
As a recent example, in 2015 LÜCKING and others at Bayer Pharma claimed the utility of sul-
fondiimine-based disubstituted 5-fluoro pyrimidines 67 (Figure 1-9) for the treatment and
prophylaxis particularly of hyper-proliferative disorders and virally induced infectious diseases,
or cardiovascular diseases.[50]
Figure 1-9: Pharmacologically active sulfondiimine-based 5-fluoropyrimidines 67.[50]
The mitogen-activated protein kinase (MAPK) interacting protein kinases 1 and 2 (MNK1 and
MNK2) are of high importance in the control of signals involved in mRNA translation. Hence,
the represe t ke ediators of o ogenic progression, drug resistance, production of proin-
flammatory cytokines, and cytokine signaling .[51]
18 | I n t r o d u c t i o n
Contextually, WIEDENMAYER and others at Boehringer-Ingelheim recently reported on the syn-
thesis of sulfondiimine-containing substituted pyrrolotriazines 68, their inhibitory activity
against MNK1 and MNK2 kinases, and their use as agents for the treatment or amelioration of
MNK1- and MNK2-mediated disorders.[52]
Figure 1-10: Sulfondiimine-containing pyrrolotriazines 68 as MNK1 and MNK2 kinase inhibitors.[52]
In addition, TAMURA and others (Shionogi) very recently discovered the activating effects of
sulfondiimine-incorporating azaindole 69 (Figure 1-11) on the adenosine monophosphate-
activated protein kinase (AMPK), and claimed the use of 69 as antidiabetic agent.[53] In close
connection, the same effects of related sulfondiimine-based molecules have been claimed by
GOTTSCHLING and others (Boehringer Ingelheim) to be particularly useful against type 2 diabe-
tes.[54]
Figure 1-11: Sulfondiimine 69 with AMPK-activating effect.[53]
Sulfondiimines in pesticides
In terms of sulfondiimines incorporated in pesticides, in 1996[55] and 2000,[56] LOWDER and
others at Rhone-Poulenc Agrochimie investigated S-pyrazole, S-pyrrole, and S-imidazole sul-
fondiimines useful for controlling arthropod, nematodes, helminth, or protozoan pests, and
their applications as pesticides. More specifically describing the structure of the relevant
acrylamide-based sulfondiimine derivatives 70 (Figure 1-12), BINDSCHÄDLER and others (BASF)
more recently claimed the utility of these compounds for the control of invertebrate pests, in
particular of arthropod pests and nematodes, and their use as pesticides.[57]
Figure 1-12: Acrylamide-based sulfondiimine derivatives 70 useful as pesticides.[57]
I n t r o d u c t i o n | 19
Subsequently, PITTERNA and others (Syngenta) investigated an N-cyanated sulfondiimine 71
(Figure 1-13) in the context of bis-amide derivatives with insecticidal, acaricidal, nematicidal,
and molluscicidal activities, and their use as insecticides.[58]
Figure 1-13: Bis-amide-substituted sulfondiimine 71 was investigated as insecticide.[58]
1.1.3.2 In synthetic organic chemistry
In general, the applications of sulfondiimines most frequently focus on synthetic organic chem-
istry. As an example discovered by HAAKE and coworkers, NH,N'H-S,S-dimethyl sulfondiimine
(15) proved as a valuable reagent for the one-step transformation of aromatic aldehydes 72
into nitriles 73 via an eight-membered ring B isolated as the intermediate, leading to aryl-
substituted products 73 in excellent yields (95–100%; Scheme 1-32).[59]
Scheme 1-32: Thermal conversion of aromatic aldehydes 72 into nitriles 73 with sulfondiimine 15.[59]
More recently, an application of N-tosyl-N'-sulfenyl sulfondiimine 42 (Scheme 1-20) was re-
ported by YOSHIMURA and coworkers. They succeeded in the stereospecific synthesis of
N-sulfenylaziridines 74 in excellent yields by the thermolysis of reagent 42 and subsequent re-
actions with excess amounts of olefins 75 (Scheme 1-33).[37]
Scheme 1-33: Synthesis of N-sulfenylaziridines 74 from N-tosylated sulfondiimines 42.[37]
20 | I n t r o d u c t i o n
Moreover, S,S-dialkyl sulfondiimines 1 have found application in the synthesis of pseudopep-
tides. In 2005, BOLM and coworkers reported the transformation of N-protected amino acid 76
with different sulfondiimines 1 towards C2- or pseudo-C2-symmetric pseudopeptides 77 in good
yields (39–94%; Scheme 1-34).[38]
Scheme 1-34: Incorporation of S,S-dialkyl sulfondiimines 1 in pseudopeptides 77.[38]
Of special interest for this thesis is the most frequently investigated field of applications of sul-
fondiimines in synthetic organic chemistry: the heterocyclic chemistry.
1.1.3.3 In heterocyclic chemistry
Presumably due to the fact that synthetic access to NH,NH-S,S-dialkyl sulfondiimines 1 was in-
vestigated most frequently (chapter 1.1.1), these bifunctional molecules were incorporated in
most sulfondiimine building blocks applied in heterocyclic chemistry. In this chapter, the syn-
thesis and applications of heterocycles 78–80 involving C‒N o d for i g rea tio s of interest
for this thesis will be described more in detail (strategies a–c, Scheme 1-35).
Scheme 1-35: Cyclization strategies a–c apply sulfondiimines 18|19|38 as the precursors.
Contextually, by one-pot reactions of NH,NH-S,S-dialkyl sulfondiimines 1 with biselectrophiles a
variety of five- or six-membered heterocyclic products 78 can be accessed (strategy a, Scheme
1-35). As such, condensation reactions of sulfondiimines 1 with bifunctional dichlorides
81|82b|83|84[60] or malonic esters 82a
[61] have been extensively investigated by HAAKE and
coworkers.
I n t r o d u c t i o n | 21
Scheme 1-36: Heterocycles 78a–d prepared from building blocks 1 by HAAKE and coworkers.[10, 60-61]
With this synthetic strategy, differently substituted five- or six-membered heterocycles 78a–d
were accessed, including spirocyclic examples (Scheme 1-36). Typically, the reactions were car-
ried out in DCM with triethylamine.[10]
In addition, condensations of sulfondiimines 1 with diketene 85 (path a) or ethyl acetoacetates
86 (path b) were reported by RIED and PAULI to exclusively afford a range of 1λ6,2,6-
thiadiazines 78e (Scheme 1-37) in lieu of N-acetoacetylated products.[62]
Scheme 1-37: 1λ6,2,6-Thiadiazines 78e resulted from condensations of sulfondiimines 1.[62]
Interestingly, under certain conditions S-alkylated sulfondiimines are known to undergo C‒S
bond cleavage. Particularly in case of a positive charge on sulfur built up by protonation
(Scheme 1-1) or introduction of electron–withdrawing groups on one or both nitrogen atoms,
S-dealkylations (tert-alk l > e z l sec-alkyl > prim-alkyl) occur with nucleophiles.[63] This ob-
servation has been utilized in the synthesis of numerous heterocycles, including some 1,3,4-
oxathiazoles 87[64] and a variety of 1λ4,2,4,6-thiatriazines 79.[41b, 42, 65]
22 | I n t r o d u c t i o n
Of interest regarding the herbicidal activity of the products,[63a] HAAKE and coworkers recently
reported a protocol for the preparation of 1λ4,2,6-thiadiazine-3-ones 79a. The synthetic strate-
gy included addition–condensation reactions (acr) of S-alkyl-S-benzyl precursors 88 with acti-
In contrast to these one-pot protocols with biselectrophiles, multi-step cyclization strategies of
NH,N'H-sulfondiimines 1 towards heterocycles 78 and 79 have been developed as well (1. N-
functionalizations, 2. cyclization b in Scheme 1-35). Necessarily involving the isolation of
N-mono- (19) and N,N'-disubstituted (38) intermediates as additional steps, the yields achieved
with this strategy were generally lower. As such, N-vinylated sulfondiimines 52a and 52b were
prepared from NH,N'H-sulfondiimines 1 (Scheme 1-24), and converted into heterocycles
79c|78k, respectively, in dissatisfying yields. As illustrated in Scheme 1-41, upon thermal induc-
tion, intramolecular cyclization and S-debenzylation of 52a afforded heterocycles 79c in very
low yields,[43] and base-mediated cyclization of sulfondiimine 52b gave spirocyclic product 78k
(41%).[44]
Scheme 1-41: Cyclizations of N-vinylated sulfondiimines 52.[43-44]
As another example, N-carbamoylated sulfondiimines 44 prepared from NH,N'H-sulfondiimines
1 (Scheme 1-21) undergo cyclizations with phosgene 93 towards partially spirocyclic N-4-
substituted 1λ6,2,4,6-thiatriazines 78l in up to moderate yields (Scheme 1-42).[10]
24 | I n t r o d u c t i o n
Scheme 1-42: Preparatio of λ6,2,4,6-thiatriazines 78l from N-monosubstituted sulfondiimines 44.[10]
By utilizi g the possi ilit of “‒dealkylations described previously (Scheme 1-35), induced by
the addition of para-toluenesulfonic acid (PTSA; path a)[41b] or primary and secondary amines
94 (path b),[42] NH-sulfondiimines 49 generated from NH,N'H-sulfondiimines 1 and cyanoimi-
dates (Scheme 1-23) were cyclized to λ4,2,4,6-thiatriazines 79d in one step and good yields
(Scheme 1-43).
Scheme 1-43: Application of sulfondiimines 49 in the synthesis of thiatriazines 79d.[41b, 42]
In addition, N,N'-disubstituted sulfondiimines 95 have been prepared from the corresponding
NH-sulfondiimines under conditions described previously (Scheme 1-23), and employed as pre-
cursors for heterocycles 96a (strategy c in Scheme 1-35) and annulated derivatives 96b–c in
dissatisfying yields (Scheme 1-44).[41a]
Scheme 1-44: Applications of sulfondiimines 95 in the syntheses of 1,2,4-thiadiazine 1-imines 96.[41a]
I n t r o d u c t i o n | 25
More recently, in the context of palladium–catalyzed C‒N cross–couplings (Scheme 1-30)[47] of
NH-sulfondiimines 19 prepared from sulfiliminium salts 23 (Scheme 1-15),[30] BOLM and
coworkers could access the first sulfondiimine-based 2,1-benzothiazine 97. By combining NH-
sulfondiimine 17 with 2-bromobenzaldehyde as the coupling partner (Scheme 1-45) upon dif-
ferent reaction temperatures and times, either an N,N'-difunctionalized product (61, Scheme
1-30) or 2,1-benzothiazine 97 (strategy c in Scheme 1-35) was obtained with remarkably high
selectivity.[47]
Scheme 1-45: Sulfondiimine-based 2,1-benzothiazine 97 was reported by BOLM and coworkers.[47]
P r o b l e m D e f i n i t i o n a n d O b j e c t i v e s |27
II. PROBLEM DEFINITION AND OBJECTIVES
Despite the intriguing properties sulfondiimines exhibit, since their discovery in 1964 these
high-valent sulfur derivatives have received only marginal interest from the scientific communi-
ty, and syntheses and applications remained significantly restricted as reviewed in the previous
chapter. As contribution to overcome the existing limitations, the aim of this thesis included the
development of methods for the variable and selective modifications of sulfondiimine deriva-
tives. By involving one or both of the unsubstituted nitrogen atoms and the carbon substituent
of sulfur as key anchors of the sulfondiimine functional group, N- and -functionalization and
scarcely investigated cyclization strategies were the objectives of the planned investigations.
Thereby, a library of structurally diverse sulfondiimine-based products 38|98|99 of special in-
terest for possible applications, particularly as pharmacological agents, should be accessed
(Scheme II). In particular, the relatively unexplored class of NH-sulfondiimines 19 represented
the substrates of choice, readily available since the development of a synthetic approach by
BOLM and coworkers in 2012 (Scheme 1-15).[30] As such, NH-N-phenyl-S-phenyl-S-methyl sul-
fondiimine (17 ill e referred to a d utilized as the sta dard su strate for the opti izatio of the reaction conditions of the particular methods. The results of the corresponding projects
will be discussed in the following (chapters 2–4).
Scheme II: Overview on the modifications of NH-sulfondiimines 19 performed in this thesis.
R e s u l t s a n d D i s c u s s i o n | 29
III. RESULTS AND DISCUSSION
2 N-Functionalizations
2.1 N-Arylations and N-alkenylation of N-monosubstituted sul-fondiimines (Project P1)
2.1.1 Background and aim of the project
In previous work, a protocol for BUCHWALD–HARTWIG-type cross–couplings of
NH-sulfondiimines with aryl bromides has been developed, leading to a series of
N,N'-disubstituted sulfondiimines (Scheme 1-30).[47] However, this method is restricted by the
necessity for harsh reaction conditions such as high reaction temperatures and the use of ex-
pensive palladium catalysts and a glovebox. In consequence, the scope appeared limited, for
instance excluding the application of thermally labile sulfondiimines. In particular,
N-(hetero)aryl-substituted products, which appear of interest in the light of structurally related
sulfoximine analogs applied as anticancer agents[68] and agrochemicals[69] could not be ac-
cessed.
Hence, the aim of this project was to overcome the limitations of this method, and explore a
more mild, experimentally simple, and cost-efficient version. In this manner, the synthesis of a
more diverse library of N,N'-disubstituted sulfondiimines, including N-(hetero)aryl sul-
fondiimines, was envisioned.
Inspired by an N-arylation protocol previously reported for NH-sulfoximines by our group
(Scheme 2-1),[70] CHAN–LAM-type cross-couplings of NH-sulfondiimines with boronic acids 101
were attempted.[71] These reactions would have the advantage of mild and cost-effective reac-
tion conditions, as they proceed with copper catalysts at ambient temperature and without the
necessity for an external base.
Scheme 2-1: Copper– atal zed C‒N ross–couplings of sulfoximines 100 with boronic acids 101.[70]
2.1.2 Optimization
To explore the optimal reaction conditions, the cross–coupling of S-methyl-S-phenyl-N-phenyl-
N-H-sulfondiimine (17) and phenyl boronic acid (101a) was chosen as the representative test
reaction. According to the previously reported CHAN–LAM-type protocol (Scheme 2-1),[70] cop-
per acetate (0.1 equiv) was employed as the catalyst without any external base in dry methanol
while atmospheric moisture was excluded by a CaCl2-drying tube.
30 | R e s u l t s a n d D i s c u s s i o n
Favorably, this initial attempt gave the N,N'-disubstituted product in a high yield of 85%
(Scheme 2-2).
Scheme 2-2: First test reaction.
To further investigate this reaction process, the effects of all reaction parameters have been
evaluated in combination with different reaction temperatures and times. Alternative Cu(I)
[a] After column chromatography, atmospheric moisture excluded by CaCl2-drying tube. [b] Under an oxygen atmosphere. [c] Upon addition of MS 3 Å. [d] Under an argon atmosphere.
2.1.3 Substrate scope
With the optimal reaction conditions in hands (Table 2-1, entry 1), the scope of this reaction
process has been investigated with respect to the boronic acid 101 (Table 2-2) as well as the
NH-sulfondiimine 106 employed in the reaction (Scheme 2-4).
Initially, the cross–coupling of NH-sulfondiimine 17 as the representative substrate was con-
ducted with differently substituted commercially available boronic acids 101 as the coupling
partners, leading to a variety of N,N'-disubstituted sulfondiimines 61 (Table 2-2). In general, the
products were obtained in good yields and high functional–group diversity. Different electron–withdrawing as well as electron–donating substituents were tolerated on the phenylboronic
acid, affording methoxy- and thiomethyl-, as well as acetyl-, trifluoromethyl-, and nitro-
substituted products in good yields up to 90% (products 61b–f; entries 1–6). However, attempts
employing hydroxy- (entry 7) or cyanophenylboronic acid (entry 8) proved unsuccessful. It is of
note that in contrast to previous work[47] this protocol enables the preparation of halogen-
substituted products such as the N-ortho-bromo- and -chlorophenyl derivatives 61g and 61h in
very good yields up to 94% (entries 9–10). Favorably, the ar o ‒bromine bond remained ac-
cessible in the product for subsequent classical cross–coupling reactions.
Furthermore, steric factors remarkably influenced the reactivity of the substituted phenyl-
boronic acid. While para- or meta-methyl-substituted acids (101k–l) reacted smoothly, an or-
tho-methyl substituent in 101m caused a significantly lower product yield (products 61k–m,
87–85% versus 51%; entries 13–15). In accordance, attempts of applying a sterically demanding
mesitylboronic acid failed (entry 16). When butylboronic acid was tested as the coupling part-
ner, the desired product was not detected and sulfondiimine 17 partially decomposed (en-
try 17).
32 | R e s u l t s a n d D i s c u s s i o n
Table 2-2: Substrate scope with respect to the boronic acid 101.
Entry R1-, Boronic acid 101 Yield of 61[a]
[%]
1 C6H5-, a a, 85 2 4-MeO-C6H4-, b b, 72 3 4-MeS-C6H4-, c c, 67 4 4-Ac-C6H4-, d d, 90 5 3-F3C-C6H4-, e e, 89 6 2-O2N-C6H4-, f f, 56[b]
10 2-Cl-C6H4-, h h, 85 11 4-biphenyl-, i i, 84 12 2-naphthyl-, j j, 94 13 4-Me-C6H4-, k k, 87 14 3-Me-C6H4-, l l, 85 15 2-Me-C6H4-, m m, 51 16 2,4,6-Me3-C6H4- - 17 C4H9- - 18 6-Cl-pyridin-3-yl-, n n, 84 19 thiophen-3-yl-, o o, 82 20 pyridine-3-yl- - 21 furan-3-yl- - 22 benzo[b]thien-3-yl-, p p, 41[c]
23 5-indolyl-, q q, 61[c]
[a] After column chromatography, atmospheric mois-ture excluded by CaCl2-drying tube. [b] Yield deter-mined by NMR. [c] Reaction performed for 40 h.
Of special interest, the protocol opens up access towards the previously unprecedented, highly
interesting class of N-(hetero)aryl sulfondiimines. For instance, the representative chloro-
pyridinyl (61n) and thiophenyl (61o) derivatives have been formed in good yields (entries 18–19). Whereas pyridyl- and furanylboronic acid did not afford the desired products (entries 20–21), benzo[b]thienyl (61p) and indolyl derivatives (61q) proved readily accessible after elonga-
tion of the reaction time (entries 22– . Fa ora l , the N‒H oiet of the i dole su stitue t in
61q remains amenable for subsequent chemical modifications.
R e s u l t s a n d D i s c u s s i o n | 33
Furthermore, reactions of different NH-sulfondiimines 106a–h have been performed with phe-
nylboronic acid (101a) as the representative coupling partner (Scheme 2-4). In general, S-aryl-S-
alkyl-NH-sulfondiimines reacted smoothly. As reported previously for CHAN-LAM-type aryla-
tions of other nitrogen nucleophiles,[73b] electron-rich substrates gave better results compared
to electron-poor ones. As such, an electron–donating N-methoxyphenyl-substituent resulted in
a higher yield of the corresponding N-arylated product 61b (90%) compared to an electron–withdrawing N-trifluoromethylphenyl group (76%, 61e). Furthermore, the N-phenylation of N'-
PMP-substituted sulfondiimine 106a proved superior to the reaction of the N'-phenylated de-
rivative 17 and methoxyphenylboronic acid 101b (Table 2-2, entry 2), as it resulted in a signifi-
cantly increased yield of product 61b (90% versus 72%). As observed in previous studies on a
BUCHWALD–HARTWIG-protocol for the N-arylation of NH-sulfondiimines (Scheme 1-30), an
electron–withdrawing tosyl-group on the nitrogen led to degradation of the starting material,
and precluded the formation of the cross–coupling product.
Scheme 2-4: Products stemming from the coupling of different NH-sulfondiimines 106 with phenyl-
boronic acid (101a).
In addition, S-tolyl- and cyclopropyl derivatives 61s and 61u were formed in good yields. As ob-
served for product 61g (Table 2-2, entry 9), in the case of S-(para-bromophenyl)-substituted
product 61t, the bromide remained accessible for further transformations after the cross–coupling reaction. Unfortunately, for an S-benzyl and a representative S,S-dialkylated sul-
fondiimine (here: tetrahydrothiophene) degradation of the starting materials, and no formation
of the desired products were observed.
34 | R e s u l t s a n d D i s c u s s i o n
To further expand the scope of this protocol, the N-alkenylation of a sulfondiimine was pro-
posed, opening up access to another class of N,N'-disubstituted sulfondiimines. Therefore, NH-
sulfondiimine 17 was coupled with an alkenyl-substituted boronic acid 110 under the optimized
reaction conditions (Scheme 2-5).
Scheme 2-5: N-Alkenylation of a sulfondiimine.
In first attempts, according to the behavior of N-alkynylated sulfoximines previously reported
by our group,[74] purification by flash column chromatography carried out with silica gel result-
ed in a partial hydrolysis of the desired product 109, which was obtained as a mixture of iso-
mers (E/Z = 1:1). To avoid the nonseparable mixture of the partially hydrolyzed isomers and the
E/Z-isomers of the desired product, column chromatography was conducted with basic alumin-
ium oxide. In this manner, solely the (E)-isomer of product 109 was obtained in a good yield
(78%; Scheme 2-5). When performing the reaction on double scale (compared to Scheme 2-5),
the yield of N-alkenylated product 109 significantly decreased to 48%. Furthermore, the substi-
tution pattern on the alkene has proven to be critical for the outcome of the transformation. As
such, attempts to access N-(3,3-dimethylbut-1-ene)- and N-(2-chloroethene)-substituted prod-
ucts failed.
2.1.4 Upscaling attempts
As it is of potential interest for industrial applications, the synthesis of N-(2-bromophenyl)-
substituted sulfondiimine 61g was chosen for upscaling attempts. In addition, subsequent ami-
nation towards a sulfondiimine-based ligand 107 was envisioned (Scheme 2-6).
Scheme 2-6: Attempts for upscaling and a sulfondiimine-based ligand.
However, in all reactions employing sulfondiimine 17 (2.0 g) and 2-bromophenylboronic acid at
25 °C in different set-ups (differently sized schlenk tubes or round bottom flasks with CaCl2-
drying tubes), incomplete conversion was observed, and the maximum product yield obtained
was 30% (1.01 g; Scheme 2-6). This represents a decrease in yield in comparison to the afore-
Subsequent initial attempts of synthesizing a sulfondiimine-based ligand 107 by amination of
sulfondiimine 61g employing palladium-catalyzed protocols reported by BUCHWALD (Scheme
2-6),[75] or by our group for the N-arylation of NH-sulfondiimines,[47] failed.
2.1.5 Summary and outlook
In this project, a CHAN–LAM-type protocol for the copper– atal zed C‒N ross–coupling of NH-
sulfondiimines with boronic acids has been developed (Scheme 2-7).
Scheme 2-7: Copper– atal zed C‒N ross–coupling of NH-sulfondiimines 19 with boronic acids 101.
This reaction represents a complementary and revised method to a previously reported
BUCHWALD–HARTWIG-type version (Scheme 1-30).[47] Under mild and cost-effective base-free
reaction conditions, it provides access towards more diversely N,N'-disubstituted sul-
fondiimines in good to excellent yields, including previously inaccessible N-(hetero)aryl and
N-alkenylated sulfondiimines. For future work, it is of high interest to investigate the biological
activities of these products, in particular of differently substituted N-(hetero)aryl sul-
fondiimines. Furthermore, due to incomplete conversions and low yields observed in the up-
scaling process, the screening of reaction parameters such as catalyst loading and reaction
temperature should be explored. The investigation of suitable catalytic systems for the amina-
tion of building block 61g could provide access to sulfondiimine-based ligands, and
N-alkenylated product 109 could be further functionalized at the unsaturated moiety.
2.2 N-Alkylations of N-monosubstituted sulfondiimines (Project P2)
2.2.1 Background and aim of the project
N-(Amino)alkylated sulfoximines such as Suloxifen 111, which was identified as a both orally
and parentally effective spasmolytic and antiasthmatical agent and selected as clinical candi-
date at Gödecke by SATZINGER and STOSS,[76] proved attractive in medicinal chemistry.[8a]
Figure 2-1: Suloxifen (111) represents an effective spasmolytic and antiasthmatic agent.
Although the investigations of their biological activities showed interesting results as well (Fig-
ure 1-6), synthetic access to the structurally related N-(amino)alkylated sulfondiimines 56 ap-
pears surprisingly restricted (chapter 1.1.2), and no general and effective protocol for the N-
alkylation of sulfondiimines exists.
36 | R e s u l t s a n d D i s c u s s i o n
To date, mainly N-alkylamino sulfondiimines 56 have been prepared by the formation of sul-
fondiimine alkali metal salts from NH-sulfondiimines and alkali metal hydrides, their isolation,
and subsequent alkylation with alkyl halides (Scheme 1-25). However, both the metal-salt for-
mation as well as the alkylation of the weakly nucleophilic sulfondiimine nitrogen required very
long reaction times and high reaction temperatures.[45-46] Those came along with a strongly lim-
ited product scope, excluding substituents such as longer alkyl chains.
To further explore this highly underdeveloped substrate class and transformation of interest,
the aim of this project included the development of a general, mild, and effective synthetic
strategy towards structurally diverse N-alkylated sulfondiimines. HEANEY and LEY reported on
the use of a suspension of powdered KOH in DMSO, a so-called super asi reaction
medium,[77] for the effective N-alkylation of indoles and pyrroles with alkyl halides 57. In the N-
alkylations discussed by HEANEY and LEY, the strongly ionizing solvent was proposed to en-
hance the reactivity of in situ formed N-metallated intermediates in the subsequent nucleo-
philic substitutions with alkyl halides.[78] Envisioning an analogous reactivity for N-unsubstituted
sulfondiimines, we planned to perform their N-alkylations with alkyl halides by employing the
combination of KOH in DMSO.[79] Avoiding the isolation of the sulfondiimine salts, this strategy
could represent an experimentally simple and effective alternate pathway for the desired N-
alkylation reactions.
2.2.2 Optimization
For the investigation of the desired N-alkylations, S-methyl-S-phenyl-N-phenyl-N-H-
sulfondiimine (17) was employed as the standard substrate, and butyl halides 57 were selected
as the representative alkylating agents (Table 2-3).
Table 2-3: Optimization of the sulfondiimine N-alkylation reaction conditions.
Entry X, Halide 57 T [° C] Yield [%][a]
1 Br, a r.t. 84
2 I, b r.t. 79
3 Cl, c r.t. 73[b]
4 Br, a 60 59
5 Br, a 90 56
6 Br, a r.t. 57[c]
[a] After flash column chromatography. [b] Reaction performed for 6 h. [c] Use of 0.15 M DMSO.
R e s u l t s a n d D i s c u s s i o n | 37
In order to perform the reactions under mild conditions, initial attempts were conducted at
ambient temperatures. Favorably, by reacting sulfondiimine 17 with butyl bromide (57a,
1.5 equiv) and employing a combination of KOH (2.0 equiv) in anhydrous DMSO[80] N-alkylated
product 56a was directly obtained in a high yield of 84% after only 4 h (entry 1). Other alkylat-
ing agents could be used as well, however, resulting in lower yields of product 56a. As such, the
use of butyl iodide gave product 56a in a slightly lower yield of 79% (entry 2), whereas only 74%
yield was obtained with the chloride even after an elongated reaction time of 6 h (entry 3). In-
creasing the reaction temperature remarkably decreased the product yields, presumably due to
accelerated partial degradations of the starting material (entries 4–5). Finally, with a lower con-
centration of the reagents in DMSO the yield also dropped (entry 6). Considering cost, accessi-
bility, and environmental impact in addition to the best yield observed, alkyl bromides (entry 1)
were chosen as the electrophilic reagents of choice for further investigations of this N-
alkylation protocol.
2.2.3 Substrate scope
With the optimal reaction conditions in hand (Table 2-3, entry 1), the substrate scope was in-
vestigated with respect to the alkyl bromides 57 and NH-sulfondiimines 106. At first, the alkyl
bromide 57 was varied in reactions with the representative NH-sulfondiimine 17 (Table 2-4).
Favorably, the protocol proved generally applicable, giving access to diversely N-alkylated sul-
fondiimines 56 in mostly good to excellent yields. Irrespective of their chain length, various lin-
ear alkyl bromides reacted readily, resulting in products 56b–f obtained in good yields ranging
from 64–80% (entries 1–5). For the introduction of an octadecyl group, the alkyl iodide was
used, leading to sulfondiimine 56f in 70% yield (entry 5). When employing branched alkyl bro-
mides as the reagents, a strong steric influence on the yields was observed. Whereas an isobu-
tyl-substituted product 56g was still obtained in a high yield of 79% (entry 6), a sterically more
demanding isoamyl-substituent led to only 38% of product 56h even after an elongated reac-
tion time of 9 h (entry 7). Along the same lines, an isopropyl and a cyclohexyl derivative were
not formed at all (entries 8–9). In addition, the introduction of unsaturated substituents pro-
ceeded well irrespective of the double and triple bond positions in linear bromoalkenes and
alkynes. In all cases, the unsaturated moiety remained intact after the transformation, provid-
ing different N-alkenylated and alkynylated products in good yields (56i–m, 69–88%; entries
10–14). Furthermore, the conditions proved suitable for the synthesis of aryl-substituted prod-
ucts 56n and 56o (70% and 80% yield, respectively; entries 15–16). It is of note that these re-
sults demonstrated the superiority of the protocol over previous studies[30, 47] by accessing the
first N-benzylated sulfondimine 56n (entry 15) and the propargylic sulfondiimine 56l in an en-
hanced yield of 88% compared to the previously used KH in THF (68% yield[30]). Of interest, the
introduction of a sulfondiimine into a natural product was successful. The conversion of (rac)-
NH-sulfondiimine 17 with (S)-citronellyl bromide afforded the desired N-alkylated product 56q
as a mixture of nonseparable diastereomers in 65% yield (d.r. = 1:1, entry 18). With 1-bromo-4-
chlorobutane or 1,4-dibromobutane as the reagent, disappointingly, no alkylated products
were detected, but degradation of sulfondiimine 17 completed after 5–7 h (entry 19).
38 | R e s u l t s a n d D i s c u s s i o n
Table 2-4: Substrate scope with respect to the alkyl bromides 57.
Entry Residue Alkyl bromide
57 Yield of 56 [%][a]
1 d b, 72
2 e c, 80
3
f d, 76
4 g e, 64
5
h f, 70[b]
6
i g, 79
7
j h, 38[c]
8
- - [d]
9
- - [d]
10 k i, 72
11
l j, 72
12
m k, 78
13 n l, 88
14 o m, 69
15
p n, 70
16
q o, 80
17
r p, 73
18
s q, 65[e]
19 - - [f]
[a] After flash column chromatography. [b] Reaction performed with iodide. [c] Reaction performed for 9 h. [d] No product detected after 24 h. [e] Product was obtained as a mixture of diastereomers. [f] Complete degradation of sul-fondiimine 17 after 7 h.
R e s u l t s a n d D i s c u s s i o n | 39
Furthermore, reactions of different sulfondiimines 106 were performed with butyl bromide
(57a) as the representative reagent (Scheme 2-8). In general, S-aryl-S-alkyl sulfondiimines re-
acted readily. As such, different substituents on the S-phenyl moiety were well-tolerated, af-
fording methoxy-, bromo-, and methyl-substituted products 56r–t (79–85%) in comparable
yields to the corresponding nonsubstituted product 56a (84%; Table 2-3, entry 1). Favorably,
the C‒Br o d as preserved during the reaction process, and remains accessible for further
classical cross–couplings. The yield of an S-cyclopropyl derivative 56u was in the same range
(75%).
Scheme 2-8: Scope of sulfondiimines 106.
As described for the corresponding N-arylation reactions (Scheme 1-30[47] and Scheme 2-10[71]),
the substituent on the second nitrogen atom of the particular NH-sulfondiimines showed a sig-
nificant effect on the product yields. Delightfully, in contrast to the instability of N-tosylated
sulfondiimines reported for these N-arylation protocols, the N-butylation towards
N-tosyl-substituted product 56v proceeded well (78% yield). In addition, employing 12-bromo-
1-dodecene as the reagent resulted in N-PMP-substituted sulfondiimine 56w (78% yield). Con-
trary, the attempted second N-alkylation of a N-butyl-NH sulfondiimine failed. Finally, a repre-
sentative S,S-dialkylated sulfondiimine was subjected to the N-alkylation protocol, affording
tetrahydrothiophene derivative 56x in a very good yield of 94%.
Subsequently, to deprotect PMP-substituted sulfondiimine 56w, an oxidative cleavage protocol,
previously reported in our group, was chosen.[47] Disappointingly, instead of leading to the de-
sired NH-sulfondiimine, the corresponding employment of a combination of Na2CO3 and CAN in
H2O/CH3CN resulted in the decomposition of N-alkylated sulfondiimine 56w.
Notably, the N-alkylation protocol proved applicable for sulfoximines as well. Corresponding
reactions have been carried out in our group (by Dr. Hendriks),[81] affording various N-alkylated
sulfoximines in good to excellent yields.[79]
40 | R e s u l t s a n d D i s c u s s i o n
2.2.4 Application
The newly developed protocol was applied to the synthesis of an aza-analog of Suloxifen 111
(Figure 2-1). Favorably, the first attempt already showed the possibility of accessing the desired
aza-analog 56y by employing the newly developed N-alkylation protocol (Scheme 2-9). In future
work, this synthetic application needs optimization in order to increase the product yield. Fur-
thermore, it is of interest to synthesize differently substituted aza-analogs of Suloxifen and to
test them regarding their biological activities.
Scheme 2-9: Synthesis of a sulfondiimine-based Suloxifen analog.
2.2.5 Summary and outlook
In this work, the first general protocol for N-alkylations of NH-sulfondiimines is presented, em-
ploying alkyl bromides 57 with KOH in DMSO at ambient temperature. This cost-effective and
operationally simple method gives access to various previously unprecedented N-alkylated
products 56 in good to excellent yields. In this context, the sulfondiimine-based products 56, in
particular sulfondiimine-based analogs of Suloxifen, represent molecules of interest for phar-
maceutical and agrochemical applications, and should be tested regarding their biological activ-
ities.
Scheme 2-10: N-Alkylations of NH-sulfondiimines 19 mediated by KOH in DMSO.
R e s u l t s a n d D i s c u s s i o n | 41
3 -Functionalizations
3.1 -Functionalizations of N-mono- and N,N'-disubstituted sul-fondiimines (Project P3)
3.1.1 Background and aim of the project
Taking advantage of the possibility of a stereogenic center at the sulfur atom, sulfoximines—particularly the β-hydroxy sulfoximines and their NH-derivatives—established as chiral auxilia-
ries and ligands in asymmetric synthesis and enantioselective metal catalysis.[7] Considering the
higher nucleophilicity of the deprotonated nitrogen atom compared to the S-methyl group of
NH-sulfoximines 100, common syntheses of β-hydroxy sulfoximines 117 start from N-protected
sulfoximines 118, which are metallated with strong bases and subsequently trapped with car-
bonyl reagents such as aldehydes or ketones. To access the corresponding N-unsubstituted
products 119, an additional step of deprotection was crucial (Scheme 3-1).
Scheme 3-1: β-Hydroxy sulfondiimines 122 and 123 are the objectives of this project.
Surprising in light of the contributions on sulfoximines, in spite of the additional possible substi-
tutions at the second nitrogen, the stru turall related β-hydroxy sulfondiimines have not been
reported to date. Hence, the aim of this project included the synthesis of previously unprece-
dented N,N'-disubstituted (122) and N-monosubstituted (123) β-hydroxy sulfondiimines.[82]
Accordingly, the preparation of differently substituted products 122 and 123 by the metalation
of N,N'-disubstituted sulfondiimines 121 and subsequent addition of different electrophilic rea-
gents was planned. Additionally, a step-economic alternate pathway towards
N-monosubstituted β-hydroxy sulfondiimines 123 was envisioned (Scheme 3-1).[83] Of note, this
protocol would represent a significant advancement to the literature version, as it can avoid the
laborious and challenging nitrogen protection/deprotection of sulfondiimines.
42 | R e s u l t s a n d D i s c u s s i o n
3.1.2 Optimization
For optimization attempts, the generation of sulfondiimidoyl-carbanions from
N,N'-disubstituted sulfondiimine 61a and their subsequent addition to benzaldehyde (72a) was
selected as the test reaction. The results of different basic systems in this transformation are
summarized in Table 3-1.
Initial attempts included the use of KOH (2.0 equiv) in DMSO. This combination is known to
generate a so- alled super asi edium and facilitated the aforementioned N-alkylations of
NH-sulfoximines and NH-sulfondiimines (chapter 2.2).[79] However, in case of sulfondiimine 61a,
only partial substrate degradation occurred (entry 1). As advancement, lithium-based carbani-
ons generated from substrate 61a, LDA, and n-BuLi showed significantly enhanced reactivities,
affording the desired product 122a in medium yields, unfortunately, in combination with sever-
al unidentifiable side products (entries 2–3).
Table 3-1: Optimization of the reaction conditions.
Entry Base [equiv] Solvent 1) T [°C]; t [min] 2) T [°C]; t [h] Yield [%][a]
[a] After column chromatography. [b] Partial recovery of 61a. [c] Addition of TMEDA (2.0 equiv).
Favorably, reducing the amount of n-BuLi avoided the formation of side products (entry 4), and
the addition of TMEDA (2.0 equiv) resulted in complete conversion. Thereby, the desired
β-hydroxy sulfondiimine 122a was obtained in 94% yield (entry 5).
3.1.3 Substrate scope
3.1.3.1 N,N'-Disubstituted examples
With the optimal reaction conditions in hands (Table 3-1, entry 5), we investigated the sub-
strate scope of this reaction process with respect to the aldehydes 72, affording the first and
differently substituted β-hydroxy sulfondiimines. Therefore, sulfondiimine 61a was selected as
the representative substrate and subjected to the reaction with differently substituted alde-
hydes 72 (products 122a–k; Table 3-2). In all cases, reactions were monitored by TLC and
quenched upon full conversion. If the conversion was nonsatisfying at –78 °C, the reaction mix-
ture was warmed to room temperature.
R e s u l t s a n d D i s c u s s i o n | 43
In general, the transformations afforded the products in good to very good yields in short reac-
tion times, irrespective of the different functional groups in the aldehyde. Contextually, as ex-
pected for addition reactions, electron–withdrawing substituents resulted in higher product
yields than electron–donating ones. As such, nitro, trifluoromethyl, and chloro derivatives
122b–d have been obtained in very good yields (82–84%; entries 2–4), whereas corresponding
thiomethyl- and methoxy-substituted examples 122e (67%) and 122f (68%) gave comparably
lower yields (entries 5–6). In contrast, steric effects had no considerable impact on the yields of
the corresponding para- and ortho-methylated products 122g and 122h (78–81%; entries 7–8).
While crotonaldehyde reacted readily, accessing product 122i in 80% yield (entry 9), the use of
cinnamaldehyde 72i (39%; entry 10) and hexanal 72k (30%; entry 11) resulted in low yields of
the corresponding β-hydroxy sulfondiimines 122j and 122k, respectively. It can be noted that
the alkene moieties remained intact in products 122i and 122j (entries 9–10).
Table 3-2: The scope of aldehydes was investigated for the reaction of sulfondiimine 61a.
Entry R1-, Aldehyde 72 2) T [°C]; t [h] Yield of 122 [%][a]
1 C6H5-, a –78; 1 a, 94 2 4-NO2-C6H5-, b –78; 2 b, 82 3 4-CF3-C6H5-, c –78; 1 c, 83 4 4-Cl-C6H5-, d –78; 2 d, 84 5 4-SMe-C6H5-, e –78; 2 e, 67 6 4-OMe-C6H5-, f –78; 1 to r.t.; 2 f, 68 7 4-Me-C6H5-, g –78; 2 to r.t.; 2 g, 78 8 2-Me-C6H5-, h –78; 2 to r.t.; 2 h, 81
9 , i –78; 1.5 i, 80
10 , j –78; 3 j, 39
11 Me-(CH2)4-, k –78; 1 to r.t.; 23 k, 30[b]
[a] After column chromatography. [b] Yield determined by NMR.
The reaction of an alternative sulfondiimine (rac)-106l with benzaldehyde (72a) proceeded
well, affording N-PMP-substituted product 122l in a good yield as a mixture of diastereomers
(Scheme 3-2). As it was not possible to separate the diastereomers, the diastereomeric ratio
was determined by 1H NMR spectroscopy. Additional attempts of deprotecting N-PMP-
substituted product 122l failed with a protocol that recently proved effective for N,N'-
disubstituted sulfondiimines.[47]
44 | R e s u l t s a n d D i s c u s s i o n
Scheme 3-2: The alternative sulfondiimine (rac)-106l reacted readily.
Additionally, the employment of alternative electrophilic reagents was attempted. In this con-
text, an alkylation of sulfondiimine 61a with methyl iodide (124) at –78 °C proved successful
(94% yield of 125; Scheme 3-3). In contrast, no reaction occurred with representative ketones.
As such, when acetone (126) or acetophenone (127) (each 2.0 equiv) were employed as the
electrophilic reagents, even after stirring for 48 h at room temperature solely the degradation
of 61a occurred, and no desired products were detected.
Scheme 3-3: Alkylation of sulfondiimine 61a.
3.1.3.2 N-Monosubstituted examples
As outlined before, the one-pot synthesis of NH-β-hydroxy sulfondiimines 123 was attempted.
Avoiding the protection of the nitrogen atom of NH-sulfondiimine (rac)-17, the direct formation
of the correspo di g β-hydroxy-substituted products 123a|b succeeded by employing excess
amounts of n-butyllithium (Scheme 3-4). Accordingly, 123a proved directly accessible from NH-
sulfondiimine 17 and benzaldehyde in 44% yield as a mixture of diastereomers (top, d.r. = 1:1).
In addition, product 123b has been prepared from substrate 17 and 1,3-diphenylprop-2-yn-1-
one (128a) (62% yield of 123b, d.r. = 1:1). As observed previously for structurally analogous
sulfoximines,[84] the resulting diastereomers of 123b proved readily separable by simple flash
column chromatography, whereas separations of products derived from aldehydes failed.
These transformations have significant potential for the preparation of sulfondiimine-based
ligands.
Scheme 3-4: Direct syntheses of N-monosubstituted products 123.
R e s u l t s a n d D i s c u s s i o n | 45
3.1.4 Summary and outlook
The trapping of sulfondiimine-based ɑ-lithiated carbanions with differently substituted alde-
hydes led to several pre iousl u pre ede ted β-hydroxy sulfondiimines in good to excellent
yields (Scheme 3-5). In addition, the possibility of alkylation with methyl iodide was successfully
demonstrated for a representative N,N'-disubstituted sulfondiimine. Of special interest,
N- o osu stituted β-hydroxy sulfondiimines have been accessed by an improved protec-
tion/deprotection-free protocol (Scheme 3-5).
Scheme 3-5: The first β-hydroxy sulfondiimines have been prepared in this project.
Based on previous work, which demonstrated the possibility of accessing enantiopure sul-
fondiimine derivatives with a stereogenic center at the sulfur atom,[30] further studies should
i lude the preparatio of hiral β-hydroxy sulfondiimines from the corresponding enantiopure
substrates. Subsequently, their potential as chiral auxiliaries and ligands should be evaluated in
comparison to the existing applications of structurally related sulfoximines.[7]
R e s u l t s a n d D i s c u s s i o n | 47
4 Cyclizations towards 1,2-(Benzo)thiazines
The introduction of heterocycles into a small molecule can remarkably influence its binding to
major drug targets.[85] As such, heterocycles of diverse structure and shape are of high interest
for drug design, as evidenced by their ubiquity in active pharmaceutical ingredients.[86] Howev-
er, influenced by the demanding synthetic accessibility, the number and shapes of ring scaffolds
available for drug design remain strongly limited to date.[87] Hence, the development of syn-
thetic pathways towards poorly and entirely unexplored classes of heterocyclic scaffolds re-
mains a highly important field in organic chemistry.
1,2-Thiazines represent a six-membered lass of “‒N-based heterocycles known to feature mul-
tiple bioactivities. Related applications as pharmaceutical agents such as antipyretic and anti-
inflammatory examples have been reported in addition to applications as materials in electron-
ics, chiral ligands and auxiliaries, reagents in asymmetric fluorination, and in complex alkaloid
total synthesis. Among the 1,2-thiazine derivatives, the 1,1-dioxides have been well-explored,
while scope and applications of the structurally related 1-oxides 131 and 1-imines 132|133
appear highly underinvestigated (Scheme 4-1).[88]
In this context, the aim of the following projects included the expansion into poorly and essen-
tiall u e plored areas of drug-like he i al spa e [85a, 87a] and the enlargement of the limited
edi i al he ists’ tool o for drug desig .[87] This should be realized by the synthesis of
previously unprecedented 1,2-thiazine 1-oxides 131 and 1,2-thiazine 1-imines 132 (chapter
4.1), or their benzo derivatives 133 (chapter 4.2). Thereby, a combination of the valuable prop-
erties of aza and diaza-analogous sulfones as the objectives of this thesis with that of 3D-
heterocyclic motifs frequently occurring in active pharmaceutical ingredients[86] was intended.
Scheme 4-1: Heterocyclic compounds 131–133 represent the targets of the following projects.
48 | R e s u l t s a n d D i s c u s s i o n
4.1 Syntheses of 1,2-thiazine oxides and imines (Project P4)
4.1.1 Background and aim of the project
Representing a unique class of 3D, fully unsaturated heterocycles, sulfoximine-based 1,2-
thiazines 131 consist of half-boat conformations with the apex at the sulfur atom, and can best
be regarded as nonaromatic cyclic sulfur ylides with a charge delocalization over the azapentyl
moiety.[89] To date, the most frequently used synthetic protocols for 1,2-thiazine 1-oxides 131
involve the reaction of NH-sulfoximines 100 with 1,3-biselectrophiles such as 2-alkoxy malo-
nates 135,[90] ketene thioacetals 136,[91] or trifluoroalkyl enones 137[92] and subsequent base-
mediated intramolecular cyclizations (Scheme 4-2, top).[88] Avoiding the isolation of the N-
vinylated sulfoximine intermediates D, WILLIAMS and CRAM reported an enhanced alternative
protocol by utilizing a propargyl ketone 128a as the reaction partner (Scheme 4-2, bottom).[93]
In lieu of the 1,2-thiazines 1-imines 132 unprecedented to date, the structurally related and
partly annulated 1,2,4-thiadiazine 1-imine derivatives 96a–c obtained from cyclizations of N,N'-
disubstituted sulfondiimines 95 with sodium hydride in DMSO in mainly poor yields (14–55%;
Scheme 1-44) exist.[41a]
As N-vinylated sulfondiimines showed significant instability in previous studies,[71] the two-step
protocols applied in the synthesis of 1,2-thiazine 1-oxides 131 appear not suitable for their aza
analogs. Instead, inspired by WILLIAMS and CRAM,[93] the aim of this project was the develop-
ment of a mild and general protocol for the one-pot syntheses of heterocyclic motifs 131|132
from NH-sulfoximines 100, NH-sulfondiimines 120 and propargyl ketones 128. Thereby, extend-
ing the scope of 1,2-thiazine 1-oxides 131 and accessing the first 1-imine derivatives 132 was
aspired.[94]
Scheme 4-2: Common synthetic pathway and one-pot approach reported for 1,2-thiazine 1-oxides
131,[93] and their iminated derivatives 132 as the objectives of this project.
R e s u l t s a n d D i s c u s s i o n | 49
4.1.2 Optimization
Standard NH-sulfondiimine 17 was selected as the test substrate and subjected to reactions
with propargyl ketone 128a in combinations with different bases and solvents upon addition of
molecular sieves 4 Å (Table 4-1). In some cases, the results have been evaluated in comparison
to the corresponding reactions of NH-sulfoximine 100a.
Table 4-1: Optimization of the reaction conditions.
Entry Base t [h] T [°C] Solvent Yield of 132a [%]
1 NaH 24 RT DMSO 70 (131a)[a,b]
2 NaH 24 RT DMSO 31[a,b]
3 KOH 5 RT DMSO 83 (131a) 4 KOH 5 RT DMSO 53[a]
5 KOH 5 RT DMSO 53[a,c]
6 KOH 24 RT DMSO 57 7 KOH 5 40 DMSO 53
8 KOH 5 80 DMSO 49
9 KOH 5 120 DMSO 44[d]
10
Cs2CO3 5 80 DMSO 78
11 Cs2CO3 5 60 DMSO 64 12 Cs2CO3 5 100 DMSO 78
13 Cs2CO3 5 80 DMF 41[a]
14 Cs2CO3 5 80 MeCN 22[a]
15 Cs2CO3 5 80 1,4-dioxane 0[a]
16 Cs2CO3 5 80 toluene 0[a]
17 Cs2CO3 5 80 DCE 0[a]
18 K2CO3 5 80 DMSO 0[a]
19 Na2CO3 5 80 DMSO 0[a]
20 Cs2CO3 5 80 DMSO 99 (131a) [a] Partial recovery of 100|17. [b] First step performed for 45 min. [c] Use
of 128a (0.5 equiv instead of 1.5 equiv). [d] Partial decomposition of 17.
With the procedure reported by WILLIAMS and CRAM as starting point,[93] sodium hydride was
employed as the base in DMSO. As expected, this combination proved utilizable for the synthe-
sis of 1,2-thiazine 1-oxide 131a (entry 1). However, the yield of the corresponding aza analog
132a was low (entry 2), and o full o ersio s ould e a hie ed. With KOH i DM“O, a su-
per asi rea tio s ste effe ti e i the N-alkylations of NH-sulfoximines and
NH-sulfondiimines (chapter 2.2),[79] the yield of sulfoximine-based heterocycle 131a was high
(83%; entry 3).
50 | R e s u l t s a n d D i s c u s s i o n
However, in all cases, including varying amounts of NH-sulfondiimine 17, reaction times and
reaction temperatures, nonsatisfying yields of iminated heterocycle 132a were observed
57%; entries 5–9). Finally, the best results were obtained with cesium carbonate as the base
at 80 °C in DMSO, affording 1,2-thiazine 1-imine 132a in 78% yield (entry 10). Other reaction
and counter cations (Na+, K+, entries 18–19) did not improve the yield. Favorably, this combina-
tion as well proved applicable to the synthesis of the corresponding oxidized derivative (99%
yield of 131a; entry 20).
4.1.3 Selectivity
It is of note that the propargyl ketone 128a, which has been employed by WILLIAMS and
CRAM[93] and in the aforementioned optimization of the reaction conditions (chapter 4.1.2),
incorporates two identical phenyl substituents. In contrast, for further reactions, the prepara-
tions of heterocycles 131|132 with well-positioned, potentially unequal groups at C3 and C5
were planned.
An initial investigation of the selectivity comprised the transformation of NH-sulfondiimine 17
with 4-tolyl-substituted reagents 128. Based on the previous syntheses reported for
1,2-thiazine 1-oxides (Scheme 4-2), a MICHAEL-addition/cyclization/dehydration sequence was
assumed, involving the intramolecular cyclization/dehydration of in situ formed N-vinylated
sulfondiimines (Scheme 4-3).
Scheme 4-3: A MICHAEL-addition/cyclization/dehydration sequence was anticipated.
Favorably, the outcome of both reactions matched the particular substitution patterns ex-
pected for this sequences and exclusively afforded either 1,2-thiazine 1-imine 132b or 132j in
good yields (Scheme 4-3, structure evidenced by 2D NMR spectroscopy).
4.1.4 Substrate scope
With the optimal reaction conditions in hand (Table 4-1, entries 10 and 20), we explored the
substrate scope of the reaction process. In this context, the preparation of well-defined, highly
variable heterocycles 131|132 (Scheme 4-2) was intended and required different substituents
at the sulfur substrates and the propargyl ketones. Unlike in 1971 when the protocol of WIL-
LIAMS and CRAM was reported,[93] these reagents are readily available from literature proce-
dures to date.[30, 95] In general, to properly evaluate the effects of individual substituents, at
least one phenyl group was incorporated in all products.
R e s u l t s a n d D i s c u s s i o n | 51
4.1.4.1 Reactions of sulfoximines
Reactions started either from the standard NH-sulfoximine 100a with various propargyl ketones
128b–s or from different sulfoximines 100b–g with propargyl ketone 128a, affording products
131b–n|p|q (Scheme 4-4).
Generally, electron–donating groups on the substrates afforded the corresponding products in
better yields than electron–withdrawing ones irrespective of their position. As such, C5–methoxy- and methyl-substituted products 131b and 131c were obtained in good yields (85 and
82%, respectively), whereas a nitro-substituent in the same position decreased the yield of het-
erocycle 131d to 44%. Whereas an S-para-nitro-substituted sulfoximine degraded under the
reaction conditions, heterocycle 131k bearing a tolyl group at C3 was obtained in an excellent
yield.
Scheme 4-4: Scope of propargyl ketones 128 and sulfoximines 100. [a] Yield determined by NMR.
Moreover, steric effects have been observed. For example, ortho-chloro-substituted heterocy-
cle 131g was obtained in a significantly lower yield than its para-substituted counterpart 31h
(63% versus 98%). Following the same trend, para- proved superior to meta-substitution for
C3–tolyl-substituents (99% versus 88%). Heterocycle 131e with a sterically demanding 2-
naphtyl-substituent was obtained in a comparatively low yield of 53%.
It is of note that halogenated heterocycles 131f–h|o incorporating fluorinated, chlorinated, and
brominated arenes could be prepared, whereas 131o proved of special interest for further
functionalizations (chapter 4.1.5).
52 | R e s u l t s a n d D i s c u s s i o n
In terms of avoiding arene substituents, for instance, alkyl-containing 131j and 131p were pre-
pared. Noteworthy, S-methyl-substituted product 131o was obtained in a higher yield com-
pared to the procedure of WILLIAMS and CRAM (46% versus 20%).[93] Unfortunately, the syn-
thesis of alternate other derivatives, including a fused example, failed due to the degradation of
hex-3-yn-2-one, 1-phenyldec-1-yn-3-one, and tetrahydrothiophene sulfoximine. Additional at-
tempts aimed at the preparation of a C3–(2-pyridine)-substituted heterocycle. This product
would represent an interesting analog of the 2,2'-bipyridine scaffold, which is a well-known
bidentate ligand frequently employed in catalytic reactions.[96] Unfortunately, the synthesis of
the corresponding propargyl ketone proved challenging, and no heterocyclic product could be
detected in subsequent cyclization attempts. When a corresponding S-(2-pyridyl) sulfoximine
was employed, the heterocyclic product 131r could be identified in NMR (8% yield, standard:
CH2Br2). Considering a higher stability of the starting material at lower temperatures, the reac-
tion was repeated at 60 °C. However, the NMR yield slightly decreased to 7%, and different
attempts of isolation failed. In contrast, introducing a heteroaromatic 2-thiophenyl substituent
was successful and provided product 131i in an excellent yield of 99%. Furthermore, 1,1,1-
trifluorobut-3-yn-2-one, 3-phenylpropiolaldehyde, methyl propiolate, and (E)-chalcone were
employed as alternate reagents instead of propargyl ketones. However, in all these cases solely
the degradation of the reagents, but no product formation occurred.
4.1.4.2 Reactions of sulfondiimines
Subsequent studies included the reactions of standard NH-sulfondiimine 17 with different pro-
pargyl ketones 128 (products 132b–k; Scheme 4-5).
Scheme 4-5: Substrate scope with respect to the propargyl ketones 128 and sulfondiimines 106.
R e s u l t s a n d D i s c u s s i o n | 53
In general, the same steric and electronic effects as those in the reactions of sulfoximines were
observed. Accordingly, sterically more demanding substituents led to lower yields, apparent in
the series of products 132f–g and 132j–k, and substitution with electron–donating groups
proved superior to electron–withdrawing ones. In this series, products bearing a para-nitro-
group at C5 or a heptyl substituent at C3 could not be obtained.
Employing different NH-sulfondiimines 106 with propargyl ketone 128a afforded heterocycles
132l–n (Scheme 4-5), including products 132l and 132m substituted by protecting groups
(R4 = cyano and PMP, respectively) at the second nitrogen. Unfortunately, corresponding N-
methyl and N-unsubstituted heterocycles were inaccessible by this reaction sequence due to
substrate degradation. Hence, for accessing the N-unsubstituted building block 132o of high
interest regarding further N-functionalizations, deprotections of heterocycles 132l or 132m
were envisioned (chapter 4.1.5.1).
4.1.5 Applications
To expand their synthetic value, further attempts focused on functional–group modifications
and derivatizations of the newly prepared products. In this context, the N-protected heterocy-
cles 132l and 132m (R4 = PMP, CN) and bromo-substituted product 131o (R1 = para-
bromophenyl) were selected as representative substrates and subjected to deprotection (chap-
ter 4.1.5.1), palladium–catalyzed cross–couplings (chapter 4.1.5.2), and C‒H bond activation
procedures (chapter 4.1.5.3).
4.1.5.1 Deprotection
As outlined, the deprotection of a 1,2-thiazine 1-imine was planned. Initially, N-PMP-protected
derivative 132l was chosen and subjected to deprotection conditions recently applied to N,N'-
disubstituted sulfondiimines.[47] However, complete substrate decomposition was observed in
this case. Favorably, starting from N-cyano-substituted product 132m, deprotection proceeded
smoothly by employing a one-pot protocol previously reported for N-cyano sulfoximines.[95b]
Hereby, heterocyclic building block 132o was obtained in almost quantitative yield (99%;
Scheme 4-6).
Scheme 4-6: The deprotection of heterocycle 132m afforded N-unsubstituted building block 132o.
54 | R e s u l t s a n d D i s c u s s i o n
4.1.5.2 Palladium–catalyzed amination and arylation
To further demonstrate the synthetic utility of the heterocyclic products, S-(para-
bromophenyl)-substituted heterocycle 131o (Scheme 4-4) was selected as the representative
building block and subjected to palladium–catalyzed cross–coupling procedures previously re-
ported by our group for (S)-S-(para-bromophenyl)-S-methyl-NH-sulfoximine.[97] Favorably, the
palladium–catalyzed SUZUKI-type arylation and BUCHWALD–HARTWIG-type amination of sub-
4 1.5 2.5 4 tert-AmOH 66|20 [a] Yield determined by NMR (internal standard: CH2Br2). Yield after column chroma-
tography in parenthesis.
Finally, the rhodium–catalyzed regioselective ortho-alkenylation of building block 131o led to
ortho-alkenylated product 136c in a good yield of 74% (Scheme 4-8). Here, the corresponding
dialkylated 1,2-thiazine oxide 136d was observed as the byproduct in 19% yield, which proved
readily separable by column chromatography. Product 136c is of special interest as the bromo-
substituent remains accessible for further functionalizations after the regioselective alkenyla-
tion reaction. Notably, these transformations represe t the first dire ted C‒H bond functionali-
zations of molecular flexible 1,2-thiazines.
Scheme 4-8: Regioselective ortho-alkenylation of building block 131o.
Unfortunately, when a representative phenyl-substituted 1,2-thiazine 1-imine 132a was sub-
jected to these reaction conditions, substrate degradations anticipated the formation of the
desired alkenylated product 136. Further studies are necessary to enable the C‒H bond activa-
tion in this molecular scaffold.
56 | R e s u l t s a n d D i s c u s s i o n
4.1.6 Summary and outlook
Inspired by WILLIAMS and CRAM (Scheme 4-2),[93] a one-pot, regioselective, and general proto-
col for the syntheses of differently substituted, previously unprecedented 1,2-thiazines
131|132 in good to excellent yields from readily available NH-sulfoximines 100,
NH-sulfondiimines 120, and propargyl ketones 128 was developed. Noteworthy, the 1,2-
thiazine 1-imines 132 as a previously unprecedented class of heterocycles have been accessed
for the first time.
Scheme 4-9: 1,2-Thiazines prepared in this project.
The products proved of high synthetic value being readily modifiable regiosele ti e C‒H bond activations, deprotection, and classical cross–coupling reactions. In future studies, the
biological activities of the newly prepared 1,2-thiazine derivatives should be tested. In addition,
further derivatizations of the products, for instance of the N-unprotected derivative 132o, ap-
pear of interest regarding potential lead optimizations. The preparation of enantiopure oxidized
and iminated heterocycles by applying NH-sulfoximines and NH-sulfondiimines[30] readily avail-
able in enantiomerically pure form (Scheme 1-16) are encountered possible as well.
4.2 Syntheses of 1,2-benzothiazine 1-imines (Project P5)
4.2.1 Background and aim of the project
1,2-Benzothiazines represent six- e ered “‒N-based heterocycles of high commercial im-
portance due to their potent biological activity.[88, 100] In particular, the so-called oxicams as the
most biologically active benzothiazines incorporating an 1,2-benzothiazine 1,1,4-trioxide core
have been investigated in detail.[88] Contrarily, affected by their challenging synthetic accessibil-
ity the structurally related 1,2-benzothiazine 1-oxides 134 have been rather neglected in medic-
inal chemistry and crop protection.[88, 100] As single example, STOSS and SATZINGER at Gödecke
and Warner–Lambert claimed the antisecretory activity of benzothiazine derivatives 134a
(Scheme 4-10).[101]
Regarding the synthesis of 1,2-benzothiazine 1-oxides 134, seminal work of WILLIAMS and
CRAM in 1971 included the first example 134b obtained by an imination/ring-closure reaction
sequence of sulfoxide 139 with sodium azide under acidic conditions (Scheme 4-10).[93a]
R e s u l t s a n d D i s c u s s i o n | 57
Scheme 4-10: First synthesis of a 1,2-benzothiazine oxide 134b by WILLIAMS and CRAM[93a], and deriva-
tives 134a with antisecretory activity claimed by STOSS and SATZINGER.[101-102]
Subsequent synthetic protocols involved NH-sulfoximines 100 as the substrates. Besides syn-
theses of dibenzothiazines,[103] HARMATA and coworkers reported the SONOGASHIRA-type
cross–coupling of ortho-bromo sulfoximine 100h and subsequent intramolecular alkyne ami-
dation towards benzothiazines 134c (Scheme 4-11). Disadvantageously, only with alkyl-
substituted alkynes 140 high selectivities towards the heterocycles 134c proved possible,
whereas 1,2-benzoisothiazoles 141 represented the major products with alkynylarenes 140.[95c]
Scheme 4-11: SONOGASHIRA-type synthesis of benzothiazines 134c by HARMATA and coworkers.[95c]
More recently, BOLM[99f, 99g] and coworkers investigated alternative synthetic pathways towards
1,2-benzothiazine oxides 134 involving highly atom- and step-economic Cp*–rhodium(III)-
catalyzed C‒H bond activations of the S-arene ortho-C(sp2)–H of sulfoximines 100 with alkynes
142 or diazo compounds 143 (path a|b, Scheme 4-12). Subsequently, attempts by GLORIUS[104]
and coworkers involved the application of tosyl and mesyl ketones 144 as oxidized alkyne
equivalents in some redox-neutral variations (path c, Scheme 4-12). All of those reactions rep-
resent examples for the—presumably due to the potential catalyst poisoning—scarce applica-
tions of sulfur-containing directing groups in metal–catalyzed FG–directed couplings of C–H
bonds. In contrast, although they bear an increased potential for structural diversity compared
to sulfoximine-based examples 134, no 1,2-benzothiazine 1-imines 133 exist. To date, the only
sulfondiimine-based benzothiazine existing is N-unsubstituted 2,1-benzothiazine 97, which re-
sulted from a palladium–catalyzed N-arylation of NH-sulfondiimine 17 with ortho-
bromobenzaldehyde (72l) and a subsequent intramolecular addition/condensation process
(Scheme 1-45).[47]
Inspired by the recent elegant pathways towards 1,2-benzothiazine 1-oxides 134 by direct C‒H bond functionalizations reported by BOLM[99g] or GLORIUS[104] and coworkers, the aim of this
project was to access the first 1,2-benzothiazine 1-imines 133 by rhodium–catalyzed annulation
reactions of NH-sulfondiimines 106.
58 | R e s u l t s a n d D i s c u s s i o n
Scheme 4-12: Recently published protocols for the syntheses of 1,2-thiazine 1-oxides 134.[99f, 99g, 104]
Considering different reaction partners such as alkynes 142 (chapter 4.2.2.1),[99f] diazo com-
pounds 143 (chapter 4.2.2.2),[99g] and ɑ-substituted ketones 144 (chapter 4.2.2.3),[104] as varia-
ble substitution patterns as possible were attempted for the heterocyclic products 133. There-
by, broadening the scope of sulfur-based directing groups in the Cp*–rhodium(III)-catalyzed
couplings of arene C(sp2)–H bonds was envisioned.
4.2.2 Results and discussion
4.2.2.1 Alkynes
Initially, diphenylacetylene (142a) as the representative alkyne was employed as the reaction
partner inspired by a procedure previously reported by our group (Scheme 4-12).[99f] Contextu-
ally, the oxidative annulation of NH-sulfondiimine 17 towards 3,4-substituted 1,2-benzothiazine
133 was investigated (Scheme 4-13).
Scheme 4-13: The annulation of an internal alkyne failed to give the first 1,2-benzothiazine 1-imine.
With [Cp*Rh(MeCN)3][SbF6]2 as the catalyst and copper acetate monohydrate as the oxidant in
different solvents (DMF, DCE, dioxane) no heterocyclic product could be detected in all cases.
Whereas the alkyne was recovered, full degradation of NH-sulfondiimine 17 was observed after
18 h under the harsh oxidative reaction conditions. To enhance the selectivity towards the de-
sired 1,2-benzothiazines 133, subsequent attempts included the use of reaction partners differ-
ent from alkynes.
R e s u l t s a n d D i s c u s s i o n | 59
4.2.2.2 Diazo compounds
I spired a C‒H bond activation/cyclization/condensation process recently reported for sul-
foximines by our group (Scheme 4-12),[99g] further attempts focused on regioselective rhodium–catalyzed annulation reactions of substrate 17 with diazo compounds. Contrary to the previous-
ly described annulation reactions with internal alkynes under harsh oxidative reaction condi-
tions (Scheme 4-13), no external oxidants have been necessary with diazo compounds.[99g] This
combination was envisaged to result in a better selectivity of the process and a higher stability
of the sulfondiimine substrates.
Optimization
In terms of optimization, ethyl diazoacetoacetate (143a) was used as the representative rea-
gent in the initial reactions with NH-sulfondiimine 17. According to the literature protocol,[99g]
[Cp*Rh(MeCN)3][SbF6]2 was employed as the catalyst in combination with sodium acetate as
the base (Table 4-3). At 100 °C in DCE, the desired heterocycle 133a was formed in an already
good yield of 72% after only 3 h of reaction time (entry 1). Favorably, as reported previously for
the corresponding sulfoximines,[99g] exclusively the 1,2-benzothiazine with the ester moiety at
C4 was formed.
Table 4-3: Optimization of the annulation reaction conditions.[a]
HRMS (ESI): 330.1996, calcd. for C19H28N3S [M+H]+: 330.1999.
[a] N,N-Diethylaminoethyl bromide is generated in situ from the hydrobromide reagent and structurally related to a group of N-(2-chloroethyl)-substituted amine derivatives known as nitrogen mustards. Bearing a strong cytotoxic effect, these compounds are utilizable for chemical warfare purposes. Hence, this transformation was handled under specific safety precautions.
0.434 mmol, 2.00 equiv), employing an excess of n-butyllithium (1.6 M,
0.456 mmol, 143 L, 2.10 equiv) and after stirring for 1 h at –78 °C. Pu-
rification by flash column chromatography with n-pentane/ethyl ace-
tate: 8/2 to 7/3 afforded the product as mixture of diastereomers (d.r. = 1:1) and as light brown
solid (32 mg, 44%).
m.p.: 53–54 °C. 1H NMR (600 MHz, CDCl3, mixture of diastereomers): = 8.21–8.17 (each, m, 2H), 8.15–8.12
(each, m, 2H), 7.69–7.63 (both, m, 2H), 7.62–7.57 (both, m, 4H), 7.32–7.29 (both, m, 5H), 7.27–7.24 (both, m, 5H), 7.20–7.15 (both, m, 4H), 7.10–7.07 (both, m, 4H), 6.94–6.89 (both, m, 2H),
An dieser Stelle möchte ich mich bei allen Menschen bedanken, die mich in den letzten Jahren
begleitet und unterstützt haben.
Im Besonderen danke ich meinem Doktorvater und Mentor Prof. Dr. Carsten Bolm. Ich weiß es
sehr zu schätzen, dass Sie trotz Ihrer vielfältigen Verpflichtungen stets die Zeit gefunden haben
mich zu unterstützen und zu fördern. Sie ermöglichten mir die Teilnahme an dem Graduierten-
kolleg „“eleCa , de da it er u de e Fors hu gsaufe thalt a der Osaka U i ersit u d die Teilnahme an zahlreichen Konferenzen im In- und Ausland und die dortige Präsentation meiner
Forschungsergebnisse. Ich danke Ihnen für das Vertrauen, das Sie in mich gesetzt haben, be-
sonders für die Freiheiten in der Thema- und Projekteauswahl und deren Umsetzung. Ich konn-
te mir Ihrer Unterstützung stets sicher sein und dafür bin ich sehr dankbar.
I furthermore want to thank Prof. Dr. Masahiro Miura and Prof. Dr. Tetsuya Satoh for the warm
welcome in Osaka, their support during my stay, and the insights into the chemistry of C-H
bond functionalization. I am grateful to Yuki Yokoyama and Yuto Unoh for the collaborative
work in Osaka, and to Kazutaka Takamatsu as well for the help in the lab and daily life. I wish to
acknowledge Yuto Unoh for the measurement of crystal structures in Osaka (chapter 7), his
collaborative work in Aachen (chapter 4.1.5), and for helpful discussions. I wish to thank all Jap-
anese collaborators for insights into the Japanese working and living style and the Japanese
way of achieving one’s aim. うもありが うございます!
Zudem möchte ich mich herzlich bei Prof. Dr. Albrecht Salzer für seine Unterstützung im Rah-
e o „“eleCa , darü er hi aus, u d eso ders ei der Be er u g für die Bosto -Reise be-
danken.
Ein herzliches Dankeschön geht auch an alle, die in den verschiedenen Projekten in Aachen mit-
gewirkt haben: Jan-Hendrik Schöbel im Rahmen seiner Bachelor- (Kapitel 3.1.3.1) und einer
Forschungsarbeit (Kapitel 4.2), Hannah Schumacher als Forschungsstudentin und HiWi, Marina
Bohlem für die Mitarbeit am N-Alkylierungsprojekt (Kapitel 2.2.3) und Annika Bär für ihre her-
vorragende und zuverlässige Arbeit als Auszubildende in meinem Labor.
Des Weiteren danke ich Dr. Ingo Schiffers, Ingrid Voss, Daniela Gorissen und Gwenda Golm für
ihre Unterstützung in administrativen Angelegenheiten. Ich danke allen Mitarbeitern der analy-
tischen und administrativen Abteilungen des Instituts und insbesondere Dr. Christoph Räuber
für wertvolle Diskussionen bei der Auswertung der 2D-NMR-Spektren der Thiazine.
Ich danke Dr. Christine M. M. Hendriks für die Korrektur dieser Arbeit, für viele wertvolle Dis-
kussionen, und besonders für die Zusammenarbeit im Rahmen des N-Alkylierungsprojektes
(Kapitel 2.2).
Ich danke Susi Grünebaum (Danke für die tollen Doktorhüte!) und Pierre Winandy für die Syn-
these von Sulfondiimin-Precursorn, und ihnen und Dr. Christian Bohnen für die Gabe von NH-
Sulfoximinen.
I deeply thank my labmates Dr. Xiaoyun Chen (Thank you for every single conversation I could
enjoy with you!) and Dr. Shunxi Dong for a great time in lab 1.03. Thank you for the insights into
the Chinese community. 谢谢!
148 | A p p e n d i x
Particularly, I am grateful to Dr. Daniel Priebbenow for his help, the discussions, and his support
during our time together in AK Bolm. (Dan, my English wouldn’t be the same without you!)
Ich danke weiterhin allen ehemaligen und jetzigen Mitarbeitern des AK Bolm, besonders den
offee or er - und den Mensa- beziehungsweise Pontstraße-Gängern, u d alle „“eleCat’s für den ständigen Austausch von Forschungsergebnissen, viele Diskussionen, die tolle Atmo-
sphäre und viele gemeinsame Aktivitäten. Besonderer Dank gilt hierbei Dr. Hannah Baars, Dr.
Christian Bohnen, Dr. Julien Engel, Dr. Daniel Hack, Dr. Christine M. M. Hendriks, Steffen Mader,
Dr. Anne-Dorothee Steinkamp und Jens Reball, die meine Zeit im AK Bolm und bei „“eleCa zu einer ganz besonderen gemacht haben.
Ganz besonders danke ich meinen Freunden Alexander und Gian und meiner besten Freundin
Marie, der Liebe meines Lebens Tobias, meiner Schwester Sara und meinen Eltern für ihre nie
endende Unterstützung in allen Lebenslagen, ihre Freundschaft und dafür, dass sie mich so lie-
ben wie ich bin.
A p p e n d i x | 149
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