Direct Access to N -Alkylsulfoximines from Sulfides by a Sequential Imidation/Oxidation Procedure

Article abstract of DOI:10.1055/s-0034-1380536

Synthetically relevant N-alkyl-substituted sulfoximines are directly prepared from sulfides by an unprecedented one-pot imidation/oxidation sequence. In situ generated N-bromoalkylamines serve as readily accessible imidating agents leading to N-alkylsulfiliminium bromides that are subsequently oxidized providing the corresponding N-alkylsulfoximines. In this manner, gram quantities of the products can be obtained in a short period of time avoiding the use of toxic and cumbersome to handle alkylating reagents.

Full text of DOI:10.1055/s-0034-1380536

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1951–1959
paper
1951
C. A. Dannenberg et al.
Paper
Synthesis
Direct Access to N-Alkylsulfoximines from Sulfides by a Sequential
Imidation/Oxidation Procedure
1) alkyl-NH2 (2.8 equiv), Br2 (1.4 equiv)
MeOH, r.t., 15 min
Carl Albrecht Dannenberg
Vincent Bizet*
O
N
alkyl
S
S
Ph
Me
Ph
Me
2) KMnO4 (3.0 equiv), K2CO3 (2.0 equiv)
acetone, r.t., 16 h
Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
20 examples, broad scope, up to 71% yield
Received: 09.03.2015
Accepted: 14.03.2015
Published online: 16.04.2015
DOI: 10.1055/s-0034-1380536; Art ID: ss-2015-z0151-op
O
N
Me
O
OH
Me
Me
O
NH
Abstract Synthetically relevant N-alkyl-substituted sulfoximines are
directly prepared from sulfides by an unprecedented one-pot imida-
tion/oxidation sequence. In situ generated N-bromoalkylamines serve
as readily accessible imidating agents leading to N-alkylsulfiliminium
bromides that are subsequently oxidized providing the corresponding
N-alkylsulfoximines. In this manner, gram quantities of the products
can be obtained in a short period of time avoiding the use of toxic and
cumbersome to handle alkylating reagents.
N
HN
Me
O
F3C
S
NH
N
S
N
N
N
N
H
AZD6738 (2)
BAY 1000394 (1)
Me
N
Me
Key words sulfoximine, imidation, oxidation, synthetic method, sul-
Me
fide
Me
HN
O
N Me
S
F3C
S
O
N CN
N
Since their discovery, sulfoximines have been widely
studied and applied in asymmetric synthesis and cataly-
sis,1,2 medicinal chemistry,3–5 and crop protection.6 An im-
portant structural feature of these sulfur reagents is the
sulfoximine nitrogen because its functionalization allows
fine-tuning of the molecular properties of the target com-
pounds related to, for example, LADME,7 bioactivity, and/or
solubility. For a number of recent applications, NH- and
N-cyanosulfoximines proved to be the structures of choice.
For instance, BAY 1000394 (1)3,4a–c and AZD6738 (2)4d are
potent kinase inhibitors, currently in phase 1 clinical trials,
and sulfoxaflor (3) is a commercial insecticide (Figure 1).6
Recently, Goldberg and co-workers (AstraZeneca) empha-
sized the improved solubility of N-methylsulfoximines in
water compared to NH-sulfoximines and their sulfone ana-
logues.8 In their study, the N-methylsulfoximines proved
superior to the others combining a higher solubility with
equivalent isolipophilicity of the corresponding sulfone.
Noteworthy is also that sulfoximines can be chiral adding
an extra point of diversity compared to isosteric sulfones.
Me
F3C
N
N
N
H
sulfoxaflor (3)
Figure 1 Relevant bioactive sulfoximines
4
With respect to N-methylsulfoximines this attribute
proved to be important in a recent work by Walker and co-
workers (Pfizer), who found that the N-methylsulfoximine
4 (with S-configuration at sulfur) had equipotent inhibitory
activity on proline-rich tyrosine kinase 2 as its sulfone ana-
logue showing a significantly reduced hERG liability.5a
Motivated by the synthetic relevance of N-alkylated
sulfoximines 6 and 7, various approaches for their prepara-
tion have been developed (Scheme 1, a–c). Most of them,
however, have severe synthetic drawbacks as they require
preformed NH-sulfoximines 5, multi-step synthetic se-
quences, and highly reactive reagents such as strong bases
and toxic alkylating agents. For example, N-alkylated deriv-
atives 6 have been prepared by a two-step protocol involv-
ing an initial N-acylation of 5 with an acyl halide followed
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1951–1959

1952
C. A. Dannenberg et al.
Paper
Synthesis
by reduction of the resulting N-acylated intermediate with
borane.9 Although the latter transformation is well estab-
lished, it can be problematic in reactions performed on
larger scale due to the instability of the reducing agent. A
direct introduction of the N-alkyl substituent requires the
use of a (toxic) alkyl halide in combination with a strong
base such as butyllithium or an alkali metal hydride and a
phase-transfer catalyst under strictly anhydrous condi-
tions,10 or, alternatively, a super-basic system consisting of
KOH in DMSO.11 As long as the substrates are base-tolerant
and the alkyl halides can be handled, these direct alkyla-
tions might be the methods of choice. Generally, N-methyl
derivatives 7 are accessed differently (Scheme 1, b). Most
common for the preparation of these compounds are reduc-
tive amidations of NH-sulfoximines 5 with a mixture of
formaldehyde and formic acid under Eschweiler–Clark con-
ditions. After reflux for several days, many N-methylated
products can be obtained in good yields.12 The use of meth-
yl transfer agents such as methyl iodide,10b trimethyloxoni-
um tetrafluoroborate12d,13 or ‘magic methyl’ (methyl fluoro-
sulfate)14 allows the reduction of the reaction time and the
temperature. Although appealing at first glance, it is note-
worthy that these conditions are unsuitable for acid-sensi-
tive substrates, and furthermore, the pronounced toxicities
of the latter mentioned alkylating agents render such
methylations unattractive in scaled-up processes.
To the best of our knowledge, there is only a single re-
port on the direct sulfide-to-N-methylsulfoximine conver-
sion.15 It involves sulfide imidation with N-methyl-O-mesi-
tylsulfonylhydroxylamine (9)16,17 leading to sulfonium aryl-
sulfonates 10 and subsequent oxidation of 10 with m-CPBA
to N-methylsulfoximines 7 (Scheme 1, c). Unfortunately,
only four products with a rather specific substitution pat-
tern [derived from 2-(alkylthio)pyridines] have been pre-
pared in this manner, and the yields were unsatisfying (38%
over two steps at best).
Considering the importance of N-alkylated sulfoximines
6 and 7 in the aforementioned biomedical applications and
their general relevance in synthesis we wondered about a
direct access of such compounds starting from sulfides 8
utilizing straightforward reagents under easy to perform
experimental conditions. A particular need was recognized
in the synthesis of N-methylsulfoximines 7. Primary alkyl-
amines 11 were identified as ideal sources for the envis-
aged imidation process. Hence, for the preparation of 7,
simple methylamine (11a) was regarded as the reagent of
choice. In the light of the mass spectrometry work by Cook
and co-workers,18 we hypothesized that the activation of
the amine could be achieved by treatment with bromine
leading to N-bromoalkylamines 13. Reaction of 13 with the
sulfide 8 would then lead to the alkylsulfiliminium bro-
mides 14.19 Oxidations of 14 should then lead to the desired
N-alkylated sulfoximines 6. Starting from methylamine, N-
methylsulfoximines 7 could easily be accessed. To our de-
previous work:
From NH-sulfoximines:
O
N
alkyl
Me
conditions A or B
S
(a)
R1
R2
refs. 9–11
6
O
NH
R2
(alkyl =/ Me)
S
R1
O
N
5
conditions C, D, E or F
refs. 10b,12–14
(b)
S
R1
R2
7
from sulfides:
O
O
H
ArSO3
NHMe
N
S
Me
O
9
Ar
O
N Me
1) NH3, CH2Cl2
S
S
S
R1
R2
R1
R2
2) m-CPBA
R1
R2
(c)
CH2Cl2, r.t.
8
10
7
Ref. 15
Ar = 2,4,6-Me3C6H2
R1 = 2-pyridinyl, R2 = Me, i-Pr, Bu, n-C10H21
-------------------------------------------------------------------------------------------
this work:
R1NH2
R1NH2
(base)
S
R1
R2
R3
(11)
+
HN
S
KMnO4
K2CO3
Br
O
N
R1
H
N
8
R1
Br
S
Br2
R2
R3
R2
R3
13
14
6 or 7
R1NH2•HBr (12)
(base•HBr)
Scheme 1 Synthetic routes to N-alkylsulfoximines 6 and 7. Reagents
and conditions: A) 1. RCOCl, DMAP (cat.), pyridine or Et3N, CH2Cl2,
2. HBX2, CH2Cl2; B) BuLi, MH (+ PTC) or KOH in DMSO, alkyl halide;
C) H2CO, HCO2H, H2O, reflux; D) NaH, MeI, DMF; E) Me3O+BF4–, CH2Cl2;
F) FSO2OMe, MeCN.
light, this hypothesized pathway proved applicable
(Scheme 1, bottom). Using a combination of MeNH2 (11a,
2.8 equiv) and Br2 (1.4 equiv) in methanol at room tempera-
ture led to full conversion of thioanisole (8a) in only 15
minutes with N-methylsulfiliminium bromide (14a) and
sulfoxide 15a being the only products (formed in a 92:8 ra-
tio as determined by 1H NMR spectroscopy; Table 1,
entry 1).20 Attempts to avoid the formation of 15a by lower-
ing the temperature to 0 °C (entry 2), modifying the sub-
strate/reagent ratios (entries 3 and 4), or changing the sol-
vent (entries 5–9) remained unsuccessful. In all cases, sulf-
oxide 15a was observed as a by-product in considerable
amounts. An important observation was made during the
solvent screening. While MeOH could be replaced by EtOH
or H2O without significantly affecting the product forma-
tion and the 14a/15a ratio (entries 5 and 6), use of 2,2,2-tri-
fluoroethanol led to a selectivity change providing sulfox-
ide 15a as the main product (entry 7). In CH2Cl2 the ratio of
14a/15a was 54:46, and in acetone neither of the two prod-
ucts was observed (entries 8 and 9, respectively). Notice-
ably, in the latter two solvents a precipitate formed upon
mixing of MeNH2 and Br2, and this solid was identified as
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1951–1959

1953
C. A. Dannenberg et al.
Paper
Synthesis
methylammonium bromide (12a). In the subsequent opti-
mization of the process, the low solubility of 12a in acetone
proved beneficial because it allowed the separation of the
products 14 from the ammonium salts 12. Thus, for solubil-
ity reasons the initial sulfur imidation (with MeNH2 and
Br2) was performed in MeOH, where all reagents and inter-
mediates dissolved. Then, the polar, protic solvent was re-
moved under vacuum and acetone was added leading to a
solution of 14a and crystals of 12a, which could be removed
by filtration. The obtained N-methylsulfiliminium salt 14a
was stable for a few days at –20 °C, but decomposed readily
at room temperature.21 As a final note, bromine could not
be replaced by iodine.
over the alternative oxidation procedures. Reducing the re-
action time from 16 hours to just 2 hours led to a decrease
in the yield of 7a (64%). Presumably due to the instability of
14a the product yield could not be further increased. As
main by-products sulfide 8a and sulfoxide 15a were detect-
ed.
For the investigation of the substrate scope, diversely
substituted sulfides 8a–r were subjected to the optimized
reaction conditions for both steps (sulfide imidation with
MeNH2/Br2 and subsequent sulfiliminium salt oxidation
with KMnO4/K2CO3; Scheme 2). In general, para- and meta-
substituted aryl methyl sulfides 8b–i with both electron-
donating and -withdrawing groups on the arene reacted
well providing the corresponding N-methylsulfoximines
7b–i in moderate to good yields (up to 68%). The only ex-
ception was sulfoximine 7g, which was obtained in only
21% yield due to the low solubility of the starting material
(sulfide 8g) in methanol. Electronic effects of the aryl sub-
stituents had no apparent influence on the substrate reac-
tivities and product yields. Presumably, steric hindrance led
to the slightly lower yields in the conversions of ortho-sub-
stituted aryl methyl sulfides 8j and 8k affording sulfoxi-
mines 7j and 7k in 31 and 25% yield, respectively. Applying
the reaction sequence on methyl 2-pyridinyl sulfide (8l)
gave sulfoximine 7l in 46% yield illustrating that the process
was superior to the existing technology providing the same
product.15 Further variations of sulfide structure revealed
that also other substituent combinations were tolerated.
The results, however, varied. For example, whereas S-ethyl
phenyl sulfide led to 7m in good yield (53%), preparation of
the analogous S-cyclopropyl derivative 7n and N,S-dimeth-
yl-S-benzylsulfoximine (7o) proved more difficult (12% and
15% yield, respectively). Dialkyl-substituted sulfides 8p and
8q reacted well leading to 7p and 7q in 44 and 46% yield,
respectively. The latter product is of particular interest be-
cause it is a protected NMe analogue of methionine sulfoxi-
mine (MSO), which is a potent inhibitor of the γ-glutamyl-
cysteine synthetase, an essential enzyme in the glutathione
biosynthesis.2d
Table 1 Screening of the Reaction Parametersa
2 MeNH2
(11a)
+
S
Me
Ph
Me
HN
S
O
S
solvent
H
N
8a
Br
Me
+
Me
Br
Ph
Ph
Me
Br2
13a
MeNH2·HBr
14a
15a
(12a)
Entry
Solvent
Ratio of 14a/15ab
1
MeOH
MeOH
MeOH
MeOH
EtOH
92:8
2c
3d
4e
5
85:15
80:20
85:15
90:10
80:20
25:75
54:46
n.r.f
6
H2O
7
2,2,2-trifluoroethanol
CH2Cl2
8
9
acetone
a The reactions were carried out on a 0.5 mmol scale with 2.8 equiv of
MeNH2 (11a) and 1.4 equiv of Br2 at r.t.
b Determined by 1H NMR spectroscopy.
c The reaction was carried out at 0 °C.
d Use of 2.0 equiv of MeNH2 (11a) and 1.0 equiv of Br2.
e Use of 4.0 equiv of MeNH2 (11a) and 2.0 equiv of Br2.
f n.r. = no reaction.
Diphenyl sulfide (8r) did not react, which was in line
with earlier observations.22 The scalability of the process
was demonstrated in a conversion of sulfide 8a on a
10 mmol scale, which gave N-methylsulfoximine 7a in 52%
yield.
Encouraged by these results we wondered about using
other amines in direct conversions of sulfides into N-substi-
tuted sulfoximines 6. In order to allow a comparison to the
data obtained in reactions with methylamine, methyl phe-
nyl sulfide (8a) was used as the substrate. Pleasingly, such
transformations proved possible, but unfortunately, the
substrate range was rather limited, and the yields remained
comparably low. For example, using ethylamine instead of
methylamine afforded N-ethylsulfoximine 6a in 35% yield
(Scheme 3) as compared to 72% yield in the preparation of
Next, we focused on the oxidation step to convert N-al-
kylsulfiliminium salts 14 to their corresponding sulfox-
imine derivatives 6 and 7. Following the initial work de-
scribed above, 14a was selected as a representative sub-
strate. While attempts to use sodium hypochlorite or
hydrogen peroxide as oxidants remained unsuccessful, 7a
was obtained by oxidation of 14a with m-CPBA. However,
knowing about the potential hazards of this peracid we
were delighted to find that KMnO4 could also be applied. In
combination with K2CO3, it provided 7a in 71% yield after
16 hours at room temperature (for additional information,
see Supporting Information). Noteworthy is also that this
transformation proceeded in acetone, which allowed a di-
rect use of the aforementioned sulfiliminium salt solution
after removal of 12a representing an operational advantage
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1951–1959

1954
C. A. Dannenberg et al.
Paper
Synthesis
of the intermediates. Finally, ammonia was tested as the
amino component, but also in this case, no product (5a)
was observed.
1) MeNH2 (2.8 equiv), Br2 (1.4 equiv)
O
N
Me
MeOH, r.t., 15 min
S
S
R1
R2
R1
R2
2) K2CO3 (2.0 equiv), KMnO4 (3.0 equiv)
acetone, r.t., 16 h
8
7
1) RNH2 (2.8 equiv), Br2 (1.4 equiv)
MeOH, r.t., 15 min
O
N R
O
N
Me
O
N
Me
O
N
Me
S
S
Ph
Ph
Me
Ph
Me
S
S
S
2) KMnO4 (3.0 equiv), K2CO3 (2.0 equiv)
acetone, r.t., 16 h
Me
Me
Me
6a–d, 16–18, 5a
8a
Cl
Br
O
N
Et
O
N
n-Bu
O
N
c-Hex
O
N
i-Pr
O
N
t-Bu
7a, 71% (52%)
7b, 60%
7c, 53%
S
S
S
S
S
Me Ph
Me Ph
Me
Ph
Me
Ph
Me
O
N
Me
O
N
Me
O N Me
S
S
S
6a, 35%
6b, 32%
6c, 19%
6d, trace
6e, n.r.
Me
Me
Me
O
N
Allyl
O
N
Ph
O
N
CO2Me
O
N
H
Me
MeO
Ac
S
S
S
S
7d, 48%
Ph
Me
16, n.r.
Scheme 3 Scope of the sulfoximine synthesis
Ph
Me
Ph
Me
Ph
Me
7e, 57%
7f, 68%
17, n.r.
18, n.r.
5a, n.r.
O
N
Me
O
N
Me
O
S
N
Me
S
S
Br
Me
Me
Me
O2N
In conclusion, we have developed a new direct route to
N-methyl- and other N-alkylsulfoximines by an unprece-
dented imidation/oxidation sequence starting from sul-
fides. In contrast to most other synthetic methods leading
to the same products, the process avoids the intermediacy
of NH-sulfoximines, which are often cumbersome to pre-
pare. Using simple reagents under mild conditions at room
temperature various products can be accessed within a
short period of time.
7i, 52%
Me
Me
7g, 21%
7h, 58%
Me
Me
O
N
Me
O
N
O
N
S
S
S
Me
N
Br
7j, 31%
CO2Me
7k, 25%
7l, 46%
O
N Me
O
N Me
S
S
O
N
Me
S
Me
Unless otherwise stated, the starting materials were commercially
available and used as received. H, 13C and 19F NMR spectra were re-
1
7m, 53%
Me
Me
7n, 12%
7o, 15%
Me
corded either on Varian V-NMRS 600, Varian V-NMRS 400 or Varian
Mercury 300 spectrometer, in CDCl3. Chemical shifts (δ) are given in
ppm relative to TMS and calibrated to residual CHCl3. Coupling con-
stants (J) are reported in Hz and standard coupling patterns are used.
IR spectra were recorded on a PerkinElmer FT-IR Spectrum 100 as KBr
pellets or neat liquids; wave numbers are given in cm–1. Mass spectra
were recorded on a Finnigan SSQ 7000 spectrometer [electron ioniza-
tion (EI), 70 eV] and peaks are listed according to their m/z values.
High-resolution mass spectra (HRMS) were recorded on a Thermo
Scientific LTQ Orbitrap XL spectrometer with positive ion mode. Ele-
mental analyses were performed on an ElementarVario EL instru-
ment. Melting points were measured with a Büchi Melting Point B-
540 apparatus. Flash column chromatography was performed with
Merck silica gel 60 (35–70 mesh). Reactions were monitored by TLC
on silica gel 60 F254 coated on aluminum sheets from Merck with de-
tection by UV light and/or staining solutions (KMnO4). Preparative
HPLC was carried out on Varian, Kromasil-RP-18 250 × 30 mm,
MeOH–H2O; 12 mL/min, 51 bar, 254 nm, SD-1 PumpeProstar 320 UV-
Detector for compounds 7g, 7k, and 7n after column chromatography.
O
O
N
O
N
Me
O N
S
S
S
Me
OMe
NHCbz
7p, 44%
7q, 46%
7r, n.r.
Scheme 2 Scope of the NMe sulfoximine synthesis (performed on a
1.0 mmol scale). The yield of 7a shown in parentheses resulted from a
reaction on a 10 mmol scale.
N-methyl analogue 7a (Scheme 2). Applying n-butylamine
and cyclohexylamine gave sulfoximines 6b and 6c in 32 and
19% yield, respectively. Although these yields were low, the
overall synthetic value of the process was regarded high
considering the multi-step alternative providing the same
products. Attempts to prepare N-substituted sulfoximines
6d, 6e, and 16–18 were unsuccessful providing the prod-
ucts in only trace amounts at best (Scheme 3). Most likely,
the more pronounced stereoelectronic effects of the R
groups (as, for example, in tert-butylamine, aniline, or
methyl carbamate) were responsible for the low reactivity
N,S-Dimethyl-S-phenylsulfiliminium Bromide (14a)
A 100 mL round-bottomed flask, equipped with a magnetic stir bar,
was charged with MeOH (50 mL) and MeNH2 (11a, 33% in EtOH,
3.5 mL, 28.0 mmol, 2.8 equiv). Subsequently, Br2 (0.72 mL, 14.0 mmol,
1.4 equiv) was added dropwise and the reaction mixture was stirred
vigorously for 5 min. Afterwards, thioanisole (8a; 1.2 mL, 10 mmol,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1951–1959

1955
C. A. Dannenberg et al.
Paper
Synthesis
1.0 equiv) was added and the mixture was stirred for another 10 min.
After full consumption of 8a, the solvent was removed under reduced
pressure. The residue was taken up in acetone (30 mL) and filtered
over filter paper. The filtrate was concentrated under reduced pres-
sure until ca. 10 mL, which was then added dropwise to cold Et2O
(200 mL) under vigorous stirring to form a milky solution. After ca. 30
min, the solution became completely clear along with the formation
of an oily off-white precipitate sticking all around the flask. The sol-
vent was carefully removed keeping the precipitate in the flask. The
oily residue was dried under high vacuum to give 14a, which was
used without further purification; yield: 2.0 g (85%); viscous yellow
oil.
MS (EI, 70 eV): m/z (%) = 184 (6), 183 ([M+], 11), 170 (5), 169 (9), 168
(100), 142 (7), 141 (78), 140 (7), 126 (10), 125 (24), 124 (13), 97 (11),
92 (6), 91 (5), 78 (9), 77 (24), 65 (5), 63 (6), 51 (16).
HRMS (ESI): m/z [M+
+ H] calcd for C9H14NOS: 184.07906;
found: 184.07928.
N-Butyl-S-methyl-S-phenylsulfoximine (6b)
Eluent: n-pentane–EtOAc (2:1) to EtOAc; yield: 68 mg (32%); yellow
oil.
IR (ATR): 3821 (vw), 3401 (w), 3064 (vw), 2928 (s), 2863 (s), 2674
(vw), 2323 (w), 2097 (w), 1994 (vw), 1913 (vw), 1658 (w), 1581 (vw),
1531 (vw), 1447 (s), 1411 (w), 1368 (vw), 1311 (w), 1232 (vs), 1132
IR (ATR): 3860 (vw), 3741 (vw), 3428 (m), 3051 (vs), 2912 (m), 2822
(m), 2742 (vw), 2660 (vw), 2549 (vw), 2317 (s), 2110 (m), 1997 (w),
1924 (w), 1772 (vw), 1691 (w), 1580 (w), 1441 (vs), 1320 (m), 1152
(vs), 1085 (vs), 976 (vs), 863 (w), 782 (m), 742 (vs), 688 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.87–7.83 (m, 2 H), 7.55 (t, J = 7.3 Hz, 1
H), 7.51 (t, J = 7.4 Hz, 2 H), 3.03 (s, 3 H), 2.92–2.87 (m, 1 H), 2.74–2.69
(m, 1 H), 1.51–1.45 (m, 2 H), 1.33–1.23 (m, 2 H), 0.81 (t, J = 7.4 Hz, 3
H).
13C NMR (151 MHz, CDCl3): δ = 139.7, 132.8, 129.4, 128.7, 45.2, 43.6,
35.0, 20.4, 13.9.
MS (EI, 70 eV): m/z (%) = 212 ([M+], 4), 169 (5), 168 (66), 142 (8), 141
(100), 140 (7), 126 (12), 125 (34), 124 (15), 97 (13), 91 (5), 78 (11), 77
(26), 63 (6), 51 (7).
(w), 1070 (vs), 974 (vs), 840 (w), 751 (vs), 684 (vs) cm–1
.
1H NMR (600 MHz, CD3OD): δ = 8.00–7.99 (m, 2 H), 7.84–7.81 (m, 1
H), 7.78–7.76 (m, 2 H), 4.85 (s, 1 H), 3.49 (s, 3 H), 2.68 (s, 3 H).
13C NMR (151 MHz, CD3OD): δ = 135.4, 131.8, 129.8, 129.7, 29.6, 28.0.
MS (ESI): m/z (%) = 154 (51), 139 (24), 124 (100), 107 (28).
N-Alkylsulfoximines 6 and N-Methylsulfoximines 7 from Sulfides
8; General Procedure
HRMS (ESI): m/z [M+
+ H] calcd for C11H18NOS: 212.11036;
A 50 mL round-bottomed flask, equipped with a magnetic stir bar
was charged with MeOH (6 mL) and an alkylamine 11 (2.8 mmol, 2.8
equiv) for the synthesis of 6 and methylamine (11a; 33% in EtOH,
360 μL, 2.8 mmol, 2.8 equiv) for the synthesis of 7. Subsequently, bro-
mine (80 μL, 1.4 mmol, 1.4 equiv) was added dropwise. The reaction
mixture was stirred vigorously for 5 min. Afterwards, sulfide 8 (1.0
mmol, 1.0 equiv) was added and the mixture was stirred for another
10 min. The reaction progress was monitored by TLC. After full con-
sumption of 8, the solvent was removed under reduced pressure. The
residue was taken up in acetone (25 mL) and filtered over filter paper.
The filtrate was concentrated under reduced pressure to ca. 10 mL.
After the addition of K2CO3 (276.4 mg, 2.0 mmol, 2.0 equiv) and
KMnO4 (474.1 mg, 3.0 mmol, 3.0 equiv), the mixture was stirred for
16 h at r.t. Then, the solvent was removed under reduced pressure,
the mixture was diluted with CH2Cl2 (20 mL), and the CH2Cl2 layer
was washed with distilled H2O (30 mL). The aqueous phase was ex-
tracted with CH2Cl2 (3 × 10 mL) and the combined organic phases
were dried (MgSO4), filtered, and concentrated under reduced pres-
sure. The product was purified by column chromatography (silica gel,
eluent: n-pentane–EtOAc) to yield N-alkylsulfoximine 6 or N-methyl-
sulfoximine 7.
found: 212.11043.
N-Cyclohexyl-S-methyl-S-phenylsulfoximine (6c)
Eluent: n-pentane–EtOAc (2:1) to EtOAc; yield: 45 mg (19%); colorless
oil.
IR (ATR): 3854 (vw), 3400 (w), 3063 (vw), 3011 (vw), 2925 (vs), 2852
(s), 2663 (vw), 2335 (vw), 2088 (vw), 1992 (vw), 1919 (vw), 1735
(vw), 1654 (vw), 1582 (vw), 1532 (vw), 1445 (s), 1410 (w), 1366 (w),
1316 (w), 1230 (vs), 1131 (vs), 1083 (s), 1018 (vw), 971 (s), 889 (w),
839 (vw), 787 (m), 742 (vs), 689 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.92–7.89 (m, 2 H), 7.60–7.56 (m, 1 H),
7.55–7.51 (m, 2 H), 3.03 (s, 3 H), 2.86–2.80 (m, 1 H), 1.89–1.85 (m, 1
H), 1.69–1.61 (m, 3 H), 1.49–1.45 (m, 1 H), 1.40–1.34 (m, 1 H), 1.32–
1.26 (m, 1 H), 1.16–1.06 (m, 3 H).
13C NMR (151 MHz, CDCl3): δ = 140.9, 132.8, 129.3, 128.7, 54.3, 45.8,
37.7, 36.5, 25.7, 25.6, 25.4.
MS (EI, 70 eV): m/z (%) = 328 (3), 240 (6), 239 (18), 238 (100), 237
([M+ + H], 43), 236 (20), 195 (7), 194 (57), 141 (5), 125 (3), 97 (3), 91
(2), 77 (3).
HRMS (ESI): m/z [M+
found: 238.12653.
+ H] calcd for C13H20NOS: 238.12601;
N-Ethyl-S-methyl-S-phenylsulfoximine (6a)
Eluent: n-pentane–EtOAc (2:1) to EtOAc; yield: 64 mg (35%); colorless
oil.
N,S-Dimethyl-S-phenylsulfoximine (7a)
IR (ATR): 3396 (vw), 3061 (vw), 2968 (m), 2925 (w), 2855 (w), 2681
(vw), 2327 (vw), 2103 (vw), 1992 (vw), 1920 (vw), 1737 (vw), 1641
(vw), 1583 (vw), 1475 (vw), 1445 (m), 1408 (vw), 1375 (vw), 1292
(w), 1226 (vs), 1136 (vs), 1088 (s), 988 (s), 865 (vw), 814 (w), 775 (m),
Eluent: EtOAc; yield: 120 mg (71%); colorless oil.
IR (ATR): 3882 (vw), 3195 (m), 3062 (s), 2921 (s), 2314 (vw), 2098
(vw), 1999 (vw), 1912 (vw), 1672 (vs), 1446 (s), 1369 (w), 1312 (m),
1236 (vs), 1149 (s), 1093 (m), 967 (m), 847 (w), 751 (vs), 687 (s) cm–1
.
743 (vs), 689 (m) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.92–7.88 (m, 2 H), 7.64–7.60 (m, 1 H),
7.59–7.55 (m, 2 H), 3.08 (s, 3 H), 2.65 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 138.9, 133.0, 129.6, 128.9, 45.1, 29.7.
1H NMR (400 MHz, CDCl3): δ = 7.87–7.82 (m, 2 H), 7.57–7.47 (m, 3 H),
3.02 (s, 3 H), 2.98–2.90 (m, 1 H), 2.81–2.73 (m, 1 H), 1.11 (t, J = 7.2 Hz,
3 H).
MS (EI, 70 eV): m/z (%) = 172 (5), 171 (11), 170 ([M+], 100), 169 (23),
168 (14), 156 (9), 154 (42), 141 (10), 140 (6), 125 (10), 106 (19), 97
(6), 77 (17), 51 (9).
13C NMR (101 MHz, CDCl3): δ = 139.6, 132.8, 129.4, 128.7, 45.2, 38.5,
18.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1951–1959

1956
C. A. Dannenberg et al.
Paper
Synthesis
HRMS (ESI): m/z [M+ + H] calcd for C8H12NOS: 170.06341; found:
170.06325.
IR (ATR): 3555 (vw), 2925 (w), 2568 (vw), 2299 (vw), 2084 (vw), 1906
(vw), 1737 (w), 1588 (s), 1489 (m), 1309 (m), 1237 (vs), 1139 (vs),
1098 (vs), 1020 (s), 971 (s), 836 (vs), 764 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.84–7.78 (m, 2 H), 7.05–7.01 (m, 2 H),
N,S-Dimethyl-S-(4-chlorophenyl)sulfoximine (7b)
3.88 (s, 3 H), 3.06 (s, 3 H), 2.64 (s, 3 H).
Eluent: n-pentane–EtOAc (1:1) to EtOAc; yield: 65 mg (32%); colorless
13C NMR (151 MHz, CDCl3): δ = 163.4, 131.0, 130.0, 114.8, 55.8, 45.5,
oil.
29.6.
IR (ATR): 3561 (vw), 3202 (vw), 3069 (vw), 2916 (w), 2804 (vw), 2296
(vw), 2096 (vw), 1923 (vw), 1670 (s). 1575 (m), 1471 (m), 1393 (w),
1313 (w), 1237 (vs), 1146 (vs), 1086 (vs), 971 (vs), 833 (vs), 768 (vs)
MS (EI, 70 eV): m/z (%) = 201 (2), 200 (12), 199 ([M+], 30), 184 (14),
171 (8), 156 (5), 155 (35), 139 (5), 137 (8), 136 (100), 123 (10), 121
(13), 108 (11), 95 (5), 92 (12), 77 (14), 64 (6), 63 (11).
HRMS (ESI): m/z [M+ + H] calcd for C9H14NO2S: 200.07398; found:
200.07355.
cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.83 (d, J = 8.6 Hz, 2 H), 7.54 (d, J = 8.6
Hz, 2 H), 3.07 (s, 3 H), 2.64 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 139.8, 137.5, 130.4, 130.0, 45.2, 29.7.
MS (EI, 70 eV): m/z (%) = 206 (7), 205 (10), 204 (23), 203 ([M+], 26),
190 (11), 188 (27), 177 (6), 175 (18), 174 (6), 161 (11), 160 (10), 159
(33), 158 (8), 143 (8), 142 (34), 141 (8), 140 (100), 139 (7), 138 (5),
133 (6), 131 (14), 128 (9), 127 (6), 126 (13), 125 (6), 113 (14), 112
(11), 111 (40), 108 (10), 105 (9), 104 (5), 99 (10), 85 (6), 77 (12), 75
(47), 74 (13), 73 (6), 63 (19), 61 (6), 61 (7), 50 (20), 34 (5).
N,S-Dimethyl-S-(4-acetylphenyl)sulfoximine (7f)
Eluent: EtOAc; yield: 144 mg (68%); white solid; mp 72 °C.
IR (ATR): 3566 (vw), 3360 (vw), 3281 (vw), 3091 (vw), 3055 (vw),
2996 (w), 2962 (vw), 2914 (w), 2880 (w), 2801 (vw), 2637 (vw), 2298
(vw), 2175 (vw), 2081 (vw), 1945 (vw), 1841 (vw), 1684 (vs), 1573
(w), 1393 (s), 1360 (m), 1319 (vw), 1224 (vs), 1145 (vs), 1096 (s), 962
HRMS (ESI): m/z [M+
+
H] calcd for C8H11ClNOS: 204.02444;
(vs), 835 (s), 778 (vs), 742 (s) cm–1
.
found: 204.02406.
1H NMR (400 MHz, CDCl3): δ = 8.14–8.11 (m, 2 H), 8.01–7.97 (m, 2 H),
3.10 (s, 3 H), 2.67 (s, 3 H), 2.65 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 197.0, 140.5, 129.4, 129.3, 128.2, 44.9,
29.7, 27.1.
MS (EI, 70 eV): m/z (%) = 213 (11), 212 (77), 211 ([M+], 52), 210 (9),
198 (11), 197 (11), 196 (100), 183 (16), 182 (11), 167 (18), 152 (11),
149 (6), 148 (54), 132 (7), 121 (5), 106 (7), 105 (6), 104 (5), 91 (9), 76
(5).
N,S-Dimethyl-S-(4-bromophenyl)sulfoximine (7c)
Eluent: n-pentane–EtOAc (1:1) to EtOAc; yield: 131 mg (53%); white
solid; mp 59–60 °C.
IR (ATR): 3197 (vw), 2915 (m), 2807 (w), 2283 (vw), 2087 (vw), 1922
(vw), 1671 (m), 1569 (m), 1464 (m), 1383 (m), 1314 (w), 1227 (vs),
1145 (vs), 1081 (vs), 968 (vs), 826 (vs), 756 (vs) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.77–7.73 (m, 2 H), 7.72–7.68 (m, 2 H),
3.06 (s, 3 H), 2.64 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 138.1, 132.9, 130.5, 128.3, 45.2, 29.7.
Anal. Calcd for C10H13NO2S: C, 56.85; H, 6.20; N, 6.63. Found: C, 56.85;
H, 6.15; N, 6.63.
N,S-Dimethyl-S-(4-nitrophenyl)sulfoximine (7g)
MS (EI, 70 eV): m/z (%) = 255 (5), 251 (11), 250 (93), 249 (59), 248
(100), 247 ([M+], 51), 246 (13), 236 (6), 235 (7), 234 (66), 233 (6), 232
(57), 221 (10), 220 (6), 219 (11), 218 (7), 205 (18), 204 (10), 203 (18),
202 (6), 187 (8), 186 (80), 185 (10), 184 (79), 172 (6), 157 (10), 155
(10), 105 (7), 76 (6), 75 (7), 63 (5), 50 (6).
Eluent: n-pentane–EtOAc (1:1); yield: 45 mg (21%); yellow solid; mp
128 °C.
IR (ATR): 3104 (w), 3055 (vw), 2995 (vw), 2919 (m), 2810 (vw), 2635
(vw), 2450 (vw), 2289 (vw), 2207 (vw), 2164 (vw), 2093 (vw), 2007
(vw), 1945 (vw), 1821 (vw), 1707 (vw), 1604 (w), 1518 (vs), 1468 (m),
1402 (vw), 1345 (vs), 1229 (vs), 1146 (vs), 1081 (vs), 990 (vs), 966 (s),
HRMS (ESI): m/z [M+
+ H] calcd for C8H11BrNOS: 247.97429;
found: 247.97392.
856 (vs), 770 (vs), 736 (vs), 682 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.41–8.38 (m, 2 H), 8.10–8.06 (m, 2 H),
N,S-Dimethyl-S-(4-methylphenyl)sulfoximine (7d)
3.11 (s, 3 H), 2.63 (s, 3 H).
Eluent: EtOAc; yield: 88 mg (48%); colorless oil.
13C NMR (151 MHz, CDCl3): δ = 150.6, 145.4, 130.2, 124.8, 44.8, 29.6.
IR (ATR): 3399 (vw), 2919 (w), 2804 (vw), 2364 (vw), 2089 (vw), 1925
(vw), 1660 (vw), 1595 (w), 1408 (w), 1313 (w), 1234 (vs), 1142 (vs),
MS (EI, 70 eV): m/z (%) = 215 (19), 214 ([M+], 38), 213 (6), 201 (6), 200
(10), 199 (100), 186 (14), 170 (6), 153 (14), 151 (14), 150 (11), 140
(10), 105 (22), 104 (5), 92 (7), 76 (9), 75 (6), 63 (7), 50 (7).
1100 (vs), 971 (vs), 815 (s), 759 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.75 (d, J = 8.1 Hz, 2 H), 7.35 (d, J = 7.9
HRMS (ESI): m/z [M+
found: 215.04849.
+ H] calcd for C8H11N2O3S: 215.04849;
Hz, 2 H), 3.05 (s, 3 H), 2.62 (s, 3 H), 2.43 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 143.9, 135.7, 130.3, 128.9, 45.2, 29.6,
21.6.
MS (EI, 70 eV): m/z (%) = 184 (6), 183 ([M+], 23), 168 (19), 155 (14),
140 (5), 139 (27), 138 (5), 121 (10), 120 (100), 119 (5), 118 (5), 108
(6), 107 (7), 105 (6), 93 (5), 92 (14), 91 (63), 89 (10), 79 (7), 78 (8), 77
(19), 65 (32), 63 (17), 51 (6).
HRMS (ESI): m/z [M+ + H] calcd for C9H14NOS: 184.07906; found:
184.07875.
N,S-Dimethyl-S-(2-naphthyl)sulfoximine (7h)
Eluent: EtOAc; yield: 55 mg (58%); colorless oil.
IR (ATR): 3863 (vw), 3390 (w), 3014 (w), 2915 (w), 2803 (w), 2311
(w), 2093 (w), 1995 (vw), 1918 (vw), 1713 (vw), 1587 (w), 1501 (vw),
1455 (w), 1409 (w), 1341 (w), 1235 (vs), 1141 (vs), 975 (s), 845 (s),
755 (vs) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.45 (s, 1 H), 7.95 (dd, J = 12.5, 8.4 Hz, 2
H), 7.89 (d, J = 8.1 Hz, 1 H), 7.80 (dd, J = 8.6, 1.6 Hz, 1 H), 7.61 (t, J = 7.5
Hz, 1 H), 7.57 (t, J = 6.9 Hz, 1 H), 3.11 (s, 3 H), 2.64 (s, 3 H).
N,S-Dimethyl-S-(4-methoxyphenyl)sulfoximine (7e)
Eluent: EtOAc; yield: 114 mg (57%); colorless oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1951–1959

1957
C. A. Dannenberg et al.
Paper
Synthesis
13C NMR (151 MHz, CDCl3): δ = 135.7, 135.0, 132.7, 130.6, 129.7,
13C NMR (151 MHz, CDCl3): δ = 168.7, 137.3, 134.7, 132.9, 130.8,
129.2, 128.9, 127.9, 127.5, 123.5, 44.9, 29.6.
130.8, 129.1, 53.2, 45.0, 29.6.
MS (EI, 70 eV): m/z (%) = 221 (3), 220 ([M+], 10), 219 (37), 204 (11),
191 (8), 175 (25), 157 (12), 156 (100), 147 (12), 144 (5), 141 (5), 129
(17), 128 (33), 127 (72), 126 (10), 115 (31), 101 (6), 77 (9), 63 (9).
MS (EI, 70 eV): m/z (%) = 228 (20), 227 ([M+], 13), 212 (17), 200 (5),
199 (39), 198 (29), 196 (18), 184 (8), 183 (86), 169 (5), 168 (10), 167
(100), 166 (6), 165 (6), 164 (6), 153 (18), 152 (54), 148 (10), 137 (6),
136 (7), 135 (10), 133 (11), 132 (50), 125 (10), 121 (13), 120 (15), 119
(5), 118 (6), 109 (11), 108 (9), 106 (6), 105 (55), 104 (48), 97 (8), 96
(19), 95 (6), 92 (45), 91 (13), 79 (8), 78 (11), 77 (55), 76 (42), 75 (11),
74 (12), 70 (5), 69 (6), 65 (7), 64 (10), 63 (31), 59 (7), 51 (9), 50 (22).
HRMS (ESI): m/z [M+
+ H] calcd for C12H14NOS: 220.07906;
found: 220.07895.
N,S-Dimethyl-S-(3-bromophenyl)sulfoximine (7i)
HRMS (ESI): m/z [M+ + Na] calcd for C10H13NO3S + Na: 250.05084;
found: 250.05064.
Eluent: n-pentane–EtOAc (1:1); yield: 129 mg (52%); yellow oil.
IR (ATR): 3408 (vw), 2914 (m), 2809 (w), 2305 (vw), 1737 (m), 1568
(w), 1410 (m), 1238 (vs), 1134 (vs), 973 (vs), 855 (m), 777 (vs) cm–1
.
N,S-Dimethyl-S-(2-pyridinyl)sulfoximine (7l)
1H NMR (600 MHz, CDCl3): δ = 8.04–8.02 (m, 1 H), 7.82–7.79 (m, 1 H),
7.74–7.72 (m, 1 H), 7.45–7.42 (m, 1 H), 3.07 (s, 3 H), 2.63 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 141.1, 136.1, 131.8 131.1, 127.4,
123.7, 45.1, 29.7.
Eluent: EtOAc; yield: 78 mg (46%); colorless oil.
IR (ATR): 3847 (vw), 3420 (m), 2916 (m), 2804 (vw), 2694 (vw), 2296
(m), 2092 (m), 1996 (vw), 1916 (w), 1742 (w), 1643 (vw), 1569 (m),
1423 (s), 1315 (vw), 1236 (vs), 1149 (vs), 1103 (vs), 974 (s), 854 (m),
766 (vs), 689 (vw) cm–1
.
MS (EI, 70 eV): m/z (%) = 251 (10), 250 (89), 249 (37), 248 (100), 247
([M+], 31), 246 (11), 235 (5), 234 (54), 232 (52), 221 (8), 219 (8), 205
(7), 203 (7), 186 (20), 185 (7), 184 (22), 183 (6), 157 (15), 155 (13),
108 (8), 105 (14), 104 (7), 96 (8), 92 (5), 77 (9), 76 (25), 75 (27), 74
(13), 69 (5), 63 (18), 61 (5), 50 (19).
1H NMR (600 MHz, CDCl3): δ = 8.76 (m, 1 H), 8.10 (d, J = 7.8 Hz, 1 H),
7.94 (td, J = 7.7, 1.2 Hz, 1 H), 7.53–7.47 (m, 1 H), 3.23 (s, 3 H), 2.66 (s, 3
H).
13C NMR (151 MHz, CDCl3): δ = 157.5, 150.6, 137.9, 126.6, 123.6, 41.1,
29.7.
MS (EI, 70 eV): m/z (%) = 171 ([M+], 2), 155 (4), 142 (20), 127 (7), 124
(16), 107 (10), 96 (9), 95 (7), 93 (4), 92 (6), 80 (22), 79 (37), 78 (100),
76 (6), 75 (5), 67 (12), 63 (8), 52 (15), 51 (53), 47 (5).
HRMS (ESI): m/z [M+
+ H] calcd for C8H11BrNOS: 247.97392;
found: 247.97415.
N,S-Dimethyl-S-(2-bromophenyl)sulfoximine (7j)
Eluent: n-pentane–EtOAc (3:1) to EtOAc; yield: 77 mg (31%); white
solid; mp 79 °C.
Anal. Calcd for C7H10N2OS: C, 49.39; H, 5.92; N, 16.46. Found: C, 49.24;
H, 5.96; N, 16.32.
IR (ATR): 3840 (vw), 3405 (m), 2924 (m), 2662 (vw), 2320 (vw), 2206
(vw), 2104 (vw), 1908 (vw), 1733 (s), 1550 (vs), 1428 (s), 1374 (s),
1240 (vs), 1141 (s), 1094 (vs), 957 (m), 903 (m), 836 (m), 754 (vs), 690
N-Methyl-S-ethyl-S-phenylsulfoximine (7m)
Eluent: n-pentane–EtOAc (1:1) to EtOAc; yield: 97 mg (53%); colorless
oil.
(vs) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.19 (dd, J = 7.9, 1.7 Hz, 1 H), 7.74 (dd,
J = 7.9, 1.2 Hz, 1 H), 7.50 (td, J = 7.7, 1.2 Hz, 1 H), 7.42 (td, J = 7.7, 1.7
Hz, 1 H), 3.25 (s, 3 H), 2.58 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 137.7, 135.6, 134.1, 133.8, 128.4,
121.0, 42.6, 29.7.
IR (ATR): 3827 (vw), 3408 (w), 3062 (vw), 2932 (w), 2878 (w), 2804
(w), 2666 (vw), 2321 (vw), 2099 (w), 2000 (vw), 1920 (vw), 1741
(vw), 1646 (vw), 1580 (vw), 1447 (s), 1233 (vs), 1142 (vs), 981 (vw),
927 (vw), 859 (vs), 771 (s), 728 (vs), 689 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.85–7.81 (m, 2 H), 7.62–7.58 (m, 1 H),
7.57–7.53 (m, 2 H), 3.19–3.09 (m, 2 H), 2.66 (s, 3 H), 1.21 (t, J = 7.5 Hz,
3 H).
13C NMR (151 MHz, CDCl3): δ = 137.0, 133.0, 129.7, 129.5, 50.9, 29.6,
7.5.
MS (EI, 70 eV): m/z (%) = 184 (12), 183 ([M+], 7), 155 (12), 154 (21),
126 (11), 125 (24), 109 (20), 108 (6), 107 (89), 106 (60), 105 (26), 97
(21), 94 (13), 91 (6), 79 (11), 78 (50), 77 (100), 76 (5), 65 (10), 61 (7),
60 (8), 51 (48).
MS (EI, 70 eV): m/z (%) = 251 (10), 250 (96), 249 (36), 248 (100), 247
([M+], 29), 246 (9), 234 (50), 232 (48), 221 (9), 220 (7), 219 (9), 218
(7), 205 (10), 204 (5), 203 (10), 186 (32), 185 (5), 184 (36), 183 (6),
157 (17), 155 (19), 153 (16), 139 (8), 138 (16), 125 (18), 120 (5), 109
(7), 108 (25), 106 (8), 105 (51), 104 (28), 97 (11), 96 (42), 95 (8), 92
(17), 91 (30), 89 (6), 85 (9), 83 (13), 82 (6), 81 (8), 78 (16), 77 (57), 76
(68), 75 (84), 74 (41), 70 (10), 69 (20), 65 (15), 64 (13), 63 (84), 61
(16), 60 (9), 57 (6), 55 (6), 51 (18), 50 (69), 48 (8), 47 (11), 46 (6), 45
(12).
HRMS (ESI): m/z [M+
+
H] calcd for C8H11BrNOS: 247.97392;
HRMS (ESI): m/z [M+
+ H] calcd for C9H14NOS: 184.07906;
found: 247.97412.
found: 184.07909.
Methyl 2-(N,S-Dimethylsulfonimidoyl)benzoate (7k)
N-Methyl-S-cyclopropyl-S-phenylsulfoximine (7n)
Eluent: n-pentane–EtOAc (1:1); yield: 57 mg (25%); colorless oil.
Eluent: n-pentane–EtOAc (1:1) to EtOAc; yield: 23 mg (12%); colorless
oil.
IR (ATR): 3609 (vw), 3379 (vw), 3188 (vw), 3016 (vw), 2950 (w), 2879
(vw), 2806 (vw), 2329 (vw), 2174 (vw), 2095 (vw), 1990 (vw), 1729
(vs), 1663 (w), 1590 (vw), 1567 (vw), 1432 (s), 1288 (vs), 1242 (vs),
1150 (vs), 1111 (vs), 1056 (s), 959 (s), 854 (m), 829 (w), 776 (vs), 747
IR (ATR): 3573 (vw), 3394 (vw), 3059 (vw), 3014 (vw), 2915 (w), 2875
(w), 2804 (w), 2663 (vw), 2329 (vw), 2097 (w), 1990 (vw), 1908 (vw),
1733 (vw), 1640 (vw), 1581 (vw), 1444 (s), 1305 (w), 1242 (vs), 1186
(m), 1145 (vs), 1109 (s), 1082 (s), 997 (vw), 887 (vs), 857 (vs), 760 (s),
(vs) cm–1
.
724 (vs), 689 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.97–7.94 (m, 1 H), 7.61 (m, 2 H), 7.56–
7.53 (m, 1 H), 3.91 (s, 3 H), 3.23 (s, 3 H), 2.57 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1951–1959

1958
C. A. Dannenberg et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.84–7.76 (m, 2 H), 7.59–7.46 (m, 3 H),
2.65 (s, 3 H), 2.55–2.43 (m, 1 H), 1.46–1.38 (m, 1 H), 1.08–0.97 (m, 2
H), 0.82–0.73 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 171.7, 171.6, 156.1, 136.0, 128.5,
128.2, 128.2, 128.1, 128.1, 67.1, 52.7, 52.6, 52.5, 49.9, 38.6, 38.4, 29.0,
28.9, 26.1, 26.0.
13C NMR (151 MHz, CDCl3): δ = 139.2, 132.7, 129.4, 129.0, 32.9, 29.9,
5.8, 4.9.
MS (EI, 70 eV): m/z (%) = 343 (1), 342 ([M+], 2), 250 (2), 249 (3), 158
(10), 146 (2), 120 (2), 114 (11), 111 (2), 107 (3), 97 (3), 94 (9), 92 (9),
91 (100), 85 (2), 83 (3), 79 (2), 78 (10), 71 (3), 65 (4), 57 (4).
MS (EI, 70 eV): m/z (%) = 197 (6), 196 (38), 195 (44), 194 ([M+], 22),
167 (8), 166 (5), 154 (13), 147 (10), 126 (8), 125 (51), 118 (6), 117
(19), 116 (11), 115 (13), 109 (15), 107 (29), 106 (100), 105 (13), 104
(5), 97 (33), 94 (8), 91 (6), 87 (5), 85 (34), 83 (49), 79 (13), 78 (23), 77
(81), 76 (5), 65 (9), 61 (6), 53 (5), 51 (40), 50 (15), 49 (5), 48 (10), 47
(15).
HRMS (ESI): m/z [M+
+ H] calcd for C15H23N2O5S: 343.13222;
found: 343.13278.
Acknowledgment
HRMS (ESI): m/z [M+ + Na] calcd for C10H13NOS + Na: 218.06101;
found: 218.06102.
V.B. thanks the Alexander von Humboldt foundation for a postdoctor-
al fellowship. We also thank Prof. Dr. M. Rueping and C. Vermeeren for
performing preparative high-performance liquid chromatography.
N,S-Dimethyl-S-benzylsulfoximine (7o)
Eluent: n-pentane–EtOAc (1:1) to EtOAc; yield: 27 mg (15%); colorless
oil.
Supporting Information
IR (ATR): 3868 (vw), 3393 (w), 2918 (m), 2806 (w), 2323 (w), 2091
(w), 1896 (w), 1652 (w), 1454 (m), 1413 (m), 1314 (w), 1232 (vs),
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380536.
1117 (vs), 976 (m), 843 (m), 774 (m), 699 (m) cm–1
.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
1H NMR (600 MHz, CDCl3): δ = 7.41–7.35 (m, 5 H), 4.32 (s, 2 H), 2.85
(s, 3 H), 2.70 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 130.7, 129.8, 129.1, 128.9, 59.5, 38.4,
References
(1) For reviews about sulfoximines, see: (a) Reggelin, M.; Zur, C.
Synthesis 2000, 1. (b) Harmata, M. Chemtracts 2003, 16, 660.
(c) Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482. (d) Bolm, C.
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4437.
29.6.
MS (EI, 70 eV): m/z (%) = 183 ([M+], 1), 168 (3), 92 (7), 91 (100), 89 (5),
65 (21), 63 (9).
HRMS (ESI): m/z [M+ + Na] calcd for C9H13NOS + Na: 206.06101;
found: 206.06139.
N,S-Dimethyl-S-cyclohexylsulfoximine (7p)
Eluent: EtOAc; yield: 77 mg (44%); colorless oil.
(2) For recent articles dealing with sulfoximine syntheses, see:
(a) Wang, J.; Frings, M.; Bolm, C. Angew. Chem. Int. Ed. 2013, 52,
8661; Angew. Chem. 2013, 125, 8823. (b) Wang, J.; Frings, M.;
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(4) (a) Lücking, U.; Jautelat, R.; Krueger, M.; Brumby, T.; Lienau, P.;
Schaefer, M.; Briem, H.; Schulze, J.; Hillisch, A.; Reichel, A.;
Wengner, A. M.; Siemeister, G. ChemMedChem 2013, 8, 1067.
(b) Siemeister, G.; Lücking, U.; Wengner, A. M.; Lienau, P.;
Steinke, W.; Schatz, C.; Mumberg, D.; Ziegelbauer, K. Mol.
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IR (ATR): 3530 (w), 2928 (vs), 2865 (s), 2804 (w), 2323 (vw), 2089 (w),
1993 (vw), 1644 (vw), 1450 (m), 1227 (vs), 1131 (vs), 958 (m), 849
(s), 752 (vw), 694 (w) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 2.88 (tt, J = 12.3, 3.4 Hz, 1 H), 2.76 (s, 3
H), 2.73 (s, 3 H), 2.25–2.16 (m, 2 H), 1.88 (d, J = 13.5 Hz, 2 H), 1.68 (d,
J = 13.0 Hz, 1 H), 1.48–1.37 (m, 2 H), 1.30–1.22 (m, 2 H), 1.19–1.11 (m,
1 H).
13C NMR (151 MHz, CDCl3): δ = 62.5, 34.7, 29.2, 26.6, 26.5, 25.6, 25.6,
25.2.
MS (EI, 70 eV): m/z (%) = 176 ([M+], 10), 145 (5), 94 (24), 93 (23), 83
(27), 79 (6), 78 (47), 77 (5), 67 (10), 63 (139), 55 (100), 54 (5), 53 (13),
47 (5).
HRMS (ESI): m/z [M+
+ H] calcd for C8H18NOS: 176.11036;
found: 176.10951.
Methyl 2-{[(Benzyloxy)carbonyl]amino}-4-(N,S-dimethylsulfonim-
idoyl)butanoate (7q)
Eluent: EtOAc; yield: 158 mg (46%); viscous colorless oil.
(5) For bioactivities of N-methylated sulfoximines, see: (a) Walker,
D. P.; Zawistoski, M. P.; McGlynn, M. A.; Li, J.-C.; Kung, D. W.;
Bonnette, P. C.; Baumann, A.; Buckbinder, L.; Houser, J. A.; Boer,
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Chem. Lett. 2009, 19, 3253. (b) Park, S. J.; Baars, H.; Mersmann,
S.; Buschmann, H.; Baron, J. M.; Amann, P. M.; Czaja, K.; Hollert,
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IR (ATR): 3855 (vw), 3319 (w), 2943 (m), 2807 (vw), 2641 (vw), 2320
(w), 2082 (w), 1717 (vs), 1529 (s), 1446 (m), 1223 (vs), 1148 (vs),
1047 (vs), 853 (m), 744 (m) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.45–7.12 (m, 5 H), 6.22 (dd, J = 41.1,
7.9 Hz, 1 H), 5.05 (s, 2 H), 4.40 (s, 1 H), 3.69 (s, 3 H), 3.19–2.99 (m, 2
H), 2.80 (s, 3 H), 2.69 (s, 3 H), 2.39–2.27 (m, 1 H), 2.20–2.07 (m, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1951–1959

1959
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1951–1959