Microwave-Accelerated N-Acylation of Sulfoximines with Aldehydes under Catalyst-Free Conditions

Article abstract of DOI:10.1055/s-0039-1691589

An efficient catalyst-free radical cross-coupling reaction between aromatic aldehydes and sulfoximines was developed. The reaction took place in the presence of N-bromosuccinimide as the radical initiator under microwave irradiation to afford the corresponding acylated sulfoximines in moderate to excellent yields (27 examples). This protocol proved to be rapid, easy to handle, and applicable to a broad scope of substrates.

Full text of DOI:10.1055/s-0039-1691589

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–H
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K. K. Rajbongshi et al.
Paper
Synthesis
Microwave-AcceleratedN-AcylationofSulfoximineswithAldehydes
under Catalyst-Free Conditions
Kamal K. Rajbongshia
Srinivas Ambalaa
Thavendran Govenderb
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8-6
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X
O
O
O
R2
O
NBS
S
H
HN
S
R3
R2
+
N
R3
R1
R1
MW, 25 min
0
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3-
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Hendrik G. Krugera
Per I. Arvidsson*a,c
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0
0
0-0
0
0
3-
0
6
0
6-2
0
5
3
R1= alkyl, NO2, X, OMe
R2, R3 = aryl, alkyl
27 examples
up to 88% yield
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Tricia Naicker*a
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a Catalysis and Peptide Research Unit, University of KwaZuluNatal, Durban, 4001,
South Africa
naickert1@ukzn.ac.za
b Department of Chemistry, University of Zululand, Private Bag X1001,
KwaDlangezwa 3886, South Africa
c Science for Life Laboratory, Drug Discovery & Development Platform & Division of
Translational Medicine and Chemical Biology, Department of Medical Biochemistry
and Biophysics, Karolinska Institutet, Stockholm, Sweden
Per.Arvidsson@scilifelab.se
Received: 19.11.2019
Accepted after revision: 20.12.2019
Published online: 29.01.2020
(DCC) or 3-(ethyliminomethyleneamino)-N,N-dimethylpro-
pane-1-amine (EDC), in the presence of a suitable base such
as DMAP.8b,9b In 2011, a boric acid mediated N-acylation of
sulfoximine protocol was reported, using aliphatic carbox-
ylic acids as the acyl donor (Scheme 1).10 Recently, Kumagai
et al. developed the direct acylation of sulfoximines with
carboxylic acids using 1,3-dioxa-5-aza-2,4,6-triborinane
(DATB) as a catalyst (Scheme 1).11
DOI: 10.1055/s-0039-1691589; Art ID: ss-2019-t0643-op
Abstract An efficient catalyst-free radical cross-coupling reaction be-
tween aromatic aldehydes and sulfoximines was developed. The reac-
tion took place in the presence of N-bromosuccinimide as the radical
initiator under microwave irradiation to afford the corresponding acy-
lated sulfoximines in moderate to excellent yields (27 examples). This
protocol proved to be rapid, easy to handle, and applicable to a broad
scope of substrates.
Bolm and co-workers reported a copper-catalyzed oxi-
dative N-acylation of sulfoximines with aldehydes as the
acyl donors (Scheme 1).12 Similarly, Deng’s group used a
TBAI/TBHP catalytic system for the acylation with alde-
hydes (Scheme 1).13 N-Heterocyclic carbenes are also suit-
able catalysts for the direct N-acylation of sulfoximines
with aldehydes under oxidative conditions (Scheme 1).14
Very recently, visible-light-promoted acylation of sulfoxi-
mines was reported in the presence of an oxidant (Scheme
1).15 Reports on the N-acylation with methylarene as acyl
donors are also known (Scheme 1).16–19 However, in such
cases, pre-activation of the sulfoximines are essential for
the transformation. For example, Bolm and his team report-
ed the synthesis of N-acylated sulfoximines by treating N-
chlorosulfoximines with methylarenes when using MnO2 as
the catalyst.16 Later, Kotha et al. performed another N-acy-
lation reaction from N-chlorosulfoximines and methylarene
by using iron as the catalyst.17 Interestingly, Dong et al. dis-
closed iodine-catalyzed direct oxidative N-acylation with
methylarenes without activating the sulfoximine.18 Zhao
and co-workers used I2/FeCl3/TBHP as the catalyst/oxidant
system for direct oxidative N-acylation with methyl-
arenes.19 However, the most reported methods require cat-
alysts and longer reaction time with high temperature.
Consequently, the development of new, more efficient
Key words acylation, radical reactions, sulfoximines, N-bromosuccin-
imide, microwave irradiation
Direct carbon–nitrogen bond formation reactions have
been considered as one of the most effective ways to con-
struct nitrogen-containing natural products as well as sev-
eral biologically active molecules.1 The chemistry of sulfox-
imines is gaining significant attention due to their wide ap-
plication in the pharmaceutical and agricultural fields.2 In
addition, sulfoximines have been exploited as chiral li-
gands,3 chiral auxiliaries,4 and organocatalysts5 in asym-
metric synthesis, and as essential reagents6 for the con-
struction of heterocyclic molecules. Several research groups
are continually working to develop practical synthetic
methods for the synthesis of sulfoximines and derivatives.7
N-Acylated sulfoximines belong to an important class of
sulfoximines.8 N-Acylsulfoximines are usually prepared by
the treatment of sulfoximines with some activated carbox-
ylic derivative such as an acyl chloride or anhydride in the
presence of a base.9 They can also be synthesized directly
from carboxylic acids in the presence of strong carboxyl ac-
tivating agents, such as N,N′-dicyclohexylcarbodiimide
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. K. Rajbongshi et al.
Paper
Synthesis
Ar-Me
Previous work
TBHP
Long reaction times
High temperatures
Use of catalysts
O
SR2R3
I2/Na2CO3; I2/FeCl3
refs. 18,19
HN
O
SR2R3
O
SR2R3
O
O
O
O
HN
HN
R1
N
S
R3
R2
R1
H
R1
OH
TBHP
B(OH)3; DATB
refs. 10,11
CuBr; TBAI; NHC
K2S2O8, UV
refs. 12–15
80–85 °C, 12–60 h
TBHP
O
SR2R3
MnO2; FeSO4•7H2O
ClN
refs. 16,17
Ar-Me
This work
O
O
O
O
NBS
MW, 20–30 min
Catalyst-free
Rapid
R2
+
HN
S
R3
R1
N
S
R2
R1
R1 = aryl
R2, R3 = aryl, alkyl
H
R3
Scheme 1 Previous and current approaches for the synthesis of N-acylsulfoximines
methodologies with broad substrate scope is still highly de-
sirable. Microwave-assisted organic synthesis has been con-
sidered as an essential tool to accelerate rapid transforma-
Table 1 Optimization of the N-Acylation of Sulfoximine 1a with Alde-
hyde 2aa
tion in all areas of organic synthesis.20 It has some advan-
tages over conventional heating, such as the reduction in
reaction times, lower side reactions, and selectivity.21 Re-
cently, we have reported the synthesis of 1,2,4-thiadi-
azinanes from -aminoethanesulfonamides with different
methylene donors under MW conditions.20e
O
O
NH
N
S
O
NXS
H
+
S
Solvent, MW
NO2
O
O2N
2a
3a
1a
N-Bromosuccinimide (NBS) is a well-known reagent in
organic synthesis, and is safe and easy to handle.22 It has
been extensively used for different organic transformations.
Herein, we envisaged the N-acylation of sulfoximine deriva-
tives from aldehydes using readily available and inexpen-
sive NBS as the oxidant under microwave-irradiation condi-
tions (Scheme 1). To the best of our knowledge, it is the first
report of the rapid microwave-assisted synthesis of N-acyl-
sulfoximines from aldehydes without the use of a catalyst.
Initially, we investigated the reaction by choosing S-
methyl-S-phenylsulfoximine (1a) and 4-nitrobenzaldehyde
(2a) as the model substrates and NBS as oxidant (Table 1).
To a solution of S-methyl-S-phenylsulfoximine (1a) in ethyl
acetate (1 mL), 4-nitrobenzaldehyde (2a; 1.1 equiv) and
NBS (1.2 equiv) were added, and the reaction was per-
formed under microwave irradiation for 25 minutes at
80 °C. To our delight, the desired product N-(4-nitrobenzo-
yl)sulfoximine 3a was obtained in 76% yield (entry 1). Then
other halogen sources were investigated; interestingly, NCS
gave only 25% of the desired product, and no product was
observed with I2 (entries 2 and 3). Next, the reaction was
performed in various solvents, such as CH2Cl2, MeCN, THF,
1,4-dioxane, and DCE (entries 4–8). It was found that DCE
Entry
Oxidant
Solvent
Time
25 min
Yield (%)b
1
2
NBS
NCS
I2
EtOAc
EtOAc
EtOAc
CH2Cl2
MeCN
THF
76
25
–
30 min
30 min
25 min
25 min
25 min
25 min
25 min
30 min
12 h
3
4
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
68
55
–
5
6
7
1,4-dioxane
DCE
85
88
65
–
8
9c
10d
11e
DCE
DCE
DCE
6 h
85
a Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.22 mol, 1.1 equiv), oxi-
dant (0.24 mmol, 1.2 equiv), solvent (1 mL), 80 °C, MW, unless stated oth-
erwise.
b Isolated yield.
c MW, 50 °C.
d At r.t., 12 h.
e At 80 °C, 6 h, conventional heating.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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K. K. Rajbongshi et al.
Paper
Synthesis
was the solvent of choice, furnishing the product in 88%
yield. Further, performing the reaction at 50 °C under MW
conditions resulted in a lower yield of 65% (entry 9). Also,
when the reaction was carried out at room temperature for
12 hours, we did not observe any product (entry 10); in-
stead, we could isolate N-bromosulfoximine as the main
product under these conditions. However, conventional
heating of the reaction mixture at 80 °C for 6 hours gave the
desired product in 85% yield (entry 11). Thus, the results
were optimal when using aldehyde (1.1 equiv), NBS (1.2
equiv), and DCE as the solvent under microwave irradiation
(entry 8).
Having established the optimized conditions, we ex-
tended the reaction to different commercially available al-
dehydes to investigate the scope of the reaction (Table 2).
Aldehydes bearing electron-withdrawing groups such as F,
Cl, Br, and NO2 or electron-donating groups (Me, OMe, and
OBu) on the aromatic ring underwent smooth coupling and
afforded the corresponding product in good to excellent
yields (Table 2, 3a–h, 80–88%). However, aldehydes with an
electron-withdrawing substituent showed slightly better
results. The reaction was equally compatible with ortho-
and meta-substituted aryl aldehydes. The reaction was
showed to be effective with bulky 1-naphthaldehydes as
well (3l). Notably, this procedure did not work well with al-
iphatic aldehydes, which only gave minor amounts of prod-
uct as seen by LCMS; this is in consonance with the pro-
posed radical mechanism (vide infra).
Table 2 Scope of the N-Acylation of Sulfoximine 1a with Different
Aldehydes 2a
O
N
S
O
R3
NH
S
O
NBS, DCE
+
R3
H
MW, 25 min
O
3
1a
2
Table 3 Scope of the N-Acylation of Different Sulfoximines 1 with
Aldehydes 2a
O
O
O
N
S
O
N
N
NO2
Cl
Br
S
S
O
O
O
R3
NH
S
O
N
S
3a, 88%
3b, 83%
3c, 85%
NBS, DCE
+
R1
R2
R3
H
R1
R2
MW, 25–30 min
O
O
O
O
O
1
2
3
N
S
O
N
S
O
N
S
O
F
O
O
O
N
S
O
N
S
O
N
Br
OMe
3f, 80%
3d, 87%
3e, 80%
S
O
Cl
O
O
O
3p, 80%
3q, 82%
3r, 80%
Cl
N
S
O
N
S
O
N
S
O
OMe
OBu
O
O
I
O
N
N
S
O
N
S
O
O
3g, 84%
3h, 84%
3i, 70%
S
Br
O
O
O
3s, 65%
3t, 80%
3u, 85%
N
S
O
N
S
O
N
S
O
O
O
O
O
O
N
O
N
O
N
S
S
S
3j, 70%
3k, 72%
3l, 78%
NO2
Cl
3v, 88%
3w, 85%
3x, 85%
O
O
O
O
I
NO2
O
O
O
N
S
O
N
S
O
N
S
O
N
S
O
N
N
S
O
Cl
Cl
S
NO2
Br
3y, 88%
MeO
3o, 80%
3m, 82%
3n, 82%
3z, 82%
3aa, 85%
a Reaction conditions: 1a (0.2 mmol), 2 (0.22 mol), NBS (0.24 mmol), DCE
(1 mL), MW, 80 °C, 25 min; yields shown of isolated products after chro-
matographic purification.
a Reaction conditions: 1 (0.2 mmol), 2 (0.22 mol), NBS (0.24 mmol), DCE (1
mL), MW, 80 °C, 25–30 min; yields shown of isolated products after chro-
matographic purification.
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K. K. Rajbongshi et al.
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Synthesis
O
O
H
NH
S
N
S
O
O
C
(a)
NBS, TEMPO
N
O
Cl
+
O
+
DCE, MW
Cl
Cl
1a
2b
5a (30%)
3b (trace amount)
O
Br
N
NH
S
H
S
Cl
NBS
DCE, MW
O
O
3b (80% isolated yield)
(b)
DCE, MW
1a
4a
NH
S
NBS
O
(c)
(0% yield)
X
TEMPO
DCE, MW
1a
Scheme 2 Control experiments to demonstrate the involvement of a radical mechanism. The collected data suggest that the Br radical required for
formation of the acyl radical may initiate from both NBS and N-bromosulfoximine intermediate 4a.
Further, we investigated the N-acylation reactions with
different sulfoximines under the optimized conditions with
some of the aldehydes. The results are shown in Table 3. To
our delight, the reaction proceeded smoothly with various
NH-sulfoximines with reasonable to good efficiency. The
formation of products with electron-rich as well as elec-
tron-deficient substituents on S-arylsulfoximines enhances
the scope of this protocol (3z, 3aa).
suggest that a radical process is involved under our opti-
mized reaction conditions. Acyl radical 2a′ is formed by re-
action of the bromine radical with aldehyde 2a. The Br radi-
cal may be initiated from either NBS or the N-bromosulfox-
imine intermediate 4a. Finally, the desired product 3a is
formed through attack of the acyl radical 2a′ on 4a with
generation of a new Br radical, or termination by combina-
tion of the radicals.
To understand the actual reaction pathway, we conduct-
ed a series of control experiments. Initially, we performed
the reaction in the presence of a radical scavenger, i.e.
TEMPO under the optimized conditions. The reaction pro-
duced the acyl–TEMPO adduct 5a as the major product
along with trace amounts of the acylated product 3b
(Scheme 2a). The formation of the TEMPO adduct 5a estab-
lished that the reaction likely follows a radical pathway.
Furthermore, in order to investigate formation of the N-
bromosulfoximine intermediate, we conducted the reaction
in a stepwise manner (Scheme 2b). As expected, we isolated
N-bromosulfoximine 4a (90%)23 in the first step, which led
to product 3b (80%) in the following step (Scheme 2b). Iso-
lation of 4a established that the reaction proceeded via the
N-bromosulfoximine intermediate. The observation that
isolated 4a can be converted into product 3b in the absence
of NBS suggests that 4a can undergo homolytic N–Br cleav-
age upon heating, as a Br radical is needed to generate the
required acyl radical. An additional experiment with 1a and
NBS in the presence of TEMPO did not afford the desired N-
bromosulfoximine (Scheme 2c), again suggesting a radical
step under our reaction conditions.
O
NH
T
S
N
Br
Br
O
O
1a
O
N
S
O
Br
N
S
O
3a
4a
Br
O
O
H
2a′
2a
HBr
Based on these observations and existing literature,17,24
a plausible mechanism for this catalyst-free protocol is de-
picted in Scheme 3. Initially, NBS reacts with sulfoximine 1a
to give N-bromosulfoximine 4a; although this process is
known to be possible through an ionic mechanism, our data
Scheme 3 Proposed reaction mechanism. Under the reported condi-
tions, a Br radical may be initiated from either NBS or N-bromosulfox-
imine intermediate 4a. The Br radical in turn generates acyl radical 2a′
(by hydrogen abstraction), which may attack 4a to generate the prod-
uct and a new Br radical.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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K. K. Rajbongshi et al.
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Synthesis
In summary, we have developed a complementary ap-
proach for the synthesis of N-acylsulfoximines, a functional
group that is rapidly receiving interest for the design of bio-
logically active compounds. The procedure uses readily
available aldehydes with N-bromosuccinimide under mi-
crowave irradiation and proceeds without any catalyst. The
new radical-mediated methodology offers a practical route
towards a mild and convenient synthesis of N-acylsulfox-
imines. It is characterized by catalyst-free conditions, in-
sensitivity to atmospheric moisture, applicability to a wide
range of substrates, rapid transformation times, no pre-
activation of reagents, and avoidance of excess oxidant.
1H NMR (400 MHz, CDCl3):  = 8.05–8.01 (m, 4 H), 7.72–7.68 (m, 1 H),
7.64–7.60 (m, 2 H), 7.54 (d, J = 8.4 Hz, 2 H), 3.47 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 173.3, 138.8, 134.5, 133.9, 131.3,
131.1, 129.7, 127.1, 44.4.
N-(4-Fluorobenzoyl)-S-methyl-S-phenylsulfoximine (3d)12
Yield: 48 mg (87%); white solid; mp 112–114 °C.
1H NMR (400 MHz, CDCl3):  = 8.18–8.14 (m, 2 H), 8.05–8.02 (m, 2 H),
7.68 (t, J = 7.2 Hz,1 H), 7.60 (t, J = 7.6 Hz, 2 H), 7.05 (t, J = 8.8 Hz, 2 H),
3.45 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 173.1, 166.6, 164.2, 138.9, 133.8,
131.9, 131.8, 129.7, 129.4, 127.1, 115.1, 114.8, 44.3.
N-Benzoyl-S-methyl-S-phenylsulfoximine (3e)18
Yield: 42 mg (80%); white solid; mp 103–105 °C.
Starting materials (sulfoximines 1) were prepared by using literature
procedures. Aldehydes, N-bromosuccinimide (NBS), and solvents
were purchased from Aldrich and other commercial suppliers. Gravi-
ty column chromatography utilizing silica gel (60–120 mesh) as the
stationary phase and EtOAc/hexane as eluting solvents was used for
purification. All chemical reactions were monitored by either LC/MS
(Shimadzu 2020 UFLC-MS) or TLC (aluminum sheet coated with silica
gel 60, visible at 254 nm) viewed under UV light. 1H and 13C NMR
spectra were recorded on a Bruker Advance III 400 MHz instrument of
samples in CDCl3 and by using the residual signals from CDCl3 as the
reference. HRMS was carried out by using a Bruker micro TOF-Q II in-
strument operating at ambient temperatures by using a sample con-
centration of approximately 1.0 ppm. All microwave-assisted reac-
tions were carried out with a CEM Discover SP system.
1H NMR (400 MHz, CDCl3):  = 8.18–8.16 (m, 2 H), 8.05 (d, J = 7.2 Hz, 2
H), 7.68 (t, J = 7.6 Hz, 1 H), 7.60 (t, J = 8.4 Hz, 2 H), 7.50 (t, J = 7.2 Hz, 1
H), 7.41 (t, J = 7.6 Hz, 2 H), 3.46 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 174.2, 139.0, 135.6, 133.8, 132.1,
129.6, 129.4, 128.0, 127.1, 44.4.
S-Methyl-N-(4-methylbenzoyl)-S-phenylsulfoximine (3f)18
Yield: 44 mg (80%); white solid; mp 150–152 °C.
1H NMR (400 MHz, CDCl3):  = 8.06–8.03 (m, 4 H), 7.69–7.65 (m, 1 H),
7.63–7.58 (m, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 3.45 (s, 3 H), 2.39 (s, 3 H)
13C NMR (100 MHz, CDCl3):  = 174.2, 142.7, 139.1, 133.7, 132.9,
129.6, 129.5, 128.7, 127.1, 44.4, 21.6.
N-(4-Methoxybenzoyl)-S-methyl-S-phenylsulfoximine (3g)12
N-Acylation of Sulfoximines 1 with Aldehydes 2; General Proce-
dure
Yield: 49 mg (84%); white solid; mp 139–140 °C.
Aldehyde 2 (0.22 mmol) and NBS (0.24 mmol) were added to a solu-
tion of sulfoximine 1 (0.2 mmol) in DCE (1 mL). The reaction mixture
was stirred under MW at 80 °C, 200 W for the appropriate time
(tracked by TLC). The excess solvent was removed in vacuo and the
crude product was purified by column chromatography (silica gel,
EtOAc/hexane); this provided pure product 3.
1H NMR (400 MHz, CDCl3):  = 8.12. (d, J = 8.8 Hz, 2 H), 8.07–8.04 (m,
2 H), 7.69–7.65 (m, 1 H), 7.63–7.58 (m, 2 H), 6.89 (d, J = 8.8 Hz, 2 H),
3.85 (s, 3 H), 3.45 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 173.8, 162.9, 139.3, 133.7, 131.5,
129.6, 128.3, 127.2, 113.2, 55.9, 44.4.
S-Methyl-N-(4-nitrobenzoyl)-S-phenylsulfoximine (3a)18
N-(4-Butoxybenzoyl)-S-methyl-S-phenylsulfoximine (3h)
Yield: 53 mg (84%); yellow solid; mp 130–132 °C.
Yield: 54 mg (88%); yellow solid; mp 130–132 °C.
1H NMR (400 MHz, CDCl3):  = 8.10 (d, J = 8.8 Hz, 2 H), 8.06–8.03 (m, 2
H), 7.69–7.65 (m, 1 H), 7.62–7.58 (m, 2 H), 6.88 (d, J = 8.8 Hz, 2 H),
4.00 (t, J = 6.8 Hz, 2 H), 3.45 (s, 3 H), 1.81–1.74 (m, 2 H), 1.54–1.46 (m,
2 H), 0.97 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 173.8, 162.9, 139.3, 133.7, 131.5,
129.6, 128.3, 127.2, 113.2, 67.8, 44.4, 31.2, 19.2, 13.8.
1H NMR (400 MHz, CDCl3):  = 8.30 (d, J = 9.2 Hz, 2 H), 8.24 (d, J = 8.8
Hz, 2 H), 8.05 (d, J = 7.2 Hz, 2 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.65 (t, J = 7.6
Hz, 2 H), 3.50 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.0, 150.1, 141.0, 138.4, 134.2,
130.4, 129.8, 127.1, 123.2, 44.4).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H21NO3S: 332.1320; found:
332.1344.
N-(4-Chlorobenzoyl)-S-methyl-S-phenylsulfoximine (3b)18
Yield: 49 mg (83%); white solid; mp 115–117 °C.
1H NMR (400 MHz, CDCl3):  = 8.09 (d, J = 8.8 Hz, 2 H), 8.04–8.02 (m, 2
H), 7.71–7.67 (m, 1 H), 7.63–7.59 (m, 2 H), 7.36 (d, J = 8.4 Hz, 2 H),
3.46 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 173.2, 138.8, 138.5, 134.1, 133.9,
130.8, 129.7, 128.3, 127.1, 44.3.
N-(2-Chlorobenzoyl)-S-methyl-S-phenylsulfoximine (3i)17
Yield: 41 mg (70%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.03–8.01 (m, 2 H), 7.76 (dd, J = 1.6, 7.2
Hz, 1 H), 7.64–7.60 (m, 1 H), 7.57–7.52 (m, 2 H), 7.32 (dd, J = 1.2, 7.6
Hz, 1 H), 7.28–7.18 (m, 2 H), 3.40 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 174.4, 138.5, 136.3, 134.0, 132.2,
131.2, 130.8, 130.6, 129.7, 127.3, 126.5, 44.3.
N-(4-Bromobenzoyl)-S-methyl-S-phenylsulfoximine (3c)18
Yield: 58 mg (85%); white solid; mp 100–102 °C.
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Synthesis
N-(2-Bromobenzoyl)-S-methyl-S-phenylsulfoximine (3j)17
N-(4-Bromobenzoyl)-S,S-diphenylsulfoximine (3q)25
Yield: 47 mg (70%); yellow solid; mp 82–85 °C.
Yield: 63mg (82%); white solid; mp 115–118 °C.
1H NMR (400 MHz, CDCl3):  = 8.04–8.01 (m, 2 H), 7.72 (dd, J = 2 Hz,
7.2 Hz, 1 H), 7.63–7.59 (m, 1 H), 7.55–7.51 (m, 3 H), 7.27–7.23 (m, 1
H), 7.19–7.14 (m, 1 H), 3.40 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 8.03–7.95 (m, 6 H), 7.51–7.46 (m, 8 H).
13C NMR (100 MHz, CDCl3):  = 173.0, 139.7, 134.7, 133.4, 131.3,
131.1, 129.6, 127.6, 127.2.
13C NMR (100 MHz, CDCl3):  = 175.0, 138.5, 138.4, 134.0, 133.7,
N-(4-Methoxybenzoyl)-S,S-diphenylsulfoximine (3r)25
131.2, 130.5, 129.5, 127.3, 127.1, 120.3, 44.3.
Yield: 56 mg (80%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.20 (d, J = 8.8 Hz, 2 H), 8.08–8.03 (m, 4
H), 7.59–7.50 (m, 6 H), 6.92 (d, J = 8.8 Hz, 2 H), 3.86 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 173.4, 162.9, 140.1, 133.2, 132.5,
131.5, 129.5, 129.1, 128.5, 127.9, 127.6, 113.1, 55.4.
S-Methyl-N-(2-methylbenzoyl)-S-phenylsulfoximine (3k)17
Yield: 40 mg (72%); white solid; mp 88–90 °C.
1H NMR (400 MHz, CDCl3):  = 8.07–8.04 (m, 3 H), 7.70–7.66 (m,1 H),
7.63–7.59 (m, 2 H), 7.35–7.31 (m, 1 H), 7.24–7.19 (m, 2 H), 3.40 (s, 3
H), 2.59 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 176.5, 139.3, 139.0, 135.3, 133.7,
131.5, 130.9, 130.3, 129.7, 127.2, 125.4, 44.5. 21.7.
N-(2-Chlorobenzoyl)-S,S-diphenylsulfoximine (3s)
Yield: 46 mg (65%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.08–8.00 (m, 4 H), 7.83 (dd, J = 2, 7.6
Hz, 1 H), 7.54–7.42 (m, 6 H), 7.34 (dd, J = 1.6, 8 Hz, 1 H), 7.29–7.18 (m,
2 H)
13C NMR (100 MHz, CDCl3):  = 173.4, 139.5, 136.4, 133.4, 132.4,
131.3, 130.6, 129.6, 127.7, 126.6.
S-Methyl-N-(1-naphthylcarbonyl)-S-phenylsulfoximine (3l)12
Yield: 48 mg (78%); yellow sticky solid.
1H NMR (400 MHz, CDCl3):  = 9.00 (d, J = 8.4 Hz, 1 H), 8.35 (dd, J = 1.6,
7.6 Hz, 1 H), 8.11–8.08 (m, 2 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.89–7.82 (m,
1 H), 7.72- 7.66 (m, 1 H), 7.65–7.59 (m, 2 H), 7.57–7.46 (m, 3 H), 3.49
(s, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H14ClNO2S: 356.0512;
found: 356.0484.
13C NMR (100 MHz, CDCl3):  = 176.5, 139.0, 133.9, 133.8, 132.9,
132.3, 131.3, 129.8, 129.7, 128.3, 127.1, 126.4, 125.8, 124.5, 44.5.
N-(3-Iodobenzoyl)-S,S-diphenylsulfoximine (3t)
Yield: 71 mg (80%); white solid; mp 138–140 °C.
N-(3-Iodobenzoyl)-S-methyl-S-phenylsulfoximine (3m)18
1H NMR (400 MHz, CDCl3):  = 8.57 (s, 1 H), 8.18 (d, J = 7.6 Hz, 1 H),
8.05 (d, J = 7.6 Hz, 4 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.63–7.53 (m, 6 H),
7.17 (t, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 172.4, 142.3, 141.0, 139.5, 138.9,
138.4, 137.7, 133.5, 129.8, 129.3, 128.7, 127.6, 93.8.
Yield: 63 mg (82%); white solid; mp 109–111 °C.
1H NMR (400 MHz, CDCl3):  = 8.50 (t, J = 1.6 Hz, 1 H), 8.11–8.09 (m, 1
H), 8.03 (d, J = 7.2 Hz, 2 H), 7.82 (d, J = 7.2 Hz, 1 H), 7.69 (t, J = 8.0 Hz, 1
H), 7.62 (t, J = 8.0 Hz, 2 H), 7.15 (t, J = 7.6 Hz, 1 H), 3.46 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.6, 140.9, 138.7, 138.4, 137.6,
133.9, 129.8, 129.7, 128.5, 127.1, 93.7, 44.4.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H14INO2S: 447.9868;
found: 447.9834.
S-Methyl-N-(3-nitrobenzoyl)-S-phenylsulfoximine (3n)18
N-(Benzoyl)-S,S-tetramethylenesulfoximine (3u)18
Yield: 50 mg (82%); white solid; mp 108–110 °C.
Yield: 38 mg (85%); white solid; mp 94–96 °C.
1H NMR (400 MHz, CDCl3):  = 8.97 (t, J = 2 Hz, 1 H), 8.45–8.43 (m, 1
H), 8.35–8.32 (m, 1 H), 8.05–8.03 (m, 2 H), 7.73–7.69 (m, 1 H), 7.66–
7.56 (m, 3 H), 3.49 (s, 3 H)
13C NMR (100 MHz, CDCl3):  = 171.7, 148.1, 138.4, 137.4, 135.1,
134.2, 129.8, 129.2, 127.1, 126.5, 124.4, 44.4.
1H NMR (400 MHz, CDCl3):  = 8.12 (d, J = 8.4 Hz, 2 H), 7.49 (t, J = 7.6
Hz, 1 H), 7.40 (t, J = 8 Hz, 2 H), 3.74–3.67 (m, 2 H), 3.37–3.30 (m, 2 H),
2.42–2.28 (m, 4 H).
13C NMR (100 MHz, CDCl3):  = 175.0, 135.2, 132.2, 129.3, 128.0, 52.7,
23.8.
N-(2-Furylcarbonyl)-S-methyl-S-phenylsulfoximine (3o)15
N-(4-Nitrobenzoyl)-S,S-tetramethylenesulfoximine (3v)12
Yield: 40 mg (80%); white sticky solid.
Yield: 47 mg (88%); white solid; mp 168–170 °C.
1H NMR (400 MHz, CDCl3):  = 8.28–8.22 (m, 4 H), 3.74–3.69 (m, 2 H),
3.40–3.35 (m, 2 H), 2.45–2.30 (m, 4 H).
13C NMR (100 MHz, CDCl3):  = 172.7, 150.0, 140.7, 130.3, 123.2, 52.7,
1H NMR (400 MHz, CDCl3):  = 8.04 (d, J = 8 Hz, 2 H), 7.67 (t, J = 7.2 Hz,
1 H), 7.60 (t, J = 8 Hz, 2 H), 7.53 (br s, 1 H), 7.16 (d, J = 3.2 Hz, 1 H), 6.46
(br s, 1 H), 3.46 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 165.3, 150.0, 145.5, 138.7, 133.9,
129.7, 127.2, 116.8, 111.8, 44.6.
23.7.
N-(4-Chlorobenzoyl)-S,S-tetramethylenesulfoximine (3w)
N-Benzoyl-S,S-diphenylsulfoximine (3p)18
Yield: 44 mg (85%); white solid; mp 94–96 °C.
1H NMR (400 MHz, CDCl3):  = 8.05 (d, J = 8.8 Hz, 2 H), 7.36 (d, J = 8.4
Hz, 2 H), 3.73–3.66 (m, 2 H), 3.37–3.30 (m, 2 H), 2.41–2.21 (m, 4 H).
13C NMR (100 MHz, CDCl3):  = 173.9, 138.5, 133.7, 130.8, 128.3, 52.7,
Yield: 52 mg (80%); white solid; mp 120–122 °C.
1H NMR (400 MHz, CDCl3):  = 8.26 (d, J = 7.2 Hz, 2 H), 8.10–8.04 (m, 4
H), 7.59 – 7.50 (m, 7 H), 7.44 (t, J = 7.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 173.9, 139.8, 135.8, 133.3, 132.2,
129.6, 129.5, 128.1, 127.7.
23.7.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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K. K. Rajbongshi et al.
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Synthesis
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H12ClNO2S: 258.0356;
found: 258.0350.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691589.
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N-Benzoyl-S,S-dimethylsulfoximine (3x)25
Yield: 34 mg (85%); white solid; mp 110–112 °C.
1H NMR (400 MHz, CDCl3):  = 8.11–8.10 (m, 2 H), 7.52–7.47 (m, 1 H),
7.39 (t, J = 8 Hz, 2 H), 3.37 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 174.2, 135.4, 132.2, 129.2, 128.0, 41.8.
References
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S,S-Dimethyl-N-(4-nitrobenzoyl)sulfoximine (3y)12
Yield: 43 mg (88%); white solid; mp 170–173 °C.
1H NMR (400 MHz, CDCl3):  = 8.28–8.22 (m, 4 H), 3.42 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 171.9, 150.1, 140.9, 130.3, 123.2, 41.9.
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S-(4-Bromophenyl)-N-(4-chlorobenzoyl)-S-methylsulfoximine
(3z)26
Yield: 61 mg (82%); white solid; mp 110–115 °C.
1H NMR (400 MHz, CDCl3):  = 8.06 (d, J = 8.8 Hz, 2 H), 7.89 (d, J = 8.4
Hz, 2 H), 7.75 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H), 3.45 (s, 3 H).
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130.8, 129.4, 128.7, 128.3, 44.4.
N-(4-Chlorobenzoyl)-S-(4-methoxyphenyl)-S-methylsulfoximine
(3aa)
Yield: 55 mg (85%); yellow solid; mp 120–125 °C.
1H NMR (400 MHz, CDCl3):  = 8.09 (d, J = 8.4 Hz, 2 H), 7.96 (d, J = 9.2
Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.06 (d, J = 8.4 Hz, 2 H), 3.89 (s, 3 H),
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13C NMR (100 MHz, CDCl3):  = 173.1, 163.9, 138.3, 134.3, 130.8,
129.8, 129.3, 128.2, 114.9, 55.8, 44.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H15ClNO3S: 324.0461;
found: 324.0454
Control Experiment with TEMPO
To a solution of 1a (0.2 mmol) in DCE (1 mL), 2b (0.22 mmol), NBS
(0.24 mmol), and TEMPO (2 equiv) were added and the reaction mix-
ture was stirred under MW heating at 80 °C, 200 Watt for the appro-
priate time (tracked by TLC). The excess solvent was removed in vacuo
and the crude product was purified by chromatography (silica gel,
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2,2,6,6-Tetramethylpiperidin-1-yl 4-Chlorobenzoate (5a)24a
Yield: 18 mg (30%); white solid.
1H NMR (400 MHz, CDCl3):  = 8.00 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.4
Hz, 2 H), 1.81–1.57 (m, 5 H), 1.48–1.45 (m, 1 H), 1.26 (s, 6 H), 1.10 (s, 6
H).
13C NMR (100 MHz, CDCl3):  = 165.6, 139.3, 130.9, 128.8, 128.1, 60.5,
39.1, 31.9, 20.8, 16.9.
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Funding Information
The authors would like to thank the South African National Research
Foundation (grant numbers 105213 and 105236), Aspen Pharmacare,
(12) Wang, L.; Priebbenow, D. L.; Zou, L.-H.; Bolm, C. Adv. Synth.
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and the South African Medical Research Council for their support.
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n
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l
o
gAy
d
v
a
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m
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1
0
5
2
1
3)S
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u
Athfri
c
aAn
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e
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Athfri
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H