Copper catalyzed N-arylation of sulfoximines with aryldiazonium salts in the presence of DABCO under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2020.152079

N-Arylation of sulfoximines with aryldiazonium tetrafluoroborates is demonstrated in the presence of copper chloride and DABCO. A wide range of aryl and alkyl sufoximines are participated in the coupling reaction with different aryldiazonim salts bearing electron donating and withdrawing groups and provided the desired products in 67–88percent yields. The reaction proceeds through a radical mechanism.

Full text of DOI:10.1016/j.tetlet.2020.152079

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Copper catalyzed N-arylation of sulfoximines with aryldiazonium salts in the
presence of DABCO under mild conditions
Siddharth Baranwal, Jeyakumar Kandasamy
PII:
S0040-4039(20)30529-3
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152079
TETL 152079
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Tetrahedron Letters
Received Date:
Revised Date:
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23 March 2020
18 May 2020
22 May 2020
Please cite this article as: Baranwal, S., Kandasamy, J., Copper catalyzed N-arylation of sulfoximines with
aryldiazonium salts in the presence of DABCO under mild conditions, Tetrahedron Letters (2020), doi: https://
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Copper catalyzed N-arylation of
sulfoximines with aryldiazonium salts
in the presence of DABCO under mild conditions
Siddharth Baranwal and Jeyakumar Kandasamy*
R3
R3
10 mol% CuCl
DABCO
N
O
O
NH
R2
S
S
N2BF4
R1
R2
R1
CH3CN
60 oC
67-88%
R2= Aryl and Alkyl
R1= Aryl and Alkyl
R3= H, OMe, Halo,
NO2, CN, etc.

Tetrahedron Letters
1
Tetrahedron Letters
journal homepage: www.elsevier.com
Copper catalyzed N-arylation of sulfoximines with aryldiazonium salts in the
presence of DABCO under mild conditions
Siddharth Baranwal and Jeyakumar Kandasamy
Department of Chemistry, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh 221005, India
———
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Available online
N-Arylation of sulfoximines with aryldiazonium tetrafluoroborates is
 Corresponding author. Tel.: +91- 0542-6702879; fax: +91- 0542-6702876; e-mail: jeyakumar.chy@iitbhu.ac.in
demonstrated in the presence of copper chloride and DABCO. A wide range
of aryl and alkyl sufoximines are participated in the coupling reaction with
different aryldiazonim salts bearing electron donating and withdrawing
groups and provided the desired products in 67-88% yields. The reaction
proceeds through a radical mechanism.
Keywords: Sulfoximine, N-Arylation, Copper,
Aryldiazonium salts
Introduction
sulfoximines as well as biologicaly relavent N-aryl L-
methionine sulfoximines, in good to excellent yields.
However, arylboronic acids are relatively expensive, hence
the development of alternative and complementary
Sulfoximines are aza-analogues of sulfones that have been
considered as an important pharmacophore in drug
discovery (Figure 1).1 Currently few sulfoximine
compounds are in the different phases of clinical trials for
the treatment of different diseases including cancer.1b On
the other hand, sulfoximines were also explored as
building blocks, chiral ligands and auxiliaries,
organocatalysts, directing groups for CH-activation, etc. in
organic synthesis.2
method, is of great interest.
R
R
N
O
CuCl, DABCO
CH3CN
O
NH
R2
S
S
N2BF4
R1
R2
R1
Scheme 1: N-Arylation of sulfoximines using
aryldiazonium tetrafluoroborates.
O
Me
N
MeO
MeO
S
O
S
O
N
O
NH
Aryldiazonium salts are highly useful aryl donors and
that have been utilized extensively in many palladium
catalyzed cross-coupling reactions in the place of aryl
halides and arylboronic acids.6 In this context, we have
recently reported a palladium catalyzed aryldizonium
salts mediated stereo-controlled synthesis of C-aryl
glycosides from glycals at room temperature.7 Besides C-C
coupling reactions, aryldizonium salts were also explored
in many C-S bond forming reactions.8 In contrast, their
applications in C-N bond forming reactions are
underexplored.9 In the last few years, our research group
has been focused on the chemistry of sulfoximines and
explored various N-functionalization reactions, including
N
S
N
N
OCH3
CF3
N
O
N
N
N
N
H
O
S
F
H2N
CH3
HN
O
GKRP disruptor
PTEFb inhibitor
-Adrenergic receptor blocker
O
OH
MeO
N
N
N
O
Me
N
H
N
O
N
O
S
HN
O
H
N
O
NH
S
N
F3C
S
N
N
N
O
NH
F
HNE inhibitor
ATR inhibitor
pan-CDK inhibitor
Figure 1:
sulfoximines.
Structures of Some biologically important
From a synthetic as well as biological perspectives, N-
functionalization of sulfoximine received significant
interest over the decades.1-3 In this context, N-arylation of
sulfoximine has been reported with aryl halides,
arylboronic acids, diaryliodonium salts, aryl sulfonates,
aryl siloxanes, etc., in the presence of metal catalysts.4
However, most of these developed methods require harsh
reaction conditions, expensive ligands, longer reaction
time, etc. We have recently reported a copper catalysed N-
arylation of sulfoximines with different arylboronic acids.5
Our reported method provides clean access to various N-
aryl sulfoximines, including a sterically hindered N-aryl
N-arylation,5
alkylation,10
acylation11
and
phosphorylation12 using copper catalysts. In continuation
of these works, here we report a copper catalyzed N-
arylation of sulfoximines using aryldiazonium salts under
mild conditions (Scheme 1).
At the outset, the optimization of the reaction
condition was investigated using (S,S)-methylphenyl
sulfoximine
(1a)
and
4-methylbenzenediazonium
tetrafluoroborate (2a) as model substrates. Initially, the
reaction was tested in different solvents including
methanol, dimethyl sulfoxide (DMSO) and acetonitrile at

2
Tetrahedron Letters
30 °C for 10 hours in the absence of any catalyst and
diazabicyclo[2.2.2]octane (DABCO) in the presence of 10
mol% CuCl (Table 1, entry 8 to 14). Among these bases,
DABCO was found to be superior that provides 3aa in
51% yield in 10 hours. Further, the reaction was
attempted in elevated temperatures, i.e. 45-75 °C in
acetonitrile in the presence of CuCl and DABCO (Table 1,
entry 15 to 17). To our delight, the desired product 3aa
was obtained in 88% yield at 60 °C within 6 hours.
Relatively low yields of 3aa were observed at 45 °C and 75
°C.
additives (Table 1, entry 1). However, no reaction was
observed. Hence, the optimization was performed with
different copper (I) and copper (II) catalysts in acetonitrile
(Table 1, entries 2-7). Among the different copper salts,
CuCl showed better activity by providing the desired
product 3aa in 36% yield. Further, the reaction was
carried out with different bases including potassium
carbonate,
dimethylaminopyridine (DMAP), triethylamine, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-
cesium
carbonate,
pyridine,
N,N
Table 1: Optimization of the reaction conditions for N-arylation of sulfoximine.a,b
O
N
O
NH
S
S
Solvent, Cat, Base
Temp., Time
CH3
CH3
N2BF4
3aa
2a
1a
Entry
1
Solvent
Catalyst
(10 mol%)
Base
(1.0 eq.)
Temp.
(°C)
Time
(h)
Yieldb
(%)
MeOH/DMSO/
ACN
-
-
30
10
ND
2
3
Acetonitrile
CuOAc
CuBr
CuCl
-
30
30
30
30
30
30
30
30
30
30
30
30
10
10
10
10
10
10
10
10
10
10
10
10
13
10
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
-
4
-
-
36
5
Cul
17
6
CuCl2
Cu(OAc)2
CuCl
-
~10
~10
40
7
-
8
K2CO3
Cs2CO3
Pyridine
DMAP
Et3N
DBU
9
CuCl
47
10
11
12
13
CuCl
41
CuCl
45
CuCl
43
CuCl
40
14
15
16
17
18
19
20
21
22
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Water
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
30
45
60
75
60
60
60
60
60
10
6
51
63
88
81
ND
30
69
72
ND
6
6
6
MeOH
6
DMSO
6
Dioxane
6
Acetonitrile
Ni(OAc)2/Pd(OAc)2
/PdCl2
DABCO
6
aS,S-methylphenyl sulfoximine (50 mg, 0.32 mmol), 4-methylbenzenediazonium tetrafluoroborate (99 mg, 0.48 mmol)
and solvent (2 mL). bIsolated yield.
Furthermore, the optimization of the reaction condition
was investigated in different solvents in the presence of
10 mol% CuCl and DABCO. However, acetonitrile
remained the best out of the solvents used in this study.
Moreover, other metal catalysts including Ni(OAc)2,
Pd(OAc)2 and PdCl2 were failed to yield the desired

Tetrahedron Letters
3
product (Table 1, entry 22). Overall, the optimization
study indicated that N-arylation of sulfoximine with aryl
diazonium salts can be achieved efficiently using 10%
CuCl in the presence of DABCO in acetonitrile at 60 oC.
on the aryl ring underwent N-arylation with 67–79%
yields (Table 2, 3fa–3ja). It was noted that the electron
withdrawing group functionalized phenyl sulfoximines
(e.g. p-NO2, p-Br, p-Cl, etc.) required slightly longer time
for the N-arylation when compared with electron donating
group substituted sulfoximines (e.g. p-Me and p-OMe).
Likewise (S,S)-aryl-aryl, aryl-benzyl and heteroaryl-alkyl
sulfoximines were successfully arylated with 70-76%
yields (Table 2, 3ka–3ma). Furthermore, to our delight, N-
arylation of (S,S)-dialkyl sulfoximines as well as
biologically relevant L-methionine sulfoximine were also
successfully accomplished in 70-81% yields, which
demonstrates the broad applicability of the present
method (Table 2, 3na–3pa).
Having developed optimized condition, we have
investigated the scope of different of sulfoximines in C-N
bond forming reactions with 4-methylbenzenediazonium
tetrafluoroborate (2a) and summarized in Table 2. (S,S)-
alkyl-Phenyl sulfoximines bearing different length of side
alkyl chains, including sterically hindered iso-propyl,
provided the corresponding N-arylated products in good
yields under optimized condition (Table 2, 3ba–3ea). On
the other hand, (S,S)-alkyl-phenyl sulfoximines bearing
different electron donating and withdrawing substituents
Table 2: N-Arylation of various sulfoximines with 4-methylbenzenediazonium tetrafluoroborate.a,b
O
NH
R2
CuCl, DABCO
N
Me
O
S
Me
N2BF4
S
R1
CH3CN, 60 °C
R1
R2
1b-1p
2a
3ba-3pa
Me
Me
Me
Me
Me
O
N
O
O
N
N
n-Pr
O
N
i-Pr
O
N
S
S
S
S
S
n-Hept
Et
Et
Me
3fa
3ba
87%
3ca
75%
3da
70%
3ea
78%
6 h,
6 h,
6 h,
6 h,
80%
6 h,
Me
Me
Me
Me
N
Me
N
O
O
N
Me
O
N
O
O
N
Me
S
S
S
S
S
Me
Me
O2N
MeO
Cl
Br
3ia
3ja
67%
3ha
3ga
3ka
76%
79%
6 h,
69%
8 h,
10 h,
72%
8 h,
3 h,
Me
Me
Me
Me
Me
N
N
Boc-NH
tBu-O
S CH3
O
O
S
O
N
N
Et
N
n-hept
N
S
O
S
S
C4H9
C4H9
O
O
3la
3ma
70%
3oa
70%
3pa
76%
3.5 h,
3na
81%
73%
3 h,
4 h,
3 h,
3 h,
aSulfoximine (0.5 mmol), 4-methylbenzenediazonium tetrafluoroborate (1.5 eq.), DABCO (1 eq.) and acetonitrile (5 mL). b
Isolated yield.
Encouraged, we further investigated the scope of different
readily accessible aryldiazonium tetrafloroborate salts in
the arylation reaction with S,S-methylphenyl sulfoximine
(1a) and summarized in Table 3. To our delight, aryl
diazonium salts bearing electron donating and
withdrawing groups participated efficiently in the C-N
forming reactions and provided the desired N-arylated
sulfoximines in 72-82% yields (Table 3, 3ab-3aj).

4
Tetrahedron Letters
Table 3: N-Arylation of (S,S)-phenylmethyl sulfoximine with various diazonium salts.a,b
N2BF4
NH
10 mol% CuCl
DABCO
O
O
N
S
S
CH3
CH3
R
R
CH3CN
60oC
3ab-3aj
2b-2j
1a
OMe
Br
NO2
CF3
O
N
CH3
S
O
N
O
N
O
N
CH3
O
N
S
S
S
S
CH3
CH3
CH3
3ab
3ac
78%
3ad
3ae
3af
75%
75%
79%
82%
5 h,
4 h,
4 h,
4.5 h,
4.5 h,
CN
COOMe
NO2
CF3
O
N
O
N
CH3
O
N
O
S
N
CH3
S
S
S
CH3
CH3
3ah
3ai
72%
3aj
77%
5 h,
3ag
77%
73%
5 h,
5 h,
5 h,
a(S,S)-Phenylmethyl sulfoximine (0.5 mmol, 1eq), aryldiazonium tetrafloroborate (1.5 eq.) DABCO (1 eq.) and acetonitrile
(5 mL). bIsolated yield.
obtained only in trace amount, suggesting that the
reaction proceeds through a radical mechanism.
O
NH
R2
N2 + Cu(II)
Cu(I)
N2BF4
Ar
S
R1
O
N
Ar
S
Ar
R1
R2
O
NH
A
TEMPO (2.0 mmol)
10 mol% CuCl
DABCO
S
N
N
N
O
N
CH3
Cu(II)
S
N2BF4
CH3
N
H
Acetonitrile
60 oC, 6 h
3aa
trace
1a
(1. 0 mmol)
2a
(1. 5 mmol)
Cu(I)
Scheme 3. Control experiment with TEMPO
Ar
N
O
S
R1 R2
In conclusion, a simple and efficient method for the N-
arylation of sulfoximines is demonstrated using
arenediazonium salts as an aryl source in the presence of a
copper catalyst and DABCO. A wide range of aryl and alkyl
sufoximines, including a biologically relevant L-methionine
sulfoximine, are participated in the coupling reaction with
different aryldiazonim salts bearing electron donating and
withdrawing groups. The desired products i.e. N-aryl
sulfoximines were obtained in good to excellent yields.
Controlled experiment suggets that the reaction proceeds
throguh a radical mechanism. The present methodology
appears to be more general, hence expected to find
promising applications in organic synthesis.
Scheme 2. Plausible mechanism for the N-arylation of
sulfoximines.
A
plausible mechanism for the imino-arylation of
sulfoximine is shown in Scheme 2.9 In the first step, aryl
radical is generated from arenediazonium salt in the
presence of Cu(I) via single electron transfer. During this
process, Cu(I) turns into Cu(II). Simultaneously,
sulfoximine reacts with aryl radical in the presence of
DABCO and generates radical anion intermediate A. The
intermediate A converted into product in the presence of
copper (II). During this process, Cu (I) is regenerated to
resume the catalytic cycle. To strengthen the proposed
mechanism, the N-arylation reaction was performed in the
presence of radical scavenger TEMPO (2,2,6,6-
tetramethylpiperidine-1-yl)oxyl. The desired product was
Acknowledgements
J. K. acknowledges Max-Planck Society-Germany and DST-
India (DST/INT/MPG/P-09/2016) for financial support
through Indo-Max Planck partner group project. We also

Tetrahedron Letters
5
acknowledge the Central Instrumentation Facility Center
(CIFC)-IIT BHU for the NMR facilities.
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Copper catalyzed N-arylation of
sulfoximines with aryldiazonium salts
in the presence of DABCO under mild conditions
Siddharth Baranwal and Jeyakumar Kandasamy*
R3
R3
10 mol% CuCl
DABCO
N
O
O
NH
R2
S
S
N2BF4
R1
R2
R1
CH3CN
60 oC
67-88%
R2= Aryl and Alkyl
R1= Aryl and Alkyl
R3= H, OMe, Halo,
NO2, CN, etc.
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N-Arylation of sulfoximines was achieved using
aryldiazonium tetrafluoroborates as aryl donors.
The coupling reaction proceeds in the presence of
copper chloride and DABCO.
The reaction proceeds through a radical
mechanism.
Broad substrate scope and good yields are the
advantages of the current protocol