Copper-catalyzed N-arylation of sulfonimidamides

Article abstract of DOI:10.1055/s-0030-1259682

An efficient copper-catalyzed method for introducing aryl substituents on the amino end of sulfonimidamides has been developed. Microwave irradiation allows for short reaction times and good yields, and a variety of aromatics can be coupled. Georg Thieme

Full text of DOI:10.1055/s-0030-1259682

LETTER
849
Copper-Catalyzed N-Arylation of Sulfonimidamides
C
opper-Cataly
t
zedN
-
é
Arylation
o
p
f
Sulfonimid
h
amides ane Azzaro, Marine Desage-El Murr, Louis Fensterbank,* Emmanuel Lacôte,* Max Malacria*
UPMC Université Paris 6, Institut Parisien de Chimie Moléculaire (UMR CNRS 7201),
C. 229, 4 place Jussieu, 75252 Paris Cedex 05, France
Fax +33(1)44277360; E-mail: louis.fensterbank@upmc.fr; E-mail: emmanuel.lacote@upmc.fr; E-mail: max.malacria@upmc.fr
Received 19 November 2010
per(I) salts were tested in this study and electron-poor as
well as electron-rich aryl moieties could be coupled.
Abstract: An efficient copper-catalyzed method for introducing
aryl substituents on the amino end of sulfonimidamides has been
developed. Microwave irradiation allows for short reaction times
and good yields, and a variety of aromatics can be coupled.
Our first attempts to obtain N-substituted sulfonimid-
amides using Bolm’s protocol suggested that the use of
Key words: sulfonimidamides, copper catalysis, microwave, ami- microwave activation could allow for shorter reaction
no ligands, N-coupling
times and higher yields. A generic coupling between a sul-
fonimidamide and phenyl iodide was first tested (Table 1)
and a variety of copper(I) and copper(II) salts gave satis-
factory overall results, with yields ranging from 72–87%.
Sulfonimidamides are chiral analogues of sulfonamides
with a stereogenic sulfur atom.1 These compounds have
been studied for potential biological applications as ana-
logues of the aspartic acid transition state in metallopro-
teases,2a HNO (nitroxyl) donors,2b and analogues of
oncolytic sulfonylureas2c and recently in organocatalysis.3
While the first report on sulfonimidamides from the
Levchenko group4 dates back to the early 1960s, the
chemistry5 of these hexavalent sulfur derivatives has long
been overshadowed by that of their popular cousins sul-
fonamides and sulfones.6 Sulfonimidamides have been
shown to act as efficient nitrene precursors in the presence
of hypervalent iodine reagents under both copper- and
rhodium-catalyzed conditions to give aziridination,7
imination7a,8 as well as C–H insertion9 products. All these
methods make use of sulfonimidamides with a free amino
group as the reactive end of the molecule. As part of a pro-
gram devoted to the chemistry of oxidized sulfur moi-
eties,10 we thought it would be useful to develop a
straightforward access to amino-functionalized sulfonim-
idamides.
Table 1 Stoichiometric Copper-Mediated Coupling
O
O
copper salt (1 equiv)
K2CO3 (2.5 equiv)
DMSO
O
N
Ph
O
N
Ph
S
S
NH
NH2
MW, 10 min, 170 °C
I
(2 equiv)
1
2a
Entry
Copper catalyst
CuCla
Yield (%)
1
2
3
4
5
87
80
80
80
72
CuBr
CuI
b
Cu(EH)2
Cu(OAc)2
a Similar reaction performed under thermal conditions (100 °C, 20 h)
gave 65% yield.
b Cu(EH)2: copper(II) ethyl hexanoate.
Metal-mediated coupling reactions provide an efficient
and flexible pathway to form carbon–heteroatom bonds.
Moreover, the use of ligands in these systems provides an
option to introduce asymmetric versions and generate
enantiopure products. Notably, following the pioneering
work of Ullmann,11 copper-mediated couplings have been
an ever-growing area in the last decades and have been ex-
tensively used in many fields of synthesis.12
We next tried to use catalytic amounts of the copper salt
with a classic DMEDA ligand (N,N¢-dimethylethylenedi-
amine) and were pleased to see that this reaction could
perform under such catalytic conditions (Table 2). Copper
sulfate gave an initial yield of 80% (entry 4) and, while
decreasing the catalyst loading from 15–10 mol% led to
significant lowering of yield under microwave conditions
(entry 5), switching to thermal conditions gave the expect-
ed product in 93% yield (entry 6).
Regarding C–N bond formation using sulfonylated deriv-
atives, Bolm recently reported a stoichiometric copper-
mediated coupling reaction13 between sulfonimidamides
and halogenated aryl derivatives, yielding derivatives
substituted on the secondary amino group. Several cop-
Subsequent screening of the ligand (Table 3) led us to in-
vestigate copper ligands such as ethylenediamine deriva-
tives, phenanthrolines, vicinal diamines, and the
previously mentioned 4-hydroxyproline, following Ma’s
results.12c
SYNLETT 2011, No. 6, pp 0849–0851
x
x.
x
x.
2
0
1
1
While DMEDA itself gave the expected aryl-substituted
sulfonimidamide in 80% yield, switching to less hindered
Advanced online publication: 25.02.2011
DOI: 10.1055/s-0030-1259682; Art ID: D30710ST
© Georg Thieme Verlag Stuttgart · New York

850
S. Azzaro et al.
LETTER
below 50% whereas the vicinal diamine (ortho-amino-
aniline, entry 6) gave average yields, albeit slightly high-
er. However, 4-hydroxyproline (entry 7) gave very
satisfactory results, with an optimum loading of 30 mol%
that provided the final product in 91% yield.
Table 2 Catalytic Conditions for the Copper-Catalyzed Coupling
O
O
copper salt (cat.)
K2CO3 (2.5 equiv)
PhI (2 equiv), DMSO
O
N
Ph
O
N
Ph
S
S
NH2
NH
MW, 10 min, 170 °C
H
Having determined the best catalytic system, we then in-
vestigated the scope of the reaction in terms of tolerated
iodide structures along with a modification of the amide
group from phenyl to tert-butyl (Table 4). A variety of ar-
omatics was efficiently coupled with yields ranging from
50–93%. Although heteroaromatics (entries 3 and 4),
electron-donating (entries 5 and 6), electron-withdrawing
(entries 7 and 8) groups and bulky rings (entries 9 and 10)
seem well tolerated, the best results remained for the cou-
pling of simple phenyl (entries 1 and 2). However, al-
though a chiral ligand had been used, no resolution could
be observed and only racemic mixtures of products were
obtained.14
Me
N
N
Me
H
1
2a
(20 mol%)
Entry
Copper Catalyst (mol%) mol%
Yield (%)
1
2
3
4
5
6a
CuCl
15
15
15
15
10
15
50
30
74
80
60
93
Cu2O
Cu(OAc)2
CuSO4
CuSO4
CuCl
Table 4 Substrate Scope and Influence of Amide Group
a Thermal conditions: 80 °C, 16 h.
O
O
CuSO4 (15 mol%)
K2CO3 (2.5 equiv)
Table 3 Influence of the Ligand
O
N
R
O
N
R
ArI (2.5 equiv), DMSO
S
S
O
O
MW, 10 min, 170 °C
NH2
HN
Ar
HO
CuSO4 (15 mol%)
O
N
Ph
O
N
Ph
K2CO3 (2.5 equiv)
S
O (30 mol%)
S
PhI (2.5 equiv), DMSO
1, R = Ph
3, R = t-Bu
2a–e, R = Ph
4a–e, R = t-Bu
N
H
NH2
NH
OH
MW, 10 min, 170 °C
ligand
1
Entry
ArI
R
Product Yield (%)
2a
1
2
Ph
t-Bu
2a
4a
91
93
Entry
Ligand
mol%
Yield (%)
I
H
N
3
4
Ph
t-Bu
2b
4b
54
75
1
2
3
20
20
20
80
61
63
Me
N
Me
I
S
H
5
6
Ph
t-Bu
2c
4c
88
71
NH2
H2N
MeO
I
H
t-Bu
N
N
7
8
Ph
t-Bu
2d
4d
70
60
t-Bu
F3C
I
H
4
20
37
9
10
Ph
t-Bu
2e
4e
50
77
N
N
N
N
I
5
6
20
20
19
50
This method was also applied to the N-arylation of sulfon-
imidamides bearing a carbonyl-free side chain (Table 5).
Interestingly, in this series, the expected arylated sulfon-
imidamides were not isolated. Instead, N-arylated sulfin-
amide products were observed.15
NH2
NH2
HO
In conclusion, we have developed an efficient copper-
catalyzed method for introducing aryl substituents on the
amino end of sulfonimidamides. This system works on a
variety of structures but does not allow enantiomeric ex-
cesses to be obtained. This is probably due to the high
flexibility of the system and a more constrained and rigid
substrate might be better suited for that matter. A new
20
30
40
82
91
77
O
7
N
H
OH
unsubstituted ethylenediamine (entry 2) or more sterically
congested N,N¢-tert-butylethylenediamine (entry 3) only
led to lesser yields. Phenanthroline derivatives (entries 4
and 5) gave even more disappointing results with yields
Synlett 2011, No. 6, 849–851 © Thieme Stuttgart · New York

LETTER
Copper-Catalyzed N-Arylation of Sulfonimidamides
851
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Table 5 Sulfonimidamides Bearing a Carbonyl-Free Side Chain
R
CuSO4 (15 mol%)
K2CO3 (2.5 equiv)
PhI (2.5 equiv), DMSO
O
S
O
N
S
N
NH2
H
MW, 10 min, 170 °C
HO
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O
(30 mol %)
5–7
8
N
H
OH
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Entry
Compound
R
Yield (%)
1
2
5
6
Bu
65
99
cyclohexyl
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O
3
7
75
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by the UPMC, CNRS, and IUF (MM, LF).
FR2769 is gratefully acknowledged for technical assistance.
References and Notes
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Synlett 2011, No. 6, 849–851 © Thieme Stuttgart · New York

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