Copper-catalyzed sulfonamides formation from sodium sulfinates and amines

Article abstract of DOI:10.1039/c3cc41249k

A new and convenient method for the construction of sulfonamides via a copper-catalyzed oxidative coupling between sodium sulfinates and amines with 1 atm O₂ or DMSO as the oxidant was described. This method provides efficient and robust synthesis of functional sulfonamides in good yields and excellent chemoselectivity. And detailed mechanistic studies showed that this transformation may go through a single electron transfer (SET) pathway.

Full text of DOI:10.1039/c3cc41249k

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Copper-catalyzed sulfonamides formation from
sodium sulfinates and amines†
Cite this: Chem. Commun., 2013,
49, 6102
Xiaodong Tang, Liangbin Huang, Chaorong Qi, Xia Wu, Wanqing Wu and
Huanfeng Jiang*
Received 17th February 2013,
Accepted 21st May 2013
DOI: 10.1039/c3cc41249k
www.rsc.org/chemcomm
A new and convenient method for the construction of sulfonamides
via a copper-catalyzed oxidative coupling between sodium sulfinates
and amines with 1 atm O2 or DMSO as the oxidant was described.
This method provides efficient and robust synthesis of functional
sulfonamides in good yields and excellent chemoselectivity. And
detailed mechanistic studies showed that this transformation may
go through a single electron transfer (SET) pathway.
Fig. 1 Synthetic methods for the sulfonamides.
Sulfonamides are of great importance as building blocks for
pharmaceuticals and bioactive compounds, which are widely used
as anticonvulsants, HIV protease inhibitors, and anticancer, anti- Based on our research interest in transition metal-catalysis,13
bacterial, anti-inflammatory, antitumor and antiviral agents.1,2 Phar- we found a few reported examples concerning the transition
maceutically important examples include the protease inhibitor metal-catalyzed synthesis of sulfonamides from sodium sulfinates
amprenavir, the analgesic celecoxib, sildenafil for erectile dysfunc- and amines. Herein, we report a novel formation of sulfonamides by
tion and the antimigraine agent sumatriptan.3 Sulfonamide deri- a Cu-catalyzed cross-coupling reaction between sodium sulfinates
vatives of azo dyes have been reported to improve light-stability and and amines with the use of 1 atm O2 or DMSO as the oxidant. This
fibre fixation.4 Furthermore, sulfonamides have been used as method provides a variety of sulfonamides in good yields and
protecting groups for NH functionalities with easy removal excellent chemical selectivity.
under mild conditions.5 Although many efforts have been made
At first, we examined the reaction of N-benzylmethylamine (1a)
towards the development of novel sulfonamides,6 the conventional with sodium p-toluenesulfinate (2a) under various conditions and
synthesis involves the reaction of amino compounds with sulfonyl the results are summarized in Table 1. When the reaction of 1a with
chlorides7 or catalytic cross coupling of sulfonamides with organic 2a was carried out in the presence of CuBr2 (20 mol%) under N2 in
halides,8,9 alcohols or esters.10 Aminosulfonation of hydrocarbons DMF for 24 h, the yield of 3a was only 22% (entry 1). Delightfully,
has also been reported very recently (Fig. 1).11 However, these when the solvent was changed to DMSO, the yield was improved to
reactions have drawbacks such as harsh conditions, requirement 90% (entry 2), while other solvents just led to a decrease in yield
for excess base to balance the generated acid, poor tolerance of (entries 3–6). These results indicated that the choice of DMSO as the
functional groups, difficulty in handling and long-term storage and solvent was crucial for the reaction. At a lower temperature, 3a was
so on. Therefore, there is a clear need for the development of a formed in a lower yield (entry 7). Screening of different copper salts
generally applicable, environmentally benign and mild methodol- showed that CuBr2 was the best (entries 8–11). As expected, no
ogy for the synthesis of sulfonamides.
reaction occurred in the absence of Cu catalyst (entry 12). Other
Transition metal-catalyzed reactions have emerged as an effective metals such as FeCl3, PdCl2 or NiCl2 were also ineffective for this
tool for the formation of carbon–carbon and carbon–heteroatom transformation (entries13–15). When 1 atm O2 was used as an
bonds, and thus have attracted intensive synthetic attention.12 oxidant, the yield was reduced to 78%, due to the formation of
the benzaldehyde byproduct (entry 16). Thus, the optimal reaction
School of Chemistry and Chemical Engineering, South China University of
conditions for the reaction of 1a (0.5 mmol) and 2a (0.6 mmol)
include 20 mol% CuBr2 in 2 mL DMSO at 100 1C under a N2
atmosphere. The reaction was scalable and practical since a satis-
factory yield (88%) was obtained in the presence of 10 mol% CuBr2
when the reaction was performed on a 5 mmol scale (entry 17).
Technology, Guangzhou 510640, China. E-mail: jianghf@scut.edu.cn;
Fax: +86 20-87112906; Tel: +86 20-87112906
† Electronic supplementary information (ESI) available: Experimental section,
characterization of all compounds, copies of 1H and 13C NMR spectra for selected
compounds. See DOI: 10.1039/c3cc41249k
c
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Table 1 Optimization of the reaction conditions of method Aa
benzylamine was used, which might be due to its own polymeriza-
tion. When steric bulky tert-butylamine and dodecylamine were
used, the corresponding products 3c7 and 3c10 could be achieved
in moderate yields. To our delight, acrylaminde, 3-butenylamine and
pent-4-en-1-amine also provided good results (3e–g). It is especially
worth mentioning that when amino alcohols were employed as
substrates, the desired products 3m and 3n were isolated in 82%
and 75% yield, respectively. Particularly, 1a reacted exclusively with
the amino group while the hydroxyl group remained unaffected,
which could not be easily obtained with the traditional methods.
However, when the aromatic amines were subjected to this trans-
formation, the desired products were obtained in very lower yields
(o20%). After a simple screening, we found that under condition B
[sulfinate (0.5 mmol), amine (0.6 mmol), pyridine (1 mmol), DMSO
(2 mL), 100 1C, 1 balloon O2, 24 h], the aromatic amines
could convert to the corresponding sulfonamides in moderate yields
(3o–q). The observed reactivity difference between aromatic and
aliphatic amines should be due to the reason that aromatic amine
has less nucleophilicity than aliphatic amine.
Entry
Catalyst
Temp (1C)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuCl2
CuI
CuBr
Cu(OAc)2
—
PdCl2
FeCl3
NiCl2
CuBr2
CuBr2
100
100
100
100
100
100
80
100
100
100
100
100
100
100
100
100
100
DMF
22
90
15
24
12
16
67
45
15
41
29
0
Trace
Trace
Trace
78
DMSO
1,4-Dioxane
Toluene
CH3CN
THF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
10
11
12
13
14
15
16c
17d
88
Next, various sulfinic acid sodium salts were also explored in this
reaction and the results are summarized in Table 3. The nature of
sulfinic acid sodium salts had an influence on the results. Phenyl-
sulfinic acid sodium salt reacted with pyrrolidine smoothly and
gave the corresponding product 3r in 87% yield (entry 1). Halogen
functional groups such as F, Cl, Br were tolerated under the
optimized reaction conditions and gave the desired products in
moderate yields (entries 2–4). To our delight, a good yield was
a
Conditions: 1a (0.6 mmol), 2a (0.5 mmol), catalyst (0.1 mmol), solvent
b
c
(2 mL), 24 h, N2. Isolate yield based on 2a. The reaction with one
balloon O2. Conditions: 1a (6 mmol), 2a (5 mmol), catalyst (0.5 mmol),
solvent (5 mL), 24 h, N2.
d
With the optimized conditions in hand, the scope of the reaction
with respect to various amines was investigated (Table 2). N-Methyl-
benzylamine with fluoro, chloro, bromo, methoxyl and cyano groups
on aryl rings all gave good to excellent yields of corresponding
products (3a2–a6). The reactions with various aliphatic amines
proceeded smoothly to give the desired products from moderate
to good yields. A lower yield (3b, 61%) was obtained when
Table 3 Substrate scope with various sodium sulfinatesa
Table 2 Reaction of 1a with various aminesa
Entry
1
Sodium sulfinate
Product
Yield (%)
87
2
3
4
5
82
77
70
96
6
7
96
97
0
8
a
Conditions: 1a (0.5 mmol), 2 (0.6 mmol), DMSO (2 mL), 24 h, N2;
b
Isolated yield based on sulfinate. Use Method B: sulfinate (0.5 mmol),
a
amine (0.6 mmol), pyridine (1 mmol), DMSO (2 mL), 100 1C, 1 balloon O2,
24 h; Isolated yield based on sulfinate.
Conditions: sulfinate (004 mmol), amine (0.6 mmol), DMSO (2 mL),
24 h, N2; isolated yield based on sulfinate.
c
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Scheme 1 Possible mechanism.
obtained when aliphatic sulfinic acid sodium was used as the starting
material (entries 5–7). However, sodium trifluoromethanesulfonate
was not a suitable substrate for this transformation (entry 8), which
suggested that the electron-withdrawing groups might have an
influence on the product formation.
To investigate the reaction mechanism, several experiments were
performed.14 No sulfonamide product was detected in the presence of
the radical scavenger TEMPO or BHT, which indicated that a radical
pathway should be involved.15 According to the above results, a possible
mechanism is proposed in Scheme 1. Intermediate A is initially
generated by the coordination of copper to the sodium sulfinate.16,17
Release of CuBr produces the sulfonyl free radical intermediate.18
Coordination of copper to the amine produces intermediate B, which
combines with the sulfonyl free radical to give the desired product with
release of CuBr.19 Finally, the CuI can be oxidized by DMSO or O2 to
generate the CuII species.20 When we try to trap the radical inter-
molecularly by using 1,1-diphenylethylene or a tethered vinylcyclo-
propane in the presence or absence of amine, we did not observe
the radical coupling products. Therefore, an organometallic path-
way cannot be overlooked for this transformation.14
In conclusion, we have developed an efficient Cu-catalyzed
sulfonamide formation from sodium sulfinates and amines.
The reaction presents a convenient method with good func-
tional group tolerance for the synthesis of sulfonamides in
medicinal chemistry and materials science. Further studies are
underway to provide insight into the mechanism and synthetic
applications of this reaction.
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14 See the ESI† for details.
We are grateful to the National Natural Science Foundation
of China (21172076 and 20932002), the National Basic Research
Program of China (973 Program) (2011CB808600), the Changjiang
Scholars and Innovation Team Project of Ministry of Education, the
Guangdong Natural Science Foundation (10351064101000000),
China Postdoctoral Science Foundation (2011M501318) and
the Fundamental Research Funds for the Central Universities
(2012ZP0003).
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6104 Chem. Commun., 2013, 49, 6102--6104
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