Synthesis of sulfonamides via I2-mediated reaction of sodium sulfinates with amines in an aqueous medium at room temperature

Article abstract of DOI:10.1039/c4gc02115k

An efficient I₂-mediated approach for the synthesis of sulfonamides at room temperature using water as the solvent has been developed. This method for the synthesis of sulfonamides is quite convenient and environmentally friendly. In addition, the purification procedure of the desired products becomes very easy. This journal is

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DOI: 10.1039/C4GC02115K
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Synthesis of sulfonamides via I2-mediated reaction of sodium sulfinates
with amines in aqueous medium at room temperature
Xiaojun Pan, Jian Gao, Juan Liu, Junyi Lai, Huanfeng Jiang and Gaoqing Yuan*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An efficient I2-mediated approach to the synthesis of
sulfonamides at room temperature using water as the
solvent has been developed. This method for the
synthesis of sulfonamides is quite convenient and
10 environment friendly. In addition, the purification
procedure of the desired products becomes very easy.
As HIV protease inhibitors, calcitonin inducers and anticancer,
antibacterial and anti-inflammatory agents, sulfonamides have
a wide range of applications in pharmaceutical industry.1
15 During the past decade, various methods have been developed
for the synthesis of sulfonamides, including the reaction of
thiols or sulfonyl chlorides with amino compounds and
sulfonamides with organic halides, alcohols or hydrocarbons
via metal-catalyzed coupling.2 Recently, a new and attractive
20 protocol for the synthesis of sulfonamides from sodium
50
Scheme 1 Two different methods for the synthesis of
sulfonamides.
room temperature (Scheme 1b). The present synthetic route
could afford the target products in good to excellent yields
sulfinates and amines has also been reported (Scheme 1a).3 55 under green and mild conditions, showing its fascinating
However, in most of these methods, the reaction was carried
out using transition metals as catalyst and toxic solvents as
reaction media. In addition, some of them also suffer from
25 harsh reaction conditions and tedious procedures in the
application prospect.
Initially, we utilized N-methylbenzylamine (1a) and
sodium p-tolylsulfinate (2a) as model substrates to optimize
the reaction conditions, and the results are summarized in
purfication of the products. To overcome these drawbacks, it 60 Table 1. To our delight, in the presence of iodine (0.2 equiv),
is still highly desired to search for a greener and sustainable
method for the synthesis of sulfonamides.
In recent years, iodine-mediated4 or iodine-catalyzed5
30 reactions have been widely studied because iodine is cheap,
the reaction of 1a with 2a at room temperature in H2O for 3 h
gave sulfonamides (3a) in 42% yield (Table 1, entry 2). When
the amount of iodine was increased to twice (0.4 equiv), the
yield of 3a was also nearly raised to twice (Table 1, entry 4).
readily available and eco-friendly. Undoubtedly, it is very 65 When the reaction time was prolonged from 3 h to 30 h, the
attractive that iodine could substitute for transition metals as
catalysts. Some successful cases have comfirmed that iodine
could effectively replace the transition metals to catalyze
35 some organic reactions.6 In addition, water as reaction media
yield of 3a was almost unchanged (Table 1, entry 5). This
interesting result attracted our attention. We guessed that the
yield of 3a would be directly related to the amount of iodine.
In order to confirm this point, different amounts of iodine
has attracted increasing attention in organic synthesis due to 70 were added into the reaction system. When the amount of
its environmental acceptability, abundance, safety and low
cost.7 We are interested in I2-mediated or catalyzed organic
reactions performed in the aqueous phase. Herein, we report
40 an efficient I2-mediated reaction of sodium sulfinates with
amines for the synthesis of sulfonamide in aqueous media at
iodine was increased to 0.5 equiv, more than 98% yield of 3a
was obtained (Table 1, entry 6). Decreasing the stoichiometric
amount of iodine to 0.3 and 0.1 equiv led to the declined yield
of 61% and 18% (Table 1, entries 3 and 1), respectively. Next,
75 the effect of solvents on the reaction was examined.
Screening of various solvents indicated that water was the
most suitable solvent for this transformation (Table 1, entries
7–15). Unfortunately, with the use of AcOH as the solvent, no
desired product was detected by GC-MS (Table 1, entry 16).
80 In addition, the yield of 3a could be hardly improved by
increasing reaction temperature (Table 1, entry 17). Thus, the
optimized conditions for this reaction was summarized as
School of Chemistry and Chemical Engineering, South China University
of Technology, Guangzhou, 510640, P. R. China
45 E-mail: gqyuan@scut.edu.cn
† Electronic Supplementary Information (ESI) available: Detailed
experimental procedures, characterization of products, and NMR spectral
charts. See DOI: 10.1039/b000000x/
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35 Table 2 Synthesis of sulfonamides under the optimum conditions.a,b
follows: 1a (0.5 mmol), 2a (0.6 mmol), I2 (0.25 mmol), at
room temperature in water medium under air for 3 h.
Table 1 Optimization of reaction conditions.a
5
Entry
I2 (equiv)
Solvent
Time (h)
Yield (%) b
1
0.1
0.2
0.3
0.4
0.4
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.5
0.5
H2O
3
3
3
3
30
3
3
3
3
3
3
3
3
3
3
3
3
3
3
18
2
H2O
42
3
H2O
61
4
H2O
79
5
H2O
81
6
H2O
>98
92
7
MeOH
EtOH
CH3CN
DMF
DMSO
EtOAC
CH2Cl2
THF
8
89
9
93
10
11
12
13
14
15
16
17c
18d
19e
98
87
87
96
88
pyridine
AcOH
H2O
91
a Reaction conditions: 1 (0.5 mmol), 2 ( 0.6 mmol) and I2 (0.25 mmol) in
trace
19
2.0 mL of H2O at room temperature for 3 h. b Isolated yield.
In order to better understand the reaction mechanism,
40 several controlled experiments were carried out (Scheme 2).
The reaction was totally inhibited in the presence of the
H2O
96
H2O
>98
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), solvent (2.0 mL),
room temperature, 3 h, under air. b Determined by GC based on 1a. c
Reaction temperature 80 °C . d Under N2 in a sealed tube. e The reaction
was carried out in the dark background.
radical
scavenger
2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO), indicating that this transformation proceeded via a
radical pathway (Scheme 2, eq (a)). To find more evidence
45 tosupport this point, we utilized 1,1-diphenylethylene to
capture the radical. Unfortunately, no desired product (4a)
was detected in the presence or absence of N-
methylbenzylamine under the optimal reaction conditions
(Scheme 2, eq (b) and eq (c)). However, the yields of 4a
50 increased to 10% and 20%, respectively, using methanol as
solvent (Scheme 2, eq (b) and eq (c)). This is mainly due to an
intrinsically better solubility of the 1,1-diphenylethylene in
methanol. Subsequently, instead of sodium p-tolylsulfinate,
freshly prepared p-toluenesulfonyl iodide8 reacted smoothly
55 with N-methylbenzylamine in the absence of iodine, affording
the desired product in an excellent yield (Scheme 2, eq (d)).
This result indicates that p-toluenesulfonyl iodide was an
intermediate for this transformation. Under the protection of
N2, the reaction was carried out to afford the target product 3a
60 in an excellent yield (96%, Table 1, entry 18), demonstrating
that oxygen did not act as a oxidant in this transformation.
When the reaction was performed in the dark background, the
yield of the target product was not influenced (Table 1, entry
19). This means that the radicals in this reaction system does
65 not originate from the light induction. Further testing pH
value of the solution after the reaction of 1a (0.5 mmol) with
2a (0.5 mmol), we found that the solution exhibits a slightly
alkaline (pH=7.3), which was close to the pH value of NaI
solution (pH=7.0). This indicated that no HI existed in the
10
With the optimal reaction conditions established, we then
examined the scope of the reaction between different amines
and sodium p-tolylsulfinate (2a). As listed in Table 2, both
aromatic and aliphatic amines reacted smoothly with sodium
p-tolylsulfinate under the optimal reaction conditions, giving
15 the corresponding sulfonamides from moderate to excellent
yields. It was worth mentioning that benzylamine could be
effective to afford the corresponding sulfonamide in an
excellent yield (93%), which indicated that some unwanted
phenomenon such as self-polymerization almost did not occur
20 in this process. Moreover, benzylamine with either electron-
donating groups (R′=OMe, Me) or electron-withdrawing
groups (R′=F, Cl, Br) on aryl rings all afforded the
corresponding sulfonamides in good to excellent yields. When
aliphatic amines such as methylamine, allylamine and n-
25 hexylamine were utilized as the substrates, giving the desired
products (3g1–3n) in moderate to excellent yields.
Nevertheless, lower yields were obtained when the aromatic
amines coupled with 2a (3d, 3f1 and 3f2) under the same
reaction conditions. We further investigated the scope of
30 substrates of sulfinic acid sodium salts in this reaction. Para-
substituted sulfinic acid sodium salts with electron-
withdrawing groups (R′=F, Cl, Br), were suitable for this
transformation and afforded the desired products in high
yields.
2
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Green Chemistry
sulfinates and amines. Compared with previous works, this
work shows its simplicity, environmental friendliness and
low-cost, which could meet the requirement of green
chemistry. The research on iodine-mediated or iodine-
35 catalyzed reactions for the synthesis of other important
compounds is ongoing in our laboratory.
solution after the reaction.
According to the experimental results described the above,
a proposed reaction pathway is depicted in Scheme 3. Initially,
the sulfinic acid sodium salt reacts with iodine, affording the
sulfonyl iodide intermediate A.9c Due to its instability, the
5
sulfonyl iodide intermediate
A is easily subjected to
homolysis, giving a sulfonyl radical B and a iodine radical
(I·).9 Then, the sulfonyl radical B attacks on hydrogen of
amine to afford the desired sulfonamide, together with the
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21172079), the Science and Technology Planning Project
40 of Guangdong Province (2011B090400031), and Guangdong
Natural Science Foundation (10351064101000000).
10 formation of hydrogen atom (H·).10 Meanwhile, the molecular
iodine is partly re-generated via the self-coupling of the
iodine radical, which could participate in the reaction untill I2
is fully transformed to NaI. In this sense, I2 has no catalytic
characteristics in this process. In addition, the formed
15 hydrogen atom is finally converted into molecular hydrogen
via a self-coupling process. In the present reaction system, I2
practically is a reactant or inducer, which is depicted in
Scheme 4. The total reaction equation (Scheme 4) could well
explain why the full conversion of 0.5 mmol of 1a to 3a
20 requires 0.25 mmol of I2 (Table 1, entry 6).
Notes and references
1
(a) B. Masereel, S. Rolin, F. Abbate, A. Scozzafava and C. T. Supuran,
J. Med. Chem., 2002, 45, 312; (b) A. K. Ganguly, S. S. Alluri, D.
Caroccia, D. Biswas, C. -H. Wang, E. Kang, Y. Zhang, A. T.
McPhail, S. S. Carroll, C. Burlein, V. Munshi, P. Orth and C.
Strickland, J. Med. Chem., 2011, 54, 7176; (c) A. M. Gilbert, S.
Caltabiano, F. E. Koehn, Z. J. Chen, G. D. Francisco, J. W. Ellingboe,
Y. Kharode, A. M. Mangine, R. Francis, M. T. Smith and D. Gralnick,
J. Med. Chem., 2002, 45, 2342; (d) J. J. Li, M. B. Norton, E. J.
Reinhard, G. D. Anderson, S. A. Gregory, P. C. Isakson, C. M.
Koboldt, J. L. Masferrer, W. E. Perkins, K. Seibert, Y. Zhang, B. S.
Zweifel and D. B. Reitz, J. Med. Chem., 1996, 39, 1846; (e) T. Owa,
H. Yoshino, T. Okauchi, K. Yoshimatsu, Y. Ozawa, N. H. Sugi, T.
Nagasu, N. Koyanagi and K. Kitoh, J. Med. Chem., 1999, 42, 3789.
(a) X. Huang, J. C. Wang, Z. Q. Ni, S. C. Wang and Y. J. Pan, Chem.
Commun., 2014, 50, 4582; (b) K. Bahrami, M. M. Khodaei and M.
Soheilizad, J. Org. Chem., 2009, 74, 9287; (c) S. Lakrout, H. K’tir, A.
Amria, M. Berredjem and N. -E. Aouf, RSC Adv., 2014, 4, 16027; (d)
B. R. Rosen, J. C. Ruble, T. J. Beauchamp and A. Navarro, Org. Lett.,
2011, 13, 2564; (e) A. R. Massah, S. Sayadi and S. Ebrahimi, RSC
Adv., 2012, 2, 6606; (f) F. Shi, M. K. Tse, X. J. Cui, D. Gördes, D.
Michalik, K. Thurow, Y. Q. Deng and M. Beller, Angew. Chem., Int.
Ed., 2009, 48, 5912; (g) L. D. Luca and G. Giacomelli, J. Org. Chem.,
2008, 73, 3967; (h) D. A. Powell and H. Fan, J. Org. Chem., 2010, 75,
2726; (i) F. Shi, M. K. Tse, S. L. Zhou, M. -M. Pohl, J. Radnik, S.
Hübner, K. Jähnisch, A. Brückner and M. Beller, J. Am. Chem. Soc.,
2009, 131, 1775.
45
50
55
60
65
70
75
80
85
90
2
3
4
X. D. Tang, L. B. Huang, C. R. Qi, X. Wu, W. Q. Wu and H. F. Jiang,
Chem. Commun., 2013, 49, 6102.
(a) Q. H. Gao, S. Liu, X. Wu and A. X. Wu, Org. Lett., 2014, 16,
4582; (b) Y. C. Teo, S. N. Riduan and Y. Zhang, Green Chem., 2013,
15, 2365; (c) Y. X. Li, H. X. Wang, S. Ali, X. F. Xia and Y. M.
Liang, Chem. Commun., 2012, 48, 2343; (d) H. Batchu, S. Bhatta-
charyya and S. Batra, Org. Lett., 2012, 14, 6330; (e) Z. H. He, H. R.
Li and Z. P. Li, J. Org. Chem., 2010, 75, 4636; (f) T. D. Wang, H.
Zhang, F. F. Han, L. P. Long, Z. Y. Lin and H. P. Xia, Angew. Chem.,
Int. Ed., 2013, 52, 9251; (g) H. Batchu, S. Bhattacharyya and S.
Batra, Org. Lett., 2012, 14, 6330; (h) H. Zaimoku, T. Hatta, T.
Taniguchi and H. Ishibashi, Org. Lett., 2012, 14, 6088.
Scheme 2 Control experiments.
5
(a) F. L. Yang and S. K. Tian, Angew. Chem., Int. Ed., 2013, 52, 4929;
(b) Y. Z. Yan, Y. H. Zhang, C. T. Feng, Z. G. Zha and Z. Y. Wang,
Angew. Chem., Int. Ed., 2012, 51, 8077; (c) W. L. Ge and Y. Y. Wei,
Green Chem., 2012, 14, 2066; (d) Y. F. Liao, P. C. Jiang, S. P. Chen,
H. R. Qi and G. J. Deng, Green Chem., 2013, 15, 3302; (e) M. A.
Kumar, P. Swamy, M. Naresh, M. M. Reddy, C. N. Rohitha, S.
Prabhakar, A. V. S. Sarma, J. R. P. Kumar and N. Narender, Chem.
Commun., 2013, 49, 1711; (f) F. H. Xiao, H. Chen, H. Xie, S. Q.
Chen, L. Yang and G. J. Deng, Org. Lett., 2014, 16, 50; (g) Z. H. He,
W. P. Liu and Z. P. Li, Chem. Asian J. 2011, 6, 1340.
25
Scheme 3 Proposed reaction mechanism.
6
(a) S. Tang, Y. Wu, W. Q. Liao, R. P. Bai, C. Liu and A. W. Lei,
Chem. Commun., 2014, 50, 4496; (b) A. Sagar, S. Vidyacharan and D.
S. Sharada, RSC Adv., 2014, 4, 37047.
Scheme 4 A total reaction equation for this transformation.
In conclusion, we have developed a green and sustainable
30 method for the synthesis of sulfonamides from sodium
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7
(a) U. M. Lindstrom, Chem. Rev., 2002, 102, 2751; (b) C. J. Li, Chem.
Rev., 2005, 105, 3095; (c) A. P. Brogan, T. J. Dickerson and K. D.
Janda, Angew. Chem., Int. Ed., 2006, 45, 8100; (d) Y. Hayashi,
Angew. Chem., Int. Ed., 2006, 45, 8103; (e) B. H. Lipshutz and S.
Ghorai, Green Chem., 2014, 16, 3660; (f) S. Madabhushi, R. Jillella,
V. Sriramoju and R. Singh, Green Chem., 2014, 16, 3125.
(a) C. Nájera, B. Baldó and M. Yus, J. Chem. Soc., Perkin Trans. 1
1988, 1029; (b) P. Katrun, S. Chiampanichayakul, K. Korworapan, M.
Pohmakotr, V. Reutrakul, T. Jaipetch and C. Kuhakarn, Eur. J. Org.
Chem., 2010, 5633.
(a) W. E. Truce and G. C. Wolf, J. Org. Chem., 1971, 36, 1727; (b) C.
M. M. D. S. Corrêa and W. A. Waters, J. Chem. Soc. C., 1968, 1874;
(c) P. Katrun, C. Mueangkaew, M. Pohmakotr, V. Reutrakul, T.
Jaipetch, D. Soorukram and C. Kuhakarn, J. Org. Chem., 2014, 79,
1778.
5
10
15
8
9
10 (a) Y. Y. Zhao and F. G. Bordwell, J. Org. Chem., 1996, 61, 2530; (b)
A. Baroudi, J. Alicea, P. Flack, J. Kirincich and I. V. Alabugin, J.
Org. Chem., 2011, 76, 1521.
4
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DOI: 10.1039/C4GC02115K
Synthesis of sulfonamides via I2-mediated reaction of sodium
sulfinates with amines in aqueous medium at room temperature
Xiaojun Pan, Jian Gao, Juan Liu, Junyi Lai, Huanfeng Jiang and Gaoqing Yuan*
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou, China
A convenient and green synthetic route has been developed to synthesize sulfonamides in aqueous
medium at room temperature, without the use of transition metal catalysts and oxidants.
O
R S N
O
I2
R1
R2
O
H
N
+
R S ONa
R1
R2
H2O, rt
27 examples
up to 97% yield