Metal-free oxidative coupling of amines with sodium sulfinates: A mild access to sulfonamides

Article abstract of DOI:10.1039/c4ra13454k

A practical and mild procedure for the preparation of sulfonamides through TBAI-catalyzed oxidative coupling of amines with sodium sulfinates using TBHP as an oxidant was presented. A variety of amines and sodium sulfinates could go through the transformation, without impacting the hydroxyl group. This journal is

Full text of DOI:10.1039/c4ra13454k

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: J. Zhao, J. Xu, J.
Chen, X. Wang and M. He, RSC Adv., 2014, DOI: 10.1039/C4RA13454K.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

View Article Online
DOI: 10.1039/C4RA13454K
Page 1 of 3
RSC Advances
Journal Name
RSCPublishing
COMMUNICATION
Metal-free Oxidative Coupling of Amines with Sodium
Sulfinates: A Mild Access to Sulfonamides
Cite this: DOI: 10.1039/x0xx00000x
Jinwu Zhao,* Jingxiu Xu, Jiaxi Chen, Xiaoqin Wang and Minghua He
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
sulfonamides principally involve the reaction of amines with
sulfonyl chlorides and the alkylation of sulfonamides. 5, 6 Transition
metal-catalyzed oxidative cross-coupling have been a new strategy
to obtain sulfonamides. 7 In 2013, Jiang group reported an elegant
process for the synthesis of sulfonamides from sodium sulfinates and
amines under the catalysis of copper. 8 Later, Pan group disclosed
that sulfonamides could be synthesized from thiols and formamides
using stoichiometric Cu(OAc)2 and CuCl. 9 Although these methods
are useful to produce sulfonamides, they suffer from drawbacks such
as harsh conditions, requirement for excess base to balance the
generated acid, poor tolerance of functional groups, difficulty in
handling and possible metal contamination. Therefore, there is a
great demand for the development of a clean and facile methodology
for the synthesis of sulfonamides. Herein, we wish to report a metal-
free procedure for the synthesis of sulfonamides through TBAI-
catalyzed (tetra-n-butylammonium iodide) oxidative coupling of
sodium sulfinates with amines using TBHP (tert-butyl
A practical and mild procedure for the preparation of
sulfonamides through TBAI-catalyzed oxidative coupling of
amines with sodium sulfinates using TBHP as an oxidant was
presented. A variety of amines and sodium sulfinates could go
through the transformation, without impacting hydroxyl
group
.
Sulfonamides are often present in pharmaceuticals and bioactive
compounds. Sulfa drugs have been used as antimicrobial agents for a
long time, and sulfonamide compounds exhibit several other type
biological activities such as hypoglycemic, diuretic, anti-carbonic
anhydrase(CA), anti-thyroid, anti-inflammatory, anti-cancer, anti-
hypertensive and anticonvulsant properties.1 Pharmaceutically
important examples include the protease inhibitor amprenavir, the
analgesic celecoxib, sildenafil for erectile dysfunction and the
antimigraine agent sumatriptan (Figure 1). Sulfonamides also have a
wide range of applications in herbicides and dyes.2 Furthermore,
sulfonamides have been used as protecting groups for NH
hydroperoxide) as an oxidant (Scheme 1). This protocol affords a
variety of sulfonamides in satisfactory yields under mild reaction
conditions.
functionalities with easy removal under mild conditions.3
Scheme 1. TBAI-catalyzed oxidative coupling of amines and
sodium sulfinates using TBHP as an oxidant.
Our studies began by optimizing the reaction conditions for the
synthesis of sulfonamides, choosing sodium p-toluenesulfinate (1a)
and morpholine (2a) as model substrates. The results are tabulated in
Table 1. When the reaction proceeded at 50 oC for 8h under the
catalysis of 10 mol% molecular iodine in DMSO using TBHP as an
oxidant, the desired sulfonamide 3aa was obtained in 65% yield
(Table 1, entry 1). Employing 20 mol% KI as catalyst improved the
yield to 79% and TBAI was found to be the best catalyst for the
oxidative coupling (Table 1, entries 2 and 3). Our experimental
results showed that the tested solvents including DMF, water,
Figure 1. Examples of bioactive sulphonamides
Although a number of processes for the synthesis of sulfonamides
have been developed, 4 the traditional methods for the synthesis of
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 1

View Article Online
RSC Advances
DOI: 10.1039/C4RA13P45a4gKe 2 of 3
COMMUNICATION
Journal Name
dioxane and acetonitrile all afforded the target compound in lower
yields compared with DMSO (Table 1, entries 4-7). To our delight,
aqueous acetonitrile gave 3aa in an excellent yield (Table 1, entry 8).
Various oxidants were then screened. As shown in table 1, the
examined oxidants, such as dioxygen, DMSO, oxone and K2S2O8
had almost no effect on the transformation except that hydrogen
peroxide produced the corresponding molecule in a lower 78% yield
(Table 1, entries 9-13). It was finally found that increasing the
loading of n-Bu4NI could not elevate the yield and 3.0 equivalent of
TBHP was most beneficial for the coupling reaction (Table 1, entries
14-16).
Table 2. Scope of amines for the oxidative coupling. a, b
Table 1. Optimizing the reaction conditions for the coupling of
amines and sodium sulfinates. a
Entry
Catalyst
(mol%)
Oxidant
(equiv)
Solvent
DMSO
Yield
(%)b
1
2
I2 (10)
KI (20)
TBHP (2)
TBHP (2)
65
79
DMSO
3
4
5
6
7
8
9
10
11
12
13
14
15
TBAI (20) TBHP (2)
TBAI (20) TBHP (2)
TBAI (20) TBHP (2)
TBAI (20) TBHP (2)
TBAI (20) TBHP (2)
TBAI (20) TBHP (2)
TBAI (20) H2O2 (2)
DMSO
DMF
H2O
dioxane
86
74
30
trace
70
92
78
trace
trace
0
MeCN
a Conditions: 1a (1.0 mmol), 2 (1.5 mmol) in aqueous acetonitrile
MeCN /H2O (3 : 1)
MeCN /H2O (3 : 1)
MeCN /H2O (3 : 1)
MeCN /H2O (3 : 1)
MeCN /H2O (3 : 1)
MeCN /H2O (3 : 1)
MeCN /H2O (3 : 1)
MeCN /H2O (3 : 1)
MeCN /H2O (3 : 1)
(2mL). b Isolated yield.
c
TBAI (20) O2
A variety of sodium sulfinates were then examined under the
standard reaction conditions and the results are recorded in table 3.
Sodium naphthalene-2-sulfinate and 4-chlorobenzenesulfinate
reacted efficiently with morpholine to provide the target sulfonamide
in 95% and 93% yield, respectively (Table 3, 3ba and 3ca). When
sodium 4-methoxybenzenesulfinate was subjected to the optimized
reaction conditions, an excellent yield was obtained while sodium 4-
(trifluoromethyl)benzenesulfinate furnished a moderate yield (Table
3, 3da, 3ea). These results revealed that electronic effect had a
considerable effect on the coupling reaction. To our delight, it was
found that aliphatic sulfinic acid sodium salts were all outstanding
coupling partners (Table 3, 3fa-3ha). However, sodium
TBAI (20) DMSO (2)
TBAI (20) oxone (2)
TBAI (20) K2S2O8 (2)
TBAI (30) TBHP (2)
TBAI (20) TBHP (3)
TBAI (20) TBHP (4)
0
92
96
96
16
a
Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), solvent (2 mL),
8 h. b Isolate yield based on 1a. c The reaction was carried out with a
O2 balloon.
The generality and scope of the methodology was then examined
after establishing the optimal reaction conditions, and the results are
listed in Table 2. Aliphatic amines all went through the oxidative
coupling smoothly to give the desired products (Table 2, 3ab-3al).
Among them, although steric hindrance had negative impact on the
yield, bulky tert-butylamine and di-iso- butylamine produced the
target sulfonamides in the yields of 78% and 80% respectively
(Table 2, 3ae, 3aj). Benzylamine furnished the corresponding
sulfonamide in lower 60% yield because of the side reaction of
benzylic oxidation (3af). Aromatic amines were also able to undergo
the coupling reaction in lower yields compared against aliphatic
primary amines for the possible reason that aromatic amine has less
nucleophilicity than aliphatic amine (Table 2, 3am-3ao).
trifluoromethanesulfonate failed to yield the desired sulfonamide as
expected (Table 3, 3ia).
Table 3. Scope of sodium sulfinates for the oxidative coupling. a, b
Unexpectedly, amines containing a hydroxyl selectively gave the
sulfonylation products of amino groups in good to excellent isolated
yields (Table 2, 3ap-3ar), which could not be easily prepared with
the traditional methods. These experimental result suggested that
sodium sulfinate coupled exclusively with the amino group without
impacting the hydroxyl group.
a Conditions: 1 (1.0 mmol), 2 a (1.5 mmol) in aqueous acetonitrile
(2mL). b Isolated yield.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C4RA13454K
Page 3 of 3
Journal Name
RSC Advances
COMMUNICATION
4
(a) M. Ashfaq, S. S. Ahmad Shah, T. Najjam, S. Shaheen and G.
Rivera, Mini-Rev. Org. Chem., 2013, 10, 160; (b) W. Li, M. Beller
and X. Wu, Chem. Commun., 2014, 50, 9513; (c) R. R. Naredla and
D. A. Klumpp, Tetrahedron Lett., 2013, 54, 5945; (d) S. W. Wright
and K. N. Hallstrom, J. Org. Chem., 2006, 71, 1080; (e) J. D. Wilden,
L. Geldeard, C. C. Lee, D. B. Judd and S. Caddick, Chem. Commun.,
2007, 1074; (f) S. Caddick, J. D. Wilden and D. B. Judd, J. Am.
Chem. Soc., 2004, 126, 1024; (g) K. Bahrami, M. M. Khodaei and M.
Soheilizad, J. Org. Chem., 2009, 74, 9287.
Based on the above experimental results and the relevant reported
works, 10 a proposed reaction mechanism is outlined in scheme 2.
Firstly, I-/I2 redox cycle promotes TBHP to furnish tert-butoxyl and
tert-butylperoxyl radicals. Sulfinate 1 is oxidized by these oxidative
species into an oxygen-centered radical A that can resonate with the
sulfonyl radical B. Then, amine 2 attacks sulfonyl radical to generate
radical anion C with the loss of a proton. Intermediate C is able to be
oxidized by molecular iodine to produce the final sulfonamide
product 3.
5
6
K. K. Andersen, in Comprehensive Organic Chemistry, ed. D. N.
Jones, Pergamon Press, Oxford, 1979, vol. 3.
(a) G. Burton, P. Cao, G. Li and R. Rivero, Org. Lett., 2003, 5, 4373;
(b) W. Deng, L. Liu, C. Zhang, M. Liu and Q. Guo, Tetrahedron Lett.,
2005, 46, 7295
7
8
N. Taniguchi, Eur. J. Org. Chem., 2010, 2670.
X. Tang, L. Huang, C. Qi, X. Wu, W. Wu and H. Jiang, Chem.
Commun., 2013, 6102.
9
X. Huang, J. Wang, Z. Ni, S. Wang and Y. Pan, Chem. Commun.,
2014, 4582.
10 (a) X. Wu, J. Gong and X. Qi, Org. Biomol. Chem., 2014, 5807; (b) Z.
Liu, J. Zhang, S. Chen, E. Shi, Y. Xu and X. Wan, Angew. Chem. Int.
Ed., 2012, 51, 3231; (c) B. Tan, N. Toda and C. F. Barbas III, Angew.
Chem. Int. Ed., 2012, 51, 12538; (d) H. Li and G. Liu, J. Org. Chem.,
2014, 79, 509; (e) Q. Jiang, B. Xu, J. Jia, A. Zhao, Y. Zhao, Y. Li, N.
He and C. Guo, J. Org. Chem., 2014, 79, 7372; (f) F. Xiao, H. Chen,
H. Xie, S. Chen, L. Yang and G. Deng, Org. Lett., 2014, 16, 50.
Scheme 2. Proposed mechanism for TBAI-catalyzed oxidative
coupling of amines with sodium sulfinates
Conclusions
In conclusion, we have developed a practical procedure for the
preparation of sulfonamides through TBAI-catalyzed coupling
of amines with sodium sulfinates under mild conditions. This
methodology tolerates various functional groups including
hydroxyl.
We thank Guangdong Medical College (No. XB1973) for
financial support.
Notes and references
a
School of Pharmacy, Guangdong Medical College, Dongguan 523808,
China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
1
(a) C. T. Supuran, A. Casini and A. Scozzafava, Med. Res. Rev., 2003,
5, 535; (b) J. Y. Winum, A. Scozzafava, J. L. Montero and C. T.
Supuran, Med. Res. Rev., 2006, 26, 767; (c) A. Scozzafava, F. Carta
and C. T. Supuran, Expert Opin. Ther. Pat., 2013, 23, 203; (d) J. D.
Wilden, J. Chem. Res., 2010, 34, 541
2
3
(a) T. W. Jabusch and R. S. Tjeerdema, J. Agric. Food Chem., 2005,
53, 7179; (b) S. Zhang, X. Cheng and J. Yang, Dyes Pigments, 1999,
43, 167.
(a) W. Yuan, K. Fearson and M. H. Gelb, J. Org. Chem., 1989, 54,
906; (b) S. Chandrasekhar and S. Mohapatra, Tetrahedron Lett., 1998,
39, 695.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3