Palladium-catalyzed N-arylsulfonamide formation from arylsulfonyl hydrazides and nitroarenes

Article abstract of DOI:10.1039/c5ra26588f

A palladium-catalyzed construction for N-arylsulfonamide from nitroarenes and arylsulfonyl hydrazides is developed. In this protocol, abundant and stable nitroarenes serve as the nitrogen sources by in situ reduction reaction of hydrogen released from arylsulfonyl hydrazides. No external oxidants or reductants are needed for this kind of transformation.

Full text of DOI:10.1039/c5ra26588f

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Palladium-catalyzed N-arylsulfonamide formation
from arylsulfonyl hydrazides and nitroarenes†
Cite this: RSC Adv., 2016, 6, 13010
a
a
a
ab
*
Feng Zhao, Bin Li, Huawen Huang and Guo-Jun Deng
Received 13th December 2015
Accepted 21st January 2016
DOI: 10.1039/c5ra26588f
www.rsc.org/advances
A
palladium-catalyzed construction for N-arylsulfonamide from is highly desirable to develop a method for the synthesis of N-
nitroarenes and arylsulfonyl hydrazides is developed. In this protocol, arylsulfonamides from cheap and stable nitrogen sources.
abundant and stable nitroarenes serve as the nitrogen sources by in As we known, aromatic nitro compounds can undergo
situ reduction reaction of hydrogen released from arylsulfonyl reductive reactions for the preparation of the corresponding
hydrazides. No external oxidants or reductants are needed for this kind arylamines. In recent years, there have been signicant attrac-
of transformation.
tions to transition-metal-catalyzed C–N bond formations by
utilizing nitroarenes as starting materials. The nitroarenes were
reduced in situ via borrowing hydrogen strategy (hydrogen
transfer)10,11 or by adding external reducing agent.12 We envi-
sioned that it might be rational using nitroarenes instead of
aromatic amines as abundant and stable nitrogen sources for
the selective construction of S–N bond. Previously, our group
demonstrated a series of protocols by harnessing alcohols and
nitroarenes to form second amines,13 tertiary amines,14
amides15 and N-containing heterocycles.16 We also reported
a palladium-catalyzed one-pot synthesis of diarylamines from
nitroarenes and cyclohexanones.17 In these methods, nitro-
arenes successfully acted as the hydrogen acceptors and were
reduced to amines in situ through hydrogen transfer method-
ology, and no external reductants were needed to the reactions.
As part of our continuing efforts in using nitroarenes as the
coupling partners to construct C–N and N-hetero bonds, herein,
we report a palladium-catalyzed formation of N-arylsulfona-
mides from nitroarenes and arylsulfonyl hydrazides using the
hydrogen transfer strategy (Scheme 1).
It is well-known that N-arylsulfonamides are a class of crucial
building blocks that are ubiquitous in many biologically active
compounds and pharmaceutical intermediates, and these
structures have important roles in organic synthesis and bio-
logical and medicinal study.1 Therefore, the exploration of
efficient and green methods for the synthesis of sulfonamides
under mild conditions is an attractive area for organic and
pharmaceutical chemists. During the past years, various efforts
have been made for the construction of sulfonamides.2 The
conventional route mainly relies on the reaction of sulfonyl
chlorides3 or sodium sulnates4 with amino compounds due to
the simplicity and practicability. The transition-metal-catalyzed
couplings of sulfonamides with aryl halides,5 aryl boronic
acids,6 cyclohexanones,7 alcohols8 and hydrocarbons9 provide
alternative methods to synthesize N-arylsulfonamides.
However, there are still many shortcomings existing in the
current research, such as harsh reaction conditions, unstable
starting materials, poor functional group tolerance, require-
ments of additional ligand and/or base. Some of approaches
suffer from the utility of amino groups as nitrogen sources,
which are potentially toxic, volatile and thus leading to limita-
tions and tedious procedures. To overcome these drawbacks, it
aKey Laboratory of Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
E-mail: gjdeng@xtu.edu.cn; Fax: +86-0731-5829-2251; Tel: +86-0731-5829-8601
bKey Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra26588f
Scheme 1 Different pathways for the synthesis of sulphonamides.
13010 | RSC Adv., 2016, 6, 13010–13013
This journal is © The Royal Society of Chemistry 2016

View Article Online
Communication
RSC Advances
We begin our research by investigating the reaction of p- them were not efficient (entries 15 and 16). We proposed that
toluenesulfonyl hydrazides (1a) with nitrobenzene (2a) in DMF the role of pyridine was acted as a base so we tried organic base
by using Pd(OAc)2 as catalyst and the desired product was ob- triethylamine and inorganic base potassium carbonate, but the
tained in 19% yield as detected by GC and NMR methods (Table results were also unsatisfactory (entries 16–17). Notably,
1, entry 1). Aerwards, a variety of palladium catalysts were a desired yield could be obtained when the reaction was per-
examined for this reaction. Similar results were achieved when formed under an argon atmosphere and molecular sieve was
employing PdCl2, PdBr2, Pd(COD)Cl2 as the catalyst (Table 1, added to the reaction system (entries 18–20).
entries 2–4). Pd(acac)2 and Pd(TFA)2 improved the reaction yield
With the optimized reaction conditions in hand, we explored
to 36% and 35%, respectively (entries 5 and 6). Among the the scope of this transformation. As presented in Table 2,
catalysts screened, Pd(OH)2 showed the most effective and a variety of arylsulfonyl hydrazides were successfully reacted
afford 3a in 42% yield (entry 7). Solvents also played an with nitrobenzene (2a) to produce corresponding N-arylsulfo-
important role and the effect of solvents on this transformation namides in moderate to good yields. Generally, alkyl substitu-
was also examined. DMA, NMP and pyridine gave a similar ents at the para position of sulfonyl hydrazide slightly affected
result (entries 8–10). A lower yield was obtained when DMSO the reaction yield (3a–3d). Functional groups such as halogens
was employed as the solvent (entry 11). Unfortunately, when the and triuoromethoxy were well tolerated under the optimal
reaction was conducted in weak polar solvent such as dioxane reaction conditions (3e–3h). It should be noted that cleavage of
and toluene, only a trace amount of desired product was C-halogen bond was not observed during the reaction process.
acquired under the similar reaction conditions (entries 12 and When ortho-substituted arylsulfonyl hydrazides reacted with
13). In order to improve the reaction yield, we attempted to nitrobenzene, relatively lower yields were obtained probably
investigate some additives. Encouraged by the result of entry 10, due to the steric effect of the substituents (3i-3j).
we used 1 equiv. of pyridine as the additive in DMF. To our
Subsequently, a number of substituted nitroarenes were
delight, the yield of 3a was increased to 58% (entry 14). We employed to react with p-toluenesulfonyl hydrazide and the
tested some external reductants such as hydrazine hydrate and results are shown in Table 3. Methyl and methoxy nitroben-
isopropanol to enhance the reaction yield, however both of zenes reacted smoothly with 1a to give the corresponding
products in reasonable yields (3k–3m). Halogen substituents
Table 1 Optimization of the reaction conditionsa
Table 2 Reaction of 2a with various sulfonyl hydrazides (1)a
Entry
Catalyst
Additive
Solvent
Yieldb (%)
1
2
Pd(OAc)2
PdCl2
DMF
DMF
19
25
3
PdBr2
DMF
24
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19c
20d
21c,d
Pd(COD)Cl2
Pd(acac)2
Pd(TFA)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
DMF
DMF
DMF
DMF
DMF
NMP
Pyridine
DMSO
Toluene
Dioxane
DMF
DMF
DMF
DMF
DMF
42
36
35
42
36
34
37
23
Trace
Trace
58
Trace
19
21
Trace
66
Pyridine
N2H4$H2O
i-PrOH
Et3N
K2CO3
Pyridine
Pyridine
Pyridine
DMF
DMF
DMF
72
84
a
a
Conditions: 1a (0.4 mmol), 2a (0.2 mmol), catalyst (5 mol%), additive
Conditions: 1 (0.4 mmol), 2a (0.2 mmol), Pd(OH)2 (5 mol%), pyridine
(0.2 mmol), solvent (0.8 mL), 90 ꢀC, 20 h under air unless otherwise
˚
(0.2 mmol), DMF (0.8 mL), 4 A MS (100 mg), 90 ꢀC, 20 h, under argon;
isolated yield based on 2a.
b
c
˚
noted. GC yield based on 2a. 100 mg 4 A molecular sieves was
added. d Under argon.
This journal is © The Royal Society of Chemistry 2016
RSC Adv., 2016, 6, 13010–13013 | 13011

View Article Online
RSC Advances
Communication
Table 3 Reaction of 1a with various nitroarenes (2)a
Scheme 2 Proposed reaction mechanism.
Scheme 3 Deuterium labelling experiments.
To gain a mechanistic insight, deuterium labelling experi-
ments were conducted and the results were summarized in
Scheme 3. When TsNDND2 (ref. 20) (1a–D) reacted with 2a
under the standard reaction conditions, N-deuterated product
was obtained (Scheme 3, eqn (1)). When 1a reacted with 2a in
the presence of D2O, no deuterated product 3a was observed
(Scheme 3, eqn (2)). Treatment of 3a with D2O led to 3a recov-
ered and no deuterated 3a was obtained (Scheme 3, eqn (3)).
These results indicated that the hydrogen transfer process very
likely proceeded according to the proposed mechanism.
a
Conditions: 1a (0.4 mmol), 2 (0.2 mmol), Pd(OH)2 (5 mol%), pyridine
(0.2 mmol), DMF (0.8 mL), 4 A MS (100 mg), 90 ꢀC, 20 h, under argon;
isolated yield based on 2.
˚
such as triuoromethyl, uoro and chloro were well tolerated
under the optimized reaction conditions, and the target prod-
ucts were obtained in good yields (3n–3s). Other substrates
bearing electron-withdrawing group such as cyano remained
effective and gave the corresponding arylsulfonamides in good
yields (3t–3u). Notably, when 1-(2-nitrophenyl)ethanone was
subjected to this reaction system, the desired product could be
achieved in 70% yield (3v). Finally, a more steric bulky substrate
such as 1-nitronaphthelene also successfully afforded the
product in 71% yield (3w).
For the mechanism of this transformation, we proposed
a catalytic process that includes the following steps (Scheme 2).
The reaction of arylsulfonyl hydrazide with a Pd catalyst results
in a Pd complex A and sulfonyl diazene 3, which is formed
through successive hydrogen transferring and b-hydride elimi-
nation. In the presence of a Pd catalyst, liberation of N2 and H+
from 3 leads to the formation of arylsulfonylpalladium B.18 On
the other hand, nitrobenzene is reduced to nitrosobenzene with
the help of complex A.17,19 Then, the reaction of complex B with
nitrosobenzene gives N-arylsulfonyl-N-phenylhydroxyamine 6.
At last, hydrogenation of 6 affords the desired product and
regenerates the Pd catalyst.
Conclusions
In summary, we have developed a novel approach for the
synthesis of N-arylsulfonamides from nitroarenes and arylsul-
fonyl hydrazides under palladium-catalysis conditions. Nitro-
arenes were reduced in situ by hydrogen released from
arylsulfonyl hydrazides and no external reducing agent is
necessary. The reaction showed good substrate scope and various
functional groups such as halogens, acetyl, triuoromethyl and
cyano were well tolerated under the optimized reaction condi-
tions. This method affords an efficient approach using readily
available and stable nitroarenes for facile construction of N-
arylsulfonamides under mild reaction conditions with good
selectivity. Further investigations of the scope and mechanism
for this transformation are undergoing in our laboratory.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21172185, 21372187, 21572194), the
13012 | RSC Adv., 2016, 6, 13010–13013
This journal is © The Royal Society of Chemistry 2016

View Article Online
Communication
RSC Advances
Hunan Provincial Innovative Foundation for Postgraduate
(CX2014B258), and the Research Fund for the Doctoral Program
of Higher Education of China, Ministry of Education of China
(20124301110005).
M. Shibasaki, Angew. Chem., Int. Ed., 2007, 46, 409; (d)
S. Shekhar, T. B. Dunn, B. J. Kotecki, D. K. Montavon and
S. C. Cullen, J. Org. Chem., 2011, 76, 4552.
9 (a) B. Kalita, A. A. Lamar and K. M. Nicholas, Chem.
Commun., 2008, 44, 4291; (b) B. Xiao, T. J. Gong, J. Xu,
Z. J. Liu and L. Liu, J. Am. Chem. Soc., 2011, 133, 1466; (c)
H. Zhao, Y. Shang and W. Su, Org. Lett., 2013, 15, 5106; (d)
Q. Z. Zheng, Y. F. Liang, C. Qin and N. Jiao, Chem.
Commun., 2013, 49, 5654.
10 For selected reviews on hydrogen transfer reaction, see: (a)
T. Nixon, M. Whittlesey and J. M. J. Williams, Dalton
Trans., 2009, 5, 753; (b) G. Guillena, D. J. Ramon and
M. Yus, Chem. Rev., 2010, 110, 1611; (c) A. Watson and
J. M. J. Williams, Science, 2010, 329, 635.
11 For selected examples, see: (a) J. Oakdale, D. Solano,
J. Fettinger, M. Haddadin and M. J. Kurth, Org. Lett., 2009,
11, 2760; (b) X. J. Cui, Y. Zhang, F. Shi and Y. Q. Deng,
Chem.–Eur. J., 2011, 17, 2587; (c) A. Zanardi, J. A. Mata and
E. Peris, Chem.–Eur. J., 2010, 16, 10502; (d) R. Cano,
D. J. Ramon and M. Yus, J. Org. Chem., 2011, 76, 5574; (e)
C. H. Tang, L. He, Y. M. Liu, Y. Cao, H. Y. He and
K. N. Fan, Chem.–Eur. J., 2011, 17, 7172; (f) T. B. Nguyen,
L. Ermolenko and A. Al-Mourabit, J. Am. Chem. Soc., 2013,
135, 118; (g) T. B. Nguyen, L. Ermolenko and A. Al-
Mourabit, Org. Lett., 2013, 15, 4218; (h) T. B. Nguyen,
P. l. Retailleau and A. Al-Mourabit, Org. Lett., 2013, 15,
5238; (i) T. B. Nguyen, J. L. Bescont, L. Ermolenko and
A. Al-Mourabit, Org. Lett., 2013, 15, 6218; (j) X. J. Cui,
Y. Q. Deng and F. Shi, ACS Catal., 2013, 3, 808; (k)
Q. L. Peng, Y. Zhang, F. Shi and Y. Q. Deng, Chem.
Commun., 2011, 47, 6476.
12 For an excellent example on olen hydroamination with
nitroarenes using PhSiH3 as the reductant, see: J. Gui,
C. Pan, Y. Jing, T. Qin, J. Lo, B. Lee, S. Spergel,
M. Mertzman, W. Pitts, T. Cruz, M. Schmidt, N. Darvatkar,
S. Natarajan and P. Baran, Science, 2015, 348, 886.
13 Y. Liu, W. Chen, C. Feng and G. J. Deng, Chem.–Asian J.,
2011, 6, 1142.
Notes and references
1 (a) D. A. Smith and R. M. Jones, Curr. Opin. Drug Discovery
Dev., 2008, 11, 72; (b) A. Scozzafava, T. Owa,
A. Mastrolorezo and C. T. Supuran, Curr. Med. Chem., 2003,
10, 925; (c) J. D. Wilden, J. Chem. Res., 2010, 34, 541; (d)
J. B. Buckingham, Dictionary of Natural Products, Chapman
and Hall, London, 1994, vol. 1.
2 For selected reviews, see: (a) E. Valeur and M. Bradley, Chem.
Soc. Rev., 2009, 38, 606; (b) A. El-Faham and F. Albericio,
Chem. Rev., 2011, 111, 6557; (c) S. Caddick, J. D. Wilden
and D. B. Judd, J. Am. Chem. Soc., 2004, 126, 1024; (d)
J. Wilden, L. Geldeard, C. Lee, D. Judd and S. Caddick,
Chem. Commun., 2007, 10, 1074; (e) S. Lavy, J. Miller,
M. Pazicky, A. Rodrigues, C. Jaekel, D. Serra, N. Vinokurov,
M. Limbach and F. Rominger, Adv. Synth. Catal., 2010, 352,
2993; (f) S. W. Wright and K. N. Hallstrom, J. Org. Chem.,
2006, 71, 1080; (g) K. Bahrami, M. Khodaei and
M. Soheilizad, J. Org. Chem., 2009, 74, 9287.
3 (a) K. K. Andersen, in Comprehensive Organic Chemistry, ed.
D. N. Jones, Pergamon, Oxford, 1979, vol. 3, pp. 331–340,
For recent selected examples, see: (b) J. R. DeBergh,
N. Niljianskul and S. L. Buchwald, J. Am. Chem. Soc., 2013,
´
135, 10638; (c) J. Baffoe, M. Hoe and B. Toure, Org. Lett.,
2010, 12, 1532; (d) X. Deng and N. Mani, Green Chem.,
2006, 8, 835; (e) R. Sridhar, B. Srinivas, V. Kumar,
M. Narender and K. Rao, Adv. Synth. Catal., 2007, 349,
1873; (f) A. Kamal, J. Reddy, E. Bharathi and D. Dastagiri,
Tetrahedron Lett., 2008, 49, 348.
4 (a) X. Tang, L. Huang, C. Qi, X. Wu, W. Wu and H. Jiang,
Chem. Commun., 2013, 49, 6102; (b) C. Buathongjan,
D. Beukeaw and S. Yotphan, Eur. J. Org. Chem., 2015, 1575;
(c) X. Pan, J. Gao, J. Liu, J. Lai, H. Jiang and G. Yuan, Green
Chem., 2015, 17, 1400; (d) K. Yang, M. Ke, Y. Lin and
Q. Song, Green Chem., 2015, 17, 1395.
14 C. Feng, Y. Liu, S. Peng, Q. Shuai, G. J. Deng and C. J. Li, Org.
Lett., 2010, 12, 4888.
5 (a) J. Yin and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124,
6043; (b) G. Burton, P. Cao, G. Li and R. Rivero, Org. Lett.,
2003, 5, 4373; (c) B. R. Rosen, J. C. Ruble, T. J. Beauchamp
and A. Navarro, Org. Lett., 2011, 13, 2564; (d) W. Deng,
L. Liu, C. Zhang, M. Liu and Q.-X. Guo, Tetrahedron Lett.,
2005, 46, 7295.
6 (a) P. Y. S. Lam, G. Vincent, C. G. Clark, S. Deudon and
P. K. Jadhav, Tetrahedron Lett., 2001, 42, 3415; (b) C. Pan,
J. Cheng, H. Wu, J. Ding and M. Liu, Synth. Commun.,
2009, 39, 2082; (c) S. Y. Moon, J. Nam, K. Rathwell and
W. S. Kim, Org. Lett., 2014, 16, 338.
7 X. Cao, Y. Bai, Y. Xie and G. J. Deng, J. Mol. Catal. A: Chem.,
2014, 383–384, 94.
8 For selected examples, see: (a) P. Qu, C. Sun, J. Ma and F. Li,
Adv. Synth. Catal., 2014, 356, 447; (b) A. J. A. Watson,
A. C. Maxwell and J. M. J. Williams, J. Org. Chem., 2011, 76,
2328; (c) H. Qin, N. Yamagiwa, S. Matsunaga and
15 F. Xiao, Y. Liu, C. Tang and G. J. Deng, Org. Lett., 2012, 14,
984.
16 (a) H. Wang, H. Chen, Y. Chen and G. J. Deng, Org. Biomol.
Chem., 2014, 12, 7792; (b) H. Wang, X. Cao, F. Xiao and
G. J. Deng, Org. Lett., 2013, 15, 4900; (c) M. Wu, X. Hu,
J. Liu, Y. Liao and G. J. Deng, Org. Lett., 2012, 14, 2722.
17 Y. Xie, S. Liu, Y. Liu, Y. Wen and G. J. Deng, Org. Lett., 2012,
14, 1692.
18 (a) F. Yang, X. Ma and S. K. Tian, Chem.–Eur. J., 2012, 18,
1582; (b) F. Yang and S. K. Tian, Angew. Chem., Int. Ed.,
2013, 52, 4929; (c) B. Liu, J. Li, F. Song and J. S. You,
Chem.–Eur. J., 2012, 18, 10830.
19 A. Corma and P. Serna, Science, 2006, 313, 332.
20 For synthesis of TsNDND2: J. Wang, G. Burdzinski,
T. L. Gustafson and M. S. Platz, J. Am. Chem. Soc., 2007,
129, 2597.
This journal is © The Royal Society of Chemistry 2016
RSC Adv., 2016, 6, 13010–13013 | 13013