Synthesis of N-arylsulfonamides through a Pd-catalyzed reduction coupling reaction of nitroarenes with sodium arylsulfinates

Article abstract of DOI:10.1039/c8ob02226g

A novel one-step direct reductive coupling reaction between nitroarenes and sodium arylsulfinates was realized in the presence of an inexpensive Pd/C catalyst. In this procedure, readily available nitroarenes are employed as the nitrogen sources, and sodium arylsulfinates serve as both coupling partners and reductants. The method features high efficiency by using cheap Pd/C with low catalyst loading and good functional group tolerance in the absence of any additional reductants or ligands. This facile and mild synthetic method enables the high efficiency synthesis of functionalized N-arylsulfonamides from readily available substrates.

Full text of DOI:10.1039/c8ob02226g

Organic &
Biomolecular Chemistry
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Synthesis of N-arylsulfonamides through a
Pd-catalyzed reduction coupling reaction
of nitroarenes with sodium arylsulfinates†
Cite this: Org. Biomol. Chem., 2018,
16, 8150
Bo Yang,‡a Chang Lian,‡a Guanglu Yue,a Danyang Liu,a Liyan Wei,a Yi Ding,a
a
Xiancai Zheng,a Kui Lu, b Di Qiu *a and Xia Zhao
*
A novel one-step direct reductive coupling reaction between nitroarenes and sodium arylsulfinates was
realized in the presence of an inexpensive Pd/C catalyst. In this procedure, readily available nitroarenes
are employed as the nitrogen sources, and sodium arylsulfinates serve as both coupling partners and
reductants. The method features high efficiency by using cheap Pd/C with low catalyst loading and good
functional group tolerance in the absence of any additional reductants or ligands. This facile and mild syn-
thetic method enables the high efficiency synthesis of functionalized N-arylsulfonamides from readily
available substrates.
Received 9th September 2018,
Accepted 11th October 2018
DOI: 10.1039/c8ob02226g
rsc.li/obc
philic coupling partner in transition metal catalyzed cross-
coupling reactions.7–11 Moreover, nitroarenes have also been
Introduction
N-Arylsulfonamides consist of a series of important functional explored as arylamine surrogates.12 Considering that aryl-
scaffolds among biologically and medicinally active mole- amines are generally prepared by the reduction of the corres-
cules.1 Great efforts have been made to achieve their efficient ponding nitroarenes, the employment of nitroarenes as the
preparation.2 One of the most conventional methods to nitrogen source affords an atom economical and convenient
achieve the synthesis of N-arylsulfonamides involves the strategy for assembly of N-containing functional molecules.
nucleophilic substitution of sodium sulfinates or sulfonyl
By using this strategy, Luo developed a novel Fe-catalyzed
chlorides with arylamines as the nitrogen sources (Scheme 1, coupling reaction of sodium arylsulfinates with nitroarenes to
path a).3 Moreover, in the recent decades, the preparation of synthesize N-arylsulfonamides by using NaHSO3 as the reduc-
N-arylsulfonamides through transition-metal-catalyzed C–N tant (Scheme 1, path c).13 Recently, Xiang reported the
bond formation has been established as a complementary reaction of sulfonyl halides with nitroarenes to form
strategy, which uses sulfonamides as nitrogen-based nucleo- N-arylsulfonamides by using Fe dust which serves as the sole
philes (Scheme 1, path b).4 Notably, the oxidative S–N bond reductant (Scheme 1, path d).14 These two Fe-mediated
formation strategy by using thiols, disulfides and sulfonyl
hydrazides as the sulfur sources has also been explored to be
an alternative route to access the synthesis of
N-arylsulfonamides.5
Nitroarenes, which are air-stable and readily available com-
pounds, have been widely used as substrates in aromatic sub-
stitution, or as the precursors of arylamines and aryl halides.6
In recent years, nitroarenes have been employed as the electro-
aCollege of Chemistry, Tianjin Key Laboratory of Structure and Performance for
Functional Molecules, Key laboratory of Inorganic-organic Hybrid Functional
Material Chemistry, Ministry of Education, Tianjin Normal University,
Tianjin 300387, China. E-mail: qiudi@pku.edu.cn, hxxyzhx@mail.tjnu.edu.cn
bCollege of Biotechnology, Tianjin University of Science & Technology,
Tianjin 300457, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02226g
‡These authors contributed equally to this work.
Scheme 1 Synthetic methods for sulfonamides.
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Table 1 Optimization of reaction conditionsa
synthetic methods by using nitroarenes as the nitrogen
sources require an external reductant or ligand. Thus, the
concise and facile preparation of N-arylsulfonamides directly
from nitroarenes under mild conditions is still highly desir-
able.15 Considering the importance of sulfonamide scaffolds,
we herein report the Pd-catalyzed direct reductive coupling
reaction of nitroarenes and sodium arylsulfinates, which
features the advantages of low loading of the inexpensive Pd/C
catalyst and wide substrate scope, without exploring any exter-
nal reductants or ligands.
Ratio
(1a : 2a) (mol %)
Catalyst
Additive
(equiv.)
Yieldb
(%)
Entry Solvent
1
2
3
4
5
6
7
8
DMSO
NMP
1,4-Dioxane 1 : 1.5
1 : 1.5
1 : 1.5
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
Pd(PPh3)4 (5)
Pd/C (5)
NiCl2 (10)
FeCl2 (20)
CuCl2 (10)
FeCl3 (10)
CoCl2 (10)
—
38
7
15
Trace
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 3
1 : 3.5
1 : 4
1 : 4
1 : 4
1 : 4
1 : 4
1 : 4
1 : 4
1 : 4
1 : 4
1 : 4
1 : 4
1 : 5
1 : 6
Na2S2O3 (0.5) Trace
Na2SO3 (0.5)
NaHS (0.5)
PPh3 (0.5)
34
0
18
Results and discussion
9
NaHSO3 (3.0) 41
Initially, we treated 4-nitro-1,1′-biphenyl 1a with sodium
4-methylbenzenesulfinate 2a as the substrate in the Pd-cata-
lyzed cross-coupling reaction in dimethyl sulfoxide (DMSO) at
different temperatures. The corresponding N-arylsulfonamide
3a was obtained in 38% isolated yield at 120 °C (entry 1), while
only a trace product was observed at 80 °C. To optimize the
reaction conditions, we tested various solvents including
N-methyl-2-pyrrolidone (NMP), toluene and dioxane, and
found that the reaction in DMSO gave the best result (entries
2–4). The addition of a range of external reductants, including
Na2S2O3, Na2SO3, NaHS, PPh3 and NaHSO3, could not increase
the yield apparently (entries 5–9). To our delight, in terms of
substrates, on increasing the loading of 2a from 1.5 to 4.0
equiv., the yield of 3a increased to 72% (entries 10–12).
Subsequently, a series of palladium catalysts were examined in
this coupling reaction. This reaction gave the highest yield by
using the inexpensive Pd/C catalyst without the addition of any
ligand (entry 14). Moreover, other common transition-metal
catalysts were also tested in this transformation (entries
15–19). As a result, only copper(II) chloride served as an
efficient catalyst and afforded 3a in a moderate yield (entry 17).
The control experiment indicated that the palladium catalyst
was essential in this direct reductive coupling reaction
(entry 20). The reaction was conducted under air or oxygen
atmosphere, affording 3a in 48% (entry 21) and 18% (entry 22)
yields, respectively. This result demonstrates that an inert
atmosphere is necessary for this coupling reaction. Besides,
increasing of the 2a/1a molar ratio could not enhance the yield
of 3a (entries 23 and 24).
10
11
12
13
14c
15
16
17
18
19
20
21
22
23
24
59
68
72
Trace
80
0
10
44
0
0
0
Pd/C (5)
Pd/C (5)
Pd/C (5)
Pd/C (5)
48d
18e
72
68
a Reaction conditions: 4-Nitro-1,1′-biphenyl 1a (0.3 mmol, 1.0 equiv.),
sodium 4-methylbenzenesulfinate 2a (1.5 to 4.0 equiv.), solvent (1 mL),
120 °C, 12 h. b Isolated yields. c Pd/C (0.015 mmol, 5 mol%, [Pd/C]
10 wt%). d The reaction was conducted under air atmosphere. e The
reaction was conducted under an oxygen atmosphere.
With the optimized reaction conditions (Table 1, entry 14)
in hand, we first evaluated the scope of the reactions of
4-nitro-1,1′-biphenyl 1a or nitrobenzene 1b with various substi-
tuted sodium arylsulfinates (Scheme 2, 3a–3j). In most cases,
these reductive coupling reactions by using 4-nitro-1,1′-biphe-
nyl 1a or nitrobenzene 1b as the nitrogen source demonstrate
good functional group tolerance. The sodium arylsulfinates
bearing electron-donating and electron-withdrawing substitu-
ents on the aromatic rings successfully afford the corres-
ponding N-arylsulfonamides in good to excellent yields, such
as methyl (3a, 3h, 3i, and 3k), halogen (3c, 3d, 3j, 3m, and 3n),
methoxy (3e), cyano (3f), trifluoromethoxy (3g), and ethoxycar-
Scheme 2 Scope of substrates. Reaction conditions: nitroarenes
(0.3 mmol, 1.0 equiv.), sodium aryl sulfinate (1.2 mmol, 4.0 equiv.), Pd/C
bonyl groups (3o). In the case of 3h, the relatively low yield is (5 mol%, 10 wt%), DMSO (1 mL), 120 °C, 12 h.
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probably due to the steric hindrance. The major by-products
during these transformations are the biaryl compounds, diaryl
thioethers, and diaryl disulfides through the side reactions of
sodium arylsulfinates 2.16 Moreover, the reactions of nitro-
benzene with naphthyl and thiophenyl sulfinates are also
implemented, smoothly affording the desired products (3p,
3q, 3r) in moderate yields. Subsequently, a series of substi-
tuted nitroarenes are subjected to this coupling reaction with
sodium arylsulfinates. All in all, this transformation with
sodium benzenesulfinate (2b) is tolerant to either electron-rich
or -deficient substituents on the ring of the nitrobenzene
moiety, affording methyl (3s), acyl (3t), cyano (3u), trifluoro-
methyl (3v), and methoxy group (3w) substituted sulfonamides
in good yields. Furthermore, the carboxylate, formyl and
methoxy derived nitrobenzenes are also employed as the sub-
strates in this transformation with substituted sodium arylsul-
finates, giving rise to highly functionalized N-arylsulfonamides
in moderate to good yields (3x–3z). Notably, when sodium
methanesulfinate was used as the substrate, the corresponding
alkyl sulfonamide 3aa was obtained in 43% yield. However,
when nitromethane was used under standard conditions, no
desired product (3ab) was observed.
Scheme 3 Control experiments.
To demonstrate the practical application of this method,
this reductive coupling reaction was carried out on a gram
scale for two sodium aryl sulfinate substrates with 4-nitro-1,1′-
biphenyl 1a. As shown in eqn (1) and (2), the corresponding
N-arylsulfonamide derivatives (3a, 3c) were successfully
obtained in comparable good yields on about one gram scale.
Scheme 4 Possible reaction mechanism.
addition of the lone pair of the sulfur moiety to the nitro
group of 1a, generating a metallocyclic five-membered inter-
mediate B. Next, B is reduced by the second molecule of 2a to
form intermediate C, followed by the release of the aryl sulfo-
nate to afford intermediate D. Subsequently, D is reduced by
the third molecule of 2a to form palladium N-arylsulfonamide
salt E along with the generation of the aryl sulfonate. Finally,
the transmetallation and protonation afford N-arylsulfonamide
3a and regenerate the Pd(II) active species. Although the effect
of the palladium catalyst and the mechanistic details are still
not clear, this plausible mechanism can rationalize the reac-
tion pathway of this Pd-catalyzed direct coupling of nitroarenes
with sodium arylsulfinates.
ð1Þ
ð2Þ
Subsequently, some control reactions were examined to
obtain a better understanding of the details of the mechanism.
In the reaction condition optimization, we found that the
palladium catalyst exhibits higher efficiency than other tran-
sition metal catalysts, including iron, copper, nickel or cobalt
complexes. In addition, nitrosobenzene (4), aniline (5) and
azobenzene (6) were respectively subjected to this reductive
coupling reaction under standard conditions within 12 hours.
However, the reaction of nitrosobenzene (4) with 2a only gave a
trace amount of the desired product 3k. We could not observe
Experimental
General procedure for Pd-catalyzed reductive coupling reactions
3k during the coupling reaction of aniline (5) or azobenzene (6) Under a nitrogen atmosphere, sodium 4-methylbenzenesulfinate
with 2a. These results indicated that nitrosobenzene (4), aniline 2a (1.2 mmol, 4.0 equiv., 214 mg), 4-nitro-1,1′-biphenyl 1a
(5) or azobenzene (6) was not involved as the key intermediate (0.3 mmol, 1.0 equiv., 60 mg), and Pd/C (0.015 mmol, 5 mol%,
in this reductive coupling reaction (Scheme 3).
16 mg, [Pd/C] 10 wt%) were weighed in a 10 mL reaction tube.
Based on the above experimental investigation and the lit- DMSO (1 mL) was then added in succession. The resulting
erature reported before,13 a proposed mechanism was illus- reaction solution was stirred for 12 h at 120 °C. After cooling
trated to account for this Pd-catalyzed reductive cross-coupling to room temperature, the reaction system was diluted with
reaction. As shown in Scheme 4, we hypothesize that the Pd(0) 5.0 mL of ethyl acetate, and washed with water (3 × 5.0 mL).
species is oxidized to the Pd(II) species at first, which co- The organic phase was dried over Na2SO4, filtered, and concen-
ordinated with sodium arylsulfinate 2a to form palladium(II) trated under reduced pressure to yield the crude product,
arylsulfinic acid salt A. Then, Pd(II) facilitates the nucleophilic which was further purified by silica gel column chromato-
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graphy (petroleum ether/ethyl acetate = 10 : 1 to 3 : 1) to obtain
N-([1,1′-biphenyl]-4-yl)-4-methylbenzenesulfonamide (3a) in
80% isolated yield (78 mg) as a white solid.
(e) S. W. Wright and K. N. Hallstrom, J. Org. Chem., 2006,
71, 1080.
3 For select examples, see: (a) R. DeBergh, N. Niljianskul and
S. L. Buchwald, J. Am. Chem. Soc., 2013, 135, 10638;
(b) X. Tang, L. Huang, C. Qi, X. Wu, W. Wu and H. Jiang,
Chem. Commun., 2013, 49, 6102; (c) X. Pan, J. Gao, J. Liu,
J. Lai, H. Jiang and G. Yuan, Green Chem., 2015, 17, 1400;
(d) J. Baffoe, M. Y. Hoe and B. B. Touré, Org. Lett., 2010, 12,
1532.
Conclusions
In summary, we have developed a novel and concise synthetic
method towards N–S bond construction through a Pd-cata-
lyzed reductive cross-coupling reaction of sodium aryl sulfi-
nates with nitroarenes. From two readily available substrates,
the highly functionalized N-arylsulfonamides are facilely and
directly obtained in one-step in good yields. The method fea-
tures high efficiency by using cheap Pd/C with low catalyst
loading, good functional group tolerance, and no participation
of any additional reductants or ligands.
4 (a) G. Burton, P. Cao, G. Li and R. Rivero, Org. Lett., 2003, 5,
4373; (b) X. Cao, Y. Bai, Y. Xie and G.-J. Deng, J. Mol. Catal. A:
Chem., 2014, 383, 94; (c) W. Deng, L. Liu, C. Zhang, M. Liu
and Q.-X. Guo, Tetrahedron Lett., 2005, 46, 7295; (d) B. Kalita,
A. A. Lamar and K. M. Nicholas, Chem. Commun., 2008, 4291;
(e) P. Y. S. Lam, G. Vincent, C. G. Clark, S. Deudon and
P. K. Jadhav, Tetrahedron Lett., 2001, 42, 3415; (f) C. Pan,
J. Cheng, H. Wu, J. Ding and M. Liu, Synth. Commun., 2009,
39, 2082; (g) H. Qin, N. Yamagiwa, S. Matsunaga and
M. Shibasaki, Angew. Chem., Int. Ed., 2007, 46, 409; (h) P. Qu,
C. Sun, J. Ma and F. Li, Adv. Synth. Catal., 2014, 356, 447;
(i) B. R. Rosen, J. C. Ruble, T. J. Beauchamp and A. Navarro,
Org. Lett., 2011, 13, 2564; ( j) S. Shekhar, T. B. Dunn,
B. J. Kotecki, D. K. Montavon and S. C. Cullen, J. Org. Chem.,
2011, 76, 4552; (k) B. Xiao, T. J. Gong, J. Xu, Z. J. Liu and
L. Liu, J. Am. Chem. Soc., 2011, 133, 1466; (l) J. Yin and
S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 6043;
(m) Q. Z. Zheng, Y. F. Liang, C. Qin and N. Jiao, Chem.
Commun., 2013, 49, 5654.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work is supported by the Foundation of Development
Program of Future Expert in Tianjin Normal University
(WLQR201815) and the National Natural Science Foundation
of China (21602156 and 21572158).
5 For reviews, see: (a) F. A. H. Nasab, L. Z. Fekri,
A. Monfared, A. Hosseinian and E. Vessally, RSC Adv., 2018,
8, 18456; (b) O. M. Mulina, A. I. Ilovaisky and
A. O. Terent’ev, Eur. J. Org. Chem., 2018, 4648 For selected
examples, see: (c) N. Taniguchi, Eur. J. Org. Chem., 2010,
2670; (d) K. Bahrami, M. M. Khodaei and M. Soheilizad,
Tetrahedron Lett., 2010, 51, 4843; (e) A. R. Massah, S. Sayadi
and S. Ebrahimi, RSC Adv., 2012, 2, 6606; (f) X. Huang,
J. Wang, Z. Ni, S. Wang and Y. Pan, Chem. Commun., 2014,
50, 4582; (g) J.-B. Feng and X.-F. Wu, Org. Biomol. Chem.,
2016, 14, 6951; (h) M. Zhu, W. Wei, D. Yang, H. Cui,
L. Wang, G. Meng and H. Wang, Org. Biomol. Chem., 2017,
15, 4789; (i) S. Yotphan, L. Sumunnee, D. Beukeaw,
C. Buathongjan and V. Reutrakul, Org. Biomol. Chem., 2016,
14, 590; ( j) A. O. Terent’ev, O. M. Mulina, D. A. Pirgach,
M. A. Syroeshkin, A. P. Glinushkin and G. I. Nikishin,
Mendeleev Commun., 2016, 26, 538; (k) M. Sheykhan,
S. Khani, M. Abbasnia, S. Shaabanzadeh and M. Joafshan,
Green Chem., 2017, 19, 5940.
6 N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH,
New York, 2001.
7 M. R. Yadav, M. Nagaoka, M. Kashihara, R.-L. Zhong,
T. Miyazaki, S. Sakaki and Y. Nakao, J. Am. Chem. Soc.,
2017, 139, 9423.
8 F. Inoue, M. Kashihara, M. R. Yadav and Y. Nakao, Angew.
Chem., Int. Ed., 2017, 56, 13307.
9 S. S. Bahekar, A. P. Sarkate, V. M. Wadhai, P. S. Wakte and
D. B. Shinde, Catal. Commun., 2013, 41, 123.
Notes and references
1 (a) 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; (b) 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; (c) A. M. Gilbert, S. Caltabiano, F. E. Koehn,
Z.-j. Chen, G. D. Francisco, J. W. Ellingboe, Y. Kharode,
A. Mangine, R. Francis, M. TrailSmith and D. Gralnick,
J. Med. Chem., 2002, 45, 2342; (d) 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;
(e) B. Masereel, S. Rolin, F. Abbate, A. Scozzafava and
C. T. Supuran, J. Med. Chem., 2002, 45, 312; (f) L. Lixia,
D. Daoqing, H. Shuanghong and Z. L. Wang, Tetrahedron
Lett., 2018, 59, 1517; (g) W. Wei, C. Huanhuan, Y. Daoshan,
Y. Huilan, H. Chenglong, Z. Yulong and W. Hua, Green
Chem., 2017, 19, 5608; (h) J. Drew, Science, 2000, 287, 1960.
2 (a) K. Bahrami, M. M. Khodaei and M. Soheilizad, J. Org.
Chem., 2009, 74, 9287; (b) S. Caddick, J. D. Wilden and
D. B. Judd, J. Am. Chem. Soc., 2004, 126, 1024; (c) A. El-
Faham and F. Albericio, Chem. Rev., 2011, 111, 6557;
(d) E. Valeur and M. Bradley, Chem. Soc. Rev., 2009, 38, 606;
This journal is © The Royal Society of Chemistry 2018
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10 M. Kashihara, M. R. Yadav and Y. Nakao, Org. Lett., 2018, 14 J. Jiang, S. Zeng, D. Chen, C. Cheng, W. Deng and J. Xiang,
20, 1655.
Org. Biomol. Chem., 2018, 16, 5016.
11 Y. Yang, Angew. Chem., Int. Ed., 2017, 56, 15802.
12 C. W. Cheung, J.-A. Ma and X. Hu, J. Am. Chem. Soc., 2018,
140, 6789.
13 W. Zhang, J. Xie, B. Rao and M. Luo, J. Org. Chem., 2015,
80, 3504.
15 For the recent transition-metal-free coupling reactions of
nitroarenes with sodium sulfinate in water by using NaHSO3
as the reductant, see: N. Eid, I. Karamé and B. Andrioletti,
Eur. J. Org. Chem., 2018, DOI: 10.1002/ejoc.201800504.
16 See the ESI† for details.
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