Synthesis of: N -arylsulfonamides via Fe-promoted reaction of sulfonyl halides with nitroarenes in an aqueous medium

Article abstract of DOI:10.1039/c8ob01172a

A fascinating Fe-promoted protocol for the synthesis of N-arylsulfonamides has been developed. Starting from commercially available nitroarenes and sulfonyl chlorides, moderate to excellent yields of the corresponding N-arylsulfonamides can be obtained. In particular, Fe dust serves as the sole reductant in the transformation and it can be easily performed on a large scale.

Full text of DOI:10.1039/c8ob01172a

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Synthesis of N-arylsulfonamides via Fe-promoted
reaction of sulfonyl halides with nitroarenes in an
aqueous medium†
Cite this: DOI: 10.1039/c8ob01172a
Jun Jiang, Sheng Zeng, De Chen, Chaozhihui Cheng, Wei Deng* and
Jiannan Xiang
*
Received 18th May 2018,
Accepted 20th June 2018
A fascinating Fe-promoted protocol for the synthesis of N-arylsulfonamides has been developed. Starting
from commercially available nitroarenes and sulfonyl chlorides, moderate to excellent yields of the
corresponding N-arylsulfonamides can be obtained. In particular, Fe dust serves as the sole reductant in
the transformation and it can be easily performed on a large scale.
DOI: 10.1039/c8ob01172a
rsc.li/obc
N-Arylsulfonamides, as omnipresent functional scaffolds moted or reduced organic reactions performed in water.
among biologically and medicinally interesting molecules,1 are Herein, we develop a mild Fe-mediated reaction of nitroarenes
well known. As such, various efficient methods for the con- with arylsulfonyl chlorides in an aqueous medium
struction of N-arylsulfonamides have been developed.2 To (Scheme 1c). Using the Fe-mediated transfer strategy, a series
date, the most conventional methods to prepare of N-arylsulfonamides can be produced in moderate to good
N-arylsulfonamides are the reaction of sodium sulfinates3 or yields, showing its fascinating application prospects.
sulfonyl chlorides4 with amino compounds owing to the prac-
We began our investigation with the reaction of nitro-
ticability (Scheme 1a). During the past decade, generation of benzene (1a) and tosyl chloride (2a) in water by using Zn dust
N-arylsulfonamides via C–N bond formation has also been as the reductant at 70 °C and the desired product 4-methyl-N-
largely reported5 (Scheme 1a). While generally effective, these phenylbenzenesulfonamide (3aa) was obtained in 50% iso-
methods are confronted with many shortcomings, such as lated yield (Table 1, entry 1). Encouraged by this result, a
using transition metals as catalysts and unstable starting series of metal reductants were further researched (entries
materials. In addition, some of them must use amino com- 2–5). We found that a strong reductive metal (Mg or Al)
pounds as nitrogen sources, which are genotoxic andthus afforded 3aa in lower yields (entries 2 and 3), but when Fe was
result in inconveniences and tedious procedures.
used as the reductant, the yield increased to 88% (entry 5).
Recently, Luo’s group reported a new and attractive protocol Then, we studied the influence of reaction temperature
for the construction of N-arylsulfonamides via the direct coup- (entries 6–10). Increasing the reaction temperature could not
ling of sodium arylsulfinates with nitroarenes6 (Scheme 1b).
This method offers a simple strategy for the generation of
N-arylsulfonamides from nitroarenes, which are simple,
cheap, and stable nitrogen sources. However, this method has
some obvious shortcomings such as the use of organic sol-
vents and additives which are difficult to recover. To overcome
these shortcomings, it is still highly desired to find an efficient
and improved synthesis route to N-arylsulfonamides. Water, as
a green solvent, is widely used in organic synthesis.7 In
addition, Fe dust is a cheap and safe reducing agent and can
be used in many organic reactions. We are interested in Fe-pro-
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry
and Chemical Engineering, Hunan University, Changsha, 410082, P.R. China.
E-mail: jnxiang@hnu.edu.cn, weideng@hnu.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob01172a
Scheme 1 Methods for the synthesis of N-arylsulfonamides.
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Table 1 Optimization of the reaction conditionsa
Entry
Reductant
Solvent
Additive
Temperature
Yieldb (%)
1
2
3
4
5
6
7
8
Zn
Mg
Al
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
NMP
DMSO
DME
Toluene
PhCl
H2O
H2O
H2O
H2O
H2O
H2O
—
—
—
—
—
—
—
—
70 °C
70 °C
70 °C
70 °C
70 °C
80 °C
100 °C
60 °C
40 °C
rt
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
50
10
15
—
88
70
69
91
72
50
40
40
20
55
30
15
20
10
12
56
91
78
91
61
91
Mn
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
9
—
—
10
11
12
13
14
15
16
17
18
19
20c
21d
22e
23f
24g
25h
10% MeOH
2 equiv. of NH4Cl
2 equiv. of activated carbon
NaOH (1 equiv.)
—
—
—
—
—
—
—
—
—
—
—
a All reactions were performed with nitrobenzene (1a, 0.25 mmol), tosyl chloride (2a, 0.5 mmol), reductant (1 mmol) and solvent (1 mL), 36 h.
b Isolated yield. c 0.75 mmol Fe was used. d 1.25 mmol Fe was used. e 24 h. f 48 h. g 0.35 mmol tosyl chloride was used. h 0.65 mmol tosyl chloride
was used.
give higher reaction efficiency (entries 6 and 7). Reducing the fonyl chloride slightly affected the reaction yield (3aa, 3ab,
reaction temperature to 60 °C gave a higher reaction yield 3ad–3ag, 3aj, 3ak, 3am–3ap). Exceptionally, when we used
(entry 8). However, further reduction to 40 °C or rt resulted in 4-methoxybenzene-1-sulfonyl chloride (3ac) or 2,4,6-trimethyl-
a lower yield (entries 9 and 10). For the sake of improving the benzene-1-sulfonyl chloride (3ai), the yields were lower prob-
conversion yield, we tried to use additional additives (entries ably due to the hydrolysis of sulfonyl chlorides. Under identi-
11–14). We used various additives in water such as MeOH, cal reaction conditions, the use of electron-deficient sulfonyl
NH4Cl, activated carbon or NaOH, but the yield was lower. chlorides gave moderate yields of N-arylsulfonamides by
Subsequently, various kinds of solvents were studied (entries prolonging the reaction time (3ah and 3al). Meanwhile, this
15–19). Not only the polar solvents NMP and DMSO (entries 15 reaction is also tolerant of naphthalene-2-sulfonyl chloride
and 16) but also nonpolar solvents gave lower yields (entries and thiophene-2-sulfonyl chloride, and the desired products
17–19). Ultimately, the equivalent of Fe (entries 20 and 21), the 3aq and 3ar were produced in 63% and 87% yields, respect-
reaction time (entries 22 and 23), and the ratio of 1a and 2a ively. It is worth mentioning that alkyl sulfonyl chlorides such
(entries 24 and 25) were researched, but the yield was not as methyl- and cyclopropyl-sulfonyl chlorides could be
improved. Based on all of the above study results, the opti- effective at giving the corresponding N-arylsulfonamides from
mized reaction conditions to obtain 4-methyl-N-phenylben- moderate to excellent yields (3as–3av). Notably, D(+)-10-cam-
zene-sulfonamide were concluded to be those of entry 8 in phorsulfonyl chloride and 2-phthalimidoethanesulfonyl chlor-
Table 1, namely treatment of compound 1a with 2 equivalents ide were suitable for this transformation and produced the
of 2a, and 4 equivalents of Fe dust in H2O (0.25 M) at 60 °C.
corresponding products in good yields (3aw, 3ax). Finally,
With the optimized reaction conditions in hand, we turned when we use tosyl fluoride under the optimal reaction con-
our attention to the scope of this reaction. As shown in ditions, the product (3aa) was obtained in 59% yield.
Table 2, various sulfonyl chlorides were successfully reacted
Subsequently, various nitroarenes were reacted with tosyl
with nitrobenzene (1a) to generate the corresponding chloride (2a) as shown in Table 3. The reaction of 2a with
N-arylsulfonamides in medium to excellent yields. In most nitrobenzene, 4-nitrotoluene, and 4-nitrophenol gave the
cases, alkyl or halo substituents at any position of benzenesul- corresponding products 3aa, 3ba, and 3ga in good yields.
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Table 2 Substrate scope with respect to sulfonyl chloridesa,b
R = 4-Me
4-H
4-OMe
4-F
4-Cl
4-Br
3aa
3ab
3ac
3ad
3ae
3af
91 (59)c
74
59
58
71
66
4-I
3ag
3ah
3ai
76
67
59
76
4-CN
2,4,6-Me3
4-Ph
3aj
4-tBu
4-CO2Et
3-Me
3-Br
2-Me
4-F-3-Cl
3ak
3al
3am
3an
3ao
3ap
64
74
67
75
86
83
MsNHPh, 3as, 55
BuSO2NHPh, 3at, 88
a Conditions: 1a (0.25 mmol), 2 (0.5 mmol), Fe (1 mmol) and H2O (1 ml), 60 °C, 36 h. b After column chromatography. c Use TsF as 2.
Table 3 Substrate scope with respect to nitroarenesa,b
Scheme 2 Gram scale synthesis.
FG = H
4-Me
4-F
4-Cl
4-Br
3aa
3ba
3ca
3da
3ea
91
93
66
73
74
4-I
3fa
3ga
3ha
3ia
67
79
65
78
MeNHTs
3ka, trace
EtNHTs
4-OH
2-Cl
2-F
3la, trace
a Conditions: 1 (0.25 mmol), 2a (0.5 mmol), Fe (1 mmol) and H2O
(1 ml), 60 °C, 36 h. b After column chromatography.
Meanwhile, this transformation is also tolerant of iodine,
bromo, chloro, and fluoro substituents on the aromatic rings
of nitrobenzene, and the desired target products (3ca–3fa)
were generated in moderate yields. When ortho-substituted
nitrobenzene reacted with tosyl chloride, a comparatively lower
yield was obtained probably due to the steric effect of the sub-
stituent (3ha). We further investigated the scope of substrates
of N-containing heterocyclic compounds in this reaction.
3-Nitro-1H-1,2,4-triazole was suitable for this reaction and gave
the desired product in a moderate yield (3ja). When nitro-
Scheme 3 Control experiments.
Some control reactions were carried out to obtain a better
methane and nitroethane were used as the reaction substrates, understanding of the mechanism for this transformation
no desired products were generated (3ka, 3la). (Scheme 3). When we added the free radical scavenger 2,2,6,6-
To demonstrate the reaction efficiency of this Fe promoted tetramethylpiperidine-1-oxyl (TEMPO) to the transformation,
transformation, we attempted to expand the reaction to a the yield was inhibited and the more we added TEMPO, the
10 mmol scale. Treatment of nitrobenzene (1a, 10 mmol) and less we got PhNHTs (Scheme 3a). This evidence indicated that
tosyl chloride (2a, 20 mmol) with Fe dust (30 mmol) in H2O the reaction might proceed via radical particles. The release of
(10 mL) at 60 °C for 48 h gave 3aa in 85.1% yield (Scheme 2).
TsCl was then detected under standard conditions, and the
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NMR plus spectrometer using residue solvent peaks as internal
standards. Infrared spectra were recorded with an IR spectro-
meter and are reported in reciprocal centimeter (cm−1). High-
resolution mass spectra (HRMS) were obtained with a Q-TOF
Premier (ESI).
General procedure for 3
Scheme 4 Proposed reaction mechanism.
A mixture of nitroarenes (0.25 mmol), sulfonyl chlorides
(0.5 mmol), Fe dust (1.0 mmol) and H2O (1 mL) was added
into a 10 mL reaction tube, and then stirred at 60 °C for 36 h
in an air balloon. After cooling to room temperature, water
(8 mL) was added and the aqueous phase was extracted with
EtOAc (3 × 10 mL). The combined organic phases were dried
over Na2SO4, and concentrated under vacuum. The residue was
purified by chromatography on silica gel with petroleum ether/
ethyl acetate as the eluent to afford the corresponding
product.
nitrobenzene had a lot of residue with a trace amount of
PhNH2 (Scheme 3b). Finally, nitrosobenzene and TsCl were
then tested under the optimal conditions and the product 3aa
was obtained (Scheme 3c), implying that nitrosobenzene
might be involved as an intermediate in the reaction. When
the reaction was performed in deuterated water under the stan-
dard conditions, PhNDTs were formed in 92% yield
(Scheme 3d). Finally, when the reaction was conducted under
a nitrogen atmosphere, we got the product 3aa in 88% yield
(Scheme 3e). We observed that the color of the mixtures
changed from colourless to pale brown and some brown solid
was generated. So we speculated that the oxygen was not used
in the reaction and ferric hydroxide was generated in the
transformation.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
On the basis of the above observations and related literature
investigations,6,7 a possible mechanism of the Fe-promoted
protocol was proposed (Scheme 4a). Firstly, sulfochloride or
sulfofluoride was activated by Fe dust to produce a sulfonyl
radical. Then, the sulfonyl radical reacted with nitrosoarene
originating from the reduction of nitroarene by Fe dust to
form the N–S bond. Finally, the generated N–S compound
further transforms into the desired product 3 in the presence
of ferric hydroxide and water (Scheme 4b).8
We are grateful for financial support from the National Natural
Science Foundation of China (no. 21502049 and 51573040),
and the Planned Science and Technology Project of Hunan
Province, China (no. 2015WK3003).
Notes and references
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Conclusion
In conclusion, a simple and mild protocol for the synthesis of
N-arylsulfonamides has been developed. With nitroarenes and
sulfonyl chlorides as the substrates, the desired products can
be isolated in moderate to excellent yields under the Fe-pro-
moted conditions. Diverse functional groups are accepted
resulting in a wide range of substituted sulfonyl chlorides and
nitroarenes. Moreover, this protocol can be performed on a
large scale without any problems.
Experimental
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