NH4I-Catalyzed Synthesis of Sulfonamides from Arylsufonylhydrazides and Amines

Article abstract of DOI:10.1002/cjoc.201500796

A novel and efficient approach to sulfonamides has been developed. Using TBHP as the oxidant and NH₄I (20 mol%) as the catalyst, arylsulfonyl hydrazides reacted with amines to provide sulfonamides in moderate to good yields. Possible reaction pathway for the formation of the products was also discussed in this paper. Sulfonimides were synthesized through the oxidation coupling of arylsufonylhydrazides and amines by TBHP/NH4I system in moderate to good yields.

Full text of DOI:10.1002/cjoc.201500796

COMMUNICATION
DOI: 10.1002/cjoc.201500796
NH4I-Catalyzed Synthesis of Sulfonamides from
Arylsufonylhydrazides and Amines
Hui Yu* and Yonghao Zhang
Department of Chemistry, Tongji University, 1239 Siping Road, Shanghai 200092, China
A novel and efficient approach to sulfonamides has been developed. Using TBHP as the oxidant and NH4I (20
mol%) as the catalyst, arylsulfonyl hydrazides reacted with amines to provide sulfonamides in moderate to good
yields. Possible reaction pathway for the formation of the products was also discussed in this paper.
Keywords sulfonamides, arylsulfonyl hydrazides, Amines, TBHP, oxidative coupling
Introduction
reaction of arylsulfonyl hydrazides and amines for the
formation of sulfonamides at room temperature under
transition metal-free conditions.
Sulfonamides are important structural motifs of
many pharmaceuticals and bioactive compounds, which
have a wide range of applications on drug discovery as
potential anticancer, antibacterial, calcitonin inducers
agents and HIV protease inhibitors.[1] Owing to the at-
tractive medicinal properties of sulfonamides, various
methods have been developed to their synthesis. The
most frequently used methods involved the reaction of
sulfonyl chlorides with amino compounds,[2] or reaction
of sulfonamides with organic halides.[3] However, these
methods suffered from certain disadvantages such as the
formation of stoichiometric amounts of salts, which
caused low atom economy and environmental problems.
Thus, development of new synthetic pathways to sul-
fonamides is still in demand. Based on transition met-
al-catalyzed C－N bond or N－S bond formation, new
approaches to sulfonamide were continuously exploited
and proved to be effective. For example, Kim reported a
copper catalyzed synthesis of sulfonamide from sulfonyl
azides and boronic acids at room temperature, but this
method was not suitable to tertiary sulfonamides syn-
thesis.[4] Jiang reported a copper catalyzed synthesis of
sulfonamides from sodium sulfinates and amines in high
yields, and Luo reported an iron catalyzed synthesis of
sulfonamides from sodium sulfinates and nitroarenes in
the presence of NaHSO3.[5]
Experimental
General
Commercially available reagents were used as re-
ceived without further purification unless otherwise in-
dicated. Reactions were magnetically stirred and moni-
tored by thin layer chromatography (TLC) using Silica
Gel 60 F254 plates and were visualized by fluorescence
quenching at 254 nm. For chromatographic purifications,
analytically pure solvents were used and the silica gel
300－400 mesh was used as the solid support. 1H NMR
and 13C NMR chemical shifts (δ) were reported relative
to the chemical shift of residual solvent. Reference
1
peaks for chloroform in H NMR and 13C NMR spectra
were set at δ 7.26 and 77.0, respectively.
Typical experimental procedure for the synthesis of
3a: A mixture of arylsulfonyl hydrazide (0.5 mmol),
morpholine (1.0 mmol), NH4I (0.1 mmol), and TBHP
(70 wt% in H2O, 3.0 mmol) in CH3CN (2 mL) was
stirred for 16 h at room temperature. Then the mixture
was quenched with saturate sodium thiosulfate solution,
extracted with EtOAc, dried over anhydrous Na2SO4,
and evaporated in vacuum. The residue was purified by
flash column chromatography on silica gel (petroleum
ether/ethyl acetate, 8/1) to give the product 4-tosylmor-
pholine 3a.
In recent years, due to its high efficiency and envi-
ronmentally friendly properties, t-butyl hydroperoxide
(TBHP)/I system mediated oxidative coupling reac-
tions have attracted considerable attention, and
have been used successfully for the formation of car-
bon-carbon and carbon-heteroatom bonds.[6] Herein, as a
continuation of our efforts on TBHP-mediated oxidative
coupling reactions, we reported a novel NH4I-catalyzed
Results and Discussion
Initially, the reaction of p-toluenesulfonyl hydrazide
(1a) and morpholine (2a) was examined in the presence
of 20 mol% of iodine and 6.0 equiv. of TBHP (70% so-
*
E-mail: yuhui@tongji.edu.cn; Tel.: 0086-021-65981097; Fax: 0086-021-65982287
Received November 19, 2015; accepted January 7, 2016; published online March 8, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500796 or from the author.
Chin. J. Chem. 2016, 34, 359—362
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359

Yu & Zhang
COMMUNICATION
lution in water) in CH3CN at room temperature. De-
lightfully, a moderate yield (63%) was obtained after 16
h (Table 1, Entry 1). With TBHP as the oxidant, a wide
range of iodine sources were screened for the reaction
and NH4I performed slightly better over other catalysts
(Table 1, Entries 2－8). Changing the amount of NH4I
to 30 mol% or 10 mol% caused lower yield (Table 1,
Entry 7). After NH4I was selected as the catalyst, further
optimization was carried out. With CHP, DTBP, or
TBPB as the oxidant, 3a was obtained in low yields
(Table 1, Entries 9－11). When the amount of TBHP
was decreased to 4.0 equiv. and 2.0 equiv., the yields of
3a was decreased to 58% and 46%, respectively (Table
1, Entry 12). Subsequently, the effect of solvents was
investigated, and it was found that acetonitrile is supe-
rior to other solvents (Table 1, Entries 13－16). Thus,
the optimized conditions for this reaction are summa-
rized as follows: 1a (0.5 mmol), 2a (1.0 mmol), NH4I
(0.1 mmol), and TBHP (3.0 mmol, 70% solution in
water), at room temperature in CH3CN under air for 16
h.
Under the optimized reaction conditions, the sub-
strate scope was examined (Table 2). Good to excellent
yields of tertiary sulfonamides were obtained in most
cases (Table 2, 3a－3o). Piperidine and pyrrolidine re-
acted with p-toluenesulfonyl hydrazide 1a to give the
corresponding products in 76% and 84% yields, respec-
tively (Table 2, 3b, 3c). Substituted piperazines were
also suitable substrates to produce the corresponding
products in moderate yields (Table 2, 3d－3g). The het-
erocyclic substrate imidazole could also give the prod-
uct in suitable yield (Table 2, 3h). Acyclic secondary
amines such as dimethylamine, diethylamine, N-methyl-
benzylamine and N-ethylbenzylamine, also gave the
desired products under the optimized conditions, but in
relatively low yields for their low activities (Table 2, 3i
－3l). Next, different arylsulfonyl hydrazides reacted
smoothly with morpholine and pyrrolidine to give cor-
responding sulfonamides in moderate to good yields
(Table 2, 3m－3o).
Encouraged by the facile synthesis of tertiary sul-
fonamides from secondary amines, the scope of the re-
action was extended to the formation of secondary sul-
fonamides (Table 3, 5a－5n). Firstly, substituted ani-
lines were investigated, and the corresponding products
could be obtained in moderate yields, regardless of
electron-withdrawing or electron-donating groups on
the benzene ring (Table 3, 5b－5e). And in this reaction,
steric effects could be observed; 2-toluidine provided
only 27% yield of the product, lower than 3-toluidine
and 4-toluidine (Table 3, 5e－5g). 2-Animopyridine
could not afford the product (Table 3, 5h). For the ali-
phatic substrates such as n-butylamine and cyclohexyla-
mine, the desired products were obtained in suitable
yields; but tert-butylamine could not give the corre-
sponding product due to the increased steric hindrance
(Table 3, 5i－5k). Benzylamine was oxidized to ben-
zaldehyde under the reaction conditions and no product
was obtained (Table 3, 5l). Benzenesulfonyl hydrazide
and 4-nitro-benzenesulfonyl hydrazide also underwent
smooth reactions with aniline to provide the products in
moderate yields, but ethanesulfonyl hydrazide failed
(Table 3, 5m－5o).
Table 1 Optimization of reaction conditions for tertiary sul-
fonamide formationa
O
S NHNH2
O
catalyst (20 mol%)
oxidant (6.0 equiv.)
O
1a
+
S N
O
O
solvent, r.t., 16 h
HN
O
3a
2a
Catalyst
Oxidant
Entry
Solvent
Yieldb/%
(20 mol%)
(6.0 equiv.)
1
2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
CHP
CH3CN
CH3CN
63
34
56
40
45
20
TBAI
NIS
3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOAc
DCM
4
NaI
5
KI
6
CsI
7
NH4I
CuI
85 (80,c 72d)
8
73
9
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
57
10
11
12
13
14
15
16
DTBP
TBPB
TBHP
TBHP
TBHP
TBHP
TBHP
N.R.
To investigate the reaction mechanism, 1.0 equiv. of
the radical scavenger TEMPO and BHT was added to
the reaction, the yield of 3a was decreased to 42% and
37%, which indicated that a radical pathway should be
involved. According to the above results, a possible
mechanism is proposed in Scheme 1. Promoted by I,
tert-butoxyl radical A was generated from the decompo-
sition of TBHP.[7] Subsequently, the hydrogen abstrac-
tion of sulfonyl hydrazides by A gave sulfonyl radical B
with the release of molecular nitrogen.[8] Then B was
trapped by iodine to afford sulfonyl iodide C.[9] Finally,
amines reacted with sulfonyl iodide C to give the de-
sired sulfonamides D and regenerated I.[10] More de-
tails for the mechanism still need further investigations.
10
58,e 46f
61
48
H2O
N.R.
Dioxane 27
a The reaction was carried out with 1a (0.5 mmol), 2a (1.0 mmol),
oxidant (6.0 equiv.), and solvent (2.0 mL), at room temperature
for 16 h. b Isolated yields. c 30 mol% of NH4I was used. d 10
mol% of NH4I was used. e 4.0 equiv. of TBHP was used. f 2.0
equiv. of TBHP was used. CHP＝cumene hydroperoxide. DTBP
＝di-tert-butyl peroxide. TBPB＝tert-butyl perbenzoate.
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Chin. J. Chem. 2016, 34, 359—362

NH4I-Catalyzed Synthesis of Sulfonamides from Arylsufonylhydrazides and Amines
Table 2 NH4I-catalyzed synthesis of tertiary sulfonamides from arylsulfonylhydrazides and aminesa
O
NH4I (20 mol%)
R1
R1
R2
TBHP (6.0 equiv.) Ar S N
O
+
R2
Ar S NHNH2
O
HN
O
CH3CN, r.t., 16 h
3a - 3o
2a - 2l
1a - 1c
Product
Yieldb/%
Product
Yieldb/%
76%
Product
Yieldb/%
84%
O
O
O
84%
68%
68%
36%
72%
S N
O
S N
S N
O
3a
O
3b
O
3c
O
O
O
O
65%
44%
57%
65%
74%
40%c
45%
82%
S N
N
Me
S N
N
Et
S N
O
N
OEt
O
3d
O
3e
3f
O
O
O
N
S N
N
Boc
S N
S N
O
3i
O
3g
O
3h
O
O
S
O
S
S N
N
N
O
3j
O
Me
O
Et
3k
3l
O
O
O
S N
O
S N
O2N
S N
O
O
O
O
3m
3n
3o
a The reaction was performed with arylsulfonyl hydrazide (0.5 mmol), tertiary amine (1.0 mmol), NH4I ( 0.1 mmol, 20 mol%), TBHP (70
wt% in water, 3.0 mmol) in acetonitrile (2.0 mL) at room temperature for 16 h. b Isolated yields. c Dimethylamine hydrochloride salt was
used in the presence of 1.0 equiv. of CaCO3.
Table 3 NH4I-catalyzed synthesis of secondary sulfonamides
Continued
Yieldb/%
from arylsulfonylhydrazides and aminesa
Entry
R1
R2
Product
NH4I (20 mol%)
TBHP (6.0 equiv.)
O
O
11
12
13
14
15
4-MeC6H4
4-MeC6H4
C6H5
t-Butyl
Bn
5k
5l
0
0
R1 S NHNH2
R2NH2
4a - 4l
S NHR2
R1
+
CH3CN, r.t., 16 h
O
1a - 1c
O
5a - 5o
C6H5
C6H5
C6H5
5m
5n
5o
50
47
0
Entry
R1
R2
C6H5
Product
Yieldb/%
4-NO2C6H4
Et
1
2
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
5a
5b
5c
5d
5e
5f
54
49
60
51
46
50
27
0
a The reaction was performed with arylsulfonyl hydrazide (0.5
mmol), sencondary amine (1.0 mmol), NH4I (0.1 mmol, 20
mol%), TBHP (70 wt% in water, 3.0 mmol) in acetonitrile (2.0
mL) at room temperature for 16 h. b Isolated yields.
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
2-Pyridinyl
n-Butyl
3
4
5
Conclusions
6
7
5g
5h
5i
In conclusion, we have developed a facile and effi-
cient approach for the synthesis of sulfonamides with
the TBHP-NH4I system being involved. The reactions
could be carried out under environmentally friendly and
mild conditions.
8
9
40
57
10
Cy
5j
Chin. J. Chem. 2016, 34, 359—362
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361

Yu & Zhang
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Scheme 3 Proposed mechanism
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Acknowledgement
Financial support from Tongji University (No.
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Chin. J. Chem. 2016, 34, 359—362