Diiodine-Triethylsilane System: Reduction of N-Sulfonyl Aldimines to N-Alkylsulfonamides

Article abstract of DOI:10.1055/s-0040-1706544

Because molecular iodine and hydrosilanes are stable to both air and moisture, reactions using these reagents are easy to operate and require mild reaction conditions. Molecular iodine and a hydrosilane were used to reduce N-sulfonyl aldimines to the corr

Full text of DOI:10.1055/s-0040-1706544

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–D
letter
A
en
J. Jiang et al.
Letter
Synlett
Diiodine–Triethylsilane System: Reduction ofN-Sulfonyl Aldimines
to N-Alkylsulfonamides
Jin Jiang*a,b
Lili Xiaoc
Yu-Long Lia
NTs
NHTs
mild conditions
easy operation
short reaction time
I2
HSiEt3
+
R
H
R
H
DCM, rt
R = aryl, alkyl
18 examples
up to 97% yield
a School of Chemistry and Environmental Engineering,
Sichuan University of Science and Engineering,
Zigong 643000, P. R. of China
jiangjin_suse@163.com
b Key Laboratory of Green Chemistry of Sichuan
Institutes of Higher Education, Zigong 643000,
P. R. of China
c School of Materials Science and Engineering, Sichuan
University of Science and Engineering, Zigong
643000, P. R. of China
Corresponding Author
Received: 25.08.2020
Accepted after revision: 24.09.2020
Published online: 19.10.2020
the reduction of imines to amines. The main catalysts used
include metal catalysts12 such as Ti, Re, Ru, Fe, Ir, Cu, Ni, or
Zn and nonmetal catalysts such as boron compounds.13 N-
Alkylsulfonamides are an important class of nitrogen-con-
taining compounds,14 many of which display biological ac-
tivities.15 We therefore studied the synthesis of N-alkylsul-
fonamides from N-sulfonyl aldimines by reduction with hy-
drosilanes initiated by molecular iodine. Unlike existing
methods,16 the reduction of N-sulfonyl imines by iodine–
hydrosilane systems does not require a metal and has a
short reaction time.
DOI: 10.1055/s-0040-1706544; Art ID: st-2020-u0467-l
Abstract Because molecular iodine and hydrosilanes are stable to
both air and moisture, reactions using these reagents are easy to oper-
ate and require mild reaction conditions. Molecular iodine and a hydro-
silane were used to reduce N-sulfonyl aldimines to the corresponding N-
alkylsulfonamides. This transformation is a practical method for the
synthesis of N-alkylsulfonamides.
Key words imines, iodine, reduction, hydrosilanes, sulfonamides
(a) Previous work:
Molecular iodine, a readily available, inexpensive, non-
toxic, and easily handled reagent has been widely used in
organic transformations in recent years, for example, in the
functionalization of alkenes,1 electrophilic cyclizations of
alkynes,2 C–N bond formation,3 oxidative coupling reac-
tions,4 electrochemical oxidative cross-coupling reactions,5
and cross-dehydrogenative coupling reactions.6 In pursuit
of our interest in molecular-iodine-mediated reduction re-
actions, we chose hydrosilanes as reducing agents because
they also are easy to handle and inexpensive.7 We surmised
that reduction reactions employing diiodine and a hydrosi-
lane would have the characteristics of mild reaction condi-
tions and simple operations.
Several studies on I2–hydrosilane systems have been re-
ported. These include the preparation of alkyl iodides from
carbonyl compounds,8 the preparation of symmetrical
ethers from carbonyl compounds,9 and transformations in
carbohydrate chemistry.10 In a departure from these previ-
ous works, we recently reported the transformation of -
keto esters into the corresponding -hydroxy esters by us-
ing a I2–HSiEt3 system, as an example of simple reduction
application (Scheme 1a).11 Here, we describe the applica-
tion of an iodine–hydrosilane system in the reduction of al-
dimines (Scheme 1b). Hydrosilanes are frequently used for
O
I2
OH
R2
HSiEt3
+
R1
R2
R1
rt, 30 min
R2 = CO2R3
(b) This work:
NTs
I2
NHTs
H
HSiEt3
+
rt, 30 min
R
H
R
Scheme 1 Reduction reactions using I2–hydrosilane systems
Initially, we attempted to reduced N-[(1E)-ben-
zylidene]-4-methylbenzenesulfonamide (1a; 1 equiv) by
treatment with I2 (0.5 equiv) and HSiEt3 (2.0 equiv) in di-
chloromethane (2.0 mL) at room temperature for 30 min-
utes (Table 1, entry 1). To our delight, the desired reduction
product, N-benzyl-4-methylbenzenesulfonamide (2a), was
obtained in 68% yield. When another hydrosilane, 1,1,3,3-
tetramethyldisiloxane (TMDS),7 was tested, the yield de-
creased slightly (entry 2). We therefore chose HSiEt3 as a re-
ductant for our subsequent researches. Adjustment of the
amount of I2 showed that 0.5 equivalents of I2 gave the best
yield of 68% (entries 1, 3, and 4). Reducing the amount of
HSiEt3 to 1.5 equivalents gave a lower yield (entry 5). When
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Jiang et al.
Letter
Synlett
various common solvents (DCM, EtOAc, toluene, THF, EtOH,
H2O, and DMF) were screened, DCM was found to be the
most effective for this transformation (entries 1 and 6–11).
Table 2 Scope of the N-Tosyl Aldiminea
Ts
Ts
I2
DCM, rt
N
HN
HSiEt3
+
R
R
Table 1 Optimization of the Reaction Conditions
1
2
Ts
Ts
I2
N
HN
Entry
Substrate
R
Productb
Yieldc (%)
hydrosilane
+
solvent
rt, 30 min
Ph
Ph
1
2
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2e
2f
68
57
90
75
94
70
72
81
91
75
97
60
67
71
22
93
90
94
1a
2a
4-MeOC6H4
Entry
Hydrosilane
1a/hydrosilane/I2 (equiv) Solvent
Yielda (%)
3
4-Tol
4
4-MeO2CC6H4
4-O2NC6H4
4-F3CC6H4
4-FC6H4
4-BrC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
3-Tol
1
2
HSiEt3
TMDS
HSiEt3
HSiEt3
HSiEt3
HSiEt3
HSiEt3
HSiEt3
HSiEt3
HSiEt3
HSiEt3
1.0:2.0:0.5
1.0:2.0:0.5
1.0:2.0:1.0
1.0:2.0:0.3
1.0:1.5:0.5
1.0:2.0:0.5
1.0:2.0:0.5
1.0:2.0:0.5
1.0:2.0:0.5
1.0:2.0:0.5
1.0:2.0:0.5
DCM
DCM
DCM
DCM
DCM
EtOAc
toluene
THF
68
65
62
59
61
61
63
–
5
6
3
7
1g
1h
1i
2g
2h
2i
4
8
5
9
6
10
11
12
13
14
15
16
17
18
1j
2j
7
1k
1l
2k
2l
8
9
EtOH
H2O
–
1m
1n
1o
1p
1q
1r
2-Tol
2m
2n
2o
2p
2q
2r
10
11
–
1-naphthyl
2-furyl
DMF
–
a Isolated yield after purification by column chromatography.
Cy
Bu
With the optimized reaction conditions in hand, we re-
duced various N-tosyl aldimines with the I2–HSiEt3 system
at room temperature to give the corresponding N-alkylsul-
fonamides (Table 2). Aromatic aldimines containing an elec-
tron-donating methoxy or methyl group at the para-posi-
tion of the phenyl ring were competent substrates, giving
sulfonamides 2b and 2c in yields of 57 and 90%, respectively
(Table 2, entries 2 and 3). Aromatic aldimines with an elec-
tron-withdrawing methoxycarbonyl, nitro, or trifluoro-
methyl group at the para-position of the phenyl ring were
also effective substrates, giving 2d, 2e, and 2f in yields of
75, 94, and 70%, respectively (entries 4–6). Substrates with
halo groups on the benzene rings also reacted well to give
the corresponding products 1g–k in moderate to excellent
yields (entries 7–11). The reaction was not significantly af-
fected by steric hindrance, because the yields from the or-
tho-substituted substrates 1k and 1n were higher than
those from the corresponding meta-substituted substrate 1j
and 1m (entries 10–13). The 1-naphthyl aldimine 1n was
also tolerated, giving the corresponding product 2n in 71%
yield (entry 14). Moreover, the 2-furyl aldimine 1o was suc-
cessfully reduced by the I2–HSiEt3 system, but gave a low
yield (22%) of product 2o (entry 15). Note that the alkyl al-
dimines 1p–r also reacted well to give the desired products
in excellent yields (entry 16–18).
i-Bu
a Reaction conditions: imine 1 (1.0 mmol, 1.0 equiv), HSiEt3 (2.0 mmol, 2.0
equiv), I2 (0.5 mmol, 0.5 equiv), DCM (2.0 mL), rt, 30 min.
b All the products were identified by comparison of their analytical data
with those reported in the literature.
c Isolated yield after purification by column chromatography.
NTs
CO2Me
NHTs
Ph CO2Me
I2
HSiEt3
+
Ph
DCM, rt
3
4
90%
Scheme 2 Reduction of ketimine 3 by using the I2–HSiEt3 system
Next, another type of N-sulfonyl imine was tested
(Scheme 3). The N-tert-butylsulfonyl imine 5 participated
well in this reaction, giving the corresponding sulfonamide
6 in 85% yield.
O
S
O
S
O
O
I2
HSiEt3
+
N
HN
DCM, rt
Ph
Ph
5
6
85%
We then examined the reactivity of a ketimine (Scheme
2). Ketimine 3 was effectively reduced by the I2–HSiEt3 sys-
tem to give the desired product 4 in 90% yield.
Scheme 3 Reduction of the N-tert-butylsulfonyl imine 5 by using the
I2–HSiEt3 system
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
J. Jiang et al.
Letter
Synlett
To illustrate the synthetic applications of the I2–HSiEt3
system in the reduction of N-sulfonyl imines, we carried
out a large-scale reaction to produce 1.65 g of N-(4-chloro-
benzyl)-4-methylbenzenesulfonamide (2i) in 93% yield
(Scheme 4).
be generated from an iodine anion and the intermediate si-
lylenium ion 8.19 Finally, product 2 is formed through hy-
drolysis of the silylated amine 9.13b On the other hand, if HI
acts as the activating reagent (Scheme 6b), I2 first reacts
with HSiEt3 to produce HI and ISiEt3. The N-sulfonyl imine 1
is then protonated to form intermediate 10, which is re-
duced by HSiEt3 to give product 2.
Ts
Ts
N
HN
I2
HSiEt3
+
(a) ISiEt3 acts as the catalyst
DCM, rt
Cl
Cl
Ts
N
1i
2i
1.76 g, 6 mmol
1.65 g, 93%
R
1
Scheme 4 Large-scale preparation of 2i
Ts
Et3Si
To investigate the reaction mechanism, we conducted
several experiments (Scheme 5). First, reduction of imine
1a by HSiEt3 without I2 did not proceed, and the starting
material remained unreacted (Scheme 5a). It is known that
I2 can react with HSiEt3 to produce HI and ISiEt3.8,17 In the
reduction of -keto esters with the I2–HSiEt3 system, ISiEt3
proved to be the actual catalyst.11 We suspected that ISiEt3
might also be the catalyst in the reduction of N-sulfonyl
imines with the I2–HSiEt3 system. To test this hypothesis,
iodo(trimethyl)silane (TMSI), a commercially available re-
agent, was used, and N-sulfonyl imine 1a was successfully
reduced to 2a in 70% yield (Scheme 5b). However, product
2a was also obtained in 48% yield when HI was used
(Scheme 5c), so the reduction might be promoted by the
presence of HI.
N
HSiEt3 I2
+
HI
+
ISiEt
3
7
I
R
HSiEt3
Et3Si
8
Ts
Et3Si
Ts
N
hydrolysis
HN
9
R
R
2
(b) HI acts as the activating reagent
HSiEt3 I2
+
HI
ISiEt
+
(1)
(2)
3
Ts
N
Ts
HI
(a)
HN
Ts
Ts
DCM, rt
N
HN
R
HSiEt3
+
R
1
10
HN
Ph
Ph
Ph
Ts
Ts
HSiEt3
1a
2a
HN
0%
(3)
R
R
(b)
(c)
10
Ts
Ts
2
TMSI (0.5 equiv)
DCM, rt
N
HN
HSiEt3
+
Scheme 6 Possible reaction mechanisms
Ph
(1.5 equiv)
1a
2a
70%
(1.0 equiv)
In conclusion, we have reported a novel metal-free pro-
tocol for the synthesis of N-alkyl sulfonamides from N-sul-
fonyl aldimines under mild conditions.20 In this transforma-
tion, imines are reduced by HSiEt3 with initiation by molec-
ular iodine. This reaction is the first report of the reduction
of imines by using an I2–hydrosilane system, and it might
serve as a practical method for the synthesis of N-alkylsul-
fonamides.
Ts
Ts
HI (0.5 equiv)
DCM, rt
N
HN
HSiEt3
+
Ph
Ph
(1.5 equiv)
1a
2a
48%
(1.0 equiv)
Scheme 5 Control experiments
Based on these results, two possible reaction mecha-
nism are proposed (Scheme 6). If ISiEt3 acts as the catalyst
(Scheme 6a), I2 first reacts with HSiEt3 to produce HI and
ISiEt3. The N-sulfonyl imine 1 then reacts with ISiEt3 to gen-
erate the silylated iminium ion 718 and an iodine anion.
Iminium ion 7 is then reduced by another molecule of HSi-
Et3 to form the silylated amine 9 and ISiEt3. The ISiEt3 might
Funding Information
This work was supported by the Sichuan University of Science and
Engineering (2017RCL45, 2017RCL30) and the opening Project of the
Key Laboratory of Green Chemistry of Sichuan Institutes of Higher
Education (LYJ1902).
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
J. Jiang et al.
Letter
Synlett
Supporting Information
Huang, L.; Atasoylu, O.; Huryn, D. M.; Trojanowski, J. Q.; Lee, V.
M.-Y.; Brunden, K. R.; Smith, A. B. J. Med. Chem. 2011, 54, 6969.
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M. V.; Bloomer, W. D.; Rosenzweig, H. S.; Chatelain, E.; Kaiser,
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55, 5554. (e) Yang, P.; Wang, L.; Feng, R.; Almehizia, A. A.; Tong,
Q.; Myint, K.-Z.; Ouyang, Q.; Alqarni, M. H.; Wang, L.; Xie, X.-Q.
J. Med. Chem. 2013, 56, 2045.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706544. Su
p
p
ortingInformationS
u
p
p
ortingI
n
formatio
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(18) Kaboudin, B.; Moradi, K. Synthesis 2006, 2339.
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(20) N-Benzyl-4-methylbenzenesulfonamide (2a); Typical Proce-
dure
A flask was successively charged with HSiEt3 (232.6 mg, 2.0
mmol, 2.0 equiv), N-sulfonyl aldimine 1a (259.3 mg, 1.0 mmol,
1.0 equiv), DCM (2.0 mL), and I2 (126.9 mg, 0.5 mmol, 0.5 equiv),
and the mixture was stirred at rt for 30 min. DCM (20.0 mL) and
0.5 M aq Na2S2O3 (10 mL) were added to the flask, and the
organic layer was separated, washed with brine, dried (Na2SO4),
filtered, concentrated, and purified by flash column chromatog-
raphy [silica gel (200–300 mesh), PE–EtOAc (4:1)] to give a
white solid; yield: 178.2 mg (68%); mp 117–118 °C.
1H NMR (600 MHz, CDCl3):  = 7.75 (d, J = 8.4 Hz, 2 H), 7.30 (d,
J = 8.4 Hz, 2 H), 7.28–7.23 (m, 3 H), 7.22–7.16 (m, 2 H), 4.93–
4.80 (m, 1 H), 4.11 (d, J = 6.6 Hz, 2 H), 2.44 (s, 3 H). 13C NMR (150
MHz, CDCl3):  = 143.6, 136.9, 136.4, 129.9, 128.8, 128.0, 127.3,
47.4, 21.7.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D