Convenient sulfonylation of imidazoles and triazoles using NFSI

Article abstract of DOI:10.1080/17415993.2018.1480725

A protocol for the synthesis of N-sulfonyl imidazoles and triazoles has been achieved using N-Fluorobenzenesulfonimide as a sulfonyl source. This reaction proceeded well in the absence of strong bases and catalysts, providing a convenient alternative method for the preparation of N-sulfonyl imidazoles as well as triazoles.

Full text of DOI:10.1080/17415993.2018.1480725

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Convenient sulfonylation of imidazoles and
triazoles using NFSI
Kun Jie, Yufeng Wang, Ling Huang, Shengmei Guo & Hu Cai
To cite this article: Kun Jie, Yufeng Wang, Ling Huang, Shengmei Guo & Hu Cai (2018):
Convenient sulfonylation of imidazoles and triazoles using NFSI, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2018.1480725
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JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2018.1480725
SHORT COMMUNICATION
Convenient sulfonylation of imidazoles and triazoles using
NFSI
Kun Jie, Yufeng Wang, Ling Huang, Shengmei Guo and Hu Cai
College of Chemistry, Nanchang University, Nanchang, People’s Republic of China
ABSTRACT
ARTICLE HISTORY
Received 12 December 2017
Accepted 15 May 2018
A protocol for the synthesis of N-sulfonyl imidazoles and triazoles
has been achieved using N-Fluorobenzenesulfonimide as a sulfonyl
source. This reaction proceeded well in the absence of strong bases
and catalysts, providing a convenient alternative method for the
preparation of N-sulfonyl imidazoles as well as triazoles.
KEYWORDS
Sulfonylation; NFSI;
imidazoles; triazoles; base
N-Fluorobenzenesulfonimide (NFSI) plays an important role in modern organic synthe-
sis. This compound was developed early to serve as an oxidant in reaction such as C–H
activation, due to its strong oxidizability [1–5]. During the oxidation process, the fluorine
cation of NFSI was reduced to fluorine anion and, normally, a metal catalyst was oxidized.
Besides, in the catalytic fluorination of ketone, alkene and their derivates, NFSI has also
been developed to act as a fluorine source [6–14]. On the other hand, the sulfonamide
group of the NFSI generated by N–F bond cleavage was employed as a nucleophile to install
into alkenes through radical intermediates [15–27]. Moreover, both the fluorine and sul-
fonamide groups of the NFSI were installed into one molecule in one pot [28–30]. Although
great progress has been made, the NFSI providing other groups such as sulfonyl group in
a reaction is rarely explored.
The N-sulfonylation of imidazole or triazole is regarded as an efficient way to protect
the amino group due to their easy removal property [31,32]. Traditionally, the strategy to
approach the sulfonamide of imidazoles or triazoles is to treat them with a sulfonyl chlo-
ride in the strong bases’ conditions [33–38]. To overcome the drawback of strong bases,
CONTACT Shengmei Guo
smguo@ncu.edu.cn; Hu Cai
caihu@ncu.edu.cn
College of Chemistry,
Nanchang University, Nanchang, Jiangxi 330031, People’s Republic of China
This article makes reference to supplementary material available on the publisher’s website at https://doi.org/10.1080/
17415993.2018.1480725
© 2018 Informa UK Limited, trading as Taylor & Francis Group

2
K. JIE ET AL.
Scheme 1. The sulfonylation of imidazoles.
using an excess amount of imidazoles or triazoles, an organic base or lasting the reaction
time has been disclosed [39–42]. Although efficient, this method is low tolerant for the
substrates sensitive to strong bases, and the sulfonyl chlorides are sensitive to moisture
(Scheme 1 A). Alternatively, some groups employed sodium benzenesulfinate as a sulfonyl
source to directly construct the sulfonamides under mild conditions, which pushed for-
ward the development of the N-sulfonylation reaction. But the use of stoichiometric iodine
might cause pollution (Scheme 1 B) [43–46]. Recently, the group of Tang and Xu [47]
developed a copper/iodine mediated sulfonylation of benzimidazoles using stable, com-
mercially available and inexpensive disulfides under aerobic conditions. But this protocol
also met the same problem of the waste of transition metal or iodine (Scheme 1 C). Despite
various advantages, an alternative method which is convenient, catalyst-free and handle
easily to enable N-sulfonylation of imidazoles is desirable. Herein, we disclosed an alter-
native method for the N-sulfonylation of imidazoles without any catalyst, using NFSI as
the sulfonyl source and NaHCO3 as a base under air conditions (Scheme 1 D).
Initially, we chose benzimidazoles (1a) and NFSI (2) as substrates to optimize the reac-
tion conditions. The results were summarized in Table 1. When 1a mixed with 2 in CH3CN
at 70°C under air conditions for 12 h, the reaction gave the corresponding product in 60%
yield (Table 1, entry 1). This result encouraged us to further screen the reaction condi-
tions. We found that when NaHCO3 (50 mol %) was employed into the reaction, an obvious
increase of the product yield (76%) was observed (Table 1, entry 2). Then, a variety of bases
were examined, Na2CO3 and K2CO3 gave the desired products in 67% and 71% yields,
respectively (Table 1, entries 3–4). Inorganic strong bases such as NaOMe and NaOEt took

JOURNAL OF SULFUR CHEMISTRY
3
Table 1. Optimization of the reaction conditionsa.
Entry
Base (50 mol %)
T (°C)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
–
NaHCO3
Na2CO3
K2CO3
NaOMe
NaOEt
DBU
Et3N
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
50
90
70
70
70
70
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
60
76
67
71
57
51
76
19
77
65
–
9
NaHCO3 (1.2 eq.)
NaHCO3 (0.25 eq.)
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
10
11
12
13
14
15
16
17c
18d
19
20
21e
22f
23g
24h
DMSO
THF
–
39
43
20
30
87
87
56
45
86
87
86
86
Dioxane
Benzene
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
aReaction conditions: 1a (0.3 mmol), NFSI (0.36 mmol), base (50 mol %), and solvent (2 mL) at 70°C under air for 12 h.
bIsolated yield.
cUsing NFSI (0.45 mmol).
dUsing NFSI (0.6 mmol).
eCH3CN (1 mL).
fCH3CN (3 mL).
gUnder O2. Using NFSI (0.45 mmol).
hUnder N2. Using NFSI (0.45 mmol).
a negative effect on the reaction, which led the corresponding products in 57% and 51%
yields (Table 1, entries 5–6). Organic bases such as DBU (1, 8-diazabicyclo (5.4.0) undec-
7-ene) made a positive result and isolated the product in 76% yield (Table 1, entry 7), while
Et3N just delivered the product in 19% yield (Table 1, entry 8). Interestingly, increasing or
decreasing the loading of NaHCO3 (120 mol % or 25 mol %) did not promote the reac-
tion (Table 1, entries 9–10). The solvent screens showed that when DMF and DMSO were
served, the reaction did not carry out at all (Table 1, entries 11–12). THF and dioxane gave
the desired products in moderate yields, and benzene and toluene had a negative effect
on the reaction (Table 1, entries 13–16). When the loading of NFSI was increased to 1.5
equiv., the reaction led the corresponding product in 87% yield (Table 1, entry 17). A fur-
ther increase in the loading results in no improvement of the yield (Table 1, entry 18). The
reaction temperature impacted the reaction deeply. When the reaction temperature was
decreased to 50°C, the yield of product decreased to 56%, and when raising the tempera-
ture to 90°C, the reaction just gave the product with 45% yield, probably due to the easy
decomposition of NFSI above 80°C (Table 1, entries 19–20). The effect of the concentration

4
K. JIE ET AL.
Scheme 2. Screening the scope of substrates.
Notes: Reaction conditions: 1 (0.3 mmol), NFSI (0.45 mmol), NaHCO3 (50 mol %), and CH3CN (2 mL) at 70°C under air for 12 h.
Yields refer to the isolated yields. A mixture of N1- and N3-sulfonylated products.
of the mixture was studied, when 1 or 3 mL of solvents were used in reactions, the yields of
the desired product were less affected (Table 1, entries 21–22). It is noted that the outcome
of the reaction had no impact when it was under N2 or O2 (Table 1, entries 23–24), which
suggested that this transformation has a potential practical application.
With the optimal conditions in hand, the generality of this method was explored,
and the results are summarized in Scheme 2. 5-Methoxy benzimidazole gave the corre-
sponding product in 81% yield with a regioisomeric ratio of 60:40 (3b). The regioisomer
=
phenomenon of the product originates from the isomerization of C N double bond of
benzimidazole. Methyl 3H-benzoimidazole-5-carboxylate led to the corresponding prod-
uct in 81% yield with an isomeric ratio of 54:46 (3c). The electron-withdraw groups such
as nitro- and bromo on the aromatic ring would pull down the activity of benzimidazoles
which afforded the desired product in moderate yields with an isomeric ratio of 51:49 (3d).
6-Nitro benzimidazole delivered the corresponding product in 79% yield with an isomeric
ratio of 51:49 (3e). When 5,6-dimethyl benzimidazole was treated into the reaction, the

JOURNAL OF SULFUR CHEMISTRY
5
Scheme 3. Sulfonylation of benzimidazole using sulfonyl fluoride.
product was afforded in 80% (3f). The substituted group at the C-2 position had much
influence on the reaction. For instance, 2-methyl, 2-ethyl and 2-chloro benzimidazole
delivered the desired products in moderate yields (3g–3i) because of the steric hindrance,
which prohibited the attack of benzimidazole to the NFSI. To verify our assumption, sub-
strates with larger steric hindrance groups such as phenyl and pyridyl at the C-2 position
were employed in the reactions, and no products were found (3j, 3k). Furthermore, this
method could realize the N-sulfonylation of benzotriazole. The benzotriazole gave the cor-
responding product in 81% yield (3l). 5,6-Dimethyl benzotriazole delivered the desired
product in 75% yield (3m). 5-Methyl-benzotriazole led to the products in 85% yields with
an isomeric ratio of 54:46 (3n). Meanwhile, 5-cholobenzotriazole afforded the 3o in 80%
yield with an isomeric ratio of 67:33. Methyl-benzotriazole gave the desired products 3p
in 80% yield (53:47). Moreover, the 1,2,4-triazole and 1,2,3-triazole could also carry out
the N-sulfonylation, giving the corresponding products in 80% and 55% yields (3q, 3r),
independently. Even though with moderate yields, the imidazole and 2-methylimidazole
tolerated the reaction conditions (3s, 3t).
The GC-MS detection showed that benzenesulfonamide and benzenesulfonyl fluoride
exist in the reaction solution, which means that the reaction might go through a decom-
position of NFSI and a sulfonylation process. To verify our hypothesis, benzenesulfonyl
fluoride was employed into the reaction instead of NFSI under the standard conditions,
and 39% yield of desired product was isolated. Interestingly, perfluoroalkyl sulfonyl fluo-
ride such as 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride could participate in the
sulfonylation, and the desired product was obtained in 31% yield (Scheme 3).
In conclusion, we developed an efficient N-sulfonylation of imidazoles as well as tria-
zoles using the readily available NFSI as a sulfonyl source under mild conditions. Without
strong base and catalyst, the reaction tolerates a wide range of functional groups, obtaining
the desired products in moderate to good yields. Furthermore, N-perfluoroalkyl sulfonyl
benzimidazole was synthesized.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
We acknowledge the National Natural Science Foundation of China [21302084], the financial sup-
port from the National Key Basic Research Program of MOST of China [2012CBA01204] and NCU
financial support [CX2017046].

6
K. JIE ET AL.
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