Green and efficient protocol for N-alkylation of benzotriazole using basic ionic liquid [Bmim]OH as catalyst under solvent-free conditions

Article abstract of DOI:10.1080/00397910903277888

N-Alkylation of benzotriazole bearing an acidic hydrogen atom attached to nitrogen with alkyl halides is accomplished in basic ionic liquid [Bmim]OH (1-butyl-3-methylimidazolium hydroxide) under solvent-free conditions. The procedure is convenient and efficient and generally affords the N-alkylated product. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903277888

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Green and Efficient Protocol for N-
Alkylation of Benzotriazole Using Basic
Ionic Liquid [Bmim]OH as Catalyst Under
Solvent-Free Conditions
Zhang-Gao Le a b , Tao Zhong a c , Zong-Bo Xie b , Xue-Xia Lü b & Xia
Cao b
a Key Laboratory of Nuclear Resources and Environment of the
Ministry of Education, East China Institute of Technology, Nanchang,
China
b Faculty of Chemistry, Biology and Material Science, East China
Institute of Technology, Fuzhou, China
c No. 1 Gold Geological Detachment of Chinese People's Armed
Police Force, Mudanjiang, China
Published online: 05 Aug 2010.
To cite this article: Zhang-Gao Le , Tao Zhong , Zong-Bo Xie , Xue-Xia L & Xia Cao (2010) Green and
Efficient Protocol for N-Alkylation of Benzotriazole Using Basic Ionic Liquid [Bmim]OH as Catalyst
Under Solvent-Free Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:17, 2525-2530, DOI: 10.1080/00397910903277888
To link to this article: http://dx.doi.org/10.1080/00397910903277888
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Synthetic Communications1, 40: 2525–2530, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903277888
GREEN AND EFFICIENT PROTOCOL FOR
N-ALKYLATION OF BENZOTRIAZOLE USING BASIC
IONIC LIQUID [Bmim]OH AS CATALYST UNDER
SOLVENT-FREE CONDITIONS
Zhang-Gao Le,1,2 Tao Zhong,1,3 Zong-Bo Xie,2 Xue-Xia Lu¨,2
and Xia Cao2
1Key Laboratory of Nuclear Resources and Environment of the Ministry of
Education, East China Institute of Technology, Nanchang, China
2Faculty of Chemistry, Biology and Material Science, East China Institute of
Technology, Fuzhou, China
3No. 1 Gold Geological Detachment of Chinese People’s Armed Police Force,
Mudanjiang, China
N-Alkylation of benzotriazole bearing an acidic hydrogen atom attached to nitrogen with
alkyl halides is accomplished in basic ionic liquid [Bmim]OH (1-butyl-3-methylimidazo-
lium hydroxide) under solvent-free conditions. The procedure is convenient and efficient
and generally affords the N-alkylated product.
Keywords: N-Alkylation; basic ionic liquid; benzotriazole; catalyst; solvent-free conditions
INTRODUCTION
N-Alkylation of benzotriazole has been a subject of considerable research
interest over the past few years in view of its significance in the pharmaceutical, bio-
logical, and chemical industries. Benzotriazole derivatives exhibit a good degree of
analgesic, anti-inflammatory, diuretic, antiviral, and antihypertensive activities.[1]
It has been reported that the N-alkylation of benzotriazole can be achieved by
use different bases, such as potassium alkoxide,[2] sodium hydride,[3] potassium
hydroxide,[4–6] sodium hydroxide,[7] potassium carbonate,[1,8,9] or phase-transfer
catalysis (PTC) with quaternary ammonium salt,[8,10] crown ethers,[2,4] or polyethyl-
ene glycols (PEG) and their dialkyl ether (PEG ether).[5] N-Alkylation of benzotri-
azole can also be achieved without a solvent either in basic media or in the
absence of base by conventional and microwave heating.[8,9] However, some of these
methods suffer from several drawbacks, including the use of hazardous and carcino-
genic organic solvents such as dimethylsulfoxide (DMSO), dimethylformamide
Received June 27, 2009.
Address correspondence to Zhang-Gao Le, Key Laboratory of Nuclear Resources and
Environment of the Ministry of Education, East China Institute of Technology, Nanchang, China.
E-mail: lezhang_ecit@163.com
2525

2526
Z.-G. LE ET AL.
Scheme 1.
(DMF), benzene, or toluene; expensive reagents or catalysts; harsh reaction con-
ditions; difficulty in product separation; and=or long reaction times. Moreover,
the use of these strong bases may limit the processes because the experimental work
can be laborious and time-consuming, requiring special care to avoid hydrolysis. So,
the development of an efficient, convenient, and environmentally more benign
method of the N-alkylation of benzotriazole is still a major challenge.
Ionic liquids have attracted extensive research interest in recent years as envir-
onmentally benign solvents because of their favorable properties such as nonflamm-
ability, negligible vapor pressure, reusability, and high thermal stability,[11] and a
variety of catalytic reactions also have been successful using ionic liquids.[12] Increas-
ingly, research activities have focused on the design of ionic liquids to produce
task-specific ionic liquids for specific functions, for example, acidic or basic ionic
liquids.[13] The acidic ionic liquids have been successfully applied in many organic
reactions.[14] However, to the best of our knowledge, reports about the basic ionic
liquids were relatively rare. Recently, basic functionalized ionic liquids have aroused
unprecedented interest because they showed more advantages, such as convenient
recycling and greater catalytic efficiency, than the mixtures of inorganic bases and
ionic liquids for some base-catalyzed processes.[15] A basic functionalized ionic
liquid, [Bmim]OH, has been successfully applied to catalyze the Knoevenagel
condensation,[16,17] Markovnikov addition,[18] Michael addition,[19] Mannich
reaction,[15] Perkin reaction,[17] interrupted Feist–Benary reaction,[20] and Henry
reaction.[21]
The versatility of this basic ionic liquid encouraged us to study its utility for
N-alkylation of N-heterocycles. Our group previously introduced [Bmim]OH as a
catalyst and green solvent for the N-substitution of pyrrole and indole and the
corresponding N-substituted pyrrole and indole in excellent yield.[22] This interesting
observation prompted us to explore the potential of this ionic liquid for N-alkylation
of benzotriazole (Scheme 1).
RESULTS AND DISCUSSION
Initially, we examined the reaction of benzotriazole with ethyl bromide in the
presence of [Bmim]OH, which proceeded smoothly at room temperature and
afforded the corresponding N-ethylated benzotriazole in 90% yield (Table 1, entry 1).
Benzotriazole reacts with electrophiles to give mixtures of 1-substituted 3 and
2-substituted 4 products.[6] Thus, the reaction produced 3a along with 4a (ratio of
isomer, 66:34).
To recognize the generality and scope of the method, various alkyl halides were
tested with benzotriazole to give the corresponding N-alkylated benzotriazoles. The

N-ALKYLATION OF BENZOTRIAZOLE USING [Bmim]OH
2527
Table 1. N-Alkylation of benzotriazole in basic ionic liquid [Bmim]OHa
Entry
1
Alkyl halide
EtBr
Product
Time (h)
3
Yield (%)b
90
Ratio of isomer (3:4)
74:26
3a
4a
3b
4b
3c
4c
3d
4d
3e
4e
3e
4e
3f
2
3
n-PrBr
3
4
2
3
4
4
2
2
3
87
89
92
87
91
88
95
93
90
62:38
76:24
90:10
68:32
66:34
65:35
86:14
74:26
70:30
i-PrBr
=
ClCH2CH CH2
4
5
n-BuBr
n-BuCl
6
7
n-C8H17Br
BnCl
4f
8
3g
4g
3g
4g
3h
4h
9
BnBr
10
BrCH2COPh
aAll reactions were run with benzotriazole (5 mmol) and alkyl halide (7.5 mmol) in basic
ionic liquid [Bmim]OH (10 mmol).
bIsolated yield based on benzotriazole.
results are summarized in Table 1. We found that the reaction is general and
applicable to alkyl halides containing bromide and chloride, and the desired
products were obtained in good to excellent yields and moderate regioselectivity.
1
The products were characterized by H NMR, infrared (IR) spectra, and melting
points, which were consistent with the literature data.
The basic ionic liquid [Bmim]OH can be typically recovered by extracting the
product, adding KOH, and drying at vacuum. The recovered ionic liquids can be
reused with no appreciable decrease in yield. The representative results are summar-
ized in Table 2. The yields did not obviously decrease over four runs, which shows
that [Bmim]OH is an efficient catalyst.
The present method has many obvious advantages compared to those reported
in the literature, including being environmentally more benign, general and simple
Table 2. Recycling of [Bmim]OH in the butylation of benzotriazole
Entry
Run
Yielda (%)
1
2
3
4
1
2
3
4
90
88
89
88
aIsolated yield.

2528
Z.-G. LE ET AL.
operation, good yield, and potential for recycling the basic ionic liquid. For example,
the synthesis of N-butylbenzotriazole by the traditional procedure not only used the
strong base sodium hydroxide but also needed the hazardous and carcinogenic
organic solvent DMF to give N-butylbenzotriazole in 86%; the ratio of 1-=2-
butylbenzotriazole is 53:47.[7] The same synthesis was performed in 3 h in basic
ionic liquid [Bmim]OH and gave 87% yield; the ratio of 1-=2-butylbenzotriazole
is 68:32 (Table 1, entry 5). The reaction of N-benzylation of benzotriazole by a
recently reported method using K2CO3 as base needed high temperature (90 ꢀC)
to give N-benzylbenzotriazole in 53% yield.[8] The same reaction was completed
within only 2 h at room temperature and gave an excellent yield (95%) (Table 1,
entry 8).
In summary, we have demonstrated that the basic ionic liquid [Bmim]OH
could efficiently catalyze N-alkylation of benzotriazole with alkyl halides at room
temperature under solvent-free conditions. The present procedure is more environ-
mentally benign and has mild reaction conditions, relative short reaction times, wide
applicability, and easy recovery of the catalyst.
EXPERIMENTAL
Melting points were determined on a digital melting-point apparatus and were
not corrected. Infrared (IR) spectra were recorded on a Vector 22 instrument
(Bruker). Nuclear magnetic resonance (NMR) spectra were recorded on an Avance
DMX 200 spectrometer (Bruker). The ionic liquids, 1-methyl-3-butylimidazolium
hydroxide ([Bmim]OH), was synthesized according to reported procedures.[23]
The other materials are commercially available and were used without further
purification.
General Procedure for N-Alkylation of Benzotriazole Catalyzed
by [Bmim]OH
A mixture of benzotriazole (5 mmol), [Bmim]OH (10 mmol), and alkyl halide
(7.5 mmol) was stirred at room temperature (30 ꢀC) for 2–4 h (reaction condition
given in Table 1). The course of the reaction was monitored by thin-layer chroma-
tography (TLC). The reaction mixture was extracted with ethyl ether. The combined
ether extracts were evaporated under reduced pressure, and the resulting crude
product was separated by the preparative TLC on silica gel using a mixture of ethyl
acetate and petroleum ether as developer to give the corresponding pure product.
The residual ionic liquid was washed with small amount of ethyl ether, dried under
vacuum at 80 ꢀC for 2 h, and reused after KOH (5 mmol) was added.
ACKNOWLEDGMENTS
This work was financially supported by Projects NSFC (20862001) and NCET
(08-0701) of the Top Academic Leaders of JiangXi Province, the Science Foundation
of JiangXi Province (2008GZH0055), and the Science and Technology Foundation
of the Education Department of JiangXi Province (GJJ09259).

N-ALKYLATION OF BENZOTRIAZOLE USING [Bmim]OH
2529
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