An expeditious synthetic protocol for chlorination of imidazole N-oxide: Synthesis of 2-chloroimidazoles

Article abstract of DOI:10.1016/j.tetlet.2017.08.047

An expeditious, one-pot and room temperature protocol is reported for the synthesis of 2-chloroimidazoles from imidazole N-oxide. Simple mixing of the imidazole N-oxide, derived easily from diacetyl monoxime via three-component reaction, with oxalyl chlor

Full text of DOI:10.1016/j.tetlet.2017.08.047

Accepted Manuscript
An expeditious synthetic protocol for chlorination of imidazole N-oxide: Syn-
thesis of 2-chloroimidazoles
Mossaraf Hossain, Kiran Pradhan, Ashis Kumar Nanda
PII:
S0040-4039(17)31054-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.047
TETL 49237
Reference:
Tetrahedron Letters
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18 August 2017
19 August 2017
Please cite this article as: Hossain, M., Pradhan, K., Nanda, A.K., An expeditious synthetic protocol for chlorination
of imidazole N-oxide: Synthesis of 2-chloroimidazoles, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.08.047
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An expeditious synthetic protocol for
chlorination of imidazole N-oxide: Synthesis
of 2-chloroimidazoles
Mossaraf Hossaina*, Kiran Pradhanb and Ashis Kumar Nandaa
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1
Tetrahedron Letters
An expeditious synthetic protocol for chlorination of imidazole N-oxide: Synthesis of
2-chloroimidazoles
Mossaraf Hossaina, Kiran Pradhanb and Ashis Kumar Nandaa
a Department of Chemistry, University of North Bengal, Siliguri, Dist. Darjeeling, 734013, India
bDepartment of Chemistry, St. Joseph’s College, P.O. North Point, Darjeeling 734104, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An expeditious, one-pot and room temperature protocol is reported for the synthesis of 2-
chloroimidazoles from imidazole N-oxide. Simple mixing of the imidazole N-oxide, derived
easily from diacetyl monoxime via three-component reaction, with oxalyl chloride in an agate
mortar and pestle in open air affords the desired products in excellent yields. In view of versatile
applications of 2-chloroimidazoles and only two other methods are known in the literatures that
suffer from certain drawbacks, the present protocol could be of importance.
Available online
Keywords:
Imidazole N-oxides
2-chloroimidazole
Oxalyl chloride
2009 Elsevier Ltd. All rights reserved.
1. Introduction
We report herein an expeditious, one-pot and room
temperature protocol under solvent-less for the synthesis of 2-
chloroimidazoles from imidazole N-oxide in excellent yields.
The starting compounds imidazole N-oxides are easily
prepared following our previously reported protocol13
(Scheme 1).
Functionalized imidazoles are important scaffolds in many
biologically active compounds.1 For example, chloroimidazoles
are subunits of different bioactive molecules exhibiting
antifungal,2 antibacterial,3,4 antiprotozoal, anti-inflammatory,5
antihypertensive,6 and of late, anti-cancer medications.7
Chloroimidazole moiety is often used as a building block in the
development of new drugs.
Further applications of this moiety are found in coordination
chemistry, organometallic chemistry and asymmetric synthesis.9
2-Chloroimidazole also represents a valuable synthetic precursor
for further functionalizations under metal-free conditions. For
example, simple nucleophilic substitution with thiolate anion
leads to the formation of 2-sulfenylimidazole derivatives, which
serve as important candidates as anti-inflammatory drugs.10
A
Scheme 1. Synthesis of substituted imidazole N-oxides.
literature search for preparative methods for chlorination of
imidazole reveals that the reaction could be achieved from
The present procedure simply involves mixing of the
imidazole N-oxide with oxalyl chloride (1:2 ratios) in an agate
mortar and pestle in open air in the presence of triethylamine (1.5
equivalent of the starting N-oxide). It may be noted that oxalyl
chloride has been used for chlorination of pyridine N-oxide.14
Subsequently, isolating the desired product15 by column
chromatography. A comparison of previous synthetic protocols
and our method are schematically shown in Scheme 2.
11
imidazole N-oxide using POCl3 or tosyl chloride.12 However,
both procedures suffer from one or more disadvantages from
green chemistry point of views. While POCl3 is toxic and
expensive, use of tosyl chloride requires high temperature,
refluxing in anhydrous solvents like CHCl3 or THF. Therefore,
the development of mild and greener conditions for
regioselective chlorination of imidazoles is of importance.
———
 Corresponding author.
Tel.: +91 353 2776381; fax: +91 353 2699001; e-mail: hossainmossaraf@gmail.com

2
Scheme 2. Different routes of chlorination for the synthesis of 2-chloroimidazole derivative.
2. Results and discussion
complete disappearance of the starting N-oxide (on TLC) and
isolated the 2-chloroimidazole in 95% yield (Table 1, entry 3).
Changing the base with pyridine or without using any base
afforded the product in relatively lower yields (Table 1, entries 4
and 5). It is evident that the best conversion (95% yields) is
achieved with 2 equivalents of oxalyl chloride with respect to 1
equiv. of imidazole N-oxide in the presence of 1.5 equiv. of base,
and stirring for 10 minutes at room temperatures. The presence of
triethylamine promotes the reactions, since its absence the
reaction proceeds with moderate yields (67%).
We started optimization of the reaction conditions with a
mixture of imidazole N-oxide and oxalyl chloride (1:1 ratios) in
the presence triethylamine (1.5 equiv). After mixing in a mortar
(15 min.), the TLC of the reaction mixture showed the presence
of starting N-oxide. Further continuation for another 15 min. did
not show much improvement. After column chromatography, we
were able to isolate the desired product in 70% yield (Table 1,
entry 1). Increasing the quantity of oxalyl chroride up to 2 equiv
and stirring for only 10 min at room temperature showed
Table 1. Optimized conditions for chlorination of imidazole N-oxidea by oxalyl chloride
Entry
(COCl)2 (mmol)
Base (1.5 equiv)
Temp (ºC)
Time (min)
(2h)Yield (%)b
1
2
1
triethylamine
RT
30
30
10
10
10
70
90
95c
79
67
1.5
2
-
RT
3
-
RT
4
2
pyridine
no base
RT
5
2
RT
a Reactant (1mmol)
b Isolated Yield
c Optimized reaction condition
Based on the above optimization,
a
variety of 2-
carried out the reaction with imidazole N-oxide bearing a bulky
naphthalene ring, which also afforded excellent conversion
(Table 2, entry 9). Further extension of the protocol was
examined with n-butyl group (an aliphatic substituent), which
worked quite smoothly but afforded the desired product in
relatively lower yield (85%; Table 2, entry 10). The reaction
worked efficiently also from benzil monoxime yielding the
desired 2-chloroimidazole with two phenyl groups at 4 and 5
positions (95%; Table 2, entry 11). However, glyoxal monoxime
did not result in the formation of desired 2-chloroimidazole
derivative (entry 12).
chloroimidazoles were synthesized using the solvent-free
protocol (Table 2). It was observed that the presence of electron-
donating groups such as –Me, –OMe, at various position of the
N-phenyl ring afforded the product in 83-89% (Table 2, entries 2-
4). On the other hand, the presence of electron-withdrawing
groups such as –Cl, –Br, –COOH and –NO2 gave slightly better
yields and in the range of 91-95% yields (Table 2, entries 5-8).
The results however could be explained on the basis of
electrophilicity at the C-2 position of the imidazole ring system,
which is increased by the presence of electron-withdrawing
groups thereby facilitating attack by a nucleophile. We also
Table 2. Scope of various imidazole N-oxide in the synthesis of substituted 2-chloroimidazolea by varying time.
Entry
Imidazole N-oxide
Oxalyl
Chloride
Temp
(ºC)
RT
Time
(min)
15
Product (2)
Yield
(%)b
93
1

3
2
3
RT
RT
20
15
83
89
4
5
RT
RT
20
10
85
93
6
RT
10
91
7
8
RT
RT
10
10
93
95
9
RT
RT
10
20
93
10
85

4
Tetrahedron
11
12
RT
RT
15
95
15
No desired product
-
____________________________________________________________________________________________________________
aImidazole N-oxide (1mmol), Oxalyl Chloride (2 mmol), Triethylamine (1.5 equiv) were ground and stirred at room temperature.
bIsolated yield from column chromatography.
On the basis of the experimental observations, a plausible
mechanism of cine substitution,12 is presumed to be operative
(Scheme 3). Thus, initially the imidazole N-oxide (1) is activated
by oxalyl chloride to form the imidazolium chloride (3), which is
then converted to the intermediate (4). The hydrogen atom at the
C-2 position, being now more acidic, is trapped by the base NEt3
to yield the desired product 2.
Scheme 3. Plausible mechanisms for solvent-free synthesis of substituted 2-chloroimidazole.
References and notes
3. Conclusions
In summary, we have developed an expeditious and mild
synthetic route for the chlorination at C-2 position of imidazole
N-oxide under solvent-free conditions leading to the formation of
2-chloroimidazole. The protocol has been tested with diversely
substituted N-phenyl group. In all cases, the yields are excellent,
though the presence of electron-withdrawing groups favors the
reaction over electron-donating substituents. 2-chlorinated
imidazole derivatives are useful intermediates and subunits of
several pharmacologically important compounds. This simple
setup and facile method could be attractive to the synthetic
chemists from academia and pharmaceutical industries. Further
application of this protocol in other heterocyclic systems is
underway in this laboratory.
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Supporting information
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275- 277.
The detailed experimental section, all other information
such as melting point, FT-IR, NMR and Mass of all products are
provided in the supporting information.
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Tkach, Tatyana Yu Koldaeva, Chemistry of Heterocyclic
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Acknowledgements
The author (MH) thanks UGC, New Delhi, for the award of
the fellowship under UGC-BSR Scheme. The author also
acknowledges CDRI, Lucknow for mass spectra.

5
14. Ying Chen, Jinkun Huang, Tsang-Lin Hwang, Maosheng J Chen,
Jason S Tedrow, Robert P Farrell, Matthew M Bio, Sheng Cui.
Org. Lett. 2015; 17: 2948−2951.
15. General experimental procedure for the chlorination of
Imidazole N-oxides: Imidazole N-oxide (1 mmol), oxalyl chloride
(2 mmol) and triethylamine (1.5 mmol) were mixed intimately in
an agate mortar and pestle for a period of 10-20 min under
solvent-less condition. The reaction mixture was then dissolved in
dichloromethane (2 mL), washed with water and finally dried over
anhydrous MgSO4. Evaporation of the solvent afforded the
residue, which was chromatographed over silica gel column and
elution with petroleum ether/ethyl acetate mixture to furnish the
desired 2-chloroimidazole.

6
Tetrahedron
Highlights
 Room temperature reaction.
 Expeditious, 10-20 mins.
 Wide substrate scope.
 Excellent yield.