An efficient strategy for N-alkylation of benzimidazoles/imidazoles in SDS-aqueous basic medium and N-alkylation induced ring opening of benzimidazoles

Article abstract of DOI:10.1016/j.tet.2018.08.029

A sustainable route for the N-1 alkylation of imidazole and benzimidazole derivatives has been developed under volatile organic solvent free condition in alkaline water-SDS system. Incorporation of SDS in the reaction medium enhances the reaction rate by suppressing the solubility issue that arises for different substrates. This method provides high yield of the alkylated product in a shorter reaction time. For reactive alkyl halides reaction proceeds at ambient temperature whereas in the cases of less reactive alkyl halides require 55–60 °C to complete alkylation process. N-alkylation induced ring opening of the heterocyclic ring in benzimidazole derivatives to multifunctional aromatic compounds were noticed at 60 °C when more than two equivalents of alkyl halide was used.

Full text of DOI:10.1016/j.tet.2018.08.029

Accepted Manuscript
An efficient strategy for N-alkylation of benzimidazoles/ imidazoles in SDS-aqueous
basic medium and N-alkylation induced ring opening of benzimidazoles
Ankita Chakrabort, Sudipto Debnath, Tanmoy Ghosh, Dilip K. Maiti, Swapan
Majumdar
PII:
S0040-4020(18)30995-5
10.1016/j.tet.2018.08.029
TET 29749
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 May 2018
Revised Date: 11 August 2018
Accepted Date: 20 August 2018
Please cite this article as: Chakrabort A, Debnath S, Ghosh T, Maiti DK, Majumdar S, An efficient
strategy for N-alkylation of benzimidazoles/ imidazoles in SDS-aqueous basic medium and N-alkylation
induced ring opening of benzimidazoles, Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.029.
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ACCEPTED MANUSCRIPT
Graphical Abstract
An efficient strategy for N-Alkylation of benzimidazoles/
imidazoles in SDS-aqueous basic medium and N-alkylation
induced ring opening of benzimidazoles
Leave this area blank for abstract info.
Ankita Chakraborty,a Sudipto Debnath,bTanmoyGhosh,b
Dilip K. Maitib and Swapan Majumdar*a

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
An efficient strategy for N-alkylation of benzimidazoles/ imidazoles in SDS-aqueous basic medium
and N-alkylation induced ring opening of benzimidazoles
Ankita Chakraborty,a Sudipto Debnath,bTanmoyGhosh,b Dilip K. Maitib and Swapan Majumdar*a
aDepartment of Chemistry, Tripura University, Suryamaninagar, 799 022, INDIA,
E-mail: smajumdar@tripurauniv.in; Tel: +91-381-237-9070; Fax: +91-381-2374802;
bDepartment of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700 009, INDIA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A sustainable route for the N-1 alkylation of imidazole and benzimidazole derivatives
has been developed under volatile organic solvent free condition in alkaline water-
SDS system. Incorporation of SDS in the reaction medium enhances the reaction rate
by suppressing the solubility issue that arises for different substrates. This method
provides high yield of the alkylated product in a shorter reaction time. For reactive
alkyl halides reaction proceeds at ambient temperature whereas in the cases of less
reactive alkyl halides require 55-60oC to complete alkylation process. N-alkylation
induced ring opening of the heterocyclic ring in benzimidazole derivatives to
multifunctional aromatic compounds were noticed at 60oC when more than two
equivalents of alkyl halide was used.
Available online
Keywords:
N-Alkylation
benzimidazole
Sodium dodecyl sulphate
ring opening reaction
aqueous medium
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
N-1 alkylated benzimidazole/imidazole derivatives depending on
the biological importance or application in the development of
new methodologies have become a challenge in organic synthesis
and moreover the reaction in aqueous medium is of further
importance. Although Singh et al.30 reported a convenient access
of secondary/tertiary amines from primary amine under water-
SDS condition but a general approach for N-1 alkylation of
benzimidazoles/imidazoles in water are lacking. Despite of such
importance only few methods are reported for the synthesis of N-
alkylated benzimidazoles and imidazoles. Generally N-1
alkylation of amines is achieved31 by reaction with alkyl halide
using anhydrous K2CO3 or Cs2CO3 in different organic solvent
like acetone, methanol or DMF. Some other reported methods
include a convenient access for the N- alkylation of imidazoles
and benzimidazoles using powdered KOH in acetone at room
temperature with a slight excess of the alkyl halide at room
temperature to give the mono alkylated product or using a KOH
in the presence of 3-5 mol% of a crown ether, dicyclohexyl-18
crown-6 to afford the N-alkylated product.32 Direct condensation
between o-phenylene diamine and various aromatic aldehydes
under different reaction conditions such as ‘on water’ approach
or other catalysts also provides direct routes to N-1 alkylated 2-
aryl substituted benzimidazoles.33-36 In spite of having
tremendous potentiality of these reported methods they suffer
from some serious drawbacks37,38 such as low yields, harsh
reaction conditions, prolonged reaction time, selectivity issue,
solubility and competitive side reaction, application of hazardous
bases and also concomitant formation of quaternary ammonium
salts. Moreover, the synthesis of these compounds is usually
The development of novel synthetic methodologies that are
efficient and more compatible with the environment is an intense
area of research to facilitate the synthesis of target molecules of
specific interest. One of the most desirable approaches to address
this challenge is a search for surrogates for commonly employed
organic solvents those are used in large quantity due to various
health and environmental reasons associated with them. In this
regard water would be the perfect solvent to carry out chemical
operations due to the fact that it is safe, most non-toxic, and
inexpensive. However, often the poor solubility of organic
compounds in aqueous medium becomes detrimental and
therefore improving the solubility of organic compounds in water
has been drastically investigated.1-7 One of such approach is the
incorporation of surface-active agents (surfactants)8,9 in aqueous
media that not only enhance the solubility of organic substrates
but also increase the reactivity via the formation of micelles or
vesicular cavities.10-13 In recent years micelle-mediated organic
reactions become an area of rapidly growing interest.14-17 On the
other hand, imidazoles/ benzimidazoles are the most abundant
and integral scaffolds that occur ubiquitously in a large number
of bioactive natural products, synthetic drugs, pharmaceuticals
and agro-chemicals.18,19 Amongst many derivatives of
benzimidazoles, an N-1 substituted derivative represents an
important branch of this family due to their wide spectrum of
biological and pharmacological activity.20 N-1 Alkylated
benzimidazoles and imidazoles are also important intermediates
in the preparation of various ionic liquids.21-29 Thus, synthesis of

2
Tetrahedron
ACCEPTED MANUSCRIPT
carried out in polar solvents such as ethanol, methanol, acetic
Table 1: Optimization of the reaction conditiona
N
N
Br
acid, dimethyl formamide (DMF), and dimethyl sulfoxide
(DMSO), leading to complex isolation and recovery products.
Thus as a part of our ongoing program to develop a novel
methodology for N- alkylated benzimidazole or its derivatives we
herein report base mediated N-1 alkylation of substituted
benzimidazoles/imidazoles, followed by alkylation induced ring
opening of the benzimidazoles using in excellent yields under
surfactants mediated organic solvent free condition. The present
method has several advantages that include a mild reaction
condition, operational simplicity, very short reaction time,
excellent yield of products and no formation of quaternary salt.
N
Base, surfactants
10 min
N
H
3a
1a
Entry
Base
Surfactant
No
TBAB or CTAB (10 mol%)
Triton X 100 (10 mol%
SDS (10 mol%)
SDS (5 mol%)
Yield (%)
65b
1
2
3
4
5
6
7
8
9
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
Bu4OH
Et3N
Mixtureb
73b,c
97b,c
97b,c
SDS (10 mol%)
SDS (10 mol%)
SDS (10 mol%)
No
97c,d
30e
tracef
NRg
Et3N
a Reaction performed in 1mmol scale; b1mL50% aq. NaOH was
used; c isolated yield; d 0.5 mL of 50 % aq. NaOH was used;
e0.5 mL aqueous Bu4NOH was used; f reaction performed in
water; g reaction performed in dichloromethane
2. Results and discussions
Initially we consider N-1 alkylation of benzimidazole as model
reaction using allyl bromide as alkylating agent. To standardize
the condition several attempt were made by variation of different
parameter. Stirring of the suspension of benzimidazole 1a (1
mmol) in 50 % aq. NaOH (1.0 mL) with allyl bromide at room
temperature afforded N- allylated benzimidazole 3a in 65% yield
(entry 1, Table 1) after 10 min., increasing or decreasing the
amount of NaOH or reaction time did not improve the yield. We
reasoned that the solubility problem may occur between the
organic substrate and the aq. NaOH. As aqueous medium has
always been considered as beneficial for carrying out organic
reaction and the amount of aqueous solution may not good
enough to get soluble the substrates, and hence the reaction did
not occur with a satisfactory yield. Thus to improve the yield
various surfactants were planned to introduce into the system to
increase the solubility of the organic substrates in aqueous
phase.10-13,39 The uses of cationic surfactants (10 mol%) like
TBAB or CTAB gave a complex mixture with incomplete
conversion of the organic substrate as revealed by TLC (entries 2,
Table 1). The neutral surfactant Triton X 100 provides improved
yield of 3a to some extent as compared to non-surfactant
mediated reaction (entry 1 vs entry 3, Table 1). Gratifyingly,
utilization of anionic surfactant SDS (10 mol%), remaining other
reaction conditions being the same, the yield of 3a was improved
drastically to 97% (entry 4, Table 1). On decreasing the amount
of SDS to 5 mol% and amount of NaOH (0.5 mL) the yield was
again 97% (entries 5-6, Table 1). It was also observed that uses
of quaternary ammonium hydroxide (50% aq. Bu4OH) as base
yielded poor yield of the allylated product (entry 7, Table 1).
Under the similar reaction condition organic base such as Et3N
provides only trace amount of the product whereas in organic
environment no product was traced (entries 8-9, Table 1). Most
probably because of high pKa value (pKa of benzimidazole 12.8)
Et3N is unable to abstract N-H proton rather it gets quaternization
(as indicated by the formation of white precipitate and TLC) in
the presence of reactive allyl bromide. Thus it is assumed that
N-1 alkylation of different benzimidazole derivatives according to
the standard protocol as described in Table 1. The choice of alkyl
halides were made considering reactivity of alkyl halides. Reactive
alkyl halide, benzyl bromide underwent alkylation of different
benzimidazoles 1a-e to 3b-f (entries 1-5 Table 2) in excellent
yields in the range of 78-96% and 2-nitrobenzylbromide afforded
corresponding alkylated products 3g-h in 85% yields (entries 6-7,
Table 2). The substrate 2, 6-dimethyl benzimidazole (1d)
undergoes N-1 alkylation smoothly in good yields and shorter
reaction time but resulted tautomers (equal population) of N-1
benzylated benzimidazoles (entry 4, Table 2) as revealed by
NMR spectroscopy. In contrast, the less reactive alkyl bromides
like butyl or hexyl bromide or long chain alkyl bromides like
octyl, or hexadecyl bromide did not produce any alkylated
product at room temperature but at the temperature of 60oC a
clean transformation to N-1 alkylated products (as shown in
Table 2) were achieved in excellent yields within a short period
of time (entries 8-14, Table 2). Apart from benzimidazoles, we
then focused on the N-1 alkylation of imidazoles, substituted
imidazoles which gratifyingly afforded N-1 alkylation in
excellent yields and shorter reaction time. The imidazoles when
treated with cetyl bromide (entry 15, Table 2) underwent smooth
alkylation in excellent yield of 3p (95%) at 60oC. The other
imidazoles like 2-methyl imidazole also gave N-1-benzylated
(entry 16, Table 2) product 3q in 93% yield and 2, 4, 5-triphenyl
imidazole (1h) underwent N-1- allylation (entry 17, Table 2) in
20 mins at 60oC and the yield (3r) was found to be 80%. The
imidazole derivative 2-(2-(allyloxy phenyl)- 4, 5-diphenyl
imidazole (1i) also afforded N-1 allylated product 3s (entry 18,
Table 2) in 20 mins. Another important feature of the present
methodology is the alkylation of sugar based chiral
benzimidazole (1j) 42 to the formation of corresponding N-benzyl
derivative 3t in 82% yield (entry 19, Table 2).
water present in the medium40, may play pivotal role in the
41
The results summarized in Table 2 indicated that in the
cases of reactive alkyl halides the alkylation reactions proceed at
room temperature whereas elevated temperature is required for
alkyl halides of poor reactivities. Then we were curious to
observe the effect of temperature on the N-allylation or
benzylation of benzimidazole under basic SDS medium to
complete the reaction even in faster. Accordingly, 2-phenyl
alkylation process through H-bonding that facilitated substrate to
get solubilize as additional effect with SDS. Being inspired by
the optimization reaction allylation of benzimidazole (Table 1) at
the N-1 position under aqueous environment we aimed to
generalize the procedure using different substituted
benzimidazoles and imidazoles. Subsequently, we carried out the

3
Table 2: N-alkylation of Benzimidazoles and Imidazoles in 50% aq. NaOH-SDS medium
ACCEPTED MANUSCRIPT
N
N
N
N
50% NaOH
R-Br (1 eq.),
SDS (5 mol%)
room temp. or 60 oC
or
or
N
H
R1
R1
N
R
N
R
R1
R1
N
H
3
1
75-98% yield
Entry
1
Substrate (1)
RBr (2)
Product (3)
Time (mins) Yield (%)
N
N
PhCH2Br
15
96a
N
Ph
N
H
3b
3c
1a
N
N
PhCH2Br
10
20
90a
85a
2
3
4
5
N
N
Ph
H
1b
N
N
Ph
Ph
Ph
N
PhCH2Br
PhCH2Br
N
H
1c
3d
N
N
N
30
30
87b
88a
N
H
3e
1d
Ph
N
N
N
PhCH2Br
N
H
3f
Ph
1e
N
N
Br
40
40
85a
85a
N
NO2
NO2
N
3g
H
6
7
1a
N
N
N
Br
NO2
NO2
N
H
3h
1b
N
3i: R1 = H, R = nC4H9
3j: R1 = Me, R = nC4H9
N
15
20
89b
91b
R1
R2
nC4H9Br
8
9
10
1a: R2 = H
1b: R2 = Me
1c: R2 = Ph
N
N
R
H
3k: R1 = Ph, R = nC4H9
3l: R1 = H, R = nC6H13
30
20
85b
97b
N
N
R2
R1
nC6H13Br/
nC8H17Br/
nC8H17Br/
nC16H33Br
11
12
13
14
3m: R1 = H, R = nC8H17
3n: R1 = Me, R = nC8H17
3o: R1 = H, R = nC16H33
96b
90b
98b
N
H
N
R
20
30
20
1a: R2 = H
1b: R2 = Me
C16H33
N
N
NH
N
C16H33Br
PhCH2Br
20
20
95b
93a
3p
15
16
1f
N
N
N
N
3q
1g
Ph
N
H
Ph
Ph
Ph
N
20
20
80b
78b
Ph
Ph
Br
Br
17
18
N
N
Ph
1h
H
3r
Ph
Ph
Ph
Ph
N
N
N
N
H
O
O
O
1i
3s
N
O
O
O
N
O
O
PhCH2Br
20
82a
19
N
H
N
O
O
1j
Ph
3t
a reaction at room temperature, b reaction at 60 oC

4
Tetrahedron
ACCEPTED MANUSCRIPT
1
benzimidazole was heated at 60oC in the presence of one
equivalent of benzyl bromide, 5mol% of SDS and 0.5 mL of 50%
NaOH for 15 minutes, we observed a mixture of product with
incomplete conversion of starting materials and one of the
product was detected as N-1 alkylated product 3d and other was
completely different. The situation did not improve even heating
of the mixture for longer time (3hrs). To our surprise addition of
2 equivalents of benzyl bromide a clean transformation of
starting material was detected with the formation of new
compound but no N-1 alkylated product 3d was detected in this
case. Upon workup and careful purification of the reaction
product we found that benzylation of 2-phenyl benzimidazole
took place with concomitant opening of heterocyclic ring that
produced 5a (entry 1, Table 3) in excellent yield (90%). The
formation of 5a was confirmed by its 1H and 13C NMR spectra’s.
The H-NMR spectra of 5a showed the presence of two distinct
doublets at δ 4.97 ppm and δ 4.79 ppm for the two protons of –
CO-N-CH2Ph and a multiplet at δ 4.09-3.98 for the other three
protons of –NCH2 and –NH. But the later peak upon D2O
1
exchange appeared as clear two doublets in its H NMR spectra
(please see SI). In the 13C NMR spectra, a downfield shift at δ
171.5 ppm confirms the presence of carbonyl group, IR band at
1638 cm-1 and HRMS data also support the suggested structure of
5a. Ring opening reaction of N-1 alkylated benzimidazole
derivative 3d was also achieved using 1 eq. of benzyl bromide
under same reaction condition (entry 2, Table 3). It is important
to mention here that heterocyclic ring in benzimidazole moiety is
completely survived under the reaction condition if the reaction
conducts without benzyl bromide (eq.
1
in Scheme 2).
Table 3 Alkylation induced base mediated imidazole ring opening reaction of substituted benzimidazoles
Entry
Substrate
Alkylating agent
PhCH2Br
Product (5)
Time (min.)
40
Yield (%)
90a
N
Ph
NH
Ph
1
N
H
N
Ph
1c
COPh
NH
5a
5a
N
N
Ph
2
3
PhCH2Br
PhCH2Br
40
30
88a
85a
Ph
N
Ph
3d
COPh
Ph
N
H
N
Ph
Ph
N
H
N
1a
5b CHO
O2N
4
N
Br
NH
N
20
85a
NO2
N
H
NO2
1a
CHO
5c
N
H
N
5
6
Ph
Br
N
H
1c
60
40
40
85a
862
82b
N
5d COPh
Ph
Ph
N
NH
O
O
PhCH2Br
nBuBr
N
N
H
O
1m
5e
N
N
7
8
Ph
Ph
N
N
H
3m
1c
Ph
N
NH
O
PhCH2Br
40
80c
Ph
Ph
N
H
N
1b
5f
Ph
N
N
9
PhCH2Br
PhCH2Br
40
40
93b
81d
N
3s
NH
1i
O
Ph
Ph
H
H
N
O
O
10
NH
N
O
O
O
N
H
O
O
1l
O
Ph
5g
a 2.2 eq. of alkylating agent was used; b no ring opening product was observed; c 4.5 eq. of benzyl bromide was used;
d two diastereomers in equal ratios were detected by NMR due to racemization of
α
-stereocenter

5
ACCEPTED MANUSCRIPT
R
Br
N
N
50% NaOH
R2
N
or
R1
N
R1
R2
N
H
N
H
or
R1
R1
N
R
N
R
N
SDS (5 mol%)
R2
R= Benzyl, Allyl, butyl,
hexyl, octyl, cetyl, octadecyl
N
H
R1
OH
Scheme 1: Micellar aggregation leading to N-alkylation of Benzimidazoles/imidazoles
As it was well known that the ring opening reactions40-44 in different
complex mixture due to racemization about the chiral center at
C-4 of sugar backbone (α to carbonyl).
carbocycles or heterocycle provide multifunctional entity offering
different levels of practicality for varying applications in
medicinal chemistry or drug discovery. Although acylation
induced imidazole ring opening reaction in nucleic acid
chemistry under different condition was reported long back48-50
but we reasoned that the ring opening of the imidazole moiety in
benzimidazoles under induction of alkyl bromides and aqueous
base might open a simple straight forward route to the synthesis
of functionalized aromatic core which further undergo ring
closing to produce N-heterocycles of complex orientations. So
being inspired by the incidental formation of 5a we looked
forward for the general application of this alkylation induced
ring opening protocol to other benzimidazole substrates. We
then carried out a few more reactions using benzimidazole (1a)
with 2 equivalent of benzyl bromide (entry 3, Table 3) or 2-
nitro benzyl bromide (entry 4, Table 3) at 60oC and the yields
(5b and 5c) were found 85% in both the cases. Again when 2-
phenyl benzimidazole (1c) was allowed to react with allyl
bromide, we obtained ring opening product 5d in 85% yield
(entry 5, Table 3).
To investigate the course of the reaction further we carried out
the reaction using 2-phenyl benzimidazole (1c) or 1-benzyl- 2-
phenyl benzimidazole (3d) with or without benzyl bromide. As
expected without alkylating agent the heterocyclic ring of this
benzimidazole compound was survived (eq. 2 in Scheme 2)
while in the presence of alkylating agent benzyl bromide
alkylation induced ring opening reaction proceed smoothly to
give 5a in 88% of yield (Scheme 2). This observation helped us
to presume that the reaction proceeds by N-alkylation in the first
step followed by the second alkylation induced ring opening of
the benzimidazoles.
N
50% NaOH, 5 mol% SDS
Ph
No reaction.............eq. 1
60oC, 1h
N
H
1c
N
50% NaOH, 5 mol% SDS
No reaction.............eq. 2
Ph
N
N
N
3d
3d
Ph
Ph
NH Ph
..............eq. 3
NCOPh
50% NaOH, 5 mol% SDS
60oC, 1h
PhCH2Br
Ph
5a
Ph
Similar kind of alkylation driven ring opening reaction was also
observed in the case of structurally different benzimidazole
derivative 1m to afforded 5e in 85% yield (entry 6, Table 3).
But the reaction of 2-phenyl benzimidazole with less reactive
butyl bromide (2 equivalent) did not lead to the alkylation
induced ring opening product; rather usual alkylated product N-
butyl-2-phenyl benzimidazole (3m) was obtained in 85% as the
sole product (entry 7, Table 3). A different observation was
noticed when the reaction was carried out with 2-methyl
benzimidazole (1b) and excess benzyl bromide (5 equivalent).
In this case we found N-benzylation induced ring opening as
well as C-benzylation at the methyl group of benzimidazole
(entry 8, Table 3) leading to 5f. The structure of 5f was also
confirmed by 1H, 13C NMR and mass spectral studies. The
formation of 5f is attributed to the fact that the acidic nature of
the methyl group at C-2 enables the formation of the carbanion
in the presence of the base followed by reaction with reactive
benzyl bromide to form tetra-alkylated 5f in 80% yield. Then we
turned our attention to imidazole derivative such as 2-methyl
imidazole using benzyl bromide (2 equivalents) exactly under
the same condition as mentioned for benzimidazole derivatives.
Unfortunately no ring opening product was formed; only N-1-
benzylated imidazole derivative 3s was detected (entry 9, Table
3). The sugar benzimidazole 3l when subjected to ring opening
reaction with 2 equivalent benzyl bromide under identical
condition leads to ring opening product 5g (entry 10, Table 3),
however due to basic nature of the reaction medium results
Scheme 2: Control experiments in alkylation process.
The formation of the micelle aggregation by the surfactants
is stabilized by the Na+ ions at the hydrophilic periphery (shown
in Scheme 1). The reaction thus proceeded by the abstraction of
the acidic proton of the benzimidazole or imidazole by the base
50% NaOH. The anion generated so reacts with the alkyl
bromide present in the medium through the formation of a
hydrophobic pocket and finally releases the N- alkylated product
as shown in Scheme 1. Dynamic light scattering was employed
to investigate the micro structural changes taken place within
the system. Successive measurements were made within a cell
of 3 mL for normalization analysis. The average hydrodynamic
size distribution was found in (i) water-SDS system is 190 nm,
(ii) Water-SDS-substrate and reagent system at room
temperature is 570 nm and (iii) Water-SDS-substrate and
reagent system at 60oC temperature is 718 nm (Figure 2).
Enhancement of size after addition of substrate and reagent
suggested strong interrelations between SDS and substrate
during the reaction. Though the exact mechanism of the reaction
is not certain we believe that the reaction proceeds first by the
abstraction of the –NH proton of 2- substituted benzimidazole
(A) by the base that formed intermediate (B). The reaction with
alkyl bromide then forms mono alkylated derivative (D). The
intermediate (C) cannot be formed as nucleophile OH- is unable
to attack at C-2 due to more negative charge on this center by
delocalization of electrons. As soon as (D) is formed,
nucleophile OH- can attack at C-2 to form (E) under elevated

6
Tetrahedron
ACCEPTED MANUSCRIPT
temperature. Ring opening of (E) to (F) is quite impossible as it
is prevented by negative charge available on neighboring
nitrogen atom. Finally (E) undergoes simultaneous reaction with
second molecule of alkyl bromide on the second nitrogen (G)
followed by C-N bond cleavage leading to the ring opening
product (H). Again no formation of the type (C) or (G) (Scheme
3) was noticed.
alkylated product and without any quaternary ammonium salt
formation. Simultaneously, we have also developed an
operationally convenient method for N-alkylation induced
temperature mediated imidazolium ring opening of the
benzimidazoles by consequent C-N bond cleavage in good
yields without the formation of any unwanted side products.
Generally, the results open
a concise access to rare
pharmaceutically promising compounds, which may be used in
drug design.
N
OH
N
N
N
N
R
R
R
N
H
(C)
(B)
(A)
NOT FOUND
3. Experimental
All reagents were purchased from best-known commercial
R"X
R
OH
N
N
sources and used without further purification unless otherwise
stated. Thin layer chromatography was performed on E-Merck
250 Kieselgel 60 F254 silica gel plates. Silica gel 60-120 or
100-200 mesh size was used for chromatography. The TLC
spots were visualized by UV lamp followed by absorption over
iodine. Melting points were recorded in open capillaries and
were uncorrected. FT-IR spectra were recorded using KBr plates
or in neat. 1H and 13C NMR spectroscopic data were recorded at
300/400 and 75/100 MHz respectively. High-resolution mass
spectra (HRMS) were recorded on a Q-TOF mass spectrometer
using positive electrospray ionization.
N
N
OH
O H
R
R"
(E)
(D)
R"
R"X
R"
N
O
R"
N
H
N
R
R
O H
O
NHR"
R
N
R"
NH
R"
(H)
(G)
alkylation induced
benzimidazole ring opening
(F)
NOT FOUND
Scheme 3: Alkylation induced ring opening of benzimidazoles.
General procedure for N-alkylation of Benzimidazoles and
Imidazoles
To the reaction vessel containing benzimidazole or
imidazole (1mmol), alkyl halide (1 mmol), 50% NaOH (0.5 mL)
and anionic surfactant sodium dodecyl sulfate (5 mol%) was
added and the reaction mixture was vigorously stirred at room
o
temperature or 60 C. After the completion of reaction (TLC)
followed by standard workup using ethyl acetate as extracting
solvent the crude product was purified over silica-gel (60–120
mesh) using ethyl acetate–hexane (3:7) as eluent to afford pure
products. Identities of the products were judged by the
1
comparison of melting point, IR data, H NMR, 13C NMR and
HRMS analyses.
Spectral and analytical data:
1-allyl-benzimidazole(3a):51 Yield 97%, colorless syrup; IR
1
(KBr) νmax 3392, 2923, 1645, 1615, 1495, 1459 cm-1; H NMR
(300 MHz, CDCl3) δ 7.82 (s, 1H, -CH=N), 7.75-7.72 (m, 1H,
aromatic H), 7.31-7.28 (m, 1H, aromatic H), 7.23-7.20 (m, 1H,
aromatic H), 5.99-5.86 (m, 1H, HC=C), 5.21 (d, J = 10.2 Hz,
1H), 5.10 (d, J = 17.1 Hz, 1H), 5.14-5.08 (m, 1H), 4.69 (d, J =
5.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 143.8 (-C=N), 142.9,
133.8, 131.9, 122.9, 122.1, 120.3, 118.6, 109.9, 47.4 (-NCH2).
1-benzyl-benzimidazole (3b):52 Yield 98 %, colorless wax; IR
1
(KBr) νmax 3093, 3031, 2925, 1669, 1614, 1455, 1360 cm-1; H
NMR (300 MHz, CDCl3) δ 7.86 (s, 1H, -CH=N), 7.75 (d, J =
7.8 Hz, 1H, aromatic H), 7.28-7.19 (m, 5H, aromatic H), 7.18-
7.07 (m, 3H, aromatic H), 5.25 (s, 2H, -CH2Ph); 13C NMR (75
MHz, CDCl3) δ 143.9 (C=N-), 143.1, 135.4, 133.9, 129.0,
128.2, 127.0, 123.0, 122.2, 120.4, 110.0, 48.8 (-CH2Ph).
Figure 2: Microstructural changes in the reaction systems
Conclusion
In conclusion, we have developed
a
robust,
1-benzyl-2-methyl benzimidazole (3c):53 Yield 90%, yellowish
wax; IR (CHCl3) νmax 3379, 2925, 1616, 1525, 1453, 1402, 1354
environmentally benign, fast and operationally convenient
method for N-1 alkylation of benzimidazoles/imidazoles in
aqueous micellar condition using sodium dodecyl sulphate
(SDS) as surfactant with exclusive formation of the mono
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.63 (δ, J = 7.2 Hz, 1H,
aromatic H), 7.20-7.09 (m, 6H, aromatic H), 6.95 (t, J = 5.4 Hz,

7
2H, aromatic H), 5.19 (s, 2H, -NCH2), 2.45 (s, 3H, -CH3); 13C
NMR (75 MHz, CDCl3) δ 151.8 (C=N), 142.6, 135.8, 135.5,
129.0, 127.9, 126.2, 122.3, 119.1, 109.3, 47.0 (NCH2), 13.9.
1-benzyl-2-phenyl benzimidazole (3d):54 Yield: 87%, colorless
solid, m. p. 132-134oC; IR (KBr) νmax 3056, 1640, 1558, 1494,
1482, 1362 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 7.8
Hz, 1H), 7.62-7.59 (m, 2H), 7.38-7.34 (m, 3H), 7.25-7.13 (m,
6H), 7.02 (d, J = 7.2 Hz, 2H), 5.37 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 154.1, 143.1, 136.4, 136.0, 129.8, 129.2, 129.0, 128.7,
127.7, 125.9, 123.0, 122.6, 119.9, 110.5, 67.7, 48.3.
143.7, 142.9, 134.5, 122.7, 121.9, 120.3, 109.6, 44.8 (-CH2),
31.8 (-CH2), 19.9 (-CH2), 13.5 (-CH3).
ACCEPTED MANUSCRIPT
1-butyl-2-methyl-benzimidazole (3j):Yield 95 %, yellow
syrup; IR (KBr) νmax 3392, 2934, 1615, 1497, 1459, 1286, 1170
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.62-7.59 (m, 1H, aromatic
H), 7.23-7.13 (m, 3H, aromatic H), 4.01 (t, J = 7.2 Hz, 2H, -
NCH2), 2.53 (s, 3H, -CH3), 1.75-1.65 (m, 2H, -CH2), 1.35-1.27
(m, 2H, -CH2), 0.91-0.86 (t, J = 7.5 Hz, 3H, -CH3); 13C NMR
(100 MHz, CDCl3) δ 151.3, 141.9, 134.9, 122.1, 122.0, 118.8,
109.3, 43.7 (-NCH2), 31.8, 20.2, 13.8, 13.7 (-CH3); HRMS calcd
for C12H16N2 + H+ 189.1393 found 189.1398.
1-butyl-2-phenyl-benzimidazole (3k):Yield 87%, colorless
wax; IR (KBr) νmax 3063, 2959, 1614, 1456, 1330, 1133 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.77-7.74 (m, 1H, aromatic H),
7.65-7.62 (m, 2H, aromatic H), 7.48-7.36 (m, 3H, aromatic H),
7.35-7.24 (m, 1H, aromatic H), 7.23-7.18 (m, 2H, aromatic H),
4.15 (t, J = 7.8 Hz, 2H, -NCH2), 1.77-1.67 (m, 2H, -CH2), 1.26-
1.13 (m, 2H, -CH2), 0.78 (t, J = 7.2 Hz, 3H, -CH3); 13C NMR
(75 MHz, CDCl3) δ 153.6 (C=N), 142.9, 135.5, 130.6, 129.6,
129.2, 128.6, 122.5, 122.2, 119.8, 110.2, 44.4(-NCH2),
31.7(CH2), 19.8(CH2), 13.4(CH3); HRMS calcd for
C17H18N2+H+ 251.1550 found 251.1558.
1-hexyl-benzimidazole (3l): Yield 96 %, colorless syrup; IR
(KBr) νmax 3061, 2960, 2930, 2858, 1615, 1496, 1459, 1382 cm-
1; H NMR (300 MHz, CDCl3) δ 7.8 (s, 1H, -CH=N), 7.74-7.19
(m, 1H, aromatic H), 7.32 (t, J = 8.4 Hz, 1H, aromatic H), 7.25-
7.17 (m, 2H, aromatic H), 4.07 (t, J = 7.2 Hz, 2H, -NCH2), 1.79
(t, J = 6.6 Hz, 2H, -CH2), 1.23 (s, 6H, -CH2), 0.80 (t, J = 6.9 Hz,
3H, -CH3); 13C NMR (75 MHz, CDCl3) δ 143.0 (-C=N-),142.9,
133.7, 122.7, 121.9, 120.3, 109.6, 45.0 (-NCH2), 31.2 (-CH2),
29.7 (-CH2), 26.4 (-CH2), 22.4 (-CH2), 13.9 (-CH3); HRMS
calcd for C13H18N2 + H+ 203.1550 found 203. 1558.
1-benzyl-2, 6-dimethyl-benzimidazole (3e): Yield 87 %,
colorless wax; IR (KBr) νmax 3029, 2923, 1625, 1518, 1452,
1
1399 cm-1; H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 8.1 Hz,
1H), 7.48 (s, 1H, aromatic H), 7.24 (bs, 6H), 7.05-6.97 (m, 8H),
5.20 (s, 4H, -NCH2), 2.49 (s, 3H, CH3), 2.47 (s, 3H), 2.41 (s,
3H, -CH3), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.6,
151.4 (C=N), 142.6, 140.3, 135.8, 135.5, 133.3, 132.1, 131.6,
128.8, 127.7, 126.1, 126.0, 123.6, 123.5, 118.8, 118.5, 109.2,
108.8, 46.9, 46.7(-NCH2), 21.7, 21.4 (-CH3), 13.7(-CH3);
HRMS calcd for C16H16N2+H+ 237.1391 found 237.1402.
1-benzyl-2-propyl-benzimidazole (3f):Yield 88%, colorless
wax; IR (KBr) νmax 3033, 2963, 2931, 1614, 1510, 1496, 1330
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz,1H,
aromatic H), 7.21-7.06 (m, 6H, aromatic H), 6.95 (t, J = 5.7 Hz,
2H, aromatic H), 5.24 (s, 2H, -CH2Ph), 2.72 (t, J = 7.8 Hz, 2H),
1.84-1.72 (m, 2H, -CH2), 0.92 (t, J = 7.5 Hz, 3H, -CH3); 13C
NMR (75 MHz, CDCl3) δ 155.3(C=N), 142.6, 136.0, 135.3,
128.9, 127.8, 126.0, 122.2, 121.9, 119.2, 109.5, 46.8 (-NCH2),
29.4 (-CH2), 21.0 (-CH2), 13.4 (-CH3); HRMS calcd for
C17H18N2+ Na+ 273. 1367 found 273.1368.
1
1-(2-nitrobenzyl)-1H-benzimidazole (3g): Yield 85 %,
o
colorless solid, m. p. 118-120 C; IR (KBr) νmax 2955, 2932,
2865, 1639, 1524, 1425, 1049 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.21- 8.18 (m, 1H), 7.99 (s, 1H), 7.85 (d, J = 8.1 Hz,
1H, aromatic H), 7.49-7.45 (m, 2H, aromatic H), 7.34-7.18 (m,
3H, aromatic H), 6.70-6.67 (m, 1H, aromatic H), 5.8 (s, 2H, -
NCH2); 13C NMR (75 MHz, CDCl3) δ 147.2, 143.8, 143.6,
134.3, 133.7, 131.9, 129.0, 128.1, 125.6, 123.5, 122.7, 120.6,
109.7, 46.0 (-NCH2); HRMS calcd for C14H11N3O2 + H+
254.0931 found 254.0932.
1-octyl-benzimidazole (3m): Yield 96 %, yellow syrup; IR
1
(KBr) νmax 3053, 2929, 2857, 1617, 1495, 1459, 1265 cm-1; H
NMR (300 MHz, CDCl3) δ 7.81 (s, 1H), 7.75-7.72
(m, 1Η), 7.33-7.31 (m, 1H, aromatic H), 7.25-7.20 (m, 2H,
aromatic H), 4.07 (t, J = 6.3 Hz, 2H, -NCH2), 1.79 (m, 2H, -
CH2), 1.24 (m, 10H, -CH2), 0.80 (t, J = 1.8 Hz, 3H, -CH3); 13
C
NMR (75 MHz, CDCl3) δ 143.7, 142.8, 133.8, 122.7, 121.9,
120.2, 109.6, 45.0 (-NCH2), 31.6, 29.7, 29.0, 26.7, 22.5, 14.0 (-
CH3); HRMS calcd for C15H22N2 + H+ 231.1863 found 231.1871.
2-methyl-1-octyl-benzimidazole (3n): Yield 90%, yellowish
1-(2-nitrobenzyl)-2-methyl-benzimidazole (3h): Yield 85 %,
colorless solid, m. p. 120-122oC; IR (KBr) νmax 3066, 2960,
1
1
2929, 2873, 1610, 1529, 1461, 1447 cm-1; H NMR (300 MHz,
oil; IR (KBr) νmax 3389, 2927, 2855, 1616, 1518 cm-1; H NMR
CDCl3) δ 8.17 (t, J = 6.9 Hz, 1H), 7.69 (d, J = 6.9 Hz, 1H),
7.42-7.34 (m, 2H), 7.23-7.10 (m, 2H), 7.04-7.01 (m, 1H), 6.37
(d, J = 6.3 Hz, 1H), 5.68 (s, 2H), 2.46 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 151.8 (C=N), 147.0, 142.6, 135.0, 134.5, 132.0,
128.7, 127.0, 125.6, 122.6, 122.5, 119.3, 109.0, 44.6 (-NCH2),
13.6 (-CH3); HRMS calcd for C15H13N3O2+H+ 268.1088 found
268.1077.
(300 MHz, CDCl3) δ 7.64-7.57 (m, 1H, aromatic H), 7.22-7.10
(m, 3H, aromatic H), 3.99 (t, J = 7.2 Hz, 2H, -NCH2), 2.51 (s,
3H, -CH3), 1.72-1.60 (m, 2H, -CH2), 1.39 -1.17 (m, 10H, -CH2),
0.78 (t, J = 7.2 Hz, 3H, -CH3); 13C NMR (75 MHz, CDCl3) δ
151.3 (-C=N), 142.5, 134.9, 130.8, 128.7, 121.7, 121.6, 118.8,
109.0, 65.4, 43.7 (-NCH2), 31.6, 30.5, 29.6, 29.1, 29.0, 26.8,
22.5, 19.0, 13.9, 13.8 (-CH3), 13.6(-CH3); HRMS calcd for
C16H24N2 + H+ 245.2019 found 245.2021.
1-butyl-benzimidazole(3i):52 Yield 95%, yellow syrup; IR
(KBr) νmax 3392, 3091, 2959, 2934, 1615, 1497, 1459, 1364,
1-hexadecyl-benzimidazole (3o): Yield 98%, colorless wax: IR
(KBr) νmax 3057, 2956, 2853, 1615, 1495, 1459, 1330, 1285 cm-
1
1330, 1286 cm-1, H NMR (300 MHz, CDCl3) δ 7.80 (s, 1H, -
1
1; H NMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 7.75-7.72 (m,
CH=N), 7.75-7.20 (m, 1H, aromatic H), 7.34-7.31 (m, 1H,
aromatic H), 7.25-7.17 (m, 2H, aromatic H), 4.08 (t, J = 7.2 Hz,
2H, -NCH2), 1.83-1.74 (m, 2H, -CH2), 1.34-1.18 (m, 2H, -CH2),
0.87 (t, J = 7.5 Hz, 3H, -CH3); 13C NMR (75 MHz, CDCl3) δ
1H), 7.34-7.31 (m, 1H), 7.25-7.19 (m, 2H, aromatic H), 4.08 (t,
J = 7.2 Hz, 2H, -NCH2), 1.80 (t, J = 6.6 Hz, 2H, -CH2), 1.25-
1.18 (m, 26H, -CH2), 0.87 (t, J = 7.5 Hz, 3H, -CH3); 13C NMR

8
Tetrahedron
ACCEPTED MANUSCRIPT
(75 MHz, CDCl3) δ 142.8, 122.7, 121.9, 120.3, 109.6, 45.1 (-
NCH2), 31.9, 29.8, 29.6, 29.5, 29.4, 29.3, 29.0, 26.8, 22.6 (CH2),
14.0 (CH3); HRMS calcd for C23H38N2 + H+ 343. 3113 found
343. 3117.
1-hexadecyl-imidazole (3p):Yield 96 %, colorless wax; IR
(KBr) νmax 3392, 2924, 2853, 1507, 1466, 1283 cm-1; H NMR
General procedure for N-alkylation induced ring opening of
Benzimidazoles: A mixture of benzimidazole (1mmol), alkyl
halide (2 mmol), 50% NaOH (1mL) and anionic surfactant
sodium dodecyl sulfate (5 mol%) was vigorously stirred at 60
oC. After the complete consumption of starting material (TLC)
followed by standard workthe crude product was purified over
silica-gel (60–120 mesh) using ethyl acetate–hexane as eluent to
afford pure products.
1
(300 MHz, CDCl3) δ 7.37 (s, 1H, -C=NH), 6.96 (s, 1H,), 6.81 (s,
1H), 3.83 (t, J = 6.9 Hz, 2H, -NCH2), 1.68 (m, 2H, -CH2), 1.71
(s, 26H, -CH2), 0.8 (t, J = 6.9 Hz, 3H, -CH3); 13C NMR (100
MHz, CDCl3) δ 137.0, 129.2, 118.8, 47.1 (-NCH2), 31.9, 31.1,
29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 26.5, 22.7 (-CH2), 14.1 (-CH3);
HRMS calcd for C19H36N2 + H+ 293. 2958 found 293. 2925.
1-benzyl-2-methyl-imidazole (3q): Yield 93%, yellowish oil;
N-benzyl-N-(2-(benzylamino) phenyl)benzamide (5a): Yield
90%, colorless solid, m. p. 124-126oC; IR (KBr) νmax 3074,
2923, 1638, 1604, 1517, 1257 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.31- 7.14 (m, 11H), 7.08-6.99 (m, 3H, aromatic H),
6.91 (t, J = 7.5 Hz, 2H, aromatic H), 6.57(d, J = 7.5 Hz, 1H,
aromatic H), 6.37 (d, J = 5.4 Hz, 2H, aromatic H), 4.97(d, J =
13.8 Hz, 1H, -CO-NCH2Ph), 4.79 (d, J = 13.8 Hz, 1H, -CO-
NCH2Ph), 4.09-3.98 (m, 3H, -NHCH2Ph + -NH); 13C NMR (75
MHz, CDCl3) δ 171.5, 143.8, 138.7, 137.3, 135.6, 130.0,129.7,
129.3, 128.8, 128.5, 128.4, 128.2, 127.8, 127.6, 127.4, 127.1,
127.0, 116.9, 111.5, 52.2 (-CO-NCH2Ph), 47.5 (-NHCH2Ph);
HRMS calcd for C27H24N2O + H+ 393.1969 found 393.1979.
N- benzyl- N-(2- (benzylamino) phenyl) formamide (5b):
Yield 82%, colorless solid, m.p. 108-110oC; IR (KBr) νmax
IR (KBr) νmax 3398, 2961, 1641, 1559, 1498, 1283 cm-1; H
1
NMR (300 MHz, CDCl3) δ 7.31-7.21 (m, 3H), 7.01-6.98 (m,
2H), 6.91 (s, 1H), 6.78 (s, 1H), 4.99 (s, 2H, -NCH2), 2.29 (s, 3H,
-CH3); 13C NMR (100 MHz, CDCl3) δ 144.9, 136.2, 129.0,
128.0, 126.9, 126.7, 119.9, 49.8 (-NCH2), 12.9 (-CH3); HRMS
calcd for C11H12N2+H+ 173.1080 found 173.1079.
1-allyl-2,4,5-triphenyl-imidazole(3r):Yield 80%, colorless
wax; IR (KBr) νmax 3064, 2924, 1648, 1602, 1481, 1453, 1396,
1284, 1256 cm-1; H NMR (300 MHz, CDCl3) δ 7.68-7.65 (m,
1
3382, 2928, 2858, 1670, 1604, 1456, 1196 cm-1; H NMR (300
1
2H), 7.48-7.45 (m, 2H, aromatic H), 7.41-7.30 (m, 8H, aromatic
H), 7.17-7.05 (m, 3H, aromatic H), 5.70-5.07 (m, J = 6 Hz, 1H),
5.07-5.04 (m, 1H), 4.81-4.40 (t, J = 17.1 Hz, 1H, -CH=CH2),
4.38 (t, J = 2.1 Hz, 2H, -CH2); 13C NMR (75 MHz, CDCl3) δ
147.7, 137.8, 134.5, 133.8, 131.1, 130.9, 129.8, 129.0, 128.8,
128.7, 128.5, 128.0, 126.8, 126.2, 117.0, 116.0, 46.8 (-NCH2);
HRMS calcd for C24H20N2 + H+ 337.1706 found 337. 1716.
1-allyl-2-(2-(allyloxy) phenyl)-4,5-diphenyl-imidazole (3s):
Yield 75 %, yellowish syrup; IR (KBr) νmax 3063, 2932, 1602,
1501, 1479, 1449, 1394, 1326 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.50-7.36 (m, 3H, aromatic H), 7.35-7.21 (m, 6H,
aromatic H), 7.17-6.96 (m, 4H, aromatic H), 6.88 (d, J = 9Hz,
1H, aromatic Η), 5.97-5.91 (m, 1H), 5.5-5.39 (m, 1H), 5.28-
5.12 (q, J = 14.7 Hz, 2H, CH=CH2), 4.80-4.76 (d, J = 9.9 Hz,
1H), 4.5-4.47 (m, 3H), 4.27-4.20 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 156.4 (C=N), 145.2, 133.5, 132.9, 132.7, 131.5, 131.0,
130.7, 129.2, 128.8, 128.5, 127.9, 126.7, 126.0, 121.2, 116.9,
116.3, 112.7, 69.1 (-OCH2), 46.8 (-NCH2), 29.6 (-CH2). HRMS
calcd for C27H24N2O+H+ 393.1967 found 393.1967.
MHz, CDCl3) δ 8.57 (s, 1H, -CHO), 7.50-7.23 (m, 8H), 7.16 (m,
3H), 6.83-6.76 (m, 1H), 6.64-6.59 (m, 2H, aromatic H), 4.8 (s,
2H, -NCH2Ph), 4.18 (t, J = 5.4 Hz, 2H, -NHCH2Ph), 4.04 (d, J =
5.1Hz, -NH); 13C NMR (75 MHz, CDCl3) δ 163.8, 145.0,
138.4, 136.8, 129.8, 129.2, 128.7, 128.6, 127.9, 127.2, 127.0,
125.6, 117.1, 111.8, 48.0 (CO-NCH2Ph), 47.7 (NHCH2Ph);
HRMS calcd for C21H20N2O + H+ 317.1656 found 317.1650.
N-(2-nitrobenzyl-N-(2-(2-nitrobenzylamino)phenyl)
formam- ide (5c): Yield 70%, yellowish solid, m. p. 140-
142oC; IR (KBr) νmax 3384, 2939, 1673, 1606, 1523, 1146 cm-1;
1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H, CHO), 8.07- 7.99
(m, 1H, ), 7.87-7.85 (d, J = 8.1 Hz, 1H), 7.59 - 7.39 (m, 6H),
7.12 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.45 (d, J =
8.1 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 5.23 (s, 2H), 4.66 (s, 2H);
13C NMR (75 MHz, CDCl3) δ 164.0, 149.2, 148.1, 144.2, 134.2,
133.8, 133.3, 131.4, 131.1, 130.2, 129.4, 129.2, 128.7, 128.2,
125.2, 124.8, 124.7, 117.7, 111.9, 45.1, 44.4; HRMS calcd for
C21H18N4O5+H+ 407.1355 found 407.1347.
N-allyl-N-(2-(allylamino)phenyl)benzamide (5d): Yield 85%,
yellowish oil; IR (KBr) νmax 3079, 2925,1634, 1604, 1519 cm-1;
1H NMR (300 MHz, CDCl3) δ 7.46- 6.98 (m, 7H), 6.70- 6.67 (d,
J = 6.6 Hz, 1H), 6.55- 6.52 (d, J = 7.8Hz, 1H), 6.43 (t, J = 7.2
Hz, 1H), 6.06-6.00 (m, 1H, = CH), 5.99- 5.79 (m, 1H, = CH),
5.19-5.06 (m, 4H, -NCH2), 4.56- 4.49 (m, 1H), 4.26 - 4.20(m,
1H), 4.07- 4.00 (m, 1H), 3.78- 3.75 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 171.5, 143.5, 135.5, 134.7, 132.8, 130.0. 129.9,
128.8, 127.7, 127.5, 118.8, 116.8, 116.5, 111.5, 51.5, 45.9, 45.8;
HRMS calcd for C19H20N2O + H+ 293. 1654 found 293. 1663.
N-Benzyl-N-(2-(benzylamino)phenyl)-2-butoxybenzamide
(5e): Yield 86%, colourless solid, m.p 128-130oC, IR (KBr) νmax
1-Benzyl-2-[(2S, 3R, 4R, 5R)-4-allyloxy-tetrahydrofurano]
benzi-midazole (3t): Yield 82%, nature yellowish syrup, IR
1
(neat) νmax 3040, 2990, 2936, 1613, 1517, 1463, 1162 cm-1; H
NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8 Hz, 1H), 7.25- 7.16
(m, 8H), 6.08 (d, J = 3.6 Hz, 1H), 5.95 (d, J = 12.3 Hz, 1H),
5.82 (d, J = 3.2 Hz, 1H), 5.64 -5.55 (m, 1H), 5.30 -5.25 (t, 1H),
5.08 - 4.98 (m, 2H), 4.71 (d, J = 4 Hz, 1H), 4.31(d, J = 4 Hz,
1H), 3.84-3.79 (m, 1H), 3.67-3.62 (m,1H), 1.58 (s, 3H), 1.37 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 148.5, 142.1, 136.9, 136.1,
133.4, 128.6, 127.4, 126.8, 122.8, 122.3, 119.6, 117.8, 112.3,
110.6, 104.9, 84.3, 82.8, 79.3, 71.4, 49.0, 26.8, 26.3; HRMS
calcd for C24H26N2O4 406.1893 found HRMS calcd for
C24H26N2O4 + H+ 407.1973 found 407.2111.
1
3063, 2959, 2936, 1644, 1605, 1521, 1324 cm-1; H NMR (400
MHz, CDCl3) δ 7.53- 7.25 (m, 10H), 7.18- 7.08 (m, 4H), 7.01-
6.94 (m, 1H), 6.92-6.38 (m, 3H), 6.37 (d, J = 7.2 Hz, 1H),

9
10 Handa S, Fennewald JC, Lipshutz BH, Angew. Chem., Int.
5.28 (d, J = 13.6 Hz, 1H), 4.74 (d, J = 14. 4 Hz, 1H), 4.15 (s,
2H), 3.86 (t, J = 6.4 Hz, 2H), 1.74-1.58 (m, 2H), 1.50-1.41 (m,
2H), 0.98 (t, J = 7.2Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.2, 154.8, 144.0, 138.9, 137.6, 130.6, 129.8, 129.5, 129.2,
128.9, 128.6, 128.5, 128.3, 128.2, 127.6, 127.4, 127.2, 127.0,
126.6, 126.5, 119.5, 116.2, 111.5, 111.1, 68.2, 67.9, 51.0, 47.6,
31.3, 19.2, 13.9; HRMS clcd for for C31H32N2O2+H+ 465.2544
found 465.2542.
ACCEPTED MANUSCRIPT
Ed. 2014; 53: 3432–3435.
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N,2-dibenzyl-N-(2-(benzylamino)phenyl)-3-phenylpropan-
o
amide (5f):Yield 80%, colorless solid, m. p. 108-110 C; IR
1
(KBr) νmax 3067, 3027, 2922, 2939, 1651, 1602, 1514 cm-1; H
NMR (300 MHz, CDCl3) δ 7.21- 6.96 (m, 19H, aromatic H),
6.86-6.83 (m, 2H, aromatic H), 6.43 (d, J = 7.5 Hz, 1H,
aromatic H), 6.36-6.31 (m, 1H), 5.74-5.71 (dd, J = 7.8, 1.5 Hz,
1H), 4.87 (d, J = 13.8 Hz, 1H, -CO-NCH2Ph), 4.49 (d, J = 13.5
Hz, 1H, -CO-NCH2Ph), 3.84 (t, J = 6.3 Hz, 2H, -NHCH2Ph),
3.44 (d, J = 5.1 Hz, 1H, -NH), 3.08-2.91 (m, 2H), 2.75- 2.60 (m,
1H), 2.58-2.51(m, 2H); 13C NMR (75 MHz, CDCl3) δ 175.7,
143.9, 140.0, 139.5, 138.7, 137.4, 129.9, 129.3, 128.5, 128.3,
128.2, 127.4, 127.0, 126.9, 126.6, 116.8, 111.4, 51.1, 47.6, 38.7;
HRMS calcd for C36H34N2O+H+ 511.2749 found 511.2721.
(3R, 6R, 6R)-6-(allyloxy)-N-benzyl-N-(2-(benzylamino)-
phenyl)-tetrahydro-2,2-dimethylfuro[2,3-d][1,3]dioxole-5-
carboxamide (5g, 1:1 mixture of two epimer): Yield 85%,
yellowish syrup, IR (neat) νmax 3063, 2955, 1654, 1603, 1521,
26 Varma RS, Namboodiri VV. Pure Appl. Chem. 2001; 73: 1309–
1313.
1
1327, 12471cm-1; H NMR (400 MHz, CDCl3) δ 7.40-7.11(m,
14H), 6.69-6.55 (m, 3H), 5.95 (d, J = 5.2 Hz,0.5H), 5.86 (d, J =
5.2 Hz, 0.5H), 5.17-5.12 (m, 2H), 5.03-5.01 (d, J = 6.5 Hz,
0.5H), 4.99-4.98 (d, J = 6.4 Hz, 0.5H), 4.71-4.70 (m, 1H), 4.23-
4.12 (m, 3H), 1.44- 1.38 (s, 1.5H), 1.36 (s, 1.5H), 1.27 (s, 1.5H),
1.24 (s, 1.5H); 13C NMR(100 MHz, CDCl3) 162.10, 162.07,
152.5, 152.2, 144.5, 144.4, 138.7, 138.6, 136.6, 136.5, 132.9,
129.9, 129.8, 129.7, 129.6, 129.5, 128.7, 128.5, 127.9, 127.3,
127.2, 127.1, 127.0, 126.9, 126.6, 126.4, 117.4, 112.6, 112.5,
111.9, 111.8, 106.0, 105.7, 105.4, 83.2, 77.2, 52.2, 47.7, 44,6,
31.9, 29.7, 29.3, 27.8, 27.7.
27 Varma RS, Namboodiri, VV. Chem. Commun. 2001; 7: 643–
644.
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Acknowledgements
35 Kommi DN, Kumar D, Bansal R, Chebolu R, Chakraborti, AK.
Green Chem. 2012; 14: 3329-3335.
36 Chebolu R, Kommi DN, Kumar D, Bollineni N, Chakraborti
AK. J. Org. Chem. 2012; 77: 10158-10167.
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Financial supports by DST-SERB), Govt. of India is gratefully
acknowledged (Project no. EMR/2016/001537). One of the
authors (A. C.) is thankful to DST, Govt. of India for providing
DST-INSPIRE research fellowship. We are also thankful to
DST, Govt, of India for providing 400 MHz, NMR through
DST-FIST fund (No. SR/FST/CS1-263/2015) and CIC, Tripura
University for instrumental facilities.
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Tetrahedron
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