Synthesis of N-alkoxy-substituted 2H-benzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2017.11.007

Treatment of 2-nitro-N-(2-methyl-1-propen-1-yl)benzenamines with potassium tert-butoxide in tert-butanol followed by the addition of an electrophile affords N-alkoxy-2H-benzimidazoles. Electrophiles including methyl iodide, allylic bromides, propargylic bromides, benzyl bromide, and acetyl chloride gave good to excellent yields of product while 1-iodo- and 2-iodo-butane afforded very low yields.

Full text of DOI:10.1016/j.tetlet.2017.11.007

Accepted Manuscript
Synthesis of N-alkoxy-substituted 2H-benzimidazoles
Nurul H. Ansari, Björn C.G. Söderberg
PII:
S0040-4039(17)31401-6
https://doi.org/10.1016/j.tetlet.2017.11.007
TETL 49450
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
27 September 2017
26 October 2017
5 November 2017
Please cite this article as: Ansari, N.H., Söderberg, B.C.G., Synthesis of N-alkoxy-substituted 2H-benzimidazoles,
Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.11.007
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Synthesis of N-alkoxy-substituted 2H-benzimidazoles
Nurul H. Ansari and Björn C. G. Söderberg*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West
Virginia 26506-6045, United States
Graphical Abstract
Research highlights
► A synthetic methodology to N-alkoxy-2H-benzimidazoles was developed.
►
Enamines derived from condensation of 2-nitroanilines and aliphatic aldehydes were cyclized
under basic conditions were used as starting materials.
►
The alkoxy-group could be varied by the use of different reactive organic halides.
ABSTRACT Treatment of 2-nitro-N-(2-methyl-1-propen-1-yl)benzenamines with
potassium tert-butoxide in tert-butanol followed by the addition of an electrophile affords
N-alkoxy-2H-benzimidazoles. Electrophiles including methyl iodide, allylic bromides,
1

propargylic bromides, benzyl bromide, and acetyl chloride gave good to excellent yields of
product while 1-iodo- and 2-iodo-butane afforded very low yields.
1. Introduction N-alkoxy- and N-hydroxy-benzimidazoles have been shown to exhibit a
number of biological activities such as, acting as a growth inhibitor of Lactobacillus
leichmanii1 and influenza virus,2 inhibition of bacterial transcriptase factors,3 and anti-HIV-
1 activity.4 Only two general methods for the preparation of N-alkoxybenzimidazoles can
be found in the literature. The first method involves a direct alkylation of N-
hydroxybenzimidazole, or its tautomer 1H-benzimidazole-3-oxide, and this procedure has
been used to prepare, for example, N-methoxy, N-ethoxy and N-allyloxybenzimidazole.5
The second method reported by Gardiner et al is perhaps the most versatile synthesis of N-
alkoxybenzimidazoles and it involves a base-mediated reaction of 2-nitroanilines in the
presence of an alkyl halide (Scheme 1).6 A potential drawback is the formation of mixtures
of N-alkylated anilines and N-alkoxybenzimidazoles observed in many cases. In addition,
only a single case of an N-alkoxy-2H-benzimidazole was described.
Scheme 1
Gardiner et al synthesis of 1-methoxy-4-methylbenzimidazole.
We have recently developed a base-mediated cyclization-alkylation of 2-nitroaniline-
derived enamines to afford N-alkoxy-substituted benzimidazoles having an oxygenate side
chain in the 2-position.7 By simply changing the amount of base and electrophile used,
2

either a hydroxy or an alkoxy substituent could be introduced on the side chain. For
example, treatment of enamine 1 with 2.0 equivalents of sodium hydride (NaH) in DMSO at
ambient temperature followed by addition of 1.05 equivalents of methyl iodide (MeI) gave
after purification N-methoxybenzimidazole 2 (Scheme 2). When the amounts of both NaH
and MeI were increased to 3.15 equivalents, N-methoxybenzimidazole 3 was isolated in
good yield. In both reactions a very minor amount of N-methoxy-2H-benzimidazole 4 was
either isolated or observed in the crude reaction mixture. While optimizing the reaction
conditions for a divergent synthesis of either 2 or 3, we found conditions wherein 4 was
selectively formed (Scheme 2). Thus, reaction of 1 with potassium tert-butoxide in tert-
butanol for 24 h followed by addition of methyl iodide gave 4 in 76% yield after
chromatographic purification.
Scheme 2
Cyclization of enamine 1 to give either N-methoxybenzimidazole 2 or 3.
1
1) 2.0 equiv. NaH, 1 h, RT
2 (74%)
2 (-)
3 (-)
4 (2%)
2) 1.05 equiv. MeI, 1 h, 0 oC - RT
1) 3.5 equiv. NaH, 1 h, RT
2) 3.5 equiv. MeI, 1 h, 0 oC - RT
3 (71%)
3 (-)
4 (trace)
4 (76%)
1) 4 equiv. tert-BuOK/tert-BuOH, 24 h, RT
2 (-)
2) 3 equiv. MeI, 1 h, RT
3

Herein we report the scope and limitations of the formation of N-alkoxy-2H-
benzimidazoles from reactions of enamines, derived from condensation of 2-nitroanilines
with -branched aldehydes, with reactive carbon-centered electrophiles.
2. Results and Discussion
Fifteen enamines (1, 5–18, Table 1) were prepared via condensation of 4- and 5-
substututed 2-nitroanilines with 2-methylpropanal, 2-phenylpropanal, 2-
cyclohexylethanal, and 2,2-diphenylethanal in the presence of 4 Å molecular sieves, as
previously described.7 The base-mediated transformation of enamines to afford N-alkoxy-
2H-benzimidazoles is limited by the availability of the starting material. It should be noted
that we were unable to prepare enamines in synthetically useful yields from 3- or 6-
substituted 2-nitroanilines even under more forced reaction conditions.
All enamines were treated with tert-BuOK in tert-BuOH followed by the addition of MeI
under the reaction conditions depicted in Scheme 2. The expected cyclization-alkylation
products, N-methoxy-2H-benzimidazoles, were obtained in all but one case in 51-100%
isolated yield. Cyclization-alkylation of both enamines having an electron-withdrawing
ester (10) or nitro (11) group failed under the standard reaction conditions (entries 7 and
9). However, the ester-substituted enamine 10 was transformed to the corresponding N-
methoxy-2H-benzimidazoles 24 in god isolated yield using sodium hydride – MeI in
dimethylsulfoxide as described previously. No conditions were found for the cyclization of
11, neither the starting material nor any identifiable product was isolated.
4

Table 1
Formation of N-methoxybenzimidazoles from 2-nitro-N-(2-methyl-1-propen-1-
yl)benzenamines and methyl iodide.
Entry
Enaminea
Methoxybenzimidazoleb
1
5 (R=H)
19 (100%)
4 (76%)
2
1 (R=4-OMe)
6 (R=4-Me)
7 (R=4-Cl)
3
20 (76%)
21 (92%)
22 (85%)
23 (67%)
(not observed)
24 (74%)
(not observed)
25 (85%)
26 (71%)
27 (71%)
28 (73%)
4
5
8 (R=4-Br)
9 (R=4-F)
6
7
10 (R=4-CO2Me)
10c
8
9
11 (R=4-NO2)
12 (R=5-OMe)
13 (R=5-Me)
14 (R=5-Cl)
15 (R=5-Br)
10
11
12
13
14
16
22 (94%)
15
16
17
18
4 (76%)
4 (78%)d
a) A solution of the enamine in tert-BuOH was treated with tert-BuOK (4 equiv.) stirred for 24 h then treated
with MeI (3 equiv.) b) Isolated yield of pure product after chromatography on silica gel. c) A solution of 10 in
DMSO was treated with NaH (5 equiv.) stirred for 24 h then treated with MeI (5 equiv.) as described in
reference 7. d) Benzophenone was also isolated in 97% yield.
6

The scope and limitation of the electrophile was examined next using enamine 1 as the
substrate and the results are summarized in Table 2. For all entries in Table 2, 1 was
treated with potassium tert-butoxide for 24 h followed by the addition of an electrophile.
High yields of N-alkoxy-2H-benzimidazoles were obtained using benzyl bromide, allyl
bromide and 2-methyl-3-bromopropene affording 29-31, respectively (entries 1-3). A
54% yield of N-acetoxy-2H-benzimidazole (34) was obtained using acetyl chloride while
heptyl bromide, butyl iodide and 2-iodopropane gave cyclization products in low isolated
yields. The two propargylic bromides employed in entries 4-5, 3-bromo-1-propyne and 3-
bromo-1-butyne, afforded allenes by an SN2’ reaction albeit, in low yields (entries 4-5).
Based on the results shown in Tables 1-2, synthetically useful yields are obtained only from
reactions of highly reactive alkylating reagents such as methyl iodide, benzyl bromide, and
allylic bromides. Our observations parallels Gardiner’s results where lower yields of
product were isolated from reactions with hindered and less reactive electrophiles such as
2-methyl-1-iodopropane compared to primary iodides, benzylic bromides, allyl bromide.6
7

Table 2
Base mediated formation of N-alkoxy-2H-benzimidazoles from enamine 1.
Entry
Enaminea
Electrophile
Benzimidazoleb
1
2
3
4
5
6
7
8
9
1
Benzyl bromide
Allyl bromide
29 (82%)
30 (100%)
2-Methyl-3-bromopropene 31 (90%)
3-Bromo-1-propyne
3-Bromo-1-butyne
Acetyl chloride
32 (15%, R=-CH=C=CH2)
33 (12%, R=-CH=C=CHCH3)
34 (54%)
1-Bromoheptane
1-Iodobutane
35 (16%)
36 (15%)
2-Iodopropane
37 (8%)
a) A solution of the enamine in t-BuOH was treated with t-BuOK (4 equiv.), stirred for 24 h then treated with
an electrophile (3 equiv.) b) Isolated yield of pure product after chromatography on silica gel.
The transformation presented above affording N-alkoxy-2H-benzimidazoles can
mechanistically be rationalized as follows. Deprotonation of 5 would afford 38, one of
several possible resonance forms (Scheme 3). 1,7-Electrocyclization of 38 would furnish
39, followed by a ring opening to form the nitroso-imine 40. The two latter steps results in
an overall intramolecular reduction – oxidation. 1,5-Electrocyclization of 40 to give 41 is
plausible based on literature precedence.8 Aromatization of intermediate 41 via loss of
acetone would furnish anion 42 which can finally be alkylated to give an N-alkoxy-2H-
benzimidazole 43. The mechanism outlined in Scheme 3 is supported by a limited number
of related transformations described in the literature.9,10,11 Based on the mechanism
outlined, not only is an N-alkoxy-2H-benzimidazole formed but also acetone as a biproduct.
8

While acetone (entries 1-13), acetophenone (entry 14), or cyclohexanone (entry 15) were
not isolated from the reactions depicted in Table 1, an almost quantitative yield of
benzophenone was obtained from 19 (entry 16). Neither of the three former byproducts
were recovered after chromatographic purification. This is probably due to evaporative
loss upon removal of solvents.
Scheme 3
Proposed mechanism for the formation of N-alkoxy-2H-benzimidazoles.
38
39
40
41
42
43
Summary
N-Alkoxy-2H-benzimidazoles can be prepared from enamines derived from condensation
of 4- or 5-substituted 2-nitroanilines and -branched aliphatic aldehydes via a base
mediated cyclization-alkylation sequence using potassium tert-butoxide and a reactive
electrophile.
9

Supporting Information
Supplementary information associated withthis article including all experimental
procedures and 1H and 13C NMR spectra of all novel compounds can be found in the
online version, at http://dx.doixxxxxxxxx
Acknowledgements
We gratefully acknowledge the C. Eugene Bennett Department of Chemistry and funding
from the National Institutes of Health (1 R15 GM122002-01) for support. The National
Science Foundation-MRI program is also gratefully acknowledged for the funding of a 400
MHz NMR system (CHE-1228366). The authors would like to thank Dr. Gregory Donohoe
and Dr. Mahdiar Khakinejad for HRMS analyses.
10

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11

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