Accessing Benzimidazoles via a Ring Distortion Strategy: An Oxone Mediated Tandem Reaction of 2-Aminobenzylamines

Article abstract of DOI:10.1021/acs.orglett.6b01217

An exceptional oxone mediated tandem transformation of 2-aminobenzylamines to 2-substituted benzimidazoles is reported. It occurs at room temperature with aromatic, heteroaromatic, and aliphatic aldehydes. In this reaction initial condensation of 2-aminobenzylamine with appropriate aldehydes afforded a tetrahydroquinazoline intermediate which underwent oxone-mediated ring distortion to afford the desired compounds in moderate to excellent yields.

Full text of DOI:10.1021/acs.orglett.6b01217

Letter
pubs.acs.org/OrgLett
Accessing Benzimidazoles via a Ring Distortion Strategy: An Oxone
Mediated Tandem Reaction of 2‑Aminobenzylamines
Santanu Hati, Pratip Kumar Dutta, Sanjay Dutta, Parthapratim Munshi, and Subhabrata Sen*
Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Chithera, Dadri, Gautam Buddha Nagar,
UP 201314, India
*
S Supporting Information
ABSTRACT: An exceptional oxone mediated tandem transformation of 2-aminobenzylamines to 2-substituted benzimidazoles is
reported. It occurs at room temperature with aromatic, heteroaromatic, and aliphatic aldehydes. In this reaction initial condensation
of 2-aminobenzylamine with appropriate aldehydes afforded a tetrahydroquinazoline intermediate which underwent oxone-mediated
ring distortion to afford the desired compounds in moderate to excellent yields.
enzimidazole, a pharmaceutically relevant moiety, is present
Scheme 1. A Summary of Available Methods and Our
Synthesis of 2-Substituted Benzimidazole
B
in a plethora of biologically active natural products and
1
active pharmaceutical ingredients. They are successfully
implemented as antimicrobial compounds, anthelmintic and
2−8
antipsychotic drugs, and antiulcer and anticancer agents.
Owing to their intriguing biological properties, attention has
been focused toward the synthesis of these molecules. In general
the available syntheses are divided into two groups. The classical
strategy, involving the construction of the basic scaffold via
condensation followed by oxidative cyclization of benzene-1,2-
diamine with appropriate carbaldehydes or its derivatives
(
Scheme 1, pathway a), required strong acidic conditions and
9
high temperatures. A few noteworthy modern strategies
encompass oxidative cyclization of carbaldehydes and its de-
rivatives with solids support benzene-1,2-diamine (Scheme 1,
pathway b), cross-coupling based C−N bond formation of
aromatic halides followed by transition metal catalyzed aromatic
C−H activation (Scheme 1, pathway c), iodobenzene catalyzed
C−H amination of N-substituted amidines (Scheme 1, pathway d),
and cascade arylamination/condensation of o-haloaryl amides
viz. SeO , KMnO , NBS, and oxone were applied. The majority
2
4
of them afforded the desired dihydroisoquinoline and aromatic
isoquinolines. Interestingly, reaction monitoring of the oxone
mediated transformation through LCMS (liquid chromatog-
raphy mass spectroscopy) revealed a different product which
was isolated and upon complete characterization was identified
to be the 2-substituted benzimidazole 1a (Scheme 1, pathway f).
Herein we report this unprecedented synthesis of 2-substituted
benzimidazoles under oxone in dimethylformamide (DMF) and
water at room temperature (rt). Mechanistically the reaction
proceeds via a tetrahydroquinazoline intermediate that under-
went ring distortion in the presence of oxone to generate the
10−13
(Scheme 1, pathway e).
Recently, Jui et al. reported an
efficient synthesis of N-arylbenzimidazoles by harnessing cascade
14
palladium catalysis. Unfortunately, many of these methodol-
ogies are plagued with limitations, such as harsh reaction condi-
tions and low yields (due to the formation of several byproducts).
Consequently strategies under mild reaction conditions with
stable reactants and amenable reagents are desirable for the
prudent synthesis of benzimidazoles. In one of our recent
projects we devised a one-pot synthesis of aromatic quinazolines
by condensation of o-aminobenzylamine with various aldehydes
followed by in situ oxidative dehydrogenation of the tetrahydro-
hydroquinazoline intermediate with IBX (2-iodoxybenzoic acid)
Received: April 26, 2016
15
(
Scheme 1, pathway g). During this study, a variety of oxidants
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01217
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Organic Letters
Letter
benzimidazoles (1a−y). The generic utility of this procedure
was demonstrated in the synthesis of a variety of 2-substituted
benzimidazoles in moderate to excellent yield. A mechanistic
pathway is proposed along with control experiments that
supported the putative mechanism.
To begin with, 2-aminobenzylamine (1 equiv) and benzalde-
hyde (1 equiv) were reacted in the presence of oxone (1 equiv)
at room temperature (rt), in DMF (10 mL) and water (0.2 mL)
to afford the desired benzimidazole in 3 h in a moderate yield
of 62% (Table 1, entry 1) along with the formation of
tetrahydroquinazoline A as the minor product. Exploring the
reaction in various polar solvents such as dimethyl sulfoxide
(DMSO) (Table 1, entry 2), 1, 4-dioxane (Table 1, entry 3), iso-
propanol (Table 1, entry 4), and acetonitrile (Table 1, entry 5)
did not improve the yield further (58−28%). To improve the
efficiency of this transformation we investigated the reaction in
the presence of catalytic oxone. Executing the reaction with
0.1 equiv of oxone (Table 1, entry 6) resulted in the formation
of 64% of A after 72 h, with no generation of the desired
benzimidazole. The gradual increase of oxone by 0.1 equiv
improved the yield only after 0.3 equiv, and the best outcome
was obtained with 0.6 equiv, which furnished 1a in 72% isolated
yield in 8 h. Any further increase of the ratio of oxone did not
improve the yield of 1a. Hence the optimized conditions for
this transformation consisted of reacting 2-aminobenzylamine
Table 1. Reaction Optimization of the Synthesis of
Benzimidazoles from 2-Aminobenzylamine and
Benzaldehyde
a
yield (%)
(
(
1 equiv) with benzaldehyde (1 equiv) in the presence of oxone
0.6 equiv) with DMF (10 mL) and water (0.2 mL) at rt.
Having optimized the reaction protocol, we focused our
no.
solvents
Oxone (equiv)
time (h)
1a
62
A
1
2
3
4
5
6
7
8
9
DMF
DMSO
dioxane
IPA
ACN
DMF
″
″
″
″
1
6
12
10
12
08
12
64
51
42
21
ND
ND
″
″
″
″
0.1
0.2
0.3
0.4
0.5
0.6
7
58
attention on exploring the scope of our strategy with a variety
of substituted o-aminobenzylamines and aromatic, hetero-
aromatic, and aliphatic aldehydes. The results are depicted in
Scheme 2. The reaction with quinoline-2-aldehyde afforded
the corresponding product 1l in excellent yield (82%), but
5.5
6
42
28
8
34
72
70
46
14
12
8
ND
ND
14
4
-bromothiophene-2-carbaldehyde furnished 1m in moderate
yield (58%). Perhaps the presence of bromo-functionality in the
thiophene interfered during the reaction that resulted in low
yields. In general the monosubstituted aromatic aldehydes with
electron-donating functionalities such as 3-anisaldehyde and
2- and 4-tolylaldehyde afforded the desired products 1b, c, and
j in good yields (74 → 84%). Interestingly electron-donating
28
1
1
0
1
44
″
72
a
b
Isolated yield. Solvent (10 mL), oxone, water (0.2 mL), room
temperature. DMSO: dimethyl sulfoxide; IPA: isopropyl alcohol;
ACN: acetonitrile; DMF: dimethylformamide; ND: not detected.
a
Scheme 2. Scope of the Tandem Reaction of 2-Aminobenzylamine with a Variety of Aldehydes
a
The isolated yield is furnished.
B
DOI: 10.1021/acs.orglett.6b01217
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Organic Letters
Letter
disubstituted or trisubstituted aromatic aldehydes provided
slightly better yields of 59 → 94% for the products 1e, i, k, o,
and q (Scheme 2) over the monoanalogs. The aldehydes with
electron-withdrawing functionalities afforded the benzimida-
zoles 1d, f, g−h, and n in moderate yields of 45−67%. The only
aliphatic analog 1r was synthesized in 71% yield (Scheme 2).
Conversion of various substituted o-aminobenzylamines with
different aldehydes resulted in the formation of the desired
benzimidazoles (1s−1y) in 18−81% yield. 3-Nitro-2-amino-
benzylamines afforded the corresponding benzimidazoles
retro-aldol type reaction to provide dihydrobenzimidazole
intermediate G. G undergoes further oxidation to afford the
desired 1a.
To garner support for this mechanism, a reaction in the
presence of radical scavenger TEMPO furnished 1a in
substantially reduced yield (24% along with 40% of A)
(
Scheme 3b(1)). The reaction when conducted under dry
conditions provided A in quantitative yield (Scheme 3b(2)).
Similarly A was obtained exclusively in the absence of any
oxidant (Scheme 3b(3)). In a separate experiment, A was
isolated and subjected to the optimized reaction conditions, to
afford 1a in 68% yield (Scheme 3b(4)).
1u−v in low yields (18 and 26% respectively) which can be
rationalized by poor formation of the corresponding tetrahy-
droquinazoline intermediates. The benzimidazole structure was
further confirmed by single crystal X-ray diffraction studies on
There is evidence of oxone mediated oxidative bond cleavage
and Hofmann rearrangement of carboxamides to carbamates in
the literature. Those examples along with oxidation of aniline
for the formation of Mauvien inspired us to propose this
1
1
q (Scheme 2). To demonstrate the scalability of the process,
a was synthesized on the 5 g scale at 68% yield (refer to
16
mechanism.
Supporting Information (SI)).
In summary, we have demonstrated an oxone mediated facile
tandem reaction of various substituted 2-aminobenzylamines
with different aldehydes to furnish 2-substituted benzimida-
zoles. To the best of our knowledge, it constitutes the first
example of such a ring distortion strategy toward benzimida-
zole synthesis. The reaction has been proposed to advance via
a radical mechanism. Readily accessible and affordable starting
materials and catalyst, mild reaction conditions, and a robust
experimental procedure that provides the desired compounds
in good yields are some of the appealing aspects of the present
protocol. Additionally the methodology can be reproduced at a
larger scale.
A putative mechanism for the formation of benzimidazole
from 2-aminobenzylamines is described in Scheme 3. The
Scheme 3. (a) Tenable Mechanism for the Oxone Catalyzed
Tandem Reaction of 2-Aminobenzylamine to Furnish
-Substituted Benzimidazoles; (b) Control Experiments
2
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01217.
1
13
Experimental details; X-ray data for 1q; H, C NMR
and HRMS data for 1a−y and A (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: subhabrata.sen@snu.edu.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Shiv Nadar University for support.
■
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