Greener synthesis using hydrogen peroxide in ethyl acetate of alicyclic ring-fused benzimidazoles and anti-tumour benzimidazolequinones

Article abstract of DOI:10.1016/j.tetlet.2017.07.102

Environmentally-friendly and cost effective hydrogen peroxide in ethyl acetate was used to prepare in high yields pyrrolo[1,2-a]benzimidazoles from commercial o-(pyrrolidin-1-yl)anilines without the requirement for organic-aqueous extraction and chromatography. Six, seven and eight membered ring-fused analogues were similarly obtained in high yields with methanesulfonic acid required for the pyrido[1,2-a]benzimidazole. Anti-tumour benzimidazolequinone derivatives were obtained in high yield via the cyclization of 3,6-dimethoxy-2-(cycloamino)anilines.

Full text of DOI:10.1016/j.tetlet.2017.07.102

Accepted Manuscript
Greener synthesis using hydrogen peroxide in ethyl acetate of alicyclic ring-
fused benzimidazoles and anti-tumour benzimidazolequinones
Martin Sweeney, Michael Gurry, Lee-Ann J. Keane, Fawaz Aldabbagh
PII:
S0040-4039(17)30971-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.102
TETL 49184
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 June 2017
28 July 2017
29 July 2017
Please cite this article as: Sweeney, M., Gurry, M., Keane, L.J., Aldabbagh, F., Greener synthesis using hydrogen
peroxide in ethyl acetate of alicyclic ring-fused benzimidazoles and anti-tumour benzimidazolequinones,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.102
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Graphical Abstract
Greener synthesis using hydrogen peroxide
in ethyl acetate of alicyclic ring-fused
benzimidazoles and anti-tumour
benzimidazolequinones
Leave this area blank for abstract info.
Martin Sweeney, Michael Gurry, Lee-Ann J. Keane, Fawaz Aldabbagh

1
Tetrahedron Letters
Greener synthesis using hydrogen peroxide in ethyl acetate of alicyclic ring-fused
benzimidazoles and anti-tumour benzimidazolequinones
Martin Sweeney, Michael Gurry, Lee-Ann J. Keane, Fawaz Aldabbagh*
School of Chemistry, National University of Ireland, Galway, University Road, Galway, Ireland
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Environmentally-friendly and cost effective hydrogen peroxide in ethyl acetate was used to
prepare in high yields pyrrolo[1,2-a]benzimidazoles from commercial o-(pyrrolidin-1-yl)anilines
without the requirement for organic-aqueous extraction and chromatography. Six, seven and
eight membered ring-fused analogues were similarly obtained in high yields with
methanesulfonic acid required for the pyrido[1,2-a]benzimidazole. Anti-tumour
benzimidazolequinone derivatives were obtained in high yield via the cyclization of 3,6-
dimethoxy-2-(cycloamino)anilines.
Available online
Keywords:
Annulations
Green chemistry
Heterocycles
Quinones
2017 Elsevier Ltd. All rights reserved.
Introduction
It was envisaged that the weak acidic property of H2O2 would
negate the requirement for carrying out the cyclization in organic
and mineral acids, as described in literature procedures.3,23-28
Recently the preparation of alicyclic ring-fused benzimidazoles
in formic acid was reported at high temperatures using an iodine-
mediated cyclization of o-nitro-t-anilines, where corrosive HI
was generated in situ.28
Ethyl acetate is classified as a preferred solvent by Pfizer,31
while GSK give ethyl acetate high ratings for environmental
impact, health and reactivity / stability.32 Herein is disclosed the
oxidative cyclization of commercial o-(cycloamino)anilines to
give five, six, seven and eight-membered alicyclic ring-fused
[1,2-a]benzimidazoles using H2O2 in ethyl acetate. Our aim was
as much as possible to make reactions compliant with green
chemistry principles,33 including use of safer solvents and to
minimize waste / effluent generation with most reactions
requiring no aqueous extraction or chromatography. The p-
The synthesis of privileged alicyclic ring-fused [1,2-a]
benzimidazoles has attracted sustained attention,1-28 most notably
because of their conversion to potent bioreductive anti-tumour
benzimidazolequinones.3,16,29 There are drawbacks to reported
syntheses of alicyclic ring-fused benzimidazoles such as
requirements for transition metals,1-9 prior synthesis of
cyclization precursors,10-17 full equivalents of strong base,17-20
high molar mass hypervalent iodine reagents,21 and the formation
of mixtures of isomeric products.22 The most convenient protocol
remains the traditional oxidative cyclization of o-cyclic amine
substituted anilines, which was first reported in the early 1960s
using hydrogen peroxide in the presence of trifluoroacetic acid.23
Variations include converting o-tert-aminoacetanilide to
benzimidazole using H2O2 in formic acid24,25 and ring-fused
benzimidazole and imidazobenzimidazole were precipitated
without the requirement for chromatography using Oxone in
formic acid.26 Most recently, H2O2 in combination with
hydrochloric or hydrobromic acid mediated the cyclization of o-
cyclic amine substituted anilines to give respectively
dichlorinated and dibrominated ring-fused benzimidazoles in
high yields of >80%.27
dimethoxy
substituted
pyrrolo[1,2-a]benzimidazole
and
pyrido[1,2-a]benzimidazole were prepared in high yields from
their respective anilines without the requirement for
chromatography and transformed into the anti-tumour
benzimidazolequinones. New large ring-fused analogues, azepino
and azocino[1,2-a]benzimidazoles can be similarly prepared
using H2O2 in ethyl acetate, and converted to the novel
benzimidazolequinones.
From a green chemistry and commercial perspective, there are
significant advantages to using the low molar mass ubiquitous
oxidant H2O2 in synthesis since the only effluent is water, and its
cost is lower than conceivable alternatives. Hydrogen peroxide
(50% w/v) in water has a pH 4.30
———
*
Corresponding author. Tel.: +353 91 493120; fax: +353 91 525700;
E-mail address: Fawaz.Aldabbagh@nuigalway.ie (F. Aldabbagh)

Results and discussion
a]benzimidazole (4a) required purification using flash
chromatography in order to remove unidentified impurities.
Table 1. Synthesis of 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazolesa
Table 2. Synthesis of five to eight-membered ring-fused [1,2-
a]benzimidazolesa
aniline
1a
R
OMe
H
time
20 min
20 min
40 min
20 min
2 h
yield (%)
2a, 79
2b, 80
2c, 81
2d, 64
2e, 88
2f, 84
2g, 85b
2h, 93
2i, 71b
1b
1c
n
1
2
3
4
time
20 min
1 h
yield (%)
2a, 79
3a, 75b
4a, 65c
5a, 73
Me
NHAc
Br
1d
1e
80 min
2 h
1f
F
50 min
4 h
1g
CN
CF3
NO2
1h
1i
8 h
aReaction conditions and work up is the same as Table 1. bIncluded MeSO3H
(1 mmol). Extraction with EtOAc (20 mL) and saturated Na2CO3 (aq.) was
deemed necessary. cFlash column chromatography required.
4 h
aReaction conditions: Aniline 1a-1i (1.0 mmol), H2O2 (50% w/v, 20 mmol)
and EtOAc (5 mL). When GC-MS indicated all the aniline was consumed, the
reaction was quenched by addition of solid Na2CO3 (3 g) and additional
EtOAc (20 mL). The mixture was filtered and evaporated to give the ring-
fused [1,2-a]benzimidazole. bIncluded MeSO3H (0.5 mmol).
The conversion of 6,9-dimethoxy-1,2,3,4-tetrahydropyrido[1,2-
a]benzimidazole 8b into the six-membered ring-fused
benzimidazolequinone 9b using hydrobromic acid-induced
demethylation to give the hydroquinone in situ followed by room
temperature oxidation with ferric chloride has been previously
described by our group (Scheme 1).16 Pyrido[1,2-
a]benzimidazole 8b was however obtained using expensive and
environmentally damaging Bu3SnH-mediated radical cyclization
of a benzeneselenide precursor. Furthermore, the scope of radical
cyclizations is limited due to difficulties in forming constrained
ring-fused systems such as pyrrolo[1,2-a]benzimidazole 8a.
Optimized conditions used 20 equivalents of H2O2 in ethyl
actetate facilitating the conversion of commercial 2-(pyrrolidin-
1-yl)anilines
1a-1i
into
2,3-dihydro-1H-pyrrolo[1,2-
a]benzimidazoles 2a-2i in isolated yields of 64-93% (Table 1).
Longer reaction times were required for full conversion of
anilines containing an electron-withdrawing substituent at the 5-
position.
The
yield
of
2,3-dihydro-1H-pyrrolo[1,2-
a]benzimidazole-6-carbonitrile (2g) was raised to 85% from
59%, and the yield of 6-nitro-2,3-dihydro-1H-pyrrolo[1,2-
a]benzimidazole (2i) was raised to 71% from 29% by addition of
0.5 equivalents of methanesulfonic acid (MSA). MSA undergoes
biodegradation by forming CO2 and sulfate, and is considered a
green acid due to its less toxic and corrosive nature.34 In all cases
organic-aqueous extractions were avoided by addition of solid
sodium carbonate to the reaction mixture. The quenched reaction
was filtered with the ethyl acetate filtrate evaporated, and the
solvent reused in further reactions. Our protocol circumvents the
requirement for auxiliary solvents, allows solvent recycling and
there is no aqueous effluent. The solid waste generated
(containing sodium percarbonate) is sufficiently safe for disposal
in landfill.
The formation of ring expanded analogues using the reaction
conditions successfully applied to prepare pyrrolo[1,2-
a]benzimidazoles 2a-2i was investigated (Table 2). The six-
membered cyclization of 5-methoxy-2-(piperidiny-1-yl)aniline
was slow without the addition of acid with an optimized yield of
Scheme 1. Synthesis of five to eight-membered ring-fused
benzimidazolequinones
75%
for
7-methoxy-1,2,3,4-tetrahydropyrido[1,2-
a]benzimidazole (3a) obtained after 1 h when one equivalent of
MSA was added. Unfortunately the use of full equivalents of
MSA necessitated the use of saturated sodium carbonate solution
in an organic-aqueous extraction. Additional acid was not
required for the seven and eight-membered cyclizations, which
occurred in 65% and 73% yield respectively using H2O2 in ethyl
acetate, however 3-methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-
A facile synthesis of anti-tumour agents 9a-9d is now disclosed
starting from nucleophilic substitution of pyrrolidine, piperidine,
azepane, and azocane onto 1,4-dimethoxy-2,3-dinitrobenzene
followed by reduction to give the cyclization precursors 7a-7d in
26-68% yield (over two synthetic steps in Scheme 1). In
agreement with the above findings (Table 2), the five-membered

3
cyclization proceeded efficiently, although slowly using H2O2 in
EtOAc to give 8a in a yield of 81% over 18 h (Table 3). The
analogous six-membered cyclization proved difficult using H2O2
alone. The addition of a full equivalent of MSA allowed the clean
isolation of 8b in 80% yield after 12 h of reflux in ethyl acetate
without the requirement for chromatography. It may be that the
intermediate N-oxide of the six-membered ring tertiary amine is
more stable through hydrogen bonding,26 requiring acidic
conditions for oxidative cyclization. The seven and eight
membered cyclizations of 3,6-dimethoxyanilines 7c and 7d
proceeded in good yields (60-72%) in 6 h in the presence of 1
equivalent of MSA with the absence of the acid leading to lower
yields (35%) and long reaction times as shown in Table 3.
Benzimidazoles 8c and 8d were readily converted into novel
potential anti-tumour agents azepino and azocino[1,2-
a]benzimidazolequinones 9c and 9d in 52-70% yield (Scheme 1),
and will be the subject of future cytotoxicity evaluation by our
group.
College of Science, National University of Ireland Galway
(NUI Galway) for postgraduate scholarships for Michael Gurry
and Lee-Ann J. Keane.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at xxxxxx
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c
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column chromatography required
Conclusion
In summary nine pyrrolo[1,2-a]benzimidazoles have been
prepared from commercial anilines using “acid-free” H2O2 in
ethyl acetate protocol, where no aqueous-organic extraction or
chromatography is required. Where reactions are slow
environmentally acceptable MSA can be added. Six to eight-
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analogous conditions. The cyclization of 3,6-dimethoxy-2-
(cycloamino)anilines mostly required one equivalent of MSA in
order to achieve high yields in a reasonable time. Nevertheless,
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Acknowledgments
FA thanks the Irish Research Council (IRC) for a Government
of Ireland Postgraduate Scholarship for Martin Sweeney and

Highlights
 H2O2 in EtOAc is a new cost-effective and
green approach for synthesis.
 Sixteen oxidative cyclizations to give ring-
fused [1,2-a]benzimidazoles.
 The easiest approach to ring-fused
benzimidazolequinone anti-tumour agents
available.
35.