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