Synthesis of seven- and eight-membered [1,2-a] alicyclic ring-fused benzimidazoles and 3-aziridinylazepino[1,2-a]benzimidazolequinone as a potential antitumour agent

Article abstract of DOI:10.1016/j.tetlet.2008.06.121

Azepino and azocino[1,2-a]benzimidazoles were obtained either by treatment of 1-nitrophenyl-2-azacycloalkanes via a one-pot catalytic hydrogenation/acetylation or by treatment of the acetamides generated in the latter reaction with performic acid. This represents the first facile synthesis of eight-membered [1,2-a] alicyclic ring-fused benzimidazoles. 3-Methoxy-azepino[1,2-a]benzimidazole was elaborated to the novel potential cytotoxin, 3-(N-aziridinyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole-1,4-dione. The synthesis included clarification of the reactivity of methoxy-substituted benzimidazoles towards nitration.

Full text of DOI:10.1016/j.tetlet.2008.06.121

Tetrahedron Letters 49 (2008) 5235–5237
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Tetrahedron Letters
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Synthesis of seven- and eight-membered [1,2-a] alicyclic ring-fused
benzimidazoles and 3-aziridinylazepino[1,2-a]benzimidazolequinone
as a potential antitumour agent
*
Karen Fahey, Fawaz Aldabbagh
School of Chemistry, National University of Ireland, Galway, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Azepino and azocino[1,2-a]benzimidazoles were obtained either by treatment of 1-nitrophenyl-2-aza-
cycloalkanes via a one-pot catalytic hydrogenation/acetylation or by treatment of the acetamides
generated in the latter reaction with performic acid. This represents the first facile synthesis of eight-
membered [1,2-a] alicyclic ring-fused benzimidazoles. 3-Methoxy-azepino[1,2-a]benzimidazole was
elaborated to the novel potential cytotoxin, 3-(N-aziridinyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benz-
imidazole-1,4-dione. The synthesis included clarification of the reactivity of methoxy-substituted benz-
imidazoles towards nitration.
Received 26 May 2008
Revised 17 June 2008
Accepted 26 June 2008
Available online 3 July 2008
Keywords:
Annulations
Antitumour agents
Diazoles
Ó 2008 Elsevier Ltd. All rights reserved.
Heterocycles
In 1990, Skibo and co-workers introduced pyrrolo[1,2-a]benz-
imidazolequinones (PBI) as a new class of bioreductive antitumour
agents.1–4 The 6-aziridinyl analogues were shown to be most
cytotoxic against a variety of cancer cell lines (Fig. 1). Evidence
for reductive activation of PBI to the hydroquinone was reported
to lead to an intermediate that hydrogen bonds to the DNA major
groove at the AT base pair with nucleophilic alkylation at the
aziridine by the phosphate backbone of DNA resulting in hydrolytic
strand cleavage.1,3 More recently, our group has introduced [1,2-a]
alicyclic ring-fused benzimidazolequinones with (e.g., 1 and 2) and
without an additional fused cyclopropane ring.5–7 The cytotoxicity
of these compounds towards human skin fibroblast cells was found
to be in the nanomolar range (10À9 M) with cytotoxicity increasing
under the hypoxic conditions associated with solid tumours.6
Moreover, cyclopropapyrrolo[1,2-a]benzimidazolequinone 1 was
shown to be more cytotoxic than six-membered analogue 2. We
now present the synthesis of novel 3-(N-aziridinyl)-7,8,9,10-tetra-
hydro-6H-azepino[1,2-a]benzimidazole-1,4-dione 3, as part of our
investigations into the variance of cytotoxicity with the size of the
[1,2-a] alicyclic ring. The aziridine substituent in 3 is being inves-
tigated as an alkylating functionality towards cancerous cell DNA.
There are many reported synthetic approaches towards tricyclic
five-, six- and seven-membered [1,2-a] alicyclic ring-fused benz-
imidazoles dating back to the 1950s.1–4,6,8–22 The procedures can
be categorized into the following cyclization protocols: (i) metal-
O
O
O
O
6
N
N
N
N
N
R
3
7
Me
2
( )
1
n
PBI
R = OCONH2, NH2,
1, n = 1
2, n = 2
NHCOCH3, NHCONH2
O
4
4
3
MeO
3
N
N
N
6
6
7
7
2
2
N
N
1
1
8
8
11
10
O
9
9
10
3
4
Figure 1.
catalyzed reduction of aromatic nitro groups to amines (or nitroso),
which undergo acid-catalyzed cyclization onto adjacent azacyclo-
alkanes;1–4,9,11,13,14 (ii) nucleophilic displacement by the N-1
benzimidazole anion of halo substituents in 2-(x-haloalkyl)benz-
imidazoles or generation of the benzimidazol-2-yl anion to under-
go the inverse displacement reaction;10,12,17,19 (iii) Rh-catalyzed
reaction of N-alkenyl-1,2-diaminobenzene with H2 and CO fol-
lowed by annulation;16 (iv) N-alkyl nucleophilic radical substitu-
tion onto the activated 2-position of benzimidazole;6,18,21,22 and
* Corresponding author. Tel.: +353 91 493120; fax: +353 91 525700.
E-mail address: fawaz.aldabbagh@nuigalway.ie (F. Aldabbagh).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.121

5236
K. Fahey, F. Aldabbagh / Tetrahedron Letters 49 (2008) 5235–5237
H
N
NO2
Br
MeO
MeO
NO2
N
EtOH
+
reflux, 4 d
( )
n
( )
n
5, n = 1 (82%)
6, n = 2 (78%)
O
MeO
MeO
N
H
N
N
H2, Pd-C, Ac2O, AcOH, EtOH
40 psi, rt, 20 h
+
N
( )
n
( )
n
7, n = 1 (59%)
8, n = 2 (46%)
9, n = 1 (35%)
4, n = 2 (52%)
HCO2H, H2O2
7, 8
9 (64%), 4 (66%)
40 °C, 1 h
Scheme 1. Synthesis of azepino and azocino[1,2-a] alicyclic ring-fused benzimidazoles.
(v) N-nucleophilic anionic aromatic substitution using activated
aromatic amidine analogues.8,15,20 However, none of these syn-
thetic approaches have thus far been reported to give eight-mem-
bered [1,2-a] alicyclic ring-fused benzimidazoles (e.g., 4). Thus, we
now report the efficient use of the annulation protocol in category
(i) to give azepino and azocino[1,2-a]benzimidazoles. This outlines
the versatility and simplicity of this approach to give alicyclic ring-
fused benzimidazoles, and consequent elaboration to the benz-
imidazolequinone cytotoxins.
anisole by the cyclic amines, azepane and azocane (n = 1 and 2,
respectively), by heating an ethanol solution under reflux for four
days. 1-(4-Methoxy-2-nitrophenyl)azepane 5 was obtained in
82% yield directly after an aqueous/organic extraction, however,
due to the less hydrophilic nature of azocane, purification by col-
umn chromatography was required to separate 1-(4-methoxy-2-
nitrophenyl)azocane 6 in 78% yield. Preparation of acetamides 7
and 8 by one-pot catalytic hydrogenation and acetylation using
H2/Pd-C at 40 psi was carried out in respective yields of 59% and
46%. These relatively low yields for 7 and 8 were due to the unex-
pected simultaneous formation of the required ring closed adducts
9 and 4 in yields of 35% and 52%, respectively. It seems that the
cyclization is more favourable when longer hydrogenation times
and larger azacycloalkanes are used compared to the literature
pyrrolidine and piperidine series.2,9 The separated acetamides 7
and 8 were then treated with performic acid (generated in situ
from HCO2H, H2O2) to give azepino and azocino[1,2-a]benzimidaz-
oles 9 and 423 in ꢀ65% yield. The mechanism for this cyclization
probably involves oxidation to the iminium ion followed by nucleo-
philic attack by the adjacent acetamido nitrogen.1,2
Alicyclic ring-fused benzimidazoles were prepared in three
synthetic steps, according to Scheme 1. The first step involved
nucleophilic substitution of the bromine atom in 4-bromo-3-nitro-
X
MeO
MeO
Y
N
N
N
N
(i) or (ii)
9
10, X = NO2, Y = H
11, X = H, Y = NO2
12, X = NO2, Y = NO2
Zhou and Skibo reported nitration at the 5-position (in 38%
yield) when 6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimid-
azole was treated with fuming nitric acid using a salt-ice water
bath for 5 min.2 In our hands this procedure gave an almost equal
mixture of two nitro isomers 1024 and 11 when using 3-methoxy-
Scheme 2. Reagents and conditions: (i) Fuming HNO3, 0 °C, 7 min gave 10 (37%)
and 11 (35%); (ii) 50:50 Fuming HNO3: concd H2SO4, rt, 24 h gave 12 (74%).
NO2
NH2
O
MeO
MeO
MeO
N
N
N
N
N
N
(i)
(ii)
100%
78%
O
10
13
14
NH
, MeOH, rt
60%
14
3
Scheme 3. Reagents and conditions: (i) H2, Pd-C, EtOH, 40 psi; (ii) Fremy oxidation, rt.

K. Fahey, F. Aldabbagh / Tetrahedron Letters 49 (2008) 5235–5237
5237
23. 3-Methoxy-6,7,8,9,10,11-hexahydroazocino[1,2-a]benzimidazole (4): A mixture of
N-(2-azocan-1-yl-5-methoxyphenyl)acetamide 8 (0.640 g, 2.32 mmol), HCO2H
(95%, 3.2 ml) and H2O2 (30%, 1.6 ml) was stirred at 40 °C for 1 h. H2O (10 ml)
was added, and the mixture was neutralized using NH4OH and extracted into
CHCl3 (3 Â 25 ml). The combined organic extracts were dried (Na2SO4) and
evaporated to dryness. The resultant brown residue was purified by column
chromatography using silica gel as absorbent with a gradient elution of EtOAc
and MeOH to yield 4 (0.354 g, 66%) as a white solid. Rf 0.36 (CHCl3–MeOH
95:5); mp 102–103 °C; 1H NMR (CDCl3, 399.78 MHz) d 1.22–1.28 (m, 2H,
9-CH2), 1.48–1.53 (m, 2H, 8-CH2), 1.81–1.87 (m, 2H, 10-CH2), 1.88–1.94 (m, 2H,
7-CH2), 2.98 (t, J = 6.2 Hz, 2H, 6-CH2), 3.84 (s, 3H, CH3), 4.21 (t, J = 6.0 Hz, 2H,
11-CH2), 6.85–6.88 (dd, J = 2.6 Hz, 8.7 Hz, 1H, 2-H), 7.15 (d, J = 8.7 Hz, 1H, 1-H),
7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole 9 as the sub-
strate (Scheme 2). Furthermore, if the nitration time is increased or
the traditional concentrated nitric/sulfuric acid mixture is used
over a substantially longer reaction time period,6 only the 2,4-dini-
trated product 12 is obtained. This indicates that the reason for the
low yields of the required nitro isomer both in our case and most
probably in the literature example2 was due to the activating nat-
ure of the methoxy substituent facilitating electrophilic nitration at
both adjacent vacant positions.
Catalytic hydrogenation of 10 to the 4-amino adduct 13 fol-
lowed by oxidation using Fremy oxidation gave benzimidazolequi-
none 14 in 78% yield (Scheme 3). It is noteworthy that this is the
first time the intermediate aromatic amine in benzimidazolequi-
none forming reaction sequences has been successfully isolated
and partially characterized.25 Substitution of the 3-methoxy sub-
stituent of 14 by aziridine2,26 gave target 3 in 60% yield.27
In conclusion, facile preparations of novel methoxy-substituted
seven- and eight-membered [1,2-a] alicyclic ring-fused benzimi-
dazoles have been accomplished, and the former converted to
the 3-aziridinyl-substituted benzimidazolequinone. A full paper
is in preparation describing the synthesis of other [1,2-a] alicyclic
ring-fused benzimidazolequinones with associated biological
activity results assessing the influence of ring size on cytotoxicity.
7.20 (d, J = 2.6 Hz, 1H, 4-H) ppm; 13C NMR (CDCl3, 100.53 MHz)
d 23.80
(9-CH2), 25.38 (8-CH2), 26.86 (6-CH2), 29.64 (10-CH2), 31.11 (7-CH2), 41.24
(11-CH2), 55.69 (CH3), 101.62 (4-CH), 109.36 (1-CH), 111.30 (2-CH), 128.93 (C),
143.47 (C), 155.83 (C), 156.67 (C) ppm;28 IR (neat) 1031, 1111, 1151, 1202,
1340, 1414, 1442, 1489, 1620, 2858, 2925 cmÀ1; m/z (CI) 231 ([M+H]+, 100%);
HRMS (ESI): found MH+, 231.1495. C14H19N2O requires, 231.1497. Anal. Calcd
for C14H18N2O: C, 73.01; H, 7.88; N, 12.16. Found: C, 72.73; H, 7.67; N, 12.42.
24. 3-Methoxy-4-nitro-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole 10: 3-
Methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole
9
(0.100 g,
0.462 mmol) and fuming HNO3 (1 ml) were stirred at 0 °C for 7 min. H2O
(10 ml) was added, the mixture neutralized using NaHCO3 and extracted into
CHCl3 (2 Â 25 ml). The combined organic extracts were dried (Na2SO4) and
evaporated to dryness. The resultant yellow residue was purified by column
chromatography using silica gel as absorbent with EtOAc as eluent to yield 10
(45 mg, 37%) as a yellow solid. Rf 0.58 (EtOAc–MeOH 95:5); mp 144–146 °C; 1
H
NMR (CDCl3, 399.78 MHz) d 1.77–1.86 (m, 4H, CH2), 1.92–1.97 (m, 2H, CH2),
3.12 (t, J = 5.5 Hz, 2H, 6-CH2), 3.94 (s, 3H, CH3), 4.13 (t, J = 4.8 Hz, 2H, 10-CH2),
6.96 (d, J = 8.9 Hz, 1H, 2-H), 7.32 (d, J = 8.9 Hz, 1H, 1-H) ppm; 13C NMR (CDCl3,
100.53 MHz) d 24.86 (CH2), 28.17 (CH2), 29.84 (6-CH2), 30.37 (CH2), 44.73 (10-
CH2), 57.56 (CH3), 107.74 (2-CH), 112.06 (1-CH), 130.42 (C), 131.58 (C), 135.89
(C), 147.77 (C), 160.73 (Ar-5a-C) ppm;28 IR (neat) 1095, 1157, 1198, 1221,
1238, 1276, 1325 (NO2), 1358, 1414, 1438, 1468, 1486, 1507, 1523 (NO2), 1591,
1634 cmÀ1; Anal. Calcd for C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C,
59.68; H, 6.17; N, 15.76. The second fraction eluted was 3-methoxy-2-nitro-
7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole 11 (43 mg, 35%) as a yellow
solid.
Acknowledgements
This publication has emanated from research conducted with
financial support from Science Foundation Ireland (07/RFP/
CHEF227). The authors acknowledge the receipt of an embark ini-
tiative postgraduate scholarship for K.F. from the Irish Research
Council for Science, Engineering and Technology funded by the
National Development Plan.
25. 4-Amino-3-methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole
13:
A mixture of 3-methoxy-4-nitro-7,8,9,10-tetrahydro-6H-azepino[1,2-a]- benz-
imidazole 10 (90 mg, 0.344 mmol) and Pd-C (10%, 10 mg) in EtOH (50 ml)
was agitated under 40 psi H2 at 20 °C for 8 h. The catalyst was removed by
filtration and the filtrate was evaporated to dryness to yield 13 (80 mg, 100%)
as a brown residue (not purified further). 1H NMR (CDCl3, 399.78 MHz) d 1.69–
1.76 (m, 4H, CH2), 1.83–1.88 (m, 2H, CH2), 3.00 (t, J = 5.5 Hz, 2H, 6-CH2), 3.82 (s,
3H, CH3), 3.99 (t, J = 4.8 Hz, 2H, 10-CH2), 4.38 (bs, 2H, NH2), 6.51 (d, J = 8.7 Hz,
1H, Ar-H), 6.82 (d, J = 8.7 Hz, 1H, Ar-H) ppm; 13C NMR (CDCl3, 100.53 MHz) d
25.73 (CH2), 28.70 (CH2), 30.05 (CH2), 30.96 (CH2) 44.56 (10-CH2) 57.74 (CH3),
96.53 (CH), 109.20 (CH), 127.67 (C), 131.49 (C), 131.86 (C), 141.09 (C), 156.29
(Ar-5a-C) ppm.
References and notes
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297.
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26. Allen, C. F. H.; Spangler, F. W.; Webster, E. R. Org. Synth. Colloid 1963, 4, 433.
27. 3-(N-Aziridinyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole-1,4-dione 3:
A
mixture of 3-methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimi-
dazole-1,4-dione 14 (69 mg, 0.280 mmol) and ethyleneimine (0.78 ml,
14.56 mmol) in MeOH (11.0 ml) was stirred at rt for 2 h. The mixture was
evaporated and the red residue was purified by column chromatography using
silica gel as absorbent with CHCl3 as eluent. The isolated red quinone was
recrystallized from CHCl3/hexane (9:1) to yield 3 (43 mg, 60%) as a red powder.
Rf 0.52 (CHCl3–MeOH 95:5); mp 175–177 °C (dec); 1H NMR (CDCl3,
399.78 MHz) d 1.67–1.73 (m, 2H, CH2), 1.75–1.80 (m, 2H, CH2), 1.85–1.91 (m,
2H, CH2), 2.20 (s, 4H, aziridine-CH2), 2.98 (t, J = 5.6 Hz, 2H, 6-CH2), 4.54–4.61
(m, 2H, 10-CH2), 5.75 (s, 1H, 2-H) ppm; 13C NMR (CDCl3, 100.53 MHz) d 24.88
(CH2), 27.75 (aziridine CH2), 28.12 (CH2), 29.17 (6-CH2), 30.70 (CH2), 45.61 (10-
CH2), 116.04 (2-CH), 130.87 (C), 139.32 (C), 156.70 (C), 157.75 (C), 176.76
(C@O), 179.08 (C@O) ppm;28 IR (neat) 1072, 1099, 1128, 1263, 1301, 1354,
1440, 1471, 1519, 1574, 1635 (C@O), 1678 (C@O) cmÀ1; m/z (CI) 258 ([M+H]+,
100%); HRMS (ESI): found MH+, 258.1245. C14H16N3O2 requires, 258.1243;
Anal. Calcd for C14H15N3O2: C, 65.34; H, 5.88; N, 16.34. Found: C, 65.64; H,
5.51; N, 16.85.
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28. Assignments for compounds 3, 4 and 10 are supported by HMQC 1H-13C NMR
A
2D COSY 1H-1H NMR correlation was also carried out on
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2D spectra.
compound 4.