Synthesis of aryl ring-fused benzimidazolequinones using 6-exo-trig radical cyclizations

Article abstract of DOI:10.1016/j.tetlet.2009.07.023

The preparation of alicyclic ring-fused tetracyclic and pentacyclic benzimidazoles containing one and two fused aryl rings, respectively, is achieved conveniently in three steps, including Bu₃SnH-mediated 6-exo-trig cyclization of σ-aryl radica

Full text of DOI:10.1016/j.tetlet.2009.07.023

Tetrahedron Letters 50 (2009) 5251–5253
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Tetrahedron Letters
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Synthesis of aryl ring-fused benzimidazolequinones using 6-exo-trig
radical cyclizations
*
Eoin Moriarty, 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:
The preparation of alicyclic ring-fused tetracyclic and pentacyclic benzimidazoles containing one and two
Received 7 May 2009
Revised 22 June 2009
Accepted 3 July 2009
Available online 9 July 2009
fused aryl rings, respectively, is achieved conveniently in three steps, including Bu3SnH-mediated 6-exo-
trig cyclization of
r-aryl radicals generated from 1-allyl-2-(x-bromoaryl)benzimidazoles. Inclusion of
4,7-dimethoxy substituents on the radical precursors allows access to aryl ring-fused benzimidazolequi-
nones, a unique family of potential bioreductive anti-cancer agents.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Annulations
Diazoles
Heterocycles
Quinones
Many benzimidazolequinones have been reported to exhibit po-
tent anti-cancer activity.1–5 This is thought to be initiated by biore-
duction of the quinone moiety either by single electron transfer
(SET) to give a semiquinone radical,3,6–8 or by two-electron transfer
to give the hydroquinone.1,9 Recently, we reported the synthesis of
[1,2-a] alicyclic ring-fused benzimidazolequinones, such as 1 and 2
(Fig. 1), which were shown to possess cytotoxicity towards normal
human fibroblast cells in the nanomolar range (10ꢀ9 M).3 Moreover,
the only known alicyclic ring-fused tetracyclic benzimidazolequi-
nonesarethecyclopropane-fusedcompoundsreportedbyourgroup
(e.g., 2).6–8 We now report the synthesis of a new class of ben-
zimidazolequinones containing additional fused aryl rings; 5-
acid with (3,6-dimethoxy)benzene-1,2-diamine in polyphosphoric
acid (PPA), according to a modification of the literature method for
preparing 2-(2-bromophenyl)-1H-benzimidazole 5a.10 Multi-gram
quantities of aryl bromides were obtained in 50–76% yield, includ-
ing novel benzimidazoles 5b and 10a,b. N-Alkylation of benzimi-
dazoles 5a,b and 10a,b with sodium hydride and 3-bromoprop-
1-ene in THF gave novel compounds 6a,b and 11a,b in 68–88%
yield.
Initial radical cyclization attempts involved the addition of a
solution of Bu3SnH (1.4 equiv) and 1,10-azobis(cyclohexanecarbo-
nitrile) (ACN) (0.2 equiv) in toluene (50 ml) over 8 h to a refluxing
toluene solution of 6a (32 mM) (Scheme 1).11 This gave mainly
ring-closed compound 9a, but also reduced non-cyclized, 1-al-
methyl-5,6-dihydrobenzimidazo[2,1-a]isoquinoline-8,11-dione
3
and 5-methyl-5,6-dihydrobenzimidazo[2,1-a]benzo[f]isoquino-
line-8,11-dione 4 containing one and two aryl rings, respectively.
The increased conjugation offered by the aryl ring(s) is expected to
facilitate reductive activation by imparting greater stabilization to
the biologically active reduced intermediates. The described concise
synthesis of these new heterocyclic systems includes a new 6-exo-
O
O
N
N
N
N
( )
O
n
O
trigcyclizationof
r-aryl radicals generated from thereactionof 1-al-
lyl-2-(x
-bromoaryl)-1H-benzimidazole with Bu3SnÅ.
1
2: n = 1, 2
Initial investigations focused on the synthesis of non-function-
alized benzimidazo[2,1-a]isoquinoline 9a (Scheme 1) and benzim-
idazo[2,1-a]benzo[f]isoquinoline 12a (Scheme 2), before preparing
compounds with appropriately placed dimethoxy substituents for
conversion into benzimidazolequinones. The synthesis began with
condensation of 2-bromobenzoic acid or 1-bromo-2-naphthoic
O
O
O
O
1
2
4
13
14
N
10
9
10
9
N
1
3
N
2
N
5
5
6
6
4
3
3
4
* Corresponding author. Tel.: +353 91 493120; fax: +353 91 525700.
E-mail address: fawaz.aldabbagh@nuigalway.ie (F. Aldabbagh).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.023

5252
E. Moriarty, F. Aldabbagh / Tetrahedron Letters 50 (2009) 5251–5253
R
R
R
R
R
N
N
O
N
NH2
NH2
(ii)
(i)
+
N
H
HO
Br
Br
Br
R
5a, R = H (64%)
5b, R = OMe (50%)
6a, R = H (70%)
6b, R = OMe (68%)
R
R
6-exo-trig
Bu3SnH
(iii)
Bu3Sn
N
N
N
N
R
R
7
8
R
R
N
N
(iv), (v)
3 (82%)
R = OMe
9a, R = H (63%)
9b, R = OMe (67%)
Scheme 1. Reagents and conditions; (i) PAA, 150 °C, 6 h; (ii) NaH, THF, CH2@CHCH2Br, reflux, 4 h; (iii) Bu3SnH (1.4 equiv), ACN (0.2 equiv), 8 h, PhMe, reflux; (iv) 48% HBr
(aq), reflux, 3 h; (v) FeCl3 (aq), rt, 18 h.
R
OMe
OMe
O
Br
N
NH2
NH2
(i)
(ii)
HO
+
N
H
Br
R
10a, R = H (61%)
10b, R = OMe (76%)
R
R
R
R
(iv), (v)
R = OMe
(iii)
N
N
4 (76%)
N
N
Br
11a, R = H (86%)
11b, R = OMe (88%)
12a, R = H (70%)
12b, R = OMe (71%)
Scheme 2. Reagents and conditions; (i) PAA, 150 °C, 6 h; (ii) NaH, THF, CH2@CHCH2Br, reflux, 4 h; (iii) Bu3SnH (1.4 equiv), ACN (0.2 equiv), 8 h, PhMe, reflux; (iv) 48% HBr
(aq), reflux, 3 h; (v) FeCl3 (aq), rt, 18 h.
lyl-2-phenyl-1H-benzimidazole12 (11:1 by 1H NMR). The product
mixture was found to be inseparable by chromatography, and
cyclized compound 9a was separated by precipitating its HBr salt
from acetonitrile. An aqueous basified solution of 9a was then ex-
tracted with dichloromethane giving the isolated free base in 63%
yield. The efficiency of this radical cyclization is exemplified by
carrying out the reaction without the slow syringe pump addition
of Bu3SnH and ACN. The high concentration of Bu3SnH should
synthesis13–16 compared with widely used non-chain homolytic
aromatic substitutions,17 including cyclizations onto diazoles3
that require large amounts of radical initiators to give aromatic
products. Schemes 1 and 2 show that subjecting bromides 6b
and 11a,b to an analogous 8 h addition of Bu3SnH (1.4 equiv)
and ACN (0.2 equiv) gave the required cyclized compounds,
8,11-dimethoxy-5-methyl-5,6-dihydrobenzimidazo[2,1-a]isoquin-
oline 9b and 5-methyl-5,6-dihydrobenzimidazo[2,1-a]benzo[f]iso-
quinolines 12a18 and 12b in about 70% yields.
favour reduction of reactive
r-aryl radical 7 over cyclization to
the more stable radical 8, however, the 1H NMR spectrum
showed a 6:1 ratio of 9a to 1-allyl-2-phenyl-1H-benzimidazole.
Annulations via metal hydride-mediated chain reactions using
6-exo-trig cyclization of aryl radicals are under-utilized in
Formation of quinones 319 and 4 via hydrobromic acid induced
demethylation of the 8,11-dimethoxy substituents of 9b and 12b
and in situ oxidation of the reactive hydroquinones occurred in
76% and 82% yield, respectively, using a reported procedure.3,6,7

E. Moriarty, F. Aldabbagh / Tetrahedron Letters 50 (2009) 5251–5253
5253
as absorbent with gradient elution (hexane–EtOAc) to give an inseparable
mixture of 9a and 1-allyl-2-phenyl-1H-benzimidazole. HBr was added to the
residue in acetonitrile (10 ml) until the bromide salt of 9a precipitated. The salt
was dissolved in water and Na2CO3 added until pH 8. The free diazole base was
extracted with CH2Cl2 and evaporated to dryness to give 9a (0.236 g, 63%) as a
colourless oil; Rf 0.58 (1:1 EtOAc:hexane); 1H NMR (399.78 MHz, CDCl3) d
8.31–8.29 (m, 1H, Ar-H), 7.84–7.82 (m, 1H, 11-H), 7.42–7.37 (m, 2H, Ar-H),
7.34–7.29 (m, 2H, 8-H, Ar-H), 7.28–7.25 (m, 2H, 9,10-H), 4.27 (dd, J2 = 12.2 Hz,
In conclusion, an efficient 6-exo-trig cyclization of
cals has allowed access to new alicyclic ring-fused tetracyclic and
pentacyclic benzimidazoles and benzimidazolequinones. We are
r-aryl radi-
currently extending this annulation to other
clic radicals to give further
r
-aryl and heterocy-
novel ring-fused
benzimidazolequinones.
J
3 = 5.0 Hz, 1H, 6-HH), 4.04 (dd, J2 = 12.2 Hz, J3 = 5.7 Hz, 1H, 6-HH), 3.39–3.34
(m, 1H, 5-H), 1.34 (d, J = 6.9 Hz, 3 H, Me); 13C NMR (100.53 MHz, CDCl3) d
148.7, 143.9, 139.5, 134.8 (all C), 130.3, 127.5, 126.6, 125.6 (all Ar-CH), 125.5
(C), 122.5 (Ar-CH), 122.3 (Ar-CH), 119.6 (11-CH), 108.9 (8-CH), 46.6 (CH2), 32.7
Acknowledgements
(5-CH), 19.4 (Me);20 IR (neat):
m = 1228, 1264, 1287, 1325, 1408, 1481, 1529,
The PhD studies of E.M. were supported by the Environmental
Protection Agency (EPA) Doctoral Scheme (2006-PhD-ET-6). We
thank the EPA, Department of Environment, Heritage and Local
Government funded under the National Development Plan 2000-
2006 for financial support. All mass spectra were carried out by
Dr. Lisa D. Harris, Mass Spectrometry Facility, Department of
Chemistry, University College London, UK.
1615 cmꢀ1; HRMS (EI): m/z: calcd for C16H14N2: 234.1152; found: 234.1147
[M]+.
12. Ramachary, D. B.; Reddy, G. B. Org. Biomol. Chem. 2006, 4, 4463.
13. Dobbs, A. P.; Jones, K.; Veal, K. T. Tetrahedron Lett. 1995, 36, 4857.
14. Ishibashi, H.; Kawanami, H.; Nakagawa, H.; Ikeda, M. J. Chem. Soc., Perkin Trans.
1 1997, 2291.
15. Dobbs, A. P.; Jones, K.; Veal, K. T. Tetrahedron Lett. 1997, 38, 5379.
16. Zhang, X.; Guzi, T.; Pettus, L.; Schultz, A. G. Tetrahedron Lett. 2002, 43, 7605.
17. Bowman, W. R.; Storey, J. M. D. Chem. Soc. Rev. 2007, 36, 1803.
18. 5-Methyl-5,6-dihydrobenzimidazo[2,1-a]benzo[f]isoquinoline (12a): 1-Allyl-2-(1-
bromo-2-naphthyl)-1H-benzimidazole 11a (1.000 g, 2.7 mmol), Bu3SnH
(1.060 g, 3.7 mmol) and ACN (0.133 g, 0.5 mmol) gave 12a (0.540 g, 70%) as a
white solid; Rf 0.45 (1:1 EtOAc:hexane); mp 191–192 °C; 1H NMR
(399.78 MHz, CDCl3) d 8.43 (d, J = 8.6 Hz, 1H, Ar-H), 8.11 (d, J = 8.2 Hz, 1H,
Ar-H), 7.92–7.86 (m, 3H, 11-H, Ar-H), 7.62–7.53 (m, 2H, Ar-H), 7.43–7.40 (m,
1H, 8-H), 7.33–7.30 (m, 2H, Ar-H), 4.43 (dd, J2 = 12.2 Hz, J3 = 0.9 Hz, 1H, 6-HH),
4.34 (dd, J2 = 12.2 Hz, J3 = 4.6 Hz, 1H, 6-HH); 4.18–4.11 (m, 1H, 5-H), 1.37 (d,
J = 7.4 Hz, 3H, Me); 13C NMR (100.53 MHz, CDCl3) d 149.3, 144.5, 136.5, 135.4,
134.8, 130.3 (all C), 129.4, 128.2, 127.2, 126.9, 123.3, 122.9, 122.8 (all Ar-CH),
122.7 (C), 122.6 (Ar-CH), 199.9 (11-CH), 109.1 (8-CH), 46.7 (CH2), 29.1 (5-CH),
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.023.
References and notes
1. Skibo, E. B.; Islam, I.; Schulz, W. G.; Zhou, R.; Bess, L.; Boruah, R. Synlett 1996,
297.
2. Garuti, L.; Roberti, M.; Pizzirani, D.; Pession, A.; Leoncini, E.; Cenci, V.; Hrelia, S.
IL Farmaco 2004, 59, 663.
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4. Gellis, A.; Kovacic, H.; Boufatah, N.; Vanelle, P. Eur. J. Med. Chem. 2008, 43, 1858.
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6. O’Shaughnessy, J.; Cunningham, D.; Kavanagh, P.; Leech, D.; McArdle, P.;
Aldabbagh, F. Synlett 2004, 2382.
m ;
20.3 (Me);20 IR (neat): = 1173, 1244, 1322, 1410, 1446, 1474, 1507 cmꢀ1
HRMS (ESI): m/z: calcd for C20H17N2: 285.1392; found: 285.1394 [M+H]+.
19. 5-Methyl-5,6-dihydrobenzimidazo[2,1-a]isoquinoline-8,11-dione (3): 8,11-
Dimethoxy-5-methyl-5,6-dihydrobenzimidazo[2,1-a]isoquinoline 9b (0.500 g,
1.7 mmol), 48% hydrobromic acid (15 ml) and aq FeCl3 solution (0.7 M, 15 ml)
gave 3 (0.368 g, 82%) as a red solid; Rf 0.53 (1:1 EtOAc:hexane); mp 181–
182 °C; 1H NMR (399.78 MHz, CDCl3) d 8.23 (d, J = 7.6 Hz, 1H, Ar-H), 7.47–7.33
(m, 3H, Ar-H), 6.68 (AB-q, J3 = 10.6 Hz, 1H, 10(9)-H), 6.63 (AB-q, J3 = 10.6 Hz,
1H, 9(10)-H), 4.59 (dd, J2 = 13.6 Hz, J3 = 5.3 Hz, 1H, 6-HH), 4.46 (dd, J2 = 13.6 Hz,
7. O’Shaughnessy, J.; Aldabbagh, F. Synthesis 2005, 1069.
J
3 = 6.5 Hz, 1H, 6-HH), 3.40–3.34 (m, 1H, 5-H), 1.37 (d, J = 6.8 Hz, 3H, Me); 13C
8. Hehir, S.; O’Donovan, L.; Carty, M. P.; Aldabbagh, F. Tetrahedron 2008, 64, 4196.
9. Newsome, J. J.; Colucci, M. A.; Hassani, M.; Beall, H. D.; Moody, C. J. Org. Biomol.
Chem. 2007, 5, 3665.
10. Reddy, K. R.; Krishna, G. G. Tetrahedron Lett. 2005, 46, 661.
11. 5-Methyl-5,6-dihydrobenzoimidazo[2,1-a]isoquinoline (9a): Bu3SnH (0.625 g,
2.2 mmol) and ACN (78 mg, 0.32 mmol) in PhMe (50 ml) were added over
8 h via syringe pump to N-allyl-2-(2-bromophenyl)-1H-benzimidazole 6a
(0.500 g, 1.6 mmol) in PhMe (50 ml) at reflux. The cooled solution was
evaporated to dryness and purified by column chromatography using silica
NMR (100.53 MHz, CDCl3) d 181.3 (C@O), 178.4 (C@O), 149.2, 142.4, 139.0 (all
C), 136.5 (Ar-CH), 136.2 (Ar-CH), 131.4 (Ar-CH), 130.3 (C), 127.9 (Ar-CH), 126.6
(Ar-CH), 126.2 (Ar-CH), 124.1 (C), 48.3 (CH2), 32.4 (5-CH), 18.9 (Me); IR (neat):
m
= 1095, 1195, 1270, 1423, 1460, 1509, 1655 (C@O) cmꢀ1; HRMS (ESI): m/z:
calcd for C16H13N2O2: 265.0977; found: 265.0974 [M+H]+.
20. Assignments for compounds 9a and 12a are supported by HMQC 1H–13C NMR
2D spectra. DEPT analysis was carried out on all compounds.