Synthesis of dimethyl substituted benzimidazoles containing cyclopropane fused onto five to eight membered [1,2-a]alicyclic rings and influence of methyl group substituents on cytotoxicity of benzimidazolequinones

Article abstract of DOI:10.1016/j.tet.2008.02.093

Upon thermolysis 5,6-dimethyl-N-[(allyl, but-3-enyl, pent-4-enyl and hex-5-enyl-benzimidazol-2-yl)methylene]-(trans)-2,3-diphenylaziridin-1-amines (Eschenmoser hydrazones) form cyclopropane fused onto pyrrolo-, pyrido-, azepino- and azocino[1,2-a]benzimidazoles in 70, 50, 77 and 11% yield, respectively. The latter reaction also gave carbene insertion products. Dimethyl group substituents were found to significantly reduce the cytotoxicity of benzimidazolequinone towards human skin fibroblast cells.

Full text of DOI:10.1016/j.tet.2008.02.093

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4196e4203
www.elsevier.com/locate/tet
Synthesis of dimethyl substituted benzimidazoles containing cyclopropane
fused onto five to eight membered [1,2-a]alicyclic rings and influence
of methyl group substituents on cytotoxicity of benzimidazolequinones
Sarah Hehir a, Liz O’Donovan a, Michael P. Carty b, Fawaz Aldabbagh a,
*
a School of Chemistry, National University of Ireland, Galway, Ireland
b Department of Biochemistry, National University of Ireland, Galway, Ireland
Received 29 November 2007; received in revised form 10 February 2008; accepted 28 February 2008
Available online 4 March 2008
Abstract
Upon thermolysis 5,6-dimethyl-N-[(allyl, but-3-enyl, pent-4-enyl and hex-5-enyl-benzimidazol-2-yl)methylene]-(trans)-2,3-diphenyl-
aziridin-1-amines (Eschenmoser hydrazones) form cyclopropane fused onto pyrrolo-, pyrido-, azepino- and azocino[1,2-a]benzimidazoles in
70, 50, 77 and 11% yield, respectively. The latter reaction also gave carbene insertion products. Dimethyl group substituents were found to
significantly reduce the cytotoxicity of benzimidazolequinone towards human skin fibroblast cells.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Antitumor agents; Aziridinylimines; Cycloaddition; Heterocycles
1. Introduction
while the clinically used antitumour agent MMC showed
only a two-fold increase in cytotoxicity under hypoxic condi-
tions.7,8 The main reason given for the greater selectivity
towards hypoxia was CPM (Eredox vs Fc (DMF)¼ꢀ1.395 V)
being more easily reduced than MMC (Eredox vs Fc
(DMF)¼ꢀ1.421 V).8 Moreover, the benzimidazolequinones
1 (Eredox vs Fc (DMF)¼ꢀ1.052 V) and 2 (Eredox vs Fc
Hypoxic cells form a significant part of solid tumours.1
These O2-deficient cells are slow to divide, and become
resistant to conventional cancer treatments including, radia-
tion, chemotherapy (medicines), surgery or combinations of
these treatments. We are interested in preparing [1,2-a]alicy-
clic ring fused benzimidazolequinones that exhibit selective
cytotoxicity towards hypoxic cells.2 Among the compounds
we recently reported were cyclopropa[3,4]pyrrolo[1,2-a]benz-
imidazole-3,6-dione 1 and cyclopropa[3,4]pyrido[1,2-a]benz-
imidazole-5,8-dione 2 (Fig. 1), which were found to possess
cytotoxicity towards human skin fibroblast cells in the
nanomolar (10ꢀ9 M) range, as determined using the MTT
assay.2e4 This work was inspired by Moody’s work on cyclo-
propamitosene (CPM), the cyclopropane analogue of aziridi-
nomitosene {formed after reductive activation of mitomycin
C (MMC, Fig. 1)}.5e9 CPM was reported to be 34 times
more cytotoxic under hypoxic than oxygenated conditions,
O
O
OCONH2
OMe
OCONH2
H2N
Me
X
Y
Z
NH
N
N
O
O
MMC
aziridinomitosene, Z = NH
CPM, X = OMe, Y = H, Z = CH2
O
Me
N
R
R
N
N
N
Me
( )n
O
( )n
1, n = 1, R = H
2, n = 2, R = H
3, n = 1, R = Me
4, n = 1
5, n = 2
* Corresponding author. Tel.: þ353 91 493120; fax: þ353 91 525700.
E-mail address: fawaz.aldabbagh@nuigalway.ie (F. Aldabbagh).
Figure 1. Bioreductive anti-tumour agents and target compounds.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.093

S. Hehir et al. / Tetrahedron 64 (2008) 4196e4203
4197
(DMF)¼ꢀ1.074 V) are more easily reduced than both indole-
quinones MMC and CPM, which may be a reason for their
significantly greater cytotoxicity.2e4
trans-2,3-diphenylaziridin-1-amines (Eschenmoser hydra-
zones) 15e18 in good yields of 66e89%.
Under hypoxic conditions, reversible single electron reduc-
tion of CPM or the benzimidazolequinone analogues leads to
the formation of reactive semi-quinone radical anions that are
speculated to induce ring-opening of the cyclopropane ring.7e9
The cytotoxic effect is then thought to be induced by hydrogen
abstraction from DNA leading to strand cleavage. The reduc-
tive potential and thus the subsequent cytotoxicity can be mod-
ified by incorporating substituents on the oxidising quinone
moiety. Since 1 is more selective towards hypoxic conditions
than 2,2 we decided to investigate the effect of inductively
electron donating 4,5-dimethyl substituents on the cytotoxicity
of cyclopropapyrrolo[1,2-a]benzimidazolequinone. This paper
includes the synthesis of 4,5-dimethylcyclopropa[3,4]pyr-
rolo[1,2-a]benzimidazole-3,6-dione 3 and its cytotoxicity
assays under aerobic and hypoxic conditions.
The methodology used to form pyrrolo and pyrido[1,2-
a]benzimidazoles containing a fused cyclopropane ring involved
synthesis of N-aziridinyl imines (Eschenmoser hydrazones)3,4,10
and their subsequent thermolysis to diazomethines. Such reac-
tive intermediates can undergo intramolecular 1,3-dipolar cyclo-
addition to give [3þ2] pyrazoline cycloadducts.3e5,11 The latter
eliminate nitrogen on further heating to give the fused cyclopro-
pane. Regitzetal.12 reported7-alkoxy-5-(diazomethyl)-5H-ben-
zocycloheptenes, which gave pyrazoline cycloadducts that were
homolyzed in xylene under reflux to the cyclopropane fused
compounds. However, to the best of our knowledge, cycloaddi-
tion to give respective three-membered rings fused onto seven
and eight membered alicyclic rings from the decomposition of
arene-N-aziridinyl imines3e5,11,13,14 or arenesulfonylhydr-
azones5,6,9,11,13,15,16 has never been carried out. We now report
thermolysis of Eschenmoser hydrazones to form new tetracyclic
ring systems, azepino and azocino[1,2-a]benzimidazoles 4 and 5
containing a fused cyclopropane ring (Fig. 1).
N
N
N
(a)
(b)
CH2OH
CH2OH
( )n
N
H
6
7-10
Ph
O
N
H
N
N
N
N
N
(c)
Ph
H
( )n
15-18
( )n
11-14
Scheme 1. Synthesis of Eschenmoser hydrazones: (a) Et3N (2 equiv),
XCH2(CH2)nCH]CH2 (1.2 equiv), DMF, reflux, 4 h, for compound 7, n¼0,
X¼I, yield¼46%, for compound 8, n¼1, X¼Br, yield¼35%, for compound
9, n¼2, X¼Br, yield¼45% and for compound 10, n¼3, X¼Br, yield¼37%;
(b) MnO2 (w30 equiv), CH2Cl2, reflux, 30 min, for compound 11, n¼0,
yield¼75%, for compound 12, n¼1, yield¼71%, for compound 13, n¼2,
yield¼76% and for compound 14, n¼3, yield¼73%; (c) 1-amino-trans-2,3-di-
phenylaziridine (1 equiv), Et2O, 0 ꢁC, 8.5 h, for compound 15, n¼0,
yield¼84%, for compound 16, n¼1, yield¼66%, for compound 17, n¼2,
yield¼72% and for compound 18, n¼3, yield¼89%.
Thermolysis of Eschenmoser hydrazones 15 and 16 in xylene
under reflux, respectively, gave cyclopropapyrrolo[1,2-a]benz-
imidazole 19 and cyclopropapyrido[1,2-a]benzimidazole 20 in
yields of 70 and 50% (Scheme 2). In line with our previous ob-
servations into the thermolysis of benzimidazole-2-Eschen-
moser hydrazones lacking aromatic methyl substituents,3,4
thermolysis of 15 at lower temperatures (in benzene under re-
flux) resulted in the isolation of 1,3-dipolar [3þ2] pyrazoline
cycloadduct 21 in 45% yield (Scheme 3), which decomposed
to the cyclopropane 19 at higher temperatures (xylene under re-
flux). However, possibly for reasons previously discussed,4 hy-
drazone 16 decomposed to directly give cyclopropane 20 (in
50% yield) even under the mild conditions of boiling CH2Cl2.
Recently, we reported2 that cytotoxicity varies with ring
size with respect to cyclopropapyrrolo[1,2-a]benzimidazole-
quinone 1 and the six-membered alicyclic ring fused analogue
2 under hypoxic conditions making the synthesis of further
2. Results and discussion
2.1. Synthesis of dimethyl substituted [1,2-a]alicyclic ring
fused benzimidazoles
Ph
N
H
N
N
N
N
N
Synthesis of 5,6-dimethylbenzimidazole-2-hydrazone
cycloaddition precursors involved N-alkylation of 5,6-di-
methylbenzimidazole-2-methanol 6 using triethylamine and
alkenyl halides in DMF. Although this reaction under
optimised conditions only gave 5,6-dimethyl(N-alken-u-enyl)-
benzimidazole-2-methanols 7e10 in 35e46% yield, multi-
gram syntheses of 7e10 were achieved (Scheme 1). Prior
TBDMS protection of the alcohol substituent was found not
to be viable, as previously reported on the unsubstituted benz-
imidazole-2-methanol4 due to the insolubility of 6 in THF and
nearly all common organic solvents. Oxidation of alcohols
7e10 to aldehydes 11e14 was efficiently carried out using
manganese dioxide in CH2Cl2 in yields greater than 70%.
Condensation with 1-amino-trans-2,3-diphenylaziridine gave
5,6-dimethyl-N-[(alk-u-enylbenzimidazol-2-yl)-methylene]-
m-xylene, reflux, 2 h
Ph
( )n
( )n
15-17
19, n = 0, 70%
20, n = 1, 50%
4, n = 2, 77%
Scheme 2. Isolated yields of cycloadducts from thermolysis of Eschenmoser
hydrazones.
Ph
N
H
N
N
N
N
N
PhH, reflux, 2 h
45%
N
Ph
N
21
15
Scheme 3. [3þ2] Pyrazoline cycloadduct isolated at lower temperature.

4198
S. Hehir et al. / Tetrahedron 64 (2008) 4196e4203
Ph
N
N
N
m-xylene
reflux, 2 h
N
H
N
N
N
+
Ph
N
18
5, 11%
22, 22%
N
N
+
23, 33%
Scheme 4. Isolated yields of products formed from the thermolysis of N-hex-5-enyl Eschenmoser hydrazone 18.
ring expanded [1,2-a]alicyclic ring fused benzimidazoles
a worthwhile endeavour. This led us to prepare Eschenmoser
hydrazones 17 and 18, and to investigate their thermolysis in
m-xylene under reflux. Scheme 2 shows that the formation
of 7,8-dimethylcyclopropa[3,4]azepino[1,2-a]benzimidazole
4 occurred remarkably efficiently in higher yield (77%) than
the formation of the respective 5:3 and 6:3 adducts 19 and
20. Thermolysis of hydrazone 18 in m-xylene under reflux
gave the impressive 8:3 macrocyclic system, cyclopropa-
[3,4]azocino[1,2-a]benzimidazole 5 albeit in a poor yield of
11%, with products of intramolecular 22 and intermolecular
23 benzimidazolyl-2-carbenyl CH-insertion reactions formed
in, respectively, higher yields of 22 and 33% (Scheme 4).
Literature solvent CH-insertions are known, and occur when
intramolecular diazomethine cycloaddition is less favoured,13
which accounts for the formation of m-xylene adduct 23.
The formation of 1,5-CH-insertion adduct 22 is perhaps
expected given that this reaction pathway accounts for the
major products in the thermolysis of diazocyclooctane and
diazocyclononane.17
Nitration for 6 h using mixtures of concd nitric and sulfuric
acid gave a mixture of mono and dinitro derivatives 24 and
25 in 14 and 46% yield, respectively (Scheme 5). Increasing
the reaction time to 12 h gave 25 selectively in 79% yield,
which was reduced to the diamine in situ and oxidised with
ferric chloride to 3 in good yield of 76%.
2.3. Influence of methyl substituents on cytotoxicity
of benzimidazolequinones
4,5-Dimethylcyclopropapyrrolo[1,2-a]benzimidazolequi-
none 3 (IC50¼6.3 mmol dmꢀ3, ꢂ0.7 mmol dmꢀ3) was found to
be nearly one thousand times less cytotoxic than
,
1
towards
(IC50¼0.0069 mmol dmꢀ3
ꢂ0.0003 mmol dmꢀ3 2
)
human skin fibroblast GM00637 cells. The cytotoxicity of 3
was closer to that of MMC (IC50¼0.9 mmol dmꢀ3) using the
same assay.2 While, the potency of 1 almost tripled, the cyto-
toxicity of 3 did not vary significantly under hypoxic condi-
tions (Fig. 2). The inductive donation of the methyl
substituents into the oxidising quinone moiety of 3 will lead
to a more negative reductive potential,2 seemingly decreasing
the rate of conversion of the prodrug quinone to the
reductively activated biologically active forms. Similarly, the
2.2. Synthesis of 4,5-dimethylcyclopropa[3,4]pyrrolo-
[1,2-a]benzimidazole-3,6-dione 3
The presence of 4,5-dimethyl substituents on the fused
benzene part allowed conversion of 19 into benzimidazolequi-
none 3 by a nitration, reduction and oxidation sequence.2
100
80
60
40
20
0
NO2
NO2
N
N
N
N
N
N
(i) or (ii)
+
NO2
19
24
25
O
O
(iii), (iv)
N
25
0.0001
0.001
0.01
Concentration / mol dm-3
0.1
1
10
N
3
Figure 2. Cytotoxicity measurements using the MTT assay (shown using a log-
arithmic scale for concentration) on human skin fibroblast cells following
treatment with cyclopropapyrrolo[1,2-a]benzimidazolequinone 1 (C, B)
and 4,5-dimethyl analogue 3 (-, ,) under aerobic (open symbols) and
hypoxic conditions (closed symbols) for 24 h at 37 ꢁC. Each data point
represents the mean of at least three independent experiments.
Scheme 5. Preparation of benzimidazolequinone 3: (i) 50:50 mixture of concd
HNO3 and concd H2SO4, 6 h, yield¼14 and 46% for compounds 24 and 25,
respectively; (ii) 50:50 mixture of concd HNO3 and concd H2SO4, 12 h,
yield¼0 and 79% for compounds 24 and 25, respectively; (iii) PtO2, H2,
40 psi, EtOH, 17 h; (iv) FeCl3 (aq), rt, 12 h, yield¼76% for compound 3.

S. Hehir et al. / Tetrahedron 64 (2008) 4196e4203
4199
cytotoxicity and selectivity towards hypoxia of pyrido
[1,2-a]benzimidazolequinones was previously found to be
significantly decreased by the presence of 7,8-dimethyl sub-
stituents.2 These results support the analogy of single electron
reducing enzymes such as NADPH-cytochrome c reductase
being involved in biological activity.2,8,18
of Swansea). Electron impact (EI, EIþ) and chemical ionisa-
tion (CI, CIþ) mass spectra for compounds 11e14 and 20
were obtained on a Micro Mass GTC spectrometer and all el-
emental analyses were carried out on PerkineElmer 2400 Se-
ries II analyzer at NUI, Galway. Hydrazones 15e18 were
stable when stored in a freezer, but degraded within hours at
room temperature hence elemental analysis or HRMS were
not obtained.
3. Conclusion
5,6-Dimethyl-N-[(alk-u-enylbenzimidazol-2-yl)-methyl-
ene]-trans-2,3-diphenylaziridin-1-amines (Eschenmoser hy-
drazones) are shown to be valuable precursors for the
preparation of five, six and seven membered [1,2-a]alicyclic
ring fused benzimidazoles containing a fused cyclopropane
ring. Thermolysis of 5,6-dimethyl-N-[(hex-5-enyl-benzimid-
azol-2-yl)-methylene]-trans-2,3-diphenylaziridin-1-amine gave
cyclopropane fused onto an eight membered [1,2-a]alicyclic
ring as the minor product with the formation of benzimid-
azolyl-2-carbenyl CH-insertion products given in higher yields.
Nitration, reduction and oxidation of 4,5-dimethylcyclopropa-
pyrrolo[1,2-a]benzimidazole to the benzimidazolequinone is
a facile process. Dimethyl substituents on the benzimidazole-
quinones were found to significantly reduce cytotoxicity
towards human skin cells and selectivity to those grown under
hypoxic conditions, which are found inside solid tumours.
4.2. 5,6-Dimethylbenzimidazole-2-methanol 6
4,5-Diamino-o-xylene (10.00 g, 73 mmol) and glycolic
acid (8.32 g, 0.109 mol) in 4 M HCl (150 mL) were heated
under reflux for 1 h. The reaction mixture was filtered, and
basified with 6 M NH4OH until a precipitate was formed,
which was recrystallised twice from MeOH to give 6
(7.76 g, 60%), as a buff solid; mp 244e246 ꢁC, dec (mp19
244 ꢁC, dec); dH (CD3OD) 2.43 (s, 6H, CH3), 5.15 (s, 2H,
CH2), 7.54 (s, 2H, AreH), OH and NH not observed; dC
(CD3OD) 20.4 (2ꢃCH3), 56.6 (CH2), 114.5, 131.0, 137.3.
4.3. General procedure for the synthesis of 5,6-dimethyl-
(N-alken-u-enyl)benzimidazole-2-methanols
4.3.1. (1-Allyl-5,6-dimethyl-1H-benzimidazol-2-yl)-
methanol 7
4. Experimental
Triethylamine (7.8 mL, 56 mmol) was added to a stirring
solution of 6 (5.00 g, 28 mmol) in DMF (60 mL) and the mixture
heated under reflux for 1 h. Allyl iodide (3.1 mL, 34 mmol) was
added and the solution heated under reflux for 3 h. The reaction
mixture was cooled and H2O added (7 mL). The aqueous mix-
ture was extracted into EtOAc (3ꢃ20 mL), dried (MgSO4) and
evaporated to dryness. The residue was purified by column chro-
matography using silica gel as absorbent with gradient elution
using hexane and EtOAc as eluent to give 7 (2.78 g, 46%), as
4.1. General
All Chemicals were purchased from SigmaeAldrich and
reactions were carried out in freshly dried and distilled
solvents. Flash column and thin layer chromatography were,
respectively, carried out using Merck silica gel 60, 234e40
mesh as absorbent and aluminium backed plates coated with
silica gel (Merck Kieselgel 60 F254).
a pale brown solid; Rf 0.16 (EtOAc); mp 156e157 ꢁC. nmax
/
Melting points were determined on a Stuart melting point
apparatus and are uncorrected. IR spectra were determined
on a PerkineElmer Spectrum 1000 FT-IR spectrophotometer
with ATR accessory. 1H NMR (399.8 Hz) and 13C NMR
(100.5 Hz) spectra were recorded in CDCl3, unless otherwise
stated and measured on a JEOL GXFT 400 MHz instrument.
Data are expressed in parts per million downfield from
SiMe4 as internal standard or relative to CHCl3. All J values
are given in hertz. Assignments were supported by HMQC
1He13C NMR 2D spectra for compounds 3e5, 21 and 22 and
DEPT for compounds 4e8, 13, 15, 18 and 20e25. NMR
assignments for compounds 19 and 24 are based on those
previously reported for 1,1a,8,8a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-a]benzimidazole4 and 7,8-dimethyl-6-nitro-1,2,3,
4-tetrahydropyrido[1,2-a]benzimidazole,2 respectively. X-ray
crystal data for 3,3a,4,10b-tetrahydropyrazolo[30,40:3,4]-
pyrrlo[1,2-a]benzimidazole was used to support the structure
of 21.3 High resolution mass spectra were obtained on the Fin-
nigan MAT 900 XLT with accurate mass obtained by manual
peak matching using electrospray ionisation (ESI, ESþ) from
the EPSRC National Mass Spectrometry Service (University
cmꢀ1 3126 (OH), 2855, 1477, 1411, 1341, 1036, 1000; dH
2.32 (s, 3H, CH3), 2.34 (s, 3H, CH3), 4.78e4.82 (m, 4H,
NCH2 and CH2OH), 4.97 (d, 1H, J 17.0, 30-trans-H), 5.17 (d,
1H, J 11.2, 30-cis-H), 5.91e6.00 (m, 1H, 20-H), 7.01 (s, 1H, 7-
H), 7.42 (s, 1H, 4-H), OH not observed; dC 20.3 (CH3), 20.7
(CH3), 45.9 (NCH2), 56.9 (CH2OH), 110.1 (7-CH), 117.3 (30-
CH2), 119.5 (4-CH), 131.3 (C), 132.0 (C), 132.2 (20-CH),
133.3 (C), 139.6 (C), 153.0 (Im-2-C). Anal. Calcd for
C13H16N2O (%): C, 72.2; H, 7.5; N, 12.9. Found (%): C, 71.9;
H, 7.6; N, 12.8.
4.3.2. (1-But-3-enyl-5,6-dimethyl-1H-benzimidazol-2-
yl)methanol 8
Triethylamine (7.8 mL, 56 mmol), 6 (5.00 g, 28 mmol) and
4-bromo-1-butene (3.5 mL, 34 mmol) in DMF (60 mL) gave 8
(2.30 g, 35%), as a pale brown solid; Rf 0.25 (EtOAc); mp
126e127 ꢁC. nmax/cmꢀ1 3079 (OH), 2847, 1479, 1413,
1354, 1330, 1052; dH 2.33 (s, 3H, CH3), 2.36 (s, 3H, CH3),
2.54e2.59 (m, 2H, 20-CH2), 4.23 (t, J 7.5, 2H, NCH2), 4.80
(s, 2H, CH2OH), 5.03e5.07 (m, 2H, 40-CH2), 5.75e5.83 (m,
1H, 30-H), 7.05 (s, 1H, 7-H), 7.42 (s, 1H, 4-H), OH not

4200
S. Hehir et al. / Tetrahedron 64 (2008) 4196e4203
observed; dC 20.3 (CH3), 20.7 (CH3), 34.1 (20-CH2), 43.4
(NCH2), 56.8 (CH2OH), 110.0 (7-CH), 118.1 (40-CH2),
119.4 (4-CH), 131.2 (C), 132.1 (C), 133.5 (30-CH), 134.0
(C), 140.2 (C), 153.1 (Im-2-C). Anal. Calcd for C14H18N2O
(%): C, 73.0; H, 7.8; N, 12.1. Found (%): C, 73.1; H, 7.8; N
12.1.
110.8 (7-CH), 117.4 (30-CH2), 121.9 (4-CH), 132.2 (C), 133.9
(20-CH), 135.2 (C), 137.4 (C), 141.8 (C), 145.3 (Im-2-C),
184.6 (CHO); m/z (EI) 214 (Mþ, 20%), 185 (100), 121 (42);
HRMS (EI): found Mþ, 214.1102. C13H14N2O requires,
214.1106.
4.4.2. 1-But-3-enyl-5,6-dimethyl-1H-benzimidazole-2-
carbaldehyde 12
4.3.3. (1-Pent-4-enyl-5,6-dimethyl-1H-benzimidazol-2-
yl)methanol 9
Alcohol 8 (0.150 g, 0.65 mmol) and activated MnO2
(1.69 g, 19.5 mmol) in CH2Cl2 (150 mL) gave 12 (0.105 g,
71%), as a yellow solid; Rf 0.64 (EtOAc); mp 88e90 ꢁC.
nmax/cmꢀ1 1696 (C]O), 1484, 1467, 1440, 1413, 1364,
1221, 999, 930; dH 2.41 (s, 3H, CH3), 2.44 (s, 3H, CH3),
2.56e2.60 (m, 2H, 20-CH2), 4.64 (t, J 7.2, 2H, NCH2),
4.99e5.02 (m, 2H, 40-CH2), 5.74e5.82 (m, 1H, 30-H), 7.22
(s, 1H, 7-H), 7.66 (s, 1H, 4-H), 10.05 (s, 1H, CHO); dC 20.4
(CH3), 21.1 (CH3), 34.5 (20-CH2), 44.0 (NCH2), 110.6 (7-
CH), 118.0, 121.8, 133.7 (30-CH and C), 135.1, 137.2, 141.7
(all C), 145.5 (Im-2-C), 184.7 (CHO); m/z (EI) 228 (Mþ,
100%); HRMS (EI): found Mþ, 228.1267. C14H16N2O
requires, 228.1263.
Triethylamine (7.8 mL, 56 mmol), 6 (5.00 g, 28 mmol) and
5-bromo-1-pentene (4.0 mL, 34 mmol) in DMF (60 mL) gave
9 (3.10 g, 45%), as a pale brown solid; Rf 0.21 (EtOAc); mp
121e122 ꢁC. nmax/cmꢀ1 3137 (OH), 2923, 2853, 1482, 1465,
1430, 1349, 1211, 998, 972; dH 1.89e1.96 (m, 2H, CH2),
2.10e2.16 (m, 2H, CH2), 2.32 (s, 3H, CH3), 2.35 (s, 3H,
CH3), 4.17 (t, 2H, J 7.5, NCH2), 4.79 (s, 2H, CH2OH), 5.02e
5.08 (m, 2H, 50-CH2), 5.76e5.86 (m, 1H, 40-H), 7.03 (s, 1H,
7-H), 7.39 (s, 1H, 4-H), OH not observed; dC 20.3 (CH3), 20.7
(CH3), 28.9, 30.9 (both CH2), 43.4 (NCH2), 56.9 (CH2OH),
110.0 (7-CH), 115.9 (50-CH2), 119.5 (4-CH), 131.2, 132.1,
133.8 (all C), 137.1 (40-CH), 140.3 (C), 152.9 (Im-2-C). Anal.
Calcd for C15H20N2O (%): C, 73.7; H, 8.2; N, 11.4. Found
(%): C, 73.6; H, 8.2; N, 11.1.
4.4.3. 1-Pent-4-en-1-yl-5,6-dimethyl-1H-benzimidazole-2-
carbaldehyde 13
4.3.4. (1-Hex-5-enyl-5,6-dimethyl-1H-benzimidazol-2-
yl)methanol 10
Alcohol 9 (0.200 g, 0.81 mmol) and activated MnO2
(2.11 g, 24.3 mmol) in CH2Cl2 (160 mL) gave 13 (0.150 g,
76%), as a yellow solid; Rf 0.28 (CH2Cl2); mp 89e90 ꢁC.
nmax/cmꢀ1 2845, 1690 (C]O), 1486, 1468, 1413, 1360,
1264, 1003, 917; dH 1.89e1.95 (m, 2H, 20-CH2), 2.09e2.14
(m, 2H, 30-CH2), 2.39 (s, 3H, CH3), 2.42 (s, 3H, CH3), 4.55
(t, J 7.5, 2H, NCH2), 5.00e5.06 (m, 2H, 50-CH2), 5.77e5.84
(m, 1H, 40-H), 7.21 (s, 1H, 7-H), 7.65 (s, 1H, 4-H), 10.04 (s,
1H, CHO); dC 20.3 (CH3), 21.1 (CH3), 29.3, 30.7 (both
CH2), 44.2 (NCH2), 110.5 (7-CH), 115.6 (50-CH2), 121.7
(4-CH), 133.6, 135.1, 137.0 (all C), 137.1 (40-CH), 141.7
(C), 145.4 (Im-2-C), 184.5 (CHO); m/z (EI) 242 (Mþ,
100%), 227 (8); HRMS (EI): found Mþ, 242.1417.
C15H18N2O requires, 242.1419.
Triethylamine (7.8 mL, 56 mmol), 6 (5.00 g, 28 mmol) and
6-bromo-1-hexene (4.5 mL, 34 mmol) in DMF (6 mL) gave 10
(2.70 g, 37%), as a pale brown solid; Rf 0.43 (EtOAc/
10%MeOH); mp 88e89 ꢁC. nmax/cmꢀ1 3144, 2917, 2853,
1512, 1481, 1432, 1356, 1327, 1228, 998; dH 1.43e1.50 (m,
2H, 30-CH2), 1.81e1.85 (m, 2H, 20-CH2), 2.05e2.15 (m, 2H,
40-CH2), 2.33 (s, 3H, CH3), 2.36 (s, 3H, CH3), 4.17 (t, J 7.5,
2H, NCH2), 4.79 (s, 2H, CH2OH), 4.97e5.02 (m, 2H, 60-
CH2), 5.72e5.79 (m, 1H, 50-H), 7.03 (s, 1H, 7-H), 7.40 (s,
1H, 4-H), OH peak not observed; dC 20.1 (CH3), 20.5 (CH3),
26.1, 29.3, 33.2 (all CH2), 43.7 (NCH2), 56.0 (CH2OH),
110.0 (7-CH), 115.0 (60-CH2), 119.1 (4-CH), 131.0, 132.0,
133.4 (all C), 138.0 (50-CH), 140.0 (C), 153.0 (Im-2-C). Anal.
Calcd for C16H22N2O (%): C, 74.4; H, 8.6; N, 10.8. Found
(%): C, 74.2; H, 8.8; N, 10.5.
4.4.4. 1-Hex-5-en-1-yl-5,6-dimethyl-1H-benzimidazole-2-
carbaldehyde 14
4.4. General procedure for the synthesis of 5,6-dimethyl-
(N-alken-u-enyl)benzimidazole-2-carbaldehydes
Alcohol 10 (0.250 g, 0.97 mmol) and activated manganese
dioxide (2.61 g, 30.0 mmol) in CH2Cl2 (180 mL) gave 14
(0.180 g, 73%), as a yellow solid; Rf 0.37 (50:50 hexane/
Et2O); mp 95e96 ꢁC. nmax/cmꢀ1 2939, 2859, 1678 (C]O),
1485, 1468, 1413, 1248, 1184, 998; dH 1.39e1.46 (m, 2H,
30-CH2), 1.78e1.85 (m, 2H, 20-CH2), 2.02e2.08 (m, 2H,
40-CH2), 2.43 (s, 3H, CH3), 2.48 (s, 3H, CH3), 4.57 (t, J 7.4,
2H, NCH2), 4.96e5.02 (m, 2H, 60-CH2), 5.70e5.80 (m, 1H,
50-H), 7.22 (s, 1H, 7-H), 7.66 (s, 1H, 4-H), 10.05 (s, 1H,
CHO); dC 20.1 (CH3), 21.1 (CH3), 25.9, 29.7, 33.2 (all
CH2), 44.6 (NCH2), 110.6 (7-CH), 115.0 (60-CH2), 121.8
(4-CH), 133.7, 135.2, 137.2 (all C), 138.0 (50-CH), 141.1
(C), 145.8 (Im-2-C), 184.6 (CHO); m/z (EI) 256 (Mþ,
100%); HRMS (EI): found Mþ, 256.1574. C16H20N2O
requires, 256.1576.
4.4.1. 1-Allyl-5,6-dimethyl-1H-benzimidazole-2-
carbaldehyde 11
Alcohol 7 (1.20 g, 5.5 mmol) and activated MnO2 (14.50 g,
0.166 mol) were stirred and heated under reflux in CH2Cl2
(1000 mL) for 0.5 h. The cooled reaction mixture was filtered
and the filtrate was evaporated to dryness to give 11 (0.91 g,
75%), as a yellow solid; Rf 0.49 (CH2Cl2); mp 87e88 ꢁC.
nmax/cmꢀ1 1682 (CHO), 1483, 1454, 1412, 1327, 1235, 1008,
964, 920; dH 2.36 (s, 3H, CH3), 2.39 (s, 3H, CH3), 4.97 (d, 1H,
J 16.2, 30-trans-H), 5.12e5.16 (m, 3H, 30-cis-H and NCH2),
5.90e5.95 (m, 1H, 20-H), 7.17 (s, 1H, 7-H), 7.63 (s, 1H, 4-H),
10.02 (s, 1H, CHO); dC 20.5 (CH3), 21.2 (CH3), 46.8 (NCH2),

S. Hehir et al. / Tetrahedron 64 (2008) 4196e4203
4201
4.5. General procedure for the synthesis of 5,6-dimethyl-N-
4.5.4. N-[(Hex-5-enyl-5,6-dimethyl-1H-benzimidazol-2-yl)-
[(alk-u-enyl-benzimidazol-2-yl)-methylene]-trans-2,3-
methylene]-(trans)-2,3-diphenylaziridin-1-amine 18
diphenylaziridin-1-amines (Eschenmoser hydrazones)
1-Amino-trans-2,3-diphenylaziridine (0.100 g, 0.47 mmol)
and aldehyde 14 (90 mg, 0.35 mmol) in Et2O (9 mL) gave
18 (0.140 g, 89%), as a yellow solid; Rf 0.31 (60:40 hexane/
EtO2); mp 113e114 ꢁC. nmax/cmꢀ1 2915, 2856, 1601, 1484,
1449, 1430, 1330, 1157, 1000, 908; dH 1.15e1.20 (m, 2H,
30-CH2), 1.46e1.51 (m, 2H, 20-CH2), 1.90e1.95 (m, 2H, 40-
CH2), 2.34 (s, 3H, CH3), 2.37 (s, 3H, CH3), 3.80 (s, 2H,
aziridine-H), 4.13e4.17 (m, 2H, NCH2), 4.96e5.00 (m, 2H,
60-CH2), 5.70e5.77 (m, 1H, 50-H), 7.05 (s, 1H, 7-H), 7.26e
7.39 (m, 10H, AreH), 7.49 (s, 1H, 4-H), 8.47 (s, 1H,
CH]N); dC 20.3 (CH3), 20.9 (CH3), 25.9, 29.7, 33.4, 44.6
(all CH2), 110.1 (7-CH), 114.9 (60-CH2), 120.4 (4-CH),
126.6e128.9 (AreCH), 131.8, 133.8, 135.1 (all C), 138.5
(50-CH), 141.9, 145.4 (both C), 151.7 (CH]N).
4.5.1. N-[(Allyl-5,6-dimethyl-1H-benzimidazol-2-yl)-
methylene]-(trans)-2,3-diphenylaziridin-1-amine 15
1-Amino-trans-2,3-diphenylaziridine (97 mg, 0.46 mmol)
was added to a solution of aldehyde 11 (0.100 g, 0.46 mmol)
in Et2O (7 mL), and the mixture was stirred at 0 ꢁC for
8.5 h. The solution was evaporated to dryness and the residue
was purified by column chromatography using silica gel as ab-
sorbent with hexane and Et2O as eluent to give 15 (0.160 g,
84%), as a white solid; Rf 0.43 (60:40 hexane/Et2O); mp
126e127 ꢁC. nmax/cmꢀ1 2972, 1618, 1492, 1449, 1411,
1327, 1155, 1008, 964, 920; dH 2.33 (s, 3H, CH3), 2.35 (s,
3H, CH3), 3.79 (s, 2H, aziridine-H), 4.75 (d, J 17.1, 1H,
30-trans-H), 4.82e4.86 (m, 2H, NCH2), 5.00 (d, J 10.3,
1H, 30-cis-H), 5.56e5.68 (m, 1H, 20-H), 7.02 (s, 1H, 7-H),
7.27e7.48 (m, 10H, PheH), 7.51 (s, 1H, 4-H), 8.43 (s, 1H,
CH]N); dC 20.2 (CH3), 20.9 (CH3), 47.0 (NCH2 and aziri-
dine-CH), 110.3 (7-CH), 116.4 (30-CH2), 120.4 (4-CH),
126.4, 127.7, 127.9, 128.5, 128.8 (all CH), 132.3 (C), 132.8
(20-CH), 134.2, 135.1, 141.8 (all C), 145.4 (Im-2-C), 151.7
(CH]N).
4.6. General procedure for thermolysis of Eschenmoser
hydrazones
4.6.1. 4,5-Dimethyl-1,1a,8,8a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-a]benzimidazole 19
Hydrazone 15 (0.120 g, 0.295 mmol) in m-xylene (20 mL)
was heated under reflux for 2 h. The solution was evaporated
to dryness to give a residue, which was purified by column chro-
matography using silica gel as absorbent with hexane and
EtOAc as eluent to give 19 (41 mg, 70%), as a brown solid; Rf
0.51 (EtOAc/10%MeOH); mp 130e131 ꢁC. nmax/cmꢀ1 2920,
1628, 1535, 1459, 1410, 1357, 1311, 1271, 1141, 1031, 955;
dH 0.73e0.75 (m, 1H, 1-H), 1.35e1.37 (m, 1H, 1-H), 2.32 (s,
6H, CH3), 2.43e2.48 (m, 2H, 1a and 8a-H), 4.02e4.08 (m,
2H, 8-CH2), 6.95 (s, 1H, 6-H), 7.40 (s, 1H, 3-H); dC 14.7 (1a
or 8a-CH), 16.2 (1-CH2), 20.3 (CH3), 20.4 (CH3), 20.7 (1a or
8a-CH), 45.5 (8-CH2), 109.5 (6-CH), 119.8 (3-CH), 130.1,
130.8, 131.0, 146.8 (all C), 161.4 (Im-1b-C); m/z (ESI) 199
([MþH]þ, 100%), 185 (3), 52 (16); HRMS (ESI): found
MHþ, 199.1231. C13H15N2 requires, 199.1230.
4.5.2. N-[(But-3-enyl-5,6-dimethyl-1H-benzimidazol-2-yl)-
methylene]-trans-2,3-diphenylaziridin-1-amine 16
1-Amino-trans-2,3-diphenylaziridine (0.130 g, 0.61 mmol)
and aldehyde 12 (0.140 g, 0.61 mmol) in Et2O (10 mL)
gave 16 (0.170 g, 66%), as a white solid; Rf 0.80 (EtOAc);
mp 114e115 ꢁC. nmax/cmꢀ1 2925, 1617, 1604, 1496, 1450,
1429, 1331, 1006, 957, 915; dH 2.18e2.23 (m, 2H, 20-CH2),
2.35 (s, 3H, CH3), 2.38 (s, 3H, CH3), 3.83 (s, 2H, aziridine-
H), 4.21 (t, J 7.5, 2H, NCH2), 4.87e4.95 (m, 2H, 40-CH2),
5.48e5.57 (m, 1H, 30-H), 7.05 (s, 1H, 7-H), 7.25e7.40 (m,
10H, PheH), 7.49 (s, 1H, 4-H), 8.50 (s, 1H, CH]N); dC
20.3 (CH3), 20.8 (CH3), 33.8 (20-CH2), 43.9 (NCH2),
110.0 (7-CH), 116.9 (40-CH2), 120.3 (4-CH), 127.8, 128.4,
131.8, 133.8, 134.4, 134.9, 141.5, 145.2 (Im-2-C), 151.6
(CH]N).
4.6.2. 6,7-Dimethyl-1a,2,3,9b-tetrahydro-1H-cyclopropa-
[3,4]pyrido[1,2-a]benzimidazole 20
Hydrazone 16 (0.150 g, 0.36 mmol) in m-xylene (20 mL)
gave 20 (38 mg, 50%), as a brown solid; Rf 0.24 (EtOAc); mp
136e137 ꢁC. nmax/cmꢀ1 2922, 2854, 1524, 1457, 1402, 1363,
1315, 1027, 998; dH 1.01e1.05 (m, 1H, 1-H), 1.15e1.21 (m,
1H, 1-H), 1.78e1.83 (m, 1H, 2-H), 2.10e2.19 (m, 1H, 2-H),
2.29e2.43 (s, 8H, CH3 and 1a and 9b-H), 3.52e3.60 (m, 1H,
3-H), 4.12e4.17 (m, 1H, 3-H), 6.98 (s, 1H, 5-H), 7.42 (s, 1H,
8-H); dC 9.3 (CH2), 11.3 (1a-CH), 13.3 (9b-CH), 20.2 (CH3),
20.4 (CH3), 20.5 (CH2), 37.3 (3-CH2), 108.5 (5-CH), 118.8
(8-CH), 130.2, 130.3, 132.9, 141.4, 152.5 (all C); m/z (CI) 213
([MþH]þ, 100%), 114 (25); HRMS (ESI): found MHþ,
213.1388. C14H17N2 requires, 213.1386.
4.5.3. N-[(Pent-4-enyl-5,6-dimethyl-1H-benzimidazol-2-yl)-
methylene]-trans-2,3-diphenylaziridin-1-amine 17
1-Amino-trans-2,3-diphenylaziridine (0.120 g, 0.58 mmol)
and aldehyde 13 (0.140 g, 0.58 mmol) in Et2O (10 mL) gave
17 (0.180 g, 72%) as a yellow oil; Rf 0.75 (Et2O). nmax/cmꢀ1
(neat) 3028, 2926, 1602, 1497, 1450, 1416, 1328, 1165, 999;
dH 1.53e1.62 (m, 2H, 20-CH2), 1.82e1.90 (m, 2H, 30-CH2),
2.33 (s, 3H, CH3), 2.37 (s, 3H, CH3), 3.82 (s, 2H, aziridine-
H), 4.14 (t, J 7.4, 2H, NeCH2), 4.94e4.98 (m, 2H, 50-CH2),
5.65e5.72 (m, 1H, 40-H), 7.04 (s, 1H, 7-H), 7.27e7.39 (m,
10H, ArH), 7.53 (s, 1H, 4-H), 8.52 (s, 1H, CH]N); dC 20.4
(CH3), 20.9 (CH3), 33.4 (2ꢃCH2), 44.6 (NCH2), 110.1 (7-
CH), 114.8 (50-CH2), 120.4 (4-CH), 126.6e128.7 (AreCH),
131.8, 133.8, 135.1, 138.5 (CH), 141.9 (C), 145.4 (Im-2-C),
151.6 (CH]N).
4.6.3. 7,8-Dimethyl-3,3a,4,10b-tetrahydropyrazolo-
[30,40:3,4]pyrrolo[1,2-a]benzimidazole 21
Hydrazone 15 (0.120 g, 0.295 mmol) in PhH (20 mL)
gave 21 (30 mg, 45%), as
a yellow solid; Rf 0.43

4202
S. Hehir et al. / Tetrahedron 64 (2008) 4196e4203
(EtOAc/10%MeOH); mp 186e187 ꢁC; nmax/cmꢀ1 2922, 2852,
1521, 1459, 1415, 1356, 1287, 1009, 984; dH 2.34 (s, 3H,
CH3), 2.35 (s, 3H, CH3), 3.53e3.61 (m, 1H, 3a-H), 3.66e
3.70 (m, 1H, 4-H), 4.27e4.31 (m, 1H, 4-H), 4.74e4.88 (m,
2H, 3-CH2), 6.09 (d, J 8.4, 1H, 10b-H), 7.03 (s, 1H, 6-H),
7.54 (s, 1H, 9-H); dC 20.5 (CH3), 20.6 (CH3), 36.9 (3a-CH),
48.8 (4-CH2), 84.2 (3-CH2), 90.9 (10b-CH), 110.1 (6-CH),
120.9 (9-CH), 130.2, 131.5, 132.2, 147.9, 153.3 (all C).
(5-CH), 130.1, 131.0, 140.6 (all C), 141.6 (30-CH), 154.8
(Im-3a-C); m/z (ESI) 241 ([MþH]þ, 100%), 60 (4); HRMS
(ESI): found MHþ, 241.1702. C16H21N2 requires, 241.1699.
The third product eluted was 5 (10 mg, 11%), as a white solid;
Rf 0.37 (EtOAc); mp 120e122 ꢁC. nmax/cmꢀ1 2920, 1526,
1478, 1464, 1407, 1354, 1312, 1136, 1023, 996; dH 0.20e
0.26 (m, 1H), 0.91e0.93 (m, 1H), 1.16e1.23 (m, 2H), 1.53e
1.59 (m, 2H), 1.80e1.86 (m, 2H), 2.05e2.12 (m, 2H, 4-CH2),
2.36 (s, 3H, CH3), 2.38 (s, 3H, CH3), 4.24e4.38 (m, 2H, 5-
CH2), 7.03 (s, 1H, 7-H), 7.47 (s, 1H, 10-H); dC 10.3 (1a-CH),
13.5 (1-CH2), 19.9 (3-CH2), 20.3 (CH3), 20.6 (CH3), 28.4
(11b-CH), 29.0 (4-CH2), 30.2 (2-CH2), 43.6 (5-CH2), 109.3
(7-CH), 119.6 (10-CH), 130.4 (C), 131.1 (C), 137.6 (C),
140.9 (C), 153.9 (11a-C); m/z (ESI) 241 ([MþH]þ, 100%),
217 (4), 60 (4); HRMS (ESI): found MHþ, 241.1700.
C16H21N2 requires, 241.1699.
4.6.4. 7,8-Dimethyl-1,1a,2,3,4,10b-hexahydrocyclopropa-
[3,4]azepino[1,2-a]benzimidazole 4
Hydrazone 17 (0.150 g, 0.35 mmol) in m-xylene (20 mL)
gave 4 (61 mg, 77%), as yellow oil; Rf 0.56 (EtOAc/
10%MeOH). nmax/cmꢀ1 2919, 1524, 1456, 1403, 1364, 1314,
1026; dH 0.40e0.45 (m, 1H, 1a-H), 0.70e0.74 (m, 1H, 1-H),
1.23e1.28 (m, 2H, 1-H, 10b-H), 1.78e1.83 (m, 2H, 2-CH2),
2.14e2.23 (m, 2H, 3-CH2), 2.34 (s, 3H, CH3), 2.36 (s, 3H,
CH3), 4.24e4.30 (m, 1H, 4-H), 4.36e4.44 (m, 1H, 4-H), 7.03
(s, 1H, 6-H), 7.46 (s, 1H, 9-H); dC 11.9, 12.2 (1a-CH or 10b-
CH), 13.4 (1-CH2), 20.3 (CH3), 20.6 (CH3), 23.6 (CH2), 27.0
(CH2), 40.8 (4-CH2), 109.0 (6-CH), 119.5 (9-CH), 130.3,
131.2, 132.6, 141.6 (all C), 153.5 (Im-10a-C); m/z (ESI) 227
([MþH]þ, 100%), 213 (3), 52 (18); HRMS (ESI): found
MHþ, 227.1541. C15H19N2 requires, 227.1543.
4.7. General procedure for nitration
Mixture of concd H2SO4 and fuming HNO3 (50:50 5 mL)
was added to 19 (50 mg, 0.25 mmol), and the mixture stirred
at 0 ꢁC for 6 h. The reaction was basified using NH4OH to pH
12 and extracted into CHCl3 (3ꢃ20 mL). The combined organic
extracts were dried (Na2SO4) and evaporated to dryness. The
residue was purified by column chromatography using silica
gel as absorbent with hexane and EtOAc as eluent to give in
order elution 4,5-dimethyl-3,6-dinitro-1,1a,8,8a-tetrahydrocy-
clopropa[3,4]pyrrolo[1,2-a]benzimidazole 25 (33 mg, 46%),
4.6.5. 8,9-Dimethyl-1a,2,3,4,5,11b-hexahydro-1H-cyclo-
propa[3,4]azocino[1,2-a]benzimidazole 5
Hydrazone 18 (0.170 g, 0.38 mmol) in m-xylene (30 mL)
gave after column chromatography using silica gel as absorbent
with pentane and EtOAc as eluent in order of elution 1-hex-5-
en-1-yl-5,6-dimethyl-2-(3-phenylethyl)-1H-benzimidazole 23
(43 mg, 33%), as a yellow oil; Rf 0.59 (80:20 pentane/EtOAc);
nmax/cmꢀ1 2924, 2857, 1511, 1478, 1465, 1412, 1321, 998; dH
1.38e1.44 (m, 2H, 30-CH2), 1.65e1.71 (m, 2H, 20-CH2),
2.02e2.07 (m, 2H, 40-CH2), 2.32 (s, 3H, CH3), 2.36 (s, 3H,
CH3), 2.38 (s, 3H, CH3), 3.07e3.11 (m, 2H, CH2CH2),
3.16e3.20 (m, 2H, CH2CH2), 3.92 (t, J 7.5, 2H, NCH2),
4.93e5.00 (m, 2H, 60-CH2), 5.69e5.77 (m, 1H, 50-CH),
7.01e7.19 (m, 5H, 7-H and xylene-H), 7.55 (s, 1H, 4-H); dC
20.3, 20.6, 21.4 (all CH3), 26.1, 29.2, 29.7, 33.2, 34.1 (all
CH2), 43.3 (NCH2), 109.6 (7-CH), 115.2 (60-CH2), 119.3 (4-
CH), 125.4, 127.1, 128.3, 128.6, 129.2, 130.5, 131.1, 133.5,
137.9, 141.1, 153.2 (Im-2-C); m/z (ESI) 347 ([MþH]þ,
100%), 74 (3), 60 (4); HRMS (ESI): found MHþ, 347.2476.
C24H31N2 requires, 347.2482. The second product eluted was
2-but-3-enyl-6,7-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]benz-
imidazole 22 (20 mg, 22%), as a yellow solid, Rf 0.30 (50:50
pentane/EtOAc); mp 117e118 ꢁC. nmax/cmꢀ1; 2922, 2851,
1513, 1465, 1241, 1374, 1321, 1264, 1148, 997; dH 0.81e0.97
(m, 1H, 2-H), 1.66e1.76 (m, 2H), 2.06e2.10 (m, 2H), 2.35 (s,
3H, CH3), 2.38 (s, 3H, CH3), 2.89e2.95 (dd, J 14.8, 11, 1H,
3-CHH), 3.29 (d, J 14.8, 1H, 3-CHH), 3.91e3.98 (dd, J 14.5,
10.3, 1H, 1-CHH), 4.26e4.30 (m, 1H, 1-CHH), 5.01 (d,
J 10.5, 1H, 40-cis-H), 5.10 (d, J 17.1, 1H, 40-trans-H),
5.77e5.86 (m, 1H, 30-H), 7.04 (s, 1H, 8-H), 7.45 (s, 1H, 5-H);
dC 20.2 (CH3), 20.3 (CH3), 27.2, 35.0, 36.5 (all CH2), 39.7
(2-CH), 44.1 (1-CH2), 109.3 (8-CH), 113.7 (40-CH2), 119.2
as a yellow solid; Rf 0.81 (EtOAc); mp 212e213 ꢁC. nmax
/
cmꢀ1 2919, 1523 (NO2), 1445, 1417, 1391, 1366 (NO2),
1340, 1291, 1243, 1073, 910; dH 0.87e0.90 (m, 1H, 1-H),
1.47e1.53 (m, 1H, 1-H), 2.36 (s, 3H, CH3), 2.43 (s, 3H,
CH3), 2.56e2.62 (m, 2H, 1a and 8a-H), 4.12e4.26 (m, 2H,
8-CH2); dC 14.7 (8a-CH), 15.1 (CH3), 15.8 (CH3), 16.3
(1-CH2), 21.6 (1a-CH), 48.5 (8-CH2), 122.9, 125.6, 125.9,
136.0, 140.4, 144.0 (all-C), 166.0 (Im-1b-C); m/z (ESI) 289
([MþH]þ, 100%), 104 (4), 74.1 (4); HRMS (ESI): found
MHþ, 289.0934. C13H13N4O4 requires, 289.0931. The second
product eluted was 4,5-dimethyl-3-nitro-1,1a,8,8a-tetrahydro-
cyclopropa[3,4]pyrrolo[1,2-a]benzimidazole 24 (9 mg, 14%),
as a brown solid; Rf 0.46 (EtOAc); mp 160e161 ꢁC. nmax
/
cmꢀ1 2920, 1521 (NO2), 1455, 1375, 1359 (NO2), 1310,
1274, 1202, 1040; dH 0.84e0.88 (m, 1H, 1-H), 1.45e1.48 (m,
1H, 1-H), 2.33 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.54e2.59
(m, 2H, 1a and 8a-H), 4.09e4.17 (m, 2H, 8-CH2), 7.15 (s,
1H, 6-H); m/z (ESI) 244 ([MþH]þ, 100%), 215 (3), 111 (4),
105 (4), 68 (7), 60 (17); HRMS (ESI): found MHþ, 244.1080.
C13H14N3O2 requires, 244.1081.
4.8. 4,5-Dimethyl-1,1a,8,8a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-a]benzimidazole-3,6-dione 3
Dinitrobenzimidazole 25 (0.100 g, 0.35 mmol) and PdeC
(27 mg) in EtOH (60 mL) were shaken under 40 psi H2 using
a Parr apparatus for 17 h. FeCl3 (aq) (0.7 M, 20 mL) was added
and stirring continued for 12 h. The mixture was filtered through
Celite and evaporated to dryness. Saturated NaOAc (aq) was

S. Hehir et al. / Tetrahedron 64 (2008) 4196e4203
4203
added and the mixture extracted with CHCl3 (3ꢃ50 mL). The
combined organic extracts were dried (MgSO4) and evaporated
to dryness. The resultant residue was purified by column chro-
matography using silica gel as absorbent with gradient elution
of pentane and EtOAc as eluent to give 3 (60 mg, 76%), as an
orange solid; Rf 0.41 (EtOAc); mp 224e225 ꢁC. nmax/cmꢀ1
2923, 1638 (C]O), 1524, 1475, 1454, 1372, 1306, 1274,
1239, 1179, 1037; dH 0.73e0.77 (m, 1H, 1-H), 1.37e1.43 (m,
1H, 1-H), 1.98 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.45e2.51 (m,
2H, 1a-H and 8a-H), 4.19e4.29 (m, 2H, 8-CH2); dC 11.9
(CH3), 12.6 (CH3), 14.2 (1a-CH or 8a-CH), 15.6 (1-CH2),
21.1 (1a-CH or 8a-CH), 47.9 (8-CH2), 129.0, 138.7, 141.0,
145.2, 161.4, 178.1 (C]O), 181.0 (C]O); m/z (ESI) 229
([MþH]þ, 100%), 68 (3), 60 (5); HRMS (ESI): found MHþ,
229.0973, C13H13N2O2 requires, 229.0972.
Research Council for Science, Engineering and Technology
funded by the National Development Plan. We thank the
NCBES (Galway) for the use of the hypoxic chamber and
some mass spectra analysis (Brendan Harhen).
References and notes
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Acknowledgements
The authors acknowledge the receipt of embark initiative
postgraduate scholarships for S.H. and L.O’D. from the Irish