Synthesis of pyrrolo- and pyrido-[1,2-α]benzimidazolequinone anti-tumor agents containing a fused cyclopropane ring

Article abstract of DOI:10.1055/s-2005-861832

A cyclopropane ring has been fused onto tetrahydropyrrolo- and tetrahydropyrido-[1,2-a]-benzimidazoles and -benzimidazolequinones via the cycloaddition of diazomethines generated from the thermolysis of N-(allyl and but-3-enyl)benzimidazole-2-Eschenmoser hydrazones (aziridinyl imines). At lower temperatures, the 1,3-dipolar [3 + 2] cycloadduct was obtained for only the N-allylbenzimidazole-2-Eschenmoser hydrazones.

Full text of DOI:10.1055/s-2005-861832

PAPER
1069
Synthesis of Pyrrolo- and Pyrido-[1,2-a]benzimidazolequinone Anti-tumor
Agents Containing a Fused Cyclopropane Ring
S
J
ynthesis
o
of Pyrrolo-
a
h
nd Pyrido-[1
n
,2-
a
]benzimidazole
O
quinone
A
nti-tum
’
or
A
gent
S
s
haughnessy, Fawaz Aldabbagh*
Department of Chemistry, National University of Ireland, Galway, Ireland
Fax +353(91)525700; E-mail: Fawaz.Aldabbagh@nuigalway.i.e
Received 6 December 2004
tems pyrrolo- and pyrido-[1,2-a]benzimidazoles contain-
ing a fused cyclopropane ring using benzimidazole-2-
Eschenmoser hydrazone synthetic intermediates.11 The
Abstract: A cyclopropane ring has been fused onto tetrahydropyr-
rolo- and tetrahydropyrido-[1,2-a]-benzimidazoles and -benzimida-
zolequinones via the cycloaddition of diazomethines generated
from the thermolysis of N-(allyl and but-3-enyl)benzimidazole-2- methodology was extended to the preparation of
Eschenmoser hydrazones (aziridinyl imines). At lower tempera- 1,1a,8,8a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-a]benz-
tures, the 1,3-dipolar [3 + 2] cycloadduct was obtained for only the
N-allylbenzimidazole-2-Eschenmoser hydrazones.
imidazole-3,6-dione (4), which is the first prepared diaz-
ole analogue of indolequinone 3.
Key words: benzimidazoles, bioreductive, diazo-compounds, het-
erocycles, hydrazones
Many quinone derivatives are known to have anti-cancer
activity, which is initiated by the reductive activation of
1
the quinone moiety. In the case of mitomycin C (MMC
1
) and aziridinomitosene 2 reductive activation leads to
Figure 1
ring-opening of the aziridine ring and elimination of the
urethane group to create reactive sites at C-1 and C-10, re-
spectively for alkylation of DNA (Figure 1). Moody and
co-workers have prepared analogues of the aziridinomito-
sene 2 in which the aziridine ring is replaced by a cyclo-
propane ring, and named these compounds cyclo-
propamitosene (CPM, 3). The reduced electrophilicity
at C-1 in 3 resulted in selective alkylation of nucleophiles
at C-10 under chemical reducing conditions. CPM 3 was
also shown to undergo single-electron reduction; a pro-
cess that is selective under bioreductive conditions to hy-
Benzimidazolequinone 4 was shown to have a lower re-
ductive potential (–1.052 V, vs. ferrocene, Fc) than in-
dolequinones 1 (–1.421 V, vs. Fc) and 3 (–1.395 V, vs. Fc)
under analogous cyclic voltammetry conditions. A revers-
ible one electron reduction was observed at low scan rates
in contrast to other reported benzimidazolequinone anti-
tumor agents that show cytotoxic activity via a two-elec-
tron reductive activation mediated by DT-diaphorase in
2
–7
5
1
0,12
an O -independent pathway.
A full account of the syn-
2
poxic or O -deficient cells present in solid tumours, as it
is reversed in the presence of O in healthy cells. Under
hypoxic conditions, 3 was shown to be 34 and 3 times
more toxic than under aerobic conditions and MMC 1 un-
2
thesis of anti-tumor agent 4 and analogues is given in the
present paper, including a first report of the new benzim-
idazolequinone,
pa[3,4]pyrido[1,2-a]benzimidazole-5,8-dione (5).
5
,6
2
1a,2,3,9b-tetrahydro-1H-cyclopro-
5
,6
der hypoxic conditions, respectively. Bioreduction of 3
to the semiquinone radical anion was speculated to induce
radical-ring opening of the cyclopropane ring to give a
radical capable of abstracting the 4¢-hydrogen from the
deoxyribose part of DNA leading to strand cleavage.5
Therefore, the greater selectivity of CPM 3 toward hy-
poxic conditions, and the different mode of action to 1 and
The construction of the tetracyclic cyclopropapyrrolo-
and cyclopropapyrido-[1,2-a]benzimidazole skeleton was
accomplished by successful intramolecular cycloaddition
of N-(allyl and but-3-enyl)benzimidazole-2-diazo-
methines 6 and 7, respectively.
–7
Synthetic pathways toward the preparation of benzimida-
zole-2-hydrazone precursors of 6 and 7 began with the N-
alkylation of 1H-benzimidazol-2-ylmethanol 8, rather
than 1H-benzimidazole-2-carbaldehyde. N-Alkylation of
2
, makes the synthesis of structurally related heterocyclic
compounds a worthwhile endeavor. Our interest has been
in the preparation of benzimidazoles containing [1,2-a]
8
fused alicyclic rings, where literature synthetic methods
have been limited to the preparation tricyclic fused
9
,10
systems until in a recent preliminary communication,
we reported the preparation of new tetracyclic ring sys-
SYNTHESIS 2005, No. 7, pp 1069–1076
x
x
.
x
x
.2
0
0
5
Advanced online publication: 21.02.2005
DOI: 10.1055/s-2005-861832; Art ID: P14504SS
Georg Thieme Verlag Stuttgart · New York
Figure 2
©

1
070
J. O’Shaughnessy, F. Aldabbagh
PAPER
Scheme 1 Reagents and conditions: (i) Et N, CH =CH(CH ) Br, THF, reflux, 4 h, 41% for 9 and 30% for 10; (ii) MnO , CH Cl , reflux, 30
3
2
2 n
2
2
2
min, 77% for 11 and 55% for 12.
the aldehyde could not be carried out owing to its insolu-
bility in organic solvents, which has been attributed to the
1
3
formation of the dimeric hemiaminal. N-Allyl and (3-
butenyl)-1H-benzimidazole-2-methanols 9 and 10 were
prepared selectively on gram scale, but in only reasonable
to poor yields of 41% and 30%, respectively, by treatment
of alcohol 8 with a large excess of triethylamine followed
by an equal excess of allyl bromide and 4-bromo-1-butene
in refluxing THF (Scheme 1). Nevertheless, our alkyla-
tions of 8 using triethylamine compared favourably with
Scheme 3 Reagents and conditions: H N–NHTs, MeOH, r.t., 18 h,
2
2
9% for 16.
Therefore, alternative precursors for reactive intermedi-
ates 6 and 7 were required, and we turned our attention to
the preparation of Eschenmoser hydrazones or aziridinyl
imines. Jones and Moody reported the thermolysis of N-
allylindole-2-Eschenmoser hydrazone to cyclopropapyr-
literature alkylations, which under basic conditions were
not selective leading to both N- and O-alkylation.14
Improved yields of 10 of 44% overall, were achieved
when TBDMS-protection of the 2-hydroxymethyl group
of 8 was first carried out to allow alkylation using sodium
hydride and 4-bromo-1-butene with subsequent deprotec-
tion using TBAF (Scheme 2), as previously reported for
2
rolo[1,2-a]indole in reasonable yield. Benzimidazole-2-
Eschenmoser hydrazones 17 and 18 proved to be effective
isolable precursors for 6 and 7, which were obtained in
yields of 77% and 98% from the condensation of alde-
hydes 11 and 12 with trans-1-amino-2,3-diphenyl-
1
5
other benzimidazole-2-methanol alkylations. Alcohols 9
and 10 were oxidized in half an hour to the required alde-
hydes 11 and 12 in 77% and 55% yield, respectively, us-
ing a large excess of manganese dioxide in refluxing
dichloromethane (Scheme 1).
16
aziridine (Scheme 4). Hydrazones 17 and 18 upon
thermolysis in refluxing xylene for 2 hours gave novel tet-
racyclic systems, cyclopropapyrrolo- and cyclopropapyri-
do-[1,2-a]benzimidazoles 19 and 20 in 85% and 53%
yields, respectively.
Scheme 2 Reagents and conditions: (i) TBDMSCl, pyridine, r.t., 4
h, 100% for 13; (ii) NaH, CH =CH(CH ) Br, THF, reflux, 8.5 h, 58%
2
2 2
for 14; (iii) TBAF, THF, r.t., 15 min, 75% for 10.
Scheme 4 Reagents and conditions: (i) E-1-Amino-2,3-diphenyl-
aziridine, Et O, 0 °C, 8 h, 77% for 17 and 98% for 18; (ii) xylene, re-
2
flux, 2 h, 85% for 19 and 53% for 20.
The preparation 2-tosylhydrazone 15 as the diazomethine
precursor was unsuccessful, and led to the isolation of ad-
duct 16 from the attempted reaction of tosyl hydrazide Thermolysis of hydrazone 17 and 4,7-dimethoxy ana-
with benzimidazole-2-carbaldehyde 11 in methanol logue 21 at lower temperatures (refluxing benzene) for
(
(
Scheme 3). In contrast the literature preparations of N- three hours selectively gave the 1,3-dipolar [3+2] cy-
w-alkenyl)indole-2-tosylhydrazones were reported to be cloadducts 22 and 24 in 56% and 44% yield respectively
facile, and efficient intramolecular cycloadditions to form (Scheme 5), and an X-ray crystal structure of 22 was ob-
2
11
cyclopropapyrrolo[1,2-a]indoles, and precursors of CPM tained. Under the latter lower decomposition tempera-
3
,4,7
3
and analogues
occurred upon treatment with base. It tures, hydrazone 18 also decomposed to cyclopropane 20,
thus seemed that the 3-N basic nitrogen of imidazole was and no evidence of the formation of the 1,3-dipolar [3+2]
leading to a deprotonation of the 2-tosylhydrazone acidic pyrazoline cycloadduct 23 was obtained. The instability
hydrogen in 15, probably through a favoured six-mem- of 23 may be due to steric interactions between the 4,5-hy-
bered transition state to generate the 2-diazomethine 6 drogens on the [1,2-a]-fused six-membered ring and the
prematurely, which trapped methanol and lost nitrogen to fused pyrazoline 1,2-azo nitrogen atoms. 1-Pyrazoline
give 16.
fused onto six membered alicyclic rings in tricyclic sys-
Synthesis 2005, No. 7, 1069–1076 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo- and Pyrido-[1,2-a]benzimidazolequinone Anti-tumor Agents
1071
Scheme 5 Reagents and conditions: PhH, reflux, 3 h, 56%, 0% and
4% for 22, 23 and 24, respectively. Adduct 20 isolated in 23% from
4
the reaction using 18.
tems have been previously isolated, however the aromatic
1
7
ring was benzene in these cases.
Once the methodology for the incorporation of the fused
cyclopropane ring onto pyrrolo- and pyrido[1,2-a]benz-
imidazoles had been established, we turned our attention
to functionalising the benzene part in order to form target
benzimidazolequinones 4 and 5. (4,7-Dimethoxybenzim-
idazol-2-yl)methanol (25) was prepared according to the
1
8
procedure of Weinberger and Day on a multi-gram scale
in 46% yield by a modification of the Phillips
1
9
condensation between 3,6-dimethoxybenzene-1,2-di-
amine and glycolic acid. We decided to carry out alkyla-
tions on benzimidazole by the protection of the 2-
hydroxymethyl group of 25 with TBDMS, which allowed
us to carry out the N-alkylation using sodium hydride
Scheme 6 Reagents and conditions: (i) TBDMSCl, pyridine, r.t., 4
h, 90% for 26; (ii) NaH, CH =CH(CH ) Br, THF, reflux, 8.5 h, 86%
for 27 and 70% for 28; (iii) TBAF, THF, r.t., 15 min, 85% for 29 and
2
2 n
(
Scheme 6). N-Alkylation with allyl bromide and 4-bro- 30; (iv) MnO , CH Cl , reflux, 30 min, 65% for 31 and 73% for 32;
2
2
2
mo-1-butene, TBAF deprotection and manganese dioxide (v) E-1-Amino-2,3-diphenylaziridine, Et
O, 0 °C, 8 h, 83% for 21 and
2
8
4
5
6% for 33; (vi) xylene, reflux, 2 h, 68% for 34 and 58% for 35; (vii)
oxidation gave aldehydes 31 and 32 in overall yields of
4
from 25. Condensation with trans-1-amino-2,3-diphenyl-
aziridine gave the 4,7-dimethoxybenzimidazole-2-
Eschenmoser hydrazones 21 and 33 in excellent yields of
8% HBr (aq), reflux, 3 h; (viii) FeCl (aq), r.t., 5 min, 64% for 4 and
3
3% and 39%, respectively, for the four synthetic steps
after steps (vii) and (viii).
reductive potential of the former compound was not re-
8
3% and 86%, and thermolysis in refluxing xylene gave
ported. Cyclic voltammetry carried out on 5 under the
cycloadducts 34 and 35 in yields of 68% and 58%, respec-
tively. Hydrobromic acid induced demethylation of 34
and 35 gave the reactive hydroquinones 36 and 37 in situ,
which underwent oxidation almost immediately at room
temperature to give novel tetracyclic target benzimida-
zolequinones 4 and 5 using ferric chloride in identical
yields of 64%.
11
same conditions as for 4 gave a similar redox potential
of –1.074 vs ferrocene, and showed at low scan rates an
analogous reversible single electron transfer process. This
indicated a negligable effect on reductive activation of the
increase in size by one CH of the fused alicyclic ring. Cy-
2
totoxicity and selectivity of 4, 5 and related [1,2-a] fused
benzimidazolequinones toward hypoxic conditions will
It is interesting to compare our clean synthesis of 5 with be reported in a subsequent paper.
the approach by Moody and co-workers to the [1,2-a]in-
dolequinone analogue also containing cyclopropane fused
onto a six-membered alicyclic ring, in which oxidation of
the phenol to the quinone by the free radical, Fremy’s salt,
resulted in isolation of significant quantities of the by-
product due to ring-opening of the cyclopropane ring.7
This was not observed in our ferric chloride oxidations of
hydroquinones 36 and 37 to quinones 4 and 5, respective-
ly (Scheme 6). Moody suggested the ring-opened product
was evidence for one-electron initiated ring-opening of
the cyclopropane ring via the phenoxyl radical, albeit un-
der oxidative conditions. This tetrahydrocyclopropapyri-
do[1,2-a]indolequinone showed greater toxicity toward
hypoxic conditions than the analogue with a cyclopropane
In conclusion, new tetracyclic diazole ring systems based
on pyrrolo- and pyrido-[1,2-a]benzimidazoles containing
a fused cyclopropane ring were accessible using cycload-
dition reactions of diazomethines derived from the ther-
molysis of benzimidazole-2-Eschenmoser hydrazones or
aziridinyl imines in refluxing xylene. At lower tempera-
tures of refluxing benzene, the [3 + 2] pyrazoline cycload-
duct was obtained for the N-allyl-benzimidazole-2-
diazomethines, and not for the N-but-3-enyl-benz-
imidazole-2-diazomethine. The synthesis of bioreductive
benzimidazolequinones
pa[3,4]pyrrolo[1,2-a]benzimidazole-3,6-dione (4) and
a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyrido[1,2-
1,1a,8,8a-tetrahydrocyclopro-
1
a]benzimidazole-5,8-dione (5) is described in full. The
7
fused onto a five-membered alicyclic ring, however, the
Synthesis 2005, No. 7, 1069–1076 © Thieme Stuttgart · New York

1
072
J. O’Shaughnessy, F. Aldabbagh
PAPER
former compound is a diazole analogue of the indole- cis-H), 5.90–5.99 (1 H, m, 2¢-H), 7.21–7.27 (3 H, m, ArH), 7.66–
7
.68 (1 H, m, ArH), OH peak not observed.
quinone anti-tumor agent, cyclopropamitosene 3.
1
3
C NMR: d = 45.9 (NCH ), 56.6 (CH OH), 109.0 (ArCH), 117.4
2
2
(
3¢-CH ), 119.2 (ArCH), 122.3 (ArCH), 122.9 (ArCH), 131.9 (2¢-
2
Melting points were measured on a Stuart Scientific melting point
apparatus SMP3, and are uncorrected. IR spectra were determined
using neat samples on a Perkin-Elmer Spectrum 1000 FT-IR with
CH), 135.0 (C), 141.4 (C), 153.9 (Im-2-C).
Anal. Calcd for C H N O: C, 70.19; H, 6.43; N, 14.88. Found: C,
70.21; H, 6.36; N, 14.78.
11 12
2
1
13
an UATR accessory attached. H NMR (400 MHz) and C NMR
100 MHz) spectra were recorded in CDCl on a Jeol GXFT 400 in-
(
3
N-(3-Butenyl)-1H-benzimidazole-2-methanol (10)
The same procedure used for the synthesis of 9 yielded 10 as a pale
yellow solid (30%); mp 63–64 °C.
IR: 3158 (OH), 1508, 1459, 1418, 1333, 1039, 920 cm–1.
strument equipped with a DEC AXP 300 computer work station.
Chemical shifts are given in ppm, and J values are given in Hz.
Electron-impact (EI) and chemical ionization (CI) mass spectra
were recorded on a Micro Mass GTC GC-MS spectrometer. EPSRC
National Mass Spectrometry Service carried out low resolution EI
and CI on a Micromass Quattro II, and high resolution mass spec-
trometry using peak-matching techniques on the Finnigan MAT
1
H NMR: d = 2.45– 2.49 (2 H, m, 2¢-CH ), 4.15–4.19 (2 H, m,
2
NCH ), 4.76 (2 H, s, CH OH), 4.91–4.95 (2 H, m, 4¢-CH ), 5.63–
5
2
2
2
.70 (1 H, m, 3¢-H), 7.11–7.16 (3 H, m, ArH), 7.54–7.56 (1 H, d,
9
00 XLT in CI mode for compounds 5, 29 and 30. TLC was carried
J = 8.0 Hz, ArH), OH peak not observed.
out using aluminium-backed plates coated with silica gel (Merck
Kiesgel 60 F254) as absorbent or using polyester plates coated with
aluminium oxide as absorbent. Column chromatography was car-
ried out using Merck silica gel 60, 234–400 mesh or using Aldrich
aluminium oxide, activated neutral, Brockmann grade 3, STD
Grade, 150 mesh size. Cyclic voltammetry was performed on an
EcoChemie Autolab with PEGSTAT12 potentiostat controlled by
1
3
C NMR: d = 33.9 (2¢-CH ), 43.3 (NCH ), 56.5 (CH OH), 109.7
2
2
2
(ArCH), 118.0 (4¢-CH ), 119.1 (ArCH), 122.1 (ArCH), 122.7
(ArCH), 133.7 (3¢-CH), 134.7 (C), 141.4 (C), 153.9 (Im-2-C).
2
+
MS (EI): m/z (%) = 202 (M , 9), 161 (50), 131 (100).
HRMS (EI): m/z calcd for C H N O, 202.1106; found, 202.1106.
12 14
2
–
1
GPES software at scan rates 20, 50, 100 and 200 mVs . Quinones
and 5 were dissolved in DMF, containing 0.1 M tetrabutylammo-
2
-{[tert-Butyl(dimethyl)silyl]oxymethyl}-1H-benzimidazole
4
(
13)
niumperchlorate as electrolyte and 1 mM ferrocene (Fc) as refer-
ence. Cyclic voltammetry was recorded at a platinum disk electrode
in a single compartment electrochemical cell (2 mL volume) con-
taining Ag/AgCl reference electrode and a platinum wire counter
electrode. All measurements were carried out at r.t. The platinum
disc electrode was previously polished on a microcloth pad in 0.05
m alumina slurry, and nitrogen was bubbled through solvents.
TBDMSCl (2.60 g, 17.22 mmol), and 8 (1.50 g, 10.13 mmol) in py-
ridine (30 mL) were stirred at r.t. for 4 h. The resulting solution was
evaporated to dryness, and the residue was dissolved in CH Cl (40
mL). The organic layer was washed with sat. NaHCO (50 mL),
brine (50 mL), dried (MgSO ) and evaporated to dryness. The re-
sultant solid was purified by recrystallisation from hexane–EtOAc
to yield 13 as a white solid (2.651 g, 100%); mp 143–144 °C.
IR: 2953, 2857, 1435, 1258, 1103, 829 cm–1.
2
2
3
4
Eredox = –1.052, –1.074 V for 4 and 5 respectively and E -E val-
pc p/2
ues close to 0.056 V for both quinones allowed us to estimate n = 1.
All anhydrous reactions were carried under an inert atmosphere us-
ing distilled and anhydrous solvents. TBAF was a 1 M solution in
1
H NMR: d = 0.15 [6 H, s, Si(CH ) ], 0.96 [9 H, s, (CH ) ], 5.01 (2
3
2
3 3
H, s, CH O), 7.23–7.56 (4 H, m, ArH), 9.54 (1 H, br s, NH).
1
2
THF, and used as purchased from Aldrich. Benzimidazole-2-meth-
3
anols 819 and 2518 were prepared in 57% and 46% yield by conden-
C NMR: d = –5.5 [Si(CH ) ], 18.3 (SiC), 25.8 [C(CH ) ], 60.0
3 2 3 3
2
(
(
CH O), 111.3 (ArCH), 119.5 (ArCH), 122.3 (ArCH), 122.4
sation of 1,2-phenylenediamine and 3,6-dimethoxybenzene-1,2-
diamine respectively with glycolic acid in refluxing 4 M hydrochlo-
ric acid. trans-1-Amino-2,3-diphenylaziridine was prepared ac-
ArCH), 133.0 (C), 143.4 (C), 153.9 (Im-2-C).
+
HRMS (CI): m/z calcd for C14
263.1589.
H
23
N
2
OSi [M + H ], 263.1580; found,
1
6
cording to Eschenmoser’s two step procedure in 71% yield
starting from N-aminophthalimide and trans-stilbene and used im-
mediately. We have previously reported the procedure for the con-
version of N-[(3-Butenyl-1H-benzimidazol-2-yl)methylene]-E-2,3-
diphenylaziridin-1-amine (18) to 1a,2,3,9b-tetrahydrocyclo-
propa[3,4]pyrido[1,2-a]benzimidazole (20) in 53% yield and the
characterization of 18 and 1,1a,8,8a-tetrahydrocyclopropa[3,4]pyr-
rolo[1,2-a]benzimidazole-3,6-dione 4 in a preliminary communica-
tion.11
N-(3-Butenyl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-
benzimidazole (14)
TBDMS-protected alcohol 13 (1.000 g, 3.8 mmol) was added to
NaH (0.110 g, 4.6 mmol) in THF (100 mL) and refluxed for 30 min.
4-Bromo-1-butene (0.6 mL, 5.7 mmol) was added, and the solution
refluxed for a further 8 h. The mixture was cooled and water (100
mL) added, the product was extracted with Et
MgSO ) and evaporated to dryness to yield a pale yellow viscous
O (2 × 75 mL), dried
2
(
4
Synthesis of N-Allyl-1H-benzimidazole-2-methanol (9)
oil, which was purified by column chromatography using silica gel
as absorbent with hexane and EtOAc (gradient elution) to yield 14
as a clear oil (0.697 g, 58%).
Et N (23.5 mL, 0.169 mol) and 8 (5.000 g, 33.78 mmol) in THF
3
(100 mL) were refluxed for 1 h. Allyl bromide (14.6 mL, 0.169 mol)
was added and the solution refluxed for a further 3 h. Water (30 mL)
was added to the cooled reaction mixture which was extracted with
Et O (3 × 40 mL), dried (MgSO ) and evaporated to dryness. The
IR: 2954, 2929, 2856, 1463, 1414, 1252, 1073 cm–1.
1
H NMR: d = 0.13 [6 H, s, Si(CH ) ], 0.92 [9 H, s, (CH ) ], 2.59–
3 2
3 3
2
4
2
.64 (2 H, m, 2'-CH ), 4.32–4.35 (2 H, m, NCH ), 4.98 (2 H, s,
residue was purified by column chromatography using silica gel as
2
2
CH O), 5.08–5.12 (2 H, m, 4¢-CH ), 5.77–5.87 (1 H, m, 3¢-H), 7.23–
absorbent with CH Cl and EtOAc (gradient elution) to yield 9 as a
2
2
2
2
1
4
7.29 (2 H, m, ArH), 7.35–7.36 (1 H, m, ArH), 7.75–7.77 (1 H, m,
ArH).
pale yellow solid (2.610 g, 41%); mp 97–98 °C (lit. mp 96 °C).
IR: 3054 (OH) 2833, 2719, 1463, 1410, 1330, 1011, 964, 934, 855
1
3
–
1
C NMR: d = –5.5 [Si(CH ) ], 18.2 (SiC), 25.8 [C(CH ) ], 33.9 (2¢-
3 2 3 3
cm .
CH ), 43.4 (NCH ), 59.5 (CH O), 109.6 (ArCH), 117.7 (4¢-CH ),
1
(
2
2
2
2
1
H NMR: d = 4.85–4.90 (4 H, m, NCH and CH OH), 4.97–5.02 (1
2
2
20.0 (ArCH), 121.9 (ArCH), 122.6 (ArCH), 134.0 (3¢-CH), 135.4
C), 142.2 (C), 152.2 (Im-2-C).
H, d, J = 17.1 Hz, 3¢-trans-H), 5.17–5.19 (1 H, d, J = 10.3 Hz, 3¢-
MS (EI): m/z (%) = 205 (100), 131 (53), 75 (60), 57 (72).
Synthesis 2005, No. 7, 1069–1076 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo- and Pyrido-[1,2-a]benzimidazolequinone Anti-tumor Agents
1073
MS (CI): m/z (%) = 263 (100), 205 (22), 133 (12).
HRMS (EI): m/z calcd for C H N O, 202.1106; found, 202.1101.
1
2
14
2
TBDMS group was found to be labile in attempts to obtain accurate
mass.
N-[(1-Allyl-1H-benzimidazol-2-yl)methylene]-(E)-2,3-diphe-
nylaziridin-1-amine (17)
(
(
E)-1-Amino-2,3-diphenylaziridine (0.105 g, 0.48 mmol) and 11
N-(3-Butenyl)-1H-benzimidazole-2-methanol (10); TBDMS-
Deprotection of 14
TBDMS-protected alcohol 14 (0.460 g, 1.45 mmol) and TBAF
0.370 g, 1.99 mmol) in Et O (5 mL) were stirred at 0 °C for 8 h.
2
The solution was evaporated to dryness and the residue was purified
by column chromatography using neutral alumina as absorbent with
hexane and CH Cl (gradient elution) to yield 17 as a yellow oil
(
1.46 mL, 1.46 mmol) in THF (20 mL) were stirred at r.t. for 15 min.
2
2
The solution was evaporated to dryness to yield a brown residue,
which was purified by column chromatography using silica gel as
absorbent with hexane and EtOAc (gradient elution) to yield 10
(
0.146 g, 77%).
IR: 3030, 2087, 1602, 1496, 1452, 1408, 1333, 1283, 1161, 1010,
922 cm .
–
1
(
0.227 g, 75%).
1
H NMR: d = 3.81 (2 H, s, aziridine-H), 4.75–4.80 (1 H, d, J = 16.1
N-Allyl-1H-benzimidazole-2-carbaldehyde (11)
Hz, 3¢-trans-H), 4.85–4.91 (2 H, m, NCH ), 5.00–5.03 (1 H, d, J =
1
ArH), 7.73–7.76 (1 H, m, ArH), 8.46 (1 H, s, CH=N).
2
Alcohol 9 (40 mg, 0.21 mmol) and activated MnO (0.540 g, 6.21
2
0.5 Hz, 3¢-cis-H), 5.58–5.66 (1 H, m, 2¢-H), 7.22–7.38 (13 H, m,
mmol) were refluxed in CH Cl (50 mL) for 30 min. The cooled re-
2
2
action mixture was filtered through celite, and evaporated to dry-
ness to yield 11, as a yellow solid (30 mg, 77%); mp 38–39 °C.
1
3
C NMR: d = 46.9 (NCH and aziridine-CH), 110.5 (ArCH), 116.5
2
(
(
1
3¢-CH ), 120.5 (ArCH), 122.7 (ArCH), 124.2 (ArCH), 127.8
2
IR: 1688 (C=O), 1479, 1463, 1409, 1328, 1240, 1161, 994, 928
ArCH), 128.4 (ArCH), 132.5 (2¢-CH), 136.2 (C), 142.9 (CH=N),
–
1
cm .
45.9 (C), 151.3 (Im-2-C).
1
H NMR: d = 4.95–4.99 (1 H, d, J = 17.1 Hz, 3¢-trans-H), 5.12–5.15
(
5
1 H, d, J = 10.2 Hz, 3¢-cis-H), 5.19–5.20 (2 H, m, NCH ), 5.87–
N-[(3-Butenyl-1H-benzimidazol-2-yl)methylene]-(E)-2,3-diphe-
nylaziridin-1-amine (18)
The same procedure as for 17 with (E)-1-Amino-2,3-diphenylaziri-
2
.97 (1 H, m, 2¢-H), 7.31–7.40 (3 H, m, ArH), 7.86–7.88 (1 H, m,
ArH), 10.04 (1 H, s, CHO).
1
3
dine (70 mg, 0.34 mmol) and 12 (80 mg, 0.43 mmol) in Et
yielded 18, as a yellow oil (0.130 g, 98%).
2
O (5 mL)
C NMR: d = 46.6 (NCH ), 111.1 (ArCH), 117.5 (3¢-CH ), 122.2
2
2
11
(
1
ArCH), 124.1 (ArCH), 126.7 (ArCH), 131.8 (2¢-CH), 136.1 (C),
42.6 (C), 145.5 (Im-2-C), 184.6 (CHO).
1
,1a,8,8a-Tetrahydrocyclopropa[3,4]pyrrolo[1,2-a]benzimida-
+
MS (EI): m/z = 186 (M , 93), 157 (100), 130 (57), 77 (47).
zole (19)
Aziridinamine 17 (0.112 g, 0.29 mmol) in xylene (20 mL) was re-
fluxed for 2 h. The solution was evaporated to dryness to yield a res-
idue which was purified by column chromatography using neutral
HRMS (EI): m/z calcd for C H N O, 186.0793; found, 186.0789.
1
1
10
2
N-(3-Butenyl)-1H-benzimidazole-2-carbaldehyde (12)
The same procedure used for the synthesis of 11 yielded 12 as a yel-
low oil (55%).
alumina as absorbent with hexane and CH Cl (gradient elution) to
2
2
yield 19 as a yellow oil (43 mg, 85%).
–
1
IR: 3380, 3055, 2893, 1624, 1538, 1453, 1404, 1268, 1214, 1151,
IR: 1691 (C=O), 1479, 1468, 1413, 1327, 1240, 913 cm .
–
1
1
032, 931 cm .
1
H NMR: d = 2.44–2.49 (2 H, m, 2¢-CH ), 4.53–4.57 (2 H, m,
2
1
H NMR: d = 0.76–0.79 (1 H, m, 1-H), 1.36–1.42 (1 H, m, 1-H),
NCH ), 4.85–4.90 (2 H, m, 4¢-CH ), 5.62–5.72 (1 H, m, 3¢-H), 7.26–
2
2
2
7
.48–2.50 (2 H, m, 1a and 8a-H), 4.03–4.13 (2 H, m, 8-CH ), 7.16–
7
.37 (3 H, m, ArH), 7.80–7.83 (1 H, d, J = 8.3 Hz, ArH), 9.99 (1 H,
2
.18 (3 H, m, ArH), 7.64–7.66 (1 H, m, ArH).
s, CHO).
1
3
1
3
C NMR: d = 14.5 (1a-CH), 16.0 (1-CH ), 20.6 (8a-CH), 45.3 (8-
2
2
C NMR: d = 34.6 (2¢-CH ), 44.1 (NCH ), 111.0 (ArCH), 118.1
2
2
CH ), 108.8 (ArCH), 119.3 (ArCH), 121.3 (ArCH), 121.7 (ArCH),
(
4¢-CH ), 122.4 (ArCH), 124.1 (ArCH), 126.8 (ArCH), 133.7 (3¢-
2
1
32.3 (C), 148.0 (C), 161.9 (Im-1b-C).
CH), 136.3 (C), 142.8 (C), 145.9 (Im-2-C), 185.0 (CHO).
+
+
+
MS (EI): m/z (%) = 170 (M , 2), 169 (100), 156 (3).
MS (CI): m/z (%) = 201 (M + H , 100), 200 (M , 9), 172 (3), 159
39).
(
HRMS (EI): m/z calcd for C H N , 170.0844; found, 170.0838.
1
1
10
2
HRMS (CI): m/z calcd for C H N O, 200.0950; found, 200.0962.
1
2
12
2
3
,3a,4,10b-Tetrahydropyrazolo[3¢,4¢:3,4]pyrrolo[1,2-a]benzim-
idazole (22)
N-Allyl-2-(methoxymethyl)-1 H-benzimidazole (16)
Aziridinamine 17 (0.260 g, 0.68 mmol) in benzene (20 mL) was re-
fluxed for 3 h. The solution was evaporated to dryness and the crude
residue was purified by column chromatography using neutral alu-
mina as absorbent with hexane and CH Cl (gradient elution) to
yield 22 as a white solid (76 mg, 56%); mp 189–190 °C.
p-Tosyl hydrazide (0.420 g, 2.25 mmol) and 11 (0.430 g, 2.31
mmol) in MeOH (20 mL) were stirred at r.t. for 18 h. The reaction
mixture was evaporated to dryness to give a brown residue, which
was purified by column chromatography using silica gel as absor-
bent with hexane and CH Cl (gradient elution) to yield 16 as a clear
2
2
2
2
oil (0.134 g, 29%).
IR: 1621, 1552, 1517, 1483, 1452, 1416, 1324, 1219, 990 cm–1.
–
1
IR: 2823, 1615, 1511, 1462, 1409, 1332, 1157, 1088 cm .
1
H NMR: d = 3.58–3.64 (1 H, m, 3a-H), 3.72–3.76 (1 H, m, 3-
1
CHH), 4.34–4.38 (1 H, m, 3-CHH), 4.78–4.92 (2 H, m, NCH2),
H NMR: d = 3.38 (3 H, s, OCH ), 4.74 (2 H, s, CH O), 4.87–4.88
3
2
6
7
.13–6.15 (1 H, d, J = 8.3 Hz, 10b-H), 7.26–7.28 (3 H, m, ArH),
.81–7.83 (1 H, d, J = 8.1 Hz, ArH).
(
5
(
2 H, m, NCH ), 5.01–5.05 (1 H, d, J = 17.1 Hz, 3¢-trans-H), 5.19–
2
.22 (1 H, d, J = 10.3, 3¢-cis-H), 5.91–6.00 (1 H, m, 2¢-H), 7.26–7.29
3 H, m, ArH), 7.77–7.79 (1 H, m, ArH).
13
C NMR: d = 36.8 (3a-CH), 48.8 (4-CH ), 84.3 (3-CH ), 90.8 (10b-
2
2
1
3
CH), 109.9 (ArCH), 120.9 (ArCH), 122.6 (ArCH), 122.9 (ArCH),
1
C NMR: d = 46.1 (NCH ), 58.2 (OCH ), 67.1 (CH O), 109.7
2
3
2
31.9 (C), 149.3 (C), 154.4 (10a-C).
(
(
ArCH), 117.3 (3¢-CH ), 119.9 (ArCH), 122.2 (ArCH), 123.0
ArCH), 132.1 (2¢-CH), 135.4 (C) 142.7 (C) 150.4 (Im-2-C).
2
+
MS (EI): m/z (%) = 198 (M , 10), 169 (100), 156 (6).
+
MS (EI): m/z (%) = 202 (M , 60), 172 (86), 157 (75), 131 (90).
HRMS (EI): m/z calcd for C H N , 198.0905; found, 198.0910.
1
1
10
4
Synthesis 2005, No. 7, 1069–1076 © Thieme Stuttgart · New York

1
074
J. O’Shaughnessy, F. Aldabbagh
PAPER
6
,9-Dimethoxy-3,3a,4,10b-tetrahydropyrazolo[3¢,4¢:3,4]pyrro-
(ArCH), 103.1 (ArCH), 117.1 (4¢-CH ), 125.8 (C), 134.1 (C), 134.5
2
lo[1,2-a]benzimidazole (24)
(C), 141.5 (C), 146.0 (C), 151.2 (Im-2-C).
The same procedure as for 22 yielded 24 as a white solid (44%); mp
+
MS (CI): m/z (%) = 377 (M + H , 100), 376 (28), 319 (9).
1
80–181 °C.
HRMS (CI): m/z calcd for C H N O Si: 376.2182; found:
–
1
20 32
2
3
IR: 1523, 1257, 1108, 1078 cm .
3
76.2185.
1
H NMR: d = 3.45–3.51 (1 H, m, 3a-H), 3.75 (3 H, s, OCH ), 3.79–
3
3
.87 (1 H, m, 4-CHH), 3.90 (3 H, s, OCH ), 4.39–4.45 (1 H, m, 4-
(1-Allyl-4,7-dimethyloxy-1H-benzimidazol-2-yl)methanol (29)
The same procedure used for the deprotection of 14 to 10 yielded 29
as a white solid (85%); mp 154–155 °C.
3
CHH), 4.65–4.79 (2 H, m, 3-CH ), 5.95–5.97 (1 H, m, 10b-H),
2
6
.44–6.45 (2 H, AB , J = 8.3 Hz, ArH).
q
1
3
IR: 3142 (OH), 2936, 1521, 1264, 1231, 1105, 1040 cm–1.
C NMR: d = 37.0 (3a-CH), 50.6 (4-CH ), 55.7 (OCH ), 56.1
2
3
(
(
OCH ), 84.1 (3-CH ), 90.3 (10b-CH), 102.5 (ArCH), 102.7
ArCH), 123.6 (C), 140.8 (C), 141.1 (C), 146.1 (C), 152.8 (10a-C).
1
3
2
H NMR: d = 3.85 (3 H, s, OCH ), 3.95 (3 H, s, OCH ), 4.84–5.17
3
3
(
6 H, m, CH O, 3¢-CH , NCH ), 5.97–6.04 (1 H, m, 2¢-H), 6.50–
2 2 2
+
MS (CI): m/z (%) = 259 (M + H , 2), 231 (100), 230 (13).
6.56 (2 H, m, ArH), OH peak not observed.
+
13
HRMS (CI): m/z calcd for C H N O , 259.1195 [M + H ]; found,
C NMR: d = 47.3 (NCH ), 55.9 (OCH ), 57.2 (CH OH), 101.6
1
3
15
4
2
2
3
2
2
15.1192.
(ArCH), 103.6 (ArCH), 116.2 (3¢-CH ), 126.0 (C), 133.8 (2¢-CH),
2
1
41.5 (C), 145.7 (C), 152.5 (Im-2-C).
2
-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4,7-dimethoxy-1H-
+
MS (CI): m/z (%) = 249 (M + H , 100), 233 (28), 219 (7).
benzimidazole (26)
The same procedure as for 13 yielded 26 as a white solid (90%); mp
1
+
HRMS (CI): m/z calcd for C H N O [M + H ], 249.1234; found,
13 17
2
3
2
49.1233.
60–161 °C.
–
1
IR: 2930, 1519, 1449, 1264, 1253, 1095 cm .
(
1-But-3-en-1-yl-4,7-dimethoxy-1H-benzimidazol-2-yl)metha-
1
H NMR: d = 0.15 [6 H, s, Si(CH ) ], 0.96 [9 H, s, (CH ) ], 3.94 (6
nol (30)
3
2
3 3
H, s, OCH ), 4.99 (2 H, s, CH O), 6.56 (2 H, s, ArH).
The same procedure used for the deprotection of 14 to 10 yielded 30
as a white solid (85%); mp 138–139 °C.
3
2
1
3
C NMR: d = –5.3 [Si(CH ) ], 18.2 (SiC), 25.7 [C(CH ) ], 55.7
3
2
3 3
–
1
(
OCH ), 59.8 (CH O), 102.1 (ArCH), 124.6 (C), 134.7 (C), 140.3
IR: 3168 (OH), 1522, 1464, 1264, 1109, 1081, 1040 cm .
3
2
(
C), 145.5 (C), 152.1 (Im-2-C).
1
H NMR: d = 2.45–2.50 (2 H, m, 2¢-CH ), 3.79 (3 H, s, OCH ), 3.85
2
3
+
MS (CI): m/z (%) = 323 (M + H , 100), 322 (10), 286 (68).
(3 H, s, OCH ), 4.34–4.37 (2 H, m, NCH ), 4.79 (2 H, s, CH O),
3
2
2
4
.90–4.94 (2 H, m, 4¢-CH ), 5.66–5.76 (1 H, m, 3¢-H), 6.39–6.46 (2
2
HRMS (CI): m/z calcd for C H N O Si, 322.1713; found,
1
6
26
2
3
H, AB , J = 8.5 Hz, ArH), OH peak not observed.
q
3
22.1715.
1
3
C NMR: d = 35.8 (2¢-CH ), 44.9 (NCH ), 55.7 (OCH ), 55.8
2
2
3
1
-Allyl-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,7-dimeth-
(OCH ), 57.2 (CH OH), 101.5 (ArCH), 103.1 (ArCH), 117.5 (4'-
3 2
oxy-1H-benzimidazole (27)
The same procedure used for the synthesis of 14 yielded 27 as a
white solid (86%); mp 40–41 °C.
CH ), 125.8 (C), 133.7 (C), 134.2 (3'-CH), 141.4 (C), 145.6 (C),
152.4 (Im-2-C).
2
+
MS (CI): m/z (%) = 263 (M + H , 100), 249 (50), 233 (79).
–
1
IR: 2930, 1521, 1453, 1257, 1163, 1075 cm .
+
HRMS (CI): m/z calcd for C H N O [M + H ], 263.1392; found,
1
4
19
2
3
1
H NMR: d = 0.15 [6 H, s, Si(CH ) ], 0.95 [9 H, s, (CH ) ], 3.89 (3
263.1390.
3
2
3 3
H, s, OCH ), 3.99 (3 H, OCH ), 4.92–4.93 (1 H, m, 3¢-CHH), 4.97
(
NCH ), 6.03–6.08 (1 H, m, 2¢-H), 6.52–6.60 (2 H, AB-q, J = 8.8 Hz,
ArH).
3
3
2 H, s, CH O), 5.13–5.16 (1 H, m, 3¢-CHH), 5.23–5.24 (2 H, m,
1-Allyl-4,7-dimethoxy-1H-benzimidazole-2-carbaldehyde (31)
The same procedure used for the synthesis of 11 yielded 31 as a yel-
low solid (65%); mp 98–99 °C.
2
2
1
3
IR: 1690 (C=O), 1525, 1454, 1264, 1168, 1102 cm–1.
C NMR: d = –5.8 [Si(CH ) ], 17.9 (SiC), 25.5 [C(CH ) ], 47.2
3
2
3 3
(
1
1
NCH ), 55.4 (OCH ), 55.5 (OCH ), 58.9 (CH O), 100.9 (ArCH),
03.2 (ArH), 115.5 (3¢-CH ), 125.9 (C), 133.7 (C), 134.0 (2¢-CH),
41.2 (C), 145.8 (C), 151.0 (Im-2-C).
1
2
3
3
2
H NMR: d = 3.91 (3 H, s, OCH ), 4.00 (3 H, s, OCH ), 4.96–5.00
3
3
2
(
1 H, d, J = 17.3 Hz, 3¢-trans-H), 5.10–5.13 (1 H, d, J = 10.3 Hz, 3¢-
cis-H), 5.49–5.50 (2 H, m, NCH ), 5.99–6.08 (1 H, m, 2¢-H), 6.56–
2
+
MS (CI): m/z (%) = 363 (MH , 100), 362 (25), 305 (10).
6.58 (1 H, d, J = 8.5 Hz, ArH), 6.72–6.74 (1 H, d, J = 8.5 Hz, ArH),
+
10.07 (1 H, s, CHO).
HRMS (CI): m/z calcd for C H N O Si, 363.2026 [M + H ];
found, 363.2039.
1
9
31
2
3
1
3
C NMR: d = 48.2 (NCH ), 55.8 (OCH ), 56.0 (OCH ), 102.0
2 3 3
(
ArCH), 106.7 (ArH), 116.8 (3¢-CH ), 127.4 (C), 133.8 (2¢-CH),
2
1
-But-3-en-1-yl-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,7-
135.5 (C), 141.9 (C), 147.2 (Im-2-C), 184.4 (CHO).
dimethoxy-1H-benzimidazole (28)
The same procedure used for the synthesis of 14 yielded 28 as a
white solid (70%); mp 48–49 °C.
+
+
MS (CI): m/z = 247 (MH , 100), 246 (M , 8).
HRMS (CI): m/z calcd for C H N O : 246.1004; found: 246.1003.
13 14
2
3
–
1
IR: 2929, 1520, 1265, 1248, 1057 cm .
1
-But-3-en-1-yl-4,7-dimethoxy-1H-benzimidazole-2-carbalde-
1
H NMR: d = 0.15 [6 H, s, Si(CH ) ], 0.95 [9 H, s, (CH ) ], 2.62–
hyde (32)
3
2
3 3
2
4
4
.68 (2 H, m, 2¢-CH ), 3.96 (3 H, s, OCH ), 3.99 (3 H, s, OCH ),
The same procedure used for the synthesis of 11 yielded 32 as a yel-
low solid (73%); mp 72–73 °C.
IR: 2850, 1687 (C=O), 1526, 1464, 1264, 1076 cm–1.
2
3
3
.53–4.56 (2 H, m, NCH ), 4.99 (2 H, s, CH O), 5.08–5.13 (2 H, m,
2
2
¢-CH ), 5.81–5.90 (1 H, m, 3¢-H), 6.53–6.61 (2 H, ABq, J = 8.0 Hz,
2
ArH).
1
H NMR: d = 2.55–2.57 (2 H, m, 2¢-CH ), 3.93 (3 H, s, OCH ), 4.00
3 H, s, OCH ), 4.91–4.97 (4 H, m, NCH and 4¢-CH ), 5.76–5.80
1
3
2
3
C NMR: d = –5.5 [Si(CH ) ], 18.2 (SiC), 25.8 [C(CH ) ], 35.9 (2¢-
3
2
3 3
(
3
2
2
CH ), 45.2 (NCH ), 55.7 (OCH ), 55.8 (OCH ), 59.3 (CH O), 101.2
2
2
3
3
2
Synthesis 2005, No. 7, 1069–1076 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo- and Pyrido-[1,2-a]benzimidazolequinone Anti-tumor Agents
1075
1
(
1 H, m, 3¢-H), 6.55–6.71 (2 H, AB , J = 8.5 Hz, ArH), 10.07 (1 H,
H NMR: d = 0.97–1.07 (2 H, m, 1-CH ), 1.60–1.73 (1 H, m, 1a-H),
q
2
s, CHO).
2.05–2.16 (2 H, m, 2-CH ), 2.33–2.39 (1 H, m, 9b-H), 3.60–3.72 (1
2
1
3
H, m, 3-CHH), 3.76 (3 H, s, OCH
3
), 3.86 (3 H, s, OCH
3
), 4.76–4.81
C NMR: d = 36.1 (2¢-CH ), 45.5 (NCH ), 55.8 (OCH ), 55.9
2
2
3
(
1 H, m, 3-CHH), 6.39 (2 H, s, ArH).
(
1
1
OCH ), 101.9 (ArCH), 106.4 (ArCH), 117.6 (4¢-CH ), 127.8 (C),
3
2
1
3
33.9 (3¢-CH), 135.6 (C), 141.9 (C), 145.2 (C), 147.1 (Im-2-C),
C NMR: d = 8.6 (1-CH ), 11.3 (1a-CH), 13.2 (9b-CH), 20.7 (2-
2 2 3 3
2
84.8 (CHO).
CH ), 39.6 (3-CH ), 55.7 (OCH ), 55.9 (OCH ), 101.3 (ArCH),
+
102.3 (ArCH), 124.9 (C), 134.3 (C), 141.3 (C), 145.3 (C), 151.8
9a-C).
MS (EI): m/z (%) = 260 (M , 17), 130 (40), 68 (100).
(
HRMS (EI): m/z calcd for C H N O , 260.1161; found, 260.1125.
1
4
16
2
3
+
+
MS (CI): m/z (%) = 245 (M + H , 100), 244 (21, M ), 215 (2).
HRMS (CI): m/z calcd for C H N O , 244.1212; found, 244.1215.
N-(1-Allyl-4,7-dimethoxy-1H-benzimidazol-2-yl)methylidene]-
E)-2,3-diphenyl-1-aziridinamine (21)
1
4
16
2
2
(
The same procedure used for the synthesis of 17 yielded 21 as a yel-
low oil (83%).
1,1a,8,8a-Tetrahydrocyclopropa[3,4]pyrrolo[1,2-a]benzimida-
zole-3,6-dione (4)
–
1
Cyclopropapyrrolo[1,2-a]benzimidazole 34 (40 mg, 0.17 mmol)
was refluxed in 48% hydrobromic acid (10 ml) for 3 h. The solution
IR: 2934, 2088, 1523, 1451, 1262 cm .
1
H NMR: d = 3.68 (2 H, s, aziridine-H), 3.69 (3 H, s, OCH ), 3.81
3
was evaporated to dryness, and 0.7 M FeCl solution (10 mL) add-
3
(
3 H, s, OCH ), 4.55–4.59 (1 H, d, J = 17.1 Hz, 3¢-trans-H), 4.81–
3
ed. A faint yellow precipitate was observed immediately, and sat.
NaOAc solution (10 mL) was added. The solution was extracted
with CHCl (3 × 15 mL), dried (MgSO ) and evaporated to dryness
4
5
7
.84 (1 H, d, J = 9.3 Hz, 3¢-cis-H), 5.03–5.12 (2 H, m, NCH ), 5.54–
2
.64 (1 H, m, 2¢-H), 6.34–6.44 (2 H, ABq, J = 8.6 Hz, ArH), 7.13–
3
4
.40 (10 H, m, ArH), 8.36 (1 H, s, CH=N).
to yield an orange solid. The crude solid was purified by column
chromatography using silica gel as absorbent with hexane and
1
3
C NMR: d = 48.1 (NCH and aziridine-CH), 55.6 (OCH ), 55.8
2
3
1
1
EtOAc (gradient elution) to yield 4, as a red-orange solid (22 mg,
(
(
OCH ), 101.4 (ArCH), 104.7 (ArCH), 115.4 (3¢-CH ), 126.3
3
2
6
4%).
ArCH), 127.4 (ArCH), 127.6 (ArCH), 128.2 (ArCH), 134.3 (2¢-
CH), 135.2 (C), 137.4 (C), 141.5 (C), 144.9 (CH=N), 146.2 (C),
51.5 (Im-2-C).
1
a,2,3,9b-tetrahydro-1 H-cyclopropa[3,4]pyrido[1,2-a]benzim-
1
idazole-5,8-dione (5)
The same procedure used for the synthesis of 4 yielded 5 as a red-
orange solid (64%); mp 145 °C (dec.).
IR: 1657 (C=O), 1525, 1285, 1078 cm–1.
N-[(1-But-3-en-1-yl-4,7-dimethoxy-1H-benzimidazol-2-
yl)methylene]-2,3-diphenylaziridin-1-amine (33)
The same procedure used for the synthesis of 17 yielded 33 as a yel-
low oil (86%).
1
H NMR: d = 1.11–1.15 (1 H, m, 1-H), 1.23–1.29 (1 H, m, 1-H),
–
1
IR: 2084, 1521, 1261, 1078 cm .
1
.85–1.88 (1 H, m, 1a-H), 2.05–2.16 (1 H, m, 2-CHH), 2.29–2.34
1
(1 H, m, 2-CHH), 2.42–2.47 (1 H, m, 9b-H), 3.59–3.68 (1 H, 3-
CHH), 4.81–4.86 (1 H, 3-CHH), 6.48–6.62 (2 H, AB , J = 10.4 Hz,
H NMR: d = 2.23–2.25 (2 H, m, 2¢-CH ), 3.82 (2 H, s, aziridine-H),
2
3
.84 (3 H, s, OCH ), 3.92 (3 H, s, OCH ), 4.53–4.56 (2 H, m,
q
3
3
6
and 7-H).
NCH ), 4.82–4.91 (2 H, m, 4¢-CH ), 5.52–5.56 (1 H, m, 3¢-H), 6.45–
2
2
6
.55 (2 H, AB , J = 8.3 Hz, ArH), 7.28–7.49 (10 H, m, ArH), 8.51
13
q
C NMR: d = 9.3 (1-CH ), 10.9 (9b-CH), 13.7 (1a-CH), 19.7 (2-
2
(
1 H, s, CH=N).
CH ), 39.7 (3-CH ), 129.5 (C), 135.9 (6(7)-CH), 136.9 [6(7)-CH],
2
2
1
3
141.1 (C), 153.7 (9a-C), 178.2 (C=O), 181.0 (C=O).
C NMR: d = 35.4 (2¢-CH ), 45.6 (NCH and aziridine-CH), 55.7
2
2
(
(
(
OCH ), 101.3 (ArCH), 104.4 (ArCH), 116.6 (4¢-CH ), 126.5
ArCH), 127.1 (ArCH), 127.6 (ArCH), 127.8 (ArCH), 128.4
ArCH), 128.6 (ArCH), 134.7 (3¢-CH), 135.2 (C), 141.5 (CH=N),
44.9 (C), 146.2 (C), 151.8 (Im-2-C).
+
3
2
MS (CI): m/z (%) = 215 (13, M + H ), 213 (7), 198 (54), 188 (100),
39 (53).
1
+
HRMS (CI): m/z calcd for C H N O [M – H ], 213.0659; found,
1
2
9
2
2
1
2
13.0661.
3
,6-Dimethoxy-1,1a,8,8a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-a]benzimidazole (34)
Acknowledgment
The same procedure used for the synthesis of 19 yielded 34 as a yel-
low oil 68%.
We thank Paul Kavanagh and Dónal Leech for carrying out electro-
chemical measurements, Ger Fahy for mass spectra (all of National
University of Ireland, Galway), and the EPSRC Mass Spectrometry
Centre, Swansea for additional mass spectra. Financial support was
gratefully received from Enterprise Ireland and National University
of Ireland, Galway.
–
1
IR: 1542, 1518, 1387, 1253, 1092 cm .
1
H NMR: d = 0.68–0.72 (1 H, m, 1-H), 1.28–1.33 (1 H, m, 1-H),
2
.37–2.42 (2 H, m, 1a and 8a-H), 3.79 (3 H, s, OCH ), 3.90 (3 H, s,
3
OCH ), 4.25–4.26 (2 H, d, J = 4.9 Hz, 8-CH ), 6.43 (2 H, s, ArH).
3
2
1
3
C NMR: d = 14.1 (1a-CH), 15.5 (1-CH ), 20.7 (8a-CH), 47.4 (8-
2
2
CH ), 55.7 (OCH ), 56.0 (OCH ), 101.8 (ArCH), 102.1 (ArCH),
3
3
References
1
23.7 (C), 139.1 (C), 140.6 (C), 145.4 (C), 160.5 (Im-1b-C).
+
+
MS (CI): m/z (%) = 231 (M + H , 100), 230 (20, M ).
(1) Wolkenberg, S. E.; Boger, D. L. Chem. Rev. 2002, 102,
2
477.
2) Jones, G. B.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1
989, 2449.
3) Jones, G. B.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1
989, 2455.
HRMS (CI): m/z calcd for C H N O : 230.1055; found: 230.1059.
1
3
14
2
2
(
(
(
1
5
,8-Dimethoxy-1a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyri-
do[1,2-a]benzimidazole (35)
1
The same procedure used for the synthesis of 19 yielded 35 as an
off-white solid (58%); mp 145–146 °C.
4) Cotterill, A. S.; Hartopp, P.; Jones, G. B.; Moody, C. J.;
Norton, C. L.; O’Sullivan, N.; Swann, E. Tetrahedron 1994,
–
1
IR: 2927, 1541, 1516, 1401. 1260, 1084 cm .
50, 7657.
Synthesis 2005, No. 7, 1069–1076 © Thieme Stuttgart · New York

1
076
J. O’Shaughnessy, F. Aldabbagh
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(
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(
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Synthesis 2005, No. 7, 1069–1076 © Thieme Stuttgart · New York