Synthesis of benzimidazoles condensed with, or linked to, nitroxides or heterocyclic N-oxides

Article abstract of DOI:10.1055/s-2008-1067158

Pyrazino[1,2-a]benzimidazoles were synthesized starting from 2-acetyl-1H-benzimidazole. Benzimidazoles were linked to nitroxides by lithiation and ring-closure and cross-coupling reactions leading to pH-sensitive EPR probes and a paramagnetic analogue of

Full text of DOI:10.1055/s-2008-1067158

PAPER
2439
Synthesis of Benzimidazoles Condensed with, or Linked to, Nitroxides or
Heterocyclic N-Oxides
Synthesis of
L
ink
a
ed or Cond
l
e
nsed B
á
enzimidaz
z
oles s Bognár, Tamás Kálai, Kálmán Hideg*
Department of Organic and Medicinal Chemistry, University of Pécs, P.O. Box 99, 7602 Pécs, Hungary
Fax +36(72)536219; E-mail: kalman.hideg@aok.pte.hu
Received 3 April 2008
Dedicated to Professor Antal Rockenbauer on the occasion of his 70th birthday
dole skeleton by cyclization of 1-alkynyl-1H-indole-2-
carbaldehydes16 inspired us to apply this method to the
synthesis of pyrazino[1,2-a]benzimidazoles.
Abstract: Pyrazino[1,2-a]benzimidazoles were synthesized start-
ing from 2-acetyl-1H-benzimidazole. Benzimidazoles were linked
to nitroxides by lithiation and ring-closure and cross-coupling reac-
tions leading to pH-sensitive EPR probes and a paramagnetic ana-
logue of antiviral agent HBB.
N-Alkylation of 1-(1H-benzimidazol-2-yl)ethanone (1)
with propargyl bromide in acetonitrile in the presence of
potassium carbonate afforded 1-(1-propargyl-1H-benzim-
idazol-2-yl)ethanone (2). The treatment of 2 with hydrox-
ylamine in aqueous ethanol yielded an oxime that
underwent 6-exo-dig cyclization to give compound 4. A
similar reaction was carried out with compound 2 or 3 and
with methanolic ammonia solution in a sealed tube. This
reaction yielded two products in the case of 2, the cyclized
product 5a and the unexpected deacetylated derivative 6a
in a ratio of ~1:1 as identified by MS and NMR studies.
The deacetylation reaction of the quaternary salt of 2-
acetylbenzimidazolium was described by Serafin and
Glowczyk, although under more harsh conditions.17
Key words: cross-coupling, free radicals, heterocycles, lithiation,
ring closure
The synthesis and study of benzimidazoles are of interest
for several reasons.1 Derivatives of benzimidazole pos-
sess a variety of biological actions; anthelmintic2 and
antitumor3 agents, gastric acid secretion inhibitors,4 and
PARP inhibitors5 to mention a few.
Due to our interest in both benzimidazoles6 and nitrox-
ides,7 we have reported paramagnetically modified
benzimidazoles starting from spin labeled 1,2-phenyl-
enediamine8 or connecting to the 2-position of benzimid-
azole with a heterocycle fused with a nitroxide.9,10
This cyclization reaction could be extended to other N-
propargyl derivatives of compound 2. The new substrates
are readily available by Sonogashira coupling, for exam-
ple, compound 2 reacts with iodobenzene in the presence
of palladium and copper catalysts to afforded compound
3. The cyclization reaction of this with methanolic ammo-
nia solution in a sealed tube furnished blue fluorescent
compound 5b and deacetylated 6b in a 1:1 ratio
(Scheme 1).
The modification of benzimidazole-containing omepra-
zole-like compounds with nitroxide did not alter the gas-
tric acid secretion inhibitory effect and the new compound
exhibited antioxidant properties.11 So, it was a real chal-
lenge to synthesize paramagnetically modified benzimi-
dazoles with C–C bond formation in the hope of finding
new, biologically active compounds.
The above cyclization reactions gave fully aromatic ring
systems, such as compounds 4, 5a, and 5b, hence for ni-
troxides condensed with a benzimidazole a partially satu-
rated ring was required. A nitro group must be introduced
into compound 1 by alkylating with compound 8 in the
presence of sodium hydride in tetrahydrofuran–N,N-di-
methylformamide solvent. Compound 8 was obtained
previously by treating 2-methyl-2-nitropropan-1-ol with
methanesulfonyl chloride in dichloromethane in the pres-
ence of triethylamine. Reduction of compound 9 with
zinc/ammonium chloride afforded a hydroxylamine,
which cyclized in situ to give nitrone 10. Treatment of 10
with methylmagnesium iodide followed by oxidation with
activated manganese(IV) oxide gave nitroxide 11, con-
densed with benzimidazole (Scheme 2).
In this paper we describe two approaches to this problem;
synthesis of 1,2,3,4-tetrahydropyrazino[1,2-a]benzimida-
zoles as a benzimidazole ring system condensed with a
stable nitroxide free radical or attaching a nitroxide to 2-
position of the benzimidazole ring.
The pyrazino[1,2-a]benzimidazole ring systems were pre-
pared by the reaction of 1-(2-chloroethyl)-2-(chlorometh-
yl)-1H-benzimidazole and
a
primary amine,12 by
intramolecular cyclization of N-(2-hydroxyethyl)-1H-
benzimidazole-2-carboxamide,13 or by 1,3-dipolar cy-
cloaddition of 2-(azidomethyl)-1-propargyl-1H-benzimi-
dazoles.14 Pyrazino[1,2-a]benzimidazoles with anticancer
activity were achieved also by cyclization of 2-(2-acyl-
1H-benzoimidazol-1-yl)-1-arylethanones and ammonia
generated in situ.15 Construction of the pyrazino[1,2-a]in-
Another challenge was the introduction of the nitroxide
ring into the 2-position of benzimidazole. The treatment
of 1,2-phenylenediamine with 3-carboxy-2,2,5,5-tetra-
methyl-2,5-dihydro-1H-pyrrol-1-yloxyl radical in aque-
ous hydrogen chloride solution did not furnish 13.
SYNTHESIS 2008, No. 15, pp 2439–2445
Advanced online publication: 08.07.2008
DOI: 10.1055/s-2008-1067158; Art ID: P04808SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

2440
B. Bognár et al.
PAPER
a
b
O
N
N
O
O
N
N
N
N
H
3
2
1
c
d
Ph
d
N
N
N
N
N
N
O
+
N
N
4
5a R = H
5b R = Ph
6a R = H
6b R = Ph
R
R
Scheme 1 Reagents and conditions: (a) propargyl bromide (1.1 equiv), K2CO3 (1.1 equiv), MeCN, reflux, 3 h, 88%; (b) PhI (1 equiv),
PdCl2(PPh3)2 (0.1 equiv), CuI (0.05 equiv), Et3N, under N2, r.t., 5 h, 63%; (c) NH2OH·HCl (1.5 equiv), NaOAc (1.5 equiv), EtOH–H2O, reflux,
3 h, 70%; (d) 7 M NH3–MeOH (excess), 120 °C, sealed tube, 12 h, 32–45% for 5 and 35–46% for 6.
CHO
O
N
N
b
NO2
OR
N
a
N
O
N
N
H
NO2
9
O
7 R = H
8 R = SO2Me
a
13
12
c
N
N
+
Br
N
N
d
N
N
O
14
Boc
N
N
O
15
N
O
11
10
b
Scheme 2 Reagents and conditions: (a) MsCl (1.1 equiv), Et3N (1.1
equiv), CH2Cl2, 0 °C to r.t., 1 h, 88%; (b) 1 (0.5 equiv), NaH (0.5
equiv), THF–DMF, 0 °C, 30 min, then 8 (1.0 equiv), reflux, 12 h,
33%; (c) Zn powder (4.0 equiv), NH4Cl (1.5 equiv), THF–H2O >10
°C, 2 h, 48%; (d) (i) MeMgI (2.0 equiv), THF–Et2O, reflux 1 h (ii) aq
NH4Cl (iii) MnO2, O2, 15 min, 28%.
N
N
O
N
R
16 R = Boc
17 R = H
c
However, we found that acid-catalyzed Schiff base forma-
tion between aldehyde 1218 and 1,2-phenylenediamine
followed by oxidation with manganese(IV) oxide gave the
desired 2-substituted benzimidazole 13. To achieve vari-
ous 2-substituted benzimidazoles attached to the nitroxide
ring, we utilized palladium-catalyzed cross-coupling re-
actions. Sonogashira reaction of 2-bromo-1-(tert-butoxy-
carbonyl)-1H-benzimidazole (14)19 with nitroxide 15
yielded benzimidazole 16 bearing a nitroxide ring through
an alkyne spacer. The tert-butoxycarbonyl (Boc) protect-
ing group was removed by treating compound 16 with
methanolic ammonia solution in a sealed tube to yield
compound 17 (Scheme 3).
Scheme 3 Reagents and conditions: (a) (i) 1,2-phenylenediamine
(1.0 equiv), TsOH (0.05 equiv), toluene, reflux, 4 h (ii) MnO2 (2.0
equiv), CHCl3, reflux 1 h, 46%; (b) 15 (1 equiv), PdCl2(PPh3)2 (0.1
equiv), CuI (0.05 equiv), Et3N, under N2, r.t., 5 h, 59%. (c) 7 M NH3–
MeOH (excess), r.t., sealed tube, 12 h, 88%.
paramagnetic free radicals 25 and 26, respectively, after
the oxidation of the thus formed hydroxylamine with acti-
vated manganese(IV) oxide. We assumed that hyperfine
splitting constant of compounds 11, 25, and 26 exhibit
some pH-dependence, analogously to 2,2,5,5-tetrasubsti-
tuted 2,5-dihydro-1H-imidazol-1-oxyl compounds.24 Un-
fortunately, compound 11 was reduced under acidic pH to
hydroxylamine, resulting in EPR signal loss, however
compound 25 and 26 exhibited a pH sensitivity range of
pH 2 to 6 (Figure 1). The change in hyperfine splitting
constant (~0.6 G) is smaller than that of 2,2,5,5-tetrasub-
stituted 2,5-dihydro-1H-imidazol-1-oxyl (~1.5 G). We
also tested the pH sensitivity of a paramagnetic benzothi-
azole compound, synthesized by treatment of 2-lithioben-
zothiazole with nitrone 23 (Scheme 4).
Another synthetic approach to 2-substituted benzimida-
zoles was the lithiation20 of 1-(hydroxymethyl)-1H-
benzimidazole21 (18) and its treatment with electrophiles
such as 12 and 1922 aldehydes. This reaction furnished 2-
(hydroxymethyl)benzimidazole derivatives 20 and 21.
The latter is the paramagnetic analogue of 2-(a-hydroxy-
benzyl)benzimidazole (HBB), the known viral RNA syn-
thesis blocking agent.23 Oxidation of alcohol 20 with
activated manganese(IV) oxide gave ketone 22. Reaction
of lithiated 18 with nitrones 23 and 24 furnished stable
Synthesis 2008, No. 15, 2439–2445 © Thieme Stuttgart · New York

PAPER
Synthesis of Linked or Condensed Benzimidazoles
2441
a
a
N
N
N
N
OH
R
N
Li
+ RCHO
N
H
12, 19
20, 21
OH
OLi
18
( )n
c
b
N
O
R
O
N
23, 24
12, 20
19, 21
( )n
N O
N
H
N
22
N
O
N
N
H
O
N O
25, 26
d
N
S
N
S
N
O
27
28
Scheme 4 Reagents and conditions: (a) (i) BuLi (2.0 equiv), THF, –78 °C, 30 min; –20 °C, 30 min; –78 °C (ii) 13 or 19 (1 equiv), –78 °C, 1
h; –78 °C to r.t. (iii) aq NH4Cl soln, 55–72%; (b) (i) –78 °C to r.t. (iii) aq NH4Cl soln (iii) MnO2 (1.0 equiv), O2, 15 min, 15–20%; (c) MnO2
(5.0 equiv), CHCl3, reflux, 1 h, 63%; (d) (i) BuLi (1.0 equiv), –78 °C, 30 min (ii) 23 (1.0 equiv) –78 °C, 30 min; –78 °C to r.t. (iii) aq NH4Cl
soln (iv) MnO2 (1.0 equiv), O2, 15 min, 77%.
were performed on a Fisons EA 1110 CHNS elemental analyzer.
The IR (Specord 85) spectra were in each case consistent with the
assigned structure. Mass spectra were recorded on a Thermoquest
Automass Multi and VG TRIO-2 instruments and in the EI mode.
1H NMR spectra were recorded with a Varian UNITY INOVA 400
WB spectrometer. Chemical shifts are referenced to TMS. Mea-
surements were run at 298 K probe temperature in CDCl3 soln. ESR
spectra were taken on Miniscope MS 200 in 10–4 M CHCl3 soln and
all monoradicals gave triplet line aN = 14.7–16.5 G. The pH mea-
surement was performed in 10–4 M MeOH–Sorensen buffer (1:9)
soln. Fluorescence spectra were taken with Perkin Elmer LSB 50 in-
strument. Flash column chromatography was performed on Merck
Kieselgel 60 (0.040–0.063 mm). Qualitative TLC was carried out
on commercially prepared plates (20 × 20 × 0.02 cm) coated with
Merck Kieselgel GF254. Compound 7 was purchased from Fluka or
prepared as published earlier.25 All reagents were purchased from
Aldrich. Compounds 1,26 12,18 14,19 15,27 18,21 19,22 23,28 and 2429
were prepared according to published procedures.
Figure 1 pH dependence of hyperfine splitting constant of the
nitroxides 25, 26, and 28, obtained by X-band EPR
1-(1-Prop-2-ynyl-1H-benzoimidazol-2-yl)ethanone (2)
To a stirred soln of 1 (3.20 g, 20.0 mmol) and K2CO3 (3.03 g, 22.0
mmol) in MeCN (20 mL) was added propargyl bromide (2.61 g,
22.0 mmol) and the mixture was stirred and heated under reflux for
3 h. After cooling the mixture was filtered, the filtrate was evapo-
rated, the residue was dissolved in EtOAc (30 mL) and washed with
brine (10 mL), and the organic phase was separated, dried (MgSO4),
filtered, and evaporated. The residue was purified by flash column
chromatography (hexane–Et2O, 2:1) to yield a white solid; yield:
3.48 g (88%); mp 112–113 °C; Rf = 0.25 (hexane–Et2O, 2:1).
The resulting compound 28 exhibited minimal pH depen-
dence (Figure 1) supporting the necessity of the imidazole
moiety in EPR active pH sensors.
In conclusion, we have developed a new approach for syn-
thesis of pyrazino[1,2-a]benzimidazole ring system. Dur-
ing the cyclizations deacetylation processes were
observed. Nitroxides annulated or linked to benzimida-
zole were synthesized by classical ring closure, lithiation,
and palladium-catalyzed cross-coupling. Among the new-
ly synthesized benzimidazoles, pH-sensitive EPR probes
and a paramagnetic analogue of antiviral agent HBB were
described. Further biological studies of these compounds
are in progress.
IR (Nujol): 2105 (C≡C), 1687 (C=O), 1615, 1605 (C=C), 1580
(C=N) cm–1.
1H NMR: d = 7.92 (d, J = 8.4 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H),
7.49 (t, J = 7.6 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 1 H), 5.51 (s, 2 H), 2.86
(s, 3 H), 2.32 (s, 1 H).
MS (EI, 70 eV): m/z (%) = 198 (71) [M+], 169 (100), 155 (58), 43
(46).
Anal. Calcd for C12H10N2O: C, 72.71; H, 5.08; N, 14.13. Found: C,
72.65; H, 5.00; N, 14.21.
Melting points were determined with a Boetius micro melting point
apparatus and are uncorrected. Elemental analyses (C, H, N, S)
Synthesis 2008, No. 15, 2439–2445 © Thieme Stuttgart · New York

2442
B. Bognár et al.
PAPER
1-[1-(3-Phenylprop-2-ynyl)-1H-benzimidazol-2-yl]ethanone (3)
To a soln of PhI (2.04 g, 10.0 mmol) in deoxygenated anhyd Et3N
(10 mL) were added PdCl2(PPh3)2 (700 mg, 1.0 mmol) and CuI (95
mg, 0.5 mmol) and the mixture was stirred for 15 min under N2.
Then 2 (1.98 g, 10.0 mmol) dissolved in anhyd Et3N (5 mL) was
added dropwise causing an immediate brown precipitation from the
yellow soln. Within 10 min the mixture became a thick slurry and
was vigorously stirred at r.t. for 5 h. The mixture was diluted with
EtOAc (20 mL), filtered through a Celite pad, and washed with
EtOAc (5 mL) and then the solvents were evaporated off. The resi-
due was partitioned between EtOAc (30 mL) and H2O (10 mL) and
the organic phase was separated, dried (MgSO4), filtered, and evap-
orated. The residue was purified by flash column chromatography
(hexane–Et2O, 2:1) to give 3 as a white solid; yield: 1.72 g (63%);
mp 84–85 °C; Rf = 0.27 (hexane–Et2O, 2:1).
IR (Nujol): 1695 (C=O), 1610 (C=C), 1585 (C=N) cm–1.
1H NMR: d = 7.91 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 1 H),
7.47–7.28 (m, 7 H), 5.68 (s, 2 H), 2.85 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 274 (85) [M+], 231 (69), 115 (100), 43
(46).
1-Prop-2-ynyl-1H-benzimidazole (6a)30
White solid; yield: 358 mg (46%); mp 38–40 °C; Rf = 0.32 (CHCl3–
Et2O–MeOH, 8:3:1).
IR (Nujol): 2105 (C≡C), 1620 (C=C), 1590 (C=N) cm–1.
1H NMR: d = 8.17 (s, 1 H), 8.02–7.40 (m, 4 H), 4.94 (d, J = 2.4 Hz,
2 H), 2.48 (t, J = 2.4 Hz, 1 H).
Anal. Calcd For C10H8N2: C, 76.90; H, 5.16; N, 17.94. Found: C,
76.83; H, 5.20; N, 17.88.
3-Benzyl-1-methylpyrazino[1,2-a]benzimidazole (5b)
Yellow solid; yield: 432 mg (32%); mp 55–58 °C; Rf = 0.77
(CHCl3–Et2O–MeOH, 8:3:1).
IR (Nujol): 1620, 1610 (C=C), 1580 (C=N) cm–1.
1H NMR: d = 8.01 (d, J = 8.4 Hz, 1 H), 7.86 (s, 1 H), 7.78 (d, J = 8.4
Hz, 1 H), 7.53 (t, J = 7.6 Hz, 1 H), 7.38–7.25 (m, 6 H), 4.18 (s, 2
H), 2.99 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 273 (73) [M+], 272 (72), 258 (12), 77
(41), 43 (100).
Anal. Calcd For C18H15N3: C, 79.10; H, 5.53; N, 15.37. Found: C,
79.08; H, 5.49; N, 15.18.
Anal. Calcd for C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found: C,
78.77; H, 5.08; N, 10.16.
1-(3-Phenylprop-2-ynyl)-1H-benzimidazole (6b)
White solid; yield: 406 mg (35%); mp 102–103 °C; Rf = 0.50
(CHCl3–Et2O–MeOH, 8:3:1).
IR (Nujol): 1605 (C=C), 1580 (C=N) cm–1.
1H NMR: d = 8.33 (s 1 H), 7.85 (d, J = 7.2 Hz, 1 H), 7.57 (d, J = 7.2
Hz, 1 H), 7.43–7.25 (m, 7 H), 5.19 (s, 2 H).
1,3-Dimethylbenzimidazo[1,2-a]pyrazine 2-Oxide (4)
A soln of 2 (990 mg, 5.0 mmol), NH2OH·HCl (513 mg, 7.5 mmol),
NaOAc (615 mg, 7.5 mmol) in EtOH (10 mL) and H2O (4 mL) was
refluxed for 3 h. After cooling the mixture was evaporated under re-
duced pressure and the residue was partitioned between CHCl3 (30
mL) and H2O (10 mL). The organic phase was separated, dried, fil-
tered, and evaporated. After chromatographic purification (CHCl3–
Et2O–MeOH, 10:5:1), 4 was obtained as a yellow solid; yield: 745
mg (70%); mp 228–230 °C; Rf = 0.34 (CHCl3–Et2O–MeOH, 8:3:1),
blue fluorescent spot (lex/lem = 362/422 nm in MeCN).
MS (EI, 70 eV): m/z (%) = 232 (65) [M+], 115 (100).
Anal. Calcd For C16H12N2: C, 82.73; H, 5.21; N, 12.06. Found: C,
82.64; H, 5.20; N, 11.99.
IR (Nujol): 1610 (C=C), 1580 (C=N) cm–1.
2-Methyl-2-nitropropyl Methanesulfonate (8)
1H NMR: d = 8.15 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 8.4
Hz, 1 H), 7.51 (t, J = 7.6 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 1 H), 2.86 (s,
3 H), 2.52 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 213 (50) [M+], 197 (100), 155 (35), 42
(45).
To a soln of 7 (2.38 g, 20.0 mmol) and Et3N (2.22 g, 22.0 mmol) in
CH2Cl2 (20 mL) was added at 0 °C MsCl (2.52 g, 22.0 mmol) and
the mixture was stirred at r.t. for 1 h. The organic phase was washed
with brine, dried (MgSO4), filtered, and evaporated. The residue
was crystallized (hexane–Et2O) to give 8 as an off-white solid;
yield: 3.46 g (88%); mp 40–43 °C.
IR (Nujol): 1550 (NO2) cm–1.
1H NMR: d = 4.47 (s, 2 H), 3.03 (s, 3 H), 1.65 (s, 6 H).
Anal. Calcd for C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C,
67.62; H, 5.15; N, 19.65.
Pyrazino[1,2-a]benzimidazoles 5a,b; General Procedure
A 7.0 M NH3 in MeOH soln of 2 (990 mg, 5.0 mmol) or 3 (1.37 g,
5.0 mmol) was heated overnight at 120 °C in a sealed tube. After
cooling the mixture was evaporated, the residue was subjected to
flash column chromatography (CHCl3–Et2O) to give the cyclized
product 5a as a first blue fluorescent spot (lex/lem = 363/425 nm in
MeCN) or 5b again as a blue fluorescent spot (lex/lem = 365/427 nm
in MeCN) and followed by the deacetylated byproduct 6a or 6b as
a second band.
MS (EI, 70 eV): m/z (%) = 197 (1>) [M+], 151 (26), 79 (91), 55
(100).
Anal. Calcd For C5H11NO5S: C, 30.45; H, 5.62; N, 7.10; S 16.26.
Found: C, 30.21; H, 5.66; N, 7.03; S 16.11.
1-[1-(2-Methyl-2-nitropropyl)-1H-benzimidazol-2-yl]ethanone
(9)
To a suspension of NaH (240 mg, 10.0 mmol) in anhyd THF (20
mL) was added dropwise 1 (1.60 g, 10.0 mmol) in anhyd DMF (5
mL) and the mixture was stirred at 0 °C for 30 min Then 8 (3.94 g,
20.0 mmol) dissolved in anhyd DMF ( 5 mL) was added and the
mixture was stirred and heated under reflux for 12 h. After cooling
all the solvents were evaporated off and the residue was partitioned
between H2O (10 mL) and CHCl3 (30 mL). The organic phase was
separated, dried, filtered, and evaporated and the residue was puri-
fied by flash column chromatography (hexane–EtOAc 2:1) to yield
9 as a white solid: 861 mg (33%); mp 134 °C; Rf = 0.54 (hexane–
EtOAc 2:1).
1,3-Dimethylpyrazino[1,2-a]benzimidazole (5a)
Off-white solid; yield: 443 mg (45%); mp 102–104 °C; Rf = 0.40
(CHCl3–Et2O–MeOH, 8:3:1).
IR (Nujol): 1632 (C=C), 1585 (C=N) cm–1.
1H NMR: d = 8.02–7.40 (m, 5 H), 2.98 (s, 3 H), 2.55 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 197 (38) [M+], 156 (100), 129 (73), 102
(29).
Anal. Calcd For C12H11N3: C, 73.07; H, 5.62; N, 21.03. Found: C,
73.10; H, 5.55; N, 21.14.
IR (Nujol): 1685 (C=O), 1605 (C=C), 1580 (C=N), 1535 (NO2)
cm–1.
Synthesis 2008, No. 15, 2439–2445 © Thieme Stuttgart · New York

PAPER
Synthesis of Linked or Condensed Benzimidazoles
2443
1H NMR: d = 7.88 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1 H),
7.45 (t, J = 7.2 Hz, 1 H), 7.37 (t, J = 7.2 Hz, 1 H), 5.31 (s, 2 H), 2.85
(s, 3 H), 1.60 (s, 6 H).
MS (EI, 70 eV): m/z (%) = 261 (65) [M+], 215 (100), 173 (62), 43
(42).
chromatography (CHCl3–Et2O, 2:1) to give 13 as a yellow solid;
yield: 1.17 g (46%); mp 203–205 °C; Rf = 0.24 (CHCl3–Et2O, 2:1).
IR (Nujol): 3300 (NH), 1615 (C=C), 1580 (C=N).
MS (EI, 70 eV): m/z (%) = 256 (30) [M+], 242 (29), 226 (53), 211
(100).
Anal. Calcd For C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found:
C, 59.75; H, 5.81; N, 16.03.
Anal. Calcd for C15H18N3O: C, 70.29; H, 7.08; N, 16.39. Found: C,
70.27; H, 7.08; N, 16.44.
1,3,3-Trimethyl-3,4-dihydropyrazino[1,2-a]benzimidazole
2-Oxide (10)
3-{[1-(tert-Butoxycarbonyl)-1H-benzimidazol-2-yl]ethynyl}-
2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yloxyl Radical
(16)
To a stirred soln of 9 (1.305 g, 5.0 mmol) and NH4Cl (401 mg, 7.5
mmol) in THF (10 mL) and H2O (5 mL) was added Zn dust (1.3 g,
20.0 mmol) in small portions over 1.5 h, such that the temperature
inside the flask did not exceed 10 °C. The mixture was stirred for an
additional 0.5 h and then was filtered. The filtrate was combined
with MeOH washes (20 mL) of the filter cake. The solvent volume
was reduced by evaporation to 10 mL. The aqueous solvent was sat-
urated with NaCl and extracted with CHCl3 (2 × 15 mL). The com-
bined extracts were dried (MgSO4), filtered, and evaporated and the
residue was purified by flash column chromatography (CHCl3–
Et2O–MeOH, 8:3:0.5) to give 10 as a white solid; yield: 554 mg
(48%); mp 126–130 °C; Rf = 0.5 (CHCl3–Et2O–MeOH, 8:3:1).
The soln of 14 (1.48 g, 5.0 mmol), PdCl2(PPh3)2 (350 mg, 0.5
mmol), and CuI (48 mg, 0.25 mmol) in freshly distilled Et3N (30
mL) was stirred for 15 min under N2. Then alkyne 15 (820 mg, 5.0
mmol) dissolved in Et3N (10 mL) was added and the mixture was
stirred at r.t. for 5 h. The soln was filtered through Celite, washed
with EtOAc (20 mL), and evaporated under vacuum. The residue
was dissolved in CH2Cl2 (50 mL) and washed with H2O (20 mL).
The organic phase was separated and dried (MgSO4) and MnO2 (87
mg, 1.0 mmol) was added and oxygen was bubbled through the soln
for 15 min. After filtration and evaporation the residue was purified
by flash chromatography (CHCl3–Et2O, 2:1) to yield 16 as a yellow
solid; yield: 1.12 g (59%); mp 95–97 °C; Rf = 0.59 (CHCl3–Et2O,
2:1).
IR (Nujol): 1605 (C=C), 1580 (C=N) cm–1.
1H NMR: d = 7.88 (d, J = 8.4 Hz, 1 H), 7.40–7.30 (m, 3 H), 4.24 (s,
2 H), 2.58 (s, 3 H), 1.60 (s, 6 H).
IR (Nujol): 1750 (C=O), 1600 (C=C), 1570 (C=N) cm–1.
MS (EI, 70 eV): m/z (%) = 239 (100) [M+], 213 (65), 198 (32), 42
MS (EI, 70 eV): m/z (%) = 380 (1>) [M+], 279 (5), 235 (23), 149
(66).
(23), 57 (100).
Anal. Calcd for C13H15N3O: C, 68.10; H, 6.59; N, 18.33. Found: C,
68.03; H, 6.62; N, 18.38.
Anal. Calcd for C22H26N3O3: C, 69.45; H, 6.89; N, 11.04. Found: C,
69.40; H, 6.83; N, 11.12.
1,1,3,3-Tetramethyl-3,4-dihydropyrazino[1,2-a]benzimidazol-
2-yloxyl Radical (11)
3-(1H-Benzimidazol-2-ylethynyl)-2,2,5,5-tetramethyl-2,5-dihy-
dro-1H-pyrrol-1-yloxyl Radical (17)
To freshly made MeMgI in Et2O (20 mL) soln [freshly made from
Mg (24 0 mg) and MeI (1.42 g)] a soln of 10 (1.19 g, 5.0) mmol in
anhyd THF (10 mL) was added at 0 °C under N2 blank. The mixture
was warmed to r.t. and then it was stirred and heated under reflux
for 1 h. The mixture was then cooled and it was quenched with sat.
aq NH4Cl (10 mL). The organic phase was separated and the aque-
ous phase was extracted with CHCl3 (10 mL). The combined organ-
ic phases were dried (MgSO4), MnO2 (870 mg, 10.0 mmol) was
added and O2 was bubbled through for 15 min. After filtration the
solvents were evaporated and the residue was purified by flash col-
umn chromatography (CHCl3–Et2O, 2:1) to give 11 as a brownish-
yellow solid; yield: 342 mg (28%); mp 62–64 °C; Rf = 0.30 (CHCl3–
Et2O, 2:1).
Compound 16 (760 mg, 2.0 mmol) was dissolved in 7 M NH3 in
MeOH soln (5 mL) and then was allowed to stand at r.t. in a sealed
tube for 18 h. The soln was filtered and evaporated and the residue
was dissolved in CHCl3 (30 mL), washed with brine, and dried
(MgSO4). After filtration the solvent was removed under reduced
pressure to give 17 as a pale yellow solid; yield: 493 mg (88%); mp
176–179 °C; Rf = 0.62 (CHCl3–Et2O–MeOH, 8:3:1).
IR (Nujol): 3150 (NH), 1605, 1595 (C=C), 1575 (C=N) cm–1.
MS (EI, 70 eV): m/z (%) = 280 (14) [M+], 250 (100), 235 (82), 43
(81).
Anal. Calcd for C17H18N3O: C, 72.83; H, 6.47; N, 14.99. Found: C,
72.82; H, 6.43; N, 14.90.
IR (Nujol): 1600 (C=C), 1575 (C=N) cm–1.
Lithiation of 1-(Hydroxymethyl)-1H-benzimidazole (18) and
Coupling with Electrophiles To Give 20, 21, 25, 26; General
Procedure
ESR: triplet, aN = 14.9 G (CHCl3).
MS (EI, 70 eV): m/z (%) = 244 (89) [M+], 199 (100), 171 (90), 41
(71).
To the soln 1-(hydroxymethyl)-1H-benzimidazole (18, 1.48 g, 10.0
mmol) in anhyd THF (20 mL) was added dropwise 2.5 M BuLi in
hexanes (8 mL, 20.0 mmol) at –78 °C under N2. The mixture was
stirred at –20 °C for an additional 30 min. The mixture was cooled
to –78 °C, and aldehyde 12 or 19 (10.0 mmol) or nitrone 23 or 24
(10.0 mmol) dissolved in THF (10 mL) was added dropwise. Then
the soln was stirred for 45 min at this temperature and the soln was
allowed to warm to r.t. slowly, followed by quenching with sat. aq
NH4Cl (20 mL) soln. After 10 min stirring the layers were separated
and the aqueous layer was washed with CHCl3 (2 × 30 mL). The or-
ganic phase was dried (MgSO4), filtered, and evaporated. The resi-
due was dissolved in CHCl3 (30 mL), PbO2 (2.39 g, 10.0 mmol) for
compound 20 and 21 or MnO2 (870 mg, 10.0 mmol) for compound
25 or 26 was added and O2 was bubbled through the soln for 30 min,
then the mixture was filtered and evaporated. The residue was puri-
Anal. Calcd for C14H18N3O: C, 68.83; H, 7.43; N, 17.20. Found: C,
68.77; H, 7.48; N, 17.05.
3-(1H-Benzimidazol-2-yl)-2,2,5,5-tetramethyl-2,5-dihydropyr-
rol-1-yloxyl Radical (13)
A mixture of 1,2-phenylenediamine (1.08 g, 10.0 mmol) and alde-
hyde 12 (1.68 g, 10.0 mmol) and TsOH·H2O (100 mg) in toluene
(40 mL) was heated in a Dean–Stark apparatus for 4 h. After cooling
the solvents were evaporated off, the residue was dissolved in
CHCl3 (30 mL), activated MnO2 (1.74 g, 20.0 mmol) was added,
and the mixture was stirred and heated under reflux for a further 1
h. After cooling the mixture was filtered through Celite, the solvents
were evaporated off and the residue was purified by flash column
Synthesis 2008, No. 15, 2439–2445 © Thieme Stuttgart · New York

2444
B. Bognár et al.
PAPER
fied by flash chromatography (CHCl3–Et2O–MeOH, 8:3:1) to yield
nitroxides 20, 21, 25, 26 (15–72%) as yellow solids.
2-(Benzothiazol-2-yl)-2,5,5-trimethylpyrrolidin-1-yloxyl Radi-
cal (28)
To a stirred soln of 27 (1.35 g, 10.0 mmol) in anhyd THF (20 mL),
2.5 M BuLi in hexanes (4 mL, 10.0 mmol) was added dropwise un-
der N2 at –78 °C. The mixture was stirred at this temperature for 30
min, then 23 (1.27 g, 10.0 mmol) in THF (5 mL) was added drop-
wise. The mixture was allowed to warm to r.t. (~1 h) and sat. aq
NH4Cl (20 mL) soln was added. After 15 min stirring, the organic
phase was separated and the aqueous phase extracted with CHCl3
(2 × 30 mL). The organic phase was dried (MgSO4), activated
MnO2 (870 mg, 10.0 mmol) was added and O2 was bubbled through
for 20 min. After filtration the solvent was evaporated under
vacuum. The residue was purified by flash column chromatography
with (hexane–EtOAc, 2:1) to give 28 as a yellow solid; yield:
1.91 g (77%); mp 102–104 °C; Rf = 0.54 (hexane–EtOAc, 2:1).
3-[(1H-Benzimidazol-2-yl)hydroxymethyl]-2,2,5,5-tetramethyl-
2,5-dihydro-1H-pyrrol-1-yloxyl Radical (20)
Yellow solid; yield: 2.05 g (72%); mp 210–212 °C; Rf = 0.28
(CHCl3–Et2O–MeOH, 8:3:1).
IR (Nujol): 3200 (NH), 1620 (C=C), 1590 (C=N) cm–1.
MS (EI, 70 eV): m/z (%) = 286 (8) [M+], 256 (20), 239 (100), 41
(49).
Anal. Calcd for C16H20N3O2: C, 67.11; H, 7.04; N, 14.67. Found: C,
67.10; H, 7.00; N, 14.64.
5-[(1H-Benzimidazol-2-yl)hydroxymethyl]-1,1,3,3-tetramethyl-
2,3-dihydro-1H-isoindol-2-yloxyl Radical (21)
Yellow solid; yield: 1.84 g (55%); mp 206–209 °C; Rf = 0.23
(CHCl3–Et2O–MeOH, 8:3:1).
IR (Nujol): 3495 (OH), 3250 (NH), 1615 (C=C), 1585 (C=N) cm–1.
MS (EI, 70 eV): m/z (%) = 336 (7) [M+], 306 (6), 273 (15), 218 (36),
IR (Nujol): 1605 (C=C), 1585 (C=N) cm–1.
MS (EI, 70 eV): m/z (%) = 261 (38) [M+], 231 (10), 216 (8), 175
(100).
Anal. Calcd for C14H17N2OS: C, 64.34; H, 6.56; N, 10.72; S: 12.27.
Found: C, 64.28; H, 6.55; N, 10.74; S: 12.11.
118 (80), 43 (100).
Anal. Calcd for C20H22N3O2: C, 71.41; H, 6.59; N, 12.49. Found: C,
71.25; H, 6.44; N, 12.36.
Acknowledgment
This work was supported by a grant from Hungarian National
Research Fund (OTKA-NKTH K67597, T48334 and M045190).
The authors thank Krisztina Kis for elemental analysis, Gergely
Gulyas for NMR measurements (Department of Biochemistry and
Medical Chemistry) and Maria Balog for technical assistance.
2-(1H-Benzimidazol-2-yl)-2,5,5-trimethylpyrrolidin-1-yloxyl
Radical (25)
Yellow solid; yield: 488 mg (20%); mp 136–139 °C; Rf = 0.63
(CHCl3–Et2O–MeOH, 8:3:1).
IR (Nujol): 3200 (NH), 1610 (C=C), 1580 (C=N) cm–1.
MS (EI, 70 eV): m/z (%) = 244 (40) [M+], 214 (11), 190 (11), 158
(100).
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Synthesis of Linked or Condensed Benzimidazoles
2445
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Synthesis 2008, No. 15, 2439–2445 © Thieme Stuttgart · New York