Synthesis of 1-methylbenzimidazoles from carbonitriles

Article abstract of DOI:10.1055/s-0028-1087383

The NaH-mediated N-methylbenzimidazole formation starting from carbonitriles and N-methyl-1,2-phenylenediamine is reported to be a procedure compatible with acid-labile acetal protective groups within the starting materials. Products were further converte

Full text of DOI:10.1055/s-0028-1087383

LETTER
63
Synthesis of 1-Methylbenzimidazoles from Carbonitriles
Synthesis
o
of 1-Methylb
n
enzimidazol
a
e
s
s Sluiter, Jens Christoffers*
Institut für Reine und Angewandte Chemie, Carl von Ossietzky-Universität Oldenburg, 26111 Oldenburg, Germany
Fax +49(441)798 3873; E-mail: jens.christoffers@uni-oldenburg.de
Received 24 September 2008
product 3a was also not detectable. With one equivalent of
NaH conversion of starting materials 1 and 2a took place
and was quantitative within three hours. Product 3a was
isolated after column chromatography in 90% yield
Abstract: The NaH-mediated N-methylbenzimidazole formation
starting from carbonitriles and N-methyl-1,2-phenylenediamine is
reported to be a procedure compatible with acid-labile acetal protec-
tive groups within the starting materials. Products were further con-
verted in Suzuki, Sonogashira, Heck and Buchwald–Hartwig (Table 1, entry 1).11 This result could not be improved
reactions.
with more NaH (2 equiv gave 89% yield). Since NaH ob-
viously deprotonated the amine 1 under these reaction
conditions (which could be monitored by gas evolution),
also other bases might be suitable to promote this reaction.
However, when up to 2 equivalents of NaOt-Bu were
used, no conversion of starting materials was observed.
Reaction of pivalonitrile (2b) under the same reaction
conditions gave only 33% yield of product 3b. Yield in-
creased to 83% when the reaction time and temperature
were increased (16 h at 160 °C, entry 2). Higher tempera-
ture or larger amounts of NaH gave no further improve-
ment. For valeronitrile (2c) optimal results (93% yield)
were obtained at 145 °C (entry 3). Higher temperature and
more NaH gave lower yields. Reaction of isobutyronitrile
(2d) required also one equivalent of NaH to give product
3d in 84% yield (entry 4). The isopropyl-substituted prod-
uct 3d was also isolated (29% yield) in an attempt of bis-
benzimidazole formation with 2,2-dimethylmalodinitrile
(2e, entry 5), which seems to be a result of cyanide elimi-
nation of the monoaddition product under reaction condi-
tions. Monoaddition product 3e of diamine 1 to dinitrile
2e was obtained at shorter reaction time, although also
with low yield (30%, entry 6). We were, though, not able
to detect any bisbenzimidazole derived from dinitrile 2e.
Initial motivation for this work was the conversion of ni-
triles 2 with acid-labile protective groups. In particular,
we were interested in the conversion of acetal-protected
cyanohydrins like lactonitrile 2f, which indeed gave ben-
zimidazole 3f after 15 hours at 150 °C in 60% yield (entry
7). The cleavage of the 1-ethoxyethyl (EE) group yielded
quantitatively the free secondary alcohol.12 Ethoxyethyl-
protected cyanohydrin derived from cyclohexanone, com-
pound 2g, also yielded the corresponding benzimidazole
derivative 3g, although with lower yield (entry 8), which
might be due to steric constraints caused by the quaternary
center. Attempts of conversion of 3-methoxypropionitrile
under the conditions introduced in this work were not
fruitful, presumably this starting material decomposed by
an E1cb process (no entry in Table 1).
Key words: benzimidazoles, heterocycles, carbonitriles, cross-
coupling
The benzimidazole moiety is one of the privileged struc-
tures in medicinal chemistry.1 Therefore, benzimidazoles
appear quite frequently in pharmaceutical products such
as Astemizole,2 Candesartan,3 Omeprazol,4 and Pradaxa5
just to name four. The heterocycle is commonly built up
by condensation of ortho-phenylenediamine with carbox-
ylic acids, esters, or imido esters under Brønsted or Lewis
acidic conditions.6 More flexible are two-step protocols:
either condensation of the diamine with carbaldehydes
and subsequent oxidation,6 or formation of ortho-amino-
benzamides with subsequent ring closure under acidic
conditions.7 Carbonitriles have also been applied for di-
rect benzimidazole synthesis. Strong acids are always
used in these cases in order to activate the nitrile.8 A two-
step protocol leading to benzimidazoles first converts
nitriles into imido esters by nucleophilic addition of alk-
oxides.9 The resulting imido esters are then condensed
with the diamines. In certain cases, these two steps can be
performed in one flask.10 We were interested in the direct
conversion of carbonitriles to N-methylbenzimidazoles
under avoidance of even slightly acidic conditions, since
we need to retain acetal protective groups present in our
starting materials. Therefore, we aimed to develop basic
reaction conditions for this condensation reaction.
As mentioned introductorily, neutral or basic reaction
conditions were never been reported for the formation of
benzimidazoles from N-methyl-1,2-phenylenediamine (1)
and nitriles 2 (Scheme 1). With diamine 1 and cyclohex-
ane derivative 2a as a model system we first envisioned
thermal reaction conditions without any additive or cata-
lyst; however, heating equimolar amounts of starting ma-
terials 1 and 2a in EtOH or toluene up to 120 °C (sealed
reaction tube) did not result in the formation of benzimi-
dazole 3a, as monitored by GLC. When adding substoi-
chiometric amounts of NaH (0.25 or 0.5 equiv) as a base,
Although the yield of phenyl-substituted product 3h was
good (73%) when the reaction with benzonitrile 2h was
performed at 180 °C (entry 9), the formation of p-bromo
congener 3i was optimal (only 65% yield) at 150 °C (entry
11), but remained unsatisfactory. Even lower was the op-
SYNLETT 2009, No. 1, pp 0063–0066
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087383; Art ID: G30408ST
© Georg Thieme Verlag Stuttgart · New York

64
J. Sluiter, J. Christoffers
LETTER
p-Bromophenyl-substituted benzimidazole 3i was sub-
mitted to four cross-coupling reactions in order to check a
potential point of diversification. Suzuki coupling with
PhB(OH)2 was performed with Na2PdCl4 and cataCXium
FSulf as precatalyst24 and gave biphenyl-substituted benz-
imidazole 4 with 92% yield (Scheme 2).25 Disodium tet-
rachloropalladate (Na2PdCl4) and cataCXium FBu were
the precatalyst26 for Sonogashira coupling with PhC≡CH,
which gave product 5 with 84% yield.27 This compound
has very recently been reported to be a PDE 4-inihibitor.28
Stilbene derivative 6 was obtained with 48% yield in the
Heck reaction with styrene and Pd(OAc)2–Ph3P29 as pre-
catalyst.30 The olefinic coupling constant in the 1H NMR
spectrum clearly indicated E-configuration of product 6.
Finally, Buchwald–Hartwig amination with CyNH2 and
Pd(OAc)2–BINAP31 as precatalyst gave secondary aryl
amine 7 in 65% yield.32
Me
NaH (1 equiv)
NHMe
N
toluene
RCN (1 equiv)
2a–m
R
N
NH2
1
3a–m
Scheme 1 Formation of N-methylbenzimidazoles 3 from nitriles 2;
for residues R, conditions, and yields, see Table 1
Table 1 Optimal Reaction Conditions and Yields
Entry R
2
Temp Time
(°C) (h)
3
(equiv)
(yield, %)
1
2
Cyclohexyl
2a (1.0)
2b (1.0)
2c (1.0)
2d (1.0)
2e (0.5)
2e (0.5)
2f16 (1.5)
2g17 (1.0)
2h (1.0)
2h (1.0)
2i (1.0)
120
160
145
150
160
170
150
160
180
170
150
120
180
180
150
3
16
18
16
16
6
3a13 (90)
3b14 (83)
3c (93)
t-Bu
3
n-Bu
4
i-Pr
3d15 (84)
3d (29)a
3e (30)b
Me
5
NCC(Me)2
NCC(Me)2
MeCH(OEE)c
c-(CH2)5C(OEE)
Ph
N
PhB(OH)2
Ph
3i
6
a)
N
7
15
16
23
16
16
15
6
3f (60)
4 (92%)
Me
8
3g (48)
N
Ph
H
9
3h15,18 (73)d
3h (60)e
3i18a (65)
3j13b (54)
3k13b (75)
3l21 (4)
Ph
3i
3i
3i
b)
N
10
11
12
13
14
15
Ph
5 (84%)
4-BrC6H4
4-F3CC6H4
4-MeOC6H4
2-MeOC6H4
2-pyridyl
Me
2j (1.0)
N
Ph
2k19 (1.0)
2l20 (1.0)
2m (1.1)
c)
N
Ph
6 (48%)
Me
6
16
3m13b,22 (60)
N
CyNH2
d)
a Product 3d with R = i-Pr.
CyHN
b Monoaddition product 3e with R = NCC(Me)2.
c EE = 1-ethoxyethyl.
N
7 (65%)
d Scale: 2 mmol.
e Scale: 50 mmol, refluxing mesitylene.
Scheme 2 Cross-coupling reactions of p-bromophenyl-substituted
benzimidazole 3i. Reagents and conditions: (a) Na2PdCl4 (1.3 mol%),
cataCXium Fsulf (1.5 mol%), K2CO3 (3 equiv), PhB(OH)2 (1.1
equiv), H2O, n-BuOH, 16 h, 100 °C; (b) Na2PdCl4 (1.6 mol%), cata-
CXium FBu (2.3 mol%), CuI (2.5 mol%), phenylacetylene (1.2
equiv), i-PrNH2, 16 h, 100 °C; (c) Pd(OAc)2 (10 mol%), Ph3P (24
mol%), Et3N (4 equiv), styrene (2 equiv), DMF, 16 h, 100 °C; (d)
Pd(OAc)2 (5 mol%), BINAP (7.5 mol%), NaOt-Bu (1.7 equiv),
CyNH2 (1.3 equiv), toluene, 16 h, 85 °C.
timal yield of p-trifluoromethyl derivative 3j (54%, entry
12), which was obtained at comparatively low tempera-
ture of 120 °C. Whereas results for p-methoxybenzo-
nitrile (2k) were as good as for R = Ph (75%, entry 13),
the ortho-substituted congener 2l resulted in only 4%
yield of product 3l (entry 14), which could be due to steric
effects. The yield of pyridine derivative 3m (60%, entry
15) was satisfying. p-Nitrobenzonitrile was consumed in
the reaction, but afforded a mixture of several not fully
identified products (no entry in Table 1). All reactions dis-
cussed so far were performed on a 1–2 mmol scale with
toluene as solvent in a tightly closed reaction flask. In or-
der to show the feasibility of this method, the reaction of
benzonitrile (2h) was scaled up to 50 mmol in refluxing
mesitylene (ca. 170 °C) and gave 60% yield of product 3g
(entry 10).23
In summary, formation of benzimidazole derivatives from
1,2-phenylenediamines and carboxylic acid derivatives
including carbonitriles commonly require acidic reaction
conditions, which are not compatible with acid-labile pro-
tective groups such as acetals. We have reported herein on
the first benzimidazole synthesis starting from carbo-
nitriles under basic reaction conditions. The protocol re-
quires a stoichiometric amount of NaH. The reaction
proceeds in toluene in a tightly closed reaction vial at
120–180 °C on a mmol scale or alternatively in refluxing
mesitylene on a larger scale within 3 to 23 hours. A broad
Synlett 2009, No. 1, 63–66 © Thieme Stuttgart · New York

LETTER
Synthesis of 1-Methylbenzimidazoles
65
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range of aliphatic and aromatic including heteroaromatic
carbonitriles was investigated. After optimization of reac-
tion time and temperature for every single substrate yields
in the range of 50–93% can be obtained. Importantly, this
method is fully compatible with acid-labile ethoxyethyl-
protected cyanohydrins. The p-bromophenyl-substituted
product can be further converted in cross-couplings such
as Suzuki, Sonogashira, Heck, and Buchwald–Hartwig
reactions.
(16) Sims, H. J.; Parseghian, H. B.; de Benneville, P. L. J. Org.
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Acknowledgment
(17) Schlosser, M.; Brich, Z. Helv. Chim. Acta 1978, 61, 1903.
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48, 3522.
This work was generously supported by the Fonds der Chemischen
Industrie. Ligands cataCXium FSulf and FBu were a generous gift
from Evonik Degussa GmbH, Hanau, Germany.
References and Notes
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
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(20) Schareina, T.; Zapf, A.; Mägerlein, W.; Müller, N.; Beller,
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(21) (a) Douhal, A.; Amat-Guerri, F.; Lillo, M. P.; Acuna, A. U.
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(5) Eriksson, B. I.; Smith, H.; Yasothan, U.; Kirkpatrick, P. Nat.
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M. R. In Science of Synthesis, Vol. 12; Neier, R., Ed.;
Thieme: Stuttgart, 2002, 529.
(23) 1-Methyl-2-phenyl-1H-benzimidazole (3h)
Diamine 1 (6.1 g, 50 mmol), NaH (2.0 g, 60% dispersion in
mineral oil, 50 mmol) and abs. mesitylene (10 mL) were
successively added to nitrile 2h (5.2 g, 50 mmol). The
mixture was heated to reflux for 16 h (inner temp ca. 170 °C,
oil bath 210 °C). After cooling to ambient temperature, the
mixture was filtered through SiO2 (1 cm), the residue
washed with CH2Cl2 (5 mL), and the combined filtrates
evaporated. The residue was chromatographed (SiO2,
hexane–EtOAc, 1:1; Rf = 0.34) to give the title compound 3a
(6.2 g, 30 mmol, 60%) as a light yellow solid, mp 91 °C
(lit.18b 92–93 °C). 13C{1H} NMR (125 MHz, CDCl3):
d = 31.57 (CH3), 109.54 (CH), 119.76 (CH), 122.33 (CH),
122.67 (CH), 128.58 (2 CH), 129.35 (2 CH), 129.63 (CH),
130.16 (C), 136.51 (C), 142.91 (C), 153.70 (C) ppm. All
other data were in accordance with the literature.18b
(24) cataCXium FSulf = dicyclohexyl{2-sulfo-9-[3-(4-sulfo-
phenyl)propyl]-9-fluorenyl}phosphonium hydrogensulfate;
for use in Suzuki reactions, see: (a) Fleckenstein, C. A.;
Plenio, H. Green Chem. 2007, 9, 1287. (b) Fleckenstein,
C. A.; Plenio, H. Chem. Eur. J. 2007, 13, 2701.
(25) 2-(Biphenyl-4-yl)-1-methyl-1H-benzimidazole (4)
A mixture of bromophenyl compound 3i (91 mg, 0.32 mmol,
1.0 equiv), PhB(OH)2 (42 mg, 0.35 mmol, 1.1 equiv),
Na2PdCl4 (1.2 mg, 4.2 mmol, 1.3 mol%), cataCXium Fsulf
(3.3 mg, 4.5 mmol, 1.5 mol%), and K2CO3 (131 mg, 945
mmol, 3 equiv) was placed in a Schlenk tube and twice
evacuated and flushed with N2. Degassed H2O (0.5 mL) and
BuOH (0.5 mL) were added, and the resulting mixture was
stirred for 16 h at 100 °C. Subsequently, the organic layer
was separated and the aqueous layer extracted with CH2Cl2
(5 mL). The combined organic layers were dried (MgSO4),
and after filtration, the solvent was evaporated and the
residue chromatographed (SiO2, hexane–EtOAc = 1:1,
Rf = 0.48) to give the title compound 4 (82 mg, 0.29 mmol,
92%) as a yellow solid, mp 164 °C. 1H NMR (500 MHz,
(7) Duschmale, J. J.; Woltering, T. J.; Bleicher, K. H. Synlett
2008, 1467.
(8) Hölljes, E. L.; Wagner, E. C. J. Org. Chem. 1944, 9, 31.
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Narayanan, V. L.; Cruthers, L.; Szanto, J. J. Med. Chem.
1979, 22, 1113. (b) Renouard, T.; Grätzel, M. Tetrahedron
2001, 57, 8145. (c) Renouard, T.; Fallahpour, R.-A.;
Nazeeruddin, M. K.; Humphry-Baker, R.; Gorelsky, S. I.;
Lever, A. B. P.; Grätzel, M. Inorg. Chem. 2002, 41, 367.
(10) Nabulsi, N. A. R.; Gandour, R. D. J. Org. Chem. 1991, 56,
2260.
(11) 2-Cyclohexyl-1-methyl-1H-benzimidazole (3a)
Diamine 1 (244 mg, 2.00 mmol), NaH (80.0 mg, 60%
dispersion in mineral oil, 2.00 mmol), and abs. toluene (1.0
mL) were successively added to nitrile 2a (218 mg, 2.00
mmol). The mixture was stirred for 3 h at 120 °C in a tightly
closed reaction vial, then completely transferred on top of a
column (SiO2), and chromatographed (hexane–EtOAc, 1:1;
Rf = 0.32) to give the title compound 3a (384 mg, 1.79
mmol, 90%) as a light brown solid, mp 102 °C (lit.13a
104 °C). 1H NMR (500 MHz, CDCl3): d = 1.30–1.48 (m,
3 H), 1.74–2.03 (m, 7 H), 2.84 (tt, J = 3.5, 11.6 Hz, 1 H),
3.74 (s, 3 H), 7.20–7.31 (m, 3 H), 7.72–7.77 (m, 1 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): d = 25.82 (CH2), 26.32
(2 CH2), 29.52 (CH3), 31.46 (2 CH2), 36.33 (CH), 108.80
(CH), 119.27 (CH), 121.66 (CH), 121.87 (CH), 135.64 (C),
142.55 (C), 159.00 (C) ppm. IR (ATR): n = 3173 (w), 3052
(w), 2929 (s), 2851 (m), 1730 (m), 1615 (m), 1506 (m), 1441
(s), 1278 (m), 1239 (m), 842 (m), 736 (s) cm–1. MS (EI, 70
eV): m/z (%) = 214 (14) [M+], 159 (100). HRMS (CI,
isobutane): m/z calcd for C14H19N2: 215.1548; found:
215.1548 [M + H+]. Anal. Calcd for C14H18N2 (214.31): C,
78.46; H, 8.47; N, 13.07. Found: C, 78.40; H, 8.55; N, 13.05.
Synlett 2009, No. 1, 63–66 © Thieme Stuttgart · New York

66
J. Sluiter, J. Christoffers
LETTER
CDCl3): d = 3.87 (s, 3 H), 7.29–7.34 (m, 2 H), 7.35–7.40 (m,
2 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.62–7.67 (m, 2 H), 7.71–7.76
(m, 2 H), 7.81–7.87 (m, 3 H) ppm. 13C{1H} NMR (125 MHz,
CDCl3): d = 31.70 (CH3), 109.57 (CH), 119.75 (CH), 122.42
(CH), 122.74 (CH), 127.08 (2 CH), 127.26 (2 CH), 127.78
(CH), 128.86 (2 CH), 128.94 (C), 129.77 (2 CH), 136.61 (C),
140.09 (C), 142.40 (C), 142.93 (C), 153.40 (C) ppm. IR
(ATR): n = 3031 (w), 2925 (w), 1463 (m), 1375 (m), 1325
(m), 1005 (m), 850 (m), 765 (m), 737 (s), 690 (s) cm–1. MS
(EI, 70 eV): m/z (%) = 284 (98) [M+], 283 (100), 179 (10),
152 (10), 78 (12), 77 (29). HRMS (EI, 70 eV): m/z calcd for
C20H16N2: 284.1313; found: 284.1313 [M+].
1 equiv), freshly distilled styrene (44 mg, 0.42 mmol, 2.0
equiv), Pd(OAc)2 (5.0 mg, 21 mmol, 0.1 equiv), Ph3P (14 mg,
51 mmol, 0.24 equiv), Et3N (85 mg, 0.84 mmol, 4.0 equiv),
and abs. DMF (3.0 mL) was stirred for 16 h at 100 °C under
an inert atmosphere. Subsequently, all volatile materials
were removed in vacuo, the residue dissolved in CH2Cl2 (5
mL), and washed with H2O (2 × 3 mL). The organic layer
was dried (Na2SO4), and after filtration, the solvent was
evaporated. Chromatography of the residue (SiO2; hexane–
EtOAc, 2:1; Rf = 0.27) gave the title compound 6 (31 mg,
0.10 mmol, 48%) as a light yellow solid, mp 150 °C. 1H
NMR (500 MHz, CDCl3): d = 3.86 (s, 3 H), 7.15 (d, J = 16.3
Hz, 1 H), 7.21 (d, J = 16.3 Hz, 1 H), 7.23–7.34 (m, 3 H),
7.33–7.41 (m, 3 H), 7.50–7.56 (m, 2 H), 7.60–7.68 (m, 2 H),
7.72–7.79 (m, 2 H), 7.80–7.87 (m, 1 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): d = 31.74 (CH3), 109.56 (CH), 119.74
(CH), 122.45 (CH), 122.76 (CH), 126.63 (4 CH), 127.67
(CH), 127.97 (CH), 128.71 (2 CH), 129.01 (C), 129.68
(2 CH), 130.17 (CH), 136.62 (C), 136.90 (C), 138.68 (C),
142.91 (C), 153.40 (C) ppm. IR (ATR): n = 3025 (w), 2953
(w), 1461 (m), 1379 (m), 1326 (m), 960 (m), 821 (s), 741 (s),
688 (s) cm–1. MS (EI, 70 eV): m/z (%) = 310 (100) [M+], 309
(75). HRMS (EI, 70 eV): m/z calcd for C22H18N2: 310.1470;
found: 310.1470 [M+].
(26) cataCXium FBu = (9-butyl-9-fluorenyl)dicyclohexylphos-
phonium tetrafluoroborate; for use in Sonogashira reactions,
see ref. 24a
(27) 1-Methyl-2-[4-(phenylethynyl)phenyl]-1H-benzimi-
dazole (5)28
A suspension of bromophenyl compound 3i (91 mg, 0.32
mmol, 1 equiv), phenylacetylene (38 mg, 0.38 mmol, 1.2
equiv), Na2PdCl4 (1.5 mg, 5.1 mmol, 1.6 mol%), cataCXium
FBu (3.6 mg, 7.2 mmol, 2.3 mol%), and CuI (1.5 mg, 7.8
mmol, 2.5 mol%) in i-PrNH2 (1.0 mL) was stirred under an
inert atmosphere for 16 h at 100 °C. Subsequently, all
volatile materials were removed in vacuo, the residue
dissolved in CH2Cl2 (5 mL), and washed with H2O (2 ×
3 mL). The organic layer was dried (Na2SO4), and after
filtration, the solvent was evaporated. Chromatography of
the residue (SiO2; hexane–EtOAc, 2:1; Rf = 0.29) gave the
title compound 5 (81 mg, 0.26 mmol, 84%) as a light yellow
solid, mp 152 °C (lit.28 153–155 °C). 1H NMR (500 MHz,
CDCl3): d = 3.80 (s, 3 H), 7.26–7.37 (m, 6 H), 7.50–7.57 (m,
2 H), 7.63–7.68 (m, 2 H), 7.71–7.77 (m, 2 H), 7.79–7.86 (m,
1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): d = 31.63
(CH3), 88.71 (C), 91.27 (C), 109.58 (CH), 119.75 (CH),
122.47 (CH), 122.77 (C), 122.87 (CH), 124.62 (C), 128.31
(2 CH), 128.48 (CH), 129.20 (2 CH), 129.68 (C), 131.57
(2 CH), 131.70 (2 CH), 136.56 (C), 142.86 (C), 152.83 (C)
ppm. IR (ATR): n = 3058 (w), 2950 (w), 2216 (w), 1457
(m), 1437 (m), 1381 (m), 1329 (m), 1249 (m), 1103 (m),
1007 (m), 919 (m), 840 (s), 740 (s), 730 (s), 690 (s) cm–1.
MS (EI, 70 eV): m/z (%) = 308 (100) [M+], 307 (80), 203
(23), 176 (12), 154 (12). HRMS (EI, 70 eV): m/z calcd for
C22H16N2: 308.1313; found: 308.1313 [M+].
(31) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144.
(32) 2-[4-(Cyclohexylamino)phenyl]-1-methyl-1H-benzimi-
dazole (7)
A suspension of Pd(OAc)2 (3.0 mg, 11 mmol, 5.0 mol%) and
rac-BINAP (7.0 mg, 11 mmol, 7.5 mol%) in abs. toluene (1.5
mL) was stirred for 5 min at 23 °C under an inert atmo-
sphere. Bromophenyl compound 3i (60 mg, 0.21 mmol, 1
equiv), CyNH2 (27 mg, 0.27 mmol, 1.3 equiv), and NaOt-Bu
(34 mg, 0.36 mmol, 1.7 equiv) were added, and the resulting
mixture was stirred for 16 h at 85 °C. Subsequently, it was
diluted with CH2Cl2 (5 mL) and washed with sat. NaHCO3
solution (5 mL). The organic layer was dried (MgSO4), and
after filtration, the solvent was evaporated. Chromatography
of the residue (SiO2; hexane–EtOAc, 1:2; Rf = 0.44) gave the
title compound 7 (42 mg, 0.14 mmol, 65%) as a light yellow
solid, mp 145 °C. 1H NMR (500 MHz, CDCl3): d = 1.13–
1.29 (m, 3 H), 1.32–1.46 (m, 2 H), 1.62–1.70 (m, 1 H), 1.73–
1.83 (m, 2 H), 2.01–2.13 (m, 2 H), 3.25–3.39 (m, 1 H), 3.77–
3.93 (m, 4 H), 6.63–6.69 (m, 2 H), 7.23–7.28 (m, 2 H), 7.29–
7.34 (m, 1 H), 7.54–7.60 (m, 2 H), 7.74–7.80 (m, 1 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): d = 24.89 (2 CH2), 25.78
(CH2), 31.74 (CH3), 33.24 (2 CH2), 51.40 (CH), 109.23
(CH), 112.51 (2 CH), 117.80 (C), 119.20 (CH), 121.97
(CH), 122.00 (CH), 130.65 (2 CH), 136.61 (C), 142.97 (C),
148.49 (C), 154.62 (C) ppm. IR (ATR): n = 3335 (w), 3055
(w), 2928 (m), 2853 (m), 1608 (s), 1542 (m), 1456 (s), 1379
(m), 1323 (m), 1180 (m), 1006 (m), 888 (s), 828 (m), 814
(m), 743 (s), 731 (s) cm–1. MS (EI, 70 eV): m/z (%) = 305
(100) [M+], 304 (16), 263 (12), 262 (62), 222 (14), 131 (10).
HRMS (EI, 70 eV): m/z calcd for C20H23N3: 305.1892;
found: 305.1892 [M+].
(28) Vinodkumar, R.; Vaidya, S. D.; Kumar, B. V. S.; Bhise,
U. N.; Bhirud, S. B.; Mashelkar, U. C. Eur. J. Med. Chem.
2008, 43, 986.
(29) (a) Meyer, F. E.; Ang, K. H.; Steinig, A. G.; de Meijere, A.
Synlett 1994, 191. (b) Ang, K. H.; Bräse, S.; Steinig, A. G.;
Meyer, F. E.; Llebaria, A.; Voigt, K.; de Meijere, A.
Tetrahedron 1996, 52, 11503. (c) de Meijere, A.; Meyer,
F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379; Angew.
Chem. 1994, 106, 2473.
(30) (E)-1-Methyl-2-[4-(2-phenylethenyl)phenyl]-1H-benz-
imidazole (6)
A mixture of bromophenyl compound 3i (60 mg, 0.21 mmol,
Synlett 2009, No. 1, 63–66 © Thieme Stuttgart · New York

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