Stereospecific synthesis of (Z)-1,3-oxazolobenzimidazoles from imidazole- and benzene-ring-substituted benzimidazoles and α,β-acetylenic γ-hydroxynitriles

Article abstract of DOI:10.1055/s-0030-1258152

A stereospecific, facile synthesis of (Z)-1,3-oxazolobenzimidazoles from imidazole- and benzene-ring-substituted benzimidazoles and α,β- acetylenic γ-hydroxynitriles has been elaborated. The reaction proceeds smoothly in acetonitrile without catalyst (room temperature, 3-5 days or 35-40°C, 20-72 h) to afford the target compounds in 33-90% yields. The annulation involves an intermediate vinyl carbanion with zwitterionic character, which, after transformation into an O-centered zwitterion, is further inserted into the aromatic system of the imidazole ring. The synthesis contributes to the basic benzimidazole and acetylene chemistry and drug design. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258152

2828
PAPER
Stereospecific Synthesis of (Z)-1,3-Oxazolobenzimidazoles from Imidazole-
and Benzene-Ring-Substituted Benzimidazoles and a,b-Acetylenic g-Hydroxy-
nitriles
Ludmila V. Andriyankova, Kseniya V. Belyaeva, Lina P. Nikitina, Anastasiya G. Mal’kina, Andrei V. Afonin,
Boris A. Trofimov*
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk,
Russian Federation
Fax +7(3952)419346; E-mail: boris_trofimov@irioch.irk.ru
Received 16 April 2010; revised 26 April 2010
containing a 1,3-oxazolidine moiety, which are practical-
Abstract: A stereospecific, facile synthesis of (Z)-1,3-oxazolobenz-
ly unknown.
imidazoles from imidazole- and benzene-ring-substituted benzimi-
dazoles and a,b-acetylenic g-hydroxynitriles has been elaborated.
The reaction proceeds smoothly in acetonitrile without catalyst
(room temperature, 3–5 days or 35–40 °C, 20–72 h) to afford the
target compounds in 33–90% yields. The annulation involves an in-
termediate vinyl carbanion with zwitterionic character, which, after
transformation into an O-centered zwitterion, is further inserted into
the aromatic system of the imidazole ring. The synthesis contributes
to the basic benzimidazole and acetylene chemistry and drug de-
sign.
Recently, we have briefly reported on the annulation of 1-
substituted benzimidazoles with a,b-acetylenic g-hydroxy-
nitriles to furnish the first representatives of benzimida-
zoles condensed with 1,3-oxazolidine cycles with
exclusively the Z-configuration.12 However, the reaction
was exemplified by only a limited number of benzimida-
zoles having substituents in the 1-position of the imida-
zole ring and, therefore, the real scope and synthetic
importance of this synthesis remained obscure. In partic-
ular, it was unclear whether the benzene-ring-substituted
benzimidazoles could be employed in this synthesis.
Key words: substituted benzimidazoles, a,b-acetylenic g-hydroxy-
nitriles, zwitterion intermediates, annulations, 1,3-oxazolodihy-
drobenzimidazoles
The aim of this work was to evaluate the true generality of
this promising reaction. Thus, we have systematically
studied the reaction of benzimidazoles 1a–f substituted
both at the imidazole and on the benzene rings with a,b-
acetylenic g-hydroxynitriles 2a and 2b.
The benzimidazole unit is known to be an important phar-
macophore and privileged structure in medicinal chemis-
try. This scaffold is a frequent structural motif for
expressing chemical functionality in biologically active
molecules.1 Optimization of benzimidazole-based struc-
tures is important in marketed medicines such as Vitamin
B12,2 the antiulcer agent Omeprazole,1,3 Lansoprazol and
(s)-Rabeprazol,4 amongst others. Several functionalized
benzimidazoles possess antithrombic,5 antiproliferative,6
antibacterial7,8 and antifungal8 activity, and they can act as
hair-growth stimulating agents.9 The antiviral activity of a
series of substituted benzimidazole, b-L- and b-D-2¢-deoxy-
ribonucleosides against selected RNA and DNA viruses
including HIV-1 and human RSV was evaluated.10
Among the condensed benzimidazoles, imidazobenzimid-
azoles in particular were mentioned as antioxidants and
radioprotectors and some were shown to possess anti-
The experiments have shown that benzimidazoles 1a–f
substituted at the benzene ring do obey the general reac-
tion scheme, i.e., they react exactly in the same manner as
the previously described12 benzimidazoles substituted at
the 1-position of the imidazole ring. However, to reach
reasonable preparative yields, a number of modifications
had to be applied to the reaction conditions. Namely, in
this case, the reaction was better conducted in solution
(unlike the former reported protocol), and the most appro-
priate solvent appeared to be acetonitrile. Additionally, it
proved to be useful to apply slight heating (35–40 °C) to
significantly shorten the reaction time (from 3–5 days to
20–72 h) and improve the product yields (by ca. 30%). Fi-
nally, a new family (12 compounds) of functionalized
benzimidazoles 3a–l condensed with oxazolidines pos-
sessing a substituent in the benzene moiety has been syn-
thesized in up to 90% yields (Table 1).
arhythmic, spasmolytic and antisecretory properties.11
A
number of these compounds have also been shown to re-
strict the transport of calcium ions through membranes
and to reduce blood pressure.11
In all the cases, the annulation remained strictly stereospe-
cific, and delivered the products with Z-configuration
only. However, special care should be taken to avoid traces
of water in the reaction mixture because, otherwise, the
reaction becomes a three-component one involving water
as a third component that follows a multi-position rear-
rangement pathway to give furanylformamides.13
Consequently, functionalization of benzimidazole, in par-
ticular to produce new condensed derivatives, remains an
important task of organic synthesis. Of special interest are
functionalized condensed derivatives of benzimidazole
SYNTHESIS 2010, No. 16, pp 2828–2834
x
x.
x
x
.
2
0
1
0
Advanced online publication: 07.07.2010
DOI: 10.1055/s-0030-1258152; Art ID: Z09710SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Stereospecific Synthesis of (Z)-1,3-Oxazolobenzimidazoles
2829
Table 1 Synthesis of 1,3-Oxazolobenzimidazoles 3a–l from Benzimidazoles 1a–f and Nitriles 2a and 2b
NC
10
R2
4
5
R2
R5
6
R5
2
R4
5
3
N
20–25 °C (72–120 h)
or 35–40 °C (20–72 h)
3a
4
N
4a
3
6
R4
CN
R3
2
7
+
R3
1
N
1
O
MeCN
7a
7
9
N
OH
8a
9a
8
R1
R1 3a–l
1a–f
2a,b
Benzimidazole
Nitrile
Product
Yield (%)a
NC
N
N
1a
2a
3a
60
56
CN
O
N
OH
N
Me
Me
NC
1a
1b
1b
2b
3b
N
CN
OH
O
O
N
Me
NC
N
2a
2b
2a
2b
2a
2b
3c
3d
3e
3f
N
79
67
44
33
90
73
N
N
Bn
Bn
NC
N
O
N
Bn
NC
N
MeO
N
1c
MeO
MeO
MeO
MeO
N
O
O
O
O
N
Me
Me
NC
N
1c
N
Me
NC
N
N
1d
1d
MeO
3g
3h
N
N
Bn
Bn
NC
N
N
Bn
Synthesis 2010, No. 16, 2828–2834 © Thieme Stuttgart · New York

2830
L. V. Andriyankova et al.
PAPER
Table 1 Synthesis of 1,3-Oxazolobenzimidazoles 3a–l from Benzimidazoles 1a–f and Nitriles 2a and 2b (continued)
NC
10
R2
4
5
R2
R5
6
R5
2
R4
5
3
N
20–25 °C (72–120 h)
or 35–40 °C (20–72 h)
3a
4
N
4a
3
6
R4
CN
R3
2
7
+
R3
1
N
1
O
MeCN
7a
7
9
N
OH
8a
9a
8
R1
R1 3a–l
1a–f
2a,b
Benzimidazole
Nitrile
Product
Yield (%)a
NC
N
O2N
O2N
N
1e
2a
3i
79
O
N
N
Me
Me
NC
O2N
1e
2b
2a
2b
3j
3k
3l
N
43b
O
O
O
N
Me
NC
O2N
O2N
N
1f
N
54
N
N
Bn
Bn
NC
O2N
1f
54b
N
N
Bn
a Isolated yield. The reaction conditions are given in the experimental details.
b Yields are given taking into account the conversion.
Cycloadducts 3a–l were formed as either powders or oils, and the ortho-protons of the cyclohexyl moiety is ob-
and were soluble in chloroform, ethanol and dimethylsulf- served. The spectrum also contains cross-peaks between
oxide (DMSO). The structures of 1,3-oxazolobenzimida- the H-8 proton and the protons of the methyl substituent
zoles 3a–l were proved by 1H and 13C NMR analysis, IR (Figure 1).
spectroscopy and by 2D NOESY techniques.
The structure of 1,3-oxazolobenzimidazoles 3 was also
In the 1H NMR spectra of 1,3-oxazolobenzimidazoles 3a– confirmed by the fact that in the 1H and 13C NMR spectra,
l, a characteristic olefin proton singlet (H-10) at d = 4.17– the signals corresponding to H-9a and C-9a are high-field
5.65 ppm can be seen that is indicative of the formation of shifted by ~2 ppm and ~40 ppm, respectively, as com-
only one isomer. The Z-configurational assignment of the pared to signals arising from H-2 and C-2 in the starting
isomers follows from the fact that in the 2D NOESY spec- benzimidazoles 1.
trum of 1,3-oxazolobenzimidazole 3b, a cross-peak be-
tween signals of the olefin proton H-10, the H-9a proton
The IR spectra show absorption bands in the region of
2205–2217 cm–1, which can be assigned to the cyano
group at the double bond, as well as bands in the region of
1029–1149 cm–1, which are typical for the C–O–C bonds.
NC 10 H
Me
The reaction is assumed to be triggered by the nucleo-
philic addition of benzimidazoles 1a–f, as neutral nucleo-
N
H
Me
8
9a
O
philes, to the triple bond of acetylenes 2a or 2b,
generating reversible zwitterionic vinyl carbanion A,
which is further transformed into the oxygen-centered
zwitterion B via hydrogen transfer from the hydroxy
group to the carbanionic center. The A → B transforma-
tion is likely to proceed in a concerted mode, in accor-
dance with the trans-nucleophilic addition rule to
N
H
Me
3b
Figure 1 Cross-peaks in the 2D NOESY spectrum of 1,3-oxazolo-
benzimidazole 3b.
Synthesis 2010, No. 16, 2828–2834 © Thieme Stuttgart · New York

PAPER
Stereospecific Synthesis of (Z)-1,3-Oxazolobenzimidazoles
2831
NC
H
O
NC
_
R2
R3
R5
R4
R2
R3
+
N
R4
N
+
1
2
+
3a–l
R5
–O
N
R1
N
R1
A
B
Scheme 1 Tentative mechanism for the formation of the 1,3-oxazolobenzimidazoles 3a–l.
acetylenes,14 thus securing the observed Z-stereospecifi-
city. Afterwards, intramolecular insertion of the anionic
moiety of intermediate B into the imidazole aromatic sys-
tem at the positively charged C2-position takes place to
form the end products 3a–l (Scheme 1).
stirred at 35–40 °C for 20 h then cooled to r.t. After removal of the
solvent, the residue was washed with anhydrous Et2O (5 × 0.3 mL)
to give 3a.
Yield: 0.161 g (60%); orange powder; mp 146–148 °C.
IR (KBr): 432, 594, 612, 639, 730, 741, 760, 824, 847, 865, 911,
962, 990, 1004, 1045, 1076, 1149, 1178, 1191, 1208, 1224, 1259,
1291, 1372, 1392, 1432, 1459, 1479, 1504, 1627, 2217, 2874, 2941,
2984, 3075 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 1.37, 1.60 (2 × s, 6 H, 2 × CH3-
2), 2.28 (s, 3 H, CH3-6), 2.30 (s, 3 H, CH3-7), 3.41 (s, 3 H, N-CH3),
4.17 (s, 1 H, H-10), 6.05 (s, 1 H, H-9a), 6.67 (s, 1 H, H-8), 6.82 (s,
1 H, H-5).
13C NMR (100.62 MHz, CDCl3): d = 20.2 (CH3-7), 20.3 (CH3-6),
27.7, 29.1 (2 × CH3-2), 33.4 (N-CH3), 68.6 (C-10), 84.2 (C-2),
109.9 (C-9a), 110.5 (C-8), 117.8 (C-5), 119.2 (CN), 128.8 (C-6),
131.6 (C-7), 132.9 (C-4a), 139.6 (C-8a), 168.3 (C-3).
Although the effect of the substituents on the product
yields is not explicitly expressed, the low conversion (15–
34%) and longer reaction times (at 35–40 °C the reaction
requires 72 h instead of 20–24 h for other imidazoles) for
5-nitro-substituted benzimidazoles 1e and 1f is consistent
with Scheme 1, which implies that the reaction rate is re-
tarded (slower nucleophilic addition to the triple bond) for
the less electron-donating benzimidazoles.
In conclusion, benzimidazoles that are substituted both at
the N-1 atom and on the benzene ring, are annulated re-
gio- and stereospecifically with a,b-acetylenic g-hydroxy-
nitriles under mild conditions to furnish new functional
heterocyclic systems, (Z)-1,3-oxazolobenzimidazoles, in
moderate to high yields. The reaction proceeds by nucleo-
philic addition of benzimidazoles through their most nu-
cleophilic N3-atom to the triple bond via the zwitterionic
vinyl carbanion, which is further transformed into the O-
centered anion; the latter species is finally inserted into
the aromatic imidazole ring at the positively charged C2-
position. Thus, a conceptionally new general methodolo-
gy for the functionalization of the benzimidazole core has
been developed. The novel representatives of condensed
functionalized benzimidazoles are potential candidates of
medicinal value and are promising precursors for drug de-
sign.
Anal. Calcd for C16H19N3O: C, 71.35; H, 7.11; N, 15.60. Found: C,
71.42; H, 6.93; N, 15.12.
(Z)-Spiro-1,3-oxazolobenzimidazole 3b
Prepared from 1,5,6-trimethylbenzimidazole (1a; 0.160 g, 1 mmol)
and nitrile 2b (0.149 g, 1 mmol) after 22 h.
Yield: 0.173 g (56%); flesh-colored powder; mp 194–195 °C.
IR (KBr): 429, 511, 560, 603, 695, 734, 768, 846, 961, 1046, 1097,
1147, 1218, 1275, 1395, 1448, 1505, 1617, 1649, 2211, 2937, 2862,
3065 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 1.27–1.96 (m, 10 H, cycl), 2.21
(s, 3 H, CH3-6), 2.23 (s, 3 H, CH3-7), 2.89 (s, 3 H, N-CH3), 4.33 (s,
1 H, H-10), 6.22 (s, 1 H, H-9a), 6.36 (s, 1 H, H-8), 7.65 (s, 1 H, H-
5).
13C NMR (100.62 MHz, CDCl3): d = 19.9 (CH3-6), 20.3 (CH3-7),
21.6, 21.9, 24.5 (3 × CH2, cycl), 33.5 (N-CH3), 35.3, 36.6 (2 × CH2,
cycl), 67.4 (C-10), 87.3 (C-2), 109.7 (C-9a), 110.8 (C-8), 118.0 (C-
5), 119.7 (CN), 127.7 (C-6), 132.7 (C-7), 133.6 (C-4a), 140.9 (C-
8a), 168.0 (C-3).
1H and 13C NMR spectra were recorded with a Bruker DPX-400
spectrometer operating at 400.13 MHz (1H) or 100.62 MHz (13C) by
using CDCl3 as a solvent (HMDS as an internal standard); the atom
numbering for the assignment of the peaks in the NMR spectra is
that shown in Table 1. IR spectra were recorded with a Bruker IFS-
25 instrument (KBr or film). All melting points were determined
with a Kofler micro hot stage apparatus. Elemental analyses were
performed with a FLASH EA 1112 Series instrument. MeCN sol-
vent was dried by standard methods. The a,b-acetylenic g-hydroxy-
nitriles 2a and 2b were prepared by the procedure described in the
literature.15 Benzimidazoles 1a–f were prepared by alkylation ac-
cording to the literature protocol.16 The reaction was monitored by
examining the disappearance of the IR absorption bands for the
starting nitriles 2a and 2b in the reaction mixtures.
Anal. Calcd for C19H23N3O: C, 73.76; H, 7.49; N, 13.58. Found: C,
73.24; H, 7.23; N, 13.07.
(Z)-2-{9-Benzyl-2,2,6,7-tetramethyl-9,9a-dihydro[1,3]oxazo-
lo[3,2-a]benzimidazol-3(2H)-yliden}acetonitrile (3c)
Prepared from 1-benzyl-5,6-dimethylbenzimidazole (1b; 0.236 g, 1
mmol) and nitrile 2a (0.109 g, 1 mmol) after 24 h.
Yield: 0.273 g (79%); white powder; mp 121–124 °C.
IR (KBr): 429, 518, 563, 597, 628, 676, 697, 721, 734, 749, 829,
843, 864, 908, 954, 975, 990, 1012, 1025, 1074, 1085, 1143, 1157,
1193, 1223, 1254, 1278, 1287, 1317, 1360, 1410, 1422, 1441, 1456,
1469, 1502, 1612, 1645, 2206, 2855, 2900, 2925, 2970, 3031, 3070,
3087 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 1.42, 1.44 (2 × s, 6 H, 2 × CH3-
2), 2.10 (s, 3 H, CH3-6), 2.19 (s, 3 H, CH3-7), 4.40 (s, 1 H, H-10),
4.37, 4.46 (2 × d, 2JH–H = 16.4 Hz, 2 H, CH2 from N-benzyl), 6.23
(Z)-2-{2,2,6,7,9-Pentamethyl-9,9a-dihydro[1,3]oxazolo[3,2-
a]benzimidazol-3(2H)-yliden}acetonitrile (3a); Typical Proce-
dure
A mixture of 1,5,6-trimethylbenzimidazole (1a; 0.160 g, 1 mmol)
and nitrile 2a (0.109 g, 1 mmol) in anhydrous MeCN (1.0 mL) was
Synthesis 2010, No. 16, 2828–2834 © Thieme Stuttgart · New York

2832
L. V. Andriyankova et al.
PAPER
(s, 1 H, H-9a), 6.39 (s, 1 H, H-8), 7.20–7.30 (m, 5 H, Ph from N-
benzyl), 7.56 (s, 1 H, H-5).
(s, 1 H, H-8), 6.23 (s, 1 H, H-9a), 6.27 (d, 3JH5–H6 = 6.8 Hz, 1 H, H-
6), 7.71 (d, 3JH5–H6 = 6.8 Hz, 1 H, H-5).
13C NMR (100.62 MHz, CDCl3): d = 19.6 (CH3-6), 19.9 (CH3-7),
27.0, 28.6 (2 × CH3-2), 50.7 (CH2 from N-benzyl), 68.3 (C-10), 84.1
(C-2), 108.3 (C-9a), 109.1 (C-8), 117.6 (C-5), 119.0 (CN), 127.4 (p-
C, Ph from N-benzyl), 127.0 (o-C, Ph from N-benzyl), 128.7 (m-C,
Ph from N-benzyl), 129.0 (C-6), 132.7 (C-4a), 137.4 (i-C, Ph from
N-benzyl), 140.1 (C-7), 142.5 (C-8a), 168.3 (C-3).
13C NMR (100.62 MHz, CDCl3): d = 22.0, 22.3, 25.0 (3 × CH2,
cycl), 32.3 (N-CH3), 36.0, 37.1 (2 × CH2, cycl), 55.7 (O-CH3-7),
66.7 (C-10), 87.5 (C-2), 95.8 (C-8), 101.9 (C-9a), 110.5 (C-6),
117.9 (C-5), 119.3 (CN), 128.0 (C-4a), 144.7 (C-8a), 158.5 (C-7),
168.0 (C-3).
Anal. Calcd for C18H21N3O2: C, 69.43; H, 6.08; N, 13.49. Found: C,
69.00; H, 6.07; N, 13.24.
Anal. Calcd for C22H23N3O: C, 76.49; H, 6.71; N, 12.16. Found: C,
76.82; H, 6.73; N, 12.40.
(Z)-2-{9-Benzyl-7-methoxy-2,2-dimethyl-9,9a-dihydro[1,3]ox-
azolo[3,2-a]benzimidazol-3(2H)-yliden}acetonitrile (3g)
Prepared from 1-benzyl-6-methoxybenzimidazole (1d; 0.238 g, 1
mmol) and nitrile 2a (0.109 g, 1 mmol) after 20 h.
(Z)-Spiro-1,3-oxazolobenzimidazole 3d
Prepared from 1-benzyl-5,6-dimethylbenzimidazole (1b; 0.236 g, 1
mmol) and nitrile 2b (0.149 g, 1 mmol) after 24 h.
Yield: 0.259 g (67%); brown oil.
Yield: 0.312 g (90%); white powder; mp 99–100 °C.
IR (film): 429, 586, 699, 727, 738, 845, 908, 930, 954, 990, 1028,
1077, 1101, 1134, 1160, 1173, 1221, 1259, 1272, 1354, 1389, 1400,
1450, 1500, 1578, 1614, 1652, 2208, 2857, 2933, 3006, 3032, 3064,
3086 cm–1.
IR (KBr): 460, 520, 577, 608, 681, 699, 732, 745, 764, 791, 842,
913, 952, 969, 1030, 1080, 1091, 1117, 1147, 1166, 1197, 1213,
1245, 1268, 1278, 1321, 1354, 1366, 1423, 1455, 1497, 1602, 1615,
1644, 2208, 2854, 2931, 2962, 2984, 3009, 3026, 3062 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 1.20–1.90 (m, 10 H, cycl), 2.11
(s, 3 H, CH3-6), 2.19 (s, 3 H, CH3-7), 4.42 (s, 1 H, H-10), 4.38–4.45
(m, 2 H, CH2 from N-benzyl), 6.25 (s, 1 H, H-9a), 6.37 (s, 1 H, H-
8), 7.20–7.30 (m, 5 H, Ph from N-benzyl), 7.58 (s, 1 H, H-5).
13C NMR (100.62 MHz, CDCl3): d = 19.5 (CH3-6), 19.8 (CH3-7),
21.4, 21.6, 24.6, 35.2, 36.8 (5 × CH2, cycl), 50.6 (CH2 from N-ben-
zyl), 69.0 (C-10), 85.6 (C-2), 108.4 (C-9a), 109.0 (C-8), 117.5 (C-
5), 120.1 (CN), 127.3 (p-C, Ph from N-benzyl), 127.5 (o-C, Ph from
N-benzyl), 128.6 (m-C, Ph from N-benzyl), 132.7 (C-7), 134.0 (C-
4a), 137.4 (i-C, Ph from N-benzyl), 142.4 (C-8a), 168.5 (C-3).
1H NMR (400.13 MHz, CDCl3): d = 1.45, 1.47 (2 × s, 6 H, 2 × CH3-
2), 3.68 (s, 3 H, O-CH3-7), 4.35, 4.38 (2 × d, 2JH–H = 16.4 Hz, 2 H,
CH2 from N-benzyl), 4.36 (s, 1 H, H-10), 6.02 (s, 1 H, H-8), 6.26 (d,
3JH5–H6 = 6.8 Hz, 1 H, H-6), 6.45 (s, 1 H, H-9a), 7.20–7.30 (m, 5 H,
Ph from N-benzyl), 7.70 (d, 3JH5–H6 = 6.8 Hz, 1 H, H-5).
13C NMR (100.62 MHz, CDCl3): d = 27.2, 28.7 (2 × CH3-2), 50.2
(CH2 from N-benzyl), 55.6 (O-CH3-7), 67.5 (C-10), 84.9 (C-2), 96.0
(C-8), 101.9 (C-9a), 108.6 (C-6), 117.1 (C-5), 119.1 (CN), 127.5 (o-
C, Ph from N-benzyl), 127.6 (p-C, Ph from N-benzyl), 128.4 (C-4a),
128.8 (m-C, Ph from N-benzyl), 136.9 (i-C, Ph from N-benzyl),
143.6 (C-8a), 158.2 (C-7), 168.4 (C-3).
Anal. Calcd for C25H27N3O: C, 77.89; H, 7.06; N, 10.90. Found: C,
77.35; H, 7.17; N, 10.58.
Anal. Calcd for C21H21N3O2: C, 72.60; H, 6.09; N, 12.10. Found: C,
72.22; H, 6.14; N, 11.77.
(Z)-2-{7-Methoxy-2,2,9-trimethyl-9,9a-dihydro[1,3]oxazo-
lo[3,2-a]benzimidazol-3(2H)-yliden}acetonitrile (3e)
Prepared from 1-methyl-6-methoxybenzimidazole (1c; 0.162 g, 1
mmol) and nitrile 2a (0.109 g, 1 mmol) after 20 h.
(Z)-Spiro-1,3-oxazolobenzimidazole 3h
Prepared from 1-benzyl-6-methoxybenzimidazole (1d; 0.238 g, 1
mmol) and nitrile 2b (0.149 g, 1 mmol) after 22 h.
Yield: 0.119 g (44%); yellow oil.
Yield: 0.283 g (73%); yellow oil.
IR (film): 495, 617, 730, 779, 817, 986, 1035, 1091, 1125, 1176,
1215, 1290, 1325, 1349, 1465, 1509, 1585, 1620, 1649, 2208, 2875,
2933, 2977, 3070 cm–1.
IR (film): 435, 445, 504, 589, 639, 704, 739, 825, 943, 1033, 1078,
1171, 1213, 1273, 1324, 1359, 1404, 1450, 1498, 1613, 1650, 2206,
2861, 2937, 3034, 3065 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 1.44, 1.46 (2 × s, 6 H, 2 × CH3-
2), 2.87 (s, 3 H, N-CH3), 3.69 (s, 3 H, O-CH3-7), 4.36 (s, 1 H, H-10),
6.01 (s, 1 H, H-8), 6.25 (d, 3JH5–H6 = 6.8 Hz, 1 H, H-6), 6.44 (s, 1 H,
H-9a), 7.69 (d, 3JH5–H6 = 6.8 Hz, 1 H, H-5).
13C NMR (100.62 MHz, CDCl3): d = 27.2, 28.6 (2 × CH3-2), 32.2
(N-CH3), 55.6 (O-CH3-7), 67.5 (C-10), 84.9 (C-2), 96.0 (C-8),
101.9 (C-9a), 108.6 (C-6), 117.0 (C-5), 118.9 (CN), 128.4 (C-4a),
143.8 (C-8a), 158.3 (C-7), 168.2 (C-3).
1H NMR (400.13 MHz, CDCl3): d = 1.20–2.10 (m, 10 H, cycl), 3.72
2
(s, 3 H, O-CH3-7), 4.39 (s, 1 H, H-10), 4.41, 4.50 (2 × d, JH–H
=
16.4 Hz, 2 H, CH2 from N-benzyl), 6.05 (s, 1 H, H-8), 6.27 (d,
3JH5–H6 = 6.8 Hz, 1 H, H-6), 6.46 (s, 1 H, H-9a), 7.20–7.30 (m, 5 H,
Ph from N-benzyl), 7.71 (d, 3JH5–H6 = 6.8 Hz, 1 H, H-5).
13C NMR (100.62 MHz, CDCl3): d = 21.8, 22.2, 24.8, 35.8, 35.9 (5
× CH2, cycl), 50.3 (CH2 from N-benzyl), 55.6 (O-CH3-7), 68.3 (C-
10), 86.5 (C-2), 95.9 (C-8), 101.8 (C-9a), 108.8 (C-6), 117.1 (C-5),
119.2 (CN), 127.6 (o,p-C, Ph from N-benzyl), 128.8 (m-C, Ph from
N-benzyl, C-4a), 137.0 (i-C, Ph from N-benzyl), 143.3 (C-8a),
158.1 (C-7), 168.7 (C-3).
Anal. Calcd for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C,
66.85; H, 6.17; N, 15.80.
(Z)-Spiro-1,3-oxazolobenzimidazole 3f
Prepared from 1-methyl-6-methoxybenzimidazole (1c; 0.162 g, 1
mmol) and nitrile 2b (0.149 g, 1 mmol) after 20 h.
Anal. Calcd for C24H25N3O2: C, 74.39; H, 6.50; N, 10.84. Found: C,
74.72; H, 6.42; N, 10.43.
(Z)-2-{2,2,9-Trimethyl-6-nitro-9,9a-dihydro[1,3]oxazolo[3,2-
a]benzimidazol-3(2H)-yliden}acetonitrile (3i)
Prepared from 1-methyl-5-nitrobenzimidazole (1e; 0.177 g, 1
mmol) and nitrile 2a (0.109 g, 1 mmol) after 24 h.
Yield: 0.103 g (33%); white powder; mp 130–134 °C.
IR (KBr): 516, 585, 594, 654, 694, 718, 792, 865, 933, 977, 1029,
1064, 1077, 1104, 1126, 1176, 1222, 1259, 1327, 1352, 1380, 1406,
1434, 1455, 1487, 1616, 1640, 2205, 2836, 2866, 2974, 3000, 3065
cm–1.
Yield: 0.226 g (79%); red oil.
IR (film): 497, 536, 578, 607, 621, 647, 683, 712, 749, 786, 796,
809, 874, 894, 976, 1005, 1056, 1085, 1107, 1139, 1169, 1187,
1H NMR (400.13 MHz, CDCl3): d = 1.24–1.95 (m, 10 H, cycl), 2.85
(s, 3 H, N-CH3), 3.75 (s, 3 H, O-CH3-7), 4.27 (s, 1 H, H-10), 6.09
Synthesis 2010, No. 16, 2828–2834 © Thieme Stuttgart · New York

PAPER
Stereospecific Synthesis of (Z)-1,3-Oxazolobenzimidazoles
2833
1244, 1278, 1337, 1384, 1398, 1504, 1516, 1605, 1651, 2208, 2877,
2931, 2980, 3023, 3062, 3097 cm–1.
1308, 1322, 1335, 1349, 1356, 1393, 1445, 1472, 1495, 1600, 1654,
2214, 2857, 2937, 3008, 3045, 3070, 3084 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 1.36, 1.50 (2 × s, 6 H, 2 × CH3-
2), 3.07 (s, 3 H, N-CH3), 5.54 (s, 1 H, H-10), 6.65 (s, 1 H, H-9a),
6.76 (d, 3JH7–H8 = 6.8 Hz, 1 H, H-8), 7.98 (d, 3JH7–H8 = 6.8 Hz, 1 H,
H-7), 8.01 (s, 1 H, H-5).
1H NMR (400.13 MHz, CDCl3): d = 1.20–2.00 (m, 10 H, cycl),
4.61, 4.69 (2 × d, 2JH–H = 16.4 Hz, 2 H, CH2 from N-benzyl), 4.75
(s, 1 H, H-10), 6.37 (d, 3JH7–H8 = 6.8 Hz, 1 H, H-8), 6.52 (s, 1 H, H-
3
9a), 7.20–7.30 (m, 5 H, Ph from N-benzyl), 7.88 (d, JH7–H8 = 6.8
Hz, 1 H, H-7), 8.41 (s, 1 H, H-5).
13C NMR (100.62 MHz, CDCl3): d = 26.4, 28.1 (2 × CH3-2), 30.5
(N-CH3), 74.6 (C-10), 83.2 (C-2), 104.8 (C-9a), 106.7 (C-8), 108.1
(C-5), 118.9 (CN), 123.5 (C-7), 135.5 (C-4a), 138.9 (C-6), 147.6
(C-8a), 168.6 (C-3).
13C NMR (100.62 MHz, CDCl3): d = 21.7, 22.2, 24.6, 35.0, 36.9 (5
× CH2, cycl), 48.5 (CH2 from N-benzyl), 75.3 (C-10), 84.5 (C-2),
104.3 (C-9a), 106.0 (C-8), 110.1 (C-5), 118.8 (CN), 122.7 (C-7),
128.1 (o-C, Ph from N-benzyl), 128.7 (p-C, Ph from N-benzyl),
129.3 (m-C, Ph from N-benzyl), 135.2 (C-4a), 135.7 (i-C, Ph from
N-benzyl), 140.2 (C-6), 146.7 (C-8a), 168.2 (C-3).
Anal. Calcd for C14H14N4O3: C, 58.74; H, 4.93; N, 19.57. Found: C,
58.29; H, 4.70; N, 19.22.
(Z)-Spiro-1,3-oxazolobenzimidazole 3j
Prepared from 1-methyl-5-nitrobenzimidazole (1e; 0.177 g, 1
mmol) and nitrile 2b (0.149 g, 1 mmol) after 72 h.
Anal. Calcd for C23H22N4O3: C, 68.64; H, 5.51; N, 13.92. Found: C,
68.14; H, 5.31; N, 13.68.
Yield: 0.140 g (43%, conversion of 1e was 34%); brown powder;
mp 66–69 °C.
Acknowledgment
This work was supported by the Russian Fund for Basic Research
(Grant No. 08-03-00156), Presidium of RAS (Program 15) and Pre-
sidium of Department of Chemical Sciences and Materials RAS
(Grant No. 5.1).
IR (KBr): 499, 562, 616, 633, 742, 795, 822, 901, 947, 977, 1053,
1088, 1131, 1168, 1291, 1393, 1446, 1514, 1604, 1648, 2216, 2862,
2938, 3095 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 1.20–2.00 (m, 10 H, cycl), 3.06
(s, 3 H, N-CH3), 4.68 (s, 1 H, H-10), 6.36 (d, 3JH7–H8 = 6.8 Hz, 1 H,
H-8), 6.51 (s, 1 H, H-9a), 7.78 (d, 3JH7–H8 = 6.8 Hz, 1 H, H-7), 8.40
(s, 1 H, H-5).
13C NMR (100.62 MHz, CDCl3): d = 21.8, 22.2, 24.6 (3 × CH2,
cycl), 30.3 (N-CH3), 34.9, 36.9 (2 × CH2, cycl), 75.3 (C-10), 84.4
(C-2), 104.4 (C-9a), 106.1 (C-8), 109.8 (C-5), 118.9 (CN), 123.0
(C-7), 135.3 (C-4a), 140.1 (C-6), 146.9 (C-8a), 168.4 (C-3).
References
(1) VanVliet, D. S.; Gillespie, P.; Scicinski, J. J. Tetrahedron
Lett. 2005, 46, 6741.
(2) Chandra, T.; Brown, K. L. Tetrahedron Lett. 2005, 46, 8617.
(3) (a) Lindberg, P.; Nordberg, P.; Alminger, T.; Brändström,
A.; Wallmark, B. J. Med. Chem. 1986, 29, 1327.
(b) Claramunt, R. M.; López, C.; Elguero, J. ARKIVOC
2006, (v), 150.
Anal. Calcd for C17H18N4O3: C, 62.57; H, 5.56; N, 17.17. Found: C,
62.13; H, 5.35; N, 17.63.
(4) Legros, J.; Dehli, J. R.; Bolm, C. Adv. Synth. Catal. 2005,
347, 19.
(Z)-2-{9-Benzyl-6-nitro-2,2-dimethyl-9,9a-dihydro[1,3]oxazo-
lo[3,2-a]benzimidazol-3(2H)-yliden}acetonitrile (3k)
Prepared from 1-benzyl-5-nitrobenzimidazole (1f; 0.253 g, 1 mmol)
and nitrile 2a (0.109 g, 1 mmol) after 24 h.
(5) Ries, U.; Kaufmann, I.; Hauel, N.; Priepke, H.; Nar, H.;
Stassen, J.-M.; Wienen, W. Ger. Offen. DE 19962329, 2001.
(6) Sann, G. L.; Baron, A.; Mann, J.; Berg, H.; Gunaratham, M.;
Neidle, S. Org. Biomol. Chem. 2006, 4, 1305.
(7) (a) He, Y.; Yang, J.; Wu, B.; Robinson, D.; Sprankle, K.;
Kung, P.-P.; Lowery, K.; Mohan, V.; Hofstadler, S.;
Swayze, E. E.; Griffey, R. Bioorg. Med. Chem. Lett. 2004,
14, 695. (b) He, Y.; Yang, J.; Wu, B.; Risen, L.; Swayze, E.
E. Bioorg. Med. Chem. Lett. 2004, 14, 1217.
(8) Charma, S.; Gangal, S.; Rauf, A. Eur. J. Med. Chem. 2009,
44, 1751.
(9) Kobayashi, K.; Fukunishi, H.; Umishio, K.; Tajima, M. EP
989123, 2000.
(10) (a) Han, X.; Ma, H.; Wang, Y. ARKIVOC 2007, (xiii), 150.
(b) Budow, S.; Kozlowska, M.; Gorska, A.; Kazimierczuk,
Z.; Eickmeier, H.; La Colla, P.; Gosselin, G.; Seela, F.
ARKIVOC 2009, (iii), 225.
(11) Anisimova, V. A.; Spasov, A. A.; Kosolapov, V. A.;
Kucheryavenko, A. F.; Ostrovskii, O. V.; Larionov, N. P.;
Libinzon, R. E. Khim.-Farm. Zh. 2005, 26.
(12) Trofimov, B. A.; Andriyankova, L. V.; Mal’kina, A. G.;
Belyaeva, K. V.; Nikitina, L. P.; Dyachenko, O. A.;
Kazheva, O. N.; Chekhlov, A. N.; Shilov, G. V.; Afonin, A.
V.; Ushakov, I. A.; Baikalova, L. V. Eur. J. Org. Chem.
2007, 1018.
Yield: 0.196 g (54%); yellow powder; mp 207–208 °C.
IR (KBr): 455, 519, 562, 591, 644, 665, 695, 728, 737, 785, 806,
815, 839, 865, 950, 992, 1070, 1091, 1133, 1158, 1191, 1282, 1299,
1318, 1363, 1398, 1417, 1442, 1454, 1503, 1519, 1600, 1653, 2213,
2876, 2916, 2976, 3033, 3065 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 1.37, 1.50 (2 × s, 6 H, 2 × CH3-
2
2), 4.70, 4.83 (2 × d, JH–H = 16.4 Hz, 2 H, CH2 from N-benzyl),
3
5.65 (s, 1 H, H-10), 6.70 (d, JH7–H8 = 6.8 Hz, 1 H, H-8), 6.82 (s,
1 H, H-9a), 7.30–7.40 (m, 5 H, Ph from N-benzyl), 7.98 (d, 3JH7–H8
=
6.8 Hz, 1 H, H-7), 8.28 (s, 1 H, H-5).
13C NMR (100.62 MHz, CDCl3): d = 26.5, 28.2 (2 × CH3-2), 48.1
(CH2 from N-benzyl), 75.5 (C-10), 82.9 (C-2), 105.5 (C-9a), 106.0
(C-8), 108.9 (C-5), 119.0 (CN), 123.4 (C-7), 127.9 (o-C, Ph from N-
benzyl), 128.1 (p-C, Ph from N-benzyl), 129.1 (m-C, Ph from N-
benzyl), 136.0 (C-4a), 136.6 (i-C, Ph from N-benzyl), 139.5 (C-6),
146.8 (C-8a), 168.7 (C-3).
Anal. Calcd for C20H18N4O3: C, 66.29; H, 5.01; N, 15.46. Found: C,
66.02; H, 4.98; N, 15.54.
(Z)-Spiro-1,3-oxazolobenzimidazole 3l
(13) Trofimov, B. A.; Andriyankova, L. V.; Nikitina, L. P.;
Belyaeva, K. V.; Mal’kina, A. G.; Afonin, A. V. Synthesis
2010, 1536.
(14) Dickstein, I.; Miller, S. I. In The Chemistry of the Carbon-
Carbon Triple Bond, Part 2; Patai, S., Ed.; Wiley: New
York, 1978, 814.
Prepared from 1-benzyl-5-nitrobenzimidazole (1f; 0.253 g, 1 mmol)
and nitrile 2b (0.149 g, 1 mmol) after 72 h.
Yield: 0.218 g (54%, conversion of 1f was 15%); yellow powder;
mp 138–141 °C.
IR (KBr): 424, 465, 543, 596, 634, 699, 731, 741, 749, 796, 819,
887, 938, 959, 1060, 1077, 1097, 1107, 1133, 1202, 1221, 1281,
Synthesis 2010, No. 16, 2828–2834 © Thieme Stuttgart · New York

2834
L. V. Andriyankova et al.
PAPER
(15) (a) Landor, S. R.; Demetriou, B.; Grzeskowiak, R.; Pavey,
D. J. Organomet. Chem. 1975, 93, 129. (b) Hopf, H.;
Witulski, B. In Modern Acetylene Chemistry; Stang, P. J.;
Diederich, F., Eds.; VCH: Weinheim, 1995, 33–67.
2485. (d) Trofimov, B. A.; Andriyankova, L. V.;
Shaikhudinova, S. I.; Kazantseva, T. I.; Mal’kina, A. G.;
Zhivet’ev, S. A.; Afonin, A. V. Synthesis 2002, 853.
(16) Starikova, O. V.; Dolgushin, G. V.; Larina, L. I.; Komarova,
T. N.; Lopyrev, V. A. ARKIVOC 2003, (xiii), 119.
(c) Trofimov, B. A.; Mal’kina, A. G. Heterocycles 1999, 51,
Synthesis 2010, No. 16, 2828–2834 © Thieme Stuttgart · New York