Exceptionally easy ring cleavage of benzimidazoles by α,β- acetylenic γ-hydroxy nitriles and water

Article abstract of DOI:10.1055/S-0029-1218704

The three-component reaction of a benzimidazole with an α,β-acetylenic γ-hydroxy nitrile and water in acetonitrile at 20-25 °C for seven days or at 45-50 °C for six hours results in cleavage of the imidazole ring to afford the corresponding (2-{[(3E)-5-ami-nofuran-3(2H) -ylidene]amino}phenyl)formamide exclusively in 84-99% yield. The synthesis involves multipositional cascade transformations of the intermediate hemiaminals formed from the primary zwitterions and water. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218704

1536
PAPER
Exceptionally Easy Ring Cleavage of Benzimidazoles by a,b-Acetylenic
g-Hydroxy Nitriles and Water
R
ingCleavage of
o
Benzimidaz
r
oles by
a
,
b
-Ac
e
s
tylenic
g
-Hydro
A
xy
N
itrile
s
and
W
.
ater Trofimov,* Ludmila V. Andriyankova, Lina P. Nikitina, Kseniya V. Belyaeva, Anastasiya G. Mal’kina,
Andrei V. Afonin
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 27 January 2010; revised 3 February 2010
We recently11 discovered a transformation of 1-substitut-
ed benzimidazoles into densely functionalized 5-amino-3-
dihydrofurans by using readily available a,b-acetylenic g-
hydroxy nitriles12 as reactants (Scheme 1). The reaction
Abstract: The three-component reaction of a benzimidazole with
an a,b-acetylenic g-hydroxy nitrile and water in acetonitrile at 20–
25 °C for seven days or at 45–50 °C for six hours results in cleavage
of the imidazole ring to afford the corresponding (2-{[(3E)-5-ami-
nofuran-3(2H)-ylidene]amino}phenyl)formamide exclusively in proceeds via oxazolidine dihydrobenzimidazoles as anne-
84–99% yield. The synthesis involves multipositional cascade
lated intermediates that, on passage through neutral alu-
transformations of the intermediate hemiaminals formed from the
primary zwitterions and water.
mina, rearrange and abstract the molecules of water from
the alumina to give the final products.
Key words: alkynes, benzimidazoles, heterocycles, multicompo-
nent reactions, nitriles, ring opening, polycycles
R2
NH2
R3
CN
CN
N
O
OH
Al2O3
(H2O)n
R3
R2
N
R3
The dihydrofuran ring is a key structural subunit of many
natural products that have promising applications, for ex-
ample, as pharmaceuticals or flavor and fragrance com-
pounds.1 Furthermore, highly substituted furans are of
interest because they are useful and versatile intermedi-
ates for syntheses of heterocyclic or acyclic compounds.2
The group of substituted furanones includes natural and
unnatural (Z)-4-aryl-5-[1-(aryl)methylidene]-3-halofu-
ran-2(5H)-ones3 and nostoclides I and II,4 which are cyto-
toxic against human cancer.5 Much interest has focused
on the synthesis of functionalized dihydrofuranones6 as
their tetronic, ascorbic, or penicillic acid derivatives and
their metabolites, which are widespread in nature and are
of special importance in human life. Tetronic acid deriva-
tives possess antibiotic, antitumor, anticoagulant, antiepi-
leptic, antifungal, insecticidal, analgesic, and anti-
inflammatory properties and they are important as inhibi-
tors of HIV-1 protease.7 The pulvinic acid congeners, the
4-ylidenetetronic acids, are pigments present in lichens
and in higher fungi. The chemistry of analogues of L-
ascorbic acid (vitamin C) has been intensively developed
to optimize their activity.8 3(2H)-Furanone derivatives
have been studied as a novel selective inhibitors of cy-
clooxygenase-2.9 Analogues of the naturally occurring
furanones that act as inhibitors of Serratia marcescens
chitinases have recently been synthesized.10 The develop-
ment of strategies for the synthesis of new families of
N
R2
N
O
R1
N
R1
N
R1
R1 = Me, Et, CH=CH2, CH2CH=CH2
R2 = R3 = Me, R2–R3 = (CH2)5
O
Scheme 1
In our earlier study, we used only 1-substituted benzimi-
dazoles, so that the scope and the synthetic impact of the
reaction remained unclear, particularly in relation to sub-
stitution of the benzene ring. Of particular importance was
to check the possibility of the direct synthesis of function-
alized 5-amino-3-dihydrofurans from benzimidazoles,
a,b-acetylenic g-hydroxy nitriles, and water, without alu-
mina, by a one-pot three-component reaction.
We now report a new one-pot version of a synthesis of (2-
{[(3E)-5-aminofuran-3(2H)-ylidene]amino}phenyl)form-
amides substituted on both the N(1) atom and the benzene
ring; the starting materials are a benzimidazole 1a–g, an
a,b-acetylenic g-hydroxy nitrile 2a or 2b, and water, and
the synthesis proceeds in the absence of alumina. When
the three reactants in a 1:1:1 molar ratio are allowed to re-
act at 20–25 °C for seven days or at 45–50 °C for six
hours in acetonitrile, the corresponding (2-{[(3E)-5-ami-
nofuran-3(2H)-ylidene]amino}phenyl)formamides 3a–m
are obtained in yields of 84–99% (Table 1).
functionalized dihydrofuran derivatives is therefore an in- The 1H and 13C NMR spectra and IR spectra of the prod-
teresting challenge in organic chemistry.
ucts are similar to those of their analogues, the structures
of which have been previously established unambiguous-
ly by X-ray crystal structure analysis.11
SYNTHESIS 2010, No. 9, pp 1536–1542
x
x
.
x
x
.2
0
1
0
Advanced online publication: 15.03.2010
DOI: 10.1055/s-0029-1218704; Art ID: Z01610SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Ring Cleavage of Benzimidazoles by a,b-Acetylenic g-Hydroxy Nitriles and Water
1537
Table 1 Three-Component Synthesis of (2-{[(3E)-5-Aminofuran-3(2H)-ylidene]amino}phenyl)formamides (3a–m) from Benzimidazoles
1a–g, Nitrile 2a or 2b, and Water
NH2
2
R2
4
5
20–25 °C (7 d)
1
O
R5
3
N
R2
10
3
9
8
or 45–50 °C (6 h)
5
4
6
R5
R4
CN
H2O
+
7
6
+
R3
2
1
N
R3
N
R4
MeCN
OH
7
12
11
R1
14
N
13
R1
1a–g
2a,b
3a–m
O
Benzimidazole
Nitrile
Product
Yielda (%)
NH2
O
N
1a
2a
3a
99
CN
N
N
OH
Me
N
Me
O
NH2
O
1a
1b
1b
2b
2a
2b
2a
2b
2a
3b
3c
3d
3e
3f
96
84
93
93
91
98
CN
N
HO
N
N
N
Me
Bn
Bn
O
NH2
O
N
N
N
Bn
O
NH2
O
N
O
NH2
O
N
MeO
1c
MeO
MeO
MeO
N
N
Me
N
N
N
Me
O
NH2
O
1c
N
Me
O
NH2
O
N
MeO
1d
3g
N
N
Bn
Bn
O
Synthesis 2010, No. 9, 1536–1542 © Thieme Stuttgart · New York

1538
B. A. Trofimov et al.
PAPER
Table 1 Three-Component Synthesis of (2-{[(3E)-5-Aminofuran-3(2H)-ylidene]amino}phenyl)formamides (3a–m) from Benzimidazoles
1a–g, Nitrile 2a or 2b, and Water (continued)
NH2
2
R2
4
5
20–25 °C (7 d)
1
O
R5
3
N
R2
10
3
9
8
or 45–50 °C (6 h)
5
4
6
R5
R4
CN
H2O
+
7
6
+
R3
2
1
N
R3
N
R4
MeCN
OH
7
12
11
R1
14
N
13
R1
1a–g
2a,b
3a–m
O
Benzimidazole
Nitrile
Product
Yielda (%)
NH2
O
1d
2b
3h
87
MeO
N
N
N
Bn
O
NH2
O2N
O2N
O
N
1e
2a
2b
2a
2b
2a
3i
99
95
99
99
91
N
Me
N
Me
Me
Bn
O
NH2
O2N
O2N
O2N
O
1e
3j
N
N
O
NH2
O2N
O
N
1f
3k
3l
N
N
Bn
N
O
NH2
O
1f
N
N
Bn
O
NH2
O
N
1g
3m
N
N
Me
N
Me
O
a Isolated yield. The reaction conditions are discussed in the experimental details below.
In the 1H NMR spectra of adducts 3a–m, singlets for the contains distinct absorption bands assigned to the carbon-
NH2 protons are observed at d = 6.85–7.82 ppm, those for yl (1657–1688 cm–1) and NH2 fragments (3188–3395
the protons of the aldehyde fragment appear at d = 7.83– cm–1).
8.23 ppm, and H-3 protons of the dihydrofuran ring ap-
The E-configuration of the isomers was established from
the two-dimensional nuclear Overhauser effect spectrum
pear at d = 4.13–4.90 ppm. In the 13C spectra, the carbon
signal for the aldehyde moiety is observed at d = 162.7–
of adduct 3a, in which a cross-peak between the signals
163.9 ppm and that of the C4 atom in the dihydrofuran
for the H3 proton in the dihydrofuran ring and H8 proton
ring appears at d = 177.1–179.0 ppm. The IR spectrum
in the phenyl fragment and a cross-peak between the sig-
Synthesis 2010, No. 9, 1536–1542 © Thieme Stuttgart · New York

PAPER
Ring Cleavage of Benzimidazoles by a,b-Acetylenic g-Hydroxy Nitriles and Water
1539
nals for the proton of the aldehyde fragment and the pro- tion-metal catalyst, acid or base. The driving force for this
tons of the methyl group are observed. The Z- peculiar multipositional cascade transformation is proba-
configurations of the isomers is not observed (Figure 1).
bly the thermodynamically favored formation of systems
that, in solution, possess a widespread conjugation over
the entire molecule, including the phenylenediamine and
aminodihydrofuran moieties.
NH2
O
H
NH2
H
H
O
3
3
8
8
To summarize, a new, efficient, one-pot, three-compo-
nent, cascade reaction between substituted benzimida-
zoles, a,b-acetylenic g-hydroxy nitriles, and water to
give (2-{[(3E)-5-aminofuran-3(2H)-ylidene]amino}phe-
nyl)formamides has been discovered. The reaction pro-
ceeds at room temperature (or at 45–50 °C) and starts with
the extraordinarily easy cleavage of the C2–N3 bond of
the imidazole ring. This is followed by a cascade sequence
of skeleton rearrangements and prototropic isomeriza-
tions. The new reaction does not require the presence of
alumina, and it can be applied to benzimidazoles that are
substituted in the benzene ring, thereby broadening the
frontiers and the generality of our previously described
two-step alumina-assisted synthesis. The results contrib-
ute substantially to the basic chemistry of benzimidazoles
and electron-deficient acetylenes, as well as to the meth-
odology of multicomponent reactions. The family of
densely functionalized 3-dihydrofuran derivatives that are
now available as a result of the newly developed method
represent highly potent building blocks that are promising
as precursors for drug design and as potential pharmaceu-
tical candidates.
N
N
H
H
O
H
O
N
N
Me
Me
(E)-3a is observed
(Z)-3a is not observed
Figure 1 Cross-peaks in the two-dimensional nuclear Overhauser
effect spectrum of adduct 3a
The reaction is assumed to proceed via the primary zwit-
terion A, the adduct of benzimidazole with the acetylenic
nitrile, as shown in Scheme 2 for the case of the reaction
of benzimidazole 1a with nitrile 2a and water. The inter-
mediate is further attacked by a molecule of water so that
hydroxide ion adds to the C2-position, which has a cation-
ic character, and the proton quenches the carbanionic cen-
ter to give the intermediate hemiaminal B. This initiates a
cascade sequence that includes cleavage of the C2–N3
bond and rearrangement of the benzimidazole ring to the
2-aminophenylformamide moiety. The resulting interme-
diate C undergoes a double-bond shift from the acryloni-
trile moiety to the N3 atom to give the intermediate D,
which is now capable of undergoing closure of the imino-
dihydrofuran ring. The intermediate E prototropically re-
arranges to give the final product 3a.
IR spectra were recorded on a Bruker IFS-25 instrument (KBr). 1H
and 13C NMR spectra were recorded on a Bruker DPX-400 spec-
trometer at 400.13 MHz (1H) or 100.62 MHz (13C) by using DMSO-
d6 as a solvent; the atom numbering for the assignment of the peaks
in the NMR spectra is that shown in Table 1. UV/Vis spectra were
measured on a Perkin-Elmer Lambda 35 spectrometer at r.t. (EtOH,
d = 0.1 cm). All melting points were determined on a Kofler micro
hot stage. Elemental analyses were performed on a FLASH EA
1112 Series. MeCN solvent was dried by a standard method. The
a,b-acetylenic g-hydroxy nitriles 2a,b were prepared by the proce-
dure described in the literature.12 Benzimidazoles 1a–g were pre-
pared by alkylation according to the literature protocol.13 The
reaction was monitored by examining the disappearance of the IR
absorption bands for the starting nitrile 2a or 2b in the reaction mix-
tures.
Attention should be drawn to the extraordinary ease with
which the aromatic imidazole ring is opened; this reaction
occurs at room temperature in the absence of any transi-
NC
NC
+
N
H2O
N
1a + 2a
H
O–H
B
_
O
OH
N
N
Me
Me
A
NC
CN
OH
N
N
NH
(2-{[(3E)-5-Amino-2,2-dimethylfuran-3(2H)-ylidene]amino}-
4,5-dimethylphenyl)methylformamide (3a); Typical Procedure
A mixture of 1,5,6-trimethyl-1H-benzimidazole (1a; 0.160 g, 1
mmol), nitrile 2a (0.109 g, 1 mmol), and H2O (0.018 g, 1 mmol) in
dry MeCN (0.5 mL) was stirred at 45–50 °C for 6 h then cooled to
r.t. The residue that precipitated was filtered off and recrystallized
(EtOH) to give a light-yellow powder; yield: 0.286 g (99%); mp
196–198 °C.
HO
N
O
O
Me
Me
C
D
NH
NH2
O
O
IR: 456, 519, 571, 601, 662, 706, 755, 775, 886, 954, 1002, 1070,
1080, 1147, 1181, 1223, 1263, 1273, 1309, 1357, 1372, 1386, 1431,
1495, 1543, 1624, 1675, 2872, 2930, 2979, 2989, 3015, 3108, 3308,
3341 cm–1.
1H NMR (400.13 MHz, DMSO-d6): d = 1.38 (s, 6 H, 2 Me5), 2.16
(s, 6 H, 2 Me9,10), 2.97 (s, 3 H, N-Me), 4.15 (s, 1 H, H3), 6.65 (s,
1 H, H11), 6.95 (s, 1 H, H8), 7.20 (s, 2 H, NH2), 7.87 (s, 1 H, H14).
N
N
N
N
Me
O
Me
O
E
3a
Scheme 2 Tentative mechanism for the formation of the final pro-
duct 3
Synthesis 2010, No. 9, 1536–1542 © Thieme Stuttgart · New York

1540
B. A. Trofimov et al.
PAPER
13C NMR (100.62 MHz, DMSO-d6): d = 19.0 (Me10), 19.5 (Me9),
25.9 (2 Me5), 32.6 (N-Me), 70.3 (C3), 88.7 (C5), 123.8 (C11),
128.1 (C8), 130.3 (C9), 131.8 (C10), 136.2 (C12), 147.7 (C7), 163.1
(C14), 173.6 (C2), 177.4 (C4).
1496, 1541, 1567, 1602, 1612, 1660, 2853, 2864, 2880, 2923, 2936,
2950, 3028, 3064, 3085, 3109, 3286, 3322 cm–1.
1H NMR (400.13 MHz, DMSO-d6): d = 1.50–2.00 (m, 10 H, cyclo-
hexyl), 2.23 (s, 3 H, Me9), 2.27 (s, 3 H, Me10), 4.23 (s, 1 H, H3),
4.79 (s, 2 H, CH2 from N-benzyl), 6.62 (s, 1 H, H11), 6.91 (s, 1 H,
H8), 7.20 (s, 2 H, NH2), 7.20–7.40 (m, 5 H, Ph from N-benzyl), 8.04
(s, 1 H, H14).
UV/Vis (EtOH): λmax (log e) = 283 (4.41) nm.
Anal. Calcd for C16H21N3O2 (287.36): C, 66.88; H, 7.37; N, 14.62.
Found: C, 66.56; H, 7.22; N, 14.50.
13C NMR (100.62 MHz, DMSO-d6): d = 19.1 (Me9), 19.4 (Me10),
22.2, 24.8, 34.4 (5 CH2, cyclohexyl), 47.9 (CH2 from N-benzyl),
70.7 (C3), 90.3 (C5), 123.6 (C11), 127.2 (Cp, Ph from N-benzyl),
128.1 (Co, Ph from N-benzyl), 128.4 (C8), 128.8 (Cm, Ph from N-
benzyl), 129.9 (C9), 130.5 (C10), 136.0 (C12), 138.0 (Ci, Ph from
N-benzyl), 147.6 (C7), 163.7 (C14), 174.0 (C2), 177.2 (C4).
(2-{[(4E)-2-Amino-1-oxaspiro[4.5]dec-2-en-4-ylidene]amino}-
4,5-dimethylphenyl)methylformamide (3b)
This was prepared analogously from 1,5,6-trimethylbenzimidazole
(1a; 0.160 g, 1 mmol), nitrile 2b (0.149 g, 1 mmol), and H2O (0.018
g, 1 mmol) as a white powder; yield: 0.314 g (96%); mp 249–
250 °C.
Anal. Calcd for C25H29N3O2 (403.52): C, 74.41; H, 7.24; N, 10.41.
Found: C, 74.80; H, 7.35; N, 10.48.
IR: 494, 612, 663, 747, 769, 801, 841, 888, 936, 954, 993, 1024,
1064, 1112, 1141, 1192, 1233, 1255, 1304, 1349, 1379, 1436, 1454,
1539, 1620, 1666, 2718, 2767, 2859, 2892, 2931, 3104, 3313, 3357
cm–1.
(2-{[(3E)-5-Amino-2,2-dimethylfuran-3(2H)-ylidene]amino}-5-
methoxyphenyl)methylformamide (3e)
This was prepared analogously from 6-methoxy-1-methyl-1H-
benzimidazole (1c; 0.162 g, 1 mmol), nitrile 2a (0.109 g, 1 mmol),
and H2O (0.018 g, 1 mmol) as a yellow powder; yield: 0.269 g
(93%); mp 169–171 °C.
1H NMR (400.13 MHz, DMSO-d6): d = 1.50–2.00 (m, 10 H, cyclo-
hexyl), 2.15 (s, 6 H, 2 Me9,10), 2.96 (s, 3 H, N-Me), 4.13 (s, 1 H,
H3), 6.62 (s, 1 H, H11), 6.94 (s, 1 H, H8), 7.20 (s, 2 H, NH2), 7.86
(s, 1 H, H14).
IR: 505, 530, 617, 642, 694, 708, 769, 797, 868, 956, 976, 1038,
1058, 1092, 1109, 1188, 1215, 1334, 1360, 1374, 1415, 1497, 1561,
1607, 1650, 1688, 2835, 2930, 2978, 3188, 3395 cm–1.
1H NMR (400.13 MHz, DMSO-d6): d = 1.40 (s, 6 H, 2 Me5), 2.96
(s, 3 H, N-Me), 3.73 (s, 3 H, O-Me10), 4.54 (s, 1 H, H3), 6.57 (d,
3JH8,H9 = 8.8 Hz, 1 H, H8), 6.59 (d, 1 H, H9), 6.85 (s, 2 H, NH2), 7.12
(s, 1 H, H11), 7.97 (s, 1 H, H14).
13C NMR (100.62 MHz, DMSO-d6): d = 25.4 (2 Me5), 32.9 (N-
Me), 55.9 (O-Me10), 70.5 (C3), 92.5 (C5), 107.3 (C8), 108.6 (C9),
127.7 (C12), 128.6 (C11), 149.2 (C7), 159.4 (C10), 163.4 (C14),
176.6 (C2), 179.0 (C4).
13C NMR (100.62 MHz, DMSO-d6): d = 19.1 (Me9), 19.5 (Me10),
22.2, 24.7 (4 CH2, cyclohexyl), 32.6 (N-Me), 34.3 (1 CH2, cyclo-
hexyl), 70.6 (C3), 89.6 (C5), 123.8 (C11), 128.3 (C8), 130.0 (C9),
130.4 (C10), 136.1 (C12), 147.4 (C7), 163.2 (C14), 173.8 (C2),
177.1 (C4).
Anal. Calcd for C19H25N3O2 (327.43): C, 69.70; H, 7.70; N, 12.83.
Found: C, 69.42; H, 7.88; N, 12.80.
(2-{[(3E)-5-Amino-2,2-dimethylfuran-3(2H)-ylidene]amino}-
4,5-dimethylphenyl)benzylformamide (3c)
This was prepared analogously from 1-benzyl-5,6-dimethylbenzim-
idazole (1b; 0.236 g, 1 mmol), nitrile 2a (0.109 g, 1 mmol), and H2O
(0.018 g, 1 mmol) as a light-brown powder; yield: 0.305 g (84%);
mp 187–189 °C.
Anal. Calcd for C15H19N3O3 (289.33): C, 62.27; H, 6.62; N, 14.52.
Found: C 62.80; H 6.67; N 14.28.
IR: 495, 518, 576, 592, 611, 628, 636, 659, 696, 705, 729, 741, 756,
770, 846, 887, 957, 972, 998, 1020, 1074, 1110, 1139, 1183, 1205,
1231, 1264, 1295, 1319, 1329, 1345, 1364, 1372, 1435, 1454, 1498,
1544, 1620, 1659, 1673, 2874, 2925, 2968, 3028, 3064, 3084, 3318,
3361 cm–1.
1H NMR (400.13 MHz, DMSO-d6): d = 1.43 (s, 6 H, 2 Me5), 2.07
(s, 3 H, Me9), 2.11 (s, 3 H, Me10), 4.23 (s, 1 H, H3), 4.80 (s, 2 H,
CH2 from N-benzyl), 6.65 (s, 1 H, H11), 6.84 (s, 1 H, H8), 7.20 (s,
2 H, NH2), 7.20–7.40 (m, 5 H, Ph from N-benzyl), 8.05 (s, 1 H,
H14).
(2-{[(4E)-2-Amino-1-oxaspiro[4.5]dec-2-en-4-ylidene]amino}-
5-methoxyphenyl)methylformamide (3f)
This was prepared analogously from 6-methoxy-1-methyl-1H-
benzimidazole (1c; 0.162 g, 1 mmol), nitrile 2b (0.149 g, 1 mmol),
and H2O (0.018 g, 1 mmol) as a white powder; yield: 0.299 g (91%);
mp 216–217 °C.
IR: 448, 499, 540, 584, 663, 702, 748, 783, 798, 836, 872, 918, 944,
993, 1037, 1057, 1096, 1193, 1209, 1222, 1278, 1346, 1436, 1496,
1548, 1616, 1665, 2710, 2764, 2866, 2940, 3007, 3111, 3322, 3373
cm–1.
13C NMR (100.62 MHz, DMSO-d6): d = 19.2 (Me9), 19.4 (Me10),
26.0 (2 Me5), 47.9 (CH2 from N-benzyl), 70.7 (C3), 89.0 (C5),
123.6 (C11), 127.2 (Cp, Ph from N-benzyl), 127.6 (Co, Ph from N-
benzyl), 128.1 (C8), 128.3 (Cm, Ph from N-benzyl), 130.4 (C9),
130.5 (C10), 136.0 (C12), 137.7 (Ci, Ph from N-benzyl), 147.7
(C7), 163.7 (C14), 173.7 (C2), 177.3 (C4).
1H NMR (400.13 MHz, DMSO-d6): d = 1.40–1.80 (m, 10 H, cyclo-
hexyl), 2.94 (s, 3 H, N-Me), 3.71 (s, 3 H, O-Me10), 4.16 (s, 1 H,
H3), 6.34 (d, 3JH8,H9 = 8.8 Hz, 1 H, H8), 6.53 (d, 1 H, H9), 7.08 (s,
1 H, H11), 7.29 (s, 2 H, NH2), 7.83 (s, 1 H, H14).
13C NMR (100.62 MHz, DMSO-d6): d = 22.2, 24.7 (3 CH2, cyclo-
hexyl), 32.8 (N-Me), 34.3 (2 CH2, cyclohexyl), 55.7 (O-Me10),
70.5 (C3), 90.3 (C5), 107.7 (C8), 108.0 (C9), 127.8 (C12), 128.5
(C11), 151.1 (C7), 159.1 (C10), 163.3 (C14), 174.0 (C2), 177.6
(C4).
Anal. Calcd for C22H25N3O2 (363.46): C, 72.70; H, 6.93; N, 11.56.
Found: C, 72.25; H, 6.74; N, 12.00.
(2-{[(4E)-2-Amino-1-oxaspiro[4.5]dec-2-en-4-ylidene]amino}-
4,5-dimethylphenyl)benzylformamide (3d)
This was prepared analogously from 1-benzyl-5,6-dimethylbenzim-
idazole (1b; 0.236 g, 1 mmol), nitrile 2b (0.149 g, 1 mmol), and
H2O (0.018 g, 1 mmol) as a flesh-colored powder; yield: 0.375 g
(93%); mp 224–225 °C.
Anal. Calcd for C18H23N3O3 (329.40): C, 65.63; H, 7.04; N, 12.76.
Found: C, 65.22; H, 7.04; N, 12.76.
(2-{[(3E)-5-Amino-2,2-dimethylfuran-3(2H)-ylidene]amino}-5-
methoxyphenyl)benzylformamide (3g)
This was prepared analogously from 1-benzyl-6-methoxy-1H-
benzimidazole (1d; 0.238 g, 1 mmol), nitrile 2a (0.109 g, 1 mmol),
IR: 499, 507, 561, 610, 641, 695, 722, 745, 877, 886, 928, 950, 999,
1064, 1104, 1119, 1195, 1244, 1261, 1309, 1344, 1365, 1425, 1437,
Synthesis 2010, No. 9, 1536–1542 © Thieme Stuttgart · New York

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Ring Cleavage of Benzimidazoles by a,b-Acetylenic g-Hydroxy Nitriles and Water
1541
and H2O (0.018 g, 1 mmol) as a yellow powder; yield: 0.358 g
(98%); mp 211–212 °C.
(2-{[(4E)-2-Amino-1-oxaspiro[4.5]dec-2-en-4-ylidene]amino}-
4-nitrophenyl)methylformamide (3j)
This was prepared analogously from 1-methyl-5-nitro-1H-benz-
imidazole (1e; 0.177 g, 1 mmol), nitrile 2b (0.149 g, 1 mmol), and
H2O (0.018 g, 1 mmol) to give a yellow powder; yield: 0.327 g
(95%); mp 220–221 °C.
IR: 455, 502, 564, 580, 608, 655, 696, 720, 752, 796, 830, 864, 876,
967, 1002, 1028, 1044, 1066, 1133, 1175, 1184, 1204, 1234, 1282,
1308, 1364, 1375, 1400, 1432, 1448, 1498, 1544, 1584, 1609, 1650,
1679, 2834, 2927, 2980, 3060, 3112, 3309, 3361 cm–1.
IR: 495, 564, 580, 634, 693, 747, 821, 838, 907, 919, 945, 978,
1001, 1049, 1116, 1137, 1201, 1233, 1255, 1277, 1306, 1335, 1351,
1436, 1490, 1516, 1540, 1575, 1593, 1612, 1654, 1668, 2851, 2931,
3097, 3157, 3212, 3265, 3307 cm–1.
1H NMR (400.13 MHz, DMSO-d6): d = 1.50–1.80 (m, 10 H, cyclo-
hexyl), 3.10 (s, 3 H, N-Me), 4.66 (s, 1 H, H3), 7.47 (d, 3JH10,H11 = 8.8
Hz, 1 H, H11), 7.67 (s, 2 H, NH2), 7.78 (d, 1 H, H10), 8.06 (s, 1 H,
H14), 8.08 (s, 1 H, H8).
13C NMR (100.62 MHz, DMSO-d6): d = 22.1, 24.6 (3 CH2, cyclo-
hexyl), 32.5 (N-Me), 34.1 (2 CH2, cyclohexyl), 70.8 (C3), 91.2
(C5), 117.0 (C8,10), 126.5 (C11), 139.8 (C12), 146.2 (C9), 150.2
(C7), 162.8 (C14), 175.1 (C2), 178.7 (C4).
1H NMR (400.13 MHz, DMSO-d6): d = 1.49 (s, 6 H, 2 Me5), 3.73
(s, 3 H, O-Me10), 4.31 (s, 1 H, H3), 4.91 (s, 2 H, CH2 from N-ben-
zyl), 6.74 (s, 1 H, H11), 6.82–6.84 (m, 2 H, H8,9), 7.25 (s, 2 H,
NH2), 7.20–7.34 (m, 5 H, Ph from N-benzyl), 8.15 (s, 1 H, H14).
13C NMR (100.62 MHz, DMSO-d6): d = 25.2 (2 Me5), 47.7 (CH2
from N-benzyl), 55.6 (O-Me10), 69.6 (C3), 88.9 (C5), 112.8 (C9),
113.4 (C11), 123.0 (C8), 126.2 (Cp, Ph from N-benzyl), 128.0 (Co,
Ph from N-benzyl), 128.2 (Cm, Ph from N-benzyl), 133.6 (C12),
137.9 (Ci, Ph from N-benzyl), 143.0 (C7), 154.6 (C10), 163.8
(C14), 173.7 (C2), 177.4 (C4).
Anal. Calcd for C21H23N3O3 (365.43): C, 69.02; H, 6.34; N, 11.50.
Found: C, 68.72; H, 6.31; N, 11.30.
Anal. Calcd for C17H20N4O4 (344.37): C, 59.79; H, 5.85; N, 16.24.
Found: C, 59.32; H, 5.64; N, 16.70.
(2-{[(4E)-2-Amino-1-oxaspiro[4.5]dec-2-en-4-ylidene]amino}-
5-methoxyphenyl)benzylformamide (3h)
This was prepared analogously from 1-benzyl-6-methoxy-1H-
benzimidazole (1d; 0.238 g, 1 mmol), nitrile 2b (0.149 g, 1 mmol),
and H2O (0.018 g, 1 mmol) as a brown powder; yield: 0.325 g
(87%); mp 189–190 °C.
(2-{[(3E)-5-Amino-2,2-dimethylfuran-3(2H)-ylidene]amino}-4-
nitrophenyl)benzylformamide (3k)
This was prepared analogously from 1-benzyl-5-nitro-1H-benz-
imidazole (1f; 0.253 g, 1 mmol), nitrile 2a (0.109 g, 1 mmol), and
H2O (0.018 g, 1 mmol) to give a yellow powder; yield: 0.376 g
(99%); mp 197–198 °C.
IR: 495, 520, 620, 696, 724, 749, 785, 813, 829, 839, 850, 910, 933,
949, 963, 1001, 1029, 1041, 1065, 1111, 1171, 1206, 1235, 1262,
1278, 1320, 1344, 1365, 1444, 1497, 1540, 1561, 1606, 1664, 2834,
2850, 2917, 2942, 3005, 3027, 3309 cm–1.
1H NMR (400.13 MHz, DMSO-d6): d = 1.50–1.80 (m, 10 H, cyclo-
hexyl), 3.63 (s, 3 H, O-Me10), 4.26 (s, 1 H, H3), 4.85 (s, 2 H, CH2
from N-benzyl), 6.66 (s, 1 H, H11), 6.76–6.78 (m, 2 H, H8,9), 7.20
(s, 2 H, NH2), 7.20–7.40 (m, 5 H, Ph from N-benzyl), 8.10 (s, 1 H,
H14).
13C NMR (100.62 MHz, DMSO-d6): d = 22.2, 24.9, 34.4 (5 CH2,
cyclohexyl), 47.9 (CH2 from N-benzyl), 55.7 (O-Me10), 70.6 (C3),
90.4 (C5), 113.0 (C9), 113.6 (C11), 123.2 (C8), 127.3 (Cp, Ph from
N-benzyl), 127.8 (Co, Ph from N-benzyl), 128.1 (Cm, Ph from N-
benzyl), 133.6 (C12), 137.9 (Ci, Ph from N-benzyl), 143.0 (C7),
154.6 (C10), 163.8 (C14), 174.1 (C2), 177.5 (C4).
IR: 513, 607, 665, 696, 726, 745, 760, 815, 836, 900, 961, 1007,
1086, 1184, 1223, 1270, 1286, 1301, 1310, 1344, 1429, 1456, 1485,
1522, 1541, 1563, 1615, 1657, 2913, 2929, 2987, 3169, 3326, 3345
cm–1.
1H NMR (400.13 MHz, DMSO-d6): d = 1.44 (s, 6 H, 2 Me5), 4.52
(s, 1 H, H3), 4.95 (s, 2 H, CH2 from N-benzyl), 7.20–7.40 (m, 5 H,
Ph from N-benzyl), 7.41 (d, 3JH10,H11 = 8.8 Hz, 1 H, H11), 7.66 (d, 1
H, H10), 7.60 (s, 2 H, NH2), 7.73 (s, 1 H, H8), 8.19 (s, 1 H, H14).
13C NMR (100.62 MHz, DMSO-d6): d = 26.9 (2 Me5), 47.6 (CH2
from N-benzyl), 70.6 (C3), 90.3 (C5), 116.7 (C10), 116.7 (C8),
127.3 (Cp, Ph from N-benzyl), 127.9 (Co, Ph from N-benzyl), 128.8
(Cm, Ph from N-benzyl), 129.0 (C11), 136.3 (Ci, Ph from N-ben-
zyl), 139.7 (C12), 146.5 (C9), 150.1 (C7), 163.9 (C14), 175.3 (C2),
178.8 (C4).
Anal. Calcd for C24H27N3O3 (405.50): C, 70.09; H, 6.71; N, 10.36.
Found: C, 69.81; H, 6.90; N, 10.15.
Anal. Calcd for C20H20N4O4 (380.40): C, 63.15; H, 5.30; N, 14.73.
Found: C, 62.60; H, 5.19; N, 14.65.
(2-{[(3E)-5-Amino-2,2-dimethylfuran-3(2H)-ylidene]amino}-4-
nitrophenyl)methylformamide (3i)
This was prepeared analogously from 1-methyl-5-nitro-1H-benz-
imidazole (1e; 0.177 g, 1 mmol), nitrile 2a (0.109 g, 1 mmol), and
H2O (0.018 g, 1 mmol) as an orange powder; yield: 0.301 g (99%);
mp 199–200 °C.
(2-{[(4E)-2-Amino-1-oxaspiro[4.5]dec-2-en-4-ylidene]amino}-
4-nitrophenyl)benzylformamide (3l)
This was prepared analogously from 1-benzyl-5-nitro-1H-benz-
imidazole (1f; 0.253 g, 1 mmol), nitrile 2b (0.149 g, 1 mmol), and
H2O (0.018 g, 1 mmol) as a yellow powder; yield: 0.416 g (99%);
mp 177–179 °C.
IR: 499, 577, 603, 646, 706, 734, 747, 760, 822, 846, 897, 953, 991,
1004, 1073, 1120, 1132, 1185, 1201, 1212, 1247, 1290, 1335, 1362,
1376, 1429, 1457, 1485, 1508, 1537, 1621, 1674, 2877, 2931, 2983,
3106, 3292, 3352 cm–1.
IR: 501, 522, 547, 635, 661, 696, 728, 740, 754, 795, 811, 823, 837,
901, 915, 945, 1001, 1063, 1079, 1139, 1191, 1219, 1237, 1263,
1313, 1345, 1372, 1404, 1444, 1481, 1520, 1551, 1611, 1650, 1660,
2861, 2932, 3180, 3390 cm–1.
1H NMR (400.13 MHz, DMSO-d6): d = 1.50–2.00 (m, 10 H, cyclo-
hexyl), 4.62 (s, 1 H, H3), 5.00 (s, 2 H, CH2 from N-benzyl), 6.93 (s,
2 H, NH2), 7.20–7.40 (m, 5 H, Ph from N-benzyl), 7.62–7.65 (m, 2
H, H10,11), 7.98 (s, 1 H, H8), 8.23 (s, 1 H, H14).
13C NMR (100.62 MHz, DMSO-d6): d = 21.9, 24.5, 33.9 (5 CH2,
cyclohexyl), 47.3 (CH2 from N-benzyl), 70.8 (C3), 91.6 (C5), 116.1
(C10), 116.6 (C8), 126.9 (C11), 127.2 (Cp, Ph from N-benzyl),
127.9 (Co, Ph from N-benzyl), 128.1 (Cm, Ph from N-benzyl),
1H NMR (400.13 MHz, DMSO-d6): d = 1.41 (s, 6 H, 2 Me5), 3.07
3
(s, 3 H, N-Me), 4.90 (s, 1 H, H3), 7.11 (d, JH10,H11 = 8.8 Hz, 1 H,
H11), 7.67 (d, 1 H, H10), 7.82 (s, 2 H, NH2), 8.07 (s, 1 H, H14), 8.08
(s, 1 H, H8).
13C NMR (100.62 MHz, DMSO-d6): d = 25.7 (2 Me5), 32.7 (N-
Me), 71.4 (C3), 90.3 (C5), 122.4 (C10), 123.0 (C11), 123.9 (C8),
135.2 (C12), 139.7 (C9), 157.3 (C7), 163.5 (C14), 175.4 (C2), 178.6
(C4).
Anal. Calcd for C14H16N4O4 (304.31): C, 55.26; H, 5.42; N, 18.41.
Found: C, 55.20; H, 5.41; N, 18.32.
Synthesis 2010, No. 9, 1536–1542 © Thieme Stuttgart · New York

1542
B. A. Trofimov et al.
PAPER
137.3 (Ci, Ph from N-benzyl), 139.4 (C12), 146.6 (C9), 150.3 (C7),
162.7 (C14), 175.1 (C2), 179.0 (C4).
(5) Bellina, F.; Falchi, E.; Rossi, R. Tetrahedron 2003, 59, 9091.
(6) Liu, Y.; Song, F.; Song, Zh.; Liu, M.; Yan, B. Org. Lett.
2005, 7, 5409.
Anal. Calcd for C23H24N4O4 (420.47): C, 65.70; H, 5.75; N, 13.32.
Found: C, 65.41; H, 5.72; N, 13.50.
(7) (a) Roggo, B. E.; Petersen, F.; Delmendo, R.; Jenny, H. B.;
Peter, H. H.; Roesel, J. J. Antibiot. 1994, 47, 136.
(b) Effenberger, F.; Syed, J. Tetrahedron: Asymmetry 1998,
9, 817. (c) Van Quaquebeke, E.; Simon, G.; André, A.;
Dewelle, J.; Yazidi, M.; Bruyneel, F.; Tuti, J.; Nacoulma, O.;
Guissou, P.; Decaestecker, C.; Braekman, J.-C.; Kiss, R.;
Darro, F. J. Med. Chem. 2005, 48, 849. (d) Bousserouel, H.;
Litaudon, M.; Morleo, B.; Martin, M.-T.; Thoison, O.;
Nosjean, O.; Boutin, J. A.; Renard, P.; Sévenet, T.
Tetrahedron 2005, 61, 845. (e) Dai, S.-J.; Tao, J.-Y.; Liu,
K.; Jiang, Y.-T.; Shen, L. Phytochemistry 2006, 67, 1326.
(f) Zografos, A. L.; Georgiadis, D. Synthesis 2006, 3157.
(8) Tahir, H.; Hindsgaul, O. J. Org. Chem. 2000, 65, 911.
(9) Shin, S. S.; Byun, Y.; Lim, K. M.; Choi, J. K.; Lee, K.-W.;
Moh, J. H.; Kim, J. K.; Jeong, Y. S.; Kim, J. Y.; Choi, Y. H.;
Koh, H.-J.; Park, Y.-H.; Oh, Y. I.; Noh, M.-S.; Chung, S.
J. Med. Chem. 2004, 47, 792.
(2-{[(3E)-5-Amino-2,2-dimethylfuran-3(2H)-ylidene]amino}-4-
phenyl)methylformamide (3m)
This was prepared analogously from 1-methyl-1H-benzimidazole
(1g; 0.132 g, 1 mmol), nitrile 2a (0.109 g, 1 mmol), and H2O (0.018
g, 1 mmol) as a flesh-colored powder; yield: 0.235 g (91%); mp
179–180 °C. The IR and NMR spectral characteristics of form-
amide 3m were in agreement with the published data.11
Acknowledgment
This work was supported by the Russian Fund for Basic Research
(Grant No. 08-03-00156), the Presidium of RAS (Program 15), and
the Presidium of the Department of Chemical Sciences and Materi-
als RAS (Grant No. 5.1).
(10) Grossmann, G.; Jolivet, B.; Bornand, M.; Séquin, U.;
Spindler, K.-D. Synthesis 2005, 1543.
References
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Synthesis 2010, No. 9, 1536–1542 © Thieme Stuttgart · New York