C(2)-Functionalization of 1-substituted imidazoles with cyanoacetylenes and aromatic or heteroaromatic aldehydes

Article abstract of DOI:10.1016/j.tet.2010.11.072

Substituted imidazoles (substituents are Me, Et, i-Bu, n-Hexyl, (CH ₂)₂S-Bu-n, Ph, Bn) react smoothly (room temperature, without catalyst and solvent) with cyanoacetylenes (3-phenyl-2-propynenitrile and 4-(1-butoxyethoxy)-4-methyl-2-

Full text of DOI:10.1016/j.tet.2010.11.072

Tetrahedron 67 (2011) 1288e1293
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
C(2)-Functionalization of 1-substituted imidazoles with cyanoacetylenes
and aromatic or heteroaromatic aldehydes
,
a
a
a
Boris A. Trofimov a , Ludmila V. Andriyankova , Kseniya V. Belyaeva , Anastasiya G. Mal’kina ,
Lina P. Nikitina a, Oleg A. Dyachenko b, Olga N. Kazheva b, Grigorii G. Alexandrov c,
Gennadii V. Shilov b, Andrei V. Afonin a, Igor’ A. Ushakov a
*
a A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., Irkutsk 664033, Russia
b Institute of Problems of Chemical Physics, Russian Academy of Sciences, 1 Academician N.N. Semenov Str., Chernogolovka 142432, Russia
c N.S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 31 Leninskii Prosp., Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted imidazoles (substituents are Me, Et, i-Bu, n-Hexyl, (CH2)2SeBu-n, Ph, Bn) react smoothly
(room temperature, without catalyst and solvent) with cyanoacetylenes (3-phenyl-2-propynenitrile and
4-(1-butoxyethoxy)-4-methyl-2-pentynenitrile) and aromatic or heteroaromatic aldehydes (benzalde-
hyde, 4-CN-benzaldehyde, pyridine-3-aldehyde) to give 3-(2-imidazolyl)-3-aryl-2-acylpropanenitriles,
a hitherto unknown family of functionalized imidazole derivatives, in up to 62% yield. This three-com-
ponent manifold represents a novel C(2)-functionalization of the imidazole nucleus involving zwitter-
ionic, carbene and enol ether intermediates. Unlike the analogous reaction with aliphatic aldehydes,
which gives enol ethers, in this case the latter undergo the further rearrangement to 3-(2-imidazolyl)-3-
aryl-2-acylpropanenitriles.
Received 13 September 2010
Received in revised form 1 November 2010
Accepted 23 November 2010
Available online 3 December 2010
Keywords:
1-Substituted imidazoles
Cyanoacetylenes
Aldehydes
Ó 2010 Elsevier Ltd. All rights reserved.
Multicomponent reaction
1. Introduction
by intercepting the intermediate zwitterions by aliphatic aldehydes
and resulting C(2)-functionalized imidazoles, (Z)-3-(1-alkylimida-
In recent years, growing attention has been paid to the reactions
of zwitterionic adducts of neutral nucleophiles1,2 (pyridines, quin-
olines, isoquinolines, quinoxalines, phenanthridines, anabazines,
and the like) with electron-deficient acetylenes, e.g., dialkyl acety-
zol-2-yl)alkoxy-3-phenyl-2-propenenitriles 4, being isolated in up
to 62% yield (Scheme 1).6 Here, it should be emphasized that only
aliphatic aldehydes were used. The reaction is rationalized as pro-
ceeding through the formation of the intermediate carbene B (via
proton transfer from position 2 of the imidazole ring to the carba-
nionic center of the zwitterion A), which then is added to the C]O
lene dicarboxylates,1
a,b-acetylenic g-hydroxy nitriles, and 3-phe-
nyl-2-propynenitrile.2 A special family of neutral nucleophiles,
heterocyclic carbenes are capable of reacting with acetylene dicar-
boxylates to generate zwitterions, which are intercepted by a third
component (aldehydes, ketenes, isothiocyanates) to afford a variety
of valuable heterocyclic compounds.3 Particular efforts now are
focused on the exploration of these reactions for the synthesis of
diverse imidazole derivatives, since the imidazole ring is a frequent
structural scaffold of numerous natural products and drugs.4
Recently, we discovered the direct C(2)-vinylation5a,b and 1,3-
butadienylation5c of 1-substituted imidazoles 1 with 3-phenyl-2-
propynenitrile (2), which involves the zwitterionic and carbene
intermediates. Thanks to the availability of 3-phenyl-2-propyneni-
trile these reactions contribute to the chemistry and exploitation of
2-functionalized imidazoles. Recently, we extended these findings
Ph
Ph
O
CN
CN
+
R2
N
N
_
N
3
Ph
CN
+
:
N
R1
1
N
R1
N
R1
2
A
B
Ph
CN
CN
N
+
N
_
O
O
N
N
R1
R2
R2
4
R1
Ph
C
R1 = alkyl, Bn, vinyl; R2 = alkyl
* Corresponding author. Tel.: þ7 3952 421411; fax: þ7 3952 41 9346; e-mail
address: boris_trofimov@irioch.irk.ru (B.A. Trofimov).
Scheme 1. The formation of (Z)-3-(1-alkylimidazol-2-yl)alkoxy-3-phenyl-2-propene-
nitriles 4 from the zwitterion A, carbene B, and aliphatic aldehyde.6
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.072

B.A. Trofimov et al. / Tetrahedron 67 (2011) 1288e1293
1289
bond of the aldehyde to deliver the zwitterion C, rearranging to final
product 4 (Scheme 1).6
Herein we report on the reaction of 1-substituted imidazoles
with cyanoacetylenes and aromatic or heteroaromatic aldehydes,
which against expectations undergoes a further rearrangement to
end up with a different C(2)-functionalization of the imidazole ring.
The structures of propanenitriles 5aej have been unambiguously
assigned by the X-ray analysis of single crystals of products 5a,g,h
(Figs. 1e3) and confirmed by 1H, 13C, 15N NMR, 2D (NOESY, COSY,
HMBC, HSQC), and IR spectroscopy.
The presence of the 4-cyanophenyl substituent at the C-6 of
compound 5h (Fig. 4) is confirmed by the appearance of a cross-
peak caused by the correlation of H-6 proton signal (4.95 ppm) with
C-11 and C-15 carbon signals (129.6 ppm) over three bonds in the
HMBC spectra (the same picture is observed for compound 5i).
In the 1H NMR spectra of propanenitriles 5, splitting of the signals
assigned to H-6 and H-7 (Fig. 4) proton signals is observed in the
region 4.77e4.99 and 5.64e5.77 ppm, respectively, thus indicating
the existence of compounds 5 as mixtures of two diastereomers (in
a ratio of 10:1.6e2.5). In the IR spectra of propanenitriles 5, the car-
bonyl group absorption bands appears in the region 1690e1704 cmꢀ1
and the broad, low intensity bands attributable to the CN group at an
2. Results and discussion
When 1-substituted imidazoles 1aeg and cyanoacetylenes 2a,b
were allowed to react (room temperature, without solvent and
catalysts, 6 he6 days) with aromatic or heteroaromatic aldehydes
3aec, none of the expected enol ethers 4 were isolated (Scheme 1)
except for one special case (vide infra). Instead, 3-(2-imidazolyl)-3-
aryl(hetaryl)-2-acylpropanenitriles 5aej were isolated as the only
products in 17e62% yields (Table 1).
Table 1
Three-component reaction of imidazole, cyanoacetylene, and aromatic or heteroaromatic aldehydes: a new C(2)-functionalization of the imidazole ring
R2
O
N
N
O
rt
+ R2
R3
CN +
6 h-6 d
N
N
CN
2a,b
3a-c
R3
5a-j
R1
1a-g
R1
Imidazole
Cyanoacetylene
Aldehyde
Functionalized imidazole
Isolated yield (%)
54
Ph
O
N
N
O
1a
1b
1c
1d
2a
2a
2a
2a
3a
3a
3a
3a
5a
5b
5c
5d
Ph
CN
N
Ph
N
CN
Me
Ph
O
Me
Ph
N
N
51
48
52
N
N
CN
Et
Ph
O
Et
Ph
N
N
N
N
CN
Bu-i
Ph
O
Bu-i
Ph
N
N
N
N
CN
Hexyl-n
Ph
Hexyl-n
Ph
O
N
N
N
1e
1f
2a
2a
3a
3a
5e
5f
36
51
N
CN
(CH2)2SBu-n
Ph
n-BuS(CH2)2
Ph
O
N
N
N
N
CN
Ph
Ph
Ph
N
Ph
O
N
62
1g
2a
3a
5g
N
N
CN
Bn
Ph
Bn
(continued on next page)

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B.A. Trofimov et al. / Tetrahedron 67 (2011) 1288e1293
Table 1 (continued )
Imidazole
Cyanoacetylene
Aldehyde
Functionalized imidazole
Isolated yield (%)
44
Ph
O
N
O
1b
1a
2a
2a
3b
3c
5h
5i
4-CNPh
N
CN
Et
4 CN
Ph
O
Ph
N
O
17
32
3-Py
N
CN
Py-3
Me
Me
Me
Me
Me
O
CN
OBu-n
N
Me
O
1a
2b
3a
5j
O
N
CN
OBu-n
Me
Ph
Me
Fig. 1. ORTEP diagram of propanenitrile 5a.
Fig. 3. ORTEP diagram of propanenitrile 5h.
sp3 carbon are present at 2235e2245 cmꢀ1, whereas in enol ethers 4
spectra the CN function is manifested itself as narrow intense bands
at 2214e2218 cmꢀ1 6
.
Evidently, the formation of propanenitriles 5aej results from the
rearrangement of the type 4 enol ethers (Scheme 2) and hence
passes through all the steps designated on Scheme 1. The key in-
termediate of the rearrangement is carbene B. Its formation has
been distinctly detected experimentally in 13C NMR spectra (CDCl3)
of the reaction mixture where is always observed the characteristic
signal at 223.4 ppm commonly assigned in the literature7 to the
carbene carbon.
The rearrangement (Scheme 2) is triggered by the cleavage of
the ether C6eO bond with the electron pairs transfer to the anti-
bonding
p-orbital of the vinyl group to induce the carbanion-like
center at the carbon atom adjacent to the CN function thus weak-
ening the C]C bond. This facilitates the Z/E isomerization of the
acrylonitrile moiety and, finally, the formation of C6eC7 bond. In
this case, the driving force of the rearrangement is the stabilization
Fig. 2. ORTEP diagram of propanenitrile 5g.

B.A. Trofimov et al. / Tetrahedron 67 (2011) 1288e1293
20
1291
20
3. Conclusions
19
18
21
19
21
16
17
16
17
In summary, a novel facile three-component reaction between 1-
substituted imidazoles, cyanoacetylenes, and aromatic and heter-
oaromatic aldehydes to afford a hitherto unknown family of densely
C(2)-functionalized imidazoles, 3-(2-imidazolyl)-3-aryl-2-acylpro-
panenitriles, has been found. This unusual C(2)-functionalization of
the imidazole nucleus proceeds via the zwitterionic, carbene and
enol ether intermediates. In contrast to the previously reported
similar reactions with aliphatic aldehydes, the functionalization
does not stop at the step of the enol ethers formation but is
accomplished with the further rearrangement to 3-(2-imidazolyl)-
3-aryl-2-acylpropanenitriles. This reaction significantly contributes
to the basic and synthetic chemistry of imidazole, electron-deficient
acetylenes, and heterocyclic zwitterions and carbenes.
18
3
3
O
6
O
6
4
4
N
N
8
8
7
2
7
2
5
5
1
1
N
N
CN
CN
9
9
10
10
15
13
Me
Et
11
12
11
12
15
14
14
13
CN
22
5a
5h
20
21
19
18
10
3
N
2
4
CN
9
16
17
3
O
6
4
N
1
O
5
8
6
8
N
2
H
7
1
5
17
4. Experimental section
4.1. General
11
N
CN
9
Me
15
18
19
16
12
10
22
21
20
Me
11
15
13
14
N
14
12
13
NMR spectra were run on a Bruker DPX-400 spectrometer with
HMDS as an internal standard. IR spectra were recorded on a IFS 25
instrument. 1-Substituted imidazoles 1aee were prepared
according to literature procedures.7d,8 3-Phenyl-2-propynenitrile
(2a) and 4-(1-butoxyethoxy)-4-methyl-2-pentynenitrile (2b) were
synthesized as reported in protocol.9,10 Column and thin-layer
chromatography was carried out on neutral Al2O3 with chloroform/
benzene/ethanol (20:4:1) mixture as eluent. The reaction was
controlled by disappearance of spot of the initial propynenitriles 2
on fine layer of Al2O3.
5i
6
Fig. 4. Labeling of hydrogen and carbon atoms in the compounds 5a, 5h, 5i, and 6 used
for NMR assignments.
−δ
R2
9
NC
N
R2
O
6
N
8
8
7
O
7
N
R1
N
R1
CN
+δ
6
R3
R3
4
5
4.2. X-ray diffraction
Scheme 2. The rearrangement of enol ethers 4 to propanenitriles 5.
X-ray diffraction studies of the compounds 5a, 5g, and 5h were
carried out with KM-4 KUMA DIFFRACTION diffractometer, at
room temperature (u/2q-scanning, Mo Ka radiation, graphite
of the carbocation-like center at the C6 atom by the aromatic sub-
stituent R3 (the benzyl cation type stabilization), which does not
take place with aliphatic aldehydes.
monochromator). Crystalline structures were solved by direct
methods followed with Fourier synthesis by using SHELXS-97.11a
All non-hydrogen atoms were refined by using anisotropic full-
matrix approximation with the use of SHELXL-97.11b Coordinates of
hydrogen atoms were defined experimentally and refined iso-
tropically. These data are available via www.ccdc.cam.uk/con-
tsretrieving.html (or from CCDC, 12 Union CambrigeCB2 1EZ, UK,
fax: þ44 (0) 1223 336 033; or e-mail:deposit@ccdc.cam.ac.uk). Any
request to the CCDC for data should quote the full literature cita-
tion and CCDC reference numbers CCDC 709166 (5a), CCDC 709167
(5g), CCDC 782010 (5h).
The formation of two or more [in the case of 4-(1-butox-
yethoxy)-4-methyl-2-pentynenitrile (2b)] diastereomers indicates
that the rearrangement is not fully stereoselective and hence en-
tirely concerted (according to the data for aliphatic aldehydes,6 the
enol intermediates are of Z-configuration only). Meanwhile, the
isolation of the expected products 5j though in a modest yield (32%)
shows that the reaction tolerates even highly sterically strained
substrates.
As additional evidence of Scheme 2, in one case the expected
intermediate enol ether 6 was isolated in 3% yield, which kept
gradually transforming to the corresponding propanenitrile 5a
(54%, Scheme 3). Besides, enol ethers 4 previously obtained by the
same three-component reaction with aliphatic aldehydes (Scheme
1), upon storage (ca. 6 months, CDCl3, room temperature) com-
pletely rearrange to the corresponding propanenitriles, which also
exist as a diastereomer mixture. The latter supports the argument in
favor of the above-suggested non-concerted rearrangement of the
enol ethers 4. Additionally, this shows that the propanenitriles 5 are
energetically more favorable compared to enol ethers 4 and 6,
which therefore are the kinetic products.
4.3. Preparation of 3-(2-imidazolyl)-3-aryl-2-acylpropanenitriles
4.3.1. 2-Benzoyl-3-(1-methyl-1H-imidazol-2-yl)-3-phenylpro-
panenitrile (5a). To a mixture of cyanoacetylene 2a (0.127 g,
1 mmol) and benzaldehyde (3a; 0.106 g, 1 mmol) was added on
stirring 1-methylimidazole (1a; 0.082 g, 1 mmol). The reaction
mixture was stirred at 20e25 ꢁS for 24 h. Column chromatography
afforded propanenitrile 5a (0.171 g, 54%) as a faintly colored powder,
mp 170e172 ꢁC (diastereomers ratio being 10:2.0). 1O NMR
(400.13 MHz, CDCl3):
d
¼8.08e7.39 (m, 10H, 11e15, 17e21-H), 6.81
(s,1H, 4-H), 6.73 (s,1H, 5-H), 5.63 (d,1H, 7-H), 4.91 (d,1H, 6-H, 3J6-H,
CN
N
O
¼10.8 Hz), 3.45 (s, 3H, NeCH3) ppm. 13C NMR (100.62 MHz,
N
O
7-H
N
H
5a
CDCl3):
d
¼189.3 (C-8), 145.5 (C-2), 136.2 (C-10), 134.4 (C-16), 134.0
+
+
Ph
Ph
CN
N
Me
(C-19),128.8 (C-17, 21),128.7 (C-12,14),128.6 (C-18, 20),128.3 (C-11,
15),128.1 (C-13),126.7 (C-4),121.2 (C-5),115.6 (C-9), 43.7 (C-7), 42.2
2a
3a
Me
1a
(C-6), 32.1 (NeCH3) ppm. 15N NMR (40.55 MHz, CDCl3):
d
¼ꢀ123.7
(CN), ꢀ125.6 (N-3), ꢀ224.9 (N-1) ppm. Signals distinguishable for
minor stereoisomer: 1O NMR (400.13 MHz, CDCl3):
¼6.90 (s, 1H,
6
Scheme 3. Isolation of intermediate enol ether 6.
d

1292
B.A. Trofimov et al. / Tetrahedron 67 (2011) 1288e1293
3
4-H0), 6.84 (s, 1H, 5-H0), 5.54 (d, 1H, 7-H0), 4.95 (d, 1H, 6-H0, J6-H , 7-
2H, CH2 from Nen-Hexyl), 1.62 (m, 2H, CH2 from Nen-Hexyl), 1.45
(m, 2H, CH2 from Nen-Hexyl), 1.21 (m, 4H, 2CH2 from Nen-Hexyl),
0.88 (m, 3H, CH3 from Nen-Hexyl) ppm. 13C NMR (100.62 MHz,
0
0
¼10.4 Hz), 3.51 (s, 3H, NeCH3) ppm. IR (KBr): 2236 (CN),1699 (C]
H
O) cmꢀ1. Anal. Calcd for S20O17N3P: S, 76.17; O, 5.43; N, 13.32.
Found: S, 76.49; O, 5.68; N, 13.76.
CDCl3):
d
¼189.7 (C-8), 145.4 (C-2), 137.1 (C-10), 134.8 (C-16), 134.4
(C-19), 129.2 (C-17, 21), 129.2 (C-12, 14), 129.0 (C-18, 20), 128.7 (C-
11, 15), 128.5 (C-13), 127.0 (C-4), 120.1 (C-5), 116.2 (C-9), 45.9 (CH2
from Nen-Hexyl), 44.2 (C-7), 42.8 (C-6), 31.3 (CH2 from Nen-
Hexyl), 30.4 (CH2 from Nen-Hexyl), 26.3 (CH2 from Nen-Hexyl),
22.4 (CH2 from Nen-Hexyl), 14.0 (CH3 from Nen-Hexyl) ppm. Sig-
nals distinguishable for minor stereoisomer: 1O NMR (400.13 MHz,
4.3.2. (Z)-3-[(1-Methyl-1H-imidazol-2-yl)(phenyl)methoxy]-3-phe-
nyl-2-propenenitrile (6). The fraction representing an ‘ether’, pro-
penenitrile 6 (0.011 g, 3%) as a yellow oil, was isolated in the course
of propanenitrile 5a synthesis. 1O NMR (400.13 MHz, CDCl3):
d
¼7.55e7.15 (m, 10H, 12e16, 18e22-H), 6.96 (s, 1H, 4-H), 6.86 (s, 1H,
5-H), 5.80 (s, 1H, 6-H), 5.11 (s, 1H, 9-H), 3.51 (s, 3H, NeCH3) ppm. 13
NMR (100.62 MHz, CDCl3):
C
CDCl3):
d
¼6.95 (s,1H, 4-H0), 6.89 (s,1H, 5-H0), 5.57 (d,1H, 7-H0), 4.96
3
(d, 1H, 6-H0, J6-H ,
¼10.4 Hz), 3.81 (m, 2H, CH2 from Nen-
0
0
d
¼168.4 (C-8), 144.9 (C-2), 137.5 (C-11),
7-H
136.6 (C-17), 131.0 (C-14), 129.0 (C-13, 15, 19, 21), 128.8 (C-18, 22),
128.4 (C-12, 16), 126.8 (C-4), 121.8 (C-5), 117.2 (C-10, CN), 83.4 (C-6),
77.1 (C-9), 33.3 (NeCH3) ppm. IR (film): 2217 (CN), 1076
(CeOeC) cmꢀ1. Anal. Calcd for S20O17N3P: S, 76.17; O, 5.43; N,
13.32. Found: S, 76.54; O, 5.14; N, 13.10.
Hexyl) ppm. IR (KBr): 2245 (CN), 1702 (C]O) cmꢀ1. Anal. Calcd for
S25O27N3P: S, 77.89; O, 7.06; N, 10.90. Found: S, 77.63; O, 6.88; N,
10.60.
4.3.6. 2-Benzoyl-3-[1-(b-n-butylthio)ethyl-1H-imidazol-2-yl]-3-
phenylpropanenitrile (5e). Analogously, the reaction of cyanoace-
tylene 2a (0.127 g, 1 mmol), benzaldehyde (3a; 0.106 g, 1 mmol),
and 1-(b-n-butylthio)ethylimidazole (1e; 0.184 g, 1 mmol) (48 h)
4.3.3. 2-Benzoyl-3-(1-ethyl-1H-imidazol-2-yl)-3-phenylpropanenitrile
(5b). Analogously, the reaction of cyanoacetylene 2a (0.127 g,
1 mmol), benzaldehyde (3a; 0.106 g, 1 mmol), and 1-ethylimidazole
(1b; 0.096 g, 1 mmol) (48 h) gave propanenitrile 5b (0.167 g, 51%) as
a faintly colored powder, mp 160e162 ꢁC (diastereomers ratio be-
gave propanenitrile 5e (0.150 g, 36%) as a faintly colored powder,
mp 122e124 ꢁC (diastereomers ratio being 10:1.6). 1O NMR
(400.13 MHz, CDCl3):
(s,1H, 4-H), 6.92 (s,1H, 5-H), 5.77 (d,1H, 7-H), 4.99 (d,1H, 6-H, 3J6-H,
¼10.8 Hz), 4.03 (m, 2H, CH2 from N-( -n-butylthio)ethyl), 2.69
-n-butylthio)ethyl), 2.39 (m, 2H, CH2 from N-
-n-butylthio)ethyl), 1.54 (m, 2H, CH2 from N-( -n-butylthio)
ethyl), 1.44 (m, 2H, CH2 from N-( -n-butylthio)ethyl), 0.99 (m, 3H,
CH3 from N-(
-n-butylthio)ethyl) ppm. 13C NMR (100.62 MHz,
CDCl3):
d¼8.15e7.40 (m, 10H, 11e15, 17e21-H), 6.93
ing 10:1.8). 1O NMR (400.13 MHz, CDCl3):
d
¼8.06e7.40 (m, 10H,
11e15, 17e21-H), 6.79 (s, 1H, 4-H), 6.75 (s, 1H, 5-H), 5.67 (d, 1H, 7-
b
7-H
3
H), 4.88 (d, 1H, 6-H, J6-H,
¼10.8 Hz), 3.45 (m, 2H, CH2 from
(m, 2H, CH2 from N-(b
7-H
NeEt), 1.15 (t, 3H, CH3 from NeEt) ppm. 13C NMR (100.62 MHz,
CDCl3):
(b
b
d
¼189.8 (C-8), 145.2 (C-2), 136.9 (C-10), 134.7 (C-16), 134.4
b
(C-19),129.2 (C-17, 21),129.1 (C-12,14),129.0 (C-18, 20),128.7 (C-11,
15), 128.4 (C-13), 127.0 (C-4), 119.4 (C-5), 116.1 (C-9), 44.2 (C-7), 42.7
(C-6), 40.6 (CH2 from NeEt), 15.6 (CH3 from NeEt) ppm. Signals
distinguishable for minor stereoisomer: 1O NMR (400.13 MHz,
b
d
¼189.6 (C-8), 145.3 (C-2), 136.8 (C-10), 134.7 (C-16), 134.5
(C-19), 129.4 (C-17, 21), 129.2 (C-12, 14), 129.0 (C-11, 15, 18, 20),
128.7 (C-13), 127.4 (C-4), 120.6 (C-5), 116.0 (C-9), 46.2 (CH2 from N-
CDCl3):
d
¼6.91 (s,1H, 4-H0), 6.86 (s,1H, 5-H0), 5.52 (d,1H, 7-H0), 4.93
(
b
-n-butylthio)ethyl), 44.2 (C-7), 42.7 (C-6), 32.4 (CH2 from N-(
butylthio)ethyl), 32.2 (CH2 from N-( -n-butylthio)ethyl), 31.8 (CH2
from N-( -n-butylthio)ethyl), 22.0 (CH2 from N-( -n-butylthio)
ethyl), 13.7 (CH3 from N-( -n-butylthio)ethyl) ppm. Signals distin-
b-n-
3
(d, 1H, 6-H0, J6-H , 7-H ¼10.4 Hz), 3.93 (m, 2H, CH2 from NeEt), 1.24
b
0
0
(t, 3H, CH3 from NeEt) ppm. IR (KBr): 2235 (CN), 1701 (C]O) cmꢀ1
.
b
b
Anal. Calcd for S21O19N3P: S, 75.69; O, 6.03; N, 13.24. Found: S,
75.24; O, 6.02; N, 13.03.
b
guishable for minor stereoisomer: 1O NMR (400.13 MHz, CDCl3):
d
¼7.05 (s, 1H, 4-H0), 7.03 (s, 1H, 5-H0), 5.60 (d, 1H, 7-H0), 5.08 (d, 1H,
3
0
0
4.3.4. 2-Benzoyl-3-(1-i-butyl-1H-imidazol-2-yl)-3-phenylpropan-
enitrile(5c). Analogously, the reaction of cyanoacetylene 2a (0.127 g,
1 mmol), benzaldehyde (3a; 0.106 g, 1 mmol), and 1-i-butylimida-
zole (1c; 0.124 g, 1 mmol) (90 h) gave propanenitrile 5c (0.173 g,
48%) as a faintly colored powder, mp 152e154 ꢁC (diastereomers
6-H0, J6-H , 7-H ¼10.4 Hz), 4.13 (m, 2H, CH2 from N-(
b-n-butylthio)
ethyl) ppm. IR (KBr): 2244 (CN), 1697 (C]O) cmꢀ1. Anal. Calcd for
S25O27N3PS: S, 71.91; O, 6.52; N,10.06. Found: S, 71.40; O, 6.82; N,
10.40.
ratio being 10:1.8). 1O NMR (400.13 MHz, CDCl3):
10H,11e15, 17e21-H), 6.79 (s,1H, 4-H), 6.71 (s,1H, 5-H), 5.66 (d,1H,
7-H), 4.85 (d,1H, 6-H, 3J6-H, 7-H¼10.8 Hz), 3.48 (m, 2H, CH2 from Nei-
Bu),1.87 (m,1H, CH from Nei-Bu), 0.87e0.72 (m, 6H, 2CH3 from Nei-
d
¼8.04e7.35 (m,
4.3.7. 2-Benzoyl-3-(1-phenyl-1H-imidazol-2-yl)-3-phenylpro-
panenitrile (5f). Analogously, the reaction of cyanoacetylene 2a
(0.127 g, 1 mmol), benzaldehyde (3a; 0.106 g, 1 mmol), and 1-phe-
nylimidazole (1f; 0.144 g, 1 mmol) (108 h) gave propanenitrile 5f
(0.194 g, 51%) as a faintly colored powder, mp 156e158 ꢁC (di-
astereomers ratio being 10:2.3). 1O NMR (400.13 MHz, CDCl3):
Bu) ppm. 13C NMR (100.62 MHz, CDCl3):
d
¼189.8 (C-8), 145.6 (C-2),
137.1 (C-10), 134.9 (C-16), 134.4 (C-19), 129.2 (C-17, 21), 129.2 (C-12,
14), 129.0 (C-18, 20), 128.8 (C-11, 15), 128.4 (C-13), 127.0 (C-4), 120.9
(C-5),116.2 (C-9), 53.3 (CH2 from Nei-Bu), 44.4 (C-7), 42.9 (C-6), 29.5
(CH from Nei-Bu), 20.1, 19.9 (2CH3 from Nei-Bu) ppm. Signals dis-
tinguishable for minor stereoisomer: 1O NMR (400.13 MHz, CDCl3):
d
¼8.05e7.15 (m, 10H, 11e15, 17e21-H and 5H, Ho, m, p from NePh),
6.92 (s, 1H, 4-H), 6.89 (s, 1H, 5-H), 5.66 (d, 1H, 7-H), 4.77 (d, 1H, 6-H,
3J6-H, 7-H¼10.8 Hz) ppm. 13C NMR (100.62 MHz, CDCl3):
¼189.7 (C-
d
8),146.3 (C-2),146.0 (Ci from NePh),136.9 (C-10),134.5 (C-19),134.4
(C-16),129.6 (Cm from NePh),129.5 (C-17, 21),129.2 (C-12,14),129.1
(C-18, 20), 128.7 (C-11, 15), 128.6 (Co from NePh), 128.2 (C-13), 127.8
(Cp from NePh), 126.6 (C-4), 121.7 (C-5), 116.0 (C-9), 44.3 (C-7), 42.5
(C-6) ppm. Signals distinguishable for minor stereoisomer: 1O NMR
d
¼6.89 (s, 1H, 4-H0), 6.83 (s, 1H, 5-H0), 5.52 (d, 1H, 7-H0), 4.91 (d, 1H,
3
6-H0, J6-H , 7-H ¼10.4 Hz), 3.58 (m, 2H, CH2 from Nei-Bu) ppm. IR
(KBr): 2244 (CN), 1698 (C]O) cmꢀ1. Anal. Calcd for S23O23N3P: S,
77.28; O, 6.49; N, 11.76. Found: S, 76.80; O, 6.68; N, 11.85.
0
0
(400.13 MHz, CDCl3):
d
¼7.02 (s, 1H, 4-H0), 6.98 (s, 1H, 5-H0), 5.53 (d,
3
0
0
4.3.5. 2-Benzoyl-3-(1-n-hexyl-1H-imidazol-2-yl)-3-phenylpro-
panenitrile (5d). Analogously, the reaction of cyanoacetylene 2a
(0.127 g, 1 mmol), benzaldehyde (3a; 0.106 g, 1 mmol), and 1-
hexylimidazole (1d; 0.152 g, 1 mmol) (144 h) gave propanenitrile
5d (0.199 g, 52%) as a faintly colored powder, mp 124e126 ꢁC (di-
astereomers ratio being 10:1.6). 1O NMR (400.13 MHz, CDCl3):
1H, 7-H0), 4.76 (d, 1H, 6-H0, J6-H , 7-H ¼10.4 Hz) ppm. IR (KBr): 2241
(CN), 1700 (C]O) cmꢀ1. Anal. Calcd for S25O19N3P: S, 79.55; O,
5.07; N, 11.13. Found: S, 79.24; O, 5.39; N, 11.16.
4.3.8. 2-Benzoyl-3-(1-benzyl-1H-imidazol-2-yl)-3-phenylpro-
panenitrile (5g). Analogously, the reaction of cyanoacetylene 2a
(0.127 g, 1 mmol), benzaldehyde (3a; 0.106 g, 1 mmol), and 1-ben-
zylimidazole (1g; 0.158 g, 1 mmol) (72 h, 1 mL THF) gave
d
¼8.09e7.39 (m, 10H, 11e15, 17e21-H), 6.83 (s, 1H, 4-H), 6.78 (s, 1H,
5-H), 5.70 (d, 1H, 7-H), 4.90 (d, 1H, 6-H, 3J6-H, 7-H¼10.8 Hz), 3.74 (m,

B.A. Trofimov et al. / Tetrahedron 67 (2011) 1288e1293
1293
3
propanenitrile 5g (0.241 g, 62%) as a faintly colored powder, mp
136e138 ꢁC (diastereomers ratio being 10:1.9). 1O NMR (400.13 MHz,
Oe18-CH2e, JH, H¼6.4 Hz), 3.43, 3.42, 3.38, 3.36 (s, 12H, NeCH3),
1.60e1.30 (m, 40H, Ce16-(CH3)2, 19, 20-CH2e), 0.95e0.85 (m, 24H,
CDCl3):
d
¼8.05e7.37 (m, 10H, 11e15, 17e21-H and 5H, Ho, m, p from
HCe17-CH3, 21-CH3) ppm. 13C NMR (100.62 MHz, CDCl3):
d
¼204.7,
NeBn), 6.83 (s,1H, 4-H), 6.69 (s,1H, 5-H), 5.65 (d,1H, 7-H), 4.89 (s, 2H,
204.6, 203.5, 203.1 (C-8), 146.0, 145.9, 145.5, 145.3 (C-2), 136.9,
136.8, 136.6, 136.5 (C-10), 129.1, 129.0, 128.9, 128.8, 128.7, 128.6,
128.5, 128.4, 128.3, 128.2, 128.1, 128.0 (C-11e15), 126.8, 126.7, 126.6
(C-4), 121.4, 121.3, 121.2 (C-5), 116.7, 116.6, 115.8, 115.7 (C-9), 95.7,
95.1, 95.0, 94.5 (C-17), 82.8, 82.7, 81.9, 81.6 (C-16), 63.5, 63.4, 62.7,
62.1 (OeCH2-18), 43.6, 43.3, 43.0, 42.9 (C-7), 42.7, 42.4, 41.9, 41.8
(C-6), 32.5, 32.4, 31.9, 31.6 (NeCH3), 26.2, 25.3, 24.1, 23.7, 23.6, 23.2,
23.0, 22.0, 20.8, 20.7, 20.5, 20.4, 19.4, 19.4 (CHe17-CH3, C-16-(CH3)2,
CH2-19, CH2-20), 13.9 (CH3-21) ppm. IR (film): 2243 (CN), 1704 (C]
O) cmꢀ1. Anal. Calcd for S23O31N3P3: S, 69.49; O, 7.86; N, 10.57.
Found: S, 69.90; O, 8.05; N, 10.24.
CH2 from NeBn), 4.82 (d, 1H, 6-H, 3J6-H, 7-H¼10.8 Hz) ppm. 13C NMR
(100.62 MHz, CDCl3):
d¼189.5(C-8),145.9(C-2),136.6(C-10),135.5 (Ci
from NeBn), 134.7 (C-19), 134.3 (C-16), 129.1 (C-17, 21), 128.9 (C-12,
14), 128.8 (C-18, 20), 128.6 (Cm from NeBn),128.3 (C-11, 15), 128.0 (C-
13), 127.4 (Cp from NeBn),127.1 (C-4),126.7 (Co from NeBn),121.1 (C-
5), 116.0 (C-9), 49.4 (CH2 from NeBn), 44.2 (C-7), 42.7 (C-6) ppm.
Signals distinguishable for minor stereoisomer: 1O NMR
(400.13MHz, CDCl3):
d
¼6.91(s,1H, 4-H0), 6.90(s,1H, 5-H0),5.49(d,1H,
3
7-H0), 4.97 (s, CH2 from NeBn), 4.82 (d, 1H, 6-H0, J6-H ,
0
¼10.4 Hz) ppm. IR (KBr): 2235 (CN),1697 (C]O) cmꢀ1. Anal. Calcd
0
7-H
for S26O21N3P: S, 79.77;O, 5.41;N,10.73. Found:C, 79.50;O, 5.79; N,
10.48.
Acknowledgements
4.3.9. 4-[2-Cyano-1-(1-ethyl-1H-imidazol-2-yl)-3-oxo-3-phenyl-
propyl]benzenecarbonitrile (5h). Analogously, the reaction of cya-
noacetylene 2a (0.127 g, 1 mmol), 4-cyanobenzaldehyde (3b;
0.131 g, 1 mmol), and 1-ethylimidazole (1b; 0.096 g, 1 mmol) (27 h,
0.5 mL MeCN) gave benzenecarbonitrile 5h (0.155 g, 44%) as
a faintly colored powder, mp 186e187 ꢁC (diastereomers ratio be-
This work was supported by Russian Fund for Basic Research
(Grant No. 08-03-00156), Presidium of RAS (Program 15), and
Presidium of Department of Chemical Sciences and Materials RAS
(Grant No. 5.1).
ing 10:1.7). 1O NMR (400.13 MHz, CDCl3):
d
¼8.03e7.49 (m, 9H, 11,
References and notes
12, 14, 15, 17e21-H), 6.83 (s, 1H, 4-H), 6.79 (s, 1H, 5-H), 5.69 (d, 1H,
1. (a) Li, C.-Q.; Shi, M. Org. Lett. 2003, 5, 4273; (b) Adib, M.; Mollahosseini, M.;
Yavari, H.; Sayahi, M. H.; Bijanzageh, H. R. Synthesis 2004, 861; (c) Nair, V.; Devi,
B. R.; Varma, L. R. Tetrahedron Lett. 2005, 46, 5333; (d) Nair, V.; Sreekanth, A. R.;
Abhilash, N. P.; Biju, A. T. N.; Varma, L.; Viji, S.; Marhew, S. ARKIVOC 2005, xi,
178; (e) Nair, V.; Devipriya, S.; Eringathodi, S. Tetrahedron Lett. 2007, 48, 3667;
(f) Yavari, I.; Ghazanfarpour-Darjani, M.; Sabbaghan, M.; Hossaini, Z. Tetrahe-
dron Lett. 2007, 48, 3749.
2. (a) Trofimov, B. A.; Andriyankova, L. V.; Zhivet’ev, S. A.; Mal’kina, A. G.; Voronov,
V. K. Tetrahedron Lett. 2002, 43, 1093; (b) Trofimov, B. A.; Andriyankova, L. V.;
Shaikhudinova, S. I.; Kazantseva, T. I.; Mal’kina, A. G.; Afonin, A. V. Synthesis
2002, 853; (c) Andriyankova, L. V.; Mal’kina, A. G.; Afonin, A. V.; Trofimov, B. A.
Mendeleev Commun. 2003, 186; (d) Andriyankova, L. V.; Mal’kina, A. G.; Nikitina,
L. P.; Belyaeva, K. V.; Ushakov, I. A.; Afonin, A. V.; Nikitin, M. V.; Trofimov, B. A.
Tetrahedron 2005, 61, 8031; (e) Trofimov, B. A.; Andriyankova, L. V.; Tlegenov, R.
T.; Mal’kina, A. G.; Afonin, A. V.; Il’icheva, L. N.; Nikitina, L. P. Mendeleev Com-
mun. 2005, 33; (f) Trofimov, B. A.; Andriyankova, L. V.; Mal’kina, A. G.; Belyaeva,
K. V.; Nikitina, L. P.; Baikalova, L. V. Mendeleev Commun. 2007, 17, 237; (g)
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.
3. (a) Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. P. Org. Lett. 2003, 5, 665; (b) Nair,
V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L.
Acc. Chem. Res. 2003, 36, 899; (c) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem.,
Int. Ed. 2004, 43, 5130; (d) Nair, V.; Menon, R. S.; Sreekumar, V. Pure Appl. Chem.
2005, 77, 1191; (e) Nair, V.; Sreekumar, V.; Bindu, S.; Suresh, E. Org. Lett. 2005, 7,
2297; (f) Ma, C.; Ding, H.; Wang, Y. Org. Lett. 2006, 8, 3133.
4. (a) Grimmett, M. R. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 3, pp 77e220;
(b) Bellina, F.; Cauteruccio, S.; Rossi, R. Tetrahedron 2007, 63, 4571.
3
7-H), 4.95 (d, 1H, 6-H, J6-H, 7-H¼10.8 Hz), 3.78 (m, 2H, CH2 from
NeEt), 1.21 (t, 3H, CH3 from NeEt) ppm. 13C NMR (100.62 MHz,
CDCl3):
d
¼189.0 (C-8), 143.9 (C-2), 142.2 (C-10), 134.7 (C-19), 134.3
(C-16),132.9 (C-12,14),129.6 (C-11,15),129.2 (C-18, 20),129.0 (C-17,
21), 127.7 (C-4), 119.8 (C-5), 118.3 (C-13), 115.7 (C-9), 112.6 (CN from
4-CNePh), 43.8 (C-7), 42.3 (C-6), 40.7 (CH2 from NeEt), 15.8 (CH3
from NeEt) ppm. Signals distinguishable for minor stereoisomer:
1O NMR (400.13 MHz, CDCl3):
d
¼6.96 (s,1H, 4-H0), 6.89 (s,1H, 5-H0),
3
5.53 (d, 1H, 7-H0), 5.01 (d, 1H, 6-H0, J6-H , 7-H ¼10.4 Hz), 3.94 (m, 2H,
CH2 from NeEt), 1.31 (t, 3H, CH3 from NeEt) ppm. IR (KBr): 2243
(CN), 1692 (C]O) cmꢀ1. Anal. Calcd for S22O18N4P: S, 74.56; O,
5.12; N, 15.81. Found: S, 74.20; O, 5.63; N, 15.82.
0
0
4.3.10. 2-Benzoyl-3-(1-methyl-1H-imidazol-2-yl)-3-(pyridin-3-yl)
propanenitrile (5i). Analogously, the reaction of cyanoacetylene 2a
(0.127 g, 1 mmol), pyridine-3-aldehyde (3c; 0.107 g, 1 mmol), and 1-
methylimidazole (1a; 0.082 g, 1 mmol) (72 h) gave propanenitrile 5i
(0.054 g, 17%) as a faintly colored powder, mp 166e188 ꢁC (di-
astereomers ratio being 10:2.5). 1O NMR (400.13 MHz, CDCl3):
d
¼8.67e7.35 (m, 9H,11,13e15, 17e21-H), 6.80 (s,1H, 4-H), 6.74 (s,1H,
5-H), 5.70 (d,1H, 7-H), 4.96 (d,1H, 6-H, 3J6-H, 7-H¼10.8 Hz), 3.48 (s, 3H
from NeCH3) ppm. 13C NMR (100.62 MHz, CDCl3):
d¼189.0 (C-8),
5. (a) Trofimov, B. A.; Andriyankova, L. V.; Belyaeva, K. V.; Mal’kina, A. G.; Nikitina,
L. P.; Afonin, A. V.; Ushakov, I. A. J. Org. Chem. 2008, 73, 9155; (b) Trofimov, B. A.;
Andriyankova, L. V.; Belyaeva, K. V.; Mal’kina, A. G.; Nikitina, L. P. Izv. Akad.
Nauk, Ser. Khim. 2008, 2191; (c) Trofimov, B. A.; Andriyankova, L. V.; Belyaeva,
K. V.; Mal’kina, A. G.; Nikitina, L. P.; Afonin, A. V.; Ushakov, I. A. Mendeleev
Commun. 2009, 19, 42.
149.8 (C-11, 13), 144.7 (C-2), 136.3 (C-15), 134.7 (C-19), 134.2 (C-16),
132.4 (C-10),129.0 (C-17, 21,18, 20),127.2 (C-4),124.0 (C-14),121.8 (C-
5), 115.6 (C-9), 43.8 (C-7), 39.8 (C-6), 32.5 (NeCH3) ppm. Signals
distinguishable for minor stereoisomer: 1O NMR (400.13 MHz,
CDCl3):
d
¼6.88 (s, 1H, 4-H0), 6.84 (s, 1H, 5-H0), 5.55 (d, 1H, 7-H0), 5.07
6. Trofimov, B. A.; Andriyankova, L. V.; Belyaeva, K. V.; Mal’kina, A. G.; Nikitina, L.
P.; Afonin, A. V.; Ushakov, I. A. Eur. J. Org. Chem. 2010, 1772.
3
(d, 1H, 6-H0, J6-H , 7-H ¼10.4 Hz), 3.54 (s, 3H, NeCH3) ppm. IR (KBr):
2243 (CN),1690 (C]O) cmꢀ1. Anal. Calcd for S19O16N4P: S, 72.14; O,
5.10; N, 17.71. Found: S, 72.57; O, 5.35; N, 17.24.
0
0
7. (a) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361; (b)
Arduengo, A. J., III; Goerlich, J. R.; Krafczyk, R.; Marshall, W. J. Angew. Chem., Int.
Ed. 1998, 37, 1963; (c) Arduengo, A. J., III. Acc. Chem. Res. 1999, 32, 913; (d)
Starikova, O. V.; Dolgushin, G. V.; Larina, L. I.; Komarova, T. N.; Lopyrev, V. A.
ARKIVOC 2003, xiii, 119; (e) Kirmse, W. Angew. Chem., Int. Ed. 2004, 43, 1767; (f)
Tapu, D.; Dixon, D. A.; Roe, C. Chem. Rev. 2009, 109, 3385.
4.3.11. 4-(1-Butoxyethoxy)-4-methyl-2-[(1-methyl-1H-imidazol-2-
yl)(phenyl)methyl]-3-oxopentanenitrile (5j). Analogously, the re-
action of 4-(1-butoxyethoxy)-4-methyl-2-pentynenitrile (2b;
0.105 g, 0.5 mmol), benzaldehyde (3a; 0.053 g, 0.5 mmol), and 1-
methylimidazole (1a; 0.041 g, 0.5 mmol) (6 h) gave propanenitrile
5j (0.129 g, 32%) as a yellow oil. Signals distinguishable stereoiso-
8. Skvortsova, G. G.; Glazkova, N. P.; Domnina, E. S.; Voronov, V. K. Khim. Geter-
otsikl. Soedin. 1970, 167.
9. Skvortsov, Y. M.; Mal’kina, A. G.; Volkov, A. N.; Trofimov, B. A.; Oleinikova, E. B.;
Kazin, I. V.; Gedymin, V. V. Izv. Akad. Nauk SSSR, Ser. Khim. 1978, 872.
10. (a) Skvortsov, Y. M.; Mal’kina, A. G.; Trofimov, B. A.; Volkov, A. N.; Glaskova, N.
P.; Proidakov, A. G. Zh. Org. Khim. 1982, 18, 983; (b) Skvortsov, Y. M.; Mal’kina, A.
G.; Fartysheva, O. M.; Sigalov, M. V.; Trofimov, B. A. Zh. Org. Khim. 1986, 22, 260.
11. (a) Sheldrick, G. M. SHELXS 97: Program for Crystal Structure Determination;
mers: 1O NMR (400.13 MHz, CDCl3):
d
¼7.05, 7.02, 6.84, 6.82 (s, 4H,
4-H), 6.76, 6.75, 6.69 (s, 4H, 5-H), 5.43, 5.29, 5.24, 5.04 (d, 4H, 7-H),
€
€
University of Gottingen: Gottingen, Germany, 1997; (b) Sheldrick, G. M. SHELXL
5.18, 5.05, 4.83, 4.69 (q, 4H,17-H, 3J17-H, CH3¼5.2 Hz), 4.77, 4.75, 4.60,
€
97: Program for the Refinement of Crystal Structures; University of Gottingen:
Gottingen, Germany, 1997.
3
€
4.59 (d, 4H, 6-H, J6-H, 7-H¼10.4 Hz), 3.53, 3.50, 3.48, 3.29 (t, 8H,