Three-component reaction between imidazoles, isocyanates, and cyanophenylacetylene: A short-cut to N-(Z)-alkenylimidazole-2-carboxamides

Article abstract of DOI:10.1016/j.tetlet.2012.10.049

1-Substituted imidazoles, isocyanates, and cyanophenylacetylene react under mild (rt), non-catalytic solvent-free conditions to give (Z)-(2-cyano-1- phenylethenyl)imidazole-2-carboxamides in up to 72% yields and with ca. 100% stereoselectivity. The reaction starts from the initial formation of zwitterion/carbene intermediates captured by the isocyanate as the electrophile followed by migration of the alkenyl moiety from the N-3 atom to the anionic center at the carboxamide nitrogen. Thus, the reaction provides an easy access to a novel family of functionalized imidazoles.

Full text of DOI:10.1016/j.tetlet.2012.10.049

Tetrahedron Letters 53 (2012) 7040–7043
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Three-component reaction between imidazoles, isocyanates, and
cyanophenylacetylene: a short-cut to N-(Z)-alkenylimidazole-2-carboxamides
Kseniya V. Belyaeva, Ludmila V. Andriyankova, 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
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2012
Revised 18 September 2012
Accepted 11 October 2012
Available online 22 October 2012
1-Substituted imidazoles, isocyanates, and cyanophenylacetylene react under mild (rt), non-catalytic sol-
vent-free conditions to give (Z)-(2-cyano-1-phenylethenyl)imidazole-2-carboxamides in up to 72% yields
and with ca. 100% stereoselectivity. The reaction starts from the initial formation of zwitterion/carbene
intermediates captured by the isocyanate as the electrophile followed by migration of the alkenyl moiety
from the N-3 atom to the anionic center at the carboxamide nitrogen. Thus, the reaction provides an easy
access to a novel family of functionalized imidazoles.
Keywords:
Acetylene
Ó 2012 Elsevier Ltd. All rights reserved.
Imidazoles
Isocyanates
Multicomponent reactions
Zwitterion/carbene intermediates
R2
Functionalized imidazoles are known to be a source of a diver-
sity of biochemically important species such as the essential amino
acids, vitamins, alkaloids, drugs, and their precursors including his-
tidine, histamine, allantoin, pilocarpine, etc.1,2 Imidazole-tailored
pharmaceuticals such as cimetidine (an inhibitor of gastric acid
secretion), etomidate (an anesthetic), ketoconazole (an antifungal
medication),2–4 eprosartan and losartan (antihypertensives), and
metronidazole (a chemotherapeutic)5 are commonly used in
clinics. A number of imidazole derivatives exhibit antithrombic,6
antiproliferative,7 antihelminthic, antitumor, fungicidal, and anti-
inflammatory8,9 properties. Among functionalized imidazoles, rep-
resentatives with carboxamide functionality are less well studied
although they deserve much more attention in view of the fact that
dacarbazine, a novel antitumor drug, contains the carboxamide
function in the imidazole ring.5 Some imidazole-2-carboxamides
were reported to act as human CB1 receptor inverse agonists,10
that is, as promising anti-obesity and antidiabetes pharmaceuti-
cals. However, they were synthesized via 4 or 5 steps using a high
temperature (180–220 °C), benzoin cyclization or condensation,
chlorination with phosphorus oxychloride, lithiation with BuLi,
and reduction over Pd/C in an overall yield of about 20%.
+
EWG
N
N
+ R2
EWG
R3
N C O
+
N
R3
N
N
R1
_
O
R1
EWG - electron-withdrawing group
A
Scheme 1. Generation of imidazole carboxamide zwitterions A.
precursors upon melting, or in solution. Imidazoles react with iso-
cyanates upon boiling in nitrobenzene (210 °C) or diphenyl ether
(259 °C) to give imidazole-2-carboxamides in 18–92% yields
depending on the structures of the starting materials.13 Later, the
carboxamide function was introduced elegantly into position 2 of
the imidazole ring via lithiation of 1-(dimethylaminomethyl)imid-
azole with BuLi followed by the treatment with an isocyanate.14
This strategy was further developed to synthesize imidazole-2,
5-dicarboxamides.15 1,3-Dimethylimidazolium-2-carboxylate and
4-carboxylate on decarboxylation generate the corresponding
carbenes, imidazol-2-ylidene and imidazol-4-ylidene, which are
trapped by isocyanates to give imidazolium-amidates.16 Another
type of imidazolium carbene or its zwitterionic precursors origi-
nated from the nucleophilic addition of 1-substituted imidazoles
to electron-deficient acetylenes. Interception of these carbenes or
the preceding zwitterions by an appropriate electrophile is the
key step of a rapidly developing general synthetic strategy for
the functionalization of imidazole rings.17–21 Therefore, the
three-component reactions between 1-substituted imidazoles,
The reactions of imidazoles with isocyanates allow imidazole
carboxamides to be synthesized in a one-pot procedure,11,12
although unsubstituted imidazoles under mild conditions lead only
to imidazole-1-carboxamides, which partially dissociate into their
⇑
Corresponding author. Fax: +7 395 2 41 93 46.
E-mail address: boris_trofimov@irioch.irk.ru (B.A. Trofimov).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.049

K. V. Belyaeva et al. / Tetrahedron Letters 53 (2012) 7040–7043
7041
R1O2C
N
Meanwhile, against expectations, the above reaction with acet-
ylenedicarboxylates (rt, CH2Cl2, 1 h) was reported to furnish tetra-
hydroimidazo[1,2-a]pyrimidines B22 (Scheme 2).
However, when acetylenic ketones were employed as the
acetylenic components (rt, CH2Cl2, 24 h) in this reaction, imidazole
-2-carboxamides C were actually obtained, presumably via inter-
mediates of type A23 (Scheme 3).
CO2R1
O
N
CH2Cl2
1 h, rt
R1O2C
CO2R1
R2
N C O
+
+
N
N
N
R2
Me
R1 = Me, Et;
R2 = Et, Ph, 3,4-diCl-C6H3, 4-Me-3-Cl-C6H3
Me
B
Thus, it became clear that the outcome of this three-component
reaction depends strongly on the structure of the starting materi-
als, first of all, on the acetylene and on the reaction conditions.
In the light of these results we have undertaken a study of the
three-component reaction between 1-substituted imidazoles 1a–
d, isocyanates 2a,b, and cyanophenylacetylene 3 aiming at, (i)
the synthesis of a novel family of imidazole-2-carboxamides with
an acrylonitrile substituent on the amide nitrogen (Table 1), (ii) the
evaluation of the competition between imidazole-2-carboxamide
4a–h formation and C(2)-vinylation with cyanophenylacetylene
and, (iii) the simultaneous synthesis of (Z)-2-(2-cyano-1-phenyl-
ethenyl) imidazoles 5a–d.
Scheme 2. Synthesis of tetrahydroimidazo[1,2-a]pyrimidines B.
R3
N
R2
O
N
N
CH2Cl2
24 h, rt
H
+
R3
N
C
O
R2
+
N
N
R1
R1
O
O
C
R1 = Me, Bn;
2 = n-C6H13, PhCH=CH, Ph, Ar, 2-Furyl;
R3 = Cyclohexyl, Ar, EtOCOCH2
R
Scheme 3. Synthesis of imidazole-2-carboxamides C.
The reaction was carried out at room temperature without a
catalyst or solvent for 24–48 h; the reactant-molar ratio was
1:1:1. The order of mixing the reactants was important. First, cyan-
ophenylacetylene was dissolved in the isocyanate and then the
isocyanates, and electron-deficient acetylenes might be expected to
lead to the corresponding zwitterionic forms of the imidazole car-
boxamides A, similar to those described previously16 (Scheme 1).
Table 1
Synthesis of (Z)-(2-cyano-1-phenylethenyl)imidazole-2-carboxamides 4a–h
Ph
R2 CN
N
N
3
rt
24-48 h
CN
+
N
N
O
N
C
R1
O
Ph
R1
N
R2
2a,b
1a-d
4a-h
Imidazole
Isocyanate
Time (h)
Imidazole-2-carboxamide
Isolated yielda (%)
50
N
Et
N
CN
CN
CN
N
1a
1b
1c
1d
1a
1b
1c
1d
Et-N@C@O
2a
24
48
24
24
48
48
48
48
4a
4b
4c
4d
4e
4f
N
Me
N
N
O
O
O
O
O
O
O
O
Ph
Ph
Me
Et
N
N
Et-N@C@O
Et-N@C@O
Et-N@C@O
Ph-N@C@O
Ph-N@C@O
Ph-N@C@O
Ph-N@C@O
2a
2a
2a
2b
2b
2b
2b
65
N
Et
N
N
Et
Et
N
N
28
N
Allyl
N
Allyl
Ph
Ph
N
Et
N
CN
N
55b
72
N
Bn
N
Bn
N
Ph
N
CN
CN
CN
N
N
Me
N
N
Ph
Ph
Me
Ph
N
N
34
N
Et
N
N
Et
Ph
N
N
4g
4h
39
N
Allyl
N
Ph
CN
Allyl
N
Ph
N
N
69b
N
Bn
N
Bn
Ph
a
Based on imidazole 1.
For homogenization, 0.1 mL of MeCN was added to the reaction mixture (1:1:1 mmol).
b

7042
K. V. Belyaeva et al. / Tetrahedron Letters 53 (2012) 7040–7043
N
N
process was previously observed for the binary reaction between
1-substituted imidazoles and cyanophenylacetylene.24,25
Ph
+
Ph
CN
N
N
3
In some cases, N,N0-disubstituted carbamides 6a,b were isolated
from the reaction mixture. This definitely had resulted from the
commonly known hydrolytic decomposition (due to the adventi-
tious water) of the isocyanates 2a,b to carbon dioxide and amines
which then add to a second molecule of the isocyanate (Scheme 5).26
The structures of the imidazole-2-carboxamides 4a–h were
unambiguously assigned by 1H, 13C, 2D NMR, and IR spectroscopy.
In their 1H NMR spectra, the ethenyl protons H-9 appear as singlets
in the d 5.37–5.47 region. In the 13C NMR spectra, the ethenyl car-
bons C-8 and C-9 resonate at d 160.8–161.8 and d 92.9–93.4,
respectively, the C-6 carbons were observed at d 160.3–160.9 and
the CN carbons at d 116.1–116.6. In the NOESY spectra of carbox-
amides 4a–h, the correlation between the olefinic H-9 and the
ortho-protons of the phenyl ring was manifested in support of
the Z-configuration of the 2-cyano-1-phenylethenyl moiety
(Fig. 1). In the IR spectra of carboxamides 4a–h, the CBN and
C@O stretching vibrations appeared at 2213–2216 and 1655–
1670 cmꢀ1, respectively, the stretching vibration bands of the
C@C bond of the ethenyl moiety overlapped with the imidazole
R1
1a-d
R1
NC
5a-d
Scheme 4. Synthesis of (Z)-2-(2-cyano-1-phenylethenyl)imidazoles 5a–d.
R2 R2
O
H2O
H
N
2a,b
N
N
R2
N C O
2a,b
R2 NH2
R2
C
H
H
-CO2
OH
O
6a,b
Scheme 5. Formation of the N,N’-disubstituted carbamides 6a,b.
3
R2 CN
4
N
9
1
6
N 8
5
H
2
N
7
R1
O
(Z)-4a-h
and benzene ring C@C stretching at 1601–1607 cmꢀ1
.
Figure 1. Cross-peaks in the 2D NOESY spectra of imidazole-2-carboxamides 4a–h.
One of the plausible mechanisms for the formation of imidazole-
2-carboxamides is assumed to involve the zwitterionic intermediate
D, the adduct of the starting imidazole with cyanophenylacetylene,
which undergoes proton transfer from position 2 to the carbanionic
center to generate the carbene E. Due to the unfavorable trans-
orientation of the carbanionic site relative to the imidazole ring, this
process most probably occurs in an intermolecular manner (instead
of the intramolecular). The stereochemistry of a zwitterion D is the
expected result of a concerted nucleophilic addition to the triple
bond, which is known to be trans-oriented relative to the attacking
nucleophile and the proton donor species.27,28 The intermediate E
is then likely intercepted by the isocyanate molecule to form
zwitterion F with the ambident N,O-anionic moiety. The migration
of a cyanophenylethenyl radical from position 3 to the anionic nitro-
gen atom in the intermediate F entails the functionalization of the
imidazole ring (Scheme 6). Given the high stereoselectivity of this
process, it might be expected to proceed in a consistent fashion, that
is., the CN-3 bond cleavage is accompanied by simultaneous
formation of the N (of the anionic carboxamide moiety)-C bond.
Such a concerted migration explains the Z-stereochemistry of the
migrating alkenyl group.
imidazole was added. Mixing of the imidazole with cyanophenyl-
acetylene prior to the addition of an electrophile favored a compet-
itive binary C(2)-vinylation reaction24,25 (see below). The progress
of the reaction was followed by IR spectroscopy until the disap-
pearance of the absorption bands at 2250–2270 cmꢀ1 belonging
to the isocyanate N@C@O entity and CN bond attached to the acet-
ylene moiety was complete. The products were isolated by column
chromatography (neutral Al2O3 with chloroform/benzene/ethanol,
20:4:1, as eluent).
The major products were imidazole-2-carboxamides 4a–h iso-
lated in 28–72% yields (Table 1) based on imidazole 1. In some
cases, when starting imidazole was recovered, for example, for car-
boxamides 4d, 4e, 4f, and 4g, the yields when calculated on the
imidazole reacted were 73%, 98%, 55%, and 65%, respectively.
The Z-stereoselectivity of the reaction was always close to 100%
(in no case was the E-isomer detected in the 1H NMR spectrum of
the reaction mixture). This high stereoselectivity, allowing for the
first time the introduction of a (Z)-2-cyanophenylethenyl moiety
into the carboxamide function of 1-substituted imidazoles, repre-
sents an obvious advantage of this synthesis. Its other benefit, unlike
the procedures relating to similar reactions,22,23 is the solvent-free,
‘green’, ecologically benign protocol. As distinct to the recent reports
on similar reactions, we have detected a competitive stereoselective
vinylation of imidazole position 2 with an electron-deficient acety-
lene (cyanophenylacetylene) to deliver (Z)-2-(2-cyano-1-phenyl-
ethenyl)imidazoles 5a–d in trace to 37% yields (Scheme 4). This
The possible addition/elimination alternative23 might compro-
mise the stereoselectivity owing to the free rotation along the pseu-
do-ordinary C–C bond thus temporarily formed (cf. intermediate
rotamers G and H), Scheme 7. However, the absence of the (E)-4
isomer in the reaction mixture (1H NMR) may not provide the ulti-
mate argument against the addition/elimination process provided
NC
_
NC
N
Ph
Ph
Ph
Ph
N
R2
+
_
+
_
+
Ph
N
N
N
+
N
N
_
3
R2
2
CN
CN
CN
N
:
1
N
H
N
N
O
N
R1
R1
R1
R1
O
R1
NC
D
E
G
F
CN
_
Ph
+
R2
+
R2 CN
N
Ph
N
N
R2
N
R2
N
N
N
//
N
_
CN
N
N
N
N
O
R1
R1
O
R1
R1
O
Ph
O
Ph
(E)-4
F
4
H
Scheme 6. Tentative mechanism of imidazole-2-carboxamide 4a–h formation.
Scheme 7. Alternative mechanism of addition/elimination.

K. V. Belyaeva et al. / Tetrahedron Letters 53 (2012) 7040–7043
7043
Ph
Supplementary data
N
N
Ph
CN
Supplementary data (Experimental procedures for the prepara-
tion of compounds 4a–h and their spectroscopic characterization)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.10.049.
:
N
N
R1
R1
E
NC
5a-d
Scheme 8. 3,2-Stereoselective migration of the 1-phenyl-2-cyanoethenyl group.
References and notes
that the Z-isomers of the final products are much more thermody-
namically favorable over the E-isomers. At the same time, the
mutual disposition of CN and phenyl functions in the rotamer H does
not create any significant steric strain (as seen from Scheme 7) and
hence the E-isomers of the products seem not be thermodynami-
cally entirely forbidden. Nevertheless, the addition/elimination
alternative still may be operative due to the attractive interactions
between the positive and negative charges in the rotamer G that
retains the Z-configuration of the final products.
The quite different results for the same reaction with acetylen-
edicarboxylates22 may be explained by a better distribution of the
negative charge over the carboxylic group in the initial zwitterion
that makes the anionic site less basic and hence incapable of
abstracting a proton from position 2 of the imidazole ring.
The competitive C(2)-vinylation is likely to proceed via the con-
cordant 3,2-stereoselective migration (without loss of stereochem-
istry) of the 1-phenyl-2-cyanoethenyl group in the intermediate
E24,25 (Scheme 8).
In summary, we have disclosed that the three-component reac-
tion between 1-substituted imidazoles, alkyl- and arylisocyanates,
and cyanophenylacetylene proceeds at room temperature under
non-catalytic and solvent-free conditions to afford N-(Z)-alkenylim-
idazole-2-carboxamides in up to 72% yields. A particular synthetic
advantage of the reaction is its complete Z-stereoselectivity. The
reaction is accompanied by a minor competitive C(2)-vinylation of
the imidazole ring to give (Z)-2-(2-cyano-1-phenylethenyl)imida-
zoles in trace to 37% yields. In view of the high pharmacological
importance of imidazoles bearing carboxamide functions, the novel
representatives of this series synthesized with N-cyanoethenyl sub-
stituents are attractive precursors for targeted drug design. The
exploratory results obtained spread further the frontiers of the
new rapidly developing concept for functionalization of the imidaz-
ole scaffold, which is based on zwitterion/carbene intermediates,
the adducts of imidazoles with electron-deficient acetylenes.
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Acknowledgements
This work was supported by leading scientific schools by the
President of the Russian Federation (Grant NSh-1550.2012.3), Rus-
sian Fund for Basic Research (Grant No. 11-03-00203) and Presid-
ium of the Department of Chemical Sciences and Materials RAS
(Grant No. 5.1.3.).
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