A three-component reaction between 1-substituted-2-methylimidazoles, cyanophenylacetylene, and various aldehydes: Stereoselective synthesis of (Z)-(2-cyano-1-phenyl)vinyl ethers of 2-(2-hydroxyalkyl)imidazoles

Article abstract of DOI:10.1016/j.tetlet.2013.06.095

A three-component reaction between 1-substituted-2-methylimidazoles (1-Me, Bn), cyanophenylacetylene, and aliphatic (Me, i-Pr, n-Bu) and aromatic (Ph, 4-CN-, 4-O₂N-C₆H₄) aldehydes occurs without a catalyst or solvent at room temperature (20-25 C) to afford stereoselectively (Z)-(2-cyano-1-phenyl)vinyl ethers of 2-hydroxyalkylimidazoles in 26-57% yields.

Full text of DOI:10.1016/j.tetlet.2013.06.095

Tetrahedron Letters 54 (2013) 4693–4696
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A three-component reaction between 1-substituted-2-
methylimidazoles, cyanophenylacetylene, and various aldehydes:
stereoselective synthesis of (Z)-(2-cyano-1-phenyl)vinyl ethers
of 2-(2-hydroxyalkyl)imidazoles
⇑
Boris A. Trofimov , Ludmila V. Andriyankova, Lina P. Nikitina, Kseniya V. Belyaeva, Anastasiya G. Mal’kina,
Andrei V. Afonin, Igor’ A. Ushakov
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 12 February 2013
Revised 6 June 2013
Accepted 21 June 2013
Available online 29 June 2013
A three-component reaction between 1-substituted-2-methylimidazoles (1-Me, Bn), cyanophenylacety-
lene, and aliphatic (Me, i-Pr, n-Bu) and aromatic (Ph, 4-CN-, 4-O2N-C6H4) aldehydes occurs without a cat-
alyst or solvent at room temperature (20–25 °C) to afford stereoselectively (Z)-(2-cyano-1-phenyl)vinyl
ethers of 2-hydroxyalkylimidazoles in 26–57% yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Acetylene
Aldehydes
Imidazoles
Zwitterionic intermediates
Multicomponent reactions
Imidazole-based pharmaceuticals such as cimetidine (an inhib-
itor of gastric acid secretion), etomidate (an anesthetic), ketocona-
zole (an antifungal medication),1–3 eprosartan and losartan
(antihypertensives), and metronidazole (a chemotherapeutic)4
are used widely. A number of imidazole derivatives exhibit anti-
thrombic,5 antiproliferative,6 antihelminthic, antitumor, fungicidal,
and anti-inflammatory7,8 properties. Thus, significant efforts have
been focused on the development of new synthetic approaches
for imidazole ring functionalization.
Reactions between imidazoles and electron-deficient acetylenes
proceeding via zwitterionic or carbene intermediates have at-
tracted growing attention9–29 as simple and short routes to various
functionalized imidazoles. The key step of these reactions is proton
abstraction from position 2 of the imidazole by the anion of the ini-
tial zwitterion to generate carbene-like species, which is further
intercepted by an appropriate electrophile. However, similar pro-
ton abstraction from a methyl group, located at position 2 of the
imidazole ring, in the presence of electron-deficient acetylenes, re-
mains hitherto unknown.
of two molecules of DMAD at C-2, while methyl or ethyl substitu-
tents remained intact30,31 (Scheme 1).
The alkenylation of 1,2-dimethylimidazole with dipropylacety-
32
lene at position 5 in the presence of Ni(cod)2/PCyp3/AlMe3 or
Ni(cod)2/i-Pr3P/Ph-Zn-Ph33 has been reported.
In contrast, for 1,2-dimethylimidazoles, a limited number of
reactions involving deprotonation of the 2-methyl group are
known.34–38 They include the condensation with benzaldehyde un-
der the action of BuLi34 or aroyl chlorides in the presence of Et3N,35
as well as the three-component reaction between 1,2-dimethylim-
idazole, carbamoyl chloride and benzaldehyde.36 Also, 1-methyl-
2-alkylimidazoles add via the 2-alkyl group to the C@N bond of
N-tosylimine in the presence of Boc2O.37 Hydroxymethylation of
1,2-dimethylimidazole at the 2-methyl group using paraformalde-
hyde has also been described.38
These results prompted us to investigate the reactivity of the
2-methyl group of 1-substituted-2-methylimidazoles 1a,b in a
MeO2C
CO2Me
N
The reactions of 1-methyl-2-alkyl-substituted imidazoles with
dimethyl acetylenedicarboxylate (DMAD) proceed via annelation
2MeO2C
CO2Me
N
CO2Me
CO2Me
R
N
Me
R = Me, Et
Et2O, rt, 1 h
N
Me
R
⇑
Corresponding author. Fax: +7 395 2 41 93 46.
E-mail address: boris_trofimov@irioch.irk.ru (B.A. Trofimov).
Scheme 1. The annelation of 1-methyl-2-alkyl-substituted imidazoles with 2 equiv
of DMAD.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.095

4694
B. A. Trofimov et al. / Tetrahedron Letters 54 (2013) 4693–4696
three-component reaction with cyanophenylacetylene (2) and
aldehydes 3a–f. The hope was that the initial zwitterions, the ad-
ducts of the imidazoles with acetylene 2, would be able to abstract
a proton from the 2-methyl group, and that the new methylene-
centered carbanion would be intercepted by aldehydes as
electrophiles.
(C-10) and 171.1–172.7 (C-9) ppm, and the carbon of the CN-moi-
ety was detected at 116.1–116.7 ppm. Signals for the methyl group
at position 2 of the imidazole ring (1a,b) were absent in the 1H and
13C NMR spectra. This supports the fact that the C(2)-Me group of
the starting imidazole 1 participates in the reaction. The 15N NMR
spectrum (compound 4g, R1 = Bn, R2 = Me) contained the following
signals: À211.0 (N-1), À123.5 (N-3), and À120.2 ppm (nitrogen
atom at CN-11).
The Z-configuration of vinyl ethers 4 was confirmed by 2D NMR
spectroscopy (on the example of adduct 4h, R1 = Bn, R2 = Ph). In the
NOESY spectrum of vinyl ether 4h, cross-peaks between the alkene
proton (H-10) and the ortho-protons of the phenyl substituent at C-
9 were observed (Fig. 1).
This preliminary communication reports that the above reac-
tion sequence takes place to lead stereoselectively to (Z)-(2-cya-
no-1-phenyl)vinyl ethers of 2-hydroxyalkylimidazoles, that is,
(Z)-(imidazol-2-yl)organylethoxypropenenitriles 4a–h, in 26–57%
yields (Table 1). The reaction conditions were mild: no catalyst
or solvent was required with the reaction occurring at room tem-
perature. Molar ratio of the reactants 1:2:3 was 1:1:1, except for
the experiments with ethanal (3a) which was used in three-fold
excess. The conversions of the starting imidazoles ranged from
33% to 100%. The individual Z-stereoisomers of vinyl ethers 4a–h
were isolated by column chromatography (neutral Al2O3, chloro-
form/benzene/ethanol, 20:4:1, as eluent). Along with these prod-
ucts, oligomers of the same 1:1:1 composition were eluted in
4–29% yields, while some other oligomers, presumably those of
starting acetylene 2, remained on the adsorbent.
In the IR spectra of vinyl ethers 4a–h, absorption bands for the
CN, C@C and C–O–C bonds were present at 2214–2216, 1611–1619
and 1078–1098, and 1133–1151 cmÀ1, respectively.
In the 1H NMR and IR spectra of the eluted oligomers, character-
istic signals and absorption bands, similar to those of 1:1:1 vinyl
ethers 4a–h, were present, however, they were broad and con-
sisted of several close signals or bands.
Mechanistically, the assembly of vinyl ethers 4a–h is presum-
ably triggered by zwitterion A (Scheme 2), the adduct of imidazole
1 and cyanophenylacetylene (2), having the anionic center trans to
nitrogen (N-3) of the imidazole.39,40 The next step is proton
abstraction from the 2-methyl group by the anionic center of inter-
mediate A, to generate CH2-centered carbanion B. Intramolecular
proton transfer might be impossible due to the Z-configuration of
zwitterion A. The proton transfer should be facilitated in this case
The structures of vinyl ethers 4 were proved unambiguously by
1H, 13C, 15N NMR, 2D (NOESY), and IR spectroscopy.
In the 1H NMR spectra of vinyl ethers 4a–h, the alkene proton
(H-10) was present as a singlet in the region 4.63–4.82 ppm, the
two methylene protons at C-6 were observed as a doublet of dou-
blets at 2.90–3.13 and 3.04–3.43 ppm. In the 13C NMR spectra, the
carbons of the alkene fragment resonated in the regions 78.7–84.6
Table 1
Three-component reaction of 1,2-disubstituted imidazoles 1a,b, cyanophenylacetylene (2), and aldehydes 3a–f
20-25 oC
24-48 h
Ph
N
R2
O
O
N
+
+ R2
CN
Me Ph
N
N
2
3a-f
R1
1a,b
R1
CN
4a-h
1: R1 = Me (a), Bn (b);
3: R2 = Me(a), i-Pr (b), n-Bu (c), Ph (d), 4-CN-C6H4 (e), 4-O2N-C6H4 (f)
R1
R2
Product
Me Ph
Time (h)
24
Conversion of 1 (%)
Yielda (%)
26
N
4a
4b
4c
4d
O
Me
Me
N
Me
60
CN
i-Pr Ph
N
N
Me
O
Me
Me
Me
i-Pr
n-Bu
Ph
24
24
24
66
67
79
57
26
30
CN
n-BuPh
N
N
O
CN
Me
Ph Ph
O
N
N
Me
CN
4-CN
C6H4Ph
O
N
N
Me
48b
26b
4e
4f
Me
Me
4-CN-C6H4
24
24
100
33
CN
4-NO2
C6H4 Ph
O
N
N
Me
4-O2N-C6H4
CN
Me Ph
O
N
N
Bn
N
N
Bn
4g
4h
Bn
Bn
Me
Ph
48
48
100
100
49
51
CN
Ph Ph
O
CN
a
Based on consumed imidazole 1.
MeCN was added to homogenize the reaction mixture.
b

B. A. Trofimov et al. / Tetrahedron Letters 54 (2013) 4693–4696
4695
ophenylacetylene, and aldehydes, the latter including aliphatic
and aromatic (with cyano and nitro substituents) examples. The
key step is the unprecedented deprotonation of the 2-methyl
group by the anionic site of the initial zwitterion (the adduct of
the imidazole and cyanophenylacetylene). The products synthe-
sized combine reactive enol, acrylonitrile, and styrene structural
units and represent interesting precursors of new imidazole-based
drugs.
3
4
5
Ph
N
9
8
1
6
H
2
O
7
N
10
H H
CN
Bn
11
4h
Z-configuration
Figure 1. Cross-peaks in the 2D NOESY spectrum of vinyl ether 4h.
Ph
Ph
NC
N
Acknowledgements
H
_
+
+
Ph
+
N
N
N
O
_
CN
H
CN
CH2
_
3
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).
4
1 + 2
C
H
R2
N
N
H
R1
R1
R1
A
B
C
Scheme 2. A plausible mechanism for the three-component assembly of vinyl
ethers 4 from imidazoles 1, cyanophenylacetylene (2), and aldehydes 3.
Supplementary data
by the enhanced CH-acidity of the 2-methyl group adjacent to the
positive charge at the N-3 atom. The intermediate B is then inter-
cepted by the aldehyde to give the oxygen-centered zwitterion C,
which undergoes rearrangement with migration of the positively
charged vinyl moiety onto the oxygen anionic center to give vinyl
ethers 4a–h. The retention of the Z-configuration of the vinyl group
implies a concerted character for the migration.
The alternative addition/elimination mechanism (Scheme 3)
seems to be less probable, since in this case the stereoselectivity
would be compromised due to free rotation about the single C–C
bond in the intermediate zwitterion D.
The 1:1:1 oligomer formation may result from oligomerization
or cyclooligomerization of intermediate C in its resonance form in a
head-to-tail manner (Scheme 4).
As previously mentioned, the eluted oligomers, apart from the
1H NMR signals and IR bands being close to those of vinyl ethers
4a–h, contained a CBN band (2157–2205 cmÀ1) which is absent
in the IR spectra of vinyl ethers 4a–h and may be attributed to
the CN vinyl moiety in the oligomers.
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.2013.06.095.
References and notes
1. Bellina, F.; Cauteruccio, S.; Rossi, R. Tetrahedron 2007, 63, 4571–4624.
2. Sneyd, J. R. Curr. Pharm. Des. 2012, 18, 6253–6256.
3. Bhattacharyya, A.; Bajpai, M. Int. J. Pharm. Sci. Nanotechnol. 2013, 5, 1858–1865.
4. Kleeman, A.; Engel, J. In Pharmaceutical Substances (Syntheses, Patents,
Applications); Kutscher, B., Reicher, D., Eds.; ; Thieme: Stuttgart, New York,
2001; Vol. 1.
5. Chandra, T.; Brown, K. L. Tetrahedron Lett. 2005, 46, 8617–8619.
6. Leal, A. S.; Wang, R.; Salvador, J. A. R.; Jing, Y. Org. Biomol. Chem. 2013, 11, 1726–
1738.
7. Gomha, S. M.; Riyadh, S. M.; Abbas, I. M.; Bauomi, M. A. Heterocycles 2013, 87,
341–356.
8. Narasimhan, B.; Sharma, D.; Kumar, P. Med. Chem. Res. 2011, 20, 1119–1140.
9. Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. P. Org. Lett. 2003, 5, 665–667.
10. Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.;
Balagopar, L. Acc. Chem. Res. 2003, 36, 899–907.
11. Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130–5135.
12. Adib, M.; Mollahosseini, M.; Yavari, H.; Sayahi, M. H.; Bijanzadeh, H. R. Synlett
2004, 1086–1088.
13. Nair, V.; Menon, R. S.; Sreekumar, V. Pure Appl. Chem. 2005, 77, 1191–1198.
14. Nair, V.; Sreekumar, V.; Suresh, E. Org. Lett. 2005, 7, 2297–2300.
15. Adib, M.; Sheibani, E.; Mostofi, M.; Dhanbary, K.; Bijanzadeh, H. R. Tetrahedron
2006, 62, 3435–3438.
In conclusion, a novel method for functionalization of an imid-
azole ring with an alkyl cyanovinyl moiety, which is able to under-
go further transformations has been elaborated. The process is a
facile and eco-friendly (catalyst- and solvents-free) three-compo-
nent reaction between 1-substituted-2-methylimidazoles, cyan-
16. Ma, C.; Ding, H.; Wang, Y. Org. Lett. 2006, 8, 3133–3136.
17. Yavari, I.; Mirzaei, A.; Moradi, L.; Hosseini, N. Tetrahedron Lett. 2008, 49, 2355–
2358.
CN
_
NC
18. 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, 9155–9157.
19. 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, 42–44.
20. Yavari, I.; Mirzaei, A.; Hossaini, Z.; Souri, S. Mol. Divers. 2010, 14, 343–347.
21. Xia, E.-Y.; Sun, J.; Yao, R.; Yan, C.-G. Tetrahedron 2010, 66, 3569–3574.
22. 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, 1772–1777.
23. Moafi, L.; Ahadi, S.; Khavasi, H. R.; Bazgir, A. Synthesis 2011, 1399–1402.
24. Trofimov, B. A.; Andriyankova, L. V.; Belyaeva, K. V.; Mal’kina, A. G.; Nikitina, L.
P.; Dyachenko, O. A.; Kazheva, O. N.; Alexandrov, G. G.; Shilov, G. V.; Afonin, A.
V.; Ushakov, I. A. Tetrahedron 2011, 67, 1288–1293.
_
Ph
O
Ph
O
NC
Ph
_
+
+
+
N
N
N
O
elimination
addition
R2
R2
R2
N
N
N
R1
C
D
R1
D'
R1
R2 Ph
O
R2 Ph
O
N
N
CN
+
N
N
R1
R1
CN
(Z)-4a-h
(E)
25. Belyaeva, K. V.; Andriyankova, L. V.; Nikitina, L. P.; Ivanov, A. V.; Afonin, A. V.;
Ushakov, I. A.; Mal’kina, A. G.; Mikhaleva, A. I.; Trofimov, B. A. Synthesis 2011,
2843–2847.
Scheme 3. An alternative addition/elimination mechanism for the formation of
vinyl ethers 4.
26. Andriyankova, L. V.; Belyaeva, K. V.; Nikitina, L. P.; Mal’kina, A. G.; Vakul’skaya,
T. I.; Khutsishvili, S. S.; Sinegovskaya, L. M.; Trofimov, B. A. Chem. Heterocycl.
Compd. 2012, 47, 1390–1394.
Ph
+
27. Trofimov, B. A.; Andriyankova, L. V.; Belyaeva, K. V. Chem. Heterocycl. Compd.
2012, 48, 147–154.
28. Trofimov, B. A.; Andriyankova, L. V.; Nikitina, L. P.; Belyaeva, K. V.; Mal’kina, A.
G.; Afonin, A. V.; Ushakov, I. A. Synlett 2012, 2069–2072.
29. Belyaeva, K. V.; Andriyankova, L. V.; Nikitina, L. P.; Mal’kina, A. G.; Afonin, A. V.;
Trofimov, B. A. Tetrahedron Lett. 2012, 53, 7040–7043.
30. Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1932, 498, 1–49.
31. Crabtree, A.; Johnson, A. W. J. Chem. Soc. 1962, 1510–1512.
Ph
CN
CN
_
_
N
N
head-to-tail
O
O
+
oligomers
N
R2
N
R2
R1
R1
C
Scheme 4. Possible oligomer formation.

4696
B. A. Trofimov et al. / Tetrahedron Letters 54 (2013) 4693–4696
32. Kanyiva, K. S.; Löbermann, F.; Nakao, Y.; Hiyama, T. Tetrahedron Lett. 2009, 50,
3463–3466.
33. Nakao, Y. Hiyama, T. JP Patent 2009091336 A 20090430, 2009; Chem. Abstr.
2009, 150, 494752.
34. Noyce, D. S.; Stowe, G. T.; Wong, W. J. Org. Chem. 1974, 39, 2301–2302.
35. Bastiaansen, L. A. M.; Mocco, A. A.; Godefroi, E. F. J. Chem. Soc., Chem. Commun.
1974, 36.
37. Zificsak, C. A.; Hlasta, D. J. Tetrahedron Lett. 2005, 46, 4789–4792.
38. Nguyen, D. Q.; Bae, H. W.; Jeon, E. H.; Lee, J. S.; Cheong, M.; Kim, H. S.; Lee, H. J.
Power Sources 2008, 183, 303–309.
39. Miller, S. I.; Tanaka, R. In Selective Organic Transformations; Thyagarajan, B. S.,
Ed.; ; Wiley-Interscience: New York, 1970; Vol. 1, p 143.
40. Dickstein, J. I.; Miller, S. I. In The Chemistry of the Carbon–Carbon Triple Bond;
Patai, S., Ed.; ; Wiley: New York, 1978; Vol. 2, p 814.
36. Deng, Y.; Hlasta, D. J. Tetrahedron Lett. 2002, 43, 189–192.