Stereoselective C(2)-vinylation of 1-substituted imidazoles with 3-phenyl-2-propynenitrile

Article abstract of DOI:10.1021/jo801240x

(Chemical Equation Presented) First examples of direct vinylation of 1-substituted imidazoles at the 2-position of the imidazole nucleus are described. 1-Substituted imidazoles 1a-e are C(2)-vinylated with 3-phenyl-2-propynenitrile (2) at room temperature without catalyst and solvent to afford 3-(1-organyl-1H-imidazol-2-yl)-3-phenyl-2-propenenitriles 3a-e, mainly (c.a. 95%) as (Z)-isomers, in 56-88% yield. The reaction is likely to involve the zwitterionic intermediates, which prototropically isomerizes to imidazole carbene and eventually undergoes the selective 3,2-shift of the functionalized vinyl substituent.

Full text of DOI:10.1021/jo801240x

are antibiotics,8 fungicides,9 antiulceretics,10 antidiabetics, an-
tihypertensive, and anti-inflammatory agents.1b,11 Imidazole-
based drugs such as cimetidine, etomidate, and ketoconazole
are currently in clinical use.1b,12 Recent advances in the
imidazole-tailored ionic liquids (e.g., refs 1b, 13), stable
nucleophilic carbenes (e.g., refs 14a-d), and organic catalysts11,15
are other applications of imidazole derivatives.
Consequently, efforts are focused on the development of
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dazoles. 2-Vinylimidazoles are of interest as potent building
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dehydrogenation of 2-ethylimidazoles, the crude product being
a mixture of target and starting compounds.16 2-Vinylimidazole
and 1-methyl-2-vinylimidazole were also prepared by the
dehydration of the corresponding 2-hydroxyethylimidazoles in
12% yield.17 1-Methyl-2-(1-phenylethenyl)-1H-imidazole was
obtained by dehydration of the 2-(1-hydroxy-1-phenylethyl)
derivatives (in 73-80% yield).18 2-Vinylimidazoles having ester
and cyano functions in the vinyl group were synthesized from
1H-imidazole-2-carbaldehyde and active methylene com-
pounds.19 The Wittig reaction with 2-chloromethylbenzimida-
zoles led to 2-vinylbenzimidazoles.20 From 1-alkylimidazole-
2-carbaldehydes and tribenzylphosphine oxide (Wittig-Horner
reaction) 2-(2-phenylethenyl)imidazoles were synthesized in
Stereoselective C(2)-Vinylation of 1-Substituted
Imidazoles with 3-Phenyl-2-propynenitrile
Boris A. Trofimov,* Lyudmila V. Andriyankova,
Kseniya V. Belyaeva, Anastasiya G. Mal’kina,
Lina P. Nikitina, Andrei V. Afonin, and Igor A. Ushakov
A. E. FaVorsky Irkutsk Institute of Chemistry, Siberian
Branch, Russian Academy of Sciences, 1 FaVorsky Strausse,
664033, Irkutsk, Russia
boris_trofimoV@irioch.irk.ru
ReceiVed July 1, 2008
First examples of direct vinylation of 1-substituted imidazoles
at the 2-position of the imidazole nucleus are described.
1-Substituted imidazoles 1a-e are C(2)-vinylated with
3-phenyl-2-propynenitrile (2) at room temperature without
catalyst and solvent to afford 3-(1-organyl-1H-imidazol-2-
yl)-3-phenyl-2-propenenitriles 3a-e, mainly (c.a. 95%) as
(Z)-isomers, in 56-88% yield. The reaction is likely to
involve the zwitterionic intermediates, which prototropically
isomerizes to imidazole carbene and eventually undergoes
the selective 3,2-shift of the functionalized vinyl substituent.
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R. Di.; Tafi, A.; Costi, R.; Botta, M.; Artico, M.; Corelli, F.; Forte, M.;
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10.1021/jo801240x CCC: $40.75
Published on Web 10/17/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9155–9157 9155

SCHEME 1
FIGURE 1. Assignment of H and C nuclei in vinylimidazoles 3a-e.
vinyl group should lead to 2-vinylimidazole B. Recently,
nucleophilic carbenes similar to species A have been efficiently
pioneered in three component syntheses of several hetero-
cycles.14b
This paper is to check the validity of the above general
methodology for the synthesis of the C(2)-vinylated imidazoles
on the example of 1-subsituted imidazoles 1a-e and 3-phenyl-
2-propynenitrile (acetylene 2), a typical representative of
electron-deficient acetylenes.
Noteworthy, as mentioned above, until this work no clear-
cut precedent of the direct C(2)-vinylation of imidazoles with
acetylenes was published.
Our experiments have shown that the reaction of 1-substituted
imidazoles 1a-e with acetylene 2 (in 2:1 mol ratio) proceeds
smoothly under mild conditions (20-25 °C, no catalyst and
solvent) to deliver mainly (Z)-3-(1-organyl-1H-imidazol-2-yl)-
3-phenyl-2-propenenitriles 3a-e in 56-88% yield, thus corre-
sponding to the mechanism suggested in Scheme 1, that is,
through the carbene intermediate A.
42-52% yield.21 2-Vinylimidazoles were also assembled from
2,4-dicarbonyl compounds and allylamine in 40-65% yield.22
Despite the above achievements in the synthesis of 2-vinylimi-
dazoles, no straightforward C(2)-vinylation of the imidazole
nucleus with acetylenes was known until this work, though
nucleophilic addition of imidazoles by their N(1)-position to
acetylene23 and propyne24 was documented. It was also men-
tioned, that 1-methylimidazole with dimethylacetylenedicar-
boxylate gave polymer, while 1-acyl imidazole with the same
acetylene afforded a mixture of 1- and 2-imidazolyl maleates
and -fumarates in low yield.25
Recently we found that zwitterionic adducts were common
for the reactions of R,ꢀ-acetylenic γ-hydroxy nitriles with
pyridines,26 quinoline and quinoxaline,27 phenanthridines,28
natural alkaloid (anabasine),29 and 1-substituted imidazoles.15b
In the case of the reaction of 1-substituted benzimidazoles with
R,ꢀ-acetylenic γ-hydroxy nitriles, a multiposition rearrangement
of the zwitterionic adducts occurred to end up with the formation
of N-(2-{[5-amino-2,2-dialkyl-3(2H)-furanylidene]amino}phenyl)-
N-substituted formamides.30
Alternatively, the 3,2-migration of the carbanionic moiety
accompanied by a 1,5-sigmatropic shift on the imidazole, finally
followed by the 2-proton transferee to the carbanionic center,
may be considered. But in this case, the highly reactive carbon
ion should survive the above transformation, that seems less
probable.
Therefore, one might expect that 1-substituted imidazoles
would form, with electron-deficient acetylenes having no proton-
donor function, the zwitterions, which further could be converted
to 2-vinyl derivatives according to Scheme 1.
The proton is transferred from the 2-position of the imidazole
ring toward the carbanionic center in the vinyl substituent to
afford the carbene A, in which the 3,2-shift of the functionalized
The reaction is stereoselective: the content of the minor (E)-
isomer usually does not exceed 5% (1H NMR). The reaction
was monitored by TLC (until the acetylene had disappeared).
Noteworthy, that no the expected regioisomers of 3a-e resulted
from the alternative 1,2-shift of substituents R are detectable
in the reaction mixture. The driving force of 3,2-shift of the
vinyl moiety is likely the energy gain (due to the conjugation
of vinyl substituents with the imidazole ring) released upon such
a conversion.
(21) Ivanova, N. I.; Reutskaya, A. M.; Arbuzova, S. N.; Baikalova, L. V.;
Afonin, A. V.; Gusarova, N. K.; Trofimov, B. A. Chem. Heterocycl. Compd.
2002, 221–222.
(22) Veronese, A. C.; Vecchiati, G.; Sferra, S.; Orlandini, P. Synthesis 1985,
300–302.
(23) (a) Copenhaver, J. W.; Bigelow, M. H. Acetylene and carbon monoxide
chemistry; Reinhold Publishing Corp.: New York, 1949. (b) Shostakovsky, M. F.;
Skvortsova, G. G.; Glazkova, N. P.; Domnina, E. S. Khim. Geterotsikl. Soed.
1969, 1070–1072.
(24) Trofimov, B. A.; Tarasova, O. A.; Shemetova, M. A.; Afonin, A. V.;
Klyba, L. V.; Baikalova, L. V.; Mikhaleva, A. I. Zh. Org. Khim. 2003, 39, 437–
442.
(25) Kno¨lker, H.-J.; Boese, R.; Do¨ring, D.; El-Ahl, A.-A.; Hitzemann, R.;
Jones, P. G. Chem. Ber. 1992, 125, 1939–1951.
(26) (a) Trofimov, B. A.; Andriyankova, L. V.; Zhivet’ev, S. A.; Mal’kina,
A. G.; Voronov, V. K. Tetrahedron Lett. 2002, 43, 1093–1096. (b) Trofimov,
B. A.; Andriyankova, L. V.; Shaikhudinova, S. I.; Kazantseva, T. I.; Mal’kina,
A. G.; Afonin, A. V. Synthesis 2002, 853–855.
(27) Andriyankova, L. V.; Mal’kina, A. G.; Afonin, A. V.; Trofimov, B. A.
MendeleeV Commun. 2003, 186–188.
(28) 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, 8031–8034.
For the structure determination of vinylimidazoles 3a-e, 1H,
1
1
13C, 15N NMR and H-1H homonuclear and H-13C hetero-
nuclear 2D (COSY, NOESY, HMBC, HSQC) techniques have
been employed. In 1H NMR spectra of the vinylimidazoles (Z)-
3a-e, singlets of the vinyl protons (7-H) are observed at
5.78-5.98 ppm. The signal of the same proton of (E)-3b is
shifted downfield to 6.10 ppm. The vinyl moiety of vinylimi-
dazoles 3a-e is manifested itself in the 13C NMR spectrum by
the signals in the region of 151.29-151.62 ppm (C-6) and
99.51-99.90 ppm (C-7). The nitrile C-atom resonates at
116.52-116.86 ppm (C-8). The large difference between
chemical shifts of the olefinic carbon atoms C-6 and C-7 (∼50
ppm) is explained by the high polarization of the double bond
under the electron-withdrawing effect of the cyano group (Figure
1).
(29) Trofimov, B. A.; Andriyankova, L. V.; Tlegenov, R. T.; Mal’kina, A. G.;
Afonin, A. V.; Il’icheva, L. N.; Nikitina, L. P. MendeleeV Commun. 2005, 33–
35.
(30) 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, 1018–1025.
The configurational assignment and substituent location for
the compounds 3a-e were based on the values of vicinal
3
coupling constant JCH between olefinic proton 7-H and the
imidazole carbon C-2 (3JC-2, H-7 ) 10.8-11.0 Hz) as well as
9156 J. Org. Chem. Vol. 73, No. 22, 2008

carbon C-9 of the phenyl substituents (3JC-9, H-7 ) 5.2-5.4 Hz).
acetylene 2 (127 mg, 1 mmol) was stirred at 20-25 °C for 24 h.
The reaction mixture was passed through a column (neutral Al2O3
with chloroform/benzene/ethanol (20:4:1) mixture as eluent), and
the fraction containing the reaction product and initial imidazole
1a was collected. Then the fraction was passed through the column
again to obtain 2-propenenitrile 3a (153 mg, 73%, brown oil) and
initial imidazole 1a (79 mg, 0.96 mmol).
(Z and E)-3-(1-Ethyl-1H-imidazol-2-yl)-3-phenyl-2-propeneni-
trile (3b). Analogously, from 1-ethylimidazole (1b) (192 mg, 2
mmol) and acetylene 2 (127 mg, 1 mmol) (20 h) were prepared
(E, Z)-2-propenenitrile (0.3:9.7, respectively) 3b (124 mg, 56%,
brown oil) and initial imidazole 1b (90 mg, 0.94 mmol).
3
Since the trans-vicinal JCH value is always larger than the
corresponding cis-3JCH value, the 7-H atom is located in
the trans-position relative to the imidazole ring and hence in
the cis-position with respect to the phenyl substituent. Therefore,
vinylimidazoles 3a-e are (Z)-izomers. For (E)-isomers 3b
(which are discernible as weak signals in some 1H NMR spectra
3
of (Z)-isomers) the corresponding JCH values are inverted:
3
3JC-2, H-7 ) 5.3 Hz and JC-9, H-7 ) 8.5 Hz, thus indicating the
cis-orientation of the 7-H atom toward the imidazole ring (Figure
1
1). In H, 13C and 15N NMR spectra of vinylimidazoles 3a-e,
the following signals of the imidazole ring are present: 4-H,
5-H; C-2, C-4, C-5 and N-1, N-3. The C-2 atom lacks protons
thus confirming the location of the vinyl substituent at the
2-position of the imidazole ring. In the 13C NMR spectra of
compounds 3a-e, the signals of C-4 and C-5 have the similar
values as in starting imidazoles, while the C-2 signal is shifted
downfield (from 136-137 to 142-143 ppm) by the carbon
σ-effect of the functionalized vinyl substituents. As expected,
in the 15N NMR spectra of the compounds 3a-e, the N-1 and
N-3 nuclei resonate at the different regions from -195 to -220
and from -109 to -111 ppm, respectively.
Thus, the stereoselective facile (room temperature) C(2)-
vinylation of 1-substituted imidazoles 1 with electron-deficient
acetylenes represented by 3-phenyl-2-propynenitrile (2) to give
3-(1-organyl-1H-imidazol-2-yl)-3-phenyl-2-propenenitriles 3 in
56-88% yield has been discovered. The reaction is stereose-
lective: mainly (Z)-isomers of 3a-e are formed. Thus, for the
first time the direct one-pot introduction of the functionalized
vinyl group to the 2-position of the imidazole ring under
unusually mild (close to physiological) conditions has been
realized. The reaction found may be considered as a basic
contribution to both the imidazole and acetylene chemistry as
well as to synthetic application of zwitterions and their isomeric
carbenes generated from imidazoles and electron-deficient
acetylenes.
(Z)-3-(1-Amyl-1H-imidazol-2-yl)-3-phenyl-2-propenenitrile (3c).
Analogously, from 1-amylimidazole (1c) (276 mg, 2 mmol) and
acetylene 2 (127 mg, 1 mmol) (24 h) were prepared 2-propenenitrile
3c (234 mg, 88%, brown oil) and initial imidazole 1c (130 mg,
0.94 mmol).
(Z)-3-(1-Phenyl-1H-imidazol-2-yl)-3-phenyl-2-propenenitrile (3d).
Analogously, from 1-phenylimidazole (1d) (288 mg, 2 mmol) and
acetylene 2 (127 mg, 1 mmol) (24 h) were prepared 2-propenenitrile
3d (160 mg, 59%, brown oil) and initial imidazole 1d (137 mg,
0.95 mmol).
(Z)-3-(1-Allyl-1H-imidazol-2-yl)-3-phenyl-2-propenenitrile (3e).
Analogously, from 1-allylimidazole (1e) (216 mg, 2 mmol) and
acetylene 2 (127 mg, 1 mmol) (24 h) were prepared 2-propenenitrile
3e (136 mg, 58%, brown oil) and initial imidazole 1e (100 mg,
0.93 mmol).
Acknowledgment. This work was supported by Russian Fund
for Basic Research (Grant No. 08-03-00156), Presidium of RAS
(Program 18), and Presidium of Department of Chemical
Sciences and Materials RAS (Grant No. 5.1.8.). The authors
are thankful to D. Sc. L. V. Baikalova for the synthesis of
starting 1-substituted imidazoles 1a-e (A. E. Favorsky Irkutsk
Institute of Chemistry, Siberian Branch, Russian Academy of
Sciences, Russia).
1
Supporting Information Available: Spectral data and H
and 13C NMR spectra for all the compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Experimental Section
(Z)-3-(1-Methyl-1H-imidazol-2-yl)-3-phenyl-2-propenenitrile (3a).
A mixture of 1-methylimidazole (1a) (164 mg, 2 mmol) and
JO801240X
J. Org. Chem. Vol. 73, No. 22, 2008 9157