Stereoselective tandem ring opening of imidazoles with electron-deficient acetylenes and water: Synthesis of functionalized (Z, Z)-1,4-diaza-2,5-dienes

Article abstract of DOI:10.1021/ol400844x

1-Substituted imidazoles undergo exceptionally facile stereoselective ring opening under the influence of electron-deficient acetylenes and water (equimolar ratio of the reactants) in MeCN at 45-60 C without any catalysts to afford functionalized (Z,Z)-1,4-diaza-2,5-dienes, (Z,Z)- propenylaminoethenylformamides, in up to 80% yields. The reaction is rationalized to proceed in a tandem manner via zwitterionic vinyl carbanions formed by nucleophilic addition of imidazole to the triple bond. The carbanionic center is then quenched with water followed by the rearrangement of the intermediate 2-hydroxy-3-alkenylimidazolines.

Full text of DOI:10.1021/ol400844x

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Stereoselective Tandem Ring Opening
of Imidazoles with Electron-Deficient
Acetylenes and Water: Synthesis of
Functionalized (Z,Z)‑1,4-Diaza-2,5-dienes
Boris A. Trofimov,* Ludmila V. Andriyankova, Lina P. Nikitina, Kseniya V. Belyaeva,
Anastasia G. Mal’kina, Lubov N. Sobenina, Andrei V. Afonin, and Igor A. Ushakov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of
Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation
boris_trofimov@irioch.irk.ru
Received March 27, 2013
ABSTRACT
1-Substituted imidazoles undergo exceptionally facile stereoselective ring opening under the influence of electron-deficient acetylenes and water
(equimolar ratio of the reactants) in MeCN at 45À60 °C without any catalysts to afford functionalized (Z,Z)-1,4-diaza-2,5-dienes, (Z,Z)-
propenylaminoethenylformamides, in up to 80% yields. The reaction is rationalized to proceed in a tandem manner via zwitterionic vinyl
carbanions formed by nucleophilic addition of imidazole to the triple bond. The carbanionic center is then quenched with water followed by the
rearrangement of the intermediate 2-hydroxy-3-alkenylimidazolines.
Diazadienes and -trienes, particularly cyclic ones
(pyridazines, pyrimidines, pyrazines and their dihydro
derivatives), find enormous application in organic, bio-
organic, and medicinal chemistry.1 Their syntheses and
modifications are well established and keep being de-
veloped.2,3 Less studied and, respectively their syntheses
much less elaborated, are their open-chained congeners.
Meanwhile, they also attract great interest, especially
isomerically pure and functionalized ones, as important
ligands and synthetic building blocks.4,5
Most of the known diazadienes contain the CdN bonds
and, hence, are actually the Schiff base type compounds.
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Martin, M. P.; Luo, Y.; Pireddu, R.; Yang, H.; Gevariya, H.; Ozcan, S.;
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R. J.; Malysz, J.; Thorin-Hagene, K. K.; Van Handel, C. E.; Marsh,
K. C.; Lee, Ch.-H.; Gopalakrishnan, M. J. Med. Chem. 2011, 54, 7678.
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r
10.1021/ol400844x
XXXX American Chemical Society

Diazadienes with both CdC bonds have been unknown
until now, although their N-adjusent double bonds and N
functionalities warrant rich reactivity.
Here we report our serendipitous finding that 1-substi-
tuted imidazoles 1aÀe under the influence of disubstituted
electron-deficient acetylenes 2aÀd in the presence of water
in MeCN without a catalyst (the 1/2/water molar ratio =
1:1:1) undergo exceptionally easy (45À60 °C) ring opening
to afford functionalized (Z,Z)-1,4-diaza-2,5-dienes 3aÀh
in yields of up to 80% (Table 1).
The three-component reaction (Table 1) is strictly stereo-
selective: both alkenyl moieties are of the Z-configuration.
In no case were the corresponding E-isomers detectable
(1H NMR) in the crude product even in trace amounts.
The yields of 1,4-diaza-2,5-dienes 3aÀh generally range
60À80%, sharply dropping (15%) when benzoylacetylene
2d with 1-benzyltetrahydroindolyl substituent was em-
ployed, obviously due to its steric encumbrance. In this
case, both acetylene 2d and imidazole 1a were mostly
recovered, even after heating (55À60 °C) for 100 h. Also,
the steric hindrance may explain the moderate yield (50%)
in the reaction with 1-isobutylimidazole 1b.
Noteworthy, monosubstituted (terminal) electron-
deficient acetylenes almost do not give the 1,4-diaza-2,5-dienes
just as minor products under the same conditions, for
instance with benzoylacetylene, only about 5% of the
expected 1,4-diaza-2,5-diene has been detected (1H NMR)
in the reaction mixture. In this case, the major isolated
product (20% yield) was the trimer of benzoylacetylene,
1,3,5-tribenzoylbenzene (mp 113À115 °C, lit. mp 122 °C6),
the other product being an oligomer of the approximate
composition 1a/benzoylacetylene/water = 1:3:5. There-
fore, the main direction of this three-component reaction is
the imidazole catalyzed oligomerization and hydration of
the starting acetylene.
Table 1. Synthesis of Functionalized (Z,Z)-1,4-Diaza-2,5-
dienes 3 from 1-Substituted Imidazoles 1, Electron-Deficient
Acetylenes 2, and Water
The isolated 1,4-diaza-2,5-dienes 3 are colored (dark-
yellow, brown) oils (except the product 3h, a dark-yellow
powder) soluble in conventional organic solvents. Their
structures have been supported by NMR (1H, 13C, 15N)
spectroscopy using 2D techniques (COSY, NOESY,
HMBC, HSQC) and IR spectroscopy.
In the 1H NMR spectra of adducts 3aÀh, singlets of H-6
protons are observed at 5.82À6.31 ppm and those of NH
protons at 12.36À13.15 ppm. In the 13C NMR spectra, the
CdO group appears at 178.4À189.9, and the CdO group
of formamide moiety is present at 161.3À162.9 ppm.
Configurational assignment of the synthesized 1,4-diaza-
2,5-dienes 3was carried out on the basis of 2D NOESY data.
The cross-peaks between the H-2 and H-3 signals as well as
those between the H-6 and ortho-protons of the phenyl ring
suggest that all structures exist in the Z,Z-form (Figure 1).
Figure 1. Cross-peaks in the 2D NOESY spectra of compounds
3aÀg.
a The temperature of reaction mixture was 45À50 °C. b The tempera-
ture of reaction mixture was 50À55 °C. c The temperature of reaction
mixture was 55À60 °C.
(6) Elghamry, I. Synthesis 2003, 2301.
(7) Quintanilla-Licea, R.; Clunga-Valladares, J. F.; Caballero-
Quintero, A.; Rodriguez-Padilla, C.; Tamez-Guerra, R.; Gomez-Flores,
R.; Waksman, N. Molecules 2002, 7, 662.
B
Org. Lett., Vol. XX, No. XX, XXXX

Besides, the rotation around the CÀN amide bond has
been recognized7 to have a restricted character. Hence, a
mixture of the syn-andanti-rotamers (ratio ∼1:1) is observed
in the 1H and 13C NMR spectra. Assignment of the rotamers
in compounds 3 was performed using the 2D NOESY
experiment. The cross-peak between the formyl and methyl
group proton resonances is revealed in the syn-rotamer while
the cross-peaks between the formyl proton, on the one hand,
and the H-2 proton and NÀH group proton, on the other
hand, are present in the anti-rotamer (Figure 2).
Scheme 1. Tentative Scheme of the 1,4-Diaza-2,5-diene 3
Formation from Imidazoles 1, Electron-Deficient Acetylenes 2,
and Water
similar intermediate was postulated for the Bamberger
imidazole cleavage8a,b under the influence of such robust
electrophiles as acid chlorides8a,b and pyrocarbonates.8c,d
The stereochemistry of the reaction corresponds to the
proposed mechanism. Indeed, the Z-configuration of
the acylalkenyl moiety is in keeping with the trans-mode
ofthe classic nucleophilic addition toacetylenes9 leading to
the adduct of the Z-configuration. The other alkenyl
moiety possesses a Z-configuration due to its origination
from the imidazole ring cleavage at the C(2)ÀN(3) bond.
The reaction that was revealed and conceptually the
original synthesis of almost unknown 1,4-diaza-2,5-dienes
based on this reaction are the results of our systematic
studies10 of the synthetic strategy using zwitterionic vinyl
carbaniones, the adducts of neutral nucleophiles to acet-
ylene, as versatile building blocks in organic synthesis.
In conclusion, stereoselective tandem ring opening of
1-substituted imidazoles with disubstituted electron-
deficient acetylenes and water under mild conditions to
give functionalized 1,4-diaza-2,5-dienes in modest to good
yields has been unveiled. The previously unknown (Z,Z)-
diazadienes bearing the formyl and acyl functions, thus
synthesized, represent a promising family of building blocks
for organic synthesis. The results obtained contribute to the
basic chemistry of both imidazoles and acetylenes.
Figure 2. Cross-peaks in the 2D NOESY spectra of syn- and
anti-rotamers 3.
In the IR spectra, both of the carbonyl functions and
double bonds at 1667À1683 cmÀ1 are observed as broad
absorption bands.
The synthesis of 1,4-diaza-2,5-dienes, thus found, is as-
sumed to be a three-component tandem reaction trigged by
the nucleophilic attack of 1-substituted imidazole 1 at the
triple bond of acetylene 2 (Scheme 1). The carbanionic center
of the zwitterion Ais quenched by the proton of water to form
N-alkenylammonium hydroxide B. The nonionic form of the
latter, 2-hydroxy-3-alkenylimidazoline C, rearranges to the
final product 3with cleavage of the imidazole ring. A somewhat
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Triple Bond; Patai, S., Ed.; Wiley: New York, 1978; Vol. 2, p 814.
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Acknowledgment. This work was supported by leading
scientific schools by the President of the Russian Federa-
tion (Grant NSh-1550.2012.3), Russian Fund for Basic
Research (Grant No. 11-03-00203, No. 11-03-00423-a)
and Presidium of Department of Chemical Sciences and
Materials RAS (Grant No. 5.1.3.).
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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