Stereoselective metal-free reaction of imidazoles with isothiocyanates involving cyanophenylacetylene: A shortcut to N-(Z-alkenyl)imidazole-2- carbothioamides

Article abstract of DOI:10.1055/s-0031-1290442

Abstract N-(Z)-(2-Cyano-1-phenylethenyl)imidazole-2-carbothioamides have been synthesized in up to 91% yield by the new reaction between 1-substituted imidazoles and isothiocyanates in the presence of cyanophenylacetylene under catalyst- and solvent-free conditions at room temperature. The reaction proceeds via zwitterion-carbene intermediates which are trapped by isothiocyanates to form the zwitterion with ambident N-S anionic site, which then undergoes stereo- and regioselective migration of the alkenyl moiety. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1290442

LETTER
▌2069
lSettteer reoselective Metal-Free Reaction of Imidazoles with Isothiocyanates
Involving Cyanophenylacetylene: A Shortcut to N-(Z-Alkenyl)imidazole-2-
carbothioamides
N-(Z-Alkenyl)imidazole-2-carbothioamides
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
Fax +395(2)419346; E-mail: boris_trofimov@irioch.irk.ru
Received: 10.05.2012; Accepted after revision: 20.06.2012
ro[imidazoline-2,3′-pyrrole] and spiro[imidazoline-2,3′-
Abstract: N-(Z)-(2-Cyano-1-phenylethenyl)imidazole-2-carbothio-
thiophene] derivatives.12 But the use of isothiocyanates as
amides have been synthesized in up to 91% yield by the new reac-
the third electrophilic component in the three-component
reactions to trap the zwitterionic adducts of imidazoles
tion between 1-substituted imidazoles and isothiocyanates in the
presence of cyanophenylacetylene under catalyst- and solvent-free
conditions at room temperature. The reaction proceeds via zwitter- with electron-deficient acetylenes remained unknown be-
ion–carbene intermediates which are trapped by isothiocyanates to
form the zwitterion with ambident N–S anionic site, which then un-
dergoes stereo- and regioselective migration of the alkenyl moiety.
fore this work.
In this paper, we report on the regio- and stereoselective
introduction of (Z)-N-alkenyl thioamide function into the
2-position of the imidazole ring using isothiocyanates and
cyanophenylacetylene (as an auxiliary) in the three-com-
ponent reaction mode. When the reactants [1-substituted
Key words: alkynes, carbenes, multicomponent reaction, nucleo-
philic addition, stereoselectivity
imidazoles [Me, Et, i-Bu, amyl (Am), allyl (All)] 1a–e,
The functionalized imidazole structures are frequently
isothiocyanates 2a–c (Me, All, Ph), and cyanophenylacet-
met in a number of natural products1,2 and commercial
ylene 3, molar ratio 1:1:1] are allowed to react at room
drugs (e.g., cimetidine, etomidate, and ketoconazole2–4).
temperature without catalyst and solvent for 24–48 hours,
Among these compounds are those possessing antithrom-
(Z)-(2-cyano-1-phenylethenyl)imidazole-2-carbothio-
bic,5 antiproliferative,6 antihelmintic, anticancer, antifun-
amides 4a–g are assembled in 62–91% yields (Table 1).
gal, and anti-inflammatory7 activity. The thioamide
The reaction is 100% stereoselective: only Z-configura-
function is commonly considered as bioactive moiety.8
tion of the alkenyl moiety is formed, with no traces of E-
Therefore, the merging of the imidazole structure with
configuration being detectable even in the reaction mix-
thioamide function may lead to the compounds with a new
tures.
gamut of biologically important properties. However, de-
spite certain strides towards this goal,9 the chemistry of
such compounds stands underdeveloped. Meanwhile, in
the past decade, a new general acetylene-based methodol-
ogy for the imidazole functionalization is gaining
strength.10 The key step of this approach is the generation
of zwitterion–carbene intermediates, the adducts of 1-sub-
stituted imidazoles and electron-deficient acetylenes,
which then are intercepted by an appropriate electrophile,
for example, aldehydes,11 and further rearrange to final
products. It might be expected that if, in this three-compo-
nent reaction, isothiocyanates would be employed as elec-
trophiles, imidazoles functionalized by thiamide entity
will be formed. Recently, it was reported that the imidaz-
ole carbenes reacted with phenylisothiocyanate, and the
imidazolium inner salts thus formed were allowed to react
with acetylenedicarboxylates in a two-component reac-
tion (20–30 °C, DCE, 0.5 h), to afford a mixture of spi-
Upon completion of the transformation, compounds 4a
and 4c were isolated as yellow powders after washing
with diethyl ether. All the other adducts were obtained as
colored oils after purification by column chromatogra-
phy.13 Structure of the compounds has been proved by
NMR (1H, 13C, 15N) spectroscopy using 2D (COSY, NO-
ESY, HMBC, HSQC) techniques and IR spectroscopy.
1
In the H NMR spectra of imidazole-2-carbothioamides
4a–g, olefinic protons H-9 appear as singlets at δ = 5.35–
5.56 ppm. In the 13C NMR spectra of these compounds,
the signals of olefinic carbons (C-8, C-9) are observed at
δ = 161.9–164.0 and 91.1–93.8 ppm, respectively, while
carbons C-6 (C=S) and C-10 (CN) resonate in the regions
of δ = 189.2–190.9 ppm and δ = 115.5–115.8 ppm, respec-
15
tively. In the N NMR spectrum of compound 4a (R1 =
R2 = Me), the following signals are detected: δ = –218.3
(N-1), –214.3 (N-7 in thioamide fragment), –116.2 (N in
CN-10), and –114.2 (N-3) ppm.
The NOESY spectrum of imidazole-2-carbothioamides
4a–g displays the cross peaks between the olefinic H-9
proton and the ortho protons of the phenyl group thus un-
SYNLETT 2012, 23, 2069–2072
Advanced online publication: 08.08.2012
DOI: 10.1055/s-0031-1290442; Art ID: ST-2012-B0404-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2070
B. A. Trofimov et al.
LETTER
10
3
ambiguously supporting the Z-configuration of the olefin-
ic fragment (Figure 1).
4
R2
N
CN
2
9
6
8
N
5
1
N
7
H
IR spectra of imidazole-2-carbothioamides 4a–g contain
the following characteristic bands (cm–1): 2214–2217
(C≡N), 1604–1612 (C=C), and 1332–1382 (C=S).
S
R1
4a–g
The assembling of imidazole-2-carbothioamides 4 can be
rationalized as follows (Scheme 1). The nucleophilic at-
tack of imidazoles 1 at acetylene 3 leads to the zwitterion
A of E-configuration (relative to the carbanionic center) in
accordance with the rule of nucleophilic trans addition to
the triple bond.14 The proton transfer in the intermediate A
results in carbene B, having the alkenyl group of Z-config-
uration, which then is trapped by isothiocyanates 2 as
Figure 1 Cross peaks in the 2D NOESY spectra of imidazole-2-
carbothioamides 4a–g
competing electrophiles to give the next zwitterion C hav-
ing N,S-ambident anionic site. Then, stereoselective mi-
gration of the (Z)-cyanophenylethenyl group onto the
nitrogen anionic site regioselectively occurs, apparently
in a concerted manner, since Z-configuration of the mi-
grating group entirely retains. Obviously, the proton
transfer (A → B) proceeds intermolecularly, because the
intramolecular process is here forbidden due to the ad-
verse configuration of the carbanionic moiety in the zwit-
terion A. The intermolecular proton transfer for the
transformation in the zwitterion A to form carbene B (first
postulated by us15) has recently been independently con-
firmed by the quantum chemical calculations [B3LYP/6-
31G(d.p)].16
Table 1 One-Pot Synthesis of Imidazole-2-carbothioamides 4a–g
via Three-Component Reaction: 1-Substituted Imidazoles 1a–e, Iso-
thiocyanates 2a–c, and Cyanophenylacetylene 3
R2
N
CN
N
r.t.
R2
N
2a–c
C
S
Ph
+
CN
N
+
N
24–48 h
N
3
S
Ph
R1
1a–e
R1
4a–g
Entry
R1
R2
Imidazole-2-carbothioamides Isolated
4a
yield (%)
Ph
Ph
Me
N
–
CN
CN
CN
CN
N
+N
N
–
N
3
CN
CN
1
Me
Me
4a
91
+
N
H
N
N
N
S
S
S
S
S
S
Ph
Ph
Ph
Ph
Me
R1
R1
R1
A
1
All
N
N
Ph
Ph
2
3
4
5
6
7
Me
Me
Et
All
Ph
4b
4c
4d
4e
4f
81
79
78
74
62
67
N
+
N
R2
N
CN
N
CN
N
Me
2
CN
N
Ph
N
R2
N
N
–
N
N
S
Ph
S
R1
R1
R1
N
4
B
C
Me
Scheme 1 Tentative mechanism for the formation of the imidazole-
2-carbothioamides 4
Me
N
N
Me
Me
Me
Me
N
As follows from Table 1, the scope of the reaction covers
different 1-substituted imidazoles and isothiocyanates
with alkyl, alkenyl, and aromatic substituents, and hence
this new functionalization of the imidazole ring may have
a significant impact on the imidazole chemistry as a
whole.
Et
Me
N
CN
CN
N
i-Bu
Am
All
N
Ph
Ph
i-Bu
Me
N
The cyanophenylacetylene 3 appeared to be a convenient
auxiliary to accomplish the above reaction, unlike such
commonly used electron-deficient acetylenes as alkyl
propynoates or dialkyl acetylenedicarboxylates. Indeed,
methyl propiolate (5) or dimethyl acetylenedicarboxylate
(6) (under the conditions: 0 °C to 20–25 °C, MeCN),
when employed instead of acetylene 3, gave none of the
expected imidazole-2-carbothioamides, the major prod-
ucts being divinyl sulfides 717 (85% yield) or 8 and oligo-
mers (Scheme 2).
N
N
Am
N
Me
N
CN
4g
N
S
Ph
All
a The reaction time is mainly 24 h (only when R2 = Ph, adduct 4c is
formed for 48 h).
Synlett 2012, 23, 2069–2072
© Georg Thieme Verlag Stuttgart · New York

LETTER
N-(Z-Alkenyl)imidazole-2-carbothioamides
Acknowledgment
2071
Me
N
Me
N
N
N
This work was supported by leading scientific schools by the Presi-
dent of the Russian Federation (Grant NSh-1550.2012.3), Russian
Fund for Basic Research (Grant No. 11-03-00203), and Presidium
of Department of Chemical Sciences and Materials RAS (Grant No.
5.1.3.).
Me
+
+
Ph
Ph
N
N
N
H2O (trace)
5 or 6
2c
1a
+
N
CO2Me
CO2Me
S
S
HO–
_
–
Ph
S
N
H
R3
R3
R3
D
Supporting Information for this article is available online at
R3
Me
Me
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
N
N
–S
+
+
Ph
HS
+
N
+
N
CO2Me
CO2Me
Ph
References
–O
N
HO
N
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5 or 6
oligomers
+
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HS
MeO2C
7 R3 = H (85%)
8 R3 = CO2Me (trace)
CO2Me
CO2Me
Scheme 2 Probable mechanism of the reaction between 1-methyl-
imidazole (1a), methyl propiolate (5) [or dimethyl acetylenedicarbox-
ylate (6)], and phenylisothiocyanate (2с)
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Evidently, acetylenes 5 and 6 as electrophiles fail to com-
pete with isothiocyanates for imidazole nucleophile, and
hence the primary intermediates in this case are the zwit-
terions D instead of the A-type zwitterions. Eventually,
thiolate D as active nucleophile adds to the triple bond of
acetylene 5 or 6 to afford (via the common transformation
in the presence of adventitious trace water) divinyl sul-
fides 7 and 8.
In conclusion, we have found and developed a new non-
catalytic, solvent-free, stereoselective, one-pot function-
alization of the imidazoles at the 2-position with (Z)-N-
alkenyl thioamide entity by the coupling with isothiocya-
nates in the presence of cyanophenylacetylene. The key
steps of the reaction have been assumed to be (i) stereo-
selective formation of zwitterion from imidazoles and the
cyanophenylacetylene, (ii) the conversion of the zwitter-
ion to the carbene via the intermolecular proton transfer,
(iii) interception of the carbene with isothiocyanates, and
(iv) stereoselective migration of functionalized ethenyl
moiety to an anionic center. The imidazole-N-alkenyl-
carbothioamides of Z-configuration thus synthesized rep-
resent a new until now inaccessible family of
functionalized imidazole derivatives, prospective drugs
and their precursors, and potent Z-isomerically pure build-
ing blocks for the synthesis of new heterocyclic com-
pounds. The results contribute to fundamental chemistry
of imidazole, isothiocyanates, acetylene, and carbenes as
well as to a better understanding of nucleophilic addition
to the C≡C bond and proton transfers.
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(13) Typical Experimental Procedure for the Synthesis of
N-[(Z)-2-Cyano-1-phenylethenyl]-N,1-dimethyl-1H-
imidazole-2-carbothioamide (4a)
To a mixture of acetylene 3 (0.127 g, 1 mmol) and
methylisothiocyanate (2a; 0.073 g, 1 mmol) was added 1-
methylimidazole (1a; 0.082 g, 1 mmol). The mixture was
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2069–2072

2072
B. A. Trofimov et al.
LETTER
stirred at 20–25 °C for 24 h. The reaction mixture was
washed with Et2O (1 × 3 mL) to give imidazole-2-
carbothioamide 4a (0.257 g, 91%) as a yellow powder; mp
162–164 °C (EtOH). IR (KBr): ν = 2217 (CN), 1612 (C=C),
1351 (C=S) cm–1. 1H NMR (400.13 MHz, CDCl3): δ = 7.50–
7.40 [m, 5 H, C(8)Ph], 6.85 (s, 1 H, 4-H), 6.80 (s, 1 H, 5-H),
5.37 (s, 1 H, 9-H), 3.84 [s, 3 H, N(1)CH3], 3.61 [s, 3 H,
N(7)CH3] ppm. 13C NMR (100.62 MHz, CDCl3): δ = 189.7
(C-6), 164.0 (C-8), 144.7 (C-2), 134.1 [Ci, C(8)Ph], 131.6
[Cp, C(8)Ph], 129.1 [Cm, C(8)Ph], 127.9 [Co, C(8)Ph], 127.3
(C-4), 124.9 (C-5), 115.7 (C-10, CN), 91.1 (C-9), 42.7
[N(7)CH3], 36.0 [N(1)CH3] ppm. 15N NMR (40.55 MHz,
CDCl3): δ = –114.2 (N-3), –116.2 (CN-10), –214.3 (N-7),
–218.3 (N-1) ppm. Anal. Calcd for C15H14N4S (282.37): C,
63.81; H, 5.00; N, 19.84; S, 11.35. Found: C, 63.74; H, 5.07;
N, 19.87; S, 10.95.
δ = 7.60–7.40 [m, 5 H, C(8)Ph], 6.83 (s, 2 H, 4-H, 5-H), 6.06
[m, 1 H, HX, N(7)All]), 5.35 (s, 1 H, 9-H), 5.21 [d, 3JHA,HX
=
9.2 Hz, 1 H, HA, N(7)All], 5.09 [d, 3JHB,HX = 16.8 Hz, 1 H,
HB, N(7)All], 4.05 [m, 2 H, –CH2–, N(7)All], 3.88 [s, 3 H,
N(1)CH3] ppm. 13C NMR (100.62 MHz, CDCl3): δ = 189.3
(C-6), 161.9 (C-8), 144.6 (C-2), 137.6 (CHX, All), 133.5 [Ci,
C(8)Ph], 131.4 [Cp, C(8)Ph], 129.0 [Cm, C(8)Ph], 127.6 [C-
4, Co, C(8)Ph], 125.1 (C-5), 120.7 (CHA,B, All), 115.8 (C-10,
CN), 92.7 (C-9), 55.3 [(N(7)CH2, All], 35.9 [N(1)CH3] ppm.
Anal. Calcd for C17H16N4S (308.40): C, 66.21; H, 5.23; N,
18.17; S, 10.40. Found: C, 66.59; H, 5.09; N, 18.55; S,
10.01.
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N-Allyl-N-[(Z)-2-cyano-1-phenylethenyl]-1-methyl-1H-
imidazole-2-carbothioamide (4b)
To a mixture of acetylene 3 (0.127 g, 1 mmol) and
allylisothiocyanate (2b; 0.099 g, 1 mmol) was added 1-
methylimidazole (1a; 0.082 g, 1 mmol). The mixture was
stirred at 20–25 °C for 24 h. Column chromatography
afforded imidazole-2-carbothioamide (4b; 0.250 g, 81%) as
a dark-yellow oil. IR (microlayer): ν = 2216 (CN), 1607
(C=C), 1382 (C=S) cm–1. 1H NMR (400.13 MHz, CDCl3):
Synlett 2012, 23, 2069–2072
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