Unexpected Aldehyde-Catalyzed Reaction of Imidazole N -Oxides with Ethyl Cyanoacetate

Article abstract of DOI:10.1055/s-0039-1691527

The reaction of 2-unsubstituted imidazole N -oxides with ethyl cyanoacetate and aromatic aldehydes leads to the formation of ethyl 2-cyano-2-(1,3-dihydro-2 H -imidazole-2-ylidene)acetates. The reaction proceeds through an initial [3+2] cycloaddition, followed by cleavage of the cycloadduct and regeneration of the aldehyde, which essentially plays a catalytic role.

Full text of DOI:10.1055/s-0039-1691527

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
V. S. Mityanov and co-workers
Letter
Synlett
Unexpected Aldehyde-Catalyzed Reaction of Imidazole N-Oxides
with Ethyl Cyanoacetate
Anton V. Kutasevicha
Anna S. Efimovaa
Marina N. Sizonenkoa
Valery P. Perevalova
Ludmila G. Kuz’minac
Vitaly S. Mityanov*a,b
0
0
0
0-
0
0
0
2-3
6
6
4-2
9
2
4
CHO
O
H
N
EWG
CN
SMe
EWG
CN
N
+
DMF, 100 °C
N
N
R
R
0
0
00-0
0
0
2-0
6
1
6-
8
2
1
3
14 Examples, up to 86%
Gram-scale
R = Alkyl, Allyl, Benzyl, Phenethyl
EWG = CN, CO2Et, SO2Ar
Aldehyde-catalyzed
a Department of Fine Organic Synthesis and Chemistry of Dyes,
D. Mendeleyev University of Chemical Technology of Russia,
Miusskaya Sq., 9, Moscow 125047, Russian Federation
mityanovvs@yandex.ru
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy
of Sciences, Leninsky Pr., 47, Moscow 119991,
Russian Federation
c Kurnakov Institute of General and Inorganic Chemistry,
Russian Academy of Science, Leninskii Pr., 31, Moscow 117907, Russian Federation
Received: 18.10.2019
Accepted after revision: 19.11.2019
Published online: 29.11.2019
O
O
H
N
R2
R3
R2
R3
RXH
CO2Me
CO2Me
XR
CF3
N
N
R1
DOI: 10.1055/s-0039-1691527; Art ID: st-2019-v0571-l
CO2Me
CO2Me
N
R1
F
F
CF3
F
Abstract The reaction of 2-unsubstituted imidazole N-oxides with eth-
yl cyanoacetate and aromatic aldehydes leads to the formation of ethyl
2-cyano-2-(1,3-dihydro-2H-imidazole-2-ylidene)acetates. The reaction
proceeds through an initial [3+2] cycloaddition, followed by cleavage of
the cycloadduct and regeneration of the aldehyde, which essentially
plays a catalytic role.
F
O-
N+
F
F
S
O
H
R2
R3
R2
R3
H
N
R2
R3
CN
CN
N
NC CN
S
N
R1
N
R1
N
F
F
X
R1
C
Ar
R
R
N
HNRR'
O
R'
R
Key words imidazole oxides, 1,3-dipolar cycloaddition, reaction mecha-
nism, organocatalysis, multicomponent reaction, [3+2] cycloaddition
R2
R3
R2
R3
N
N
R1
N
N
N
R1
NHR
Ar
Imidazole N-oxides possess a unique reactivity profile
that, combined with their availability,1 makes them valu-
able intermediates in modern organic synthesis.1b–d Partic-
ularly attractive is the possibility of C–H functionalization
of the heterocyclic core, which permits the use of simple
precursors in the synthesis of complex functional hetero-
cycles.
There are several different approaches to C–H function-
alization. Among Pd-catalyzed selective cross-coupling re-
actions,2a,b imidazole N-oxides readily enter into nucleo-
philic cine-substitution reactions.3 Of particular interest is
the series of [3+2]-cycloaddition processes3b,4 in which the
N-oxides of 2-unsubstituted imidazoles act as 1,3-dipoles.
The initially formed adducts are very labile, and secondary
processes occur, leading to a wide range of products as
shown in Scheme 1.
Scheme 1 Imidazole N-oxide functionalizations based on an initial
[3+2] cycloaddition
Our previous work
R6
O
O–
N+
O–
N+
R5
R2
R3
R2
R3
O
R6
R4
+
R5
+
O
CHO
R4
N
R1
N
R1
O
Formal Michael-type addition
This work
O–
N+
R2
R3
H
N
R2
EWG
CN
CN
EWG
R4
+
+
CHO
N
R1
N
R1
R3
Also, we have previously described5 the ability of 2-un-
substituted imidazole N-oxides to act as C-nucleophiles in
Michael-type addition to enones formed by condensation of
aldehydes with such classic C–H acids as Meldrum’s acid,
barbituric acid, or dimedone (Scheme 2).
Via [3+2] cycloaddition
aldehyde-catalyzed
Scheme 2 Reactions of imidazole N-oxides with aldehydes and C–H
acids
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
V. S. Mityanov and co-workers
Letter
Synlett
In a continuation of our studies on the reactivity of im-
idazole N-oxides, we proposed to extend this reaction to
such C–H acids as ethyl cyanoacetate or malononitrile.
However, the reaction of equimolar amounts of the N-oxide
1a, ethyl cyanoacetate (3a) and 4-(methylsulfanyl)benzal-
dehyde (2) in acetonitrile unexpectedly led to compound 4a
as the only product in 20% yield after recrystallization from
ethanol (Scheme 3).
H
N
CO2Et
CN
CN
CO2Et
H2O
N
CHO
R
Ph
4a
retro-ene
H
O
CN
R
CN
N
N
CO2Et
A
CO2Et
R
R
O
O–
N
N
CO2Et
CN
Ph
H
N
O
N
CHO
CO2Et
CN
N
CO2Et
C
H
+
+
[3+2]
MeCN, Δ
5 h
N
CN
N
MeS
B
Ph
N
Ph
1a
1a
Ph
rearrangement
Ph
4a, 20%
H
N
3a
2
O
Scheme 3 Initial experiment
N
5
Ph
1
The structure of product 4a was confirmed by H and
13C NMR spectroscopy and HRMS. In the IR spectrum of
4a, a sharp intense CN absorption band was observed at
2183 cm–1. Single-crystal X-ray analysis also confirmed the
structure of 4a (Figure 1).6
Scheme 4 Proposed reaction mechanism
goes cleavage of the C–C bond with the elimination of the
aldehyde (retro-ene reaction).
To obtain more details, we monitored the process in
various solvents (Table 1). The yields of products were de-
termined by HPLC with external standards. It is noteworthy
that in all cases, 1-benzyl-4,5-dimethyl-1,3-dihydro-2H-
imidazol-2-one (5) was formed as a byproduct, apparently
as a result of thermal rearrangement7 of the starting N-ox-
ide. It was shown that on prolonged heating in various sol-
vents, 5 is inert to aldehyde, ethyl cyanoacetate, and their
mixtures. Also, various amounts of the unreacted ylidene
derivative ethyl (2Z)-2-cyano-3-[4-(methylsulfanyl)phe-
nyl]acrylate (6) were detected in all cases. Note that in chlo-
roform (entry 4) and, especially, ethanol (entry 6) as the re-
action medium, the reaction showed a significantly differ-
ent course in which almost all the aldehyde and ethyl
cyanoacetate were converted into the ylidene derivative 6,
Table 1 Reaction Monitoringa
Entry Solventb
Yield (%) of 4a Yield (%) of 5 Conversion of 2
Figure 1 X-ray crystal structure of compound 4a
1
2
3
4
5
6
7
benzene
PhMe
86
88
42
17
69
2
8
12
2
0.26
0.29
0.62
0.86c
0.36
0.97c
0.20
Because the product does not contain an aldehyde frag-
ment and because, in the absence of an aldehyde, the reac-
tion between 1a and 3a failed, we assumed that the alde-
hyde performs a catalytic function and that the process
proceeds according to the mechanism shown in Scheme 4.
In the first stage, a [3+2] cycloaddition occurs between
the ylidene A and the N-oxide. The initially formed unstable
isoxazolidine cycloadduct B readily undergoes rearomatiza-
tion and ring-opening to give intermediate C, which under-
1,4-dioxane
CHCl3
0
MeCN
2
EtOH
0
DMFd
96
4
a Yields and conversions were determined by HPLC analysis.
b Reaction was carried out at the reflux temperature unless otherwise stated.
c 6 was the major product.
d At 100 °C.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

C
V. S. Mityanov and co-workers
Letter
Synlett
but interaction with the N-oxide did not occur. When a
similar effect was reported for the reaction of imidazole N-
oxides with 1,1-difluorostyrenes in methanol,4f the authors
suggested that the low reactivity of the N-oxide was caused
by hydrogen bonding and solvation by MeOH. It is possible
that residual HCl might have had an effect in the case of
chloroform. The highest yield of the desired product was
obtained in DMF (entry 7), when the conversion of the al-
dehyde was only 20%.
Table 3 Reaction Scopea,b
O
N
CHO
H
N
EWG
CN
2
CN
MeS
DMF
+
N
R1
EWG
N
R1
100 °C, 5 h
1
4
3
H
N
H
N
H
N
CO2Et
CN
CO2Et
CN
CO2Et
N
N
N
CN
To reveal the catalytic role of the aldehyde 2 more clear-
ly, we carried out a series of experiments using it in re-
duced amounts. The results are summarized in Table 2.
However, although just 5 mol% of the aldehyde led to the
formation of the product in 48% yield, the amount of the
imidazole-2-one byproduct also increased (Table 2, entry
4). Furthermore, increasing duration of the reaction led to a
significant resinification of the reaction mixture, and the
conversion of starting N-oxide did not exceed 50%. Also, the
process was not affected by replacing 4-(methylsulfa-
nyl)benzaldehyde (2) with benzaldehyde, but the use of
formaldehyde (in the form of an aqueous solution) or acet-
aldehyde led to the formation of a complex mixture of un-
identified byproducts.
Ph
Cl
Ph
4b, 79%
4c, 39%
4a, 86%
H
N
H
N
H
N
CO2Et
CN
CO2Et
CN
CO2Et
CN
N
N
N
O
Cl
4f, 64%
OMe
4e, 58%
OMe
4d, 62%
H
N
H
N
H
N
CO2Et
CN
CO2Et
CN
CO2Et
CN
N
N
N
MeO
HO
Table 2 Monitoring of the Effects of the Amount of Aldehydea
OMe
4h, 64%
4i, 56%
4g, 30%
H
N
H
N
Entry
2 (mol%)
Time (h)
Yield (%) of 4a Yield (%) of 5
H
N
CN
CN
CN
S
CN
CN
1
2
3
5
20
20
5
4
16
4
36
54
2
1
3
O
N
N
N
O
Ph
4l, 18%
0
4j, 36%
OMe
4k, 45%
5
16
48
13
Cl
a Yields and conversions were determined by HPLC analysis.
H
N
H
N
CN
CN
O
S
O
S
N
N
O
Under optimal conditions (Table 1, entry 7), a number of
derivatives were obtained from various 2-unsubstituted
imidazole N-oxides 1. Besides ethyl cyanoacetate, malono-
nitrile (3b), 2-tosylacetonitrile (3c), and 2-[(4-chlorophe-
nyl)sulfonyl]acetonitrile (3d) were used as C–H acids (Table
3).8 In the case of derivative 4i, we showed that even the la-
bile acetal group was inert under the reaction conditions.
Although the configuration of the CN and CO2Et groups
in compounds 4a–i is apparently the same as that in 4a
(which is assumed to exist as the E-isomer as a result of the
possibility of strong intramolecular hydrogen bonding and
from X-ray crystallography data), this problem has not been
investigated for derivatives 4l–n; however, NMR studies
suggested that all compounds 4 exist as single diastereo-
mers.
O
Ph
4n, 51%
Ph
4m, 28%
Cl
a Reaction conditions: 1 (2 mmol), 3 (2 mmol), 2 (2 mmol), DMF (4 mL),
100 °C, 5 h.
b Isolated yields are reported.
O
H
N
CN
CO2Et
CN
N
2
+
CO2Et
N
N
DMF (5 mL)
100 °C, 5 h
3a
Ph
1a (10 mmol)
Ph
4a (2.5 g, 85%)a
Scheme 5 Gram-scale synthesis of 4a. When the reaction was complete,
the solvent was removed under vacuum and the residue was crystallized
from EtOAc to give pure 4a.
Furthermore, under the optimized conditions, gram-
scale quantities of compound 4a were obtained in 85% iso-
lated yield (Scheme 5), indicating the utility of our transfor-
mation as a synthetic method.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

D
V. S. Mityanov and co-workers
Letter
Synlett
Note that the previously obtained ylidene 7, based on
cyclohexanone, can also be introduced into the reaction to
give 4a in 61% yield (Scheme 6). However, 1,1-difluoro-
alkenes containing an aliphatic instead of an aromatic sub-
stituent have been shown to be completely inert with re-
spect to the imidazole N-oxide, even under rather harsh
conditions (DMF, 100 °C, 7 d).4f
(4) (a) Mlostoń, G.; Gendek, T.; Heimgartner, H. Helv. Chim. Acta
1998, 81, 1585. (b) Mlostoń, G.; Gendek, T.; Heimgartner, H. Tet-
rahedron 2000, 56, 5405. (c) Mlostoń, G.; Jasiński, M.;
Heimgartner, H. Eur. J. Org. Chem. 2011, 2542. (d) Loska, R.;
Mąkosza, M. Mendeleev Commun. 2006, 16, 161. (e) Loska, R.;
Mąkosza, M. Chem. Eur. J. 2008, 14, 2577. (f) Loska, R.;
Szachowicz, K.; Szydlik, D. Org. Lett. 2013, 15, 5706. (g) Loska,
R.; Bukowska, P. Org. Biomol. Chem. 2015, 13, 9872. (h) Szpunar,
M.; Loska, R. Eur. J. Org. Chem. 2015, 2133. (i) Mlostoń, G.;
Jasiński, M.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2006,
89, 1304.
(5) (a) Mityanov, V. S.; Kutasevich, A. V.; Krayushkin, M. M.;
Lichitsky, B. V.; Dudinov, A. A.; Komogortsev, A. N.; Kuzmina, L.
G. Tetrahedron Lett. 2016, 57, 5315. (b) Mityanov, V. S.;
Kutasevich, A. V.; Krayushkin, M. M.; Lichitsky, B. V.; Dudinov,
A. A.; Komogortsev, A. N.; Koldaeva, T. Y.; Perevalov, V. P. Tetra-
hedron 2017, 73, 6669. (c) Kutasevich, A. V.; Perevalov, V. P.;
Mityanov, V. S.; Lichitsky, B. V.; Komogortsev, A. N.; Krayushkin,
M. M.; Koldaeva, T. Y.; Miroshnikov, V. S. Chem. Heterocycl.
Compd. (Engl. Transl.) 2019, 55, 147.
CO2Et
CN
4a, 61%
1a
+
DMF
100 °C, 5 h
7
Scheme 6 Reaction of N-oxide 1a with ethyl cyano(cyclohexylidene)-
acetate (7)
In summary, therefore, we have identified the possibility
of condensation of 2-unsubstituted imidazole N-oxides
with ethyl cyanoacetate and related nitriles in the presence
of an aromatic aldehyde that plays the role of a catalyst. Fur-
ther investigations of this reaction are currently ongoing.
(6) CCDC 1948977 contains the supplementary crystallographic
data for compound 4a. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
(7) Antonova, M. M.; Baranov, V. V.; Kravchenko, A. N. Chem. Het-
erocycl. Compd. (Engl. Transl.) 2015, 51, 395.
Supporting Information
(8) Compounds 4a–n; General Procedure
Supporting information for this article is available online at
A solution of the appropriate imidazole N-oxide 1 (1 mmol),
nitrile 3 (1 mmol), and aldehyde 2 (1 mmol) in DMF (4 mL) was
stirred at 100 °C for 5 h. The solvent was removed under
reduced pressure, and the residue was purified by column chro-
matography (silica gel, EtOAc).
https://doi.org/10.1055/s-0036-1691527.
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References and Notes
Ethyl (2E)-(1-Benzyl-4,5-dimethyl-1,3-dihydro-2H-imidazol-
2-ylidene)(cyano)acetate (4a)
(1) (a) Nikitina, P. A.; Perevalov, V. P. Chem. Heterocycl. Compd.
(Engl. Transl.) 2017, 53, 123. (b) Mlostoń, G.; Jasiński, M.;
Wróblewska, A.; Heimgartner, H. Curr. Org. Chem. 2016, 20,
1359. (c) Mlostoń, G.; Celeda, M.; Urbaniak, K.; Jasiński, M.;
Bakhonsky, V.; Schreiner, P. R.; Heimgartner, H. Beilstein J. Org.
Chem. 2019, 15, 497. (d) Mlostoń, G.; Romański, J.; Jasiński, M.;
Heimgartner, H. Tetrahedron: Asymmetry 2009, 20, 1073.
(2) (a) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle,
M.; Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.;
Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291.
(b) Campeau, L.-C.; Bertrand-Laperle, M.; Leclerc, J.-P.;
Villemure, E.; Gorelsky, S.; Fagnou, K. J. Am. Chem. Soc. 2008,
130, 3276.
(3) (a) Adiulin, E. I.; Kutasevich, A. V.; Mityanov, V. S.; Tkach, I. I.;
Koldaeva, T. Y. Chem. Heterocycl. Compd. (Engl. Transl.) 2015, 51,
500. (b) Ferguson, I. J.; Schofield, K. J. Chem. Soc., Perkin Trans. 1
1975, 275. (c) Wróblewska, A.; Mlostoń, G.; Heimgartner, H. Tet-
rahedron: Asymmetry 2015, 26, 505. (d) Antonova, M. M.;
Baranov, V. V.; Nelyubina, Y. V.; Kravchenko, A. N. Chem. Hetero-
cycl. Compd. (Engl. Transl.) 2014, 50, 1203. (e) Mlostoń, G.;
Wróblewska, A.; Heimgartner, H. J. Fluorine Chem. 2016, 189, 1.
(f) Laufer, S.; Wagner, G.; Kotschenreuther, D. Angew. Chem. Int.
Ed. 2002, 41, 2290.
White solid; yield: 255 mg (86%); mp 164–166 °C. IR (KBr):
3208, 2983, 2183 (CN), 1639, 1568, 1475, 1440, 1369, 1321,
1305, 1261, 1248, 1209, 1132, 1087, 1034, 975, 779, 732, 705,
693, 533, 457 cm–1. 1H NMR (300 MHz, DMSO-d6):  = 11.91 (s,
1 H), 7.40–7.25 (m, 2 H), 7.05 (d, J = 7.1 Hz, 3 H), 5.41 (s, 2 H),
4.06 (q, J = 7.1 Hz, 2 H), 2.12 (s, 3 H), 1.95 (s, 3 H), 1.17 (t, J = 7.1
Hz, 3 H). 13C NMR (151 MHz, DMSO-d6):  = 168.40, 145.23,
136.31, 128.72, 127.44, 126.61, 125.98, 121.11, 120.75, 120.08,
58.38, 46.33, 14.71, 8.91, 7.85. HRMS-ESI: m/z [M + H]+ calcd for
C
17H20N3O2: 298.1555; found: 298.1550.
(1-Benzyl-4,5-dimethyl-1,3-dihydro-2H-imidazol-2-
ylidene)[(4-chlorophenyl)sulfonyl]acetonitrile (4n)
White solid; yield: 204 mg (51%); mp 203–205 °C. IR (KBr):
3294, 2160 (CN), 1651, 1558, 1474, 1435, 1389, 1335, 1312,
1296, 1273, 1142, 1088, 1049, 1011, 933, 825, 795, 756, 717,
633, 579, 478 cm–1. 1H NMR (400 MHz, DMSO-d6):  = 12.44 (s,
1 H), 7.58 (d, J = 11.1 Hz, 2 H), 7.49 (d, J = 11.2 Hz, 2 H), 7.34–
7.06 (m, 3 H), 6.81 (d, J = 8.1 Hz, 2 H), 5.22 (s, 2 H), 2.15 (s, 3 H),
1.94 (s, 3 H). 13C NMR (101 MHz, DMSO-d6):  = 147.63, 143.24,
138.95, 138.03, 132.00, 131.47, 130.39, 129.49, 128.84, 126.46,
126.01, 122.83, 54.62, 49.75, 11.86, 11.04. HRMS-ESI: m/z [M +
H]+ calcd for C20H19ClN3O2S: 400.0886; found: 400.0881.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D