Electrocatalytic multicomponent cyclization of an aldehyde, malononitrile and a malonate into 3-substituted-2,2-dicyanocyclopropane-1,1-dicarboxylate-the first one-pot synthesis of a cyclopropane ring from three different molecules

Article abstract of DOI:10.1016/j.tetlet.2006.10.075

Electrolysis of an aldehyde, malononitrile and a malonate in an alcohol in an undivided cell in the presence of sodium acetate-sodium halide as a double mediatory system results in the formation of 3-substituted-2,2-dicyanocyclopropane-1,1-dicarboxylates

Full text of DOI:10.1016/j.tetlet.2006.10.075

Tetrahedron Letters 47 (2006) 9129–9133
Electrocatalytic multicomponent cyclization of an aldehyde,
malononitrile and a malonate into 3-substituted-2,2-
dicyanocyclopropane-1,1-dicarboxylate—the first one-pot synthesis
of a cyclopropane ring from three different molecules
*
Michail N. Elinson, Sergey K. Feducovich, Anatolii N. Vereshchagin,
Sergey V. Gorbunov, Pavel A. Belyakov and Gennady I. Nikishin
N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, 119991 Moscow, Russia
Received 4 August 2006; revised 4 October 2006; accepted 12 October 2006
Available online 3 November 2006
Abstract—Electrolysis of an aldehyde, malononitrile and a malonate in an alcohol in an undivided cell in the presence of sodium
acetate–sodium halide as a double mediatory system results in the formation of 3-substituted-2,2-dicyanocyclopropane-1,1-dicarb-
oxylates in 40–60% yields.
Ó 2006 Elsevier Ltd. All rights reserved.
Cyclopropane is a basic structural element in a wide
range of natural compounds and occupies a significant
place in synthetic organic chemistry. The cyclopropyl
The well-known MIRC leading to substituted cyclopro-
panes involves the addition of halogenosubstituted C–H
acid anions (A), generated by the action of a base on the
corresponding C–H acid (AH), to the conjugated acti-
vated olefins followed by cyclization with elimination
1
group is also a vital structural unit in many synthetic
and naturally occurring compounds, exhibiting a wide
spectrum of biological properties ranging from enzyme
inhibition to herbicidal, antibiotic, antitumour and anti-
5
of halide (Scheme 1).
2
,3
viral activities. Insecticidal pyrethrins (derivatives of
chrysanthemic acid) are perhaps the best known exam-
Anion (A) generation and its reactions with activated
olefins have been accomplished in biphasic systems in
1
6
ple of their use. Thus, the prevalence of cyclopro-
the presence of a phase transfer catalyst. The electro-
pane-containing compounds with biological activity,
whether isolated from natural sources or rationally
designed pharmaceutical agents, has inspired chemists
to find novel and diverse approaches to their synthesis.
chemical reduction of dihalogeno substituted malonates
followed by the addition of anion A (X@Y@COOR) to
activated double bonds provides an improvement of this
7
reaction scheme.
Although the synthetic methods for cyclopropanes have
long been documented, so far, all consist of two main
groups: (1) intramolecular cyclization or, (2) interaction
of two different molecules (addition of carbenes to ole-
fins or Michael initiated ring closure (MIRC) are the
The next essential step was to exclude halogen-contain-
ing organic compounds as initial reagents. Hence a
novel electrochemical approach to functionally substi-
tuted cyclopropanes was performed by the electrolysis
1
,3
best known examples of this type). MIRC plays an
important role in organic chemistry and many synthetic
R1
2
R1
R2
R
_
4
X
Y
applications are described in the literature.
X
Y
X
Y
+
CHalXY
C
C
_
Hal-
A
Keywords: Electrolysis, Electrocatalytic transformation; Mediators;
X = COOR
Hal = Br, I
Aldehydes; Malononitrile; Malonate; Cyclopropanes.
Y = COOR, CN, C(O)NR2
*
Corresponding author. Tel.: +7 495 137 38 42; fax: +7 495 135 53
8; e-mail: elinson@ioc.ac.ru
2
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.075

9130
M. N. Elinson et al. / Tetrahedron Letters 47 (2006) 9129–9133
of alkylidenemalonates and malonate in an undivided
cell in methanol in the presence of halides as mediators.
hyde and malononitrile into bicyclic pyrrolines in the
presence of the new double mediatory system NaOAc–
NaBr (Scheme 6).
8
1
3
The co-electrolysis of alkylidenecyanoacetic and malo-
nic esters resulted in the stereoselective syntheses of
In the present study, we report our results on the one-
pot, multicomponent electrocatalytic transformation of
aldehydes 1a–i, malononitrile and malonate into 3-
substituted-2,2-dicyanocyclopropane-1,1-dicarboxylates
2a–i in methanol in the presence of the double media-
tory system sodium acetate–sodium bromide in an undi-
vided cell, which to our knowledge is the first example of
cyclopropane ring formation from three different mole-
cules (Scheme 7, Table 1).
(
E)-isomers of trialkyl 3-substituted-2-cyanocycloprop-
9
ane-1,1,2-tricarboxylates (Scheme 2).
Recently, we accomplished the electrocatalytic transfor-
mation of alkylidenemalononitriles and malonate into
dialkyl 3-substituted-2,2-dicyanocyclopropane-1,1-dicarb-
1
0
oxylates (Scheme 3).
It has also been found that tetracyanocyclopropanes, on
electrolysis in alcohols in an undivided cell, were very
easily attacked by alkoxide anions generated at the
cathode to afford substituted 2-amino-4,4-dialkoxy-1,5-
In the mediatory system, NaOAc acts as a catalyst for
the Knoevenagel condensation of the aldehyde and mal-
ononitrile. When electricity was not passed, the alde-
hyde and malononitrile, in the presence of NaOAc,
were condensed into alkylidenemalononitriles in a time
less than half of that of the electrochemical reaction
(30 min). Earlier NaOAc was used as a catalyst in
1
1
dicyano-3-azabicyclo[3.1.0]hex-2-enes (Scheme 4).
Combining these two methods, we accomplished the
stereoselective electrocatalytic transformation of alkyl-
idenemalononitriles and malononitrile into bicyclic
1
5
the Perkin condensation and in the Knoevenagel
1
2
13
pyrrolines containing a cyclopropane ring (Scheme 5).
reaction.
The next step of our research was a one-pot stereoselec-
tive electrocatalytic transformation of an aromatic alde-
Taking into consideration the above results, the data on
the mechanism of the electrocatalytic variant of the
R2
H
CO2R1
CN
1
2
electrolysis
R O C
CN
R2
CH2
+
1
1
1
CO2R1
NaBr, R OH
R O C
CO R
CO2R1
2
2
Scheme 2.
R2
CO2R1
CN
CN
H
1
electrolysis
R O C
CN
CN
2
R2
CH2
+
1
1
CO2R1
NaBr, R OH
R O2C
Scheme 3.
R1
R2
R1
R2
CN
NC
NC
NC
CN
electrolysis, 0.05-0.10 F/mol
3
R O
CN
3
NH2
R OH
3
R O
N
Scheme 4.
R1
CN
NC
CN
NH2
electrolysis
CH=C(CN)2
+
2
R1
2
R O
CN
NaBr, R OH
2
R O
N
Scheme 5.

M. N. Elinson et al. / Tetrahedron Letters 47 (2006) 9129–9133
9131
R1
CN
CN
NC
CN
NH2
electrolysis
CH
O
+
2
2
R1
2
R O
NaOAc-NaBr, R OH
2
R O
N
Scheme 6.
R
CN
CO2Me
CO2Me NaOAc-NaBr, MeOH
electrolysis
CH
O
+
+
NC
NC
CO Me
2
R
CN
CO2Me
1a-i
2a-i
Scheme 7.
Table 1. Electrocatalytic transformation of an aldehyde, malononitrile
and malonate into 3-substituted-2,2-dicyanocyclopropane-1,1-
dicarboxylates 2a–i
NaOAc
a
CH=C(CN)2
CH2(CN)2 +
CH=O
a,14
R
R
b
Aldehyde
R
Cyclopropane
Yield (%)
Scheme 8.
c
1
1
1
1
1
1
1
1
1
1
1
a
a
a
b
c
d
e
f
H
H
H
4-Me
4-MeO
2-MeO
4-Cl
2-Cl
4-Br
4-F
2a
2a
2a
2b
2c
2d
2e
2f
35
54
41
52
47
45
58
48
46
63
46
d
2 Hal-
Anode:
-
2e
2e
Hal2
2 MeO-
Hal = Br, I
Cathode: 2 MeOH +
Scheme 9.
+
H2
g
h
i
2g
2h
2i
was conducted without stirring the reaction mixture.
The evolution of hydrogen occurred at the cathode.
2-F
a
1
2 mmol of malononitrile, 10 mmol of dimethyl malonate, 10 mmol
of aldehyde, 5 mmol of NaBr, 5 mmol of NaOAc, 20 ml of methanol,
Fe-cathode, C-anode, current density 100 mA/CM , 2.5 F/mol elec-
tricity passed at 0 °C.
Isolated yields.
The reaction in solution between an alkoxide ion and
malonate leads to the formation of a malonate anion.
Halogenation of the malonate anion by the halogen
generated at the anode, then the formation of the halo-
genomalonate anion, followed by the addition to the
alkylidenemalonitrile gives rise to a 3-substituted 2,2-
dicyanocyclopropane-1,1-dicarboxylate (Scheme 10).
2
b
c
10 °C.
d
Mediator: NaI–NaOAc.
Wideqvist reaction11 and the mechanism of electrocata-
lytic transformation of alkylidenemalononitriles and
malonate into dialkyl 3-substituted-2,2-dicyanocyclo-
Sodium bromide is more efficient as a mediator for the
above process than sodium iodide. This result is directly
related to the fact that the intermediate bromomalonate
is a stronger CH acid than iodomalonate and thus the
proton abstraction step with the formation of the halo-
genomalonate anion [Scheme 10, stage (3)] is faster in
the case of bromomalonate.
1
0
propane-1,1-dicarboxylates, the following mechanism
for the one-pot electrocatalytic transformation of an
aldehyde, malononitrile and a malonate into 3-sub-
stituted-2,2-dicyanocyclopropane-1,1-dicarboxylates is
suggested. Knoevenagel condensation of malononitrile
and the aldehyde is catalyzed by NaOAc (Scheme 8).
Thus, the simple electrocatalytic system can produce un-
der mild conditions one-pot electrocatalytic multicom-
ponent transformations of an aldehyde, malononitrile
and malonate into 3-substituted-2,2-dicyanocyclo-
propane-1,1-dicarboxylates 2a–i. This process, to our
knowledge, is the first example of cyclopropane ring
formation from three different molecules.
The reactions occurring at the electrodes, are shown
below (Scheme 9).
The formation of iodine or bromine at the anode is a
well-known process and the corresponding halogen
colour was observed at the anode when the electrolysis

9132
M. N. Elinson et al. / Tetrahedron Letters 47 (2006) 9129–9133
+
+
MeO-
Hal2
CH(CO Me)
-
2
2
+
MeOH
(1)
(2)
CH2(CO2Me)2
-
Hal-
CH(CO2Me)2
CH(Hal)(CO2Me)2
+
-
-
CH(Hal)(CO2Me)2
+
MeO
C(Hal)(CO Me)
(3)
2
2
+
MeOH
R
NC
NC
CO2Me
-
-
CHal(CO2Me)2
+
CH=C(CN)2
+
Hal
(4)
R
CO Me
2
Scheme 10.
Using classical organic chemistry, this transformation
could only be accomplished as a three-step process com-
prising (i) Knoevenagel condensation of the aldehyde
and malononitrile with formation of an alkylidenemal-
Rosen, T. C.; Meyer, O. G. J.; Sloan, M. J.; Ye, S.; Haufe,
G.; Kirk, K. L. Bioorg. Med. Chem. 2004, 12, 2645–2652.
3
. For reviews see: (a) Faust, R. Angew. Chem., Int. Ed. 2001,
0, 2251–2253; (b) Donaldson, W. A. Tetrahedron 2001,
57, 8589–8627; (c) Brandt, W.; Thiemann, T. Chem. Rev.
003, 103, 1625–1647.
. (a) Little, R. D.; Dawson, J. R. J. Am. Chem. Soc. 1978,
00, 4607–4609; (b) Little, R. D.; Dawson, J. R. Tetra-
4
1
6
17
ononitrile, (ii) halogenation of the malonate and,
iii) addition of the halogenomalonate to the double
bond of the alkylidenemalononitrile followed by
2
(
4
1
1
8
cyclization.
hedron Lett. 1980, 21, 2609–2612; For reviews see: (c)
Caine, D. Tetrahedron 2001, 57, 2643–2684; (d) Lebel, H.;
Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem. Rev.
2003, 1015–1036.
. Bonavent, G.; Causse, M.; Guittard, M.; Fraisse-Julien,
R. Bull. Soc. Chim. Fr. 1964, 2462–2471.
. Kryshtal’, G. V.; Shtemenko, N. I.; Yanovskaya, L. A.
Izv. Akad. Nauk SSSR Ser. Khim. 1980, 2420–2423.
. Le Menn, J. C.; Sarrazin, J.; Tallec, A. Electrochim. Acta
This new electrochemical process is an efficient and con-
venient method for the synthesis of 3-substituted-2,2-
dicyanocyclopropane-1,1-dicarboxylates. The procedure
utilizes inexpensive reagents, simple equipment and an
undivided cell, it is easily carried out and the work-up
is not complicated.
5
6
7
8
1
990, 35, 563–566.
To our knowledge this is also the first example using
a multicomponent strategy for the synthesis of cyclo-
propanes.
. Elinson, M. N.; Feducovich, S. K.; Bushuev, S. G.;
Zakharenkov, A. A.; Pashchenko, D. V.; Nikishin, G. I.
Mendeleev Commun. 1998, 15–17.
9
. Elinson, M. N.; Feducovich, S. K.; Starikova, Z. A.;
Olessova, O. S.; Vereshchagin, A. N.; Nikishin, G. I.
Tetrahedron Lett. 2000, 41, 4937–4941.
Acknowledgement
1
0. Elinson, M. N.; Feducovich, S. K.; Zaimovskaya, T. A.;
Vereshchagin, A. N.; Gorbunov, S. V.; Nikishin, G. I. Izv.
Akad. Nauk Ser. Khim. 2005, 1547–1552.
The authors gratefully acknowledge the financial sup-
port of the Russian Foundation for Basic Research
(
Project No. 03-03-32068a).
References and notes
. (a) Yanovskaya, L. A.; Dombrovsky, V. A.; Khusid, A.
11. Elinson, M. N.; Feducovich, S. K.; Lizunova, T. L.;
Nikishin, G. I. Tetrahedron 2000, 56, 3063–3069.
1
2. Elinson, M. N.; Feducovich, S. K.; Starikova, Z. A.;
Vereshchagin, A. N.; Nikishin, G. I. Tetrahedron 2004, 60,
1
1743–11749.
1
13. Elinson, M. N.; Feducovich, S. K.; Zaimovskaya, T. A.;
Vereshchagin, A. N.; Nikishin, G. I. Izv. Akad. Nauk Ser.
Khim. 2005, 663–667.
Kh. Tsiklopropani s funktsionalnimi gruppami. Sintez i
primenenie. (Cyclopropanes with Functional Groups. Syn-
thesis and Application); Nauka: Moscow, 1980; (b) The
Chemistry of the Cyclopropyl Group; Tsuji, T., Nishida, S.,
Eds.; Wiley and Sons: New York, 1987; (c) Boche, G.;
Walbirsky, H. M. Cyclopropane Derived Intermediates;
John Wiley and Sons: New York, 1990; (d) Rappoport, Z.
The Chemistry of the Cyclopropyl Group; Wiley and Sons:
New York, 1996.
14. General electrolysis procedure. A solution of aldehyde
(10 mmol), malononitrile (12 mmol), dimethyl malonate
(10 mmol), sodium bromide (5 mmol) and sodium acetate
(5 mmol) in methanol (20 ml) was electrolyzed in an
undivided cell equipped with a C-anode and an Fe-
cathode, a thermometer, external cooling and a magnetic
2
stirrer under constant current density of 100 mA/cm at
2
. (a) Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.;
Ibuka, T.; Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001,
0 °C. At the end of the electrolysis, when 2.5 F/mol
electricity had been passed, the dimethyl 3-substituted-2,2-
dicyanocyclopropane-1,1-dicarboxylates were removed by
filtration and washed with cold methanol. All compounds
(2a–i) gave expected NMR spectra. For new compounds
(2d,g,h), satisfactory elemental analyses were obtained.
Mass-spectra (70 eV) were determined directly using
Finningan MAT INCOS 50 spectrometer.
66, 81–88; (b) Boger, D. L.; Hughes, T. V.; Hedrick, M. P.
J. Org. Chem. 2001, 66, 2207–2216; (c) Graham, D. W.;
Ashton, W. T.; Barash, L.; Brown, J. E.; Brown, R. D.;
Canning, L. F.; Chen, A.; Springer, J. P.; Rogers, E. F.
J. Med. Chem. 1987, 30, 1074–1090; (d) Salaun, J.; Baird,
M. S. Curr. Med. Chem. 1995, 2, 511–519; (e) Yoshida, S.;

M. N. Elinson et al. / Tetrahedron Letters 47 (2006) 9129–9133
9133
Dimethyl 3-(2-methoxyphenyl)-2,2-dicyanocyclopropane-
NMR
m
C
2252, 1756, 1748, 1440, 1272. Anal. Calcd for
11BrN : C, 49.61; H, 3.05; Br, 22.00; N, 7.71.
1
1
,1-dicarboxylate 2d: mp 114–115 °C;
H
15
H
2 4
O
(
250 MHz, CDCl ): d = 3.80 (s, 3H, CH O), 3.84 (s, 1H,
Found: C, 49.43; H, 3.01; Br, 21.79; N,7.58.
Dimethyl 3-(4-fluorophenyl)-2,2-dicyanocyclopropane-1,1-
dicarboxylate 2h: mp 126–127 °C; H NMR (250 MHz,
3 3
CDCl ): d = 3.79 (s, 3H, CH O), 3.94 (s, 1H, CH), 3.98 (s,
3
3
CH), 3.93 (s, 3H, CH
3
O), 3.96 (s, 3H, CH
3
O), 6.90–7.00
1
(
m, 2H, Ar), 7.21 (d, 1H, Ar, J = 7.8), 7.33–7.44 (m, 1H,
13
Ar); C NMR (62.5 MHz, CDCl
3
): d = 17.2 (C), 36.9
(
1
1
CH), 46.4 (C), 53.9 (CH O), 54.7 (CH O), 55.7 (CH O),
10.0 (CN), 111.1 (CH, Ar), 112.4 (CN), 115.8 (C, Ar),
20.7, 128.6, 131.3 (all CH, Ar), 158.2 (C–O, Ar), 162.0
3H, CH O), 7.11 (t, 2H, Ar, J = 8.7), 7.38 (dd, 2H, Ar,
3
13
3
3
3
J
1
= 5.1, J
2
= 8.7);
C NMR (62.5 MHz, CDCl
3
):
d = 16.6 (C), 39.6 (CH), 46.4 (C), 54.1 (CH
3
O), 55.0
(
%
(
1
C@O), 163.7 (C@O). MS (70 eV) m/z (relative intensity
(CH O), 109.7 (CN), 111.7 (CN), 116.4 (d, CH, Ar,
3
+
2
4
): 314 (M , 24), 282 (79), 255 (34), 239 (20), 223 (25), 181
J
CF = 22.9), 123.2 (d, C, Ar, JCF = 3.5), 130.9 (d, CH,
À1
3
44), 59 (100). IR (KBr, cm ): m 2256, 1762, 1748, 1440,
Ar, JCF = 9.1), 161.5 (C@O), 163.3 (d, CF, J = 248.8),
163.4 (C@O). MS (70 eV) m/z (relative intensity %): 302
(M , 12), 271 (67), 258 (44), 243 (50), 158 (100), 139 (90),
288. Anal. Calcd for C16
14 2 5
H N O : C, 61.14; H, 4.49; N,
+
8
Dimethyl 3-(4-bromophenyl)-2,2-dicyanocyclopropane-1,1-
dicarboxylate 2g: mp 107–108 °C; H NMR (250 MHz,
CDCl
.91. Found: C, 60.93; H, 4.53; N, 8.69.
À1
59 (91). IR (KBr, cm ): m 2256, 1760, 1740, 1512,
1
2 4
1436, 1236. Anal. Calcd for C15H11FN O : C, 59.61; H,
3.67; F, 6.29; N, 9.27. Found: C, 59.43; H, 3.58; F, 6.14; N,
9.19.
3
): d = 3.78 (s, 3H, CH
3
O), 3.93 (s, 1H, CH), 3.97 (s,
3
H, CH O), 7.23 (d, 2H, Ar, J = 8.4), 7.53 (d, 2H, Ar,
3
13
J = 8.4); C NMR (62.5 MHz, CDCl
(
1
1
(
3
): d = 16.5 (C), 36.6
15. Leake, P. H. Chem. Rev. 1956, 56, 27–48.
16. Mirek, J.; Adamczyk, M.; Mokrosz, M. Synthesis 1980,
296–299.
17. Kochergin, P. M.; Titkova, R. M. Russ. J. Org. Chem.
1994, 30, 1042–1044.
CH), 46.3 (C), 54.2 (CH
3
O), 55.1 (CH O), 109.5 (CN),
3
11.6 (CN), 124.3 (C, Ar), 126.3 (C, Ar), 130.5, 130.5,
32.5, 132.5 (all CH, Ar), 161.4 (C@O), 163.3 (C@O). MS
+
+
70 eV) m/z (relative intensity %): 364 (M , 18), 362 (M ,
2
2), 332 (41), 330 (38), 305 (39), 303 (38), 220 (83), 218
18. LeMenn, J.-C.; Tallec, A.; Sarrazin, J. Can. J. Chem. 1991,
69, 761–767.
À1
(
75), 201 (65), 199 (76), 165 (60), 59 (100). IR (KBr, cm ):