Efficient cyclopropanation of active methylene compounds. A serendipitous discovery

Article abstract of DOI:10.1016/j.tetlet.2005.08.050

Cyclopropanation of active methylene compounds has been achieved in good yields with ethylene carbonate as the cyclopropanating agent in the presence of a simple base.

Full text of DOI:10.1016/j.tetlet.2005.08.050

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7247–7248
Efficient cyclopropanation of active methylene compounds.
A serendipitous discovery
Veera Reddy Arava,a,* Udaya Bhaskara Rao Siripalli and Pramod Kumar Dubey
a
b
a
Research and Development Laboratories, Suven Life Sciences Ltd, # 18, Phase-III, Jeedimetla, Hyderabad 500055, India
b
Department of Chemistry, J.N.T. University, Hyderabad 500072, India
Received 25 June 2005; revised 3 August 2005; accepted 11 August 2005
Available online 2 September 2005
Abstract—Cyclopropanation of active methylene compounds has been achieved in good yields with ethylene carbonate as the cyclo-
propanating agent in the presence of a simple base.
ꢀ
2005 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives 5 (Eq. 2). A possible mechanism is shown in
Scheme 1.
Cyclopropanation of active methylene compounds is a
1
,2
very useful reaction in organic synthesis. In general,
it is carried out using either ethylene dichloride or ethyl-
ene dibromide as the alkylating agent in the presence of
O
3
K CO
3
CN
CN
O
O
2
+
X
X
a strong base like sodium hydride or 50% aqueous
sodium hydroxide in the presence of a phase transfer
catalyst (PTC), and the yields are moderate to good.
During the course of our investigations on the mono-
methylation of arylacetonitriles 1 with dimethyl carbon-
1
45-150°c
4
5
a) X = H, b) 3-phenoxy, c) X = 3,4-dimethoxy, d) X = 4-chloro,
e) X = 3,4-dichloro f) X = 4-bromo, g) X = 4-fluoro, h) X = 4-methylthio
i) X = 4-methoxy, j) X = 3-methoxy, k) X = 4-methyl, l) X = 3-chloro.
4
,5
ate (DMC) as a selective alkylating agent, we explored
the reaction of arylacetonitriles 1 with ethylene carbon-
6
,7
ate
for generating hydroxyethyl substituted com-
ð2Þ
pounds 3 (Eq. 1).
O
To check the versatility of this reaction, a series of aryl-
acetonitriles were subjected to the cyclopropanation
reaction, and the results are summarized in Table 1.
All the cyclopropanes were characterized by spectral
Ar
NC
O
O
2
K CO3
OH
CN
Ar
+
1
13
1
data ( H and C NMR and IR).
2
3
ð1Þ
2. Typical experimental procedure
The treatment of arylacetonitriles 1 with ethylene car-
bonate 2 in the presence of potassium carbonate at
2.1. 1-Arylcyclopropanecarbonitriles (5a–l)
1
40–150 ꢁC, to our surprise, generated the cyclopropane
To a magnetically stirred solution of the nitrile (4a–l,
2.7 mmol) and ethylene carbonate (0.284 mol) was
4
added potassium carbonate (36.2 mmol) at room tem-
perature. The reaction temperature was raised to 145–
150 ꢁC and maintained for 1 h. After the consumption
of the starting material (by TLC), the reaction mixture
Keywords: Cyclopropanation; Ethylene carbonate; Arylacetonitriles.
*
Corresponding author. Tel.: +91 40 30923856; fax: +91 40
3193541; e-mail: reddyvenis@rediffmail.com
2
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.050

7248
V. R. Arava et al. / Tetrahedron Letters 46 (2005) 7247–7248
O
O
O
Ar
Ar
OH
-
-
O
O
O
Ar
NC
O
-
O
NC
NC
O
O
O
O
Ar
OH
O
O
NC
Ar
NC
OH
CO2
Ar
O
-
Ar
CN
O
O
O
NC
O
O
-
O
O
-
OH
Scheme 1.
Table 1.
1
13
H and C NMR data
Starting material
Yield (%)
46
1
1
1
1
(a) X = H
3
H NMR (CDCl ) d, 1.37–1.40 (2H), 1.68–1.71 (2H), 7.24–7.36 (5H).
3
C NMR (CDCl
3
) d, 13.4, 17.73, 122, 125.15, 127.3, 128.65, 135.6
) d, 1.37–1.41 (2H), 1.68–1.72 (2H), 6.89–7.36 (9H).
(b) X = 3-phenoxy
54
H NMR (CDCl
3
3
3
C NMR (CDCl ) d, 13.54, 18.17, 122.05, 115.81, 117.43, 118.82, 120.33, 123.50, 129.69, 130.03,
1
37.96, 156.42, 157.65
1
(
(
(
(
(
(
(
(
(
(
c) X = 3,4-dimethoxy
d) X = 4-chloro
e) X = 3,4-dichloro
f) X = 4-bromo
56
53
53
53
27
47
46
52
43
53
H NMR (CDCl
3
) d, 1.33–1.36 (2H), 1.64–1.67 (2H), 3.86 (3H), 3.90 (3H), 6.81–6.86 (3H).
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3
C NMR (CDCl
3
) d, 13.00, 16.88, 55.452, 109.49, 110.875, 118.05, 122.46, 127.93, 148.19, 148.69
H NMR (CDCl
3
) d, 1.36–1.39 (2H), 1.72–1.75 (2H), 7.20–7.34 (4H).
3
C NMR (CDCl
3
) d, 13.25, 18.11, 121.98, 127.04, 128.89, 133.38, 134.49
H NMR (CDCl
3
) d, 1.38–1.42 (2H), 1.75–1.80 (2H), 7.12–7.44 (3H).
3
C NMR (CDCl
3
) d, 13.04, 18.36, 121.33, 124.88, 127.51, 130.56, 131.53, 132.79, 136.2
H NMR (CDCl
3
) d, 1.36–1.40 (2H), 1.73–1.76 (2H), 7.14–7.49 (4H).
3
C NMR (CDCl
3
) d, 13.3, 18.13, 121.34, 121.85, 127.27, 131.79, 135.0
) d, 1.34–1.37 (2H), 1.69–1.72 (2H), 7.01–7.29 (4H).
g) X = 4-fluoro
H NMR (CDCl
3
3
C NMR (CDCl
3
) d, 13.00, 17.57, 115.47, 115.69, 122.23, 127.71, 131.63, 160.64, 163.09
) d, 1.34–1.37 (2H), 1.68–1.71 (2H), 2.47 (3H), 7.01–7.29 (4H).
h) X = 4-methylthio
i) X = 4-methoxy
j) X = 3-methoxy
k) X = 4-methyl
l) X = 3-chloro
H NMR (CDCl
3
3
C NMR (CDCl
3
) d, 12.9, 15.2, 17.6, 122.08, 125.57, 126.43, 132.27, 137.83
H NMR (CDCl
3
) d, 1.30–1.33 (2H), 1.63–1.66 (2H), 3.78 (3H), 6.80–7.25 (4H).
3
C NMR (CDCl
3
) d, 12.6, 16.94, 54.8, 113.88, 122.49, 126.35, 127.41
H NMR (CDCl
3
) d, 1.37–1.40 (2H), 1.67–1.71 (2H), 3.80 (3H), 6.79–7.27 (4H).
3
C NMR (CDCl
3
) d, 13.47, 17.89, 54.90, 111.51, 112.45, 117.38, 122.18, 129.65, 137.31, 159.67
H NMR (CDCl
3
) d, 1.27–1.29 (2H), 1.65–1.68 (2H), 2.31 (3H), 7.12–7.23 (4H).
3
C NMR (CDCl
3
) d, 13.07, 17.51, 20.46, 122.35, 125.4, 129.2, 132.67, 136.97, 137.27
H NMR (CDCl
3
) d, 1.39–1.42 (2H), 1.73–1.76 (2H), 7.17–7.30 (4H).
3
3
C NMR (CDCl ) d, 13.25, 18.08, 121.56, 123.6, 125.6, 127.45, 129.5, 137.85, 138.87
was cooled to 45–50 ꢁC, treated with water (75 ml) and
extracted with toluene (2 · 50 ml). The combined organ-
ic extract was washed with water (25 ml) and then dried
over Na SO . Evaporation of the solvent and purifica-
tion of the residue by column chromatography on silica
gel furnished the 1-arylcyclopropanecarbonitriles 5a–l
References and notes
1. Singh, R. K. U.S. Patent 4,859,232, 1989 (Monsanto
company).
. Fedorynski, M.; Jonczyk, A. Org. Prep. Proc. Int. 1995, 27,
2
4
2
3
4
3
55.
. Makosza, M.; Serafinowa, B. Rocz. Chem. 1966, 40, 1647;
Chem. Abs. 1967, 66, 94792x.
. Tundo, P.; Rossi, L.; Loris, A. J. Org. Chem. 2005, 70,
(
Table 1).
2
219.
3. Conclusions
5
6
. Tundo, P.; Selva, M. Org. Synth. Coll. Vol. X, 640.
. Carlson, w. w.; Cretcher, L. H. J. Am. Chem. Soc. 1947, 69,
We have developed the use of the simple, cheap and ver-
satile ethylene carbonate as an efficient cyclopropanat-
ing reagent of active methylene compounds.
1
952–1956.
7. Morgan, M.; Cretcher, L. H. J. Am. Chem. Soc. 1946, 68,
782–784.