Synthesis and some chemical transformations of N-cyclohexyl-2-imino-4- methyl-5,5-pentamethylene-2,5-dihydrofuran-3-carboxamide

Full text of DOI:10.1134/S1070428009100303

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 10, pp. 1578–1580. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.A. Avetisyan, L.V. Karapetyan, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 10, pp. 1589–1590.
SHORT
COMMUNICATIONS
Synthesis and Some Chemical Transformations
of N-Cyclohexyl-2-imino-4-methyl-5,5-pentamethylene-
2,5-dihydrofuran-3-carboxamide
A. A. Avetisyan and L. V. Karapetyan
Erevan State University, ul. Aleka Manukyana 1, Erevan, 0025 Armenia
e-mail: lousine_karapetyan@yahoo.com
Received April 3, 2009
DOI: 10.1134/S1070428009100303
Functionally substituted derivatives of unsaturated
γ-lactones are widespread in nature, and they often
exhibit pronounced biological activity. Apart from
monocyclic unsaturated γ-lactones, some natural com-
pounds are derivatives of spiro and fused bicyclic
systems including a six-membered ring. The natural
terpenoid andirolactone is a spiro-fused unsaturated
γ-lactone possessing valuable properties [1]. The
natural alkaloid cerpegin in which unsaturated lactone
ring is fused to a pyridine ring, exhibits antiphlogistic,
analgesic, antiulcer, and tranquilizing activity and is
used in folk medicine [2–4]. Therefore, synthesis of
spiro systems including both γ-lactone and six-mem-
bered ring is an important problem.
Taking into account that nitrogen analogs of various
oxygen-containing biologically active substances often
possess equally useful properties, we continued our
studies on condensations of tertiary α-keto alcohols
with compounds having an activated methylene group
[5] and examined the reaction of 1-acetylcyclohexanol
with N-cyclohexyl(cyano)acetamide. The reaction was
carried out in anhydrous methanol in the presence of
sodium methoxide at 40°C (reaction time 5 h). As
a result, we isolated N-cyclohexyl-2-imino-4-methyl-
5,5-pentamethylene-2,5-dihydrofuran-3-carboxamide
(I) in high yield (Scheme 1). Imine I readily underwent
hydrolysis in weakly acidic medium (pH 4–5, 85–
90°C, 3 h) to produce 2,5-dihydrofuran-2-one II. This
reaction sequence may be regarded as a new method
for the synthesis of functionally substituted unsaturated
γ-lactones.
Scheme 1.
O
Compound I was readily and quantitatively con-
verted into the corresponding hydrochloride III by
passing gaseous hydrogen chloride through a solution
of I in benzene. Hydrochloride III can be titrated with
a 0.1 N solution of sodium hydroxide, whereas treat-
ment of III with a solution of potassium carbonate
recovers initial 2-imino derivative I. Hydrolysis of
HO
Me
H
N
CN
+
O
O
Me
MeONa
N
H
Scheme 2.
O
NH
I
O
Me
HCl
I
N
O
NaOH, K2CO3
H
Me
HCl, H2O, pH 4–5
O
N
NH·HCl
H
III
O
O
H2O
II
II
1578

SYNTHESIS AND SOME CHEMICAL TRANSFORMATIONS
1579
hydrochloride III at 85–90°C in 2 h also yields 2,5-di-
hydrofuran-2-one II (Scheme 2).
extracted with diethyl ether (3×5 ml). The extract was
dried over magnesium sulfate and evaporated, and the
residue was recrystallized from petroleum ether. Yield
79%, mp 142–143°C. IR spectrum, ν, cm–1: 3280
(NH), 1780 (C=O), 1680 (C=O), 1620 (C=C). 1H NMR
spectrum, δ, ppm: 1.19–1.49 m (6H, C6H11), 1.58–
1.95 m (14H, C6H11), 2.33 s (3H, CH3), 3.73 m (1H,
NHCH), 9.35 d (1H, NHCH, J = 7.9 Hz). Found, %:
C 70.24; H 8.73; N 4.94. C17H25NO3. Calculated, %:
C 70.07; H 8.65; N 4.81.
We also examined the reaction of 2-imino-2,5-dihy-
drofuran I with malononitrile. The reaction occurred at
room temperature with equimolar amounts of the reac-
tants and afforded 2-dicyanomethylidene-2,5-dihydro-
furan IV in quantitative yield (ammonia no longer
evolved by the end of the process; Scheme 3).
Scheme 3.
N-Cyclohexyl-2-imino-4-methyl-5,5-pentameth-
ylene-2,5-dihydrofuran-3-carboxamide hydrochlo-
ride (III). Gaseous hydrogen chloride was passed
through a solution of 2 mmol of compound I in ben-
zene. The precipitate was filtered off and washed with
O
Me
CH2(CN)2
–NH3
N
H
I
CN
O
1
diethyl ether. Yield 97%, mp 236–240°C. H NMR
NC
spectrum, δ, ppm: 1.19–1.49 m (6H, C6H11), 1.58–
1.95 m (14H, C6H11), 2.33 s (3H, CH3), 3.71 m (1H,
NHCH), 9.22 d (1H, NHCH, J = 7.9 Hz), 10.34 br.s
(2H, NH·HCl). Found, %: C 62.57; H 8.34; N 8.69.
C17H27ClN2O2. Calculated, %: C 62.47; H 8.26; N 8.57.
IV
The structure of the isolated compounds was
proved by the IR and H NMR spectra and elemental
1
analyses. Compounds I–IV were tested for antibacte-
rial activity at the Chemotherapy Laboratory, Mndzho-
yan Institute of Fine Organic Chemistry, National
Academy of Sciences of Armenian Republic. Moderate
antibacterial activity of these compounds was revealed
in vitro; therefore, further studies in this line seem to
be promising.
Reaction of hydrochloride III with potassium
carbonate. A concentrated aqueous solution of potas-
sium carbonate was added to a solution of 0.5 mmol of
hydrochloride III in water until pH 7–8. The precip-
itate was filtered off and washed with water. Yield of
iminolactone I 95%, mp 124–125°C. No depression
of the melting point was observed on mixing with
a sample of I prepared as described above.
N-Cyclohexyl-2-imino-4-methyl-5,5-pentameth-
ylene-2,5-dihydrofuran-3-carboxamide (I). 1-Ace-
tylcyclohexanol and N-cyclohexyl(cyano)acetamide,
10 mmol each, were added to a solution of sodium
methoxide in methanol prepared from 1 mmol of
metallic sodium and 20 ml of methanol. The mixture
was heated for 5 h at 40°C, the solvent was removed
under reduced pressure, the residue was treated with
water, and the precipitate was filtered off, washed with
water, and recrystallized from ethanol. Yield 95%,
mp 124–125°C. IR spectrum, ν, cm–1: 3360, 3180 (NH);
1680 (C=O); 1670 (C=N); 1620 (C=C). 1H NMR spec-
trum, δ, ppm: 1.19–1.49 m (6H, C6H11), 1.58–1.95 m
(14H, C6H11), 2.33 s (3H, CH3), 3.72 m (1H, NHCH),
7.23 s (1H, =NH), 9.35 d (1H, NH, J = 7.9 Hz). Found,
%: C 70.44; H 9.14; N 9.77. C17H26N2O2. Calculated,
%: C 70.31; H 9.02; N 9.65.
Hydrolysis of compound III. A mixture of 1 mmol
of hydrochloride III and 5 ml of water was heated for
2 h at 85–90°C. The mixture was cooled and extracted
with diethyl ether (3×5 ml), the extract was dried over
magnesium sulfate and evaporated, and the residue
was recrystallized from petroleum ether. Yield of com-
pound II 82%; its melting point coincided with that
given above.
N-Cyclohexyl-2-dicyanomethylidene-4-methyl-
5,5-pentamethylene-2,5-dihydrofuran-3-carbox-
amide (IV). A mixture of 2.5 mmol of compound I,
0.17 g (2.5 mmol) of malononitrile, and 5 ml of anhy-
drous ethanol was stirred at room temperature until
ammonia no longer evolved. The solvent was distilled
off, the residue was treated with water, and the precip-
itate was filtered off, washed with water, and recrys-
tallized from benzene. Yield 90%, mp 166–167°C.
IR spectrum, ν, cm–1: 3280 (NH), 2225 (CN), 1680
N-Cyclohexyl-4-methyl-5,5-pentamethylene-2-
oxo-2,5-dihydrofuran-3-carboxamide (II). A mixture
of 1.5 mmol of compound I and 5 ml of water was
adjusted to pH 4–5 by adding hydrochloric acid, and
the mixture was heated for 3 h at 85–90°C, cooled, and
1
(C=O), 1635 (C=C), 1620 (C=C). H NMR spectrum,
δ, ppm: 1.19–1.49 m (6H, C6H11), 1.58–1.95 m (14H,
C6H11), 2.33 s (3H, CH3), 3.72 m (1H, NHCH), 9.35 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 10 2009

AVETISYAN, KARAPETYAN
1580
(1H, NH, J = 7.9 Hz). Found, %: C 70.92; H 7.51;
N 12.44. C20H25N3O2. Calculated, %: C 70.77; H 7.42;
N 12.38.
REFERENCES
1. Orduna, A., Zepeda, L.G., and Tamariz, J., Synthesis,
1993, p. 375.
The IR spectra were recorded on a Specord 75IR
spectrometer from samples dispersed in mineral oil.
2. Adibatti, N.A., Thirugnanasambantham, P., Kulothun-
gan, C., Viswanathan, S., Kameswaran, L., Balakrish-
na, K., and Sukumar, E., Phytochemistry, 1991, vol. 30,
p. 2449.
1
The H NMR spectra were obtained on a Varian
Mercury-300 spectrometer at 300 MHz using
DMSO-d6–CCl4 (1:3) as solvent and tetramethylsilane
as internal reference. The purity of the isolated com-
pounds was checked by thin-layer chromatography on
Silufol UV-254 plates using acetone–benzene (1:2) as
eluent; spots were visualized under UV light and by
treatment with iodine vapor.
3. Kelly, T.R. and Walsh, J.J., J.Org. Chem., 1992, vol. 57,
p. 6657.
4. Villemin, D. and Liao, L., Tetrahedon Lett., 1996, vol. 37,
p. 8733.
5. Avetisyan, A. and Karapetyan, L., Synth. Commun., 2009,
vol. 39, p. 7.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 10 2009