Synthesis of functionally substituted 2-imino-3-aryl-2,5-dihydrofurans and their chemical reactiosns

Full text of DOI:10.1134/S107042801102028X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 2, pp. 308311. Pleiades Publishing, Ltd., 2011.
Original Russian Text  A.A. Avetisyan, A.G. Alvandzhyan, K.S. Avetisyan, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 2, pp. 313315.
SHORT
COMMUNICATIONS
Synthesis of Functionally Substituted
2-Imino-3-aryl-2,5-dihydrofurans
and Their Chemical Reactions
A. A. Avetisyan, A. G. Alvandzhyan, and K. S. Avetisyan
Yerevan State University, Yerevan, 375025 Armenia
e-mail: avetisyan_ks@yahoo.com
Received March 17, 2010
DOI: 10.1134/S107042801102028X
3-Functionalized 2(5H)-furanones are known to be
contained in the composition of many biologically active
compounds and are widely applied in the medicine, agri-
culture, perfumery, etc. [1]. Depending on the character
of substituents the derivatives of 2(5Н)-furanones exhibit
various pharmacological actions [2–4].
containing aromatic substituents in the position 3 we
investigated in this study the reactions of α-ketols
with aromatic nitriles. In this reaction unlike that with
the malononitrile only 2-imino-3-aryl-4-methyl-5,5-
substituted2,5-dihydrofurans Iа–Id formed in high
yields (up to 90%).
In our previous publications we reported on the
structure and the process of the formation of the corre-
sponding substituted 2,5-dihydrofurans by condensation
of α-ketols with the amides of cyanoacetic acid [5] and
with malononitrile [6]. Unlike the reaction with the am-
ides of cyanoacetic acid the reaction of α-ketols with the
malonodinitrile led to the simultaneous formation in good
yields of two types of compounds, 2-imino derivatives
of the corresponding dihydrofurans, and the products of
their further reaction with the malonodinitrile, 2-dicya-
nomethylenedihydrofurans [6].
Various factors were studied affecting the course of
the reaction, optimum conditions were developed, and it
was established that the process easily occurred at room
temperature and equimolar amounts of the reagents in
the presence of a catalytic quantity of sodium ethylate
(1 : 1 : 0.1) in contrast to data of [7] where the sodium
ethylate was used in an equimolar amount as a reagent,
and the reaction was carried out under the microwave
activation (250 MHz, 100 W).
The reaction of 2-imino derivatives Iа–Id with malo-
nonitrile in the ratio 1 : 1 at room temperature in benzene
or ethanol within ~20 h furnished in nearly quantitative
yield the corresponding 2-dicyanomethylene derivatives
IIа–IId.
In extension of the research on the synthesis of new
functionally substituted derivatives of 2,5-dihydrofurans
and aiming at the preparation of 2-imino derivatives
C6H4R3
C6H4R3
H2C
Me
Me
Me
R1
R2
O
C6H4R3
C
N
CH2(CN)2
Ia_Id
R1
R2
R1
R2
_NH3
CN
CN
NH
O
OH
O
Ia_Id
IIa_IId
R1 = R2 = Me, R3 =H (a), Cl (b), OMe (c); R1,R2 =
C5H10, R3 = H (d).
R1 = R2 = Me, R3 = H (a), Cl (b), OMe (c); R1, R2 =
C5H10, R3 = H (d).
308

SYNTHESIS OF FUNCTIONALLY SUBSTITUTED 2-IMINO-3-ARYL-2,5-DIHYDROFURANS
309
At treating with hydrochloric and sulfuric acids at
pH 1–2 compounds Iа–Id readily and in the quantitative
yield formed salts IIIа–IIId, IVа–IVd. Hydrochlorides
IIIа–IIId were also obtained at passing gaseous hydrogen
chloride through the benzene solutions of compounds
Iа–Id. The salts obtained are easily titrated with 0.1 N
NaOH solution, and at the treatment with the solution of
potassium carbonate they are readily converted into the
initial imino derivatives Iа–Id.
H 7.51; N 6.96.
2-Imino-4,5,5-trimethyl-3-(4-chlorophenyl)-2,5-
dihydrofuran (Ib). Yield 10.1g (86%) mp 91–92°С
[7]. 1Н NMR spectrum, δ, ppm: 1.45 s (6Н, 2CH3),
1.85 and 1.90 s (3Н, СН3), 6.50 s (0.3Н, NΗ), 6.80 s
(0.7Н, NΗ), 7.20–7.55 m (4Нarom). Found, %: C 66.01;
H 5.73; Cl 15.28; N 5.67. C13H14ClNO. Calculated, %:
C 66.24; H 5.99; Cl 15.04; N 5.94.
2-Imino-4,5,5-trimethyl-3-(4-methoxyphenyl)-2,5-
dihydrofuran (Ic). Yield 8.37 г (72%) oily substance [7].
1Н NMR spectrum, δ, ppm: 1.40 s (6Н, 2CH3), 1.90 s
(3Н, СН3), 2.76 s (3Н, OСН3), 6.55 s (0.3Н, NΗ), 6.80 s
(0.7Н, NΗ), 7.18–7.50 m (4Нarom). Found, %: C 72.57;
H 7.20; N 6.32. C14H17NO2. Calculated, %: C 72.70;
H 7.41; N 6.06.
HCl,
H2SO4
C6H4R3
NH
C6H4R3
Me
R
R
Me
R
.
NH HX
IIIa_IIId, IVa_IVd
K2CO3
R
O
O
Ia_Id
2-Imino-4-methyl-5,5-pentamethylene-3-phenyl-
2,5-dihydrofuran (Id). Yield 10.88 g (90%), mp
126–127°С (125–126°С [7]). 1Н NMR spectrum, δ,
ppm: 1.25–1.80 m [10Н, (CH2)5], 1.95 s (3Н, СН3),
6.45 s (0.3Н, NΗ), 6.82 s (0.7Н, NΗ), 7.20–7.45 m
(5Нarom). Found, %: C 79.18; H 7.44; N 6.12. C16H19NO.
Calculated, %: C 79.63; H 7.94; N 5.80.

H+, H2O
Me
pH 4_5
H2O
C6H4R3
O
R
R
O
Va_Vd
2-Dicyanomethylene-4-methyl-3-phenyl-5,5-
substituted 2,5-dihydrofurans IIа–IId. A mixture of
0.01 mol of compound Iа–Id and 0.66 g (0.01 mol) of
malononitrile in 10 ml of anhydrous ethanol (or benzene)
was maintained at room temperature for ~20 h. The pre-
cipitate formed after partial distilling off the solvent in
a vacuum was filtered off and recrystallized from a mix-
ture ethanol–water, 2:1.
R1 = R2 = Me, R3 = H (a), Cl (b), OMe (c); R1,R2 = C5H10,
R3 = H (d); X = Cl (III), HSO4 (IV).
In the presence of acids (pH 4–5) at heating (70–80°C)
compounds Iа–Id within 3 h are hydrolyzed into the
corresponding 3-aryl-4-methyl-5,5-substituted 2(5Н)-
furanones Vа–Vd. Under similar conditions salts IIIа–
IIId, IVа–IVd in water or ethanol hydrolyze with the
formation of the corresponding furanones Vа–Vd.
2-Dicyanomethylene-4,5,5-trimethyl-3-phenyl-2,5-
dihydrofuran (IIа). Yield 2.34 g (93%), mp 207–208°С.
IR spectrum, ν, cm–1: 2228, 1620, 1588, 1560, 1435,
1390. 1Н NMR spectrum, δ, ppm: 1.55 s (6Н, 2CH3),
2.30 s (3Н, СН3), 7.2–7.5 m (5Нarom). Found, %: C 76.57;
H 5.41; N 11.61. C16H14N2O. Calculated, %: C 76.78;
H 5.60; N 11.19.
2-Imino-3-aryl-4-methyl-5,5-substituted 2,5-di-
hydrofurans Iа-Id. To a solution of 0.115 g (0.005 mol)
of sodium in 10 ml of anhydrous ethanol was added
0.05 mol of tertiary α-ketoalcohol and 0.05 mol of substi-
tuted benzonitrile. The reaction mixture was maintained at
room temperature for ~20 h (TLC monitoring). The sepa-
rated precipitate was filteref off, dried, and recrystallized
from heptane ( or from a mixture benzene–hexane,1:2).
2-Dicyanomethylene-4,5,5-trimethyl-3-(4-chloro-
phenyl)-2,5-dihydrofuran (IIb). Yield 2.8 g (99%),
mp 194–195°С. 1Н NMR spectrum, δ, ppm: 1.47 s
(6Н, 2CH3), 1.85 and 1.90 s (3Н, СН3), 7.25–7.50 m
(4Нarom). Found, %: C 67.12; H 4.21; Cl 12.57; N 9.47.
C16H13ClN2O. Calculated, %: C 67.49; H 4.60; Cl 12.45;
N 9.84.
2-Imino-4,5,5-trimethyl-3-phenyl-2,5-dihydro-
furan (Iа). Yield 8.6 g (86%), mp 81–82°С (49–50°С
[7]). IR spectrum, ν, cm–1: 3283 (NH), 1648 (C=N),
1602 (C=C), 1580 (arom), 1440 (CH3), 1390 (CH3), 1140
(C–O–C). 1Н NMR spectrum, δ.ppm: 1.47 s (6Н, 2CH3),
1.95 and 2.00 s (3Н, СН3), 6.52 s (0.3Н, NΗ), 6.84 s
(0.7Н, NΗ), 7.18–7.52 m (5Нarom). Found, %: C 77.97;
H 7.57; N 6.88. C13H15NO. Calculated, %: C 77.58;
2-Dicyanomethylene-4,5,5-trimethyl-3-(4-
methoxyphenyl)-2,5-dihydrofuran (IIc). Yield 2.36 g
1
(89%), mp 154–155°С. Н NMR spectrum, δ, ppm: 1.40 s
(6Н, 2CH3), 1.90 s (3Н, СН3), 2.75 s (3Н, OCH3), 7.20–
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AVETISYAN et al.
310
7.50 m (4Нarom). Found, %: C 77.01; H 6.32; N 10.74.
C17H16N2O. Calculated, %: C 77.25; H 6.10; N 10.60.
mp 193–195°С. Found, %: C 52.23, H 5.74; N 4.51;
S 10.62. C13H15NO.H2SO4. Calculated, %: C 52.16;
H 5.72; N 4.68; S 10.71.
2-Dicyanomethylene-4-methyl-5,5-penta-
methylene-3-phenyl-2,5-dihydrofuran (IId). Yield
2.75 g (95%), mp 188–189°С. 1Н NMR spectrum, δ,
ppm: 1.25–1.75 m [10Н, (CH2)5], 1.95 s (3Н, 2CH3),
7.20–7.45 m (5Нarom). Found, %: C 78.39; H 6.38; N 9.25.
C19H18N2O. Calculated, %: C 78.59; H 6.25; N 9.65.
2-Imino-4,5,5-trimethyl-3-(4-chlorophenyl)-2,5-di-
hydrofuran hydrogen sulfate (IVb). Yield 2.82 g (85%).
mp 229–231°С. Found, %: C 46.64; H 4.51; Cl 10.53;
N 4.30; S 9.67. C13H14NOCl·H2SO4. Calculated, %:
C 46.78; H 4.83; Cl 10.62; N 4.20; S 9.61.
2-Imino-3-aryl-4-methyl-5,5-substituted 2,5-di-
hydrofurans hydrochlorides IIIа–IIId. а. To a solution
of 5 mmol of compound Iа–Id in anhydrous ethanol was
added 0.01 mol (0.5 ml) of 35% HCl till pH 1–2. The
separated precipitate was filtered off and washed with
anhydrous ethanol.
2-Imino-4,5,5-trimethyl-3-(4-methoxyphenyl)-
2,5-dihydrofuran hydrogen sulfate (IVc). Yield 2.68 g
(82%), mp 223–225°С. Found, %: C 50.98; H 5.57;
N 4.31; S 9.85. C14H17NO2·H2SO4. Calculated, %:
C 51.05; H 5.81; N 4.25; S 9.73.
2-Imino-4-methyl-5,5-pentamethylene-3-phenyl-
2,5-dihydrofuran hydrogen sulfate (IVd). Yield 2.8
g (84%), mp 248–250°С. Found, %: C 56.71; H 6.23;
N 4.21; S 9.52. C16H19NO·H2SO4. Calculated, %:
C 56.62; H 6.24; N 4.13; S 9.45.
b. Through a benzene solution of 5 mmol of compound
Iа–Id was parred gaseous HCl, the separated precipitate
was filtered off and washed with anhydrous benzene.
2-Imino-4,5,5-trimethyl-3-phenyl-2,5-dihydro-
furan hydrochloride (IIIа). Yield 1.05 g (89%) (а),
1.15 g (97%) (b), mp 220–222°С. IR spectrum, ν, сm–1:
3480 (+NH2), 1609 (C=C), 1645 (C=N), 1580 (arom),
1445 (CH3), 1390 (CH3). Found, %: C 65.37; H 6.21;
Cl 14.27; N 5.32. C13H15NO·HCl. Calculated, %:
C 65.68; H 6.78; N 5.89; Cl 14.91.
Reaction of compounds IIIа–IIId, IVа–IVd with
potassium carbonate. а. To a water solution of 0.01 mol
of compound IIIа–IIId (pH 2–3) was added a concn.
solution of K2CO3 till pH 7–8. The separated precipitate
was filtered off and recrystallized from heptane to obtain
compounds Iа–Id .
2-Imino-4,5,5-trimethyl-3-(4-chlorophenyl)-2,5-
dihydrofuran hydrochloride (IIIb). Yield 1.15 g (84%)
(а), 1.34 g (98%) (b), mp 210–213°С. Found, %: C 57.51;
H 5.67; Cl 26.33; N 5.41. C13H14NOCl·HCl. Calculated,
%: C 57.37; H 5.55; N 5.15; Cl 26.05.
b. To a water solution of 0.01 mol of compound IVа–
IVd was added a concn. solution of K2CO3 till Ph 7–8.
Further workup as described in а.
Compound Ia. Yield 1.85 g (92%) (а), 1.76 g (88%)
(b), mp 81–82°С.
2-Imino-4,5,5-trimethyl-3-(4-methoxyphenyl)-2,5-
dihydrofuran hydrochloride (IIIc). Yield 1.1 g (83%)
(а), 1.15 g (86%) (b), mp 207–210°С. Found, %: C 62.61;
H 6.29; Cl 13.32; N 5.47. C14H17NO2·HCl. Calculated,
%: C 62.80; H 6.78; Cl 13.24; N 5.23.
Compound Ib. Yield 2.1 g (90%) (а), 2.25 g (96%)
(b), mp 91–92°С.
Compound Ic. Yield 1.95 g (85%) (а), 1.65 g (72%)
(b), oily substance.
Compound Id. Yield 2.27 g (94%) (а), 2.3 g (96%)
(b), mp 126–127°С.
2-Imino-4-methyl-5,5-pentamethylene-3-phenyl-
2,5-dihydrofuran hydrochloride (IIId). Yield 1.2 g
(88%) (а), 1.30 g (94%) (b). mp 223–226°С. Found,
%: C 69.42; H 7.41; Cl 12.79; N 5.27. C16H19NO·HCl.
Calculated, %: C 69.18; H 7.26; Cl 12.76; N 5.04.
3-Aryl-4-methyl-5,5-substituted 2(5Н)-furanones
Vа–Vd. а. To 0.01 mol of compound Iа–Id in 5 ml of
water was added HCl till pH 4–5, and the solution was
heated on a water bath over 3 h. The separated precipitate
was filtered off, washed with water, and recrystallized
from ethanol.
2-Imino-3-aryl-4-methyl-5,5-substituted 2,5-di-
hydrofurans hydrogen sulfates IVа–IVd. To a solution
of 0.01 mol of compound Iа–Id in anhydrous ethanol was
added 0.01 mol (2.2 ml, 45%) of H2SO4. The separated
precipitate was filtered off and washed with anhydrous
ethanol.
b. A solution of 0.01 mol of compound IIIа–IIId in
10 ml of ethanol (or water) was heated on a water bath
over 3 h. The separated precipitate was filtered off and
recrystallized from ethanol.
2-Imino-4,5,5-trimethyl-3-phenyl-2,5-dihydro-
c. A solution of 0.01 mol of compound IVа–IVd in
furan hydrogen sulfate (IVа). Yield 2.6 g (87%).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 2 2011

SYNTHESIS OF FUNCTIONALLY SUBSTITUTED 2-IMINO-3-ARYL-2,5-DIHYDROFURANS
311
10 ml of ethanol (or water) was heated on a water bath
on Silufol UV-254 plates, eluent acetone–benzene, 1 : 2,
development under the iodine vapor or UV irradiation.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 2 2011