Synthesis and some chemical transformations of novel functionalized 2-imino-2,5-dihydrofurans

Article abstract of DOI:10.1007/s11172-010-0192-2

Hitherto unknown functionalized 2-imino-3-(N-cyclohexylcarbamoyl)-2,5- dihydrofurans were synthesized by the reactions of tertiary α-hydroxy ketones with N-cyclohexyl(cyano-acetamide). Several reactions of thus synthesized compounds at the imino group wer

Full text of DOI:10.1007/s11172-010-0192-2

Russian Chemical Bulletin, International Edition, Vol. 59, No. 5, pp. 974—976, May, 2010
974
Synthesis and some chemical transformations
of novel functionalized 2ꢀiminoꢀ2,5ꢀdihydrofurans
A. A. Avetisyan†, L. V. Karapetyan, and M. D. Tadevosyan
Yerevan State University,
1 ul. Alek Manoukyan, 0025 Yerevan, Armenia.
Eꢀmail: avetchem@yahoo.com
Hitherto unknown functionalized 2ꢀiminoꢀ3ꢀ(Nꢀcyclohexylcarbamoyl)ꢀ2,5ꢀdihydrofurans
were synthesized by the reactions of tertiary αꢀhydroxy ketones with Nꢀcyclohexyl(cyanoꢀ
acetamide). Several reactions of thus synthesized compounds at the imino group were
carried out.
Key words: αꢀhydroxy ketones, imines, dihydrofuranones, malononitrile, heterocyclization.
Functionalized 2ꢀiminoꢀ2,5ꢀdihydrofurans1 and
h furnished the corresponding 2,5ꢀdihydrofuranꢀ2ꢀones
4a—c (Scheme 2).
2,5ꢀdihydrofuranꢀ2ꢀones2—5 are the promising heteroꢀ
cyclic compounds and of practical and scientific interest.
Synthesis of these compounds is an important problem.
In continuation of our research on condensation of
tertiary αꢀhydroxy ketones with compounds bearing the
active methylene group,1 in the present work we involved
Nꢀcyclohexyl(cyanoacetamide) (1) in the condensations
with αꢀhydroxy ketones (Scheme 1). At an equimolar
reactant ratio, the reaction of αꢀhydroxy ketones 2a—c
with compound 1 in MeOH in the presence of MeONa
at 40 °C for 5 h resulted in 2ꢀiminoꢀ3ꢀ(Nꢀcyclohexylꢀ
carbamoyl)ꢀ4ꢀmethylꢀ5,5ꢀdialkylꢀ2,5ꢀdihydrofurans
3a—c in high yields.
Scheme 2
R1 = R2 = Me (a); R1 = Me, R2 = Et (b); R1 + R2 = (CH2)4 (c)
i. H2O, HCl, pH = 4—5, 85–90 °C
Hydrolysis of the resulting imino derivatives 3a—c unꢀ
der weakly acidic conditions (pH 4—5) at 85—90 °C for 3
Bubbling of gaseous HCl through a benzene solution
of 2ꢀiminoꢀ2,5ꢀdihydrofurans 3a—c afforded the correꢀ
sponding hydrochlorides 5a—c in quantitative yields
(Scheme 3). The resulting hydrochlorides 5a—c can
readily be converted into the starting 2ꢀimino derivatives
3a—c by treatment with 0.1 M NaOH or aqueous K2CO3
solution. Aqueous hydrolysis of hydrochlorides 5a—c
at 85—90 °C for 2 h resulted in 2,5ꢀdihydrofuranꢀ2ꢀones
4a—c.
Scheme 1
With the aim of synthesizing of dicyanomethylidene
dihydrofuran derivatives bearing the chromophores, we
performed the reactions of 2ꢀiminoderivatives 3a—c
with malononitrile (Scheme 4). These reactions carried
out at an equimolar reactant ratio in anhydrous EtOH at
room temperature gave the corresponding 2ꢀdicyanoꢀ
methylideneꢀ2,5ꢀdihydrofurans 6a—c with quantitative
yields (the reactions completed when the evolution of
ammonia ceased).
R1 = R2 = Me (a); R1 = Me, R2 = Et (b); R1 + R2 = (CH2)4 (c)
Methylation of 2ꢀiminoꢀ2,5ꢀdihydrofurans 3a—c
with dimethyl sulfate in the presence of Na2CO3 at room
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 953—955, May, 2010.
1066ꢀ5285/10/5905ꢀ0974 © 2010 Springer Science+Business Media, Inc.

2ꢀIminoꢀ2,5ꢀdihydrofurans
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
975
Scheme 3
R1 = R2 = Me (a); R1 = Me, R2 = Et (b); R1 + R2 = (CH2)4 (c)
mixture was heated at 40 °C for 5 h, and the solvent was removed
in vacuo. Water was added to the residue, the precipitate that
formed was filtered off, washed with water, and recrystallized
from EtOH.
Scheme 4
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ2ꢀiminoꢀ4,5,5ꢀtrimethylꢀ
2,5ꢀdihydrofuran (3a). The yield was 92%, m.p. 57—58 °C.
1H NMR, δ: 1.42 (s, 6 H, 2 CH3); 1.58—1.95 (m, 10 H, C6H11);
2.34 (s, 3 H, CH3); 3.71 (m, 1 H, NH—CH); 7.25 (s, 1 H,
=NH); 9.24 (d, 1 H, NH, J = 7.9 Hz). IR, ν/cm–1: 3360 (NH),
3180 (NH), 1680 (C=O), 1670 (C=N), 1620 (C=C). Found (%):
C, 67.34; H, 8.97; N, 11.34. C14H22N2O2. Calculated (%):
C, 67.17; H, 8.86; N, 11.19.
R1 = R2 = Me (a); R1 = Me, R2 = Et (b); R1 + R2 = (CH2)4 (c)
i. CH2(CN)2
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ5ꢀethylꢀ2ꢀiminoꢀ4,5ꢀdimethylꢀ
2,5ꢀdihydrofuran (3b). The yield was 98%, m.p. 55—57 °C.
1H NMR, δ: 0.95 (t, 3 H, CH2CH3, J = 8.5 Hz); 1.45 (s, 3 H,
CH3); 1.58—1.90 (m, 10 H, C6H11); 1.95 (q, 2 H, CH2CH3,
J = 8.5 Hz); 2.33 (s, 3 H, CH3); 3.71 (m, 1 H, NH—CH); 7.25
(s, 1 H, =NH); 9.24 (d, 1 H, NH, J = 7.9 Hz). IR, ν/cm–1: 3360
(NH), 3180 (NH), 1680 (C=O), 1670 (C=N), 1620 (C=C).
Found (%): C, 68.34; H, 9.29; N, 10.74. C15H24N2O2. Calculꢀ
ated (%): C, 68.15; H, 9.15; N, 10.60.
temperature furnished the corresponding 2ꢀ(Nꢀmethylꢀ
imino)ꢀ2,5ꢀdihydrofurans 7a—c (Scheme 5).
The structures of the synthesized compounds were
established based on the data from IR and 1H NMR specꢀ
troscopy and confirmed by elemental analysis. The perꢀ
formed chemical reactions of compounds 3a—c confirmed
that compounds 3a—c are actually iminodihydrofurans
but not isomeric pyrrolinones.6
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ2ꢀiminoꢀ4ꢀmethylꢀ1ꢀoxaspiroꢀ
[4.4]nonꢀ3ꢀene (3c). The yield was 95%, m.p. 180—182 °C.
1H NMR, δ: 1.19—1.49 (m, 4 H, C6H11); 1.58—1.95 (m, 14 H,
C5H9, C6H11); 2.33 (s, 3 H, CH3); 3.72 (m, 1 H, NH—CH);
Scheme 5
7.23 (s, 1 H, =NH); 9.35 (d, 1 H, NH, J = 7.9 Hz). IR, ν/cm–1
:
3360 (NH), 3180 (NH), 1680 (C=O), 1670 (C=N), 1620 (C=C).
Found (%): C, 69.74; H, 8.94; N, 10.37. C16H24N2O2. Calculꢀ
ated (%): C, 69.53; H, 8.75; N, 10.14.
5,5ꢀDialkylꢀ3ꢀ(Nꢀcyclohexylcarbamoyl)ꢀ4ꢀmethylꢀ2,5ꢀ
dihydrofuranꢀ2ꢀones 4a—c (general procedure). A mixture of
2ꢀiminoꢀ2,5ꢀdihydrofuran 3 (1.5 mmol) and water (5 mL) was
acidified to pH 4—5 with HCl and heated at 85—90 °C for 3 h.
The reaction mixture was cooled, extracted with diethyl ether
(3×5 mL), the combined organic layer was dried with MgSO4,
the solvent was removed in vacuo, and the residue was recrysꢀ
tallized from hexanes.
R1 = R2 = Me (a); R1 = Me, R2 = Et (b); R1 + R2 = (CH2)4 (c)
i. Me SO
2
4
Experimental
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ4,5,5ꢀtrimethylꢀ2,5ꢀdihydroꢀ
furanꢀ2ꢀone (4a). The yield was 76%, m.p. 90—91 °C. 1H NMR,
δ: 1.42 (s, 6 H, 2 CH3); 1.58—1.95 (m, 10 H, C6H11); 2.33 (s, 3 H,
CH3); 3.71 (m, 1 H, NH—CH); 9.24 (d, 1 H, NH, J = 7.9 Hz).
IR, ν/cm—1: 3280 (NH), 1780 (C=O), 1680 (C=O), 1620
(C=C). Found (%): C, 67.03; H, 8.59; N, 5.74. C14H21NO3.
Calculated (%): C, 66.91; H, 8.42; N, 5.57.
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ5ꢀethylꢀ4,5ꢀdimethylꢀ2,5ꢀ
dihydrofuranꢀ2ꢀone (4b). The yield was 72%, m.p. 58—60 °C.
1H NMR, δ: 0.95 (t, 3 H, CH2CH3, J = 8.5 Hz); 1.45 (s, 3 H,
CH3); 1.58—1.90 (m, 10 H, C6H11); 1.95 (q, 2 H, CH2CH3,
J = 8.5 Hz); 2.33 (s, 3 H, CH3); 3.71 (m, 1 H, NH—CH); 9.24
(d, 1 H, NH, J = 7.9 Hz). IR, ν/cm–1: 3280 (NH), 1780 (C=O),
1680 (C=O), 1620 (C=C). Found (%): C, 67.98; H, 8.75;
N, 5.34. C15H23NO3. Calculated (%): C, 67.90; H, 8.74; N, 5.28.
The IR spectra (in Nujol) were recorded on a Specord 571R
spectrophotometer. The 1H NMR spectra were obtained on a
Mercuryꢀ300 Varian instrument at 300 MHz in a DMSOꢀd6—CCl4
(1 : 3) mixture. The individuality of the synthesized compounds
was monitored by TLC on precoated plates Silufol UVꢀ254 using
a 1 : 2 acetone—benzene mixture as the eluent, the spots were
visualized by iodine vapors. The tertiary αꢀhydroxy ketones
2a—c were synthesized by the known procedure,7 Nꢀcyclohexylꢀ
(cyanoacetamide) (1) was prepared by the reaction of ethyl
cyanoacetate with cyclohexylamine.6
5,5ꢀDialkylꢀ3ꢀ(Nꢀcyclohexylcarbamoyl)ꢀ2ꢀiminoꢀ4ꢀmethylꢀ
2,5ꢀdihydrofurans 3a—c (general procedure). To a solution of
MeONa in anhydrous MeOH (1 mmol Na in 20 mL of MeOH),
the tertiary αꢀhydroxy ketone 2 (10 mmol) and Nꢀcyclohexylꢀ
(cyanoacetamide) (1) (10 mmol) were added. The reaction

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Avetisyan et al.
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ4ꢀmethylꢀ1ꢀoxaspiro[4.4]nonꢀ
1.58—1.95 (m, 14 H, C5H9, C6H11); 2.33 (s, 3 H, CH3); 3.72
3ꢀenꢀ2ꢀone (4c). The yield was 80%, m.p. 115—117 °C. 1H NMR,
δ: 1.19—1.49 (m, 4 H, C6H11); 1.58—1.95 (m, 14 H, C5H9,
C6H11); 2.33 (s, 3 H, CH3); 3.72 (m, 1 H, NH—CH); 9.35 (d,
1 H, NH, J = 7.9 Hz). IR, ν/cm–1: 3280 (NH), 1780 (C=O),
1680 (C=O), 1620 (C=C). Found (%): C, 69.44; H 8.52; N 5.21.
C16H23NO3. Calculated (%): C, 69.29; H, 8.36; N, 5.05.
5,5ꢀDialkylꢀ3ꢀ(Nꢀcyclohexylcarbamoyl)ꢀ2ꢀiminoꢀ4ꢀmethylꢀ
2,5ꢀdihydrofuran hydrochlorides 5a—c (general procedure).
Gaseous HCl was bubbled through a solution of 2ꢀiminoꢀ2,5ꢀ
dihydrofuran 3 (2 mmol) in benzene (5 mL). Precipitate that
formed was filtered off and washed with diethyl ether.
(m, 1 H, NH—CH); 9.34 (d, 1 H, NH, J = 7.9 Hz). IR, ν/cm—1
:
3280 (NH), 2219 (C≡N), 1680 (C=O), 1670 (C=N), 1635 (C=C),
1620 (C=C). Found (%): C, 70.36; H, 7.42; N, 12.99. C19H23N3O2.
Calculated (%): C, 70.13; H, 7.13; N, 12.91.
5,5ꢀDialkylꢀ3ꢀ(Nꢀcyclohexylcarbamoyl)ꢀ4ꢀmethylꢀ
2ꢀ(Nꢀmethylimino)ꢀ2,5ꢀdihydrofurans 7a—c (general procedure).
To a solution of 2ꢀiminoꢀ2,5ꢀdihydrofuran 3 (2 mmol) in dioxane
(10 mL), conc. Na2CO3 solution (10 mL) and dimethyl sulfate
(0.76 g, 6 mmol) were added. The reaction mixture was stirred at
room temperature for 5 h, then water (50 mL) was added, and the
stirring was continued for 1 h. The precipitate that formed was
filtered off, washed with water, and recrystallized from heptane.
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ4,5,5ꢀtrimethylꢀ2ꢀ(Nꢀmethylꢀ
imino)ꢀ2,5ꢀdihydrofuran (7a). The yield was 76%, m.p.103—105 °C.
1H NMR, δ: 1.42 (s, 6 H, 2 CH3); 1.58—1.95 (m, 10 H, C6H11);
2.33 (s, 3 H, CH3); 2.98 (s, 3 H, =NCH3); 3.72 (m, 1 H, NH—CH);
9.46 (d, 1 H, NH, J = 7.9 Hz). IR, ν/cm–1: 3260 (NH), 1680
(C=O), 1670 (C=N), 1620 (C=C). Found (%): C, 68.44; H,
9.46; N, 10.92. C15H24N2O2. Calculated (%): C, 68.15; H, 9.15;
N, 10.60.
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ5ꢀethylꢀ4,5ꢀdimethylꢀ
2ꢀ(Nꢀmethylimino)ꢀ2,5ꢀdihydrofuran (7b). The yield was 74%,
m.p. 115—117 °C. 1H NMR, δ: 0.95 (t, 3 H, CH2CH3, J = 8.5 Hz);
1.45 (s, 3 H, CH3); 1.58—1.90 (m, 10 H, C6H11); 1.95 (q, 2 H,
CH2CH3, J = 8.5 Hz); 2.35 (s, 3 H, CH3); 3.00 (s, 3 H, =NCH3);
3.72 (m, 1 H, NH—CH); 9.24 (d, 1 H, NH, J = 7.9 Hz). IR,
ν/cm–1: 3340 (NH), 1680 (C=O), 1670 (C=N), 1620 (C=C).
Found (%): C, 69.47; H, 9.74; N, 10.25. C16H26N2O2. Calculꢀ
ated (%): C, 69.03; H, 9.41; N, 10.06.
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ2ꢀiminoꢀ4,5,5ꢀtrimethylꢀ
2,5ꢀdihydrofuran hydrochloride (5a). The yield was 94%,
m.p. 230—234 °C. 1H NMR, δ: 1.42 (s, 6 H, 2 CH3); 1.58—1.96
(m, 10 H, C6H11); 2.33 (s, 3 H, CH3); 3.72 (m, 1 H, NH—CH);
9.24 (d, 1 H, NH, J = 7.9 Hz); 10.34 (br.s, 2 H, NH•HCl).
Found (%): C 58.74; H, 8.23; N, 9.84. C14H22N2O2•HCl.
Calculated (%): C, 58.63; H, 8.08; N, 9.78.
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ5ꢀethylꢀ2ꢀiminoꢀ4,5ꢀdimethylꢀ
2,5ꢀdihydrofuran hydrochloride (5b). The yield was 95%,
m.p. 178—185 °C. 1H NMR, δ: 0.95 (t, 3 H, CH2CH3, J = 8.5 Hz);
1.45 (s, 3 H, CH3); 1.58—1.90 (m, 10 H, C6H11); 1.95 (q, 2 H,
CH2CH3, J = 8.5 Hz); 2.33 (s, 3 H, CH3); 3.71 (m, 1 H, NH—CH);
9.24 (d, 1 H, NH, J = 7.9 Hz); 10.34 (br.s, 2 H, NH•HCl).
Found (%): C, 59.94; H, 8.42; N, 9.34. C15H24N2O2•HCl.
Calculated (%): C, 59.89; H, 8.38; N, 9.31.
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ2ꢀiminoꢀ4ꢀmethylꢀ1ꢀoxaspiroꢀ
[4.4]nonꢀ3ꢀene hydrochloride (5c). The yield was 93%, m.p. >350 °C.
1H NMR, δ: 1.19—1.49 (m, 4 H, C6H11); 1.58—1.95 (m, 14 H,
C5H9, C6H11); 2.33 (s, 3 H, CH3); 3.72 (m, 1 H, NH—CH);
7.23 (s, 1 H, =NH); 9.35 (d, 1 H, NH, J = 7.9 Hz); 10.44 (br.s,
2 H, NH•HCl). Found (%): C, 61.64; H, 8.24; N, 9.01.
C16H24N2O2•HCl. Calculated (%): C, 61.43; H, 8.05; N, 8.95.
5,5ꢀDialkylꢀ3ꢀ(Nꢀcyclohexylcarbamoyl)ꢀ2ꢀdicyanomethylꢀ
ideneꢀ4ꢀmethylꢀ2,5ꢀdihydrofurans 6a—c (general procedure).
A mixture of 2ꢀiminoꢀ2,5ꢀdihydrofuran 3 (2.5 mmol) and malonoꢀ
nitrile (0.17 g, 2.5 mmol) in anhydrous EtOH (5 mL) was stirred
at room temperature until evolution of ammonia ceased, and
the solvent was removed in vacuo. To the residue water was
added, the precipitate that formed was filtered off, washed with
water, and recrystallized from ethanol—water (2 : 1).
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ2ꢀdicyanomethylideneꢀ
4,5,5ꢀtrimethylꢀ2,5ꢀdihydrofuran (6a). The yield was 95%,
m.p. 230—232 °C. 1H NMR, δ: 1.42 (s, 6 H, 2 CH3); 1.58—1.95
(m, 10 H, C6H11); 2.33 (s, 3 H, CH3); 3.71 (m, 1 H, NH—CH);
9.24 (d, 1 H, NH, J = 7.9 Hz). IR, ν/cm—1: 3280 (NH), 2219
(C≡N), 1680 (C=O), 1670 (C=N), 1635 (C=C), 1620 (C=C).
Found (%): C, 68.45; H, 7.39; N, 14.32. C17H21N3O2. Calculꢀ
ated (%): C, 68.20; H, 7.07; N, 14.04.
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ4ꢀmethylꢀ2ꢀ(Nꢀmethylimino)ꢀ
1ꢀoxaspiro[4.4]nonꢀ3ꢀene (6c). The yield was 71%, m.p. 108—
110 °C. 1H NMR, δ: 1.19—1.49 (m, 4 H, C6H11); 1.58—1.95
(m, 14 H, C5H9, C6H11); 2.33 (s, 3 H, CH3); 2.98 (s, 3 H,
=NCH3); 3.72 (m, 1 H, NH—CH); 9.34 (d, 1 H, NH,
J = 7.9 Hz). IR, ν/cm–1: 3280 (NH), 1680 (C=O), 1670 (C=N),
1635 (C=C), 1620 (C=C). Found (%): C, 70.44; H, 9.14; N, 9.77.
C17H26N2O2. Calculated (%): C, 70.31; H, 9.02; N, 9.65.
References
1. A. Avetisyan, L. Karapetyan, Synth. Commun., 2009, 39, 7.
2. J. S. Rao, Chem. Rev., 1976, 76, 625.
3. A. A. Avetisyan, M. T. Dangyan, Usp. Khim., 1977, 7, 1250
[Russ. Chem. Rev. (Engl. Transl.), 1977, 46, 643].
4. A. A. Avetisyan, G. G. Tokmadzhyan, Khim. Geterotsikl.
Soedin., 1987, 6, 723 [Chem. Heterocycl. Comp. (Engl. Transl.),
1987, 23, 595].
5. A. A. Avetisyan, G. G. Tokmadzhyan,, Arm. Khim. Zh.,
1993, 3—4, 219 [Arm. Chem. J. (Engl. Transl.), 1993, 3—4].
6. G. Melikian, F. Rouessac, C. Alexandre, Synth. Commun.,
1993, 23, 2631.
7. V. I. Nikitin, Tretichnye glitseriny atsetilenovogo i etilenovogo
ryadov i ikh khimicheskie prevrashcheniya [Tertiary Glycerols
of Acetylene and Ethylene Series and their Chemical Reacꢀ
tions], Dushanbe, 1961 (in Russian).
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ2ꢀdicyanomethylideneꢀ5ꢀethylꢀ
4,5ꢀdimethylꢀ2,5ꢀdihydrofuran (6b). The yield was 96%,
m.p. 195—197 °C. 1H NMR, δ: 0.95 (t, 3 H, CH2CH3, J = 8.5 Hz);
1.45 (s, 3 H, CH3); 1.58—1.90 (m, 10 H, C6H11); 1.95 (q, 2 H,
CH2CH3, J = 8.5 Hz); 2.33 (s, 3 H, CH3); 3.71 (m, 1 H,
NH—CH); 9.24 (d, 1 H, NH, J = 7.9 Hz). IR, ν/cm—1: 3280
(NH), 2219 (C≡N), 1680 (C=O), 1670 (C=N), 1635 (C=C),
1620 (C=C). Found (%): C, 69.29; H, 7.51; N, 13.58. C18H23N3O2.
Calculated (%): C, 68.98; H, 7.40; N, 13.41.
3ꢀ(NꢀCyclohexylcarbamoyl)ꢀ2ꢀdicyanomethylideneꢀ
4ꢀmethylꢀ1ꢀoxaspiro[4.4]nonꢀ3ꢀene (6c). The yield was 95%,
m.p. 164—166 °C. 1H NMR, δ: 1.19—1.49 (m, 4 H, C6H11);
Received June, 29 2009;
in revised form January, 15 2009