Synthesis and hydrolysis of bicyclic 2-Imino-2,5-dihydrofurans fused to a pyridine ring

Full text of DOI:10.1134/S1070428010080257

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 8, pp. 1259–1261. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.A. Avetisyan, L.V.Karapetyan, M.D. Tadevosyan, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 8,
pp. 1257–1258.
SHORT
COMMUNICATIONS
Synthesis and Hydrolysis of Bicyclic 2-Imino-2,5-dihydrofurans
Fused to a Pyridine Ring
A. A. Avetisyan†, L. V. Karapetyan, and M. D. Tadevosyan
Erevan State University, ul. Aleka Manukyana 1, Erevan, 0025 Armenia
e-mail: lousine_karapetyan@yahoo.com
Received July 10, 2009
DOI: 10.1134/S1070428010080257
Numerous fused pyridine derivatives are widely
used in medicine as cardiotonics [1] and antiphlogistic
agents [2]. Functionally substituted derivatives of un-
saturated γ-lactones are widespread in nature, and they
often exhibit pronounced biological activity. Apart
from monocyclic unsaturated γ-lactones, derivatives of
spiro and fused bicyclic systems are present in natural
sources [3–6]. Taking into account that nitrogen-con-
taining analogs of various oxygen-containing biologi-
cally active compounds often possess equally useful
properties, we continued studies in this field with
a view to synthesize new derivatives of functionally
substituted 2-imino-2,5-dihydrofurans [7]. For this
purpose, 2-imino-2,5-dihydrofurans Ia–Id were
brought into reaction with N,N-dimethyl(dimethoxy)-
methanamine (N,N-dimethylformamide dimethyl
acetal), and optimal conditions were found for this
reaction. The best results were obtained by heating
a mixture of 2-imino-2,5-dihydrofuran I and dimethyl-
formamide dimethyl acetal at a ratio of 1 : 1.1 in
boiling anhydrous benzene. Presumably, the reaction
involves intermediate formation of enamine with
elimination of two methanol molecules and subsequent
cyclization to furanopyridines IIa–IId with liberation
of dimethylamine which was detected in the reaction
mixture on a qualitative level (Scheme 1).
Scheme 1.
Me
R2
R3
CONHR1
Fused furanopyridine derivatives IIa–IId readily
underwent acid hydrolysis (pH 4–5, 85–90°C, 2 h),
yielding the corresponding furo[3,4-c]pyridine-
3,4(1H,5H)-diones IIIa–IIId which may be regarded
as analogs of natural alkaloid cerpegin (Scheme 2).
MeO
NMe2
OMe
+
NH
O
Ia–Id
NMe2
CONHR1
Scheme 2.
R2
R3
–MeOH
R2
NH
O
R3
O
HCl, H2O, pH 4–5
N
R2
R3
R1
IIa–IId
O
O
O
IIIa–IIId
N
–Me2NH
R1
Me
NH
O
Me
IIa–IId
O
N
R1 = H (a, c), Me (b, d); R2 = R3 = Me (a, b);
Me
R2R3 = (CH2)5 (c, d).
O
O
† Deseased.
Cerpegin (IIIb)
1259

AVETISYAN et al.
1260
The structure of the isolated compounds was con-
85–90°C. The mixture was cooled and extracted with
diethyl ether (3 ×5 ml), the extract was dried over
magnesium sulfate, the solvent was distilled off, and
the residue was recrystallized from appropriate solvent.
1,1-Dimethylfuro[3,4-c]pyridine-3,4(1H,5H)-di-
one (IIIa). Yield 90%, mp 257–260°C (from petro-
leum ether). IR spectrum, ν, cm–1: 3280 (NH); 1760,
1670 (C=O); 1625, 1620 (C=C). 1H NMR spectrum, δ,
ppm: 1.42 s (6H, CH3), 4.86 d (1H, 7-H, J = 4.9 Hz),
5.68 d.d (1H, 6-H, J = 4.9, 5.6 Hz), 9.36 d (1H, NH,
J = 4.9 Hz). Found, %: C 60.59; H 5.34; N 7.97.
C9H9NO3. Calculated, %: C 60.33; H 5.06; N 7.82.
1
firmed by their IR and H NMR spectra and elemental
analyses.
3-Iminofuro[3,4-c]pyridin-4(5H)-ones IIa–IId
(general procedure). A mixture of 1 mmol of 2-imino-
2,5-dihydrofuran Ia–Id and 1.1 mmol of N,N-dimeth-
ylformamide dimethyl acetal in 20 ml of anhydrous
benzene was heated for 30–35 h under reflux until
dimethylamine no longer evolved. The solvent was re-
moved under reduced pressure, the residue was treated
with diethyl ether, and the precipitate was filtered off
and washed with water.
3-Imino-1,1-dimethylfuro[3,4-c]pyridin-4(5H)-
one (IIa). Yield 90%, mp 168–170°C. IR spectrum, ν,
cm–1: 3360, 3180 (NH); 1680 (C=O); 1640 (C=N);
1,1,5-Trimethylfuro[3,4-c]pyridine-3,4(1H,5H)-
dione (cerpegin, IIIb). Yield 89%, mp 268–270°C
(from CH2Cl2–EtOH). IR spectrum, ν, cm–1: 1760,
1670 (C=O); 1625, 1620 (C=C). 1H NMR spectrum, δ,
ppm: 1.42 s (6H, CH3), 3.4 s (3H, NCH3), 4.86 d (1H,
7-H, J = 4.9 Hz), 5.66 d (1H, 6-H, J = 7.9 Hz).
13C NMR spectrum, δC, ppm: 24.18 (CH3), 37.75
(NCH3), 82.51, 98.38, 112.17, 145.96, 157.90, 166.88,
170.86. Mass spectrum (70 eV), m/z (Irel, %): 193
(34.58) [M]+, 178 (100) [M – CH3]+, 150 (4.79) [M –
CH3CO]+, 136 (3.65), 108 (12.87), 79 (5.79), 42
(49.67). Found, %: C 62.36; H 5.95; N 7.49.
C10H11NO3. Calculated, %: C 62.17; H 5.74; N 7.25.
M 193.20.
1,1-Pentamethylenefuro[3,4-c]pyridine-
3,4(1H,5H)-dione (IIIc). Yield 91%, mp 160–161°C
(from petroleum ether). IR spectrum, ν, cm–1: 3280
(NH), 1760, 1670 (C=O); 1625, 1620 (C=C). 1H NMR
spectrum, δ, ppm: 1.58–1.88 m (10H, (CH2), 4.86 d
(1H, 7-H, J = 4.9 Hz), 5.66 d.d (1H, 6-H, J = 4.9, J =
5.6 Hz), 9.36 d (1H, NH, J = 4.9 Hz). Found, %:
C 65.97; H 6.14; N 6.71. C12H13NO3. Calculated, %:
C 65.74; H 5.98; N 6.39.
1
1625, 1620 (C=C). H NMR spectrum, δ, ppm: 1.42 s
(6H, CH3), 4.86 d (1H, 7-H, J = 4.9 Hz), 5.66 d.d (1H,
6-H, J = 4.9, 5.6 Hz), 7.23 s (1H, =NH), 9.36 d (1H,
NH, J = 4.9 Hz). Found, %: C 60.91; H 5.87; N 15.89.
C9H10N2O2. Calculated, %: C 60.66; H 5.66; N 15.72.
3-Imino-1,1,5-trimethylfuro[3,4-c]pyridin-4(5H)-
one (IIb). Yield 87%, mp 123–124°C. IR spectrum, ν,
cm–1: 3240 (NH); 1680 (C=O); 1640 (C=N); 1625,
1
1620 (C=C). H NMR spectrum, δ, ppm: 1.42 s (6H,
CH3), 3.4 s (3H, NCH3), 4.86 d (1H, 7-H, J = 4.9 Hz),
5.66 d (1H, 6-H, J = 7.9 Hz), 7.23 s (1H, NH). Found,
%: C 62.64; H 6.44; N 14.77. C10H12N2O2. Calculated,
%: C 62.49; H 6.29; N 14.57.
3-Imino-1,1-pentamethylenefuro[3,4-c]pyridin-
4(5H)-one (IIc). Yield 87%, mp 201–203°C. IR spec-
trum, ν, cm–1: 3360, 3180 (NH); 1680 (C=O); 1640
(C=N); 1625, 1620 (C=C). 1H NMR spectrum, δ, ppm:
1.58–1.88 m (10H, (CH2), 4.86 d (1H, 7-H, J =
4.9 Hz), 5.66 d.d (1H, 6-H, J = 4.9, 5.6 Hz), 7.23 s
(1H, =NH), 9.36 d (1H, NH, J = 4.9 Hz). Found, %:
C 66.35; H 6.64; N 12.97. C12H14N2O2. Calculated, %:
C 66.04; H 6.47; N 12.84.
3-Imino-5-methyl-1,1-pentamethylenefuro[3,4-c]-
pyridin-4(5H)-one (IId). Yield 85%, mp 128–130°C.
IR spectrum, ν, cm–1: 3240 (NH); 1680 (C=O); 1640
(C=N); 1625, 1620 (C=C). 1H NMR spectrum, δ, ppm:
1.56–1.86 m (10H, (CH2), 3.4 s (3H, NCH3), 4.86 d
(1H, 7-H, J = 4.9 Hz), 5.66 d (1H, 6-H, J = 7.9 Hz),
7.24 s (1H, NH). Found, %: C 67.44; H 7.14; N 12.27.
C13H16N2O2. Calculated, %: C 67.22; H 6.94; N 12.06.
5-Methyl-1,1-pentamethylenefuro[3,4-c]pyri-
dine-3,4(1H,5H)-dione (IIId). Yield 87%, mp 101–
102°C (from hexane). IR spectrum, ν, cm–1: 1760,
1670 (C=O); 1625, 1620 (C=C). 1H NMR spectrum, δ,
ppm: 1.56–1.86 m (10H, (CH2), 3.4 s (3H, NCH3),
4.86 d (1H, 7-H, J = 4.9 Hz), 5.66 d (1H, 6-H, J =
7.9 Hz). Found, %: C 67.14; H 6.79; N 6.37.
C13H15NO3. Calculated, %: C 66.94; H 6.48; N 6.00.
The IR spectra were recorded on a Specord 75IR
spectrometer from samples dispersed in mineral oil.
The NMR spectra were measured on a Varian
Furo[3,4-c]pyridine-3,4(1H,5H)-diones IIIa–IIId
(general procedure). A mixture of 1 mmol of com-
pound IIa–IId and 5 ml of water was acidified to pH
4–5 with hydrochloric acid and was heated for 3 h at
1
Mercury-300 instrument (300 MHz for H), using
tetramethylsilane as internal reference and DMSO-d6–
CCl4 (1:3) as solvent. The purity of the products was
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SYNTHESIS AND HYDROLYSIS OF BICYCLIC 2-IMINO-2,5-DIHYDROFURANS
1261
3. Orduna, A., Zepeda, L.G., and Tamariz, J., Synthesis,
checked by TLC on Silufol UV-254 plates using
acetone–benzene (1:2) as eluent; development with
iodine vapor or under UV light.
1993, p. 375.
4. Adibatti, N.A., Thirugnanasambantham, P., Kulothun-
gan, C., Viswanathan, S., Kameswaran, L., Balakrishna, K.,
and Sukumar. E., Phytochemistry, 1991, vol. 30, p. 2449.
REFERENCES
5. Kelly, T.R. and Walsh, J.J., J. Org. Chem., 1992, vol. 57,
p. 6657.
1. Kaiho, T., Otsuka, K., Ito, T., Kitano, T., Muryama, M.,
and Hirayama, M., JPN Patent no. 62-19570, 1987;
Chem. Abstr., 1987, no. 176194n.
6. Villemin, D. and Liao, L., Tetrahedon Lett., 1996, vol. 37,
p. 8733.
2. Negwer, M., Organic Chemical Drugs and Their
7. Avetissyan, A. and Karapetyan, L., Synth. Commun.,
Synonyms, Berlin: Academie, 1987, vol. 1, p. 671.
2009, vol. 39, p. 7.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 8 2010