Synthesis of 5,6-dihydrothieno(and furo)pyrimidines bearing an active methine group at the 4-position

Article abstract of DOI:10.1002/jhet.5570380140

The reactions of 2-benzamido-4,5-dihydro-3-thiophene(and -3-furan)carbonitriles (1a-c and 4a-c) with ethyl acetoacetate in the presence of tin(IV) chloride and triethylamine provided the corresponding ethyl 2-(5,6-dihydro-2-phenylthieno(and furo)[2,3-d]pyrimidin-4-yl)-3-oxobutanoates (2a-c and 9a-c). Similarly, compounds 1a-c and 4a-c reacted with dialkyl malonates to give the corresponding dialkyl(5,6-dihydro-2phenylthieno(and furo)[2,3-d]pyrimidin-4-yl)propanedioates (5a-c, 6a-c, 10a-c and 11a-c).

Full text of DOI:10.1002/jhet.5570380140

Jan-Feb 2001
Synthesis of 5,6-Dihydrothieno(and furo)pyrimidines Bearing an
269
Active Methine Group at the 4-Position
Hiroshi Maruoka, Kenji Yamagata and Motoyoshi Yamazaki*
Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
Received June 28, 2000
The reactions of 2-benzamido-4,5-dihydro-3-thiophene(and -3-furan)carbonitriles (1a-c and 4a-c) with
ethyl acetoacetate in the presence of tin(IV) chloride and triethylamine provided the corresponding ethyl
2-(5,6-dihydro-2-phenylthieno(and furo)[2,3-d]pyrimidin-4-yl)-3-oxobutanoates (2a-c and 9a-c). Similarly,
compounds 1a-c and 4a-c reacted with dialkyl malonates to give the corresponding dialkyl(5,6-dihydro-2-
phenylthieno(and furo)[2,3-d]pyrimidin-4-yl)propanedioates (5a-c, 6a-c, 10a-c and 11a-c).
J. Heterocyclic Chem., 38, 269 (2001).
In search of new methods [1-4] for synthesizing
acetoacetate in the presence of tin(IV) chloride, the inter-
mediate β-enaminoester B initially formed may undergo
cyclization to furnish the expected 2a. Although the reac-
tion of 1a with ethyl acetoacetate in the presence of tin(IV)
chloride gave the 4-amino-2,3-dihydrothieno[2,3-b]-
pyridine derivative 3 [13] in 44% yield, the desired 2a
could not be isolated. Iimori and co-workers [7] reported
that this carbon-carbon bond formation is successfully
effected by using a combination of Lewis acid and tertiary
amine. Therefore, we examined the reaction of 1a with
ethyl acetoacetate in the presence of tin(IV) chloride and
triethylamine, and found that the reaction proceeded
smoothly to give 2a. The present paper deals with the reac-
tion of 1a-c and 2-benzamido-4,5-dihydro-3-furancarbo-
nitriles 4a-c [14] with active methylene compounds.
5,6-dihydrothieno[2,3-d]pyrimidines from 2-amino-4,5-
dihydro-3-thiophenecarbonitriles, we showed that 2-ben-
zamido-4,5-dihydro-3-thiophenecarbonitrile (1a) [5]
reacts with malononitrile in the presence of sodium
hydride to give the malononitrile derivative [3]. This reac-
tion probably occurs via addition of the cyano group of 1a
to malononitrile to form the intermediate β-enaminonitrile
A, which undergoes cyclization to give the malononitrile
derivative. However, when 1a was treated with active
methylene compounds lacking cyano group such as ethyl
acetoacetate and diethyl malonate under the same condi-
tions, no reaction occurred, and 1a was recovered
unchanged. Hence, in order to overcome this limitation,
we attempted to find the reaction conditions for the reac-
tion of 1a with ethyl acetoacetate.
When a mixture of 1a-c, ethyl acetoacetate (1.5 equiva-
lents), triethylamine (1.5 equivalents) and tin(IV) chloride
(3 equivalents) in 1,2-dichloroethane was refluxed, 2a-c
were obtained in moderate yields. In a similar fashion, the
reaction of 1a-c with diethyl and dimethyl malonates
resulted in the formation of the corresponding malonic
CH (CN)
2
2
1
NaH
ester derivatives 5a-c and 6a-c in good yields. The H nmr
spectra of 2a and 2b in deuteriochloroform show two sin-
glets at near δ 2.00 and δ 2.40 for acetyl groups, a singlet at
near δ 4.80 for a methine and a singlet at near δ 13.20 for a
chelated amino group, whereas 2c appears as a singlet δ
2.20 for an acetyl group and a singlet at δ 4.33 for a
methine group, and the signal due to an amino group is not
observed. These observations indicate that 2a and 2b exist
as a tautomeric mixture of the 5,6-dihydrothieno[2,3-d]-
pyrimidine forms C and the 3,4,5,6-tetrahydrothieno-
[2,3-d]pyrimidine forms D in deuteriochloroform, while
2c exists as the 5,6-dihydrothieno[2,3-d]pyrimidine form
C. Compounds 2a-c were easily hydrolyzed to the corre-
sponding ethyl acetate derivatives 7a-c when heated with
aqueous triethylamine. These products 2a-c, 5a-c, 6a-c
and 7a-c were characterized by elemental analyses and
spectral data. The reaction of 7a with ethyl chloroformate
in the presence of sodium hydride afforded 5a in 60%
yield. Compound 5a was also obtained by treatment of
4-chloro-5,6-dihydro-2-phenylthieno[2,3-d]pyrimidine (8)
[1] with diethyl malonate and sodium hydride.
3
Tin(IV) chloride has been shown to facilitate the carbon-
carbon bond formation between the cyano group of nitriles
and active methylene compounds [6-12]. This reaction
suggests the possibility that when 1a is treated with ethyl

270
H. Maruoka, K. Yamagata and M. Yamazaki
Vol. 38
preparation of the 5,6-dihydrothieno(and furo)pyrimidines
bearing an active methine group at the 4-position.
EXPERIMENTAL
All melting points are uncorrected. The ir spectra were
1
recorded on a JASCO A-302 spectrometer. The H nmr spectra
were recorded on a HITACHI R-90 H spectrometer (90 MHz) or
a JEOL JNM-MH-100 spectrometer (100 MHz). Chemical shifts
(δ) are reported in parts per million (ppm) relative to tetramethyl-
silane as internal standard. Elemental analyses were performed
on a HERAUS CHNO-RAPID analyzer.
General Procedure for the Preparation of 5,6-Dihydro-2-phenyl-
thieno(and furo)[2,3-d]pyrimidines 2, 5, 6, 9, 10 and 11.
Tin(IV) chloride (7.82 g, 30 mmoles) was added dropwise to an
ice-cooled and stirred solution of 1 or 4 (10 mmoles) and ethyl ace-
toacetate (1.95 g, 15 mmoles), diethyl malonate (2.40 g, 15
mmoles) or dimethyl malonate (1.98 g, 15 mmoles) and triethyl-
amine (1.52 g, 15 mmoles) in 1,2-dichloroethane (10 ml). After the
mixture had been refluxed for 5 hours, anhydrous sodium carbonate
(10 g) and a saturated aqueous sodium carbonate solution (5 ml)
were successively added to the reaction mixture with stirring and
ice-cooling. The solid was removed by filtration and washed with
hot chloroform. The combined filtrates were concentrated in vacuo
and the residue was purified by column chromatography on silica
gel with chloroform as the eluent to give 2, 5, 6, 9, 10 and 11.
Subsequently, the reactions of 4a-c with ethyl acetoacetate
or diethyl and dimethyl malonates under the same conditions
gave the corresponding ethyl acetoacetate derivatives 9a-c or
malonate derivatives 10a-c and 11a-c. On hydrolysis with
aqueous triethylamine, 9a-c provided the corresponding
1
ethyl acetate derivatives 12a-c in good yields. The H nmr
Ethyl 2-(5,6-Dihydro-2-phenylthieno[2,3-d]pyrimidin-4-yl)-3-
oxobutanoate (2a).
spectra of 9a-c in deuteriochloroform indicate that 9a-c con-
sist of a tautomeric mixture of the dihydrofuro[2,3-d]-
pyrimidine forms C and the tetrahydrofuro[2,3-d]pyrimidine
forms D. Elemental analyses and the spectral data of 9-12 are
consistent with the proposed structures. Compounds 12a-c
were converted into 10a-c by treatment with ethyl chlorofor-
mate and sodium hydride.
Finally, we synthesized 11a by an alternative route.
Generally, o-acylaminonitriles undergo acid-catalyzed
intramolecular cyclization on treatment with an acid to give
condensed 4(3H)-pyrimidinones [1,15-17]. Compound 4a
was cyclized to 5,6-dihydro-2-phenylfuro[2,3-d]-
pyrimidin-4(3H)-one (13) by heating it with benzoic acid in
ethyl orthoformate. Chlorination of 13 with thionyl chloride
and N,N-dimethylformamide [18, 19] provided 4-chloro-5,6-
dihydro-2-phenylfuro[2,3-d]pyrimidine (14) in 50% yield.
The reaction of 14 with dimethyl malonate led to the desired
11a. This method has obviously proved to have several dis-
advantages such as a long reaction time and the low yield.
In conclusion, the reactions of 1 and 4 with active meth-
ylene compounds in the presence of tin(IV) chloride and
triethylamine seem to provide an efficient method for the
This compound was obtained as colorless needles (1.90 g,
56%), mp 133-134° (acetone-petroleum ether); ir (potassium
-1
1
bromide): ν 1725 (C=O) cm ; H nmr (deuteriochloroform): δ
1.23 (t, J = 7 Hz, 1.5H, CO CH CH ), 1.29 (t, J = 7 Hz, 1.5H,
2
2
3
CO CH CH ), 2.01 (s, 1.5H, COCH ), 2.37 (s, 1.5H, COCH ),
2
2
3
3
3
3.19-3.40 (m, 4H, 5-H, 6-H), 4.23 (q, J = 7 Hz, 1H,
CO CH CH ), 4.28 (q, J = 7 Hz, 1H, CO CH CH ), 4.82 (s,
2
2
3
2
2
3
0.5H, methine H), 7.40-7.54 (m, 3H, aromatic H), 8.18-8.44 (m,
2H, aromatic H), 13.25 ppm (s, 0.5H, NH).
Anal. Calcd. for C
H N O S: C, 63.14; H, 5.30; N, 8.18.
18 18 2 3
Found: C, 63.01; H, 5.41; N, 8.28.
Ethyl 2-(5,6-Dihydro-6-methyl-2-phenylthieno[2,3-d]-
pyrimidin-4-yl)-3-oxobutanoate (2b).
This compound was obtained as colorless needles (1.99 g, 56%),
mp 113-114° (acetone-petroleum ether); ir (potassium bromide): ν
-1
1
1730 (C=O) cm ; H nmr (deuteriochloroform): δ 1.22 (t, J = 7
Hz, 1.5H, CO CH CH ), 1.29 (t, J = 7 Hz, 1.5H, CO CH CH ),
2
2
3
2
2
3
1.50 (d, J = 7 Hz, 1.5H, 6-CH ), 1.51 (d, J = 7 Hz, 1.5H, 6-CH ),
3
3
1.99 (s, 1.5H, COCH ), 2.37 (s, 1.5H, COCH ), 2.70-3.06 (m, 1H,
3
3
5-H), 3.14-3.56 (m, 1H, 5-H), 3.87-4.41 (m, 1H, 6-H), 4.22 (q, J =
7Hz, 1H, CO CH CH ), 4.28 (q, J = 7 Hz, 1H, CO CH CH ), 4.84
2
2
3
2
2
3

Jan-Feb 2001
Synthesis of 5,6-Dihydrothieno(and furo)pyrimidines
271
(s, 0.5H, methine H), 7.40-7.55 (m, 3H, aromatic H), 8.16-8.45 (m,
2H, aromatic H), 13.23 ppm (s, 0.5H, NH).
1H, methine H), 7.38-7.47 (m, 3H, aromatic H), 8.32-8.43 ppm
(m, 2H, aromatic H).
Anal. Calcd. for C
H
N O S: C, 64.02; H, 5.66; N, 7.86.
Anal. Calcd. for C H N O S: C, 59.29; H, 4.68; N, 8.13.
19 20
2
3
17 16 2 4
Found: C, 64.02; H, 5.71; N, 7.99.
Found: C, 59.34; H, 4.74; N, 8.24.
Ethyl 2-(5,6-Dihydro-2,5-diphenylthieno[2,3-d]pyrimidin-4-yl)-
3-oxobutanoate (2c).
Dimethyl (5,6-Dihydro-6-methyl-2-phenylthieno[2,3-d]pyrim-
idin-4-yl)propanedioate (6b).
This compound was obtained as colorless needles (1.68 g,
40%), mp 139-141° (acetone-petroleum ether); ir (potassium
This compound was obtained as colorless prisms (2.95 g,
82%), mp 103-104° (acetone-petroleum ether); ir (potassium bro-
-1
1
-1 1
bromide): ν 1729, 1720 (C=O) cm ; H nmr (deuteriochloro-
form): δ 1.10 (t, J = 7 Hz, 3H, CO CH CH ), 2.20 (s, 3H,
mide): 1760, 1725 (C=O) cm ; H nmr (deuteriochloroform): δ
1.51 (d, J= 6.5 Hz, 3H, 6-CH ), 2.92 (dd, J = 6, 16 Hz, 1H, 5-H),
2
2
3
3
COCH ), 3.29 (dd, J = 5.5, 11 Hz, 1H, 6-H), 3.87 (dd, J = 9, 11
3.39 (dd, J = 7.5, 16 Hz, 1H, 5H), 3.82 (s, 6H, 2xCO CH ),
3
2 3
Hz, 1H, 6-H), 4.00 (q, J = 7 Hz, 2H, CO CH CH ), 4.33 (s, 1H,
methine H), 4.74 (dd, J = 5.5, 9 Hz, 1H, 5-H), 7.16-7.52 (m, 8H,
aromatic H), 8.35-8.47 ppm (m, 2H, aromatic H).
3.82-4.13 (m, 1H, 6-H), 4.91 (s, 1H, methine H), 7.36-7.50 (m,
3H, aromatic H), 8.33-8.44 ppm (m, 2H, aromatic H).
2
2
3
Anal. Calcd. for C
H N O S: C, 60.32; H, 5.06; N, 7.82.
18 18 2 4
Anal. Calcd. for C
H
N O S: C, 68.88; H, 5.30; N, 6.69.
Found: C, 60.35; H, 5.12; N, 7.93.
24 22
2 3
Found: C, 68.99; H, 5.39; N, 6.83.
Dimethyl (5,6-Dihydro-2,5-diphenylthieno[2,3-d]pyrimidin-
4-yl)propanedioate (6c).
Diethyl (5,6-Dihydro-2-phenylthieno[2,3-d]pyrimidin-4-yl)-
propanedioate (5a).
This compound was obtained as colorless needles (3.49 g,
84%), mp 157-158° (acetone-petroleum ether); ir (potassium bro-
This compound was obtained as colorless needles (3.38 g,
91%), mp 93-94° (methylene chloride-petroleum ether); ir
(potassium bromide): ν 1735 (C=O) cm ; H nmr (deuterio-
chloroform): δ 1.29 (t, J = 7 Hz, 6H, 2xCO CH CH ), 3.03-3.60
-1
1
mide): ν 1745 (C=O) cm ; H nmr (deuteriochloroform): δ 3.29
-1
1
(dd, J = 5.5, 11 Hz, 1H, 6-H), 3.55 (s, 3H, CO CH ), 3.66 (s, 3H,
2
3
CO CH ), 3.88 (dd, J = 9, 11 Hz, 1H, 6-H), 4.40 (s, 1H, methine
2
3
2
2
3
H), 4.75 (dd, J = 5.5, 9 Hz, 1H, 5-H), 7.12-7.51 (m, 8H, aromatic
H), 8.35-8.46 ppm (m, 2H, aromatic H).
(m, 4H, 5-H, 6-H), 4.29 (q, J = 7 Hz, 4H, 2xCO CH CH ), 4.86
(s, 1H, methine H), 7.31-7.47 (m, 3H, aromatic H), 8.34-8.46
ppm (m, 2H, aromatic H).
2
2
3
Anal. Calcd. for C
H N O S: C, 65.70; H, 4.79; N, 6.66.
23 20 2 4
Found: C, 65.78; H, 4.92; N, 6.74.
Anal. Calcd. for C
H N O S: C, 61.27; H, 5.41; N, 7.52.
19 20 2 4
Found: C, 61.31; H, 5.50; N, 7.57.
Ethyl 2-(5,6-Dihydro-2-phenylfuro[2,3-d]pyrimidin-4-yl)-3-
oxobutanoate (9a).
Diethyl (5,6-Dihydro-6-methyl-2-phenylthieno[2,3-d]pyrimidin-
4-yl)propanedioate (5b).
This compound was obtained as yellow columns (1.86 g,
57%), mp 98-100° (methylene chloride-petroleum ether); ir
This compound was obtained as colorless prisms (3.48 g,
90%), mp 59-60° (diethyl ether-petroleum ether); ir (potassium
-1
1
(potassium bromide): ν 1695 (C=O) cm ; H nmr (deuterio-
chloroform): δ 1.24 (t, J = 7 Hz, 2.1 H, CO CH CH ), 1.37 (t,
-1
1
bromide):ν 1730 (C=O) cm ; H nmr (deuteriochloroform): δ
1.30 (t, J = 7 Hz, 6H, 2xCO CH CH ), 1.51 (d, J = 7 Hz, 3H,
2
2
3
J = 7 Hz, 0.9H, CO CH CH ), 2.07 (s, 0.9H, COCH ), 2.32 (s,
2
2
3
3
2
2
3
2.1H, COCH ), 3.01-3.25 (m, 2H, 5-H), 4.13-4.42 (m, 2H,
6-CH ), 2.93 (dd, J = 6, 16 Hz, 1H, 5-H), 3.41 (dd, J = 7.5, 16
3
3
CO CH CH ), 4.69 (t, J = 9 Hz, 2H, 6-H), 4.93 (s, 0.3H,
Hz, 1H, 5-H), 3.90-4.13 (m, 1H, 6-H), 4.29 (q, J = 7 Hz, 4H,
2
2
3
methine H), 7.40-7.55 (m, 3H, aromatic H), 8.18-8.46 (m, 2H,
aromatic H), 13.38 ppm (s, 0.7 H, NH).
2xCO CH CH ), 4.87 (s, 1H, methine H), 7.34-7.51 (m, 3H, aro-
2
2
3
matic H), 8.29-8.47 ppm (m, 2H, aromatic H).
Anal. Calcd. for C N O S: C, 62.16; H, 5.74; N, 7.25.
Anal. Calcd. for C
H N O : C, 66.25; H, 5.56; N, 8.58.
H
18 18 2 4
20 22
2 4
Found: C, 66.35; H, 5.59; N, 8.65.
Found: C, 62.34; H, 5.82; N, 7.38.
Ethyl 2-(5,6-Dihydro-6-methyl-2-phenylfuro[2,3-d]pyrimidin-
4-yl)-3-oxobutanoate (9b).
Diethyl (5,6-Dihydro-2,5-diphenylthieno[2,3-d]pyrimidin-4-yl)-
propanedioate (5c).
This compound was obtained as colorless needles (1.44 g,
42%), mp 72-73° (diethyl ether-petroleum ether); ir (potassium
This compound was obtained as colorless prisms (3.95 g,
88%), mp 132-133° (acetone-petroleum ether); ir (potassium bro-
-1
1
-1
1
bromide): ν 1722 (C=O) cm ; H nmr (deuteriochloroform): δ
1.38 (t, J = 7 Hz, 3H, CO CH CH ), 1.53 (d, J = 6.5 Hz, 3H,
mide): ν 1755, 1740 (C=O) cm ; H nmr (deuteriochloroform):
δ l.13 (t, J = 7 Hz, 3H, CO CH CH ), 1.21 (t, J = 7 Hz, 3H,
2
2
3
2
2
3
6-CH ), 2.07 (s, 0.6H, COCH ), 2.33 (s, 2.4H, COCH ), 2.69
CO CH CH ), 3.29 (dd, J = 5.5, 11 Hz, 1H, 6-H), 3.76-4.26 (m,
3
3
3
2
2
3
(dd, J = 7, 16.5 Hz, 1H, 5-H), 3.24 (dd, J = 9, 16.5 Hz, 1H, 5-H),
5H, 6-H, 2xCO CH CH ), 4.35 (s, 1H, methine H), 4.76 (dd, J =
2
2
3
4.13-4.60 (m, 2H, CO CH CH ), 4.92 (s, 0.2H, methine H),
4.92-5.18 (m, 1H, 6-H), 7.40-7.66 (m, 3H, aromatic H), 8.18-
8.52 (m, 2H, aromatic H), 13.37 ppm (s, 0.8H, NH).
5.5, 9 Hz, 1H, 5-H), 7.13-7.51 (m, 8H, aromatic H), 8.35-8.47
ppm (m, 2H, aromatic H).
2
2
3
Anal. Calcd. for C
H N O S: C, 66.95; H, 5.39; N, 6.25.
25 24 2 4
Anal. Calcd. for C
H N O : C, 67.05; H, 5.92; N, 8.23.
Found: C, 66.93; H, 5.43; N, 6.30.
19 20 2 4
Found: C, 66.81; H, 6.08; N, 8.44.
Dimethyl (5,6-Dihydro-2-phenylthieno[2,3-d]pyrimidin-4-yl)-
propanedioate (6a).
Ethyl 2-(5,6-Dihydro-2,5-diphenylfuro[2,3-d]pyrimidin-4-yl)-3-
oxobutanoate (9c).
This compound was obtained as colorless needles (2.77 g,
80%), mp 123-124° (acetone-petroleum ether); ir (potassium
This compound was obtained as colorless needles (2.62 g, 65%),
-1
1
bromide): ν 1740 (C=O) cm ; H nmr (deuteriochloroform): δ
3.20-3.50 (m, 4H, 5-H, 6-H), 3.82 (s, 6H, 2xCO CH ), 4.90 (s,
mp 152-153° (acetone-petroleum ether); ir (potassium bromide): ν
-1 1
1740, 1722 (C=O) cm ; H nmr (deuteriochloroform): δ 1.04 (t, J =
2
3

272
H. Maruoka, K. Yamagata and M. Yamazaki
Vol. 38
7 Hz, 1.2H, CO CH CH ), 1.15 (t, J = 7 Hz, 1.8H, CO CH CH ),
1.54 (d, J = 6.5 Hz, 3H, 6-CH ), 2.83 (dd, J = 7, 16.5 Hz, 1H, 5-H),
3
2
2
3
2
2
3
1.58 (s, 1.2H, COCH ), 2.20 (s, 1.8H, COCH ), 4.09 (q, J = 7 Hz,
3.39 (dd, J = 9, 16.5 Hz, 1H, 5-H), 3.81 (s, 6H, 2xCO CH ), 4.94
3
3
2 3
2H, CO CH CH ), 4.34 (s, 0.4H, methine H), 4.37-4.79 (m, 2H,
6-H), 4.81-5.29 (m, 2H, 5-H), 6.95-7.59 (m, 8H, aromatic H), 8.24-
8.48 (m, 2H, aromatic H), 12.93 ppm (s, 0.6H, NH).
(s, 1H, methine H), 4.94-5.19 (m, 1H, 6-H), 7.38-7.50 (m, 3H, aro-
matic H), 8.34-8.45 ppm (m, 2H, aromatic H).
2
2
3
Anal. Calcd. for C
H N O : C, 63.15; H, 5.30; N, 8.18.
18 18 2 5
Anal. Calcd. for C
H
N O : C, 71.63; H, 5.51; N, 6.96.
Found: C, 63.19; H, 5.35; N, 8.32.
24 22
2 4
Found: C, 71.41; H, 5.50; N, 6.90.
Dimethyl (5,6-Dihydro-2,5-diphenylfuro[2,3-d]pyrimidin-4-yl)-
propanedioate (11c).
Diethyl (5,6-Dihydro-2-phenylfuro[2,3-d]pyrimidin-4-yl)-
propanedioate (10a).
This compound was obtained as colorless prisms (3.05 g,
75%), mp 108-109° (diethyl ether-petroleum ether); ir (potassium
This compound was obtained as colorless columns (2.85 g,
80%), mp 72-73° (diethyl ether-petroleum ether); ir (potassium
-1
1
bromide): ν 1745 (C=O) cm ; H nmr (deuteriochloroform): δ
3.61 (s, 3H, CO CH ), 3.66 (s, 3 H, CO CH ), 4.41 (s, 1H,
-1
1
bromide): ν 1735 (C=O) cm ; H nmr (deuteriochloroform): δ
1.30 (t, J = 7 Hz, 6H, 2xCO CH CH ), 3.29 (t, J = 8.5 Hz, 2H,
2
3
2
3
methine H), 4.44-4.81 (m, 2H, 6-H), 5.06 (dd, J = 7.5, 9 Hz, 1H,
5-H), 7.09-7.51 (m, 8H, aromatic H), 8.35-8.47 ppm (m, 2H, aro-
matic H).
2
2
3
5-H), 4.28 (q, J = 7 Hz, 4H, 2xCO CH CH ), 4.70 (t, J = 8.5
Hz, 2H, 6-H), 4.92 (s, 1H, methine H), 7.36-7.48 (m, 3H, aro-
matic H), 8.35-8.47 ppm (m, 2H, aromatic H).
2
2
3
Anal. Calcd. for C
H N O : C, 68.31; H, 4.98; N, 6.93.
23 20 2 5
Anal. Calcd. for C
H
N O : C, 64.04; H, 5.66; N, 7.86.
Found: C, 68.23; H, 5.01; N, 7.10.
19 20
2 5
Found: C, 64.12; H, 5.72; N, 7.99.
The Reaction of 1a with Ethyl Acetoacetate in the Presence of
Diethyl (5,6-Dihydro-6-methyl-2-phenylfuro[2,3-d]pyrimidin-4-yl)
propanedioate (10b).
Tin(IV) Chloride.
To an ice-cooled and stirred solution of 1a (2.30 g, 10 mmoles)
and ethyl acetoacetate (2.60 g, 20 mmoles) in 1,2-dichloroethane
(10 ml) was added tin(IV) chloride (7.82 g, 30 mmoles), and the
resulting mixture allowed to reflux for 5 hours. After work-up as
described for the preparation of 5,6-dihydro-2-phenylthieno(and
furo)[2,3-d]pyrimidines, ethyl 4-amino-2,3-dihydro-6-methyl-
thieno[2,3-b]pyridine-5-carboxylate (3) (1.05 g, 44%) was
obtained. The melting point and ir spectrum of this compound
coincided with those of an authentic sample [13].
This compound was obtained as colorless prisms (3.02 g,
82%), mp 89-90° (diethyl ether-petroleum ether); ir (potassium
-1
1
bromide): ν 1750, 1740 (C=O) cm ; H nmr (deuteriochloro-
form): δ 1.30 (t, J = 7 Hz, 6H, 2xCO CH CH ), 1.54 (d, J = 6
2
2
3
Hz, 3H, 6-CH ), 2.85 (dd, J = 7, 16.5 Hz, 1H, 5-H), 3.41 (dd, J =
3
9, 16.5 Hz, 1H, 5-H), 4.28 (q, J = 7 Hz, 4H, 2xCO CH CH ),
2
2
3
4.94 (s, 1H, methine H), 4.94-5.19 (m, 1H, 6-H), 7.35-7.50 (m,
3H, aromatic H), 8.35-8.47 ppm (m, 2H, aromatic H).
Anal. Calcd. for C
Found: C, 64.84; H, 6.06; N, 7.59.
H N O : C, 64.85; H, 5.99; N, 7.56.
20 22 2 5
General Procedure for the Preparation of Ethyl (5,6-Dihydro-2-
phenylthieno(and furo)pyrimidin-4-yl)acetates 7 and 12.
Diethyl (5,6-Dihydro-2,5-diphenylfuro[2,3-d]pyrimidin-4-yl)-
propanedioate (10c).
A solution of 2 or 9 (5 mmoles) and triethylamine (2 ml) in
water (3 ml) was refluxed for 2 hours. The reaction mixture was
acidified with 10% hydrochloric acid and extracted with chloro-
form. The extract was washed with water, dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was
recrystallized from an appropriate solvent to yield 7 and 12.
This compound was obtained as colorless columns (3.83 g,
89%), mp 106-108° (diethyl ether-petroleum ether); ir (potassium
-1
1
bromide): ν 1745, 1725 (C=O) cm ; H nmr (deuteriochloro-
form): δ 1.17 (t, J = 7 Hz, 3H, CO CH CH ), 1.21 (t, J = 7 Hz,
2
2
3
3H, CO CH CH ), 3.97-4.27 (m, 4H, 2xCO CH CH ), 4.36 (s,
2
2
3
2
2
3
Ethyl (5,6-Dihydro-2-phenylthieno[2,3-d]pyrimidin-4-yl)acetate
(7a).
1H, methine H), 4.48 (dd, J = 7, 15 Hz, 1H, 6-H), 4.71 (dd, J =
8.5, 15 Hz, 1H, 6-H), 5.06 (dd, J = 7, 8.5 Hz, 1H, 5-H), 7.10-7.50
(m, 8H, aromatic H), 8.36-8.48 ppm (m, 2H, aromatic H).
This compound was obtained as colorless needles (1.45 g,
96%), mp 64-65° (diethyl ether-petroleum ether); ir (potassium
Anal. Calcd. for C
H N O : C, 69.43; H, 5.59; N, 6.48.
25 24 2 5
-1
1
bromide): ν 1715 (C=O) cm ; H nmr (deuteriochloroform): δ
1.27 (t, J = 7 Hz, 3H, CO CH CH ), 3.19-3.55 (m, 4H, 5-H,
Found: C, 69.22; H, 5.64; N, 6.45.
2
2
3
Dimethyl (5,6-Dihydro-2-phenylfuro[2,3-d]pyrimidin-
4-yl)propanedioate (11a).
6-H), 3.75 (s, 2H, CH CO CH CH ), 4.20 (q, J = 7 Hz, 2H,
2
2
2
3
CO CH CH ), 7.38-7.48 (m, 3H, aromatic H), 8.33-8.45 ppm
2
2
3
This compound was obtained as colorless scales (2.15 g, 66%),
mp 124-125° (acetone-petroleum ether); ir (potassium bromide):
(m, 2H, aromatic H).
Anal. Calcd. for C
Found: C, 64.19; H, 5.38; N, 9.34.
H N O S: C, 63.98; H, 5.37; N, 9.33.
16 16 2 2
-1
1
ν 1755, 1742 (C=O) cm ; H nmr (deuteriochloroform): δ 3.26
(t, J = 8.5 Hz, 2H, 5-H), 3.81 (s, 6H, 2xCO CH ), 4.70 (t, J =
2
3
Ethyl (5,6-Dihydro-6-methyl-2-phenylthieno[2,3-d]pyrimidin-
4-yl)acetate (7b).
8.5 Hz, 2H, 6-H), 4.95 (s, 1H, methine H), 7.35-7.49 (m, 3H, aro-
matic H), 8.33-8.44 ppm (m, 2H, aromatic H).
This compound was obtained as colorless prisms (1.18 g,
75%), mp 47-48° (diethyl ether-petroleum ether); ir (potassium
bromide): ν 1730 (C=O) cm ; H nmr (deuteriochloroform): δ
1.27 (t, J = 7 Hz, 3H, CO CH CH ), 1.52 (d, J = 7 Hz, 3H,
Anal. Calcd. for C
H N O : C, 62.19; H, 4.91; N, 8.53.
17 16 2 5
Found: C, 62.16; H, 4.91; N, 8.63.
-1
1
Dimethyl (5,6-Dihydro-6-methyl-2-phenylfuro[2,3-d]pyrimidin-
4-yl)propanedioate (11b).
2
2
3
6-CH ), 2.96 (dd, J = 6.5, 16 Hz, 1H, 5-H), 3.46 (dd, J = 8, 16
3
This compound was obtained as colorless columns (2.28 g,
67%), mp 74-75° (diethyl ether-petroleum ether); ir (potassium bro-
mide): ν 1750, 1735 (C=O) cm ; H nmr (deuteriochloroform): δ
Hz, 1H, 5-H), 3.75 (s, 2H, CH CO CH CH ), 3.84-4.32 (m, 1H,
2 2 2 3
6-H), 4.20 (q, J = 7 Hz, 2H, CO CH CH ), 7.39-7.50 (m, 3 H,
2
2
3
-1
1
aromatic H), 8.34-8.45 ppm (m, 2H, aromatic H).

Jan-Feb 2001
Synthesis of 5,6-Dihydrothieno(and furo)pyrimidines
273
Anal. Calcd. for C
Found: C, 65.09; H, 5.81; N, 8.99.
H
N O S: C, 64.94; H, 5.77; N, 8.91.
10% hydrochloric acid and extracted with chloroform. The
extract was dried over anhydrous sodium sulfate and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy on silica gel with chloroform as the eluent to give 5a (1.11
g, 60%), 10a (0.70 g, 39%), 10b (0.54 g, 28%) and 10c (1.09 g,
50%). These compounds were shown to be identical with sam-
ples prepared from diethyl malonate and 1a or 4a-c on the basis
of a mixed melting point determination and a comparison of the ir
spectra.
17 18
2 2
Ethyl (5,6-Dihydro-2,5-diphenylthieno[2,3-d]pyrimidin-4-yl)-
acetate (7c).
This compound was obtained as colorless needles (1.72 g,
91%), mp 120-121° (acetone-petroleum ether); ir (potassium bro-
mide): ν 1727 (C=O) cm ; H nmr (deuteriochloroform): δ 1.20
(t, J = 7 Hz, 3H, CO CH CH ), 3.29 (dd, J = 5.5, 11 Hz, 1H,
-1
1
2
2
3
6-H), 3.37 (AB quartet, J = 16 Hz, 2H, CH CO CH CH ), 3.89
2
2
2
3
The Preparation of 5a from Diethyl Malonate and 4-Chloro-5,6-
dihydro-2-phenylthieno[2,3-d]pyrimidine (8).
(dd, J = 9, 11 Hz, 1H, 6-H), 4.08 (q, J = 7 Hz, 2H,
CO CH CH ), 4.84 (dd, J = 5.5, 9 Hz, 1H, 5-H), 7.14-7.52 (m,
2
2
3
8H, aromatic H), 8.37-8.48 ppm (m, 2H, aromatic H).
Anal. Calcd. for C N O S: C, 70.19; H, 5.36; N, 7.44.
Found: C, 70.28; H, 5.41; N, 7.52.
To an ice-cooled and stirred solution of diethyl malonate (2.40 g,
15 mmoles) in dimethyl sulfoxide (10 ml) was added 60% sodium
hydride (0.60 g, 15 mmoles). Stirring was continued at room temper-
ature until the evolution of gas ceased, and then compound 8 (1.24 g,
5 mmoles) was added. The reaction mixture was stirred at 120° for 7
hours. After removal of the solvent in vacuo, cold water was added
to the residue. The resulting mixture was acidified with 10%
hydrochloric acid and extracted with chloroform. The extract was
dried over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified by column chromatography on silica gel with
chloroform as the eluent to give 5a (0.62 g, 33%). The melting point
and ir spectrum of this compound coincided with those of an authen-
tic sample prepared from 1a and diethyl malonate.
H
22 20
2 2
Ethyl (5,6-Dihydro-2-phenylfuro[2,3-d]pyrimidin-4-yl)acetate
(12a).
This compound was obtained as colorless columns (1.31 g,
92%), mp 82-83° (diethyl ether-petroleum ether); ir (potassium
-1
1
bromide): ν 1745 (C=O) cm ; H nmr (deuteriochloroform): δ
1.29 (t, J = 7 Hz, 3 H, CO CH CH ), 3.25 (t, J = 8.5 Hz, 2H,
2
2
3
5-H), 3.77 (s, 2H, CH CO CH CH ), 4.21 (q, J = 7 Hz, 2H,
2
2
2
3
CO CH CH ), 4.70 (t, J = 8.5 Hz, 2H, 6-H), 7.36-7.48 (m, 3H,
2
2
3
aromatic H), 8.35-8.46 ppm (m, 2H, aromatic H).
Anal. Calcd. for C N O : C, 67.59; H, 5.67; N, 9.85.
H
16 16
2 3
5,6-Dihydro-2-phenylfuro[2,3-d]pyrimidin-4(3H)-one (13).
Found: C, 67.58; H, 5.79; N, 9.93.
A solution of 4a (2.14 g, 10 mmoles) and benzoic acid (1.22 g,
10 mmoles) in ethyl orthoformate (5 ml) was stirred at 145-150°
for 6 hours. After removal of the solvent in vacuo, the residue
was washed with diethyl ether and then recrystallized from
methanol-chloroform (1:5) to give 13 (0.92 g, 43%) as colorless
Ethyl (5,6-Dihydro-6-methyl-2-phenylfuro[2,3-d]pyrimidin-
4-yl)acetate (12b).
This compound was obtained as pale yellow oil (1.39 g, 94%);
-1 1
ir (neat): ν 1733 (C=O) cm ; H nmr (deuteriochloroform): δ
1.28 (t, J = 7 Hz, 3H, CO CH CH ), 1.55 (d, J = 6 Hz, 3H,
2
2
3
needles, mp 269-270°; ir (potassium bromide): ν 1650 (C=O)
6-CH ), 2.83 (dd, J = 6.5, 16 Hz, 1H, 5-H), 3.40 (dd, J = 9, 16
3
-1 1
cm ; H nmr (DMSO-d ): δ 3.00 (t, J = 9 Hz, 2H, 5-H), 4.64 (t,
6
Hz, 1H, 5-H), 3.76 (s, 2H, CH CO CH CH ), 4.21 (q, J = 7 Hz,
2
2
2
3
J = 9 Hz, 2H, 6-H), 7.44-7.62 (m, 3H, aromatic H), 8.01-8.14 (m,
2H, aromatic H), 12.45 ppm (br s, 1H, NH).
2H, CO CH CH ), 4.94-5.20 (m, 1H, 6-H), 7.34-7.51 (m, 3H,
2
2
3
aromatic H), 8.32-8.49 ppm (m, 2H, aromatic H).
Anal. Calcd. for C N O : C, 68.44; H, 6.08; N, 9.39.
Anal. Calcd. for C
H N O : C, 67.28; H, 4.71; N, 13.08.
12 10 2 2
H
17 18
2 3
Found: C, 67.29; H, 4.68; N, 12.97.
Found: C, 68.15; H, 6.11; N, 9.27.
4-Chloro-5,6-dihydro-2-phenylfuro[2,3-d]pyrimidine (14).
Ethyl (5,6-Dihydro-2,5-diphenylfuro[2,3-d]pyrimidin-4-yl)-
acetate (12c).
To a suspension of 13 (2.14 g, 10 mmoles) and N,N-dimethyl-
formamide (4 ml) in 1,2-dichloroethane (30 ml) was added drop-
wise thionyl chloride (1.31 g, 11 mmoles) with stirring and
ice-cooling. The mixture was refluxed for 3 hours. After removal
of the solvent, cold water was added to the residue. The resulting
mixture was basified with a saturated aqueous sodium hydrogen
carbonate and extracted with chloroform. The extract was dried
over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified by column chromatography on alumina with
methylene chloride as the eluent to afford 14 (1.17 g, 50%) as
This compound was obtained as colorless needles (1.41 g,
79%), mp 77-78° (diethyl ether-petroleum ether); ir (potassium
-1
1
bromide): ν 1723 (C=O) cm ; H nmr (deuteriochloroform): δ
1.21 (t, J = 7 Hz, 3H, CO CH CH ), 3.42 (AB quartet, J = 16
2
2
3
Hz, 2H, CH CO CH CH ), 4.09 (q, J = 7 Hz, 2H,
2
2
2
3
CO CH CH ), 4.46-4.88 (m, 2H, 6-H), 5.07 (dd, J = 7.5, 9 Hz,
2
2
3
1H, 5-H), 7.11-7.52 (m, 8H, aromatic H), 8.39-8.50 ppm (m, 2H,
aromatic H).
Anal. Calcd. for C
H N O : C, 73.32; H, 5.59; N, 7.77.
22 20 2 3
1
colorless needles (acetone-petroleum ether), mp 163-165°; H
Found: C, 73.28; H, 5.65; N, 7.89.
nmr (deuteriochloroform): δ 3.30 (t, J = 8.5 Hz, 2H, 5-H), 4.74
(t, J = 8.5 Hz, 2H, 6-H), 7.25-7.61 (m, 3H, aromatic H), 8.34-
8.45 ppm (m, 2H, aromatic H).
General Procedure for the Preparation of 5a and 10a-c from 7a
and 12a-c.
Anal. Calcd. for C H ClN O: C, 61.95; H, 3.90; N, 12.04.
Found: C, 61.99; H, 3.99; N, 12.01.
To an ice-cooled and stirred solution of 7a or 12a-c (5 mmoles)
in tetrahydrofuran (10 ml) was added 60% sodium hydride (0.24
g, 6 mmoles). Stirring was continued at room temperature until
the evolution of gas ceased, and then ethyl chloroformate (1.09 g,
10 mmloes) was added. The reaction mixture was stirred at 60°
for 5 hours. After removal of the solvent in vacuo, cold water was
added to the residue. The resulting mixture was acidified with
12
9
2
The Preparation of 11a from Dimethyl Malonate and 14.
A solution of dimethyl malonate (1.98 g, 15 mmoles), 14 (1.16
g, 5 mmoles) and 60% sodium hydride (0.60 g, 15 mmoles) in
dimethyl sulfoxide (10 ml) was heated at 120° for 7 hours. After

274
H. Maruoka, K. Yamagata and M. Yamazaki
Vol. 38
[9] F. Scavo and P. Helquist, Tetrahedron Letters, 26, 2603
(1985).
[10] A. C. Veronese, V. Gandolfi, M. Basato and B. Corain, J.
Chem. Res. (S), 246 (1988).
[11] A. C. Veronese, R. Callegari and S. A. A. Salah,
Tetrahedron Letters, 31, 3485 (1990).
[12] T. Charvát, M. Potácˇek and J. Marek, Monatsh. Chem.,
126, 333 (1995).
work-up as described for the preparation of 5a from diethyl mal-
onate and 8, compound 11a (0.30 g, 18%) was obtained. The melt-
ing point and ir spectrum of this compound coincided with those of
an authentic sample prepared from 4a and dimethyl malonate.
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