β-enaminoesters as building blocks in heterocyclic synthesis. A novel synthesis of fused azines by using biaise reaction as a key step

Article abstract of DOI:10.1002/(SICI)1521-3897(199902)341:2<147::AID-PRAC147>3.0.CO;2-I

Ethyl bromoacetate 4 reacts with nitriles in the presence of activated zinc dust to afford the beta-enaminoesters 7 and 19. Compounds 7 and 19 show high reactivity towards a variety of reagents to give polyfunctional heterocyclic compounds. For example, the enaminoesters 7 and 19 react with benzaldehyde to give the 1,4 dihydropyridine derivatives 9 and 20, respectively. Isothiocyanates 24 (R = Ph, OEt) added to 19 to furnish pyrimidine-thiones 26 and 27 respectively. Structures and conceivable mechanisms are discussed. Wiley-VCH Verlag GmbH, 1999.

Full text of DOI:10.1002/(SICI)1521-3897(199902)341:2<147::AID-PRAC147>3.0.CO;2-I

FULL PAPER
β-Enaminoesters as Building Blocks in Heterocyclic Synthesis.
A Novel Synthesis of Fused Azines by Using Blaise Reaction as a Key Step
Ayman W. Erian*
Giza, (A. R. Egypt), Chemistry Department, Faculty of Science, Cairo University
Received April 28th, 1998, respectively July 30th, 1998
Keywords: Bioorganic chemistry, Heterocycles, Antimalarial agents, β-Enaminoesters, Pyrimethamine
Abstract. Ethyl bromoacetate 4 reacts with nitriles in the
presence of activated zinc dust to afford the beta-enami-
noesters 7 and 19. Compounds 7 and 19 show high reactivi-
ty towards a variety of reagents to give polyfunctional hete-
rocyclic compounds. For example, the enaminoesters 7 and
19 react with benzaldehyde to give the 1,4 dihydropyridine
derivatives 9 and 20, respectively. Isothiocyanates 24 (R =
Ph, OEt) added to 19 to furnish pyrimidine-thiones 26 and
27 respectively. Structures and conceivable mechanisms are
discussed.
well-known Hantzsch type synthesis of 1,4-dihydropy-
ridine-3,5-diesters [6, 7]. The reaction apparently involv-
es the formation of diamine 8 as an intermediate, which
cyclizes via loss of NH3 to give the 1,4-dihydropyrid-
ine derivative 9. Further, the oxidation of 9 was attempt-
ed. When compound 9 was stirred with ceric ammoni-
um nitrate [8] in acetone at room temperature, the pyri-
dine derivative 10 was obtained. Compound 10 with its
ester and active methylene groups reacted readily with
a variety of electrophiles to give unique heterocyclic
compounds. Thus, fusion of 10 with ammonium ace-
tate at 120 °C afforded a product m.p. 210 °C, the mass
spectral data of which revealed a molecular formula
C17H11N3O4 (m/z 321) consistent with the pyrido [3,4:
2',3']pyrido[3,4-b]-pyridine derivative 11.
Pyrimethamine 1 is a folic acid reductase inhibitor. In
this molecule the ring nitrogen is flanked by two func-
tional groups, which is essential to the biological activ-
ity of pyrimethamine. Also, a plethora of aminopterin
2 and 2,4-diamino-6-substituted quinazoline antifolates
3 exhibit strong antimalarial effects against sensitive
and drug-resistant lines of plasmodium berghei in mice,
plasmodium gallinaceum in chicks and plasmodium
cyanomolgi in rhesus monkeys [1–5]. In spite of the
importance of bifunctionally substituted heterocycles the
synthetic approach of these compounds are rather lim-
ited. In this paper a novel and convenient synthesis of
bi-functionally heterocycles are reported using Blaise
reaction as a key step.
Cl
NH
2
CO2Et
Zn
N
ZnBr
C
CH2CO2Et
N
N
N
NH
Br
N
NH
2
Ar
HN
2
N
EtO2C
EtO2C
EtO2C
Ph
NZnBr
- NH3
N
N
X
H C
N
NH
2
5
2
4
5
6
NH
NH
2
2
1
2
3
CO2Et
NH2
EtO2C
R
CO2Et
50% K2CO3
PhCHO
EtO2C
R
Treatment of ethyl cyanoacetate with 3–5 molar ex-
cess of ethyl bromoacetate 4 in the presence of activat-
ed zinc dust in refluxing THF yielded the correspond-
ing enaminoester 7 via the iminatozinc bromide inter-
mediate 6. This enaminoester with its active methylene
group could be used as versatile reagent for the synthe-
sis of several antifolates. The enaminoester 7 reacted
with benzaldehyde to give only the 1:2 condensation
product, the dihydropyridine 9. The latter resembles the
NH
2 H2N
7
8
Ph
Ph
EtO2C
EtO2C
CO2Et
EtO2C
EtO2C
CO2Et
CAN/benzene
CO2Et
CO2Et
N
H
N
9
10
Scheme 1
J. Prakt. Chem. 1999, 341, No. 2
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999 1436-9966/99/3410X-147 $ 17.50 + .50/0
147

A. W. Erian
FULL PAPER __________________________________________________________________________
Compound 10 was readily coupled with benzenedia-
zonium salt to give the hydrazone 12 which cyclized
readily on boiling in ethanol/sodium acetate to give the
highly conjugated fused heterocyclic compound 13.
ridine 20. Compound 19 reacted also with diethyl acet-
ylenedicarboxylate 21 to afford the pyridine derivative
23. It is believed that compound 23 was obtained via
Michael addition of the β-amino-crotonate 19 to the
acetylenic moiety in 21 to give the adduct 22, which
under the reaction conditions would cyclize to afford
the final isolable pyridine 23.
Ph
N
N
Cl
AcONH
4
10
Ph
EtO C
2
CO Et
2
EtO2C
H2N
5
S
OH
Ph
N
Ph
N
S
N
C
OH
Ph
EtO2C
N
CO2Et
N
N
21
N
N
Ph
Ph
N
HO
N
OH
N
18
19
CO2Et
H
H
EtO2C
S
CO2Et
CO2Et
PhCHO
11
Ph
12
O
N
NH2
EtO
AcONa
Ph
22
EtO2C
CO2Et
N
O
Ph
N
O
- EtOH
Ph
Ph
N
N
N
N
H
CO2Et
N
EtO2C
S
N
S
S
Ph
CO2Et
CO2Et
N
Ph
Ph
N
O
H
Scheme 2
13
20
23
S h
2
Scheme 4
Attempts to prepare the 1:1 condensation product 15
via the reaction of malononitrile 14 with ethyl bromo-
acetate in the presence of activated Zn dust failed; the
reaction giving instead the 1:2 condensation product 17.
Compound 17 is believed to be formed via the addition
of the α-halozinc ester 5 to both cyano groups in malo-
nonitrile to give the acyclic intermediate 16. The latter
cyclized under the reaction conditions by loss of etha-
nol to afford the final isolable pyridine derivative 17.
S
O
C
EtO C
2
NH
COR
R
N
C
S
+
19
R
R'
NH2
24
25
S
EtO C
2
R = Ph
- H2O
S
NH
Ph
N
N
O
S
H
EtO C
2
CN
S
27
NH
Ph
N
S
EtO2C
NH2
N
Ph
N
N
EtO C
2
15
26
NH
C
C
5
CH2
Ph
N
ClCH2CN/K2CO3
- EtOH
N
H
N
Ph
NH2
NH2
O
- EtOH
14
N
S
C
NC
EtO2C
OEt
EtO2C
S
H2N
N
H
O
Ph
HO
S
16
N
17
Ph
29
N
Scheme 3
N
Ph
- EtOH
S
28
O
Next, it was important to study the effect of the Blaise
reaction on a heterocyclic compound having an ace-
tonitrile moiety. A novel synthesis of a β-enaminoester
having a heterocyclic moiety was achieved. Thus,
4-phenylthiazole-2-acetonitrile 18 reacted with ethyl
bromoacetate in the presence of activated zinc to afford
the β-enaminoester 19. Compound 19 was found to un-
dergo a wide variety of further transformations. It read-
ily reacted with benzaldehyde to afford the dihydropy-
Ph
N
N
NH
N
Ph
N
S
Ph
30
S h
5
Scheme 5
148
J. Prakt. Chem. 1999, 341, No. 2

β-Enaminoesters as Building Blocks in Heterocyclic Synthesis
FULL PAPER
CH2), 4.31 (q, 2H, J/Hz = 7.7, CH2), 4.53 (s, 1H, CH), 6.15
(br, s, 2H, NH2). – 13C NMR (CDCl3): δ/ppm = 14.32, 14.52
(2CH3); 60.12, 60.42 (2CH2); 69.58 (CH2); 110.61 (C-2);
142.38 (C-3); 197.42, 202.45 (2C=O). – MS: m/z = 201 (M+).
Isothiocyanates 24 reacted with 19 in acetonitrile with
the formation of 1:1 cyclocondensation product 26 via
addition intermediates 25. In the case of ethoxycarbo-
nyl isothiocyanate the isolated product was the pyri-
midinone derivative 27. S-Alkylation of the compound
26 with equimolar of chloroacetonitrile in ethanol/
K2CO3 solution under reflux results in the formation of
the corresponding thieno[2,3-d]pyrimidine derivative 28
via loss of ethanol. Also, the methylene group in 26
proved to be highly reactive towards electrophilic rea-
gents. For instance, compound 26 underwent elec-
trophilic substitution upon coupling with equimolar
amounts of the appropriate benzenediazonium chloride
in ethanol/NaOH solutions gives the acyclic hydrazone
intermediate 29, which spontaneously intramolecularly
cyclized via ethanol elimination to yield the final isola-
ble pyrimidinopyridazine 30 (Scheme 5). This is the first
reported simple and convenient synthesis of a β-enam-
inoester [1] by using the Blaise reaction which at the
same time, leads to a key step in preparation of com-
pounds having a thiamine-type structure [9, 10].
C9H15NO4
(201.22)
calcd.: C 53.72 H 7.46 N 6.96
found: C 54.10 H 7.40 N 6.80.
Ethyl 3-amino-4-(4'-phenylthiazol-2'-yl)but-2-enoate (19)
Yield 1.8 g (62%). – m.p. 76 °C (benzene). – IR (KBr): νmax
/
cm–1 = 3400, 3350 (NH2), 1680 (C=O). – 1H NMR (CDCl3):
δ/ppm = 1.20 (t, 3H, J/Hz = 8.1, CH3), 2.34 (s, 2H, CH2),
4.19 (q, 2H, J/Hz = 8.1, CH2), 4.68 (s, 1H, CH), 6.61 (s, 1H,
thiazole H), 6.71–6.95 (m, 7H, Ph protons and NH2). – MS:
m/z = 288 (M+).
C15H16N2O2S calcd.: C 62.50 H 5.55 N 9.72S 11.11
(288.47)
found: C 62.20 H 5.40 N 9.80S 11.30.
Diethyl (3,5-diethoxycarbonyl-1,4-dihydro-4-phenylpyridin-
2,6-diyl)-2,6-diacetate (9)
To a solution of 7 (4 g, 0.02 mol) in 20 ml ethanol/acetic acid
(1:1), benzaldehyde (1.06 g, 0.01 mol) was added. The reac-
tion mixture was refluxed for 15 min and then left at room
temperature overnight. The crystals obtained were filtered off
and crystallized from ethanol. – m.p. 125 °C yield 65%. IR
(KBr): νmax/cm–1 = 3250 (NH), 1715, 1685 (C=O), 1650
(C=C). – 1H NMR (CDCl3): δ/ppm = 0.83 (t, 6H, J/Hz = 7.8,
2CH3), 1.19 (t, 6H, J/Hz = 7.8, 2CH3), 2.37 (s, 4H, 2CH2),
3.87 (q, 4H, 2CH2), 4.05 (q, 4H, 2CH2), 5.13 (s, 1H, CH),
6.12 (br, s, 1H, NH), 6.70–6.87 (m, 5H, aromatic protons). –
MS: m/z = 473 (M+).
Experimental
All melting points are uncorrected. IR spectra were recorded
1
from KBr pellets on a Pa-9712 IR-spectrophotometer. H
NMR spectra were recorded on a Varian EM-360 (60 MHz)
and Jeol (270 MHz) spectrometer with DMSO-d6 and CDCl3
as solvents and TMS as internal reference. 13C NMR spectra
were measured on a Jeol (MHz) spectrometer. Analytical data
were obtained from the Microanalytical Data Unit at Cairo
University. The mass spectra were recorded on a Kratos (75
eV) Ms spectrometer.
C25H31NO8 calcd.: C 63.42 H 6.55 N 2.95
(473.52)
found: C 63.20 H 6.50 N 3.10.
Diethyl (3',5'-diethoxycarbonyl-4'-phenylpyridin-2',6'-diyl)-
2,6-diacetate (10)
To a solution of the dihydropyridine 9 (0.95 g, 0.002 mol) in
acetone (15 ml) was added a solution of ceric ammonium
nitrate (CAN; 2.19 g, 4 mmol) in H2O (3.5 ml) fairly rapidly
dropwise at room temperature. The orange color of the rea-
gent disappeared immediately on addition of each drop. Af-
ter stirring for 10 min, the resulting solution was concentrat-
ed to a small volume under reduced pressure. H2O (20 ml)
was added, and the mixture was extracted with chloroform.
The organic phase is washed with water, dried with MgSO4
and evaporated under reduced pressure. The resulting pyrid-
ine crystallized from benzene/petroleum ether (40–60 °C). –
m.p. 115 °C, yield 70%. – IR (KBr): νmax/cm–1 = 1695, 1670
(C=O), 1660, 1645 (C=C). – 1H NMR (CDCl3): δ/ppm = 1.09–
1.28 (m, 12H, 4CH3), 2.72 (s, 4H, 2CH2), 4.10–4.35 (m, 8H,
4CH2), 6.91–7.10 (m, 5H, aromatic protons). – MS: m/z =
471 (M+).
Enaminoesters 7 and 19 (General Procedure)
To prepare the activated zinc, zinc dust was washed sequen-
tially with 3N hydrochloric acid, distilled water, ethanol, and
ether and drying in vacuo. Next, the α-bromoester is added
over 30–60 min to minimize self-condensation. To a suspen-
sion of 327 mg (5 equiv.) of activated zinc dust in 3 ml of
refluxing anhydrous THF under N2 were added 4 drops of the
α-bromoester (0.1 g, 0.6 mmol). After the appearance of a
green color, 1 mmol of the nitrile was added in one portion,
and then α-bromoester (0.6 g, 4 mmol) were injected by sy-
ringe pump over 45 min. The mixture was refluxed for addi-
tional 10 min, diluted with 9 ml of THF, quenched with 1.3
ml of 50% aqueous K2CO3 and rapid stirred for 30 min. to
give two sepa-rated layers. The upper organic layer was sep-
arated and dried with MgSO4, then concentrated and purified
by passing through a short silica gel column and eluted with
a (1:1) hexa-ne : Et2O mixture to give an almost pure (95%)
enaminoester product.
C25H29NO8 calcd.: C 63.69 H 6.15 N 2.97
(471.50)
found: C 63.80 H 6.30 N 3.20.
1,3,7,9-Tetrahydroxy-10-phenylpyrido[3,4:3',2']pyrido [3,2-
c]pyridine (11)
Diethyl 3-aminopent-2-endioate (7)
Yield 1.4 g (70%). – m.p. 27 °C. – IR (KBr): νm1ax/cm–1
=
A mixture of 10 (2.35 g, 0.005 mol) and ammonium acetate
(2 g, 0.02 mol) was heated in an oil bath at 120 °C for 2 h.
The resulting residue was dissolved in ethanol and then dilut-
ed with water. The aqueous solution was neutralized by sodi-
3350, 3300 (NH2), 1720 (C=O), 1695 (C=O). – H NMR
(CDCl3): δ/ppm = 1.21 (t, 3H, J/Hz = 7.7, CH3), 1.30 (t, 3H,
J/Hz = 7.7, CH3), 2.67 (s, 2H, CH2), 4.05 (q, 2H, J/Hz = 7.7,
J. Prakt. Chem. 1999, 341, No. 2
149

A. W. Erian
FULL PAPER __________________________________________________________________________
um carbonate. The precipitate was filtered off and crystal-
Diethyl 1,4-dihydro-2,6-di(4'-phenylthiazol-2'-ylmethyl)-4-
phenylpyridine-3,5-di-carboxylate (20)
lized from DMF. – m.p. 255 °C, yield 55%. – IR (KBr): νmax
/
cm–1 = 3450–3300 (OH), 1660, 1620, 1600 (C=C). – 1H NMR
[(CD3)2SO]:δ/ppm = 3.50 (br, 4H, 4OH), 6.82–7.89 (m, 7H,
aromatic protons). – MS: m/z = 321 (M+).
To a solution of 19 (2.8 g, 0.01 mol) in acetic acid (20 ml),
benz-aldehyde (1.06 g, 0.01 mol) was added. The reaction
mixture was refluxed for 15 min, and the formed precipitate
was filtered off and crystallized from acetic acid. – m.p. 210
°C; yield 70%. – IR (KBr): νmax/cm–1 = 3350 (NH), 1695
C17H11N3O4 calcd.: C 63.50 H 3.42 N 13.08
(471.50)
found: C 63.20 H 3.40 N 12.80.
1
(C=O), 1600 (C=O). – H NMR [(CD3)2SO]: δ/ppm = 0.89
Diethyl (3',5'-diethoxycarbonyl-4'-phenylpyridin-2',6'-diyl)-
2,6-diphenylhydrazono-diacetate (12)
(t, 6H, J/Hz = 7.8, 2CH3), 2.51 (s, 4H, 2CH2), 3.89 (q, 4H, J/
Hz = 7.8, 2CH2), 5.19 (s, 1H, CH), 6.61 (s, 2H, thiazole H),
6.81–7.25 (m, 12H, aromatic protons and NH), 7.45–7.70
(m, 4H, aromatic protons). – MS: m/z = 647 (M+).
To a solution of 10 (4.7 g, 0.01 mol) in ethanol (30 ml) con-
taining sodium acetate (5 g, 0.06 mol), an ice-cold solution of
benzenediazonium chloride [0.02 mol, prepared by adding
sodium nitrite (2.7 g, 0.04 mol) to the appropriate quantity of
aniline (1.86 g, 0.02 mol) in 10 ml concentrated hydrochloric
acid] was added dropwise with stirring. After 30 min the sol-
id product was collected by filtration and crystallized from
C37H33N3O4S2 calcd.: C 68.62 H 5.10 N 6.49 S 9.89
(647.81)
found: C 68.50 H 5.00 N 6.60 S 10.10.
Diethyl 1,2-dihydro-6-(4'-phenylthiazol-2'-ylmethyl)-2-oxo-
pyridine-4,5-dicarboxylate (23)
ethanol. – m.p. 221 °C; yield (80%). – IR (KBr): νmax/cm–1
=
To a solution of 19 (2.8 g, 0.01 mol) in 20 ml dioxane, diethy-
lacetylene dicarboxylate (1.7 g, 0.01 mol) and a few drops of
acetic acid were added. The reaction mixture was refluxed
for 2 h., left to cool and the precipitate was filtered off and
crystallized from dioxane. – m.p. 195 °C; yield (70%). – IR
(KBr): νmax/cm–1 = 3320 (NH), 1720, 1680 (C=O). – 1H NMR
[(CD3)2SO]: δ/ppm = 0.96–1.21 (m, 6H, 2CH3), 2.62 (s, 2H,
CH2), 3.98–4.10 (m, 4H, 2CH2), 6.61 (s, 1H, thiazole H),
6.71–7.19 (m, 6H, aromatic protons), 12.40 (s, 1H, NH);
C21H20N2O5S calcd.: C 61.16 H 4.85 N 6.79 S 7.76
3400, 3350 (NH), 1695–1685 (C=O), 1660, 1630, 1600
(C=C). – 1H NMR [(CD3)2 SO]: δ/ppm = 0.85–1.16 (m, 12H,
4CH3), 3.95–4.16 (m, 8H, 4CH2), 6.85–7.31 (m, 10H, aro-
matic H); 7.45–7.69 (m, 5H, aromatic H), 12.4 (br, 2H, 2NH).
– MS: m/z = 679 (M+).
C37H37N5O8 calcd.: C 65.39 H 5.44 N 10.30
(679.72)
found: C 65.50 H 5.50 N 10.20.
Diethyl 1,9-dioxo-1,2,8,9-tetrahydro-2,8,10-triphenylpyrid-
azino[3,5:2',3']pyrido[2,3-d]pyridazine-4,6-dicarboxylate
(13)
(412.46)
found: C 60.80 H 4.90 N 6.60 S 7.50.
Synthesis of Pyrimidine-thiones 26 and 27 (General Pro-
cedure)
A solution of 12 (6.7 g, 0.01 mol), in ethanol (20 ml) was
refluxed with sodium acetate (3 g, 0.03 mol) for 1 h. The
solid formed during reflux was collected by filtration and crys-
tallized from acetic acid. – m.p. 265 °C; yield 95%. – IR (KBr):
To a suspension of ammonium thiocyanate (0.77 g, 0.0l mol)
in acetonitrile (25 ml), benzoyl chloride (1.4 g, 0.01 mol) or
ethyl chloroformate (1.08 g, 0.01 mol) was added. The reac-
tion mixture was refluxed for 5 min, then treated with β-enam-
inoester (2.8 g, 0.01 mol). The reaction mixture was refluxed
for an additional 15 min. To the reaction mixture sodium hy-
droxide (0.2 g, 5 mmol) was added, and reflux continued for
further 2 min. The cooled reaction mixture was poured into
water. The solid products were collected by filtration and crys-
tallized from ethanol.
1
νmax/cm–1 = 1695, 1665 (C=O), 1640 (C=C). – H NMR
[(CD3)2SO]: δ/ppm = 1.02 (t, 6H, 2CH3), 4.15 (q, 4H, 2CH2),
6.81–7.42 (m, 11H, aromatic protons), 7.50–7.71 (m, 4H,
aromatic protons).
C32H25N5O6 calcd.: C 66.78 H 4.34 N 12.17
(575.58)
found: C 66.90 H 4.20 N 12.40.
Ethyl 4-amino-1,6-dihydro-6-oxopyridine-2-acetate (17)
Ethyl 1,6-dihydro-2-phenyl-4-(4'-phenylthiazol-2'-yl)methyl-
6-thiopyrimidine-5-carboxylate (26)
To a suspension of 327 mg (5 equiv.) of activated zinc dust in
3 ml of refluxing anhydrous THF under N2 atmosphere were
added 4 drops of ethyl bromoacetate (0.1 g, 0.6 mmol). After
the appearance of the green color, malononitrile (0.66 g, 0.01
mol) was added and then ethyl bromoacetate (0.6 g, 4 mmol)
were injected by syringe pump over 45 min. The mixture was
refluxed for an additional 10 min, diluted with THF (9 ml)
and 50% aqueous K2CO3 (10 ml) was added. The brown sol-
id product was formed on dilution with K2CO3 solution. The
precipitate obtained was filtered off and crystallized from eth-
anol : DMF (1:1) mixture. – m.p. 235 °C; yield 45%. – IR
(KBr): νmax/cm–1 = 3400, 3350, 3300 (NH), 1715 (C=O), 1665
(C=O). – 1H NMR [(CD3)2SO]: δ/ppm = 1.16 (t, 3H, J/Hz =
8.0, CH3), 3.60 (s, 2H, CH2), 4.16 (q, 2H, J/Hz = 8.0, CH2),
6.31 (s, 1H, pyridine H), 6.51 (s, 1H, pyridine H), 7.29 (br,
2H, NH2), 12.40 (s, 1H, NH). – MS: m/z = 196 (M+).
Yield (65%). – m.p. 228 °C. – IR (KBr): νmax/cm–1 = 3350
1
(NH), 1685 (C=O), 1620 (C=C). – H NMR [(CD3)2SO]: δ/
ppm = 1.2 (t, 3H, J/Hz = 7.6, CH3), 2.55 (s, 2H, CH2), 2.91
(s, 1H, NH), 4.20 (q, 2H, J/Hz = 7.6, CH2), 6.61 (s, 1H,
thiazole proton), 6.78–7.45 (m, 8H, aromatic proton), 8.20–
8.35 (m, 2H, aromatic proton).
C23H19N3O2S2 calcd.: C 63.74 H 4.38 N 9.69 S 14.78
(433.55)
found: C 63.90 H 4.40 N 9.60 S 15.00.
Ethyl 6-(4'-phenylthiazol-2'-ylmethyl)-2-oxo-1,2,3,4-tetra-
hydro-4-thiopyrimidine-5-carboxylate (27)
Yield (70%). – m.p. 240 °C. – IR (KBr): νmax/cm–1 = 3400,
1
3350 (NH), 1690 (C=O). – H NMR [(CD3)2SO]: δ/ppm =
1.21 (t, 3H, J/Hz = 7.6, CH3), 2.61 (s, 2H, CH2), 2.95 (s, 1H,
NH), 4.20 (q, 2H, J/Hz = 7.6, CH2), 6.61 (s, 1H, thiazole
proton), 6.70–6.9 (m, 5H, aromatic proton), 12.42 (br, 1H,
C9H12N2O3 calcd.: C 55.10 H 6.12 N 14.28
(196.20)
found: C 54.80 H 6.00 N 14.40.
150
J. Prakt. Chem. 1999, 341, No. 2

β-Enaminoesters as Building Blocks in Heterocyclic Synthesis
FULL PAPER
NH). – MS: m/z = 373 (M+).
C17H15N3O3S2 calcd.: C 54.69 H 4.02 N 11.26 S 17.15
C27H17N5OS2 calcd.: C 65.98 H 3.46 N 14.25 S 13.03
(491.59)
found: C 66.10 H 3.40 N 14.10 S 13.20.
(373.45)
found: C 54.50 H 3.90 N 11.40 S 17.20.
References
3-Hydroxy-4-(4'-phenylthiazol-2'-yl)methyl-6-phenylthie-
no[2,3-d]pyrimidine-2-carbonitrile (28)
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Command Contract DA-49-193-MD-2754. This is contribu-
tion No. 1484 to the Army Research Program on Malaria.
[4] J. Davoll, A. M. Johnson, H. J. Davies, O. D. Bird, J. Clarke,
E. F. Elslager, J. Med. Chem. 1972, 15, 812
[5] P. E. Thompson, A. Bayles, B. Olszewski, Am. J. Trop. Med.
Hyg. 1970, 19, 12
[6] B. Loev, M. M. Goodman, K. M. Snader, R. Tedeshi, E.
Macko, J. Med. Chem. 1974, 17, 956
To a solution of 26 (0.86 g, 0.002 mol) in ethanol (30 ml),
K2CO3 (0.3 g, 0.002 mol) in 1 ml H2O and chloroacetonitrile
(1.5 g, 0.002 mol) were added. The reaction mixture was re-
fluxed for 2 h, left to cool at room temperature and poured
onto water. The solid product so-formed was collected by fil-
tration and crystallized from dioxane. – m.p. 261 °C: yield
(70%). – IR (KBr): νmax/cm–1 = 3500–3450 (OH), 2221 (CN).
– H NMR [(CD3)2SO]: δ/ppm = 2.61 (s, 2H, CH2), 4.6 (s,
1H, OH), 6.68 (s, 1H, thiazole-H), 6.72–7.92 (m, 10H, aro-
matic protons).
C23H14N4OS2 calcd.: C 64.78 H 3.28 N 13.14 S 15.02
1
(426.52)
found: C 64.80 H 3.10 N 13.30 S 14.90.
[7] T. McInally, C. J. Tinker, J. Chem. Soc., Perkin Trans. 1,
1988, 1837
[8] J. R. Pfister, Synthesis, 1990, 689
2,6-Diphenyl-8-(4'-phenylthiazol-2'-yl)methyl-1,4,5,6-tetra-
hydro-6-thioxopyrimidino[4,5-d]pyridazin-5-one (30)
[9] Biosynthesis of Some Heterocyclic Natural Product. In Com-
prehensive Heterocyclic Chemistry, Ed. A. R. Katritzky and
C. W. Rees, Pergamon Press, Oxford, 1984, 1, p. 95, 96
[10] A. Fürstner, Synthesis, 1989, 571 and references cited therein
To a stirred solution 26 (2 g, 0.005 mol) in ethanol (50 ml)
containing NaOH (2 g, 0.05 mol), the appropriate benzenedi-
azonium chloride (0.005 mol) [prepared by adding NaNO2
(0.3 g, 0.005 mol) to the appropriate aniline (0.46 g, 0.005
mol) in concentrated HCl (2 ml) at 0–5 °C while stirring]
was added dropwise while cooling at 0–5 °C and stirring.
The reaction mixture was kept at 0–5 °C for 2 h, whereby the
solid product was collected by filtration and crystallized from
acetic acid. – m.p. 235 °C: yield (55%). – IR (KBr):νmax/cm–1
= 3430 (NH), 1665 (C=O). – 1H NMR [(CD3)2SO]: δ/ppm =
3.20 (s, 1H, NH), 6.62 (s, 1H, thiazole-H), 6.74–8.22 (m,
15H, aromatic protons).
Address for correspondence:
Dr. Ayman W. Erian
Chemistry Department
Faculty of Science
Cairo University
Giza, Egypt
J. Prakt. Chem. 1999, 341, No. 2
151