Synthesis of pyrido[2′,3′:4,5]thieno[2,3-d]pyrimidines through Friedlaender reactions

Article abstract of DOI:10.3184/030823407X269961

A variety of tri-, tetra- and penta-cyclic pyrido[2′,3′:4,5] thieno[2,3-d]pyrimidines have been synthesised from 5-amino-6-formyl-4-methyl-2- phenylthieno[2,3-d]pyrimidine by Friedlaender condensation with aliphatic, alicyclic, and heterocyclic ketones and other active methylene compounds.

Full text of DOI:10.3184/030823407X269961

JOURNAL OF CHEMICAL RESEARCH 2007
DECEMBER, 689–692
RESEARCH PAPER 689
Synthesis of pyrido[2',3':4,5]thieno[2,3-dꢀ]pyrimidines through Friedländer
reactions
Shawkat A. Abdel-Mohsen* and Ahmed A. Geies
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
A variety of tri-, tetra- and penta–cyclic pyrido[2',3':4,5]thieno[2,3-d]pyrimidines have been synthesised from
5-amino-6-formyl-4-methyl-2-phenylthieno[2,3-d]pyrimidine by Friedländer condensation with aliphatic, alicyclic,
and heterocyclic ketones and other active methylene compounds.
Keywords: fused thiophenes, pyridines, pyrimidines, amino-aldehydes, Friedländer reactions
1
Annelation reactions involving suitable aromatic hydrocarbon
compounds carrying the aminoaldehyde moiety provide a
synthetic entry into heterocyclic systems,1 and the formation of
ring structures from substituted heterocyclic aminoaldehydes
is often the method of choice for preparation of polycondensed
heterocycles.2-5
respectively. The H NMR spectra of the isolated compounds
4a–d showed a characteristic singlets at 7.80–8.20 ppm for the
H-10 hydrogen. Furthermore, the IR spectra revealed the absence
of the characteristic absorption bands at 3450–3300 cm-1 for the
amino group which indicated the condensation products to be
4a–d.
Similarly, the aminoaldehyde 3 was allowed to react with
indane-1,3-dione under Friedländer condensation conditions
to give the indenopyridothienopyrimidine 5. The IR spectrum
of 5 showed a strong absorption band at 1700 cm-1 due to
C=O. Also the H NMR spectrum showed a characteristic
singlet at 7.95 ppm for the H-11 hydrogen. (Scheme 1).
Thienopyrimidines have been the subject of chemical and
biological studies due to their interesting pharmacology,6
including analgesic,7 antipyretic,8 herpes virus inhibitory9
and anti-inflammatory10,11 properties. In view of the above
activities and in continuation of our work in the synthesis and
reactions of various fused thiophenes,12,13 we report here the
preparation of some new fused pyrido-thieno-pyrimidines.
1
Annelation reactions of β-diketones with 3 are greatly
facilitated by the presence of a doubly activated α-methylene
group, and gave different 6,7-disubstituted pyrido-
thienopyrimidines according to the direction of ring closure.
Thus, treatment of 3 with ethyl acetoacetate and acetylacetone
inethanolicKOHfurnishedethyl3,6-dimethyl-2-phenylpyrido
[2',3':4,5]thieno[2,3-d]pyrimidine-7-carboxylate (6a) and
7-acetyl-3,6-dimethyl-2-phenylpyrido[2',3':4,5]thieno[2,3-d]
pyrimidine (6b). With ethyl benzoylacetate, compound 3
underwent another route for ring closure, giving 7-benzoyl-
4-methyl-2-phenylpyrido[2',3':4,5]thieno[2,3-d]pyrimidine-
6(5H)-one (6c). The structure of compound 6c was confirmed
by IR which gave characteristic absorption bands at 1700,
Results and discussion
The synthesis of the desired compounds started with 5-amino-
6-formyl-4-methyl-2-phenylthieno[2,3-d]pyrimidine (3), which
was prepared by the reaction of 6-methyl-4-phenyl-2-thioxo-1,2-
dihydropyimidine-5-carbonitrile (1) with α-chloroacetaldehyde
in ethanol containing sodium acetate to give the intermediate
6-(formylmethylthio)derivative2.Upontreatmentwithethanolic
sodium ethoxide, compound 2 underwent cyclisation to afford
the starting compound 3. The heterocyclic aminoaldehyde 3
opens a direct route to the synthesis of condensed heterocycles
of the pyridine series. Thus, Friedländer condensation14 of
3 with aliphatic cyclic and/or heterocyclic ketones in the
presence of ethanolic potassium hydroxide solution leads to
the formation of fused tetrahydropyrimidothienoquinoline,
pyrimidothienonaphthyridine, pyranopyridothienopyrimidine
and thiopyranopyridothienopyrimidine compounds 4a–d,
1
1650 cm-1 for 2 CO groups and the H NMR revealed the
absence of absorptions for the ester group.
In the case of bifunctional compounds (X-CH2-Y; X, Y
= cyano, alkoxycarbonyl, carbamoyl and thiocarbamoyl
groups), the amino group in 3 attacked the more electrophilic
group to form functionalised pyridothienopyrimidines. Thus,
CH3
CH3
CH3
N
CN
S
CN
N
N
a
N
Ph
Ph
SCH2CHO
N
S
Ph
N
H
1
N
O
5
2
b
e
NH2
CHO
CH3
CH3
N
CH3
N
R1
N
N
N
N
c
d
X
N
S
R2
Ph
Ph
Ph
S
N
S
6a-c
4a-d
3
Reagents: a, ClCH2CHO/NaOAc/EtOH; b, NaOH/EtOH;
c, O=C(CH2CH2)2X/KOH/EtOH;
6
R1 R2
4 a X = CH2
b
c
d
X = NCH3
X = O
a
b
c
Me CO2Et
d, R1COCH2R2/KOH/EtOH;
Me COMe
OH COPh
X = S
e, indane-1,3-dione/KOH/EtOH
Scheme 1
* Correspondent. E-mail: shawk662001@yahoo.com
PAPER: 07/4874

690 JOURNAL OF CHEMICAL RESEARCH 2007
CH3
H
CH3
CH3
N
N
S
N
NH2
NH2
N
N
N
N
b
Ph
Ph
CHO
CN
Ph
Ph
N
S
N
S
CO2Et
S
3
8
c
9
a
CH3
CH3
N
H
N
N
7
R
NH2
O
N
a
b
CN
CONH2
Ph
R
CN
N
S
S
10
7a,b
7a
CH3
H
N
CH3
N
N
S
N
N=CHOEt
N
N
f
d
NH
Ph
Ph
N
S
Ph
CN
S
S
N
11
13
e
g
CH3
N
CH3
N
SCH3
N
N
N
N
N
N
S
Ph
N
S
NH2
SCH3
NH
12
14
Reagents: a, NCCH2-CN/CONH2/piperidine/EtOH; b, NCCH2-CSNH2/piperidine/EtOH;
c, NCCH2-CO2Et/piperidine/EtOH; d, CS2/pyridine; e, CH3I/acetone/K2CO3;
f, HC(OEt)3/Ac2O; g, N2H4/EtOH
Scheme 2
the reaction of 3 with malononitrile and cyanoacetamide in
ethanol containing a few drops of piperidine took place via
intramolecular addition of the amino group in compound
3 to the cyano function to form the cyclised products 6,7-
substituted pyridothienopyrimidines 7a,b. Unexpectedly,
with cyanothioacetamide 3 afforded 7-cyano-4-methyl-2-
phenylpyrido[2',3':4,5]thieno[2,3-d]pyrimidine-6(5H)-thione
(8), formed by the loss of an ammonia molecule. (Scheme 2)
The structures of compounds 7a,b and 8 were consistent with
theirelementalanalysesandspectraldata.ThustheIRspectrum
of 7a (R1 = NH2, R2 = CN) reveals characteristic absorption
bands at 3450, 3350 cm-1 for the NH2 and at 2230 cm-1 for the
iminopyrimidopyridothienopyrimidine derivative 14 in good
yield. (Scheme 2). The structure of 14 was established on the
basis of IR, which showed the absence of CN absorption at
2220 cm-1, while its 1H NMR spectrum showed signals due to
the pyrimidine CH at 8.65 ppm.
Experimental
All melting points were determined on a Gallenkamp apparatus.
IR spectra were recorded on a Pye-Unicam spectrophotometer
1
using the KBr wafer technique. H NMR spectra were obtained on
a Bruker 250 MHz NMR spectrometer. It should be noted that, to
enhance the solubility of a number of samples to a level sufficient
to provide an adequate spectrum, several drops of TFA-d1 were added
to the CDCl3 or DMSO-d6 indicated as the solvent. This probably
gave rise to the anomalous deshielding of some of the methyl signals
which are reported here. MS were registered on a Jeol JMS-600 mass
spectrometer. Elemental analyses were determined using a Perkin-
Elmer 240C microanalyser.
1
cyano group. Its H NMR spectrum presents a characteristic
singlet at 6.8 for NH2 and at 8.30 ppm corresponding to H-8
hydrogen. The structure of 8 was confirmed by IR spectrum
which revealed the absence of characteristic absorption
bands for the NH2 and showed a band at 2230 cm-1 due to
CN. The reaction of 3 with ethyl cyanoacetate under the same
conditions afforded a mixture of ethyl 6-amino-4-methyl-2-
phenylpyrido[2',3':4,5]thieno[2,3-d]pyrimidine-7-carboxylate
(9) and 7-cyano-6-hydroxy-4-methyl-2-phenylpyrido[2',3':
4,5]thieno[2,3-d]pyrimidine (10) which could be separated
through fractional crystallisation using acetic acid as a
solvent.
The pyridothienopyrimidine derivative 7a was used as
precursor for the synthesis of new pyrimidopyridothieno-
pyrimidines 11, 12 and 14 based on the high reactivity of
the β-enaminonitrile moiety. Thus, condensation of 7a with
carbon disulfide in pyridine afforded the corresponding
4-methyl-2-phenylpyrimido[5",4":5',6']pyrido[2',3':4,5]thieno
[2,3-d]pyrimidine-6,8(7H,9H)-dithione (11), which was easily
S-methylated by methyl iodide to give the corresponding
7,9-bismethylthio derivative 12. Furthermore, treatment of
7a with triethylorthoformate in refluxing acetic anhydride
afforded the intermediate ethoxymethyleneamino derivative
13. Hydrazinolysis of 13 in ethanol yielded the 8-amino-9-
6-Methyl-4-phenyl-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile
(1): This compound was synthesised according to a literature
procedure; m.p. 228–230°C (lit.15 m.p. 228–232°C).
5-Cyano-6-(formylmethylthio)-4-methyl-2-phenylpyrimidine (2):
A mixture of the nitrile 1 (2.27 g, 0.01 mol), fused sodium acetate
(2 g) and α-chloroacetaldehyde (0.86 g, 0.01 mol) in ethanol (30 ml)
was heated under reflux for 30 min, cool and then poured into water.
The solid product obtained was filtered off and crystallised from
ethanol to give white crystals (2.30 g, 84%) of 2, m.p. 155–156°C.
IR: νmax 2220 (CN), 1710 cm-1 (C=O). NMR (CDCl3): δH 2.80 (s,
3H, CH3), 4.30 (s, 2H, CH2), 7.40–7.80 (m, 5H, ArH), 9.60(s, 1H,
CHO). Anal. calcd. for C14H11N3OS (269.32): C, 62.44; H, 4.12; N,
15.6; S, 11.9. Found: C, 62.55; H, 4.08; N, 15.71; S, 11.77%.
5-Amino-4-methyl-2-phenylthieno[2,3-d]pyrimidine-6-
carbaldehyde (3): To compound 2 (2.7 g, 0.001 mol) in absolute
ethanol (30 ml) was added a few drops of sodium ethoxide solution,
and the mixture was stirred at room temperature for 30 min. The solid
product was collected and recrystallised from ethanol to give yellow
crystals of 3 (1.90 g 71%), m.p. 200–201°C. IR: νmax 3450, 3300
(NH2), 1630 cm-1 (C=O). NMR (DMSO-d6): δH 2.90 (s, 3H, CH3),
7.20 (s, 2H, NH2), 7.40–7.80 (m, 5H, ArH), 10.20 (s, 1H, CHO).
MS: m/z (%) 269 (100) [M+]. Anal. calcd. for C14H11N3OS (269.32):
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JOURNAL OF CHEMICAL RESEARCH 2007 691
C, 62.44; H, 4.12; N, 15.60; S, 11.90. Found: C, 62.61; H, 4.18; N,
15.78; S, 12.02%.
pyrimidine (7a): From malononitrile, yellow crystals (0.99 g, 62%)
from dioxan, m.p. 285–286°C. IR: νmax 3450, 3350 (NH2), 2220
cm-1 (CN). NMR (DMSO-d6): δH 3.40 (s, 3H, CH3), 6.8 (s, 2H,
NH2), 7.30–7.70 (m, 5H, ArH), 8.30 (s, 1H, H-8). Anal. calcd. for
C17H11N5S (317.37): C, 64.34; H, 3.49; N, 22.07; S, 10.10. Found: C,
64.41; H, 3.42; N, 22.18; S, 9.97%.
6-Amino-4-methyl-2-phenylpyrido[2',3'-4,5]thieno[2,3-d]
pyrimidine-7-carboxamide (7b): From cyanoacetamide, orange plates
(1.37 g, 82%) from acetic acid, m.p. 243–244°C. IR: νmax 3500,
3450, 3300 (NH2), 1640 cm-1 (CO). NMR (DMSO-d6): δH 3.18 (s,
3H, CH3), 5.60 (s, 2H, NH2), 6.80 (s, 2H, NH2), 7.40–7.50 (m, 5H,
ArH), 7.85 (s, 1H, H-8). Anal. calcd. for C17H13N5OS (335.38): C,
60.88; H, 3.91; N, 20.88; S, 9.56. Found: C, 60.69; H, 3.88; N, 20.97;
S, 9.64%.
7-Cyano-4-methyl-2-phenylpyrido[2',3'-4,5]thieno[2,3-d]
pyrimidine-6(5H)-thione (8): From cyanothioacetamide, red crystals
(1.15 g, 60%) from acetic acid, m.p. 175–176°C. IR: νmax 3200 (NH),
2230 cm-1 (CN). NMR (DMSO-d6): δH 2.95 (s, 3H, CH3), 7.30–7.60
(m, 5H, ArH), 8.20 (s, 1H, H-8), 9.25 (s, 1H, NH). Anal. calcd. for
C17H10N4S2 (334.41): C, 61.06; H, 3.01; N, 16.75; S, 19.17. Found:
C, 61.15; H, 2.97; N, 16.65; S, 19.12%.
Reaction of aminoaldehyde 3 with cyclic and heterocyclic ketones;
formation of 4a–d, 5 and 6a–c. General procedure
A mixture of 3 (1.35 g, 0.005 mol), the appropriate ketone
(0.0055 mol) and a few drops of ethanolic KOH (10%) in ethanol
(30 ml) was refluxed for 3–6 h. The solid which separated from the
hot mixture was filtered off and recrystallised from the indicated
solvent.
4-Methyl-2-phenyl-6,7,8,9-tetrahydropyrimido[4',5':5,4]thieno
[3,2-b]quinoline (4a): Orange crystals (1.30 g, 79%) from dioxan,
m.p. 222–223°C. IR: νmax 2900 (CH aliphatic), 1540 cm-1 (C=N).
NMR (DMSOd6): δH 1.80 (m, 4H, 2 CH2), 2.60 (m, 2H, CH2),
2.72(m, 2H, CH2), 2.95 (s, 3H, CH3), 7.20–7.50 (m, 5H, ArH), 7.80
(s, 1H, H-10). Anal. calcd. for C20H17N3S (331.44): C, 72.48; H, 5.17;
N, 12.68; S, 9.67. Found: C, 72.37; H, 5.26; N, 12.80; S, 9.75%.
4,8-Dimethyl-2-phenyl-6,7,8,9-tetrahydropyrimido[4',5':5,4]
thieno[3,2-b][1,6]naphthyridine (4b): Red crystals (1.14 g, 66%)
from dioxan, m.p.190–191°C. IR: νmax 2900 (CH aliphatic), 1550 cm-1
(C=N). NMR (CF3COOD): δH 2.80 (s, 3H, CH3), 2.80 (t, 2H,
J = 5.2 Hz, CH2), 3.20 (t, 2H, J = 4.8 Hz, CH2), 3.45 (s, 3H, CH3),
4.20 (s, 2H, CH2-N), 7.20–7.60 (m, 5H, ArH), 8.20 (s, 1H, H-10).
Anal. calcd. for C20H18N4S (346.45): C, 69.34; H, 5.24; N, 16.17; S,
9.25. Found: C, 69.49; H, 5.17; N, 16.31; S, 9.36%.
4-Methyl-2-phenyl-6,7,8,9-tetrahydropyrano[3'',4'':5',6']pyrido
[2',3':4,5]thieno[2,3-d]pyrimidine (4c): Red crystals (1.08 g, 65%)
from acetic acid, m.p. 235–236°C. IR: νmax 2950 (CH aliphatic),
1530 cm-1 (C=N). NMR (CF3COOD): δH 2.75 (t, 2H, J = 5.6 Hz,
CH2), 2.95 (s, 3H, CH3), 3.30 (t, 2H, J = 4.8 Hz, CH2), 4.80 (s, 2H,
CH2-O), 7.10–7.40 (m, 5H, ArH), 7.65 (s, 1H, H-10). Anal. calcd. for
C19H15N3OS (333.41): C, 68.45; H, 4.53; N, 12.60; S, 9.62. Found:
C, 68.61; H, 4.48; N, 12.71; S, 9.53%.
Reaction of 3 with ethyl cyanoacetate. Preparation and separation of
compounds 9 and 10
A mixture of 3 (1.16 g, 4 mmol), ethyl cyanoacetate (4 mmol) and
a few drops of piperidine in ethanol (20 ml) was refluxed for 3 h.
A precipitate was collected by filtration. First examination (IR spectra
and TLC) showed the product to contain two compounds. This
mixture was heated in acetic acid and filtered while hot. The solid
compound was collected, washed with ethanol and rerystallised from
DMF which was shown to be compound 10. After cooling, the filtrate
gave further solid material which was assigned as compound 9.
Ethyl
6-amino-4-methyl-2-phenylpyrido[2',3':4,5]thieno[2,3-d]
4-Methyl-2-phenyl-6,7,8,9-tetrahydrothiopyrano[3'',4'':5',6']pyrido
[2',3':4,5]thieno[2,3-d]pyrimidine (4d): Red crystals (1.23 g, 71%)
from dioxan, m.p. 227–228°C. IR(KBr) ν = 2950 (CH aliphatic),1540
(C=N) cm-1. NMR (CF3COOD): δH 2.55 (t, 2H, J = 4.6 Hz, CH2),
2.80 (t, 2H, J = 5.2 Hz, CH2), 2.90 (s, 3H, CH3), 3.80 (s, 2H, CH2-
S), 7.10–7.45 (m, 5H, ArH), 7.61(s, 1H, H-10). Anal. calcd. for
C19H15N3S2 (349.47): C, 65.30; H, 4.33; N, 12.02; S, 18.35. Found:
C, 65.43; H, 4.29; N, 12.20; S, 18.48%.
4-Methyl-2-phenyl-10H-indeno[2'',3'':5',6']pyrido[2',3':4,5]thieno
[2,3-d]pyrimidin-10-one (5): Yellow crystals (1.28 g, 68%) from
acetic acid, m.p. 301–302°C. IR: νmax 2950 (CH aliphatic), 1720 cm-1
(C=O). NMR (DMSO-d6): δH 2.85 (s, 3H, CH3), 6.90–7.70 (m, 9H,
ArH), 7.95 (s, 1H, H-11). Anal. calcd. for C23H13N3OS (379.44): C,
72.81; H, 3.45; N, 11.07; S, 8.45. Found: C, 73.01; H, 3.47; N, 10.92;
S, 8.36%.
Ethyl-3,6-dimethyl-2-phenylpyrido[2',3':4,5]thieno[2,3-d]pyrimidine-
7-carboxylate (6a): Orange crystals (1.47 g, 81%) from dioxan,
m.p. 180–181°C. IR: νmax 2950 (CH aliphatic), 1720 cm-1 (C=O).
NMR (DMSO-d6): δH 1.50 (t, 3H, J = 7.2 Hz, CH3), 3.20 (s, 3H,
CH3), 3.70 (s, 3H, CH3), 4.60 (q, 2H, J = 6.8 Hz, CH2), 7.50–7.90 (m,
5H, ArH), 9.20 (s, 1H, H-8). Anal. calcd. for C20H17N3O2S (363.43):
C, 66.10; H, 4.71; N, 11.56; S, 8.80. Found: C, 66.26; H, 4.63; N,
11.65; S, 8.68%.
7-Acetyl-3,6-dimethyl-2-phenylpyrido[2',3':4,5]thieno[2,3-d]
pyrimidine (6b): Orange crystals (1.20 g, 72%) from ethanol,
m.p. 212–213°C. IR: νmax 2900 (CH aliphatic), 1720 cm-1 (C=O).
1H NMR (CDCl3): δH 2.45 (s, 3H, COCH3), 2.90 (s, 3H, CH3), 3.30
(s, 3H, CH3), 7.40–7.60 (m, 5H, ArH), 8.20 (s, 1H, H-8). Anal. calcd.
for C19H15N3OS (333.41): C, 68.45; H, 4.53; N, 12.60; S, 9.62.
Found: C, 68.58; H, 4.47; N, 12.71; S, 9.56%.
pyrimidine-7-carboxylate (9): Orange crystals 0.65 g (45%) from
acetic acid, m.p. 260–261°C. IR: νmax 3450, 3300 (NH2), 1700 cm-1
(CO). NMR (DMSO-d6): δH 1.30 (t, 3H, J = 7.0 Hz, CH3), 2.85 (s,
3H, CH3), 4.30 (q, 2H, J = 6.8 Hz, CH2), 6.75 (s, 2H, NH2), 7.40–
7.50 (m, 5H, ArH), 8.00 (s, 1H, H-8). Anal. calcd. for C19H16N4O2S
(364.42): C, 62.62; H, 4.43; N, 15.37; S, 8.80. Found: C, 62.71; H,
4.40; N, 15.41; S, 8.74%.
7-Cyano-4-methyl-2-phenylpyrido[2',3':4,5]thieno[2,3-d]
pyrimidine-6(5H)-one (10): Yellow crystals (0.27 g 22%) from DMF,
m.p. 280–281°C. IR: νmax 3250 (NH), 2220 (CN), 1650 cm-1 (C=O).
NMR (CF3COOD): δH 3.30 (s, 3H, CH3), 7.25–7.55 (m, 5H, ArH),
8.30 (s, 1H, H-8). MS: m/z (%) 318 (100) [M+]. Anal. calcd. for
C17H10N4OS (318.35): C, 64.14; H, 3.17; N, 17.60; S, 10.07. Found:
C, 64.23; H, 3.09; N, 17.71; S, 10.16%.
4-Methyl-2-phenylpyrimido[5'',4'':5',6']pyrido[2',3':4,5]thieno[2,3-d]
pyrimidine-7,9(6H,8H)-dithione (11): To a solution of 7a (0.32 g,
0.001 mol) in pyridine (20 ml), carbon disulfide (5 ml) was added.
The mixture was refluxed for 24 h. The solid product formed was
filtered off, washed several times with ethanol and crystallised from
DMF to afford orange crystals (0.35 g (88%), m.p. >300°C. IR: νmax
3340, 3300 cm-1 (2NH). NMR (DMSO-d6): δH 2.95 (s, 3H, CH3),
7.30–7.60 (m, 5H, ArH), 7.70 (s, 1H, H-10), 9.30 (s, 1H, NH),
10.25 (s, 1H, NH). MS: m/z (%) 393 (100) [M+]. Anal. calcd. for
C18H11N5S3 (393.50): C, 54.94; H, 2.82; N, 17.80; S, 24.44. Found:
C, 55.09; H, 2.79; N, 17.73; S, 24.35%.
4-Methyl-7,9-bis(methylthio)-2-phenylpyrimido[5'',4'':5',6']pyrido
[2',3':4,5]thieno[2,3-d]pyrimidine (12): A mixture of compound 11
(0.39 g, 0.003 mol), methyl iodide (1.40 g, 0.01 mol) and anhydrous
potassium carbonate (0.5 g) in acetone (30 ml) was refluxed 3 h, then
allowed to cool, and poured into cold water. The solid product was
collected, washed thoroughly with water, dried and recrystallised
from ethanol to give yellow crystals, m.p. 270–271°C, yield 0.88 g
(70%). IR: νmax 2980 cm-1 (CH-aliphatic). NMR (DMSO-d6): δH 2.78
(s, 6H, 2CH3), 3.10 (s, 3H, CH3), 7.30–7.60 (m, 5H, ArH), 7.90 (s,
1H, H-10). Anal. calcd. for C20H15N5S3 (421.55): C, 56.98; H, 3.59;
N, 16.61; S, 22.82. Found: C, 56.89; H, 3.62; N, 16.49; S, 22.89%.
7-Cyano-6-(ethoxymethyleneamino)-4-methyl-2-phenylpyrido
[2',3'-4,5]thieno[2,3-d]pyrimidine (13): A mixture of o-aminonitrile
7a (0.95 g, 0.003 mol), triethylorthoformate (5 ml) and acetic
anhydride (5 ml) was refluxed for 6 h. The solvent was removed
under reduced pressure and the resulting solid was recrystallised
from dioxan to give white plates (0.89 g, 79%), m.p. 195–196°C.
IR: νmax 2980 (CH-aliphatic), 2220 cm-1 (CN). NMR (DMSO-d6):
δH 1.25(t,3HJ=6.8Hz,CH3),3.55(s,3H,CH3),4.20(q,2H,J=7.2Hz,
CH2), 7.30–7.60 (m, 5H, ArH), 8.25 (s, 1H, H-8), 8.75 (s, 1H, N=CH).
Anal. calcd. for C20H15N5OS (373.43): C, 64.33; H, 4.05; N, 18.75;
7-Benzoyl-4-methyl-2-phenylpyrido[2',3':4,5]thieno[2,3-d]
pyrimidine-6(5H)-one (6c): Orange crystals (1.63 g, 77%) from
acetic acid, m.p. 205–206°C. IR: νmax 3320 (NH), 2950 (CH
1
aliphatic), 1700 (C=O), 1650 cm-1 (C=O). H NMR (CF3COOD):
δH 3.25 (s, 3H, CH3), 7.40–8.50 (m, 10H, ArH), 9.60 (s, 1H, H-8).
MS: m/z (%) 397 (100) [M+]. Anal. calcd. for C23H15N3O2S (397.45):
C, 69.51; H, 3.80; N, 10.57; S, 8.07. Found: C, 69.42; H, 3.73; N,
10.63; S, 7.89%.
Reaction of 3 with activated nitriles; preparation of compounds 7a–d:
General procedure
A solution containing 3 (1.35 g, 0.005 mol), the appropriate
carbonitrile (0.065 mol) and a few drops of piperidine in ethanol
(20 ml) was refluxed for 3 h. A solid which separated from the hot
mixture was filtered off, washed with ethanol and recrystallised.
6-Amino-7-cyano-4-methyl-2-phenylpyrido[2',3':4,5]thieno[2,3-d]
PAPER: 07/4874

692 JOURNAL OF CHEMICAL RESEARCH 2007
4
5
B.Y. Riad, S.E. Negm and H.A. Daboun, Heterocycles, 1987, 26, 205.
C.T. Alabaster, A.S. Bell, S.F. Campbell, P. Ellis, C.G. Henderson,
D.S. Morris, D.A. Roberts, K.S. Ruddock, G.M.R. Samuels and
M.H. Stefaniak, J. Med.Chem., 1989, 32, 575.
B. Ralf, P. Runland, L. Dieter, L. Gunter and P. Brigitte, Ger. (East) DD,
234, 268; Chem. Abstr., 1986, 105, 226 631e.
C.G. Dave, P.R. Shah, K.C. Dave and V.J. Patel, J. Indian Chem. Soc.,
1989, 66, 48.
E. Bousquet, G. Romero, F. Guerrera, A. Caruso and M.A. Roxas,
Farmaco., Ed. Sci., 1985, 40, 869.
S, 8.59. Found: C, 64.40; H, 3.98; N, 18.67; S, 8.61%.
8-Amino-9-imino-4-methyl-2-phenylpyrimido[5'',4'':5',6']pyrido
[2',3':4,5]thieno[2,3-d]pyrimidine (14): To a well stirred cold solution
of 12 (0.75 g, 0.002 mol) in ethanol (10 ml), 99% hydrazine hydrate
(3 ml) was added over 2 h, then the mixture was stirred at room
temperature for 6 h and left overnight. The solid that precipitated
was filtered off and recrystallised from acetic acid to give yellow
crystals (0.55 g, 77%), m.p. 305–306°C. IR: νmax 3350, 3200 (NH,
NH2), 2980 cm-1 (CH-aliphatic). NMR (DMSO-d6): δH 3.10 (s, 3H,
CH3), 7.45–7.70 (m, 5H, ArH), 8.00 (s, 1H, H-7 pyrimidine), 8.78 (s,
1H, H-10), 9.35 (m, 3H, NHNH2). MS: m/z (%) 359 (74) [M+]. Anal.
calcd. for C18H13N7S (359.41): C, 60.15; H, 3.65; N, 27.28; S, 8.92.
Found: C, 60.22; H, 3.70; N, 27.34; S, 8.90%.
6
7
8
9
N.N. Kaplina, V.L. Shedov, A.N. Fomina, I.S. Nikolaeva, T.V. Pushkina
and L.N. Filitis, U.S.S.R. 1993, SUI, 389, 23; Chem. Abstr., 1993, 123,
27 5971w.
10 S. Leistner, G. Wagner, M. Guetscharo and E. Glusa, Pharmazie, 1986,
41, 54.
Received 8 October 2007; accepted 14 December 2007
Paper 07/4874
doi: 10.3184/030823407X269961
11 M. Modica, M. Santagati, A. Santagati, V. Cutuli, N. Mangano and
A. Caruso, Pharmazie, 2000, 55, 500.
12 Z.H. Khalil,A.S. Yanni,A.M. Gaber and S.A.Abdel-Mohsen, Phosphorus,
Sulfur Silicon, 2000, 166, 57.
13 A.M. Kamal El-Dean, A.A. Geies, H.S. El-Kashef, S. Rault,
P. D'Allemagne and J.C. Lancelot, J. Heterocycl. Chem., 2000, 37, 1520.
14 P. Friedländer, Org. Reactions, 1982, 28, 37.
References
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P. Caluwe, Tetrahedron, 1980, 36, 2359.
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