Synthesis of pyrido and pyrazinodithienodipyrimidine-4,8(3H,9H)-dione derivatives by the aza-Wittig methodology

Article abstract of DOI:10.1016/j.tet.2003.11.021

A one-pot synthesis of the hitherto unreported pyrido[5″,6″:4, 5;3″2″:4′,5′]dithieno[3,2-d:3′,2′-d′] dipyrimidine-4,8(3H,9H)-dione 6a-o and pyrazino[5″,6″:4, 5;3″2″:4′,5′]dithieno[3,2-d:3′,2′-d′] dipyrimidine-4,8(3H,9H)-dione 6p-y pentaheterocyclic systems, based on the tandem aza-Wittig heterocumulene-mediated annulation strategy is described.

Full text of DOI:10.1016/j.tet.2003.11.021

Tetrahedron 60 (2004) 275–283
Synthesis of pyrido and pyrazinodithienodipyrimidine-
4,8(3H,9H)-dione derivatives by the aza-Wittig methodology
*
´ ´ ´
David Vazquez Vilarelle, Carlos Peinador Veira and Jose M. Quintela Lopez
´
Departamento de Quımica Fundamental, Facultad de Ciencias, Universidad de La Corun˜a, Campus de A Zapateira,
E-15071 La Corun˜a, Spain
Received 29 July 2003; revised 10 November 2003; accepted 11 November 2003
Abstract—A one-pot00synthesis00of th0e hitherto unreported pyrido[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-4,8(3H,9H)-dione
6a–o and pyrazino[5 ,600:4,5;3 200:4 ,50]dithieno[3,2-d:30,20-d0]dipyrimidine-4,8(3H,9H)-dione 6p–y pentaheterocyclic systems, based on
the tandem aza-Wittig heterocumulene-mediated annulation strategy is described.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
compounds can react with carbonyl compounds to form
imines, and with isocyanates, isothiocyanates, carbon
dioxide and carbon disulfide, giving rise to the correspond-
ing heterocumulenes.10 Aza-Wittig reactions can be divided
into an intramolecular and an intermolecular variant. The
intramolecular aza-Wittig reaction is a powerful tool
reaction for the synthesis of 5–7 membered ring hetero-
cycles11 and the intermolecular aza-Wittig reaction fol-
lowed by electrocyclization, intramolecular cycloaddition
or heterocyclization, has been utilized for the synthesis of
many important nitrogen heterocycles,12 and, on the other
hand, the utilization of the aza-Wittig reaction in the
synthesis of biologically important heterocyclic natural
products has been recently reviewed.13
Synthetic heterocycles have widespread interest as herbi-
cides, insecticides, dyes, organic-conductors, and drugs.
Nitrogen-containing heterocycles are of broad pharmaceu-
tical interest and this justifies continuing efforts in the
development of structure-activity relationship in this series
and of new synthetic strategies.1 There is a enormous
interest in the synthesis of new heterocyclic rings stimulated
by recent reports that showed antitumor activity in a wide
range of polyheterocyclic compounds isolated from marine
organisms.2 Compounds containing a fused pyrimidine ring
have significant biological activity, particularly in cancer
and virus research.3 Among these heterocycles, thienopyri-
midine derivatives are an important class of heterocyclic
compounds in pharmaceutical discovery research. Anti-
allergic,4 antianaphilactic,5 anti-inflammatory,6 analgesic
and antipyretic,7 and antineoplasic8 activities have been
described for these compounds.
Iminophosphoranes derived from N-aminoheterocycles are
valuable precursors for the preparation of fused heterocycles
which may be neutral, cationic or mesoionic.14 Recently, we
have reported the synthesis of fused pyrimidines based on
the tandem aza-Wittig heterocumulene-mediated annulation
strategy.15
The aza-Wittig reaction has become one of the most
important synthetic methods for constructing novel CvN,
NvN, and SvN double bonds containing compounds,
especially in modern nitrogen heterocyclic synthesis. In
recent years, there has been a significant interest in the
chemistry of iminophosphoranes (l5-phosphazenes, phos-
phine imines) because of their utility for the construction of
nitrogen-containing heterocycles compounds, and many
interesting heterocyclization reactions involved functional-
ized iminophosphoranes have been reviewed.9 These
2. Results and discussion
Work in our laboratories has been recently concerned with
the discovery and development of synthesis of new
heterocycles systems containing thienopyrimidine moiety
in order to search for new pharmacological or biologically
active compounds. We have previously reported on the
synthesis of novel tri- and tetracyclic ring systems,
containing the thienopyrimidine skeleton, with antiinflam-
matory and antihistaminic activity.16 We now describe here,
as a further extension of the aza-Wittig-type methodology
the synthesis of the hitherto unreported pyrido
Keywords:
Aza-Wittig;
Pyrazinodithienodipyrimidine;
Pyridodithienodipyrimidine.
*
Corresponding author. Tel.: þ34-981-167000; fax: þ34-981-167065;
e-mail address: jqqoqf@udc.es
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.021

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D. Vazquez Vilarelle et al. / Tetrahedron 60 (2004) 275–283
276
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,2000-d000]dipyr0i0midine-
4,8(3H,9H)-dione 6a–o and pyrido[5 ,6 :4,5;3 200:40,50]
dithieno[3,2-d:30,20-d0]dipyrimidine-4,8(3H,9H)-dione 6p–y,
utilizing for the first time 2,6-dichloropyridine-3,5-dicarbo-
nitrile 1a and 3,5-dichloropyrazine-2,6-dicarbonitrile 1b as
the starting materials. The strategy used for the development
of these compounds was focused as shown in Scheme 1.
The bis N-heteroaryliminophosphoranes 3a,b appear to
serve as a good building block for these heterocycles. They
can be synthesized from 2,6-dichloropyridine-3,5-dicarbo-
nitrile and 2,6-dichloropyrazine-3,5-dicarbonitrile,
respectively.
Pentaheterocyclic compounds 6a–o and 6p–y were
obtained in a one-pot reaction of the corresponding
iminophosphoranes of heteroaromatic b-enamino esters 3a
and 3b with isocyanates, followed by heterocyclization on
addition of amines.
The starting compounds for the aza-Wittig reaction
heterocyclization sequence were prepared from the readily
available heterocyclic b-enaminoesters 2a–b. First, 2,6-
dichloropyridine-3,5-dicarbonitrile 1a and 2,6-dichloropyr-
azine-3,5-dicarbonitrile 1b were formed by nitrosation
reaction of the corresponding 2-aminoderivatives17 follow-
ing a previously described procedure.18 The thiophene rings
were added on the pyridine and pyrazine rings by
condensing 1a–b with ethyl 2-mercaptoacetate in the
presence of an equimolecular amount of potassium
carbonate in0 refluxing ethanol to give ethyl 3,5-diamino-
dithieno[30,2 -e:2,3-b]pyridine-2,6-dicarboxylate 2a and
ethyl 3,5-diamino-dithieno[30,20-e:2,3-b]pyrazine-2,6-dicar-
boxylate 2b in good yields.
Scheme 2.
do[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]di-pyrimi-
dine-4,8(3H,9H)-dione
6a–o
and
pyrazino
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione 6p–y. Reaction of bis-imino-phospho-
ranes with arylisocyanates and secondary amines at room
temperature resulted in the formation of the corresponding
guanidine-type intermediate derivatives 5a–f, the key
intermediates for the processes, that could be isolated in
the above mentioned conditions. Pyrimido-annulation
occurs via a heterocumulene moiety, available from the
reaction of the N-heteroaryliminophosphorane and the
isocyanate as highly reactive intermediates.
The key iminophosphoranes 3a–b were obtained by a
modified Kirsanov reaction of the b-enamino esters 2a–b
with in situ prepared dichlorotriphenylphosphorane using
Those carbodiimide derivatives 4a–e have been isolated by
treatment of bis-triphenyliminophosphoranes 3a–b with
aryl isocyanates in dry CH2Cl2 at room temperature.
Addition of a secondary amine to the highly reactive
cumulenic system followed by intramolecular heteroconju-
gate addition annulation gives the final penta- and hexaaza-
indenefluorenediones 6a–o and 6p–y. Direct cyclization of
the initially formed carbodiimide via 1,3-OEt migration
followed by electrocyclization (Wamhoff’s pyrimidoanne-
lation)20 was not observed in this case. In the presence of
anhydrous sodium carbonate, the separated guanidine-type
intermediate derivatives 5a–f underwent intramolecular
heterocyclization across the electrophilic ester functionality
to give the fused heterocyclic compounds 6a–o and 6p–y
(Scheme 3).
a
hexachloroethane-triphenylphosphine-triethylamine
reagent system (Scheme 2).19 The molecular structure of
the iminophposphoranes were supported by the general data
(IR, H NMR, 13C NMR, 31P NMR, and mass spectra) and
elemental analysis.
1
Aza-Wittig reaction of bisimonophosphoranes 3a–b with
arylisocyanates, followed by heterocyclization on addition
of secondary amines directly affords substituted pyri-
The structures of carbodiimide compounds 4a–e, guanidine
compounds 5a–f, and fused pyrimidines 6a–o and 6p–y
were confirmed by their elemental analyses and spectro-
scopic data. The mass spectra showed the expected
molecular ion peak and the IR spectra of guanidine-type
intermediates 5a–f showed a strong absorption at n¼3320–
1
3373 cm21 attributed to the NH group, while in the H
NMR spectra, the NH proton appear at d¼5.77–6.92 ppm
as a singlet, in addition to the set of signals due to the ethoxy
group. Also, the 13C NMR spectra showed signals between
d¼14.28–14.49 and 60.5–66.4 ppm due to ethoxy groups.
Scheme 1.

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D. Vazquez Vilarelle et al. / Tetrahedron 60 (2004) 275–283
277
Scheme 3.
After heterocyclization, the spectra of compounds 6a–o and
6p–y did not include those type of signals.
isopropyl or butyl groups.21 Mass and spectroscopic data are
in good agreement with the proposed structures. The FAB-
mass spectra show the expected molecular ion peaks and the
fragmentation pattern is in accord with the proposed
Two isomeric pyrimidothieno derivatives, 9 and 10, may be
produced in the treatment of bis-N-heteroarylimino-phos-
phoranes 3a–b with ArNCO/R2NH2 or R2NCO/ArNH2 via
guanidine-type intermediates 7 and 8 (Scheme 4), but these
reactions afforded only 9, compound 10 not being formed.
In addition, only pentacyclic compound 9 was obtained by
the reaction of carbodiimide 4a–e with primary amines (the
guanidine intermediate 5f was isolated). These selectivity
results can probably be explained by the large difference in
cyclization rates due the steric hindrance around the Ph and
1
structures. In particular, in the H NMR spectra, the NH-
isopropyl groups of compounds 6l–o and 6 s appear
characteristically as broad doublets at d¼4.05–6.29 ppm.
In addition, the NH-butyl proton in compound 6k resonates
as a triplet confirming the proposed structures.
In conclusion, the present study demonstrates that the
tandem aza-Wittig-heterocumulene-mediated annulation
strategy affords a facile, efficient and general one-pot
route to previously unreported pentacyclic dipyrimidodi-
thienopyridine 6a–o and dipyrimidodithienopyrazine 6p–y
systems bearing various substituents on the pyrimidine ring.
Pentaheterocyclic compounds 6a–o and 6p–y can be useful
compounds in medicinal chemistry since the pyrimido and
thiophene moieties display a broad range of biological
activities and have been widely used as pharmaceuticals.
3. Experimental
All reagents used were comercial grade chemicals from
freshly opened containers. Melting points were determinated
on a Bibby SMP3 apparatus and are uncorrected. IR spectra
were recorded as potassium bromide disks on a Bruker vector
22 FT-IR. 1H and 13C NMR spectra were obtained on a Bruker
AC 200F instrument at room temperature. Mass spectra were
obtained on a VG-QUATTRO spectrometer. The Silica gel
60F-254 used for analytical thin layer chromatography were
Scheme 4.

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D. Vazquez Vilarelle et al. / Tetrahedron 60 (2004) 275–283
278
purchased from Merck. Microanalyses for C, H, N, and S were
performed by the elemental analyses general services of the
University of La Corun˜a.
C14H14N4O4S2: C, 45.89; H, 3.85; N, 15.29; S, 17.50. Found
C, 46.13; H, 3.72; N, 14.96; S, 17.54.
3.2.3. Synthesis of diethyl 3,5-di[(trifenilfosforanilidene)
amino]ditieno[30,20-e:2,3-b]pyridine-2,6-dicarboxylate
(3a). Method A. A solution of the 2a (0.2 g, 0.55 mmol)
triphenylphosphine (0.43 g, 1.64 mmol), hexachloroethane
(0.39 g, 1.64 mmol) and triethylamine (0.28 g, 2.74 mmol)
in toluene (3 mL), was heated in a sealed tube at 100 8C for
48 h. After cooling, the solid formed was filtered off,
washed with water and recrystallized from EtOH/CH2Cl2, to
yield 3a (0.39 g, 80%).
3.1. Synthesis of 2,6-dichloropyridine-3,5-dicarbonitrile
(1a) and 3,5-dichloro-pyrazine-2,6-dicarbonitrile (1b)
To a solution of 2-amino-6-chloropyridine-3,5-dicarbo-
nitrile or 3-amino-5-chloropyrazine-2,6-dicarbonitrile
(22.4 mmol) and CuCl2 (33.6 mmol) in dry CH3CN
(200 mL), isoamilnitrite was added (33.6 mmol). The
mixture was heated at 65 8C for 5 h (10 h for 1b). The
solution was acidified (HCl, 2 N) to pH¼3 and extracted
with CH2Cl2 (3£50 mL) and dried with Na2SO4. The
solvent was removed under reduced pressure and the crude
product was purified by flash chromatography using CH2Cl2
as eluent to yield 1a,b.
Method B. A mixture of 2a (1.5 g, 4.11 mmol), triphenyl-
phosphine (3.23 g, 12.3 mmol), hexachloroethane (2.92 g,
12.3 mmol) and triethylamine (2.07 g, 20.5 mmol) in dry
THF (60 mL), was heated in a sealed tube at 60 8C for 48 h.
After cooling, the solid formed was filtered off and washed
with THF, and the filtrate and the washings were combined
and evaporated. The solid obtained was purified by flash
chromatography using CH2Cl2/AcOEt as eluent to yield 3a
(3.5 g, 96%). Mp 265–266 8C; IR (KBr. cm21): 1686
(CvO), 1542, 1376, 1194, 527. 1H NMR (CDCl3): 8.80 (s,
1H, CH); 7.42 (m, 30H, Ph); 3.80 (q, 4H, OCH2, J¼7.1 Hz);
1.00 (t, 6H, CH3, J¼7.1 Hz). 13C NMR (CDCl3): 14.35
(OCH2CH3); 59.47 (OCH2); 128.11; 128.36; 128.68;
130.85; 131.22; 131.20; 131.29; 131.45; 132.35; 132.55;
133.54; 134.58; 149.67; 161.12; 163.38. 31P NMR (CDCl3):
8.26. MS (FAB, m/z %): 886 (MHþ, 9);. Anal. calcd for
C51H41N3O4P2S2 C, 69.14; H, 4.66; N, 4.74; S, 7.24. Found
C, 68.85; H, 4.65; N, 4.70; S, 7.35.
3.1.1.
2,6-Dichloropyridine-3,5-dicarbonitrile
(1a).
(96%). Mp 198–200 8C. Lit22 210–214 8C. IR (KBr,
cm21): 2740 (CN). 1H NMR (CDCl3): 8.27 (s, CH).
13CNMR (CDCl3): 110.3 (C3, C5); 112.2 (CN); 146.9
(C4); 155.7 (C2, C6). MS (EI, m/z %): 197 (Mþ, 100); 162
(Mþ2Cl, 59). Anal. calcd for C7HCl2N3 C, 42.46; H, 0.51;
N, 21.22. Found C, 42.63; H, 0.60; N, 21.33.
3.1.2. 3,5-Dichloro-pyrazine-2,6-dicarbonitrile (1b).
(84%). Mp 177–179 8C. IR (KBr, cm21): 2361–2342
(CN). 13C NMR (CD3COCD3): 113.33 (CN); 129.69
(CCN); 153.23 (CCl). MS (EI, m/z %): 198 (Mþ, 100);
200 (Mþþ2, 62). Anal. calcd for C6Cl2N4 C, 36.21; N,
28.15. Found C, 36.32; N, 28.01.
3.2.4. Synthesis of diethyl 3,5-di[(triphenylphosphor-
anylidene)amino]ditieno[30,20-e:2,3-b]pyrazine-2,6-
dicarboxylate (3b). A mixture of the heterocyclic amine 2b
(0.2 g, 0.55 mmol) triphenylphosphine (0.43 g, 1.64 mmol),
hexachloroethane (0.39 g, 1.64 mmol) and triethylamine
(0.28 g, 2.74 mmol) in toluene (3 mL), was heated in a
sealed tube at 100 8C for 48 h. After cooling, the solid
formed was filtered off, washed with water and recrystal-
lized from EtOH/CH2Cl2, to yield 3b (0.40 g, 84%). Mp
269–271 8C. IR (KBr, cm21): 1699 (CvO), 1524, 1437,
3.2. Synthesis of diethyl 3,5-diaminodithieno[30,20-e:2,3-
b]pyridine-2,6-dicarboxylate (2a) and diethyl 3,5-diami-
nodithieno[30,20-e:2,3-b]]pyrazine-2,6-dicarboxylate (2b)
To a solution of 1a or 1b (18.27 mmol) and ethyl
tioglycolate (43.7 mmol) in a mixture of EtOH/THF (5:1)
(240 mL), K2CO3 (43.7 mmol) was added, and the mixture
was refluxed for 1 h. After cooling, the solid was filtered and
washed with water. The product is pure enough to be used in
the next step, but it can be purified by recristallization from
EtOH/DMF (2a) or purified by flash chromatography using
CH2Cl2 as eluent to yield 2b.
1
1222, 1183, 721. H NMR (CDCl3): 7.24–7.97 (m, 30H,
Ph); 3.83 (q, 4H, OCH2, J¼7.1 Hz); 1.08 (t, 6H, CH3,
J¼7.1 Hz). 13C NMR (CDCl3): 14.36 (CH3); 59.80 (OCH2);
88.45; 110.79; 128.05; 128.29; 130.97; 131.24; 131.29;
132.82; 133.02; 145.66; 148.79; 154.43; 163.51; 163.54. 31P
NMR (CDCl3): 5.53. MS (FAB, m/z %) 887 (MHþ, 30); 279
(100). Anal. calcd for C50H40N4O4P2S2 C, 67.71; H, 4.55;
N, 6.32; S, 7.23. Found C, 67.53; H, 4.50; N, 6.31; S, 7.35.
3.2.1. Diethyl 3,5-diaminodithieno[30,20-e:2,3-b]pyridine-
2,6-dicarboxylate (2a). (6.0 g, 90%). Mp .300. IR (KBr,
cm21): 3378, 3280 (NH2), 1678 (CvO). 1H NMR (DMSO):
9.09 (s, 1H, CH); 7.09 (s, 4H, NH2); 4.26 (q, 4H, OCH2,
J¼7.1 Hz); 1.29 (t, 6H, OCH2CH3, J¼7.1 Hz). 13C NMR
(DMSO): 17.73 (OCH2CH3); 60.52 (OCH2); 93.89; 123.13;
127.05 (CH); 148.18; 161.18; 164.55. MS (IE, m/z %): 365
(Mþ, 100). Anal. calcd for C15H15N3O4S2, C, 49.30; H, 4.14;
N, 11.50; S, 17.55. FoundC, 49.59; H, 4.21; N,11.26; S, 17.31.
3.3. Synthesis of diethyl 3,5-bis(arylimino-methylenami-
no)dithieno[30,20-e:2,3-b]pyridine(or pyrazine)-2,6-
dicarboxylate (4a–e)
To a solution of 3 (0.23 mmol) in CH2Cl2 (10 mL) (THF for
3b) was added the appropriate isocyanate (0.54 mmol).
After the mixture was stirred at room temperature for 3–5 h
(p-tolylisocyanate: reflux). The solvent was evaporated,
ether (5 mL) was added, and the mixture was stirred at room
temperature for 0.5 h. The solid formed was filtered off and
purified by flash chromatography using hexanes/CH2Cl2
(1:1 v/v) as eluent.
3.2.2. Diethyl 3,5-diaminodithieno[30,20-e:2,3-b]pyra-
zine-2,6-dicarboxylate (2b). (55%). Mp 240–242 8C. IR
1
(KBr, cm21): 3474–3330 (NH2), 1680 (CvO). H NMR
(CD3Cl): 6.24 (s, 4H, NH2); 4.41 (q, 4H, OCH2, J¼7.1 Hz);
1.44 (t, 6H, CH3, J¼7.1 Hz). 13C NMR (CD3Cl): 14.45
(CH3); 61.06 (OCH2); 99.63; 138.30; 144.71; 155.85;
164.85. MS (EI, m/z %) 366 (Mþ, 100). Anal. calcd for

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D. Vazquez Vilarelle et al. / Tetrahedron 60 (2004) 275–283
279
3.3.1. Diethyl 3,5-bis(phenyliminomethyleneamino)di-
thieno[30,20-e:2,3-b]pyridine-2,6-dicarboxylate
(4a).
stirred at room temperature (p-tolylisocyanate: reflux) until
the iminophosphorane had disappeared (TLC monitored)
and it was therefore treated with an appropriate amine
(0.55 mmol). The resultant solution was stirred at room
temperature for 2 h. The solvent was evaporated, ether
(5 mL) was added, and the mixture was stirred at room
temperature for 0.5 h. The solid formed was filtered off and
purified by recristallization from EtOH/CH2Cl2.
(54%). Mp 200–203 8C. IR (KBr, cm21): 2150 (NCN);
1706 (CO); 1460; 1259; 760. 1H NMR (CDCl3): 8.79 (s, 1H,
CH); 7.27 (m, 10H, Ph); 4.40 (q, 4H, OCH2, J¼7.1 Hz);
1.39 (t, 6H, CH3, J¼7.1 Hz). 13C NMR (CDCl3): 14.31
(CH3); 61.89 (OCH2); 118.40; 124.76; 15.48; 125.96;
126.71; 127.64; 129.42; 134.34; 136.49; 160.09; 162.19.
Anal. calcd for C29H21N5O4S2 C, 61.36; H, 3.73; N, 12.34;
S, 11.30. Found C, 61.50; H, 3.98; N, 12.51; S, 11.63.
3.4.1. Diethyl 3,5-bis[anilino(thiomorpholino)methylene-
amino]dithieno[30,20-e:2,3-b]pyridine-2,6-dicarboxylate
(5a). (60%). Mp .300 8C. IR (KBr, cm21): 3329 (NH),
3.3.2. Diethyl 3,5-bis(4-chlorophenyliminomethylene-
amino)dithieno[30,20-e:2,3-b]pyridine-2,6-dicarboxylate
(4b). (53%). Mp 174–175 8C. IR (KBr, cm21): 2158
1
1687 (CvO), 1624, 1230, 1052, 933. H NMR (CDCl3):
8.28 (s, 1H, CH); 7.11 (m, 10H, Ph); 6.92 (br s, 2H, NH);
4.25 (m, 4H, OCH2); 3.84 (m, 8H, H2CNCH2); 2.76 (m, 8H,
H2CSCH2); 1.27 (m, 6H, CH3). 13C NMR (CDCl3): 30.21
(SCH2); 49.50 (NCH2); 66.00 (OCH2); 115.77; 125.38;
126.38; 128.65; 128.79; 129.05; 136.73; 149.75; 157.47;
158.89; 163.93. MS (FAB, m/z %): 774 (MHþ, 22). Anal.
calcd for C37H39N7O4S4 C, 57.41; H, 5.08; N, 12.67; S,
16.57. Found C, 57.64; H, 5.22; N, 12.35; S, 16.29.
1
(NCN); 1698 (CvO); 1258; 827. H NMR (CDCl3): 8.75
(s, 1H, CH); 7.32 (m, 8H, Ph); 4.40 (q, 4H, OCH2,
J¼7.1 Hz); 1.39 (t, 6H, CH3, J¼7.1 Hz). RMN 13C
(CDCl3): 14.29 (CH3); 61.84 (OCH2); 118.49; 126.00;
126.61; 127.46; 129.52; 129.79; 131.42; 134.04; 135.19;
160.06; 162.18. MS (FAB, m/z %): 636 (MHþ, 2). Anal.
calcd for C29H19Cl2N5O4S2 C, 54.72; H, 3.01; N, 11.00; S,
10.08. Found C, 54.84; H, 3.05; N, 10.84; S, 10.09
3.4.2. Diethyl 3,5-bis[anilino(diethylamino)methylene-
amino]dithieno[30,20-e:2,3-b]pyridine-2,6-dicarboxylate
(5b). (55%). Mp 205–206 8C. IR (KBr, cm21): 3373–3291
(NH), 1706 (CvO), 1594, 1583, 1239, 1049. 1H NMR
(CDCl3): 8.39 (s, 1H, CH); 6.73 (m, 10H, Ph); 5.77 (s, 2H,
NH); 4.30 (q, 4H, OCH2, J¼7.1 Hz); 3.55 (q, 4H, NCH2,
J¼7.1 Hz); 1.35 (m, 18H, CH3). 13C NMR (CDCl3): 13.25
(NCH2CH3); 14.49 (OCH2CH3); 42.94 (NCH2); 60.54
(OCH2); 118.57; 122.18; 126.92; 128.08; 140.74; 151.89;
161.11; 163.32. MS (FAB, m/z %): 714 (MHþ, 53); 641
(MHþ2CO2Et, 11). Anal. calcd for C37H43N7O4S2 C,
62.25; H, 6.07; N, 13.73; S, 8.98. Found C, 62.41; H, 5.94,
N, 13.50; S, 8.92.
3.3.3. Diethyl 3,5-bis(4-methylphenyliminomethylene-
amino)dithieno[30,20-e:2,3-b]pyridine-2,6-dicarboxylate
(4c). (63%). Mp 160–162 8C. IR (KBr, cm21): 2151
(NCN); 1697 (CvO); 1467; 1261; 558. 1H NMR
(CDCl3): 8.81 (s, 1H, CH); 7.23 (m, 8H, Ph); 4.40 (q, 4H,
OCH2, J¼7.1 Hz); 2.35 (s, 6H, CH3); 1.39 (t, 6H,
OCH2CH3, J¼7.1 Hz). 13C NMR (CDCl3): 14.32 (CH3);
21.04 (CH3); 61.75 (OCH3); 124.57; 126.78; 127.53;
127.73; 129.50; 130.01; 133.56; 134.75; 135.86; 162.22.
Anal. calcd for C31H25N5O4S2 C, 62.50; H, 4.23; N, 11.76;
S, 10.77. Found C, 62.70; H, 4.36; N, 11.53; S, 10.31
3.3.4. Diethyl 3,5-bis(4-methoxyphenylimino-methylene-
amino)dithieno[30,20-e:2,3-b]pyridine-2,6-dicarboxylate
(4d). (56%). Mp 155 8C. IR (KBr, cm21): 2150 (NCN);
1698 (CvO); 1500; 1247; 830. 1H NMR (CDCl3): 8.78 (s,
1H, CH); 6.93 (m, 8H, Ph); 4.4 (q, 4H, OCH2, J¼7.1 Hz);
3.82 (s, 6H, CH3); 1.39 (t, 6H, OCH2CH3, J¼7.1 Hz). 13C
NMR (CDCl3): 14.33 (CH3); 55.48 (CH3); 61.69 (OCH2);
114.67; 117.84; 125.88; 126.75; 127.00; 127.68; 128.78;
129.47; 135.13; 157.75; 160.13; 162.25. Anal. calcd for
C31H25N5O6S2 C, 59.32; H, 4.01; N, 11.16; S, 10.22. Found
C, 58.98; H, 3.93; N, 10.99; S, 10.14.
3.4.3. Diethyl 3,5-bis[anilino(morpholino)methylene-
amino]dithieno[30,20-e:2,3-b]pyridine-2,6-dicarboxylate
(5c). (50%). Mp 210–211 8C. IR (KBr, cm21): 3320 (NH),
1702 (CvO), 1614, 1600, 1237, 1108, 1049, 966. 1H NMR
(CDCl3): 8.30 (s, 1H, CH); 7.13 (m, 10H, Ph); 6.92 (s, 2H,
NH); 4.23 (m, 4H, OCH2); 3.60 (m, 8H, H2COCH2); 3.44
(m, 8H, H2CNCH2); 1.23 (m, 6H, CH3). 13C NMR (CDCl3):
14.28 (CH3); 47.62 (NCH2); 60.84 (H2COCH2); 66.35
(OCH2); 119.99; 122.90; 126.90; 127.89; 129.02; 134.91;
140.54; 153.18; 160.98; 162.86. MS (FAB, m/z %): 742
(MHþ, 54). Anal. calcd for C37H39N7O6S2 C, 59.90; H,
5.30; N, 13.22; S, 8.64. Found C, 59.52; H, 5.38; N, 12.95;
S, 8.75.
3.3.5. Diethyl 3,5-bis(phenyliminomethyleneamino)di-
thieno[30,20-e:2,3-b]pyrazine-2,6-dicarboxylate
(4e).
(75%). Mp 165–167 8C. IR (KBr, cm21): 2152 (NCN);
1686 (CO); 1228, 1061, 752. 1H NMR (CDCl3): 7.11–7.45
(m, 10H, Ph); 4.50 (q, 4H, OCH2, J¼7.1 Hz); 1.45 (t, 6H,
CH3, J¼7.1 Hz). 13C NMR (CDCl3): 14.26 (CH3); 62.18
(OCH2); 124.92, 125.92, 129.34 (Ph); 122.23; 134.79;
136.11; 142.50; 153.84; 161.53. Anal. calcd for
C28H20N6O4S2 C, 59.14; H, 3.55; N, 14.78; S, 11.28.
Found C, 58.87; H, 3.34; N,14.46; S, 11.52.
3.4.4. Diethyl 3,5-bis[4-methoxyanilino(morpholino)
methyleneamino]dithieno[30,20-e:2,3-b]]pyridine-2,6-
dicarboxylate (5d). (55%). Mp 238–239 8C. IR (KBr,
cm21): 3333 (NH), 1712 (CvO), 1625, 1511, 1111, 823. 1H
NMR (CDCl3): 8.25 (s, 1H, CH); 7.11 (m, 8H, Ph); 6.59 (s,
2H, NH); 4.17 (m, 4H, OCH2,); 3.72 (m, 14H, CH2OCH2þ
OCH3); 3.48 (m, 8H, CH2NCH2); 1.24 (m, 6H, CH3). 13C
NMR (CDCl3): 14.31 (CH3); 47.62 (NCH2); 55.38 (OCH3)
60.75 (OCH2); 66.39 (CH2OCH2); 111.31; 114.24; 122.39;
127.00; 127.92; 131.97; 132.17, 133.66; 148.50; 153.95;
155.76; 151.04; 162.84. MS (FAB, m/z %): 802 (MHþ, 16).
Anal. calcd for C39H43N7O8S2 C, 58.41; H, 5.40; N, 12.23;
S, 8.00. Found C, 58.15; H, 5.32; N, 11.93; S, 7.70.
3.4. Synthesis of diethyl dithieno[30,20-e:2,3-b]pyridine-
2,6-dicarboxylates (5a–f)
A solution of the appropriate isocyanate (0.55 mmol) and 3a
(0.2 g, 0.23 mmol) in CH2Cl2 (10 mL). The mixture was

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280
3.4.5. Diethyl 3,5-bis[4-chloroanilino(piperidino)methyl-
eneamino]dithieno[30,20-e:2,3-b]pyridine-2,6-dicarboxy-
late (5e). (54%). Mp 237–238 8C. IR (KBr, cm21): 3337
(NH), 1714 (CvO), 1620, 1233, 1053, 824. 1H NMR
(CDCl3): 8.21 (s, 1H, CH); 7.13 (m, 8H, Ph); 6.60 (s, 2H,
NH); 4.20 (m, 4H, OCH2,); 3.45 (m, 8H, H2CNCH2); 1.39
(m, 18H, NCH2CH2CH2þCH3). 13C NMR (CDCl3): 14.30
(CH3); 24.7 (NCH2CH2CH2); 25.4 (NCH2CH2) 48.3
(NCH2); 60.80 (OCH2); 120.93; 127.26, 128.06; 139.70;
152.70; 161.00. MS (FAB, m/z %): 806 (MHþ, 16). Anal.
calcd for C39H41Cl2N7O4S2 C, 58.06; H, 5.12; N, 12.15; S,
7.95. Found C, 57.94; H, 5.15; N, 11.76; S, 7.79.
3.5.3. 2,10-Dimorpholino-3,9-diphenylpyrido
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6c). (75%). Mp .300 8C. IR (KBr,
cm21): 2856, 1677 (CvO), 1529, 1118, 918. 1H NMR
(CDCl3): 8.86 (s, 1H, CH); 7.47 (m, 10H, Ph); 3.54 (m, 8H,
OCH2); 3.32 (m, 8H, NCH2). MS (FAB, m/z %): 650 (MHþ,
10). Anal. calcd for C33H27N7O4S2 C, 61.00; H, 4.19; N,
15.09; S, 9.87. Found C, 61.45; H, 4.18; N, 15.08; S, 9.73.
3.5.4.
3,9-Diphenyl-2,10-dipiperidinopyrido
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6d). (60%). Mp .300 8C. IR (KBr,
cm21): 2929, 1675 (CvO), 1589, 1532, 1251, 707. 1H
NMR (CDCl3): 8.90 (s, 1H, CH); 7.42 (m, 10H, Ph); 3.30
(m, 8H, NCH2); 1.49–1.35 (m, 12H, NCH2CH2CH2). 13C
NMR (CDCl3): 24.13 (NCH2CH2CH2); 24.94 (NCH2CH2);
50.48 (NCH2); 115.06; 125.49; 126.48; 128.16; 128.79;
128.98; 137.48; 150.12; 158.48; 159.22; 163.96. MS (FAB,
m/z %): 646 (MHþ, 8). Anal. calcd C35H31N7O2S2 C, 65.09;
H, 4.84; N, 15.18; S, 9.93. Found C, 64.71; H, 4.83; N,
14.94; S, 10.01.
3.4.6. Diethyl 3,5-bis[anilino(isopropylamino)methyl-
eneamino]dithieno[30,20-e:2,3-b]pyridine-2,6-dicarboxy-
late (5f). (40%). Mp .300 8C. IR (KBr, cm21): 3345 (NH),
1
1677 (CvO), 1633, 1530, 1491, 1051. H NMR (CDCl3):
8.45 (s, 1H, CH); 7.35 (m, 10H, Ph); 7.08 (m, 4H,
NHþNHPh); 4.29 (m, 6H, HNCHþOCH2); 1.23 (m, 18H,
HNCH2CH3þOCH2CH3). 13C NMR (CDCl3): 14.34
(CH3); 23.04 (HNCHCH3); 43.33 (HNCH); 60.74
(OCH2); 124.02, 124.57; 128.35; 128.67; 129.43; 138.68;
148.37; 149.23; 160.85; 163.17. MS (FAB, m/z %): 686
(MHþ, 100); 687 (MHþþ1, 39); 688 (MHþþ2.18). Anal.
calcd for C35H39N7O4S2 C, 61.29; H, 5.73; N, 14.30; S,
9.35. Found C, 61.42; H, 5.85; N, 14.41; S, 9.49.
3.5.5. 3,9-Bis(4-chlorophenyl)-2,10-dimorpholinopyrido-
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimi-dine-
4,8(3H,9H)-dione (6e). (54%). Mp .300 8C. IR (KBr,
cm21): 2847, 1678 (CvO), 1635, 1530, 1250, 833. 1H
NMR (CDCl3): 7.46 (m, 8H, Ph); 6.40 (s, 1H, CH); 3.70
(m, 8H, OCH2,); 3.40 (m, 8H, NCH2); 13C NMR (CDCl3):
44.2 (NCH2); 66.4 (OCH2); 121.25; 128.30; 128.44;
128.85; 131.90; 132.09; 137.33; 154.85. Anal. calcd for
C33H25Cl2N7O4S2 C, 55.15; H, 3.51; N, 13.64; S, 8.92.
Found C, 55.48; H, 3.85; N, 13.54; S, 8.66.
3.5. Synthesis of pyrido(or pyrazino)[500,600:4,5;300200:40,50]
dithieno[3,2-d:30,20-d0]dipyrimidine-4,8(3H,9H)-diones
(6a–y)
A solution of the appropriate isocyanate (0.55 mmol) and 3a
or 3b (0.23 mmol) in CH2Cl2 (10 mL). The mixture was
stirred at room temperature (p-tolylisocyanate: reflux) until
the iminophosphorane had disappeared (3 h, TLC mon-
itored) and it was therefore treated with an appropriate
amine (0.55 mmol). The resultant solution was stirred at
room temperature for 2 h. The solvent was evaporated and
the residue was solved in acetone (8 mL), a catalytic amount
of K2CO3 was added, the mixture was refluxed for 0.5 h and
the solid obtained was filtered off, washed with water,
acetone and recrystallized from EtOH/CH2Cl2. Compounds
6a and 6f could not be purified because their insolubility in
ordinary solvents.
3.5.6. 3,9-Bis(4-chlorophenyl)-2,10-dipiperidinopyrido-
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6f). (67%). Mp .300 8C. IR (KBr,
cm21): 2935, 1677 (CvO), 1530, 1403, 1253, 769. MS
(FAB, m/z %) 714 (MHþ, 3); 716 (MHþþ2, 3).
3.5.7. 2,10-Dimorpholino-3,9-di-p-tolylpyrido
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6g). (77%). Mp .300 8C. IR (KBr,
1
cm21): 2852, 2360, 1674 (CvO), 1534, 1117. H NMR
(CDCl3): 8.84 (s, 1H, CH); 7.31 (m, 8H, Ph); 3.56 (m, 8H,
OCH2); 3.33 (m, 8H, NCH2); 2.45 (s, 6H, Me). 13C NMR
(CDCl3): 21.24 (Me); 49.47 (NCH2); 66.05 (OCH2);
115.65; 125.39; 126.24; 128.43; 129.66; 134.06; 138.58;
149.68; 157.55 Ms (FAB, m/z %): 678 (MHþ, 12). Anal.
calcd for C35H31N7O4S2 C, 62.02; H, 4.61; N, 14.47; S,
9.46. Found C, 62.13; H, 4.39; N, 14.41; S, 9.33.
3.5.1. 2,10-Bis(diethylamino)-3,9-diphenylpyrido
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6a). (69%). Mp .300 8C. IR (KBr,
cm21): 1675 (CvO), 1530, 1378, 1282, 699. MS (FAB, m/z
%): 622 (MHþ, 10); 623 (MHþþ1, 4); 550 (MHþ2
diethylamine, 3).
3.5.8. 2,10-Dipiperidino-3,9-di-p-tolylpyrido
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6h). (64%). Mp .300 8C. IR (KBr,
cm21): 2932, 1675 (CvO), 1586, 1530, 1407, 1254, 751.
1H NMR (CDCl3): 8.96 (s, 1H, CH); 7.30 (m, 8H, Ph); 3.29
(m, 8H, NCH2); 2.44 (s, 6H, Me); 1.35 (m, 12H,
NCH2CH2CH2). 13C NMR (CDCl3): 21.23 (CH3); 24.15
(NCH2CH2CH2); 24.98 (NCH2CH2); 50.41 (NCH2);
115.10; 125.69; 126.45; 128.52; 129.47; 134.80; 138.04;
150.12; 158.55; 159.37; 164.08. MS (FAB, m/z %): 674
(MHþ, 8). Anal. calcd for C37H35N7O2S2 C, 65.95;H, 5.24; N,
14.55; S, 9.52. Found C, 65.87; H, 5.30; N, 14.73; S, 9.59.
3.5.2. 3,9-Diphenyl-2,10-dithiomorpholinpyrido
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6b). (89%). Mp .300 8C. IR (KBr,
1
cm21): 1677 (CvO), 1534, 1409. H NMR (CDCl3): 8.91
(s, 1H, CH); 7.47 (m, 10H, Ph); 3.62 (m, 8H, NCH2); 2.39
(m, 8H, SCH2). 13C NMR (CDCl3): 26.49 (SCH2); 51.93
(NCH2); 125.42; 128.64; 129.01; 135.12; 137.05; 149.68;
158.17; 159.05. MS (FAB, m/z %): 682 (MHþ, 4); 580
(MHþ2thiomorpholine, 4). Anal. calcd for C33H27N7O2S4
C, 58.13; H, 3.99; N, 14.38; S, 18.81. Found C, 58.40; H,
4.03; N, 14.58; S, 19.02.

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3.5.9. 3,9-Bis(4-methoxyphenyl)-2,10-dimorpholinopy-
rido[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyri-
midine-4,8(3H,9H)-dione (6i). (61%). Mp .300 8C. IR
(KBr, cm21): 2963, 1676 (CvO), 1536, 1507, 1246, 917.
1H NMR (CDCl3): 8.66 (s, 1H, CH); 7.15 (m, 8H, Ph); 3.87
(s, 6H, OCH3); 3.36 (m, 8H, OCH2); 3.34 (s, 8H, NCH2).
13C NMR (CDCl3): 49.49 (NCH2); 55.47 (OCH3); 66.12
(OCH2); 114.14; 115.47; 125.19; 126.1; 129.85; 149.58;
157.68; 159.09; 159.36; 163.72. MS (FAB, m/z %): 710
(MHþ, 13). Anal. calcd for C35H31N7O6S2 C, 59.22; H,
4.40;N,13.81;S, 9.04. FoundC, 59.25;H, 4.41;13.55;S,9.13.
3.5.14. 2,10-Bis(isopropylamino)-3,9-di-p-tolylpyrido-
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6n). (70%). Mp .300 8C. IR (KBr,
cm21): 3412 (NH), 2970; 1675 (CvO), 1546, 1320, 1176,
773. 1H NMR (CD2Cl2/CDCl3): 9.07 (s, 1H, CH); 7.30 (m,
8H, Ph); 4.50 (m, 2H, NCH); 4.12 (d, 2H, HN, J¼7.8 Hz);
2.48 (s, 6H, CH3) 1.24 (d, 12H, NCHCH3, J¼6.6 Hz). 13C
NMR (CDCl3): 21.53 (CH3); 22.92 (CH3); 44.46 (NCH);
126.51; 126.92; 128.89; 131.72; 132.02; 133.61; 140.83;
152.30; 153.30; 158.97; 164.65. MS (FAB, m/z %): 622
(MHþ, 88). Anal. calcd for C33H31N7O2S2 C, 63.75; H,
5.03; N, 15.77; S, 10.31. Found C, 63.90; H, 4.99; N, 15.64;
S, 10.21.
3.5.10. 3,9-Bis(4-methoxyphenyl)-2,10-dipiperidinopyri-
do[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimi-
dine-4,8(3H,9H)-dione (6j). (62%). Mp .300 8C. IR (KBr,
cm21): 2933, 1675 (CvO), 1532, 1511, 1251, 915. 1H NMR
(CDCl3): 8.89 (s, 1H, CH); 7.13 (m, 8H, Ph); 3.88 (s, 6H,
OCH3); 3.31 (m, 8H, NCH2); 1.45 (m, 12H, NCH2CH2CH2).
13C NMR (CDCl3): 24.15 (NCH2CH2CH2); 25.08
(NCH2CH2); 50.44 (NCH2); 55.47 (OCH3); 114.06;
115.06; 125.61; 126.41; 129.87; 130.01; 150.06; 158.68;
159.06; 159.50; 164.01. MS (FAB, m/z %): 706 (MHþ, 52).
Anal. calcd for C37H35N7O4S2 C, 62.96; H, 5.00; N, 13.89;
S, 9.09. Found C, 62.46; H, 4.97; N, 13.68; S, 8.89.
3.5.15. 2,10-Bis(isopropylamino)-3,9-bis(4-methoxyphe-
nyl)pyrido[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-
d0]dipyrimidine-4,8(3H,9H)-dione (6o). (86%). Mp
.300 8C. IR (KBr, cm21): 3383–3428 (NH), 2967; 1674
1
(CvO), 1511, 1246, 1039, 771. H NMR (CD5N): 9.71 (s,
1H, CH); 7.44 (m, 4H, Ph); 6.90 (m, 4H, Ph); 6.29 (d, 2H,
HN, J¼8.3 Hz); 4.70 (m, 2H, NCH,); 3.52 (s, 6H, OCH3);
1.20 (d, 12H, NCHCH3, J¼6.8 Hz). MS (FAB, m/z %): 654
(MHþ, 10). Anal. calcd for C33H31N7O4S2 C, 60.63; H, 4.78;
N, 15.00; S, 9.81. Found C, 60.55; H, 4.70; N, 14.59; S, 9.62.
3.5.11. 2,10-Bis(butylamino)-3,9-diphenylpyrido
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6k). (40%). Mp .300 8C. IR (KBr,
cm21): 3429–3368 (NH), 2931; 1678 (CvO), 1549, 1324,
772. 1H NMR (CDCl3): 8.93 (s, 1H, CH); 7.41 (m, 10H, Ph);
4.28 (t, 3H, NH); 3.60 (m, 4H, NCH2); 1.61 (m, 4H,
NCH2CH2); 1.38 (m, 4H, NCH2CH2CH2); 1.00 (t, 6H, CH3).
13C NMR (CDCl3): 13.76 (CH3); 20.00 (NCH2CH2CH2);
31.24 (NCH2CH2); 41.98 (NCH2); 110.84; 125.61; 126.49;
129.00; 130.01; 130.62; 134.38; 151.78; 153.23; 158.44;
164.37. MS (FAB, m/z %): 622 (MHþ, 100). Anal. calcd for
C33H31N7O2S2 C; 63.75; H, 5.03; N, 15.77;S, 10.31. Found C,
63.36; H, 4.97; N, 15.54; S, 10.26.
3.5.16. 3,9-Diphenyl-2,10-dithiomorpholinopyrazino-
[500,600:4,5:300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6p). (30%). Mp .300 8C. IR (KBr,
cm21): 2911, 1678 (CvO), 1531, 1197, 761. 1H NMR
(CDCl3): 7.41–7.63 (m, 10H, Ph); 3.67 (m, 8H, NCH2);
2.35 (m, 8H, SCH2). 13C NMR (CDCl3): 26.39 (SCH2);
51.86 (NCH2); 128.67, 128.93, 129.41 (Ph); 137.04; 158.48;
159.36. MS (FAB, m/z %): 683 (MHþ, 10). Anal. calcd for
C32H26N8O2S4: C, 56.28; H, 3.84; N, 16.41; S, 18.78. Found
C, 56.34; H, 4.03; N, 16.58; S, 19.02.
3.5.17. 2,10-Dimorpholino-3,9-diphenylpyrazino
[500,600:4,5:300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6q). (40%). Mp .300 8C. IR (KBr,
cm21): 2855, 2368, 1679 (CvO), 1532, 1200, 922. 1H
NMR (CDCl3): 7.45–7.61 (m, 10H, Ph); 3.51 (m, 8H,
OCH2); 3.36 (m, 8H, NCH2). 13C NMR (CDCl3): 49.36
(NCH2); 65.93 (OCH2); 128.34, 128.96, 129.37 (Ph);
136.75; 142.21; 148.47; 157.72; 159.23. MS (FAB, m/z
%): 651 (MHþ, 85); (MHþ2morpholine, 40). Anal. calcd
for C32H26N8O4S2: C, 59.06; H, 4.03; N, 17.22; S, 9.86.
Found C, 58.72; H, 3.94; N, 17.62; S, 9.80.
3.5.12. 2,10-Bis(isopropylamino)-3,9-diphenylpyrido-
[500,600:4,5:300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6l). (45%). Mp .300 8C. IR (KBr,
cm21): 3436 (NH), 3061, 2974; 1676 (CvO), 1547, 1289,
1
1176, 770. H NMR (CDCl3): 8.89 (s, 1H, CH); 7.52 (m,
10H, Ph); 4.50 (m, 2H, NCH); 4.05 (d, 2H, HN, J¼7.3 Hz);
1.26 (d, 12H, CH3, J¼6.4 Hz). 13C NMR (CDCl3): 22.84
(CH3); 44.09 (NCH); 110.76; 125.55, 126.44, 129.02;
129.94; 130.57, 134.34; 151.81; 152.54; 158.45; 164.35.
MS (FAB, m/z %): 594 (MHþ, 32). Anal. calcd for
C31H27N7O2S2 C, 62.71; H, 4.58; N, 16.51; S, 10.80.
Found 62.61; H, 4.47; N, 16.84; S, 10.92.
3.5.18. 3,9-Diphenyl-2,10-dipiperidinopyrazino
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6r). (30%). Mp .300 8C. IR (KBr,
cm21): 2934, 1678 (CvO), 1531, 1193, 922. 1H NMR
(CDCl3): 7.41–7.59 (m, 10H, Ph); 3.34–1.31 (m, 12H,
NCH2CH2CH2). 13C NMR (CDCl3): 23.96 (NCH2CH2CH2);
24.84 (NCH2CH2); 50.35 (NCH2); 128.52, 128.47, 129.12
(Ph); 118.74; 137.45; 142.24; 148.82; 157.78; 158.78;
159.57. MS (FAB, m/z %): 647 (MHþ, 100); 648 (MHþþ1,
50). Anal. calcd for C34H30N8O2S2: C, 63.14; H, 4.68; N,
17.32; S, 9.92. Found C, 63.12; H, 4.59; N, 17.28; S, 9.77.
3.5.13. 3,9-Bis(4-chlorophenyl)-2,10-bis(isopropylami-
no)pyrido[500,600:4,5;300200:40,500]dithieno[3,2-d:30,20-
d0]dipyrimidine-4,8(3H,9H)-dione (6m). (33%). Mp
.300 8C. IR (KBr, cm21): 3323 (NH), 2973; 1627
1
(CvO), 1560, 1238. H NMR (CD3COCD3): 7.80 (s, 1H,
CH); 7.30 (m, 8H, Ph); 5.58 (d, 2H, NH, J¼7.3 Hz); 3.87
(m, 2H, NCH,); 1.12 (d, 12H, CH3, J¼6.8 Hz). 13C
NMR (CD3COCD3): 23.30 (CH3); 42.30 (NCH); 120.11;
126.17; 129.23; 140.66; 155.18; 194.49. Anal. calcd for
C31H25Cl2N7O2S2 C, 56.19; H, 3.80; N, 14.80; S, 9.68.
Found C, 56.58; H, 4.12; N, 14.79; S, 10.01.
3.5.19. 2,10-Bis(isopropylamino)-3,9-diphenylpyrazino-
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6s). (46%). Mp .300 8C. IR (KBr,

´
D. Vazquez Vilarelle et al. / Tetrahedron 60 (2004) 275–283
282
cm21): 3431 (NH), 1678 (CvO), 1548, 1200, 759. 1H NMR
(CDCl3): 7.26–7.72 (m, 10H, Ph); 4.64 (m, 2H, NCH); 4.13
.300 8C. IR (KBr, cm21): 2960, 1680 (CvO), 1508,
1521, 1249. 1H NMR (CDCl3): 7.04–7.39 (m, 8H, Ph); 3.89
(d, 2H, HN, J¼8.3 Hz); 1.21 (d, 12H, CH3, J¼6.8 Hz). 13
C
(s, 6H, OMe); 3.54 (m, 8H, OCH2); 3.37 (s, 8H, NCH2). 13
C
NMR (CDCl3): 22.89 (NCHCH3); 44.10 (NCH); 128.63,
130.36, 130.88 (Ph); 120.68; 129.15; 134.05; 142.11;
150.32; 152.19; 158.67 MS (FAB, m/z %): 595 (MHþ,
100); 596 (MHþþ1, 50). Anal. calcd for C30H26N8O2S2 C,
60.59; H, 4.41; N, 18.84; S, 10.78. Found C, 60.69; H, 4.14;
N, 18.62; S, 10.53.
NMR (CDCl3): 49.36 (NCH2); 55.57 (OCH3); 66.05
(OCH2); 114.56, 129.34 (Ph); 119.55; 129.34; 142.21;
148.37; 157.75; 157.93; 159.50; 159.59. MS (FAB, m/z %):
711 (MHþ, 85); (MHþ2morpholine, 15). Anal. calcd for
C34H30N8O6S2 C, 57.45; H, 4.25; N, 15.76; S, 9.02. Found
C, 57.82; H, 3.96; N, 15.59; S, 8.96.
3.5.20. 3,9-Bis(4-chlorophenyl)-2,10-dimorpholinopyra-
zino[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]di-pyrimi-
dine-4,8(3H,9H)-dione (6t). (27%). Mp .300 8C. IR (KBr,
cm21): 2962, 2855, 1680 (CvO), 1533, 1201, 922. 1H
NMR (CDCl3): 7.39–7.57 (m, 8H, Ph); 3.56 (m, 8H,
OCH2,); 3.36 (m, 8H, NCH2); 13C NMR (CDCl3): 49.43
(NCH2); 65.96 (OCH2); 129.59, 129.70 (Ph); 134.96;
135.02; 142.04; 148.38; 157.52; 157.56; 158.98. MS
(FAB, m/z %): 719 (MHþ, 5); 217 (100). Anal. calcd for
C32H24Cl2N8O4S2: C, 53.41; H, 3.36; N, 15.57; S, 8.91.
Found C, 53.48; H, 3.35; N, 15.74; S, 8.61.
3.5.25. 3,9-Bis(4-methoxyphenyl)-2,10-dipiperidino-pyr-
azino[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyri-
midine-4,8(3H,9H)-dione (6y). (26%). Mp .300 8C. IR
(KBr, cm21): 2934, 1679 (CvO), 1508, 1530, 1252, 1190,
920. 1H NMR (CDCl3): 7.02–7.39 (m, 8H, Ph); 3.89 (s, 6H,
OCH3); 3.34–3.37 (m, 8H, NCH2); 1.35–1.48 (m, 12H,
NCH2CH2CH2). 13C NMR (CDCl3): 24.02 (NCH2CH2CH2);
24.99 (NCH2CH2); 50.32 (NCH2); 55.54 (OCH3); 114.64,
129.48 (Ph); 118.68; 129.97; 142.35; 148.78; 157.75;
158.93; 159.26; 159.86. MS (FAB, m/z %): 707 (MHþ,
90). Anal. calcd for C36H34N8O4S2 C, 61.17; H, 4.85;
N, 15.85; S, 9.07. Found C, 61.46; H, 4.97; N, 15.68; S,
8.89.
3.5.21. 3,9-Bis(4-chlorophenyl)-2,10-dipiperidinopyra-
zino[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]di-pyrimi-
dine-4,8(3H,9H)-dione (6u). (42%). Mp .300 8C. IR
1
(KBr, cm21): 2937, 1675 (CvO), 1530, 1193, 1092. H
Acknowledgements
NMR (CDCl3): 7.26–7.55 (m, 8H, Ph); 3.32 (m, 8H, NCH2);
1.26–1.50 (m, 12H, NCH2CH2CH2). 13C NMR (CDCl3):
23.89 (NCH2CH2CH2); 24.88 (NCH2CH2); 50.39 (NCH2);
129.33, 129.85 (Ph); 118.79; 134.42; 135.75; 142.12; 148.74;
157.78; 158.56; 159.30. MS (FAB, m/z %) 715 (MHþ, 5).
Anal. calcd for C34H28Cl2N8O2S2 C, 57.06; H, 3.94; N, 15.66;
S, 8.96. Found C, 57.30; H, 3.96; N, 15.29; S, 9.10.
The authors are grateful to the Xunta de Galicia
´
(PGDIT00PXI 10306PR) and Ministerio de Educacion y
Cultura (BQU2000-0237) for the support of this research
work. D.V.V. acknowledges a predoctoral fellowship from
the Xunta de Galicia.
3.5.22. 2,10-Dimorpholino-3,9-di-p-tolylpyrazino
[500,600:4,5;300200:40,50]dithieno[3,2-d:30,20-d0]dipyrimidine-
4,8(3H,9H)-dione (6v). (27%). Mp .300 8C. IR (KBr,
References and notes
1
cm21): 2963, 2853, 1679 (CvO), 1530. H NMR (CDCl3):
7.27–7.35 (m, 8H, Ph); 3.52 (m, 8H, OCH2); 3.37 (m, 8H,
NCH2); 2.46 (s, 6H, Me). 13C NMR (CDCl3): 21.28 (Me);
49.32 (NCH2); 65.97 (OCH2); 127.97, 129.96 (Ph); 119.60;
120.19; 134.07; 139.05; 142.32; 148.48; 157.76; 159.38. MS
(FAB, m/z %): 679 (MHþ, 60); 592 (MHþ2morpholine, 30).
Anal. calcd for C34H30N8O4S2 C, 60.16; H, 4.45; N, 16.51; S,
9.45. Found C, 60.13; H, 4.39; N, 16.41; S, 9.33.
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