Efficient synthesis of pyrimido[5,4-c]pyridazines and of thiino[2,3-d]pyrimidines based on an aza-wittig reaction/heterocyclization strategy

Article abstract of DOI:10.1002/jhet.646

A simple one-pot and efficient method is described for the synthesis of pyrimido[5,4-c]pyridazines 5 and of thiino[2,3-d] pyrimidines 15 by a domino process involving an aza-Wittig reaction/heterocyclization. The iminophosphorane 2 reacted with phenylisoc

Full text of DOI:10.1002/jhet.646

388
Efficient Synthesis of Pyrimido[5,4-c]pyridazines and of
Thiino[2,3-d]pyrimidines Based on an Aza-Wittig
Reaction/Heterocyclization Strategy
Vol 49
Magda A. Barsy,* Eman A. El Rady, and Mostafa A. Ismael
Department of Chemistry, Faculty of Science, South Valley University, Aswan 81528, Egypt
*E-mail: magdabarsy@hotmail.com
Received April 12, 2010
DOI 10.1002/jhet.646
Published online 13 January 2012 in Wiley Online Library (wileyonlinelibrary.com).
A simple one-pot and efficient method is described for the synthesis of pyrimido[5,4-c]pyridazines 5
and of thiino[2,3-d] pyrimidines 15 by a domino process involving an aza-Wittig reaction/heterocycliza-
tion. The iminophosphorane 2 reacted with phenylisocyanate, followed by heterocyclization on addition
of amines to give the corresponding guanidine intermediates 4. The guanidine intermediates were
cyclized in the presence of catalytic amount of sodium ethoxide to pyrimido[5,4-c]pyridazines 5. Simi-
larly, iminophosphorane 12 reacted with phenylisocyanate and amines to give thiino[2,3-d]pyrimidines
15 in moderate yields. Furthermore, pyridazino[4,3-d]oxazines 10 and thiino[2,3-d]oxazines 19 were
synthesized by the intremolecular aza-Wittig reaction of phosphazenes 2 and 12, respectively, with acid
chlorides followed by heterocylization via imidoyl chloride intermediates.
J. Heterocyclic Chem., 49, 388 (2012).
INTRODUCTION
ities [9] while several pyrimido[4,5-d]pyridazines are use-
ful as diuretics [10]. From these isomers, pyrimido[5,4-
c]pyridazines are less studied and they show antifungal
activities and also have effective diuretic action [10,11].
So far the methods described for the preparation of
some representative derivatives of this ring system
involve as either the conversion of pyrimidine or uracil
moiety to pyrimido[5,4-c]pyridazines, by treatment with
a formylating agent [12], from Hofmann reaction on
6-methypyridazine-3,4-dicarboxamid or from 4-amino-
pyridazine-3-carboxylate on fusion with urea [13]. How-
ever, these methods are conducted under harsh condi-
tions, incur expensive materials, and involve several steps
in which a mixture of pyrimidopyridazine isomers were
inevitably obtained, which lead us to the investigation of
the alternative, more regioselective, synthesis of pyri-
mido[5,4-c]pyridazines via the intermolecular aza-Wittig
reaction heterocyclization.
The pyrimidine moiety have been widely used in the
design of biologically active agents, structures contain-
ing such units often play an essential role owing to their
wide range of biological activity particularly in cancer
and virus research [1,2]. The presence of a fused pyrimi-
dine scaffold in the framework of various pharmacologi-
cally active compounds continues to spur synthetic
efforts regarding their acquisition [3,4].
On the other hand, pyridazines and heterocyclic annu-
lated pyridazines have been investigated intensively for
their applications in agriculture and in particular for their
biological activity for use as potential drugs [5–8]. In par-
ticular, fused bicyclic pyrimidopyridazines are of great im-
portance because of their remarkable biological activities.
For example, some derivatives of pyrimido[4,5-c]pyrida-
zines have shown good antimicrobial and antifungal activ-
C
V
2012 HeteroCorporation

March 2012
Efficient Synthesis of Pyrimido[5,4-c]pyridazines and of Thiino[2,3-d]pyrimidines
Based on an Aza-Wittig Reaction/Heterocyclization Strategy
389
Scheme 1
Nitrogen- and sulfur-containing rings are among the
most useful heterocycles and their utility have been
widely demonstrated as a consequence of their exciting
biological properties and their role as pharmacophores
of considerable historical importance [14,15].
Whereas pyrimidine annulated sulfur containing het-
erocycles have been studied, surprisingly aza-analogous
compounds incorporating a six-membered S-heterocycle
fused to a pyrimidine nucleus have remained relatively
rare. Among these heterocycles, thiopyranopyrimidines
are an important class of compounds in pharmaceutical
discovering research. Some of them show excellent hypo-
glycemic activity, blood sugar lowering activity platelet
aggregation inhibitory activity, antihistamine, anti-inflam-
matory, and antilergiy activities. They also have beta-
adrenergic blocking properties proving useful in the treat-
ment of cardiovascular ailments known to be amenable to
beta-blocker therapy. Certain compounds are useful in the
treatment of elevated intraocular pressure [16–20].
In the development of strategies for the preparation of
heterocycles, the aza-Wittig reaction has proved to be a
powerful tool for the synthesis of five-to-eight-mem-
bered nitrogen heterocycles [21–30] including natural
products [31–36]. The iminophosphorane of heterocyclic
and heteroaromatic b-enamino esters have proved to be
very versatile intermediates for the construction of mani-
fold hetero-condensed system. Synthesis of many impor-
tant nitrogen heterocycles via aza-Wittig reaction of
b-ethoxy carbonyl iminophosphorane with aromatic iso-
cyanate and subsequent heterocyclization on reaction
with various nucleophiles under mild condition have
been utilized [37–47].
2 with primary amines via a guanidine-type intermediate,
it is interesting to note that the reaction is chemoselective
to afford 5 in excellent yields.
The EI mass spectrum for 5a showed the expected
molecular ion peaks in moderate to high intensity and the
fragmentation pattern is in accord with the proposed struc-
ture, it showed m/z at 384 (Mþ, 70%). The IR spectrum
(KBr) showed a strong absorption at m ¼ 3220 cmꢀ1
attributed to the NH group, 1690 and 1703 cmꢀ1 assigned
to the CO groups. In the 1H-NMR spectrum, the NH
proton appears at d 4.14 ppm as a broad singlet, in addi-
tion to the aromatic proton multiplet.
Likewise, reaction of iminophosphorane 2 with phe-
nylisocyanate and dimethylamine at room temperature
resulted in the formation of triphenylphosphine oxide
and the corresponding guanidine-type intermediate 7. In
the presence of NaOEt, 7 underwent heterocyclization
across the electrophilic ester functionality to give the
fused pyrimidine 5f (Scheme 1).
RESULTS AND DISCUSSION
The starting compound for the aza-Wittig reaction/
heterocyclization sequence, iminophosphorane 2 was
prepared in 97% yield using Appel’s method [48,49]
(the modified Kirsanov reaction) from the readily avail-
able ethyl 4-amino-1,6-dihydro-5-cyano-6-oxo-1-phenyl-
pyridazino-3-carboxylate (1) [50] with in situ generated
dichlorophenylphosphorane using a hexachloroethane/
triphenylphosphine/triethylamine reagent system by reflux-
ing in dry benzene for 1 h.
On the other hand, when iminophosphorane 2 was
treated with acid chlorides by refluxing in acetonitrile in
presence of small excess of triethylamine, pyrida-
zino[4,3-d]oxazines 10a,b were readily obtained in 69%
and 67%, respectively. Here, the tertiary amine seems to
be essential for the reaction as only 15% products were
obtained without Et3N. The IR spectrum of 10a result-
ing from the reaction of iminophosphorane 2 with acetyl
chloride revealed absorption bands at m ¼ 2220, 1692,
and 1638 cmꢀ1 due to cyano and two carbonyl groups,
When the resulting iminophosphorane 2 reacted with
phenylisocyanate, triphenylphosphine oxide was formed. On
addition of primary amines in dry ethylene chloride in pres-
ence of a catalytic amount of NaOEt at room temperature to
the carbodiimide function, heterocyclization occurred via
nucleophilic displacement of the ester ethoxide group to give
the corresponding pyrimido[5,4-c]pyridazine.
1
respectively. Moreover, its H-NMR spectrum revealed
a signal at d 2.11 corresponding to CH3, in addition to
the phenyl H multiplet at d 7.17–7.89.
While two isomeric pyrimido[5,4-c]pyridazine 5 and
6 may be produced in the reaction of iminophosphorane
Journal of Heterocyclic Chemistry
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390
M. A. Barsy, E. A. El Rady, and M. A. Ismael
Vol 49
strong bands at m ¼ 3320–3129 cmꢀ1, attributed to the NH
Scheme 2
group, and a C¼¼O absorption band at 1682–1695 cmꢀ1
.
The reaction of iminophosphorane 12 with phenyliso-
cyanate and dimethylamine at room temperature resulted
in the formation of triphenylphosphine oxide and the
corresponding guanidine-type intermediate 16, and in
the presence of NaOEt, 16 underwent intramolecular
heterocyclization across the electrophilic ester function-
ality to give the fused pyrimidine 15f (Scheme 3).
The next step of this study was the preparation of
thiino[2,3-d]oxazine by an initial aza-Wittig reaction
between the phosphazine 12 and alkanoyl or aroyl chlor-
ides and subsequent heterocyclization. Chloroimidoyl
derivatives 17 are assumed to be the key intermediates
in the consecutive reactions even though they could not
be detected due to its high reactivity, these reactive
intermediates were cyclized to give 18 then 19 through
elimination of ethyl chloride (Scheme 4).
Similarly, the aza-Wittig reaction of iminophosphor-
ane 2 with benzoyl chloride under the same reaction
conditions furnished pyridazino[4,3-d]oxazine 10b.
Formation of 10 proceeds via aza-Wittig reaction
between iminophosphorane 2 with acid chloride to yield
imidoyl chloride intermediate 8 [51–53]. The newly
generated amidoyl carbon atom of the later is then
attacked by ester ethoxy group forming the thermody-
namically favored six-membered ring intermediate 9.
Elimination of alkyl halide afforded the stable pyrida-
zino[4,3-d]oxazine 10 (Scheme 2).
The b-enamino ester (6-amino-5-ethoxycarbonyl-3-
phenyl thiinthione) (11) [54] was converted to the imi-
nophosphorane 12 on reaction with the triphenylphos-
phine/triethylamine/hexachloroethane reagent system
[48,49], this phosphazine was isolated as stable com-
pound in good yield (83%) and can be used as synthetic
intermediate of new substituted thiinopyrimidines 15 by
a domino processes involving an aza-Wittig reaction/
heterocyclization.
EXPERIMENTAL
Melting points were determined on a Gallenkamp electro-
thermal melting point apparatus and are uncorrected, IR spec-
tra were recorded as potassium bromide pellets using a FTIR
unit Bruker-vector 22 spectrophotometer, 1H- and 13C-NMR
spectra were obtained in deuterated dimethyl sulfoxide as
solvent at 300 MHz and 75 MHz, respectively, on a Varian
Gemini NMR spectrometer using TMS as internal standard.
Chemical shifts are reported in d units (ppm). Mass spectra
were recorded on a Hewlett Packard MS-5988 spectrometer at
70 eV. Elemental analysis was carried out at the Microanalytical
Center of Cairo University, Egypt.
Ethyl-5-cyano-4-(triphenylphosphoranylideneamino)-6-oxo-
1-phenyl-1,6-dihydropyridazine-3-carboxylate (2). To
stirred mixture of 1 (0.284 g, 1.0 mmol), hexachloroethane
(0.473 g, 2.0 mmol, 1.0 eq.) and triphenylphosphine (0.52 g,
2.0 mmol, 1.0 eq.) in benzene (50.0 mL) triethylamine (0.4
mL, 4.0 mmol, 2.0 eq.) was added dropwise. The resultant
a
Scheme 3
Structure of 12 was confirmed based on spectral data
and elemental analysis. For example, its mass spectrum
revealed a molecular ion peak at m/z 551. Moreover, its
IR spectrum showed the absence of absorption band cor-
responding to amino group. The reaction pattern of com-
pound 12 is indicated in Scheme 3. The first step in the
reaction sequence was the aza-Wittig-type reaction
between iminophosphorane and phenylisocyanate to pro-
vide triphenylphosphine oxide and carbodiimide moiety
13 as a highly reactive intermediate. This reactive
cumulene in turn reacts with primary amines in presence
of catalytic amounts NaOEt to give the guanidine 14
followed by heterocyclization to afford the thiino[2,3-
d]pyrimidine 15.
The mass spectra of compounds 15 showed the
expected molecular ion peaks and the IR spectra showed a
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Efficient Synthesis of Pyrimido[5,4-c]pyridazines and of Thiino[2,3-d]pyrimidines
Based on an Aza-Wittig Reaction/Heterocyclization Strategy
391
Scheme 4
35%). Anal Calcd for C25H24N6O2 (440.51): C, 68.17; H,
5.49; N, 19.08; Found: C, 67.76; H, 5.37; N, 18.94.
4-Cyano-2,7-diphenyl-6-(n-octylamino)-pyrimido[5,4-c]pyrid-
azine-3,8-dione 5d. White crystals from ethanol; yield: 318 mg
(68%); mp: 251–53ꢁC, ir: m 3280 (NH), 2215 (CN), 1707,
1699 (CO) cmꢀ1 1H-NMR (DMSO) d: 1.10 (t, 3H, CH3),
;
3.20–3.45 (m, 2H, NCH2), 4.18 (br, 1H, NH), 4.30–4.61 (m,
12H, 6CH2), 7.26–7.79 (m, 10H, Ar-H); ms: m/z ¼ 468 (Mþ,
15%). Anal Calcd for C27H28N6O2 (468.56): C, 69.21; H,
6.02; N, 17.94; Found: C, 69.07; H, 5.87; N, 17.82.
4-Cyano-2,7-diphenyl-6-(phenylmethylamino)-pyrimido[5,4-c]-
pyridazine-3,8-dione 5e. White crystals from ethanol; yield:
307 mg (68%); mp: 160–62ꢁC, ir: m 3270 (NH), 2215 (CN),
1
1710, 1698 (CO) cmꢀ1; H-NMR (DMSO) d: 4.50 (d, J ¼ 5.7
Hz, 2H, NCH2), 4.70 (br, 1H, NH), 7.19–7.58 (m, 15H, Ar-H);
ms: m/z ¼ 446 (Mþ, 55%). Anal Calcd for C26H18N6O2
(446.47): C, 69.95; H, 4.06; N, 18.82; Found: C, 69.83; H,
3.96; N, 18.72.
solution was heated at reflux for 1.5 h. The mixture was fil-
tered while still hot to remove the precipitates and the filtrate
was evaporated under reduced pressure to give a solid product
which was crystallized from ethanol as white crystals; yield:
528 mg (97%); mp: 189–91ꢁC, ir: m 2221 (CN), 1657 (CO)
4-Cyano-2,7-diphenyl-6-(dimethylamino)-pyrimido[5,4-c]-
pyridazine-3,8-dione 5f. White crystals from ethanol; yield:
272 mg (71%); mp: 175–77ꢁC, ir: m 2217 (CN), 1720, 1715
cmꢀ1 1H-NMR (DMSO) d: 1.35 (t, 3H, CH3), 4.45 (q, 2H,
;
CH2), 7.30–7.81 (m, 20H, Ar-H); 13C-NMR: d ¼ 165.9, 164,
163, 155, 137, 129, 124, 121, 61.5, 13.9; ms: m/z ¼ 544 (Mþ,
31%). Anal Calcd for C32H25N4O3P (544.55): C, 70.58; H,
4.63; N, 10.29; Found: C, 70.64; H, 4.33; N, 10.17.
(CO) cmꢀ1 1H-NMR (DMSO) d: 1.61 (s, 6H, 2CH3), 7.19–
;
7.58 (m, 10H, Ar-H); ms: m/z ¼ 384 (Mþ, 65%). Anal Calcd
for C21H16N6O2 (384.40): C, 65.62; H, 4.20; N, 21.86; Found:
C, 65.86; H, 4.47; N, 21.55.
6-Alkylamino-4-cyano-2,7-diphenylpyrimido[5,4-c]pyrid-
azine-3,8-diones 5a–e. General procedure: To a solution of
iminophosphorane 2 (1.6 g, 3 mmol) in dry methylene dichlor-
ide (20 mL) was added phenyl isocyanate (0.36 g, 3 mmol)
under nitrogen at room temperature. After the reaction mixture
was stood for 24 h at 0–5ꢁC, alkylamine was added to the
reaction solution and stirred for 1 h. Then the solvent was
removed off under reduced pressure and 25 mL of anhydrous
ethanol and 1.5 mL of sodium ethoxide in ethanol (3M) were
added to the mixture. After stirring for 3–4 h, the solid formed
was removed off. Concentrating the residue under reduced
pressure, and cooling, furnishing a white solid which was puri-
fied by crystallization.
Preparation of the pyridazino[4,3-d]oxazinones 10 a,b. To a
solution of iminophosphorane 2 (10 mmol) in acetonitrile (15
mL) was added acid chloride (12 mmol) and triethylamine
(0.29 g, 20 mmol) under nitrogen. The resultant solution was
heated at reflux for 3 h. After cooling, the white precipitate
ammonium salt was separated by filtration. The filtrate was
concentrated, the residue was recrystallized from ethanol.
4-Cyano-6-methyl-2-phenyl-2H-pyridazino[4,3-d][1,3]oxazine-
3,8-dione 10a. White crystals from ethanol; yield: 193 mg
(69%); mp: 220–22ꢁC, ir: m 2220 (CN), 1692, 1638 (CO)
1
cmꢀ1; H-NMR (DMSO) d: 2.11 (s, 3H, CH3), 7.17–7.89 (m,
5H, Ar-H); ms: m/z ¼ 282 (M þ 2, 69%). Anal Calcd for
C14H8N4O3 (280.24): C, 60.00; H, 2.88; N, 19.99; Found: C,
60.26; H, 2.77; N, 19.78.
4-Cyano-2,7-diphenyl-6-ethylamino-pyrimido[5,4-c]pyridazine-
3,8-dione 5a. White crystals from ethanol; yield: 288 mg
(75%); mp: 232–34ꢁC, ir: m 3220 (NH), 2217 (CN), 1703,
4-Cyano-2,6-diphenyl-2H-pyridazino[4,3-d][1,3]oxazine-3,8-
dione 10b. White crystals from ethanol; yield: 214 mgꢀ(167%);
1690 (CO) cmꢀ1
;
1H-NMR (DMSO) d: 1.10 (t, J ¼ 7.2 Hz,
mp: 234–36ꢁC, ir: m 2219 (CN), 1697, 1649 (CO) cm
;
1H-
3H, CH3), 3.33–3.40 (m, 2H, NCH2), 4.14 (br, 1H, NH), 7.26–
7.74 (m, 10H, Ar-H); ms: m/z ¼ 384 (Mþ, 70%). Anal Calcd
for C21H16N6O2 (384.40): C, 65.62; H, 4.20; N, 21.86; Found:
C, 65.41; H, 4.07; N, 21.73.
NMR (DMSO) d: 7.17–7.88 (m, 10H, Ar-H); ms: m/z ¼ 344
(M þ 2, 67%). Anal Calcd for C19H10N4O3 (342.31): C,
66.67; H, 2.94; N, 16.37; Found: C, 66.29; H, 2.67; N, 15.98.
5-Ethoxycarbonyl-3-phenyl-6-(triphenylphosphoranylide-
neamino)-thiin-2-thione 12. To a stirred mixture of 11 (0.291
g, 1.0 mmol), hexachloroethane (0.473 g, 2.0 mmol, 1.0 eq.)
and triphenylphosphine (0.52 g, 2.0 mmol, 1.0 eq.) in anhy-
drous benzene (50.0 mL) triethylamine (0.4 mL, 4.0 mmol, 2.0
eq.) was added dropwise. The resultant solution was heated at
reflux for 2 h. The mixture was filtered while still hot to
remove the precipitates and the filtrate was evaporated under
reduced pressure to give crystals which was recrystallized
from ethanol as white crystals; yield: 457 mgꢀ1(83%); mp:
4-Cyano-6-(n-butylamino)-2,7-diphenyl-pyrimido[5,4-c]pyrid-
azine-3,8-dione 5b. White crystals from ethanol; yield: 301 mg
(73%); mp: 130–32ꢁC, ir: m 3320 (NH), 2210 (CN), 1707,
1695 (CO) cmꢀ1
;
1H-NMR (DMSO) d: 0.98 (t, J ¼ 7.7 Hz,
3H, CH3), 1.30–1.53 (m, 4H, 2CH2), 3.33 (m, 2H, NCH2),
4.14 (br, 1H, NH), 7.26–7.74 (m, 10H, Ar-H); ms: m/z ¼ 412
(Mþ, 55%). Anal Calcd for C23H20N6O2 (412.45): C, 66.98;
H, 4.89; N, 20.38; Found: C, 66.84; H, 4.76; N, 20.23.
4-Cyano-2,7-diphenyl-6-(n-hexylamino)-pyrimido[5,4-c]pyrid-
azine-3,8-dione 5c. White crystals from ethanol; yield: 308 mg
(70%); mp: 197–99ꢁC, ir: m 3230 (NH), 2217 (CN), 1710,
173–75ꢁC, ir: m 1699 (CO), 1159 (C¼¼S) cm
;
1H-NMR
(DMSO) d: 1.34 (t, 3H, CH3), 4.19 (q, 2H, CH2), 7.26–7.82
(m, 21H, Ar-H and thiin-c-proton); ms: m/z ¼ 551 (Mþ, 89%).
Anal Calcd for C32H26NO2S2P (551.66): C, 69.68; H, 4.75; N,
2.54; Found: C, 69.32; H, 4.49; N, 2.39.
1697 (CO) cmꢀ1 1H-NMR (DMSO) d: 1.32 (t, 3H, CH3),
;
2.10–2.40 (m, 8H, 4 CH2), 3.33–3.43 (m, 2H, NCH2), 4.26
(br, 1H, NH), 7.28–7.94 (m, 10H, Ar-H); ms: m/z ¼ 440 (Mþ,
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M. A. Barsy, E. A. El Rady, and M. A. Ismael
Vol 49
64.42; H, 4.38; N, 10.73; S 16.38; Found: C, 64.23; H, 4.15;
N, 10.93; S 16.49.
2-Alkylamino-3,6-diphenyl-7-thioxo-3H-thiino[2,3-d]pyrimi-
dine-4-one 15a–e. General procedure: To a solution of imino-
phosphorane 12 (3 mmol) in dry methylene dichloride (20 mL)
was added phenyl isocyanate (0.36 g, 3 mmol) under nitrogen at
room temperature. After the reaction mixture was stood for 24 h
at 0–5ꢁC, alkyl amine was added to the reaction solution and
stirred for 1 h. Then the solvent was removed off under reduced
pressure and 25 mL of anhydrous ethanol and 1.5 mL of sodium
ethoxide in ethanol (3M) were added to the mixture. After stirring
for 3–4 h, the solid formed was removed off. Concentrating the
residue under reduced pressure, and cooling, furnishing an orange
solid which was purified by crystallization.
Preparation of thiino[4,3-d]oxazinones 19 a,b. To a solu-
tion of iminophosphorane 12 (10 mmol) in acetonitrile (15
mL) was added acid chloride (12 mmol) and triethylamine
(0.29 g, 20 mmol) under nitrogen. The resultant solution was
heated at reflux for 2 h. After cooling, the white precipitate
ammonium salt was separated by filtration. The filtrate was
concentrated, the residue was recrystallized from ethanol/meth-
ylene chloride (1:1) mixture.
2-Methyl-6-phenyl-7-thioxo-7H-thiino[2,3-d[1,3]oxazin-4-one
19a. Deep red crystals from ethanol; yield: 192 mg (67%);
1
mp: 136–38ꢁC, ir: m 1699, 1648 (CO), 1158 (C¼¼S) cmꢀ1; H-
2-Ethylamino-3,6-diphenyl-7-thioxo-3H-thiino[2,3-d]pyrimi-
dine-4-one 15a. Orange crystals from ethanol; yield: 264 mg
(67%); mp: 157–59ꢁC, ir: m 3320 (NH), 1682 (CO), 1148
NMR (DMSO) d: 2.12 (s, 3H, CH3), 7.19–7.90 (m, 6H, Ar-H
and thiin-c-proton); ms: m/z ¼ 287 (Mþ, 35%). Anal Calcd for
C14H9NO2S2 (287.35): C, 58.52; H, 3.16; N, 4.87; S 22.31;
Found: C, 58.26; H, 3.17; N, 4.76; S 22.42.
(C¼¼S) cmꢀ1
;
1H-NMR (DMSO) d: 1.23 (t, 3H, CH3), 4.14
(m, 2H, NCH2), 4.32 (br, 1H, NH), 7.30–7.81 (m, 11H, Ar-H
and thiin-c-proton); ms: m/z ¼ 392 (M þ 1, 43%). Anal Calcd
for C21H17N3OS2 (391.51): C, 64.43; H, 4.38; N, 10.73; S
16.29; Found: C, 64.22; H, 4.37; N, 10.37; S 16.55.
2,6-Diphenyl-7-thioxo-7H-thiino[2,3-d[1,3]oxazin-4-one
19b. Deep red crystals from ethanol; yield: 231 mg (66%);
1
mp: 140–42ꢁC, ir: m 1699, 1658 (CO), 1155 (C¼¼S) cmꢀ1; H-
NMR (DMSO) d: 7.12–7.79 (m, 11H, Ar-H and thiin-c-pro-
ton); ms: m/z ¼ 349 (Mþ, 18%). Anal Calcd for C19H11NO2S2
(349.42): C, 65.31; H, 3.17; N, 4.01; S 18.35; Found: C,
65.44; H, 3.28; N, 4.36; S 18.27.
2-N-Butylamino-3,6-diphenyl-7-thioxo-3H-thiino[2,3-d]pyrim-
idine-4-one 15b. Orange crystals from ethanol; yield: 293 mg
(70%); mp: 160–161ꢁC, ir: m 3225 (NH), 1690 (CO), 1159
(C¼¼S) cmꢀ1
;
1H-NMR (DMSO) d: 1.08 (t, J ¼ 7.7 Hz, 3H,
CH3), 1.61–1.66 (m, 4H, 2CH2), 3.11 (m, 2H, NCH2), 4.16
(br, 1H, NH), 7.27–7.76 (m, 11H, Ar-H and thiin-c-proton);
ms: m/z ¼ 419 (Mþ, 59%). Anal Calcd for C23H21N3OS2
(419.56): C, 65.84; H, 5.05; N, 10.02; Found: C, 65.61; H,
5.32; N, 10.15.
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rol-Bass, D.; Bailly, C.; Aubertin, A.-M.; Condom, R. Org Biomol
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2-N-Hexylamino-3,6-diphenyl-7-thioxo-3H-thiino[2,3-d]pyrim-
idine-4-one 15c. Orange crystals from ethanol; yield: 332 mg
(74%); mp: 135–136ꢁC, ir: m 3230 (NH), 1695 (CO), 1160
1
(C¼¼S) cmꢀ1; H-NMR (DMSO) d: 1.10 (t, 3H, CH3), 2.15–2.55
[3] Ganjgee, A.; Adair, O.; Queener, S. F. J Med Chem 2003,
46, 5074; and references cited therein.
(m, 8H, 4 CH2), 3.41–3.52 (m, 2H, NCH2), 4.27 (br, 1H, NH),
7.17–7.95 (m, 11H, Ar-H and thiin-c-proton); ms: m/z ¼ 449 (M
þ 2, 5%). Anal Calcd for C25H25N3OS2 (447.62): C, 67.08; H,
5.63; N, 9.39; S 14.33; Found: C, 67.26; H, 5.47; N, 9.12; S
14.25.
[4] Ding, M.-W.; Huang, N.-Y.; He, H.-W. Synthesis 2005,
1601; and references cited therein.
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Chemistry; Ellis, G. P., West, G. B., Eds.; Elsevier Science Publishers:
Amsterdam, 1990; Vol. 27, p 1.
2-N-Octylamino-3,6-diphenyl-7-thioxo-3H-thiino[2,3-d]pyrim-
idine-4-one 15d. Orange crystals from ethanol; yield: 334 mg
(70%); mp: 160–62ꢁC, ir: m 3129 (NH), 1695 (CO), 1150
[6] Heinisch, G.; Kopelent-Frank, H. In Progress In Medicinal
Chemistry; Ellis, G. P., Luscombe, D. K., Eds.; Elsevier Science Pub-
lishers: Amsterdam, 1992; Vol. 29, p 141.
(C¼¼S) cmꢀ1
;
1H-NMR (DMSO) d: 1.32 (t, 3H, CH3), 3.12–
[7] Tisler, M.; Stanovnik, B. In Advances In Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic Press, Inc.: London, 1990;
Vol 49, p 385.
3.55 (m, 2H, NCH2), 4.11 (br, 1H, NH), 4.35–4.57 (m, 12H,
6CH2), 7.16–7.89 (m, 11H, Ar-H and thiin-c-proton); ms: m/z
¼ 476 (M þ 1, 11%). Anal Calcd for C27H29N3OS2 (475.67):
C, 68.18; H, 6.15; N, 8.83; S 13.48; Found: C, 68.28; H, 6.33;
N, 8.37; S 13.25.
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1978, 43, 2536.
3,6-Diphenyl-2-phenylmethylamino-7-thioxo-3H-thiino[2,3-d]-
pyrimidine-4-one 15e. Orange crystals from ethanol; yield: 299
mg (66%); mp: 153–55ꢁC, ir: m 3266 (NH), 1694 (CO), 1160
(C¼¼S) cmꢀ1
;
1H-NMR (DMSO) d: 4.10 (d, J ¼ 5.7 Hz, 2H,
[13] Nakagome, T.; Castle, R. N.; Murakami, H. J Heterocyclic
Chem 1968, 5, 523.
NCH2), 4.55 (br, 1H, NH), 7.19–7.58 (m, 16H, Ar-H and
thiin-c-proton); ms: m/z ¼ 454 (M þ 1, 12%). Anal Calcd for
C26H19N3OS2 (453.58): C, 68.85; H, 4.22; N, 9.26; S 14.14;
Found: C, 68.23; H, 4.15; N, 9.45; S 14.39.
[14] Palacios, F.; Alonso, C.; Amezua, P.; Rubiales, G. J Org
Chem 2002, 67, 1941; and references cited therein.
[15] Renslo, A. R.; Danheiser, R. L. J Org Chem 1998, 63, 7840.
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1992, 50, 375.
3,6-Diphenyl-2-(dimethylamino)-7-thioxo-3H-thiino[2,3-d]-
pyrimidine-4-one 15f. Orange crystals from ethanol; yield:
262 mg (67%); mp: 163–55ꢁC, ir: m 3223 (NH), 1688 (CO),
[18] Yen, T. T.; Dininger, N. B.; Broderick, C. L.; Gill, A. M.
Arch Int Pharmacodyn Ther 1990, 308, 137.
1158 (C¼¼S) cmꢀ1
;
1H-NMR (DMSO) d: 1.56 (s, 6H, 2CH3),
7.19–7.77 (m, 11H, Ar-H and thiin-c-proton); ms: m/z ¼ 392
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159.
(M þ 1, 12%). Anal Calcd for C21H17N3OS2 (391.51): C,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
Efficient Synthesis of Pyrimido[5,4-c]pyridazines and of Thiino[2,3-d]pyrimidines
Based on an Aza-Wittig Reaction/Heterocyclization Strategy
393
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