Fused pyrimidine systems: XIII. Synthesis and some transformations of 1,3-thiazolo(thiazino)-fused pyrido[3,4-d]pyrimidines

Article abstract of DOI:10.1134/S1070428014020201

2-[Allyl(propargyl)sulfanyl]pyrido[3,4-d]pyrimidin-4-ones at heating in polyphosphoric acid undergo an intramolecular cyclization with the formation of pyrido[4,3-e]thiazolo-[3,2-a]pyrimidin-5-ones of angular structure. Under similar conditions the cyclization of 2-(cinnamylsulfanyl)pyrido[3,4-d]- pyrimidin-4-one results in a linear pyrido[3?,4?:4,5]pyrimido-[2,1-b][1,3] thiazin-6-one. The iodocyclization of the same substrates affords the corresponding 9-(iodomethyl)(iodomethylidene)pyrido[4,3-e][1,3]thiazolo-[3,2-a] pyrimidin-5-ones and 3-iodopyrido[3?,4?:4,5]pyrimido[2,1-b][1,3]thiazin-6-one of angular structure. 9-(Iodomethyl)-8,9-dihydro-5H-pyrido[4,3-e][1,3]thiazolo[3, 2-a]pyrimidin-5-one treated with sodium azide gave 9-(azidomethyl) derivative whose cyclization with substituted alkynes in the presence of copper compounds provided pyrido [4,3-e][1,3]thiazolo[3,2-a]pyrimidinylmethyltriazoles.

Full text of DOI:10.1134/S1070428014020201

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 2, pp. 263−270. © Pleiades Publishing, Ltd., 2014.
Original English Text © I.V. Dyachenko, R.I. Vas’kevich, M.V. Vovk, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 2, pp. 270−277.
Fused Pyrimidine Systems: ХIII.*
Synthesis and Some Transformations
of 1,3-Thiazolo(thiazino)-fused Pyrido[3,4-d]pyrimidines
I. V. Dyachenko, R. I. Vas’kevich, and M. V. Vovk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Kiev, 02094 Ukraine
e-mail: vaskevich@ioch.kiev.ua
Received November 5, 2013
Abstract—2-[Allyl(propargyl)sulfanyl]pyrido[3,4-d]pyrimidin-4-ones at heating in polyphosphoric acid
undergo an intramolecular cyclization with the formation of pyrido[4,3-e]thiazolo-[3,2-a]pyrimidin-5-
ones of angular structure. Under similar conditions the cyclization of 2-(cinnamylsulfanyl)pyrido[3,4-d]-
pyrimidin-4-one results in a linear pyrido[3',4':4,5]pyrimido-[2,1-b][1,3]thiazin-6-one. The iodocyclization
of the same substrates affords the corresponding 9-(iodomеthyl)(iodomethylidene)pyrido[4,3-е][1,3]thiazolo-
[3,2-а]pyrimidin-5-ones and 3-iodopyrido[3',4':4,5]pyrimido[2,1-b][1,3]thiazin-6-one of angular structure.
9-(Iodomethyl)-8,9-dihydro-5Н-pyrido[4,3-е][1,3]thiazolo[3,2-а]pyrimidin-5-one treated with sodium
azide gave 9-(azidomethyl) derivative whose cyclization with substituted alkynes in the presence of copper
compounds provided pyrido[4,3-e][1,3]thiazolo[3,2-а]pyrimidinylmethyltriazoles.
DOI: 10.1134/S1070428014020201
Derivatives of pyrido[3,4-d]pyrimidin-4-one (7-aza-
quinazolin-4-one) belong to the pharmacologically
promising type of fuzed diazine systems as proved by
finding in this series compounds with malaricidal [2, 3],
antitumor [4–7], antidiabetes [8], and also antiarthritis
[9] action. To provide the pyridopyrimidine scaffold with
the cited properties the pyridine ring is as a rule modi-
fied with versatile linear biophore fragments. Its cyclo-
functionalization has not been investigated up till now,
although in the literature several examples are described
of compounds with fused at the a side of the pyrimidine
ring isoindole [10,11], imidazole [12], and pyridine [13,
14] structures where the tricyclic system is built in the
stage of pyrimidine scaffold formation. Note that among
this type of fused pyridopyrimidine derivatives 8-(trifluo-
romethoxy)indolo[2,1-b]-3-azo-quinazolin-6,12-dione
[11] exhibits a pronounced tuberculocidal effect.
cient method to this end we regarded the intramolecular
electrophilic cyclization of its 2-S-alkenyl, alkynyl,
and cinnamyl derivatives. This type approach was suc-
cessfully used before for electrophilic cyclization of
the corresponding 2-S-alkenyl(alkynyl)-functionalized
quinazolones [15–17], thieno[2,3-d]pyrimidones [15, 18,
19], and pyrazolo[3,4-d]-pyrimidones [20, 21]. Unlike the
mentioned fused pyrimidones their pyrido fused analogs
considered in our study are characterized by reduced
basicity of nitrogen atoms due to the electron-deficiency
of the pyridine ring. We believe that this fact should es-
sentially affect both the conditions and the regiochemistry
of the cyclization reaction.
The selected as main objects of the study previously
unknown 2-(allyl- (ІІа), propargyl- (ІІb) and
cinnamyl- (ІІc) sulfanyl)pyrido[3,4-d]pyrimidin-4-
ones were synthesized by alkylation of 2-thioxo-2,3-
dihydropyrido[3,4-d]pyrimidin-4-one (I) with allyl
bromide, propargyl bromide, and cinnamyl chloride
respectively.
We believe that the development of a convenient
synthetic approach to new tricyclic systems underlain
by pyrido[3,4-d]pyrimidin-4-one is important. As effi-
_____________
First experiments of compounds IІа–IIc cyclization
* For Communication XII, see [1].
under the treatment with sulfuric acid showed the
263

DYACHENKO et al.
264
inefficiency of the latter. Therefore we used as proton-
donor reagent and environment the polyphosphoric acid
(PPA) which we had formerly successfully used in the
cyclization of styrylacetic acids amides [22].
one bond (HMQC) and through 2–3 bonds (НMВСGP),
which made it possible to obtain unambiguous assumption
of the signals of the protonated and nodal carbon atoms
respectively.
It was established that 2-(allyl- and propargylsulfanyl)-
pyrido[3,4-d]pyrimidines IIа, IIb at the action of PPA at
110°C underwent intramolecular cyclization forming
pyrido[4,3-e]thiazolo[3,2-a]pyrimidin-5-ones of angular
structure ІII, ІV. This behavior fundamentally differed
from those of the corresponding quinazolones and
thieno[2,3-d]pyrimidones [15,18], which in the reaction
with sulfuric acid gave thiazolo fused products of linear
structure. Yet in the case of 2-(cinnamylsulfanyl)-
pyrido[3,4-d]pyrimidine (IIc) the cyclization took
another route leading to the formation of pyrido[3',4':4,5]-
pyrimido[2,1-b][1,3]thiazin-6-one (V).
The correlation between the Н4 atom of the thiazine
ring (6.23 ppm) and atom С6 of the pyrimidin-4-one
ring (159.92 ppm) indicates the linear structure of this
polycyclic compound. An interesting feature of the
НMВСGPspectrum is the absence of correlation between
the proton Н7 of pyridine ring (δ 7.85 ppm) and atom С6
removed from it by 3 chemical bonds. It is most likely
because the coupling constant between these atoms is
close to zero. Similar situation was formerly observed in
the other compounds of analogous structure [20].
1
The assignments of the signals in Н and 13С NMR
spectra and also the principal correlations in the НMВС
spectrum of compound V are shown in the figure.
The angular structure of compound III was proved
using the method of homonuclear correlation in 1Н NMR
spectroscopy. At the irradiation of proton Н1 its coupling
was observed with proton Н9 (20%) and the protons of
methyl group (2%). The structure of compound ІV was
confirmed by the data of 13С and IR spectra where like
in the IR spectrum of compound IІI the absorption of
the carbonyl group was observed in the region 1640–
1660 cm–1, and the chemical shift of the carbonyl carbon
atom appeared in the 13С NMR spectrum at 169–170 ppm.
Iodocyclization of compounds ІIа–IIc was carried
out along the previously approved general procedure [23]
involving the use of 3-fold excess of iodine in chloroform
and the subsequent treatment of the primary formed
product first with sodium iodide and later with sodium
acetate. The yield of the isolated products of angular
structure VI–VIII depended essentially on the character
of the initial substrate: 69 (VI), 40 (VII), 20% (VIII).
The characteristic feature of compound VIII
consists in the tendency of its thiazine fragment to
suffer contraction at high temperature. Maintaining
The structure of compound V was established based on
the method of heteronuclear 13С–1Н correlation through
O
N
R =
N
N
S
III
O
N
O
O
N
R =
PPA
RHlg
NH
NH
N
_
S
MeONa MeOH
N
R
N
N
IIa_IIc
S
N
H
S
IV
I
O
Ph
S
Ph
R =
N
N
N
V
Ph
(c)
.
,
(a)
,
(b)
R =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 2 2014

FUSED PYRIMIDINE SYSTEMS: ХIII.
265
its structure a iodomethyl group capable of further
transformations. When treated with sodium acetate in
DMF it suffers dehydrohalogenation to give 9-methylene
derivative X. Reactions with sodium azide or thiocyanate
in DMF at 60°С proceed as nucleophilic substitution
and result in the corresponding 9-[thiocyanato(azido)
methyl] derivatives XI, ХII, and in the latter case
dehydroiodination product X also forms in 15% yield
(Scheme 1).
In compound VII containing an exocyclic iodo-
methylene group we also succeeded to replace the iodine
for azido group. Probably compound VII first underwent
the prototropic isomerization into intermediate А that
then suffered the nucleophilic substitution with sodium
azide (Scheme 2).
Correlations in НMВСGP spectrum of 4-phenyl-3,4-dihydro-
2Н,6Н-pyrido[3',4':4,5]pyrimido[2,1-b][1,3]thiazin-6-one (V).
compound VIII at 60оС in a mixture DMSO–ethanol,
1 : 1, for 30 min leads to the formation of 8-(iodomethyl)
pyrido[4,3-е][1,3]thiazolo[3,2-а]pyrimidin-5-one (IX).
Similar conversion was formerly found for 1,3-thiazinо
fused thieno(pyrazolo)pyrimidines [19, 21].
The structure of compound XIII is confirmed by the
1
presence in the Н NMR spectrum of singlets from the
endocyclic proton Н8 at 7.57 ppm and from the exocyclic
methylene group at 5.16 ppm.
The structure of angular tricyclic systems VI–IX
was confirmed by their IR spectra where the stretching
vibrations of the carbonyl groups appeared in the region
1650–1655 cm–1 [18–22], as well as by the 13С NMR
spectra where the signal of the carbon atom of the
carbonyl group C=O was observed at 170 ppm.
Lately the reaction of 1,3-dipolar addition of azides
to alkynes catalyzed by copper has been applied to the
preparation of triazole-containing biologically active
compounds [24–26]. Heterylmethyl azides ХII, ХIIІ
in this kind reaction undergo [3+2]-cycloaddition with
substituted acetylenes ХIVа, XIVb at room temperature
in the mixture THF–water in the presence of copper
9-(Iodomethyl)-8,9-dihydro-5Н-pyrido[4,3-е]-
[1,3]thiazolo[3,2-а]pyrimidin-5-one (VI) contains in
O
N
N
N
S
I
VI
O
3I
N
2
_
IIa–IIc
IIà
NaI, NaOAc
N
N
I
S
VII
O
N
O
N
N
N
N
N
S
S
Ph
VIII
Ph
I
I
IX
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 2 2014

DYACHENKO et al.
266
Scheme 1.
O
N
O
N
AcONa
KSCN
N
N
VI
N
N
S
S
NaN
3
N
S
X
XI
O
N
X
+
N
N
S
N3
XII
Scheme 2.
O
O
NaN
N
3
DMF
N
S
VII
N
N
N
S
N
N3
I
XIII
A
Scheme 3.
R = CH2OH (а), CO2Me (b).
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FUSED PYRIMIDINE SYSTEMS: ХIII.
267
9-Methyl-8,9-dihydro-5Н-pyrido[4,3-e][1,3]-
thiazolo[3,2-а]pyrimidin-5-one (III), 9-methyl-5Н-
pyrido[4,3-e][1,3]thiazolo[3,2-а]pyrimidin-5-one (IV),
and 4-phenyl-3,4-dihydro-2Н,6Н-pyrido[3',4':4,5]-
pyrimido[2,1-b][1,3]thiazin-6-one (V). 2 mmol of
compound IIа–IIc was heated at stirring in 12 g of PPA
at 110 (IIа), 160 (IIb), and 130°С (IIc) for 30–45 min.
The solution was cooled, poured on ice, neutralized with
sodium hydrogen carbonate, the reaction product was
extracted into dichloromethane. The organic layer was
separated, dried with magnesium sulfate, and evaporated.
The residue was crystallized from an appropriate solvent.
sulfate and sodium ascorbate providing pyrido[4,3-e]-
[1,3]thiazolo[3,2-а]pyrimidinylmethyltriazole systems
ХVа, XVb, XVI (Scheme 3).
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer
Bruker Vertex 70 from pellets with KBr. 1Н and 13С NMR
spectra of compounds II–XVI were registered on a
spectrometer Varian VXR-400 (399.97 and 125.74 MHz,
respectively), internal reference TMS. GC-MS spectra of
compounds ХVа, XVb, XVI were obtained on an instru-
ment Agilent 1100/DAD/HSD/VLG119562.
Compound III. Yield 0.28 g (64%), mp 225–227°С
(ethanol). IR spectrum ν, cm–1: 1660, 1580, 1520, 1450,
1390, 1300, 1260, 1200, 1170, 1130, 1100, 1080, 900,
860, 810, 710. 1Н NMR spectrum, δ, ppm: 1.43 d (3Н,
СН3, J 4.8 Hz), 3.33–3.36 m (1Н, СН), 3.89–3.94 m (1Н,
СН), 5.52–5.59 m (1Н, СН), 7.86 d (1Н, Н4, J 4.0 Hz),
8.64 d (1Н, Н3, J 3.2 Hz), 9.05 s (1Н, Н1). 13С NMR
spectrum, δ, ppm: 17.41 (СН3), 34.1 (С8), 58.41 (С9),
120.09 (С4), 123.06 (С4a), 134.49 (С10a), 139.83 (С1),
145.70 (С3), 166.08 (С6a), 169.7 (С5). Found, %: C 54.60;
H 4.03; N 19.02; S 14.58. C10H9N3ОS. Calculated, %:
C 54.78; H 4.14; N 19.16; S 14.62.
2-R-Sulfanyl-substituted pyrido[3,4-d]pyrimidin-
4(3Н)-ones IIа–IIc. To a solution of 0.69 g (0.03 mol)
of Na in 50 mL of methanol was added at stirring
5.38 g (0.03 mol) of 2-thioxo-2,3-dihydropyrido[3,4-d]-
pyrimidin-4(1Н)-one, then dropwise was added a solu-
tion of 0.035 mol of an appropriate halide in 10 mL of
methanol. The mixture was heated at 80–90°С for 1.5 h
and cooled; the solvent was distilled off in a vacuum.
The residue was washed with water and with methanol
and ether on the filter.
2-(Allylsulfanyl)pyrido[3,4-d]pyrimidin-4(3Н)-
one (IIа). Yield 4.14 g (63%), mp 271–273°С. 1Н NMR
spectrum, δ, ppm: 3.94 d (2Н, СН2, J 7.2 Hz), 5.18 d (1Н,
СН=, J 10.0 Hz), 5.40 d (1Н, СН=, J 17.6 Hz), 5.94–
6.04 m (1Н, СН), 7.86–7.87 m (1Н, Н4), 8.57–8.58 m
(1Н, Н3), 8.93 s (1Н, Н1), 12.93 s (1Н, NH). Found, %:
C 54.61; H 4.02; N 19.03; S 14.58. C10H9N3ОS. Calcu-
lated, %: C 54.78; H 4.14; N 19.16; S 14.62.
Compound IV. Yield 0.35 g (80%), mp 302–303°С
(methanol). IR spectrum ν, cm–1: 1640, 1565, 1505, 1470,
1450, 1365, 1280, 1150, 1010, 910, 810, 690. 1Н NMR
spectrum, δ, ppm: 2.92 s (3Н, СН3), 7.11 s (1Н, Н8),
8.06 d (1Н, Н4, J 4.8 Hz), 8.81 d (1Н, Н3, J 4.8 Hz),
9.63 s (1Н, Н1). 13С NMR spectrum, δ, ppm: 19.69
(СН3), 106.54 (С8), 120.60 (С4), 124.35 (С4а), 135.06
(С10а), 136.51 (С9), 140.16 (С1), 147.19 (С3), 163.65
(С6а), 169.3 (С5). Found, %: C 55.13; H 3.17; N 19.22;
S 14.68. C10H7N3ОS. Calculated, %: C 55.29; H 3.25;
N 19.34; S 14.76.
2-(Propargylsulfanyl)pyrido[3,4-d]pyrimidin-
4(3Н)-one (IIb). Yield 3.71g (57%), mp 230–232°С.
1Н NMR spectrum, δ, ppm: 3.23 m (1Н, СН), 4.13–
4.14 m (2Н, СН2), 7.84 d (1Н, Н4, J 4.5 Hz), 8.58 d (1Н,
Н3, J 5.0 Hz), 8.92 s (1Н, Н1), 12.99 s (1Н, NH). Found,
%: C 55.12; H 3.16; N 19.23; S 14.68. C10H7N3ОS. Cal-
culated, %: C 55.29; H 3.25; N 19.34; S 14.76.
Compound V. Yield 0.41 g (70%), mp 164–166°С
(acetone). IR spectrum ν, cm–1: 3440, 2930, 1685,
1530, 1450, 1415, 1230, 1145, 1035, 840, 800, 750,
1
700. Н NMR spectrum, δ, ppm: 2.34–2.43 m (1Н,
2-(Cinnamylsulfanyl)pyrido[3,4-d]pyrimidin-
4(3Н)-one (IIc). Yield 7.00 g (79%), mp 279–282°С.
1Н NMR spectrum, δ, ppm: 4.13 d (2Н, СН2, J 6.8 Hz),
6.40–6.49 m (1Н, СНPh), 6.78 d (1Н, СН, J 16.0 Hz),
7.23–7.26 m (1Нarom), 7.30–7.33 m (2Нarom), 7.44–7.45 m
(2Нarom), 7.87–7.88 m (1Н, Н4), 8.56–8.58 m (1Н, Н3),
9.00 s (1Н, Н1), 12.93 s (1Н, NH). Found, %: C 64.93;
H 4.36; N 14.17; S 10.77. C16H13N3ОS. Calculated, %:
C 65.06; H 4.44; N 14.23; S 10.86.
СН), 2.62–2.67 m (1Н, СН), 2.74–2.77 m (1Н, СН),
3.08–3.11 m (1Н, СН), 6.23–6.24 m (1Н, СН), 7.20 d
(2Нarom, J 6.8 Hz), 7.31–7.33 m (1Нarom), 7.36–7.38 m
(2Нarom), 7.85 d (1Н, Н4, J 4.8 Hz), 8.55 d (1Н, Н3,
J 4.8 Hz), 8.94 s (1Н, Н1). 13С NMR spectrum, δ, ppm:
23.55 (C2), 28.42 (C3), 54.30 (C4), 119.00 (C7), 124.05
(C6а), 125.95 (2Carom), 128.03 (Carom), 129.27 (2Carom),
138.64 (Carom), 142.38 (C10a), 144.99 (C10), 149.49 (C8),
157.55 (C11a), 159.92 (С6). Found, %: C 64.94; H 4.35;
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DYACHENKO et al.
268
N 14.17; S 10.78. C16H13N3ОS. Calculated, %: C 65.06;
H 4.44; N 14.23; S 10.86.
СН), 7.43–7.47 m (5Нarom), 7.93 d (1Н, Н4, J 5.0 Hz),
8.66 d (1Н, Н3, J 5.0 Hz), 8.87 s (1Н, Н1). 13С NMR
spectrum, δ, ppm: 22.59 (C9), 33.18 (C8), 65.13 (C10),
120.06 (C4), 125.45 (C4а), 126.09 (Carom), 126.79 (Carom),
130.03 (Carom), 136.57 (Carom), 136.81 (C10a), 138.50
(C1), 146.81 (C3), 163.27 (C6a), 163.53 (C5). Found, %:
C 45.54; H 2.76; I 30.09; N 9.82; S 7.53. C16H12IN3ОS.
Calculated, %: C 45.62; H 2.87; I 30.12; N 9.97; S 7.61.
9-(Iodomethyl)-8,9-dihydro-5Н-pyrido[4,3-е]-
[1,3]thiazolo[3,2-а]pyrimidin-5-one (VI), 9-(iodo-
methylene)-5-oxo-5,6,8,9-tetrahydropyrido[4,3-е]-
thiazolo[3,2-а]pyrimidin-5-one (VII), and 4-phenyl-
3-iodo-3,4-dihydro-2Н,6Н-pyrido[3',4':4,5]-
pyrimido[2,1-b][1,3]thiazin-6-one (VIII). To 9 mmol
of compound IIа–IIc in 20 mL of chloroform was
slowly added at stirring a solution of 6.86 g (27 mmol)
of iodine in 200 mL of chloroform. After 48 h the pre-
cipitated pentaiodide salt was filtered off, washed with
chloroform, hexane, and dissolved in 70 mL of acetone.
To the obtained solution was gradually added at cooling
with ice water a solution of sodium iodide in acetone.
The formed iodide precipitate was filtered off, washed
with acetone, hexane, and then it was dispersed in 5 mL
of methanol. To the obtained slurry a double excess of
sodium acetate was added, and the mixture was stirred for
8 h. The formed base VI–VIII was filtered off, washed
with water, methanol, and hexane.
8-(Iodomethyl)-9-phenyl-8,9-dihydro-5Н-
pyrido[4,3-е][1,3]thiazolo[3,2-а]pyrimidin-5-one
(IX). 0.42 g (1 mmol) of compound VIII was heated at
60°С while stirring in 10 mL of a mixture DMSO–etha-
nol, 1 : 1, for 30 min. The solution was cooled, diluted
with 10 mL of water, the formed precipitate was filtered
off, washed with water, and dried in air. Yield 0.35 g
(83%), mp 143–145°С. IR spectrum ν, cm–1: 1660, 1580,
1510, 1450, 1380, 1260, 1190, 1085, 850, 800, 750, 700.
1Н NMR spectrum, δ, ppm: 3.87–3.97 m (2Н, СН2),
4.03–4.06 m (1H, CH), 6.27 s (1H, CH), 7.35–7.44 m
(5Нarom), 7.89 d (1Н, Н4, J 4.8 Hz), 8.60 d (1Н, Н3,
J 4.8 Hz), 8.70 s (1Н, Н1). 13С NMR spectrum, δ, ppm:
12.05 (CН2I), 52.95 (C8), 68.61 (C9), 119.85 (C4), 122.84
(C4а), 125.67 (Carom), 129.07 (Carom), 129.43 (Carom),
134.36 (Carom), 136.37 (C10a), 139.55 (C1), 145.77 (C3),
165.74 (C6a), 169.16 (C5). Found, %: C 45.54; H 2.76; I
30.09; N 9.82; S 7.53. C16H12IN3ОS. Calculated, %: C
45.62; H 2.87; I 30.12; N 9.97; S 7.61.
Compound VI. Yield 2.13 g (69%), mp 194–196°С.
IR spectrum ν, cm–1: 1670, 1570, 1510, 1480, 1420, 1330,
1
1270, 1190, 1140, 1080, 830, 790. Н NMR spectrum,
δ, ppm: 3.54–3.63 m (2Н, СН2I), 3.71–3.76 m (1Н,
СН), 3.95–4.00 m (1Н, СН), 5.66–5.71 m (1Н, СН),
7.87–7.90 m (1Н, Н4), 8.66–8.69 m (1Н, Н3), 9.03 s
(1Н, Н1). 13С NMR spectrum, δ, ppm: 5.73 (СН2I), 32.47
(С8), 61.46 (С9), 120.19 (С4), 122.90 (С4a), 134.26 (С10a),
139.63 (С1), 146.09 (С3), 165.97 (С6a), 170.34 (С5).
Found, %: C 34.71; H 2.30; I 36.65; N 12.08; S 9.31.
C10H8IN3ОS. Calculated, %: C 34.80; H 2.34; I 36.77;
N 12.17; S 9.29.
9-Methylidene-8,9-dihydro-5Н-pyrido[4,3-е]-
thiazolo[3,2-а]pyrimidin-5-one (X). 0.35 g (1 mmol) of
compound VI and 0.25 g (3 mmol) of sodium acetate in
20 mL of DMF was heated at 60°С for 1 h. The solvent
was distilled off, the residue was diluted with 20 mL of
water, separated precipitate was filtered off, washed with
water and hexane. Yield 0.19 g (89%), mp 253–259°С.
IR spectrum ν, cm–1: 1680, 1570, 1520, 1470, 1440,
1370, 1280, 1250, 1210, 1175, 1100, 1065, 1040, 920,
880, 860, 800, 710. 1Н NMR spectrum, δ, ppm: 4.31 m
(2Н, СН2), 5.45 m (1Н, СН), 5.72 m (1Н, СН), 7.90 d
(1Н, Н4, J 5.1 Hz), 8.68 d (1Н, Н3, J 5.1 Hz), 9.31 s (1Н,
Н1). 13С NMR spectrum, δ, ppm: 33.17 (С8), 103.03
(СН2), 120.31 (С4), 123.66 (С4а), 133.99 (С10а), 139.98
(С1), 141.03 (С9), 146.41 (С3), 165.23 (С6а), 170.15
(С5). Found, %: C 55.17; H 3.17; N 19.26; S 14.65.
C10H7N3ОS. Calculated, %: C 55.29; H 3.25; N 19.34;
S 14.76.
Compound VII. Yield 0.78 g (40%), mp 218–220°С.
IR spectrum ν, cm–1: 1655, 1570, 1500, 1470, 1280, 1230,
1205, 1100, 900, 810, 700. 1Н NMR spectrum, δ, ppm:
4.33 m (2Н, СН2), 7.37 s (1Н, =СНI), 7.90–7.91 m (1Н,
Н4), 8.69–8.70 m (1Н, Н3), 9.27 s (1Н, Н1). 13С NMR
spectrum, δ, ppm: 36.17 (C8), 72.07 (=CНI), 120.21
(C4), 123.74 (C4а), 133.93 (C10а), 139.81 (C1), 140.27
(C9), 146.52 (C3), 164.87 (C6а), 169.95 (C5). Found, %:
C 34.87; H 1.70; I 36.85; N 12.12; S 9.23. C10H6IN3ОS.
Calculated, %: C 35.00; H 1.76; I 36.98; N 12.25; S 9.34.
Compound VIII. Yield 0.76 g (20%), mp 188–190°С.
IR spectrum ν, cm–1: 1650, 1575, 1495, 1450, 1350, 1280,
1255, 1230, 1210, 1180, 1160, 1140, 1090, 1060, 855,
800, 755, 700. 1Н NMR spectrum, δ, ppm: 3.05–3.19 m
(2H, CH2), 5.58–5.59 m (1H, CH), 6.60–6.61 m (1Н,
9-(Thiocyanatomethyl)-8,9-dihydro-5Н-pyrido-
[4,3-е]thiazolo[3,2-а]pyrimidin-5-one (XI). A mixture
of 0.35 g (1 mmol) of compound VI and 0.12 (1.2 mmol)
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FUSED PYRIMIDINE SYSTEMS: ХIII.
269
of potassium thiocyanate in 5 mL of DMF was heated at
80°С while stirring for 3 h and was left overnight at room
temperature. The solvent was distilled off, the formed oily
residue was triturated in ethyl ether. Yield 0.24 g (88%),
mp 232–235°С. IR spectrum ν, cm–1: 2165, 1650, 1580,
1505, 1450, 1390, 1290, 1240, 1200, 1085, 900, 860,
810, 710. 1Н NMR spectrum, δ, ppm: 3.56–3.65 m (2Н,
SСН2), 3.73–3.77 m (1Н, СН), 4.01–4.05 m (1Н, СН),
5.84–5.88 m (1Н, СН), 7.86 d (1H, Н4, J 4.5 Hz), 8.65 d
(1H, Н3, J 5.0 Hz), 9.02 s (1H, Н1). 13С NMR spectrum,
δ, ppm: 30.86 (СН2S), 35.35 (С8), 61.13 (С9), 113.71
(СN), 120.17 (С4), 122.97 (С4a), 134.59 (С10a), 139.43
(С1), 146.00 (С3), 166.05 (С6а), 170.47 (С5). Found, %:
C 47.72; H 2.87; N 20.17; S 23.05. C11H8N4ОS2. Calcu-
lated, %: C 47.81; H 2.92; N 20.27; S 23.21.
C10H6N6ОS. Calculated, %: C 46.51; H 2.34; N 32.54;
S 12.42.
9-[(4-Hydroxy-1Н-1,2,3-triazol-1-yl)methyl]-8,9-
dihydro-5Н-pyrido[4,3-е]thiazolo[3,2-а]-pyrimidin-
5-one (XVа), methyl 1-{(5-oxo-8,9-dihydro-5Н-
pyrido[4,3-е][1,3]thiazolo[3,2-а]-pyrimidin-9-yl)-
methyl}-1Н-1,2,3-triazolo-4-carboxylate (XVb), and
9-[(4-hydroxymethyl)-1Н-1,2,3-triazol-1-yl]-5H-
pyrido[4,3-е]thiazolo[3,2-а]pyrimidin-5-one (XVI). To
a slurry of 1 mmol of azide XII, XIII and 1.2 mmol of
acetylene derivatives in 10 mL of a mixture THF–water,
4 : 1, was added at stirring 0.79 g (4 mmol) of a freshly
prepared water solution of sodium ascorbate and then
0.50 g (2 mmol) of water solution of copper sulfate. The
reaction mixture was stirred for 24 h, and then it was
evaporated to dryness. Compounds ХVа, XVI were
extracted from the residue with 50 mL of water, the ex-
tract was evaporated, the solid residue was washed with
methanol. In the case of compound ХVb the residue was
purified by crystallization from acetone.
9-(Azidomethyl)-8,9-dihydro-5Н-pyrido[4,3-е]-
thiazolo[3,2-а]pyrimidin-5-one (XII). A mixture of
0.68 g (2 mmol) of compound VI and 0.39 g (6 mmol) of
sodium azide in 100 mL of DMF was heated at 60°С for
1.5–2 h and was left overnight at room temperature. The
solvent was distilled off in a vacuum, the resinous resi-
due was triturated in water and in methanol. The formed
precipitate containing according to GC-MS analysis 15%
of compound Х and 85% of compound XII was filtered
off, washed with water and hexane. Compound XII was
isolated by fractional crystallization from methanol. Yield
0.42 g (80%), mp 201–203°С. IR spectrum ν, cm–1: 2120,
1640, 1600, 1580, 1510, 1480, 1390, 1300, 1280, 1250,
1090, 1070, 860, 810, 710. 1Н NMR spectrum, δ, ppm:
3.50–3.53 m (1Н, СН), 3.85–3.96 m (3Н, СН + СН2N3),
5.67–5.74 m (1Н, СН), 7.87 d (1Н, Н4, J 5.2 Hz), 8.66 d
(1Н, Н3, J 5.2 Hz), 9.13 s (1Н, Н1). 13С NMR spectrum, δ,
ppm: 30.30 (C8), 51.15 (CH2N3), 60.74 (C9), 119.99 (C4),
122.68 (C4а), 134.70 (C10а), 140.12 (C1), 145.87 (C3),
166.03 (C6а), 170.75 (C5). Found, %: C 46.04; H 3.05;
N 32.18; S 12.24. C10H8N6ОS. Calculated, %: C 46.15;
H 3.10; N 32.29; S 12.32.
Compound XVа. Yield 0.25 g (79%), mp 219–221°С.
IR spectrum ν, cm–1: 3460, 3120, 1660, 1590,1510,
1480, 1395, 1350, 1300, 1090, 1050, 1015, 910, 800,
1
700. Н NMR spectrum, δ, ppm: 3.52–3.54 m (1Н,
СН), 3.93–3.97 m (1Н, СН), 4.47–4.49 m (2Н, СН2),
4.81–4.95 m (2Н, СН2), 5.19–5.21 m (1Н, ОН),
5.91–5.93 m (1Н, СН), 7.86 d (1Н, Н4, J 4.5 Hz), 8.14 s
(1Н, СHtriazole), 8.64–8.65 m (1Н, Н3), 8.98 s (1Н, Н1).
13С NMR spectrum, δ, ppm: 30.11 (C8), 49.33 (CH2),
55.48 (CH2OH), 60.82 (C9), 120.08 (C4), 122.73 (C4а),
124.78 (Ctriazole), 134.72 (C10а), 139.47 (C3), 145.85
(C1), 148.82 (Ctriazole), 166.08 (C6а), 170.58 (C5). Mass
spectrum: m/z 317 [M + 1]+. Found, %: C 49.44; H 3.78;
N 26.58; S 10.09. C13H12N6О2S. Calculated, %: C 49.36;
H 3.82; N 26.57; S 10.14. M 316.343.
Compound XVb. Yield 0.15 g (44%), mp 285–286°С.
IR spectrum ν, cm–1: 3430, 3130, 2960, 1725, 1645, 1580,
1510, 1470, 1395, 1350, 1290, 1235, 1110, 1080, 1040,
1015, 860, 805, 775, 700, 665. 1Н NMR spectrum, δ, ppm:
3.58–3.61 m (2Н, СН2), 3.84 s (3Н, OСН3), 3.94–4.00 m
(1Н, СН), 4.87–5.04 m (2Н, СН2), 5.95–5.99 m (1Н, СН),
7.94–7.95 m (1Н, Н4), 8.65–8.69 m (1Н, Н3), 8.98 s (1Н,
Н1), 9.01–9.17 m (1Н, СHtriazole). 13С NMR spectrum, δ,
ppm: 29.99 (C8), 50.03 OCH3), 52.36 (CH2), 60.44 (C9),
120.57 (C4), 122.71 (C4a), 131.34 (Ctriazole), 133.92 (C10а),
139.14 (Ctriazole), 139.54 (C3), 145.88 (C1), 161.00 [C(O)
O], 166.06 (C6а), 170.59 (C5). Mass spectrum: m/z 345
[M + 1]+. Found, %: C 48.70; H 3.47; N 24.30; S 9.22.
9-(Azidomethyl)-5H-pyrido[4,3-е]thiazolo[3,2-а]-
pyrimidin-5-one (XIII) was obtained analogously to
compound XII. Yield 0.36 g (70%), mp 189–192°С. IR
spectrum ν, cm–1: 3430, 3055, 2107, 1645, 1565, 1515,
1440, 1370, 1280, 1145, 1015, 910, 795. 1Н NMR spec-
trum, δ, ppm: 5.16 s (2Н, СН2), 7.57 s (1Н, Н8), 8.05 d
(1Н, Н4, J 3.5 Hz), 8.81 d (1Н, Н3, J 3.5 Hz), 9.35 s (1Н,
Н1). 13С NMR spectrum, δ, ppm: 49.12 (CН2N3), 112.28
(C8), 120.58 (C4), 124.15 (C4а), 133.92 (C10а), 134.23
(C9), 140.43 (C1), 147.44 (C3), 163.61 (C6а), 169.37
(C5). Found, %: C 46.48; H 2.30; N 32.41; S 12.28.
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DYACHENKO et al.
270
9. Li, J.J., Nahra, J., Johnson, A.R., Bunker, A., O’Brien, P.,
Yue, W.S., Ortwine, D.F., Man, C.F., Baragi, V., Kilgore, K.,
Dyer, R.D., and Han, H.K., J. Med. Chem., 2008, vol. 51,
no. 4, p. 835.
10. Servais, A., Azzouz, M., Lopes, D., Courillon, C., and
Malacria, M., Angew. Chem., 2007, vol. 46, no. 4, p. 576.
11. Hwang, J.M., Oh, T., Kaneko, T., Upton, A.M., Franzb-
lau, S.G., Ma, Z., Cho, S.N., and Kim, P., J. Nat. Prod.,
2013, vol. 76, p. 354.
12. Larraufie, M.H., Ollivier, C., Fensterbank, L., Malacria, M.,
and Lacote, E., Angew. Chem., 2010, vol. 49, p. 2178.
13. Bentabed-Ababsa, G., Cheikh, Sid, Ely, S., Hesse, S.,
Nassar, E., Chevallier, F., Nguyen, T.T., Derdour, A., and
Mongin, F., J. Org. Chem., 2010, vol. 75, no. 3, p. 839.
14. Dunn, A.D., Kinnear, K.I., and Norrie, R., Z. Chem., 1986,
vol. 26, no. 8, p. 290.
C14H12N6О3S. Calculated, %: C 48.83; H 3.51; N 24.41;
S 9.31. M 344.354.
Compound XVI. Yield 0.21 g (67%), mp 238–242°С.
IR spectrum ν, cm–1: 3375, 3070, 1650, 1565, 1515,
1430, 1355, 1280, 1225, 1130, 1050, 795, 690. 1Н NMR
spectrum, δ, ppm: 4.53 m (2Н, СН2OH), 5.25 m (1H,
ОH), 6.37 m (2H, CH2), 7.16 m (1Н, Н8), 8.12–8.14 m
(2Н, Н4, Сtriazole), 8.81–8.87 m (1Н, Н3), 9.02 m (1Н,
Н1). 13С NMR spectrum, δ, ppm: 49.38 (СН2), 55.48
(CН2ОН), 112.29 (C8), 121.18 (C4), 123.74 (Ctriazole),
124.01 (C4а), 133.61 (C10а), 133.90 (C1), 140.03 (C3),
147.48 (Ctriazole), 149.28 (C9), 163.50 (C6а), 169.40 (C5).
Mass spectrum: m/z 315 [M + 1]+. Found, %: C 49.75;
H 3.18; N 26.63; S 10.14. C13H10N6О2S. Calculated, %:
C 49.68; H 3.21; N 26.74; S 10.20. M 314.327.
15. Wippich, P., Hendreich, C., Gutschow, M., and Leistner, S.,
Synthesis, 1996, p. 741.
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