Amide acetals in the synthesis of pyridothienopyrimidines

Article abstract of DOI:10.1007/s11172-010-0338-2

Methyl 3-amino-4-arylaminothieno[2,3-b]pyridine-2-carboxylates containing various substituents in the benzene ring were synthesized by the Thorpe-Ziegler reaction of 4-arylamino-2-chloropyridine-3-carbonitriles with methyl thioglycolates. The influence of the substituent in the benzene ring, acetal structure, the solvent and the process temperature on the reactions of obtained compounds with amide acetals was studied. It was established that reactions with dimethylacetamide dimethylacetal in toluene smoothly results in amidine derivatives, viz., methyl 4-arylamino-3-[1-(dimethylamino)ethylidene] aminothieno[2,3-b]pyridine-2-carboxylates, regardless of the substituent in the benzene ring. Analogous reaction of p-fluoroderivative with dimethylacetamide dimethylacetal in refluxing anhydrous ethanol leads to intramolecular cyclocondensation to produce substituted pyridothienopyrimidines, viz., 5H-1-thia-3,5,8-triazaacenaphthenes, in good yields. Amidine derivatives were the major products in the case of the coupling of aminothienopyridines with dimethylformamide dimethylacetal under the same conditions. A new approach to the synthesis of substituted pyridothienopyrimidines, viz., 3H-1-thia-3,5,8- triazaacenaphthylenes, based on the prolonged heating of methyl 4-arylamino-3-[1-(dimethylamino)ethylidene]aminothieno[2,3-b] pyridine-2-carboxylates in the excess of acetic anhydride was elaborated. Putative mechanisms of the processes concerned are given.

Full text of DOI:10.1007/s11172-010-0338-2

Russian Chemical Bulletin, International Edition, Vol. 59, No. 10, pp. 1946—1958, October, 2010
1946
Amide acetals in the synthesis of pyridothienopyrimidines
M. I. Medvedeva,a N. Z. Tugusheva,b L. M. Alekseeva,b V. V. Chernyshev,c G. V. Avramenko,a and V. G. Granikb
aD. I. Mendeleev University of Chemical Technology of Russia,
9 Miusskaya pl., 125047 Moscow, Russian Federation.
Eꢀmail: marinacasper@gmail.com
bCenter for Drug Chemistry,
Build. 3, 7 ul. Zubovskaya, 119815 Moscow, Russian Federation.
Eꢀmail: vggranik@mail.ru
cDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Eꢀmail: cher@biocryst.phys.msu.su
Methyl 3ꢀaminoꢀ4ꢀarylaminothieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylates containing various subꢀ
stituents in the benzene ring were synthesized by the ThorpeꢀZiegler reaction of 4ꢀarylaminoꢀ
2ꢀchloropyridineꢀ3ꢀcarbonitriles with methyl thioglycolates. The influence of the substituent
in the benzene ring, acetal structure, the solvent and the process temperature on the reactions
of obtained compounds with amide acetals was studied. It was established that reactions with
dimethylacetamide dimethylacetal in toluene smoothly results in amidine derivatives, viz.,
methyl 4ꢀarylaminoꢀ3ꢀ[1ꢀ(dimethylamino)ethylidene]aminothieno[2,3ꢀb]pyridineꢀ2ꢀcarbꢀ
oxylates, regardless of the substituent in the benzene ring. Analogous reaction of pꢀfluoroderivꢀ
ative with dimethylacetamide dimethylacetal in refluxing anhydrous ethanol leads to intraꢀ
molecular cyclocondensation to produce substituted pyridothienopyrimidines, viz., 5Hꢀ1ꢀthiaꢀ
3,5,8ꢀtriazaacenaphthenes, in good yields. Amidine derivatives were the major products in the
case of the coupling of aminothienopyridines with dimethylformamide dimethylacetal under
the same conditions. A new approach to the synthesis of substituted pyridothienopyrimidines,
viz., 3Hꢀ1ꢀthiaꢀ3,5,8ꢀtriazaacenaphthylenes, based on the prolonged heating of methyl
4ꢀarylaminoꢀ3ꢀ[1ꢀ(dimethylamino)ethylidene]aminothieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylates in
the excess of acetic anhydride was elaborated. Putative mechanisms of the processes concerned
are given.
Key words: 4ꢀarylaminoꢀ2ꢀchloropyridineꢀ3ꢀcarbonitriles, methyl 3ꢀaminoꢀ4ꢀarylamiꢀ
nothieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylates, amide acetals, methyl 4ꢀarylaminoꢀ3ꢀ[1ꢀ(dimethylꢀ
amino)ethylidene]aminothieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylates, pyridothienopyrimidines,
5Hꢀ1ꢀthiaꢀ3,5,8ꢀtriazaacenaphthenes, 3Hꢀ1ꢀthiaꢀ3,5,8ꢀtriazaacenaphthylenes, the Thorpeꢀ
Ziegler reaction, Xꢀray diffraction.
Numerous compounds with marked biological activity
thiophenes and various heterocyclic systems is the Thorꢀ
peꢀZiegler reaction.10,11
were found among thieno[2,3ꢀb]pyridines.1—3 In particuꢀ
lar, recently,4 thieno[2,3ꢀb]pyridine derivatives fused to
the pyrimidine ring have been shown to be potent antagoꢀ
nists of glutamate receptors.
In the present work, synthesis and some reactions of
thienopyridines containing monoꢀ and dihalogenoaniline
substituents in the position 4 were studied. This choice of
the starting compounds is not fortuitous. Firstly, it was of
interest to examine the influence of halogen atoms in the
benzene ring located at a considerable distance from the
reaction centers on the reactivity of compounds under
study. Secondly, and it is not the least of the factors, the
present work envisages subsequent study of the biological
activity of compounds synthesized and modification of
their derivatives. We take into account the fact that the
presence of halogens as the substituents usually appreciaꢀ
3ꢀAminothieno[2,3ꢀb]pyridines are convenient startꢀ
ing compounds for the synthesis of polyheterocyclic sysꢀ
tems. Earlier,5,6 aminothieno[2,3ꢀb]pyridines have been
obtained by Sꢀalkylation of 3ꢀcyanopyridineꢀ2ꢀthiones and
subsequent intramolecular ThorpeꢀZiegler cyclization.
Moreover, such thieno[2,3ꢀb]pyridines and polyheteroꢀ
cyclic systems synthesized therefrom can be obtained based
on 2ꢀchloroꢀ3ꢀcyanopyridines.7—9 The most versatile proꢀ
cedure for the synthesis of 3ꢀaminopyrroles and 3ꢀaminoꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1896—1908, October, 2010.
1066ꢀ5285/10/5910ꢀ1946 © 2010 Springer Science+Business Media, Inc.

Pyridothienopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
1947
bly increases penetration through the lipophilic biological
membranes. This fact, in turn, often causes an increase in
the biological effect.
Earlier,12 we have synthesized 4ꢀarylaminoꢀ2ꢀoxoꢀ1,2ꢀ
dihydropyridineꢀ3ꢀcarbonitriles 1a,b. Pyridones 1c,d were
prepared from 2ꢀcyanoꢀ3ꢀdimethylaminocrotonamide (2)
according to the known procedure13 via intermediate
enaminoamides 3c,d and pyrimidinones 4c,d (Scheme 1).
fluxing 2ꢀchloropyridines 5a—e with methyl thioglycolate
in the presence of sodium methoxide in methanol (see
Scheme 2). The putative mechanism of the reaction 5→6
is shown in Scheme 3.
We further investigated the reaction of obtained amiꢀ
nothiophene derivatives 6a—e with amide acetals 7a,b.
Stirring of amines 6b—e with dimethylacetamide dimethꢀ
ylacetal (7a) at 80 °C in anhydrous toluene leads unamꢀ
biguously to the corresponding amidines 8b—e in 74—93%
yields (Scheme 4). In the reaction of 6a with 7a, a mixture
of amidine 8a and pyrimidine 9a in 96 : 4 ratio (based on
1H NMR spectroscopy) was obtained.
Scheme 1
If these reactions are carried out in refluxing toluene,
resinification took place and it was possible to isolate anaꢀ
lytically pure amidines 8a—e in considerably smaller yields.
The reaction of dimethylacetamide dimethylacetal (7a)
with aminothiophenes 6a—e in anhydrous ethanol is comꢀ
plicated by transesterification and, in addition to methꢀ
oxycarbonyl compounds, ethoxycarbonyl homologs
formed (8´ and 9´, respectively) (see Scheme 4). It should
be noted that sharp difference was observed for the reacꢀ
tions of pꢀFꢀ and pꢀClꢀsubstituted derivatives in anhydrous
ethanol, other reaction conditions (the ratio of the reacꢀ
tants, the reaction time, the workꢀup of the reaction mixꢀ
ture and isolation of the products being the same). Reacꢀ
tion of pꢀchloroanilinothienopyridine 6a with acetal 7a
proceeds as expected to give a mixture of amidines 8a and
8´a. In the case of pꢀfluoroanilinothienopyridine 6b, the
reaction was not stopped at the step of formation of amidꢀ
ine 8b and subsequent cyclization to pyrimidine took place
and tricyclic compound 9b was isolated in 74% yield (crude
product, the yield of recrystallized product was 51%). The
mother liquor after isolation of the major reaction prodꢀ
ucts contained only the intramolecular condensation prodꢀ
ucts (9b and 9´b) (1H NMR data).
R1 = H, R2 = F (c); R1 = R2 = F (d)
The corresponding 2ꢀchloropyridines 5a—d were obꢀ
tained in high yields by refluxing compounds 1a—d in the
excess of phosphoryl chloride in the presence of triethyꢀ
lamine hydrochloride (Scheme 2).
Methyl 3ꢀaminoꢀ4ꢀarylaminothieno[2,3ꢀb]pyridineꢀ2ꢀ
carboxylates 6a—e were obtained (without isolation of inꢀ
termediate mercapto derivatives) in 77—94% yield by reꢀ
Analogous reaction of pꢀfluoroanilinothienopyridine
6b with dimethylacetamide dimethylacetal (7a) in methaꢀ
nol was carried out to prevent transesterification of the
product with ethanol. In this case, based on the 1H NMR
Scheme 2
R1 = Cl, R2 = H (a); R1 = F, R2 = H (b); R1 = H, R2 = F (c); R1 = R2 = F (d); R1 = R2 = H (e)
i. POCl3, Et3N•HCl, reflux; ii. HSCH2COOMe, MeONa, MeOH, reflux.

1948
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
Medvedeva et al.
Scheme 3
B = MeO–, MeOC(O)CH2S–
Scheme 4
The following ratios of the reaction products were deterꢀ
mined when carrying out analogous reactions in refluxing
anhydrous ethanol: the ratio of total amount of amidines 10
and 10´ to the total amount of pyrimidines 11 and 11´ in the
case of pꢀFꢀsubstituted derivative (10b + 10´b) : (11b + 11´b)
was 80 : 20, and in the case of pꢀClꢀsubstituted derivative
(10a + 10´a) : (11a + 11´a) was 90 : 10. It also confirms
the fact that cyclocondensation of pꢀfluorophenylꢀsubꢀ
stituted aminothienopyridine with formation of pyrimidine
derivatives in refluxing anhydrous ethanol occurs two times
faster than that of pꢀchlorophenyl analog (the results obꢀ
tained with dimethylformamide and dimethylacetamide
dimethylacetals (7a) and (7b) coincided qualitatively).
Scheme 5
6, 8, 8´, 9, 9´: R1 = Cl, R2 = H (a); R1 = F, R2 = H (b); R1 = H,
R
2 = F (c); R1 = R2 = F (d); R1 = R2 = H (e)
8, 9: R3 = Me
8´, 9´: R3 = Et
data, a mixture of amidine 8b and pyrimidine derivative 9b
in the ratio 1 : 1 formed. Hence, higher temperature is
required for the quantitative transformation, which can be
achieved on refluxing in ethanol.
Investigation of the influence of acetal structure on the
course of this process showed that crystalline products
obtained upon the reaction of compounds 6a,b with diꢀ
methylformamide dimethylacetal (7b) in dry toluene
(80 °C, 4 h) represent mixtures of the corresponding
amidines 10 and pyrimidines 11 in 89 : 11 ratio in the case
of pꢀFꢀsubstituted and in 84 : 16 ratio in the case of
pꢀClꢀsubstituted derivatives (1H NMR data) (Scheme 5).
R1 = Cl (a), F (b); R2 = Me (10a,b, 11a,b);
R
2 = Et (10´a,b, 11´a,b)
Thus, the extent of transformation of fluorosubstituted
derivative (10b) into fused pyrimidines 11b and 11´b is

Pyridothienopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
1949
20% in refluxing ethanol and of chloroꢀsubstituted deꢀ
rivative 10a into pyrimidines 11a and 11´a is 10%,
whereas in toluene the pattern was slightly different and
pꢀchlorophenyl derivative undergoes cyclization in
a somewhat greater extent then pꢀfluorophenylꢀsubstiꢀ
tuted amidine. This was in contrast to the results obꢀ
tained with acetal 7a. We will adduce the putative interꢀ
pretation of these contradictions after discussion of the
presumable mechanisms of intramolecular cyclizations
observed.
The results obtained allow us to suggest a putative
mechanism of the reaction of amines 6a—e with acetals
7a,b (Scheme 6).
Halogens exert the negative inductive effect (–I) and
positive mesomeric effect (+M). The differences in the
behavior of pꢀClꢀ and pꢀFꢀsubstituted derivatives is interꢀ
preted from comparison of σ constants of these substituꢀ
ents. Despite the plurality of these constants (for example
see Ref. 14) based on them it is possible to obtain quite
distinct qualitative pattern of the influence of the substituꢀ
ents on the reaction. Thus σꢀconstant for the pꢀFꢀsubstitꢀ
uent in the benzene ring is +0.062 and for the pꢀClꢀsubꢀ
stituent it is +0.227 (electrophylic σ+ꢀconstants are –0.073
and +0.114, respectively), i.e., the fluorine atom is either
a weak electronꢀwithdrawing or a weak electronꢀdonor
group, but the chlorine atom is a strong electronꢀwithꢀ
drawing group. The fluorine atom in the paraꢀposition of
the benzene ring increases the electron density on the reacꢀ
tion center, which is the NH group in this case, and facilꢀ
itates the intramolecular cyclocondensation with formaꢀ
tion of a substituted pyrimidine. If the florine atom is in
the metaꢀposition of the benzene ring or the mꢀFꢀatom is
in addition to the pꢀFꢀatom, the cyclization to pyrimꢀ
idines under the conditions used becomes virtually imposꢀ
We succeed in isolation of tricyclic compounds 11a,b
in good yields under longꢀterm refluxing (~20 h) of amines
6a,b with dimethylformamide dimethylacetal (7b) in
toluene.
For the explanation of the reasons for different courses
of the reaction and elucidation of its presumable mechaꢀ
nism, we synthesized mꢀfluoroꢀ and 3,4ꢀdifluoroanilinoꢀ
thienopyridine derivatives (6c,d). In both cases, the reacꢀ
tions of these compounds with dimethylacetamide diꢀ
methylacetal (7a) in refluxing anhydrous ethanol leads to
amidines virtually exclusively (see Scheme 4). Traces of
pyrimidine derivatives were observed only in the mother
liquors obtained after isolation of the major products
(1H NMR data).
Scheme 6
6, 8—11: R1 = Cl, R2 = H (a); R1 = F, R2 = H (b); R1 = H, R2 = F (c); R1 = R2 = F (d); R1 = R2 = H (e)
8, 9: R = Me
10, 11: R = H

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
Medvedeva et al.
sible due to significant negative inductive effect. Trace
amounts of the corresponding pyrimidine derivatives 9
were observed only in the mother liquors (reactions of
aminothiophene derivatives 6c,d with acetal 7a in ethaꢀ
nol) (1H NMR data). These compounds could be identiꢀ
fied based on the fact that amidine derivatives (comꢀ
pounds 8) and pyrimidine derivatives (compounds 9) can
distinctly be differentiated by the location of the signals
for protons of the pyridine ring in the 1H NMR spectra: in
the case of amidine derivatives, the proton H(5) is obꢀ
served at δ 6.89—7.02, and the proton H(6) of pyrimidine
derivatives is observed at δ 5.78—5.83. The difference in
chemical shifts of other signals is also evident: protons
H(6) of amidines are observed at δ 8.14—8.24 and analoꢀ
gous protons H(7) of pyrimidine derivatives are observed
at δ 8.22—8.26. A broadened singlet for the aniline NH
proton and a singlet for the dimethylamino group are also
observed in the 1H NMR spectra of amidine derivatives 8.
Analogously, amidines 10 can be distinguished from pyriꢀ
midine derivatives 11.
It should be noted that besides the presumable mechaꢀ
nism of cyclization (see Scheme 6), it is necessary to conꢀ
sider yet another mechanism, which is possible for the
reaction in nonpolar aprotic solvent (for example, in toluꢀ
ene) (Scheme 7). Probably, in this case, ionization is the
dominant process due to the presence of the NH group at
the pyridine ring. The process of ionization is realized to
a small extent (NH acidity of the substituted anilines is
very low), but in longꢀterm reactions with amide acetals
different behavior of pꢀfluoroꢀ and pꢀchloroꢀsubstituted
derivatives was observed: for the latter cyclization to
pyrimidines proceeds faster. Obviously, the presence of elecꢀ
tronꢀwithdrawing substituent (pꢀchloroanilino group inꢀ
stead of electronꢀdonating pꢀfluoroanilino group) stabiꢀ
lizes anion A (see Scheme 7), which accounts for the conꢀ
tradictions observed in studies of the reactions of aminoꢀ
thiophene derivatives 6a,b with amide acetals 7a and 7b.
Thus, the following factors influence the course of the
reaction of aminothiophene derivatives 6 with amide acetals 7:
1) the electronic effect of the substituents in the benzene
ring: in the case of electronꢀdonating group (pꢀF, the overꢀ
all –I and +M effect), cyclocondensation of amidines into
pyrimidine tricyclic compounds is observed with acetal
7a, but in the case of electronꢀwithdrawing group (pꢀCl)
the process is stopped mainly in the step of amidine forꢀ
mation;
2) the influence of the solvent: in the case of a nonꢀ
polar aprotic solvent (toluene), amidines are formed in all
reactions with amide acetal 7a regardless of the electron
effect of the substituent in the benzene ring; in a polar
protic solvent (ethanol), cyclization to pyrimidine is the
dominant process in the case of pꢀFꢀsubstituted derivative
in contrast to pꢀCl one;
3) the reaction temperature: the reaction of pꢀFꢀsubꢀ
stituted aminothienopyridine derivative 6b with dimethylꢀ
acetamide dimethylacetal (7a) in refluxing methanol (lowꢀ
er temperature), other conditions being the same (the reꢀ
action time is 4 h) leads to amidine 8b and pyrimidine 9b
in the ratio 1 : 1 (1H NMR data);
4) the influence of the acetal: the presumable mechaꢀ
nism of the reaction of aminothienopyridine derivatives
6a—e with amide acetals (7a or 7b) (see Scheme 6) points
to the formation of trisaminomethane derivatives. In the
case of acetal 7a, this system is more sterically hindered
and transforms into pyrimidine derivative 9 preferably with
elimination of the bulky dimethylamino group with acꢀ
quirement of aromaticity and gain in energy.
Virtually no cyclocondensation into pyrimidine derivꢀ
ative is observed in the reaction of phenylꢀsubstituted comꢀ
pound 6e with acetal 7a in toluene or ethanol as in the
cases of 4ꢀchloro, 3ꢀfluoro and 3,4ꢀdifluoro derivatives.
It should be noted that we succeded in obtaining
pꢀchlorophenylꢀsubstituted pyrimidine 9a in 35% yield
only by heating amidine 8a in diphenyl oxide at 200 °C in
the presence of catalytic amounts of pꢀtoluenesulfonic acid
(Scheme 8). All other attempts to carry out intramolecuꢀ
lar cyclocondensation of compound 8a were unsuccessful:
fusion with pꢀtoluenesulfonic acid or refluxing in DMF in
the presence of pꢀtoluenesulfonic acid lead only to resiniꢀ
fication of the reaction mixtures. Earlier,15 tricyclic pyriꢀ
midine derivatives (of the type 9) have been obtained by
heating of the corresponding amidines in 70% aqueous
Scheme 7
R = Me, H; R1 = Cl, F

Pyridothienopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
1951
Scheme 9
acetic acid for 30 min. An attempt to carry out such
a reaction with compound 8a lead only to hydrolysis of the
amidine fragment of the molecule and compound 12 was
isolated in 75% yield as a result of refluxing for 14 h.
Scheme 8
i. Ac2O, reflux.
R1 = Cl (a), F (b)
and 13C NMR and IR spectroscopy, mass spectrometry,
and elemental analysis. A characteristic feature of the
1H NMR spectra of these compounds is the presence of
singlets at δ 14.5. Therefore, one can suppose that an inꢀ
tramolecular hydrogen bond exists in the structures 15a,b.
It is stabilized by strong interaction of the proton at the
nitrogen atom N(3) with the acetyl group, which results in
formation of a sixꢀmembered ring (see Scheme 9). The
13C NMR spectrum of compound 15b without 1Hꢀ13C
spinꢀspin decoupling shows a signal at δ 196.8 as a quartet
due to the interaction with the protons of the adjacent
methyl group. The chemical shift and coupling constant
of this signal suggest that compound 15b exists in the keto
form. An analogous set of signals is observed in the
13C NMR spectrum of compound 15a.
It should be noted that the mechanism of formation of
compounds 15a,b is quite not that simple and it is hardly
possible to designate the intermediates of this process withꢀ
out additional experiments. Heating in acetic anhydride
lasts for a long time (34 h), i.e., the reactions rate under
these rather drastic conditions is low. This fact, in particꢀ
ular, can imply the presence of many intermediates, which
rather slowly transform into the final products. However,
the yields of tricycles obtained are quite satisfactory (61%
for 15a and 76% for 15b).
i. 70% aqueous AcOH, reflux; ii. pꢀTsOH, H2O, 200 °C; iii. AcOH,
reflux; iv. 1) ButONa, ButOH. 2) AcOH, H2O.
R1 = 4ꢀClC6H4, R2 = H (13, 14), But (13´, 14´)
Compound 13 was isolated in 84% yield as the main
product upon attempted intramolecular cyclocondensaꢀ
tion 8a→9a under the action of a strong base (1.5 equiv.
ButONa) in refluxing tertꢀbutyl alcohol for 3 h and subseꢀ
quent treatment of reaction mixture with water and glacial
acetic acid. The reaction proceeds towards the formation
of substituted pyrimidine 14, which was confirmed by the
presence of the signal for the proton H(6) of the pyridine
1
ring at δ 5.57 in the H NMR spectrum. The mass specꢀ
trum shows a peak of the molecular ion of compound 14.
Thus, cyclocondensation of pꢀchloroꢀsubstituted amidine
8a into substituted pyrimidine 9a under the action of 70%
aqueous AcOH, base or mere refluxing in a solvent either
does not proceed at all or proceeds very slowly and the
yield is small. The formation of pyrimidine derivative 9a
smoothly occurs under longꢀterm refluxing (18 h) of
amidine 8a in glacial acetic acid (see Scheme 8).
Amidines 8a—e are interesting and promising syntons
for the synthesis of polyheterocyclic systems. The presꢀ
ence of various functional groups in compounds 8a—e,
such as the amidine fragment, an ester group, and the
aniline group, assumes various directions of heterocyclizaꢀ
tion.
We suggest here one of the variants of the mechanism
according to which these cyclizations can proceed
(Scheme 10).
Powder Xꢀray diffraction analysis (see Ref. 16) of comꢀ
pounds 15a,b was carried out to prove their structures. All
geometrical characteristics of the molecules in the crystal
structures of 15a and 15b (Fig. 1) have values similar to
those found in the Cambridge Crystallographic Dataꢀ
base (CCDC).17 In both molecules, the benzene ring
C(13)—C(18) is almost perpendicular to the plane of the
tricycle, being turned relative the latter by 87.3(5)° and
88.1(4)° in 15a and 15b, respectively. The crystal packings
in both compounds are very similar and characterized first
of all by the presence of centrosymmetrical dimers where
We developed a new procedure for the synthesis of
pyridothienopyrimidines (3Hꢀ1ꢀthiaꢀ3,5,8ꢀtriazaacenaphꢀ
thylenes) 15a,b from amidines 8a,b (Scheme 9).
Compounds 15a,b were isolated in good yields upon
prolonged refluxing of amidines 8a,b in acetic anhydride.
1
Their structures were established based on data from H

1952
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
Medvedeva et al.
Scheme 10
O(21)
O(26) O(23)
N(9)
S(1)
N(7)
N(1)
F(24)
3.51Å
F(24)´
N(3)´
N(7)´
S(1)´
N(9)´
O(26)´
O(23)´
O(20)´
Fig. 2. Centrosymmetrical dimer in the crystal structure of 15b,
π—π interaction is indicated by dashed lines. Code of symmetry:
(i) 1 – x, 1 – y, 1 – z.
3.599(12) Å in 15a and 3.506(9) Å in 15b. The dimer in
the molecular packing of 15b is shown in Fig. 2. The
amine proton is involved in the intramolecular hydrogen
bonding N—H...O, so weak intermolecular interactions
C—H...O, C—H...Cl (in 15a) and C—H...F (in 15b) play
the dominant role in the formation of threeꢀdimensional
packings (Table 1).
Experimental
The IRꢀspectra were recorded on an FSMꢀ1201 instrument
in Nujol mulls and on a SpecordꢀM82 instrument in KBr pellets.
Mass spectra (EI, 70 eV, temperature of the ionization chamber
is 250 °C) were obtained on a Kratos MSꢀ30 mass spectrometer
using a direct inlet system and on a Waters ZQꢀ2000 mass
spectrometer using the electrospray ionization technique with
Table 1. Characteristics of hydrogen bonds in compounds 15a
and 15b
R1 = 4ꢀClC6H4, 4ꢀFC6H4; R2 = COMe
Comꢀ
pound
D—H...A
D—H H...A D...A D—H...A
the aromatic rings C(2)N(3)C(4)C(5)C(6)C(12) of two
molecules, which form the dimer, are related by π—π inꢀ
teraction with short distances between their centers,
/deg
Å
15a N(9)—H(9)...O(21)
N(9)—H(9)...O(23)
0.86 1.90 2.576(18) 134
0.86 2.52 3.050(19) 121
C(17)—H(17)...O(23)i
C(18)—H(18)...O(21)i
0.93 2.54 3.09(2)
119
C(22)
C(19)
C(20)
0.93 2.59 3.490(18) 163
O(21)
C(15)—H(15)...O(26)ii 0.93 2.57 3.466(19) 163
C(4)—H(4)...O(23)iii
C(19)—H(19)...C(l24)iv 0.93 2.72 3.569(16) 152
0.93 2.34 3.17(2)
148
O(23)
C(8)
N(9)
C(15)
C(14)
N(7)
C(27)
O(26)
C(16)
15b N(9)—H(9)...O(21)
0.86 1.89 2.569(14) 135
0.86 2.53 3.051(16) 120
C(10)
C(11)
N(9)—H(9)...O(23)
C(15)—H(15)...O(26)ii 0.93 2.60 3.450(15) 153
C(25)
S(1)
C(13)
C(6)
Cl(24)
C(4)—H(4)...O(23)iii
0.93 2.45 3.256(16) 146
C(17)
C(18)
C(12)
C(4)
C(18)—H(18)...O(21)v 0.93 2.51 3.404(13) 160
C(19)—H(19)...F(24)vi 0.93 2.41 3.288(13) 157
C(27)—H(27)B...F(24)vii 0.96 2.47 3.367(14) 156
C(2)
N(3)
C(5)
Fig. 1. Molecular structure and atomic numbering of comꢀ
pound 15a. Spheres of atom displacements are presented with
50% probability for nonhydrogen atoms.
Code of symmetry: (i) 1 – x, 1 – y, 1 – z; (ii) x, 1 + y, z; (iii) 1 + x, y, z;
(iv) 1 – x, 2 – y, 1 – z; (v) –x, 1 – y, –z; (vi) –x, 2 – y, –z;
(vii) x, y – 1, 1 + z.

Pyridothienopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
1953
the inlet omitting a chromatographic column. The 1H NMR
spectra were recorded on Bruker ACꢀ300, Bruker AMꢀ300,
and Varian Unity+400 spectrometers in DMSOꢀd6, CDCl3,
DMSOꢀd6—CD3OD (10 : 1). The 13C NMR spectra were reꢀ
corded on a Varian Unity+400 (operating frequency 100 MHz)
in CDCl3—F3CCOOH without 1Hꢀ13C spinꢀspin decoupling.
The course of the reactions was monitored and the purity of the
compounds was checked by TLC on Merck Silica gel 60 F254
plates (chloroform, ethyl acetate, ethyl acetate—ethanol (10 : 1
and 1 : 1)). The melting points were determined on an Electroꢀ
termal 9100 instrument (UK). Elemental analysis was performed
at the Laboratory for Microanalysis of the N. D. Zelinsky Instiꢀ
tute of Organic Chemistry, Russian Academy of Sciences.
The following reagents (Lancaster) were used: N,Nꢀdimethꢀ
ylacetamide dimethylacetal (7a) (purity 90%), N,Nꢀdimethylꢀ
formamide dimethylacetal (7b) (purity 95%), mꢀfluoroaniline
(purity 98%), 3,4ꢀdifluoroaniline (purity 99%). 2ꢀChloroꢀ4ꢀ
phenylpyridineꢀ3ꢀcarbonitrile (5e) was prepared according to
a known procedure.13
4ꢀ(3ꢀFluoroanilino)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile
(1c). A mixture of enaminoamide 3c (6.00 g, 27.4 mmol) and
acetal 7b (38.6 mL, 0.274 mmol) in anh. ethanol (150 mL) was
refluxed for 5 h. The reaction mixture was cooled to 20 °C and
kept for 3 days. The yellow precipitate that formed was filtered
off, washed with ethanol, and dried. Pyrimidinone 4c obtained
in a yield of 5.59 g was refluxed for 1 h without purification in 4%
aqueous NaOH (75 mL). The reaction mixture was cooled to
20 °C, diluted with 3 volumes of water, insoluble products were
filtered off through a paper filter. Clear solution obtained was
neutralized with concentrated HCl. The white precipitate that
formed was filtered off, washed with water to pH 7, and dried.
Compound 1c was obtained in a yield of 3.26 g (52%). The
mother liquor obtained after separation of pyrimidinone 4c was
concentrated in vacuo almost to dryness, 4% aqueous NaOH
(75 mL) was added to red oily residue obtained and the mixture
was processed as described above. Compound 1c was aditionally
obtained in a yield of 2.70 g (43%). The total yield was 95%, m.p.
272—274 °C (PriOH). IR (KBr), ν/cm–1: 3236 (NH); 2224 (CN);
1652 (CONH). 1H NMR (DMSOꢀd6), δ: 5.90 (d, 1 H, H(5),
Jo = 7.55 Hz); 7.02—7.16 (m, 3 H, Ar); 7.39 (d, 1 H, H(6),
Jo = 7.55 Hz); 7.41—7.47 (m, 1 H, Ar); 9.44 (br.s, 1 H, NHC(4));
11.43 (br.s, 1 H, N(1)H). Found (%): C, 62.78; H, 3.62;
N, 18.47. C12H8FN3O. Calculated (%): C, 62.88; H, 3.52; N, 18.33.
4ꢀ(3,4ꢀDifluoroanilino)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboꢀ
nitrile (1d). A mixture of enaminoamide 3d (7.50 g, 31.6 mmol)
and acetal 7b (44.6 mL, 0.310 mol) in anh. ethanol (150 mL) was
refluxed for 13 h. The reaction mixture was cooled to 20 °C, the
solvent and excess of acetal were evaporated in vacuo, 4% aqueꢀ
ous NaOH (150 mL) was added to red oily residue and then the
reaction mixture was processed as described for the preparation
of carbonitrile 1c. Compound 1d was obtained in a yield of 5.43 g
(70%), m.p. 293 °C (PriOH). 1H NMR (DMSOꢀd6), δ: 5.82 (d, 1 H,
H(5), Jo = 7.60 Hz); 7.10—7.14 (m, 1 H, Ar); 7.38 (d, 1 H, H(6),
Jo = 7.60 Hz); 7.40—7.51 (m, 2 H, Ar); 9.40 (br.s, 1 H, NHC(4));
11.42 (br.s, 1 H, N(1)H). Found (%): C, 58.58; H, 2.98; N, 16.90.
C12H7F2N3O. Calculated (%): C, 58.30; H, 2.85; N, 17.00.
2ꢀCyanoꢀ3ꢀ(3ꢀfluoroanilino)crotonamide (3c). A mixture of
2ꢀcyanoꢀ3ꢀdimethylaminocrotonamide 2 (10.00 g, 65.4 mmol)
and mꢀfluoroaniline (8.89 g, 80 mmol) in glacial acetic acid
(120 mL) was refluxed for 6 h. The reaction mixture was kept at
20 °C for 16 h and concentrated in vacuo almost to dryness. Ethyl
acetate (10 mL) was added to semicrystalline residue obtained,
then it was triturated, the white precipitate that formed was filꢀ
tered off and washed with ethyl acetate. The crude product was
obtained in a yield of 7.00 g (49%), recrystallization from anh.
ethanol afforded pure compound 3c in a yield of 6.39 g (45%),
m.p. 184—185 °C (EtOH). IR (KBr), ν/cm–1: 3392, 3264 (NH,
NH2); 2196 (CN); 1644 (CONH2). 1H NMR (DMSOꢀd6), δ:
2.24 (s, 3 H, CH3); 6.90—7.36 (m, 5 H, Ar, CONH2); 7.40—7.50
(m, 1 H, Ar); 12.76 (br.s, 1 H, NH). Found (%): C, 60.14;
H, 4.68; N, 19.13. C11H10FN3O. Calculated (%): C, 60.27;
H, 4.60; N, 19.17.
2ꢀCyanoꢀ3ꢀ(3,4ꢀdifluoroanilino)crotonamide (3d) was preꢀ
pared analogously to 3c from compound 2 and 3,4ꢀdifluoroꢀ
aniline, the reaction time was 11 h. The yield was 49%, m.p.
1
215—217 °C (toluene). H NMR (DMSOꢀd6), δ: 2.19 (s, 3 H,
CH3); 6.86—7.39 (m, 3 H, Ar, CONH2); 7.38—7.66 (m, 2 H,
Ar); 12.63 (br.s, 1 H, NH). Found (%): N, 17.68. C11H9F2N3O.
Calculated (%): N, 17.71.
6ꢀ[2ꢀ(Dimethylamino)vinyl]ꢀ1ꢀ(3ꢀfluorophenyl)ꢀ4ꢀoxoꢀ1,4ꢀ
dihydropyrimidineꢀ5ꢀcarbonitrile (4c). A mixture of enaminoꢀ
amide 3c (0.20 g, 0.913 mmol) and acetal 7b (1.29 mL,
9.13 mmol) in anh. ethanol (3 mL) was refluxed for 5.5 h. The
reaction mixture was kept at 20 °C for 48 h, the yellow precipiꢀ
tate that formed was filtered off, washed with anh. ethanol, and
dried. Compound 4c was obtained in a yield of 0.17 g (66%),
m.p. 242 °C (PriOH). IR (KBr), ν/cm–1: 2204 (CN); 1624 (CO).
1H NMR (DMSOꢀd6), δ: 2.64, 3.14 (both br.s, 3 H each, NMe2);
4.06 (d, 1 H, H(α), Jtrans = 13.00 Hz); 7.32—7.39 (m, 2 H, Ar);
7.43—7.46 (m, 1 H, Ar); 7.60—7.65 (m, 1 H, Ar); 7.95 (d, 1 H,
H(β), Jtrans = 13.00 Hz); 8.07 (s, 1 H, H(2)). Found (%): C, 63.42;
H, 4.82; N, 19.93. C15H13FN4O. Calculated (%): C, 63.37;
H, 4.61; N, 19.71.
1ꢀ(3,4ꢀDifluorophenyl)ꢀ6ꢀ[2ꢀ(dimethylamino)vinyl]ꢀ4ꢀoxoꢀ
1,4ꢀdihydropyrimidineꢀ5ꢀcarbonitrile (4d) was prepared analoꢀ
gously from compound 3d, the reaction time was 8 h. The yield
1
was 43%, m.p. 243 °C (PriOH). H NMR (DMSOꢀd6), δ: 2.61,
3.09 (both br.s, 3 H each, NMe2); 4.03 (d, 1 H, H(α), Jtrans
=
= 12.60 Hz); 7.44—7.45 (m, 1 H, Ar); 7.66—7.73 (m, 1 H, Ar);
7.83—7.88 (m, 1 H, Ar); 7.94 (d, 1 H, H(β), Jtrans = 12.60 Hz);
8.20 (s, 1 H, H(2)). Found (%): C, 59.83; H, 4.29; N, 18.53.
C15H12F2N4O. Calculated (%): C, 59.60; H, 4.00; N, 18.53.
2ꢀChloroꢀ4ꢀ(4ꢀchloroanilino)pyridineꢀ3ꢀcarbonitrile (5a).
A mixture of compound 1a (5.15 g, 20.98 mmol), triethylamine
hydrochloride (3.09 g, 22.31 mmol), and phosphoryl chloride
(100 mL) was refluxed for 7 h. The reaction mixture was cooled
to 20 °C, concentrated in vacuo to dryness, dry residue was trituꢀ
rated with toluene, and concentrated in vacuo to dryness again.
An excess of ice was added to the residue obtained, and a white
precipitate formed. The suspension obtained was refluxed for 1 h
and cooled. The white precipitate was filtered off and washed
with water to pH 7. The crude product 5a was obtained in a yield
of 5.40 g, which was recrystallized from dry toluene (50 mL).
The yield was 4.77 g (86%), m.p. 215 °C (EtOH), 213—214 °C
(toluene) (cf. Ref. 13: m.p. 221—222 °C (EtOH)). IR (Nujol
mulls), ν/cm–1: 3289 (NH); 2224 (CN). MS (ES), m/z: 266
[M + H]+•, 228 [M – Cl]+•, 531 [2 M + H]+
.
1H NMR
•
(DMSOꢀd6), δ: 6.85 (d, 1 H, H(5), Jo = 6.30 Hz); 7.30, 7.43
(A2B2, 4 H, Ar, Jo = 8.70 Hz); 8.05 (d, 1 H, H(6), Jo = 6.30 Hz);
9.50 (s, 1 H, NH).
2ꢀChloroꢀ4ꢀ(4ꢀfluoroanilino)pyridineꢀ3ꢀcarbonitrile (5b) was
prepared analogously from compound 1b, the reaction time was

1954
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
Medvedeva et al.
5.5 h. The yield was 80%, m.p. 181.6—182.2 °C (toluene). IR
(Nujol mulls), ν/cm–1: 3312 (NH); 2224 (CN). MS (ES), m/z:
248 [M + H]+•, 212 [M + H – Cl]+•. 1H NMR (DMSOꢀd6), δ:
6.71 (d, 1 H, H(5), Jo = 6.11 Hz); 7.18, 7.28 (both m, 4 H, Ar);
7.99 (d, 1 H, H(6), Jo = 6.11 Hz); 9.38 (s, 1 H, NH). Found (%):
C, 58.27; H, 2.90; N, 16.99. C12H7ClFN3. Calculated (%):
C, 58.20; H, 2.85; N, 16.97.
2ꢀChloroꢀ4ꢀ(3ꢀfluoroanilino)pyridineꢀ3ꢀcarbonitrile (5c) was
prepared analogously to 5a from compound 1c, the reaction
time was 7.5 h. The yield was 77%, m.p. 165 °C (hexane). IR
(KBr), ν/cm–1: 3296 (NH); 2228 (CN). 1H NMR (DMSOꢀd6),
δ: 6.97 (d, 1 H, H(5), Jo = 6.10 Hz); 7.03—7.12 (m, 1 H, Ar);
7.18 (m, 2 H, Ar); 7.35—7.53 (m, 1 H, Ar); 8.12 (d, 1 H, H(6),
Jo = 6.10 Hz); 9.63 (s, 1 H, NH). Found (%): C, 58.03; H, 3.04;
N, 16.78. C12H7ClFN3. Calculated (%): C, 58.20; H, 2.85;
N, 16.97.
2ꢀChloroꢀ4ꢀ(3,4ꢀdifluoroanilino)pyridineꢀ3ꢀcarbonitrile (5d)
was prepared analogously to 5a from compound 1d, the reaction
time was 6 h. The yield was 58%, m.p. 197 °C (toluene). 1H NMR
(DMSOꢀd6), δ: 6.88 (d, 1 H, H(5), Jo = 6.20 Hz); 7.15—7.20
(m, 1 H, Ar); 7.43—7.54 (m, 2 H, Ar); 8.10 (d, 1 H, H(6), Jo =
= 6.20 Hz); 9.59 (s, 1 H, NH). Found (%): C, 54.46; H, 2.31;
N, 15.89. C12H6ClF2N3. Calculated (%): C, 54.26; H, 2.28;
N, 15.82.
Found (%): C, 56.83; H, 3.85; N, 13.26. C15H12FN3O2S. Calcuꢀ
lated (%): C, 56.77; H, 3.81; N, 13.24.
Methyl 3ꢀaminoꢀ4ꢀ(3,4ꢀdifluoroanilino)thieno[2,3ꢀb]pyridineꢀ
2ꢀcarboxylate (6d) was prepared analogously from compound
5d, the reaction time was 9 h. The yield was 86%, m.p. 271 °C
(toluene). 1H NMR (DMSOꢀd6), δ: 3.79 (s, 3 H, COOCH3);
6.85 (d, 1 H, H(5), Jo = 4.70 Hz); 6.95—7.19 (m, 3 H, Ar, NH2);
7.27—7.40 (m, 1 H, Ar); 7.45 (m, 1 H, Ar); 8.25 (d, 1 H, H(6),
Jo = 4.70 Hz); 8.63 (br.s, 1 H, NH). Found (%): C, 53.70;
H, 3.44; N, 12.65. C15H11F2N3O2S. Calculated (%): C, 53.73;
H, 3.31; N, 12.53.
Methyl 3ꢀaminoꢀ4ꢀanilinothieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylate
(6e) was prepared analogously from compound 5e, the reaction
time was 12.5 h. The yield was 77%, m.p. 232—233 °C (MeOH).
1H NMR (DMSOꢀd6), δ: 3.79 (s, 3 H, COOCH3); 6.81 (d, 1 H,
H(5), Jo = 5.60 Hz); 6.99—7.22 (m, 3 H, Ar, NH2); 7.23—7.54
(m, 4 H, Ar); 8.22 (d, 1 H, H(6), Jo = 5.60 Hz); 8.53 (br.s, 1 H,
NH). Found (%): C, 60.17; H, 4.65; N, 14.04. C15H13N3O2S.
Calculated (%): C, 60.19; H, 4.38; N, 14.04.
Methyl 3ꢀ[1ꢀ(dimethylamino)ethylidene]aminoꢀ4ꢀ(4ꢀchloroꢀ
anilino)thieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylate (8a). A. Acetal 7a
(9.73 mL, 59.9 mmol) was added to a suspension of compound
6a (2.50 g, 7.49 mmol) in anh. toluene (6 mL). The yellow
solution obtained was stirred at 78—80 °C for 6 h. The reaction
mixture was cooled to 20 °C, the solvent and excess of acetal was
evaporated in vacuo, the crystalline residue obtained was trituꢀ
rated with methanol, the yellow precipitate that formed was filꢀ
tered off, washed with methanol, and dried. Analytically pure
compound 8a was obtained in a yield of 2.81 g (93%), m.p.
179—180 °C (MeOH). IR (KBr), ν/cm–1: 3450, 3228 (NH);
1696 (COOCH3). MS (EI), m/z, (Irel (%)): 402 [M]+• (91), 357
Methyl 3ꢀaminoꢀ4ꢀ(4ꢀchloroanilino)thieno[2,3ꢀb]pyridineꢀ2ꢀ
carboxylate (6a). Methyl thioglycolate (2.34 mL, 25.62 mmol)
was added to a solution of sodium methoxide (1.06 g, 19.6 mmol,
prepared from sodium (0.45 g)). The solution obtained was stirred
at 20 °C for 30 min, and compound 5a (4.51 g, 17.08 mmol) was
added. The reaction mixture was refluxed for 6 h and kept at
10 °C for 12 h. The yellow precipitate was filtered off, washed
with methanol, and dried. Analytically pure compound 6a was
obtained in a yield of 4.52 g (79%), m.p. 223—225 °C (DMF). IR
[M – NHMe2]+ (100), 326 [M – NHMe2 – OCH3]+ (17).
1H NMR (DMSOꢀd6), δ: 1.98 (s, 3 H, NCCH3N(CH3)2); 3.12
(s, 6 H, N(CH3)2); 3.71 (s, 3 H, COOCH3); 6.89 (d, 1 H, H(5),
Jo = 5.70 Hz); 7.32, 7.44 (A2B2, 4 H, Ar, Jo = 8.70 Hz); 8.19
(d, 1 H, H(6), Jo = 5.70 Hz); 9.99 (br.s, 1 H, NH). Found (%):
C, 56.57; H, 4.81; N, 13.87. C19H19ClN4O2S. Calculated (%):
C, 56.64; H, 4.75; N, 13.91.
•
•
(Nujol mulls), ν/cm–1: 3329, 3367 (NH2, NH); 1668 (COOCH3).
MS (ES), m/z: 334 [M + H]+•, 667 [2 M + H]+•, 1000 [3 M + H]+
,
•
302 [M – OCH3]+•, 274 [M – COOCH3]+•, 241 [M – H –
– COOCH3 – S]+
.
1H NMR (DMSOꢀd6), δ: 3.78 (s, 3 H,
•
COOCH3); 6.83 (d, 1 H, H(5), Jo = 5.30 Hz); 7.03 (br.s, 2 H,
NH2); 7.27, 7.42 (A2B2, 4 H, Ar, Jo = 8.60 Hz); 8.22 (d, 1 H,
H(6), Jo = 5.30 Hz); 8.58 (br.s, 1 H, NH). Found (%): C, 53.72;
H, 3.88; N, 12.61; S, 9.47. C15H12ClN3O2S. Calculated (%):
C, 53.97; H, 3.62; N, 12.59; S, 9.61.
B. Acetal 7a (0.273 mL, 1.677 mol) was added to a suspenꢀ
sion of compound 6a (0.070 g, 0.210 mmol) in dry toluene (3 mL).
The mixture was refluxed for 11 h and cooled to 20 °C. The
solvent and excess of acetal was evaporated in vacuo, semicrysꢀ
talline brown residue was triturated with methanol, the yellow
precipitate that formed was filtered off and washed with methanol.
Compound 8a was obtained in a yield of 0.020 g (24%), its physꢀ
icochemical properties were identical to those of the sample
prepared by method A.
Methyl 3ꢀaminoꢀ4ꢀ(4ꢀfluoroanilino)thieno[2,3ꢀb]pyridineꢀ2ꢀ
carboxylate (6b) was prepared analogously from compound 5b,
the reaction time was 5 h. The yield was 92%, m.p. 257 °C
(DMF). IR (Nujol mulls), ν/cm–1: 3374 (NH, NH2); 1668
(COOCH3). MS (ES), m/z: 318 [M + H]+•, 286 [M + H – S]+
,
•
258 [M – COOCH3]+•, 635 [2 M + H]+•. 1H NMR (DMSOꢀd6),
δ: 3.80 (s, 3 H, COOCH3); 6.65 (d, 1 H, H(5), Jo = 5.60 Hz);
7.03 (br.s, 2 H, NH2); 7.21—7.34 (m, 4 H, Ar); 8.18 (d, 1 H,
H(6), Jo = 5.56 Hz); 8.41 (br.s, 1 H, NH). Found (%): C, 56.68;
H, 3.95; N, 13.24; S, 10.55. C15H12FN3O2S. Calculated (%):
C, 56.77; H, 3.81; N, 13.24; S, 10.10.
Methyl 3ꢀaminoꢀ4ꢀ(3ꢀfluoroanilino)thieno[2,3ꢀb]pyridineꢀ2ꢀ
carboxylate (6c) was prepared analogously from compound 5c,
the reaction time was 7 h. The yield was 94%, m.p. 256 °C
(toluene). IR (KBr), ν/cm–1: 3176, 3344 (NH, NH2); 1680
(COOCH3). 1H NMR (DMSOꢀd6), δ: 3.80 (s, 3 H, COOCH3);
6.91 (t, 1 H, Ar, Jo = 8.30 Hz); 6.98 (d, 1 H, H(5), Jo = 5.50 Hz);
7.04 (br.s, 2 H, NH2); 7.09 (m, 2 H, Ar); 7.47—7.31 (m, 1 H,
Ar); 8.29 (d, 1 H, H(6), Jo = 5.50 Hz); 8.71 (br.s, 1 H, NH).
Methyl 3ꢀ[1ꢀ(dimethylamino)ethylidene]aminoꢀ4ꢀ(4ꢀfluoroꢀ
anilino)thieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylate (8b) was prepared
analogously to 8a (method A), the reaction time was 5.5 h. The
yield was 93%, m.p. 179—180 °C (MeOH). MS (EI), m/z,
(Irel (%)): 386 [M]+ (35), 341 [M – NHMe2]+ (100), 310
•
•
[M – NHMe2 – OCH3]+ (72), 283 [M – NHMe2 – OCH3 –
•
–HCN]+ (49). 1H NMR (DMSOꢀd6), δ: 1.98 (s, 3 H,
•
NCCH3N(CH3)2); 3.11 (s, 6 H, N(CH3)2); 3.70 (s, 3 H,
COOCH3); 6.76 (d, 1 H, H(5), Jo = 5.70 Hz); 7.05—7.44 (m, 4 H,
Ar); 8.14 (d, 1 H, H(6), Jo = 5.70 Hz); 9.84 (br.s, 1 H, NH).
Found (%): C, 58.92; H, 5.11; N, 14.58. C19H19FN4O2S. Calcuꢀ
lated (%): C, 59.05; H, 4.96; N, 14.50.
Methyl 3ꢀ[1ꢀ(dimethylamino)ethylidene]aminoꢀ4ꢀ(3ꢀfluoroꢀ
anilino)thieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylate (8c) was prepared

Pyridothienopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
1955
analogously to 8a (method A), the reaction time was 6 h. The
yield was 74%, m.p. 181 °C (MeOH). 1H NMR (DMSOꢀd6), δ:
2.00 (s, 3 H, NCCH3N(CH3)2); 3.16 (s, 6 H, N(CH3)2); 3.73
(s, 3 H, COOCH3); 6.97—7.02 (m, 2 H, Ar, H(5)); 7.14—7.23
(m, 2 H, Ar); 7.42—7.46 (m, 1 H, Ar); 8.24 (d, 1 H, H(6),
Jo = 6.00 Hz); 10.03 (br.s, 1 H, NH). Found (%): C, 59.16;
H, 5.02; N, 14.51. C19H19FN4O2S. Calculated (%): C, 59.05;
H, 4.96; N, 14.50.
Methyl 3ꢀ[1ꢀ(dimethylamino)ethylidene]aminoꢀ4ꢀ(3,4ꢀdiꢀ
fluoroanilino)thieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylate (8d) was preꢀ
pared analogously to 8a (method A), the reaction time was 4 h.
The yield was 83%, m.p. 157 °C (MeOH). 1H NMR (DMSOꢀd6),
δ: 1.99 (s, 3 H, NCCH3N(CH3)2); 3.14 (s, 6 H, N(CH3)2); 3.73
(s, 3 H, COOCH3); 6.90 (d, 1 H, H(5), Jo = 5.70 Hz); 7.07—7.26
(m, 1 H, Ar); 7.35—7.61 (m, 2 H, Ar); 8.21 (d, 1 H, H(6), Jo =
= 5.70 Hz); 9.96 (br.s, 1 H, NH). Found (%): C, 56.32; H, 4.67;
N, 13.74. C19H18F2N4O2S. Calculated (%): C, 56.43; H, 4.49;
N, 13.85.
Methyl 3ꢀ[1ꢀ(dimethylamino)ethylidene]aminoꢀ4ꢀanilinoꢀ
thieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylate (8e) was prepared analoꢀ
gously to 8a (method A), the reaction time was 4 h. The yield was
85%, m.p. 158 °C (MeOH). 1H NMR (DMSOꢀd6), δ: 2.00 (s, 3 H,
NCCH3N(CH3)2); 3.15 (s, 6 H, N(CH3)2); 3.73 (s, 3 H,
COOCH3); 6.93 (d, 1 H, H(5), Jo = 5.70 Hz); 7.08—7.26 (m, 1 H,
Ar); 7.32 (d, 2 H, Ar, Jo = 7.80 Hz); 7.43 (t, 2 H, Ar, Jo = 7.80 Hz);
8.19 (d, 1 H, H(6), Jo = 5.70 Hz); 9.98 (br.s, 1 H, NH).
Found (%): C, 61.92; H, 5.49; N, 15.01. C19H20N4O2S. Calcuꢀ
lated (%): C, 61.94; H, 5.47; N, 15.21.
A mixture of methyl and ethyl 3ꢀ[1ꢀ(dimethylamino)ethylꢀ
idene]aminoꢀ4ꢀanilinothieno[2,3ꢀb]pyridineꢀ2ꢀcarboxylate (8e
and 8´e) was prepared analogously in a ratio 1.5 : 1. 1H NMR spectꢀ
rum of compound 8´e (DMSOꢀd6), δ: 1.22 (t, 3 H, COOCH2CH3,
J = 7.10 Hz); 2.00 (s, 3 H, NCCH3N(CH3)2); 3.15 (s, 6 H,
N(CH3)2); 4.19 (q, 2 H, COOCH2CH3, J = 7.10 Hz); 6.93 (d, 1 H,
H(5), Jo = 5.70 Hz); 7.08—7.26 (m, 1 H, Ar); 7.32 (d, 2 H, Ar,
Jo = 7.80 Hz); 7.43 (t, 2 H, Ar, Jo = 7.80 Hz); 8.19 (d, 1 H, H(6),
Jo = 5.70 Hz); 9.95 (br.s, 1 H, NH).
Methyl 5ꢀ(4ꢀchlorophenyl)ꢀ4ꢀmethylꢀ5Hꢀ1ꢀthiaꢀ3,5,8ꢀtriꢀ
azaacenaphtheneꢀ2ꢀcarboxylate (9a). A. Diphenyl oxide (2.00 g)
was heated up to 200 °C, compound 8a (0.10 g) and pꢀtolueneꢀ
sulfonic acid (catalytic amount) were added to the liquid obꢀ
tained. The reaction mixture was stirred at 215 °C for 8 h, then
cooled to 30 °C, and poured into cold hexane. The brown preꢀ
cipitate that formed was filtered off and washed with cold hexane.
Crude compound 9a was obtained in a yield of 0.03 g (35%),
m.p. 264 °C. MS (EI), m/z, (Irel (%)): 357 [M]+ (100), 343
•
[M – CH3 + H]+ (16), 326 [M – OCH3]+ (17). 1H NMR
(DMSOꢀd6), δ: 2.01 (s, 3 H, C(4)CH3); 3.78 (s, 3 H, COOCH3);
5.83 (d, 1 H, H(6), Jo = 5.45 Hz); 7.63, 7.74 (A2B2, 4 H, Ar,
Jo = 8.60 Hz); 8.26 (d, 1 H, H(7), Jo = 5.45 Hz).
•
•
B. Compound 8a (0.05 g, 0.124 mmol) was dissolved in glacial
acetic acid (2 mL), the yellow solution obtained was refluxed for
18 ч. The reaction mixture was concentrated in vacuo. The
residue was triturated with ethyl acetate and concentrated.
Compound 9a was obtained in a yield of 0.04 g (90%), m.p.
267 °C (MeCN). Found (%): C, 56.85; H, 3.48; N, 11.75.
C17H12ClN3O2S. Calculated (%): C, 57.07; H, 3.38; N, 11.74.
Methyl 5ꢀ(4ꢀfluorophenyl)ꢀ4ꢀmethylꢀ5Hꢀ1ꢀthiaꢀ3,5,8ꢀtriꢀ
azaacenaphtheneꢀ2ꢀcarboxylate (9b). Acetal 7a (2.33 mL,
0.014 mol) was added to a suspension of compound 6b (0.57 g,
1.79 mmol) in anh. ethanol (2 mL). The mixture was refluxed
under argon for 3 h and then kept at 10 °C for 24 h. The yellow
precipitate that formed was filtered off, washed with anh. ethaꢀ
nol, and dried. Crude compound 9b was obtained in a yield of
0.45 g (74%), recrystallization from MeCN afforded the analytiꢀ
cally pure compound 9b in a yield of 0.31 g (51%), m.p.
A mixture of methyl and ethyl 3ꢀ[1ꢀ(dimethylamino)ethylꢀ
idene]aminoꢀ4ꢀ(4ꢀchloroanilino)thieno[2,3ꢀb]pyridineꢀ2ꢀcarbꢀ
oxylate (8a and 8´a). Acetal 7a (1.56 mL, 9.587 mmol) was
added to a suspension of compound 6a (0.40 g, 1.2 mmol) in
anh. ethanol (2 mL), the mixture was refluxed for 4 h, and cooled
to 20 °C. The solvent and excess of acetal were evaporated
in vacuo, the yellow precipitate was obtained, which represents
a mixture of compounds 8a and 8´a in 1 : 2 ratio based on the
1
1H NMR and mass spectra, m.p. 165 °C. H NMR spectrum of
compound 8´a (DMSOꢀd6), δ: 1.22 (t, 3 H, COOCH2CH3,
J = 7.10 Hz); 1.98 (s, 6 H, NCCH3N(CH3)2); 3.12 (s, 3 H,
N(CH3)2); 4.16 (q, 2 H, COOCH2CH3, J = 7.10 Hz); 6.89 (d, 1 H,
H(5), Jo = 5.70 Hz); 7.32, 7.44 (A2B2, 4 H, Ar, Jo = 8.70 Hz);
8.19 (d, 1 H, H(6), Jo = 5.70 Hz); 9.95 (br.s, 1 H, NH). MS (EI),
m/z, (Irel (%)): 371 [M8´a – NHMe2]+• (65).
A mixture of methyl and ethyl 3ꢀ[1ꢀ(dimethylamino)ethylꢀ
idene]aminoꢀ4ꢀ(3ꢀfluoroanilino)thieno[2,3ꢀb]pyridineꢀ2ꢀcarboxꢀ
ylate (8c and 8´c) was prepared analogously in a ratio 1 : 2. 1H
NMR spectrum of compound 8´c (DMSOꢀd6), δ: 1.23 (t, 3 H,
COOCH2CH3, J = 7.10 Hz); 1.98 (s, 3 H, NCCH3N(CH3)2);
3.14 (s, 6 H, N(CH3)2); 4.17 (q, 2 H, COOCH2CH3, J = 7.10 Hz);
6.97—7.02 (m, 2 H, Ar, H(5)); 7.14—7.23 (m, 2 H, Ar);
7.42—7.46 (m, 1 H, Ar); 8.24 (d, 1 H, H(6), Jo = 6.00 Hz); 10.00
(br.s, 1 H, NH).
A mixture of methyl and ethyl 3ꢀ[1ꢀ(dimethylamino)ethylꢀ
idene]aminoꢀ4ꢀ(3,4ꢀdifluoroanilino)thieno[2,3ꢀb]pyridineꢀ2ꢀcarbꢀ
oxylate (8d and 8´d) was prepared analogously in a ratio 1 : 2.
1H NMR spectrum of compound 8´d (DMSOꢀd6), δ: 1.24 (t, 3 H,
COOCH2CH3, J = 7.10 Hz); 1.99 (s, 3 H, NCCH3N(CH3)2);
3.14 (s, 6 H, N(CH3)2); 4.18 (q, 2 H, COOCH2CH3, J = 7.10 Hz);
6.90 (d, 1 H, H(5), Jo = 5.85 Hz); 7.07—7.26 (m, 1 H, Ar);
7.35—7.61 (m, 2 H, Ar); 8.24 (d, 1 H, H(6), Jo = 5.85 Hz); 9.92
(br.s, 1 H, NH).
228—230 °C (MeCN). IR (Nujol mulls), ν/cm–1: 1690 (COOCH3).
MS (ES), m/z: 342 [M + H]+•, 364 [M + Na]+•, 683 [2 M + H]+
,
•
705 [2 M + Na]+•, 310 [M – OMe]+•. 1H NMR (DMSOꢀd6), δ:
2.06 (s, 3 H, CH3); 3.83 (s, 3 H, COOCH3); 5.78 (d, 1 H, H(6),
Jo = 5.40 Hz); 7.44 (t, 2 H, Ar, J = 5.60 Hz); 7.63 (m, 2 H, Ar);
8.22 (d, 1 H, H(7), Jo = 5.40 Hz). Found (%): C, 59.81; H, 3.63;
N, 12.20. C17H12FN3O2S. Calculated (%): C, 59.82; H, 3.54;
N, 12.31.
A mixture of methyl and ethyl 4ꢀmethylꢀ5ꢀ(4ꢀfluorophenyl)ꢀ
5Hꢀ1ꢀthiaꢀ3,5,8ꢀtriazaacenaphtheneꢀ2ꢀcarboxylate (9b and 9´b).
A. Acetal 7a (0.41 mL, 2.52 mmol) was added to a suspension of
compound 6b (0.10 g, 0.32 mmol) in anh. ethanol (2 mL), the
mixture was refluxed for 4 h. The reaction mixture was cooled to
10 °C and kept for 12 h. The yellow precipitate that formed was
filtered off, washed with anh. ethanol, and dried. The precipitate
represented a mixture of compounds 9b and 9´b in 1 : 4 ratio
based on the 1H NMR and mass spectra, yield 0.10 g, m.p. 225 °C.
1H NMR spectrum of compound 9´b (DMSOꢀd6), δ: 1.28 (t, 3 H,
COOCH2CH3, J = 7.10 Hz); 2.06 (s, 3 H, CH3); 4.23 (q, 2 H,
COOCH2CH3, J = 7.10 Hz); 5.80 (d, 1 H, H(6), Jo = 5.50 Hz);
7.51 (t, 2 H, J = 5.60 Hz, Ar); 7.66 (d.d, 2 H, Ar, J = 8.80 Hz,
J = 5.00 Hz); 8.25 (d, 1 H, H(7), Jo = 5.50 Hz). MS (EI),
m/z, (Irel (%)): 283 [M6a – COOCH3, M6´a – COOEt]+
•

1956
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
Medvedeva et al.
+
+
•
•
(100), 355 [M6´a
]
(65), 341 [M6a
]
(22), 310 [M6a – OMe,
J = 7.10 Hz); 3.07, 3.12 (both s, 3 H each, N(CH3)2); 4.21
(q, 2 H, COOCH2CH3, J = 7.10 Hz); 6.80 (d, 1 H, H(5), Jo =
= 5.70 Hz); 7.30—7.19 (m, 2 H, Ar); 7.34—7.44 (m, 2 H, Ar);
8.03 (s, 1 H, NCHNMe2); 8.17 (d, 1 H, H(6), Jo = 5.70 Hz);
10.37 (br.s, 1 H, NH). 1H NMR spectrum of compound 11´b
(DMSOꢀd6), δ: 1.30 (t, 3 H, COOCH2CH3, J = 7.10 Hz); 4.30
(q, 2 H, COOCH2CH3, J = 7.10 Hz); 6.25 (d, 1 H, H(6),
Jo = 5.50 Hz); 7.52 (t, 2 H, Ar, J = 8.70 Hz); 7.72 (d.d, 2 H, Ar,
J = 8.90 Hz, J = 4.90 Hz); 7.99 (s, 1 H, H(4)); 8.35 (d, 1 H,
H(7), Jo = 5.50 Hz).
B. Acetal 7b (0.36 mL, 2.52 mmol) was added to a suspenꢀ
sion of compound 6b (0.10 g, 0.32 mmol) in anh. toluene (3 mL),
the mixture was refluxed for 4 h. The solvent and excess of acetal
were evaporated in vacuo, the yellow precipitate was obtained,
which represents a mixture of compounds 10b and 11b in 8 : 1
ratio (1H NMR).
Methyl 3ꢀacetamidoꢀ4ꢀ(4ꢀchloroanilino)thieno[2,3ꢀb]pyridꢀ
ineꢀ2ꢀcarboxylate (12). An aqueous solution of acetic acid (70%,
3 mL) was added to compound 8a (0.10 g, 0.25 mmol), the
yellow solution was refluxed for 14 h. The reaction mixture was
cooled to 20 °C and concentrated in vacuo almost to dryness.
The brown semicrystalline residue obtained was triturated with
methanol, the white precipitate that formed was filtered off,
washed with methanol, and dried. Compound 12 was obtained
in a yield of 0.07 g (75%), m.p. 210 °C (MeCN). MS (EI),
M6´a – OEt]+• (17).
B. A mixture of compounds 9b and 9´b was prepared analoꢀ
gously to a mixture of compounds 8a and 8´a. 9b : 9´b ratio
was 1 : 4.
Methyl 5ꢀ(4ꢀchlorophenyl)ꢀ5Hꢀ1ꢀthiaꢀ3,5,8ꢀtriazaacenaphthꢀ
eneꢀ2ꢀcarboxylate (11a). Acetal 7b (0.64 mL, 4.80 mmol) was
added to a suspension of compound 6a (0.20 g, 0.60 mmol) in
anh. toluene (5 mL). The mixture obtained was refluxed for 20 h.
The reaction mixture was cooled to 20 °C, the yellow precipitate
that formed was filtered off, washed with anh. toluene, and dried.
Compound 11a was obtained in a yield of 0.15 g (72%), m.p.
253 °C (MeOH). 1H NMR (DMSOꢀd6), δ: 3.80 (s, 3 H, COOCH3);
6.28 (d, 1 H, H(6), Jo = 5.50 Hz); 7.66, 7.71 (A2B2, 4 H, Ar,
Jo = 8.70 Hz); 7.96 (s, 1 H, H(4)); 8.33 (d, 1 H, H(7), Jo = 5.50 Hz).
Found (%): C, 55.96; H, 2.94; N, 12.12. C16H10ClN3O2S. Calꢀ
culated (%): C, 55.90; H, 2.93; N, 12.22.
Methyl 5ꢀ(4ꢀfluorophenyl)ꢀ5Hꢀ1ꢀthiaꢀ3,5,8ꢀtriazaacenaphthꢀ
eneꢀ2ꢀcarboxylate (11b) was prepared analogously from comꢀ
pound 6b, the reaction time was 19 h. The yield was 74%, m.p.
253 °C (MeOH). 1H NMR (DMSOꢀd6), δ: 3.81 (s, 3 H, COOCH3);
6.25 (d, 1 H, H(6), Jo = 5.50 Hz); 7.52 (m, 2 H, Ar); 7.72 (m, 2 H,
Ar); 7.99 (s, 1 H, H(4)); 8.35 (d, 1 H, H(7), Jo = 5.50 Hz).
Found (%): C, 58.64; H, 3.23; N, 12.89. C16H10FN3O2S. Calcuꢀ
lated (%): C, 58.71; H, 3.08; N, 12.84.
Reaction of compound 6a with acetal 7b. A. Acetal 7b (0.34 mL,
2.40 mmol) was added to a suspension of compound 6a (0.10 g,
0.30 mmol) in anh. ethanol (3 mL). The mixture was refluxed for
4 h. The solvent and excess of acetal were evaporated in vacuo,
the yellow precipitate was obtained, which contains comꢀ
pounds 10a and 11a, and also small amount of compound 10´a
(1H NMR), (10a + 10´a) : 11a ratio was 9 : 1. 1H NMR specꢀ
trum of compound 10a (DMSOꢀd6), δ: 3.08, 3.12 (both s, 3 H each,
m/z, (Irel (%)): 375 [M]+ (41), 357 [M – H2O]+ (48), 344
•
•
[M – OCH3]+• (33), 333 [M – CH2CO]+• (48), 326 [M – H2O –
– OCH3]+ (53), 301 [M – COOCH3 – CH3]+ (80), 274
•
•
[M – COOCH3 – CO + H]+ (57), 265 [M – H2O – OCH3 –
•
– Cl – CN]+ (96), 238 [M – COOCH3 – CO – Cl + H]+
•
•
(100), 229 [M – H2O – OCH3 – Cl – CH3 – NH – S]+ (68).
1H NMR (DMSOꢀd6), δ: 2.08 (s, 3 H, COCH3); 3.82 (s, 3 H,
COOCH3); 6.89 (d, 1 H, H(5), Jo = 5.60 Hz); 7.29, 7.45 (A2B2,
4 H, Ar, Jo = 8.70 Hz); 8.27 (d, 1 H, H(6), Jo = 5.60 Hz); 8.37
(br.s, 1 H, NHCOCH3); 9.90 (br.s, 1 H, NHC(4)). 1H NMR
(DMSOꢀd6—CD3OD), δ: 2.08 (s, 3 H, COCH3); 3.83 (s, 3 H,
COOCH3); 6.89 (d, 1 H, H(5), Jo = 5.60 Hz); 7.28, 7.42 (A2B2,
4 H, Ar, Jo = 8.70 Hz); 8.25 (d, 1 H, H(6), Jo = 5.60 Hz).
Found (%): C, 54.02; H, 3.67; N, 11.19. C17H14ClN3SO3. Calꢀ
culated (%): C, 54.33; H, 3.75; N, 11.18.
•
N(CH3)2); 3.75 (s, 3 H, COOCH3); 6.94 (d, 1 H, H(5), Jo
=
= 5.70 Hz); 7.38, 7.47 (A2B2, 4 H, Ar, Jo = 8.70 Hz); 8.06 (s, 1 H,
NCHNMe2); 8.21 (d, 1 H, H(6), Jo = 5.70 Hz); 10.53 (br.s, 1 H,
NH). 1H NMR spectrum of compound 10´a (DMSOꢀd6), δ:
1.25 (t, 3 H, COOCH2CH3, J = 7.10 Hz); 3.08, 3.12 (both s,
3 H each, N(CH3)2); 4.21 (q, 2 H, COOCH2CH3, J = 7.10 Hz);
6.94 (d, 1 H, H(5), Jo = 5.70 Hz); 7.38, 7.47 (A2B2, 4 H, Ar, Jo =
= 8.70 Hz); 8.03 (s, 1 H, H(4)); 8.21 (d, 1 H, H(6), Jo = 5.70 Hz);
10.50 (br.s, 1 H, NH).
B. Acetal 7b (0.34 mL, 2.40 mmol) was added to a suspenꢀ
sion of compound 6a (0.10 g, 0.30 mmol) in anh. toluene (3 mL),
the mixture was refluxed for 4 h. The solvent and excess of acetal
were evaporated in vacuo, the yellow precipitate was obtained,
which represents a mixture of compounds 10a and 11a in 5.3 : 1
ratio (1H NMR).
Reaction of compound 6b with acetal 7b. A. Acetal 7b (0.36 mL,
2.52 mmol) was added to a suspension of compound 6b (0.10 g,
0.32 mmol) in anh. ethanol (3 mL), the mixture was refluxed for
4 h. The solvent and excess of acetal were evaporated in vacuo,
the yellow precipitate was obtained, which contained compounds
10b and 11b, and also small amount of compounds 10´b and
11´b (1H NMR), (10b + 10´b) : (11b + 11´b) ratio was 4 : 1.
1H NMR spectrum of compound 10b (DMSOꢀd6), δ: 3.07, 3.12
(both s, 3 H each, N(CH3)2); 3.75 (s, 3 H, COOCH3); 6.80
(d, 1 H, H(5), Jo = 5.70 Hz); 7.30—7.19 (m, 2 H, Ar); 7.34—7.44
(m, 2 H, Ar); 8.06 (s, 1 H, NCHNMe2); 8.17 (d, 1 H, H(6),
Jo = 5.70 Hz); 10.37 (br.s, 1 H, NH). 1H NMR spectrum of
compound 10´b (DMSOꢀd6), δ: 1.26 (t, 3 H, COOCH2CH3,
3ꢀAcetamidoꢀ4ꢀ(4ꢀchloroanilino)thieno[2,3ꢀb]pyridineꢀ2ꢀ
carboxylic acid (13). Compound 8a (0.24 g, 0.60 mmol) was
added at 30 °C to a solution of sodium tertꢀbutoxide (0.08 g,
0.87 mmol prepared from sodium (0.02 g)) in tertꢀbutyl alcohol
(12.42 g) and the red solution obtained was refluxed for 3 h.
The reaction mixture was cooled to 20 °C, concentrated in vacuo,
anh. ethanol was added to the red oily residue obtained, and it
was concentrated in vacuo again. Cold water (200 mL) was addꢀ
ed to the semicrystalline residue and the suspension obtained
was stirred for 30 min. The red precipitate that has not been
dissolved was filtered off and washed with water to pH 7. The
precipitate was obtained in a yield of 0.05 g, which represented
a mixture of four products: compound 14 was the main product
and 13, 13´, 14´ were the minor ones. Glacial acetic acid
was added dropwise to weakly alkaline mother liquor until acid
reaction. The white precipitate that formed was filtered off and
washed with water to pH 7. Compound 13 was obtained in a yield
of 0.18 g (84%), m.p. 206 °C (H2O). MS (EI), m/z, (Irel (%)): 361
+
[M]+ (32), 343 [M – H2O]+ (100), 299 [343 – CO2] (42).
1H NMR spectrum of compound 13 (DMSOꢀd6), δ: 2.08
(s, 3 H, COCH3); 6.92 (d, 1 H, H(5), Jo = 5.60 Hz); 7.29, 7.46
•
•
•

Pyridothienopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
1957
(A2B2, 4 H, Ar, Jo = 8.75 Hz); 8.26 (d, 1 H, H(6), Jo = 5.60 Hz);
8.42 (br.s, 1 H, NHCOCH3); 10.08 (br.s, 1 H, NHC(4)).
Found (%): C, 53.69; H, 3.61; N, 11.64. C16H12ClN3O3S. Calꢀ
culated (%): C, 53.12; H, 3.34; N, 11.61.
of compounds 15a and 15b were solved by the method of systemꢀ
atic search19 in the centrosymmetrical Pꢀ1 group. Rigid threeꢀ
dimensional molecule model obtained as a result of the optimiꢀ
zation by the density functional method using the PRIRODA
program20 was used. Then the solution obtained was refined
by the Rietveld method using the MRIA program,21 peak proꢀ
files were described by the modified Voight function.22 In
the refinement, restriction to the permissible deflections of
the interatomic distances in the molecule and to the planarity of
the rings were applied. Parameters of thermal fluctuations of
nonhydrogen atoms were refined in an isotropic approximation.
Hydrogen atoms were placed at the calculated positions and
were not refined. The principal crystallographic characteristics
and experimental parameters of compounds 15a and 15b are givꢀ
en in Table 2. The experimental powder diagram and the differꢀ
ence curve as a result of refinement using the Rietveld method
are shown in Fig. 3. All structural data were deposited with the
Cambridge Crystallographic Database (CCDC 773568 and
CCDC 773569).
Methyl (4E)ꢀ4ꢀ(2ꢀoxopropylidene)ꢀ5ꢀ(4ꢀchlorophenyl)ꢀ4,5ꢀ
dihydroꢀ3Hꢀ1ꢀthiaꢀ3,5,8ꢀtriazaacenaphthyleneꢀ2ꢀcarboxylate
(15a). A suspension of amidine 8a (0.90 g) in acetic anhydride
(20 mL) was refluxed for 34 h. The reaction mixture was cooled
to 20 °C, the yellow precipitate was filtered off, washed with
methanol, and dried. Analytically pure compound 15a was obꢀ
tained in a yield of 0.55 g (61%), m.p. 315 °C (decomp.). IR
(KBr), ν/cm–1: 3400, 3092 br.s. (NH); 1696, 1632 (COCH3,
COOCH3). MS (EI), m/z, (Irel (%)): 399 [M]+ (79), 368
•
[M – OMe]+ (18), 352 [M – MeOH – NH]+ (87), 339
[M – CH3COOH]+• (31), 325 [M – COOCH3 – CH3]+• (100),
•
•
297 [325 – CO]+ (12). H NMR (DMSOꢀd6), δ: 1.91 (s, 3 H,
1
•
COCH3); 3.89 (s, 3 H, COOCH3); 4.44 (s, 1 H, C(4)=CH); 5.94
(d, 1 H, H(6), Jo = 5.50 Hz); 7.58, 7.77 (A2B2, 4 H, Ar, Jo
=
= 8.60 Hz); 8.32 (d, 1 H, H(7), Jo = 5.50 Hz); 14.56 (s, 1 H,
NH). 1H NMR (CDCl3), δ: 1.99 (s, 3 H, COCH3); 3.99 (s, 3 H,
COOCH3); 4.42 (s, 1 H, C(4)=CH); 5.82 (d, 1 H, H(6),
Jo = 5.50 Hz); 7.29, 7.63 (A2B2, 4 H, Ar, Jo = 8.60 Hz); 8.26
(d, 1 H, H(7), Jo = 5.50 Hz); 14.56 (s, 1 H, NH). Found (%):
C, 56.84; H, 3.78; N, 10.60. C19H14ClN3O3S. Calculated (%):
C, 57.07; H, 3.53; N, 10.51.
a
I (arb. units)
20000
Methyl (4E)ꢀ4ꢀ(2ꢀoxopropylidene)ꢀ5ꢀ(4ꢀfluorophenyl)ꢀ4,5ꢀ
dihydroꢀ3Hꢀ1ꢀthiaꢀ3,5,8ꢀtriazaacenaphthyleneꢀ2ꢀcarboxylate
(15b) was prepared analogously from compound 8b. The yield
was 76%, m.p. 310 °C (decomp.). IR (KBr), ν/cm–1: 3400, 3116
br.s. (NH); 1696, 1632 (COCH3, COOCH3). MS (EI), m/z,
×5
10000
(Irel (%)): 383 [M]+ (72), 353 [M – OMe]+ (7), 336 [M –
•
•
– MeOH – NH]+ (65), 323 [M – CH3COOH]+ (24), 309
[M – COOCH3 – CH3]+• (100), 281 [325 – CO]+• (37). 1H NMR
(DMSOꢀd6), δ: 1.91 (s, 3 H, COCH3); 3.89 (s, 3 H, COOCH3);
4.42 (s, 1 H, C(4)=CH); 5.92 (d, 1 H, H(6), Jo = 5.50 Hz);
7.45—7.67 (m, 4 H, Ar); 8.33 (d, 1 H, H(7), Jo = 5.50 Hz); 14.56
(s, 1 H, NH). 1H NMR (CDCl3), δ: 1.99 (s, 3 H, COCH3); 4.00
(s, 3 H, COOCH3); 4.42 (s, 1 H, C(4)=CH); 5.82 (d, 1 H, H(6),
Jo = 5.50 Hz); 7.28—7.38 (m, 4 H, Ar); 8.27 (d, 1 H, H(7), Jo =
= 5.50 Hz); 14.59 (s, 1 H, NH). 13C NMR (CDCl3—F3CCOOH),
1
1
2
•
•
0
10 20 30
40 50 60 70
2θ/deg
I (arb. units)
40000
b
δ: 29.3 (q, CH3CO, 1JCH = 128 Hz); 52.7 (q, COOCH3, 1JCH
= 148 Hz); 87.0 (d, C(α), 1JCH = 175 Hz); 102.8 (d.d, C(6), 1JCH
=
= 173 Hz, 2JCH(7) = 8.0 Hz); 117.2 (t, C(2b), 3JCH(6) = 3JCH(3)
=
=
1
3
= 5.1 Hz); 118.9 (d.d.d, C(2´), C(6´), JCH = 168 Hz, JCF
×5
3
3
= 23 Hz, JC(2´)H(6´) = 4 Hz, JC(6´)H(2´) = 4 Hz); 129.8 (m,
C(1´)); 130.3 (d.d.d, C(3´), C(5´), 1JCH = 166 Hz, 3JCF = 8.9 Hz,
20000
3JC(3´)H(5´) = 5.6 Hz; JC(5´)H(3´) = 5.6 Hz); 131.2; 151.8; 152.4
3
(C(2), C(2a), C(4), C(8a)); 147.3 (d.d, C(5a), JCH(7) = 8.8 Hz,
JCH(6) = 3 Hz); 148.2 (d.d, C(7), 1JCH = 187 Hz, 2JCH(6) = 3.4 Hz);
1
2
3
161.8 (q, COOCH3, JCO,CH3 = 4.1 Hz); 163.6 (d.m, C(4´),
1JCF = 254 Hz); 196.8 (q, COCH3, 2J = 4.0 Hz). Found (%):
C, 59.20; H, 3.72; N, 11.00. C19H14FN3O3S. Calculated (%):
C, 59.52; H, 3.68; N, 10.96.
0
10 20 30 40 50 60 70 80 90 2θ/deg
XꢀRay diffraction analysis of compounds 15a,b. The strucꢀ
tures of compounds 15a,b were established by powder Xꢀray
diffraction.16 Powder diagram was measured in the Guinier camꢀ
era Huber G670 containing bent germanium monochromator.
The positions of first 30 peaks were refined on the powder diaꢀ
gram. Using these positions, indicating in the triclinic cell was
carried out with the TREOR90 program.18 The crystal structures
Fig. 3. The result of elucidation of crystal structure of comꢀ
pounds 15a (a) and 15b (b) by the Rietveld method: experimenꢀ
tal curve (1), the difference between the experimental and calꢀ
culated curves as a result of refinement (2); highꢀangle area
(2θ > 40°) is presented on a large scale. The calculated positions
of reflexes are indicated as vertical segments.

1958
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
Medvedeva et al.
Table 2. Crystallographic characteristics of compounds 15a
and 15b
5. A. V. Kadushkin, I. F. Faermark, G. Ya. Shvarts, V. G. Granik,
Khim. Pharm. Zh., 1992, 26, 62 [Pharm. Chem. J. (Engl. Transl.),
1992, 26, 870].
6. A. S. Ivanov, N. Z. Tugusheva, L. M. Alekseeva, V. G. Granik,
Izv. Akad. Nauk, Ser. Khim., 2004, 837 [Russ. Chem. Bull.,
Int. Ed., 2004, 53, 873].
7. M. Yu. Yakovlev, A. V. Kadushkin, V. G. Granik, Khim.
Pharm. Zh., 1997, 31, 18 [Pharm. Chem. J. (Engl. Transl.),
1997, 31, 350].
8. A. S. Ivanov, N. Z. Tugusheva, N. P. Solov´eva, V. G. Granik,
Izv. Akad. Nauk, Ser. Khim., 2002, 1966 [Russ. Chem. Bull.,
Int. Ed., 2002, 51, 2121].
9. A. S. Ivanov, N. Z. Tugusheva, L. M. Alekseeva, V. G. Granik,
Izv. Akad. Nauk, Ser. Khim., 2003, 1120 [Russ. Chem. Bull.,
Int. Ed., 2003, 52, 1182].
Compound
15a
15b
Molecular formula
Crystal system
Space group
a/Å
b/Å
c/Å
C19H14ClN3O3S C19H14FN3O3
Triclinic
Pꢀ1
Triclinic
Pꢀ1
9.7539(11)
11.938(2)
8.8749(8)
100.58(2)
109.65(2)
66.950(18)
894.0(2)
27
9.7922(9)
11.4999(17)
8.8545(7)
98.749(17)
109.52(2)
66.270(15)
860.15(16)
32
α/deg
β/deg
γ/deg
V/Å3
M20
*
10. V. G. Granik, A. V. Kadushkin, J. Liebsher, Adv. Heterocycl.
Chem., 1998, 72, 79.
F30
*
35 (0.011, 57)
2
44 (0.009, 54)
2
Z
11. F. S. Babichev, Yu. A. Sharanin, V. P. Litvinov, V. K.
Ponomarenko, Yu. M. Volovenko, Vnutrimolekulyarnoe vzaꢀ
imodeistvie nitril´noi i CHꢀ, OHꢀ i SHꢀgrupp [Intramolecular
Interaction of Nitrile and CHꢀ, OHꢀ and SHꢀgroups], Naukoꢀ
va dumka, Kiev, 1985, 200 pp. (in Russian).
12. M. I. Medvedeva, N. Z. Tugusheva, L. M. Alekseeva, M. I.
Evstratova, S. S. Kiselev, V. V. Chernyshev, G. V. Avramenꢀ
ko, V. G. Granik, Izv. Akad. Nauk, Ser. Khim., 2009, 2265
[Russ. Chem. Bull., Int. Ed., 2009, 58, 2336].
13. V. G. Granik, S. I. Kaimanakova, Khim. Geterotsikl. Soedin.,
1983, 19, 816 [Chem. Heterocycl. Compd. (Engl. Transl.),
1983, 19, 714].
14. O. A. Zhdanov, V. I. Minkin, Korrelyatsionnyi analiz v organꢀ
icheskoi khimii [Correlation Analysis in Organic Chemistry],
RSU, RostovꢀnaꢀDonu, 1966, 470 pp. (in Russian).
15. A. V. Kadushkin, N. P. Solov´eva, V. G. Granik, Khim.
Pharm. Zh., 1993, 27, 40 [Pharm. Chem. J. (Engl. Transl.),
1993, 27, 251].
Dx (g cm–3
Radiation
)
1.485
1.480
CuꢀKα (1.5406) CuꢀKα (1.5406)
1
1
(waveꢀlength (Å))
Powder diagram:
2θmin—2θmax/deg
Step of measurement/deg
Rp*
4.00—80.00
4.00—90.00
0.01
0.01
0.0280
0.0358
0.0274
1.703
0.0300
0.0391
0.0232
2.829
Rwp*
Rexp
χ *
*
2
* Indicators of indication quality M20 (see Ref. 23) and F30
(see Ref. 24) were determined previously, Rp, Rwp, Rexp and
2
χ — see Ref. 25.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 10ꢀ03ꢀ00061ꢀa).
16. V. V. Chernyshev, Izv. Akad. Nauk, Ser. Khim., 2001, 2171
[Russ. Chem. Bull., Int. Ed., 2001, 50, 2273].
17. F. H. Allen, Acta Crystallogr., Sect. B: Struct. Sci., 2002,
58, 380.
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Received June 2, 2010;
in revised form July 21, 2010