Synthesis of substituted 4-oxo-3,4-dihydro-thieno[3,4-d]pyrimidines and comparison of their properties with those of positionally isomeric thienopyrimidinones and benzo isosteres

Article abstract of DOI:10.1007/s10593-010-0613-z

2-Arylmethyl- and 2-arylmethyl-3-methyl-substituted 3,4-dihydrothieno[3,4- d]pyrimidin-4-ones were synthesized starting from 2-cyanomethylbenzoic acid and methyl 3-amino-4-thiophenecarbonate, obtained in situ from its hydrochloride by a new method which g

Full text of DOI:10.1007/s10593-010-0613-z

Chemistry of Heterocyclic Compounds, Vol. 46, No. 8, 2010
SYNTHESIS OF SUBSTITUTED 4-OXO-3,4-DIHYDRO-
THIENO[3,4-d]PYRIMIDINES AND COMPARISON OF
THEIR PROPERTIES WITH THOSE OF POSITIONALLY
ISOMERIC THIENOPYRIMIDINONES AND BENZO
ISOSTERES
A. V. Zadorozhny1, A. V. Turov1, and V. A.Kovtunenko1*
2-Arylmethyl- and 2-arylmethyl-3-methyl-substituted 3,4-dihydrothieno[3,4-d]pyrimidin-4-ones were
synthesized starting from 2-cyanomethylbenzoic acid and methyl 3-amino-4-thiophenecarbonate,
obtained in situ from its hydrochloride by a new method which gives an increased yield of the desired
products. The physicochemical properties and the biological potential of the compounds synthesized
have been compared with analogous substituted 2,3-dimethylthieno[2,3-d][pyrimidinones,
thieno[3,2-d]pyrimidinones, and their benzene isosteres. The differences associated with the position of
the sulfur atom, are most clearly reflected in the electronic spectra. On the basis of calculated data, the
transition from derivatives of 4-oxo-3,4-benzopyrimidines to their analogous thieno isosteres leads to
changes in the profiles of their biological activities.
Keywords: isosteres, positionally isomers, derivatives of 4-oxo-3,4-dihydrothieno[3,4-d]pyrimidine,
calculation of biological activity, cyclization.
In a continuation of our investigation of positionally isomeric thienopyrimidones [1] in this work we
describe the synthesis of some substituted thieno[3,4-d]pyrimidin-4-one system (A) and compare the properties
of these compounds with those of known analogous derivatives of the thieno[2,3-d]pyrimidin-4-one (B) and
thieno[3,2-d]pyrimidin-4-one (C) systems and also their benzene isosteres of the quinazolin-4-one (D) system.
Derivatives of system A have been studied far less than those of derivatives of systems B and C. According the
date of Beilstein at the beginning of 2009 the number of references to compounds of series A, B, and C were in
the ratio 1:100:40. However even the small number of publications indicates the wide pharmacological profile of
derivatives of thieno[3,4-d]pyrimidin-4-one.
For example, substances are known which possess potential anticancer [2-4] and vasodilator [5]
properties, and aldose inhibitors of aldose reductase [6]. The representatives of this series which are under
_______
* To whom correspondence should be addressed, e-mail: vkovtunenko@univ.kiev.ua, shura_zd@ukr.net.
1Taras Shevchenko Kiev National University, Kiev 01033, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1227-1234, August, 2010. Original
article submitted March 4, 2009. Submitted after modification July 12, 2009. Submitted after second
modification May 5, 2009.
0009-3122/10/4608-0991©2010 Springer Science+Business Media, Inc.
991

investigations for treatment of AIDS [7], H2- [8] and H1-histamine receptors [9] antagonists have reached the
high level of pharmacological investigations. Derivatives of thieno[3,4-d]pyrimidin-4-one with benzyl or
modified benzyl substituents in position 2 have not been described.
Starting from 2-cyanomethylbenzoic acid (1) and methyl 3-amino-4-thiophenecarboxylate we have
synthesized compounds of types 3-6 of system A (series A) by the scheme shown below – these are analogs of
the derivatives of systems B, C, and D which we prepared previously: 3B-6B, 3C-6C [1], and 3D-6D [10, 11].
In connection with the known instability of the amino ester starting material [12], the latter was obtained in situ
from its hydrochloride 2 by adding to the reaction mixture the calculated amount of Et3N. The proposed new
method allowed the yield of product 3A to increase to 90%.
O
5
3
COOMe
CH2CN
COOH
Et3N
PhCl
NH
S
S
+
NH2
-o
·
HCl
N
CH2C6H4COOH
7
1
2
1
3A
O
O
Me
N
EtI
NH
MeI
K2CO3, DMSO
DMSO, Et3N
-o
N
O
CH2C6H4COOEt
-o
N
CH2C6H4COOEt
4A
6A
PhCOCH2Br
MeCN, Et3N
NH
-o
N
CH2C6H4(COOCH2COPh)
5A
Me
S
Me
S
3B–6B
3D–6D
3C–6C
For the others the conditions for obtaining derivatives 3-6 of series A were analogous to those we
described previously for the synthesis of compounds 3-6 of series B-D [1, 10, 11].
Acid 3A is a colorless finely crystalline substance which, like its analogs 3B-3D, has amphoteric
properties: it dissolves both in 2 N base solution and partially in 2 N HCl. The melting points of these acids fall
in the following order: 3C > 3D > 3B ≈ 3A. A different sequence is observed for the ethyl esters 4A-4D: 4B >
4D > 4C > 4A, which is retained for the phenacyl esters 5A-5D, and for the products of alkylation of the esters 4
– methyl-substituted 6A-6D. So among the compounds compared, derivatives of series A are the most readily
melted. Differences in chemical behavior and also in yields for the positional isomers 3-5 for series A-C were
not noted.
Table 1. IR Spectra of the Compounds Synthesized
ν, cm–1
Compound
O–С
С(=О)ОH
C=N
C(4)=O
C6H4C=О
PhC=O
3А
4А
5А
6А
1254
1262
1280
1267
—
1620
1608
1625
1598
1682
—
—
1077
1128
1082
1681
1669
1712
1692
1724
—
1686
992

The structure of compound 6A was established on the basis of its spectral characteristics. It is known
[13] that alkylation of the well studied thienopyrimidin-4-ones is possible both at atoms N(1), N(3), and the
1
oxygen atom. We excluded the structure of the O-methylated product on the basis of analysis of the IR and H
NMR spectra (Tables 1 and 2 respectively).
It was shown previously that alkylation at atom N(1) led to a shift of the carbonyl stretching vibration to
1630 cm-1, whereas the alternative alkylation at atom N(3) led to a shift to 1655-1660 cm-1 [11]. In the infrared
spectrum of compound 6A the band discussed was found at 1686 cm-1 (see Table 1). Since the possible
1-methyl- and 3-methyl-substituted compounds have identical structural fragments the spectra for the 1H and 13C
do not permit a conclusion on the direction of alkylation. Therefore we obtained two-dimensional NMR spectra
1
for product 6A with homonuclear (COSY, NOESY) and heteronuclear H-13C correlations across one (HMQC)
or 2-3 bonds (HMBC). In the NOESY spectrum there is only a single cross peak between the signals of the
protons of the NCH3 and CH3 groups which completely confirms the structure of 6A: on alkylation at N(1) a
cross peak with the signal of proton H-7 also would appears.
A basic indicator for the structure of 6A is the correlation signal of the protons of the NCH3 group at
3.53 ppm with the signal of the carbon atom of either the carbonyl group (C(4)=O) or COOEt) at 158.7 ppm.
Such a correlation is impossible for the group N(1)CH3 since the carbon atoms of the C=O groups are more than
three chemical bonds away. The HMQC, HMBC, and NOESY correlations are cited in Table 3. The signals of
the protons of the benzene ring can be assigned if it is assumed that the protons of the phenyl group neighboring
the COOEt substituent correspond to the chemical shift 7.95 ppm. The assignments of the remaining signals of
the spin systems then follow from the COSY correlation.
1
The H NMR spectral data for all the synthesized compounds 3-6 of series A are cited in Table 2.
Comparison with the known spectral data of the 3-6 analogs of series B, C [1] and D [10, 11] shows that change
in the position of the S atom and its replacement by the CH=CH unit affects the chemical shifts of the signal of
proton H-3 and the signals of the protons of the 2-CH3 and 3-CH3 groups: in all the compounds of series A these
signals are found at a stronger field, and the signals of their analogs in series C are at a weaker field. However
these differences are not very large and the most notable for the signals of the NH group was no more than
0.65 ppm.
8.27
O
H
29.8
CH33.53
5
127.4
158.7
N 3
147.4
NOESY
S
125 155.2
1 '
CH24.49
117.2
O
N
7
40.6
1
2" 1.22
4.17
7 '
1" CH2CH3
H
7.39
3 '
7.29
7.51
H
167
60.9
14.6
O
138.1
132
4 '
130.5
131
6 '
127.5
132.75 '
H
H
7.95
H
7.39
6A
HMQC and HMBC Correlation spectra for compound 6A.
Signals are assigned for all carbon atoms, the arrows show the most
important HMBC correlations, on which all the assignments are based.
993

994

TABLE 3. Results of Homonuclear (NOESY) and Heteronuclear (HMBC
and HMQC) Correlation Experiments for Compound 6A
Atom position
(see diagram)
δ, ppm
HMQC
127.4
HMBC
NOESY
5
6'
8.27
7.95
7.39
117.2; 125.0; 147.4; 158.7
132.7; 138.1; 167.0
125.0 (сл); 127.4; 130.5;
132.0; 147.4 (сл)
131.0; 132.0; 138.1
40.6; 127.5; 130.5; 132.7;
167.0 (сл)

131.0
7.39
7, 5'
117.2; 127.5
7.51; 7.95
4'
3'
7.51
7.29
132.7
132.0
7.29; 7.39
4.49; 7.51
3
3.53
4.49
29.8
40.6
155.2; 158.7
4.49
1'
130.5; 132; 138.1; 155.2;
167.0 (sl)
3.53; 7.29
1''
2''
4.17
1.22
60.9
14.6
14.6; 167.0
1.22
4.17
60.9
The IR spectra of the compared compounds 3-6 of series A-D are similar (see Table 1 and [1, 10, 11]).
For all of the esters 4-6 both intense "ester bands" of the C–O–C stretching vibration in the 1075-1128 range and
carbonyl bands in the 1260-1280 cm-1 range. In the spectra of acids 3 of series A, B, D and the esters 6 of series
A and D the absorptions of the C(4)=O and COOEt groups are observed as a single broad band.
Esters 4 of series A-C have intense absorptions in the UV region 220-315 nm. A notable difference in
their electronic spectra (see Table 4 and [1, 10]) is the position of the long wavelength maxima of the absorption
of the positional isomers A, B (313 and 312 respectively) and 4C (293 nm).The shift of these maxima (similar in
intensity) relative to the less intense absorption maximum of the isostere 4D should be noted: bathochromic
(~8-9 nm) in the case of compounds 4A, 4B and hypsochromic (~ 11 nm) for compound 4C. The spectra of the
acids 3A-D differ only in intensity from the spectra of their ethyl esters 4A-D. Alkylation at atom N(3) also does
not change the electron density distribution which is reflected in the similar spectra of the esters 6 of series A-D.
To elucidate the biological potentials of the substances synthesized with the help of the PASS programs
(Prediction of Activity Spectra for Substances) [14-16] an estimate of the spectra of their biological activity was
produced. The basis for the choice of the active compounds was the position in a multilevel estimate of the
surrounding atoms and a comparison of the calculated 2D descriptors with a choice of either high activity or an
absence of activity. The find results of the program are presented as a probability of the appearance of activity
(pa) or inactivity (pi) as parts of the unit. For each compound the spectrum of more than 3000 types of activities
was estimated, a threshold for activity was chosen pa > 0.8, pi < 0.2. From the analysis of the results of the
calculations (see Table 5) it was unexpectedly shown that none of the compounds 3-6 of series B fell within the
limits chosen. According to the predictive data, on transition from derivatives of series D to their thiophene
isosteres a change in the profile of biological activity occurs.
TABLE 4. Electronic Spectra of Esters 4 of series A-D
λmax, nm (log ε)
А
В [1]
С [1]
D [10]
235 (4.72)
266 (4.24)
313 (4.30)
220 (4.68) 236 (4.81) 230 (4.80)
260 (4.27) 265 (4.25) 266 (4.22)
312 (4.41) 293 (4.40) 304 (3.94)
995

TABLE 5. Results of Estimates of Biological Activity of the Compounds
Synthesized According to the PASS Program
Compound
3А
Probable type of biological activity
ра
Agonist of dopamine D4-receptor
Agonist of dopamine D4-receptor
Antiischemic (cerebral)
0.808
0.858
0.836
0.831
0.809
3С
Antiischemic
3D
Inhibitor of arylalkylacylamidazes
Inhibitor of (4S)-limonene synthetase
Agonist of dopamine D4-receptor
Antiischemic (cerebral)
4А,D, 6А
4С
0.814-0.853
0.840
0.830
Antiischemic
0.826
Inhibitor of (4S)-limonene synthetase
Antiischemic
0.803
5С
6С
0.835
Agonist of dopamine D4-receptor
Agonist of dopamine D4-receptor
Inhibitor of (4S)-limonene synthetase
0.822
0.838
0.807
EXPERIMENTAL
IR spectra (KBr tablets) were recorded with a Perkin-Elmer Spectrum BX instrument, UV spectra of
5·10-5 M DMF solutions were recorded with a Perkin-Elmer Lambda 20 UV-Vis spectrometer. 1H and 13C NMR
1
spectra of the compounds synthesized, two-dimensional H NMR spectroscopy, and also HMQC and HMBC
heteronuclear correlation spectra were recorded with a Varian Mercury 400 (400 and 100 MHz) instrument. All
two-dimensional experiments were carried with gradient selection of the beneficial signals. The mixing time of
1
2-3
the impulse sequences corresponded to JCH = 140.0 and
J
CH
= 8.0 Hz. The quantity of increments in the
1
COSY and HMQC spectra was 128, and in the HMBC spectra was 400. The H NMR spectra of the remaining
compounds were measured with a Bruker Avance DRX 500 (500 MHz). In all cases the solvent was DMSO-d6
and the internal standard was TMS. The individuality of the compounds synthesized was confirmed with an
Agilent 1100 series mass-chromatograph with an Agilent LC/MSD SL selective detector. Samples were
introduced in a trifluoroacetic acid matrix, an ionization was by EI. Melting points were measured in Pyrex
capillaries in a Thiele apparatus and were corrected.
The hydrochloride of the amino ester 2 was prepared using method [2].
2-(4-Oxo-3,4-dihydrothieno[3,4-d]pyrimidin-2-yl)methylbenzoic Acid (3A). To a suspension of
hydrochloride 2 (20 mmol) in chlorobenzene (5ml) were added successively triethylamine (3 ml, 40 mmol), then
with stirring 2-cyanomethylbenzoic acid (1.61 g, 10 mmol). The mixture was boiled for 10 min. After
evaporating the solvent in vacuum 1,4-dioxane (40 ml) was added to the residue and the suspension was boiled
for 2 h. After cooling, the precipitate was filtered off and washed with diethyl ether to give compound 3A,
2.57 g (90%); mp 270-271°C (DMF). Mass spectrum, m/z: 287 [M++1]. Found, %: C 58.75; H 3.50; N 9.80;
S 11.22. C14H10N2O3S. Calculated, %: C 58.73; H 3.52; N 9.78; S 11.20.
Esters 4-6 of series A were prepared by the method of paper [1].
Ethyl 2-(4-oxo-3,4-dihydrothieno[3,4-d]pyrimidin-2-yl)methylbenzoate (4A) was obtained from the
reaction of EtI with acid 3A. Yield 85%; mp 85-86°C (DMF). Mass spectrum, m/z: 315 [M++1]. Found, %:
C 61.15; H 4.50; N 8.89; S 10.19. C16H14N2O3S. Calculated, %: C 61.13; H 4.49; N 8.91; S 10.20.
2-Oxo-2-phenyl 2-(4-oxo-3,4-dihydrothieno[3,4-d]pyrimidin-2-yl)methylbenzoate (5A) was obtained
from acid 3A and phenacyl bromide. Yield 92%; mp 200-201°C (DMF). Mass spectrum, m/z: 405 [M++1]. Found:
%: C 68.00; H 4.12; N 7.25; S 8.29. C22H16N2O3S. Calculated, %: C 68.03; H 4.15; N 7.21; S 8.25.
996

Ethyl 2-(3-Methyl-4-oxo-3,4-dihydrothieno[3,4-d]pyrimidin-2-yl)methylbenzoate (6A) was obtained
from ester 4A and MeI. Yield 85%; mp 115-116°C (DMF). Mass spectrum, m/z: 329 [M++1]. Found, %:
C 62.16; H 4.88; N 8.52; S 9.78. C17H16N2O3S. Calculated, %: C 62.18; H 4.91; N 8.53; S 9.76.
The authors thank the firm "Enamin" (Kiev) for supporting this project.
REFERENCES
1.
T. T. Kucherenko, A. V. Zadorozhny, and V. A. Kovtunenko, Khim. Geterotsikl. Soed., 932 (2008).
[Chem. Heterocycl. Comp., 44, 750 (2008)].
2.
3.
4.
5.
6.
A. E. Shinkwin, W. J. D. Whish, and M. D. Threadgill, Bioorg. & Med. Chem., 7, 297 (1999).
Z. Brzozowski and F. Sączewski, Eur. J. Med. Chem., 43, 1188 (2008).
S. A. Patil, B. A. Otter, and R. S. Klein, J. Heterocycl. Chem., 30, 509 (1993).
R. K. Russel, J. B. Press and R. A. Rampulla, J. Med. Chem., 31, 1786 (1988).
K. Ogawva, I. Yamawaki, Y. I. Matsusita, N. Nomura, P. F. Kador, and J. H. Kinoshita, Eur. J. Med.
Chem., 28, 769 (1993).
7.
8.
9.
Z. Brzozowski and F. Sączewski, J. Heterocycl. Chem., 44, 261 (2007).
M. Sugiyama, T. Sakamoto, and K. Tabata, Chem. Pharm. Bull., 37, 2122 (1989).
D. T. Connor, R. J. Sorenson, and W. A. Cetenko, J. Med. Chem., 27, 528 (1984).
V. A. Kovtunenko, T. T. Kucherenko, O. V. Shishkin, and V. M. Kisel, Khim. Geterotsikl. Soed., 1408
(2002). [Chem. Heterocycl. Comp., 38, 1242 (2002)].
10.
11.
12.
V. A. Kovtuneko, T. T. Kucherenko, R. I. Zubatyuk, O. V. Shishkin, and D. A. Yushchenko, Khim.
Geterotsikl. Soed., 1532 (2007). [Chem. Heterocycl. Comp., 43, 1301 (2007)].
B. R. Baker, J. P. Joseph, R. E. Schaub, F. J. McEvoy, and J. H. Williams, J. Org. Chem., 18, 138
(1953).
13.
14.
M. S. Manhas and S. D. Sharma, J. Heterocycl. Chem., 8, 1051 (1971).
D. A. Filimonov, V. V. Poroikov, Yu. V. Borodina, and T. Gloriozova, J. Chem. Inf. Comput. Sci., 39,
666 (1999).
15.
16.
V. V. Poroikov, D. A. Filimonov, Yu. V. Borodina, A. A. Lagunin, and A. Kos, J. Chem. Inf. Comput.
Sci., 40, 1349 (2000).
V. V. Poroikov and D. A Filimonov, J. Comput. Aided Mol. Des., 16, 819 (2002).
997