Positional isomers of thienopyrimidinones

Article abstract of DOI:10.1007/s10593-008-0100-y

Condensation of o-cyanomethylbenzoic acids with esters of 2-aminothiophene-3-carboxylic and 3-amino-thiophene-2-carboxylic acids to give isomeric 2-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-ylmethyl)-benzoic acids and their ethyl and phenacyl esters. Met

Full text of DOI:10.1007/s10593-008-0100-y

Chemistry of Heterocyclic Compounds, Vol. 44, No. 6, 2008
POSITIONAL ISOMERS
OF THIENOPYRIMIDINONES
T. T. Kucherenko, A. V. Zadorozhny, and V. A. Kovtunenko
Condensation of o-cyanomethylbenzoic acids with esters of 2-aminothiophene-3-carboxylic and 3-amino-
thiophene-2-carboxylic acids to give isomeric 2-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-ylmethyl)-
benzoic acids and their ethyl and phenacyl esters. Methylation of esters occurs at N-3. The
spectroscopic characteristics of the positional isomers are compared at the level of carboxylic acids,
their esters, and methylated products.
Keywords: 4-oxopyrimidinones, thienopyrimidinones, thiophenes.
We have shown previously that derivatives of 4-oxo-2-quinazolinylmethylbenzoic acids are formed by
the reaction of o-cyanomethylbenzoic acid (1) with anthranilic [1] and N-methylanthranilic acids [2]. In a
continuation of this work we have used in the condensation with acid 1 any derivatives of vicinal enaminoacids
– esters of isomeric amino acids of the thiophene series.
It was established that boiling a chlorobenzene solution of acid 1 with 2 equivalents of the esters of the
amino acids 2 or 3 for 10 min gave derivatives of thienopyrimidinones 4 and 5 in yields of not less than 70%
(Table 1).
The yields of the required products were halved when equivalent amounts of the reagents were used.
The structures of the products as the derivatives 2-(4-oxo-3,4-dihydrothieno[2,3-d]- and –[3,2-d]pyrimidin-
2-ylmethyl)benzoic acids of the series 4 and 5 respectively were assigned on the basis of previous experiments
on the condensation of acid 1 with vicinal enamine acids and spectroscopic data for the compounds synthesized.
For this purpose comparisons with previously synthesized quinazolinones 10a-c are given in Tables 2 and 3.
Compounds of the 4-oxo-3,4-dihydrothieno[2,3-d]series were synthesized more than 35 years ago [3]. It
was established that 2-benzyl-substituted compounds of this system exhibit analgesic and anti-inflammatory
properties [4]. However isomeric structures of type 5 have not been investigated until now.
2-(4-Oxo-3,4-dihydrothieno[2,3-d]- and –[3,2-d]pyrimidin-2-ylmethyl)benzoic acids of the 4 and 5
series have amphoteric properties similar to normal amino acids: they dissolve in 2 N alkaline solution and
selectively in 2N HCl ( derivatives of the [2,3-d] series dissolve considerably better). In this connection
esterification of these amino acids is possible only by reaction of compounds with ethyl bromide (in DMSO) or
with phenacyl bromide (in acetonitrile) in the presence of triethylamine [5].
No difference in chemical behavior of the positional isomers was noted. By alkylation at atom N-3 by
standard methods [6] we obtained esters 8 and 9 of N-methylated 2-(4-oxo-3, 4-dihydrothieneo[2,3-d]- and –
[3,2-d]pyrimidin-2-ylmethyl)benzoic acids.
__________________________________________________________________________________________
Taras Shevchenko Kiev National University, Kiev 01033, Ukraine; e-mail: vkovtunenko@univ.kiev.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 932-941, June, 2008. Original article
submitted July 17, 2006. Revised version submitted April 18, 2007.
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0009-3122/08/4406-0750©2008 Springer Science+Business Media, Inc.

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Table 1. Characteristics of the Compounds Synthesized.
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C*
Yield, %
С
H
N
S
4a
4b
4c
4d
5a
5b
5c
6a
6b
6c
6d
6e
6f
C16H14N2O3S
C17H14N2O3S
C18H16N2O3S
C20H14N2O3S
C14H10N2O3S
61.21
61.13
62.82
62.56
63.60
63.51
66.02
66.29
4.38
4.49
4.22
4.32
4.61
4.74
3.91
3.89
3.63
3.52
3.42
3.30
3.30
3.44
5.41
5.30
4.46
4.66
5.01
5.12
4.46
4.53
5.36
5.47
4.96
4.84
4.63
4.49
4.08
3.99
5.57
5.66
8.76
8.91
8.33
8.58
8.13
8.23
7.55
7.73
9.52
9.78
6.92
7.06
7.13
7.36
8.35
8.18
6.23
6.48
7.76
7.90
6.15
6.30
7.58
7.60
6.03
6.11
9.04
8.91
6.82
6.93
7.78
7.86
10.12
10.20
9.75
9.83
9.33
9.42
8.95
8.85
11.08
11.20
8.14
8.08
8.24
8.43
9.55
9.36
7.55
7.41
9.20
9.05
7.23
7.21
8.84
8.70
6.87
6.99
10.45
10.20
8.04
7.93
9.14
9.00
338
333
350
290
265
290*2
305*2
210
240
240
245
242
245
130
200*2
160
120
73
85
88
90
70
92
90
80
92
84
88
82
90
80
90
83
80
58.93
58.73
C20H13ClN2O3S 60.82
60.53
C20H13FN2O3S
C18H18N2O3S
C24H20N2O4S
C19H18N2O3S
C25H20N2O4S
C20H20N2O3S
C26H22N2O4S
C16H14N2O3S
C22H16N2O4S
С19Н20N2O3S
C17H16N2O3S
63.12
63.15
63.41
63.14
66.78
66.65
64.62
64.39
67.88
67.55
65.62
65.20
68.56
68.10
61.79
61.13
7a
7b
8
65.92
65.33
63.91
64.02
61.52
62.18
9
4.86
4.91
8.68
8.53
9.92
9.76
_______
* Solvent: DMF (compounds 4a-d, 6c, 8), HOAc (compounds 5a, 7a, 9),
DMSO (compounds 6a,b)
*2 Conversion temperature.
1
Comparison of the H NMR spectra of the acids with structures 4 and 5 (Table 2) showed that the
hydrogen-containing groups of the o-carboxybenzyl substituent are practically unaffected by the change in
position of the sulfur atom in the bicyclic system. The resonances of the 1′-CH2 group, and the protons in
positions 3′,4′,5′, and 6′ are observed at standard resonances with minimal shift of 0.03 ppm in either direction.
1
The same may be observe on comparing the H NMR spectra of the esters 6a-f and 7a,b and the N-methylated
compounds 8 and 9.
In the IR spectra of the acids 4 and 5 (Table 3) in the 3200-2500 cm-1 region there are broad absorption
bands, frequently with several maxima. These bands arise, at least frequently, as a result of absorption of
dimmers of the acids and are assigned to bond vibrations of the O-H bond. From the massive vibration in this
region one can isolate the 2700-2500 cm-1, assigned to bonding vibrations of the hydroxyl OH. Examination of
the intermolecular association assists in resolving the intermolecular solution. The extremely low frequency of
the valence vibration of the carbonyl group (or the COOH group) is a direct reflection of this effect. The band of
the carbonyl absorption of the carboxyl group is superimposed on valence vibration of the carbonyl group of the
pyrimidin-4-one unit, the latter being also an active participant in association.
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753

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Table 3. IR and Mass Spectra
IR spectrum, ν, cm–1
Mass-spectrum,
m/z [M+ + 1]
(I 100%)*
Com-
pound
C=O
C=O
(carb)
C=O
(phenacyl)
C−O
С−C−O
C=N
(pyrim)
4a
4b
4c
4d
5a
5b
5c
10а
6a
6b
6c
6d
6e
6f
1274
1274
1271
—
—
1594
1594
1592
1592
1599
1598
1597
1600
1595
1593
1592
1595
1590
1594
1600
1595
1608
1551
1564
1595
1665
—
—
—
—
—
—
—
315/314
327/326
1664
1671
—
—
1664
1664
1712
1705
1268
—
287/286
—
1687
1683
1270
1250
1263
—
—
1670
1653
1667
1664
1671
1671
1670
1666
1654
1670
1676
1668
1670
1710
1711
1692*2
1710
1699
1721
1695
1708
1692
1710
1704
1705
1700
1081
1090
1081
1092
1070
1093
1079
1095
1078
1080
1081
1085
—
1723
—
343/342
355/354
369/368
315/314
1260
1267
1257
1269
1268
1278
1260
1258
1270
1265
1723
—
1712
7a
7b
10b
8
−
1724
—
—
9
—
10c
—
_______
* Most intense peak in the spectrum.
*2 Inflection
The carbonyl absorption of the pyrimidin-4-one unit as a participant in more complex structural
combination was investigated in the classical work of Brown [7] and is well tabulated [8]. In the same way in the
carboxylic acids 4d and 5a the shift of the νC=O band (from COOH, close to 1710 cm-1) is not large. The
carbonyl absorption of the pyrimidin-4-one unit remains close to 1670 cm-1. We attribute the former difference
to the influence of the phenacyl group at C-5 on the effectiveness of the hydrogen bond with participation of the
carbonyl at C-4, and the latter to the electronic effect on this centre of the heteroatom in the neighboring
position. On moving to the esters with structures 6-9 the picture in the carbonyl absorption region is simplified.
In all cases individual bands for νC=O (from COOR) and νC=O (from the pyrimidin-4-one unit) are observed, and
in the case of a phenacyl substituent, νC=O from the ketone carbonyl. Despite the remarkably low value of νC=O
,
especially for the esters with structures 6-9, these data agree with the recorded νC=O frequencies for quinazolone-
4s [9]. Intense “alcoholic” bands of the O-C-C unit close to 1070-1080 cm-1 and “acidic” (the unit C-(C=O)-O
close to 1260 cm-1 were observed for all the ethyl esters.
The electronic spectra of the carboxylic acids of the series 4 and 5 differ from that of acid 10a not only
in the number of absorption bands, but also in the distribution of their intensities in their limits (Fig. 1),
While for acid 10a three sharp bands of different intensity and two minima are observed in the region
analyzed, the contours for acids 4 and 5 are more complex and the maxima and minima described cannot be
contrasted. The principal reason from the point of view of analysis of the different positional isomers is the
bathochromic shift of ≈20 nm of the absorptions in the derivatives of the [2,3-d] series in comparison with their
positions for the [3,2-d] positional isomers, and ≈ 15 nm for the quinazolone-4 (10a). The spectra of the esters
with structure 6 and 7 differ little from the corresponding acids 4 and 5 Alkylation at atom N-3 (esters 8 and 9)
also does not change the electron density distribution in the esters 6 and 7 which is reflected in the similarity of
their UV spectra.
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nm
Fig. 1. UV spectra of carboxylic acids λ, nm (logε): 1 – acid 10a: 261 (4.19), 268*,
300 (3.69), 308 (3.62). 2 – acid 4a: 2.37 (4.59), 247*, 275 (4.20), 302 (4.31),
314 (4.36), 327*. 3 – acid 5a: 234 (4.71), 285 (4.30), 296 (4.31), 305*.
_______
* Inflexion.
EXPERIMENTAL
IR spectra of CsI and KBr tablets were recorded on Pye-Unicam SP3-300 and Nicolett Nexus
spectrometers. 1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded on a Varian
Mercury 400 (400 MHz). UV spectra of 5·10-5 M methanol solutions were recorded on a Specord M-40
spectrophotometer. Mass spectra were recorded on an Agilent 1100 series machine with an Agilent LC/MSD SL
selective detector, the samples were injected in a trifluoroacetic acid matrix, EI ionization, [M+ +1] molecular
ion peak. Melting points of the compounds synthesized were measured in a Pyrex capillary in a Tyl apparatus
and were corrected.
2-Cyanomethylbenzoic acid (1) was prepared by a known method [10].
Compounds 3b and 3c were obtained from Aldrich, and compounds 2a-d were obtained by a known
method [12].
Methyl 3-amino-2-thiophenecarboxylate (3a), mp 65°C, was obtained by method [11].
2-(4-Oxo-3,4-dihydrothieno[2,3-d]-pyrimidin-2-ylmethyl)benzoic Acids 4a-d and 2-(4-Oxo-3,4-
dihydrothieno[3,2-d]-pyrimidin-2-ylmethyl)benzoic Acids 5a-c (General Method). A mixture of 2-cyano-
methylbenzoic acid (1) (10 mmol) and the corresponding amino ester 2 or 3 (20 mmol) in chlorobenzene (5 ml)
was boiled with stirring for 10 min, the solvent was removed in vacuum, 1,4-dioxane (40 ml) was added to the
residue and the mixture was refluxed for 2h. The residue was filtered off and washed with diethyl ether.
Ethyl Esters 6a,c,e, and 7a (General Method). The corresponding thienopyrimidine 4a,c,e or 5a
(1 mmol) was dissolved in boiling DMSO, the solution was cooled and added dropwise with stirring to
triethylamine (0.1 ml, 1.5 mmol) and ethyl iodide (0.15 ml (1.5 mmol). The mixture was kept for 1 day, diluted
with water, the precipitate which formed was filtered off and washed in turn with saturated sodium hydrogen
carbonate solution, water, and diethyl ether.
Phenacyl Esters 6b,d,f, 7b (General Method). Triethylamine (0.2 ml, 3 mmol) was added to a
suspension of the corresponding acid 4a-c or 5a (3 mmol) in acetonitrile (5 ml) and phenacyl bromide (3 mmol)
in acetonitrile (2 ml) was added with stirring. After standing for a day, the solution was diluted with water, the
precipitate which formed was filtered off and washed in turn with a saturated solution of sodium hydrogen
carbonate, water, and diethyl ether.
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3,5,6-Trimethyl-4-oxo-2-(2-ethoxycarbonylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine (8) and
3-methyl-4-oxo-2-(2-ethoxycarbonylbenzyl)-3,4-dihydrothieno[3,2-d]pyrimidine (9) (General Method).
The corresponding ethyl ester (1 mmol) was dissolved in boiling DMSO. To the cooled solution were added
freshly prepared potash solution (0.14 g, 1 mmol) and methyl iodide (0.08 ml, 1 mmol). The mixture was left for
one day, diluted with water, the precipitate was filtered off and washed with water.
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