Synthesis of 5-methyl-4-oxo-2-(coumarin-3-yl)-N-aryl-3,4-dihydrothieno[2,3- d]-pyrimidine-6-carboxamides

Article abstract of DOI:10.1002/hc.20303

Possible approaches to synthesis of 5-methyl-4-oxo-2- (coumarin-3-yl)-N- aryl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamides 4 have been discussed. It is shown that the preferable approach is cyclization of 2-iminocoumarin-3- carboxamides 1, utilizing

Full text of DOI:10.1002/hc.20303

Heteroatom Chemistry
Volume 18, Number 4, 2007
Synthesis of 5-Methyl-4-oxo-2-(coumarin-
3-yl)-N-aryl-3,4-dihydrothieno[2,3-d]-
pyrimidine-6-carboxamides
Sergiy M. Kovalenko, Sergiy V. Vlasov, and Valentin P. Chernykh
National University of Pharmacy 53, Pushkinska str., Kharkiv, 61002, Ukraine
Received 30 March 2006; revised 20 April 2006
d]pyrimidine-6-carboxamides were patented as
ABSTRACT: Possible approaches to synthesis of
medicaments to cure obesity or diabetes [4]. How-
5-methyl-4-oxo-2-(coumarin-3-yl)-N-aryl-3,4-dihydro-
ever, compounds of this class, modified with a
thieno[2,3-d]pyrimidine-6-carboxamides 4 have been
coumarin moiety, have not been reported yet.
discussed. It is shown that the preferable approach
Earlier, we reported the interaction of 2-imino-
is cyclization of 2-iminocoumarin-3-carboxamides
coumarin-3-carboxamides with 2-aminothiophene-
1, utilizing 5-amino-3-methyl-N2-arylthiophene-2,4-
3-carboxamides, which leads to the formation
dicarboxamides 2 as binucleophilic reagents. The
of 2-(coumarin-3-yl)thieno[2,3-d]pyrimidin-4-ones,
proposed procedure allowed us to easily obtain
and developed a method for the synthesis of this
ꢀ
C
4 in two stages, using common reagents.
2007
class of compounds via cyclization of 2-(3-carba-
moyl-2-thienylimino)coumarine-3-carboxamides in
DMF [5–7]. To scrutinize the scope and limitations of
this method, we studied its capability with respect
to the synthesis of 5-methyl-4-oxo-2-(coumarin-
3-yl)-N-aryl-3,4-dihydrothieno[2,3-d]pyrimidine-6-
carboxamides 4.
Wiley Periodicals, Inc. Heteroatom Chem 18:341–
346, 2007; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20303
INTRODUCTION
It is known that 5-methyl-4-oxo-3,4-dihydrothieno-
[2,3-d]pyrimidine-6-carboxamides exhibit different
types of biological activities. Among them, there
are compounds that have been reported as sero-
toninergic receptor antagonists [1], and some of
them can be useful for treatment of cerebral is-
chemia [2]. Substances with related structures are
cyclin-dependent kinase 4 (Cdk4) inhibitors hav-
ing antitumor activity owing to cell cycle regulation
[3]. Some of 5-methyl-4-oxo-3,4-dihydrothieno[2,3-
RESULTS AND DISCUSSION
For the synthesis of 4, a few routes can be
considered. The most common approach is the
Knoevenagel condensation of salicylic aldehydes
with hetaryl acetates [8–16]. However, in spite of
the wide synthetic potential of this reaction, its
adaptation in this case is inconvenient due to the
difficulties faced in the preparation of 2-(4-oxo-
3,4-dihydrothieno[2,3-d]pyrimidine-2-yl)acetic acid
derivatives [17–19].
As an alternative approach to the synthesis
of 4, previously discovered rearrangement of 2-
iminocoumarin-3-carboxamides can be suggested
[8,9,20]. It can be presumed that the cyclization
This article is Part 7 of the series “Recyclization of 2-Imino-2H-
1-Benzopyrans Under the Action of Nucleophilic Reagents.”
Correspondence to: Sergiy M. Kovalenko; e-mail: kosn@
ukrfa.kharkov.ua
Contract grant sponsor: INTAS.
Contract grant number: 03-51-4915.
2007 Wiley Periodicals, Inc.
c
ꢀ
341

342 Kovalenko, Vlasov, and Chernykh
O
N
NH2
O
R
O
CH3
H2N
O
NH2
O
NH2
AcOH
reflux
R
O
+
S
H2N
O
NH
S
NHAr
ArHN
CH3
2
1
O
O
N
CH3
3
O
HN
S
NHAr
DMF
R
reflux
O
O
4
SCHEME 1
of 2-iminocoumarin-3-carboxamides
the action of 5-amino-4-carbamoyl-3-methyl-2-
thiophene-3-carboxylate will result in the formation
1
under
nitrobenzene or AcOH, barring hydrolysis or
decarboxylation.
The progress of the reaction was monitored by
the release of ammonia. The resulting 4 was isolated
as bright yellow solid and was not further purified.
Their data are listed in the Table 1.
of
ethyl
5-methyl-4-oxo-2-(coumarin-3-yl)-3,4-
dihydrothieno[2,3-d]pyridine-6-carboxylate. The
proposed intermediate for this synthesis—5-amino-
4-carbamoyl-3-methyl-2-thiophene-3-carboxylate—
has not been obtained yet, neither using the Gewald
synthetic procedure nor with the application of
other methods [21]. In the synthesis of this com-
pound, our experiments also gave unfavourable
results.
Therefore for the synthesis of 4, we propose
the use of 5-amino-3-methyl-N2-arylthiophene-2,4-
dicarboxamides 2 as N,N-binucleophilic reagents
(Scheme 1). It is noteworthy that compounds 2 are
also not much reported [22], notwithstanding the
fact that they can be easily obtained using the stan-
dard Gewald procedure for 2-aminothiophene syn-
thesis [23].
With regard to the above-mentioned conditions
in order to obtain 4, we studied the interaction of
2 with 1. It was discovered that heating, as well
as continuous refluxing of 1 and 2 in glacial acetic
acid, does not result in the formation of 4, although
the similar rearrangement readily proceeds at reflux-
ing in AcOH in this case when anthranilamide or
2-amino-1-benzenesulfonamide is used as a binucle-
ophile [8,20,24]. In our experiment, only the prod-
ucts of iminogroup substitution, 2-(3-carbamoyl-
2-thienylimno)coumarin-3-carboxamides 3, were
isolated. The desired cyclization proceeds only when
products 3 are refluxed in DMF for 4–6 h. Evi-
dently, the use of DMF as a solvent facilitates open-
ing of the iminolactone ring [25], thereby promoting
the reaction. At the same time, DMF medium sim-
plifies the synthetic procedure comparatively with
Structures of the synthesized compounds 4{1–
1
14} were assigned by elemental analyses H-NMR,
IR, and UV spectral data. 1H NMR spectra of all the
derivatives 4 show the signals of protons of coumarin
moiety at δ = 9.12–6.89 ppm, the broad signal cor-
responding to position 3 of thieno[2,3-d]pyrimidin-
4-one ring system at δ = 12.07–12.23 ppm, and the
signal of amide NH proton at δ = 10.45–9.63. The
signal of methyl group at position 5 of thieno[2,3-
d]pyrimidin-4-one moiety is shifted downfield com-
paratively with the starting compounds 2 and can be
observed at δ = 2.79–2.69 ppm.
The IR spectra of all compounds 4{1–14} exhibit
strong absorption bands 1720–1668 cm−1 (C O) and
3464–3152 cm−1 (N H). Bands at 3092–2862 cm−1
(C H) and 1616–1528 cm−1 (C C, C N) are also
present in all the spectra.
The UV–VIS absorption spectra of compounds
4{1–14} are very typical for 3-heterylcoumarins
[26]. Almost all of them possess two or three in-
tensive absorption maxima; the location of which
much depends upon the electronic nature of the
substituent in the coumarin ring. For the unsubsti-
tuted derivatives 4{1,10,13}, there are two maxima
at 33,600–33,580 cm−1 and at 25,500–25,260 cm−1;
in a similar manner, two maxima at 33,820–33,700
cm−1 and at 25,100–24,720 cm−1 are observed for
6-chlorocubstituted analogs 4{3,4,8,14}. The spec-
tra of compounds with electron-donating sub-
stituents (OMe) at positions 7 or 8 are characterized
by the appearance of the third maxima with lower
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of 5-Methyl-4-oxo-2-(coumarin-3-yl)-N-aryl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamides 343
TABLE 1 1H NMR Spectral and UV–VIS Data 4
R/Ar
Yields (%)
CH3
3-NH
ν cm−1 (logε)
4{1}
4{2}
H/Ph
8-OCH3/Ph
83
79
2.69
2.71
12.19
12.19
33,600 (4.70), 25,260 (4.63)
39,260 (4.45), 32,520 (4.53), 25,420
(4.47)
4{3}
4{4}
4{5}
6-Cl/Ph
6-Cl/4-CH3Ph
8-OC2H5/4-CH3Ph
75
73
87
2.67
2.73
2.69
12.19
12.18
12.19
33,700 (4.46), 25,100 (4.37)
33,820 (4.38), 24,940 (4.29)
39,000 (4.37), 32,540 (4.44), 25,240
(4.39)
4{6}
4{7}
7-OCH3/4-CH3Ph
8-OCH3/4-OCH3Ph
67
68
2.70
2.68
12.08
12.21
38,920 (4.35), 32,000 (4.39), 29,040
(4.24), 24,780 (4.58)
39,180 (4.53), 32,560 (4.64), 25,100
(4.53)
4{8}
4{9}
6-Cl/4-OCH3Ph
7-OCH3/4-OCH3Ph
65
58
2.69
2.72
12.19
12.12
33,740 (4.38), 24,720 (4.27)
39,080 (4.45), 31,820 (4.52), 29,280
(4.35), 24,700 (4.69)
4{10}
4{11}
H/3-FPh
8-OCH3/3-FPh
65
72
2.72
2.68
12.23
12.19
33,580 (4.31), 25,240 (4.23)
39,160 (4.20), 32,540 (4.29), 25,340
(4.24)
4{12}
7-OCH3/3-FPh
82
2.69
12.07
32,040 (4.45), 29,000 (4.29), 24,900
(4.65)
4{13}
4{14}
H/2,4-CH3Ph
6-Cl/2,4-CH3Ph
79
75
2.79
2.79
12.19
12.17
33,640 (4.33), 25,500 (4.27)
33,740 (4.44), 24,900 (4.38)
intensity at 39,260–38,920 cm−1. It should also be no-
ticed that in the case of 7-methoxysubstituted com-
pounds 4{6,9,12}, the long-wave maxima is shifted
to 24,900–24,700 cm−1 and its intensity noticeably
increases.
General Procedure for Synthesis of 2
To well-stirred equimolar suspension of acetoac-
etanilide, sulfur, and cyanoacetamide in ethanol
quintuple, excess of morpholine was added at once.
The mixture was stirred at 80◦C for 1–2 h. The precip-
itate formed after cooling was filtered off and washed
with propanol-2.
CONCLUSION
N2-Phenyl-5-amino-3-methyl-2,4-thiophenecarbox-
amide 2{1}. Yield, 67%, mp 234–235◦C; IR (cm−1):
3415, 3260, 3157, 3053, 3037, 3010, 2881, 1636,
The synthesis of 4 has been performed using the
rearrangement of 1, utilizing 5-amino-3-methyl-
N2-arylthiophene-2,4-dicarboxamides 2 as binucle-
ophilic reagents. The proposed procedure appeared
to be the most convenient as a two-step approach for
the synthesis of 4 using available reagents.
1
1595, 1578, 1531, 1489; H NMR: 2.55 (s, 3H, CH3),
7.0 (m, 3H, NH2 + 4ꢁ-H), 7.26 (m, 4H, 3ꢁ-H + 5ꢁ-H +
CONH2), 7.59 (d, 2H, J = 6.6 Hz, 2ꢁ−H + 6ꢁ-H), 9.48
(s, 1H, CONHAr). Calcd for C13H13N3O2S (275.33):
H, 4.76; C, 56.71; N, 15.26. Found: H, 4.65; C, 56.73;
N, 15.24.
N2-(4-Methylphenyl)-5-amino-3-methyl-2,4-thio-
phenecarboxamide 2{2}. Yield, 78%; mp 231–
233◦C; IR (cm−1): 3481, 3408, 3269, 3034, 2917,
EXPERIMENTAL
Melting points (◦C) were measured with Buchi B-520
melting point apparatus and were not corrected. IR
spectra were recorded on Specord M-80 spectrome-
ter in KBr. 1H-NMR spectra were recorded on Varian
Mercury 200 (200 MHz) spectrometer in DMSO-d6
using TMS as an internal standard (chemical shifts
are reported in ppm). UV–VIS absorption spectra
were registered at Specord M-40 spectrophotome-
ter in 1,4-dioxane. Elemental analyses were within
0.4% of the theoretical value.
1
1633, 1616, 1593, 1557, 1538; H NMR: 2.15 (s, 3H,
ArCH3), 6.94 (br s, 2H, NH2), 7.07 (d, 2H, J = 8.3
Hz, 3ꢁ-H + 5ꢁ-H), 7.24 (br s, 2H, CONH2), 7.46 (d,
2H, J = 8.3 Hz, 2ꢁ-H + 6ꢁ-H), 9.37 (s, 1H, CONHAr).
Calcd for C14H15N3O2S (289.36): H, 5.23; C, 58.11;
N, 14.52. Found: H, 5.18; C, 58.04; N, 14.57.
2-Iminocoumarin-3-carboxamides 1 was pre-
pared according to the reported methods [25,27,28].
∗In some cases in 1H NMR spectra, the signal of methyl group
is masked with DMSO signal.
Heteroatom Chemistry DOI 10.1002/hc

344 Kovalenko, Vlasov, and Chernykh
N2-(4-Methoxyphenyl)-5-amino-3-methyl-2,4-thio-
phenecarboxamide 2{3}. Yield, 84%; mp 223–225◦C;
IR (cm−1): 3480, 3411, 3264, 2962, 2915, 2839, 1629,
N6-Phenyl-5-methyl-4-oxo-2-(8-methoxycoumarin-
3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carbox-
amide 4{2}. Yield 79%; mp >300◦C; IR (cm−1):
3376, 3224, 3040, 2936, 1712, 1700, 1680, 1608,
1596, 1532. 1H NMR: 2.71 (s, 3H, CH3), 3.93 (s,
3H, OCH3), 7.11 (t, 1H, J = 6.9 Hz, 4ꢁ-H), 7.44
(m, 5H, 5H + 6-H + 7-H + 3ꢁ-H + 5ꢁ-H), 7.66 (d, 2H,
J = 7.8 Hz, 2ꢁ-H + 6ꢁ-H), 9.08 (s, 1H, 4-H), 10.25
(s, 1H, CONHAr), 12.19 (br s, 1H, NH). UV–Vis
(dioxane), νmax (log ε): 39,260 (4.45), 32,520 (4.53),
25,420 cm−1 (4.47) Calcd for C24H17N3O5S (459.48):
H, 3.73; C, 62.74; N, 9.15. Found: H, 3.63; C, 62.71;
N, 9.19.
1
1579, 1531, 1510; H NMR: 3.69 (s, 3H, ArOCH3),
6.83 (d, 2H, J = 8.4 Hz, 3ꢁ-H + 5ꢁ-H), 6.97 (br s,
2H, NH2), 7.23 (br s, 2H, CONH2), 7.38 (d, 2H,
J = 8.4 Hz, 2ꢁ-H + 6ꢁ-H), 9.39 (s, 1H, CONHAr).
Calcd for C14H15N3O3S (305.36): H, 4.95; C, 55.07;
N, 13.76. Found: H, 4.98; C, 55.18; N, 13.81.
N2-(3-Fluorophenyl)-5-amino-3-methyl-2,4-thio-
phenecarboxamide 2{4}. Yield 58%; mp 236–238◦C;
IR (cm−1): 3462, 3416, 3267, 3158, 3072, 2773, 1639,
1
1605, 1579, 1534; H NMR: 6.93 (t, 1H, J = 8.3 Hz,
5ꢁ-H), 6.99 (br s, 2H, NH2), 7.3 (m, 4H, 2ꢁ-H + 4ꢁ-H +
CONH2), 7.61 (d, 1H, J = 12.6 Hz, 6ꢁ-H), 9.62 (s,
1H, CONHAr).∗ Calcd for C13H12FN3O2S (293.32):
H, 4.12; C, 53.23; N, 14.33. Found: H, 4.27; C, 53.15;
N, 14.37.
N6-Phenyl-5-methyl-4-oxo-2-(6-chlorocoumarin-
3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carbox-
amide 4{3}. Yield 75%; mp >300◦C; IR (cm−1):
3420, 3352, 3216, 3052, 1716, 1684, 1668, 1600,
1528; 1H NMR: 2.67 (s, 3H, CH3), 7.11 (t, 1H,
J = 7.1 Hz, 4ꢁ-H), 7.34 (t, 2H, J = 7.3 Hz, 3ꢁH + 5ꢁH),
7.63 (m, 3H, 8-H + 2ꢁ-H + 6ꢁ-H), 7.80 (dd, 1H, J = 8.8,
2.7 Hz, 7-H), 8.15 (d, 1H, J = 2.7 Hz, 5-H), 9.00
(s, 1H, 4-H), 10.24 (s, 1H, CONHAr), 12.19 (br s,
1H, NH). UV–Vis (dioxane), νmax (log ε): 33,700
(4.46), 25,100 cm−1 (4.37) Calcd for C23H14ClN3O4S
(463.90): H, 3.04; C, 59.55; N, 9.06. Found: H, 2.95;
C, 59.59; N, 9.12.
N2-(2,4-Dimethylphenyl)-5-amino-3-methyl-2,4-
thiophenecarboxamide 2{5}. Yield 81%; mp 243–
245◦C; IR (cm−1): 3473, 3270, 3000, 2918, 1630,
1
1560, 1535, 1455; H NMR: 2.07 + 2.18 (s + s, 6H,
2,4-CH3Ar), 6.95 (m, 4H, 3ꢁ-H + 5ꢁ-H + NH2), 7.19
(m, 3H, 6ꢁ-H + CONH2), 8.89 (s, 1H, CONHAr).∗
Calcd for C15H17N3O2S (303.39): H, 5.65; C, 59.39;
N, 13.85. Found: H, 5.73; C, 59.21; N, 13.79.
N6-(4-Methylphenyl)-5-methyl-4-oxo-2-(6-chloro-
coumarin-3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-
carboxamide 4{4}. Yield 73%; mp >300◦C; IR
(cm−1): 3356, 3232, 3064, 2964, 1720, 1672, 1616,
1596, 1540; 1H NMR: 2.21 (s, 3H, CH3), 2.73 (s,
3H, CH3), 7.13 (d, 2H, J = 8.6 Hz, 3ꢁ-H + 5ꢁ-H), 7.55
(m, 3H, 8-H + 2ꢁ-H + 6ꢁ-H), 7.81 (dd, 1H, J = 9.2,
3.8 Hz, 7-H), 8.15 (d, 1H, J = 3.8 Hz, 5-H), 9.02
(s, 1H, 4-H), 10.17 (s, 1H, CONHAr), 12.18 (br s,
1H, NH). UV–Vis (dioxane), νmax (log ε): 33,820
(4.38), 24,940 cm−1 (4.29) Calcd for C24H16ClN3O4S
(477.93): H, 3.37; C, 60.32; N, 8.79. Found: H, 3.43;
C, 60.41; N, 8.84.
General Procedure for Synthesis of 4
To warm solution of 2 (2 mmol) in 20 mL of glacial
acetic acid, 1 (2 mmol) was added. The mixture was
refluxed for 1 h. The formed crystals of 3 were fil-
tered off and thoroughly washed with 2-propanol
and dried. The obtained product 3 (1.65 mmol) was
refluxed in DMF for 4–6 h and then cooled. The pre-
cipitate was filtered off and washed with 2-propanol
to give 4.
N6-Phenyl-5-methyl-4-oxo-2-(coumarin-3-yl)-3,4-
dihydrothieno[2,3-d]pyrimidine-6-carboxamide 4{1}.
Yield, 83%; mp >300◦C; IR (cm−1): 3336, 3240,
N6-(4-Methylphenyl)-5-methyl-4-oxo-2-(8-ethoxy-
coumarin-3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-
carboxamide 4{5}. Yield 84%; mp >300◦C; IR
(cm−1): 3440, 3248, 3092, 2976, 1684, 1604, 1596,
1
3048, 1712, 1684, 1612, 1600, 1536; H NMR: 2.69
(s, 3H, CH3), 7.11 (t, 1H, J = 8.0 Hz, 4ꢁ-H), 7.33 (t,
2H, J = 7.4 Hz, 3ꢁ-H + 5ꢁ-H), 7.45 (m, 2H, 8H + 6H);
7.65 (d, 2H, J = 7.6 Hz, 2ꢁ-H + 6ꢁ-H); 7.77 (t, 1H,
J = 7.4 Hz, 7H); 8.04 (d, 1H, J = 7.2 Hz, 5-H), 9.09
(s, 1H, 4-H), 10.25 (s, 1H, CONHAr), 12.9 (br s, 1H,
NH). UV–Vis (dioxane), νmax (log ε): 33,600 (4.70),
25,260 cm−1 (4.63). Calcd for C23H15N3O4S (429.46):
H, 3.52; C, 64.33; N, 9.78. Found: H, 3.64; C, 64.26;
N, 9.81.
1
1576; H NMR: 1,39 (t, 3H, J = 7.1 Hz, CH2CH3),
2.22 (s, 3H, CH3) 2.69 (s, 3H, CH3), 4.19 (q, 2H,
J = 7.1 Hz, OCH2CH3), 7.14 (d, 2H, J = 8.2 Hz,
3ꢁ-H + 5ꢁ-H), 7.47 (m, 5H, 5-H + 6-H + 7-H + 2ꢁ-
H + 6ꢁ-H), 9.03 (s, 1H, 4-H), 10.15 (s, 1H. CONHAr),
12.19 (br s, 1H, NH). UV–Vis (dioxane), νmax (log ε):
39,000 (4.37), 32,540 (4.44), 25,240 cm−1 (4.39).
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of 5-Methyl-4-oxo-2-(coumarin-3-yl)-N-aryl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamides 345
(4.45), 31,820 (4.52), 29,280 (4.35), 24,700 cm−1
(4.69). Calcd for C25H19N3O6S (489.51): H, 3.91; C,
61.34; N, 8.58. Found: H, 3.97; C, 61.29; N, 8.61.
Calcd for C26H21N3O5S (487.54): H, 4.34; C, 64.05;
N, 8.62. Found: H, 4.37; C, 64.17; N, 8.68.
N6-(4-Methylphenyl)-5-methyl-4-oxo-2-(7-methoxy-
coumarin-3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-
carboxamide 4{6}. Yield 67%; mp >300◦C; IR
(cm−1): 3388, 3244, 2924, 1680, 1616, 1600, 1536; 1H
NMR: 2.23 (s, 3H, CH3), 2.70 (s, 3H, CH3), 3.90 (s,
3H, CouOCH3), 7.12 (m, 4H, 6-H + 8-H + 3ꢁ-H + 5ꢁ-
H), 7.54 (d, 2H, J = 8.5 Hz, 2ꢁ-H + 6ꢁ-H), 7.98 (d,
1H, J = 9.6 Hz, 5-H), 9.11 (s, 1H, 4-H), 10.12 (s, 1H,
CONHAr), 12.08 (br s, 1H, NH). UV–Vis (dioxane),
νmax (log ε): 38,920 (4.35), 32,000 (4.39), 29,040
(4.24), 24,780 cm−1 (4.58). Calcd for C25H19N3O5S
(473.51): H, 4.04; C, 63.42; N, 8.87. Found: H, 4.07;
C, 63.35; N, 8.95.
N6-(3-Fluorophenyl)-5-methyl-4-oxo-2-(coumarin-
3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carbox-
amide 4{10}. Yield 65%; mp >300◦C; IR (cm−1):
3340, 3232, 3046, 2928, 1712, 1684, 1604, 1568,
1536; 1H NMR: 2.72 (s, 3H, CH3), 6.95 (t, 1H,
J = 6.7 Hz, 5ꢁ-H), 7.5 (m, 5H, 7-H + 8-H + 6ꢁ-H + 2ꢁ-
H + 4ꢁ-H), 7.79 (t, 1H, J = 8.6 Hz, 7-H), 8.04 (d, 1H,
J = 8.7 Hz, 5-H), 9.09 (s, 1H, 4-H), 10.45 (s, 1H,
CONHAr), 12.23 (br s, 1H, NH). UV–Vis (dioxane),
νmax (log ε): 33,580 (4.31), 25,240 cm−1 (4.23). Calcd
for C23H14FN3O4S (447.45): H, 3.15; C, 61.74; N,
9.39. Found: H, 3.09; C, 61.80, N, 9.44.
N6-(4-Methoxyphenyl)-5-methyl-4-oxo-2-(8-me-
thoxycoumarin-3-yl)-3,4-ydihydrothieno[2,3-d]pyrimi-
dine-6-carboxamide 4{7}. Yield 68%; mp >300◦C;
IR (cm−1): 3364, 3196, 2948, 1696, 1656, 1608,
1576, 1536; 1H NMR: 2.68 (s, 3H, CH3), 3.93 (s,
3H, CouOCH3), 3.74 (s, 3H, ArOCH3), 6.92 (d, 2H,
J = 8.4 Hz, 3ꢁ-H + 5ꢁ-H), 7.5 (m, 5H, 5-H + 6-H + 7-
H + 2ꢁ-H + 6ꢁ-H), 9.07 (s, 1H, 4-H), 10.12 (s, 1H,
CONHAr), 12,21 (br s, 1H, NH). UV–Vis (dioxane),
νmax (log ε): 39,180 (4.53), 32,560 (4.64), 25,100 cm−1
(4.53). Calcd for C25H19N3O6S (489.51): H, 3.91; C,
61.34; N, 8.58. Found: H, 3.89; C, 61.35; N, 8.55.
N6-(3-Fluorophenyl)-5-methyl-4-oxo-2-(8-methoxy-
coumarin-3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-
carboxamide 4{11}. Yield 72%; mp >300◦C; IR
(cm−1): 3356, 3224, 2924, 2886, 1684, 1604, 1576,
1536; 1H NMR: 2.68 (s, 3H, CH3), 3.92 (s, 3H,
CouOCH3), 6.95 (t, 1H, J = 7.9 Hz, 5ꢁ-H), 7.5 (m, 6H,
5-H + 6-H + 7-H + 6ꢁ-H + 2ꢁ-H + 4ꢁ-H), 9.04 (s, 1H,
4-H), 10.39 (s, 1H, CONHAr), 12,19 (br s, 1H, NH).
UV–Vis (dioxane), νmax (log ε): 39,160 (4.20), 32,540
(4.29), 25,340 cm−1 (4.24). Calcd for C24H16FN3O5S
(477.47): H, 3.38; C, 60.37; N, 8.80. Found: H, 3.43;
C, 60.39, N, 8.75.
N6-(4-Methoxyphenyl)-5-methyl-4-oxo-2-(6-chloro-
coumarin-3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-
carboxamide 4{8}. Yield 65%; mp >300◦C; IR
(cm−1): 3336, 3228, 2936, 1720, 1672, 1616, 1596,
1532; 1H NMR: 2.69 (s, 3H, CH3), 3.73 (s, 3H,
ArOCH3), 6.89 (d, 2H, J = 9.8 Hz, 3ꢁ-H + 5ꢁ-H), 7.56
(m, 3H, 8-H + 2ꢁ-H + 6ꢁ-H), 7.79 (dd, 1H, J = 9.1,
2.7 Hz, 7-H), 8.15 (d, 1H, J = 2.7 Hz, 5-H), 9.00
(s, 1H, 4-H), 10.09 (s, 1H, CONHAr), 12.19 (br s,
1H, NH). UV–Vis (dioxane), νmax (log ε): 33,740
(4.38), 24,720 cm−1 (4.27). Calcd for C24H16ClN3O5S
(493.93): H, 3.27; C, 58.36; N, 8.51. Found: H, 3.24;
C, 58.28; N, 8.64.
N6-(3-Fluorophenyl)-5-methyl-4-oxo-2-(7-methoxy-
coumarin-3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-
carboxamide 4{12}. Yield 82%; mp >300◦C; IR
(cm−1): 3245, 3236, 2862, 1684, 1616, 1604, 1540;
1H NMR: 2.69 (s, 3H, CH3), 3.89 (s, 3H, CouOCH3),
6.93 (t, 1H, J = 8.4 Hz, 5ꢁ-H), 7.04 (d, 1H, J = 9.1 Hz,
6-H), 7.12 (s, 1H, 8-H), 7.4 (m, 2H, 2ꢁ-H + 4ꢁ-H), 7.61
(d, 1H, J = 10.9 Hz, 6-H), 7.97 (d, 1H, J = 9.1 Hz,
5-H), 9.08 (s, 1H, 4-H), 10.39 (s, 1H, CONHAr),
12.07 (br s, 1H, NH). UV–Vis (dioxane), νmax (log
ε): 32,040 (4.45), 29,000 (4.29), 24,900 cm−1 (4.65)
Calcd for C24H16FN3O5S (477.47): H, 3.38; C, 60.37;
N, 8.80. Found: H, 3.46; C, 60.43, N, 8.84.
N6-(4-Methoxyphenyl)-5-methyl-4-oxo-2-(7-me-
thoxycoumarin-3-yl)-3,4-dihydrothieno[2,3-d]pyrimi-
dine-6-carboxamide 4{9}. Yield 58%; mp >300◦C;
IR (cm−1): 3328, 3244, 2932, 1704, 1672, 1620,
1604, 1536; 1H NMR: 2.72 (s, 3H, CH3), 3.74 (s,
3H, ArOCH3), 3.92 (s, 3H, CouOCH3), 6.89 (d,
2H, J = 9.3 Hz, 3ꢁ-H + 5ꢁ-H), 7.09 (dd, 1H, J = 9.1,
2.6 Hz, 6-H); 7.16 (d, 1H, J = 2.6 Hz, 8-H); 7.56 (d,
2H, J = 9.3 Hz, 2ꢁ-H + 6ꢁ-H); 7.99 (d, 1H, J = 9.1 Hz,
5-H), 9.12 (s, 1H, 4-H), 10.09 (s, 1H, CONHAr), 12.12
(br s, 1H, NH). UV–Vis (dioxane), νmax (log ε): 39,080
N6-(2,4-Dimethylphenyl)-5-methyl-4-oxo-2-(cou-
marin-3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-
carboxamide 4{13}. Yield 79%; mp >300◦C; IR
(cm−1): 3456, 3188, 3152, 2969, 2920, 1684, 1652,
1608, 1536; 1H NMR: 2.12 + 2.22 (s + s, 6H, ArCH3),
2.79 (s, 3H, CH3), 6.98 (d, 1H, J = 8.2 Hz, 5ꢁ-H), 7.05
(s, 1H, 3ꢁ-H), 7.23 (d, 1H, J = 8.2 Hz, 6ꢁ-H), 7.5 (m,
2H, 8-H + 6-H), 7.77 (t, 1H, J = 7.8 Hz, 7-H), 8.03 (d,
1H, J = 7.9 Hz, 5-H), 9.09 (s, 1H, 4-H), 9.65 (s, 1H,
CONHAr), 12,19 (br s, 1H, NH). UV–Vis (dioxane),
νmax (log ε): 33,640 (4.33), 25,500 cm−1 (4.27). Calcd
Heteroatom Chemistry DOI 10.1002/hc

346 Kovalenko, Vlasov, and Chernykh
[9] Kovalenko, S. N.; Zubkov, V. A.; Chernykh, V. P.;
Turov, A. V.; Ivkov, S. M. Chem Heterocyclic Comp
1996, 32, 186–192.
for C25H19N3O4S (457.51): H, 4.19; C, 65.63; N, 9.18.
Found: H, 4.12; C, 65.72, N, 9.21.
[10] Bragg, D. R.; Wibberley, D. G. J Chem Soc 1961,
5074–5077.
[11] Wolfbeis, O. S.; Marhold, E. H. Chem Ber 1985, 118,
3664–3672.
[12] Matei, S.; Russu, J.; Coltea, P.; Grecu, R. Rev Chim
(Bucharest, Rom.) 1982, 33, 527–530.
[13] Fathy, N. M.; Abdel Motti, F. M.; Elgemeie, G. E. H.
Arch Pharm 1988, 321, 509–512.
[14] Sabnis, R. W.; Kazemi Ghadir, J.; Rangnekar, D. W.
Phosphorus Sulfur Silicon Relat Elem 1992, 71, 1–6.
[15] Honna, T.; Ogawa, K.; Hashimoto, S.; Suzue, T.
Patent JP 52077087, CAN 87:184494.
[16] Elnagdi, M. H.; Abdallah, S. O.; Ghoneim, K. M.;
Ebeid, E. M.; Kassab, K. N. J Chem Res, Synop 1997,
44–45.
[17] Boehm, R.; Pech, R.; Petzold, B.; Lohmann, D.;
Laban, G. Patent DD 234269, CAN 105:208925.
[18] Shishoo, C. J.; Devani, M. B.; Ananthan, S.; Jain,
K. S.; Bhadti, V. S.; Mohan, S.; Patel, L. Indian J
Chem 1989, 28B, 1039–1047.
N6-(2,4-Dimethylphenyl)-5-methyl-4-oxo-2-(6-
chlorocoumarin-3-yl)-3,4-dihydrothieno[2,3-d]pyrimi-
dine-6-carboxamide 4{14}. Yield 75%; mp >300◦C;
1
IR (cm−1): 3408, 3225, 2919, 1671, 1541; H NMR:
2.16 + 2.22 (s + s, 6H, ArCH3), 2.79 (s, 3H, CH3),
6.98 (d, 1H, J = 9.4 Hz, 5ꢁ-H), 7.04 (s, 1H 3ꢁ-H); 7.19
(d, 1H, J = 9.4 Hz, 6ꢁ-H), 7.58 (d, 1H, J = 9.6 Hz,
8-H), 7.7 (dd, 2H, J = 9.6, 2.0 Hz, 7-H), 8.12 (d,
1H, J = 2.0 Hz, 5-H), 8.99 (s, 1H, 4-H), 9.63 (s, 1H,
CONHAr), 12.17 (br s, 1H, NH). UV–Vis (dioxane),
νmax (log ε): 33,740 (4.44), 24,900 cm−1 (4.38) Anal.
Calcd for C25H18ClN3O4S (491.96): H, 3.69; C, 61.04;
N, 8.54. Found: H, 3.67, C, 61.12, N, 8.48.
REFERENCES
[19] Pech, R.; Boehm, R. Pharmazie 1989, 44, 790–791.
[20] Kovalenko, S. N.; Chernykh, V. P.; Shkarlat, A. E.;
Ukrainets, I. V.; Gridasov, V. I.; Rudnev, S. A. Chem
Heterocyclic Comp 1998, 34, 791.
[21] Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J
Heterocyclic Chem 1999, 36, 333–345.
[22] Lockhart, D. J.; Patel, H. K.; Mehta, S. A.;
Milanov, Z. V.; Grotzfeld, R. M.; Lai, A. G. Patent
WO 2004110357, CAN 142:69180.
[1] Steiner, G.; Dullweber, U.; Starck, D.; Bach, A.;
Wicke, K.; Teschendorf, H-J.; Garcia-Ladona, F-J.;
Emling, F. Patent WO 9856792, CAN 130:66510.
[2] Steiner, G.; Schellhaas, K.; Lubisch, W.;
Holzenkamp, U.; Starck, D.; Knopp, M. S. L.;
Emling, F.; Garcia-Ladona, F. J.; Hofmann, H-P.;
Unger, L. Patent DE 19900545 CAN 133:89541.
[3] Uoto, K.; Horiuchi, T.; Akabane, K.; Takeda, Y. Patent
WO 2002051849, CAN 137:63255.
[23] Gewald, K.; Schinke, E.; Bottcher, H. Chem Ber 1966,
99, 94–100.
[4] Witter, D.; Castelhano, A. L. Patent WO 2003053944,
CAN 139:85360.
[24] Kovalenko, S. M.; Bylov, I. E.; Sytnik, K. M.;
Chernykh, V. P.; Bilokin, Y. V. Molecules 2000, 5,
1146–1165.
[5] Bilokin, Y. V.; Vasylyev, M. V.; Branytska, O. V.;
Kovalenko, S. M.; Chernykh, V. P. Tetrahedron 1999,
55, 13757–13766.
[25] O’Callaghan, C. N.; McMurry, T. B. H.; O’Brien J. E.
J Chem Soc, Perkin Trans 2 1998, 2, 425–429.
[26] Doroshenko, A. O.; Ivanov, V. V.; Kovalenko, S. N.,
Zhuravel’, I. A.; Yarmolenko, S. N.; Ponomarev, O. A.
Chem Phys Rep 1997, 16, 1973–1980.
[6] Vasylyev, M. V.; Bilokin, Y. V.; Branytska, O. V.;
Kovalenko, S. M.; Chernykh, V. P. Heterocycl Com-
mun 1999, 5, 241–242.
[7] Kovalenko, S. M.; Vlasov, S. V.; Chernykh, V. P. Syn-
thesis 2006, 847–852.
[27] Schiemenz, G.P. Chem Ber 1962, 95, 483.
[28] Czerney, P.; Hartmann, H. J Prakt Chem 1981, 323,
691.
[8] Kovalenko, S. N.; Bylov, I. E.; Belokon’, Y. V.;
Chernykh, V. P. Chem Heterocycl Comp 2000, 36,
1026–1031.
Heteroatom Chemistry DOI 10.1002/hc