Convenient synthesis of substituted 2-(2-iminocoumarin-3-yl)-thieno[2,3-d] pyrimidin-4-ones

Article abstract of DOI:10.1002/jhet.219

(Chemical Equation Presented) The interaction of both 2-iminocoumarin-3- carbonitriles and 2-iminocoumarin-3-carbothioamides with 2-aminothiophen-3- carboxamides lead to formation of 3-(4-oxo-3,4-dihydrothieno [2,3-d]pyrimidin-2-yl)-2-iminocoumarins in tw

Full text of DOI:10.1002/jhet.219

800
Convenient Synthesis of Substituted 2-(2-Iminocoumarin-3-yl)-
thieno[2,3-d]pyrimidin-4-ones
Vol 47
Pavlo E. Shynkarenko,a Sergiy V. Vlasov,a Sergiy M. Kovalenko,a*
Svitlana V. Shishkina,b Oleg V. Shishkin,b and Valentin P. Chernykha
aNational University of Pharmacy, Kharkiv, 61002, Ukraine
bSTC ‘Institute for Single Crystals,’ NAS of Ukraine, 61001, Kharkiv, Ukraine
*E-mail: kosn@ukrfa.kharkov.ua
Received November 4, 2008
DOI 10.1002/jhet.219
Published online 27 May 2010 in Wiley InterScience (www.interscience.wiley.com).
The interaction of both 2-iminocoumarin-3-carbonitriles and 2-iminocoumarin-3-carbothioamides with
2-aminothiophen-3-carboxamides lead to formation of 3-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-
2-iminocoumarins in two steps. The simplicity of the procedure, as well as the high yields of the target
products make this method to be a good alternative of Knoevenagel condensation for the synthesis of
3-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-2-iminocoumarins.
J. Heterocyclic Chem., 47, 800 (2010).
INTRODUCTION
yl)-2-iminocoumarins based on intramolecular rearrange-
ment of 2-iminocoumarins, so-called ‘‘recyclization’’
approach.
3-Substituted-2-iminocoumarins are known not only
due to their versatile biological activity, such as anti-
inflammatory [1,2], antimicrobial, antifungal [3,4], and
antitumor [5–9], but also as luminescent indicators [10]
and laser dyes [11–13]. They can also be useful as
effective reagents for 2-substituted 2H-1-benzopyrans
syntheses [14]. Therefore, the development of a simple
methodology for synthesis 2-iminocoumarins substituted
with heterocyclic moiety at position 3 is important prob-
lem of benzopyrans chemisrty.
Recently it was shown that ‘‘recyclization’’ of 2-imino-
coumarin-3-carboxamides under the action of binu-
cleophlic reagents results in various 3-heterylcoumarins
[25,26,32–37]. According to the proposed mechanism of
these reactions the carboxamide group of 2-iminocou-
marin-3-carboxamide serves as precursor of lactone C¼¼O
group of the resulting 3-heterylcoumarin. Thus, it was
worthy to assume that utilization of 2-iminocoumarin-3-
carbonitriles in a similar rearrangement would lead to the
formation of products with the C¼¼NH moiety in the 2
position of benzopyran ring. Therefore, we studied the
interaction between 2-iminocoumarin-3-carbonitriles and
2-aminothiophen-3-carboxamides as the possible conven-
ient approach for synthesis of desired 3-(4-oxo-3,4-dihy-
drothieno[2,3-d]pyrimidin-2-yl)-2-iminocoumarins.
With regard to the pharmacological potential of
thieno[2,3-d]pyrimidines [15–24] as the part of our
research work on the synthesis of 3-heteryl-2-iminocou-
marins [25,26], we focused our efforts on the synthesis
of 3-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-2-
iminocoumarins.
The most commonly used method for synthesis of 3-
heteryl-2-iminocoumarins is the Knoevenagel condensa-
tion of salicylic aldehydes with nitriles of heterylacetic
acids [27–30]. However, for synthesis of 3-(4-oxo-3,4-
dihydrothieno[2,3-d]pyrimidin-2-yl)-2-iminocoumarins
this approach is not convenient enough due to the diffi-
culties in the starting building-blocks, the corresponding
2-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)acetoni-
triles, preparation [31]. With the aim to develop more
suitable method, we tested the alternative route for syn-
thesis of 3-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-
RESULTS AND DISCUSSION
It is known that the interaction of 2-iminocoumarin-3-
carboxamides with arylamines in the glacial acetic acid
leads to formation of 2-N-aryliminocoumarin-3-carboxa-
mides [34–38]. We applied a similar reaction to obtain
the key-intermediates, which apparently were 2-(3-car-
bamoyl-2-thienylimino)-coumarin-3-carbonitriles 3 by
interaction between 2-iminocoumarin-3-carbonitriles 1
C
V
2010 HeteroCorporation

July 2010
Convenient Synthesis of Substituted 2-(2-Iminocoumarin-3-yl)-
thieno[2,3-d]pyrimidin-4-ones
801
Scheme 1
and 2-aminothiophen-3-carboxamides 2. The compounds
3 were isolated from glacial acetic acid as red solids
and used without any additional purification.
Unfortunately the compounds 5 appeared to be slightly
soluble in the suitable solvents to measure 13C NMR
spectra. Thus with the aim to prove the presence of im-
ino-group in the molecule of these derivatives we per-
formed their acidic hydrolysis (HCl) in 2-propanol-water
mixture. The obtained products appeared to be the same
as previously reported 3-(4-oxo-3,4-dihydrothieno[2,3-
d]pyrimidin-2-yl)coumarins 7a–c [34–36] (Table 1).
Also the presence of the imino group in the structure
of 5 allowed us to obtain 2-N-aryliminoproducts 6
(using reaction of 5 with m-anisidine in glacial acetic
acid) as crystalline substances.
The ‘‘recyclization’’ of 2-(3-carbamoyl-2-thienylimi-
no)coumarin-3-carbonitriles 3 was performed by heating
in DMF. The anhydrous solvent was used to avoid hy-
drolysis of the imino group of product 5 formed
(Scheme 1). The proposed mechanism of ‘‘recycliza-
tion’’ reaction is depicted on the Scheme 2.
The compounds 5a–m were obtained in the high
yields (65–89%) (Method A).
1
In the H NMR spectra of the compounds 5a–m, the
1
signal of proton in the position 4 of coumarin resonate
in the range d 8.66–8.83 ppm, as well as the signal of
imino group proton (d 9.31–9.51 ppm) and aromatic
protons (d 7.20–7.94 ppm) are present. All these spectra
also contain signal of thieno[2,3-d]pyrimidine fragment
NH (14.08–14.50 ppm). Though the LC/MS spectra for
compound 5 show their high purity, in most cases the
1H NMR spectra of derivatives 5 in DMSO-d6 contain
some additional signals, possibly from the open form of
the iminolactone ring.
In the H NMR spectra of the compounds 6a–d the
signals of methoxygroup (3.76–3.78 ppm) and aromatic
protons (6.73–7.53 ppm) of 3-methoxyphenyl substituent
appear.
The crystals of compound 6a appeared to be suitable
for X-ray diffraction analysis after the crystallization
from DMF. In the crystal phase of the compound 6 was
observed as hemisolvate with DMF.
According to X-ray diffraction data the 2-minocou-
marin fragment and 4-oxo-3,4-dihydrothieno[2,3-d]pyri-
˚
midin fragment are coplanar within 0.04 A (Fig. 1).
The IR-spectra (KBr) of the compounds 5a–m have
the strong absorption bands of t C¼¼O and t C¼¼N at
1700–1621 cmꢀ1, the broad band of t NAH (pyrimidine
and imino-group) at 3500–3150 cmꢀ1. In the spectra of
the products 5, the signal of t CN is absent compara-
tively with the spectra of intermediates 3 (2240–2220
cmꢀ1).
Such arrangement of these fragments relatively
each other is stabilized by the formation of the
N(2)AH(2N). . .N(3) intramolecular hydrogen bond
ꢁ
˚
(H. . .N 1.96 A NAH. . .N 138 ) and the H(19). . .N(1)
˚
attractive interaction (2.39 A when compared with the
˚
van der Waals radii sum [39] 2.67 A). The
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

802
P. E. Shynkarenko, S. V. Vlasov, S. M. Kovalenko, S. V. Shishkina, O. V. Shishkin,
and V. P. Chernykh
Vol 47
Table 1
aminothiophen-3-carboxamides 2 in glacial acetic acid.
Further ‘‘recyclization’’ have been performed by heating
compounds 9 in DMF. Though instead of the desired 2-
(2-thiocoumarin-3-yl)thieno[2,3-d]pyrimidin-4-ones 10
3-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-2-imi-
nocoumarins 5 were isolated (Scheme 3). Thus it can be
deduced that in this case the hydrogen sulfide cleavage
is preferable way for recyclization the 2-iminocoumarin-
3-carbothioamides (Scheme 4) (Method B).
Synthesis of compounds 5a–m, 6a–d, and 7a–c.
No.
R
Yielda (%)
5a
5b
5c
5d
6a
6b
6c
7a
H
6-Cl
8-OMe
8-OEt
6-Cl
8-OMe
8-OEt
H
74
65
84
88
83
90
92
90
CONCLUSION
It was established that interaction of both 2-iminocou-
marin-3-carbonitriles and 2-iminocoumarin-3-carbothio-
amides with 2-aminothiophen-3-carboxamides after the
rearrangement of arylimino intermediates lead to forma-
tion of 3-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-
yl)-2-iminocoumarins. The simplicity of the proposed
procedure as well as the high yields of the target prod-
ucts make this method to be a good alternative of Knoe-
venagel condensation for the synthesis of derivatives 5.
The further reaction of 5 with m-anisidine allowed us to
obtain 2-(2-(3-methoxyphenylimino)-coumarin-3-yl)th-
ieno[2,3-d]pyrimidin-4-ones 6.
5e
5f
H
6-Cl
66
69
75
78
89
88
89
5g
5h
6d
7b
7c
8-OMe
8-OEt
8-OMe
H
8-OMe
5i
H
68
5j
5k
5l
H
6-Cl
85
65
79
80
8-OMe
8-OEt
5m
EXPERIMENTAL
Melting points were measured with a Buchi B-520 melting
point apparatus and were not corrected. Elemental analyses
were within 6 0.4% of the theoretical value. IR spectra were
recorded on Specord M80 spectrometers in KBr. 1H NMR
spectra were recorded on Varian Mercury-200 spectrometer in
DMSO-d6 and CDCl3 using TMS as an internal standard.
Mass spectral analyses were obtained on a PE SCIEX API
150EX mass spectrometer.
a Isolated yields of 5 based on 1 used (Method A); Isolated yields of 6
and 7 based on 5 used.
tetrahydrocycle is disordered over two half-chair confor-
mation (A and B) with population 75:25%. Deviations
of the C(4) and C(5) atoms from the mean plane of the
X-ray study. The colourless crystals of 6a (C26H20N3O3SCl
0.5 C3H7NO) are triclinic. At 293 K, a ¼ 8.760(1), b ¼
˚
remaining atoms of the ring are ꢀ0.50 and 0.19 A,
˚
ꢁ
ꢁ
˚
respectively for conformer A and 0.31 and ꢀ0.47 A,
11.321(1), c ¼ 13.895(1) A, a ¼ 86.85(1) , b ¼ 83.36(1) , c
3
ꢁ
˚
¼ 85.46(1) , V ¼ 1363.0(3) A , Mr ¼ 562.0, Z ¼ 2, space
respectively for B. The methoxyphenyl substituent is
located in the cis-conformation relatively the C(12)AO(2)
bond [the C(20)AN(3)AC(12)AO(2) torsion angle is
1.7(5)ꢁ] and it adopts –sc conformation relatively the
C(12)AN(3) bond [the C(12)AN(3)AC(20)AC(25) tor-
sion angle is -43.4(5)ꢁ]. The methoxy group is coplanar
to
the
plane
of
the
aromatic
ring
[the
C(26)AO(3)AC(24)AC(25) torsion angle is 2.0(6)ꢁ].
The structures of the products 6 have been also con-
firmed using elemental analyses, IR, and LC/MS-
spectra.
Following the mechanism of ‘‘recyclization’’ reaction,
we tested whether the 2-iminocoumarin-3-carbothioa-
mides were suitable precursors for 2-thiocoumarins syn-
thesis. We obtained the intermediate 2-(3-carbamoyl-2-
thienylimino)-coumarin-3-carbothioamides 9 by reaction
of 2-iminocoumarin-3-carbothioamides 8 [40] with 2-
Figure 1. The molecular structure of the compound 6a according to
X-ray diffraction data.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
Convenient Synthesis of Substituted 2-(2-Iminocoumarin-3-yl)-
thieno[2,3-d]pyrimidin-4-ones
803
Scheme 3
group P1, dcalc ¼ 1.282 g/cm3, l(MoKa) ¼ 0.253 mmꢀ1
,
H), 7.80 (br.s, 1 H); Anal. calcd. for C10H5ClN2O: H, 3.15; C,
53.66; N, 10.01. Found: H, 3.22; C, 53.33; N, 9.77.
F(000) ¼ 547. Intensities of 7751 reflections (4600 independ-
ent, Rint ¼ 0.038) were measured using the ‘‘Xcalibur-3’’ dif-
fractometer (graphite monochromated MoKa radiation, CCD
detector, x-scanning, 2Tmax ¼ 50ꢁ). The structure was solved
by direct method using SHELXTL package [41]. The restrains
for bond lengths in the disordered fragment were applied dur-
2-Imino-8-methoxy-coumarin-3-carbonitrile
(1c). This
compound was obtained in 70% yield as a yellow solid, mp
165–167ꢁC; IR (cmꢀ1): 3287, 3054, 2226, 1651, 1607, 1477;
1H NMR (CDCl3): d 3.84 (s, 3 H), 6.89 (d, J ¼ 6.71 Hz, 1 H),
7.05 (m, 2 H), 7.67 (br.s, 1 H), 7.78 (br.s, 1 H); Anal. calcd.
for C11H8N2O2: H, 3.44; C, 54.95; N, 10.05. Found: H, 3.40;
C, 54.70; N, 9.82.
2
3
3
3
˚
˚
ing refinement (Csp ACsp 1.51 A, Csp ACsp 1.54 A). Posi-
tions of the hydrogen atoms were located from electron density
difference maps and refined by ‘‘riding’’ model with Uiso
¼
8-Ethoxy-2-iminocoumarin-3-carbonitrile (1d). This com-
pound was obtained in 78% yield as a yellow solid, mp 161–
163ꢁC; IR (cmꢀ1): 3320, 3036, 2228, 1655, 1604, 1467; 1H
NMR (CDCl3): d 1.36 (t, J ¼ 6.71 Hz, 3 H), 4.03 (q, J ¼ 6.71
Hz, 2 H), 6.84 (m, 1 H), 6.98 (m, 2 H), 7.61 (br.s, 1 H) 7.71
(br.s, 1 H); Anal. calcd. for C12H10N2O2: H, 3.57; C, 55.33;
N, 9.93. Found: H, 3.31; C, 55.25; N, 9.67.
2-Aminothiophene-3-carboxamides. 2a–d were obtained
from cyclohexanone, 4-methyl-cyclohexanone, and N-substi-
tuted piperidin-4-ones according to the Gewald procedure [43–
45].
nUeq of the carrier atom (n ¼ 1.5 for methyl group and n ¼ 1.2
for other hydrogen atoms). Full-matrix least-squares refinement
against F2 in anisotropic approximation for nonhydrogen atoms
using 4517 reflections was converged to wR2 ¼ 0.191 (R1
¼
0.063 for 2815 reflections with F > 4r(F), S ¼ 1.156). The
final atomic coordinates, and crystallographic data for molecule
6a have been deposited to with the Cambridge Crystallographic
Data Centre, 12 Union Road, CB2 1EZ, UK and are available
on request quoting the deposition numbers CCDC 705029.
2-Iminocoumarin-3-carbonitriles. 1a–d were obtained
starting of malononitrile by interaction with corresponding sal-
icylic aldehydes [42]. 2-Iminocoumarin-3-carbothioamides 8a-
c were synthesized by interaction of salicylic aldehydes of 2-
cyanoethanethioamide [40].
2-Amino-6-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-
carboxamide 2(b). This compound was obtained in 62% yield
as a colorless solid, mp 187–189ꢁC; IR (cmꢀ1): 3400, 3259,
1
3180, 2944, 1632, 1584, 1561, 1499; H NMR (DMSO-d6): d
2-Iminocoumarin-3-carbonitrile (1a). This compound was
obtained in 65% yield as a yellow solid, mp 160–162ꢁC; IR
(cmꢀ1): 3293, 3038, 2228, 1651, 1601, 1450; 1H NMR
(CDCl3): d 7.12 (m, 2 H), 7.32 (d, J ¼ 6.41 Hz, 1 H), 7.46 (t,
J ¼ 7.63 Hz, 1 H), 7.64 (br.s, 1 H), 7.70 (br.s, 1 H); Anal.
calcd. for C10H6N2O: H, 3.34; C, 55.36; N, 10.33. Found: H,
3.20; C, 55.08; N, 10.14.
6-Chloro-2-Iminocoumarin-3-carbonitrile (1b). This com-
pound was obtained in 72% yield as a yellow solid, mp 172–
174ꢁC; IR (cmꢀ1): 3307, 3046, 2233, 1649, 1599, 1478; 1H
NMR (CDCl3): d 7.09 (d, J ¼ 8.85 Hz, 1 H), 7.37 (d, J ¼
2.14 Hz, 1 H), 7.47 (dd, J ¼ 8.85, 2.44 Hz, 1 H), 7.69 (br.s, 1
0.97 (t, J ¼ 6.22 Hz, 3 H), 1.25 (m, 1 H), 1.74 (m, 2 H), 2.05 (m,
1 H), 2.58 (m, 2 H), 3.31 (br.s, 1 H), 6.49 (br.s, 2 H), 6.87 (s, 2 H).
6-Acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-
3-carboxamide 2(c). This compound was obtained in 65%
yield as a colorless solid, mp 250–252ꢁC; IR (cmꢀ1): 3497,
1
3394, 3280, 3159, 1651, 1563, 1480; H NMR (DMSO-d6): d
2.01, 2.05 (s, 3 H), 2.63 (br.s, 2 H), 2.73 (br.s, 2 H), 3.57
(br.s, 2 H), 4.35, 4.39 (s, 2 H), 6.56 (br.s, 2 H), 6.92 (s, 1 H),
6.98 (s, 1 H).
Ethyl 2-amino-3-(aminocarbonyl)-4,7-dihydrothieno[2,3-
c] pyridine-6(5H)-carboxylate 2(d). This compound was
obtained in 60% yield as a colorless solid, mp 185–187ꢁC; IR
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

804
P. E. Shynkarenko, S. V. Vlasov, S. M. Kovalenko, S. V. Shishkina, O. V. Shishkin,
and V. P. Chernykh
Vol 47
(cmꢀ1): 3431, 3365, 3319, 3172, 1690, 1638, 1572, 1427; 1H
NMR (DMSO-d6): d 1.18 (t, J ¼ 7.32 Hz, 3 H), 2.68 (t, J ¼
5.49 Hz, 2 H), 3.55 (t, J ¼ 5.49 Hz, 2 H), 4.06 (q, J ¼ 7.32
Hz, 2 H), 4.29 (s, 2 H), 6.48 (s, 2 H), 6.88 (s, 2 H).
(m, 2 H), 7.57 (t, J ¼ 7.6 Hz, 1 H), 7.85 (d, J ¼ 7.3 Hz, 1 H), 8.80
(s, 1H, H-4), 9.35 (br.s, 1H, ¼¼NH), 14.23 (br.s, 1H, ANHCO);
lcms: m/z (MHþ) 364. Anal. calcd. for C20H17N3O2S: H, 4.71; C,
66.10; N, 11.56. Found: H, 4.52; C, 65.84; N, 11.32.
General procedure for the preparation of 2-(2-iminocou-
marin-3-yl)thieno[2,3-d]pyrimidin-4-ones 5a–m. To the warm
(40–50ꢁC) solution of 2-aminothiophene-3-carboxamide 2 (2
mmol) in glacial acetic acid (3 mL) the solution of either 2-imi-
nocoumarine-carbonitrile 1 (Method A) or 2-iminocoumarine-3-
carbothioamide 8 (Method B) (2 mmol) in glacial acetic acid (3
mL) was added and the mixture was heated at 70–80ꢁC for 30
min. Then the reaction mixture was cooled. The precipitate that
formed was collected by filtration and dried. The product 3
(Method A) or 9 (Method B) was dissolved in DMF (5 mL) at
140–150ꢁC and heated for 3 h. The precipitate of 5 formed after
cooling was filtered out, washed with 2-propanol and dried.
2-(2-Iminocoumarin-3-yl)-5,6,7,8-tetrahydro-benzo[4,5]-
thieno[2,3-d]pyrimidin-4-one (5a). This compound was ob-
tained in 74% yield (Method A) and 72% (Method B) as a red
solid, mp 280–282ꢁC; IR (cmꢀ1): 3451, 3156, 2932, 2846,
2-(6-Chloro-2-iminocoumarin-3-yl)-7-methyl-5,6,7,8-tetra-
hydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
(5f). This
compound was obtained in 69% yield (Method A) and 63%
(Method B) as a yellow solid, mp 290–292; IR (cmꢀ1): 3440,
3251, 2931, 2823, 1671, 1595, 1552, 1492, 1446; 1H NMR
(DMSO-d6): d 1.01 (d, J ¼ 6.1 Hz, 3 H), 1.31 (m, 1 H), 1.82 (m, 2
H), 2.25 (m, 1 H), 2.72 (m, 2 H), 3.00 (m, 1 H), 7.20 (d, J ¼ 8.9
Hz, 1 H), 7.53 (d, J ¼ 8.9 Hz, 1 H), 7.90 (s, 1 H), 8.66 (s, 1H, H-
4), 9.42 (br.s, 1H, ¼¼NH), 14.08 (br.s, 1H, NHCO); lcms: m/z
(MHþ) 399. Anal. calcd. for C20H16ClN3O2S: H, 4.05; C, 60.37;
N, 10.56. Found: H, 3.91; C, 60.11; N, 10.22.
2-(2-Imino-8-methoxycoumarin-3-yl)-7-methyl-5,6,7,8-tet-
rahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (5g). This
compound was obtained in 75% yield as a yellow solid, mp 268–
270ꢁC; IR (cmꢀ1): 3446, 3328, 2930, 1681, 1658, 1604, 1576,
1479; 1H NMR (DMSO-d6): d 1.03 (d, J ¼ 6.4 Hz, 3 H), 1.38 (m,
1 H), 1.86 (m, 2 H), 2.23 (m, 1 H), 2.79 (m, 2 H), 3.07 (m, 1 H),
3.89 (s, 3 H), 7.25 (m, 2 H), 7.42 (dd, J ¼ 7.3 Hz, 1 H), 8.79 (s,
1H, H-4), 9.43 (br.s, 1H, ¼¼NH), 14.31 (br.s, 1H, ANHCO); lcms:
m/z (MHþ) 394. Anal. calcd. for C21H19N3O3S: H, 4.87; C,
64.11; N, 10.68. Found: H, 4.68; C, 64.29; N, 10.42.
1
1654, 1615, 1535, 1473; H NMR (DMSO-d6): d 1.72 (br.s, 4
H), 2.63 (br.s, 2 H), 2.79 (br.s, 2 H), 7.21 (m, 2 H), 7.53 (t, J
¼ 6.7 Hz, 1 H), 7.79 (d, J ¼ 6.4 Hz, 1 H), 8.71 (s, 1H, H-4),
9.31 (br.s, 1H, ¼NH), 14.17 (br.s, 1H, -NHCO); lcms: m/z
(MHþ) 350. Anal. calcd. for C19H15N3O2S: H, 4.33; C, 65.31;
N, 12.03. Found: H, 4.12; C, 65.55; N, 11.72.
2-(6-Chloro-2-iminocoumarin-3-yl)-5,6,7,8-tetrahydro-benzo
[4,5]thieno[2,3-d]pyrimidin-4-one (5b). This compound was
obtained in 65% yield as a orange solid, mp 294–296ꢁC; IR
(cmꢀ1): 3450, 3232, 2932, 2854, 1679, 1651, 1592, 1554,
1477; 1H NMR (DMSO-d6): d 1.74 (br.s, 4 H), 2.67 (br.s, 2
H), 2.82 (br.s, 2 H), 7.20 (d, J ¼ 8.9 Hz, 1 H), 7.54 (d, J ¼
8.9 Hz, 1 H), 7.89 (s, 1 H), 8.68 (s, 1H, H-4), 9.45 (br.s, 1H,
¼NH), 14.10 (br.s, 1H, -NHCO); lcms: m/z (MHþ) 384. Anal.
calcd. for C19H14ClN3O2S: H, 3.68; C, 59.45; N, 10.95.
Found: H, 3.40; C, 59.28; N, 10.57.
2-(8-Ethoxy-2-iminocoumarin-3-yl)-7-methyl-5,6,7,8-tetra-
(5h). This
hydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
compound was obtained in 78% yield as a yellow solid, mp
265–267ꢁC; IR (cmꢀ1): 3445, 3169, 2976, 2950, 1685,
1656,1603, 1573,1467; 1H NMR (DMSO-d6): d 1.01 (d, J ¼
6.4 Hz, 3 H), 1.37 (t, J ¼ 6.7 Hz, 3 H), 1.81 (m, 2 H), 2.24
(m, 1 H), 2.72 (m, 2 H), 3.02 (m, 1 H), 4.14 (q, J ¼ 7.0 Hz, 2
H), 7.25 (m, 3 H), 8.67 (s, 1H, H-4), 9.36 (br.s, 1H, ¼¼NH),
14.24 (br.s, 1H, ANHCO); lcms: m/z (MHþ) 408. Anal. calcd.
for C22H21N3O3S: H, 5.19; C, 64.85; N, 10.31. Found: H,
5.00; C, 64.72; N, 10.04.
2-(2-Imino-8-methoxycoumarin-3-yl)-5,6,7,8-tetrahydro-
benzo[4,5]thieno[2,3-d]pyrimidin-4-one (5c). This compound
was obtained in 84% yield as a yellow solid, mp 275–277; IR
(cmꢀ1): 3436, 3326, 2925, 2842, 1679, 1660, 1605, 1574,
1533; 1H NMR (DMSO-d6): d 1.76 (br.s, 4 H), 2.74 (br.s, 2
H), 2.88 (br.s, 2 H), 3.89 (s, 3 H), 7.32 (m, 3 H), 8.81 (s, 1H,
H-4), 9.49 (br.s, 1H, ¼NH), 14.32 (br.s, 1H, -NHCO); lcms:
m/z (MHþ) 379. Anal. calcd. for C20H17N3O3S: H, 4.52; C,
63.31; N, 11.07. Found: H, 4.22; C, 63.65; N, 10.73.
2-(8-Ethoxy-2-iminocoumarin-3-yl)-5,6,7,8-tetrahydro-benzo
[4,5]thieno[2,3-d]pyrimidin-4-one (5d). This compound was
obtained in 88% yield as a yellow solid, mp 278–280ꢁC; IR
(cmꢀ1): 3442, 3188, 2985, 2936, 1651, 1603, 1573, 1484; 1H
NMR (DMSO-d6): d 1.37 (t, J ¼ 7.0 Hz, 3 H), 1.75 (br.s, 4
H), 2.69 (br.s, 2 H), 2.83 (br.s, 2 H), 4.17 (q, J ¼ 7.0 Hz, 2
H), 7.26 (m, 3 H), 8.74 (s, 1H, H-4), 9.38 (br.s, 1H, ¼¼NH),
14.25 (br.s, 1H, ANHCO); lcms: m/z (MHþ) 394. Anal. calcd.
for C21H19N3O3S: H, 4.87; C, 64.11; N, 10.68. Found: H,
4.68; C, 64.25; N, 10.30.
7-Acetyl-2-(2-iminocoumarin-3-yl)-3,4,5,6,7,8-hexa-hydro-
pyrido[40,30:4,5]thieno[2,3-d]pyrimidin-4-one (5i). This com-
pound was obtained in 68% yield as a brown solid, mp 284–
286ꢁC; IR (cmꢀ1): 3442, 3317, 3050, 2930, 1650, 1599, 1565,
1
1453, 1427; H NMR (DMSO-d6): d 2.11 (s, 3 H), 2.99 (m, 2
H), 3.73 (s, 2 H), 4.71 (m, 2 H), 7.27 (m, 2 H), 7.58 (t, J ¼
7.3 Hz, 1 H), 7.84 (d, J ¼ 7.3 Hz, 1 H), 8.83 (s, 1H, H-4),
9.32 (br.s, 1H, ¼¼NH), 14.31 (br.s, 1H, ANHCO); lcms: m/z
(M) 392. Anal. calcd. for C20H16N4O3S: H, 4.11; C, 61.21; N,
14.28. Found: H, 4.04; C, 61.39; N, 14.03.
Ethyl 4-oxo-2-(2-iminocoumarin-3-yl)-3,4,5,6,7,8-hexahy-
dropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7-carboxylate (5j).
This compound was obtained in 85% yield as a yellow solid,
mp 274–276ꢁC; IR (cmꢀ1): 3437, 3261, 2979, 2929, 1673,
1
1653, 1537, 1693, 1429; H NMR (DMSO-d6): d 1.21 (t, J ¼
6.8 Hz, 3 H), 2.88 (s, 2 H), 3.64 (t, J ¼ 5.1 Hz, 2 H), 4.09 (q,
J ¼ 6.8 Hz, 2 H), 4.58 (s, 2 H), 7.23 (m, 2 H), 7.55 (td, J ¼
7.7 Hz, 1 H), 7.81 (d, J ¼ 6.8 Hz, 1 H), 8.78 (s, 1H, H-4),
9.36 (br.s, 1H, ¼¼NH), 14.34 (br.s, 1H, ANHCO); lcms: m/z
(MHþ) 423. Anal. calcd. for C21H18N4O4S: H, 4.29; C, 59.71;
N, 13.26. Found: H, 4.17; C, 59.46; N, 12.96.
2-(2-Iminocoumarin-3-yl)-7-methyl-5,6,7,8-tetrahydro-benzo
[4,5]thieno[2,3-d]pyrimidin-4-one (5e). This compound was
obtained in 66% yield as a yellow solid, mp 282–284ꢁC; IR
(cmꢀ1): 3446, 3165, 2944, 2921, 1654, 1613, 1602, 1535, 1475;
1H NMR (DMSO-d6): d 1.02 (d, J ¼ 6.4 Hz, 3 H), 1.36 (m, 1 H),
1.85 (m, 2 H), 2.31 (m, 1 H), 2.78 (m, 2 H), 3.06 (m, 1 H), 7.26
Ethyl 4-oxo-2-(6-chloro-2-iminocoumarin-3-yl)-3,4,5,6,7,8-
hexahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7-carboxy-
late (5k). This compound was obtained in 65% yield as a
yellow solid, mp 287–289ꢁC; IR (cmꢀ1): 3440, 3322, 2914,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
Convenient Synthesis of Substituted 2-(2-Iminocoumarin-3-yl)-
thieno[2,3-d]pyrimidin-4-ones
805
1
2853, 1675, 1649,1592, 1563, 1698, 1452; H NMR (DMSO-
d6): d 1.22 (t, J ¼ 7.3 Hz, 3 H), 2.96 (m, 2 H), 3.68 (s, 2 H),
4.10 (q, J ¼ 6.8 Hz, 2 H), 4.64 (s, 2 H), 7.25 (d, J ¼ 9.0 Hz,
1 H), 7.57 (dd, J ¼ 8.5, 2.6 Hz, 1 H), 7.94 (s, 1 H), 8.78 (s,
1H, H-4), 9.43 (br.s, 1H, ¼¼NH), 14.15 (br.s, 1H, ANHCO);
lcms: m/z (M) 457. Anal. calcd. for C21H17ClN4O4S:
H, 3.75; C, 55.20; N, 12.26. Found: H, 3.65; C, 55.52; N,
11.88.
2-(8-Ethoxy-2-(3-methoxyphenylimino)-coumarin-3-yl)-5,6,
7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (6c).
This compound was obtained in 92% yield as a yellow solid,
mp >300ꢁC; IR (cmꢀ1): 3440, 2931, 2833, 1667, 1642, 1604,
1
1587; H NMR (DMSO-d6): d 1.30 (t, J ¼ 7.0 Hz, 3 H), 1.73
(br.s, 4 H), 2.68 (br.s, 2 H), 2.83 (br.s, 2 H), 4.04 (q, J ¼ 7.0
Hz, 2 H), 3.78 (s, 3H, 3-OCH3), 6.76 (d, J ¼ 7.4 Hz, 1 H),
7.23 (m, 6 H), 8.72 (s, 1H, H-4), 13.82 (br.s, 1H, ANHCOA).
Anal. calcd. for C28H25N3O4S: H, 5.04; C, 67.32; N, 8.41.
Found: H, 5.80; C, 67.21; N, 8.22.
Ethyl 4-oxo-2-(2-imino-8-methoxycoumarin-3-yl)-3,4,5,6,7,8-
hexahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7-carboxy-
late (5l). This compound was obtained in 79% yield (Method
A) and 70% (Method B) as a yellow solid, mp 280–282ꢁC; IR
(cmꢀ1): 3449, 3328, 2974, 2929, 1672, 1653, 1604,
2-(2-(3-Methoxyphenylimino)-8-methoxycoumarin-3-yl)-7-
methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
4-one (6d). This compound was obtained in 89% yield as a yel-
low solid, mp >300ꢁC; IR (cmꢀ1): 3426, 2931, 2833, 1676, 1640,
1
1574,1697, 1472; H NMR (DMSO-d6): d 1.19 (t, J ¼ 6.8 Hz,
1
3 H), 2.94 (s, 2 H), 3.66 (t, J ¼ 5.1 Hz, 2 H), 3.89 (s, 3 H),
4.08 (q, J ¼ 7.3 Hz, 2 H), 4.62 (s, 2 H), 7.25 (m, 2 H), 7.40
(d, J ¼ 7.3 Hz, 1 H), 8.81 (s, 1H, H-4), 9.51 (br.s, 1H, ¼¼NH),
14.44 (br.s, 1H, ANHCO); lcms: m/z (MHþ) 453. Anal. calcd.
for C22H20N4O5S: H, 4.46; C, 58.40; N, 12.38. Found: H,
4.31; C, 58.24; N, 12.17.
1603, 1526; H NMR (DMSO-d6): d 1.00 (d, J ¼ 6.4 Hz, 3 H),
1.31 (m, 1 H), 1.79 (m, 2 H), 2.20 (m, 1 H), 2.71 (m, 2 H), 3.03
(m, 1 H), 3.77 (s, 3 H), 3.77 (s, 3H, 3-OCH3), 6.73 (d, J ¼ 7.4 Hz,
1 H), 6.97 (d, J ¼ 7.6 Hz, 1 H), 7.25 (m, 5 H), 8.70 (s, 1H, H-4),
13.83 (br.s, 1H, ANHCOA). Anal. calcd. for C28H25N3O4S: H,
5.04; C, 67.32; N, 8.41. Found: H, 4.82; C, 67.13; N, 8.09.
General procedure for the preparation of 2-(coumarin-3-
yl)thieno[2,3-d]pyrimidin-4-ones 7a–c. Corresponding 2-(2-
iminocoumarin-3-yl)thieno[2,3-d]pyrimidin-4-ones 5a, e, g (2
mmol) was dissolved at 60–70ꢁC in mixture of 2-propanol (10
mL) and concentrated hydrochloric acid (1 mL). The reaction
mixture was heated with reflux for 20 min, then cooled and
the precipitate was collected by filtration and dried.
Ethyl 4-oxo-2-(2-imino-8-ethoxycoumarin-3-yl)-3,4,5,6,7,8-
hexahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7-carboxy-
late (5m). This compound was obtained in 80% yield as a yel-
low solid, mp 273–275ꢁC; IR (cmꢀ1): 3452, 3159, 2979, 2928,
1651, 1603, 1546, 1698, 1425; 1H NMR (DMSO-d6): d 1.20
(t, J ¼ 7.3 Hz, 3 H), 1.39 (t, J ¼ 6.8 Hz, 3 H), 2.97 (br.s, 2
H), 3.67 (t, J ¼ 6.4 Hz, 2 H), 4.08 (q, J ¼ 7.3 Hz, 2 H), 4.19
(q, J ¼ 6.4 Hz, 2 H), 4.65 (s, 2 H), 7.25 (m, 2 H), 7.42 (dd, J
¼ 7.7 Hz, 1 H), 8.86 (s, 1H, H-4), 9.50 (br.s, 1H, ¼¼NH),
14.50 (br.s, 1H, ANHCO); lcms: m/z (MHþ) 467. Anal. calcd.
for C23H22N4O5S: H, 4.75; C, 59.22; N, 12.01. Found: H,
4.61; C, 59.43; N, 11.66.
General procedure for the preparation of 2-(2-(3-methoxy-
phenylimino)-coumarin-3-yl)thieno[2,3-d]pyrimidin-4-ones
6a-d. To a solution of corresponding 2-(2-iminocoumarin-3-
yl)thieno[2,3-d]pyrimidin-4-ones 5 (2mmol) in glacial acetic
acid (10 mL) 3-methoxy-phenylamine (2 mmol) was added at
40–50ꢁC. The reaction mixture was heated at 70–80ꢁC and
stirred for 30 min. After cooling down to room temperature
the precipitate was filtered out, washed with 2-propanol and
recrystallized form DMF.
2-(Coumarin-3-yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]
pyrimidin-4-one (7a). This compound was obtained in 92%
yield as a yellow solid, mp >300ꢁC.
2-(Coumarin-3-yl)-7-methyl-5,6,7,8-tetrahydro-benzo[4,5]
thieno[2,3-d]pyrimidin-4-one (7b). This compound was ob-
tained in 88% yield as a yellow solid, mp 235–237ꢁC.
2-(8-Methoxy-coumarin-3-yl)-7-methyl-5,6,7,8-tetrahydro-
benzo[4,5]thieno[2,3-d]pyrimidin-4-one (7c). This compound
was obtained in 89% yield as a yellow solid, mp 277–279ꢁC.
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