Recyclization of 2-iminocoumarin-3-carbonitriles with 2-aminothiobenzamide: A new synthetic route to substituted 2-(2-iminocoumarin-3-yl)quinazoline-4(3H)- thiones

Article abstract of DOI:10.1080/17415993.2010.509506

The reaction of 2-aminothiobenzamide with either 2-iminocoumarin-3- carbonitrile or 2-iminocoumarin-3-thiocarboxamides has been studied. It has been established that in both cases, 2-(2-iminocoumarin-3-yl)quinazoline-4(3H)- thiones are formed as the result of a two-step procedure. The reactions of 2-(2-iminocoumarin-3-yl)quinazoline-4(3H)-thiones with arylamines and alkylating agents have been studied.

Full text of DOI:10.1080/17415993.2010.509506

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Recyclization of 2-iminocoumarin-3-
carbonitriles with 2-
aminothiobenzamide: a new
synthetic route to substituted 2-(2-
iminocoumarin-3-yl)quinazoline-4(3H)-
thiones
Pavlo E. Shynkarenko a , Sergiy V. Vlasov a , Sergiy M. Kovalenko a
& Valentin P. Chernykh a
a Organic Chemistry Department, National University of Pharmacy,
53 Pushkinska str., Kharkiv, 61002, Ukraine
Published online: 28 Sep 2010.
To cite this article: Pavlo E. Shynkarenko , Sergiy V. Vlasov , Sergiy M. Kovalenko & Valentin P.
Chernykh (2010) Recyclization of 2-iminocoumarin-3-carbonitriles with 2-aminothiobenzamide: a
new synthetic route to substituted 2-(2-iminocoumarin-3-yl)quinazoline-4(3H)-thiones, Journal of
Sulfur Chemistry, 31:5, 447-456, DOI: 10.1080/17415993.2010.509506
To link to this article: http://dx.doi.org/10.1080/17415993.2010.509506
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Journal of Sulfur Chemistry
Vol. 31, No. 5, October 2010, 447–456
Recyclization of 2-iminocoumarin-3-carbonitriles with
2-aminothiobenzamide: a new synthetic route to substituted
2-(2-iminocoumarin-3-yl)quinazoline-4(3H)-thiones
Pavlo E. Shynkarenko, Sergiy V. Vlasov, Sergiy M. Kovalenko* and Valentin P. Chernykh
Organic Chemistry Department, National University of Pharmacy, 53 Pushkinska str., Kharkiv 61002,
Ukraine
(Received 16 May 2010; final version received 10 July 2010)
The reaction of 2-aminothiobenzamide with either 2-iminocoumarin-3-carbonitrile or 2-iminocoumarin-
3-thiocarboxamides has been studied. It has been established that in both cases, 2-(2-iminocoumarin-3-
yl)quinazoline-4(3H)-thiones are formed as the result of a two-step procedure. The reactions of 2-(2-
iminocoumarin-3-yl)quinazoline-4(3H)-thiones with arylamines and alkylating agents have been studied.
Keywords: iminocoumarin, quinazoline, thiobenzamide, rearrangement, recyclization
1. Introduction
3-Substituted 2-iminocoumarins have versatile biological activities such as anti-inflammatory
(1, 2), antimicrobial, antitumor (3–6) and antifungal (7, 8). Also, they can be used in the synthesis
of 2-substituted 2H-1-benzopyrans (9).
On the other hand, among 3,4-dihydroquinazolin-4-thione derivatives, selective estrogen recep-
torbetamodulators(10)aswellasaurora2kinaseinhibitors(11)andantiulceragents(12)hadbeen
found. Similar compounds have been also reported as fungicides (13) and herbicides (14). Some
S-alkylquinazolin-4-thiones display antimicrobial activity (15–19). 3,4-Dihydroquinazolin-4-
thiones can be successfully applied as the precursors for annulated heterocyclic systems syntheses
(18, 20–25).
As the part of our research work on the synthesis of 3-heteroaryl-2-iminocoumarins (26, 27),
we focused our efforts on the synthesis of 2-(2-iminocoumarin-3-yl)quinazoline-4(3H)-thiones.
2. Results and discussion
Mostofquinazolin-4-thionessyntheticmethodsinvolvereactionsofquinazolin-4-oneswiththion-
ating reagents (28–34) or the cyclization 2-aminothiobenzamides (35–38). Some other methods
which are less common were also reported (23, 39).
*Corresponding author. Email: kosn@ukrfa.kharkov.ua
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2010 Taylor & Francis
DOI: 10.1080/17415993.2010.509506
http://www.informaworld.com

448 P.E. Shynkarenko et al.
Recently, the advantages of 2-iminocoumarin-3-carboxamides rearrangement (26, 27, 40–
45) under the action of 2-aminothiobenzamide for synthesis of 2-(coumarin-3-yl)quinazolin-
4(3H)-thiones, which can be easily performed in glacial acetic acid (15 min) have been
approved (38). According to the proposed mechanism of these rearrangement, the carboxam-
=
ide group of 2-iminocoumarin-3-carboxamide serves as a precursor of lactone C O group
of the resulting 3-heteroarylcoumarin. Thus, it was worthy to assume that utilization of 2-
iminocoumarin-3-carbonitriles in the similar rearrangement will lead to the formation of the
products with imino-group (C=NH) in the 2-position of benzopyran ring and the products
should be 2-(2-iminocoumarin-3-yl)quinazoline-4(3H)-thiones. While the rearrangement of 2-
iminocoumarin-3-carbothioamide under the action of 2-aminothiobenzamide could be the way
for 2-(2-thioxocoumarin-3-yl)quinazolin-4(3H)-thiones.
We performed the interaction of 2-iminocoumarin-3-carbonitrile 1a with 2-aminothio-
benzamide in boiling glacial acetic acid; likewise, it was previously applied for one-step synthesis
of 2-(coumarin-3-yl)quinazolin-4(3H)-thiones (38). The isolated product appeared to be the same
as in the case of 2-iminocoumarin-3-carboxamide interaction with 2-aminothiobenzamide – 2-
(coumarin-3-yl)quinazolin-4(3H)-thione 7a. Possibly, the traces of water in glacial acetic acid
promoted the hydrolysis of imino group of the target product.
Thus, we had to improve the procedure. First, we performed the interaction of either
2-iminocoumarin-3-carbonitriles 1a–c or 2-iminocoumarin-3-carbothioamides 2a and b with 2-
aminothiobenzamide in glacial acetic acid at relatively low temperature (40–50◦C) at stirring.
As a result, 2-[(3-cyanocoumarin-2-ylidene)amino]benzenecarbothioamides 3a–c and 2-{[2-
(aminocarbonothioyl)phenyl]imino}-coumarin-3-carbothioamides 4a and b were precipitated out
from acetic acid as yellow solids in high yields. The rearrangements of 3 and 4 have been per-
formed in boiling anhydrous DMF in order to avoid any possibility of hydrolytic processes at the
second step of the reaction (Scheme 1).
The rearrangement of 2-[(3-cyanocoumarin-2-ylidene)amino]benzenecarbothioamides 3a–c is
likely to proceed according to the mechanism represented in Scheme 2. It involves an intramolecu-
larnucleophilicattackofthioamideNH2 grouponthecarbonatomatposition2oftheiminolactone
ring followed by a ring opening to produce the corresponding quinazoline-4(3H)-thione. The
cis–trans-isomerization of the quinazoline-4(3H)-thione followed by a nucleophilic attach of the
OH group at the carbon of the nitrile group afforded the most thermodynamically stable product
5 (Scheme 2).
It is noteworthy that the rearrangement of 4a and b in DMF unexpectedly resulted in
2-(2-iminocoumarin-3-yl)quinazoline-4(3H)-thiones 5a and c but not 2-(2-thioxo-coumarin-3-
yl)quinazolin-4(3H)-thiones (Scheme 3). Thus, it can be deduced that in this case the hydrogen
CN
R
O
N
NH2
NH2
CN
NH
S
S
R
H2N
N
3a–c
O
ii
1a–c
N
H
S
S
R
S
i
O
NH
NH2
R
NH2
R
5a–c
O
N
NH2
O
NH
S
4a and b
2a and b
Scheme 1. Reagents and conditions: (i)AcOH, 40–50◦C, 30 min; (ii) DMF, 140-150◦C, 20 min.
Substituents R are given in Table 1 and Section 4.

Journal of Sulfur Chemistry 449
S
CN
3
2
CN
N
N
HN
2
R
NH
R
N
N
H
S
O
NH2
N
S
3
R
OH
C
O
NH
S
R
N
OH
5a–c
3a–c
Scheme 2. The suggested mechanism of 2-[(3-cyanocoumarin-2-ylidene)amino]benzene-
carbothioamides 3a-c rearrangement.
N
S
S
S
N
H
S
NH2
NH
R
3
2
NH2
NH2
-H2S
-NH3
O
NH
HN
2
R
R
5a and c
N
O
N
N
S
3
OH
N
C
NH2
S
R
S
OH
N
H
S
4a and b
R
O
S
Scheme 3. The suggested mechanism of 2-{[2-(aminocarbonothioyl)phenyl]imino}-coumarin-
3-carbothioamides 4a and b rearrangement.
sulfide cleavage, at the lactone-closure step of the proposed mechanism, is the preferable way for
2-{[2-(aminocarbonothioyl)phenyl]imino}-coumarin-3-carbothioamides 4a and b recyclization
(Scheme 3).
1
The H NMR spectra of compounds 3 and 4 showed that the protons at position 4 of the
coumarin ring resonated at δ 8.49–8.96 region. Also, the carbothioamide group protons and the
1
aromatic protons resonated with the regions at δ 9.4–11.4 and 7.1–7.9, respectively. In the H
NMR spectra of compounds 5a–c, the signal of proton in position 4 of coumarin in the range
δ 8.88–8.97 ppm, as well as the signal of imino-group proton (δ 9.55–9.61 ppm) and the signal
of quinazoline-4(3H)-thione fragment NH (δ 15.77–16.00 ppm) are present. The LC-MS spectra
for compounds 3, 4 and 5 show their high purity. Compounds 5 are slightly soluble in solvents
and therefore their 13C NMR spectra were not measured.
The structures compounds 5 were further confirmed by their reactions with anilines in glacial
acetic acid to produce the corresponding 6 (Scheme 4) as yellow solids in high yields (Table 1).
Also, compounds 5 could be easily converted to their oxoanalogues 7, previously described in
our work (38), by acidic hydrolysis with hydrochloric acid and glacial acetic acid (Scheme 4).
1
The H NMR spectra of compounds 6 do not have the signal of imino-group proton, but
they have more signals of aromatic protons than the spectra of compounds 5. The substituents
of phenylimino fragment resonated at 1.21 (t, 3H CH2CH3) and 2.63 (q, 2H CH2CH3) for 6b
and at 3.72 (s, 6H, 2OCH3) for 6c. The signals of the proton in position 4 (δ 8.93–8.95 ppm) and
quinazoline-4(3H)-thione fragment NH (δ 15.55–16.06 ppm) for compounds 6 are almost similar
to the same signals of compounds 5.
The alkylation of compounds 5 with alkyl halides in absolute aprotic solvents should be a con-
venient approach for synthesis of 3-(4-alkylthioquinazolin-2-yl)-2-iminocoumarins 8. However,
the spectra of the solids obtained after the alkylation of compounds 5 showed the mixture of
different products. Most likely, compounds 8 are extremely unstable due to the high reactivity of
imino group as well as their ability for pyran ring opening (especially in DMSO or DMSO-d6)
(46). The instability of S-alkyl compounds 8 relatively with the starting thione 5, which are stable

450 P.E. Shynkarenko et al.
Table 1. Synthesis of compounds 3–7 and 9.
X
No.
R
Ar
Alk
Yield (%)
CN
3a
3b
3c
H
8-OMe
8-OEt
–
–
–
–
–
–
80
86
85
CSNH2
4a
4b
H
8-OEt
–
–
–
–
76
79
5a
5b
5c
6a
6b
6c
7a
7b
7c
9a
9b
H
–
–
–
–
–
–
–
–
–
–
–
–
70 (A), 61 (B)
88(A)
85 (A), 69 (B)
8-OMe
8-OEt
H
H
8-OEt
H
8-OMe
8-OEt
8-OMe
8-OEt
4-FC6H4
4-EtC6H4
3,5-di-OMeC6H3
62
66
70
89
82
88
61
65
–
–
–
–
–
CH2C(O)NH(4-MeC6H4)
3-MeC6H4CH2
N
N
N
H
S
i
R
N
N
O
N
iv
iii
N
H
S
Alk
6a–c
Ar
Alk
N
S
R
N
S
R
R
O
NH
O
O
O
NH
ii
5a–c
N
9a and b
8
N
H
S
R
O
O
7a–c
Scheme 4. Reagents and conditions: (i) anilines, AcOH, 70–80◦C, 30 min; (ii) HCl, AcOH; (iii)
AlkHal, DMF, triethylamine, 70◦C, 40 min; (iv) HCl, i-PrOH. Substituents R, Ar and Alk are
given in Table 1 and Section 4.
in DMSO-d6, can be possibly explained by the break of intramolecular bound between the NH
fragment of quinazoline-4-thione and imino group specific for 5. The absence of hydrogen binding
makes 2-iminopyran cycle of compounds 8 less stable and increases imino-group reactivity. The
hydrolysis of the isolated compounds 8 with hydrochloric acid allowed us to obtain the previously
reported 3-(4-alkylthioquinazolin-2-yl)coumarins 9a and b (38) with high yields.
3. Conclusion
Reactions of thioanthranilamide with 2-iminocoumarin-3-carbonitriles and 2-iminocoumarin-3-
carbothioamides according to the two-step procedure gave 2-(2-iminocoumarin-3-yl)quinazoline-
4(3H)-thiones. The procedure is simple and high yielding and therefore provides an alternative
for the Knoevenagel reaction. Reactions of quinazoline-4(3H)-thiones with phenylamines gave
the corresponding 2-(2-phenylimino-coumarin-3-yl)quinazolin-4(3H)-thiones. Alkylations of 2-
(2-iminocoumarin-3-yl)quinazoline-4(3H)-thiones produce the corresponding iminocoumarins
which are highly unstable. The structures of iminocoumarins were confirmed by their hydrolysis
to the corresponding 3-(4-alkylthioquinazolin-2-yl)coumarins.

Journal of Sulfur Chemistry 451
4. Experimental section
Melting points were measured with a Buchi B-520 melting point apparatus and were not corrected.
Elemental analysis was within 0.4% of the theoretical value. IR spectra were recorded on
1
Specord M80 spectrometers in KBr. H and 13C NMR spectral data were reordered at 200 and
75 MHz, respectively, on Varian Mercury-200 and Varian Geminy-300 spectrometers using TMS
as an internal standard. Mass spectral analyses were obtained on a PE SCIEX API 150EX mass
spectrometer.
4.1. 2-Iminocoumarin-3-carbonitriles 1 and 2-iminocoumarin-3-carbothioamides 2
2-Iminocoumarin-3-carbonitriles 1 and 2-iminocoumarin-3-carbothioamides were obtained from
corresponding salicylic aldehydes, malononitrile and 2-cyanoacetothioamide according to the
Knoevenagel reaction (47–52).
4.1.1. 2-Iminocoumarin-3-carbonitrile (1a)
Yield65%;m.p. 160–162◦C, lit. m.p. 160◦C(48), 164◦C(49);yellowsolid. IR(cm−1):3293, 3038,
2228 (CN), 1651, 1601, 1450. 1H NMR (200 Hz, CDCl3): δ 7.12 (m, 2 H), 7.32 (d, J = 6.4 Hz,
1 H), 7.46 (t, J = 7.6 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.
4.1.2. 2-Imino-8-methoxy-coumarin-3-carbonitrile (1b)
Yield 70%; m.p. 165–167◦C, lit. m.p. 170◦C (50); yellow solid. IR (cm−1): 3287, 3054, 2226
(CN), 1651, 1607, 1477. 1H NMR (200 Hz, CDCl3): δ 3.84 (s, 3 H), 6.89 (d, J = 6.7 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.
4.1.3. 8-Ethoxy-2-iminocoumarin-3-carbonitrile (1c)
Yield 78%; m.p. 161–163◦C; yellow solid. IR (cm−1): 3320, 3036, 2228 (CN), 1655, 1604, 1467.
1H NMR (200 Hz, CDCl3): δ 1.36 (t, J = 6.7 Hz, 3 H), 4.03 (q, J = 6.7 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.
4.1.4. 2-Iminocoumarine-3-carbothioamide (2a)
Yield 72%; m.p. 140–142◦C, lit. m.p. 146◦C (52); orange solid. IR (cm−1): 3286, 3231, 3013,
1
1649, 1626, 1562, 1406. H NMR (200 Hz, CDCl3): δ 7.17 (m, 2 H), 7.52 (m, 2 H), 7.72 (br.s,
1 H), 8.22 (br.s, 1 H), 9.10 (s, 1 H), 12.14 (br.s, 1 H). Anal. calcd. for C10H8N2OS: H, 3.95; C,
58.81; N, 13.72; S, 15.70. Found: H, 3.91; C, 58.68; N, 13.65; S, 15.59.
4.1.5. 8-Etoxy-2-iminocoumarine-3-carbothioamide (2b)
Yield 75%; m.p. 174–176◦C; orange solid. IR (cm−1): 3302, 3237, 3042, 1650, 1626, 1594, 1469.
1H NMR (200 Hz, CDCl3): δ 1.47 (t, J = 7.0 Hz, 3 H), 4.14 (q, J = 7.0 Hz, 2 H), 7.11 (m, 3 H),

452 P.E. Shynkarenko et al.
8.14 (br.s, 2 H), 9.09 (s, 1 H), 12.14 (br.s, 1 H). Anal. calcd. for C12H12N2O2S: H, 4.87; C, 58.05;
N, 11.28; S, 12.91. Found: H, 4.81; C, 57.88; N, 11.18; S, 12.77.
4.2. General procedure for the synthesis of 3 and 4
A solution of 2-aminothiobenzamide (2 mmol) in glacial acetic acid (3 ml) was added to a sus-
pension of 1 or 2 (2 mmol) in glacial acetic acid (3 ml). The mixture was stirred at 40–50◦C for
30 min and the reaction mixture was left to cool. The solid obtained was filtered and dried.
4.2.1. 2-[(3-Cyanocoumarin-2-ylidene)amino]benzenecarbothioamide (3a)
Yield 80%; m.p. 165–167◦C; yellow solid. IR (cm−1): 3245, 3129, 2229, 1639, 1553, 1453. 1H
NMR (200 Hz, DMSO-d6): δ 7.13 (m, 3 H), 7.35 (m, 2 H), 7.61 (m, 3 H), 8.52 (s, 1 H), 9.35 (br.s,
1 H), 9.93 (br.s, 1 H). 13C NMR (75 Hz, DMSO-d6): δ 185,63, 156.04, 147.35, 145.94, 144.64,
140.04, 135.31, 133.54, 130.19, 129.24, 128.13, 127.99, 124.56, 118.7, 117.42, 116.36, 115.20.
LC-MS: m/z (MH+) 306. Anal. calcd. for C17H11N3OS: H, 3.63; C, 66.87; N, 13.76; S, 10.50.
Found: H, 3.42; C, 66.76; N, 13.50; S, 10.42.
4.2.2. 2-[(3-Cyano-8-methoxycoumarin-2-ylidene)amino]benzenecarbothioamide (3b)
Yield 86%; m.p. 223–225◦C; yellow solid. IR (cm−1): 3207, 2229, 1644, 1603, 1470. 1H NMR
(200 Hz, DMSO-d6): δ 3.75 (s, 3 H), 7.27 (m, 6 H), 7.81 (d, J = 7.6 Hz, 1 H), 8.49 (s, 1 H), 9.37
(br.s, 1 H), 9.99 (br.s, 1 H). LC-MS: m/z (MH+) 336. Anal. calcd. for C18H13N3O2S: H, 3.91; C,
64.46; N, 12.53; S, 9.56. Found: H, 3.88; C, 64.32; N, 12.40; S, 9.38.
4.2.3. 2-[(3-Cyano-8-ethoxycoumarin-2-ylidene)amino]benzenecarbothioamide (3c)
Yield 85%; m.p. 210–212◦C; yellow solid. IR (cm−1): 3198, 2978, 2228, 1645, 1604, 1450. 1H
NMR (200 Hz, DMSO-d6): δ 1.21 (t, J = 6.7 Hz, 3 H), 4.05 (q, J = 6.7 Hz, 2 H), 7.23 (m, 6 H),
7.87 (d, J = 7.7 Hz, 1 H), 8.50 (s, 1 H), 9.42 (br.s, 1 H), 10.08 (br.s, 1 H). 13C NMR (75 Hz,
DMSO-d6): δ 185.12, 155.28, 146.86, 144.85, 144.13, 142.71, 139.82, 134.80, 128.73, 127.62,
127.58, 127.49, 123.97, 121.18, 118.96, 117.67, 116.92, 64.61, 14.13. LC-MS: m/z (MH+) 350.
Anal. calcd. for C19H15N3O2S: H, 4.33; C, 65.31; N, 12.03; S, 9.18. Found: H, 4.20; C, 65.12; N,
11.88; S, 9.12.
4.2.4. 2-{[2-(Aminocarbonothioyl)phenyl]imino}-coumarin-3-carbothioamide (4a)
Yield 76%; m.p. 180–182◦C; yellow solid. IR (cm−1): 3439, 3282, 3150, 3030, 1651, 1566, 1404,
1
1298. H NMR (200 Hz, DMSO-d6): δ 7.18 (m, 3 H), 7.35 (m, 2 H), 7.56 (m, 2 H), 7.84 (d,
J = 7.6 Hz, 1 H), 8.95 (s, 1 H), 9.43 (s, 1 H), 9.82 (s, 1 H), 10.48 (s, 1 H), 11.03 (s, 1 H). LC-MS:
m/z (MH+) 340. Anal. calcd. for C17H13N3OS2: H, 3.86; C, 60.15; N, 12.38; S, 18.89. Found:
H, 3.77; C, 60.02; N, 12.28; S, 18.75.
4.2.5. 2-{[2-(Aminocarbonothioyl)phenyl]imino}-8-ethoxy-coumarin-3-carbothioamide (4b)
Yield 79%; m.p. 140–142◦C; yellow solid. IR (cm−1cm−1): 3444, 3251, 3149, 2977, 1631, 1620,
1469, 1273. 1H NMR (200 Hz, DMSO-d6): δ 1.24 (t, J = 6.7 Hz, 3 H), 4.01 (q, J = 6.7 Hz, 2 H),
7.16 (m, 1 H), 7.33 (m, 4 H), 7.50 (dd, J=7.6, 1.8 Hz, 1 H), 7.61 (d, J=7.9 Hz, 1 H), 8.96 (s, 1 H),

Journal of Sulfur Chemistry 453
9.49 (s, 1 H), 9.89 (s, 1 H), 10.43 (s, 1 H), 11.25 (s, 1 H). LC-MS: m/z (MH+) 384. Anal. calcd.
for C19H17N3O2S2: H, 4.47; C, 59.51; N, 10.96; S, 16.72. Found: H, 4.40; C, 59.42; N, 10.85; S,
16.47.
4.3. Synthesis of compounds 5
A solution of either 3 (method A) or 4 (method B) in DMF (5 ml) was heated at 140–150◦C for
20 min. The solid obtained after cooling was filtered, washed with 2-propanol and dried to give 5.
4.3.1. 2-(2-Iminocoumarin-3-yl)quinazolin-4(3H)-thione (5a)
Yields 70% (Method A) and 61% (Method B); m.p. 238–240◦C; yellow solid. IR (cm−1): 3320,
2912, 1655, 1607, 1556, 1498, 1462. 1H NMR (200 Hz, DMSO-d6): δ 7.33 (t, J = 7.7 Hz, 2 H),
7.61 (qd, J = 8.1, 1.5 Hz, 2 H), 7.86 (m, 4 H), 8.55 (dd, J = 8.1, 1.1 Hz, 1 H), 8.97 (s, 1 H), 9.59
(br.s, 1 H), 15.86 (br.s, 1 H). LC-MS: m/z (MH+) 306. Anal. calcd. for C17H11N3OS: H, 3.63; C,
66.87; N, 13.76; S, 10.50. Found: H, 3.46; C, 66.75; N, 13.51; S, 10.31.
4.3.2. 2-(2-Imino-8-methoxycoumarin-3-yl)quinazolin-4(3H)-thione (5b)
Yield 88% (Method A); m.p. 288–290◦C; yellow solid. IR (cm−1): 3313, 2834, 1655, 1605, 1559,
1
1494, 1430. H NMR (200 Hz, DMSO-d6): δ 3.90 (s, 3 H), 7.32 (m, 2 H), 7.56 (t, J = 7.7 Hz,
1 H), 7.83 (m, 2 H), 8.55 (d, J = 8.1 Hz, 1 H), 8.88 (s, 1 H), 9.55 (br.s, 1 H), 15.77 (br.s, 1 H).
LC-MS: m/z (MH+) 336. Anal. calcd. for C18H13N3O2S: H, 3.91; C, 64.46; N, 12.53; S, 9.56.
Found: H, 3.62; C, 64.74; N, 12.32; S, 9.50.
4.3.3. 2-(2-Imino-8-ethoxycoumarin-3-yl)quinazolin-4(3H)-thione (5c)
Yields 85% (Method A) and 69% (Method B); m.p. 262–264◦C; yellow solid. IR (cm−1): 3330,
2927, 1656, 1602, 1557, 1465. 1H NMR (200 Hz, DMSO-d6): δ 1.40 (t, J = 7.0 Hz, 3 H), 4.17
(q, J = 7.0 Hz, 2 H), 7.25 (m, 2 H), 7.42 (d, J = 7.3 Hz, 1 H), 7.59 (td, J = 8.1, 1.1 Hz, 1 H),
7.79 (d, J = 8.4 Hz, 1 H), 7.90 (t, J = 8.1 Hz, 1 H), 8.55 (d, J = 8.1 Hz, 1 H), 8.91 (s, 1 H), 9.61
(br.s, 1 H), 16.00 (br.s, 1 H). LC-MS: m/z (MH+) 350. Anal. calcd. for C19H15N3O2S: H, 4.33;
C, 65.31; N, 12.03; S, 9.18. Found: H, 4.60; C, 65.11; N, 11.85; S, 9.02.
4.4. General procedure for the synthesis of 6
To a solution of corresponding aniline (1 mmol) in glacial acetic acid (5 ml) 2-(2-iminocoumarin-
3-yl)quinazoline-4(3H)-thione 3 (1mmol) was added at 40–50◦C under stirring. The reaction
mixturewasheatedat70–80◦Cfor30 min.Aftercoolingdowntoroomtemperature, theprecipitate
formed was filtered, washed with 2-propanol and recrystallized form DMF.
4.4.1. 2-[2-(4-Fluoro-phenylimino)-coumarin-3-yl]quinazolin-4(3H)-thione (6a)
Yield 62%; m.p. 278–280◦C; yellow solid. IR (cm−1): 2861, 1641, 1549, 1499, 1461. 1H NMR
(200 Hz, DMSO-d6): δ 7.30 (m, 4 H), 7.57 (m, 4 H), 7.84 (m, 3 H), 8.53 (d, J = 8.1 Hz, 1 H),
8.94 (s, 1 H), 15.55 (s, 1 H). LC-MS: m/z (MH+) 400. Anal. calcd. for C23H14FN3OS: H, 3.53;
C, 69.16; N, 10.52; S, 8.03. Found: H, 3.41; C, 68.94; N, 10.43; S, 7.85.

454 P.E. Shynkarenko et al.
4.4.2. 2-[2-(4-Ethyl-phenylimino)-coumarin-3-yl]quinazolin-4(3H)-thione (6b)
Yield 66%; m.p. 259–261◦C; yellow solid. IR (cm−1): 2964, 1640, 1592, 1548, 1493, 1466.
1H NMR (200 Hz, DMSO-d6): δ 1.21 (t, J = 7.3 Hz, 3 H), 2.63 (q, J = 7.3 Hz, 2 H), 7.31 (m,
4 H), 7.45 (d, J = 8.4 Hz, 2 H), 7.60 (m, 2 H), 7.79 (d, J = 7.7 Hz, 1 H), 7.90 (m, 2 H), 8.54
(d, J = 7.3 Hz, 1 H), 8.95 (s, 1 H), 15.78 (s, 1 H). LC-MS: m/z (MH+) 410. Anal. calcd. for
C25H19N3OS: H, 4.68; C, 73.33; N, 10.26; S, 7.83. Found: H, 4.60; C, 73.22; N, 10.12; S, 7.77.
4.4.3. 2-[8-Ethoxy-2-(3,5-dimethoxy-phenylimino)-coumarin-3-yl]quinazolin-4(3H)-thione
(6c)
Yield 70%; m.p. 218–220◦C; yellow solid. IR (cm−1): 2832, 1649, 1589, 1550, 1493, 1468. 1H
NMR (200 Hz, DMSO-d6): δ 1.34 (t, J = 7.0 Hz, 3 H), 3.72 (s, 6 H), 4.10 (q, J = 7.0 Hz, 2 H),
6.36 (t, J = 2.2 Hz, 1 H), 6.97 (d, J = 2.2 Hz, 2 H), 7.25 (m, 2 H), 7.40 (dd, J = 6.6, 1.8 Hz,
1 H), 7.58 (td, J = 8.1, 1.1 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.90 (td, J = 8.1, 1.1 Hz, 1 H),
8.50 (dd, J = 8.1, 1.1 Hz, 1 H), 8.93 (s, 1 H), 16.06 (s, 1 H). LC-MS: m/z (MH+) 486. Anal.
calcd. for C27H23N3O4S: H, 4.77; C, 66.79; N, 8.65; S, 6.60. Found: H, 4.66; C, 66.67; N, 8.53;
S, 6.42.
4.5. General procedure for the synthesis of 7
A mixture of 5 (0.5 mmol) in acetic acid (5 ml) containing hydrochloric acid (0.5 ml) was heated
at 80–90◦C for 20 min. The solid obtained after cooling was collected by filtration and dried.
4.5.1. 2-(Coumarin-3-yl)quinazolin-4(3H)-thione (7a)
Yield 89%; m.p. 275–277◦C, lit. m.p.. 275–276◦C (38); yellow solid. 1H NMR (200 Hz, DMSO-
d6): δ 7.55 (m, 3Í), 7.80 (m, 2H), 8.00 (m, 2H), 8.58 (d, J = 8.1 Hz, 1H), 9.03 (s, 1H), 13.62 (br
s, 1H, NH).
4.5.2. 2-(8-Methoxycoumarin-3-yl)quinazolin-4(3H)-thione (7b)
Yield 82%; m.p. 295–297◦C, lit. m.p. 295◦C (38); yellow solid. 1H NMR (200 Hz, DMSO-d6):
δ 3.95 (s, 3H, OCH3), 7.5 (m, 4H), 7.79 (d, J = 7.4 Hz, 1H), 7.94 (t, J = 7.4 Hz, 1H), 8.57 (d,
J = 8.6 Hz, 1H), 9.03 (s, 1H), 13.62 (br s, 1H, NH).
4.5.3. 2-(8-Ethoxycoumarin-3-yl)quinazolin-4(3H)-thione (7c)
Yield 88%; m.p. 270–272◦C, lit. m.p. 269–271◦C (38); yellow solid. 1H NMR (200 Hz, DMSO-
d6): δ 1.42 (t., J = 8.6 Hz, 3H, OCH2CH3); 4.22 (q, J = 8.6 Hz, 2H, OCH2CH3), 7.25–7.70 (m,
4H), 7.82 (d, J = 7.9 Hz, 1H), 7.96 (t, J = 7.6 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 9.03 (s, 1H),
13.61 (br s, 1H, NH).
4.6. General procedure for the synthesis of 9
To a suspension of 5 (0.5 mmol) in DMF (5 ml) and TEA (0.53 mmol), an alkylating agent
(0.53 mol) was added. The mixture was stirred at 70◦C for 40 min and allowed to cool. The
mixture was diluted with of 2-propanol (5 ml) and the solid obtained was collected by filtration,

Journal of Sulfur Chemistry 455
washed with 2-propanol and dried to give 8. A mixture of 8, 2-propanole (5 ml) and hydrochloric
acid (0.5 ml) was refluxed for 20 min. The solid obtained after cooling was filtered, dried and
recrystallized from DMF.
4.6.1. N-(4-Methylphenyl)-2-[2-(8-methoxycoumarin-3-yl)-4-quinazolinylthio]acetamide (9a)
Yield 61%; m.p. 240–241◦C, lit. m.p. 241–243◦C (38); colorless solid. 1H NMR (200 Hz, DMSO-
d6): δ 2.18 (s, 3H, ArCH3), 3,91 (s, 3H, CouOCH3), 4.33 (s, 2H, ArCH2S), 6,89 (d, J = 9.5 Hz,
1H), 7.01 (d, J = 10.5 Hz, 2H), 7.18 (t, J = 9.7 Hz, 1H), 7.38 (m, 3H, H-5+ H-2ꢀꢀ’ + H-6ꢀꢀ),
7,75 (m, 1H), 8.02 (m, 2H), 8.19 (d, J = 8.7 Hz, 1H), 8.62 (s, 1H), 10.27 (br s, 1H, NH).
4.6.2. 8-Ethoxy-3-[4-(3-methylbenzylthio)quinazolin-2-yl]coumarin (9b)
Yield 65%; m.p. 162–163◦C, lit. m.p. 162–164◦C (38); yellow solid. 1H NMR (200 Hz, DMSO-
d6): δ 1.42 (t, J = 7.8 Hz, 3H, OCH2CH3); 2.15 (s, 3H, ArCH3), 4.22 (q, J = 7.8 Hz, 2H,
OCH2CH3), 4.69 (s, 2H, ArCH2S), 6.95–7.40 (m, 7H), 7,71 (m, 1H), 7.98 (m, 2H), 8.08 (d,
J = 8.6 Hz, 1H), 8.77 (s, 1H).
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