New syntheses of 2-alkylthio-4-oxo-3,4-dihydroquinazolines, 2-alkylthioquinazolines, as well as their hetero analogues

Article abstract of DOI:10.3987/COM-00-8954

N-Chloroacetylanthranilic acid ethyl ester reacts with potassium thiocyanate in the presence of alcohol to give the (4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)acetic acid ester (3a). In the presence of water or amines the acetic acid derivative (3b) or the acetamide derivatives (3c,d) are obtained. 2-Amino-4-oxo-3,4-dihydroquinazolines (4) arise if vigorous reaction conditions are employed. Analogously, N-chloroacetyl derivatives of 5-membered heterocycles with enaminocarbonyl structure (5, 7, 9, 11, 13, 20, 23) react with potassium thiocyanate to yield thieno[2,3-d]-, thieno[3,2-d]-, imidazo[4,5-d]-, pyrrolo[3,2-d]-, and thiazolo[4,5-d]pyrimidines (6, 8, 10, 12, 14, 21, 24). Quinazolines (18, 19) are formed from the reaction of 2-chloroacetylaminoacetophenone (16a) and 2-chloroacetylaminobenzophenone (16b) with potassium thiocyanate and subsequent treatment of the intermediates with amines.

Full text of DOI:10.3987/COM-00-8954

HETEROCYCLES, Vol. 53, No11, 2000, pp. 2363 - 2377, Received, 22nd May, 2000
NEW SYNTHESES OF 2-ALKYLTHIO-4-OXO-3,4-DIHYDRO-
QUINAZOLINES, 2-ALKYLTHIOQUINAZOLINES, AS WELL AS
THEIR HETERO ANALOGUES
Margit Gruner*, Matthias Rehwald, Katrin Eckert, and Karl Gewald
Institut of Organic Chemistry, Technical University Dresden, D-01062 Dresden,
Germany
Abstract - N-Chloroacetylanthranilic acid ethyl ester reacts with potassium thio-
cyanate in the presence of alcohol to give the (4-oxo-3,4-dihydroquinazolin-2-yl-
sulfanyl)acetic acid ester (3a). In the presence of water or amines the acetic acid
derivative (3b) or the acetamide derivatives (3c,d) are obtained. 2-Amino-4-oxo-
3,4-dihydroquinazolines (4) arise if vigorous reaction conditions are employed.
Analogously, N-chloroacetyl derivatives of 5-membered heterocycles with ena-
minocarbonyl structure (5, 7, 9, 11, 13, 20, 23) react with potassium thiocyanate to
yield thieno[2,3-d]-, thieno[3,2-d]-, imidazo[4,5-d]-, pyrrolo[3,2-d]-, and
thiazolo[4,5-d]pyrimidines (6, 8, 10, 12, 14, 21, 24). Quinazolines (18, 19) are
formed from the reaction of 2-chloroacetylaminoacetophenone (16a) and 2-
chloroacetylaminobenzophenone (16b) with potassium thiocyanate and subse-
quent treatment of the intermediates with amines.
In our investigations about the synthesis of quinolines and quinazolines from N-chloroacetylanthranilic
acid derivatives, we continued our experimental work in order to examine the synthetic potentials of N-
chloroacetylanthranilic acid ethyl esters and hetero analogues in reactions with potassium thiocyanate
under various reaction conditions. In earlier publications we demonstrated that the ring closure reactions
starting from N-chloroacetylanthranilic acid derivatives give access to a multitude of different substitution
patterns, if the chloro atom is substituted by an aminoalkyl 1 or preferably an electron withdrawing group
such as cyano, pyridinio,2 or sulfonio.3 Thieno[2,3-d]pyrimidines were reported to furnish various
pharmacological activities.4 With the described reaction here a new access opened up to the 2-alkylthio-
quinazolines and their hetero analogues.

RESULTS AND DISCUSSION
N-Chloroacetylanthranilic acid ethyl ester (1) was expected to yield a quinoline derivative after substi-
tution of the chloro atom by the thiocyanato group and subsequent ring closure reaction by Dieckmann
condensation under alkaline conditions. On heating of a suspension of N-chloroacetyl-anthranilic acid
ethyl ester (1) and potassium thiocyanate in acetonitrile the primary substitution product 2-thiocyanato-
acetylaminobenzoic acid ethyl ester was obtained. In case that an alcohol was used as a solvent the
reaction proceeded further to furnish a 4-oxo-3,4-dihydroquinazoline derivative (3).
CO2Et
CO2Et
KSCN
RH
NHCOCH2Cl
NHCOCH2SCN
70%
1
2
O
CO2Et
NH
N
N
S
N
S
O
O
B
A
R
yields (%)
3
O
N
OEt
OH
72
80
a
b
NH
NHCH2Ph
NEt2
54
43
c
d
S
COR
3
O
yields (%)
R
4
RNH2
NH
3a
NH2
33
39
a
b
R
CH2CH2NEt2
N
N
H
4
Scheme 1
As described in an earlier publication,5 we observed the same course of reaction with 2-chloroacetyl-
aminobenzonitrile, which gave rise to 4-aminoquinazoline derivative on reaction with potassium
thiocyanate in the presence of alcohol. The indicated intermediates cannot be isolated, but can be

rationalized as follows (Scheme 1). The 2-iminothiazolidin-4-one intermediate was found to be isolable in
the reaction of 2-chloroacetylaminoacetophenone with potassium thiocyanate. The subsequent
intermediate representing a thiazolo [3,2-a] quinazoline system is a probable structure because
experiments failed to open the 2-imino-3-phenylthiazolidin-4-one ring, which was prepared from
chloroacetanilide and potassium thiocyanate, by treatment with alcohol. An similar but mesoionic isolable
thiazole structure was reported to arise from the reaction of 2-thioxo-4-oxoquinazolines with acetic
anhydride in the presence of pyridine.6
R1
O
R1
CO2Et
Cl
NH
KSCN
3
R2
R3
2
R
R H
O
S
N
H
S
N
S
6
O
5
O
H
NC
N
NC
N
O
S
CO2Et
Cl
MeS
CO2Et
NH
MeS
S
S
7
8
R1
R2
R3
yields (%) of 6
5,6
a
b
c
d
e
Me
Me
Me
OEt
OEt
OEt
OH
34
40
51
CO2Et
- (CH2)4 -
Me
Me
Me
Me
28
41
N(CH2CH2)2O
Scheme 2
An earlier described synthesis of (4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)acetic acid derivatives were
employed the alkylation of 2-mercapto-4-oxoquinazolines with haloacetic acid derivatives.7-10
9,10
Compound (3a) was earlier described
without indication of the preferred tautomeric structure in
solution. One would have to differentiate between three lactam-lactim tautomers, which must be taken in
consideration (see Figure 1). We were able to prove by 2D-NMR spectroscopy that structure (C) is
existent in DMSO-d6 solution. From the NOESY spectrum as well as from 1H/13C correlated HSQC and
HMBC spectra an assignment of the 1H- and 13C-NMR signals was accomplished, whereby on account of

the rapid proton exchange it was not possible to decide unambiguously in favour of one of the tautomers
(C) or (E).
O
O
OH
10
3
NH
4
.5.
6
9
8
N
N
R
R
R
2
N
H
N
S
S
N
S
7
1
C
D
E
O
13
Numbering of C-atoms relates to NMR spectra
11
CH2
12
14
O
R =
1
Figure 1
2D - 1H/15N-HSQC and H/15N-HMBC-NMR spectra of 3a in DMSO-d6
A decision in favor of structure (C) was possible, because the 15N-NMR-spectrum of 3a exhibits two
signals at -219.1 ppm and -153.8 ppm (reference to δ(15N) CH3NO2 = 0 ppm), which we correlated in the
1H/15N-correlated HSQC and HMBC spectra to the proton signals at 12.69 ppm (1J, H-3/N-3) and 7.41
ppm (3J, H-7/N-3) respectively (see Figure 1).
N-Chloroacetylanthranilic acid ethyl ester (1) reacts also in a solvent mixture of acetonitrile and water to
give 2-thiocyanatoacetylaminobenzoic acid ethyl ester, but this intermediate is directly converted to the
(4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)acetic acid (3b). When primary or secondary amines are used
instead of alcohol in the reaction with 2-thiocyanatoacetyl-aminobenzoic acid ethyl ester (2) or the

precursor N-chloroacetyl anthranilic acid ethyl ester /potassium thiocyanate, the (4-oxo-3,4-dihydro-
quinazolin-2-ylsulfanyl)acetic acid amides (3c and d) are formed.
CH2Cl
CH2Cl
H
H
N
NC
N
N
O
O
R1
CO2Et
CO2Et
N
R
N
R2
9
11
KSCN, EtOH
KSCN, EtOH
NC
N
O
S
CO2Et
N
S
CO2Et
N
N
R1
NH
NH
N
R
R2
O
12
10
R1
H
R2
9,10
11,12
R
Yields (%)
Yields (%)
65
55
a
b
p-Cl-C6H4
42
79
p-MeO-C6H4
a
b
p-MeO-C6H4
MeS
H
CH2Cl
O
H
N
N
MeS
CO2Et
S
13
73%
KSCN, EtOH
O
NH2
8,9
N
O
S
CO2Et
2
N
OEt
4
3
1
piperidine
N
N
S
MeS
NH
S
55%
7
5
O
6
15
Numbering of C-atoms relates to NMR spectra
14
Scheme 3

Treatment of 3a with primary amines leads to the formation of 2-amino-4-oxo-3,4-dihydro-quinazolines
(4a and b) under elimination of the thioacetic acid moiety.
Further investigations involved N-chloroacetyl derivatives of 5-membered heterocycles with enamino-
carbonyl structure. The employed 5-membered heterocycles were synthesized according to well-known
literature procedures.11-14 The syntheses of N-chloroacetyl derivatives were carried out following ageneral
applicable method as described by Sauter.15
The utilization of the method for the synthesis of various hetero-condensed pyrimidin-4-ones starting
from N-chloroacetylated amino-heterocycles was examined. Analogously, N-chloroacetyl derivatives of 5-
membered amino-heterocycles with carboxylic acid ester groups gave the same reaction with potassium
thiocyanate and alcohol as observed with N-chloroacetylanthranilic acid ethyl ester (1). Schemes 2 and 3
illustrate the structure of respective starting materials (5, 7, 9, 11, and 13) and products (6, 8, 10, 12, and
14).
O
O
R1
R1
R2
R2
NH
KSCN
EtOH
NH
N
S
CH2Cl
O
O
17
16
morpholine
benzylamine
21%
R2
Ph
R1
Cl
N
N
H
N
N
S
N
N
O
O
18
19
Yields (%) of 17 Yields (%) of 18
R1
R2
16 - 18
a
H
Me
Ph
43
33
25
40
b
Cl
Scheme 4
The thiazolo[4,5-d]pyrimidine (14) proved to be exceptionally unstable on treatment with piperidine as an
amine for further derivatization, and at this, complete cleavage of the condensed heterocyclic system was
observed.
For further investigations (see Schemes 4 and 5) we extended our synthetic method to 2-chloro-acetyl-
aminoacetophenone (16a) and 2-chloroacetylamino-4-chlorobenzophenone (16b) and obtained as primary

reaction product with potassium thiocyanate the anticipated 2-iminothiazolidin-4-one intermediates (17).
A conversion of 17 with amines yield either (quinazolin-2-ylsulfanyl)acetamides (18) or 2-
aminoquinazolines (19) depending obviously on the nucleophilicity of the amine. Ketones of 5-membered
aminoheterocylces were also included in the investigation of pyrimidine ring formation. N-
chloroacetylaminothiazole (20) yields the thiazolo[4,5-d]pyrimidine (21), which was further derivatized
with amines to amino-substituted compounds (22), and N-chloroacetylaminoimidazole (23) gives the
respective imidazo[4,5-d]pyrimidine derivative (24).
O
Cl
NH
Me
N
S
CO2Et
N
S
N
S
KSCN
MeS
MeS
EtOH
61%
N
O
Me
21
20
O
R1
NHNH2
R2
Yields (%)
N
N
S
22
R2
R1
NHNH2
62
44
a
b
N
S
N(CH2CH2)2O OEt
Me
22
O
Cl
N
S
CO2Et
N
NH
N
KSCN
N
EtOH
46%
N
O
N
Ph
Me
Ph
Me
24
23
Scheme 5
The yields were not optimized. Therefore nothing can be said about possible side reactions.
ACKNOWLEDGEMENT
The authors are indebted to Mrs. Pinske for microanalyses.

EXPERIMENTAL
1
13
15
The corrected melting points were measured on a Kofler hot-stage apparatus. H-, C-, and N-NMR
spectra and 2D-NMR spectra were obtained in DMSO-d6 using the Bruker AC-200 MHz and DRX-500
1
13
MHz spectrometers. H- and C-chemical shifts are reported in ppm downfield from TMS as a internal
15
standard. The 15N-chemical shifts are downfield positive to CH3 NO2 = 0 ppm as a external standard.
The IR spectra were recorded on a spectrophotometer Specord 75 (Fa. Carl-Zeiss Jena). Elemental
analyses were determined on an EA 1108 (Fa. Carlo Erba Hofheim). The MS spectra were obtained by the
HP-Bruker Esquire-LC-MS System.
Chloroacetylation - general procedure 15
10 mmol of amino-substituted heterocyclic compound or amino-substituted benzene derivative are
suspended in dioxane (10 mL). Chloroacetyl chloride (1.36 g, 12 mmol) are added dropwise to the stirred
suspension within 30 min. After stirring for additional 2 h, the reaction mixture is poured into water (100
mL), the precipitate collected by filtration, and the crude product recrystallized from ethanol.
2-Thiocyanatoacetylaminobenzoic acid ethyl ester (2)
A suspension of 1 (2.42 g, 10 mmol) and potassium thiocyanate (3.0 g, 30 mmol) in MeCN (50 mL) was
heated to reflux for 3 h. The reaction mixture was cooled and poured into water (150 mL) and after 1 h,
the crude product was collected by filtration. Yield: 1.85 g (70 %), mp 62-63 °C (EtOH); IR (KBr): 2150
(SCN), 1695 (CO), 1670, 1580 (CO, secondary amide) cm-1; 1H-NMR (DMSO-d6) δ : 10.92 (1H, s, NH),
7.11-8.08 (4H, m, benzo-H), 4.20 (2H, q, J =6.95 Hz, OCH2 and 2H, s, SCH2), 1.22 (3H, t, J =6.95 Hz,
CH3); EI-MS m/z : 264 (M+). Anal. Calcd for C12H12N2O3S : C, 54.53; H, 4.58; N, 10.6; S, 12.13. Found:
C, 54.82 ; H, 5.01; N, 11.02; S, 11.93.
(4-Oxo-3,4-dihydroquinazolin-2-ylsulfanyl)acetic acid ethyl ester (3a)
A suspension of 1 (2.42 g, 10 mmol) and potassium thiocyanate (3.0 g, 30 mmol) in EtOH (50 mL) was
heated to reflux for 3 h. The reaction mixture was cooled and poured into water (150 mL) and after 1 h,
the crude product was collected by filtration. Yield: 2.1 g (72 %), mp 179-180 °C (MeOH), lit.2, mp 186-
187 °C (EtOH); IR (KBr): 3450 (br, NH), 1692, 1734 (CO) cm-1; 1H-NMR (DMSO-d6) δ : 12.69 (1H, br
s, NH), 7.40-8.10 (4H, m, benzo-H), 4.13 (2H, q, J =7.15 Hz, OCH2), 4.07 (2H, s, SCH2), 1.19 (3H, t, J
=7.14 Hz, CH3); 13C-NMR (DMSO-d6) δ : 14.16 (CH3, C-14), 32.46 (SCH2, C-11), 61.17 (OCH2, C-13),
119.97 (C-5), 125.80 (CH=, C-9), 125.92 (CH=, C-7), 126.12 (CH=, C-10), 134.68 (CH=, C-8), 148.22
(C-6), 154.76 (C-2), 161.15 (C-4), 168.32 (C-12); 15N-NMR (DMSO-d6) δ : -153.8 (N-1), -219.1 (NH, N-
3). El-MS m/z : 265 (M+).
(4-Oxo-3,4-dihydroquinazolin-2-ylsulfanyl) acetic acid (3b)
A suspension of 1 (2.42 g, 10 mmol) and potassium thiocyanate (3.0 g, 30 mmol) in a mixture of aceto-

nitrile (50 mL) and water (20 mL) was heated to reflux for 3 h. The reaction mixture was cooled and
poured into water (100 mL) and after 1 h, the crude product was collected by filtration. Yield: 1.9g (80 %),
1
mp 220-222 °C (1,4-dioxane); H-NMR (DMSO-d6) δ : 12.82 (2H, br s, OH, NH), 7.11-8.10 (4H, m,
benzo-H), 4.05 (2H, s, SCH2); Anal. Calcd for C10H8N2O3S : C, 50.84; H, 3.41; N, 11.86; S, 13.57.
Found: C, 51.12; H, 3.61; N, 11.74; S, 13.18.
(4-Oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-N-benzylacetamide (3c)
A suspension of 1 (4.84 g, 20 mmol) and potassium thiocyanate (6.0 g, 60 mmol) in EtOH (60 mL) and
benzylamine (4 mL, 40 mmol) was heated to reflux for 3 h. The reaction mixture was cooled and poured
into water (200 mL) and after 1 h, the precipitate was collected by filtration and washed with water.
Yield: 3.5 g (54 %), mp 205-208°C (decomp) (AcOH); IR (KBr): 3288 (br, NH), 1672, 1588 (CO,
1
secondary amide) cm-1, H-NMR (DMSO-d6) δ : 12.31 (1H, s, NH), 8.68 (1H, t, J =5.7 Hz, NH), 7.11-
8.03 (9H, m, phenyl-H, benzo-H), 4.21 (2H, d, J =5.7 Hz, NCH2), 4.03 (2H, s, SCH2); Anal. Calcd for
C17H15N3O2S : C, 62.75; H, 4.65; N, 12.91; S, 9.85. Found: C, 62.93; H, 4.75; N, 13.09; S, 9.77.
(4-Oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-N,N-diethylacetamide (3d)
A suspension of 2 (5.28 g, 20 mmol) and some crystals of potassium thiocyanate in diethylamine (50 mL)
was heated to reflux for 3 h. The reaction mixture was cooled and poured into water (200 mL) and after
acidification with hydrochloric acid, a yellow precipitate was collected by filtration and washed with
water. Yield: 2.5 g (43 %), mp 143-147 °C (decomp) (EtOH); IR (KBr): 3430 (br, NH), 1698 (CO) cm-1;
1H-NMR (DMSO-d6) δ : 12.73 (1H, s, NH), 7.50-8.01 (4H, m, benzo-H), 4.19 (2H, s, SCH2), 3.52 (4H,
m, 2NCH2), 1.02 and 1.09 (6H, each t, J =7.15 Hz, 2×CH3) ; Anal. Calcd for C14H17N3O2S : C, 57.71; H,
5.88; N, 14.42; S, 11.00. Found: C, 57.94; H, 5.47; N, 13.56; S, 11.01.
2-Hydrazino-4-oxo-3H-quinazoline (4a)
A suspension of 3a (1.32 g, 5 mmol) in a mixture of EtOH (15 mL) and hydrazine hydrate (5 mL, 80 %,
80 mmol) is stirred at 20ºC for 2 h and then allowed to react completely over a period of 2 d.
Subsequently, the solution is filtrated and diluted with water (5 mL) and the precipitate separated by
filtration. The filtrate is concentrated by evaporation, the formed precipitate separated again and combined
with the first crop. Yield: 0.29 g (33 %), mp 355 °C(decomp), lit.,5: mp 360 °C(decomp); IR (KBr): 3305,
3190 (NH) cm-1; Anal. Calcd for C8H8N4O : C, 54.54; H, 4.58; N, 31.80. Found: C, 54.63; H, 4.62; N,
32.12.
2-Diethylaminoethylamino-4-oxo-3H-quinazoline (4b)
A suspension of 3a (6.34 g, 24 mmol) and ammonium chloride (0.1 g, 2mmol) indiethylaminoethylamine
(7 mL, 50 mmol) is stirred and the temperature slowly elevated up to 120 °C. After start of evolution of
methyl mercaptan, the mixture is heated to boiling for 30 min in order to complete the reaction. After
cooling of the mixture, warm EtOH (10 mL) is added and then the reaction mixture is poured into water

(150 mL) and the precipitate separated by filtration. Yield: 2.6 g (39 %), mp 72-75 °C (EtOH/H2O=1:1);
IR (KBr): 3400, 3230 (NH) cm-1; 1H-NMR (DMSO-d6) δ : 7.13-7.89 (4H, m, benzo-H), 6.31 (1H, s, NH),
3.38 (4H, m, 2×NCH2), 2.50 (4H, m, 2×NCH2), 1.03 (6H, t, J =7.10 Hz, 2×CH3) ; Anal. Calcd for
C14H22N4O2 : C, 60.41; H, 7.97; N, 20.13. Found: C, 60.25; H, 8.32; N, 19.86.
(6,7-Dimethyl-1-oxo-1,2-dihydrothieno[2,3-d]pyrimidin-3-ylsulfanyl)acetic acid ethyl ester (6a)
A suspension of 5a (2.76 g, 10 mmol, prepared from 2-amino-4,5-dimethyl-3-thiophenecarboxylic acid
ethyl ester by chloroacetylation according to the general method 15) and potassium thiocyanate (3.0 g, 30
mmol) in abs. EtOH (50 mL) is stirred and heated to reflux for 3 h. After cooling the mixture is poured
into water (50 mL), the precipitate is allowed to settle for 12 h and then separated by filtration. Yield: 1.0
g (34 %), mp 174-175 °C (MeNO2); 1H-NMR (DMSO-d6) δ : 12.72 (1H, br s, NH), 4.13 (2H, q, J = 6.90
Hz, OCH2), 4.00 (2H, s, SCH2), 2.32 (6H, s, 2CH3), 1.18 (3H, t, J =6.90 Hz, CH3); EI-MS m/z : 299 (M+).
Anal. Calcd for C12H14N2O3S2 : C, 48.30; H, 4.73; N, 9.39; S, 21.49. Found: C, 47.93; H, 4.44; N, 9.52;
S, 21.22.
(6-Carbethoxycarbonyl-7-methyl-1-oxo-1,2-dihydrothieno[2,3-d]pyrimidin-3-ylsulfanyl)acetic acid
ethyl ester (6b)
As described in the procedure for 6a, compound (6b) is obtained from 5b (3.34 g, 10 mmol, prepared from
2-amino-4-methyl-3,5-thiophenedicarboxylic acid diethyl ester by chloroacetylation according to the
general method).15 Yield: 1.41 g (40 %), mp 174-176 °C (EtOH); Anal. Calcd for C14H16N2O5S2 : C,
47.18; H, 4.52; N, 7.86; S, 17.99. Found: C, 47.32; H, 4.71; N, 7.65; S, 17.81.
(6,7-Tetramethylene-1-oxo-1,2-dihydrothieno[2,3-d]pyrimidin-3-ylsulfanyl)acetic acid ethyl ester
(6c)
As described in the procedure for 6a, compound (6c) is obtained from 5c (3.02 g, 10 mmol, prepared from
2-amino-4,5-tetramethylene-3-thiophenecarboxylic acid ethyl ester by chloroacetylation according to the
general method).15 Yield: 1.65 g (51 %), mp 183-185 °C (MeNO2); Anal. Calcd for C14H16N2O3S2 : C,
51.83; H, 4.97; N, 8.63; S, 19.77. Found: C, 51.38; H, 5.01; N, 8.37; S, 19.76.
6,7-Dimethyl-1-oxo-1,2-dihydrothieno[2,3-d]pyrimidin-3-ylsulfanyl)acetic acid (6d)
A suspension of 5a (5.52 g, 20 mmol, prepared from 2-amino-4,5-dimethyl-3-thiophenecarboxylic acid
ethyl ester by chloroacetylation according to the general method)15 and potassium thiocyanate (6.0 g, 60
mmol) in acetonitrile (60 mL) is heated to reflux for 1 h. Subsequently, dimethylaminoethanol (3 mL, 30
mmol) is added and the mixture heated to reflux for additional 1 h. After cooling the reaction mixture is
poured into water (300 mL) and neutralized by addition of 5% hydrochloric acid. The precipitate is
separated by filtration. Yield: 1.52 g (28 %), mp 211-215 °C (DMF); IR (KBr): 3400 (NH), 1679 (CO)
1
cm-1; H-NMR (DMSO-d6) δ : 12.60 (2H, s, OH, NH), 4.00 (2H, s, SCH2), 2.28 (6H, s, 2×CH3) ; Anal.

Calcd for C10H10N2O3S2 : C, 44.43; H, 3.73; N, 10.36; S, 23.72. Found: C, 45.02; H, 4.04; N, 10.40; S,
23.45.
6,7-Dimethyl-1-oxo-1,2-dihydrothieno[2,3-d]pyrimidin-3-ylsulfanyl)acetic acid morpholide (6e)
A suspension of 5a (5.52 g, 20 mmol, prepared from 2-amino-4,5-dimethyl-3-thiophenecarboxylic acid
ethyl ester by chloroacetylation according to the general method)15 and potassium thiocyanate (6.0 g, 60
mmol) in a mixture of abs. EtOH (100 mL) and morpholine (2 mL, 23 mmol) is heated to reflux for 3 h.
After cooling the reaction mixture is poured into water (300 mL), the precipitate is separated by filtration
and washed with water. Yield: 2.80 g (41 %), mp 166-169 °C (MeNO2); IR (KBr): 3300-3400 (br s, NH),
1
1650 (CO) cm-1; H-NMR (DMSO-d6) δ : 12.78 (1H, s, NH), 4.08 (2H, s, SCH2), 3.50 (8H, m, 2NCH2,
2OCH2), 2.23 (6H, s, 2×CH3); Anal. Calcd for C14H17N3O3S2 : C, 49.54; H, 5.05; N, 12.38; S, 18.89.
Found: C, 49.31; H, 5.03; N, 12.56; S, 19.23.
7-Cyano-6-methylthio-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-ylsulfanyl)acetic acid ethyl ester
(8)
A suspension of 7 (3.19 g, 10 mmol, prepared from 2-amino-4-cyano-5-methylthio-2thiophenecarboxylic
acid ethyl ester by chloroacetylation according to the general method)15 and potassium thiocyanate (3.0 g,
30 mmol) in abs. EtOH (60 mL) is heated to reflux for 2 h. After cooling the reaction mixture is poured
into water (300 mL), the precipitate is separated by filtration and washed with water. Yield: 2.90 g
(85 %), mp 169-171 °C (abs. EtOH); IR (KBr): 3315 (OH), 2229 (CN), 1734 (CO) cm1; 1HNMR (DMSO-
d6) δ : 9.58 (1H, s, NH), 4.33 and 4.39 (2H, AB, SCH2), 4.27 (2H, q, J =7.10 Hz, OCH2), 2.91 (3H, s,
CH3), 1.3 (3H, t, J =7.10 Hz, CH3); EI-MS m/z : 341 (M+), Anal. Calcd for C12H11N3O3S3 : C, 42.21; H,
3.25; N, 12.31; S, 28.17. Found: C, 42.51; H, 3.61; N, 11.98; S, 28.05.
[1-(4-Chlorophenyl)-7-oxo-6,7-dihydroimidazo[4,5-d]pyrimidin-5-ylsulfanyl]acetic acid ethyl ester
(10a)
A suspension of 9a (4.45 g, 13 mmol, prepared from 4-amino-1-(4-chlorphenyl)-1H-5-
imidazolecarboxylic acid ethyl ester by chloroacetylation according to the general method)15and
potassium thiocyanate (3.9 g, 40 mmol) in abs. EtOH (60 mL) is heated to reflux for 3 h. After cooling the
reaction mixture is poured into water (200 mL), the precipitate is separated by filtration and washed with
water. Yield: 2.0 g (42 %), mp 200-204 °C (decomp)(EtOH) ); IR (KBr): 3430, 3170 (NH), 1700 (CO)
cm-1; 1H-NMR (DMSO-d6) δ : 11.61 (1H, s, NH), 8.00 (1H, s, CH), 7.45-7.57 (4H, AA`XX`, J =8.1 Hz,
phenyl-H), 4.04 (2H, q, J =7.0 Hz, OCH2), 3.95 (2H, s, SCH2), 1.05 (3H, t, J =7.0 Hz, CH3); Anal. Calcd
for C15H13N4O3ClS : C, 49.38; H, 3.59; N, 15.36; Cl, 9.72; S, 8.79. Found: C, 49.42; H, 3.63; N, 15.21;
Cl, 9.86; S, 8.25.
[1-(4-Methoxyphenyl)-7-oxo-6,7-dihydroimidazo[4,5-d]pyrimidin-5-ylsulfanyl]acetic acid ethyl ester
(10b)

A suspension of 9b (6.76 g, 20 mmol, prepared from 4-amino-1-(4-methoxyphenyl)-1H-5-imidazole-
carboxylic acid ethyl ester by chloroacetylation according to the general method)15 and potassium
thiocyanate (6.0 g, 60 mmol) in abs. EtOH (100 mL) is heated to reflux for 3 h. After cooling the reaction
mixture is poured into water (200 mL), the precipitate is separated by filtration and washed with water.
1
Yield: 5.36 g (74 %), mp 198-200 °C (EtOH) ); IR (KBr): 3450 (NH), 1715 (CO) cm-1; H-NMR
(DMSO-d6) δ : 11.78 (1H, s, NH), 7.91 (1H, s, CH), 7.01-7.31 (4H, AA`XX`, J =8.25 Hz, phenyl-H), 4.02
(2H, q, J =7.0 Hz, OCH2), 3.93 (2H, s, SCH2), 3.35 (3H, s, OCH3), 1.05 (3H, t, J =7.0 Hz, CH3); Anal.
Calcd for C16H16N4O4S : C, 53.32; H, 4.47; N, 15.55; S, 8.89. Found: C, 53.66; H, 4.54; N, 15.49; S,
8.42.
[7-Cyano-5-(4-methoxyphenyl)-4-oxo-3,4-dihydropyrrolo[3,2-d]pyrimidin-2-ylsulfanyl]acetic acid
ethyl ester (12a)
A suspension of 11a (4.34 g, 12 mmol, prepared from 3-amino-4-cyano-1-(4-methoxyphenyl)-1H-2-
pyrrolecarboxylic acid ethyl ester by chloroacetylation according to the general method)15 and potassium
thiocyanate (3.6 g, 37mmol) in abs. EtOH (120 mL) is heated to reflux for 5 h. After cooling the reaction
mixture is poured into water (300 mL), the precipitate is separated by filtration and washed with water.
1
Yield: 3.0 g (65 %), mp 183-186 °C (EtOH) ; IR (KBr): 3450 (NH), 2233 (CN), 1731 (CO) cm-1; H-
NMR (DMSO-d6) δ : 9.50 (1H, s, NH), 8.21 (1H, s, CH), 7.05 and 7.38 (4H, AA`XX`, J =8.25 Hz,
phenyl-H), 4.28 (2H, q, J =7.1 Hz, OCH2), 4.01 (2H, s, SCH2), 3.85 (3H, s, OCH3), 1.07 (3H, t, J =7.1
Hz, CH3); Anal. Calcd for C18H16N4O4S : C, 56.24; H, 4.65; N, 14.57; S, 8.34. Found: C, 56.41; H, 4.84;
N, 14.55; S, 8.36.
(7-Cyano-6-methylthio-4-oxo-3,4-dihydropyrrolo[3,2-d]pyrimidin-2-ylsulfanyl)acetic acid ethyl
ester (12b)
A suspension of 11b (4.53 g, 15 mmol, 3-amino-4-cyano-5-methylthio-1H-2-pyrrolecarboxylic acid ethyl
ester by chloroacetylation according to the general method)15 and potassium thiocyanate (4.5 g, 45 mmol)
in abs. EtOH (60 mL) is heated to reflux for 3 h. After cooling the reaction mixture is poured into water
(300 mL), the precipitate is separated by filtration and washed with water. Yield: 2.7 g (55 %), mp 188-
191 °C (EtOH) ; IR (KBr): 3296 br (NH), 2226 (CN), 1742 (CO) cm-1; 1H-NMR (DMSO-d6) δ : 9.45 (1H,
s, NH), 4.29 (4H, m, OCH2, SCH2), 2.61 (3H, s, SCH3), 1.08 (3H, t, J =7.0 Hz, CH3); Anal. Calcd for
C12H12N4O3S2 : C, 44.43; H, 3.73; N, 17.27; S, 19.77. Found: C, 44.80; H, 4.06; N, 16.93; S, 19.58.
(2-Methylthio-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-5-ylsulfanyl)acetic acid ethyl ester (14)
A suspension of 13 (2.95 g, 10 mmol, prepared from 4-amino-2-methylthio-5-thiazolecarboxylic acid
ethyl ester by chloroacetylation according to the general method)15 and potassium thiocyanate (3.0 g, 30
mmol) in abs. EtOH (60 mL) is heated to reflux for 3 h. After cooling the reaction mixture is poured into
water (200 mL), the precipitate is separated by filtration and washed with water. Yield: 2.45 g (73 %), mp

140-143 °C (MeNO2); IR (KBr): 3450, 3250 (NH), 1706 (CO) cm-1; 1H-NMR (DMSO-d6) δ : 12.05 (1H,
s, NH), 4.21 (2H, q, J =7.0 Hz, OCH2), 3.99 (2H, s, SCH2), 2.72 (3H, s, SCH3), 1.24 (3H, t, J =7.0 Hz,
CH3); Anal. Calcd for C10H11N3O3S3 ⋅ H2O : C, 35.81; H, 3.91; N, 12.53; S, 28.67. Found: C, 36.10; H,
3.67; N, 12.80; S, 28.19.
N-(1-Piperidinylcarbonyl)-S-(ethoxycarbonylmethyl)isothiourea (15)
A solution of 14 (3.17 g, 10 mmol) in piperidine (10 mL) is heated to reflux for 20 h. After cooling the
reaction mixture is poured into water (200 mL), the precipitate is separated by filtration and washed with
water. Yield: 1.5 g (55 %), mp 139-141 °C (EtOH); IR (KBr): 3426, 3307 (NH2), 1645, 1614 (CO) cm-1;
1H-NMR (DMSO-d6) δ : 6.75 (2H, s, NH2), 4.10 (2H, q, J =6.9 Hz, OCH2), 3.45 (2H, s, SCH2), 1.55
13
(10H, m, piperidinyl-H), 1.20 (3H, t, J =6.9 Hz, CH3); C-NMR (DMSO-d6) δ : 169.98 (s, C-1), 23.46
(2t, C-2 and C-7), 163.8 and 163.4 (2s, C-3 and C-4), 48.37 (t, C-5 and C-5´), 24.78 (t, C-6 and C-6´),
58.62 (t, C-8), 14.68 (q, C-9) ppm; Anal. Calcd for C11H19N3O3S : C, 48.33; H, 7.00; N, 15.37; S, 11.73.
Found: C, 48.82; H, 6.99; N, 15.88; S, 12.02.
2-(2-Imino-4-oxothiazol-3-yl)acetophenone (17a)
A suspension of 16a (4.22 g, 20 mmol, prepared from 2-aminoacetophenone by chloroacetylation
according to the general method)15 and potassium thiocyanate (6.0 g, 60 mmol) in abs. EtOH (60 mL) is
heated to reflux for 8 h. After cooling the reaction mixture is poured into water (200 mL), the precipitate
is separated by filtration and washed with water. Yield: 2.0 g (43 %), mp 230-235 °C (MeNO2/MeOH);
IR (KBr): 3400 (NH), 1727, 1656 (CO) cm-1; 1H-NMR (DMSO-d6) δ : 7.52-8.05 (4H, m, benzo-H), 4.12
(2H, s, SCH2), 2.68 (3H, s, CH3), NH signal not detected (br, > 12 ppm); Anal. Calcd for C11H10N2O2S :
C, 56.40; H, 4.30; N, 11.96; S, 13.68. Found: 56.03; H, 4.31; N, 11.96; S, 13.50.
5-Chloro-2-(imino-4-oxothiazol-3-yl)benzophenone (17b)
A suspension of 16b (3.08 g, 10 mmol, prepared from 2-amino-5-chlorobenzophenone by chloro-
acetylation according to the general method)15 and potassium thiocyanate (3.0 g, 30 mmol) in MeCN (60
mL) is heated to reflux for 3 h. After cooling the reaction mixture is poured into water (300 mL), the
precipitate is separated by filtration and washed with water. Yield: 1.1 g (33 %), mp 204-207 °C
(MeNO2); IR (KBr): 3454 (NH), 1731, 1650 (CO) cm-1; Anal. Calcd for C16H11N2O2ClS : C, 58.10; H,
3.35; N, 8.47; Cl, 10.72; S, 9.69. Found: C, 58.39; H, 3.44; N, 8.41; Cl, 10.73; S, 9.62.
(4-Methylquinazolin-2-ylsulfanyl)-N-benzylacetamide (18a)
17a (2.34 g, 10 mmol) in a mixture of abs. EtOH (3 mL) and benzylamine (5 mL, 50 mmol) are heated to
reflux for 8 h. After cooling the reaction mixture is diluted with water (70 mL) on which a yellow oil
deposits. The solidified material is separated by filtration and washed with water. Yield: 0.8 g (25 %), mp
1
110-112 °C (EtOH); IR (KBr): 3288 (NH), 1651, 1547 (CO, secondary amide) cm-1; H-NMR (DMSO-
d6) δ : 8.68 (1H, t, J =5.7 Hz, NH), 7.53-8.15 (4H, m, benzo-H), 7.21 (5H, m, phenyl-H), 4.31 (2H, d, J

=5.7 Hz, CH2), 4.01 (2H, s, SCH2), 2.84 (3H, s, CH3); Anal. Calcd for C18H17N3OS : C, 66.85; H, 5.30;
N, 12.99; S, 9.91. Found: C, 66.77; H, 5.38; N, 12.85; S, 9.68.
(6-Chloro-4-phenylquinazolin-2-ylsulfanyl)-N-benzylacetamide (18b)
17b (3.30 g, 10 mmol) in a mixture of abs. EtOH (10 mL) and benzylamine (5 mL, 50 mmol) is heated to
reflux for 15 h. After cooling the reaction mixture is poured into water (100 mL), the precipitate is separa-
ted by filtration and washed with water. Yield: 1.7 g (40 %), mp 193-196 °C (n-BuOH); IR (KBr): 3306
1
(NH), 1638, 1557 (CO, secondary amide) cm-1; H-NMR (DMSO-d6) δ : 8.71 (1H, t, J =5.8 Hz, NH),
7.72-8.06 (5H, m, phenyl-H), 7.60 (3H, m, benzo-H), 7.20 (5H, m, phenyl-H), 4.33 (2H, d, J =5.8 Hz,
NCH2), 4.08 (2H, s, SCH2); Anal. Calcd for C23H18N3OClS : C, 65.78; H, 4.32; N, 10.01; Cl, 8.44; S,
7.63. Found: C, 65.72; H, 4.37; N, 9.89; Cl, 8.72; S, 7.37.
6-Chloro-2-(morpholin-4-yl)-4-phenylquinazoline (19)
17b (3.3 g, 10 mmol) is heated to reflux in a mixture of absolute EtOH (5 mL) and morpholine (10 mL,
115 mmol) for 4 h. After cooling the reaction mixture is diluted with water (10 mL), the precipitate is
1
separated by filtration and washed with n-propanol. Yield: 0.7 g (21 %), mp 163-165 °C(EtOH); H -
NMR (DMSO-d6) δ : 7.71 (8H, m, benzo-H, phenyl-H), 3.72 (8H, m, 2NCH2, 2OCH2); Anal. Calcd for
C18H16N3OCl : C, 66.36; H, 4;94; N, 12.89; Cl, 10.88. Found: C, 66.12; H, 4.86; N, 12.66; Cl, 10.92.
(7-Methyl-2-methylthiothiazolo[4,5-d]pyrimidin-5-ylsulfanyl)acetic acid ethyl ester (21)
A suspension of 20 (12.5 g, 47 mmol, prepared from 4-amino-2-methylthio-5-thiazolyl methyl ketone by
chloroacetylation according to the general method)15 and potassium thiocyanate (14.0 g, 140 mmol) in
abs. EtOH (200 mL) is heated to reflux for 3 h. After cooling the reaction mixture is poured into water
(500 mL), the precipitate is separated by filtration and washed with water. Yield: 8.4 g (61 %),mp 93-94
°C (EtOH); IR (KBr): 1744 (CO) cm-1; 1H-NMR (DMSO-d6) δ : 4.14 (2H, q, J =7.0 Hz, OCH2), 4.05
(2H, s, SCH2), 2.84 (3H, s, CH3), 2.61 (3H, s, SCH3), 1.20 (3H, t, J =7.0 Hz, CH3); Anal. Calcd for
C11H13N3O2S3 : C, 41.89; H, 4.15; N, 13.32; S, 30.49. Found: C, 41.89; H, 4.19; N, 13.33; S, 30.47.
(2-Hydrazino-7-methylthiazolo[4,5-d]pyrimidin-5-ylsulfanyl)acetic acid hydrazide (22a)
21 (1.43 g, 4.5 mmol) is stirred in a mixture of EtOH (4 mL) and hydrazine hydrate (5 mL, 80 %, 80
mmol) for 7 h at rt. Subsequently, the reaction mixture is poured into water (100 mL), the precipitate is
separated by filtration and washed with water. Yield: 0.8 g (62 %), mp 225-226 °C (DMF); IR (KBr):
1
3360-3120 (NH, NH2), 1682, 1553 (CO, amide) cm-1; H-NMR (DMSO-d6) δ : 10.22 (1H, s, NH), 9.20
(1H, s, NH), 5.38 (2H, s, NH2), 4.33 (2H, s, NH2), 3.84 (2H, s, SCH2), 2.45 (3H, s, CH3); Anal. Calcd for
C8H11N7OS2 : C, 33.67; H, 3.89; N, 34.36; S, 22.47. Found: C, 33.35; H, 4.16; N, 34.28; S, 22.37.
[7-Methyl-2-(morpholin-4-yl)thiazolo[4,5-d]pyrimidin-5- ylsulfanyl]acetic acid ethyl ester (22b)
21 (2.86 g, 9 mmol) dissolved in a mixture of EtOH (5 mL) and morpholine (10 mL, 115 mmol) was
heated to reflux for 16 h. After cooling the reaction mixture is poured into ice water (100 mL), the

precipitate is separated by filtration and washed with water. Yield: 1.4 g (44 %), mp 163-165 °C (EtOH);
IR (KBr): 1744 (CO) cm-1; 1H-NMR (DMSO-d6) δ : 4.12 (2H, q, J =7.0 Hz, OCH2), 3.97 (2H, s, SCH2),
3.70 (8H, m, 2NCH2, 2OCH2), 2.45 (3H, s, CH3), 1.19 (3H, t, J =7.0 Hz, CH3); EI-MS m/z : 355 (M+).
Anal. Calcd for C14H18N4O3S2 : C, 47.44; H, 5.12; N, 15.81; S, 18.09. Found: C, 47.75; H, 5.25; N, 15.78;
S, 17.90.
(7-Methyl-1-phenylimidazolo[4,5-d]pyrimidin-5-ylsulfanyl)acetic acid ethyl ester (24)
A suspension of 23 (2.78 g, 10 mmol, prepared from 4-amino-1-phenyl-1H-imidazolyl methyl ketone by
chloroacetylation according to the general method)15 and potassium thiocyanate (3.0 g, 30 mmol) in abs.
EtOH (50 mL) is heated to reflux for 3 h. After cooling the reaction mixture is poured into water (150
mL), the precipitate is separated by filtration and washed with water. Yield: 1.5 g (46 %), mp 113-116 °C
1
(EtOH); IR (KBr): 1727 (CO) cm-1; H-NMR (DMSO-d6) δ : 8.71 (1H, s, CH), 7.60 (5H, m, phenyl-H),
4.12 (2H, q, J =7.0 Hz, OCH2), 4.02 (2H, s, SCH2), 2.24 (3H, s, CH3), 1.20 (3H, t, J =7.0 Hz, CH3);
El-MS m/z : 329 (M+). Anal. Calcd for C16H16N4O2S : C, 58.52; H, 4.91; N, 17.06, S, 9.76. Found: C,
58.46; H, 4.94; N, 16.72; S, 9.84.
REFERENCES
1.
2.
3.
4.
5.
6.
M. Rehwald, K. Gewald, H.-J. Lankau, and K. Unverferth, Heterocycles, 1997, 45, 483.
K. Gewald, H. Schäfer, P. Bellmann, and H. Müller, Chem. Ber., 1991, 124, 1237.
K. Gewald, M. Rehwald, and M. Gruner, Liebigs Ann. Chem., 1993, 457.
S. Leistner, M. Gütschow, and G. Wagner, Arch. Pharm. (Weinheim, Ger.), 1989, 322, 227.
K. Gewald, H. Schäfer, K. Eckert, and T. Jeschke, J. Prakt. Chem., 1996, 338, 206.
P. B. Talukdar, S. K. Sengupta, A. K. Datta, and T. K. Roy, Indian J. Chem., Sect. B, 1977, 15, 41
[Chem. Abstr., 1977, 87, 84933].
7.
A. K. El-Shafei and A. H. El-Sayed, Rev. Roum. Chim., 1988, 33, 291 [Chem. Abstr., 1988,
109, 190359].
8.
J. D. Kendall and G. F. Duffin, Brit. Pat. 634 951, 29 March 1950 [Chem. Abstr., 1950, 44, 9287].
A. A. Morozova and I. A. Mazur, Farm. Zh. (Kiev), 1980, 66 [Chem. Abstr., 1981, 95, 7194].
K. M. Muraveva, Pharm. Chem. J. (Engl. Transl.), 1967, 1, 678.
D. Wobig, Liebigs Ann. Chem., 1972, 764, 125.
9.
10.
11.
12.
13.
14.
15.
16.
K. Gewald, Chimia, 1980, 34, 101.
K. Gewald and G. Heinhold, Monatsh. Chem., 1976, 107, 1413.
K. Gewald, H. Schäfer, P. Bellmann, and U. Hain, J. Prakt. Chem., 1992, 334, 491.
F. Sauter and P. Stanetty, Monatsh. Chem., 1975, 106, 1111.
K. Kottke and H. Kühnstedt, Pharmazie, 1978, 33, 19.