Microwave assisted synthesis of some novel thiadiazolothienopyrimidines

Article abstract of DOI:10.3184/0308234070X206582

3-Amino-2-mercapto-3,5,6,7,8,9-hexahydro-4H-cyclohepta[4,5]thieno[2,3-d] pyrimidin-4-one (4) was prepared, and from this a series of 2-(arylaminomethyl)- 7,8,9,10-tetrahydro-6H,11H-cyclohepta[4,5]thieno[2,3-d][1,3,4]thiadiazolo [3,2-a]pyrimidin-11-ones (6

Full text of DOI:10.3184/0308234070X206582

JOURNAL OF CHEMICAL RESEARCH 2007
MARCH, 133–135
RESEARCH PAPER 133
Microwave assisted synthesis of some novel thiadiazolothienopyrimidines
M. Raghu Prasad*, S. Raziya, and D. Pran Kishore
Department of Pharmaceutical Chemistry, P.E.S. College of Pharmacy, Hanumanthnagar, Bangalore 560 050, Karnataka, India
3-Amino-2-mercapto-3,5,6,7,8,9-hexahydro-4H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one (4) was prepared, and
from this a series of 2-(arylaminomethyl)-7,8,9,10-tetrahydro-6H,11H-cyclohepta[4,5]thieno[2,3-d][1,3,4]thiadiazolo
[3,2-a]pyrimidin-11-ones (6a–d) were synthesised through the corresponding 2-chloromethyl compound (5) with
aromatic amines under microwave irradiation.
Keywords: fused pyrimidines, 1,3,4-thiadiazoles, thiophenes; microwave heating
Pyrimidine derivatives are very important in biochemistry and
CO2Et
CO2Et
biotransformations.1 The ring system is present in cytosine,
adenine, guanine and thiamine, constituents of DNA and
RNA, and in vitamins such as B2 and B6. Heterocondensed
quinazolines such as thiadiazoloquinazolines and its
thidiazolothienopyrimidine isosteres, analogues of the purines,
exhibit various medicinal properties such as antihypertensive,2
antibacterial,3 antiallergic,4 anticonvulsant,5 analgesic6 and
i
NH-CS2Me
NH2
S
S
1
2
ii
O
NH2
CO2Et
5
N
4
3
5HT1A-antagonistic7
activities.
Thiadiazolopyrimidines
2
have been reported to possess antibacterial,8 fungicidal and
herbicidal9 activities. These observations prompted us to
attempt the synthesis of thiadiazolothienopyrimidines.
Microwave-assisted organic synthesis has had a significant
impact on synthetic organic chemistry since 1986, with the
introduction of controlled, precise microwave reactors,10 and
has gained popularity due to enhanced selectivity, improved
reaction rates, ease of manipulation and eco-friendliness
of the reactions. Here we report a microwave-assisted
route for the preparation of 2-(arylaminomethyl)-7,8,9,10-
tetrahydro-6H,11H-cyclohepta[4,5]thieno[2,3-d][1,3,4]thia-
diazolo[3,2-a]pyrimidin-11-ones (6a–d).
SH
1
N
9
NH-CSNHNH2
10
S
S
4
3
Reagents: i, (a) CS2/NaOH, (b) Me2SO4/DMSO; ii, N2H4.H2O, MW
Scheme 1
dithiocarbamate (2) was obtained by reacting the thiophene
1 with carbon disulfide, sodium hydroxide and then dimethyl
sulfate in DMSO. The disappearance of two peaks between
3200 and 3400 cm-1 and the appearance of a single peak in
the same range indicated the conversion of primary amine
1
to secondary amide. The H NMR spectrum showed SCH3
Results and discussion
protons as a singlet at δ 2.65. This material was converted
into the fused pyrimidine 4 by heating in isopropanol with
hydrazine hydrate in a microwave oven at 960 W for 300 s.
The appearance of two peaks of the primary amino group at
3250 and 3353 cm-1 in the IR and the shift of the C=O peak
from 1690 to 1670 cm-1 consistent with formation of the
cyclised product. The NMR spectrum showed the primary
amino protons at δ 4.7 as a broad singlet which, together with
the loss of the OEt and SMe signals, further confirmed the
formation of 4. The mass spectrum showed the molecular ion
as the base peak.
2-(Arylaminomethyl)-7,8,9,10-tetrahydro-6H,11H-cyclo-
hepta[4,5]thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-11-
ones (6a–d) were prepared by following the route depicted in
Scheme 2. The 2-chloromethyl compound 5 was prepared by
two methods. In the first, equimolar quantities of compound
4 and chloroacetic acid were fused in a microwave oven in
presence of a catalytic amount of conc. sulfuric acid to give
the target compound in moderate yields. In the second method,
equimolar quantities of 4 and chloroacetyl chloride were
heated for 180 s in a microwave oven to provide compound
5, identical (m.p., TLC, IR) with the former sample.
The disappearance of the IR peaks at 3250 and 3353 cm-1, and
appearance of C–Cl peak at 780 cm-1 indicated the formation
of the product. The disappearance of amino signal at δ 4.7
and appearance of CH2Cl signal at δ 4.92 as a singlet in the
1H NMR gave further confirmation of structure 5.
Only few reports are available in the literature on the synthesis
of condensed 3-amino-2-mercaptothieno[2,3-d]pyrimidin-
4(5H)-ones. Modica et al.7 reported the synthesis of
2,3,5,6,7,8-hexahydro-3-amino-2-thioxobenzo[b]thieno[2,3-
d]pyrimidin-4(1H)-one from the reaction of the corresponding
ethyl 2-isothiocyanatobenzothiophene-3-carboxylate with
hydrazine hydrate. However, this route was not attractive as
it involves the use of the highly toxic thiophosgene, making it
less environment friendly, and it proceeds in low yield.7 Here
a novel, simple route for the preparation of compound 4 is
described. (Scheme 1)
Although ortho-aminothiophenecarboxylic esters have
been prepared by various methods,12,13 Gewald’s synthesis
is the most popular route.14 However, we found that the
required starting material, ethyl 2-amino-5,6,7,8-tetrahydro-
4H-cyclohepta[b]thiophene-3-carboxylate (1), could not
be prepared by the direct Gewald method, and so it was
made by a modification of that route. Cycloheptanone, ethyl
cyanoacetate, ammonium acetate and benzene were heated to
reflux for 8 h in a Dean-Stark apparatus with constant removal
of water. The solution was washed with 10% aqueous sodium
carbonate solution and dried, and the benzene was removed.
The residue was stirred with sulfur in ethanol for one hour,
with slow addition of diethylamine. The reaction mixture was
then cooled in a refrigerator for 12 h to provide the target
compound (1), evidently identical (m.p., IR) with material
previously12 reported.
The chloromethyl compound 5 was taken in dioxan with
various arylamines in the presence of an equimolar quantity
of triethylamine and irradiated in a microwave oven to give
2-(arylaminomethyl)-7,8,9,10-tetrahydro-6H,11H-cyclohepta-
[4,5]thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-11-ones
The dithiocarbamate derivative, methyl N-(3-ethoxy-
carbonyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-2-yl)
* Correspondent. E-mail: raghumrp@mailcity.com
PAPER: 06/4355

134 JOURNAL OF CHEMICAL RESEARCH 2007
O
10
O
O
i
N
NH2
SH
ii
11
N
S
1
12N
N
N
6
2
CH2NH
R
CH2Cl
5
S
3
S
4
N
S
S
N
N
4
5
6a-d
R = (a) H, (b) OMe, (c) CH3, (d) NO2
Reagents: i, ClCH2CO2H or ClCH2COCl; MW; ii, RC6H4NH2,/Et3N, MW
Scheme 2
δ 1.65–1.72 (m, 4H, CH2), 1.84–1.87 (p, 2H, CH2, J = 3.55 Hz),
2.74–2.76 (t, 2H, CH2, J = 3.65 Hz), 3.21–3.24 (t, 2H, CH2, J = 3.65
Hz). MS: m/z 267 (M+). Anal. Calcd for C11H13N3OS2: C, 49.41; H,
4.90; N, 15.72. Found: C, 49.65; H, 5.10; N, 15.89%.
(6a–d) in fair to good yields. These compounds showed the
disappearance of the C-Cl peak at 780 cm-1 in IR and shift of
the signal from δ 4.92 (CH2Cl) to ca 5.5 (CH2NHAr) in the
NMR. The mass spectra of the products showed the molecular
ion peaks at their respective molecular weights, and the
fragmentation patterns were in accordance with the assigned
structures. The physical and spectral data of all the newly
synthesised compounds are presented in the Experimental
section.
2-Chloromethyl-7,8,9,10-tetrahydro-6H,11H-cyclohepta[4,5]
thieno[2,3-d]
[1,3,4]thiadiazolo[3,2-a]pyrimidin-11-one
(5):
Method A. Fusion of compound 4 (0.267 g, 0.001 mole) and
chloroacetic acid (0.095 g, 0.001 mole) was carried out in the
presence of a catalytic amount of sulfuric acid by irradiating
the mixture for 300 s at 960 W in a domestic microwave oven.
The reaction mixture was cooled and ice-water was added to
extract the unreacted chloroacetic acid. The solid obtained was
filtered off, dried, and recrystallised from benzene as white crystals
(0.265 g, 82%).
Method B: Fusion of compound 4 (0.267 g, 0.001 mole) and
chloroacetyl chloride (0.113 g, 0.001 mole) was carried out by
irradiating the mixture for 180 s at 960 W in a domestic microwave
oven. The reaction mixture was cooled and ice water was added to
neutralise the unreacted chloroacetyl chloride. The solid obtained
was filtered off, washed with water to remove the traces of acid,
dried, and recrystallised from benzene as white crystals, m.p. 226°C.
IR: 784, 1677, 2976 cm-1. 1H NMR: δ 1.62–1.66 (m, 4H, CH2), 1.87
(p, 2H, CH2, J = 8.0 Hz), 2.78–2.80 (t, 2H, CH2, J = 8.0 Hz), 3.28–
3.30 (t, 2H, CH2, J = 8.0 Hz), 4.92 (s, 2H, CH2Cl). MS: m/z 325
(M+). Anal. Calcd for C13H12ClN3OS2: C, 47.92; H, 3.71; N, 12.90.
Found: C, 48.28; H, 3.85; N, 13.15%.
Experimental
Analytical TLC was performed on silica gel F254 plates (Merck) with
visualisation by UV or iodine vapor. Melting points were determined
in open capillaries on a Gallenkamp melting point apparatus (Sanyo
Gallenkamp, Loughborough, UK). The IR spectra (KBr discs) were
run on a Perkin-Elmer Spectrophotometer model 577. 1H NMR
(CDCl3) spectra were recorded using a Bruker WM-400 spectrometer
with TMS as internal standard (Bruker, Flawil, Switzerland). Mass
spectra were recorded on JEOL D-300 (EI/CI) spectrometer (JEOL,
Tokyo, Japan). Elemental analyses were performed on a Carlo Erba
1108 elemental analyser (Milan, Italy). All the chemicals used were
of analytical grade (Merck). Microwave irradiations were carried out
in an unaltered domestic microwave oven (LG-Intello Chef-MOD-
MS-257PL, 960 W).
Ethyl 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-
carboxylate (1): A mixture of cycloheptanone (4.48 g, 0.04 mole),
ethyl cyanoacetate (4.52 g, 0.04 mole) and ammonium acetate (2.0 g,
0.023 mole) with glacial acetic acid (2.0 ml) was taken in benzene
(80 ml) and heated to reflux for 8 h in a Dean-Stark apparatus,
removing benzene–water mixture and replacing it with fresh
benzene. After 8 h, heating was stopped and 10% sodium bicarbonate
solution was added to mixture in separating funnel and upper layer
was collected and dried over anhydrous sodium sulfate. The solvent
was distilled off until 7–8 ml solution was left and this was added
to a heated solution of sulfur (1.28 g, 0.04 g-atom) in ethanol
(40 ml). It was stirred for 60 min with constant slow addition of
diethylamine (2.92 g, 0.04 mole). The stirring was continued until the
sulfur dissolved. The solution was cooled in refrigerator over night.
The precipitate obtained was filtered and dried, and the crystalline
product was recrystallised from ethanol as a pale yellow crystalline
material (7.33 g, 78%), m.p. 85°C (lit.12 m.p. 84–85ºC).
2-(Arylaminomethyl)-7,8,9,10-tetrahydro-6H,11H-cyclohepta[4,5]
thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-11-ones
(6a–d):
A mixture of compound 5 (0.325 g, 1 mmol), triethylamine
(0.101 ml, 1 mmol) and the aromatic amine (1 mmol) in dioxan
(1.0 ml) was taken in a test tube and irradiated for 180 s at 960
W in a domestic microwave oven by switch off/on method.
(The irradiation was carried out for 30 s, switched off and again
switched on after adding dioxan to maintain the losses due to
evaporation). The reaction mixture was cooled to room temperature,
poured into ice-cold water, and the excess of amine was neutralised
by dilute hydrochloric acid (10%). The precipitate obtained was
filtered, dried and recrystallised from ethanol.
2-(Phenylaminomethyl)-7,8,9,10-tetrahydro-6H,11H-cyclohepta
[4,5]thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-11-one (6a):
Light brown crystals, (0.275 g, 72%), m.p. 250°C. IR: 1673, 2917,
1
3297 cm-1. H NMR: δ 1.69–1.71 (m, 6H, CH2), 2.77–2.80 (t, 2H,
CH2, J = 4.43 Hz), 3.33–3.36 (t, 2H, CH2, J = 4.1 Hz), 5.68 (s, 2H,
CH2NH), 6.66–6.70 (t, 1H, CH, J = 8.0 Hz), 6.77–6.79 (d, 2H, CH,
J = 8.0 Hz), 7.11–7.15 (t, 2H, CH, J = 7.8 Hz), 7.61 (s, 1H, NH). MS:
m/z 382 (M+). Anal. Calcd for C19H18N4OS2: C, 59.68; H, 4.71; N,
14.65. Found: C, 59.85; H, 4.96; N, 14.89%.
Methyl
N-(3-ethoxycarbonyl-5,6,7,8-tetrahydro-4H-cyclohepta
[b]thien-2-yl)dithiocarbamate (2): To a vigorously stirred solution
of the amino-ester 1 (4.78 g, 0.02 mole) in DMSO (10.0 ml) at
room temperature, carbon disulfide (1.6 ml, 0.026 mole) and
aqueous sodium hydroxide (1.2 ml, 20 mole) were added dropwise.
After 30 min stirring the containing flask was surrounded by an ice
bath and dimethyl sulfate (1.2 ml, 0.025 mole) was added dropwise
to the solution. Stirring was continued for 3 h. The reaction mixture
was poured into ice-water mixture. The precipitate so obtained
was filtered, dried and recrystallised from ethanol as a pale yellow
amorphous powder (5.35 g, 81%), m.p. 80°C. IR: 1685, 3231 cm-1.
1H NMR: δ 1.39–1.42 (t, 2H, CH2, J = 4.1 Hz), 1.60–1.69 (m, 4H,
CH2), 1.81–1.84 (t, 2H, CH2, J = 3.9 Hz), 2.68 (s, 3H, SCH3), 2.71–
2.73 (t, 3H, OCH2CH3, J = 3.8 Hz), 3.04–3.06 (t, 2H, CH2, J = 4.0
Hz), 4.36–4.41 (q, 2H, OCH2CH3, J = 3.8 Hz), 12.9 (s, 1H, NH, D2O
exchangeable). MS: m/z 329 (M+). Anal. Calcd for C14H19NO2S3: C,
51.06; H, 5.77; N, 4.25. Found: C, 51.25; H, 6.10; N, 4.45%.
3-Amino-2-mercapto-3,5,6,7,8,9-hexahydro-4H-cyclohepta[4,5]
thieno[2,3-d]pyrimidin-4-one (4): Compound 2 (0.329 g, 0.001 mole)
in isopropanol (1.0 ml) was heated at 960 W in a domestic microwave
oven with hydrazine hydrate (99%) (0.5 g, 0.001 mole), until the
evolution, of methyl mercaptan ceased (300 s). After cooling, the solid
obtained was filtered, dried and recrystallised from ethanol as white
needles (0.165 g, 61%), m.p. 242°C. IR: 1680, 3353 cm-1. 1H NMR:
2-[(4-Methoxyphenyl)aminomethyl]-7,8,9,10-tetrahydro-6H,11H-cyclo-
hepta[4,5]thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-11-one
(6b): Pale yellow crystals (0.272 g, 66%), m.p. 216°C. IR: 2848, 3004
1
cm-1. H NMR: δ 1.66–1.70 (m, 6H, CH2), 2.77–2.80(t, 2H, CH2,
J = 4.8 Hz), 3.32–3.34 (t, 2H, CH2 (6), J = 5.0 Hz), 3.68 (s, 3H,
OCH3), 5.48 (s, 2H, CH2NH), 5.94–5.95 (d, 2H, CH, J = 5 Hz), 6.72–
6.73 (d, 2H, CH, J = 5 Hz), 7.81 (s, 1H, NH). MS: m/z 412 (M+).
Anal. Calcd for C20H20N4O2S2: C, 58.25; H, 4.85; N, 13.59. Found:
C, 58.35; H, 5.05; N, 13.75%.
2-(4-Tolylaminomethyl)-7,8,9,10-tetrahydro-6H,11H-cyclohepta
[4,5]thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-11-one (6c):
Brownish crystals (0.277 g, 70%), m.p. 276°C. IR: 2918, 3364 cm-1.
1H NMR: δ 1.66–1.70 (m, 6H, CH2), 2.25 (s, 3H, CH3), 2.79–2.82
(t, 2H, CH2, J = 4.85 Hz), 3.30–3.33 (t, 2H, CH2, J = 4.9 Hz), 5.55
(s, 2H, CH2NH), 6.65–7.15 (m, 4H, ArH), 7.52 (s, 1H, NH). CI-MS:
m/z 397 (M+ + 1). Anal. Calcd for C20H20N4OS2: C, 60.60; H, 5.05;
N, 14.14. Found: C, 60.85; H, 5.25; N, 14.35%.
2-[(4-Nitrophenyl)aminomethyl]-7,8,9,10-tetrahydro-6H,11H-cyclo-
hepta[4,5]thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-11-one
(6d): Brownish crystals (0.295 g, 69%), m.p. 127°C. IR: 1550, 2916,
PAPER: 06/4355

JOURNAL OF CHEMICAL RESEARCH 2007 135
1
3364 cm-1. H NMR: δ 1.66–1.70 (m, 6H, CH2), 2.82–2.85 (t, 2H,
2
3
4
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CH2, J = 5.2 Hz), 3.33–3.35 (t, 2H, CH2, J = 5.2 Hz), 5.54 (s, 2H,
CH2NH), 7.67 (s, 1H, NH), 8.01–8.03 (d, 2H, ArH, J = 7.2 Hz),
8.81–8.83 (d, 2H, ArH, J = 7.2 Hz). MS: m/z 427 (M+). Anal. Calcd
for C19H17N5O3S2: C, 53.39; H, 3.98; N, 16.39. Found: C, 53.55; H,
4.19; N, 16.5%.
5
6
7
8
9
One of the authors (M. Raghu Prasad) is thankful to All
India Council for Technical Education (AICTE) for granting
Career Award for Young Teachers (CAYT). We profusely
thank Management/Principal, P.E.S. College of Pharmacy
for providing the facilities to carry out this work and Prof.
Dr. Akkinepally Raghuram Rao, UCPSC, Panjab University,
Chandigarh for moral support. We thank IISC, Bangalore and
IICT, Hyderabad for spectral and analytical data.
A.M. Farghaly, N.S. Habib, M.A. Khalil and O.A. El Syed, Alexandria
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Received 12 December 2006; accepted 7 March 2007
Paper 06/4355 doi:10.3184/0308234070X206582
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