Polarized ketene dithioacetals-versatile synthons for different heterocycles

Article abstract of DOI:10.1002/cjoc.201200312

The reactivity of polarized ketene dithioacetals to develop a variety of heterocycles under different conditions was studied.

Full text of DOI:10.1002/cjoc.201200312

FULL PAPER
DOI: 10.1002/cjoc.201200312
Polarized Ketene Dithioacetals-Versatile Synthons for Different
Heterocycles
Venkatesh, B. C.
Premakumari, C.
Padmaja, A.
Padmavathi, V.*
Department of Chemistry, Sri Venkateswara University, Tirupati-517502, Andhra Pradesh, India
The reactivity of polarized ketene dithioacetals to develop a variety of heterocycles under different conditions
was studied.
Keywords polarized ketene dithioacetals, thienothiophenes, bis-benzoxazolyl/benzothiazolyl/benzimidazolyl-
pyrazolidine diones/isoxazolidinediones/pyrimidinetriones/thioxopyrimidinediones, cyclocondensation
Introduction
140 W to 700 W. Built-in magnetic stirring (Teflon-
coated stirring bar) was used in all operations. The
temperature was measured throughout the reaction by
flexible probe. The IR spectra were recorded on a
Heterocyclic chemistry has attracted a lot of interest
during recent years as many useful drugs have emerged
in this branch. Ketene dithioacetals are versatile syn-
thons for the development of a wide variety of hetero-
cyclic systems.[1-5] In fact, nitroketene S,S-acetals have
been used as intermediates for the synthesis of pyrroles
with diverse functionalities.[6,7] The highly regioselec-
tive cyclocondensation of α-oxoketene N,S-acetals with
arylhydrazines produced substituted pyrazoles.[8-11] The
cyclocondensation of α-oxo/α-nitro ketene N,S-acyl-
acetals either with Vilsmier reagent[12] or in the presence
of POCl3 in acetonitrile led to substituted quinoxaline
derivatives.[13] Ring closer reactions involving a nitrile
group have also been studied. When dicyano dithiolate
was treated with p-bromophenacyl bromide instead of
an S,S'-bis(bromophenacyl) derivative an aminothio-
phene was formed.[14] Besides, ketene dithiolates gener-
ated in situ from active methylene compounds and car-
bon disulfide in the presence of base and α-haloesters
cyclized to thienothiophene derivatives.[15] Recently, we
have studied the reactivity of ketene S,S-acetals having
gem diester and gem cyanoester functionalities towards
the development of biologically potent heterocycles,
pyrazoline, isoxazoline, pyrimidine and their deriva-
tives.[16]
Thermo Nicolet IR 200 FT-IR spectrometer as KBr pel-
－
1
1
lets and the wave numbers were given in cm . The H
NMR spectra were recorded in DMSO-d6 on a
Brucker-400 spectrometer (400 MHz). The 13C NMR
spectra were recorded in DMSO-d6 on a Brucker spec-
trometer operating at 100 MHz. All chemical shifts are
reported in δ using TMS as an internal standard. The
mass spectra were recorded on Jeol JMS-D 300 and
Finnigan Mat 1210 B at 70 eV with an emission current
of 100 μA. The microanalyses were performed on a
Perkin-Elmer 240C elemental analyzer. The compounds
2-(chloromethyl)benzoxazole (1), 2-(chloromethyl)-
benzothiazole (2) and 2-(chloromethyl)-1H-benzimi-
dazole (3) were prepared by the literature proce-
dure.[18-20]
Typical procedure for the preparation of diethyl 2-
(bis((benzo[d]oxazol-2'-yl)methylthio)methylene)-
malonate (4)/diethyl 2-(bis((benzo[d]thiazol-2'-yl)-
methylthio)methylene)malonate (5)/diethyl 2-(bis((1'H-
benzo[d]imidazol-2'-yl)methylthio)methylene)malo-
nate (6)
To a solution of dried potassium carbonate (1.38 g,
0.01 mol) in DMF (2 mL), diethyl malonate (1.60 g,
0.01 mol) in DMF (1 mL) followed by carbon disulfide
(1.14 g, 0.015 mol) were added dropwise under vigor-
ous stirring. After 30 min, the reaction mixture was
cooled to 0 ℃ and to this 2-(chloromethyl)benzox-
azole (1)/2-(chloromethyl) benzothiazole (2)/2-(chloro-
methyl)-1H-benzimidazole (3) (0.02 mol) in DMF (5
mL) was added in 20—30 min. The reaction mixture
was then stirred for 1 h at room temperature and poured
Experimental
Melting points were determined in open capillaries
on a Mel-Temp apparatus and are uncorrected. The pu-
rity of the compounds was checked by TLC (silica gel H,
BDH, ethyl acetate/hexane, 1∶3, V/V). The microwave
irradiation was carried out by using scientific micro-
wave system CATA-2R operating at power levels from
*
E-mail: vkpuram2001@yahoo.com; Tel.: 0091-877-2289303; Fax: 0091-877-2249532
Received April 10, 2012; accepted May 29, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200312 or from the author.
1886
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1886—1892

Polarized Ketene Dithioacetals-Versatile Synthons for Different Heterocycles
into cold water. The precipitate was collected, dried and
recrystallized from aqueous methanol.
(3) (0.02 mol) in DMF (5 mL) was added in 20—30 min.
The reaction mixture was then refluxed for 2 h and
poured into cold water. The precipitate was collected,
dried and recrystallized from 2-propanol.
Diethyl 2-(bis((benzo[d]oxazol-2'-yl)methylthio)-
methylene)malonate (4) Yield 71%, m.p. 157—159
1
℃; H NMR (400 MHz, DMSO-d6) δ: 1.36 (t, J＝7.06
2,5-Di(benzo[d]oxazol-2'-yl)thieno[2,3-b]thiophene-
3,4(2H,5H)-dione (7) Yield 76% (method A), 69%
Hz, 6H, CH2CH3), 4.22 (q, J＝6.56 Hz, 4H, CH2CH3),
4.42 (s, 4H, CH2), 7.17—7.48 (m, 8H, Ar-H); 13C NMR
(100 MHz, DMSO-d6) δ: 13.5 (CH2CH3), 30.8 (CH2-S),
61.3 (CH2CH3), 104.7 (＝C-CO), 161.5 (C-2'), 165.3
(C＝CS(S)), 174.8 (C＝O), 117.1, 120.6, 122.2, 124.6,
138.7, 148.9 (aromatic carbons); IR (KBr) ν: 1715 (CO),
1
(method B), m.p. 188—190 ℃; H NMR (400 MHz,
DMSO-d6) δ: 4.59 (s, 2H, C2-H & C5-H), 7.20—7.35 (m,
8H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ: 60.1
(C-2 & C-5), 116.7 (＝C-CO), 161.3 (C-2'), 172.7 (C＝
CS(S)), 182.1 (C＝O), 117.1, 120.6, 122.2, 124.6, 138.5,
147.4 (aromatic carbons); IR (KBr) ν: 1734 (CO), 1636
－
1
1620 (C＝C), 1610 (C＝N) cm ; MS (70 eV) m/z:
＋
•
－
1
498.31 (M ). Anal. calcd for C24H22N2O6S2: C 57.82, H
(C＝C), 1615 (C＝N) cm ; MS (70 eV) m/z: 406.16
＋
•
4.45, N 5.62; found C 57.65, H 4.61, N 5.49.
(M ). Anal. calcd for C20H10N2O4S2: C 59.10, H 2.48,
Diethyl
2-(bis((benzo[d]thiazol-2'-yl)methylthio)-
N 6.89; found C 59.31, H 2.54, N 6.93.
methylene)malonate (5) Yield 76%, m.p. 165—167
℃; H NMR (400 MHz, DMSO-d6) δ: 1.31 (t, J＝7.05
2,5-Di(benzo[d]thiazol-2'-yl)thieno[2,3-b]thiophene-
3,4(2H,5H)-dione (8) Yield 78% (method A), 70%
1
1
Hz, 6H, CH2CH3), 4.25 (q, J＝7.05 Hz, 4H, CH2CH3),
4.45 (s, 4H, CH2), 7.46—8.01 (m, 8H, Ar-H); 13C NMR
(100 MHz, DMSO-d6) δ: 13.8 (CH2CH3), 31.2 (CH2-S),
62.5 (CH2CH3), 102.8 (＝C-CO), 169.5 (C-2'), 167.8
(C＝CS(S)), 175.4 (C＝O), 120.4, 121.8, 124.3, 126.1,
135.7, 149.8 (aromatic carbons); IR (KBr) ν: 1728 (CO),
(method B), m.p. 207—209 ℃; H NMR (400 MHz,
DMSO-d6) δ: 4.61 (s, 2H, C2-H & C5-H), 7.48—8.11 (m,
8H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ: 60.7
(C-2 & C-5), 117.4 (＝C-CO), 168.3 (C-2'), 172.1 (C＝
CS(S)), 182.9 (C＝O), 120.6, 122.2, 124.6, 125.4, 135.5,
151.1 (aromatic carbons); IR (KBr) ν: 1740 (CO), 1630
－
－
1
1
1630 (C＝C), 1605 (C＝N) cm ; MS (70 eV) m/z:
(C＝C), 1610 (C＝N) cm ; MS (70 eV) m/z: 438.21
＋
•
＋
•
530.48 (M ). Anal. calcd for C24H22N2O4S4: C 54.32, H
(M ). Anal. calcd for C20H10N2O2S4: C 54.77, H 2.30,
4.18, N 5.28; found C 54.55, H 4.03, N 5.43.
N 6.39; found C 54.52, H 2.41, N 6.54.
Diethyl 2-(bis((1'H-benzo[d]imidazol-2'-yl)methyl-
thio)methylene)malonate (6) Yield 78%, m.p. 174—
176 ℃; H NMR (400 MHz, DMSO-d6) δ: 1.28 (t, J＝
2,5-Di(1'H-benzo[d]imidazol-2'-yl)thieno[2,3-b]-
thiophene-3,4(2H,5H)-dione (9) Yield 75% (method
A), 68% (method B), m.p. 220—222 ℃; 1H NMR (400
MHz, DMSO-d6) δ: 4.54 (s, 2H, C2-H & C5-H), 7.23—
7.62 (m, 8H, Ar-H), 12.80 (br s, 2H, NH); 13C NMR
(100 MHz, DMSO-d6) δ: 59.4 (C-2 & C-5), 117.0
(＝C-CO), 152.0 (C-2'), 171.2 (C＝CS(S)), 183.7 (C＝
O), 118.9, 122.2, 123.6, 123.9, 133.2, 142.1 (aromatic
carbons); IR (KBr) ν: 3335 (NH), 1731 (CO), 1638 (C
1
6.92 Hz, 6H, CH2CH3), 4.21 (q, J ＝ 6.92 Hz, 4H,
CH2CH3), 4.38 (s, 4H, CH2), 7.28—7.53 (m, 8H, Ar-H),
12.89 (br s, 2H, NH); 13C NMR (100 MHz, DMSO-d6)
δ: 14.2 (CH2CH3), 30.1 (CH2-S), 63.2 (CH2CH3), 103.1
(＝C-CO), 151.3 (C-2'), 166.2 (C＝CS(S)), 173.8 (C＝
O), 119.1, 121.4, 122.6, 127.9, 132.5, 138.8 (aromatic
carbons); IR (KBr) ν: 3323 (NH), 1720 (CO), 1625
－
1
＝C), 1612 (C＝N) cm ; MS (70 eV) m/z: 404.14
－
1
＋
•
(C＝C), 1615 (C＝N) cm ; MS (70 eV) m/z: 496.17
(M ). Anal. calcd for C20H12N4O2S2: C 59.39, H 2.99,
＋
•
(M ). Anal. calcd for C24H24N4O4S2: C 58.05, H 4.87,
N 13.85; found C 59.63, H 2.87, N 13.68.
N 11.28; found C 58.32, H 4.62, N 11.41.
Typical procedure for the preparation of 4-(bis-
((benzo[d]oxazol-2'-yl)methylthio)methylene)pyrazo-
lidine-3,5-dione (10)/4-(bis((benzo[d]thiazol-2'-yl)-
methylthio)methylene)pyrazolidine-3,5-dione (11)/4-
(bis((1'H-benzo[d]imidazol-2'-yl)methylthio)methyl-
ene)pyrazolidine-3,5-dione (12)
Typical procedure for the preparation of 2,5-di-
(benzo[d]oxazol-2'-yl)thieno[2,3-b]thiophene-3,4-
(2H,5H)-dione (7)/2,5-di(benzo[d]thiazol-2'-yl)-
thieno[2,3-b]thiophene-3,4(2H,5H)-dione (8)/2,5-
di(1′H-benzo[d]imidazol-2'-yl)thieno[2,3-b]thiophene-
3,4(2H,5H)-dione (9)
A solution of 4/5/6 (0.005 mol), hydrazine hydrate
(0.0075 mol) and piperidine (3 mL) in ethanol (10 mL)
was refluxed for 6—8 h. After completion of the reac-
tion, it was cooled and poured into ice-cold water con-
taining conc. HCl. The solid obtained was filtered on a
Buchner funnel, dried and recrystallized from
2-propanol.
4-(Bis((benzo[d]oxazol-2'-yl)methylthio)methylene)-
pyrazolidine-3,5-dione (10) Yield 75%, m.p. 180—
182 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 4.43 (s, 4H,
CH2), 7.26—7.36 (m, 8H, Ar-H), 9.12 (br s, 2H,
CO-NH); 13C NMR (100 MHz, DMSO-d6) δ: 31.4
(CH2-S), 102.5 (C-4), 162.3 (C-2'), 168.1 (C＝CS(S)),
174.9 (C-3 & C-5), 117.1, 120.6, 122.2, 124.6, 139.4,
Method A To a solution of dried potassium car-
bonate (1.38 g, 0.01 mol) in DMF (2 mL), 4/5/6 (0.005
mol) was added and refluxed for 1 h and poured into
cold water. The precipitate was collected, dried and re-
crystallized from 2-propanol.
Method B To a solution of dried potassium car-
bonate (4.14 g, 0.03 mol) in DMF (2 mL), diethyl
malonate (1.60 g, 0.01 mol) in DMF (1 mL) followed
by carbon disulfide (1.14 g, 0.015 mol) were added
dropwise under vigorous stirring. After 30 min, the re-
action mixture was cooled to 0 ℃ and to this
2-(chloromethyl)benzoxazole
(1)/2-(chloromethyl)-
benzothiazole (2)/2-(chloromethyl)-1H-benzimidazole
Chin. J. Chem. 2012, 30, 1886—1892
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1887

Venkatesh et al.
FULL PAPER
148.3 (aromatic carbons); IR (KBr) ν: 3420 (NH), 1690
136.2, 150.1 (aromatic carbons); IR (KBr) ν: 3431 (NH),
1732 (CO-O), 1687 (CO-NH), 1618 (C＝C), 1609 (C＝
N) cm ; MS (70 eV) m/z: 471.6 (M ). Anal. calcd for
C20H13N3O3S4: C 50.94, H 2.78, N 8.91; found C 50.73,
H 2.89, N 8.79.
－
1
(CO), 1622 (C＝C), 1613 (C＝N) cm ; MS (70 eV)
＋
－
＋
•
•
1
m/z: 438.25 (M ). Anal. calcd for C20H14N4O4S2: C
54.78, H 3.22, N 12.78; found C 54.96, H 3.10, N 12.92.
4-(Bis((benzo[d]thiazol-2'-yl)methylthio)methy-
lene)pyrazolidine-3,5-dione (11) Yield 78%, m.p.
4-(Bis((1'H-benzo[d]imidazol-2'-yl)methylthio)-
methylene)isoxazolidine-3,5-dione (15) Yield 78%,
1
193—195 ℃; H NMR (400 MHz, DMSO-d6) δ: 4.41
1
(s, 4H, CH2), 7.32—7.79 (m, 8H, Ar-H), 9.10 (br s, 2H,
CO-NH); 13C NMR (100 MHz, DMSO-d6) δ: 32.7
(CH2-S), 103.8 (C-4), 169.1 (C-2'), 167.2 (C＝CS(S)),
173.6 (C-3 & C-5), 119.2, 122.7, 124.1, 126.2, 135.7,
151.4 (aromatic carbons); IR (KBr) ν: 3431 (NH), 1687
m.p. 196—198 ℃; H NMR (400 MHz, DMSO-d6) δ:
4.40 (s, 4H, CH2), 7.36—7.78 (m, 8H, Ar-H), 10.08 (br
s, 1H, CO-NH), 12.88 (br s, 2H, NH); 13C NMR (100
MHz, DMSO-d6) δ: 33.0 (CH2-S), 102.8 (C-4), 151.7
(C-2'), 167.9 (C＝CS(S)), 172.8 (C-3), 178.6 (C-5),
124.2, 125.1, 126.2, 128.2, 132.4, 139.7 (aromatic car-
bons); IR (KBr) ν: 3416 (NH), 1725 (CO-O), 1672 (CO-
－
1
(CO), 1618 (C＝C), 1609 (C＝N) cm ; MS (70 eV)
＋
•
m/z: 470.38 (M ). Anal. calcd for C20H14N4O2S4: C
51.04, H 3.00, N 11.91; found C 51.29, H 3.13, N 11.79.
4-(Bis((1'H-benzo[d]imidazol-2'-yl)methylthio)-
methylene)pyrazolidine-3,5-dione (12) Yield 80%,
－
1
NH), 1628 (C＝C), 1605 (C＝N) cm ; MS (70 eV) m/z:
＋
•
437.07 (M ). Anal. calcd for C20H15N5O3S2: C 54.91, H
3.46, N 16.01; found C 54.65, H 3.58, N 16.17.
1
m.p. 202—204 ℃; H NMR (400 MHz, DMSO-d6) δ:
Typical procedure for the preparation of 5-(bis-
((benzo[d]oxazol-2'-yl)methylthio)methylene)pyrimi-
dine-2,4,6(1H,3H,5H)-trione (16)/5-(bis((benzo[d]-
thiazol-2'-yl)methylthio)methylene)pyrimidine-2,4,6-
(1H,3H,5H)-trione (17)/5-(bis((1'H-benzo[d]imi-
dazol-2'-yl)methylthio)methylene)pyrimidine-2,4,6-
(1H,3H,5H)-trione (18)
4.37 (s, 4H, CH2), 7.54—7.97 (m, 8H, Ar-H), 9.14 (br s,
2H, CO-NH), 12.86 (br s, 2H, NH); 13C NMR (100
MHz, DMSO-d6) δ: 31.6 (CH2-S), 103.2 (C-4), 151.7
(C-2'), 168.7 (C＝CS(S)), 174.4 (C-3 & C-5), 120.5,
122.2, 125.7, 127.1, 131.5, 137.9 (aromatic carbons); IR
(KBr) ν: 3392 (NH), 1675 (CO), 1620 (C＝C), 1613
－
＋
•
1
(C＝N) cm ; MS (70 eV) m/z: 436.16 (M ). Anal.
calcd for C20H16N6O2S2: C 55.03, H 3.69, N 19.25;
found C 55.31, H 3.78, N 19.37.
Method A The compound 4/5/6 (0.005 mol), urea
(0.60 g, 0.01 mol), piperidine (4 mL) and ethanol (10
mL) were refluxed for 8—10 h. The contents of the
flask were cooled and poured into ice-cold water con-
taining conc. HCl. The solid separated was filtered,
dried and purified by recrystallization from 2-propanol.
Method B To a well stirred solution of barbituric
acid (0.64 g, 0.005 mol) in dimethyl sulfoxide (5 mL),
triethylamine (1.01 g, 0.01 mol) and carbon disulfide
(0.38 g, 0.005 mol) were added in succession. The mix-
ture was stirred for 1 h at room temperature and then
1/2/3 (0.01 mol) in dimethyl sulfoxide (5 mL) was
added. The stirring was continued for another 4—5 h at
room temperature and poured into ice water. The solid
separated was filtered, dried and recrystallized from
2-propanol.
Typical procedure for the preparation of 4-(bis-
((benzo[d]oxazol-2'-yl)methylthio)methylene)isoxazol
idine-3,5-dione (13)/4-(bis((benzo[d]thiazol-2'-yl)-
methylthio)methylene)isoxazolidine-3,5-dione (14)/4-
(bis((1'H-benzo[d]imidazol-2'-yl)methylthio)methy-
lene)isoxazolidine-3,5-dione (15)
A mixture of 4/5/6 (0.005 mol), hydroxylamine hy-
drochloride (0.42 g, 0.006 mol), piperidine (5 mL) in
ethanol (10 mL) was refluxed for 5—7 h. It was cooled
and poured into ice-cold water containing conc. HCl.
The solid separated was collected on a Buchner funnel,
dried and recrystallized from 2-propanol.
4-(Bis((benzo[d]oxazol-2'-yl)methylthio)methylene)-
isoxazolidine-3,5-dione (13) Yield 75%, m.p. 175—
177 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 4.39 (s, 4H,
CH2), 7.14—7.70 (m, 8H, Ar-H), 10.14 (br s, 1H,
CO-NH); 13C NMR (100 MHz, DMSO-d6) δ: 32.8
(CH2-S), 101.6 (C-4), 161.8 (C-2'), 167.5 (C＝CS(S)),
172.5 (C-3), 178.3 (C-5), 122.2, 125.7, 127.1, 128.2,
141.0, 149.9 (aromatic carbons); IR (KBr) ν: 3420 (NH),
1729 (CO-O), 1685 (CO-NH), 1622 (C＝C), 1614 (C＝
5-(Bis((benzo[d]oxazol-2'-yl)methylthio)methylene)-
pyrimidine-2,4,6(1H,3H,5H)-trione (16) Yield 72%
1
(method A), 76% (method B), m.p. 222—224 ℃; H
NMR (400 MHz, DMSO-d6) δ: 4.42 (s, 4H, CH2), 7.12
—7.64 (m, 8H, Ar-H), 10.06 (br s, 2H, CO-NH); 13C
NMR (100 MHz, DMSO-d6) δ: 32.7 (CH2-S), 103.1
(C-5), 152.5 (C-2), 161.5 (C-2'), 166.6 (C＝CS(S)),
168.6 (C-4 & C-6), 120.9, 122.7, 124.1, 126.2, 139.2,
151.1 (aromatic carbons); IR (KBr) ν: 3281 (NH), 1675
－
＋
•
1
N) cm ; MS (70 eV) m/z: 439.13 (M ). Anal. calcd for
C20H13N3O5S2: C 54.66, H 2.98, N 9.56; found C 54.89,
H 2.86, N 9.73.
－
1
(CO), 1620 (C＝C), 1605 (C＝N) cm ; MS (70 eV)
＋
•
m/z: 466.22 (M ). Anal. calcd for C21H14N4O5S2: C
54.07, H 3.02, N 12.01; found C 54.35, H 3.14, N 11.86.
5-(Bis((benzo[d]thiazol-2'-yl)methylthio)methy-
lene)pyrimidine-2,4,6(1H,3H,5H)-trione (17) Yield
70% (method A), 77% (method B), m.p. 236—238 ℃;
1H NMR (400 MHz, DMSO-d6) δ: 4.47 (s, 4H, CH2),
7.34—7.84 (m, 8H, Ar-H), 9.98 (br s, 2H, CO-NH); 13C
NMR (100 MHz, DMSO-d6) δ: 32.8 (CH2-S), 102.7
4-(Bis((benzo[d]thiazol-2'-yl)methylthio)methylene)-
isoxazolidine-3,5-dione (14) Yield 70%, m.p. 187—
189 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 4.37 (s, 4H,
CH2), 7.27—7.89 (m, 8H, Ar-H), 10.15 (br s, 1H,
CO-NH); 13C NMR (100 MHz, DMSO-d6) δ: 32.5
(CH2-S), 103.7 (C-4), 166.4 (C＝CS(S)), 168.9 (C-2'),
173.7 (C-3), 179.4 (C-5), 121.3, 123.9, 124.6, 126.5,
1888
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1886—1892

Polarized Ketene Dithioacetals-Versatile Synthons for Different Heterocycles
(C-5), 152.2 (C-2), 167.2 (C＝CS(S)), 169.1 (C-2'),
169.4 (C-4 & C-6), 122.7, 124.1, 125.2, 127.0, 136.3,
150.4 (aromatic carbons); IR (KBr) ν: 3290 (NH), 1684
(20) Yield 68% (method A), 75% (method B), m.p.
220—222 ℃; H NMR (400 MHz, DMSO-d6) δ: 4.40
1
(s, 4H, CH2), 7.37—7.88 (m, 8H, Ar-H), 10.12 (br s, 2H,
CO-NH); 13C NMR (100 MHz, DMSO-d6) δ: 32.6
(CH2-S), 101.5 (C-5), 165.5 (C＝CS(S)), 168.3 (C-2'),
167.6 (C-4 & C-6), 175.4 (C-2), 122.5, 124.7, 126.4,
127.0, 135.1, 151.3 (aromatic carbons); IR (KBr) ν:
3339 (NH), 1694 (CO), 1618 (C＝C), 1612 (C＝N),
－
1
(CO), 1622 (C＝C), 1612 (C＝N) cm ; MS (70 eV)
＋
•
m/z: 498.16 (M ). Anal. calcd for C21H14N4O3S4: C
50.58, H 2.83, N 11.24; found C 50.79, H 2.94, N 11.13.
5-(Bis((1'H-benzo[d]imidazol-2'-yl)methylthio)-
methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (18)
Yield 69% (method A), 74% (method B), m.p. 240—
242 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 4.39 (s, 4H,
CH2), 7.45—8.21 (m, 8H, Ar-H), 9.91 (br s, 2H,
CO-NH), 12.82 (br s, 2H, NH); 13C NMR (100 MHz,
DMSO-d6) δ: 32.2 (CH2-S), 103.5 (C-5), 151.1 (C-2'),
153.7 (C-2), 165.9 (C＝CS(S)), 169.6 (C-4 & C-6),
121.4, 123.5, 126.8, 127.4, 131.1, 137.9 (aromatic car-
－
＋
•
1
1495 (C＝S) cm ; MS (70 eV) m/z: 514.46 (M ).
Anal. calcd for C21H14N4O2S5: C 49.01, H 2.74, N 10.89;
found C 49.23, H 2.63, N 10.97.
5-(Bis((1'H-benzo[d]imidazol-2'-yl)methylthio)-
methylene)dihydro-2-thioxopyrimidine-4,6(1H,5H)-
dione (21) Yield 74% (method A), 79% (method B),
1
m.p. 228—230 ℃; H NMR (400 MHz, DMSO-d6) δ:
－
1
bons) cm ; IR (KBr) ν: 3310 (NH), 1692 (CO), 1618
4.42 (s, 4H, CH2), 7.29—7.84 (m, 8H, Ar-H), 9.95 (br s,
2H, CO-NH), 12.80 (br s, 2H, NH); 13C NMR (100
MHz, DMSO-d6) δ: 33.2 (CH2-S), 103.4 (C-5), 152.5
(C-2'), 167.3 (C＝CS(S)), 169.4 (C-4 & C-6), 174.7
(C-2), 119.4, 122.2, 125.6, 127.7, 132.5, 139.3 (aro-
matic carbons); IR (KBr) ν: 3369 (NH), 1676 (CO),
＋
•
(C＝C), 1615 (C＝N); MS (70 eV) m/z: 464.24 (M ).
Anal. calcd for C21H16N6O3S2: C 54.30, H 3.47, N 18.09;
found C 54.13, H 3.58, N 18.23.
Typical procedure for the preparation of 5-(bis-
((benzo[d]oxazol-2'-yl)methylthio)methylene)dihydro-
2-thioxopyrimidine-4,6(1H,5H)-dione (19)/5-(bis-
((benzo[d]thiazol-2'-yl)methylthio)methylene)dihydro-
2-thioxopyrimidine-4,6(1H,5H)-dione (20)/5-(bis((1'H-
benzo[d]imidazol-2'-yl)methylthio)methylene)di-
hydro-2-thioxopyrimidine-4,6(1H,5H)-dione (21)
－
1
1620 (C＝C), 1608 (C＝N), 1490 (C＝S) cm ; MS (70
＋
•
eV) m/z: 480.08 (M ). Anal. calcd for C21H16N6O2S3: C
52.48, H 3.36, N 17.49; found C 52.75, H 3.22, N 17.61.
Results and Discussion
Method A A mixture of 4/5/6 (0.005 mol), thio-
urea (0.57 g, 0.0075 mol), piperidine (4 mL) and etha-
nol (10 mL) was refluxed for 9—11 h. The reaction
mixture was cooled and poured into ice-cold water con-
taining conc. HCl. The solid separated was filtered on a
Buchner funnel, dried and recrystallized from
2-propanol.
Method B To a well stirred solution of thiobarbi-
turic acid (0.72 g, 0.005 mol) in dimethyl sulfoxide (5
mL), triethylamine (1.01 g, 0.01 mol) and carbon disul-
fide (0.38 g, 0.005 mol) were added in succession. The
mixture was stirred for 1 h at room temperature and then
1/2/3 (0.01 mol) in dimethyl sulfoxide (5 mL) was
added. The stirring was continued for another 5—6 h at
room temperature and poured into ice water. The solid
separated was filtered, dried and recrystallized from
2-propanol.
In continuation of our interest to study the reactivity
of ketene dithiolates towards the development of a new
class of heterocycles,[17] the following work has been
taken up. The reactive intermediates, 2-(chloromethyl)-
benzoxazole (1) and 2-(chloromethyl)benzothiazole (2)
were prepared by the irradiation of 2-aminophenol/2-
aminothiophenol and chloroacetyl chloride for 10 min at
a power of 500 W.[18] However, 2-(chloromethyl)-1H-
benzimidazole (3) was obtained by treating o-phe-
nylenediamine with chloroacetic acid in the presence of
5 mol•L－1 HCl[20] (Scheme 1).
Scheme 1
NH2
O
N
X
AcOH, MW
+
Cl
Cl 500 W, 10 min
XH
Cl
1/2
5-(Bis((benzo[d]oxazol-2'-yl)methylthio)methy-
lene)dihydro-2-thioxopyrimidine-4,6(1H,5H)-dione
(19) Yield 72% (method A), 78% (method B), m.p.
1: X = O
2: X = S
NH2
NH2
5 mol L-1 HCl
O
N
.
+
1
Cl
206—208 ℃; H NMR (400 MHz, DMSO-d6) δ: 4.45
OH
reflux, 5 6 h
N
H
Cl
(s, 4H, CH2), 7.10—7.77 (m, 8H, Ar-H), 9.96 (br s, 2H,
CO-NH); 13C NMR (100 MHz, DMSO-d6) δ: 33.4
(CH2-S), 102.7 (C-5), 162.1 (C-2'), 166.8 (C＝CS(S)),
168.9 (C-4 & C-6), 172.2 (C-2), 120.2, 122.4, 125.3,
126.8, 138.7, 150.3 (aromatic carbons); IR (KBr) ν:
3350 (NH), 1689 (CO), 1621 (C＝C), 1605 (C＝N),
3
A one-pot reaction of diethyl malonate, carbon di-
sulfide and 1/2/3 in the presence of K2CO3 in DMF led
to gem difunctionalized synthetic intermediates, diethyl
2-(bis((benzo[d]oxazol-2'-yl)methylthio)methylene)-
malonate (4), diethyl 2-(bis((benzo[d]thiazol-2'-
yl)methylthio)methylene)malonate (5) and diethyl 2-
(bis((1'H-benzo[d]imidazol-2'-yl)methylthio)methylene)-
－
＋
•
1
1492 (C＝S) cm ; MS (70 eV) m/z: 482.37 (M ).
Anal. calcd for C21H14N4O4S3: C 52.27, H 2.92, N 11.61;
found C 52.43, H 2.83, N 11.73.
1
malonate (6) (Scheme 2). The H NMR spectra of 4, 5
and 6 displayed a singlet at δ 4.42, 4.45, 4.38 for me-
5-(Bis((benzo[d]thiazol-2'-yl)methylthio)methy-
lene)dihydro-2-thioxopyrimidine-4,6(1H,5H)-dione
Chin. J. Chem. 2012, 30, 1886—1892
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1889

Venkatesh et al.
FULL PAPER
1
thylene protons, a triplet and a quartet at δ 1.36, 1.31,
1.28 and 4.22, 4.25, 4.21 for carboethoxy protons, re-
spectively. In addition to these, compound 6 displayed a
broad singlet at δ 12.89 due to NH which disappeared
on deuteration. In our endeavor to exploit the gem
diester functionality to develop different heterocycles,
the compound 4 was treated with hydrazine hydrate in
the presence of K2CO3 in DMF. Instead of the expected
tris heterocyclic compound, intramolecular cyclization
of 4 took place resulting in the formation of 2,5-
di(benzo[d]oxazol-2'-yl)thieno[2,3-b]thiophene-3,4-
(2H,5H)-dione (7) in low yield [28%] (Scheme 2). Later
the reaction was repeated in the absence of hydrazine
hydrate where the product was obtained in 78% yield. In
the presence of polar aprotic solvent, the methylene
group in compound 4 is readily deprotonated by K2CO3.
It is followed by the intramolecular attack on carbonyl
carbon of ester which is then transformed into 7 by the
elimination of alcohol (Scheme 3). Similar cyclization
took place when 5 and 6 were treated with K2CO3 re-
sulting in the formation of 2,5-di(benzo[d]thiazol-
2'-yl)thieno[2,3-b]thiophene-3,4(2H,5H)-dione (8) and
2,5-di(1'H-benzo-[d]imidazol-2'-yl)thieno[2,3-b]thio-
phene-3,4(2H,5H)-dione (9). On the other hand, the
compounds 7, 8 and 9 were obtained directly by the re-
action of 1, 2 and 3 with diethyl malonate and carbon
disulfide in the presence of three-fold excess K2CO3.
Though the aromaticity of 7—9 was possible by in-
tramolecular H-bonding, the compounds existed as
diketo tautomers which were confirmed by H and 13C
1
NMR spectra. The H NMR spectra of 7, 8 and 9 dis-
played a singlet at δ 4.59, 4.61, 4.54 for methine protons
whereas in 13C NMR spectra a singlet was observed at
60.1, 60.7, 59.4 for methine carbon, respectively. The
70 eV mass spectra of 7, 8 and 9 displayed M＋• peak at
m/z 406.1, 437.9 and 404.1, respectively.
However when the reaction was repeated by adding
4/5/6 in ethanol dropwise into a solution of hydrazine
hydrate in piperidine and ethanol, 4-(bis((benzo[d]-
oxazol-2'-yl)methylthio)methylene)pyrazolidine-3,5-
dione (10), 4-(bis((benzo[d]thiazol-2'-yl)methylthio)-
methylene)pyrazolidine-3,5-dione (11) and 4-(bis((1'H-
benzo[d]imidazol-2'-yl)methylthio)methylene)pyrazoli-
dine-3,5-dione (12) were obtained (Scheme 4). Simi-
larly, 4-(bis((benzo[d]oxazol-2'-yl)methylthio)meth-
ylene)isoxazolidine-3,5-dione (13), 4-(bis((benzo[d]-
thiazol-2'-yl)methylthio)methylene)isoxazolidine-3,5-
dione (14) and 4-(bis((1'H-benzo[d]imidazol-2'-
yl)methylthio)methylene)isoxazolidine-3,5-dione (15)
were prepared by the reaction of 4/5/6 with hydroxyl-
amine hydrochloride. Likewise, the reaction of 4/5/6
with urea produced 5-(bis((benzo[d]oxazol-2'-yl)meth-
ylthio)methyene)pyrimidine-2,4,6(1H,3H,5H)-trione
(16), 5-(bis((benzo[d]thiazol-2'-yl)methylthio)-
methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (17) and
5-(bis((1'H-benzo[d]imidazol-2'-yl)methylthio)meth-
ylene)pyrimidine-2,4,6(1H,3H,5H)-trione (18). Adopt-
ing similar methodology, 5-(bis((benzo[d]oxazol-2'-yl)-
Scheme 2
EtO2C
CO2Et
S
O
O
1 equiv. K2CO3
S
2 equiv. K2CO3
DMF/
N
X
N
X
3'
DMF/0 oC to r.t.
N
N
9'
S
S
4'
6'
2'
X
X
7 / 8 / 9
Method A
5'
1'
N
8'
EtO2C
CS
+
7'
+
4/5/6
2
X
1/2/3
Cl
EtO2C
1, 4, 7: X = O;
2, 5, 8: X = S;
3, 6, 9: X = NH
O
O
3 equiv. K2CO3
N
N
DMF/
X
S
S
X
Method B
7/8/9
Scheme 3
-
EtO2C
S
CO2Et
S
O
S
O
S
O
S
O
OEt
N
-OEt
EtO
X
EtO
OEt
Base
-
3'
N
N
S
X
N
N
N
9'
4'
6'
2'
X
X
X
X
5'
1'
8'
7'
4/5/6
O
O
-
O
O
O
O
N
X
EtO
EtO
-OEt
N
N
N
X
N
-
S
N
S
X
S
S
X
S
X
S
X
7/8/9
1890
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1886—1892

Polarized Ketene Dithioacetals-Versatile Synthons for Different Heterocycles
Scheme 4
1
2
HN NH
5
3
4
O
O
1'
.
NH2NH2 H2O, piperidine,
X
X
9'
S
S
4'
6'
2'
ethanol/
N
N
3'
5'
8'
10/11/12
7'
2
1O NH
EtO2C
S
CO2Et
S
5
3
4
O
O
.
NH2OH HCl, piperidine,
X
3'
X
S
S
N
N
ethanol/
9'
4'
6'
2'
N
N
X
X
5'
13/14/15
1'
8'
7'
4/5/6
Y
2
HN1 3NH
NH2CONH2, NH2CSNH2,
5
4
6
O
O
piperidine,
ethanol/
X
X
S
S
N
N
16/17/18
19/20/21
Y
4, 10, 13, 16, 19: X = O;
5, 11, 14, 17, 20; X = S;
6, 12, 15, 18, 21; X = NH;
16, 17, 18: Y = O;
2
HN1 3NH
5
4
6
O
O
O
O
HN
HN
19, 20, 21: Y = S
N
X
X
X
Et3N/DMSO
0 oC to r.t.
S
S
Y
+
CS2
+
N
N
Cl
16 /17/18
19/20/21
1/2/3
16/17/18
19/20/21
methylthio)methylene)dihydro-2-thioxopyrimidine-4,6-
(1H,5H)-dione (19), 5-(bis((benzo[d]thiazol-2'-yl)meth-
ylthio)methylene)dihydro-2-thioxopyrimidine-4,6(1H,
5H)-dione (20) and 5-(bis((1'H-benzo[d]imidazol-2'-yl)-
methylthio)methylene)dihydro-2-thioxopyrimidine-4,6-
(1H,5H)-dione (21) were prepared by treating 4/5/6 with
thiourea (Scheme 4). The compounds 16, 17 and 18
were also prepared in a one pot reaction of barbituric
acid with carbon disulfide and 1/2/3 in the presence of
triethylamine in DMSO. Similarly, 19, 20 and 21 were
obtained by the reaction of thiobarbituric acid with car-
bon disulfide and 1/2/3 (Scheme 4). The absence of
pyrimidinediones were obtained. The structures of the
compounds were established by spectral parameters.
Acknowledgement
The authors are thankful to University Grants Com-
mission (UGC), New Delhi for financial assistance un-
der major research project. One of the authors B.C.
Venkatesh is thankful to Council of Scientific and In-
dustrial Research (CSIR), New Delhi, India for the
sanction of Senior Research Fellowship.
1
References
signals corresponding to carboethoxy protons in the H
NMR spectra of 10—21 indicated their formation. The
structures of these compounds were further established
by IR, 13C NMR and mass spectra.
[1] Kolb, M. Synthesis 1990, 171.
[2] Mashraqui, S. H.; Hariharasubramanian, H. J. Chem. Res. (S) 1999,
492.
[3] Zhao, Y. L.; Liu, Q.; Sun, R.; Xu, X. X.; Pan, L. Chem. J. Chin.
Univ. 2002, 23, 1901 (in Chinese).
[4] Li, Z.-F.; Zhang, Y.-M. Chin. J. Chem. 2001, 19, 996.
[5] Wang, M.; Ai, L.; Zhang, J.-Y.; Liu, Q.; Gao, L.-X. Chin. J. Chem.
2002, 20, 1591.
[6] Tripathy, P. K.; Roy, J.; Mukerjee, A. K. Indian J. Chem. 1986, 25B,
1275.
[7] Misra, N. C.; Panda, K.; Ila, H.; Junjappa, H. J. Org. Chem. 2007, 72,
1246.
[8] Peruncheralathan, S.; Yadav, A. K.; Ila, H.; Junjappa, H. J. Org.
Chem. 2005, 70, 9644.
[9] Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa, H. J. Org.
Chem. 2005, 70, 10030.
Conclusions
The reactivity of polarized ketene dithioacetals was
exploited to develop a new class of heterocycles. In the
presence of K2CO3, self condensation of ketene di-
thiolates took place with the formation of substituted
thienothiophene derivatives. However in the presence of
piperidine and appropriate nucleophiles, tris-hetero-
cyclic compounds, bis-benzoxazolyl/benzothiazolyl/
benzimidazolylmethylthiomethylenepyrazolidine-
diones/isoxazolidinediones/pyrimidinetriones/thioxo-
Chin. J. Chem. 2012, 30, 1886—1892
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1891

Venkatesh et al.
FULL PAPER
[10] Zhao, W.-G.; Li, Z.-M.; Yuan, P.-W.; Wang, W.-Y. Chin. J. Chem.
2001, 19, 184.
[11] Li, M.; Wen, L.-R.; Fu, W.-J.; Zhao, G.-L.; Hu, F.-Z.; Yang, H.-Z.
Chin. J. Chem. 2004, 22, 1064.
[12] Mahata, P. K.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa,
H. J. Org. Chem. 2003, 68, 3966.
[13] Venkatesh, C.; Singh, B.; Mahata, P. K.; Ila, H.; Junjappa, H. Org.
Lett. 2005, 7, 2169.
Hergue, N.; Frere, P. Org. Biomol. Chem. 2007, 5, 3442.
[16] Padmavathi, V.; Sudhakar Reddy, G.; Deepti, D.; Padmaja, A. J.
Heterocycl. Chem. 2008, 45, 1089.
[17] (a) Padmavathi, V.; Dinneswara Reddy, G.; Nagi Reddy, S.; Mahesh,
K. Eur. J. Med. Chem. 2011, 46, 1367; (b) Padmavathi, V.; Dinnes-
wara Reddy, G.; Venkatesh, B. C. Archiv. Pharm. 2011, 11, 165.
[18] Gellis, A.; Boufatah, N.; Vanelle, P. Green Chem. 2006, 8, 483.
[19] Kristinsson, H. Synthesis 1979, 102.
[14] Jensen, K. A.; Henriksen, L. Acta Chem. Scand. 1968, 22, 1107.
[15] (a) Comel, A.; Kirsch, G. J. Heterocycl. Chem. 2001, 38, 1167; (b)
[20] Morton, R.; Chang, H.; Edwin, H. L. C. J. Org. Chem. 1985, 50,
2205.
(Cheng, F.)
1892
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1886—1892