One-pot three-component synthesis of 1,4-bis[thiazolo[4,5-d]pyrimidin-7(6H) -one]piperazine derivatives

Article abstract of DOI:10.3184/174751912X13460803277147

A simple one-pot efficient method is described for the synthesis of 1,4-bis[thiazolo[4,5-d]pyrimidin-7(6H)-one] piperazine derivatives by a domino three-component process involving an aza-Wittig reaction/heterocyclisation in the presence of sodium ethoxide as catalyst. Ethyl 4-[(triphenylphosphanylidene) amino]-2,3-dihydro-3-phenyl-2- thioxothiazole-5-carboxylate reacted with aromatic isocyanates to give carbodiimide intermediates. This was followed by the addition of piperazines to give the corresponding guanidine intermediates. The guanidine intermediates were then cyclised in the presence of catalytic amount of sodium ethoxide to give 1,4-bis[thiazolo[4,5-d]pyrimidin- 7(6H)-one]piperazine derivatives in good yields.

Full text of DOI:10.3184/174751912X13460803277147

612 RESEARCH PAPER
OCTOBER, 612–614
JOURNAL OF CHEMICAL RESEARCH 2012
One-pot three-component synthesis of 1,4-bis[thiazolo[4,5-d]pyrimidin-
7(6H)-one]piperazine derivatives
Zheng Dong Fang* and Xian Hong Wei
College of Chemistry and Environmental Engineering, Hubei Normal University, Huangshi, 435002, P. R. China
A simple one-pot efficient method is described for the synthesis of 1,4-bis[thiazolo[4,5-d]pyrimidin-7(6H)-one]
piperazine derivatives by a domino three-component process involving an aza-Wittig reaction/heterocyclisation in
the presence of sodium ethoxide as catalyst. Ethyl 4-[(triphenylphosphanylidene)amino]-2,3-dihydro-3-phenyl-2-
thioxothiazole-5-carboxylate reacted with aromatic isocyanates to give carbodiimide intermediates. This was
followed by the addition of piperazines to give the corresponding guanidine intermediates. The guanidine intermedi-
ates were then cyclised in the presence of catalytic amount of sodium ethoxide to give 1,4-bis[thiazolo[4,5-d]pyrimidin-
7(6H)-one]piperazine derivatives in good yields.
Keywords: thiazolo[4,5-d]pyrimidinone, multicomponent reactions, piperazine
In recent years, multicomponent reactions (MCRs) have
become important tools in modern preparative synthetic chem-
istry because these reactions increase efficiency by combining
several operational steps without the need for isolation of
intermediates or changes in the conditions.1−3 This principle,
therefore, is highly efficient in terms of time as well as
resources. Among the known MCRs some useful reactions are
those based on isocyanides. In the development of strategies
for the preparation of heterocycles, the aza-Wittig reaction
has proved to be a powerful tool for the synthesis of 5–8
membered nitrogen heterocycles.4–6 The iminophosphoranes
of heterocyclic and heteroaromatic β-enamino esters have
proved to be versatile intermediates for the construction of
many hetero-condensed systems. Many important nitrogen
heterocycles have been synthesized via the aza-Wittig reaction
of β-ethoxycarbonyl iminophosphorane with an aromatic
isocyanate and a subsequent heterocyclisation reaction with
various nucleophiles under mild conditions.7–10
The iminophosphorane 1 reacted with an aromatic isocya-
nate to give the carbodiimides 2. The reaction proceeded
smoothly in THF at room temperature. The reaction of car-
bodiimides 2 with piperazine derivatives at room temperature
gave intermediate guanidines 3 via the initial double nucleo-
philic addition of piperazine to the carbodiimide. Even in
refluxing toluene, 3 did not cyclise. However, in dry ethylene
chloride and in the presence of a catalytic amount of EtONa,
compounds 3 were converted smoothly to the 1,4-bis[thia-
zolo[4,5-d]pyrimidin-7(6H)-one] piperazine derivatives 4 in
satisfactory yields at room temperature. The results are given
in Table 1.
We found that the heterocyclisation occurred via nucleo-
philic displacement of the neighbouring ester ethoxide group
to give the corresponding target compounds 4 by intramolecu-
lar heteroconjugate addition and annulation. Irrespective of the
fact whether substituted piperazines or unsubstantiated pipera-
zine, the cyclisation proceeded very smoothly with the same
Thiazolo[4,5-d]pyrimidines are widely recognised as phar-
maceutically and biologically useful heterocycles because of
their structural similarities to the purine bases. As such, thia-
zolo[4,5-d]pyrimidines have been found to possess anti-HIV,
anticancer, anti-inflammatory and antimicrobial activities.11–13
An important synthetic route for thiazolo[4,5-b]pyrimidines in
previous reports is the condensation reaction of 4-aminothia-
zole-5-carboxylate and isothiourea. However, this method is
characterized by a long reaction time and low yield14.Recently,
we have been investigated the synthesis of fused pyrimidi-
nones via the aza-Wittig reaction. As a continuation of our
search for new biologically-active heterocycles,15–16 we now
report an efficient synthesis (Scheme 1) of 1,4-bis[thiazolo[4,5-d]
pyrimidin-7(6H)-one]piperazine derivatives, a series of com-
pounds which have not been reported before.
Table 1 Preparation of 1,4-bis[thiazolo[4,5-d]pyrimidin-7(6H)-
one]piperazine derivatives
Compd
Ar
R
Yield/%a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
Ph
H
89
87
76
75
81
80
74
72
73
75
86
80
77
78
82
Ph
2-Me
Ph
2,5-diMe
2,6-diMe
2-Et
H
2-Me
2,5-diMe
2,6-diMe
2-Et
H
2-Me
Ph
Ph
4-Me–C6H4
4-Me–C6H4
4-Me–C6H4
4-Me–C6H4
4-Me–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-Cl–C6H4
2,5-diMe
2,6-diMe
2-Et
Results and discussion
The key iminophosphorane 1 was synthesised according to the
literature.17
aIsolated yields based on iminophosphorane 1.
Scheme 1
* Correspondent. E-mail: zdfang2007@163.com

JOURNAL OF CHEMICAL RESEARCH 2012 613
Scheme 2
guanidines 3. After the reaction mixture was left to stand for 2–3 h, the
solvent was removed and EtONa in anhydrous EtOH (8 mL,10%) was
added. The mixture was stirred for 3–5 h at room temperature. The
solution was concentrated and the residue was recrystallised from
EtOH to give the target compound 4. TLC was used to follow the
progress of all the above reactions.
regioselectivity.No matter whether the substituents on the
benzene ring were electron-withdrawing or electron-donating
groups, the cyclisation was completed easily under mild condi-
tions. The reaction pathway was showed as Scheme 2.
The structures of compounds 4 were fully confirmed by IR,
1H NMR, MS spectroscopic data. For example, the electro-
spray ionisation mass spectrum (ESI-MS) for 4a showed
the expected molecular ion peaks m/z at 757.1 (M++H) and
the two-dimensional ionization pattern was in accord with the
proposed structure. The IR spectrum (KBr) showed a strong
absorption at 1698 cm−1 assigned to the C=O group. In the
1H NMR spectrum, the –CH2 proton appears at 2.65 ppm, in
addition to the aromatic proton multiplets.
1,4-Bis[4-oxo-3,6-diphenyl-2-thioxothiazolo[4,5-d]pyrimidin-2(4H)-
yl]piperazine (4a): White crystals; m.p. 218–219 °C; IR (KBr):
1
3341, 2946, 1698 (C=O), 1551, 1437, 1349 cm−1; H NMR (CDCl3,
300 MHz): δ 2.65 (t, J = 7.2 Hz, 8H, 4CH2), 6.62–7.15 (m, 12H, ArH),
7.23 (m, 4H, ArH), 7.54 (m, 4H, ArH); ESI-MS m/z: 757.1 (M++H).
Anal. Calcd for C38H28N8O2S4: C, 60.30; H, 3.73; N, 14.80. Found:
C, 60.28; H, 3.77; N 14.77%.
1,4-Bis[4-oxo-3,6-diphenyl-2-thioxothiazolo[4,5-d]pyrimidin-2(4H)-
yl]-2-methyl piperazine (4b): White crystals; m.p. 253–254 °C; IR
1
(KBr): 3342, 2946, 1689 (C=O), 1551, 1443, 1358 cm−1; H NMR
Experimental
(CDCl3, 300 MHz): δ 1.15 (d, J = 6.4 Hz, 3H, CH3), 2.42 (d, J =
7.2 Hz, 2H, CH2), 2.51 (t, J = 7.2 Hz, 4H, 2CH2), 2.98 (m, 1H, CH),
6.46–7.20 (m, 12H, ArH), 7.24 (m, 4H, ArH), 7.55 (m, 4H, ArH); ESI-
MS m/z: 771.1 (M++H). Anal. Calcd for C39H30N8O2S4: C, 60.76; H,
3.92; N, 14.58. Found: C, 60.73; H, 3.89; N, 14.54%.
1,4-Bis[4-oxo-3,6-diphenyl-2-thioxothiazolo[4,5-d]pyrimidin-2(4H)-
yl]-2,5-dimethyl piperazine (4c): White crystals; m.p. 238–239 °C;
IR (KBr): 3345, 2946, 1687 (C=O), 1540, 1451, 1342 cm−1; 1H NMR
(CDCl3, 300 MHz): δ 1.15 (d, J = 7.0 Hz, 6H, 2CH3), 2.55 (d, J =
7.2 Hz, 4H, 2CH2), 3.04 (t, J = 6.2 Hz, 2H, 2CH), 6.46–7.25 (m,
12H, ArH), 7.24 (m, 4H, ArH), 7.56 (m, 4H, ArH); ESI-MS m/z: 785.1
(M++H). Anal. Calcd for C40H32N8O2S4: C, 61.20; H, 4.11; N, 14.27.
Found: C, 61.21; H, 4.15; N, 14.25%.
Melting points were determined using an X-4 model apparatus and
were uncorrected. IR spectra were recorded on a Nicolet 7500 NXR
1
IR spectrometer as KBr pellets with absorption given in cm−1. H
NMR spectra were recorded in CDCl3 on a Varian Mercury Plus 300
(300Hz) spectrometer and chemical shifts (δ) were given in ppm using
(CH3)4Si as an internal reference (δ = 0). Mass spectral (MS) data
were obtained on a Finnigan LCQ Advantage MAX mass spectrome-
ter. Elemental analyses were obtained with a Perkin-Elmer CHN 2400
elemental analysis instrument.
Synthesis of 1,4-Bis[thiazolo [4,5-d]pyrimidin-7(6H)-one]piperazine
derivatives 4; general synthesis
The aromatic isocyanate was added (0.006 mol) to the solution of
iminophosphorane 1 (0.006 mol) in THF (10 mL) at 0–5 °C. When
the resulting iminophosphorane 1 reacted with aromatic isocyanate,
triphenylphosphine oxide was formed. After the reaction mixture was
left to stand for 5–6 h at 0–5 °C, the solvent was removed under
reduced pressure and Et2O/petroleum ether (1:2, 12 mL) was added
to precipitate triphenylphosphine oxide. Removal of the solvent
gave carbodiimides 2, which were used directly without further
purification. The piperazine derivatives (0.003 mol) were added to the
solution of 2 prepared above in CH2Cl2 (10 mL) to give intermediate
1,4-Bis[4-oxo-3,6-diphenyl-2-thioxothiazolo[4,5-d]pyrimidin-
2(4H)-yl]-2,6-dimethyl piperazine (4d): White crystals; m.p. 262–263
1
°C; IR (KBr): 3342, 2943, 1688 (C=O), 1543, 1455, 1344 cm−1; H
NMR (CDCl3, 300 MHz): δ 1.15 (d, J = 7.0 Hz, 6H, 2CH3), 2.51 (d,
J = 7.2 Hz, 4H, 2CH2), 3.04 (t, J = 6.8 Hz, 2H, 2CH), 6.46–7.20 (m,
12H, ArH), 7.24 (m, 4H, ArH), 7.53 (m, 4H, ArH); ESI-MS m/z: 785.1
(M++H). Anal. Calcd for C40H32N8O2S4: C, 61.20; H, 4.11; N, 14.27.
Found: C, 61.18; H, 4.09; N, 14.24%.
1,4-Bis[4-oxo-3,6-diphenyl-2-thioxothiazolo[4,5-d]pyrimidin-2(4H)-
yl]-2-ethyl piperazine (4e): White crystals; m.p. >300 °C; IR (KBr):

614 JOURNAL OF CHEMICAL RESEARCH 2012
1
3338, 2940, 1685 (C=O), 1552, 1458, 1359 cm−1; H NMR (CDCl3,
2.42 (d, J = 7.0 Hz, 2H, CH2), 2.51 (t, J = 7.2 Hz, 4H, 2CH2), 2.98
(m, 1H, CH), 6.46–7.20 (m, 10H, ArH), 7.24 (m, 4H, ArH), 7.53
(m, 4H, ArH); ESI-MS m/z: 839.2 (M++H). Anal. Calcd for
C39H28N8O2S4Cl2: C, 55.77; H, 3.36; N, 13.34. Found: C, 55.78; H,
3.33; N, 13.35%.
300 MHz): δ 0.98 (t, J = 7.0 Hz, 3H, CH3), 1.37 (m, 2H, 2CH2), 2.53
(d, J = 7.2 Hz, 2H, CH2), 2.56 (t, J = 7.2 Hz, 4H, 2CH2), 6.54–7.13 (m,
12H, ArH), 7.24 (m, 4H, ArH), 7.53 (m, 4H, ArH); ESI-MS m/z: 785.1
(M++H). Anal. Calcd for C40H32N8O2S4: C, 61.20; H, 4.11; N, 14.27.
Found: C, 61.24; H, 4.10; N, 14.26%.
1,4-Bis[4-oxo-3-phenyl-6-(4-chlorophenyl)-2-thioxothiazolo[4,5-d]
pyrimidin-2(4H)-yl]-2,5-dimethyl piperazine (4m): White crystals;
m.p. 238–239 °C; IR (KBr): 3342,2963, 1689 (C=O), 1547, 1453,
1,4-Bis[4-oxo-3-phenyl-6-(4-methylphenyl)-2-thioxothiazolo[4,5-d]
pyrimidin-2(4H)-yl]piperazine (4f): White crystals; m.p. >300 °C; IR
(KBr): 3328, 2941, 1688 (C=O), 1553, 1466, 1349 cm−1; H NMR
1352 cm−1; H NMR (CDCl3, 300 MHz): δ 1.15 (d, J = 7.0 Hz, 6H,
1
1
(CDCl3, 300 MHz): δ 2.35 (s, 6H, 2CH3), 2.65 (t, J = 7.2 Hz, 8H,
4CH2), 6.62–7.20 (m, 10H, ArH), 7.28 (m, 4H, ArH), 7.58 (m, 4H,
ArH); ESI-MS m/z: 785.1 (M++H). Anal. Calcd for C40H32N8O2S4: C,
61.20; H, 4.11; N, 14.27. Found: C, 61.19; H, 4.10; N, 14.29%.
1,4-Bis[4-oxo-3-phenyl-6-(4-methylphenyl)-2-thioxothiazolo[4,5-d]
pyrimidin-2(4H)-yl]-2-methyl piperazine (4g): White crystals; m.p.
253–254 °C; IR (KBr): 3332, 2943, 1686 (C=O), 1550, 1466, 1368
2CH3), 2.55 (d, J = 7.2 Hz, 4H, 2CH2), 3.04 (t, J = 6.2 Hz, 2H, 2CH),
6.46–7.25 (m, 10H, ArH), 7.27 (m, 4H, ArH), 7.55 (m, 4H, ArH); ESI-
MS m/z: 853.1 (M++H). Anal. calcd for C40H30N8O2S4Cl2: C, 56.26; H,
3.54; N, 13.12. found: C, 56.22; H, 3.51; N, 13.10%.
1,4-Bis[4-oxo-3-phenyl-6-(4-chlorophenyl)-2-thioxothiazolo[4,5-d]
pyrimidin-2(4H)-yl]-2,6-dimethyl piperazine (4n): White crystals; m.
p. 262–263 °C; IR (KBr): 3331, 2940, 1687 (C=O), 1548, 1546, 1348
cm−1; 1H NMR (CDCl3, 300 MHz): δ 1.15 (d, J = 7.0 Hz, 6H,
2CH3), 2.51 (d, J = 7.2 Hz, 4H, 2CH2), 3.04 (t, J = 6.8 Hz, 2H, 2CH),
6.46–7.20 (m, 10H, ArH), 7.25 (m, 4H, ArH), 7.55 (m, 4H, ArH); ESI-
MS m/z: 853.2 (M++H). Anal. Calcd for C40H30N8O2S4Cl2: C, 56.26;
H, 3.54; N, 13.12. Found: C, 56.27; H, 3.56; N, 13.14%.
1,4-Bis[4-oxo-3-phenyl-6-(4-chlorophenyl)-2-thioxothiazolo[4,5-d]
pyrimidin-2(4H)-yl]-2-ethyl piperazine (4o): White crystals; m.p.
>300 °C; IR (KBr): 3338, 2944, 1685 (C=O), 1539, 1441, 1343 cm−1;
1H NMR (CDCl3, 300 MHz): δ 0.98 (t, J = 7.0 Hz, 3H, CH3), 1.37 (m,
2H, 2CH2), 2.53 (d, J = 7.2 Hz, 2H, CH2), 2.56 (t, J = 6.8 Hz, 4H,
2CH2), 6.54–7.13 (m, 10H, ArH), 7.24 (m, 4H, ArH), 7.53 (m, 4H,
ArH); ESI-MS m/z: 853.1 (M++H). Anal. Calcd for C40H30N8O2S4 Cl2:
C, 56.26; H, 3.54; N, 13.12. Found: C, 56.27; H, 3.55; N 13.15%.
1
cm−1; H NMR (CDCl3, 300 MHz): δ 1.15 (d, J = 6.4 Hz, 3H, CH3),
2.35 (s, 6H, 2CH3), 2.42 (d, J = 7.0 Hz, 2H, CH2), 2.51 (t, J = 7.2 Hz,
4H, 2CH2), 2.98 (m, 1H, CH), 6.46–7.20 (m, 10H, ArH), 7.24 (m, 4H,
ArH), 7.53 (m, 4H, ArH); ESI-MS m/z: 799.2 (M++H). Anal. Calcd
for C41H34N8O2S4: C, 61.63; H, 4.29; N, 14.02. Found: C, 61.61; H,
4.25; N, 14.03%.
1,4-Bis[4-oxo-3-phenyl-6-(4-methylphenyl)-2-thioxothiazolo[4,5-d]
pyrimidin-2(4H)-yl]-2,5-dimethyl piperazine (4h): White crystals; m.
p. 238–239 °C; IR (KBr): 3342, 2965, 1689 (C=O), 1553, 1457, 1348
cm−1; 1H NMR (CDCl3,300 MHz): δ 1.15 (d, J = 7.0 Hz, 6H,
2CH3), 2.35 (s, 6H, 2CH3), 2.55 (d, J = 7.2 Hz, 4H, 2CH2), 3.04 (t,
J = 6.2 Hz, 2H, 2CH), 6.46–7.20 (m, 10H, ArH), 7.24 (m, 4H, ArH),
7.53 (m, 4H, ArH); ESI-MS m/z: 813.1 (M++H). Anal. Calcd for
C42H36N8O2S4: C, 62.04; H, 4.46; N, 13.78. Found: C, 62.05; H, 4.44;
N, 13.80%.
1,4-Bis[4-oxo-3-phenyl-6-(4-methylphenyl)-2-thioxothiazolo[4,5-d]
pyrimidin-2(4H)-yl]-2,6-dimethyl piperazine (4i): White crystals; m.
p. 262–263 °C; IR (KBr): 3338, 2932, 1687 (C=O), 1548, 1462, 1348
cm−1; 1H NMR (CDCl3, 300 MHz): δ 1.15 (d, J = 7.0 Hz, 6H, 2CH3),
2.35 (s, 6H, 2CH3), 2.51 (d, J = 7.2 Hz, 4H, 2CH2), 3.04 (t, J =
6.8 Hz, 2H, 2CH), 6.46–7.20 (m, 10H, ArH), 7.24 (m, 4H, ArH), 7.53
(m, 4H, ArH); ESI-MS m/z: 813.2 (M++H). Anal. Calcd for
C42H36N8O2S4: C, 62.04; H, 4.46; N, 13.78. Found: C, 62.02; H, 4.43;
N, 13.76%.
1,4-Bis[4-oxo-3-phenyl-6-(4-methylphenyl)-2-thioxothiazolo[4,5-d]
pyrimidin-2(4H)-yl]-2-ethyl piperazine (4j): White crystals; m.p.
>300 °C; IR (KBr): 3338, 2937, 1695 (C=O), 1564, 1447, 1349 cm−1;
1H NMR (CDCl3, 300 MHz): δ 0.98 (t, J = 7.0 Hz, 3H, CH3), 1.37 (m,
2H, 2CH2), 2.35 (s, 6H, 2CH3), 2.53 (d, J = 7.2 Hz, 2H, CH2), 2.56 (t,
J = 6.8 Hz, 4H, 2CH2), 6.54–7.13 (m, 10H, ArH), 7.24 (m, 4H, ArH),
7.53 (m, 4H, ArH); ESI-MS m/z: 813.2 (M++H). Anal. Calcd for
C42H36N8O2S4: C, 62.04; H, 4.46; N, 13.78. Found: C, 62.07; H, 4.47;
N, 13.81%.
Received 19 July 2012; accepted 14 August 2012
Paper 1201418 doi: 10.3184/174751912X13460803277147
Published online: 28 September 2012
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219 °C; IR (KBr): 3328, 2942, 1688 (C=O), 1552, 1453, 1341 cm−1;
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cm−1; H NMR (CDCl3, 300 MHz): δ 1.15 (d, J = 6.4 Hz, 3H, CH3),

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