Regioselective synthesis of 5H-thiazolo[3,2-a]pyrimidin-5-ones from Morita-Baylis-Hillman adduct acetates under solvent-free and base-free conditions

Article abstract of DOI:10.1055/s-0028-1088051

5H-Thiazolo[3,2-a]pyrimidin-5-ones were easily prepared in good to excellent yields with high regioselectivity by nucleophilic addition of thiazol-2-amines to Morita-Baylis-Hillman adduct acetates, followed by cyclization and a thermo-sigmatropic shift pr

Full text of DOI:10.1055/s-0028-1088051

PAPER
1615
Regioselective Synthesis of 5H-Thiazolo[3,2-a]pyrimidin-5-ones from
Morita–Baylis–Hillman Adduct Acetates under Solvent-Free and
Base-Free Conditions
Synthesis of
5H
-Thiazol
e
o[3,2-
a
]pyr
i
imidin
h
-5-one
s
ui Zhong, Baoming Guo, Fuliang Lin, Yongliang Liu, Weike Su*
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88320752; E-mail: suweike@zjut.edu.cn
Received 2 December 2008; revised 20 January 2009
F
Abstract: 5H-Thiazolo[3,2-a]pyrimidin-5-ones were easily pre-
pared in good to excellent yields with high regioselectivity by nu-
cleophilic addition of thiazol-2-amines to Morita–Baylis–Hillman
adduct acetates, followed by cyclization and a thermo-sigmatropic
shift procedure under solvent-free and base-free conditions.
O
Key words: fused-ring systems, heterocycles, a,b-unsaturated es-
ters, thiazol-2-amines, solvent-free, base-free
N
F
N
S
N
Figure 1 Structure of ritanserin
5H-Thiazolo[3,2-a]pyrimidin-5-ones are very important
intermediates and widely used in pharmaceutical chemis-
try.1 The compound ritanserin (Figure 1) has been de-
scribed to have significant properties as a selective
serotonin (5-HT2) receptor antagonist. The starting mate-
rials in the reported synthetic routes for the 5H-thiazo-
lo[3,2-a]pyrimidin-5-one moiety remain synthetic
bottlenecks.2 During the last decades, several other re-
searchers have focused on the synthesis of 5H-thiazo-
lo[3,2-a]pyrimidin-5-ones by different routes, but product
yield and operational convenience have still remained a
problem.3
cal chemistry.5 During our previous studies towards the
exploitation of the Baylis–Hillman reaction in heterocy-
clic chemistry to synthesize pharmaceutically valuable in-
termediates, we became aware that polyhydrochromenes,
polyhydroquinolines, and 1,2,4-triazole derivatives are
readily synthesized from Morita–Baylis–Hillman adduct
acetates under solvent-free conditions.6
Today ‘green chemistry’ is becoming increasingly impor-
tant. The synthesis of regioselective molecules is another
important area, and the development of regioselective re-
actions that proceed under environmentally benign condi-
tions is an extensively investigated field.7
The Baylis–Hillman reaction has proved to be a powerful
tool for C–C bond-forming reactions, and has been used
in an interesting series of densely functionalized mole-
cules in operationally simple, one-pot, and completely
atom-economical procedures.4 Baylis–Hillman adducts
can be widely used in organic synthesis and pharmaceuti-
Our approach to 5H-thiazolo[3,2-a]pyrimidin-5-ones 1 is
summarized by the retrosynthetic analysis under consid-
eration of ‘green chemistry’ aspects shown in Scheme 1.
Y
R4
O
O
R4
O
H2N
N
N
R2
Z
+
NH2
+
R1
R3
R3
R1
X
S
S
O
N
R4
R2
R1
R2
2
7
3
6
N
R3
S
R2
R1
R3
R4
HS
N
OAc
1
?
R4
N
+
+
CO2R5
HN
W
R6
R3
NH2
S
O
O
2
8
4
5
R1 = CH2R6; R2 = H
5 = Me, Et; R6 = aryl, alkyl
R
1 = R2 = R3 = R4 = alkyl
W = Z = OR5 (R5 = alkyl), OH, halo, etc.
R
Scheme 1
SYNTHESIS 2009, No. 10, pp 1615–1622
x
x.
x
x
.
2
0
0
9
Advanced online publication: 20.04.2009
DOI: 10.1055/s-0028-1088051; Art ID: F24408SS
© Georg Thieme Verlag Stuttgart · New York

1616
W. Zhong et al.
PAPER
By analogy with our previous work, 5H-thiazolo[3,2- try 7); this implied that triethylamine is not essential for
a]pyrimidin-5-ones 1 and the relatively unstable interme- the reaction. To consider the steric effects on the reaction,
diates 6-benzylidene-6,7-dihydro-5H-thiazolo[3,2-a]py- 8ab was used as the starting material under the same con-
rimidin-5-ones 10 were formed by the reaction of thiazol- ditions, and the corresponding product 10a was formed in
2-amine (2a) with the Morita–Baylis–Hillman adduct a yield of 65% (Table 2, entry 1), with an intermediate 9ab
acetates 8 (Scheme 2).
isolated from the residue. Other substrates 8 were also in-
vestigated under these solvent-free and base-free condi-
tions, and the corresponding products 10b–f were isolated
in satisfying yields (Table 2, entries 2–6). When the reac-
tion temperature was increased to 80 °C for three hours, a
mixture of 1a (47%) and 10a (43%) was obtained
(Table 1, entry 8), and when the reaction time was extend-
ed to six hours, a higher yield of 1a (64%) was obtained
(entry 9). This finding encouraged us to conduct the reac-
tion at 130 °C under solvent-free and base-free conditions
for six hours, and, as expected, only product 1a was iso-
lated (90% yield) (Table 1, entry 10). Thus, the transfor-
mation from product 10a to 1a can be carried out at
130 °C for six hours in 98% yield (Scheme 2). This
straightforward route represents an original and regio-
selective pathway to these pharmaceutically valuable het-
erocycles.
Initially, the experiments were performed in ethanol solu-
tion in the presence of triethylamine with Morita–Baylis–
Hillman adduct acetate 8aa (R1 = 2-ClC6H4, R2 = Me)
and thiazol-2-amine (2a) as the substrates under different
conditions; the results are summarized in Table 1. When
the reaction mixture was stirred at room temperature for
six hours, 10a was the main product in a yield of 88%
(Table 1, entry 1), but was partially transformed into
product 1a at a higher reaction temperature (entry 2).
When the reaction was carried out for a prolonged time at
80 °C, a slightly higher yield was obtained (entry 3). For
higher yields of 1a, the reaction under refluxing solvents
such as toluene and xylene was studied (entries 4 and 5),
but the results were unsatisfactory.
Our previous studies indicated that solvent-free condi-
tions may result in increased reaction efficiency. The re-
action was tried under solvent-free conditions at room
temperature for six hours, and a 91% yield of 10a was iso-
lated (Table 1, entry 6). Surprisingly, a similar result
could also be obtained in the absence of triethylamine (en-
With the optimal reaction conditions established, a repre-
sentative class of Morita–Baylis–Hillman adduct acetates
8 was examined, and the full results are summarized in
Table 3. All reactions proceeded smoothly under the opti-
mized conditions to produce products 1 in moderate to
O
O
O
OAc
O
N
OR2
N
R1
R1
R1
N
+
+
N
R1
OR2
+
NH2
S
S
N
H
N
S
N
S
9
8
2a
1
10
130 °C, 6 h
98%
Scheme 2 The reaction of Morita–Baylis–Hillman adduct acetates 8 with thiazol-2-amine (2a) under various conditions
Table 1 The Reaction of Morita–Baylis–Hillman Adduct Acetate 8aa (R1 = 2-ClC6H4, R2 = Me) with Thiazol-2-amine (2a) under Various
Conditionsa
Entry
Ratio 8aa/2a/Et3N Solvent
Temp (°C)
r.t.
Time (h)
Yield of 10ab (%) Yield of 1ab (%)
1
2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:0
EtOH
EtOH
EtOH
toluene
xylene
none
6
3
5
3
3
6
6
3
6
6
88
43
44
25
15
91
90
43
25
–
–
80
44c
49c
55c
36c
–
3
80
4
110
150
r.t.
5
6
7
none
r.t.
–
8
1:1:0
none
80
47c
64c
90
9
1:1:0
none
80
10
1:1:0
none
130
a See also Scheme 2. Reagents and conditions: 8aa (1.0 mmol), 2a (1.0 mmol), Et3N (0 or 1.2 mmol), solvent or solvent-free.
b Isolated yield of 10a (R1 = 2-ClC6H4) and 1a (R1 = 2-ClC6H4) based on 8aa (R1 = 2-ClC6H4, R2 = Me).
c Isolated yields after purification by column chromatography (silica gel, CH2Cl2–MeOH, 30:1).
Synthesis 2009, No. 10, 1615–1622 © Thieme Stuttgart · New York

PAPER
Synthesis of 5H-Thiazolo[3,2-a]pyrimidin-5-ones
1617
Table 3 Synthesis of 6-(Arylmethyl)-5H-thiazolo[3,2-a]pyrimidin-
5-ones 1a
Table 2 Synthesis of 6-Benzylidene-6,7-dihydro-5H-thiazolo[3,2-
a]pyrimidin-5-ones 10a
Entry Substrate R1
R2
Timeb Product Yieldc
Entry
Substrate R1
R2
Product Yieldb
8
(h)
6
4
4
6
5
5
3
4
4
3
4
6
6
6
6
1
(% )
90
92
82
65
73
65
90
84
85
91
91
65
60
61
62
8
10
(%)
65c
91
1
2
8aa
8ba
8ca
8ab
8bb
8cb
8da
8ea
8fa
8ga
8ha
8ia
2-ClC6H4
Ph
Me
Me
Me
Et
1a
1b
1c
1a
1b
1c
1d
1e
1f
1
2
3
4
5
6
8ab
8ba
8da
8ea
8fa
2-ClC6H4
Et
10a
10b
10c
10d
10e
10f
Ph
Me
Me
Me
Me
Me
3
4-ClC6H4
2-ClC6H4
Ph
4-ClC6H4
2-Cl-6-FC6H3
4-FC6H4
3-MeOC6H4
91
4
86
5
Et
87
6
4-ClC6H4
2-Cl-6-FC6H3
4-FC6H4
3-MeOC6H4
3,4-Me2C6H3
3-O2NC6H4
2-thienyl
2-furyl
Et
8ha
80
a See also Scheme 2. Reagents and conditions: 8 (1.0 mmol), 2a (1.0
mmol), no solvent, r.t., 6 h.
7
Me
Me
Me
Me
Me
Me
Me
b Isolated yields of products 10 based on 8.
c Product 9ab was isolated in 20% yield after column chromatography
(silica gel, PE–EtOAc, 4:1).
8
9
10
11
12
13
14
15
1g
1h
1i
high yields. A range of aryl- and hetaryl-substituted sub-
strates 8, with various steric and electronic influences,
were examined. As shown in Table 3, aryl-substituted
substrates 8 were found to be suitable for this transforma-
tion, generally providing the corresponding products 1 in
good to excellent yields and regioselectivities. To investi-
gate the steric effect of the ester moiety, an ethyl ester was
used in place of the methyl ester; this resulted in decreased
yields of 1 with increased bulk of the ester moiety
(Table 3, entries 4–6), matching the results of our previ-
ous studies.6
8ja
8ka
8la
1j
4-methylthiazol-5-yl Me
2-chloro-3-quinolyl Me
1k
1l
a See also Scheme 2. Reagents and conditions: 8 (1.0 mmol), 2a (1.0
mmol), no solvent, 130 °C.
b The reaction progress was monitored by TLC.
c Isolated yields of products 1 based on 8.
Interestingly, the reaction of thiazol-2-amine 2a with the
Morita–Baylis–Hillman adduct acetate 8m, derived from
3-methylbutanal and methyl acrylate, gave the normal
product 1m, rather than the Michael-addition-type prod-
ucts 11a or 11b (Scheme 3), analogously to our previous
report.6 The reactions of 4-methylthiazol-2-amine (2b)
and 5-methylbenzothiazol-2-amine (2c) with acetates 8
were also examined, and the results are summarized in
Table 4.
gives SN2¢ intermediates 9, which readily isomerize into
12; cyclization follows to produce compounds 10, which,
finally, via a thermo-sigmatropic proton shift provide tar-
get compounds 1.
In conclusion, we have developed a simple, efficient, and
‘green’ method for the synthesis of various 5H-thiazo-
lo[3,2-a]pyrimidin-5-ones 1 and benzylidene-6,7-dihy-
dro-5H-thiazolo-[3,2-a]pyrimidin-5-ones 10 in high
yields under solvent-free and base-free conditions. To the
best of our knowledge, it is the first time that Morita–
Baylis–Hillman adduct acetates have been applied under
solvent-free and base-free conditions in the synthesis of
heterocycles.
The above results provided a possible explanation for the
formation of compounds 1, and this is shown in Scheme 4.
The formation of compounds 1 might include a three-step
successive reaction. Firstly, the reaction of Morita–
Baylis–Hillman adduct acetates 8 with thiazol-2-amines 2
O
O
MeO
N
MeO
N
N
+
OAc
O
NH2
S
S
N
N
S
2a
11b
11a
OMe
O
8m
N
S
N
1m 30%
Scheme 3 Reagents and conditions: 8m (1 equiv), 2a (1 equiv), K2CO3 (1.1 equiv), 70 °C, 1 h, then 130 °C, 3 h.
Synthesis 2009, No. 10, 1615–1622 © Thieme Stuttgart · New York

1618
W. Zhong et al.
PAPER
Table 4 Reactions of Thiazol-2-amine Derivatives 2b and 2c with Acetates 8a
Entry Substrate 8
Substrate 2
Product 10 or 1
Yieldb (%)
89
O
OAc
N
S
1c
8ga
8ga
2b
10g
CO2Me
N
N
NH2
S
S
N
O
2
2b
2c
1n
1o
87
82
N
N
OAc
O
N
N
S
CO2Me
3
4
8ba
8ha
NH2
S
OAc
O
MeO
CO2Me
2c
1p
85
MeO
N
S
N
a Reagents and conditions: 8 (1 equiv), 2 (1 equiv), no solvent, no base, 130 °C, 3 h.
b Isolated yield based on 8.
c Reagents and conditions: 8ga (1 equiv), 2b (1 equiv), no solvent, no base, r.t., 6 h.
O
O
N
R3
OR2
N
OR2
OAc
O
R1
R1
N
H
R3
R4
R3
R4
N
R1
OR2
+
H2N
••
R4
N
H
S
AcOH
S
S
2
12
8
9
– R2OH
O
N
R3
O
N
R3
sigmatropic
proton shift
R1
R1
N
N
R4
R4
heat
S
S
10
1
Scheme 4 Proposed mechanism for the formation of 5H-thiazolo[3,2-a]pyrimidin-5-ones
Melting points were determined on a Büchi B-540 capillary melting
point apparatus and are uncorrected. IR spectra were recorded on a
Nicolet Aviatar-370 instrument; samples were prepared as KBr
plates. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a Varian 400-MHz spectrometer. Samples were pre-
pared in CDCl3 or DMSO-d6 with TMS (d = 0) as internal standard
or in TFA-d (d = 11.5) with 1,4-dioxane (d = 3.85) as standard at r.t.
Elemental analyses were carried out on a Vario EL III instrument.
Mass spectra were obtained on a Thermo Finnigan LCQ-Advantage
spectrometer. HRMS (EI) was carried out on an APEX (Bruker)
mass III spectrometer. Analytical grade solvents and commercially
available reagents were used as received. For chromatography, sili-
ca gel (200–300 mesh) purchased from Qingdao Haiyang Chemical
Co., Ltd. was used. The Morita–Baylis–Hillman adduct acetates 84b
and thiazol-2-amines 28 were synthesized according to literature
procedures.
with EtOH (2 × 5 mL), filtered, and dried in vacuo to give the cor-
responding pure product 10.
Ethyl (E)-3-(2-Chlorophenyl)-2-[(thiazol-2-ylamino)meth-
yl]acrylate (9ab); Typical Procedure
A mixture of 8ab (282 mg, 1 mmol) and 2a (101 mg, 1 mmol) was
stirred at r.t. for 6 h. The mixture was washed with EtOH (2 × 5
mL), filtered, and dried in vacuo; this gave pure product 10a. Con-
centration of the filtrate and purification of the residue by column
chromatography (silica gel, PE–EtOAc, 4:1) afforded 9ab.
6-(Arylmethyl)-5H-thiazolo[3,2-a]pyrimidin-5-ones 1; General
Procedure
A magnetically stirred mixture of the appropriate acetate 8 (1
mmol) and thiazol-2-amine 2 (1 mmol) was heated to 130 °C under
an atmosphere of N2 for the amount of time indicated in Table 3.
The mixture was washed with EtOH (2 × 5 mL), filtered, and dried
in vacuo; this gave pure product 1.
(E)-6-Benzylidene-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-
ones 10; General Procedure
A mixture of the appropriate acetate 8 (1 mmol) and thiazol-2-
amine 2 (1 mmol) was stirred at r.t. for 6 h. The mixture was washed
Synthesis 2009, No. 10, 1615–1622 © Thieme Stuttgart · New York

PAPER
Synthesis of 5H-Thiazolo[3,2-a]pyrimidin-5-ones
1619
Ethyl (E)-3-(2-Chlorophenyl)-2-[(thiazol-2-ylamino)meth-
yl]acrylate (9ab)
(E)-6-(2-Chloro-6-fluorobenzylidene)-6,7-dihydro-5H-thiazo-
lo[3,2-a]pyrimidin-5-one (10d)
Yellow solid; mp 235.2–235.6 °C; Rf = 0.35 (CH2Cl2–MeOH,
16:1).
Pale solid; mp 125.2–126.6 °C; Rf = 0.40 (PE–EtOAc, 4:1).
IR (KBr): 3141, 3045, 1704, 1602, 1507, 749, 715 cm–1.
IR (KBr): 3136, 3094, 1655, 1609, 1505, 907, 790 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.25 (t, J = 7.0 Hz, 3 H, CH2CH3),
1.62 (br, 1 H, NH), 3.72 (q, J = 7.0 Hz, 2 H, CH2CH3), 3.98 (d, J =
1.0 Hz, 2 H, NHCH2), 6.82 (d, J = 4.5 Hz, 1 H, NCH=CHS), 7.11
(d, J = 5.0 Hz, 1 H, SCH=CHN), 7.24–7.27 (m, 2 H, ArH), 7.33 (s,
1 H, CHCC=O), 7.40 (d, J = 7.0 Hz, 1 H, ArH), 7.41 (d, J = 7.0 Hz,
1 H, ArH).
13C NMR (125 MHz, CDCl3): d = 18.4, 32.0, 58.4, 109.9, 123.7,
124.1, 127.3, 128.6, 129.8, 131.9, 132.0, 134.4, 135.3, 163.8, 167.2.
MS (EI): m/z (%) = 321.1 [M+], 241.1 (100).
HRMS (EI): m/z [M+] calcd for C15H15ClN2O2S: 322.0543; found:
1H NMR (500 MHz, DMSO-d6): d = 4.85 (s, 2 H, CH2), 6.94 (d,
J = 4.5 Hz, 1 H, NCH=CHS), 7.28 (d, J = 4.5 Hz, 1 H, SCH=CHN),
7.36 (s, 1 H, COC=CH), 7.39 (t, J = 9 Hz, 1 H, ArH), 7.47 (d, J =
7.5 Hz, 1 H, ArH), 7.52 (dd, J = 7.0, 8.0 Hz, 1 H, ArH).
13C NMR (125 MHz, DMSO-d6): d = 47.2 (d, J = 10.0 Hz), 106.6,
115.0 (d, J = 22.5 Hz), 120.7, 121.5 (d, J = 18.8 Hz), 125.7, 128.5,
129.5, 131.5, 133.8 (d, J = 5 Hz), 159.3 (d, J = 250 Hz), 165.5,
172.9.
MS (EI): m/z (%) = 294.1 [M+] (5), 259.1 (100).
HRMS (EI): m/z [M+] calcd for C13H8ClFN2OS: 294.0030; found:
322.0536.
294.0033.
(E)-6-(2-Chlorobenzylidene)-6,7-dihydro-5H-thiazolo[3,2-
a]pyrimidin-5-one (10a)
Pale yellow solid; mp 201.7–202.5 °C; Rf = 0.35 (CH2Cl2–MeOH,
(E)-6-(4-Fluorobenzylidene)-6,7-dihydro-5H-thiazolo[3,2-a]py-
rimidin-5-one (10e)
16:1).
Yellow solid; mp 226.3–228.5 °C; Rf = 0.30 (CH2Cl2–MeOH,
16:1).
IR (KBr): 3141, 3045, 1647, 1602, 1507, 747, 718 cm–1.
IR (KBr): 3141, 3043, 1644, 1584, 1523, 1506, 820, 705 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 5.16 (s, 2 H, CH2), 6.92 (d,
J = 4.4 Hz, 1 H, NCH=CHS), 7.29 (d, J = 4.5 Hz, 1 H, SCH=CHN),
7.40–7.48 (m, 3 H, ArH), 7.57–7.60 (m, 1 H, ArH), 7.66 (s, 1 H,
COC=CH).
13C NMR (125 MHz, DMSO-d6): d = 47.1, 106.3, 125.3, 127.2,
129.4, 129.6, 130.4, 130.4, 131.3, 132.6, 133.3, 165.9, 172.6.
ESI-MS: m/z (%) = 277.2 [M+ + 1] (100).
HRMS (EI): m/z [M+] calcd for C13H9ClN2OS: 276.0124; found:
1H NMR (500 MHz, DMSO-d6): d = 5.26 (s, 2 H, CH2), 6.92 (d,
J = 4.5 Hz, 1 H, NCH=CHS), 7.31 (d, J = 4.5 Hz, 1 H, SCH=CH),
7.33 (d, J = 9 Hz, 2 H, ArH), 7.51 (dd, J = 6, 9 Hz, 2 H, ArH), 7.60
(s, 1 H, COC=CHN).
13C NMR (125 MHz, DMSO-d6): d = 47.6, 106.2, 115.7 (d, J = 21
Hz, CH × 2), 122.7, 129.5, 131.2, 132.2 (d, J = 8.7 Hz, CH × 2),
133.8, 161.2 (d, J = 246 Hz), 166.1, 172.4.
ESI-MS: m/z (%) 261.2 [M+ + 1] (100).
HRMS (EI): m/z [M+] calcd for C13H9FN2OS: 260.0420; found:
276.0126.
(E)-6-Benzylidene-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-
260.0426.
one (10b)
Pale yellow solid; mp 194.7–195.8 °C; Rf = 0.40 (CH2Cl2–MeOH,
16:1).
(E)-6-(3-Methoxybenzylidene)-6,7-dihydro-5H-thiazolo[3,2-
a]pyrimidin-5-one (10f)
Yellow solid; mp 192.5–193.9 °C; Rf = 0.30 (CH2Cl2–MeOH,
16:1).
IR (KBr): 3106, 3043, 1638, 1586, 1524, 1507, 821, 706 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.81 (s, 3 H, CH3O), 3.81 (s, 3
H, CH2), 6.91 (d, J = 4.8 Hz, 1 H, NCH=CHS), 6.99 (s, 1 H, ArH),
7.00 (m, 2 H, ArH), 7.35 (d, J = 4.8 Hz, 1 H, SCH=CHN), 7.40 (t,
J = 8 Hz, 1 H, ArH), 7.59 (s, 1 H, COC=CHN).
13C NMR (100 MHz, DMSO-d6): d = 47.5, 55.1, 106.1, 114.4,
115.3, 122.0, 123.3, 129.5, 129.7, 134.9, 135.9, 159.3, 166.1, 172.3.
IR (KBr): 3129, 3037, 1653, 1601, 1518, 750, 692 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 5.28 (s, 2 H, CH2), 6.91 (d,
J = 4.5 Hz, 1 H, NCH=CHS), 7.32 (d, J = 4.5 Hz, 1 H, SCH=CHN),
7.41–7.45 (m, 3 H, ArH), 7.48–7.50 (m, 2 H, ArH), 7.62 (s, 1 H,
COC=CH).
13C NMR (125 MHz, DMSO-d6): d = 48.1, 106.6, 123.3, 129.2
(CH × 2), 129.3, 130.0, 130.4 (CH × 2), 135.1, 135.4, 166.6, 172.8.
ESI-MS: m/z (%) = 242.1 [M+] (100).
HRMS (EI): m/z [M+] calcd for C13H10N2OS: 242.0514; found:
ESI-MS: m/z (%) = 273.4 [M+ + 1] (100).
HRMS (EI): m/z [M+] calcd for C14H12N2O2S: 272.0619; found:
242.0520.
(E)-6-(4-Chlorobenzylidene)-6,7-dihydro-5H-thiazolo[3,2-
a]pyrimidin-5-one (10c)
Yellow solid; mp 228.9–229.8 °C; Rf = 0.30 (CH2Cl2–MeOH,
272.0624.
(E)-6-(3,4-Dimethylbenzylidene)-3-methyl-6,7-dihydro-5H-thi-
azolo[3,2-a]pyrimidin-5-one (10g)
16:1).
Pale yellow solid; mp 162.3–163.7 °C; Rf = 0.35 (CH2Cl2–MeOH,
16:1).
IR (KBr): 3182, 3121, 1705, 1592, 1512, 989 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.25 (s, 3 H, CH3), 2.25 (s, 3
H, CH3), 2.26 (s, 3 H, CH3), 5.18 (s, 2 H, CH2), 6.55 (d, J = 1.2 Hz,
1 H, CH3C=CHS), 7.19 (d, J = 8 Hz, 1 H, ArH), 7.25 (s, 1 H, ArH),
7.26 (d, J = 7.2 Hz, 1 H, ArH), 7.56 (s, 1 H, COC=CH).
13C NMR (100 MHz, DMSO-d6): d = 13.1, 19.2, 19.3, 46.1, 100.1,
120.6, 127.3, 129.8, 131.3, 132.3, 134.8, 136.6, 137.3, 137.5, 165.6,
172.4.
IR (KBr): 3137, 3062, 1634, 1591, 1482, 813 cm–1.
1H NMR (400 MHz, TFA-d): d = 5.57 (s, 2 H, CH2), 7.26 (d, J = 8.8
Hz, 2 H, ArH), 7.36–7.41 (m, 3 H, ArH), 7.53 (d, J = 4 Hz, 1 H,
SCH=CHN), 7.16 (s, 1 H, COC=CH).
13C NMR (100 MHz, TFA-d): d = 49.8, 115.2, 125.4, 130.4
(CH × 2), 131.9, 131.0, 132.5 (CH × 2), 140.0, 141.2, 147.7, 162.3.
ESI-MS: m/z (%) = 277 [M+ + 1] (100).
HRMS (EI): m/z [M+] calcd for C13H9ClN2OS: 276.0124; found:
276.0128.
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6-(4-Fluorobenzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1e)
ESI-MS: m/z (%) = 285.2 [M+ + 1] (100).
Yellow solid; mp 241.5–242.8 °C; Rf = 0.30 (CH2Cl2–MeOH,
16:1).
IR (KBr): 3113, 3067, 1638, 1614, 1484, 803 cm–1.
HRMS (EI): m/z [M+] calcd for C16H16N2OS: 284.0983; found:
284.0988.
6-(2-Chlorobenzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1a)
Colorless crystals; mp 201.5–202.2 °C; Rf = 0.35 (CH2Cl2–MeOH,
16:1).
IR (KBr): 3108, 3072, 1645, 1630, 1496, 721 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 3.66 (s, 2 H, CH2), 7.09–7.13
(m, 2 H, ArH), 7.26 (d, J = 4.8 Hz, 1 H, NCH=CHS), 7.31–7.34 (m,
2 H, ArH), 7.72 (d, J = 4.8 Hz, 1 H, SCH=CHN), 7.16 (s, 1 H,
COC=CHN).
1H NMR (400 MHz, DMSO-d6): d = 3.77 (s, 2 H, CH2), 7.26 (d,
J = 4.8 Hz, 1 H, NC=CHS), 7.29–7.32 (m, 2 H, ArH), 7.37 (dd, J =
3.6, 6.0 Hz, 1 H, ArH), 7.47 (dd, J = 3.6, 5.6 Hz, 1 H, ArH), 7.75 (d,
J = 4.8 Hz, 1 H, SCH=CHN), 7.99 (s, 1 H, COC=CHN).
13C NMR (100 MHz, DMSO-d6): d = 31.3, 109.7, 121.5, 125.3,
127.2, 128.3, 129.2, 131.3, 1313, 133.3, 135.7, 163.8, 166.2.
13C NMR (125 MHz, DMSO-d6): d = 32.7, 109.7, 114.9 (d, J = 21
Hz, CH × 2), 123.2, 125.3, 130.7 (d, J = 7 Hz, CH × 2), 133.8,
134.8, 160.9 (d, J = 240 Hz), 163.7, 166.4.
ESI-MS: m/z (%) = 261 [M+ + 1] (100).
HRMS (EI): m/z [M+] calcd for C13H9FN2OS: 260.0420; found:
260.0424.
ESI-MS: m/z (%) = 277 [M+ + 1] (100).
6-(3-Methoxybenzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1f)
Gray solid; mp 204.0–204.8 °C; Rf = 0.35 (CH2Cl2–MeOH, 16:1).
IR (KBr): 3104, 3025, 1637, 1606, 781, 705 cm–1.
HRMS (EI): m/z [M+] calcd for C13H9ClN2OS: 276.0124; found:
276.0128.
6-Benzyl-5H-thiazolo[3,2-a]pyrimidin-5-one (1b)
Pale yellow crystals; mp 229.9–227.5 °C; Rf = 0.30 (CH2Cl2–
MeOH, 16:1).
IR (KBr): 3104, 3061, 1637, 1619, 1487, 698 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.87 (s, 2 H, CH2), 7.21–7.98
(m, 6 H, ArH), 7.73 (d, J = 4.4 Hz, 1 H, SCH=CHN), 8.16 (s, 1 H,
COC=CHN).
1H NMR (400 MHz, DMSO-d6): d = 3.65 (s, 2 H, CH2), 3.73 (s, 3
H, CH3O), 6.79 (dd, J = 2.8, 8.4 Hz, 1 H, ArH), 6.82 (d, J = 9.2 Hz,
1 H, ArH), 6.87 (s, 1 H, ArH), 7.21 (t, J = 7.2 Hz, 1 H, ArH), 7.26
(d, J = 4.4 Hz, 1 H, NCH=CHS), 7.73 (d, J = 4.4 Hz, 1 H,
SCH=CHN), 8.13 (s, 1 H, COC=CHN).
13C NMR (100 MHz, DMSO-d6): d = 33.5, 54.89, 109.7, 111.6,
114.8, 121.1, 123.3, 125.4, 129.3, 133.8, 140.2, 159.3, 163.7, 166.5.
13C NMR (100 MHz, DMSO-d6): d = 33.5, 109.7, 123.3, 125.4,
126.2, 128.3 (CH × 2), 128.9 (CH × 2), 133.8, 138.7, 163.7, 166.5.
ESI-MS: m/z (%) = 243.2 [M+ + 1] (100).
ESI-MS: m/z (%) = 273 [M+ + 1] (100).
HRMS (EI): m/z [M+] calcd for C14H12N2O2S: 272.0619; found:
272.0623.
HRMS (EI): m/z [M+] calcd for C13H10N2OS: 242.0514; found:
242.0519.
6-(3,4-Dimethylbenzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1g)
Pale yellow solid; mp 231.2–232.5 °C; Rf = 0.35 (CH2Cl2–MeOH,
16:1).
IR (KBr): 3135, 1642, 1620, 1400, 766 cm–1.
6-(4-Chlorobenzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1c)
Gray solid; mp 237.8–238.6 °C; Rf = 0.35 (CH2Cl2–MeOH, 16:1).
IR (KBr): 3135, 3108, 1642, 1595, 1482, 794, 729, 766 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 2.18 (s, 6 H, CH3), 3.58 (s, 2
H, CH2), 6.98 (d, J = 7.5 Hz, 1 H, ArH), 7.03 (s, 1 H, ArH), 7.05 (d,
J = 7.5 Hz, 1 H, ArH), 7.24 (d, J = 4.5 Hz, 1 H, NCH=CHS), 7.72
(d, J = 4.5 Hz, 1 H, SCH=CHN), 8.06 (s, 1 H, COC=CHN).
13C NMR (125 MHz, DMSO-d6): d = 19.4, 19.9, 33.6, 110.1, 124.2,
125.9, 126.8, 129.9, 130.6, 134.1, 134.4, 136.3, 136.4, 164.1, 167.0.
ESI-MS: m/z (%) = 271 [M+ + 1] (100).
HRMS (EI): m/z [M+] calcd for C15H14N2OS: 270.0827; found:
1H NMR (400 MHz, TFA-d, 1,4-dioxane): d = 3.81 (s, 2 H, CH2),
7.02 (d, J = 7.2 Hz, 2 H, ArH), 7.15 (d, J = 7.2 Hz, 2 H, ArH), 7.51
(d, J = 4.0 Hz, 1 H, NCH=CHS), 7.75 (d, J = 4 Hz, 1 H,
SCH=CHN), 8.15 (s, 1 H, COC=CHN).
13C NMR (100 MHz, TFA-d, 1,4-dioxane): d = 33.0, 117.4, 125.4,
128.0, 128.8, 130.0 (CH × 2), 131.0 (CH × 2), 133.1, 135.0, 138.1,
162.2.
ESI-MS: m/z (%) = 277 [M+ + 1] (100), 279 (35).
270.0830.
HRMS (EI): m/z [M+] calcd for C13H9ClN2OS: 276.0124; found:
276.0128.
6-(3-Nitrobenzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1h)
Gray solid; mp 256.2–257.2 °C; Rf = 0.30 (CH2Cl2–MeOH, 16:1).
6-(2-Chloro-6-fluorobenzyl)-5H-thiazolo[3,2-a]pyrimidin-5-
one (1d)
Pale solid; mp 239.8–240.7 °C; Rf = 0.30 (CH2Cl2–MeOH, 16:1).
IR (KBr): 3156, 3046, 1645, 1618, 1490, 720 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.80 (s, 2 H, CH2), 7.25–7.33
(m, 2 H, NCH=CHS, ArH), 7.41–7.45 (m, 2 H, ArH), 7.73 (d, J =
4.4 Hz, 1 H, SCH=CHN), 7.76 (s, 1 H, COC=CHN).
13C NMR (100 MHz, DMSO-d6): d = 24.9, 109.8, 114.6 (d, J = 23
Hz), 120.7, 123.2 (d, J = 18 Hz), 125.5 (d, J = 24 Hz), 129.5 (d, J =
18 Hz), 129.7, 132.5, 134.8 (d, J = 5 Hz), 161.1 (d, J = 246 Hz),
163.9, 166.1.
IR (KBr): 3141, 3106, 1638, 1620, 1484, 796, 735 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.83 (s, 2 H, CH2), 7.28 (d,
J = 4.0 Hz, 1 H, NCH=CHS), 7.59 (t, J = 8.0 Hz, 1 H, ArH), 7.71
(d, J = 4.0 Hz, 1 H, SCH=CHN), 7.78 (d, J = 8.0 Hz, 1 H, ArH), 8.09
(d, J = 4.0 Hz, 1 H, ArH), 8.17 (s, 1 H, COC=CHN), 8.32 (s, 1 H,
ArH).
13C NMR (100 MHz, DMSO-d6): d = 33.7, 110.5, 121.8, 122.7,
124.0, 125.9, 130.2, 134.9, 136.3, 141.8, 148.3, 164.5, 166.9.
MS (EI): m/z (%) = 287.1 [M+] (100), 257 (90), 241 (10).
HRMS (EI): m/z [M+] calcd for C13H9N3O3S: 287.0365; found:
287.0366.
ESI-MS: m/z (%) = 295 [M+ + 1] (100).
6-(2-Thienylmethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1i)
Gray solid; mp 192.5–193.2 °C; Rf = 0.30 (CH2Cl2–MeOH, 16:1).
HRMS (EI): m/z [M+] calcd for C13H8ClFN2OS: 294.0030; found:
294.0035.
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Synthesis of 5H-Thiazolo[3,2-a]pyrimidin-5-ones
1621
IR (KBr): 3144, 3062, 1645, 1618, 1488, 723 cm–1.
IR (KBr): 3139, 2956, 1638, 1608, 1474 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.89 (s, 2 H, CH2), 6.96 (m, 2
H, NCH=CHS, SC=CH), 7.28 (d, J = 4.8 Hz, 1 H, SCH=CH), 7.34
(t, J = 3.6 Hz, 1 H, SCH=CH), 7.76 (d, J = 4.4 Hz, 1 H, SCH=CHN),
8.27 (s, 1 H, COC=CHN).
1H NMR (400 MHz, CDCl3): d = 0.88 (s, 6 H, CH3), 1.43 (q, J = 8
Hz, 2 H, (CH3)2CHCH2), 1.55–1.60 (m, 1 H, (CH3)2CH), 2.46 (t,
J = 8 Hz, 2 H, CH2), 6.84 (d, J = 4.8 Hz, 1 H, NCH=CHS), 7.41 (d,
J = 4.8 Hz, 1 H, SCH=CHN), 7.86 (s, 1 H, COC=CHN).
13C NMR (100 MHz, DMSO-d6): d = 27.7, 109.9, 122.8, 124.5,
125.4, 126.0, 126.9, 133.9, 140.8, 163.8, 166.2.
13C NMR (100 MHz, CDCl3): d = 22.4 (CH3 × 2), 26.1, 27.8, 36.4,
109.5, 124.1, 126.1, 131.3, 163.6, 167.8.
ESI-MS: m/z (%) = 249 [M+ + 1] (100).
ESI-MS: m/z (%) = 223 [M+ + 1] (100).
HRMS (EI): m/z [M+] calcd for C11H8N2OS2: 248.0078; found:
HRMS (EI): m/z [M+] calcd for C11H14N2OS: 222.0827; found:
248.0081.
222.0830.
6-(2-Furylmethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1j)
Orange solid; mp 179.2–180.9 °C; Rf = 0.30 (CH2Cl2–MeOH,
16:1).
6-(3,4-Dimethylbenzyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-
5-one (1n)
Yellow crystals; mp 201.4–203.1 °C; Rf = 0.25 (CH2Cl2–MeOH,
16:1).
IR (KBr): 3135, 3041, 1643, 1609, 1520, 735 cm–1.
IR (KBr): 3170, 313102, 1638, 1605, 1487, 773 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.72 (s, 2 H, CH2), 6.20 (d,
J = 4 Hz, 1 H, OC=CH), 6.39 (dd, J = 4, 6 Hz, 1 H, OCH=CH), 7.28
(d, J = 4 Hz, 1 H, NCH=CHS), 7.55 (d, J = 4 Hz, 1 H, OCH=CH),
7.77 (d, J = 4 Hz, 1 H, SCH=CHN), 8.19 (s, 1 H, COC=CHN).
13C NMR (100 MHz, DMSO-d6): d = 26.2, 106.9, 109.9, 110.6,
120.4, 125.4, 134.0, 141.9, 151.7, 163.9, 166.2.
MS (EI): m/z (%) = 232 [M+] (100), 203 (60), 175 (15).
HRMS (EI): m/z [M+] calcd for C11H8N2O2S: 232.0306, found:
1H NMR (400 MHz, DMSO-d6): d = 2.15 (s, 3 H, CH3), 2.16 (d,
J = 7.5 Hz, 3 H, CH3), 2.36 (d, J = 7.5 Hz, 3 H, CH3), 3.62 (s, 2 H,
CH2), 6.94 (s, 1 H, ArH), 7.00 (s, 2 H, ArH), 7.07 (s, 1 H, ArH), 8.22
(s, 1 H, COC=CHN).
13C NMR (100 MHz, DMSO-d6): d = 12.9, 18.9, 19.3, 33.2, 104.3,
122.6, 126.0, 129.1, 129.8, 131.9, 132.6, 133.5, 135.6, 136.5, 163.8,
166.1.
ESI-MS: m/z (%) = 285.2 [M+ + 1] (100).
HRMS (EI): m/z [M+] calcd for C16H16N2OS: 284.0983; found:
232.0311.
6-[(4-Methylthiazol-5-yl)methyl]-5H-thiazolo[3,2-a]pyrimidin-
5-one (1k)
Gray solid; mp 255.4–256.3 °C; Rf = 0.25 (CH2Cl2–MeOH, 16:1).
IR (KBr): 3137, 3038, 1646, 1616, 1488, 766 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.37 (s, 3 H, CH3), 3.83 (s, 2
H, CH2), 7.28 (d, J = 4.8 Hz, 1 H, NCH=CHS), 7.76 (d, J = 4.8 Hz,
1 H, SCH=CHN), 8.21 (s, 1 H, COC=CHN), 8.84 (s, 1 H,
N = CHS).
13C NMR (100 MHz, DMSO-d6): d = 14.7, 24.4, 109.9, 122.2,
125.4, 127.4, 133.7, 149.5, 150.9, 163.9, 166.1.
284.0986.
3-Benzyl-8-methyl-4H-benzothiazolo[3,2-a]pyrimidine-4-one
(1o)
Green solid; mp 280.6–282.1 °C; Rf = 0.20 (CH2Cl2–MeOH, 16:1).
IR (KBr): 3089, 1702, 1639, 1493, 702 cm–1.
1H NMR (400 MHz, TFA-d): d = 2.47 (s, 3 H, CH3), 3.99 (s, 2 H,
CH2), 7.19–7.29 (m, 5 H, ArH), 7.54 (d, J = 7.6 Hz, 1 H, ArH), 7.68
(d, J = 7.6 Hz, 1 H, ArH), 7.74 (s, 1 H, ArH), 8.43 (s, 1 H,
COC=CHN).
13C NMR (100 MHz, TFA-d): d = 22.0, 35.3, 115.3, 125.8, 126.2,
130.1, 130.4, 131.1 (CH × 2), 131.4 (CH × 2), 133.4, 133.8, 136.3,
136.9, 144.9, 163.3, 164.6.
ESI-MS: m/z (%) 264 [M+ + 1] (100).
HRMS (EI): m/z [M+] calcd for C11H9N3OS2: 263.0187; found:
263.0191.
ESI-MS: m/z (%) = 307 [M+ + 1] (100).
6-[(2-Chloro-3-quinolyl)methyl]-5H-thiazolo[3,2-a]pyrimidin-
5-one (1l)
HRMS (EI): m/z [M+] calcd for C18H14N2OS: 306.0827; found:
306.0830.
Yellow solid; mp >300 °C; Rf = 0.20 (CH2Cl2–MeOH, 16:1).
3-(3-Methoxybenzyl)-8-methyl-4H-benzothiazolo[3,2-a]pyrimi-
dine-4-one (1p)
Pale green solid; mp 226.0–227.2 °C; Rf = 0.25 (CH2Cl2–MeOH,
16:1).
IR (KBr): 3142, 3049, 1638, 1607, 1476, 758 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.93 (s, 2 H, CH2), 7.28 (d,
J = 4.8 Hz, 1 H, NCH=CHS), 7.65 (t, J = 7.2 Hz, 1 H, ArH), 7.71
(d, J = 4.8 Hz, 1 H, SCH=CHN), 7.79 (t, J = 7.2 Hz, 1 H, ArH), 7.97
(d, J = 10 Hz, 1 H, ArH), 8.00 (d, J = 7.6 Hz, 1 H, ArH), 8.18 (s, 1
H, COC=CHN), 8.35 (s, 1 H, ArH).
13C NMR (100 MHz, DMSO-d6): d = 31.3, 109.9, 120.8, 125.3,
127.3, 127.5, 127.6, 130.1, 130.3, 134.5, 139.2, 146.0, 149.1, 150.6,
164.1, 166.3.
IR (KBr): 3103, 3055, 1641, 1582, 1508, 823, 778 cm–1.
1H NMR (400 MHz, TFA-d): d = 2.47 (s, 3 H, CH3), 3.85 (s, 3 H,
OCH3), 3.99 (s, 2 H, CH2), 6.89–6.96 (m, 3 H, ArH), 7.27 (t, J = 7.6
Hz, 1 H, ArH), 7.55 (d, J = 8 Hz, 1 H, ArH), 7.73 (s, 1 H, ArH), 7.80
(d, J = 8.8 Hz, 1 H, ArH), 8.61 (s, 1 H, COC=CHN).
13C NMR (100 MHz, TFA-d): d = 33.7, 35.2, 57.9, 115.3, 115.9,
118.5, 121.8, 125.6, 125.9, 126.4, 129.6, 133.0, 133.6, 134.0, 137.5,
139.0, 144.8, 160.8, 164.2.
ESI-MS: m/z (%) = 328 [M+ + 1] (100), 329 (40).
HRMS (EI): m/z [M+] calcd for C16H10ClN3OS: 327.0233; found:
327.0236.
ESI-MS: m/z (%) = 337 [M+ + 1] (100).
6-Isopentyl-5H-thiazolo[3,2-a]pyrimidin-5-one (1m)
Brown crystals; mp 145.8–146.4 °C; Rf = 0.50 (CH2Cl2–MeOH,
16:1).
HRMS (EI): m/z [M+] calcd for C19H16N2O2S: 336.0932; found:
336.0936.
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Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 2563.
(g) Toche, R. B.; Ghotekar, B. K.; Kazi, M. A.; Kendre, D.
B.; Jachak, M. N. Tetrahedron 2007, 63, 8157. (h) Jakše,
R.; Svete, J.; Stanovnik, B.; Golobič, A. Tetrahedron 2004,
60, 4601.
Acknowledgment
We thank the National Key Technology Research & Development
Program [No: 2007BAI34B01], National Natural Science Founda-
tion of China [20676123], and Zhejiang Province Project of Sci-
ences and Technology [No: 2006C11018] for financial support.
(4) (a) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev.
2007, 36, 1581. (b) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811.
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Synthesis 2009, No. 10, 1615–1622 © Thieme Stuttgart · New York