3816
S. Singh et al. / Tetrahedron Letters 52 (2011) 3814–3817
Table 2
The corresponding thiazolo[3,2-a]pyrimidine derivatives 3 were
obtained in a synthetically useful manner using the one-pot reac-
tion strategy (Table 2 and 3). All received products were purified
by flash chromatography using silica columns with ethyl acetate/
hexane 20:80) eluent. All purified compounds were carefully char-
acterized by IR, 1H NMR, 13C NMR, LC–MS and HR-MS analyses (see
Supplementary data for details).
Reactions of 5-ethoxycorbonyl-6-methyl-4-phenyl-3,4-dihydro-2(1H)-pyrimidin-
2-thione 1a with Br2/enolizable ketones
O
O
Ph
R1
O
Ph
R2
(2 eq.)
R1
EtO
NH
EtO
N
Br2/Et3N(2 eq.)
80 oC/DCE/2h
R2
S
N
H
S
N
1a
3a-h
3. Summary
Entry
Ketone
Product
R1
R2
Isolated
yield (%)
In summary, we developed a convenient and selective one-pot
method for the synthesis of 5H-thiazolo[3,2-a]pyrimidine deriva-
tives by exploiting the reaction of in-situ formed a-brominated ke-
tones with dihydropyrimidine-2-thiones of type 1. Moreover, the
possibility of introducing a variety of substituents at different posi-
tions of the thiazolo[3,2-a]pyrimidine ring system was achieved by
this method. The presented method delivers new screening candi-
dates in an easy way and is well suited for robotic synthesis. The
achievable 5H-thiazolo[3,2-a]pyrimidine derivatives may help in
the understanding of the privileged nature of the DHPM core.
1
2
3
4
5
6
7
8
9
2-Butanone
3a
Me
Et
Me
H
Pr
H
–COMe
–COOEt
83
67
30
82
65
72
70
75
69
1-Bromo-2-butanonea
2-Hexanone
3a0
3b
3c
3d
3e
3f
Me
Me
Me
Me
Me
Me
Acetoneb
Acetylacetone
Ethylacetoacetate
Benzylacetoacetate
2,5-Hexadinone
Cyclohexanone
–COOBn
–CH2COMe
3g
3h
–CH2CH2CH2CH2–
a
Reaction was performed in acetone using K2CO3 as the base.
Reaction was performed in acetone as the solvent and the reactant.
b
Acknowledgments
2,5-hexadione was executed and the corresponding product 3g
was obtained in 75% isolated yield. When cyclohexanone was used
the tricyclic product 3h was isolated in 69% yield.
This work was generously supported by Federal Ministry of
Education and Research, Germany (BMBF) (FKZ16SV3701) and
Thuringian Ministry of Culture (FKZ 03ZIK062, FKZ 03ZIK465, FKZ
B714-09064). We thank Katrin Risch and Susan Günther for carry-
ing out spectroscopic analysis.
The scope of the optimized method was further extended by
implementing it on various C4-substituted DHPMs with electron
releasing and withdrawing substituents (Table 3). In this case ace-
tone was used as the ketone of choice and reaction was performed
in acetone as the solvent as well. This method is efficient for most
of the substances used and furnishes the desired product in good
yields. However in the case of ortho-NO2 (1h) and 2,4-Cl2Ph (1k)
substituted DHPM-C4 phenyl, the desired product could not be ob-
tained. While other ortho substituted DHPM-C4 phenyl, such as
2,4-(OMe)2Ph (1c); 2,6-Cl2Ph (1j); could yield the corresponding
product 3j and 3q in 78% and 79% isolated yields, respectively.
Therefore the reaction failure seems not to be due to the steric hin-
drance at the ortho position. In another example (Table 3; entry
11) where 2-thiophene substituted DHPM (1l) was used as the pre-
cursor, the desired product 3s was obtained in high yield (82%). In
order to check the scope of this method for a large scale produc-
tion, an independent experiment in a 50 mL volume vial under stir-
ring conditions was performed. A reaction of 1 g DHPM (1a) with
acetone under a similar set of conditions (Table 2; entry 4) fur-
nishes the required 3c (984 mg) in 86% yield.
Supplementary data
Supplementary data (experimental procedures, analytical char-
acterization data and copy of 1H/13C NMR spectra) associated with
this article can be found, in the online version, at doi:10.1016/
References and notes
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Table 3
Conversion of C4-substituent DHPM derivatives
O
R1
O
R1
N
Acetone/Br2/Et3N
80 oC/30 min.
EtO
NH
EtO
N
S
N
H
1b-m
S
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3i-r
Entry
DHPM 1
R1
Product 3
Isolated yield (%)
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1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
4-OMe-C6H4
2,4-(OMe)2-C6H3
3,4,5-(OMe)3-C6H2
2,3-(OMe)2-C6H3
3-OMe-C6H4
4-NO2-C6H4
3i
3j
84
78
72
70
77
67
-
71
79
-
3k
3l
3m
3n
-
2-NO2-C6H4
4-Br-C6H4
3o
3p
-
3q
3r
9
1j
1k
1l
2,6-Cl2-C6H3
2,4-Cl2-C6H3
2-Thiophene
4-NMe2-C6H4
10
11
12
82
69
9. Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.;
Mitchison, T. J. Science 1999, 286, 971–974.
1m