Facile and efficient synthesis of 5, 7-disubstituted thiazolo [5,4-d] pyrimidine-4, 6 (5H, 7H)-diones

Article abstract of DOI:10.1016/j.cclet.2012.04.007

A facile and efficient approach was developed to access 5, 7-disubstitued thiazolo[5,4-d]pyrimidine-4, 6(5H, 7H)-diones through condensation of N-substituted 5-amino-4-carbethoxythiazole with structurally diverse isocyanates in the presence of sodium hydride. The easy availability of substrates and tolerance of structural diversity in this reaction make it attractive to be used for construction of libraries in drug discovery process.

Full text of DOI:10.1016/j.cclet.2012.04.007

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 695–698
www.elsevier.com/locate/cclet
Facile and efficient synthesis of 5, 7-disubstituted
thiazolo [5,4-d] pyrimidine-4, 6 (5H, 7H)-diones
Liang Chen a,b, Zhan Mei Li a,b, Jie Zhou a, Hong Rui Song b, Bai Ling Xu a,
*
a Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica Chinese Academy of Medical
Sciences & Peking Union Medical College, Beijing 100050, China
b Department of Pharmacy Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Received 23 February 2012
Available online 11 May 2012
Abstract
A facile and efficient approach was developed to access 5, 7-disubstitued thiazolo[5,4-d]pyrimidine-4, 6(5H, 7H)-diones
through condensation of N-substituted 5-amino-4-carbethoxythiazole with structurally diverse isocyanates in the presence of
sodium hydride. The easy availability of substrates and tolerance of structural diversity in this reaction make it attractive to be used
for construction of libraries in drug discovery process.
# 2012 Bai Ling Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Thiazolo[5,4-d]pyrimidine-4; 6(5H; 7H)-dione; Isocyanate; Isothiocyanate; Sodium hydride
Thiazolo[5,4-d] pyrimidine-4, 6(5H, 7H)-diones are of great medicinal interest since it can be considered as a
bioisostere of adenine, guanine and xanthinewhich are the important physiological active molecules. By now, only a few
examples have been reported on the preparation and properties of thiazolo[5,4-d] pyrimidine-4, 6(5H, 7H)-dione
derivatives. Ithasbeendemonstratedthatthiazolo[5,4-d]pyrimidinescanactasantagonistsofthevanilloid-1receptorfor
the treatment of pain [1] and inhibitors of PI3K for the treatment of cancer [2]. Several methods of preparation of
thiazolo[5,4-d]pyrimidine-4,6(5H, 7H)-diones have been developed starting either from uracil [3,4], or from 4, 5-
disubstituted thiazole derivatives [5,6]. To our best knowledge, only the synthesis of 5,7-dimethyl thiazolo[5,4-
d]pyrimidine-4, 6(5H, 7H)-dione was reported from 1,3-dimethyl uracil [7–9]. However, no examples have been
presented about the synthesis of other 5,7-disubstituted thiazolo[5,4-d]pyrimidine-4, 6(5H, 7H)-dione analogs. Herein,
we wish to present an efficient and concise approach for construction of 5,7-disubstituted thiazolo [5,4-d]pyrimidine-4,
6(5H, 7H)-dione derivatives using ethyl 5-aminothiazole-4-carboxylate as starting materials in details.
The synthetic strategy of 5,7-disubstituted thiazolo[5,4-d] pyrimidine-4, 6(5H, 7H)-dione derivatives was shown in
Scheme 1. Starting from ethyl 5-aminothiazole-4-carboxylate 1, which was prepared from ethyl 2-cyano-2-
(hydroxyimino)acetate in three steps according to the literature method [10–13], the reductive amination reaction was
successfully performed with different aldehydes or ketones in the presence of trifluoroacetic acid and sodium
triacetoxyborohydride, thus providing the N-alkylated intermediates 2 in good yields. Upon treatment of 1.0
* Corresponding author.
E-mail address: xubl@imm.ac.cn (B.L. Xu).
1001-8417/$ – see front matter # 2012 Bai Ling Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.04.007

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L. Chen et al. / Chinese Chemical Letters 23 (2012) 695–698
O
O
O
O
R2
OC2H5
X
N
S
N
S
N
S
N
N
S
OC2H5
R1
OC2H5
A
B
R2
N
R1
X
N
R1
3
N
H
NH2
N
2a R1 = CH2CH=CHPh
2b R1 = CH2Ph
2c R1 = CH(CH3)2
1
4
X = O, S
Scheme 1. Reagents and conditions: (A) R1CHO, NaBH(OAc)3, TFA, THF; (B) R2NCO or R2NCS, NaH, THF.
equivalent of N-substituted 4-amino-5-carbethoxythiazoles 2 with 3.0 equivalents of NaH for 30 min, followed by
reacted with 2.0 equivalents of isocyanates or isothiocyanates, the final products thiazolo[5,4-d]pyrimidine-4, 6(5H,
7H)-diones (4a–4k, 4n–4r) or thiazolo[5,4-d]pyrimidine-4(5H)-one-6(7H)-thione (4l and 4m) were obtained within
1 h in moderate to excellent yields (49–96%) as shown in Table 1.
Table 1
Condensation of N-substituted 5-amino-4-carbethoxythiazoles 2 with various isocyanates or isothiocyanates.a
Entry
1
Compound
R1
R2NCO/R2NCS
Time (min)
10
Yield (%)b
73
Mp (8C)
NCO
4a
CH2CH CHPh
186–187
F
NCO
2
3
4b
4c
CH2CH CHPh
CH2CH CHPh
50
10
85
83
112–113
96–97
F
NCO
CF3
NCO
4
5
6
4d
4e
4f
CH2CH CHPh
CH2CH CHPh
CH2CH CHPh
10
10
40
78
62
60
182–183
208–209
108–109
F3C
NCO
O2N
NCO
F
F
NCO
7
4g
CH2CH CHPh
6
69
108–109
O
8
9
4h
4i
CH2CH CHPh
CH2CHCHPh
NCO
40
40
71
77
114–115
108–109
NCO
S
NCO
10
11
12
4j
4k
4l
CH2CH CHPh
CH2CH CHPh
CH2CHCHPh
10
15
6
76
83
63
147–148
185–186
115–116
NCO
NCS
O
NCS
13
4m
CH2CH CHPh
15
49
246–247

L. Chen et al. / Chinese Chemical Letters 23 (2012) 695–698
697
Table 1 (Continued )
Entry
14
Compound
R1
R2NCO/R2NCS
Time (min)
15
Yield (%)b
68
Mp (8C)
NCS
4n
4o
CH2CH CHPh
232–233
F
NCO
15
CH2Ph
5
70
221–222
F
NCO
F
16
17
4p
4q
CH2Ph
50
10
62
96
235–236
103–104
NCO
CH(CH3)2
F
NCO
F
18
4r
CH(CH3)2
10
65
105–106
a
All reactions were carried out in THF at room temperature in the presence of NaH.
Isolated yields after silica gel column chromatography.
b
It was suggested that in the presence of NaH, compound 2 was condensed with isocyanates or isothiocyanates to
generate the urea anion 3, which was ready for the nucleophilic attack at the ethyloxycarbonyl group on the thiazole
ring, giving rise to the target compounds (4a–4r) after aqueous workup. It has been demonstrated that the use of NaH
was necessary to initiate the reaction due to the weak nucleophilicity of nitrogen on thiazole fragment. In the absence
of NaH, the same reaction did not take place at all.
In order to extend the scope of this reaction, a number of aldehydes, isocyanates and isothiocyanates were utilized.
Initially, cinnamaldehyde was chosen for the introduction of R1 substituent using the determined reductive amination
based on the purpose of our ongoing drug discovery project. The resulting intermediate 2a was subjected to reaction
with electron-poor (entries 1–6) or electron-rich (entries 7–9) aromatic isocyanates or alkyl isocyanates (entries 10–
11) providing the corresponding thiazolo[5,4-d]pyrimidine-4, 6(5H, 7H)-diones (4a–4k) in moderate to high yields
(60–85%). While isothiocyanates (entries 12–13) were condensed with compound 2a to produce the corresponding
thiazolo[5,4-d]pyrimidine-4(5H)-one-6(7H)-thiones (4l and 4m) in somewhat low yields (63% and 49%) in
comparison with those of compounds 4h and 4g mainly due to the lower electrophilicity of isothiocyanates. In addition
to the cinnamaldehyde, benzaldehyde and acetone were employed to broaden R1 substituent. The benzyl and isopropyl
substituted compounds 2b and 2c underwent condensation with isocyanates smoothly and afforded the corresponding
products 4n–4r in yields from 62% to 96%.
In summary, a concise and efficient protocol was developed for the synthesis of 5,7-disubstitued thiazolo[5,4-d]
pyrimidine-4, 6(5H, 7H)-diones or 5,7-disubstitued thiazolo[5,4-d]pyrimidine-4(5H)-one-6(7H)-thiones. This
approach was well tolerated to structurally diverse substrates such as aldehydes, ketones, aromatic isocyanates,
alkyl isocyanates and isothiocyanates. Therefore, it could be used to construct a library of thiazolo[5,4-d]pyrimidine-
4, 6(5H, 7H)-diones featuring a great deal of structural diversity. Further exploration of this method to our drug
discovery program is in progress.
Acknowledgments
This work is supported by the National Natural Science Foundation of China (No. 30500634) and NSF of Beijing
(No. 7102112).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/
j.cclet.2012.04.007.

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L. Chen et al. / Chinese Chemical Letters 23 (2012) 695–698
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synthesized products were characterized by 1H NMR and ESI-HRMS. For example, compound 4h: light yellow solid; 1H NMR (400 MHz,
Acetone-d6): d 8.74 (s, 1H), 7.48 (d, 2H, J = 7.6 Hz), 7.32–7.40 (m, 3H), 7.27 (t, 2H, J = 7.2 Hz), 7.15 (d, 2H, J = 7.2 Hz), 6.88 (d, 1H,
J = 16.0 Hz), 6.35–6.40 (dt, 1H, J1 = 16.0 Hz, J2 = 6.0 Hz), 4.87 (d, 2H, J = 6.0 Hz), 2.38 (s, 3H); 13C NMR (100 MHz, Acetone-d6): d
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