A novel and convenient synthesis of thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones using Vilsmeier reagent

Article abstract of DOI:10.1016/j.cclet.2012.05.025

A novel route for the synthesis of thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones from acetylated 2-aminothiazoles and 2-aminopyridines under Vilsmeier conditions has been developed. The plausible mechanism has also been proposed.

Full text of DOI:10.1016/j.cclet.2012.05.025

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 911–914
www.elsevier.com/locate/cclet
A novel and convenient synthesis of thiazolo[3,2-a]pyrimidin-7-
ones and pyrido[1,2-a]pyrimidin-2-ones using Vilsmeier reagent
*
Yi Yi Weng, Lei Ming Ying, Qi Xu Chen, Wei Ke Su
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, China
Received 10 April 2012
Available online 4 July 2012
Abstract
A novel route for the synthesis of thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones from acetylated 2-
aminothiazoles and 2-aminopyridines under Vilsmeier conditions has been developed. The plausible mechanism has also been
proposed.
# 2012 Wei Ke Su. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Thiazolo[3,2-a]pyrimidin-7-ones; Pyrido[1,2-a]pyrimidin-2-ones; Bis-(trichloromethyl) carbonate; Vilsmeier–Haack reaction
In recent years, there has been increasing interest in thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-
2-ones because of their useful and important physiological properties. The thiazolo[3,2-a]pyrimidin-7-ones are
present some useful and important biologically activities, such as antifungal and anti-inflammatory [1]. On the other
hand, the pyrido[1,2-a]pyrimidin-2-ones are known to exhibit a broad range of interesting biological activities,
including anti-inflammatory [2] antiplatelet activity [3] and antibacterial activity [4].
Due to their wide range of biological activities, intensive researches have developed a lot of synthetic ways to
synthesis thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones. The methods for the preparation of
pyrido[1,2-a]pyrimidin-2-ones are via cyclization of 2-aminopyridine with ethyl cyanoacetate at high temperature and
pressure [5] or reaction of substituted fused pyrimidones from the acetates of Baylis–Hillman adducts [6]. On the other
hand, thiazolo[3,2-a]pyrimidin-7-ones can be synthesized by one-pot intramolecular cyclization 2-aminothiazole with
1-benzotriazol-1-yl-3-phenylpropynone in reflux MeCN [7] and cyclocondensation 2-aminobenzothiazoles with
acetylenic acid [8]. However, some of the methods suffer from harsh reaction conditions, longer reaction times and
difficult to prepare starting materials. Therefore, more simple, efficient conversion processes for synthesis pyrido[1,2-
a]pyrimidin-2-ones and thiazolo[3,2-a]pyrimidin-7-ones are highly desirable.
Vilsmeier-type reaction has become a useful tool for the construction of heterocycles [9–11]. In our work group,
we prepare Vilsmeier reagent from environmentally friendly bis-(trichloromethyl)carbonate (BTC, triphosgene)
and DMF that avoids the formation of inorganic phosphoric acid salts [12] and we have already reported the utilities of
the Vilsmeier reagent (DMF/BTC) in organic synthesis [13–15]. Therefore, following on our research interest in
the synthesis of valuable heterocycles with Vilsmeier reagent, we describe herein a convenient synthesis of
* Corresponding author.
E-mail address: pharmlab@zjut.edu.cn (W.K. Su).
1001-8417/$ – see front matter # 2012 Wei Ke Su. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.05.025

[(Scheme_1)TD$FIG]
912
Y.Y. Weng et al. / Chinese Chemical Letters 23 (2012) 911–914
O
N
BTC/DMF
N
O
N
H
N
ClCH2CH2Cl, 65oC, 2h
S
S
1a
2a
Scheme 1. Reaction of N-(thiazol-2-yl)acetamide (1a) under Vilsmeier conditions.
thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones from acetylated 2-aminothiazoles and 2-amino-
pyridines using Vilsmeier reagent (DMF/BTC) under mild reaction conditions.
Substrates N-(thiazol-2-yl)acetamide (1a) was easily prepared from readily available 2-aminothiazole with acetyl
chloride, pyridine as absorption agent of HCl in reflux CH2Cl2 in excellent yields. And we chose 1a as a model
compound to study its reaction behavior under Vilsmeier conditions (Scheme 1). The reaction of 1a with Vilsmeier
reagent BTC/DMF (2.0 equiv.) was first tried at room temperature. However no target product was obtained. When 1a
was treated with BTC/DMF (2.0 equiv.) at 50 8C, the mixture turned into a solution and finally turned into yellow
solid. The product was purified and it was characterized as 7H-thiazolo[3,2-a]pyrimidin-7-one (2a; 55% yield) based
on its spectral and analytical data (Table 1, entry 2). In order to optimize the reaction conditions, the reaction
temperature, solvent and the feed ratio of 1a to BTC/DMF were investigated. The best results were obtained when
reaction of 1a with 2.0 equiv. of BTC/DMF was performed at 65 8C for 2 h, which gave a yield of 2a in 77% (Table 1,
entry 3). The structures of the compounds were confirmed by NMR spectroscopy.
Encouraged by the results and the transformation 1a to 2a, we explored the scope of the substrates under the
optimized conditions (Scheme 2). As expected, most of acetylated 2-aminothiazoles worked well under the reaction
conditions (Table 2, entries 1–8). We also used acetylated 2-aminopyridines in order to form the pyrido[1,2-
a]pyrimidin-2-ones under Vilsmeier conditions. Fortunately, pyrido[1,2-a]pyrimidin-2-ones were also obtained in
moderate yields (61–73%) by using this methodology (Table 2, entries 9–l2).
According to all the results obtained, we proposed the plausible reaction mechanism for the synthesis of 7H-
thiazolo[3,2-a]pyrimidin-7-one as shown in Scheme 3. Substrate 1a is fist mediated by Vilsmeier reagent [17,18] to
form enolate A, and then the active methylene group of A undergoes formylation reaction to generate intermediate B.
Table 1
Reaction of N-(thiazol-2-yl)acetamide (1a) under Vilsmeier conditions.
Entry
Ratio of 1a:BTC:DMF
Solvent
Condition
Yield (%)
1
2
3
4
5
6
7
8
9
1:2/3:2.4
1:2/3:2.4
1:2/3:2.4
1:2/3:2.4
1:1/3:1.2
1:1:3.6
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
THF
rt, 10 h
Trance
55
50 8C, 4 h
65 8C, 2 h
Refulx, 1 h
65 8C, 2 h
65 8C, 2 h
65 8C, 2 h
40 8C, 4 h
65 8C, 2 h
77
60
55
72
1:2/3:2.4
1:2/3:2.4
1:2/3:2.4
70
CH2Cl2
59
MeCN
66
[(Scheme_2)TD$FIG]
R
R'
R'
O
N
N
R
R
O
N
H
N
N
S
BTC/DMF
ClCH2CH2Cl
S
1
2
or
or
O
R
O
N
N
N
H
3
4
R=H, CH3, Ph, 2-thienyl
R'=H, CH3
Scheme 2. Synthesis of pyrido[1,2-a]pyrimidin-2-ones and thiazolo[3,2-a]pyrimidin-7-ones by the Vilsmeier–Haack reaction of acetylated 2-
aminopyridines and 2-aminothiazoles.

Y.Y. Weng et al. / Chinese Chemical Letters 23 (2012) 911–914
913
Table 2
Synthesis of pyrido[1,2-a]pyrimidin-2-ones and thiazolo[3,2-a]pyrimidin-7-ones by the Vilsmeier–Haack reaction of acetylated 2-aminopyridines
and 2-aminothiazoles.
Entry
Product
R
Yield (%)
R
1
2
3
4
H (2a)
77
66
77
71
CH3 (2b)
Ph (2c)
2-Thienyl (2d)
N
[DT$INLE]
O
N
S
(2a~2d)
5
6
7
8
H (2e)
63
60
62
50
R
CH3 (2f)
Ph (2g)
2-Thienyl (2h)
N
[DT$INLE]
O
N
S
(2e~2h)
9
10
11
12
H (4a) [16]
CH3 (4b)
Ph (4c)
61
60
65
73
N
O
R
[DT$INLE]
N
(4a~4d)
2-Thienyl (4d)
[(Scheme_3)TD$FIG]
O
Cl
Cl
Cl3C
CCl3
N
N
+DMF
1/3
O
O
H
N
Cl
Cl
O-
N
O-
O
N
N
N
N
NH
H
H
N
O-
N
N
H
S
N
S
S
H
S
H
1a
A
B
C
N
N
N
O-
O
N
N
S
S
N
2a
D
H
Scheme 3. A plausible mechanism for the formation of 7H-thiazolo[3,2-a]pyrimidin-7-one.
After an intramolecular hydrogen transfer, B leads to formation of intermediate C, which then undergoes
intramolecular cyclization reaction to afford D. After it sheds dimethylamine, D finally can led to formation of 7H-
thiazolo[3,2-a]pyrimidin-7-one (2a).
In conclusion, the use of the Vilsmeier reagent has permitted us to develop a novel way to synthesis of thiazolo[3,2-
a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones. The synthetic protocol described in this paper provides
advantages such as readily available reagents, mild reaction conditions and simple workup.
Typical procedure: 50 mL flask containing DMF (0.61 g, 8.3 mmol) in anhydrous ClCH2CH2Cl(5 mL) at À5 8C,
bis-(trichloromethyl)carbonate (0.69 g, 2.3 mmol) was added drop by drop and the resulting mixture was stirred for
40 min at room temperature (25 8C), then N-(thiazol-2-yl)acetamide (1a) (0.5 g, 3.5 mmol) was added. The resulting
reaction mixture was heated to 65 8C for 2 h (monitored by TLC) and then cooled to room temperature. After
evaporating the solvent, the product was purified by flash chromatography to provide 2a in 77% yield.
7H-Thiazolo[3,2-a]pyrimidin-7-one (2a): Yellow solid; mp: 250.5–251.7 8C (lit.1 263–266 8C), yield 77%; 1H NMR
(400 MHz, DMSO-d6,): d 6.38 (dd, 1H, J1 = 2.0 Hz, J2 = 7.6 Hz), 7.39 (dd, 1H, J1 = 1.6 Hz, J2 = 4.4 Hz), 7.83 (dd, 1H,
J1 = 2.0 Hz, J2 = 4.8 Hz), 8.47 (dd, 1H, J1 = 2.0 Hz, J2 = 7.6 Hz); 13C NMR (100 MHz, D2O): d 112.1, 115.7, 127.1,
140.6, 165.5, 167.8; MS (ESI): m/z = 153.0 [M + 1]+; HRMS-ESI: calcd. for C6H5N2OS: 153.0123, found: 153.0120.
Acknowledgment
We are grateful to Zhejiang Key Innovation Team of Green Pharmaceutical Technology (Project No.:
2012R20043-12).

914
Y.Y. Weng et al. / Chinese Chemical Letters 23 (2012) 911–914
References
[1] D. Evans, GB1345148A (30 January 1974).
[2] J.G. Lombardino, J. Med. Chem. 24 (1981) 39.
[3] G. Roma, N. Cinone, M.D. Bracci, et al. Bioorg. Med. Chem. 8 (2000) 751.
[4] P. Brown, S. Dabbs, US20100087424 (30 October 2008).
[5] V.A. Dorokhov, S.V. Baranin, Izv. Akad. Nauk SSSR Seriya Khim. 1 (1990) 229.
[6] D. Basavaiah, T. Satyanarayana, Tetrahedron Lett. 43 (2002) 4301.
[7] A.R. Katritzky, J.W. Rogers, R.M. Witek, et al. ARKIVOC viii (2004) 52.
[8] O.P. Suri, K.A. Suri, B.D. Gupta, Synth. Commun. 32 (2002) 741.
[9] I.M. Downie, M.J. Earle, H. Heaney, et al. Tetrahedron 49 (1993) 4015.
[10] C. Jutz, in: E.C. Taylor (Ed.), Advances in Organic Chemistry in Iminium Salts in Organic Chemistry Part I, vol. 9, John Wiley, New York,
1976, p. 225.
[11] M. Damodiran, N.P. Selvam, P.T. Perumal, Tetrahedron Lett. 50 (2009) 5474.
[12] W.K. Su, Y.Y. Weng, C. Zheng, et al. Org. Prep. Proced. Int. 41 (2009) 96.
[13] W.K. Su, C. Jin, Org. Lett. 9 (2007) 993.
[14] W.K. Su, Z.H. Li, C. Zheng, J. Heterocycl. Chem. 45 (2008) 195.
[15] W.K. Su, C. Jin, J. Chen, Heterocycles 83 (2011) 153.
[16] I.J. Pachter, J. Org. Chem. 26 (1961) 4157.
[17] D.W. Dong, R. Zhang, D.Y. Zhang, et al. J. Org. Chem. 73 (2008) 9504.
[18] C.M. Marson, Tetrahedron 48 (1992) 3659.