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Synthesis 2009(10): 1615-1622  
DOI: 10.1055/s-0028-1088051
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Regioselective Synthesis of 5H-Thiazolo[3,2-a]pyrimidin-5-ones from Morita-Baylis-Hillman Adduct Acetates under Solvent-Free and Base-Free Conditions

Weihui 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;

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Publication History

Received 2 December 2008
Publication Date:
20 April 2009 (online)

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Abstract

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 procedure under solvent-free and base-free conditions.

Key words

fused-ring systems - heterocycles - α,β-unsaturated esters - thiazol-2-amines - solvent-free - base-free

5H-Thiazolo[3,2-a]pyrimidin-5-ones are very important intermediates and widely used in pharmaceutical chemistry. [¹] The compound ritanserin (Figure  [¹] ) has been described to have significant properties as a selective serotonin (5-HT2) receptor antagonist. The starting materials in the reported synthetic routes for the 5H-thiazolo[3,2-a]pyrimidin-5-one moiety remain synthetic bottlenecks. [²] During the last decades, several other researchers have focused on the synthesis of 5H-thiazolo[3,2-a]pyrimidin-5-ones by different routes, but product yield and operational convenience have still remained a problem. [³]

Scheme 1

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 molecules in operationally simple, one-pot, and completely atom-economical procedures. [4] Baylis-Hillman adducts can be widely used in organic synthesis and pharmaceutical chemistry. [5] During our previous studies towards the exploitation of the Baylis-Hillman reaction in heterocyclic chemistry to synthesize pharmaceutically valuable intermediates, 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]

Figure 1 Structure of ritanserin

Today ‘green chemistry’ is becoming increasingly important. The synthesis of regioselective molecules is another important area, and the development of regioselective reactions that proceed under environmentally benign conditions is an extensively investigated field. [7]

Our approach to 5H-thiazolo[3,2-a]pyrimidin-5-ones 1 is summarized by the retrosynthetic analysis under consideration of ‘green chemistry’ aspects shown in Scheme  [¹] . By analogy with our previous work, 5H-thiazolo[3,2-a]pyrimidin-5-ones 1 and the relatively unstable intermediates 6-benzylidene-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-ones 10 were formed by the reaction of thiazol-2-amine (2a) with the Morita-Baylis-Hillman adduct acetates­ 8 (Scheme  [²] ).

Scheme 2 The reaction of Morita-Baylis-Hillman adduct acetates 8 with thiazol-2-amine (2a) under various conditions

Initially, the experiments were performed in ethanol solution in the presence of triethylamine with Morita-Baylis-Hillman adduct acetate 8aα (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.

Table 1 The Reaction of Morita-Baylis-Hillman Adduct Acetate 8aα (R¹ = 2-ClC6H4, R² = Me) with Thiazol-2-amine (2a) under Various Conditionsa
Entry Ratio 8aα/2a/Et3N Solvent Temp (˚C) Time (h) Yield of 10a b (%) Yield of 1a b (%)
 1 1:1:1.2 EtOH  r.t. 6 88 -
 2 1:1:1.2 EtOH  80 3 43 44c
 3 1:1:1.2 EtOH  80 5 44 49c
 4 1:1:1.2 toluene 110 3 25 55c
 5 1:1:1.2 xylene 150 3 15 36c
 6 1:1:1.2 none  r.t. 6 91 -
 7 1:1:0 none  r.t. 6 90 -
 8 1:1:0 none  80 3 43 47c
 9 1:1:0 none  80 6 25 64c
10 1:1:0 none 130 6 - 90
a See also Scheme  [²] . Reagents and conditions: 8aα (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 8aα (R¹ = 2-ClC6H4, R² = Me).
c Isolated yields after purification by column chromatography (silica gel, CH2Cl2-MeOH, 30:1).

Our previous studies indicated that solvent-free conditions may result in increased reaction efficiency. The reaction was tried under solvent-free conditions at room temperature for six hours, and a 91% yield of 10a was isolated (Table  [¹] , entry 6). Surprisingly, a similar result could also be obtained in the absence of triethylamine (entry 7); this implied that triethylamine is not essential for the reaction. To consider the steric effects on the reaction, 8aβ was used as the starting material under the same conditions, and the corresponding product 10a was formed in a yield of 65% (Table  [²] , entry 1), with an intermediate 9aβ isolated from the residue. Other substrates 8 were also investigated under these solvent-free and base-free conditions, and the corresponding products 10b-f were isolated in satisfying yields (Table  [²] , entries 2-6). When the reaction 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 extended to six hours, a higher yield of 1a (64%) was obtained (entry 9). This finding encouraged us to conduct the reaction at 130 ˚C under solvent-free and base-free conditions for six hours, and, as expected, only product 1a was isolated (90% yield) (Table  [¹] , entry 10). Thus, the transformation 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 regio­selective pathway to these pharmaceutically valuable heterocycles.

Table 2 Synthesis of 6-Benzylidene-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-ones 10 a
Entry Substrate 8 R¹ R² Product 10 Yieldb (%)
1 8aβ 2-ClC6H4 Et 10a 65c
2 8bα Ph Me 10b 91
3 8dα 4-ClC6H4 Me 10c 91
4 8eα 2-Cl-6-FC6H3 Me 10d 86
5 8fα 4-FC6H4 Me 10e 87
6 8hα 3-MeOC6H4 Me 10f 80
a See also Scheme  [²] . Reagents and conditions: 8 (1.0 mmol), 2a (1.0 mmol), no solvent, r.t., 6 h.
b Isolated yields of products 10 based on 8.
c Product 9aβ was isolated in 20% yield after column chromatography (silica gel, PE-EtOAc, 4:1).

With the optimal reaction conditions established, a representative 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 optimized conditions to produce products 1 in moderate to high yields. A range of aryl- and hetaryl-substituted substrates 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 transformation, generally providing the corresponding products 1 in good to excellent yields and regioselectivities. To investigate 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 previous studies. [6]

Table 3 Synthesis of 6-(Arylmethyl)-5H-thiazolo[3,2-a]pyrimidin-5-ones 1 a
Entry Substrate 8 R¹ R² Timeb (h) Product 1 Yieldc (% )
 1 8aα 2-ClC6H4 Me 6 1a 90
 2 8bα Ph Me 4 1b 92
 3 8cα 4-ClC6H4 Me 4 1c 82
 4 8aβ 2-ClC6H4 Et 6 1a 65
 5 8bβ Ph Et 5 1b 73
 6 8cβ 4-ClC6H4 Et 5 1c 65
 7 8dα 2-Cl-6-FC6H3 Me 3 1d 90
 8 8eα 4-FC6H4 Me 4 1e 84
 9 8fα 3-MeOC6H4 Me 4 1f 85
10 8gα 3,4-Me2C6H3 Me 3 1g 91
11 8hα 3-O2NC6H4 Me 4 1h 91
12 8iα 2-thienyl Me 6 1i 65
13 8jα 2-furyl Me 6 1j 60
14 8kα 4-methylthiazol-5-yl Me 6 1k 61
15 8lα 2-chloro-3-quinolyl Me 6 1l 62
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 products 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] .

Scheme 3 Reagents and conditions: 8m (1 equiv), 2a (1 equiv), K2CO3 (1.1 equiv), 70 ˚C, 1 h, then 130 ˚C, 3 h.

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 gives SN2′ intermediates 9, which readily isomerize into 12; cyclization follows to produce compounds 10, which, finally, via a thermo-sigmatropic proton shift provide target compounds 1.

Table 4 Reactions of Thiazol-2-amine Derivatives 2b and 2c with Acetates 8 a
Entry Substrate 8
Substrate 2
Product 10 or 1
Yieldb (%)
1c 8gα

2b

10g

89
2 8gα 2b 1n

87
3 8bα

2c

1o

82
4 8hα

2c 1p

85
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: 8gα (1 equiv), 2b (1 equiv), no solvent, no base, r.t., 6 h.

Scheme 4 Proposed mechanism for the formation of 5H-thiazolo[3,2-a]pyrimidin-5-ones

In conclusion, we have developed a simple, efficient, and ‘green’ method for the synthesis of various 5H-thiazolo[3,2-a]pyrimidin-5-ones 1 and benzylidene-6,7-dihydro-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.

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 prepared in CDCl3 or DMSO-d 6 with TMS (δ = 0) as internal standard or in TFA-d (δ = 11.5) with 1,4-dioxane (δ = 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, silica gel (200-300 mesh) purchased from Qingdao Haiyang Chemical Co., Ltd. was used. The Morita-Baylis-Hillman adduct acetates 8 [4b] and thiazol-2-amines 2 [8] were synthesized according to literature procedures.

( E )-6-Benzylidene-6,7-dihydro-5 H -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 with EtOH (2 × 5 mL), filtered, and dried in vacuo to give the corresponding pure product 10.

Ethyl ( E )-3-(2-Chlorophenyl)-2-[(thiazol-2-ylamino)methyl]acrylate (9aβ); Typical Procedure

A mixture of 8aβ (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. Concentration of the filtrate and purification of the residue by column chromatography (silica gel, PE-EtOAc, 4:1) afforded 9aβ.

6-(Arylmethyl)-5 H -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.

Ethyl ( E )-3-(2-Chlorophenyl)-2-[(thiazol-2-ylamino)methyl]acrylate (9aβ)

Pale solid; mp 125.2-126.6 ˚C; R f  = 0.40 (PE-EtOAc, 4:1).

IR (KBr): 3141, 3045, 1704, 1602, 1507, 749, 715 cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.0 Hz, 3 H, CH2CH 3), 1.62 (br, 1 H, NH), 3.72 (q, J = 7.0 Hz, 2 H, CH 2CH3), 3.98 (d, J = 1.0 Hz, 2 H, NHCH 2), 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): δ = 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: 322.0536.

( E )-6-(2-Chlorobenzylidene)-6,7-dihydro-5 H -thiazolo[3,2- a ]pyrimidin-5-one (10a)

Pale yellow solid; mp 201.7-202.5 ˚C; R f  = 0.35 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3141, 3045, 1647, 1602, 1507, 747, 718 cm-¹.

¹H NMR (500 MHz, DMSO-d 6): δ = 5.16 (s, 2 H, CH 2), 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-d 6): δ = 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: 276.0126.

( E )-6-Benzylidene-6,7-dihydro-5 H -thiazolo[3,2- a ]pyrimidin-5-one (10b)

Pale yellow solid; mp 194.7-195.8 ˚C; R f  = 0.40 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3129, 3037, 1653, 1601, 1518, 750, 692 cm-¹.

¹H NMR (500 MHz, DMSO-d 6): δ = 5.28 (s, 2 H, CH 2), 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-d 6): δ = 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: 242.0520.

( E )-6-(4-Chlorobenzylidene)-6,7-dihydro-5 H -thiazolo[3,2- a ]pyrimidin-5-one (10c)

Yellow solid; mp 228.9-229.8 ˚C; R f  = 0.30 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3137, 3062, 1634, 1591, 1482, 813 cm-¹.

¹H NMR (400 MHz, TFA-d): δ = 5.57 (s, 2 H, CH 2), 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): δ = 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.

( E )-6-(2-Chloro-6-fluorobenzylidene)-6,7-dihydro-5 H -thiazolo[3,2- a ]pyrimidin-5-one (10d)

Yellow solid; mp 235.2-235.6 ˚C; R f  = 0.35 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3136, 3094, 1655, 1609, 1505, 907, 790 cm-¹.

¹H NMR (500 MHz, DMSO-d 6): δ = 4.85 (s, 2 H, CH 2), 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-d 6): δ = 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: 294.0033.

( E )-6-(4-Fluorobenzylidene)-6,7-dihydro-5 H -thiazolo[3,2- a ]pyrimidin-5-one (10e)

Yellow solid; mp 226.3-228.5 ˚C; R f  = 0.30 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3141, 3043, 1644, 1584, 1523, 1506, 820, 705 cm-¹.

¹H NMR (500 MHz, DMSO-d 6): δ = 5.26 (s, 2 H, CH 2), 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-d 6): δ = 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: 260.0426.

( E )-6-(3-Methoxybenzylidene)-6,7-dihydro-5 H -thiazolo[3,2- a ]pyrimidin-5-one (10f)

Yellow solid; mp 192.5-193.9 ˚C; R f  = 0.30 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3106, 3043, 1638, 1586, 1524, 1507, 821, 706 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 3.81 (s, 3 H, CH 3O), 3.81 (s, 3 H, CH 2), 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-d 6): δ = 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.

ESI-MS: m/z (%) = 273.4 [M+ + 1] (100).

HRMS (EI): m/z [M+] calcd for C14H12N2O2S: 272.0619; found: 272.0624.

( E )-6-(3,4-Dimethylbenzylidene)-3-methyl-6,7-dihydro-5 H -thiazolo[3,2- a ]pyrimidin-5-one (10g)

Pale yellow solid; mp 162.3-163.7 ˚C; R f  = 0.35 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3182, 3121, 1705, 1592, 1512, 989 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 2.25 (s, 3 H, CH 3), 2.25 (s, 3 H, CH 3), 2.26 (s, 3 H, CH 3), 5.18 (s, 2 H, CH 2), 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-d 6): δ = 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.

ESI-MS: m/z (%) = 285.2 [M+ + 1] (100).

HRMS (EI): m/z [M+] calcd for C16H16N2OS: 284.0983; found: 284.0988.

6-(2-Chlorobenzyl)-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1a)

Colorless crystals; mp 201.5-202.2 ˚C; R f  = 0.35 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3108, 3072, 1645, 1630, 1496, 721 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 3.77 (s, 2 H, CH 2), 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-d 6): δ = 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.

ESI-MS: m/z (%) = 277 [M+ + 1] (100).

HRMS (EI): m/z [M+] calcd for C13H9ClN2OS: 276.0124; found: 276.0128.

6-Benzyl-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1b)

Pale yellow crystals; mp 229.9-227.5 ˚C; R f  = 0.30 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3104, 3061, 1637, 1619, 1487, 698 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 3.87 (s, 2 H, CH 2), 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).

¹³C NMR (100 MHz, DMSO-d 6): δ = 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).

HRMS (EI): m/z [M+] calcd for C13H10N2OS: 242.0514; found: 242.0519.

6-(4-Chlorobenzyl)-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1c)

Gray solid; mp 237.8-238.6 ˚C; R f  = 0.35 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3135, 3108, 1642, 1595, 1482, 794, 729, 766 cm-¹.

¹H NMR (400 MHz, TFA-d, 1,4-dioxane): δ = 3.81 (s, 2 H, CH 2), 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): δ = 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).

HRMS (EI): m/z [M+] calcd for C13H9ClN2OS: 276.0124; found: 276.0128.

6-(2-Chloro-6-fluorobenzyl)-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1d)

Pale solid; mp 239.8-240.7 ˚C; R f  = 0.30 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3156, 3046, 1645, 1618, 1490, 720 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 3.80 (s, 2 H, CH 2), 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-d 6): δ = 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.

ESI-MS: m/z (%) = 295 [M+ + 1] (100).

HRMS (EI): m/z [M+] calcd for C13H8ClFN2OS: 294.0030; found: 294.0035.

6-(4-Fluorobenzyl)-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1e)

Yellow solid; mp 241.5-242.8 ˚C; R f  = 0.30 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3113, 3067, 1638, 1614, 1484, 803 cm-¹.

¹H NMR (500 MHz, DMSO-d 6): δ = 3.66 (s, 2 H, CH 2), 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).

¹³C NMR (125 MHz, DMSO-d 6): δ = 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.

6-(3-Methoxybenzyl)-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1f)

Gray solid; mp 204.0-204.8 ˚C; R f  = 0.35 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3104, 3025, 1637, 1606, 781, 705 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 3.65 (s, 2 H, CH2), 3.73 (s, 3 H, CH 3O), 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-d 6): δ = 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.

ESI-MS: m/z (%) = 273 [M+ + 1] (100).

HRMS (EI): m/z [M+] calcd for C14H12N2O2S: 272.0619; found: 272.0623.

6-(3,4-Dimethylbenzyl)-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1g)

Pale yellow solid; mp 231.2-232.5 ˚C; R f  = 0.35 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3135, 1642, 1620, 1400, 766 cm-¹.

¹H NMR (500 MHz, DMSO-d 6): δ = 2.18 (s, 6 H, CH 3), 3.58 (s, 2 H, CH 2), 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-d 6): δ = 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: 270.0830.

6-(3-Nitrobenzyl)-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1h)

Gray solid; mp 256.2-257.2 ˚C; R f  = 0.30 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3141, 3106, 1638, 1620, 1484, 796, 735 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 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-d 6): δ = 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.

6-(2-Thienylmethyl)-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1i)

Gray solid; mp 192.5-193.2 ˚C; R f  = 0.30 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3144, 3062, 1645, 1618, 1488, 723 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 3.89 (s, 2 H, CH 2), 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).

¹³C NMR (100 MHz, DMSO-d 6): δ = 27.7, 109.9, 122.8, 124.5, 125.4, 126.0, 126.9, 133.9, 140.8, 163.8, 166.2.

ESI-MS: m/z (%) = 249 [M+ + 1] (100).

HRMS (EI): m/z [M+] calcd for C11H8N2OS2: 248.0078; found: 248.0081.

6-(2-Furylmethyl)-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1j)

Orange solid; mp 179.2-180.9 ˚C; R f  = 0.30 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3135, 3041, 1643, 1609, 1520, 735 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 3.72 (s, 2 H, CH 2), 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-d 6): δ = 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: 232.0311.

6-[(4-Methylthiazol-5-yl)methyl]-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1k)

Gray solid; mp 255.4-256.3 ˚C; R f  = 0.25 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3137, 3038, 1646, 1616, 1488, 766 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 2.37 (s, 3 H, CH 3), 3.83 (s, 2 H, CH 2), 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-d 6): δ = 14.7, 24.4, 109.9, 122.2, 125.4, 127.4, 133.7, 149.5, 150.9, 163.9, 166.1.

ESI-MS: m/z (%) 264 [M+ + 1] (100).

HRMS (EI): m/z [M+] calcd for C11H9N3OS2: 263.0187; found: 263.0191.

6-[(2-Chloro-3-quinolyl)methyl]-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1l)

Yellow solid; mp >300 ˚C; R f  = 0.20 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3142, 3049, 1638, 1607, 1476, 758 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 3.93 (s, 2 H, CH 2), 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-d 6): δ = 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.

ESI-MS: m/z (%) = 328 [M+ + 1] (100), 329 (40).

HRMS (EI): m/z [M+] calcd for C16H10ClN3OS: 327.0233; found: 327.0236.

6-Isopentyl-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1m)

Brown crystals; mp 145.8-146.4 ˚C; R f  = 0.50 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3139, 2956, 1638, 1608, 1474 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 0.88 (s, 6 H, CH 3), 1.43 (q, J = 8 Hz, 2 H, (CH3)2CHCH 2), 1.55-1.60 (m, 1 H, (CH3)2CH), 2.46 (t, J = 8 Hz, 2 H, CH 2), 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, CDCl3): δ = 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 (%) = 223 [M+ + 1] (100).

HRMS (EI): m/z [M+] calcd for C11H14N2OS: 222.0827; found: 222.0830.

6-(3,4-Dimethylbenzyl)-3-methyl-5 H -thiazolo[3,2- a ]pyrimidin-5-one (1n)

Yellow crystals; mp 201.4-203.1 ˚C; R f  = 0.25 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3170, 313102, 1638, 1605, 1487, 773 cm-¹.

¹H NMR (400 MHz, DMSO-d 6): δ = 2.15 (s, 3 H, CH 3), 2.16 (d, J = 7.5 Hz, 3 H, CH 3), 2.36 (d, J = 7.5 Hz, 3 H, CH 3), 3.62 (s, 2 H, CH 2), 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-d 6): δ = 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: 284.0986.

3-Benzyl-8-methyl-4 H -benzothiazolo[3,2- a ]pyrimidine-4-one (1o)

Green solid; mp 280.6-282.1 ˚C; R f  = 0.20 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3089, 1702, 1639, 1493, 702 cm-¹.

¹H NMR (400 MHz, TFA-d): δ = 2.47 (s, 3 H, CH 3), 3.99 (s, 2 H, CH 2), 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): δ = 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 (%) = 307 [M+ + 1] (100).

HRMS (EI): m/z [M+] calcd for C18H14N2OS: 306.0827; found: 306.0830.

3-(3-Methoxybenzyl)-8-methyl-4 H -benzothiazolo[3,2- a ]pyrimidine-4-one (1p)

Pale green solid; mp 226.0-227.2 ˚C; R f  = 0.25 (CH2Cl2-MeOH, 16:1).

IR (KBr): 3103, 3055, 1641, 1582, 1508, 823, 778 cm-¹.

¹H NMR (400 MHz, TFA-d): δ = 2.47 (s, 3 H, CH 3), 3.85 (s, 3 H, OCH 3), 3.99 (s, 2 H, CH 2), 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): δ = 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 (%) = 337 [M+ + 1] (100).

HRMS (EI): m/z [M+] calcd for C19H16N2O2S: 336.0932; found: 336.0936.

Acknowledgment

We thank the National Key Technology Research & Development Program [No: 2007BAI34B01], National Natural Science Foundation of China [20676123], and Zhejiang Province Project of Sciences and Technology [No: 2006C11018] for financial support.

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Scheme 1

Figure 1 Structure of ritanserin

Scheme 2 The reaction of Morita-Baylis-Hillman adduct acetates 8 with thiazol-2-amine (2a) under various conditions

Scheme 3 Reagents and conditions: 8m (1 equiv), 2a (1 equiv), K2CO3 (1.1 equiv), 70 ˚C, 1 h, then 130 ˚C, 3 h.

Scheme 4 Proposed mechanism for the formation of 5H-thiazolo[3,2-a]pyrimidin-5-ones