Scientific paper
A Convenient Synthesis of Some New Bioactive Diheterocylic Thioether and Thiazolopyrimidine Derivatives
Mohamed Abdel-Megid,1* Mohamed Awas,1 Magdy Seada,1 Kamelia Elmahdy1 and Mortta El-Sayed2
1 Chemistry Department, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt 2 Environmental Research Laboratory, Theodor Bilharz Research Institute * Corresponding author: E-mail: mabdelmegid@yahoo.com
Received: 18-01-2009
Abstract
2-Carbethoxymethylthiopyrimidinone derivative 1b was utilized for the synthesis of some new diheterocyclic thioethers via its reaction with some acetals followed by cyclization of the products with 2-aminoheterocyclic compounds or through the reaction of 1b with p-tolyldiazonium chloride followed by the reaction of the product with active methylene compounds. Also, some new thiazolopyrimidines were synthesized from 2-mercaptopyrimidine 1a or from 5-pyrimi-dinylmercaptoacetic acid derivative 1c. The molluscicidal activity of some synthesized compounds towards Biomphala-ria alexandrina snails, the intermediate host of Schistosoma mansoni, was investigated.
Keywords: Diheterocyclic thioethers, thiazolopyrimidines, molluscicidal activity.
1. Introduction
Schistosomiasis, commonly known as bilharzias, is a parasitic disease caused by threadworms of the genus schistosoma and is endemic throughout South America, Africa and the Far East. The reproductive cycle of schistosoma involves a stage implicating aquatic snails of the genus Biomphalaria and Bulinus in which the parasite multiples into cercariae. These cercariae can penetrate the skin of a human who comes into contact with contaminated water. Thus, the habits of Egyptian farmers being in daily contact with the Nile water canals and streams during irrigation process cause Schistosomiasis to still represent one of the main national health problems in Egypt. Great national and international efforts are being done to combat this disease. Therefore, snails control by mollusci-cidal agents is considered essential in schistosomal control. Copper sulphate and miclosamide were used in Egypt within a program developed by Bayer AG, however, due to their hazardous environmental effects,1 the program was stopped. Therefore, the search for synthetic or naturally occurring molluscicides is still ongoing. Pre-
viously, as a part of our program directed towards syntheses of some new heterocyclic systems, we have tested pyrazole derivatives, pyrazolopyrimidines,2 and indole de-rivatives3 as mollouscicidal agents against Biomphalaria alexandrina snails. The present work explores some novel pyrimidinyl heterocyclic thioethers and thiazolopyrimidi-nes and tests some of them as molluscicidal agents.
2. Results and Discussion
The reactivity of thiols is in most instances sufficient to achieve the direct replacement of halides without catalyst resulting in the formation of an aryl sulfur bond.4 The synthesis of bispyrimidine thioethers has been accomplished previously through direct nucleophilic attack of a thiolate anion on a pyrimidine halide5-8 using Pd (PPh3)4 as a catalyst. Previously, we reported the synthesis of pyrimidinyl pyridyl thioether and pyrimidinyl phthala-zinyl thioether from the reaction of 4(3^)-pyrimidinethio-ne with 2-chloropyridine derivative and 1-chlorophthala-zine derivative, respectively.9 The present investigation deals with the synthesis of some pyrimidinyl heterocyclic
thioethers via a new route different than the reaction between thiols and heterocyclic halides.
It has been reported that pyrimidinethiols are readily alkylated on the exocyclic sulphur atom when treated with haloesters and haloacids in basic medium. Thus, when 4-(4-methoxyphenyl)-6-oxo-2-sulfanyl-1,6-dihydro-5-pyrimidine carbonitrile (1a)10 was allowed to react with ethyl chloroacetate and with chloroacetic acid in ethanolic potassium hydroxide solution, ethyl {[5-cyano-4-(4-met-hoxyphenyl)-6-oxo-1,6-dihydro-2-pyrimidinyl]sulfanyl} acetate (1b) and 2-carboxymethylthiopyrimidine derivative 1c11 were obtained, respectively. Compound 1c was also obtained from alkaline hydrolysis of 1b.
NH COOEt
sA
a,R=	H: Ar=4-MeOC6Hj
b,R=	CHjCOOEtiAr^ 4-MeOCgH^
c,R=	CH^COOH; Ar= 4-MeOC6H^
R
a,R=	Me; Ar=4-MeOCeH4
b,R=	COMe;Ar= 4-MeOCeH,
c,R=	NMSji Ar= 4-MeOC5H4
Structures of compounds 1a,b were elucidated with the help of elemental analysis and spectral data. The 1H NMR spectra (DMSO-rf6) of 1b revealed the presence of one triplet and one quartet signal at 5 1.12 and 4.13 ppm
N-N
H	'
2c.

NC
NH
N-N
AJ
N' "N H
' -I -N
Schema 1
attributed to CH3CH2 of ethyl ester, while that of compound 1c revealed the absence of these two signals. Condensation of the active methylene compound 1b with some acetals such as acetaldehyde diethylacetal, pyruval-dehyde dimethylacetal and dimethylformamide dimethy-lacetal in apolar solvents (toluene or xylene) yielded ethyl pyrimidin-2-yl thiobutenoate 2a, ethyl pyrimidin-2-yl thiopentanenoate 2b and pyrimidin-2-ylthio(dimethyla-mino)arylate 2c.
Structure of compounds 2a-c was confirmed on the basis of elemental analyses and spectral data. The mass spectrometry of the enaminone 2c did not exhibit a molecular ion peak but it showed a peak at m/z 372 attributed to M-CO. The 1H NMR of 2c furnished a signal at 5 3.19 ppm for six protons of dimethylamino group. When the
Schema 2
enaminone 2c was allowed to react with 3-amino-1,2,4-triazole (3) and with 2-aminobenzothiazole (4) in boiling acetic acid, the thioethers 5 and 6, were obtained, respectively (Scheme 1). The mass spectrometry of 6 showed a molecular ion peak at m/z 459.
On the other hand, compound 2b with its active methylene group was readily coupled with p-tolyldiazo-nium chloride 7 to afford 2-carbethoxy^-tolylhydrazo-no)methylthiopyrimidine 8. Treatment of 8 with ethyl cyanoacetate in benzene and ammonium acetate mixture yielded a thioether with two possible structures: either 9 or 10. Compound 10 was ruled out based on the 1H NMR spectrum (DMSO-rf6) which revealed the absence of a triplet and quartet signals of ethyl ester. The trial to prepare another 3-pyridazinyl-2-pyrimidinyl thioether 12 from the reaction of the hydrazone 8 with malononitrile failed, however the Michael adduct 11 was obtained (Scheme 2) as clearly shown by its 1H NMR spectrum (DMSO-rf6) exhibiting signals at 5 1.12 and 4.11 ppm attributed to CH3 and CH2 protons of ethyl ester group.
reas its isomer 1416 was formed when compound 1c was boiled in acetic anhydride, sodium acetate and acetic acid mixture (Scheme 3). Alkylation of 1a with chloroacetoni-trile in boiling ethanol containing triethyl amine afforded 3-aminothiazolopyrimidine 15; whereas the reaction of 1a with dioxalyl chloride gave 2,3,5-trioxothiazolopyrimidi-ne 16 (Scheme 3).
The presence of an active methylene group in compound 14 was exploited via its ability to couple with p-tolyldiazonium chloride leading to the formation of hydrazono compound 17. The mass spectrum of 17 showed a molecular ion peak at m/z 417. Also, condensation of 14 with benzaldehyde confirmed the presence of an active methylene group in 14 and led to the formation of 2-benzylidenethiazolopyrimidine derivative 18. Assignment of the structure 18 was established via its alternative synthesis from 1a and benzaldehyde, monochloroacetic acid, acetic anhydride, acetic acid and sodium acetate.
Moreover, the reactivity of the cyclic enone moiety in compound 18 towards bifunctional nucleophiles such
Schema 3
Also, in continuation of our work on the chemistry of pyrimidines,12-13 and thiazoles,14-15 it was of interest to combine thiazole and pyrimidine moieties in a molecular framework to study their potential molluscicidal activity. Thus, some new thiazolopyrimidines were synthesized from 2-mercaptopyrimidine 1a or from 5-pyrimidinemer-captoacetic acid 1c. Therefore, thiazolopyrimidine 13 was obtained on reacting 1a with chloroacetyl chloride whe-
as phenylhydrazine and thiourea is a good support for its structure. Thus, when compound 18 was allowed to react with phenylhydrazine, the pyrazolothiazolopyrimidinone
19	was obtained, whereas pyrimidothiazolopyrimidinone
20	was formed via cyclocondensation of 18 with thiourea in boiling ethanol containing catalytic amount of piperidi-ne. Further, treatment of 18 with malononitrile in basic medium furnished the pyranothiazolopyrimidine 21. The
Schema 4
latter compound is also obtained on reacting 14 with a-cyanocinnamonitrile in boiling pyridine.
2. 1. Molluscicidal Activity
A stock solution of 1000 ppm of each tested compound was separately prepared using dechlorinated tap water on the basis of weight/volume, with the pH of water 7-7.7 and at temperature 25-27 °C. Series of 6 concentrations expressed in terms of ppm would permit to calculate the half and nearly full-lethal doses LC50 and LC90 according to Litchfield and Wilcexon method.17 The snails were exposed to each concentration for 24 h followed by 24 h recovery period in only dechlorinated water. The molluscicidal activity of some novel thioethers and thia-zolopyrimidine derivatives against Biomphalaria alexandrina snails is shown in Table 1.
Table 2: Susceptibility of Biomphalaria alexandrina snails to certain compounds after 24 and 48 h.
Compound Time (h)		LC50 ppm	LC90 ppm S (slope)
18	24	42 (32.95-53.82)	73 1.32
	48	40 (28.54-50.91)	70 1.31
20	24	44 (32.89-58.43)	70 1.31
	48	41 (29.75-49.82)	68 1.26
The results showed that the introduction of arylide-ne moiety to the thiazolopyrimidine or another pyrimidi-nethione moiety to thiazolopyrimidine led to an increase in the mollouscicidal activity. Also, the presence of sulfur in their structures enhances the mollouscicidal activity compared with that shown in the case of our previous studies on pyrazolopyrimidines2 and indole derivati-
ves.3
Table 1: The molluscicidal activity of some new synthesized compounds
Compound			Concentration (ppm)			
	200	100	75	50	20	10
1a	0	0	0	0	0	0
1b	0	0	0	0	0	0
13	50	10	0	0	0	0
15	0	0	0	0	0	0
17	0	0	0	0	0	0
18	100	100	80	40	20	0
20	100	60	10	0	0	0
21	0	0	0	0	0	0
3. Experimental
All reported melting points are uncorrected. The IR spectra were recorded on FTIR Bruker Vector 22 spectrophotometer using KBr wafer technique. 1H NMR spectra were measured on Varian Gemini spectrophotometer 200 MHz using TMS (5 ppm) as an internal standard. Mass spectra were obtained using GCMS Qp 1000 ex Schimadzu instrument (70 eV). Elemental analyses were carried out at Microanalysis center, Cairo University.
4-(4-Methoxyphenyl)-6-oxo-2-sulfanyl-1,6-dihydro-5-pyrimidine carbonitrile (1a). This compound was prepared using the reported method.10
Ethyl {[5-cyano-4-(4-methoxyphenyl)-6-oxo-1,6-dihy-dro-2-pyrimidinyl]sulfanyl}acetate (1b).11 A mixture of 1a (10 mmol) and ethyl chloroacetate (15 mmol) in etha-nolic potassium hydroxide solution (prepared by dissolving 0.56 g (10 mmol) of KOH in 50 mL ethanol) was heated under reflux for 5 h. The reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained was filtered off and recrystallized from ethanol. Yield 78%, mp 180-182 °C, yellow crystals. IR (KBr) v 3488 (NH), 3030 (aromatic CH), 2982 (aliphatic CH), 2221 (CN), 1738 (C=O of ester), 1653 (C=O of cyclic amide), 1599, 1554 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-rf6) 5 1.12 (t, J = 7.5 Hz, 3H, CH3 of ethyl ester), 3.36 (s, 2H, SCH2CO), 3.86 (s, 3H, OCH3), 4.13 (q, J = 7.5 Hz, 2H, CH2 of ethyl ester), 7.99-8.09 (m, 4H, ArH), 8.27 (s, 1H, NU). MS m/z 345 (M, 2), 301 (M-CO2, 1), 228 (100%). Anal. Calcd for C16H15N3O4S: C, 55.6^; H, 4.34; N, 12.17; S, 9.27. Found: C, ^5.40; H, 4.30; N, 12.19; S, 9.22.
{[5-Cyano-4-(4-methoxyphenyl)-6-oxo-1,6-dihydro-2-pyrimidinyl]sulfanyl}acetic acid (1c).11 Method A: A
mixture of 1a (10 mmol) and chloroacetic acid (10 mmol) in ethanolic potassium hydroxide solution (prepared by dissolving 0.56 g (10 mmol) of KOH in 50 mL ethanol) was heated under reflux for 5 h. The solid obtained upon dilution with water was filtered off and recrystallized from methanol. Yield 65%, mp 208-210 °C.
Method B: A mixture of 1b (30 mmol) and aqueous sodium hydroxide (100 mL, 2.0 M NaOH) was heated under reflux for 2 h, then filtered while hot. The filtrate was acidified with hydrochloric acid and the solid formed was filtered off. The crude material was purified by dissolving in aqueous sodium carbonate and then reprecipitated using hydrochloric acid. The solid obtained was filtered off and recrystallized from methanol. Yield 75%, mp 208-210 °C, yellow crystals. IR (KBr) v 3600-3250 (broad OH), 3100 (NH), 3015 (aromatic CH), 2978 (aliphatic CH), 2222 (CN), 1715 (C=O of carboxylic group), 1668 (C=O of cyclic amide), 1600, 1536 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-dg) 5 3.88 (s, 3H, OCH3), 4.07 (s, 2H, CH2), 7.20-8.04 (m, 5H, ArH, NH), 8.33 (s, 1H, OH). MS m/z 317 (M, 6), 273 (M-CO2), 229 (100%). Anal. Calcd for C14H11N3O4S: C, 52.99; H, 3.47; N, 13.24; S, 10.09. Found: C, 52.445; H, 3.43; N, 13.30; S, 10.40.
Reaction of 1b with acetals; formation of 2a-c. To
a solution of 1b (10 mmol) in dry xylene (15 mL) acetal-dehyde diethyl acetal, pyruvaldehyde dimethyl acetal or dimethylformamide dimethyl acetal (0.01 mol) was added. The reaction mixture was heated under refluxed for 3
h. The solid obtained on evaporation of the excess solvent was filtered off and recrystallized from methanol to produce 2a-c.
Ethyl 2-{[5-cyano-4-(4-methoxyphenyl)-6-oxo-1,6-di-hydro-2-pyrimidinyl]sulfanyl}-2-butenoate (2a). Yield 72%, mp 210-212 °C, colourless crystals. IR (KBr) v 3311 (NH), 3010 (aromatic CH), 2937 (aliphatic CH), 2216 (CN), 1736 (C=O of ester), 1661 (C=O of cyclic amide), 1604, 1548 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-dg) 5 1.12 (t, J = 7.5 Hz, 3H, CH3 of ethyl ester), 2.08 (s, 3H, CH3 of ethylidene group), 3.^5 (s, 3H, OCH3), 4.10 (q, J = 7.5 Hz, 2H, CH2 of ethyl ester), 7.09-7.12 (m, 4H, ArH), 7.95 (s, 1H, olefinic CH), 7.98 (s, 1H, NH). MS m/z 371 (M, 2), 340 (1), 228 (100%). Anal. Calcd for C18H17N3O4S: C, 58.22; H, 4.58; N, 11.32. Found: C, 58.30; H, 4.^0; N, 11.10.
Ethyl 2-{[5-cyano-4-(4-methoxyphenyl)-6-oxo-1,6-di-hydro-2-pyrimidinyl]sulfanyl}-4-oxo-2-pentenoate (2b). Yield 58%, mp 204-206 °C, colourless crystals. IR (KBr) v 3442 (NH), 3005 (aromatic CH), 2971 (aliphatic CH), 2208 (CN), 1731, 1700 (C=O of ester and acetyl), 1660 (C=O of cyclic amide), 1600, 1571 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-dg) 5 1.12 (t, J = 7.4 Hz, 3H, CH3 of ethyl ester), 2.49 (s, 3H, CH3CO), 3.85 (s, 3H, OCH3), 4.12 (q, J = 7.4 Hz, 2H, CH2 of ethyl ester), 7.09-7.12 (m, 4H, ArH), 7.96 (s, 1H, olejfinic CH), 7.98 (s, 1H, NH). MS m/z 339 (M, 9), 356 (12), 229 (100%). Anal. Calcd for C15H17N3O5S: C, 57.14; H, 4.26; N, 10.52. Found: C, 57.25; H, 4.30; N, 10.60.
Ethyl 2-{[5-cyano-4-(4-methoxyphenyl)-6-oxo-1,6-di-hydro-2-pyrimidinyl]sulfanyl}-3-(dimethylamino)-2-propenoate (2c). Yield 60%, mp 110-112 °C, yellow crystals. IR (KBr) v 3394 (NH), 3020 (aromatic CH), 2936 (aliphatic CH), 2206 (CN), 1734 (C=O of ester), 1654 (C=O of cyclic amide), 1607, 1588 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-dg) 5 1.12 (t, J = 7.4 Hz, 3H, CH3 of ethyl ester), 3.19 (s, 6H, 2CH3 of ^,^-dimethyla-mino group), 3.72 (s, 3H, OCH3), 4.2^ (q, J = 7.4 Hz, 2H, CH2 of ethyl ester), 6.98-7.13 (m, 4H, ArH), 7.77 (s, 1H, olefinic CH), 7.80 (s, 1H, NH). MS m/z 372 (M-CO, 1), 242 (C11H4N3O2S, 100%), 303 (2), 270 (35), 214 (28), 200 (81), 159 (59), 148 (44). Anal. Calcd for C19H20N4O4S: C, 56.99; H, 5.03; N, 13.99; S, 8.01. Found: C1 57.304 H, 4.94; N, 13.91; S, 8.11.
4-(4-Methoxyphenyl)-6-oxo-2-[(7-oxo-3,7-dihydro [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)sulfanyl]-1,6-dihy-dro-5-pyrimidinecarbonitrile (5). A mixture of 2c (10 mmol) and 2-aminotriazole (3) (10 mmol) in acetic acid (5 mL) was refluxed for 2 h. The solid obtained was filtered off and recrystallized from butan-1-ol. Yield 55%, mp 312-314 °C, yellow crystals. IR (KBr) v 3337, 3211 (NH), 3060 (aromatic CH), 2929 (aliphatic CH), 2215
(CN), 1700, 1655 (C=O), 1599, 1550 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-rf6) 5 3.84 (s, 3H, OCH3),
7.07-7.89	(m, 8H, ArH, C2-H, C7-H, 2 x NH). MS m/z 393 (M, 2), 339. Anal. Calc;d for C17H11N7O3S: C, 51.90; H, 2.79; N, 24.93. Found: C, 51.46; H, ^.83; N, 24.80.
4-(4-Methoxyphenyl)-6-oxo-2-[(4-oxo-4H-pyrimi-do[2,1-^][1,3]benzothiazol-3-yl)sulfanyl]-1,6-dihydro-
5-pyrimidinecarbonitrile	(6). A mixture of 2c (1 mmol) and 2-aminobenzothiazole (4) (1 mmol) in acetic acid (5 mL) was refluxed for 2.5 h. The solid obtained was filtered off and recrystallized from DMF. Yield 60%, mp > 320 °C, colourless crystals. IR (KBr) v 3422 (NH), 3069 (aromatic CH), 2968 (aliphatic CH), 2221 (CN), 1710, 1650 (C=O), 1606, 1573 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-rfg) 5 3.75 (s, 3H, OCH3), 6.89 (m, 10H, Ar-H, NH). MS m/z 459 (M, 2), 84 (C3H4N20,100), 383 (6), 313 (11), 264 (12), 213 (15), 157 (13), 129 (36), 55 (93%). Anal. Calcd for C22H13N5O3S2: C, 57.51; H, 2.83; N, 15.25; S, 13.94. Found: C, 57.95; 2.89; N, 15.47; S, 13.75.
Ethyl {[5-cyano-4-(4-methoxyphenyl)-6-oxo-1,6-dihy-dro-2-pyrimidinyl]sulfanyl}[(4-methylphenyl) hydra-zono]ethanoate (8). To a cold solution of compound 1b (10 mmol) in ethanol (80 mL), containing sodium acetate (2 g) was added p-tolyl diazonium chloride (7) [prepared by adding concentrated hydrochloric acid (3 mL) to p-to-luidine (10 mmol) at 0-5 °C and treating the resulting hydrochloride solution with a cold solution of sodium nitrite (10 mmol) in water (5 mL)] dropwise with stirring at 0-5 °C. The reaction mixture was stirred at room temperature for 2 h and then diluted with (30 mL) water. The solid obtained was filtered off and recrystallized from methanol. Yield 68%, mp 200-202 °C, orange crystals. IR (KBr) v 3468, 3295 (NH), 3060 (aromatic CH), 2979 (aliphatic CH), 2218 (CN), 1741 (C=O of ester), 1653 (C=O of cyclic amide), 1599, 1556 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-d6) 5 1.12 (t, J = 7.3 Hz, 3H, CH3 of ethyl ester), 3.30 (s, 3H, CH3 of p-tolyl), 3.85 (s, 3H, 0CH3), 4.11 (q, J = 7.3 Hz, 2H, CH2 of ethyl ester),
7.08-7.98	(m, 10H, ArH, 2 x NH). MS m/z 463 (M, 4), 419 (6), 373 (14), 229 (100%). Anal. Calcd for C23H21N504S: C, 59.61; H, 4.53; N, 15.11; S, 6.91. Found: C, 59.33; H, 4.50; N, 15.17; S, 6.74.
6-{[5-Cyano-4-(4-methoxyphenyl)-6-oxo-1,6-dihydro-2-pyrimidinyl]sulfanyl}-3-hydroxy-2-(4-methylp-henyl)-5-oxo-2,5-dihydro-4-pyridazinecarbonitrile (9).
A suspension of 8 (1 mmol), ethyl cyanoacetate (1 mmol) in benzene (30 mL) and ammonium acetate (1.0 g) was heated at 180 °C for 5 min. The reaction mixture was left overnight at room temperature and then triturated with et-hanol. The solid obtained was filtered off and recrystalli-zed from ethanol. Yield 60%, mp 215-217 °C, colourless crystals. IR (KBr) v 3250, 3177, 3100 (NH2, NH), 3005
(aromatic CH), 2937 (aliphatic CH), 2207 (CN), 1740 (C=O of ester), 1680, 1655 (C=O), 1604, 1550 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-dg) 5 1.13 (t, J =
7.4	Hz, 3H, CH3 of ethyl ester), 2.50 (s, 63H, CH3 of p-tolyl), 3.64 (s, br, 2H, NH2), 3.86 (s, 3H, OCH3), 4.10 (q, J = 7.4 Hz, 2H, CH2 of ejthyl ester), 7.08-7.99 (m, 9H, ArH, NH). MS m/z 530 (M, 1), 489 (7), 442 (2), 314 (100%). Anal. Calcd for C^^H^^N^OjS: C, 58.86; H, 4.15; N, 15.84; S, 6.03. Found: C, 58.63; H, 4.22; N, 15.54; S, 6.40.
Ethyl [(2-Cyanoethanimidoyl)(4-methylphenyl)hydra-zono]{[5-cyano-4-(4-methoxyphenyl)-6-oxo-1,6-dihy-dro-2-pyrimidinyl]sulfanyl}ethanoate (11). A suspension of 8 (1 mmol), malononitrile (1 mmol) in benzene (30 mL) and ammonium acetate (1.0 g) was heated at 180 °C for 5 min. The reaction mixture was left overnight at room temperature and then triturated with ethanol. The solid obtained was filtered off and recrystallized from et-hanol. Yield 58%, mp 218-219 °C, yellow crystals. IR (KBr) v 3453, 3220 (NH), 3004 (aromatic CH), 2970 (aliphatic CH), 2220, 2208 (CN), 1750 (C=O of ester), 1651 (C=O of cyclic amide), 1602, 1550 cm-1 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-dg) 5 1.12 (t, J =
7.5	Hz, 3H, CH3 of ethyl ester), 2.07 (s, 63H, CH3 of p-tolyl), 3.29 (s, br, 2H, NH2), 3.85 (s, 3H, OCH3), 4.11 (q, J = 7.5 Hz, 2H, CH2 of ethyl ester), 7.07-7.9^ (m, 10H, ArH, =CH, NH). MS m/z 529 (M, 28), 497 (16), 441 (12), 228 (100%). Anal. Calcd for C2gH23N7O4S: C, 58.97; H, 4.34; N, 18.52. Found: C, 59.14, H, 4.35; N, 18.46.
7-(4-Methoxyphenyl)-2,5-dioxo-2,3-dihydro-5H-[1,3] thiazolo[3,2-a]pyrimidine-6-carbonitrile (13). To a solution of 1a (16 mmol) in benzene (15 mL), triethyl amine (0.3 mmole) and chloroacetyl chloride (16 mmol) were added in small portions with stirring and the mixture was refluxed for 3 h on a water-bath. The solid obtained was filtered off and recrystallized from ethanol. Yield 87%, mp 258-260 °C, yellow crystals. IR (KBr) v 3040 (aromatic CH), 2940 (aliphatic CH), 2225 (CN), 1797 (C=O of thiazolidinone ring), 1672 (C=O of pyrimidine ring), 1591, 1556 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-d6) 5 3.84 (s, 3H, OCH3), 6.55 (s, 2H, CH2, thia-zolidine), 7.06-7.96 (m, 4H, ^H). MS m/z 301 (M+2, 25), 259 (M-CH2CN, 100), 231 (21), 200 (8), 186 (34), 158 (32), 134 (51), 69 (17%). Anal. Calcd for C14H9N303S: C, 56.18; H, 3.01; N, 14.04; S, 10.70. Found: C, 56.23; H, 3.00; N, 14.20; S, 10.86.
7-(4-Methoxyphenyl)-3,5-dioxo-2,3-dihydro-5H-[1,3] thiazolo[3,2-a]pyrimidine-6-carbonitrile (14).16 A mixture of 1c (10 mmol) and 2 g of anhydrous sodium acetate was refluxed in 30 mL of glacial acetic acid and 15 mL of acetic anhydride for 3 h. The reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained was filtered off and recrystallized from ethanol. Yield
80%, mp 250-252 °C, brown crystals. IR (KBr) v 3069 (aromatic CH), 2936 (aliphatic CH), 2212 (CN), 1751 (C=O of thiazolidinone ring), 1684 (C=O of pyrimidine ring), 1579, 1550 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-d6) 5 3.34 (s, 2H, cyclic CH2), 3.90 (s, 3H, OCH3), 7.17-8.1^ (m, 4H, ArH). Anal. Calc;d for C14H9N3O3S: C, 56.18; H, 3.01; N, 14.04. Found: C, 56.28; H, 3.02; N, 14.10.
3-Amino-7-(4-methoxyphenyl)-5-oxo-5H-[1,3]thiazolo [3,2-a]pyrimidine-6-carbonitrile (15). To a solution of 1a (10 mol) in ethanol (10 mL), triethyl amine (15 mL) and chloroacetonitrile (112 mmol) were added in small portions while stirring and the mixture was refluxed for 30 min. The solid obtained upon dilution with water and acidification with HCl was filtered off and recrystallized from ethanol. Yield 60%, mp 214-216 °C, brown crystals. IR (KBr) v 3554, 3459 (NH2), 3086 (aromatic CH), 2984 (aliphatic CH), 2222 (CN), 1683 (C=O of pyrimidine ring), 1602, 1541 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-d6) 5 3.89 (s, 3H, OCH3), 4.37 (br s, 2H, NH2), 7.15-8.1^ (m, 5H, ArH, C2-H). MS m/z 298 (M+, 34), 84 (C3H4N2O, 100), 297 (38), 271 (14), 256 (17), 227 (16), 185 (16), 149 (18), 129 (45), 97 (64), 57 (85%). Anal. Calcd for C14H10N4O2S: C, 56.37; H, 3.35; N, 18.79; S, 10.73. Found: C, 56.30; H, 3.33; N, 18.70; S, 10.48.
7-(4-Methoxyphenyl)-2,3,5-trioxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carbonitrile (16). A
solution of 1a (10 mmol) in benzene (10 mL) was stirred at room temperature for 10 min and then oxalyl chloride (10 mmol) in benzene (10 mL) was added dropwise in the presence of triethyl amine (1 mL) during 30 min. The mixture was stirred for 4 h and then left over night; the solid obtained was filtered off and recrystallized from etha-nol. Yield 65%, mp 255-257 °C, yellow crystals. IR (KBr) v 3010 (aromatic CH), 2940 (aliphatic CH), 2221 (CN), 1760, 1710 (C=O of thiazolidinone ring), 1672 (C=O of pyrimidine ring), 1585, 1559 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-d6) 5 3.86 (s, 3H, OCH3), 7.15-8.16 (m, 4H, ArH). MS m/z 287 (M-CN, 2^), 259 (M-[CO+CN], 100), 231 (23), 201 (72), 158 (19), 134 (35), 114 (29), 78 (41%). Anal. Calcd for C14H7N3O4S: C, 53.67; H, 2.23; N, 13.41; S, 10.22. Found: C, 53.52; H, 2.20; N, 13.49; S, 10.10.
7-(4-Methoxyphenyl)-2-[(4-methylphenyl)hydrazono]-3,5-dioxo-2,3-dihydro-5H-[1,3]thiazolo [3,2-a]pyrimi-dine-6-carbonitrile (17). To a cold solution of compound 14 (10 mmol) in ethanol (80 mL), containing sodium acetate (2 g) was added p-tolyl diazonium chloride [prepared by adding concentrated hydrochloric acid (3 mL) to p-to-luidine (10 mmol) at 0-5 °C and treating the resulting hydrochloride solution with a cold solution of sodium nitrite (10 mmol) in water (5 mL)] dropwise with stirring at
0-5 °C. The reaction mixture was stirred at room temperature for 2 h and then diluted with (30 mL) water. The solid obtained was filtered off and recrystallized from ethanol. Yield 62%, mp 289-291 °C, yellow crystals. IR (KBr) v 3394 (NH), 3009 (aromatic CH), 2936 (aliphatic CH), 2212 (CN), 1751 (C=O of thiazolidinone ring), 1684 (C=O of pyrimidine ring), 1579, 1552 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-d6) 5 3.32 (s, 3H, CH3 of p-tolyl), 3.89 (s, 3H, OCH3), ^.17-8.10 (m, 8H, ArH), 8.15 (s, 1H, NH). MS m/z 417 (M, 44), 344 (100), 200 (40), 164 (51), 134 (47), 102 (34), 69 (42%). Anal. Calcd for C21H15N5O3S: C, 60.43; H, 3.59; N, 16.78; S, 7.67. Found: C, 60.35; H, 3.56; N, 16.80; S, 7.30.
2-Benzylidene-7-(4-methoxyphenyl)-3,5-dioxo-2,3-di-
hydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carbonitri-
le (18).11 Method A: A mixture of 1a (10 mmol), chloroa-cetic acid (10 mmol), benzaldehyde (10 mmol) and 2 g of anhydrous sodium acetate was refluxed in 30 mL of glacial acetic acid and 15 mL of acetic anhydride for 5 h. The reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained was filtered off and recry-stallized from the mixture of dioxane and water.
Method B: A mixture of 14 (10 mmol), benzaldehyde (10 mol) and 2 g of anhydrous sodium acetate was ref-luxed in 30 mL of glacial acetic acid and 15 mL of acetic anhydride for 5 h. The reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained was filtered off and recrystallized from the mixture of dioxane and water. Yield 75%, mp 170-172 °C, pale brown crystals. IR (KBr) v 3017 (aromatic CH), 2934 (aliphatic CH), 2218 (CN), 1762 (C=O of thiazolidinone ring), 1695 (C=O of pyrimidine ring), 1595, 1574 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-d6) 5 3.86 (s, 3H, OCH3), 5.56 (s, 1H, =CH), 7.07 (m, 9H, ArH). MS m/z 387 (M3+, 47), 360 (100), 281 (24), 226 (15), 159 (23), 134 (43), 112 (55), 91 (21), 69 (60%). Anal. Calcd for C21H13N3O3S: C, 65.11; H, 3.35; N, 10.85; S, 8.26. Found: C, 65.28; H, 3.32; N, 10.78; S, 8.50.
6-(4-Methoxyphenyl)-8-oxo-2,3-diphenyl-2,3-dihydro-1H,8H-pyrazolo- [3',4':4,5][1,3]thiazolo[3,2-a]pyrimi-dine-7-carbonitrile (19). A mixture of 18 (10 mmol) and phenylhydrazine (10 mmol) in ethanol (30 mL) and few drops of piperidine was refluxed for 4 h. The solid obtained was filtered off and recrystallized from methanol. Yield 77%, mp 163-165 °C, brown crystals. IR (KBr) v 3445 (NH), 3006 (aromatic CH), 2936 (aliphatic CH), 2215 (CN), 1654 (C=O of pyrimidine ring), 1602, 1540 (C=N, C=C) cm-1.1H NMR (200 MHz, DMSO-dg) 5 3.67 (s, 3H, OCH3), 6.98 (m, 16H, ArH, NH). MS m/z 461 (M-NH2, 54), 77 (100), 390 (41), 361 (51), 310 (30), 259 (20), 134 (88), 84 (51%). Anal. Calcd for C27H19N5O2S: C, 67.92; H, 3.98; N, 14.67; S, 6.70. Found: C, 67.80; H, 4.00; N, 14.63; S, 6.39.
2-Mercapto-7-(4-methoxyphenyl)-9-oxo-4-phenyl-1,4-dihydro-9H-pyrimido[4',5':4,5][1,3]thiazolo[3,2-a]py-rimidine-8-carbonitrile (20). A mixture of 18 (10 mmol) and thiourea (10 mmol) in ethanol (30 mL) and few drops of piperidine was refluxed for 3 h. The solid obtained was filtered off and recrystallized from the mixture of ethanol and water. Yield 83%, mp 210-212 °C, yellow crystals. IR (KBr) V 3424 (NH), 3020 (aromatic CH), 2937 (aliphatic CH), 2371 (SH), 2213 (CN), 1645 (C=O of pyrimidine ring), 1601, 1570 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-rf6) 5 3.45 (s, 3H, OCH3), 3.78 (d, 1H, C4-H), 3.89 (d, 1H, bridged C-H), 4.96 (s, 1H, SH), 6.42-8.05 (m, 9H, ArH). MS m/z 447 (M+2, 1), 310 (M-[anisole+HCN], 100), 295 (37), 281 (64), 271 (25), 267 (26), 227 (19), 201 (18), 134 (24), 84 (25%). Anal. Calcd for C22H15N5O2S2: C, 59.32; H, 3.37; N, 15.73; S, 14.38. Found: C, ^9.30; H, 3.34; N, 15.80; S, 14.60.
2-Amino-7-(4-methoxyphenyl)-9-oxo-4-phenyl-4H,9H -pyrano[2',3':4,5][1,3]thiazolo [3,2-a]pyrimidine-3,8-di-carbonitrile (21). Method A: A solution of 18 (10 mmol) and malononitrile (10 mmol) in ethanol (30 mL) and few drops of piperidine was refluxed for 3 h. The solid obtained was filtered off and recrystallized from methanol.
Method B: A mixture of 14 (10 mmol) and a-cya-nocinnamonitrile (10 mmol) in pyridine (25 mL) was ref-luxed for 12 h. The reaction mixture was poured onto cold water then neutralized with diluted HCl, filtered off and recrystallized from methanol. Yield 72%, mp 138-140 °C, brown crystals. IR (KBr) v 3400, 3336 (NH2), 3005 (aromatic CH), 2939 (aliphatic CH), 2209, 2190 (CN), 1644 (C=O of pyrimidine ring), 1602, 1560 (C=N, C=C) cm-1. 1H NMR (200 MHz, DMSO-d6) 5 3.82 (s, 3H, OCH3), 5.65 (br s, 2H, NH2), 7.06-7.98 (m, 10H, ArH). MS tn/z 452 (M-1, 1), 84 (C3H4N20, 100), 379 (1), 313 (1), 256 (4), 213 (6), 199 (3), 1^1 (10), 129 (15), 77 (13%). Anal. Calcd for C(4H15N5O3S: C, 63.57; H, 3.31; N, 15.45; S, 7.06. Found: C, ^3.50; H, 3.33; N, 15.40; S, 7.55.
4.	Conclusion
Enaminones and hydrazones produced from the interaction of ethyl 1-pyrimidinyl acetate with DMFDMA and aryldiazonium salts are suitable synthons for the preparation of diheterocyclic thioethers. Also, ethyl 1-pyri-midinylacetae is considered a good intermediate for the synthesis of thiazolopyrimidinederivatives.
5.	References
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Povzetek
(-Karbetoksimetiltiopi^imidinonski derivat 1b smo uporabili za sintezo novih diheterociklicnih tioetrov s pomočjo reakcije z nekaterimi acetali s sledečo ciklizacijo produktov z (-aminoheterocikličnimi spojinami ali pa s pomočjo re-kacije 1b s p-tolildiazonijevim kloridom s sledečo reakcijo produkta preko aktivne metilenske skupine. Iz (-merkapto-pirimidina 1a ali iz derivata 5-pirimidinilmerkaptoocetne kisline 1c smo tudi pripravili nekaj novih tiazolopirimidinskih derivatov. Raziskali smo moluskicidno aktivnost pripravljenih spojin proti polžem Biomphalaria alexandrina, ki so gostitelji zajedalca Schistosoma mansoni.