A New Convenient Synthesis of

Anatoly D. Shutalev*, Ekaterina A. Kishko, Natalie V. Sivova and Aleksei Yu. KuznetsovDepartment of Organic Chemistry, State Academy of Fine Chemical Technology, Vernadsky Ave. 86, Moscow 117571,Russian Federation, FAX +7-095-431-6332 (shutalev@orc.ru)Received: 28 January 1998 / Accepted: 18 February 1998 / Published: 9 March 1998Abstract: An efficient one-pot synthesis of 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones is described.The synthesis is based on the reaction of readily available α-tosyl substituted thioureas or ureas with enolatesof β-oxoesters or 1,3-dicarbonyl compounds followed by acid-catalyzed dehydration of the obtained 5-acyl-4-hydroxyhexahydropyrimidine-2-thiones/ones.Keywords: α -Tosyl substituted (thio)ureas, 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones.IntroductionIn recent years 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones (“Biginelli compounds”, i.e., 5a-h ) receivedsignificant attention owing to their diverse range ofbiological properties. For example, some of thesecompounds are very potent calcium channel blockers [1].The presence of several interacting functional groups inBiginelli compounds also determines their great syntheticpotential [2].At the present time there are a few general methods forthe synthesis of 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones. One of them is the Biginelli reaction [2,3].This very simple method involves acid-catalyzed three-component condensation of (thio)ureas, aldehydes and β-oxoesters or 1,3-dicarbonyl compounds. The maindisadvantage of this synthesis is quite often low yields ofthe desired pyrimidines because various side reactionsoccur. For instance, the reaction of urea and ethylacetoacetate with aliphatic aldehydes gives ethyl 4-alkyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in yieldsless than 30-40 % [4]. A very attractive approach to thesynthesis of Biginelli compounds has been developed byAtwal and co-workers [5]. This approach is based on thereaction of α-arylidene- β -oxoesters with S-(4-methoxybenzyl)isothiourea or O-methylisourea in thepresence of sodium bicarbonate followed bytransformation of the obtained 2-(4-methoxybenzylthio)-or 2-methoxy-1,4-dihydropyrimidine-5-carboxylates into2-thioxo- or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates.Recently we have demonstrated [6,7] that Biginellicompounds can be easily prepared by reaction of α-azidoor α-tosyl substituted thioureas and ureas with sodiumenolates of β-oxoesters or 1,3-dicarbonyl compoundsfollowed by acid-catalyzed dehydration of the obtained 5-acyl-4-hydroxyhexahydropyrimidine-2-thiones/ones. Boththese stages of synthesis proceed under mild conditionsand usually in high yields. This method is very flexible andmakes it possible to prepare a large number of 1,2,3,4-tetrahydropyrimidine-2-thiones/ones bearing varioussubstituents in the pyrimidine ring.

Recently we have demonstrated [6,7] that Biginelli compounds can be easily prepared by reaction of α-azido or α-tosyl substituted thioureas and ureas with sodium enolates of β-oxoesters or 1,3-dicarbonyl compounds followed by acid-catalyzed dehydration of the obtained 5acyl-4-hydroxyhexahydropyrimidine-2-thiones/ones.Both these stages of synthesis proceed under mild conditions and usually in high yields.This method is very flexible and makes it possible to prepare a large number of 1,2,3,4tetrahydropyrimidine-2-thiones/ones bearing various substituents in the pyrimidine ring.
Continuing our work in this area we have developed an improved one-pot procedure for the synthesis of 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones, starting from α-tosyl substituted thioureas and ureas without isolation of the intermediate 4-hydroxyhexahydropyrimidine-2thiones/ones.In the present paper we report some preliminary results of the investigation.

Results and Discussion
The α-tosyl substituted thioureas 1a-c and ureas 1d,e were chosen as starting compounds for the present investigation.These compounds were conveniently prepared in 1-2 steps from thiourea or urea in good yields using two different procedures (Scheme 1).N-(Tosylmethyl)thiourea 1a was synthesized by reaction of readily available hydroxymethylthiourea 2 with p-toluenesulfinic acid in water (r.t., 24 h) in 94 % yield.
For the synthesis of α-substituted N-(tosylmethyl)thioureas and ureas we used methods based on a threecomponent condensation of thiourea or urea with aldehydes and p-toluenesulfinic acid.The main problem of the synthesis was the formation not only of the desired Nmonosubstituted (thio)ureas of the type 1 but also of N,N'disubstituted products.We showed that the amount of the latter depends on the molar ratio of the reagents, reaction conditions and the solvent [8].Thus N-(1-tosylpropyl)thiourea 1b and N-(α-tosylbenzyl)thiourea 1c were synthesized by treatment of thiourea with p-toluenesulfinic acid and propionic aldehyde or benzaldehyde in water at r.t. for 21 h in good yields using an equimolar ratio of the reagents (Table 1).According to NMR spectra of the obtained products, the corresponding N,N'-bis(1tosylpropyl)thiourea and N,N'-bis(α-tosylbenzyl)thiourea were also formed as by-products in these reactions.
However, the amount of these disubstituted thioureas in relation to the monosubstituted products 1b,c under the above conditions was only 1-2.5 mol%.
We found that the reaction of urea with ptoluenesulfinic acid and propionic aldehyde or benzaldehyde in water afforded significantly more N,N'bis-products than in the case of thiourea under the described above conditions.In order to decrease the formation of the bis-products we used a three-fold molar excess of urea and a short reaction time (2 h).Thus we prepared N-(1-tosylpropyl)urea 1d and N-(αtosylbenzyl)urea 1e in 85-90 % yields.According to NMR spectra, the amount of N,N'-bis(1-tosylpropyl)urea and N,N'-bis(α-tosylbenzyl)urea in relation to the compounds 1d,e was 5.5 mol% and less than 1 mol%, respectively.The obtained α-tosyl substituted (thio)ureas 1a-e owing to their good purity (> 94 %) were used in the pyrimidine synthesis without further purification.It should be noted, that earlier Engberts and co-workers demonstrated [9] that the reaction of thiourea or urea with benzaldehyde and sodium p-toluenesulfinate in the presence of an excess of formic acid (water-ethanol, r.t.) gave, respectively, a mixture of 1c and N,N'-bis(αtosylbenzyl)thiourea or a mixture of 1e (37 %) and N,N'bis(α-tosylbenzyl)urea (43 %).The authors were only able to isolate a 1c from these mixtures.
As a second building block for the pyrimidine synthesis in the present work we used β-oxoesters 3a,b or 1,3-dicarbonyl compounds 3c,d.
For the first time we studied the reaction of the thioureas 1a-c with the sodium enolate of ethyl acetoacetate obtained previously from 3a or generated in situ by treatment of 3a with NaH in acetonitrile.We found that the reaction of 1a with the sodium enolate of 3a (1.15 equiv.)easily proceeded in acetonitrile at r.t. for 3 h to afford 4-hydroxyhexahydropyrimidine-2-thione 4a which was dehydrated after the addition of TsOH (0.3 equiv.)followed by refluxing of the reaction mixture for NaH or KOH Scheme 2. Synthesis of 5-acyl-1,2,3,4tetrahydropyrimidine-2-thiones/ones.
1.5 h.Thus we obtained the target 1,2,3,4-tetrahydropyrimidine-2-thione 5a in 86 % yield and in a spectroscopically and TLC pure form (Method A) (Scheme 2).It should be noted that a workable catalyst for the dehydration is p-toluenesulfinic acid which is generated by the reaction of TsOH with sodium p-toluenesulfinate obtained in the first stage of the synthesis.
The described approach was also applied to the one-pot synthesis of 1,2,3,4-tetrahydropyrimidine-2-ones 5g,h by reaction of the ureas 1d,e with the sodium enolate of 3a in acetonitrile followed by acidification and refluxing of the reaction mixtures.The yield of the pyrimidines 5g,h was 73 and 65 %, correspondingly (Table 2).
We also found that for the pyrimidine synthesis potassium hydroxide in ethanol can be effectively used for generation of enolates from CH acids 3a-d instead of NaH in acetonitrile.Thus reaction of the tosylthiourea 1a with the potassium enolates of 3a-d (1.2 equiv.for 3a,c and 1.05 equiv.for 3b,d) obtained by treatment of 3a-d with KOH in ethanol afforded (r.t., 4.5 h) the corresponding hydroxypyrimidine-2-thiones 4a-d which were dehydrated after addition of TsOH (0.27 equiv.for 4a,c,d and 1.08 equiv.for 4b) and refluxing of the reaction mixtures for 1.5 h to give the tetrahydropyrimidine-2-thiones 5a-d in 71-87% yields (Table 2) (Method B).Analogously, we prepared the pyrimidine 5e starting from 1b and 3a in 77 % yield.[4], 40 [11], 79 [12] a After washing of the crude product with a small portion of cold diethyl ether (-15 o C). b Overall yield for two stages from the corresponding thioureas 1a-c.c Overall yield for two stages from N-(azidomethyl)thiourea.
A comparison of Method A and Method B shows that, even though both methods give similar yields of the target pyrimidines (Table 2), Method B is preparatively more convenient.

Conclusion
Thus the present work demonstrates that 5-acyl-1,2,3,4tetrahydropyrimidine-2-thiones/ones ("Biginelli compounds") can be efficiently prepared by a one-pot reaction of readily available α-tosyl substituted thioureas or ureas with enolates of β-oxoesters or 1,3-dicarbonyl compounds followed by an acid treatment of the reaction mixtures.The application of this method provides a simple powerful tool for the synthesis of a large number of multifunctional pyrimidine-2-thiones/ ones.Mild reaction conditions, good overall yields, and flexibility make the described method very attractive.

General
IR spectra (in Nujol) were recorded on a Shimadzu IR 435 spectrophotometer.Peak intensities in the IR spectra are defined as strong (s), medium (m) or weak (w).UV spectra (in methanol) were obtained on a Beckman DU 6 spectrophotometer. 1 H NMR (200.13MHz) spectra were recorded on a Bruker MSL 200 spectrometer using DMSO-d 6 or CDCl 3 as solvents.Chemical shifts (δ) are given in ppm relative to TMS.Multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q), some combination of these, multiplet (m).Thin layer chromatography (TLC) was performed on silica gel plates Silufol UV 254 (Czech Republic) or Kieselgel 60 F 254 (Merck) in chloroform-methanol (20:1, v/v) and chloroform-methanol (9:1, v/v) as solvent systems.Plates were visualised with iodine vapor or UV light.
p-Toluenesulfinic acid was synthesized by reduction of tosyl chloride with sodium sulfite in water [13], dried over P 2 O 5 and stored at 0 o C. Hydroxymethylthiourea 2 was prepared according to the literature procedure [14].Propionic aldehyde and benzaldehyde were distilled before use.For the pyrimidine synthesis we used commercially available ethanol (96 %) and anhydrous acetonitrile dried by distillation from P 2 O 5 and then from CaH 2 .Ethyl acetoacetate and acetylacetone were dried over CaCl 2 and distilled under vacuum, ethyl benzoylacetate and benzoylacetone were commercially available products.Sodium hydride (80 % suspension in mineral oil) was washed with dry hexane, dried in vacuum desiccator prior to use.The sodium enolate of ethyl acetoacetate was obtained by reaction of ethyl acetoacetate with NaH in dry acetonitrile followed by filtration of the resulting product.α-Tosyl substituted (thio)ureas 1a-e were used in the syntheses freshly prepared because these compounds (especially 1b-e) decomposed slightly during prolonged storage.

N-(Tosylmethyl)thiourea (1a)
A mixture of hydroxymethylthiourea 2 (1.356 g, 12.77 mmol) and p-toluenesulfinic acid (2.399 g, 15.36 mmol) in 15 mL of water was stirred at r.t. for 24 h, then cooled to 0 o C. The solid was collected by filtration, washed carefully with ice water, hexane and dried to give 2.943 g (94 %) of 1a as a white powder.The obtained product was used in the pyrimidine syntheses without further purification.Analytically pure material was obtained by recrystallisation from acetone, mp 156. 5

N-(1-Tosylpropyl)thiourea (1b)
To a mixture of propionic aldehyde (0.519 g, 8.94 mmol) and water (7 mL) was added thiourea (0.648 g, 8.51 mmol) and then p-toluenesulfinic acid (1.397 g, 8.94 mmol).The resulting suspension was stirred at r.t. for 21 h, cooled to 0 o C, the solid was collected by filtration, washed carefully with ice water, hexane and dried to give 2.192 g (95 %) of 1b as a white solid.According to the NMR spectrum, the crude product also contained about 1 mol% of N,N'-bis(1-tosylpropyl)thiourea.The obtained product was stored at 0 o C and used in the pyrimidine syntheses without further purification.Analytically pure material was obtained by recrystallisation from acetonitrile, mp 123. 5

N-(1-Tosylpropyl)urea (1d)
To a mixture of propionic aldehyde (2.124 g, 36.57mmol) and water (40 mL) was added p-toluenesulfinic acid (5.719 g, 36.61mmol) followed by the addition of urea (6.594 g, 109.80 mmol).The resulting suspension was stirred at r.t. for 2 h, cooled to 0 o C, the solid was filtered, washed with ice water, hexane and dried to yield 7.942 g (85 %) of 1d as a white powder.According to the NMR spectrum, the crude product also contained 5.5 mol% of N,N'-bis (1-tosylpropyl)

N-( -Tosylbenzyl)urea (1e)
This compound (10.611g, 90 %) was obtained as a white powder by the reaction of urea (6.995 g, 116.48 mmol), benzaldehyde (4.119 g, 38.81 mmol) and ptoluenesulfinic acid (6.074 g, 38.88 mmol) in 40 mL of water according to the procedure described for 1d.According to the NMR spectrum, the crude product contained less than 1 mol% of N,N'-bis(αtosylbenzyl)urea.The obtained product was stored at 0 o C and used in the pyrimidine syntheses without further purification.

5-Acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones; General Procedures
Method A To a stirred suspension of NaH (0.257 g, 10.71 mmol) in dry acetonitrile (10 mL) at 0 o C was added a solution of ethyl acetoacetate 3a (1.394 g, 10.71 mmol) in dry acetonitrile (10 mL) dropwise over a period of 5 min and the resulting mixture was stirred at r.t. for 30 min.To the obtained suspension of the sodium enolate of ethyl acetoacetate was added the appropriate (thio)urea 1 (9.31 mmol) all at once.After stirring for 3 h at r.t.(for 1a,b,d) or for 3 h at r.t. and then 2 h under reflux (for 1c,e), the reaction mixture was acidified by addition of TsOH .H 2 O (0.532 g, 2.80 mmol) and refluxed for 1.5 h.The solvent was removed under reduced pressure and the solid residue was treated with water (10 mL).The mixture was cooled to 0 o C over 1 h, the precipitate was filtered, washed carefully with ice water, hexane and dried to give the corresponding pyrimidine 5 (Table 2).
Analogously and in similar yields the pyrimidines 5a,eh were also obtained by modification of Method A based on the reaction of an appropriate (thio)urea 1 (3.71 mmol) with the previously prepared sodium enolate of ethyl acetoacetate (0.648 g, 4.26 mmol) in acetonitrile (18 mL) followed by addition of TsOH .H 2 O (0.285 g, 1.50 mmol).

Method B
To a stirred solution of KOH (0.308 g, 5.49 mmol) in ethanol (10 mL) was added a solution of CH acid 3 (5.49mmol for 3a,c or 4.81 mmol for 3b,d) in ethanol (15 mL) at r.t. in one portion and the resulting mixture was stirred for 15 min.Tosylthiourea 1a or 1b (4.58 mmol) was added all at once.After stirring for 4.5 h at r.t., the reaction mixture was acidified by addition of TsOH .H 2 O (0.235 g, 1.24 mmol in the case of 3a,c,d or 0.942 g, 4.95 mmol in the case of 3b) and refluxed for 1.5 h.The solvent was removed under reduced pressure and the solid residue was treated with water (5 mL).The mixture was cooled to 0 o C over 1 h, the precipitate was filtered, washed carefully with ice water, hexane and dried to give the corresponding pyrimidine 5 (Table 2).