A New Synthesis of Biginelli Compounds

Anatoly D. Shutalev, Natalie V. Sivova

Department of Organic Chemistry, State Academy of Fine Chemical Technology, Vernadsky Avenue 86, Moscow 117571, Russian Federation

Abstract

Efficient one-pot synthesis of 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones are described. The synthesis is based on the reaction of readily available a-tosyl substituted thioureas or ureas with enolates of b-oxoesters or 1,3-dicarbonyl compounds followed by acid-catalyzed dehydration of the obtained 5-acyl-4-hydroxyhexahydropyrimidine-2-thiones/ones.

Introduction

Results and Discussion

Conclusion

References

Introduction

In recent years 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones 1 ("Biginelli compounds") have received significant attention owing to their diverse range of biological properties. For example, some of these compounds are very potent calcium channel blockers [1]. The presence of several interacted functional groups in Biginelli compounds determines also their great synthetic potential [2].

At the present time there are a few general methods of the synthesis of 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones. One of them is the Biginelli reaction [2,3] (Scheme 1). This very simple method involves acid-catalyzed three-component condensation of (thio)ureas, aldehydes and b-oxoesters or 1,3-dicarbonyl compounds. The main disadvantage of this synthesis quite often is low yields of the desired pyrimidines because various side reactions occur. For instance, reaction of urea and ethyl acetoacetate with aliphatic aldehydes gives ethyl 4-alkyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in yields less than 30-40 % [4].

Very attractive approach to the synthesis of Biginelli compounds was developed by Atwal and co-workers [5] (Scheme 2). This approach is based on the reaction of a-arylidene-b-oxoesters with S-(4-methoxybenzyl)isothiourea or O-methylisourea in the presence of sodium bicarbonate followed by transformation of the obtained 2-(4-methoxybenzylthio)- or 2-methoxy-1,4-dihydropyrimidine-5-carboxylates into 2-thioxo- or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates.

Recently we have demonstrated [6,7] that Biginelli compounds can be easily prepared by reaction of a-azido or a-tosyl substituted thioureas and ureas with sodium enolates of b-oxoesters or 1,3-dicarbonyl compounds followed by acid-catalyzed dehydration of the obtained 5-acyl-4-hydroxyhexahydropyrimidine-2-thiones/ones (Scheme 3). Both the stages of the synthesis proceed under mild conditions and usually in high yields. This method is very flexible and gives possibility to prepare a large number of 1,2,3,4-tetrahydropyrimidine-2-thiones/ones bearing various substituents in pyrimidine ring.

In continuation of our work in this area we developed an improved one-pot procedure for the synthesis of 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones starting from a-tosyl substituted thioureas and ureas without isolation of the intermediate 4-hydroxyhexahydropyrimidine-2-thiones/ones. Some preliminary results of the investigation were published in our recent paper [8].

Results and Discussion

The first stage of the pyrimidine synthesis involves preparation of a-tosyl substituted thioureas and ureas. We developed two convenient methods for the synthesis of these compounds. One of them is suitable for the synthesis of (tosylmethyl)thioureas or (tosylmethyl)ureas unsubstituted at the a-position to nitrogen. The method is based on reaction of thioureas or ureas with formaldehyde followed by treatment of the obtained (hydrohymethyl)thioureas or (hydroxymethyl)ureas with p-toluenesulfinic acid in water. For example, N-(tosylmethyl)thiourea 2 was synthesized by the reaction of readily available (hydroxymethyl)thiourea 3 with p-toluenesulfinic acid in water (r.t., 24 h) in 94 % yield (Scheme 4).

For the synthesis of a-substituted N-(tosylmethyl)thioureas and ureas we used method based on three-component condensation of thiourea or urea with aliphatic or aromatic aldehydes and p-toluenesulfinic acid (Scheme 5). The main problem of the synthesis was formation not only the desired N-monosubstituted (thio)ureas but also N,N'-disubstituted products. We showed that amount of the latter depends on structure of the starting reagents, their molar ratios, solvent, reaction time and temperature. In the best conditions we were able to obtain the target monosubstituted (thio)ureas practically in pure form. The maximal amount of disubstituted products was not more than a few per cent. Thus a-substituted N-(tosylmethyl)thioureas 4a-f were synthesized by the treatment of thiourea with p-toluenesulfinic acid and aldehydes in water at r.t. for about 24 h in 61-95 % yields using equimolar ratio of the reagents (Table 1).

Table 1. Synthesis of a-tosyl substituted thioureas 4a-f and ureas 4g-l.

Product	X	R	Yield, %	Product	X	R	Yield, %
4a	S	Me	84	4g	O	Et	85
4b	S	Et	95	4h	O	Ph	90
4c	S	Pr	64	4i	O	4-MeC₆H₄	72
4d	S	Ph	83	4j	O	4-MeOC₆H₄	95
4e	S	4-MeC₆H₄	67	4k	O	3,4-(MeO)₂C₆H₃	93
4f	S	4-MeOC₆H₄	61	4l	O	4-Me₂NC₆H₄	81

Reaction of urea with p-toluenesulfinic acid and aldehydes in water afforded significant more N,N'-bis-products than in the case of thiourea under the described above conditions. In order to decrease formation of the bis-products we used three-fold molar excess of urea and short reaction time (2-6 h). Thus we prepared a-substituted N-(tosylmethyl)ureas 4g-l in 72-95 % yields (Table 1). The obtained a-tosyl substituted (thio)ureas 4a-l owing to their good purity (> 94 %) were used in the pyrimidine synthesis without further purification.

As second building block for the pyrimidine synthesis in the present work we used 1,3-dicarbonyl compounds (acetylacetone 5a, benzoylacetone 5b) or b-oxoesters (ethyl acetoacetate 5c, ethyl benzoylacetate 5d, ethyl butyrylacetate 5e).

We found that N-(tosylmethyl)thiourea 2 readily reacted with the potassium enolates of the CH acids 5a-d (1.05-1.20 equiv.) generated by treatment of 5a-d with KOH in ethanol to afford the corresponding 5-acyl-4-hydroxyhexahydropyrimidine-2-thiones 6a-d (r.t., 4.5 h). The latter without their isolation were dehydrated after addition of TsOH (0.3-0.4 equiv. for 5a-c and 1.08 equiv. for 5d) to the reaction mixtures and subsequent refluxing for 1-1.5 h. Thus we obtained the 4-unsubstituted 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones 7a-d in 71-87 % yields (Table 2) (Scheme 1). It should be noted that workable catalyst of the dehydration of 6a-d is p-toluenesulfinic acid which is generated by 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 the 4-alkyl substituted 1,2,3,4-tetrahydropyrimidine-2-thiones 7e-n and 4-aryl substituted 1,2,3,4-tetrahydropyrimidine-2-thiones 7o-s by reaction of the corresponding thioureas 4a-f with the potassium enolates of 5a-f in ethanol (r.t., 4.5-6 h) followed by acidification and refluxing of the reaction mixtures. The yields of the pyrimidines 7e-s were 46-98 % (Table 2). Similarly, starting from the a-aryl substututed (tosylmethyl)ureas 4h-l we obtained the corresponding 5-acyl-4-aryl-1,2,3,4-tetrahydropyrimidine-2-ones 7t-z in 40-85 % yields.

Table 2. Synthesis of 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones 7a-z.

(Thio)urea	CH acid	Product	X	R	R¹	R²	Yield, %
2	5a	7a	S	H	Me	Me	74
2	5b	7b	S	H	Ph	Me	74
2	5c	7c	S	H	OEt	Me	87
2	5d	7d	S	H	OEt	Ph	71
4a	5a	7e	S	Me	Me	Me	81
4a	5b	7f	S	Me	Ph	Me	68
4a	5c	7g	S	Me	OEt	Me	95
4a	5d	7h	S	Me	OEt	Ph	76
4a	5e	7i	S	Me	OEt	Pr	66
4b	5a	7j	S	Et	Me	Me	98
4b	5b	7k	S	Et	Ph	Me	72
4b	5c	7l	S	Et	OEt	Me	77
4b	5d	7m	S	Et	OEt	Ph	57
4c	5a	7n	S	Pr	Me	Me	60
4d	5a	7o	S	Ph	Me	Me	58
4d	5b	7p	S	Ph	Ph	Me	56
4d	5c	7q	S	Ph	OEt	Me	58
4e	5a	7r	S	4-MeC₆H₄	Me	Me	46
4f	5a	7s	S	4-MeOC₆H₄	Me	Me	50
4h	5a	7t	O	Ph	Me	Me	62
4i	5c	7u	O	4-MeC₆H₄	OEt	Me	40
4j	5a	7v	O	4-MeOC₆H₄	Me	Me	65
4j	5c	7w	O	4-MeOC₆H₄	OEt	Me	83
4k	5a	7x	O	3,4-(MeO)₂C₆H₃	Me	Me	77
4k	5c	7y	O	3,4-(MeO)₂C₆H₃	OEt	Me	85
4l	5a	7z	O	4-Me₂NC₆H₄	Me	Me	67

The proposed method for the one-pot pyrimidine synthesis is general and very flexible. This approach was successfully used by us in the cases when the Biginelli reaction and the Atwal procedure failed to give the disired products (see above). Moreover, our method can be applied not only for preparation of Biginelli compounds but also for synthesis of a large variety of hydrogenated pyrimidines. For example, reaction of N-(1-tosylethyl)thiourea 4a with the potassium enolate of tosyl acetone (r.t., 4.5 h) generated by treatment of the CH acid with KOH in ethanol gave the 4-hydroxy-5-tosylhexahydropyrimidine-2-thione 8 which was dehydrated without isolation after addition of TsOH to the reaction mixture and subsequent refluxing for 1 h. Thus we obtained 4,6-dimethyl-5-tosyl-1,2,3,4-tetrahydropyrimidine-2-thione 9 in 55 % yield (Scheme 7).

Conclusion

Thus the present work demonstrates that 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones ("Biginelli compounds") can be efficiently prepared by one-pot reaction of readily available a-tosyl substituted thioureas or ureas with enolates of b-oxoesters or 1,3-dicarbonyl compounds followed by acid treatment of 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, flexibility make the described method very attractive.

References

1. Atwal, K.S.; Swanson, B.N.; Unger, S.E.; Floyd, D.M.; Moreland, S.; Hedberg, A.; O'Reilly, B.C.; Corrie, J. E. T. J. Med. Chem. 1991, 34, 806-811.

2. Kappe, C.O. Tetrahedron 1993, 49, 6937-7963.

3. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360-416.

4. Shutalev, A.D.; Sivova, N.V. Khim. Geterotsicl. Soedin. 1998, in press, and references cited herein.

5. O'Reilly, B.C.; Atwal, K.S. Heterocycles 1987, 26, 1185-1188. Atwal, K.S.; O'Reilly, B.C.; Gougoutas, J.Z.; Malley, M.F. Heterocycles 1987, 26, 1189-1192. Atwal, K.S.; Rovnyak, G.C.; O'Reilly, B.C.; Schwartz, J. J.Org.Chem. 1989, 54, 5898-5907.

6. Shutalev, A.D.; Kuksa, V.A. Chemistry of Heterocyclic compounds 1995, 31, 86-91. Engl. transl. from Khim. Geterotsicl. Soedin. 1995, 97-102.

7. Shutalev, A.D.; Kuksa, V. Khim. Geterotsicl. Soedin. 1997, 105-109.

8. Shutalev, A.D.; Kishko, E.A.; Sivova, N.V.; Kuznetsov, A.Yu. Molecules 1998, 3, 100-106.