Multicomponent Biginelli's synthesis of 3,4-dihydropyrimidin-2(1H)-ones promoted by SnCl2.2H2O

COMMUNICATION

Multicomponent Biginelli's synthesis of 3,4-dihydropyrimidin-2(1H)-ones promoted by SnCl₂.2H₂O

Dennis RussowskyI, ^*; Fabrício A. Lopes^I; Victor S. S. da Silva^I; Karen F. S. Canto^I; Marcelo G. Montes D'Oca^II; Marla N. Godoi^II

^IInstituto de Química, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre - RS, Brazil

^IIDepartamento de Química, Fundação Universidade do Rio Grande 96201-900, Rio Grande - RS, Brazil

ABSTRACT

The ability of SnCl₂.2H₂O as catalyst to promote the Biginelli three-component condensation reaction from a diversity of aromatic aldehydes, ethyl acetoacetate and urea or thiourea is described. The reaction was carried out in acetonitrile or ethanol as solvents in neutral media and represents an improvement of the classical Biginelli protocol and an advantage in comparison with FeCl₃.6H₂O, NiCl₂.6H₂O and CoCl₂.6H₂O which were used with HCl as co-catalyst. The synthesis of 3,4-dihydropyrimidinones was achieved in good to excelent yields.

Keywords: Biginelli reaction, multicomponent reaction, dihydropyrimidinones, tin(II) chloride hydrate, Lewis acid

RESUMO

Neste trabalho é descrita a habilidade do SnCl₂.2H₂O como catalisador na reação de Biginelli tricomponente. Uma variedade de aldeídos aromáticos mono- e dissubstituidos foi utilizada na condensação com acetoacetato de etila e uréia ou tiouréia. A reação foi efetuada em etanol ou acetonitrila como solventes em meio neutro e os resultados representam um melhoramento com relação ao procedimento clássico de Biginelli e uma vantagem com relação ao uso de FeCl₃.6H₂O, NiCl₂.6H₂O e CoCl₂.6H₂O que são utilizados juntamente com HCl como co-catalisador. A síntese das 3,4-diidropirimidinonas foi conseguida em bons rendimentos.

Introduction

The multicomponent reactions (MCRs) are one of the most important protocols in organic synthesis and medicinal chemistry.¹ The diversity, efficiency and rapid access to small and highly functionalized organic molecules makes this approach of central current interest in the construction of combinatorial libraries and optimization in drug discovery process.²

The 3,4-dihydropyrimidin-2(1H)-ones (DHPMs–1, Figure 1) have recently emerged as important target molecules due to their therapeutic and pharmacological properties³ such as antiviral,⁴ antimitotic,⁵ anticarcinogenic,⁶ antihypertensive⁷ and noteworthy, as calcium channel modulators.⁸ Additionally, their particular structure has been found in natural marine alkaloid batzelladine A and B which are the first low molecular weight natural products reported in the literature to inhibit the binding of HIV gp-120 to CD4 cells, so disclosing a new field towards the development of AIDS therapy.⁹ Also, due to the close related structure of DHPMs with the known dihydropyridine calcium channel modulators of the Hantzsch-type (DHPs - 2, Figure 1), an intensive research has been devoted to synthesize the dihydropyrimidinone nucleus and this subject was recently reviewed.¹⁰

The original one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones was firstly reported by Pietro Biginelli in 1893 performing the three-component cyclocondensation reaction of ethyl acetoacetate, benzaldehyde and urea under Brönsted acid catalysis.¹¹ However, this reaction suffers from the harsh conditions, high reaction times and frequently low yields. Among the diversity of available methodologies in the literature that use lithium salts,¹² TMSI,¹³ reactions performed under ionic liquids,¹⁴ solid phase,¹⁵ polymer-supported,¹⁶ heterogeneous catalysis by silicas¹⁷ and montmorillonites¹⁸ or activation by ultrasound¹⁹ and microwave²⁰ energies as synthetic protocols to prepare DHPMs, special attention has been dedicated to Lewis acids catalysis.

Recently, BF₃.OEt₂ complex was shown to be an excellent promoter of the three-component reaction²¹ but anhydrous conditions were required. High yields of DHPMs were obtained using metals halides, such as NiCl₂.6H₂O and FeCl₃.6H₂O,²² CoCl₂.6H₂O,²³ BiCl₃,²⁴ In(III)-halides,²⁵ and ZrCl_4,²⁶ or lanthanide halides such as LaCl₃.7H₂O,²⁷ and CeCl₃.7H₂O²⁸ as Lewis acid catalysts. Metal triflates, such as Zn(OTf)₂,²⁹ Cu(OTf)₂,³⁰ Bi(OTf)₃,³¹ and Sc(OTf)₃³² or lanthanide triflates as Yb(OTf)₃,³² and La(OTf)₃.³³ were also reported.

Results and Discussion

In connection with our research on the use of SnCl₂.2H₂O in multicomponent Mannich reaction,³⁴ we would like to disclose here our preliminary results employing this catalyst as a new and mild Lewis acid which, to our best knowledge, has not yet been reported promote the multicomponent Biginelli reaction (Scheme 1, Table 1). It should be noted, that SnCl₂.2H₂O was used as the sole promoter agent in neutral media while for the others previously reported hydrates of metallic halides such as Fe(III), Ni(II) and Co(II) a catalytic amount of conc. HCl was needed as a Brönsted acid co-catalyst.

To evaluate the ability of SnCl₂.2H₂O as catalyst in this reaction, we performed the three component condensation reaction of benzaldehyde (3a), ethyl acetoacetate (4) and urea (5a) in EtOH and CH₃CN as solvents. To establish the optimal conditions, we carried out a set of experiments varying the reaction time, amounts of the catalysts and the quantities of urea.

The best condition to prepare the dihydropyrimidinone 6a were achieved when 20 mol% of SnCl₂.2H₂O, 1 equivalent of both aldehyde 3a and ethyl acetoacetate (4) and 1.2 equivalents of urea (5a) were mixed under reflux for 6 hours, affording the desired product in good yield (>90%, Entry 1, Table 1). This condition was applied to a series of substituted aromatic aldehydes 3b-m with urea (5a) affording the desired products 6b-m.

The ability of SnCl₂.2H₂O to promote the Biginelli reaction in EtOH was comparable to those performed in CH₃CN, affording good yields in all cases (Entries 2-26). The reactions of aldehydes 3a and 3d with thiourea (5b) also afforded the desired products in good yields for both the solvents (entries 27-30). Apparently, for the employed rection conditions (reflux for 6 hours) the nature of the substituents does not affect significantly the yield of the reactions. The product 6c, which has an electron-donanting substituent attached at C-4 position of the aromatic ring was produced in 98% yield while the dihydropyrimidinone 6l with an electron-withdrawing group yielded 96% (see entries 6 and 24, respectively).

The ¹H NMR and ¹³C NMR data of compounds 6a-o were compatible with the proposed structures as well as the melting points were in accordance with those reported in the literature.

A general procedure for the synthesis of 3,4-dihydropyrimidinones is described as follow: a 50 cm³ round-bottom flask was charged with 3.6 mmol of urea or thiourea, 3.0 mmol of the aldehyde, 3.0 mmol of ethyl acetoacetate, 0.6 mmol of SnCl₂.2H₂O and 4.0 cm³ of ethanol (or acetonitrile). The mixture was heated to reflux for 6 hours period under magnetic stirrer. The solution was cooled to room temperature and 10 cm³ of cold water was added, the mixture was additionally stirred for 15 minutes. The resulting solid was filtered under suction, washed with cold ethanol (3 cm³) and recrystalized from hot ethanol to afford the product.

In some cases (compounds 6c, 6d and 6g, entries 5, 7 and 13, respectively), the crude isolated solid compound was dried under vacuum pump and shown essentially the same purity as the recrystallized sample.

Although different mechanistic pathways have been previously proposed,^{35, 36} we believe that the reaction may proceed through an initially N-acylimine 7 formed from aldehyde 3 and urea 5 (Scheme 2).

The coordination of the lone-pair of the nitrogen atom in the N-acylimine 7 with the Lewis acid could lead to the in situ formation of an N-carbamoyliminium ion 7a, which is sufficiently electrophilic to react with the enol form of ethyl acetoacetate 4 affording the open chain intermediate 8. Further intramolecular cyclization, with lost of H₂O, produce the 2,3-dihydropyrimidin-2-(1H)-ones 6.

Spectroscopic evidences for such mechanism from ¹H NMR and ¹³C NMR studies were reported by Kappe, supporting the intervenience of a N-carbamoyliminium ion as a possible intermediate.³⁷

Conclusion

In summary, we have demonstrated the ability of SnCl₂.2H₂O as a new and mild Lewis acid promoter in the multicomponent Biginelli reaction. Besides its simplicity, neutral reaction conditions and use of commercial solvents without previous purifications or drying, this method was effective with a variety of substituted aromatic aldehydes independently of the nature of the substituents in the aromatic ring, representing an improvement to the classical Biginelli's methodology.

Acknowledgments

The authors would like to acknowledge the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq) for the financial support. F. A. L. acknowledges FAPERGS for the fellowship.

Received: January 14, 2004

Published on the web: April 20, 2004

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Publication Dates

• Publication in this collection
  29 June 2004
• Date of issue
  Apr 2004

History

• Accepted
  20 Apr 2004
• Received
  14 Jan 2004