Synthesis of 3,4-dihydro-2(1H)-pyrimidinones and the mechanism of the Biginelli reaction

Abstract

The acid-catalyzed synthesis of substituted 3,4-dihydro-2(l//)-pyrimidinones from a variety of precursors was studied. The major products of the condensation of 3-methoxyacrylate with urea and monomethylurea are 5-carbomethoxy-4-carboxymethyl-3,4-dihydro-2(l//)-pyrimidinone and its N-l methyl derivative. The decarboxylated derivatives, 5-carbomethoxy-4-methyl-3,4-dihydro-2(l//)-pyrimidinone and 5-carbomethoxy-l ,4dimethyl-3,4-dihydro-2( 1 //j-pyrimidinone, are minor products of the same reaction. syw-Dimethylurea produces 5-carbomethoxy-3,4-dihydro-l,3,4-trimethyl-2(l//)-pyrimidinone and 1,3-dimethyluracil, both in small yield. An integrated mechanism for these reactions is proposed involving a preliminary acid-catalyzed aldol condensation and subsequent reactions of a carbonium ion formed from the aldol intermediate. An interaction, probably through hydrogen bonding, is shown to occur between the carboxylic group on the substituent at C-4 and the N-3 group in 5-carbomethoxy-4-carboxymethyl-3,4-dihydro-2(l//)-pyrimidinone. Its effect upon the hydrolysis of an ester of the same carboxylic group has been demonstrated. The reaction of methyl 2-dimethoxymethyl-3-methoxypropionate with ureas also produces 5-carbomethoxy-3,4-dihydro-2(l//)-pyrimidinones. Factors influencing the orientation of these condensations are considered. It is concluded that the more nucleophilic of the two nitrogens in a substituted urea reacts first by displacing the protonated alkoxy group, which is activated through an enol-allyl system derived from the aldehyde function. Cyclization to the 3,4-dihydro-2(l//)-pyrimidinone is completed by reaction of the free ureide nitrogen with the aldehyde group. The results of the condensations of 2-dimethoxymethyl-3-methoxy-l-propanol and 2-hydroxymethyl-1,1,3,3-tetramethoxypropane with ureas are consistent with the proposed enhanced reactivity of an allylic center as compared to an aldehyde function and with the corollary carbonium ion mechanism. This mechanism also applies to the Biginelli pyrimidine synthesis in which the limiting step is now considered to be an in situ aldol condensation required to produce the reactive unit which condenses with a urea to give the corresponding 3,4-dihydro-2(l//)-pyrimidinone. The mechanism proposed here for the Biginelli synthesis explains the course of reactions which had previously been considered "anomalous."

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

“…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).…”

4-Aryldihydropyrimidines via the Biginelli Condensation: Aza-Analogs of Nifedipine-Type Calcium Channel Modulators

“…the primary bimolecular condensation product of benzaldehyde and urea, is the first intermediate in this reaction [16]. In 1973 Sweet and Fissekis proposed that a carbenium ion, produced by an acid-catalyzed aldol reaction of benzaldehyde with ethyl acetoacetate, is the key intermediate and is formed in the first and limiting step of the Biginelli reaction [17]. We reinvestigated the mechanism in 1997 [18] DHPM calcium channel modulators [9].…”

Síntese do monastrol e novos compostos de Biginelli promovida por In(OTf)3

“…Foram obtidos melhores rendimentos na presença de acetonitrila, e a formação das DHPMs 8a-j ocorreu empregandose condições reacionais idênticas aquelas utilizadas com etanol como solvente (Tabela 1, entradas [8][9][10][11][12][13][14][15][16][17][18]. A abrangência da metodologia foi alcançada através da utilização de tiouréia (7, X=S) levando a síntese de 3,4-diidropirimidin-2(1H)-tionas 8l-q (Tabela 1, entradas 19,20 e 22-26).…”

“…As análises de ressonância magnéti-ca nuclear (RMN) de 1 H e 13 C foram realizadas em um equipamento Varian VXR200 (3,1T), utilizando DMSO-d 6 e como padrão interno de referência, tetrametilsilano (TMS). Os dados de infravermelho (IV) foram obtidos em um espectrômetro FTIR MATTson 3020 e as análises elementares foram realizadas em equipamento Perkin Elmer CHNS Analyser, Série II.…”