Biginelli cyclocondensation

Benzo-derivatives 46,48 Benzopyranopyrroles 55 Benzothiazoles 67 Benzothiophenes 62 Benzoxazines 253 Benzoxazoles 249 Biginelli cyclocondensation 34 Bis(indole)alkaloids 271 Bromination 20... 

Fig. 5.4 Efficiencies of several Lewis acids in Biginelli cyclocondensation (AcOH/EtOH, 120 °C, 10 min).

Fig. 5.5 Optimization of reaction temperature and time forthe Biginelli cyclocondensation in AcOH/EtOH (3 1) with 10 mol% ofYb(OTf)3.

Surprisingly, the synthetic potential of this heterocycle synthesis remained unexplored for quite some time. In the 1970s and 1980s interest for the original Biginelli cyclocondensation reaction slowly increased and... 

Bismuth(m) nitrate catalyzes Michael addition of a,/Yunsaturated ketones with amines, thiols, and carbamates, although the promoting role of Bi(N03)3 is not fully understood (Equation (91)).100 The Biginelli cyclocondensation of a mixture of (3-keto esters, aldehydes, and urea is mediated by BiCl3, affording 3,4-dihydropyrimidin-2(lH)-ones (Equation (92)).149 Bi(OCOCF3)3 is an efficient catalyst for the regio- and chemoselective synthesis of /3-enaminones in water.150... 

An MS investigation of the three-component base-mediated Biginelli synthesis of dihydropyrimidines has found evidence for a hemiacetal intermediate (117), but no sign of a bis-ureide (118). ° A prolinamide gives up to 99% ee in Biginelli cyclocondensations of urea, aldehyde, and ethyl acetoacetate. ... 

A general and practical green chemical route to the Biginelli cyclocondensation reaction using cerium(III) chloride as the catalyst (25 %mol) has been described under three different sets of reaction conditions [9]. Three different sets of reaction conditions were examined (1) traditional ethanol reflux, (2) water reflux, and (3) solvent-free conditions. The second and third set of conditions provides an efficient and much improved modification of the original Biginelli reaction reported in 1893, in terms of high yields, short reaction times, and simple workup procedure, and it... 

Scheme 1 Biginelli cyclocondensation reaction for the synthesis of DHPMs 4...

Substantial MW rate enhancements have been reported in the Biginelli synthesis of dihydropyrimidines [50, 51] under homogeneous conditions. The synthesis involves a one-pot cyclocondensation of a /i-ketoester with an aryl aldehyde and urea or thiourea in the presence of a catalytic amount of HC1 in ethanol solution. An example of this synthesis is shown in Scheme 4.17. 

The Biginelli reaction is a cyclocondensation between ethylacetoacetate, an arylal-dehyde and urea derivatives to obtain dihydropyrimidines. Transfer this reaction to the solid-phase chemistry, allow the preparation of libraries of this kind of products (Scheme 3.18) [288]. 

When R2 substituent is flourocontaining alkyl group, the transformation 17 18 becomes hindered and its proceeding requires some special methods. For example, in [48] Biginelli-like cyclocondensations based on three-component treatment of 3-amino-l,2,4-triazole or 5-aminotetrazole with aldehydes and fluorinated 1,3-dicarbonyl compounds were investigated. It was shown that the reaction can directly lead to dihydroazolopyrimidines 20, but in the most cases intermediate tetrahydroderivatives 19 were obtained (Scheme 10). To carry out dehydration reaction, refluxing of tetrahydroderivatives 19 in toluene in the presence of p-TSA with removal of the liberated water by azeotropic distillation was used. The same situation was observed for the linear reaction proceeding via the formation of unsaturated esters 21. 

In 1893, the Italian chemist Pietro Biginelli (University of Florence) for the first time reported on the acid-catalyzed cyclocondensation reaction of ethyl acetoacetate 1, benzaldehyde 2, and urea 3 [1], The reaction was carried out by simply heating a mixture of the three components dissolved in ethanol with a catalytic amount of HC1 at reflux temperature. The product of this novel one-pot, three-component synthesis that precipitated on cooling the reaction mixture was identified as 3,4-dihydropyrimidin-2(lH)-one 4 (Scheme 4.1) [2]. This reaction is nowadays referred to as the Biginelli reaction , Biginelli condensation or as the Biginelli dihydropyrimidine synthesis . 

While the early examples of this cyclocondensation process typically involved a / -ketoester, aromatic aldehyde and urea, the scope of this heterocycle synthesis has now been extended considerably by variation of all three building blocks, allowing access to a large number of multifunctionalized pyrimidine derivatives. For this particular heterocyclic scaffold the acronym DHPM has been adopted in the literature and is also used throughout this chapter. Owing to the importance of multi-component reactions in combinatorial chemistry there has been renewed interest in the Biginelli reaction, and the number of publications and patents describing... 

The classic Biginelli reaction features the cyclocondensation of an aldehyde, a urea and an active methylene compound to form dihydropyrimidinones (Fig. 4). The reaction has been extensively utilized and reviewed [20] and its applications to drug discovery have also been highlighted [21]. This chapter will focus on some of the most recent developments and applications of Biginelli reactions to the discovery of biologically active molecules. 

Dondoni, A., Massi, A., Minghini, E., Sabbatini, S., Bertolasi, V. Model Studies toward the Synthesis of Dihydropyrimidinyl and Pyridyl a-Amino Acids via Three-Component Biginelli and Hantzsch Cyclocondensations. J. Org. Chem. 2003, 68, 6172-6183. 

Another procedure for preparation of valuable heterocyclic scaffolds involves the Biginelli condensation on a PEG Support [75, 76]. Polymer-bound acetoacetate was prepared by reacting commercially available PEG 4000 with 2,2,6-trimethyl-4H-l,3-dioxin-4-one in toluene under reflux (Scheme 16.52). The microwave-assisted cyclocondensation was performed with nonvolatile polyphosphoric acid (PPA) as a catalyst in a domestic microwave oven [76]. During microwave heating the PEG-bound substrate melted, ensuring a homogeneous reaction mixture. After the reaction diethyl ether was added to precipitate the polymer bound products. The desired compounds were released by treatment with sodium methoxide in methanol at room temperature. All dihydropyrimidines were obtained in high yield purification was achieved by recrystallization from ethanol. 

Nitro DHPM 256 was synthesized through a modified Biginelli condensation involving cyclocondensation of ot-nitro acetophenone 255 with an aldehyde and urea in the presence of cone. HCl (Scheme 98, Method A) (06BMC1418) or etidronic acid in THE under microwave irridation (Method B, Scheme 98) (09MI3). 

Kurmach and coworkers reported the synthesis of A/-Ar -4-Ar -6-R -1 -R -2-oxo(thioxo)-l,2,3,4-tetrahydropyrimidine-5-carbothioamides 39 via a [2 + 1 + 3]-cyclocondensation reaction, using Biginelli reaction conditions (Scheme 26) (14CHC1770).It was determined that the regioselectivity of this reaction followed the hard/soft Lewis acids and bases principle. 

The Biginelli reaction, that is, a one-pot cyclocondensation of aldehyde, 1,3-keto ester, and either urea or thiourea, is a useful multicomponent reaction which... 

In a three-component process, a P-ketoester, a (preferentially aromatic) aldehyde, and urea undergo cyclocondensation catalyzed by acids, Lewis acids or metal ions to give 3,4-dihydropyrimidin-2-ones (33), whose dehydrogenation [260] leads to pyrimidin-2-ones (34) (Biginelli synthesis) [261-264] ... 

In 1893,11 years after the publication of the Hantzsch dihydropyridine synthesis, the Italian chemist Pietro Biginelli reported a related three-component reaction based on the cyclocondensation of aldehydes, p-ketoesters, and urea, for the synthesis of... 

Khosropour et al. [239] investigated the Biginelli type one-pot oxidation-cyclocondensation reaction of primary alcohols instead of aldehydes, )S-ketoesters, and Bi(N()3)3-5H20 using TBAB (33.5 mol%) to afford pyrimidinones 138 (Scheme 78). The methodology demonstrated significant tolerance toward the ether, halide, and nitro functionalities present in substrates. The same reaction when carried out in acetonitrile furnished product is about 80% yield in 40 min. 

---