Biginelli Multicomponent Reactions

The Gong group utilized 2a in the multicomponent Biginelli reaction to provide structurally diverse 3,4-dihydropyrimidin-2(lH)-ones in high yields and ee s (Scheme 5.19) [33]. Notably, the authors found that bulky 3,3 subshtuents on the catalyst had a deleterious effect with respect to yields and enantioselectivities. 

Arunkhamkaew et al. [174] reported the synthesis of racemic tetrahydro cur cumin- (THC-), tetrahydrodemethoxycurcumin-(THDC-), and tetrahydrobisdemethoxycurcumin- (THBDC) dihy-dropyrimidinone (DHPM) analogs utilizing the multicomponent Biginelli reaction in the presence of copper sulfate as a catalyst. THBDC-DHPM demonstrated the most potent inhibitory activity. 

N. Sharma, U. K. Sharma, R. Kumar, Richa, A. K. Sinha, RSC Adv. 2012, 2, 10648-10651. Green and recyclable glycine nitrate (GlyNO ) ionic liquid triggered multicomponent Biginelli reaction for the efficient synthesis of dihy dropyrimidinones. 

Contemporaneously, Feng s group disclosed a trans-4-hydroxyprolinamide-derived 38 as chiral secondary amine catalyst in this enantioselective multicomponent Biginelli reaction [51]. The final products 39 were obtained with high yields and better enantioselectivities compared with the latter example (Scheme 9.14). 

An important multicomponent transformation for the synthesis of dihydropyrimidines is the Biginelli reaction, which involves the acid-catalyzed condensation... 

Heterocyclic chemistry has been a major beneficiary of MW-expedited solvent-lfee chemistry utilizing mineral supported reagents. It has been exploited for parallel synthesis, a strategy that is adaptable for multicomponent reactions, such as Ugi " and Biginelli reactions " , for rapid assembly of a library of compoimds. A representative multi-component condensation reaction to create a small-molecule library of imidazo[l,2-a]pyridines, imidazo[l,2-a] pyrazines, and imidazo[l,2-a]pyrimidines is depicted in Scheme 3. 

Potentially useful heterocyclic libraries can also be prepared by the application of solution-phase combinatorial chemistry. Although multiple reactions in solution have often been complicated by the difficulties with liquid-liquid extractions the introduction of solid scavengers and equipment to automate these extraction processes allows hundreds of reactions to be managed simultaneously. A typical example is a series of aminothiazole derivatives which has been prepared starting from acyclic precursors (Scheme 3.9). Naturally one-pot multicomponent condensations such as the Ugi (library 84) [332], Passerini or Biginelli reactions present one of the simplest... 

Dihydropyridines can be prepared via the three-eomponent coupling of cinnamaldehyde, aniline and p-keto esters under solvent-free conditions by means again of L-Pro as catalyst in the transformation. The three-component reaction of 1,3-indanedione, isatins and enamines as the nucleophiles is also possible in the presence of L-Pro for the one-pot synthesis of highly functionalised spirooxindoles derivatives. While only some examples are highlighted here, ° ° the possibilities of L-Pro in multicomponent reactions are tremendous. It has also shown good catalytie activity in classic multicomponent reactions such as Biginelli reactions and Hantzsch dihydropyridine synthesis. 

Biginelli reaction is one of the most remarkable examples of multicomponent reactions (MCRs) discovered in 1891 [1, 2], and proof of its importance is the high number of articles reported in the last decade covering this field. Very recently, an amazing and comprehensive review has appeared covering this reaction with more than 500 references [3], In this chapter, we will just cover only some aspects overlooked in the incredible revision performed by Suresh and Sandhu and reported since 2006. 

J.-P. Wan, Y. Liu, Synthesis 2010, 3943-3953. Synthesis of dihydropyiimidinones and thiones by multicomponent reactions strategies beyond the classical Biginelli reaction. 

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 number of multicomponent condensation reactions, TMSCl has also been utilized to inprove the yield or efficacy of the desired product, or is directly incorporated into the final molecules. Examples include the s)fnthesis of Al-aryl-3-arylamino acids from a three-component reaction of phenols, glyoxylates, and anilines, preparation of 2,4,5-trisuhstituted oxazoles, or 4-cyanooxazoles, and the three-component Biginelli reaction (eq 92) and Biginelli-like Mannich reaction of carhamates, aldehydes, and ketones. 

Despite the chemical complexity of multicomponent reactions (MCRs), the dawn of MCRs was fairly early in the history of organic chemistry. The first MCR was the so-called Strecker reaction discovered in 1850 [1, 2], which generates amino acids via a three-component reactiOTi between amines, aldehydes (or ketones), and hydrogen cyanide (Scheme 1). Since then, organic chemists have devoted much effort to the discovery of additional MCRs. Thus, we now can find a number of MCRs, including the Biginelli reaction [3], the Gewald reaction [4], the van Leusen three-component reaction [5], the Hantzsch reaction [6], the Mannich reaction [7], the Kabachnik-Fields reaction [8, 9], the Passerini reaction [10], the Ugi reaction [11, 12] and numerous variations thereof [13]. 

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