Michael multicomponent reaction

M. N. Elinson, R. F. NasybuUin, G. I. Nikishin, C. R. Chim. 2013, 16, 789-794. Sodium acetate catalyzed tandem Knoevenagel-Michael multicomponent reaction of aldehydes, 2-pyrazolin-5-ones, and cyano-functionalized C-H acids facile and efficient way to 3-(5-hydroxypyrazol-4-yl)-3-aryl-propionitriles. 

Ramachary, D.B. Barbas, C.R III (2004) Towards Organo-Click Chemistry Development of Organocatalytic Multicomponent Reactions Through Combinations of Aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen Cycloaddition Reactions. Chemistry A European Journal, 10, 5323-5331. 

Other interesting multicomponent sequences utilizing isocyanides have been elaborated by Nair and coworkers. In a recent example, this group exploited the nucleophilic nature of the isocyanide carbon, which allows addition to the triple bond of dimethyl acetylenedicarboxylate (DMAD) (9-90) in a Michael-type reaction (Scheme 9.19) [59]. As a result, the 1,3-dipole 9-91 is formed, which reacts with N-tosylimines as 9-92 present in the reaction vessel to give the unstable iminolactam 9-93. Subsequently, this undergoes a [1,5] hydride shift to yield the isolable aminopyrroles 9-94. In addition to N-tosylimine 9-92 and cyclohexyl isocyanide (9-89), substituted phenyl tosylimines and tert-butyl isocyanide could also be used here. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

Multicomponent reactions of this type, in the concepts of Tietze, who introduced the term domino reactions (96CRV115), can also be regarded as domino reactions of the type Knoevenagel-Michael-ljef-ero-Thorpe-Ziegler in accordance with the probable mechanistic scheme (Scheme 32). 

Palladium chemistry has been used in the synthesis of tetrahydroisoquinolines. Different combinations of iodoaryl-amine-alkene can be used in these multicomponent reactions. For example, the metal-mediated o-alkylated/alkenyl-ation and intramolecular aza-Michael reaction (Scheme 109) give moderate yields of heterocycle <2004TL6903>, whereas the palladium-catalyzed allene insertion-nucleophilic incorporation-Michael addition cascade (Equation 172) produces good yields of tetrahydroisoquinolines in 15 examples <2003TL7445> with further examples producing tetrahydroquinolines (Scheme 110) <2000TL7125>. 

The first multicomponent reaction initiated by a Michael addition combining enamine and iminium ion activations was reported by j0rgensen et al., in 2005... 

As initially stated, the definition of multicomponent reaction could be extended also to those reactions that implicate the addition of further reagents only after a suitable time from the very beginning of the procedure. Among others, few Chinese groups reported two notable examples of one-pot Michael addition/Pictet-Spengler cyclization sequence. In particular, in 2011, Zhao et al. developed a high enantioselective organocatalytic synthesis of several... 

Regarding carbon nucleophiles, phosphoric acids have been applied as organocatalysts in multicomponent reactions between diazo compounds, alcohols, or amines, and aldehydes, imines, or Michael acceptors [76]. Diazo compounds can be converted into the respective metallocarbenes in the presence of dirhodium (n) carboxylates complexes [77], Such intermediates can suffer a nucleophilic attack from alcohols or amines generating oxygen or nitrogen ylides that may undergo a proton shift, furnishing the respective O-H or N-H insertion products (insertion pathway. Scheme 26.14). 

Other types of multicomponent reactions have also been successfully developed, such as the first practical three-component imino-Reformatsky reaction, and a pseudo-three-component reaction between allenes and isocyanates, providing excellent levels of enantioselectivity. Finally, excellent results were described for several novel enantioselective tandem sequences. For example, very high enantioselectivities were reached in tandem Michael/ intramolecular cyclisation sequences, as well as in a remarkable multicat-alytic Michael sequence occurring between enones, alkynes, and DIBAL, which stereoselectively afforded a range of chiral p-alkenyl ketones bearing an all-carbon-substituted quaternary stereogenic centre in excellent enantioselectivities. 

Another diarylprolinol ether has been used to catalyse several asymmetric domino Michael reactions. Therefore, Jorgensen et al. have demonstrated its efficiency for the asymmetric synthesis of 1,4-dihydropyridines, which are closely related to the NADH system, a biological system of utmost importance, and moreover these molecules are important drugs used in the treatment of a number of diseases, such as cardiovascular diseases and Alzheimer s disease. Thus, a series of chiral 1,4-dihydropyridines were prepared on the basis of a one-pot multicomponent reaction between a a,p-unsaturated aldehyde, a P-diketone... 

Keywords Michael acceptors, amines, carbon disulfide (CS2), neat condition, room temperature, one-pot multicomponent reaction, dithiocarbamates... 

Catalyst 5-Hydroxypentylammonium acetate (5-HPAA reusable task-specific ionic liquid) Keywords Alkyl/aryl/heteroaryl aldehydes, nitromethane, trialkylphosphites, 5-HPAA, solvent-free, room temperature, one-pot tandem Henry-Michael reaction, multicomponent reaction, terminal vinylphosphonates... 

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