Multicomponent reactions carbonyl compounds

It should be noted that carbonyl compounds, more often aldehydes, are usual second reagent in both the groups. Other building-blocks in these multicomponent processes, leading to the formation of five-, six-, and seven-membered heterocycles, can be numerous acids and their derivatives, p-dicarbonyl compounds or other CH-acids, isocyanides, etc. At this, three-component reactions of ABC and ABB types [32] are the most typical for aminoazole, although some four-component ABCC processes were also published. 

The same research group has further performed radical carbonylation reactions on the same microreactor system [36]. First, alkyl halides were initiated and effectively reacted with pressurized carbon monoxide to form carbonyl compounds. The principle was subsequently successfully extrapolated to the multicomponent coupling reactions. 1-Iodooctane, carbon monoxide and methyl vinyl ketone were reacted in the presence of 2,2 -azobis(2,4-dimethylvaleronitrile) (V-65) as an initiator and tributyltin hydride or tris(trimethylsilyl)silane (TTMSS) as catalyst (Scheme 15). 

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. 

Unlike amidines, the multicomponent reaction of a,(3-unsaturated ketones 96 (aliphatic [94] or aromatic [95, 96]) with carbonyl compounds 97 and ammonia, which are the synthetic precursors of amidines, yielded 1,2,5,6-tetrahydropyrimidines 98 instead of dihydroheterocycles. When R3 is not the same as R4 tetrahydropyrimidines 98 were mixtures of diastereomers A and B, in which the relative configurations of stereogenic centers were also established [95, 96]. In contrast to conventional mechanical shaking requiring about 48 h [95], sonicated reactions were completed within 90 min at room temperature and provided the target heterocycles in high yields and purities [96]. Ultrasonic irradiation also significantly expanded the possibilities of such three-component reactions (Scheme 3.29). 

There are a series of communications about the formation of dihydroazines by direct reaction of urea-like compounds with synthetic precursors of unsaturated carbonyls—ketones, containing an activated methyl or methylene group. The reaction products formed in this case are usually identical to the heterocycles obtained in reactions of the same binuclephiles with a,(3-unsatu-rated ketones. For example, interaction of 2 equiv of acetophenone 103 with urea under acidic catalysis yielded 6-methyl-4,6-diphenyl-2-oxi- 1,6-dihydro-pyrimidine 106 and two products of the self-condensation of acetophenone— dipnone 104 and 1,3,5-triphenylbenzene 105 [100] (Scheme 3.32). When urea was absent from the reaction mixture or substituted with 1,3-dimethylurea, the only isolated product was dipnon 104. In addition, ketone 104 and urea in a multicomponent reaction form the same pyrimidine derivative 106. All these facts suggest mechanism for the heterocyclization shown in Scheme 3.32. 

One-electron oxidation systems can also generate radical species in non-chain processes. The manganese(III)-induced oxidation of C-H bonds of enolizable carbonyl compounds [74], which leads to the generation of electrophilic radicals, has found some applications in multicomponent reactions involving carbon monoxide. In the first transformation given in Scheme 6.49, a one-electron oxidation of ethyl acetoacetate by manganese triacetate, yields a radical, which then consecutively adds to 1-decene and CO to form an acyl radical [75]. The subsequent one-electron oxidation of an acyl radical to an acyl cation leads to a carboxylic acid. The formation of a y-lactone is due to the further oxidation of a carboxylic acid having an active C-H bond. As shown in the second equation, alkynes can also be used as substrates for similar three-component reactions, in which further oxidation is not observed [76]. 

The Gewald reaction can be conveniently performed via a multicomponent condensation between sulfur, an -methylene carbonyl compound, and an -cyanoester. The use of ionic liquids as solvents <2004SC3801>, or performing this condensation under microwave irradiation without solvent (Scheme 84) <2005SC1351>, leads to generally better yields of 2-aminothiophenes . 

The reaction of aldehydes 3 with crotyl silanes (e.g. 5) yields 3-methylated homoallylic products such as 6 and 9. Since crotyl silanes are only weak nucleophiles, the carbonyl compound 3 must be activated. This can be done by addition of a Lewis acid (LA) to form the C2ixhony -Lewis acid complex 4. After addition of 5 and aqueous workup, the homoallylic alcohol 6 is obtained. An alkyl-oxo-carbenium ion 8 is available when treating an acetal 7 with acid or when the aldehyde 3 reacts with a silyl ether 10 in the presence of a Lewis or a Brousted acid (multicomponent crotylation). Crotylation of this alkyl-oxocarbenium ion 8 yields homoallylic ethers 9. 

Passerini multicomponent reaction Condensation of isocyanides with carboxylic acids and carbonyl compounds to afford a-acyloxycarboxamides. 330... 

Another type of multicomponent [2 + 2+1] cycloaddition is achieved with diazo carbonyl compounds in the presence of rhodium or copper catalysts. Reaction with additional carbonyl groups within the substrate gives carbonyl ylides. These, as formal 1,3-dipoles, can undergo [3 + 2] cycloaddition with alkenes or alkynes to form heterocyclic ring systems,7 83... 

One may consider the Strecker reaction as the prototypical multicomponent reaction.15 Three reactants, an amine, a carbonyl compound, and a source of cyanide, come together in a single reaction vessel to afford a single product, an a-aminonitrile. Variations on this reaction process include the Bucherer-Bergs, Petasis, Ugi, and amidocarbonylation reactions. 

Other reactions, in which carbenium ion addition to an isocyanide is the key step, are the Passerini and Ugi reactions and reactions of similar type. These multicomponent transformations have recently been reviewed The Passerini reaction starts from an isocyanide, a carbonyl compound and a carboxylic acid. 

T.J.J. MiiUer, In T.J.J. Muller, editor Multicomponent Reactions 1. General Discussion and Reactions Involving a Carbonyl Compound as Electrophilic Component, The Science of Synthesis, Georg Thieme Verlag Stuttgart (2014), p 5. 

The Gewald reaction involves synthesis of 2-aminothiophenes via multicomponent condensation of a-methylene carbonyl compounds, cyano compounds, and sulfur. Recently, Tayebee et al. (2013) have successfully accomplished a rapid and efficient synthesis of 2-aminothiophenes (105) from ketones or aldehydes (103), malononi-trile (16), and sulfur (104) via a one-pot three-component Gewald reaction in the presence of a catalytic amount of ZnO nanoparticles (Scheme 9.31). The catalyst required for the reaction was synthesized through sedimentation of zinc acetate dihydrate in ethanol. 

In this chapter, only the most recent multicomponent versions of the Hosomi-Sakurai reaction will be covered [68b], in particular those that allowed the synthesis of homoallylic ethers through the combination of an aldehyde (or ketone) with a silyl ether or the corresponding alcohol and an allylsilane (Scheme 12.13, Eq. 1). And also, the synthesis of homoallylic amines where the allylsilane reacts with an imine in situ formed from the carbonyl compound and an amine is known as aza-Sakurai reaetion (Scheme 12.13, Eq. 2). 

Finally, Chen s work on the direct allylation of carbonyl compounds using benzyl alcohol in the multicomponent Sakurai reaction catalyzed by selective and green solid acids, such as sihcomolybdic acid (SMA-SiO ) [92] or perchloric acid (HClO -SiOj) [93], both supported on silica gel, should be mentioned. In some cases, the use of preformed acetals as substrates provided better results. These methods allowed the synthesis of a broad number of homoallylic ethers in moderate to high yields in a short reaction time. Significantly, catalyst loading of HClO -SiOj is only 2mol%. 

HomoallyUc amines are useful intermediates in the synthesis of biologically active compounds such as statin, conine, lobeline, sedamine, SKF-1(K)330-A, epothilone, p-lactams, p-amino acids, and many natural products. The synthesis of those interesting precursors is also possible starting from an imine instead of a carbonyl compound, through this kind of reactivity, known in this case as aza-Sakurai reaction [94, 95]. Its multicomponent version involves the in situ formation of that imine, and few recent examples are shown here. 

A convenient and clean water-mediated synthesis of a series of 4-amino-2-ar-yl-1,2-dihydro pyrimido[l,2-a]benzimidazoles has been reported using alternative nonconventional energy sources [37]. The products were obtained in shorter times with excellent yields (78-89 %) from the multicomponent reaction of 2-ami-nobenzimidazole, malononitrile/ethylcyanoacetate, and carbonyl compounds (Scheme 8.26). The procedure does not involve the use of aity additional reagent/ catalyst, produces no waste, and represents a green synthetic protocol with high atom economy. The combination of microwave irradiation, ultrasonic irradiation, and aqueous-mediated conditions using multicomponent reactions leads to enhanced reaction rates, higher yields of pure products, easier workup, and sometimes selective conversions. Consequently, this protocol should be welcome in these environmentally aware days. 

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