Multicomponent condensations three-component

In a further example of a multicomponent synthesis, dihydrobenz[/] 1,4 oxazepin-5-ones were prepared in good yields in two steps by combining an initial three-component Ugi condensation with a subsequent Mitsunobu cyclisation to give (124 e.g. R1 = H, R2 = i-Pr, R3 = cyclohexyl, 65%) <06OBC4236>. 

Another frequently used multicomponent reaction is the Kindler thioamide synthesis (the condensation of an aldehyde, an amine, and sulfur). The Kappe group has described a microwave-assisted protocol utilizing a diverse selection of 13 aldehyde and 12 amine precursors in the construction of a representative 34-member library of substituted thioamides (Scheme 6.114) [226]. The three-component con-... 

A different multicomponent route to imidazoles has been described by the group of O Shea, involving the diversity-tolerant three-component condensation of an aldehyde, a 2-oxo-thioacetamide, and an alkyl bromide (5 equivalents) in the presence of ammonium acetate (Scheme 6.201) [364]. This allowed the preparation of a 24-membered 4(5)-alkylthio-lH-imidazole demonstration library from 21 different aldehydes, 12 alkyl bromides, and two 2-oxo-thioacetamides. The library was synthesized in a parallel format using a custom-built reaction vessel. Alkylthioimidazoles... 

Multicomponent reaction systems are highly valued in solid-phase organic synthesis because several elements of diversity can be introduced in a single transformation.1 The Mannich reaction is a classic example of a three-component system in which an active hydrogen component, such as a terminal alkyne, undergoes condensation with the putative imine species formed from the condensation of an amine with an aldehyde.2 The resultant Mannich adducts contain at least three potential sites for diversification specifically, each individual component—the amine, aldehyde, and alkyne—can be varied in structure and thus provide an element of diversity. 

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. 

Groebke, K., Weber, L. and Mehlin, E, Synthesis ofimidazo[l,2-a] annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation, Synlett, 1998, 661 Blackburn, C., Guan, B., Shiosaki, K. and Tsai, S., Parallel synthesis of 3-aminoimidazo[l,2-a] pyridines and pyrazines by a new three-component condensation, Tetrahedron, 1998, 3635-3638 Bienayme, H. and Bouzid, K., A new heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-aminoimidazoles, Angew. Chem., Int. Ed. Engl, 1998, 37, 2234-2237. 

The multicomponent reactions of noncyclic ketosulfones with 3-amino-1,2,4-triazole and 2-aminobenzoimidazole were described in [196]. It was found (Scheme 3.65) that the microwave-assisted three-component condensation... 

Chebanov et al. [202] noted that condensation of the unsaturated acids 236 with 5-aminopyrazoles 220-222 never yielded isomers with opposite location of the aryl and carboxyl groups on the pyridine or pyrimidine rings, respectively. In the case of the multicomponent reaction of aminopyrazoles 220-222 with pyruvic acid 239 and aromatic aldehydes a different direction was observed. Refluxing of the starting materials in acetic acid led exclusively to pyrazolo[3,4-Z ]pyridine-4-carboxylic acids 249-251 instead of the anticipated carboxylic acids 243-248 (Scheme 3.69). The three-component procedures led only to the formation of heteroaromatized compounds even under a nitrogen atmosphere [202]. 

The three-component reaction of pyruvic acid, aldehydes and anilines can also yield pyrrolidine-2,3-dione [198], but in most cases the products of such multicomponent condensations are quinoline carboxylic acids identical to compounds obtained via the reaction of arylidenepyruvic acids [217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228]. 

The catalyst for cleavage of peptide deformylase was searched with a library of catalyst candidates synthesized by the Ugi reaction (Scheme 2) (134). In this multicomponent condensation reaction, the mixture of a carboxylic acid, an amine, an aldehyde, and an isocyanide produces an iV-acyl amino acid amide. The catalyst candidates, therefore, are iV-acylamino acid amides containing various polar and nonpolar pendants as well as the Co(III) complex of cyclen. The Co(III) complex of cyclen (135) was chosen as the proteolytic center in view of the results described in Section V.A. Cyclen with three secondary amines protected with ferf-butyloxycarbonyl (t-boc) groups was incorporated in either the carboxyl or the amine component of the Ugi reaction. Later, the t-boc groups were removed and Co(III) ion was inserted to the cyclen portion. 

In a number of multicomponent condensation reactions, TMSCl has also been utilized to improve the yield or efficacy of the desired product, or is directly incorporated into the final molecules. Examples include the synthesis of Al-aryl-3-arylamino acids from a three-coir onent reaction of phenols, glyoxylates, and anilines, preparation of 2,4,5-trisubstituted oxazoles, or 4-cyanooxazoles, and the three-component BigmeUi reaction... 

The first multicomponent reaction was the Strecker reaction reported in 1850 by Adolf Strecker [241aj. It is a three-component coupling between carbonyl derivatives, amines, and cyanide source, such as hydrogen cyanide, to provide a-aminonitriles which constitute potent starting materials to achieve important a-amino acids by simple hydrolysis. The mechanism of the Strecker reaction involves the initial formation of an imine from condensation of the amine component to the carbonyl component, after which addition of the cyanide component to this imine intermediate follows. Although the first enantioselective, metal-catalyzed Strecker... 

Ramachary and Reddy developed one of these sequences using an amino acid-catalyzed three-component reductive alkylation (TCRA) as the first reaction of their MCC. This multicomponent reaction involved an aldehyde 21, a malonate 22, and the Hantzsch ester 24 under amino acid catalysis starting with a Knoevenagel condensation, which was followed by hydrogenation of the formed olefin 23 to form... 

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. 

Later, these columns were independently rediscovered (Petlyuk, Platonov, Slavinskii, 1965 Platonov, Petlyuk, Zhvanetskiy, 1970) on the basis of theoretical analysis of thermodynamically reversible distillation because this distillation complex by its configuration coincides with the sequence of thermodynamically reversible distillation of three-component mixture (see Chapter 4), but in contrast to this sequence it contains regular adiabatic columns. The peculiarities of Petlyuk columns for multicomponent mixtures are (1) total number of sections is n(n - 1) instead of 2(n - 1) in regular separation sequences (2) it is sufficient to have one reboiler and one condenser (3) the lightest and the heaviest components are the key components in each two-section constituent of the complex and (4) n components of a set purity are products. 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

As mentioned previously in this book, the quest for sustainable, atom-economical, and environmentally friendly chemical processes is a big current issue. Besides one-pot, sequential reaction processes (generally catalyzed by either metals or enzymes), multicomponent reactions have become very important [51]. The Petasis reaction, alternatively called Petasis horono Mannich reaction, is a mUd multicomponent reaction, which was reported first by Petasis and Akritopoulou in 1993 [52]. This reaction allows the one-pot three-component condensation of an aryl- or alkylboronic acid, an amine, and an aldehyde (or generally a carbonylic compound) to generate substituted amines at room temperature (Scheme 6.38). 

Sc(OTf)3 was found to be a versatile catalyst for multicomponent reactions such as Biginelli condensation [55] for the three-component synthesis of a-amino phosphonates [56], and benzothiazoline [57, 58]. A Catalytic amount of Sc(OTf)3 was sufficient for condensation of o-phenylenediamines with ketones to give 2,3-dihydro-IH-1,5-benzodiazepine derivatives in excellent yields under solvent-free conditions (Scheme 12.26) [59]. 

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