Multicomponent synthesis

A -(l-Haloalkyl)pyridinium halides have been advantageously employed in the Hantzsch multicomponent synthesis, yielding alkyl 1,4-dihydropyri-dine-3,5-dicarboxylates, which are a well-known class of calcium channel modulators (81AGE762). Tire halides readily interact with an excess of an ethyl 3-aminobut-2-enoate 82 (R = H) in dichloromethane at room temperature to afford the heterocycles 83 (R = H) in good to excellent yields (65-95%) (92T1263). Tliis observation has been exploited to perform a quantitative study of the reactivity of the salts (93CB1251).Tlie results have... 

A highly efficient multicomponent synthesis of pyridones and pyrimidones by a [2 + 2 + 2] strategy [159]... 

Fig. 21 Microwave-promoted multicomponent synthesis of polysubstituted thiophenes on solid-phase. Reagents and conditions a RCOCH2R (R = H, Me, Et, Bn R = Me, i-Bu, i-Pn, Ph, Bn, cyclohexyl), Ss, DBU, toluene, MW 120 °C, 20 min, closed vessel, 100% b R"COCl (R" = Me, Pr, Ph or COOMe), diisopropylethylamine, toluene, MW 100 °C, 10 min, closed vessel c TEA, H2O, CH2CI2, rt, 2h...

Fig. 29 Microwave-promoted multicomponent synthesis of polysubstituted thiophenes on soluble PEG support. Reagents and conditions a NCCH2OOH, DCC, DMAP, CHCI3, MW 130 W, 5 min b RCOCH2R, S8, diisopropylethylamine, MW 130 W, 15 min c R"COCl, di-isopropylethylamine, 0 °C to rt, 3 h d 1% KCN in CH3OH, o.n. R = H or alkyl R = alkyl or acyl R" = CH3, Ph...

A family of interesting polycychc systems 106 related to pyrrolidines was obtained in a one-pot double intermolecular 1,3-dipolar cycloaddition, irradiating derivatives of o-allyl-sahcylaldehydes with microwaves in toluene for 10 min in presence of the TEA salt of glycine esters [71]. A very similar approach was previously proposed by Bashiardes and co-workers to obtain a one-pot multicomponent synthesis of benzopyrano-pyrrolidines 107 and pyrrole products 108 (Scheme 37). The latter cycloadducts were obtained when o-propargylic benzaldehydes were utihzed instead of o-allyhc benzalde-hydes, followed by in situ oxidation [72]. 

Likewise, an efficient one-pot multicomponent synthesis of annelated 2-amino pyridines (e.g., 17) utilizing [4+2] cycloadditions has been described <06JOC3494>. The process involves the in situ generation of 1-aza-1,3-butadiene from a palladium-catalyzed coupling-isomerization reaction of aryl halides (e.g., 18) with propargyl V-tosylamines (e.g., 19). The resulting butadiene then undergoes cycloadditions with V.S -ketene acetals (e.g., 20) to form annelated pyridines (e.g., 17). 

Another multicomponent synthesis giving N-3-substituted compounds 28 consisted of the sequential reaction of metallated phosphonoacetates, in one pot, with a nitrile then an aldehyde and finally an isocyanate. This was an extensive study of the scope and limitations of the different substituents on all the components. The most important feature was that, for good yields, the isocyanate should bear an electron-withdrawing group - tosyl was the most successful. However, an exchange reaction could be carried out by reaction of the tosyl products with aryl isocyanates under microwave irradiation, giving the N-3-aryl derivatives 29 <06CEJ7178>. 

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>. 

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

Scheme 6.242 Multicomponent synthesis of pyrido-fused tetrahydroquinolines.

Maison W, Schlemminger I, Westerhoff O, Martens J (2000) Multicomponent synthesis of novel amino acid-nucleobase chimeras a versatile approach to PNA-monomers. Bioorg Med Chem 8 1343-1360... 

Banfi L, Basso A, Guanti G, Kielland N, Repetto C, Riva R (2007) Ugi multicomponent reaction followed by an intramolecular nucleophilic substitution convergent multicomponent synthesis of 1 -sulfonyl 1,4-diazepan-5-ones and of their benzo-fused derivatives. J Org Chem 72 2151-2160... 

Banfi L, Basso A, Guanti G, Lecinska P, Riva R (2008) Multicomponent synthesis of benzoxazinones via tandem Ugi/Mitsunobu reactions an unexpected cine-substitution. Mol Div 12 187-190... 

Bohn Rhoden CR, Westermann B, Wessjohann LA (2008) One-pot multicomponent synthesis of N-substituted tryptophan-derived diketopiperazines. Synthesis (Stuttg) 13 ... 

Neo AG, Carrillo RM, Barriga S, Moman E, Marcaccini S, Marcos CE (2007) Multicomponent synthesis of highly substituted 2-pyridones. Synlett 2 327-329... 

Banfi L, Basso A, Guanti G, Riva R (2003) Application of tandem Ugi reaction/ring-closing metathesis in multicomponent synthesis of unsaturated nine-memhered lactams. Tetrahedron Lett 44 7655-7658... 

Rhoden CRB, Westermann B, Wessjoharm LA (2008) One-pot multicomponent synthesis of N-substituted tryptophan-derived diketopiperazines. Synthesis (Stuttg) (13) 2077-2082 Szardenings AK, Burkoth TS, Lu HH, Tien DW, Campbell DA (1997) A simple procedure for the solid phase synthesis of diketopiperazine and diketomorpholine derivatives. Tetrahedron 53(19) 6573-6593... 

In 2007, Tron and Zhu reported the multicomponent synthesis of 5-iminoox-azolines (42) starting from a,a-disubstituted secondary isocyano amides (41), amines, and carbonyl components (see Fig. 15) [155]. The reaction presumably follows a similar mechanism as in the 2,4,5-trisubstituted oxazole MCR (described in Fig. 11) however, because of the absence of a-protons at the isocyano amide 41, the nonaromatized product is obtained. As in the 2,4,5-trisubstituted oxazole MCR, toluene was found to be the optimal solvent in combination with a weak Brpnsted acid. The reaction was studied for a range of aldehydes and secondary amines. In addition, a variety of functionalities such as acetate, free hydroxyl group, carbamate, and esters are tolerated. Clean conversions were observed for this MCR as indicated by NMR analysis of the crude products (isolated yield 50-68%). The... 

Wiles C, Watts P (2008) An integrated microreactor for the multicomponent synthesis of alpha-aminonitriles. Org Process Res Dev 12(5) 1001-1006... 

Scheme 16 Multicomponent synthesis of cyclic guanidine derivatives...

Scheme 35 TMAH-catalyzed multicomponent synthesis of tetrahydrochromenes...

Scheme 40 Multicomponent synthesis of dihydropyrans from substituted styrene...

Scheme 55 Multicomponent synthesis of substituted pyridines and tetrahydroquinolinones...

Wender PA, Handy ST, Wright DL (1997) Towards the ideal synthesis. Chem Ind 765-768 14. Zhu JP (2003) Recent developments in the isonitrile-based multicomponent synthesis of heterocycles. Eur J Org Chem 1133-1144... 

Allais C, Constantieux T, Rodriguez J (2009) Use of p, y-unsaturated a-ketocarbonyls for a totally regioselective oxidative multicomponent synthesis of polyfunctionalized pyridines. ChemEur J 15 12945-12948... 

M11 Yu.M. Litvinov, Multicomponent synthesis of 2-amino-4H-pyrans and... 

A gold(III) catalyzed multicomponent synthesis of aminoindolizines was recently reported by Liu and Yan. This reaction of heteroaryl aldehydes, amines and alkynes took place under solvent-free conditions or in water and represented a high atom economic process. Especially noteworthy was the obtainment of N-indolizine-incor-porated amino acid derivatives by enantiomerically-enriched amino acid substrates without loss of enantiomeric purity [117]. 

Reaction of arylidenecycloalkanones with derivatives of 6-aminouracil is not described in the literature but there are examples of multicomponent synthesis involving cyclic 1,3-diketones and aldehydes. In [244] the treatment of 1,3-dimethyl-6-aminouracil 305 with 1,3-diketones 320 and aliphatic aldehydes in boiling acetic acid was reported to lead to the formation of 1,3-dimethyl-8,9-dihydropyrimido[4,5-/ ]quinoline-2,4,6-trione 321 in yields of 50 60% (Scheme 3.87). 

The hydroamination of alkynes is an efficient way to obtain aldimines with the advantage of avoiding formation of by-products. As shown in Scheme 8.65, the method has been developed into a multicomponent synthesis of a-branched amines. Aldimines 154 are formed using a titanium derivative as catalyst and reacted in situ with an organolithium reagent [141]. 

The following revue deals with Pd-mediated multicomponent synthesis of heterocydes Balme, G. ... 

Scheme 21 Microwave-promoted multicomponent synthesis of pyrazoles and isoxazoles...

Scheme 1.2.1. Multicomponent synthesis of model tripeptides 1 and 2 and the structure of cis-6-tert-butylpipecolic acid 3.

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