Cycloadditions multi-component reactions

In an exploration of multi-component reactions for the synthesis of a diverse array of heterocyclic scaffolds Martin et al. demonstrated a cascade reaction involving the imine, formed from the condensation of 2-azidobenzaldehyde 97 with propargylamine, acetyl chloride and ketene acetal 98 to furnish the triazolo-fused benzodiazepine 99 via an intramolecular [3+2] cycloaddition <07OL4223>. 

Solution-phase multicomponent methodology for the synthesis of heterocyclic compounds, (non-catalytic syntheses, catalysis with acids and metals, multi-component reactions including cycloaddition are reviewed) 03S1471. 

A straightforward synthesis of fused dihydrotriazolo[l,5-Q ]pyrazinones and triazolobenzodiazepines by sequential Ugi/alkyne-azide cycloaddition reactions was recently demonstrated by Djuric et al. [55]. The couphng of the Ugi multi-component reaction with the intramolecular alkyne-azide cycloaddition provides access to highly functionaUzed heterocyclic ring systems in just two steps. 

Parsons and co-workers reported a multi-component reaction (74 -i- 75 + 76 -i- 77) involving sequential [ l-i-3] and [2-i-3] cycloadditions for the synthesis... 

B. Groenendaal, E. Ruijter, R. V. A. Orru, Chem. Commun. 2008, 5474-5489. 1-Azadienes in cycloaddition and multi-component reactions towards A -heterocycles. 

For this multi-component reaction (MCR [28]) proceeding without the need for a further catalyst, a mechanism is suggested which involves primary attack of the isocyanide to the triple bond of DMAD followed by 1,3-dipolar cycloaddition of the resulting dipole 87 to the aldehyde C=0 group (87 88) subsequent (l,5)-H-shift in 88 complements formation of the aminofuran system 86. 

Wright DL, Robotham CV, Aboud K (2002) Studies on the sequential multi-component coupling/Diels-Alder cycloaddition reaction. Tetrahedron Lett 43 943-946... 

Multi-component couplings open up an economic and straightforward route to very different compound libraries. For example, 1,3-dipolar cycloaddition reactions of nitrones with alkenes furnish isoxazolines, which can be transformed reductively to hydroxyketones or )8-amino alcohols. In 1997, two groups reported on the synthesis of isoxazolines by rare earth metal-catalyzed [3 + 2] cycloadditions (Scheme 4) [13,14]. 

For representative reviews on metal-catalyzed MCRs, see (a) D. M. D Souza, T. J. J. Muller, Chem. Soc. Rev. 2007, 36, 1095-1108. Multi-component syntheses of heterocycles by transition-metal catalysis, (b) J. A. Varela, C. Saa, Synlett 2008, 2571-2578. Recent advances in the synthesis of pyri-dines by transition-metal-catalyzed [2+2+2] cycloaddition, (c) H. Clavier, H. PeUissier, Adv. Synth. Catal. 2012, 354, 3347-3403. Recent developments in enantioselective metal-catalyzed domino reactions. 

Z. N. Tisseh, M. Dabiri, M. Nobahar, H. R. Khavasi, A. Bazgir, Tetrahedron 2012, 68,1769-1773. Catalyst-free, aqueous and highly diastereoselective synthesis of new 5-substituted H-tetrazoles via a multi-component domino Knoevenagel condensation/l,3-dipolar cycloaddition reaction. 

A transannular 4 + 2-cycloaddition initiates the tandem 4 + 2/3+2-cycloaddion cascade of 1,3,4-oxadiazoles (1) to yield cycloadduct intermediates (2) used for the synthesis of analogues of vinblastine (Scheme 1)." The multi-component 4+ 2/3+2-domino cycloaddition reactions of 3-nitroindole derivatives with vinyl ethers and acrylates were studied computationally and experimentally. The 4+2-reaction follows a classical concerted asynchronous process while the 3 + 2-addition involves an electron donation by an electron-deficient reaction partner. ... 

S.M. Rajesh, B.D. Bala, S. Perumal, Multi-component, 1,3-dipolar cycloaddition reactions for the chemo-, regio- and stereoselective synthesis of novel hybrid spiroheterocycles in ionic liquid. Tetrahedron Lett. 53 (2012) 5367-5371. 

Bora and co-workers44 have developed a microwave-assisted three-component synthesis of indolizines. The reaction involves a 1,3-dipolar cycloaddition reaction between the in situ generated dipole (from the bromoacetophenone and pyridine) and acetylene, Scheme 5.26. The developed method provides fast access to cycloadducts, which otherwise are accessible only through multi-step synthesis. 

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