Condensation/cycloaddition cascade

Coldham, A. J. M. Burrell, L. Watson, N. Oram, N. G. Martin, Synthesis of fused tricyclic heterocycles by condensation, cyclization, dipolar cycloaddition cascade of a-benzenesulfonyl and a-phenylthio substituted aldehydes. Heterocycles 84 (2012) 597-613. 

Stabilized azomethine ylides can easily be formed using amino acids and their esters to generate an imine that is subsequently alkylated to generate an iminium ion. Decarboxylation or deprotonation then affords the reactive azomethine yhde. Coldham and coworkers examined the scope of this type of condensation—alkylation—cycloaddition cascade wherein the... 

Coldham and coworkers reported a tandem condensation/cyclization/intramolec-ular cycloaddition cascade process to form fused tricychc amines, using azomethine ylides (derived from a-amino-acids or esters). This chemistry was apphed for the constmction of the pyrrolo[l,2-a]azepine ring system of the Stemona alkaloids (Scheme 4.20) [39]. Condensation of the aldehyde 96 bearing a dipolarophile (an... 

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>. 

Furans are also useful 4ji components for tandem Ugi condensation/intra-molecular Diels-Alder cascade reactions. For example, stirring a methanolic mixture of compounds 127-129 and benzylamine at rt provided the Ugi condensation product 130 that underwent a subsequent intramolecular Diels-Alder cycloaddition to furnish 131 in 70-90% yield (Scheme 23) (99TL1851). This methodology also allowed for a solid phase synthesis by using an ArgoGel-Rink resin as the amine component, providing cycloadducts 131 (after cleavage from the resin) in ca. 90-95% yields. 

Taylor and Raw recently designed a tethered imine-enamine cascade sequence that converts 1,2,4-triazenes into substituted pyridines. In the presence of molecular sieves, A-methylethylenediamine (147) underwent condensation with excess cyclic ketone 148 (n — 1-4) to give imine-enamine 150 (04CC508). The enamine portion of the molecule then participated in an inverse-demand Diels-Alder cycloaddition reaction with 149 to provide intermediate 151. Cycloreversion of 151 with loss of N2 then gave 152 in which the tertiary amino group underwent addition to the adjacent imine functionality to afford zwiterionic 153. Finally, an intramolecular Cope elimination produced 154 in 74-100% yield. Several other triazines were also shown to participate in this novel cascade (Scheme 27). 

Blechert et developed a multicomponent cascade reaction for the synthesis of indole derivatives as depicted in Scheme 1.8.5.17. The first step of the sequence involves formation of a nitrone derivative starting from phenylhydroxylamines and aldehydes. The resulting nitrones were not isolated but captured by a cyanoallene in a 1,3-dipolar cycloaddition reaction followed by hetero-Cope rearrangement, ring-opening and condensation to yield an indole derivative. 

Coldham et al. reported on a cascade reaction sequences involving condensation, cyclization, intramolecular dipolar cycloaddition for preparation of fused tricyclic heterocycles which can be converted in two steps to a 1,3-oxazine present in some yuzurimine-type Daphniphyllum alkaloids under some conditions [57], In another study, addition of hydroxylamine to substituted 4-chlorobutanals gives intermediate nitrones that imdergo tandem cyclization and then intramolecular dipolar cycloaddition to give the core... 

Coldham, L. Watson, H. Adams, N. G. Martin, Synthesis of the core ring system of the yuzurimine-type Daphniphyllum alkaloids by cascade condensation, cyclization, cycloaddition chemistry, J. Org. Chem. 76 (2011) 2360-2366. 

Enders described a fascinating organocatalytic one-pot asymmetric synthesis of tricyclic compounds using a triple-cascade/Diels-Alder reaction sequence. Combination of dieneal 110 with enal 111 and nitro alkene 112 in the presence of a chiral amine catalyst results in a Michael/Michael/aldol condensation sequence to yield cycloaddition precursor 113. Cooling the reaction mixture and addition of a Lewis acid promotes the desired intramolecular Diels-Alder reaction to selectively afford the highly functionalized tricyclic target 114. ... 

Murugavel and Punniyamurthy developed a Cul-catalyzed one-pot synthesis of iminocoumarin aryl methyl ethers from ynal, phenol, and sulfonyl azide via a cascade [3-1-2]-cycloaddition, 1,3-pseudopericyclic ketenimine rearrangement, 1,4-conjugate addition, and aldol-type condensation at room temperature under air [195] (Scheme 8.120). 

In 2012, Mark J. Kurth et al. developed an operationally simple, one-pot, two-step cascade method to afford quinazolino[l,2,3]triazolo[l,4]benzodiazepines 112 (Scheme 4.43) [44]. Fascinatingly, this unique, atom-economical transformation engaged five reactive centers (amide, aniline, carbonyl, azide, and alkyne) and employed environmentally benign iodine as a catalyst. The method seemed to proceed via sequential quinazolinone-forming condensation and intramolecular azide-alkyne 1,3-dipolar cycloaddition reactions. The substrate... 

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