Four-component cyclocondensation

Scheme 4.11. Pseudo-four-component cyclocondensation leading to spiroheterobicycles.

Four-component cyclocondensation of 1, aromatic aldehydes, mal-ononitrile, and ammonium acetate proceeded under MW irradiation in solvent-free conditions to give highly functionalized hexahydroquino-lines in excellent yield. The crystal structure of 2-amino-3-cyano-4-phe-nyl-7,7-dimethyl-5-oxo-l, 4,5,6,7,8-hexahydroquinoline was determined (06JHC985). 

Rostamnia and Lamei (2012) have described a simple SSA-catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2-(l//)-one derivatives via a four-component cyclocondensation reaction of diketene, alcohols, and aldehydes with urea (Schane 6.4). The present method has several advantages, such as the reaction can be performed under one-pot neat conditions, and, in addition to the aldehyde component, the alcohols component can be modified to synthesize derivatives. The easy approach and the variability in derivatives in the presence of a heterogeneous catalyst make it an alternative to the three-component approaches. 

This multigeneration strategy for the synthesis of pyrimidines combines efficiently a novel cyclocondensation reaction using the highly reactive acetylenic ketones 153215,218 to build the pyrimidine skeleton, with a multicomponent reaction, and a multidirectional cleavage procedure. The Ugi four component reaction is especially useful in the context of building peptidomimetic-derived combinatorial libraries as it affords directly dipeptide analogues of type 159. 

The use of palladium-based chemistry continues to generate methods for heterocyclic synthesis. In a four-component reaction, ring-fused pyridines can be synthesized in one pot, referred to as a coupling-isomerization-enamine addition-cyclocondensation sequence (Scheme 106) <2005EJ01834>. 

Therefore, based on the known cyclocondensation of arylidenemalonodinitriles and 1-arylethylidenemalonodinitriles in the presence of piperidine to give 1,6-di-cyanoanilines [66a], Wang and coworkers [67] have developed a straightforward microwave irradiation-assisted pseudo-four-component synthesis of the anilines 62. Thus, the reaction of (hetero)aromatic aldehydes 63, acyclic and cyclic ketones 64 and 2 equiv. of malononitrile in the presence of triethylamine or piperidine furnishes, after 2 min of 300 W-irradiation power, 51-63% of 2,6-dicyanoanilines 62 (Scheme 5.12). 

MUller reports a four component, one-pot synthesis of pyridines <02TL6907>. For example, aryl halide 15 and propargylic alcohol 16 were combined in the presence of copper and palladium to afford enone 17. The addition of cyclic enamine 18 led to Michael addition and the subsequent cyclocondensation was achieved by adding ammonium chloride and acetic acid (19—>20). Other multicomponent approaches to substituted pyridines have been reports by Litvinov <02RCBIE362>, Elkholy <02SC3493> and Veronese <02T9709>. 

Scheme 22 Couplmg-addition-cyclocondensation-coupling four-component s)mthesis of P5oazole 31...

Scheme 25 Carbonylation-coupling-addition-cyclocondensation four-component synthesis of pyrimidines 33...

Scheme 35 Coupling-transacetalization-addition-cyclocondensation-Suzuki coupling four-component synthesis of 3-aryl furans 61...

Scheme 54 Cl-cycloaddition-cyclocondensation four-component synthesis of dihydropyrindines 99, tetrahydroquinolines 100, naphthyridines 101, and substituted pyridines 102...

Muller and co-workers demonstrated the synthesis of pyridines using a one-pot, four-component process they refer to as a coupling-isomerization-enamine addition-cyclocondensation sequence (Scheme 5) <05EJOl 834>. In a stepwise fashion, this sequence can be explained as an initial reaction of an electron-deficient halide 15 with a terminal alkyne 16,... 

A four-component reaction involving tandem indium chloride-catalyzed cyclocondensation of ammonium acetate 124, glyoxal derivatives 125,2-azidobenzaldehyde derivatives 126, and propargylamines 127 followed by intramolecular azide-alkyne 1,3-dipolar cycloaddition reactions afforded highly functionalized benzo-imidazo-triazolodiazepines 128 (130L4492). 

Perumal has described a four-component sequential protocol that allows the synthesis in good yields of antitubercular 2-aryl-5-methyl-2,3-dihydro-l/f-3-pyrazolones 18 from atylhydrazines, methyl acetoacetate, aromatic aldehydes and 5-naphthol in the presence of / -TSA in water under reflux conditions [13], The reaction proceeds by an initial acid-catalyzed cyclocondensation of the hydrazine and dicarbonyl components to give pyrazolinone 19. A parallel acid-catalyzed condensation between p-naphthol and the aromatic aldehyde affords the intermediate quinone methide 20, and Michael addition of the enol form of 19 onto the exocyclic double bond of 20 furnishes the final product (Scheme 1.9). 

Muller s group developed a one-pot three-step four-component process for the construction of dihydropyrindines and tetrahydroquino-lines [96]. Through a coupling-isomerization-Stork-enamine alkylation-cyclocondensation sequence of an electron poor (hetero)aryl halide, a... 

Yan et al. (2007) reported that polysubstituted annulated pyridines can be synthesized in high yields by four-component, one-pot cyclocondensation reactions of N-phenacyl pyridinium bromide, aromatic aldehydes, acetophenones or cyclic ketones in the presence of ammonium acetate and acetic acid, assisted by microwave irradiation. Cyclic ketones with two a-CH groups yield annulated pyridines with additional a-benzylidene groups, which are derived in situ from double aldol condensation of cyclic ketones with two moles of aromatic aldehydes. 

Typically, these heterocycles are synthesized by the cyclocondensation of 2-aminopyrimidine with a suitable R-bromoacetophenone in polar solvents [129-131]. Shaabani et al. reported a three-component condensation reaction of aldehydes, 2-amino-5-methyl-[Br]pyridines, and isocyanides to afford 3-aminoimidazo[l,2-fl]pyridines 65 in good yield (Scheme 25) at RT in the presence of [BMlM][Br] in a molar ratio of 1 1.4 (reactant/IL) [132]. In the absence of IL, the yield of 65 could not exceed beyond 25% at RT even after 12 h, which established [BMIM][Br] as an essential component of the reaction. On four times recycling and reuse of IL, a gradual decrease in the yield of 65 (95%, 92%,... 

There is at least one multicomponent reaction that uses four different components that lead to formation of four of the five bonds within a 3-pyrrolin-2-one ring. Zeng, Ye, and coworkers developed a Pd-catalyzed type acde multicomponent approach to amine-substituted 3-pyrrolin-2-ones (Scheme 112 20120L5640). Mixing three equivalents of ethyl glyoxalate (423) and two equivalents of p-anisidine (405) with a Pd catalyst led to formation of the 3-arylamino-3-pyrrolin-2-one 426. A suggested mechanism includes the Pd-mediated formation of imine 424 and enamine 425 and subsequent cyclocondensation leading to 426. 

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