Condensed-phase cycloadditions

The retro-1,3-dipolar cycloaddition of imidazo[l,5- ][l,2,4]oxadiazoles 40, promoted by reaction with triphenylphos-phine at reflux in THF, gives the cyclic nitrones 187 (unreported yields) (Equation 15) <1997T13873>. The ring opening of compounds 40 leading to heterocycles 187 (Equation 15) can also be achieved thermally in the condensed phase under vacuum <1997TL2299>. 

The photoreactions of a-dicarbonyl compounds are quite different in the vapor and condensed phases. In the vapor phase, carbon-carbon bond cleavage is the preferred mode of reaction but in the condensed phase, many of the observed reactions can be rationalized by a mechanism involving hydrogen abstraction. Internal hydrogen abstraction, when possible, is generally preferred over abstraction from the solvent. With the exception of diethyl oxalate, which undergoes photoreactions typical of an ester, only those compounds that are reasonably strained or can yield reasonably stable free radicals give decarbonylation products. In the presence of suitable substrates, cycloaddition reactions have also been observed. 

An in situ method for the preparation of N-methyleneamines has been devised by Overman and Osawa for use in condensation reactions with enolates and organometallic reagents. These species, with the exception of very hindered N-methyleneamines, cannot be isolated in the condensed phase because they rapidly trimerize to hexahydro-l,3,5-triazines. In this in situ method, A -methyleneamines (230) are generated from N-(cyanomethyl)amines (228) by deprotonation with an equivalent of enolate to give an intermediate amide (229) which loses LiCN (equation 22). When two equivalents of enolate are present, addition to the N-methyleneamine occurs and 3-lactams (233) are obtained in 60-70% yield upon warming the reaction mixture to 25 C (Scheme 48 Table 26). Uncyclized 3-amino esters can be isolated if the reaction is quenched at lower temperature a possible cycloaddition mechanism is thus ruled out. It is not clear to what extent, if any, the reaction is limited to a,a-disubstituted enolates. N-Methyleneamines, like oxime ethers, are useful for the synthesis of 4-unsubstituted 3-lactams and should also have important applications in the synthesis of monobactam antibiotics. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

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. 

Resin-bound nitroalkenes were synthesized via a Knoevenagel condensation of resin-bound nitro acetic acid with aryl and alkyl substituted aldehyde (Scheme 9.29). In this way an extra site of diversity can be introduced into the cycloaddition products of these nitroalkenes. Furthermore, the resin-bound nitroalkenes can serve as activated alkenes in other cycloaddition reactions (Diels-Alder, 1,3-dipolar cycloaddition, [2 + 2] cycloaddition) and therefore lead to the solid phase synthesis of other interesting compoimd classes (see also Scheme 9.3, Sect. 9.2). Formation of the resin-bound nitroalkenes 73a-e was realized in one step via a microwave-assisted condensation of aldehyde 72a-e (10 equiv.) with the resin-bound nitro acetic acid 71, followed by dehydration of the intermediate y -nitroalcohol [6] (Scheme 9.29). THF was used as the solvent in order to obtain optimal diffusion of the aldehyde in the polystyrene resin. 

An elegant method for the solid-phase synthesis of quinolinone 9 derivatives has been developed by Pei et al. [43]. Using the teabag technology, the synthesis of a 4-amino-3,4-dihydro-2(l//)-quinolinone library was carried out through the rearrangement of /3-lactam intermediates on the solid phase. The condensation of o-nitrobenzaldehyde with a resin-bound amino acid yielded an imine that, following [2-1-2] cycloaddition with ketenes, afforded the -lactams (Fig. 3g). 

Solid-phase and combinatorial synthesis of 6-lactams using the Staudinger reaction has widely been studied. Carbohydrates as a chiral pool, however, were not employed except for one report [148]. The polymer supported-imines were employed to prepare several -lactams by enolate/imine condensation and ketene/imine cycloaddition (Scheme 46) [146]. The reactions carried out on the polymer-boimd imines showed a remarkable similarity to those in solution, both in terms of yield and stereoselectivity [54,55]. )S-Lactams were removed from the polymer by CAN oxidation [ 148]. 

Solid-phase synthesis of pyrroles was reported by Mjalli et al. " Pyrroles were prepared via Rink resin-bound mesoionic munchnones (Scheme 11.12). Munchnones behave as azomethine ylides in 1,3-dipolar cycloaddition. Cycloadditions with alkynes give pyrroles after aromatization and spontaneous release of carbon dioxide. A set of compounds was obtained from simple starting materials, aldehyde, amine, carboxylic acid, and isocyanide via the Ugi four-component condensation. Trifluoroacetic acid released highly substituted pyrroles as amides from the Rink resin in high overall yield and purity. A related method via the miinchnone pathway was reported by Strocker et al., and two pyrroles were obtained in 4% and 17% yields. 

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