Azadienes reaction with alkynes

Since the initial demonstrations of the participation of substituted l,2,4,S-tetrazines ° and oxa-zoles ° ° in [4 + 2] cycloaddition reactions with alkene and alkyne dienophiles, the investigation and application of the Diels-Alder reactions of heteroaromatic systems possessing reactive azadienes have been pursued extensively. A number of general reviewshave treated the spectrum of heteroaromatic azadienes that participate in [4 + 2] cycloaddition reactions and many of the individual heteroaromatic systems have been reviewed separatcly. ° ° An extensive account was published recently and should be consulted for descriptions of the [4 + 2] cycloaddition reactions of the common heteroaromatic azadienes that have been observed to date. 

Oxazoles represent the most widely recognized heteroaromatic azadiene capable of [4 + 2] cycloaddition reactions. The course of the oxazole Diels-Alder reaction and the facility with which it proceeds are dependent upon the dienophile structure (alkene, alkyne), the oxazole and dienophile substitution, and the reaction conditions. Alkene dienophiles provide pyridine products derived from fragmentation of the [4 + 2] cycloadducts which subsequently aromatize through a variety of reaction pathways to provide the substituted pyridines (Scheme 14). In comparison, alkyne dienophiles provide substituted fiirans that arise from the retro Diels-Alder reaction with loss of R CN from the initial [4 + 2] cycloadduct (Scheme 15,206 Representative applications of the [4 + 2] cycloaddition reactions of oxazoles are summarized in Table 14. Selected examples of additional five-membered heteroaromatic azadienes participatiitg in [4 + 2] cycloaddition reactions have been detailed and include the Diels-Alder reactions of thiazoles, - 1,3,4-oxadiazoles, isoxazoles, pyrroles and imidazoles. ... 

Intramolecular Diels-Alder reactions with the inverse electron demand of cyclic azadienes can be set up in pyrimidines which have a dienophilic side-chain such as a terminal alkyne group (360) (Scheme 60). Upon heating, an intramolecular Diels-Alder reaction (361) and a subsequent retro Diels-Alder reaction with loss of HCN take place to yield annelated pyridines (362). This reaction is exemplified by the preparation of furo[3,4-i]pyridin-7(5//)-one (363). The reactivity of intramolecular Diels-Alder reactions is strongly related to the conformational properties of the side-... 

Triazene 257 can also serve as the 1-azadiene to undergo inverse-electron demand Diels-Alder reactions with alkynes or enamines such as 259 to give substituted pyridines 258 or 260. Anderson and Boger recently reported a systematic study of this reaction, demonstrating that the... 

Alkynes can also undergoes consecntive process under silylformylation conditions. Thus, rhodium catalyzed silylformylation of alkyne 217 in the presence of primary or secondary amines leads directly to the azadiene 221 by silylformylation and enamine formation [ 139]. These azadienes undergoes Diels-Alder reaction with dimethyl acetylendicarboxilate to give dihydropyridiaes 222. 

Since the hybridization and structure of the nitrile group resemble those of alkynes, titanium carbene complexes react with nitriles in a similar fashion. Titanocene-methylidene generated from titanacyclobutane or dimethyltitanocene reacts with two equivalents of a nitrile to form a 1,3-diazatitanacyclohexadiene 81. Hydrolysis of 81 affords p-ketoena-mines 82 or 4-amino-l-azadienes 83 (Scheme 14.35) [65,78]. The formation of the azati-tanacyclobutene by the reaction of methylidene/zinc halide complex with benzonitrile has also been studied [44]. 

Enantiopure alkynyl(alkoxy)carbene (37) complexes were produced by formal alkyne insertion into Fisher carbene complexes 39 Reaction of (37) with 1-azadiene gave functionalized 1,4-dihydropyridine (38) with high enantiomeric excess. 

The electron-rich alkyne 14 reacts with the electron-deficient 1,2,4,5-tetrazine 15 in a thermal inverse electron-demand azadiene Diels-Alder cycloaddition reaction (see Key Chemistry). 

Thermal isomerization of amino-substitued 2i/-azirines (e.g. 183 -> 184) results in the formation of 2-azadienes. They react with activated alkynes, e.g. with acetylenedicarboxylic ester (ADE), in a hetero-Diels-Alder reaction, giving dihydropyridines (e.g. 185), which aromatize with elimination of amine yielding pyridine-3,4-dicarboxylic esters (e.g. 186). 

The [4 + 2] cycloaddition of azadienes with alkynes is a poor reaction. However, the reactivity of dienes with Fisher carbenes has been applied to the azadiene 11 providing the 1,4-... 

The synthetic utility of oxazoles as azadienes was further advanced when Grigg and co-workers reported that the Diels-Alder reactions of oxazoles with alkynes provided furans via a tandem Diels-Alder retro-Diels-Alder sequence. Thus 5-ethoxy-4-substituted oxazoles 119 reacted with dimethyl acetylenedicar-boxylate in cold ether to yield 2-ethoxy-3,4-furandicarboxylic acid dimethyl ester 121 in >50% yield (Fig. 3.33). In this case, the intermediate cycloaddition adduct 120 extrudes a molecule of hydrogen cyanide or a nitrile derived from the C-4 substituent of the oxazole, via a retro-Diels-Alder reaction to provide a substituted... 

The 3 -I- 2-cycloaddition reactions of A-alkylsufonylimines with alkenes, enamines, ynamines, diazo compounds, azirines, silyloxydienes, and azadienes have been extensively reviewed. Rhodium(III)-catalysed cycloaddition of cyclic sulfonylketimines with internal alkynes afforded multifunctional spirocyclic sultam products in high... 

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