Heteroaromatic Azadienes

Few examples of the preparation of six-membered heteroaromatic compounds using Fischer-type carbene complexes have been reported [224,251,381]. One intriguing pyridine synthesis, reported by de Meijere, is sketched in Figure 2.35. In this sequence a (2-aminovinyl)carbene complex first rearranges to yield a complexed 1 -azadiene, which undergoes intermolecular Diels-Alder reaction with phenylacetylene. Elimination of ethanol from the initially formed adduct leads to the final pyridine. 

Five-membered heteroaromatic systems that possess an electron-deficient azadiene substructure, e.g., oxazoles and thiazoles, are suitable for participation in Diels-Alder reactions with inverse electron-demand [49JA3062 59JA4342 62AG(E)329]. The introduction of strongly electron-donating substituents in many cases is sufficient to overcome the electron-deficient nature of the azadiene moiety and permits normal HOMO diene/ LUMO dienophile controlled Diels-Alder reactions (87MI6). 

A limited number of examples of this class of reactions exist. One heteroaromatic compound which has been used as an azadiene in inverse electron demand reactions with electron-rich imines is tetrazine... 

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. 

As with the simple heterodienes, the electron-deficient heteroaromatic azadienes have proven ideally suited for 4Tt participation in LUMOdiene-controlled Diels-Alder reactions. In fact, it was Ae recognition of this electron-deficient nature of heteroaromatic azadienes that led to the proposed and demonstrated rate acceleration that may accompany the reversal of the electronic properties of the Diels-Alder diene-dienophile partners and subsequently led to the full investigation of the LUMOdiene-controlled Diels-Alder reaction. 

Jil.l Five-membered Ring Heteroaromatic Azadienes... 

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. ... 

Table 15 Representative [4 + 2] Cycloaddition Reactions of Six-membered Heteroaromatic Azadienes...

Heteroaromatic systems that possess an electron-deficient azadiene are ideally suited for participation in inverse electron-demand Diels-Alder reactions. Additional substitution of the heterocyclic azadiene system with electron-withdrawing groups accents the electron-deficient nature of the heterodiene and permits the use of electron-rich, strained or even simple olefins as dienophiles. 

Since the early demonstrations of the participation of substituted 1,2,4,5-tetrazines1 and oxazoles2 in Diels-Alder reactions with olefinic and acetylenic dienophiles, the potential utilization of the [4 + 2] cycload dition reactions of heteroaromatic systems possessing a suitable azadiene arrangement has been the focus of extensive investigations.3-8 In general, the heteroaromatic systems which possess an electron-deficient azadiene... 

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