Azadienes reactions with enamines

Phthalazines undergo [2 + 4] cycloaddition with enamines to give naphthalene derivatives. Pyrimidines also react as azadienes in reactions with enamines, e.g. (398 — 399). 

Pyridine annelation.1 1,2,4-Triazine can function as a reactive azadiene in Diels-Alder reactions with enamines, particularly pyrrolidine enamines, to form substituted pyridines. 

A simple preparation of electron-poor 2-azadienes and the preliminary study of their ability to participate in [4 + 2] cycloadditions was done almost simultaneously by out group (87CC1195) (Scheme 49). The preparation of 2-azadienes 212 with two appended methoxycarbonyl groups was achieved, in a multigram scale and in nearly quantitative yield, by the insertion reaction of N- trimethylsilyl imines 210 into the carbon—carbon triple bond of dimethyl acetylenedicarboxylate to give 211 followed by protodesilylation with CsF/MeOH. Azadienes 212 underwent at room temperature inverse-electron demand [4 + 2] cycloaddition with cyclic enamines to give exclusively exo-cycloadducts 213 in 82-95% yield. Acid hydrolysis of them resulted in their aromatization to yield 2-pyrindine (n = 1] and isoquinoline (n = 2) derivatives 214. 

VI. Enamines as Electron-Rich Synthons in Reactions with Electron-Deficient Azadienes... 

Nitro-3-phenylisoxazole-5-carboxylates (290) act as heterocyclic 1-azadiene components in [4 + 2] cycloaddition reaction with some enamines affording bicyclo derivatives 295 probably via a stepwise ionic cycloaddition involving the Michael adducts 292 as primary intermediates. Further intramolecular attack by the isoxazole nitrogen on the immonium carbon followed by elimination of the amine and aromatization of dihydropyridine 293 afforded 294, which was transformed into pyridine 295 by simple reduction164 (equation 63). 

AAAcylimines, e.g., 4, are the most widely recognized and the most extensively investigated hetero-2-azadiene system capable of participation in Diels-Alder reactions, and comprehensive reviews have been published.7,71 In general, substituents X and Y are strongly electron-withdrawing groups and consequently the AAacylimines participate as electron-deficient partners in cycloaddition reactions with electron-rich dienophiles. Diels-Alder reactions of electron-deficient /V-acylimines with vinyl ethers, enamines, olefins, sulfenes, acetylenes, and the carbon-carbon or carbon-oxygen double bond of ketenes have been detailed.57 71 This 47t participation of electron-deficient AAacylimines does complement the ability of many simple AAacylimines to behave as 2ir dienophile components in Diels-Alder reactions with typical electron-rich dienes.6... 

There are no reports of simple isoxazoles participating in [4 + 2] cycloadditions in which the isoxazole nucleus functions as a heteroaromatic 1-azadiene system. However, one of the early reports of the successful participation of a 1-azadiene system in [4 + 2] cycloadditions does include the Diels-Alder reactions of benzisoxazoles (Chapter 9, Section 1, Table 9-1, entries 1-7).61 An additional report has detailed the participation of substituted 4,5-dihydro-3-vinylisoxazoles in [4 + 2] cycloadditions (Chapter 9, Section 1, Table 9-1, entry 8).62a Isoxazolium salts react with enamines to provide pyridinium salts via a [4+ + 2] reaction (Chapter 9, Section 10).62b... 

The ring enlargement of pyrroles providing 3-chloropyridines has already been described (see p 93). Oxazoles react as masked 2-azadienes with alkenes yielding pyridine derivatives of various types (see p 131). With enamines and ynamines, diazines and triazines undergo Diels-Alder reactions with inverse electron demand (see p 441). This leads to pyridines (e.g. 201) by the enamine cycloaddition of the 1,2,4-triazine, as shown below ... 

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. 

The phosphonates (31) react with aldehydes and ketones to give 2-azadienes which form metallo-enamines on reaction with butyl-lithium trapping of these metallo-enamines occurred with a high degree of regioselectivity (Scheme 46). ... 

At present, researchers are attracted to the reactions of various enamines, enediamines, and related compounds with azadienes containing... 

The key step to the tricyclic compound 17 seems to be the stereoselective aza Diels-Alder reaction (20) of the intermediate enamine dienophile 18 with azadiene adduct 19 to produce the imine complex 21. Allylboration of C=N bond in the latter proceeds also stereoselectively (21, arrow) furnishing the diborylated compound 22. 

A simple, efficient, one-step synthesis of quinoxaline 1,4-dioxides from the reaction of benzo-furazan oxide (171) with activated alkenes such as enamines was named the Beirut reaction in honor of the city of its discovery. Earlier developments to 1981 were surveyed by Porter <84CHEC-I(3)157>, and later progress has been reviewed by Haddadin and Issidorides <93H(35)1503> who first demonstrated this reaction. Dienamines and azadienes (172) also react with benzofurazan oxide to yield... 

Di- and trihalohydrazones react with enol ethers or enamines in the presence of base to give pyridazines via the intermediacy of an azadiene. The final pyridazine may be formed directly in the reaction mixture or with intermediate di- or tetrahydro-intermediate isolated and further treated with base. ... 

Cationic 2-azadienes have also proven to be good diene partners in IDA cycloaddition reactions [17], As an example, the reaction of A-tosyl indole (14) with the A-alkenyl iminium species 13 (generated in situ from the corresponding A -alkoxymethyl enamine derivative 12), followed by deprotonation, produced the tricyclic indole product 15 with excellent stereochemical control (Scheme 5). The choice of tosyl group for indole protection proved crucial, as A-tosyl indole (14) is electron-rich enough to effect the [4-t-2] cycloaddition reaction but lacks the nucleophilicity to add to the resulting cycloadduct intermediate [18]. 

Additionally, Pd-catalyzed cross-coupling reactions were explored in pyridines synthesis also. In 2007, a multicomponent sequential process for the synthesis of trisubstituted pyridines was reported [59]. The reaction involves the formation of an enamine by Pd-catalyzed amination of an alkenyl bromide, formation of a 2-aza-1,3-butadiene by Pd-catalyzed cross-coupling of a trimethylsilylimine with an alkenyl bromide, and Lewis acid (Yb(OTf)3 (20mol%)) catalyzed cycloaddition between the enamine and the azadiene. Moderate yields can be achieved (Scheme 3.26). A zinc-mediated tandem reaction of nitriles... 

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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