AZA-ENE REACTION

An interesting pyrrolo[l,2-tf]pyrimidine was described as the product of the reaction of the heterocyclic ketene-aminals 236 that was synthesized by cyclocondensation of ketene dithioacetals 237 and 1,3-diamino propane. These compounds reacted with diethyl oxomalonate that behaves as an hetero-enophile, yielding the corresponding products 238 in acceptable to good yield (Scheme 31). A mechanism that involves an aza-ene reaction, via adduct 239 which isomerizes to ketene aminal 240 to produce the lactam ring of 238, has been proposed <1999J(P1)321>. 

Treatment of the cyclic ketene aminal 267 with diethyl azodicarboxylate results in formation of the reduced ring system 268 (Equation 52), probably via an initial aza-ene reaction, followed by fragmentation and ring closure <2002T7791>. 

Gunter Kresze, Hans Braxmeier, and Heribert MUnsterer 159 ALLYLCARBAMATES BY THE AZA-ENE REACTION METHYL N-(2-METHYL-2-BUTENYL(CARBAMATE... 

Heathcook et al. have performed a diastereoselective aza-ene reaction using chiral di-(+)-menthyl diazenedicarboxylate 91 as the nitrogen source [54]. Compound 91 was found to react with various alkenes in the presence of 2 equiv. SnCl4, and the corresponding allylic aminated product was obtained in good yield and with de up to 42 %. The problem with this approach was the removal of the chiral menthyl ester auxiliary, which was found to be rather difficult. 

In a related context, 2-(/Koiuenesulfonyl)ethy]amine was used as an ammonia equivalent in an aza-ene reaction by which aldehyde 92.1 was converted to the bicycle 912 [Scheme 8.92].223 After N-acetylation and Pd(0)-catalysed hydro-stannylation, the alkenylstannane 914 dintensed under copper(II) nitrate catalysis. The 2-(p-toiuenesulfonyl)ethyl group was then discharged by p-elimination with potassium rm-butoxide. 

The aza-ene reaction recently found application in the synthesis of imidazo[1,2-a]pyridine and imidazo[1,2,3- y][1,8]naphthyridine derivatives in the laboratory of Z.-T. Huang.The reaction of heterocyclic ketene aminals with enones such as MVK proceeded via an aza-ene addition, followed by intramolecular cyclization to afford the products. The aroyl-substituted heterocyclic ketene aminals (Ar=Ph, 2-furyl, 2-thienyl) underwent two subsequent aza-ene reactions when excess MVK was used. 

Zhang, J.-H., Wang, M.-X., Huang, Z.-T. The aza-ene reaction of heterocyclic ketene aminals with enones an unusual and efficient... 

Kobayashi and coworkers pioneered the use of enamides or enecarbamates as nucleophiles in enantioselective reactions with either glyoxylates or glyoxylate derived imines catalyzed by chiral copper complexes [65]. The reaction using enamides or enecarbamates as nucleophilic components, namely, the aza ene reaction, with imines provides P amino imines that can be readily transformed into... 

The mechanism of the alkylation of imines with electrophilic alkenes has been discussed by D Angelo and coworkers S who conclude that reaction occurs via an aza-ene reaction-like transition state 206 involving concerted proton transfer from the nitrogen and carbon-carbon bond formation (Scheme 206). ITiey further propose that the remarkable regiocontrol observed in these reactions originates from this crucial internal proton transfer which would not be possible in a conformation such as 207 of the less substituted enamine tautomer, since the N—H bond would be anti to the enamine double bond. However, although this seems probable, it is by no means proven. Inconsistencies in the argument and the evidence presented cast some doubt on the validity of these conclusions. For example ... 

Three enantiomerically pure starting materials ensure remote stereochemical control Tandem iminium ion formation and vinyl silane cyclisation Part IV - Tandem Pericyclic Reactions Electrocyclic Formation of a Diene for Diels-Alder Reaction Tandem Ene Reactions Tandem [3,3]-Sigmatropic Rearrangements Tandem Aza-Diels-Alder and Aza-Ene Reactions... 

The second reaction amounts to an aza-ene reaction with the most remote alkene providing the ene partner and the imine. The molecule folds up 179 to give a chair conformation in the developing six-membered ring and the product 176 is easily transformed into ( )-methyl homo-secodaphniphyllate 180. 

Allylcarbamates by tbe Aza-ene Reaction Metbyl N-(2-metbyl- 2 -butenyl) carbamate... 

This method affords an easy access to this privileged scaffold by a [3 + 2+1] annulation catalyzed by EtjN. The mechanism of the reaction is shown in Scheme 11.22. First, the Knoevenagel reaction of aromatic aldehydes 53 with 2-hydroxy-1,4-naphthoquinone 113 affords 116 that undergoes the aza-ene reaction with the ketene aminal 114 rendering 117. Next, the intramolecular hemiaminal 118 formation and dehydration afford the corresponding benzolylimidazo [l,2-a]quinolinediones 115 in good yields (60-88%). 

In the Michael reaction of HC=C-COMe with primary amines having an a-substituent containing impaired electrons (methoxylamine, ethyl glycinate, hydrazine, etc.), an unexpectedly small influence of this substituent (the a-effect) was observed. The reaction of heterocyclic enamines with HC C-COaEt and Et02C-C=C-C02Et has been systematically studied. In contrast to their heterocyclic ketene aminai analogues, heterocyclic enamines (178) reacted with electrophilic alkynes via the Michael addition pathway (178) -> (179) rather than via the aza-ene reaction mechanism (181). In the presence of a strong base, such as EtONa and NaH,... 

Heterocyclic ketene aminals have been found to be good aza-ene compounds which can undergo hetero-ene reactions readily with activated carbonyl compounds and enones " to provide novel and efficient synthetic routes to y-lactam-fused diaza-heterocycles and fused di- and tri-heterocycles, respectively. Such aminals bearing a secondary enamine moiety have been found to undergo an efficient aza-ene reaction with 4-phenyl-l,2,4-triazoline-3,5-dione under very mild conditions. The regio- and diastero-selectivity of the ene reaction of 4-phenyl-l,2,4-triazoline-3,5-dione with chiral allylic alcohols and their derivatives have been studied, " while Singleton and Hang have proposed a new mechanism for the ene reactions of triazolinediones which involves an open biradical as the key intermediate. This biradical is assumed either to form the ene product or to form reversibly an intermediate aziridinium imide which would be a shunt off the main ene mechanistic pathway. 

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