Acyliminium ion, formation

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

SCHEME 3.14 Previous examples of oxidative iminium and acyliminium ion formation. 

Formation of C — C Bonds by Addition to Imino Groups via yV-Acyliminium Ions... 

For reactions of A-acyliminium ions with alkenes and alkynes one has to distinguish between A-acyliminium ions locked in an s-trans conformation and those which (can) adopt an s-cis conformation. The former type reacts as a (nitrogen stabilized) carbocation with a C —C multiple bond. Although there are some exceptions, the intramolecular reaction of this type is regarded as an anti addition to the 7t-nucleophile, with (nearly) synchronous bond formation, the conformation of the transition state determining the product configuration. 

A possible side reaction in A-acyliminium chemistry is caused by deprotonation, giving rise to the formation of an enamide. Though this tautomerization is in principle reversible in acid media, this is not always the case. The enamide may react as a nucleophile with the /V-acyliminium ion still present, to produce dimers14. 

These side reactions may occur if the /V-acyliminium ion is not trapped quickly enough by a nucleophile. So problems may arise with relatively poor nucleophiles or if there is too much steric hindrance, while in the case of intramolecular reactions, unfavorable stereoelectronic factors or intended formation of medium- or large-sized rings may play a role. The reaction conditions, such as the nature of the (acidic) catalyst and the solvent, may also be of importance. 

Formation of A-acyliminium ions via protonation of enamides or enecarbamatcs is occasionally utilized. 

Formation of a vinyl-substituted pyrrolizidine derivative is also observed in case of an allylstan-nane cyclization94. Since the allylstannane moiety is acid sensitive, the iV-acyliminium ion is generated by exposure of the hydroxylactam to methanesulfonyl chloride and triethylamine in dichloromethane. The very rapid cyclization produces the endo-vinyl compound with very high stereoselectivity. 

Optically active five- or six-membered cyclic A -acyliminium ions of this type are generated from the a-inethoxy derivatives, easily obtainable through anodic methoxylation of intermediates that are prepared via ex-chiral-pool syntheses from certain natural amino acids. Reaction of 5-substituted five-membered cyclic A -acyliminium ions with various nucleophiles leads to the predominant formation of cw-products with moderate selectivity. The trans-selective reaction with alkyl copper reagents appears to be an exception. 

Alkylations of 6-methoxycarbonyl six-membered cyclic (V-acyliminium ions show a strong preference for the formation of m-products. This is explained by the A0-3 strain between the substituent and the (V-mcthoxycarbonyl group of the iminium ion, forcing the substituent into an axial position. Stereoelectronically preferred axial attack by the nucleophile then leads to the 2,6-d.v-disubstituted piperidine derivatives. 

Predominant formation of s-products on reaction of A -acyliminium ions, containing an additional conjugated double bond, with propylzinc iodide likewise arises from A(1 3) strain as discussed133. 

Cyclizations of A-acyliminium ions containing a 3-alkenyl substituent tethered to nitrogen usually proceed with preferential formation of a six-mentbered ring via a chair-like transition state, if the alkene does not have an electronic bias. 

With certain substituents, such as methoxy150 or (substituted) phenyl53 functions, in the allylie position the reaction outcome completely changes, giving rise to predominant or exclusive formation of five-membered ring products via a preceding 2-aza-Cope rearrangement of the initially formed A -acyliminium ion. These substituents clearly stabilize the intermediary carbo-cation 3. 

The reactivity of triflate-substituted pyridopyrrolizines has been investigated. In the presence of a polar aprotic solvent and a nucleophile, these compounds undergo Sn reactions, leading to the a-substituted 3//-3-pyrrolones. This process is thought to involve loss of the trifluoromethanesulfinate ion, formation of an acyliminium ion intermediate, and nucleophilic attack on the latter <1995JOC5382> (Scheme 44). 

When the pyrrolo[l,2-c]oxazole 269 was treated with trimethyl orthoformate in the presence of BF3 Et20, in dichloromethane at — 78 °C, a mixture of compounds was obtained from which the expected 5-dimethoxymethyl derivative, 270, was isolated in poor yield (12%) with another dimethoxylated compound 271 (23%). The formation of 271 could be explained by the addition of the formyl cation equivalent at C-7, followed by the protonation at C-6 of the resulting enamide 272 leading to the electrophilic iV-acyliminium ion 273 (Scheme 40). The regioselectivity of this electrophilic addition of trimethylorthoformate to the silyloxypyrrole 269 at C-7, in a non-vinylogous manner, is unusual <1999TL2525>. 

It is well known that oxidation of carbamates leads to the formation of N-acyliminium ions via dissociation of the C-H bond a. to nitrogen. The electrochemical,4 metal-catalyzed,5 and chemical methods6 have been reported in the literature to accomplish this transformation. The transformation serves as a useful tool for organic synthesis, although only compounds of high oxidation potentials such as methanol and cyanide ion can be used as nucleophile. It... 

Af-Acyliminium ions are known to serve as electron-deficient 4n components and undergo [4+2] cycloaddition with alkenes and alkynes.15 The reaction has been utilized as a useftil method for the construction of heterocycles and acyclic amino alcohols. The reaction can be explained in terms of an inverse electron demand Diels-Alder type process that involves an electron-deficient hetero-diene with an electron-rich dienophile. Af-Acyliminium ions generated by the cation pool method were also found to undergo [4+2] cycloaddition reaction to give adduct 7 as shown in Scheme 7.16 The reaction with an aliphatic olefin seems to proceed by a concerted mechanism, whereas the reaction with styrene derivatives seems to proceed by a stepwise mechanism. In the latter case, significant amounts of polymeric products were obtained as byproducts. The formation of polymeric byproducts can be suppressed by micromixing. 

The electrochemical reduction of W-acyliminium ion pool 2 gave rise to the formation of the corresponding homo-coupling product 13 (Scheme 8).23 Presumably, a radical intermediate 14 was generated by one electron reduction of 2 and homo-coupling of the radical led to the formation of the dimer 13. However, a mechanism involving two-electron reduction to give anion 15 followed by the reaction with cation 2 cannot be ruled out. 

Radical addition to an Af-acyliminium ion is also an interesting feature of the cation pool chemistry. We found that an alkyl iodide reacted with an N-acyliminium ion pool in the presence of hexabutyldistannane to give coupling product 19.24 A chain mechanism shown in Scheme 10, which involves the addition of the alkyl radical to the N-acyliminium ion to form the corresponding radical cation, seems to be reasonable. The present reaction opens a new possibility for radical-cation crossover mediated carbon-carbon bond formation. 

The reactions did prove to be compatible with the use of a-stannyl amides. In these cases, the cyclization reaction involved the trapping of an iV-acyliminium ion by the olefin and led to the formation of substituted piperidines. 

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