Organometallic and Other Nucleophilic Additions

Organometallic reagents add very readily to A-alkyl-, A-aryl- and, with important synthetic significance, A-alkoxy- or iV-aryloxycarbonyl-pyridinium salts. In A-aUcyl- or iV-aryl-pyridininm cations, addition is to an a-carbon the resnlting 2-substituted-l,2-dihydropyridines are nnstable, bnt can be handled and spectroscopically identified, with care, and more importantly can be easily oxidised to a 2-snbstitnted pyridininm salt.  

The great significance of the later discovery, that exactly comparable additions to iV-aUcoxycarbonyl- or iV-aryloxycarbonyl-pyridinium cations, generated and reacted in situ, is that the dihydro-pyridines that resnlt are stable, and can be further manipulated. If re-aromatisation is required, the iV-substituent can be easily removed to give a substituted pyridine. It is worth noting the contrast to the use of A-acyl-pyridinium salts for reaction with alcohol, amine nncleophiles (8.1.1.7), when attack is at the carbonyl carbon the nse of an iV-alkoxy/aryloxycarbonyl-pyridininm salt in the present context diverts attack to a ring carbon. 

The dihydropyridines produced by the methods described above are multifunctional and can be manipulated, for example the enamide character in these products can be utilised by interaction with an electrophile (iodine in the example) which brings about intramolecular attack and formation of a lactone.  

4-Substituents tend to direct attack to an a-carbon the use of a removable 4-blocking group -trimethyltin in the example below - can be made the means for the production of 2-substituted 

The use of chiral chloroformates, such as that derived from tranx-2-(a-cumyl)cyclohexanol, allows diastereoselective additions to 4-methoxypyridine. The introduction of a tri-ixo-propylsilyl group at C-3 greatly enhances the diastereoselectivity. The products of these reactions are multifunctional chiral piperidines which have found use in the asymmetric synthesis of natural products.  

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