Treatment of N-arylisonicotinamides with trifluoromethanesulfonic anhydride triggers intramolecular nucleophilic attack of the aryl ring on the 4-position of the pyridinium intermediate. The products are spirocyclic dihydropyridines which can be converted to valuable spirocyclic piperidines related to biologically active molecules such as MK-677.

Isonicotinamides carrying N-furanylmethyl, N-pyrrolylalkyl or N-thiophenylmethyl substituents at nitrogen undergo cyclisation induced by an electrophile, giving spirocyclic compounds or doubly spirocyclic compounds in which both the nucleophilic and electrophilic heterocycles are dearomatised.

On treatment with acylating or sulfonylating agents, N-alkenyl pyridine carboxamides (N-pyridinecarbonyl enamines) undergo a dearomatizing cyclization initiated by pyridine acylation and followed by intramolecular trapping of the resulting pyridinium cation. The products are spirocyclic dihydropyridines which may be further elaborated to spirocyclic heterocycles with drug-like features.

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SummaryThe silyl enol ether derivatives of ketones or esters tethered by a hydrocarbon or ether linkage to the 3-position of a pyridine ring undergo dearomatising nucleophilic attack on the ring once it is activated (as an acylpyridinium species) by the addition of methyl chloroformate. The bicyclic dihydropyridine products are in some cases unstable, but may be isolated after hydrogenation as fused bicyclic piperidines.

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N-alkenyl pyridinecarboxamides undergo dearomatizing spirocyclization initiated by pyridine acylation and followed by intramolecular trapping of the resulting pyridinium cation. The products are spirocyclic dihydropyridines which are readily convertible into drug-like scaffolds. -(SENCZYSZYN, J.; BRICE, H.; CLAYDEN*, J.; Org. Lett. 15 (2013) 8, 1922-1925, http://dx.doi.org/10.1021/ol400571j ; Sch. Chem., Univ. Manchester, Manchester M13 9PL, UK; Eng.) -Bartels 35-091

Pyridine derivatives R 0380Doubly Dearomatizing Intramolecular Coupling of a Nucleophilic and an Electrophilic Heterocycle. -Isonicotinamides, carrying N-furanylmethyl, N-pyrrolylalkyl or N-thiophenylmethyl substituents at nitrogen, e.g. compounds (I), (IV) and (VI), undergo cyclization induced by an electrophile such as triflic anhydride (II). Spirocyclic or doubly spirocyclic compounds (III) and (VIII) are obtained in which both the nucleophilic and electrophilic heterocycles are dearomatized. The intermediate oxonium ion derived from (VI) can be trapped by an external nucleophile such as triphenylmethanol (VII) to give compound (VIII). -(BRICE, H.; CLAYDEN*, J.; Chem. Commun. (Cambridge) 2009, 15, 1964-1966; Sch. Chem., Univ. Manchester, Manchester M13 9PL, UK; Eng.) -M. Paetzel 35-142