Heterocycles from intramolecular Michael addition

The Mannich reaction is a very common process that occurs in many tandem reaction sequences. For example, the Overman Aza-Cope cascade sequence is terminated by a Mannich reaction (cf. Scheme 35). Several groups have used variants of the Mannich reaction to initiate cascades that lead to the formation of heterocyclic molecules. For example, the Lewis acid-catalyzed intermolecular vinylogous Mannich reaction (01T3221) of silyloxy furan 281 with nitrone 282 produced a diastereomeric mixture (49 3 42 6) of azabicycles 284a-d in 97% combined yield (Scheme 52) (96TA1059). These products arose from an intramolecular Michael addition of the initially formed oxonium ion 283. 

Majumdar and coworkers used a combination of a 3,3-sigmatropic rearrangement followed by an intramolecular [1,6]-Michael addition for the synthesis of py-rimidine-annulated heterocycles as 4-308 from 4-307 (Scheme 4.66) [103]. 

Various ways of functionalization of the lactol 205 leading to C-nucleoside analogs were described.Compound 205 readily reacted with carboethoxymethylenetriphenylphosphorane with formation of trans ester 212, whereas the Wittig reagent prepared from pyruvate ester gave a product of an intramolecular Michael reaction (221). Acrylate ester 212 was converted on addition of diazomethane into pyrazoline 213, and further, by successive brom-ination-dehydrobromination followed by acid hydrolysis, was transformed into DL-3-(carboxamido)-4-P-ribofuranosylpyrazole 214. Another precursor of heterocyclic C-ribofuranosides (215) was obtained in the reaction of lactol 205 with... 

Fluoroalkyl chromone derivatives can be obtained from the base catalysed reaetion between 2,2-dihydropolyfluoroalkanoates and phenols. Initial loss of HF allows Michael addition of the phenol and subsequent cyclisation of the enol ether yields the heterocycle. m-Substituted phenols give the expected mixture of 5- and 7-substituted chromones, whilst dihydroxy aromatic compounds give polycyclic materials (94JFC263). In a more conventional approach Z-3-(aryloxy)-polyfluoroalkenoic adds, derived from Michael addition of phenols to polyfluoro-2-alkynoic acids, undergo intramolecular Friedel-Crafts acylation to 2-polyfluoro-alkylchromones (94JFC25). 

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