Aspects of the chemistry of the Mannich reaction
thesisposted on 12.11.2015 by George Papageorgiou
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The work described in the thesis is concerned with the development of new methodologies for the aminoalkylation of a wide range of aromatic substrates using non-aqueous conditions. The Mannich reagents derived from secondary amines, bis(N,N-dialkylamino)methanes laminalsl, and alkoxy(N,N-dialkylamino)methanes laminol ethersl, were used in "in situ" reactions activated by various Lewis acids. The objective was to devise new methods whereby a high concentration of hydrogen chloride did not accumulate in the reaction mixture. It was established that aminals activated by acetyl chloride or sulphur dioxide can be used for the aminoalkylation of n-excessive heterocycles. Good regioselective control was achieved for orthaaminoalkylation of phenols, especially 2,5-dimethylphenol, by both aminals and aminol ethers in the presence of sulphur dioxide. The use of chlorosilane derivatives in "in situ" reactions of aromatic heterocycles was investigated. Good yields of monosubstitution products were obtained using trichloromethyl-, dichlorodimethyl- and chlorotrimethyl-silane with aminol ethers in reactions with N-methylpyrrole. Aminals, however, activated by chlorotrimethylsilane afforded the 2,5-diaminoalkylated pyrroles. The catalytic effect of chlorotrimethylsilane in this system was established. The ipso addition-with-elimination reactions of aryltrialkylstannanes with aminals and aminol ethers in the presence of chlorosilane derivatives were examined. The Mannich reagents derived from primary amines bis(N-alkoxymethyl)-alkyl and -aralkyl amines lbis(aminol ethers)1 have been used in reactions with electron rich aromatic compounds. The aim was to activate an alkoxymethyl group and to protect the product by the same functional group. A versatile method for the preparation of secondary amine Mannich bases was developed. The possibility of carrying out tandem reactions with two different nucleophiles was investigated briefly. Bis(aminol ethers) derived from B -phenylethylamines, possessing a methoxy substituent at the 3-position of the ring, afforded a convenient method for the preparation of N-arylmethyltetrahydroisoquinoline derivatives