New Chemistry of Imidazolinium ylides

Lory, Pedro M. J. (2001). New Chemistry of Imidazolinium ylides. PhD thesis The Open University.



Previous work in this group has shown 4,5-dihydroimidazolium ylides, formed by N- alkylation of 4,5-dihydroimidazoles, to undergo 1,3-dipolar cycloadditions with a range of dipolarophiles in a highly regio- and stereoselective fashion.
We have investigated two further aspects of this chemistry: (1) the synthesis of 4,5-dihydroimidazoles substituted with a heteroatom at C-2 and the subsequent N-alkylation of those templates followed by deprotonation to potentially access novel azomethine ylides; and (2) an intramolecular variant of the 1,3-dipolar cycloaddition, synthesising for this purpose a series of bromomethyl(co-l)-oxoalkenoates as dipolarophiles and subsequently reacting these with some 4,5-dihydroimidazole templates.

The synthesis of 4,5-dihydroimidazoles substituted with a heteroatom at C-2 was developed from 1-enzyltetrahydroimidazol-2-thione 131. Methylation of this with either iodomethane or methyl trifluoromethanesulfonate provided a key methylthioimidazolium iodide intermediate 135 from which 2-alkanethio- (136), 2-alkoxy (137) and 2-dialkylamino- (138) 4,5-dihydroimidazoles could be prepared by deprotonation, reaction with an alkoxide or reaction with a dialkylamine, respectively. N-Alkylation of the heterocycles was found to be unsuccessful. An alternative strategy, involving the synthesis of l-benzyl-3-methoxycarbonylmethyltetrahydroimidazol-2-one 143a and -2-thione 143b, was developed. The oxygen-containing compound 143a was transformed into its corresponding 0-substituted salts by treatment with triethyloxonium tetrafluoroborate, trimethylsilyl trifluoromethanesulfonate or trifluoromethanesulfonic anhydride. The sulfur analogue 143b was S-methylated using methyl trifluoromethanesulfonate. However, neither of the salts was found to undergo a 1,3-dipolar cycloaddition reaction upon treatment with DBU followed by methyl acrylate.

Intramolecular 1,3-dipolar cycloaddition reactions of a variety of ɑ-bromoketones with 1- benzyl4,5-dihydroimidazoles proved successful. Thus, reaction of 1-benzyl-4,5- dihydroimidazole 29 with methyl E-8-bromo-7-oxooct-2-enoate 196a followed by treatment with DBU afforded the tricyclic pyrroloquinoxaline adducts methyl 1-benzyl-2,3,7,8,9,9a-hexahydro-1H-pyrrolo[1,2,3-de]quinoxaline-6-carboxylate 217. This arises from the primary cycloadduct undergoing a cascade involving an eliminative ring-opening, recyclisation, loss of water and prototropic shift cascade. Seven other examples of this reaction, involving 2- and 4-phenyl-4,5-dihydroimidazoles, and ethyl and tertbutyl E-8-bromo-7-oxooct-2-enoate, as well as with 2- and 3-methyl substituted octenoates (i.e trisubstituted double bonds). In these cases no cycloaddition reaction involving the double bond occurs. In one instance, the reaction of (R)-4-phenyl-4,5-dihydroimidazole 112 with tert-butyl E-8-bromo-7-oxooct-2-enoate 278, we were able to isolate the primary cycloadduct, tert-butyl (3R,4aR,8aS,9S,9aR)-1-benzyl-5-oxo-3-phenyldecahydro-1H-imidazo[1,2-ɑ] indole-9-carboxylate 283. It would appear that the combination of sterically demanding phenyl and tert-butyl groups precludes eliminative ring-opening.

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