1-R-3,3-dialkyl-6,7-ethylenedioxy-3,4-dihydroisoquinolines

Глушков, В. А.; Rozhkova, Yu. S.; Вахрин, М. И.; Shklyaev, Yu. V.

doi:10.1007/s10593-005-0272-7

Chem Heterocycl Compd

2005

DOI: 10.1007/s10593-005-0272-7

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1-R-3,3-dialkyl-6,7-ethylenedioxy-3,4-dihydroisoquinolines

В. А. Глушков

Yu. S. Rozhkova

М. И. Вахрин

et al.

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Cited by 4 publications

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“…We previously reported [1][2][3] that isobutyraldehyde, 2-ethylhexanal, and cyclohexanecarbaldehyde react with activated arenes and nitriles in concentrated sulfuric acid to give 3,3-dialkyl-3,4-dihydroisoquinoline derivatives. It is also known that 3,3,4,4-tetramethyl-3,4-dihydroisoquinoline derivatives exhibiting a broad spectrum of biological activity [4] can be synthesized via retropinacol rearrangement of 3,3-dimethyl-2-phenylbutan-2-ol [5].…”

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Retropinacol rearrangement in the synthesis of 3,3,4-trimethyl-3,4-dihydroisoquinoline derivatives

2009

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Three-component condensation of veratrole with pivalaldehyde and nitriles (ethyl cyanoacetate, cyanoacetamide, and benzonitrile) in concentrated sulfuric acid leads to the formation of 1-substituted 6,7-dimethoxy-3,3,4-trimethyl-3,4-dihydroisoquinolines.We previously reported [1-3] that isobutyraldehyde, 2-ethylhexanal, and cyclohexanecarbaldehyde react with activated arenes and nitriles in concentrated sulfuric acid to give 3,3-dialkyl-3,4-dihydroisoquinoline derivatives. It is also known that 3,3,4,4-tetramethyl-3,4-dihydroisoquinoline derivatives exhibiting a broad spectrum of biological activity [4] can be synthesized via retropinacol rearrangement of 3,3-dimethyl-2-phenylbutan-2-ol [5].We expected analogous retropinacol rearrangement to occur in the three-component reaction of an activated arene with nitriles and pivalaldehyde. In this case, the first step is formation of the corresponding carbinol I according to Baeyer [1]. Dehydration of I in sulfuric acid yields carbocation A which should undergo retropinacol rearrangement with formation of carbocation B as key intermediate in the synthesis of 3,4-dihydroisoquinolines according to Ritter [1] (Scheme 1).In fact, the reaction of equimolar amounts of veratrole, pivalaldehyde, and ethyl cyanoacetate in concentrated sulfuric acid gave ethyl 6,7-dimethoxy-3,3,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-1-ylideneacetate (II) (Scheme 2). Compound II was also synthesized by reaction of ethyl cyanoacetate with 2-(3,4-dimethoxyphenyl)-3-methylbutan-2-ol (III) which can readily be prepared from 3,4-dimethoxyacetophenone and isopropylmagnesium bromide in tetrahydrofuran. The yield of compound II in the first case (method a, 21%) was thrice as small as in the second (method b, 65%). Presumably, the three-component condensation (method a) is accompanied by Danilov rearrangement [6] of initial pivalaldehyde (Scheme 3), which is responsible for the poor yield of II.Analogous rearrangement was also observed in the reaction with isobutyraldehyde, but its rate was considerably lower than that for pivalaldehyde. This fol-

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