- A one-pot bicycloannulation method for the synthesis of tetrahydroisoquinoline systems
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A highly effective method for the synthesis of the core indolo[2,3- α]quinolizidine skeleton found in yohimbine is described. The reaction of N- monosubstituted thioamides with bromoalkenoyl chlorides furnishes thioisomunchnones as transient 1,3-dipoles that undergo ready intramolecular cycloaddition across the tethered π-bond to give thio-bicycloannulated products in a one-pot operation. The stereochemical outcome of the intramolecular reaction is the consequence of an endo cycloaddition of the neighboring π-bond across the transient thioisomunchnone dipole. A major limitation of the method is that when a hydrogen is present in the α- position of the thioamide the initially formed thio-N-acyliminium ion undergoes proton loss to produce a S,N-ketene acetal at a faster rate than dipole formation. Treatment of tetrahydro-β-carboline-1-thione with 2- bromooct-7-enoyl chloride followed by reductive removal of sulfur from the cycloadduct resulted in the formation of (±)-alloyohimbanone. Attempts to cycloadd the thioisomunchnone dipole across several nucleophilic π-bonds failed, and instead, products derived from cyclization of the π-bond onto the initially formed thio-N-acyliminium ion were formed. The resulting N,S- ketals were further converted into several tetrahydroisoquinoline alkaloids in good yield.
- Padwa, Albert,Beall, L. Scott,Heidelbaugh, Todd M.,Liu, Bing,Sheehan, Scott M.
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p. 2684 - 2695
(2007/10/03)
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- SYTHESIS OF N-(ARYLETHYL)ARYLTHIOACETAMIDES BY THE WILLGERODT-KINDLER REACTION AND THEIR CONVERSION TO SUBSTITUTED 1-BENZYL-1,2,3,4-TETRAHYDROISOQUINOLINES
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N-(Arylethyl)arylthioacetamides were synthesized by the reaction of substituted acetophenones with 2-arylethylamines.The reaction gives good yields when compounds with substituted hydroxyl groups are used. 2,4-Diarylthiazoles were isolated as side products from the Wilgerodt-Kindler reaction.The thioamides were converted into substituted 1-benzyl-1,2,3,4-tetrahydroisoquinolines by the Bischler-Napieralski cyclization, N-methylation, and reduction of the corresponding 3,4-dihydroisoquinoline methiodide derivatives.
- Nakova, E.P.,Tolkachev, O.N.,Evstigneeva, R.P.
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p. 550 - 555
(2007/10/02)
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