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Synthesis of methylenedioxy-bearing 1-aryl-3-carboxylisoquinolines using a modified Ritter reaction procedure

Abstract : This paper describes original approaches aimed at the preparation of electron-rich 1-aryl-3-carboxylisoquinolines. Our first attempt led to an efficient preparation of 1-hydroxyisoquinoline-3-carboxylic acid methyl ester starting from bromophthalide via a rearrangement of 2-acetylamino-2-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-malonic acid dimethyl ester. However, as its eventual application to the synthesis of methylenedioxy-bearing substrates seemed rather long, a second approach involving an extension of the Ritter reaction to safrole was devised. We thus report that, under proper experimental settings, the use of 54% tetrafluoroboric acid in ether enables a Ritter reaction between safrole and 3,4,5-trimethoxybenzonitrile yielding 17% of 7-methyl-5-(3,4,5-trimethoxyphenyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline. This acidic reagent avoids the extensive decomposition seen when using the classical Ritter reaction conditions (i.e.: concentrated sulfuric acid). Further chemical transformations of this methyl-bearing dihydroisoquinoline led to the methylenedioxy-bearing 1-aryl-3-carboxylisoquinoline. These derivatives are related to the peripheral benzodiazepine receptor ligand PK 11195 as well as falcipain-2 inhibitors and other potential antitumor agents.
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Contributor : Yves Janin Connect in order to contact the contributor
Submitted on : Thursday, August 16, 2007 - 9:27:01 AM
Last modification on : Thursday, April 7, 2022 - 10:10:20 AM

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Yves L Janin, Didier Decaudin, Claude Monneret, Marie-France Poupon. Synthesis of methylenedioxy-bearing 1-aryl-3-carboxylisoquinolines using a modified Ritter reaction procedure. Tetrahedron, 2004, 60 (25), pp.5481-5485. ⟨10.1016/j.tet.2004.05.004⟩. ⟨pasteur-00167161⟩



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