Isoquinoline 1-methyl-, ring synthesis

A palladium-catalyzed three-component reaction with 2-iodobenzoyl chloride or methyl 2-iodobenzoate, allene and primary aliphatic or aromatic amines to prepare fV-substituted 4-methylene-3,4-dihydro-1 (27/)-isoquinolin-1 -ones was disclosed <02TL2601>. A synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines via a Cp2TiMe2-catalyzed, intramolecular hydroamination/cyclization of aminoalkynes was also reported <02TL3715>. Additionally, a palladium-catalyzed one-atom ring expansion of methoxyl allenyl compounds 79 to prepare compounds 80 that can serve as precursors to isoquinolones was reported <02OL455,02SL480>. 

Most work has been in the isoquinoline area, principally because of the usefulness of isoquinoline Reissert compounds in the synthesis of isoquinoline alkaloids.2 Aside from 5-chloro-7 and 3-acetylaminomethylquinoline9 and a few halo,5-16-18 methyl,16,19 and carbomethoxyisoquinolines,20 all the substituted quinoline or isoquinoline Reissert compounds have involved oxygen-type functions in one or more of positions 4-, 5-, 6-, 7-, and 8- of the isoquinoline ring.6,8,15,20-38... 

As mentioned, naphthylisoquinoline alkaloids are structurally unusual on account of the methyl group at the 3-position and oxygenation at the 8- and/or 6-position of the isoquinoline ring which points to a polyketide origin. This postulate has been supported by extensive studies conducted by Btingmann on the in vitro biomimetic synthesis of the naphthalene and isoquinoline portions of these compounds (ref. 13,14) and this work is worth briefly mentioning in a discussion on the total synthesis of these compounds. 

Both platinum and palladium catalysts can be used for the hydrogenation of heteroaryl derivatives, although platinum is more common. Selective reduction of the heterocyclic ring in 8-methyl-7-hydroxy isoquinoline (440) gave 441 in 67% yield, in Woodward and von E. Doering s synthesis of quinine. 33... 

Alkoxyoxazoles have also proven to be valuable heterodienes in the synthesis of highly substituted furans and biologically active natural products via oxazole-aUtyne Diels-Alder reactions. Thus the synthesis of a synthon for the DEF ring system of fredericamycin began with the cycloaddition of 5-ethoxy-4-methyl-oxazole 8 with enyne ester 149 (Fig. 3.45). This reaction proceeded in 24 h in refluxing toluene to afford a 65% yield of the 2-ethoxyfuran 150. Furan 150 was then converted to the isoquinoline 151 in six steps. ... 

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