1-Isoquinolones ring synthesis

The parent, unsubstituted isochromanone has been caused to react with a variety of aromatic amines to prepare Ar-substituted 1,4-dihydro-3(2.ff)-isoquinolones,4 and with amines to give amides.5 The 6,7-methylenedioxy-3-isochromanone was an intermediate in the synthesis of protopine and its allied alkaloids,6 and for the synthesis of the berberine ring system.7 The 6-methoxy analog was prepared as a potential intermediate in a camptothecin synthesis8 and 8-methoxy-4,5,6,7-tetramethyl-3-isochromanonc was an intermediate in the synthesis of sclerin.9 The compound herein described was the basis of a facile synthesis of ( l )-xylopmins,10 and its reaction with hydrazine has been reported.11... 

Carbanions derived from side chain tertiary amides have also been cyclized to provide isoquinolones and isoindoles (equation 36).125 126 While benzyne intermediacy in the formation of the former is likely, the latter seems to arise through a SrnI reaction pathway. Synthesis of indole from the meta bromo compound (87), on the other hand, clearly involves an aryne cyclization. 27 A more versatile route to indoles is based on intramolecular addition of aminyl anions to arynes (equation 38).128 A somewhat similar dihydroindole preparation constitutes the first step in a synthesis of lycoranes (equation 39).129 The synthesis of (88) also falls in the same category of reactions, but it is noteworthy because only a few examples of ring closure of heteroarynes are mentioned in literature.27 28... 

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>. 

Electron-releasing substituents in the me a-position of the A-(2-arylethyl)amide facilitate ring closure and lead to 6-substituted 3,4-dihydroisoquinolines, whereas /7ara-substituents can prevent the cyclization. The scope of the Bischler-Napieralski synthesis is illustrated by the cyclization of the amide 52 to produce hexahydroisoquinolines 53, styrylisocyanates 54 to yield 1-isoquinolones 55, and 2-acylaminobiphenyls which provides phenanthridines (see p 357) ... 

As described in this chapter, transition-metal catalysts promote various types of cyclization reactions between C=N, C=0, N—H, O—H, and S—H bonds and alkynes in 5/6-endo/exo-dig manners. These reaction modes provide facile and atom-economical pathways to aromatic compounds such as pyrroles, indoles, isoquinolines, quinolines, furans, thiophenes, oxazoles, pyrones, and isoquinolones and their aza analogs and fused-ring congeners. Particularly notable is their utility in cascade reactions, which are step-economical approaches to target molecules, which increase rapidly in structural complexity. Therefore, these reactions can help provide solutions to meet the increasing demands of environmentally benign synthesis in modern organic chemistry. 

One strategy which has been successfully utilized in yohimbine alkaloid synthesis involves the use of cyclization reactions of either pyridinium or isoquinolinium cations to install the respective D or DE-ring units. Wenkert and his coworkers have popularized this methodology, as exemplified by their synthesis of hexahydroyohimbine (473) (Scheme 3.82) (131). In this sequence, AT-tryptophylpyridinium salt 468, prepared by reaction of 3-formylpyridine and tryptophyl bromide, was treated with the enolate anion of methyl aceto-acetate to afford isoquinolone 469. Methylation of this material provided isoquinolinium salt 472 which upon reduction followed by acid mediated cyclization provided yohimbane 473. This methodology represents a rather... 

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