Isoquinolones synthesis

Ruthenium-Catalyzed C-HIN-0 Bond Functionalization Green Isoquinolone Synthesis in Water... 

By introduction of an oxidizing directing group, Li and Wang demonstrated a regioselective ruthenium(ll)-catalyzed isoquinolone synthesis through oxidative cyclization of JV-methoxybenzamides with internal alkynes (Eq. (7.24)) [31]. This redox-neutral strategy circumvents the use of wasteful metal oxidants, and the reaction could take place at much milder conditions with broad substrate scope. 

The reaction is essentially that described by the submitters.8 The procedure illustrates a convenient method for the synthesis of a type of lactone which could serve as an important intermediate in the synthesis of isoquinolones, tetrahydroisoquinolines, and isoquinoline alkaloids Several analogous and closely related lactones have been reported. 

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... 

In a related type of reaction, the styryl isocyanates, readily available by Curtius rearrangement of cinnamoyl azides, undergo thermal cyclization to l-isoquinolones in good yield (equation 34) the reaction can also be carrried out using Friedel-Crafts catalysts. 2,3-Dihydro-4( 1//)- isoquinolones are obtained by Dieckmann cyclization of N- (o- carbalkoxy-benzyl)glycine ester derivatives (equation 35). The same reaction has been used for the synthesis of a range of non-aromatic heterocycles (equations 36 and 37). 

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>. 

Davis and Andermichael recently described a new method for the asymmetric synthesis of 3-substituted-1 -(2//)-isoquinolones which are important chiral building blocks for alkaloid synthesis.83 This procedure involved the highly diastereose-... 

R = H). Bromination gave the 4-bromo-derivative which afforded (16 R = CN) and (16 R = CHO) by successive cyanization and Raney nickel reduction/ The reported synthesis of the isoquinolone alkaloid thalactamine from 2,3.4-trimethoxyphenethylamine is unexceptional but an alternative synthesis involving bromination of 6,7-dimethoxy-2-methyl-l(2//)-isoquinolone followed by methan-nolysis in methanolic sodium methoxide is somewhat surprising/ A number of new methods for preparing AT-substituted l(2//)-isoquinolones include reaction of homophthalic acids with Vilsmeier reagentand borohydride reduction of homophthalimides. The effect of various substituents on the fluorescence of such isoquinolones has been studied. 

Homophthalic anhydrides are valuable synthons for the synthesis of isocoumarins, isoquinolones and particularly for several berbine alkaloids. 

Particularly, isoquinolonic acids are useful precursors for the total synthesis of naturally occurring phenanthridine alkaloids such as corynoUne, oxocorynoline, and epicorynoline as well as indenoisoquinolines possessing sigiuflcant antitumor activity. 

Yadav JS, Reddy BVS, Raj KS, Prasad AR (2003) Room temperature ionic Uquids promoted three- component coupling reactions a fadle synthesis of cix-isoquinolonic acids. Tetrahedron 59 1805-1809... 

In the realm of synthesis, two groups74,75 have reported a facile preparation of the 3-isoquinolone derivative (40) by the same method, and one of these has used this compound as an intermediate for entries into tetrahydropapaverine (41 R = H) and ( )-laudanosine (41 R = Me) as shown in Scheme 3.75 Inter-molecular acylation of 3,4-dimethoxyphenylacetic acid with polyphosphoric acid gave (39) in 60 %75 or 95 %74 yield. The latter compound was readily converted into tetrahydropapaverine (41 R = H) in three steps. On the other hand, treatment of (42), prepared by dehydration of (39) in refluxing decalin, with methylamine followed by identical steps to those used in the synthesis of (41 R = H) gave (+)-laudanosine (41 R = Me). 

Analogous condensations using lithium enolates of MA -diethyl-o-toluamide (149) have been described by Clark and Jahangir for the synthesis of 3,4-dihydro-l(2//)-isoquinolones (151 Scheme 31). It is fortunate that the enolate-imine addition-cyclization process occurs at low temperature, since warming the reaction mixture to room temperature, a common practice in many enolate-imine additions, leads to side reactions due to the instability of the 4-Iithiated derivative (150) formed by release of lithium diethylamide. The authors have exploited the in situ formation of (150) for the synthesis of 4-sub-stituted isoquinolones by trapping it with electrophiles. A cycloaddition mechanism via an... 

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