Esters arylation tetrahydroisoquinoline

The synthesis of 1-substituted tetrahydroisoquinolines using an intramolecular Pd-catalyzed a-enolate arylation was described. Treatment of a-amino esters such as 71 and 73 with LiOr-Bu, Pd2(dba)3 and ligand 75 or 76 afforded the corresponding isoquinolines 72 and 74. Investigations to develop an asymmetric version of this reaction were reported to be ongoing <02JOC465>. 

The imide 6 is an excellent proton source for returning lithium enolates to chiral ketones in ether. The ee value is also greatly influenced by an additive, and LiBr appears to have the best effect. Deracemization of amides by protonation of their enolates in the presence of a chiral l-aryl-l,2,3,4-tetrahydroisoquinoline (catalytic amount) and that of the potassium enolates of A-(2-hydroxypinan-3-ylidene)-a-amino esters have remarkable efficiencies. 

Intramolecular arylation of the amino acid ester 77 afforded the tetrahydroisoin-dole carboxylate 78, and the tetrahydroisoquinoline carboxylate 80 was obtained from the amino acid ester 79. In the cyclizations, ligand IV-12 was used [45]. 

Shortly after, the development of the intramolecular variant of this reaction was reported by Gaertzen and Buchwald [106]. A simple and flexible route to obtain dihydroisoindole and tetrahydroisoquinoline carboxylic acid derivatives was developed using the palladium-catalyzed intramolecular a-arylation of readily available a-amino acid esters (Scheme 8.58). The construction of quaternary carbon centers that tolerate a number of different substituents around the enolate center, including phenyl or bulky isopropyl groups, was reported. A number of different Af-substituents including alkyl, aryl, or carboxyl groups could be employed [106]. 

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