Asymmetric Synthesis of 1-Substituted 1,2,3,4-Tetrahydroisoquinolines by Asymmetric Electrophilic α-Amidoalkylation Reactions

An efficient method for the asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines via chiral N-acyliminium ions is presented.The N-acyl-1,2-dihydroisoquinolines (8) and ( 9) underwent smooth oxidation reactions with Ph 3 C + BF 4 -to give the chiral N-acylisoquinolinium ions (10) and(13), respectively.Stereoselective addition of organomagnesium and organozinc compounds to intermediates (10) and ( 13) provided the corresponding 1-substituted N-acyl-1,2-dihydroisoquinolines (11/12) and (14/15) in good yields.The diastereoselectivity of these reactions appeared to be dependent on the structure of the N-acyliminium ion intermediates (10) and ( 13) and on the nature of the trapping reagent with the zinc reagents in general leading to markedly improved stereoselectivities. Pure diastereomers were obtained by preparative HPLC and readily transformed into enantiopure 1-substituted 1,2,3,4-tetrahydroisoquinolines by catalytic hydrogenation and reductive removal of the chiral auxiliary.By treatment of the carboxylic acid chloride ( 7) -derived from 6 -with isoquinoline and Bu 3 SnH as a trapping reagent for the intermediate N-acylisoquinolinium ion the N-acyl-1,2-dihydroisoquinoline (8) was obtained in high yield (80 %).However, for 8-methylisoquinoline 8 the same transformation could be accomplished only when forcing conditions -heating the reaction mixture to reflux in toluene instead of stirring at room temperature in CH 2 Cl 2 -were applied.Obviously, the 8-methyl group present in 8-methylisoquinoline must give rise to severe steric hindrance resulting in a significant drop of reactivity in this transformation reaction.But, fortunately, this lack in reactivity could be overcome by the modified reaction conditions providing 9 in a reasonable yield as well (71 %).Compounds ( 8) and ( 9) proved to be well-suited precursors for the generation of the N-acylisoquinolinium ions (10) and ( 13), respectively.As for related systems 3h,9 the conversion could be efficiently effected by hydride abstraction with Ph 3 C + BF 4 -. 10 According to TLC the oxidation was almost complete within several hours at room temperature, but for convenience was always run overnight (16 h).The formation of the N-acylisoquinolinium ions could be verified unequivocally by NMR spectroscopic methods (see below).In both cases the N-acyliminium ions resulted in almost pure form from the oxidation step.Therefore, as there was no need for purification, the reaction mixtures obtained from the oxidation process (in CH 2 Cl 2 ) were used without change for the subsequent trapping reactions.It should also be stated, that the generation of N-acyliminium ions according to this protocol is irreversible.Thus it does not suffer from any unfavorable equilibria, which often occur when N-acyliminium are generated more directly e.g. by reacting the corresponding imine or nitrogen heterocycle with an acid chloride. 11In order to determine the influence of the nature of the organometallic species on the result of the addition reactions to the N-acyliminium salts Grignard and zinc reagents were employed as nucleophiles in each case except for the methylation reaction.The methylation reaction of 10 with CH 3 MgCl proceeded with good yield whereas the diastereoselectivity was far from being satisfying (ds 11a/12a 60.6/39.4,see Table 1, Entry 1).The introduction of an ethyl group by means of C 2 H 5 MgBr led to a similar result the yield HETEROCYCLES, Vol.61, 2003