Phenolic Activation in Chiral Brønsted Acid-Catalyzed Intramolecular α-Amidoalkylation Reactions for the Synthesis of Fused Isoquinolines

Abstract

An organolithium addition–intramolecular α-amidoalkylation sequence on N -phenethylimides has been developed for the synthesis of fused tetrahydroisoquinoline systems using 1,1′-bi-2-naphthol (binol)-derived Brønsted acids. This transformation is the first in which activated benzene derivatives are used as internal nucleophiles, instead of electron-rich heteroaromatics, generating a quaternary stereocenter. Phenolic substitution on the aromatic ring of the phenethylamino moiety and the use of binol-derived N -triflylphosphoramides as catalysts are determinants to achieve reasonable levels of enantioselection, that is, up to 75% enantiomeric excess, in the α-amidoalkylation step. The procedure is complementary to the intermolecular α-amidoalkylation process, as opposite enantiomers are formed, and to the Pictet–Spengler cyclization, which allows the formation of tertiary stereocenters.

Crystal structure, DFT calculations and evaluation of 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione as AChE inhibitor

“…The absence of strong hydrogen bonding donors results in the participation of only one imide carbonyl in hydrogen bonding. The selective activation of one imide carbonyl group of the N -phenethylimides by Brønsted acids, such as BBr 3 [ 34 ], TfOH [ 35 ] or organometallics [ 36 ], leads to regioselective intramolecular cyclization to deliver tetrahydroisoquinoline derivatives [ 37 , 38 ]. This selective regiochemical polarization could be involved in the mode of action of compound 1 as an AChEI, as previously proposed [ 39 ].…”

Comprehensive Strategies for the Synthesis of Isoquinolines: Progress Since 2008

“…The present protocol rely on organolithium addition-intramolecular α-amidoalkylation pattern on N-phenethylimides 487 (Scheme 295). [293] Chen et al have demonstrated a protecting-groupfree intramolecular thermal cyclization of methyl 2-[(diphenylmethylidene)amino]-acetates 490 to access 1-phenylisoquinolin-4-ols 491. It was found that substitutions on Schiff's base affecting the yields of the reaction products (Scheme 296).…”

Ferrocene as a Privileged Framework for Chiral Organocatalysts

“…Since the elegantc ontribution of chiral phosphoric acids as Brønsteda cid catalysts independently discovered by the groups of Akiyama [39] and Te rada [40] in 2004, continuous attentions have been attracted by chiral Brønsted acid catalysis and these catalysts have been regarded as powerful organocatalysts for asymmetrics ynthesis. [41] The different kinds of chiral Brønsteda cids have been prepared and exhibited to enable numberso fe nantioselective transformations.…”