Facile and diastereoselective arylation of the privileged 1,4-dihydroisoquinolin-3(2H)-one scaffold

Abstract

A practically convenient and streamlined protocol for the trans-diastereoselective introduction of an aryl substituent at position 4 of the 1,4-dihydroisoquinol-3-one (1,4-DHIQ) scaffold is presented. The protocol involves direct Regitz diazo transfer onto readily available 3(2H)-isoquinolones followed by TfOH-promoted hydroarylation by an arene molecule. Screening of the novel 1,2,4-trisubstituted 1,4-DHIQs against cancer cell lines confirmed high cytotoxicity of selected analogs, which validates this new chemotype for further investigations as anticancer cytotoxic agents.

Chemo- and Diastereoselective Entries into All-Carbon α-Quaternary Aldehydes via C–C Insertion of 4-Diazoisoquinolin-3-ones into C–CHO Bonds

“…Aldehydes were commercially available and used as received. 4-Diazo-3­(2 H )-isoquinolones 3 were synthesized according to the previously reported method unless otherwise stated . 4-Diazoisochroman-3-one was synthesized according to the previously described procedure …”

“…Quantitative yield, 47 mg, dr 56:44; colorless oil. Major diastereomer was assigned as (1 RS ,4 RS ) according to the literature data …”

“…Considering this a significant void to fill, recently we proposed a practically convenient method for the synthesis of various 1,2-disubstituted 4-diazo-3­(2 H )-isoquinolones 3 and investigated their diastereoselective TfOH-promoted arylation with arenes (Scheme b) . Intending to avoid the regioselectivity issue, arising when some substituted arenes were used in the reaction, we envisioned that aryl aldehydes could serve as alternative and regiospecific arylation reagents in accordance with recently reported procedures. , Nevertheless, as a result of the BF 3 -promoted reaction between diazo compound 3a and p -tolualdehyde, instead of obtaining C -arylation product 4 (as in the previously described transformation 1 → 2 ), the diastereoselective formation of stable to deformylation 3-oxo-1,2,3,4-tetraisoquinoline-4-carbaldehyde 5a via the formal insertion reaction of the diazo reagent 3a into the C–C aldehyde bond was observed (Scheme c).…”