An expedient approach to 1,2-dihydroisoquinoline derivatives via cobalt catalysed 6-endo dig cyclization followed by Mannich condensation of o-alkynylarylaldimines

Abstract

A highly effective 6-endo dig cyclisation of o-alkynylaldimines to 1,2-dihydroisoquinolines has been described via direct and nitro Mannich condensation using inexpensive and readily available cobalt chloride as catalyst. This strategy provides an effective procedure for the synthesis of substituted 1,2-dihydroisoquinolines derivatives in moderate to high yields. An addition of pronucleophiles, such as nitromethane, acetone and α-hydroxyacetone, to o-alkynylarylaldimines has been achieved via isoquinolinium intermediate.

Design, Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors

“…The type I 1,2-dihydroisoquinolines 4a – h were synthesized by the reaction of o -alkynyl aldehyde 1a – b with ketones 2a – c and amines 3a – f via dual activation process as per the reported literature. − Under the effective catalysis of inexpensive anhydrous CoCl 2 , intermolecular attack of enamine (generated by the reaction l -proline with ketones) onto o -alkynylaldimines (formed by the reaction of o -alkynylaldehyde with amine) resulted in the desired 6- endo - dig cyclized products 4a – h (Scheme ). Reactions of 2-alkynylbenzaldehydes 1a – b with propanone ( 2a ) and 4-aminophenol ( 3a ) afforded the desired products 4a and 4h in 65 and 68% yields, respectively, after 12 h; whereas reaction of substrate 1b with propanone and p -toluidine 3e provided the product 4f in 87% yield in less reaction time (4 h).…”

“…Type III, 1,2-dihydroisoquinolines (Figure ) were prepared by nitro-Mannich condensation by our reported procedure . Dihydroisoquinolines 6a – e were synthesized in 58–90% yields via attack of aci-nitromethane on o -alkynylaldimines under cobalt-catalysis (Scheme ).…”

Silver-catalyzed tandem cycloisomerization/hydroarylation reactions and mechanistic investigations for an efficient access to 1,2-dihydroisoquinolines

“…3,21 More recently, Han and Lu's team reported a Pd-catalyzed reaction for the synthesis of 1,2-dihydroisoquinolines with the concomitant insertion at position 1 of 3-indoles. 22 Such scaffolds can also be obtained using cobalt catalysts, as reported by Tandon et al 23 There is only one report with few examples described in the presence of a silver catalyst. 17 Following our interest in Ag-catalyzed cycloisomerization reactions to form furoquinoline/pyranoquinoline, 24,25 isochromene 26 or pyranoquinoline 27 derivatives as well as isobenzofurane or isoindoline derivatives, 28 we envisioned to establish efficient reaction conditions for the formation of a wider variety of isoquinoline derivatives compared to previous literature reports.…”

The Stereoselective Nitro-Mannich Reaction in the Synthesis of Active Pharmaceutical Ingredients and Other Biologically Active Compounds

“…Since the HIV-1 virus has high mutation ability, the development of novel and potent INs is the subject of much research. In 2015 Tandom and coworkers developed methods for the synthesis of new 1,2dihydroisoquinolines, and found in an in vitro strand transfer assay, that some of them were potent integrase inhibitors, with IC 50 values of 0.7-0.8 µM, e.g., 136a (Figure 9C; Urvashi et al, 2015). In an antiviral assay, one even reduced the level of the p24 viral antigen by 91%, which is comparable to RAL, an FDA approved antiviral drug.…”