Nucleophilic Addition of β-Amino Carbanions to Arynes: One-Pot Synthesis of 4-Aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines

Abstract

A novel approach for the direct C-4 arylation of N-methyl-1,2,3,4-tetrahydroisoquinolines by nucleophilic addition of β-aminocarbanions to benzynes is described which provides a one-pot procedure for synthesis of the title compounds.

Aryne-Mediated Arylation of the 3-Benzazepine Scaffold: One-Pot Synthesis of 1-Aryl-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepines

“…9,10 Recently, we reported our findings involving reactions of amino carbanions 5 and 4a•Li with in situ generated arynes that successfully led to the synthesis of 1-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines 6b 11 and 4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines 8c (Scheme 2). 12 We were interested in exploring coupling reactions of the β-lithiated intermediate 7a•Li with in situ generated arynes, 13 which can lead to a onestep synthesis of 1-aryl-3-methyl-2,3,4,5-tetrahydro-1H-3benzazepines.…”

“…16 The highest yield (32%) was obtained for 10c employing 3-chloroanisole (9c) as the aryne precursor while the lowest yield (10b, 24%) was obtained with 4-fluoroanisole (9b). 12 In order to further explore the scope and generality of the reaction, the developed strategy was also applied to 7,8disubstituted benzazepines 7b and 7c. These were reacted with aryne precursors 9a-f under the optimized reaction conditions and C1-arylated benzazepines 1a-l were obtained in moderate yields (Scheme 5).…”

Intermolecular Nucleophilic Addition of N‐Diaminophosphinoyl‐Protected α‐Carbanions Derived from Secondary Amines to Arynes: Synthesis of 1‐Aryl‐1,2,3,4‐tetrahydroisoquinolines

“…Our group recently established a new approach which involved the coupling reaction of β‐amino carbanions, derived from tertiary amines, with in situ generated benzynes for a one pot synthesis of 4‐aryl‐ N ‐methyl‐1,2,3,4‐tetrahydroisoquinolines [Scheme , Equation (1)] . This approach was extended to the synthesis of 1‐aryl‐ N ‐methyl‐1,2,3,4‐tetrahydroisouinolines and 1‐aryl‐3‐methyl‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepines [Scheme , Equation (2) and (1)] .…”

Experimental and Theoretical Observations on the Intramolecular Nucleophilic Addition of α‐Amino Carbanions to Arynes: Synthesis of 1‐Aryl‐1,2,3,4‐tetrahydroisoquinolines

“…Recently, our group developed a new transition‐metal‐free and oxidant‐free protocol for the C‐4 arylation of N ‐methyl‐1,2,3,4‐tetrahydroisoquinolines that involved the intermolecular nucleophilic addition of β‐amino carbanions to in‐situ‐generated arynes [Scheme , Equation (1)] . This method was also extended to the C‐1 arylation of 3‐benzazepines and Lewis‐acid‐complexed tetrahydroisoquinolines [Scheme , Equations (2) and (3)].…”