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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.

Phenyldiazenyl moiety has been utilized both as a protective and activating group to synthesize C-1-substituted tetrahydroisoquinolines via lithiation–substitution strategy. This reaction sequence involves generation of α-amino carbanions, derived from N -phenyldiazenyl tetrahydroisoquinolines, followed by coupling with various electrophiles, e.g., aldehyde, ketones, alkyl halide, oxiranes, isocyanates, and with in situ generated arynes. Deprotection of the protecting group was carried out under acidic conditions to afford the desired α-substituted products in moderate to good yields. So, triazene as a protecting/directing group and its compatibility with strong bases provide a good synthetic utility for the synthesis of a variety of α-substituted secondary amines via lithiation substitution reaction. [ABSTRACT FROM AUTHOR]

1-Aryl-1,2,3,4-tetrahydroisoquinolines are important structural motifs and are widely found in bioactive molecules, pharmaceuticals and synthetic drugs. In view of increasing environmental awareness, the development of transition-metal-free strategies for the synthesis of these compounds is highly desirable. Metal-free oxidative coupling and lithiation methodologies have emerged as effective tools in this area as they exclude the use of transition-metal catalysts and help in reducing unwanted and toxic-metal-based chemical waste in the environment. This review highlights recent advances on the direct arylation of tetrahydroisoquinolines for the synthesis of the title compounds in the absence of a metal salt. Also, the emphasis has been placed on mechanistic considerations of these reactions. 1 Introduction 2 Arylation of Tetrahydroisoquinolines via Oxidative Coupling 2.1 Arylation Using Grignard Reagents 2.2 Arylation Using Other Organometallic Reagents 2.3 Arylation Using Aryl Organoboranes or Arenes 3 Arylation of Tetrahydroisoquinolines via Lithiation 3.1 Intermolecular Arylation 3.2 Intramolecular Arylation 4 Conclusion and Outlook [ABSTRACT FROM AUTHOR]

A simple protocol for the C1 arylation of tetrahydroisoquinolines with aryl Grignard reagents via diethyl azodicarboxylate (DEAD) mediated oxidative C-H activation under metal-free conditions has been developed. The target compounds, including some naturally occurring alkaloids, were obtained in moderate to good yields. [ABSTRACT FROM AUTHOR]

Direct cross-coupling between N-methyltetrahydroiso-quinolines and alkynes using CuI-DEAD is presented. It affords the regioselective C-1-alkynylated products in good yield. This regio-selectivity is in contrast to the results reported earlier in the reaction of N,N-dimethylbenzyl amine where the N-methyl alkynylated product was formed exclusively or predominantly. The C-1-substi-tuted propargylic isoquinolines were easily reduced to phenethyl-isoquinolines with Pd/C. This reaction sequence provides a short route to synthesize methopholine, homolaudanosine and other phenethylisoquinoline alkaloids. [ABSTRACT FROM AUTHOR]

The method is applied to the synthesis of cryptostyline II (IXa) and cryptostyline III (IXb). [ABSTRACT FROM AUTHOR]