Preparation of Substituted Tetrahydroisoquinolines by Pd(II)-Catalyzed NH₂-Directed Insertion of Michael Acceptors into C–H Bonds Followed by NH₂-Conjugated Addition

Abstract

Disubstituted tetrahydroisoquinolines are prepared in one step from Michael acceptors and 2phenylethylamines under Pd catalysis and Ag 2 CO 3 as an oxidant. Presumably, activation of an ortho C−H bond of the aromatic ring with Pd(II) is directed by the primary amine to form a palladacycle. Insertion of the olefin, subsequent conjugated addition of the amine, and reductive elimination of Pd(0) affords the expected products. Silver carbonate is not necessary when 2-phenylethylamines are converted previously to N-benzoyloxy-2-phenylethylamines.

Site‐Selective C(sp3)−H and C(sp2)−H Functionalization of Amines Using a Directing‐Group‐Guided Strategy

“…studied the insertion of alkenes 154 at the δ‐position of free 2‐phenylethylamines 153 to form six‐membered palladacycles that yielded tetrahydroisoquinolines 155 upon intramolecular Michael addition (Scheme 38). [105] The reaction mechanism supported by computational studies shows that the Pd(II) catalyst activates the aromatic C( sp 2 )−H bond. The deprotonation was facilitated by acetato ligand to provide Pd‐intermediate which upon coordination with alkene forms eight membered palladacycle.…”

Comprehensive Strategies for the Synthesis of Isoquinolines: Progress Since 2008

“…[151] The strategy of C(sp 2 )-H olefination of phenethylamine substrates 258 was described by 2 different groups towards the synthesis of tetrahydroisoquinolines. In 2017, Mancinelli et al [152] utilized primary 2phenethylamines bearing a quaternary carbon at the αposition and Fan et al [153] have utilized primary and secondary 2-phenethylamines to access tetrahydroisoquinolines under Pd-catalyzed reaction conditions (Scheme 152).…”

“…The strategy of C( sp 2 )‐H olefination of phenethylamine substrates 258 was described by 2 different groups towards the synthesis of tetrahydroisoquinolines. In 2017, Mancinelli et al [152] . utilized primary 2‐phenethylamines bearing a quaternary carbon at the α‐position and Fan et al [153] .…”

Site‐Selective γ‐C(sp3)−H and γ‐C(sp2)−H Arylation of Free Amino Esters Promoted by a Catalytic Transient Directing Group

“…Severalc oncerns apply for using free amino esters as substrates in Pd-catalyzed C(sp 3 )ÀHand C(sp 2 )ÀHbond activation with aldehyde TDGs, including:( 1) the formation of unreactiveP d(RNH 2 ) 2 X 2 complexes; [14] (2) amino acid formationl eading to bidentate palladium complexes retardingr eactionp rogress (3) amino acid formation following CÀHi nsertion complicating product isolation; (4) aminoestersb earing an a-hydrogen accelerate a-hydride elimination, and the production of Pd 0 and iminoester by-products; [15] (5) b-imino esters formed from a-amino esters and aldehydes can tautomerize to a-imino esters, which hydrolyze to give a-keto esters. [12] Although g-C(sp 2 )ÀHa rylation of benzylamines was reported 12 years ago (Scheme 1c), [16] to the best of our knowledge, no site-selective g-C(sp 3 )ÀHa nd g-C(sp 2 )ÀHa rylation of free amino esters have yet been reported. Herein we report our efforts towards the first site-selective g-C(sp 3 )ÀH and g-C(sp 2 )ÀHa rylation of free amino esters promoted by catalytic TDGs (Scheme 1d).…”

“…No product was found in the absence of palladium catalyst (Table 1, entry 13). Other TDGs were employed, but none of them provided ab etter yield than TDG-1 (Table 1, entries [14][15][16][17][18][19][20][21]. The reaction did not go to completion in 8hours (Table 1, entry 22), but prolonging the reactiont ime beyond1 2hours did not increase the yield (Table 1, entry 23).…”