Palladium(II)/N‐Heterocyclic Carbene‐Catalyzed Regioselective Heteroannulation of Tertiary Propargyl Alcohols and o‐Haloanilines to form 2‐Alkenylindoles

Abstract

Monometallic and bimetallic palladium(II)/N-heterocyclic carbenec omplexes appended with naphthalimide or bisnaphthalimide moieties were designed, synthesized, and characterized. Employment of these catalysts brings about the stepeconomic and regioselective heteroannulationo f tertiary propargyl alcohols with o-haloanilines resulting in biologically and pharmaceutically relevant 2-alkenylindoles.Basis for the regioselective heteroannulation is unraveled by coordination of the propargylic hydroxy moiety to palladium during insertion. Embracing this methodology,asingle regioisomer of unsymmetrical 2,3-disubstitutedi ndoles could be achieved throughl ate-stage modification. Ther ole of the naphthalimide or bisnaphthalimide appended to the NHC on the catalytic efficiency has been studied.

Recent advances in the synthesis of indoles from alkynes and nitrogen sources

“…Expanding upon the use of alkynes in the Larock indole synthesis, very recently, the palladium(II)/N-heterocyclic naphthalimide carbene complex heteroannulation of tertiary propargyl alcohols with ortho-haloanilines, resulting in the formation of 2-alkenylindoles 222, has been reported (Scheme 179). 209 A single regioisomer was obtained and this high regioselectivity was attributed to the coordination of the palladium catalyst to the propargyl hydroxyl moiety during the palladium insertion step. In addition, the authors concluded through experimental evidence that the in situ generation of HBr is the promotor of terminal double bond formation by a dehydration process.…”

Synthesis of Indoles via Intermolecular and Intramolecular Cyclization by Using Palladium-Based Catalysts

“…Ethyl-3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates (231) also afforded 2-alkylindoles (232) in the presence of HCOOH, with base Et3N, and catalyst Pd(PPh3)4 in solvent CH3CN 80 °C (Scheme 70) [214]. In 2014, Thirupathi and colleagues developed 2-indolylacetamides (235) by a Pdcatalyzed tandem annulation of (amino aryl)propargyl alcohols (233) and isonitriles (234) in excellent yields. The transformation was carried out in the presence of a Pd(TFA) 2 catalyst, Cs 2 CO 3 base, and CH 3 CN solvent in the open air at 60 • C (Scheme 71).…”

“…For this reaction, palladium in its two oxidation states Pd (0) and Pd (II) activated the reactants and carried out the annulation process without additional oxidants [216]. In 2014, Thirupathi and colleagues developed 2-indolylacetamides ( 235) by a Pd-catalyzed tandem annulation of (amino aryl)propargyl alcohols (233) and isonitriles ( 234) in excellent yields. The transformation was carried out in the presence of a Pd(TFA)2 catalyst, Cs2CO3 base, and CH3CN solvent in the open air at 60 °C (Scheme 71).…”

“…Deprotection of haloanilines took place during the cyclization. The substrates having -F, -OMe, -MeCO, -EtOOC, -Me, and -CN substituents at position-4 were readily tolerable [233].…”

Tandem Annulations of Propargylic Alcohols to Indole Derivatives

“…Gandhi et al . reported in 2017 a straightforward and one‐pot synthesis of 2‐alkenylindoles through a Pd‐NHCs catalysed tandem reactions from o ‐haloanilines and tertiary propargylic alcohols [32] . The reaction tolerated broad scope of not only o ‐haloanilines bearing I, Br and Cl and functional groups such as CN, CO 2 Et and MeCO etc .…”