Direct oxidative C–H alkynylation ofN-carbamoyl tetrahydroisoquinolines and dihydroisoquinolines

Abstract

An efficient oxidative C-H alkynylation of N-carbamoyl tetrahydroisoquinolines mediated by a TEMPO oxoammonium salt has been established. A variety of electronically varied N-carbamoyl tetrahydroisoquinolines reacted with a range of alkynyl potassium trifluoroborates smoothly under mild metal-free conditions. Dihydroisoquinolines were also suitable components for the reaction. The synthetic applicability of the method for facile access to structurally diverse bioactive molecules was further demonstrated.

Transition-Metal-Free Oxidative Cross-Coupling of Triorganoindium Reagents with Tetrahydroisoquinolines

“…It should be also noted that the reactions with N -Cbz-THIQs furnished with electron-withdrawing groups (such as 5-Cl or 5-Br) did not afford the coupling products or gave low yields (<15%). On the other hand, the reactions using the 6,7-dimethoxy-substituted THIQ 1c resulted in improved yields, a behavior previously observed in the reactivity of iminium and oxonium intermediates generated under oxidative conditions. ,, Here, the reaction of triphenylindium with 1c afforded 2l in a good 80% yield, and using tribenzylindium, 2m was obtained in an excellent 93% yield. In addition, the more reactive 1c was also successfully coupled with alkylindium reagents, such as methyl and butyl, affording 2n and 2o in 63% and 83% yields, respectively.…”

“…The selective functionalization of tetrahydroisoquinolines at the C-1 position constitutes one attractive approach for the synthesis of derivatives. Several methods have been developed including transition-metal-catalyzed reactions, metal-free oxidative coupling reactions, photocatalytic and electrochemical methods, and dehydrogenative cross-coupling reactions …”

Organic Synthesis Using Nitroxides

“…Tetrahydroisoquinolines have been successfully used as substrates in oxidative α-functionalization, mostly applying oxoammonium salts as stoichiometric oxidants (Scheme ). − In the first step, an iminium ion is generated via hydride transfer to an oxoammonium salt (TEMPO + BF 4 – or Bobbitt’s salt). This iminium ion is trapped in the second step with various nucleophiles.…”

“…As examples, electron-rich alkenes can add to the intermediate iminium ion and the formed carbenium ion is trapped by the carbonyl O atom of the N -carbamate protecting group (e.g., Boc), resulting after O -dealkylation in an oxidative annulation of the isoquinoline (Scheme a). Amides can act as internal nucleophiles in an enantioselective cyclization in the presence of chiral phosphoric acids (Scheme b). , Further, the iminium ion trapping with cyanide (Scheme c), , azide (Scheme h), an allyl silane (Scheme d), and alkynes (Scheme e and g) ,, was reported. A very elegant approach was presented by the group of García Mancheño using diazomethane derivatives as nucleophiles, leading to a ring expansion to obtain valuable 3-benzazepines (Scheme f) .…”

“…(d) Allyltrimethylsilane,665 (e) Alkyne, CuBr, Chiral BOX Ligand, Yb(OTf) 3 , EtOH, KOH, and H 2 O, 666 (f) R″CHN 2 , 667 (g) AlkynylBF 3 K,668 (h) TMSN 3 , 669 (i) NaN 3 , R′NC, 670 and (j) H 2 O with Catalytic TEMPO Oxidized with Hypobromite In Situ-Generated Electrochemically b,671 CO 2 R′, COR′, SO 2 R′. b Newly formed bonds are highlighted in bold.…”