Palladium-Catalyzed Regioselective Syn-Chloropalladation–Olefin Insertion–Oxidative Chlorination Cascade: Synthesis of Dichlorinated Tetrahydroquinolines

Abstract

A palladium catalyzed cascade process involving synchloropalladation, intramolecular olefin insertion, and oxidative C− Cl bond formation reactions was demonstrated for the synthesis of dichlorinated tetrahydroquinolines in high yields (up to 93%). The N-propargyl arylamines having a tethered α,β-unsaturated carbonyl moiety underwent a regioselective syn-chloropalladation followed by a Heck-type reaction to deliver the tetrahydroquinoline scaffold. The rare insertion of the second chlorine atom was rationalized comprising a Pd II/IV catalytic cycle and oxidative cleavage of the C−Pd II bond.

Synthesis of Highly Conjugated Functionalized 2-Pyridones by Palladium-Catalyzed Aerobic Oxidative Dicarbonation Reactions of N-(Furan-2-ylmethyl) Alkyne Amides and Alkenes as Coupling Partners

“…Pd-catalyzed difunctionalization of alkynes is a powerful method for preparing N -heterocyclic compounds (Scheme a). This method involves nucleopalladation of the alkyne with a nucleophile (such as acetic acid, an amide or amine, a halide or pseudohalide, a carbonyl oxygen, a boronic acid, or an electronic-rich alkene) to generate vinylpalladium species A , which is captured by another nucleophile or an electrophile. Varying the nucleophile(s) or the electrophile allows for the synthesis of a diverse array of structurally novel products.…”

Direct Access to 9-Chloro-1H-benzo[b]furo[3,4-e]azepin-1-ones via Palladium(II)-Catalyzed Intramolecular syn-Oxypalladation/Olefin Insertion/sp2-C–H Bond Activation Cascade

“…12,13 Recently, we established a syn-chloropalladation/olefin insertion/oxidative chlorination cascade for the synthesis of dichlorinated tetrahydroquinolines 2 starting from N-propargyl arylamines 1 tethered with α,β-unsaturated ketones in the presence of a palladium catalyst and CuCl 2 •2H 2 O as the chloride source (Scheme 2, eq 1). 14 When we swapped the α,β-unsaturated ketone moiety of 1 with α,β-unsaturated ester (compound 3), the reactivity was entirely altered and the unpredicted 1H-benzo [b]furo [3,4-e]azepin-1-ones 4 bearing an Ar−Cl substituent was obtained as the major product (Scheme 2, eq 2). This interesting cascade transformation intrigued us to further explore the reactivity of compounds 3 to obtain the biologically significant tricyclic 1H-benzo [b]furo- [3,4-e]azepin-1-ones 4 and to investigate the mechanism of the annulation/sp 2 -C−Cl bond formation cascade.…”

“…Recently, we established a syn -chloropalladation/olefin insertion/oxidative chlorination cascade for the synthesis of dichlorinated tetrahydroquinolines 2 starting from N -propargyl arylamines 1 tethered with α,β-unsaturated ketones in the presence of a palladium catalyst and CuCl 2 ·2H 2 O as the chloride source (Scheme , eq 1) . When we swapped the α,β-unsaturated ketone moiety of 1 with α,β-unsaturated ester (compound 3 ), the reactivity was entirely altered and the unpredicted 1 H -benzo­[ b ]­furo­[3,4- e ]­azepin-1-ones 4 bearing an Ar–Cl substituent was obtained as the major product (Scheme , eq 2).…”

“…Initially, we tested the reaction conditions established for the syn -chloropalladation-initiated cascade using N -propargyl arylamine 3a bearing an α,β-unsaturated ester functionality as the model substrate, and only traces of product 4a were observed in the presence of 10 mol % of Pd­(OAc) 2 and 2 equiv of CuCl 2 ·2H 2 O in THF and DME at ambient temperature (Table , entries 1 and 2). Remarkably, an increase of the reaction temperature to 50 °C in THF triggered the cascade transformation to allow access to the desired product 4a in 58% yield, and the results in DME were inferior (entries 3 and 4).…”

Palladium-Catalyzed Nitrile-Assisted C(sp3)–Cl Bond Formation for Synthesis of Dichlorides

“…In their strategy, bulky trialkylphosphine ligands or other additives were required. (ii) The other, mainly for the case that contains a β-hydrogen atom, has been developed by Lu, 13 Liu, 14 Sridharan, 15 and our group. 16 In these methods, introducing a rigid cycle structure to the β-site is the key to the increase in difficulty of β-hydride elimination from alkylpalladium(II) halides (Scheme 1b).…”