Synthesis of Heterocyclic Compounds through Palladium-Catalyzed C–H Cyclization Processes

Abstract

Herein, we describe our development of synthetic methods for heterocyclic compounds based on the palladium-catalyzed carbon-hydrogen bond (C-H) functionalization/intramolecular carbon-heteroatom (nitrogen or sulfur) bond formation process. By this C-H cyclization method, we efficiently prepared various N-heterocycles, including indazoles, indoles, and 2-quinolinones, as well as S-heterocycles such as benzothiazoles and benzo[b]thiophenes. Yields are typically good to high and good functional-group tolerance is observed for each process, thereby indicating that the method provides a novel, highly applicable synthetic route to the abovementioned biologically important heterocyclic frameworks. As an application of this approach, an auto-tandem-type, one-pot process involving the oxidative Heck reaction and subsequent C-H cyclization using cinnamamides and arylboronic acids as starting materials in the presence of a palladium catalyst was also developed for the rapid construction of the 2-quinolinone nucleus.

Palladium-Catalysed Synthesis and Transformation of Quinolones

“…Pd-catalysed intramolecular amidation of N -substituted-3,3-diarylacrylamides 89 was efficiently performed in the presence of a catalytic amount of PdCl 2 and Cu(OAc) 2 under O 2 atmosphere, affording a range of diversely substituted 4-arylquinolin-2(1 H )-ones 90 and 91 (Scheme 29) [47,48]. The cyclization of the 3,3-diarylacrylamides having tosyl, acetyl or a t -butyl group on the nitrogen atom of the amide moiety proceeded with concomitant loss of the protecting group, whereas the use of free amide or alkyl amides led to the product in poor yields.…”

“…A tandem process consisting of two mechanistically independent sequential Pd(II)-catalysed reactions, the oxidative Heck reaction of cinnamamides 92 with arylboron compounds (Ar′–“B”) followed by the intramolecular C–H amidation reaction, represented a facile and novel route to various substituted 4-arylquinolin-2(1 H )-one derivatives (Scheme 30) [48,49]. The coupling of N -methoxycinnamamide 92 with phenylboronic acid using a catalytic combination of Pd(OAc) 2 /1,10-phenanthroline, Cu(TFA) 2 ·nH 2 O (200 mol%) and Ag 2 O (100 mol%) in AcOH successfully delivered the expected quinolin-2(1 H )-one 93 .…”

“…During the process, the use of a large excess of re-oxidants may inhibit the undesired N–O bond cleavage in which palladium and/or copper salt(s) are involved. This tandem process is also applicable to the synthesis of quinolin-2(1 H )-ones via the formation of symmetrical 3,3-diarylacrylamides [48,49]. Reactions of cinnamamides with a methyl group or a halogen atom at the p -position of the benzene ring proceeded efficiently (59–76%), whereas that of cinnamamide with a methoxy group at the same position, resulted in the formation of the corresponding quinolin-2(1 H )-one 95 (R 1 = 4-OMe) in only 12% yield, along with the recovery of the starting material in 85% yield.…”

“…Reactions via the formation of unsymmetrical 3,3-diarylacrylamides were also investigated (Scheme 30) [48,49]. Although 4-methoxyphenylboronic acid was not suitable for this process, other arylboronic acids possessing a trifluoromethyl group, a methoxycarbonyl group or a halogen atom on the benzene ring (R 2 ) successfully underwent reaction, affording different substituted 4-arylquinolin-2(1 H )-ones 96 and/or 96 ′.…”

“…Synthesis of 4-arylquinolin-2(1 H )-ones 90 , 90 ′ and 91 by Pd-catalysed intramolecular amidation of 3,3-diarylacrylamides 89 [47,48]. …”