CN-121494773-B - Synthesis method of thioether ligand and palladium-catalyzed 2-aryl indole compound

Abstract

The invention provides a synthesis method of a thioether ligand and a palladium-catalyzed 2-aryl indole compound, and designs application of the diphenyl thioether ligand and a palladium catalyst in preparation of the 2-aryl indole compound. Indole and arylboronic acid are carried out under the action of palladium catalyst and biphenyl thioether ligand: wherein, the structural formula of the biphenyl thioether ligand is as follows: Ar is phenyl, furyl, thienyl, naphthyl or phenyl substituted by one or more substituents, R 1 is methyl, methoxy, fluorine, chlorine or bromine or methyl ester, R 2 is the same or different and is methyl, ethyl, isopropyl, isobutyl, cyclohexyl, benzyl, n-butyl or n-hexyl, R 3 is alkoxy, alkylthio, substituted amino or halogen, and the palladium catalyst is a divalent palladium compound.

Inventors

• HAN XIAOQING
• YIN XUESONG
• DONG HEWEI
• LIU CHENGCHENG
• HUA YUNYU
• YAN PUCHA
• LI YUANQIANG

Assignees

• 九洲药业(杭州)有限公司

Dates

Publication Date

20260512

Application Date

20260114

Claims (5)

1. 1. The preparation method of the 2-aryl indole compound is characterized in that in the presence of an organic solvent and an oxidant, the indole compound and the aryl boric acid compound are subjected to an oxidation Suzuki coupling reaction under the catalysis of a palladium catalyst and a biphenyl thioether ligand: , wherein the biphenyl thioether ligand specifically comprises: ; R 1 is a chlorine atom; Ar is phenyl or fluorophenyl; the palladium catalyst is palladium trifluoroacetate; the organic solvent is 1, 2-dichloroethane; the oxidant is a co-oxidation system of copper acetate or silver acetate and air or oxygen.
2. 2. The method according to claim 1, wherein the reaction temperature is 50 to 120 ℃.
3. 3. The preparation method according to claim 1, wherein the biphenyl thioether ligand preparation reaction is: 。
4. 4. The process according to claim 3, wherein the biphenyl sulfide ligand preparing reaction is carried out in the presence of a base.
5. 5. The method according to claim 4, wherein the base is sodium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate or potassium phosphate.

Description

Synthesis method of thioether ligand and palladium-catalyzed 2-aryl indole compound Technical Field The invention relates to the technical field of organic synthesis, in particular to a thioether ligand, a palladium-catalyzed synthesis method of a 2-aryl indole compound and application of the ligand in synthesizing the 2-aryl indole by high-selectivity oxidative coupling of indole and aryl boric acid under the catalysis of divalent palladium. Background Indole is an important nitrogen-containing heterocyclic compound, and arylation derivatives thereof, particularly 2-aryl indole, are widely existing in natural products and drug molecules, for example OXi-8006 is a tubulin inhibitor with anticancer activity, ARCYRIACYANIN A is a tyrosine kinase inhibiting drug, and can be used for targeted treatment of cancers. Therefore, the development of a method for efficiently and selectively constructing 2-aryl indole has important value, 。 In direct functionalization of the c—h bond of indoles, achieving regioselective arylation of the C2 site is a long standing challenge due to the higher reactivity of both the C2 and C3 positions. The transition metal catalysis provides a powerful tool for the direct functionalization of the C-H bond. The group of Larrosa problems in 2008 realized for the first time the direct C-2 arylation of indole with aryl iodides at room temperature without phosphine ligand, which is applicable to indole substrates with protected N atoms (j. Am. Chem. Soc. 2008, 130, 2926-2927). The Ackermann group 2011 uses removable directing groups to effect ruthenium-catalyzed C2-position C-H bond activated arylation of indoles (org. Lett. 2011,13,3332-3335). In 2017 Song Maoping, under the air condition, co (acac) 2 is used as a catalyst, mn (OAc) 2·4H2 O is used as a Co-oxidant, and pyrimidine is used as a guide group to realize the oxidation arylation reaction of indole C2 (org. Lett. 2017, 19, 596-599). The C2 coupling reaction of indole and aryl chloride was achieved in 2019 Punji under Ni catalysis and 2-pyridine guiding (j. Org. Chem. 2019, 84, 12800-12808). However, in the coupling reaction of indole and arylboronic acid, how to precisely control the regioselectivity (C2 vs C3) of the reaction through ligand design, while using an environmentally friendly oxidation system, remains a technical problem addressed by those skilled in the art. The prior art either suffers from poor selectivity or requires the use of expensive, complex ligands and non-environmentally friendly stoichiometric oxidants, limiting its practical application. Therefore, a catalytic system which can realize high C2 selectivity, has mild conditions, is environment-friendly and has simple and easily available ligand is developed, and has urgent requirements and wide application prospect. Disclosure of Invention The application of the thioether ligand/palladium catalytic system in the preparation of the 2-aryl indole compound is less researched or a breakthrough research result is lacked. The first object of the invention is to provide a diphenyl sulfide ligand and a synthetic method for preparing a 2-aryl indole compound by oxidizing Suzuki coupling of palladium-catalyzed indole and phenylboronic acid. The second object of the invention is to provide a method for synthesizing biphenyl thioether ligands. In order to achieve the technical purpose, the invention adopts the following technical scheme: in a first aspect, the invention provides a biphenyl thioether ligand and an application of a palladium catalyst in preparation of a 2-aryl indole compound. The invention provides a preparation method of a 2-aryl indole compound with participation of biphenyl thioether ligands. In the presence of an organic solvent and an oxidant, an indole compound and an arylboronic acid compound are subjected to an oxidation Suzuki coupling reaction under the catalysis of a palladium catalyst and a biphenyl thioether ligand, wherein the reaction formula is as follows: , Wherein R 1 is methyl, methoxy, fluorine atom, chlorine atom, bromine atom or methyl ester group; Ar is phenyl, furyl, thienyl, naphthyl or phenyl substituted with one or more substituents each independently methyl, tert-butyl, phenyl, methoxy, trifluoromethyl or halogen. The oxidation Suzuki coupling reaction of the invention is carried out under the participation of biphenyl thioether ligands, and a palladium catalyst is also required to be added in the reaction. The palladium catalyst can be palladium acetate, palladium trifluoroacetate, palladium chloride and the like. The oxidant is a co-oxidation system of copper acetate or silver acetate and air or oxygen, such as a co-oxidation system consisting of oxygen and copper acetate (Cu (OAc) 2). Adding indole compounds, arylboronic acid, palladium catalyst, ligand, oxidant and organic solvent into a reaction bottle, replacing nitrogen for three times, connecting to an oxygen ball, heating the reaction to 50-120 ℃ for reaction for 8-24 h