CN-118026995-B - Dihydrotriazole aromatization precursor and application thereof in deacylating and arylating reaction of ketone

Abstract

The invention discloses a precursor for aromatization of dihydrotriazole, a preparation method and the application of the precursor for aromatization of dihydrotriazole in deacylating and arylating ketone, wherein the application comprises (1) dissolving ketone and 2-pyridylhydrazone amide in a solvent, adding an activating additive, and heating and activating under inert gas atmosphere to obtain the precursor for aromatization of dihydrotriazole; and (2) mixing the product obtained in the step (1) with aryl halide with or without purification, and carrying out photocatalytic reaction under the conditions of photocatalyst, nickel catalyst, alkali, solvent and light to obtain the deacylated arylate product of ketone. The deacylation and arylation reaction method of ketone has the advantages of simple and easily obtained raw materials, mild reaction conditions, wide substrate applicability and the like, and meets the requirement of developing green environment-friendly chemistry.

Inventors

• Zhang Xiaheng
• ZHAN BEIBEI
• ZHANG BOYI
• YANG HONGXIANG

Assignees

• 国科大杭州高等研究院

Dates

Publication Date

20260508

Application Date

20231228

Claims (3)

1. 1. A method for the deacylation and arylation reaction of a visible light-induced aromatization-driven ketone, comprising: (1) Dissolving ketone and MPHA in a solvent, adding an activating additive, and heating and activating under an inert gas atmosphere to obtain a dihydrotriazole aromatization precursor; (2) Mixing the product obtained in the step (1) with aryl halide with or without purification, and carrying out photocatalytic reaction under the conditions of a photocatalyst, a nickel catalyst, alkali, a solvent and illumination to obtain a deacylated arylate product of ketone; the structural formula of the precursor for aromatization of the dihydrotriazole is shown as a formula (I) or a formula (II): r 1 、R 2 and Cy are derived from raw ketone; The aryl halide is selected from at least one of the following compounds: ; The ketone is 2-acetylindane, acetylcyclohexane, cyclopentyl ethyl ketone, cyclobutylmethyl ketone, 1-BOC-3-acetylacridine, 1-N-BOC-4-acetylpiperidine, phenoxyethyl ketone, 4- (3, 4-dimethoxyphenyl) butane-2-ketone, 4- (benzyloxy) butane-2-ketone, 6-methyl-2-heptanone, methyl 4-acetylbutyrate, ethyl levulinate, 4-acetylbutylethyl ester, N-propyl levulinate, methyl 5-acetylvalerate, 4- (4-methoxyphenyl) -2-butanone, 6-methyl-5-hepten-2-one cyclohexylacetone, nabumetone, BETA-dihydroionone, 1- (tetrahydro-2H-pyran-4-yl) ethanone, 3, 7-dimethyl-1- (5-oxohexyl) -3, 7-dihydro-1H-purine-2, 6-dione, 8R,9S,13S, 14S) -13-methyl-3- (5-oxohexyl) oxy) -6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopentaphenanthren-17-one, 5-nonone, cyclohexanone, tetrahydropyranone, 4-propylcyclohexane-1-one, 4-phenylcyclohexane-1-one, 2- (4-oxocyclohexyl) isoindoline-1, 3-dione, N-t-butoxycarbonyl-4-piperidone, at least one of 4 (4' -benzonitrile) cyclohexanone, 1, 4-cyclohexanedione monoethylene glycol ketal, ethyl p-cyclohexanone carboxylate, 1-t-butoxycarbonyl-2-methyl-piperidone, N-BOC-3-methyl-4-piperidone, 4-N-benzyloxycarbonylamino cyclohexanone, N-t-butoxycarbonyl-nortopinone, cis-5-oxohexahydrocyclopenta [ C ] pyrrole-2 (1H) -carboxylate tert-butyl ester, 2- ((4-oxocyclohexyl) carbamoyl) pyrrolidine-1-carboxylate tert-butyl ester, (S) -2- (6-methoxynaphthalen-2-yl) -N- (4-oxocyclohexyl) propionamide, 5- (2, 5-dimethylphenoxy) -2, 2-dimethyl-N- (4-oxocyclohexyl) pentanamide, 2- (3-benzoylphenyl) -N- (4-oxocyclohexyl) propionamide, 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-N- (4-oxocyclohexyl) thiazole-5-carboxamide; The activating additive is at least one of camphorsulfonic acid, p-toluenesulfonic acid and acidic alumina; The photocatalyst is at least one of 2,4,5, 6-tetra (diphenylamino) m-phthalonitrile, [2,2 '-bi (4-tert-butylpyridine) ] bis [2- (4-fluorophenyl) pyridine ] iridium (III) hexafluorophosphate, [4,4' -bis (1, 1-dimethylethyl) -2,2 '-bipyridyl-K, N ] bis [ 5-fluoro-2- (5-methyl-2-pyridyl-K, N) phenyl ] C ] iridium hexafluorophosphate, 4' -bis (trifluoromethyl) -2,2 '-bipyridyl bis [3, 5-difluoro-2- [ 5-trifluoromethyl-2-pyridyl) phenyl ] iridium (III), (4, 4' -di-tert-butyl-2, 2 '-bipyridyl) bis [ (2-pyridyl) phenyl ] iridium (III) hexafluorophosphate, bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2' -bi (4-tert-butylpyridine) ] iridium (III) hexafluorophosphate; The nickel catalyst is at least one of (1, 1' -bis (diphenylphosphine) ferrocene) nickel dichloride, dibromo-bis (tributylphosphine) nickel (II), dibromo-bis (triphenylphosphine) nickel dichloride and 1, 3-bis (diphenylphosphine propane) nickel dichloride; The reaction route is as follows: Or: r 3 is a triazole substituent formed by Cy ring opening and connected with MPHA residue.
2. 2. The method for deacylation and arylation reaction of visible light-induced aromatization driving ketone according to claim 1, wherein in the step (1), the molar amount of ketone is 100-120% of MPHA mol amount, and the molar amount of activating additive is MPHA mol amount 2-10%; in the step (2), the molar amount of the photocatalyst is 1-2% of that of MPHA, the molar amount of the nickel catalyst is 10-20% of that of MPHA, and the molar amount of the alkali is 300-400% of that of MPHA.
3. 3. The method for deacylated arylation reaction of visible light induced aromatization driven ketone according to claim 1, wherein in the step (1), the temperature of ketone activation reaction is 78-95 ℃, the reaction time is 12-24 h, and in the step (2), the photocatalytic reaction temperature is room temperature to 80 ℃ and the reaction time is 24-48 h.

Description

Dihydrotriazole aromatization precursor and application thereof in deacylating and arylating reaction of ketone Technical Field The invention relates to the technical field of chemical synthesis, in particular to a precursor for aromatization of dihydrotriazole and application of the precursor in deacylation and arylation of ketone. Background Carbon-carbon bonds are widely present in organic compounds, however, due to the greater steric hindrance of carbon-carbon bonds, the bond energy is higher, etc., leading to a lag in the study of their activation reactions. Ketones are one of the most common organic substances, which are widely present in natural products and drug molecules, and furthermore, ketones are one of the most common functional groups in organic synthesis, which can be easily converted from other functional groups and can undergo various derivatization reactions at the α and β positions. It is therefore important how to achieve carbon-carbon bond activation (deacylation) and efficient conversion of ketones. Transition metal-catalyzed ketone carbon-carbon bond activation has been actively developed in recent years, but in contrast, research on carbon radical generation through ketone carbon-carbon bond activation has been relatively delayed, mainly due to weak reaction driving force and lack and instability of radical precursors. Aromatization plays an important role as a thermodynamic driver in enzyme-catalyzed bioconversion and organic synthesis, and around organic chemistry, free radicals appear as key intermediates in many valuable synthetic transformations, and strategies that drive the generation of free radicals have begun to gain attention as free radical precursors continue to be studied in depth. The group of Dong Anbin professor topics at chicago, U.S. has long been engaged in the field of C-C bond activation. In 2019, the subject group completed the deacetylation conversion of ketones by aromatization driven activation of C-C bonds (Nature, 2019,567,373), which involved the formation of a pre-aromatic intermediate of a ketone substrate with two activators (hydrazine and 1, 3-diene) that was broken down via Ir (III) mediated C-C bonds to produce aromatic heterocyclic pyrazoles and highly reactive alkyl radical-metal complexes, followed by reduction of the C-H bonds to give deacylated products. However, the conversion needs to be carried out at a high temperature of 160 ℃, thereby limiting the substrate range of the reaction and the synthetic applications. In recent years, the deacylation conversion of ketone is advanced by using aromatization as driving force, but the method has the defects that 1) means for generating carbon free radicals are limited, high temperature or equivalent oxidizing agents are needed, and 2) reaction types are limited, and whether the strategy has universality and can be applied to wider reaction types or substrate types is very challenging. It is therefore of great importance to develop a high-efficiency and gentle process for the deacylation conversion of ketones. Disclosure of Invention The invention provides a precursor for aromatization of dihydrotriazole and application thereof in deacylation and arylation reaction of ketone, which realize high-efficiency and mild deacylation conversion of ketone. The technical scheme of the invention is as follows: the structural formula of the precursor for aromatization of the dihydrotriazole is shown as formula (I) or formula (II): in the formula (I), R 1、R2 is independently selected from optionally substituted alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, alkoxy and alkyl ester group; in the formula (II), cy is an optionally substituted 5-to 7-membered cycloalkyl group, or Cy is an optionally substituted heterocyclic group containing one or more nitrogen or oxygen atoms as ring members. Preferably, in formula (I), R 1、R2 is independently selected from: Optionally substituted C 1-C6 alkyl, optionally substituted C 3-C6 cycloalkyl, optionally substituted C 1-C6 alkoxy, In formula (II), cy is selected from: In Cy, refers to the position of attachment to the parent nucleus. The invention also provides a preparation method of the precursor for aromatization of the dihydrotriazole, which comprises the steps of dissolving ketone and 2-pyridylhydrazone amide in a solvent, adding an activating additive, and heating to 50-100 ℃ in an inert gas atmosphere for activation reaction. The invention also discloses a deacylation and arylation reaction method of the visible light induced aromatization driving ketone, which comprises the following steps: (1) Dissolving ketone and 2-pyridylhydrazone amide in a solvent, adding an activating additive, and heating and activating under an inert gas atmosphere to obtain a dihydro triazole aromatization precursor; (2) And (3) mixing the product obtained in the step (1) with aryl halide with or without purification, and carrying out photocatalytic reaction under the conditions o