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CN-122010833-A - Method for catalyzing tension ring heteroaryl by iron

CN122010833ACN 122010833 ACN122010833 ACN 122010833ACN-122010833-A

Abstract

The invention discloses a method for catalyzing C (sp 3 ) -H heteroaryl of a tension ring by iron, which comprises the following steps of catalyzing the C (sp 3 ) -H heteroaryl reaction of the tension ring by taking a heteroaromatic compound and the tension ring compound as substrates and peroxide as an oxidant and taking iron as a catalyst and amino acid and derivatives thereof as ligands in a solvent to generate the heteroaryl-substituted tension ring compound. The method has the advantages of wide catalyst source, low cost and environmental protection, wide oxidant source, low cost, mild reaction condition, high selectivity, good compatibility of substrate functional groups, wide application range of substrates, compatibility of complex molecules and natural products, and realization of C (sp 3 ) -H bond functionalization reaction of the tension ring. Under optimized reaction conditions, the yield of the separated target product can reach 80 percent.

Inventors

  • HAN WEI
  • ZHOU QIUBAO

Assignees

  • 南京师范大学

Dates

Publication Date
20260512
Application Date
20260211

Claims (10)

  1. 1. A method for catalyzing C (sp 3 ) -H heteroaryl of a tension ring by iron is characterized by comprising the following steps of taking the tension ring compound as a substrate, taking a heteroaromatic compound as an arylating reagent, taking peroxide as an oxidant, taking iron as a catalyst, taking amino acid or a derivative thereof as a ligand, and carrying out heteroaryl reaction on C (sp 3 ) -H bond of the tension ring compound in a solvent to generate heteroaryl substituted tension ring compound; The general reaction formula is shown as follows: ; R 1 represents a substituent on a heteroaromatic compound, R 2 represents a substituent on a tension ring compound, and n is not equal to 1 or 2 when the tension ring compound is spiro or bicyclic.
  2. 2. The method for the iron-catalyzed tension ring C (sp 3 ) -H heteroaryl according to claim 1, wherein the heteroaromatic compound is pyridine, pyrazine, pyridazine, pyrimidine, quinoline, thiazole, benzothiazole or 2, 3-naphthyridine, and the tension ring is cyclopropane, cyclobutane, cyclopropane, cyclobutanol, N-heterocyclobutane, spiro [3.3] heptane or bicyclo [1.1.1] pentane.
  3. 3. The method of iron catalyzed tension ring C (sp 3 ) -H heteroaryl of claim 1, wherein R 1 is hydrogen, halogen, methyl, ester, acetyl, cyano, trifluoromethyl, nitro, ester, acetamido, N-diethyl acetamido, sulfonamide, ethanol, or tocopheryl.
  4. 4. The method of iron catalyzed tension ring C (sp 3 ) -H heteroaryl of claim 1, wherein R 2 is hydrogen, N-t-butoxycarbonyl, hydroxy, N-methylsulfonyl, methyl, carboxyl, ester, cyano or acetyl.
  5. 5. The method of iron-catalyzed tension ring C (sp 3 ) -H heteroaryl according to claim 1, characterized in that the iron is selected from any one or more of potassium ferricyanide, potassium trioxalato ferrite, ferric thiocyanate, ferrocene, ferric acetylacetonate, ferrous sulfide, ferric fluoride, sodium ferrite, ferrous carbonate, ferrous phosphate, ferrous ammonium sulfate, ferrous oxalate, ferrous carbonate, ferrous chloride, ferric chloride, ferrous oxalate, ferric perchlorate.
  6. 6. The method of iron catalyzed tension ring C (sp 3 ) -H heteroaryl according to claim 1, wherein the ligand is selected from any one or more of L-cystine, N-acetyl-L-cysteine, β -thiovaline, aspartic acid, N-Boc-L-leucine, N-Boc-L-proline, N-Boc-D-phenylalanine, N-Boc0 amino-glycine, N' -bis (t-butoxycarbonyl) -L-cystine, N-Boc-L-leucine, L-citrulline, S-adenosylmethionine, N-acetyltryptophan, norleucine, homocysteine or N-fluorenylmethoxycarbonyl-L-lysine.
  7. 7. The method of iron catalyzed tension ring C (sp 3 ) -H heteroaryl according to claim 1, wherein the oxidant is selected from any one or more of peracetic acid, t-butyl hydroperoxide, benzoyl peroxide, perbenzoic acid, mono-t-butyl peroxymaleate, tetrabutylammonium persulfate, potassium monopersulfate complex salts, sodium peroxodisulfate, hydrogen peroxide, sodium peroxodisulfate, ammonium persulfate.
  8. 8. The method for the iron-catalyzed tension ring C (sp 3 ) -H heteroaryl according to claim 1, wherein the solvent is an organic solvent, water or an aqueous solution of an organic solvent, the organic solvent is selected from diethyl ether, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, diisopropyl ether, ethylene glycol dimethyl ether, acetone, butanone, cyclohexanone, dimethyl carbonate, isopropyl acetate, isopropanol, N-butanol, cyclohexane, benzene, toluene, xylene, ethylbenzene, cumene, chlorobenzene, 1, 2-dichloroethane, pyridine, N-dimethylacetamide, acetonitrile, dimethylsulfoxide, triethylamine or carbon tetrachloride, and when the solvent is an aqueous solution of the organic solvent, the volume ratio of the organic solvent to water is 1 (0.5-20).
  9. 9. The method for the C (sp 3 ) -H heteroaryl of the iron catalytic tension ring according to claim 1, wherein the molar ratio of the heteroaromatic compound, the tension ring compound, the peroxide, the amino acid or the derivative thereof to the iron catalyst is 1 (2.5-40): (1-50): (0.005-30): (0.002-15).
  10. 10. The method for the iron-catalyzed tension ring C (sp 3 ) -H heteroaryl according to claim 1, wherein the reaction temperature is 25-110 ℃ for 0.5-12 hours.

Description

Method for catalyzing tension ring heteroaryl by iron Technical Field The invention belongs to the fields of catalytic synthesis technology and fine chemical synthesis, and particularly relates to a method for catalyzing heteroaryl of a tension ring by iron, in particular to a method for realizing direct heteroaryl of a small ring C (sp 3) -H bond by oxidizing the tension ring by an appropriate oxidant through iron catalysis. Background Tension ring and its derivatives have unique structural features and physicochemical properties, and are widely used in the design of small molecule drugs, and the university of san John, U.S. university of san Jose, U.S. drug college Tanaji T Talele professor reviewed (J. Med. Chem. 2016, 59 (19), 8712-8756.) summarizing the use of cyclopropane in drugs, for example, to enhance potency, reduce non-target effects, increase metabolic stability, etc., to obtain pitavastatin by substituting isopropyl with a more metabolically stable cyclopropyl group, and to obtain higher bioavailability and longer duration of action. In addition, the first experiment in 1996 research of Roberto Pellicciari proves the benzene ring isostere effect of bicyclo [1.1.1] pentane (BCPs) (J. Med. Chem. 1996, 39, 2874-2876.) and the discovery not only promotes the development of novel bioelectrode isostere, but also provides an important strategy for breaking through patent protection and optimizing the pharmaceutical property. In summary, the functional search of small rings by researchers has never been stopped, and heteroaryl rings are also important building blocks of drug molecules and natural active molecules, and the heteroarylation reaction of tension rings has been greatly progressed. The progress of the heteroaromatics cyclization of the strained ring has been made since Walter Kurtz (chem. Ber. 1975, 108, 3415-3432) had been achieved with metal reagents such as cyclopropyllithium to the aromatic heterocycle, and subsequently, the coupling of the strained ring by transition metal catalyzed C (sp 2)-C(sp3) has also been widely used in this reaction, for example, by the Satoshi Shuto team (adv. Synth. Catalyst. 2015, 357, 1022-1028) using boric acid substituted (hetero) aromatic ring and alkyl iodide reactions in 2015, the heteroarylation reaction of the strained ring has been achieved by free radical history, but the pre-functionalization of the substrate has increased the steps and cost, the palladium catalyzed cyclobutane derivatives and (hetero) aromatic ring coupling reactions have been reported in 2020, 59, 9594-9600) by the Yu Jinquan subject group (angelw. Int. Ed. 2020, which used equivalent silver salts as additives, and the nickel sulfide (angelw 2024, 3-202314617) was synergistically coupled with the strained ring by the silver sulfide in the light of 3-344. Compared with the prior researches, the method has the advantages that the cheap and easily available metal catalyst is selected, the substrate is not required to be pre-functionalized, the high-selectivity and high-efficiency heteroaryl reaction of C (sp 3) -H of the tension ring is directly researched, the requirement of drug research and development on high-efficiency, low-cost and various compounds for synthesizing the tension ring-heteroaryl compound is met, and the problems of pre-functionalization, noble metal dependence, insufficient selectivity, harsh conditions and the like are limited. Thus, the development of inexpensive metal (e.g., iron) catalyzed, direct C (sp 3) -H heteroarylation processes that do not require pre-functionalization, with high selectivity, is a key research direction in this field. Disclosure of Invention Aiming at the problems in the prior art, the invention provides a method for heteroaryl of an iron catalytic tension ring compound, which directly realizes high-selectivity heteroaryl of tension ring C (sp 3) -H bonds by using cheap and easily available iron and amino acid ligands under the action of a proper oxidant. The method has the core characteristics of no need of pre-functionalization of tension ring or heteroaromatic ring substrates, simplification of synthesis steps and improvement of atom economy, elimination of expensive additives such as noble metal catalysts and equivalent silver salts, substantial reduction of reaction cost, mild reaction conditions, simplicity and convenience in operation, no need of special light sources and strict anhydrous and anaerobic environments, suitability for large-scale production, broad-spectrum substrate compatibility, capability of being efficiently applied to dehydrogenation cross-coupling reaction of various tension rings such as cyclopropane, bicyclo [1.1.1] pentane and cyclobutane with different substitution types of heteroaromatic rings, capability of effectively reducing side reactions such as ring opening, rearrangement and oxidation, and guarantee of product purity and yield. The invention successfully solves the technical pain points that the