CN115141138A - Method for constructing fluoride by decarboxylation of alkyl carboxylic acid - Google Patents

Method for constructing fluoride by decarboxylation of alkyl carboxylic acid Download PDF

Info

Publication number
CN115141138A
CN115141138A CN202210740947.0A CN202210740947A CN115141138A CN 115141138 A CN115141138 A CN 115141138A CN 202210740947 A CN202210740947 A CN 202210740947A CN 115141138 A CN115141138 A CN 115141138A
Authority
CN
China
Prior art keywords
substituted
carboxylic acid
unsubstituted
reaction
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202210740947.0A
Other languages
Chinese (zh)
Other versions
CN115141138B (en
Inventor
胡鹏
张宇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Yat Sen University
Original Assignee
Sun Yat Sen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Yat Sen University filed Critical Sun Yat Sen University
Priority to CN202210740947.0A priority Critical patent/CN115141138B/en
Publication of CN115141138A publication Critical patent/CN115141138A/en
Application granted granted Critical
Publication of CN115141138B publication Critical patent/CN115141138B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
    • C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
    • C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
    • C07C22/08—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings containing fluorine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C23/00—Compounds containing at least one halogen atom bound to a ring other than a six-membered aromatic ring
    • C07C23/18—Polycyclic halogenated hydrocarbons
    • C07C23/20—Polycyclic halogenated hydrocarbons with condensed rings none of which is aromatic
    • C07C23/34—Halogenated completely or partially hydrogenated indenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C23/00—Compounds containing at least one halogen atom bound to a ring other than a six-membered aromatic ring
    • C07C23/18—Polycyclic halogenated hydrocarbons
    • C07C23/20—Polycyclic halogenated hydrocarbons with condensed rings none of which is aromatic
    • C07C23/36—Halogenated completely or partially hydrogenated naphthalenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/14—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/48—Halogenated derivatives
    • C07C35/52—Alcohols with a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/17—Unsaturated ethers containing halogen
    • C07C43/174—Unsaturated ethers containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/457—Saturated compounds containing a keto group being part of a ring containing halogen
    • C07C49/467—Saturated compounds containing a keto group being part of a ring containing halogen polycyclic
    • C07C49/473—Saturated compounds containing a keto group being part of a ring containing halogen polycyclic a keto group being part of a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/63—Halogen-containing esters of saturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/75—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of acids with a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/38—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to the technical field of organic compound synthesis, in particular to a method for constructing fluoride by decarboxylation of alkyl carboxylic acid. The method is carried out under the conditions of heat energy and/or light energy and/or microwave to obtain the product with the formula
Figure DDA0003717955120000011
Alkyl carboxylic acid with the structure is used as a reaction raw material, and is obtained by the decarboxylation fluorination reaction of free radicals under the combined action of an iron catalyst, a ligand, a fluorine-containing reagent and alkali

Description

Method for constructing fluoride by decarboxylation of alkyl carboxylic acid
Technical Field
The invention relates to the technical field of organic compound synthesis, in particular to a method for constructing fluoride by decarboxylation of alkyl carboxylic acid.
Background
Organofluoro compounds have a very wide and important role in the scientific fields of medicine, pesticides and materials science. For example, in the pharmaceutical field, introduction of fluorine atoms into drugs can change the physical and chemical properties of the compound and improve the metabolic stability of the compound. In another aspect, the isotope is labelled 18 F into compounds such as deoxyglucose mayThe method is used for PET (positron emission tomography) so as to carry out medical tracing diagnosis on certain diseases such as cancer spread and the like.
Despite the numerous applications of fluorine-containing organic compounds, the variety of fluorine-containing compounds in nature is very small, and therefore, how to synthesize fluorine-containing compounds having specific structures simply, efficiently, and with high selectivity presents challenges to organic chemists. The traditional method for synthesizing the fluorine-containing compound comprises nucleophilic fluorination and electrophilic fluorination, for the former, a series of different inorganic and organic fluorine sources have been developed at present, the application is wider, the defects are that the nucleophilicity of fluorine anions is weaker, and the reaction usually needs a phase transfer catalyst, high temperature and longer reaction time; for the latter, fluorine gas with high toxicity and high activity is used as an electrophilic fluorine reagent in the early period, but the operation is dangerous, the reaction selectivity is poor, and then organic chemists develop a series of electrophilic fluorine reagents including NFSI, NFPY, selectfluor and the like, so that the fluorination reaction can be carried out under safe and mild conditions, and the development of electrophilic fluorination reaction is greatly promoted, but the method can only introduce fluorine atoms in alpha position of carbonyl-containing compound. Therefore, in addition to the above-mentioned introduction of fluorine atoms via fluorine anion or fluorine cation pathway, how to achieve a highly efficient, highly selective and widely applicable fluorination method becomes the center of research, and a method of free radical fluorination provides possibility for solving the challenge.
Figure BDA0003717955110000011
In 2012, li Chaozhong reports decarboxylation and fluorination reaction of silver-catalyzed alkyl carboxylic acid (formula 1), and high-selectivity decarboxylation of primary, secondary and tertiary alkyl carboxylic acids can be achieved under thermodynamic conditions to construct various fluorine-containing compounds, so that a new method is provided for synthesizing fluorine-containing compounds, but the application of the fluorine-containing compounds in drug synthesis is limited due to the use of expensive and toxic noble metal silver as a catalyst.
Figure BDA0003717955110000012
Figure BDA0003717955110000021
In 2014, the Sammis topic group firstly applies photocatalysis to decarboxylation and fluorination reaction (formula 2), and realizes the decarboxylation and fluorination reaction of the phenoxyacetic acid derivative under the catalysis of ruthenium. However, this method is only suitable for activated carboxylic acid substrates such as phenoxyacetic acid or phenylacetic acid, and requires the use of powerful light sources, which limits the application to some extent. In 2015, the MacMillan group improved this reaction by using iridium as a photocatalyst (formula 3) so that various alkyl carboxylic acid compounds could be efficiently converted to the corresponding fluorides. Next, the leaf Venus topic group reported Mes-AcrClO 4 As the decarboxylation fluorination reaction of the organic photocatalyst, the reaction condition is green, transition metal is not needed, but the catalytic activity is reduced to a certain extent for some substrates. The reaction formula is as follows:
Figure BDA0003717955110000022
although decarboxylation fluorination reactions have achieved some success, the use of toxic noble metals and expensive photocatalysts have limited the practical application of the reaction to some extent, especially in large-scale industrial production.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention provides a method for constructing fluoride by decarboxylation of alkyl carboxylic acid, which avoids the use of toxic and expensive heavy metal catalysts and develops cheap, easily-obtained and environment-friendly catalysts; meanwhile, the efficient and high-selectivity decarboxylation fluorination reaction of various types of carboxylic acids can be realized; the method can be carried out on a larger scale without the problem of a significant decrease in yield upon scale-up.
The technical scheme provided by the invention is as follows:
a method for decarboxylation of an alkyl carboxylic acid to produce a fluoride, comprising the steps of:
under the conditions of heat energy and/or light energy and/or microwaves, alkyl carboxylic acid with a structure shown as a formula (I) is used as a reaction raw material, and under the combined action of an iron catalyst, a ligand, a fluorine-containing reagent and alkali, fluoride shown as a formula (II) is obtained through a free radical decarboxylation fluorination reaction;
Figure BDA0003717955110000023
wherein R is 1 Selected from the group consisting of hydrogen, heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted alkyl; r 2 Selected from the group consisting of hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted alkyl; r 3 Selected from the group consisting of hydrogen, heterocycles, substituted or unsubstituted aryls, and substituted or unsubstituted alkyls.
Compared with the prior art, the method adopts the iron catalyst to catalyze the alkyl carboxylic acid, the iron catalyst is cheap and easy to obtain, and is environment-friendly, and the use of toxic and expensive heavy metal catalysts is avoided. Meanwhile, the method is suitable for various types of carboxylic acids, the application range of the substrate is wide, and efficient and high-selectivity decarboxylation fluorination reaction of various types of carboxylic acids can be realized; the method can be used for large-scale preparation, and has no problem of obvious yield reduction during scale-up.
In some examples of the present invention, the substituents in the substituted aryl group and the substituted hydrocarbyl group are each independently selected from one or more of halogen (any one or more of fluorine, chlorine, bromine, iodine), hydroxyl group, carboxyl group, acetal group, amino group, primary amino group, secondary amino group, ester group, carbonyl group, amide group, cyano group, substituted or unsubstituted aliphatic alkyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted sulfonyl group, and substituted or unsubstituted sulfonic group.
In some embodiments of the invention, the heterocycle is selected from any of N, S, OOne or more of C 5～20 The heterocyclic ring is an n-ring, and when the heterocyclic ring is the n-ring, the rings are connected in a mode of sharing one atom or one side by a single bond. The monocyclic or n-ring of the heterocycle may have a substituent(s) thereon selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, acetal, amino, primary amino, secondary amino, ester, carbonyl, amide, phosphoryl, cyano, substituted or unsubstituted C 1～20 Aliphatic alkyl, substituted or unsubstituted C 1～20 Alkoxy, substituted or unsubstituted C 3～20 One or more of cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted sulfonyl, and substituted or unsubstituted sulfonic acid.
In some embodiments of the invention, the heterocycle is selected from any one of substituted or unsubstituted: piperidine, N-phthalimido, phthaloyl, pyrrole or dioxaspiro C 5～15 An alkane.
In some embodiments of the invention, the heterocycle is selected from any one of the following:
Figure BDA0003717955110000031
Figure BDA0003717955110000032
a is selected from O, S, N, and a plurality of A in the same group can be the same or different; r is a 、R b Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, acetal group, amino, primary amino, secondary amino, ester group, carbonyl, amido, phosphoryl, cyano and substituted or unsubstituted C 1～20 Aliphatic alkyl, substituted or unsubstituted C 1～20 Alkoxy, substituted or unsubstituted C 3～20 Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfonic acid. Preferably, R a 、R b Are respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl and C 1～6 Carboxyl, amino, primary aminoRadical, secondary amino group, ester group, C 1～6 Alkylcarbonyl, benzyloxycarbonyl, cyano, C 1～6 Alkyl radical, C 1～6 Alkoxy, phenyl, substituted phenyl, ts.
In some embodiments of the invention, the aryl group is selected from indenyl, naphthalene, hydronaphthalene, benzyl, benzyloxy, or phenyl.
In some embodiments of the invention, the hydrocarbyl group is selected from C 1～20 Fatty alkyl or C 3～20 A cycloalkyl group. The substituents in the substituted hydrocarbon group are selected from C 1～6 Alkoxycarbonyl radical, C 1～6 Alkoxycarbonyl amino group, C 1～6 Alkane base, C 1～6 Ester group, hydroxyl group, phenylphosphoryl group, phenyl group, substituted phenyl group, benzyloxycarbonyl group, benzyloxycarbonylamino group, halogen, phenyl group C 1～6 Acyl, substituted phenyl C 1～6 Any one or more of acyl, N-phthalimido and substituted phenoxy.
In some embodiments of the invention, C 1～20 The fatty alkyl group of (A) is selected from C 1～10 The fatty alkyl group of (2). Said substituted hydrocarbyl being substituted C 1～10 Wherein the substituent is selected from phenylphosphoryl, phenyl, substituted phenyl, benzyloxycarbonyl, benzyloxycarbonylamino, halogen, phenyl C 1～6 Acyl, substituted phenyl C 1～6 Any one or more of acyl, N-phthalimido and substituted phenoxy.
In some embodiments of the invention, the hydrocarbyl group is selected from C 3～20 Cycloalkyl, preferably C 3～10 Cycloalkyl, said substituted hydrocarbyl being substituted C 3～20 Cycloalkyl (or preferably substituted C) 3～10 Cycloalkyl) wherein the substituents are selected from C 1～6 Alkoxycarbonyl radical, C 1～6 Alkoxycarbonyl amino group, C 1～6 Alkyl radical, C 1～6 Any one or more of ester group, hydroxyl and phenyl phosphoryl.
In some embodiments of the invention, R 1 Selected from the group consisting of heterocyclic ring, substituted or unsubstituted aryl group, substituted or unsubstituted alkyl group.
In some embodiments of the invention，R 2 Selected from hydrogen, phenyl, substituted phenyl, C 1～6 An alkyl group.
In some embodiments of the invention, R 3 Selected from hydrogen, phenyl, substituted phenyl, C 1～6 An alkyl group.
In some embodiments of the invention, the alkyl carboxylic acid is selected from any one or more of the following compounds: 1- [ (4-tolyl) sulfonyl group]-4-piperidinecarboxylic acid
Figure BDA0003717955110000041
1-Boc-4-piperidinecarboxylic acid
Figure BDA0003717955110000042
N-benzyloxycarbonyl-3-piperidinecarboxylic acid
Figure BDA0003717955110000043
(1R, 3S) -3- ((tert-butoxycarbonyl) amino) cyclopentanecarboxylic acid
Figure BDA0003717955110000044
(R) -2- (N-phthalimido) -3-methylbutyric acid
Figure BDA0003717955110000045
3- (2,5-dioxopyrrolidin-1-yl) -2-methylpropanoic acid
Figure BDA0003717955110000046
1,4-dioxaspiro decane [4.5]]-8-carboxylic acid
Figure BDA0003717955110000047
Trans-1,4-cyclohexanedicarboxylic acid monomethyl ester
Figure BDA0003717955110000048
Trans-4- (Boc-amino) cyclohexanecarboxylic acids
Figure BDA0003717955110000049
2-indene carboxylic acid
Figure BDA00037179551100000410
1,2,3,4-tetrahydro-2-naphthoic acid
Figure BDA00037179551100000411
1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid
Figure BDA00037179551100000412
2-Benzylpropanic acid
Figure BDA00037179551100000413
3- (diphenylphosphinoyl) -2- ((diphenylphosphinoyl) methyl) propionic acid
Figure BDA00037179551100000414
DL-benzylsuccinic acid
Figure BDA00037179551100000415
2,3 Diphenylpropionic acid
Figure BDA00037179551100000416
3-methyl-1-Boc-3-piperidinecarboxylic acid
Figure BDA00037179551100000417
3-hydroxyadamantane-1-carboxylic acid
Figure BDA00037179551100000418
2,2-dimethyl-3- (Boc-amino) propionic acid
Figure BDA00037179551100000419
3- (benzyloxy) -2,2-dimethylpropionic acid
Figure BDA00037179551100000420
2,2-dimethyl-5-phenylpentanoic acid
Figure BDA00037179551100000421
3,3 Diphenylpropionic acid
Figure BDA0003717955110000051
4- (4-fluorobenzoyl) butyric acid
Figure BDA0003717955110000052
6- (N-phthalimido) hexanoic acid
Figure BDA0003717955110000053
2,4-D
Figure BDA0003717955110000054
Phthalic acid phenylglycine
Figure BDA0003717955110000055
2- (1- (((Boc) amino) methyl) cyclohexyl) acetic acid
Figure BDA0003717955110000056
Isosteviol ((4R, 4aS,6aR,9S,11aR, 11bS) -4,9, 11b-trimethyl-8-oxodecatetrahydro-6a, 9-methanocyclohepta [ a]Naphthalene-4-carboxylic acid)
Figure BDA0003717955110000057
Z-glutamic acid methyl ester
Figure BDA0003717955110000058
Ketobrofen
Figure BDA0003717955110000059
4- (((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) -4-oxobutanoic acid
Figure BDA00037179551100000510
2,3O-isopropylidene-1-O-methyl-d-ribonic acid
Figure BDA00037179551100000511
In some examples of the invention, the iron catalyst comprises any one or more of a ferric compound, a ferrous compound, and zero valent iron.
In some examples of the invention, the ferric iron compound comprises at least one or more of ferric chloride, ferric triflate, ferric tetrafluoroborate, ferric hexafluorophosphate, ferric sulfate, ferric nitrate, ferric acetate, ferric trifluoroacetate, ferric citrate, ferric oxalate, ferric acrylate, tris (2,2,6,6-tetramethyl-3,5-heptanedionate), ferric hydroxide, ferric acetylacetonate, ferric fluoride, and hydrates thereof.
In some examples of the invention, the divalent iron compound includes at least one or more of ferrous chloride, ferrous iodide, ferrous trifluoromethanesulfonate, ferrous tetrafluoroborate, ferrous hexafluorophosphate, ferrous sulfate, ferrous nitrate, ferrous acetate, ferrous trifluoroacetate, ferrous citrate, ferrous oxalate, ferrous acrylate, ferrous bis (2,2,6,6-tetramethyl-3,5-heptanedionate), ferrous hydroxide, ferrous acetylacetonate, ferrous fluoride, and hydrates thereof.
In some examples of the invention, the zero valent iron includes iron powder, supported type iron, and alloy iron.
In some embodiments of the present invention, the catalyst is used in an amount of 0.1% to 50%, preferably 0.5% to 40%, more preferably 1% to 30%, and still more preferably 5% to 20% of the alkyl carboxylic acid having the structure of formula (I) on a molar basis. For example, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%.
In some embodiments of the invention, the ligand comprises one or more of bipyridine, phenanthroline, and terpyridyl compounds. Preferably, the ligand comprises bipyridine, 4,4 '-dimethyl-2,2' -bipyridine, 5,5 '-dimethyl-2,2-bipyridine, 6,6' -dimethyl-2,2-bipyridine, 4,4 '-dimethoxy-2,2' -bipyridine, 4,4 '-di-tert-butyl-2,2' -bipyridine, 4,4 '-bis (trifluoromethyl) -2,2' -bipyridine, 2,2 '-bipyridine-4,4' -methyl dicarboxylate, 2,2 '-bipyridine-5,5' -methyl dicarboxylate, 2,2 '-bipyridine-74' -dicarboxylic acid methyl ester, 3567-34zphenanthrine, 3592-35zxft 3292 '-bipyridine-5,5' -diformate methyl ester, 2,2 '-bipyridine-74' -diformate methyl ester, 3567-35zphenanthrine, 35zffe-3552-42xft-4252- α -pyridine, and one or more of the derivatives thereof.
In some embodiments of the invention, the ligand is used in an amount of 0.1% to 50%, preferably 0.5% to 40%, more preferably 1% to 30%, and even more preferably 5% to 20% of the alkyl carboxylic acid having the structure of formula (I) on a molar basis. For example, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%.
In some embodiments of the invention, the ligand to iron catalyst ratio, in molar units, is from 1:0.2 to 2, preferably 1:0.5 to 1.5, more preferably 1:0.8 to 1.2. For example, 1:0.2,1:0.5,1:0.8,1:1,1:1.2,1:1.5,1:1.8,1:2.
in some examples of the invention, the fluorine-containing reagent is an electrophilic fluorine source, including one or more of 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor), 1-fluoro-4-methyl-1,4-diazabicyclo [2.2.2] octane tetrafluoroborate, and derivatives thereof.
In some embodiments of the present invention, the fluorine-containing agent is used in an amount of 0 to 20 equivalents, preferably 0.5 to 20 equivalents, more preferably 1 to 10 equivalents, and still more preferably 1.5 to 5 equivalents, based on moles, of the alkyl carboxylic acid having the structure represented by formula (I). E.g., 0.1, 0.5,1, 1.5, 2, 2.1, 2.5, 3,4, 5,6, 7,8, 9, 10, 15, 20 equivalents.
In some examples of the invention, the base comprises an organic base and an inorganic base. <xnotran> , ( , , , , N- , N- , , , , , N, N- , 4232 zxft 4232- [5.4.0] -7- , 4234 zxft 4234- [2.2.2] , ( ,4- ,2- ,2- ,2- ,2- ,2- , 5364 zxft 5364- , 8652 zxft 8652- ,2- -6- , 3265 zxft 3265- , 3579 zxft 3579- , 3525 zxft 3525- , 3735 zxft 3735- -4- , 3856 zxft 3856- , 5283 zxft 5283- , 5329 zxft 5329- ( ) , , ,2- , ) . , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , </xnotran> One or more of potassium benzoate.
In some embodiments of the invention, the base is preferably an organic base. Strong inorganic bases such as sodium hydroxide may make the functional group of the reaction system less tolerant and may be prone to cause unwanted side reactions, which may be avoided by using mild organic bases.
In some embodiments of the present invention, the base is used in an amount of 0 to 20 equivalents, preferably 0.5 to 20 equivalents, more preferably 1 to 10 equivalents, and still more preferably 1 to 5 equivalents, based on moles, of the alkyl carboxylic acid having the structure of formula (I). E.g., 0.1, 0.5,1, 1.5, 1.8, 2, 2.5, 3,4, 5,6, 7,8, 9, 10, 15, 20 equivalents.
In some embodiments of the invention, the thermal energy is provided by subjecting the reaction system to a temperature of from-78 to 300 deg.C, preferably from-50 to 200 deg.C, more preferably from-30 to 200 deg.C, still more preferably from-10 to 150 deg.C, and even more preferably from 0 to 100 deg.C. For example-78 deg.C, -50 deg.C, -30 deg.C, -20 deg.C, -10 deg.C, -5 deg.C, 0 deg.C, 10 deg.C, 20 deg.C, 25 deg.C, 30 deg.C, 40 deg.C, 50 deg.C, 60 deg.C, 70 deg.C, 80 deg.C, 90 deg.C, 100 deg.C, 150 deg.C, 200 deg.C, 250 deg.C, 300 deg.C. The reaction of the present invention can be carried out in a wide temperature range depending on the activity of the reaction substrate, and can be carried out under a freezing condition, a room temperature or a heating condition.
In some embodiments of the present invention, the light energy is provided by exposing the reaction system to any one of ultraviolet light and visible light. The visible light comprises monochromatic or mixed light with the wavelength of less than or equal to 600nm, and preferably comprises monochromatic or mixed light with the wavelength of less than or equal to 500 nm. The invention can be carried out under visible light besides ultraviolet light, and compared with a reaction system which only adopts medium-wave ultraviolet light harmful to human eyes, the reaction system is more green and safe.
In some examples of the present invention, the light used for the illumination has a wavelength of 350 to 550nm, preferably 350 to 525nm, more preferably 350 to 500nm, further preferably 350 to 450nm, for example, 350nm,380nm,400nm,420nm,450nm,455nm,500nm,525nm,550nm.
In some examples of the invention, the power of the microwaves is 0-800W, such as 5W,10W,20W,30W,40W,50W,60W,70W,80W,90W,100W,200W,300W,400W,500W,600W,700W,800W.
In some embodiments of the invention, the reaction is carried out in the absence of a solvent or solvents, preferably in a solvent. The solvent comprises one or a mixture of water and an organic solvent; preferably, the solvent is water or a mixture of water and an organic solvent.
In some examples of the present invention, the organic solvent includes one or more of a hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrohydrocarbon solvent, an ether solvent, a nitrile solvent, an ester solvent, a ketone solvent, an alcohol solvent, an amine solvent, an amide solvent, a sulfone solvent, and a sulfoxide solvent.
In some examples of the invention, the hydrocarbon solvent comprises one or more of benzene, toluene, saturated alkane compounds;
the halogenated hydrocarbon solvent comprises one or more of trifluoromethylbenzene, chlorobenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform and carbon tetrachloride;
the nitrohydrocarbon solvent comprises one or more of nitrobenzene and nitromethane;
the ether solvent comprises one or more of tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether and diethyl ether;
the nitrile solvent comprises one or more of acetonitrile, benzonitrile and tert-butyl acetonitrile;
the ester solvent comprises one or more of ethyl acetate, n-butyl acetate and isobutyl acetate;
the ketone solvent comprises one or more of acetone, methyl ethyl ketone, 2-methyl-3-butanone, 3,3-dimethyl-2-butanone, 2,4-dimethyl-3-pentanone and acetophenone;
the alcohol solvent comprises one or more of methanol, ethanol, tert-butanol and n-butanol;
the amine solvent comprises one or more of triethylamine, diethylamine and diisopropylethylamine;
the amide solvent comprises one or more of dimethylformamide and dimethylacetamide;
the sulfone solvent comprises dimethyl sulfone;
the sulfoxide solvents include dimethyl sulfoxide.
In some examples of the present invention, the solvent is water, a mixture of a hydrocarbon solvent and water, a mixture of a nitrohydrocarbon solvent and water, a mixture of an ether solvent and water, a mixture of a nitrile solvent and water, a mixture of an ester solvent and water, a mixture of a ketone solvent and water, a mixture of an alcohol solvent and water, a mixture of an amine solvent and water, a mixture of an amide solvent and water, a mixture of a sulfone solvent and water, or a mixture of a sulfoxide solvent and water. Preferably, the solvent is water, a mixture of a ketone solvent and water, or a mixture of a nitrile solvent and water. More preferably, the solvent is water, a mixture of acetone and water, or a mixture of acetonitrile and water.
In some embodiments of the invention, the volume ratio of water to organic solvent is 1:0.2 to 2, preferably 1:0.5 to 1.5, more preferably 1:0.8-1.2. For example, 1:0.2,1:0.5,1:0.8,1:1,1:1.2,1:1.5,1:1.8,1:2.
in some embodiments of the present invention, the amount of the solvent is an appropriate amount, which can be adjusted according to the general techniques in the art and the actual requirements, and can sufficiently dissolve or disperse the reaction raw materials. As an example, the ratio of the solvent to the alkyl carboxylic acid of the structure shown in formula (I) is 1mL:0.01 to 2mmol, preferably 1mL:0.05 to 1.5mmol, more preferably 1mL: 0.1-1 mmol. For example, 1mL:0.01mmol,1mL:0.02mmol,1mL:0.05mmol,1mL:0.1mmol,1mL:0.12mmol,1mL:0.15mmol,1mL:0.2mmol,1mL:0.3mmol,1mL:0.4mmol,1mL:0.5mmol,1mL:0.6mmol,1mL:0.7mmol,1mL:0.8mmol,1mL:0.9mmol,1mL:1mmol,1mL:1.5mmol,1mL:2mmol of the organic solvent, and the like,
according to the invention, after the solvent is mixed with the alkyl carboxylic acid, the catalyst, the ligand and the alkali, all raw materials can be fully dissolved or dispersed by stirring, and the reaction can be carried out by applying heat energy/illumination/microwave after the materials are fed. The photoreaction is preferably carried out immediately after the charge is completed. The reaction of the invention has lower operation severity than the prior art, the illumination is carried out after the raw materials are completely dissolved without long-time stirring, and the solvent system can well dissolve all the raw materials, so that the heat energy/illumination/microwave can be applied for reaction after the materials are fed.
In some embodiments of the invention, the reaction is carried out in a non-oxidizing atmosphere, preferably a protective atmosphere, for example nitrogen, argon. In order to avoid the adverse effect of oxygen on the reaction, the solvent used in the reaction needs to be deoxygenated before use.
In some embodiments of the invention, the reaction time is from 0.1h to 10 days, preferably from 0.1h to 7 days, more preferably from 2h to 5 days, still more preferably from 2 to 72h, more preferably from 2 to 48h. For example, 0.1h,0.2h,0.5h,1h,1.5h,2h,3h,4h,5h,6h,7h,8h,9h,10h,15h,20h,24h,30h,35h,40h,45h,48h,50h,3 days, 3.5 days, 4 days, 4.5 days, 5 days, 5.5 days, 6 days, 6.5 days, 7 days, 8 days, 9 days, 10 days. The reaction time varies depending on the scale of the reaction, the reaction temperature, the ratio of the reaction materials, and the like.
In some embodiments of the present invention, after the reaction is completed, the mixture obtained after the reaction may be further separated and purified to obtain a purer final product. The method for separation and purification is well known to those skilled in the art, and for example, extraction, column chromatography, distillation, decantation, filtration, centrifugation, washing, evaporation, stripping, and adsorption, or a combination of at least two thereof can be used for separation and purification, such as extraction, column chromatography.
Of course, the obtained reaction mixture can be directly introduced into other processes for direct reaction to produce other products, if desired. Alternatively, the reaction mixture may be subjected to a pretreatment such as one or more of concentration, extraction and distillation under reduced pressure before being introduced into other processes to obtain a crude product or a pure product, which is then introduced into other processes.
In some embodiments of the invention, the post-treatment step after the reaction is completed may be as follows: after the reaction, the reaction mixture was cooled, concentrated under reduced pressure, and the concentrated residue was subjected to column chromatography. The eluent used in the column chromatography process comprises any one or more of dichloromethane, n-hexane, ethyl acetate, n-pentane, methanol and petroleum ether, such as n-hexane-ethyl acetate, dichloromethane-methanol, petroleum ether-ethyl acetate, n-hexane: ethyl acetate, and the like.
As an example of the above, the eluent used for the column chromatography is n-hexane-ethyl acetate, wherein the volume ratio of n-hexane to ethyl acetate is 5-100: 1, e.g. 5:1,10: 1,20: 1,30: 1,40: 1,50: 1,60: 1,70: 1,80: 1,90: 1,100: 1. as a second example, the eluent used for column chromatography is dichloromethane-methanol, wherein the volume ratio of dichloromethane to methanol is 20 to 80:1, preferably 30 to 60:1, e.g. 20:1,30: 1,40: 1,50: 1,60: 1,70: 1,80: 1. as a third example, the eluent used for column chromatography is petroleum ether-ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 10 to 200, such as 10:1,30: 1,40: 1,50:1, 80:1, 100. As a third example, the eluent used for column chromatography is dichloromethane-methanol, wherein the volume ratio of dichloromethane to methanol is 50-150: 1, e.g. 50:1,60: 1,70: 1,90: 1,100: 1,120: 1,150: 1; in the elution, dichloromethane alone may be used for elution, and then dichloromethane-methanol may be used for elution.
In some examples of the present invention, the column chromatography is performed using a silica gel column, wherein the silica gel is 300-400 mesh silica gel.
In some embodiments of the invention, the column chromatography is preceded by an extraction step. As an example, the extraction step employs an extraction solvent comprising water-dichloromethane, and the product after extraction is enriched in the organic phase.
In some embodiments of the invention, the yield of the fluoride is ≥ 5%, e.g. ≥ 10%, ≥ 15%, ≥ 20%, ≥ 25%, ≥ 30%, ≥ 35%, > 40%, > 45%, > 50%, > 55%, > 60%, > 65%, > 70%, > 75%, > 80%, > 85%, > 90%.
In addition, the invention also provides the fluoride obtained by the method.
Compared with the prior art, the method for constructing the fluoride has the following beneficial effects:
a) The iron catalyst has rich reserves, is cheap and easy to obtain and is environment-friendly; b) The reaction condition is mild, and the method has high efficiency and high selectivity; c) The tolerance of the functional group of the reaction substrate is high, the substrate source is wide, and besides being compatible with the prior art suitable phenylacetic acid or phenoxyacetic acid substrates, other types of carboxylic acids such as fatty acid, alicyclic acid and other non-activated primary, secondary and tertiary functionalized carboxylic acids can be adopted; d) The reaction can be amplified to gram-scale for preparation; e) The yield and purity of the product are high.
In short, the method takes primary, secondary or tertiary alkyl carboxylic acid which is cheap and easy to obtain as a reaction raw material, and the decarboxylation and fluorination reaction is carried out under the combined promotion effect of an iron catalyst, a ligand, alkali and a fluorine-containing reagent in a nitrogen reaction atmosphere to obtain the corresponding alkyl fluoride.
Detailed Description
The technical solution of the present invention is further described below with reference to specific examples. The starting materials used in the following examples, unless otherwise specified, are available from conventional commercial sources; the processes used, unless otherwise specified, are conventional in the art.
Example 1
Synthesis of 4-fluoro-1-tosylpiperidine
Figure BDA0003717955110000091
1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid (0.4 mmol, 1equiv), ferrous acetate (0.04mmol, 0.1equiv), 4,4 '-dimethoxy-2,2' -bipyridine (0.04mmol, 0.1equiv), 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (0.82mmol, 2.1equiv), 2,6-lutidine (0.72mmol, 1.8equiv) were added to a 25mL Shi Laike reaction tube at room temperature (20 ℃), inert gas was replaced three times, acetonitrile and water each previously purged with oxygen were added, the reaction was stirred under 400nm LED lamp illumination for 2h, after completion of the reaction was monitored by thin layer chromatography, water and dichloromethane were added for extraction, organic phase was collected and extracted with anhydrous sodium sulfate, and the product was dried to obtain a white solid product (76% yield); the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.64–7.61(m,2H),7.32–7.29(m,2H),4.78–4.64(m,1H),3.33–3.27(m,2H),2.89–2.83(m,2H),2.41(s,3H),1.96–1.85(m,4H).
19 F NMR(376MHz,CDCl 3 )δ-185.44.
13 C NMR(101MHz,CDCl 3 )δ143.6,132.9,129.6,127.6,86.3(d,J＝20.3Hz),41.7(d,J＝4.3Hz),30.4(d,J＝171.5Hz),21.4.
HRMS(ESI):calcd for C 12 H 16 FNO 2 SNa + [M+Na] + :280.0778；found 280.0780.
example 2
Synthesis of 1-tert-butyloxycarbonyl-4-fluoropiperidine
Figure BDA0003717955110000101
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 1-tert-butoxycarbonyl-4-piperidinecarboxylic acid. The other operations were the same as in example 1. The product of this example was a colorless oily liquid, yield 61%; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ4.83–4.67(m,1H),3.59–3.38(m,4H),1.82–1.71(m,4H),1.42(s,9H).
19 F NMR(377MHz,CDCl 3 )δ-182.22(s,1F).
13 C NMR(151MHz,CDCl 3 )δ154.6,88.1(d,J＝171.2Hz),79.6,39.8,31.1(d,J＝19.8Hz),28.3.
HRMS(EI):calcd for C 10 H 18 FNO 2 (M) + :203.1316；found 203.1314.
example 3
Synthesis of N-benzyloxycarbonyl-3-fluoropiperidine
Figure BDA0003717955110000102
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of N-benzyloxycarbonyl-3-piperidinecarboxylic acid. The other operations were the same as in example 1. The product of this example was a yellow oily liquid in 78% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.38–7.32(m,5H),5.16(s,2H),4.69–4.57(m,1H),3.83–4.57(m,1H),3.71–3.47(m,2H),3.31(s,1H),1.93–1.79(m,3H),1.52(d,J＝12.4Hz,1H).
19 F NMR(376MHz,CDCl 3 )δ-184.69(d,J＝73.3Hz,1F).
13 C NMR(101MHz,CDCl 3 )δ155.3,136.5,128.3,127.8,127.6,86.0(d,J＝175.5Hz),67.02,47.8(d,J＝25.3Hz),43.6,29.4(d,J＝20.5Hz),20.9(d,J＝27.6Hz).
HRMS(ESI):calcd for C 13 H 16 FNO 2 Na + [M+Na] + :260.1057；found 260.1058.
example 4
Synthesis of (S) -1- ((tert-butoxycarbonyl) amino) -3-fluorocyclopentane
Figure BDA0003717955110000111
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of (1R, 3S) -3- ((tert-butoxycarbonyl) amino) cyclopentanecarboxylic acid. The other operations were the same as in example 1. The product of this example was a white solid in 63% yield, dr (1.8; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(600MHz,Chloroform-d)δ5.18–5.07(m,1H),4.88(brs,0.38H),4.67(brs,0.61H),4.19–4.17(m,1H),1.97–1.52(m,3H),1.97–1.51(m,3H),1.42(s,9H).
19 F NMR(377MHz,CDCl 3 )δ-167.54,-169.24.
13 C NMR(151MHz,CDCl 3 )δ155.3,96.2(d,J＝170.2Hz)(minor),94.9(d,J＝172.1Hz)(major),79.1(minor),79.0(major),50.3(major),50.2(minor),40.9(d,J＝21.6Hz)(minor),40.6(d,J＝21.0Hz)(major),32.1(d,J＝22.2Hz)(major),31.6(d,J＝22.3Hz)(minor),31.4(major),30.7(minor),28.3.
HRMS(ESI):calcd for C 10 H 19 FNO 2 + [M+H] + :204.1394；found 204.1393.
example 5
Synthesis of 2- (2-fluoro-3-methylbutyl) isoindole-1,3-dione
Figure BDA0003717955110000112
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of (R) -2- (N-phthalimido) -3-methylbutanoic acid. The other operations were the same as in example 1. The product of this example was a colorless oily liquid, yield 88%; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.75–7.73(m,2H),7.64–7.62(m,2H),4.52–4.36(m,1H),3.97–3.88(m,1H),3.73–3.60(m,1H),1.90–1.79(m,1H),0.97(d,J＝6.8Hz,6H).
19 F NMR(376MHz,CDCl 3 )δ-193.45(s,1F).
13 C NMR(101MHz,CDCl 3 )δ167.8,133.8,131.7,123.0,94.5(d,J＝177.5Hz),39.7(d,J＝23.1Hz),30.6(d,J＝19.3Hz),18.0(d,J＝5.3Hz),16.5(d,J＝6.3Hz).
HRMS(ESI):calcd for C 13 H 14 FNO 2 Na + [M+Na] + :258.0900；found 258.0902.
example 6
Synthesis of 1- (2-fluoropropyl) pyrrolidine-2,5-dione
Figure BDA0003717955110000121
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 3- (2,5-dioxopyrrolidin-1-yl) -2-methylpropionic acid. The other operations were the same as in example 1. The product of this example was a colorless oily liquid in 69% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ4.86–4.69(m,1H),3.78–3.68(m,1H),3.49–3.36(m,1H),2.67(s,4H),1.33–1.25(m,3H).
19 F NMR(377MHz,CDCl 3 )δ-180.59(s,1F).
13 C NMR(101MHz,CDCl 3 )δ176.9,86.9(d,J＝171.5Hz),43.4(d,J＝22.5Hz),27.9,18.4(d,J＝21.8Hz).
HRMS(ESI):calcd for C 7 H 10 FNO 2 Na + [M+Na] + :182.0587；found 182.0589.
example 7
Synthesis of 1,4-dioxaspiro-decane [4.5] -8-fluoro
Figure BDA0003717955110000122
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 1,4-dioxaspiro decane [4.5] -8-carboxylic acid and the eluent used for column chromatographic separation was n-hexane: ethyl acetate = 100. The other operations were the same as in example 1. The product of this example was a colorless oily liquid in 64% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(600MHz,Chloroform-d)δ4.77–4.68(m,1H),3.97–3.91(m,4H),1.99–1.92(m,2H),1.89–1.83(m,4H),1.61–1.57(m,2H).
19 F NMR(376MHz,CDCl 3 )δ-183.83(s,1F).
13 C NMR(151MHz,CDCl 3 )δ107.9,89.3(d,J＝169.4Hz),64.3(d,J＝4.2Hz),30.1(d,J＝5.3Hz),29.0(d,J＝20.7Hz).
HRMS(EI):calcd for C 8 H 13 O 2 F(M) + :160.0894；found 160.0896.
example 8
Synthesis of methyl 4-fluorocyclohexanecarboxylate
Figure BDA0003717955110000131
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of trans-1,4-cyclohexanedicarboxylic acid monomethyl ester and the eluent used for column chromatographic separation was petroleum ether: ethyl acetate = 40. The product of this example was a colorless oily liquid, yield 84%, dr (2.8; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ4.80–4.67(m,0.74H)(major),4.58–4.39(m,0.26H)(minor),3.64(s,2.06H)(major),3.63(s,0.79H)(minor),2.36–2.27(m,1H),2.08–1.93(m,2.5H),1.89–1.70(m,3H),1.62–1.44(m,2.6H).
19 F NMR(377MHz,CDCl 3 )δ-172.72,-183.21.
13 C NMR(101MHz,CDCl 3 )δ175.4,90.8(d,J＝172.7Hz)(minor),88.1(d,J＝169.5Hz)(major),51.6(minor),51.5(major),41.5(major),41.2(minor),31.0(d,J＝19.7Hz),29.8(d,J＝21.2Hz),25.7(d,J＝10.4Hz),23.1(d,J＝2.8Hz).
HRMS(EI):calcd for C 8 H 13 FO 2 (M) + :160.0894；found 160.0894.
example 9
Synthesis of tert-butyl (4-fluorocyclohexyl) carbamate
Figure BDA0003717955110000132
The synthesis of the examples differs from example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of trans-4- (Boc-amino) cyclohexanecarboxylic acid. The other operations were the same as in example 1. The product of this example was a white solid in 75% yield, dr (2.3; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ4.78–4.65(m,0.85H)(major),4.54(brs,1H),4.51–4.40(m,0.27H)(minor),3.45(s,1H),2.00–1.94(m,3H),1.77–1.72(m,2H),1.63–1.45(m,4H),1.40(s,9H).
19 F NMR(377MHz,CDCl 3 )δ-174.22(minor),-184.05(major).
13 C NMR(101MHz,CDCl 3 )δ155.1,90.8(d,J＝172.6Hz)(minor),87.8(d,J＝169.0Hz)(major),79.2(minor),79.1(major),48.1,30.4(d,J＝19.7Hz),29.7(minor),29.6(major),29.4,28.3,27.4.
HRMS(EI):calcd for C 10 H 15 FO(M) + :170.1101；found 170.1101.
example 10
Synthesis of 2-fluoro-indan
Figure BDA0003717955110000133
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 2-indene carboxylic acid, and the eluent used for column chromatography was n-pentane. The other operations were the same as in example 1. The product of this example was a colorless oily liquid, yield 64%; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.36–7.34(m,2H),7.30–7.27(m,2H),5.63–5.46(m,1H),3.33(d,J＝2.4Hz,2H),3.26(d,J＝2.4Hz,2H).
19 F NMR(377MHz,CDCl 3 )δ-173.68(s,1F).
13 C NMR(151MHz,CDCl 3 )δ139.9,126.8,124.8,94.6(d,J＝176.7Hz),40.5(d,J＝23.5Hz).
HRMS(EI):calcd for C 9 H 9 F(M) + :136.0682；found 136.0681.
example 11
Synthesis of 2-fluoro-1,2,3,4-tetrahydronaphthalene
Figure BDA0003717955110000141
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 1,2,3,4-tetrahydro-2-naphthoic acid and the eluent used for column chromatographic separation was n-pentane. The other operations were the same as in example 1. The product of this example was a colorless oily liquid, yield 54%; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.20–7.13(m,4H),5.21–5.03(m,1H),3.23–3.01(m,3H),2.88–2.81(m,1H),2.22–2.03(m,2H).
19 F NMR(376MHz,CDCl 3 )δ-177.41(s,1F).
13 C NMR(101MHz,CDCl 3 )δ135.4,132.9(d,J＝6.0Hz),129.3,128.5,126.1,126.0,88.7(d,J＝170.8Hz),35.3(d,J＝22.2Hz),28.5(d,J＝20.4Hz),25.5(d,J＝8.2Hz).
HRMS(EI):calcd for C 10 H 11 F(M) + :150.0839；found 150.0837.
example 12
Synthesis of 1-benzyl-4-fluoropyrrolidin-2-one
Figure BDA0003717955110000142
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with equimolar amounts of 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid and column chromatography was performed using dichloromethane followed by dichloromethane as eluent: methanol = 100. The other operations were the same as in example 1. The product of this example was a pale yellow oily liquid, yield 55%; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.36–7.27(m,3H),7.26–7.22(m,2H),5.29–5.13(m,1H),4.54–4.45(m,2H),3.61–3.41(m,2H),2.78–2.68(m,2H).
19 F NMR(376MHz,CDCl 3 )δ-173.10(s,1F).
13 C NMR(101MHz,CDCl 3 )δ171.2,135.6,128.7,127.8,127.6,85.8(d,J＝179.1Hz),53.4(d,J＝25.1Hz),46.0,38.6(d,J＝23.7Hz).
HRMS(ESI):calcd for C 11 H 12 FNONa[M+Na] + :216.0795；found 216.0796.
example 13
Synthesis of (2-fluoropropyl) benzene
Figure BDA0003717955110000151
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 2-benzylpropionic acid, and the eluent used for column chromatography was n-pentane. The other operations were the same as in example 1. The product of this example was a colorless oily liquid in 66% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.38–7.34(m,2H),7.30–7.25(m,2H),5.01–4.81(m,1H),3.09–2.99(m,1H),2.94–2.83(m,1H),1.39(dd,J＝23.6,6.0Hz,3H).
19 F NMR(376MHz,CDCl 3 )δ-170.70(s,1F).
13 C NMR(151MHz,CDCl 3 )δ137.2(d,J＝5.6Hz),129.4,128.4,126.5,91.1(d,J＝168.2Hz),43.3(d,J＝21.3Hz),20.6(d,J＝22.5Hz).
HRMS(EI):calcd for C9H11F(M) + :138.0839；found 138.0839.
example 14
Synthesis of (2-fluoro-1,3-propanediyl) bis (diphenylphosphine oxide)
Figure BDA0003717955110000152
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 3- (diphenylphosphino) -2- ((diphenylphosphino) methyl) propionic acid, and the eluent used for column chromatography was dichloromethane: methanol = 50. The other operations were the same as in example 1. The product of this example was a white solid in 42% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.79–7.65(m,8H),7.51–7.39(m,12H),5.34–5.17(m,1H),3.18–3.04(m,2H),2.94–2.81(m,2H).
19 F NMR(376MHz,Chloroform-d)δ-163.61(t,J＝18.8Hz).
31 P NMR(162MHz,CDCl 3 )δ27.62(d,J＝19.4Hz).
13 C NMR(151MHz,CDCl 3 )δ132.3(dd,J＝101.8Hz,J＝35.9Hz),130.6(d,J＝9.4Hz),128.7(d,J＝5.0Hz),128.6(d,J＝4.8Hz),84.9(d,J＝178.0Hz),37.0(dd,J＝21.6Hz,J＝6.5Hz),36.6(dd,J＝21.7Hz,J＝6.3Hz).
HRMS(ESI):calcd for C 27 H 25 FO 2 P 2 Na + [M+Na] + :485.1206；found 485.1205.
example 15
Synthesis of 3-fluoro-4-phenylbutyric acid
Figure BDA0003717955110000161
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of DL-benzylsuccinic acid, and the eluent used for column chromatography was dichloromethane: methanol = 100. The other operations were the same as in example 1. The product of this example was a white solid in 61% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ10.44(brs,1H),7.39–7.26(m,5H),5.28–5.13(m,1H),3.16–2.96(m,2H),2.81–2.61(m,2H).
19 F NMR(376MHz,CDCl 3 )δ-177.71(s,1F).
13 C NMR(101MHz,CDCl 3 )δ176.5(d,J＝5.6Hz),135.8(d,J＝5.3Hz),129.4,128.6,127.0,90.0(d,J＝174.0Hz),40.9(d,J＝21.3Hz),39.3(d,J＝24.2Hz).
HRMS(ESI):calcd for C 10 H 10 FO 2 - [M-H] - :181.0670；found 181.0667.
example 16
Synthesis of 1-fluoro-1,2-diphenylethane
Figure BDA0003717955110000162
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 2,3-diphenylpropanoic acid, and the eluent used for column chromatographic separation was petroleum ether. The other operations were the same as in example 1. The product of this example was a white solid in 53% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.43–7.28(m,8H),7.24–7.22(d,J＝6.8,2H),5.74–5.59(m,1H),3.37–3.27(m,1H),3.22–3.10(m,1H).
19 F NMR(376MHz,CDCl 3 )δ-173.09(s,1F).
13 C NMR(151MHz,CDCl 3 )δ139.8(d,J＝19.8Hz),136.7(d,J＝4.1Hz),129.5,128.4,128.3,126.7,125.7,125.6,95.3(d,J＝174.3Hz),43.9(d,J＝24.3Hz).
HRMS(EI):calcd for C 14 H 13 F(M) + :200.0996；found 200.0995.
example 17
Synthesis of 3-fluoro-3-methylpiperidine-1-carboxylic acid tert-butyl ester
Figure BDA0003717955110000171
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 3-methyl-1-Boc-3-piperidinecarboxylic acid, and the eluent used for column chromatography was dichloromethane. The other operations were the same as in example 1. The product of this example was a colorless oily liquid in 92% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ3.76(d,J＝13.4Hz,2H),2.91–2.84(m,2H),1.89–1.75(m,2H),1.57–1.44(m,2H),1.41(s,9H),1.28(d,J＝45.3Hz,3H).
19 F NMR(376MHz,CDCl 3 )δ-152.23,-152.90.
13 C NMR(101MHz,CDCl 3 )δ154.9,91.0(d,J＝173.0Hz),79.5,52.7(d,J＝25.8Hz),51.5(d,J＝26.7Hz),,43.7,42.7,35.1(d,J＝22.8Hz),28.3,24.2(d,J＝24.0Hz),21.3.
HRMS(ESI):calcd for C 11 H 20 FNO 2 Na + [M+Na] + :240.1370；found 240.1370.
example 18
Synthesis of 3-fluoroadamantan-1-ol
Figure BDA0003717955110000172
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 3-hydroxyadamantane-1-carboxylic acid and the eluent used for column chromatography was dichloromethane. The other operations were the same as in example 1. The product of this example was a white solid in 47% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ2.36–2.33(m,2H),1.98(s,1H),1.88(d,J＝5.8Hz,2H),1.79(dd,J＝5.4,3.2Hz,4H),1.64(s,4H),1.48(d,J＝3.2Hz,2H).
19 F NMR(377MHz,CDCl 3 )δ-132.90(s,1F).
13 C NMR(101MHz,CDCl 3 )δ93.3(d,J＝186.2Hz),70.9(d,J＝11.8Hz),50.3(d,J＝17.5Hz),43.67,41.3(d,J＝17.6Hz),34.3(d,J＝2.1Hz),31.3(d,J＝10.4Hz).
HRMS(EI):calcd for C 10 H 15 FO(M) + :170.1101；found 170.1101.
example 19
Synthesis of tert-butyl (2-fluoro-2-methylpropyl) carbamate
Figure BDA0003717955110000173
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 2,2-dimethyl-3- (Boc-amino) propionic acid, and the eluent used for column chromatography was dichloromethane. The other operations were the same as in example 1.
The product of this example was a pale yellow oily liquid in 86% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ4.94(brs,1H),3.24–3.17(m,2H),1.38(s,9H),1.30(s,3H),1.24(s,3H).
19 F NMR(376MHz,CDCl 3 )δ-144.71(s,1F).
13 C NMR(101MHz,CDCl 3 )δ156.1,95.2(d,J＝167.0Hz),79.2,48.9(d,J＝22.2Hz),28.2,24.0(d,J＝24.1Hz).
HRMS(ESI):calcd for C 9 H 18 FNO 2 Na + [M+Na] + :214.1213；found 214.1214.
example 20
Synthesis of ((2-fluoro-2-methylpropyl) methyl) benzene
Figure BDA0003717955110000181
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 3- (benzyloxy) -2,2-dimethylpropionic acid, and the eluent used for column chromatography was petroleum ether: ethyl acetate =100:1. the other operations were the same as in example 1. The product of this example was a colorless oily liquid, yield 73%; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.38(d,J＝4.4Hz,4H),7.34–7.30(m,1H),4.64(s,2H),3.49(d,J＝18.8Hz,2H),1.45(s,3H),1.39(s,3H).
19 F NMR(376MHz,CDCl 3 )δ-144.73(s,1F).
13 C NMR(101MHz,CDCl 3 )δ138.1,128.3,127.5,127.5,94.9(d,J＝168.1Hz),75.8(d,J＝24.8Hz),73.4,23.9(d,J＝24.3Hz).
HRMS(ESI):calcd for C 11 H 15 FONa + [M+Na] + :205.0999；found 205.0999.
example 21
Synthesis of (4-fluoro-4-methylpentyl) benzene
Figure BDA0003717955110000182
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 2,2-dimethyl-5-phenylpentanoic acid, and the eluent used for column chromatography was n-pentane. The other operations were the same as in example 1. The product of this example was a colorless oily liquid in 73% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(600MHz,Chloroform-d)δ7.38(t,J＝7.6Hz,2H),7.30–7.27(m,3H),2.84–2.81(m,2H),2.05–1.99(m,2H),1.52(s,3H),1.49(s,3H).
19 F NMR(377MHz,CDCl 3 )δ-138.77(s,1F).
13 C NMR(151MHz,CDCl 3 )δ142.0,128.4,128.3,125.8,95.1(d,J＝165.8Hz),43.3(d,J＝23.0Hz),30.2(d,J＝5.3Hz),26.6(d,J＝24.9Hz).
HRMS(EI):calcd for C14H13F(M) + :166.1152；found 166.1150.
example 22
Synthesis of N-benzyloxycarbonyl-3-fluoropiperidine
Figure BDA0003717955110000191
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 3,3-diphenylpropanoic acid, and the eluent used for column chromatographic separation was petroleum ether. The other operations were the same as in example 1. The product of this example was a colorless oily liquid in 66% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.42(t,J＝7.6Hz,4H),7.34(d,J＝8.0Hz,6H),5.07(d,J＝6.8Hz,1H),4.95(d,J＝6.8Hz,1H),4.54–4.46(m,1H).
19 F NMR(376MHz,CDCl 3 )δ-214.49(s,1F).
13 C NMR(101MHz,CDCl 3 )δ140.3(d,J＝4.8Hz),128.6,128.3,126.9,85.2(d,J＝175.9Hz),51.2(d,J＝19.3Hz).
HRMS(EI):calcd for C14H13F(M) + :200.0995；found 200.0994.
example 23
Synthesis of 4-fluoro-1- (4-fluorophenyl) butane-1-one
Figure BDA0003717955110000192
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 4- (4-fluorobenzoyl) butyric acid, and the eluent used for column chromatography was petroleum ether: ethyl acetate = 10. The other operations were the same as in example 1. The product of this example was a colorless oily liquid in 51% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ8.02–7.97(m,2H),7.13(t,J＝8.6Hz,2H),4.61(t,J＝6.0Hz,1H),4.49(t,J＝5.6Hz,1H),3.11(t,J＝6.8Hz,2H),2.21–2.07(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-105.17,-220.23.
13 C NMR(151MHz,CDCl 3 )δ197.4,165.8(d,J＝255.2Hz),133.2,130.6(d,J＝9.4Hz),115.7(d,J＝21.7Hz),83.2(d,J＝164.7Hz),33.9(d,J＝3.9Hz),24.8(d,J＝19.9Hz).
HRMS(EI):calcd for C 10 H 10 F 2 O(M) + :184.0694；found 184.0694.
example 24
Synthesis of 2- (5-fluoropentyl) isoindole-1,3-dione
Figure BDA0003717955110000201
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 6- (N-phthalimido) hexanoic acid and the eluent used for column chromatography was dichloromethane. The other operations were the same as in example 1. The product of this example was a yellow oily liquid in 79% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.79–7.76(m,2H),7.69–7.66(m,2H),4.39(dt,J＝47.2,6.0Hz,2H),3.65(t,J＝7.2Hz,2H),1.76–1.63(m,4H),1.46–1.38(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-218.46(s,1F).
13 C NMR(101MHz,CDCl 3 )δ168.2,133.8,132.0,123.0,83.6(d,J＝165.1Hz),37.6,29.8(d,J＝19.8Hz),28.0,22.4(d,J＝5.3Hz).
HRMS(ESI):calcd for C 13 H 14 FNO 2 Na + [M+Na] + :258.0900；found 258.0902.
example 25
Synthesis of 2,4-dichloro-1- (fluoromethoxy) benzene
Figure BDA0003717955110000202
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 2,4-D and the eluent used for column chromatographic separation was petroleum ether. The other operations were the same as in example 1. The product of this example was a white solid in 56% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.43(d,J＝2.4Hz,1H),7.26–7.23(m,1H),7.16–7.14(m,1H),5.80(s,1H),5.67(s,1H).
19 F NMR(377MHz,CDCl 3 )δ-149.60(t,J＝53.9Hz,1F).
13 C NMR(101MHz,CDCl 3 )δ151.2(d,J＝2.9Hz),151.2,130.3,129.2,127.9,125.0(d,J＝2.7Hz),125.00,118.29,101.0(d,J＝222.9Hz).
HRMS(EI):calcd for C 7 H 5 Cl 2 FO(M) + :193.9696；found 193.9699.
example 26
Synthesis of 2- (fluoromethyl) isoindole-1,3-dione
Figure BDA0003717955110000211
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of phthaloylglycine and the eluent used for column chromatography was dichloromethane. The other operations were the same as in example 1. The product of this example was a white solid in 50% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.93–7.91(m,2H),7.80–7.78(m,2H),5.80(s,1H),5.67(s,1H).
19 F NMR(376MHz,CDCl 3 )δ-174.20(s,1F).
13 C NMR(101MHz,CDCl 3 )δ166.3(d,J＝2.6Hz),134.8,131.5,124.0,74.8(d,J＝199.2Hz).
HRMS(EI):calcd for C 9 H 6 FNO 2 (M) + :179.0377；found 179.0375.
example 27
Synthesis of tert-butyl ((1- (fluoromethyl) cyclohexyl) methyl) carbamate
Figure BDA0003717955110000212
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 2- (1- (((Boc) amino) methyl) cyclohexyl) acetic acid and the eluent used for column chromatographic separation was petroleum ether: ethyl acetate = 50. The other operations were the same as in example 1. The product of this example was a colorless oily liquid in 51% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ4.71(brs,1H),4.28(s,1H),4.16(s,1H),3.16(d,J＝6.6Hz,2H),1.52–1.37(m,8H),1.41(s,9H),1.34–1.30(m,4H).
19 F NMR(376MHz,CDCl 3 )δ-229.84(s,1F).
13 C NMR(101MHz,CDCl 3 )δ156.2,89.0(d,J＝171.6Hz),76.68,45.2,38.2(d,J＝16.0Hz),29.4(d,J＝5.3Hz),28.31,25.94,21.12.
HRMS(ESI):calcd for C 13 H 24 FNO 2 Na + [M+Na] + :268.1683；found 268.1684.
example 28
Synthesis of (4aS, 6aR,9S, 111bS) -4-fluoro-4, 9, 11b-trimethyl 10H-6a, 9-methanocyclohepta [ a ] naphthalen-8 (7H) -one
Figure BDA0003717955110000213
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with equimolar amounts of isosteviol ((4R, 4aS,6aR,9S,11aR, 11bS) -4,9, 11b-trimethyl-8-oxodecatetrahydro-6a, 9-methanocyclohepta [ a ] naphthalene-4-carboxylic acid) and the eluent used for column chromatography was first petroleum ether: ethyl acetate =200, petroleum ether: ethyl acetate = 100. The other operations were the same as in example 1. The product of this example was a white solid in 41% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ2.64(dd,J＝18.4,3.6Hz,1H),1.89–1.86(m,1H),1.82–1.75(m,2H),,1.68–1.53(m,9H),1.47–1.36(m,4H),1.30–1.21(m,6H),0.97(s,3H),0.80(s,3H).
19 F NMR(377MHz,CDCl 3 )δ-119.61(s,1F).
13 C NMR(101MHz,Chloroform-d)δ222.5,97.1(d,J＝165.5Hz),55.2,55.3,54.8,54.3,48.7,48.6,40.1,39.5,39.3(d,J＝8.2Hz),38.3(d,J＝9.3Hz),38.2,37.2,21.5(d,J＝27.5Hz),20.0(d,J＝38.5Hz),19.3(d,J＝11.5Hz),19.1,14.2.
HRMS(EI):calcd for C 19 H 29 FO(M) + :292.2197；found 292.2198.
example 29
Synthesis of methyl (S) -2- (((benzoyl) carbonyl) amino) -4-fluorobutyrate
Figure BDA0003717955110000221
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of methyl Z-glutamate and the eluent used for column chromatography was dichloromethane. The other operations were the same as in example 1. The product of this example was a white solid in 51% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.35–7.31(m,5H),5.64(brs,1H),5.11(s,2H),4.60–4.55(m,1H),4.54–4.43(m,2H),3.74(s,3H),2.32–2.05(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-220.10(s,1F).
13 C NMR(151MHz,CDCl 3 )δ172.1,155.8,136.0,128.4,128.1,128.0,80.2(d,J＝165.6Hz),67.0,52.5,50.9(d,J＝3.6Hz),32.8(d,J＝19.8Hz).
HRMS(ESI):calcd for C 13 H 16 FNO 4 Na + [M+Na] + :292.0955；found 292.0955.
example 30
Synthesis of (4- (1-fluoroethyl) phenyl) (phenyl) methanone
Figure BDA0003717955110000222
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of ketoprofen, and the eluent used for column chromatography was petroleum ether: ethyl acetate = 50. The other operations were the same as in example 1. The product of this example was a colorless oily liquid in 76% yield; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.81–7.79(m,3H),7.74(d,J＝7.6Hz,1H),7.61–7.57(m,2H),7.51–7.46(m,3H),5.77–5.60(m,1H)1.69(d,J＝6.4Hz,2H),1.63(d,J＝6.4Hz,2H).
19 F NMR(376MHz,CDCl 3 )δ-168.52(s,1F).
13 C NMR(101MHz,CDCl 3 )δ196.3,141.8(d,J＝20.2Hz),137.7,137.3,132.5,129.9,129.8,129.0(d,J＝6.6Hz),128.4,128.3,126.5(d,J＝6.7Hz),90.3(d,J＝169.8Hz),22.9(d,J＝24.8Hz).
HRMS(ESI):calcd for C 15 H 13 FONa + [M+Na] + :251.0842；found 251.0842.
example 31
Synthesis of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-3-fluoropropionate
Figure BDA0003717955110000231
The synthesis method of this example differs from that of example 1 in that: carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 4- (((1r, 2s, 5r) -2-isopropyl-5-methylcyclohexyl) oxy) -4-oxobutyric acid, and the eluent used for column chromatography was petroleum ether: ethyl acetate = 100. The other operations were the same as in example 1. The product of this example was a colorless oily liquid, yield 42%; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ4.77–4.62(m,3H),2.68(dt,J＝25.0,6.0Hz,2H),2.00–1.97(m,1H),1.89–1.81(m,1H),1.70–1.64(m,2H),1.50–1.46(m,1H),1.41–1.35(m,1H),1.07–1.02(m,1H),0.98(d,J＝11.2Hz,1H),0.89(dd,J＝6.8,4.4Hz,6H),0.75(d,J＝7.0Hz,3H).
19 F NMR(376MHz,CDCl 3 )δ-219.21(s,1F).
13 C NMR(101MHz,CDCl 3 )δ169.7(d,J＝6.1Hz),79.42(d,J＝167.3Hz),74.8,46.9,40.8,35.9(d,J＝22.4Hz),34.2,31.3,26.2,23.4,22.0,20.7,16.2.
HRMS(ESI):calcd for C 13 H 23 FO 2 Na + [M+Na] + :253.1574；found 253.1574.
example 32
Synthesis of (3aS, 6R, 6aR) -4-fluoro-6-methoxy-2,2-dimethyltetrahydrofuran [3,4-d ] [1,3] dioxole
Figure BDA0003717955110000232
The synthesis method of this example differs from that of example 1 in that: the carboxylic acid 1- [ (4-tolyl) sulfonyl ] -4-piperidinecarboxylic acid was replaced with an equimolar amount of 2,3-o-isopropylidene-1-o-methyl-d-ribonic acid and the eluent used for column chromatography was dichloromethane. The other operations were the same as in example 1. The product of this example was a colorless oily liquid, yield 77%; the nuclear magnetic resonance spectrum and high resolution data of the obtained product are as follows:
1 H NMR(400MHz,Chloroform-d)δ5.84(s,0.5H),5.69(s,0.5H),5.15(dd,J＝3.0,1.2Hz,1H),4.80(t,J＝6.0,1H),4.65(d,J＝6.0,1.2Hz,1H),3.40(d,J＝1.6Hz,3H),1.42(s,3H),1.30(s,3H).
19 F NMR(377MHz,CDCl 3 )δ-119.47(s,1F).
13 C NMR(101MHz,CDCl 3 )δ116.8,114.6,112.9,111.4(d,J＝2.0Hz),83.9(d,J＝40.2Hz),83.2,55.3,26.1,24.7.
HRMS(EI):calcd for C 7 H 13 FO 4 (M-Me) + :177.0558；found 177.0558.
examples 33 to 47
Examples 33-47 differ from example 1 in that: condition optimization is carried out on the scale of 0.1mmol of carboxylic acid, a series of different ligands are screened, the initial selection of the ligand dosage is 0.2 equivalent of carboxylic acid, and the light source is 455nm.
Other raw materials, feed ratio, solution concentration, reaction temperature and reaction time were the same as those in example 1. The yields of the corresponding products of examples 33-47 are shown in Table 1 below.
TABLE 1
Numbering Ligands Reaction yield (%)
Example 33 Bipyridine 16
Example 34 4,4 '-dimethyl-2,2' -bipyridine 35
Example 35 5,5' -dimethyl-2,2-bipyridine 23
Example 36 6,6' -dimethyl-2,2-bipyridine 8
Example 37 4,4 '-dimethoxy-2,2' -bipyridine 73(76 a )
Example 38 4,4 '-di-tert-butyl-2,2' -bipyridine 18
Example 39 4,4' -bis (trifluoro)Methyl) -2,2' -bipyridine 49
Example 40 2,2 '-bipyridine-4,4' -dicarboxylic acid methyl ester 35
Example 41 2,2 '-bipyridine-5,5' -dicarboxylic acid methyl ester 33
Example 42 2,2 '-bipyridine-6,6' -dicarboxylic acid methyl ester 20
Example 43 1,10-phenanthroline 14
Example 44 3,4,7,8-tetramethyl-1,10-phenanthroline 24
Example 45 4,7-dimethoxy-1,10-phenanthroline 56
Example 46 1,10-phenanthroline-5,6-dione 41
Example 47 Alpha, alpha-terpyridine 27
a : the yield under the conditions of example 1.
As can be seen from Table 1 above, when other bidentate and tridentate nitrogen-containing ligands are used, the influence of the type and position of the ligand substituent on the yield is very significant, and the reaction yield is significantly improved when an electron-donating substituent, especially methoxy group, is attached to the pyridine 4 position. Furthermore, a comparison of example 37 with example 1 shows that the effect is better when the ligand to metal ratio is adjusted to 1:1, which gives a 76% yield.
Examples 48 to 59
Based on the optimal conditions for example 37 (carboxylic acid 0.1mmol scale, ligand 0.1 equivalent carboxylic acid), different ferric, ferrous catalysts were screened for the conditions used for the reaction, and the yields of the corresponding products are shown in table 2 below.
TABLE 2
Numbering Iron catalyst Reaction yield (%)
Example 48 Ferric acetate 55
Example 49 Trifluoro methanesulfonic acid iron salt 66
Example 50 Ferric chloride 57
Example 51 Iron tribromide Trace amount of
Example 52 Ferric sulfate 65
Example 53 Iron acetylacetonate 66
Example 54 Ferric nitrate nonahydrate 71
Example 55 Ferrous triflate 73
Example 56 Ferrous acetylacetonate 74
Example 57 Ferrous chloride 58
Example 58 Ferrous bromide Trace amount of
Example 59 Boron Tetrafluoride (TFB)Iron salt hexahydrate 63
As can be seen from table 2 above, the reaction can also proceed mostly when other ferrous or ferric iron is used, but when ferric bromide or ferrous bromide is used, only trace amounts of product are produced, indicating that the effect of the counter ions of different valency of the iron ions on the reaction is also critical.
Examples 60 to 68
Based on the optimal conditions of example 37, different inorganic and organic bases were used for the condition screening of the reaction, and the yields of the corresponding products are shown in table 3 below.
TABLE 3
Number of Alkali Reaction yield (%)
Example 60 Sodium hydroxide 6
Example 61 Cesium carbonate 9
Example 62 Sodium bicarbonate 37
Example 63 Sodium monohydrogen phosphate 9
Example 64 Cesium fluoride 21
Example 65 4-dimethylaminopyridine 18
Example 66 2,6-Di-tert-butylpyridine 31
Example 67 2,4,6-Trimethylpyridine 58
Example 68 2,6-Di-tert-butyl-4-methylpyridine 13
As can be seen from table 3 above, when different types of inorganic bases were used, substantially little product was detected; and when a pyridine type organic base is used, the reaction yield is high. This demonstrates that organic bases are more suitable for the reaction to occur. The 2,6-lutidine used in example 37 was finally found to work best for alkali screening.
Examples 69 to 72
Based on the optimal conditions of example 37, different fluorine-containing reagents were used for the condition screening of the reaction, and the yields of the corresponding products are shown in table 4 below.
TABLE 4
Figure BDA0003717955110000261
As can be seen from Table 4 above, when other electrophilic fluorine sources were used, little or no product was detected by the reaction. The reaction proceeded well only with a similar type of fluorine source as example 37 (1-fluoro-4-methyl-1,4-diazabicyclo [2.2.2] octane tetrafluoroborate), with the best effect being obtained for the 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt used in example 37.
Examples 73 to 78
Examples 73 to 78 were each carried out in the same manner as in example 37 having the highest product yield except that the mixed acetonitrile aqueous solutions therein were each replaced with the following solvents, and the solvents used and the yields of the respective products were as shown in Table 5 below.
TABLE 5
Numbering Solvent(s) Reaction yield (%)
Example 73 Acetonitrile Not monitored
Example 74 Acetone (II) Trace amount of
Example 75 Methylene dichloride Not monitored
Example 76 Water (W) 15
Example 77 Acetone: water =1:1 72
Example 78 Dichloromethane: water =1:1 Trace amount of
As can be seen from Table 5 above, when other single organic solvents were used, little or no product was substantially detected; in different mixed solvents, only acetone and water can be mixed to give better yield, and other mixed solvents only have trace amount of products. This demonstrates that the proper choice of mixed solvent has a significant, even decisive, effect on the ability of the reaction to proceed. Screening of the final solvent found that the mixed solvent of acetonitrile and water (1:1) worked best.
Examples 79 to 81
Based on the optimal conditions of example 37, light sources of different wavelengths were used for the condition screening of the reaction, and the yields of the corresponding products are shown in table 6 below.
TABLE 6
Figure BDA0003717955110000262
Figure BDA0003717955110000271
As can be seen from Table 6 above, the efficiency of the light source used for the reaction also plays a crucial role, the reaction can be further improved to 82% when violet light (400 nm) having a shorter wavelength than that of blue light (455 nm) of example 37 is used, the reaction yield is rather significantly reduced when green light (525 nm) having a longer wavelength than that of blue light (455 nm) of example 37 is used, and the reaction effect is also significantly deteriorated when white light as a mixed light source is used instead of blue light (455 nm) of example 37, further indicating that the light source has a critical influence on the reaction.
Examples 82 to 84
Based on the optimal conditions of example 79, scale-up experiments on different scales were carried out to explore the practical utility value of the reaction, and the yields of the corresponding products are shown in Table 7 below.
TABLE 7
Figure BDA0003717955110000272
As can be seen from Table 7 above, when the reaction was scaled up to 2mmol, the reaction was still efficient, and further, when the reaction was scaled up to 5mmol, 0.99g of the product was obtained in 78% yield; on the basis, the dosage of the catalyst and the ligand is reduced to 0.01 equivalent, and the separation yield of 70% can be obtained through the reaction, so that the catalytic system is proved to still show good catalytic activity after the reaction scale is enlarged, and a powerful strategy is provided for drug synthesis and large-scale production.
Example 85
Based on the optimal conditions of example 79, the catalyst, ligand, base and light source are omitted correspondingly, and the yields of the corresponding products are shown in the following table 8.
TABLE 8
Figure BDA0003717955110000273
Figure BDA0003717955110000281
Reaction conditions are as follows: 1- [ (4-tolyl) sulfonyl group]-4-piperidinecarboxylic acid (1 eq, 0.1 mmol), ferrous acetate (0.1 eq), 4,4 '-dimethoxy-2,2' -bipyridine (0.1 eq), 1-chloromethyl-4-fluoro-1,4-diazabicyclo [ 2.2.2.2 ] pyridine]Octane bis (tetrafluoroborate) salt (2.1 equiv.), 2,6-lutidine (1.8 equiv.), acetonitrile and water (1:1), stirred at room temperature for 2 hours; b the yield was determined by nuclear magnetic hydrogen spectrometry using 4-fluorophenylacetic acid as an internal standard.
As can be seen from table 8 above, to obtain satisfactory reaction results, an iron catalyst and a ligand, a base are necessary: under 455nm blue light irradiation, the reaction hardly occurs without one or both of an iron catalyst, a ligand, and a base (items 1 to 5); whereas, under 400nm violet light, the reaction can take place in the presence of an iron catalyst but without a ligand (item 7), but only in moderate yields, whereas in the presence of a ligand but without a catalyst (item 6), the reaction can only be obtained in lower yields. Comparison with the results of the optimum conditions for simultaneous addition of the iron catalyst and the ligand (item 8) can show that the participation of the iron catalyst and the ligand together promotes efficient progress of the reaction.
The reaction mechanism in each example may be: taking ferrous acetate as a catalyst and 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) as a fluorine-containing reagent, firstly, ferrous acetate and a ligand are coordinated and oxidized into a ferric complex by 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate), the ferric complex and a carboxylic acid undergo coordination position exchange under the action of alkali to obtain a ferric carboxylate species, the ferric carboxylate species generate a charge transfer process of the ligand to a metal under the excitation of (purple light or blue light) illumination to generate a ferrous complex and a carboxyl radical, the alkyl carboxyl radical can generate an alkyl radical through decarboxylation due to instability, and then the alkyl radical and 1-chloromethyl-4-fluoro-3532 zft 3532-diazabicyclo [ 2.2.2.2 ] octane bis (tetrafluoroborate) are subjected to fluorine atom transfer reaction to obtain final fluoride, and the ferrous complex is simultaneously subjected to regeneration reaction by 1-343425-fluoro-3532 zft 3532-diazabicyclo [ 2.2.2.2 ] octane bis (tetrafluoroborate) to generate a fluorine atom transfer reaction so as to obtain a final fluoride, and then the ferric complex is regenerated.
From the above, it is clear from all the above examples that when the method of the present invention is adopted, namely a reaction system comprising an iron compound as a catalyst (especially ferrous acetate), a ligand (especially 4,4 '-dimethoxy-2,2' -bipyridine), a fluorine-containing reagent (especially 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt), a base (especially 2,6-dimethylpyridine) and a suitable organic solvent (especially acetonitrile: mixed solvent of water = 1:1), decarboxylation and fluorination reactions of different alkyl carboxylic acids can be performed to obtain corresponding fluorides, thereby providing a completely new synthetic route for efficient and rapid synthesis of such compounds.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.

Claims (10)

1. A method for constructing fluoride by decarboxylation of alkyl carboxylic acid is characterized in that: the method comprises the following steps:
under the conditions of heat energy and/or light energy and/or microwaves, alkyl carboxylic acid with a structure shown as a formula (I) is used as a reaction raw material, and under the combined action of an iron catalyst, a ligand, a fluorine-containing reagent and alkali, fluoride shown as a formula (II) is obtained through a free radical decarboxylation fluorination reaction;
Figure FDA0003717955100000011
wherein R is 1 Selected from the group consisting of hydrogen, heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted alkyl; r 2 Selected from hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted alkyl; r is 3 Selected from the group consisting of hydrogen, heterocycles, substituted or unsubstituted aryls, and substituted or unsubstituted alkyls.
2. The method of claim 1, wherein: the substituent groups in the substituted aryl and the substituted hydrocarbyl are respectively and independently selected from one or more of halogen, hydroxyl, carboxyl, acetal group, amino, primary amino, secondary amino, ester group, carbonyl, amide group, cyano, substituted or unsubstituted fatty alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted sulfonyl and substituted or unsubstituted sulfonic group.
3. The method of claim 1, wherein: the iron catalyst comprises any one or more of a ferric compound, a ferrous compound and zero-valent iron.
4. The method of claim 3, further comprising: the dosage of the catalyst is 0.1 to 50 percent of the alkyl carboxylic acid with the structure shown in the formula (I) by taking mol as a metering unit.
5. The method of claim 1, wherein: the ligand comprises one or more of bipyridine compounds, phenanthroline compounds and terpyridyl compounds.
6. The method of claim 5, wherein: the dosage of the ligand is 0.1 to 50 percent of the alkyl carboxylic acid with the structure shown in the formula (I) by taking mol as a metering unit.
7. The method of claim 1, wherein said step of treating is carried out in a single step, the method is characterized in that: the fluorine-containing reagent comprises one or more of 1-chloromethyl-4-fluorine-1,4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor), 1-fluorine-4-methyl-1,4-diazabicyclo [2.2.2] octane tetrafluoroborate and derivatives thereof.
8. The method of claim 7, further comprising: the fluorine-containing reagent is used in an amount of 0 to 20 equivalents based on moles of the alkyl carboxylic acid having the structure represented by the formula (I).
9. The method of claim 1, further comprising: the light energy is provided by placing the reaction system under any one of ultraviolet light and visible light.
10. Fluoride obtainable by a process according to any one of claims 1 to 9.
CN202210740947.0A 2022-06-28 2022-06-28 Method for constructing fluoride by decarboxylation of alkyl carboxylic acid Active CN115141138B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210740947.0A CN115141138B (en) 2022-06-28 2022-06-28 Method for constructing fluoride by decarboxylation of alkyl carboxylic acid

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210740947.0A CN115141138B (en) 2022-06-28 2022-06-28 Method for constructing fluoride by decarboxylation of alkyl carboxylic acid

Publications (2)

Publication Number Publication Date
CN115141138A true CN115141138A (en) 2022-10-04
CN115141138B CN115141138B (en) 2023-11-28

Family

ID=83410961

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210740947.0A Active CN115141138B (en) 2022-06-28 2022-06-28 Method for constructing fluoride by decarboxylation of alkyl carboxylic acid

Country Status (1)

Country Link
CN (1) CN115141138B (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102675015A (en) * 2012-06-11 2012-09-19 中国科学院上海有机化学研究所 Decarboxylation and fluorination method for carboxylic acid
WO2013028639A1 (en) * 2011-08-19 2013-02-28 The Trustees Of Princeton University C-halogen bond formation
CN113698325A (en) * 2021-08-27 2021-11-26 上海应用技术大学 Method for preparing alkyl sulfonyl fluoride

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013028639A1 (en) * 2011-08-19 2013-02-28 The Trustees Of Princeton University C-halogen bond formation
CN102675015A (en) * 2012-06-11 2012-09-19 中国科学院上海有机化学研究所 Decarboxylation and fluorination method for carboxylic acid
CN113698325A (en) * 2021-08-27 2021-11-26 上海应用技术大学 Method for preparing alkyl sulfonyl fluoride

Also Published As

Publication number Publication date
CN115141138B (en) 2023-11-28

Similar Documents

Publication Publication Date Title
González-Esguevillas et al. Photoredox-catalyzed deoxyfluorination of activated alcohols with Selectfluor®
Song et al. Metal-catalyzed C–H functionalization involving isocyanides
Zhang et al. Enantioselective epoxidation of unfunctionalized olefins catalyzed by salen manganese complexes
Wei et al. The first transition metal–ligand complex-catalyzed regioselective and stereoselective aminohalogenation of cinnamic esters
Kancherla et al. Recent developments in palladium-catalysed non-directed C–H bond activation in arenes
Gooßen Pd-catalyzed synthesis of arylacetic acid derivatives from boronic acidsDedicated to Professor KB Sharpless on the occasion of his 60th birthday.
JPH08231438A (en) Production of aromatic olefin
Larhed et al. Intermolecular Heck reaction: Scope, mechanism, and other fundamental aspects of the intermolecular Heck reaction
Shee et al. Cooperative photoredox and palladium catalysis: recent advances in various functionalization reactions
Wang et al. Asymmetric hydroesterification of styrene using catalysts with planar-chiral ferrocene oxazoline ligands
CN112724168B (en) Chiral pyridine derived N, B ligand, preparation method and application in iridium-catalyzed asymmetric boronation reaction
Mashima et al. Synthesis, Structure, and Reactions of Stable Titanacyclopentanes.
CN115141138A (en) Method for constructing fluoride by decarboxylation of alkyl carboxylic acid
CN114940654B (en) Method for synthesizing adiponitrile and adipate compound by reductive dimerization of olefin under photocatalysis
Mingzhong et al. Silica-supported poly-γ-methylselenopropylsiloxane palladium complex: An efficient catalyst for Heck carbonylation of aryl halides
Barberis et al. Enantioselective synthesis of sabina ketone
Xi et al. Copper-Catalyzed Enantioselective Radical Esterification of Propargylic C–H Bonds
CN105198806B (en) A kind of method using aromatic amine, diketone synthesis of quinoline derivatives
Lal et al. Allylsilane as a versatile handle in photoredox catalysis
AU701315B2 (en) Process for preparing intermediates for the synthesis of antifungal agents
González-Esguevillas et al. Photoredox-catalyzed deoxyfluorination of activated alcohols with Selectfluor®
Mala Utilising a novel Ni/Zn catalytic system in small molecule synthesis
Abd-El-Aziz et al. Synthesis of isomeric ethyl tolylcyanoacetates using organo-iron complexes
CN116462607B (en) Cyano compound and preparation method and application thereof
CN110256249B (en) Preparation method of aromatic ketone compound substituted by beta, delta-position different functional groups

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant