Method for preparing aromatic and heteroaromatic compounds from outer ring pi system

Abstract

The invention discloses a peroxide / superoxide-free and gaseous hydrogen-free one-pot method for preparing aromatic and heteroaromatic compounds from an outer ring pi system through a carbene coordinated transition metal catalyst. # imgabs0 #

Description

Technical Field

[0001] The present application belongs to the technical field of organic synthetic chemistry, and specifically discloses a method for preparing aromatic and heteroaromatic compounds from a saturated cyclic structure with an external ring π system. Background Art

[0002] The synthesis of aromatic and heteroaromatic compounds is one of the most important areas in organic synthetic chemistry. They are the core structures of many important functional materials and bioactive molecules. These compounds can serve as starting materials for subsequent transformations such as electrophilic and nucleophilic aromatic substitutions, aromatic CH activation and dearomatization. Transition metal-catalyzed dehydrogenation is one of the key methods for converting saturated hydrocarbons to aromatic compounds. Currently known catalytic methods include systems with or without acceptors.

[0003] The main obstacles that currently limit the realization of the full potential of these indispensable transformations may come from the limited substrate scope, harsh reaction conditions, raw material costs and their difficulty in preparation. Most systems show only limited functional group tolerance, especially those that rely on high temperatures, stoichiometric amounts of strong oxidants or non-neutral pH conditions.

[0004] Endocyclic olefins, cyclic ketones, enamines, etc. are the most effective substrate categories. Saturated cyclic structures can be directly dehydrogenated to endocyclic olefins by high temperature. Due to the low efficiency and incomplete isomerization of exocyclic to endocyclic olefins in existing systems, exocyclic olefins are poor substrates. Therefore, they have not yet become common substrates for the synthesis of aromatic compounds, and a step-by-step approach is required. The cumbersome isomerization and separation steps significantly reduce the efficiency of the synthesis. Therefore, it is urgent to develop methods for the efficient preparation of aromatic compounds from these challenging starting materials, preferably a one-pot method and applicable to a wide range of substitution patterns.

[0005] Exocyclic olefins are abundant and useful substrates in catalytic organic synthesis. In the synthesis of aromatic compounds, two key transformations need to be carried out: exocyclic to endocyclic olefin isomerization and endocyclic olefin dehydrogenation. However, these two processes are difficult to complete in one pot because the oxidants and reductants generated during the dehydrogenation process may deactivate the isomerization catalyst through redox side reactions, and the gaseous hydrogen and superoxide / peroxides produced in the system are hazardous. Therefore, step-by-step operations and tedious separation of olefin mixtures are required. Summary of the invention

[0006] In view of the deficiencies of the prior art, the object of the present invention is to provide a one-pot isomerization-dehydrogenation method without peroxide / superoxide and gaseous hydrogen, which is used to prepare a compound of formula (III) from compounds of formula (I) and formula (II) in the presence of carbene, a hydride source and a transition metal catalyst or its precursor: in, - the transition metal catalyst is selected from Groups 3 to 12; - Carbene optionally contains any member of a divalent carbon atom; - The hydride source is a compound that can generate transition metal hydride from the corresponding transition metal catalyst in a conventional manner, such as silane, alcohol, alkoxy, borane, Grignard reagent, etc.; - X is an optionally substituted non-aromatic cyclic saturated hydrocarbon or heterocyclic structure, the ring size of which is fixed to form the corresponding aromatic or heteroaromatic ring Z; each carbon of ring X has at least one hydrogen for dehydrogenation, or the carbon has an exocyclic π system (such as ketones, exocyclic olefins, etc.); - Y is an optionally substituted alkyl chain having at least one hydrogen atom on each carbon spacer and optionally linked to R² to form a non-aromatic structure X; - n is an integer, starting from 1 and up to the same integer as the ring size, and the outer ring π system is selected independently; - R¹, R², R³ are independently selected from hydrogen, halogen, heteroatom, metalloid, or optionally substituted alkyl, heterosubstituted alkyl and unsaturated structure (such as hydrocarbon, aryl, heteroaryl, alkenyl, alkynyl, carbonyl, ester, amide, sulfonate, etc.); - R¹, R², and R³ in formula (I) and formula (II) need not be the same; - The substituents on the compounds of formula (I) and formula (II) are optionally linked via an alkylene chain. DETAILED DESCRIPTION

[0007] definition In the following description, many specific details are set forth to provide a thorough understanding of the specification. However, one skilled in the relevant art will recognize that other methods, components, materials, etc. can be used to implement the invention without one or more of these specific details.

[0008] Unless the context requires otherwise, throughout the specification and the appended claims, the word "comprise" and variations such as "include" and "comprising" are to be interpreted in an open, inclusive sense, i.e., "including, but not limited to."

[0009] References throughout this specification to "one embodiment", or "an embodiment", or "in another embodiment", or "some embodiments", or "in certain embodiments" mean that a particular referenced feature, structure, or characteristic associated with an embodiment is included in at least one embodiment. Therefore, phrases such as "in one embodiment", or "in an embodiment", or "in another embodiment", or "in certain embodiments" that appear throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0010] It should be noted that, in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. In this application, "or" is used to mean "and / or" unless otherwise stated.

[0011] Certain chemical groups described herein are preceded by a shorthand notation indicating the total number of carbon atoms found in the chemical group shown. 7 -C 12 Alkyl refers to an alkyl group as defined below having a total of 7 to 12 carbon atoms, C 4 -C 12 Cycloalkyl refers to a cycloalkyl group as defined below having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may be present in substituents of the group.

[0012] The “C m To C n " or "C m至n ”, where “m” and “n” are integers referring to the number of carbon atoms in the alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of the cycloalkyl or cycloalkenyl group. That is, the ring of the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group may contain from “m” to “n” (including “m” and “n”) carbon atoms. Thus, for example, “C 1 To C 4 The "alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms, i.e., CH 3 -、CH 3 CH 2 -、CH 3 CH 2 CH 2 -、(CH 3 ) 2 CH-、CH 3 CH 2 CH 2 CH 2 -、CH 3 CH 2 CH(CH3 )- and (CH 3 ) 3 C-. If "m" and "n" are not specified for alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl, the broadest range described in these definitions is assumed.

[0013] Therefore, as used in the specification and the appended claims, the following terms shall have the following meanings unless otherwise indicated: The term "alkyl" as used herein alone or as part of a group refers to any unbranched or branched, substituted or unsubstituted saturated hydrocarbon group. The alkyl portion may be branched or straight chain. The alkyl group may have 1 to 20 carbon atoms (whenever it appears in this article, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although this definition also covers the occurrence of the term "alkyl" where no numerical range is specified). The alkyl group may also be a medium-sized alkyl group having 1 to 10 carbon atoms. The alkyl group may also be a low-sized alkyl group having 1 to 5 carbon atoms. The alkyl group may be referred to as a "C 1 -C 4 Alkyl" or similar designation. By way of example only, "C 1 -C 4 "Alkyl" means having 1 to 4 carbon atoms in the alkyl chain, i.e. the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0014] The alkyl group may be substituted or unsubstituted. When substituted, the substituents are one or more independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, heterocyclyl, heterocyclyloxy, heteroalicyclic, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, acyl, thiol, substituted or unsubstituted thioalkoxy, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, acyl alkyl, acylamino, acyloxy, aminoacyl, aminoacyloxy, oxyacylamino, keto, thioketo, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and substituted or unsubstituted amino, including monosubstituted -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -Aryl and -SO 2 -heteroaryl.

[0015] Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc. When a substituent is described as "optionally", the substituent may be substituted with one or more of the above substituents.

[0016] The term "alkenyl" as used herein alone or as part of a group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, and connected to the rest of the molecule by a single bond, such as ethenyl, propenyl, butenyl, pentenyl, penta-1,4-dienyl, cyclohexenyl, and the like.

[0017] The term "alkynyl" as used herein alone or as part of a group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, and connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0018] The term "aryl" as used herein alone or as part of a group refers to a carbocyclic aromatic ring or ring system. The aryl group may be unsubstituted or substituted. In addition, the term "aryl" includes fused ring systems in which at least two aryl rings, or at least one aryl and at least one C 3-8 -Cycloalkyl groups share at least one chemical bond.Some examples of "aryl" rings include optionally substituted phenyl, naphthyl, phenanthrenyl, anthracenyl, tetrahydronaphthyl, fluorenyl, indenyl, and indanyl.

[0019] The term "aryl" relates to aromatic groups, including for example benzyl groups, attached via a ring-forming carbon atom, and optionally bearing one or more substituents selected from the group consisting of heterocyclyl, heteroaryl, halogen, hydroxy, amino, cyano, nitro, alkylamido, acyl, C 1-6 -alkoxy, C 1-6 -alkyl, C 1-6 -Hydroxyalkyl, C 1-6 -aminoalkyl, C 1-6 -alkylamino, alkylsulfinyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl or trifluoromethyl. The aryl group may optionally be substituted in the para-, ortho- and / or meta-position.

[0020] The term "heteroaryl" as used herein alone or as part of a group refers to a heterocyclic aromatic group in which one or more carbon atoms of the aromatic ring are replaced by one or more heteroatoms such as nitrogen, sulfur and oxygen.

[0021] Additionally, as used herein, the term "heteroaryl" includes fused ring systems wherein at least one aromatic ring and at least one heteroaromatic ring, at least two heteroaromatic rings, at least one heteroaromatic ring and at least one heterocyclyl ring, or at least one heteroaromatic ring and at least one cycloalkyl ring share at least one chemical bond.

[0022] The term "heteroaryl" is understood to refer to an aromatic C 2-amino group containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms. 3-8 Cyclic groups, and their substituted and benzo and pyrido fused derivatives, for example, linked via a ring-forming carbon atom. The heteroaryl group may carry one or more substituents selected from halogen, hydroxy, amino, cyano, nitro, alkylamido, acyl, C 1-6 -alkoxy, C 1-6 -alkyl, C 1-6 -Hydroxyalkyl, C 1-6 -aminoalkyl, C 1-6 -alkylamino, alkylsulfinyl, alkylsulfinyl, alkylsulfonyl or trifluoromethyl. In some embodiments, the heteroaryl group can be a five-membered and six-membered aromatic heterocyclic ring system with 0, 1 or 2 substituents, which can be the same or different from each other, selected from the above list.

[0023] Representative examples of heteroaryl include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine, and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, borazine, triazole, benzotriazole, pteridine, benzoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halogen, hydroxy, cyano, OC 1-6 -alkyl, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl and amino-C 1-6 -alkyl.

[0024] As used herein, the terms "optional," "optional," or "optionally" mean that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0025] Unless otherwise indicated, when a substituent is considered to be "optional", it means that the substituent is a group that may be substituted by one or more groups individually and independently selected from morpholinoalkanoate, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-carbamyl, S-sulfonylamino, N-sulfonylamino, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl and amino, including mono- and di-substituted amino, and protected derivatives thereof.

[0026] For example, "optionally aryl" means that the aryl group may or may not be substituted and that the description includes substituted aryl groups and unsubstituted aryl groups.

[0027] As used herein, the term "transition metal" refers to any element in the d-block of the periodic table. This corresponds to Groups 3 (IIIB) to 12 (IIB) on the periodic table.

[0028] The term "ligand" in chemistry usually refers to an atom, ion, or molecule that bonds to a central metal, generally involving the formal donation of one or more electrons. The bonding between the metal and the ligand ranges from covalent to ionic.

[0029] As used herein, the term "carbene" refers to an organic molecule containing a carbon atom with six valence electrons and having the general formula RRC:.

[0030] The term "alkylene" or "alkylene chain" as used herein alone or as part of a group refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group consisting of only carbon and hydrogen, containing no unsaturated bonds, and having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and to the group by a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the group can be through one carbon or any two carbons within the chain.

[0031] The term "alkenylene" or "alkenylene chain", as used herein alone or as part of a group, refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical consisting solely of carbon and hydrogen, containing at least one double bond and having from 2 to 12 carbon atoms, such as vinylene, propenylene, n-butenyl, etc. The alkenylene chain is connected to the rest of the molecule by a single bond and to the radical by a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical can be through one carbon or any two carbons within the chain.

[0032] The term "alkynylene" or "alkynylene chain" as used herein alone or as part of a group refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group consisting of only carbon and hydrogen, containing at least one triple bond and having 2 to 12 carbon atoms, such as propynylene, n-butynylene, etc. The alkynylene chain is connected to the rest of the molecule by a single bond and to the group by a double bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the group can be through one carbon or any two carbons within the chain.

[0033] The term "amine" as used herein refers to a compound containing an amino group. The term "amino" as used herein alone or as part of a group refers to a substituted N-group.

[0034] Metalloids, or semimetals, are terms used in chemistry to classify chemical elements. Almost every element in the periodic table can be called a metal or a nonmetal, depending on their general physical and chemical properties. However, a few elements are called metalloids. There is no strict definition of the term, but the following properties are generally considered to be characteristic of metalloids: (1) metalloids often form amphoteric oxides; and (2) metalloids often behave as semiconductors (B, Si, Ge).

[0035] The following elements are generally considered metalloids: boron (B), silicon (Si), germanium (Ge), arsenic (As), antimony (Sb), tellurium (Te), and polonium (Po).

[0036] On the one hand, the present application relates to a peroxide / superoxide-free, gaseous hydrogen-free one-pot isomerization-dehydrogenation method for preparing a compound of formula (III) from compounds of formula (I) and formula (II) in the presence of a carbene, a hydride source and a transition metal catalyst or its precursor: in, - the transition metal catalyst is selected from Groups 3 to 12; - Carbene optionally contains any member of a divalent carbon atom; - The hydride source is a compound that can generate transition metal hydride from the corresponding transition metal catalyst in a conventional manner, such as silane, alcohol, alkoxy, borane, Grignard reagent, etc.; - X is an optionally substituted non-aromatic cyclic saturated hydrocarbon or heterocyclic structure, the ring size of which is fixed to form the corresponding aromatic or heteroaromatic ring Z; each carbon of ring X has at least one hydrogen for dehydrogenation, or the carbon has an exocyclic π system (such as ketones, exocyclic olefins, etc.); - Y is an optionally substituted alkyl chain having at least one hydrogen atom on each carbon spacer and optionally linked to R² to form a non-aromatic structure X; - n is an integer, starting from 1 and up to the same integer as the ring size, and the outer ring π system is selected independently; - R¹, R², R³ are independently selected from hydrogen, halogen, heteroatom, metalloid, or optionally substituted alkyl, heterosubstituted alkyl and unsaturated structure (such as hydrocarbon, aryl, heteroaryl, alkenyl, alkynyl, carbonyl, ester, amide, sulfonate, etc.); - R¹, R², and R³ in formula (I) and formula (II) need not be the same; - The substituents on the compounds of formula (I) and formula (II) are optionally linked via an alkylene chain.

[0037] In some embodiments of the present application, X is optionally cyclohexyl, cyclopentyl, cycloheptyl, pyrrolidinyl, piperidinyl, tetrahydronaphthyl, tetrahydrothienyl, 2,3-dihydrobenzo[b]thienyl, tetrahydrofuranyl, decahydrotolyl, and the like.

[0038] In some embodiments of the present application, the compound of formula (I) is selected from allylcyclohexane, 3-cyclohexyl acrylate, (3-cyclohexylprop-1-en-1-yl)dimethyl(phenyl)silane, limonene and substituted derivatives.

[0039] In some embodiments of the present application, the compound of formula (I) is methyl 2-cyclohexylidene acetate, wherein Y and R² are connected to form a non-aromatic ring structure X. The transition metal catalyst of the present invention may include any catalytic transition metal and / or catalyst precursor, when it is introduced into the reaction vessel, and if necessary, it can be converted into an active form in situ, as well as an active form of the catalyst participating in the reaction. In some embodiments of the present application, the transition metal is optionally Groups 3-12.

[0040] Exemplary transition metals that can be used in the present application include, but are not limited to, scandium (SC), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), technetium (TC), ruthenium (Ru), rhodium (Rh), palladium (PD), silver (Ag), cadmium (CD), hafnium (HF), tantalum (Ta), tungsten (W), rhenium (Re), osmium (OS), iridium (IR), platinum (Pt), gold (Au), mercury (Hg), dubn (Db), sulphide (SG), boron (BH), potassium (Hs), metal (Mt), darmstein (DS), roentgen (Rg), and unubidium (Uub).

[0041] In some embodiments of the present application, the transition metal is selected from Group 10.

[0042] In some embodiments of the present application, the transition metal is selected from nickel (Ni), palladium (Pd) and platinum (Pt). In some embodiments of the present application, the transition metal is palladium (Pd).

[0043] In some embodiments of the present application, the ligand on the transition metal catalyst is selected from carbene, heterocyclic carbene (NHCs), dicarbene, diheterocyclic carbene, phosphine, amine, imine, arsine and hybrids, combinations and derivatives thereof.

[0044] In some embodiments of the present application, the ligand or metal carries a weak or non-nucleophilic stabilizing ion, including but not limited to halogens, borates, sulfonates, and phosphonates.

[0045] The ligand may be added to the reaction mixture in the form of a metal complex or as a separate reagent. The ligand, if chiral, may be added as a racemic mixture or as an optically pure stereoisomer.

[0046] In some embodiments of the present application, a transition metal catalyst is provided in a catalytic amount in the reaction. In a specific embodiment, the catalytic amount is less than 10 mol % relative to the equivalent reagent of formula (I).

[0047] In some embodiments of the present application, the reaction can be carried out in an optional solvent, which is selected from aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, nitriles and diol derivatives.

[0048] Exemplary aromatic hydrocarbons that can be used in the present application include, but are not limited to, benzene, toluene, xylene, etc. Exemplary aliphatic hydrocarbons that can be used in the present application include, but are not limited to, pentane, hexane, heptane, octane, etc. Exemplary alicyclic hydrocarbons that can be used in the present application include, but are not limited to, cyclohexane, cyclohexanone, methylcyclohexanone, etc. Exemplary alcohols that can be used in the present application include, but are not limited to, methanol, ethanol, isopropanol, etc. Exemplary ethers that can be used in the present application include, but are not limited to, diethyl ether, methyl ethyl ether, propyl ether, propylene oxide, etc. Exemplary esters that can be used in the present application include, but are not limited to, methyl formate, ethyl formate, butyl formate, pentyl formate, methyl acetate, ethyl acetate, propyl acetate, benzyl phenylacetate, etc. Exemplary ketones that can be used in the present application include, but are not limited to, acetone, methyl butyl ketone, methyl isobutyl ketone, etc. Exemplary nitriles that can be used in the present application include, but are not limited to, acetonitrile, propionitrile, acrylonitrile, etc. Exemplary diol derivatives that can be used in the present application include, but are not limited to, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, etc.

[0049] In some embodiments of the present application, the solvent is an ether. In some embodiments of the present application, the solvent is selected from tetrahydrofuran, diethyl ether, and dioxane.

[0050] Alternatively, the reaction can be carried out without solvent. Ionic liquids such as imidazolium salts can also be used as reaction media.

[0051] In some embodiments of the present application, the method can be carried out in an optional buffer to minimize problems associated with substrate, product, and catalyst decomposition. Examples of buffers that can be used in the present application include, but are not limited to, ammonium salts, phosphate buffers, and substituted pyridines. Example

[0052] The reaction is sensitive to oxygen and moisture, and the substrate should be dried and degassed (usually in CaH 2 or CaCl 2 Powder overnight). Unless otherwise stated, all reactions were performed under an oxygen-free atmosphere of nitrogen or argon with strict exclusion of moisture from reagents and glassware. Pd(TFA) 2 (CAS: 42196-31-6) was purchased from Sigma-Aldrich, TCI or J&K, stored under nitrogen atmosphere, and used without further purification. IPr (CAS: 244187-81-3) was purchased from TCI, stored under nitrogen atmosphere, and used without further purification. HBpin (CAS: 25015-63-8) was purchased from J&K or Energy, stored under nitrogen atmosphere, and used without further purification. Anhydrous THF (without BHT) was purchased from J&K and was heated in CaH 2 All commercially available and synthesized exocyclic olefins (Formula I) and olefins (Formula II) were dried over CaH 2 , Na 2 SO 4 Or dry over molecular sieves.

[0053] Analytical thin layer chromatography (TLC) was performed using EM Science silica gel 60 F254 plates. UV light (254 nm) and ethanolic phosphomolybdic acid (PMA) or potassium permanganate (KMnO 4 ) Analytical developed chromatograms. Liquid chromatography was performed using forced flow (flash chromatography) of the indicated solvent systems on silica gel (230–400 mesh). 1 H and 13 C NMR spectra were obtained on a Bruker 400 MHz or 500 MHz spectrometer in CDCl 3 Recorded in. 1 Chemical shifts in H NMR spectra are expressed in ppm on the delta scale with an internal standard of residual chloroform (7.27 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, m = multit, br = broad), coupling constant in Hertz (Hz), and integral. 13 The chemical shifts of C NMR spectra are from CDCl 3The central peak (77.16 ppm) is reported in ppm on the delta scale. High resolution mass spectra (HRMS) were recorded on a Finnigan MAT 95XL GC mass spectrometer.

[0054] In this case, as an example, a catalyst of the general formula (NHC)PdH(TFA) can be prepared according to, but not limited to, the following method: IPr, Pd(TFA) in a ratio of 1:1 2 After stirring in THF at room temperature for 15 min, HBpin (1.5 eq.) was added and the mixture was stirred at room temperature for 10 min.

[0055] (NHC)PdH(TFA) catalysts may also be generated by other methods, including but not limited to mixing a Pd source with 1) an imidazolium salt or ionic liquid, with or without a base; or 2) an alkyl, aryl, benzyl, vinyl, alkenyl, or alkynyl X; or 3) other common organometallic transformation and manipulation techniques, such as metathesis or elimination steps and substitutions.

[0056] The experimental results indicate that the one-pot isomerization-dehydrogenation reaction can be sensitive to the carbene catalyst structure, the counterion used, and the generation method.

[0057] General steps for catalyst preparation: In a glove box, Pd(TFA) 2 (0.025 mmol, 10 mol%) and NHC (0.025 mmol, 10 mol%) were added to a dry test tube and a magnetic bar was added. The mixture was dissolved in anhydrous THF (1 mL) and stirred for 15 minutes. Then, HBpin (0.0375 mmol, 15 mol%) was added to the mixture and the test tube was rinsed with anhydrous THF (0.5 mL). The whole mixture was stirred for another 10 minutes to produce the catalyst.

[0058] General procedure for the synthesis of aromatic or heteroaromatic compounds: Compounds of formula (I) and (II) (0.25 mmol, 100 mol% and 0.5 mmol, 200 mol%) were added to (NHC)PdH(TFA) or its equivalent. The residue on the inner wall of the test tube was rinsed with anhydrous THF (0.5 mL) and transferred to the reaction mixture. The test tube was properly sealed and then stirred for the specified reaction time (24 to 48 hours at room temperature or in a preheated oil bath). The mixture was then cooled, diluted with n-hexane (4 mL) and stirred in the open at room temperature for 30 minutes. The mixture was then filtered through a short column of silica gel and rinsed with 20% ethyl acetate / hexane (50 mL). The solvent was removed under reduced pressure and purified by flash chromatography on silica gel to obtain the product.

[0059] According to the above general steps, the following compounds were synthesized from the corresponding starting materials, and their characterization data are provided.

[0060] Example 1 1 H NMR (500 MHz, CDCl 3 ) δ7.32 – 7.27 (m, 2H), 7.23 – 7.18 (m, 3H), 4.13 (q, J = 7.1 Hz, 2H), 2.95 (t, J = 7.9 Hz, 2H), 2.62 (t, J = 7.9 Hz, 2H), 1.23(t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 173.1, 140.7, 128.6, 128.4, 126.4, 60.6, 53.6, 36.1, 31.1, 14.3.

[0061] HRMS-ESI (m / z): [M+H] + : Calculated value C 11 H 15 O 2 :179.1067; measured value 179.1062.

[0062] Example 2 1 H NMR (400 MHz, CDCl 3 ) δ7.15 – 7.04 (m, 2H), 6.87 (t, J = 7.4 Hz, 1H),6.76 (d, J = 7.9 Hz, 1H), 4.74 (s, 1H), 2.58 (t, J = 7.8 Hz, 2H), 1.70 – 1.59 (m,2H), 0.98 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 153.6, 130.4, 128.5,127.2, 120.8,115.3, 32.1, 23.0, 14.2.

[0063] HRMS-ESI (m / z): [M+H] + : Calculated value C 9 H 13 O:137.0961; measured value 137.0960.

[0064] Example 3 1 H NMR (500 MHz, CDCl 3 ) δ7.39 (s, 2H), 6.39 (s, 1H), 3.72 (s, 3H), 3.48 (s, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ 171.8, 143.2, 140.5, 117.4, 111.5, 52.2, 30.8.

[0065] MS (m / z): M + : Calculated value C 7 H 8 O 3 :140.0; measured value 140.0.

[0066] Example 4 1 H NMR (500 MHz, CDCl 3 ) δ7.22 – 7.13 (m, 4H), 4.15 (q, J = 7.1 Hz, 2H),3.63 (s, 2H), 2.32 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ171.7, 137.0, 133.0, 130.4, 130.3, 127.5, 126.2, 60.9, 39.4, 19.8, 14.3.

[0067] HRMS-ESI (m / z): [M+H] + : Calculated value C 11 H 15 O 2 :179.1067; measured value 179.1063.

[0068] The entire contents of all of the above-mentioned U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and / or listed in the Application Data Sheet are incorporated into this specification by reference.

[0069] It can be seen from the above that although the specific embodiments of the present application are only for illustration purposes, various modifications can be made without departing from the spirit and scope of the present application. Therefore, the present application is not limited except for the attached claims.

Claims

1. A one-pot isomerization-dehydrogenation method without peroxide / superoxide and gaseous hydrogen, for preparing a compound of formula (III) from compounds of formula (I) and formula (II) in the presence of a carbene, a hydride source and a transition metal catalyst or its precursor, wherein the reaction equation is as follows: It is characterized in that - the transition metal catalyst is selected from Groups 3 to 12; - Carbene optionally contains any member of a divalent carbon atom; - The hydride source is a compound that can generate transition metal hydride from the corresponding transition metal catalyst in a conventional manner, such as silane, alcohol, alkoxy, borane, Grignard reagent, etc.; - X is an optionally substituted non-aromatic cyclic saturated hydrocarbon or heterocyclic structure, the ring size of which is fixed to form the corresponding aromatic or heteroaromatic ring Z; each carbon of ring X has at least one hydrogen for dehydrogenation, or the carbon has an exocyclic π system (such as ketones, exocyclic olefins, etc.); - Y is an optionally substituted alkyl chain having at least one hydrogen atom on each carbon spacer and optionally linked to R² to form a non-aromatic structure X; - n is an integer, starting from 1 and up to the same integer as the ring size, and the outer ring π system is selected independently; - R¹, R², R³ are independently selected from hydrogen, halogen, heteroatom, metalloid, or optionally substituted alkyl, heterosubstituted alkyl and unsaturated structure (such as hydrocarbon, aryl, heteroaryl, alkenyl, alkynyl, carbonyl, ester, amide, sulfonate, etc.); - R¹, R², and R³ in formula (I) and formula (II) need not be the same; - The substituents on the compounds of formula (I) and formula (II) are optionally linked via an alkylene chain.

2. The method according to claim 1, characterized in that The compound of formula (I) is selected from substituted cycloalkanes or heterocyclic compounds containing exocyclic olefins, including allyl cyclohexane, methyl-2-(dihydrofuran-3(2H)-ylidene) acetate, diethyl 2,2'-(cyclohexane-1,4-ylidene)(2E,2'E)-diacetate, ethyl-3-cyclohexyl acrylate, and 2-allylcyclohexanone.

3. The method according to claim 1, characterized in that The compound of formula (II) is selected from 4-methylpent-3-en-2-one, pent-3-en-2-one, methacrylate, and 2-buten-2-ylbenzene.

4. The method according to claim 1, characterized in that: The transition metal catalyst is [(IPr)Pd(TFA)2] or its equivalent generated in situ from Pd(TFA)2 and IPr, and the hydride source is HBpin, which is used to generate palladium hydride [(IPr)PdH(TFA)] in situ; wherein IPr is 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene (CAS: 244187-81-3).

5. The method according to claim 1, characterized in that The ligand on the transition metal catalyst is selected from carbene, heterocyclic carbene, biscarbene, bisheterocyclic carbene and derivatives thereof.

6. The method according to claim 1, characterized in that The catalyst carries a weakly nucleophilic or non-nucleophilic stabilizing ion including a halogen, borate, sulfonate or phosphonate.

7. The method according to claim 1, characterized in that The reaction is carried out in a solvent, and the solvent is selected from aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, nitriles, diol derivatives or imidazolium salt ionic liquids.

8. The method according to claim 1, characterized in that The reaction is carried out in a buffer system.

9. The method according to claim 1, characterized in that: The side chain having a racemic or enantiomeric structure in the compound of formula (III) is synthesized by using a chiral ligand.

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