Chemically selective mono alpha-arylation of O-protected hydroxyacetone under palladium catalysis

Abstract

The present invention relates to a novel process for the preparation of benzyl alpha-hydroxyketone derivatives by mono alpha-arylation of O-protected hydroxyacetone under palladium catalysis and subsequent deprotection.

Description

[0001] This invention relates to a novel method for preparing benzyl α-hydroxy ketone derivatives, which involves the mono-α-arylation of O-protected hydroxyacetone under palladium catalysis and subsequent deprotection.

[0002] The benzyl α-hydroxy ketone derivatives of formula (I) are valuable precursors for active agrochemicals and pharmaceuticals. This type of benzyl α-hydroxy ketone has broad synthetic applicability in classical heterocyclic synthesis (e.g., the synthesis of Hantzsch pyrrole or thiophene, the Weidenhagen reaction, the Bredereck synthesis, etc.) and in synthetic routes for 1,2-amino alcohols (e.g., via reductive amination or biocatalytic transamination). In particular, as disclosed in WO 2020 / 127780 A1, the benzyl α-hydroxy ketone derivatives of formula (I) are important intermediates for the preparation of compounds with antifungal activity.

[0003] Several oxidation methods have been reported for the synthesis of benzyl α-hydroxy ketones. For example, they can be synthesized by oxidizing olefin substrates. This often involves the combined use of a catalyst and a stoichiometric oxidant (Plietker et al., Org. Biomol. Chem. 2004, 2, 2403-2407; Rubottom et al., Tetrahedron Lett. 1974, 15, 4319-4322; and Pullez et al., Eur. J. Org. Chem. 2006, 80-83). The disadvantages are that regioselectivity is often poor when using non-directional substrates, and the generation of potentially toxic chemical waste due to the stoichiometric use of a co-oxidant. Alternatively, they can be prepared by the single oxidation of diols (Waymouth et al., J. Am. Chem. Soc. 2018, 140, 748-757). Unfortunately, this reaction is slow and requires expensive catalysts. Finally, the α-oxidation of ketones was carried out directly using electrophilic oxygen reagents (Davis et al., J. Am. Chem. Soc., 1990, 112, 6679-6690 and Li et al., Adv. Synth. Catal., 2022, 364, 1757-1762). However, these reagents are both dangerous and expensive.

[0004] Besides direct oxidation, benzyl α-hydroxy ketones can also be synthesized by selective bromination of phenylacetaldehyde followed by reaction with an oxygen nucleophile (Merck & Co., DE946446C, 1956-08-02). Alternatively, phenylpropynyl alcohol can be reacted with a thiol reagent, followed by acidic hydrolysis to obtain the corresponding hydroxy ketone (Waters et al., Tetrahedron Lett. 2000, 41, 141-144). These methods require multiple steps and generate significant amounts of chemical waste.

[0005] Finally, N-heterocyclic carbene can be used as a catalyst to couple aldehydes with formaldehyde for a coupling reaction (Inoue et al., J. Org. Chem. 1985, 50, 603-606). This can also be accomplished via enzymatic reactions (Ma et al., Angew. Chem. Int. Ed. 2022, 61, e2021163). These methods rely on the synthesis and isolation of aldehyde intermediates that are typically reactive.

[0006] Metal-catalyzed α-arylation of carbonyl compounds using (hetero)aryl halides or pseudohalides as electrophiles provides a useful method for preparing benzyl ketone synthons. However, selective mono-α-arylation can also present problems (Stradiotto et al., “New Trends in Cross-Coupling: Theory and Applications”, Colacot, TJ, Ed. Royal Society of Chemistry: Cambridge, UK, 2014; 228-253), particularly in methyl carbonyl compounds, where the resulting arylated product is characterized by a benzyl CH2 group, which is more acidic than the methyl carbonyl starting material. Despite significant progress in the chemistry of metal-catalyzed α-arylation, we note that, to date, no similar conversions of terminally selective hydroxyacetone (or O-protected variants) have been reported (Stradiotto et al., Eur. J. Org. Chem. 2012, 6042-6050; Waters SM et al., Tet. Lett. 41 (2000), 141-144).

[0007] Surprisingly, it was found that in catalytic systems containing palladium catalysts and bisphosphine ligands, O-protected hydroxyacetone undergoes highly efficient methyl-selective mono-α-arylation reactions with ortho-substituted aryl bromides, aryl iodides, fluorosulfonates, and trifluorosulfonates (in the presence of potentially competing functional groups including chlorine atoms).

[0008] In view of the above-mentioned prior art, the object of the present invention is to provide an efficient and selective route for preparing benzyl α-hydroxy ketone derivatives of formula (I) under mild conditions, while achieving high yield, broad substrate range, high purity, low chemical waste and easy separation of the final product.

[0009] The above objective is achieved by a method for preparing compounds of general formula (I).

[0010]

[0011] R 1 It is phenyl, naphthyl, or 5 to 10-membered heteroaryl.

[0012] The phenyl, naphthyl, and 5- to 10-membered heteroaryl groups are optionally substituted by 1 to 3 substituents, which are independently selected from: fluorine, chlorine, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, di-C1-C6-alkylamino, or 3- to 10-membered heterocyclic groups.

[0013] The 3- to 10-membered heterocyclic group is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from: oxo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, and C1-C6-haloalkoxy.

[0014] R 2 It is hydrogen or (C1-C6)-alkyl.

[0015] Characterized in that, in step A, the compound of formula (II) is reacted with the compound of formula (III) in a suitable solvent, in the presence of a palladium catalyst, a bisphosphine ligand, and a suitable base, to generate the compound of formula (IV).

[0016] R 1 -X 1 (II),

[0017] Where R 1 As defined above, and

[0018] X 1 It is composed of bromine, iodine, fluorosulfonic acid, or trifluoromethanesulfonic acid groups.

[0019]

[0020] Where R 2 As defined above, and

[0021] PG is a hydroxyl protecting group, preferably methyl, tert-butyl, tetrahydropyranyl, or benzyl.

[0022]

[0023] Where R 1 R 2 And PG as defined above,

[0024] In step B, the protecting group PG is subsequently removed.

[0025] General definition

[0026] Unless otherwise stated, the following definitions apply to substituents and residues used throughout this specification and claims:

[0027] As used herein, the term "C1-C6-alkyl" refers to a saturated, branched, or straight hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of C1-C6-alkyl include, but are not limited to: methyl, ethyl, propyl (n-propyl), 1-methylethyl (isopropyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, Hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl. In particular, the hydrocarbon chain contains 1, 2, 3, or 4 carbon atoms (“C1-C4 alkyl”), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

[0028] As used herein, the term "C1-C6-haloalkyl" refers to a C1-C6-alkyl group as defined above, in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. Examples of C1-C6-haloalkyl groups include, but are not limited to: chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and 1,1,1-trifluoropropyl-2-yl. Preferred compounds include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and 1,1,1-trifluoropropyl-2-yl.

[0029] As used herein, the term “C1-C6-alkoxy” refers to a group of the formula (C1-C6-alkyl)-O, wherein the term “C1-C6-alkyl” is as defined herein. Examples of C1-C6 alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, n-hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, and 1-ethyl-2-methylpropoxy. Unless otherwise defined, this definition also applies to alkoxy groups that are part of a complex substituent, such as alkoxyalkyl and alkoxyalkoxy.

[0030] As used herein, the term "C1-C6-haloalkoxy" refers to a C1-C6-alkoxy group as defined above, in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. Examples of C1-C6-haloalkoxy groups include, but are not limited to: chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and 1,1,1-trifluoroprop-2-oxy.

[0031] As used herein, the term "di-(C1-C6)-alkylamino" refers to a substance having two independent amino groups selected from C1-C6-alkyl groups as defined herein. Examples of C1-C6-dialkylamino include, but are not limited to, N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, and N-tert-butyl-N-methylamino.

[0032] As used herein, the term "C3-C8-cycloalkyl" refers to a saturated monocyclic hydrocarbon ring containing 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of C3-C8-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, the cycloalkyl group contains 3 to 6 carbon atoms.

[0033] As used herein, the term "3- to 10-membered heterocyclic group" refers to a saturated or partially unsaturated 3, 4, 5, 6, 7, 8, 9, or 10-membered ring system containing 1 to 4 independent heteroatoms selected from oxygen, nitrogen, and sulfur. If the ring system contains more than one oxygen atom, these oxygen atoms are not directly adjacent to each other. Heterocyclic rings include, but are not limited to, 3- to 7-membered monocyclic heterocycles and 8- to 10-membered bicyclic heterocycles. The 3- to 10-membered heterocycles can be partially connected to the parent molecule via any carbon or nitrogen atom contained within the heterocycle. Examples of saturated heterocycles include, but are not limited to: 3-membered rings, such as oxopropyl and azirropropyl; 4-membered rings, such as azirrobutyl, oxobutyl, and thiobutyl; 5-membered rings, such as tetrahydrofuranyl, 1,3-dioxolanecycloyl, tetrahydrothiophene, pyrrolidinyl, pyrazolyl, imidazoyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazoyl, isothiazolyl, thiazoyl, isothiazolyl, thiazoyl; 6-membered rings, such as piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, triazinyl, hexahydrotriazinyl, tetrahydropyranyl, dioxyl, tetrahydrothiaranyl, dithiohexyl, morpholinyl, 1,2-oxazinyl, oxothiohexyl, thiomorpholinyl; or 7-membered rings, such as oxeheptyl, azirrohexyl, 1,4-diazahexyl, and 1,4-oxazahexyl. Examples of unsaturated heterocycles include, but are not limited to: five-membered rings, such as dihydrofuranyl, 1,3-dioxacyclopentenyl, dihydrothiophenyl, pyrrolinyl, dihydroimidazolyl, dihydropyrazolyl, isoxazolinyl, dihydrooxazolyl, and dihydrothiazolyl; or six-membered rings, such as pyranyl, thiaranyl, thiazinyl, and thiadiazinyl. Bicyclic heterocycles can be formed by fusion of a monocyclic heteroaryl group with a monocyclic C3-C8-cycloalkyl group, a monocyclic C3-C8-cycloolefin, or a monocyclic heterocycle as defined herein, or by fusion of a monocyclic heterocycle with an aryl group (e.g., phenyl), a C3-C8-cycloalkyl group, a C3-C8-cycloolefin, or with a monocyclic heterocycle (e.g., dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydroindolyl, 1,3-benzodioxacyclopentenyl, dihydro-1,4-benzodioxacyclohexenyl, tetrahydroquinolinyl, dihydro-5H-cyclopentano[b]pyridyl, benzodihydropyranyl, isobenzodihydropyranyl, dihydrobenzothiaranyl, isodihydrobenzothiaranyl). When two monocyclic heterocycles or one monocyclic heterocycle is fused with a nitrogen-containing monocyclic heteroaryl group, the nitrogen atom can be located at the bridgehead position (e.g., [1,3]dioxo[4,5-b]pyridyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl).

[0034] The terms “3- to 7-membered heterocyclic group” and “3- to 7-membered heterocyclic group-ring” used in this article refer to saturated 3, 4, 5, 6 or 7-membered ring systems containing one or two heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples include, but are not limited to: oxacyclopropyl, azircyclopropyl, azircyclobutyl, oxacyclobutyl, thiohexacyclobutyl, tetrahydrofuranyl, 1,3-dioxapentanyl, tetrahydrothiophene, pyrrolyl, pyrazolyl, imidazoyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazoyl, isothiazolyl, thiazoyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrimidinyl, piperazine, triazineyl, hexahydrotriazineyl, tetrahydropyranyl, dioxyl, tetrahydrothiaranyl, dithiohexyl, morpholinyl, 1,2-oxazineyl, oxothiohexyl, thiomorpholinyl, oxacycloheptyl, azircycloheptyl, 1,4-diazacycloheptyl, and 1,4-oxaazacycloheptyl. Preferred 3- to 7-membered heterocyclic groups are: oxetyl, aziridine, aziridine, oxetyl, tetrahydrofuranyl, 1,3-dioxolanecycloyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxyl, morpholinyl, and thiomorpholinyl.

[0035] As used herein, the term "5- to 10-membered heteroaryl" refers to an aromatic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. If the ring system contains more than one oxygen atom, these oxygen atoms are not directly adjacent to each other. Aromatic heterocycles include 5- or 6-membered monocyclic heteroaryl and 7- to 10-membered bicyclic heteroaryl. The 5- to 10-membered heteroaryl can be partially attached to the parent molecule via any carbon or nitrogen atom contained within the heterocycle.

[0036] As used herein, the term "5- or 6-membered heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of 5-membered monocyclic heteroaryl groups include, but are not limited to: furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxtriazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and thiatriazolyl. Examples of 6-membered monocyclic heteroaryl groups include, but are not limited to: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetraazinyl.

[0037] As used herein, the term "7- to 10-membered heteroaryl" refers to a 7-, 8-, 9-, or 10-membered aromatic bicyclic ring system containing one, two, or three independent heteroatoms selected from oxygen, nitrogen, and sulfur. Bicyclic heteroaryls can be formed by fusion of a monocyclic heteroaryl group (as defined herein) with an aryl group (e.g., phenyl) or with a monocyclic heteroaryl group. Examples of bicyclic heteroaryls include, but are not limited to: 9-membered rings such as indolyl, indolazinyl, isoyindolyl, benzimidazolyl, imidazopyridyl, indolyl, benzotriazolyl, purinyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, and benzoisoxazolyl; or 10-membered rings such as quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxolinyl, phthalazinyl, naphthidyl, pteridyl, and benzodioxanehexenyl. In a 9- or 10-membered bicyclic heteroaryl group containing two fused 5- or 6-membered monocyclic heteroaryl groups, the nitrogen atom may be located at the bridgehead position (e.g., imidazo[1,2-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[2,1-b]oxazolyl, furano[2,3-d]isooxazolyl).

[0038] Formula (I) provides a general definition of a benzyl α-hydroxy ketone obtained by the method described in this invention. Preferred groups of Formula (I) shown above and below are defined as follows. These definitions apply to the final product of Formula (I), as well as to all starting materials and intermediates containing their respective groups.

[0039] R 1 Preferably, it is phenyl, naphthyl, pyridyl, or benzothiophene.

[0040] The phenyl, naphthyl, pyridyl, or benzothiophene group is optionally substituted with 1 to 3 substituents, which are independently selected from fluorine, chlorine, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C3-C6-cycloalkyl, di-C1-C4-alkylamino, or 4- to 7-membered heterocyclic groups.

[0041] The 4- to 7-membered heterocyclic group is optionally substituted by one or two substituents, wherein the substituents are independently selected from oxo, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy.

[0042] R 1 More preferably, the group of the following formula is preferred.

[0043]

[0044] in

[0045] *Connect to X respectively 1 Or on the terminal carbon atom,

[0046] R 3 and R 4 Independently selected from fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6-cycloalkyl, dimethylamino, diethylamino, and piperazine.

[0047] The piperazine group is substituted by one or two substituents independently selected from methyl and ethyl.

[0048] Similarly,

[0049] R 1 More preferably, the group of the following formula is preferred.

[0050]

[0051] in

[0052] *Connect to X respectively 1 Or on the terminal carbon atom,

[0053] R 3 Selected from chlorine and methyl,

[0054] R 4 Selected from chlorine, bromine, and methyl.

[0055] R 1 Even more preferably, it is 2-chloro-4-methylphenyl.

[0056] R 2 Preferably, it is hydrogen or C1-C4-alkyl.

[0057] R 2 More preferably, it is hydrogen or methyl.

[0058] R 2 Even better is hydrogen.

[0059] PG is preferably methyl, tetrahydropyranyl, or benzyl.

[0060] PG is more preferably tetrahydropyranyl or benzyl.

[0061] PG is even more preferably tetrahydropyranyl.

[0062] X 1 Preferably, it contains bromine, fluorosulfonic acid, or trifluoromethanesulfonic acid groups.

[0063] X 1 More preferably, it is a bromine, fluorosulfonic acid group or a trifluoromethanesulfonic acid group.

[0064] X 1 Even more preferred is a fluorosulfonic acid group.

[0065] Therefore, particularly preferred is the method for preparing compound of formula (I-1),

[0066]

[0067] Characterized in that, in step A, in a suitable solvent, in the presence of a palladium catalyst, a bisphosphine ligand, and a suitable base, compound (IIa) reacts with compound (III-1) to generate compound (IV-1).

[0068]

[0069] in

[0070] X 1 It is a bromine, fluorosulfonic acid group or a trifluoromethanesulfonic acid group.

[0071]

[0072] In step B, the protecting group PG is subsequently removed.

[0073] The above-mentioned R 1 R 2 The definitions of PG (broad and preferred, more preferred, and even more preferred and most preferred) can be combined in various ways. These combinations of definitions thus provide subclasses of compounds of the present invention, such as those disclosed below.

[0074] The compounds of preferred formula (I) are those compounds for which each of the definitions (substituents and variants) has the preferred meanings described above.

[0075] Each of the definitions (substituents and variants) in the compounds of particular preference (I) refers to those compounds having the meanings of the more preferred, even more preferred and / or most preferred above.

[0076] As mentioned above, among the useful compounds in the field of synthetic crop protection, especially among the heterocyclic substituted pyridazine derivatives disclosed in WO 2020 / 127780A1, the compound of formula (I) is an important intermediate.

[0077] Another object of the present invention is the compound of formula (I).

[0078]

[0079] in

[0080] R 1 It is phenyl, naphthyl, or 5 to 10-membered heteroaryl.

[0081] The phenyl, naphthyl, and 5- to 10-membered heteroaryl groups are optionally substituted by 1 to 3 substituents, which are independently selected from fluorine, chlorine, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, di-C1-C6 alkylamino, or 3- to 10-membered heterocyclic groups.

[0082] The 3- to 10-membered heterocyclic group is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from oxo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, and C1-C6-haloalkoxy.

[0083] R 2 It is hydrogen or (C1-C6)-alkyl.

[0084] For the given R with respect to equation (I) 1 R 2 The definitions of preferred, more preferred, even more preferred and most preferred of PG are also applicable.

[0085] Another object of the present invention is compound (II).

[0086] R 1 -X 1 (II),

[0087] in

[0088] R 1 It is phenyl, naphthyl, or 5 to 10-membered heteroaryl.

[0089] The phenyl, naphthyl, and 5- to 10-membered heteroaryl groups are optionally substituted by 1 to 3 substituents, which are independently selected from fluorine, chlorine, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, di-C1-C6-alkylamino, or 3- to 10-membered heterocyclic groups.

[0090] The 3- to 10-membered heterocyclic group is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from oxo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, and C1-C6-haloalkoxy.

[0091] as well as

[0092] X 1 It has a fluorosulfonic acid group or a trifluoromethanesulfonic acid group.

[0093] For the given R with respect to equation (I) 1 R 2 X 1The definitions of preferred, more preferred, even more preferred and most preferred of PG are also applicable.

[0094] Another object of the present invention is compound (III).

[0095]

[0096] in

[0097] R 2 It is hydrogen or (C1-C6)-alkyl.

[0098] as well as

[0099] PG is a hydroxyl protecting group, preferably methyl, tetrahydropyranyl, or benzyl.

[0100] For the given R with respect to equation (I) 1 R 2 The definitions of preferred, more preferred, even more preferred and most preferred of PG are also applicable.

[0101] Another object of the present invention is a compound of formula (IV).

[0102]

[0103] in

[0104] R 1 It is phenyl, naphthyl, or 5 to 10-membered heteroaryl.

[0105] The phenyl, naphthyl, and 5- to 10-membered heteroaryl groups are optionally substituted by 1 to 3 substituents, which are independently selected from fluorine, chlorine, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, di-C1-C6-alkylamino, or 3- to 10-membered heterocyclic groups.

[0106] The 3- to 10-membered heterocyclic group is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from oxo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, and C1-C6-haloalkoxy.

[0107] R 2 It is hydrogen or (C1-C6)-alkyl.

[0108] as well as

[0109] PG is a hydroxyl protecting group, preferably methyl, tetrahydropyranyl or benzyl.

[0110] For the given R with respect to equation (I) 1 R 2The definitions of preferred, more preferred, even more preferred and most preferred of PG are also applicable.

[0111] Method Description

[0112] The method of the present invention will be described in Scheme 1 below.

[0113] Option 1

[0114]

[0115] In step A of the present invention, an arylation of O-protected hydroxyacetone at the α-position is carried out using a palladium catalyst in combination with a bisphosphine ligand, a base, an optional salt additive, and a solvent.

[0116] Preferably, the palladium catalyst is a palladium(II) salt, particularly [Pd(cinnamyl)Cl]2, Pd(OAc)2, and Pd(dba)2. [Pd(cinnamyl)Cl]2 is the most preferred.

[0117] Preferably, a catalytic amount of palladium is used. More preferably, the ratio of the compound of formula (II) to the palladium catalyst is 10:1 to 100:1. Even more preferably, the ratio of the compound of formula (II) to the palladium catalyst is 20:1 to 80:1.

[0118] Suitable bisphosphine ligands are (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl]phosphino]ferrocene[(4-CF3Ph)PF-tBu, CAS Registry No. 246231-79-8], (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]-2-[bis[4-(trifluoromethyl)phenyl)phosphino]ferrocene][(4-CF3Ph)PF-tBu, CAS Registry No. 849924-37-4], and (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene[PhPF -tBu, CAS-registration number 155830-69-6], (2S)-1-[(1S)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene [PhPF-tBu, CAS-registration number 277306-29-3], (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene [CyPF-tBu, CAS-registration number 158923-11-6], (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene [CyPF-tBu, CAS-registration number 1246841-00- 8) (1R)-1-(dicyclohexylphosphino)-2-[(1R)-1-(dicyclohexylphosphino)ethyl]ferrocene [CyPF-Cy, CAS Registry No. 167416-28-6], (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene [CyPF-Cy, CAS Registry No. 246231-77-6], (2R)-1-[(1R)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene [PhPF-Cy, CAS Registry No. 155806-35-2], (2S)-1-[(1S)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene Benzylphosphine (Ferrocene) [CAS Registry No. 162291-02-3], di(1-adamantyl)-2-morpholinophenylphosphine [Mor-DalPhos, CAS Registry No. 1237588-12-3], 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene [XantPhos, CAS Registry No. 161265-03-8], 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl [Xphos, CAS Registry No. 564483-18-7] and 1-((1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantane-8-yl)-2-(1,3,5,7-tetramethyl-2,4,6-Trioxa-8-phosphaadamantane-8-yl)benzene [PAd2-DalPhos],

[0119]

[0120] Even more preferred are (4-CF3Ph)PF-tBu and PhPF-tBu.

[0121] The bisphosphine ligand used in the reaction of the present invention can be either an R-enantiomer, an S-enantiomer, or a mixture of the two enantiomers, wherein the ratio of R to S is in the range of 1:100 to 100:1, preferably in the range of 1:50 to 50:1, more preferably in the range of 1:20 to 20:1, and even more preferably in the range of 1:5 to 5:1.

[0122] The ratio of bisphosphine ligand to palladium catalyst is 20:1 to 1:20, preferably 10:1 to 1:10, more preferably 3:1 to 1:1, and even more preferably 1.25:1.0 to 1.20:1.0.

[0123] If X 1 If the base is bromine, iodine, or trifluorosulfonic acid group, then the base suitable for the reaction of the present invention is an alkali metal carbonate, alkali metal halide, dialkali metal phosphate, and alkali metal phosphate, such as cesium carbonate, cesium fluoride, dipotassium hydrogen phosphate, and potassium phosphate. Cesium carbonate is particularly preferred.

[0124] It is preferable to use an excess of alkali.

[0125] If X 1 If the base is trifluoromethanesulfonic acid, then the dual-base conditions are suitable for the reactions of this invention. The base suitable for the dual-base conditions is DBU, which is used in conjunction with salt additives (such as sodium trifluoroacetate, sodium trifluoromethanesulfonate, and potassium trifluoromethanesulfonate).

[0126] Under dual-alkali conditions, an excess of the dual-alkali system is used. Preferably, the ratio of (II): dual alkali is in the range of 1:10 to 1:1, more preferably in the range of 1:5 to 1:1.5, and even more preferably the ratio of (II): dual alkali is 1:2.

[0127] Preferably, an excess of (III) relative to (II) is used. More preferably, the ratio of (III):(II) is 3:1 to 2:1.

[0128] Solvents suitable for the reactions of this invention include, for example, aromatic hydrocarbons such as toluene, xylene, or decahydronaphthalene; ethers such as 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me-THF), 1,2-dimethoxyethane (DME), 1,2-diethoxyethane, diglyme, cyclopentylmethyl ether (CPME), or anisole; or mixtures of the above solvents.

[0129] More preferably, it is 1,4-dioxane, THF, 2-MeTHF or cyclopentylmethyl ether; even more preferably, it is 1,4-dioxane or toluene.

[0130] Preferably, (II) is diluted with an appropriate amount of solvent to achieve a final concentration in the range of 0.1 M to 0.8 M, more preferably in the range of 0.2 M to 0.5 M. Even more preferably, the final diluted concentration is 0.24 M to 0.36 M.

[0131] Step A can be carried out at a reaction temperature ranging from +80°C to +150°C, preferably from +90°C to +130°C, and more preferably from +110°C to +120°C.

[0132] The reaction time is generally 4 to 24 hours.

[0133] Most preferably, step A of the present invention is carried out under conditions of using [Pd(cinnamyl)Cl]2 as a palladium catalyst, combined with the use of (4-CF3Ph)PF-tBu or PhPF-tBu as a bisphosphine ligand, and cesium carbonate as a base, wherein the ratio of the bisphosphine ligand to the palladium catalyst is from 1.25:1.0 to 1.20:1.0.

[0134] Most preferably, step A of the present invention is carried out in a solvent at a dilution concentration of 0.24M to 0.36M and at a temperature of +110°C to +120°C, wherein the solvent is 1,4-dioxane or toluene.

[0135] In step B of the method of the present invention, the O-protected hydroxyacetone of formula (IV) is deprotected using acidic conditions and a suitable solvent to provide the corresponding arylated hydroxyacetone of formula (I). The product is then separated by crystallization or silica gel column chromatography.

[0136] Preferably, the acid used in the deprotection step is hydrochloric acid (HCl) or SiO2-supported NaHSO4.

[0137] Preferably, HCl is used in excess relative to (IV); more preferably, the ratio of (IV) to HCl used is in the range of 1:1.5 to 1:10, even more preferably in the range of 1:3 to 1:7, and even more preferably in the range of 1:5.

[0138] Preferably, NaHSO4-SiO2 is used in a catalytic amount relative to (IV); more preferably, NaHSO4-SiO2 is used in an amount of 20 to 400 mg / mmol (IV); even more preferably, NaHSO4-SiO2 is used in an amount of 50 to 280 mg / mmol (IV).

[0139] The solvent suitable for step B is a polar solvent, such as alcohol, ether or water, more preferably methanol, 1,4-dioxane or water, and even more preferably water.

[0140] Method step B is typically carried out at a temperature of +10°C to +150°C, preferably +20°C to +100°C, more preferably +40°C to +90°C, and most preferably at a reaction temperature of about +90°C.

[0141] The time it takes for protection to wear off often lasts from 10 minutes to 1 hour.

[0142] Most preferably, step B of the present invention is carried out under acidic conditions in a solvent, wherein the acid is selected from HCl or SiO2-supported NaHSO4, and wherein the solvent is selected from methanol, 1,4-dioxane, or water.

[0143] The present invention is illustrated by the following embodiments, but the present invention is not limited thereto: Example

[0144] A-1. Abbreviations

[0145]

[0146]

[0147] A-2. Generally considered

[0148] Unless otherwise stated, all experiments were conducted in a nitrogen-filled, inert atmosphere glove box using dried glassware and purified solvents, except for the post-treatment of the catalytic reaction mixture, which was performed on the lab bench using unpurified solvents in air. For solvents and reagents used in the glove box, the following purification method was employed: toluene was deoxygenated by nitrogen purging, then passed through a dual-column solvent purification system containing alumina and copper-Q5 reactants, and subsequently stored in an activated atmosphere. On molecular sieves; sodium-benzophenone free radicals are removed by THF distillation, and then stored in activated... On the molecular sieve; 2-MeTHF, 1,4-dioxane, DCM (i.e., CH2Cl2), DMF, DMA, ACN (i.e., MeCN), NMP, DMSO, and anisole were all anhydrous products purchased from Sigma-Aldrich, which were deoxygenated by nitrogen purging and stored in an active container. On the molecular sieve; EtOAc, CPME, DME, diethylene glycol dimethyl ether, and 4-MeTHP were degassed through three repeated freeze-vacuum-thaw cycles, and then activated. Drying on molecular sieves; deoxygenating pentane by nitrogen purging, then activating... Dry on molecular sieves. Cs₂CO₃ and K₂CO₃ were purchased from Sigma-Aldrich as anhydrous sources and ground into fine powder using a mortar and pestle. O-protected starting materials 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone and 3-[(tetrahydro-2H-pyran-2-yl)oxy]-2-butanone, along with all trifluoromethanesulfonate / salt electrophilic reagents, were synthesized according to the methods described below. NaHSO₄-SiO₂ was prepared according to literature methods. 1 Prepared from NaHSO4 and silica. All other solvents, reagents, and materials were used directly from commercial sources. All catalyst loadings listed in "%" are "molar percentages" relative to the aryl electrophilic reagent.

[0149] Gas chromatography (GC) data were obtained using a calibrated instrument (Shimadzu GC-2030 GC) equipped with an SGE BP-5 column (30 m, 0.25 mm inner diameter), an SFID1 detector, a column oven temperature of 100 °C, an SFID1 temperature of 305 °C, an SPL1 temperature of 200 °C, a linear velocity of 45.4 cm / sec, a total flow rate of 45.1 mL / min, and a column flow rate of 2.1 mL / min. The program was: 2 min at 100 °C, 10 min at 200 °C, and 15 min at 220 °C (times are hold times).

[0150] The automated rapid column chromatography method uses normal-phase SiliCycle SiliSep TM The chromatography was performed using a 10, 25, or 40 g column or a 100 g normal phase Biotage SNAP KP-Sil column; “CV” refers to the column volume during the chromatographic purification process.

[0151] all 1 H NMR (500MHz and 300MHz), 13 C{ 1 H NMR (125.8MHz and 75.4MHz) and 19 F NMR (471 MHz) spectra were all recorded at 300 K, and referenced to the residual proton solvent peaks ( 1 H), deuterated solvent peak ( 13 C{ 1 The added 0.5% (CF3)C6H5 in H}) or CDCl3 is located at -63.7ppm ( 19 The peaks of F). The splitting modes are as follows: br, broad peak; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. All coupling constants (J) are recorded in Hertz (Hz).

[0152] The mass spectra were obtained using an ion trap (ESI) instrument, operated in the described positive or negative charge mode.

[0153] A-3. General Process

[0154] A-3.1. General procedure for the mono-α-arylation reaction of 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone with (hetero)aryl bromide using [Pd(cinnamyl)Cl]2 / PhPF-tBu (GP1).

[0155] Unless otherwise specified, 0.625 mol% [Pd(cinnamyl)Cl]2 (CAS 12131-44-1) (1.25 mol% Pd) and 1.5 mol% PhPF-tBu (CAS155830-69-6 and CAS277306-29-3) were added to a 1-dram screw-top flask equipped with a magnetic stirrer and dissolved in 1.33 mL of 1,4-dioxane (0.36 M, in aryl bromide). Then, aryl bromide (0.48 mmol, 1.0 equivalent) and Cs2CO3 (2 equivalent) were added, followed by 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (3 equivalent). The screw-top bottle was sealed with a PTFE liner cap, wrapped with insulating tape, and then removed from the glove box. It was placed in a temperature-controlled aluminum heater set to 110°C and allowed to react for 4.5 hours with magnetic stirring at 900 rpm.

[0156] A-3.2. General procedure for the mono-α-arylation reaction of 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone with aryl trifluoromethanesulfonate using [Pd(cinnamyl)Cl]2 / (4-CF3Ph)PF-tBu (GP2).

[0157] Unless otherwise specified, 2.5 mol% [Pd(cinnamyl)Cl]₂ (5 mol% Pd) and 6.25 mol% (4-CF₃Ph)PF-tBu (CAS 246231-79-8 and CAS 849924-37-4) were added to a 1-valve screw-top flask equipped with a magnetic stirrer and dissolved in 2 mL of toluene (0.24 M, in aryl-OTf). Then, DBU (2 equivalents) and NaOTf (2 equivalents), aryl trifluoromethanesulfonate (0.48 mmol, 1.0 equivalent), and 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (2 equivalents) were added. The flask was sealed with a PTFE-lined cap, wrapped with insulating tape, removed from the glove box, and placed in a temperature-controlled aluminum heater set to 120 °C, where it was reacted with magnetic stirring at 900 rpm for 12 hours.

[0158] A-3.3. General procedure for the synthesis of aryl trifluoromethanesulfonates from phenol (GP3).

[0159] Phenol (5.4 mmol, 1 equivalent) was dissolved in CH₂Cl₂ (10 mL) and stirred at 0 °C under a nitrogen atmosphere. Triethylamine (904 μL, 6.5 mmol, 1.2 equivalent) was added dropwise over 5 minutes, followed by trifluoromethanesulfonic anhydride (1.0 mL, 5.9 mmol, 1.1 equivalent) dropwise over 30 minutes. The reaction mixture was warmed to room temperature and stirred overnight. Once the reaction was complete, the reaction mixture was cooled to 0 °C, 2 M hydrochloric acid (2 equivalent) was added, and the mixture was stirred for 1 hour and then warmed to room temperature. The reaction mixture was extracted with CH₂Cl₂ (3 × 5 mL), and the organic layer was washed with NaHCO₃, water, and brine. The organic layer was dried over Na₂SO₄ and filtered through a silica / diatomaceous earth mat. The solvent was removed under vacuum to give the aryl trifluoromethanesulfonate product.

[0160] A-3.4. General procedure for the mono-α-arylation reaction of 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone with (hetero)aryl bromide using [Pd(cinnamyl)Cl]2 / (4-CF3Ph)PF-tBu (GP4).

[0161] Unless otherwise specified, 1.5 mol% [Pd(cinnamyl)Cl]₂ (3 mol% Pd) and 3.75 mol% (4-CF₃Ph)PF-tBu (CAS 246231-79-8 and CAS 849924-37-4) were added to a 1-valve-top flask equipped with a magnetic stirrer and dissolved in 2 mL of THF (0.24 M, in aryl bromide). Then, aryl bromide (0.48 mmol, 1.0 equivalent) and Cs₂CO₃ (2 equivalent) were added, followed by 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (2 equivalent). The flask was sealed with a PTFE-lined cap, wrapped with insulating tape, removed from the glove box, and placed in a temperature-controlled aluminum heater set to 90 °C, where it was reacted with magnetic stirring at 900 rpm for 12 hours.

[0162] A-3.5. General procedure for the mono-α-arylation reaction of 1-(benzyloxy)prop-2-one with (hetero)aryl bromide using [Pd(cinnamyl)Cl]2 / PhPF-tBu (GP5).

[0163] Unless otherwise specified, 0.625 mol% [Pd(cinnamyl)Cl]₂ (1.25 mol% Pd) and 1.5 mol% PhPF-tBu were added to a 1-fold screw-top flask equipped with a magnetic stirrer and dissolved in 1.33 mL of 1,4-dioxane (0.36 M, in aryl bromide). Then, aryl bromide (0.48 mmol, 1.0 equivalent) and Cs₂CO₃ (2 equivalent) were added, followed by 1-(benzyloxy)prop-2-one (3 equivalent). The flask was sealed with a PTFE-lined cap, wrapped with insulating tape, removed from the glove box, and placed in a temperature-controlled aluminum heater set to 110 °C, where it was reacted with magnetic stirring at 900 rpm for 4.5 hours.

[0164] A-3.6. General procedure for mono-α-arylation of methoxyacetone with (hetero)aryl bromides using [Pd(cinnamyl)Cl]2 / PhPF-tBu (GP6).

[0165] Unless otherwise stated in the text, 0.625 mol% [Pd(cinnamyl)Cl]₂ (1.25 mol% Pd) and 1.5 mol% PhPF-tBu were added to a 1-fold screw-top flask equipped with a magnetic stirrer and dissolved in 1.33 mL of 1,4-dioxane (0.36 M, in aryl bromide). Then, aryl bromide (0.48 mmol, 1.0 equivalent) and Cs₂CO₃ (2 equivalents) were added, followed by methoxyacetone (3 equivalents). The flask was sealed with a PTFE-lined cap, wrapped with insulating tape, removed from the glove box, and placed in a temperature-controlled aluminum heater set to 110 °C, where it was reacted with magnetic stirring at 900 rpm for 4.5 hours.

[0166] A-3.7. General procedure for mono-α-arylation of O-protected hydroxyacetone in an optimized approach (GP7).

[0167] An inorganic base and / or salt additive is added to a 1-fold screw-top flask equipped with a magnetic stirrer. Then, [Pd(cinnamyl)Cl]₂ and the ligand are added as a combined stock solution, containing ≥5 mg of [Pd(cinnamyl)Cl]₂ in the prepared reaction solvent, followed by the addition of an o-chloroaryl halide / pseudohalide (0.12-0.24 mmol, 1.0 equivalent), O-protected hydroxyacetone (2-3 equivalents), and DBU (if used). The screw-top flask is sealed with a PTFE-lined cap, wrapped with insulating tape, and then removed from the glove box and placed in a temperature-controlled aluminum heater set to 70-130°C, and reacted with magnetic stirring at 900 rpm for 3-48 hours, as described above.

[0168] A-4. Post-processing methods

[0169] A-4.1A. Post-processing method A (deprotection and purification of 1-phenyl-3-hydroxypropane-2-one product)

[0170] After GP1 reaction with 0.48 mmol of aryl bromide, the resulting mixture was cooled to room temperature and filtered through a thin-layer silica / diatomaceous earth filter (saturated with hexane and eluted with ethyl acetate (~20 mL)) into a 4-fold screw-top flask. The collected eluent was then dried under vacuum for 30 min to obtain a crude residue. A stir bar and 10 mL of water preheated to 95 °C were then added, followed by 200 μL of concentrated HCl. The screw-top flask was sealed with a PTFE-lined cap and placed in a temperature-controlled aluminum heater set to 95 °C, and reacted with magnetic stirring at 1500 rpm for 10 min. The mixture was then thermogravimetrically filtered through a glass filter plate lined with a Whatman 1 filter pad; the glass filter plate, filter pad, and collection flask were used immediately after being removed from an oven set to 120 °C. The eluent was cooled to room temperature and then placed in a refrigerator set to 3 °C overnight to crystallize the desired product. Then, benzyl α-hydroxy ketone (I) crystals were separated by vacuum filtration.

[0171] A-4.1B. Post-processing method A' (Deprotection and purification of 1-phenyl-3-hydroxypropane-2-one product)

[0172] After GP1 with 0.48 mmol of aryl bromide, the resulting mixture was cooled to room temperature, filtered through a thin-layer silica / diatomaceous earth filter plate, and eluted with ethyl acetate (~20 mL) into a 4-fold screw-top flask. The collected eluent was then dried under vacuum to obtain a crude residue. A stir bar and 10 mL of water preheated to 95 °C were then added, followed by 200 μL of concentrated HCl. The screw-top flask was sealed with a PTFE-lined cap and placed in a temperature-controlled aluminum heater set to 95 °C, where it was reacted with magnetic stirring at 1500 rpm for 10 min. The mixture was then thermogravimetrically filtered through a glass filter plate lined with a Whatman 1 filter pad; the glass filter plate, filter pad, and collection flask were used immediately after being removed from an oven set to 120 °C. The eluent was cooled to room temperature, extracted with 3 × 10 mL of ethyl acetate, the organic layers were combined, and then dried over Na₂SO₄. The solvent was then removed under vacuum, yielding a crude residue, which was dissolved in DCM and then loaded into a normal-phase Silicycle SiliSep. TM The product was then purified using a 10g column elution. The relevant UV-active column fractions were combined and dried under vacuum to obtain the target product for each case.

[0173] A-4.1C. Post-processing method A” (Deprotection and purification of the 1-phenyl-3-hydroxypropane-2-one product)

[0174] It is the same as post-processing method A′, but without the thermogravimetric filtration step.

[0175] A-4.2. Post-processing method C (deprotection and purification of 1-phenyl-3-hydroxypropane-2-one product)

[0176] After GP1 with 0.24 mmol of aryl bromide, the resulting mixture was cooled to room temperature, filtered through a thin-layer silica / diatomaceous earth filter, and eluted with ethyl acetate (~20 mL). The collected eluent was then dried under vacuum to obtain a crude residue, which was subsequently dissolved in 2 mL of methanol and added to a 1-fold screw-top flask containing 200 mg NaHSO4-SiO2 and a magnetic stirrer. The flask was sealed with a PTFE-lined cap and placed in a temperature-controlled aluminum heater set to 50 °C, and reacted with magnetic stirring at 900 rpm for 45 minutes. The resulting solution was then filtered through a silica gel column and eluted with ~10 mL of ethyl acetate into a 4-fold screw-top flask. The solvent was then dried under vacuum to obtain a crude residue, which was dissolved in DCM and loaded into a normal-phase SilicycleSiliSep flask. TM The product was then purified using a 10g column elution. The relevant UV-active column fractions were combined and dried under vacuum to obtain the target product for each case.

[0177] A-4.3. Post-processing method D (purification of 1-phenyl-3-[(oxacyclohexan-2-yl)oxy]propane-2-one, 1-phenyl-3-methoxypropane-2-one products and 1-(benzyloxy)-3-phenylpropane-2-one products)

[0178] After GP1, GP2, and GP4-GP6, the resulting mixture was cooled to room temperature and filtered through a thin-layer silica / diatomaceous earth filter plate (saturated with hexane and eluted with ethyl acetate (~50 mL)). The collected eluent was then dried under vacuum to obtain the crude residue, which was dissolved in ethyl acetate and loaded onto either a silica-based rapid chromatography column or a normal-phase Silicycle SiliSep column. TM The product was then purified using a 10, 25, or 40 g column and eluted with a hexane-ethyl acetate mixture. The relevant UV-active column fractions were combined and dried under vacuum to obtain the target product for each case.

[0179] A-4.4. Post-processing method E (purification of 1-phenyl-3-[(oxecyclohexan-2-yl)oxy]propane-2-one product)

[0180] After GP1 with 0.48 mmol of aryl bromide, the resulting mixture was cooled to room temperature and filtered through a diatomaceous earth filter plate (using DCM as the eluent (~50 mL)). The collected eluent was then dried under vacuum to obtain a crude residue, which was dissolved in DCM and loaded into a normal-phase Silicycle SiliSep. TM The product was then purified using a 10g column and eluent mixture of methanol and DCM. The relevant UV-active column fractions were combined and dried under vacuum to obtain the target product for each case.

[0181] A-4.5. Post-processing method F (a process used to determine the GC-FID yield of IV-1 before deprotection and separation of I-1)

[0182] The following post-processing method is used in conjunction with post-processing method A or A” to obtain the catalytic reaction yield of (IV-1). Unless otherwise stated herein, after GP1 with 1.00 mmol of aryl bromide, the reactants are filtered through a silica / diatomaceous earth filter and eluted with ethyl acetate as described in post-processing method A or A”. The eluent is then transferred to a 50 mL graduated cylinder and brought to a final volume of 50 mL with ethyl acetate. Subsequently, using a 10 mL volumetric pipette, 5 mL of the eluent (10%) is transferred to a 4-fold screw-top flask, using o-xylene as an internal standard (12.1 μL, 0.1 mmol). A portion of the solution is then transferred to a GC flask for analysis. After GC injection, the remaining 5 mL of sample is combined with the eluent and the remainder of post-processing method A or A” is performed.

[0183] A-4.6. Post-processing method G (GC sample preparation process)

[0184] After GP1, GP2, and GP4-GP7 (scales of 0.12–0.24 mmol in (hetero)aryl halides) were performed at room temperature, 100 μL aliquots of the reaction mixture were loaded onto a small pipette filter (a Kimwipe column packed with diatomaceous earth and silica gel), eluted with ethyl acetate, and the eluent was collected in a GC flask. Based on data obtained from authentic materials, calibrated GC-FID estimates were given using o-xylene, mesitylene, or dodecylbenzene as internal standards.

[0185] A-5. Deprotection screening

[0186] A-5.1. Optimization process of deprotection / separation method (D1)

[0187] All deprotection methods used in this screening were performed from the same catalytic reaction (results summarized in Table S8). After GP1 with 4.00 mmol of aryl bromide, the reactants were filtered through a hexane-saturated silica / diatomaceous earth filter and eluted with ethyl acetate (~60 mL). The eluent was then transferred to a 100 mL graduated cylinder and brought to 80 mL with ethyl acetate. The solution was then transferred to beakers, and using a 10 mL volumetric pipette, 6 × 9.6 mL aliquots of the eluent (each equivalent to 0.48 mmol of aryl bromide reactant) were transferred to six 4-fold screw-top flasks. Thus, six variations of post-treatment method A were performed, referring to Experiments 1-6. For Experiments 7-10 (post-treatment methods A′, A′, B, and C), a similar procedure was performed using 4 × 4.8 mL aliquots of the eluent (each equivalent to 0.24 mmol of aryl bromide reactant). The remaining 2 mL of eluent (equivalent to 0.1 mmol of aryl bromide reactant) was then transferred to a 4-cell screw-top flask, using o-xylene as an internal standard (12.1 μL, 0.1 mmol). A portion of the solution was then transferred to a GC flask for analysis, and the GC-FID yield of IV-1 was determined to be 81%.

[0188] A-5.2. Optimization process of post-processing method C—Deprotection of IV-1 and III-1 using NaHSO4-SiO2 (C1)

[0189] In Table S9, (IV-1) (0.12 mmol), (III-1) (0.24 mmol), and 1 mL of 99% methanol were added to a 1-flask containing NaHSO4-SiO2 (18-100 mg) and a magnetic stirrer. For all experiments, the NaHSO4-SiO2 was used immediately after being removed from an oven set at 120 °C. The flasks were sealed with PTFE lined caps, wrapped with insulating tape, and placed in a temperature-controlled aluminum heater set to a specific temperature, and allowed to react at 900 rpm for 15 minutes to 48 hours.

[0190] B. Implementation Examples

[0191] B-1. Screening Results

[0192] Table S1. Screening of auxiliary ligands involved in the cross-coupling reaction of 3-chloro-4-bromotoluene

[0193]

[0194]

[0195] condition: a Three parallel experiments were conducted; data were taken as the average of the three reactions. b 1 mol% [Pd(cinnamyl)Cl]2 (2 mol% Pd) and 2.5 mol% ligand, reaction d 18 hours. Yields were determined using standard samples based on GC data calibrated with response factor. Three parallel experiments were conducted, and data were taken as the average of the three reactions. b 1 mol% [Pd(cinnamyl)Cl]2 (2 mol% Pd) and 2.5 mol% ligand.

[0196]

[0197] Table S2: Screening of protecting groups involved in the cross-coupling reaction of 3-chloro-4-bromotoluene

[0198]

[0199] PG = Bn,Me

[0200] experiment PG IIa Remaining (IVa) <![CDATA[Other products a <!-- 17 -->]]> 1 Bn 13％ 65％ (IV-8): 20% 2 Me 14％ 64％ (IV-9): 25%

[0201] Yields were recorded using standard samples and GC data calibrated to the response factor. The α value is the sum of the ArH yield and the yield of additional unwanted α-arylated products (based on GC retention time), using the product's response factor as a calibration estimate. Neopentanoyl, acetate, and SiMe2(tBu) protecting groups were found to be unsuitable for the reaction conditions and no products were generated.

[0202] Table S3. Screening of bases, solvents, and additives involved in the cross-coupling reaction of 3-chloro-4-bromotoluene

[0203]

[0204]

[0205]

[0206] Yields were recorded using standard samples and GC data calibrated to the response factor. aTBAB additive (0.25 equivalents). b NaTFA additive (2 equivalents). c NaOTf additive (2 equivalents). d with a 1:1 solvent mixture of 1,4-dioxane.

[0207] Table S4. Other optimization experiments: Time and loading are related to base and solvent.

[0208]

[0209]

[0210]

[0211] Yields were recorded based on GC data calibrated using standard samples and response factor. Similar reactivity was observed under the following conditions: 0.36 M, using 1,4-dioxane or 4-MeTHP as solvent, at 110 °C (5 h); or 0.48 M, using 1,4-dioxane as solvent (100 °C, 3 h). For moderately scaled-up reactions, when carried out at 4 mmol of aryl bromide (0.36 M in 1,4-dioxane), using [Pd(cinnamyl)Cl]₂ (1.25% palladium), PhPF-tBu (1.5%), Cs₂CO₃ (2 equivalents), and THP-protected hydroxyacetone (3 equivalents), at 110 °C – 81% yield (IV-1) was obtained after 4.5 h. b In all cases, when using less than two equivalents of Cs2CO3, the yield of (IV-1) was significantly reduced (<65%), even under other optimized conditions.

[0212] Table S5. Summary of some optimized conditions for the production of IV-1 from 3-chloro-4-bromotoluene

[0213]

[0214] The yield was recorded using standard samples and GC data calibrated based on the response factor. a 100℃ b [Pd(cinnamyl)Cl]2 (1.25% Pd), PhPF-tBu (2.5%).

[0215] Table S6. Screening of conditions for the cross-coupling reaction involving the formation of 2-chloro-4-methylphenyltrifluoromethanesulfonate and THP-protected hydroxyacetone (IV-1).

[0216]

[0217]

[0218] The reaction procedure was as described in GP3. Yields were recorded based on GC data calibrated to the response factor, using standard samples. No reaction was observed without DBU (2 equivalents). However, the data in the table below confirm that a significant conversion to (IV-1) can be achieved even with amounts as low as 0.1 equivalents of NaOTf.

[0219] experiment NaOTf equivalent (IV-1) (II-1) Remaining <![CDATA[(II-1)-X 1 ]]> 1 0 0％ 58％ 0％ 2 0.1 58％ 11％ 6％ 3 0.25 69％ 3％ 14％ 4 0.5 75％ 0％ 10％ 5 1 80％ 0％ 7％ 6 1.5 86％ 0％ 8％

[0220] Table S7. Investigating the effect of salt additives in the cross-coupling of 2-chloro-4-methylphenyltrifluoromethanesulfonate with THP-protected hydroxyacetone to generate (IV-1).

[0221]

[0222] experiment Salt additives Ether additives (IV-1) (II-1) Remaining <![CDATA[(IIa)-X 1 ]]> 1 NaTFA - 89％ 0％ 0％ 2 NaOTf - 90％ 0％ 8％ 3 KOTf - 88％ 6％ 4％ 4 LiOTf - 13％ 24％ 31％ 5 AgOTf - 0％ 3％ 0％ 6 AgTFA - 0％ 72％ 0％ 7 <![CDATA[[nBu4N]OTf]]> - 4％ 95％ 0％ 8 NaCl - 2％ 65％ 0％ 9 LiCl - 8％ 58％ 0％ 10 KCl - 0％ 0％ 0％ 11 NaOAc - 8％ 22％ 9％ 12 KOAc - 7％ 55％ 6％ 13 <![CDATA[NaPF6]]> - 72％ 0％ 11％ 14 <![CDATA[NaOTf / [nBu4N]OTf]]> - 18％ 0％ 11％ 15 NaCl / LiOTf - 10％ 17％ 15％ 16 NaOTf 18-crown-6 65％ 3％ 12％ 17 KOTf 18-crown-6 40％ 20％ 10％

[0223] Yields were recorded using standard samples based on GC data calibrated to the response factor; no reaction was observed without DBU (2 equivalents).

[0224] Table S8. Generation of optimization (IV-1), and subsequent deprotection generation (I-1).

[0225]

[0226] Post-processing method:

[0227] A: HCl (2.5-5 equivalents), H2O (0.048-0.096 M) 95℃, 10 min

[0228] B: 10% HCl / 1,4-dioxane

[0229] C: NaHSO4-SiO2, methanol

[0230]

[0231] a HCl and water were added as a 10% HCl solution (2 ml). Both A' and A” used the optimized conditions of A (Experiment 2), but the difference is that A' and A” include a chromatographic purification step, while A does not. Furthermore, A” does not include a thermogravimetric filtration step. For complete details, please refer to the experimental instructions related to these post-processing methods.

[0232] Table S9. Deprotection of (IV-1) and (III-1) using NaHSO4-SiO2 (Optimization of post-treatment method C)

[0233]

[0234]

[0235] The yield was recorded using standard samples and GC data calibrated based on the response factor.

[0236] B.2 Example

[0237] Example (III-1): 1-[(oxacyclohexane-2-yl)oxy]-2-propanone

[0238]

[0239] The title compound was prepared using a modified method from the referenced publication (Kim, DS et al., Bioorg Med Chem Lett 2001, 11(18), 2541-3) (using 1.5 equivalents of 3,4-dihydro-2H-pyran instead of 2.0 equivalents). Hydroxyacetone (2.05 mL, 30 mmol, 1.0 equivalent) and 3,4-dihydro-2H-pyran (4.11 mL, 45 mmol, 1.5 equivalent) were added to a 40 mL vial containing pyridinium p-toluenesulfonate (0.754 g, 3 mmol, 0.1 equivalent), a magnetic stir bar, and 25 mL of anhydrous DCM. The vial was sealed with a PTFE-lined cap, wrapped with insulating tape, removed from the glove box, and placed in a temperature-controlled aluminum heater set to 50 °C, where it was reacted with magnetic stirring at 900 rpm for 18 hours. Purification was performed on silica using rapid column chromatography with a gradient elution of hexane containing 10% ethyl acetate. The fractions were stained with vanillin, combined, and the solvent was removed under vacuum to give the title compound as a clear oil in 72% (3.41 g, 21.6 mmol) separation. 1 H NMR (300MHz, CDCl3) δ4.68-4.59 (m, 1H), 4.24 (d, J = 17.3Hz, 1H), 4.10 (d, J = 17. 3Hz,1H),3.90-3.74(m,1H),3.57-3.44(m,1H),2.17(s,3H),1.97-1.42(m,5H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ206.86,98.90,72.47,62.50,30.41,26.63,25.40,19.31.

[0240] Example (III-2): 3-[(oxacyclohexane-2-yl)oxy]-2-butanone

[0241]

[0242] 3-Hydroxy-2-butanone (1.02 mL, 12.5 mmol, 1.0 equivalent) and 3,4-dihydro-2H-pyran (2.28 mL, 25 mmol, 2 equivalent) were added to a 40 mL vial containing pyridinium p-toluenesulfonate (0.314 g, 1.25 mmol, 0.1 equivalent), a magnetic stir bar, and 25 mL of anhydrous DMC. The vial was sealed with a PTFE-lined cap, wrapped with insulating tape, and then removed from the glove box and placed in a temperature-controlled aluminum heater set to 50 °C, where it was reacted with magnetic stirring at 900 rpm for 18 hours. The homogeneous reaction mixture was then dried under vacuum and loaded onto silica, and subsequently loaded into a normal-phase Biotage SNAP KP-Sil 100 g column. Purification was performed on silica using rapid column chromatography with a gradient elution using hexane containing 5% ethyl acetate (1CV), hexane containing 5-15% ethyl acetate (10CV), followed by hexane containing 15% ethyl acetate (2CV). Staining with vanillin, the relevant fractions were combined, and the solvent was removed under vacuum to give the title compound as a clear oil, a 1:0.08 diastereomer mixture, in a separation yield of 42% (0.901 g, 5.23 mmol). The diastereomer ratio was determined by the ratio of the proton integrals of -CH-CH3 as shown in the 1H NMR spectrum. The following are listed... 1 H and 13 C{ 1 H NMR peaks correspond to the main set of diastereomers, in 1 There is considerable overlap between the diastereomeric peaks in the H NMR spectrum. 1 H NMR (300MHz, CDCl3) δ4.57 (dd, J=4.5, 2.9Hz, 1H), 4.25 (q, J=7.0Hz, 1H), 3.92-3.7 9(m,1H),3.56-3.42(m,1H),2.15(s,3H),1.96-1.46(m,8H),1.36(d,J=7.0Hz,3H). 13 C{ 1 H}NMR (75MHz, CDCl3) δ210.91,98.61,77.91,62.87,30.82,25.56,25.45,19.57,18.22. HRMS-ESI(m / z):C9H 16 NaO3[M+Na] + Calculated value: 195.0992; Measured value: 195.0992.

[0243] Example (II-1): 2-Chloro-4-methylphenyltrifluoromethanesulfonate

[0244]

[0245] The title compound was synthesized from the corresponding phenol (5.4 mmol) according to GP3, with a separation yield of 96% (1.43 g, 5.2 mmol) of the title compound as a dark red oil. 1 HNMR (500MHz, CDCl3) δ7.33-7.32(m,1H),7.22(d,J=8.4Hz,1H),7.14-7.12(m,1H),2.37(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ143.69,140.02,131.73,129.03,126.84,122.69,118.80(q,J CF =320.5Hz), 20.88. 19 F NMR (471MHz CDCl3) δ-73.55. HRMS-ESI(m / z):C8H6ClF3NaO3S[M+Na] + Calculated value: 296.9576; Measured value: 296.9570.

[0246] Example (II-2): 4-Chloro-2-methylphenyltrifluoromethanesulfonate

[0247]

[0248] The title compound was synthesized from the corresponding phenol (5.4 mmol) according to GP3, with a separation yield of 98% (1.45 g, 5.3 mmol) of the title compound as a deep red oil. 1 HNMR (500MHz, CDCl3) δ7.30 (d, J = 2.6 Hz, 1H), 7.23 (d, J = 8.8, 2.6, 0.5 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 2.36 (s, 3H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ152.92(d,J CF =252.0Hz),134.36(m),130.10(m),129.15,118.76(q,J CF =320.3Hz),114.98,114.88,19.95. 19 F NMR(471MHz CDCl3)δ-73.03(d,J FF =11Hz), -126.16(q,J FF=11Hz). HRMS-ESI(m / z):C8H6ClF3NaO3S[M+Na] + Calculated value: 296.9577; Measured value: 296.9568.

[0249] Example (II-3): 2-Chloro-6-fluoro-3-methylphenyltrifluoromethanesulfonate

[0250]

[0251] The title compound was synthesized from the corresponding phenol (5.4 mmol) according to GP3, with a separation yield of 95% (1.64 g, 5.1 mmol) of the title compound as a deep red oil. 1 HNMR (500MHz, CDCl3) δ7.23 (dd, J=8.7, 5.5, 1H), 7.09 (t, J=8.9Hz, 1H), 2.41 (s, 3H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ152.93(m),134.36(m),130.10(m),129.15,118.70(q,J CF =321Hz),115.13,114.98,19.95. 19 F NMR(471MHz CDCl3)δ-73.04(d,J FF =11Hz), -126.18(q,J FF =11Hz). HRMS-ESI(m / z):C8H5ClF4NaO3S[M+Na] + Calculated value: 314.9482; Measured value: 314.9476.

[0252] Example (II-4): 4-chloro-2-cyclohexylphenyl trifluoromethanesulfonate

[0253]

[0254] The title compound was synthesized from the corresponding phenol (5.4 mmol) according to GP3, with a separation yield of 77% (1.43 g, 4.2 mmol) of the title compound as a dark red oil. 1 HNMR(500MHz,CDCl3)δ7.34(d,J=2.5,1H),7.22(d,J=8.8,2.5Hz,1H),7.17 (d,J=8.8Hz,1H),2.87-2.83(m,1H),1.90-1.81(m,5H),1.48-1.30(m,5H). 13C{ 1 H}NMR(126MHz,CDCl3)δ145.55,142.41,134.42,128.82,127.52,126.74(q,J CF =92Hz),122.72,37.77,35.55,26.68,26.01. 19 F NMR (471MHz CDCl3) δ-73.78. HRMS-ESI(m / z):C 13 H 14 ClF3NaO3S[M+Na] + Calculated value: 365.0202. Measured value: 365.0210.

[0255] Example (II-5): 2-Chloro-4-methylphenylfluorosulfonate

[0256]

[0257] In a round-bottom flask equipped with a PTFE-coated stir bar and a rubber diaphragm, 2-chloro-4-methylphenol (20.0 g, 136.1 mmol, 1.0 equivalent), diisopropylethylamine (52.6 g, 129.3 mmol, 3.0 equivalent), and acetonitrile (312 g) were charged. The flask was evacuated under vacuum and then backfilled with thioyl fluoride. The reaction mixture was then stirred at room temperature for 4 hours, at which point HPLC analysis showed complete consumption of the starting material. The remaining thioyl fluoride was removed under vacuum (equipped with a gas scrubber). The acetonitrile was removed using a rotary evaporator. The reaction mixture was diluted with ethyl acetate (100 mL), transferred to a separatory funnel, and washed twice with water (2 × 100 mL), followed by washing with brine (2 × 50 mL). The product was then purified by distillation (65 °C, 8 mbar to 85 °C, 6 mbar), yielding the title compound with a purity of 97% and a yield of 85.6%.

[0258] 1 H NMR (400MHz, CDCl3) δ7.31 (dd, J=8.4, 1.4Hz, 1H), 7.31 (dd, J=8.4, 1.4Hz, 1H), 7.17-7.13 (m, 1H), 2.38 (s, 3H).

[0259] Example (I-1): 1-(2-chloro-4-methylphenyl)-3-hydroxypropane-2-one

[0260]

[0261] The title compound was synthesized using three different methods. Method 1. The THP-protected analog of the title compound was synthesized according to GP1 from the corresponding aryl bromide (4 mmol) in 1,4-dioxane (0.36 M) at 110 °C in a four-valve screw-top flask containing 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu, providing IV-1, with a yield of 81%, as determined by calibrated GC analysis. Deprotection / purification was performed according to post-treatment method A at a scale of 0.48 mmol (screening D1, experiment 2), providing a 68% (0.065 g, 0.327 mmol) isolated title compound as a white crystalline solid. Method 2. The THP-protected analogue of the title compound was synthesized according to GP1 from the corresponding aryl bromide (1 mmol) in 4-MeTHP (0.36 M) at 110 °C for 4 h using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu, providing IV-1, yielding 86%, as determined by calibrated GC analysis via post-treatment method F. Deprotection / purification was performed according to post-treatment method A”, using 400 μL of concentrated hydrochloric acid and 15 mL of H2O (0.67 M). The chromatogram was obtained by rapid chromatography on silica using Silicycle SiliSep. TMPurification was performed using a 40 g column with an elution gradient of DCM containing 0% methanol (2 CV), followed by DCM containing 0–4% methanol (20 CV), thereby providing a 75% isolated title compound (0.148 g, 0.745 mmol) as a white solid. Method 3. Experimental synthesis of the title compound: 4-bromo-3-chlorotoluene (1.0 mmol, 1.0 equivalent), 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (3 equivalents) and 4-MeTHP (2.8 mL, pretreated as generally considered, but here carried out in air, 0.36 M) were added to a 4-duralumin vial. Subsequently, 0.625 mol% [Pd(cinnamyl)Cl]₂ (1.25 mol% Pd), 1.5 mol% PhPF-tBu, and Cs₂CO₃ (2 equivalents) were added to a 1-dozen-valve equipped with a magnetic stirrer. Both vials were sealed in air with PTFE-lined caps, wrapped with insulating tape, and placed in a temperature-controlled aluminum heater set to 25°C. The 4-MeTHP solution was purged with N₂ through an inserted needle for 5 minutes, while the 1-dozen-valve was purged with N₂ through an inserted needle (the needle remained inserted to provide positive pressure nitrogen throughout the reaction). Under continuous nitrogen pressure, the 4-MeTHP solution was transferred to the 1-dozen-valve via a syringe. The mixture was reacted under positive nitrogen pressure at 110°C and magnetic stirring at 900 rpm for 4 hours, yielding IV⁻¹ in 81% yield, as determined by calibrated GC analysis via post-treatment method F. Deprotection / purification was performed according to post-treatment method A”, using 400 μL of concentrated hydrochloric acid and 15 mL of H2O (0.67 M). The purification was carried out by rapid chromatography on silica using Silicycle SiliSep. TM Purification was performed using a 40 g column with an elution gradient of DCM containing 0% methanol (2 CV) followed by DCM containing 0-4% methanol (20 CV), thereby providing a separation of the title compound (0.129 g, 0.745 mmol) as a white solid in 65% yield. 1 HNMR (300MHz, CDCl3) δ7.22(d,J=1.7Hz,1H),7.13(d,J=7.7Hz,1H),7.05(dd,J=7.6,1.9Hz,1H),4.31(s,2H),3.81(s,2H),2.89(s,1H),2.33(s,3H). 13 C{ 1H} NMR (75MHz, CDCl3, 0.05% (v / v) TMS) δ 206.73, 139.56, 134.08, 131.54, 130.32, 128.20, 68.11, 43.31, 20.97. HRMS-ESI(m / z):C 10 H 11 ClNaO2[M+Na] + Calculated value: 221.0340; Measured value: 221.0337.

[0262] Example (I-2): 1-(2-chloro-4-fluorophenyl)-3-hydroxypropane-2-one

[0263]

[0264] The THP-protected analogue of the title compound was synthesized according to GP1 from the corresponding aryl bromide (0.48 mmol) at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu, and protection / purification was performed according to a variation of post-treatment method A. After cooling to room temperature, the aqueous eluent was extracted with 3 × 5 mL DCM, and the solvent was removed under vacuum. Then, 2 mL of water was added to the resulting crude oil, and the mixture was heated on a hot plate while being rapidly swirled until homogeneous. The mixture was cooled to room temperature and then placed in a refrigerator set to 3 °C overnight to give the title compound (0.038 g, 0.188 mmol) as a white crystalline solid in a 39% isolated yield. Alternatively, deprotection / purification can be performed using post-treatment method A'. The protection / purification was carried out by rapid column chromatography on silica using 10 g Silicycle SiliSep. TM Purification was performed using a 10 g column with an elution gradient of DCM containing 0% methanol (2 CV) followed by DCM containing 0-4% methanol (20 CV), thereby providing a separation of the title compound as a white solid in a 52% yield (0.051 g, 0.252 mmol). 1 H NMR (300MHz, CDCl3, 0.05% (v / v) TMS) δ7.27-7.12 (m, 2H), 7.00 (td, J = 8.2, 2.6Hz, 1H), 4.35 (d, J = 4.3Hz, 2H), 3.83 (s, 2H), 2.98 (t, J = 4.9Hz, 1H). 13 C{ 1 H}NMR (75MHz, CDCl3, 0.05% (v / v) TMS) δ206.10,162.01(d,J CF=248Hz), 132.75(d,J CF =15Hz), 127.34, 117.47-117.14 (overlap), 114.69 (d, J) CF =35Hz), 68.23, 42.76. 19 F NMR (282MHz, CDCl3, 0.05% (v / v) TMS) δ-112.08. HRMS-ESI(m / z):C9H8ClFNaO2[M+Na] + Calculated value: 225.0089; Measured value: 225.0089.

[0265] Example (I-3): 1-[2-chloro-5-(trifluoromethyl)phenyl]-3-hydroxypropane-2-one

[0266]

[0267] The THP-protected analogue of the title compound was synthesized according to GP1 from the corresponding aryl bromide (0.48 mmol) at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu. Deprotection / purification was performed according to post-treatment method A using 8 mL of water (0.06 M), yielding a 35% isolated title compound (0.042 g, 0.166 mmol) as a white crystalline solid. Alternatively, deprotection / purification can be performed using post-treatment method A'. The separation was achieved by rapid column chromatography on silica using SilicycleSiliSep. TM Purification was performed using a 10 g column with an elution gradient of DCM containing 0% methanol (2 CV) followed by DCM containing 0-4% methanol (20 CV), thereby providing a separation of the title compound (0.060 g, 0.238 mmol) as a white solid in a 49% yield. 1 H NMR (300MHz, CDCl3, 0.05% (v / v) TMS) δ 7.58-7.47 (m, 3H), 4.39 (d, J = 4.9Hz, 2H), 3.92 (s, 2H), 2.99 (t, J = 4.9Hz, 1H). 13 C{ 1 ¹H NMR (75MHz, CDCl₃, 0.05% (v / v) TMS) δ 205.24, 138.30, 132.52, 130.35–128.76 (overlap), 126.00, 126.08, 123.03 (q, J) CF =330Hz), 68.38, 43.29. 19F NMR (282MHz, CDCl3, 0.05% (v / v) TMS) δ-62.61.HRMS-ESI (m / z): C9H7ClF3O2[MH] - Calculated value: 251.0092; Measured value: 251.0091.

[0268] Example (I-4): 1-(2-chloro-4-methoxyphenyl)-3-hydroxypropane-2-one

[0269]

[0270] The THP-protected analogue of the title compound was synthesized according to GP1 from the corresponding aryl bromide (0.48 mmol) at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu. Deprotection / purification was performed according to post-treatment method A using 8 mL of water (0.06 M), yielding a 51% isolated title compound (0.053 g, 0.247 mmol) as a white crystalline solid. Alternatively, deprotection / purification can be performed using post-treatment method A”. The separation was achieved by rapid column chromatography on silica using SilicycleSiliSep. TM Purification was performed using a 10 g column with an elution gradient of DCM containing 0% methanol (2 CV) followed by DCM containing 0-4% methanol (20 CV), thereby providing a separation of the title compound (0.068 g, 0.317 mmol) as a white solid in a yield of 66%. 1 H NMR (300MHz, CDCl3, 0.05% (v / v) TMS) δ7.15 (d, J = 8.5Hz, 1H), 6.96 (d, J = 2.6Hz, 1H), 6.8 0(dd,J=8.5,2.6Hz,1H),4.30(d,J=4.8Hz,2H),3.83-3.76(m,5H),3.02(t,J=4.8Hz,1H. 13 C{ 1 H} NMR (75MHz, CDCl3, 0.05% (v / v) TMS) δ 206.92, 159.89, 134.92, 132.25, 123.20, 115.22, 113.52, 68.07, 55.70, 42.88. HRMS-ESI(m / z):C 10 H 11 ClNaO3[M+Na] + Calculated value: 237.0289; Measured value: 237.0289.

[0271] Example (I-5): 1-(2,4-dichlorophenyl)-3-hydroxypropane-2-one

[0272]

[0273] Method 1. The THP-protected analogue of the title compound was synthesized according to GP1 from the corresponding aryl bromide (0.48 mmol) at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu. Deprotection / purification was performed according to post-treatment method A using 8 mL of water (0.06 M), yielding a 55% separation of the title compound (0.058 g, 0.265 mmol) as a white crystalline solid. Method 2. Deprotection / purification was performed using the same catalytic process as described above, with post-treatment method A”. This was achieved by rapid column chromatography on silica using Silicycle SiliSep. TM Purification was performed using a 10g column with an elution gradient of DCM (2CV) containing 0% methanol followed by DCM (20CV) containing 0-4% methanol, thus providing a 72% isolated title compound (0.076g, 0.347mmol) as a white solid. Method 3. The THP-protected analog of the title compound was synthesized according to GP4 from the corresponding aryl bromide (0.48mmol) at 90°C using 1 mol% [Pd(cinnamyl)Cl]2 (2 mol% Pd) and 2.5 mol% (4-CF3Ph)PF-tBu, and deprotection / purification was performed according to post-treatment method B. This was achieved by rapid column chromatography on silica using Silicycle SiliSep. TM Purification was performed using a 10 g column with an elution gradient of DCM containing 0% methanol (2 CV) followed by DCM containing 0-4% methanol (20 CV), thereby providing a separation of the title compound (0.086 g, 0.393 mmol) as a white solid in 82% yield. 1 H NMR (300MHz, CDCl3, 0.05% (v / v) TMS) δ7.43 (d, J = 2.0Hz, 1H), 7.30-7.15 (m, 2H), 4.35 (d, J = 4.9Hz, 2H), 3.83 (s, 2H), 2.98 (t, J = 4.9Hz, 1H). 13 C{ 1H} NMR (75MHz, CDCl3, 0.05% (v / v) TMS) δ 205.79, 135.12, 134.48, 132.60, 129.99, 129.70, 127.69, 68.28, 42.91. HRMS-ESI(m / z):C 10 H7Cl2O2[MH] - Calculated value: 216.9829; Measured value: 216.9828.

[0274] Example (I-6): 1-Hydroxy-3-(naphth-1-yl)propane-2-one

[0275]

[0276] The THP-protected analogue of the title compound was synthesized according to GP1 from the corresponding aryl bromide (0.48 mmol) at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu. Deprotection / purification was performed according to post-treatment method A, which yielded the title compound (0.058 g, 0.290 mmol) in a white crystalline solid in a 60% isolated yield. 1 H NMR (500MHz, CDCl3) δ7.92-7.81(m,3H),7.58-7.48(m,2H),7.45(dd,J=8.1,7.0Hz,1H) ,7.40(dd,J=6.9,1.2Hz,1H),4.25(d,J=4.5Hz,2H),4.19(s,2H),2.98(t,J=4.8Hz,1H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ207.88,134.11,132.10,129.36,129.11,128.75,128.47,126.98,126.28,125.70,123.55,67.64,44.28. HRMS-ESI(m / z):C 13 H 12 NaO2[M+Na] + Calculated value: 223.0730; Measured value: 223.0731.

[0277] Example (I-7): 1-Hydroxy-3-(2-methoxy-4-methylphenyl)propane-2-one

[0278]

[0279] The THP-protected analogue of the title compound was synthesized according to GP1 from the corresponding aryl bromide (0.48 mmol) at 90 °C with 1.25 mol% [Pd(cinnamyl)Cl]2 (2.5 mol% Pd) and 3 mol% PhPF-tBu for 12 h, and deprotection / purification was performed according to post-treatment method A”. The deprotection / purification was carried out by rapid chromatography on silica using Silicycle SiliSep. TM Purification was performed using a 40 g column with an elution gradient of 0% ethyl acetate in hexane (2 CV), followed by 15-50% ethyl acetate in hexane (15 CV), which provided a clear oily separation of the title compound in 70% yield (0.076 g, 0.347 mmol). 1 H NMR (300MHz, CDCl3) δ7.03 (d, J = 7.5Hz, 1H), 6.79-6.66 (m, 2H), 4.25 (s, 2H), 3.79 (s, 3H), 3.65 (s, 2H), 3.00 (br s, 1H), 2.35 (s, 3H). 13 C{ 1 H}NMR (75MHz, CDCl3) δ208.46,157.16,139.29,131.09,121.55,118.87,111.59,67.78,55.42,40.62,21.74. HRMS-ESI(m / z):C 11 H 14 NaO3[M+Na] + Calculated value: 217.0835; Measured value: 217.0835.

[0280] Example (I-8): 1-Hydroxy-3-[2-chloro-4-(4-methylpiperazin-1-yl)phenyl]propane-2-one

[0281]

[0282] The THP-protected analogue of the title compound was synthesized according to GP1 from the corresponding aryl bromide (0.24 mmol) at 110 °C using 0.75 mol% [Pd(cinnamyl)Cl]2 (1.5 mol% Pd) and 2 mol% PhPF-tBu, and deprotection / purification was performed according to a variation of post-treatment method A'. After thermogravimetric filtration and cooling to room temperature, the aqueous layer was extracted with 10 mL DCM, and the organic layer was discarded. The aqueous layer was then neutralized with saturated NaHCO3 solution and extracted with 3 × 10 mL DCM. The organic layers were combined and dried over Na2SO4. The solution was then analyzed by rapid column chromatography on silica using Silicycle SiliSep.TM Purification was performed using a 10 g column with an elution gradient of DCM (2 CV) containing 0% methanol followed by hexane (20 CV) containing 0-20% ethyl acetate, which provided a separation of the title compound (0.040 g, 0.141 mmol) in 59% as a white solid. 1 H NMR (500MHz, CDCl3) δ7.10(d,J=8.5Hz,1H),6.92(d,J=2.6Hz,1H),6.78(dd,J=8.5,2. 6Hz,1H),4.29(s,2H),3.75(s,2H),3.24-3.18(m,4H),2.59-2.53(m,4H),2.35(s,3H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ207.27,151.81,135.05,132.02,121.25,116.49,114.63,68.02,54.97,48.54,46.21,42.94. HRMS-ESI(m / z):C 14 H 20 ClN2O2[M+H] + Calculated value: 283.1208; Measured value: 283.1206.

[0283] Example (I-9): 1-Hydroxy-1-methyl-3-(naphth-2-yl)propane-2-one

[0284]

[0285] The THP-protected analogue of the title compound was synthesized according to GP1 from the corresponding aryl bromide (0.24 mmol) at 90 °C using 0.75 mol% [Pd(cinnamyl)Cl]2 (1.5 mol% Pd) and 2 mol% PhPF-tBu, and deprotection / purification was performed according to post-treatment method C. The synthesis was carried out by rapid column chromatography on silica using Silicycle SiliSep. TM Purification was performed using a 10 g column with an elution gradient of hexane containing 0% ethyl acetate (2 CV) followed by hexane containing 15-50% ethyl acetate (15 CV), which provided a separation of the title compound (0.029 g, 0.271 mmol) in 56% yield as a white solid. 1H NMR (300MHz, CDCl3) δ7.88-7.74(m,3H),7.71-7.64(m,1H),7.55-7.43(m,2H),7.32(dd,J=8.4,1.8H z, 1H), 4.40 (qd, J = 7.0, 4.0Hz, 1H), 4.06-3.88 (m, 2H), 3.43 (d, J = 4.8Hz, 1H), 1.46 (d, J = 7.1Hz, 3H). 13 C{ 1 H}NMR (75MHz, CDCl3) δ210.25,133.67,132.70,130.70,128.75,128.44,127.91,127.82,127.48,126.57,126.24,72.52,44.98,20.08. HRMS-ESI(m / z):C 14 H 14 NaO2[M+Na] + Calculated value: 237.0886; Measured value: 237.0884.

[0286] Example (IV-1): 1-(4-chloro-2-methylphenyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-one

[0287]

[0288] The title compound was synthesized according to GP1 from the corresponding aryl bromide (0.26 mmol) at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu, and purified according to post-treatment method D. The purification was performed by rapid column chromatography on silica using Silicycle SiliSep. TM10 g was purified by an elution gradient of hexane containing 0% ethyl acetate (2 CV), followed by hexane containing 0-20% ethyl acetate (20 CV), which provided a clear oily separation of the title compound (0.054 g, 0.191 mmol) in 73% yield. Furthermore, the title compound was synthesized according to GP2 from the corresponding aryl trifluoromethanesulfonate (0.48 mmol) at 120 °C using 2.5 mol% [Pd(cinnamyl)Cl]2 (5 mol% Pd) and 6.25 mol% (4-CF3Ph)PF-tBu, and purification was performed according to post-treatment method D. Purification was then performed by rapid column chromatography on silica using hexane containing 10% ethyl acetate, providing a pale yellow oily separation of the title compound (0.097 g, 0.343 mmol) in 71% yield. The title compound can also be synthesized using GP1 or GP2 from the corresponding fluorosulfonate (II-5) in yields of 50% and 25%, respectively. 1 H NMR (500MHz, CDCl3, 0.05% (v / v) TMS) δ7.21 (d, J = 1.7Hz, 1H), 7.10 (d, J = 7.8Hz, 1H), 7.03 (dd, J = 7.8, 1.7Hz, 1H), 4.65 (t, J = 3.6Hz, 1H ), 4.34 (d, J = 17.3Hz, 1H), 4.22 (d, J = 17.3Hz, 1H), 3.90 (s, 2H), 3.88-3.79 (m, 1H), 3.55-3.47 (m, 1H), 2.31 (s, 3H), 1.93-1.50 (m, 6H). 13 C{ 1 H}NMR (75MHz, CDCl3) δ205.17,138.89,134.12,131.55,130.07,129.14,127.88,98.96,72.00,62.43,43.85,30.36,25.38,20.89,19.24. HRMS-ESI(m / z):C 15 H 19 ClNaO3[M+Na] + Calculated value: 305.0915; Measured value: 305.0914.

[0289] Example (IV-2): 1-[(oxacyclohexan-2-yl)oxy]-3-[4-(trifluoromethyl)pyridin-3-yl]propane-2-one

[0290]

[0291] The title compound was synthesized according to GP1 from the corresponding aryl bromide (0.24 mmol) at 90 °C using 0.75 mol% [Pd(cinnamyl)Cl]2 (1.5 mol% Pd) and 2.5 mol% PhPF-tBu, and purified according to post-treatment method D. The purification was performed by rapid column chromatography on silica using 10 g Silicycle SiliSep. TM Purification was performed using a rapid column chromatography with an elution gradient of hexane containing 0% ethyl acetate (2CV) followed by hexane containing 15-50% ethyl acetate (18CV), which provided a separation of the title compound (0.063 g, 0.208 mmol) in a pale yellow oil in 87% yield. 1 H NMR (300MHz, CDCl3) δ8.69 (d, J=5.1Hz, 1H), 8.56 (s, 1H), 7.52 (d, J=5.1Hz, 1H), 4.65 (dd, J= 4.7,2.6Hz,1H),4.40-4.00(m,4H),3.92-3.79(m,1H),3.63-3.45(m,1H),1.97-1.47(m,6H). 13 C{ 1 H}NMR(75MHz,CDCl3)δ204.46,153.99,149.37,136.83(q,J CF =31.5Hz), 127.02, 123.10(q,J) CF =273Hz),119.74,99.60,72.44,62.94,40.64,30.46,25.32,19.53. 19 F NMR (282MHz, CDCl3) δ-62.36. HRMS-ESI(m / z):C 14 H 15 F3NO2[MH] - Calculated value: 302.1010; Measured value: 302.1017.

[0292] Example (IV-3): 1-[2-chloro-4-(4-methylpiperazin-1-yl)phenyl]-3-[(oxacyclohexan-2-yl)oxy]propane-2-one

[0293]

[0294] The title compound was synthesized according to GP4 from the corresponding aryl bromide (0.48 mmol) at 90 °C using 1.5 mol% [Pd(cinnamyl)Cl]2 (3 mol% Pd) and 3.75 mol% (4-CF3Ph) PF-tBu, and purified according to post-treatment method E. The purification was performed by rapid column chromatography on silica using 10 g SilicycleSiliSep. TM Purification was performed using a rapid column chromatography with an elution gradient of DCM containing 0% methanol (2CV) followed by DCM containing 0–10% methanol (24CV), which provided a pale green oily separation of the title compound in 83% yield (0.146 g, 0.398 mmol). 1 H NMR (300MHz, CDCl3, 0.05% (v / v) TMS) δ7.07 (d, J = 8.5Hz, 1H), 6.91 (d, J = 2.6Hz, 1H), 6.77 (dd, J = 8.5, 2.6Hz, 1H), 4.64 (t, J = 3.4Hz, 1H), 4.33 (d, J = 17.3Hz,1H),4.20(d,J=17.3Hz,1H),3.87-3.77(m,3H),3.56-3.43(m,1H ),3.24-3.15(m,4H),2.60-2.50(m,5H),2.34(s,3H),1.97-1.46(m,6H). 13 C{ 1 H NMR (75MHz, CDCl3, 0.05% (v / v) TMS) δ 205.58, 151.50, 135.06, 132.03, 122.39, 116.51, 114.59, 98.93, 71.92, 62.42, 55.03, 48.69, 46.23, 43.52, 30.39, 25.42, 19.25. We were unable to obtain HRMS data for this THP-protected product due to its rapid fragmentation in MS; we provide data for the unprotected product. HRMS-ESI (m / z): C 14 H 20 ClN2O2[M+H] + Calculated value: 283.1208; Measured value: 283.1205.

[0295] Example (IV-4): 1-(1-benzothiophene-4-yl)-3-[(oxacyclohexane-2-yl)oxy]propane-2-one

[0296]

[0297] The title compound was synthesized according to GP1 from the corresponding aryl bromide (0.24 mmol) at 100 °C in 1,4-dioxane (0.48 M) using 0.5 mol% [Pd(cinnamyl)Cl]2 (1 mol% Pd) and 1.5 mol% PhPF-tBu, and purified according to post-treatment method D. The purification was performed by rapid column chromatography on silica using 10 g Silicycle SiliSep. TM Purification was performed using a rapid column chromatography with an elution gradient of hexane containing 0% ethyl acetate (2CV) followed by hexane containing 0-30% ethyl acetate (24CV), which provided a clear, oily separation of the title compound in 92% yield (0.064 g, 0.220 mmol). 1 H NMR (300MHz, CDCl3) δ7.81(dt,J=8.0,1.0Hz,1H),7.47(d,J=5.5Hz,1H),7.39(dd,J=5.6,0.9Hz,1H),7.35-7.26(m,1H),7.26-7.18(m,1H),4.5 8(dd,J=4.1,2.9Hz,1H),4.31(d,J=17.2Hz,1H),4.22-4.09(m,3H),3.8 3-3.67(m,1H),3.52-3.39(m,1H),1.94-1.53(m,3H),1.58-1.44(m,3H). 13 C{ 1 H}NMR(75MHz,CDCl3)δ205.80,140.44,139.24,128.68,126.85,125.85,1 24.48,122.00,121.80,99.17,71.75,62.54,45.16,30.39,25.36,19.34. HRMS-ESI(m / z):C 16 H 18 NaO3S[M+Na] + Calculated value: 313.0869; Measured value: 313.0867.

[0298] Example (IV-5): 1-(4-chloro-2-methylphenyl)-3-[(oxacyclohexan-2-yl)oxy]propane-2-one

[0299]

[0300] The title compound was synthesized according to GP2 from the corresponding aryl trifluoromethanesulfonate (0.48 mmol) at 120 °C using 2.5 mol% [Pd(cinnamyl)Cl]2 and 6.25 mol% (4-CF3Ph)PF-tBu, and purified according to post-treatment method D. Purification was performed by rapid column chromatography on silica using hexane containing 10% ethyl acetate, yielding a yellow oily separation of the title compound (0.100 g, 0.355 mmol) in 74% yield. 1 H NMR (500MHz, CDCl3) δ7.17(d,J=2.1Hz,1H),7.12(dd,J=8.1,2.1Hz,1H),7.04(d,J=8.1Hz,1H),4.61(dd,J=4.2,3.2Hz,1H),4.28( d,J=17.1Hz,1H),4.15(d,J=17.1Hz,1H),3.85-3.76(m,3H),3.52-3.48(m,1H),3.55-3.51(m,1H),2.21(s,3H),1.89-1.53(m,6H). 13 C{ 1 H}NMR (75MHz, CDCl3) δ205.75,139.00,133.00,131.72,131.08,130.36,126.26,99.30,72.10,62.72,43.84,30.43,25.35,19.67,19.43. HRMS-ESI(m / z):C 15 H 19 ClNaO3[M+Na] + Calculated value: 305.0915; Measured value: 305.0924.

[0301] Example (IV-6): 1-(2-chloro-6-fluoro-3-methylphenyl)-3-[(oxacyclohexan-2-yl)oxy]propane-2-one

[0302]

[0303] The title compound was synthesized according to GP2 from the corresponding aryl trifluoromethanesulfonate (0.48 mmol) at 120 °C using 2.5 mol% [Pd(cinnamyl)Cl]2 and 6.25 mol% (4-CF3Ph)PF-tBu, and purified according to post-treatment method D. Purification was performed by rapid column chromatography on silica using hexane containing 10% ethyl acetate, yielding a yellow oily separation of the title compound (0.087 g, 0.289 mmol) in 60% yield.1 H NMR (500MHz, CDCl3) δ7.13(dd,J=8.3,6.3Hz,1H),6.91(t,J=8.6Hz,1H),4.68(t,J=3.6Hz,1H),4.37(d,J=17.1Hz,1 H), 4.24 (d, J = 17.2Hz, 1H), 4.09-4.00 (m, 2H), 3.88-3.84 (m, 1H), 3.55-3.51 (m, 1H), 2.34 (s, 3H), 1.89-1.53 ​​(m, 6H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ204.12,159.86(d,J CF =246Hz), 135.46(d,J) CF =5.9Hz), 132.30(d,J CF =3.9Hz), 130.06(d,J CF =10.0Hz), 120.80(d,J CF =18.4Hz), 113.35(d,J CF =22.4Hz),99.05,72.14,62.51,37.94,30.41,25.41,20.33,19.29. 19 F NMR (471MHz CDCl3) δ-116.11. HRMS-ESI(m / z):C 15 H 18 ClFNaO3[M+Na] + Calculated value: 323.0821; Measured value: 332.0822.

[0304] Example (IV-7): 1-(4-chloro-2-cyclohexylphenyl)-3-[(oxacyclohexan-2-yl)oxy]propane-2-one

[0305]

[0306] The title compound was synthesized according to GP2 from the corresponding aryl trifluoromethanesulfonate (0.48 mmol) at 120 °C using 2.5 mol% [Pd(cinnamyl)Cl]2 and 6.25 mol% (4-CF3Ph)PF-tBu, and purified according to post-treatment method D. Purification was performed by rapid column chromatography on silica using hexane containing 10% ethyl acetate, yielding a yellow oily separation of the title compound (0.118 g, 0.336 mmol) in 70% yield. 1H NMR(500MHz, CDCl3)δ7.24(d,J=2.1Hz,1H),7.10(dd,J=8.1,2.2Hz,1H),7.06-7.02(m,1H),4.61(t,J=3.6Hz,1H),4.29 (d,J=17.1Hz,1H),4.16(d,J=17.1Hz,1H),3.88-3.80(m,3H),3.53-3.49(m,1H),2.51-2.46(m,1H),1.87-1.26(m,16H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ206.11,148.51,133.47,132.16,129.66,126.79,126.0 0,99.29,72.04,62.72,43.32,40.57,34.01,30.44,27.02,26.16,25.35,19.44. HRMS-ESI(m / z):C 20 H 27 ClNaO3[M+Na] + Calculated value: 373.1541; Measured value: 373.1539.

[0307] Example (IV-8): 1-(benzyloxy)-3-(2-chloro-4-methylphenyl)propane-2-one

[0308]

[0309] The title compound was synthesized according to GP5, from the corresponding aryl bromide (0.48 mmol) and 1-(benzyloxy)propane-2-one (3 equivalents), at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2 and 1.5 mol% PhPF-tBu, and purified according to post-treatment method D. The purification was performed by rapid column chromatography on silica using 40 g Silicycle SiliSep. TM Purification was performed using a rapid column chromatography with an elution gradient of hexane containing 0% ethyl acetate (2CV) followed by hexane containing 0-10% ethyl acetate (20CV), which provided a clear, oily separation of the title compound in 70% yield (0.097 g, 0.336 mmol). 1 H NMR (300MHz, CDCl3) δ7.43-7.18(m,6H),7.15-6.99(m,2H),4.62(s,2H),4.19(s,2H),3.89(s,2H),2.32(s,3H). 13 C{ 1H}NMR(75MHz,CDCl3)δ205.12,138.99,137.30,134.12,131.60,130.11,12 9.04,128.62,128.43,128.13,128.07,127.94,74.95,73.57,43.82,20.92. HRMS-ESI(m / z):C 17 H 17 ClNaO2[M+Na] + Calculated value: 311.0809; Measured value: 311.0810.

[0310] Example (IV-9): 1-(2-chloro-4-methylphenyl)-3-methoxypropane-2-one

[0311]

[0312] The title compound was synthesized according to GP6, from the corresponding aryl bromide (0.48 mmol) and methoxyacetone (3 equivalents), at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2 and 1.5 mol% PhPF-tBu, and purified according to post-treatment method D. The purification was performed by rapid column chromatography on silica using 10 g SilicycleSiliSep. TM Purification was performed using a rapid column chromatography with an elution gradient of hexane containing 0% ethyl acetate (2CV) followed by hexane containing 0-20% ethyl acetate (20CV), which provided a clear, oily separation of the title compound in 65% yield (0.066 g, 0.310 mmol). 1 H NMR (300MHz, CDCl3) δ7.34-7.23(m,1H),7.20-7.04(m,3H),4.15(s,3H),3.90(s,3H),3.48(s,4H),2.37(s,4H). 13 C{ 1 H}NMR (75MHz, CDCl3) δ204.98,139.06,134.12,131.59,130.15,128.99,127.99,77.49,59.51,43.72,20.92. HRMS-ESI(m / z):C 11 H 12 ClNaO2[M+Na] + Calculated value: 235.0496; Measured value: 235.0504.

[0313] Example (IV-10): 1-(2-chloro-4-methoxyphenyl)-3-methoxypropane-2-one

[0314]

[0315] The title compound was synthesized according to GP6, from the corresponding aryl bromide (0.24 mmol) and methoxyacetone (3 equivalents), underwent at 100 °C for 8 hours with 0.625 mol% [Pd(cinnamyl)Cl]2 and 1.5 mol% PhPF-tBu, and purification was performed according to post-treatment method D. The purification was carried out by rapid column chromatography on silica using 10 g Silicycle SiliSep. TM Purification was performed using a rapid column chromatography with an elution gradient of hexane containing 0% ethyl acetate (2CV) followed by hexane containing 0-20% ethyl acetate (15CV), which provided a clear oily separation of the title compound in 62% yield (0.034 g, 0.297 mmol). 1 H NMR (300MHz, CDCl3) δ7.12 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.5, 2.6 Hz, 1H), 4.10 (s, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 3.43 (s, 3H). 13 C{ 1 H}NMR (75MHz, CDCl3) δ205.22,159.60,134.93,132.30,124.00,115.08,113.34,77.48,59.55,55.67,43.33. HRMS-ESI(m / z):C 11 H 13 ClNaO3[M+Na] + Calculated value: 251.0445; Measured value: 251.0444.

[0316] Example (IV-11): 1-(benzyloxy)-3-(2-(dimethylamino)phenyl)propane-2-one

[0317]

[0318] The title compound was synthesized according to GP5, from the corresponding aryl bromide (0.24 mmol) and 1-(benzyloxy)propane-2-one (3 equivalents), at 110 °C for 6 h using 1.25 mol% [Pd(cinnamyl)Cl]2 (2.5 mol% Pd) and 3 mol% PhPF-tBu, and purified according to post-treatment method D. The purification was performed by rapid column chromatography on silica using 40 g Silicycle SiliSep. TM Purification was performed using a rapid column chromatography with an elution gradient of hexane containing 0% ethyl acetate (2CV) followed by hexane containing 0-20% ethyl acetate (20CV), which provided a separation of the title compound (0.045 g, 0.159 mmol) in a pale yellow oil in 63% yield. 1 H NMR (500MHz, CDCl3) δ7.36-7.22(m,6H),7.17-7.13(m,2H),7.09-7.02(m,1H),4.56(s,2H),4.12(s,2H),3.77(s,2H),2.55(s,6H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ206.05,152.74,137.60,131.32,131.06,128.58,128.37,128.05,128.02,124.33,120.73,74.51,73.40,44.67,43.02. HRMS-ESI(m / z):C 18 H 21 NNaO2[M+Na] + Calculated value: 306.1465; Measured value: 306.1460.

[0319] byproducts

[0320] 1,1-Di(2-chloro-4-methylphenyl)-3-[(oxecyclohexan-2-yl)oxy]propane-2-one (4a)

[0321]

[0322] The title compound was synthesized from (IV-1) and its corresponding aryl bromide (IIa) (0.24 mmol). 2 mol% [Pd(cinnamyl)Cl]₂ (4 mol% Pd) and 5 mol% XPOS were added to a 1-valve screw-top flask equipped with a magnetic stirrer and dissolved in 1 mL of THF. Then, Cs₂CO₃ (2 equivalents), 3-chloro-4-bromotoluene (32.2 μL, 0.24 mmol, 1 equivalent), and (IV-1) (0.1131 g, 0.40 mmol, 1.67 equivalents) were added. The flask was sealed with a PTFE-lined cap, wrapped with insulating tape, and then removed from the glove box and placed in a temperature-controlled aluminum heater set to 90 °C, where it was reacted with magnetic stirring at 900 rpm for 12 hours. Purification was performed according to post-treatment method D. The purification was carried out by rapid column chromatography on silica using Silicycle SiliSep. TM Purification was performed using an HP 40g column with an elution gradient of hexane containing 0% ethyl acetate (2CV), hexane containing 0-20% ethyl acetate (24CV), followed by hexane containing 20% ​​ethyl acetate (2CV), which provided a clear oily separation of the title compound in 26% yield (0.025g, 0.061mmol). 1 H NMR (300MHz, CDCl3) δ7.25(s,2H),7.02(dt,J=8.0,1.9Hz,2H),6.86(dd,J=9.2,7.9Hz,2H),6.16(s,1H),4.58(t,J=3.2Hz,1H),4.43(d,J=17.6 Hz,1H),4.28(d,J=17.6Hz,1H),3.62(ddd,J=11.2,9.7,3.1Hz,1H),3.42(dtd,J=11.2,4.1,1.5Hz,1H),2.36-2.27(m,6H),1.86-0.71(m,16H). 13 C{ 1 H}NMR (75MHz, CDCl3) δ206.42,139.22,139.15,134.45,131.76,131.52,130.58,130. 53,130.08,130.02,127.87,98.37,71.72,61.68,53.54,30.14,25.43,20.93,18.70. HRMS-ESI(m / z):C 22 H 24 Cl2NaO3[M+Na] + Calculated value: 429.0995; Measured value: 429.0999.

[0323] 1,3-Di(2-chloro-4-methylphenyl)-1-[(oxecyclohexan-2-yl)oxy]propane-2-one (4b)

[0324]

[0325] The title compound was synthesized from IV-1 and its corresponding aryl bromide (0.24 mmol). 1 mol% [Pd(cinnamyl)Cl]₂ (2 mol% Pd) and 2.5 mol% PhPF-tBu were added to a 1-valve with a magnetic stirrer and dissolved in 0.67 mL of 1,4-dioxane. Then, Cs₂CO₃ (2 equivalents), 3-chloro-4-bromotoluene (32.2 μL, 0.24 mmol, 1 equivalent), and (IV-1) (0.679 g, 0.24 mmol, 1 equivalent) were added. The flask was sealed with a PTFE-lined cap, wrapped with insulating tape, and then removed from the glove box and placed in a temperature-controlled aluminum heater set to 110 °C, where it was reacted with magnetic stirring at 900 rpm for 16 hours. Purification was performed according to post-treatment method D. The purification was carried out by rapid column chromatography on silica using 40 g Silicycle SiliSep. TM Purification was performed using an HP rapid chromatography column with an elution gradient of hexane containing 0% ethyl acetate (2CV), followed by hexane containing 0-20% ethyl acetate (26CV), which provided a clear, oily separation of the title compound in 29% yield (0.028 g, 0.069 mmol). 1 The -O-CH-O- proton integral ratio (4.88ppm(t,J=3.1Hz,0.60H):4.56ppm(t,J=3.6Hz,1.00H)) determined in the 1H NMR spectrum that the isolated title compound was a 1:0.6 mixture of two pairs of diastereomers. 1H NMR (500MHz, CDCl3) δ7.42(d,J=7.9Hz,1H),7.34(d,J=7.9Hz,1H),7.28-7.20(m,2H),7.18-7.06(m,3H),7. 06-6.91(m,3H),5.81(s,1H),5.73(s,1H),4.88(t,J=3.1Hz,1H),4.56(t,J=3.6Hz,1H),4.06(d,J=2.9Hz,2 H),3.94(ddd,J=11.7,8.3,3.8Hz,1H),3.81(d,J=17.4Hz,1H),3.73(d,J=17.5Hz,1H),3.65(ddd,J=11.2,9 .8,3.2Hz,1H),3.59-3.52(m,1H),3.45(dtd,J=11.3,4.2,1.5Hz,1H),2.37-2.27(m,9H),1.98-1.40(m,7H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ203.81,203.17,140.25,138.78,138.62,134.35,134.28,134 .19,133.45,131.68,131.61,131.40,130.43,130.27,129.99,129.94,129.54,129.50 ,129.41,129.20,128.31,128.16,127.72,127.65,97.88,96.64,79.30,78.70,62.69 ,62.03,43.56,43.39,30.52,30.26,25.49,25.42,21.09,21.05,20.93,19.32,18.84. HRMS-ESI(m / z):C 22 H 24 Cl2NaO3[M+Na] + Calculated value: 429.0995; Measured value: 429.1007.

[0326] A mixture containing 1-(2-chloro-4-methylphenyl)-1-[(oxacyclohexan-2-yl)oxy]propane-2-one

[0327]

[0328] The title compound was synthesized from the corresponding aryl bromide and isolated from a mixture containing 4c, 4a, and 4b. 2 mol% [Pd(cinnamyl)Cl]₂ (4 mol% Pd) and 5 mol% XPOS were added to a 1-valve screw-top flask equipped with a magnetic stirrer and dissolved in 2 mL of tetrahydrofuran. Then, Cs₂CO₃ (2 equivalents), 3-chloro-4-bromotoluene (0.48 mmol, 1 equivalent), and 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (2 equivalents) were added. The flask was sealed with a PTFE-lined cap, wrapped with insulating tape, and then removed from the glove box and placed in a temperature-controlled aluminum heater set to 90 °C, where it was reacted with magnetic stirring at 900 rpm for 12 hours. Purification was performed according to post-treatment method D. The purification was carried out by rapid column chromatography on silica using 25 g of Silicycle SiliSep. TM Purification was performed using a rapid column chromatography method with an elution gradient of hexane containing 0% ethyl acetate (2CV), hexane containing 0-20% ethyl acetate (24CV), followed by hexane containing 20% ​​ethyl acetate (2CV), providing a clear oily separation of (IV-1) (0.010 g, 0.035 mmol) in 7% yield, and a clear oily mixture containing 4c, 4a, and 4b (0.032 g). Mass spectrometry of the mixture: HRMS-ESI (m / z): C 15 H 19 ClNaO3(4c)[M+Na) + Calculated value: 305.0915; Measured value: 305.0917. HRMS-ESI (m / z): C 22 H 24 Cl2NaO3(4a / 4b)[M+Na] + Calculated value: 429.0995; Measured value: 429.0998.

Claims

1. A method for preparing compounds of general formula (I) in R 1 It is phenyl, naphthyl, or 5 to 10-membered heteroaryl. The phenyl, naphthyl, and 5- to 10-membered heteroaryl groups are optionally substituted by 1 to 3 substituents, which are independently selected from fluorine, chlorine, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, di-C1-C6-alkylamino, or 3- to 10-membered heterocyclic groups. The 3- to 10-membered heterocyclic group is optionally substituted by 1 to 3 substituents. The substituents are independently selected from oxo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, and C1-C6-haloalkoxy. R 2 It is hydrogen or (C1-C6)-alkyl; Its features In step A, in a suitable solvent, in the presence of a palladium catalyst, a bisphosphine ligand, and a suitable base, the compound of formula (II) reacts with the compound of formula (III) to produce the compound of formula (IV). 1 -X 1 (II), Where R 1 As defined above, and X 1 It is composed of bromine, iodine, fluorosulfonic acid, or trifluoromethanesulfonic acid groups. Where R 2 As defined above, and PG is a hydroxyl protecting group, preferably methyl, tert-butyl, tetrahydropyranyl, or benzyl. Where R 1 R 2 And PG as defined above, In step B, the protecting group PG is subsequently removed.

2. The method according to claim 1, wherein in step A, the palladium catalyst is a palladium(II) salt, particularly [Pd(cinnamyl)Cl]2, Pd(OAc)2 or Pd(dba)2.

3. The method according to claim 1 or 2, wherein in step A, the bisphosphine ligand is selected from (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl]phosphino]ferrocene[(4-CF3Ph)PF-tBu, CAS Registry No. 246231-79-8], (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]-2-[bis[4-(trifluoromethyl)phenyl)phosphino]ferrocene][(4-CF3Ph)PF-tBu, CAS Registry No. 849924-37-4], (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl)phosphino]ferrocene][(4-CF3Ph)PF-tBu, CAS Registry No. 849924-37-4], (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl] ...-2-[bis[4-CF3Ph)PF-tBu, CAS Registry No. 849924-37-4], (2R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2- [1,1-Dicyclohexylphosphino]-2-(diphenylphosphino)ferrocene [PhPF-tBu, CAS Registry No. 155830-69-6], (2S)-1-[(1S)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene [PhPF-tBu, CAS Registry No. 277306-29-3], (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene [CyPF-tBu, CAS Registry No. 158923-11-6], (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino] Ferrocene [CyPF-tBu, CAS Registry No. 1246841-00-8], (1R)-1-(dicyclohexylphosphino)-2-[(1R)-1-(dicyclohexylphosphino)ethyl]ferrocene [CyPF-Cy, CAS Registry No. 167416-28-6], (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene [CyPF-Cy, CAS Registry No. 246231-77-6], (2R)-1-[(1R)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene [PhPF-Cy, CAS Registry No. 155806-35- 2], (2S)-1-[(1S)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene [CAS-registered number 162291-02-3], di(1-adamantyl)-2-morpholinophenylphosphine [Mor-DalPhos, CAS-registered number 1237588-12-3], 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene [XantPhos, CAS-registered number 161265-03-8], 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [Xphos, CAS-registered number 564483-18-7] and 1-((1,3,5,7-tetramethyl-2,4,6-Trioxa-8-phosphaadamantane-8-yl)-2-(1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantane-8-yl)benzene [PAd2-DalPhos], 4. The method according to any one of claims 1 to 3, wherein if X 1 If the base is bromine, iodine, or trifluorosulfonic acid, then the base suitable for the reaction of this invention is an alkali metal carbonate, alkali metal halide, dialkali metal phosphate, and alkali metal phosphate, such as cesium carbonate, cesium fluoride, dipotassium hydrogen phosphate, and potassium phosphate; or, if X 1 If the trifluoromethanesulfonate group is used, a dual-base condition is employed, wherein DBU is selected together with a salt additive, such as sodium trifluoroacetate, sodium trifluoromethanesulfonate, and potassium trifluoromethanesulfonate.

5. The method according to any one of claims 1 to 4, wherein step A is carried out in a solvent selected from toluene, xylene or decahydronaphthalene, 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me-THF), 1,2-dimethoxyethane (DME), 1,2-diethoxyethane, di(2-methoxyethyl) ether (diglyme), cyclopentylmethyl ether (CPME), or anisole.

6. The method according to any one of claims 1 to 5, wherein R 1 Groups of the following formula in *Connect to X respectively 1 Or on the terminal carbon atom, R 3 and R 4 Independently selected from fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6-cycloalkyl, dimethylamino, diethylamino, and piperazine. The piperazine group is substituted by one or two substituents independently selected from methyl and ethyl.

7. The method according to any one of claims 1 to 6, for preparing compounds of formula (I-1) Its features are, In step A, in a suitable solvent, in the presence of a palladium catalyst, a bisphosphine ligand, and a suitable base, compound (IIa) reacts with compound (III-1) to produce compound (IV-1). in X 1 It is a bromine, fluorosulfonic acid group or a trifluoromethanesulfonic acid group. In step B, the protecting group PG is subsequently removed.

8. The method according to any one of claims 1 to 7, wherein step A is carried out using [Pd(cinnamyl)Cl]2 as a palladium catalyst, in combination with (4-CF3Ph)PF-tBu or PhPF-tBu as a bisphosphine ligand, and cesium carbonate as a base, wherein the ratio of the bisphosphine ligand to the palladium catalyst is from 1.25:1.0 to 1.20:1.

0.

9. The method according to any one of claims 1 to 8, wherein step B is carried out under acidic conditions in a solvent, wherein the acid is selected from HCl or SiO2-supported NaHSO4, and wherein the solvent is selected from methanol, 1,4-dioxane, or water.

10. Compound of formula (I) in R 1 Groups of the following formula in *Connect to X respectively 1 Or on the terminal carbon atom, R 3 and R 4 Independently selected from fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6-cycloalkyl, dimethylamino, diethylamino, and piperazine. The piperazine group is substituted by one or two substituents independently selected from methyl and ethyl groups. R 2 It is hydrogen or (C1-C6)-alkyl.

11. Compounds of formula (IV) in R 1 Groups of the following formula in *Connect to X respectively 1 Or on the terminal carbon atom, R 3 and R 4 Independently selected from fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6-cycloalkyl, dimethylamino, diethylamino, and piperazine. The piperazine group is substituted by one or two substituents independently selected from methyl and ethyl groups. R 2 It is hydrogen or (C1-C6)-alkyl. as well as PG is a hydroxyl protecting group, preferably methyl, tetrahydropyranyl or benzyl.

12. Compounds of formula (II) R 1 -X 1 (II), in R 1 It is phenyl, naphthyl, or 5 to 10-membered heteroaryl. The phenyl, naphthyl, and 5- to 10-membered heteroaryl groups are optionally substituted by 1 to 3 substituents, which are independently selected from fluorine, chlorine, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, di-C1-C6-alkylamino, or 3- to 10-membered heterocyclic groups. The 3- to 10-membered heterocyclic group is optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from oxo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, and C1-C6-haloalkoxy. as well as X 1 It has a fluorosulfonic acid group.

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