Palladium-catalyzed chemoselective mono-α-arylation of O-protected hydroxyacetone

Abstract

The present invention relates to a novel method for preparing a benzyl α-hydroxyketone derivative by mono-α-arylating O-protected hydroxyacetone with a palladium catalyst, followed by deprotection.

Description

[Technical Field]

[0001] The present invention relates to a novel method for producing a benzyl α-hydroxyketone derivative by mono-α-arylating O-protected hydroxyacetone with a palladium catalyst, followed by deprotection. [Background technology]

[0002] The benzyl α-hydroxyketone derivative of formula (I) is a valuable precursor for effective agrochemicals and pharmaceutical ingredients. This type of benzyl α-hydroxyketone has broad synthetic utility in classical heterocyclic synthesis (e.g., Hantsch's pyrrole synthesis or thiophene synthesis, Weidenhagen reaction, Bredereck synthesis, etc.) and as an intermediate to 1,2-amino alcohols (e.g., by reductive amination or biocatalytic aminotransfer). In particular, the benzyl α-hydroxyketone derivative of formula (I) is an important intermediate for producing the bactericidal active compounds disclosed in International Publication No. 2020 / 127780.

[0003] Several oxidation methods have been reported for the synthesis of benzyl α-hydroxyketone. For example, it can be synthesized by oxidizing an olefinic substrate. This usually involves using a combination of a catalyst and a stoichiometric oxidizing agent (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, 2006, 80-83). Disadvantages include the often low regioselectivity when using unbiased substrates and the generation of large amounts of potentially hazardous chemical waste due to the stoichiometric use of co-oxidizing agents. Alternatively, it can be produced by mono-oxidation of the diol (Waymouth et al. J. Am. Chem. Soc. 2018, 140, 748-757). Unfortunately, this reaction is slow and requires an expensive catalyst. Finally, there is the direct α-oxidation of the ketone 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 dangerous and expensive.

[0004] Instead of a direct oxidation reaction, benzyl α-hydroxyketone can be synthesized by selectively brominating phenylacetaldehyde and then reacting it with an oxygen nucleophile (Merck & Co., DE946446C, 1956-08-02). Alternatively, the corresponding hydroxyketone can be produced by reacting phenylpropargyl alcohol with a thiol reagent and then performing acidic hydrolysis (Waters et al. Tetrahedron Lett. 2000, 41, 141-144). These methods require multiple steps and generate large amounts of chemical waste.

[0005] Finally, an acyloin coupling reaction between an aldehyde and formaldehyde can be carried out using an N-heterocyclic carbene as a catalyst (Inoue et al. J. Org. Chem. 1985, 50, 603-606). This reaction can also be carried out enzymatically (Ma et al. Angew. Chem. Int. Ed. 2022, 61, e2021163). These methods rely on the synthesis and separation of aldehyde intermediates, which tend to be highly reactive.

[0006] α-arylation of carbonyl compounds with metal catalysts using halogenating or pseudohalogenated (hetero)aryl electrophiles provides a useful means for producing benzyl ketone equivalents. However, selective mono-α-arylation can also present problems. This is particularly true for methylcarbonyl compounds, where the arylation product may feature a benzyl CH2 group that is more acidic than the methylcarbonyl starting material (Stradiotto et al. in “New Trends in Cross-Coupling: Theory and Applications”, Colacot, TJ, Ed. Royal Society of Chemistry: Cambridge, UK, 2014; 228-253). Despite significant progress in α-arylation chemistry using metal catalysts, no similar transformation reactions exhibiting terminal selectivity for hydroxyacetone (or O-protected variants) have been reported to date (Stradio 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 by using O-protected hydroxyacetone in combination with a catalytic system consisting of a palladium catalyst and a bisphosphine ligand, efficient methyl-selective mono-α-arylation of ortho-substituted aryl bromides, aryl iodides, fluorosulfonates, and trifluorosulfonates can be achieved in the presence of potentially competing functional groups including chloro groups.

[0008] Based on the prior art described above, the object of the present invention is to provide an efficient and selective synthetic route to benzyl α-hydroxyketone derivatives of formula (I) characterized by high yield, broad substrate range, high purity, less chemical waste, and easy separation of the final product under mild conditions. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] International Publication No. 2020 / 127780 Brochure [Non-patent literature]

[0010] [Non-Patent Document 1] 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, 2006, 80-83 [Non-Patent Document 2] Waymouth et al. J. Am. Chem. Soc. 2018, 140, 748-757 [Non-Patent Document 3] Davis et al. J. Am. Chem. Soc., 1990, 112, 6679-6690 and Li et al., Adv. Synth. Catal., 2022, 364, 1757-1762 [Non-Patent Document 4] Merck & Co., DE946446C, 1956-08-02 [Non-Patent Document 5] Waters et al. Tetrahedron Lett. 2000, 41, 141-144 [Non-Patent Document 6] Inoue et al. J. Org. Chem. 1985, 50, 603-606 [Non-Patent Document 7] Ma et al. Angew. Chem. Int. Ed. 2022, 61, e2021163 [Non-Patent Document 8] Stradiotto et al. in “New Trends in Cross-Coupling: Theory and Applications”, Colacot, TJ, Ed. Royal Society of Chemistry: Cambridge, UK, 2014; 228-253 [Non-Patent Document 9] Stradiotto et al., Eur. J. Org. Chem. 2012, 6042-6050; Waters SM et al., Tet. Lett. 41 (2000), 141-144 [Overview of the project]

[0011] The objective described above was achieved by a method for producing the compound of the following general formula (I):

[0012] [ka] [In the formula, R 1 These are phenyl, naphthyl, or 5-10 membered ring heteroaryl compounds. The phenyl, naphthyl, and 5-10 membered ring heteroaryl compounds are optionally substituted with 1-3 substituents independently selected from the group consisting of fluoro, chloro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, di-C1-C6 alkylamino, or 3-10 membered ring heterocyclyl compounds. Here, the 3-10 membered heterocyclyl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of oxo, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. R 2 [is hydrogen or (C1~C6)-alkyl] In step A, the compound of formula (II)

[0013] [ka] [In the formula, R 1 As defined above, X 1 [These are bromo, iodine, fluorosulfonate, or trifluoromethylsulfonate] The compound of formula (III) is prepared in a suitable solvent in the presence of a palladium catalyst, a bisphosphine ligand, and a suitable base.

[0014] [ka] [In the formula, R 2 It is defined as described above, PG is a hydroxy protecting group, preferably a methyl group, a tert-butyl group, a tetrahydropyranyl group, or a benzyl group. Reacting with it, the compound of formula (IV)

[0015] [ka] [In the formula, R 1 , R2 , and PG are defined as described above. It is characterized by forming, and The process is characterized by subsequently removing the protective group PG in step B. [Modes for carrying out the invention]

[0016] General definition Unless otherwise specified, the following definitions of substituents and residues apply throughout this specification and the claims.

[0017] As used herein, the term "C1-C6 alkyl" refers to a saturated, branched or linear hydrocarbon chain having one, two, three, four, five, or six carbon atoms. Examples of C1-C6 alkyl groups 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 has one, two, three, or four carbon atoms ("C1-C4 alkyl"), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

[0018] As used herein, the term “C1-C6 haloalkyl” refers to the C1-C6 alkyl group as defined above, where one or more hydrogen atoms are replaced by one or more identical or different halogen atoms. Examples of C1-C6 haloalkoxys 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-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and 1,1,1-trifluoropropane-2-yl. Fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and 1,1,1-trifluoropropane-2-yl are preferred.

[0019] As used herein, the term "C1-C6 alkoxy" refers to a group of the formula (C1-C6 alkyl)-O-. Here, the term "C1-C6 alkyl" is defined herein. Examples of C1-C6 alkoxys include 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-hexyloxy, 1-methylpentoxy, and 2-methylpentoxy. Examples include, but are not limited to, 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. This definition also applies to alkoxys as part of a composite substituent, e.g., alkoxyalkyls and alkoxyalkoxys, unless otherwise defined.

[0020] As used herein, the term "C1-C6 haloalkoxy" refers to the C1-C6 alkoxy group as defined above, where one or more hydrogen atoms are replaced by one or more identical or different halogen atoms. Examples of C1-C6 haloalkoxys 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-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and 1,1,1-trifluoropropa-2-oxy.

[0021] As used herein, the term “di-(C1-C6)-alkylamino” refers to an amino group having two independently selected C1-C6 alkyl groups as defined herein. Examples of C1-C6 dialkylaminos include, but are not limited to, N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, and N-tert-butyl-N-methylamino.

[0022] As used herein, the term "C3-C8 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring containing three, four, five, six, seven, or eight carbon atoms. Examples of C3-C8 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, such cycloalkyls have three to six carbon atoms.

[0023] As used herein, the term “3- to 10-membered heterocyclyl” refers to a saturated or partially unsaturated ring system consisting of 3, 4, 5, 6, 7, 8, 9, or 10 members, containing 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. If the ring system contains one or more oxygen atoms, those oxygen atoms are not directly adjacent. Examples of heterocycles include, but are not limited to, monocyclic heterocycles of 3 to 7 members and bicyclic heterocycles of 8 to 10 members. 3- to 10-membered heterocycles may be connected to the parent molecule via any carbon or nitrogen atom contained within the heterocycle. Examples of saturated heterocycles include 3-membered rings, e.g., oxylanil, azilidinyl; 4-membered rings, e.g., azetidinyl, oxetanil, thietanil; 5-membered rings, e.g., tetrahydrofuranil, 1,3-dioxolanil, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl, isoxazolidinyl, oxazolidinyl, oxadiazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl; and 6-membered rings, e.g. Examples include piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, triazinyl, hexahydrotriazinyl, tetrahydropyranil, dioxanil, tetrahydrothiopyranil, dithianil, morpholinil, 1,2-oxazinyl, oxathianil, thiomorpholinil, etc., or 7-membered rings such as oxepanil, azepanil, 1,4-diazepanil, and 1,4-oxazepanil, but are not limited to these. Examples of unsaturated heterocycles include 5-membered rings such as dihydrofuranil, 1,3-dioxolyl, dihydrothienyl, pyrrolinil, dihydroimidazolyl, dihydropyrazolyl, isoxazolinil, dihydrooxazolyl, dihydrothiazolyl, etc., or 6-membered rings such as pyranil, thiopyranil, thiadinyl, and thiadiazinzyl, but are not limited to these.The bicyclic heterocycle may consist of a monocyclic C3-C8 cycloalkyl, a monocyclic C3-C8 cycloalkenyl, or a monocyclic heteroaryl as defined herein, condensed with a monocyclic heterocycle; or it may consist of a monocyclic heteroaryl condensed with any of the following: aryl (e.g., phenyl), C3-C8 cycloalkyl, C3-C8 cycloalkenyl, or a monocyclic heterocycle (e.g., dihydrobenzofuranyl, dihydroisobenzofuranyl, indlinyl, 1,3-benzodioxolyl, dihydro-1,4-benzodioxynyl, tetrahydroquinolinyl, dihydro-5H-cyclopenta[b]pyridinyl, chromanil, isochromanil, thiochromanil, isothiochromanil). When two monocyclic heterocycles or one monocyclic heterocycle is condensed with one monocyclic heteroaryl containing a nitrogen atom, the nitrogen atom may be located at the bridgehead (e.g., [1,3]dioxolo[4,5-b]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl).

[0024] As used herein, the terms “3- to 7-membered heterocyclyl” and “3- to 7-membered heterocyclyl ring” refer to a saturated 3-, 4-, 5-, 6-, or 7-membered ring system containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples include, but are not limited to, oxylanil, azilidinil, azetidinil, oxetanil, thietanil, tetrahydrofuranil, 1,3-dioxolanil, tetrahydrothienyl, pyrrolidinil, pyrazolidinil, imidazolidinil, triazolidinil, isoxazolidinil, oxazolidinil, oxadiazolidinil, thiazolidinil, isothiazolidinil, thiadiazolidinil, piperidinil, hexahydropyridazinil, hexahydropyrimidinil, piperazinil, triazinil, hexahydrotriazinil, tetrahydropyranil, dioxanil, tetrahydrothiopyranil, dithianil, morpholinil, 1,2-oxazinanil, oxathianil, thiomorpholinil, oxepanil, azepanil, 1,4-diazepanil, and 1,4-oxazepanil. Preferred 3-7 membered heterocyclyl rings are oxyranil, azilidinil, azetidinil, oxetanil, tetrahydrofuranil, 1,3-dioxolanil, pyrrolidinil, piperidinil, piperazinil, tetrahydropyranil, dioxanil, morpholinil, and thiomorpholinil.

[0025] As used herein, the term “5- to 10-membered heteroaryl ring” refers to an aromatic ring system containing one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur. If the ring system contains more than one oxygen atom, those oxygen atoms are not directly adjacent. Aromatic heterocycles include 5- or 6-membered monocyclic heteroaryl rings and 7- to 10-membered bicyclic heteroaryl rings. 5- to 10-membered heteroaryl rings may be connected to the parent molecule via any carbon or nitrogen atom contained within the heterocycle.

[0026] As used herein, the term “five-membered or six-membered ring heteroaryl” refers to a five-membered or six-membered ring aromatic monocyclic system containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of five-membered ring monocyclic heteroaryls include, but are not limited to, furyl (furanyl), thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and thiatriazolyl. Examples of six-membered ring monocyclic heteroaryls include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetradinyl.

[0027] As used herein, the term “7- to 10-membered heteroaryl ring” refers to an aromatic bicyclic ring system of 7, 8, 9, or 10 members containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur. The bicyclic heteroaryl ring may consist of a monocyclic heteroaryl ring as defined herein, condensed with an aryl (e.g., phenyl) or a monocyclic heteroaryl ring. Examples of bicyclic heteroaryls include, but are not limited to, nine-membered rings such as indolyl, indolidinyl, isoindolyl, benzimadozolyl, imidazopyridinyl, indazolyl, benzotriazolyl, prinyl, benzofuranil, benzothiophenyl, benzothiazolyl, benzoxazolyl, and benzisoxazolyl, or ten-membered rings such as quinolinyl, isoquinolinyl, cinnoline, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl, pteridinal, and benzodioxynyl. In bicyclic heteroaryls consisting of two fused monocyclic heteroaryls of five- or six-membered rings, the nitrogen atom may be located at the bridgehead (e.g., imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]oxazolyl, flu[2,3-d]isoxazolyl).

[0028] Formula (I) provides a general definition of the benzyl α-hydroxy ketone obtained by the method according to the present invention. The definitions of the preferred radicals of Formula (I) shown above and below are shown below. These definitions apply to the final product of Formula (I) and similarly apply to all starting materials and intermediates having the corresponding radicals.

[0029] R 1 is preferably phenyl, naphthyl, pyridyl, or benzothienyl, wherein the phenyl, naphthyl, pyridyl, and benzothienyl are optionally substituted by 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, di-C1-C4 alkylamino, and 4- to 7-membered heterocyclyl, wherein the 4- to 7-membered heterocyclyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of oxo, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy. R 1 is more preferably a group of the following formula

[0030] [Chemical formula] [wherein, * is the bonding part to X 1 or each terminal carbon atom, R 3 and R 4 are independently selected from the group consisting of fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6 cycloalkyl, dimethylamino, diethylamino, and piperazinyl, Here, the piperazinyl is substituted with one or two substituents independently selected from the group consisting of methyl and ethyl.

[0031] Similarly, R 1 More preferably, the basis of the following equation

[0032] [ka] [In the formula, * is X 1 The bonding site to, or each of the terminal carbon atoms, R 3 It is selected from the group consisting of chloro and methyl, R 4 This is selected from the group consisting of chloro, bromo, and methyl. R 1 More preferably, it is 2-chloro-4-methylphenyl. R 2 Preferably, it is hydrogen or a C1-C4 alkyl group. R 2 More preferably, it is hydrogen or methyl. R 2 More preferably, it is hydrogen. The PG is preferably methyl, tetrahydropyranyl, or benzyl. PG is more preferably tetrahydropyranyl or benzyl. PG is more preferably tetrahydropyranyl. X 1 Preferably, it is bromo, fluorosulfonate, or trifluoromethylsulfonate. X 1 More preferably, this is bromo, fluorosulfonate, or trifluoromethylsulfonate. X 1 More preferably, it is a fluorosulfonate.

[0033] Therefore, the compound of formula (I-1)

[0034] [ka] A method for producing a compound of formula (IIa), wherein in step A,

[0035] [ka] [In the formula, X 1 [This is bromo, fluorosulfonate, or trifluoromethylsulfonate.] The compound of formula (III-1) is prepared in a suitable solvent in the presence of a palladium catalyst, a bisphosphine ligand, and a suitable base.

[0036] [ka] Reacting with it, the compound of formula (IV-1) is formed.

[0037] [ka] It is characterized by forming, and A particularly preferred method for producing the compound is one in which the protecting group PG is subsequently removed in step B.

[0038] The R identified above 1 , R 2 The definitions of , and PG (including the broad definition, as well as preferred, more preferred, even more preferred, and most preferred definitions) can be combined in various ways. Thus, combinations of these definitions provide subclasses of the compounds of the present invention, such as those disclosed below.

[0039] Preferably, in the compound of formula (I), each definition (substituent and variable) has the preferred meaning described above.

[0040] Particularly preferably, in the compound of formula (I), each definition (substituent and variable) has the more preferred, even more preferred, and / or most preferred meanings described above.

[0041] As outlined above, the compound of formula (I) is a valuable intermediate in the synthesis of compounds useful in the field of crop protection, particularly in the field of heterocyclic pyridazine derivatives disclosed in International Publication No. 2020 / 127780.

[0042] A further object of the present invention is a compound of formula (I)

[0043] [ka] [In the formula, R 1 These are phenyl, naphthyl, or 5-10 membered ring heteroaryl compounds. The phenyl, naphthyl, and 5-10 membered ring heteroaryl compounds are optionally substituted with 1-3 substituents independently selected from the group consisting of fluoro, chloro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, di-C1-C6 alkylamino, or 3-10 membered ring heterocyclyl compounds. Here, the 3-10 membered heterocyclyl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of oxo, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. R 2 [These are hydrogen or (C1-C6)-alkyl].

[0044] R related to equation (I) 1 , R 2 The preferred definition, more preferred definition, even more preferred definition, and most preferred definition of PG shall apply mutatis mutandis with the necessary modifications as appropriate.

[0045] A further object of the present invention is a compound of formula (II).

[0046] [ka] [In the formula, R 1 These are phenyl, naphthyl, or 5-10 membered ring heteroaryl compounds. The phenyl, naphthyl, and 5-10 membered ring heteroaryl compounds are optionally substituted with 1-3 substituents independently selected from the group consisting of fluoro, chloro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, di-C1-C6 alkylamino, or 3-10 membered ring heterocyclyl compounds. Here, the 3-10 membered heterocyclyl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of oxo, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. and, X 1 [These are fluorosulfonates or trifluoromethylsulfonates.]

[0047] R related to equation (I) 1 , R 2 , X 1 The preferred definition, more preferred definition, even more preferred definition, and most preferred definition of PG shall apply mutatis mutandis with the necessary modifications as appropriate.

[0048] A further object of the present invention is a compound of formula (III)

[0049] [ka] [In the formula, R 2 is hydrogen or (C1~C6)-alkyl, and, PG is a hydroxy protecting group, preferably a methyl group, a tetrahydropyranyl group, or a benzyl group.

[0050] The preferred, more preferred, even more preferred, and best preferred definitions of R1, R2, and PG with respect to formula (I) shall be applied mutatis mutandis with the necessary modifications as appropriate.

[0051] A further object of the present invention is a compound of formula (IV).

[0052] [ka] [In the formula, R 1 These are phenyl, naphthyl, or 5-10 membered ring heteroaryl compounds. The phenyl, naphthyl, and 5-10 membered ring heteroaryl compounds are optionally substituted with 1-3 substituents independently selected from the group consisting of fluoro, chloro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, di-C1-C6 alkylamino, or 3-10 membered ring heterocyclyl compounds. Here, the 3-10 membered heterocyclyl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of oxo, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. R 2 is hydrogen or (C1~C6)-alkyl, and, PG is a hydroxy protecting group, preferably a methyl group, a tetrahydropyranyl group, or a benzyl group.

[0053] R related to equation (I) 1 , R 2 The preferred definition, more preferred definition, even more preferred definition, and most preferred definition of PG shall apply mutatis mutandis with the necessary modifications as appropriate.

[0054] Method explanation The method of the present invention is described in the following scheme 1.

[0055] Scheme 1

[0056] [ka]

[0057] In step A of the present invention, O-protected hydroxyacetone is arylated at the α-position using a combination of a palladium catalyst, a bisphosphine ligand, a base, optionally a salt additive, and a solvent.

[0058] Preferably, the palladium catalyst is a salt of palladium(II), particularly [Pd(cinnamyl)Cl]2, Pd(OAc)2, or Pd(dba)2. [Pd(cinnamyl)Cl]2 is the most preferred.

[0059] Preferably, a catalytic amount of palladium is used. More preferably, the ratio of the compound of formula (II) to the palladium catalyst is in the range of 10:1 to 100:1. Even more preferably, the ratio of the compound of formula (II) to the palladium catalyst is in the range of 20:1 to 80:1.

[0060] A suitable bisphosphine ligand is given by formula (B)

[0061] [ka] (B) (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl]phosphino]ferrocene[(4-CF3Ph)PF-tBu, CAS number 246231-79-8], (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl]phosphino]ferrocene[(4-CF3Ph)PF-tBu, CAS number 849924-37-4], (2R)-1-[(1R)-1-[bis(1,1 (2S)-1-[(1S)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene[PhPF-tBu, CAS No. 155830-69-6], (2S)-1-[(1S)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene[PhPF-tBu, CAS No. 277306-29-3), (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene[CyPF-tBu, CAS No. 158923-11-6](2S)-1- [(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene[CyPF-tBu, CAS No. 1246841-00-8), (1R)-1-(dicyclohexylphosphino)-2-[(1R)-1-(dicyclohexylphosphino)ethyl]ferrocene[CyPF-Cy, CAS No. 167416-28-6](2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene[CyPF-Cy, CAS No. 246231-77-6), (2R)-1-[(1R)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene [PhPF-Cy, CAS No. 155806-35-2], (2S)-1-[(1S)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene [CAS No. 162291-02-3], di(1-adamantyl)-2-morpholinophenylphosphine [Mor-DalPhos, CAS No. 1237588-12-3], 4,5-bis(diphenylphosphino)-9,These are 9-dimethylxanthene [XantPhos, CAS number 161265-03-8], 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl [Xphos, CAS number 564483-18-7], and 1-((1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantan-8-yl)-2-(1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantan-8-yl)benzene [PAd2-DalPhos].

[0062] (4-CF3Ph)PF-tBu and PhPF-tBu are even more preferred.

[0063] The bisphosphine ligand can be applied to the reaction according to the present invention as either the R- or S-enantiomer, or as a mixture of both enantiomers. On the other hand, 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.

[0064] The ratio of the bisphosphine ligand to the palladium catalyst is in the range of 20:1 to 1:20, preferably in the range of 10:1 to 1:10, more preferably in the range of 3:1 to 1:1, and even more preferably in the range of 1.25:1.0 to 1.20:1.0.

[0065] X 1 When is bromo, iodine, or trifluorosulfonate, suitable bases for the reaction according to the present invention are alkali metal carbonates, alkali metal halides, dialkali metal phosphates, and alkali metal phosphates, such as cesium carbonate, cesium fluoride, dipotassium phosphate, and potassium phosphate. Cesium carbonate is particularly preferred.

[0066] Preferably, an excess amount of base is used.

[0067] X 1When is a trifluoromethylsulfonate, a double base condition is applied to the reaction according to the present invention. Suitable bases for the double base condition are DBUs applied together with salt additives such as sodium trifluoroacetate, sodium trifluoromethanesulfonate, and potassium trifluoromethanesulfonate.

[0068] Under the bibase conditions, an excess amount of bibase system is applied. Preferably, the ratio of (II):binary base 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):binary base is 1:2.

[0069] Preferably, an excess amount of (III) is used relative to (II). More preferably, (III):(II) is used in a ratio of 3:1 to 2:1.

[0070] Suitable solvents for the reaction according to the present invention include, for example, aromatic hydrocarbons such as toluene, xylene, or decalin; ethers such as 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me-THF), 1,2-dimethoxyethane (DME), 1,2-diethoxyethane, bis(2-methoxyethyl) ether (diglym), cyclopentyl methyl ether (CPME), or anisole; or mixtures of the aforementioned solvents.

[0071] 1,4-dioxane, THF, 2-MeTHF, or cyclopentyl methyl ether are more preferred, and 1,4-dioxane or toluene are even more preferred.

[0072] (II) is preferably diluted with an appropriate amount of solvent so that the final concentration is in the range of 0.1 M to 0.8 M, more preferably in the range of 0.2 M to 0.5 M. A final dilution concentration of 0.24 M to 0.36 M is even more preferable.

[0073] Step A can be carried out at a reaction temperature in the range of +80°C to +150°C, preferably in the range of +90°C to +130°C, and more preferably in the range of +110°C to +120°C.

[0074] The reaction time is typically in the range of 4 to 24 hours.

[0075] Most preferably, step A of the present invention is carried out in combination of [Pd(cinamyl)Cl]2 as a palladium catalyst with (4-CF3Ph)PF-tBu or PhPF-tBu as a bisphosphine ligand, where the ratio of the bisphosphine ligand to the palladium catalyst is in the range of 1.25:1.0 to 1.20:1.0, and cesium carbonate is used as the base.

[0076] Most preferably, step A of the present invention is carried out in a solvent which is 1,4-dioxane or toluene, at a dilution concentration of 0.24 M to 0.36 M, and at a temperature in the range of +110°C to +120°C.

[0077] In step B of the present invention, the O-protected hydroxyacetone of formula (IV) is deprotected under acidic conditions using a suitable solvent to obtain the corresponding arylated hydroxyacetone of formula (I). The product can then be separated by crystallization or silica gel column chromatography.

[0078] Preferably, the acid used in the deprotection step is HCl or SiO2-supported NaHSO4.

[0079] Preferably, HCl is used in excess of (IV). More preferably, the ratio of (IV) to HCl is in the range of 1:1.5 to 1:10, more preferably in the range of 1:3 to 1:7, and even more preferably 1:5.

[0080] 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 per mmol of (IV), and even more preferably, NaHSO4-SiO2 is used in an amount of 50 to 280 mg per mmol of (IV).

[0081] Suitable solvents for step B are polar solvents such as alcohols, ethers, or water, more preferably methanol, 1,4-dioxane, or water, and even more preferably water.

[0082] Step B is typically carried out in a temperature range of +10°C to +150°C, preferably in the range of +20°C to +100°C, and more preferably in the range of +40°C to +90°C. A reaction temperature of approximately +90°C is most preferred.

[0083] The deprotection time is typically 10 minutes to 1 hour.

[0084] Most preferably, step B of the present invention is carried out using an acid, where the acid in the solvent is selected from HCl or SiO2-supported NaHSO4, and the solvent is selected from methanol, 1,4-dioxane, or water.

[0085] The present invention is illustrated by, but is not limited to, the following embodiments: [Examples]

[0086] A-1. Abbreviations

[0087] [Table 1] JPEG2026511779000018.jpg236166JPEG2026511779000019.jpg169168

[0088] A-2. General Considerations Unless otherwise specified, all experimental procedures were performed in a glove box filled with nitrogen in an inert atmosphere, using oven-dried glassware and purified solvents. However, the work-up of the catalytic reaction mixture was performed on a benchtop in air using unpurified solvent. The following purification methods were used for the solvents and reagents used in the glove box: Toluene was deoxygenated by sparging with nitrogen gas, then passed through a double-column solvent purification system packed with alumina and copper-Q5 reagents, and stored on an operating 4Å molecular sieve; THF was distilled from sodium benzophenone ketyl and stored on an operating 4Å molecular sieve; 2-MeTHF, 1,4-dioxane, DCM (i.e., CH2Cl2), D MF, DMA, ACN (i.e., MeCN), NMP, DMSO, and anisole were purchased anhydrous from Sigma-Aldrich, deoxygenated by sparging with nitrogen gas, and stored on an operating 4Å molecular sieve; siRNA, CPME, DME, diglym, and 4-MeTHP were degassed by three freeze-degassing cycles and then dried on an operating 4Å molecular sieve; pentane was deoxygenated by sparging with nitrogen gas and then dried on an operating 4Å molecular sieve. Cs2CO3 and K2CO3 were purchased anhydrous from Sigma-Aldrich and ground into fine powders using a mortar and pestle. The O-protecting starting materials, 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone and 3-[(tetrahydro-2H-pyran-2-yl)oxy]-2-butanone, and all triflate electrophiles were synthesized as described below. NaHSO4-SiO2 is mentioned in the literature. 1 It was prepared from NaHSO4 and silica gel according to the specified method. All other solvents, reagents, and materials were commercially available. All catalyst addition amounts indicated in "%" are based on "mol%" relative to the aryl electrophile.

[0089] GC data was acquired using a calibrated instrument (Shimadzu GC-2030 gas chromatograph) equipped with an SGE BP-5 column (30 m, inner diameter 0.25 mm): detector SFID1, column oven temperature 100°C, SFID1 temperature 305°C, SPL1 temperature 200°C, linear velocity 45.4 cm / sec, total flow rate 45.1 mL / min, column flow rate 2.1 mL / min. Program: 2 minutes at 100°C, 10 minutes at 200°C, 15 minutes at 220°C (times are retention times).

[0090] Automated flash column chromatography was performed using 10g, 25g, or 40g normal-phase SiliCycle SilliSep® column cartridges, or a 100g normal-phase Biotage SNAP KP-Sil column cartridge; "CV" refers to the column volume in chromatographic purification.

[0091] all 1 1H NMR (500 MHz and 300 MHz), 13 C{ 1 ¹H NMR (125.8 MHz and 75.4 MHz), and 19 The F NMR (471 MHz) spectrum was recorded at 300 K, and the residual prothio solvent peak was observed. 1 H), deuterated solvent peak ( 13 C{ 1 The measurements were taken at -63.7 ppm, relative to {H} or external 0.5% (CF3)C6H519F) in CDCl3. The splitting patterns are shown as follows: br, broad line; s, single line; d, double line; t, triple line; q, quadruple line; m, multiline. All coupling constants (J) are reported in Hertz (Hz).

[0092] Mass spectra were acquired using an ion trap (ESI) instrument operating in a specified positive or negative mode.

[0093] A-3. General Procedure A-3. A general procedure for mono-α-arylating 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone using [Pd(cinnamyl)Cl]2 / PhPF-tBu(GP1) and (hetero)aryl bromide. Unless otherwise specified, 0.625 mol% [Pd(cinnamyl)Cl]2 (CAS No. 12131-44-1) (1.25 mol% Pd) and 1.5 mol% PhPF-tBu (CAS No. 155830-69-6 and CAS No. 277306-29-3) were added to a 1-drum screw-cap vial equipped with a magnetic stirring bar and dissolved in 1.33 mL of 1,4-dioxane (0.36 M in aryl-Br). Then, aryl bromide (0.48 mmol, 1.0 equivalent) and Cs2CO3 (2 equivalents) were added, followed by 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (3 equivalents). The vials were sealed with PTFE-lined caps, wrapped in insulating tape, then removed from the glove box and placed on a temperature-controlled aluminum heating block set to 110°C, where they were reacted at 900 rpm for 4.5 hours under magnetic stirring.

[0094] A-3.2. General procedure for mono-α-arylating 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone using [Pd(cinnamyl)Cl]2 / (4-CF3Ph)PF-tBu(GP2) and aryl triflate. Unless otherwise specified, 2.5 mol% [Pd(cinnamyl)Cl]2 (5 mol% Pd) and 6.25 mol% (4-CF3Ph)PF-tBu (CAS numbers 246231-79-8 and 849924-37-4) were added to a single-drum screw-cap vial equipped with a magnetic stirrer and dissolved in 2 mL of toluene (0.24 M in aryl-OTf). Next, DBU (2 equivalents), NaOTf (2 equivalents), aryl triflate (0.48 mmol, 1.0 equivalent), and 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (2 equivalents) were added. The vial was sealed with a PTFE-lined cap, wrapped with insulating tape, then removed from the glove box and placed on a temperature-controlled aluminum heating block set to 120°C, where it was reacted at 900 rpm for 12 hours under magnetic stirring.

[0095] A-3.3. General procedure for synthesizing aryl triflates from phenols (GP3). Phenol (5.4 mmol, 1 equivalent) was dissolved in CH2Cl2 (10 mL) and stirred at 0°C under an N2 atmosphere. Triethylamine (904 μL, 6.5 mmol, 1.2 equivalents) was added dropwise over 5 minutes, followed by trifluoromethanesulfonic anhydride (1.0 mL, 5.9 mmol, 1.1 equivalents) dropwise over 30 minutes. The reaction mixture was warmed to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was cooled to 0°C, 2 M HCl (2 equivalents) was added, and the mixture was stirred for 1 hour, 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 / Celite pad. The solvent was removed under vacuum to obtain the aryl triflate product.

[0096] A-3.4. General procedure for mono-α-arylating 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone using [Pd(cinnamyl)Cl]2 / (4-CF3Ph)PF-tBu(GP4) and (hetero)aryl bromide. Unless otherwise specified, 1.5 mol% [Pd(cinnamyl)Cl]2 (3 mol% Pd) and 3.75 mol% (4-CF3Ph)PF-tBu (CAS numbers 246231-79-8 and 849924-37-4) were added to a 1-drum screw-cap vial equipped with a magnetic stirrer and dissolved in 2 mL of THF (0.24 M in aryl-Br). Then, aryl bromide (0.48 mmol, 1.0 equivalent) and Cs2CO3 (2 equivalents) were added, followed by 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (2 equivalents). The vial was sealed with a PTFE-lined cap, wrapped with insulating tape, then removed from the glove box and placed on a temperature-controlled aluminum heating block set to 90°C, where it was reacted at 900 rpm for 12 hours under magnetic stirring.

[0097] A-3.5. A general procedure for mono-α-arylating 1-(benzyloxy)propan-2-one using [Pd(cinnamyl)Cl]2 / PhPF-tBu(GP5) and (hetero)aryl bromide. Unless otherwise specified, 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu were added to a screw-cap vial with a magnetic stirrer in a single drum, and dissolved in 1.33 mL of 1,4-dioxane (0.36 M in aryl-Br). Then, aryl bromide (0.48 mmol, 1.0 equivalent) and Cs2CO3 (2 equivalents) were added, followed by 1-(benzyloxy)propan-2-one (3 equivalents). The vial was sealed with a PTFE-lined cap, wrapped with insulating tape, then removed from the glove box and placed on a temperature-controlled aluminum heating block set to 110°C, where it was reacted at 900 rpm for 4.5 hours under magnetic stirring.

[0098] A-3.6. A general procedure for mono-α-arylating methoxyacetone using [Pd(cinnamyl)Cl]2 / PhPF-tBu(GP6) and (hetero)aryl bromide. Unless otherwise specified, 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu were added to a screw-cap vial with a magnetic stirrer in a single drum, and dissolved in 1.33 mL of 1,4-dioxane (0.36 M in aryl-Br). Then, aryl bromide (0.48 mmol, 1.0 equivalent) and Cs2CO3 (2 equivalents) were added, followed by methoxyacetone (3 equivalents). The vial was sealed with a PTFE-lined cap, wrapped with insulating tape, then removed from the glove box and placed on a temperature-controlled aluminum heating block set to 110°C, where it was reacted at 900 rpm for 4.5 hours under magnetic stirring.

[0099] A-3.7. General procedure for mono-α-arylating O-protected hydroxyacetone in the optimization process (GP7). Inorganic bases and / or salt additives were added to a single-drum vial equipped with a magnetic stirrer. Then, [Pd(cinnamyl)Cl]2 and ligands were added as a mixed stock solution in the corresponding reaction solvent containing 5 mg or more of [Pd(cinnamyl)Cl]2. Next, halogenated / pseudohalogenated o-chloroaryl (0.12-0.24 mmol, 1.0 equivalent), O-protected hydroxyacetone (2-3 equivalents), and DBU (if used) were added. The vial was sealed with a PTFE-lined cap, wrapped with insulating tape, then removed from the glove box and placed on a temperature-controlled aluminum heating block set to 70-130°C, and reacted at 900 rpm for 3-48 hours under magnetic stirring.

[0100] A-4. Workup Method A-4.1A. Workup Method A (Deprotection and Purification of 1-phenyl-3-hydroxypropan-2-one Product) After performing GP1 with 0.48 mmol scale aryl bromide, the resulting mixture was cooled to room temperature, filtered through a thin layer of silica / celite frit saturated with hexane, and eluted into a 4-drum vial with ethyl acetate (approximately 20 mL). The recovered eluate was then dried under vacuum for 30 minutes to obtain the crude residue. Subsequently, a stirring bar and 10 mL of water preheated to 95°C were added, followed by 200 μL of concentrated HCl. The vial was sealed with a PTFE-lined cap and placed on a temperature-controlled aluminum heating block set to 95°C, where it was reacted at 1500 rpm for 10 minutes under magnetic stirring. Then, thermogravimetric filtration was performed through glass frit padded with a Whatman 1 filter pad. The glass frit, filter pad, and collection flask were used immediately after being removed from an oven set to 120°C. The eluate was cooled to room temperature and then crystallized overnight in a refrigerator set to 3°C to obtain the desired product. Next, the benzyl α-hydroxyketone(I) crystals were separated by suction filtration.

[0101] A-4.1B. Workup Method A' (Deprotection and Purification of 1-phenyl-3-hydroxypropan-2-one Product by Chromatography) After performing GP1 with 0.48 mmol scale aryl bromide, the resulting mixture was cooled to room temperature, filtered through thin-layer silica / celite frit, and eluted into 4-drum vials with ethyl acetate (approximately 20 mL). The recovered eluate was then dried under vacuum to obtain the crude residue. Subsequently, a stirring bar and 10 mL of water preheated to 95°C were added, followed by 200 μL of concentrated HCl. The vials were sealed with PTFE-lined caps and placed on a temperature-controlled aluminum heating block set to 95°C, where they were reacted at 1500 rpm for 10 minutes under magnetic stirring. Then, thermal gravity filtration was performed through glass frit padded with a Whatman 1 filter pad. The glass frit, filter pad, and collection flask were used immediately after being removed from an oven set to 120°C. The eluate was cooled to room temperature, extracted with 3 × 10 mL of ethyl acetate, the organic layers were combined, and dried over Na₂SO₄. The solvent was then removed under vacuum to obtain the crude residue. The residue was dissolved in DCM and then packed into a normal-phase SiliCycle SiliSep® 10g column cartridge. The product was then purified using a methanol-DCM eluate mixture. The relevant UV-activated column fractions were combined and dried under vacuum to obtain the target product in each case.

[0102] A-4.1C. Workup Method A'' (Deprotection and Purification of 1-phenyl-3-hydroxypropan-2-one Product) This method is identical to workup method A', but does not include the thermal gravity filtration step.

[0103] A-4.2. Workup Method C (Deprotection and Purification of 1-phenyl-3-hydroxypropan-2-one Product) After performing GP1 with 0.24 mmol scale aryl bromide, the resulting mixture was cooled to room temperature, filtered through thin-layer silica / celite frit, and eluted with ethyl acetate (approximately 20 mL). The recovered eluate was dried under vacuum to obtain the crude residue. This residue was then dissolved in 2 mL of methanol and added to a 1-drum vial containing 200 mg of NaHSO4-SiO2, along with a magnetic stir bar. The vial was sealed with a PTFE-lined cap and placed on a temperature-controlled aluminum heating block set to 50°C, where it was reacted under magnetic stirring at 1500 rpm for 45 minutes. The resulting solution was then filtered through a silica plug and eluted with approximately 10 mL of siRNA into 4-drum vials. The solvent was then dried under vacuum to obtain the crude residue. This residue was dissolved in DCM and then packed into a normal-phase SiliCycle SiliSep® 10 g column cartridge. The product was then purified using a methanol-DCM eluate mixture. The relevant UV-activated column fractions were combined and dried under vacuum to obtain the target product in each case.

[0104] A-4.3. Work-up method D (Purification of 1-phenyl-3-[(oxan-2-yl)oxy]propan-2-one, 1-phenyl-3-methoxypropan-2-one product, and 1-(benzyloxy)-3-phenylpropan-2-one product). GP1, GP2, and GP4-GP6 were performed, and the resulting mixtures were cooled to room temperature, filtered through a thin layer of silica / celite frit saturated with hexane, and eluted with ethyl acetate (approximately 50 mL). The recovered eluate was then dried under vacuum to obtain the crude residue. This residue was dissolved in ethyl acetate and then packed into either a silica-based flash column or a 10 g, 25 g, or 40 g column cartridge of SiliCycle's SiliSep®. The product was then purified using an eluate mixture of hexane and ethyl acetate. The relevant UV-activated column fractions were combined and dried under vacuum to obtain the target product in each case.

[0105] A-4.4. Workup Method E (Purification of 1-phenyl-3-[(oxan-2-yl)oxy]propan-2-one product) After performing GP1 with aryl bromide on a 0.48 mmol scale, the resulting mixture was cooled to room temperature and filtered through Celite frit using DCM (approximately 50 mL) as the eluate. The recovered eluate was then dried under vacuum to obtain the crude residue. This residue was dissolved in DCM and then packed into a normal-phase SiliCycle SiliSep® 10 g column cartridge. The product was then purified using a methanol-DCM eluate mixture. The relevant UV-activated column fractions were combined and dried under vacuum to obtain the target product in each case.

[0106] A-4.5. Workup Method F (Procedure for measuring GC-FID yield before deprotection of IV-1 and separation of I-1) The following workup method was used in combination with workup method A or A'' to obtain the catalytic reaction yield of (IV-1). Unless otherwise specified in the text, GP1 was performed with 1.00 mmol scale aryl bromide, the reaction mixture was filtered through silica / celite frit, and eluted with ethyl acetate as described in workup method A or A''. The eluate was then transferred to a 50 mL graduated cylinder and supplemented with ethyl acetate up to a maximum of 50 mL. Subsequently, using a 10 mL volumetric pipette, 5 mL (10%) of the eluate was transferred to a 4-drum vial containing o-xylene (12.1 μL, 0.1 mmol) as an internal standard. A portion of the solution was then transferred to a GC vial for analysis. After GC injection, the entire 5 mL sample was combined again with the remainder of the eluate, and the remaining steps of workup method A or A'' were performed.

[0107] A-4.6. Workup Method G (Procedure for manufacturing GC samples) After performing GP1, GP2, and GP4-GP7 (with (hetero)aryl halides on a 0.12-0.24 mmol scale) at room temperature, 100 μL aliquots of the reaction mixture were packed into small-volume pipette filters (Kimwipes containing Celite and silica gel), eluted with ethyl acetate, and the eluate was collected in a GC vial. Calibrated GC-FID estimates are shown based on data obtained from standard materials using o-xylene, mesitylene, or phenyl dodecane as internal standards.

[0108] A-5. Deprotection Screening A-5.1. Procedure for optimizing the deprotection / isolation method (D1) All deprotection methods in this screening were performed from the same catalytic reaction (results are outlined in Table S8). After GP1 with 4.00 mmol scale aryl bromide, the resulting reaction product was filtered through thin-layer silica / celite frit saturated with hexane and eluted with ethyl acetate (approximately 60 mL). The eluate was then transferred to a 100 mL graduated cylinder and refilled with ethyl acetate up to a maximum of 80 mL. The solution was then transferred to a beaker, and using a 10 mL volumetric pipette, 6 × 9.6 mL volumes of eluate (each corresponding to a 0.48 mmol aryl bromide reaction) were transferred to six separate 4-drum vials. From there, six variations of workup method A were performed as shown in entries 1-6. In entries 7-10 (workup methods A', A'', B, and C), the same procedure was performed with 4 × 4.8 mL volumes of eluate (each corresponding to a 0.24 mmol aryl bromide reaction). Subsequently, the remaining 2 mL of eluate (corresponding to the 0.1 mmol aryl bromide reaction) was transferred to a 4-drum vial containing o-xylene (12.1 μL, 0.1 mmol) as an internal standard. A portion of the solution was transferred to a GC vial for analysis, and the GC-FID yield of IV-1 was determined to be 81%.

[0109] A-5.2. Procedure for optimizing work-up method C (deprotection of IV-1 and III-1 with NaHSO4-SiO2) (C1) As shown in Table S9, (IV-1) (0.12 mmol), (III-1) (0.24 mmol), and 1 mL of methanol (99%) were added to a vial containing NaHSO4-SiO2 (18-100 mg) and a magnetic stirring bar in one drum. In all entries, the NaHSO4-SiO2 was used immediately after being removed from an oven set to 120°C. The vial was sealed with a PTFE-lined cap, wrapped in insulating tape, placed on a temperature-controlled aluminum heating block set to a specific temperature, and reacted under magnetic stirring at 900 rpm for 15 minutes to 48 hours.

[0110] B. Experiment Section B-1. Screening Results

[0111] [Table 2]

[0112] [ka]

[0113] Table S2. Screening of protecting groups in cross-couplings containing 3-chloro-4-bromotoluene.

[0114] [ka] PG=Bn, Me

[0115] [Table 3]

[0116] Table S3. Screening of substrates, solvents, and additives in cross-couplings containing 3-chloro-4-bromotoluene.

[0117] [ka]

[0118] [Table 4] JPEG2026511779000026.jpg233169

[0119] Table S4. Further optimization: Time and load amounts for substrate and solvent.

[0120] [ka]

[0121] [Table 5] JPEG2026511779000029.jpg118166

[0122] Table S5. Summary of some optimization conditions for the production of IV-1 from 3-chloro-4-bromotoluene.

[0123] [ka]

[0124] [Table 6]

[0125] [Table 7] JPEG2026511779000033.jpg250169

[0126] [Table 8]

[0127] Examination of the effect of salt additives in the reaction of cross-coupling 2-chloro-4-methylphenyl trifluoromethanesulfonate and THP-protected hydroxyacetone to obtain (IV-1).

[0128]

Chemical formula

[0129]

Table 9

[0130] Table S8. Optimization of the formation of (IV-1) and subsequent deprotection to (I-1).

[0131]

Chemical formula

[0132]

Table 10

[0133] Table S9. Deprotection of (IV-1) and (III-1) by NaHSO4-SiO2 (optimization of work-up method C)

[0134]

Chemical formula

[0135]

Table 11

[0136] B-2. Example Example (III-1): 1-[(oxan-2-yl)oxy]-2-propanone

[0137] [ka]

[0138] The title compound was prepared by a modified procedure of the method described in the reference (Kim, DS et al., Bioorg Med Chem Lett 2001, 11 (18), 2541-3) (3,4-dihydro-2H-pyran was used in an amount of 1.5 equivalents 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 equivalents) were added to a 40 mL vial containing pyridinium p-toluenesulfonate (0.754 g, 3 mmol, 0.1 equivalent), a magnetic stirring bar, and 25 mL of anhydrous DCM. The vial was sealed with a PTFE-lined cap, wrapped with insulating tape, then removed from the glove box and placed on a temperature-controlled aluminum heating block set to 50°C, where it was reacted at 900 rpm for 18 hours under magnetic stirring. The compound was purified by applying a solvent gradient of 10% ethyl acetate in hexane using silica flash column chromatography. The relevant fractions were combined by vanillin staining, and the solvent was removed under vacuum to obtain the title compound as a clear oily substance with an isolation yield of 72% (3.41 g, 21.6 mmol).

[0139] 1 H NMR (300 MHz, CDCl3) δ 4.68 - 4.59 (m, 1H), 4.24 (d, J = 17.3 Hz, 1H), 4.10 (d, J = 17.3 Hz, 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{ 1H} NMR (126 MHz, CDCl3) δ 206.86, 98.90, 72.47, 62.50, 30.41, 26.63, 25.40, 19.31.

[0140] Example (III-2): 3-[(oxan-2-yl)oxy]]-2-butanone

[0141] [ka]

[0142] 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 equivalents) were added to a 40 mL vial containing pyridinium p-toluenesulfonate (0.314 g, 1.25 mmol, 0.1 equivalent), a magnetic stirrer, and 25 mL of anhydrous DCM. The vial was sealed with a PTFE-lined cap, wrapped with insulating tape, removed from the glove box, placed on a temperature-controlled aluminum heating block set to 50°C, and reacted at 900 rpm for 18 hours under magnetic stirring. The homogeneous reaction mixture was then dry-packed into silica under vacuum and subsequently packed into a 100 g normal-phase Biotage SNAP KP-Sil column cartridge. The compound was purified by sequentially applying solvent gradients of 5% (1 CV) ethyl acetate in hexane, 5–15% (10 CV) ethyl acetate in hexane, and then 15% (2 CV) ethyl acetate in hexane using flash column chromatography with silica. The relevant fractions were combined by vanillin staining, and the solvent was removed under vacuum to obtain the title compound, a 1:0.08 mixture of diastereomers, as a clear oily substance with an isolation yield of 42% (0.901 g, 5.23 mmol). The ratio of the diastereomers was: 1 This was determined by the ratio of the -CH-CH3 proton integrals shown in the 1H NMR spectrum. 1 H and 13 C{ 1 The 1H NMR peak corresponds to the main diastereomerset.1 Significant overlap is observed between the diastereomer peaks in the 1H NMR spectrum.

[0143] 1 H NMR (300 MHz, CDCl3) δ 4.57 (dd, J = 4.5, 2.9 Hz, 1H), 4.25 (q, J = 7.0 Hz, 1H), 3.92 - 3.79 (m, 1H), 3.56 - 3.42 (m, 1H), 2.15 (s, 3H), 1.96 - 1.46 (m, 8H), 1.36 (d, J = 7.0 Hz, 3H). 13 C{ 1 H} NMR (75 MHz, CDCl3) δ 210.91, 98.61, 77.91, 62.87, 30.82, 25.56, 25.45, 19.57, 18.22. HRMS-ESI (m / z): Calc'd for C9H 16 NaO3[M+Na] + : 195.0992. Found: 195.0992.

[0144] Example (II-1): 2-chloro-4-methylphenyltrifluoromethanesulfonate

[0145] [ka]

[0146] The title compound was obtained as a dark red oily substance with a 96% isolation yield (1.43 g, 5.2 mmol) by synthesizing the corresponding phenol (5.4 mmol) according to GP3.

[0147] 1 H NMR (500 MHz, CDCl3) δ 7.33 - 7.32 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.14 - 7.12 (m, 1H), 2.37 (s, 3H). 13 C{ 11H NMR (126 MHz, CDCl3) δ 143.69, 140.02, 131.73, 129.03, 126.84, 122.69, 118.80 (q, J CF = 320.5 Hz), 20.88. 19 19F NMR (471 MHz CDCl3) δ -73.55. HRMS-ESI (m / z): Calc’d for C8H6ClF3NaO3S [M+Na] + : 296.9576. Found: 296.9570.

[0148] Example (II-2): 4-Chloro-2-methylphenyl trifluoromethanesulfonate

[0149]

Chemical Structure

[0150] The title compound was obtained as a dark red oil with an isolated yield of 98% (1.45 g, 5.3 mmol) by synthesizing the corresponding phenol (5.4 mmol) according to GP3.

[0151] 1 1H NMR (500 MHz, CDCl3) δ 7.30 (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 13C{ 1 1H} NMR (126 MHz, CDCl3) δ 152.92 (d, J CF = 252.0 Hz), 134.36 (m), 130.10 (m), 129.15, 118.76 (q, J CF = 320.3 Hz), 114.98, 114.88, 19.95. 19 19F NMR (471 MHz CDCl3) δ -73.03 (d, J FF = 11 Hz), -126.16 (q, J FF= 11 Hz). HRMS-ESI (m / z): Calc'd for C8H6ClF3NaO3S [M+Na] + : 296.9577. Found: 296.9568

[0152] Example (II-3): 2-chloro-6-fluoro-3-methylphenyltrifluoromethanesulfonate

[0153] [ka]

[0154] The title compound was obtained as a dark red oily substance with a 95% isolation yield (1.64 g, 5.1 mmol) by synthesizing the corresponding phenol (5.4 mmol) according to GP3.

[0155] 1 H NMR (500 MHz, CDCl3) δ 7.23 (dd, J = 8.7, 5.5, 1H), 7.09 (t, J = 8.9 Hz, 1H), 2.41 (s, 3H). 13 C{ 1 H} NMR (126 MHz, CDCl3) δ 152.93 (m), 134.36 (m), 130.10 (m), 129.15, 118.70 (q, J CF = 321 Hz), 115.13, 114.98, 19.95. 19 F NMR (471 MHz CDCl3) δ -73.04 (d, J FF = 11 Hz), -126.18 (q, J FF = 11 Hz). HRMS-ESI (m / z): Calc'd for C8H5ClF4NaO3S [M+Na] + : 314.9482. Found: 314.9476.

[0156] Example (II-4): 4-chloro-2-cyclohexylphenyltrifluoromethanesulfonate

[0157] [Chemical formula]

[0158] The title compound was obtained as a dark red oil with an isolated yield of 77% (1.43 g, 4.2 mmol) by synthesizing the corresponding phenol (5.4 mmol) according to GP3.

[0159] 1 H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 2.5, 1H), 7.22 (d, J = 8.8, 2.5 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 2.87 - 2.83 (m, 1H), 1.90 - 1.81 (m, 5H), 1.48 - 1.30 (m, 5H). 13 C{ 1 H} NMR (126 MHz, CDCl3) δ 145.55, 142.41, 134.42, 128.82, 127.52, 126.74 (q, J CF = 92 Hz), 122.72, 37.77, 35.55, 26.68, 26.01. 19 F NMR (471 MHz CDCl3) δ -73.78. HRMS-ESI (m / z): Calc’d for C 13 H 14 ClF3NaO3S [M+Na] + : 365.0202. Found: 365.0210.

[0160] Example (II-5): 2-Chloro-4-methylphenylsulfuryl fluoride

[0161] [Chemical formula]

[0162] A round-bottom flask equipped with a Teflon-coated stirring bar and a rubber septum was packed with 2-chloro-4-methylphenol (20.0 g, 136.1 mmol, 1.0 equivalent), diisopropylethylamine (52.6 g, 129.3 mmol, 3.0 equivalents), and acetonitrile (312 g). The reaction flask was evacuated under vacuum and then repacked with sulfuryl difluoride. The reaction mixture was then stirred at room temperature for 4 hours, at which point complete consumption of the starting materials was confirmed by HPLC analysis. The remaining sulfuryl difluoride was removed under vacuum (with a gas washer). Acetonitrile was removed using a rotary evaporator. The reaction mixture was diluted with ethyl acetate (100 mL), transferred to a separatory funnel, washed twice with water (2 × 100 mL), and then washed with brine (2 × 50 mL). Next, the product was purified by distillation (65°C, 8 mbar to 85°C, 6 mbar) to obtain the title compound with a purity of 97% and a yield of 85.6%.

[0163] 1 H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 8.4, 1.4 Hz, 1H), 7.31 (dd, J = 8.4, 1.4 Hz, 1H), 7.17 - 7.13 (m, 1H), 2.38 (s, 3H).

[0164] Example (I-1): 1-(2-chloro-4-methylphenyl)-3-hydroxypropan-2-one

[0165] [ka]

[0166] The title compound was synthesized by three different methods. Method 1. The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (4 mmol) according to GP1 in 1,4-dioxane (0.36 M) in a 4-drum vial at 110°C using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu to obtain IV-1 in 81% yield. This yield was determined by calibrated GC analysis. Deprotection / purification was performed on a 0.48 mmol scale (screening D1, entry 2) according to workup method A to obtain the title compound as a white crystalline solid in 68% isolation yield (0.065 g, 0.327 mmol). Method 2. The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (1 mmol) according to GP1, using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu in 4-dioxane (0.36 M) at 110 °C for 4 hours, yielding IV-1 in 86% of the original compound. This yield was determined by GC analysis calibrated according to workup method F. Deprotection / purification was performed according to workup method A'' using 400 μL of concentrated HCl and 15 mL of H2O (0.67 M). The title compound was purified by flash column chromatography using a 40g SiliCycle SiliSep® column cartridge in silica by applying a solvent gradient of 0% methanol (2 CV) in DCM followed by 0-4% methanol (20 CV) in DCM, and obtained as a white solid in a 75% isolation yield (0.148 g, 0.745 mmol). Method 3. Benchtop synthesis of the title compound: Without evacuation, 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 described in the General Considerations section, but handled in air as specified herein, 0.36 M) were added to a 4-drum vial.Next, a 1-drum screw-cap vial containing a magnetic stir bar was charged with 0.625 mol% of [Pd(cinnamyl)Cl]2 (1.25 mol% Pd), 1.5 mol% of PhPF-tBu, and Cs2CO3 (2 equivalents). Each vial was sealed with a cap equipped with a PTFE septum, wrapped with insulating tape, and placed in a temperature-controlled aluminum heating block at 25 °C. The 4-MeTHP solution was sparged with N2 for 5 minutes using an inserted needle. On the other hand, the 1-drum vial was washed with N2 using an inserted needle (this needle was retained to maintain a positive nitrogen pressure during the reaction). The 4-MeTHP solution was transferred to the 1-drum vial using a syringe under a continuous nitrogen pressure. The mixture was reacted at 110 °C and 900 rpm for 4 hours by magnetic stirring under a positive nitrogen pressure to obtain IV-1 in 81% yield. This yield was determined by calibrated GC analysis according to workup method F. Deprotection / purification was performed using 400 μL of HCl (concentrated) and 15 mL of H2O (0.67 M) according to workup method A''. Purification was carried out by flash column chromatography on silica using a SiliCycle SiliSep™ 40 g column cartridge, applying a solvent gradient of 0% methanol in DCM (2 CV), followed by 0 - 4% methanol in DCM (20 CV), to obtain the title compound as a white solid in 65% isolated yield (0.129 g, 0.745 mmol).

[0167] 1 H NMR (300 MHz, CDCl3) δ 7.22 (d, J = 1.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.05 (dd, J = 7.6, 1.9 Hz, 1H), 4.31 (s, 2H), 3.81 (s, 2H), 2.89 (s, 1H), 2.33 (s, 3H). 13 C{ 1H} NMR (75 MHz, 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): Calc'd for C 10 H 11 ClNaO2[M+Na] + : 221.0340. Found: 221.0337.

[0168] Example (I-2): 1-(2-chloro-4-fluorophenyl)-3-hydroxypropan-2-one

[0169] [ka]

[0170] The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1 using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu at 110°C, and deprotected / purified according to a modified workup method A. After cooling to room temperature, the aqueous solution of the eluate was extracted with 3 × 5 mL of 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 with stirring until homogeneous. The mixture was cooled to room temperature and then left overnight in a refrigerator set to 3°C to obtain the title compound as a white crystalline solid in 39% isolation yield (0.038 g, 0.188 mmol). Alternatively, workup method A' can be used for deprotection / purification. The title compound was purified by flash column chromatography using a SiliCycle SiliSep® 40g column cartridge in silica by applying a solvent gradient of 0% methanol (2 CV) in DCM followed by 0-4% methanol (20 CV) in DCM, and obtained as a white solid with an isolation yield of 52% (0.051 g, 0.252 mmol).

[0171] 1 H NMR (300 MHz, CDCl3, 0.05% (v / v) TMS) δ 7.27 - 7.12 (m, 2H), 7.00 (td, J = 8.2, 2.6 Hz, 1H), 4.35 (d, J = 4.3 Hz, 2H), 3.83 (s, 2H), 2.98 (t, J = 4.9 Hz, 1H). 13 C{ 1 H} NMR (75 MHz, CDCl3, 0.05% (v / v) TMS) δ 206.10, 162.01 (d, J CF = 248 Hz), 132.75 (d, J CF = 15 Hz), 127.34, 117.47-117.14 (overlapping), 114.69 (d, J CF (= 35 Hz), 68.23, 42.76. 19 F NMR (282 MHz, CDCl3, 0.05% (v / v) TMS) δ -112.08. HRMS-ESI (m / z): Calc'd for C9H8ClFNaO2[M+Na] + : 225.0089. Found: 225.0089.

[0172] Example (I-3): 1-[2-chloro-5-(trifluoromethyl)phenyl]-3-hydroxypropan-2-one

[0173] [ka]

[0174] The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1 using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu at 110°C. Deprotection / purification was performed using 8 mL of H2O (0.06 M) according to workup method A to obtain the title compound as a white crystalline solid in a 35% isolation yield (0.042 g, 0.166 mmol). Alternatively, workup method A' can be used for deprotection / purification. The title compound was purified by flash column chromatography using a silica flash column cartridge of SiliCycle's SiliSep™ by applying a solvent gradient of 0% methanol (2 CV) in DCM followed by 0-4% methanol (20 CV) in DCM, and obtained as a white solid with an isolation yield of 49% (0.060 g, 0.238 mmol).

[0175] 1 H NMR (300 MHz, CDCl3, 0.05% (v / v) TMS) δ 7.58 - 7.47 (m, 3H), 4.39 (d, J = 4.9 Hz, 2H), 3.92 (s, 2H), 2.99 (t, J = 4.9 Hz, 1H). 13 C{ 1 H} NMR (75 MHz, CDCl3, 0.05% (v / v) TMS) δ 205.24, 138.30, 132.52, 130.35-128.76 (overlapping), 126.00, 126.08, 123.03 (q, J CF = 330 Hz), 68.38, 43.29. 19 F NMR (282 MHz, CDCl3, 0.05% (v / v) TMS) δ -62.61. HRMS-ESI (m / z): Calc'd for C9H7ClF3O2[MH] - : 251.0092. Found: 251.0091.

[0176] Example (I-4): 1-(2-chloro-4-methoxyphenyl)-3-hydroxypropan-2-one

[0177] [ka]

[0178] The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1 using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu at 110°C. Deprotection / purification was performed using 8 mL of H2O (0.06 M) according to workup method A to obtain the title compound as a white crystalline solid in 51% isolation yield (0.053 g, 0.247 mmol). Alternatively, workup method A'' can be used for deprotection / purification. The title compound was purified by flash column chromatography using a SiliCycle SiliSep™ 10g column cartridge in silica, applying a solvent gradient of 0% methanol (2 CV) in DCM followed by 0-4% methanol (20 CV) in DCM, and obtained as a white solid with an isolation yield of 66% (0.068 g, 0.317 mmol).

[0179] 1 H NMR (300 MHz, CDCl3, 0.05% (v / v) TMS) δ 7.15 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 2.6 Hz, 1H), 6.80 (dd, J = 8.5, 2.6 Hz, 1H), 4.30 (d, J = 4.8 Hz, 2H), 3.83 - 3.76 (m, 5H), 3.02 (t, J = 4.8 Hz, 1H). 13 C{ 1HRMS-ESI (m / z): Calc'd for C 10 H 11 ClNaO3[M+Na] + : 237.0289. Found: 237.0289.

[0180] Example (I-5): 1-(2,4-dichlorophenyl)-3-hydroxypropan-2-one

[0181] [ka]

[0182] Method 1. The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1 using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu at 110 °C. Deprotection / purification was performed using 8 mL of H2O (0.06 M) according to work-up method A to obtain the title compound as a white crystalline solid in 55% isolation yield (0.058 g, 0.265 mmol). Method 2. The same catalytic reaction procedure as above can be used, and work-up method A'' can be used for deprotection / purification. The title compound was purified by flash column chromatography using a 10g SiliCycle SiliSep™ column cartridge in silica by applying a solvent gradient of 0% methanol (2 CV) in DCM followed by 0-4% methanol (20 CV) in DCM, and obtained as a white solid in 72% isolation yield (0.076 g, 0.347 mmol). Method 3. The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP4 using 1 mol% [Pd(cinnamyl)Cl]2 (2 mol% Pd) and 2.5 mol% (4-CF3Ph)PF-tBu at 90°C, and deprotected / purified according to a modified version of Workup Method B. The title compound was purified by flash column chromatography using a SiliCycle SiliSep™ 10g column cartridge in silica by applying a solvent gradient of 0% methanol (2 CV) in DCM followed by 0-4% methanol (20 CV) in DCM, and obtained as a white solid with an isolation yield of 82% (0.086 g, 0.393 mmol).

[0183] 1 H NMR (300 MHz, CDCl3, 0.05% (v / v) TMS) δ 7.43 (d, J = 2.0 Hz, 1H), 7.30 - 7.15 (m, 2H), 4.35 (d, J = 4.9 Hz, 2H), 3.83 (s, 2H), 2.98 (t, J = 4.9Hz, 1H). 13 C{ 1H} NMR (75 MHz, 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): Calc'd for C 10 H7Cl2O2[MH] - : 216.9829. Found: 216.9828.

[0184] Example (I-6): 1-hydroxy-3-(naphthalene-1-yl)propan-2-one

[0185] [ka]

[0186] The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1 using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu at 110°C. Deprotection / purification according to workup method A yielded the title compound as a white crystalline solid in 60% isolation yield (0.058 g, 0.290 mmol).

[0187] 1 H NMR (500 MHz, CDCl3) δ 7.92 - 7.81 (m, 3H), 7.58 - 7.48 (m, 2H), 7.45 (dd, J = 8.1, 7.0 Hz, 1H), 7.40 (dd, J = 6.9, 1.2 Hz, 1H), 4.25 (d, J = 4.5 Hz, 2H), 4.19 (s, 2H), 2.98 (t, J = 4.8 Hz, 1H). 13 C{ 1H} NMR (126 MHz, CDCl3) δ 207.88, 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): Calc'd for C 13 H 12 NaO2[M+Na] + : 223.0730. Found: 223.0731.

[0188] Example (I-7): 1-Hydroxy-3-(2-Methoxy-4-methylphenyl)propan-2-one

[0189] [ka]

[0190] The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1 at 90°C using 1.25 mol% [Pd(cinnamyl)Cl]2 (2.5 mol% Pd) and 3 mol% PhPF-tBu, and deprotected / purified according to workup method A''. Purification was performed by flash column chromatography in silica using a SiliCycle SiliSep™ 40 g column cartridge, applying a solvent gradient of 0% ethyl acetate in hexane (2 CV) followed by 15-50% ethyl acetate in hexane (15 CV), to obtain the title compound as a clear oily substance in 70% isolation yield (0.076 g, 0.347 mmol).

[0191] 1 H NMR (300 MHz, CDCl3) δ 7.03 (d, J = 7.5 Hz, 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{ 1H} NMR (75 MHz, CDCl3) δ 208.46, 157.16, 139.29, 131.09, 121.55, 118.87, 111.59, 67.78, 55.42, 40.62, 21.74. HRMS-ESI (m / z): Calc'd for C 11 H 14 NaO3[M+Na] + : 217.0835. Found: 217.0835.

[0192] Example (I-8): 1-hydroxy-3-[2-chloro-4-(4-methylpiperazine-1-yl)phenyl]propan-2-one

[0193] [ka]

[0194] The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (0.24 mmol) according to GP1 using 0.75 mol% [Pd(cinnamyl)Cl]2 (1.5 mol% Pd) and 2 mol% PhPF-tBu at 110°C, and deprotected / purified according to a modified workup method A'. After thermal gravity filtration and cooling to room temperature, the aqueous layer was extracted with 10 mL of DCM, and the organic layer was discarded. The aqueous layer was then neutralized with saturated NaHCO3 and extracted with 3 × 10 mL of DCM. The organic layers were combined and dried over Na2SO4. The title compound was purified by flash column chromatography using a SiliCycle SiliSep™ 10g column cartridge in silica, applying a solvent gradient of 0% methanol (2 CV) in DCM followed by 0-20% ethyl acetate (20 CV) in hexane. The title compound was obtained as a white solid with an isolation yield of 59% (0.040 g, 0.141 mmol).

[0195] 1H NMR (500 MHz, CDCl3) δ 7.10 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 6.78 (dd, J = 8.5, 2.6 Hz, 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 HRMS-ESI (m / z): Calc'd for C 14 H 20 ClN2O2[M+H] + : 283.1208. Found: 283.1206.

[0196] Example (I-9): 1-Hydroxy-1-methyl-3-(naphthalene-2-yl)propan-2-one

[0197] [ka]

[0198] The THP-protected analog of the title compound was synthesized from the corresponding aryl bromide (0.24 mmol) according to GP1 using 0.75 mol% [Pd(cinnamyl)Cl]2 (1.5 mol% Pd) and 2 mol% PhPF-tBu at 90°C, and deprotected / purified according to workup method C. Purification was performed by flash column chromatography in silica using a SiliCycle SiliSep™ 10 g column cartridge, applying a solvent gradient of 0% ethyl acetate in hexane (2 CV) followed by 15-50% ethyl acetate in hexane (15 CV), to obtain the title compound as a white solid in isolation yield of 56% (0.029 g, 0.271 mmol).

[0199] 1 H NMR (300 MHz, CDCl3) δ 7.88 - 7.74 (m, 3H), 7.71 - 7.64 (m, 1H), 7.55 - 7.43 (m, 2H), 7.32 (dd, J = 8.4, 1.8 Hz, 1H), 4.40 (qd, J = 7.0, 4.0 Hz, 1H), 4.06 - 3.88 (m, 2H), 3.43 (d, J = 4.8 Hz, 1H), 1.46 (d, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (75 MHz, CDCl3) δ 210.25, 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): Calc'd for C 14 H 14 NaO2[M+Na] + : 237.0886. Found: 237.0884.

[0200] Example (IV-1): 1-(4-chloro-2-methylphenyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-one

[0201] [ka]

[0202] The title compound was synthesized from the corresponding aryl bromide (0.26 mmol) according to GP1 using 0.625 mol% [Pd(cinnamyl)Cl]2 (1.25 mol% Pd) and 1.5 mol% PhPF-tBu at 110°C, and purified according to workup method D. Purification was performed by flash column chromatography in silica using a SiliCycle SiliSep™ 10 g column cartridge, applying a solvent gradient of 0% ethyl acetate in hexane (2 CV), followed by 0-20% ethyl acetate in hexane (20 CV), to obtain the title compound as a clear oily substance in 73% isolation yield (0.054 g, 0.191 mmol). In addition, the title compound was synthesized from the corresponding aryl triflate (0.48 mmol) according to GP2 using 2.5 mol% [Pd(cinnamyl)Cl]2 (5 mol% Pd) and 6.25 mol% (4-CF3Ph)PF-tBu at 120°C, and purified according to a modified workup method D. The title compound was obtained as a pale yellow oily substance in 71% isolation yield (0.097 g, 0.343 mmol) by flash chromatography with silica using 10% ethyl acetate in hexane. The title compound could also be synthesized from the corresponding fluorosulfonate (II-5) in 50% and 25% yields using GP1 or GP2.

[0203] 1 H NMR (500 MHz, CDCl3, 0.05% (v / v) TMS) δ 7.21 (d, J = 1.7 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.03 (dd, J = 7.8, 1.7 Hz, 1H), 4.65 (t, J = 3.6 Hz, 1H), 4.34 (d, J = 17.3 Hz, 1H), 4.22 (d, J = 17.3 Hz, 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{ 1H} NMR (75 MHz, CDCl3) δ 205.17, 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): Calc'd for C 15 H 19 ClNaO3[M+Na] + : 305.0915. Found: 305.0914.

[0204] Example (IV-2): 1-[(oxan-2-yl)oxy]-3-[4-(trifluoromethyl)pyridine-3-yl]propan-2-one

[0205] [ka]

[0206] The title compound was synthesized from the corresponding aryl bromide (0.24 mmol) according to GP1 using 0.75 mol% [Pd(cinnamyl)Cl]2 (1.5 mol% Pd) and 2.5 mol% PhPF-tBu at 90°C, and purified according to workup method D. Purification was performed by silica flash column chromatography using a 10 g SiliCycle SiliSep® flash cartridge, applying a solvent gradient of 0% ethyl acetate in hexane (2 CV) followed by 15-50% ethyl acetate in hexane (18 CV), yielding the title compound as a pale yellow oil in 87% isolation yield (0.063 g, 0.208 mmol).

[0207] 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J = 5.1 Hz, 1H), 8.56 (s, 1H), 7.52 (d, J = 5.1 Hz, 1H), 4.65 (dd, J = 4.7, 2.6 Hz, 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 (75 MHz, CDCl3) δ 204.46, 153.99, 149.37, 136.83 (q, J CF = 31.5 Hz), 127.02, 123.10 (q, J CF = 273 Hz), 119.74, 99.60, 72.44, 62.94, 40.64, 30.46, 25.32, 19.53. 19 F NMR (282 MHz, CDCl3) δ -62.36. HRMS-ESI (m / z): Calc'd for C 14 H 15 F3NO2[MH] - : 302.1010. Found: 302.1017.

[0208] Example (IV-3): 1-[2-chloro-4-(4-methylpiperazine-1-yl)phenyl]-3-[(oxan-2-yl)oxy]propan-2-one

[0209] [ka]

[0210] The title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP4 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 workup method E. Purification was performed by silica flash column chromatography using a 10 g Silicycle SiliSep® flash cartridge, applying a solvent gradient of 0% methanol in DCM (2 CV) followed by 0-10% methanol in DCM (24 CV), yielding the title compound as a pale green oily substance in 83% isolation yield (0.146 g, 0.398 mmol).

[0211] 1 H NMR (300 MHz, CDCl3, CDCl3, 0.05% (v / v) TMS) δ 7.07 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 2.6 Hz, 1H), 6.77 (dd, J = 8.5, 2.6 Hz, 1H), 4.64 (t, J = 3.4 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 4.20 (d, J = 17.3 Hz, 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 (75 MHz, 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.

[0212] HRMS data could not be obtained for this THP-protected product due to rapid fragmentation during MS. Data for the deprotected product is presented below.

[0213] HRMS-ESI (m / z): Calc'd for C 14 H 20 ClN2O2[M+H] + : 283.1208. Found: 283.1205.

[0214] Example (IV-4): 1-(1-benzothiophen-4-yl)-3-[(oxan-2-yl)oxy]propan-2-one

[0215] [ka]

[0216] The title compound was synthesized from the corresponding aryl bromide (0.24 mmol) according to GP1 using 0.5 mol% [Pd(cinnamyl)Cl]2 (1 mol% Pd) and 1.5 mol% PhPF-tBu at 100°C, and purified according to workup method D. Purification was performed by silica flash column chromatography using a 10 g SiliCycle SiliSep® flash cartridge, applying a solvent gradient of 0% ethyl acetate in hexane (2 CV), followed by 0-30% ethyl acetate in hexane (24 CV), to obtain the title compound as a clear oily substance in 92% isolation yield (0.064 g, 0.220 mmol).

[0217] 1H NMR (300 MHz, CDCl3) δ 7.81 (dt, J = 8.0, 1.0 Hz, 1H), 7.47 (d, J = 5.5 Hz, 1H), 7.39 (dd, J = 5.6, 0.9 Hz, 1H), 7.35 - 7.26 (m, 1H), 7.26 - 7.18 (m, 1H), 4.58 (dd, J = 4.1, 2.9 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 4.22 - 4.09 (m, 3H), 3.83 - 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 (75 MHz, CDCl3) δ 205.80, 140.44, 139.24, 128.68, 126.85, 125.85, 124.48, 122.00, 121.80, 99.17, 71.75, 62.54, 45.16, 30.39, 25.36, 19.34. HRMS-ESI (m / z): Calc'd for C 16 H 18 NaO3S [M+Na] + : 313.0869. Found: 313.0867.

[0218] Example (IV-5): 1-(4-chloro-2-methylphenyl)-3-[(oxan-2-yl)oxy]propan-2-one

[0219] [ka]

[0220] The title compound was synthesized from the corresponding aryl triflate (0.48 mmol) according to GP2 using 2.5 mol% [Pd(cinnamyl)Cl]2 and 6.25 mol% (4-CF3Ph)PF-tBu at 120°C, and purified according to workup method D. The title compound was obtained as a yellow oily substance in 74% isolation yield (0.100 g, 0.355 mmol) by flash chromatography with silica using 10% ethyl acetate in hexane.

[0221] 1 H NMR (500 MHz, CDCl3) δ 7.17 (d, J = 2.1 Hz, 1H), 7.12 (dd, J = 8.1, 2.1 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 4.61 (dd, J = 4.2, 3.2 Hz, 1H), 4.28 (d, J = 17.1 Hz, 1H), 4.15 (d, J = 17.1 Hz, 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 (75 MHz, CDCl3) δ 205.75, 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): Calc'd for C 15 H 19 ClNaO3[M+Na] + : 305.0915. Found: 305.0924.

[0222] Example (IV-6): 1-(2-chloro-6-fluoro-3-methylphenyl)-3-[(oxan-2-yl)oxy]propan-2-one

[0223] [ka]

[0224] The title compound was synthesized from the corresponding aryl triflate (0.48 mmol) according to GP2 using 2.5 mol% [Pd(cinnamyl)Cl]2 and 6.25 mol% (4-CF3Ph)PF-tBu at 120°C, and purified according to workup method D. The title compound was obtained as a yellow oily substance in a 60% isolation yield (0.087 g, 0.289 mmol) by flash chromatography with silica using 10% ethyl acetate in hexane.

[0225] 1 H NMR (500 MHz, CDCl3) δ 7.13 (dd, J = 8.3, 6.3 Hz, 1H), 6.91 (t, J = 8.6 Hz, 1H), 4.68 (t, J = 3.6 Hz, 1H), 4.37 (d, J = 17.1 Hz, 1H), 4.24 (d, J = 17.2 Hz, 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 (126 MHz, CDCl3) δ 204.12, 159.86 (d, J CF = 246 Hz), 135.46 (d, J CF = 5.9 Hz), 132.30 (d, J CF = 3.9 Hz), 130.06 (d, J CF = 10.0 Hz), 120.80 (d, J CF = 18.4 Hz), 113.35 (d, J CF = 22.4 Hz), 99.05, 72.14, 62.51, 37.94, 30.41, 25.41, 20.33, 19.29. 19F NMR (471 MHz CDCl3) δ -116.11. HRMS-ESI (m / z): Calc'd for C 15 H 18 ClFNaO3[M+Na] + : 323.0821. Found: 332.0822.

[0226] Example (IV-7): 1-(4-chloro-2-cyclohexylphenyl)-3-[(oxan-2-yl)oxy]propan-2-one

[0227] [ka]

[0228] The title compound was synthesized from the corresponding aryl triflate (0.48 mmol) according to GP2 using 2.5 mol% [Pd(cinnamyl)Cl]2 and 6.25 mol% (4-CF3Ph)PF-tBu at 120°C, and purified according to workup method D. The title compound was obtained as a yellow oily substance in 70% isolation yield (0.118 g, 0.336 mmol) by flash chromatography with silica using 10% ethyl acetate in hexane.

[0229] 1 H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 8.1, 2.2 Hz, 1H), 7.06 - 7.02 (m, 1H), 4.61 (t, J = 3.6 Hz, 1H), 4.29 (d, J = 17.1 Hz, 1H), 4.16 (d, J = 17.1 Hz, 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{ 1H} NMR (126 MHz, CDCl3) δ 206.11, 148.51, 133.47, 132.16, 129.66, 126.79, 126.00, 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): Calc'd for C 20 H 27 ClNaO3[M+Na] + : 373.1541. Found: 373.1539.

[0230] Example (IV-8): 1-(benzyloxy)-3-(2-chloro-4-methylphenyl)propan-2-one

[0231] [ka]

[0232] The title compound was synthesized at 110°C according to GP5 from the corresponding aryl bromide (0.48 mmol) and 1-(benzyloxy)propan-2-one (3 equivalents) using 0.625 mol% [Pd(cinnamyl)Cl]2 and 1.5 mol% PhPF-tBu, and purified according to workup method D. Purification was performed by silica flash column chromatography using a 40 g SiliCycle SiliSep® flash cartridge, applying a solvent gradient of 0% ethyl acetate in hexane (2 CV), followed by 0-10% ethyl acetate in hexane (20 CV), to obtain the title compound as a clear oily substance in a 70% isolation yield (0.097 g, 0.336 mmol).

[0233] 1 H NMR (300 MHz, CDCl3) δ 7.43 - 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{1 H} NMR (75 MHz, CDCl3) δ 205.12, 138.99, 137.30, 134.12, 131.60, 130.11, 129.04, 128.62, 128.43, 128.13, 128.07, 127.94, 74.95, 73.57, 43.82, 20.92. HRMS-ESI (m / z): Calc'd for C 17 H 17 ClNaO2[M+Na] + : 311.0809. Found: 311.0810.

[0234] Example (IV-9): 1-(2-chloro-4-methylphenyl)-3-methoxypropan-2-one

[0235] [ka]

[0236] The title compound was synthesized at 110°C from the corresponding aryl bromide (0.48 mmol) and methoxyacetone (3 equivalents) according to GP6, using 0.625 mol% [Pd(cinnamyl)Cl]2 and 1.5 mol% PhPF-tBu, and purified according to workup method D. Purification was performed by silica flash column chromatography using a 10 g SiliCycle SiliSep® flash cartridge, applying a solvent gradient of 0% ethyl acetate in hexane (2 CV), followed by 0-20% ethyl acetate in hexane (20 CV), to obtain the title compound as a clear oily substance in 65% isolation yield (0.066 g, 0.310 mmol).

[0237] 1 H NMR (300 MHz, CDCl3) δ 7.34 - 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{ 1H} NMR (75 MHz, CDCl3) δ 204.98, 139.06, 134.12, 131.59, 130.15, 128.99, 127.99, 77.49, 59.51, 43.72, 20.92. HRMS-ESI (m / z): Calc'd for C 11 H 12 ClNaO2[M+Na] + : 235.0496. Found: 235.0504.

[0238] Example (IV-10): 1-(2-chloro-4-methoxyphenyl)-3-methoxypropan-2-one

[0239] [ka]

[0240] The title compound was synthesized from the corresponding aryl bromide (0.24 mmol) and methoxyacetone (3 equivalents) according to GP6, using 0.625 mol% [Pd(cinnamyl)Cl]2 and 1.5 mol% PhPF-tBu over 8 hours at 100°C, and purified according to workup method D. Purification was performed by silica flash column chromatography using a 10 g SiliCycle SiliSep® flash cartridge, applying a solvent gradient of 0% ethyl acetate in hexane (2 CV), followed by 0-20% ethyl acetate in hexane (15 CV), to obtain the title compound as a clear oily substance in 62% isolation yield (0.034 g, 0.297 mmol).

[0241] 1 H NMR (300 MHz, CDCl3) δ 7.12 (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{ 1H} NMR (75 MHz, CDCl3) δ 205.22, 159.60, 134.93, 132.30, 124.00, 115.08, 113.34, 77.48, 59.55, 55.67, 43.33. HRMS-ESI (m / z): Calc'd for C 11 H 13 ClNaO3[M+Na] + : 251.0445. Found: 251.0444.

[0242] Example (IV-11): 1-(benzyloxy)-3-(2-(dimethylamino)phenyl)propan-2-one

[0243] [ka]

[0244] The title compound was synthesized from the corresponding aryl bromide (0.24 mmol) and 1-(benzyloxy)propan-2-one (3 equivalents) according to GP5, using 1.25 mol% [Pd(cinnamyl)Cl]2 (2.5 mol% Pd) and 3 mol% PhPF-tBu over 6 hours at 110°C, and purified according to workup method D. Purification was performed by silica flash column chromatography using a 40 g SiliCycle SiliSep® flash cartridge, applying a solvent gradient of 0% ethyl acetate in hexane (2 CV), followed by 0-20% ethyl acetate in hexane (20 CV), to obtain the title compound as a pale yellow oil in isolation yield of 63% (0.045 g, 0.159 mmol).

[0245] 1 H NMR (500 MHz, CDCl3) δ 7.36 - 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{ 1H} NMR (126 MHz, CDCl3) δ 206.05, 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): Calc'd for C 18 H 21 NNaO2[M+Na] + : 306.1465. Found: 306.1460.

[0246] by-product 1,1-di(2-chloro-4-methylphenyl)-3-[(oxan-2-yl)oxy]propan-2-one(4a)

[0247] [ka]

[0248] The title compound was synthesized from (IV-1) and the corresponding aryl bromide (IIa) (0.24 mmol). 2 mol% [Pd(cinnamyl)Cl]2 (4 mol% Pd) and 5 mol% XPhos were added to a 1-drum screw-cap vial 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 vial was sealed with a PTFE-lined cap, wrapped with insulating tape, then removed from the glove box and placed on a temperature-controlled aluminum heating block set to 90°C, where it was reacted at 900 rpm for 12 hours under magnetic stirring. Purification was performed according to Workup Method D. The title compound was purified by flash column chromatography using a 40g column cartridge of SiliCycle's SiliSep(trademark)HP silica column by sequentially applying solvent gradients of 0% ethyl acetate in hexane (2 CV), 0-20% ethyl acetate in hexane (24 CV), and then 20% ethyl acetate in hexane. The title compound was obtained as a clear oily substance with an isolation yield of 26% (0.025 g, 0.061 mmol).

[0249] 1 H NMR (300 MHz, CDCl3) δ 7.25 (s, 2H), 7.02 (dt, J = 8.0, 1.9 Hz, 2H), 6.86 (dd, J = 9.2, 7.9 Hz, 2H), 6.16 (s, 1H), 4.58 (t, J = 3.2 Hz, 1H), 4.43 (d, J = 17.6 Hz, 1H), 4.28 (d, J = 17.6 Hz, 1H), 3.62 (ddd, J = 11.2, 9.7, 3.1 Hz, 1H), 3.42 (dtd, J = 11.2, 4.1, 1.5 Hz, 1H), 2.36 - 2.27 (m, 6H), 1.86 - 0.71 (m, 16H). 13 C{ 1H} NMR (75 MHz, CDCl3) δ 206.42, 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): Calc'd for C 22 H 24 Cl2NaO3[M+Na] + : 429.0995. Found: 429.0999.

[0250] 1,3-di(2-chloro-4-methylphenyl)-1-[(oxan-2-yl)oxy]propan-2-one(4b)

[0251] [ka]

[0252] The title compound was synthesized from IV-1 and the 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 single-drum screw-cap vial equipped 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 vial was sealed with a PTFE-lined cap, wrapped with insulating tape, removed from the glove box, placed on a temperature-controlled aluminum heating block set to 110°C, and reacted at 900 rpm for 16 hours under magnetic stirring. Purification was performed according to Workup Method D. The title compound was purified by silica flash column chromatography using a 40g SiliCycle SiliSep® flash cartridge, applying a solvent gradient of 0% (2CV) ethyl acetate in hexane and 0-20% (26CV) ethyl acetate in hexane. The title compound was obtained as a clear oily substance in a 29% isolation yield (0.028g, 0.069 mmol). The title compound is: 1 The two diastereomers were isolated as a 1:0.6 mixture, determined by the ratio of the -O-CH-O-proton integrals in the 1H NMR spectrum (4.88 ppm (t, J = 3.1 Hz, 0.60H) : 4.56 ppm (t, J = 3.6 Hz, 1.00H)).

[0253] 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 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 = 3.1 Hz, 1H), 4.56 (t, J = 3.6 Hz, 1H), 4.06 (d, J = 2.9 Hz, 2H), 3.94 (ddd, J = 11.7, 8.3, 3.8 Hz, 1H), 3.81 (d, J = 17.4 Hz, 1H), 3.73 (d, J = 17.5 Hz, 1H), 3.65 (ddd, J = 11.2, 9.8, 3.2 Hz, 1H), 3.59 - 3.52 (m, 1H), 3.45 (dtd, J = 11.3, 4.2, 1.5 Hz, 1H), 2.37 - 2.27 (m, 9H), 1.98 - 1.40 (m, 7H). 13 C{ 1 H} NMR (126 MHz, CDCl3) δ 203.81, 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): Calc’d for C 22 H 24 Cl2NaO3[M+Na] + : 429.0995. Found: 429.1007.

[0254] A mixture containing 1-(2-chloro-4-methylphenyl)-1-[(oxan-2-yl)oxy]propan-2-one

[0255] [ka]

[0256] 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% XPhos were added to a 1-drum screw-cap vial equipped with a magnetic stirrer and dissolved in 2 mL of THF. 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 vial was sealed with a PTFE-lined cap, wrapped with insulating tape, then removed from the glove box and placed on a temperature-controlled aluminum heating block set to 90°C, where it was reacted at 900 rpm for 12 hours under magnetic stirring. Purification was performed according to Workup Method D. By flash column chromatography using a 25g SiliCycle SiliSep® flash cartridge with silica, the following solvent gradients were applied: 0% ethyl acetate in hexane (2CV), 0-20% ethyl acetate in hexane (24CV), followed by 20% ethyl acetate in hexane (2CV). This yielded (IV-1) as a clear oily substance with an isolation yield of 7% (0.010g, 0.035 mmol), and a mixture containing 4c, 4a, and 4b as a clear oily substance (0.032g).

[0257] Mass spectrum of the mixture: HRMS-ESI (m / z): Calc'd for C 15 H 19 ClNaO3(4c) [M+Na] + : 305.0915. Found: 305.0917. HRMS-ESI (m / z): Calc'd for C 22 H24 Cl2NaO3(4a / 4b) [M+Na] + : 429.0995. Found: 429.0998.

Claims

1. Compounds of general formula (I) 【Chemistry 1】 [In the formula, R １ These are phenyl, naphthyl, or a 5-10 membered heteroaryl ring. The phenyl, naphthyl, and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, C ３ -C ８ cycloalkyl, di-C １ -C ６ alkylamino, or 3- to 10-membered heterocyclyl, Here, the 3-10 membered ring heterocyclyl is oxo, hydroxy, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy and C １ ~C ６ It is optionally substituted with one to three substituents independently selected from the group consisting of haloalkoxys. R ２ is hydrogen or (C １ ~C ６ A method for producing [which is alkyl], In step A, the compound of formula (II) 【Chemistry 2】 [In the formula, R １ As defined above, X １ [These are bromo, iodine, fluorosulfonate, or trifluoromethylsulfonate] The compound of formula (III) is prepared in a suitable solvent in the presence of a palladium catalyst, a bisphosphine ligand, and a suitable base. 【Transformation 3】 [In the formula, R ２ It is defined as described above, PG is a hydroxy protecting group, preferably a methyl group, a tert-butyl group, a tetrahydropyranyl group, or a benzyl group. Reacting with it, the compound of formula (IV) 【Chemistry 4】 [In the formula, R １ , R ２ , and PG are defined as above. It is characterized by forming, and, In step B, the protective group PG is subsequently removed, method.

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

3. The bisphosphine ligand in step A is of formula (B) 【Transformation 5】 (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl]phosphino]ferrocene[(4-CF ３ Ph)PF-tBu, CAS number 246231-79-8], (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl]phosphino]ferrocene[(4-CF ３ Ph)PF-tBu, CAS No. 849924-37-4], (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene[PhPF-tBu, CAS No. 155830-69-6], (2S)-1-[(1S)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene[PhPF-tBu, CAS No. 277306-29-3], (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]- 2-(dicyclohexylphosphino)ferrocene [CyPF-tBu, CAS No. 158923-11-6](2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene [CyPF-tBu, CAS No. 1246841-00-8], (1R)-1-(dicyclohexylphosphino)-2-[(1R)-1-(dicyclohexylphosphino)ethyl]ferrocene [CyPF-Cy, CAS No. 167416-28-6](2S)-1-[(1S)-1-[Bi (1,1-dimethylethyl)phosphinoethyl]-2-(dicyclohexylphosphino)ferrocene [CyPF-Cy, CAS No. 246231-77-6], (2R)-1-[(1R)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene [PhPF-Cy, CAS No. 155806-35-2], (2S)-1-[(1S)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene [CAS No. 162291-02-3], di(1-adamantyl)-2-mo 1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantan-8-yl)-2-(1,3,5,7-tetramethyl-2,4,6-tetramethyl-2,4-tetramethyl-2,4-tetramethyl-2,6-tetramethyl-2,6-tetramethyl-2,6-tetramethyl-2,6-tetramethyl-2,6-tetramethyl-2,6-tetramethyl-2,6-tetramethyl-2,6-tetramethyl-2,6-tetramethyl-2,6-tetramethyl-2The method according to claim 1 or 2, selected from the group consisting of 6-trioxa-8-phosphaadamantan-8-yl)benzene [PAd2-DalPhos].

4. In the case of bromo, iodine, or trifluorosulfonates, suitable bases for the reaction according to the present invention are alkali metal carbonates, alkali metal halides, dialkali metal phosphates, and alkali metal phosphates, such as cesium carbonate, cesium fluoride, dipotassium phosphate, and potassium phosphate, or X １ The method according to any one of claims 1 to 3, wherein, if is a trifluoromethylsulfonate, a double base condition is applied, combining DBU 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, where the solvent is selected from the group consisting of toluene, xylene, or decalin, 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me-THF), 1,2-dimethoxyethane (DME), 1,2-diethoxyethane, bis(2-methoxyethyl) ether (diglym), cyclopentyl methyl ether (CPME), or anisole.

6. R １ However, the following formula 【Transformation 6】 [In the formula, *But, X １ The bonding site to, or each of the terminal carbon atoms, R ３ and R ４ However, fluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl, ethoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, C ３ ~C ６ Independently selected from the group consisting of cycloalkyl, dimethylamino, diethylamino, and piperazinyl, Here, the piperazinyl is substituted with one or two substituents independently selected from the group consisting of methyl and ethyl. The method according to any one of claims 1 to 5.

7. Compound of formula (I-1) 【Transformation 7】 A method according to any one of claims 1 to 6 for preparing, In step A, the compound of formula (IIa) 【Transformation 8】 [In the formula, X １ However, it is bromo, fluorosulfonate, or trifluoromethylsulfonate. The compound of formula (III-1) is prepared in a suitable solvent in the presence of a palladium catalyst, a bisphosphine ligand, and a suitable base. 【Chemistry 9】 Reacting with it, the compound of formula (IV-1) is formed. 【Chemistry 10】 Forming, In step B, the protective group PG is subsequently removed, method.

8. Step A is performed using [Pd(cinamyl)Cl] as a palladium catalyst. ２ (4-CF) as a bisphosphine ligand ３ The method according to any one of claims 1 to 7, which is carried out in combination with Ph)PF-tBu or PhPF-tBu, wherein the ratio of the bisphosphine ligand to the palladium catalyst is in the range of 1.25:1.0 to 1.20:1.0, and cesium carbonate is used as the base.

9. Step B is carried out using an acid, where the acid in the solvent is HCl or SiO ２ Supported NaHSO ４ The method according to any one of claims 1 to 8, wherein the solvent is selected from methanol, 1,4-dioxane, or water.

10. Compound of formula (I) 【Chemistry 11】 [In the formula, R １ This is based on the following formula 【Chemistry 12】 (In the formula, * is X １ The bonding site to, or each of the terminal carbon atoms, R ３ and R ４ Fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C ３ ~C ６ Independently selected from the group consisting of cycloalkyl, dimethylamino, diethylamino, and piperazinyl, Here, the piperazinyl is substituted with one or two substituents independently selected from the group consisting of methyl and ethyl. And, R ２ is hydrogen or (C １ ~C ６ ) - Alkyl].

11. Compound of formula (IV) 【Chemistry 13】 [In the formula, R １ However, the following formula 【Chemistry 14】 (In the formula, * is X １ The bonding site to, or each of the terminal carbon atoms, R ３ and R ４ Fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C ３ ~C ６ Independently selected from the group consisting of cycloalkyl, dimethylamino, diethylamino, and piperazinyl, Here, the piperazinyl is substituted with one or two substituents independently selected from the group consisting of methyl and ethyl. And, R ２ is hydrogen or (C １ ~C ６ ) - Alkyl, and, PG is a hydroxy protecting group, preferably a methyl group, a tetrahydropyranyl group, or a benzyl group.

12. Compound of formula (II) 【Chemistry 15】 [In the formula, R １ is a phenyl, naphthyl, or 5-10 membered ring heteroaryl, The aforementioned phenyl, naphthyl, and 5-10 membered ring heteroaryls are fluoro, chloro, and C. １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C ３ ~C ８ Cycloalkyl, di-C １ ~C ６ It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylaminos or 3- to 10-membered heterocyclines. Here, the 3-10 membered ring heterocyclyl is oxo, hydroxy, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy and C １ ~C ６ It is optionally substituted with one to three substituents independently selected from the group consisting of haloalkoxys. and, X １ It is a fluorosulfonate.

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