Palladium-catalyzed chemoselective mono-alpha-arylation of o-protected hydroxyacetone

Abstract

The present invention relates to a new process for preparing benzyl alpha-hydroxy ketone derivatives via palladium-catalyzed mono-alpha-arylation of O-protected hydroxyacetone and subsequent deprotection.

Description

[0001]BCS223046 FC 2024-03-18 KJ / Rak - 1 - Palladium-Catalyzed Chemoselective Mono- ^-Arylation of O-Protected Hydroxyacetone The present invention relates to a new process for preparing benzyl ^-hydroxy ketone derivatives via palladium-catalyzed mono- ^-arylation of O-protected hydroxyacetone and subsequent deprotection. Benzyl ^-hydroxy ketone derivatives of formula (I) are valuable precursors of active agrochemical and pharmaceutical ingredients. There is a broad synthetic utility of benzyl ^ -hydroxy ketones of this type in the classical synthesis of heterocycles (e.g., Hantzsch pyrrole or thiophene synthesis, the Weidenhagen reaction, the Bredereck synthesis, etc.), as well as en route to 1,2-aminoalcohols (e.g., via reductive amination or biocatalytic transamination). In particular, benzyl ^-hydroxy ketone derivatives of formula (I) are important intermediates for the preparation of fungicidally active compounds as disclosed in WO 2020 / 127780 A1. Several oxidative methods have been reported for the synthesis of benzyl ^-hydroxy ketones. For example, they can be synthesized through the oxidation of an olefinic substrate. This usually involves the use a of a catalyst in combination with a stoichiometric oxidant (Plietker et al. Org. Biomol. Chem.2004, 2, 2403-2407, Rubottom et al. Tetrahedron Lett. 1974, 15, 4319-4322 and Pullez et al. Eur. J. Org. Chem.2006, 2006, 80-83). The downside is that there is often little regioselectivity when using unbiased substrates and because the stoichiometric use of a co-oxidant results in large amounts of potentially toxic chemical waste. Alternatively, they can be prepared via mono-oxidation of diols (Waymouth et al. J. Am. Chem. Soc. 2018, 140, 748-757). Unfortunately, the reaction is slow and uses an expensive catalyst. Finally, the direct ^-oxidation of ketones 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 hazardous and costly. Alternative to the direct oxidation reactions, it is possible to synthesize benzyl ^-hydroxy ketones through the selective bromination of phenyl acetaldehydes followed by reaction with an oxygen nucleophile (Merck & Co., DE946446C, 1956-08-02). It is also possible to react phenyl propargyl alcohols with thiol reagents, followed by acidic hydrolysis to obtain the corresponding hydroxyketone (Waters et al. Tetrahedron Lett. 2000, 41, 141-144). These methodologies require multiple steps and generate large amounts of chemical waste. Finally, it is possible to carry out an acyloin coupling between an aldehyde and formaldehyde using an N- Heterocyclic carbene as a catalyst (Inoue et al. J. Org. Chem. 1985, 50, 603-606). This can also be done enzymatically (Ma et al. Angew. Chem. Int. Ed.2022, 61, e2021163). These methods rely on the synthesis and isolation of often reactive aldehyde intermediates. The metal-catalyzed ^-arylation of carbonyl compounds with (hetero)aryl-halide or -pseudohalide electrophiles provides a useful means of preparing benzyl ketone synthons. However, selective mono- ^-   BCS223046 FC - 2 - arylation can also be problematic (Stradiotto et al. in “New Trends in Cross-Coupling: Theory and Applications”, Colacot, T. J., Ed. Royal Society of Chemistry: Cambridge, UK, 2014; 228-253) especially in methyl carbonyl compounds whereby the arylated product features benzylic CH2groups whose acidity is greater than that found in the methyl carbonyl starting material. Despite significant progress that has been made in metal-catalyzed ^-arylation chemistry, we noted that analogous transformations of hydroxyacetone (or O-protected variants) with terminal selectivity have not been reported so far (Stradiotto et al., Eur. J. Org. Chem.2012, 6042–6050; Waters S.M. et al., Tet. Lett.41 (2000), 141-144). Surprisingly, it has been found that O-protected hydroxyacetone, in combination with the use of a catalyst system comprising of a palladium catalyst and bis-phosphine ligands, allowed for efficient methyl- selective mono- ^-arylation with ortho-substituted aryl bromides, aryl iodides, fluorosulfonates and trifluorosulfonates in the presence of potentially contending functionalities including chloro groups. In the light of the prior art described above, it is an object of the present invention to provide an efficient and selective route to benzyl ^-hydroxy ketone derivatives of formula (I) under mild conditions, with high yield, broad substrate scope, high purity, less chemical waste and a facile isolation of the final product. The object described above was achieved by a process for the preparation of a compound of the general the formula (I) wherein R1is phenyl, naphthyl or 5- to 10-membered heteroaryl, wherein said phenyl, naphthyl and 5- to 10-membered heteroaryl are optionally substituted by 1 to 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- to 10-membered heterocyclyl, wherein said 3- to 10-membered heterocyclyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of oxo, hydroxy, C1-C6- alkyl, C1-C6-haloalkyl, C1-C6-alkoxy and C1-C6-haloalkoxy, R2is hydrogen or (C1-C6)-alkyl, characterized in that in step A, a compound of formula (II)     BCS223046 FC - 3 - (II), wherein R1is as defined above and X1is bromo, iodo, fluorosulfonate or trifluoromethylsulfonate, is reacted in a suitable solvent in the presence of a palladium catalyst, a bis-phosphine ligand and a suitable base with a compound of formula (III) (III), wherein R2is defined as above and PG is a hydroxy-protecting group, preferably methyl, tert-butyl, tetrahydropyranyl or benzyl, to form a compound of formula (IV) (IV), wherein R1, R2and PG are defined as above, and in step B, the protecting group PG is subsequently removed. General definition Unless otherwise stated, the following definitions apply for the substituents and residues used throughout this specification and claims: The term “C1-C6-alkyl” as used herein refers to a saturated, branched or straight hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of C1-C6-alkyl include but are not limited to methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1-dimethylethyl (tert-butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethyl- propyl, 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-dimethyl-     BCS223046 FC - 4 - butyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-tri- methylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Particularly, said hydrocarbon chain has 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), e.g. methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso- butyl or tert-butyl. The term “C1-C6-haloalkyl” as used herein refers to a C1-C6-alkyl group as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different. Examples of C1-C6-haloalkoxy include but are not limited to chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoro- methyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoro- ethyl, 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-trifluoroprop-2-yl. Preferred are fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 2-fluoroethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl. The term “C1-C6-alkoxy” as used herein refers to a group of formula (C1-C6-alkyl)-O-, in which the term "C1-C6-alkyl" is as defined herein. Examples of C1-C6-alkoxy include but are not limited to methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, n-hexyloxy, 1-methylpentoxy, 2-methylpentoxy, 3-methyl- pentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethyl- butoxy, 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 alkoxy as part of a composite substituent, for example alkoxyalkyl, alkoxyalkoxy, unless defined elsewhere. The term “C1-C6-haloalkoxy” as used herein refers to a C1-C6-alkoxy group as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different. Examples of C1-C6-haloalkoxy include but are not limited to chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoro- methoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoro- ethoxy, 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- trifluoroprop-2-oxy. The term “di-(C1-C6)-alkylamino” as used herein refers to an amino radical having two independently selected C1-C6-alkyl groups as defined herein. Examples of C1-C6-dialkylamino include but are not limited to N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N- methyl-N-n-propylamino, N-isopropyl-N-n-propylamino and N-tert-butyl-N-methylamino.     BCS223046 FC - 5 - The terms “C3-C8-cycloalkyl” as used herein refers to a saturated, monocyclic hydrocarbon ring containing 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of C3-C8-cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Particularly, said cycloalkyl has 3 to 6 carbon atoms. The term “3- to 10-membered heterocyclyl” as used herein refers to a saturated or partially unsaturated 3-, 4-, 5-, 6-, 7-,8-, 9- or 10-membered membered ring system comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. If the ring system contains more than one oxygen atoms, they are not directly adjacent. Heterocycles include but are not limited to 3- to 7-membered monocyclic heterocycles and 8- to 10-membered bicyclic heterocycles. The 3- to 10-membered heterocycle can be connected to the parent molecular moiety through any carbon atom or nitrogen atom contained within the heterocycle. Examples of saturated heterocycles include but are not limited to 3-membered ring such as oxiranyl, aziridinyl, 4-membered ring such as azetidinyl, oxetanyl, thietanyl, 5-membered ring such as tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl, isoxazolidinyl, oxazolidinyl, oxadiazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, 6-membered ring such as piperidinyl, hexahydropyridazinyl, hexa- hydropyrimidinyl, piperazinyl, triazinanyl, hexahydrotriazinyl, tetrahydropyranyl, dioxanyl, tetra- hydrothiopyranyl, dithianyl, morpholinyl, 1,2-oxazinanyl, oxathianyl, thiomorpholinyl or 7-membered ring such as oxepanyl, azepanyl, 1,4-diazepanyl and 1,4-oxazepanyl. Examples of unsaturated hererocyles include but are not limited to 5-membered ring such as dihydrofuranyl, 1,3-dioxolyl, dihydrothienyl, pyrrolinyl, dihydroimidazolyl, dihydropyrazolyl, isoxazolinyl, dihydrooxazolyl, dihydrothiazolyl or 6- membered ring such as pyranyl, thiopyranyl, thiazinyl and thiadiazinyl. Bicyclic heterocycles may consist of a monocyclic heteroaryl as defined herein fused to a monocyclic C3-C8-cycloalkyl, a monocyclic C3- C8-cycloalkenyl or a monocyclic heterocycle or may consist of a monocyclic heterocycle fused either to an aryl (e.g. phenyl), a C3-C8-cycloalkyl, a C3-C8-cycloalkenyl or a monocyclic heterocycle (e.g dihydrobenzofuranyl, dihydroisobenzofuranyl, indolinyl, 1,3-benzodioxolyl, dihydro-1,4-benzodioxinyl, tetrahydroquinolinyl, dihydro-5H-cyclopenta[b]pyridinyl, chromanyl, isochromanyl, thiochromanyl, iso- thiochromanyl). When two monocyclic heterocycles or one monocyclic heterocycle and one monocyclic heteroaryl comprising nitrogen atoms are fused, nitrogen atom may be at the bridgehead (e.g. [1,3]di- oxolo[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). The terms “3- to 7-membered heterocyclyl” and “3- to 7-membered heterocyclyl-ring” as used herein refers to a saturated 3-, 4-, 5-, 6- or 7-membered ring system comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Examples include but are not limited to oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl, isoxazolidinyl, oxazolidinyl, oxadiazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, triazinanyl, hexahydrotriazinyl, tetrahydropyranyl, dioxanyl,     BCS223046 FC - 6 - tetrahydrothiopyranyl, dithianyl, morpholinyl, 1,2-oxazinanyl, oxathianyl, thiomorpholinyl, oxepanyl, azepanyl, 1,4-diazepanyl and 1,4-oxazepanyl. Preferred 3- to 7-membered heterocyclyl are oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, morpholinyl and thiomorpholinyl. The term “5- to 10-membered heteroaryl” as used herein refers to an aromatic ring system comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. If the ring system contains more than one oxygen atom, they are not directly adjacent. Aromatic heterocycles include 5- or 6-membered monocyclic heteroaryls and 7- to 10-membered bicyclic heteroaryls. The 5- to 10-membered heteroaryl can be connected to the parent molecular moiety through any carbon atom or nitrogen atom contained within the heterocycle. The term “5- or 6-membered heteroaryl” as used herein refers to a 5- or 6-membered aromatic monocyclic ring system containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Examples of 5-membered monocyclic heteroaryl 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 6-membered monocyclic heteroaryl include but are not limited to pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl. The term “7- to 10-membered heteroaryl” as used herein refers to a 7-, 8-, 9- or 10-membered aromatic bicyclic ring system containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Bicyclic heteroaryls may consist of a monocyclic heteroaryl as defined herein fused to an aryl (e.g. phenyl) or to a monocyclic heteroaryl. Examples of bicyclic heteroaryls include but are not limited to 9-membered ring such as indolyl, indolizinyl, isoindolyl, benzimadozolyl, imidazopyridinyl, indazolyl, benzotriazolyl, purinyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl and benzisoxazolyl or 10-membered ring such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pteridinal and benzodioxinyl. In 9- or 10- membered bicyclic heteroaryls comprising two fused 5- or 6-membered monocyclic heteroaryls, nitrogen atom may be 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, furo[2,3-d]isoxazolyl). Formula (I) provides a general definition of the benzyl ^-hydroxy ketones obtainable by the process according to the invention. Preferred radical definitions for formula (I) shown above and below are given below. These definitions apply to the end products of formula (I) and likewise to all starting materials and intermediates bearing the respective radical(s). R1preferably is phenyl, naphthyl, pyridyl or benzothienyl, wherein said 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-     BCS223046 FC - 7 - C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C3-C6-cycloalkyl, Di-C1-C4-alkylamino and 4- to 7-membered heterocyclyl, wherein said 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. R1more preferably is a group of formula , wherein * is the attachment to X1or the terminal carbon atom respectively, R3and R4are independently selected from the group consisting of fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6-cycloalkyl, dimethylamino, diethylamino and piperazinyl, wherein said piperazinyl is substituted by 1 or 2 substituents indepen- dently selected from the group consisting of methyl and ethyl. Likewise R1more preferably is a group of formula , wherein * is the attachment to X1or the terminal carbon atom respectively, R3is selected from the group consisting of chloro and methyl, R4is selected from the group consisting of chloro, bromo and methyl.     BCS223046 FC - 8 - R1even more preferably is 2-chloro-4-methylphenyl. R2preferably is hydrogen or C1-C4-alkyl. R2more preferably is hydrogen or methyl. R2even more preferably is hydrogen. PG preferably is methyl, tetrahydropyranyl or benzyl PG more preferably is tetrahydropyranyl or benzyl. PG even more preferably is tetrahydropyranyl. X1preferably is bromo, fluorosulfonate or trifluoromethylsulfonate. X1more preferably is bromo, fluorosulfonate or trifluoromethylsulfonate. X1even more preferably is fluorosulfonate. Hence, particularly preferred is a process for preparing the compound of formula (I-1) characterized in that in step A, a compound of formula (IIa) wherein X1is bromo, fluorosulfonate or trifluoromethylsulfonate, is reacted in a suitable solvent in the presence of a palladium catalyst, a bis-phosphine ligand and a suitable base with a compound of formula (III-1)     BCS223046 FC - 9 - (III-1), to from a compound of formula (IV-1) (IV-1), and in a step B, the protecting group PG subsequently is removed. The above specified definitions of R1, R2and PG (broad definition as well as preferred, more preferred, even more preferred and most preferred definitions) can be combined in various manners. These combinations of definitions thus provide sub-classes of compounds according to the invention, such as for instance the ones disclosed below. Preference is given to those compounds of formula (I) in which each of the definitions (substituents and variables) have the abovementioned preferred meanings. Particular preference is given to those compounds of formula (I) in which each of the definitions (substituents and variables) have the abovementioned more, even more and / or most preferred meanings. As outlined above, compounds of formula (I) are valuable intermediates in the synthesis of compounds useful in the field of crop protection, in particular the heterocyclic-substituted pyridazine derivatives disclosed in WO 2020 / 127780 A1. A further object of the present invention are compounds of formula (I) wherein R1is phenyl, naphthyl or 5- to 10-membered heteroaryl,     BCS223046 FC - 10 - wherein said phenyl, naphthyl and 5- to 10-membered heteroaryl are optionally substituted by 1 to 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- to 10-membered heterocyclyl, wherein said 3- to 10-membered heterocyclyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of oxo, hydroxy, C1-C6- alkyl, C1-C6-haloalkyl, C1-C6-alkoxy and C1-C6-haloalkoxy, R2is hydrogen or (C1-C6)-alkyl. The preferred, more preferred, even more preferred and most preferred definitions of R1, R2and PG given with regard to formula (I) apply mutatis mutandis. A further object of the present invention are compounds of formula (II) (II), wherein R1is phenyl, naphthyl or 5- to 10-membered heteroaryl, wherein said phenyl, naphthyl and 5- to 10-membered heteroaryl are optionally substituted by 1 to 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- to 10-membered heterocyclyl, wherein said 3- to 10-membered heterocyclyl is optionally substituted by 1 to 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 X1is fluorosulfonate or trifluoromethylsulfonate. The preferred, more preferred, even more preferred and most preferred definitions of R1, R2, X1and PG given with regard to formula (I) apply mutatis mutandis. A further object of the present invention are compounds of formula (III)     BCS223046 FC - 11 - wherein R2is hydrogen or (C1-C6)-alkyl. and PG is a hydroxy-protecting group, preferably methyl, tetrahydropyranyl or benzyl. The preferred, more preferred, even more preferred and most preferred definitions of R1, R2and PG given with regard to formula (I) apply mutatis mutandis. A further object of the present invention are compounds of formula (IV) (IV), wherein R1is phenyl, naphthyl or 5- to 10-membered heteroaryl, wherein said phenyl, naphthyl and 5- to 10-membered heteroaryl are optionally substituted by 1 to 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- to 10-membered heterocyclyl, wherein said 3- to 10-membered heterocyclyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of oxo, hydroxy, C1-C6- alkyl, C1-C6-haloalkyl, C1-C6-alkoxy and C1-C6-haloalkoxy, R2is hydrogen or (C1-C6)-alkyl. and PG is a hydroxy-protecting group, preferably methyl, tetrahydropyranyl or benzyl. The preferred, more preferred, even more preferred and most preferred definitions of R1, R2and PG given with regard to formula (I) apply mutatis mutandis.     BCS223046 FC - 12 - Process description The process of the present invention is illustrated in Scheme 1 below. Scheme 1 In step A of the present invention, O-protected hydroxyacetone is arylated in the ^-position using a palladium catalyst in combination with a bis-phosphine ligand, a base, optionally salt additive and a solvent. Preferably, the palladium catalyst is a salt of palladium (II), in particular [Pd(cinnamyl)Cl]2, Pd(OAc)2and Pd(dba)2. Most preferred is [Pd(cinnamyl)Cl]2. Preferably, a catalytic amount of palladium is used. More preferably, the ratio of the compound of formula (II) to palladium catalyst is in the range from 10:1 to 100:1. Even more preferably, the ratio of the compound of formula (II) to palladium catalyst is from 20:1 to 80:1. Suitable bis-phosphine ligands are 2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(tri- fluoromethyl)phenyl]phosphino]ferrocene [(4-CF3Ph)PF-tBu, CAS-No. 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-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-(Dicyclohexylphosphi no)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-(Dicyclo-     BCS223046 FC - 13 - hexylphosphino)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(di- phenylphosphino)-9,9-dimethylxanthene [XantPhos, CAS-No.161265-03-8], 2-Dicyclohexylphosphino- 2′,4′,6′-triisopropylbiphenyl [Xphos, CAS-No.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] of formula (B) (B). Even more preferred are (4-CF3Ph)PF-tBu and PhPF-tBu. The bis-phosphine ligand may be applied to the reaction according to the invention as both R- and S- enantiomer, as well as a mixture of the two enantiomers whereas 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, even more preferably in the range of 1:5 to 5:1. The ratio of bis-phosphine ligand to palladium catalyst is in the range from 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 from 1.25:1.0 to 1.20:1.0. If X1is bromo, iodo or trifluorosulfonate, suitable bases for the reaction according to the invention are alkali metal carbonates, alkali metal halides, di alkali metal phosphates and alkali metal phosphates, such as cesium carbonate, cesium fluoride, dipotassium phosphate and potassium phosphate. Particularly preferred is cesium carbonate. Preferably an excess of base is used. If X1is trifluoromethylsulfonate, dual-base conditions are applied to the reaction according to the invention. Suitable bases for the dual-base conditions are DBU which is applied together with salt additive such as sodium trifluoroacetate, sodium trifluoromethanesulfonate and potassium trifluoromethane- sulfonate.     BCS223046 FC - 14 - In case of the dual-base conditions an excess of the dual basic system is applied. Preferably the ratio of (II):Dual Base is in the range of 1:10 to 1:1, more preferably in the range of 1:5 to 1:1.5, even more preferably the ratio of (II):dual base is 1:2. Preferably, an excess of (III) in relation to (II) is used. More preferable is a ratio of (III) : (II) of 3:1 to 2:1 is used . Suitable solvents for the reaction according to the present invention are, for example aromatic hydrocarbons, for example 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-methoxy- ethyl) ether (diglyme), cyclopentyl methyl ether (CPME) or anisole; or mixtures of the aforementioned solvents. More preferred are 1,4-dioxane, THF, 2-MeTHF or cyclopentyl methyl ether, even more preferred are 1,4-dioxane or toluene. Preferable is (II) diluted with an appropriate amount of solvent so that the final concentration is in the range of 0.1 M to 0.8M, more preferably in the range of 0.2 M to 0.5 M. Even more preferred is a final dilution of 0.24 M to 0.36 M. Step A can be performed at reaction temperatures in the range of +80°C to +150°C, preferably in the range of +90°C to +130 °C, more preferably in the range of +110°C to +120°C. The reaction time typically lies in the range from 4 to 24 hours. Most preferably, step A of the present invention is carried out with [Pd(cinnamyl)Cl]2as palladium catalyst in combination with (4-CF3Ph)PF-tBu or PhPF-tBu as bis-phosphine ligand, wherein the ratio of bis-phosphine ligand to palladium catalyst is in the range from 1.25:1.0 to 1.20:1.0, and cesium carbonate as base. Most preferably, step A of the present invention is carried out in a solvent, wherein the solvent is 1,4- dioxane or toluene, at a dilution of 0.24 M to 0.36 M and at a temperature in the range of +110°C to +120°C. In step B of the process according to the present invention, the O-protected hydroxyacetone of formula (IV) is deprotected, using acidic conditions with a suitable solvent to furnish the corresponding arylated hydroxyacetone of formula (I). The products can then be isolated using crystallization, or silica gel column chromatography. Preferably, the acid used in the deprotection step is HCl or SiO2-supported NaHSO4.     BCS223046 FC - 15 - Preferably, HCl is used in excess in relation to (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, even more preferably a ratio of 1:5 is used. Preferably, NaHSO4-SiO2is used in catalytic amounts in relation to (IV), more preferably NaHSO4-SiO2is used in an amount of 20 to 400 mg / mmol of (IV), even more preferably NaHSO4-SiO2is used in an amount of 50 to 280 mg / mmol of (IV). Suitable solvents for process step B are polar solvents, such as alcohols, ethers or water, more preferably methanol, 1,4-dioxane or water, even more preferably water. Process step B is typically carried out at a temperature range of +10°C to +150°C, preferably in a temperature range of +20°C to +100°C, more preferably in a temperature range of +40°C to +90°C, most preferably is a reaction temperature of about +90°C The deprotection time for usually lasts from 10 minutes to 1 hour. Most preferably, step B of the present invention is carried with an acid, wherein the acid is selected from HCl or SiO2-supported NaHSO4, in a solvent, wherein the solvent is selected from methanol, 1,4-dioxane or water. The invention is illustrated by but not limited to the following examples:     BCS223046 FC - 16 - EXAMPLES A-1. Abbreviations ACN, MeCN acetonitrile (4-CF3Ph)PF-tBu (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl) phosphino]ethyl]-2-[bis[4-(trifluoromethyl) phenyl]phosphino]ferrocene and (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino] ethyl]-2-[bis[4-(trifluoromethyl)phenyl] phosphino]ferrocene CPME Cyclopentyl methyl ether CV Column volume CyPF-Cy (1R)-1-(dicyclohexylphosphino)-2-[(1R)-1- (dicyclohexylphosphino)ethyl]ferrocene and (1S)-1-(dicyclohexylphosphino)-2-[(1S)-1- (dicyclohexylphosphino)ethyl]ferrocene CyPF-tBu (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl) phosphino]ethyl]-2-(dicyclohexylphosphi no)ferrocene and (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino] ethyl]-2-(dicyclohexylphosphino)ferrocene DCM dichloromethane diglyme Bis(2-methoxyethyl) ether DMA dimethylacetamide DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide EtOAc Ethyl acetate 2-MeTHF 2-methyltetrahydrofuran 2-MeTHP 2-ethyltetrahydropyran Mor-DalPhos Di(1-adamantyl)-2-morpholinophenylphosphine NMP N-methyl-2-pyrrolidone OTf trifluoromethanesulfonate     BCS223046 FC - 17 - PAd2-DalPhos 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 PhPF-Cy (2R)-1-[(1R)-1-(Dicyclohexylphosphino)ethyl]-2- (diphenylphosphino)ferrocene and (2S)-1-[(1S)-1-(Dicyclohexylphosphino)ethyl]-2- (diphenylphosphino)ferrocene PhPF-tBu (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl) phosphino]ethyl]-2-(diphenylphosphino) ferrocene and (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino] ethyl]-2-(diphenylphosphino)ferrocene PTFE Polytetrafluoroethylene THF tetrahydrofuran Triflate trifluoromethansulfonate Xantphos 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene XPhos 2-Dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl A-2. General Considerations Unless otherwise indicated, all experimental procedures were conducted in a nitrogen-filled, inert atmosphere glovebox using oven-dried glassware and purified solvents, with the exception of the workup of catalytic reaction mixtures, which was conducted on the benchtop in air using unpurified solvents. For solvents and reagents used within the glovebox, the following purification methods were used: toluene was deoxygenated by sparging with nitrogen gas followed by passage through a double column solvent purification system packed with alumina and copper-Q5 reactant and stored over activated 4 Å molecular sieves; THF was distilled from sodium benzophenone ketyl and stored over activated 4 Å molecular sieves; 2-MeTHF, 1,4-dioxane, DCM (i.e., CH2Cl2), DMF, DMA, ACN (i.e., MeCN), NMP, DMSO, and anisole were purchased anhydrous from Sigma-Aldrich, deoxygenated by sparging with nitrogen gas, and stored over activated 4 Å molecular sieves; EtOAc, CPME, DME, diglyme, and 4-MeTHP were degassed by way of three repeated freeze-pump-thaw cycles, and then dried over activated 4 Å molecular sieves; pentane was deoxygenated by sparging with nitrogen gas, and then dried over activated 4 Å molecular sieves. Cs2CO3and K2CO3were purchased anhydrous from Sigma-Aldrich and milled to a fine powder using a mortar and pestle. O-protected starting materials 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone     BCS223046 FC - 18 - and 3-[(tetrahydro-2H-pyran-2-yl)oxy]-2-butanone, as well as all triflate electrophiles, were synthesized as described below. NaHSO4-SiO2was prepared from NaHSO4and silica gel according to literature.1All other solvents, reagents, and materials were used as received from commercial sources. All catalyst loadings listed as “%” are in reference to “mol%”, relative to the aryl electrophile. GC data was obtained on a calibrated instrument (Shimadzu Gas Chromatograph GC-2030) equipped with an SGE BP-5 column (30 m, 0.25 mm i.d.), detector SFID1, temperature column oven 100°C, temperature SFID1305°C, temperature SPL1200°C, linear velocity 45.4cm / sec, total flow 45.1 mL / min, column flow 2.1mL / min. Programm: 2 min 100°C, 10 min 200°C, 15 min 220°C (time is hold time). Automated flash column chromatography was carried out using a normal-phase SiliCycle SiliSepTM10, 25 or 40 g column cartridge or a 100 g normal-phase Biotage SNAP KP-Sil column cartridge; ‘CV’ is in reference to column volume for the chromatographic purification. All1H NMR (500 and 300 MHz),13C{1H} NMR (125.8 and 75.4 MHz), and19F NMR (471 MHz) spectra were recorded at 300 K and were referenced to residual protio solvent peaks (1H), deuterated solvent peaks (13C{1H}), or external 0.5% (CF3)C6H5in CDCl3at -63.7 ppm (19F). Splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. All coupling constants (J) are reported in Hertz (Hz). Mass spectra were obtained using an ion trap (ESI) instrument operating in positive or negative mode as indicated. A-3. General Procedures A-3.1. General Procedure for the Mono-α-Arylation of 1-[(Tetrahydro-2H-pyran-2-yl)oxy]-2- propanone with (Hetero)aryl Bromides with [Pd(cinnamyl)Cl]2 / PhPF-tBu (GP1). Unless otherwise indicated, 0.625 mol% [Pd(cinnamyl)Cl]2(CAS 12131-44-1) (1.25 mol% Pd) and 1.5 mol% PhPF-tBu (CAS 155830-69-6 and CAS 277306-29-3) were added to a 1-dram screw-capped vial containing a magnetic stir bar and dissolved in 1.33 mL of 1,4- dioxane (0.36 M in aryl-Br). Aryl bromide (0.48 mmol, 1.0 equiv) and Cs2CO3(2 equiv) and were then added, followed by 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (3 equiv). The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature-controlled aluminum heating block set to 110 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 4.5 h.     BCS223046 FC - 19 - A-3.2. General Procedure for the Mono-α-Arylation of 1-[(Tetrahydro-2H-pyran-2-yl)oxy]-2- propanone with Aryl Triflates with [Pd(cinnamyl)Cl]2 / (4-CF3Ph)PF-tBu (GP2). Unless otherwise indicated, 2.5 mol% [Pd(cinnamyl)Cl]2(5 mol% Pd) and 6.25 mol% (4-CF3Ph)PF-tBu (CAS 246231-79-8 and CAS 849924-37-4) were added to a 1-dram screw-capped vial containing a magnetic stir bar and dissolved in 2 mL of toluene (0.24 M in aryl-OTf). Then, DBU (2 equiv), NaOTf (2 equiv), aryl triflate (0.48 mmol, 1.0 equiv), and 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (2 equiv) were added. The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature-controlled aluminum heating block set to 120 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 12 h. A-3.3. General Procedure for the synthesis of Aryl Triflates from Phenols (GP3). The phenol (5.4 mmol, 1 equiv) was dissolved in CH2Cl2(10 mL) and stirred at 0°C under a N2atmosphere. Triethylamine (904 μL, 6.5 mmol, 1.2 equiv) was added dropwise over 5 minutes followed by the addition of trifluoromethanesulfonic anhydride (1.0 mL, 5.9 mmol, 1.1 equiv) dropwise over 30 minutes. The reaction was allowed to warm to room temperature and with continuous stirring overnight. Upon completion, the reaction mixture was cooled to 0°C and 2M HCl (2 equiv) was added and stirred for 1 hour, allowing the mixture to warm to room temperature. The reaction mixture was extracted with CH2Cl2(3 x 5 mL), and the organic layers washed with NaHCO3, water and brine. The organic layer was dried over Na2SO4and filtered through a pad of silica / Celite. The solvent was removed in vacuo to obtain the aryl triflate product. A-3.4. General Procedure for the Mono-α-Arylation of 1-[(Tetrahydro-2H-pyran-2-yl)oxy]-2- propanone with (Hetero)aryl Bromides with [Pd(cinnamyl)Cl]2 / (4-CF3Ph)PF-tBu (GP4). Unless otherwise indicated, 1.5 mol% [Pd(cinnamyl)Cl]2(3 mol% Pd) and 3.75 mol% (4-CF3Ph)PF-tBu (CAS 246231-79-8 and CAS 849924-37-4) were added to a 1-dram screw-capped vial containing a magnetic stir bar and dissolved in 2 mL of THF (0.24 M in aryl-Br). Aryl bromide (0.48 mmol, 1.0 equiv) and Cs2CO3(2 equiv) and were then added, followed by 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (2 equiv). The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature-controlled aluminum heating block set to 90 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 12 h. A-3.5. General Procedure for the Mono-α-Arylation of 1-(Benzyloxy)propan-2-one with (Hetero)aryl Bromides with [Pd(cinnamyl)Cl]2 / PhPF-tBu (GP5). Unless otherwise indicated, 0.625 mol% [Pd(cinnamyl)Cl]2(1.25 mol% Pd) and 1.5 mol% PhPF-tBu were added to a 1-dram screw-capped vial containing a magnetic stir bar and dissolved in 1.33 mL of 1,4- dioxane (0.36 M in aryl-Br). Aryl bromide (0.48 mmol, 1.0 equiv) and Cs2CO3(2 equiv) and were then     BCS223046 FC - 20 - added, followed by 1-(benzyloxy)propan-2-one (3 equiv). The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature- controlled aluminum heating block set to 110 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 4.5 h. A-3.6. General Procedure for the Mono-α-Arylation of Methoxyacetone with (Hetero)aryl Bromides with [Pd(cinnamyl)Cl]2 / PhPF-tBu (GP6). Unless otherwise indicated in the text, 0.625 mol% [Pd(cinnamyl)Cl]2(1.25 mol% Pd) and 1.5 mol% PhPF-tBu were added to a 1-dram screw-capped vial containing a magnetic stir bar and dissolved in 1.33 mL of 1,4-dioxane (0.36 M in aryl-Br). Aryl bromide (0.48 mmol, 1.0 equiv) and Cs2CO3(2 equiv) and were then added, followed by methoxyacetone (3 equiv). The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature- controlled aluminum heating block set to 110 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 4.5 h. A-3.7 General Procedure for the Mono-α-Arylation of O-Protected Hydroxyacetone in the Optimization Process (GP7). Inorganic base and / or salt additive were added to a 1dram vial containing a magnetic stir bar. [Pd(cinnamyl)Cl]2and ligand were then added as a combined stock solution in the corresponding reaction solvent made with ≥ 5 mg of [Pd(cinnamyl)Cl]2. The o-chloro-aryl halide / pseudohalide (0.12-0.24 mmol, 1.0 equiv), O-protected hydroxyacetone (2-3 equiv), and DBU (if used) were then added. The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature-controlled aluminum heating block set to 70-130 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 3-48 h as stated. A-4. Workup Methods A-4.1A. Workup Method A (Deprotection and purification of 1-phenyl-3-hydroxypropan-2-one products) Following GP1 at 0.48 mmol scale of aryl bromide, the resultant mixture was cooled to room temperature and filtered through a thin silica / Celite frit saturated with hexanes and eluted with ethyl acetate (~20 mL) into a 4 dram vial. The resulting collected eluent solution was then dried in vacuo for 30 min to afford a crude residue. A stir bar, and 10 mL of water preheated to 95 °C was then added, followed by 200 µL of concentrated HCl. The vial was sealed with a cap containing a PTFE lining and placed in a temperature- controlled aluminum heating block set to 95 °C and was allowed to react under the influence of magnetic stirring at 1500 rpm for 10 minutes. A hot gravity filtration was then performed through a glass frit padded with a Whatman 1 filter pad; the glass frit, filter pad, and collection flask were used immediately after     BCS223046 FC - 21 - removing from an oven set to 120 °C. The eluent was left to cool to room temperature, and then placed in a fridge set to 3 °C overnight to crystallize out the desired product. The crystals of the benzyl a-hydroxy ketone (I) were then isolated by suction filtration. A-4.1B. Workup Method A’ (Deprotection and purification of 1-phenyl-3-hydroxypropan-2-one products with chromatography) Following GP1 at a 0.48 mmol scale of aryl bromide, the resultant mixture was cooled to room temperature and filtered through a thin silica / Celite frit and eluted with ethyl acetate (~20 mL) into a 4 dram vial. The resulting collected eluent solution was then dried in vacuo to afford a crude residue. A stir bar, and 10 mL of water preheated to 95 °C was then added, followed by 200 µL of concentrated HCl. The vial was sealed with a cap containing a PTFE lining and placed in a temperature-controlled aluminum heating block set to 95 °C and was allowed to react under the influence of magnetic stirring at 1500 rpm for 10 minutes. A hot gravity filtration was then performed through a glass frit padded with a Whatman 1 filter pad; the glass frit, filter pad, and collection flask were used immediately after removing from an oven set to 120 °C. The eluent was left to cool to room temperature, extracted with 3 x 10 mL ethyl acetate, and the organic layers were combined and dried over Na2SO4. The solvent was then removed in vacuo to afford a crude residue which was dissolved in DCM before being loaded onto a normal-phase SiliCycle SiliSepTM10 g column cartridge. The product was then purified using a methanol-DCM eluent mixture. The relevant UV-active column fractions were combined and dried in vacuo to afford the target product in each case. A-4.1C. Workup Method A” (Deprotection and purification of 1-phenyl-3-hydroxypropan-2-one products) Identical to Workup method A’ but without the hot gravity filtration step. A-4.2. Workup Method C (Deprotection and purification of 1-phenyl-3-hydroxypropan-2-one products) Following GP1 at a 0.24 mmol scale of aryl bromide, the resultant mixture was cooled to room temperature and filtered through a thin silica / Celite frit and eluted with ethyl acetate (~20 mL). The resulting collected eluent solution was then dried in vacuo to afford a crude residue, which was then dissolved in 2 mL of methanol, and added to a 1 dram vial containing 200 mg of NaHSO4-SiO2and a magnetic stir bar. The vial was sealed with a cap containing a PTFE lining and placed in a temperature- controlled aluminum heating block set to 50 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 45 minutes. The resulting solution was then filtered through a silica plug and eluted with ~10 mL of EtOAc into a 4 dram vial. The solvent was then dried in vacuo to afford a crude residue which was dissolved in DCM before being loaded onto a normal-phase SiliCycle SiliSepTM10 g column     BCS223046 FC - 22 - cartridge. The product was then purified using a methanol-DCM eluent mixture. The relevant UV-active column fractions were combined and dried in vacuo to afford the target product in each case. A-4.3. Workup Method D (Purification of 1-phenyl-3-[(oxan-2-yl)oxy]propan-2-one, 1-phenyl- 3-methoxypropan-2-one products, and 1-(benzyloxy)-3-phenylpropan-2-one products). Following GP1, GP2, and GP4-GP6, the resultant mixture was cooled to room temperature and filtered through a thin silica / Celite frit saturated with hexanes and eluted with ethyl acetate (~50 mL). The resulting collected eluent solution was then dried in vacuo to afford a crude residue which was dissolved in ethyl acetate before being loaded onto either a silica-based flash column or a normal-phase SiliCycle SiliSepTM10, 25, or 40 g column cartridge. The product was then purified using a hexanes-ethyl acetate eluent mixture. The relevant UV-active column fractions were combined and dried in vacuo to afford the target product in each case. A-4.4. Workup Method E (Purification of 1-phenyl-3-[(oxan-2-yl)oxy]propan-2-one products) Following GP1 at 0.48 mmol scale of aryl bromide, the resultant mixture was cooled to room temperature and filtered through a Celite frit employing DCM as an eluent (~50 mL). The resulting collected eluent solution was then dried in vacuo to afford a crude residue which was dissolved in DCM before being loaded onto a normal-phase SiliCycle SiliSepTM10 g column cartridge. The product was then purified using a methanol-DCM eluent mixture. The relevant UV-active column fractions were combined and dried in vacuo to afford the target product in each case. A-4.5. Workup Method F (Procedure for the Determination of GC-FID Yields of IV-1 prior to Deprotection and Isolation of I-1) The following workup method is used in conjunction with Workup Method A or A” to obtain a catalytic reaction yield of (IV-1). Unless otherwise indicated in the text, following GP1 at a 1.00 mmol scale of aryl bromide, the reaction was filtered through a silica / Celite frit and eluted with ethyl acetate as described in Workup Method A or A”. The eluent was then transferred to a 50 mL graduated cylinder and topped up to 50 mL with ethyl acetate. Then, using a 10 mL volumetric pipette, 5 mL of the of the eluent (10%) was transferred to a 4 dram vial with o-xylene as an internal standard (12.1 µL, 0.1 mmol). A portion of the solution was then transferred to a GC vial for analysis. After GC injection, the entire 5 mL sample was recombined with the rest of the eluent, and the remainder of Workup Method A or A” was carried out. A-4.6. Workup Method G (Procedure for the Preparation of GC Samples) Following GP1, GP2, and GP4-GP7 (0.12-0.24 mmol scale in (hetero)aryl halide) at room temperature, a 100 µL aliquot of the reaction mixture was loaded onto a small pipette filter (Kimwipe plug containing Celite and silica gel) and eluted with ethyl acetate, with the eluent collected in a GC vial. Calibrated GC-     BCS223046 FC - 23 - FID estimates are given on the basis of data obtained from authentic materials using o-xylene, mesitylene, or phenyldodecane as an internal standard. A-5. Deprotection Screens A-5.1. Procedure for Optimization of the Deprotection / Isolation Method All deprotection methods in this screen were conducted from the same catalytic reaction (results are summarized in Table S8). Following GP1 at a 4.00 mmol scale of aryl bromide, the reaction was filtered through a silica / Celite frit saturated with hexanes and eluted with ethyl acetate (~60 mL). The eluent was then transferred to a 100 mL graduated cylinder and topped up to the 80 mL graduation with ethyl acetate. The solution was then transferred to a beaker, and using a 10 mL volumetric pipette, 6 x 9.6 mL portions of the eluent (each equivalent to a 0.48 mmol aryl bromide reaction) were transferred to 6 separate 4 dram vials. From there, 6 variations of Workup Method A were carried out as seen in Entries 1-6. For Entries 7-10 (Workup Methods A’, A”, B, and C), the analogous procedure was conducted with 4 x 4.8 mL portions of eluent (each equivalent to a 0.24 mmol aryl bromide reaction). Then 2 mL of the remaining eluent (equivalent to a 0.1 mmol aryl bromide reaction) was transferred to a 4 dram vial with o-xylene as an internal standard (12.1 µL, 0.1 mmol). A portion of the solution was then transferred to a GC vial for analysis, and the GC-FID yield of IV-1 was determined to be 81%. A-5.2. Procedure for the Optimization of Workup Method C – Deprotection of IV-1 and III-1 with NaHSO4-SiO2(C1) In Table S9, (IV-1) (0.12 mmol), (III-1) (0.24 mmol) and 1 mL of methanol (99%) were added to a 1 dram vial containing NaHSO4-SiO2(18-100 mg) and a magnetic stir bar. For all entries, NaHSO4-SiO2was used immediately after removing from an oven set to 120 °C. The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, and placed in a temperature-controlled aluminum heating block set to the specified temperature and was allowed to react under the influence of magnetic stirring at 900 rpm for 15 min to 48 h.     BCS223046 FC - 24 - B. Experimental Section B-1. Screening Results Table S1. Ancillary Ligand Screen for Cross-Couplings Involving 3-Chloro-4-Bromotoluene (IIa)1Decomp / Entry Ligand (IV-1) (IIa) -X 4c 4a+4b remaining Unknown 1 (4-CF3Ph)PF-tBu 69% 0% 0% 9% 4% 14% 2aPhPF-tBu 86% 0% 1% 4% 3% 3% 3 CyPF-tBu 13% 57% 10% 2% 3% 12% 4 CyPF-Cy 10% 63% 10% 6% 1% 9% 5 PhPF-Cy 30% 56% 5% 3% 0% 6% 6 Mor-DalPhos 2% 78% 4% 3% 0% 14% 7 XantPhos 32% 0% 6% 30% 9% 14% 8 XPhos 31% 0% 7% 32% 6% 20% 9 PAd2-DalPhos 43% 31% 7% 5% 7% 0% 10 CyPAd-DalPhos 4% 76% 10% 0% 0% 10% 11 PhPAd-DalPhos 0% 89% 3% 0% 0% 9% 12b(4-CF3Ph)PF-tBu 80% 0% 1% 8% 5% 0% 13b,dPhPF-tBu 79% 0% 4% 2% 6% 3% Conditions:aTriplicate entry; values averaged over 3 reactions.b1 mol% [Pd(cinnamyl)Cl]2(2 mol% Pd) and 2.5 mol% ligand,d18 h reaction. Yields reported on the basis of response-factor calibrated GC data, using authentic samples.aTriplicate entry. Values averaged over 3 reactions.b1 mol% [Pd(cinnamyl)Cl]2(2 mol% Pd) and 2.5 mol% ligand. 4c (IIa)-X1    BCS223046 FC - 25 - Table S2. Protecting Group Screen for Cross-Couplings Involving 3-Chloro-4-Bromotoluene. (IIa) (IIIa)(IVa)  PG = Bn, Me  Entry PG IIa remaining (IVa) Other Producta1 Bn 13% 65% (IV-8): 20% 5  2 Me 14% 64% (IV-9): 25% Yields reported on the basis of response-factor calibrated GC data, using authentic samples.aValues are a sum of ArH yield and the yield of additional undesired alpha-arylated products based on GC retention time, using the response factor for product as a calibration estimate. Pivaloyl, acetate, and SiMe2(tBu) protecting groups proved unsuitable to reaction conditions, yielding no product. Table S3. Base, Solvent, and Additives Screen for Cross-Couplings Involving 3-Chloro-4-Bromotoluene. Base (2 eq. 1 Decomp / Entry unless Solvent (IV-1) (IIa) (IIa)-X 4c 4a+4b Unknown specified) 1 Cs2CO3THF 79% 0% 4% 2% 6% 9% 2 K3PO4THF 71% 20% 2% 3% 2% 3% 3 CsF THF 10% 82% 1% 1% 0% 6% 4 K2CO3THF 2% 102% 2% 0% 0% 0% 5 DBU / NaTFA THF 0% 93% 4% 0% 0% 3% 6 Cs2CO31,4-Dioxane 82% 5% 4% 4% 3% 3% 7 Cs2CO32-MeTHF 78% 0% 2% 3% 6% 11% 8 Cs2CO3Ethyl acetate 55% 20% 2% 3% 0% 21%     BCS223046 FC - 26 - Base (2 eq. 1 Decomp / Entry unless Solvent (IV-1) (IIa) (IIa)-X 4c 4a+4b Unknown specified) 9 Cs2CO3Toluene 75% 0% 3% 4% 4% 14% 10 Cs2CO3CPME 70% 7% 3% 3% 3% 12% 11 Cs2CO3DME 66% 1% 6% 2% 2% 23% 12 Cs2CO3Diglyme 69% 0% 0% 2% 4% 25% 13aCs2CO31,4-Dioxane 0% 28% 2% 3% 0% 66% 14bCs2CO31,4-Dioxane 18% 54% 2% 1% 0% 23% 15cCs2CO31,4-Dioxane 25% 47% 1% 2% 1% 23% 16 K3PO41,4-Dioxane 51% 27% 3% 3% 2% 14% 17 K3PO4(3) 1,4-Dioxane 68% 13% 3% 3% 4% 9% 18 K3PO4(4) 1,4-Dioxane 75% 0% 4% 3% 5% 13% 19 K2CO31,4-Dioxane 4% 95% 2% 0% 0% 0% 20dK2CO3(4) DMF 0% 77% 0% 0% 0% 23% 21a,dK2CO3(4) DMF 0% 84% 0% 0% 0% 16% 22dK2CO3(4) ACN 0% 91% 0% 0% 0% 9% 23dK2CO3(4) NMP 0% 85% 0% 0% 0% 15% 24dK2CO3(4) DMSO 0% 76% 0% 0% 0% 24% 25dK2CO3(4) DMA 0% 64% 6% 0% 0% 30% Yields reported on the basis of response-factor calibrated GC data, using authentic samples.aTBAB additive (0.25 equiv).bNaTFA additive (2 equiv).cNaOTf additive (2 equiv).d1:1 solvent mixture with 1,4-dioxane. Table S4. Additional Optimization: Time and Loading as Related to Base and Solvent. (0.12 mmol)(2-3 equiv)(IIa) (III-1)(IV-1)1Unknown / Time Entry (IV-1) (IIa) (IIa)-X 4c 4a+4b Legend Decomp 1 59% 21% 1% 4% 1% 13% 1,4-Dioxane 8 h 2 58% 26% 0% 5% 0% 11% CPME 3 64% 13% 2% 5% 0% 15% Cs2CO3    BCS223046 FC - 27 - 1 Unknown / Time Entry (IV-1) (IIa) (IIa)-X 4c 4a+4b Legend Decomp (2 equiv.)bK3PO44 46% 34% 0% 4% 0% 16% (4 equiv.) 2 equiv. 5 53% 29% 4% 4% 3% 7% ketone 3 equiv. 6a80% 7% 4% 5% 3% 1% ketone 7 58% 23% 3% 4% 4% 8% 12 h 8 76% 0% 3% 5% 4% 12% 9 45% 21% 5% 4% 3% 22% 10 61% 0% 6% 5% 3% 26% 11 59% 3% 5% 4% 6% 24% 12 51% 0% 4% 4% 3% 37% 13 61% 11% 4% 4% 4% 15% 14 64% 7% 4% 4% 5% 17% 15 56% 10% 10% 4% 3% 18% 16 75% 0% 3% 5% 3% 15% 18 h 17 65% 0% 8% 4% 4% 19% 18 50% 0% 6% 5% 1% 37% 19 60% 0% 4% 4% 3% 28% 20 60% 0% 5% 5% 1% 29% Yields reported on the basis of response-factor calibrated GC data, using authentic samples.aSimilar reactivity observed at 0.36 M using either 1,4-dioxane or 4-MeTHP as solvent at 110 °C (5 h), or at 0.48 M using 1,4-dioxane as solvent (100 °C, 3 h). In terms of modest scale-up, when conducted on a 4 mmol scale in the aryl bromide (0.36 M in 1,4-dioxane), with [Pd(cinnamyl)Cl]2(1.25% Pd), PhPF-tBu (1.5%), Cs2CO3(2 equiv), and THP-protected hydroxyacetone (3 equiv) at 110 °C, 81% yield (IV-1) was achieved after 4.5 h.bIn all cases using less than two equiv Cs2CO3resulted in significantly reduced yields of (IV-1) (< 65%) under otherwise optimized conditions.     BCS223046 FC - 28 - Table S5. Summary of Some Optimal Conditions for the Formation of IV-1 from 3-chloro-4- bromotoluene. En- Conc. Time14a+ Decomp / Solvent Base (IV-1) (IIa) (IIa) -X 4c try (M) (h) 4b Unknown 1,4- 1 Dioxane 0.36 Cs2CO35 82% 3% 2% 5% 2% 5% 1,4- 2aDioxane 0.48 Cs2CO34 83% 7% 1% 4% 2% 1% 3bDioxane 0.36 Cs2CO34.5 85% 0% 2% 4% 2% 5% 4- 4 MeTHP 0.36 Cs2CO35 81% 0% 2% 5% 4% 4% 5 Anisole 0.24 K3PO44 71% 0% 3% 4% 2% 19% 6 CPME 0.24 K3PO46 73% 0% 2% 4% 2% 20% Yields reported on the basis of response-factor calibrated GC data, using authentic samples.a100 °C.b[Pd(cinnamyl)Cl]2(1.25% Pd), PhPF-tBu (2.5%). Table S6. Screening Conditions for Cross-Couplings Involving 2-Chloro-4-methylphenyl trifluoromethanesulfonate and THP-Protected Hydroxyacetone, Leading to (IV-1). (II-1) En- Temp Loading (IV- (II-1)- Solvent Base Ligand Remai- try (°C) (Pd / L) 1) X1ning 1 90 THF Cs2CO3(4-CF3Ph)PF-tBu 2% / 2.5% 13% 16% 37% 2 5% / 90 1,4-Dioxane Cs2CO3(4-CF3Ph)PF-tBu 6.25% 19% 6% 22% 3 5% / 90 1,4-Dioxane Cs2CO3(4-CF3Ph)PF-tBu 6.25% 39% 2% 8% 4 5% / 110 1,4-Dioxane Cs2CO3(4-CF3Ph)PF-tBu 6.25% 42% 13% 0%     BCS223046 FC - 29 - (II-1) En- Temp Loading (IV- (II-1)- Solvent Base Ligand Remai- try (°C) (Pd / L) 1) X1ning 5% / 5 120 1,4-Dioxane Cs2CO3CyPF-Cy 6.25% 11% 0% 40% 6 5% / 120 1,4-Dioxane Cs2CO3CyPF-tBu 6.25% 17% 0% 54% 7 5% / 120 1,4-Dioxane Cs2CO3PhPF-Cy 6.25% 7% 0% 34% 8 5% / 120 1,4-Dioxane Cs2CO3PhPF-tBu 6.25% 20% 0% 22% 9 5% / 120 Toluene Cs2CO3(4-CF3Ph)PF-tBu 6.25% 10% 0% 0% 10 5% / 120 1,4-Dioxane DBU (4-CF3Ph)PF-tBu 6.25% 4% 55% 0% 11 DBU / 5% / 120 1,4-Dioxane NaTFA (4-CF3Ph)PF-tBu 6.25% 41% 9% 14% 12 DBU / 5% / 120 1,4-Dioxane NaOTf (4-CF3Ph)PF-tBu 6.25% 42% 0% 17% 13 DBU / 5% / 120 Toluene NaTFA (4-CF3Ph)PF-tBu 6.25% 90% 0% 0% 14 DBU / 5% / 120 Toluene NaOTf (4-CF3Ph)PF-tBu 6.25% 90%a0% 0% 15 DBU / 5% / 90 Toluene NaOTf (4-CF3Ph)PF-tBu 6.25% 26% 22% 0% 16 DBU / 5% / 110 Toluene NaOTf (4-CF3Ph)PF-tBu 6.25% 40% 0% 0% 17 DBU / 120 Toluene NaOTf (4-CF3Ph)PF-tBu 2% / 2.5% 47% 13% 11% Reaction as outlined in GP3. Yields reported on the basis of response-factor calibrated GC data, using authentic samples. No reaction observed in the absence of DBU (2 equiv). However, the data in the chart below confirm that substantial conversion to (IV-1) is achieved even when using as low as 0.1 equiv NaOTf. Entry NaOTf Equiv (IV-1) (II-1) remaining (II-1)-X11 0 0% 58% 0% 2 0.1 58% 11% 6%     BCS223046 FC - 30 - Entry NaOTf Equiv (IV-1) (II-1) remaining (II-1)-X13 0.25 69% 3% 14% 4 0.5 75% 0% 10% 5 1 80% 0% 7% 6 1.5 86% 0% 8% Table S7. Probing the Effect of Salt Additives in Cross-couplings of 2-Chloro-4-methylphenyl trifluoromethanesulfonate and THP-Protected Hydroxyacetone, leading to (IV-1). (0.12 mmol)(2 equiv)(II-1) (III-1)(IV-1)(II-1) Entry Salt Additive Ether Additive (IV-1) remaining (IIa)-X11 NaTFA - 89% 0% 0% 2 NaOTf - 90% 0% 8% 3 KOTf - 88% 6% 4% 4 LiOTf - 13% 24% 31% 5 AgOTf - 0% 3% 0% 6 AgTFA - 0% 72% 0% 7 [nBu4N]OTf - 4% 95% 0% 8 NaCl - 2% 65% 0% 9 LiCl - 8% 58% 0% 10 KCl - 0% 0% 0% 11 NaOAc - 8% 22% 9% 12 KOAc - 7% 55% 6% 13 NaPF6- 72% 0% 11% 14 NaOTf / [nBu4N]OTf - 18% 0% 11% 15 NaCl / LiOTf - 10% 17% 15% 16 NaOTf 18-crown-6 65% 3% 12% 17 KOTf 18-crown-6 40% 20% 10% Yields reported on the basis of response-factor calibrated GC data, using authentic samples, with no reaction observed in the absence of DBU (2 equiv).     BCS223046 FC - 31 - Table S8. Optimizing the Formation of (IV-1), and Subsequent Deprotection to (I-1). 1. [Pd(cinnamyl)Cl]2(0.625 mol% Pd) (4 mmol)(3 equiv)(IIa) (III-1) (I-1)   Workup Method : A : HCl (2.5-5 equiv.), H2O (0.048-0.096 M) 95°C, 10 min B : 10% HCl / 1,4-dioxane C : NaHSO4-SiO2, methanol Entry 1 2 3 4 5 6 7 8 9a10 Workup A A’ A” B C Method HCl (37%, 200 200 200 100 200 100 200 200 540 - conc.) (mL) Water (mL) 10 10 10 10 5 5 10 10 1.46 - Time [min] 5 10 15 20 5 15 10 10 300 45 1a Yield (g) 0.052 0.065 0.059 0.06 0.052 0.042 0.063 0.069 0.059 0.052 1a Yield (mmol) 0.26 0.33 0.30 0.30 0.26 0.21 0.32 0.35 0.30 0.26 1a Yield (%) 55 68 62 63 55 44 66 72 62 55aHCl and water added as a 10% HCl solution (2 mL). Both A’ and A” employ the optimal conditions from A (entry 2), but differ in that A’ and A” involve chromatographic purification, whereas A does not. Moreover, A’ and A” differ in that A” does not involve a hot gravity filtration step. See the associated experimental descriptions for these workup methods for full details.     BCS223046 FC - 32 - Table S9. Deprotection of (IV-1) and (III-1) with NaHSO4-SiO2(Optimization of Workup Method C) 0.24 mmol Catalyst Reaction Temp Time Catalyst (mg) (mg / mmol THP- (I-1) (IV-1) (III-1) ether) 1 rt 60 min 18 50 35% 74% 93% 2 rt 48 h 18 50 74% 1% 6% 3 rt 150 min 100 278 92% 4% 8% 4 40 °C 30 min 100 278 89% 0% 8% 5 50 °C 30 min 50 139 59% 53% 39% 6 50 °C 15 min 100 278 81% 14% 11% 7 50 °C 30 min 100 278 99% 0% 0% Yields reported on the basis of response-factor calibrated GC data, using authentic samples.     BCS223046 FC - 33 - B-2. Examples Example (III-1): 1-[(oxan-2-yl)oxy]-2-propanone The title compound was prepared using a modified procedure from the referenced publication(Kim, D. S. et al., Bioorg Med Chem Lett 2001, 11 (18), 2541-3) (1.5 equiv of 3,4-dihydro-2H-pyran instead of 2.0). Hydroxyacetone (2.05 mL, 30 mmol, 1.0 equiv) and 3,4-dihydro-2H-pyran (4.11 mL, 45 mmol, 1.5 equiv) were added to a 40 mL vial containing pyridinium p-toluenesulfonate (0.754 g, 3 mmol, 0.1 equiv), a magnetic stir bar, and 25 mL of anhydrous DCM. The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature-controlled aluminum heating block set to 50 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 18 h. Purified by flash column chromatography on silica using an eluent gradient of 10% ethyl acetate in hexanes. Using a vanillin stain, the relevant fractions were combined, and the solvent was removed in vacuo which afforded the title compound in an 72% isolated yield (3.41 g, 21.6 mmol) as a clear oil.1H 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).13C{1H} NMR (126 MHz, CDCl3) δ 206.86, 98.90, 72.47, 62.50, 30.41, 26.63, 25.40, 19.31. Example (III-2): 3-[(oxan-2-yl)oxy]]-2-butanone 3-hydroxy-2-butanone (1.02 mL, 12.5 mmol, 1.0 equiv) and 3,4-Dihydro-2H-pyran (2.28 mL, 25 mmol, 2 equiv) were added to a 40 mL vial containing pyridinium p-toluenesulfonate (0.314 g, 1.25 mmol, 0.1 equiv), a magnetic stir bar, and 25 mL of anhydrous DCM. The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature- controlled aluminum heating block set to 50 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 18 h. The homogeneous reaction mixture was then dry loaded onto silica in vacuo, then loaded onto a normal-phase Biotage SNAP KP-Sil 100 g column cartridge. Purified by flash column chromatography on silica using an eluent gradient of 5% ethyl acetate in hexanes (1 CV), 5-15% ethyl acetate in hexanes (10 CV), followed by 15% ethyl acetate in hexanes (2 CV). Using a vanillin stain, the relevant fractions were combined, and the solvent was removed in vacuo which afforded the title     BCS223046 FC - 34 - compound as a 1:0.08 mixture of diastereomers 42% isolated yield (0.901 g, 5.23 mmol) as a clear oil. The ratio of diastereomers was determined by the ratio of -CH-CH3proton integrations as shown in the1H NMR spectrum. The1H and13C{1H} NMR peaks listed below correspond to the major set of diastereomers, with considerable overlap between diastereomer peaks in the1H NMR spectrum.1H 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).13C{1H} 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 C9H16NaO3[M+Na]+: 195.0992. Found: 195.0992. Example (II-1): 2-chloro-4-methylphenyl trifluoromethanesulfonate The title compound was synthesized from the corresponding phenol (5.4 mmol) according to GP3 which afforded the title compound in a 96% isolated yield (1.43 g, 5.2 mmol) as a dark red oil.1H 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).13C{1H} NMR (126 MHz, CDCl3) δ 143.69, 140.02, 131.73, 129.03, 126.84, 122.69, 118.80 (q, JCF= 320.5 Hz), 20.88.19F NMR (471 MHz CDCl3) δ -73.55. HRMS-ESI (m / z): Calc’d for C8H6ClF3NaO3S [M+Na]+: 296.9576. Found: 296.9570. Example (II-2): 4-chloro-2-methylphenyl trifluoromethanesulfonate The title compound was synthesized from the corresponding phenol (5.4 mmol) according to GP3 which afforded the title compound in a 98% isolated yield (1.45 g, 5.3 mmol) as a dark red oil.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).13C{1H} NMR (126 MHz, CDCl3) δ 152.92 (d, JCF= 252.0 Hz), 134.36 (m), 130.10 (m), 129.15, 118.76 (q, JCF= 320.3 Hz), 114.98, 114.88, 19.95.19F NMR (471 MHz CDCl3) δ -73.03 (d, JFF= 11 Hz), -126.16 (q, JFF= 11 Hz). HRMS-ESI (m / z): Calc’d for C8H6ClF3NaO3S [M+Na]+: 296.9577. Found: 296.9568     BCS223046 FC - 35 - Example (II-3): 2-chloro-6-fluoro-3-methylphenyl trifluoromethanesulfonate The title compound was synthesized from the corresponding phenol (5.4 mmol) according to GP3 which afforded the title compound in a 95% isolated yield (1.64 g, 5.1 mmol) as a dark red oil.1H 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).13C{1H} NMR (126 MHz, CDCl3) δ 152.93 (m), 134.36 (m), 130.10 (m), 129.15, 118.70 (q, JCF= 321 Hz), 115.13, 114.98, 19.95.19F NMR (471 MHz CDCl3) δ -73.04 (d, JFF= 11 Hz), -126.18 (q, JFF= 11 Hz). HRMS-ESI (m / z): Calc’d for C8H5ClF4NaO3S [M+Na]+: 314.9482. Found: 314.9476. Example (II-4): 4-chloro-2-cyclohexylphenyl trifluoromethanesulfonate The title compound was synthesized from the corresponding phenol (5.4 mmol) according to GP3 which afforded the title compound in a 77% isolated yield (1.43 g, 4.2 mmol) as a dark red oil.1H 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).13C{1H} NMR (126 MHz, CDCl3) δ 145.55, 142.41, 134.42, 128.82, 127.52, 126.74 (q, JCF= 92 Hz), 122.72, 37.77, 35.55, 26.68, 26.01.19F NMR (471 MHz CDCl3) δ -73.78. HRMS-ESI (m / z): Calc’d for C13H14ClF3NaO3S [M+Na]+: 365.0202. Found: 365.0210. Example (II-5): 2-chloro-4-methylphenyl sulfurofluoridate       BCS223046 FC - 36 - A round bottom flask equipped with teflon-coatled stir bar and rubber septa was charged with 2-chloro- 4-methylphenol (20.0 g, 136.1 mmol, 1.0 equiv.), diisopropylethylamine (52.6 g, 129.3 mmol, 3.0 equiv) and acetonitrile (312 g). The reaction flask was evacuated under vacuum and then backfilled with sulfuryl difluoride. The reaction was then stirred for 4 hours at room temperature, at which time HPLC analysis indicated complete consumption of the starting material. The remaining sulfury difluoride was removed under vacuum (equipped with gas washer). The acetonitrile was removed using a rotary evaporator. The reaction mixture was diluted with ethyl acetate (100 mL), transferred to a separatory funnel and washed twice with water (2x100 mL), then washed with brine (2x50 mL). The product was then purified by distillation (65 °C, 8 mbar to 85 °C, 6 mbar) to afford the title compound with 97% purity and 85.6% yield.1H 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). Example (I-1): 1-(2-chloro-4-methylphenyl)-3-hydroxypropan-2-one   The title compound was synthesized using three different methods. Method 1. The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (4 mmol) according to GP1, conducted in 1,4-dioxane (0.36 M) at 110 °C in a 4 dram vial with 0.625 mol% [Pd(cinnamyl)Cl]2(1.25 mol% Pd) and 1.5 mol% PhPF-tBu, affording IV-1 in an 81% yield, as determined by calibrated GC analysis. Deprotected / purified according to Workup Method A at a 0.48 mmol scale (screen D1, Entry 2), which afforded the title compound in a 68% isolated yield (0.065 g, 0.327 mmol) as a white crystalline solid. Method 2. The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (1 mmol) according to GP1, conducted in 4-MeTHP (0.36 M) at 110 °C for 4 h using 0.625 mol% [Pd(cinnamyl)Cl]2(1.25 mol% Pd) and 1.5 mol% PhPF-tBu, affording IV-1 in an 86% yield, as determined by calibrated GC analysis via Workup Method F. Deprotected / purified according to Workup Method A'', using 400 µL HCl (conc.) and 15 mL H2O (0.67 M). Purified by flash column chromatography on silica using a Silicycle SiliSepTM40 g column cartridge with an eluent gradient of 0% methanol in DCM (2 CV), followed by 0-4% methanol in DCM (20 CV) which afforded the title compound in a 75% isolated yield (0.148 g, 0.745 mmol) as a white solid. Method 3. For a benchtop synthesis of the title compound: Without exclusion of air, 4-bromo-3-chlorotoluene (1.0 mmol, 1.0 equiv), 1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-propanone (3 equiv), and 4-MeTHP (2.8 mL, pre-treated as described in the General Considerations but herein handled in air, 0.36 M) were added to a 4 dram vial. A 1 dram screw-capped vial containing a magnetic stir bar was then charged with 0.625 mol%     BCS223046 FC - 37 - [Pd(cinnamyl)Cl]2(1.25 mol% Pd), 1.5 mol% PhPF-tBu, and Cs2CO3(2 equiv). Both vials were sealed in air with caps containing PTFE septa, wrapped with electrical tape, and placed in a temperature-controlled aluminum heating block at 25 °C. For 5 minutes, the 4-MeTHP solution was sparged with N2by way of an inserted needle, while the 1 dram vial was flushed with N2via an inserted needle (this needle was retained to provide a positive pressure of nitrogen throughout the reaction). The 4-MeTHP solution was transferred to the 1 dram vial via syringe under continued pressure of nitrogen. The mixture was allowed to react under the influence of magnetic stirring at 110 °C and 900 rpm for 4 h under a positive pressure of nitrogen, affording IV-1 in an 81% yield, as determined by calibrated GC analysis via Workup Method F. Deprotected / purified according to Workup Method A'', using 400 µL HCl (conc.) and 15 mL H2O (0.67 M). Purified by flash column chromatography on silica using a Silicycle SiliSepTM40 g column cartridge with an eluent gradient of 0% methanol in DCM (2 CV), followed by 0-4% methanol in DCM (20 CV) which afforded the title compound in a 65% isolated yield (0.129 g, 0.745 mmol) as a white solid.1H 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).13C{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 C10H11ClNaO2[M+Na]+: 221.0340. Found: 221.0337. Example (I-2): 1-(2-chloro-4-fluorophenyl)-3-hydroxypropan-2-one   The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1, conducted at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2(1.25 mol% Pd) and 1.5 mol% PhPF-tBu, and deprotected / purified according to a variation of Workup Method A. After cooling to room temperature, the aqueous eluent was extracted with 3 x 5 mL of DCM, and the solvent was removed in vacuo. 2 mL of water was then added to the resulting crude oil and the mixture was heated on a hotplate with swirling until homogeneous. The mixture was allowed to cool to room temperature, and then placed in a fridge set to 3oC overnight to yield the title compound in a 39% isolated yield (0.038 g, 0.188 mmol) as a white crystalline solid. Alternatively, Workup Method A' can be used for deprotection / purification. Purified by flash column chromatography on silica using a 10 g Silicycle SiliSepTM10 g column cartridge with an eluent gradient of 0% methanol in DCM (2 CV), followed by 0- 4% methanol in DCM (20 CV) which afforded the title compound in an 52% isolated yield (0.051 g, 0.252 mmol) as a white solid.1H 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).13C{1H} NMR (75 MHz, CDCl3, 0.05% (v / v) TMS) δ 206.10, 162.01 (d, JCF= 248 Hz), 132.75 (d, JCF= 15 Hz), 127.34, 117.47-117.14 (overlapping), 114.69 (d, JCF= 35 Hz), 68.23, 42.76.19F NMR (282 MHz, CDCl3, 0.05%     BCS223046 FC - 38 - (v / v) TMS) δ -112.08. HRMS-ESI (m / z): Calc’d for C9H8ClFNaO2[M+Na]+: 225.0089. Found: 225.0089. Example (I-3): 1-[2-chloro-5-(trifluoromethyl)phenyl]-3-hydroxypropan-2-one The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1, conducted at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2(1.25 mol% Pd) and 1.5 mol% PhPF-tBu, and deprotected / purified according to Workup Method A with 8 mL of H2O (0.06 M), which afforded the title compound in a 35% isolated yield (0.042 g, 0.166 mmol) as a white crystalline solid. Alternatively, Workup Method A' can be used for deprotection / purification. Purified by flash column chromatography on silica using a Silicycle SiliSepTM10 g column cartridge with an eluent gradient of 0% methanol in DCM (2 CV), followed by 0-4% methanol in DCM (20 CV) which afforded the title compound in an 49% isolated yield (0.060 g, 0.238 mmol) as a white solid.1H 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).13C{1H} 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, JCF= 330 Hz), 68.38, 43.29.19F NMR (282 MHz, CDCl3, 0.05% (v / v) TMS) δ -62.61. HRMS-ESI (m / z): Calc’d for C9H7ClF3O2[M−H]−: 251.0092. Found: 251.0091. Example (I-4): 1-(2-chloro-4-methoxyphenyl)-3-hydroxypropan-2-one The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1, conducted at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2(1.25 mol% Pd) and 1.5 mol% PhPF-tBu, and deprotected / purified according to Workup Method A with 8 mL of H2O (0.06 M), which afforded the title compound in a 51% isolated yield (0.053 g, 0.247 mmol) as a white crystalline solid. Alternatively, Workup Method A'' can be used for deprotection / purification. Purified by flash column chromatography on silica using a Silicycle SiliSepTM10 g column cartridge with an eluent gradient of 0% methanol in DCM (2 CV), followed by 0-4% methanol in DCM (20 CV) which afforded the title compound in an 66% isolated yield (0.068 g, 0.317 mmol) as a white solid.1H NMR (300 MHz,     BCS223046 FC - 39 - 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).13C{1H} NMR (75 MHz, CDCl3, 0.05% (v / v) TMS) δ 206.92, 159.89, 134.92, 132.25, 123.20, 115.22, 113.52, 68.07, 55.70, 42.88. HRMS-ESI (m / z): Calc’d for C10H11ClNaO3[M+Na]+: 237.0289. Found: 237.0289. Example (I-5): 1-(2,4-dichlorophenyl)-3-hydroxypropan-2-one Method 1. The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1, conducted at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2(1.25 mol% Pd) and 1.5 mol% PhPF-tBu, and deprotected / purified according to Workup Method A with 8 mL of H2O (0.06 M), which afforded the title compound in a 55% isolated yield (0.058 g, 0.265 mmol) as a white crystalline solid. Method 2. Using the same catalytic procedure as above, Workup Method A'' can be used for deprotection / purification. Purified by flash column chromatography on silica using a Silicycle SiliSepTM10 g column cartridge with an eluent gradient of 0% methanol in DCM (2 CV), followed by 0-4% methanol in DCM (20 CV) which afforded the title compound in an 72% isolated yield (0.076 g, 0.347 mmol) as a white solid. Method 3. The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP4, conducted at 90 °C using 1 mol% [Pd(cinnamyl)Cl]2(2 mol% Pd) and 2.5 mol% (4-CF3Ph)PF-tBu, and deprotected / purified according to Workup Method B. Purified by flash column chromatography on silica using a Silicycle SiliSepTM10 g column cartridge with an eluent gradient of 0% methanol in DCM (2 CV), followed by 0- 4% methanol in DCM (20 CV) which afforded the title compound in an 82% isolated yield (0.086 g, 0.393 mmol) as a white solid.1H 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 = 4.9 Hz, 1H).13C{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 C10H7Cl2O2[M-H]- : 216.9829. Found: 216.9828. Example (I-6): 1-hydroxy-3-(naphthalen-1-yl)propan-2-one     BCS223046 FC - 40 - The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1, conducted at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2(1.25 mol% Pd) and 1.5 mol% PhPF-tBu, and deprotected / purified according to Workup Method A, which afforded the title compound in a 60% isolated yield (0.058 g, 0.290 mmol) as a white crystalline solid.1H 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).13C{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 C13H12NaO2[M+Na]+: 223.0730. Found: 223.0731. Example (I-7): 1-hydroxy-3-(2-methoxy-4-methylphenyl)propan-2-one The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP1, conducted at 90 °C for 12 h 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''. Purified by flash column chromatography on silica using a Silicycle SiliSepTM40 g column cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), followed by 15-50% ethyl acetate in hexanes (15 CV) which afforded the title compound in a 70% isolated yield (0.076 g, 0.347 mmol) as a clear oil.1H 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).13C{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 C11H14NaO3[M+Na]+: 217.0835. Found: 217.0835. Example (I-8): 1-hydroxy-3-[2-chloro-4-(4-methylpiperazin-1-yl)phenyl]propan-2-one The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (0.24 mmol) according to GP1, conducted at 110 °C using 0.75 mol% [Pd(cinnamyl)Cl]2(1.5 mol% Pd) and 2 mol% PhPF-tBu, and deprotected / purified according to a variation of Workup Method A'. After hot gravity filtration and cooling to room temperature, the aqueous layer was extracted with 10 mL of     BCS223046 FC - 41 - DCM, and the organic layer was discarded. The aqueous layer was then neutralized with saturated NaHCO3and extracted with 3 x 10 mL DCM. The organic layers were combined, and dried over Na2SO4. Purified by flash column chromatography on silica using a Silicycle SiliSepTM10 g column Cartridge with an eluent gradient of 0% methanol in DCM (2 CV), followed by 0-20% ethyl acetate in hexanes (20 CV) which afforded the title compound in an 59% isolated yield (0.040 g, 0.141 mmol) as a white solid.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).13C{1H} NMR (126 MHz, CDCl3) δ 207.27, 151.81, 135.05, 132.02, 121.25, 116.49, 114.63, 68.02, 54.97, 48.54, 46.21, 42.94. HRMS-ESI (m / z): Calc’d for C14H20ClN2O2[M+H]+: 283.1208. Found: 283.1206. Example (I-9): 1-hydroxy-1-methyl-3-(naphthalen-2-yl)propan-2-one The THP-protected analogue of the title compound was synthesized from the corresponding aryl bromide (0.24 mmol) according to GP1, conducted at 90 °C using 0.75 mol% [Pd(cinnamyl)Cl]2(1.5 mol% Pd) and 2 mol% PhPF-tBu, and deprotected / purified according to Workup Method C. Purified by flash column chromatography on silica using a Silicycle SiliSepTM10 g column Cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), followed by 15-50% ethyl acetate in hexanes (15 CV) which afforded the title compound in an 56% isolated yield (0.029 g, 0.271 mmol) as a white solid.1H 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).13C{1H} 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 C14H14NaO2[M+Na]+: 237.0886. Found: 237.0884. Example (IV-1): 1-(4-chloro-2-methylphenyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-one The title compound was synthesized from the corresponding aryl bromide (0.26 mmol) according to GP1, conducted at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2(1.25 mol% Pd) and 1.5 mol% PhPF-tBu, and purified according to Workup Method D. Purified by flash column chromatography on silica using a     BCS223046 FC - 42 - Silicycle SiliSepTM10 g column Cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), followed by 0-20% ethyl acetate in hexanes (20 CV) which afforded the title compound in an 73% isolated yield (0.054 g, 0.191 mmol) as a clear oil. In addition, the title compound was synthesized from the corresponding aryl triflate (0.48 mmol) according to GP2, conducted at 120 °C using 2.5 mol% [Pd(cinnamyl)Cl]2(5 mol% Pd) and 6.25 mol% (4-CF3Ph)PF-tBu, and purified according to Workup Method D. Purified by flash chromatography on silica using 10% ethyl acetate in hexanes which afforded the title compound in a 71% isolated yield (0.097 g, 0.343 mmol) as a light yellow oil. The title compound could also be synthesized using GP1 or GP2 from the corresponding fluorosulfonate (II-5)) in 50% and 25% yield.1H 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).13C{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 C15H19ClNaO3[M+Na]+: 305.0915. Found: 305.0914. Example (IV-2): 1-[(oxan-2-yl)oxy]-3-[4-(trifluoromethyl)pyridin-3-yl]propan-2-one The title compound was synthesized from the corresponding aryl bromide (0.24 mmol) according to GP1, conducted at 90 °C using 0.75 mol% [Pd(cinnamyl)Cl]2(1.5 mol% Pd) and 2.5 mol% PhPF-tBu, and purified according to Workup Method D. Purified by flash column chromatography on silica using a 10 g Silicycle SiliSepTMFlash Cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), followed by 15-50% ethyl acetate in hexanes (18 CV) which afforded the title compound in an 87% isolated yield (0.063 g, 0.208 mmol) as a light yellow oil.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).13C{1H} NMR (75 MHz, CDCl3) δ 204.46, 153.99, 149.37, 136.83 (q, JCF= 31.5 Hz), 127.02, 123.10 (q, JCF= 273 Hz), 119.74, 99.60, 72.44, 62.94, 40.64, 30.46, 25.32, 19.53.19F NMR (282 MHz, CDCl3) δ -62.36. HRMS-ESI (m / z): Calc’d for C14H15F3NO2[M−H]−: 302.1010. Found: 302.1017.     BCS223046 FC - 43 - Example (IV-3): 1-[2-chloro-4-(4-methylpiperazin-1-yl)phenyl]-3-[(oxan-2-yl)oxy]propan-2-one The title compound was synthesized from the corresponding aryl bromide (0.48 mmol) according to GP4, conducted 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. Purified by flash column chromatography on silica using a 10 g Silicycle SiliSepTMFlash Cartridge with an eluent gradient of 0% methanol in DCM (2 CV), followed by 0-10% methanol in DCM (24 CV) which afforded the title compound in an 83% isolated yield (0.146 g, 0.398 mmol) as a light green oil.1H 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).13C{1H} 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. We could not obtain HRMS data for this THP-protected product, due to rapid fragmentation in the MS; we provide data for the deprotected product. HRMS-ESI (m / z): Calc’d for C14H20ClN2O2[M+H]+: 283.1208. Found: 283.1205. Example (IV-4): 1-(1-benzothiophen-4-yl)-3-[(oxan-2-yl)oxy]propan-2-one The title compound was synthesized from the corresponding aryl bromide (0.24 mmol) according to GP1, conducted at 100 °C in 1,4-dioxane (0.48 M) using 0.5 mol% [Pd(cinnamyl)Cl]2(1 mol% Pd) and 1.5 mol% PhPF-tBu, and purified according to Workup Method D. Purified by flash column chromatography on silica using a 10 g Silicycle SiliSepTMFlash Cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), followed by 0-30% ethyl acetate in hexanes (24 CV) which afforded the title compound in an 92% isolated yield (0.064 g, 0.220 mmol) as a clear oil.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).13C{1H} NMR (75 MHz, CDCl3) δ     BCS223046 FC - 44 - 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 C16H18NaO3S [M+Na]+: 313.0869. Found: 313.0867. Example (IV-5): 1-(4-chloro-2-methylphenyl)-3-[(oxan-2-yl)oxy]propan-2-one The title compound was synthesized from the corresponding aryl triflate (0.48 mmol) according to GP2, conducted at 120 °C using 2.5 mol% [Pd(cinnamyl)Cl]2and 6.25 mol% (4-CF3Ph)PF-tBu, and purified according to Workup Method D. Purified by flash chromatography on silica using 10% ethyl acetate in hexanes which afforded the title compound in a 74% isolated yield (0.100 g, 0.355 mmol) as a yellow oil.1H 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).13C{1H} 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 C15H19ClNaO3[M+Na]+: 305.0915. Found: 305.0924. Example (IV-6): 1-(2-chloro-6-fluoro-3-methylphenyl)-3-[(oxan-2-yl)oxy]propan-2-one The title compound was synthesized from the corresponding aryl triflate (0.48 mmol) according to GP2, conducted at 120 °C using 2.5 mol% [Pd(cinnamyl)Cl]2and 6.25 mol% (4-CF3Ph)PF-tBu, and purified according to Workup Method D. Purified by flash chromatography on silica using 10% ethyl acetate in hexanes which afforded the title compound in a 60% isolated yield (0.087 g, 0.289 mmol) as a yellow oil.1H 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).13C{1H} NMR (126 MHz, CDCl3) δ 204.12, 159.86 (d, JCF= 246 Hz), 135.46 (d, JCF= 5.9 Hz), 132.30 (d, JCF= 3.9 Hz), 130.06 (d, JCF= 10.0 Hz), 120.80 (d, JCF= 18.4 Hz), 113.35 (d, JCF= 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 C15H18ClFNaO3[M+Na]+: 323.0821. Found: 332.0822.     BCS223046 FC - 45 - Example (IV-7): 1-(4-chloro-2-cyclohexylphenyl)-3-[(oxan-2-yl)oxy]propan-2-one The title compound was synthesized from the corresponding aryl triflate (0.48 mmol) according to GP2, conducted at 120 °C using 2.5 mol% [Pd(cinnamyl)Cl]2and 6.25 mol% (4-CF3Ph)PF-tBu, and purified according to Workup Method D. Purified by flash chromatography on silica using 10% ethyl acetate in hexanes which afforded the title compound in a 70% isolated yield (0.118 g, 0.336 mmol) as a yellow oil.1H 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).13C{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 C20H27ClNaO3[M+Na]+: 373.1541. Found: 373.1539. Example (IV-8): 1-(benzyloxy)-3-(2-chloro-4-methylphenyl)propan-2-one The title compound was synthesized from the corresponding aryl bromide (0.48 mmol) and 1- (benzyloxy)propan-2-one (3 equiv) according to GP5, conducted at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2and 1.5 mol% PhPF-tBu, and purified according to Workup Method D. Purified by flash column chromatography on silica using a 40 g Silicycle SiliSepTMFlash Cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), followed by 0-10% ethyl acetate in hexanes (20 CV) which afforded the title compound in an 70% isolated yield (0.097 g, 0.336 mmol) as a clear oil.1H 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).13C{1H} 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 C17H17ClNaO2[M+Na]+: 311.0809. Found: 311.0810.     BCS223046 FC - 46 - Example (IV-9): 1-(2-chloro-4-methylphenyl)-3-methoxypropan-2-one The title compound was synthesized from the corresponding aryl bromide (0.48 mmol) and methoxyacetone (3 equiv) according to GP6, conducted at 110 °C using 0.625 mol% [Pd(cinnamyl)Cl]2and 1.5 mol% PhPF-tBu, and purified according to Workup Method D. Purified by flash column chromatography on silica using a 10 g Silicycle SiliSepTMFlash Cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), followed by 0-20% ethyl acetate in hexanes (20 CV) which afforded the title compound in an 65% isolated yield (0.066 g, 0.310 mmol) as a clear oil.1H 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).13C{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 C11H12ClNaO2[M+Na]+: 235.0496. Found: 235.0504. Example (IV-10): 1-(2-chloro-4-methoxyphenyl)-3-methoxypropan-2-one The title compound was synthesized from the corresponding aryl bromide (0.24 mmol) and methoxyacetone (3 equiv) according to GP6, conducted at 100 °C for 8 h using 0.625 mol% [Pd(cinnamyl)Cl]2and 1.5 mol% PhPF-tBu, and purified according to Workup Method D. Purified by flash column chromatography on silica using a 10 g Silicycle SiliSepTMFlash Cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), followed by 0-20% ethyl acetate in hexanes (15 CV) which afforded the title compound in an 62% isolated yield (0.034 g, 0.297 mmol) as a clear oil.1H 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).13C{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 C11H13ClNaO3[M+Na]+: 251.0445. Found: 251.0444.     BCS223046 FC - 47 - Example (IV-11): 1-(benzyloxy)-3-(2-(dimethylamino)phenyl)propan-2-one The title compound was synthesized from the corresponding aryl bromide (0.24 mmol) and 1- (benzyloxy)propan-2-one (3 equiv) according to GP5, conducted at 110 °C for 6 h using 1.25 mol% [Pd(cinnamyl)Cl]2(2.5 mol% Pd) and 3 mol% PhPF-tBu, and purified according to Workup Method D. Purified by flash column chromatography on silica using a 40 g Silicycle SiliSepTMFlash Cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), followed by 0-20% ethyl acetate in hexanes (20 CV) which afforded the title compound in a 63% isolated yield (0.045 g, 0.159 mmol) as a light yellow oil.1H 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).13C{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 C18H21NNaO2[M+Na]+: 306.1465. Found: 306.1460. Side products 1,1-di(2-chloro-4-methylphenyl)-3-[(oxan-2-yl)oxy]propan-2-one (4a) 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-dram screw-capped vial containing a magnetic stir bar and dissolved in 1 mL of THF. Then, Cs2CO3(2 equiv), 3-chloro-4- bromotoluene (32.2 μL, 0.24 mmol, 1 equiv), and (IV-1) (0.1131 g, 0.40 mmol, 1.67 equiv) were added. The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature-controlled aluminum heating block set to 90 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 12 h. Purified according to Workup Method D. Purified by flash column chromatography on silica using a Silicycle SiliSepTMHP 40 g column cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), 0-20% ethyl acetate in hexanes (24 CV) followed by 20% ethyl acetate in hexanes (2 CV) which afforded the title compound in an 26%     BCS223046 FC - 48 - isolated yield (0.025 g, 0.061 mmol) as a clear oil.1H 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).13C{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 C22H24Cl2NaO3[M+Na]+: 429.0995. Found: 429.0999. 1,3-di(2-chloro-4-methylphenyl)-1-[(oxan-2-yl)oxy]propan-2-one (4b) 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 1-dram screw-capped vial containing a magnetic stir bar and dissolved in 0.67 mL of 1,4-dioxane. Then, Cs2CO3(2 equiv), 3-chloro- 4-bromotoluene (32.2 μL, 0.24 mmol, 1 equiv), and IV-1 (0.679 g, 0.24 mmol, 1 equiv) were added. The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature-controlled aluminum heating block set to 110 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 16 h. Purified according to Workup Method D. Purified by flash column chromatography on silica using a 40 g Silicycle SiliSepTMHP Flash Cartridge with an eluent gradient of 0% ethyl acetate in hexanes (2 CV), 0-20% ethyl acetate in hexanes (26 CV) which afforded the title compound in a 29% isolated yield (0.028 g, 0.069 mmol) as a clear oil. The title compound was isolated as a 1:0.6 mixture of two sets of diastereomers as determined by the ratio of -O-CH-O- proton integrations in the1H NMR spectrum (4.88 ppm (t, J = 3.1 Hz, 0.60H) : 4.56 ppm (t, J = 3.6 Hz, 1.00H)).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).13C{1H} 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 C22H24Cl2NaO3[M+Na]+: 429.0995. Found: 429.1007.     BCS223046 FC - 49 - A Mixture Containing 1-(2-chloro-4-methylphenyl)-1-[(oxan-2-yl)oxy]propan-2-one 4a4bThe title compound was synthesized from the corresponding aryl bromide and isolated in 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-dram screw-capped vial containing a magnetic stir bar and dissolved in 2 mL of THF. Then, Cs2CO3(2 equiv), 3-chloro-4-bromotoluene (0.48 mmol, 1 equiv), and 1-[(Tetrahydro-2H-pyran-2-yl)oxy]-2- propanone (2 equiv) were added. The vial was sealed with a cap containing a PTFE lining, wrapped with electrical tape, then removed from the glovebox and placed in a temperature-controlled aluminum heating block set to 90 °C and was allowed to react under the influence of magnetic stirring at 900 rpm for 12 h. Purified according to Workup Method D. Purified by flash column chromatography on silica using a 25 g Silicycle SiliSepTMFlash Cartridge using an eluent gradient of 0% ethyl acetate in hexanes (2 CV), 0- 20% ethyl acetate in hexanes (24 CV) followed by 20% ethyl acetate in hexanes (2 CV) which afforded (IV-1) in a 7% isolated yield (0.010 g, 0.035 mmol) as a clear oil, and a mixture containing 4c, 4a, and 4b (0.032 g) as a clear oil. Mass spectrum of the mixture: HRMS-ESI (m / z): Calc’d for C15H19ClNaO3(4c) [M+Na]+: 305.0915. Found: 305.0917. HRMS-ESI (m / z): Calc’d for C22H24Cl2NaO3(4a / 4b) [M+Na]+: 429.0995. Found: 429.0998.

Claims

BCS223046 FC - 50 - CLAIMS:

1. A process for the preparation of a compound of the general formula (I)(I), wherein R1is phenyl, naphthyl or 5- to 10-membered heteroaryl, wherein said phenyl, naphthyl and 5- to 10-membered heteroaryl are optionally substituted by 1 to 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- to 10-membered heterocyclyl, wherein said 3- to 10-membered heterocyclyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of oxo, hydroxy, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy and C1-C6-haloalkoxy, R2is hydrogen or (C1-C6)-alkyl, characterized in that in step A, a compound of formula (II) (II), wherein R1is as defined above and X1is bromo, iodo, fluorosulfonate or trifluoromethylsulfonate, is reacted in a suitable solvent in the presence of a palladium catalyst, a bis-phosphine ligand and a suitable base with a compound of formula (III)wherein R2is defined as above and    BCS223046 FC - 51 - PG is a hydroxy-protecting group, preferably methyl, tert-butyl, tetrahydropyranyl or benzyl, to form a compound of formula (IV)wherein R1, R2and PG are defined as above, and in step B, the protecting group PG is subsequently removed.

2. The process according to claim 1, wherein the palladium catalyst in process step A is a salt of palladium (II), in particular [Pd(cinnamyl)Cl]2, Pd(OAc)2or Pd(dba)23. The process according to claim 1 or 2, wherein the bis-phosphine ligand in process step A is selected from the group consisting of 2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2- [bis[4-(trifluoromethyl)phenyl]phosphino]ferrocene [(4-CF3Ph)PF-tBu, CAS-No. 246231-79-8], (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl]phos- phino]ferrocene [(4-CF3Ph)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]ferro- cene [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)-9,9-dimethylxanthene [XantPhos, CAS-No. 161265-03-8], 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [Xphos, CAS-No. 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] of formula (B)    BCS223046 FC - 52 -(B).

4. The process according to any one of claims 1 to 3, wherein if bromo, iodo or trifluorosulfonate, suitable bases for the reaction according to the invention are alkali metal carbonates, alkali metal halides, di alkali metal phosphates and alkali metal phosphates, such as cesium carbonate, cesium fluoride, dipotassium phosphate and potassium phosphate or if X1is trifluoromethylsulfonate, dual-base conditions are applied, wherein DBU together with salt additive such as sodium trifluoroacetate, sodium trifluoromethanesulfonate and potassium trifluoromethanesulfonate is selected.

5. The process according to any one of claims 1 to 4, wherein process step A is carried out in a solvent, wherein 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 (diglyme), cyclopentyl methyl ether (CPME) or anisole.

6. The process according to any one of claims 1 to 5, wherein R1is a group of formula, wherein * is the attachment to X1or the terminal carbon atom respectively, R3and R4are independently selected from the group consisting of fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, di- fluoromethoxy, trifluoromethoxy, C3-C6-cycloalkyl, dimethylamino, diethylamino and piperazinyl,    BCS223046 FC - 53 - wherein said piperazinyl is substituted by 1 or 2 substituents independently selected from the group consisting of methyl and ethyl.

7. The process according to any one of claims 1 to 6 for the preparation of a compound of formula (I-1)(I-1), characterized in that in step A, a compound of formula (IIa)wherein X1is bromo, fluorosulfonate or trifluoromethylsulfonate, is reacted in a suitable solvent in the presence of a palladium catalyst, a bis-phosphine ligand and a suitable base with a compound of formula (III-1)(III-1), to form a compound of formula (IV-1)(IV-1), and in step B, the protecting group PG is subsequently removed.    BCS223046 FC - 54 - 8. The process according to any of claim 1 to 7, wherein step A is carried out with [Pd(cinnamyl)Cl]2as palladium catalyst in combination with (4-CF3Ph)PF-tBu or PhPF-tBu as bis-phosphine ligand, wherein the ratio of bis-phosphine ligand to palladium catalyst is in the range from 1.25:1.0 to 1.20:1.0, and cesium carbonate as base.

9. The process according to any of claims 1 to 8, wherein step B is carried with an acid, wherein the acid is selected from HCl or SiO2-supported NaHSO4, in a solvent, wherein the solvent is selected from methanol, 1,4-dioxane or water.

10. Compound of formula (I)wherein R1is a group of formula, wherein * is the attachment to X1or the terminal carbon atom respectively, R3and R4are independently selected from the group consisting of fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6-cycloalkyl, dimethylamino, diethylamino and piperazinyl, wherein said piperazinyl is substituted by 1 or 2 substituents inde- pendently selected from the group consisting of methyl and ethyl, R2is hydrogen or (C1-C6)-alkyl.

11. Compound of formula (IV)    BCS223046 FC - 55 -wherein R1is a group of formula, wherein * is the attachment to X1or the terminal carbon atom respectively, R3and R4are independently selected from the group consisting of fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6-cycloalkyl, dimethylamino, diethylamino and piperazinyl, wherein said piperazinyl is substituted by 1 or 2 substituents indepen- dently selected from the group consisting of methyl and ethyl, R2is hydrogen or (C1-C6)-alkyl. and PG is a hydroxy-protecting group, preferably methyl, tetrahydropyranyl or benzyl 12. Compound of formula (II) (II), wherein R1is phenyl, naphthyl or 5- to 10-membered heteroaryl, wherein said phenyl, naphthyl and 5- to 10-membered heteroaryl are optionally substituted by 1 to 3 substituents independently selected from the group consisting of    BCS223046 FC - 56 - fluoro, chloro, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8- cycloalkyl, Di-C1-C6-alkylamino or 3- to 10-membered heterocyclyl, wherein said 3- to 10-membered heterocyclyl is optionally substituted by 1 to 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 X1is fluorosulfonate.

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