Interconversion of ligands enables biomimetic c-h hydroxylation under molecular oxygen

Abstract

Disclosed herein are methods for preparing compounds of formula (2) by (hetero)aromatic C-H hydroxylation of compounds of formula (1) catalyzed by palladium (II) and a bidentate ligand in the presence of O2. The methods can be used, for example, for late-stage modification of important heterocycles in pharmaceuticals.

Description

[0001] Priority requirements

[0002] This application claims priority to U.S. Provisional Application No. 63 / 124,544, filed December 11, 2020, which is incorporated herein as fully described herein.

[0003] Government-supported statement

[0004] This invention was completed with government support under grant number R01GM102265 from the National Institutes of Health. The government holds certain rights to this invention. Background Technology

[0005] Hydroxylation of aromatic compounds is a crucial chemical transformation in various metabolic pathways and organic synthesis due to the prevalence of phenolic motifs. The most attractive catalytic system for achieving this transformation is the enzymatic hydroxylation of aryl CH bonds under molecular oxygen catalyzed by monooxygenases. 10 As exemplified by camphor (cytochrome P450). 1，2 Driven by these enzymatic processes, long-term efforts have been made to ultimately develop synthetic catalysts capable of performing aromatic hydroxylation in a similar manner under O2. Mechanistic studies of heme and non-heme iron-containing enzymes using multidisciplinary tools have revealed details of how iron centers activate O2 to produce reactive substances with different valences. Biomimetic CH hydroxylation using organometallic iron complexes in the presence of H2O2 as an oxidant has also been extensively investigated. 11 These studies have spurred efforts to develop synthetic transition metal models that can simulate how iron centers activate O2, which is an important component of the eventual design of transition metal catalysts that can catalyze the hydroxylation of CH under O2.

[0006] Based on the Shilov system 12 Some studies have focused on the reactivity of L2Pt(II)-Me2 with O2. 3 For example, Pt(II)-alkyl complexes loaded with tripod-type ligands have shown that they react with O2 to produce Pt-OOH substances similar to heme-enzymes. 9 Although similar Pd(II)-alkyl complexes can react with O2 via a free radical chain mechanism 5，6 However, recent evidence supports the biomimicry of O2 by Pd(II) alkyl substances loaded with tripod-type ligands. 7，8Specially designed tripod-type ligands facilitate the oxidation of Pd(II)alkyl complexes to Pd(IV)alkyl (OOH) compounds and the subsequent CO reductive elimination. However, combining this fundamental step with CH activation to complete the catalytic cycle remains a significant challenge, as no ligand is compatible with both events: (1) activation of the CH bond in the synthetically relevant substrate and (2) sequential oxidation with O2 and subsequent reductive C-OH elimination under the same catalytic conditions.

[0007] Although mechanistic insights have been accumulated regarding the fundamental steps of the proposed catalytic cycles for Pd-catalyzed aerobic CH hydroxylation and other Pd-catalyzed aerobic oxidation under O2, 13，14 However, the development of the desired catalyst has only achieved limited success. The use of tripod-type ligands has induced the acetylation of benzyl CH bonds using O2 as the oxidant, although the mechanistic role of O2 remains to be explained. 15 Furthermore, the reactivity is limited to quinoline-directed cyclopalladium alkylation. A single instance of aryl CH hydroxylation catalyzed by Pd(OAc)2 salt was observed, but without any supported ligands or well-defined catalysts, and the substrate range was limited to benzoic acid, with some cases even requiring O2 at 5 atmospheres to achieve suitable reactivity. Summary of the Invention

[0008] This disclosure overcomes these challenges and others by providing methods for preparing compounds of formula (2) in several embodiments:

[0009]

[0010] The method involves contacting a compound of formula (1) with a Pd(II) source in the presence of O2 and a ligand of formula (L):

[0011]

[0012] This forms the compound of formula (2).

[0013] part For C6-C 10 -Aryl or 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl ring members are independently selected from O, S, and N). Partial Optionally, further fusion can be achieved by independently selecting one or two rings from the following: C6-C 10 -Aryl, C3-C 14 -Cycloalkyl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl ring members are independently selected from O, S and N), 3- to 14-membered heterocycloalkyl (where 1 to 4 heterocycloalkyl ring members are independently selected from N, O and S), and fused combinations thereof.

[0014] Each ring in the ring is independently and optionally substituted by one to four substituents selected from the following: -CN, halogenated, oxo-substituted, NR-substituted. A R B C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C(O)C1-C6-alkyl, C(O)NR A R B S(O)NR A R B S(O)2NR A R B C3-C 14 -Cycloalkyl, C6-C 10 -Aryl, C6-C 10 -aryloxy, 3- to 14-membered heterocyclic alkyl and -(C1-C6-alkyl)-(3- to 14-membered heterocyclic alkyl) (wherein 1 to 4 ring members are independently selected from N, O and S), and 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S), wherein each alkyl, aryl, cycloalkyl, heterocyclic alkyl and heteroaryl moiety is optionally substituted by one to four substituents selected from: halo, oxo, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C(O)NR A R B C1-C6-alkoxy, C6-C 10 -aryl (optionally substituted with one to three halogens and C1-C6-alkyl) and 5- to 10-membered heteroaryl (wherein one to four heteroaryl members are independently selected from N, O and S; optionally substituted with one to three substituents selected from C1-C6-alkyl and 5- to 10-membered heteroaryl).

[0015] R A and R B Independently selected from H, C1-C6-alkyl, C1-C6-haloalkyl, -C1-C6-alkyl-C6-C 10 -Aryl, C(O)C1-C6-alkyl, C(O)C1-C6-alkyl-C6-C 10 -Aryl, C(O)OC1-C6-alkyl, C6-C 10 -Aryl (optionally fused to C3-C) 14 -cycloalkyl, the C3-C 14-The cycloalkyl group is optionally substituted with one to four halogenated and C1-C6-alkyl groups, wherein each aryl group is optionally substituted with one to three substituents selected from C1-C6-alkyl, halogenated, C1-C6-halogenated alkyl and 3- to 14-membered heterocyclic alkyl groups (wherein one to four ring members are independently selected from N, O and S); and wherein each alkyl group is optionally substituted with one to three substituents selected from halogenated, NRR' (wherein R and R' are independently selected from H, C1-C6-alkyl, C(O)C1-C6-alkyl and C(O)C6-C 10 One to three substituents are substituted in (-aryl).

[0016] R 1L and R 2L Independently selected from H, C1-C6-alkyl, C6-C 10 -aryl, -(C1-C6-alkyl)C6-C 10 -Aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl ring members are independently selected from O, S, and N) and C3-C 14 -Cycloalkyl, wherein each aryl group is optionally substituted by one to three substituents independently selected from C1-C6-alkyl, halogen, C1-C6-haloalkyl and C1-C6-alkoxy.

[0017] R 3L and R 4L Each case is independently selected from C1-C6-alkyl, halogenated, C1-C6-alkoxy, and C1-C6-haloalkyl.

[0018] The subscript n is an integer selected from 1, 2, and 3. The subscript o is an integer selected from 0, 1, 2, and 3. The subscript p is an integer selected from 0, 1, 2, and 3.

[0019] Further embodiments of this disclosure are disclosed in the accompanying drawings and detailed descriptions herein. Attached Figure Description

[0020] Figure 1 Single-crystal X-ray structure of the [Pd2Cl2(L42)2] complex.

[0021] Figure 2 Single-crystal X-ray structure of the [Pd2(TFA)2(L27)2] complex. Detailed Implementation

[0022] Although ligands have been developed to accelerate Pd-catalyzed CH activation reactions, none have been able to also support the oxidation / hydroxylation step. More specifically, the known O2 activation mechanism and the understanding of ligand coordination in CH activation are not conducive to a single conventional ligand with a single coordination mode that can provide both reactivity. In contrast, this disclosure relates in part to the unexpected discovery of ligand scaffolds that can be tautomerized to coordinate with the Pd center in two distinct modes: one mode accelerates CH activation, and the other promotes O2 activation.

[0023] definition

[0024] "Alkyl" refers to a straight-chain or branched hydrocarbon group containing 1 to 20 carbon atoms. For example, an alkyl group can have 1 to 10 carbon atoms or 1 to 6 carbon atoms. Exemplary alkyl groups include straight-chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc., and also include branched isomers of straight-chain alkyl groups, such as, but not limited to: -CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CH3)3, C(CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2CH3), -CH2CH(CH2CH3)2. -CH2C(CH3)3, -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2CH(CH3)2, -CH(CH3)CH(CH3)CH(CH3)2, etc. Therefore, alkyl groups include primary alkyl, secondary alkyl, and tertiary alkyl groups. Alkyl groups can be unsubstituted or optionally substituted with one or more substituents as described below.

[0025] The phrase “substituted alkyl” refers to an alkyl group that is substituted at one or more positions (e.g., 1, 2, 3, 4, 5, or even 6 positions), with the substituents connected at any available atom to produce a stable compound, wherein the substitutions are as described herein. “Optionally substituted alkyl” refers to an alkyl group or a substituted alkyl group.

[0026] The terms “halogen,” “halide,” and “halogenated” refer to –F (fluorinated), –Cl (chlorinated), –Br (bromine), or –I (iodinated), respectively.

[0027] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 20 carbon atoms and having 1 to 3, 1 to 2, or at least one carbon-carbon double bond. Alkenyl groups may be unsubstituted or optionally substituted with one or more substituents as described below.

[0028] "Substituted alkenyl" refers to an alkenyl group that is substituted at one or more (e.g., 1, 2, 3, 4, 5, or even 6) positions, with the substituents connected at any available atom to produce a stable compound, wherein the substitutions are as described herein. "Optionally substituted alkenyl" refers to an alkenyl group or a substituted alkenyl group.

[0029] "Alkyne" or "alkynyl group" refers to a straight-chain or branched unsaturated hydrocarbon having a specified number of carbon atoms and at least one triple bond. Examples of (C2-C8) alkynyl groups include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, and 4-octyne. The alkynyl group may be unsubstituted or optionally substituted with one or more substituents as described below.

[0030] "Substituted alkynyl" refers to an alkynyl group that is substituted at one or more (e.g., 1, 2, 3, 4, 5, or even 6) positions, with the substituents connected at any available atom to produce a stable compound, wherein the substitution is as described herein. "Optionally substituted alkynyl" refers to an alkynyl group or a substituted alkynyl group.

[0031] The term "alkoxy" refers to an -O-alkyl group having a specified number of carbon atoms. For example, (C1-C6)alkoxy groups include -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, -O-hexyl, -O-isohexyl, and -O-neohexyl.

[0032] The term "cycloalkyl" refers to saturated monocyclic, bicyclic, tricyclic, polycyclic, and optionally spirocyclic fused 3- to 14-membered ring systems. Cycloalkyl groups include 3- to 10-membered, 3- to 8-membered, and 3- to 6-membered ring systems. Cycloalkyl groups can be linked by any atom. Representative examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and adamantyl. The carbocyclic group can be unsubstituted or optionally substituted with one or more substituents as described below.

[0033] "Substituted cycloalkyl" refers to a cycloalkyl group that is substituted at one or more (e.g., 1, 2, 3, 4, 5, or even 6) positions, with the substituents connected at any available atom to produce a stable compound, wherein the substitutions are as described herein. "Optionally substituted carbocycloyl" refers to a carbocycloyl group or a substituted carbocycloyl group.

[0034] When used alone or as part of another term, "aryl" means an optionally fused carbocyclic aromatic group having a specified number of carbon atoms, or, if not specified, a carbocyclic aromatic group having up to 14 carbon atoms, such as C6-C6. 14 -Aryl or C6-C 10 -Aryl. Exemplary aryl groups are phenyl, naphthyl, biphenyl, phenanthrene, tetraphenyl, etc. (see, for example, Lang's Handbook of Chemistry (Dean, JA editor), 13th edition, Table 7-2

[1985] ). A specific aryl group is phenyl. "Aryl" may optionally be fused with a carbocyclic ring as defined herein. Aryl groups may be unsubstituted or optionally substituted with one or more substituents as described below.

[0035] "Substituted aryl" refers to an aryl group that is independently substituted with one or more substituents, which are connected at any available atom to produce a stable compound, wherein the substituents are as described herein. "Optionally substituted aryl" refers to an aryl group or a substituted aryl group.

[0036] The term "heteroatom" refers to N, O, and S. Compounds containing N or S atoms in this disclosure may optionally be oxidized to the corresponding N-oxide, sulfoxide, or sulfone compound.

[0037] "Heteroaryl" alone or in combination with any other part described herein refers to a monocyclic aromatic ring structure containing 5 to 10 (e.g., 5 or 6) ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, comprising one or more (e.g., 1 to 4, 1 to 3, or 1 to 2) heteroatoms independently selected from O, S, and N. Heteroaryls are also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of three-membered ring nitrogen. The carbon or heteroatom is the connecting point of the heteroaryl ring structure, resulting in a stable compound. Examples of heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, quinoxalinyl, indoleazinyl, benzo[b]thiopheneyl, quinazolinyl, purine, indole, quinolinyl, pyrimidinyl, pyrroleyl, pyrazolyl, and pyrazolyl. azole group, thiazolyl group, thiophene group, iso azole group, Thiamethazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuranyl, and indoleyl. The heteroaryl group may be unsubstituted or optionally substituted with one or more substituents as described below.

[0038] "Substituted heteroaryl" is a heteroaryl group that is independently substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents, or even 1, 2, or 3 substituents, or even 1 substituent) unless otherwise specified, the substituents being connected at any available atom to produce a stable compound, wherein the substituents are as described herein. "Optionally substituted heteroaryl" refers to a heteroaryl or a substituted heteroaryl group.

[0039] "Heterocyclic alkyl" means a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, tricyclic, or polycyclic system having 3 to 14 atoms (e.g., 3 to 10 or 3 to 6) of atoms, in which 1 to 3 carbon atoms in the ring are replaced by heteroatoms O, S, or N. Heterocyclic alkyl includes oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of three-membered nitrogen rings. The linking point of the heterocyclic alkyl ring is at a carbon or heteroatom, thus maintaining a stable ring. Examples of heterocyclic alkyl include, but are not limited to, morpholinyl, tetrahydrofuranyl, dihydropyridyl, piperidinyl, pyrrolidinyl, piperazine, dihydrobenzofuranyl, and dihydroindolyl. Heterocyclic alkyl can be unsubstituted or optionally substituted with one or more substituents as described below.

[0040] "Optionally substituted heterocyclic alkyl" means a heterocyclic alkyl group substituted with 1 to 3 substituents (e.g., 1, 2 or 3 substituents), which are connected at any available atom to produce a stable compound, wherein the substituents are as described herein.

[0041] The terms “nitrile” or “cyano” are used interchangeably and refer to the -CN group, which is attached to the carbon atom of a heteroaryl ring, aryl ring, or heterocyclic alkyl ring.

[0042] The term "oxo" refers to the =O atom bonded to an atom that is part of a saturated or unsaturated part. Therefore, the =O atom can bond to carbon, sulfur, or nitrogen atoms that are part of a cyclic or acyclic part.

[0043] "Hydroxyl" or "hydroxyl" refers to the -OH group.

[0044] The substituent -CO2H can be replaced by bioisosteres such as the following:

[0045]

[0046] etc., where R has the same characteristics as defined in this paper.A The same limitation applies. See, for example, THE PRACTICE OF MEDICINAL CHEMISTRY (Academic Press: New York, 1996), on page 203.

[0047] The compounds described herein can exist in a variety of isomeric forms, including configurational isomers, geometric isomers, and conformational isomers, including, for example, cis or trans conformations. The compounds can also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term "isomer" is intended to cover all isomeric forms of the compounds of this disclosure, including tautomeric forms of the compound. The compounds of this disclosure can also exist in open-chain or cyclized forms. In some cases, one or more of the cyclized forms can be generated by dehydration. The specific composition of the open-chain and cyclized forms can depend on how the compound is isolated, stored, or administered. For example, the compound may exist primarily in the open-chain form under acidic conditions but cyclize under neutral conditions. All forms are included in this disclosure.

[0048] Some of the compounds described herein may have an asymmetric center and thus exist in different enantiomeric and diastereomeric forms. Compounds as described herein may be in the form of optical isomers or diastereomeric isomers. Therefore, this disclosure covers compounds as described herein in the form of their optical isomers, diastereomeric isomers, and mixtures thereof (including racemic mixtures), and their uses. Optical isomers of the compounds of this disclosure can be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed techniques, or by chemical separation of stereoisomers using an optically active resolving agent.

[0049] Unless otherwise specified, the term "stereoisomer" means a stereoisomer of a compound that is substantially free of other stereoisomers of the compound. Thus, a stereoisomerically pure compound having one chiral center is substantially free of its opposite enantiomers. A stereoisomerically pure compound having two chiral centers is substantially free of its other diastereomers. A typical stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound, or more than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of other stereoisomers of the compound. The stereoisomers described above can be considered as a composition comprising two stereoisomers present in their respective weight percentages as described herein.

[0050] If there is a difference between the illustrated structure and its given name, the illustrated structure shall prevail. Furthermore, if the stereochemistry of a structure or part thereof is not indicated by, for example, a thick or dashed line, the structure or part thereof shall be interpreted as encompassing all its stereoisomers. However, in some cases where more than one chiral center is present, the structure and name may be represented as a single enantiomer to aid in describing the relevant stereochemistry. Those skilled in the art of organic synthesis know whether a compound is prepared as a single enantiomer by the method used to prepare it.

[0051] method

[0052] This disclosure relates in part to a method in which a ligand of formula (L) can facilitate both the oxidation and hydroxylation steps in CH activation. The method achieves this advantage because the ligand is designed to precisely switch between coordination modes at a specified point in the catalytic cycle: one tautomer for CH activation and another tautomer for O2 activation.

[0053] In several embodiments, this disclosure provides methods for preparing compounds of formula (2):

[0054]

[0055] The method involves contacting a compound of formula (1) with a Pd(II) source in the presence of O2 and a ligand of formula (L):

[0056]

[0057] This forms the compound of formula (2).

[0058] part It is a C6-C10-aryl or 5- to 10-membered heteroaryl group (where 1 to 4 heteroaryl ring members are independently selected from O, S, and N). (Partial) Optionally, further fusion can be achieved by independently selecting one or two rings from the following: C6-C 10 -Aryl, C3-C 14 -Cycloalkyl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl ring members are independently selected from O, S and N), 3- to 14-membered heterocycloalkyl (where 1 to 4 heterocycloalkyl ring members are independently selected from N, O and S), and fused combinations thereof.

[0059] Each ring in the ring is independently and optionally substituted by one to four substituents selected from the following: -CN, halogenated, oxo-substituted, NR-substituted. A R B C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-haloalkoxy, -C(O)H, C(O)C1-C6-alkyl, C(O)NR A R B S(O)NR A R B S(O)2NR A R B C3-C 14 -Cycloalkyl, C6-C 10 -Aryl, C6-C 10 -aryloxy, 3- to 14-membered heterocyclic alkyl and -(C1-C6-alkyl)-(3- to 14-membered heterocyclic alkyl) (wherein 1 to 4 ring members are independently selected from N, O and S) and 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S), wherein each alkyl, aryl, cycloalkyl, heterocyclic alkyl and heteroaryl moiety is optionally substituted by one to four substituents selected from: halogen, oxo, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C(O)NR A R B C1-C6-alkoxy, C6-C 10 -aryl (optionally substituted with one to three halogens and C1-C6-alkyl) and 5- to 10-membered heteroaryl (wherein one to four heteroaryl members are independently selected from N, O and S; optionally substituted with one to three substituents selected from C1-C6-alkyl and 5- to 10-membered heteroaryl).

[0060] R A and RB Independently selected from H, C1-C6-alkyl, C1-C6-haloalkyl, -C1-C6-alkyl-C6-C 10 -Aryl, C(O)C1-C6-alkyl, C(O)C1-C6-alkyl-C6-C 10 -Aryl, C(O)OC1-C6-alkyl, C6-C 10 -Aryl (optionally fused to C3-C) 14 -cycloalkyl, the C3-C 14 -The cycloalkyl group is optionally substituted with one to four halogenated and C1-C6-alkyl groups, wherein each aryl group is optionally substituted with one to three substituents selected from C1-C6-alkyl, halogenated, hydroxylated, C1-C6-halogenated alkyl and 3- to 14-membered heterocyclic alkyl groups (wherein one to four ring members are independently selected from N, O and S); and wherein each alkyl group is optionally substituted with one to three substituents selected from halogenated, NRR' (wherein R and R' are independently selected from H, C1-C6-alkyl, C(O)C1-C6-alkyl and C(O)C6-C 10 One to three substituents are substituted in (-aryl).

[0061] R 1L and R 2L Independently selected from H, C1-C6-alkyl, C6-C 10 -aryl, -(C1-C6-alkyl)C6-C 10 -Aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl ring members are independently selected from O, S, and N) and C3-C 14 -Cycloalkyl, wherein each aryl group is optionally substituted by one to three substituents independently selected from C1-C6-alkyl, halogen, C1-C6-haloalkyl and C1-C6-alkoxy.

[0062] R 3L and R 4L Each case is independently selected from C1-C6-alkyl, halogenated, C1-C6-alkoxy, and C1-C6-haloalkyl.

[0063] The subscript n is an integer selected from 1, 2, and 3. The subscript o is an integer selected from 0, 1, 2, and 3. The subscript p is an integer selected from 0, 1, 2, and 3.

[0064] In some implementation schemes, It is an optional substituted monocyclic ring. In other embodiments, This is an optional, substituted bicyclic system. In some further embodiments, For optional, replaced three-ring system. Examples are selected from the following rings that have been substituted:

[0065]

[0066] In some implementation schemes, For optional replacement Showing multiple The implementation scheme is in the exemplary compound of formula (1) shown in Table 1 below.

[0067] Table 1: Examples of compounds of formula (1)

[0068]

[0069]

[0070]

[0071]

[0072] In some embodiments, n in formula (L) is 1 or 2. As shown by the data disclosed herein, coordination of the ligand of formula (L) with palladium promotes at least a 6-membered (n=1) or 7-membered (n=2) chelate, wherein the ligand (L) binds to palladium more weakly than in the 5-membered chelate.

[0073] In several implementations, R in equation (L) 1L and R2 L Independently selected from C1-C6-alkyl, C6-C 10 -Aryl and -(C1-C6-alkyl)C6-C 10 -Aryl. In some embodiments, the pyridone ring in formula (L) is substituted, where p is 1, 2, or 3. In other embodiments, the ring is unsubstituted, where p is 0.

[0074] In other embodiments, the pyridine ring in formula (L) is substituted, where o is 1, 2, or 3. Examples of substitution include where R3 L Embodiments that are independently C1-C6-alkyl or halogenated. In other embodiments, the ring is unsubstituted, where p is 0.

[0075] The amount of ligands of formula (L) can be adjusted, and is typically from about 0.5 mol% to about 15 mol%, from about 5 mol% to about 13 mol%, or from about 7 mol% to about 12 mol% (based on the amount of the compound of formula (1)). Exemplary amounts of ligands of formula (L) include about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, and about 10 mol%. According to one embodiment, a typical amount is about 10 mol%.

[0076] The specific implementation schemes of the ligands of formula (L) are shown in Table 2 below.

[0077] Table 2: Examples of ligands for formula (L).

[0078]

[0079]

[0080] The method of this disclosure occurs in the presence of a palladium(II) source. Palladium(II) is commercially available or otherwise supplied by a variety of reagents known to those skilled in the art, including those that generate palladium(II) in situ, such as those derived from palladium(O) compounds. The method is suitable for direct and readily available palladium(II) sources, including any palladium(II) salt. Exemplary palladium(II) salts include Pd(OAc)2 (OAc = acetic acid), Pd(TFA)2 (TFA = trifluoroacetic acid), PdCl2, and Pd(CH3CN)2Cl2. In a particular embodiment, the palladium(II) source is Pd(OAc)2. The amount of Pd(II) can be adjusted and is typically from about 0.5 mol% to about 15 mol%, from about 5 mol% to about 13 mol%, or from about 7 mol% to about 12 mol% (based on the amount of the compound of formula (1)). Exemplary amounts of Pd(II) include about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, and about 10 mol%. According to one embodiment, a typical amount is about 10 mol%. In another embodiment, the amount of the ligand of formula (L) and the amount of the Pd(II) source are each about 10 mol%.

[0081] One advantage of the method disclosed herein is that O2 is used without a specific O2 pressure, although increased pressure may be used. Thus, according to one embodiment, CH activation and hydroxylation according to the method are carried out in the presence of O2 at approximately one atmosphere (atm). The O2 may be pure or, in several embodiments, entrained in another gas or gas mixture (including nitrogen, argon, and air).

[0082] In several embodiments, the contact step of the method further occurs in the presence of a nonnucleophilic base. Exemplary nonnucleophilic bases include inorganic bases, such as salts selected from KOAc, NaOAc, CsOAc, K3PO4, K2HPO4, KH2PO4, and K2CO3. In one embodiment, the nonnucleophilic base is KOAc. The amount of base can be from about 1 equivalent to about 10 equivalents. In one embodiment, the amount of base is about 2 equivalents.

[0083] In yet another embodiment, the contact described herein occurs in the presence of a polar aprotic solvent. Various polar aprotic solvents are well known to those skilled in the art of organic synthesis. Examples of polar aprotic solvents include N-methylpyrrolidine (NMP), dimethylacetamide (DMA), dimethylformamide (DMF), tetrahydrofuran (THF), acetone, acetonitrile, ethyl acetate, hexamethylphosphoric triamine (HMPT), and dimethyl sulfoxide (DMSO). In one exemplary embodiment, the solvent is DMF. The methods described herein are suitable for various reaction temperatures. As a practical consideration, suitable reaction rates and / or yields can be achieved at elevated temperatures (e.g., about 70°C, about 80°C, about 90°C, about 100°C, about 110°C, about 120°C, or about 130°C). Those skilled in the art will select a polar aprotic solvent that is advantageous to the desired reaction temperature and pressure. In an exemplary embodiment, the method is carried out in DMF at about 110°C.

[0084] In several embodiments, the contact step of the method described herein further occurs in the presence of benzoquinone (BQ). While not mandatory, the addition of BQ can improve the yield of the method. The amount of BQ can be from about 0.1 equivalents to about 3.0 equivalents, from about 0.3 equivalents to about 2.0 equivalents, and from about 0.5 equivalents to about 1.5 equivalents. Exemplary amounts include about 0.3 equivalents, about 0.5 equivalents, about 0.7 equivalents, about 1.0 equivalents, about 1.3 equivalents, about 1.5 equivalents, about 2.0 equivalents, about 2.5 equivalents, and about 3.0 equivalents.

[0085] In other embodiments, the effect of ligands was investigated using isonicotinic acid substrates that had previously shown no reactivity under ligand-free conditions, with a wide range of pyridone ligands. The desired products were not observed with a wide range of pyridone ligands L1 to L19 (Example 21, Table 4a). Various pyridine-pyridone ligands (L20 to L25) forming five-membered chelates with Pd(II) were synthesized and tested under standard conditions; however, CH hydroxylation was still not observed (Example 21, Table 4b). While both L, L-type and L, X-type coordination of these ligands are feasible, as demonstrated by the synthesis of the corresponding complexes, 18 However, without being bound by theory, it is considered that the five-membered chelate formed by the L,L-pyridine-pyridine mode is too stable to allow tautomerization to form the L,X-pyridine-pyridone form, which unexpectedly promotes CH cleavage in the method disclosed herein.

[0086] In contrast, in several embodiments, the ligands of formula (L) of the present invention, when n is 1, form less stable six-membered chelates, thereby reducing the barrier to switching between L,L-coordination modes and L,X-coordination modes (L26 to L45). Unexpectedly, ligand L33 yielded the desired ortho-hydroxylated product in 48% yield, demonstrating the feasibility of this ligand scaffold. Ligand optimization improved the yield to 72% (L42). 18 The use of O2 (97% purity) resulted in a product containing 95% 18 The desired product of O supports the proposed biomimetic hydroxylation pathway. To obtain evidence supporting the use of tautomerization as a ligand design principle, we used IR to monitor the coordination modes of L20 and L42 by titrating the ligands into a solution of Pd(OAc)2. At 1639 cm⁻¹, L42 showed a ligand coordination mode at 1639 cm⁻¹. -1 The appearance of the peak is consistent with the pyridone binding motif, while the absence of a corresponding carbonyl signal for the five-membered counterpart L20 indicates that L,L-type pyridine-pyridine binding is dominant.

[0087] In several embodiments, the method is suitable for a wide range of pharmaceutically important heterocyclic benzoic acids (see Examples). For example, isonicotinic acid containing electron-withdrawing substituents (1b), electron-donating substituents (1c, 1d), and halogen substituents (1e, 1f) is reactive, providing hydroxylated products at less hindered sites. Heterocyclic biaryl base compounds (1g, 1h), which are common scaffolds in drug molecules, are also readily hydroxylated in high yields. Unsubstituted nicotinic acid yields a mixture of 2-hydroxynicotinic acid (2i, major) and 4-hydroxynicotinic acid (2i', minor). Compounds 1j and 1k of formula (1) selectively provide ortho-hydroxylated products without any trace of benzyl CH oxidation, making the radical pathway impossible. Various 2-substituted nicotinic acids, regardless of their electronic properties, yield 4-hydroxylated products (2l to 2o) in high yields. An unexpected advantage of this method is demonstrated by the fact that 2-alkylamino and 2-arylamino groups, which are often incompatible with CH activation reactions due to their strong coordination properties, are both readily accepted (2n, 2o). Furthermore, both 2-hydroxylated and 4-hydroxylated products were obtained for 6-substituted nicotinic acid (2p to 2r). Pyridinecarboxylic acid (2s to 2u) is also a compatible substrate for this reaction, yielding the corresponding 3-hydroxypyridinecarboxylic acid in high yield, a favorable result as pyridinecarboxylic acid is typically a non-reactive substrate in CH activation due to its bidentate chelation. The remarkable compatibility of this method with isonicotinic acid, isonicotinic acid, and pyridinecarboxylic acid provides a highly versatile synthetic tool for synthesizing a wide range of pharmaceutically valuable heterocycles.

[0088] To further explore the scope of this hydroxylation reaction, in other embodiments, we evaluated other heterocyclic carboxylic acids in which the heteroatom and carboxyl group are located on different aryl rings. Quinoline and tetrahydroquinoline are both compatible, yielding the hydroxylated products in good yields (2v to 2x). Indole, which is typically unstable under oxidizing conditions, is also accepted under our reaction conditions (2y, 2z). Benzothiophene (2aa), benzothiazole (2ab), benzofuran (2ac), and benzodioxane (2aa, 2ab, 2ac ... Carboxylic acids characterized by structures such as alkyl (2ad), morpholine (2ae), pyrrole (2af), carbazole (2ag), dibenzothiophene (2ah), and dibenzothiophene (2ai) were all successfully hydroxylated. Hydroxylation of a pharmaceutically important diaryl heterocyclic carboxylic acid (2aj) also yielded the desired product in 68% yield (see Examples).

[0089] The unexpected compatibility of the method with heterocycles without the use of strongly oriented groups prompted us to explore site selectivity in the presence of multiple oriented groups. In this context, transforming heterocycle-oriented CH activation into simple carboxylic acid-oriented CH activation remains an unsolved challenge for Pd(II) catalysts. Since the 2-pyridyl group is considered to be C(sp... 2 As one of the strongest directional groups activated by )-H, we investigated biaryl compounds in which the nitrogen and carboxyl groups of the pyridinium group are on the same or different aryl rings. Notably, the weakly coordinated carboxyl group outperformed all pyridinium-directed compounds in this process. 2-Arylisonicotinic acid and 6-arylpyridinecarboxylic acid consistently yielded carboxyl-directed hydroxylated products (2ak to 2aq) in 60% to 70% yields. Different scaffolds of the 2-pyridinium and carboxyl groups on different rings also yielded carboxyl-dependent site selectivity (2ar, 2as). Desired site selectivity (2at to 2av) was also obtained in the presence of many other commonly used natural directional groups, including -NHAc, -NHBoc, and aldehydes.

[0090] Late-stage modification of complex natural products and drug molecules via site-selective CH activation can be a powerful method for rapidly optimizing the bioactivity of lead compounds. In a wide range of Pd-catalyzed CH activation reactions, the lack of heterocyclic compatibility and site selectivity are major practical obstacles to this approach. Given the unique importance of setting hydroxyl groups in drug molecules, we have enabled many commercial drugs to undergo the methods described herein. For example, in one embodiment, the antihypertensive drug Telmisartan (1aw) was ortho-hydroxylated in 60% yield. In some exemplary embodiments, probenecid (1ax), betimololide (1ay), meclofenamic acid (1az), repaglinide (1ba), clonixin (1bb), tamibarotene (1bc), and ataluren (1bd) were all successfully ortho-hydroxylated with high efficiency. These derivatives are valuable not only for potential drug reuse for different diseases, but also for studying drug metabolism and pharmacokinetics.

[0091] The references numbered in the preceding sections are as follows:

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[0093] 2. Guroff, G, et al. Hydroxylation-Induced Migration: The NIHShift. Science. 157, 1524-1530 (1967).

[0094] 3. Rostovtsev, VV, Labinger, JA, Bercaw, JE, Lasseter, TL & Goldberg, KIOxidation of dimethylplatinum(II)complexes with dioxygen. Organometallics 17, 4530-4531 (1998).

[0095] 4.Denmey,M.C.,Smythe,N.A,Cetto,K.L.,Kemp,R.A.&Goldberg,K.I.Insertionof molecular oxygen into a palladium(II)hydride bond.J.Am.Chem.Soc.128,2508-2509(2006).

[0096] 5.Boisvert,L.,Denney,M.C.,Hanson,S.K.&Goldberg,K.I.Insertion ofmolecular oxygen into a palladium(II)methyl bond:A radical chain mechanisminvolving palladium(III)intermediates,J.Am.Chem.Soc,131,15802-15814(2009).

[0097] 6.Zeitler,H.E.,Kaminsky,W.A.&Goldberg,K.I,Insertion of MolecularOxygen into the Metal-Methyl Bonds of Platinum(II)and Palladium(II)1,3-Bis(2-pyridylimino)isoindolate Complexes.Organometallics 37,3644-3648(2018).

[0098] 7.Tang,F.,Zhang,Y.,Rath,N.P.&Mirica,L.M.Detection of Pd(III)and Pd(IV)intermediates during the aerobic oxidative C-C bond formation from a Pd(II)dimethyl complex.Organometallics 31,6690-6696(2012).

[0099] 8.Qu,F.,Khusnutdinova,J.R.,Rath,N.P.&Mirica,L.M.Dioxygen activationby an organometallic Pd(ii)precursor:formation of a pd(iv)-OH complex and itsC-O bond formation reactivity.Chem.Commun.50,3036-3039(2014).

[0100] 9.Rostovtsev,V.V.,Henling,L.M.,Labinger,J.A.&Bercaw,J.E Structuraland mechanistic investigations of the oxidation of dimethylplatinum(II)complexes by dioxygen.Inorg.Chem.41,3608-3619(2002).

[0101] 10.Dennig,A.,Lülsdorf,N.,Liu,H.&Schwaneberg,U.Regioselective o-hydroxylation of monosubstituted benzenes by P450BM3.Angew.Chemie-Int.Ed.52,8459-8462(2013).

[0102] 11.Taktak,S.,Flook,M.,Foxman,B.M.,Que,L.&Rybak-Akirnova,E.V.ortho-Hydroxylation of benzoic acids with hydrogen perozide at a non-heme ironcenter.Chem.Commun.5301-5303(2005).

[0103] 12.Shilov,A.F.&Shul′pin,G.B.Activation of C-H bonds by metalcomplexes.Chem.Rev.97,2879-2932(1997).

[0104] 13.Ten Brink,G.J.,Arends,I.W.C.E.&Sheldon,R.A.Green,catalyticoxidation of alcohols in water.Science 287,1636-1639(2000).

[0105] 14.Piera,J.& J.E.Catalytic oxidation of organie substrates bymolecular oxygen and hydrogen peroxide by multistep electron transfer-Abiomimetic approach.Angew.Chemie-Int.Ed.47,3506-3523(2008).

[0106] 15.Wang,D.,Zavalij,P.Y.&Vedernikov,A.N.Aerobic C-H acetoxylation of8-methylquinoline in PdII-pyridinecarboxylic acid systems: Some structure-reactivity relationships.Organometallics 32,4882-4891(2013).

[0107] 16.Zhang,Y.H.&Yu,J.Q.Pd(II)-catalyzed hydroxylation of arenes with 1atm of O2 or air.J.Am.Chem.Soc.131,14654-14655(2009).

[0108] 17.Wang,P.et al.Ligand-accelerated non-directed C-H functionalizationof arenes.Nature 551,489-493(2017).

[0109] 18. Salamanca, V., Toledo, A. & Albéniz, AC[2,2′-bipyridin]-6(1H)-one, a Truly Cooperating Ligand in the Palladium-Mediated CH Activation Step: Experimental Evidence in the Direct C-3 Arylation ofPyridine. J. Am. Chem. Soc. 140, 17851-17856 (2018).

[0110] Example

[0111] Further embodiments of this disclosure are illustrated in the following non-limiting examples.

[0112] General Information. Pd(OAc)₂ was purchased from Strem. 1,4-Benzoquinone (BQ) was used after sublimation in its pure state. Solvents were obtained from Sigma-Aldrich, Alfa-Aesar, and Acros and used directly without further purification. Unless otherwise specified, other reagents were purchased at the highest commercial quality and used without further purification. Analytical thin-layer chromatography was performed on 0.25 mm silica gel 60-F254 or Merck pre-coated aluminum-backed silica gel F254 plates. Recordings were made on a Bruker AMX-400 or Bruker DRX-600 instrument. 1 1H NMR spectrum. The following abbreviations (or combinations thereof) are used to indicate multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak. The coupling constant J is reported in Hertz (Hz). Recorded on a Bruker DRX-600. 13 C10 NMR spectra were obtained and completely decoupled via broadband proton decoupling. Recorded on a Bruker AMX-400 spectrometer (376 MHz). 19 F NMR spectra, and complete decoupling was achieved through broadband proton decoupling. Chemical shifts were referenced to appropriate residual solvent peaks. 1 Column chromatography was performed using E. Merck silica (60, particle size 0.043 mm to 0.063 mm), and pTLC was performed on Merck silica plates (60F-254). Biotage Isolera columns with both ZIP and SNAP types and their C18 counterparts were used. TMOne-step automated reversed-phase chromatography was performed. High-resolution mass spectra (HRMS) were recorded on an Agilent mass spectrometer using ESI-TOF (electrospray ionization-time-of-flight). A Mettler-Toledo ReactIR system equipped with a DST 6.35m Dicomp ATR probe was used. TM FT-IR analysis was performed using a 45m instrument.

[0113] Preparation of aromatic and heteroaromatic carboxylic acids. The following examples describe the acquisition and synthesis of compounds of formula (1).

[0114] Compounds 1g, 1h, 1m to 1o, 1x to 1z, 1af, 1ag, 1ai, 1az to 1bc were obtained from the Bristol-Myers Squibb compound collection. Other compounds were obtained from commercial sources. Compounds 1al, 1am, 1ao to 1aq were prepared by the following general procedure:

[0115]

[0116] A Schlenk flask containing a magnetic rod was loaded with Pd(PPh3)4 (87.9 mg, 0.125 mmol, 5 mol%), 2-bromopyridinecarboxylic acid (507 mg, 3.0 mmol), phenylboronic acid (604 mg, 4.5 mmol, 1.5 equivalents), and Na2CO3 (3180 mg, 30.0 mmol, 10.0 equivalents), evacuated, and backfilled three times with nitrogen. Then, THF (15 mL) and water (30 mL) were added. The reaction mixture was stirred at 100 °C for 24 hours. After the reaction, the mixture was filtered and concentrated to remove THF. The aqueous phase was extracted twice with DCM, and the organic phase was discarded. The mixture was acidified to pH < 3 with the addition of 1.0 N HCl, and the resulting precipitate was collected by filtration, washed with ice-cooled water, and dried to give the crude product. The crude product was then processed using Biotage Isolera. TM The product was purified by reversed-phase column chromatography (40% to 100% MeCN:H2O) to obtain the pure product after evaporation to dryness.

[0117] Example 1: 2-(4-(trifluoromethyl)phenyl)isonicotinic acid (1al)

[0118]

[0119] White solid, 0.360 g, 45% yield.

[0120] 1H NMR (600MHz, DMSO-d6) δ8.90 (d, J=4.9Hz, 1H), 8.38 (s, 1H), 8.34 (d, J=8.1Hz, 2H), 7.89-7.82 (m, 3H). 13 C NMR (151MHz, DMSO-d6) δ166.09, 155.50, 150.93, 141.72, 139.84, 129.58 (q, J CF =31.4Hz), 127.52, 125.80 (q, J CF =3.9Hz), 124.24(q, J) CF =270.5Hz), 122.48, 119.74.

[0121] Example 2: 6-(naphth-1-yl)pyridinecarboxylic acid (1am)

[0122]

[0123] White solid, 0.545 g, 73% yield.

[0124] 1 H NMR (600MHz, DMSO-d6) δ8.08-7.98 (m, 5H), 7.73 (dd, J=6.4, 2.4Hz, 1H), 7.67-7.60 (m, 2H), 7.55 (dd, J=8.1, 6.7Hz, 1H), 7.50 (dd, J=8.3, 6.7Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ167.51, 157.67, 152.24, 137.88, 137.58, 133.42, 130. 62, 128.75, 128.32, 127.58, 126.64, 126.58, 125.98, 125.45, 125.33, 122.72.

[0125] Example 3: 6-(p-Tolyl)pyridinecarboxylic acid (1ao)

[0126]

[0127] White solid, 0.480 g, 75% yield.

[0128] 1H NMR (600MHz, DMSO-d6) δ8.16 (dd, J=8.0, 1.4Hz, 1H), 8.09 (d, J=8.1Hz, 2H), 8. 03 (t, J=7.8Hz, 1H), 7.96 (d, J=7.6Hz, 1H), 7.33 (d, J=7.8Hz, 2H), 2.37 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ166.23, 155.97, 148.17, 139.19, 138.51, 135.00, 129.41, 126.78, 122.98, 122.92, 20.87.

[0129] Example 4: 6-(4-methoxyphenyl)pyridinecarboxylic acid (1ap)

[0130]

[0131] White solid, 0.563 g, 82% yield.

[0132] 1 H NMR (600MHz, DMSO-d6) δ8.14 (d, J=8.8Hz, 2H), 8.11 (d, J=8.0Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=7.6Hz, 1H), 7.05 (d, J=8.9Hz, 2H), 3.81 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ166.26, 160.53, 155.76, 148.07, 138.42, 130.21, 128.32, 122.54, 122.39, 114.17, 55.28.

[0133] Example 5: 6-(4-(trifluoromethyl)phenyl)pyridinecarboxylic acid (1aq)

[0134]

[0135] White solid, 0.441 g, 55% yield.

[0136] 1 H NMR (600MHz, DMSO-d6) δ8.41 (d, J=8.2Hz, 2H), 8.31 (d, J=7.9Hz, 1H), 8.13 (t, J=7.8Hz, 1H), 8.07 (d, J=7.7Hz, 1H), 7.89 (d, J=8.2Hz, 2H). 13C NMR (151MHz, DMSO-d6) δ166.02, 154.35, 148.55, 141.58, 138.97, 129.59 (q, J CF =31.8Hz), 127.65, 125.73 (q, J CF =3.9Hz), 124.25(q, J) CF =270.5Hz), 124.14, 124.04.

[0137] Preparation of bidentate pyridine-pyridone ligands

[0138]

[0139] Example 6: Synthesis of 2-(1-(6-fluoropyridin-2-yl)ethyl)-5-methylpyridine (Lb).

[0140]

[0141] At -78 °C, n-butyllithium (2.5 M, 40 mmol, 2.0 equivalent) was added dropwise to a solution of 2,5-rutidine (4.289 g, 40 mmol, 2.0 equivalent) in anhydrous THF (80 mL). The resulting solution was stirred at -78 °C for 1 hour, followed by the addition of 2,6-difluoropyridine (2.30 g, 20 mmol, 1.0 equivalent) in single batches. The resulting solution was gradually heated to room temperature and stirred for 3 hours, then treated with a saturated aqueous solution of NH4Cl. The resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting crude material La was used for the next step without further purification.

[0142] NaH (1.20 g, 30 mmol, 1.5 equivalent) was added to a solution of La in anhydrous THF (30 mL) at 0 °C. The resulting solution was stirred at 0 °C for 1 hour, followed by the dropwise addition of MeI (1.9 mL, 30 mmol, 1.5 equivalent). The solution was gradually heated to room temperature and stirred for 5 hours. The reaction was quenched with a saturated aqueous NH4Cl solution. The product was extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Rapid chromatography (eluent: ethyl acetate / hexane = 1 / 6 to 1 / 2) yielded Lb (dark red liquid, 1.99 g, 46% two-step yield).

[0143] 1H NMR (600MHz, CDCl3) δ8.35 (d, .J=2.5Hz, 1H), 7.69-7.61 (m, 1H), 7.41 (dd, J=8.1, 2.4Hz, 1H), 7.20 (d, .J=8.0Hz, 1H), 7.12 (dd, J=7.5, 2.1Hz, 1H), 6.71 (dd, J=8.2, 2.6Hz, 1H), 4.34 (q, J=7.2Hz, 1H), 2.27 (s, 3H), 1.70 (d, J=7.3Hz, 3H). 13 C NMR (151MHz, CDCl3) δ163.42 (d, J CF =12.6Hz), 163.14 (d, J) CF =236.9Hz), 160.31, 149.66, 141.42 (d, J CF =7.7Hz), 137.33, 131.11, 121.98, 119.63, 106.93 (d, J CF =36.9Hz), 48.86, 19.73, 18.15.

[0144] Synthesis of ligands L33 to L45. To a solution of Lb (216 mg, 1.0 mmol, 1.0 equivalent) in anhydrous THF (15 mL), n-butyllithium (2.5 M, 1.5 mmol, 0.6 mL, 1.5 equivalent in hexane) was added dropwise at 0 °C. The resulting solution was stirred at 0 °C for 1 h, followed by the addition of alkyl-Br, aryl-F, or benzyl-Cl (3.0 mmol, 3.0 equivalent). The resulting solution was heated to 65 °C and stirred overnight. The reaction was cooled and then treated with a saturated aqueous solution of NH4Cl. The product was extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Rapid chromatography (eluent: ethyl acetate / hexane = 1 / 6 to 1 / 3) yielded Lc33 to Lc45.

[0145] The suspension of Lc33 to Lc45 in 4N HCl (20 mL) in water was refluxed for 12 hours, cooled, and concentrated under vacuum. The resulting solution was then treated with saturated NaHCO3. S The aqueous solution was quenched to neutral pH. The product was extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. Rapid chromatography (eluent: ethyl acetate / methanol = 10 / 1 to 5 / 1) yielded L33 to L45. Yields were calculated in two steps.

[0146] Example 7: 2-(1-cyclohexyl-1-(6-fluoropyridin-2-yl)ethyl)-5-methylpyridine (Lc42)

[0147]

[0148] White solid, 0.193 g, 65% yield.

[0149] 1 H NMR (600MHz, CDCl3) δ8.35 (s, 1H), 7.65-7.58 (m, 1H), 7.36 (s, 2H), 7.30 (dd, J=7.6, 3.1Hz, 1H), 6.65 (dd, J=8.0, 3.3Hz, 1H), 2.81 ( td, J=11.9, 2.7Hz, 1H), 2.25 (s, 3H), 1.74 (s, 3H), 1.66 (d, J=12.1Hz, 3H), 1.37-1.26 (m, 4H), 1.11-1.08 (m, 1H), 1.06-0.95 (m, 2H). 13 C NMR (151MHz, CDCl3) δ165.94 (d, J CF =12.2Hz), 162.54 (d, J) CF =233.0Hz), 162.33, 148.82, 140.73 (d, J CF =8.7Hz), 136.68, 130.17, 121.87, 119.64 (d, J CF =6.0Hz), 106.09 (d, J) CF =37.5Hz), 53.56, 45.85, 28.48, 28.38, 27.14, 26.94, 18.37, 18.03.

[0150] Example 8: 6-(2-(5-methylpyridin-2-yl)-1-phenylprop-2-yl)pyridin-2(1H)-one (L33)

[0151]

[0152] White solid, 0.219 g, 72% yield.

[0153] 1 H NMR (600MHz, CDCl3) δ11.26 (brs, 1H), 8.59 (s, 1H), 7.45 (dd, J=8.2, 2.3Hz, 1H), 7.24 (dd, J=9.2, 7.0Hz, 1H), 7.16-7.10 (m, 4H), 6.75 (d, J = 7.8Hz, 2H), 6.40 (d, J = 9.2Hz, 1H); 5.96 (d, J = 6.9, 1H), 3.45-3.34 (m, 2H); 2.35 (s, 3H), 1.57 (s, 3H).13 C NMR (151MHz, CDCl3) δ163.79, 159.32, 151.90, 149.51, 140.67, 137.87, 136.95, 132 .14, 130.33, 127.95, 126.75, 120.64, 118.77, 102.91, 48.91, 46.48, 21.12, 18.15.

[0154] Example 9: 6-(1-(4-methoxyphenyl)-2-(5-methylpyridin-2-yl)propyl-2-yl)pyridin-2(1H)-one (L34)

[0155]

[0156] White solid, 0.250 g, 75% yield.

[0157] 1 H NMR (600MHz, CDCl3) δ11.26 (brs, 1H), 8.59 (d, J=1.8Hz 1H), 7.45 (dd, J=8.2, 2.4Hz, 1H), 7.24 (dd, J=9.1, 7.0Hz, 1H), 7.15 (d, J=8.1Hz, 1H), 6.66 (s, 4H), 6.40 (d, J=9.1Hz 1H), 5.97 (d, J=7.0Hz, 1H), 3.73 (s, 3H), 3.39-3.28 (m, 2H), 2.35 (s, 3H), 1.57 (s, 3H). 13 C NMR (151MHz, CDCl3) δ163.81, 159.40, 158.40, 152.03, 149.47, 140.71, 137.86, 132.04 , 131.27, 128.94, 120.67, 118.66, 113.34, 102.97, 55.26, 48.16, 46.58, 21.07, 18.14.

[0158] Example 10: 6-(2-(5-methylpyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)prop-2-yl)pyridin-2(1H)-one (L35)

[0159]

[0160] White solid, 0.234 g, 63% yield.

[0161] 1H NMR (600MHz, CDCl3) δ11.24 (s, 1H), 8.60 (d, J=2.4Hz, 1H), 7.49-7.46 (m, 1H), 7.38 (d, J=8.0Hz, 2H), 7.28-7.22 (m, 1H), 7.15 (d, J =8.1Hz, 1H), 6.86 (d, J = 7.9Hz, 2H), 6.41 (d, J = 9.1Hz, 1H), 5.96 (d, J = 7.0Hz, 1H), 3.46 (d, J = 1.3Hz, 2H), 2.37 (s, 3H), 1.57 (s, 3H). 13 C NMR (151MHz, CDCl3) δ163.74, 158.76, 151.33, 149.60, 141.14, 140.67, 138.09, 132.47, 130.58, 129.11 (q, J CF =26.8Hz), 124.89(q, J) CF =3.9Hz), 124.29(q, J) CF =270.3Hz), 120.71, 119.09, 102.88, 48.46, 46.32, 21.03, 18.15. 19 F NMR (376MHz, CDCl3) δ-65.13.

[0162] Example 11: 6-(2-(5-methylpyridin-2-yl)-1-(naphth-2-yl)propyl-2-yl)pyridin-2(1H)-one (L36)

[0163]

[0164] White solid, 0.173 g, 49% yield.

[0165] 1H NMR (600MHz, CDCl3) δ11.31 (brs, 1H), 8.64 (d, J=1.4Hz, 1H), 7.76-7.73 (m, 1H), 7.67-7.62 (m, 1H) , 7.58 (d, J=8.4Hz, 1H), 7.46 (dd, J=8.1, 2.4Hz, 1H), 7.43-7.39 (m, 2H), 7.25 (d, J=1.7Hz, 1H), 7.2 2 (dd, J=9.2, 7.0Hz, 1H), 7.16 (d, J=8.1Hz, 1H), 6.81 (dd, J=8.4, 1.8Hz, 1H), 6.43 (d, J=9.2Hz, 1H) , 5.94 (d, J=6.9Hz, 1H), 3.62 (d, J=13.4Hz, 1H), 3.51 (d, J=13.4Hz, 1H), 2.38 (s, 3H), 1.61 (s, 4H). 13 C NMR (151MHz, CDCl3) δ163.85, 159.36, 151.82, 149.55, 140.70, 137.95, 134.58, 133.18, 132.35, 132.23, 129 .13, 128.52, 127.73, 127.61, 127.35, 126.03, 125.71, 120.68, 118.82, 103.08, 49.10, 46.63, 21.18, 18.16.

[0166] Example 12: 6-(1-(3,5-di-tert-butylphenyl)-2-(5-methylpyridin-2-yl)propyl-2-yl)pyridin-2(1H)-one (L37)

[0167]

[0168] White solid, 0.287 g, 69% yield.

[0169] 1 H NMR (600MHz, CDCl3) δ11.38 (s, 1H), 8.60 (d, J=2.3Hz, 1H), 7.43 (dd, J=8.2, 2.4Hz, 1H), 7.27-7.23 (m, 1H), 7.18 (t, J=1.8Hz, 1H), 7.13 (d . 13C NMR (151MHz, CDCl3) δ163.83, 159.56, 152.30, 150.10, 149.38, 140.75, 137.75, 135.75, 13 2.03, 124.66, 120.76, 120.39, 118.61, 102.94, 49.62, 46.58, 34.70, 31.49, 21.13, 18.07.

[0170] Example 13: 6-(2-(5-methylpyridin-2-yl)-1-(pyridin-2-yl)propyl-2-yl)pyridin-2(1H)-one (L38)

[0171]

[0172] White solid, 0.119 g, 39% yield.

[0173] 1 H NMR (600MHz, CDCl3) δ11.96 (brs, 1H), 8.49 (d, J = 2.4Hz, 1H), 8.48 (d, J = 4.9Hz, 1H ), 7.41 (td, J=7.6, 1.8Hz, 2H), 7.27-7.20 (m, 1H), 7.10 (d, J=8.9Hz, 1H), 7.06 (dd , J=7.5, 4.9Hz, 1H), 6.71 (d, J=7.9Hz, 1H), 6.40 (d, J=10.1Hz, 1H), 5.96 (d, J=8.0 Hz, 1H), 3.69 (d, J=13.7Hz, 1H), 3.50 (d, J=13.6Hz, 1H), 2.32 (s, 3H), 1.71 (s, 3H). 13 CNMR (151MHz, CDCl3) δ164.09, 159.74, 157.70, 152.32, 149.46, 148.64, 140.67, 137.75 , 136.23, 131.88, 124.74, 121.72, 120.77, 118.75, 103.21, 50.07, 47.27, 23.06, 18.13.

[0174] Example 14: 6-(2-(5-methylpyridin-2-yl)-4-phenylbut-2-yl)pyridin-2(1H)-one (L39)

[0175]

[0176] White solid, 0.206 g, 65% yield.

[0177] 1H NMR (600MHz, CDCl3) δ10.80 (s, 1H), 8.61 (s, 1H), 7.58 (d, J=8.2Hz, 1H), 7.42 (dd, J=9.0, 7.0Hz, 1H), 7.37-7.31 (m, 3H), 7.26 (dd, J =7.4, 1.6Hz, 1H), 7.19 (d, J = 8.3Hz, 2H), 6.47 (d, J = 8.9Hz, 1H), 6.30 (d, J = 6.8Hz, 1H), 2.68-2.38 (m, 4H), 2.42 (s, 3H), 1.90 (s, 3H). 13 C NMR (151MHz, CDCl3) δ163.77, 159.31, 152.57, 149.77, 141.59, 140.76, 137.80, 131.96 , 128.40, 128.39, 126.10, 120.45, 118.65, 102.30, 46.00, 44.42, 31.12, 21.68, 18.09.

[0178] Example 15: 6-(1-(5-methylpyridin-2-yl)-1-phenylethyl)pyridin-2(1H)-one (L40)

[0179]

[0180] White solid, 0.148 g, 51% yield.

[0181] 1 H NMR (600MHz, CDCl3) δ10.97 (brs, 1H), 8.48 (d, J=2.3Hz, 1H), 7.50 (dd, J=8.2, 2.3Hz, 1H), 7.35 (dd, J=9.2, 7.0Hz, 1H ), 7.28-7.21 (m, 4H), 6.89 (d, J=7.3Hz, 2H), 6.44 (d, J=9.2Hz, 1H), 6.17 (d, J=7.0Hz, 1H), 2.34 (s, 3H), 2.01 (s, 3H). 13 C NMR (151MHz, CDCl3) δ163.57, 160.13, 152.19, 149.69, 146.89, 140.49, 137.61, 132.06, 128.58, 127.98, 127.08, 121.51, 119.14, 104.45, 52.17, 28.11, 18.15.

[0182] Example 16: 6-(1-(5-methylpyridin-2-yl)-1-(perfluorophenyl)ethyl)pyridin-2(1H)-one (L41)

[0183]

[0184] White solid, 0.133 g, 35% yield.

[0185] 1 H NMR (600MHz, CDCl3) δ10.94 (s, 1H), 8.39 (d, J=2.4Hz, 1H), 7.53 (dd, J=8.2, 2.3Hz, 1H), 7.32 (dd, J=9.2, 7 .0Hz, 1H), 7.27 (d, J=6.8Hz, 1H), 6.42 (d, J=9.2Hz, 1H), 6.21 (d, J=7.0Hz, 1H), 2.34 (s, 3H), 2.11 (s, 3H). 13 C NMR (151MHz, CDCl3) δ163.43, 158.19, 149.78, 149.22, 140.57, 138.40, 132.74, 119.80, 118.92, 102.42, 48.68, 24.12, 18.15. 19 FNMR (376MHz, CDCl3) δ-140.29, -140.33, -157.47, -164.12, -164.14.

[0186] Example 17: 6-(1-cyclohexyl-1-(5-methylpyridin-2-yl)ethyl)pyridin-2(1H)-one (L42)

[0187]

[0188] White solid, 0.155 g, 80% yield in step 2.

[0189] 1 H NMR (600MHz, CDCl3) δ11.59 (s, 1H), 8.52 (d, J=2.4Hz, 1H), 7.44 (dd, J=8.1, 2.4Hz, 1H), 7.29-7.20 (m, 2H), 6.34 (dd, J=9.1, 2.0Hz, 1H), 6.10 (d d, J=7.1, 1.8Hz, 1H), 2.57-2.52(m, 1H), 2.31(s, 3H), 1.70-1.60(m, 3H) , 1.58(s, 3H), 1.26-1.18(m, 2H), 1.16-0.95(m, 3H), 0.91-0.88(m, 2H). 13C NMR (151MHz, CDCl3) δ163.41, 158.97, 151.76, 148.98, 139.72, 136.90, 130.95, 120. 14, 117.66, 102.47, 48.03, 47.76, 27.46, 27.07, 26.41, 26.29, 26.06, 17.45, 14.87.

[0190] Example 18: 6-(1-cyclohexyl-1-(5-methylpyridin-2-yl)propyl)pyridin-2(1H)-one (L43)

[0191]

[0192] White solid, 0.112 g, 36% yield.

[0193] 1 H NMR (600MHz, CDCl3) δ11.46 (s, 1H), 8.49 (s, 1H), 7.53-7.48 (m, 1H), 7.43-7.36 (m, 1H ), 7.19 (d, J=8.3Hz, 1H), 6.41 (dd, J=9.1, 1.5Hz, 1H), 6.20 (d, J=7.5Hz, 1H), 2.34 (s, 3H), 2.23-2.13(m, 2H), 2.00(td, J=11.8, 5.9Hz, 1H), 1.72-1.43(m, 5H), 1.22-1.09( m, 2H), 096-0.92 (m, 1H), 0.86-0.81 (m, 1H), 0.77 (t, J=7.3Hz, 3H), 0.74-0.65 (m, 1H), 13 C NMR (151MHz, CDCl3) δ163.80, 158.03, 151.46, 148.76, 140.64, 137.21, 131.47, 123 .44, 117.70, 105.58, 55.13, 47.93, 28.69, 28.39, 27.13, 27.10, 26.48, 18.09, 9.48.

[0194] Example 19: 6-(1-cyclohexyl-1-(5-methylpyridin-2-yl)-2-phenylethyl)pyridin-2(1H)-one (L44)

[0195]

[0196] White solid, 0.152 g, 41% yield.

[0197] 1H NMR (600MHz, CDCl3) δ11.20 (s, 1H), 8.65 (d, J=2.4Hz, 1H), 7.48 (dd, J=8.3, 2.4Hz, 1H), 7.38 (dd, J=9.1, 7.1Hz, 1H), 7.26-7.21 (m, 3H), 7.10 (d, J=8.2Hz, 1H), 6.89 (d d, J=7.3, 2.3Hz, 2H), 6.52 (d, J=9.1Hz, 1H), 6.19-6.11 (m, 1H), 3.70 (s, 2H), 2.46 ( s, 3H), 2.21-2.17 (m, 1H), 1.89-1.69 (m, 4H), 1.42-1.26 (m, 2H), 1.18-0.87 (m, 4H). 13 C NMR (151MHz, CDCl3) δ163.71, 157.35, 150.62, 148.83, 140.26, 137.00, 136.58, 131.64, 130.09, 127. 84, 126.20, 124.45, 117.88, 106.61, 55.07, 46.87, 39.06, 28.61, 28.60, 26.96, 26.94, 26.45, 18.06.

[0198] Example 20: 6-(cyclohexyl(5-methylpyridin-2-yl)methyl)pyridin-2(1H)-one (L45)

[0199]

[0200] White solid, 0.191 g, 68% yield.

[0201] 1 H NMR (600MHz, CDCl3) δ11.01 (s, 1H), 8.46 (d, J = 2.3Hz, 1H), 7.41 (dd, J = 7.7, 2.3Hz, 1H), 7.26-7.21 (m, 1H), 7.02 (d, J = 7.8Hz, 1H), 6.37 (d, J = 9.2Hz, 1H) , 6.01 (d, J = 6.8Hz, 1H), 3.28 (m, 1H), 2.31 (s, 3H), 2.04 (d, J = 10.7Hz, 1H), 1 .73-1.50(m, 4H), 1.26-1.17(m, 2H), 1.16-1.06(m, 2H), 0.95-0.75(m, 2H). 13C NMR (151MHz, CDCl3) δ163.96, 156.16, 150.25, 148.18, 140.62, 137.38, 131.93, 1 23.91, 118.64, 105.63, 56.48, 43, 09, 31, 68, 31.45, 26.32, 26.10, 26.06, 18.22.

[0202] Example 21: The purpose of this example is to demonstrate the screening of ligand effects on the exemplary CH hydroxylation process:

[0203]

[0204] Reaction conditions: 1a (0.1 mmol), Pd(OAc)₂ (10 mol%), L (10 mol% for bidentate ligands or 20 mol% for monodentate ligands), KOAc (2.0 equivalents), DMF (0.8 mL), 110 °C in N₂ with 25% O₂ at 60 psi for 24 hours. The crude product was analyzed using 1,3,5-trimethoxybenzene as an internal standard. 1 1H NMR analysis was used to determine the yields as shown in Table 4a (“nr” = no reaction).

[0205] Table 4a. Ligand Influence

[0206]

[0207]

[0208]

[0209] General conditions: 1a (0.1 mmol), Pd(OAc)2 (10 mol%), L (10 mol%), KOAc (2.0 equivalent), DMF (0.8 mL), 110 °C, in N2 with 25% O2, 60 psi, for 24 hours. The crude product was analyzed using 1,3,5-trimethoxybenzene as an internal standard. 1 1H NMR analysis was used to determine the yields as shown in Table 4b (“nr” = no reaction).

[0210] Table 4b. Ligand Influence

[0211]

[0212]

[0213] Example 22: The purpose of this example is to demonstrate the effect of different bases on the following exemplary reaction.

[0214]

[0215] General conditions: 1a (0.1 mmol), Pd(OAc)2 (10 mol%), L (10 mol%), base (2.0 equivalent), DMF (0.8 mL), 110 °C, in N2 with 25% O2, 60 psi, for 24 hours. The crude product was analyzed using 1,3,5-trimethoxybenzene as an internal standard. 1 H NMR analysis was used to determine the yields as shown in Table 5.

[0216] Table 5: Effect of Alkali

[0217]

[0218] Example 23: The purpose of this example is to demonstrate the effect of the solvent on the exemplary reaction:

[0219]

[0220] General conditions: 1a (0.1 mmol), Pd(OAc)2 (10 mol%), L (10 mol%), KOAc (2.0 equivalent), solvent (0.8 mL), 110 °C, in N2 with 25% O2, 60 psi, for 24 hours. The crude product was analyzed using 1,3,5-trimethoxybenzene as an internal standard. 1 H NMR analysis was used to determine the yields as shown in Table 6.

[0221] Table 6: Effect of Solvents

[0222]

[0223] Example 24: The purpose of this example is to demonstrate the effect of the palladium(II) source on the exemplary reaction:

[0224]

[0225] General conditions: 1a (0.1 mmol), Pd source (10 mol%), L (10 mol%), KOAc (2.0 equivalent), DMF (0.8 mL), 110 °C, 25% O2 in N2, 60 psi, 24 hours. The crude product was analyzed using 1,3,5-trimethoxybenzene as an internal standard. 1 H NMR analysis was used to determine the yields as shown in Table 7.

[0226] Table 7: Effects of Pd(II) source

[0227] Pd(II) source Yield (%) Pd(OAc)2 72 Pd(TFA)2 39 PdCl2 040 Pd(CH3CN)2Cl 45 No PD 0

[0228] Example 25: The purpose of this example is to demonstrate the effect of benzoquinone (BQ) on the exemplary reaction:

[0229]

[0230] General conditions: 1a (0.1 mmol), Pd source (10 mol%), L (10 mol%), KOAc (2.0 equivalent), DMF (0.8 mL), 110 °C, 25% O2 in N2, 60 psi, 24 hours. The crude product was analyzed using 1,3,5-trimethoxybenzene as an internal standard. 1 H NMR analysis was used to determine the yields as shown in Table 8.

[0231] Table 8: Effects of Pd(II) source

[0232] X equivalent BQ Yield (%) 0 45 1 72 1.5 78 (72 separation yield) 2 67

[0233] General procedures and characterization data. Compounds of formula (2) are prepared by the following reactions and by either general procedure A or general procedure B.

[0234]

[0235] General Procedure A: Pd(OAc)₂ (2.2 mg, 0.01 mmol, 10 mol%), ligand L42 (3.0 mg, 0.01 mmol, 10 mol%), BQ (16.2 mg, 0.15 mmol, 1.5 equivalents), KOAc (19.6 mg, 0.2 mmol, 2.0 equivalents), and carboxylic acid 1 (0.1 mmol) were added to a tube with a septum stopper. The tube was evacuated and backfilled three times with O₂. DMF (0.8 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes, then heated to 110 °C for 24 hours in the presence of an O₂ balloon. After cooling to room temperature, 0.1 mL of HCOOH was added. The mixture was filtered through a 5 mL DMF diatomaceous earth pad and the solvent was removed under vacuum. The residue was purified by reversed-phase column chromatography (0% to 50% MeCN: H₂O) using a Biotage Isolera™ one equipped with SNAP Sampler to obtain a pure product after evaporation to dryness.

[0236] General Procedure B: Pd(OAc)₂ (2.2 mg, 0.01 mmol, 10 mol%), ligand L42 (3.0 mg, 0.01 mmol, 10 mol%), BQ (16.2 mg, 0.15 mmol, 1.5 equivalents), KOAc (19.6 mg, 0.2 mmol, 2.0 equivalents), and carboxylic acid 1 (0.1 mmol) were added to a tube with a septum stopper. The tube was evacuated and backfilled three times with O₂. DMF (0.8 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes, then heated to 110 °C for 24 hours in the presence of an O₂ balloon. After cooling to room temperature, 0.1 mL of HCOOH was added. The mixture was filtered through a 5 mL DMF diatomaceous earth pad and the solvent was removed under vacuum. The resulting mixture was purified by pTLC using DCM / MeOH (10 / 1) with AcOH (1% v / v) as the eluent.

[0237] Example 26: 3-Hydroxyisonicotinic acid (2a)

[0238]

[0239] General Procedure A, light gray solid, 10.0 mg, 72% yield.

[0240] 1 H NMR (600MHz, DMSO-d6) δ 8.05 (s, 1H), 7.86 (d, J = 4.8Hz, 1H), 7.46 (d, J = 4.7Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ169.67, 158.54, 139.52, 137.51, 125.84, 122.65.

[0241] 1 H NMR data and reported data 2 Matching.

[0242] Example 27: 5-Hydroxy-2-(trifluoromethyl)isonicotinic acid (2b)

[0243]

[0244] General Procedure A, light gray solid, 15.7 mg, 76% yield.

[0245] 1 H NMR (600MHz, DMSO-d6) δ8.47 (s, 1H), 7.94 (s, 1H). 13 C NMR (151MHz, DMSO-d6) δ168.01, 157.71, 141.92, 136.44 (q, JCF =34.6Hz), 122.38, 121.88 (q, J CF =271.2Hz), 120.45(q, J) CF =3.3Hz).

[0246] Example 28: 5-Hydroxy-2-methoxyisonicotinic acid (2c)

[0247]

[0248] General Procedure A, light gray solid, 10.2 mg, 60% (total) yield.

[0249] 1 ¹H NMR (600MHz, DMSO-d⁶) δ major: 7.91 (s, 1H), 7.00 (s, 1H), 3.79 (s, 3H); minor: 7.62 (d, J = 5.3Hz, 1H), 7.17 (d, J = 5.3Hz, 1H), 3.88 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ major: 170.36, 168.90, 156.73, 149.49, 135.44, 108.57, 53.45.

[0250] Example 29: 2-(tert-butyl)-5-hydroxyisonicotinic acid (2d)

[0251]

[0252] General Procedure A, white solid, 10.1 mg, 52% yield.

[0253] 1 H NMR (600MHz, DMSO-d6) δ8.21 (s, 1H), 7.61 (s, 1H), 1.29 (s, 9H). 13 C NMR (151MHz, DMSO-d6) δ169.48, 156.68, 154.80, 137.69, 124.14, 118.02, 36.20, 30.05.

[0254] Example 30: 2-Chloro-5-hydroxyisonicotinic acid (2e)

[0255]

[0256] General Procedure A, white solid, 11.6 mg, 67% yield.

[0257] 1H NMR (600MHz, DMSO-d6) δ7.87 (s, 1H), 7.46 (s, 1H). 13 C NMR (151MHz, DMSO-d6) δ168.02, 158.18, 138.89, 136.56, 129.41, 122.69.

[0258] Example 31: 2-Bromo-5-hydroxyisonicotinic acid (2f)

[0259]

[0260] Standard procedure A, 48 hours, pale yellow solid, 8.7 mg, 40% yield.

[0261] 1 H NMR (600MHz, DMSO-d6) δ8.12 (s, 1H), 7.68 (s, 1H). 13 C NMR (151MHz, DMSO-d6) δ167.58, 154.96, 140.89, 128.33, 126.46, 126.18.

[0262] Example 32: 2-(2-chloro-6-methoxyphenyl)-5-hydroxyisonicotinic acid (2g)

[0263]

[0264] General Procedure A, light gray solid, 19.0 mg, 68% yield.

[0265] 1 H NMR (600MHz, DMSO-d6) δ8.15 (s, 1H), 8.13 (s, 1H), 7.73 (d, J=2.8Hz, 1H), 7.33 (dd, J=8.8, 2.8Hz, 1H), 7.13 (d, J=8.8Hz, 1H), 3.84 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ169.66, 158.36, 155.17, 141.06, 139.32, 130.46, 129.21, 127.74, 125.42, 124.42, 124.03, 113.74, 56.00.

[0266] Example 33: 5-Hydroxy-2-(2-methoxy-6-(trifluoromethyl)phenyl)isonicotinic acid (2h)

[0267]

[0268] General Procedure A, light gray solid, 23.5 mg, 75% yield.

[0269] 1 H NMR (600MHz, DMSO-d6) δ8.17 (s, 1H), 8.16 (s, 1H), 8.05 (d, J=2.5Hz, 1H), 7.64 (dd, J=8.7, 2.5Hz, 1H), 7.29 (d, J=8.7Hz, 1H), 3.93 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ170.04, 159.45, 159.01, 141.24, 139.96, 129.62, 127.12 (q, J CF =3.8Hz), 125.91(q, J CF =3.8Hz), 125.84, 125.28 (q, J CF =272.3Hz), 124.50, 121.54 (q, J CF =32.1Hz), 112.85, 56.81.

[0270] Example 34: 4-Hydroxynicotinic acid (2i)

[0271]

[0272] General Procedure A, white solid, 7.8 mg, 56% yield.

[0273] 1 H NMR (400MHz, DMSO-d6) δ8.60 (d, J=1.5Hz, 1H), 8.07 (dd, J=7.2, 1.6Hz, 1H), 6.72 (d, J=7.2Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ179.01, 166.48, 143.19, 141.18, 117.69, 115.36.

[0274] 1 H NMR data and reported data 2 Matching.

[0275] Example 35: 4-Hydroxy-2-methylnicotinic acid (2j)

[0276]

[0277] General Procedure A, white solid, 11.5 mg, 75% yield.

[0278] 1H NMR (600MHz, DMSO-d6) δ7.95 (d, J=7.1Hz, 1H), 6.65 (d, J=7.1Hz, 1H), 2.72 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ179.51, 166.94, 156.31, 139.25, 115.93, 113.35, 20.11.

[0279] Example 35: 4-Hydroxy-2,6-dimethylnicotinic acid (2kJ)

[0280]

[0281] General Procedure A, white solid, 10.8 mg, 65% yield.

[0282] 1 H NMR (600MHz, DMSO-d6) δ6.50 (s, 1H), 2.72 (s, 3H), 2.33 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ179.45, 166.98, 156.08, 149.91, 114.77, 111.59, 19.67, 18.46.

[0283] Example 36: 4-Hydroxy-2-(trifluoromethyl)nicotinic acid (2l)

[0284]

[0285] General Procedure A, light gray solid, 16.8 mg, 81% yield.

[0286] 1 H NMR (600MHz, Methanol-d4) δ8.33 (d, J=5.6Hz, 1H), 7.05 (d, J=5.8Hz, 1H). 13 CNMR (151MHz, DMSO-d6) δ165.67, 162.72, 150.58, 143.27 (q, J CF =32.7Hz), 121.45(q, J) CF =273.6Hz), 119.35, 114.50.

[0287] Example 37: 4-Hydroxy-2-(3,3,3-trifluoropropoxy)nicotinic acid (2m)

[0288]

[0289] General Procedure A, white solid, 13.1 mg, 52% yield.

[0290] 1 H NMR (600MHz, DMSO-d6) δ7.59 (d, J=5.9Hz, 1H), 615 (d, J=5.8Hz, 1H), 4.39 (t, J=6.6Hz, 2H), 2.70 (dt, J=11.5, 6.6Hz, 2H). 13 C NMR (151MHz, DMSO-d6) δ176.59, 16843, 163.76, 147.04, 127.21 (q, J CF =274.7Hz), 110.61, 58.10 (q, J CF =3.8Hz), 33.38(q, J) CF =27.2Hz).

[0291] Example 38: 4-Hydroxy-2-((2,2,2-trifluoroethyl)amino)nicotinic acid (2n)

[0292]

[0293] General Procedure A, white solid, 18.4 mg, 78% yield.

[0294] 1 H NMR (600MHz, DMSO-d6) δ9.97 (s, 1H), 7.64 (d, J=6.7Hz, 1H), 6.12 (d, J=6.7Hz, 1H), 4.33 (td, J=9.6, 6.9Hz, 2H). 13 C NMR (151MHz, DMSO-d6) δ176.14, 172.00, 156.23, 125.96 (q, J CF =274.9Hz), 107.34, 96.57, 41.54 (q, J CF =32.6Hz).

[0295] Example 39: 4-Hydroxy-2-((2-(trifluoromethyl)phenyl)amino)nicotinic acid (2o)

[0296]

[0297] General Procedure A, light gray solid, 19.4 mg, 65% yield.

[0298] 1H NMR (600MHz, DMSO-d6) δ 11.68 (brs, 1H), 11.51 (s, 1H), 7.83 (d, J = 2.0Hz, 1H), 7.71 (m, 3H), 7.49 (d, J = 7.3Hz, 1H), 6.27 (d, J = 7.3Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ179.44, 171.51, 153.09, 138.02, 136.99, 131.56, 131.07 (q, J CF =31.8Hz), 129.97, 124.27 (q, J CF =271.1Hz), 123.95(q, J) CF =3.9Hz), 122.87(q, J) CF =4.2Hz), 110.09, 96.60.

[0299] Example 40: 4-Hydroxy-6-methylnicotinic acid (2p)

[0300]

[0301] General Procedure A, white solid, 9.2 mg, 60% yield.

[0302] 1 H NMR (600MHz,

[0303] Methanol (d4) δ 8.56 (s, 1H), 6.65 (s, 1H), 245 (s, 3H) 13 C NMR (151 MHz, methanol-d4) δ 177.22, 169.04, 153.98, 144.18, 115.38, 113.97, 18.53.

[0304] Example 41: 2-Hydroxy-6-methylnicotinic acid (2p')

[0305]

[0306] Using 1,3,5-trimethoxybenzene as an internal standard, the procedure was passed. 1 NMR determines yield.

[0307] 1 H NMR (600MHz, DMSO-d6) δ8.27 (d, J=7.4Hz, 1H), 6.54 (d, J=7.5Hz, 1H), 2.37 (s, 3H).

[0308] Example 42: 4-Hydroxy-6-(trifluoromethyl)nicotinic acid (2q)

[0309]

[0310] General Procedure A, white solid, 13.9 mg, 67% yield.

[0311] 1 ¹H NMR (600 MHz, methanol-d⁴) δ 9.20 (s, 1H), 7.59 (s, 1H). 13 C NMR (151 MHz, methanol-d4) δ 170.80, 168.82, 150.14, 148.55 (q, J) CF =35.3Hz), 120.22(q, J CF =272.1Hz), 113.48, 111.04.

[0312] Example 43: 2-Hydroxy-6-(trifluoromethyl)nicotinic acid (2q')

[0313]

[0314] Using 1,3,5-trimethoxybenzene as an internal standard, the procedure was passed. 1 NMR determines yield.

[0315] 1 ¹H NMR (600 MHz, methanol-d⁴) δ 8.52 (d, J = 7.7 Hz, 1H), 7.32 (dd, J = 7.7, 1.8 Hz, 1H).

[0316] Example 44: 6-Chloro-4-hydroxynicotinic acid (2r)

[0317]

[0318] General Procedure A, white solid, 11.2 mg, 65% yield.

[0319] 1 ¹H NMR (600 MHz, methanol-d⁴) δ 8.66 (s, ¹H), 6.99 (s, ¹H). 13 C NMR (151 MHz, methanol-d4) δ 177.25, 168.97, 151.89, 149.24, 112.87, 111.23.

[0320] Example 45: 6-Chloro-4-hydroxynicotinic acid (2r')

[0321]

[0322] Using 1,3,5-trimethoxybenzene as an internal standard, the procedure was passed. 1 NMR determines yield.

[0323] 1 ¹H NMR (600 MHz, methanol-d⁴) δ 8.34 (d, J = 7.8 Hz, ¹H), 6.99 (d, J = 7.8 Hz, ¹H).

[0324] Example 46: 3-Hydroxy-6-methylpyridinecarboxylic acid (2s)

[0325]

[0326] General Procedure A, white solid, 8.3 mg, 54% yield.

[0327] 1 H NMR (600MHz, DMSO-d6) δ7.68 (d, J=8.6Hz, 1H), 7.57 (d, J=8.7Hz, 1H), 2.54 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ166.32, 158.72, 144.68, 132.13, 130.14, 130.06, 20.12.

[0328] Example 47: 3-Hydroxy-6-methoxypyridinecarboxylic acid (2t)

[0329]

[0330] General Procedure A, white solid, 10.3 mg, 61% yield.

[0331] 1 H NMR (600MHz, DMSO-d6) δ7.07 (d, J=8.7Hz, 1H), 6.66 (d, J=8.7Hz, 1H), 3.75 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ170.61, 155.58, 154.47, 133.17, 128.96, 114.03, 53.15.

[0332] Example 48: 3-Hydroxy-6-(trifluoromethyl)pyridinecarboxylic acid (2u)

[0333]

[0334] General Procedure A, light gray solid, 14.5 mg, 70% yield.

[0335] 1 H NMR (600MHz, DMSO-d6) δ7.59 (d, J=8.6Hz, 1H), 7.17 (d, J=8.6Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ168.50, 164.34, 137.48, 132.68 (q, J CF =33.9Hz), 125.26, 123.53 (q, J CF =2.6Hz), 122.44(q, J) CF =270.8Hz).

[0336] Example 49: 3-Hydroxyquinoline-4-carboxylic acid (2v)

[0337]

[0338] General Procedure A, white solid, 10.3 mg, 57% yield.

[0339] 1 H NMR (600MHz, DMSO-d6) δ8.74 (s, 1H), 8.13 (d, J=8.2Hz, 1H), 7.96 (dd, J=7.9, 1.7Hz, 1H), 7.62-7.58 (m, 2H). 13 C NMR (151MHz, DMSO-d,) δ168.46, 149.93, 144.37, 141.52, 128.89, 128.12, 126.26, 125.03, 124.07, 118.64.

[0340] Example 50: 7-Hydroxyquinoline-6-carboxylic acid (2w)

[0341]

[0342] General Procedure A, white solid, 11.4 mg, 60% yield.

[0343] 1 H NMR (600MHz, DMSO-d6) δ8.80 (d, J=4.5Hz, 1H), 8.49 (s, 1H), 8.48 (d, J=7.8Hz, 1H), 7.33 (dd, J=8.1, 4.5Hz, 1H), 7.13 (s, 1H). 13 C NMR (151MHz, DMSO-d6) δ169.94, 164.43, 149.49, 148.24, 139.75, 131.45, 122.28, 121.12, 117.47, 107.87.

[0344] Example 51: 1-(4-(2,3-dimethylphenoxy)butyryl)-6-hydroxy-1,2,3,4-tetrahydroquinoline-5-carboxylic acid (2x)

[0345]

[0346] General Procedure B, white solid, 24.5 mg, 64% yield.

[0347] 1 H NMR (600MHz, DMSO-d6) δ6.98 (dt, J=16.6, 7.8Hz, 2H), 6.70 (d, J=7.8Hz, 2H), 6.51 (d, J=8.5Hz, 1H), 3.84 (brs, 2H) , 3.58 (t, J=6.9Hz, 2H), 3.26-3.12 (m, 2H), 2.48 (brs, 2H), 2.17 (s, 3H), 1.95-1.89 (m, 5H), 1.68 (d, J=8.7Hz, 2H). 13 C NMR (151MHz, DMSO-d6) δ172.54, 171.23, 161.50, 156.27, 138.28, 137.15, 129.24, 127.79, 125.82, 124.16, 121.90, 117.30, 113.60, 109.15, 66.96, 41.31, 30.05, 25.14, 23.99, 23.55, 19.74, 11.24.

[0348] Example 52: 7-Hydroxyquinoxaline-6-carboxylic acid (2y)

[0349]

[0350] General Procedure A, white solid, 12.8 mg, 68% yield.

[0351] 1 H NMR (600MHz, DMSO-d6) δ8.89 (d, J=1.8Hz, 1H), 8.80 (d, J=1.8Hz, 1H), 8.49 (s, 1H), 7.42 (s, 1H). 13 C NMR (151MHz, DMSO-d6) δ170.22, 159.00, 147.95, 145.68, 144.09, 136.05, 132.55, 120.22, 111.91.

[0352] Example 53: 1-Acetyl-3-(3-amino-3-oxopropyl)-5-hydroxy-1H-indole-4-carboxylic acid (2z)

[0353]

[0354] General Procedure A, white solid, 12.2 mg, 42% yield.

[0355] 1 H NMR (600MHz, DMSO-d6) δ8.08 (d, J=8.7Hz, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 6.89 (d, J=2.4Hz, 1H), 6. 82 (s, 1H), 6.76 (dd, J=8.7, 2.4Hz, 1H), 2.80 (t, J=7.7Hz, 2H), 2.54 (s, 3H), 2.44 (t, J=7.7Hz, 2H). 13 C NMR (151MHz, DMSO-d6) δ173.65, 169.06, 168.37, 153.76, 131.56, 129.01, 123.63, 120.81, 116.64, 113.40, 103.94, 34.48, 23.50, 20.43.

[0356] Example 54: 6-Hydroxybenzo[b]thiophene-5-carboxylic acid (2aa)

[0357]

[0358] General Procedure B, light gray solid, 14.9 mg, 77% yield.

[0359] 1 H NMR (600MHz, DMSO-d6) δ8.25 (s, 1H), 7.34 (d, J=5.4Hz, 1H), 7.28 (d, J=5.4Hz, 1H), 7.20 (s, 1H). 13 C NMR (151MHz, DMSO-d6) δ171.92, 159.69, 143.21, 130.69, 125.20, 124.20, 122.76, 118.45, 107.37.

[0360] Example 55

[0361]

[0362] General Procedure B, light gray solid, 15.0 mg, 65% gross yield.

[0363] 1 ¹H NMR (600MHz, DMSO-d⁶) δ 9.32 (m, 1.54H, major + minor), 8.48 (s, 0.54H, minor), 7.83 (d, J = 8.2Hz, 1H), 7.31 (s, 0.54H, minor), 7.26 (d, J = 8.1Hz, 1H).13 C NMR (151MHz, DMSO-d6) δ171.84, 169.72, 161.35, 160.97, 158.23, 156.89, 156. 72, 156.24, 128.17, 123.83, 122.03, 121.73, 116.31, 113.11, 109.68, 108.07.

[0364] Example 56

[0365]

[0366] General Procedure B, white solid, 13.9 mg, 78% gross yield.

[0367] 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.07 (s, 1H), 7.80 (d, J = 2.1Hz, 0.51H, minor), 7.75 (d, J = 2.2Hz, 1H), 7.71 (d, J = 9.0Hz, 0.49H, minor), 6.91 (d, J = 8.4Hz, 0.58H, minor), 6.88–6.85 (m, 1.49H, major + minor), 6.81 (d, J = 2.2Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ160.71, 158.85, 157.81, 157.44, 144.44, 143.98, 126 .81; 122.99, 12230, 119.90, 117.85, 116.41, 106.91; 104.88, 100.31, 97.39.

[0368] Example 57: 6-Hydroxy-2,3-dihydrobenzo[b][1,4]di 5-Carboxylic Acid (2ad)

[0369]

[0370] General Procedure B, white solid, 12.9 mg, 66% yield.

[0371] 1 H NMR (600MHz, DMSO-d6) δ6.75 (d, J=8.8Hz, 1H), 6.29 (d, J=8.7Hz, 1H), 4.21 (brs, 2H), 4.13 (brs, 2H). 13C NMR (151MHz, DMSO-d6) δ170.32, 154.48, 143.04, 135.28, 119.64, 109.27, 108.10, 64.43, 63.21.

[0372] Example 58: 2-Hydroxy-4-morpholinobenzoic acid (2ae)

[0373]

[0374] General Procedure B, white solid, 18.1 mg, 81% yield.

[0375] 1 H NMR (600MHz, DMSO-d6)) δ7.73-7.43 (m, 1H), 6.40 (d, J=7.5Hz, 1H), 6.25 (s, 1H), 3.69 (t, J=4.9Hz, 4H), 3.17 (t, J=4.8Hz, 4H). 13 C NMR (151MHz, DMSO-d6) δ171.93, 163.02, 156.15, 131.13, 105.79, 102.54, 99.76, 65.83, 46.63.

[0376] Example 59: 2-Hydroxy-4-(4-oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid (2af)

[0377]

[0378] General procedure B, white solid, 27.8 mg, 80% yield.

[0379] 1 H NMR (600MHz, DMSO-d6) δ7.81 (d, J=8.3Hz, 1H), 7.28-7.23 (m, 2H), 7.22-7.19 (m, 1H), 7.14-7.11 (m, 2H), 6.91 (d, J=2.1Hz , 1H), 6.75 (dd, J=8.4, 2.1Hz, 1H), 6.64 (s, 1H), 2.68 (t, J=6.1Hz, 2H), 2.40 (dd, J=7.2, 5.5Hz, 2H), 2.04 (t, J=63Hz, 2H). 13C NMR (151MHz, DMSO-d6) δ193.12, 171.13, 161.37, 145.90, 142.93, 135.07, 131.41, 131.30 , 128.42, 127.83, 127.17, 120.71, 118.68, 116.18, 113.06, 105.80, 37.57, 23.25, 22.40.

[0380] Example 60: 2-Hydroxy-9H-carbazole-1-carboxylic acid (2 ag)

[0381]

[0382] General Procedure B, white solid, 17.3 mg, 76% yield.

[0383] 1 H NMR (600MHz, DMSO-d6) δ11.03 (s, 1H), 8.20 (d, J = 8.0Hz, 1H), 7.98 (d, J = 7.3Hz, 1H), 7.6 6(d, J=7.6Hz, 1H), 7.28 (d, J=7.5Hz, 1H), 7.13 (t, J=7.1Hz, 1H), 6.73 (d, J=7.9Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ172.31, 161.47, 139.55, 138.96, 127.48, 124.29, 122.27, 119.44, 118.84, 115.80, 111.97, 108.14, 96.93.

[0384] Example 61: 3-Hydroxydibenzo[b,d]furan-4-carboxylic acid (2ah)

[0385]

[0386] General Procedure B, light gray solid, 13.0 mg, 57% yield.

[0387] 1 H NMR (600MHz, DMSO-d6) δ7.92-7.87 (m, 1H), 7.83 (d, J=8.4Hz, 1H), 7.60 (d, J= 8.1Hz, 1H), 7.33-7.29 (m, 1H), 7.27 (d, J=7.4Hz, 1H), 6.70 (d, J=8.4Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ168.98, 165.28, 156.20, 155.33, 124.45, 124.35, 122.77, 122.53, 118.96, 113.08, 112.98, 111.16, 105.70.

[0388] Example 62: 3-Hydroxydibenzo[b,d]thiophene-4-carboxylic acid (2ai)

[0389]

[0390] General Procedure B, white solid, 17.1 mg, 70% yield.

[0391] 1 H NMR (600MHz, DMSO-d6) δ 8.12-8.09 (m, 2H), 7.84 (d, J = 7.8Hz, 1H), 7.36 (t, J = 7.4Hz, 1H), 7.30 (t, J = 7.4Hz, 1H), 6.85 (d, J = 8.4Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ171.66, 163.43, 141.08, 140.47, 135.14, 125, 55, 124.51, 124.35, 123.86, 122.19, 119.92, 114.64, 113.09.

[0392] Example 63: 2-Hydroxy-4-(pyridin-3-yl)benzoic acid (2aj)

[0393]

[0394] General Procedure A, white solid, mg, 68% yield.

[0395] 1 H NMR (600MHz, DMSO-d6) δ8.99-8.93 (m, 1H), 8.63 (d, J=4.9Hz, 1H), 8.16 (dd, J=8.0, 2.4Hz, 1H), 7 .90 (d, J=8.2Hz, 1H), 7.53 (dd, J=8.0, 4.8Hz, 1H), 7.34 (d, J=1.8Hz, 1H), 7.31 (d, J=8.2Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ171.66, 162.86, 161.57, 149.29, 147.69, 143.91, 134.58, 131.06, 117.72, 115.10, 112.83, 103.46.

[0396] Example 64: 5-Hydroxy-2-phenylisonicotinic acid (2ak)

[0397]

[0398] General Procedure A, white solid, 14.2 mg, 66% yield.

[0399] 1 H NMR (600MHz, DMSO-d6) δ 8.46 (s, 1H), 8.09 (s, 1H), 7.98 (d, J = 8.4Hz, 2H), 7.47 (t, J = 7.7Hz, 2H), 7.39 (t, J = 7.3Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ169.21, 154.29, 146.67, 140.19, 137.69, 128.82, 128.34, 125.85, 122.62, 119.08.

[0400] Example 65: 5-Hydroxy-2-(4-(trifluoromethyl)phenyl)isonicotinic acid (2al)

[0401]

[0402] General Procedure A, white solid, 14.1 mg, 50% yield.

[0403] 1 H NMR (600MHz, DMSO-d6) δ8.21 (s, 1H), 8.16 (d, J = 8.2Hz, 2H), 8.13 (s, 1H), 7.75 (d, J = 8.2Hz, 2H). 13 C NMR (151MHz, DMSO-d6) δ169.50, 159.58, 143.19, 142.22, 140.08, 127.34 (q, J CF =31.8Hz), 126.16, 125.82, 125.55 (q, J CF =3.8Hz), 124.56(q, J) CF =270.6Hz), 119.78.

[0404] Example 66: 3-Hydroxy-6-(Naphth-1-yl)pyridinecarboxylic acid (2am)

[0405]

[0406] General Procedure A, white solid, 14.6 mg, 55% yield.

[0407] 1 H NMR (600MHz, DMSO-d6) δ8.08 (d, J=8.4Hz, 1H), 7.97 (d, J=8.1Hz, 1H), 7.93 (dd, J=7.6, 1.9Hz, 1H), 7.58-7.50 (m, 3H), 7.47 (ddd, J=8.3, 6.7, 1.4Hz, 1H), 7.43 (d, J=8.4Hz, 1H), 7.22 (d, J=84Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ170.28, 159.53, 145.65, 138.77, 137.57, 133.52, 131. 01, 128.17, 127.62, 127.57, 126.90, 126.10, 125.85, 125.71, 125.48, 124.52.

[0408] Example 67: 3-Hydroxy-6-phenylpyridinecarboxylic acid (2an)

[0409]

[0410] General Procedure A, white solid, 14.1 mg, 65% yield.

[0411] 1 H NMR (600MHz, DMSO-d6) δ8.00-7.95 (m, 2H), 7.75 (d, J=8.5Hz, 1H), 7.41 (t, J=7.7Hz, 2H), 7.30 (t, J=7.3Hz, 1H), 7.13 (d, J=8.5Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ170.15, 160.07, 143.76, 139.57, 137.43, 128.48, 127.25, 125.75, 124.87, 123.05.

[0412] Example 68: 3-Hydroxy-6-(p-Tolyl)pyridinecarboxylic acid (2ao)

[0413]

[0414] Standard procedure A, 14.5 mg, 63% yield.

[0415] 1H NMR (600MHz, DMSO-d6) δ7.85 (d, J=7.9Hz, 2H), 7.71 (d, J=8.6Hz, 1H), 7.22 (d, J=7.8Hz, 2H), 7.12 (d, J=8.5Hz, 1H), 2.32 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ170.33, 159.66, 144.06, 137.34, 136.88, 136.43, 129.11, 125.69, 124.85, 122.82, 20.76.

[0416] Example 69: 3-Hydroxy-6-(4-methoxyphenyl)pyridinecarboxylic acid (2ap)

[0417]

[0418] General Procedure A, white solid, 13.4 mg, 55% yield.

[0419] 1 H NMR (600 NHz, DMSO-d6) δ7.90 (d, J=8.8Hz, 2H), 7.67 (d, J=8.5Hz, 1H), 7.10-7.07 (m, 1H), 6.97 (d, J=8.9Hz, 2H), 3.79 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ170.17, 159.40, 158.78, 143.75, 137.30, 132.31, 126.96, 124.77, 122.27, 113.82, 55.11.

[0420] Example 70: 3-Hydroxy-6-(4-(trifluoromethyl)phenyl)pyridinecarboxylic acid (2aq)

[0421]

[0422] General Procedure A, white solid, 22.3 mg, 79% yield.

[0423] 1 H NMR (600MHz, DMSO-d6) δ8.21 (d, J=8.2Hz, 2H), 7.88 (d, J=8.6Hz, 1H), 7.76 (d, J=8.2Hz, 2H), 7.17 (d, J==8.6Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ169.83, 161.27, 14334, 141.63, 137.66, 127.35 (q, J CF=31.6Hz), 126.18, 125, 39 (q, J CF =3.8Hz), 124.59(q, J) CF =270.3Hz), 125.08, 123.75.

[0424] Example 71: 2-Hydroxy-4-(pyridin-2-yl)benzoic acid (2ar)

[0425]

[0426] General Procedure A, white solid, 13.6 mg, 63% yield.

[0427] 1 H NMR (600MHz, DMSO-d6) δ8.70 (d, J=4.8Hz, 1H), 8.03 (dd, J=8.0, 2.8Hz, 1H), 7.94-7.88 (m, 2H), 7.68-7.63 (m, 2H), 7.42 (dd, J=7.4, 4.8Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ171.68, 161.36, 154.37, 149.63, 145.23, 137.54, 130.76, 123.68, 121.14, 117.38, 114.76, 113.26.

[0428] Example 72: 2-Hydroxy-5-(pyridin-2-yl)benzoic acid (2as)

[0429]

[0430] General Procedure A, white solid, 15.1 mg, 70% yield.

[0431] 1 H NMR (600MHz, DMSO-d6) δ8.59 (d, J=4.7Hz, 1H), 8.52 (s, 1H), 8.06 (d, J=8.5Hz, 1H), 7.85-7.79 (m, 2H), 7.25 (dd, J-7.1, 4.7Hz, 1H), 6.89 (d, J=8.5Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ169.62, 163.23, 155.83, 149.31, 137.11, 131.42, 128.59, 128.10, 121.52, 119.01, 117.30, 116.87.

[0432] Example 73: 4-Acetamino-2-hydroxybenzoic acid (2 at)

[0433]

[0434] General Procedure B, white solid, 13.7 mg, 70% yield.

[0435] 1 H NMR (600MHz, DMSO-d6) δ10.24 (s, 1H), 7.66 (d, J=8.5Hz, 1H), 7.26 (s, 1H), 6.99 (d, J=8.1Hz, 1H), 2.05 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ172.43, 169.35, 162.77, 144.95, 131.19, 110.72, 109.67, 106.16, 24.65.

[0436] Example 74: 2-((tert-butoxycarbonyl)amino)-6-hydroxybenzoic acid (2au)

[0437]

[0438] General Procedure B, white solid, 19.2 mg, 76% yield.

[0439] 1 H NMR (600MHz, DMSO-d6) δ 12.74 (s, 1H), 7.54 (d, J = 8.2Hz, 1H), 7.04 (t, J = 8.2Hz, 1H), 6.28 (d, J = 8.1Hz, 1H), 1.44 (s, 9H). 13 C NMR (151MHz, DMSO-d6) δ174.04, 163.57, 152.50, 142.12, 131.20, 109.53, 105.93, 105.73, 78.55, 28.15.

[0440] Example 75: 5-Formyl-2-hydroxybenzoic acid (2av)

[0441]

[0442] General Procedure A, white solid, 12.1 mg, 73% yield.

[0443] 1 H NMR (600MHz, DMSO-d6) δ9.87 (s, 1H), 8.34 (d, J=2.2Hz, 1H), 7.97 (dd, J=8.6, 2.2Hz, 1H), 7.08 (d, J=8.6Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ190.91, 170.97, 166.57, 134.74, 133.93, 127.77, 118.27, 114.42.

[0444] Example 76: 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-dibenzo[d]imidazolium]-3'-yl)methyl)-3-hydroxy-[1,1'-biphenyl]-2-carboxylic acid (2aw)

[0445]

[0446] General Procedure B, white solid, 31.8 mg, 60% yield.

[0447] 1 H NMR (600MHz, CDCl3) δ 8.40-8.33 (m, 1H), 7.39 (ddt, J=7.5, 4.8, 1.4Hz, 4H), 7.28 (d, J=7.7Hz, 3H), 7.12 (d, J=7.8Hz, 2H), 7.07-7.02 (m, 2H), 6.89 ( d, J=1.6Hz, 1H), 6.83 (dd, J=7.4, 1.2Hz, 1H), 5.45 (s, 2H), 3.80 (s, 3H), 3 .20-3.12(m, 2H), 2.74(s, 3H), 2.07-1.98(m, 2H), 1.19(t, J=7.4Hz, 3H). 13 C NMR (151 MHz, chloroform-d) δ 174.11, 157.04, 153.50, 144.78, 144.03, 139.11, 134.95, 132.96, 132.51, 129.25, 129.08, 126.51, 123.84, 123.75, 123.37, 120.19, 120.15, 119.21, 116.86, 114.37, 111.81, 109.68, 48.99, 31.94, 30.14, 22.42, 16.99, 14.15.

[0448] Example 78: 4-(N,N-dipropylaminosulfonyl)-2-hydroxybenzoic acid (2ax)

[0449]

[0450] General Procedure B, white solid, 25.6 mg, 85% yield.

[0451] 1H NMR (600MHz, DMSO-d6) δ7.95 (d, J=8.0Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 7, 26 (s, 1H), 3.04 (t, J=7.5Hz, 5H), 1.46 (q, J=7.3Hz, 4H), 0.80 (t, J=7.3Hz, 6H). 13 C NMR (151MHz, DMSO-d6) δ170.17, 163.64, 141.83, 130.71, 123.28, 114.27, 113.65, 49.72, 21.65, 11.03.

[0452] Example 79: (S)-4-(2-benzoylamino-3-(4-hydroxyphenyl)propionylamino)-2-hydroxybenzoic acid (2ay)

[0453]

[0454] General Procedure B, white solid, 29.8 mg, 71% yield.

[0455] 1 H NMR (600MHz, DMSO-d6) δ10.48 (s, 1H), 9.21 (s, 1H), 8.74 (d, J=7.9Hz, 1H), 7.88-7.81 (m, 2H), 7.75 (d, J=8.7Hz, 1H), 7.56-7.50 (m, 1H), 7.46 (dd, J =8.3, 6.9Hz, 2H), 7.41 (d, J = 2.0Hz, 1H), 7.24-7.17 (m, 2H), 7.11 (dd, J = 8 .7, 2.1Hz, 1H), 6.74-6.60(m, 2H), 4.84-4.72(m, 1H), 3.06-2.97(m, 2H). 13 C NMR (151MHz, DMSO-d6) δ171.65, 171.53, 166.67, 162.15, 155.89, 145.31, 133.87, 131.48 , 131.12, 130.22, 128.28, 127.99, 127.56, 114.99, 110.42, 107.84, 106.16, 56.48, 36.29.

[0456] Example 80: 2-((2,6-dichloro-3-methylphenyl)amino)-6-hydroxybenzoic acid (2az)

[0457]

[0458] General Procedure A, white solid, 21.2 mg, 68% yield.

[0459] 1 H NMR (600MHz, DMSO-d6) δ11.47 (s, 1H), 7.41 (d, J = 8.2Hz, 1H), 7.22 (d, J = 8.3Hz, 1H), 6.76 (t, J=8.1Hz, 1H), 5.96 (dd, J=8.0, 1.1Hz, 1H), 5.36 (dd, J=8.1, 1.1Hz, 1H), 2.35 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ174.89, 164.85, 147.95, 137.31, 136.50, 133.97, 130.90, 130.85, 128.37, 128.25, 105.59, 104.60, 100.99, 20.70.

[0460] Example 81: (S)-2-ethoxy-6-hydroxy-4-(2-((3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)amino)-2-oxoethyl)benzoic acid (2ba)

[0461]

[0462] General Procedure A, white solid, 26.2 mg, 56% yield.

[0463] 1 H NMR (600MHz, DMSO-d6) δ8.40 (d, J=8.6Hz, 1H), 7.30 (d, J=7.7Hz, 1H), 7.16 (t, J=7.6Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 7.04 (t, J=7.5Hz, 1H), 6.37(s, 1H), 6.36(s, 1H), 5.37(td, J=9.3, 4.9Hz, 1H), 4.03-3.88(m, 2H), 3.09(s, 2H), 1.74-1.64(m, 2H), 1.59-1.55(m, 2H), 1.52-1.46(m ， 2H), 1.29 (t, J = 7.0 Hz) ， 3H), 0.90 (t, J=6.4Hz, 6H). 13C NMR (151MHz, DMSO-d6) δ169.37, 168.79, 157.44, 151.50, 140.88, 140.48, 127.18, 126.02, 124.00, 12 0.50, 109.54, 107.65, 103.83, 63.94, 46.56, 45.90, 42.83, 26.33, 24.85, 23.84, 23.21, 21.79, 14.64.

[0464] Example 82: 2-((3-chloro-2-methylphenyl)amino)-4-hydroxynicotinic acid (2bb)

[0465]

[0466] General Procedure A, white solid, 18.1 mg, 65% yield.

[0467] 1 H NMR (600MHz, DMSO-d6) δ11.35 (s, 1H), 7.52 (dd, J=7.5, 1.7Hz, 1H), 7.42-7.34 (m, 3H), 6, 22 (d, J=7.3Hz, 1H), 2.24 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ179.02, 171.17, 153.07, 137.32, 135.37, 134.65, 133.52, 128.67, 128.31, 126.41, 109.37, 95.40, 14.94.

[0468] Example 83: 2-Hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)carbamoyl)benzoic acid (2bc)

[0469]

[0470] General Procedure B, white solid, 25.7 mg, 70% yield.

[0471] 1 H NMR (600MHz, DMSO-d6) δ9.99 (s, 1H), 7.82 (d, J = 7.9Hz, 1H), 7.69 (d, J = 1.9Hz, 1H ), 7.58 (dd, J=8.5, 1.9Hz, 1H), 7.30-7.17 (m, 3H), 1.64 (m, 4H), 1.23 (m, 12H). 13CNMR (151MHz, DMSO-d6) δ171.36, 165.16, 162.32, 144.44, 139.68, 138.12, 136.69, 130.03, 126.34 , 122.28, 118.26, 118.07, 115.59, 115.08, 34.66, 34.60, 34.00, 33.54, 31.68, 31.65, 30.71, 29.62.

[0472] Example 85: 5-(5-(2-fluorophenyl)-1,2,4- (2bd)-2-hydroxybenzoic acid (3-diazolyl)-2-hydroxybenzoic acid

[0473]

[0474] General Procedure A, white solid, 24.3 mg, 81% yield.

[0475] 1 H NMR (600MHz, DMSO-d6) δ8.46 (s, 1H), 8.23 ​​(t, J=7.6Hz, 1H), 7.89 (d, J=8.4Hz, 1H), 7.81- 7.75 (m, 1H), 7.54 (dd, J=11.1, 8.4Hz, 1H), 7.48 (t, J=7.6Hz, 1H), 6.82 (d, J=8.5Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ171.89, 171.86, 168.06, 166.47, 160.79, 159.08, 135.52, 135.46, 131.14, 130.88, 129.71, 125.49, 125.47, 117.52, 117.36, 117.22, 113.80, 112.03, 111.95.

[0476] Example 86: Single-crystal X-ray structure of [Pd2Cl2(L42)2] complex

[0477]

[0478] L42 (14.8 mg, 0.05 mmol) was added to a solution of Pd(OAc)2 (11.2 mg, 0.05 mmol) in CHCl3 (1 mL). The mixture was stirred at 65 °C for 8 hours. After filtration through a diatomaceous earth pad, the solution was concentrated under vacuum to give a brown powder (17.4 mg, 74% yield). Crystals were grown in toluene, and the structure was determined by X-ray diffraction. Figure 1 ).

[0479]

[0480] Correction method = #Reported T limit: T 最小 =0.364 T 最大 =0.491

[0481] AbsCorr = Multiple Scans

[0482] Data integrity = 0.995θ (maximum) = 26.435

[0483] R(reflection))=0.0339(8381)wR2(reflection)=0.0801(9731)

[0484] S = 1.091Npar = 606.

[0485] Example 87: Single-crystal X-ray structure of [Pd2(TFA)2(L27)2] complex

[0486]

[0487] General procedure: L27 (14.5 mg, 0.05 mmol) was added to a solution of Pd(TFA)2 (16.6 mg, 0.05 mmol) in CDCl3 (1 mL). The mixture was stirred at 20 °C for 24 hours. After filtration through a diatomaceous earth pad, the solution was concentrated under vacuum to obtain a brown powder (15.0 mg, 61% yield). Crystals were grown in toluene, and the structure was determined by X-ray diffraction. Figure 2 ).

[0488]

[0489] Correction method = #Reported T limit: T 最小 =0.694 T 最大 =0.746

[0490] AbsCorr = Multiple Scans

[0491] Data integrity = 0.999θ (maximum) = 28.307

[0492] R(reflection) = 0.0444(8236)wR2(reflection) = 0.1188(9412)

[0493] S = 1.073Npar = 552.

[0494] The references numbered in the above embodiments are as follows:

[0495] 1.Gottlieb,H.E.,Kotlyar,V.,Nudelman, A.NMR chemical shifts of commonlaboratory solvents as trace impurities.J.Org.Chem.62,7512-7515(1997).

[0496] 2.Di Marco,V.B.,Yokel,R.A.,Ferlin,M.G.,Tapparo,A.,Bombi,G.G.:Evaluation of 3,4-hydroxypyridinecarboxylic acids as possible bidentatechelating agents for aluminium(III):synthesis and metal-ligand solutionehemistry.Eur.J.Inorg.Chem.2648-2655(2002).

Claims

1. A method for preparing a compound of formula (2): comprising contacting a compound of formula (1) with Pd 2+ source contact: This forms the compound of formula (2), wherein: For C6-C 10 -aryl; or 5- to 10-membered heteroaryl, wherein 1 to 4 heteroaryl ring members are independently selected from O, S, and N, wherein the C6-C 10 -Aryl or 5- to 10-membered heteroaryl groups are optionally further fused to independently select one or two rings from the following: C6-C 10 -aryl; 5- to 10-membered heteroaryl, wherein 1 to 4 heteroaryl ring members are independently selected from O, S, and N; C3-C 14 -Cycloalkyl; 3- to 14-membered heterocycloalkyl, wherein 1 to 4 heterocycloalkyl ring members are independently selected from N, O, and S; and fused combinations thereof, wherein: each Independently and optionally substituted with one to four of the following: -CN; halogenated; oxidized; NR A R B C1-C6-alkyl; C1-C6-haloalkyl; C2-C6-alkenyl; C2-C6-alkynyl; C1-C6-alkoxy; C1-C6-haloalkoxy; -C(O)H; C(O)C1-C6-alkyl; C(O)NR A R B ;S(O)NR A R B ;S(O)2NR A R B C3-C 14 -Cycloalkyl; C6-C 10 -Aryl; C6-C 10 -Aryloxy; 3- to 14-membered heterocyclic alkyl and -(C1-C6-alkyl)-(3- to 14-membered heterocyclic alkyl), wherein 1 to 4 ring members are independently N, O or S; or 5- to 10-membered heteroaryl, wherein 1 to 4 heteroaryl members are independently N, O or S, wherein: Each alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl moiety is optionally substituted with one to four of the following: halogenated; oxo-substituted; C1-C6-alkyl; C1-C6-haloalkyl; C1-C6-alkoxy; C(O)NR A R B C1-C6-alkoxy group; C6-C 10 -aryl, optionally substituted with one to three halogens and C1-C6-alkyl; or 5- to 10-membered heteroaryl, wherein one to four heteroaryl members are independently selected from N, O and S, and the 5- to 10-membered heteroaryl is optionally substituted with one to three substituents selected from C1-C6-alkyl and 5- to 10-membered heteroaryl; R A and R B Each independently represents: H; C1-C6-alkyl; C1-C6-haloalkyl; -C1-C6-alkyl-C6-C 10 -aryl; C(O)C1-C6-alkyl; C(O)C1-C6-alkyl-C6-C 10 -Aryl; C(O)OC1-C6-alkyl; or C6-C 10 -Aryl, the C6-C 10 -Aryl groups are optionally fused to C3-C 14 -cycloalkyl, the C3-C 14 -The cycloalkyl group is optionally substituted with one to four halogens and C1-C6-alkyl groups, wherein: Each aryl group may optionally be substituted with one to three of the following: C1-C6-alkyl; halo; hydroxyl; C1-C6-haloalkyl; or 3- to 14-membered heterocyclic alkyl, wherein one to four ring members are independently selected from N, O, and S; and Each alkyl group is optionally substituted with one to three of the following: halogenated; or NRR', wherein R and R' are each independently H, C1-C6-alkyl, C(O)C1-C6-alkyl, or C(O)C6-C 10 -Aryl; R 1L and R 2L Each independently represents: H; C1-C6-alkyl; C6-C 10 -aryl; -(C1-C6-alkyl)C6-C 10 -aryl; 5- to 10-membered heteroaryl, wherein 1 to 4 heteroaryl ring members are independently selected from O, S, and N; or C3-C 14 -cycloalkyl, wherein: Each aryl group may optionally and independently be substituted with one to three of the following: C1-C6-alkyl, halo, C1-C6-haloalkyl, or C1-C6-alkoxy. R 3L and R 4L Each is independently C1-C6-alkyl, halo, C1-C6-alkoxy, or C1-C6-haloalkyl; n is 1, 2, or 3; o is 0, 1, 2, or 3; and p can be 0, 1, 2, or 3.

2. The method according to claim 1, wherein It is an arbitrarily substituted monocyclic ring.

3. The method according to claim 1, wherein It is an optional substituted bicyclic system.

4. The method according to claim 1, wherein For optional, replaced three-ring system.

5. The method according to claim 1, wherein For optional replacement: 。 6. The method according to claim 5, wherein For optional replacement or .

7. The method according to claim 1, wherein the compound of formula (1) is selected from one of the following: 。 8. The method according to any one of claims 1 to 7, wherein n is 1 or 2.

9. The method of claim 8, wherein n is 1.

10. The method according to any one of claims 1 to 7, wherein R 1L and R 2L Each is independently C1-C6-alkyl, C6-C 10 -aryl or -(C1-C6-alkyl)C6-C 10 -Aryl.

11. The method according to any one of claims 1 to 7, wherein p is 0.

12. The method according to any one of claims 1 to 7, wherein o is 1.

13. The method according to any one of claims 1 to 7, wherein each R 3L It is independently C1-C6-alkyl or halogenated.

14. The method according to any one of claims 1 to 7, wherein the ligand of formula (L) is selected from one of the following tables: 。 15. The method according to any one of claims 1 to 7, wherein the Pd 2+ Source is Pd 2+ Salt.

16. The method of claim 15, wherein the Pd 2+ The salts are Pd(OAc)2, Pd(TFA)2, PdCl2 or Pd(CH3CN)2Cl2.

17. The method according to any one of claims 1 to 7, wherein the contact further occurs in the presence of a nonnucleophilic base.

18. The method according to claim 17, wherein the nonnucleophilic base is K3PO4, K2HPO4 or K2CO3.

19. The method according to any one of claims 1 to 7, wherein the contact is further performed in the presence of KOAc, NaOAc, CsOAc or KH2PO4.

20. The method according to any one of claims 1 to 7, wherein the contact occurs in the presence of a polar aprotic solvent.

21. The method according to claim 20, wherein the polar aprotic solvent is N-methylpyrrolidine, dimethylacetamide, dimethylformamide, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, hexamethylphosphoric triamine, or dimethyl sulfoxide.

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