BACKGROUND

[0001] Suzuki-Miyaura coupling is a valuable synthetic method for coupling a first aromatic compound to a second aromatic compound, thereby forming a new carbon-carbon bond between the aromatic compounds. In one common Suzuki reaction the first aromatic compound is substituted by a halide. In one common Suzuki reaction the second aromatic compound includes a boron-containing substituent. In general, the Suzuki reaction is mediated by a metal catalyst and is conducted in the presence of an external base.

[0002] Complex heteroaryl molecules are key components found in many specialty product applications including the agrosciences, electronic materials pharmaceuticals and novel ligands for catalysis. The palladium mediated Suzuki reaction has emerged as one of the more versatile methods for constructing biaryl heteroaryl compounds. Unfortunately, Suzuki reactions of heteroaryl molecules, especially those containing basic nitrogen centers, are often plagued by slow reaction rates and low yields. To overcome these issues, additional protection / deprotection manipulations are often employed to help mitigate the inhibitory binding of the nitrogen center and thus allow for lower catalyst loadings and higher yields of product. Alternatively, the Suzuki reaction may also be performed at an earlier stage of the manufacturing process prior to the installation of the nitrogen center. These solutions are very costly due to the introduction of additional processes steps before and after the precious metal mediated reaction.

[0003] A Suzuki-style reaction scheme using one or more heteroaryl molecules is desired. A Suzuki-style reaction scheme performed without the addition of an external base is desired where the initial pH of the reaction mixture is less than 11 and the final pH is less than 7.

STATEMENT OF INVENTION

[0004] The present disclosure describes a method of coupling a first aromatic compound to a second aromatic compound, the method comprising: (a) preparing a reaction mixture comprising the first aromatic compound, the second aromatic compound, a catalyst and water; the reaction mixture does not contain an external base, the reaction mixture having an initial pH of from 11 to 1; the catalyst having at least one group 10 atom; the first aromatic compound having a halogen, triflate or sulfonate substituent; the second aromatic compound having a boron-containing substituent; wherein, at least one of the first aromatic compound or the second aromatic compound includes one or more heteroatom; and (b) reacting the first aromatic compound and the second aromatic compound in the reaction mixture, the reaction mixture having a final pH of less than 7 following reaction of the first aromatic compound and the second aromatic compound.

DETAILED DESCRIPTION

[0005] Unless otherwise indicated, numeric ranges, for instance "from 2 to 10," are inclusive of the numbers defining the range (e.g., 2 and 10).

[0006] Unless otherwise indicated, ratios, percentages, parts, and the like are by weight.

[0007] As used herein, unless otherwise indicated, the phrase "molecular weight" refers to the number average molecular weight as measured in conventional manner.

[0008] "Alkyl," as used in this specification, whether alone or as part of another group (e.g., in dialkylamino), encompasses straight, branched and cyclic chain aliphatic groups having the indicated number of carbon atoms. If no number is indicated (e.g., aryl-alkyl-), then 1- 12 alkyl carbons are contemplated. Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl and tert-octyl.

[0009] The term "heteroalkyl" refers to an alkyl group as defined above with one or more heteroatoms (nitrogen, oxygen, sulfur, phosphorus) replacing one or more carbon atoms within the radical, for example, an ether or a thioether.

[0010] "Aromatic compound" refers to a ring system having 4n+2 pi electrons where n is an integer greater than or equal to zero.

[0011] An "aryl" group refers to any functional group or substituent derived from an aromatic compound. In one instance, aryl refers to an aromatic moiety comprising one or more aromatic rings. In one instance, the aryl group is a C ₆ -Ci ₈ aryl group. In one instance, the aryl group is a C ₆ -Cio aryl group. In one instance, the aryl group is a Cio-Ci ₈ aryl group. Aryl groups contain 4n+2 pi electrons, where n is an integer. The aryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Preferred aryls include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. Unless otherwise indicated, the aryl group is optionally substituted with 1 or more substituents that are compatible with the syntheses described herein. Such substituents include, but are not limited to, sulfonate groups, boron- containing groups, alkyl groups, nitro groups, halogens, cyano groups, carboxylic acids, esters, amides, C2-C ₈ alkene, amines and other aromatic groups. Other substituents are known in the art. Unless otherwise indicated, the foregoing substituent groups are not themselves further substituted.

[0012] "Heteroaryl" refers to any functional group or substituent derived from an aromatic ring and containing at least one heteroatom within the ring and selected from nitrogen, oxygen, and sulfur. Preferably, the heteroaryl group is a five or six-membered ring. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Examples of heteroaryl groups include, without limitation, pyridine, pyrimidine, pyridazine, pyrrole, triazine, imidazole, triazole, furan, thiophene, oxazole, thiazole. The heteroaryl group may be optionally substituted with one or more substituents that are compatible with the syntheses described herein. Such substituents include, but are not limited to, fluorosulfonate groups, boron-containing groups, Ci-C ₈ alkyl groups, nitro groups, halogens, cyano groups, carboxylic acids, esters, amides, C2-C8 alkenes, amines and other aromatic groups. Other substituents are known in the art. Unless otherwise indicated, the foregoing substituent groups are not themselves further substituted.

[0013] An "external base" refers to a base that is added to the reaction scheme separate from the reactants. The reaction mixture described herein does not include an external base. Further, the reaction mixture described herein has an initial pH, as measured after all of the reactants have been combined. In one instance, the initial pH is from 11 to 1. More preferably, the initial pH is from 10 to 4.

[0014] "Heteroatom" refers to an atom that is not carbon or hydrogen. Examples of suitable heteroatoms include N, O, S, P, CI, Br, or I.

[0015] As noted above, the present disclosure describes a process for coupling a first aromatic compound to a second aromatic compound. This process is shown generally in Equation 1, where A ¹ refers to a first aromatic compound, A ² refers to a second aromatic compound, X refers to a halogen, triflate or fluorosulfonate and B ^Y refers to a boron- containing substituent. In one instance, one or both of A ¹ and A ² are further substituted. Examples of suitable substituents include, but are not limited to, C1-C10 alkyl, C1-C10 amino, and C1-C10 heteroalkyl. At least one of A ¹ or A ² includes a heteroatom. In one instance, the heteroatom of at least one of A ¹ or A ² is a member of an aromatic ring. In one instance, the heteroatom of at least one of A ¹ or A ² is a member of a substituent to one of the aromatic rings. The heteroatom of at least one of A ¹ or A ² is separate from any heteroatoms present in X or B ^Y . In one instance the heteroatom is nitrogen. The result of the reactions shown in Equation 1 is the formation of a new carbon-carbon bond between the first aromatic compound and the second aromatic compound, thereby coupling the first aromatic compound to the second aromatic compound. Unexpectedly, it has been found that the reaction of Equation 1 may be performed without adding external base with a reaction mixture having an initial pH of less than 11 and a final pH of less than 7.

A ¹ -X + A ² — B ^Y " A ¹ A ²

Equation 1

[0016] As noted above, the second aromatic compound includes a boron-containing substituent as identified in Equation 1 as B ^Y . In one instance, the boron-containing substituent is of the formula -BF ₃ M ^"1" where M ⁺ is an alkali metal cation or an unsubstituted ammonium ion. Unsubstituted ammonium ion refers to NH ₄ ⁺ . In one instance, the boron of the boron-containing substituent has one or more alkyl substituent, for example, 9- borabicyclo[3.3.1]nonane. In another instance, the boron-containing substituent is of the formula shown in Equation 2.

Equation 2

[0017] In Equation 2 R ¹ and R ² are each independently Ci_i ₈ alkyl, C3-18 cycloalkyl, C ₆ -i8 aryl, or H. In another instance, R ¹ and R ² are covalently linked to each other to form a ring that includes— R ¹ — O— B— O— R ² — . In one instance one or more of R ¹ and R ² are boron, for example, in a boroxane. Boron-containing substituents which are known to be suitable for typical Suzuki reactions are suitable here.

[0018] As noted above in Equation 1, the first aromatic compound is reacted with the second aromatic compound in a reaction mixture. The reaction mixture comprises the first aromatic compound, the second aromatic compound, water and a catalyst. As mentioned above, the reaction mixture does not include an external base. As mentioned above, the reaction mixture has an initial pH of from 11 to 1. In one instance, the reaction mixture has an initial pH of from 9 to 1. The reaction mixture has a final pH following reaction of the first aromatic compound and the second aromatic compound. The final pH being less than 7.

[0019] The catalyst includes at least one group 10 atom. The group 10 atoms include nickel, palladium and platinum. [0020] In one instance, the catalyst is generated in-situ from a palladium precatalyst, the palladium precatalyst is selected from the group consisting of: Palladium(II) acetate, Palladium(II) chloride, Dichlorobis(acetonitrile)palladium(II),

Dichlorobis(benzonitrile)palladium(II), Allylpalladium chloride dimer, Palladium(II) acetylacetonate, Palladium(II) bromide, Bis(dibenzylideneacetone)palladium(0), Bis(2- methylallyl)palladium chloride dimer, Crotylpalladium chloride dimer, Dichloro(l,5- cyclooctadiene)palladium(II) , Dichloro(norbornadiene)palladium(II) , Palladium(II) trifluoroacetate, Palladium(II) benzoate, Palladium(II) trimethylacetate, Palladium(II) oxide, Palladium(II) cyanide, Tris(dibenzylideneacetone)dipalladium(0), Palladium(II)

hexafluoroacetylacetonate, cis-Dichloro(N,N,N',N'- tetramethylethylenediamine)palladium(II), Cyclopentadienyl[(l,2,3-n)-l-phenyl-2- propenyl]palladium(II), [l,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) dichloride, (l,3-Bis(2,6-diisopropylphenyl)imidazolidene) ( 3- chloropyridyl) palladium(II) dichloride, Bis(tri-tert-butylphosphine)palladium(0) and a mixture of two or more thereof.

[0021] In one instance, the catalyst is generated in-situ from a nickel precatalyst, the nickel precatalyst is selected from the group consisting of: nickel(II) acetate, nickel(II) chloride, Bis(triphenylphosphine)nickel(II) dichloride, Bis(tricyclohexylphosphine)nickel(II) dichloride, [1,1 '-Bis(diphenylphosphino)ferrocene]dichloronickel(II) , Dichloro [ 1 ,2- bis(diethylphosphino)ethane]nickel(II), Chloro(l-naphthyl)bis(triphenylphosphine) nickel(II), l,3-Bis(2,6-diisopropylphenyl)imidazolium chloride, Bis(l,5- cyclooctadiene)nickel(O), Nickel(II) chloride ethylene glycol dimethyl ether complex, [1,3- Bis(diphenylphosphino)propane]dichloronickel(II), [ 1 ,2-

Bis(diphenylphosphino)ethane]dichloronickel(II), Bis(tricyclohexylphosphine)nickel(0).

[0022] The catalyst is provided in a form suitable to the reaction conditions. In one instance, the catalyst is provided on a substrate. In one instance, nickel-based catalysts are used. In another instance, platinum-based catalysts are used. In yet another instance, a catalyst including one or more of nickel, platinum and palladium -based catalysts are used.

[0023] In one instance, pyridine-enhanced precatalyst preparation stabilization and initiation (PEPPSI) type catalysts are used, for example, [1,3-Bis(2,6- Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)pallad ium(II) dichloride, and (1,3- Bis(2,6-diisopropylphenyl)imidazolidene) ( 3-chloropyridyl) palladium(II) dichloride. [0024] Examples of nickel precatalysts include, but are not limited to, nickel(II) acetate, nickel(II) chloride, Bis(triphenylphosphine)nickel(II) dichloride,

Bis(tricyclohexylphosphine)nickel(II) dichloride, [Ι, - Bis(diphenylphosphino)ferrocene]dichloronickel(II), Dichloro[l,2- bis(diethylphosphino)ethane]nickel(II), Chloro(l- naphthyl)bis(triphenylphosphine)nickel(II), l,3-Bis(2,6-diisopropylphenyl)imidazolium chloride, Bis(l,5-cyclooctadiene)nickel(0), Nickel(II) chloride ethylene glycol dimethyl ether complex, [l,3-Bis(diphenylphosphino)propane]dichloronickel(II), [1,2- Bis(diphenylphosphino)ethane]dichloronickel(II), and

Bis(tricyclohexylphosphine)nickel(0).

[0025] In one instance, the halogen of the first aromatic compound is bromine and the reaction mixture does not include a ligand. In one instance, the halogen of the first aromatic compound is chlorine and the reaction mixture further comprises a ligand. In one instance, the reaction mixture further comprises a ligand. In one instance, the reaction mixture does not contain a ligand. In one instance the ligand is a phosphine ligand, for example, tricyclophosphine, (2-Biphenylyl)di-tert-butylphosphine, 2-(Di-tert-butyl-phosphino)- 1- phenyl-lH-pyrrole, l,l '-Bis(di-tert-butylphophino)ferrocene, or tri-tert-butylphosphine.

[0026] As described above, the reaction mixture includes water. In some instances, a solvent is also included in the reaction mixture and is selected such that it is compatible with the reaction mixture. For example, suitable solvents include toluene, xylenes (ortho- xylene, m<?ia-xylene, p r -xylene or mixtures thereof), benzene, methanol, ethanol, 1- propanol, 2-propanol, n-butanol, 2-butanol, pentanol, hexanol, i<?ri-butyl alcohol, feri-amyl alcohol, ethylene glycol, 1,2-propanedioal, 1,3 -propanediol, glycerol, N-methyl-2- pyrrolidone, acetonitrile, NN-dimethylformamide, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, triacetin, acetone, methyl ethyl ketone, and ethereal solvents, such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethylether, cyclopenyl methyl ether, 2-butyl ethyl ether, dimethoxy ethane, polyethyleneglycol. In one instance, the solvent includes any combination of the solvents described herein, in, or in the absence of, a surfactant.

[0027] The present disclosure describes a method of coupling a first aromatic compound to a second aromatic compound, the method comprising: (a) preparing a reaction mixture comprising the first aromatic compound, the second aromatic compound, a catalyst and water; the reaction mixture having an initial pH of from 11 to 1 ; the catalyst having at least one group 10 atom; the first aromatic compound having a halogen, triflate or sulfonate substituent; the second aromatic compound having a boron-containing substituent; wherein, at least one of the first aromatic compound or the second aromatic compound includes one or more heteroatom; and (b) reacting the first aromatic compound and the second aromatic compound in the reaction mixture, the reaction mixture having a final pH of less than 7 following reaction of the first aromatic compound and the second aromatic compound.

[0028] The present disclosure describes a method of coupling a first aromatic compound to a second aromatic compound, the method comprising: (a) preparing a reaction mixture consisting of the first aromatic compound, the second aromatic compound, a catalyst, a ligand and water; the reaction mixture having an initial pH of from 11 to 1 ; the catalyst having at least one group 10 atom; the first aromatic compound having a halogen, triflate or sulfonate substituent; the second aromatic compound having a boron-containing substituent; wherein, at least one of the first aromatic compound or the second aromatic compound includes one or more heteroatom; and (b) reacting the first aromatic compound and the second aromatic compound in the reaction mixture, the reaction mixture having a final pH following reaction of the first aromatic compound and the second aromatic compound.

[0029] The present disclosure further describes a method of coupling a first aromatic compound to a second aromatic compound, the method comprising: (a) preparing a reaction mixture comprising the first aromatic compound, the second aromatic compound, a catalyst and water; the reaction mixture does not contain an external base, the reaction mixture having an initial pH of from 11 to 1; the catalyst having at least one group 10 atom; the first aromatic compound having a halogen, triflate or sulfonate substituent; the second aromatic compound having a boron-containing substituent; wherein, at least one of the first aromatic compound or the second aromatic compound includes one or more heteroatom; and (b) reacting the first aromatic compound and the second aromatic compound in the reaction mixture, the reaction mixture having a final pH following reaction of the first aromatic compound and the second aromatic compound, the final pH less than 7.

[0030] Some embodiments of the invention will now be described in detail in the following Examples. Unless stated otherwise, reported yields are + 5%.

[0031] Example 1. Reaction of 4-amino-2-bromopyridine with phenylboronic acid without added base in water, as shown in Equation 3:

100 °C, N ₂

Equation 3

[0032] A mixture of 4-amino-2-bromopyridine (1.730 g, 10 mmol, 1.0 equiv),

phenylboronic acid (1.341 g, 11 mmol, 1.1 equiv), Pd(OAc) ₂ ((0.0449 g, 0.2 mmol, 0.02 equiv) or (0.0898 g, 0.4 mmol, 0.04 equiv) as identified in Table 1) and H ₂ 0 (25 mL, 1384 mmol) in a 3 -neck round-bottom flask was well stirred under reflux at 100 °C in a N ₂ atmosphere for the time listed in Table 1. The initial and final pH values of the aqueous phase were measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 °C, and listed in Table 1. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 °C; the time to reach this temperature was approximately 20 - 30 minutes. The reactions were biphasic with an aqueous phase and a solid phase. The cooled reaction mixture was basified to pH > 12 using 30% NaOH aqueous solution, and then thoroughly extracted with ethyl acetate. The combined organic phase was dried over anhydrous MgSC _, filtered, and then concentrated in vacuo. The crude product was analyzed by GC and ^! Η NMR, as provided in Table 1.

Table 1

acid in the presence of added external base in water, as shown in Equation 4:

100 °C, N ₂

Equation 4

[0034] A mixture of 4-amino-2-bromopyridine (1.730 g, 10 mmol, 1.0 equiv),

phenylboronic acid (1.341 g, 11 mmol, 1.1 equiv), K ₃ PO ₄ (as specified in Table 2), Pd(OAc) ₂ (0.0449 g, 0.2 mmol, 0.02 equiv) and H ₂ 0 (25 mL, 1384 mmol) in a 3-neck round-bottom flask was well stirred under reflux at 100 °C in a N ₂ atmosphere for 2 h. The initial and final pH values of the aqueous phase were measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 °C, and listed in Table 2. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 °C; the time to reach this temperature is approximately 20 - 30 minutes. The reactions were biphasic with an aqueous phase and a solid phase. The cooled reaction mixture was thoroughly extracted with ethyl acetate. The combined organic phase was dried over anhydrous MgSC _, filtered, and then concentrated in vacuo. The crude product was analyzed by GC and ^! Η NMR, as provided in Table 2.

Table 2

[0035] Example 2. Reactions of additional bromopyridine substrates with phenyl boronic acid without added base, as shown in Equation 5:

Pd(OAc) ₂

N ₂ , 100 °C

Equation 5 [0036] A mixture of A -X (as provided in Table 3, 10 mmol, 1.0 equiv), phenylboronic acid (as provided in Table 3), Pd(OAc) ₂ (0.4 mmol, 0.04 equiv) and H ₂ 0 (25 mL, 1384 mmol) in a 3 -neck round-bottom flask was stirred under reflux at 100 °C in a N ₂ atmosphere for the time listed in Table 1. The initial and final pH values of the aqueous phase were measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 °C, and listed in Table 3. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 °C; the time to reach this temperature was approximately 20 - 30 minutes. The reactions were biphasic with an aqueous phase and a solid phase. The cooled reaction mixture was basified to pH > 12 using 30% NaOH aqueous solution, and then was thoroughly extracted with ethyl acetate. The combined organic phase is dried over anhydrous MgSC _, filtered, and then concentrated in vacuo. The crude product was analyzed by GC and 1H NMR, as provided in Table 3.

Table 3

[0037] Example 3. Reactions of aliphatic amines containing aryl bromides with phenylboronic acid without added base in water, as shown in Equation 6:

100 °C, N ₂

Equation 6

[0038] A mixture of aryl bromides (10 mmol, 1.0 equiv, listed in Table 4), phenylboronic acid (1.829 g, 15 mmol, 1.5 equiv), Pd(OAc) ₂ (0.0898 g, 0.4 mmol, 0.04 equiv) and H ₂ 0 (25 mL, 1384 mmol) in a 3 -neck round-bottom flask was stirred under reflux at 100 °C in a N ₂ atmosphere for the time listed in Table 4. The initial and final pH values of the aqueous phase was measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 °C. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 °C; the time to reach this temperature was approximately 20 - 30 minutes. The reactions were biphasic with an aqueous phase and a solid phase. The cooled reaction mixture was basified to pH > 12 using 30% NaOH aqueous solution, and then was thoroughly extracted with CHCI ₃ . The combined organic phase was dried over anhydrous MgSC _, filtered, and then concentrated in vacuo. The crude product was analyzed by GC and 1H NMR, as provided in Table 4. [0039]

Table 4

[0040] Example 4. Pd(OAc) ₂ /2-(Di-tert-butyl-phosphino)-l -phenyl- lH-pyrrole (PtB) catalyzed Suzuki reactions of basic nitrogen-containing aryl chlorides with PhB(OH)2 in water in the absence of added base, as shown in Equation 7.

N ₂ , 100 °C

[0041] Equation 7A mixture of aryl chlorides (10 mmol, 1.0 equiv, listed in Table 5), phenylboronic acid (1.829 g, 15 mmol, 1.5 equiv), Pd(OAc)2 (as listed in Table 5), PtB (as listed in Table 5) and ¾0 (25 mL, 1384 mmol) in a 3-neck round-bottom flask was stirred under reflux at 100 °C in a N2 atmosphere for the time listed in Table 5. The initial and final pH values of the aqueous phase was measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 °C, as reported in Table 5. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 °C; the time to reach this temperature was approximately 15-20 minutes. The cooled reaction mixture was basified to pH > 12 using 30% NaOH aqueous solution, and then was thoroughly extracted with organic solvent (chloroform for aliphatic amine-containing substrates and ethyl acetate for aminopyridine substrates). The combined organic phase was dried over anhydrous MgSC _, filtered, and then concentrated in vacuo. The crude product was analyzed by GC and ^! Η NMR, as provided in Table 5.

Table 5

lyltrifluoroborate without added base in water, as shown in Equation 3

Equation 8

[0043] A mixture of 4-amino-2-bromopyridine (1.730 g, 10 mmol, 1.0 equiv), potassium phenyltrifluoroborate (2.760 g, 15 mmol, 1.5 equiv), Pd(OAc) ₂ (0.0898 g, 0.4 mmol, 0.04 equiv) and ¾0 (25 mL, 1384 mmol) in a 3-neck round-bottom flask was well stirred under reflux at 100 °C in a N ₂ atmosphere for 4 h. The initial and final pH values of the aqueous phase were measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 °C. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 °C; the time to reach this temperature was approximately 20 - 30 minutes. The reaction was biphasic with an aqueous phase and a solid phase. The cooled reaction mixture was basified to pH > 12 using 30% NaOH aqueous solution, and then thoroughly extracted with ethyl acetate. The combined organic phase was dried over anhydrous MgS0 _4, filtered, and then concentrated in vacuo. The crude product was analyzed by GC, as provided in Table 6.

Table 6

[0044] Example 6. Reaction of 2-bromobenzene with (3-aminophenyl)boronic acid without added base in water, as shown in Equation 3

Equation 9

[0045] A mixture of bromobenzene (1.570 g, 10 mmol, 1.0 equiv), 3-aminophenylboronic acid (2.054 g, 15 mmol, 1.5 equiv), Pd(OAc) ₂ (0.0898 g, 0.4 mmol, 0.04 equiv) and H ₂ 0 (25 mL, 1384 mmol) in a 3-neck round-bottom flask was well stirred under reflux at 100 °C in a N ₂ atmosphere for 4 h. The initial and final pH values of the aqueous phase were measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 °C. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 °C; the time to reach this temperature was approximately 20 - 30 minutes. The reaction was triphasic: an aqueous phase, an organic phase, and a solid phase (catalyst). The cooled reaction mixture was basified to pH > 12 using 30% NaOH aqueous solution, and then thoroughly extracted with dichloromethane. The combined organic phase was dried over anhydrous MgSC^ _, filtered, and then concentrated in vacuo. The crude product was analyzed by GC, as provided in Table 7.

Table 7