WO2018106336A1

WO2018106336A1 - Mono-ligated palladium catalyts, their synthesis and use in suzuki coupling

Info

Publication number: WO2018106336A1
Application number: PCT/US2017/055736
Authority: WO
Inventors: Chunming Zhang; Kelli A. OGAWA; Siyu TU; James W. Ringer; Christopher W. Derstine
Original assignee: Dow Global Technologies LLC
Current assignee: Dow Global Technologies LLC
Priority date: 2016-12-06
Filing date: 2017-10-09
Publication date: 2018-06-14
Anticipated expiration: 2019-06-06

Abstract

The invention is certain mono-ligated palladium catalysts that are easy to synthesize and are effective in Suzuki coupling reactions. The mono-ligated catalysts comprise a ring structure having a substituent group with a nitrogen atom adjacent the ring structure and an oxygen atom associated with the palladium atom.

Description

MONO-LIGATED PALLADIUM CATALYSTS, THEIR SYNTHESIS

AND USE IN SUZUKI COUPLING

FIELD OF THE INVENTION

[001] This invention relates generally to palladium catalysts and their method of manufacture.

INTRODUCTION

[002] Transition metal (e.g. palladium, nickel, or platinum) catalyzed reactions of aryl halide (iodide, bromide, chloride), and aryl pseudohalides (e. g. triflate, tosylate, mesylate, fluorosulfonate) with various substrates is a general method employed for the formation of C-C, C-N, C-0 bonds, which plays an important role in synthesis of fine chemicals, agricultural and pharmaceutical products, and advanced materials. The activity of transition metal catalysts is greatly influenced by the structural features and the number of associated ligands to the metal. Mono-ligated Pd(0) catalysts, bearing one bulky and electron-rich ligand, have been demonstrated to be effective. Mono-ligated Pd(0) catalysts have been generated in situ from mono-ligated palladium (II) precatalysts, such as the biphenyl palladacycle precatalyst described in prior art WO2013/184198 Al by Buchwald, and the mono-ligated allylpalladium (II) complex described in prior art WO2011161451 Al by Colacot. See also Chen et. al, Tri(l-adamantyl)phosphine: Expanding the Boundary of Electron-Releasing Character Available to Organophosphorous Compounds, J. Am. Chem. Soc. 2016, 138, 6392-6395.

SUMMARY OF INVENTION

[003] The present inventors have discovered mono-ligated palladium catalysts that are easy to synthesize and are effective in Suzuki coupling reactions.

[004] Thus, according to one aspect, the invention is a composition comprising a

compound of formula I

Formula I

wherein X is an anion, L is a ligand,

Y is OR₆ where R₆ is alkyl or aryl, or Y is NR₇Rs wherein R₇, Rs are each independently, H, alkyl, aryl; and

Ri - R₄ are each independently, H, alkyl, aryl, alkoxy, aryloxy; Ri and R2, R2 and R3, or R3 and R₄ form a cycle; and

R5 is H, alkyl, or aryl.

[005] A method for making the compound of formula I comprising reacting formula III in a solvent with a Pd(II) source and an acid (HX) at a temperature in the range of 0 °C to 100 °C and then reacting Formula II with two ligands, L, at 0 °C to 40 °C in a polar aprotic

Formula III Formula II Formula I

[006] A method comprising reacting an aryl halide or pseudohalide with an organoboron compound in the presence of compound of Formula I.

Detailed Description

The Precatalyst of the Invention

[007] For the precatalysts of Formula I, preferably Ri - R₄ are selected from hydrogen, alkyl, and alkyloxy, where the alkyl and alkyloxy, preferably have from 1 to 20, more preferably 1 to 10, and most preferably 1-6 carbon atoms. R5 is preferably selected from hydrogen and alkyl (of preferably 1 to 20, more preferably 1 to 10, and most preferably 1-6 carbon atoms).

[008] In certain embodiments, the precatalyst has the formula 1-1 (An embodiment of Formula I, wherein Y = OR₆ , R₆ is alkyl or aryl, preferably of 1 to 20, more preferably 1 to 10, and most preferably 1-6 carbon carbon atoms, and Ri - R5 are as defined above and X and L are as defined herein):

1-1

[009] In certain embodiments, the precatalyst has Formula 1-2 (An embodiment of Formula I, wherein Y = NR₇Rs and Ri - R₅ are as defined above, and X and L are as defined herein):

1-2

Preferably, R₇ and Rs are hydrogen and alkyl groups (preferably of 1 to 20, more preferably 1 to 10, and most preferably 1-6 carbon atoms). R₇ and Rs may by alkyl groups which combine to form a cyclic group.

[0010] In certain embodiments, the precatalyst has Formula 1-3 (An embodiment of Formula I and Formula 1-1, wherein Ri, R2, R4, and R5 are H and Y = OR₆, R3 and R₆ are as defined above and X and L are as defined herein)

1-3

[0011] In certain embodiments, the precatalyst has Formula 1-4 (An embodiment of Formula I and Formula 1-2, wherein Ri, R2, R₄, and R5 are H and Y =NR₇Rs and R₇, Rs, X, and L are as defined herein)

1-4 [0012] In certain embodiments, the precatalyst has Formulae 1-5 or 1-6 (Embodiments of Formula I and Formula 1-1 and where Ri, R2, R₄, and R5 are H, R3 is as shown, and Y is OR₆ and R₆ is as defined above, and X and L are as defined herein)

1-5 1-6

[0013] In certain embodiments, the precatalyst has Formulae 1-7 or 1-8 (embodiments of

Formula I and Formula 1-2 wherein Ri, R2, Rt, and R5 are H, R3 is as shown (methyl, Me, in

1-8), Y is NR7R8 and R7 and Rs are as defined above, and X and L are as defined herein)

1-7 1-8

[0014] In certain embodiments, the precatalyst has Formulae 1-9 or I- 10 (subspecies of

Formulae 1-5 and 1-6 where R₆ is ethyl, Et, and X and L are as defined herein)

1-9 1-1 0

[0015] In certain embodiments, the precatalyst has Formulae 1-11 or 1-12 (subspecies of Formula 1-7 and 1-8 where R₇ and Rs are methyl ("Me"))

1-1 1 '-^{1 2}

-5- 17] Specific preferred species of precatalysts include those selected from the group of

6 7

The Ligand and Anion

[0018] The precatalyst of this invention can contain any of a variety of known ligands. Among the preferred ligands are trialkylphosphine, triarylphosphine, dialkylarylphosphine, alkyldiarylphosphine, bis(phosphine), phosphoramide, or N-heterocyclic carbene.

The ligands may be selected from the group consisting of triphenylphosphine (PI13P), tri-t- butylphosphine(P(t-Bu)3), tricyclohexylphosphine (P(Cy)3) , tri(o-tolyl)phosphine( P(o- tol)₃), (+)-2,2'-Bis(diphenylphosphino)- 1 , 1 '-binaphthalene((+)-BINAP), 1,1'-

XantPhos

Johnphos Sphos RuPhos DavePhos

-7-

-8-

where Me is methyl, i-Pr is isopropyl, Cy is cyclohexyl, tBu is t-butyl, Ad is adamantyl, Xi is N or CH, R is alkyl, cycloalkyl or aryl of 1-20, preferably 1-10, more preferably 1-6 carbon atoms.

R^x is alkyl (such as butyl, adamantyl (Ad), benzyl, aryl

N-heterocyclic carbene, selected from imidazoline-2- lidenes of the formula

• ·

or protonated salts thereof (which generate imidazoline-2-ylidenes in the presence of a base), wherein Ar is an aryl, R' and R", each are independently, hydrogen, halo, alkyl, or aryl. R' and R" are structures

[0019] The anion X may be any anion but is preferably selected from group consisting of halide, alkylcarboxylate, boron tetrafluoride, tetraarylborates (such as B(C6H₅)4^", and (B[3,5-(CF3)2C6H3]₄)^"), alkylsulfonate, haloalkylsulfonate, and arylsulfonate. According to one preferred embodiment, the anion is a halide selected from fluoride, chloride, bromide or iodide. According to another preferred embodiment, X is alkylcarboxylate, and the alkyl is substituted or unsubstituted alkyl of 1 to 12 carbon atoms. Suitable substituents include halides (fluoro, chloro) and alkoxyl, aryloxyl, cyano, nitro, carbonyl. X may be acetate. X may be a haloalkylcarboxylate such as triflouroacetate (TFA) or trichloroacetate.

[0020] According to another embodiment X is alkylsulfonate, cycloalkyl or arylsulfonate, and the alkyl is a substituted or unsubstituted alkyl of 1 to 4 carbon atoms and the aryl may be a substituted or unsubstitued aryl of preferably 6 to 12 carbon atoms. X may be methylsulfonate, ethylsulfonate, methylphenylsulfonate or p-toluenesulfonate (TsO ). Suitable substituents include halides and alkoxyl, aryloxyl,cyano, nitro, carbonyl. X may be fluoroalkylsulfonate, such as trifluoromethylsulfonate (TfO ), nonafluorobutane sulfonate (NfO-).

Method of Making Precatalysts

[0021] In certain emodiments, the invention relates to a method of making any one of the aforementioned precatalysts, according to Scheme 1 from a palladacycle dimer of Formula II

Formula II

Scheme 1

[0022] Preferably the above reaction is run in a polar aprotic solvent such as

tetrahydrofuran (THF) or methylene chloride (CH2CI2). Conditions for the reaction may be in the range of 0 °C to about 40 °C. The reaction should be allowed to run until substantially complete which may occur in the range of 30 minutes to 20 hours. It is preferable to perform the reactions under an inert atmosphere using a gas such as nitrogen or argon.

[0023] The dimers of Formula II may be obtained from any known source or may be made according to Scheme 2

Formula II

Scheme 2 wherein the substrate of Formula III is obtained from a commercial source or prepared by known methods; X, Ri - R₅, and Y are defined above. The Pd(II) source may be any known suitable source but is preferably palladium acetate (Pd(OAc)2). The solvent may be a non- polar or a polar aprotic solvent. Preferred solvents are toluene, methylene chloride, THF, or 1,4-dioxane. The reaction in scheme 2 takes place at 20 °C to about 100 °C. The reaction is typically complete after about 30 minutes to 20 hours.

Methods/Application of the Invention Suzuki Coupling

[0024] This invention also relates to the application of any one of the aforementioned precatalysts in Suzuki-Miyaura cross-coupling reactions of Scheme 3:

precatalyst

~^X1 + Ri o-B^ *^■ R9-R10

solvent

organoboron tepmerature

Scheme 3

wherein,

the precatalyst is any one of the aforementioned precatalysts;

R9 is aryl, heteroaryl, alkyl, or alkenyl

Xi is I, Br, CI, or sulfonate (such as triflate, nonflate, tosylate, mesylate, fluorosulfonate);

Rio is aryl, alkenyl, or alkyl, preferably of from 1 to 20, more preferably 1 to 10, and most preferably 1-6 carbon atoms ;

i_{s a} boron functional group, which is preferably selected from a group consisting of boronic acid, boronic ester (e.g. boronic acid binacol ester (BPin)), potasium trifluoroborate (-BF3K), N-methyliminodiacetic acid boronate (BMIDA), etc. [0025] An embodiment of this invention provides a process which comprises mixing, in a liquid medium, i) at least one base; ii) at least one aryl halide or aryl pseudohalide (as defined below) in which all substituents are other than boron functionalized groups, wherein the aryl halide has, directly bonded to the aromatic ring(s), at least one halogen atom selected from the group consisting of a chlorine atom, a bromine atom, and an iodine atom, wherein aryl pseudohalide has, directly bonded to the aromatic ring(s), at least one pseudohalide group selected from sulfonates consisting of triflate (OTf), tosylate (OTs), nonflate, mesylate (OMs), and fluorosulfonate (SO2F); iii) at least one organoboron compound selected from arylboronic acid, arylboronic ester, aryltrifluoroborate, aryl-9- BBN (9-BBN refers to 9-borabicyclo[3.3.1]nonane), aryl-BMIDA, alkylboronic acid, alkylboronic ester, alkyl-9-BBN in which all substituents are other than chlorine atoms, bromine atoms, iodine atoms, or pseudohalide groups; iv) at least one of the aforementioned precatalysts, or in situ generated one of the aforementioned precatalysts via mixing of any one of aforementioned dimers and any one of the aforementioned ligands.

[0026] The liquid medium for the processes in this invention can include any of a wide range of solvents, and mixtures of solvents are also usable. The types of solvents that can be used include hydrocarbons, ethers, amides, ketones, alcohols, nitriles (acetonitrile), dimethyl sulfoxide, and water. Polar solvents are preferred. Ethers that may be used include, for example, 1 ,4-dioxane, tetrahydrofuran, glyme, diglyme.

[0027] A large variety of bases are suitable for the processes in this invention. Generally, these are inorganic bases. Alkali metal salts are a preferred group of inorganic bases.

Examples of suitable alkali metal salts include, but are not limited to, sodium acetate, sodium bicarbonate, sodium carbonate, sodium tert-butoxide, sodium hydroxide, potassium bicarbonate, potassium carbonate, potassium phosphate, potassium hydroxide, potassium tert-botoxide, cesium bicarbonate, and cesium carbonate. Alkali metal salts of carboxylic acid anions (e.g., acetate) are also suitable for use as an inorganic base in this invention. Amines (e.g. triethylamine, pyridine) are also suitable for use as a base in this invention. Choice(s) of base will vary with the particular system of aryl halide or pseudohalide and organoboron compound involved.

[0028] The aryl halide or pseudohalide has at least one halogen atom directly bonded to the aromatic ring(s) selected from a chlorine atom, a bromine atom, and a iodine atom, or at least one pseudohalide group. The term "pseudohalide group" includes such groups as arylsulfonate (e.g., p-toluenesulfonate (tosylate)), alkylsulfonate (e.g., methanesulfonate, OMs; trifluoromethanesulfonate (triflate)), and fluorosulfonate. The aryl moiety for the aryl halide or pseudohalide can be homocyclic or heterocyclic. Examples of suitable homocyclic aryl moieties include, but are not limited to benzene, naphthalene, anthracene,

phenanthrene, pyrene, biphenyl, fluorine and indene. Heterocyclic aryl moieties that can be used include, for example, furan, thiophene, oxathiolane, nitrogen-containing heterocycles, such as pyridine, indole, and isoxazole, and the like.

[0029] The organoboron compond in this invention is selected from aryl organoboron compounds, alkenyl organoboron compounds, and alkyl organoboron compounds. Suitable aryl organoboron compounds include arylboronic acid, arylboronic ester, aryl-BMIDA, aryltrifluoroborate, the aryl moieties are homocyclic or heteroyclic. Corresponding alkenyl and alkyl boron compounds may also be used in this invention.

[0030] Suitable reaction temperature ranges are from 0 - 200 °C, preferably 20 - 80 °C.

[0031] An embodiment of this invention is the Suzuki coupling of aryl halide/pesudohalide and aryl boron compound to generate biaryl compounds, illustrated in Scheme 3a

Precatalyst

Ar— X Ar-|— B; base

+ Ar-Ar

solvent

temaperature

Scheme 3 a wherein, Ar, Ari are each, independently, aryl groups (homocyclic or heterocyclic). The other components and reaction conditions are as discussed above.

[0032] The second embodiment of this invention is the Suzuki coupling of aryl

halides/pseudohalides and alkyl boron compounds, illustrated in Scheme 3b

Precatalyst

Ar— X . Ri i-E< ½_s_e_- - Ar— R

^{+ ¾} solvent ¹

temaperature

Scheme 3b

Wherein, Ar is aryl groups (homocyclic or heterocyclic), Rn is an alkyl group, which can be non-cyclic or cyclic. The other components and reaction conditions are as discussed above.

[0033] The third embodiment of this invention is the Suzuki coupling of alkyl

halides/pseudohalides and alkyl boron compounds, illustrated in Scheme 3c Precatalyst

X R B base

+ solvent

temaperature

Scheme 3c

wherein, R12 and R13 are each, independently, alkyl groups or cycloalkyl groups. The other components and reaction conditions are as discussed above.

Examples

General Procedure A for the Preparation of Palladacycle Dimers of Formula II

[0034] A flask (e.g. 20 mL) equipped with a magnetic stir bar and fitted with a rubber septum is charged with a substrate of Formula III ( e.g. 5 mmol), Pd(OAc)2 ( e.g. 5 mmol), and a solvent (5 mL). After stirring for 5 min at room temperature, an acid HX (such as e.g. trifluoroacetic acid (TFA), /?ara-toluenesulfonic acid monohydrate (TsOH),

methanesulfonic acid (MsOH), or trifluoromethanesulfonic acid (TfOH), 5 mmol)) is added. The mixture is stirred at room temperature until the reaction was deemed complete (30 min to 20 h) by H-NMR analysis. The mixture is then either filtered or precipitated with methyl t-butyl ether and then filtered, rinsed with methyl t-butyl ether and hexane, and dried to afford the desired palladacycle dimer.

Example 1- Di^-tosyloxy-bis(3,3-dimethylureido-m-tolyl-2C,0)dipalladium (II) (1)

[0035] Following substantially General Procedure A, compound 1 below was made by reacting N,N-dimethyl-N'-m-tolylurea and p r -toluenesulfonic acid monohydrate in the presence of 1,4-dioxane and Pd(OAc)2 at ambient temperature for about 2 hours. Compound 1 was obtained as a yellow solid in 94% yield. ^!H-NMR (400 HMz/DMSO-d₆) δ 9.41 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7. 11 (d, J = 8.4 Hz, 2H), 6.88 (s, 1H), 6.74 (br, d, J = 8.0 Hz, 1H), 3.57 (s, 8 H, see note), 3.11 (s, 6 H), 2.29 (s, 3H), 2.23 (s, 3H). Note: The compound contains two 1,4-dioxane groups.

1

Example 2- Di^-tosyloxy-bis(2-ethoxycarbonylamino-m-tolyl-2C,0)dipalladium (II) (2) [0036] Following substantially General Procedure A, compound 2 below was made by reacting ethyl m-tolylcarbamate and p r -toluenesulfonic acid monohydrate in the presence of 1,4-dioxane and Pd(OAc)2 at ambient temperature for about 18 hours.

Compound 2 was obtained as a green solid in 62% yield. Ή-ΝΜΡν (400 HMz/DMSO-d₆) δ 10.64 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7. 11 (d, J = 8.0 Hz, 2H), 6.88 (s, 1H), 6.76 (br, d, J = 8.0 Hz, 1H), 4.34 (q, J = 6.8 Hz, 2H), 3.57 (s, 8 H, see note), 3.11 (s, 6 H), 2.29 (s, 3H), 2.22 (s, 3H), 1.33 (t, J = 6.8 Hz, 3H). Note: The compound contains two 1,4-dioxane groups.

2

General Procedure B for Preparation of mono-ligated arylpalladacycle Precatalysts of Formula I

[0037] A flask (e.g. 25 mL) equipped with a magnetic stir bar, a nitrogen pad, and a rubber septum is charged with a palladacycle dimmer of Formula II (e.g. 0.5 mmol) and a solvent, such as THF (e.g. 5 mL) under nitrogen atmosphere. A ligand (1.0 mmol) in a solution or neat is then added. The mixture is stirred at room temperature until the reaction is deemed complete (30 min to 20 h) by H-NMR or ³¹P-NMR analysis. When the product precipitates out from the mixture, hexane (10 mL) is added to the reaction mixture and stirred for 10 min. The mixture is filtered, rinsed with hexane, and dried to afford the desired mono- ligated palladacycle precatalyst. If product does not precipitate, the solvent is evaporated under reduced pressure. The resulting residue is tritrated with hexane, filtered, rinsed with hexane, and dried to afford the desired mono-ligated palladacycle precatalyst.

Example 3- (Tosyloxy)(3,3-dimethylureido-m-tolyl-2C,0)(tri-t-butylphophosphine)palladium (ID (3)

[0038] Following substantially General Procedure B, compound 3 below was made. Thus, to a 100 mL flask charged with the palladacycle dimmer 1 (2.0 mmol) and degassed THF (20 mL) was added a solution of 1.0 M tri-t-butylphosphine (4.0 mL, 4.0 mmol). The mixture was stirred at ambient temperature for 2 h. The resulting slurry was diluted with hexane (40 mL), filtered, rinsed with hexane (20 mL), and dried in a vacuum oven at reduced pressure to give the desired precatalyst as a yellow solid (2.43 g, 92% yield). ¾- NMR (400 HMz/CDCh) δ 9.71 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.32 (br, 1H), 7. 11 (d, J = 8.4 Hz, 2H), 7.01 (m, 1H), 6.48 (br, d, J = 8.0 Hz, 1H), 3.17 (s, 3H), 2.33 (s, 3H), 2.37 (s, 3H), 1.50 (d, J = 12.8 Hz, 27H).³¹P-NMR (CDCb) δ 69.46.

Example 4- (Tosyloxy)(3,3-dimethylureido-m-tolyl-2C,0)(tri-cyclohexylphosphine)palladium (ID (4)

[0039] Following substantially General Procedure B, compound 4 below was made. Thus, a 25 mL flask equipped with a magnetic stir bar and a septum under nitrogen atmosphere was charged with the palladacycle dimmer 1 (0.50 mmol) and degassed THF (5 mL). Then tricyclohexylphosphine (280 mg, 1.0 mmol) was added. The mixture was stirred at ambient temperature for 2 h, resulting in a brown solution. The reaction mixture was concentrated under reduced pressure to approximately 2 mL. Hexane (10 mL) was added to precipitate out the product, which was filtered, rinsed with hexane (10 mL),and dried in a vacuum oven at reduced pressure to give the desired precatalyst as a yellow solid (0.68 g, 92.5% yield). ¾-NMR (400 HMz/CDCh) δ 7.82 (d, J = 8.0 Hz, 2H), 7. 12 (d, J = 8.0 Hz, 2H), 6.98 (m, 2H), 6.60 (d, J = 7.8 Hz, 1 H), 6.46 (br s, 1H), 3.14 (s, 6H), 2.33 (s, 3H), 2.18 (s, 3H), 2.08 (m, 3H), 0.98-1.88 (m, 30H); ³¹P-NMR (CDCb) δ 42.78.

Example 5- (Tosyloxy)(3,3-dimethylureido-m-tolyl-2C,0)(amphos)palladium (II) (5)

[0040] Following substantially General Procedure B, compound 5 below was made. The palladacycle 1 (0.50 mmol), amphos (265 mg, .0 mmol), and degassed THF (5 mL) was added into a round bottom flask under nitrogen. The mixture was stirred at ambient temperature. The slurry gradually became a dark brown solution in a few minute, and then turned into a thick slurry with off-gray solid. The mixture was diluted with THF (5 mL) and was continued to stir for 2 h at ambient temperature. Hexane (10 mL) was added and stirred for 5-10 min. The resulting solid was filtered, rinsed with hexane (10 mL), and dried in a vacuum oven at 40-45 °C to give the desired precatalyst as an off-white solid (0.72 g, 99.9% yield). Ή-ΝΜΡν (400 HMz/CDCh) δ 7.79 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.94 (br s, H), 6.47 (d, J = 8.0 Hz, 2H), 6.40 (s, 1H), 6.08 (d, J = 8.0 Hz, 1H), 3.20 (s, 6H), 2.94 (s, 6H), 2.33 (s, 3H), 2.03 (s, 3H), 1.32 (d, J 14.0 Hz, 18H); ³¹P-NMR (CDCh) δ 68.42.

5

Example 6- (Tosyloxy)(3,3-dimethylureido-m-tolyl-2C,0)(IPr)palladium (II) (6)

[0041] Following substantially General Procedure B, compound 6 below was obtained as a gray solid in 94% yield from palladacycle dimer 1 and IPr in. In a 25-mL flask was added palladacycle dimer I (0.445 g, 0.82 mmol), IPr (0.34 g, 0.875 mmol), and THF (5 mL). The mixture was stirred at ambient temperature under nitrogen overnight. Hexane (10 mL) was added and stirred for 10 min. The solid was collected by filtering, rinsing with hexane, and drying at reduced pressure. It gave 0.65 g (94% yield) of product as a gray solid.

Example 7-Tosyloxy-(2-ethoxycarbonylamino-m-tolyl-2C,0)(tri-t-butylphosphine)palladium (ID (7)

7

[0042] Following substantially General Procedure B, compound 7 was obtained as yellow solid in 98% yield from palladacycle dimer 2 and tri-tert-butylphosphine in THF. Into a 25- mL flask was added palladacycle dimer 2 (0.5 mmol) and THF (5 mL). Then a solution of 1.0 M t-Bu3P in toluene (1.0 mL, 1.0 mmol) under nitrogen was added. The mixture was stirred at ambient temperature for 2 h, resulting in a brown solution. The reaction mixture was concentrated under reduced pressure to approximately 2 mL. Hexane (10 mL) was added to precipitate out the product, which was filtered, rinsed with hexane (10 mL), and dried in a vacuum oven at reduced pressure to give the desired precatalyst (0.65 g, 98% yield). ^-NMR (400 HMz/CDC13) δ 7.82 (d, J = 8.0 Hz, 2H), 7.80 (br s, 1H), 7.40 (br s, 1H), 7. 21 (d, J = 8.0 Hz, 2H), 7.12 (m, 1H), 6.54 (d, J = 7.8 Hz, 1 H), 4.22 (q, J = 7.2 Hz, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 1.49 (d, J = 13.2 Hz, 27H), 1.31 (t, J = 7.2 Hz,3H).

Example 8 - Suzuki Coupling Reactions

General Procedure C for the Suzuki Coupling of lboronic Acid

Pd precatalyst

Base, solvent,

temperature

[0043] In a flask (e.g. 25 mL tube flask) equipped with a stir bar anda nitrogen pad was added an aryl halide (e.g. 1.0 mmol), an arylboronic acid (e.g. 1.1 mmol, 1.1 equiv.), octadecanol (internal standard, e.g. 0.50 mmol, 0. 50 equiv.), an organic solvent (e.g. 5 mL), water (e.g. 1 mL), and a base (e.g. 2.2 mmol, 2.20 equiv.). The mixture was purged with nitrogen (e.g. for 10 min), then a palladacycle precatalyst (e.g. 1 - 3 mol%) was added and the resulting mixture was stirred under nitrogen at the temperature indicated in the table below until the reaction was deemed complete by H NMR analysis. Aliquots (-0.05 mL) were immediately diluted with CDCb and analyzed by H NMR spectroscopy to determine the conversion and yield (yield was determined against the internal standard,

octadecanol). Table 1 shows data for Suzuki couplings conducted according to the scheme above using the stated precatalysts. Entries 6, 8, and 9 are comparative. Tables 2 and 3 show data for Suzuki couplings conducted according to the scheme above using precatalyst 3.

Table 1. Suzuki coupling of p-chlorotoluene and phenyl boronic acid with different palladacycle precatalysts.

Entry Pd Precatalyst yield³

1 3 91 %

2 4 55%

3 5 31 %

4 6 95 %^b

5 7 36%

6 tBusP-Pd-amide 81 %

8 tBu₃P-Pd-G2(Buchwald) 89%

9 Pd(OAc)₂ PtBu₃(l :l) 0%

"Yields were determined by H NMR spectroscopy usin;

an internal standard and are the average of 2 runs.

bRun for 20 minutes using 1 mol% precatalyst.

Table 2. Aryl Halide screen for Suzuki coupling using precatalyst

Entry Aryl Halide yield³

1 4-c loro toluene 89%

2 2-chlorobenzonitrile 95%

3 4-chloroanisole 85%

4 2-chloro toluene 81 %

5 2,6-dimethyl-chlorobenzene 59%^b

6 4-bromotoluene 90%^c

7 4-bromoanisole 94%^c

"Yields were determined by H NMR spectroscopy an internal standard and are the average of 2 runs.

bData is from a single run.

cRun for 20 min.

Table 3. Results of Suzuki coupling of different arylboronic acid using precatalyst 3.

Entry Arylboronic Acid yield³

1 Phenyl boronic acid 89%

2 4-tolyl boronic acid 83%

3 Naphthalene boronic acid 90%

4 2-methylphenyl boronic acid 81 %

5 2,4,6-trimethylphenyl boronic acid 43 %^b

"Yields were determined by H NMR spectroscopy using an

internal standard and are the average of 2 runs.

bData is from a single run.

Commonly used solvents tetrahydrofuran (THF), 1 ,4-dioxane, toluene, acetonitrile, and alcohols (methanol, ethanol, and isopropanol) were tested. THF/water and toluene/water solvent systems gave poor yields (<20%). 1,4-dioxane/water and acetonitrile/water, gave similar low yields. A noticeable increase in yield was observed when alcohol solvents were used. Ultimately, ethanol/water proved to be the best solvent system, giving an 89% yield after 1 h. After determining that the best solvent system was ethanol/water (5:1), various inorganic bases were screened to find the optimal base. The base screen showed that CS2CO3 was the most effective base, giving 89% yield in 1 h. The use of K2CO3 also resulted in good yields (63%). However, tripotassium phosphate (K3PO4) and sodium hydroxide (NaOH) resulted in poor yields.

Claims

WHAT IS CLAIMED IS:

1. A composition comprising a compound of Formula I

Formula I

wherein X is an anion,

L is a ligand,

Y is OR₆ where R₆ is alkyl or aryl, or Y is NR7R8 wherein R7, Rs are each independently, H, alkyl, aryl, or R7, Rs combine to form a cycle group; and

Ri - R₄ are each independently, H, alkyl, aryl, alkoxy, aryloxy, or Ri and R2, R2 and

R3, or R3 and R4 form a cycle group; and

R5 is H, alkyl, aryl.

2. The composition according to claim 1 wherein Y is NR₇Rs and R₇, Rs are

independently H, alkyl of 1 to 20 carbon atoms, or R₇, Rs combine to form a cycle group.

3. The composition according to claim 1 whereinY is OR6 where R₆ is alkyl of 1 to 4 carbon atoms.

4. The composition according to claim 2 wherein R₇ and Rs are methyl.

5. The composition according to any one of claims 1-4 wherein Ri, R2, R3, R4 are independently, alkyl, alkoxyl, of 1 to 20 carbon atoms, or H, provided at least one of Ri, R2, R3, R4 is alkyl or alkoxyl.

6. The composition according to claim 5 wherein Ri, R2, and R4 are H and R3 is methyl or methoxy.

7. The composition according to any one of claims 1-4 wherein Ri, R2, R3, R4 are H.

8. The composition according to any one of claim 1-7 wherein R5 is H or alkyl of 1 to 20 carbon atoms.

9. The composition according to any one of claim 1-7 wherein L is selected from

trialkylphosphine, dialkylarylphosphine, alkyldiarylphosphine, and N-heterocylic carbene.

10. The composition of claim 8 wherein L is tri-t-butylphospine.

11. The composition according to any one of claims 1-9, wherein X is selected from the group consisting of boron tetrafluoride, tetraarylborates; hexafluoroantimonate, phosphorus tetrafluoride, phosphorus hexafluoride, alkylsulfonate,

haloalkylsulfonate, arylsulfonate, perchlorate, bis(alkylsulfonyl)amide,

bis(fluoroalkylsulfonyl)amide, bis(arylsulfonyl)amide,

(fluoroalkylsulfonyl)(fluoroalkylcarbonyl)amide, nitrate, nitrite, sulfate, hydrogensulfate, alkylsulfate, aryl sulfate, carbonate, carboxylate, phosphate, hydrogen phosphate, dihydrogen phosphate, phosphinate, and hypochlorite.

12. A process for making the compound of any one of claims 1-10 comprising the

reaction of Formula III in a solvent with a Pd(II) source and an acid, HX, at a

Formula III Formula II

wherein Y is OR₆ where R₆ is alkyl or aryl, or Y is NR₇Rs wherein R₇, Rs are each independently, H, alkyl, aryl, or R₇, Rs combine to form a cyclic group. .

Ri - R₄ are each independently, H, alkyl, aryl, alkoxy, aryloxy; Ri and R2, R2 and

R3, or R3 and R₄ may form a cycle;

R5 is H, alkyl, aryl; and X is an anion

and then reacting Formula II with ligand, L, at 0 ⁰ to 40 °C in a polar aprotic solvent to form the compound of any one of claims 1-11 .

13. A process comprising reacting an aryl or alkyl halide or aryl or alkyl or sulfonate with an organoboron compound in an organic solvent/water system in the presence of base and a composition of any of claims 1-12.

14. The process of claim 13 wherein an aryl halide or aryl sulfonate is reacted with the organoboron compound which has the formula ¹⁰ where is a boron functional group, selected from a group consisting of boronic acid, boronic ester, potasium trifluoroborate, and N-methyliminodiacetic acid boronate, and R10 is an aryl group.