BIARYL LIGANDS FOR TRANSITION METAL-CATALYZED REACTIONS

Abstract

In one embodiment, the present application discloses ligands of the formula A, wherein the variables are as described herein, and methods for using the ligands in cross-coupling reactions in organic and polar media:

##STR00001##

Claims

1. A ligand of the formula A: ##STR00049## wherein: X is selected from OR.sup.1 or NRR where R and R is independently selected from the group consisting of H, C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and C.sub.4-12heteroaryl; X is selected from OR.sup.3 or NRR where R and R is independently selected from the group consisting of H, C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and C.sub.4-12heteroaryl; each R.sup.1 and R.sup.3 is independently selected from a group consisting of C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and C.sub.4-12heteroaryl; R.sup.2 is selected from the group consisting of C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and substituted C.sub.6-14aryl and C.sub.4-12heteroaryl; R.sup.4 is H or is selected from the group consisting of OC.sub.1-10alkyl, C.sub.1-10alkyl, C.sub.3-6cycloalkyl, SR.sup.8, NR.sup.8R.sup.9, C.sub.6-14aryl and C.sub.4-12heteroaryl; each R.sup.5 and R.sup.6 is H or R.sup.5 and R.sup.6 together with the aryl group to which they are attached to form a fused substituted or unsubstituted aromatic ring or heteroaromatic ring; R.sup.7 is H or is selected from the group consisting of OC.sub.1-10alkyl, C.sub.1-10alkyl, SR.sup.8, NR.sup.8R.sup.9, C.sub.6-14aryl and C.sub.4-12heteroaryl; and each R.sup.8 and R.sup.9 is independently H or C.sub.1-10alkyl.

2. The ligand of claim 1, wherein the ligand is of the formula A-1: ##STR00050## wherein: each R.sup.1 and R.sup.3 is independently selected from a group consisting of C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and C.sub.4-12heteroaryl; R.sup.2 is selected from the group consisting of C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and substituted C.sub.6-14aryl and C.sub.4-12heteroaryl; R.sup.4 is H or is selected from OC.sub.1-10alkyl and C.sub.3-6cycloalkyl; each R.sup.5 and R.sup.6 is H or R.sup.5 and R.sup.6 are each independently an aryl or a heteroaryl ring, or R.sup.5 and R.sup.6 together with the aryl group to which they are attached to form a substituted or unsubstituted aromatic ring; and R.sup.7 is H or is selected from the group consisting of OC.sub.1-10alkyl, C.sub.1-10alkyl, SR.sup.8, NR.sup.8R.sup.9, C.sub.6-14aryl and C.sub.4-12heteroaryl.

3. The ligand of claim 1, wherein R.sup.5 and R.sup.6 together form a substituted or unsubstituted aromatic ring or a substituted or unsubstituted heteroaromatic ring.

4. The ligand of claim 1, wherein the ligand is of the formula B or C: ##STR00051## wherein: R.sup.7 is H or is selected from the group consisting of OC.sub.1-10alkyl, C.sub.1-10alkyl, SR.sup.8, NR.sup.8R.sup.9, C.sub.6-14aryl and C.sub.4-12heteroaryl.

5. The ligand of claim 1 selected from the group consisting of A-2 to A-31: ##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057##

6. A catalyst composition comprising: a) organometallic nanoparticles comprising: a nanoparticle (NP) catalyst, prepared by a reduction of an iron salt in an organic solvent, wherein the catalyst comprises at least one other metal selected from the group consisting of Pd, Pt, Au, Ni, Co, Cu, Mn, Rh, Ir, Ru and Os or mixtures thereof; b) a ligand of the formula A: ##STR00058## wherein: X is selected from OR.sup.1 or NRR where R and R is independently selected from the group consisting of H, C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and C.sub.4-12heteroaryl; X is selected from OR.sup.3 or NRR where R and R is independently selected from the group consisting of H, C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and C.sub.4-12heteroaryl; each R.sup.1 and R.sup.3 is independently selected from a group consisting of C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and C.sub.4-12heteroaryl; R.sup.2 is selected from the group consisting of C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and substituted C.sub.6-14aryl and C.sub.4-12heteroaryl; R.sup.4 is H or is selected from the group consisting of OC.sub.1-10alkyl, C.sub.1-10alkyl, SR.sup.8, NR.sup.8R.sup.9, C.sub.6-14aryl and C.sub.4-12heteroaryl; each R.sup.5 and R.sup.6 is H or R.sup.5 and R.sup.6 together with the aryl group to which they are attached to form a substituted or unsubstituted aromatic ring or heteroaromatic ring; R.sup.7 is H or is selected from the group consisting of OC.sub.1-10alkyl, C.sub.1-10alkyl, SR.sup.8, NR.sup.8R.sup.9, C.sub.6-14aryl and C.sub.4-12heteroaryl; and each R.sup.8 and R.sup.9 is independently H or C.sub.1-10alkyl; c) a surfactant; and d) a reaction solvent or a reaction medium; wherein the metal or mixtures thereof is present in less than or equal to 50,000 ppm relative to the iron salt.

7. An aqueous micellar composition for enabling cross-coupling reactions containing organometallic nanoparticles (NPs) as catalyst, comprising: a) an element selected from the group consisting of Fe, C, H, O, Mg, and a halide, or the entire combination thereof; and b) palladium, or at least one other metal selected from the group consisting of Pt, Au, Ni, Co, Cu and Mn, or a mixture thereof; wherein the catalyst (NPs) is prepared from a reduction of an iron salt in a solvent and in the presence of a ligand using a reducing agent; wherein the ligand is of the formula A: ##STR00059## wherein: X is selected from OR.sup.1 or NRR where R and R is independently selected from the group consisting of H, C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and C.sub.4-12heteroaryl; X is selected from OR.sup.3 or NRR where R and R is independently selected from the group consisting of H, C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and C.sub.4-12heteroaryl; each R.sup.1 and R.sup.3 is independently selected from a group consisting of C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and C.sub.4-12heteroaryl; R.sup.2 is selected from the group consisting of C.sub.1-10alkyl, C.sub.3-6cycloalkyl, C.sub.6-14aryl and substituted C.sub.6-14aryl and C.sub.4-12heteroaryl; R.sup.4 is H or is selected from the group consisting of OC.sub.1-10alkyl, C.sub.1-10alkyl, C.sub.3-6cycloalkyl, SR.sup.8, NR.sup.8R.sup.9, C.sub.6-14aryl and C.sub.4-12heteroaryl; each R.sup.5 and R.sup.6 is H or R.sup.5 and R.sup.6 together with the aryl group to which they are attached to form a substituted or unsubstituted aromatic ring or heteroaromatic ring; R.sup.7 is H or is selected from the group consisting of OC.sub.1-10alkyl, C.sub.1-10alkyl, SR.sup.8, NR.sup.8R.sup.9, C.sub.6-14aryl and C.sub.4-12heteroaryl; and each R.sup.8 and R.sup.9 is independently H or C.sub.1-10alkyl.

8. The composition of claim 6, wherein the ligand is of the formula D: ##STR00060## wherein: each R.sup.1 and R.sup.2 is independently a C.sub.1-3alkyl; R.sup.3 is absent or is selected from the group consisting of OC.sub.1-3alkyl, C.sub.1-6alkyl and C.sub.3-6cycloalkyl; and R.sup.4 is absent or is selected from the group consisting of OC.sub.1-3alkyl and C.sub.1-6alkyl.

9. The composition of claim 6, wherein the iron is selected from the group consisting of a Fe(II) or Fe(III) salt, a Fe(II) salt precursor or Fe(III) salt precursor.

10. The composition of claim 6, wherein the palladium is naturally present in the iron salt in amounts less than or equal to 1 ppm, 10 ppm, 50 ppm, 100 ppm, 200 ppm, 300 ppm, 400 ppm or 500 ppm relative to the iron salt or iron complex.

11. The composition of claim 10, where the amount of Pd present is controlled by external addition of a Pd salt to an iron salt.

12.-18. (canceled)

19. The composition of claim 7, wherein the iron is selected from the group consisting of a Fe(II) or Fe(III) salt, a Fe(II) salt precursor or Fe(III) salt precursor.

20. The composition of claim 7, wherein the palladium is naturally present in the iron salt in amounts less than or equal to 1 ppm, 10 ppm, 50 ppm, 100 ppm, 200 ppm, 300 ppm, 400 ppm or 500 ppm relative to the iron salt or iron complex.

Description

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0125] Unless specifically noted otherwise herein, the definitions of the terms used are standard definitions used in the art of organic synthesis. Exemplary embodiments, aspects and variations are illustratived in the figures and drawings, and it is intended that the embodiments, aspects and variations, and the figures and drawings disclosed herein are to be considered illustrative and not limiting.

[0126] An alkyl group is a straight, branched, saturated or unsaturated, aliphatic group having a chain of carbon atoms, optionally with oxygen, nitrogen or sulfur atoms inserted between the carbon atoms in the chain or as indicated. A (C.sub.1-C.sub.20)alkyl, for example, includes alkyl groups that have a chain of between 1 and 20 carbon atoms, and include, for example, the groups methyl, ethyl, propyl, isopropyl, vinyl, allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl and hexa-1,3,5-trienyl. An alkyl group may also be represented, for example, as a (CR.sup.1R.sup.2).sub.m group where R.sup.1 and R.sup.2 are independently hydrogen or are independently absent, and for example, m is 1 to 8 or 1 to 10, and such representation is also intended to cover both saturated and unsaturated alkyl groups.

[0127] An alkyl as noted with another group such as an aryl group, represented as arylalkyl for example, is intended to be a straight, branched, saturated or unsaturated aliphatic divalent group with the number of atoms indicated in the alkyl group (as in (C.sub.1-C.sub.20)alkyl, for example) and/or aryl group (as in (C.sub.5-C.sub.14)aryl, for example) or when no atoms are indicated means a bond between the aryl and the alkyl group. Nonexclusive examples of such group include benzyl and phenethyl.

[0128] An aryl is a monocyclic or polycyclic ring assembly where each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. Examples of aryl rings include phenyl, naphthlyl, anthracenyl and phenanthrenyl. If one or more ring atoms is not carbon such as an N or S, then the aryl is a heteroaryl. C.sub.X aryl and C.sub.X-Y aryl are used where X and Y indicate the number of atoms in the ring.

[0129] An aromatic is a group where the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp.sup.2 hybridized and the total number of pi electrons is equal to 4n+2. An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms, such as a heteroaryl, including pyridine, thiophene, furan, carbazole, indole, isoindole and as defined herein.

[0130] A bicycloalkyl means a saturated or partially unsaturated fused bicyclic or bridged polycyclic ring assembly.

[0131] A bicycloaryl means a bicyclic ring assembly where the rings are linked by a single bond or are fused and at least one of the rings of the assembly is aromatic. A C.sub.Xbicycloaryl and C.sub.X-Ybicycloaryl are used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring. Examples of a bicycloaryl ring include, for example, naphthyl and anthracenyl. A bicycloaryl ring can also be a heterobicyclyl ring where the ring assembly may contain one or more heteroatom such as N or S, such as benzo[b]furan, benzo[b]thiophene, benzimidazole, quinazoline, indolizine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, pteridine, purine, acridine, phenazine and phenoxazine.

[0132] An alkylene group is a straight, branched, saturated or unsaturated aliphatic divalent group with the number of atoms indicated in the alkyl group; for example, a (C.sub.1-C.sub.3)alkylene- or (C.sub.1-C.sub.3)alkylenyl-.

[0133] A cyclyl such as a monocyclyl or polycyclyl group includes monocyclic, or linearly fused, angularly fused or bridged polycycloalkyl or combinations thereof. Such cyclyl group is intended to include the heterocyclyl analogs. A cyclyl group may be saturated, partically saturated or aromatic.

[0134] Halogen or halo means fluorine, chlorine, bromine or iodine.

[0135] A heterocyclyl or heterocycle is a cycloalkyl wherein one or more of the atoms forming the ring is a heteroatom that is a N, O, or S. Non-exclusive examples of heterocyclyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, 1,4-diazaperhydroepinyl and 1,3-dioxanyl.

[0136] Substituted or unsubstituted or optionally substituted means that a group such as, for example, alkyl, aryl, heterocyclyl, (C.sub.1-C.sub.8)cycloalkyl, hetrocyclyl(C.sub.1-C.sub.8)alkyl, aryl(C.sub.1-C.sub.8)alkyl, heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkyl, and the like, unless specifically noted otherwise, may be unsubstituted or, may substituted by 1, 2 or 3 substitutents selected from the group such as halo, NO.sub.2, CF.sub.3, CF.sub.3O, CH.sub.3O, COOH, NH.sub.2, OH, SH, NHCH.sub.3, N(CH.sub.3).sub.2, SMe and cyano.

EXPERIMENTAL

Synthesis of the Ligands:

[0137] The following procedures may be employed for the preparation of the compounds of the present invention. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methods well known to a person of ordinary skill in the art, following procedures described in such references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.

[0138] In some cases, protective groups may be introduced and finally removed. Suitable protective groups for amino, hydroxy, and carboxy groups are described in Greene et al., Protective Groups in Organic Synthesis, Second Edition, John Wiley and Sons, New York, 1991. Standard organic chemical reactions can be achieved by using a number of different reagents, for examples, as described in Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.

[0139] In one variation, a variety of distinct ligands disclosed in the present application can be synthesized by the general steps outlined in Scheme 1.

##STR00030##

[0140] An aryl halide derivative, such as the commercially available compound 1-bromo-2,4-dimethoxybenzene, may be coupled with an aromatic compound under standard Suzuki reaction conditions to provide a bi-aryl intermediate compound. Similarly, the mono-amino analog as well as the 1,3-diaminobenzene analog and its amino-alkyl (NHC.sub.1-10alkyl) and amino-dialkyl (N(C.sub.1-10alkyl).sub.2 derivatives, for example, may be used as starting materials to prepare the corresponding amino derivatives and analogs. Regioselective lithiation under standard conditions provides the lithiated aryl that may be coupled with a phosphorous halide, such as R.sub.2PCl, to provide the Ligand with the desired functionality, depending on the nature of the starting halide, the aryl coupling partner in the Suzuki reaction, as well as the nature of the phosphorous halide.

##STR00031##

[0141] (1) 1-(2,4-Dimethoxyphenyl)naphthalene: An oven dried 5 mL microwave vial with a 10 mm stir bar was charged with naphthalene-1-boronic acid (172 mg, 1.0 mmol) and tribasic potassium phosphate monohydrate (288 mg, 1.25 mmol). The vial was equipped with a septum and subjected to 3 evacuation/argon backfill cycles. 2,4-Dimethoxybromobenzene (0.071 mL, 0.5 mmol) was added to the vial via syringe followed by the addition of a toluene solution (0.1 mL) of Pd(OAc).sub.2 (0.56 mg, 0.0025 mmol) and EvanPhos (1.8 mg, 0.0038 mmol) via syringe. A 2 wt % solution of TPGS-750-M in degassed water (0.9 mL) was added and the reaction was stirred in an oil bath at 40 C. under argon. GC/MS monitoring showed complete consumption of the halide after 90 min. The vessel was cooled to rt and the crude mixture was extracted in flask with EtOAc (31 mL). The combined organic phases were flushed through a short plug of silica gel in a pipette and then washed with EtOAc. Volatiles were removed in vacuo. The mixture was chromatographed over silica gel eluting with 1:9 diethyl ether:hexanes (R.sub.f=0.42, 1:4 diethyl ether:hexanes) to yield a white powder (116 mg, 88%). .sup.1H NMR (500 MHz, chloroform-d) 7.87 (dt, J=8.1, 0.8 Hz, 1H), 7.84 (dt, J=8.4, 1.1 Hz, 1H), 7.61 (dq, J=8.4, 1.0 Hz, 1H), 7.53-7.49 (m, 1H), 7.47-7.43 (m, 1H), 7.40-7.36 (m, 2H), 7.21-7.18 (m, 1H), 6.64-6.60 (m, 2H), 3.90 (s, 3H), 3.68 (s, 3H). .sup.13C NMR (101 MHz, chloroform-d) 160.69, 158.30, 136.87, 133.61, 132.58, 132.38, 128.22, 127.68, 127.59, 126.62, 125.68, 125.62, 125.51, 122.33, 104.36, 98.87, 55.67, 55.59.

##STR00032##

[0142] (L1) Dicyclohexyl(2,6-dimethoxy-3-(naphthalen-1-yl)phenyl)phosphane: A flame dried 100 mL 3-neck round bottom flask containing a magnetic stir bar was charged with biaryl 1 (2.0 g, 7.57 mmol) under a flow of argon. The vessel was evacuated and back-filled with argon 3 times. The vessel was charged with anhydrous THF (35 mL) and stirred until dissolution of the biaryl was visually complete. The vessel was submerged in an ice bath and stirred for 10 min. n-Butyllithium (2.35 M in hexanes, 3.07 mL, 7.21 mmol) was added to the stirring solution dropwise via syringe over 15 min. Upon complete addition of n-butyllithium, the solution was stirred in the ice bath for 30 min. and the vessel was removed and stirring continued for another 30 min. The vessel was re-submerged in an ice bath and chlorodicyclohexyl-phosphine (1.55 mL, 7.04 mmol) was added dropwise via syringe over 10 min. The solution was stirred in the ice bath for 30 min. and the vessel was removed from the ice bath. Stirring was continued at rt for 3 h. The solution was quenched with water (30 mL) and diluted with diethyl ether (100 mL). The phases were separated and the aqueous phase was extracted with diethyl ether (335 mL). The combined organic phases were washed with a solution of 10% sulfuric acid/water (520 mL). The combined acidic phases were mixed with diethyl ether (150 mL) and a saturated solution of sodium carbonate in water was slowly added while gently swirling until gas evolution had ceased. The phases were separated and the aqueous phase was extracted with diethyl ether (250 mL). The ether was dried over anhydrous MgSO.sub.4 and concentrated in vacuo yielding a flocculent white solid (3.22 g, 99%). .sup.1H NMR (400 MHz, chloroform-d) 7.90-7.83 (m, 2H), 7.67 (d, J=8.3 Hz, 1H), 7.55-7.27 (m, 5H), 6.73 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 3.18 (s, 3H), 2.39 (dddt, J=18.4, 11.4, 6.7, 3.4 Hz, 2H), 2.01-1.02 (m, 20H). .sup.13C NMR (101 MHz, chloroform-d) 163.82, 163.68, 163.13, 137.05, 134.05, 133.56, 132.11, 128.01, 127.53, 127.43, 126.36, 126.16, 125.79, 125.60, 125.30, 105.95, 61.15, 55.48, 34.90-34.10 (m), 32.59, 32.35, 31.10-30.22 (m), 27.62-26.95 (m). .sup.31P NMR (162 MHz, chloroform-d) -9.22.

##STR00033##

[0143] (2) 1-(2,4-Dimethoxyphenyl)-2-methoxynaphthalene: A flame dried 250 mL 3-neck round bottomed flask containing a magnetic stir bar was charged with 2-methoxybromonaphthalene (3.56 g, 15.0 mmol), 2,4-dimethoxyphenylboronic acid (5.46 g, 30.0 mmol), and tribasic potassium phosphate monohydrate (8.64 g, 37.5 mmol) under a flow of argon. The vessel was evacuated and backfilled with argon 3 times. A solution of Pd(OAc) (33.7 mg, 0.15 mmol) and L1 (0.104 g, 0.225 mmol) in THF (1.5 mL) was added via syringe to the vessel followed by THF (1.5 mL) and a degassed solution of 2 wt % TPGS-750-M in water (27 mL). The vessel was placed in an oil bath at 35 C. and stirred vigorously. GC/MS and TLC monitoring showed complete consumption of the bromide after 4 h. The crude mixture was transferred to a separatory funnel and extracted with EtOAc (320 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 followed by solvent removal in vacuo. The mixture was chromatographed on silica gel eluting with 1:4 diethyl ether:hexanes (R.sub.f=0.20 1:4 diethyl ether:hexanes). The pure product was collected. The impure fractions were collected separately, concentrated and the product was recrystallized from a 1:1 mixture of EtOAc:hexanes yielding an off-white/gray powder (combined 1.54 g, 70%). .sup.1H NMR (500 MHz, chloroform-d) 7.87 (d, J=9.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.44-7.40 (m, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.34-7.29 (m, 2H), 7.13 (d, J=7.8 Hz, 1H), 6.67-6.63 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.68 (s, 3H). .sup.13C NMR (101 MHz, chloroform-d) 160.38, 158.63, 154.47, 133.97, 132.63, 129.04, 128.90, 127.80, 126.03, 125.31, 123.33, 121.77, 117.67, 114.10, 104.40, 99.03, 56.93, 55.66, 55.34.

##STR00034##

[0144] Dicyclohexyl(2,6-dimethoxy-3-(2-methoxynaphthalen-1-yl)phenyl)phosphane (EvanPhos): A flame dried 100 mL 3-neck round bottom flask containing a magnetic stir bar was charged with biaryl 2 (1.70 g, 5.78 mmol) under a flow of argon. The vessel was evacuated and back-filled with argon 3 times. The vessel was charged with anhydrous THF (30 mL) and stirred until dissolution of the biaryl was visually complete. The vessel was submerged in an ice bath and stirred for 10 min. n-Butyllithium (2.45 M in hexanes, 2.25 mL, 5.52 mmol) was added to the stirring solution dropwise via syringe over 10 min. Upon complete addition of n-butyllithium, the solution stirred in the ice bath for 30 min. and the vessel was removed and stirring continued for another 30 min. The vessel was re-submerged in an ice bath and chlorodicyclohexylphosphine (1.16 mL, 5.26 mmol) was added dropwise via syringe over 10 min. The solution was stirred in the ice bath for 30 min., and the vessel was removed from the ice bath. Stirring was continued at rt for 12 h. The solution was quenched with water (25 mL) and diluted with diethyl ether (100 mL). The phases were separated and the aqueous phase was extracted with diethyl ether (250 mL). The combined organic phases were washed with a solution of 10% sulfuric acid/water (515 mL). The combined acidic phases were mixed with diethyl ether (150 mL) and a saturated solution of sodium carbonate in water was slowly added while gently swirling until gas evolution had ceased. The phases were separated and the aqueous phase was extracted with diethyl ether (250 mL). The ether was dried over anhydrous MgSO.sub.4 and concentrated in vacuo. The product was purified by chromatography over basic alumina eluting with 1:3 diethyl ether:hexanes (R.sub.f=0.26 1:3 diethyl ether:hexanes) which yielded a flocculent white solid (1.54 g, 58%). .sup.1H NMR (400 MHz, chloroform-d) 7.88 (d, J=9.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.48-7.43 (m, 1H), 7.39-7.29 (m, 3H), 7.18 (d, J=8.3 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.22 (s, 3H), 2.46-2.30 (m, 2H), 2.01-1.88 (m, 2H), 1.81-1.54 (m, 8H), 1.37-1.06 (m, 10H). .sup.13C NMR (101 MHz, chloroform-d) 164.78, 164.65, 163.30, 154.43, 134.41, 133.87, 129.17, 129.14, 127.95, 126.42, 125.39, 123.56, 122.56, 121.98, 113.93, 106.20, 61.05, 56.90, 55.58, 34.76 (d, J=11.5 Hz), 34.32 (d, J=11.7 Hz), 32.71 (d, J=24.5 Hz), 32.34 (d, J=22.2 Hz), 30.70 (dd, J=8.8, 6.4 Hz), 27.64-27.15 (m), 26.67. .sup.31P NMR (162 MHz, chloroform-d) -9.24.

##STR00035##

[0145] 6-(3-Methoxyphenyl)benzo[d][1,3]dioxole-5-carbaldehyde: An oven dried 5 mL microwave vial with a 10 mm stir bar was charged with 6-bromopiperonal (115 mg, 0.5 mmol), 3-methoxybenzeneboronic acid (152 mg, 1.0 mmol) and tribasic potassium phosphate monohydrate (288 mg, 1.25 mmol). The vial was equipped with a septum and subjected to three evacuation/argon backfill cycles. A toluene solution (0.1 mL) of Pd(OAc).sub.2 (0.56 mg, 0.0025 mmol) and EvanPhos (1.8 mg, 0.0038 mmol) was added via syringe followed by toluene (0.9 mL). The reaction was stirred in an oil bath at 40 C. under an argon atmosphere. GC/MS monitoring showed complete consumption of the halide after 7 h. The vessel was cooled to rt and diluted with water (1 mL). The aqueous phase was extracted in flask with EtOAc (31 mL). The combined organic phases were flushed over a short plug of silica gel in a pipette and washed with EtOAc. Volatiles were removed in vacuo. The mixture was chromatographed over silica gel eluting with 1:4 diethyl ether:hexanes (R.sub.f=0.25, 1:4 diethyl ether:hexanes) which yielded a colorless viscous oil (119 mg, 93%). .sup.1H NMR (400 MHz, chloroform-d) 9.76 (s, 1H), 7.45 (s, 1H), 7.34 (t, J=7.9 Hz, 1H), 6.96 (dd, J=8.3, 2.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.88-6.86 (m, 1H), 6.84 (s, 1H), 6.08 (s, 2H), 3.83 (s, 3H). .sup.13C NMR (101 MHz, chloroform-d) 190.75, 159.50, 152.10, 147.88, 143.54, 138.97, 129.44, 128.89, 122.82, 115.83, 113.67, 110.21, 110.11, 106.25, 102.21, 66.66, 55.43.

##STR00036##

[0146] 5-(Naphthalen-1-yl)pyrimidine: An oven dried 5 mL microwave vial with a 10 mm stir bar was charged with 5-bromopyrimidine (115 mg, 0.5 mmol), naphthalene-1-boronic acid (152 mg, 1.0 mmol) and tribasic potassium phosphate monohydrate (288 mg, 1.25 mmol). The vial was equipped with a septum and subjected to three evacuation/Argon backfill cycles. A toluene solution (0.1 mL) of Pd(OAc).sub.2 (0.56 mg, 0.0025 mmol) and EvanPhos (1.8 mg, 0.0038 mmol) was added via syringe followed by toluene (0.9 mL). The reaction was stirred in an oil bath at 40 C. under argon. GC/MS monitoring showed complete consumption of the halide after 6 h. The vessel was cooled to rt and diluted with water (1 mL). The aqueous phase was extracted in flask with EtOAc (31 mL). The combined organic phases were flushed over a short plug of silica gel in a pasteur pipette and then washed with EtOAc. Volatiles were removed in vacuo. The mixture was chromatographed over silica gel eluting with 1:3 diethyl ether:hexanes (R.sub.f=0.20, 3:7 diethyl ether:hexanes) which yielded an off-white powder (99 mg, 96%). .sup.1H NMR (400 MHz, chloroform-d) 9.31 (s, 1H), 8.89 (s, 2H), 7.95 (dd, J=8.4, 3.7 Hz, 2H), 7.75 (d, J=8.2 Hz, 1H), 7.61-7.48 (m, 3H), 7.42 (d, J=7.0 Hz, 1H). .sup.13C NMR (101 MHz, chloroform-d) 157.72, 157.40, 134.44, 133.87, 132.50, 131.26, 130.95, 129.53, 128.78, 127.84, 127.18, 126.54, 125.52, 124.65.

[0147] Results from Representative Coupling Reactions:

##STR00037## ##STR00038##

[0148] 1-Bromo-4-isopropyl-2-nitrobenzene (2): Nitrating mixture was prepared by adding concentrated sulphuric acid (72.3 mmol, 3.9 mL) to nitric acid (48.4 mmol, 3.0 mL) at 0 C. This nitrating mixture was added to 1-bromo-4-isopropylbenzene 1 (32.3 mmol, 6.4 g) dropwise by maintaining temperature to 0 C. The mixture was stirred at RT for 5 h before pouring it on ice water. The aqueous reaction mixture was extracted with ethyl acetate (315 mL). Evaporation of ethyl acetate lead to crude yellow oil. This oil was then purified using chromatography on SiO.sub.2 with eluent ethyl acetate:hexanes (0 to 5%). The product was pale yellow oil at RT and freezes upon cooling (30%, 2.3 g).

[0149] 2-Bromo-5-isopropylaniline (3): 1-Bromo-4-isopropyl-2-nitrobenzene 2 (4.76 mmol, 1.23 g) and sodium dithionate (17.6 mmol, 3.0 g) was added to mixture of glycol monomethylether:water (1:1) 15 mL at room temperature and this reaction mixture was refluxed at 115 C. for 6 hours. The reaction mixture was cooled to room temperature and 50% HCl was added to this mixture and refluxed again for 20 min. The reaction mixture was poured on ice water, neutralized with solid Na.sub.2CO.sub.3, and extracted with ethyl acetate (320 mL). Evaporation of ethyl acetate lead to crude yellow oil. This oil was then purified using chromatography on SiO.sub.2 with eluent ethyl acetate:hexanes (0 to 3%). The product was yellow oil (53%, 504 mg).

[0150] 4,4-Diisopropyl-[1,1-biphenyl]-2-amine (4): 2-Bromo-5-isopropylaniline 3 (1.1 mmol, 237 mg), 4-isopropylphenyl boronic acid (1.43 mmol, 236 mg), K.sub.3PO.sub.4.H.sub.2O (3.3 mmol, 753 mg), SPhos (5 mol %, 0.055 mmol, 22.6 mg), Pd(OAc).sub.2 (2 mol %, 0.022 mmol, 4.9 mg) was added to 1 dram screw cap vial with rubber septum. The vial was degassed and backfilled with argon (this procedure was repeated 3 times). Three mL of 2% TPGS-750-M:THF (1:2) was added and stirred at 45 C. for 6 h. The reaction mixture was extracted with ethyl acetate (31 mL). Evaporation of ethyl acetate lead to crude oil, which was then purified using chromatography on SiO.sub.2 with eluent ethyl acetate:hexanes (0 to 5%). The product was dark yellow oil (67%, 188 mg).

[0151] Representative procedure to prepare 4,4-diisopropyl-[1,1-biphenyl]-2-amine mesylate salt (5):

[0152] In a two-necked round-bottomed flask, 4,4-diisopropyl-[1,1-biphenyl]-2-amine (4) (0.29 mmol, 75 mg) was dissolved in 2 ml. anhydrous diethyl ether. Methanesulfonic acid (0.29 mmol, 28.4 mg) was slowly added to the reaction mixture. Reaction mixture was stirred at RT for additional 30 min. Appearance of white solid suspension in a reaction mixture was indicative of salt formation. Solid was filtered through a frit and washed with additional 3 ml cold ether. Solid was dried under reduced pressure to obtain pure compound as white solid (81%, 81.2 mg).

[0153] Representative procedure to prepare -OMs dimer 4,4-diisopropyl-[1,1-biphenyl]-2-amine mesylate (6):

[0154] 4,4-Diisopropyl-[1,1-biphenyl]-2-amine mesylate (81.2 mg, 0.232 mmol) and palladium acetate (52.2 mg, 0.232 mmol) were transferred in to a sealable reaction vessel. Reaction vessel was evacuated and backfilled with argon for couple of times. Reaction vessel was opened under the counter-flow of argon, and 2 ml anhydrous toluene was added via syringe. The mixture was stirred at 50 C. for 2 h. The appearance of solid suspension was the indicative of complex formation. Reaction mixture was cooled to RT, and solid was filtered through a frit. Resulting solid was washed with addition 10 ml hexanes to obtain pure compound as brown solid (92%, 194 mg).

[0155] Similarly, mesylate salts of other biarylamines were prepared. In addition to mesylates, other sulfonates such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethane sulfonate, camphosulfonate may also be used in the disclosed process.

[0156] Representative procedure to prepare EphosPdCycle of 4,4-diisopropyl-[1,1-biphenyl]-2-amine mesylate (7n):

[0157] -OMs dimer 4,4-diisopropyl-[1,1-biphenyl]-2-amine mesylate (28 mg, 0.03 mmol) and Ephos (29.4 mg, 0.06 mmol) were transferred to a sealable reaction vessel. Reaction vessel was sealed, evacuated and backfilled with argon by at least three times. Reaction vessel was opened under the counter-flow of argon, and 2 ml dry CH.sub.2Cl.sub.2 was added to it via syringe. The mixture was stirred at RT under argon flow for 2 h. Solvent was evaporated under reduced pressure to obtain solid. Resulting solid was washed several times with dry pentanes to obtain pure complex a reddish brown solid (99%, 56.6 mg).

[0158] Representative palladacycles, such as EvanPhos-PdCycle, may be prepared according to the disclosed procedures.

##STR00039##

[0159] wherein R.sup.10 is H or is selected from the group consisting of OC.sub.1-10alkyl, C.sub.1-10alkyl, SR.sup.8, NR.sup.8R.sup.9, C.sub.6-14aryl and C.sub.4-12heteroaryl.

[0160] Similarly, the following palladacycles were prepared:

##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044##

Preparation of Stock Solution of Palladacycle 7n:

[0161] Add 14.4 mg of the palladacycle 7n (molecular weight: 944.5 g/mol) in a glass vial and dissolve it in 1.0 mL of dry dichloromethane to get clear solution after stirring for about 2 minutes. This solution corresponds to 30,000 ppm of Pd.

Procedure for Suzuki-Miyuara Reaction:

[0162] ##STR00045##

[0163] Procedure for the preparation of the analogous aminonapthyl analog of EvanPhos: In a 1 dram screw cap vial, 100 l (3000 ppm Pd) solution of above stock solution was added. Dichloromethane was then evacuated to dryness for about 1 h under high vacuum. To this vial, aryl halide A (0.5 mmol), boronic acid B (0.75 mmol) and K.sub.3PO.sub.4.H.sub.2O (0.75 mmol) was added, and it was sealed with a rubber septum. Vial was evacuated and backfilled with argon for three times before adding 1.0 mL of 2% TPGS-750-M under positive flow argon. The rubber septum was quickly replaced with screw cap and reaction was stirred at 55 C. until the completion (as monitored by GC-MS or TLC).

Procedure for Suzuki Coupling Reactions:

[0164] ##STR00046##

[0165] Pd(OAc).sub.2 (4.5 mg, 0.02 mmol), and an aminonaphthyl analog to EvanPhos Ligand, above, (25.7 mg, 0.04 mmol) are dissolved in 2 mL of toluene and set to stir for about 15 min in a microwave vial under a bed of argon. A solution of DIBAL-H in DCM (0.1 mL, 1.0 M solution) is added to the solution dropwise and set to stir for an additional 10 min. A color change is observed. The solution turned from a yellow/gold color to a dark brown/black color indicating the formation of Pd.sup.0.

##STR00047##

[0166] A 1 dram vial was charged with aryl bromide (122 mg, 0.5 mmol), aryl boronic acid (196 mg, 0.75 mmol) and K.sub.3PO.sub.4 (172 mg, 0.75 mmol). 2 wt % TPGS is added to the vial (1 mL) and the mixture is set to stir for about 5 min. The catalyst solution is added to the reaction mixture (0.25 mL, 0.5 mol % Pd) and the reaction vessel is purged with argon, sealed with Teflon and set to stir for 1.5 hrs at 45 C.

##STR00048##

[0167] Following the general procedure from above, the aryl bromide (110 mg, 0.5 mmol), aryl boronic acid (118 mg, 0.75 mmol), K.sub.3PO.sub.4 (172 mg, 0.75 mmol), 2 wt % TPGS (1 mL), and the catalyst solution (0.25 mL). Reaction was stirred for 3 hours at 45 C.

[0168] While a number of exemplary embodiments, aspects and variations have been provided herein, those of skill in the art will recognize certain modifications, permutations, additions and combinations and certain sub-combinations of the embodiments, aspects and variations. It is intended that the following claims are interpreted to include all such modifications, permutations, additions and combinations and certain sub-combinations of the embodiments, aspects and variations are within their scope. The entire disclosures of all documents cited throughout this application are incorporated herein by reference.

REFERENCES

[0169] [1] a) C. C. C. J Seechurn et al., Angew. Chem., Int. Ed. 2012, 51, 5062-5085; b) H. Li et al., ACS Catal. 2012, 2, 1147-1164. [0170] [2] a) S. Z. Tasker et al., Nature 2014, 509, 299-309; b) S. D. Ramgren et al., Org. Lett. 2013, 15, 3950-3953; c) F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270-5298; d) F. Gonzalez-Bobes et al., J. Am. Chem. Soc. 2006, 128, 5360-5361; e) L. Hie et al., J. Chem. Educ. 2014; f) A. H. Christian et al., Organometallics 2014, 33, 2134-2137; g) L. Chen et al., Eur. J. Org. Chem. 2014, 2014, 4953-4957; h) X. Wu et al., J. Am. Chem. Soc. 2014, 136, 1789-1792; i) J. C. Tellis et al., Science 2014, 345, 433-436. [0171] [3] a) S. K. Gurung et al., Org. Lett. 2014, 16, 1264-1267; b) Y. Zhou et al., Angew. Chem., Int. Ed. 2014, 126, 3543-3547; c) N. He et al., Org. Lett. 2015; d) L. Cheng et al., RSC Adv. 2014, 4, 44312-44316; e) Y.-Y. Sun et al, Chem. Commun. 2014, 50, 11060-11062; f) C.-T. Yang et al., Angew. Chem., Int. Ed. 2011, 50, 3904-3907; g) J. Mao et al., Tetrahedron 2008, 64, 3905-3911. [0172] [4] a) N. Zhang et al., J. Org. Chem. 2012, 77, 5956-5964; b) M. B. Thathagar et al., J. Am. Chem. Soc. 2002, 124, 11858-11859; c) M. R. Netherton et al., Adv. Synth. Catal. 2004, 346, 1525-1532; d) G. D. Allred et al., J. Am. Chem. Soc. 1996, 118, 2748-2749; e) L. Xu et al., Org. Lett. 2010, 12, 884-887.