Process for Preparing Substituted Biphenyls via Suzuki Coupling of Aryl-Chlorides

Abstract

A process for preparing substituted biphenyls of the formula (I) which comprises reacting a compound of the formula (II) in the presence of a base and of a palladium catalyst, with an organoboron compound of the formula (IV).

##STR00001##

Claims

1. A process for preparing a substituted biphenyl of the formula I ##STR00062## in which the substituents are each defined as follows: R.sup.1 is cyano, nitro, F, Cl, C1-C4-alkyl, C1-C4-haloalkyl, C3-C10-cycloalkyl which may carry 1, 2, 3 or 4 C1-C4-alkyl substituents; C3-C10-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, or C1-C6-haloalkoxycarbonyl; R.sup.2 is cyano, nitro, F, Cl, C1-C4-alkyl, C1-C4-haloalkyl, C3-C10-cycloalkyl which may carry 1, 2, 3 or 4 C1-C4-alkyl substituents; C3-C10-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, or C1-C6-haloalkoxycarbonyl; and n is 0, 1, 2, or 3, where, in case that n is 2 or 3, the R.sup.1 radicals may have identical or different definitions; and m is 0, 1, 2, or 3, where, in case that n is 2 or 3, the R.sup.2 radicals may have identical or different definitions which comprises reacting a compound of formula II ##STR00063## in which R.sup.1 and n is as defined as above, in the presence of a base and a palladium catalyst, where the palladium catalyst is introduced into the reaction in the form of a palladium source and a phosphorus ligand of formula III or a salt thereof ##STR00064## in which R.sup.3 is C3-C18-alkyl or C3-C10-cycloalkyl which is connected to the phosphor atom at a secondary or tertiary carbon atom of the C3-C18-alkyl or C3-C10-cycloalkyl substituent; R.sup.4 is C1-C18-alkyl or C3-C10-cycloalkyl; and R.sup.5 is C1-C18-alkyl or C3-C10-cycloalkyl; or a palladium complex containing at least one phosphorus ligand of the formula III as defined above or a salt thereof; with water as solvent, wherein a total solvent comprises at least 95 wt. % water based on the total solvent without the use of an additional surfactant or phase transfer catalyst with an organoboron compound of formula IV ##STR00065## wherein R.sup.2 and m are as defined as above and the compound of formula IV is selected from the group consisting of (i) boronic acids with o=0, p=2; q=1 and Z=hydroxyl groups, or their trimers; (ii) boronic acid derivates with o=0, p=2; q=1 and Z=halogen; C1-C4-alkyl, C1-C6-alkoxy or C6-C10-aryloxy; (iii) boronic acids or boronic acid derivatives with o=0, p=1; q=2 and Z=hydroxy, halogen, C1-C4-alkyl, C1-C6-alkoxy or C6-C10-aryloxy; (iv) mixed boronic acids or boronic acid derivatives with o=1, p=1; q=1, A=C1-C4-alkyl and Z=hydroxy, halogen, C1-C4-alkyl, C1-C6-alkoxy or C6-C10-aryloxy; (v) cyclic boronic esters with o=0, p=2 and q=1, wherein the two Z groups form together a bridging group O(CH.sub.2).sub.rO, wherein r is 2 or 3, so that the two Z groups, together with the boron atom to which they are attached, form a 5- or 6-membered ring, where the CH.sub.2 groups are optionally substituted by one or two C1-C4-alkyl groups; (vi) boronates with o=0, p=3, q=1 and Z=hydroxyl, halogen, C1-C4-alkyl, C1-C6-alkoxy or C6-C10-aryloxy, and accompanied by a cation which compensates the negative charge of the boronate anion; (vii) triarylboranes with o=0, p=0 and q=3; (viii) tetraarylborates with 0=0, p=0 and q=4, and accompanied by a cation which compensates the negative charge of the borate anion; and where the reaction is carried out at a temperature of from 60 to 150? C.

2. The process according to claim 1, wherein the palladium catalyst is 0.01 to 0.001 mol % relating to the compound of formula II.

3. The process according to claim 1, wherein the solvent comprises less than 5 wt.-% of organic solvents, which are only partially or not miscible with water, based on the total solvent.

4. The process according to claim 1, wherein the total solvent comprises at least 98 wt.-% water based on the total solvent.

5. The process according to claim 1, wherein the solvent comprises less than 2 wt.-% of organic solvents, which are only partially or not miscible with water, based on the total solvent.

6. The process according to claim 1, wherein the solvent comprises no other solvent miscible with water.

7. The process according to claim 1, wherein no additional organic solvent is present.

8. The process according to claim 1, wherein in the formula III R.sup.3 and R.sup.4=cyclohexyl and R.sup.5=tertbutyl.

9. The process according to claim 1, wherein in the formula I, R.sup.1=nitro, n=1, R.sup.2?Cl and m=1.

10. The process according to claim 1, wherein formula I is 2-nitro-4-C1-biphenyl

11. The process according to claim 1, wherein in formula IV, o=0, Z=OH, p=1, R.sup.2=para-chloro, m=1, and q=2.

Description

EXAMPLES

Investigation on the Surfactant Effects

[0127] ##STR00020##

TABLE-US-00001 entry surfactant conversion [%].sup.[b] yield [%].sup.[b] 1*) SPGS-550-M >99 93 2*) TPGS-750-M >99 95 3*) Brij 30 >99 87 4*) Brij S100 >99 93 5*) IGEPAL CA720 >99 90 6*) Sorbitan monopalmitate >99 70 7*) Sodium Dodecyl Sulfate >99 89 8*) Benzethonium chloride >99 88 9 no surfactant >99 97 (93).sup.c [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.50 mmol of the aryl halide 1, 1.0 equiv of 4-chlorophenylboronic acid 2, K.sub.3PO.sub.4 (3.0 equiv) and 10 mL of Pd(OAc).sub.2 + Pt-BuCy.sub.2 solution (0.05M in cyclohexane) (0.10 mol %) in 1.0 mL of the respective surfactant in H.sub.2O (2.0 wt %) at 50? C. for 20 h. .sup.[b]Determined by GC analysis after calibration, using mesitylene as internal standard. .sup.cIsolated yield. *)not according to the invention

Screening of Tri-Alkylphosphines at [Pd] Ppm Level Under Optimized Conditions

[0128] ##STR00021##

TABLE-US-00002 entry catalytic system conversion [%].sup.[b] yield [%].sup.[b] 1 Pd(OAc).sub.2 + PCy.sub.3 61 44.sup.[c] 2 Pd(OAc).sub.2 + PtBu.sub.3 60 45 3*) Pd(OAc).sub.2 + PnBu.sub.3 28 5 4 Pd(OAc).sub.2 + PAd.sub.3 78 62 5*) Pd(OAc).sub.2 + PMe.sub.3 23 8.sup.[d] 6*) Pd(OAc).sub.2 + PnOct.sub.3 36 10 7 Pd(OAc).sub.2 + PAd.sub.2nBu >99 88 8*) Pd(OAc).sub.2 + PBn.sub.3 25 3.sup.[c] 9 Pd(OAc).sub.2 + PCp.sub.3 48 31 [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl halide 1, 0.55 mmol of the boronic acid 2, 0.5 mmol of Na.sub.2CO.sub.3 (1.0 equiv) and 5 ?L of the respective catalytic system (Pd:L = 1:4) in cyclohexane (0.005 mol %), in 0.5 mL of H.sub.2O at 100? C. for 1 h. .sup.[b]Determined by GC analysis using mesitylene as internal standard. .sup.[c]In the GC chromatogram is present a peak at 23.77 min. .sup.[d]The stock solution presented solid precipitate. *)not according to the invention

##STR00022##

TABLE-US-00003 entry catalytic system conversion [%].sup.[b] yield [%].sup.[b] 1 Pd(OAc).sub.2 + PCy.sub.3 96 82 (75).sup.[c] 2 Pd(OAc).sub.2 + PtBu.sub.3 >99 80 (85).sup.[c, d] 3*) Pd(OAc).sub.2 + PnBu.sub.3 35 13 4*) Pd(OAc).sub.2 + PnOCt.sub.3 39 12 5*) Pd(OAc).sub.2 + PMe.sub.3 23 2.sup.[e] [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl halide 1, 0.55 mmol of the boronic acid 2, 0.5 mmol of Na.sub.2CO.sub.3 (1.0 equiv) and 5 mL of the respective catalytic system (Pd:L = 1:4) in cyclohexane (0.005 mol %), in 0.5 mL of H.sub.2O at 100? C. for 5 h. .sup.[b]Determined by GC analysis using mesitylene as internal standard. .sup.[c]Isolated yield. .sup.[d]The isolated product contains also another unknown species. .sup.[e]The stock solution presented a solid precipitate. *)not according to the invention
Experiments (Entry 1-5) which are not According to the Invention (for Comparison)

##STR00023##

TABLE-US-00004 entry catalytic system conversion [%].sup.[b] yield [%].sup.[b] 1 Pd(OAc).sub.2 + PPh.sub.3 25 2 2 Pd(OAc).sub.2 + PPhCy.sub.2 53 33 3.sup.c Pd(OAc).sub.2 + PPhCy.sub.2 53 28 4 Pd(OAc).sub.2 + PPh.sub.2Cy 30 4 5 Pd(OAc).sub.2 + SPhos 36 16 [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl halide 1, 0.55 mmol of the boronic acid 2, 0.5 mmol of Na.sub.2CO.sub.3 (1.0 equiv) and 5 mL of the respective catalytic system (Pd:L = 1:4) in cyclohexane (0.005 mol %), in 0.5 mL of H.sub.2O at 100? C. for 5 h. .sup.[b]Determined by GC analysis using mesitylene as internal standard. .sup.cThe reaction was run for 5 h.
Effect of Different Solvent Using Na.sub.2CO.sub.3 as Base with Pd(OAc).sub.2+PtBuCy.sub.2 (0.005 Mol %):

##STR00024##

TABLE-US-00005 entry cyHex addition (?L) conversion [%].sup.[b] yield [%].sup.[b] 1 none >99 91 2 10 >99 91 3 100 87 62 [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl halide 1, 0.55 mmol of the boronic acid 2, 0.5 mmol of NaOH (1.0 equiv) and 5 ?L of Pd(OAc).sub.2 + PtBuCy.sub.2 solution (Pd:L = 1:4) in cyclohexane (0.005 mol %), in 0.5 mL of H.sub.2O at 100? C. for 1 h. .sup.[b]Determined by GC analysis using mesitylene as internal standard.

##STR00025##

TABLE-US-00006 entry THF addition (?L) conversion [%].sup.[b] yield [%].sup.[b] 1 none >99 86 2 10 >99 90 3 100 >99 93 (95).sup.c [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl halide 1, 0.55 mmol of the boronic acid 2, 0.5 mmol of NaOH (1.0 equiv) and 5 ?L of Pd(OAc).sub.2 + PtBuCy.sub.2 solution (Pd:L = 1:4) in tetrahydrofurane (0.005 mol %), in 0.5 mL of H.sub.2O at 100? C. for 20 h. .sup.[b]Determined by GC analysis using mesitylene as internal standard. .sup.cIsolated yield.

##STR00026##

TABLE-US-00007 entry toluene addition (?L) conversion [%].sup.[b] yield [%].sup.[b] 1 none >99 89 2 10 >99 90 3 100 >99 93 [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl halide 1, 0.55 mmol of the boronic acid 2, 0.5 mmol of NaOH (1.0 equiv) and 5 ?L of Pd(OAc).sub.2 + PtBuCy.sub.2 solution (Pd:L = 1:4) in toluene (0.005 mol %), in 0.5 mL of H.sub.2O at 100? C. for 1 h. .sup.[b]Determined by GC analysis using mesitylene as internal standard.

##STR00027##

TABLE-US-00008 entry EA addition (?L) conversion [%].sup.[b] yield [%].sup.[b] 1 none >99 97 (91).sup.[c] 2 10 >99 86 3 100 >99 97 [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl halide 1, 0.55 mmol of the boronic acid 2, 0.5 mmol of NaOH (1.0 equiv) and 5 ?L of Pd(OAc).sub.2 + PtBuCy.sub.2 solution (Pd:L = 1:4) in ethyl acetate (0.005 mol %), in 0.5 mL of H.sub.2O at 100? C. for 1 h. .sup.[b]Determined by GC analysis using mesitylene as internal standard. .sup.[c]Isolated yield.

Temperature Screening Under Optimized Conditions:

[0129] ##STR00028##

TABLE-US-00009 entry temperature (? C.) conversion [%].sup.[b] yield [%].sup.[b] 1 80 >99 81 2 90 >99 84 3 120 >99 78 4 140 >99 80.sup.[c] [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl halide 1, 0.55 mmol of the boronic acid 2, 0.5 mmol of Na.sub.2CO.sub.3 (1.0 equiv) and 5 ?L of Pd(OAc).sub.2 + PtBuCy.sub.2 (Pd:L = 1:4) in cyclohexane (0.005 mol %), in 0.5 mL of H.sub.2O at the given temperature for 1 h. .sup.[b]Determined by GC analysis using mesitylene as internal standard.

Investigation of Suzuki-Miyaura Cross-Coupling at Lower [Pd] Ppm Level:

[0130] ##STR00029##

TABLE-US-00010 entry ?L of catalyst added conversion [%].sup.[b] yield [%].sup.[b] 1 5 (0.0005 mol %) 65 35 2 10 (0.001 mol %) 75 51 3 25 (0.0025 mol %) 81 67 [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl halide 1, 0.55 mmol of the boronic acid 2, 0.5 mmol of Na.sub.2CO.sub.3 (1.0 equiv) and the respective ?L of Pd(OAc).sub.2 + PtBuCy.sub.2 in cyclohexane (Pd:L = 1:4), in 0.5 mL of H.sub.2O at 100? C. for 20 h. .sup.[b]Determined by GC analysis using mesitylene as internal standard.

Kinetic Experiment on Suzuki-Miyaura Cross Coupling at 50 ppm Catalyst Loading:

[0131] ##STR00030##

NOTE: 5 different reactions were set at the same to. After dedicated time, the respective tube was opened and analyzed by GC using mesitylene as internal standard. After 60 min isolated 103.6 mg of yellow solid (89%).
Investigation with 1.0 Equiv of Base:

##STR00031##

TABLE-US-00011 entry base conversion [%].sup.[b] yield [%].sup.[b] 1 K.sub.3PO.sub.4 89 68 2 K.sub.2CO.sub.3 >99 83 3 NaOH 97 81 4 KOH 82 64 [a] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl halide 1, 0.55 mmol of the boronic acid 2, 0.5 mmol of respective base (1.0 equiv) and 5 ?L of Pd(OAc).sub.2 + PtBuCy.sub.2 (Pd:L = 1:4) in cyclohexane (0.005 mol %), in 0.5 mL of H.sub.2O at 100? C. for 1 h. .sup.[b]Determined by GC analysis using mesitylene as internal standard.
Test Experiment Removing Cyclohexane from the Reaction Mixture:

##STR00032##

Test Reaction Using a Different Borane Reagent:

[0132] ##STR00033##

Test Reaction Using Different Pd Sources:

[0133] [Pd(allyl)Cl].sub.2 as Pd(0) catalyst

##STR00034##

General Procedure for Cross-Coupling Reaction

General Procedure for the Preparation of the Catalyst Stock Solutions

[0134] In a glovebox, a 10.0 mL vial was charged with 6.0 mg of Pd(OAc).sub.2 (0.25 mmol) and 25.0 mg of Pt-BuCy.sub.2 (0.10 mmol, Pd:L=1:4) and diluted in 5.0 mL of the respective solvent, obtaining a 0.005M solution of the catalytic system. The mixture was left stirring in the glovebox and the desired amount (5 ?L, 0.002 ?mol) was taken with a micropipette and directly injected in the reaction vessel.

General Procedure for Suzuki-Miyaura Cross-Coupling of Aryl Chloride with Aryl Boronic

##STR00035##

[0135] In a glovebox, a 2.0 mL pressure tube was equipped with a magnetic stir bar, 0.55 mmol of the corresponding aryl boronic acid (2a-2j) was added with 0.50 mmol of Na.sub.2CO.sub.3 (53.0 mg, 1.0 equiv), 5 ?L of Pd(OAc).sub.2 and PfBuCy.sub.2 solution (0.005M in cyclohexane) (0.002 ?mol, 0.005 mol %, Pd:L=1:4) and 0.50 mmol of 1-chloro-2-nitrobenzene (79.0 mg, 1.0 equiv). The tube was sealed and transferred outside the glovebox, where 0.50 mL of H.sub.2O were added under a flow of Ar. The tube was finally placed in a preheated 100? C. oil bath for 3 h. After this time, the mixture was diluted with 5.0 mL of brine and extracted with EtOAc (3?2.0 mL). The combined organic phases were dried over MgSO.sub.4 and filtered. After concentration under reduce pressure, the crude product was purified by flash column chromatography on silica gel using petrol ether:ethyl acetate=95:5 as eluent to get spectroscopically pure product.

##STR00036##

[0136] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the aryl chloride 1, 1.1 equiv of the respective boronic acid 2a-j, Na.sub.2CO.sub.3 (1.0 equiv) and 5 mL of Pd(OAc).sub.2+Pt-BuCy.sub.2 solution in cyclohexane (0.005 mol %) [Pd:L=1:4], in 0.5 mL of H.sub.2O at 100? C. for 3 h. [a] The reaction was set with 10 ?L of Pd(OAc).sub.2+Pt-BuCy.sub.2 solution in cyclohexane (0.010 mol %) [Pd:L=1:4].

General Procedure for Suzuki-Miyaura Cross-Coupling of Aryl Halides

[0137] ##STR00037##

[0138] In a glovebox, a 2.0 mL pressure tube was equipped with a magnetic stir bar, 0.55 mmol of 4-chlorophenylboronic acid (5a) was added with 0.50 mmol of Na.sub.2CO.sub.3 (53.0 mg, 1.0 equiv), 5 ?L of Pd(OAc).sub.2 and Pt-BuCy.sub.2 solution (0.005M in cyclohexane) (0.002 ?mol, 0.005 mol %, Pd:L=1:4) and 0.50 mmol of the corresponding aryl chloride (4k-r). The tube was sealed and transferred outside the glovebox, where 0.50 mL of H.sub.2O were added under a flow of Ar. The tube was finally placed in a preheated 100? C. oil bath for 5 h. After this time, the mixture was diluted with 5.0 mL of brine and extracted with EtOAc (3?2.0 mL). The combined organic phases were dried over MgSO.sub.4 and filtered. After concentration under reduce pressure, the crude product was purified by flash column chromatography on silica gel using petrol ether:ethyl acetate=95:5 as eluent to get spectroscopically pure product.

##STR00038## [0139] Unless otherwise noted, all reactions were performed in a glovebox with 0.5 mmol of the respective aryl chloride 1k-r, 1.1 equiv of the boronic acid 2a, Na.sub.2CO.sub.3 (1.0 equiv) and 5 mL of Pd(OAc).sub.2+Pt-BuCy.sub.2 solution in cyclohexane (0.005 mol %) [Pd:L=1:4], in 0.5 mL of H.sub.2O at 100? C. for 5 h. [a] The reaction was set with 10 ?L of Pd(OAc).sub.2+PtBuCy.sub.2 solution in cyclohexane (0.010 mol %) [Pd:L=1:4].

Scale-Up Experiments

1. Bixafen Precursor

[0140] ##STR00039##

TABLE-US-00012 Mw wt (g/mol) mmol eq V [00040] 880 mg 175.54 5.0 1 [00041] 1.15 g 190.82 5.5 1.1 Na.sub.2CO.sub.3 530 mg 106 5.0 1 Pd(OAc).sub.2 + PtBuCy.sub.2 0.0005 0.005 50 ?L mol % in CH H.sub.2O 5.0 mL

[0141] In a glovebox, a 25.0 mL pressure tube equipped with a stirrer bar was charged with 1.15 g of boronic acid 2B (1.2 equiv), 530 mg of Na.sub.2CO.sub.3 (1.0 equiv), 50 ?L of a 0.005 M solution of Pd(OAc).sub.2+PtBuCy.sub.2 (Pd:L=1:4) in cyclohexane and 880 mg of the aryl chloride 1h. The vial was capped and transferred outside the glovebox, where 5.0 ml of H.sub.2O were added under a flow of Ar. The tube was heated at 100? C. for 6 h. After this time, the tube was cooled down to rt and the mixture was diluted with 2.0 mL brine and extracted with EtOAc (3?5.0 mL), the combined organic extracts were dried over MgSO.sub.4 and concentrate in vacuo. Subsequently, the final product was recrystallized using 10 mL EtOH to obtain 1.36 g of product 3B as yellow solid (74%). The product was characterized by 1H and 13C NMR, HRMS analysis as well as elemental analysis. The results fit the previously reported data for 3B.

5 g-Experiment Boscalid Precursor

##STR00042##

TABLE-US-00013 Mw wt (g/mol) mmol eq V [00043] 4.56 g 157.55 29 1 [00044] 5.0 g 156.37 32 1.1 Na.sub.2CO.sub.3 3.4 g 106 29 1 Pd(OAc).sub.2 + PtBuCy.sub.2 0.0005 0.005 290 ?L mol % in CyHex H.sub.2O 29.0 mL

[0142] In a glovebox, a glass autoclave equipped with a spherical stirrer bar was charged with 5.0 g of boronic acid 2 (1.1 equiv), 3.4 g of Na.sub.2CO.sub.3 (1.0 equiv) and 290 ?L of a 0.005 M solution of Pd(OAc).sub.2+PtBuCy.sub.2 (Pd:L=1:4) in cyclohexane and 4.56 g of the aryl chloride 1. The autoclave was screwed inside the glovebox and transferred outside, where 29.0 mL of H.sub.2O were added under a flow of Ar. The glass autoclave was finally heated in an oil bath at 100? C. for 6 h. After this time the mixture was diluted with 10.0 mL of brine and subsequently extracted with EtOAc (2?5.0 mL) and the combined organic phases were dried over MgSO.sub.4, filtered and then analyzed by GC. Subsequently, the final product was recrystallized using 10 mL EtOH to obtain 5.477 g of product 3 as yellow solid (81%). The product was characterized by 1H and 13C NMR, HRMS analysis as well as elemental analysis. The results fit the previously reported data for 3.

1. 50 g-Experiment Boscalid Precursor

##STR00045##

TABLE-US-00014 Mw wt (g/mol) mmol eq V [00046] 46 g 157.55 290 1 [00047] 50 g 156.37 320 1.1 Na.sub.2CO.sub.3 30.7 g 106 290 1 Pd(OAc).sub.2 4.0 mg 224.51 1.78 .Math.10.sup.?5 0.005 mol % Pt-BuCy.sub.2 16.0 mg 254.39 6.29 .Math.10.sup.?5 0.02 mol % H.sub.2O 290 mL

[0143] A 1-L Schlenk flask equipped with a spherical stirrer bar was charged with 50 g of boronic acid 2 (1.1 equiv), 30.7 g of Na.sub.2CO.sub.3 (1.0 equiv) and and 46 g of the aryl chloride 1. The flask was transferred into a glovebox, where 4.0 mg of Pd(OAc).sub.2 (1.78.Math.10-5, 0.005 mol %) and 16.0 mg of the ligand PtBuCy.sub.2 (6.29.10.sup.?5, 0.02 mol %, Pd:L=1:4) were added into the solid aryl chloride 1. The flask was then transferred outside, where 290 mL of H.sub.2O were added under a flow of Ar. The flask was finally heated in an oil bath at 100? C. for 8 h. After this time the mixture was diluted with 100 mL of brine and subsequently extracted with EtOAc (2?100 mL) and the combined organic phases were dried over MgSO.sub.4, filtered and then analyzed by GC.

General Procedure for Boscalid Three-Step One-Pot Synthesis:

[0144] ##STR00048##

TABLE-US-00015 Mw wt (g/mol) mmol eq V [00049] 79 mg 86 mg 53 mg 0.5 mL 157.55 156.37 106 0.5 0.55 0.5 0.0005 1 1.1 1 0.005 mol % 5?LinCyHex [00050] ~110mg 10mg 1.0:0.5mL 233.65 ~0.47 0.005 1 1mol% [00051] ~90mg 203.65 ~0.47 1.0 1 2 0.14mL [00052] 133mg 176 0.75

[0145] In a glovebox, a 2 mL_pressure tube equipped with a spherical stirrer bar was charged with 86 mg of boronic acid 2 (1.1 equiv), 53 mg of Na.sub.2CO.sub.3 (1.0 equiv) and 5 ?L of a 0.005 M solution of Pd(OAc).sub.2+PtBuCy.sub.2 (Pd:L=1:4) in cyclohexane and 79 mg of the aryl chloride 1. The tube was capped and transferred outside the glovebox, where 0.5 mL of H.sub.2O were added under a flow of Ar. The vial was heated in an oil bath at 100? C. for 1 h. After this time, the reaction mixture was cooled down to rt and was filtered through a pad of activated charcoal to remove Pd catalyst. The mixture in the pressure tube was transferred into a 10 mL vial equipped with a stirrer bar and a bended needle on the septum (?110 mg of product 3), filtering it through a pad of celite. The pressure tube was rinsed with 0.5 mL of water and 0.5 mL of EtOAc. Subsequently, the vial was charged with 10 mg of Pt/C (10 wt %, 1 mol %) and the crimp cap was closed. The vial was placed in a TALL PREMEX autoclave and charged with 10 bar of H.sub.2. The autoclave was then placed at 45? C. for 30 min. After this time, the autoclave was cooled to rt and the vial was filtered over a pad of celite to remove the Pt/C catalyst. The vial was rinsed with 0.5 mL of EtOAc. Subsequently, the vial was charged with 0.14 mL of Et.sub.3N (2.0 equiv) and the mixture was left stirring gently at rt for 10 min. After this time, the vial was quickly opened and 133 mg of 2-chloronicotinoyl chloride (1.5 equiv) was added inside and the vial was left stirring at 60? C. for 18 h. The reaction was monitored by TLC to follow the full consumption of the starting material. The mixture was the cooled down and extracted with EtOAc (3?2.0 mL) and brine (5.0 mL). After drying it over MgSO.sub.4 and filtering, the mixture was concentrated in vacuo. Finally, the product was purified by column chromatography (form petrol ether:ethyl acetate=95:5 to petrol ether:ethyl acetate=60:40) to yield 130.2 mg of white solid, characterized as Boscalid? by 1H and 13C NMR spectroscopy, X-Ray analysis as well as HRMS analysis. The results fit the previously reported data for Boscalid?.

General Procedure for Xemium Three-Step One-Pot Synthesis:

[0146] ##STR00053##

TABLE-US-00016 wt Mw(g/mol) mmol eq V [00054] 79mg 97mg 53mg 0.5mL 157.55 175.90 106 0.5 0.55 0.5 0.0005 1 1.1 1 0.005mol% 5?LinCyHex [00055] ~110mg 10mg 0.5:0.5mL 233.65 ~0.47 0.005 1 1mol% [00056] ~90mg 223.20 -0.47 1.0 1 2 0.14mL [00057] 244mg 0.5:1.0mL 194.56 1.25 2.5

[0147] In a glovebox, a 2 mL_pressure tube equipped with a spherical stirrer bar was charged with 97 mg of boronic acid 2-F (1.1 equiv), 53 mg of Na.sub.2CO.sub.3 (1.0 equiv) and 5 ?L of a 0.005 M solution of Pd(OAc).sub.2+PtBuCy.sub.2 (Pd:L=1:4) in cyclohexane and 79 mg of the aryl chloride 1. The tube was capped and transferred outside the glovebox, where 0.5 mL of H.sub.2O were added under a flow of Ar. The vial was heated in an oil bath at 100? C. for 3 h. The mixture in the pressure tube was transferred into a 10 mL vial equipped with a stirrer bar and a bended needle on the septum (?110 mg of product 3-F). The pressure tube was rinsed with 0.5 ml of water and 0.5 mL of EtOAc. Subsequently, the vial was charged with 10 mg of Pt/C (10 wt %, 1 mol %) and the crimp cap was closed. The vial was placed in a HEL CAT 7 autoclave and charged with 10 bar of H.sub.2. The autoclave was then placed at 45? C. for 30 min. After this time, the autoclave was cooled to rt and the vial was filtered over a pad of celite to remove the Pt/C catalyst. The vial was rinsed with 0.5 mL of EtOAc. Subsequently, the vial was charged with 0.14 mL of Et.sub.3N (2.0 equiv) and the mixture was left stirring gently at rt for 10 min. After this time, the vial was quickly opened and 107 mg of PO-539 (1.1 equiv) was added inside and the vial was left stirring at 60? C. The reaction was monitored by TLC to follow the full consumption of the starting material. The mixture was the cooled down and extracted with EtOAc (3?1.0 mL). After drying it over MgSO.sub.4 and filtering, the mixture was concentrated in vacuo. Finally, the product was purified by column chromatography (form petrol ether:ethyl acetate=95:5 to petrol ether:ethyl acetate=60:40) to yield 126 mg of white solid, characterized as Xemium? by .sup.1H and .sup.13C NMR spectroscopy, X-Ray analysis as well as HRMS analysis. The results fit the previously reported data for Xemium?.

Comparative Experiments Using Aryl-Substituted Phosphine Ligands:

Investigation on Aryl Substituted Phosphines:

[0148] using Pd(OAc).sub.2+PPh.sub.3 (0.005 mol %):

##STR00058## [0149] using Pd(OAc).sub.2+PCy.sub.2Ph (0.005 mol %):

##STR00059## [0150] using Pd(OAc).sub.2+PCyPh.sub.2 (0.005 mol %):

##STR00060## [0151] using Pd(OAc).sub.2+SPhos (0.005 mol %) [Buchwald ligand]:

##STR00061##