meta‐Selective C−H Borylation of Benzylamine‐, Phenethylamine‐, and Phenylpropylamine‐Derived Amides Enabled by a Single Anionic Ligand

Abstract Selective functionalization at the meta position of arenes remains a significant challenge. In this work, we demonstrate that a single anionic bipyridine ligand bearing a remote sulfonate group enables selective iridium‐catalyzed borylation of a range of common amine‐containing aromatic molecules at the arene meta position. We propose that this selectivity is the result of a key hydrogen bonding interaction between the substrate and catalyst. The scope of this meta‐selective borylation is demonstrated on amides derived from benzylamines, phenethylamines and phenylpropylamines; amine‐containing building blocks of great utility in many applications.


General Information
All reagents, unless otherwise stated, were used as supplied from commercial sources without further purification. [Ir(COD)OMe] 2 was purchased from Sigma-Aldrich, used as received and stored in a desiccator. CH 2 Cl 2 , THF and Et 2 O were purified by distillation on site under inert atmosphere via the following processes: THF and Et 2 O were pre-dried over sodium wire then distilled from calcium hydride and lithium aluminium hydride. CH 2 Cl 2 , n-hexane and toluene were distilled from calcium hydride. NEt 3 and i Pr 2 NEt were purified by distillation from calcium hydride and stored over 4 Å molecular sieves. Ligand 1a was prepared according the procedure detailed in our previous publication. [1] Reactions were carried out in 4 mL 15x45mm crimp top vials, which were purged with Argon. Vials were heated in deep-welled heating blocks (IKA DB 5.2).
NMR spectra: 1 H NMR spectra were recorded on a 600 MHz Bruker Avance DRX-600 spectrometer, 500 MHz Bruker DCH Cryoprobe or 400 MHz QNP Cryoprobe. Chemical shifts are reported in parts per million (ppm) and the spectra are calibrated to the resonance resulting from incomplete deuteration of the solvent (CDCl 3 : 7.26 ppm, CD 3 OD: 3.31 ppm, (CD 3 ) 2 SO: 2.50 ppm). 13 C NMR spectra were recorded the same spectrometer with complete proton decoupling. Chemical shifts are reported in ppm with the solvent resonance as the internal standard ( 13 CDCl 3 : 77.16 ppm, t; DMSO-d 6 : 39.51 ppm, s). Data are reported as follows: chemical shift δ/ppm, integration ( 1 H only), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet or combinations thereof; 13 C signals are singlets unless otherwise stated), coupling constants J in Hz, assignment. 1 H-COSY, DEPT-135, HMQC, HMBC and NOESY were used where appropriate to facilitate structural determination of regioisomers. The carbon attached to boron was generally not observed by 13 C spectroscopy due to quadrupolar relaxation. 19 F NMR spectra were recorded on a 400 MHz Bruker Avance III HD Spectrometer. Chromatography: Analytical thin layer chromatography was performed using precoated Merck glass backed silica gel plates (Silicagel 60 F254). Visualisation was by ultraviolet fluorescence (λ = 254 nm) and/or staining with cerium ammonium molybdate (CAM) or potassium permanganate (KMnO 4 ). Flash column chromatography was performed using silica gel 60 (0.040-0.063 μm) from Fluorochem.

Evaluation of H-bond accepting ligands on 2a:
Ligand

N-(2-(trifluoromethyl)phenethyl)methanesulfonamide (4b)
(E)-1-(2-nitrovinyl)-2-(trifluoromethyl)benzene (600 mg; 2.76 mmol; 1eq) was dissolved in dry THF (5 ml) under argon atmosphere and cooled to 0 o C. A solution of LiAlH 4 (2.4M in THF; 3.45 ml; 8.28 mmol; 3eq) was added dropwise at this temperature and the reaction mixture was then stirred at room temperature for 4 hours. The reaction was carefully quenched with water at 0 o C and then acidified with conc. HCl. The mixture was washed with diethyl ether (2x30 ml) and the aqueous layer was brought to basic pH with 10% NaOH solution. It was extracted with CH 2 Cl 2 (2x40 ml) and the organic layer was dried with MgSO 4 and concentrated to give a light yellow oil (522 mg). The crude was dissolved in dry CH 2 Cl 2 (10 ml) and mixture was put under argon atmosphere. Then methanesulfonyl chloride (0.12 ml; 1.59 mmol; 1.1eq) and triethylamine (0.40 ml; 2.89 mmol; 2eq) were added dropwise, and the reaction was left stirring at room temperature for 16 hours. The mixture was washed with sat. NaHCO 3 (50 ml), the organic layer was dried with MgSO 4 and concentrated to give a yellow oil. The crude was then purified by column chromatography (SiO 2 , 30% to 40% EtOAc in Petroleum Ether 40-60 o C) to give the final product as an off-white solid (291 mg; 39% over two steps).

tert-butyl (2-(trifluoromethyl)phenethyl)carbamate (4c)
(E)-1-(2-nitrovinyl)-2-(trifluoromethyl)benzene (750 mg; 3.45 mmol; 1eq) was dissolved in dry THF (5 ml) under argon atmosphere and cooled to 0 o C. A solution of LiAlH 4 (2.4M in THF; 4.31 ml; 10.35 mmol; 3eq) was added dropwise at this temperature and the reaction mixture was then stirred at room temperature for 16 hours. The reaction was carefully quenched with water at 0 o C and then acidified with conc. HCl. The mixture was washed with diethyl ether (2x30 ml) and the aqueous layer was brought to basic pH with 10% NaOH solution. It was extracted with CH 2 Cl 2 (2x40 ml) and the organic layer was dried with MgSO 4 and concentrated to give a light orange oil (619 mg). Then di-tertbutyl dicarbonate (718 mg; 3.29 mmol; 1eq) and triethylamine (0.92 ml; 6.58 mmol; 2eq) were added dropwise, and the reaction was left stirring at room temperature for 16 hours. The mixture was washed with sat. NaHCO 3 (50 ml), the organic layer was dried with MgSO 4 and concentrated to give a brown oil. The crude was then purified by column chromatography (SiO 2 , 85% CH 2 Cl 2 in Petroleum Ether 40-60 o C) to give the final product as an off-white solid (241 mg; 25% over two steps).

3-(2-(Trifluoromethyl)phenyl)propan-1-amine
Following general procedure D with 1-(bromomethyl)-2-(trifluoromethyl)benzene (3.59 g, 15.0 mmol) and purified by silica gel chromatography Pet. Ether (40-60):EtOAc (19:1) the nitrile was isolated, with a close running impurity, as a colourless oil and used directly in the next step. Separately, a flask was charged with AlCl 3 (636 mg, 4.77) in THF (15 mL) and cooled to 0 °C. LiAlH 4 (2.4M in THF, 2.6 mL, 6.2 mmol) was added over 5 mins and stirred for a further 10 mins before the addition of the crude nitrile in THF (5 mL) dropwise over 5 mins. The mixture was warmed to rt and stirred overnight before cooling again to 0 °C, diluting with Et 2 O (20 mL) and quenching, slowly, with water (2 mL). The mixture was acidified with 3 M HCl to pH 1 and the organic layer separated and further extracted with 3 M HCl (2 x 10 mL). The aqueous phases were combined and basified with 10% NaOH to ca. pH 10 and extracted with CH 2 Cl 2 (3 x 30 mL), dried (MgSO 4 ) and solvents removed in vacuo to yield the amine as a colourless oil (496 mg, 2.44 mmol, 16% over 2 steps).

N-(3-(2-fluorophenyl)propyl)-2,2,2-trifluoroacetamide (6e)
To a solution of 2-fluorobenzaldehyde (2.10 ml, 20 mmol) in CH 2 Cl 2 (20 ml) was added tetrabutylammonium iodide (74 mg, 0.2 mmol) and 2M NaOH solution (20 ml). With rapid stirring, diethyl cyanomethylphosphonate (3.5 ml, 22 mmol) was added and a mild exotherm was observed. After stirring for 12 h at room temperature, the phases were separated and the organic phase washed S24 with water and brine, dried (Na 2 SO 4 ) and evaporated in vacuo. The crude residue was purified on silica gel to give the title compound as a mixture of E and Z isomers (2.06 g, 14.0 mmol, 70% yield). This matched literature data. [11] This compound was taken up in methanol (50 ml), pTsOH (4.0g, 21.0 mmol) and Pd/C (200 mg) were added and the reaction stirred under a balloon of hydrogen for 20h. After this time, it was filtered through Celite and the solvent evaporated. The crude residue was taken up in CH 2 Cl 2 (50 ml) and triethylamine (7.7 ml, 56 mmol) and trifluoroacetic anhydride (2.9 ml, 21.0 mmol) were added at 0 o C. After stirring at rt for 3h, water was added and the organics were washed with satd bicarb solution, dried (Na 2 SO 4 ) and evaporated. The crude residue was purified on silica gel to give the title compound as a colourless oil (1.95 g, 7.83 mmol, 56% yield over two steps).

N-(3-(3-fluorophenyl)propyl)-2,2,2-trifluoroacetamide (6f)
To a solution of 3-fluorobenzaldehyde (2.12 ml, 20 mmol) in CH 2 Cl 2 (20 ml) was added tetrabutylammonium iodide (74 mg, 0.2 mmol) and 2M NaOH solution (20 ml). With rapid stirring, Diethyl cyanomethylphosphonate (3.5 ml, 22 mmol) was added and a mild exotherm was observed. After stirring for 12h at room temperature, the phases were separated and the organic phase washed with water and brine, dried (Na 2 SO 4 ) and evaporated in vacuo. The crude residue was purified on silica gel to give the title compound as a mixture of E and Z isomers (1.62g, 11.0 mmol, 55% yield). This matched literature data. [11] This compound was taken up in methanol (40 ml), pTsOH (3.1g, 16.5 mmol) and Pd/C (200 mg) were added and the reaction stirred under a balloon of hydrogen for 20h. After this time, it was filtered through Celite and the solvent evaporated. The crude residue was taken up in CH 2 Cl 2 (50 ml) and triethylamine (6.0 ml, 44 mmol) and trifluoroacetic anhydride (2.3 ml, 16.5 mmol) were added at 0 o C. After stirring at rt for 3h, water was added and the organics were washed with satd bicarb solultion, dried (Na 2 SO 4 ) and evaporated. The crude residue was purified on silica gel to give the title compound as an oil that solidified on standing (1.64g, 6.59 mmol, 60% yield over two steps).

Methyl 2-(3-(2,2,2-trifluoroacetamido)propyl)benzoate (6g)
To a solution of NaH (60%) (144 mg, 3.6 mmol) in THF (5 ml) was added diethyl cyanomethylphosphonate (580 mg, 3.3 mmol) at 0 o C. After 15 mins, methyl 2-formylbenzoate (500 mg, 3.05 mmol) in THF (2 ml) was added dropwise. The ice bath was removed and after stirring for 2h at room temperature, the reaction was diluted with diethyl ether and the organic phase washed with water and brine, dried (Na 2 SO 4 ) and evaporated in vacuo. The crude residue was purified on silica gel eluting with 25% Et 2 O/Petrol to give the title compound as a mixture of E and Z isomers (440 mg, 2.35 mmol, 77% yield). This material was taken up in methanol (20 ml), pTsOH (760 mg, 4.0 mmol) and Pd/C (100 mg) were added and the reaction stirred under a balloon of hydrogen for 20h. After this time, it was filtered through Celite and the solvent evaporated. The crude residue was taken up in CH 2 Cl 2 (20 ml) and triethylamine (1.4 ml, 10 mmol) and trifluoroacetic anhydride (0.56 ml, 4.0 mmol) were added at 0 o C. After stirring at rt for 3h, water was added and the organics were washed with satd. bicarb solution, dried (Na 2 SO 4 ) and evaporated. The crude residue was purified twice on silica gel to remove close running impurities (25% Et 2 O/Petrol) to give the title compound as a colourless oil (132 mg, 0.46 mmol, 20% yield over two steps).

2,2,2-Trifluoro-N-(3-(o-tolyl)propyl)acetamide (6i)
To a solution of NaH (60%) (560 mg, 14.0 mmol) in THF (20 ml) was added diethyl cyanomethylphosphonate (1.94 ml, 12.0 mmol) at 0 o C. After 15 mins, 2-methylbenzaldehyde (1.15 ml, 10 mmol) was added dropwise. The ice bath was removed and after stirring for 2 h at room temperature, the reaction was diluted with diethyl ether and the organic phase washed with water and brine, dried (Na 2 SO 4 ) and evaporated in vacuo. The crude residue was purified on silica gel to give the title compound as a mixture of E and Z isomers (1.20 g, 8.39 mmol, 84% yield). This matched literature data. [11][12] This material was taken up in methanol (40 ml), pTsOH (2.28 g, 12.0 mmol) and Pd/C (250 mg) were added and the reaction stirred under a balloon of hydrogen for 20h. After this time, it was filtered through Celite and the solvent evaporated. The crude residue was taken up in CH 2 Cl 2 (40 ml) and triethylamine (4.1 ml, 30 mmol) and trifluoroacetic anhydride (1.7 ml, 12.0 mmol) were added at 0 o C. After stirring at rt for 3h, water was added and the organics were washed with satd. bicarb solution, dried (Na 2 SO 4 ) and evaporated. The crude residue was purified twice on silica gel to remove close running impurities (20% Et 2 O/Petrol) to give the title compound as a colourless oil that solidified on standing (692 mg, 2.82 mmol, 34% yield over two steps).

2,2,2-Trifluoro-N-(3-(o-tolyl)propyl)acetamide (6j)
To a solution of 2-methoxybenzaldehyde (2.72 g, 20 mmol) in CH 2 Cl 2 (20 ml) was added tetrabutylammonium iodide (74 mg, 0.2 mmol) and 2M NaOH solution (20 ml). With rapid stirring, Diethyl cyanomethylphosphonate (3.5 ml, 22 mmol) was added and a mild exotherm was observed. After stirring for 12 h at room temperature, the phases were separated and the organic phase washed with water and brine, dried (Na 2 SO 4 ) and evaporated in vacuo. The crude residue was eluted on silica gel to give the cyanoacrylate as a mixture of E and Z isomers together with unreacted aldehyde. This mixture was taken up in methanol (50 ml), pTsOH (4.8g, 25.1 mmol) and Pd/C (300 mg) were added and the reaction stirred under a balloon of hydrogen for 20 h. After this time, it was filtered through Celite and the solvent evaporated. The crude residue was taken up in CH 2 Cl 2 (40 ml) and triethylamine (9.2 ml, 67 mmol) and trifluoroacetic anhydride (3.5 ml, 25.1 mmol) were added at 0 o C. After stirring at rt for 3 h, water was added and the organics were washed with satd bicarb solution, dried (Na 2 SO 4 ) and evaporated. The crude residue was purified on silica gel to give the title compound as an oil that solidified on standing (1.75 g, 6.7 mmol, 34% yield over three steps).

Borylation of substrates General procedure F:
To a vial was weighed substrate, ligand, B 2 pin 2 , and [Ir(COD)OMe] 2 in succession. The vial was sealed and backfilled with argon before the addition of solvent and stirred for the specified time at the specified temperature. Solvents were removed and regioselectivity analysed before and after the purification as described. For consistency the meta and para isomers are described with respect to the directing amide substituent.  By subtracting the resonances for the meta isomer, the NMR data of the para isomer can be assigned as follows:

Dtbpy in THF:
Following general procedure F using 2,2,2-trifluoro-N-(3-fluorobenzyl)acetamide (55.3 mg, 0.25 mmol), B 2 pin 2 (127 mg, 0.50 mmol), [Ir(COD)OMe] 2 (2.5 mg, 0.00375 mmol) and dtbpy (2.0 mg, 0.0075 mmol) in THF (1.25 mL). The reaction was stirred at 50 °C for 20 hours before cooling and the solvents removed. Analysis of crude 1 H NMR using internal standard 1,2-dimethoxyethane showed 1.5:1 meta:para borylation in 53% yield. The crude product was subjected to silica gel chromatography (Pet. Ether (40-60):EtOAc (9:1) however significant decomposition was observed. A small para enriched fraction (1:2.7 meta:para isomer ration by 1 H NMR) was isolated as an off white solid (8 mg, 0.02 mmol, 9%). By subtracting the resonances for the meta isomer, the NMR data of the para isomer can be assigned as follows:   From an identical experiment a small fraction of the mono-meta isomer was isolated also a colourless oil (11 mg, 0.03 mmol, 13%) described below. By subtracting the resonances for the dimeta and meta isomers, the NMR data of the para isomer can be assigned as follows: *conducting reaction at 35 °C avoided borylation of the amide nitrogen which complicated product assignment from the crude 1 H NMR.

1A in THF:
Following general procedure F using ( *Yield calculated from a weighted average mass of B 2 pin 2 , mono and diborylated products.

1A in THF:
Following general procedure F using 2,2,2-trifluoro-N- *Yield calculated from a weighted average mass of mono and diborylated products.

Dtbpy in THF:
Following general procedure F using N-(2-(trifluoromethyl)benzyl)methanesulfonamide (63.3 mg, 0.25 mmol), B 2 pin 2 (95 mg, 0.375 mmol), [Ir(COD)OMe] 2 (2.5 mg, 0.00375 mmol) and dtbpy (2.0 mg, 0.0075 mmol) in THF (1.25 mL). The reaction was stirred at 35 °C* for 20 hours before cooling and the solvents removed. Analysis of crude 1 H NMR using internal standard 1,2-dimethoxyethane showed 1:2 meta:para borylation in 72% yield. The crude product was purified by silica gel chromatography (Pet. Ether (40-60):EtOAc (7:3) to give the title compound (as a 26:52:18 mixture of meta:para:SM ratio as determined by 1 H NMR) as a colourless oil (91.6 mg) due to the presence of the SM the NMR yield was used for all comparisons. By subtracting the resonances for the meta isomer and the SM, the NMR data of the para isomer can be assigned as follows: *A lower temperature was required to avoid amide N-H borylation which confused the ratio in the crude reaction mixture.
*A lower temperature was required to avoid amide N-H borylation which confused the ratio in the crude reaction mixture.

Dtbpy in THF:
Following general procedure F using N-(2-(trifluoromethyl)benzyl)acetamide (54.3 mg, 0.25 mmol), B 2 pin 2 (95 mg, 0.375 mmol), [Ir(COD)OMe] 2 (2.5 mg, 0.00375 mmol) and dtbpy (2.0 mg, 0.0075 mmol) in THF (1.25 mL). The reaction was stirred at 50 °C for 20 hours before cooling and the solvents removed. Analysis of crude 1 H NMR using internal standard 1,2-dimethoxyethane showed 1:1.1 meta:para borylation in 92% yield. The crude product was purified by silica gel chromatography (Pet. Ether (40-60):EtOAc (7:3) to give the title compound (as a 1:1.9 mixture of meta:para ratio with pinacol and B 2 pin 2 as determined by 1 H NMR) as a white solid (59.7 mg), due to multiple impurities, the NMR yield was used for all comparisons. By subtracting the resonances for the meta isomer, the NMR data of the para isomer can be assigned as follows:

Dtbpy in THF:
Following general procedure F using 4j (61.8 mg, 0.25 mmol), B 2 pin 2 (127 mg, 0.50 mmol), [Ir(COD)OMe] 2 (2.5 mg, 0.00375 mmol) and dtbpy (2.0 mg, 0.0075 mmol) in THF (1.25 mL). Stirred in vial at 50 °C for 20 hours. Analysis of crude 1 H NMR using internal standard 1,2-dimethoxyethane showed 1:2.4 meta:para borylation in 85% yield. The crude product was purified by silica gel chromatography (15% EtOAc in Petroleum Ether 40-60 o C) gave the title compound (as a 1:2.3 mixture of meta:para ratio, as determined by 1 H NMR) as a colourless oil (76 mg, 0.2 mmol, 82%). By subtracting the resonances for the meta isomer, the NMR data of the para isomer can be assigned as follows:  ). The mass quoted above is the actual mass of the isolated mixture of products, whilst the amount of substance in mmol has been calculated by examining the ratios of the dimeta to monoborylated products and accouting for the extra mass due to the higher molecular weight of the dimeta product.

Meta
By subtracting the resonances for the dimeta isomer, the NMR data of the meta and para isomers can be assigned as follows:

Meta Para
Di (3,5) 1a in THF: Following general procedure F using 4m (54.  (3,5) borylation (overall meta:para borylation 4.7:1) in 94% yield. Purification by silica gel chromatography proved not to be possible, leading to product decomposition. As such, the compounds were characterised from the crude, which contained pinacol borane impurity, and NMR yield was quoted in manuscript.  (3,5) borylation (overall meta:para borylation 1.4:1) in 99% yield. Purification by silica gel chromatography proved not to be possible, leading to product decomposition. As such, the compounds was characterised from the crude, which contained pinacol borane impurity.
By subtracting the resonances for the meta isomer, the NMR data of the para and di (3,5) borylated isomer can be assigned as follows:

Dtbpy in THF:
Following general procedure F using 2,2,2-trifluoro-N- (  *Yield calculated from a weighted average mass of mono and diborylated products.

Dtbpy in THF:
Following general procedure F using N- (  *Yield calculated from a weighted average mass of mono and diborylated products.

Dtbpy in THF:
Following general procedure F using N- (
By subtracting the resonances for the meta isomer, the NMR data of the para isomer can be assigned as follows:

1A in THF:
Following general procedure F using N- (
The mixture was then filtered through celite, filter cake washed with methanol and the volatiles were removed in vacuo. The crude was treated with concentrated HCl aq (4 ml) and water (30 ml) and extracted with diethyl ether (2x 30 ml). The aqueous was treated with 10% NaOH aq until pH basic and extracted with diethyl ether (3x 30 ml). Organics evaporated to give a yellowish oil which was retaken into DCM (30 ml), cooled to 0 o C and TFAA (1.25 ml; 9 mmol; 1.2eq) and triethylamine (2.1 ml; 15 mmol; 2eq) were added slowly. Stirred at room temperature for 2 hours. The mixture was washed with sat. NaHCO 3 (30 ml), the organic layer was dried with MgSO 4 and concentrated to give an orange oil which solidifies upon staying. The crude was then purified by column chromatography (SiO 2 , 5% EtOAc in Petroleum Ether 40-60 o C) to give the cis isomer (1.18 g; 4.35 mmol) and the trans isomer (291 mg; 1.07 mmol) as white solids with overall yield of 72% over two steps.

Dtbpy in THF:
Following general procedure F using cis-12a (67.8 mg, 0.25 mmol), B 2 pin 2 (127 mg, 0.50 mmol), [Ir(COD)OMe] 2 (2.5 mg, 0.00375 mmol) and dtbpy (2.0 mg, 0.0075 mmol) in THF (1.25 mL). Stirred in vial at 50 °C for 20 hours. Analysis of crude 1 H NMR using internal standard 1,2-dimethoxyethane showed 1:2.5:1.5 meta:dimeta:para borylation (overall meta:para ratio of 2.3:1) in 99% yield. The crude product was purified by silica gel chromatography (10% EtOAc in Petroleum Ether 40-60 o C) and gave the title compound (as a 1:2.5:1.5 meta:dimeta:para ratio or overall meta:para ratio of 2.3:1, as determined by 1 H NMR) as a colourless oil (101.4 mg, 0.22 mmol, 88%). The mass quoted above is the actual mass of the isolated mixture of products, whilst the amount of substance in mmol has been calculated by examining the ratios of the dimeta to monoborylated products and accounting for the extra mass due to the higher molecular weight of the dimeta product. By subtracting the resonances for the meta isomer, the NMR data of the dimeta and para isomer can be assigned as follows:  . Stirred in vial at 50 °C for 20 hours. Analysis of crude 1 H NMR using internal standard 1,2-dimethoxyethane showed 11.2:3.9:1 meta:dimeta:para borylation (overall meta:para ratio of 15.1:1) in 91% yield (with 9% unreacted starting material). The crude product was purified by silica gel chromatography (10% EtOAc in Petroleum Ether 40-60 o C) and the monoborylated products were partially separated from the dimeta product. Mono borylated products were isolated as colourless oil (52 mg) with 14:1 meta:para ratio (as determined by 1 H NMR). A small amount of B 2 Pin 2 impurity was found to be inseparable from the final product on silica. Corrected yield -60 mg, 0.15 mmol, 60%.

Dtbpy in THF:
Following general procedure F usin trans-12a (67.8 mg, 0.25 mmol), B 2 pin 2 (127 mg, 0.50 mmol), [Ir(COD)OMe] 2 (2.5 mg, 0.00375 mmol) and dtbpy (2.0 mg, 0.0075 mmol) in THF (1.25 mL). Stirred in vial at 50 °C for 20 hours. Analysis of crude 1 H NMR using internal standard 1,2-dimethoxyethane showed 1:1.4:1.3 meta:dimeta:para borylation (overall meta:para ratio of 1.8:1) in 98% yield. The crude product was purified by silica gel chromatography (10% EtOAc in Petroleum Ether 40-60 o C) gave the title compound (as a 1:1.3:1.2 meta:dimeta:para ratio or overall meta:para ratio of 1.9:1, as determined by 1 H NMR) as a white solid (104.3 mg, 0.24 mmol, 94%). The mass quoted above is the actual mass of the isolated mixture of products, whilst the amount of substance in mmol has been calculated by examining the ratios of the dimeta to monoborylated products and accounting for the extra mass due to the higher molecular weight of the dimeta product. By subtracting the resonances for the meta isomer, the NMR data of the dimeta and para isomer can be assigned as follows:

N-(3-(2-Bromophenyl)propyl)-N-ethyl-2,2,2-trifluoroacetamide (15)
A flask was charged with (7c) (900 mg, 2.90 mmol) in THF (10 mL) and cooled to 0 °C before the portion wise addition of NaH (174 mg, 4.35 mmol, 60% on mineral oil Substrates 13, 14 and 15 were submitted to borylation with ligand 1a and in all cases regioselectivity was found to be poor, implicating the crucial aspect of hydrogen bonding in the transition state for high meta-selectivity to be achieved. Procedures and characterisation data for the borylation of these compounds is given below.

meta para
Following general procedure F using N-

Synthesis of Bipyridine Ligands General procedure A for the preparation benzyl substituted bipyridines from 4,4'-dimethyl-2,2'bipyridine:
Di-isopropylamine (1.05 eq) was dissolved in THF (0.5 M) and cooled to 0 °C before the dropwise addition of n-BuLi (0.95 eq). The resulting solution was stirred for 30 mins at 0 °C before the quick addition of a solution of 4,4'-dimethyl-2,2'-bipyridine (1 eq) in THF (0.14 M). The reaction was warmed to RT and stirred for 2 hours before cooling to -78 °C and the appropriate electrophile (1.1 -2.5 eq dissolved in THF if required) added quickly. The reaction was quenched at the specified temperature after a specified time (water or EtOH). Ethyl acetate was added and the aqueous layer separated and further extracted with 2 portions of ethyl acetate. The organic layers were combined, dried (MgSO 4 ) and solvents removed in vacuo. The crude product was subjected to column chromatography.
General procedure B for the preparation benzyl substituted bipyridines from 5,5'-dimethyl-2,2'bipyridine: Di-isopropylamine (1.2 eq) was dissolved in THF (3.3 M) and cooled to -78 °C before the dropwise addition of n-BuLi (1.1 eq). The resulting solution was stirred for 30 mins at -78 °C before the quick addition of a solution of 5,5'-dimethyl-2,2'-bipyridine (1 eq) in THF (0.18 M) and stirred for 2 hours at this temperature. The appropriate electrophile (1.1 -2.5 M) was added in a drop-wise fashion and the reaction was quenched at the specified temperature after a specified time (water of EtOH). Ethyl acetate was added and the aqueous layer separated and further extracted with 2 portions of ethyl acetate. The organic layers were combined, dried (MgSO 4 ) and solvents removed in vacuo. The crude product was subjected to column chromatography.
mCPBA (dried on high vac at rt for 30 mins, assume 85%) (101 mg, 0.5 mmol) was added to the sulphide redissolved in CH 2 Cl 2 (3 mL) and cooled to 0 °C. The mixture was stirred for 1 h at the same temperature before the solvents were removed in vacuo and the product purified by silica gel chromatography with EtOAc to yield 1e as a white solid (92 mg, 0.3 mmol, 30%).

2-(5'-Methyl-[2,2'-bipyridin]-5-yl)acetic acid
Di-isopropylamine (1.61 mL, 13.0 mmol) was dissolved in THF (5 mL) and cooled to -78 °C before the dropwise addition of n-BuLi (7.04 mL 11.3 mmol). The resulting solution was stirred for 30 mins at -78 °C before the quick addition of a solution of 5,5'-dimethyl-2,2'-bipyridine (2.0 g, 10.9 mmol) in THF (25 mL) and stirred for 2 hours at this temperature. CO 2 was bubbled through at the same temperature for 1 h and the reaction warmed to rt with CO 2 still being bubbled through. Water (ca. 5 drops) was added to quench the reaction and solvents were removed in vacuo. The residue was taken up in 1M NaOH (50 mL), washed with hexane (50 mL), and the organic phase extracted with 1M NaOH (2 x 50 mL). The acidity of the combined aqueous phases was adjusted to pH = 5 by the addition of 3M HCI, and the solvents removed in vacuo once more. Preparation adapted from and data in accordance with those previously reported. [15]