Monoselective o-C–H Functionalizations of Mandelic Acid and α-Phenylglycine

Pd-catalyzed C–H functionalization of mandelic acid and α-phenylglycine is reported. We have developed different protocols for the arylation, iodination, acetoxylation, and olefination of these substrates based on two different (Pd(II)/Pd(IV) and Pd(II)/Pd(0)) catalytic cycles. Four crucial features of these protocols are advantageous for practical applications. First, the α-hydroxyl and amino groups are protected with simple protecting groups such as acetates (Ac, Piv) and carbamates (Boc, Fmoc), respectively. Second, these protocols do not involve installation and removal of a directing group. Third, monoselectivity is accomplished. Fourth, no epimerization occurs at the vulnerable α-chiral centers.

Compounds 3g, 3h, and 3l were isolated as the corresponding methyl ester. Therefore, the residue after the workup and filtration was dissolved in toluene/MeOH (3:1, 0.5 mL) and 150 µl TMSCHN 2 (2N solution in hexane, CAUTION!!! Inhalation of TMSCH 2 N 2 is potentially fatal and the chemical should be handled in the fume hood carefully.) was added dropwise to the reaction mixture. The solution was stirred for 30 min at r.t. and subsequently quenched witch 0.5 mL AcOH. The mixture was concentrated in vacuo and purified by preparative TLC using 9:1 hexanes:EtOAc to give the corresponding methy ester.

General Procedure for the Acetoxylation of Mandelic acid
A 8 mL vial with fully covered solid Teflon lined screw cap equipped with a magnetic stir bar was charged with the substrate (0.1 mmol, 1.0 equiv), PhI(OAc) 2 (64 mg, 0.2 mmol, 2.0 equiv), Pd(OAc) 2 (1.1 mg, 0.005 mmol, 5 mol%), KOAc (29 mg, 0.3 mmol, 3.0 equiv) and HFIP (1 mL). The vial was closed and stirred at 50 °C for 24 h. The reaction vessel was then cooled to rt. A 1.0 N HCl solution (1 mL) was then added, and the mixture was extracted with Et 2 O (3 × 3 mL). The organic layers were combined, filtered through a pad of Celite® 545 and concentrated in vacuo. The resulting residue was purified by preparative TLC using 2:1 hexanes:EtOAc (with 1% HOAc) as the eluent.

General Procedure for the Iodination of Mandelic acid
A 8 mL vial with fully covered solid Teflon lined screw cap equipped with a magnetic stir bar was charged with the substrate (0.1 mmol, 1.0 equiv), I 2 (51 mg, 0.2 mmol, 2.0 equiv), Pd(OAc) 2 (1.1 mg, 0.005 mmol, 5 mol%), AgOAc (33 mg, 0.2 mmol, 2.0 equiv), KOAc (29 mg, 0.3 mmol, 3.0 equiv) and HFIP (1 mL). The vial was closed and stirred at 50 °C for 24 h. The reaction vessel was then cooled to rt. A 1.0 N HCl solution (1 mL) was then added, and the mixture was extracted with Et 2 O (3 × 3 mL). The organic layers were combined, filtered through a pad of Celite® 545 and concentrated in vacuo. The resulting residue was dissolved in toluene/MeOH (3:1, 0.5 S11 mL) and 150 µl TMSCHN 2 (2N solution in hexane, CAUTION!!! Inhalation of TMSCH 2 N 2 is potentially fatal and the chemical should be handled in the fume hood carefully.) was added dropwise to the reaction mixture. The solution was stirred for 30 min at r.t. and subsequently quenched witch 0.5 mL AcOH. The mixture was concentrated in vacuo and purified by preparative TLC using 9:1 hexanes:EtOAc to give the corresponding methy ester.

General Procedure for the Olefination Reaction
A 8 mL vial with septum screw cap quipped with a magnetic stir bar was charged with the substrate (0.1 mmol, 1.0 equiv), Pd(OAc) 2 (1.1 mg, 0.005 mmol, 5 mol%), Ac-Leu-OH (2.6 mg, 0.015 mmol, 15 mol%) and KHCO 3 (20 mg, 0.2 mmol, 2.0 equiv). The vial was evacuated and flushed with O 2 (three times). After adding dry t-AmylOH (0.5 mL) and the olefin coupling partner (0.2 mmol, 2.0 mmol) to the reaction mixture, the vial was closed with a fully covered solid Teflon lined cap and stirred at 80 °C for 3 h (CAUTION!!! The reaction is run in a sealed vessel at elevated temperature under a 1 atm O 2 environment. Though no incidents have been encountered in the submitters' laboratory, it is nonetheless recommended that a blast shield be used is used while heating in larger scale). The reaction vessel was then cooled to rt. A 1.0 N HCl solution (1 mL) was then added, and the mixture was extracted with Et 2 O (3 × 3 mL). The organic layers were combined, filtered through a pad of Celite® 545 and concentrated in vacuo. The resulting residue was purified by preparative TLC using 2:1 hexanes:EtOAc (with 1% HOAc) as the eluent.

(R,E)-2-(2-(3-(benzyloxy)-3-oxoprop-1-en-1-yl)-5-chlorophenyl)-2-(pivaloyloxy)acetic acid (9h):
The compound 9h was prepared according to the general procedure and was obtained as a colorless oil (31.1 mg, 72% yield  37, 172.84, 166.24, 140.79, 136.13, 135.70, 134.61, 132.45, 129.75, 129.27, 128.65, 128.55, 128.27, 121.36, 71.28, 66.62, 38.73, 26.89 The side arm is fitted with a piece of rubber tubing, which, in turn, is connected to a three-way stopcock attached by rubber tubing to a high vacuum line and to a balloon filled with O 2 . The reaction tube was evacuated briefly and charged with O 2 ; this process was repeated three times, and the vessel was sealed tightly. The reaction mixture was stirred at room temperature for 5 min, during which time it is yellow to orange in color. The temperature was them increased to 80 °C for 4 h (CAUTION!!! The reaction is run in a sealed vessel at elevated temperature under a 1 atm O 2 environment. Though no incidents have been encountered in the submitters' laboratory, it is nonetheless recommended that a blast shield be used while heating). The reaction was allowed to cool to room temperature and a 1.0 N HCl solution (25 mL) was added to the solution. The solution was extracted with EtOAc (3 x 25 mL) and the combined organic extract was dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by column chromatography (hexanes:EtOAc:HOAc = 66:33:1) to yield 11a (1.29 g, 74%). S20