Oxalyl amide assisted palladium-catalyzed synthesis of pyrrolidones via carbonylation of γ-C(sp3)–H bonds of aliphatic amine substrates

The first Pd-catalyzed regioselective γ-carbonylation of oxalyl amide protected aliphatic amines with carbon monoxide leading to synthesis of pyrrolidones has been developed.


A 1a
A mixture of 1a (10.2 mg, 0.04 mmol, 1.0 eq), Pd(OAc) 2 (9.0 mg, 0.04 mmol, 1 equiv) and Benzene-d 6 (0.5 mL) in NMR tube was heated in an oil bath at 60 o C and 100 o C respectively for 10 h. The reaction mixtures were cooled to room temperature and further analyzed by 1 H NMR. From the NMR analysis we can speculated that the C-H activation could be happened at 100 o C. Thus, the palladium intermediate A might be formed during the catalytic cylcle. However, the palladium black was observed in the NMR tube reactions at 100 o C. We had tried to added nitrile compounds or benzoic acid derivaties, no one of them could prevent the decompsition of the palladium intermediates. Oxalyl amide protected tert-butylamine, which lack γ C-H bonds, was treated with Pd(OAc) 2 (1 equiv), AcOD (10 equiv) under CO atmosphere in mesitylene at 140 o C for 10 h. If the carbon monoxide could insert into Pd-N bonds, the complex 10 might be formed. Then, either 11 or 12 could be formed through reductive elimination from the complex 10. However, proton NMR analysis revealed that neither 11 nor 12 were generated. Based   Although the mechanistic details were unclear, based on our previously studies and pioneering reports, [1] we proposed a plausible mechanism for this γ-C(sp 3 )-H carbonylation reaction. The palladium complex A could be generated through a concerted metalation-deprotonation (CMD) pathway. One molecule of CO combined with Pd(II) center, followed by a 1,1-migratory insertion of CO into the Pd-C bonds, giving the key palladium intermediate B.

Reaction of Oxalyl Amide protected tert-Butylamine
The six-membered palladacycle B then underwent reductive elimination affording the desired product. Table S1. Optimization of Reaction Conditions  A 20 mL Schlenk-type tube (with a Teflon high pressure valve and side arm) was charged with 1a (1.28 g, 5 mmol, 1.0 eq), Pd(OAc) 2 (112.2 mg, 0.1 eq), AgOAc (2g, 2.5 eq), m-CF 3 PhCO 2 H (28.5 mg, 0.3 eq) and mesitylene (1.5 mL). The reaction tube was evacuated and back-filled with CO (3times), and connected with a 100 mL CO balloon. The vial was heated at 140 o C in an oil bath for 24 hours, then the reaction mixture was cooled to rt, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to give 2a as white solid in 72% yield. [ Compound 2a (55.3 mg, 0.2 mmol, 1.0 eq) was dissolved in a mixture of THF/MeOH (0.8/0.2 mL); NaOH (24 mg, 0.6 mmol, 3.0 eq) was then added. The mixture was heated to 50 o C and stirred for 24 hours. Water was added and the mixture was extracted with DCM. The combined organic layers was washed with water and brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the product in Compound 4a (55.3 mg, 0.2 mmol, 1.0 eq) was dissolved in a mixture of THF/MeOH (0.8/0.2 mL); NaOH (24 mg, 0.6 mmol, 3.0 eq) was then added. The mixture was heated to 50 o C and stirred for 24 hours. Water was added and the mixture was extracted with DCM. The combined organic layers was washed with water and brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the product in 96 % yield. 1  To a solution of 3,3-dimethylbutan-2-amine (20 mmol) in dichloromethane (40 mL) was added triethylamine (2.8 mL, 20 mmol, 1.0 equiv) at 0 °C. After stirring for 5 min, benzyl carbonochloridate (8.8 mL, 22 mmol, 1.1 equiv) was added dropwise and then the mixture was stirred for 6 h at rt overnight. Water was added and the mixture was extracted with DCM. The combined organic layers was washed with water and brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to give the desired picolinamide product in 93% yield. [3] Et 3 N, DCM

Preparation of trifluoromethanesulfonamide
To a solution of 3,3-dimethylbutan-2-amine (50 mmol) in dichloromethane (100 mL) was added triethylamine (7.0 mL, 50 mmol, 1.0 equiv) at -78 °C under nitrogen. After stirring for 5 min at -78 °C, trifluoromethanesulfonic anhydride (8.8 mL, 52.5 mmol, 1.05 equiv) was added dropwise and then the mixture was stirred for 1 h at that temperature before being quenched by ice water (100 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL × 2). The combined organic phase was washed with brine (30 mL), and then dried over anhydrous Na 2 SO 4 . Evaporation and column chromatography on silica gel afforded the product as colorless oil in 92% yield. [4] S7

Preparation of oxalamide substrates
.1. Preparation of N, N-Diisopropyloxamoyl chloride S1 [5] A solution of Diisopropylamine (7.01 mL, 50 mmol, 1.0 equiv) in CH 2 Cl 2 (50 mL) was added dropwise to a solution of oxalyl chloride (6.44 ml, 75 mmol, 1.5 equiv) in CH 2 Cl 2 (100 mL) at 0 °C, after stirring for 5 min, triethylamine (7.30 mL, 52.5 mmol, 1.05 equiv) was added dropwise. The solution was warmed to room temperature and stirred for 6 hours. The excess of oxalyl chloride and the solvent were removed under reduce pressure and CH 2 Cl 2 (30 mL) was added and evaporated. This operation was performed twice to give 1a as a pale yellow solid. The crude product was used in the next step without any purification. 9.2. General procedures for the preparation of oxalamide substrates 1a, 1d, 1g, 1j-m, 1p, 3a-3h, 5, 7 [6] A solution of amine (20 mmol, 1.0 eq) in CH 2 Cl 2 (40 mL) was added dropwise to a solution of N,N-Diisopropyloxamoyl chloride S1 (25 mmol, 1.25 equiv) in CH 2 Cl 2 (50 mL) at 0 °C, after stirring for 5 min, triethylamine (2.92 ml, 21 mmol, 1.05 equiv) was added dropwise and then the mixture was stirred for 6 hours at room temperature before quenched by water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (20 mL × 2). The combined organic phase was washed with brine (30 mL), and then dried over anhydrous Na 2 SO 4 . Evaporation and column chromatography on silica gel afforded corresponding amide substrates as white solid or colourless liquid in >90% yield. To a solution of amino acid (20 mmol, 1.0 eq) in MeOH (30 mL), at 0 o C, was added SOCl 2 (4.35 mL, 60 mmol, 3.0 eq) dropwise. The resulting mixture was allowed to stir from 0 o C to room temperature overnight. The solvent was removed under reduced pressure to afford a white solid, which was used directly for next step. The second step followed the general oxalamide coupling procedure, to give the product in about 75% yield.

AcO
To a solution of 1a (3.00 g, 10 mmol, 1.0 eq) in MeOH (10 ml) at room temperature, was added NaBH 4 (0.76 g, 20 mmol, 2.0 eq) in portions. Water was added after the reaction was determined by TLC, and the mixture was extracted with DCM. The combined organic layers was washed with water and brine, dried over anhydrous Na 2 SO 4 , the resulting solution was used directly for next step. The solution was treated with AcCl (0.78 mL, 11 mmol, 1.1 eq) and Et 3 N (2.78 mL, 20 mmol, 2.0 eq) at room temperature overnight. Water was added and the mixture was extracted with DCM. The combined organic layers was washed with water and brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to give the product 1b 2.74 g, 87%.

S9
The first step using 3-amino-2,2-dimethylpropan-1-ol (2.06 g, 20 mmol, 1.0 eq) as starting material followed the general oxalamide coupling procedure, affording a white solid. The solid was dissolved in DCM (30 mL), and then added imidazole (2.72 g, 40 mmol, 2.0 eq) at rt. When the solution turned clear again, it was cooled to 0 °C and TBSCl (4.52 g, 30 mmol, 1.5 eq ) was added in small portions. Then the mixture was stirred for 6 hours at room temperature before quenched by water (20 mL). The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (20 mL × 2). The combined organic phase was washed with brine (15 mL), and then dried over anhydrous Na 2 SO 4 . Evaporation and column chromatography on silica gel to give the product 1e 5.81 g, 78%.

Preparation of 1f
The first step using 3-amino-2,2-dimethylpropan-1-ol (2.06 g, 20 mmol, 1.0 eq) as starting material followed the general oxalamide coupling procedure, affording a white solid. The solid was dissolved in DCM (30 mL), and the solution was treated with AcCl (1.56 mL, 22 mmol, 1.1 eq) and Et 3 N (2.78 mL, 20 mmol, 1.0 eq) at room temperature overnight. Water was added and the mixture was extracted with DCM. The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (20 mL × 2). The combined organic phase was washed with brine (15 mL), and then dried over anhydrous Na 2 SO 4 . Evaporation and column chromatography on silica gel to give the product 1f 4.92 g, 81%.

Palladium-catalyzed carbonylation of γ-C(sp 3 )-H bonds
A mixture of oxalamide (0.2 mmol, 1.0 eq), Pd(OAc) 2 (4.5 mg, 0.1 eq), AgOAc (83.4 mg, 2.5 eq), m-CF 3 PhCO 2 H (11.4 mg, 0.3 eq) and mesitylene (0.3 mL) in a 20 mL glass vial was purged with CO (3-times,), and sealed with a teflon septa. The vial was heated at 140 o C in an oil bath for 24 hours, then the reaction mixture was cooled to rt, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to give the product 2.   173.27, 170.81, 164.12, 162.73, 69.32, 52.37, 51.02, 45.  X-Ray Data for 2n-trans: Intensity data were collected with a Rigaku Mercury CCD area detector in ω scan mode using Mo Kαradiation (λ = 0.71070 Å). The diffracted intensities were corrected for Lorentz polarization effects and empirical absorption corrections. Details of the intensity data collection and crystal data are given in Table 2. The structures were solved by direct methods and refined by fullmatrix least-squares procedures based on |F| 2 . All the non-hydrogen atoms were refined anisotropically. All the H atoms were held stationaryand included in the structure factor calculation in the final stage of full-matrix least-squares refinement. The structures were solved and refinedusing SHELEXL-97 programs. This compound was known. [5] 11. Palladium-catalyzed carbonylation of γ-C(sp 2 )-H bonds A mixture of oxalamide (0.2 mmol, 1.0 eq), Pd(OAc) 2 (4.5 mg, 0.1 eq), AgOAc (83.4 mg, 2.5 eq), m-CF 3 PhCO 2 H (11.4 mg, 0.3 eq) and mesitylene (0.3 mL) in a 20 mL glass vial was purged with CO (3-times), and sealed with a teflon septa. The vial was heated in an oil bath for 24 hours, then the reaction mixture was cooled to rt, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to give the product 4.

Allylamine reaction (Scheme 2)
A mixture of allylamine 5 or 7 (0.2 mmol, 1.0 eq), Pd(OAc) 2 , AgOAc (83.4 mg, 2.5 eq), m-CF 3 PhCO 2 H (11.4 mg, 0.3 eq) and mesitylene (0.3 mL) in a 20 mL glass vial was purged with CO (3-times), and sealed with a teflon septa. The vial was heated in an oil bath for 24 hours, then the reaction mixture was cooled to rt, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to give the product 6 or 8.