A two-step approach to achieve secondary amide transamidation enabled by nickel catalysis

A long-standing challenge in synthetic chemistry is the development of the transamidation reaction. This process, which involves the conversion of one amide to another, is typically plagued by unfavourable kinetic and thermodynamic factors. Although some advances have been made with regard to the transamidation of primary amide substrates, secondary amide transamidation has remained elusive. Here we present a simple two-step approach that allows for the elusive overall transformation to take place using non-precious metal catalysis. The methodology proceeds under exceptionally mild reaction conditions and is tolerant of amino-acid-derived nucleophiles. In addition to overcoming the classic problem of secondary amide transamidation, our studies expand the growing repertoire of new transformations mediated by base metal catalysis.


General
Unless stated otherwise, reactions were conducted in flame-dried glassware under an atmosphere of nitrogen and commercially obtained reagents were used as received. Non-commercially available substrates were synthesized following protocols specified beginning on page S46.
Ligand SI-41 was obtained from Stream Chemicals, Inc. Reaction temperatures were controlled using an IKAmag temperature modulator, and unless stated otherwise, reactions were performed at room temperature (approximately 23 °C). Thin-layer chromatography (TLC) was conducted with EMD gel 60 F254 pre-coated plates (0.25 mm for analytical chromatography and 0.50 mm for preparative chromatography) and visualized using a combination of UV, anisaldehyde, and potassium permanganate staining techniques. Silicycle Siliaflash P60 (particle size 0.040-0.063 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on Bruker spectrometers (at 500 MHz) and are reported relative to residual solvent signals. Data for 1 H NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz), integration. Data for 13 C NMR are reported in terms of chemical shift (at 125 MHz). Data for 19 F NMR are reported in terms of chemical shift (at 282 MHz). IR spectra were recorded on a Perkin-Elmer UATR Two FT-IR spectrometer and are reported in terms of frequency absorption (cm -1 ). High-resolution mass spectra were obtained on Thermo Scientific™ Exactive Mass Spectrometer with DART ID-CUBE. Determination of enantiopurity was carried out on a Mettler Toledo SFC (supercritical fluid chromatography) using a Daicel ChiralPak OJ-H column.

Procedure for Activated Amide Transamidation via Nickel-Catalysis
Representative Procedure (coupling of amide SI-11 and morpholine (9) is used as an example). Amide 11 (Figure 3 entry 1). A 1-dram vial containing a magnetic stir bar was flame-dried under reduced pressure, and then allowed to cool under N 2 . The vial was charged with amide substrate SI-11 (79.3 mg, 0.200 mmol, 1.0 equiv), and the vial was flushed with N 2 .
Morpholine (9) (43.1 µL, 0.500 mmol, 2.5 equiv) was added to the vial, which was then taken into a glove box and charged with Ni(cod) 2 (5.5 mg, 0.020 mmol, 10 mol%) and SIPr (7.8 mg, 0.020 mmol, 10 mol%). Subsequently, toluene (0.20 mL, 1.0 M) was added. The vial was sealed with a Teflon-lined screw cap, removed from the glove box, and stirred at 35 C for 14 h. After cooling to 23 °C, the mixture was diluted with hexanes (0.5 mL) and filtered over a plug of silica gel (10 mL of EtOAc eluent). The volatiles were removed under reduced pressure, and the crude residue was purified by preparative thin-layer chromatography (1:1 Hexanes:EtOAc  100% EtOAc) to yield amide product 11 (83% yield, average of two experiments) as a white solid.
Amide 11: R f 0.32 (100% EtOAc). Spectral data match those previously reported. 7 Any modifications of the conditions shown in the representative procedure above are specified in the following schemes, which depict all of the results shown in Figure 3.

Amino Ester Scope
Representative procedure for free-basing amino esters and subsequent reaction with substrate SI-7 (coupling of amide SI-7 and alanine tert-butyl ester (SI-27) is used as an example).
Amide 32 (Figure 4 entry 1): A 25 mL flask with a magnetic stir bar was flame-dried under reduced pressure, and then allowed to cool under N 2 . The vial was charged with NH-Ala-OtBu HCl (500 mg, 2.76 mmol, 1.0 equiv), and the vial was flushed with N 2 . CH 2 Cl 2 (14.5 mL, 0.19 M) and Amberlyst ® A21 free base (1.0 g, 200 wt%) were added and the resulting mixture was stirred vigorously at 23 °C for 3 h. The mixture was then filtered over a plug of celite (15 mL of CH 2 Cl 2 ). The volatiles were removed under reduced pressure to yield the free-based amino ester (80% yield), which was used directly in the nickel-catalyzed transamidation.
A 1-dram vial containing a magnetic stir bar was flame-dried under reduced pressure, and then allowed to cool under N 2 . The vial was charged with substrate SI-7 (90.1 mg, 0.200 mmol, 1.0 equiv) and the free-based NH-Ala-OtBu (SI-27) (34.9 mg, 0.240 mmol, 1.2 equiv). The vial was flushed with N 2 , then taken into a glove box, and charged with Ni(cod) 2 (5.5 mg, 0.020 mmol, 10 mol%) and SIPr (15.6 mg, 0.040 mmol, 20 mol%). Subsequently, toluene (0.20 mL, 1.0 M) was added. The vial was sealed with a Teflon-lined screw cap, removed from the glove box, and stirred at 35 C for 14 h. After cooling to 23 °C, the mixture was diluted with hexanes (0.5 mL) and filtered over a plug of silica gel (10 mL of EtOAc eluent). The volatiles were removed under reduced pressure, and the crude residue was purified by preparative thin-layer chromatography (5:1 Hexanes:EtOAc) to yield amide product 32 (99% yield, average of two experiments) as an amorphous solid. Amide 32: R f 0.15 (5:1 Hexanes:EtOAc); 1 H NMR (500