Highly chemoselective synthesis of hindered amides via cobalt-catalyzed intermolecular oxidative hydroamidation

α-Tertiary amides are of great importance for medicinal chemistry. However, they are often challenging to access through conventional methods due to reactivity and chemoselectivity issues. Here, we report a single-step approach towards such amides via cobalt-catalyzed intermolecular oxidative hydroamidation of unactivated alkenes, using nitriles of either solvent- or reagent-quantities. This protocol is selective for terminal alkenes over groups that rapidly react under known carbocation amidation conditions such as tertiary alcohols, electron-rich alkenes, ketals, weak C−H bonds, and carboxylic acids. Straightforward access to a diverse array of hindered amides is demonstrated, including a rapid synthesis of an aminoadamantane-derived pharmaceutical intermediate.


General Procedure for Substrate Preparation
To a 250 mL oven-dried round bottom flask equipped with a magnetic stir bar was added methyltriphenylphosphonium bromide (10 g, 28 mmol, 1.4 equiv.) and anhydrous THF (35 mL). Potassium tert-butoxide (3.4 g, 30 mmol, 1.5 equiv.) was added and the reaction mixture was stirred for 30 min at r.t., during which time the reaction mixture turned yellow. A solution of ketone (20 mmol, 1.0 equiv.) in anhydrous THF (20 mL) was added drop-wise to the reaction mixture. The reaction mixture was stirred for an additional 1.5 h at r.t. before quenched by the addition of 50 mL H2O. The resulting mixture was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel chromatography to get 1,1-disubstituted alkenes. Following this procedure, 2a, 7 2b, 8 2c, 9 2i, 10 2m, 11 2p, 12 2q 13 , 2w 14 were prepared, and their spectroscopic data matches literature reports.

S12
Following General Procedure A, the title compound was synthesized from alpha-terpineol (2h) (78.0 mg, 0.50 mmol). Diastereomeric ratio (3:1) was determined by 1 H NMR analysis of the crude reaction mixture. The product was purified by silica gel flash column chromatography (PE: ethyl acetate = 10:1 to 1:1) to afford 3h (57.7 mg, 54%, mixture of diastereoisomers) as a colorless solid. The stereochemistry of the major diastereomer (shown above) was determined by X-ray single crystal diffraction of a

diacetamide)
Adapted from a literature procedure. 22 An oven-dried 10 mL re-sealable screw-cap vial equipped with a Teflon-coated magnetic stir bar was charged with concentrated sulfuric acid (1 mL) and glacial acetic acid (2 mL). MeCN (1 mL) was added at 0 o C. Then 2o (112.2 mg, 0.5 mmol in 1 mL MeCN) was added dropwise. The mixture was stirred for 5 h at r.t. before quenched with 5 mL H2O. The pH of reaction mixture was adjusted to 7 -8 with saturated aqueous Na2CO3 (10 mL) and extracted with diethyl ether (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo and   Compound 3p (N-(8-methyl-1,4

Supplementary Figure 2. Reaction mixture of the gram-scale experiment.
A mixture of potassium hydroxide (powder, 0.34 g, 6.0 mmol), water (33 μL), and propylene glycol (0.25 mL) was stirred at room temperature for 1 h, to which was added 3i (0.12 g, 0.50 mol). The mixture was stirred at 170 °C for 12 h, cooled to r.t. followed by the addition of ice-cold water (10 mL). The reaction mixture was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford 8 (69. 8

IV-A. With Deuterium-Labeled Silane (Figure 5a)
An oven-dried 10 mL re-sealable screw-cap vial equipped with a Teflon-coated magnetic stir bar was charged with Co catalyst 1a (3.0 mg, 0.0050 mmol, 0.050 equiv.) and oxone (100 mesh, 184 mg, 0.30 mmol, 3.0 equiv.). The reaction vessel was then briefly evacuated and backfilled with nitrogen (this sequence was repeated a total of three times).
The levels of deuteration in each position (1, 1' and 3) were measured by 1 H NMR spectroscopy. 3u with multiple deuterium substitution at the 1,1' position was noticed by 1 H and 13 C NMR, as well as GCMS analysis. The 1 H NMR spectrum of 3u showed that 127% deuterium incorporation at C1 and no deuterium incorporation at C3.

IV-B. Test for Proton-Activation (Figure 5b)
An oven-dried 10 mL re-sealable screw-cap vial equipped with a Teflon-coated magnetic stir bar was charged with Co catalyst 1a (6.0 mg, 0.010 mmol, 0.010 equiv.) and oxone (100 mesh, 123 mg, 0.20 mmol, 2.0 equiv.). The reaction vessel was then briefly evacuated and backfilled with nitrogen (this sequence was repeated a total of three times).

S31
The level of deuteration at C(a) were measured by 1 H NMR spectroscopy to be 8% and confirmed by GCMS analysis.

IV-G. Effect of the H2O
An oven-dried 10 mL re-sealable screw-cap vial equipped with a Teflon-coated magnetic stir bar was charged with Co catalyst 1a (6.0 mg, 0.010 mmol, 0.10 equiv.) and oxone (100 mesh, 123 mg, 0.20 mmol, 2.0 equiv.). The reaction vessel was then briefly evacuated and backfilled with nitrogen (this sequence was repeated a total of three times). Anhydrous acetonitrile (1.0 mL), 2a (18.1 mg, 0.10 mmol, 1.0 equiv.), degassed H2O and 1,1,3,3-tetramethyldisiloxane (73 μL, 0.40 mmol, 4.0 equiv.) were added to the reaction vessel via syringe sequentially. The reaction mixture was stirred at r.t. for 18 h before an NMR internal standard (phenanthrene) was added. The mixture was filtered through a S34 short pad of silica gel with another 5 mL CH2Cl2/MeOH (20/1) as an eluent. The solvents were removed in vacuo and the residue was analyzed by 1 H NMR spectroscopy.

Crystallographic Data of Compound 3h
Compound 3h was dissolved in diethyl ether. The solvent was slowly evaporated at ambient temperature to afford the single crystal.