Mechanistic investigation into the C(sp3)–H acetoxylation of morpholinones† †Electronic supplementary information (ESI) available: Experimental procedures, characterization data and kinetic details. See DOI: 10.1039/c8sc03434f

The study of a selective palladium(ii)-catalyzed C(sp3)–H acetoxylation reaction on a class of cyclic alkyl amines is reported.


4-(3,3-diethyl-5,5-dimethyl-2-oxopiperazin-1-yl)benzonitrile 1j
To a stirred solution of the diamine (338 mg, 1.79 mmol), chloroform (215 uL, 2.68 mmol), 3-penttanone (2.3 mL, 21.7 mmol) at 0 °C was added portion wise KOH (502 mg, 8.94 mmol) ensuring the temperature of the reaction remained below 5 °C. After the addition was complete, the reaction was allowed to warm to room temperature and was held for 18 h. The organic phase was then separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with brine, dried (MgSO4), then concentrated in vacuo to afford the crude product which was purified by flash column chromatography (Silica, 33% EtOAc in Petroleum ether 40-60 o C) to yield the title compound as a colourless oil (

General Procedure 6: Acetoxylation of Morpholinones
The morpholinone (1 equiv) was dissolved in acetic acid/acetic anhydride (4:1, 0.1 M), palladium(II) acetate (10 mol%) and PIDA (1.5 equiv) were added to the reaction flask and stirred for a specified time at 70 °C. The reaction was cooled to rt, quenched by the addition of sat. aq. NaHCO3 and extracted with CH2Cl2 (3x 20 mL). The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo.

3-((1-hydroxy-2-methylpropan-2-yl)amino)-3-propyldihydrofuran-2(3H)-one
A 10 mL microwave vial equipped with stir bar was charged with SX (51.4 mg, 0.2 mmol). To this was added concentrated hydrochloric acid (1.0 mL, 12 M) and the vial was sealed. The reaction mixture was heated at 90 o C for 16 h before being allowed to cool to room temperature. Mixture was neutralized to pH 6 by addition of solid sodium carbonate, diluted with dichloromethane (5 mL) and extracted. Organic layer was dried and concentrated in vacuo . The crude material was purified by flash column chromatography (dichloromethane to 20% ethyl acetate in dichloromethane) to provide the title compound as a colourless oil (30.9 mg, 72% yield).

2-(4-(4-(aminomethyl)phenyl)-2-ethyl-6,6-dimethylpiperazin-2-yl)ethanol 3
An oven dried 25 mL round bottom flask equipped with a condenser and stir bar was charged with 2j (67.1 mg, 0.2 mmol) and anhydrous tetrahydrofuran (3 mL). To this was added lithium aluminium hydride (40 mg, 1 mmol) at room temperature portionwise. After addition complete, mixture was heated at 60 o C for 3 h then cooled to room temperature. The mixture was quenched with a saturated solution of Rochelle's salt (2 mL) and stirred for 16 h. Organic layer was extracted with dichloromethane (3 x 5 mL), dried (Na2SO4) and concentrated in vaacuo . The crude mixture was purified using SCX-2 column eluting with a solution of ammonia in methanol

Trinuclear five-membered ring palladacycle
3-Ethyl-5,5-dimethyl-3-propylmorpholin-2-one (99.5 mg, 0.5 mmol) and palladium(II) acetate (168 mg, 0.75 mmol) were stirred in chloroform (4 mL) at 60 °C for 16 hours under air. The solution was cooled to room temperature and filtered through celite, eluting with chloroform. The solvent was then removed in vacuo and the residue was re-dissolved in a minimum amount of chloroform. This solution was added dropwise to 40-60 ºC petroleum ether (15 mL) and the resulting precipitate was filtered, washed with 40-60 ºC petroleum ether and dried in vacuo to afford the title palladacycle as a green solid (147 mg, 30% yield).
Mononuclear five-membered ring palladacycle-d5-pyridine complex: Resolved NMR spectra were obtained by treating the trinuclear palladacycle int-V with pyridine-d5 (2 drops added to 15 mg of palladacycle in CDCl3) to generate the corresponding pyridine complex

Stoichiometric C-H acetoxylation
A 5 mL vial equipped with a magnetic stir bar was charged with palladacycle (0.02 mmol), PhI(OAc)2 (38 mg, 0.12 mmol), and 1,2-dichloroethane (0.5 mL). Then the vial was sealed under air with a screw cap and Teflon septum, and placed in a pre-heated oil bath at 70 ºC stirred for 1 hours. The reaction mixture was cooled to room temperature and filtered through celite, eluting with ethyl acetate. Yields were determined by 1H NMR against 1,1,2,2-tetrachloroethylene as internal standard.

Entry
Equivalents

Order in Amine -Table S3
An oven dried microwave vial equipped with a stir bar was charged with PhI(OAc)2 (145 mg, 0.45 mmol, 1.5 equiv), 1,1,2,2-tetrachloroethane (30.6 µL), stock A (x ml), stock B (1.5 ml) and AcOH/Ac2O (4:1) (y ml). The vial was sealed with a Teflon cap, placed in a pre-heated oil bath at 70 °C and aliquots were analysed by GC/FID for 1 hour.  Table S3. The straight line of the graph also confirms the initial order of substrate to be -1 st with respect to reaction.

Same excess experiments -Table S4
We ran the reaction at 20% completion. If we were to see either product inhibition or catalyst deactivation, then the reaction starting at 20% completion would be faster than that started at 0% completion. Time adjusting the 20% completion reaction and overlaying onto the 0% completion plot, such that the initial amine concentrations are equivalent, indicates there are negligible differences between the two plots. We also tested the effect of adding the product (0.2 equivalents of acetoxylated product) to the 20% completion reaction and again negligible differences were observed.   S t a n d a r d r e a c t io n S a m e " e x c e s s " r e a c t io n mmol, 1.0 equiv.) in dichloromethane (2 mL) was added. The reaction was heated at this temperature for 1 hour. After the reaction was complete, the crude mixture was cooled to room temperature and filtered through a plug of silica (1.0 cm), eluting with dichloromethane (6 × 1 mL). The filtrate was concentrated in vacuo then the residue was purified by flash column chromatography to afford the acetoxylated product in 39% yield with 70%ee.

General considerations
Calculations were performed using the Amsterdam Density Functional (ADF) program 1-3 with Zero-Order Regular Approximation (ZORA) scalar relativistic BLYP-D3 exchange correlation (XC) potential, a small frozen core, 'good' numerical integration quality and solvent effects were considered using an implicit conductor like screening model (COSMO). This combination of exchange-correlation potential and basis set has been previously benchmarked for palladium catalysis by others 4,5 and also used previously within our group for studying C(sp 3 )-H activation reactions of amines with palladium. 6,7 Proposed intermediates were first optimised using the Universal Forcefield (UFF) molecular mechanics forcefield. 8 The resultant structures were then subjected to DFT geometry optimisation using a TZP basis set for palladium and iodine and a DZP basis set for all other atoms. Vibrational frequency analysis was then performed on structures using a TZ2P basis set for all atoms to confirm that the structures were minima. Transition states were found from DFT minimised intermediates using a series of linear transits employing a TZP basis set for palladium and a DZP basis set for all other atoms. Transition state structures were then confirmed by vibrational frequency analysis, with one negative frequency observed corresponding to the reaction co-ordinate.
Coordinates are listed in angstroms. All enthalpies and Gibbs free energies are given in kcal mol -1 , entropy is reported in kcal mol -1 K -1 .
All species were modelled at 333.15 K at 1 atm in dichloroethane.

3,3-diethyl-5,5-dimethyl-morpholin-2-one
Bonding Energy diagram for amine dissociation Figure S4: An energy level diagram to show the amine dissociation pathway. The Gibbs energy for Int-1 has been set to zero and all other energies are relative to Int-1.