Ligand‐Promoted [Pd]‐Catalyzed α‐Alkylation of Ketones through a Borrowing‐Hydrogen Approach

Abstract A new class of palladium complexes bearing bidentate 2‐hydroxypyridine based ligands have been prepared and fully characterized. The applications of these new complexes towards ketone alkylation reactions with alcohols through a metal‐ligand cooperative borrowing‐hydrogen (BH) process were demonstrated.


General considerations
Unless otherwise noted, all solvents were freshly distilled under vacuum from sodium/benzophenone ketyl radical, except acetonitrile which was dried over calcium hydride. All experiments were carried out under an atmosphere of argon or nitrogen using standard Schlenk or high vacuum line techniques unless otherwise noted. Unless stated otherwise, commercially available reagents were purchased from Sigma Aldrich or Acros Organics and used as received. NMR-spectra were recorded on Bruker Ascend 500 MHz, Varian Unity INOVA 500 MHz or Bruker Advance 400 MHz spectrometers. Multiplicities are abbreviated as follows: (s) singlet, (d) doublet, (t) triplet, (q) quartet, (m) multiplet, (b) broad. IR spectra were recorded on a Bruker Alpha spectrometer, with diamond ATR-FT IR detection. Gas chromatographic analyses (GC) were made using a Hewlett-Packard 5890 II instrument with a flame ionization detector (FID) and a capillary column (CP-Sil 19CB 14% cyanopropyl-phenyl/86% dimethylpolysiloxane, 0.2 μm, 0.2 mm, 25 m) with decane as an internal standard. The retention times of different compounds in the gas chromatogram were identified using commercially available and synthesized pure compounds. X-ray data was collected with an Oxford Diffraction Excalibur 3 system, using ω scans and Mo Kα (λ = 0.71073 Å) radiation. The data were extracted and integrated using Crysalis RED. The structures were solved by direct methods and refined by full-matrix least-squares calculations on F 2 using SHELXT, SHELXL and OLEX2.
It was obtained as a colourless solid in 85% yield (87 mg). 1

Synthesis of Ligand L-1
Following literature procedures, 2-(benzyloxy)-8-bromoquinoline compound 11 was obtained in 82% yield starting from 2-bromoaniline and trans-cinnamoyl chloride. To a solution of 2-(benzyloxy)-8bromoquinoline and piperidine in toluene, Pd2(dba)3 (10 mol%), rac-BINAP (10 mol%) and Cs2CO3 (2 equiv.) were added at room temperature. Air from the reaction mixture was evacuated and refilled with nitrogen and the same process was repeated for three times at room temperature. Then, the reaction mixture was stirred at 110 °C for 72 h under N2 atmosphere. After cooling down to RT, water was added to the reaction mixture, and then compound was extracted with ethyl acetate, dried over MgSO4 and
The compound was extracted with chloroform, dried over MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel, dichloromethane/methanol) to get pure 8-(Piperidin-1-yl)quinolin-2-ol. It was obtained as a colourless solid in 69% yield (0.8 g). IR

6-(benzyloxy)picolinaldehyde 16 12 :
It is prepared according to the literature procedure. It was obtained as a colourless liquid in 93% yield

2-(Benzyloxy)-6-(piperidin-1-ylmethyl)pyridine:
6-(Benzyloxy)picolinaldehyde (1 equiv.) was added to a solution of piperidine (1.2 equiv.) in dry methanol at room temperature under nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for overnight. 1.2 equiv. of NaBH4 was added to the reaction mixture at 0 °C in the two batches in 1 h interval time. After 2 h, the reaction mixture was neutralized with saturated NH4Cl solution and compound was extracted using dichloromethane and dried over MgSO4. Dichloromethane was evaporated in reduced pressure and the crude was purified by column chromatography (silica gel, dichloromethane/methanol) to furnish pure 2-(Benzyloxy)-6-(piperidin-1-ylmethyl)pyridine as a yellow liquid in 94% yield (0.75 g). IR (cm -

Synthesis of Ligand L-3 N-((6-(benzyloxy)pyridin-2-yl)methyl)-N-ethylethanamine:
6-(Benzyloxy)picolinaldehyde (1 equiv.) was added to a solution of diethyl amine (1.2 equiv.) in dry methanol at room temperature under nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for overnight. 1.2 equiv. of NaBH4 was added to the reaction mixture at 0 °C in the two batches in 1 h interval time. After 2 h, the reaction mixture was neutralized with saturated NH4Cl solution and compound was extracted using dichloromethane and dried over MgSO4. Dichloromethane was evaporated in reduced pressure and the crude was purified by column chromatography (silica gel, dichloromethane/methanol) to furnish pure N-((6-(benzyloxy)pyridin-2-yl)methyl)-N-

Scheme 6: Preparation of ligand 4 (L4)
The deoxy-ligand L4 was synthesized according to the reported literature procedure. 15 The key starting