Near-Ambient-Temperature Dehydrogenative Synthesis of the Amide Bond: Mechanistic Insight and Applications

The current existing methods for the amide bond synthesis via acceptorless dehydrogenative coupling of amines and alcohols all require high reaction temperatures for effective catalysis, typically involving reflux in toluene, limiting their potential practical applications. Herein, we report a system for this reaction that proceeds under mild conditions (reflux in diethyl ether, boiling point 34.6 °C) using ruthenium PNNH complexes. The low-temperature activity stems from the ability of Ru–PNNH complexes to activate alcohol and hemiaminals at near-ambient temperatures through the assistance of the terminal N–H proton. Mechanistic studies reveal the presence of an unexpected aldehyde-bound ruthenium species during the reaction, which is also the catalytic resting state. We further utilize the low-temperature activity to synthesize several simple amide bond-containing commercially available pharmaceutical drugs from the corresponding amines and alcohols via the dehydrogenative coupling method.


General Information
All dehydrogenation experiments were carried out under an inert atmosphere (with N2 or Ar) using standard Schlenk techniques. Complexes RuHCl(CO)P tBu NNtBuH (1), 1 RuHCl(CO)P tBu NNBnH (2), 1 RuHCl(CO)P Ph NNtBuH (3), 2 RuHCl(CO)P tBu NNEt (4), 3 RuHClP tBu NN Bpy (5), 4 RuHClP Ph NN Bpy (6), 5 Mn(CO)2BrP tBu NN BPy (7), 6 and Mn(CO)2BrP tBu NNtBuH (8) 7 were prepared according to the previously reported procedures. All catalysts were weighed inside nitrogen filled glove box. Reagent grade amines, alcohols and hexyl hexanoate were purchased from commercial sources and used without further purification. All solvents were purified according to standard procedures under an argon atmosphere, sparged with argon, and stored over 4 Å molecular sieves. Liquid amines, alcohols and esters were purged with argon for half an hour prior to their use. 1,3,5trimethylbenzene (mesitylene) and potassium tert-butoxide were purchased from commercial sources and used as received. NMR spectra were recorded at room temperature on a Bruker AMX-300 (300 MHz) or AMX-400 (400 MHz) or AMX-500 (500 MHz) spectrometers. Chemical shifts of the NMR spectra are reported relative to residual signals of CDCl3 ( 1 H NMR: δ = 7.26 ppm, 13 C NMR: δ = 77.16 ppm), benzene-D6 ( 1 H NMR: δ = 7.16 ppm, 13 C NMR: δ = 128.06 ppm), CD2Cl2 ( 1 H NMR: δ = 5.32 ppm, 13 C NMR: δ = 54.00 ppm) or the internal standard mesitylene. 31 P{ 1 H} NMR chemical shifts are reported in ppm downfield from H3PO4 and referenced to an external 85% solution of phosphoric acid in D2O. GC-MS was carried out on HP 6890 / 5973 (MS detector) instruments equipped with a 30 m column (Restek 5MS, 0.32 mm internal diameter) with a 5% phenylmethylsilicone coating (0.25 mm) and helium as carrier gas. GC was carried out on HP 6890 or Agilent 7890B Series GC System with N2 or Helium as carrier gas. IR spectra were recorded on a Nicolet FTIR spectrophotometer (KBr, thin Film). Optical rotations were measured in a PerkinElmar 341 series polarimeter with sodium lamp. Figure S1. Complexes screened for near-ambient temperature dehydrogenative amide synthesis in this study. S3 2. 1 H and 31 P{ 1 H} NMR spectra of selected complexes Figure S2. 1 H (top, 300 MHz) and 31 P{ 1 H} (bottom, 121 MHz) NMR spectra of complex 1 in C6D6. Figure S3. 1 H (top, 300 MHz) and 31 P{ 1 H} (bottom, 121 MHz) NMR spectra of complex 2 in C6D6. S5 3. Standard procedure for the dehydrogenative coupling In a N2 glove box, 5 µmol of ruthenium catalyst and 10 µmol of t-BuOK were dissolved in 1 mL of dry solvent (diethyl ether or methyl tert-butyl ether (MTBE) or toluene) in a 5 mL vial. The solution was stirred for 5 mins after which a solution of pre-dissolved alcohol (0.5 mmol) and amine (0.55 mmol) in 1 mL dry solvent was added to the initial solution. The resulting solution was transferred to a Schlenk tube. The tube was sealed, taken out of the box, and was connected to a condenser (ethylene glycol/ water: T = 1 o C) under argon flow. The Schlenk tube was subsequently dipped into a preheated oil bath (50 o C for Et2O; 70 o C for MTBE; and 130 o C for toluene as solvent) and the solution was refluxed under argon flow for the given time. Afterwards, the reaction solution was cooled to room temperature. A known amount of mesitylene was added to the solution as an internal standard. For some reactions where amide precipitation from solution was observed, THF was added to produce a homogeneous solution. A sample of the resulting solution was then analyzed by GC-MS and 1 H NMR with CDCl3 as the deuterated solvent. NMR yields were calculated from integration ratios between amide characteristics peaks and mesitylene methyl protons peak (δ ~ 2.2 ppm). The amides were isolated as described below.

S4
For Table 2, entries 2, 4, 16 The solvent, mesitylene standard, and any unreacted alcohol and amine were removed in vacuo to afford almost pure amide. The resulting solid was washed with pentane and subsequently recrystallized in cold ethyl acetate / hexane solvent mixture.
For Table 2, entries 1, 3,5,7,11,13 For amides which were viscous oils, after removing all the volatile solvent and reactants the remaining oily substance was extracted with hexane. Afterwards the hexane was removed in vacuo to obtain pure amides.
For Table 2, entry18, diamide White precipitation of the amide was observed during the reaction. The amide was isolated by filtering the solid from the solution after the reaction and then was washed with pentane to afford pure amide.
The chiral amides from Table 2, entries 19-20 were purified via column chromatography (ethyl acetate/ hexane) S6 Figure S4. Schematic representation of the reaction setup Figure S5. Detection of H2 gas after the reaction in a closed vessel. Helium was used as the carrier gas. S7 4. 1 H NMR spectra of selected crude reaction mixtures Figure S6. 1 H NMR spectra of the crude reaction mixture after dehydrogenative synthesis of Nbenzyllhexanamide ( Table 2, entry 2) in CDCl3. Figure S7. 1 H NMR spectra of the crude reaction mixture after dehydrogenative synthesis of Nbenzylbenzamide ( Table 2, entry 4) in CDCl3. THF was added after the reaction to dissolve precipitating amide. Acetone impurity from NMR tube. S8 5. Mechanistic reactions 5.1. Binding of different substrates to the dearomatized/ deprotonated PNNH complexes A scheme summarizing the different binding modes of different substrates to the dearomatized/ deprotonated ruthenium PNNH complexes is shown below, as observed during the course of this study.

Synthesis of complex 1d
In a 20 mL vial, 30 mg (63 µmol) of complex 1 was dissolved in 1 mL diethylether. 14.1 mg of t-BuOK was then added to the solution upon which the solution color changed to violet from light yellow. The solution was stirred for 5 mins after which 26 mg of 1-hexanol (pre-dissolved in 1 mL Et2O) was added to the solution. Subsequently, the resulting green colored solution was filtered through a short Celite® pad and transferred to a J. Young NMR tube. The tube was then heated at 45 o C for half an hour and the green solution turned yellow. Afterwards, the tube was taken back inside the box and the solvent and excess hexanol was removed in vacuum to afford complex 1d.C6H13OH. For 1d.C13H19NO, 4 eq of amine was also added alongside 4 eq of 1-hexanol with rest of the procedure being unchanged. 1 H and 31 P NMR spectra suggests that at room temperature, 1d exist as two isomers in 9:1 ratio. Single crystals of 1d suitable for XRD analysis were grown by dissolving 1d in a mixture of THF/pentane followed by slow evaporation of the solvent. IR (thin film, KBr) = 1900 cm -1 (νCO). S10 Figure S8. 1 H NMR spectrum of complex 1d.C6H13OH in C6D6.    In a 20 mL vial, 100 mg of the precursor was dissolved in 1 mL propylamine. 4 mL dioxane was added to the solution and the resulting mixture was heating at 100 o C in an oil bath with stirring for 16 h inside a closed Schlenk flask. Afterwards, the flask was cooled to room temperature followed by the removal of flask atmosphere through vacuum. The flask was then filled with argon and was heated at 100 o C for an additional 30 min. Afterwards, the flask was cooled down to room temperature and the dioxane and excess amine were removed under vacuum. 10 mL pentane was added to the remaining sticky white solid, stirred and the resulting solution was filtered through a short Celite® pad. The remaining solid was washed again with 10 mL pentane, which was also filtered. Both pentane solutions were combined from which the removal of pentane afforded the desired ligand as a colorless oily liquid with 78% yield.

Synthesis of the complex
In a 20 mL vial, 120 mg (0.126 mmol) of RuHCl(CO)(PPh3)3 was suspended in 3 mL THF. A solution of 55 mg PNNH(n-Pr) ligand (0.178 mmol) in 5 mL THF was added dropwise to the stirring suspension. The resulting solution was transferred to a pressure tube and heated at 66 o C for 3` hours. THF was then removed from the yellow solution under vacuum till the solution volume became 2 mL. Afterwards, 10 mL of pentane was slowly added to the solution while stirring resulting in the formation of pale yellow precipitates. The supernatant was decanted, and the pale yellow solid was washed with pentane (2x10 mL) and ether (2x5 mL) to afford complex 9 in 72% (43 mg) yield.    Data were collected on a Rigaku Xtalab Pro diffractometer dual source equipped with Dectris Pilatus 200K detector and microfocus, with CuK (=1.54184 Å). The data were processed with CrysAlis PRO . Structure was solved by direct methods with SHELXT. 8 Data were refined as Fullmatrix least-squares refinement based on F 2 with SHELXL 9 and OLEX2 10 . All non-hydrogen atoms were further refined with anisotropic displacement coefficients. Hydrogen atoms were assigned isotropic displacement coefficients, and their coordinates were allowed to ride on their respective carbons. Hydride was located in the electron density map. Crystallographic data and refinement parameters are summarized in Supplementary Table S1.

Procedure for the dehydrogenative synthesis of pharmaceuticals
Moclobemide: 5 µmol of catalyst 1 and 10 µmol of t-BuOK were mixed in a 5 mL vial and 1 mL MTBE was added. The resulting brown solution was stirred for 5 min. In a separate 5 mL vial, 0.5 mmol of pchlorobenzyl alcohol and 0.6 mmol of 4-(2aminoethyl)morpholine (CAS# 2038-03-1) were dissolved in 1 mL MTBE. The latter solution was then added to the former brown solution at which the color disappeared to give a light red solution. The whole solution was then transferred to a 20 mL Schlenk flask with a side arm. The flask was sealed, taken outside the box, and connected to a condenser (1 o C, EG/H2O). The solution was then refluxed for 60 h under argon flow (bath temperature 70 o C). After the given time, the flask was cooled down to room temperature, and a known amount of mesitylene was added to the solution as a standard. A portion of the solution was analyzed by 1 H NMR with CDCl3 as the solvent to determine the NMR yield. The CDCl3 solution was then added back to the parent solution and pure moclobemide was obtained from the crude solution by removing the solvent in vacuo, followed by recrystallization in a cold diethylether pentane solvent mixture (85%). Alternatively, moclobemide can also be purified by flash column chromatography (MeOH 1-2% in CH2Cl2) and obtained as a white powder (88% yield Itopride: 5 µmol of catalyst 1 and 10 µmol of t-BuOK were mixed in a 5 mL vial and 1 mL MTBE was added. The resulting dark brown solution was stirred for 5 min. In a separate 5 mL vial, 0.5 mmol of 3,4-dimethoxybenzyl alcohol and 0.6 mmol of 4-[2-(dimethylamino)ethoxy]benzylamine (CAS# 20059-73-8) were dissolved in 1 mL MTBE. The latter solution was then added to the former dark brown solution at which the brown color disappeared to give a light red solution. The whole solution was then transferred to a 20 mL Schlenk flask with a side arm. The flask was sealed, taken outside the box, and connected to a condenser (1 o C, EG/H2O). The solution was then refluxed for 60 h under argon flow (bath temperature 70 o C). After the given time, the flask was cooled down to room temperature, and a known amount of mesitylene was added to the solution as a standard. A portion of the solution was analyzed by 1 H NMR with CDCl3 as the deuterated solvent to determine the NMR yield. The NMR solution was then added back to the parent solution and pentane was added S29 to the solution. Formation of a white precipitate was observed which was filtered, washed with copious amounts of pentane and diethyl ether and dried to afford pure itopride in 92% yield.  N, N-Diethyl-meta-toluamide (DEET): 10 µmol of catalyst 1 and 20 µmol of t-BuOK were mixed in a 5 mL vial and 1 mL dioxane was added. The resulting violet solution was stirred for 5 min. In a separate 5 mL vial 0.5 mmol of 3-methylbenzyl alcohol and 5 mmol of diethylamine were dissolved in 1 mL dioxane. The latter solution was then added to the former violet solution at which the violet color disappeared to give a light red solution. The resulting solution was then transferred to a 50 mL Schlenk tube. 0.5 mmol of powdered K3PO4 was subsequently added to the reaction flask. Afterwards, the tube was sealed and heated at a bath temperature of 130 o C for 60 h. The generated gas mixture was released in the 6 th , 28 th and 50 th hour. After the given time, the reaction mixture was cooled down to room temperature and filtered via a short Celite pad to remove the K3PO4 affording a light yellow color solution. A known amount of mesitylene was added to the solution and a part of the solution was analyzed by 1 H NMR with CDCl3 as the deuterated solvent to determine the NMR yield (32%). The product was not isolated due to low yield. S31 8. 1 H and 13 C{ 1 H} spectra of isolated compounds   Gibbs free energies were computed by adding the free energy correction terms from the frequency calculations to the single point energies according to