Transition metal-free catalytic reduction of primary amides using an abnormal NHC based potassium complex: integrating nucleophilicity with Lewis acidic activation†

An abnormal N-heterocyclic carbene (aNHC) based potassium complex was used as a transition metal-free catalyst for reduction of primary amides to corresponding primary amines under ambient conditions. Only 2 mol% loading of the catalyst exhibits a broad substrate scope including aromatic, aliphatic and heterocyclic primary amides with excellent functional group tolerance. This method was applicable for reduction of chiral amides and utilized for the synthesis of pharmaceutically valuable precursors on a gram scale. During mechanistic investigation, several intermediates were isolated and characterized through spectroscopic techniques and one of the catalytic intermediates was characterized through single-crystal XRD. A well-defined catalyst and isolable intermediate along with several stoichiometric experiments, in situ NMR experiments and the DFT study helped us to sketch the mechanistic pathway for this reduction process unravelling the dual role of the catalyst involving nucleophilic activation by aNHC along with Lewis acidic activation by K ions.


Materials and Methods.
The pre-catalyst [aNHC.KN(SiMe 3 ) 2 ] 2 was prepared by following reported literature procedure. 1 All manipulations were carried out using standard Schlenk techniques using high-vacuum or inside a glovebox maintained below 0.1 ppm of O 2 and H 2 O. All glassware were oven-dried at 130 °C and evacuated while hot prior to use. All solvents were distilled from Na/benzophenone prior to use. All other chemicals were purchased from Sigma Aldrich and used as received. Elemental analyses were carried out using a Perkin-Elmer 2400 CHN analyzer and samples were prepared by keeping under reduced pressure (10 -2 mbar) for overnight. Analytical TLC was performed on a Merck 60F254 silica gel plate (0.25 mm thickness). NMR spectra were recorded on a JEOL ECS 400 MHz spectrometer and on a Bruker Avance III 500 MHz spectrometer. All chemical shifts were reported in ppm using tetramethylsilane as a reference. Crystallographic data for structural analysis of 1a was deposited at the Cambridge Crystallographic Data Center, CCDC number 1900619. These data can be obtained free of charge from the Cambridge Crystallographic Data Center.
Subsequently, 4-nitrobenzamide (0.5 mmol) was added to the reaction mixture and stirred for different time interval at different temperature ( o C). After completion of the reaction, 1.0 mL 2.0 (M) NaOH solutions was added to the reaction mixture drop-wise along with 1.0 mL Et 2 O and stirred for another 1h.

Control experiments for mechanistic investigation.
To proof the mechanistic course for the reduction of benzamides, we performed several stoichiometric reactions.
5a. Investigation into the radical or non-radical nature of 1 catalyzed benzamide reduction.
To evaluate whether the reduction of benzamide proceeds through a radical pathway or not, we performed the reaction in presence of a radical scavenger (

5b. Detection of molecular hydrogen in non-catalytic and catalytic hydroboration of benzamide.
An oven dried screw-cap NMR tube was charged with benzamide, 2a (0.1 mmol), pinacolborane (29 L, 0.2 mmol, 2 equivalent) and benzene-d 6 (600 L) in non-catalytic reaction and immediate evolution of molecular hydrogen was observed which was characterized through 1 H NMR spectroscopy.

5c. Preparation and characterization of aNHC-HBPin adduct.
An oven dried 5 mL borosil vial was charged with [aNHC.KN(SiMe 3 ) 2 ] 2 , 1 (0.2 mmol), pinacolborane (64 L, 0.44 mmol, 2.2 equivalent) and toluene (700 L) in a nitrogen filled glovebox. The green color of the reaction mixture was changed to colorless within few minutes and the reaction mixture was stirred for 12 h at room temperature. Subsequently, the reaction mixture was kept for crystallization at -35 o C.

X-ray crystallographic details.
Single crystals of compound 1a were mounted on a glass pip. Intensity data were collected on a SuperNova, Dual, Mo at zero, Eos diffractometer. The crystals were kept at 100K during data collection.
Atomic coordinates, isotropic and anisotropic displacement parameters of all the non-hydrogen atoms of two compounds were refined using Olex2, S15 and the structure was solved with the Superflip S16 structure solution program using Charge Flipping and refined with the ShelXL S17 refinement package using Least Squares minimization. Structure graphics shown in the figures were created using the Olex2 and X-Seed software package version 2.0. S18 Figure S2. View of the molecular structure of 1a. Ellipsoids are set at 50% probability level; hydrogen atoms of 1a have been omitted for the sake of clarity. Obsdreflns 5448 Table S3. Selected bond distances (Å) and angles (°) observed in 1a Bond Distance Bond Angles NMR characterization of aNHC-HBPin adduct (1a). Figure S3. 1 H NMR spectrum of aNHC-HBPin adduct (1a) recorded in C 6 D 6 . Figure S4. 13 C{ 1 H} NMR spectrum of aNHC-HBPin adduct (1a) recorded in C 6 D 6 . Figure S5. 11 B{ 1 H} NMR spectrum of aNHC-HBPin adduct (1a) recorded in C 6 D 6 .

Preparation and characterization of borylated-amide (2a').
An oven dried screw cap NMR tube was charged with benzamide (24.2 mg, 0.2 mmol), HBPin (58 L, 0.4 mmol, 2.0 equivalent) and THF-d 8 (600 L) in a nitrogen filled glovebox. Subsequently, the reaction mixture was kept at room temperature for 14 h and during the reaction, evolution of hydrogen gas was monitored through 1 H NMR spectroscopy. After completion of the reaction, borylated-amide (2a') was characterized through 1 H, 13 C, and 11 B NMR spectroscopies.

In situ NMR study to characterize the interaction between borylated-amide (2a') and KN(SiMe 3 ) 2 .
An oven dried screw cap NMR tube was charged with borylated-amide, 2a' (0.2 mmol), KN(SiMe 3 ) 2 (39.9 mg, 0.2 mmol) and THF-d 8 (600 L) in a nitrogen filled glovebox. Subsequently, the reaction mixture was repeatedly shaken at room temperature. Next, the interaction between borylated-amide, 2a' and KN(SiMe 3 ) 2 was characterized through 1 H, 13 C, and 11 B NMR spectroscopies. In 13 C NMR spectrum, ~ δ 9.9 ppm downfield shift of carbonyl carbon was observed as compared to that of 2a', and relatively low downfield shift was noticed in 11 B NMR (~ δ 1.3 ppm) spectroscopy. These observations clearly suggest the interaction between the K ion and carbonyl oxygen and along with this observation as well as taking into account the DFT calculations, formation of 7 was proposed.

5e. Characterization of in situ generated intermediate imine.
A screw cap NMR tube was charged with benzamide (12.1 mg, 0.1 mmol), or 4-chloro benzamide (15.6 mg, 0.1 mmol), HBPin (58 L, 0.4 mmol), 1 (2.9 mg, 0.002 mmol, 2 mol%) and toluene-d 8 (600 L) in a nitrogen filled glovebox and the reaction mixture was kept at 40 o C. Next, 1 H NMR spectroscopy of the reaction mixture was recorded after 2 h, when a resonance at δ 10.34 ppm for benzamide and δ 9.78 ppm for 4-chloro benzamide was observed in 1 H NMR spectroscopy. Also a resonance at δ 172.7 ppm for benzamide appeared in 13 C NMR spectrum, which clearly indicates the formation of an imine intermediate (Scheme S9).
Subsequently benzamide (0.5 mmol) was added to the reaction mixture and stirred for 12h at 40 o C. After completion of the reaction NMR was recorded in toluene-d 8 . S19 Scheme S10. Synthetic scheme for the formation of N,N-diborylated amine from benzamide.  Figure S18. 13 C{ 1 H} NMR spectrum of p-tolylmethanamine hydrochloride (3b) recorded in DMSO-d 6 .

Computational details and Coordinates.
All theoretical calculations for geometry optimization and Natural Bonding Orbital (NBO) analysis of all the complexes were carried out with the help of Gaussian16 S20 at B3LYP level of theory by using 6-31+g(2d,p) bases set S21 .