Regiospecific α-methylene functionalisation of tertiary amines with alkynes via Au-catalysed concerted one-proton/two-electron transfer to O2

Regioselective transformations of tertiary amines, which are ubiquitously present in natural products and drugs, are important for the development of novel medicines. In particular, the oxidative α-C–H functionalisation of tertiary amines with nucleophiles via iminium cations is a promising approach because, theoretically, there is almost no limit to the type of amine and functionalisation. However, most of the reports on oxidative α-C–H functionalisations are limited to α-methyl-selective or non-selective reactions, despite the frequent appearance of α-methylene-substituted amines in pharmaceutical fields. Herein, we develop an unusual oxidative regiospecific α-methylene functionalisation of structurally diverse tertiary amines with alkynes to synthesise various propargylic amines using a catalyst comprising Zn salts and hydroxyapatite-supported Au nanoparticles. Thorough experimental investigations suggest that the unusual α-methylene regiospecificity is probably due to a concerted one-proton/two-electron transfer from amines to O2 on the Au nanoparticle catalyst, which paves the way to other α-methylene-specific functionalisations.

room temperature. After the resulting mixture was refluxed for 24 h and cooled to room temperature, it was added to an aqueous solution of NaOH (2 M, 50 mL) and extracted with diethyl ether. The organic layers were washed with brine and dried over K2CO3. After the filtration of K2CO3, the solvent was evaporated under reduced pressure, and the residue was purified by distillation, affording the desired N-methylamine.
8 the reaction was quenched by deionized water and 2M NaOH aqueous solution. After filtration of white solids and washing by dry diethyl ether, the filtrate was dried over Na2SO4. After filtration, an aqueous solution of 12M HCl (0.2 mL) was added to the solution with stirring. The resulting solution was evaporated in vacuo using azeotrope with toluene several times to afford the desired HCl salt (94.9 mg). 1 H NMR of 1a-d4 was measured in toluene-d8 after treatment with NaOD/D2O (40wt%) and filtration, determining the deuteration ratio (>95%).

Supplementary Tables
Supplementary Table 1 Fig. 3 (continued) X-ray photoelectron spectra around Au 4f components: (e) Au/TiO2, (f) Au/CeO2, and (g) Au/LDH. Black lines and blue broken lines indicate the deconvoluted signals and the sum of these lines. Red dotted lines indicate the data plots. The binding energies were calibrated by using the C 1s signal at 284.8 eV.  Fig. 4 Influence of the mid-reaction removal by hot filtration of catalyst Au/HAP on the profile of the reaction of 1-methylpiperidine (1a) with phenylacetylene (2a) to produce 1-methyl-
Yields were determined by gas chromatography analysis using biphenyl as internal standard.   Fig. 11 The effect of a radical scavenger (1 mmol, 1 equivalent with respect to 1a) on the -methylene-selective alkynylation of 1-methylpiperidine with phenylacetylene. The reaction conditions were the same as those described in Supplementary Fig. 4. GC-determined yields of 1methyl-2-(phenylethynyl)piperidine (3aa) are shown in the vertical axis. BHT: 2,6-di-tert-butyl-4methylphenol. before/after the reaction only with Au/HAP, (b) the spectra of 1a before/after the reaction with NaBD4 and Au/HAP, and (c) the spectra of 1a before/after the reaction with D2O and Au/HAP, recorded at ~25 °C in toluene-d8 at 500 MHz.  Fig. 17 13 C NMR spectra to detect the deuterium scrambling using several substrates and toluene-d8 solvent under the reaction conditions indicated in Fig. 2b: (a) the spectra of 1a-d2 before/after the reaction only with Au/HAP, (b) the spectra of 1a before/after the reaction with NaBD4 and Au/HAP, and (c) the spectra of 1a before/after the reaction with D2O and Au/HAP, recorded at ~25 °C in toluene-d8 at 126 MHz.  Supplementary Fig. 18 -Alkynylation of 1a with 2a in the presence of Au/HAP without any cocatalysts under an Ar atmosphere. Reaction conditions are indicated in the figure, and the yields were determined by GC using biphenyl as internal standard. Supplementary Fig. 19 The dependence of the initial condensation of 1a (0.1 mM, 0.15 mM, 0.2 mM, or 0.25 mM) on 3aa production rate using the present hybrid catalytic system comprising Au/HAP and    Fig. 32 Optimized structures of (a) Au20 cluster with no charge, the corresponding iminium cation of 1a, and (b) Au20 cluster adsorbed by the corresponding iminium cation of 1a based on DFT calculation. The Au20 cluster model was constructed by referring to our previous report S28 .
Although three types of initial adsorbed structures were investigated (adsorption site A, B, or C of Au20 cluster shown in this figure (a)), all the structures converged to the adsorbed structure at the site C as shown in this figure (b). The adsorption energy was calculated based on Gibbs energies of Au20 cluster, the corresponding iminium cation of 1a, and Au20 cluster adsorbed by the corresponding iminium cation of 1a in this figure.