Methyl‐Selective α‐Oxygenation of Tertiary Amines to Formamides by Employing Copper/Moderately Hindered Nitroxyl Radical (DMN‐AZADO or 1‐Me‐AZADO)

Abstract

Methyl-selective a-oxygenation of tertiary amines is ahighly attractive approach for synthesizing formamides while preserving the amine substrate skeletons.Therefore,the development of efficient catalysts that can advance regioselective aoxygenation at the N-methyl positions using molecular oxygen (O 2 )a st he terminal oxidant is an important subject. In this study,w es uccessfully developed ah ighly regioselective and efficient aerobic methyl-selective a-oxygenation of tertiary amines by employingaCu/nitroxyl radical catalyst system. The use of moderately hindered nitroxyl radicals,s uch as 1,5dimethyl-9-azanoradamantaneN -oxyl( DMN-AZADO) and 1-methyl-2-azaadamanane N-oxyl (1-Me-AZADO), was very important to promote the oxygenation effectively mainly because these N-oxyls have longer life-times than less hindered N-oxyls.V arious types of tertiary N-methylamines were selectively converted to the corresponding formamides.A plausible reaction mechanism is also discussed on the basis of experimental evidence,t ogether with DFT calculations.T he high regioselectivity of this catalyst system stems from steric restriction of the amine-N-oxyl interactions.

Transition‐Metal‐Free Multiple Functionalization of Piperidines to 4‐Substituted and 3,4‐Disubstituted 2‐Piperidinones

“…N ‐Methyl piperidine 29 was the most complicated substrate: under standard reaction conditions, N ‐formyl piperidine 31 was obtained as the major product; however, when buffer is changed to AcOH, the expected unsaturated lactam 30 is obtained in moderate chemical yield (see the Supporting Information for details). It is important to note that this unexpected result might signify an eco‐friendly alternative to the recently reported copper‐catalyzed formylation of N‐methyl amines to N‐formamides . Thus, trans ‐3,4‐disubstituted piperidone 33 was obtained from 30 when PhMgBr and formaldehyde were used as nucleophile and electrophile, respectively; then carbonyl reductions of 33 with LiAlH 4 followed by reported procedure gave Femoxetine (Scheme ) .…”

Organophotocatalytic Late-stage N-CH3 Oxidation of Trialkylamines with O2 in Continuous Flow

“…The inherent back pressure on the flow by the microfluidic module was sufficient to ensure precise, reproducible, low flow rates (down to 0.1 mL/min) up to 60 o C. To our delight, tropine 1b afforded 2b in 60% under reaction conditions at T = 40 o C and R T = 27 min (entry 10) despite its free 2 o alcohol typically prone to oxidation under similar oxidative conditions. 50,51,55,82 Decreasing catalyst loading decreased the yield (entries 11 and 12). Similarly to the case of substrate 1a, a marginal increase of yield to 61% occurred at 60 o C (entry 13).…”

“…Recently, Yamaguchi and co-workers circumvented this via an elegant Cu(II)/Cu(I) and Nitroxyl radical catalyst system. 55 Song and co-workers reported a transition metal free deconstructive formylation reaction. 56 The main drawbacks of such previous methods are i) the incompatibility of redox sensitive functionalities (commonly found on complex pharmaceuticals) hence limiting their application to relatively simple amines, ii) the expense of reagents (hindered nitroxyl radicals and excess difluorocarbene reagents) which are economically impractical for scale-up.…”

Copper‐Catalyzed Cascade N‐Dealkylation/N‐Methyl Oxidation of Aromatic Amines by Using TEMPO and Oxygen as Oxidants

“…Cu/nitroxyl catalyzed aerobic oxidation of C sp3 −H adjacent to nitrogen atom has been well established during past twenty years [20] . Recently, Yamaguchi and co‐workers reported a copper/nitroxyl radical catalyzed N ‐methyl oxidation of tertiary aliphatic amines generated formamide [5c] . Herein, we developed a copper‐TEMPO‐catalyzed tandem N ‐dealkylation and N ‐methyl aerobic oxidation of N ‐alkyl‐ N ‐methylarylamines to produce N ‐arylformamides (Scheme 1d).…”