9-Azanoradamantane N-Oxyl (Nor-AZADO): A Highly Active Organocatalyst for Alcohol Oxidation

Abstract

A highly active organocatalyst for alcohol oxidation has been developed. 9-Azanoradamantane N-oxyl (Nor-AZADO 4), constituting an unhindered, stable nitroxyl radical, exhibits superior catalytic activity to 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and AZADOs in the oxidation of alcohols to their corresponding carbonyl compounds.Key words organocatalyst; nitroxyl radical; alcohol oxidation; aerobic oxidation; 2-azaadamantane N-oxyl AZADO The oxidation of alcohols to their corresponding carbonyl compounds is one of the most fundamental transformations in both laboratory synthesis and industrial manufacturing, and numerous methods of such oxidation have been developed.1,2) In recent years, a stable class of nitroxyl radicals, as exemplified by TEMPO [2,2,6,6-tetramethyl piperidinyl 1-oxyl (1); Fig. 1], has been extensively used as a catalyst for the oxidation of alcohols in a wide range of chemistry. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] In particular, TEMPO-catalyzed alcohol oxidation has high priority in the pharmaceutical industry as an efficient, mild, and environmentally acceptable method. However, TEMPO is often inefficient in the oxidation of structurally hindered alcohols, posing a problem in the oxidation of secondary alcohols.We have recently reported that a less-hindered class of nitroxyl radicals, namely, 2-azaadamantane N-oxyls [AZADOs; AZADO (2a) and 1-Me-AZADO (2b)] and 9-azabicyclo[3.3.1]nonane N-oxyl [ABNO (3)], exhibit significantly enhanced reactivity compared with TEMPO.20-26) They exhibit extremely high activities toward a wide range of alcohols, including structurally hindered secondary alcohols that TEMPO fails to efficiently oxidize. 20,21) A structure-activity comparison indicated that the steric congestion near the active center exerts a critical impact on catalytic efficiency. 20) In our continuous interest in nitroxyl-radical-based oxidation, we envisaged that the catalytic activity of nitroxyl radicals can further be enhanced by reducing the steric factors around their active center. We herein report the advanced catalytic activity of 9-azanoradamantane N-oxyl [Nor-AZADO (4); Fig. 1]. This new catalyst exhibits superior catalytic efficiency to AZADO, 1-Me-AZADO and ABNO as well as to TEMPO.Nor-AZADO (4) was firstly synthesized in 1978 by Dupeyre and Rassat and reported to be a stable class of nitroxyl radicals.27) To the best of our knowledge, however, no study of Nor-AZADO has been reported since then. We were particularly interested in determining whether Nor-AZADO, which is a constraint variant of AZADO, produces the oxoammonium ions, which are useful for alcohol oxidation.Nor-AZADO was prepared in five steps from acetonedicarboxylic acid (5), glutaraldehyde, and benzylamine, by a previous method (Chart 1) with slight modification.

Discovery and Exploitation of AZADO: The Highly Active Catalyst for Alcohol Oxidation

“…A 0.003 mol% catalyst loading was sufficient to complete the reaction with Nor-AZADO. Nor- AZADO also exhibited efficient catalytic activity in the oxidation of primary alcohol compared with TEMPO, although AZADO and 1-Me-AZADO also worked well in this case 42,43) ( Table 6). The operationally facile and scalable features in synthesizing ABNO and Nor-AZADO should make their use applicable in many types of alcohol oxidation.…”

Electrochemical Oxidation of Amines Using a Nitroxyl Radical Catalyst and the Electroanalysis of Lidocaine

“…Iwabuchi and colleagues [22] reported that 2-azaadamantane N-oxyl (AZADO), which lacks steric hindrance around the active site, exhibited greater activity than TEMPO in organic synthesis reactions. Less-hindered nitroxyl radicals with various steric environments have been synthesized, and those with less bulky functionality exhibited greater activity [23][24][25][26]. Therefore, nortropine N-oxyl (NNO), which was modeled on AZADO, was synthesized in one step as a novel nitroxyl radical compound [27].…”

Selective Aerobic Oxidation of Alcohols with NO3− Activated Nitroxyl Radical/Manganese Catalyst System

“…[1] Traditionally,t his reactioni sp erformed using stoichiometric oxidants such as CrO 3 , [2,3] MnO 2 , [4,5] hypervalenti odine [6,7] or activated DMSO. Cost efficient and environmentally benign catalytic approaches employing O 2 [11][12][13][14][15][16] or NaOCl [17][18][19][20][21] as oxidanth ave lately received great attention because their use would ease the environmental and economic burden of alcoholo xidation. Cost efficient and environmentally benign catalytic approaches employing O 2 [11][12][13][14][15][16] or NaOCl [17][18][19][20][21] as oxidanth ave lately received great attention because their use would ease the environmental and economic burden of alcoholo xidation.…”

“…[8][9][10] These reagents are all costly and their use in industrial-scale reactions result in large quantities of hazardous waste. Cost efficient and environmentally benign catalytic approaches employing O 2 [11][12][13][14][15][16] or NaOCl [17][18][19][20][21] as oxidanth ave lately received great attention because their use would ease the environmental and economic burden of alcoholo xidation. Especially aerobic oxidation has gained prominence owing to its advantages,s uch as abundance of O 2 in the atmosphere and water as the only byproduct.…”