Safe and Scalable Aerobic Oxidation by 2-Azaadamantan-2-ol (AZADOL)/NO_x Catalysis: Large-Scale Preparation of Shi’s Catalyst

Abstract

A method for safe and scalable aerobic alcohol oxidation using 2-azaadamantan-2-ol (AZADOL), an azaadamantane-type hydroxylamine catalyst, with a NO x cocatalyst in a conventional batch reactor has been developed. The use of 2 mol % AZADOL and 10 mol % NaNO2 was determined to promote aerobic alcohol oxidation quantitatively within a reasonable time (8 h). Safety is ensured by controlling the reaction temperature below the flash point of the acetic acid solvent. The robustness of the developed method is demonstrated by the 500 g scale oxidation of diacetone fructose into Shi’s catalyst for asymmetric epoxidation.

4‐Chloro‐2‐azaadamantane N‐Oxyl (4‐Cl‐AZADO): A Readily Preparable Organocatalyst for NOx Co‐catalyzed Aerobic Alcohol Oxidation

“…For the time course of the oxidation of l ‐menthol ( 1 a ), 4‐Cl‐AZADO ( 7 b ) and 5‐F‐AZADO ( 4 ) had almost the same reactivity, while 4‐Cl‐AZADO ( 7 b ) has slightly improved initial reaction rate. Previous studies have reported that the use of nitroxyl radical catalysts without electron‐withdrawing groups (AZADO ( 8 ) and ABNO ( 9 )) resulted in a drastic decrease in reaction rate due to the deactivation of the catalyst caused by H 2 O [4a,5b] . 4‐Cl‐AZADO ( 7 b ) did not result in such deactivation, similar to 5‐F‐AZADO ( 4 ) and other heteroatom‐containing azaadamantane‐type nitroxyl radicals.…”

“…Furthermore, close investigation of the role of fluorine atom in 5‐F‐AZADO ( 4 ) revealed that the fluorine atom at C5 imparts 5‐F‐AZADO ( 4 ) catalytic robustness under acidic conditions by attenuating the basicity [5b] . Although non‐substituted AZADO ( 8 ) also completed the NOx‐cocatalyzed aerobic alcohol oxidation, a larger amount of AZADO ( 8 ) was necessary to promote the reaction [4a] . This critical finding on the role of the fluorine atom on the azaadamantane skeleton led our group to synthesize a scalable surrogate for 5‐F‐AZADO ( 4 ).…”

Electrochemical Evaluation of Nitroxyl Radical Catalysts and Electrochemical Detection of Cyclosporin A

“…TEMPO, A-TEMPO, AZADOL and NHPI were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). AZADOL is reported to be converted to AZADO by oxidation and has comparable oxidation activity for alcohols [18][19][20]. NNO [11] and Nor-AZADO [21] were synthesized according to the literature.…”

Applications of Sodium Nitrite in Organic Synthesis

“…Further, the same authors disclosed a scalable method for aerobic oxidation of alcohol by using nitroxyl radical catalyst 2‐azaadamantan‐2‐ol (AZADOL) and NaNO 2 as co‐catalyst (Scheme ) . In a conventional batch reactor the developed protocol oxidized diacetone fructose 108 into Shi's catalyst 109 , which is used as organocatalyst for the asymmetric epoxidation.…”