A Simple and Highly Practical Oxidation of Primary Alcohols to Acids Mediated by 2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO)

Abstract

Conversion of alcohols to the corresponding acids is an important transformation in organic and pharmaceutical synthesis and a number of methods have been developed to date. These include the classical and most well known methods using chromium(VI) oxides, represented by Jones reagent, 1,2) Collins reagent, 3,4) and pyridinium chlorochromate (PCC). 5,6) Although these methods are commonly applied on a laboratory scale, and are efficient enough to give materials in gram quantities, the highly toxic chromium salts produced in the reaction, strict control of reaction temperature (ca. Ϫ20°C) or preparation of unstable reagent are problematic from the standpoint of large scale synthesis of pharmaceutical products. The Parikh-Doering reaction was found to be useful to solve these problems and has been applied to the large scale synthesis of pharmaceutical intermediate. 7) However, this method involves stench (dimethyl sulfide), and in addition, pyridine-sulphur trioxide complex is rather expensive and should be stored under low humidity conditions. As an alternative reagent, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) is especially attractive since this reagent is inexpensive and readily available in large quantities from Koei Chemical Co. and Degussa AG. A number of oxidative methods mediated by TEMPO have been reported to convert alcohols to the corresponding aldehydes and ketones. 8,9) Recently Ley and Yasuda reported one-pot conversion of primary alcohols to the corresponding carboxylic acids using polymer-supported TEMPO. 10) However there appears to be few practical methods for direct conversion to acids amenable to a large scale synthesis. Conceptually, alcohols are converted to the corresponding aldehydes in the presence of catalytic amounts of TEMPO and sodium hypochlorite (NaClO) as cooxidant, followed by oxidation to acids by sodium chlorite (NaClO 2 ). Both NaClO and NaClO 2 are inexpensive and readily available in large quantities. The problematic feature in the process is that NaClO easily reacts with NaClO 2 . Zhao et al. developed a one-pot conversion of primary alcohols to the corresponding acids in the presence of catalytic amount of TEMPO in a mixture of acetonitrile and sodium phosphate buffer (pHϭ6.7). 11) The success of this process was attributed to the dilute conditions and reduced quantities of NaClO (10 mol%) to avoid the side reaction between NaClO and NaClO 2 . Whilst efficient enough to afford the materials in less than several hundreds grams quantities, the reported methods involved several drawbacks from the viewpoints of multi-kilogram scale manufacturing; (1) productivity is low due to diluted reaction conditions, (2) simultaneous addition of both NaClO and NaClO 2 , which easily react with each other, over 2 h is difficult to control on a large scale, (3) conversion of alcohols to aldehydes proceeded sluggishly due to the presence of the reduced amount of NaClO in the system. In addition, the mixture of NaClO 2 and NaClO appears to be unstable under the reported condition (pHϭ6.7) as...

Oxoammonium‐ and Nitroxide‐Catalyzed Oxidations of Alcohols

“…Nitroxide/hypochlorite-and chlorite-mediated oxidations have been carried out in two steps, albeit in the same reaction vessel. 187 The primary alcohol is oxidized to the aldehyde with sodium hypochlorite and TEMPO. Then, sodium chlorite is added to the reaction mixture to complete the oxidation.…”

Nitroxide‐Catalyzed Alcohol Oxidations in Organic Synthesis

“…It is found that a slightly lower pH, of 4-6, enhances the reactivity of the latter step. 79 For further examples of tandem reactions, see Section 12.10.…”

CuO and Ag2O/CuO Catalyzed Oxidation of Aldehydes to the Corresponding Carboxylic Acids by Molecular Oxygen

“…The transformation of aldehydes to carboxylic acids is an important reaction in organic synthesis. The commonly used oxidants for this transformation are NaClO 2 [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ], K 2 Cr 2 O 7 [ 8 , 9 ], pyridinium chlorochromate [ 10 ], quinolinium dichromate [ 11 , 12 , 13 ], KMnO 4 [ 14 , 15 , 16 ], H 2 O 2 [ 17 , 18 ] and so on. Organic solvents such as CH 3 CN, CH 2 Cl 2 , cyclohexane, formic acid and benzene are usually needed.…”