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J. Org. Chem. 1999, 64, 2564-2566
Oxidation of Primary Alcohols to Carboxylic Acids with Sodium Chlorite Catalyzed by TEMPO and Bleach
Table 1. TEMPO-Catalyzed Oxidation of Primary Alcohols
Mangzhu Zhao,* Jing Li, Eiichi Mano,† Zhiguo Song, David M. Tschaen, Edward J. J. Grabowski, and Paul J. Reider Process Research Department, Merck Research Laboratories, Merck & Co. Inc., P.O. Box 2000, Rahway, New Jersey 07065 Received October 26, 1998
Introduction Oxidation is one of the most fundamental transformations in organic synthesis and numerous methods have been developed.1 However, relatively few good general methods exist for the oxidation of primary alcohols to carboxylic acids. Conditions for this transformation include Jones oxidation,2 the RuCl3/H5IO6 protocol,3 and TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxy)-catalyzed oxidation with sodium hypochlorite (NaOCl, or bleach).4 A two-step process involving Swern oxidation5 followed by oxidation of the resulting aldehyde with sodium chlorite (NaClO2) is another option.6 All of these methods have some limitations, and therefore alternative methods are still desirable. Recently, we reported a novel chromium-catalyzed oxidation of primary and secondary alcohols to the acids and ketones with periodic acid (H5IO6).7 Noyori et al. also published a Na2WO4-catalyzed oxidation of primary and secondary alcohols.8 We herein report a TEMPO-catalyzed oxidation of primary alcohols to the corresponding carboxylic acids, using NaClO2 as the stoichiometric oxidant. Results and Discussion In our recent work involving the oxidation of a primary alcohol similar to 1j (Table 1) to the carboxylic acid, we † Process R & D, Banyu Pharmaceutical Co. Ltd. Okazaki, Aichi 4440858, Japan. (1) Hudlicky, M. Oxidations in Organic Chemistry. ACS Monograph 186; 1990. (2) (a) Bowden; Heilbron; Jones; Weedon J. Chem. Soc. 1946, 3945. (b) Bowers; H.; Jones; L. J. Chem. Soc. 1953, 2548-2560. (c) Millar, J. G.; Oehlschlager, A. C.; Wong, J. W. J. Org. Chem. 1983, 48, 44044407. (3) Carlsen, P. H. J.; Katsuki, T.; Martin V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936-3938. (4) (a) Nooy, A. E. J. de; Besemer, A. C.; Bekkum, H. V. Synthesis 1996, 1153-1174. (b) Bobbitt, J. M.; Flores, M. C. L. Heterocycles 1988, 27, 509-533. (c) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559-2562. (d) Miyazawa, T.; Endo, T.; Shiihashi, S.; Okawara, M. J. Org. Chem. 1985, 50, 1332-1334. (e) Rychnovsky, S. D.; Vaidyanathan, R. J. Org. Chem. 1999, 64, 310-312. (5) (a) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480-2482. (b) Mancuso, A. J.; Brownfan, D. S.; Swern, D. J. Org. Chem. 1979, 44, 4148-4150. (c) Ireland, R.; Norbeck, D. J. Org. Chem. 1985, 50, 2198-2200. (6) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888890. (b) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567569. (7) Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 53235326. (8) Sato, K.; Aoki, M., Takagi, J.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 12386-12387.
desired a method that is economical and can tolerate sensitive functional groups such as neighboring chiral centers and electron-rich aromatic rings. We found that the RuCl3/H5IO6 protocol3 gave low yield ( 2 appeared to minimize the chlorination side product. Optimally, the substrate is dissolved in acetonitrile and mixed with pH ) 6.7 phosphate buffer. A catalytic amount (2-7 mol %) of TEMPO is added followed by simultaneous10 addition of NaClO2 and a catalytic amount (1-4 mol %) of bleach at 35 °C. This method is mild and efficient and has been demonstrated on a variety of primary alcohols (Table 1). Benzylic alcohols, including those with either electronwithdrawing or electron-donating groups, were oxidized to the benzoic acids 2a-2c in quantitative yield (entries 1-3). 2-Arylethanols were also converted to the arylacetic acids 2d-2g in excellent yields (entries 4-7). For comparison purposes, substrates with electron-rich aromatic rings were also subjected to the TEMPO/NaOCl oxidation4c (entries 3, 5-7, 10). In all of these cases, improved yields were obtained with this new procedure. The most striking example is 1g. The yield of the desired product 2g was only 42% using stoichiometric NaOCl4 in contrast to the quantitative yield obtained using NaClO2 with catalytic NaOCl (entry 7). One of the major side products in the oxidation with stoichiometric NaOCl was isolated and identified as the chlorinated compound 4 (Figure 1) based on NOE experiments. Similarly, 3-phenylpropargyl alcohol (1h) was oxidized to the acid 2h in 90% yield using our procedure vs
