Selective oxidation at carbon adjacent to aromatic systems with IBX.

Department of Chemistry and The Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, California 92037 Department of Chemistry and Biochemistry UniVersity of California, San Diego 9500 Gilman DriVe, La Jolla, California 92093 ReceiVed December 5, 2000 A number of new synthetic technologies based on the reactivity of the periodinane reagents DMP and IBX have recently been reported from these laboratories.1 These reactions include the IBXinduced cyclization of unsaturated anilides (Figure 1A),1b whose single-electron transfer (SET) mechanism was recently elucidated,2 and the introduction of unsaturation next to carbonyl groups,1d now also believed to proceed, by analogy, via a SET mechanism (Figure 1B). On the basis of these mechanistic rationales, we hypothesized that benzylic positions could be oxidized by IBX via a SET mechanism as postulated in Figure 1C. If selective and easily controllable, such a process could be a valuable tool in organic synthesis in view of the ready availability and robustness of the potential substrates and widespread utility of the corresponding oxidized products.4 Herein, we report the realization, scope, and generality of such a process, and demonstrate the remarkable chemoselectivity of IBX-mediated processes based on simple modification of reaction conditions. As shown in Table 1, the IBX-induced oxidation of benzylic positions is quite general and proceeds efficiently in fluorobenzene/DMSO (2:1) or DMSO at 80-90 °C. The reaction is not affected by the presence of water (entry 3), o-substituents (entries 4, 9, 11, 14, 17), or the presence of halogens (entries 5, 6). Over-oxidation to the corresponding carboxylic acid was not observed even in the presence of electron-rich substrates (entry 7). n-Butylbenzene enters the reaction smoothly, furnishing n-butyrophenone, and so do methylnaphthalenes (entry 7) and tetrahydronaphthalenes (entries 9, 22), furnishing the corresponding ketones. The expected retardation of the reaction by electronwithdrawing substituents (Vide infra) (entries 23, 24) allows selective oxidation of xylenes and tetrahydronaphthalenes to mono-carbonyl systems (entries 11, 12, 9, 22). Noteworthy is the observation that whereas the presence of olefins, N-heterocycles, amides, and aldehydes would ordinarily interfere with such benzylic oxidations by a variety of reagents the present IBXbased method performs admirably in such circumstances. Thus, oxidation of the unsaturated substituted toluenes in entries 13 and 14 with IBX proceeds smoothly as compared to the use of DDQ, PDC, or CAN, all of which led to low conversion or decomposition.5 It was also interesting to observe the stepwise oxidation of the substrate of entry 15 leading, at 65 °C (2.5 equiv IBX), to the R,â-unsaturated aldehyde1d and, under more forcing conditions (85 °C, 4.0 equiv IBX), to the bis-aldehyde shown in entry 16. In an intermolecular competition experiment, cyclodecanol and p-tert-butyltoluene were allowed to react with IBX (2.5 equiv, 65 °C, fluorobenzene/DMSO 2:1) leading only to 2-cyclodecen1-one and no aromatic aldehyde. While slightly longer times or higher temperatures were necessary for the oxidation of Ncontaining aromatic systems, it is noteworthy that no N-oxidation was observed in such cases (entries 17, 18). The amide functionality did not hamper the oxidation reaction as demonstrated in entries 19 and 20, but remarkably, the reaction could be turned toward the oxazolidinone pathway by modulating the reactivity of the reagent simply by switching from fluorobenzene/DMSO to THF/DMSO as solvent (entry 21).2,6 On the basis of mechanistic insights gained during these studies, a number of observations could be rationalized. Thus, we have previously found that the generality of the IBX-mediated cyclization depicted in Figure 1A is highly dependent on the oxidation potential of the substrate involved.2 Anilides with higher oxidation potentials (electron-donating substituents) were found to cyclize faster than those with lower oxidation potentials (electronwithdrawing substituents). Since the present reaction is also believed to be a SET process, the same correlation should be operative. Here, therefore, may lie the explanation for the failure of the substituted toluenes shown in entries 23 and 24 (electronpoor) to enter the reaction. The clean mono-oxidation of xylenes in entries 11 and 12 can also be attributed to the inability of the (1) (a) Nicolaou, K. C.; Zhong, Y.-L. Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 622-625. (b) Nicolaou, K. C.; Zhong, Y.-L. Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 625-628. (c) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Vega, J. A. Angew. Chem., Int. Ed. 2000, 39, 2525-2529. (d) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596-7597. (e) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y.-L. Angew. Chem., Int. Ed. 2001, 40, 207-210. (2) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong, Y.-L.; Sugita, K.; Zou, N. Angew. Chem., Int. Ed. 2001, 40, 202-206. (3) The originally postulated ionic mechanism1d is less favored in view of the findings reported in ref 2. (4) Franz, G.; Sheldon, R. A. In Ullmann’s Encyclopedia of Industrial Chemistry, 5th ed.; Wolfgang, G., Yamamoto, Y. S., Campbell, F. T., Pfefferkorn, R., Rounsaville, J. F.; VCH: Weinheim, 1991. (5) Larock, R. C. ComprehensiVe Organic Transformations; John Wiley & Sons: New York, 1999; pp 1205-1207. (6) Although it was not necessary, dry solvents (Aldrich, EM Science) were employed in these reactions; thus, the oxygen may be derived from IBX itself. Labeling studies to determine the origin of oxygen in the products will be reported in due course. Figure 1. Mechanistic blueprints for IBX-mediated SET oxidation adjacent to carbonyl groups (B) and aromatic systems (C), inspired by the recently elucidated mechanism of the IBX-cyclization (A). SET ) single electron transfer; IBX ) o-iodoxy benzoic acid. 3183 J. Am. Chem. Soc. 2001, 123, 3183-3185