J. Am. Chem. Soc. 2001, 123, 3183-3185
3183
Selective Oxidation at Carbon Adjacent to Aromatic
Systems with IBX
K. C. Nicolaou,* Phil S. Baran, and Yong-Li Zhong
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 IBX-
induced cyclization of unsaturated anilides (Figure 1A),1b whose
single-electron transfer (SET) mechanism was recently eluci-
dated,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 wide-
spread 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 fluoro-
benzene/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 correspond-
ing ketones. The expected retardation of the reaction by electron-
withdrawing 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 IBX-
based 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 decomposi-
tion.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
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.
(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-cyclodecen-
1-one and no aromatic aldehyde. While slightly longer times or
higher temperatures were necessary for the oxidation of N-
containing aromatic systems, it is noteworthy that no N-oxidation
was observed in such cases (entries 17, 18). The amide function-
ality 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 cycliza-
tion 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 (electron-
withdrawing 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 (electron-
poor) 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.
10.1021/ja004218x CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/10/2001