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 Figure 1. Mechanistic blueprints for IBX-mediated SET oxidation
not affected by the presence of water (entry 3), o-substituents adjacent to carbonyl groups (B) and aromatic systems (C), inspired by
(entries 4, 9, 11, 14, 17), or the presence of halogens (entries 5, the recently elucidated mechanism of the IBX-cyclization (A). SET )
6). Over-oxidation to the corresponding carboxylic acid was not single electron transfer; IBX ) o-iodoxy benzoic acid.
observed even in the presence of electron-rich substrates (entry
7). n-Butylbenzene enters the reaction smoothly, furnishing (85 °C, 4.0 equiv IBX), to the bis-aldehyde shown in entry 16.
n-butyrophenone, and so do methylnaphthalenes (entry 7) and In an intermolecular competition experiment, cyclodecanol and
tetrahydronaphthalenes (entries 9, 22), furnishing the correspond- p-tert-butyltoluene were allowed to react with IBX (2.5 equiv,
ing ketones. The expected retardation of the reaction by electron- 65 °C, fluorobenzene/DMSO 2:1) leading only to 2-cyclodecen-
withdrawing substituents (Vide infra) (entries 23, 24) allows 1-one and no aromatic aldehyde. While slightly longer times or
selective oxidation of xylenes and tetrahydronaphthalenes to higher temperatures were necessary for the oxidation of N-
mono-carbonyl systems (entries 11, 12, 9, 22). Noteworthy is the containing aromatic systems, it is noteworthy that no N-oxidation
observation that whereas the presence of olefins, N-heterocycles, was observed in such cases (entries 17, 18). The amide function-
amides, and aldehydes would ordinarily interfere with such ality did not hamper the oxidation reaction as demonstrated in
benzylic oxidations by a variety of reagents the present IBX- entries 19 and 20, but remarkably, the reaction could be turned
based method performs admirably in such circumstances. Thus, toward the oxazolidinone pathway by modulating the reactivity
oxidation of the unsaturated substituted toluenes in entries 13 and of the reagent simply by switching from fluorobenzene/DMSO
14 with IBX proceeds smoothly as compared to the use of DDQ, to THF/DMSO as solvent (entry 21).2,6
PDC, or CAN, all of which led to low conversion or decomposi- On the basis of mechanistic insights gained during these studies,
tion.5 It was also interesting to observe the stepwise oxidation of a number of observations could be rationalized. Thus, we have
the substrate of entry 15 leading, at 65 °C (2.5 equiv IBX), to previously found that the generality of the IBX-mediated cycliza-
the R,β-unsaturated aldehyde1d and, under more forcing conditions tion depicted in Figure 1A is highly dependent on the oxidation
potential of the substrate involved.2 Anilides with higher oxidation
(1) (a) Nicolaou, K. C.; Zhong, Y.-L. Baran, P. S. Angew. Chem., Int. Ed. potentials (electron-donating substituents) were found to cyclize
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, faster than those with lower oxidation potentials (electron-
Y.-L.; Vega, J. A. Angew. Chem., Int. Ed. 2000, 39, 2525-2529. (d) Nicolaou, withdrawing substituents). Since the present reaction is also
K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596-7597. believed to be a SET process, the same correlation should be
(e) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y.-L. Angew. Chem.,
Int. Ed. 2001, 40, 207-210. operative. Here, therefore, may lie the explanation for the failure
(2) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong, Y.-L.; Sugita, K.; of the substituted toluenes shown in entries 23 and 24 (electron-
Zou, N. Angew. Chem., Int. Ed. 2001, 40, 202-206. poor) to enter the reaction. The clean mono-oxidation of xylenes
(3) The originally postulated ionic mechanism1d is less favored in view of
the findings reported in ref 2. in entries 11 and 12 can also be attributed to the inability of the
(4) Franz, G.; Sheldon, R. A. In Ullmann’s Encyclopedia of Industrial
Chemistry, 5th ed.; Wolfgang, G., Yamamoto, Y. S., Campbell, F. T., (6) Although it was not necessary, dry solvents (Aldrich, EM Science) were
Pfefferkorn, R., Rounsaville, J. F.; VCH: Weinheim, 1991. employed in these reactions; thus, the oxygen may be derived from IBX itself.
(5) Larock, R. C. ComprehensiVe Organic Transformations; John Wiley Labeling studies to determine the origin of oxygen in the products will be
& Sons: New York, 1999; pp 1205-1207. reported in due course.

10.1021/ja004218x CCC: $20.00 © 2001 American Chemical Society

Published on Web 03/10/2001
3184 J. Am. Chem. Soc., Vol. 123, No. 13, 2001 Communications to the Editor

Table 1. Oxidation of Benzylic Positions Using IBX

a
All substrates were commercially available except for those in entries 13-16 and 19-21 which were prepared by standard methods. b For a
general procedure see Supporting Information. c Isolated yield of spectroscopically pure compounds. For full characterization of new compounds,
see Supporting Information.

electron-poor monoaldehyde products to participate in further substrates in which more than one aromatic position had the
oxidation.7 On the other hand, the failure of 2,4,6-trimethoxy- potential to be oxidized. The bis-methyl substituted pyridyl
toluene (entry 25) to yield the corresponding aldehyde (starting oxazoles 1-3 (Scheme 1) were chosen for their resistance to
material recovered) can be explained by the requirement of a free undergo oxidation at either methyl group with a variety of known
o-position for benzylic oxidation just as it is the case for anilide oxidants.8 In the event, compounds 1-3 were oxidized at 110
cyclization (see Figure 1 C and A).2 °C employing 10 equiv of IBX in DMSO, furnishing aldehydes
Armed with important information regarding the limitations 4-6 in 75-78% isolated yield along with ∼20% recovered
of the methodology, we then turned our attention to more complex starting material. HMQC and HMBC NMR experiments con-
(7) Selectivity in the mono-oxidation of xylenes is often a challenging (8) Finney, N.; Fang, A. Department of Chemistry, University of California,
problem; see, for example: Ohkubo, K.; Fukuzumi, S. Org. Lett. 2000, 2, San Diego, unpublished results. Professor N. Finney is gratefully acknowledged
3647-3650. for generous samples of oxazoles 1-3.
Communications to the Editor J. Am. Chem. Soc., Vol. 123, No. 13, 2001 3185

Scheme 1. Selective Oxidation of Substituted Oxazoles with Scheme 4. Selective Chemical Transformations with IBX
IBX

Scheme 2. Postulated Mechanistic Rationale for the Selective

Oxidation of 2-Methyl-3-tolyl-5-pyridyl Oxazoles to
2-Formyl-3-tolyl-5-pyridyl Oxazoles

at 120 °C for 24 h in DMSO led to this compound as the sole

aldehyde (50% yield).
Finally, to probe the selectivity and controllability of the
recently discovered IBX-based oxidations, we designed and
synthesized compound 11 (Scheme 4) to be used as a substrate.
Using only three standard conditions, 11 could be easily converted
into 12-17. Thus, treatment of 11 with 2.0 equiv of IBX at 65
°C in fluorobenzene/DMSO (2:1) in the presence of catalytic
amounts of TsOH (conditions B, Scheme 4) led to R,β-unsaturated
aldehyde 13 in 85% isolated yield. Further oxidation of 13 with
Scheme 3. Chemoselective Oxidation of Trioxsalen (9) to 3.0 equiv of IBX in DMSO at 90 °C (conditions C) furnished
Furanaldehyde 10 Using IBX fully oxidized compound 14 in 76% isolated yield. Compounds
11-14 could be converted to 15-17 simply by employing IBX
and THF/DMSO as the solvent system (conditions A). Alterna-
tively, 15 could also be cleanly converted to 16 by conditions B,
which, in turn, was smoothly transformed to 17 by conditions C.
In conclusion, we have developed, on the basis of mechanistic
rationale, a selective oxidation reaction of benzylic and other
firmed that the oxazole-bearing methyl group had been oxidized similarly activated positions based on IBX and demonstrated its
rather than the benzylic methyl group. When trimethyl oxazole scope, generality, and usefulness in organic synthesis. Most
was submitted to the same conditions, none of the corresponding significantly, this reaction appears to fit well as a chemospecific
aldehyde was detected, and more forcing conditions led only to tool within the family of IBX-mediated reactions recently reported
traces of aldehyde accompanied by several unidentified products. from these laboratories.1b-d It is expected that applications of this
The intriguing mechanistic rationale presented in Scheme 2 (which process to the construction of building blocks will facilitate
seemingly contradicts the observations, Vide supra, that a free molecular diversity construction and provide further enabling
o-position is required for oxidation) may explain this transforma- technologies for biology and medicine.
tion. Specifically, it is postulated that the aryl system of 2-methyl-
Acknowledgment. We thank Dr. D. H. Huang and Dr. G. Siuzdak
3-tolyl-5-pyridyl oxazoles such as 3 initiates the reaction by for NMR spectroscopic and mass spectrometric assistance, respectively.
transferring one electron to IBX, leading to species 7a which is This work was financially supported by the Skaggs Institute for Chemical
simply a resonance structure of 7b. Loss of a proton from 7b Biology, the National Institutes of Health (U.S.A.), a predoctoral
leads to 8a which, in resonance form 8b, leads to 2-formyl-3- fellowship from the National Science Foundation (P.S.B) and grants from
tolyl-5-pyridyl oxazoles such as 6 via the mechanism depicted ArrayBiopharma, Pfizer, Glaxo, Merck, Schering Plough, Hoffmann-La
in Figure 1C. Roche, Boehringer Ingelheim, DuPont, and Abbott Laboratories.
The above results and mechanistic considerations led us to
speculate on the IBX-mediated oxidation product of 5,5′,8- Supporting Information Available: Experimental procedures and
trimethylpsoralen (trioxsalen) 9 (Scheme 3). All evidence and spectral data for new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
mechanistic insights pointed to the furanaldehyde 10 as the most
logical outcome, and indeed, treatment of 9 with IBX (5.0 equiv) JA004218X