Regioselective oxidation of phenols to o-quinones with o-iodoxybenzoic acid (IBX)

Article abstract of DOI:10.1021/ol017068j

Chemical equation presented An efficient regioselective method for oxidation of phenols to o-quinones is reported. When this procedure is combined with a subsequent reduction, it proves to be useful for the construction of a variety of catechols.

Full text of DOI:10.1021/ol017068j

ORGANIC
LETTERS
2002
Vol. 4, No. 2
285-288
Regioselective Oxidation of Phenols to
o-Quinones with o-Iodoxybenzoic Acid
(IBX)
Derek Magdziak, Andy A. Rodriguez,† Ryan W. Van De Water, and
Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106
pettus@chem.ucsb.edu
Received November 19, 2001
ABSTRACT
An efficient regioselective method for oxidation of phenols to o-quinones is reported. When this procedure is combined with a subsequent
reduction, it proves to be useful for the construction of a variety of catechols.
o-Quinones undergo a variety of reactions. For example,
these species can be reduced to the corresponding catechol.1,2
In addition, as a highly reactive 8π-electron system, o-
quinones display two 4π components as potential sites for
Diels-Alder reactions.3 The selectivity between sites results
from the polarizability of the complementary 2π component.
For example, polarized alkenes such as enamines add to the
external dione to restore aromaticity and yield a dioxin,4
while less polarized alkenes such as styrene add to the
cyclohexadiene portion to yield a [2.2.2]bicyclooctane.5
Because o-quinones display four 2π components, there are
varieties of [3 + 2] cycloaddition formats as well. The dipolar
addition can be controlled so that either a carbonyl or an
olefin moiety undergoes reaction.6 In addition, there are many
other reactions where the functional groups of o-quinones
can be distinguished. For example, cesium fluorosulfate
converts the most electrophilic carbonyl group of an o-
quinone to 2,2-difluorocyclohexadienone,7 while addition of
a Wittig reagent can generate a benzopyran-2-one.8 The ring
olefins can be distinguished in nonsymmetric o-quinones:
the most nucleophilic olefin is either oxidized or cleaved
with peroxyacid9 and Pb10 reagents, respectively.
Such versatility clearly suggests that unsymmetric o-
quinones should be of considerable synthetic use. However,
a convenient means to access a range of differently substi-
tuted o-quinones has been lacking due in part to the difficulty
in accessing the appropriately substituted catechol. A thor-
ough survey of the literature reveals a few methods that allow
for the regioselective conversion of a phenol to an o-
catechol.11 To the best of our knowledge, there are no
previous examples of a regioselective procedure for the direct
(6) (a) Nair, V.; Nair, J. S.; Vinod, A. U.; Rath, N. P. J. Chem. Soc.,
Perkin Trans. 1 1997, 21, 3129-3130. (b) Nair, V.; Sheela, K. C.;
Radhakrishnan, K. V.; Rath, N. P. Tetrahedron Lett. 1998, 39, 5627-5630.
(c) Takuwa, A.; Kai, R.; Kawasaki, K.-I.; Nishigaichi, Y.; Iwamoto, H. J.
Chem. Soc., Chem. Commun. 1996, 703-704.
* To whom correspondence should be addressed.
† Undergraduate research participant supported by the California Alliance
for Minority Participation (CAMP) in science.
(1) Cooksey, C. J.; Land, E. J.; Riley, P. A. Org. Prep. Proced. Int.
1996, 28, 463-467.
(7) Stavber, S.; Zupan, M. Tetrahedron 1992, 48, 5875-5882.
(8) Osman, F. H.; Abd El-Rahman, N. M.; El-Samahy, Fatma A.
Tetrahedron 1993, 49, 8691-8704.
(2) Dutta, D. K.; Boruah, R. C.; Sandhu, J. S. Indian J. Chem., Sect. B
1992, 31B, 780-781.
(3) Danishefsky, S. J.; Mazza, S. J. Org. Chem. 1974, 39, 3610-3611.
(4) Omote, Y.; Tomotake, A.; Kashima, C. J. Chem. Soc., Perkin Trans.
1 1988, 2, 151-156.
(5) Nair, V.; Maliakal, D.; Treesa, P. M.; Rath, N. P.; Eigendorf, G. K.
Synthesis 2000, 850-856.
(9) Viallon, L.; Reinaud, O.; Capdevielle, P.; Maumy, M. Tetrahedron
Lett. 1995, 36, 6669-6672.
(10) Pieken, W. A.; Kozarich, J. W. J. Org. Chem. 1989, 54, 510-512.
(11) Julia, M.; Pfeuty-Saint Jalmes, V.; Ple, K.; Verpeaux, J.-N. Bull.
Soc. Chim. Fr. 1996, 133, 15-24.
10.1021/ol017068j CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/04/2002

conversion of a phenol into an o-quinone. Oxidants such as
Fremy’s radical,12 MeReO3-H2O2,13 dimethyldioxirane,14
and benzeneseleninic anhydride15 are indiscriminate or favor
oxidation of the para position unless blocked with a sub-
stituent.
Table 1. Oxidations of Phenols with IBX at 25 °C
While investigating oxidative dearomatizations of 4-alky-
lated resorcinol derivatives16 with hypervalent iodine re-
agents, we discovered another useful oxidative property of
o-iodoxybenzoic acid, a reagent otherwise known as IBX
(1).17 Instead of the cyclohexa-2,5-dienone 3 observed with
IIII reagents,18 the o-quinone 4 smoothly emerged from phenol
2 in 69% yield (Figure 1).
Figure 1. An undesired but useful result.
Because of this unexpected yet pleasing transformation,
we paused to investigate the potential of this novel trans-
formation.
Table 1 illuminates the scope of this procedure. The
oxidation of an array of phenols (0.1 M in a respective
solvent) with a suspension of IBX (1 equiv) at room
temperature was investigated. A double oxidation was found
to ensue that produced a range of o-quinones. The reaction
times varied from 6 to 53 h and depended primarily upon
the polarity of the solvent and the functional groups
distributed within the starting phenol. The transformation
proved to be surprisingly general and regioselective, with
the limitation that the starting phenol material must contain
at least one electron-donating group.19 Phenols without
electron-donating substituents and those containing electron-
withdrawing groups such as -C(O)R, -CHO, and -NO2
failed to undergo oxidation.
Because most of the o-quinone products proved to be
volatile and highly reactive, the overall yield for this process
1
was estimated by H NMR. This was accomplished by
(12) Deya, P. M.; Dopico, M.; Raso, A. G.; Morey, J.; Saa, J. M.
Tetrahedron 1987, 43, 3523-3532. Compare oxidation of 22 in this article
with that of Fremy’s radical in: Zimmer, H.; Lankin, D. C.; Horgan, S. W.
Chem. ReV. 1970, 71, 229-246.
(13) Saladino, R.; Neri, V.; Mincione, E.; Marini, S.; Coletta, M.;
Fiorucci, C.; Filippone, P. J. Chem. Soc., Perkin Trans. 1 2000, 4, 581-
586.
(14) Crandall, J. K.; Zucco, M.; Kirsch, R. S.; Coppert, D. M.
Tetrahedron Lett. 1991, 32, 5441-5444.
(15) Barton, D. H. R.; Finet, J. P.; Thomas, M. Tetrahedron 1988, 44,
6397-406.
conducting the reactions in a deuterated solvent that was
1
doped upon completion with 1 equiv of a H NMR active
standard such as EtOAc or DMF. The percent conversion
was then estimated by comparing the integration of a proton
of the product with a proton of the standard.20
DMF proved to be the superior solvent. For example,
oxidation of 7 f 8 in CDCl3 required 14 h and proceeded
in 85% yield. Application of d7-DMF speeded the conversion
of 7 f 8 to 1.5 h in essentially quantitative yield. Similar
improvements were observed in the conversion of 9 f 8 by
exchanging d7-DMF for CDCl3. However, CDCl3 worked
well as a solvent in some instances. Oxidation of 5 f 6 in
(16) (a) Van De Water, R. W.; Magdziak, D.; Chau, J.; Pettus, T. R. R.
J. Am. Chem. Soc. 2000, 122, 6502-6503. (b) Jones, R. M.; Van De Water,
R. W.; Lindsey, C. C.; Hoarau, C.; Ung, T.; Pettus, T. R. R. J. Org. Chem.
2001, 66, 3435-3441.
(17) IBX (1), which is best known as the penultimate [I(V)] intermediate
in the synthesis of Dess-Martin periodinane, has gained popularity in its
own right as a mild oxidant for alcohols, particularly diols, and for the
selective oxidations of the carbon atom adjacent to aromatic systems, when
1 is applied in polar solvents: (a) Chaudhari, S. S. Synlett 2000, (2), 278.
(b) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2001,
123, 3183-3185. IBX is easily formulated by treatment of 2-iodobenzoic
acid with oxone. See: Frigerio, M.; Santagostino, M.; Sputore, S. J. Org.
Chem. 1999, 64, 4537-4538.
(19) Phenol itself failed to undergo oxidation with IBX.
(20) No correction was made for differences between the relaxation times
of the examined proton in the product and standard. However, protons with
similar characteristics and in similar chemical environments were compared
if possible. The crude spectra that are available for 6, 8, 11, 13, 15, 17, and
19 contain the 2-iodobenzoic acid byproduct of IBX.
(18) Pettus, L. H.; Van de Water, R. W.; Pettus, T. R. R. Org. Lett.
2001, 3, 905-908.
286
Org. Lett., Vol. 4, No. 2, 2002

CDCl3 required 19 h and afforded 6 in 92% yield, while
oxidations of 10 f 11, 12 f 13, and 16 f 17 proceeded in
96, 84, and 99% yields, respectively. The low-yielding
oxidation of 18 f 19 in both d7-DMF and CDCl3 is further
evidence of the requirement that the starting substrate contain
an electron-donating substituent, while the poor conversion
of 14 f 15 is believed to reflect a solubility problem of 14.
Reduction of the o-quinone product occurs upon hydro-
genation or exposure to Na2S2O4 (Figure 2). After an
Figure 2. One-pot procedure converting phenols to catechols.
Figure 3. Plausible mechanism.
oxidation conducted in DMF was complete, K2CO3 (2.5
equiv), Ac2O (2.1 equiv), and Pd/C (5 mol %) were added
to the crude product mixture and the resulting suspension
was stirred under a hydrogen atmosphere for 24 h. The bis-
acetylated catechol that emerged facilitated isolation. The
protected hydroquinone proved to be much more stable and
less volatile than the corresponding o-quinone and catechol
precursors. Since oxidation, reduction, and acylation occur
successiVely in the same pot, this procedure embodies a high-
yielding 1-pot conVersion of an electron-rich phenol into a
catechol. The isolated yields of the bis-acylated products 20
and 21, 87 and 76%, respectively, substantiated the validity
To test the validity of this mechanism, the phenol 22 was
exposed to IBX (1) (Figure 4). Because phenol 22 has no
1
of our H NMR method for estimating the yields of the
o-quinones.
This highly regioselective oxidation of phenols to o-
quinones with IBX (1) is remarkable because it represents a
double oxidation; a hydroxy residue is regioselectively
installed, and the resulting catechol intermediate is oxidized.
The process most likely follows the pathway shown in Figure
3. The starting material combines with IBX to extrude H2O
producing the IV intermediate A, which serves to intramo-
lecularly deliver the oxygen to the most nucleophilic and
least congested ortho site on the starting phenol. During this
delivery process, the IV atom is concurrently reduced to the
IIII species B, which in turn undergoes tautomerization to
intermediate C. The oxidation of catechols to o-quinones by
IIII reagents is well documented.21 These types of reactions
are believed to proceed by exchange of an IIII ligand for the
phenol to produce a structure similar to C that oxidatively
collapses with concurrent reduction of the iodine atom to
produce an o-quinone and an II reagent.
Figure 4. Evidence for the proposed mechanism.
R-hydrogens, the cyclohexa-2,4-dienone cannot tautomerize
and further oxidize. Instead, structure 23, which results from
a Diels-Alder dimerization of the corresponding methylated
intermediate B, emerges as the sole diastereomeric product.
This IIII dimer could be isolated but proved to be unstable
toward chromatography. Reduction of 23 with sodium
dithionite (Na2S2O4) furnished diol 24 in 51% (isolated yield),
and this structure was fully characterized. A 1H NOE study
of compound 24 established the relative stereochemical
configuration to be that which emerges from dimerization
of the cyclohexa-2,4-dienone intermediate on the face of the
alkoxy residue.
(21) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29(6), 677-680.
Org. Lett., Vol. 4, No. 2, 2002
287

In conclusion, the regioselective oxidation of electron-rich
phenols with IBX (1) proves to be useful as an efficient
method for the construction of a variety of catechols and
o-quinones using mild, nontoxic conditions. Furthermore,
such a procedure might find application in syntheses of
dimeric structures such as bisorbicillinol and trichodimerol.
California Alliance for Minority Participation in science
(CAMP), which is a statewide initiative funded by the
National Science Foundation (HRD-9624189). R.W.V. ap-
preciates the financial support of a 2001-2002 ACS Organic
Division Graduate Fellowship sponsored by Organic Syn-
thesis, Inc. We are also thankful for the support of our MS
facility, funded in part by DAAD19-00-1-0026.
Acknowledgment. Research support from the University
of California Cancer Research Coordinating Committee in
the form of two awards (19990641 and SB010064) is greatly
appreciated along with additional financial support from NSF
(CHE-9971211), PRF (PRF34986-G1), NIH (GM64831), the
UC-AIDS Initiative (K00-SB-039), NSF Career (0135031),
and Research Corporation (R10296). D.M. recognizes the
financial assistance of the UCSB Graduate Division Mentor
Fellowship. A.A.R. is indebted for summer support to the
Supporting Information Available: A general experi-
mental procedure along with the crude 1H NMR spectra used
to estimate yields for o-quinones 4, 6, 8, 11, 13, 15, 17, 19,
and 23 and full spectral characterization of 5, 20, 21, and
24. This material is available free of charge via the Internet
at http://pubs.acs.org.
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