Bismuth-catalyzed benzylic oxidations with tert-butyl hydroperoxide

Article abstract of DOI:10.1021/ol051765k

(Chemical Equation Presented) Oxidation of alkyl and cycloalkyl arenes with tert-butyl hydroperoxide catalyzed by bismuth and picolinic acid in pyridine and acetic acid gave the corresponding benzylic ketones (48-99%). Alternatively, oxidation of methyl arenes gave the corresponding substituted benzole acids (50-95%). Preliminary mechanistic studies were consistent with a radical mechanism rather than a bismuth(III)-bismuth(V) cycle.

Full text of DOI:10.1021/ol051765k

ORGANIC
LETTERS
2
005
Vol. 7, No. 21
549-4552
Bismuth-Catalyzed Benzylic Oxidations
with tert-Butyl Hydroperoxide
4
†
†
†
†
Yannick Bonvin, Emmanuel Callens, Igor Larrosa, David A. Henderson,
†
‡
,†
James Oldham, Andrew J. Burton, and Anthony G. M. Barrett*
Department of Chemistry, Imperial College London, Exhibition Road,
London SW7 2AZ, England, and Chemical DeVelopment, GlaxoSmithKline,
Medicines Research Centre, SteVenage SG1 2NY, England
agmb@imperial.ac.uk
Received July 26, 2005
ABSTRACT
Oxidation of alkyl and cycloalkyl arenes with tert-butyl hydroperoxide catalyzed by bismuth and picolinic acid in pyridine and acetic acid gave
the corresponding benzylic ketones (48 99%). Alternatively, oxidation of methyl arenes gave the corresponding substituted benzoic acids
50 95%). Preliminary mechanistic studies were consistent with a radical mechanism rather than a bismuth(III) bismuth(V) cycle.
−
(
−
−
The oxidation of activated benzylic C-H bonds is of
reagents are their toxicity, the costs of waste disposal, and
the removal of residual metal from the aromatic product. In
consequence, the development of a benzylic oxidation
reaction with a readily available and inexpensive catalyst of
low toxicity would be of considerable importance.
fundamental importance in the large scale synthesis of
1
specialty chemicals. Traditionally, these reactions involve
the use of stoichiometric quantities of potent oxidants such
2
as potassium permanganate or potassium dichromate. In the
past decade, several metal complex catalyzed processes for
effecting these transformations have also been reported, using
Co, Cr, Mn, Rh, Ru, Zn, and Fe species among others.
During the past few years the use of bismuth-based
11
reagents in several processes has gained popularity. Indeed,
3
4
5
6
7
8
9
10
12
despite being a heavy metal, bismuth has low toxicity. In
Nevertheless, the main disadvantages of the use of such
1998, Banik reported the use of sodium bismuthate for
13
benzylic oxidation reactions. However, the major drawback
of this process is the poor solubility of the bismuthate (a
compound with the ilmenite mineral structure), necessitating
the use of a large excess of the salt and prolonged reaction
times. From our understanding, bismuth has hitherto not been
used as a catalyst in the oxidation of substrates with benzylic
†
Imperial College London.
GlaxoSmithKline.
‡
(
1) Sheldon, R. A.; Kochi, J. K. In Metal-Catalysed Oxidation of Organic
Compounds; Academic Press: New York, 1981.
2) Hudlicky, M. In Oxidations in Organic Chemistry; ACS Monograph
No. 186; American Chemical Society: Washington, DC, 1990.
(
(
3) Lei, P.; Alper, H. J. Mol. Catal. 1990, 61, 51.
(4) (a) Muzart, J.; Ajjou, A. N. A. J. Mol. Catal. 1991, 66, 155. (b)
14
methylene or methyl groups.
Muzart, J. Tetrahedron Lett. 1987, 28, 2131. (c) Muzart, J. Tetrahedron
Lett. 1986, 27, 3139.
Herein, we now wish to report the use of bismuth-
catalyzed oxidations of alkylarenes to the corresponding
ketones and of methylarenes to arenecarboxylic acids using
(
(
5) Lee, N. H.; Lee, C.-S.; Jung, D. Tetrahedron Lett. 1998, 39, 1385.
6) Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004,
1
26, 13622.
7) Murahashi, S.-I.; Komiya, N.; Oda, Y.; Kuwabara, T.; Naota, T. J.
Org. Chem. 2000, 65, 9186.
8) Gupta, M.; Paul, S.; Gupta, R.; Loupy, A. Tetrahedron Lett. 2005,
6, 4957.
(
(11) (a) Matano, Y.; Nomura, H. J. Am. Chem. Soc. 2001, 123, 6443.
(b) Firouzabadi, H.; Iranpoor, N.; Amani, K. Synth. Commun. 2004, 34,
3587. (c) Organobismuth Chemistry; Suzuki, H., Matano, Y., Eds.;
Elsevier: New York, 2001.
(12) (a) Fabre, R.; Picon, M. J. Pharm. Chim. 1928, 8, 249. (b) Tillman,
L. A.; Drake, F. M.; Dixon, J. S.; Wood, J. R. Aliment. Pharmacol. Ther.
1996, 10, 459.
(
4
2
3
(9) Kim, S. S.; Sar, K. S.; Tamrakar, P. Bull. Korean Chem. Soc. 2002,
3, 937.
(10) (a) Santamaria, J.; Jroundi, R.; Rigaudy, J. Tetrahedron Lett. 1989,
0, 4677. (b) Remias, J. E.; Sen, A. J. Mol. Catal. A: Chem. 2003, 201, 63.
(
c) Punniyamurthy, T.; Iqba, J. Tetrahedron Lett. 1994, 35, 4003. (d) Paul,
(13) Banik, B. K.; Venkatraman, M. S.; Mukhopadhyay, C.; Becker, F.
F. Tetrahedron Lett. 1998, 39, 7247.
S.; Nanda, P.; Gupta, R. Synlett 2004, 531.
1
0.1021/ol051765k CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/16/2005

an excess of tert-butyl hydroperoxide as the oxidant in a
V
15
GoAgg -like system, using pyridine and acetic acid.
Initial experiments were focused on the oxidation of
tetrahydronaphthalene to R-tetralone with NaBiO as a
Table 1. Bismuth-Catalyzed Oxidations of Cyclic and Acyclic
Alkylarenesa
3
catalyst (Scheme 1). Several oxidants were examined and
Scheme 1. Bismuth-Catalyzed Oxidation of
Tetrahydronaphthalene to R-Tetralone
tert-butyl hydroperoxide was found to be superior to
hydrogen peroxide, peracids, and oxygen. The background
reaction with tert-butyl hydroperoxide, in the absence of any
bismuth catalyst, gave R-tetralone albeit in erratic yields
(14-54%), possibly due to traces of metal impurities in one
of the reagents. We next investigated the effect of the source
of bismuth on the reaction. Both sodium and potassium
bismuthate proved to be poor catalysts with low conversions
to R-tetralone. The use of alternative bismuth(III) sources
2 3 3 2 3 3 3
such as (BiO) CO , BiCl , Bi O , or Bi(NO ) and tert-butyl
hydroperoxide resulted in low to moderate conversions to
R-tetralone. Surprisingly, the most efficient oxidation condi-
tions utilized elemental bismuth (20 mol %) as a precatalyst.
This probably resulted from an enhancement of the solubility
or reduction in the particle size of the bismuth catalyst
16
generated in situ on reaction with tert-butyl hydroperoxide.
The catalyst loading could be reduced to 5 mol % but
increased reaction times were needed to achieve equivalent
conversions. Additives, particularly pyridine and pyrazine,
enhanced the rate of benzylic oxidation. The use of equimolar
quantities of picolinic acid and bismuth(0) in pyridine and
acetic acid (9:1) were especially effective and gave R-te-
tralone in 77% yield. The optimized procedure involved the
use of bismuth(0) (20 mol %), picolinic acid (20 mol %),
and 70% tert-butyl hydroperoxide in water (6 equiv), in
pyridine and acetic acid (9:1) at 100 °C.17,18 The benzylic
oxidation reaction was applied to a range of substrates (Table
1).
Excellent yields were obtained with substrates containing
doubly activated benzylic positions (entries 2-6 and 13) or
highly activated rings (entry 9). A substrate bearing a strongly
electron-withdrawing substituent underwent oxidation in
good yield albeit after longer reaction times (entry 12). It is
noteworthy that the regioselective oxidation of a benzylic
methylene group was possible in the presence of an arene
methyl substituent (entry 10) and a cyclic benzylic ether was
(14) The oxidation of allylic CH2 groups to provide enones with use of
t-BuOOH catalyzed by BiCl3 has been recently reported, see: Salvador, J.
A. R.; Silvestre, S. M. Tetrahedron Lett. 2005, 46, 2581.
(
15) (a) Barton, D. H. R.; Chavasiri, W. Tetrahedron 1994, 50, 19. (b)
Barton, D. H. R.; Wang, T.-L. Tetrahedron 1994, 50, 1011.
16) Although commercially available bismuth (Aldrich; 100 mesh) could
a Reaction conditions: see general procedure, ref 17. b Yields after
chromatography (the samples were all g95% pure by comparisons of 1H
and 13C NMR spectra of samples with commercial materials or, for
(
be used, higher yields were obtained with bismuth(0) generated from Bi2O3
by reduction with NaBH4. This is likely to be related to the generation of
higher surface area bismuth particles.
noncommercial compounds in entries 7, 13, 14, and 15, by comparisons
with published data). c The mixture was allowed to react for 46 h.
4550
Org. Lett., Vol. 7, No. 21, 2005

oxidized to the corresponding lactone in excellent yield (entry
3). Conveniently, the oxidation reaction was also effective
with heterocyclic systems (entries 15-17) without ap-
preciable oxidation of the heteroatom. Finally, benzylcyclo-
propane was smoothly oxidized to the corresponding ketone
without rearrangement (entry 18).
In addition to the bismuth-catalyzed tert-butyl hydroper-
2
oxide oxidation of substrates with alkyl-CH groups to
ketones, we also examined the oxidation of methylarenes to
produce arenecarboxylic acids. The use of the standard
oxidation17 on a variety of substrates resulted in moderate
to good conversions (entries 1-4; Table 2) albeit with 40
oxidant, capable of oxidizing lower valent manganese salts
24
1
to permanganate. In addition sodium bismuthate is also able
to bring about benzylic oxidation, as reported by Banik.13
On the other hand, it is known that peroxides can oxidize
25
bismuth(III) to bismuth(V) under alkaline conditions. These
facts underscore the seductive appeal of a catalytic cycle in
which bismuth(V) is the oxidizing species giving rise to the
ketones and is, in turn, regenerated by reoxidation with tert-
butyl hydroperoxide. Nevertheless, none of our experiments
support this hypothesis. First, the yields of ketones were poor
when bismuthate was used for the reaction (even with
stoichiometric amounts). Second, the background reaction
in the absence of bismuth is consistent with a radical
oxidation mechanism. Third, when other Lewis acids were
used, such as hafnium triflate, trimethylsilyl triflate, or boron
trifluoride etherate, enhanced rates of benzylic oxidation were
Table 2. Bismuth-Catalyzed Oxidations of Methylarenes
2
6,27
observed.
III) acting as a Lewis acid thereby modifying the reactivity
of the peroxide rather than acting in a bismuth(V)-bismuth-
These results are consistent with the bismuth-
(
2
8
(
III) cycle. The role of the picolinic acid in the reaction
was also examined. This could be acting as a ligand
facilitating the solubilization of the bismuth(III) species or
it could be oxidized to the corresponding N-oxide and thereby
2
9
be directly involved in the oxygen transfer. When the
oxidation of tetrahydronaphthalene was carried out in the
presence of picolinic acid N-oxide instead of picolinic acid,
R-tetralone was formed but in reduced yield (59%). In
addition, the use of 6 equiv of picolinic acid N-oxide instead
of tert-butyl hydroperoxide failed to bring about the oxida-
(18) It should be noted that the system does not require the use of special
precautions and could be carried out in the presence of water and under
air. The use of sealed vessels was merely for convenience on the scale of
these experiments (0.8 mmol).
(
19) For the product ketone see: Nashed, N. T.; Sayer, J. M.; Jerina, D.
M. J. Am. Chem. Soc. 1993, 115, 1723.
20) For the product ketone see: Lehmann, J.; Nieger, M.; Witt, T.
Heterocycles 1994, 38, 511.
21) For the product ketone see: Crabb, T.; Soilleux, S. L. J. Chem.
(
(
Soc., Perkin Trans. 1 1985, 1381.
(22) For the product ketone see: Langhals, E.; Langhals, H.; Ruechardt,
C. Liebigs Ann. Chem. 1982, 930.
a
Reactions carried out following ref 23 but with Bi(0) (40 mol %) at
1
10 °C instead of 100 °C. b Approximate yield, based on GC/MS. Yields
after chromatography (the samples were all g95% pure by comparisons of
(23) General procedure for the oxidation of methylarenes to aren-
ecarboxylic acids: A suspension of Bi(OTf)3 (105 mg, 0.16 mmol), pyridine
(0.8 mL), AcOH (0.13 mL), picolinic acid (10 mg, 0.08 mmol), substrate
(0.8 mmol), and t-BuOOH in H2O (70%; 0.77 mL, 5.6 mmol) was sonicated
for 30 min and then heated at 110 °C for 20 h (sealed vessel). After cooling,
EtOAc was added and the resulting suspension was washed with aqueous
HCl (10%; 10 mL) and brine (10 mL). The organic layer was dried (MgSO4)
and rotary evaporated and the resulting oil was analyzed (NMR and GCMS)
and subsequently chromatographed to yield the corresponding carboxylic
acid.
1
13
c
H and C NMR spectra of samples with commercial materials). Reactions
d
carried out following the procedure in ref 23. Reaction carried out with
Bi(OTf)3 (5 mol %), picolinic acid (2.5 mol %), and Me2CO (0.5 mL) as
a cosolvent. Reaction carried out with Bi(OTf)3 (10 mol %), picolinic acid
e
(10 mol %), and t-BuOOH in PhH (1.78 M; 7 equiv).
mol % catalyst and 48 h reaction times. The use of bismuth
triflate (20 mol %) gave superior yields of the carboxylic
acids23 (Table 2).
(
24) (a) Scholder, R.; Stobbe, H. Z. Anorg. Chem. 1941, 247, 392. (b)
Rigby, W. J. Chem. Soc., Abstr. 1950, 1907-13.
25) Barth, J. A. Z. Anorg. Allg. Chem. 1980, 470, 25.
(
The mechanism of these oxidation processes has not yet
been established. Bismuth(V) is known to be a very potent
(26) Hf(OTf)4, Sc(OTf)3, and Yb(OTf)3 showed excellent catalytic
1
activity giving R-tetralone ( H NMR; 85%, 78%, and 87%, respectively),
•
presumably by accelerating the rate of formation of t-BuO .
(
27) Example of an oxidation in the presence of a Lewis acid: Sc-
(
17) General procedure for the oxidation of alkylarenes to ketones:
(OTf)3 (78 mg, 0.16 mmol) was added with vigorous stirring to picolinic
acid (20 mg, 0.16 mmol) in pyridine (0.8 mL) and AcOH (0.08 mL) at
room temperature giving a white precipitate. Tetrahydronaphthalene (0.8
mmol) and t-BuOOH in PhH (1.78 M.; 4.8 mmol) were added and the
mixture was sonicated for 30 min and heated at 100 °C for 18 h (sealed
vessel), then it was cooled, diluted with CH2Cl2, filtered through Celite,
and rotary evaporated to give R-tetralone (78%).
(28) Gmouh, S.; Yang, H.; Vaultier, M. Org. Lett. 2003, 5, 2219.
(29) Ueyama, N.; Yoshinaga, N.; Okamura, T.; Zaima, H.; Nakamura,
A. J. Mol. Catal. 1991, 64, 256.
NaBH4 (18 mg, 0.48 mmol) was added with vigorous stirring to a suspension
of Bi2O3 (37 mg, 0.08 mmol) in distilled H2O (1.5 mL) at room temperature
giving a finely divided, black precipitate of bismuth metal. This was washed
with H2O (2 × 2 mL), then pyridine (0.8 mL), AcOH (0.08 mL), picolinic
acid (20 mg, 0.16 mmol), substrate (0.8 mmol), and t-BuOOH in H2O (70%;
.66 mL, 4.8 mmol) were added. The mixture was sonicated for 30 min
and heated at 100 °C for 16 h (sealed vessel), cooled, diluted with CH2Cl2,
0
filtered through Celite, and rotary evaporated. The resulting oil was analyzed
NMR and GCMS) and chromatographed to yield the corresponding ketone.
(
Org. Lett., Vol. 7, No. 21, 2005
4551

tion. These results preclude picolinic acid N-oxide as a
significant intermediate in the reaction pathway.
use of the less effective hydrogen bond acceptor 3-cyan-
opyridine led to a lower conversion (47%). These results
are consistent with an enhancement of the rate of formation
of the tert-butoxyl radical in Gif-GoAgg oxidations where
the iron is replaced by bismuth.
Finally, mechanisms involving free radicals have been
6,7,9
reported in tert-butyl hydroperoxide mediated oxidations.
Indeed, when 2 equiv of 2,6-di-tert-butyl-4-methylphenol,
a well-known oxyl radical trap,30 were added during the
oxidation of tetrahydronaphthalene, unreacted starting mate-
rial was recovered unchanged. On the other hand, 2-methyl-
In conclusion, bismuth has proved to be a useful catalyst
for the oxidation of alkylarenes to the corresponding ketones
or carboxylic acids with use of tert-butyl hydroperoxide as
the stoichiometric oxidant. These procedures should find
considerable use in synthesis.
1
-phenylprop-2-yl hydroperoxide (MPPH) has been used as
31
a mechanistic probe for tert-butoxyl radical formation. This
probe relies on the fact that if the corresponding tert-alkoxyl
radical was formed it would rapidly undergo â-scission
preventing hydrogen abstraction from the substrate. Indeed,
when MPPH was used as the oxidant only 4% of the
R-tetralone was obtained and dibenzyl was isolated as the
Acknowledgment. We thank GlaxoSmithKline for the
generous endowment (to A.G.M.B.), the Royal Society and
the Wolfson Foundation for a Royal Society Wolfson
Research Merit Award (to A.G.M.B.), the Ministerio de
Educacion y Ciencia for kindly granting a postdoctoral
fellowship (to I.L.), the Wolfson Foundation for establishing
the Wolfson Centre for Organic Chemistry in Medical
Sciences at Imperial College London, and the Engineering
and Physical Sciences Research Council for generous support
of our studies.
32
major byproduct (17%). Additionally, according to Minisci,
pyridine acts as a hydrogen bond acceptor with tert-butyl
hydroperoxide thereby decreasing the reaction rate of the
•
formation of the tert-butylperoxyl radical (t-BuOO ) but not
•
the tert-butoxyl radical (t-BuO ). Indeed, when the oxidation
of tetrahydronaphthalene was carried out in the presence of
the stronger hydrogen bond acceptors 4-methylpyridine or
4
7
-methoxypyridine, similar yields of R-tetralone (76% and
9%, respectively) were observed. On the other hand, the
Supporting Information Available: Experimental pro-
(
30) Leising, R. A.; Jinheung, K.; Perez, M. A.; Que, L. J. Am. Chem.
Soc. 1993, 115, 9524.
31) Arends, I. W. C. E.; Ingold, K. U.; Wayner, D. M. J. Am. Chem.
Soc. 1995, 117, 4710.
32) Minisci, F.; Fontana, F.; Araneo, S.; Recupero, F.; Banfi, S.; Quici,
S. J. Am. Chem. Soc. 1995, 117, 226.
cedures, characterization data for 4-bromo-1-naphthoic acid,
and representative H and C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
13
(
(
OL051765K
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Org. Lett., Vol. 7, No. 21, 2005