A remarkable effect of ionic liquids in transition-metal-free aerobic oxidation of benzylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2011.08.053

The transition-metal-free aerobic oxidation of benzylic alcohols is uniquely accelerated by a 1-butyl-3-methylimidazolium hexafluorophosphate (BMI-PF₆)/PhCF₃ biphasic system and Cs₂CO ₃ to afford the corresponding ketones in good yields. The reaction system is also applicable to an oxidative cross-esterification of primary benzyl alcohols with a higher aliphatic alcohol.

Full text of DOI:10.1016/j.tetlet.2011.08.053

Tetrahedron Letters 52 (2011) 5392–5394
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A remarkable effect of ionic liquids in transition-metal-free aerobic oxidation
of benzylic alcohols
⇑
⇑
Yoshiro Oda, Koji Hirano , Tetsuya Satoh, Susumu Kuwabata, Masahiro Miura
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The transition-metal-free aerobic oxidation of benzylic alcohols is uniquely accelerated by a 1-butyl-3-
methylimidazolium hexafluorophosphate (BMI-PF )/PhCF biphasic system and Cs CO to afford the
corresponding ketones in good yields. The reaction system is also applicable to an oxidative cross-
esterification of primary benzyl alcohols with a higher aliphatic alcohol.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 9 July 2011
Revised 5 August 2011
Accepted 8 August 2011
Available online 16 August 2011
6
3
2
3
Keywords:
Aerobic oxidation
Alcohol
Ester
Ionic liquid
Ketone
The oxidation of alcohols to the corresponding carbonyls is one
of the most fundamental and important functional transformations
in the fields of both academic research and chemical industry. In
particular, oxidation using an ideal and abundant oxidant, molecu-
lar oxygen has been received significant attention from the
6
the oxidation aptitude of some metal nanoparticles in BMI-PF for
the aerobic oxidation of 1-phenyl-1-pentanol (1a) as a model sub-
strate. During the course of this study, we serendipitously found
that oxidation to the desired 1-phenyl-1-pentanone (2a) occurred
smoothly even in the absence of any transition-metal catalysts (Ta-
ble 1). Namely, a mixture of 1a (0.20 mmol) and a substoichiomet-
1
economical and environmental points of view, and various transi-
2
tion-metal-based systems involving homogeneous as well as het-
2 3 6
ric amount of Cs CO (0.10 mmol) in a BMI-PF (0.060 mL,
0.30 mmol)/trifluoromethylbenzene (0.10 mL) biphasic system
3
erogeneous catalysts have been widely explored for the aerobic
oxidation of alcohols. However, recent rapidly growing environ-
mental concerns need much greener transition-metal-free oxida-
tion protocols. Herein, we report a transition-metal-free, ionic
liquid-promoted oxidation of benzylic alcohols with molecular
oxygen as the sole oxidant. The reaction proceeds uniquely in a
was heated at 105 °C under atmospheric conditions to afford 2a
in 90% NMR yield (entry 1). Although similar transition-metal-free
7
4
alcohol oxidations in ionic liquids have been reported, these prece-
8
dents required sodium hypochlorite as the oxidant. Thus, our aer-
obic oxidation system is appealing from the viewpoint of atom
economy. Subsequent investigations into the solvent system are
to be noted: (1) the reaction efficiency was highly dependent upon
the counter anion of imidazolium salts (entries 2–5), (2) the Me
substitution at the C2 position in the imidazolium ring decreased
the yield, but the oxidation still occurred (entry 6), (3) the oxida-
tion completely failed in common organic solvents such as toluene,
DMSO, DMF, and CPME (entries 7–10), (4) the co-solvent also gave
a large impact on the yield of 2a (entries 11–15), and (5) an appro-
1
6
-butyl-3-methylimidazolium hexafluorophosphate (BMI-PF )/tri-
fluoromethylbenzene biphasic system under mild atmospheric
conditions to furnish the corresponding aromatic ketones in good
yields. Moreover, an oxidative cross-esterification of primary ben-
zylic alcohols with a higher aliphatic alcohol is also described.
Ionic liquids are now recognized as a useful reaction medium in
organic synthesis due to their unique properties such as thermal
stability, nonvolatility, and high polarity. We previously reported
the preparation of palladium nanoparticles in BMI-PF
6
by a sputter
6
priate amount of BMI-PF as the solvent was necessary for the
9
deposition and uncovered their high catalytic activity for the aque-
completion of the reaction (entries 1 and 16–18). Similar effects
of the counter anion were observed in the related NaOCl-promoted
5
ous Suzuki–Miyaura coupling. Inspired by recent advances in the
6
8b
metal-catalyzed oxidation in ionic liquids, we subsequently tested
oxidation. The superiority of trifluoromethylbenzene as the co-
2
solvent might be due to its relatively high O solubility.
By using the reaction conditions employed for entry 1 in Table
, we conducted the aerobic oxidation of an array of benzylic alco-
⇑
Corresponding authors. Tel.: +81 6 6879 7360; fax: +81 6 6879 7362.
E-mail addresses: k_hirano@chem.eng.osaka-u.ac.jp (K. Hirano), miura@chem.-
1
eng.osaka-u.ac.jp (M. Miura).
hols (Table 2). The electron-donating methyl and methoxy groups
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.053

Y. Oda et al. / Tetrahedron Letters 52 (2011) 5392–5394
5393
Table 1
Table 2
Optimization for aerobic oxidation of 1-phenyl-1-pentanol (1a) into 1-phenyl-1-
BMI-PF
6
-Promoted aerobic oxidation of various secondary benzylic alcohols 1a
pentanone (2a)a
Entry
Ar, R 1
2, Yield (%)b
Entry
Solvent system
BMI-PF (0.30 mmol)/PhCF
BMI-BF (0.19 mmol)/PhCF
BMI-TFSI (0.30 mmol)/PhCF
BMI-Cl (0.30 mmol)/PhCF
BMI-Br (0.30 mmol)/PhCF
IDMI-PF (0.30 mmol)/PhCF
Toluene (0.10 mL)
DMSO (0.10 mL)
DMF (0.10 mL)
CPME (0.10 mL)
Yield of 2a (%)b
1
2
Ph, Bu (1a)
4-MeC H , Bu (1b)
6 4
4-MeOC
4-MeOC
2a, 86
2b, 60
2c, 69
2d, 73
1
2
3
4
5
6
7
8
9
6
3
(0.10 mL)
(0.10 mL)
90
76
0
20
2
57
0
0
0
0
4
31
5
4
3
c
2
6
H
H
4
, Bu (1c)
, Me (1d)
3
(0.10 mL)
(0.10 mL)
(0.10 mL)
4
5
6
7
8
9
6
4
3
d
4-CF
3
C
6
H
4
, Bu (1e)
2e, 4
3
d
Ph, i-Pr (1f)
Ph, Ph (1g)
2f, 40
2g, 80
2h, 97
2i, 84
2j, 77
2k, 54
2l, 29
2m, 84
6
3
(0.10 mL)
4-MeOC
4-CF
3-Thienyl, Bu (1j)
2-Furyl, n-C 17 (1k)
6
H
4
, Ph (1h)
3 6 4
C H , Ph (1i)
10
11
12
13
10
11
12
13
14
15
16
17
18
8
H
BMI-PF
BMI-PF
BMI-PF
BMI-PF
BMI-PF
BMI-PF
BMI-PF
BMI-PF
6
6
6
6
6
6
6
6
(0.30 mmol)
2-Pyridyl, Bu (1l)
Ph, cyclopropyl (1m)
(0.30 mmol)/toluene (0.10 mL)
(0.30 mmol)/DMSO (0.10 mL)
(0.30 mmol)/DMF (0.10 mL)
(0.30 mmol)/CPME (0.10 mL)
(0.19 mmol)/PhCF
(0.10 mmol)/PhCF
a
b
c
17
75
73
38
0
Reaction conditions: see Table 1, entry 1.
Isolated yield.
3
(0.10 mL)
(0.10 mL)
3
(0.10 mL)
With 1.0 equiv of Cs
2 3
CO .
d
Determined by 1H NMR.
3
(0.020 mmol)/PhCF
a
A mixture of 1a (0.20 mmol) and Cs
2
CO
3
(0.10 mmol) in the indicated solvent
carbinol 1m also proceeded without any difficulties to furnish the
corresponding cyclopropyl ketone 2m exclusively (entry 13). On
the other hand, an attempt to apply aliphatic and allylic alcohols
remained unsuccessful (not shown).
was heated at 105 °C for 20 h under air. The structure of imidazolium salts
employed is shown below.
b
Determined by 1H NMR.
Next, we performed the oxidation of a primary benzylic alcohol
(Scheme 1). Upon exposure of 4-methoxybenzyl alcohol (3a) into
slightly modified conditions, the corresponding carboxylic acid
derivative 4a was isolated in 12% yield after methylation with
iodomethane (Eq 1). At the same time, an oxidatively dimerized es-
0
ter 4a was also detected. This intriguing phenomena promoted us
did not interfere with the reaction (entries 2–4), whereas the
electron-deficient trifluoromethyl-substituted 1e showed lower
reactivity (entry 5). The sterically demanding 2-methyl-1-phenyl-
to evaluate an oxidative cross-esterification of benzylic alcohols
with aliphatic alcohols, which still remains a challenge even with
the aid of precious palladium catalysts. With 1.0 equiv of Cs CO ,
2 3
1
0
1
-propanol (1f) was converted to the corresponding ketone 2f in
3a reacted with octanol under otherwise identical conditions to
furnish octyl 4-methoxybenzoate (5a) in 57% yield (Eq 2). The sim-
ple benzyl alcohol (3b) was also available for use. Although preli-
minary, these outcomes are suggestive of high potential of the
ionic liquid-promoted aerobic oxidation system.
a moderate yield (entry 6). In contrast to the above results, diaryl-
methanols underwent transition-metal-free aerobic oxidation
effectively irrespective of the electronic nature of substituents (en-
tries 7–9). The reaction accommodated heterocyclic cores, thio-
phene and furan, to provide the heteroaryl ketones 2j and 2k in
synthetically useful yields (entries 10 and 11). However, the pyri-
dine ring was resistant to oxidation, and 2l was obtained in only
Although the detailed mechanism is not clear at this stage, we
now speculate an autoxidation pathway similar to the literature.11
The possibility including an N-heterocyclic carbene (NHC)
1
2
2
9% yield (entry 12). Notably, the aerobic oxidation of cyclopropyl
species could not be completely excluded, but it is not consistent
Scheme 1. Oxidative esterification of benzyl alcohols.

5
394
Y. Oda et al. / Tetrahedron Letters 52 (2011) 5392–5394
with the result in Table 1, entry 6.13 Thus, BMI-PF
might play an
6
important role as the component of solvent mixture to facilitate
the benzylic oxidation in the initiation step.14 Further efforts on
the clarification of the mechanism are ongoing.
Lett. 2010, 51, 2450; (f) Chrobok, A.; Baj, S.; Pudlo, W.; Jarzebski, A. Appl. Catal.
A: Gen. 2010, 389, 179.
7
.
Without Cs
CO instead of Cs
94% and 91%, respectively.
2
CO
3
, no desired ketone 2a was detected. The use of Na
2 3
CO and
K
2
3
2
CO resulted in no formation of 2a and recovery of 1a in
3
8
.
.
(a) Xie, H.; Zhang, S.; Duan, H. Tetrahedron Lett. 2004, 45, 2013; (b) Rong, M.;
Liu, C.; Han, J.; Wang, H. Catal. Commun. 2009, 10, 362.
In conclusion, we have developed a transition-metal-free,
6
BMI-PF -promoted aerobic oxidation of benzylic alcohols to aryl
An analysis of a crude mixture of entry 1 in Table 1 by 1H NMR in DMSO-d
9
6
1
5
ketones. In addition, the system is applied to a more challenging
oxidative cross-esterification reaction. The aerobic oxidation pro-
cess shows a new aspect of ionic liquids in organic synthesis.
showed a recovery of 0.20 mmol of BMI-PF
corresponding imidazolone.
6
and a trace amount of the
1
1
0. Limited successful examples: (a) Gowrisankar, S.; Neumann, H.; Beller, M.
Angew. Chem., Int. Ed. 2011, 50, 5139; (b) Liu, C.; Wang, J.; Meng, L.; Deng, Y.;
Lei, A. Angew. Chem., Int. Ed. 2011, 50, 5144.
1. (a) Doering, W. E.; Haines, R. W. J. Am. Chem. Soc. 1954, 76, 482; (b) Lewis, G. E.
J. Org. Chem. 1965, 30, 2433; (c) Ohta, S.; Tachi, T.; Okamoto, M. Synthesis 1983,
Acknowledgments
2
91; (d) Kruszewska, A.; Wilczewska, A. Z.; Wojtkielewicz, A.; Morzycki, J. W.
This work was partly supported by the Grants-in-Aid from
MEXT and JSPS, Japan. K.H. acknowledges Kansai Research Founda-
tion for the Promotion of Science.
Pol. J. Chem. 2006, 80, 611; (e) Siu, T.; Qin, D.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2001, 40, 4713; (f) Wang, X.; Wang, D. Z. Tetrahedron 2011, 67, 3406.
2. Some NHCs are known to catalyze the oxidative transformations of
benzaldehydes and cinnamaldehydes with molecular oxygen. (a) Liu, Y.-K.;
Li, R.; Yue, L.; Li, B.-J.; Chen, Y.-C.; Wu, Y.; Ding, L.-S. Org. Lett. 2006, 8, 1521; (b)
Lin, L.; Li, Y.; Du, W.; Deng, W.-P. Tetrahedron Lett. 2010, 51, 3571; (c) Park, J. H.;
Bhilare, S. V.; Youn, S. W. Org. Lett. 2011, 13, 2228; (d) Chiang, P.-C.; Bode, J. W.
Org. Lett. 2011, 13, 2422; (e) Maji, B.; Vedachalan, S.; Ge, X.; Cai, S.; Liu, X.-W. J.
Org. Chem. 2011, 76, 3016; Also see: (f) Gu, L.; Zhang, Y. J. Am. Chem. Soc. 2010,
1
Supplementary data
Supplementary data associated (experimental details and char-
acterization data for compounds) with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.053.
1
32, 914; (g) Nair, V.; Varghese, V.; Paul, R. R.; Jode, A.; Sinu, C. R.; Menon, R. S.
Org. Lett. 2010, 12, 2653.
1
1
3. The reaction of 1a in the presence of common NHC precursors, IMesꢀHCl and
IPrꢀHCl, or a free carbene, It-Bu in PhCF
3
resulted in no formation of 2a.
4. It is not clear whether the initiation step at the benzylic position occurs
through a homolytic C–H cleavage by the triplet oxygen or a single electron
transfer from the corresponding anionic species to oxygen. See: Amorati, R.;
Valgimigli, L.; Pedulli, G. F.; Grabovskiy, S. A.; Kabal’nova, N. N.; Chatgilialoglu,
C. Org. Lett. 2010, 12, 4130. and Ref. 11f.
References and notes
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2
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1
5. Typical experimental procedure. Aerobic oxidation of benzylic alcohols: the
oxidation of 1-phenyl-1-pentanol (1a) is representative (Table 2, entry 1). BMI-
PF
6 2 3
(85 mg, 0.30 mmol), 1-phenyl-1-pentanol (1a, 33 mg, 0.20 mmol), Cs CO
(
33 mg, 0.10 mmol), and trifluoromethylbenzene (0.10 mL) were placed in a
reaction flask with a reflux condenser and a drying tube lined with calcium
chloride. The resulting mixture was stirred for 20 h at 105 °C (bath
temperature). The reaction mixture was diluted with ethyl acetate and
poured into water. The mixture was extracted with ethyl acetate three
3
.
.
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Conte, M.; Miyamura, H.; Kobayashi, S.; Chechik, V. J. Am. Chem. Soc. 2009, 131,
2 4
times. The combined organic layer was dried over Na SO , filtered through a
pad of neutral alumina, and concentrated under reduced pressure. Purification
by column chromatography on silica gel with hexane/ethyl acetate (10:1, v/v)
as an eluent afforded 1-phenyl-1-pentanone (2a, 28 mg, 0.17 mmol) in 86%
yield.
7
1
189; (f) Kaizuka, K.; Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc. 2010, 132,
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M.; Osada, Y.; Sasano, Y.; Tomizawa, M.; Iwabuchi, Y. J. Am. Chem. Soc. 2011,
Oxidative cross-esterification: the oxidative cross-esterification of 4-
methoxybenzyl alcohol (3a) with octanol is representative. BMI-PF
.30 mmol), 4-methoxybenzyl alcohol (3a, 28 mg, 0.20 mmol), octanol
104 mg, 0.80 mmol), Cs CO (65.0 mg, 0.20 mmol), and trifluoromethyl-
6
(85 mg,
0
(
2
3
benzene (0.10 mL) were placed in a reaction flask with a drying tube lined
with calcium chloride. The resulting mixture was stirred for 20 h at 100 °C (bath
temperature). The reaction mixture was diluted with ethyl acetate and poured
into water. The mixture was extracted with ethyl acetate three times. The
133, 6497.
5
.
.
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Lett. 2010, 39, 1069.
2 4
combined organic layer was dried over Na SO , filtered through a pad of neutral
6
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Hallett, J. P.; Welton, T. Chem. Rev. 2011, 111, 3508; Recent examples: (c) Liu, L.;
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J.; Sheng, W.; Zhang, Y.; Wang, H. Catal. Lett. 2008, 125, 52; (e) Kodama, S.;
Yoshida, J.; Nomoto, A.; Ueta, Y.; Yano, S.; Ueshima, M.; Ogawa, A. Tetrahedron
alumina, and concentrated under reduced pressure. Purification by column
chromatography on silica gel with hexane/ethyl acetate (10:1, v/v) as an eluent
afforded octyl 4-methoxybenzoate (5a, 30 mg, 0.11 mmol) in 57% yield.