Oxidation of benzylic methylenes to ketones with Oxone-KBr in aqueous acetonitrile under transition metal free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.06.036

A green and highly efficient protocol for the oxidation of benzylic methylenes to their corresponding ketones with a combination of Oxone and KBr in aqueous acetonitrile is developed. The H₂¹⁸O labeling experiment demonstrated that the oxygen introduced into ketone originated from water. A plausible mechanism was also suggested.

Full text of DOI:10.1016/j.tetlet.2012.06.036

Tetrahedron Letters 53 (2012) 4418–4421
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidation of benzylic methylenes to ketones with Oxone–KBr in aqueous
acetonitrile under transition metal free conditions
⇑
Lixia Yin, Jingjing Wu, Juan Xiao, Song Cao
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A green and highly efficient protocol for the oxidation of benzylic methylenes to their corresponding
Received 4 May 2012
Revised 4 June 2012
Accepted 8 June 2012
Available online 15 June 2012
18
ketones with a combination of Oxone and KBr in aqueous acetonitrile is developed. The H
2
O labeling
experiment demonstrated that the oxygen introduced into ketone originated from water. A plausible
mechanism was also suggested.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Oxidation
Oxone
Benzylic methylenes
Labeling experiment
The oxidation of benzylic C–H bond is one of the most useful
and fundamental transformations due to its wide variety of appli-
cations in the synthesis of pharmaceuticals and fine chemicals. It
Desai prepared a series of azo-bis nitriles by oxidation of corre-
sponding 1,2-bis-dialkylcyano hydrazines using Oxone–KBr in
1
9
aqueous medium. In 2006, Desai developed a simple and efficient
is a powerful tool to generate high value chemicals from less
expensive raw materials such as alkyl aromatics.2 Up to now,
numerous methods have been developed for the oxidation of ben-
zylic methylenes into the corresponding ketones.3 Traditionally,
these benzylic oxidation reactions involve the use of stoichiometric
amounts of metal oxidants, such as potassium permanganate,
potassium dichromate, or cerium triflate. During the last decades,
great efforts have been made to improve these transformations
with catalytic amount of transition metal complexes in combina-
method for the chemoselective dethioacetalization of dithioacetals
to aldehydes and ketones using Oxone–KBr in aqueous acetonitrile
1
0
at room temperature. In 2009, Vinod described a novel approach
to aromatic ketones by the oxidation of the corresponding alkyla-
renes using 2-iodobenzoic acid (2IBAcid) in combination with co-
1
1
oxidant Oxone. More recently, Yu reported the selective oxida-
tion of sulfides to sulfoxides or sulfones by employing Oxone as
oxidant without the utilization of any catalyst/additive.12 In this
Letter, we report a green and efficient approach for the oxidation
of benzylic methylenes to their corresponding ketones with Oxone
and KBr in aqueous acetonitrile (Scheme 1).
4
2 2 2
tion with various environmentally benign oxidants like O , H O ,
IBX, PhIO, and tert-butylhydroperoxide (TBHP) under homoge-
5
neous and heterogeneous conditions. Although the present meth-
In the course of studies on the synthesis of 1-bromo-4-isobutyl-
ods could successfully be used to convert alkylarenes to aromatic
ketones, complicated, expensive, or toxic metal catalysts are re-
quired in most of these systems. Therefore, there is a high demand
for the development of clean and economical processes for the
selective oxidation of alkylarenes to higher value added phenyl ke-
tones with readily available, inexpensive, and non-toxic oxidants
and catalysts.
benzene 3 by the reaction of isobutylbenzene 1a with NH
4
Br and
1
3
Oxone in undried CH CN according to the literature procedure,
3
6
we found the results were different and an unexpected oxidative
product 2a was observed in addition to small amount of the nor-
mal brominated product 3 (Scheme 2). Most of the starting mate-
rial 1a was recovered.
On the other hand, as an efficient, cheap, versatile, and environ-
mentally friendly oxidizing agent, Oxone(2KHSO
5
ꢀKHSO
4
ꢀK
2 4
SO )
has attracted increasing interest in organic synthesis in recent
CH R2 KBr (0.5equiv), Oxone (2.2equiv)
2
COR2
7
years. It has found many applications in oxidation of amines, alco-
R1
R1
8
hols, aldehydes, and epoxidation of alkenes. For example, in 2002,
3
2
CH O (0.5mL), 45 °C
CN (6mL), H
1
a-l
2a-l
CN–H
⇑
Corresponding author.
E-mail address: scao@ecust.edu.cn (S. Cao).
Scheme 1. Oxidation of benzylic methylenes by Oxone–KBr–CH
3
2
O system.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.036

L. Yin et al. / Tetrahedron Letters 53 (2012) 4418–4421
4419
O
Table 3
a
Effect of amount of catalyst (KBr) on the formation of 2b
NH Br, Oxone
4
+
Yieldb (%)
Entry
KBr (equiv)
Time (h)
CH CN, 45 °C
3
Br
3 (expected, 5%)
1
2
3
4
5
0.1
0.2
0.5
1.1
2.2
120
99
6
6
6
7
1
a
2a (unexpected, 15%)
60
86
79
5
4 3
Scheme 2. Reaction of 1a with NH Br in the presence of Oxone in CH CN (Note:
acetonitrile and other solvents were purchased commercially and used without
further drying, except those indicated in the Letter).
a
Reaction conditions: CH
Yields were based on GC analysis.
3
CN (6 mL), H
2
O (0.5 mL), Oxone (2.2 equiv), 45 °C.
b
Table 1
Optimization of the reaction conditions
3
ing the amount of water to 0.1 mL (entry 9). When dried CH CN
was used without the addition of water, no expected oxidative
product 2b was detected and most of ethylbenzene (1b) remained
unconverted (entry 8).
4
NH Br or KBr, Oxone
PhCH
CH
2 3
PhCOCH
3
Solvent, 45 °C
1
b
2b
The effect of amount of Oxone on the oxidation of 1b was inves-
tigated (Table 2). The results indicated that 2.2 equiv Oxone affor-
ded the oxidation product 2b in good yield (entry 4). An increase in
the amount of Oxone to 2.5 equiv showed no significant improve-
ment in yield (entry 5), whereas the yield was reduced by decreas-
ing the amount of Oxone (entries 1–3).
Using the same substrate 1b, the effect of amount of KBr on the
oxidation of 1b was also examined (Table 3). To obtain a reason-
able yield of 2b, 0.5 equiv KBr had to be used (entry 3). Too little
KBr would lead to incomplete conversion of 1b (entries 1 and 2),
whereas too much KBr would result in the formation of undesired
bromination products (entries 4 and 5).
Entry Solvent (6 mL)
Bromide
Oxone
(equiv)
Yielda
(%)
(
1.1 equiv)
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
DMSO
DMF
3
3
3
3
CN
CN
CN
CN
NH
NH
4
4
Br
Br
1.1
2.2
1.1
2.2
2.2
2.2
2.2
2.2
2.2
15
29
30
50
0
0
7
0
44
KBr
KBr
KBr
KBr
KBr
KBr
KBr
CH
3
CH
3
CH
3
OH
CN (dried)
CN, H
2
O
(
0.1 mL)
CH CN, H
0.5 mL)
1
0
3
2
O
KBr
2.2
79
(
The yield of the oxidation product was also affected by the reac-
tion temperature. The results are shown in Table 4. The reaction
proceeded smoothly at 45 °C, yielding the expected product in
86% yield. However, decreasing the reaction temperature would
lead to a decrease in yield, whereas a further increase in tempera-
ture showed no improvement in the yield (entries 4 and 5).
To investigate the generality and scope of the novel transition
metal-free system, a range of structurally diverse hydrocarbons
were examined under the optimized reaction conditions (Table
1
1
1
2
CH
CH
3
CN, H
CN, H
2
O (1 mL)
O (2 mL)
KBr
KBr
2.2
2.2
68
35
3
2
a
Yields were based on GC analysis.
Encouraged by this result, ethylbenzene 1b was selected as rep-
resentative reactant for optimization of the unexpected reaction
conditions (Table 1). For our initial studies, efforts were directed
toward the evaluation of the bromide in the oxidation reaction. It
1
5
5). Most benzylic methylenes could be successfully oxidized with
this new Oxone–KBr–CH CN–H O system to give the correspond-
4
was found that KBr is more effective than NH Br (entries 1–4).
3
2
Thus, we used KBr as bromine source in the following
investigation.
The reaction was significantly affected by the solvent (Table 1,
entries 4–7). Only acetonitrile afforded a moderate yield (entry 4,
ing ketones in high to excellent yields (entries 1–11). When 1,4-
diethylbenzene (1d), isochroman (1e), 1,3-dihydroisobenzofuran
(1f), 1,2,3,4-tetrahydronaphthalene (1k) and indan (1l) were used
as substrates, which have two –CH – (methylene) groups attached
2
5
0%) of the expected product 2b and no oxidative product was ob-
to the benzene ring, only one benzyl group can be converted to a
served in other solvents even after prolonged reaction time (entries
carbonyl group, and another methylene group cannot be oxidized
even after more Oxone was added (entries 4–6, 11 and 12). 1,4-
Diethylbenzene (1d) could not be directly oxidized to 1,1 -(1,4-
5
–7). Usually, water plays an important role in the oxidation of
2b,c,8b,14
0
benzylic methylenes to ketones.
Thus, the effect of the
amount of water in the system on the conversion was examined
by varying the amount of water in the presence of Oxone and
KBr using CH CN as solvent at 45 °C (entries 8–12). It was found
3
that 0.5 mL of water was sufficient to carry out this reaction
smoothly (entry 10). An increase in the amount of water to more
than 1 or 2 mL led to a decrease of the yield of oxidative product
phenylene)diethanone (2g) in one pot, it was oxidized to 1-(4-eth-
ylphenyl)ethanone (2d) in the first step. The 2d should be sepa-
rated and purified, and then used as substrate (1g, 1-(4-
ethylphenyl)ethanone which is the same as 2d) to further oxidize
0
to 1,1 -(1,4-phenylene)diethanone (2g).
(
entries 11 and 12), furthermore the yield was reduced by decreas-
Table 4
a
Table 2
Effect of reaction temperature on the oxidation of 1b
a
Effect of amount of Oxone on the oxidation of 1b
Entry
Temperature (°C)
Time (h)
Yieldb (%)
Entry
Oxone (equiv)
Yieldb (%)
1
2
3
4
5
0
48
18
6
4
2
30
70
82
86
85
1
2
3
4
5
1.1
1.5
1.9
2.2
2.5
34
54
68
79
60
25
35
45
65
a
Reaction conditions: CH
(1.1 equiv).
3 2
CN (6 mL), H O (0.5 mL), Oxone (2.2 equiv), KBr
a
3 2
Reaction conditions: CH CN (6 mL), H O (0.5 mL), KBr (1.1 equiv), 45 °C.
Yields were based on GC analysis.
b
b
Yields were based on GC analysis.

4
420
L. Yin et al. / Tetrahedron Letters 53 (2012) 4418–4421
Table 5
18O
O
O system for benzylic oxidationa
3 2
The Oxone–KBr–CH CN–H
KBr (0.5equiv), Oxone (2.2equiv
)
+
18O (0.5mL), 45 °C
Entry
1
Substrate
Product
Yieldb (%)
81
CH CN (dried), H
3
2
1
b
2b
2b'
O
1
a
Scheme 3. An isotopic labeling investigation of the mechanism of the oxidation.
2
a
1
b
2
3
4
5
2b
87
99
94
94
visible light
Oxone (~ 1equiv
Br
)
O
KBr
Br2
Br
2Br
OH
O
1
c
O
Oxone (~ 1equiv)
2c
2
H O
ArCH R
Ar CHR
Ar CHR
Ar CR
2
I
II
III
IV
O
1d
2d
Scheme 4. A plausible mechanism for the oxidation.
1
e
2e
O
O
electron-withdrawing group on the ethylbenzene ring (1p) disfa-
vored benzylic oxidation and bromination of benzyl group pro-
ceeded smoothly, and 2p was obtained in high yield. If a strong
electron-donating group such as CH O was present on the aromatic
3
ring, the aromatic ring bromination occurred and afforded 2q in
high yield.
To explain the mechanism of the oxidation reaction, several
additional experiments were conducted using 1b as a substrate un-
der the optimized reaction conditions. When the reaction was car-
ried out under an argon atmosphere, the reaction proceeded
smoothly and afforded 2b in good yield. It is indicated that oxygen
in the air has no influence on the formation of 2b. If the reaction
was performed under dark conditions, almost no oxidative product
2b could be detected and aromatic ring bromination obtained in-
stead of benzylic C–H oxidation. In addition, no reaction was ob-
O
O
O
1f
1
6
94
2f
O
O
7b
8
1g
94
90
98
78
2g
O
O
h
2h
O
O
Br
1i
Br
2i
2j
9
O
1j
1
1
0
1
served in the absence of water or KBr.
1
k
In order to further probe the origin of oxygen in ketone, the 18O-
2k
71
labeling experiment was also performed under the optimized reac-
tion conditions (Scheme 3). When H
O was incorporated into acetophenone. The ratio of 2b and O-
labeled acetophenone 2b was 1:2. The O labeled water experi-
ment clearly demonstrated that oxygen introduced into ketone
originated from water.
Finally, a possible mechanism for the oxidation of benzylic
methylenes (I) to ketones (IV) with Oxone–KBr–CH CN–H O sys-
3 2
tem is depicted in Scheme 4. Initially, potassium bromide reacts
with Oxone to produce molecular bromine. Homolytic cleavage
of bromine under visible light irradiation generates the bromine
radical. This reactive intermediate initiates benzylic hydrogen
abstraction leading to the formation of the stable benzyl bromide
intermediate (II), which undergoes hydrolysis to give the corre-
sponding alcohol (III). The benzylic alcohol is further oxidized by
O
18
2
O was added to the reaction,
1
8
18
1
l
2
l
0
18
1
2
47
O
13
14
15
PhCH
PhCH
PhCH
2
2
3
OCH
2
Ph 1m
PhCHO 2m and PhCO
PhCO H 2n
PhCH Br 2o
2
H 2n
67/22
81
88
OH 1n
2
1o
2
CH3
O N
1p
O N
1
6
7
2
2
2p
94
95
Br
Br
H CO
1q
3
1
H CO
2q
3
a
Reaction conditions: CH
1.1 equiv).
Yields were based on GC analysis.
3 2
CN (6 mL), H O (0.5 mL), Oxone (2.2 equiv), KBr
(
2
b,3e,5b
b
the second molecule of Oxone to give ketone.
In summary, we reported a novel and practical approach for the
oxidation of benzylic methylenes to the corresponding ketones
1
8
When the oxygen atom is present in the ring adjacent to the
with novel Oxone–KBr–CH
3 2 2
CN–H O system. The H O labeling
benzylic position, such as isochroman (1e), 1,3-dihydroisobenzofu-
ran (1f), the desired products, lactones (2e and 2f) were obtained
in excellent yields. In the case of indan (1l), the reaction did not
proceed smoothly and only 47% of 1-indanone (2l) was formed.
Oxidation of dibenzyl ether (1m) did not afford the desired product
but gave benzaldehyde (2m) in 67% yield along with 22% of ben-
zoic acid (2n). When benzyl alcohol (1n) was subjected to oxida-
tion with this novel system, benzoic acid (2n) was exclusively
obtained in 81% yield with no formation of benzaldehyde. It is indi-
cated that benzyl alcohol is more easily oxidized. Interestingly, oxi-
dation of toluene (1o) provided benzyl bromide (2o) as the only
product formed under these reaction conditions and no oxidized
products were observed. However, substrates bearing a strongly
experiment demonstrated that the oxygen atom incorporated into
1
6
ketone is derived from water.
Acknowledgments
We are grateful for financial supports from the National Natural
Science Foundation of China (Grant No. 21072057), the National
Basic Research Program of China (973 Program, 2010CB126101),
the Key Project in the National Science & Technology Pillar Pro-
gram of China in the twelfth five-year plan period
(2011BAE06B01-15), and the National High Technology Research
and
Development
Program
of
China
(863
Program,
2011AA10A204).

L. Yin et al. / Tetrahedron Letters 53 (2012) 4418–4421
4421
Campos-Martin, J. M.; Al-Zahrani, S. M.; Fierro, J. L. G.; Alonso, J. A. Angew.
Chem., Int. Ed. 2011, 50, 6557.
Supplementary data
7.
(a) Hull, J. F.; Balcells, D.; Sauer, E. L. O.; Raynaud, C.; Brudvig, G. W.; Crabtree, R.
H.; Eisenstein, O. J. Am. Chem. Soc. 2010, 132, 7605; (b) Yusubov, M. S.;
Nemykin, V. N.; Zhdankin, V. V. Tetrahedron 2010, 66, 5745; (c) Thottumkara, P.
P.; Vinod, T. K. Org. Lett. 2010, 12, 5640; (d) Liu, P.; Liu, Y.-G.; Wong, E. L.; Xiang,
S.; Che, C.-M. Chem. Sci. 2011, 2, 2187.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
0
6.036.
8
.
.
(a) Gella, C.; Ferrer, E.; Alibés, R.; Busqué, F.; de March, P.; Figueredo, M.; Font, J.
J. Org. Chem. 2009, 74, 6365; (b) Yusubov, M. S.; Zagulyaeva, A. A.; Zhdankin, V.
V. Chem. Eur. J. 2009, 15, 11091; (c) Travis, B. R.; Sivakumar, M.; Hollist, G. O.;
Borhan, B. Org. Lett. 2003, 5, 1031.
Tamhankar, B. V.; Desai, U. V.; Mane, R. B.; Kulkarni, P. P.; Wadgaonkar, P. P.
Synth. Commun. 2002, 32, 3643.
References and notes
1
.
(a) Godula, K.; Sames, D. Science 2006, 312, 67; (b) Li, X.-H.; Chen, J.-S.; Wang,
X.-C.; Sun, J. –H.; Antonietti, M. J. Am. Chem. Soc. 2011, 133, 8074; (c) Ni, L.-L.;
Ni, J.; Lv, Y.; Yang, P.; Cao, Y. Chem. Commun. 2009, 2171; (d) Kesavan, L.;
Tiruvalam, R.; Ab Rahim, M. H.; bin Saiman, M. I.; Enache, D. I.; Jenkins, R. L.;
Dimitratos, N.; Lopez-Sanchez, J. A.; Taylor, S. H.; Knight, D. W.; Kiely, C. J.;
Hutchings, G. J. Science 2011, 331, 195; (e) Xia, J.–B.; Cormier, K. W.; Chen, C.
Chemical Science, 2012, online, DOI: http://dx.doi.org/10.1039/c2sc20178j.
(a) Bonvin, Y.; Callens, E.; Larrosa, I.; Henderson, D. A.; Oldham, J.; Burton, A. J.;
Barrett, A. G. M. Org. Lett. 2005, 7, 4549; (b) Dohi, T.; Takenaga, N.; Goto, A.;
Fujioka, H.; Kita, Y. J. Org. Chem. 2008, 73, 7365; (c) Yi, C. S.; Kwon, K.-H.; Lee, D.
W. Org. Lett. 2009, 11, 1567.
9
10. Desai, U. V.; Pore, D. M.; Tamhankar, B. V.; Jadhav, S. A.; Wadgaonkar, P. P.
Tetrahedron Lett. 2006, 47, 8559.
11. Ojha, L. R.; Kudugunti, S.; Maddukuri, P. P.; Kommareddy, A.; Gunna, M. R.;
Dokuparthi, P.; Gottam, H. B.; Botha, K. K.; Parapati, D. R.; Vinod, T. K. Synlett
2009, 1, 117.
2
.
.
1
1
2. Yu, B.; Liu, A.-H.; He, L.-N.; Li, B.; Diao, Z.-F.; Li, Y.-N. Green Chem. 2012, 14, 957.
3. (a) Narender, N.; Srinivasu, P.; Kulkarni, S. J.; Raghavan, K. V. Synth. Commun.
2002, 32, 279; (b) Kumar, M. A.; Rohitha, C. N.; Kulkarni, S. J.; Narender, N.
Synthesis 2010, 10, 1629.
3
(a) Wang, J.-Q.; He, L.-N. New J. Chem. 2009, 33, 1637; (b) Li, H.-R.; Li, Z. –P.; Shi,
Z.-J. Tetrahedron 2009, 65, 1856; (c) Zhang, J.-T.; Wang, Z.-T.; Wang, Y.; Wan, C.-
F.; Zheng, X.-Q.; Wang, Z.-Y. Green Chem. 2009, 11, 1973; (d) Kumar, R. A.;
Maheswari, C. U.; Ghantasala, S.; Jyothi, C.; Reddya, K. R. Adv. Synth. Catal. 2011,
1
4. (a) Lee, Y.-M.; Dhuri, S. N.; Sawant, S. C.; Cho, J.; Kubo, M.; Ogura, T.; Fukuzumi,
S.; Nam, W. Angew. Chem., Int. Ed. 2009, 48, 1803; (b) Zhou, M.; Schley, N. D.;
Crabtree, R. H. J. Am. Chem. Soc. 2010, 132, 12550.
1
5. General procedure of the oxidation reactions: To
compound (1 mmol) in CH CN (6 mL) and H O (0.5 mL) were added KBr
0.5 mmol) and Oxone (2.2 mmol), and the mixture was stirred at 45 °C. After
a solution of aromatic
3
4
53, 401; (e) Tada, N.; Ban, K.; Hirashima, S.; Itoh, A. Org. Biomol. Chem. 2010, 8,
701.
(a) Shaabani, A.; Mirzaei, P.; Naderia, S.; Lee, D. G. Tetrahedron 2004, 60, 11415;
b) Mohammadpoor-Baltork, I.; Sadeghi, M. M.; Adibi, A. H. Molecules 2001, 6,
00; (c) Laali, K. K.; Herbert, M.; Cushnyr, B.; Bhatt, A.; Terrano, D. J. Chem. Soc.,
3
2
(
4
.
.
completion (monitored by TLC), the reaction mixture was filtered and the
solvent was evaporated under reduced pressure. The residue was dissolved in
(
9
2 2 3
ethyl acetate, washed with saturated aqueous Na S O and brine, dried over
Perkin Trans. 1 2001, 578.
(a) Dapurkar, S. E.; Kawanami, H.; Yokoyama, T.; Ikushima, Y. Catal. Commun.
2
Tetrahedron Lett. 2007, 48, 2271; (c) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L. J.
Am. Chem. Soc. 2001, 123, 3183; (d) Lee, N. H.; Byun, J. C.; Oh, T.-H. Bull. Korean
Chem. Soc. 2005, 26, 454; (e) Zhu, M.-X.; Wei, X.; Li, B.-D.; Yuan, Y.-Z.
Tetrahedron Lett. 2007, 48, 9108.
(a) Mohapatra, S. K.; Selvam, P. J. Catal. 2007, 249, 394; (b) Singh, S. J.; Jayaram,
R. V. Catal. Commun. 2009, 10, 2004; (c) Vanover, E.; Huang, Y.; Xu, L.-B.;
Newcomb, M.; Zhang, R. Org. Lett. 2010, 12, 2246; (d) Aguadero, A.; Falcon, H.;
anhydrous Na SO . Removal of the solvent under vacuum afforded the crude
2
4
5
product, which was purified by column chromatography using hexane/ethyl
acetate as eluent (20–80: 1).
009, 10, 1025; (b) Khan, A. T.; Parvin, T.; Choudhury, L. H.; Ghosh, S.
16. Just during we submitted our manuscript and in the course of the manuscript
was reviewed, Hideo Togo reported a new approach to aromatic ketones by
oxidation of alkylarenes with Oxone–KBr–CH
3 2 2 2
NO or Oxone–KBr–CH Cl –
2
H O: Moriyama, K.; Takemura, M.; Togo, H. Org. Lett. 2012, 14, 2414. They
6
.
used nitromethane (CH
explode.
3 2
NO ) as one of the main solvent, which is easy to