I2/TBHP-mediated oxidative coupling of ketones and toluene derivatives: a facile method for the preparation of α-benzoyloxy ketones

Article abstract of DOI:10.1039/c7ra02298k

An efficient oxidative approach was developed for the α-benzoyloxylation of ketones using tert-butyl hydroperoxide (TBHP). This process provided facile access to a wide range of α-benzoyloxy ketones in good to excellent yields via the direct oxidative α-benzoyloxylation of a structurally diverse series of ketones using simple arylmethane compounds.

Full text of DOI:10.1039/c7ra02298k

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I2/TBHP-mediated oxidative coupling of ketones
and toluene derivatives: a facile method for the
preparation of a-benzoyloxy ketones†
Cite this: RSC Adv., 2017, 7, 20394
a
a
a
b
*
*
Peng Zhou and Hailing Liu
Cui Chen, Weibing Liu,
Received 24th February 2017
Accepted 30th March 2017
An efficient oxidative approach was developed for the a-benzoyloxylation of ketones using tert-butyl
hydroperoxide (TBHP). This process provided facile access to a wide range of a-benzoyloxy ketones in
good to excellent yields via the direct oxidative a-benzoyloxylation of a structurally diverse series of
ketones using simple arylmethane compounds.
DOI: 10.1039/c7ra02298k
rsc.li/rsc-advances
one were found to be unsuitable for this transformation. In
addition, this method afforded low yields of the desired product.
Introduction
Hence, the development of novel, environmentally benign and
high yielding procedures for the preparation of a-acetoxy ketones
from simple and readily available starting materials with a broad
substrate scope is still highly desirable.
a-Acyloxycarbonyl compounds have received considerable interest
from the organic chemistry community during the last few years
because of their unique structural properties. Furthermore,
compounds belonging to this structural class can be found in
a wide variety of biologically interesting natural products, phar-
maceuticals and synthetic intermediates.1 Traditionally, these
compounds are prepared by the substitution reaction of a func-
tionalized carbonyl compound with an alkaline carboxylate or
carboxylic acid,2 as well as the direct oxidative coupling of a ketone
with a carboxylic acid (or surrogates),3 all of which require the use
of a highly toxic heavy metal oxidant.4 Several interesting alter-
natives have been developed to avoid the many drawbacks asso-
ciated with the use of toxic heavy metals. Most notably,
organohypervalent iodine reagents and peroxides have been
widely used as surrogates for heavy metal oxidants to promote the
a-benzoyloxylation of ketones.5 More recently, there have been
several reports pertaining to the use oxyacylating reagents, such as
aldehydes, benzylic alcohols and acetophenones, as surrogates of
carboxylic acids.6 However, to the best of our knowledge, there
have been very few reports describing the a-benzoyloxylation of
ketones using toluene derivatives as oxyacylating reagents. Li and
co-workers recently reported an efficient method for the a-ben-
zoyloxylation of ketones using toluene derivatives as oxyacylating
reagents under metal-free conditions (eqn (1)).7 However, the
substrate scope of this procedure was limited to a-substituted
ketones, whereas acetophenones and 2-iodo-1-phenylpropan-1-
Rather than only serving as effective solvents,8 toluene and
its derivatives can also be used as reagents in organic synthesis
for the construction of structurally complex compounds.9
Herein, we report the development of a novel route for the facile
a-benzoylxoylation of a wide range of ketone substrates (e.g.,
acetophenones, propiophenones, butyrylbenzenes, heterocyclic
arones and aliphatic ketones) using toluene and its derivatives
as oxyacylating precursors in the presence of tert-butyl hydro-
peroxide (TBHP) and iodine to the synthesis of a-benzoylxoy
ketones (eqn (2)). The key features of this new oxidation system
include (i) metal-free oxidation conditions; (ii) the use of
toluene and its derivatives as readily available and inexpensive
oxyacylating precursors; (iii) a broad substrate scope, including
aryl ketones, heterocyclic ketones, aliphatic ketones, toluenes,
phenylmethanols, benzaldehydes, benzoic acids and ethyl-
benzenes; and (iv) milder reaction conditions than existing
methods for this transformation.
(1)
aCollege of Chemical Engineering, Guangdong University of Petrochemical Technology,
2 Guandu Road, Maoming 525000, P. R. China. E-mail: cc161002@gdupt.edu.cn; Fax:
+86-668-2923575; Tel: +86-668-2923956
bCollege Analytical & Testing Centre, Beijing Normal University, No. 19 Xinjiekouwai
St., Haidian District, Beijing 100875, People's Republic of China. E-mail: liuhailing@
bnu.edu.cn
(2)
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra02298k
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the reaction. The results of these screening experiments indi-
cated that 1.0 equivalent was the optimal charge for both I2 and
Na2CO3 (Table 1, entries 14–17). Notably, this reaction failed to
afford the desired product when it was conducted in the
absence of Na2CO3 (Table 1, entry 17). Finally, we did not
observe any changes in the product yield when the reaction was
performed under a N2 atmosphere (Table 1, entry 18).
With the optimized conditions in hand, we proceeded to
explore the scope of this newly developed a-benzoyloxylation
reaction using a wide range of different ketones with toluene
(1a) (Scheme 2). Acetophenones 2a–h and propiophenones 2l–o
bearing a variety of electron-rich and electron-poor substituents
were all tolerated under the optimized reaction conditions.
Substrates bearing electron-withdrawing substituents (i.e., Fꢀ,
Clꢀ and O2Nꢀ) performed more effectively in this reaction than
those bearing electron-donating substituents (i.e., Meꢀ and
Methoxyꢀ), to give the corresponding a-oxyacylated products 2
in relatively high yield. It is noteworthy that the yield of this a-
benzoyloxylation reaction appeared to be largely unaffected by
the position of the substituents on the phenyl ring. For example,
1-p-tolylethanone, 1-o-tolylethanone and 1-m-tolylethanone
Results and discussion
The reaction of toluene (1a) with acetophenone (2a) was initially
selected as a model reaction to determine the optimum condi-
tions for this transformation (Table 1). The results revealed that
the reaction was completed aer 24 h, with no further increases
observed in the product yield following extended reaction time
(Table 1, entries 1–3). It is noteworthy that no reaction occurred
in the absence of TBHP or iodine (I2), which indicated that these
two reagents were critical to the success of the reaction (Table 1,
entries 4–5). Notably, we observed a remarkable increase in the
product yield when the amount of TBHP was increased to 5.0
equivalents. Further increasing the amount of TBHP to 7.0 or
9.0 equivalents did not result in any further increases in the
yield, indicating that the optimum value of this reagent was 5.0
equivalents (Table 1, entries 6–8). We subsequently evaluated
a variety of different peroxides in this reaction, including di-tert-
butyl peroxide (DTBP), benzoyl peroxide, dicumyl peroxide
(DCP), cumene hydroperoxide (CHP) and potassium hydrogen
persulfate. However, all of these peroxides afforded much lower
yields of the desired product than TBHP except benzoyl
peroxide (Table 1, entries 9–13). We then proceeded to investi-
gate the effects of adding different amounts of I2 and Na2CO3 to
Table 1 Optimization of reaction conditionsa
Cat.
Entry (1.0 equiv.) Peroxide (equiv.)
Time (h) Yieldb%
1
I2
Tert-butyl hydroperoxide
(TBHP) (3)
12
17
2
3
4
5
6
7
8
9
I2
I2
I2
—
I2
I2
I2
I2
TBHP (3)
TBHP (3)
—
TBHP (3)
TBHP (5)
TBHP (7)
TBHP (9)
24
36
24
24
24
24
24
24
24
24
0
0
79
86
86
39
Di-tert-butyl peroxide
(DTBP) (5)
10
11
12
I2
I2
I2
Benzoyl peroxide (5)
Dicumyl peroxide (DCP) (5) 24
Cumene hydroperoxide
(CHP) (5)
24
83
58
36
24
13
I2
Potassium hydrogen
persulfate (5)
TBHP (5)
TBHP (5)
TBHP (5)
24
71
14c
15d
16e
17f
18g
I2
I2
I2
I2
I2
24
24
24
24
24
59
86
66
0
TBHP (5)
TBHP (5)
86
a
Unless otherwise specied, all of these reactions were carried out as
follows: 2a (0.25 mmol scale), catalyst (1.0 equiv.) and Na2CO3 (1.0
b
c
d
Scheme
1 a-Benzoyloxylation of different ketones (all of these
equiv.) in toluene (2.0 mL). GC yield. Iodine (0.2 equiv.). Iodine
(1.5 equiv.). e Na2CO3 (0.5 equiv.). Without Na2CO3. g N2 (balloon).
f
reactions were carried out on 2 (1.0 mmol) in toluene (2.0 mL)).
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Scheme 2 a-Benzoyloxylation of acetophenone with different aryl-
methanes (all of these reactions were carried out on 2a (1.0 mmol) with
2.0 mL of 1).
Scheme 4 Control experiments to determine the reaction mechanism.
afford 1-oxo-1-phenylethyl benzoate (3aa) in 67–93% yields.
Benzoic acid, in particular, afforded the desired product with
almost quantitative yield. These results therefore clearly indi-
cate that phenylmethanol, benzaldehyde, benzoic acid and
ethylbenzene are suitable alternatives of toluene for this
transformation, thereby greatly expanding the substrate scope
of this reaction.
gave almost identical yields of the corresponding products. In
addition, the inclusion of different R2 groups (R2 ¼ H, Me, Et)
had no discernible impact on the outcome of this trans-
formation. Pleasingly, we found that this newly developed
procedure was also amenable to heteroaryl (such as thienyl and
furyl, see 3ai, 3aj and 3ap) and alkyl (3ak) ketones.
The following control experiments were carried out to gain
an insight into the mechanism of our newly developed reaction
(Scheme 4). The addition of an excess of the radical scavenger
TEMPO under the standard conditions completely inhibited
the a-benzoyloxylation reaction, suggesting that this trans-
formation proceeds via a radical pathway. Fortunately, 2-iodo-1-
phenylethanone worked well as a surrogate for acetophenone
under our standard reaction conditions, affording an almost
quantitative yield of the desired a-oxyacylated products, which
suggested that 2-iodo-1-phenylethanone was being formed as
an intermediate in this reaction. However, this reaction failed to
afford the desired a-oxyacylated products when it was con-
ducted in the absence of TBHP. Remarkably, the addition of
tert-butylperoxybenzoate to 2a resulted in the formation of the
desired a-benzoxylation product 3aa in 93% yield. In addition,
we noticed that these reactions afforded 3aa in excellent
yields when phenylmethanol, benzaldehyde and benzoic acid
were used as surrogates for acetophenone (Scheme 2). These
ndings therefore suggested that benzoic acid or tert-butylper-
oxybenzoate was being formed in situ as an intermediate from
toluene.
We also investigated the scope of substituted arylmethane
used in this reaction and the results are summarized in Scheme
2. The results revealed that a variety of different substituents,
such as Meꢀ, Clꢀ and Fꢀ, were tolerated on the phenyl group of
the toluene additive, with no discernible difference in the yield of
the a-oxyacylated products compared with toluene. Most notably,
2-methylnaphthalene (1e) reacted with acetophenone (2a) to give
the corresponding product 3ea in an isolated yield of 57%.
To further extend the scope of this reaction, we also tested
the possibility of using phenylmethanol, benzaldehyde, benzoic
acid and ethylbenzene as substrates (Scheme 3). Pleasingly, all
of these substrates reacted efficiently with acetophenone to
Based on the results above and previous reports from the
literature, we proposed a plausible mechanism for the current
a-benzoyloxylation reaction, which is shown in Scheme 5. The
intial reaction of acetophenone (2a) with molecular iodine
would afford 2-iodo-1-phenylethanone A,10 which would be
oxidized by TBHP to produce a-carbonyl radical B.11 Toluene
(1a) would also be oxidized by TBHP to produce the radical
intermediate C, which would be further oxidized to form the
tert-butylperoxybenzoate intermediate E.12 The subsequent
coupling of B and E would lead to the formation of the desired
product 3aa, in a manner similar to that reported by Li.7
Scheme 3 a-Benzoyloxylation reactions of acetophenone with phe-
nylmethanol, benzaldehyde, benzoic acid and ethylbenzene.
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using simple arylmethane compounds in good to excellent
yields. It is noteworthy that the TBHP oxidant used in this
reaction also acted as a source of oxygen for the introduction of
the benzoyloxy group.
Acknowledgements
We thank the Guangdong Provincial Department of Science and
Technology (No. 916014) and the Department of Education of
Guangdong Province (No. 916021) for nancial support.
Notes and references
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Scheme 5 A reaction pathway for the formation of 3aa.
Alternatively, in the presence of TBHP, C could be further
converted to carboxylate anion D.7,13 Finally, the reaction of A
with D affords the nal product 3aa.
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Experimental
General information
ꢁ
All the reactions were carried out at 80 C for 24 h in a round-
bottom ask equipped with magnetic stir bar. Unless other-
wise stated, all reagents and solvents were purchased from
commercial suppliers and used without further purication.
Melting points were measured on a melting point apparatus
equipped with a thermometer. H NMR and 13C NMR spectra
1
were recorded on a 400 MHz spectrometer in solutions of CDCl3
using tetramethylsilane as the internal standard, d values are
given in ppm and coupling constants (J) in Hz. HR-MS were
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Typical procedure: 1-oxo-1-phenylethyl benzoate (Scheme 1, 3aa)
A mixture of acetophenone (2a) (120 mg, 1.0 mmol), Na2CO3
(106 mg, 1.0 mmol), TBHP (70% aqueous solution, 0.65 g, 5.0
mmol), iodine (254 mg, 1.0 mmol) and toluene (2.0 mL) was
added successively in a round-bottom ask, and the resulting
soln stirred for 24 h at 80 ꢁC. The mixture was puried by
column chromatography on silica gel to afford product 3aa with
PE/ethyl acetate as the eluent.
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Conclusions
¨
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facile preparation of a-benzoyloxy ketones by the direct oxida-
tive a-benzoyloxylation of a structurally diverse range of ketones
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and G. Sekar, Tetrahedron Lett., 2008, 49, 2457.
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