Metal-free oxidation of secondary benzylic alcohols using aqueous TBHP

Article abstract of DOI:10.1080/00397911.2016.1223307

We report a simple, yet efficient metal-free oxidation of secondary benzylic alcohols in the presence of t-butyl hydroperoxide (70% TBHP) with high yields of up to 98%. This type of reaction can be carried out using a wide variety of substrates, requires no other organic solvent, and proves to be tolerant toward a variety of different functional groups.

Full text of DOI:10.1080/00397911.2016.1223307

Metal-free oxidation of secondary benzylic alcohols using aqueous TBHP
Jianglong Wu1, Yan Liu1, Xiaowei Ma1, Ping Liu1, Chengzhi Gu1, Bin Dai1
1School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of
Chemical Engineering of Xinjiang Bingtuan, Shihezi University, P. R. China
Abstract
We report a simple, yet efficient metal-free oxidation of secondary benzylic alcohols in
the presence of t-butyl hydroperoxide (70% TBHP) with high yields of up to 98%. This
type of reaction can be carried out using a wide variety of substrates, requires no other
organic solvent and proves to be tolerant towards a variety of different functional groups.
GRAPHICAL ABSTRACT
KEYWORDS: Oxidation, secondary benzylic alcohols, TBHP, metal-free
INTRODUCTION
The oxidation of alcohols to carbonyl compounds is a fundamental reaction step in many
protocols in organic synthesis.[1] Traditionally, this transformation type is performed
with a stoichiometric amount of oxidants such as permanganate and dichromate.
1

However, such reagents prove to be toxic and produce large quantities of hazardous
waste resulting in serious environmental problems.[2] Although the repertoire of different
oxidative reactions is enormous, the development of alternative methodologies that may
be advantageous in terms of selectivity, availability and catalyst affordability, operational
simplicity, functional-group tolerance and environmental sustainability, represents the
main focus of ongoing research. Over the last decades, gold-, palladium-, ruthenium-, and
iridium-catalyzed oxidative reactions have emerged as elementary reaction types in
organic synthesis.[3-6] More recently, great effort has been devoted to the search for
analogous catalytic processes based on more cost efficient and environmentally less
harmful metals, e.g. manganese, copper, iron, cobalt, zirconium, and several other
important catalysts and reagents.[7-14] In spite of the large number of different methods
available, advantageous methodologies in terms of selectivity, availability of catalyst,
functional-group tolerance, environmental sustainability and economy are in steadily high
demand. Most of the established protocols are suffered from various disadvantages,
including the use of toxic chemicals, harsh conditions, high catalyst loadings as well as
less efficient and expensive catalytic systems. This is why the development of new
oxidative systems that utilize catalysts based on inexpensive as well as non-toxic metals
remains a crucial goal of ongoing studies. Conversely, efficient processes that do not
require a metal catalyst are of equally high interest. As a consequence, the discovery of
efficient processes that do not require a metal catalyst is of great importance since such
procedures would eliminate the need for disposing the catalysts from reaction residues
and would spare potential further steps in the workup to remove metal traces from the
target compounds.[15-22] Tert-butyl hydroperoxide (tBuOOH) is an organic peroxide
2

widely used in a variety of oxidation processes.[23-29] Recently, Gawande et al.
developed an efficient protocol for the oxidation of benzylic alcohols by combining a
CoFe2O4 catalyst with 70% TBHP in dimethyl sulfoxide (DMSO).[30] Herein, we report
a simpler and more efficient metal-free oxidation of secondary benzylic alcohols in the
presence of 70% TBHP and without addition of any other organic solvent (Scheme 1.).
RESULTS AND DISCUSSION
Initially, we chose 1-phenylethanol (1.0 mmol) as a model substrate for the oxidative
reaction catalyzed by transition metal catalysts (1 mol%) in the presence of 70% TBHP
(3 equiv.) at 80 °C for 3 hours in methanol (2 mL) and recorded the corresponding yield
via GC-MS. As shown in Table 1, the desired products were obtained in 23-35% yields
(Table 1, entries 1-3). Similarly, in the absence of any catalyst, only 12% yield was
obtained (Table 1, entry 4). Fortunately, Cu(OAc)2∙H2O (1 mol%) demonstrated a good
catalytic activity for this oxidative reaction in water or CH3CN (Table 1, entries 5 and 6),
resulting in the formation of the desired product in 70% yield. However, a very low yield
was obtained with acetone as a solvent (Table 1, entry 7). The results obtained show that
methanol or acetone as solvents appears to inhibit the catalytic oxidation of 1-
phenylethanol. Indeed, further investigations revealed that this reaction could be carried
out without the presence of any organic solvent up to a high yield of 95%(Table 1, entry
8). Interestingly, in the absence of catalyst and solvent, the desired product could still be
obtained in 63% yield (Table 1, entry 9). Noteworthy in this context is the finding that the
product could be obtained in 89% yield (Table 1, entry 10) when the amount of 70%
TBHP was increased to 6 equivalents, with the reaction temperature increased to 100 °C.
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Furthermore, when the reaction time was extended to 24 hours, the yield of product 2a
increased to 97% (Table 1, entry 11). However, when aqueous hydrogen peroxide was
used as the oxidant, a significantly lower yield was obtained (Table 1, entry 12).
Similarly, the oxidative reaction of 1- phenylethanol using 10% TEMPO as a catalyst in
the presence of oxygen also resulted in a low yield of 37% (Table 1, entry 13). Only 12%
yield is obtained at room temperature, the result is consistent with those reported in
literature[31]. Consequently, 70% TBHP (6 equivalents) at 100 ºC without addition of
any other solvents or metal catalysts were found to be the most optimized reaction
conditions.
With the optimized reaction conditions in hand, we surveyed the scope of secondary
alcohols substrates that could be used for this oxidation type. As shown in Table 2, the
position of the substituents on the molecules played no significant role on the catalytic
efficacy. For example, 1-(4-bromophenyl)ethan-1-ol were oxidized in the presence of
70% TBHP (6 equivalents) to afford the desired products 2b in 75% yield. 1-(3-
bromophenyl)ethan-1-ol and 1-(3-(trifluoromethyl)phenyl)ethan-1-ol could also be
successfully transformed to result in the formation of products 2c and 2d in
corresponding yields of 81% and 70%, respectively. Oxidation reactions of naphthyl
substituted secondary alcohols were also attempted using the optimized reaction
conditions described above. The substrates 1-naphthyl ethanol derivative could be
oxidized to the desired products 2e and 2f with yields 73% and 98%, respectively. To
further investigate the range of substrates that could be used in this process, a variety of
diaryl methanol derivatives were investigated. The oxidative reactions involving
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substituted diaryl methanol afforded the corresponding products 2g-2m in yields ranging
from 73% to 95%. Similarly, the use of 9H-xanthen-9-ol, 9H-fluoren-9-ol derivatives,
and 5H-dibenzo[a,d][7]annulen-5-ol as substrates resulted in the formation of the product
compounds 2n-2q in 88-98% yields. Noteworthy, the selective oxidation of benzyl
alcohol derivatives to aromatic aldehydes was also attempted using standard reaction
conditions and the desired products 4a and 4b were obtained in 72% and 63% yields,
respectively. This yield was close to the result reported by Gawande et al. using
combination of CoFe2O4/TBHP in a dimethyl sulfoxide (DMSO) catalytic system. [30]
Considering the broad application spectrum and large demand of aryl ketones in many
industrial fields, particularly as raw materials in the production of pharmaceuticals and
drug stabilizers, we attempted to conduct a scaled-up preparation of aryl ketones using
the optimized conditions. The reaction was performed with 15 mmol of 1-phenylethanol,
and proceeded with a yield of 89%, resulting in the production of 1.602 g of the
corresponding target compound 2a.
In addition, we found if oxidative reaction of some benzyl alcohol substrates were carried
out smoothly that required 10 equivalents of 70% TBHP at least. As shown in Table 3, 1-
(4-methoxyphenyl)ethan-1-ol were oxidized in the presence of 70% TBHP (10
equivalents) to afford the desired products 2r in 73% yield. Furthermore, any steric
hindrance caused by secondary alcohol functional groups were found to be well tolerated
and furnished the corresponding products 2s and 2t with yields of 89% and 72%. The
substrate 1-(naphthalen-1-yl)ethan-1-ol could be oxidized to the desired products 2u with
5

yield 70%. Moreover, 1,2,3,4-tetrahydronaphthalen-1-ol, and 2,3-dihydro-1H-inden-1-ol
derivatives were found to produce the desired oxidation products 2v-2y in 82-92% yields.
The oxidative reaction of bis(4-chlorophenyl)methanone afforded the corresponding
products 2z in 89% yield.
It is worth mentioning that 9H-xanthene can be oxidized to 9H-xanthen-9-one in the
presence of 70% TBHP at 100 ºC. The corresponding product 2w was obtained in 83%
isolated yield and the potential side product 9H-xanthen-9-ol 2w′ could not be detected in
the GC-MS spectrum. Similarly, 2-nitro-9H-fluorene and 3,6-di-tert-butyl-9H-fluorene
can also be converted to the corresponding diaryl ketones 4c and 4d in 91% and 78%
yields, respectively, using the same conditions (Scheme 2.).
It has been proposed that the oxidation of metal-catalyzed secondary alcohols using
aqeuous TBHP proceeds via a radical path [32]. As shown in Table 4, we observed that
the yield of the reaction was not greatly influenced by the presence of N2 (entry 1). Using
standard conditions with the reaction carried out in the dark, the yield dropped to 46%
(entry 2). Similarly, if TEMPO as radical scavenger was added to the reaction mixture,
the yield also decreased significantly (entries 3-7, Figure 1). The reaction rate was very
slow in the beginning of the oxidation, and the yield was greatly enhanced with the
increase of reaction time (entries 8-13, Figure 2). This may be related to the rate and
concentration of oxidation free radicals product by the tert-butyl hydroperoxide
decomposition in the course of the reaction. In addition, we found that the yield will be
6

significantly reduced with the decrease of the amount of the TBHP (entries 14-17, Figure
3).
Based on the experimental results mentioned above and other related reports [33-36], a
plausible radical mechanism was proposed and can be found outlined in Scheme 3. The
first step involves the decomposition of tert-butyl hydroperoxide to form tert-butoxy
radicals and hydroxyl radicals via photolysis and thermolysis. Then the tert-butoxy
radical reacts with benzyl alcohol to produce a radical (B). The radical (B) combine with
another tert-butoxy radical to generate an intermediate (C). Finally, the intermediate (C)
loss a tert-butanol to give the oxidation products. Therefore, we can conclude that the
oxidation of one molecule of benzyl alcohol required two molecules of TBHP.
EXPERIMENTAL SECTION
Materials And Instruments
Chemicals were obtained commercially and used as received. NMR spectra were
recorded on a Bruker DPX–400 spectrometer using TMS as the internal standard. EI–
Mass spectrum was measured on a LC/Q–TOF MS (Micromass, England) All products
were isolated by short chromatography on a silica gel (200–300 mesh) column using
petroleum ether (60–90 ºC), unless otherwise noted. Secondary benzylic alcohols, and
diarylmethanes were of analytical grade quality, purchased from Adamas-beta
Pharmaceuticals, Inc.
General Procedure For The Oxidative Reaction
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Caution! Tert-butyl hydroperoxide is an exceptionally dangerous chemical that is highly
reactive, flammable and toxic. It is corrosive to skin and mucous membranes and causes
respiratory distress when inhaled.
A solution of secondary alcohol (1 mmol), and 70% TBHP (6 or 10 equiv.) was stirred at
100 ºC for 24 h. The reaction mixture was quenched with the saturated solution of
sodium thiosulfate (5 mL) and extracted with dichloromethane (3 × 10 mL). The
combined dichloromethane extracts were dried over anhydrous Na2SO4, filtrated, and
then the solvent was removed under reduced pressure. The residue was purified by flash
column chromatography on silica gel with PE or PE/EtOAc as the eluent to obtain the
desired products.
Acetophenone (2a), product 2a was obtained by flash column chromatography on silica
gel with PE:EA = 80:1 as the eluent. Colourless liquid, 97% (116 mg). 1H NMR (400
MHz, CDCl3) δ 6.76 – 6.73 (m, 2H), 6.37 – 6.32 (m, 1H), 6.27 – 6.22 (m, 2H), 1.39 (s,
3H). GC-MS (m/z): 120.
CONCLUSION
In conclusion, a simple, yet facile and efficient method for the synthesis of aryl ketones
via metal-free oxidation of secondary benzylic alcohols in presence of TBHP in aqueous
media and without addition of any organic solvent has been successfully developed. The
corresponding target molecules could be obtained in good to excellent yields. Potential
substrates for this reaction are diverse, exhibiting a superior functional group tolerance.
8

In particular, the system may also be suitable for the synthesis of aryl ketones on a multi-
gram scale. This protocol may also be applied to the oxidation of diarylmethane
substrates. Studies to further investigate this catalytic system to other related reactions are
currently underway in our laboratory.
CONFLICT OF INTEREST
We state that none of the authors have any conflict of interest in the context of this
communication.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGMENT
We gratefully acknowledge financial support of this work by the National Natural
Science Foundation of China (No. 21563025, No.21463022), Shihezi University Training
Programme for Distinguished Youth Scholars (No. 2014ZRKXJQ05), and Start-Up
Foundation for Young Scientists of Shihezi University (RCZX201408).
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18

Table 1. Optimization of the reaction conditionsa
Entry Catalyst
Solvent Oxidant
T(ºC) T(h) Yield(%)b
1
CuCl(1%)
CuI(1%)
MeOH TBHP(3 equiv.)
MeOH TBHP(3 equiv.)
60
10
10
10
10
10
10
10
10
10
10
24
24
24
24
23
26
35
12
70
81
43
95
63
89
97
9.8
37
12
2
60
3
Cu(OAc)2∙H2O(1%) MeOH TBHP(3 equiv.)
no MeOH TBHP(3 equiv.)
Cu(OAc)2∙H2O(1%) H2O TBHP(3 equiv.)
60
4
60
5
60
6
Cu(OAc)2∙H2O(1%) CH3CN TBHP(3 equiv.)
Cu(OAc)2∙H2O(1%) acetone TBHP(3 equiv.)
60
7
60
8
Cu(OAc)2∙H2O(1%) no
TBHP(3 equiv.)
TBHP(3 equiv.)
TBHP(6 equiv.)
TBHP(6 equiv.)
H2O2(1 mL)
60
9
no
no
no
no
no
no
no
no
no
no
no
no
60
10
11
12
13
14
100
100
100
TEMPO(10%), O2 100
TBHP(6 equiv.) 25
a Reaction conditions: 1 mmol of 1-phenylethanol, 2 mL solvent.
b GC-MS yield.
19

Table 2. The oxidation of secondary benzylic alcohols with 6 equiv. of 70% TBHPa
a Reaction conditions: 1 mmol of secondary benzylic alcohols, 6 equiv. of 70% TBHP, 24
h, 100 ºC. The yields of isolated products are given.
b The result was reported by Gawande et al [30].
c 15 mmol of 1-phenylethanol was used.
20

Table 3. The oxidation of secondary benzylic alcohols with 10 equiv. of 70% TBHPa
a
Reaction conditions: 1 mmol of secondary benzylic alcohols, 10 equiv. of 70% TBHP,
24 h, 100 ºC. The yields of isolated products are given.
21

Table 4. Mechanistic insightsa
Entry
1
TBHP(equiv.)
TEMPO
Addition
N2
Time(h)
24
24
24
24
24
24
24
2
Yield(%)b
89
6
6
6
6
6
6
6
6
6
6
6
6
6
4
3
2
no
2
no
in dark
no
46
3
5%
29
4
1.2(equiv.)
no
15
5
2.4(equiv.)
no
11
6
4.8(equiv.)
no
9
7
6.0(equiv.)
no
trace
13
8
no
no
no
no
no
no
no
no
no
no
9
no
5
43
10
11
12
13
14
15
16
no
7
58
no
10
15
24
24
24
24
89
no
93
no
97
89
no
65
no
27
no
22

1
trace
17
no
no
24
a Reaction conditions: 1 mmol of 1-phenylethanol, 70% TBHP, 100 ºC.
b The yields of isolated products are given.
23

Figure 1. Effect of the amount of TEMPO on the oxidation of 1-phenylethanol
24

Figure 2. Effect of time on the oxidation of 1-phenylethanol
25

Figure 3. Effect of the amount of 70% TBHP on the oxidation of 1-phenylethanol
26

Scheme 1. Strategies towards oxidation of secondary benzylic alcohols.
27

Scheme 2. Oxidation of diarylmethanes.
28

Scheme 3. The proposed reaction mechanism.
29