Clean and efficient benzylic C-H oxidation using a microflow system

Article abstract of DOI:10.1080/00397911.2010.517611

An efficient procedure using microreactors for the oxidation of benzylic compounds is described. This new method is facile, economical, and environmentally friendly. By using microreactors, this oxidation can be accomplished with good yields within 10s at room temperature. Copyright

Full text of DOI:10.1080/00397911.2010.517611

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Clean and Efficient Benzylic C-H
Oxidation Using a Microflow System
Xiao-Ming Lv a , Ling-Jie Kong a , Qi Lin a , Xiao-Feng Liu a , Ya-Ming
Zhou a & Yu Jia a
a Department of Chemistry, Fudan University, Shanghai, China
Published online: 27 Jul 2011.
To cite this article: Xiao-Ming Lv , Ling-Jie Kong , Qi Lin , Xiao-Feng Liu , Ya-Ming Zhou & Yu
Jia (2011): Clean and Efficient Benzylic C-H Oxidation Using a Microflow System, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:21, 3215-3222
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Synthetic Communications1, 41: 3215–3222, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517611
CLEAN AND EFFICIENT BENZYLIC C-H OXIDATION
USING A MICROFLOW SYSTEM
Xiao-Ming Lv, Ling-Jie Kong, Qi Lin, Xiao-Feng Liu,
Ya-Ming Zhou, and Yu Jia
Department of Chemistry, Fudan University, Shanghai, China
GRAPHICAL ABSTRACT
Abstract An efficient procedure using microreactors for the oxidation of benzylic
compounds is described. This new method is facile, economical, and environmentally
friendly. By using microreactors, this oxidation can be accomplished with good yields within
10 s at room temperature.
Keywords Benzylic C-H oxidation; microreactors; tert-butyl hydroperoxide
INTRODUCTION
In recent years, microreactor technology has received a great deal of attention
in both academia and industry.[1–4] Compared with conventional macroscale batch
reactors, microreactors exhibit numerous practical advantages, including added
efficiency, control, safety, and easy scale-up for industrial production. Because the
controlled mixing of reagents and the reaction time with a substrate can be varied
by adjusting the lengh of a microchannel and flow speed, microflow systems could
serve as a powerful tool for mechanistic studies on extremely fast reactions,[5] and
the careful control of reaction temperature and residence time has a beneficial effect
on the outcome of a reaction with respect to yield, purity, and selectivity.[6]
Received October 27, 2009.
Address correspondence to Yu Jia, Department of Chemistry, Fudan University, Shanghai,
200433, China. E-mail: yujia-fudan@hotmail.com
3215

3216
X.-M. LV ET AL.
Many organic reactions using microreactors have been reported in the past few
years, including various reaction types, such as nitration,[7] Swern oxidation,[8]
coupling reactions,[9] o-bromophenyllithium reaction,[10] and droplet reactions.[11]
However, the study of benzylic C-H oxidation in microreactors at room temperature
has not been reported so far.
As a conversion of alkylarenes to the corresponding carbonyl compounds,
benzylic oxidation is a useful fundamental transformation. Various methods have
been developed using a variety of oxidants and conditions. Employing transition-
metal oxidants such as chromium,[12] copper,[13] and ruthenium compounds,[14]
tert-butyl hydroperoxide–assisted alkylarene oxidation has been the subject of
numerous investigations.
However, use of tert-butyl hydroperoxide solution in combination with
transition-metal salts is usually not desired, especially when carried out on a large
scale, because such oxidations are exothermic and require more precautions.[15]
Furthermore, transition-metal salts have additional disadvantages that often
make such processes unattractive, for example, the toxicity of oxochromium(VI)
reagents, high cost of some specialty reagents such as ruthenium, and contamination
of products with trace metallic impurities.[15]
Marwah et al.[15] have reported a new procedure for the synthesis of benzylic
carbonyl compounds utilizing sodium hypochlorite, in combination with tert-butyl
hydroperoxide. However, to gain good yields of the product, NaClO solution has
to be added continuously in the form of fine droplets for 9–10 h while the tempera-
ture has to be subambient. These requirements cause limitations on this reaction in
industrial use.
Herein, we report that this oxidation can be accomplished in a good yield
within 10 s at room temperature using microreactors.
RESULTS AND DISCUSSION
We performed the benzylic C-H oxidation by using a microscale flow system,
as represented in Fig. 1. We used xanthene (Scheme 1) as our model substrate. The
Figure 1. Setup of a microflow system. It consists of two syringe pumps, one T-shaped micromixers, and
one microtube reactor (inner diameter u ¼ 0.25 mm, length L ¼ 50 cm).

OXIDATION IN MICROFLOW SYSTEM
3217
Scheme 1. C-H oxidation of xanthene.
effect of residence time and temperature on the reaction yield was studied. The resi-
dence time was adjusted by changing the flow rate of the substrate. At room tem-
perature, a solution of xanthene and tert-butyl hydroperoxide in ethyl acetate
(flow rate: 0.1 mL=min or 0.01 mmol=min, xanthone–tert-butyl hydroperoxide
1:10, mol=mol) and an aqeous solution of NaClO (flow rate: 0.059 mL=min,
0.07 mmol=min) were pumped through a micromixer (M1) by syringe pumps (P1,
P2). The calculated residence time was 10 s. However, the real residence time is hard
to detect and supposed to be shorter than 10 s because of the gas generation that can
accelerate the flow. The outlet solution was quenched with saturated aqueous
Na2SO3. The crude product was purified by column chromatography to give com-
pound 1b, xanthone, at 92% yield.
The NaClO reacted fast with tert-butyl hydroperoxide at room temperature to
generate a lot of oxygen gas. The closed system design of the microreactors can
trap the oxygen gas and showed inherent advantages for this type of reaction. In
addition, this reaction was exothermic. In a batch reactor, the reaction between
NaClO and tert-butyl hydroperoxide is sharp and quick, releasing a lot of heat,
which makes this reaction hard to control. So, a conventional reaction is required
to be performed, preferably at 2–5 ꢀC.[15] In a microreactor, we can obtain a yield
of 87% at subambient temperature and an even better yield at room temperature
(Fig. 2). All data indicated that the reaction temperature does not affect the yield
significantly.
When the residence time was 5 s, column chromatographic analysis of the
crude product showed that the major component of the impurities was the unreacted
Figure 2. Effect of residence time on the yield of the reaction of substrate 1 at different temperatures.

3218
X.-M. LV ET AL.
starting material; this residence time is not enough for full transformation. When the
residence time was 10 s or much longer, the conversion of starting material reached
100% (detected by high-performance liquid chromatography HPLC). This indicates
that residence time is an important factor for this reaction, and it requires no more
than 10 s to achieve conversion.
We further studied the effect of ratios between tert-butyl hydroperoxide and
NaClO (Table 1). These oxidation reactions have been proved to use free radical
pathways.[15] When tert-butyl hydroperoxide–NaClO ¼ 10:1 (mol=mol), the isolated
yield is only 3%, and the most impurity was the unreacted starting material
1
(detected by both H NMR and HPLC). When the mol. equiv. of NaClO was
gradually raised to 8, the yield increased correspondingly to 92%. When tert-butyl
hydroperoxide–NaClO ¼ 4:8 (mol=mol), the isolated yield is only 12%, and the
yield also increased correspondingly as the mol. equiv. of tert-butyl hydroperoxide
gradually raised from 4 to 10. This indicates that ratio of reactants is a key factor
for the reaction.
Based on these findings, we expanded the study to a number of other substrates
(Table 2) using the optimized conditions. The results are summarized in Table 2.
Unlike the conventional reaction, this reaction in the microflow system is a
continuous process in the channel. Once the reaction occurs, the product flows out
of reaction channel and is quenched to avoid further oxidation. Cyclic compounds,
such as tetralin (entry 3) and indan (entry 4), afforded the corresponding arylketones
in good yields, and gas chromatography–mass spectrometry (GC-MS) data of these
crude products showed there was no presence of dione. This indicates a highly selec-
tive reaction. Furthermore, reaction conditions were also found to be suitable for the
oxidation of olefins to a,b-enones (entries 7 and 8), and the corresponding enones
were obtained in good yields. Among the variety of olefins substrates, the oxidation
of d-5-steroids (entry 8) to their corresponding 5-en-7-ones has attracted particular
interest because 7-keto-d-5-steroids are known as inhibitors of mammalian steroidal
hormones biosynthesis. In microsystems, the high efficiency of this method makes
application in industry feasible.
Table 1. Effect of ratios between TBHP and NaClOa
TBHPb
(mol equiv)
NaClOc
(mol equiv)
Temp.
(ꢀC)
Entry
Time
Yieldd (%)
1
2
3
4
5
6
7
8
10
10
10
10
10
8
1
2
25
25
25
25
25
25
25
25
10
10
10
10
10
10
10
10
3
17
50
92
90
74
30
12
4
8
10
8
6
8
4
8
a1 mol equiv. of xanthene was used for all the entries.
btert-butylhydroperoxide (70% aqueous solution).
cSodium hypochlorite solution (5.25% aqueous solution).
dIsolated yield.

OXIDATION IN MICROFLOW SYSTEM
3219
Table 2. Benzylic C-H oxidation by using a microscale flow systema
Entry
1
Substrate
Product
Yieldb (%)
92
2
92
3
4
5
90
94
88
6
7
94
75c
8
68
aReaction conditions: room temperature, 10 s, substrate=TBHP=NaClO ¼ 1:10:8 (mol ratio).
bIsolated yield.
cYield determined by GC.
CONCLUSIONS
In conclusion, for the first time, the benzylic C-H oxidation has been studied in
microreactors. We have developed a new synthetic method in a microreactor system
to synthesize carbonyl compounds in high efficiency. Compared with the conven-
tional method, good to excellent yields have been obtained within much shorter

3220
X.-M. LV ET AL.
reaction times. Studies on more substrates of different classes are on the way to
expand the application of this method.
EXPERIMENTAL
1H NMR spectra was recorded on Jeol ECA-400 NMR spectrometer. Infrared
(IR) spectra were recorded on Nicolet Avatar-360. Conversions were determined by
HPLC analysis using an Agilent 1200 [DAD: 215 nm, column: agilent zorbax eclipse
XDB-C18 (4.6 ꢁ 150 mm, I.D. 5 mm)].
Fabrication of Microreactor System
The continuous flow microreactor system used for our studies mainly consists
of three parts: two microsyringe pumps, a microchannel (250 mm in i.d.), and collec-
tion devices. The microchannel is a 50-cm-long polyetheretherketone (PEEK) pipe.
Typical Procedure for the Preparation of Xanthenone
Using the Microreactor
At room temperature, a solution of xanthene and tert-butyl hydroperoxide in
ethyl acetate (flow rate: 0.1 mL=min or 0.01 mmol=min, xanthene–tert-butyl hydro-
peroxide ¼ 1:10, mol=mol) was mixed with a solution of the NaClO (flow rate:
0.059 mL=min or 0.07 mmol=min) in the micromixer. We have known that this oxi-
dation could be accomplished in a good yield within 10 s; if we prolong the length of
the microchannel, the flow rate will be much faster correspendingly. The outlet sol-
ution was quenched with saturated aqueous Na2SO3. The residence time is 10 s. The
mixture was extracted with ethyl acetate (3 ꢁ 30 mL). The combined organic phases
were dried over sodium sulfate and then concentrated. The crude product was pur-
ified by column chromatography on silica gel (300–400 mesh) using ethyl acetate=
petroleum ether m (1:10, v=v) as eluent to afford pure xanthenone as a bright white
solid (180.5 mg, 92%).
EXPERIMENTAL DATA
Xanthenone (1b)
White powder; mp 176–177 ꢀC; 1H NMR (400 MHz, CDCl3) d 7.39 (t,
J ¼ 7.1 Hz, 2H), 7.51 (d, J ¼ 8.4 Hz, 2H), 7.74 (m, 2H), 8.34 (dd, J ¼ 8.1, 1.8 Hz,
2H); IR (KBr) cmꢂ1: 1659, 1607, 1481, 1460, 1333, 758.
Fluoren-9-one (2b)
1
Yellow powder; mp 75–77 ꢀC; H NMR (400 MHz, CDCl3) d 7.26–7.31 (m,
2H), 7.45–7.53 (m, 4H), 7.64–7.67 (m, 2H); IR (KBr) cmꢂ1: 1715, 1601, 1454,
1300, 912, 743, 650.

OXIDATION IN MICROFLOW SYSTEM
3221
3,4-Dihydro-2H-naphthalen-1-one (3b)
1
Colorless oil; H NMR (400 MHz, CDCl3) d 2.14 (q, J ¼ 6.3 Hz, 2H), 2.66 (t,
J ¼ 6.0 Hz, 2H), 2.97 (t, J ¼ 6.0 Hz, 2H), 7.24–7.35 (m, 2H), 7.44–7.49 (m, 1H),
8.02–8.05 (m, 1H); IR (KBr) cmꢂ1: 2945, 1682, 1601, 1454, 1323, 1286, 1225, 764,
735.
Indan-1-one (4b)
1
Pale yellow solid; mp 38–39 ꢀC; H NMR (400 MHz, CDCl3) d 2.67–2.71 (m,
2H), 3.15 (t, J ¼ 5.7 Hz, 2H), 7.37 (t, J ¼ 7.7 Hz, 1H), 7.48 (d, J ¼ 7.7 Hz, 1H), 7.59
(t, J ¼ 7.1 Hz, 1H), 7.76 (d, J ¼ 7.5 Hz, 1H); IR (KBr) cmꢂ1: 2930, 2251, 1682,
1614, 1441, 1279, 1244, 1204, 1151, 1088, 912, 745.
Diphenylmethanone (5b)
1
Colorless oil; H NMR (400 MHz, CDCl3) d 7.47 (t, J ¼ 7.5 Hz, 4H), 7.58 (t,
J ¼ 7.2 Hz, 2H), 7.79–7.81 (m, 4H); IR (KBr) cmꢂ1: 3059, 1659, 1599, 1578, 1447,
1275, 1177, 920, 810, 638.
Anthraquinone (6b)
1
Yellow crystals; mp 284–285 ꢀC; H NMR (400 MHz, CDCl3) d 7.79–7.85 (m,
4H), 8.30–8.36 (m, 4H).
2-Cyclohexen-1-one (7b)
1
Bp 168 ꢀC; H NMR (400 MHz), d 6.57 (m, 1H), 6.07 (s, 1H), 2.90 (t, 2H),
1.40–1.93 (m, 4H); IR (KBr) cmꢂ1: 1679, 2944.
3-Acetoxyandrost-5-en-7,17-dione (8b)
Mp 185–187 ꢀC;1H NMR (400 MHz), d 5.72 (s, 1H, 6-H), 4.69 (m, 1H, H-3),
2.02 (s, 3-AcO), 1.21 (s, 19-CH3), 0.89 (s, 3H, 18-CH3); IR (KBr) cmꢂ1: 1734,
1670, 1630, 1026.
ACKNOWLEDGMENT
The authors thank the National Research Program of China (973 Program),
Grant No. 2007CB714504.
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