Direct electrosynthesis of ketones from benzylic methylenes by electrooxidative C-H activation

Article abstract of DOI:10.1002/chem.201204207

Electrify your chemistry! Direct electrosynthesis of ketones from benzylic methylenes in an undivided cell was realized in moderate to good yields (see scheme). In this electrosynthesis, electrons instead of conventional oxidants and catalysts are employed to make the reaction environmentally benign. Moreover, the reaction intermediate radical was detected by ESR spectroscopy and the reaction mechanism was clarified.

Full text of DOI:10.1002/chem.201204207

DOI: 10.1002/chem.201204207
Direct Electrosynthesis of Ketones from Benzylic Methylenes by
À
Electrooxidative C H Activation
Li Meng,[a] Jihu Su,[b] Zhenggen Zha,*[a] Li Zhang,[a] Zhenlei Zhang,[a] and
Zhiyong Wang*[a]
À
Direct oxidative activation of benzylic C H bonds under
mild conditions is of importance due to its wide applications,
especially in organic synthesis. Many chemists have made
great contributions to this important transformation.[1] The
generated ketones can not only act as building blocks for
the synthesis of pharmaceuticals and agrochemicals, but can
also form important intermediates in natural products.[2] Tra-
ditionally, benzylic oxidation usually required oxidants
based on heavy metals in stoichiometric amounts, such as
potassium permanganate, potassium dichromate, or ammo-
nium cerium nitrate.[3] Recently, great progress has been
made in terms of catalysts or oxidants, such as metal cata-
lysts[4] involving Cr, Mn, Co, Bi, Ru, Rh, Fe, and Au and
metal-free oxidants[5] including 2-Iodoxybenzoic acid (IBX),
NaClO/TBHP, and HBr/H2O2. Although these methods
afford good results, the toxicity of expensive metal catalysts,
harsh reaction conditions, and tedious work-up procedures
limits their application in organic synthesis. Therefore,
green oxidant of mass-free electrons, wide substrate scope,
and mild conditions.
Initially, we chose the oxidation of diphenylmethane as a
model reaction. To the best of our knowledge, smooth plati-
num can stand the large overpotential for oxygen and hy-
drogen evolution in solution.[10] Therefore, in the presence
of two platinum electrodes, various different solvents were
tested (Table 1, entries 1–7). It was obvious that water could
Table 1. Optimization for the oxidation of diphenylmethane into benzo-
phenone.[a]
Entry Electrode (anode/ Electrolyte Current Solvent
Yield
[%][b]
cathode)
[mA]
[mL]
1
2
3
4
5
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/Pt
Pt/C
C/Pt
C/C
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
20
20
20
20
20
20
20
CH3CN
CH3CN/H2O 24
–
À
simple and efficient methods for the benzylic C H oxidation
are highly desirable.
CH2Cl2/H2O trace
MeOH/H2O trace
EtOH/H2O
THF/H2O
H2O
CH3CN/H2O 65
CH3CN/H2O 79
CH3CN/H2O 84
CH3CN/H2O 72
CH3CN/H2O 62
CH3CN/H2O 82
CH3CN/H2O 62
CH3CN/H2O 55
As for electrochemical oxidation, our group has made
some progress, such as the one-pot synthesis of homoallylic
alcohols[6] and electrosynthesis imidines from aliphatic
amines and sulfonyl azides.[7] Previously, we employed
iodine–pyridine–tert-butylhydroperoxide (I2-Py-TBHP)[5f] as
a catalytic system to achieve benzylic oxidation. Intrigued
by the electrochemical redox catalysts[8] and electroredox in-
tegrated with chemical oxidation,[9] we realized direct elec-
trosynthesis of ketones from benzylic methylenes through
trace
trace
–
6
7[c]
8
Bu4NClO4 20
Bu4NHSO4 20
9
10[d]
11
12
13
14
15
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
20
30
10
20
20
20
À
an electrooxidative C H activation. This method features a
[a] Reaction conditions: diphenylmethane (0.5 mmol), electrolyte
(1 mmol), solvent/H2O=18:1 (9.5 mL); the electrolysis was conducted at
a constant current for 5 h in an undivided cell. [b] Yields of the isolated
products. [c] KNO3 (1 mmol) was added. [d] Caution! lithium perchlorate
is a potential explosive.
[a] L. Meng,+ Z. Zha, L. Zhang, Z. Zhang, Prof. Dr. Z. Wang
Hefei National Laboratory for Physical Sciences at Microscale
CAS Key Laboratory of Soft Matter Chemistry and
Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui, 230026 (P. R. China)
Fax : (+86)551-63603185
promote the reaction to some extent (entry 2). On the other
hand, no product was obtained when the reaction was per-
formed in net water. Among all tested solvents, CH3CN/
H2O was the best choice (entries 2–7). Afterwards, the elec-
trolytes, such as Bu4NBF4, Bu4NClO4, Bu4NHSO4, and
LiClO4 were examined in this reaction. It was found that
LiClO4 was the most efficient in the electrochemical reac-
tion (entries 2 and 8–10). Under these conditions, various
combinations of the electrodes were attempted and plati-
E-mail: zwang3@ustc.edu.cn
[b] Prof. Dr. J. Su+
Hefei National Laboratory for Physical Sciences at Microscale
and Department of Modern Physics, University of Science
and Technology of China, Hefei, Anhui, 230026 (P. R. China)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204207.
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Chem. Eur. J. 2013, 19, 5542 – 5545

COMMUNICATION
num proved to be the best one for the electrochemical oxi-
dation. Moreover, the current of the oxidation was also opti-
mized. Below 20 mA of the current the reaction proceeded
slowly in a low yield, while no improvement was observed
beyond the 20 mA (entries 10–12). Therefore, we chose
20 mA as the current of electrolysis in the reaction. Eventu-
ally, the optimal conditions were obtained as below: LiClO4
(1 mmol) as the electrolyte, CH3CN/H2O (9/0.5 mL) as the
solvent, platinum as both the anode and the cathode. All
the reactions were electrolyzed at a constant current of
20 mA.
Under the optimized reaction conditions, various benzylic
methylenes were investigated and the results are summar-
ized in Table 2. Diarylmethane (1a) was efficiently oxidized
to benzophenone (2a) in 84% yield (Table 2, entry 1). The
oxidation of diarylalkanes can be carried out well regardless
of the electron-withdrawing or -donating ability of R1 on the
phenyl ring (entries 2–10). However, a steric effect could be
observed since ortho substitution gave a lower yield relative
to meta and para substitution (entry 14 vs. 11 and 2; entry 15
vs. 12 and 3; entry 16 vs. 13 and 10). When R2 was alternat-
ed from an aromatic group to an aliphatic group, the reac-
tion could still be carried out smoothly to afford the corre-
sponding ketones with moderate to good yields (entries 18,
19). Moreover, tetralin (1u), bearing a cyclic aliphatic
group, also led to a medium yield (entry 20). When R2 was
an electron-deficient substituent, the reaction hardly occur-
red, as shown in entry 20. More importantly, the reaction
conditions were so mild that the nitro group could survive
the reaction even when the electrolysis time was 7 h
(entry 6).
From the cyclic voltammogram curves, we observed that
the oxidation potentials for diphenylmethanol and diphenyl-
methane were about 1.23 and 1.18 V, respectively, as shown
in Figure S1 of the Supporting Information. To gain more in-
sight into the reaction mechanism, reaction progress was in-
vestigated by ESR spectroscopy. The ESR spectrum of the
diphenylmethane radical[11] (2 in Scheme 1) was observed, as
Table 2. Scope of the electrosynthesis of ketones from benzylic meth
enes.[a]
ACHTUNGERTNyNUNG l-
ACHTUNGTRENNUNG
Scheme 1. Proposed mechanism for the oxidation of methylenes.
Entry
R1
R2
Faradaic yield
[%]
Yield
[%][b]
shown in Figure 1. The two-band hyperfine structure in the
spectrum centered at the calibrated giso ꢀ2.004 indicates that
in the radical there is a strong magnetic-coupled nucleus
possessing the I=1/2 nuclear spin leading to the 2I+1=2
hyperfine peaks. This nucleus is assigned to the proton (I=
1/2) on the methyl group, that is, the unpaired electron is lo-
calized in the methyl carbon atom. In the meantime, the
weaker hyperfine interactions between the electron and the
protons (2,6,2’,6’-position of the phenyl rings) is not resolved
in the 150 K ESR spectrum relative to those measured at
room temperature. With the simulation, the hyperfine cou-
pling constant for the proton on the methyl is 16.5 G, and
those for the four equivalent protons (2,6,2’,6’-position of
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
H
4-F
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
62
56
56
51
54
54
43
56
65
65
51
54
54
69
51
65
65
54
54
–
84
87
86
83
84
48
42
82
63
83
83
71
75
66
67
64
56
49
42
–
4-Cl
4-Br
4-CF3
4-NO2
4-Ph
4-OAc
4-OCH3
4-CH3
3-F
3-Cl
3-CH3
2-F
2-Cl
2-CH3
4-CH3
H
the phenyl rings) ꢀ4 G. Besides, when we added 1,1-di
ACHTUNGTRENNUNGphen-
4-CH3Ph
CH3
CH2CH2CH3
2-Py
AHCTUNGTREGyNNNU lethylene to the reaction mixture and performed the reac-
tion for 2 h, the radical coupling product of 1,1,3,3-tetra-
phenyl-1-propene was observed by GCMS analysis.[12] In
contrast, we didnꢁt find the signal of any radical in the ab-
sence of diphenylmethane under the same conditions.[12]
H
H
21
65
72
Also, a stable intermediate, di
by GCMS analysis.[12] Moreover, under the same conditions,
diphenylmethanol was also electrolyzed and the desired
ACHTUNGTRNEUpNG henACUTHNTGRENNUyGN lAHCTUNRTGEGmNNUN ethAHTCUNGRTENaNUNG nACTHUNTGNRUEoGN l, was detected
A
E
N
ACHTUNGTRENNUNG
[a] The reactions were carried out on a 0.5 mmol scale. [b] Yields of the
isolated products.
product was obtained with a yield of 90%.
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Z. Wang et al.
15 mL). The combined organic phase was dried with Na2SO4. The solvent
was removed with a rotary evaporator. The residue was purified by
column chromatography on silica gel and the product was dried under
high vacuum before it was weighed and characterized by NMR spectro-
scopy.
Acknowledgements
We are grateful for financial support from the Natural Science Founda-
tion of China (21172205, 21272222, 20972144, 91213303, 20932002,
31070211, and J1030412) and from the Ministry of Science and Technolo-
gy of China (2010CB912103).
Figure 1. ESR spectrum obtained for the diphenylmethane radical
(black) and the simulation (red) measured at 150 K. In the simulation,
the calibrated isotropic g-value for the radical is giso ꢀ2.004, the principal
isotropic hyperfine constants of the methyl proton and of the four equiv-
alent protons (2,6,2’,6’-position of the phenyl rings) are 16.5 and 4 G, re-
spectively, and the molecular correlation time of 10À9 s is included to
show the known increasing asymmetry of the spectrum when the molecu-
lar motion is significantly slowed at liquid nitrogen temperature. Stand-
ard conditions: diphenylmethane (0.5 mmol), LiClO4 (1 mmol), and
Bu4NClO4 (0.5 mmol) in CH2Cl2 (10 mL) were electrolyzed for 20 min at
a current of 20 mA between Pt/Pt electrodes; thereafter, the electrolyte
was transferred with a cooled syringe at 150 K to the ESR tube.
À
Keywords: C H activation · electrochemistry · ketones ·
oxidation · synthetic methods
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oxidized to give radical cation 1 on the surface of the anode.
The initially formed radical cation deprotonates into the
benzyl radical 2, which undergoes subsequent oxidation to
afford a diarylcarbenium ion, intermediate 3. Intermediate 3
is attacked by H2O following deprotonation to generate a
substituted benzyl alcohol 4, which is further oxidized to
give the desired product. Water is electrolyzed to release hy-
drogen gas as a result of cathodic reduction.
In conclusion, an electrochemical method was developed
that converts the benzyl group into a keto group under mild
conditions. By virtue of electrochemistry, an environmental
À
friendly and metal-free C H activation was realized with a
wide scope of the reaction substrates. More importantly, this
transformation mechanism was investigated in detail. A key
intermediate 2 was detected by ESR spectroscopy. We will
continue to work on the study of electrochemical oxidation
of hydrocarbons and broaden the application of electro-
chemistry in organic synthesis.
Experimental Section
General procedure:
A mixture of benzylic methylenes (0.5 mmol),
LiClO4 (1 mmol), and CH3CN (9 mL)/H2O (0.5 mL) were added to an
undivided cell. The cell was equipped with platinum (1.0ꢂ1.0 cm2) as the
anode and cathode. The electrolyte was allowed to stir and electrolyzed
at
a constant current of 20 mA. Upon completion of the reaction,
CH3CN was removed with a rotary evaporator and added to H2O
(10 mL). The resulting mixture was extracted with ethyl acetate (3ꢂ
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Direct Electrosynthesis of Ketones
COMMUNICATION
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Received: November 26, 2012
Revised: February 7, 2012
Published online: March 12, 2013
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