DDQ-catalyzed oxidative C-O coupling of sp3 C-H bonds with carboxylic acids

Article abstract of DOI:10.1002/cssc.201200458

Da-ddy, DDQ: By using catalytic amounts of DDQ combined with MnO ₂ as oxidant, an efficient oxidative C-O coupling of benzylic sp ³ C-H bonds with carboxylic acids affords a series of carboxylic esters in 70-98 % yields. A wide range

Full text of DOI:10.1002/cssc.201200458

DOI: 10.1002/cssc.201200458
DDQ-Catalyzed Oxidative CÀO Coupling Of sp3 CÀH Bonds With Carboxylic
Acids
Hong Yi,[a] Qiang Liu,[a] Jie Liu,[a] Ziqi Zeng,[a] Yuhong Yang,[a] and Aiwen Lei*[a, b]
Cross-dehydrogenative coupling (CDC) reactions go beyond
traditional cross-couplings and have significantly advanced
modern organic synthetic methodologies.[1] Pioneered by Li
Scheme 1. Oxidative CÀO coupling reaction of benzylic sp3 CÀH bonds with
and co-workers, these reactions are becoming a powerful tool
for the construction of CÀC and CÀheteroatom bonds.[2] Com-
carboxylic acids.
pared to traditional cross-couplings, an advantage of CDC reac-
tions is that they do not require substrates with highly func-
tionalized groups, such as organohalides or organometallic
species. However, CÀH bonds that act as electrophiles and that
are oxidized in CDC reactions are usually adjacent to heteroa-
toms or double bonds.[3] The benzylic CÀH bond, lacking an
adjacent heteroatom or double bond, is more difficult to acti-
vate owing to its low reactivity, selectivity problems, and the
absence of a coordination site for the transition-metal cata-
lyst.[4] Although some examples of CDC reactions with benzylic
CÀH bonds not adjacent to heteroatoms or double bonds with
carbon and activated nitrogen nucleophiles have been report-
ed,[4–5] oxidative CÀO coupling with OÀH bonds are still rare.[6]
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a well-
known oxidizing reagent in organic synthesis, and has been
used for CÀC and CÀO bond formations through activation of
CÀH bonds.[7] However, these reactions usually require stoi-
chiometric amounts of DDQ, although the compound is not
cheap and has a modest toxicity (LD50 =82 mgkgÀ1). Hence, it
is important to find economical and environmentally benign
oxidants that can regenerate DDQ from its reduced hydroqui-
none form, promoting its use as a catalytic oxidant.[8] MnO2,
with its low cost and negligible toxicity (LD50 =3478 mgkgÀ1),
is an ideal choice.[9]
We started our evaluation of the reaction parameters with
diphenylmethane (1a) and acetic acid (2a) as standard sub-
strates (Table 1). To study which conditions are optimal for this
Table 1. Impact of reaction parameters on the efficiency of DDQ-mediat-
ed oxidative CÀO coupling of 1a with 2a.[a]
Entry
Oxidant
T
[8C]
Solvent
Yield[b]
[%]
1
2
3
4
5
6
7
8
DDQ
tBuOOH
tBuOOtBu
BQ
H2O2
DDQ
DDQ
DDQ
DDQ
DDQ
80
80
80
80
80
80
80
80
80
60
100
DCE
DCE
DCE
DCE
99
0
0
0
0
81
35
0
0
48
95
DCE
C6H5Cl
toluene
DMF
CH3NO2
DCE
9
10
11
DDQ
DCE
[a] Reaction conditions: 1a (0.25 mmol), 2a (1 mmol), oxidant (0.3 mmol)
and 100 mg 3 ꢀ molecular sieve in 2 mL of DCE for 24 h. [b] GC yields.
Herein, we report a DDQ-catalyzed oxidative CÀO coupling
of benzylic sp3 CÀH bonds with various carboxylic acids in the
presence of MnO2 as oxidant (Scheme 1). Although CDC reac-
tions of CÀH bonds adjacent to oxygen, sulfur, or double
bonds with carboxylic acids or alcohols were reported very re-
cently,[7d,e,10] this work is, to the best of our knowledge, the
first example of DDQ-catalyzed oxidative CÀO coupling reac-
tion involving challenging benzylic sp3 CÀH bonds that are not
adjacent to heteroatoms or double bonds.
reaction, we tried different oxidants as hydrogen acceptors
with a range of solvents and other additives. After exploring
a wide array of conditions, we found that the CÀO bond for-
mation product 3a was obtained in a quantitative yield in the
presence of 1.2 equiv DDQ, 4 equiv 2a, 3 ꢀ molecular sieve,
and dichloroethane (DCE) as the solvent at 808C (entry 1).
Other data in Table 1 illustrates the impact of different condi-
tions on the efficiency of this reaction. Other tested oxidants
did not promote this reaction at all (entries 2–5). Among the
screened solvents, nonpolar solvents afforded the product 2a
in moderate to good yields, while polar solvents completely in-
hibited the reaction (entries 6–9). Increasing or reducing the
reaction temperature from 808C led to a lower yield of 2a (en-
tries 10 and 11). Small amounts of benzophenone were gener-
ated as byproduct in the absence of molecular sieves.
[a] H. Yi,+ Q. Liu,+ J. Liu, Z. Zeng, Y. Yang, Prof. A. Lei
The College of Chemistry and Molecular Sciences, Wuhan University
Wuhan, Hubei 430072 (PR China)
Fax: (+86)27-68754672
E-mail: aiwenlei@whu.edu.cn
[b] Prof. A. Lei
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences
Lanzhou 730000 (PR China)
Encouraged by these results involving stoichiometric
amounts of DDQ, we attempted to regenerate DDQ and so
use it as a catalytic oxidant (Table 2). MnO2 proved to be a suit-
able oxidant for this purpose (entries 1, 8, and 9). There was
no reaction when using MnO2 as the sole oxidant, without
[+] These authors contributed equally to this work.
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201200458.
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tion reaction may be a radical process because the reaction
was completely inhibited by the nitro group. Notably, sub-
strates bearing groups that cause steric hindrance were trans-
formed smoothly (entries 5, 9–10). However, the reaction rates
and yields of reactions involving electron-deficient substrates
were lower than those involving electron-rich substrates (en-
tries 6 and 7, 1–4).
Table 2. Impact of reaction parameters on the efficiency of DDQ-cata-
lyzed oxidative CÀO coupling of 1a with 2a.[a]
Entry
Amount of
DDQ [mol%]
Oxidant
Amount
[equiv]
Amount of
HOAc [equiv]
Yield[b]
[%]
1
2
3
4
5
6
7
8
9
20
20
20
20
10
0
20
20
20
20
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
FeCl3
CuO
5
6
4
3
6
6
5
5
5
5
4
4
4
4
4
4
3
2
4
4
96(93)
86(86)
83
78
57
0
92
84
trace
21
Next, we investigated DDQ-catalyzed oxidative CÀO cou-
pling reactions of various carboxylic acids (Table 4). A wide
range of carboxylic acids, including long-chain aliphatic (en-
tries 2 and 3), aromatic (entries 5–8), and vinyl (entry 10) car-
boxylic acids successfully coupled with 1a. Several functional
10
Table 4. DDQ-catalyzed oxidative CÀO coupling of diphenylmethanes 1a
with carboxylic acids 2.[a]
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.5–1 mmol), DDQ (0–
0.05 mmol) and oxidant (0.75–1.5 mmol) in 2 mL of DCE for 24 h. [b] GC
yields. The data in the parenthesis are isolated yields.
Entry
Carboxylic acid
Yield[b] [%]
DDQ +MnO2
(0.05+1.25 mmol)
DDQ
(0.3 mmol)
DDQ as the catalyst (entry 6). The reaction temperature was in-
creased to 1008C to improve reaction conversion and yield.
Upon exploring the scope of the reaction, a number of sub-
stituted diphenylmethanes 1 combined with acetic acid 2a
were tested under the optimal reaction conditions (Table 3).
The data in Table 3 shows the yields to be good to excellent.
This CÀO bond coupling reaction was compatible with aryl-
OMe, Me, Cl, and F groups. However, there was no reaction for
1-benzyl-4-nitrobenzene, indicating that this CÀO bond forma-
1
CH3COOH
2a
2b
2c
2d
2e
93
76
63
50
92
98
98
94
99
95
2[c]
3[c]
4
C7H15COOH
C17H35COOH
PhCH2COOH
PhCOOH
5[d]
6[d]
2 f
79
52
98
89
7
2g
8
2h
35
70
9[d]
10
2i
2j
73
92
80
98
Table 3. DDQ-catalyzed oxidative CÀO coupling of substituted diphenyl-
methanes 1 with 2a.[a]
[a] Reaction conditions: 1a (0.25 mmol), 2 (1 mmol), DDQ (0.05 mmol)
and MnO2 (1.25 mmol) in 2 mL of DCE for 24 h. The yield data in the
second column were obtained by the use of DDQ (0.3 mmol) in the ab-
sence of MnO2. [b] Isolated yields. [c] CF3COOH (0.75 mmol) was used.
[d] CF3COOH (0.5 mmol) was used.
Entry Diphenylmethane
t [h] Yield[b] [%]
DDQ +MnO2
DDQ
(0.05+1.25 mmol) (0.3 mmol)
1
2
3
4
5[c]
6[c]
7[c]
8
R=H
1a 24
1b 24
1c 24
1d 24
1e 48
93
85
98
92
97
63
66
0
98
97
98
98
92
89
87
0
R=4-OMe
R=4-Me
R=3-Me
R=2-Me
R=4-Cl
R=4-F
groups were tolerated as well, especially aryl iodide and aryl
bromides (entries 7–9). In particular, the acidic phenolic hy-
droxyl group at the ortho position relative to the carboxylic
group was preserved after the reaction (entry 7). The structure
of the coupled product of 1a and 2g was confirmed by single-
crystal X-ray experiments (Figure 1). When employing catalytic
amounts of DDQ the weakly acidic carboxylic acids afforded
low conversions. To increase the reactivity of these substrates,
strongly acidic and weakly nucleophilic trifluoroacetic acid was
utilized as an additive, which probably enhanced the oxidation
capacity of MnO2, facilitating the regeneration of DDQ (en-
tries 2–3, 5, 6, and 9).
1 f
48
1g 48
1h 24
R=4-NO2
9
1i
24
97
88
10
1j
24
86
90
11
12
1k 24
1l 24
85
71
95
89
As mentioned before, the benzylic CÀH bonds adjacent to
double bonds are usually more readily activated in CDC reac-
tions. A typical example, allylbenzene 4, was examined in this
DDQ-promoted CÀO bond coupling reaction with acetic acid
2a (Scheme 2). This reaction occurred at room temperature
[a] Reaction conditions: 1 (0.25 mmol), 2a (1 mmol), DDQ (0.05 mmol)
and MnO2 (1.25 mmol) in 2 mL of DCE for 24 h. The yield data in the
second column were obtained by the use of DDQ (0.3 mmol) in the ab-
sence of MnO2. [b] Isolated yields.
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Table 5. DDQ-mediated oxidative CÀO coupling of cinnamyl acetate 6a
with carboxylic acids 2.[a]
Entry
1
Product
Yield[b] [%]
87
7a
7b
7c
7d
2
3
4
78
75
59
[a] Reaction conditions: 6a (0.5 mmol), 2 (2 mmol), DDQ (0.6 mmol), and
100 mg 3 ꢀ molecular sieve in 2 mL of DCE for 4 h. [b] Isolated yields.
Figure 1. X-ray crystal structure of the CÀO coupling product of 1a and 2g
(Table 4, entry 7).[11]
1, 1-dibenzenethene were employed (Scheme 3). The reactions
were completely inhibited by 2 equivalents of TEMPO. The re-
action conversion was reduced to 25% in the presence of
Scheme 3. Radical trapping experiments.
Scheme 2. DDQ-mediated oxidative CÀO coupling of 4 with 2a and the syn-
thetic routes toward the trisubstituted olefin 9.
2 equivalents of 1, 1-dibenzenethene. These results indicate
that this transformation may involve radical intermediates.
In addition, experiments focusing on kinetic isotopic effects
were also done to gain additional insight into this reaction
(Scheme 4). The intra- and intermolecular KH/KD ratios were
4.8:1 and 1.6:1 respectively. This result suggests that CÀH
bond cleavage is the rate-determining step.
and produced diacetate 7a in 78% yield, which is a suitable
substrate for the Tsuji–Trost reaction. The diarylation of 7a was
accomplished in a good yield in the presence of 5 mol% Pd
catalyst at 408C. The diarylated product 8 underwent the
DDQ-promoted CÀO bond coupling reaction, using water as
the nucleophile, and sequential alcohol oxidation efficiently to
generate the trisubstituted olefin 9. We speculate that allylben-
zene 4 is oxidized by DDQ to form the allylic cation 5. Then
nucleophilic attack of acetic acid 2 at the terminal site of inter-
mediate 5 (less steric hindrance) affords cinnamyl acetate 6a,
which then undergoes the above process again to provide 7a
(Scheme 2). In addition, the allylic CÀH bond adjacent to the
oxygen of 6a is very reactive in the presence of DDQ.
As a result, 6a could not be isolated, even from allylbenzene 4
with 1 equivalent of acetic acid 2a and DDQ as oxidant.
We synthesized cinnamyl acetate 6a and employed it in the
DDQ-mediated CÀO coupling reactions as well (Table 5). As ex-
pected, 6a coupled with four different carboxylic acids at
room temperature smoothly.
The proposed mechanism is shown in Scheme 5. The reac-
tion is initiated by single electron transfer (SET) oxidation to
form the benzyl radical, which can be further oxidized to the
benzyl cation and DDQHÀ anion. A subsequent abstraction of
the proton of acetic acid 2a by DDQHÀ generates the CÀO-
To assess whether radical species are formed in this oxida-
tive CÀO coupling reaction, the radical scavengers TEMPO and
Scheme 4. Kinetic isotopic effect experiments.
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Acknowledgements
This work was supported by the National Natural Science Foun-
dation of China (21025206, 20832003, and 20972118) and the
973 Program (2012CB725302).
Keywords: CÀH activation · cross-coupling · homogeneous
catalysis · oxidation · quinones
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Scheme 5. Proposed mechanism.
coupled product 3a and reduced hydroquinone DDQH2. The
catalyst DDQ is regenerated by the oxidation of DDQH2 using
MnO2 as the oxidant.
In conclusion, we report a DDQ-catalyzed oxidative cross-
coupling between benzylic sp3 CÀH and OÀH bonds (carboxyl-
ic acids). The reaction accomplishes both CÀH functionalization
and CÀO bond formation, and also serves as the first example
of cross-dehydrogenative CÀO coupling reactions of challeng-
ing benzylic sp3 CÀH bonds that are not adjacent to hetero-
atoms or double bonds, catalyzed by DDQ. A wide range of
functional groups and various types of carboxylic acids are tol-
erated. Investigations towards a more detailed mechanism and
further synthetic applications of this chemistry are ongoing in
our laboratory.
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Experimental Section
A 20 mL Schlenk tube equipped with a stir-bar was charged with
substituted diphenylmethanes 1 (0.25 mmol), carboxylic acid 2
(1 mmol), DDQ (0.05 mmol) and MnO2 (1.25 mmol). The reaction
tube was purged with nitrogen. 2 mL of DCE was then added to
the reaction tube via a syringe. The Schlenk tube was placed in an
oil-bath and heated to 1008C for 24 h. Then it was quenched by
diluted NaHCO3 solution and extracted with ethyl acetate (3ꢂ
10 mL). The residue was then purified by flash chromatography on
silica gel with a mixture of petroleum ether and ethyl acetate as
eluent. After concentrating the fractions containing the product,
the residue was dried under reduced pressure.
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[11] CCDC 850075 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: July 2, 2012
Published online on November 5, 2012
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