Copper-catalyzed oxidative coupling of acids with alkanes involving dehydrogenation: Facile access to allylic esters and alkylalkenes

Article abstract of DOI:10.1039/c4cc09393c

We here describe a new copper-catalyzed oxidative coupling of acids with alkanes for the selective synthesis of allylic esters and alkylalkenes. This method achieves multiple dehydrogenation and esterification, representing a new unactivated C(sp³

Full text of DOI:10.1039/c4cc09393c

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Copper-Catalyzed Oxidative Coupling of Acids with Alkanes Involving
Dehydrogenation: Facile Access to Allylic Esters and Alkylalkenes
Cheng-Yong Wang,a Ren-Jie Song,a Wen-Ting Wei,a Jian-Hong Fan,a and Jin-Heng Li*a
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
5
with alkanes for accessing alkylalkenes.9
We here describe a new copper-catalyzed oxidative coupling of
acids with alkanes for the selective synthesis of allylic esters and
alkylalkenes. This method achieves multiple dehydrogenation
10 and esterification, representing a new unactivated C(sp3)−H
oxidative esterification of acids with common alkanes.
Esters are versatile building blocks with wide applications in
synthesis,1 as well as are importantly ubiquitous cores in
many natural products, pharmaceutical molecules and fine
15 chemicals.1,2 As
a
result, much attention has been
Scheme 1 Oxidative Coupling of Acids with Alkanes.
longstanding attracted for the development of the practical
and efficient strategies for ester synthesis.1,3-5 The classic
methods for the synthesis of esters mainly include the reaction
of acids and their derivatives (acyl chlorides and anhydrides)
20 with alcohols.1 However, these methods suffer from several
disadvantages, including limited substrate scope, harsh
reaction conditions (eg. high temperatures and/or strong acids),
large amounts of unwanted by-products and the requirement
of additional purification steps. Thus, new efficient strategies
25 for assembling various functionalized esters would be
desirable and mandatory.
55
Our initial investigation began with the oxidative coupling
of 4-methoxybenzoic acid (1a) with cyclohexane (2a) to
optimize the reaction conditions (Table 1). In the presence of
Cu(NO3)2 and DTBP, acid 1a successfully coupled with
cyclohexane (2a) through the multiple dehydrogenation
60 process, furnishing the desired cyclohex-2-en-1-yl 4-
methoxybenzoate (3aa) in 38% yield (entry 1). Gratifyingly, a
series of bases, namely K2CO3, Ag2CO3, NaOAc and Et3N,
were found to improve the reaction (entries 2-6), and 20 mol%
K2CO3 gave the best results. The reason may be that bases can
65 stabilize the radical intermediate.10 Among the reaction
The C-H oxidative functionalization has become an
important and highly atom-economic method for the
formation of various chemical bonds.6 In this field, two new
30 C-H oxidation strategies for ester synthesis using alkanes as
the starting materials have been reported:3-5 one is the direct
oxidative C-H activation/esterification of acids with alkanes,3
and the other involves the tandem C-H oxidation/
o
temperature examined, it turned out that 120 C was preferred
in terms of yields (entry 2 vs. entries 7 and 8). In light of
these results, a number of other Cu catalysts, including CuCl2,
Cu(OAc)2, CuO and Cu2O, were investigated(entries 9-12).
70 The results demonstrated that all the Cu catalysts effected the
reaction, and CuO displayed the highest catalytic activity
(entry 11 vs. entries 9,10 and 12). It should be noted that
Cu2O was also an efficient catalyst for the reaction (entry 12).
When varying the amounts of DTBP, we found that the
75 reaction with four equivalents of DTBP offered the best
results (entry 11 vs. entries 13 and 14). However, in the
absence of DTBP, the reaction did not result in the formation
of detectable amounts of 3aa (entry 15). Finally, there other
oxidants, such as tert-butyl hydroperoxide (TBHP), dicumyl
80 peroxide (DCP) and K2S2O8, were evaluated (entries 16-18).
The yield in the presence of TBHP (entry 16) or DCP (entry
17) was inferior to that of DTBP (entry 11), but the coupling
was completely suppressed by using K2S2O8 (entry 18).
esterification
between
acid
precursors
(aldehydes,
35 arylmethanes, alkenes or alkynes) and alkanes.4,5 However,
these transformations are restricted to the requirement of the
directing3 or nono-directing5b-d activation groups in alkanes,
limited substrate scope or/and expensive catalysts. In addition,
only a paper has been described by Han and co-workers on the
40 oxidative esterification of acids with the unactivated C(sp3)−H
bonds in ethers using Fe catalysts and di-tert-butyl peroxide
(DTBP) oxidant (Scheme 1a).5a To our knowledge, the
oxidative esterification of acids with the unactivated C(sp3)−H
bonds of common alkanes has not been reported.4o Herein, we
45 report a new Cu-catalzyed oxidative coupling of acids with
common alkanes for the synthesis of allylic esters7 using
DTBP as oxidant and a catalytic amount of K2CO3 as
promoter (Scheme 1b), which is successfully realized through
the C-H oxidative esterification and dehydrogenation
50 cascade.4m-o,8 Gratifyingly, this Cu/DTBP system can be
applicable to the decarboxylative coupling of cinnamic acid
After establishing the optimal reaction conditions, we next
85 probe the scope of this oxidative coupling protocol with a
range of alkanes (Scheme 2) and acids (Table 2). Initially, a
variety of alkanes, including cycloalkanes 2b-d and linear
alkanes 2e-g were employed to couple with 4-methoxybenzoic
acid (1a) in the presence of CuO, DTBP and K2CO3, and the
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DOI: 10.1039/C4CC09393C
Table 1 Screening for Optimal Reaction Conditionsa
25 substrate to assemble 3ba in 74% yield. Me-substituted acid
1c offered 3ca in 75% yield, whereas CN-substituted acid 1h
and CO2Me-susbtituted acid 1i had lower reactivity leading to
3ha and 3ia in 43% and 40% yields, respectively.
Interestingly, halide substituents (I, Br, Cl, and F) were
30 consistent with these oxidative coupling conditions (3da-ga
and 3la), thereby serving as handles for further synthetic
manipulations. For acids 1j-l with two substituents, esters 3ja-
la were also formed in moderate to good yields. It is
O
O
[Cu], [O]
MeO
CO2H
+
MeO
base
1a
3aa
2a
Entry
1
[Cu]
[O] (equiv)
DTBP (4)
DTBP (4)
DTBP (4)
T (oC) Yield (%)b
Base (mol%)

K2CO3 (20)
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
CuCl2
120
120
120
120
120
120
100
130
120
120
120
120
120
120
120
120
120
120
38
68
53
57
60
59
15
65
66
18
79
75
57
78
0
2
noteworthy
that
1-naphthoic
acid
(1m)
and
3
K2CO3 (50)
35 pentafluorobenzoic acid (1n) are viable for the construction of
3ma and 3na in high yields. Subsequently, a variety of alkyl
acids 1o-r were tested under the optimal conditions: they were
suitable substrates, albeit with lower yields (3oa-ra).
However, hexanoic acid (1s) showed lower reactivity (3sa).
4
DTBP (4) Ag2CO3 (20)
5
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (3)
DTBP (5)

NaOAc (20)
Et3N (20)
6
7
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
8
9
40 Table 2 Variation of Acids (1)a
10
11
12
13
14
15
16
17
18
Cu(OAc)2
CuO
O
O
CuO, DTBP
K2CO3, 120 oC, 24 h
Cu2O
R1 CO2H
+
R1
CuO
1
2a
3
CuO
CuO
CuO
TBHP (4)
24
57
trace
CuO
DCP (4)
CuO
K2S2O8 (4) K2CO3 (20)
a
Reaction conditions: 1a (0.3 mmol), 2a (1 mL), [M] (10 mol%), [O],
and base in argon for 24 h. b Isolated yield.
5
results are summarized in Scheme 2. To our delight, the
optimal conditions were compatible with cycloalkanes 2b-d,
giving the corresponding allylic esters 3ab-ad in good yields.
Using linear alkanes 2e-g to react with acid 1a delivered a
10 mixture of regioselective isomers 3ae-ag. For example, the
reaction of hexane (2e) gave four isomers 3ae with the ratio of
46:32:19:3.
a
Reaction conditions: 1 (0.3 mmol), 2a (1 mL), CuO (10 mol%), DTBP
(4 equiv), and K2CO3 (20 mol%) at 120 oC in argon for 24 h.
45
We also applied the optimal conditions in the coupling of
cinnamic acid (1t) with alkanes 2 (Scheme 3). However, the
coupling delivered the decarboxylative coupled products 4ta-
td,9 not the expected allylic esters 3, in good yields.
Scheme 2 Variation of Alkanes (2). Reaction conditions: 1a (0.3 mmol),
15 2 (1 mL), CuO (10 mol%), DTBP (4 equiv), and K2CO3 (20 mol%) at 120
oC in argon for 24 h. The regioselectivity ratio is given in the parenthesis.
50
Scheme 3 Coupling of Cinnamic Acid (1s) with Alkanes (2).
To understand the mechanism, some control experiments
were carried out (Scheme 4). The reaction of acid 1a with
cyclohexene (5a) successfully constructed ester 3aa in 81%
yield (Eq 1). However, substrate 6a could not be converted
As show in Table 2, the optimal conditions were applicable
to a wide range of acids, namely aryl acids 1b-n, benzyl acids
1o-q and alkyl acid 1r (3ba-pa). Gratifyingly, several
20 substituents, such as Me, MeO, F, Cl, Br, I, CN and CO2Me,
on the aromatic ring were well-tolerated, and their reactivity
decreased from electron-donating to electron-withdrawing
substitution (3ca-na). In the presence of cyclohexane (2a),
CuO, DTBP and K2CO3, benzoic acid (1b) was a suitable
55 into ester 3aa (Eq 2). The results suggest that the reaction
may proceed via the formation of alkene. Notably, radical
inhibitors, TEMPO, hydroquinone or BHT, completely
suppressed the reaction, and offered product 7a (Eq 3),
implying that the coupling includes a radical process.
2
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DOI: 10.1039/C4CC09393C
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CuO (10 mol%)
DTBP (4 equiv)
K2CO3, 120 oC, 24 h
O
(1)
MeO
MeO
CO2H
MeO
MeO
+
50
O
1a (0.3 mmol)
5a (1 mL)
3aa, 81%
CuO (10 mol%)
DTBP (4 equiv)
O
O
(2)
K2CO3, c-hexane (1 mL)
3
120 oC, 24 h
O
O
6a, 81%
3aa, <5%
55
c-hexane (2a)
O
CuO (10 mol%)
DTBP (4 equiv)
N
(3)
MeO
CO2H
3aa, <5%
+
TEMPO (4.8 equiv)
K2CO3, 120 oC, 24 h
1a
7a, 78%
60
Scheme 4 Control Experiments.
The possible mechanism outlined in Scheme
5
was
proposed.4-9 Abstraction of the hydrogen atom of cyclohexane
(1a) by tBuOO⋅,4-9 which is generated from DTBP under
heating with the aid of the active CuI species4-9 and base,10
occurs to afford alkyl radical A and CuII(OtBu), followed by
dehydrogenation of intermediate A with CuII(OtBu) gives
intermediate 5a and regenerates the active CuI species.
65
70
5
4
10 Intermediate 5a undergoes the reported Kharasch-Sosnovsky
mechanism5,8 to offer the desired product 3aa.
75
80
85
Scheme 5 Possible Mechanism.
In summary, we have developed
a new oxidative
90
15 dehydrogenation strategy for the selective synthesis of allylic
esters by copper-catalyzed oxidative coupling of acids with
alkanes using DTBP as oxidant. Moreover, this Cu and DTBP
system were applicable to the decarboxylative coupling of
cinnamic acid with cycloalkanes leading to alkylalkenes.
20 Further studies on applications of this oxidative coupling
method in synthesis are currently underway in our laboratory.
This research was supported by the NSFC (Nos. 21472039
and 21172060) and Hunan Provincial Natural Science
Foundation of China (No. 13JJ2018).
5
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25 Notes and references
a State Key Laboratory of Chemo/Biosensing and Chemometrics, College
of Chemistry and Chemical Engineering, Hunan University, Changsha
410082, China. Fax: 0086731 8871 3642; Tel: 0086731 8882 2286; E-
mail: jhli@hnu.edu.cn
7
30 † Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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to but not central to the matter under discussion, limited experimental and
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