Cu-catalyzed C(sp3)-H bond activation reaction for direct preparation of cycloallyl esters from cycloalkanes and aromatic aldehydes

Article abstract of DOI:10.1021/ol5009119

Cu-catalyzed dehydrogenation-olefination and esterification of C(sp ³)-H bonds of cycloalkanes with TBHP as an oxidant has been developed. The reaction involves four C-H bond activations and gives cycloallyl ester products directly from cycloalkanes and aromatic aldehydes.

Full text of DOI:10.1021/ol5009119

Letter
pubs.acs.org/OrgLett
Cu-Catalyzed C(sp3)−H Bond Activation Reaction for Direct
Preparation of Cycloallyl Esters from Cycloalkanes and Aromatic
Aldehydes
Jincan Zhao,† Hong Fang,† Jianlin Han,*,†,‡,§ and Yi Pan†
†School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
‡High-Tech Research Institute of Nanjing University, Changzhou, 213164, China
§Institute for Chemistry & BioMedical Sciences, Nanjing University, Nanjing, 210093, China
S
* Supporting Information
ABSTRACT: Cu-catalyzed dehydrogenation−olefination and
esterification of C(sp3)−H bonds of cycloalkanes with TBHP
as an oxidant has been developed. The reaction involves four
C−H bond activations and gives cycloallyl ester products
directly from cycloalkanes and aromatic aldehydes.
activation of the C(sp3)−H bonds, adjacent to an oxygen atom,
atalytic dehydrogenation of alkanes to alkenes might have
Ca great impact on the chemical industry in the following double bonds, or phenyl group, and subsequent coupling to
form C−O bonds. However, direct functionalization of the
nonactivated cycloalkanes has been virtually unexplored.
Recently, the Liu group reported a copper-catalyzed cascade
alkylarylation of alkenes with simple cycloalkanes.13 Our group
reported an Fe-catalyzed direct alkenylation of C(sp3)−H
bonds of cycloalkanes with DTBP as an oxidant.14 Here, we
would like to report our further significant progress in this area,
the synthesis of cycloallyl esters directly from cycloalkanes
through four C−H bond activations by copper catalysis.
Our initial investigation focused on examining the coupling
reaction of benzaldehyde (1, 0.3 mmol) with CuI (0.03 mmol)
using 4.0 equiv of tert-butyl hydroperoxide (TBHP, 1.2 mmol)
as an oxidant in cyclohexane (2 mL) at 140 °C with stirring for
24 h under nitrogen, which provided cyclohex-2-en-1-yl
benzoate 1a in 23% yield (entry 1, Table 1). The byproduct
of this reaction was found to be benzoic acid, isolated in 72%
yield. We were quite encouraged by this initial result, as the
overall process formally involved four C−H bond activations.
Consequently further efforts were directed to improving the
outcome of this novel C(sp3)−H activation reaction. Other
potential catalysts such as Cu(OCCF3)2, CuCl2, CuBr2, TBAI,
and Cu(OAc)2 were evaluated (entries 2−6). Among these
Cu(OAc)2 was found to be the most effective catalyst (entry 6).
Using 1,10-phenanthroline (30 mol %) as the ligand or an
increased loading of Cu(OAc)2 up to 20 mol % gave no
improvement of the target product (entries 7 and 8). TBHP as
an oxidant was found to be superior over the other oxidants
screened, such as di-tert-butyl peroxide (DTBP), benzoyl
peroxide [(PhCOO)2], and K2S2O8 (entries 9−11). Decreasing
or increasing the amounts of TBHP in the range between 2.0 to
6.0 equiv or differing the temperature from 120 to 150 °C, as
decades, due to the abundance of alkanes and increasing use of
olefins as raw materials. In recent years, catalytic dehydrogen-
ation of alkanes to alkenes has witnessed remarkable
progress.1,2 Among the known examples of catalytic dehydro-
genation of cyclohexane described to date, the catalytic systems
based on Ir,3 Pt,4 and Re5 complexes are the most studied.
́
Recently, Perez and cowokers discovered that the dehydrogen-
ation of cycloalkanes to cycloalkenes can be accomplished by
the reaction between hydrocarbons and hydrogen peroxide
with copper complexes as a catalyst.6 Although the chemical
yields of the these conversions into cycloalkenes were only 4%,
the potential of copper-based catalysts could not be under-
appreciated as it is much more economical compared with the
Ir, Pt, and Re derived catalysts. Therefore, Cu-catalyzed
dehydrogenation−olefination of cycloalkanes is a research
area of great scientific significance.
The formation of C−O bonds is a fundamental trans-
formation in synthetic organic chemistry.7 In particular, C−O
construction through C−H activation is of great current
interest. In the late 1950s, Kharasch and Sosnovsky reported
the allylic oxidation of olefins using tert-butyl perbenzoate
catalyzed by cuprous bromide.8 Afterwards, a great deal of
research effort has been invested to improve the efficiency of
this copper-catalyzed allylic oxidation of olefins due to its
potential utility in organic synthesis.9
More recently, the direct and catalytic transformation of
C(sp3)−H bonds to esters via C−H activation has attracted
much scientific attention. In 2012, Patel’s group developed a
Cu(OAc)2-catalyzed cross dehydrogenative coupling (CDC)
reaction of aldehydes and alkyl benzenes using TBHP as the
oxidant.10a This group also reported a metal-free CDC reaction
for the synthesis of benzylic esters from alkyl benzenes.10b The
Wan group11 and Wang group12 also have reported their
important contribution to this field using Bu4NI for the
Received: March 27, 2014
© XXXX American Chemical Society
A
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a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Cu-Catalyzed Dehydrogenation−Olefination and
a
Esterification of Cycloalkanes
b
entry
catalyst (mol %)
oxidant (equiv) temp (°C) yield (%)
1
2
3
4
5
6
7
8
CuI (10)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
DTBP (4)
TBPB (4)
K2S2O8 (4)
TBHP (6)
TBHP (2)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
−
140
140
140
140
140
140
140
140
140
140
140
140
140
120
150
140
140
140
140
23
0
Cu(OCCF3)2 (10)
CuCl2 (10)
5
CuBr2 (10)
8
TBAI (20)
32
41
39
41
28
38
0
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (20)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
−
c
d
9
10
11
12
13
14
15
16
17
18
19
40
28
19
39
40
0
d
e
Cu(OAc)2 (10)
0
Cu(OAc)2 (10)
TBHP (4)
20
a
Conditions: 1 (0.3 mmol), a (2 mL), catalyst, oxidant, 140 °C, 24 h.
b
c
Isolated yields based on 1. Using 1,10-phenanthroline (30 mol %) as
d
e
the ligand. 48 h. Without protection of nitrogen.
well extending the reaction time to 48 h, did not lead to any
noticeable increase in the yield of the desired product (entries
12−16). Control experiments carried out in the absence of
either Cu(OAc)2 or TBHP failed to give the target product
(entries 17 and 18) strongly suggesting the requirement of both
the metal catalyst and oxidant. A lower chemical yield was
obtained when the reaction was performed without protection
of the nitrogen (entry 19).
a
Reaction conditions: aromatic aldehydes (0.3 mmol), cycloalkanes (2
Under the optimized reaction conditions, the substrate scope
was studied. As can be seen from Scheme 1, benzaldehyde with
the electron-donating groups on the phenyl ring, such as
methyl, ethyl, and methoxy groups, reacted smoothly with
cyclohexane and gave the corresponding products (2a−8a) in
41−49% yields. Meanwhile, benzaldehyde with electron-
withdrawing groups, such as Br, Cl, and NO2 groups, also
reacted with cyclohexane giving rise to the products 9a−11a in
39%, 37%, and 23% yields, respectively. Thus, the electron-
donating groups on the phenyl rings clearly favored the
reaction as compared to the electron-withdrawing groups
resulting in lower yields. Furthermore, the steric effects of the
aromatic substitution had a rather insignificant impact on the
yields (6a and 7a). In addition, heterocyclic aromatic
aldehydes, such as 2-thenaldehyde, were also tested in this
reaction, and the desired products 12a were obtained in the
noticeably highest yield (53%), probably because 2-thenalde-
hyde can be considered as an electron-rich substrate. However,
almost no desired product was obtained when furaldehyde was
used as the substrate (13a). This may be due to the fact that
the electron-donating ability of the furyl group is weaker than
that of the thienyl group. To test the generality of this reaction
in terms of the cycloalkane part, other derivatives, such as
cyclopentane and cycloheptane, were reacted under the optimal
reaction conditions. Cyclopentane, which has greater ring
tension than cyclohexane, reacted with benzaldehyde giving rise
mL), Cu(OAc)2 (10 mol %), TBHP (4.0 equiv), 140 °C, 24 h, N2.
to the corresponding product 1b in 18% yield. However,
cycloheptane reacted with benzaldehyde affording cyclohept-2-
en-1-yl benzoate 1c in <5% yield. This outcome was similar to
the previous report on the iron-catalyzed allylic arylation of
olefins via C(sp3)−H activation.15 Then, an example of
substituted cycloalkane, methylcyclohexane, was tried for this
reaction, which unfortunately gave a complex mixture of
products (see Supporting Information). Finally, a linear alkane,
hexane, was examined as a substrate. The reaction proceeded to
form the desired cycloallyl esters in an overall 26% yield.
However, the product contains several isomers which cannot be
isolated in a chemically pure state (see Supporting
Information).
Several key control experiments were performed to probe the
reaction mechanism (Scheme 2). We found that the addition of
radical scavengers, such as azobis(isobutyronitrile) (AIBN) or
TEMPO (Scheme 2a), completely inhibited the reaction, and
almost no desired products were obtained. Instead, the adduct
from TEMPO with an acyl radical was found (see Supporting
Information). This result indicated that the current trans-
formation might proceed via formation of radical species. Next,
instead of benzaldehyde, benzoic acid was used to react with
cyclohexane under the optimal reaction conditions. Again,
B
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Letter
sp3 C−H bond cleavage should be involved in the rate-
determining step of this procedure.
Scheme 2. Investigation of the Reaction Mechanism
On the basis of these results as well as the literature
data,10−12 we propose a plausible mechanism including
dehydrogenation of cycloalkanes to cycloolefins followed by a
cross-coupling process, as illustrated in Scheme 4. Initially, the
Scheme 4. Possible Mechanism
Cu(II) reacts with TBHP forming the tert-butylperoxy radical
A, Cu(I), and H+ according to the mechanism suggested by
Sasson and co-workers.16 The cyclohexane radical B is
generated by the reaction between A and cyclohexane, which
undergoes dehydrogenation to cyclohexene, according to the
almost no desired product was obtained in this case (Scheme
2b). We assumed that the cyclohexyl benzoate, cyclohexanol,
cyclohexanone, or cyclohexene could be intermediates in the
catalytic cycle. However, when cyclohexyl benzoate reacted
with Cu(OAc)2 using 2.0 equiv of TBHP at 140 °C with
stirring for 24 h under nitrogen, the desired product was not
obtained (Scheme 2c). The reactions of benzaldehyde and
cyclohexanol (Scheme 2d) or cyclohexanone (Scheme 2e)
under the same conditions did not produce the desired product
either. Finally, the reaction of benzaldehyde with cyclohexene
(Scheme 2f), conducted under the standard conditions, gave
rise to the desired product in 48% yield. When the reaction was
carried out in the absence of benzaldehyde, cyclohexene and
cyclohexanol were detected in the reaction mixture by 1H NMR
in a ratio of 5:1 (31% and 6% yields respectively, Scheme 2g).
This positive result strongly suggested that the catalytic cycle
might proceed via cyclohexene as the intermediate.
process described by Per
́
ez and co-workers.6 Cyclohexene
reacts with Cu(II) and TBHP forming intermediate C, which
reacts with Cu(II) to give the intermediate D. The reaction of
D with acyl radical E, generated from the hydrogen atom
abstraction of benzaldehyde by a tert-butoxy radical,17 gives
final product 1a along with HCuOAc for the next reaction
cycle.10a
In conclusion, this work describes the first example of the
Cu-catalyzed dehydrogenation-olefination and esterification of
the C(sp3)−H bond of cycloalkanes with aromatic aldehydes in
the presence of TBHP as the oxidant. This reaction involves
four formal C−H bond activations. An appreciable range of
aromatic aldehydes can be used in this reaction with
cycloalkanes allowing a direct preparation of the corresponding
cycloallyl esters in 18−53% yields. Based on the extensive
experimental data, we propose a plausible mechanism, which
includes dehydrogenation−olefination of cycloalkanes followed
by a cross dehydrogenative coupling reaction. Further studies
to refine the mechanism and to expand the synthetic scope of
this reaction are currently underway in our laboratory.
An intermolecular competing kinetic isotope effect (KIE)
experiment was also carried out (Scheme 3). As a result, a
significant KIE was observed with the kH/kD = 0.84/0.16 = 5.25
(see Supporting Information). These results indicated that the
Scheme 3. KIE Experiment
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, full spectroscopic data for com-
1
pounds 1a−12a and 1b and copies of H and 13C NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
C
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hanjl@nju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21102071)
and the Fundamental Research Funds for the Central
Universities (Nos. 1107020522 and 1082020502). The Jiangsu
333 program (for Pan) and Changzhou Jin-Feng-Huang
program (for Han) are also acknowledged.
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