Copper catalyzed direct alkenylation of simple alkanes with styrenes

Article abstract of DOI:10.1039/c4sc00093e

A novel Cu-catalyzed direct alkenylation of simple alkanes with styrenes was described. In the presence of a catalytic amount of Cu(OTf)₂, a diverse range of alkenes undergo coupling with cycloalkanes to produce (E)-alkyl alkenes. This transformation is proposed to proceed via a radical process. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4sc00093e

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Copper catalyzed direct alkenylation of simple
alkanes with styrenes†
Cite this: DOI: 10.1039/c4sc00093e
*
Yefeng Zhu and Yunyang Wei
Received 10th January 2014
Accepted 20th February 2014
A novel Cu-catalyzed direct alkenylation of simple alkanes with styrenes was described. In the presence of a
catalytic amount of Cu(OTf)2, a diverse range of alkenes undergo coupling with cycloalkanes to produce
(E)-alkyl alkenes. This transformation is proposed to proceed via a radical process.
DOI: 10.1039/c4sc00093e
www.rsc.org/chemicalscience
Transition metal catalyzed C–H alkenylation reactions have from traditional Heck reactions, mechanistically, the reactions
attracted much attention and emerged as a tremendous chal- were believed to involve a radical process: rstly, alkyl halides
lenge in recent years.1 These transformations provide atom obtained a single electron from the transition metal to generate
economical methods for replacing simple C–H bonds with an alkyl radical, which then undergoes radical addition and
readily derivatizable alkene functional groups. As early as 1967, oxidation to generate the desired products (Scheme 2, Path A).
Fujiwara and Moritani reported the rst example of Pd-medi- Usually, alkyl halides are obtained by the halogenation reaction
ated C–H alkenylation of benzene (Scheme 1, eqn (1)).2 Since of alkanes7 (Scheme 2, Path B). The fact that alkanes could be
then, signicant advances have been made in the alkenylation easily converted into the corresponding alkyl radicals in the
of aromatic C–H bonds through C–H activation catalyzed by a presence of peroxides8 inspired us to try the directly coupling of
variety of different metals (for example, Pd, Cu, Ni, Co, Rh and alkanes with alkenes in a novel C–H alkenylation reaction in the
Ru).3 In contrast, the similar process at unactivated alkyl C–H presence of peroxides and appropriate metal catalysts. As our
sites remains extremely rare. As far as we know, only two preliminary results, herein, we report a novel Cu-catalyzed
examples of unactivated sp3 C–H olenation were disclosed by direct alkenylation of simple alkanes with styrenes (Scheme 2,
the groups of Yu4 and Sanford5 using a palladium catalyst and Path C).
employing N-arylamide or pyridine as a neighboring directing
The reaction of 4-chlorostyrene and cyclohexane was chosen
group by means of metal insertion. The direct C–H alkenylation as a model reaction to screen the catalysts and conditions.
of simple alkane substrates (lacking directing or activating
groups) is still a great challenge (Scheme 1, eqn (2)).
The results are listed in Table 1. Firstly, various Cu precur-
sors were screened for the reaction at 100 ꢀC in the presence of
Recently, great achievements have been made in transition di-tert-butyl peroxide (TBP). No reaction occurred with common
metal catalyzed Heck-type reactions of alkyl halides.6 Different Cu(I) salts or a common complex as the catalyst (Table 1, entries
1–4). However, the reaction did proceed when CuOTf or CuCl2
was used and afforded the coupling product in 16% and 12%
yield, respectively (Table 1, entries 5–6). To our delight, upon
switching the catalyst to Cu(OTf)2, the yield of 3a was increased
to 55% (Table 1, entry 8). Note that no product 3a could be
observed in the absence of any catalyst (Table 1, entry 19). The
efficiency of this transformation was dramatically affected by
the choice of oxidant. When other oxidants, such as K2S2O8, tert-
butyl hydroperoxide (TBHP), benzoyl peroxide (BPO) and O2
Scheme 1 Transition metal catalyzed C–H alkenylation reactions.
School of Chemical Engineering, Nanjing University of Science and Technology,
Nanjing 210094, P. R. China. E-mail: ywei@mail.njust.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4sc00093e
Scheme 2 Coupling reactions of alkenes with alkyl halides or alkanes.
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Table 1 Screening of reaction conditionsa
naphthalenyl groups were also employed (3o and 3p). Speci-
cally, all these reactions exclusively formed the (E)-alkyl
product.
Substituents on the a-position of the styrene (3m and 3n)
had little or no effect on the yield; however, a 2.5 : 1 olen
isomerization mixture was obtained for 3n. The protocol was
ineffective for aliphatic olens; when allyl benzene and quinone
were used in the catalytic system, only trace amounts of product
Entry
[Cu]
Oxidant
CyH (mL)
Yieldb (%)
1
were detected by H NMR (3q and r).
This protocol is also compatible with a range of cyclic olens
and heterocyclic aromatics such as indenes, furans and
coumarins (3s–w). It is worth pointing out that our Cu-catalyzed
oxidative coupling process only gave single isomers for these
substrates, which contrasts sharply with the typical outcome of
1
2
3
4
5
6
7
8
CuI
CuBr
CuCl
Cu(MeCN)4PF6
CuOTfe
CuCl2
Cu(OAc)2
Cu(OTf)2
Cu(acac)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
—
TBP
TBP
TBP
TBP
TBP
TBP
TBP
TBP
TBP
K2S2O8
TBHP
BPO
O2
TBP
TBP
TBP
TBP
TBP
TBP
3
3
3
3
3
3
3
3
3
3
3
3
3
2
4
5
4
4
4
<5
<5
<5
<5
16
12
<5
55
<5
0
0
0
0
51
82
83
61c
65d
0
Table 2 Generality of substratesa
9
10
11
12
13
14
15
16
17
18
19
a
Reaction conditions: Cu(OTf)2 (0.1 mmol), 4-chlorostyrene (0.5 mmol),
TBP (1.5 mmol) at 100 ꢀC for 12 h. b Isolated yield. c Temperature was 80
d
e
ꢀC. 10 mmol% Cu(OTf)2 was used. (CuOTf)2$C6H6 was used as the
source of CuOTf.
were used instead of TBP, no desired product was detected
(Table 1, entries 10–13). The effects of temperature and the
amount of cyclohexane on the reaction were also investigated,
and the best yield could be obtained when the reaction was
performed in the presence of 4 mL cyclohexane for 0.5 mmol
ꢀ
alkene at 100 C (Table 1, entry 14). Therefore, the optimized
reaction conditions are: Cu(OTf)2 (20 mol%), TBP (3 equiv.), at
100 ꢀC for 12 h in the presence of 4 mL cyclohexane for 0.5
mmol alkene (for more details, see ESI†).
With the above optimized conditions in hand, the scope of
the double C–H coupling of cyclohexane with other styrene
derivatives was tested and the results were listed in Table 2. On
the whole, the reaction was aided by electron donating groups
and hindered by electron withdrawing groups attached to the
styrene aromatic ring. Styrene bearing electron donating groups
and weak electron withdrawing groups reacted smoothly under
the optimized conditions to form the corresponding esters in
good yields (3a–f, 3h–i). With strong electron withdrawing
groups, the yield of the product decreased remarkably (3j). In
the extreme, substrates bearing highly electron-withdrawing
groups, such as p-nitrostyrene, were completely unreactive (3g).
It was evident that the steric properties of the substituents had
no effect on the yield of the desired product. For example, a
sterically demanding substrate such as 2,4,6-trimethylstyrene
also worked well in this catalytic system and afforded the
corresponding product in 75% yield (3k). Additionally,
a
Reaction conditions: Cu(OTf)2 (0.1 mmol), alkene (0.5 mmol),
b
cyclohexane (4 mL) and TBP (1.5 mmol) at 100 ꢀC for 12 h. Isolated
yield. c Yield determined by H NMR. d E/Z was 3 : 1.
1
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Table 3 Generality of substratesa
Scheme 5 Proposed reaction mechanism.
experiments under the standard reaction conditions. Radical
scavengers, such as TEMPO and BHT, were employed in the
standard reaction, and no desired coupling product was
detected. This result suggested that a single electron transfer
process (SET) was involved in the present oxidative Heck reac-
tion. Further, a kinetic isotope effect was determined by
comparing the product ratio of 3b with 3b–D11 under the
standard conditions (Scheme 4, see ESI†). The observed
signicant primary isotopic effects (kH/kD ¼ 5.67) indicated that
the sp3 C–H bond cleavage step was involved in the rate-limiting
step of this transformation.
a
Reaction conditions: Cu(OTf)2 (0.1 mmol), alkene (0.5 mmol),
b
cycloalkanes (4 mL) and TBP (1.5 mmol) at 100 ꢀC for 12 h. Isolated
yield.
Although the mechanistic details of this transformation are
not clear at the moment, on the basis of the above results and
previous reports,10 a plausible mechanism for the present
process can be proposed as shown in Scheme 5. First, Cu(OTf)2
donates an electron to TBP to generate Cu(III) species A and the
tert-butoxy radical, which then abstracts a hydrogen atom from
the alkane to generate the alkyl radical B. The radical addition
of B to the alkene gives the benzylic radical C, which is believed
to undergo direct oxidation by deprotonation to release the nal
product. Meanwhile, the Cu(OTf)2 is regenerated to continue
the catalytic cycle.
Scheme 3 Reaction of styrene and hexane.
Conclusions
In summary, a rst example of intermolecular Cu-catalyzed
double C–H coupling of styrenes with unfunctionalized hydro-
carbons was reported. This process constitutes a user-friendly
and operationally simple reaction for preparing (E)-alkyl
substituted alkenes under mild reaction conditions. Studies of
the detailed mechanistic aspects and applications of this C–H
bond functionalization strategy in other C–H functionalization
reactions are currently in progress in our lab.
Scheme 4 Kinetic isotope effect experiment.
Heck reactions on these substrates. Usually, Heck reactions on
indenes and furans afford mixtures of positional isomers.9
In an endeavor to expand the scope of the methodology, the
catalytic system was applied to other alkanes. We were pleased
to nd that other cycloalkanes such as cyclopentane, cyclo-
heptane and cyclooctane also worked well and all gave the
desired products in good yields (Table 3, 4a–e). However, when
hexane was used in the catalytic system, mixed products were
obtained due to the existence of three different C–H bonds in
hexane (Scheme 3, see ESI†).
Acknowledgements
The authors are grateful to a project funded by the Priority
To gain insight into the catalytic pathway of this Cu-cata- Academic Program Development of Jiangsu Higher Education
lyzed C–H alkenylation reaction, we conducted some control Institutions (PAPD).
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