CuBr-mediated oxyalkylation of vinylarenes under aerobic conditions via cleavage of sp3 C-H bonds α to oxygen

Article abstract of DOI:10.1021/ol900947d

A novel difunctionalization reaction of vinylarenes with cyclic ethers has been developed by copper catalysis via direct activation of α-sp ³ C-H bonds of oxygen In the presence of 1 -1.2 equiv of TBHP under mild aerobic conditions. The reactio

Full text of DOI:10.1021/ol900947d

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2908-2911
CuBr-Mediated Oxyalkylation of
Vinylarenes under Aerobic Conditions
via Cleavage of sp3 C-H Bonds r to
Oxygen
Kai Cheng, Lehao Huang, and Yuhong Zhang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, People’s Republic of China
yhzhang@zju.edu.cn
Received April 30, 2009
ABSTRACT
A novel difunctionalization reaction of vinylarenes with cyclic ethers has been developed by copper catalysis via direct activation of r-sp3
C-H bonds of oxygen in the presence of 1-1.2 equiv of TBHP under mild aerobic conditions. The reaction shows excellent regioselectivities
and good functional group tolerance to give the oxyalkylated products of vinylarenes.
Transition-metal-catalyzed reactions are versatile methods
for C-C bond formations that have found broad applications
in organic synthesis and related disciplines.1 In particular,
transition-metal-catalyzed functionalization of C-H bonds
has attracted considerable attention because it offers more
efficient ways for the construction of complex chemical
frameworks.2 Vinylarenes are common intermediates,3 and
their difunctionalization is an important objective in organic
synthesis.4 In the past decades, remarkable progress has been
made in the transition-metal-catalyzed difunctionalization of
vinylarenes, including diamination,5 dihydroxylation,6 hy-
droxyacetoxylation,7 and aminoacetoxylation.8 Despite the
vast structural complexity of the products that these methods
for the difunctionalization of vinylarenes offer, they are
mainly limited to CX-CX bond-forming reactions. In this
regard, manipulation of C-H bonds in the difunctionalization
of vinylarenes to form CX-CC bonds should have great
synthetic potential.9 Herein, we report a new type of
difunctionalization reaction of vinylarenes where CuBr
catalyzes the regioselective oxyalkylation of vinylarenes
through the cleavage of an sp3 C-H bond adjacent to the
oxygen atom to give the R-carbonyled ꢀ-alkylated aryl
products in the presence of tert-butyl hydroperoxide (TBHP)
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10.1021/ol900947d CCC: $40.75
Published on Web 06/08/2009
 2009 American Chemical Society

under mild aerobic conditions. This is an unprecedented
reactivity mode for vinylarenes, in which the alkylation is
spontaneously processed with the Wacker oxidation.3a
Copper has been widely studied in organic synthesis
because of its promise as a high efficiency catalyst, and Cu-
catalyzed C-H activation reactions have been described.10
The use of this cheap and convenient catalyst in difunction-
alization of vinylarenes is still unknown. In the exploration
of new metal-catalyzed reactions via C-H bond activation,
we evaluated the copper-catalyzed reaction of styrene and
tetrahydrofuran in the presence of 1 equiv of TBHP, which
showed special effects in the Cu-catalyzed C-H activation
processes.11 It was found that the reaction led to none of
the expected adduct of tetrahydrofuran into styrene but
instead afforded oxidative oxyalkylation product 2-(tetrahy-
drofuran-2-yl) phenylethanone in 61% yield (Table 1, entry
TBHP or CuBr did not afford a at all (entries 2 and 3). In
addition, only a trace of the product was detected under
dinitrogen (entry 4), and the reaction could not be improved
under pure dioxygen. It is noteworthy that aqueous TBHP
was tolerated (entry 5). The use of other generally employed
peroxides and additives in C-H bond activation, such as
2,2′-azobisisobutyronitrile (AIBN), N-bromosuccinimide
(NBS), benzoic peroxide, and 2,3-dichloro-5,6-dicyanoben-
zoquinone (DDQ), failed to give the product (entries
6-10).12 The increase of CuBr loading did not improve the
reaction further, and the high loading (>20 mol %) led to
decrease of the yield (entries 12-14). The other metal
catalysts tested were either less efficient (AuClPPh3) or
incompetent (Pd(OAc)2, CuCl, CuI, Cu2O, Cu(OAc)2,
Cu(OTf)2) (entries 15-21). The use of CH3CN as solvent
afforded the desired product, while other solvents such as
CH2Cl2, toluene, and DME were deleterious to the reaction
(entries 22-23 and Supporting Information).
To test the scope of this copper-catalyzed oxyalkylation
reaction, we subjected a variety of vinylarenes to the reaction
conditions (Table 2). In general, both electron-rich and
electron-deficient vinylarenes are reactive (entries 1-14).
Substitution at the 2-position of vinylarenes had only a slight
impact on the yields (entries 3, 6, and 13). It should be
pointed out that the carbon-halogen bonds tolerated the
reaction conditions and the halogen-containing products were
afforded smoothly (entries 9-13). The reaction also ap-
plicable to 2-vinylnaphthalene. However, efforts to effect the
oxidative oxyalkylation of 1,4-dioxane and tetrahydropyran
were not so successful (entries 16 and 17). Excellent
regioselectivities were observed in this transformation. The
Table 1. Effect of Metals and Additives on the Reactiona
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a Reaction conditions: styrene (52 mg, 0.5 mmol), catalyst (0.05 mmol),
additive (1 equiv), 0.10 mL TBHP (1-1.2 equiv), 5-6 M in decane, THF
(5 mL), 60 °C, 12 h. b Isolated yields. c Reaction was carried out under N2
atmosphere. d T-HYDRO, 0.11 g (1 equiv). e 5-6 equiv of TBHP was used
(5-6 M in decane, 0.50 mL) under N2 atmosphere.
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the oxidative carbonyalkylation. Thus, the reaction without
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addition of the R-C-H bond of oxygen to vinylarenes yielded
anti-Markovnikov alkylated products, and the oxidative
carbonylation occurred at the R-position of vinylarenes.
This reaction can be applied to 1,3-dioxolane, which
possesses two types of C-H bonds adjacent to oxygen.
The cleavage of the C-H bond at the 2-position of 1,3-
dioxolane took place preferentially to give the major
products of aryl ꢀ-aldehyde protected ketones as shown
in Figure 1. The yields in parentheses were obtained under
Table 2. Copper-Catalyzed Oxyalkylation of Vinylarenesa
Figure 1. The reaction of vinylarenes with dioxolane. Reaction
conditions: vinylarene (0.5 mmol), CuBr (0.05 mmol), dioxolane
(5 mL), 0.10 mL TBHP, 5-6 M in decane, 60 °C, 12 h under
aerobic condition. Isolated yields.
pure dioxygen. In this case, the pure dioxygen atomsphere
was more effective and higher yields were afforded. The
oxidative products at the 4-position were not identified
under the reaction conditions.
Although the reaction was not effective under dinitrogen
using 1-1.2 equiv of TBHP, product a was isolated in 58%
yield using 5-6 equiv of TBHP under anaerobic conditions
(Table 1, entry 11), illustrating that the peroxide is involved
in the catalysis. Since peroxides are the most common source
of spontaneously induced free radicals and transition metals
such as copper(I) usually promote the generation of this kind
of free radicals, it was supposed that a free-radical process
might be involved in the addition reaction. The preliminary
mechanistic studies support our assumption and the addition
of 1 equiv of free-radical scavenger 2ꢀ-di-tert-butyl-4-
methylphenol (BHT) suppressed the reaction. In addition,
phenyl R-hydroxylalkylated product is detected by GC-MS
analysis (see Supporting Information), which is possibly
a Reaction conditions: vinylarene (0.5 mmol), CuBr (0.05 mmol),
THF (5 mL), 0.10 mL TBHP, 5-6 M in decane, 60 °C, 12 h under
aerobic condition. b Isolated yields. c Dioxane (5 mL), 100 °C.
d Tetrahydro-2H-pyran (5 mL), 100 °C.
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Org. Lett., Vol. 11, No. 13, 2009

generated from the combination of hydroxyl radical and
intermediate 1 (eq 5). We found that phenyl R-hydroxyla-
lkylated product could be oxidized under aerobic conditions
in the presence of 10 mol % CuBr and 1-1.2 equiv of TBHP
to give the aryl R-oxyalkylated product in 81% isolated yield
(eq 6). On the basis of these results, a plausible mechanism
is proposed as shown in Scheme 1. The tetrahydrofuran
subsquent oxidation (eq 4) or combination of hydroxyl
radical and intermediate 1 (eq 5) produce the phenyl
R-oxyalkylated product and phenyl R-hydroxylalkylated
product. The phenyl R-hydroxylalkylated product can be
further converted to phenyl R-oxyalkylated product under
the reaction conditions. Wacker oxidation product was not
found under the reaction conditions in the absence of THF,
and no reaction was observed using acetophenone as the
substrate. Therefore, a tandem reaction mechanism is un-
likely. However, the mechanistic scenario involving copper-
mediated oxidative coupling processes is not able to be
excluded at the current stage. Further studies are required
for the elucidation of detailed mechanism.
Scheme 1. A Plausible Mechanism
In conclusion, we have developed a novel copper-catalyzed
protocol for the difunctionalization of vinylarenes with cyclic
ethers to give the oxyalkylation products. The reaction allows
the regioselective oxidative insertion of vinylarenes into the
R-sp3 C-H bond of oxygen. Current research is focused on
extending this finding to a C-H bond in a wider range of
hydrocarbons and gaining more information on the reaction
mechanism.
Acknowledgment. Funding from Natural Science Foun-
dation of China (No. 20872126) and Zhejiang Provincial
Natural Science Foundation of China (R407106) is acknowl-
edged.
Supporting Information Available: Experimental pro-
cedure and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
radical is generated by the initiator TBHP, which selectively
adds to styrene to produce intermediate 1 (eq 3). The
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