Palladium(II)-catalyzed ortho -olefination of arenes applying sulfoxides as remote directing groups

Article abstract of DOI:10.1021/ol402921w

A novel palladium-catalyzed ortho-C(sp²)-H olefination protocol has been developed by the use of sulfoxide as the directing group. Importantly, relatively remote coordination can be accessed to achieve the ortho olefination of benzyl, 2-arylethyl, and 3-arylpropenyl sulfoxide substrates, and the olefinated sulfoxide can be easily transformed to other functionalities.

Full text of DOI:10.1021/ol402921w

Letter
pubs.acs.org/OrgLett
Palladium(II)-Catalyzed ortho-Olefination of Arenes Applying
Sulfoxides as Remote Directing Groups
Binjie Wang,† Chuang Shen,† Jinzhong Yao,† Hong Yin,† and Yuhong Zhang*,†,‡
†ZJU-NHU United R&D Center, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: A novel palladium-catalyzed ortho-C(sp2)−H olefination protocol has been developed by the use of sulfoxide as
the directing group. Importantly, relatively remote coordination can be accessed to achieve the ortho olefination of benzyl, 2-
arylethyl, and 3-arylpropenyl sulfoxide substrates, and the olefinated sulfoxide can be easily transformed to other functionalities.
he directing group strategy of transition-metal-catalyzed
C−H activation has emerged as a powerful method for
the additive (see Supporting Information (SI)). Under the
optimal reaction conditions, a variety of olefins, including ethyl
acrylate, n-butyl acrylate, phenyl acrylate, and benzyl acrylate,
participated in the reaction smoothly to give the products in
good yields (Scheme 1, 3aa−3ae). It is notable that all of the
products presented excellent regioselectivity at the ortho-
position of the arenes with the E-configuration. This direct
aromatic C−H olefination displayed good functional group
tolerance with various arenes. For example, arenes bearing
either electron-donating or -withdrawing groups could be
olefinated, although the electron-rich arenes presented higher
reactivity (Scheme 1, 3ba−3gc). More Selectfluor (2 equiv)
and a higher reaction temperature were required in order to
obtain comparable yields for arenes with electron-withdrawing
groups. In addition, hexafluoroisopropanol (HFIP) was a better
solvent for the reaction of electronic-deficient arenes (Scheme
1, 3ha−ma). Diverse functionalities such as methyl, tert-butyl,
−F, −Cl, −Br, and −CF3 groups were tolerated, assessing the
generality of this catalytic olefination process. Substituents of
the sulfoxide moiety were found to influence the reactivity of
this ortho-olefination reaction considerably (3pa−3ta).
Encouraged by the efficiency of the olefination via a five-
membered sulfoxide palladacycle, we next tested the coupling
of phenylethyl sulfoxide substrates (Scheme 2). To our delight,
the coupling of phenylethyl sulfoxide 4a with methyl acrylate
proceeded effectively to give the olefinated product 6aa in 67%
yield in DCE at 100 °C for 24 h. Ethyl and phenyl acrylate were
active as well in delivering the olefinated products in good
yields (6ba and 6ca). A wide range of phenylethyl sulfoxide
substrates were found to be compatible with this reaction
(6da−6la). The presence of electron-withdrawing substituents
on the aromatic ring plays a negative effect on the olefination,
leading to the lower yields (6ga−6ja). Products containing
T
selective and efficient C−C and C−X bond formations.1 The
value of this strategy stems from its atom and step economic
features and prevalence of diverse C−H bonds in the organic
molecules. Currently, a wide variety of functional groups have
been studied as the directing groups through monodentate and
bidentate coordination2 including hydroxyl groups,3 amides,4
amines,5 carbonic acids,6 esters,7 ethers,8 ketones,9 N-
containing heterocycles,10,11 and others.12 Significant success
has been achieved in protocols for the construction of complex
molecules.13 Despite the tremendous progress made in this
field, the development of simple and commonly encountered
functional groups as directing groups is still highly desired,
which will allow the successful conversion of diverse molecules
to the requisite functionality for a given synthetic need via C−
H activation.
Inspired by the coordination power of sulfur to metals in
organic chemistry,14 we have studied the ortho-olefination and
arylation using thioether as DG.15 However, related trans-
formations of sulfoxide derivatives remain elusive within the
synthetic community.16 Sulfoxides are simple organic structures
that allow expedient access to a diversity of synthetically useful
architectures. In addition, they are prevalent in many natural
products and pharmaceutical compounds.17 Herein, we report a
practical Pd-catalyzed ortho-olefination of C(sp2)−H using
sulfoxide as the directing group. It was demonstrated for the
first time that both five- and six-membered palladacycles of
sulfoxide could be formed, leading to the successful ortho-
olefination of benzyl, 2-phenylethyl, and 3-phenylpropenyl
sulfoxide substrates. The sulfoxide group can be transformed
into useful functionalities through oxidation, Pummerer
rearrangement, and reduction reactions.
Initially we optimized the reaction conditions and discovered
that 1.1 equiv of Selectfluor efficiently promoted this Pd(II)-
catalyzed alkenylation of benzyl p-tolyl sulfoxide with methyl
acrylate at 100 °C after 24 h in DCE using 10.0 equiv of TFA as
Received: October 17, 2013
© XXXX American Chemical Society
A
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a
a
Scheme 1. Olefination of Benzyl Sulfoxide Substrates
Scheme 2. Olefination of Phenylethyl Sulfoxide Substrates
a
Isolated yields are given. Reaction conditions: Sulfoxide 1 (0.2
mmol), acrylate 2 (0.4 mmol), Pd(OAc)2 (4 mg, 0.02 mmol),
CF3COOH (200 mg, 2.0 mmol), and Selectfluor (84 mg, 0.24 mmol)
a
Isolated yields are given. Reaction conditions: sulfoxide 5 (0.2
mmol), acrylate 2 (0.4 mmol), Pd(OAc)2 (4 mg, 0.02 mmol),
CF3COOH (200 mg, 2.0 mmol), and Selectfluor (84 mg, 0.24 mmol)
in DCE (2 mL) at 100 °C for 24 h, in a sealed tube. b CH3COOH was
used instead of CF3COOH. c HFIP was used as solvent at 110 °C, and
2 equiv Selectfluor were used.
b
in DCE (2 mL) at 90 °C for 24 h. CH3COOH was used instead of
c
CF3COOH. HFIP was used as solvent at 110 °C, and 2.0 equiv of
d
Selectfluor were used. 130 °C.
chloride (6ia), fluoride (6ga and 6ha), and bromide (6ja) were
obtained, which offered an opportunity for a subsequent cross-
coupling reaction for the synthesis of complex molecules. In the
case of meta-substituent arenes, the olefination occurred
regioselectively at the less hindered position (6ca, 6ha−6ja).
2-Naphthalenyl sulfoxide underwent the reaction smoothly, and
a 60% yield was afforded (Scheme 2, 6ka). Notably, the
substitution pattern at the α-position was tolerated to give the
product in 62% yield (6la).
During this investigation, we also discovered that phenyl-
propyl sulfoxide substrates could dramatically afford the ortho-
olefination products under the reaction conditions with HFIP
as the optimal solvent (Scheme 3). For example, using methyl
acrylate, ethyl acrylate, and butyl acrylate, the corresponding
olefinated products were obtained in 63%, 58%, and 65% yields,
respectively. This synthetic flexibility stemmed from the special
effect of the sulfoxide directing group expanding the range of
core structures that can subsequently be accessed.
a
Scheme 3. Olefination of Phenylpropyl Sulfoxide Substrates
a
Reaction conditions: sulfoxide 8 (0.2 mmol), acrylate 2 (0.4 mmol),
Pd(OAc)2 (4 mg, 0.02 mmol), CF3COOH (200 mg, 2.0 mmol), and
Selectfluor (84 mg, 0.24 mmol) in HFIP (2 mL) at 100 °C for 24 h in
a sealed tube.
Scheme 4. Preparation and ORTEP of the C−H Activation
Intermediates
Fortunately, we obtained the two palladacycle complexes
through a stoichiometric reaction of sulfoxides with Pd(OAc)2
in the presence of 1 equiv of TFA in DCE at 80 °C for 8 h
(Scheme 4). Single crystal XRD analysis of compounds 5 and 7
revealed that sulfur was indeed the anchoring atom in the
palladacycles.18 The corresponding olefination products 3aa
and 6aa were delivered in good yields by the treatment of
palladacycle 5 and 7 with methyl acrylate (see SI).
To gain insight into the mechanism, an intermolecular
isotope kinetic experiment was performed. Benzyl p-tolyl
B
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Letter
sulfoxide 1a and its deuterated analogue 1a-d5 were
equivalently subjected to the reaction (Scheme 5, eq 3). An
isotope kinetic effect (KIE) of 2.57 was observed, indicating
that the C−H cleavage might be the rate-determing step in the
catalytic cycle.
NaBH4 in the subsequent step to afford benzyl alcohol 12 in
85% yield (eq 6).
In conclusion, we have shown that sulfoxide can be
successfully used as a directing group in Pd-catalyzed
olefination through C(sp2)−H activation. A variety of alkenes
can be selectively incorporated to arenes, leading to economic
synthesis of sulfoxide containing compounds in high efficiency.
The ability of sulfoxide to activate the ortho C−H bond with
different tether lengths (n = 1, 2, 3) is a distinctive feature of
this process. In addition, the advantage of using sulfoxide as the
directing group for C−H activation also lies in its
extraordinarily easy transformation to other functionalities.
Further studies toward broadening the scope of sulfoxide
directed C−H activation are underway and will be reported in
due course.
Scheme 5. Intermolecular Isotope Kinetic Experiment
A possible pathway leading to the olefination is proposed
(Scheme 6). The initial sulfoxide assisted ortho-palladation
ASSOCIATED CONTENT
■
Scheme 6. Plausible Mechanism
S
* Supporting Information
Experimental procedures, characterization data (1H NMR, 13C
NMR, HRMS). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhzhang@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding from Zhejiang Province (No. 2011C11097), NBRP
(No. 2011CB936003), and NSFC (No. 21272205) is highly
acknowledged. The work was also supported by the Program
for Zhejiang Leading Team of S&T Innovation.
leads to the formation of five- or six-membered palladacycle B,
which has been verified partially by the preparation and
reaction reactivity of complex 5 and 7. The sulfoxide
palladacycle species B undergoes 1,2-migratory insertion with
olefin to give the intermediate C. The subsequent β-hydride
elimination generates the olefinated products and Pd(II)
species, which undergoes the reduction elimination to liberate
Pd(0). Pd(II) is regenerated by oxidation of Pd(0) to re-enter
the catalytic cycle.
The transformation of the sulfoxide moiety was also
investigated. Oxidation of the olefinated benzylsulfoxide 3aa
by m-CPBA at 0 °C produced the corresponding sulfone 10 in
high yields (Scheme 7, eq 4). The sulfoxide moiety can be
almost quantitatively transformed into aldehyde 11 in the
presence of acetic anhydride through Pummerer rearrangement
(eq 5).19Without separation, the aldehyde could be reduced by
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