Palladium-catalyzed C-H alkenylation of arenes using thioethers as directing groups

Article abstract of DOI:10.1021/ol3006997

Thioethers have been proven to be reliable directing groups for palladium catalyzed alkenylation of arenes via C-H activation. Mechanistic investigation reveals that the C-H cleavage of arenes is the turnover-limiting step, and an acetate-bridged dinuclear cyclopalladation intermediate is involved. The alkenylated thioethers can be easily removed and transformed into a variety of useful groups.

Full text of DOI:10.1021/ol3006997

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2164–2167
Palladium-Catalyzed CÀH Alkenylation of
Arenes Using Thioethers as Directing
Groups
Ming Yu, Yongju Xie, Chunsong Xie, and Yuhong Zhang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
yhzhang@zju.edu.cn
Received March 20, 2012
ABSTRACT
Thioethers have been proven to be reliable directing groups for palladium catalyzed alkenylation of arenes via CÀH activation. Mechanistic
investigation reveals that the CÀH cleavage of arenes is the turnover-limiting step, and an acetate-bridged dinuclear cyclopalladation
intermediate is involved. The alkenylated thioethers can be easily removed and transformed into a variety of useful groups.
Transition metal-catalyzed aromatic CÀH activation
arouses substantial interest currently for its step- and
atom-economic advantages.1 In particular, chelation-
assisted CÀH functionalization has emerged as a powerful
method because of its excellent regioselectivity and
reactivity.2 The efficiency of these CÀH activation
transformations are profoundly influenced by chelation.
The success of chelation-assisted CÀH activation relies
on the compatibility and synergism of metal and ligand.
Strong binding between metal and ligand may quit the
CÀH activation process. Typical N- and O-based direct-
ing groups,3 including anilides,3a,b ketones,3c,d esters,3e
amines,3f oxazoline,3g,h carboxylic acid,3iÀk alcohol,3l as
well as silanol4 and pyridylsulfoxide,5À7 have been in-
tensively investigated. Sulfur has received much atten-
tion by the chemists of organic synthesis, coordination
chemistry, biomaterials, and functionl materials. How-
ever, there is an extremely rare example for utilizing
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Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666. (g) Gericke, K. M.;
Chai, D. I.; Bieler, N.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48,
1447. (h) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 9602. (i) Giri,
R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082. (j) Wang, D.-H.; Mei,
T. S.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 17676. (k) Engle, K. M.;
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r
10.1021/ol3006997
Published on Web 04/06/2012
2012 American Chemical Society

sulfur as chelation groups in CÀH activation,8 possibly
due to its strong coordination ability. Herein, we describe
thefirst exampleofthe useofthioetherastheonlydirecting
group for the Pd-catalyzed olefination of arenes. The
thioethers can be easily removed or engaged in a variety
of useful transformations.9,10 This result established that
sulfur can be used as chelation group in CÀH activation,
which may lead to the creation of economical synthetic
methods for sulfur containing compounds.
Thioether is an important structural motif in a wide
range of molecules with numerous and important appli-
cations.11 It has been widely used as coordination groups
with various metals in many useful complexes.12 The
important applications of thioether derivatives in drug
discovery and natural product synthesis11 prompted us to
develop a Pd-catalyzed ortho-alkenylation of aryl thioethers
(Figure 1).13 Initially, we examined a variety of S-involving
groups as directing group for the palladium catalyzed direct
alkenylation of aromatic CÀH bond with methyl acrylate 2a.
It was found that the length of the tether group between arene
and sulfur exerted a drastic effect on the reaction, and the
benzyl thioethers showed the best efficiency. Smaller groups
in thioether facilitate the transformation as shown when
benzyl was replaced by methyl group, possibly due to the
more efficient coordination. Arylthio presented better reac-
tivity, although dialkenylated product was formed. Notably,
the reaction of other S-containing groups such as sulfoxide,
sulfone, and thioesters are sluggish, indicating that the
properties of the sulfur play crucial role on the chelation with
palladium. Analogous O-based groups such as phenylether
had proven to be totally inactive.
Figure 1. S-containing Directing Groups for Aromatic C-H
Alkenylation. Reaction conditions: arenes (0.3 mmol), 2a
(51.6 mg, 0.6 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), and AgOAc
(100.2 mg, 0.6 mmol) in DCE (2 mL) under air at 120 °C for 12 h.
a AgOTFA was used instead of AgOAc.
this Pd(II)-catalyzed alkenylation of (2-methylbenzyl)-
(phenyl)sulfane 1f with butyl acrylate under 100 °C for
12 h in DCE (see the Supporting Information for details).
The substrate scope of the reaction is summarized in Figure 2.
Various acrylic esters had proven to be reliable sub-
strates in the reaction, and the yields increased from 55
to 72% with the elevation of the boiling point of the acrylic
ester (3aa, 3ab, and 3ac). When phenylthio 1b and
p-tolylthio 1c were used as directing groups, dialkenylation
product was observed (3ba and 3ca). The electron-rich
arenes were readily alkenylated to give the antici-
pated products fast in good yields (3dcÀ3fc). Notably,
the reaction presented excellent regioselectivity with
the alkenylation at the ortho-position of the less steric
side of the arenes (3dcÀ3ec, 3ga, 3gc, and 3jc). The
ortho-substituent arylthioethers participated in the reac-
tion smoothly to afford the desired alkenylated products in
good yields (3faÀ3fc). The electronic-deficient arenes
furnished the alkenylated products in good yields as well,
but longer reaction time was required (3gaÀ3ia). The
arenes bearing a strong electron-withdrawing group such
as CN showed lower reactivity to give low yield even after
prolongation of reaction time (3jc).
After extensive screening the reaction conditions, we
discovered that 2 equiv of Ag(OTFA) promoted efficiently
(9) (a) HO, K. M.; Lam, C. H.; Luh, T.-Y. J. Org. Chem. 1989, 54,
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2011, 13, 1447.
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M. S.; Lee, E. Org. Lett. 2007, 9, 141. (c) Chandrasekhar, S.; Jagadeshwar,
V.; Prakash., S. J. Tetrahedron Lett. 2005, 46, 3127.
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C. D.; Fitzgerald, C. E.; O’Keefe, S. J.; Zaller, D. M.; Schmatz, D. M.;
Doherty, J. B. Bioorg. Med. Chem. Lett. 2003, 13, 3979. (f) Fishkin, N.;
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Chemother. 2004, 1, 53. (h) Wishka, D. G.; Graber, D. R.; Seest, E. P.;
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Arenes bearing double electron-donating groups were
also subjected to the reaction. It was surprising that
no expected product was observed. After switching the
oxidant to AgOAc, the reaction was smooth, with mono-
alkenylation occurring on the less steric side of the arenes
(3ka and 3lc). In contrast, double electron-withdrawing
group substituted arenes such as 3m were compatible with
AgOTFA, giving the regioselective alkenylaion product
3mc in a 37% yield.
It should be pointed out that dialkenylation product was
not detected in the reactions involving meta- and ortho-
substituted arenes. However, in the case of unsubstituted
(14) Bhawmick, R.; Bandyopadhyay, P. Polyhedron 1996, 15, 2923.
Org. Lett., Vol. 14, No. 8, 2012
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(1b and 1c) and para-substituted arenes (1n and 1o),
dialkenylation products were produced spontaneously
under the reaction conditions. The absence of dialkenylated
products might be attributed to the steric hindrance of
meta-substituents. The dialkenylation could be avoided
by the replacement of p-tolyl thioether with smaller methyl
thioether, which selectively delivered the monoalkenylation
products 3pa and 3pc in moderate yields.
the arenes. Direct subjection of 4a to react with alkene 2a
provided the alkenylation product 3aa in a 78% yield
(Scheme 2). These results clearly indicated that 4a was
the key catalytic intermediate and responsible for the CÀH
activation reaction.
Scheme 2. ORTEP of the CÀH Activation Intermediate 4aa
a
˚
Selected bond lengths (A): Pd1ÀC5, 1.983; Pd1ÀS1, 2.243; Pd1ÀO1,
2.061; Pd1ÀO3, 2.138; Pd1ÀPd2, 2.948.
Figure 2. Reaction conditions: ArCH2SR 1 (0.3 mmol), alkenes
2 (0.36 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), and AgOTFA
(132.0 mg, 0.6 mmol) in DCE (2 mL) under air at 100 °C for 12 h.
a 0.6 mmol of alkenes 2 were used, and the dialkenylation product
was isolated in the parentheses. b Regioselective product {(E)-
methyl 3-[2-fluoro-6-(p-tolylthiomethyl)phenyl] acrylate} was ob-
tained. c AgOTFA was replaced by AgOAc.
Scheme 3. Plausible Mechanism
To probe the mechanism of this reaction, an intermole-
cular isotope kinetic experiment was performed. Benzyl-
(p-tolyl)sulfane 1c and its deuterated analogue 1c-d5 were
equivalently subjected to the reaction (Scheme 1). An
isotope kinetic effect (KIE) of 1.78 was disclosed, implying
that the palladium mediated CÀH cleavage was the rate-
determining step (RDS) in the catalytical cycle.
Since the arylthioethers with electron-withdrawing sub-
stituents showed relatively less reactivity (3gaÀ3ia, 3jc),
the intermediate A is possibly formed through an electro-
philic palladation process.14 However, the proton abstract
mechanism15 can not be fully excluded at the moment.
After that, the insertion of alkenes affords the carbopalla-
dation intermediate B, which undergoes the β-hydrogen
elimination to produce the alkenylated benzyl thioethers
and liberate the species HPdOAc. The reductive elimina-
tion of HPdOAc gives Pd(0), which is oxidized Pd(II) in
situ by Ag(I) (Scheme 3).
Scheme 1. Isotope Kinetic Experiment
We succeeded in isolating an intermediate complex 4a
through the stoichiometric reaction of 1a and Pd(OAc)2.
Single crystal XRD analysis of 4a revealed a dinuclear bis-
μ-acetatopalladium structure. The bondlength between Pd
(15) (a) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066. (b) Lafrance, M.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
˚
and S was 2.243 A, suggesting sulfur was indeed the
anchoring atom in the palladium catalyzed olefination of
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Org. Lett., Vol. 14, No. 8, 2012

synthetically very useful sulfoxide 3caÀ3 and sulfone
3caÀ4 in high yields (Scheme 4).5c
Scheme 4. Removal and Transformation of Thioethers
In conclusion, we have demonstrated that thioethers are
elegant directing groups in transition metal catalyzed CÀH
activation. A variety of alkenes can be selectively incorpo-
rated to arenes, leading to the economic synthesis of cinnamic
esters in high efficiency. Mechanistic investigation reveals
that the thioether-directed CÀH cleavage is the turnover-
limiting step, and the reaction proceeds through an acetate-
bridged dinuclear Pd(II) intermediate. The directing group
of the alkenylated arylthioethers can be easily removed or
converted into a variety of useful functional groups. Further
studies on the application of thioether directed CÀH activa-
tion are currently ongoing in our laboratory.
Acknowledgment. Funding from NSFC (No. 20872126,
No. 21072169) and Fundamental Research Funds for the
Central Universities (2010QNA3011) is acknowledged.
The ortho-alkenyl benzylsulfane 3ca can be easily hydro-
genated by NaÀHg to give the ortho-alkyl benzylsulfane
3caÀ2 with a transesterification in a 75% yield. Changing
the reductant to Renay Ni completely removed the
phenylthio group, resulting in the formation of the
2-methyl cinnamic ester 3caÀ1 in a 72% yield with no
effect on the R,β-unsaturated ester moiety. By adjusting
the loading of the oxidant m-CPBA, control oxida-
tion of 3ca could be fastly realized, producing the
Supporting Information Available. Experimental pro-
cedures, characterization of all compounds, and crystal
data 4a (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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