Late-Stage Direct o-Alkenylation of Phenols by PdII-Catalyzed C?H Functionalization

Article abstract of DOI:10.1002/chem.201900530

o-Alkenylation of unprotected phenols has been developed by direct C?H functionalization catalyzed by Pd^II. This work features phenol group as a directing group and realizes highly site-selective C?H bond functionalization of phenols to achieve the corresponding products in moderate to excellent yields at 60 °C. The advantages of this reaction include unprecedented C?H functionalization using phenol as a directing group, high regioselectivity, good substrate scope, mild reaction conditions, and high efficiency. To the best of our knowledge, this is the first example of a regioselective C?H alkenylation of unprotected phenols utilizing phenolic hydroxyl group as a directing group. The alkenylation of unprotected tyrosine and intramolecular cyclization are also successfully carried out under this catalytic system in good yields. Furthermore, this novel method enables a late-stage modification of complex phenol-containing bioactive molecules toward a diversity-oriented drug discovery.

Full text of DOI:10.1002/chem.201900530

A Journal of
Accepted Article
Title: Regioselective Direct o-Alkenylation of Unprotected Phenols via
Pd(II)-catalyzed C-H Functionalization
Authors: Yandong Dou, Kenry Kenry, Jiang Liu, Jianze Jiang, and Qing
Zhu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201900530
Link to VoR: http://dx.doi.org/10.1002/chem.201900530
Supported by

10.1002/chem.201900530
Chemistry - A European Journal
COMMUNICATION
Late-Stage Direct o-Alkenylation of Phenols via Pd(II)-catalyzed
C-H Functionalization
Yandong Dou, [a],+ Kenry, [b],+ Jiang Liu, [a] Jianze Jiang,[a] and Qing Zhu*[a]
Abstract: An unprecedented o-alkenylation of unprotected phenols
is developed via direct C-H functionalization catalyzed by Pd(II). This
work features phenol group as a directing group and realizes highly
site-selective C-H bond functionalization of phenols to achieve the
corresponding products in moderate to excellent yields at 60 ℃. The
advantages of this reaction include unprecedented C-H
functionalization using phenol as directing group, high
regioselectivity, good substrate scope, mild reaction conditions, and
high efficiency. To the best of our knowledge, this is the first
example of regioselective C-H alkenylation of unprotected phenols
an additional directing group is employed in the transition metal-
catalyzed C−H activation (Scheme 1b).8 For example, an
efficient Rh(III)-catalyzed trans selective ortho-olefination of 2-
aryloxypyridines, in which 2-pyridyloxyl is used as a directing
group, has been successfully established by Wang group.8c
Gevorgyan et al. has further developed silanol as a traceless
directing group for a Pd(II)-catalyzed directed o-C-H alkenylation
of phenols, which allows for the quick synthesis of diverse
alkenylated phenols.8d Although these strategies can enable the
preparation of highly site-selective products, the introduction of
directing group and its removal present the problems of poor
atom economy and long synthetic routes. Recently, Maiti's group
has reported the Pd-catalyzed synthesis of benzofurans through
the reaction of phenols with unactivated olefins, as well as the
isolation of the ortho-alkenylated phenol.9 However, it is still
challenging to obtain effective ortho-alkenylated phenol. It is
noteworthy that, because of the high natural abundance and
prevalence of tyrosine on the surfaces of proteins, its
functionalization would have a wide applicability for peptide
derivatization. Moreover, these catalytic systems are not
compatible with the modification of tyrosine and tyrosine-based
peptides. Hence, the development of an effective methodology
for the site-selective functionalization of unprotected phenols,
including tyrosine, is highly desirable.
utilizing phenolic hydroxyl group as
a directing group. The
alkenylation of unprotected tyrosine and intramolecular cyclization
are also successfully carried out under this catalytic system in good
yields. Furthermore, this novel method enables
a late-stage
modification of complex phenol-containing bioactive molecules
toward a diversity-oriented drug discovery.
Phenol is one of the key core moieties in bioactive natural
products, polymers, amino acid, peptides and pharmaceuticals.1
In the last few years, ortho-vinylated phenols have emerged as
important building blocks for synthetic organic chemistry,
particularly for the late-stage modification of phenol-containing
molecules and tyrosine in diversity-oriented drug discovery.2
Thus, the development of methods to achieve site-selective
alkenylation of phenols is highly attractive. Conventionally, the
ortho-alkenylated phenols can be assembled via a consecutive
ortho-halogenation/Mizoroki-Heck cross-coupling reaction with
alkenes (Scheme 1a).3 However, these methods suffer from
limited functional group (FG) compatibility, poor atom economy,
and harsh synthetic conditions.4 Besides, the reagents should be
pre-halided, through which high site-selective of phenols is
difficult to be achieved.5 Moreover, due to the strong electron-
donating and directing effects of the hydroxyl group, the
functionalization of phenols usually leads to ortho- and para-
substituted products.6 Thus, the development of new approach
to obtain ortho-vinylated phenols with good atom economy and
high regioselectivity is highly essential.
Herein, we report a novel and efficient Pd-catalyzed C−H
alkenylation of unprotected phenols under mild synthetic
conditions. This methodology offers attractive features, such as:
1) high atomic economy due to the elimination of direct groups
(DGs), 2) high regioselectivity and ortho-substituted products in
good yields, and 3) wide functional group compatibility and
capability for a late-stage modification of complex phenol-
containing bioactive molecules
Since the report of the Fujiwara-Moritani reaction,7 the
transition metal-catalyzed C–H bond alkenylation has served as
an efficient approach to functionalize the inert C–H bonds in the
past few decades, and many efforts have been devoted to
realizing regioselective vinylation of phenol.7 In most instances,
Scheme 1. Scheme 1. C-H activation strategies for the synthesis of phenols.
We commenced our study by investigating the C−H
alkenylation of phenols based on the model reaction, which uses
phenol as the starting compound, ethyl acrylate as the
alkeylation source, and Pd(OAc)2 as the catalyst (Table 1).
When the reaction was performed in the presence of the oxidant
K2S2O8, ethyl (E)-3-(2-hydroxyphenyl)acrylate (2a) was obtained
in 25% yield at 80 °C in DMSO (Table 1, entry 1). To further
optimize the reaction conditions, oxidants were screened and
K2S2O8 provided the highest yield (Entries 2-5). Additionally,
various transition metal catalysts, such as Pd(TFA)2, PdCl2,
CuCl2, Fe(OAc)2, NiCl2, were evaluated in the reaction.
[a]
[b]
Y. Dou, Dr. J. Liu, J Jiang, Y. Prof. Zheng, Prof. Q. Zhu
College of Biotechnology and Bioengineering & Collaborative
Innovation Center of Yangtze River Delta Region Green
Pharmaceuticals, Zhejiang University of Technology, Hangzhou
310014, China，E-mail: zhuq@zjut.edu.cn
Dr. Kenry
Department of Chemical and Biomolecular Engineering
National University of Singapore
4 Engineering Drive 4, 117585, Singapore (Singapore)
Supporting information for this article is given via a link at the end of
the document.
+These authors contributed equally to this work.
This article is protected by copyright. All rights reserved.

10.1002/chem.201900530
Chemistry - A European Journal
COMMUNICATION
Interestingly, Pd(acac)2 showed superior catalytic activity,
affording the highest yield (Entry 11, 51%) of compound 2a,
whereas Fe(OAc)2 and NiCl2 did not give the desired product
higher yields as compared to their electron deficient
counterparts. Remarkably, the phenol bearing carboxyl structure
(2p) could undergo this Pd(II)-catalyzed olefination reaction in
(entry 9, 10). To improve the yield of ortho-alkenylation of phenol, 75% yield. Meanwhile, some polycyclic aromatic compounds,
we next screened different additives (Entry 12-16) and found
that, when AgOAc was chosen as the additive, 2a could be
obtained in 55% yield (Entry 15). Considering that solution is an
important factor for site-selective and reaction yield of metal
catalytic reaction,10 solvent optimization was performed. AcOH
was found to be the most optimal solvent, which resulted in the
highest yield in 95%, while no side product was generated as
confirmed by liquid chromatography-mass spectrometry (LCMS)
(Entry 20). On the other hand, other solvents, such as H2O, DCE,
MeCN, and DMF, gave poor yields or even no product. Finally,
based on the optimized conditions, the reaction was carried out
under different temperatures (Table S1). The results showed
that the highest yield could be obtained at 60 ℃ (Entry 20), while
reaction at 80℃ could yield para-substitution product in 68%
(Entry 21).
such as naphthyl (2q, 2r), 6-hydroxy-2H-chromen-2-one (2s),
and 8-hydroxyquinoline (2t), could be processed using this
catalytic system and generate the desired products.
Table 2. Alkenylation of unprotected phenols.
Table 1. Optimization of reaction of ethyl acrylate with
Entry
1
Cata.
Oxidant
K2S2O8
Additive
--
Solv.
Yield/%b
25
Pd(OAc)2
DMSO
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
TBHP
MnO2
--
--
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCE
20
10
15
0
aReaction conditions: Phenol (1.0 mmol), ethyl acrylate (1.2 mmol),
Solution 2 mL (AcOH/H2O= 3:7)), Pd(acac)2 (0.05 equiv.), AgOAc(1.2
equiv.), K2S2O8(1.2 equiv.), Temperatures at 60 °C.
4
PhI(OAc)2
Air
--
5
--
Next, we turned our attention to the scope of olefins and
various types of olefins were examined in this catalytic system.
As anticipated, other acrylates with similar reactivity to ethyl
acrylate 2a were also compatible with this reaction. Moreover,
different acrylic amides, including N-phenylacrylamide (3f) and
N-butylacrylamide (3g), were successfully employed in this
transformation (Table 3). Alkylene with electron withdrawing
group, including alkyl vinyl ketones (3h), vinylsulfone (3i) and
acrylonitrile (3g), also readily reacted with phenol to generate
the corresponding olefinated products in 60-85% yields. In
addition, styrene and its derivatives containing electron-donating
and -withdrawing substituents reacted well with phenol to give
(E)-2-styrylphenols 3k, 3l, and 3m in reasonable yields. It is also
noteworthy that a benzophenone connected with acrylic ester
could be successfully reacted with phenols (3e), where
benzophenone has been known to serve as a photo-crosslinking
group for activity-based profiling probes (ABPP) and to improve
the biological activity of target drug molecules.11
6
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
--
20
45
27
0
7
Pd(TFA)2
CuCl2
--
8
--
9
Fe(OAc)2
NiCl2
--
10
11
12
13
14
15
16
17
18
19
20
21
--
0
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
--
51
5
KOAc
NaOAc
AgTFA
AgOAc
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
10
53
55
0
5
MeCN
DMF
10
89
95
68
AcOHc
AcOH
Table 3. Scope of olefins and various types of olefins
aReaction conditions: phenol (1.0 mmol), ethyl acrylate (1.2 mmol), AcOH (2
mL), Pd(acac)2 (5 mol %), 60 °C; bYields of the isolated products given; c
AcOH contained 70% H2O.
Subsequent to elucidating the optimal reaction conditions,
the scope of phenol compounds was investigated. As depicted
on Table 2, the positions of substituents on the phenyl rings of
phenol did not affect the reaction efficiency, as exemplified by o-
Cresol (2b), m-cresol, (2c), and p-cresol (2d). Moreover, a
variety of phenols bearing electron-donating (2g) and
-
withdrawing (2h~2o) substituents could give the desired
products in moderate to excellent yields. In general, the
electron-rich phenols contributed to olefinated products with
aReaction conditions: Phenol (1.0 mmol), ethyl acrylate (1.2 mmol),
This article is protected by copyright. All rights reserved.

10.1002/chem.201900530
Chemistry - A European Journal
COMMUNICATION
Solution 2 mL (AcOH/H2O= 3:7)), Pd(acac)2 (0.05 equiv.), AgOAc(1.2
equiv.), K2S2O8(1.2 equiv.), Temperatures at 60 °C.
be seen from Figure S2, o-alkenylated phenols displayed a
much stronger fluorescence than phenols. It is worth noting that,
when the phenol contained an electron-donating group, the
maximum emission peak located at around 460 nm (2g). In
contrast, the emission peak would red-shift to 550 nm when the
phenol ring contained an electron withdrawing group (2k). This
implies that a new class of fluorescent dyes could be developed
easily using this unique C-H activation method. Moreover, the
quantum yield of the o-alkenylated phenol could reach 0.68 (2k)
in pure water due to the good water solubility (other details in SI).
It is important to highlight that the phenolic O-H and C=C
groups in the olefination product could provide flexibility for
further structural diversification (Scheme 2a). To further show
the wide applicability of this method, 2a was converted into a
benzofuran derivative 4a and a coumarin derivative 4b in good
yields. The intramolecular cyclization of olefinic phenol was
further carried on under the same conditions. No surprisingly, a
11-member ring product 4c was successfully obtained in 76%
yield. Subsequently, to demonstrate the application of this novel
alkenylation methodology on the late-stage modification of
biologically active molecules with structural diversity, typical
phenol-containing bioactive compounds, such as estrones,
estradiol, and ethinylestradiol, were selected for the next
investigation. It was found that these three compounds
underwent a smooth alkenylation process to generate olefinated
estrone, estradiol, and ethinylestradiol (4d~f) as a single
regioisomer in reasonable yields. The biological activities of the
ortho-olefinated compounds (4d~f) were then evaluated by
assessing their cytotoxicity on MCF-7 and PC-3 cancer cell lines,
whose proliferations have been reported to be highly inhibited by
estrone, estradiol, and ethinylestradiol.12 As can be seen from
Table 4, in comparison to the original starting compounds, the o-
olefinated compounds (4d-f) showed enhanced inhibitory
activities towards the cancer cells. The inhibition of MCF-7
activity by 4e improved by 2.5 folds as compared to that by
estradiol, and 1.55 times for PC-3. These examples
demonstrated the feasibility of this method for the late-stage
modification of molecules with phenolic hydroxyl group,
illustrating its potential application for a diversity-oriented drug
discovery.
Figure 1. Fluorescence imaging of the olefination drugs in HeLa cell. Cells
incubated with 4d, 4e and 4f (5 μM) for 1 h. Ex = 405 nm, Em = 480-540 nm.
More importantly, the olefinated drugs also showed obvious
fluorescence (Figure S2). With this information in hand, we
further performed cell imaging experiments to evaluate the
localization of the drugs in living cells. As illustrated in Figure 1,
an evident green signal could be observed in HeLa cells after 1
h incubation, demonstrating clearly that the drugs mostly
localized in the cytoplasm instead of nucleus. In addition, a
remarkable change in the cell shape was observed after 3 h
incubation with olefinated drugs due to its high cytotoxicity
towards HeLa cells (Figure S6).
Scheme 3. Scope of alkenylation of unprotected tyrosine and its derivatives.
The chemoselective modification of amino acids is essential
in proteomics, biochemistry, and drug delivery.13 In particular,
the chemical modifications of tyrosine residues are of great
significance due to their important roles in signal transduction
and regulation of enzymatic activity, and thus, have wide
applications in chemical biology, synthetic biology, and
medicinal chemistry.14 Although the modifications of various
non-natural amino acids have been demonstrated in numerous
reports,15 most of these reported methods could not be applied
to modify natural amino acids. Therefore, C-H functionalization
of natural amino acids and peptides has attracted increasing
interests.16 As tyrosine contains phenol group, we sought to
examine the possibility of vinylating tyrosine. Firstly, using ethyl
acrylate as a vinylating reagent, the 20 natural amino acids were
tested under optimized conditions. We found that only tyrosine
generated the desired o-acrylated product in 76% yield.
Furthermore, the tyrosine derivatives whose amino group is
protected by fluorenylmethyloxycarbonyl (Fmoc) and acetyl (Ac)
groups (5a-5c) also produced the desired products under this
condition (Scheme 3). Additionally, different alkenyl compounds,
such as styrene and methyl acrylate, could react with phenol
and give the desired vinylated tyrosine in moderate yields from
Scheme 2. Synthetic applications of this transformation.
Table 4. Inhibition of proliferation of estradiol and its derivates.
MCF-7
IC50/μM
PC-3
IC50/μM
Compounds
Estrone
3.0 ± 1.2
2.5 ± 0.5
5.1 ± 0.4
2.2 ± 0.7
4.1 ± 0.5
2.3 ± 0.4
4.9 ± 0.3
4.1 ± 0.4
3.1 ± 0.4
2.0 ± 0.5
3.8 ± 0.4
2.2 ± 0.6
4a
Estradiol
4b
Ethinylestradiol
4c
During the investigation of the C-H phenolic vinylation, it is
interesting to note that the ortho-alkenylation of phenols
produced a strong yellow fluorescent signal under UV light
excitation. Their fluorescent properties, notably absorbance,
emission, and quantum yields, were then characterized. As can
This article is protected by copyright. All rights reserved.

10.1002/chem.201900530
Chemistry - A European Journal
COMMUNICATION
process, as shown in Scheme 4. Firstly, in the presence of
acetate, phenol coordinated with the palladium catalyst to form
intermediate A. Then, 1,3-migration of palladium via B generated
the C–H bond metalated intermediate C.21 The insertion of
alkene, followed by the β-H elimination, released the alkenylated
product and the Pdacac species, which was oxidized to the
Pd(II) species to complete the catalytic cycle. Eventually, the
intramolecular esterification generated the final product.
61-72% (5d-5e). Interestingly, the free tyrosine could also
tolerate this reaction (5f). These results demonstrated that a
novel and effective method for direct C-H functionalization of
tyrosine has been established successfully.
In summary, an unprecedented o-alkenylation of
unprotected phenols has been developed via direct C-H
functionalization catalyzed by Pd(II). In this work, phenol group,
for the first time, was utilized as a directing group and the highly
regioselective C-H bond functionalization of phenols and
intramolecular cyclization could be achieved to generate the
corresponding products in moderate to excellent yields at mild
condition. The salient features of this reaction include readily
available starting materials, unprecedented C-H functionalization
rather than X-H insertion, good substrate scope, mild reaction
condition, high regioselectivity, and ease in further
transformation. Moreover, this novel method enables a late-
stage modification of complex phenol-containing bioactive
molecules, including natural products and tyrosine toward a
diversity-oriented drug discovery and peptide/protein chemical
modification.
Scheme 4. Mechanism studies.
To understand the mechanism of these C–H activation
reactions, several control experiments were performed. Firstly,
the incorporation of 2.0 equiv. of 2,2,6,6-(tetramethylpiperidin-1-
yl)oxyl (TEMPO) as a radical scavenger into these reactions
generated product 2a in 87% yield (Scheme 4a). This suggests
that the reaction might not involve a radical process.17 To
examine the function of the hydroxyl group, methoxylbenzene
instead of phenol, was used. In the presence of
methoxylbenzene, no vinylation was observed, suggesting that
the hydroxyl group played a key role in the catalytic process
(Scheme 4b). Then, kinetic experiments were also performed to
gain mechanistic insights into the catalytic C-H alkenyl
reaction.18 To examine the H/D exchange pattern on the phenol
substrate, the reaction of phenol-d2 (1.0 mmol) with methyl
acrylate (1.2 mmol) was carried out under standard conditions. A
significant kinetic isotope effect (kH/D = 2.1) was observed
(Scheme 4c). This phenomenon indicates that the C-H bond
cleavage was most likely involved in the rate limiting step of the
transformation. Moreover, the ESI-MS obtained from the in situ
monitoring of the partial reaction mixture contained m/z 358 and
399, which correspond to the loss of a proton from palladium
complex A and C in the reaction (Figure S4). XPS (X-ray
photoelectron spectroscopy) experiments were then employed
to further explore the mechanism of these C–H functionalization.
As can be seen from Figure S5, the binding energy of the
Pd(3d5/2) peak at 338.3 eV showed the presence of Pd(acac)2,
indicating the absence of oxidation of Pd(II) during the catalytic
reaction.19
Acknowledgements
The authors are grateful to the National Natural Science
Foundation of China (Nos. 21472172, 21272212, 51603186 &
21572190), Natural Science Foundation of Zhejiang Province
(No. LY17B060009).
Keywords: phenols • alkenylation • late-stage modification •
tyrosine
1
a) A. Dennig, E. Busto, W. Kroutil, K. Faber, ACS. Cata. 2015, 5, 7503–
7506; b) S. Bhilare, S. S. M. Bandaru, J. Shah, N. Chrysochos, C.
Schulzke, Y. S. Sanghvi, A. R. Kapdi, J. Org. Chem. 2018, 83,
13088−13102; c) S. Bloom, C. Liu, D. K. Kölmel, J. X. Qiao, Y. Zhang,
M. A. Poss, D. W. C. MacMillan, Nat. Chem. 2017, 10, 205–211; d) J.
Wang, Y. Lin, L. Chen, The Anal. 1993, 118, 277-280.
2
3
4
a) J. D. Williams, A. R. Khan, S. C. Cardinale, M. M. Butler, T. L. Bowlin,
N. P. Peet, Bio. Med. Chem. 2014, 22, 419–434; b) J.-B. Zhu, P. Wang,
S. Liao, Y. Tang, Org. Lett. 2013, 15, 3054–3057.
a) R. Martinez, F. Voica, J. P. Genet, S. Darses, Org. Lett. 2007, 9,
3213–3216; b) J. K. Belardi, G. C. Micalizio, J. Am. Chem. Soc. 2008,
130, 16870–16872;
a) K. Singh, S. J. Staig, J. D. Weaver, J. Am. Chem. Soc. 2014, 136,
5275–5278. b) H. Zhang, X. Huang, Adv. Synth. Catal. 2016, 358,
3736–3742; c) W. Ma, P. Gandeepan, J. Lid, L. Ackermann, Org.
Chem. Front., 2017, 4, 1435–1467
5
a) S. Adimurthy, G. Ramachandraiah, A. V. Bedekar, S. Ghosh, B. C.
Ranu, P. K. Ghosh, Green. Chem. 2006, 8, 916-922; b) J. M. Lévêque,
M. Fujita, A. Bosson, H. Sohmiya, C. Pétrier, N. Komatsu, T. Kimura,
Ultrason. Sonochem. 2011, 18, 753–756.
6
7
X. Xiong, Y. Y. Yeung, ACS Catal. 2018, 8, 4033–4043.
a) X. Chen, K. M. Engle, D.-H. Wang, J.-Q Yu, Angew. Chem. Int. Ed.
2009, 48, 5094–5115; b) D. A. Colby, R. G. Bergman, J. A. Ellman,
Chem. Rev. 2010, 110, 624–655; c) Z. Huang, J.-P. Lumb, ACS Catal.
2019, 9, 521−555; d) X. Hu, G. T. Zhang, F. X. Bu, X. Luo, K. Yi, H.
Zhang, A. W. Lei, Chem. Sci., 2018, 9, 1521–1526; e) L. Zhou, W. J.
Lu, Chem. Eur. J. 2014, 20, 634–642；f) X. Z. Liu, K. K. Hii, J. Org.
Chem. 2011, 76, 8022–8026; g) K. Naksomboon, C. Valderas, M. G.
Martnez, Y. A. Casao, M. A. FernandezIbanez, ACS Catal. 2017, 7,
6342−6346.
8
a) R.-J. Mi, J. Sun, F. E. Kühn, M.-D. Zhou, Z. Xu, Chem. Comm. 2017,
53, 13209–13212; b)Y. Shen, G. Liu, Z. Zhou, X. Lu, Org. Lett. 2013,
15, 3366–3369; c) A. J. Borah, G. Yan, L. Wang, Eur. J. Org. Chem.
2015, 4782–4787; d) C. Huang, B. Chattopadhyay, V. Gevorgyan, J.
Am. Chem. Soc. 2011, 133, 12406–12409.
Scheme 5. Proposed catalytic mechanism.
9
a) U. Sharma, T. Naveen, A. Maji, S. Manna, D. Maiti, Angew. Chem. Int.
Ed. 2013, 52, 12669 –12673; b) A. Maji, Y. Reddi, R. B. Sunoj, D. Maiti,
ACS Catal. 2018, 8, 10111−10118.
Y. X. Luan, T. Zhang, W. W. Yao, K. Lu, L. Y. Kong, Y. T. Lin, M. Ye, J.
Am. Chem. Soc. 2017, 139, 1786–1789.
Based on the above results and the previously reported
ones,20 we proposed the action mechanism driving the catalytic
10
This article is protected by copyright. All rights reserved.

10.1002/chem.201900530
Chemistry - A European Journal
COMMUNICATION
11
12
Z. Ye, G. J. Williams, Biochemistry. 2014, 53, 7494–7502.
a) N. M. Howarth, A. Purohit, J. J. Robinson, N. Vicker, M. J. Reed, B. V.
L Potter, Biochemistry. 2002, 41, 14801-14814; b) R. Devraj, J. F.
Barrett, J. A. Fernandez, J. A. Katzenellenbogen, M. Cushman, J. Med.
Chem. 1996, 39, 3367–3374
9. 1-8.
17
18
Y. Li, A. Studer, Angew. Chem. Int. Ed. 2012, 51, 8221–8224
a) P. Christopher, H. Xin, S. Linic, Nat. Chem. 2011, 3, 467–472; b) O.
Herbinet, W. J. Pitz, C. K. Westbrook, Combust. Flame. 2010, 157,
893–908.
13
a) T. Hermann, Science. 2000, 287, 820–825; b) F. Fülöp, T. A. Martinek,
G. K. Tóth, Chem. Soc. Rev. 2006, 35, 323-334.
19
20
A. R. Mouat, C. L. Whitford, B. Chen, S. Liu, F. A. Perras, M. Pruski, M.
J. Bedzyk, M. Delferro, P. C. Stair, T. J. Marks, Chem. Mater. 2018, 30,
1032−1044.
a) F. Roudesly, L. F. Veiros, J. Oble, G. Poli, Org. Lett. 2018, 20, 2346–
2350; b) M. R. Kuram, M. Bhanuchandra, A. K. Sahoo, Angew. Chem.
Int. Ed. 2013, 52, 4607–4612; c) D. Kim, S. Hong, Org. Lett. 2011, 13,
4466–4469; d）J. A. Leitch, P. B. Wilson, C. L. McMullin, M. F. Mahon,
Y. Bhonoah, I. H. Williams, C. G. Frost, ACS Catal. 2016, 6, 5520–
5529.
14
15
J. M. Denu, K. G. Tanner, Biochemistry. 1998, 37, 5633–5642.
a) L. Mendive-Tapia, S. Preciado, J. García, R. Ramón, N. Kielland, F.
Albericio, R. Lavilla, Nat. Comm. 2015, 6, 7160; b) F. Le Vaillant, M. D.
Wodrich, & J. Waser, Chem. Sci. 2017, 8, 1790-1800; c) Y. Zhu, X.
Chen, C. Yuan, G. Li, J. Zhang, Y. Zhao, Nat. Comm. 2017, 8, 1-8; d) K.
A. Teegardin, L. Gotcher, J. D. Weaver, Org. Lett. 2018, 20, 7239-
7244.
a) B.-F. Shi, N. Maugel, Y. H. Zhang, J. Q. Yu, Angew. Chem. Int. Ed.
2008, 47, 4882- 4886; b) N. Ichiishi, J. P. Caldwell, M. Lin, W. Zhong, X.
Zhu, E. Streckfuss, S. W. Krska, Chem. Sci. 2018, 9, 4168–4175; c) J.
Tang, H. Chen, Y. He, W. Sheng, Q. Bai, H. Wang, Nat. Comm. 2018,
16
21
a) W. Rao, D. Susanti, P. W. H. Chan, J. Am. Chem. Soc. 2011, 133,
15248–15251; b) J. J. Finnerty, C. Wentrup, J. Org. Chem. 2004, 69,
1909–1918.
This article is protected by copyright. All rights reserved.

10.1002/chem.201900530
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Yandong Dou, [a],+ Kenry, [b],+ Jiang Liu,
[a] Jianze Jiang,[a] and Qing Zhu*[a]
Page No. – Page No.
Late-Stage Direct o-Alkenylation of
Phenols via Pd(II)-catalyzed C-H
Functionalization
This article is protected by copyright. All rights reserved.