Ligand-accelerated non-directed C-H functionalization of arenes

Article abstract of DOI:10.1038/nature24632

The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.

Full text of DOI:10.1038/nature24632

LeTTer
doi:10.1038/nature24632
Ligand-accelerated non-directed C–H
functionalization of arenes
Peng Wang1, Pritha verma1, Guoqin Xia1, Jun Shi2, Jennifer X. Qiao3, Shiwei Tao2, Peter T. W. Cheng2, michael A. Poss3,
marcus e. Farmer1, Kap-Sun Yeung4 & Jin-Quan Yu1
The directed activation of carbon–hydrogen bonds (C–H) is of a pre-catalyst Pd3(μ2-OH)(L69)5 and of a 1,10-phenanthroline-
important in the development of synthetically useful reactions, stabilized Pd(Phen)(L69)2 complex (where L69 is the highly electron-
owing to the proximity-induced reactivity and selectivity that is deficient ligand 3,5-bis(trifluoromethyl)-pyridin-2(1H)-one) using
enabled by coordinating functional groups1–6. Palladium-catalysed X-ray crystallography (Fig. 1c), which provide insight into the
non-directed C–H activation could potentially enable further useful coordination mode of these ligands with a palladium catalyst. Kinetic
reactions, because it can reach more distant sites and be applied and density functional theory (DFT) studies indicate that the pyridone
to substrates that do not contain appropriate directing groups; ligand is likely to serve as an X-type ligand to palladium and can also act
however, its development has faced substantial challenges associated as an internal base to cleave the C–H bond via the concerted metalation
with the lack of sufficiently active palladium catalysts7,8. Currently deprotonation mechanism (Fig. 1b). Simple and heterocyclic arenes are
used palladium catalysts are reactive only with electron-rich both compatible with this protocol. We also apply these reactions to
arenes, unless an excess of arene is used9–18, which limits synthetic the late-stage modification of amino acids, dyes and pharmaceuticals.
applications. Here we report a 2-pyridone ligand that binds to Although site selectivity is predominantly dictated by the intrinsic elec-
palladium and accelerates non-directed C–H functionalization tronic and steric bias of the arene substrates, the presence of the ligand
with arene as the limiting reagent. is protocol is compatible leads to unprecedented enhancement in selectivity with a few classes
with a broad range of aromatic substrates and we demonstrate of arenes (Fig. 1d).
direct functionalization of advanced synthetic intermediates, drug
Guided by recent success in developing ligand-accelerated directed
molecules and natural products that cannot be used in excessive C–H activation22, we set out to develop highly active ligands for Pd(ii)
quantities. We also developed C–H olefination and carboxylation to achieve non-directed C–H activation with arene as the limiting
protocols, demonstrating the applicability of our methodology to reagent (for details see Methods section ‘Ligand optimization for
other transformations. The site selectivity in these transformations non-directed C–H activation of simple arenes’ and Supplementary
is governed by a combination of steric and electronic effects, with Information, Schemes S1–S5). In short, we evaluated the ligands with
the pyridone ligand enhancing the influence of sterics on the 1,2-dichlorobenzene (1u) as a model substrate because it displayed
selectivity, thus providing complementary selectivity to directed poor reactivity and low β/α selectivity under previously reported
C–H functionalization.
conditions13. After evaluating various mono-protected 3-amino-2-
Extensive research on various directing-group designs1–6 and hydroxypyridine ligands and 2-pyridone ligands, we found that L69
strategies19–21 for C–H functionalization, as well as the development promoted the reaction, allowing formation of the olefinated product
of ligands that accelerate it22, has greatly improved the practicality (3u) in 70% yield with improved site selectivity (β/α=3.0/1.0). The
and utility of this approach. Ligand-induced acceleration has enabled yield was further improved to 85% (82% isolated yield) by using
palladium catalysts to functionalize remote C–H bonds of aromatic 30 mol% L69 and 2.0 equiv. ethyl acrylate.
substrates by ‘recognizing’ distance and geometry23,24 (Fig. 1a). Despite
To elucidate the role of L69 and the origin of this unprecedented
the potential of directed C–H activation reactions where proximal or reactivity when using arene as the limiting reagent, we carried out
distal site selectivity can be controlled, non-directed C–H functionali- structural characterization, kinetic studies and DFT studies. We
zation can reach sites that are not currently accessible by a directed first obtained and characterized Pd(Phen)(L69)2 and the trimeric
approach, as demonstrated by Ir(iii)-catalysed C–H borylation Pd3(μ2-OH)(L69)5 complexes using X-ray crystallography (Fig. 1c).
chemistry25,26. Furthermore, substrates that do not contain appropriate The coordination mode of L69 in these complexes is shown to be
directing groups can be functionalized only when using a non-directed analogous to that found with carboxylates29 and consistent with the
approach. The challenges involved in achieving Pd(ii)-catalysed most favourable transition state proposed by our DFT studies (Fig. 1b).
non-directed C–H activation reactions are best illustrated by the lack The kinetic-isotope-effect experiments (kH/kD =2.9) using benzene as a
of progress over the past 60 years in the Fujiwara–Moritani olefination model substrate with ethyl acrylate indicate that the C–H bond cleavage
reaction of arenes, for which a large excess of arene is still required is the rate-limiting step. Further kinetic investigation shows that L69
to achieve sufficient reactivity with palladium catalysts. Furthermore, increases the initial rate by a factor of 1.4 (see Supplementary Fig. S5).
such electrophilic palladation reactions, which are analogous to elec- In addition, the reaction profile using 1u as the substrate indicates
trophilic aromatic substitution reactions, are limited to electron-rich that the ligand has a dual role in this reaction: it not only accelerates
arenes27,28
.
the initial rate of the reaction by a factor of three, but also prevents cata-
We discovered an electron-deficient 2-pyridone ligand that enables lyst decomposition by forming a more stable complex with palladium.
palladium-catalysed non-directed C–H olefination and carboxylation Such a stabilizing effect is crucial for maintaining the catalyst effi-
of both electron-deficient and electron-rich arenes, allowing arene to ciency in this non-directed C–H activation reaction with arene as the
be used as the limiting reagent (Fig. 1b). We characterize the structures limiting reagent.
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. 2Discovery Chemistry, Bristol-Myers Squibb Company, 350 Carter
Road, Princeton, New Jersey 08540, USA. 3Discovery Chemistry, Bristol-Myers Squibb Company, PO Box 4000, Princeton, New Jersey 08543, USA. 4Discovery Chemistry, Bristol-Myers Squibb
Company, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
2 3 n o v e m b e r 2 0 1 7
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© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

reSeArCH Letter
Figure 1 | C–H functionalization of
a
Directed C–H functionalization
Non-directed C–H functionalization
arenes. a, Directed (left) and non-directed
DG
Template
(right) palladium-catalysed C(sp2)–H
H
H
Simple arenes:
• Excess substrate
• Poor regioselectivity
Pd
Het
Ar
functionalization. DG, directing group. The
current limitations in non-directed C–H
activation are that excess substrate is required
and regioselectivity is poor. b, Ligand-
N
Pd
Proximal C–H
Remote C–H
‡
b
c
F3C
F3C
O
N
H
accelerated Pd-catalysed C–H functionalization
(left). L, Ligand; FG, functional group. The
DFT-optimized C–H activation transition state
at the M06/SDD,6-311+G(d,p)(SMD)//B3LYP/
LANL2DZ,6-31G(d) level of theory is shown
on the right; the double dagger represents
transition state. c, Crystal structures of the
palladium–L69 complexes. d, Ligand effects
on reactivity and site selectivity for selected
substrates. HFIP, hexafluoroisopropanol;
CHCl3, chloroform. For 1m, 1o and 1u, HFIP
was used; for 1r, 1t and 1y, CHCl3 was used.
The yield and selectivity were determined
by 1H NMR; the red colouring highlights the
enhancement in the regioselectivity. m/p is the
ratio of olefination products at the meta- and
para- positions; β/α is the ratio of olefination
products at the β- and α- positions.
F3C
L69
CF3
OH
Pd
H
FG
N
Ar
Ar
N
O
[Pd]–L69
FG–X
1 equiv.
CF3
F3C
CF3
F3C
F3C
CF
3
CF3
F3C
F3C
O
O
N
N
N
N
N
N
O
O
Pd
Pd
Pd
N
O
O
H
Pd
O
N
N
F3C
CF3
CF3
O
CF3
Pd3(μ2-OH)(L69)5
F3C
Pd(Phen)(L69)2
CF3
CF3
d
Pd(OAc)2 (10 mol%)
L69 (30 mol%)
H
CO2Et
Ligand
R
+
CO2Et
R
AgOAc (3.0 equiv.)
HFIP or CHCl3, 100 ºC
1 (1.0 equiv.)
2a (2.0 equiv.)
3
β/α
Substrate
Ligand
Yield (%)
m/p
Substrate
Ligand
Yield (%)
β/α
Substrate
Me
Yield (%)
CO2Me
α
Cl
α
β
None
9
1.4/1.0
4.4/1.0
None
8
1.0/1.0
3.0/1.0
None
14
82
0.45/1.0
17.0/1.0
β
β
L69
72
L69
83
L69
Cl
Me
1o
1u
1y
CF3
α
α
Me
None
8
2.8/1.0
3.3/1.0
None
12
83
4.4/1.0
None
18
69
1.4/1.0
β
L69
69
L69
>20/1.0
L69
13.5/1.0
Me
1m
1t
1r
Interestingly, electron-deficient arenes are nearly unreactive in the both suitable substrates, delivering the mono-olefinated products in
absence of L69. With C–H cleavage being the rate-limiting step in this moderate to high yields (3a–3ak). Di-olefinated products were also
reaction, it is plausible that the observed rate enhancement is due to the formed as minor products when using highly reactive substrates (see
involvement of pyridone ligands in the C–H cleavage step. To obtain Supplementary Information section 3.4). The use of chloroform as the
support for this hypothesis, we performed DFT studies to calculate the solvent reduces the amount of di-olefination products; for example,
transition-state energies for the C–H cleavage step using palladium benzene afforded the mono-olefinated product 3a in 64% yield and a
complexes containing two acetates, one acetate and one pyridone, or mixture of di-olefinated products in 18% yield in CHCl3 (compared
two pyridone ligands. We observed that with each successive replace- with 45% mono-olefinated product and 36% di-olefinated products
ment of an acetate with a pyridone ligand, the relative Gibbs free energy in HFIP). Mono-alkylated arenes were olefinated at the less sterically
and the Gibbs free energy of activation for the C–H activation transi- hindered meta- and para-positions in good yields (3b–3e). Anisole
tion state decrease. The most favourable transition state (as shown in provided the ortho- and para-isomers as the main products, owing to
Fig. 1b) consists of palladium coordinated to two pyridone ligands, electronic effects (3f), whereas the bulkier silyl-protected phenol gave
one of which serves as an X-type ligand and binds in a κ-2 fashion. The the para-olefinated product as the main isomer (3g and 3h).
second pyridone ligand coordinates to palladium through the nitrogen
Less-reactive electron-deficient arenes are also olefinated using this
centre and serves as an internal base to cleave the C–H bond via the catalytic system, highlighting the importance of the ligand acceleration.
concerted metalation deprotonation mechanism (see Supplementary Subjecting substrates with strongly electron-withdrawing groups, such
Information section 3.17). The Gibbs free energy of activation for this as nitro, trifluoromethyl, aldehyde, ester, ketone and nitrile, to these ole-
transition state is 4.8kcal mol−1 lower than that for the corresponding fination conditions afforded the corresponding products in moderate
transition state with two acetates as the ligand. Although our prelimi- to good yields with synthetically useful meta-selectivity (3l–3q and
nary DFT studies overestimate the rate enhancement of relatively 3af). Naphthalene also provided the mono-olefinated product (3r) in
reactive benzene by the new ligand, the rate enhancement observed 68% yield, with a 13.5/1.0 selectivity ratio (β/α). The improvement in
with electron-deficient 1u is more marked. Detailed studies are the regioselectivity by the ligand is particularly noteworthy (Fig. 1d);
underway to help to understand the effect of hexafluoroisopropanol it seems that the ligand enhances the contribution of sterics in
(HFIP) and silver acetate on the reaction rate to obtain a more quan- determining the selectivity. We also examined di-substituted and
titative prediction, which could then be used for further catalyst tri-substituted aromatics (3s–3ag and 3ah–3ak, respectively). The selec-
design and development. Finally, the compelling site selectivity that tivity of symmetric 1,2-disubstituted arenes and of 1,3-disubstituted
we observed with the naphthalene contrasts the α-selectivity of the arenes is primarily governed by sterics; for example, 1,2,3,4-tetra-
conventional Friedel–Crafts-type palladation pathway by favouring the hydronaphthalene, o-xylene and m-xylene afforded the β-olefinated
β-position instead (see Supplementary Information, Scheme S6).
products (3s, 3t and 3y, respectively) in excellent selectivity. Substrates
Using these optimal conditions, we next examined the generality with less sterically hindered substituents such as 1,2-dichlorobenzene
of the substrate by using ethyl acrylate as the coupling partner. As and 1,2-difluorobenzene reacted to provide a mixture of α- and
summarized in Fig. 2, electron-rich and electron-deficient arenes are β-olefinated products (3u and 3v), although the β-olefinated products
4 9 0
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© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Letter reSeArCH
Figure 2 | C–H olefination of
arenes and heterocycles. TBS,
tert-butyldimethylsilyl; TIPS,
triisopropylsilyl; Pin, pinacolate;
Ts, 4-toluenesulfonyl. The
values under each structure
indicate isolated yields. Reaction
conditions: Pd(OAc)2 (10 mol%),
L69 (30 mol%), AgOAc
L69 or L31 (30 mol%)
H
CO2Et
F3C
CF3
OH
F3C
NHCOCF3
OH
Pd(OAc)2 (10 mol%)
Ar
Ar
+
CO2Et
or
N
L69
N
L31
AgOAc (3.0 equiv.)
HFIP or CHCl3, 100 ºC
1 (1.0 equiv.)
2a (2.0 equiv.)
3
Simple arenes
tBu
OTBS
OTIPS
H
OMe
Me
Et
H
H
H
H
H
H
H
(3.0 equiv.), HFIP (0.5 ml), 100 °C,
24 h; for 3a, 3r, 3t, 3w, 3y, 3ai,
3aj, 3ak, 3an, 3ao, 3ay, 3az and
3bb, CHCl3 (0.5 ml) was used
instead of HFIP; for 3j and 3k,
2,2,2-trifluoro-N-(2-hydroxy-5-
(trifluoromethyl)pyridin-3-yl)
acetamide (L31; 20 mol%) was
used instead of L69; for 3l and
3ab, Pd(OAc)2 (20 mol%), L69
(60 mol%) and ethyl acrylate
(1.2 equiv.) were used; for 3as–3ax,
the reaction was conducted at
90 °C; for 3al, 3am, 3aq and 3ar,
Ag2CO3 (1.5 equiv.) was used
instead of AgOAc; for 3am, the
reaction time was shortened to
12 h; for 3ap, the reaction was
conducted at 60 °C; for 3ar, the
reaction time was shortened to
8 h; for 3bd, substrate (0.2 mmol),
ethyl acrylate (0.1 mmol) were
used in CHCl3. The red bonds
signify the site for C–H activation
corresponding to the major
product.
3a, 64%
3b, 83%
o/m/p = 1.0/12.2/13.8
3c, 69%
m/p = 1.0/1.6
3d, 70%
m/p = 1.0/1.4
3e, 69%
m/p = 1.0/1.4
3f, 67%
3g, 81%
3h, 61%
o/p = 1.0/4.4
o/m/p = 1.8/1.0/3.7 o/p = 1.0/3.5
CO2Et
O
H
O
Me
CO2Me
NO2
CF3
F
Cl
H
H
H
H
H
H
H
3i, 65%
H
3j, 68%
3k, 75%
3l, 45%
m/p = 14.1/1.0
3m, 69%
m/p = 3.3/1.0
3n, 65%
o/m/p = 1.0/9.5/2.3
3o, 71%
3p, 62%
m/p = 1.25/1.0 o/m/p = 2.9/1.0/1.6 o/m/p = 1.1/1.3/1.0
m/p = 4.4/1.0 o/m/p = 1.0/3.8/1.2
O
Et
O
α
α
α
α
α
α
H
4
β
F
F
H
Me
Me
H
Cl
H
H
H
H
O
O
β
β
β
β
β
O
6
Cl
H
3x, 61%
4/6 = 1.5/1.0
3q, 58%
3r, 68%
3s, 64%
β/α > 20/1
3t, 81%
β/α > 20/1
3u, 82%
β/α = 3.0/1.0
3v, 60%
3w, 51%
β/α = 1.8/1.0
o/m/p = 1.0/3.8/1.2 β/α = 13.5/1.0
β/α = 1.1/1.0
Cl
Me
CO2Me
CN
MeO2C
H
α
α
α
H
Me
H
F
H
Cl
H
H
β
β
β
α′
α′
H
H
CF3
Cl
Me
F
Cl
Me
3ac, 51%
OMe
3ae, 65%
OMe
3y, 80%
β/α = 17/1.0
3z, 50%
β/α/α′ = 10.4/6.3/1.0
3aa, 70%
β/α/α′ = 6.5/2.2/1.0
3ab, 41%
3ad, 60%
3af, 43%
4
NO2
α
α
4
3
F
OMe
H
Me
Cl
H
Me
H
4
H
β
β
H
H
5
Me
H
S
5
5
O
PinB
Me
S
Et
H
O
F
F
MeO
OMe
Me
O
OMe
3ag, 71%
3ah, 88%
3ai, 80%
3aj, 57%
β/α = 13.4/1.0
3ak, 61%
β/α > 20/1
3al, 82%
3am, 62%
3an, 84%
5/4 = 12.3/1.0 5/others = 11.4/1.0/1.0
Heterocycles
4
5
H
3
Me
4
H
H
5
3
3
H
5
H
5
H
H
H
O
5
H
O
N
Ts
N
Ts
2
2
6
6
H
N
N
Ts
3ap, 61%
2/3 = 1.0/1.3
S
6
N
Me
O
Ts
Ts
3ao, 80%
5/others = 24.6/1.6/1.0
3aq, 71%
2/3 = 14.3/1.0
3ar, 78%
3as, 78%
3at, 75%
5/4 = 3.2/1.0
3au, 80%
5/6 = 3.9/1.0
3av, 82%
5/6 = 3.9/1.0
5/6 = 3.5/1.0
Alkenes
O
H
2
H
O
3
6
H
3
H
4
5
1
2
H
Me
O
H
H
H
N
N
N
7
N
Ts
N
N
Ts
N
Me
O
O
Ts
Me
3aw, 75%
6/7 = 1.5/1.0
3ax, 65%
4/5 = 1.0/5.1
3ay, 60%
3az, 54%
3ba, 32%
3bb, 72%
3bc, 64%
3bd, 64%
3/2 = 1.8/1.0 2/3/others = 4.0/1.1/1.0
predominate as the major isomer. Methyl 3-(trifluoromethyl)benzoate served as particularly effective coupling partners for this palladium-
was transformed to the meta-product (3ab) as a single isomer, owing catalysed olefination reaction (4a–4r); for example, the reactions
to a combination of electronic and steric influence. Symmetric with acrylate derivatives proceeded in 55%–85% yields (4a–4d).
1,4-disubstituted aromatics are also suitable substrates for this reac- Other electron-withdrawing groups attached to the olefins, including
tion and generally undergo mono-functionalization in high yields carboxylic acid, amide, aldehyde, ketone, nitrile, sulfone, sulfonamide
(3ac and 3ad). 4-substituted anisoles are olefinated exclusively at and phosphonate, are also compatible with these reaction conditions,
the ortho-position, owing to electronic effects (3ae–3ag). 1,3,5- and providing the desired olefinated products in moderate to excellent
1,2,3-trisubstituted arenes also react smoothly, providing the desired yields (4e–4o). We note that acrylic acid, acrylamide and acrolein
products in high yields (3ah–3ak). 2,6-Disubstituted aryl boronate are often incompatible with palladium-catalysed C–H olefination
ester is also compatible under the conditions (3ak).
reactions. 1,2-Disubstituted α,β-unsaturated olefins including
We then investigated various heterocyclic aromatics. Olefination crotonate (4p), maleate (4q) and cyclic tri-substituted olefin (4r) were
of thiophene, furan, benzothiophene and benzofuran occurred at also found to be suitable coupling partners. Although both the aryl
the electron-rich positions to give the desired products selectively C–H bonds and vinylic C–H bonds of styrenes are reactive under
(3al–3ar). Use of pyrrole led to a mixture of 2- and 3-olefinated these conditions, electron-deficient styrene derivatives can be used as
products (3ap), probably owing its high reactivity. Indolines, coupling partners (4s and 4t). We also performed a gram-scale C–H
1,2,3,4-tetrahydroquinoline, isoindoline, carbazole, dibenzofuran and olefination of o-xylene with acrolein using 5 mol% Pd(OAc)2 and
indazole are also compatible with this non-directed C–H activation, 15mol% L69, which provided the desired product in 83% yield; L69
generating the desired products in moderate to good yields (3as–3ba). was recovered in 87% yield.
Furthermore, vinylic C–H bonds in cyclic alkenes were olefinated to
To demonstrate the potential generality of ligand-accelerated non-
directed C–H activation to provide a wide range of transformations, we
provide the corresponding diene products (3bb–3bd).
We evaluated the scope of the olefin coupling partners by using have also developed a non-directed C–H carboxylation reaction (Fig. 3b).
o-xylene as the model substrate (Fig. 3a). α,β-Unsaturated olefins We found that L69 can promote the C–H carboxylation of arenes with
2 3 n o v e m b e r 2 0 1 7
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© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

reSeArCH Letter
CF3
Figure 3 | Scope of olefin partners and
carboxylation. a, Scope of olefin coupling
partners. HFIP, hexafluoroisopropanol.
Reaction conditions: o-xylene (0.1 mmol),
olefin (2.0 equiv.), Pd(OAc)2 (10 mol%),
L69 (30 mol%), AgOAc (3.0 equiv.), HFIP
(0.5 ml), 100 °C, 24 h; for 4a–4d, 4i, 4l and
4p, the reaction was conducted in CHCl3;
for 4c, the reaction time was shortened to
16 h. b, Carboxylation of simple arenes. Phth,
phthaloyl. Reaction conditions: substrate
(0.2 mmol), CO (1 atm), Pd(OAc)2 (10 mol%),
L69 (30 mol%), AgOAc (3.0 equiv.), HFIP
(2.0 ml), 100 °C, 24 h; then NaOH (1.5 ml,
2 M), MeOH (2.0 ml), 12 h; for 5d and 5e,
substrate (0.1 mmol) was used; for 5c and 5d,
the products were isolated before hydrolysis.
F3C
a
(30 mol%)
N
OH
α
Me
Me
H
Me
Me
R
Pd(OAc)2 (10 mol%)
β
+
R
AgOAc, CHCl3 or HFIP
100 ºC, 24 h
4, β/α > 20/1
3u (1.0 equiv.)
2 (2.0 equiv.)
Me
Me
CO2Me
Me
Me
CO2nBu
Me
Me
CO2tBu
Me
Me
CO2Bn
4a, 85%
4e, 72%
4b, 82%
4c, 62%
4g, 91%
4d, 55%
4h, 76%
O
O
O
O
N
Me
Me
Me
Me
tBu
Me
Me
Me
Me
Me
NH
N
H
N
2
Me
O
4f, 65%
O
O
O
Me
Me
Me
Me
Me
Me
Me
Me
CN
OH
H
Et
4i, 52%
4j, 89%
4k, 86%
4o, 85%
4l, 55%
O
Me
O
O
O
O
OEt
Me
Me
Me
Me
Me
Me
Me
Me
S
S
Me
P
CO2Me
N
Ph
OEt
Me
4m, 72%
4n, 66%
4p, 46%
F
F
F
F
CF3
CO2Me
CO2Me
Me
Me
Me
Me
Me
Me
Me
Me
CO2Me
F
4q, 82%
4r, 74%
4s, 83%
4t, 55%
Z/E = 1.2/1.0
O
O
O
O
b
L69 (30 mol%)
Pd(OAc)2 (10 mol%)
H
NaOH (2 M)
OR
OH
OH
OH
Ar
Ar
Ar
Ar
Ar
O
+
+
MeOH,
room temperature
AgOAc, CO (1 atm)
HFIP, 100ºC, 24 h
1.0 equiv.
O
O
Mono-5
Di-5
R = H or (CF3)2CH–
O
O
O
O
Me
Me
Me
OH
OH
OH
OH
OH
OH
Me
5a, 79%
(Mono-5a, 36%; di-5a, 43%)
5b, 85%
(Mono-5b, 40%; di-5b, 45%)
O
O
O
Me
OMe
O
CF3
CF3
O
HO
RO2C
MeO
CO2Me
NPhth
H
O
H
H
OMe
5c, 92%
MeO
MeO
5d, 46%
(R = H, 32%; R = (CF3)2CH–, 14%)
5e, 52%
arene as the limiting reagent under an atmosphere of carbon monoxide. was olefinated in 45% yield (7c). Fluorescein derivative (6d), a well-
The reaction produces a mixture of the mono-HFIP ester and phthalic known dye and fluorescence probe, was olefinated in 53% yield (7d).
anhydride derivatives. The phthalic anhydride derivatives arise from Interestingly, the most active site for 6d is the α-position of the carbonyl
an ortho-C–H carboxylation reaction directed by the product of the group adjacent to the oxo-bridge. In addition, natural products includ-
first carboxylation. A mixture of mono-acid and phthalic acid deriva- ing caffeine, estrone, podocarpic-acid derivatives and camptothecin
tives can be obtained after treatment with an aqueous NaOH solution were tested under the standard conditions, delivering the targets in
in methanol. Benzene and o-xylene were tested under the standard moderate yields (7e–7h). Various pharmaceuticals including fenofi-
conditions and transformed to the mono- and di-acids in 79% and brate, gemfibrozil, diflunisal, viloxazine and betaxolol were also olefi-
85% combined yield, respectively (5a and 5b). Direct carboxylation nated to give the products in 47%–91% yield (7i–7m).
of 1,3,5-trimethoxybenzene gave the corresponding HFIP-ester in
In summary, the 2-pyridone ligand scaffold affords a much more
92% yield (5c). Bioactive molecules O-methyl-tyrosine deriva- reactive and stable Pd(ii) catalyst for non-directed C–H functionali-
tive (5d) and estrone 3-methyl ether (5e) were also subjected to the zation. Through the development of the ligand L69, we achieved non-
carboxylation procedure, affording the desired products in moderate directed C–H olefination and carboxylation with arene as the limiting
yields.
reagent. We also observed that the ligand has a substantial influence
The development of ligand-accelerated, non-directed C–H func- on site selectivity in a few classes of arene substrates. Owing to the
tionalization with one equivalent of arene presents an opportunity for compatibility of both electron-rich and electron-deficient arenes, this
late-stage functionalization of C–H bonds that are not accessible by reaction provides a way to diversify advanced synthetic intermediates,
directing group strategies, owing to distance, geometry or compati- natural products, dyes and drug molecules.
bility (Fig. 4). C–H olefination of amino-acid derivatives proceeded
Online Content Methods, along with any additional Extended Data display items and
Source Data, are available in the online version of the paper; references unique to
these sections appear only in the online paper.
smoothly to give the desired products in 68% and 52% yield (7a and 7b,
respectively). [2.2]Paracyclophane, a commonly used ligand scaffold,
4 9 2
| n A T U r e | v o L 5 5 1 | 2 3 n o v e m b e r 2 0 1 7
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Letter reSeArCH
Pd(OAc)2 (10 mol%)
L69 (30 mol%)
Figure 4 | Late-stage
F3C
CF3
OH
H
CO2Et
CO2Et
+
functionalization of natural
Ar
Ar
AgOAc, HFIP or CHCl3
100 ºC, 24 h
L69
N
products and drug molecules. Phth,
phthaloyl; Ts, 4-toluenesulfonyl;
HFIP, hexafluoroisopropanol; Phe,
phenylalanine; Tyr, tyrosine. The
values under each structure indicate
isolated yields. Reaction conditions:
substrate (0.1 mmol), ethyl acrylate
(0.2 mmol), Pd(OAc)2 (10 mol%),
L69 (30 mol%), AgOAc (3.0 equiv.),
HFIP (0.5 ml), 100 °C, 24 h; for 7d,
7f and 7i, the reaction time was
shortened to 16 h; for 7g, chloroform
was used instead of HFIP.
6 (1.0 equiv.)
2a (2.0 equiv.)
7
H
MeO
O
O
CO2Me
NPhth
CO2Me
H
4
NPhth
H
MeO
3
MeO2C
H
H
N-Phth-Phe-OMe
7a, 68%
3/4 = 1.0/1.1
N-Phth-Tyr-OMe
7b, 52%
[2.2]Paracyclophane
Dimethylꢁuorescein
ether ester
7c, 45%
7d, 53%
OMe
O
N
O
O
Me
O
Me
H
6
Me
N
Me
Me
N
N
iPrO2C
H
H
5
H
H
O
N
H
O
N
Me
H
H
O
Cl
Me
H
MeO
OH
O
MeO2C
Caffeine
7e, 50%
Estrone-OMe
7f, 51%
Methyl O-methylpodocarpate
7g, 58%
Camptothecin
7h, 46%
Fenoꢀbrate
7i, 56%
6/5 = 11.4/1.0
Me
O
CO2Me
OMe
O
Ts
N
H
H
3
4
O
CO2Me
N
O
H
H
O
O
H
H
5
4
O
5′
Me
2
3
F
F
O
3′
H
Gemꢀbrozil-CO2Me
7j, 47%
Diꢁunisal derivative
7k, 71%
Viloxazine-NTs
7l, 81%
Betaxolol derivative
7m, 47%
3/4 = 1.0/1.1
3′/5′ = 1.0/1.0
Di-7k′, 20%
4/5 = 1.0/1.0
2/3 = 2.5/1.0
19. Huang, C., Chattopadhyay, B. & Gevorgyan, V. Silanol: a traceless directing
group for Pd-catalyzed o-alkenylation of phenols. J. Am. Chem. Soc. 133,
12406–12409 (2011).
20. Bedford, R. B., Coles, S. J., Hursthouse, M. B. & Limmert, M. E. The catalytic
intermolecular orthoarylation of phenols. Angew. Chem. Int. Ed. 42, 112–114 (2003).
21. Zhang, F.-L., Hong, K., Li, T.-J., Park, H. & Yu, J.-Q. Functionalization of C(sp3)–H
bonds using a transient directing group. Science 351, 252–256 (2016).
22. Engle, K. M. & Yu, J.-Q. Developing ligands for palladium(II)-catalyzed C–H
functionalization: intimate dialogue between ligand and substrate. J. Org.
Chem. 78, 8927–8955 (2013).
23. Leow, D., Li, G., Mei, T.-S. & Yu, J.-Q. Activation of remote meta-C–H bond
assisted by an end-on template. Nature 486, 518–522 (2012).
24. Chu, L. et al. Remote meta-C–H activation using a pyridine-based template:
achieving site-selectivity via the recognition of distance and geometry.
ACS Cent. Sci. 1, 394–399 (2015).
25. Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F. C–H
activation for the construction of C–B bonds. Chem. Rev. 110, 890–931 (2010).
26. Cho, J.-Y., Tse, M. K., Holmes, D., Maleczka, R. E. Jr & Smith, M. R. III.
Remarkably selective iridium catalysts for the elaboration of aromatic
C–H bonds. Science 295, 305–308 (2002).
received 27 March; accepted 12 September 2017.
1. Whisler, M. C., MacNeil, S., Snieckus, V. & Beak, P. Beyond thermodynamic
acidity: a perspective on the complex-induced proximity effect (CIPE) in
deprotonation reactions. Angew. Chem. Int. Ed. 43, 2206–2225 (2004).
2. Kakiuchi, F. et al. Catalytic addition of aromatic carbon–hydrogen bonds to
olefins with the aid of ruthenium complexes. Bull. Chem. Soc. Jpn 68, 62–83
(1995).
3. Daugulis, O., Do, H.-Q. & Shabashov, D. Palladium- and copper-catalyzed
arylation of carbon–hydrogen bonds. Acc. Chem. Res. 42, 1074–1086 (2009).
4. Engle, K. M., Mei, T.-S., Wasa, M. & Yu, J.-Q. Weak coordination as powerful
means for developing broadly useful C–H functionalization reactions.
Acc. Chem. Res. 45, 788–802 (2012).
5. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H
functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).
6. Colby, D. A., Bergman, R. G. & Ellman, J. A. Rhodium-catalyzed C–C bond
formation via heteroatom-directed C–H bond activation. Chem. Rev. 110,
624–655 (2010).
7. Kuhl, N., Hopkinson, M. N., Wencel-Delord, J. & Glorius, F. Beyond directing
groups: transition-metal-catalyzed C–H activation of simple arenes. Angew.
Chem. Int. Ed. 51, 10236–10254 (2012).
8. Hartwig, J. F. & Larsen, M. A. Undirected, homogeneous C–H bond
functionalization: challenges and opportunities. ACS Cent. Sci. 2, 281–292
(2016).
9. Moritani, I. & Fujiwara, Y. Aromatic substitution of styrene-palladium chloride
complex. Tetrahedr. Lett. 8, 1119–1122 (1967).
10. Dams, M., De Vos, D. E., Celen, S. & Jacobs, P. A. Toward waste-free production
of Heck products with a catalytic palladium system under oxygen. Angew.
Chem. Int. Ed. 42, 3512–3515 (2003).
27. Grimster, N. P., Gauntlett, C., Godfrey, C. R. A. & Gaunt, M. J. Palladium-catalyzed
intermolecular alkenylation of indoles by solvent-controlled regioselective C–H
functionalization. Angew. Chem. Int. Ed. 44, 3125–3129 (2005).
28. Ueda, K., Yanagisawa, S., Yamaguchi, J. & Itami, K. A general catalyst for the
β-selective C–H Bond arylation of thiophenes with iodoarenes. Angew. Chem.
Int. Ed. 49, 8946–8949 (2010).
29. Bedford, R. B. et al. Facile hydrolysis and alcoholysis of palladium acetate.
Angew. Chem. Int. Ed. 54, 6591–6594 (2015).
Supplementary Information is available in the online version of the paper.
11. Yokota, T., Tani, M., Sakaguchi, S. & Ishii, Y. Direct coupling of benzene with
olefin catalyzed by Pd(OAc)2 combined with heteropolyoxometalate under
dioxygen. J. Am. Chem. Soc. 125, 1476–1477 (2003).
12. Zhang, Y.-H., Shi, B.-F. & Yu, J.-Q. Pd(II)-catalyzed olefination of electron-
deficient arenes using 2,6-dialkylpyridine ligands. J. Am. Chem. Soc. 131,
5072–5074 (2009).
Acknowledgements We acknowledge The Scripps Research Institute, the
NIH (NIGMS, 2R01 GM102265), Bristol-Myers Squibb and Shanghai RAAS
Blood Products Co., Ltd. for their financial support. We also thank Novartis for
providing the drug molecules.
Author Contributions P.W. developed the ligands and the reactions.
P.V. performed the DFT calculations. G.X. performed the kinetic study. J.S., S.T.
and P.T.W.C. separated the isomers using preparative HPLC. J.X.Q. and M.A.P.
participated in the screening of acrylamide-derived coupling partners and
investigation of the C–H olefination reaction for amino acid substrates. M.E.F.
performed preliminary studies on 2-hydroxypyridine ligands. K.-S.Y. helped with
the screening of sulphonamide-derived coupling partners. J.-Q.Y. conceived the
concept and prepared the manuscript with feedback from P.W., P.V. and G.X.
13. Kubota, A., Emmert, M. H. & Sanford, M. S. Pyridine ligands as promoters in
PdII/0-catalyzed C–H olefination reactions. Org. Lett. 14, 1760–1763 (2012).
14. Ying, C.-H., Yan, S.-B. & Duan, W.-L. 2-Hydroxy-1,10-phenanthroline vs
1,10-phenanthroline: significant ligand acceleration effects in the palladium-
catalyzed oxidative Heck reaction of arenes. Org. Lett. 16, 500–503 (2014).
15. Li, R., Jiang, L. & Lu, W. Intermolecular cross-coupling of simple arenes via C–H
activation by tuning concentrations of arenes and TFA. Organometallics 25,
5973–5975 (2006).
16. Shrestha, R., Mukherjee, P., Tan, Y., Litman, Z. C. & Hartwig, J. F. Sterically
controlled, palladium-catalyzed intermolecular amination of arenes. J. Am.
Chem. Soc. 135, 8480–8483 (2013).
17. Fujiwara, Y., Taniguchi, H. & Taniguchi, H. Palladium-promoted one-step
carboxylation of aromatic compounds with carbon monoxide. J. Chem. Soc.
Chem. Commun. 220–221 (1980).
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial
interests. Readers are welcome to comment on the online version of the paper.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations. Correspondence and
requests for materials should be addressed to J.-Q.Y. (yu200@scripps.edu).
18. Yoneyama, T. & Crabtree, R. H. Pd(II) catalyzed acetoxylation of arenes with
iodosyl acetate. J. Mol. Catal. A 108, 35–40 (1996).
reviewer Information Nature thanks J. de Vries and the other anonymous
reviewer(s) for their contribution to the peer review of this work.
2 3 n o v e m b e r 2 0 1 7
| v o L 5 5 1 | n A T U r e | 4 9 3
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

reSeArCH Letter
MethOdS
3-acetylamino group has a positive influence on the reaction, but the pyridone
Ligand optimization for non-directed C–H activation of simple arenes. moiety is crucial to the reactivity30. This prompted us to perform further ligand
To best evaluate the ligand effects on reactivity and site selectivity, we selected screening with a focus on evaluating a diverse range of substituted 2-pyridones.
1,2-dichlorobenzene (1u) as a model substrate because it displayed poor reactivity We found that the highly electron-deficient 3,5-bis(trifluoromethyl)-pyridin-
and low β/α selectivity under previously reported conditions13. In the absence 2(1H)-one (L69) greatly promoted the reaction, allowing formation of 3u in
of ligand, olefination of 1u was found to proceed in the presence of a catalytic 70% yield with improved site selectivity (β/α=3.0/1.0). The yield was further
amount of Pd(OAc)2 and 3.0 equiv. silver acetate in HFIP to provide the olefinated improved to 85% (82% isolated yield) by using 30mol% L69 and 2.0 equiv. ethyl
products in 8% yield with poor site selectivity (β/α=1.0/1.0). A wide range of acrylate.
ligands that are commonly used in catalysis were then evaluated. Phosphine General procedure for the palladium/pyridone-promoted non-directed C–H
ligands, N-heterocyclic carbene ligands, oxazoline ligands, pyridine ligands, activation of simple arenes. Substrate (0.1mmol), ethyl acrylate (0.2mmol),
phenanthroline and 1,10-phenanthrolin-2-ol did not display an improvement in Pd(OAc)2 (2.2mg, 10mol%), L69 (3.0mg, 20mol%), AgOAc (50.1mg, 0.3mmol)
reactivity for this reaction (see Supplementary Information, Scheme S1). The first and HFIP or CHCl3 (0.5ml) were added to a 2-dram vial. The vial was capped
noticeable ligand enhancement was observed with mono-protected amino acid and closed tightly, then the reaction mixture was stirred at 100°C for 24h. After
ligands, which improved the combined yield to 16%. The improved selectivity cooling to room temperature, the mixture was filtered through a pad of Celite and
(α/β = 1.6/1.0) is evidence of ligand involvement in the C–H activation step. washed with dichloromethane as the eluent to remove the insoluble precipitate. The
Although further screening of other mono-protected amino acid ligands did not resulting solution was concentrated and purified by preparative thin-layer chro-
improve the yield, we found that the ligand 3-acetylamino-2-hydroxypyridine matography to afford the desired arylated product. Full experimental details and
(L19), previously disclosed for meta-C–H functionalization30, provided an improve- characterization of new compounds are provided in Supplementary Information.
ment of the reactivity by a factor of nearly three (21% versus 8% yield). Following Data availability. The data that support the findings of this study are available
this lead, we evaluated various mono-protected 3-amino-2-hydroxypyridine within the paper and its Supplementary Information. Metrical parameters for the
ligands (L20–L50) and found that trifluoroacetyl-protected 3-amino-5- structures of Pd(Phen)(L69)2, the Pd3(μ2-OH)(L69)5 complex and 7d are available
(trifluoromethyl)pyridin-2-ol (L31) afforded a substantial improvement in yield free of charge from the Cambridge Crystallographic Data Centre (https://www.
(62%) and selectivity (β/α = 2.3/1.0). Interestingly, L51 (5-trifluoromethyl- ccdc.cam.ac.uk/) under reference numbers CCDC 1552055, CCDC 1538821 and
2-pyridone), which is devoid of the trifluoroacetyl-protected amino moiety, CCDC 1538820, respectively.
also imparts reactivity to the palladium catalyst, albeit less substantially than
does L31 (24% yield). This finding is in line with a previous report on the use
of 3-acetylamino-2-hydroxypyridine ligands, wherein it was shown that the
30. Wang, P. et al. Ligand-promoted meta-C–H arylation of anilines, phenols, and
heterocycles. J. Am. Chem. Soc. 138, 9269–9276 (2016).
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.