Activation of remote meta-C-H bonds assisted by an end-on template

Article abstract of DOI:10.1038/nature11158

Functionalization of unactivated carbon-hydrogen (C-H) single bonds is an efficient strategy for rapid generation of complex molecules from simpler ones. However, it is difficult to achieve selectivity when multiple inequivalent C-H bonds are present in t

Full text of DOI:10.1038/nature11158

LETTER
doi:10.1038/nature11158
Activation of remote meta-C–H bonds assisted by an
end-on template
Dasheng Leow1*, Gang Li1*, Tian-Sheng Mei1 & Jin-Quan Yu1
Functionalization of unactivated carbon–hydrogen (C–H) single disconnections. In this endeavour, controlling the positional selectivity
bonds is an efficient strategy for rapid generation of complex of C–H cleavage in molecules that contain multiple C–H bonds is
molecules from simpler ones. However, it is difficult to achieve an outstanding challenge that must be addressed before widespread
selectivity when multiple inequivalent C–H bonds are present in synthetic applications. Currently, s-chelation-directed metalation of
the target molecule. The usual approach is to use s-chelating C–H bonds has been used as a powerful means of achieving ortho-
directing groups, which lead to ortho-selectivity through the selectivity1–6. Diverse carbon–carbon and carbon–heteroatom bond-
formation of a conformationally rigid six- or seven-membered forming reactions with broadly useful substrates have recently been
cyclic pre-transition state1–14. Despite the broad utility of this developed using Pd(II)7–9, Rh(III)10–13, and Ru(II)14 catalysts. In
approach, proximity-driven reactivity prevents the activation of directed C–H activation, assembly of a conformationally rigid cyclic
remote C–H bonds. Here we report a class of easily removable
pre-transition state is required (I in Fig. 1a), which introduces two
nitrile-containing templates that direct the activation of distal inherent limitations. First, despite extensive and innovative efforts
towards remote C–H functionalization reactions15–18, the difficulties
meta-C–H bonds (more than ten bonds away) of a tethered arene.
We attribute this new mode of C–H activation to a weak ‘end-on’
interaction15 between the linear nitrile group and the metal
centre. The ‘end-on’ coordination geometry relieves the strain of
the cyclophane-like pre-transition state of the meta-C–H activa-
tion event. In addition, this template overrides the intrinsic
electronic and steric biases as well as ortho-directing effects with
two broadly useful classes of arene substrates (toluene derivatives
and hydrocinnamic acids).
associated with forming a macrocyclic pre-transition state larger than
a seven-membered ring generally preclude the activation of remote
C–H bonds. Second, the high energy associated with well-defined
cyclophane-like pre-transition states prevents meta- or para-selective
C–H activation reactions (II in Fig. 1a). Although significant progress
has been made in the development of meta- and para-selective C–H
functionalization reactions19–27, the positional selectivity is largely
governed by steric (1,3-substituted arenes)19,20, or electronically biased
The development of new transformations in which inert C–H (mono-substituted arenes)20–25 properties of the arene substrates. A
bonds react as dormant functional groups holds great promise for generally applicable approach for remote meta-C–H activation that
expediting organic synthesis by providing unprecedented retrosynthetic controls positional selectivity by overriding the intrinsic electronic
R
Template
a
DG
H
C
N
Pd
5
2
8
6
O
7
Pd
R
Substrate
4
3
9
Removable
linker
1
N
10
H
Pd
H
Pd
I
II
III
IV
Cyclic pre-
transition state
Cyclophane-like pre-
transition state
12-membered ring
6- or 7-membered ring
≥12-membered ring
8
NC
9
R
5
b
d
c
CF3
Me
H
7
Me
COOH
COOH
COOH
6
8
6
10
5
7
R
O
O
N
4
11
3
2
2
4
9
NC
1
Br
Me
1
H
10
3
N
H
H
H
H
1
2
Me B(OH)2
N
N
NH2
COOH
CO2H
H
Me
H
NH
N
N
N
N
Me
O
H
HN
N
O
N
HO2C
Me
H
Cl
H
Me
N
N
N
Me
n-Bu
O
n-Pr
Baclofen
(Lioresal)
Bortezomib
(Velcade)
Telmisartan
(Micardis)
Valsartan
(Diovan)
Figure 1
|
A template strategy for the activation of distal meta-C–H bonds the targeted C–H bonds. b, Templates for toluenes and hydrocinnamic acids.
(more than ten bonds away). a, Remote meta-C–H activation is a challenge. I: c, Unprecedented positional selectivity in C–H activation, overriding electronic
ortho-directed C–H activation. DG, directing group. II, III and IV: Remote and steric biases, and ortho-directing effects.. d, Structurally related drug
meta-C–H activation using an ‘end-on’ template. The dotted blue lines divide molecules (brand names in parentheses).
the arene template into four quadrants. The blue bonds in all figures highlight
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
*These authors contributed equally to this work.
5 1 8
| N A T U R E | V O L 4 8 6 | 2 8 J U N E 2 0 1 2
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LETTER RESEARCH
Table 1
|
Optimization of template
and steric properties of arene substrates, especially mono-substituted
arenes, has remained a challenge.
R1
R1
R1
O
R1
Here we report the discovery of a class of nitrile-containing tem-
plates that deliver palladium to the vicinity of tethered arene substrates
to promote C–H olefination of distal meta-C–H bonds with excellent
selectivity (Fig. 1). This linear ‘end-on’ coordinating nitrile group15 is
proposed to accommodate a macrocyclic cyclophane-like pre-transition
state, thus overcoming the inherent limitations of traditional directed
C–H activation. We demonstrate the generality of this template
approach with two categorically different classes of substrates (toluene
and hydrocinnamic acid derivatives 1 and 2) (Fig. 1b). Remarkably, the
template overrides the intrinsic electronic and steric biases as well as
ortho-directing effects of the arene substrates, consistently securing high
meta-selectivity in most cases (Fig. 1c). This meta-selective C–H olefina-
tion reaction is also compatible with ortho,ortho-disubstituted arene
and 2-biphenylcarboxylic acid substrates. Both hydrocinnamic and
2-biphenylcarboxylic acids are key structural motifs in many drug
molecules, including the GABAB receptor agonist drug Baclofen
(Fig. 1d).
Considering that the major limitations of directed C–H activation
arise from the stringent requirement of assembling a rigid cyclic pre-
transition state, we began to devise a removable chelating template
that would recruit the Pd(II) catalyst through a less rigid assembly
involving reversible weak coordination. We suspected that the weakly
binding end-on nitrile group would either make the cyclophane-like
pre-transition state less strained or would lead to release of the Pd(II)
catalyst in the vicinity of the target C–H bond, thereby providing high
effective concentration (III in Fig. 1a). The latter ‘catch and release’
scenario would obviate the need to assemble a cyclophane-like pre-
transition state all together. Although weak coordination is not as
effective as strong coordination in terms of compensating for the
entropic cost during the assembly of the pre-transition state, the
Pd(OPiv)2
Ag(OPiv)
p
O
CO2Et
R2
R2
+
R2
R2
o
DCE, 90 °C
18 h
H
m
C
H
N
C
N
H
CO2Et
3–10
11a
12–19
Entry Substrate
R1
R2
Yield (%)
(mono)
Yield
Selectivity
(%) (di) (meta:para:ortho)
1
2
3
4
5
6
7
8
9
3
3
3
4
5
6
7
8a
9
10
tert-butyl
tert-butyl
tert-butyl
tert-butyl
tert-butyl
tert-butyl
tert-butyl
tert-butyl
H
H
H
H
Trace
4
0
0
0
—
56:26:18
59:33:8
91:7:2
93:6:1
88:7:5
91:5:4
95:4:1
—
15
60
52
50
51
63
—
Methyl
Ethyl
17
16
11
15
20
—
10
–(CH2)4–
–(CH2)5–
Isobutyl
Isobutyl
Isobutyl
10
Methyl
39
91:8:1
The reaction scheme is shown above the table. Unless otherwise noted, the reaction conditions were as
follows: benzyl ethers 3–10 (0.05 mmol), olefin 11a (1.5 equiv.), Pd(pivalate)2 (10 mol%), Ag-pivalate
(2.1 equiv.), 1,2-dichloroethane (0.5 ml), 90 uC, 18 h. The isolated yield was obtained by silica gel
column chromatography. The ratio of meta:para:ortho mono-olefinated products was determined by 1H
NMR analysis of the unpurified reaction mixture; the variance is estimated to be within 5%. For entry 1,
O
2 was used as the oxidant instead of Ag-pivalate. For entry 2, Pd(OAc)2 and AgOAc were used instead of
Pd(OPiv)2 and AgOPiv respectively and NMR yield was determined by using o-xylene as an internal
standard. For entry 9, C–H olefination occurred on both the arene substrate and template with a
combined yield of approximately 20% yield.
mixture of mono- and di-olefinated products 17amono and 17adi in
83% combined yield (entry 8). The mono- and di-olefinated products
can be readily separated by chromatography. Importantly, the meta-
selectivity was found to be 95%. We also confirmed through control
experiments that the presence of the bulky tert-butyl blocking groups
on the template was essential for reactivity (entries 9, 10). Replacement
nitrile-bound Pd(II) centre is more reactive because it is highly elec- of the nitrile by a methyl group also resulted in complete loss of
trophilic, which is beneficial for C–H activation. We also anticipated reactivity and selectivity (see Supplementary Information).
that the linear coordination mode of the nitrile group would be more
likely to anchor the palladium to the meta position rather than the
ortho position. In this putative structure, the interaction with the
ortho-C–H bond would incur high levels of cyclophane ring strain
caused by the linear geometry of the nitrile group. Encouragingly,
Schwarz’s pioneering studies showed that this mode of end-on coor-
dination of alkyl nitriles with Fe(II) in the gas phase can guide the
metal to perform remote C–H activation15.
With thisnewly established meta-selective C–Holefinationprocedure
in hand, we carried out olefination on a variety of substituted arenes
(Fig. 2). Meta-substituted arenes were olefinated at the remaining meta
position with excellent selectivity regardless of the electronic properties
of the substituents (17b–g). With ortho-substituted arene substrates,
high meta-selectivity was also achieved with both an electron-donating
methyl group and electron-withdrawing fluoro and bromo groups
(17h–j). Notably, in the absence of the template, the para- and meta-
To put this hypothesis into practice, we engineered a nitrile- C–H bonds of these 1,2-substituted arene substrates are often difficult
containing template in which the substrate was attached through a todistinguish, yet the templatedirectedmeta-C–Hactivation with high
removable benzyl ether linkage (IV in Fig. 1a). At the outset, we selectivity. For example, meta-selective olefination places the newly
hypothesized that the flat arene would help to keep the substrate installed functional group at the position para to the bromo group,
moiety and nitrile group as coplanar as possible. Given that the plane which is synthetically enabling owing to the diverse reactivities of the
in which the arene template lies could be spatially divided into four bromo group (17j). Despite the steric hindrance, para-substituted
distinct quadrants (see IV in Fig. 1a), we further hypothesized that arenes are also olefinated at the meta-position in excellent selectivity
sterically bulky tert-butyl groups at the ortho positions of the arene (17k–n). In sharp contrast to previously reported meta-selective C–H
template could serve as blocking groups to ensure that the pendant functionalization reactions21, the template also effectively overrides the
substrate and the nitrile group were kept in the same quadrant to electronic effect of bromide or ester groups at the para position, afford-
achieve high effective concentration of the Pd(II) catalyst. In our first ing predominantly the meta-olefinated products (17m, 17n).
design, we used a nitrile-containing phenol as the template, which Intriguingly, the template can guide the catalyst to reach and activate
could easily be attached to benzyl bromide to give benzyl ether 3 as the meta-C–H bond in a selective manner in the presence of
the model substrate for testing meta-selective C–H activation ortho,ortho-di-fluoro substitution (17o). Meta-C–H functionalization
(Table 1).
of ortho,ortho-disubstituted arenes provides a powerful disconnection
for constructing 1,2,3,4-tetrasubstituted arenes. Finally, meta-C–H
olefination of naphthalene 8p also proceeded to give 17p in 79% yield.
We next extensively surveyed the scope of the olefin coupling
Using olefination of 3 as the model reaction28,29, we extensively
screened catalysts, oxidants and solvents (see Supplementary Informa-
tion) and found that a combination of Pd(OPiv)2 as the catalyst and
AgOPiv as the oxidant gave a 15% yield with encouraging levels of partners. Olefination with commonly used electron-deficient a,b-
meta-selectivity (m:p:o 5 59:33:8) (Table 1, entries 1–3). To improve unsaturated esters, ketones and phosphonates gave desired products
the reactivity further via the Thorpe–Ingold effect, we installed two in good yields (17b2–b5). Given that the lack of reactivity with disub-
alkyl groups at the a-position adjacent to the nitrile group. Both the stituted olefins in directed C–H olefination reactions is a significant
yield and the meta-selectivity steadily improved with increasing size of drawback28,29, we tested a series of di- or tri-substituted olefins. We
the alkyl groups (entries 4–8). The isobutyl-substituted template gave a were pleased to find that olefination with all of these olefins proceeded
2 8 J U N E 2 0 1 2
| V O L 4 8 6 | N A T U R E | 5 1 9
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RESEARCH LETTER
a
Pd(OPiv)2 (10 mol.%)
AgOPiv (3.0 equiv.)
T1
NC
O
T1
X
R′
X
t-Bu
i-Bu
T1
=
+
i-Bu
DCE, 90 °C
30–48 h
R
R′
H
1.1–2.0 equiv.
t-Bu
R
8a–p
11a–n
17a–p
o′
o′
o′
o′
o′
Me
F
Cl
Br
bm′
NC
T1
T1
T1
T1
T1
T1
o
o
o
o
o
o
p
p
p
p
p
p
m
m
m
m
m
m
CO2Et
CO2Et
17b1, 86%
CO2Et
CO2Et
17d, 75%
CO2Et
17e, 63%
CO2Et
17f, 54%
17amono, 55%
17c, 52%
m:p:(o+o′)= 75:18:7
m:(p+o+o′) = 97:3
m:(p+o+o′) = 93:7
m:(p+o+o′) = 98:2
m:p:o = 93:5:2
17adi, 31%
m:(p+o+o′)= 94:6
(m,m′):others= 88:12
Br
Me
F
o′
F3C
m′
m′
T1
T1
T1
T1
T1
m′
T1
m′
m′
o
p
o
o
o
o
o
p
p
p
Me
F
m
m
m
m
m
m
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
17g, 54%
m:(p+o+o′) = 98:2
17h, 89%
m:(p+o+m′) = 91:9
17imono, 70%
m:(p+o+m′) =98:2
17idi, 18%
17j, 77%
m:(p+o+m′) =90:10
17kmono, 54%
m:o = 96:4
17kdi, 26%
17lmono, 45%
m:o = 95:5
17ldi, 44%
(m,m′):others = 88:12
(m,m′):others = 90:10
(m,m′):others = 89:11
F
o′
o′
Me
Me
m′
m′
m′
T1
T1
T1
T1
T1
T1
p
o
o
o
o
p
t-BuO2C
p
o
p
Br
F
m
m
m
m
m
m
CO2Et
CO2Et
CO2Et
CO2Et
CO2Bn
CO2t-Bu
17mmono, 39%
m:o = 97:3
17mdi, 13%
17nmono, 42%
m:o = 92:8
17ndi, 8%
17omono, 55%
m:p = 98:2
17odi, 29%
17p, 79%
m:(p+o) = 96:4
17b2, 73%
m:(p+o+o′) = 92:8
17b3, 88%
m:(p+o+o′) = 93:7
(m,m′):others = 93:7
(m,m′):others = 82:18
(m,m′):(m,p) = 96:4
o′
o′
o′
o′
Me
o′
o′
Me
T1
T1
Me
Me
Me
Me
T1
T1
T1
T1
o
p
p
o
o
o
o
p
p
o
p
p
m
m
m
m
m
m
N-phthaloyl
Me
CO2Me
Et
CO2Me
Ph
CO2Me
(EtO)2
P
O
CO2Et
O
Et
17b4, 54%
m:(p+o+o′) = 91:9
17b5, 74% (E:Z = 55:1)
m:(p+o+o′) = 93:7
17b6, 67% (E:Z = 1:9)
m:(p+o+o′) = 94:6
17b7, 70% (E:Z = 23:1) 17b8, 81% (E:Z = 26:1) 17b9, 63% (E:Z = 49:1)
m:(p+o+o′) = 100:0
m:(p+o+o′) = 100:0
m:(p+o+o′) = 98:2
o′
o′
o′
Me
o′
Me
Me
T1
T1
Me
T1
o′
T1
Me
T1
o
p
o
o
p
p
o
p
O
m
m
m
o
p
m
MeO2C
m
CO2Et
CO2Et
MeO2C
Me
MeO2C
CO2Me
17b10, 80% (E:Z = 21:1)
m:(p+o+o′) = 100:0
17b11, 98% (E:Z = 1:75)
m:(p+o+o′) = 100:0
17b12, 79%
m:(p+o+o′) = 95:5
17b13, 46%
m:(p+o+o′) = 96:4
17b14, 61%
m:(p+o+o′) = 95:5
Figure 2
|
Template-directed meta-selective C–H olefination of toluene
applicable) is shown along with the selectivity. See Supplementary Information
for experimental details. Selectivity of the mono- and di-olefinated products
derivatives. a, Arenes (8a–p) with a variety of substitution patterns undergo
facile olefination. b, In the box, many election-deficient olefins and various di- was determined by 1H NMR analysis and confirmed by one-dimensional
and tri-substituted olefins were used. The isolated yield of the mono-olefinated selective NOESY experiments; the variance is estimated to be within 5%. OPiv,
product (and also the isolated yield of the di-olefinated product when
pivalate.
stereoselectively30 to give the trisubstituted olefins (17b6–b14) in in 49% yield along with 11% para- and 2% ortho-olefinated products,
moderate to excellent yields. For example, olefination products as determined by 1H nuclear magnetic resonance (NMR) analysis. To
17b10 and 17b11 were formed when diethyl maleate and diethyl further improve the reactivity, we turned to mono-N-protected
fumarate were used respectively. Unlike in conventional directed amino acid ligands, which were recently found to accelerate C–H
ortho-C–H olefination reactions where the coordinated directing olefination reactions29. We found through extensive ligand screening
group could prevent sterically hindered olefins from binding28,29, in that N-acetyl-protected glycine was most effective in promoting the
this case the nitrile group on the template is weakly coordinated to the olefination reaction, allowing for full conversion to be achieved (see
[Pd(II)–Ar] intermediate and can be effectively displaced by disubsti- Supplementary Information). The meta-selectivity of the mono-
tuted olefins, allowing carbopalladation to proceed. Lastly, we found olefinated product 21amono was also enhanced from 79% to 95%
that the template could be readily removed through a Pd/C-mediated (Fig. 3). Notably, highly meta-selective C–H functionalization of elec-
hydrogenolysis to afford meta-alkylated toluenes in excellent yields tronically unbiased monosubstituted arenes has not been reported so
(see Supplementary Information).
far19–27. Control experiments showed that replacement of the nitrile
group on the template with a trifluoromethyl group resulted in poor
reactivity and selectivity giving a m:p:o 1:1:2 mixture of mono-
olefinated products in 38% yield under the optimized conditions.
The efficiency of this template was first demonstrated by the excellent
Having demonstrated the concept of using a nitrile-containing
end-on template to activate meta-C–H bonds that are ten bonds away
from the chelating atom, we tested whether this approach would be
generally applicable toother broadlyuseful substrates, after appropriate
tuning of the template. Therefore, we used a readily cleavable amide observedreactivitywiththeelectron-deficientmeta-trifluoromethylarene
linkage to attach a benzonitrile template to hydrocinnamic acid to form 20b. To showcase the power of the template in controlling the meta-
20a. Using the established olefination protocol from above (Fig. 2), we selectivity,meta-methoxyandortho-trifluoromethylgroupswereintro-
screened various reaction parameters with substrate 20a and observed duced onto the aromatic rings (20c and 20d respectively), two func-
significant solvent effects, presumably owing to the dramatic influence tional groups known to exert strong electronic effects on traditional
of the solvent medium on the assembly of the pre-transition state via electrophilic aromatic substitution reactions. Remarkably, excellent
weak coordination (see Supplementary Information). Olefination of meta-selectivity was maintained in the olefination of both meta-
20a in hexafluoroisopropanol gave meta-olefinated product 21amono methoxyarene 20c and ortho-trifluoromethylarene 20d to give 21c
5 2 0
| N A T U R E | V O L 4 8 6 | 2 8 J U N E 2 0 1 2
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LETTER RESEARCH
C–H activation overrides ortho-directing effects as well as electronic
and steric biases on the appended arene substrates. The template
design is predicated on the weak interaction between Pd(II) and a
nitrile group, where the nitrile group coordinates in an end-on fashion
and can overcome the difficulties associated with assembling a cyclo-
phane-like pre-transition state. This new strategy for directing remote
C–H activation provides a novel route for the preparation of toluene
derivatives, hydrocinnamic acids, 2-biphenylcarboxylic acids, unnat-
ural amino acids, and drug molecules with sophisticated substitution
patterns that are difficult to access using conventional C–H activation
methods. We expect that this end-on nitrile-based template can be
structurally modified to suit other classes of synthetically useful arene
substrates.
T2
a
T2
+
NC
OMe
OMe
NC
Pd(OAc)2 (10 mol.%)
N-acetyl glycine (20 mol.%)
CO2Et
O
O
H
T2
=
N
N
T3
=
X
X
AgOAc (3.0 equiv.)
HFIP, 90 °C
24 h
2.0 equiv.
CO2Et
NC
NC
20a–h
11a
21a–h
b
T2
T2
T3
T2
F3C
m′
O
O
O
O
o
o
o
o
o′
o′
m
m
m
m′
m
CO2Et
F3C
CO2Et MeO
CO2Et
CO2Et
p
p
p
p
21amono, 37%
m:p:o = 95:3:2
21adi, 42%
21b, 82%
m:(p+o+o′) = 95:5
21c, 67%
m:(p+o+o′) = 86:14
21d, 87%
m:(p+o+m′) = 96:4
(m,m′):others = 88:12
Electronic biases overridden
m
c
O
T2
o
p
N-phthaloyl
N-phthaloyl
T2
T2
T2
m′
o1′
(S)
METHODS SUMMARY
Me
m′
Me
1O
O
O
o
o
o
m
General procedure for template-directed meta-selective C–H olefination
of toluene derivatives. A 15-ml sealed tube (with a Teflon cap) equipped
with a magnetic stir bar was charged with substrate (46.1 mg, 0.10 mmol),
Pd(OPiv)2 (3.0 mg, 0.010 mmol, 0.10 equiv.), and AgOPiv (62.7 mg, 0.30 mmol,
3.0 equiv.). Ethyl acrylate (16.5 ml, 0.15 mmol, 1.5equiv.) was added, followed by
1,2-dichloroethane (1.0 ml). The tube was then capped and submerged into a pre-
heated 90 uC oil bath. The reaction was stirred for a total of 42 h and cooled to
room temperature. The crude reaction mixture was filtered through a pad of Celite
and washed with Et2O (2 ml3 3). The filtrate was concentrated in vacuo, and the
resulting residue was purified by column or preparative thin layer chromato-
graphy using hexanes/EtOAc as the eluent. The positional selectivity was deter-
mined by 1H NMR of the unpurified reaction mixture. Full experimental details
and characterization of new compounds can be found in the Supplementary
Information.
m1
m1′
m
m′
m
m′
CO2Et
CO2Et
CO2Et
CO2Et
p
p1
p
Cl
21emono, 49%
m:p = 91:9
21edi, 22%
21fmono, 45%
21gmono, 40% (98% e.e.)
m:(p+o) = 95:5
21gdi, 44%
(m,m′):others = 95:5
21hmono, 40%
m:o = 93:7
21hdi, 42%
(m,m′):others = 90:10
m1:others = 95:5
21fdi, 48%
(m,m′):(m,p) = 94:6
(m1,m1′):others = 95:5
Tetrasubstituted
arene
Novel
biphenyl
Amino acid
modification
Baclofen
diversification
d
NC
HN
NC
NC
CO2H
LiOH
MeOH/THF/H2O
N
+
O
NC
Room temperature, 18 h
CO2H
CO2Et
21amono
23, 65% recovered
22, 95%
Received 13 February; accepted 20 April 2012.
Figure 3
|
Template-directed meta-selective C–H olefination of
1. Hartung, C. G. & Snieckus, V. in Modern Arene Chemistry (ed. Astruc, D.) 330–367
(Wiley, 2004).
2. Flemming, J. P., Berry, M. B. & Brown, J. M. Sequential ortho-lithiations; the
sulfoxide group as a relay to enable meta-substitution. Org. Biomol. Chem. 6,
1215–1221 (2008).
3. Ryabov, A. D. Cyclopalladated complexes in organic synthesis. Synthesis 233–252
(1985).
4. 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).
5. Jun, C.-H., Hong, J.-B. & Lee, D.-Y. Chelation-assisted hydroacylation. Synlett 1–12
(1999).
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. Daugulis, O., Do, H.-Q. & Shabashov, D. Palladium- and copper-catalyzed arylation
of carbon–hydrogen bonds. Acc. Chem. Res. 42, 1074–1086 (2009).
8. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H
functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).
9. Engle, K. M., Mei, T.-S., Wasa, M. & Yu, J.-Q. Weak coordination as a powerful means
for developing broadly useful C–H functionalization reactions. Acc. Chem. Res.,
(2011).
10. Satoh, T. & Miura, M. Oxidative coupling of aromatic substrates with alkynes and
alkenes under rhodium catalysis. Chem. Eur. J. 16, 11212–11222 (2010).
11. Guimond, N., Gorelsky, S. I. & Fagnou, K. Rhodium(III)-catalyzed heterocycle
synthesis using an internal oxidant: improved reactivity and mechanistic studies.
J. Am. Chem. Soc. 133, 6449–6457 (2011).
12. Rakshit, S., Grohmann, C., Besset, T. & Glorius, F. Rh(III)-catalyzed directed C–H
olefination using an oxidizing directing group: mild, efficient, and versatile. J. Am.
Chem. Soc. 133, 2350–2353 (2011).
13. Park, S. H., Kim, J. Y. & Chang, S. Rhodium-catalyzed selective olefination of arene
esters via C–H bond activation. Org. Lett. 13, 2372–2375 (2011).
14. Ackermann, L. & Pospech, J. Ruthenium-catalyzed oxidative C–H bond
alkenylations in water: expedient synthesis of annulated lactones. Org. Lett. 13,
4153–4155 (2011).
hydrocinnamic acid derivatives. a, Four representative hydrocinnamic acids
(20a–d). b, Challenging substrates and synthetic applications. c, Removal of
template under mild hydrolysis conditions. S denotes the absolute
configuration of thechiralcentre; e.e., enantiomericexcess. The isolated yield of
the mono-olefinated product (and also the isolated yield of the di-olefinated
product when applicable) is shown along with the selectivity. Selectivity of the
mono- and di-olefinated products was determined by 1H NMR analysis and
confirmed by one-dimensional selective NOESY experiments; the variance is
estimated to be within 5%. See Supplementary Information for experimental
details. HFIP, hexafluoroisopropanol. Room temperature was 24 uC.
and 21d respectively, suggesting that the template effectively overrides
the electronic effects of both electron-donating and -withdrawing
groups. To further demonstrate the potential synthetic applications
of this method, we first constructed a sterically encumbered tetrasub-
stituted arene 21e via meta-selective olefination of the ortho,ortho-di-
methylarene 20e, in which case the steric hindrance was overcome by
the template. Intriguingly, meta-selective C–H olefination of biphenyl
substrate (20f) also proceeded at the remote aryl ring to afford syn-
thetically useful biphenyl 21f with unprecedented site-selectivity.
Importantly, the unnatural chiral amino acid 21g was also prepared
via meta-selective olefination of N-phthaloyl-protected phenylalanine
20g without racemization. Both 2-biphenylcarboxylic acid (20f) and
phenylalanine (20g)arekeystructuralmotifsindrugmoleculessuchas
Micardis and Velcade. Finally, N-phthaloyl-protected Baclofen (20h)
was selectively olefinated at the meta-position to give 21h in 82% yield,
providing access to a novel library of molecules of medicinal interest.
The reactivity and selectivity patterns observed with 20a–h have not
15. Schwarz, H. Remote functionalization of C–H and C–C bonds by naked transition-
metal ions (cosi fan tutte). Acc. Chem. Res. 22, 282–287 (1989).
been reported in previous studies towards meta-selective C–H activa- 16. Breslow, R. Biomimetic control of chemical selectivity. Acc. Chem. Res. 13,
tion19–21. To establish scalability, the reaction of 20d was also run at the
0.5 g (1.2 mmol) scale to give 21d in 77% yield. The removal of the
170–177 (1980).
17. Das, S., Incarvito, C. D., Crabtree, R. H. & Brudvig, G. W. Molecular recognition in the
selective oxygenation of saturated C–H bonds by a dimanganese catalyst. Science
template in 21amono was readily accomplished by hydrolysis at room
temperatureusingLiOH asa basetogivediacid22in95%yield(Fig. 3).
In summary, we have developed a template approach to activate
remote meta-C–H bonds of two categorically distinct classes of sub-
strates with high meta-selectivity. Template-assisted meta-selective
312, 1941–1943 (2006).
18. Li, J.-J., Giri, R. & Yu, J.-Q. Remote C–H bond functionalization reveals the distance-
dependent isotope effect. Tetrahedron 64, 6979–6987 (2008).
19. 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).
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RESEARCH LETTER
20. Ishiyama, T. et al. Mild iridium-catalyzed borylation of arenes. High turnover
numbers, room temperature reactions, and isolation of a potential intermediate.
J. Am. Chem. Soc. 124, 390–391 (2002).
29. Wang, D.-H., Engle, K. M., Shi, B.-F. & Yu, J.-Q. Ligand-enabled reactivity and
selectivity in a synthetically versatile aryl C–H olefination. Science 327, 315–319
(2010).
21. 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).
30. Gu¨rtler, C. & Buchwald, S. L. A phosphane-free catalyst system for the Heck
arylation of disubstituted alkenes: application to the synthesis of trisubstituted
olefins. Chem. Eur. J. 5, 3107–3112 (1999).
22. Wang, X., Leow, D. & Yu, J.-Q. Pd(II)-catalyzed para-selective C–H arylation of
monosubstituted arenes. J. Am. Chem. Soc. 133, 13864–13867 (2011).
23. Ueda, K., Yanagisawa, S., Yamaguchi, J. & Itami, K. A general catalyst for the
b-selective C–H bond arylation of thiophenes with iodoarenes. Angew. Chem. Int.
Edn 49, 8946–8949 (2010).
24. Ye, M., Gao, G.-L. & Yu, J.-Q. Ligand-promoted C-3 selective C–H olefination of
pyridines with Pd catalysts. J. Am. Chem. Soc. 133, 6964–6967 (2011).
25. Saidi, O. et al. Ruthenium-catalyzed meta-sulfonation of 2-phenylpyridines. J. Am.
Chem. Soc. 133, 19298–19301 (2011).
26. Phipps, R. J. & Gaunt, M. J. A meta-selective copper-catalyzed C–H bond arylation.
Science 323, 1593–1597 (2009).
27. Duong, H. A., Gilligan, R. E., Cooke, M. L., Phipps, R. J. & Gaunt, M. J. Copper(II)-
catalyzed meta-selective direct arylation of a-aryl carbonyl compounds. Angew.
Chem. Int. Edn 50, 463–466 (2011).
Supplementary Information is linked to the online version of the paper at
www.nature.com/nature.
Acknowledgements We thank The Scripps Research Institute and the NIH (NIGMS, 1
R01 GM084019-03) for their financial support. We also thank the Agency for Science,
Technology and Research (A*STAR) in Singapore for a postdoctoral fellowship (to D.L.).
Author Contributions D.L., G.L. and T.-S.M. performed the experiments and analysed
the data. D.L., G.L. and J.-Q.Y. designed the templates and developed the reactions.
J.-Q.Y. conceived this concept and prepared this manuscript with feedback from D.L.
and G.L.
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 this article at
www.nature.com/nature. Correspondence and requests for materials should be
addressed to J.-Q.Y. (yu200@scripps.edu).
28. Boele, M. D. K. et al. Selective Pd-catalyzed oxidative coupling of anilides with
olefins through C2H bond activation at room temperature. J. Am. Chem. Soc. 124,
1586–1587 (2002).
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