Cross-coupling of remote meta -c-h bonds directed by a u-shaped template

Article abstract of DOI:10.1021/ja410760f

meta-C-H arylation and methylation of 3-phenylpropanoic acid and phenolic derivatives were developed using an easily removable nitrile template. The combination of a weakly coordinating U-shaped template and mono-protected amino acid ligand was crucial fo

Full text of DOI:10.1021/ja410760f

Communication
pubs.acs.org/JACS
Cross-Coupling of Remote meta-C−H Bonds Directed by a U‑Shaped
Template
Li Wan, Navid Dastbaravardeh, Gang Li, and Jin-Quan Yu*
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
Scheme 1. meta-C−H Functionalization Using Nitrile
Template
ABSTRACT: meta-C−H arylation and methylation of 3-
phenylpropanoic acid and phenolic derivatives were
developed using an easily removable nitrile template.
The combination of a weakly coordinating U-shaped
template and mono-protected amino acid ligand was
crucial for the cross-coupling of C−H bonds with
organoborons.
ransition-metal-catalyzed functionalization of unactivated
TC−H bonds is a highly attractive strategy for the synthesis
of organic molecules, owing to the omnipresent nature of C−H
bonds in organic substances.1 Due to the subtle difference in
reactivity of multiple C−H bonds in a given molecule, however,
controlling the regioselectivity or positional selectivity remains
a central challenge in the field. In addition, when an intrinsically
less reactive C−H bond needs to be preferentially function-
alized to meet a synthetic task, a chemical approach must be
developed to override the intrinsic bias. In this context, σ-
chelation-directed C−H activation has been successful in
developing a wide range of C−H functionalization reactions.2
While these reactions are broadly useful, the tremendous
opportunity of activating C−H bonds that are relatively distal
to existing functional groups remains to be exploited. Notably,
functionalizations of C−H bonds with different distance from a
functional group will lead to distinct structural motifs.3 In our
efforts to seek solutions for this problem, we found that the
development of remote C−H functionalization reactions using
C−H palladation process suffers from the difficulty of forming
palladacycles larger than six-membered rings which has been a
major obstacle.4 More arduous still is the formation of
palladacycles consisting of strained ring systems, as is the case
with cyclophanes formed from directed palladation of meta- and
para-C−H bonds.5 Herein we report the first example of Pd-
catalyzed cross-coupling of meta-C−H bonds with arylboronic
acids (Scheme 1). The observed meta-selectivity was achieved
through directed C−H palladation via an U-shaped nitrile
template weakly coordinated to a Pd(II) catalyst.6,7 Addition-
ally, tuning the properties of the Pd(II) catalyst with a mono-
protected amino acid (MPAA) ligand was vital to successful
cross-coupling.
We have recently reported the first example of remote meta-
C−H olefination of hydrocinnamic acids using an end-on nitrile
template.6 This reaction provides important evidence for the
formation of 12-membered cyclophane-like palladacycles,
although Friedel−Crafts-type olefination catalyzed by Pd(II)
salts as Lewis acids cannot be ruled out. To further establish the
feasibility of remote C−H activation via large and strained
palladacycles, we embarked on the development of remote-
meta-C−H cross-coupling with aryl boronic acids which would
require the formation of discrete arylpalladium species.
Whether this highly strained cyclophane organopalladium
intermediates could accommodate transmetalation and reduc-
tive elimination steps remained to be tested. This reaction
would provide a novel C−H activation disconnection for the
synthesis of biaryls with different substitution patterns to those
prepared from ortho-C−H arylation reactions. Thus, we began
to develop remote-meta-C−H cross-coupling with aryl boronic
acids using our recently designed nitrile template.
Our exploratory experiments were guided by our previous
discovery that MPAA ligands promote C−H coupling with
organoborons.8 Through extensive screening of various
reaction parameters including bases, oxidants, and solvents,
we found that the combination of Pd(OAc)2/Ac-Gly-OH/
Ag2CO3/KHCO3 and arylboronic ester facilitated the arylation
of 1a containing template T2 to give the mono- and diarylated
products 2amono and 2adi in 36% and 17% yield, respectively
(Table 1, entry 1). In order to increase the yield, we started to
examine different additives. It has been shown that
tetrabutylammonium (TBA) salts can have a dramatic influence
on the catalytic performance of palladium in cross coupling
reactions.9 The enhanced reactivity can be attributed to the
ability of surfactants to prevent undesired agglomeration of
This coupling reaction affords synthetic chemists a novel C−
H activation disconnection for biaryl synthesis. The trans-
metalation process required for the coupling also provides
concrete evidence in support of a C−H palladation pathway
directed by remote weak coordination.
Received: October 21, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja410760f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
a b
Communication
,
Table 1. Screening of Additive and Base
Table 2. meta-Arylation of 3-Phenylpropanoic Acid and
ab
,
Phenolic Derivatives
yield (%)
entry
additive
base
mono
di
1
−
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
K2CO3
Cs2CO3
NaOAc
KOAc
36
11
0
17
2
2
TBAF· 3H2O
TBAC
3
0
4
TBAB
16
20
37
41
26
0
4
5
TBAOAc
TBABF4
TBAPF6
TBAPF6
TBAPF6
TBAPF6
TBAPF6
TBAPF6
TBAPF6
TBAPF6
8
6
16
21
14
0
7
8
9
10
11
12
13
24
25
42
43
48
12
11
17
31
CsOAc
CsF
c
14
CsF
35
(34)
d
d
(46)
a
Conditions: 1a (0.1 mmol), Ar-Bpin (0.3 mmol), Pd(OAc)2 (10 mol
%), Ac-Gly-OH (20 mol%), Ag2CO3 (0.2 mmol), additive (0.3 mmol),
b
base (0.2 mmol), HFIP (1 mL), 90 °C, 24 h. Yield was determined
c
by 1H NMR analysis using CH2Br2 as internal standard. 70 °C.
d
Isolated yield.
Pd(0) species to form unreactive palladium black. Furthermore,
the anionic counterion can play an important role in stabilizing
cationic palladium intermediates.10 The addition of TBAPF6
increased the total yield (2amono+di) from 53% to 62% (entry 7),
while TBA halides, such as fluoride (13%), chloride (0%), and
bromide (20%), inhibited the reaction (entries 2−4). Addi-
tionally, we tested different bases in our transformation
because, according to our experience, the nature of the base
can have a crucial impact on cross-coupling reactions. CsF
(entries 13 and 14), a mild base successfully employed in
different cross-coupling reactions,11 proved to be the most
effective compared to carbonates and acetates (entries 8−12),
which did not show a positive effect. It has been reported that
fluoride can play an important role in activating the boronic
acid ester, facilitating the transmetalation step.12 Notably, the
temperature could be decreased to 70 °C, affording 48% and
35% of 2amono and 2adi, respectively (entry 14). Next, we
investigated the scope of the reaction, testing different
substituted 3-phenylpropanoic acids (Table 2). We were
delighted to find that this reaction proved general for both
electron withdrawing (2b−2g) and electron-donating sub-
stituents (2h−2j). Substitution of the benzylic position with a
methyl group was also tolerated (2kmono+di). Interestingly,
[1,1′-biphenyl]-2-carboxylic acid was also smoothly arylated at
the remote-meta-position instead of the meta-position that is
closer to the template (2l). The meta-selectivities of this
reaction are in general excellent, although minor formation of
different isomers were observed with nonsubstituted or meta-
substituted substrates. As expected, only mono-meta-arylation
was observed in the case of ortho-substituted substrates (2b, 2f,
2h). With the exception of the ortho-fluorinated substrate (2d)
the remaining meta-position is sterically hindered, preventing
a
Conditions: substrate (0.1 mmol), Ar-Bpin (0.3 mmol), Pd(OAc)2
(10 mol%), Ac-Gly-OH (20 mol%), Ag2CO3 (0.2 mmol), TBAPF6
b
(0.3 mmol), CsF (0.2 mmol), HFIP (1 mL), 70 °C, 24 h. Isolated
yield. Mixture of meta-arylated isomers.
c
diarylation. In contrast to the meta-olefination reaction,6 the
reactivity of di-ortho-substituted (2m) substrates are poor
under these conditions.
We have previously employed the nitrile template T1 to
perform meta-C−H olefination reactions of phenols.6b We were
pleased to find that meta-arylation of phenol substrates attached
to T1 also proceeded to give the desired products in moderate
to good yields (2n−2r). Further optimizations of conditions
and template may lead to a novel route for preparing meta-
arylated phenols.
The scope of the arylboron coupling partners was also
surveyed (Table 3). We found that arylboronic acid esters
containing both electron-withdrawing (2t−2v) and donating
(2w, 2x) substituents afforded good yields. In light of the
B
dx.doi.org/10.1021/ja410760f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
remote weak coordination and signals future development of a
wide range of transformations based upon the template-assisted
remote C−H activation.
Table 3. meta-Arylation of 1h with Arylboronic Acid
Esters
a b
,
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge The Scripps Research Institute and
the National Institutes of Health (NIGMS 1 R01 GM102265-
01) for financial support. We thank China Scholarship Council
(fellowship to L. W., Nanjing University of Science and
Technology) and the Austrian Science Foundation (FWF,
postdoctoral fellowship to N.D., J 3424-N28).
a
Conditions: 1h (0.1 mmol), Ar-Bpin (0.3 mmol), Pd(OAc)2 (10 mol
%), Ac-Gly-OH (20 mol%), Ag2CO3 (0.2 mmol), TBAPF6 (0.3
b
mmol), CsF (0.2 mmol), HFIP (1 mL), 70 °C, 24 h. Isolated yield.
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C
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Journal of the American Chemical Society
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