Pd-Catalyzed Remote Meta-C-H Functionalization of Phenylacetic Acids Using a Pyridine Template

Article abstract of DOI:10.1021/acs.orglett.7b03336

An effective pyridine based U-shaped template has been developed to enable a diverse range of meta-C-H functionalizations of phenylacetic acid scaffolds. This new template has extended the reaction scope to cross-coupling with ArBF₃K as well as iodination using 1,3-diiodo-5,5-dimethylhydantoin as the iodination reagent.

Full text of DOI:10.1021/acs.orglett.7b03336

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Remote Meta-C−H Functionalization of Phenylacetic
Acids Using a Pyridine Template
Zhong Jin,† Ling Chu,† Yan-Qiao Chen, 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
ABSTRACT: An effective pyridine based U-shaped template has
been developed to enable a diverse range of meta-C−H functionaliza-
tions of phenylacetic acid scaffolds. This new template has extended
the reaction scope to cross-coupling with ArBF3K as well as iodination
using 1,3-diiodo-5,5-dimethylhydantoin as the iodination reagent.
lthough cyclometalation to generate rigid five- or six-
membered palladacycle intermediates has been extensively
To overcome these limitations, we have recently developed a
novel pyridine-based template for the meta-C−H activation of
benzyl alcohols and phenyl ethyl alcohols based on the
following rationale: the strongly coordinating pyridyl group is
beneficial for recruiting metal catalysts in the presence of other
coordinating functional groups; on the other hand, the large
ring size as well as the cyclophane structure of the
cyclopalladacycle affords these intermediates with lower
stability and hence high reactivity.9 This new template enabled
the development of the first example of meta-C−H iodination,
thereby demonstrating the utility of this pyridine-based
template. Considering the prevalence of the phenylacetic acid
scaffold in synthetic intermediates and drug molecules, we have
launched extensive efforts to develop both ortho- and meta-C−
H functionalization reactions of these substrates. However, only
meta-C−H olefination of phenyl acetic acids has been achieved
to date.5e,g Herein, we report a new pyridine-based template
that enables meta-C−H olefination, cross-coupling, and
iodination of phenylacetic acids, thus providing highly versatile
methods for rapid diversification of phenylacetic acid scaffolds
that are of importance in drug discovery. These results
demonstrate that pyridyl groups can be engineered to direct
remote C−H activation by tuning the distance and geometry.
The well-defined coordination of the pyridyl group also
provides valuable insights into the geometry of the
pretransition state required for meta-C−H activation.
A
exploited to achieve ortho-selectivity in a wide range of C−H
activation reactions, meta-selective C−H activation through
directed metal insertion remains highly limited. Such a
challenge escalates when the directing functional groups are
further away from the arenes.1 One potential advantage of
directed meta-C−H activation over other nondirected meta-C−
H activation2 lies in its ability to override the innate steric or
electronic bias of arenes. While a number of relay strategies
have been established to direct meta-selective C−H activa-
tion,3,4 we have also initiated efforts to develop directed metal
insertion into the meta-C−H bond using a U-shaped nitrile-
directing template (Figure 1).1,5 Importantly, by recognition of
Figure 1. Meta-C−H functionalization using a U-shaped template.
To overcome the limitations of the U-shaped nitrile-based
templates, we have recently developed a pyridine-based
template. Through engineering the distal and geometric
relationship between the 3-pyridyl group and the target C−H
bonds, meta-C−H activation of benzyl alcohols has been made
possible. Prompted by the broad synthetic utility of phenyl-
acetic acid scaffolds, we began our investigation by testing the
meta-C−H functionalizations of a variety of phenylacetic acid
derivatives containing a 3-subsituted pyridine-based templates
(Table S1). Under C−H olefination conditions, a mixture of
distance and geometry, meta-selectivity can be achieved
regardless of the substitution pattern or electronic nature of
the substrate. Notably, this approach is compatible with
substrates when the directing functional groups are 10 bonds
away from the arene. Recently, such a remote directing effect
has also been incorporated into catalyst design to achieve meta-
C−H6,7 or even remote C−H activation8 at other locations
without the installation of a non-native directing group.
However, in all of these cases, the substrate scope and the
number of transformations that could be achieved are limited
due to the relatively weak directing effect.
Received: December 3, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b03336
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Organic Letters
Letter
products was obtained with pyridine-based template 1. Careful
analysis showed that the C−H olefination reaction occurred
mainly on the aniline moiety. To prevent undesired competitive
C−H activation on the aniline ring, a methyl group was
introduced at the ortho-position of the aniline group in
substrate 2. However, this template failed to promote the
meta-C−H olefination. Incorporating an electron-withdrawing
fluoro group at the C-2 position of the pyridine ring (3)
provided C−H olefination products in 58% yield, albeit with
moderate meta-selectivity (meta/others = 7:1). Changing the
fluoro group to an electron-donating methoxy group (4) shuts
down the reaction. Satisfyingly, switching the 2-fluoro-5-pyridyl
group to a 2-fluoro-3-pyridyl group improved both yield and
meta-selectivity (5, 84% yield, meta/others >20:1). Introducing
a second fluoro group on the pyridine ring decreased both the
yield and regioselectivity (6, 46% yield, meta/others = 9:1).
Scheme 1. Scope of Phenylacetic Acids for Meta-C−H
a−c
Olefination
i
Notably, incorporation of two bulky Pr groups on the aniline
ring led to significantly improved yield and meta-selectivity (8a,
93% yield, meta/others >30:1). This improvement is
presumably attributed to the conformational restriction posed
by the bulky isopropyl group, which promotes a more rigid
transition state conformation.
With the optimal template in hand, a variety of phenylacetic
acids were covalently linked to the template and subjected to
the meta-C−H olefination reaction conditions (Scheme 1).
meta-C−H olefination of phenylacetic acid provided the meta-
olefinated products in an overall yield of 89% (16amono, 61%,
16adi, 28%) with high regioselectivity. Phenylacetic acids
bearing methyl or methoxy substitutions at the 2- or 3-position
gave exclusively the mono meta-olefinated product in high
yields (16b−d). m-Chloro-substituted phenylacetic acidic
provided moderate yield and regioselectivity (16e). Para-
substitutions were well tolerated, affording both the mono- and
di-products in moderate to good isolated yields regardless of its
electronic properties (16f−i). For 1-naphthalenylacetic acid
16j, olefination occurred at both the 3- and 7-position,
affording the mono- and di-products 16j3‑mono, 16j7‑mono, and
16j3,7‑di in isolated yields of 35%, 21%, and 32%, respectively. In
contrast, olefination of 2-naphthalenylacetic acid 8k gave
exclusively 4,8-diolefinated product (16k). Furthermore,
olefination of α-substituted phenylacetic acids afforded
excellent yields and regioselectivities (16l−o). More impor-
tantly, this protocol is also compatible with cyclic and
heterocyclic substrates, thus opening new avenues for its
potential utility in C−H functionalization of advanced
intermediates and late-stage modifications (16p−s). The
scope of the olefin partners was also examined using substrate
8c. α,β-Unsaturated olefins containing various functional
groups such as sulfone (16c1), phosphonate (16c2), and
aldehyde (16c5) are all well tolerated, providing the desired
products in good yields. Reaction with di-substituted olefin
16c3 afforded the corresponding product with moderate to
good yields. Notably, this reaction is also compatible with cyclic
α,β-unsaturated olefins, providing the nonconjugated products
in good yields (16c4, 16c5). Excellent meta-selectivities were
obtained in all cases (meta/others >20:1).
a
Reaction conditions: substrate 8 (0.1 mmol), Pd(OAc)2 (0.1 mmol),
ethyl acrylate (0.3 mmol), AgOAc (0.3 mmol), HFIP (1.0 mL), air, 80
°C, 24 h. Isolated yield. Meta-regioselectivity based on analysis of
crude H NMR spectra. 16c3 was isolated as a Z/E mixture (Z/E =
b
c
d
1
1
1:9) based on analysis of H NMR.
methoxycarbonyl phenylboronic acid pinacol ester as the
coupling partner (Table S2). Template 8a was identified as
the optimal template, giving the meta-arylated product in 30%
overall yield with >20:1 meta-selectivity. The use of potassium
trifluoroborate improved the yield to 46% (Table S3). Reaction
optimization revealed that silver carbonate was the best oxidant
(Table S4). A combination of cesium fluoride and potassium
trifluoroacete could improve the overall yield to 50%.
Tetrabutylammonium (TBA) salts have been shown to
To demonstrate the versatility of this new pyridine-based
template, we next developed a new protocol for meta-C−H
cross-coupling of phenylacetic acids. Notably, the previous
nitrile-based template is not compatible with the meta-C−H
coupling of phenylacetic acid derivatives. We began by
evaluating different pyridine-based templates with our
previously established cross-coupling conditions using 4-
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DOI: 10.1021/acs.orglett.7b03336
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Organic Letters
Letter
improve C−H cross-coupling reactions dramatically.10,5a
Evaluation of different TBA salts showed that the addition of
tetrabutylammonium tetrafluoroborate improved the yield to
57% with (entry 12, Table S4). Addition of catalytic amounts of
sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate further
improved the yield to 75% (entry 17, Table S4). The overall
yield was improved to 81% when the temperature was lowered
to 80 °C (entry 18, Table S4).
arylboron coupling partners was then investigated. Electron-
deficient arylborons containing ketone, aldehyde, trifluoro, and
fluoro groups were all tolerated (17q1−q4). Excellent meta-
selectivity was observed in all cases.
Aryl iodides are versatile intermediates in organic synthesis.
Using a recently developed protocol,9a meta-iodination of
phenylacetic acid derivatives could be achieved with high yields
and regioselectivity. Both electron-donating (Scheme 3, 18b,e)
The substrate scope of this meta-C−H cross-coupling
protocol was subsequently investigated (Scheme 2). Phenyl-
Scheme 3. Scope of Phenylacetic Acids for Meta-C−H
a,b
Iodination
Scheme 2. Scope of Phenylacetic Acids for Meta-C−H
a,b
Arylation
a
Reaction conditions: substrate 8 (0.1 mmol), 1,3-diiodo-5,5-
dimethylhydantoin (0.1 mmol), Pd(OAc)2 (0.01 mmol), AgOAc
(0.05 mmol), TFA-Gly-OH (0.02 mmol), HOAc (0.2 mL), HFIP (0.8
b
mL), air, 80 °C, 24 h. Isolated yield.
and electron-withdrawing substitutions (18c,d,f,g) were
tolerated to give moderate to good yields and high
regioselectivity. Finally, the directing template could be
removed with high yield using a previously reported
procedure.11
In summary, we have developed a new class of pyridine-
based template for the meta-C−H activation of phenylacetic
acids, demonstrating that a commonly used ortho-directing
group can be engineered to activate remote C−H bonds by
tuning the distance and geometry.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03336.
a
Reaction conditions: substrate 8 (0.1 mmol), ArBF3K (0.3 mmol),
Pd(OAc)2 (0.01 mmol), Ag2CO3 (0.2 mmol), CsF (0.2 mmol), KTFA
(0.2 mmol), Bu4NBF4 (0.05 mmol), NaB(3,5-CF3Ph)4 (0.02 mmol),
b
Experimental procedures and NMR spectra (PDF)
HFIP (2 mL), air, 80 °C, 24 h. Isolated yield.
AUTHOR INFORMATION
■
acetic acid derivatives containing electron-donating and
electron-withdrawing substitutions were all tolerated to give
moderate to good yields (17a−f). Disubstituted phenylacetic
acids afforded the corresponding arylation products in
moderate yield (17g,h). α-Substituted phenylacetic acids were
also compatible in this reaction (17i−l), providing the desired
products in moderate to good yields. The versatility of this
protocol was further validated by meta-C−H cross-coupling of
cyclic and heterocyclic substrates (17m−p). The scope of the
Corresponding Author
*E-mail: yu200@scripps.edu.
ORCID
Zhong Jin: 0000-0001-5722-7175
Jin-Quan Yu: 0000-0003-3560-5774
Author Contributions
†Z.J. and L.C. contributed equally.
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Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Science Foundation
(CHE-1465292) and the Scripps Research Institute for
financial support. Z.J. is a visiting scholar from Nankai
University and sponsored by the China Scholarship Council
(No. 201406205013). We thank Marcus E. Farmer (The
Scripps Research Institute) for helpful suggestions with the
manuscript.
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