Palladium-Catalyzed ?±-Arylation of Aryl Acetic Acid Derivatives via Dienolate Intermediates with Aryl Chlorides and Bromides

Article abstract of DOI:10.1021/ol503545j

To date, examples of ?±-arylation of carboxylic acids remain scarce. Using a deprotonative cross-coupling process (DCCP), a method for palladium-catalyzed ?3-arylation of aryl acetic acids with aryl halides has been developed. This protocol is applicable to a wide range of aryl bromides and chlorides. A procedure for the palladium-catalyzed ?±-arylation of styryl acetic acids is also described.

Full text of DOI:10.1021/ol503545j

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed α‑Arylation of Aryl Acetic Acid Derivatives via
Dienolate Intermediates with Aryl Chlorides and Bromides
Sheng-Chun Sha, Jiadi Zhang, and Patrick J. Walsh*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
*
S Supporting Information
ABSTRACT: To date, examples of α-arylation of carboxylic acids remain scarce. Using a deprotonative cross-coupling process
DCCP), a method for palladium-catalyzed γ-arylation of aryl acetic acids with aryl halides has been developed. This protocol is
(
applicable to a wide range of aryl bromides and chlorides. A procedure for the palladium-catalyzed α-arylation of styryl acetic
acids is also described.
ransition-metal-catalyzed α-arylation of enolates and their
both cases, the reaction required use of excess acetic acid (3.5 to
>50 equiv) and supra-stoichiometric silver acetate and gave poor
to moderate yields (18−68%).
T
derivatives is of great importance due to the diversity of
1
compounds that can be accessed. In 1997 pioneering studies on
palladium-catalyzed α-arylation of ketones with aryl bromides
In 2000, Wolfe and co-workers reported the reaction of phenyl
acetic acid dienolate with aryl bromides and iodides in liquid
ammonia under near-UV irradiation to afford alpha and para
2
3
was independently reported by the Miura, Buchwald, and
4
Hartwig groups. Since these seminal works, intensive studies on
α-arylation of carbonyl compounds have been reported. To
date, however, examples of α-arylation of simple carboxylic acids
5,6
10
arylation products via a proposed SRN1 process (Scheme 1B).
The inconvenient reaction conditions (NH3(l), hv) preclude
large-scale applications of this chemistry.
7
−9
remain scarce.
In 2007, Daugulis and co-workers studied the palladium-
catalyzed ortho arylation of benzoic acids. They reported a
byproduct derived from the α-arylation of acetic acid with 3,5-
During the preparation of this manuscript, Mori and co-
workers described α-arylation of carboxylic acids in a two-step
process (Scheme 1C). The substrates are first irreversibly
deprotonated using EtMgCl to generate dienolates followed by9
palladium-catalyzed α-arylation with aryl bromides and iodides.
Our approach to the α-arylation of carboxylic acids differs from
that of Mori and co-workers. We envisioned reversible
deprotonation of the substrate in the presence of the catalyst,
allowing the use of less reactive bases. Under these conditions,
the carboxylate would be in equilibrium with the dienolate, as
shown in Scheme 1D. To develop this approach, a few issues
must be considered. Prior studies on the generation of dienolates
7
dimethyl iodobenzene (Scheme 1A). The scope and mechanism
8
of this reaction were recently investigated by Han and Zhao. In
Scheme 1. Previous Examples of α-Arylation of Carboxylic
Acid Derivatives
11−14
by double deprotonation of carboxylic acids
indicate strong
n
bases (e.g., BuLi, LDA, Grignard reagents) are needed to
achieve the second deprotonation.
Other challenges include control of chemoselectivity,
undesired reactivity of the aryl acetic acid starting materials,
and decomposition/further reactions of the diaryl acetic acid
product. As noted above, aryl acetic acid derivatives are known to
undergo palladium-catalyzed ortho arylation via a C−H
1
5,16
activation pathway.
In this process the carboxylate moiety
serves as a directing group to facilitate the C−H bond cleavage.
Received: October 17, 2014
©
XXXX American Chemical Society
A
DOI: 10.1021/ol503545j
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Organic Letters
Letter
For example, Yu and co-workers demonstrated that ortho-C−H
activation of phenyl acetic acid derivatives by palladium could be
followed by cross-coupling (Scheme 2A). Furthermore, aryl
Scheme 2. Selectivity in Arylation of Aryl Acetic Acid
Derivatives
cyclopentyl methyl ether (CPME), an excellent solvent for
DCCPs, failed to afford an arylation product (Scheme 3, entry 1).
a
Scheme 3. Optimization of Phenyl Acetic Acid α-Arylation
acetates have been reported to be unstable in the presence of
palladium catalysts and undergo decarboxylative cross-cou-
1
7−23
pling.
This reaction pathway is exemplified by the report
of Liu and co-workers, who demonstrated diarylmethanes can be
formed using 2-pyridyl or nitroaryl acetates with aryl halides via
2
2,23
palladium-catalyzed decarboxylative coupling (Scheme 2B).
These studies indicate a potential side reaction involving
intermediates such as those in Scheme 1D that may compete
with the desired α-arylation of dienolates.
a
Reaction conducted on a 0.1 mmol scale. b Yield determined by 1H
Despite these issues, our experience with deprotonative cross-
c
NMR spectroscopy of the crude reaction mixture. Isolated yield after
coupling processes (DCCP) of weakly acidic substrates (pK >
chromatographic purification. d 2.5 mol % Pd(OAc) /3.75 mol %
a
2
24−31
25) positioned us to pursue the α-arylation of acids.
An
NiXantphos.
important feature of the DCCP is an in situ reversible metalation
of the substrate via C−H deprotonation under catalytic cross-
coupling conditions. Herein, we describe a general protocol for
the palladium-catalyzed α-arylation of carboxylic acids with aryl
chlorides and bromides involving reversible deprotonation of the
carboxylate.
The first step in our reaction development focused on
deprotonation of phenyl acetic acid to form the dienolate
intermediate. To evaluate bases to deprotonate the carboxylate
substrate, we employed a benzylation reaction with benzyl
chloride to trap the dienolate (eq 1).
Dioxane initially appeared promising, with a 56% yield (entry 2).
Attempts to increase the yield, however, were unsuccessful. THF,
2
-methyl-THF, and DME (entries 3−5) were examined at 80 °C,
with DME giving up to 80% yield. Likewise, toluene at 110 °C
afforded the product in 80% yield (entry 6). Both THF and DME
resulted in generation of 5−10% of an inseparable byproduct that
was not observed in toluene, making toluene a better choice for
further optimization. In the reaction in toluene (entry 6), some
decomposition of phenyl acetic acid was observed, presumably
resulting in lower yields. To address this issue, the equivalents of
aryl acetic acid and base were increased to 1.5 and 3, respectively,
resulting in an 83% yield (entry 7). Reducing the reaction
1
concentration to 0.05 M resulted in a >95% yield by H NMR of
the crude product (entry 8). Lowering the temperature (entry 9)
or catalyst loading (entry 10) resulted in lower yields.
With the optimized conditions of Scheme 3 (entry 8), the
scope of aryl halides in the α-arylation of phenyl acetic acid was
examined (Scheme 4). 1-Bromo- and 1-chloro-4-tert-butylben-
zene gave 3aa in 93% and 84% yield, respectively (entry 1).
Substrates with electron-donating groups, such as 4-bromo- and
4-chloroanisole, exhibited good reactivity, generating 87% and
80% yields of the arylation products (entry 2). 4-Bromo-N,N-
dimethylaniline furnished 3ac in 86% yield. Aryl bromides and
chlorides with electron-withdrawing groups, such as 4-F, 4-Cl,
We chose to use KN(SiMe ) as the base, because it exhibits
3
2
good compatibility with catalysts, reagents, and products in
2
8
deprotonative cross-coupling processes. Employing KN-
SiMe ) at 80 °C (eq 1), the benzylation product 1aa was
(
3
2
isolated in 80% yield, indicating formation of the dienolate under
these conditions. With this result in hand, we chose the
NiXantphos/Pd(OAc) -based catalyst due to its ability to arylate
2
weakly acidic substrates, such as diphenylmethanes (pK =
a
3
2
28
3
2.3, eq 2).
and 3-CF , were all tolerated. 1-Bromo- and 1-chloro-4-
3
We examined the α-arylation of phenyl acetic acid 1a (1.2
equiv) with 1-bromo-4-tert-butylbenzene 2a (limiting reagent)
fluorobenzene furnished diaryl acetic acid in 75% and 62%
yield, respectively, while 1-bromo-4-chlorobenzene underwent
coupling to give 3ae in 65% yield. In the latter case, no
byproducts derived from oxidative addition of the C−Cl bond
in the presence of KN(SiMe ) (2.5 equiv) and catalytic
3
2
Pd(OAc) (5 mol %) and NiXantphos (7.5 mol %). These
2
studies were initiated with a solvent screen. The reaction in
were observed. Aryl bromide bearing a 3-CF substituent
3
B
DOI: 10.1021/ol503545j
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Letter
a
,b
Scheme 4. Scope of Aryl Halides in the α-Arylation of Phenyl
Acetic Acid
Scheme 5. Scope of α-Arylation with Aryl Acetic Acids
a
,b
a
b
Reaction conducted on a 0.1 mmol scale at 0.05 M. Isolated yield
c
after chromatographic purification. Reaction conducted on a 5 mmol
scale at 0.05 M; 1.1 g of product was obtained. 2 equiv of acid and 4
equiv of KN(SiMe ) . 2 equiv of acid and 6 equiv of NaO Bu.
d
e
t
3
2
the reaction. We next examined 3-pyridyl acetic acid in the α-
arylation. With our standard reaction conditions, only decom-
position of the acid was observed. We then screened bases
t
t
KN(SiMe ) , NaN(SiMe ) , LiN(SiMe ) , KO Bu, NaO Bu, and
3
2
3 2
3 2
t
t
LiO Bu and identified NaO Bu as a better option, generating a
0% isolated yield in the coupling (entry 7). In order to
7
a
b
Reaction conducted on a 0.1 mmol scale at 0.05 M. Isolated yield
demonstrate the scalability of the protocol, a gram-scale reaction
was performed with 4-methoxy phenyl acetic acid (1b) and 4-
tert-butyl bromobenzene (2a). The arylation product 3ba (1.1 g)
was isolated in 74% (Scheme 5, entry 1).
c
after chromatographic purification. 2 equiv of 1a and 4 equiv of
KN(SiMe ) . 10 mol % Pd(OAc) /15 mol % NiXantphos.
d
3
2
2
After demonstrating the scope of aryl halides and aryl acetic
acids, we turned our attention to styryl acetic acids (Scheme 6).
furnished the product in 77% yield. Sterically hindered 2-
bromotoluene and 1-bromonaphthalene gave 3ag and 3ah in
7
1% and 80% yields, respectively. In the case of 1-bromo-3-
Scheme 6. Arylation of trans-Styryl Acetic Acid 4a
(
trifluoromethyl)benzene, both the aryl acetic acid and base
equivalents were increased to 2 and 4, respectively. For the more
challenging 2-chlorotoluene, 10% Pd(OAc) was required to
2
render 3ag in 63% isolated yield. Heterocyclic N-methyl-5-
bromoindole exhibited good reactivity with phenyl acetic acid to
form 3ai in 82% yield. The TIPS silyl ether derived from 4-
bromophenol was subjected to the reaction conditions and
afforded 3ai in 53% yield (Scheme 4, entry 10). Unfortunately,
aryl bromides containing ketone, ester, or amide groups failed to
give desired products.
The scope of α-arylation with substituted aryl acetic acids was
examined with 1-bromo-4-tert-butylbenzene 2a (Scheme 5).
Electron-neutral 2-naphthyl acetic acid afforded the coupling
product in 73% yield. Electron-donating 4-methoxy phenyl acetic
acid underwent coupling in 86% yield. Aryl acetic acids with
trans-Styryl acetic acid 4a is an interesting substrate, because it
has two sites that can potentially undergo arylation. After
screening different bases with this substrate, we observed that,
with NaN(SiMe ) , only one regioisomeric arylation product was
obtained. It appears that the initially formed product undergoes
isomerization of the double bond to form the more conjugated
product 4ap in 70% isolated yield. This product could also be
envisioned to arise from a Heck reaction. We are unaware,
3
2
withdrawing 4-F, 4-Cl, and 3-CF groups furnished coupling
3
products in 81%, 58%, and 65% yield, respectively. Sterically
hindered 2-tolyl acetic acid proved to be a challenging substrate
with a 53% yield obtained despite repeated attempts to optimize
C
DOI: 10.1021/ol503545j
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Letter
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acids undergoing Heck-type reactions.
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4
with different aryl bromides. Both 4-tert-Bu and 4-F groups
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In summary, we have developed a general method for
palladium-catalyzed α-arylation of aryl acetic acids with aryl
bromides and chlorides. The reaction also affords product with
trans-styryl acetic acid, which provides intermediates in route to
biologically active compounds. We anticipate that this protocol
will be an important complement to the existing arsenal of
palladium-catalyzed α-arylation reactions.
(
Walsh, P. J. Angew. Chem., Int. Ed. 2013, 53, 260−264.
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ASSOCIATED CONTENT
Supporting Information
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■
J. Am. Chem. Soc. 2012, 134, 13765−13772.
*
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Procedures, characterization data for all new compounds. This
material is available free of charge via the Internet at http://pubs.
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AUTHOR INFORMATION
Corresponding Author
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Headache 1998, 38, 453−457.
■
*
(
E-mail: pwalsh@sas.upenn.edu.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Patterson, T. L.; Grant, I.; Wahlgren, D. R.; Abramson, I.; Garfin, S. R.
We thank the National Science Foundation (CHE-1152488) and
National Institutes of Health (NIGMS 104349) for financial
support.
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L. Bioorg. Med. Chem. 2006, 14, 8366−8378.
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Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naph-
thalenamine, U.S. Patent 4,536,518, August 20, 1985.
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DOI: 10.1021/ol503545j
Org. Lett. XXXX, XXX, XXX−XXX