Pd-Catalyzed β-C(sp3)?H Arylation of Propionic Acid and Related Aliphatic Acids

Article abstract of DOI:10.1002/chem.201705449

A generally applicable Pd-catalyzed protocol for the β-C(sp³)?H arylation of propionic acid and related α-branched aliphatic acids is reported. Enabled by the use of N-acetyl-β-alanine as ligand our protocol delivers a broad range of arylation products. Notably, the highly challenging substrate, propionic acid, which lacks any acceleration through the Thorpe–Ingold effect, can be employed as substrate with synthetically useful yields. Furthermore, the scalability and synthetic applicability of the protocol are demonstrated.

Full text of DOI:10.1002/chem.201705449

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Title: Pd-Catalyzed β-C(sp3)-H Arylation of Propionic Acid and Related
Aliphatic Acids
Authors: Kiron Kumar Ghosh and Manuel van Gemmeren
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Pd-Catalyzed -C(sp3)–H Arylation of Propionic Acid and Related
Aliphatic Acids
Kiron K. Ghosh,[a] and Manuel van Gemmeren*[a],[b]
Abstract: A generally applicable Pd-catalyzed protocol for the -
C(sp3)–H arylation of propionic acid and related -branched aliphatic
acids is reported. Enabled by the use of N-acetyl--alanine as ligand
our protocol delivers a broad range of arylation products. Notably, the
highly challenging substrate, propionic acid, which lacks any
acceleration through the Thorpe-Ingold effect, can be employed as
substrate with synthetically useful yields. Furthermore, the scalability
and synthetic applicability of the protocol are demonstrated.
The carboxylic acid moiety is one of the most elementary and
widespread functional groups in organic chemistry. Its importance
is reflected by the presence of both carboxylic acids and their
derivatives in a variety of natural products and pharmacologically
relevant compounds, as well as the plethora of synthetic methods
that have been developed for their synthesis and further
functionalization.[1] In light of their importance it is not surprising
that substantial efforts have been directed towards the use of
these compounds as substrates in C–H activation reactions.
While carboxylic acids could be utilized with great success as
directing groups in C(sp2)–H activation reactions,[2] the
corresponding activation of C(sp3)–H bonds of such weakly
directing carboxylic acid substrates has remained highly
challenging. In order to make use of aliphatic carboxylic acids as
substrates, they typically have to be derivatized into suitable
directing groups.[3] The drawbacks associated with the need to
introduce and remove the directing group render methods directly
employing the unmodified carboxylic acid inherently more
desirable.
Scheme 1. Key studies towards the direct C-H arylation of aliphatic carboxylic
acids. Ac = acetyl, HFIP = 1,1,1,3,3,3-hexafluoro-iso-propanol, Gly = glycine.
Following early studies on Pt-catalyzed C–H oxidation
reactions,[4] the group of Yu reported a Pd-catalyzed C(sp3)–H
arylation of pivalic acid and similar -quaternary substrates in
2007 (Scheme 1a).[5] It should be noted that substrates devoid of
-quaternary centers have proven highly challenging in this type
of transformation,[3d] presumably due to the absence of an
accelerating Thorpe–Ingold effect.[6] Recently, the same group
reported a 32% yield of acid 3a from the arylation of 2-
methylvaleric acid (1a) with 4-iodotoluene (2a) as part of a study
focusing on the ligand enabled C(sp3)–H arylation of N-phthaloyl
alanine and analogous compounds using pyridine-derived ligands
(Scheme 1b).[7] The group of Zhao developed a catalytic system
relying on N-acetylglycine as
a ligand, which delivered
comparable results with N-phthaloyl alanine as a substrate. Using
this catalytic system, the authors also obtained promising results
with aliphatic carboxylic acids. For example acid 3b was
synthesized from 4-methoxyiodobenzene (2b). It should be noted,
however, that the carboxylic acid reaction partner 1a was
employed in excess to achieve the reported yield relative to the
aryl iodide as the limiting reagent (Scheme 1c).[8] Despite the
substantial advances reported in the studies described above,
current methodologies for the arylation of simple aliphatic acids
have remained limited in terms of yields and/or the requirement to
use an excess of the carboxylic acid substrate. In parallel to these
studies, we directed our research specifically towards the
-C(sp3)–H arylation of otherwise unfunctionalized carboxylic acid
substrates such as 2-methylvaleric acid (1a) or propionic acid
(1b), which would give access to hydrocinnamic acid derivatives,
a structural motif found in a variety of natural products and
medicinally relevant compounds (Scheme 1d).[1c] Herein we
report the development of a catalytic system for the Pd-catalyzed
[a]
[b]
K. K. Ghosh, Dr. M. van Gemmeren
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
E-mail: mvangemmeren@uni-muenster.de
Dr. M. van Gemmeren
Max Planck Institute for Chemical Energy Conversion
Stiftstraße 34-36, 45470 Mülheim an der Ruhr (Germany)
Supporting information for this article is given via a link at the end of
the document.
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-C(sp3)–H arylation of propionic acid and its derivatives. We
initiated our studies using 2-methylvaleric acid (1a) as a model
substrate and 4-iodotoluene (2a) as arylating agent (Table 1).[9]
Table 1. Selected examples from the optimization of the reaction conditions for
the Pd-catalyzed -C(sp3)–H arylation of carboxylic acids.
NMR-
Entry
Ligand
none
Ag-source
AgOAc
AgOAc
AgOAc
AgOAc
Ag2O
Base
Yield[a]
Na2HPO4 · 7 H2O
(1.5 equiv)
Na2HPO4 · 7 H2O
(1.5 equiv)
Na2HPO4 · 7 H2O
(1.5 equiv)
Na2HPO4 · 7 H2O
(1 equiv)
Na2HPO4 · 7 H2O
(1 equiv)
Na2HPO4 · 7 H2O
(1 equiv)
Na2HPO4 · 7 H2O
(1 equiv)
1[b]
2[b]
3
22%
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Phe-OH
Ac--Ala-OH
39%
44%
49%
56%
60%
Scheme 2. Scope of the direct -C(sp3)–H arylation with respect to the aliphatic
carboxylic acids. Unless noted otherwise the reactions were conducted on a 0.2
mmol scale. Phth = Phthaloyl protecting group. [a] The aryl iodide was used as
the limiting reagent with 2.5 equivalents of isobutyric acid. [b] The aryl iodide
was used as the limiting reagent with 6 equivalents of pivalic acid. [c] Using
AgOAc as Ag-source.
4
5
6
Ag2O
68%
(70%)
obtained in 70% yield. We proceeded to investigate the influence
of varied substituents in the -position of the acid substrate and
could obtain the n-pentyl- and benzyl-substituted products 5 and
6 in 69% and 57% yield respectively. By modifying the
stoichiometry and utilizing the aryl iodide as the limiting reagent
the mono-substituted products of both isobutyric acid (7, 51%)
and pivalic acid (8, 71%) could be obtained selectively. Finally,
we could demonstrate that N-phthaloyl alanine can also be
arylated by slightly modifying our reaction conditions and the
corresponding product 9 was obtained in 84% yield.
7
Ag2O
Na2HPO4 · 7 H2O
(1 equiv)
None
Na2HPO4 · 7 H2O
(1 equiv)
8
9
Ac--Ala-OH
Ac--Ala-OH
Ac--Ala-OH
none
Ag2O
Ag2O
9%
24%
0%
10[c]
[a] Reactions were conducted on a 0.2 mmol scale. Yields were determined by
1H-NMR spectroscopic analysis of the crude reaction mixture using CH2Br2 as
internal standard. Isolated yields are given in parentheses. [b] These reactions
were conducted at 100 °C. [c] No Pd(OAc)2 was added. Phe = L-phenylalanine,
-Ala = -alanine.
In light of the suitability of our catalytic system for propionic acid
(1b), we became interested in exploring the scope of aryl iodides
with this substrate (Scheme 3a).[11]
We were surprised to find that, contrary to the results reported for
N-phthaloyl alanine,[7] a modest degree of product formation
occurred even in the absence of an additional ligand (Entry 1). In
fact, a substantial number of prospective ligands tested had a
detrimental effect on the formation of acid 3a.[9] We identified N-
acetyl glycine as a first promising ligand (Entry 2). Improved
results were obtained upon lowering the reaction temperature to
80 °C (Entry 3). Subsequently, we discovered that a reduced
amount of base (Entry 4) and the use of silver oxide as a silver-
source (Entry 5) further increased the yield. Having identified the
otherwise best reaction conditions, we returned our attention to
the ligand. After some experimentation we discovered a beneficial
effect exerted by ligands leading to a 6- rather than 5-membered
ring chelation of the Pd-catalyst,[10] and obtained good yields of
acid 3a using N-acetyl--alanine as ligand (Entries 6 and 7). Final
control experiments confirmed the necessity of all reaction
components for the success of the reaction (Entries 8–10).
With suitable reaction conditions in hand, we proceeded to
explore the scope of this transformation and began by varying the
carboxylic acid component (Scheme 2). The product of our model
reaction 3a was obtained in 70% yield. Encouraged by this
finding, we applied our reaction conditions to the even more
challenging propionic acid (1b) as substrate.[8] We were delighted
to find that this substrate could be converted with equal efficiency
under our reaction conditions and the hydrocinnamic acid
derivative 4a was
We began by studying the influence of substitution patterns of the
aryl iodide on the outcome of the reaction. The products derived
from unsubstituted iodobenzene (4c, 83%), the para-substituted
analogs 4d (75%) and 4e (71%) and the 3,5-disubstituted 4f
(76%) could all be obtained with similar efficiency.[12] Electron
donating substituents on the aryl iodide were likewise well
tolerated (4b, 4g–i). Next, the influence of halide substituents on
the aryl iodide was probed. The fluorine-substituted 4j, chlorine-
substituted 4k, and bromine-substituted 5l products were
obtained in 68%, 78%, and 50% yield respectively. We also tested
the influence of electron-withdrawing substituents on the reaction
outcome. A para-nitro substituent was well tolerated and the
corresponding product 4m was obtained in 59% yield. Both acyl-
and ester substituents in meta- or para-position were tolerated
and the desired products 4n–q were obtained in 61%–81% yield.
Finally, in order to probe whether the aryl iodide scope observed
with propionic acid (1b) would be transferable to the other acids
presented in the acid scope, a selection of representative aryl
iodides was also tested with 2-methylvaleric acid (1a) as substrate
(Scheme 3b). The corresponding products 3b (74%), 3f (77%),
3g (81%), and 3j (62%) were all obtained in yields comparable to
the analogous products derived of propionic acid (4b, 4f, 4g, and
4j).
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Scheme 4. Synthetic utility of the direct -C(sp3)–H arylation of aliphatic
carboxylic acids.
Triple iodination of acid 12 using Me3BnNICl2 as a reagent
allowed us to obtain iophenoxic acid (14), a compound employed
in bait acceptance studies for wildlife research and formerly
marketed under the name Teridax® as a cholecystographic
agent.[13]
In summary, we have developed a generally applicable method
for the -C(sp3)–H arylation of simple aliphatic acids. The method
enables the arylation not only of -branched and -quaternary
acids, but also of the particularly challenging propionic acid. The
method was shown to display a broad scope with respect to the
aryl iodide reagent and its applicability in a synthetic context was
highlighted. Due to the ubiquity of aliphatic carboxylic acids in
natural and synthetic compounds, we expect that this catalytic
system will prove to be a valuable addition to the methods
currently available to the synthetic community.
Scheme 3. Scope of the direct -C(sp3)–H arylation with respect to the aryl
iodide using propionic acid (1b) and 2-methylvaleric acid (1a) as reaction
partners. Unless noted otherwise the reactions were conducted on a 0.2 mmol
scale.
In order to further probe the synthetic utility of our protocol, we
began by testing the scalability of the process. Two representative
products, 4n (71% on a 1 mmol scale vs. 70% on a 0.2 mmol
scale) and 4g (82% on a 5 mmol scale vs. 86% on a 0.2 mmol
scale), could be obtained with equal efficiency on an increased
scale (Scheme 4a). We furthermore realized that our reaction
conditions might serve as a general entry into non-symmetrical -
benzylhydrocinnamic acid derivatives from isobutyric acid (1c). In
order to showcase this synthetic potential, the compound 7 was
prepared by mono-arylation of isobutyric acid (1c) and then
further transformed to the target compound 10 (Scheme 4b). The
arylation of 2-methylbutanoic acid 1d with 3-methoxyiodobenzene
delivered acid 11 in 79% yield, which could be converted to the
Furthermore, we foresee that this demonstration of a generally
applicable -C(sp3)–H functionalization of aliphatic carboxylic
acids, without the need for installing any more strongly
coordinating directing group, will pave the way for the
development of further analogous transformations employing
other electrophilic coupling partners.
analogous
methyl
ester
13
by
treatment
with
trimethylsilyldiazomethane (Scheme 4c). In order to probe the
conservation of stereochemical information in our arylation
process, we analogously synthesized the enantioenriched ester
(R)-13 with an enantiomeric ratio of 98:2 from commercially
available (S)-1d (e.r. = 99:1). Acid 11 was easily de-methylated
by treatment with boron tribromide, giving the phenol-derived acid
12 in 84% yield.
Experimental Section
General experimental procedure for the -C(sp3)–H arylation of aliphatic
carboxylic acids: An oven dried 10 mL Schlenk tube was charged with the
acid substrate 1 (0.2 mmol), aryl iodide 2 (0.5 mmol, 2.5 equiv), Pd(OAc)2
(4.5 mg, 0.020 mmol, 10 mol %), N-acetyl--alanine (5.2 mg, 0.040 mmol
20 mol %), Ag2O (92.7 mg, 0.400 mmol, 2 equiv), Na2HPO4·7H2O (53.3
mg, 0.199 mmol, 1 equiv), and HFIP (2 mL). The reaction vessel was tightly
sealed and placed into an aluminum block with a tightly fitting recess on a
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magnetic stirrer. The reaction mixture was stirred vigorously at room
temperature for 10 minutes. The aluminum block was heated to 80 °C and
stirring was continued at this temperature for 24 h. The reaction mixture
was allowed to cool to room temperature and AcOH (0.1 mL) was added.
The resulting mixture was filtered through Celite® using dichloromethane
to complete the elution. The reaction mixture was concentrated under
reduced pressure and the product was purified by silica gel column
chromatography.
[11] The importance of N-acetyl--alanine as ligand becomes even more
pronounced for propionic acid (1b) as substrate. A control experiment
with N-acetyl glycine under otherwise optimized conditions resulted in an
NMR-yield of 45%.
[12] Ortho-substituted aryl iodides were found to result in low yields of the
desired products. For example a reaction between 2-methylvaleric acid
(1a) and 2-methoxyiodobenzene resulted in an isolated yield of 40%.
[13] a) S. Margolin, I. R. Stephens, M. T. Spoerlein, A. Makovsky, G. B.
Belloff, J. Am. Pharm. Assoc. 1953, 42, 476-481; b) D. Papa, H. F.
Ginsberg, I. Lederman, V. DeCamp, J. Am. Chem. Soc. 1953, 75, 1107-
1110; c) R. Shapiro, E. B. Man, J. Am. Med. Assoc. 1960, 173, 1352-
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Chem. 1970, 13, 997-999; e) C. Ballesteros, J. Vicente, R. Carrasco-
García, R. Mateo, J. de la Fuente, C. Gortázar, Eur. J. Wildl. Res. 2011,
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Rossi, Environ. Sci. Pollut. Res. 2013, 20, 2893-2904.
Acknowledgements
The authors gratefully acknowledge financial support from the
Max Planck Society (Otto Hahn Award to M.v.G.), the FCI (Liebig
Fellowship to M.v.G. and doctoral fellowship to K.K.G.), the
Alexander von Humboldt Foundation (Return Fellowship to
M.v.G.), and the WWU Münster. We thank Philipp Wedi for
verifying the reproducibility of the general procedure and Prof. F.
Glorius for his generous support.
Keywords: Arylation • Carboxylic Acids • C–H Activation •
Palladium • Propionic Acid
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Kiron K. Ghosh and Manuel
van Gemmeren*
Page No. – Page No.
Pd-Catalyzed -C(sp3)–H Arylation of
Propionic Acid and Related Aliphatic
Acids
No Thorpe-Ingold effect required: A generally applicable Pd-catalyzed protocol
for the -C(sp3)–H arylation of propionic acid and its -substituted derivatives was
developed. The use of N-acetyl--alanine as ligand enabled a broad scope and
synthetically useful yields with unsubstituted propionic acid as substrate for the first
time.
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