Ligand-Enabled PdII-Catalyzed Iterative γ-C(sp3)?H Arylation of Free Aliphatic Acid

Article abstract of DOI:10.1002/anie.201907262

C?H functionalization of aliphatic carboxylic acids without attaching exogenous auxiliary has been so far limited at the proximal β-position. In this work, we demonstrate a ligand enabled palladium catalyzed first regioselective distal γ-C(sp3)?H function

Full text of DOI:10.1002/anie.201907262

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Accepted Article
Title: Ligand-Enabled Pd(II)-Catalyzed Iterative γ-C(sp3)−H Arylation of
Free Aliphatic Acid
Authors: Pravas Dolui, Jayabrata Das, Hediyala B. Chandrashekar, S.
S. Anjana, and Debabrata Maiti
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907262
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Ligand-Enabled Pd(II)-Catalyzed Iterative -C(sp3)H Arylation of
Free Aliphatic Acid
Pravas Dolui, §,† Jayabrata Das, §,† Hediyala B. Chandrashekar, † S. S. Anjana, † Debabrata Maiti*†
Abstract: CH Functionalization of aliphatic carboxylic acids without
attaching exogenous auxiliary has been so far limited at the proximal
-position. In this work, we demonstrate a ligand enabled palladium
catalyzed first regioselective distal -C(sp3)H functionalization of
aliphatic carboxylic acid without incorporating an exogenous directing
group. Aryl iodides containing versatile functional groups including
complex organic molecules are well tolerated with good to excellent
yields during the -C(sp3)H arylation reaction. Interestingly, weak
coordination of carboxylate group can be further extended for
sequential hetero di-arylation. Application of the protocol has been
showcased by synthesizing substituted -tetralone. Mechanistic
investigations have been carried out to shed light on the reaction
pathway.
Scheme 1. Our Experimental Evidence in Favour of Five Membered
Metallacycle over Six Membered Metallacycle
Preference for a five-membered metallacycle formation over a
six-membered one is clearly overwhelming. To attain the
functionalization at the distal -position regioselectively, a more
convenient strategy has to be hypothesized with the help of a
suitable ligand since it requires the formation of
thermodynamically less favored six membered metallacycle
involving weakly coordinating carboxylate group. A free carboxylic
acid can coordinate with the transition metal either in 2 or 1
mode which are in equilibrium (Scheme 2). Of these two, only 1
coordination mode, where metal is bound with a single oxygen
lone pair may provide a conformation with suitable alignment
between the metal center and the CH bond to be activated.
Whereas in 2 coordination mode, the active metal catalyst may
become inaccessible to further activate -C(sp3)‒H bond. The
equilibrium thus can be switched towards 1 mode by using
electropositive alkali metal.[5a] Under such conditions, transition
metal possessing a vacant coordination site is expected to
facilitate the activation of distal -C(sp3)‒H bond via formation of
a six membered metallacycle.
Aliphatic carboxylic acids are versatile synthons in organic
synthesis due to their structural diversity and wide availability.
Their ubiquitous presence in many natural products as well as in
pharmaceutically relevant compounds shows the importance of
such molecules. Keeping in mind the diverse range of functions
these acids performs in synthetic chemistry,[1] biological
processes,[1c] and in rhizosphere ecology,[1d] further
transformation of such acids becomes extremely valuable to
increase their utility. Over the last decade, directed CH
functionalization using a covalently attached exogenous directing
group has contributed significantly for aliphatic systems.[2] Various
functionalization such as arylation, oxygenation, iodination,
alkylation, silylation, thioarylation, olefination, amidation,
carbonylation reactions have been developed via attaching a
template to the acid substrate covalently.[3] However, this strategy
bears certain limitations of using additional steps for pre-
installation and removal of directing group post functionalization,
as they are not an essential moiety in the target molecules.
Exploring the potential of free carboxylic acid without an
exogenous directing group is more desirable.[4] Till date,
functionalization of free carboxylic acid has been mostly restricted
up to proximal -position due to preferred formation of five
membered metallacyale.[5]
A crystal structure (CCDC1894534, Scheme 1) we obtained
t
during a competition experiment between pivalic acid and butyl
acetic acid is quite informative in this regard.
[†]
P. Dolui, J. Das, H. B. Chandrashekar, S. S. Anjana, and Prof. Dr.
D. Maiti*
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai 400076, India
Scheme 2. C(sp3)H Arylation of Aliphatic Carboxylic Acid
E-mail: dmaiti@chem.iitb.ac.in
Herein, we demonstrate the first example of regioselective -
C(sp3)H functionalization of free aliphatic acids (Scheme 2). To
surmount the challenge of forming thermodynamically less stable
[§]
These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/anie.XXXXXXXX.
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six-membered metallacycle necessary for -C(sp3)H activation,
we initiated -arylation of tbutyl acetic acid with 4-iodo anisole as
an arylating partner. Interestingly, despite no six membered
metallacycle formation during competition with pivalic acid, we
found 25% desired -arylated product using Pd(OAc)2 as a
catalyst and Boc-Val-OH (L1) as a ligand in presence of an alkali
metal base. However, homo-coupling of 4-iodo anisole was found
to form as the major side product in the reaction. Pyridine,
quinoline and phosphine based ligands were found to be
ineffective. In this context, N-Ac-Gly-OH (L6, Scheme 3) turned
out to be the most effective ligand for the present transformation.
Carboxylate group of the carboxylic acid in combination with a
bidentate mono-protected amino acid ligand help in -C(sp3)H
activation.[5b] Role of base is thought to be crucial as it facilitates
to switch the equilibrium from 2 to 1 mode and thus palladium
have an opportunity to activate the distal -C(sp3)H bond. Crystal
structures obtained with sodium (CCDC 1917072, Scheme 2a)
and palladium (CCDC 1905290, Scheme 2a) in this regard are
quite informative. Among various bases, Na2HPO4 was found to
enhance the yield of the -arylation product significantly. Additives
such as 1-AdCO2H, I2, Cu and Ca salts failed to improve the yield
of the desired arylated product. After extensive optimization with
various reaction parameters it was observed that the use of
Pd(OAc)2 (10 mol%), N-Ac-Gly-OH (L6, 20 mol%), AgOAc (2
nitrile, aldehyde and ester underwent the -arylation reaction
smoothly with synthetically useful yields (1f-1i). Presence of
electron withdrawing trifluoromethyl moiety (1o and 1p) did not
affect the efficiency of the protocol. Electron releasing groups like
methyl, methoxy and bulkier tertiary butyl substituted aryl partner
were well tolerated under the standard condition (1q-1t).
º
equiv.), and Na2HPO4 (0.5 equiv.) in HFIP solvent at 90 C
provided significant formation of -arylated product.
Scheme 4. Ligand-Enabled Pd(II) Catalyzed -C(sp3)–H Arylation of
Free Carboxylic Acid with Various Aryl Iodides
Scheme 3. Effect of Ligand on -C(sp3)–H Arylation of Aliphatic
Carboxylic Acid
With optimum condition, we first diversified the scope of aryl
iodides (Scheme 4). Aryl partners containing electron withdrawing
substituents such as acetyl, nitro, chloro, bromo, and fluoro gave
good to excellent yield of monoarylated product (1b-1n). It was
intriguing to find aryl iodides containing functional groups like
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10.1002/anie.201907262
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º
to 110 C (see supporting information). Aryl iodides containing
electron withdrawing group as well as electron releasing group
were well tolerated to give moderate to good yield of diarylated
product (Scheme 7, 4a-4i).
Scheme 5. Scope of various acids
Scheme 7. Ligand-Enabled Pd(II) Catalyzed Diarylation of -C(sp3)–
H Bond of Free Carboxylic Acid
Scheme 6. Complex Organic Molecules Containing Aryl Iodides as
Coupling Partner in -C(sp3)–H Arylation of Carboxylic Acid
To gain mechanistic insight of the present transformation, we
carried out several kinetic experiments (Scheme 8). Reversibility
studies involving CH activation step with butyl acetic acid in
Interestingly, aryl iodides having ortho-substitutents such as
methoxy, fluoro, chloro, and bromo underwent the reaction well
without much compromise in yields (1j, and 1t-1v). It is worth
mentioning that bulkier and electron deficient aryl partners such
as biphenyl (1k) and naphthyl (1l) also performed well under the
reaction condition. A range of aryl iodides derived from different
complex organic molecules viz. menthol and fenchyl alcohol could
be effectively utilized in the reaction (Scheme 6, 3a and 3b). Also
the derivatives of drug molecules, ibuprofen and ketoprofen were
successfully incorporated at -position of aliphatic acid (3c and
3d). Compatibility of such natural products shows the robustness
of the present -arylation methodology. To show the compatibility
of the protocol, we varied aliphatic free carboxylic acids containing
-C(sp3)H bonds. Expectedly, isovaleric acid was found to be a
challenging substrate. Nevertheless, it was found to produce the
desired -arylated product under the optimized reaction condition,
albeit in relatively low yield (2a-2b). Despite our best effort, butyric
acid failed to generate arylated product under the standard
reaction condition.
t
presence of deuterated acetic acid showed no deuterium
scrambling in the recovered substrate. This observation indicates
irreversible nature of CH activation step. Order determination
study both w.r.t. substrate and aryl iodide were performed. The
reaction follows first order kinetics w.r.t. aliphatic acid and
fractional order w.r.t. aryl iodide. These result further support CH
activation as the rate determining step of the reaction. A first order
rate dependency was obtained with respect to catalyst via a
Polyarylated products are of utmost importance in functional
organic materials and material chemistry due to their exceptional
physical properties.[6] These structures are also a frequent
constituent of natural products and pharmaceuticals. Having
realized the importance of such compounds, we wished to arylate
the acid substrate sequentially. To the best of our knowledge,
there are no reports of sequential arylation of free carboxylic acids
or carboxamide at distal -position even with covalently attached
directing group approach.[7] Interestingly, we found the present
protocol with weakly coordinating carboxylate group was able to
activate -C(sp3)H bonds sequentially. Initial attempt to get
º
sequential diarylation was unsuccessful at 90 C temperature.
Diarylated product was obtained by slight increase in temperature
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We propose a Pd(II/IV) catalytic cycle (Scheme 10), where
aliphatic acid initially coordinate with metal center. Further, -
C(sp3)H bond activation takes place to form a six membered
metallacycle with the assistance of an alkali metal ion. Oxidative
addition of the aryl iodide to the metal center results a Pd(IV)
intermediate, which upon reductive elimination generates the -
arylated product regioselectively. However, there is also a finite
possibility of Pd(II)/(III) cycle to be operative in absence of strong
donor ligands.[10]
Scheme 8. Kinetic Studies to Provide Mechanistic Insights
Scheme 10. Plausible Mechanism of -C(sp3)–H Arylation of Free
Carboxylic Acid
In conclusion, for the first time, a method for -C(sp3)H
functionalization of free aliphatic acids without installing
exogenous directing group has been developed. The protocol
exhibits high levels of monoselectivity for ligand-enabled
palladium catalyzed distal -arylation. This methodology is
compatible with a variety of aryl iodides including complex organic
molecule containing aryl partners. Sequential arylation has been
promoted by utilizing weakly coordinating carboxylate group.
Iterative arylation introducing varied aryl groups at other -
positions will tune the properties of polyarylated acids for use in
functional material. Application of the protocol has been
showcased by converting the arylated acids into -tetralone.
Additionally, we have also investigated the reaction mechanism
to get insights into the the -C(sp3)–H arylation of free carboxylic
acids. Efforts to further understand the mechanism and
application of the -arylation protocol with free carboxylic acids
are currently underway in our laboratory.
Scheme 9. Synthetic Applications of -C(sp3)–H Arylation
Acknowledgements
We thank SERB India (CRG/2018/003915) for financial support.
Fellowship from CSIR India (JD), UGC India (PD and CHB) are
greatly acknowledged.
graphical normalized time scale method (see supporting
information).[8] Further, kinetic isotope study showed kH/kD value
to be 2.4, which is consistent with CH activation being the rate
determining step of the overall transformation.
Keywords: • -arylation • natural product incorporation • iterative
arylation • -tetralone synthesis • mechanistic studies
The practicality of the developed protocol has been demonstrated
by scaling up the reaction up to gram scale. To further exhibit the
application of the arylation reaction, we have utilized the -
arylated acids as the starting material to form -tetralone, which
is prevalent in many natural products and biologically active
compounds.[9] The intramolecular cyclization of arylated acid has
been achieved by heating it in polyphosphoric acid for one hour.
Unsubstituted arene as well as arene containing different
substitutions like methoxy, methyl, bromo, chloro, and nitro have
been cyclized to form substituted -tetralone (Scheme 9, 5a-5f),
which can act as a building block to further synthesize complex
molecules.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
A ligand enabled
palladium
P. Dolui, J. Das, H. B.
Chandrashekar,
catalyzed
Anjana, S. S., and Prof.
Dr. D. Maiti*
protocol has been
developed
for
regioselective -
C(sp3)H
functionalization
Page No. – Page No.
of
aliphatic
acid
Ligand
Enabled
carboxylic
without
Pd(II)-Catalyzed
Iterative -C(sp3)H
Arylation of Free
Aliphatic Acids
incorporating any
exogenous
directing group for
the first time. The
multi-faceted
aspects of this
transformation
have
been
illustrated
through:
synthesis
various
(i)
of
-
C(sp3)H arylated
acids (ii)
incorporation of
complex organic
molecules
drug molecules in
the acid. (iii)
and
iterative
heteroarylation
and (iv) synthesis
of substituted -
tetralone
from
arylated acids.
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