Synthesis of Cyclic Anhydrides via Ligand-Enabled C–H Carbonylation of Simple Aliphatic Acids

Article abstract of DOI:10.1002/anie.202104645

The development of C(sp³)–H functionalizations of free carboxylic acids has provided a wide range of versatile C?C and C?Y (Y=heteroatom) bond-forming reactions. Additionally, C–H functionalizations have lent themselves to the one-step preparation of a number of valuable synthetic motifs that are often difficult to prepare through conventional methods. Herein, we report a β- or γ-C(sp³)–H carbonylation of free carboxylic acids using Mo(CO)₆ as a convenient solid CO source and enabled by a bidentate ligand, leading to convenient syntheses of cyclic anhydrides. Among these, the succinic anhydride products are versatile stepping stones for the mono-selective introduction of various functional groups at the β position of the parent acids by decarboxylative functionalizations, thus providing a divergent strategy to synthesize a myriad of carboxylic acids inaccessible by previous β-C–H activation reactions. The enantioselective carbonylation of free cyclopropanecarboxylic acids has also been achieved using a chiral bidentate thioether ligand.

Full text of DOI:10.1002/anie.202104645

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Accepted Article
Title: Syntheses of Cyclic Anhydrides via Ligand-Enabled C−H
Carbonylation of Simple Aliphatic Acids
Authors: Jin-Quan Yu, Zhe Zhuang, and Alastair Neale Herron
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Syntheses of Cyclic Anhydrides via Ligand-Enabled C−H
Carbonylation of Simple Aliphatic Acids
Zhe Zhuang,[a] Alastair N. Herron,[a] and Jin-Quan Yu*[a]
Dedicated to Professor Dale Boger on the occasion of his receiving the Tetrahedron Prize
Abstract: The development of C(sp3)−H functionalizations of free
carboxylic acids has provided a wide range of C−C and C−Y (Y =
heteroatom) bond-forming reactions that both complement and
expand upon what can be achieved through conventional methods.
Additionally, C−H functionalizations have lent themselves to the one-
step preparation of a number of valuable, synthetic motifs, that are
often difficult to prepare through conventional methods. Herein, we
report a β- or γ-C(sp3)−H carbonylation of free carboxylic acids using
Mo(CO)6 as a convenient solid CO source and enabled by a bidentate
ligand, leading to convenient syntheses of cyclic anhydrides. Among
these, the succinic anhydride products are versatile stepping stones
for the mono-selective introduction of alkyl, alkenyl, aryl, alkynyl, boryl,
silyl, fluoro, iodo, and thiophenyl groups at the β position of the parent
acids by decarboxylative functionalizations, thus providing a divergent
strategy to synthesize a myriad of carboxylic acids inaccessible by
previous β-C−H activation reactions. The enantioselective
carbonylation of free cyclopropanecarboxylic acids has also been
achieved using a chiral bidentate thioether ligand.
might have for synthetic chemistry, the development of new
C(sp3)−H activation reactions to prepare common structural
motifs from native functional groups remains a significant
challenge.
Aliphatic carboxylic acids are ubiquitous and highly versatile
motifs and are often inexpensive reagents in organic chemistry;
as such, they are privileged starting materials in synthesis
campaigns. While conjugate addition to α,β-unsaturated carbonyl
compounds remains a strategic disconnection to install β-
substituents, the past two decades have witnessed rapid
developments in the β-C(sp3)−H functionalizations of carboxylic
acids, enabling the construction of C−C and C−Y (Y =
heteroatom) bonds far beyond what can be achieved through
established methods.[1−3] Among these endeavors, the use of
native carboxylic acids as directing groups (DGs) is highly
desirable, since it obviates the need to install and remove
bespoke DGs.[3] Moreover, C(sp3)−H functionalization reactions
directed by native functional groups enable the one-step
synthesis of synthetically important structural motifs from the
parent compounds, which is otherwise impossible if using
exogenous DGs. For example, we recently reported a β-C(sp3)−H
activation reaction to synthesize β-lactones from inexpensive and
abundant free aliphatic acids.[3i] This appealing system, which
uses inexpensive and practical peroxide oxidants, was further
extended to allow the preparation of γ-, δ-, and ε-lactones as well
as tetralin, chromane, and indane motifs from free carboxylic
acids (Scheme 1A).[3j,l] Despite the great value these protocols
Scheme 1. Construction of common structural motifs using a C(sp3)−H
functionalization strategy.
Herein, we report a β- or γ-C(sp3)−H carbonylation of free
carboxylic acids using Mo(CO)6 as a convenient, solid CO source
and a single Pd(II) catalyst bearing a bidentate ligand for the
syntheses of a wide range of substituted cyclic anhydrides
(Scheme 1B). The formation of cyclic anhydride-based products
ensures exclusive mono-selectivity in the presence of multiple
C−H bonds. The newly installed carboxyl groups are versatile
linchpins for the introduction of diverse alkyl, alkenyl, aryl, alkynyl,
boryl, silyl, fluoro, iodo, and thiophenyl groups at the β position of
the parent acids via decarboxylative functionalizations, and so
provide a divergent strategy to synthesize a myriad of carboxylic
acids inaccessible through previous β-C−H activation reactions
(Scheme 1C). The enantioselective carbonylation of free
cyclopropanecarboxylic acids has also been achieved using a
chiral bidentate thioether ligand.
[a]
Z. Zhuang, A. N. Herron, Prof. Dr. J.-Q. Yu, Department of
Chemistry, The Scripps Research Institute, 10550 North Torrey
Pines Road, La Jolla, CA 92037 (USA).
The first example of Pd-catalyzed β-C(sp3)−H carbonylation
of carboxylic acid derivatives using acidic aryl amides as the DGs
was disclosed previously.[4] Further efforts on β-C(sp3)−H
carbonylations from other groups have focused on the use of
different DGs, transition metal catalysts, and CO sources for
E-mail: yu200@scripps.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202104645
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various substrates.[5−7] However, the requisite exogenous DGs on
the final succinimide products were difficult to remove and so
hampered the synthetic utility of these protocols. Bearing this in
mind, we initiated our investigation of β-C(sp3)−H carbonylation
reactions by selecting free aliphatic carboxylic acid 1c as a model
substrate. Following our recent disclosure of the β-C(sp3)−H
olefination of free carboxylic acids,[3f] we were delighted to
in synthetically useful yields (38−51%). Cyclopropanecarboxylic
acids (1v−ad) were all amenable substrates, delivering cis-
cyclopropanedicarboxylic anhydrides in yields ranging from
modest to good (47−70%). Other free cyclic carboxylic acids (e.g.,
cyclobutane, cyclopentane, and cyclohexane) failed to afford
succinic anhydride products. Among these, cyclic rings, including
six- (2f), five- (2o and 2t), four- (2e), and three-membered (2s and
2v−ad) rings, were viable in the carbonylation reaction; a variety
of functionalities such as fluoro (2i), trifluoromethyl (2j),
tetrahydropyran (2f), methoxy (2k), Bn-protected hydroxyl (2l),
methoxymethyl (MOM)-protected hydroxyl (2m), and phthalimide
(2ad) were all well-tolerated, with the protected hydroxyls (2l and
2m) serving as useful synthetic handles for subsequent
derivatization. While carboxylic acids containing α-phenyl groups
(e.g., 2-phenylpropionic acid) afforded C(sp2)−H carbonylation
product,[7d] free carboxylic acids bearing β- or γ-phenyl groups (2g,
2h, and 2y−ab) were compatible with the current conditions and
remained intact despite the potentially reactive aryl C(sp2)−H
bonds.[7a,b,e] A range of substituents on the aryl ring from electron-
withdrawing (fluoro and chloro) groups (2h, 2u, 2ab, and 2ac) to
electron-donating (benzyloxy and methyl) groups (2z and 2aa)
were also well-tolerated. This protocol could be extended to form
synthetically valuable glutaric anhydride 2ae via γ-C(sp3)−H
carbonylation, albeit in moderate yield (38%) under the current
conditions. Current conditions failed to synthesize adipic
anhydrides probably due to sluggish δ-C(sp3)−H activation via
seven-membered palladacycle.
1
observe a 5% H NMR yield of the desired succinic anhydride
product 2c and trace amounts of product 2cʹ, derived from
opening of the anhydride (2cʹ could be quantitatively cyclized to
2c by refluxing with 1 equiv. Ac2O in toluene), using the optimal
catalyst of the olefination under 1 atm. CO. Further investigation
of the CO source and terminal oxidant revealed that the
combination of Mo(CO)6 as a convenient and air-stable solid
source of CO[6d,g] and AgNO3 could further improve the yield to
57% (see Table S2). The use of AgNO3 as an effective oxidant
has been reported in other C−H activation reactions such as
fluorination and acetoxylation.[8] In light of recent advances in
ligand-accelerated Pd(II)-catalyzed C−H activation,[9] we next
searched for ligands that could substantially improve the reactivity
of the catalyst (Table 1). A range of representative monodentate
ligands developed in our laboratory, such as pyridine L1,
quinoline L2, and 2-pyridone L3, were first tested but yields were
unsatisfactory (10−15%).[10] Guided by previous MPAA ligand-
enabled C(sp3)−H activation reactions of free carboxylic acids, we
tested
a
series of previously optimal MPAA ligands
(L4−L7):[3c,d,g,i,j,l,9b] these ligands promoted the carbonylation
reaction slightly, delivering the carbonylation product in 20−31%
yields. Bidentate ligands (L8−L11), previously found to promote
enantioselective C(sp3)−H activation, gave poor yields
(4−22%).[3e,11] To our delight, the optimal ligand L12, developed
for the olefination of free carboxylic acids, significantly improved
the yield to 74% (72% isolated yield of the benzyl (Bn)-protected
diacid 2c’).[3f,12] Notably, the thioether ligand L12 could be easily
prepared in one step with a single recrystallization in nearly
quantitative yield (95%) by refluxing 2-methyl-2-oxazoline and
thiophenol in toluene (see the preparation of ligand L12 in the
Supporting Information). Efforts to introduce substitution on the
ligand backbone (L13 and L14) did not further enhance the
reactivity. Control experiments showed that the yields were low in
the absence of the ligand or in the presence of the bidentate
sulfoxide ligand L15 (2% or 1%, respectively), indicating the
importance of the soft σ donor thioether for reactivity. We
reasoned that, in addition to promote C(sp3)−H activation,
thioether ligand might stabilize Pd(0) species and promote
oxidation of Pd(0) by Ag, which might contribute to its superior
reactivity over other ligands.
Table 1. Ligand Investigation for the β-C(sp3)−H Carbonylation of Free
Carboxylic Acids[a,b]
With the optimal ligand and reaction conditions in hand, we
evaluated the scope of the C(sp3)−H carbonylation reaction
(Table 2). The cyclic anhydride products were hydrolyzed and
subsequently protected by Bn for ease of purification and analysis.
A wide range of tertiary aliphatic acids bearing an α-gem-dimethyl
group (1a−m) or a single α-methyl group (1n and 1o) were all
compatible, affording the succinic anhydrides containing α-
quaternary centers in moderate to good yields (36−75%), which
are inconvenient to access from maleic anhydride. Less reactive
free carboxylic acids containing α-hydrogens (1p−u) also reacted
[a] Conditions: 1c (0.1 mmol), Pd(OAc)2 (10 mol%), ligand (L) (10 mol%),
Mo(CO)6 (0.5 equiv), AgNO3 (2.0 equiv), HFIP (1.0 mL), 80 °C, 24 h. [b] Sum of
2c and 2c’. The yields were determined by 1H NMR analysis of the crude
product using CH2Br2 as the internal standard. [c] Isolated yield of Bn-protected
diacid 2c’.
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Table 2. Substrate Scope of the C(sp3)−H Carbonylation of Free Carboxylic Acids[a,b]
[a] Conditions: 1 (0.1 mmol), Pd(OAc)2 (10 mol%), L12 (10 mol%), Mo(CO)6 (0.5 equiv), AgNO3 (2.0 equiv), HFIP (1.0 mL), 80 °C, 24 h. [b] Isolated yields of Bn-
protected diacid 2’ are shown. [c] The yield was determined by 1H NMR analysis of the crude product (4% yield of 2v and 64% yield of 2v’). [d] Conditions: 1ae
(0.1 mmol), Pd(OAc)2 (10 mol%), Ac-Val-OH (15 mol%), Mo(CO)6 (0.3 equiv), AgNO3 (2.0 equiv), HFIP (1.0 mL), 90 °C, 24 h.
This protocol could also be extended to the enantioselective
β-C(sp3)−H carbonylation of cyclopropanecarboxylic acids (Table
3).[3e,g] Through systematic modifications to the backbone of the
bidentate thioether ligand, we found that introduction of a methyl
group (L13) gave optimal reactivity and enantioselectivity; a range
of cyclopropanecarboxylic acids (1y−ac) were compatible with the
current protocol, affording cyclopropane-fused succinic
anhydrides with good enantioselectivities (up to 96:4 er) and
moderate yields (36−60%).
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Table 3. Substrate Scope of the Enantioselective β-C(sp3)−H Carbonylation of
Cylcopropanecarboxylic Acids[a,b]
β-Alkynyl ester 4d was directly accessible in a synthetically useful
yield (39%) through a mild decarboxylative alkynylation with more
general and diverse alkynyl Grignard reagents.[16e] For C−Y (Y =
heteroatom) bond-forming reactions, boryl (B(pin), 4e),[16f] silyl
(4f),[16g] and iodo (4g)[16h] groups could be efficiently installed at
the β position of the parent acid in modest yields (39−43%),
producing versatile linchpins for further elaboration. The CH2F
fragment, a highly sought-after bioisostere in medicinal chemistry,
could be successfully introduced by decarboxylative fluorination,
albeit in low yield (4h, 11%).[16i] Finally, the formal β-
chalcogenation product 4i was obtained in moderate yield
(56%).[16j]
Table 4. Scope of the Decarboxylative Functionalizations[a,b]
[a] Conditions: 1 (0.1 mmol), Pd(OAc)2 (10 mol%), L13 (10 mol%), Mo(CO)6 (0.5
equiv), AgNO3 (2.0 equiv), HFIP (1.0 mL), 70 °C, 24 h. [b] Isolated yields of Bn-
protected diacid 2’ are shown. The er values were determined on the SFC
system using commercially available chiral columns.
The succinic anhydride products of this reaction are
versatile linchpins for the mono-selective introduction of C−C and
C−Y (Y = heteroatom) bonds at the β position of the parent acids.
For example, the Ni-catalyzed decarbonylative cross-coupling of
cyclic anhydrides (e.g., 2a) with alkyl bromides delivers free acid
products featuring formal β-alkylation, with decarbonylation
occurring regioselectively at the sterically less hindered side of
the parent anhydride.[13] This protocol features the use of readily
available alkyl bromides as well as compatibility with secondary
alkyls, which are usually unreactive in Pd-catalyzed C−H
alkylation reactions.[2d,f,h] In addition, the regioselective opening of
anhydride products to unmask just one of the carboxyl groups has
been demonstrated.[14] The resultant carboxyl groups are
themselves versatile synthetic handles: in addition to their
conversion to amide, ketone, ester or hydroxyl moieties, via
addition of appropriate nucleophiles or reducing agents, they can
t
[a] Conditions for regioselective opening of 2a: 2a, DMAP (30 mol%), BuOH,
80 °C, 12 h; K2CO3 (2.0 equiv), BnBr (2.0 equiv), CH3CN, 80 °C, 6 h; TFA (2.0
equiv), DCM, rt, 3 h. Conditions for decarboxylative functionalization: 4a−g and
4i from redox-active ester (RAE) of 3b; 4h from 3b. See Supporting Information
for details. [b] Isolated yields are shown.
In summary, we have realized an effective C−H
carbonylation of ubiquitous aliphatic acids enabled by a single
Pd(II) catalyst bearing a bidentate ligand. This reaction affords a
new method for the syntheses of a wide range of cyclic
anhydrides using Mo(CO)6 as a convenient solid CO source.
Exploitation of the versatile reactivity of the newly installed
carboxyl group provides access to diverse β-functionalized
aliphatic acids in exclusive mono-selectivity and unparalleled
also engage in
a
wide range of decarboxylative
functionalizations.[15,16] To demonstrate the utility of our succinic
anhydride products, 2a was converted to the β-carboxyl ester 3b ,
a stepping stone for the mono-selective installation of a range of
aryl, alkenyl, alkynyl, boryl, silyl, fluoro, iodo, and thiophenyl
groups (Table 4). Aza-heterocycles could be efficiently installed
by either decarboxylative cross-coupling with a pyridinylboronic
acid (4a, 55%)[16b] or a decarboxylative Minisci-type reaction with
isoquinoline (4b, 48%).[16c,d] Notably, aza-heterocyclic halides are
usually incompatible with Pd-catalyzed C−H arylation reactions
due to catalyst poisoning from coordination of these aza-
heterocycles.[2c,d,f,3a−e,g,l] The analogous decarboxylative cross-
coupling with a vinyl boronic acid delivered β-vinyl ester 4c in
moderate yield (53%),[16b] which provided a complementary
strategy to Pd-catalyzed β-C−H olefination of acids and their
derivatives, where only electron-deficient olefins are effective.[2e,3f]
scope.
The
enantioselective
C−H
carbonylation
of
cyclopropanecarboxylic acids has also been achieved using a
chiral bidentate thioether ligand.
Acknowledgements
We gratefully acknowledge the NIH (NIGMS, R01GM084019) and
The Scripps Research Institute for financial support. We thank
Kessil Lighting for a kind loan of PR160L-370nm and PR160L-
390nm lamps.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: C−H activation • Palladium • Ligand design •
Carboxylic acids • Carbonylation
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10.1002/anie.202104645
Angewandte Chemie International Edition
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Pd(II)-catalyzed β- or γ-C(sp3)−H carbonylation of free carboxylic acids is reported. This protocol affords a new method for the syntheses
of a wide range of cyclic anhydrides. Decarboxylative functionalization of the installed carboxyl group provides access to diverse β-
functionalized aliphatic acids. The enantioselective C−H carbonylation of cyclopropanecarboxylic acids is also achieved.
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