Rh-Catalyzed General Method for Directed C-H Functionalization via Decarbonylation of in-Situ-Generated Acid Fluorides from Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.1c01103

A Rh-catalyzed decarbonylative C-H coupling of in-situ-generated acid fluorides with amide substrates bearing ortho-Csp2-H bonds has been developed. This method enables alkyl, aryl, and alkenyl carboxylic acids to undergo decarbonylative coupling with C-H bonds of (hetero)aromatic or alkenyl amides in generally good yields via the in situ conversion of carboxylic acids into acid fluorides and also allows for the functionalization of a series of structurally complex carboxyl-containing natural products and pharmaceuticals as well as pharmaceutical amide derivatives.

Full text of DOI:10.1021/acs.orglett.1c01103

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Letter
Rh-Catalyzed General Method for Directed C−H Functionalization
via Decarbonylation of in-Situ-Generated Acid Fluorides from
Carboxylic Acids
Bangyue He, Xiaojie Liu, Hongyi Li, Xiaofeng Zhang, Yuxi Ren,* and Weiping Su*
Cite This: Org. Lett. 2021, 23, 4191−4196
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ABSTRACT: A Rh-catalyzed decarbonylative C−H coupling of in-situ-
generated acid fluorides with amide substrates bearing ortho-Csp2−H bonds
has been developed. This method enables alkyl, aryl, and alkenyl carboxylic
acids to undergo decarbonylative coupling with C−H bonds of (hetero)-
aromatic or alkenyl amides in generally good yields via the in situ conversion of
carboxylic acids into acid fluorides and also allows for the functionalization of a
series of structurally complex carboxyl-containing natural products and
pharmaceuticals as well as pharmaceutical amide derivatives.
y virtue of the ubiquity, structural diversity, and
Bnontoxicity of carboxylic acids, the exploration of catalytic
methods for their conversion to valuable products has been an
attractive area of chemical research.1 The last two decades have
witnessed dramatic advances in the development of decarbox-
ylative cross-coupling reactions.1−5 Specifically, (hetero)aryl
carboxylic acids have been demonstrated to participate in a
considerable variety of decarboxylative cross-coupling reactions
via Ag- or Cu-mediated nonredox decarboxylation with high
functional group tolerance, which, however, requires ortho-
substituted groups. The oxidative decarboxylation-based cross-
coupling reactions of aryl carboxylic acids allow the substrate
scope to be expanded beyond ortho-substituted (hetero)aryl
carboxylic acids, but they are currently limited to only a few
types of reactions.3 As for alkyl carboxylic acids, the
widespread adoption of an oxidative decarboxylation mode
has brought about the discoveries of diverse decarboxylative
cross-coupling reactions,1a,4,5 which have recently been
facilitated by the strategy of the merger of photocatalysis and
transition-metal catalysis.1a,5 As a result of the formation of
alkyl radical intermediates in the oxidative decarboxylation,
these reactions preferentially work for alkyl carboxylic acids
that generate relatively stable radical intermediates, such as
benzylic, α-amino, α-oxy, and secondary alkyl carboxylic
acids.1a,4,5 Recently, the catalytic methods for decarbonylative
cross-coupling reactions of carboxylic acid derivatives have
been significantly developed to provide an alternative approach
to the utility of abundant carboxylic acids as starting materials
for organic syntheses.6−10 The remarkable achievements in this
area showcase that nearly all kinds of carboxylic acid
derivatives including esters,7 acid anhydrides,8 amides,9 and
acid halides10 can undergo such reactions. To date, the vast
majority of these established catalytic methods have applied to
only (hetero)aryl carboxylic acid derivatives. The challenges
posed by the achievement of efficient decarbonylative cross-
coupling reactions of common alkyl carboxylic acid derivatives
may stem from the lower activity of their C(O)−X bonds (X =
heteroatom) toward oxidative addition to low-valent metal
catalyst species compared with (hetero)aryl carboxylic acid
counterparts and the tendency of alkyl carboxylic acid
derivatives to generate olefin side products via β-hydride
elimination upon the occurrence of oxidative addition and
subsequent decarbonylation.11 The realization of decarbon-
ylative cross-coupling reactions of alkyl carboxylic acid
derivatives by overcoming the aforementioned challenges is
highly desired in that they are much more available than the
currently used alkylating reagents.
Our interest in the decarboxylative cross-coupling of
carboxylic acids12 prompted us to explore the transition-
metal-catalyzed general method for decarbonylative coupling
of both (hetero)aryl and alkyl carboxylic acid derivatives with
(hetero)arenes via functional-group-directed C−H activa-
tion.13 We envisioned that in this target reaction, the directing
groups of substrates not only enhance the reactivity of the C−
H bonds and the reaction selectivity by positioning metal
centers closely proximal to the C−H bonds13 but also exert an
effect on the activation and transformation of carboxylic acid
derivatives as coupling partners by turning the electron density
of metal catalyst centers (Scheme 1A). In light of this
speculation, the proper directing groups used for C−H bond
Received: April 2, 2021
Published: May 12, 2021
https://doi.org/10.1021/acs.orglett.1c01103
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4191−4196
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to deliver the expected product in 82% yield, as shown in entry
1 of Table 1. No reaction occurred when using N or Pd
Scheme 1. (A) Working Hypothesis, (B) Previous Work,
and (C) This Work
Table 1. Optimization Studies of Decarbonylative C−H
Coupling
a
entry
variation from the standard conditions
yield (%)
b
1
2
3
4
5
6
7
8
none
82 (80 )
c
Ni(COD)2 instead of [Rh(COD)Cl]2
Pd2(dba)3 instead of [Rh(COD)Cl]2
without proton sponge
without BTFFH
NA
NA
d
62
NA
NA
NA
76
46
68
without K3PO4
without [Rh(COD)Cl]2
TFFH instead of BTFFH
Na2CO3 instead of K3PO4
without 3 Å MS
120 °C instead of 140 °C
100 °C instead of 140 °C
toluene instead of dioxane
1.0 mmol 1 scale
9
10
11
12
13
14
54
29
activation may improve the activity of metal catalysts toward
the oxidative addition of acyl C−X (X = heteroatom) bonds in
carboxylic acid derivatives and also accelerate decarbonylation
of the resulting acyl−metal intermediates via flexible ligand
dissociation and association process.7,10b In addition, the
coordination of the directing groups to metal catalysts may
prevent β-hydride elimination of the alkyl−metal complex
intermediates to olefin side products.14 Realizing the dual roles
of the directing group, we established a general method for the
Rh-catalyzed decarbonylative Csp2−H coupling of in-situ-
generated alkyl, alkenyl, and (hetero)aryl acyl fluorides with
aromatic and olefinic N-(quinolin-8-yl) carboxamides.15 Here-
in we report the discovery and development of this method.
Considering that acyl fluorides feature a good balance
between stability and reactivity due to their moderate
electrophilicity and are easy to handle and readily synthesized
from abundant carboxylic acids,6a,b our exploration of the
catalytic transformation of carboxylic acid derivatives focused
on acyl fluorides. Inspired by the success made in the
development of the catalytic method for the conversion of
in-situ-generated acyl fluorides (Scheme 1B),10c,e we aimed at a
one-pot procedure consisting of the in situ conversion of
carboxylic acids to corresponding acyl fluorides and the metal-
catalyzed cross-coupling of directing-group-containing arenes
with the resultant acyl fluorides (Scheme 1C). After screening
a series of arenes with varying mono- or bidentate directing
groups (see the SI, Section III.C) as well as other reaction
parameters, we achieved a Rh-catalyzed ortho-C−H alkylation
of 2-methyl-N-(quinolin-8-yl)benzamide (1) with 2 equiv of
cyclobutanecarboxylic acid (2) that was conducted under a
dinitrogen atmosphere in dioxane (0.1 M) at 140 °C for 12 h
in the presence of 2.5 mol % [Rh(COD)Cl]2 as a catalyst, 2
equiv of 1-(fluoro(pyrrolidin-1-yl)methylene)pyrrolidin-1-ium
hexafluorophosphate(V) (BTFFH), a proton sponge (2
equiv), K3PO4 (3 equiv), and 3 Å molecular sieves (150 mg)
37
76
b
a
b
c
GC yield of 3. Yield of isolated 3. Ni(COD)2 (10 mol %).
d
Pd2(dba)3 (5 mol %).
catalysts, which are regularly used for C−H activation and
decarbonylation (entries 2 and 3).6−10,13,15 According to
literature reports,10c fluoro-formamidinium TFFH and a
proton sponge were used as additives for the stoichiometric
conversion of carboxylic acid 2 into acyl fluoride. A control
experiment revealed that in the absence of a proton sponge,
the C−H alkylation of 1 with 2 still proceeded, albeit in a
lower yield of 3 (entry 4). However, BTFFH, K3PO4, and
[Rh(COD)Cl]2 all proved to be essential to this reaction
(entries 5−7). The role of K3PO4 is to deprotonate the N−H
bond of the directing group. Using TFFH as a fluorinating
reagent gave a slightly lower yield than BTFFH (entry 8).
Na2CO3 was used as a base, leading to much lower yield than
K3PO4 (entry 9 vs entry 6). The removal of 3 Å molecular
sieves from the reaction system reduced the yield (entry 10),
presumably because a trace amount of water existing in
reagents was detrimental to the reaction. When the reaction
temperature was decreased from 140 to 120 or 100 °C, the
reaction still occurred, the yields decreased (entries 11 and
12). A nonpolar solvent such as toluene led to a notable drop
in yield (entry 13). When the reaction scale was increased from
0.2 to 1.0 mmol, the reaction yield was still maintained at a
high level (entry 14).
With the optimized reaction condition in hand, we explored
the generality of this method with respect to aliphatic
carboxylic acids using 1 as the substrate (Scheme 2). To our
delight, the expected alkylation was achieved with a vast set of
primary and secondary alkyl groups successfully introduced on
the ortho position of benzamides (4−8). Cyclic alkyl
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of the aryl carboxylic acids with different positions (24−40),
whether they were electron-withdrawing or electron-donating
groups, were tolerated well. Intriguingly, among these
compatible functional groups, some were reactive groups, for
instance, the formyl group (34) and Bpin substituents (36),
which provided an entry into the further modification of these
products. Various heteroaryl carboxylic acids (41−44)
including quinoline carboxylic acid (44) as well as naphthalene
carboxylic acid (45) were all amenable to this method. Both
cyclic (46) and linear alkenyl carboxylic acids (47) also proved
to be viable substrates to give the corresponding C−H
alkenylation products in good yields. As such, investigating the
scope of carboxylic acids demonstrated the great generality of
this decarbonylative coupling reaction with respect to
carboxylic acids.
Scheme 2. Scope of Carboxylic Acids in Rh-Catalyzed
Decarbonylative C−H Coupling
Diversely decorated 8-aminoquinoline amides were eval-
uated for this method using cyclobutanecarboxylic acid as a
coupling partner (Scheme 3). A wide range of 8-aminoquino-
Scheme 3. Scope of 8-Aminoquinoline Amides and the
Reaction of Benzo[h]quinoline with Aryl and Alkenyl
Carboxylic Acids
carboxylic acids with different ring sizes (3, 9−12), including
tetrahydropyran-4-yl-carboxylic acid (11) and 4-oxocyclohex-
anecarboxylic acid (12), delivered the corresponding alkylation
products. No alkene side product was observed in the reactions
of β-aryl-substituted propanoic acids (14−16) that are prone
to forming stable styrene derivatives via β-hydride elimination,
indicating that this transformation effectively excludes the
undesired β−H elimination. Various functional groups on the
linear aliphatic carboxylic acid scaffolds, such as chloro (17),
bromo (18), ester (19), alkenyl (20), alkyne (21), acylamido
(22), and phenyl alkyl ether groups (23), were all compatible.
Interestingly, this method tolerated terminal C−Cl, C−Br, and
CC bonds (17, 18, and 20), demonstrating its chemo-
selectivity for acyl fluorides over alkyl chlorides or bromides
and therefore offering a complement to the previous
established C−H alkylation reactions using alkyl halides15a,b,17b
or terminal olefins16,17 as alkylating reagents. In addition, this
reaction was allowed varying substituents from electron-
donating methoxy (13) and hydroxy (15) groups to
electron-withdrawing, active bromo (16) and chloro (23)
groups on aryl rings existing in alkyl carboxylic acids.
line benzamides that incorporate electron-neutral, electron-
donating and electron-withdrawing substituents on arene rings
underwent decarbonylative C−H alkylation in generally good
yields (48−61). Heteroaryl substrates (62−65) also proved to
be competent substrates for this C−H alkylation reaction.
Interestingly, cyclohex-1-ene-1-carboamide was able to cross-
couple both alkyl and alkenyl carboxylic acids to afford
alkylation and alkenylation products, respectively, via the
selective activation of the ortho-alkenyl C−H bond (66, 67).
Notably, benzo[h]quinolin bearing a monodentate directing
group, which failed to work with alkyl carboxylic acids (see the
SI, Section III.C), was found to react with both alkenyl and
aryl carboxylic acids under the conditions established for 8-
aminoquinoline amides. As shown in Scheme 3, benzo[h]-
quinoline was able to react with cyclohex-1-ene-1-carboxylic
Moreover, this method also enabled (hetero)aryl carboxylic
acids to act as coupling partners for the ortho-C−H arylation of
1. A broad spectrum of functional groups on the phenyl rings
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acid and benzoic acid to deliver the expected C−H
alkenylation and arylation products (68, 69), respectively.
To further explore the synthesis application of this method,
we applied this protocol to the late-stage diversification of
carboxyl-containing natural products and pharmaceuticals
(Scheme 4). Structurally complex carboxylic acids including
C−H coupling of in-situ-generated acyl fluorides from
carboxylic acids.
The observed conversion of 3-phenylpropanoic acid into
styrene using benzo[h]quinoline as a substrate (see the SI,
Section III.C) points to the possibility that this decarbonylative
C−H coupling reaction may occur via the decarbonylative
elimination of alkyl acid fluorides to alkenes and the
subsequent hydrocarbonation of the resultant alkenes (see
the SI, Section IV.E).16,17 If this mechanism was operable, then
the reactions of some structurally symmetrical alkyl acids, such
as tetrahydropyran-4-yl-carboxylic acid and 4-oxocyclohexane-
carboxylic acid, would produce a mixture of two regioisomers
because two carbon atoms of the double bond of the supposed
alkenes from these carboxylic acids have no electronic bias;
however, the decarbonylative C−H coupling reactions of
tetrahydropyran-4-yl-carboxylic acid and 4-oxocyclohexanecar-
boxylic acid occurred exclusively at their ipso-carbon atoms,
which rules out the possibility that the reaction of alkyl
carboxylic acids goes through the formation of alkene
intermediates. The previously mentioned observation and
illation demonstrate that the β-hydride elimination of the
alkyl−metal complex intermediates to olefin side products is
restrained by using the transformable 8-aminoquinoline
bidentate directing group.
Scheme 4. Late-Stage Diversification of Natural Products
and Pharmaceuticals
In conclusion, we have developed a general method for the
Rh-catalyzed decarbonylative C−H coupling of readily
available carboxylic acids with (hetero)aromatic and alkenyl
amides containing transformable 8-aminoquinoline as a
bidentate directing group via the in situ generation of acid
fluorides from the corresponding carboxylic acids. By
implementing this protocol, a diverse variety of alkyl, aryl,
and alkenyl carboxylic acids all acted as building blocks for the
8-aminoquinoline-directed ortho-C−H functionalization of a
broad range of (hetero)aromatic amides and alkenyl amides.
Additionally, this Rh-catalyzed protocol possesses a high
compatibility with functional groups and a structural diversity
of substrates, as exemplified by the late-stage functionalization
of a series of complex natural products and pharmaceuticals.
Moreover, we consider that the key to achieving this Rh-
catalyzed general method is the identification of 8-amino-
quinoline as a bidentate directing group for C−H bond
activation, which concurrently engages in the activation and
transformation of acid fluorides, in particular, avoiding β-
hydride elimination by coordinating to metal catalysts.
natural products such as oleic acid (70) and pharmaceuticals
such as chlorambucil (71), indomethacin (72), dehydrocholic
acid (73), adapalene (74), and probenecid (75) smoothly
underwent decarbonylative coupling reaction in good yields.
Intriguingly, the high regioselectivity of this method was
observed in the case of the pharmaceutical amide derivative
cinchophen, a carboxyl-containing medicine. As shown in
Scheme 4, the 8-aminoquinoline amide derivative of
cinchophen possesses four possible reaction positions in the
directed C−H functionalization reaction: 8-aminoquinoline-
directed C3−H and C5−H bonds on the quinoline framework
and two quinoline nitrogen-directed ortho-C−H bonds on the
phenyl substituent. Interestingly, the amide derivative of
cinchophen reacted with cyclobutanecarboxylic acid to
exclusively generate the C5−H alkylation product in 66%
yield (76).
Aiming at the identification of acyl fluorides as active
intermediates, a series of control experiments were performed.
3-Phenylpropanoyl fluoride in 93% yield was detected in the
fluorating process (see the SI, Section IV.A); then, the
generated 3-phenylpropanoyl fluoride successfully reacted with
1 to afford 14 in 86% yield (see the SI, Section IV.B).
Moreover, The reaction of 1 with benzoyl fluoride directly
generated 24 in 85% yield (see the SI, Section IV.C). In
addition, a great amount of CO was determined under the
standard conditions (see the SI, Section IV.D). All of these
results verify that this reaction undergoes the decarbonylative
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01103.
X-ray crystallographic data for the product 12, 60, and
76; detailed experimental procedures; characterization
data; 1H, 13C, and 19F NMR spectra of compounds; and
mechanistic studies (PDF)
Accession Codes
CCDC 2061286, 2061288, and 2061290 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
Yuxi Ren − State Key Laboratory of Structural Chemistry,
Center for Excellence in Molecular Synthesis, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou 350002, China; Email: yxren@fjirsm.ac.cn
Weiping Su − State Key Laboratory of Structural Chemistry,
Center for Excellence in Molecular Synthesis, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou 350002, China; University of Chinese
Academy of Sciences, Beijing 100049, China; orcid.org/
0000-0001-5695-6333; Email: wpsu@fjirsm.ac.cn
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Authors
Bangyue He − State Key Laboratory of Structural Chemistry,
Center for Excellence in Molecular Synthesis, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou 350002, China; University of Chinese
Academy of Sciences, Beijing 100049, China
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Xiaojie Liu − State Key Laboratory of Structural Chemistry,
Center for Excellence in Molecular Synthesis, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou 350002, China
Hongyi Li − State Key Laboratory of Structural Chemistry,
Center for Excellence in Molecular Synthesis, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou 350002, China
Xiaofeng Zhang − State Key Laboratory of Structural
Chemistry, Center for Excellence in Molecular Synthesis,
Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences, Fuzhou 350002, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Key Research and
Development Program of China (2018FYA0704502), the
National Natural Science Foundation of China (grant nos.
21931011 and 22071241), the Strategic Priority Research
Program of the Chinese Academy of Sciences (XDB20000000
and XDB10040304), and the Key Research Program of
Frontier Sciences, CAS (QYZDJ-SSW-SLH024).
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