Palladium-Catalyzed Decarbonylative Difluoromethylation of Acid Chlorides at Room Temperature

Article abstract of DOI:10.1002/anie.201811139

Methods for the direct synthesis of difluoromethylated arenes are sparse, despite the importance of the difluoromethyl group in medical, agro-, and materials chemistry. A palladium-catalyzed decarbonylative cross-coupling reaction of acid chlorides with a difluoromethyl zinc reagent is achieved to access difluoromethylated compounds. The transformation proceeds at room temperature and shows broad functional group tolerance, thus providing a general and efficient method for decarbonylative difluoromethylation of a wide range of aromatic carboxylic acids.

Full text of DOI:10.1002/anie.201811139

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Accepted Article
Title: Palladium-Catalyzed Decarbonylative Difluoromethylation of Acid
Chlorides at Room Temperature
Authors: Fei Pan, Gregory Boursalian, and Tobias Ritter
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811139
Angew. Chem. 10.1002/ange.201811139
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10.1002/anie.201811139
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Palladium-Catalyzed Decarbonylative Difluoromethylation of Acid
Chlorides at Room Temperature
Fei Pan,[a] Gregory B. Boursalian,[a] and Tobias Ritter*[a]
Abstract: Methods for the direct synthesis of difluoromethylated
arenes are sparse, despite the importance of the difluoromethyl
group in medical, agro-, and materials chemistry. A palladium-
catalyzed decarbonylative cross-coupling reaction of acid chlorides
bromides.[10] MacMillan reported the metallaphotoredox
difluoromethylation of aryl bromides with bromodifluoromethane
as a direct source of CF2H radical via a silyl radical-mediated
halogen abstraction pathway.[11] Zhang has reported
a
with
a
difluoromethyl zinc reagent is achieved to access
palladium-catalyzed difluoromethylation of arylboronic acids,
which required reaction temperatures greater than 100 °C and
difluoromethylated compounds. The transformation proceeds at
room temperature and shows broad functional group tolerance, thus
made use of the gaseous reagent CClF2H as the difluoromethyl
[12]
providing
a
general and efficient method for decarbonylative
source.[5d],
Also, Hu reported the iron-catalyzed
difluoromethylation of a wide range of aromatic carboxylic acids.
difluoromethylation of arylzinc reagents with difluoromethyl 2-
pyridyl sulfone via selective C-S bond cleavage.[13] However, the
required diaryl zinc reagents are strongly basic and nucleophilic,
and are thus moisture sensitive and have limited functional
group tolerance. The method we report here for
difluoromethylation is orthogonal to the procedures enumerated
above because it operates from benzoic acids as starting
materials. Importantly, the novel mechanistic implications we
detail rationalize the rare room-temperature decarbonylation that
enables reaction conditions that are conducive to broad
substrate scope and functional group tolerance, which is often a
problem in conventional difluoromethylation reactions.
The difluoromethyl group (-CF2H) is of importance in
pharmaceuticals and agrochemicals because of its ability to act
as a bioisostere of alcohols, thiols, or amide groups, and
because of its unique electronic properties, which enable it to
serve as a lipophilic hydrogen bond donor.[1-3] Transition-metal-
mediated or -catalyzed difluoromethylation reactions have been
established as a direct approach to produce difluoromethyl
arenes.[4-6] However, these reported methods are either limited
in scope to electron-deficient arene substrates, or require high
reaction temperatures, which precludes their applicability to
functionally complex substrates. Herein, we present a new
strategy for aromatic difluoromethylation that proceeds at room
temperature through decarbonylative cross coupling of benzoic
acid derivatives. This transformation exhibits broad substrate
scope and functional group tolerance, which enables
difluoromethylation of a wide range of aromatic carboxylic acids,
including drug molecules.[7] Furthermore, our transformation is
enabled by an unusual example of room temperature
decarbonylation of an organopalladium(II) intermediate, which
offers insight that may aid the development of other mild
decarbonylative reactions that have been elusive for decades.
Here, we detail the first decarbonylative difluoromethylation
reaction of benzoic acids.
In 2012, Prakash and Hartwig independently reported the
copper-mediated difluoromethylation of aryl iodides with
TMSCF2H (5 equiv.) or nBu3SnCF2H (2–3 equiv.), respectively,
as difluoromethyl sources, both requiring temperatures in excess
of 100 oC.[8] In 2014, Shen reported the first catalytic
difluoromethylation of aryl halides with TMSCF2H (2 equiv.),
which proceeds at 80 °C through cooperative palladium/silver
Scheme 1. Recent Developments in catalytic difluoromethylation protocol and
novel decarbonylative approach.
catalysis.[9] In 2016, Vicic reported
a
nickel-catalyzed
difluoromethylation reaction using (DMPU)2Zn(CF2H)2 that could
produce difluoromethyl arenes at room temperature, but was
limited in scope to relatively electron-deficient aryl iodides and
Compared to aryl halides, aryl boronic acids, and aryl metal
reagents, aromatic carboxylic acids are advantageous starting
materials since they are often much cheaper and more readily
available.[14] They are ubiquitous in important classes of organic
molecules, including natural products, pharmaceuticals, and
materials, and thus decarbonylative cross coupling offers an
opportunity for expedient derivatization of such compounds that
the known methods cannot provide. Indeed, recent studies on
decarbonylative cross-coupling reactions of carboxylic acid
[a]
Dr. F. Pan, Dr. G. B. Boursalian, Prof. Dr. T. Ritter
Department Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
E-mail: ritter@mpi-muelheim.mpg.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201811139
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COMMUNICATION
derivatives have demonstrated the viability of this approach for
the construction of various types of C-X bonds,[15-18] including
examples such as decarbonylative Heck,[16] Suzuki,[17] and
addition[18] reactions. Herein, we present a new strategy for
aromatic difluoromethylation through direct decarbonylative
cross coupling of aromatic acid chlorides, obtained in situ from
carboxylic acids, at room temperature. Although various
transition-metal-catalyzed decarbonylative transformations of
aromatic acids have been reported, these transformations
usually require high temperatures and long reaction times, which
limits substrate scope, especially for late-stage applications. For
example, in 2017, Schoenebeck reported the first ever
decarbonylative trifluoromethylation of acid fluorides, in which
they found that high temperature (at least 160 °C) is needed to
overcome the barrier of the decarbonylation from an aroyl Pd(II)
decarbonylative reactions did not show promising results in our
reaction (Table, 1, for details, see supporting information
[19]
(SI)).[15g],
The use of the analogous trifluoromethyl zinc
reagent, (DMPU)2Zn(CF3)2,[21] did not lead to trifluoromethylation,
presumably due to the higher barrier of C–CF3 reductive
elimination.
The coupling exhibits broad electronic scope, and proceeds
efficiently with electron-poor (2b-f), -neutral (2a), and -rich (2g
and 2j) aroyl chlorides. A variety of functional groups were found
to be tolerated, including nitro (2b), nitrile (2c), ester (2d),
ketone (2e, 2f, 2m), ether (2g), alkynyl (2k), chloro (2o),
trifluoromethyl (2p) and amide (3s) groups. Basic heterocycles,
often considered a liability in transition metal catalyzed coupling
reactions, are well tolerated in the present reaction, with
substrates containing pyrazole (2n), oxadiazole (2q), and
intermediate.[19] Our reaction constitutes
a
highly unusual
quinoxaline (2r) rings furnishing high difluoromethylation yields.
Table 2. Decarbonylative Difluoromethylation of Acid Chlorides.[a]
example of decarbonylative cross coupling of a carboxylic acid
derivative that proceeds at rapid rates (as little as 5 minutes to
full conversion) at room temperature.[20]
Table 1. Optimization of the Reaction Conditions.[a], [b]
entry
change of reaction conditions
none
yield (%)
94 (91)[c]
1
2
3
4
5
6
7
8
XPhos instead of RuPhos
SPhos instead of RuPhos
XantPhos instead of RuPhos
dppf instead of RuPhos
Pd(OAc)2 instead of Pd(dba)2
PhMe instead of dioxane
47
76
4
0
81
88
5-24
THF, MeCN, or DMSO instead of
dioxane
9
TMSCF2H
instead
of
0
(DMPU)2Zn(CF2H)2
10
11
no RuPhos
no Pd(dba)2
0
0
[a] Reactionion conditions: aroyl chloride (0.20 mmol), zinc reagent (0.20
mmol, 1.0 equiv.), Pd(dba)2 (5 mol%), RuPhos (6 mol%) in 1,4-dioxane (2
mL, 0.1 M), at room temperature for 1 h. [b] Yields were determined by 19
F
NMR with 4,4’-difluorobenzophenone as an internal standard. [c] Isolated
yield.
We began our investigations by studying the reaction of biaryl
acid chloride 1a with (DMPU)2Zn(CF2H)2,
a nucleophilic
difluoromethylating reagent first reported by Vicic,[10] and found
that a catalyst system consisting of Pd(dba)2 and RuPhos in 1,4-
dioxane at room temperature provided the best results, affording
2a in 91% isolated yield after 1 hour. Upon closer examination, it
was found that the acid chloride is completely consumed within
5 minutes. This outcome was unexpected as the available
literature data on catalytic decarbonylative cross couplings
unanimously indicated a requirement for elevated temperatures
and long reaction times. We observed a strong dependence of
the reaction rate on the phosphine ligand, with bulky
monodentate phosphines being key for an efficient
transformation: evaluation of various ligands that have
previously demonstrated effectiveness in Pd-catalyzed
[a] Reaction conditions: aroyl chloride (0.20 mmol), zinc reagent (0.20 mmol,
1.0 equiv.), Pd(dba)2 (5 mol%), RuPhos (6 mol%) in 1,4-dioxane (2 mL, 0.1
M), at room temperature for 1 h. [b] 5.0 mmol scale.
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In addition to aroyl chlorides, α, β-unsaturated acid chlorides can
serve as electrophiles, yielding difluoromethylalkenes (2t).[22] We
have found the reaction to be scalable, and observed little
diminution of yield in gram-scale difluoromethylation of 2a.
To evaluate its potential applicability to functional molecules, we
have utilized the method to synthesize difluoromethyl
compounds 3a-e from the acid-containing drugs diacetylrhein
(3a), probenecid (3b), ataluren (3c), adapalene (3d), and
bexarotene (3e). In all cases, difluoromethylation of the aroyl
chloride proceeded smoothly to give the difluoromethyl
derivative in high yield.
That this decarbonylative cross coupling proceeds rapidly at
room temperature bears emphasis. Previously reported
transition metal catalyzed decarbonylative transformations have
generally required elevated temperatures (in excess of 80 °C,
most commonly in excess of 140 °C) and extended reaction
times, which led us to assume that decarbonylation from aroyl
metal complexes must necessarily overcome a large activation
barrier.[23] In order to address the question of why this
decarbonylative coupling proceeds so rapidly, we have
synthesized the hypothetical intermediate aroyl–Pd(II) complex
4a through oxidative addition of (RuPhos)Pd(0) and 4-
phenylbenzoyl chloride (Scheme 2).[24] Complex 4a is stable in
toluene solution, with no appreciable decomposition observed
up to 120 °C, consistent with all other previous reports that
indicate slow decarbonylation, even at elevated temperature.
However, when a toluene solution of 4a was treated with
(DMPU)2Zn(CF2H)2 at –78 °C and subsequently warmed to only
–13 °C, appearance of the 4-difluoromethyl-biphenyl was
observed by 19F NMR, ultimately reaching a yield of 87% upon
further warming to 7 °C. No evidence of significant buildup of a
difluoromethyl–Pd(II) intermediate was found at any temperature,
which is consistent which rate-determining transmetallation to
form a (RuPhos)Pd(II)(C(O)Ar)(CF2H) complex followed by rapid
decarbonylation and reductive elimination.
Table 3. Decarbonylative Difluoromethylation of carboxylic acid-containing
drugs.[a]
In the aforementioned decarbonylative trifluoromethylation of
aroyl fluorides reported by Schoenebeck, temperatures
approaching 180 °C are required to effect decarbonylation from
an (aroyl)(CF3)Pd(II) intermediate ligated by the bidentate
phosphine XantPhos.[19] We believe that the remarkably low
barrier of decarbonylation observed in our RuPhos-ligated
catalyst relative to Schoenebeck’s XantPhos-based system is
explainable in terms of the coordination number of the relevant
intermediates.[25] The RuPhos-ligated complex 4a is a 3-
coordinate Pd(II) complex (disregarding its weak dative
isopropoxy–Pd interaction) that possesses an open coordination
site that is able to accept the carbonyl ligand resulting from
decarbonylation, while the XantPhos-ligated system is
coordinatively saturated and cannot easily accept the new
ligand.[26]
[a] Reaction conditions: aroyl chloride (0.20 mmol), zinc reagent (0.2 mmol,
1.0 equiv.), Pd(dba)2 (5 mol%), RuPhos (6 mol%) in 1,4-dioxane (2 mL, 0.1 M),
at room temperature for 1 h.
It is noteworthy that the chloro complex 4a does not
undergo decarbonylation, even substantially above room
temperature, but once the chloro ligand is replaced by the
difluoromethyl ligand, decarbonylation appears to occur rapidly
below room temperature. Relevant to these results is a study by
Sanford, in which it is reported that a reaction temperature of
130 °C is required for a Pd-BrettPhos catalyst to effect
decarbonylation of aroyl chlorides to form aryl chlorides,
consistent with the relative inertness of the chloro complex
4a.[15g] We propose that the scenario depicted in Scheme 3 may
account for the observed discrepancy in behavior between the
aroyl palladium(II) difluoromethyl and chloride complexes.
According to this proposal, decarbonylation is reversible, with an
equilibrium constant favoring the starting aroyl complex. Thus,
the apparently faster rate of decarbonylation of the
difluoromethyl complex 5 actually reflects the more rapid
reductive elimination of aryl difluoromethane relative to aryl
chloride in the respective aryl palladium(II) complexes. Indeed,
we have found that treatment of the aryl palladium(II) complex 6
with CO at room temperature quantitatively produces aroyl
Scheme 2. Synthesis and difluoromethylation of aroyl palladium(II) complex
4a.
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10.1002/anie.201811139
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palladium(II) complex 4b, consistent with decarbonylation as an
energetically uphill process for these complexes (Scheme 3).
The high selectivity observed for decarbonylated
difluoromethylarene products rather than difluoromethyl ketones
is presumably
a
consequence of unfavorable reductive
elimination between the difluoromethyl group and an aroyl group,
two electron-deficient ligands. Notably, palladium-catalyzed
cross-coupling of aroyl chlorides with carbon nucleophiles such
as aryl stannanes and boronic acids to give ketones is well-
known, which reflects a favorable electronic synergy between an
electron-rich aryl ligand and an electron-deficient aroyl ligand.[27]
We have observed that some electron-rich aroyl chlorides such
as 4-iso-propoxybenzoyl chloride give small amounts of the
difluoromethyl ketone product in addition to decarbonylated
product, indicating that aroyl-difluoromethyl reductive elimination
becomes competitive as the aroyl ligand becomes more
electron-rich.
Scheme 4. Proposed Mechanism.
In summary, we have documented a surprisingly facile Pd-
catalyzed decarbonylative difluoromethylation reaction from a
wide range of aromatic acid chlorides that operates at room
temperature. RuPhos is crucial to promoting both the
decarbonylation and the challenging C–C bond-forming
reductive elimination. This current method is complementary to
the well-established difluoromethylation of aryl halides and
represents a valuable addition to the synthetic method for the
organofluorine chemistry. Our study not only provides a new
aromatic difluoromethylation method, but also gives new insights
into the decarbonylative step at room temperature, which may
be relevant for several other decarboxylative transformations as
well, many of which still require temperatures in excess of
140 °C.
Acknowledgements
We thank the Max-Planck-Institut fꢀr Kohlenforschung for
funding. We thank Nils Noethling for X-ray crystallographic
analysis. We thank MS department for technical assistance.
Keywords: difluoromethylation• Palladium • catalysis •
decarbonylation • room temperature
Scheme 3. Plausible scenario for decarbonylation of complexes 4.
[1]
(a) R. D. Chambers, Fluorine in Organic Chemistry, Blackwell
publishing, Oxford, 2004. (b) K. Müller, C. Faeh, F. Diederich, Science
2007, 317, 1881-1886. (c) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320-330. (d) D. O´Hagan,
Chem. Soc. Rev. 2008, 37, 308-319. (e) J. Wang, M. Sánchez-Roselló,
J. L. Aceňa, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A.
Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432-2506. (f) Q.-H. Liu,
C.-F. Ni, J.-B. Hu, Natl. Sci. Rev. 2017, 4, 303-325.
Shown in Scheme 4 is our proposed catalytic cycle for the
reaction, which is consistent with all of the available data. We
propose that oxidative addition of the aroyl chloride yields an
(aroyl)Pd(II)(Cl) intermediate II, of the same kind as complex 4.
Transmetallation between II and the zinc reagent yields an
(aroyl)Pd(II)(CF2H)
decarbonylation
(aryl)Pd(II)(CF2H) complex IV. Reductive elimination thus yields
complex
III,
which
of CO
undergoes
to yield
[2]
[3]
(a) S. Swallow, Prog. Med. Chem. 2015, 54, 65-133. (b) E. P. Gillis, K.
J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med. Chem.
2015, 58, 8315-8359. (c) Y. Zhou, J. Wang, Z.-N. Gu, S.-N. Wang, W.
Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa, H. Liu, Chem. Rev. 2016,
116, 422-518.
and
dissociation
the difluoromethyl arene product and closes the catalytic cycle.
(a) J. A. Erickson, J. I. McLoughlin, J. Org. Chem. 1995, 60, 1626-1631.
(b) M. A. Chowdhury, K. R. A. Abdellatif, Y. Dong, D. Das, M. R. Suresh,
This article is protected by copyright. All rights reserved.

10.1002/anie.201811139
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COMMUNICATION
E. E. Knaus, J. Med. Chem. 2009, 52, 1525-1529. (c) C. D. Sessler, M.
Rahm, S. Becker, J. M. Goldberg, F. Wang, S. L. Lippard, J. Am. Chem.
Soc. 2017, 139, 9325-9332.
2016, 55, 8718-8722. (g) C. A. Malapit, N. Ichiishi, M. S. Sanford, Org.
Lett. 2017, 19, 4142-4145. (h) R. Takise, R. Isshiki, K. Muto, K. Itami, J.
Yamaguchi, J. Am. Chem. Soc. 2017, 139, 3340-3343. (i) H. Ochiai, Y.
Uetake, T. Niwa, T. Hosoya, Angew. Chem. 2017, 129, 2522-2526.;
Angew. Chem. Int. Ed. 2017, 56, 2482-2486. (j) T. Okita, K. Kumazawa,
R. Takise, K. Muto, K. Itami, J. Yamaguchi, Chem. Lett. 2017, 46, 218-
220. (k) A. Dey, S. Sasmal, K. Seth, G. K. Lahiri, D. Maiti, ACS Catal.
2017, 7, 433-437. (l) X.-Q. Liu, J.-Q. Jia, M. Rueping, ACS Catal. 2017,
7, 4491-4496. (m) G.-R. Meng, M. Szostak, ACS Catal. 2017, 7, 7251-
7256. (n) A. Chatupheeraphat, H. Liao, S. Lee, M. Rueping, Org. Lett.
2017, 19, 4255-4258. (o) M. D. L. H. Macias, B. A. Arndtsen, J. Am.
Chem. Soc. 2018, 140, 10140-10144. (p) A. Chatupheeraphat, H. Liao,
W. Srimontree, L. Guo, Y. Minenkov, A. Poater, L. Cavallo, M. Rueping,
J. Am. Chem. Soc. 2018, 140, 3724-3735. (q) N. Ichiishi, C. A. Malapit,
L. Woźniak, M. S. Sanford, Org. Lett. 2018, 20, 44-47.
[4]
[5]
For recent reviews, see: (a) P. Xu, S. Guo, L.-Y. Wang, P.-P. Tang,
Synlett 2014, 26, 36-39. (b) B. Chen, D. A. Vicic, Top. Organomet.
Chem. 2015, 52, 113-142. (c) M. C. Belhomme, T. Besset, T. Poisson,
X. Pannecoucke, Chem. – Eur. J. 2015, 21, 12836-12865. (d) J. Rong,
C.-F. Ni, J.-B. Hu, Asian J. Org. Chem. 2017, 6, 139-152. (e) D. E.
Yerien, S. Barata-Vallejo, A. Postigo, A. Chem. – Eur. J. 2017, 23,
14676-14701.
For selected examples, see: (a) X.-L. Jiang, Z.-H. Chen, X.-H. Xu, F.-L.
Qing, Org. Chem. Front. 2014, 1, 774-776. (b) C. Matheis, K. Jouvin, L.
J. Goossen, Org. Lett. 2014, 16, 5984-5987. (c) J. R. Bour, S. K.
Kariofillis, M. S. Sanford, Organometallics 2017, 36, 1220-1223. (d) Z.
Feng, Q.-Q. Min, X.-G. Zhang, Org. Lett. 2016, 18, 44-47. (e) X.-Y.
Deng, J.-H. Lin, J.-C. Xiao, Org. Lett. 2016, 18, 4384-4387. (f) K.
Aikawa, H. Serizawa, K. Ishii, K. Mikami, Org. Lett. 2016, 18, 3690-
3693. (g) H. Serizawa, K. Ishii, K. Aikawa, K. Mikami, Org. Lett. 2016,
18, 3686-3689. (h) J. Sheng, H.-Q. Ni, K.-J. Bian, Y. Li, Y.-N. Wang, X.-
S. Wang, Org. Chem. Front. 2018, 5, 606-610.
[16] For selected examples about decarbonylative Heck reactions, see: (a)
H. Blaser, A. Spencer, J. Organomet. Chem. 1982, 233, 267-274. (b)
M. S. Stephan, A. J. J. M. Teunissen, G. K. M. Verzijl, J. G. de Vries,
Angew. Chem. 1998, 110, 688-690.; Angew. Chem. Int. Ed. 1998, 37,
662-664. (c) L. J. Goossen, J. Paetzold, Angew. Chem. 2002, 114,
1285-1289.; Angew. Chem. Int. Ed. 2002, 41, 1237-1241. (d) T.
Sugihara, T. Satoh, M. Miura, M. Nomura, Angew. Chem. 2003, 115,
4820-4822.; Angew. Chem. Int. Ed. 2003, 42, 4672-4674. (e) G.-R.
Meng, M. Szostak, Angew. Chem. 2015, 127, 14726-14730.; Angew.
Chem. Int. Ed. 2015, 54, 14518. (f) C.-W. Liu, G.-R. Meng, M. Szostak,
J. Org. Chem. 2016, 81, 12023-12030.
[6]
(a) Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter, D. D. Dixon,
M. R. Collins, D. G. Blackmond, P. S. Baran, J. Am. Chem. Soc. 2012,
134, 1494-1497. (b) Y. Fujiwara, J. A. Dixon, F. O’Hara, E. D. Funder,
D. D. Dixon, R. A. Rodriguez, R. D. Baxter, B. Herle, N. Sach, M. R.
Collins, Y. Ishihara, P. S. Baran, Nature 2012, 492, 95-99. (c) S. Mizuta,
I. S. R. Stenhagen, M. O’Duill, J. Wolstenhulme, A. K. Kirjavainen, S. J.
Forsback, M. Tredwell, G. Sandford, P. R. Moore, M. Huiban, S. K.
Luthra, J. Passchier, O. Solin, V. Gouverneur, Org. Lett. 2013, 15,
2648-2651. (d) J.-B. Xia, C. Zhu, C. Chen, J. Am. Chem. Soc. 2013,
135, 17494-17500. (e) P. Xu, S. Guo, L. Wang, P.-P. Tang, Angew.
Chem. 2014, 126, 6065-6068.; Angew. Chem. Int. Ed. 2014, 53, 5955-
5958.
[17] For selected examples about decarbonylative Suzuki reactions, see: (a)
L. J. Goossen, J. Paetzold, Adv. Synth. Catal. 2004, 346, 1665-1668.
(b) K. Muto, J. Yamaguchi, D. G. Musaev, K. Itami, Nat. Commun.
2015, 6, 7508. (c) N. A. Weires, E. L. Baker, N. K. Garg, Nat. Chem.
2016, 8, 75-79. (d) S.-C. Shi, G.-R. Meng, M. Szostak, Angew. Chem.
2016, 128, 7073-7077.; Angew. Chem. Int. Ed. 2016, 55, 6959-6963.
(e) J. Masson-Makdissi, J. K. Vandavasi, S. G. Newman, Org. Lett.
2018, 20, 4094-4098.
[7]
[8]
(a) D. R. Dodds, R. A. Gross, Science 2007, 318, 1250-1251. (b) R. A.
Sheldon, Green Chem. 2014, 16, 950-963.
(a) P. S. Fier, J. F. Hartwig, J. Am. Chem. Soc. 2012, 134, 5524-5527.
(b) G. K. S. Prakash, S. K. Ganesh, J.-P. Jones, A. Kulkarni, K. Masood,
J. K. Swabeck, G. A. Olah, Angew. Chem. 2012, 124, 12256-12260.;
Angew. Chem. Int. Ed. 2012, 51, 12090-12094.
[18] For selected examples about decarbonylative addition reactions, see:
(a) Y. Kajita, T. Kurahashi, S. Matsubara, J. Am. Chem. Soc. 2008, 130,
17226-17227. (b) Y. Ochi, T. Kurahashi, S. Matsubara, Org. Lett. 2011,
13, 1374-1377. (c) E. N. Jenkins, W. L. Czaplyski, E. J. Alexanian, Org.
Lett. 2017, 19, 2350-2353.
[9]
(a) Y. Gu, X.-B. Leng, Q.-L. Shen, Nat. Commun. 2014, 5, 5405. (b) Y.
Gu, D.-L. Chang, X.-B. Leng, Y.-C. Gu, Q.-L. Shen, Organometallics
2015, 34, 3065-3071. (c) D.-L. Chang, Y. Gu, Q.-L. Shen, Chem. – Eur.
J. 2015, 21, 6074-6078.
[19] S. T. Keaveney, F. Schoenebeck, Angew. Chem. 2018, 130, 4137-
4141.; Angew. Chem. Int. Ed. 2018, 57, 4073-4077.
[20] For selected examples about transition-metal-mediated decarbonylation
process at room temperature, see: (a) J. Tsuji, K. Ohno, Tetrahedron
Lett. 1965, 6, 3969-3971. (b) K. Ohno, J. Tsuji, J. Am. Chem. Soc. 1968,
90, 99-107. (c) G. R. Clark, W. R. Roper, L. J. Wright, V. P. D. Yap,
Organometallics 1997, 16, 5135-5136. (d) R. Ciganda, M. A. Garralda,
L. Ibarlucea, C. Mendicute-Fierro, M. C. Torralba, M. R. Tprres, Inorg.
Chem. 2012, 51, 1760-1768.
[10] L. Xu, D. A. Vicic, J. Am. Chem. Soc. 2016, 138, 2536-2539.
[11] V. Bacauanu, S. Cardinal, M. Yamauchi, M. Kondo, D. F. Fernández, R.
Remy, D. W. C. MacMillan. Angew. Chem. 2018, 130, 12723-12728.;
Angew. Chem. Int. Ed. 2018, 57, 12543-12548.
[12] Z. Feng, Q.-Q. Min, X.-P. Fu, L. An, X.-G. Zhang, Nat. Chem. 2017, 9,
918-923.
[13] W.-J. Miao, Y.-C. Zhao, C.-F. Ni, B. Gao, W. Zhang, J.-B. Hu, J. Am.
Chem. Soc. 2018, 140, 880-883.
[21] K. Aikawa, Y. Nakamura, Y. Yokota, W. Toya, K. Mikami, Chem. – Eur.
J. 2015, 21, 96-100.
[14] For selected reviews, see: (a) L. J. Goossen, N. Rodríguez, K.
Goossen, Angew. Chem. 2008, 120, 3144-3164.; Angew. Chem. Int. Ed.
2008, 47, 3100-3120. (b) W. I. Dzik, P. P. Lange, L. J. Goossen, Chem.
Sci. 2012, 3, 2671-2678. (c) R. Takise, K. Muto, J. Yamaguchi, Chem.
Soc. Rev. 2017, 46, 5864-5888. (d) T. Patra, D. Maiti, Chem. – Eur. J.
2017, 23, 7382-7401. (e) L. Guo, M. Rueping, Chem. – Eur. J. 2018, 24,
7794-7809. (f) L. Guo, M. Rueping, Acc. Chem. Res. 2018, 51, 1185-
1195.
[22] A. J. Borah, G.-B. Yan, Org. Biomol. Chem. 2015, 13, 8094-8115.
[23] Y. Obora, Y. Tsuji, T. Kawamura, J. Am. Chem. Soc. 1993, 115, 10414-
10415.
[24] (a) J. S. Quesnel, B. A. Arndtsen, J. Am. Chem. Soc. 2013, 135,
16841-16844. (b) J. S. Quesnel, L. V. Kayser, A. Fabrikant, B. A.
Arndtsen, Chem. – Eur. J. 2015, 21, 9550-9555.
[25] (a) R. Martin, S. L. Buchwald, Acc. Chem. Res. 2008, 41, 1461-1473.
(b) T. Iwai, T. Fujihara, J. Terao, Y. Tsuji, J. Am. Chem. Soc. 2009, 131,
6668-6669.
[15] For selected examples, see: (a) B. M. Trost, F. Chen, Tetrahedron Lett.
1971, 12, 2603-2607. (b) E. M. O´Brien, E. A. Bercot, T. Rovis, J. Am.
Chem. Soc. 2003, 125, 10498-10499. (c) X. Zhao, Z.-K. Yu, J. Am.
Chem. Soc. 2008, 130, 8136-8137. (d) A. Correa, J. Cornella, R.
Martin, Angew. Chem. 2013, 125, 1928-1930.; Angew. Chem. Int. Ed.
2013, 52, 1878-1880. (e) A. Maleckis, M. S. Sanford, Organometallics
2014, 33, 2653-2660. (f) J.-F. Hu, Y. Zhao, J.-J. Liu, Y.-M. Zhang, Z.-Z.
Shi, Angew. Chem. 2016, 128, 8860-8864.; Angew. Chem. Int. Ed.
[26] K. Taksumi, R. Hoffmann, A. Yamamoto, J. K. Stille, Bull. Chem. Soc.
Jpn. 1981, 54, 1857-1867.
[27] For selected reviews, see: (a) J. K. Stille, Angew. Chem. 1986, 98, 504-
519.; Angew. Chem. Int. Ed. 1986, 25, 508-524. (b) M. Blangetti, H.
Rosso, C. Prandi, A. Deagostino, P. Venturello, Molecules 2013, 18,
1188-1213. For selected examples, see: (c) D. Milstein, J. K. Stille, J.
Am. Chem. Soc. 1978, 100, 3636-3638. (d) D. Milstein, J. K. Stille, J.
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Org. Chem. 1979, 44, 1613-1618. (e) A. M. Forbes, G. P. Meier, E.
Jones-Mensah, J. Magolan, Eur. J. Org. Chem. 2016, 2983-2987.
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Entry for the Table of Contents
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Fei Pan, Gregory B. Boursalian, and
Tobias Ritter*
Page No. – Page No.
Palladium-Catalyzed Decarbonylative
Difluoromethylation of Acid Chlorides
at Room Temperature
A palladium-catalyzed decarbonylative cross-coupling reaction of acid chlorides
with a difluoromethyl zinc reagent is achieved to access difluoromethylated
compounds. The transformation proceeds at room temperature and shows broad
functional group tolerance, thus providing a general and efficient method for
decarbonylative difluoromethylation of a wide range of aromatic carboxylic acids.
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