Development and Mechanistic Investigations of a Base-Free Suzuki-Miyaura Cross-Coupling of α,α-Difluoroacetamides via C-N Bond Cleavage

Article abstract of DOI:10.1021/acscatal.9b05159

This study describes the development and understanding of a palladium-catalyzed cross-coupling of fluoroacetamides with boronic acids, under base-free conditions, to selectively give valuable α,α-difluoroketone derivatives. Detailed mechanistic studies were conducted to assess the feasibility of each elementary step, that is, C(acyl)-N bond oxidative addition, followed by base-free transmetallation and reductive elimination. These investigations allowed the structural characterization of palladium(II)fluoroacyl intermediates derived from C-N bond oxidative addition of an amide electrophile. They also revealed the high reactivity of these intermediates for transmetallation with boronic acids without exogenous base. The mechanistic studies also provided a platform to design a practical catalytic protocol for the synthesis of a diversity of α,α-difluoroketones, including CF₂H-ketones. Finally, the synthetic potential of this fluoroacylation methodology is highlighted in sequential, orthogonal C-Br and C-N bond functionalization of an α-bromo-α,α-difluoroacetamide with a focus on compounds of potential biological relevance.

Full text of DOI:10.1021/acscatal.9b05159

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Article
Development and Mechanistic Investigations of a Base-Free Suzuki-
Miyaura Cross-Coupling of #,#-Difluoroacetamides via C–N Bond Cleavage
Antonio Reina, Tetiana Krachko, Killian Onida, Didier Bouyssi,
Erwann Jeanneau, Nuno Monteiro, and Abderrahmane Amgoune
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b05159 • Publication Date (Web): 13 Jan 2020
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ACS Catalysis
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Development and Mechanistic Investigations of a Base-Free Suzuki-
Miyaura Cross-Coupling of ,-Difluoroacetamides via C–N Bond
Cleavage.
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Antonio Reina,†,‡ Tetiana Krachko,†,‡ Killian Onida,† Didier Bouyssi,† Erwann Jeanneau,# Nuno
Monteiro,*,† and Abderrahmane Amgoune*,†,§
† Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR 5246 du CNRS, Université Lyon 1, 1 rue Victor
Grignard, 69100 Villeurbanne, France
# Centre de Diffractométrie Henri Longchambon, Université Lyon 1, 5 rue de la Doua, 69100 Villeurbanne, France
§ Institut Universitaire de France (IUF)
ABSTRACT: This study describes the development and understanding of a palladium-catalyzed cross-coupling of fluoroacetamides
with boronic acids, under base-free conditions, to selectively give valuable α,α-difluoroketone derivatives. Detailed mechanistic
studies were conducted to assess the feasibility of each elementary step, i.e C(acyl)–N bond oxidative addition, followed by base-free
transmetallation and reductive elimination. These investigations allowed the structural characterization of palladium(II) fluoroacyl
intermediates derived from C–N bond oxidative addition of an amide electrophile. They also revealed the high reactivity of these
intermediates for transmetallation with boronic acids without exogenous base. The mechanistic studies also provided a platform to
design a practical catalytic protocol for the synthesis of a diversity of α,α-difluoroketones, including CF2H-ketones. Finally, the
synthetic potential of this fluoroacylation methodology is highlighted in sequential, orthogonal C–Br and C–N bond functionalization
of an α-bromo-α,α-difluoroacetamide with a focus on compounds of potential biological relevance.
KEYWORDS: cross-coupling, palladium catalysis, mechanism, transmetallation, synthetic method, difluoroketone
reactive organolithium and Grignard reagents that need to be
prepared and handled under inert conditions.[6]
INTRODUCTION
On the other hand, carboxylic acid derivatives such as
amides, esters and acyl fluorides have been recently recognized
as suitable electrophilic partners for catalytic cross-coupling
reactions via C–N, C–O or C–F bond activation, respectively.[7]
Amides, which are present in a wide range of important natural
and synthetic molecules, have long been regarded as inert
substrates to catalytic transformations. But they have received
considerably more attention, over the last few years, as a new
type of electrophiles in cross-coupling reactions. Notably, in
2015, Szostak,[8] Zou,[9] and Garg[10] independently reported the
palladium- or nickel-catalyzed Suzuki-Miyaura-type (SM)
cross-coupling of these Cacyl–N electrophiles, making it a
valuable addition to the repertoire of acylative methods for
ketone synthesis.[11] However, this methodology has not been
explored so far as a tool to perform gem-difluoroacylation of a
specific substrate.[12]
Within this context, the development of a palladium-
catalyzed cross-coupling of α,α-difluoroacetamides with
organoboron compounds would provide a valuable strategy for
the direct and simple preparation of diversely substituted
difluoroketones. It would also generate significant synthetic
perspectives for halodifluoroacetamides as dual-function
templates. Selective orthogonal connective pathways could be
envisioned with these substrates acting alternatively as
difluoroalkylating and difluoroacetylating reagents (Figure
1A).
Nowadays, the gem-difluoromethylene (CF2) group is well
established as a key structural unit in many compounds of
pharmaceutical and agrochemical interest due to the recognition
of its significant impact on chemical and biological activity.[1]
Rapid progress in the strategic incorporation of CF2-containing
functional groups into high-value scaffolds is therefore
extremely desirable to satisfy the supreme demand for new drug
candidates. For instance, the past recent years have seen
tremendous advances in the development of efficient catalytic
strategies for the gem-difluoroalkylation of unsaturated organic
substrates including cross-coupling reactions or direct C–H
bond functionalization via transition metal (TM)[2] or visible
light-driven photoredox catalysis.[3] In this area, functionalized
difluoromethyl halides (e.g., Hal-CF2-FG, with FG = CO2R,
CONR2, SO2Ph, PO(OR)2) have been established as privileged
reagents in that they are readily available, robust and
practical.[4] These substrates proved to be efficient coupling
partners in metal-catalyzed fluoroalkylation reactions, via C–
halogen bond activation (I, Figure 1A).[2c] These reactions give
access to a broad range of gem-difluorinated products
containing functional groups that can provide opportunities for
further downstream elaboration. In this context, α,α-
difluoroacetamide derivatives (II, Figure 1A) are particularly
appealing because they open access to high-value α,α-
difluoroketones (III), which are privileged substructures in
chemical biology and drug design.[5] However, the rare
derivatization methods rely on nucleophilic additions of highly
Importantly, fluoroacetylation methodologies are very rare
compared to fluoroalkylation protocols. A recent successful
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Page 2 of 10
strategy, reported independently by the groups of Skrydstrup[13]
characterized. Other critical aspects to consider are the stability
and Zhang,[14] relies on carbonylative Suzuki-Miyaura
substitution of functionalized difluoromethyl halides (Figure
1B, left). The reaction proceeds via the generation of a
palladium-fluoroalkyl intermediate ensuing from C–Br bond
activation, followed by insertion of carbon monoxide and
carbon-carbon bond reductive elimination. The main challenge
of this approach is the intrinsic reluctance of strong metal-
and the reactivity of the putative difluoroacyl intermediate
towards organometallic nucleophiles, and finally, the
adjustment of suitable conditions with compatible reactants to
allow selective formation of the desired ketone under catalytic
conditions.
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Herein, we disclose our investigations going from
stoichiometric organometallic studies to the development of a
practical and robust catalytic protocol for the synthesis of α,α-
difluoroketones. The most significant features of our
mechanistic studies include the first structural characterization
of key difluoroacyl palladium intermediates and evidences for
their ability to undergo base-free transmetallation with
arylboronic acid. These mechanistic investigations served as a
basis for the discovery of a base-free palladium-catalyzed cross-
coupling reaction of amide electrophiles under mild conditions
to yield a variety of α,α-difluorinated (hetero)aryl ketones,
including alkylCF2- and CF2H-ketones. Finally, the synthetic
potential of this methodology was highlighted by addressing the
challenges associated with orthogonal reactivity of α-halo-α,α-
difluoroacetamides.
fluoroalkyl
bonds
to
undergo
carbon
monoxide
insertion.[14a,15,16] Moreover, this approach was typically applied
for the synthesis of α,α-difluorinated 1,3-dicarbonyl
compounds.
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We envisioned that the direct difluoroacetylative approach
using difluoroacetamide electrophiles (Figure 1B, right) via C–
N bond cleavage could provide a valuable complementary
strategy to directly introduce C(O)CF2 moiety. Besides the
development of a practical catalytic protocol, we were also
eager to address fundamental mechanistic questions about this
transformation. From a mechanistic point of view, the
information about the C–N bond activation of amides with
palladium complexes is scarce, and the transient difluoroacyl
palladium(II) intermediates have never been structurally
A. Halodifluoroacetamides as dual-function templates: New orthogonal connective pathways
CN bond cleavage
CBr bond cleavage
O
O
O
R1
R1
Widely exploited
Unknown
Br
R2
R2N
R2N
Pd cat. / R2BX2
F
F
R1
F
F
Y with Y = Hal, BX2, H
F
F
III
II
I
- TM catalysis or mediation
- Photocatalysis
challenges associated
with orthogonal catalysis
Difluoroalkylation
Difluoroacetylation
B. Fluoroacylation strategies: Challenges and mechanistic considerations
Br
R1
[Pd0]
Br[Pd]II
R1
F
F
CBr oxidative addition
F
F
ArBX2 + CO
Pd
# CN bond cleavage of difluoroacetamides
# Base-free cross-coupling
Fluororoalkylation/carbonylation
(Cu) cat
CO insertion
base (2 equiv)
Challenging with
M-Fluoroalkyl bond
# Works with ArCF2, MeCF2, HCF2
Zhang & Skrydstrup
O
O
R1
ArBX2
Transmetallation
without base
R1
Br[Pd]II
Base
Ar
F
F
Ar
B(OH)2
F
F
O
This study:
Acylative approach
PdII
Predominantly for -dicarbonyl compounds
R2N
Ar
B(OH)2
R1
O
O
Pd/PCy3 (cat)
via C N bond activation
F

=
F
of amides
NR2
OR
No base
Difluoroacyl intermediate
O
R1
[Pd0] CN bond
R2N
F
F
activation
Figure 1. (A) New strategy towards α,α-difluoroketones exploiting the orthogonality of difluoroalkylative and difluoroacetylative reactions
of halodifluoroacetamides. (B) Recent catalytic developments in the synthesis of difluorocarbonyl compounds via a carbonylative approach,
and proposed novel approach with mechanistic considerations.
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ACS Catalysis
complex were unsuccessful. The slow reactivity of 1a towards
RESULTS AND DISCUSSION
1
Pd(0) compared to the cross-coupling reaction rate may suggest
that the transient difluoroacyl palladium intermediate rapidly
reacts with boronic acid to drive the reaction towards the
formation of the final difluoroketone. Willing to isolate and
characterize the difluoroacyl palladium intermediate, we
studied the oxidative addition reaction in the presence of
additives such as LiCl, ZnCl2 or B(OH)3 in order to facilitate
the oxidative addition of the CacylN bond.[23-24] Gratifyingly,
the reaction of 1a with Pd(PCy3)2 in the presence of ZnCl2 or
B(OH)3 proceeded smoothly to give difluoroacyl palladium(II)
complexes IIb (δ31P{1H} = 22.4 ppm) and IIc (δ31P{1H} = 21.8
ppm) as major phosphorus-containing compounds, in 91% and
78% spectroscopic yield, respectively (Scheme 1).[22]
To evaluate the feasibility of this new protocol we decided to
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use N-(difluoroacetyl)-glutarimide 1a as a model substrate. This
twisted amide handle, introduced by Szostak,[8,
has been
17]
shown to be a versatile and robust precursor in metal-catalyzed
cross-coupling reactions involving Cacyl–N bond activation. The
glutarimide function is easily installed starting from readily
available carboxylic acids to afford the corresponding, bench-
stable difluoroacetamide in multigram scale.
9
Stoichiometric investigations
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Preliminary experiments exploring the palladium-catalyzed
cross-coupling of N-(difluoroacetyl)-glutarimide 1a with
phenylboronic acid using catalytic conditions classically
reported for the SM cross-coupling of amides[8, 17] resulted in
complete degradation of the starting reactant. Rapid control
experiments indicated that compound 1a decomposes over time
in the presence of inorganic bases. Thus, stoichiometric studies
were first conducted to set-up suitable conditions allowing
efficient coupling of 1a with phenylboronic acid without the
addition of exogenous base. Gratifyingly, the cross-coupling
reaction in the presence of stoichiometric amount of Pd(PCy3)2
in toluene proceeded at room temperature to give the
corresponding difluoroketone 2a in 89% yield, as determined
by 19F NMR spectroscopy, after 10 min.
Scheme 1. C–N bond oxidative addition of 1a to Pd(PCy3)2.
X
O
Cy3P
RT
F
F
+
Pd
F
Pd(PCy3)2
O
N
a
b
c
: no additives
: ZnCl2
: B(OH)3
PCy3
Ph
O
O
Ph
F
IIa
: X = glutarimidate
1a
(not isolated, detected by ESI/MS)
: X = Cl, 91% yield
: X = OCOCF2Ph, 78% yield
IIb
IIc
Most diagnostic NMR data are the 13C{1H} NMR signals of
the fluoroacyl ligand. The 13C{1H} NMR resonances of IIb and
IIc corresponding to the carbonyl moiety are shifted downfield
upon oxidative addition from 171.5 ppm (for 1a) to 234.8 (IIb)
and 229.0 ppm (IIc), which is typical for fluoroacyl-palladium
species.[25] The signals corresponding to the CF2 moiety appear
as triplet of triplets due to coupling to fluorine and phosphorus
atoms. Also, the 19F NMR resonance of fluoroacyl moiety is
shifted downfield from –102.3 (for 1a) to –90.1 (IIb) and –89.8
ppm (IIc). For complex IIc, the 19F and 13C NMR spectra
display additional signals corresponding to a difluoroacetate
ligand bound to Pd.[22] The molecular structures of IIb and IIc
were unambiguously confirmed by single crystal X-Ray
diffraction analysis (Figure 2). The palladium center adopts a
square planar environment and is ligated by two phosphorus
atoms and a difluoroacyl ligand in each case. The coordination
sphere is completed by a chlorine atom in complex IIb and by
a difluoroacetate ligand in IIc. The formation of complex IIc is
proposed to occur via a ligand exchange between the transient
amidate complex IIa and difluorophenylacetic acid generated
in situ in the presence of B(OH)3. In line with this proposition,
the formation of the same complex is observed when the
oxidative addition reaction is carried out in the presence of
difluorophenylacetic acid instead of B(OH)3. Notably,
complexes IIb and IIc represent the first examples of fluoroacyl
palladium complexes structurally characterized, and their
formation provides direct evidence for the Cacyl–N bond
oxidative addition to Pd(0).[26,27]
The development of SM cross-coupling reactions without
exogenous base is of high interest in regards to sustainable
catalysis, furthermore, it will allow to extend the scope to base
sensitive compounds. Very few reports describe efficient base-
free methodologies for SM reactions.[18,19] Two main strategies
have been recently developed to by-pass the requirement for
stoichiometric amount of exogenous base. The first one relies
on the use of pre-designed cationic palladium complexes.[18]
The second one is based on the generation of metal-fluoride
intermediates by oxidative addition of C–F bonds, that are
highly reactive towards transmetallation without additives.[7i, 19]
Taking into account these considerations, we were keen to get
more insight into the structure of the palladium intermediate
generated by oxidative addition of the difluoroacetamide and its
subsequent reactivity with boronic acids.
Oxidative addition of Cacyl–N bond of difluoroacetamide to
generate palladium(II) difluoroacyl complexes
In the context of recent developments of palladium-catalyzed
cross-coupling reactions of amides, acylpalladium-amidate
species are proposed as key intermediates, but their isolation
and characterization have not been reported.[20,21] With this
information in mind, we first investigated the CacylN bond
activation step. The reaction of 1a with Pd(PCy3)2 was carried
out under the same conditions as the cross-coupling reaction.
Surprisingly, monitoring of the reaction by 19F NMR
spectroscopy indicated that after 20 min only trace amount of
the starting amide is converted to a species that appears as a
broad signal (δ19F = −90.8 ppm). After few days of reaction, the
conversion slowly reaches a maximum of 40% that do not
evolve with time unless to give decomposition products. 31P
NMR monitoring revealed that the starting Pd(PCy3)2 also
slowly converts to unidentified species.[22] ESI mass
spectroscopy analyses of the reaction mixture clearly indicated
the formation of a cationic difluoroacyl palladium intermediate
(mass peak at 821.3978 m/z for [C44H71F2OP2Pd+]), but all
attempts to isolate and further characterize the corresponding
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Scheme 2. Reactivity of difluoroacyl palladium complexes
with phenylboronic acid.
1
2
3
4
5
X
Cy3P
O
O
Pd
F
Ph
Ph
B(OH)2
PCy3
IIa c
Ph
F
F
Ph
F
6
2a

7
8
9
IIa
: X = glutarimidate,
89% (10 min, RT)
in situ generated
w/o base
with K2CO3 (2 equiv)
1.5% (1.5 h, 80 °C)
65% (48 h, 80 °C)
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IIb
: X = Cl
IIc
: X = OCOCF2Ph
73% (1.5 h, 80 °C)
Overall, these stoichiometric studies clearly substantiate the
CN bond oxidative addition of a fluoroacetamide to palladium
to form a fluoroacyl intermediate that is highly reactive towards
transmetallation with phenylboronic acid without the
requirement of exogenous base. Furthermore, these results
provide interesting insights that may be of high relevance to
cross-coupling reactions of amides involving the formation of
acyl-metal amidate intermediates. Next, we were eager to
translate these mechanistic insights into the development of a
palladium-catalyzed difluoroacetylation of boronic acids with
difluoroacetamide electrophiles.
Figure 2. Molecular structures of the Pd(II) difluoroacyl
complexes IIb (top) and IIc (bottom). Hydrogen atoms and solvent
molecules are omitted for clarity; one crystallographic independent
molecule is shown.
Catalytic optimization studies
First, we assessed the feasibility of the cross-coupling
reaction under base-free conditions using 3 mol% of Pd(PCy3)2.
The coupling product 2a was formed in quantitative yield after
18 h at 80 °C, as indicated by 19F NMR spectroscopy.
Difluoroacetylation of phenylboronic acid with 1a proceeded
equally well at 80 °C in various solvents (N,N-
dimethylformamide, 1,4-dioxane, toluene) by using 3 mol% of
Pd(OAc)2 in combination with 6 mol% of PCy3 as an optimal
catalyst system (Table S2 in Supporting Information). Then, we
were keen to set up catalytic conditions with an emphasis on the
identification of catalysts and reaction conditions amenable to
standard bench-top protocols obviating the need for Schlenk or
glovebox techniques (Table 1). Importantly, the reaction proved
amenable to set-up on the bench top, using Pd(OAc)2 with the
air-stable PCy3HBF4 salt in the presence of triethylamine (12
mol%) that releases the free phosphine. The desired ketone was
formed in 94% yield after 18 h at 80 °C in DMF. A screening
of the solvents indicated that DMF was the best solvent for
carrying out the cross-coupling reaction without the use of any
air-free techniques. Other solvents, including 1,4-dioxane and
toluene, provide much lower conversions (Table 1, entries 4–
7).[29] Notably, further screening of Pd-based catalysts and
ligands including phosphorous and nitrogen-based bidentate
ligands did not allow for the identification of other effective
catalytic systems (Table 1, entries 10–14). Lastly, neopentyl
phenylboronic ester was also evaluated but proved unreactive
under these conditions (Table 1, entry 15). However, the same
cross-coupling reaction proceeded efficiently in the presence of
2 equivalents of B(OH)3 (Table 1, entry 16).[8a]
Transmetallation reactivity of palladium(II) difluoroacyl
intermediates with phenylboronic acid
Next, we investigated the reactivity of complexes IIa–c with
phenylboronic acid to compare the ability of the difluoroacyl
palladium(II)–X
intermediates
(X
=
glutarimidate,
fluoroacetate, chloride) to undergo transmetallation reaction
without exogenous base (Scheme 2). The reaction of IIa, in situ
generated, with PhB(OH)2 proceeded very rapidly at room
temperature to give directly the difluoroketone product in 89%
yield after 10 min. No intermediate is detected indicating that
the carbon-carbon bond reductive elimination is significantly
faster than transmetallation. The difluoroacetate complex IIc
also reacts with PhB(OH)2 but at lower rate (73% yield after 1.5
h at 80 °C). In contrast, no reaction was observed between the
chloro complex IIb and PhB(OH)2 under the same conditions.
When 2 equivalents of K2CO3 were added and the reaction
mixture was heated to 80 C for 48 h, the desired product 2a
was formed in 65% yield, along with side products.[28] These
results highlight the key role of the amidate ligand in the
reactivity of the difluoroacyl palladium(II) intermediate
towards transmetallation with boronic acids and confirm its
ability to undergo the reaction under base-free conditions.
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Table 1. Selected optimization experiments for thiophenyl ketone 2n. Disappointingly, however, alkylboronic
1
2
3
4
5
6
7
8
difluoroacetylation of phenylboronic acid with 1a under
bench-top conditions.[a]
acids remained reluctant to participate in the cross-coupling
reaction. Next we briefly investigated the scope of N-(α-
arylacetyl)-glutarimides with a special emphasis on the effect
of para substituents in the α-aryl moiety. Notably, substrates
with electron-withdrawing para substituents afforded the
products (2p) in higher yields than those bearing electron-
donating substituents (2o). Remarkably, an α-alkyl amide (see
2q) participated as well in the cross-coupling reaction. Overall,
the method holds promise as a direct connective approach to
difluoroketones that tolerates diverse substitution patterns not
always accessible by other methods, notably those employing
stoichiometric organometallic reagents. Finally, the robustness
of this transformation was demonstrated by performing the
synthesis of 2e on a gram scale (65% isolated yield).
O
3 mol% Pd(OAc)2
6 mol% PCy3HBF4
O
O
Ph
Ph
N
Ph
B(OH)2
+
Ph
F
F
12 mol% Et3N
DMF, 80°C, 16 h
F
F
O
(2 equiv)
2a
1a
Yield
(%)[b]
Entry
Deviation from standard conditions
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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1
2
None
94 (99)
<5 (99)
31 (65)
24 (97)
8 (90)
19
PCy3 instead of PCy3HBF4/Et3N
Without PCy3HBF4/Et3N
3
4
1,4-dioxane instead of DMF
Toluene instead of DMF
Table 2. Scope of the reaction.[a]
5
6
NMP instead of DMF
O
3 mol% Pd(OAc)2
6 mol% PCy3HBF4
O
O
R
R
7
MeCN, THF, DMSO, or DMAc instead of DMF
1 equiv of Et3N
<5
N
Ar
B(OH)2
+
Ar
F
F
12 mol% Et3N
DMF, 80 °C, 16 h
F
F
8
36
O
(2 equiv)
2
1
9
25 °C instead of 80 °C
10
10
11
12
13
<5
O
nBu3PHBF4 instead of PCy3HBF4
Dcype2HBF4 (3 mol%) instead of PCy3HBF4
PPh3 instead of PCy3HBF4/Et3N
O
O
O
Ph
Ph
Ph
Ph
Ph
O
O
<5
F
F
F
F
F
F
F
F
<5
2a
2b
; 77% (71%)
2c
2d
; 94% (90%)
; 74% (72%)
; 80% (75%)
Pd-PEPPSI-IPr instead of
Pd(OAc)2/PCy3HBF4/Et3N
<5
O
O
O
O
OMe
Ph
Ph
Ph
14
15
<5
Bipy (3 mol%) instead of PCy3HBF4/Et3N
F
F
F
F
F
F
F F
Cl
N
OMe
PhBnep/Pd(PCy3)2 (5 mol%) instead of
PhB(OH)2/Pd(OAc)2/PCy3HBF4/Et3N
(1.5)
2e
2f
2g
2h
; 14% (11%)
; 93% (82%)
69% (65%)[b]
; 99% (86%)
; 68% (59%)
O
O
O
F
O
16
PhBnep/B(OH)3 (2 equiv)/Pd(PCy3)2 (5 mol%)
instead of PhB(OH)2/Pd(OAc)2/PCy3HBF4/Et3N
(87)
Ph
Ph
Ph
Ph
F
F
F
F
F
F
F
F
CO2Me
CF3
; 67% (55%)
F
[a] Reactions performed on 0.5 mmol scale in 2 mL of solvent. Yields
were determined by 19F NMR spectroscopy using fluorobenzene as an
internal standard. Dcype = 1,2-Bis(dicyclohexylphosphino)ethane; bipy
= 2,2’-bipyridine; Pd-PEPPSI-IPr = [1,3-Bis(2,6-
diisopropylphenyl)imidazol-2-ylidene] (3-chloropyridyl)palladium(II)
dichloride; nep = neopentyl glycolato. [b] Yields in parentheses refer to
reactions performed under inert atmosphere of a glovebox (0.25 mmol
scale; 1 mL of solvent)
F
2l
; 54% (52%)
2k
2j
2i
; 99% (93%)
; 84% (79%)
O
O
O
Unsuccessfull boronic acids
Ph
Ph
F
F
(HO)2B
F
(HO)2B
F
F
F
F
F
S
(HO)2B
F
2n
; 8%
2m
; 86% (65%)
78% (72%)[c]
O
O2N
MeO
O
F
O
Me
F
F
Scope and limitations of the protocol
F
F
F
Having established optimal reaction conditions, we screened
the scope of the reaction (Table 2). The cross-coupling reaction
proceeded well with a diversity of arylboronic acids bearing
electron-donating and electron-withdrawing groups (2a-2m).
Remarkably, the yields were not affected by the steric hindrance
of ortho-substituted substrates. Various substituents and
functional groups were tolerated, including carboxylic ester and
ketone, thus offering opportunities for further diversification.
The reactivity of halide-substituted arylboronic acids was also
examined, including base-sensitive[19a] polyfluorophenyl
derivatives. Pleasingly, mono- and bis-fluorinated arylketones
(2i and 2j, respectively) were formed in high yield, but
production of the corresponding pentafluoroaryl derivative
proved unsuccessful. One notable exception to the general good
behavior of arylboronic acids in this reaction was the p-chloro-
substituted derivative that only afforded low yields of the
desired arylketone (2h).[22] Gratifyingly, inherently unstable 2-
heterocyclic boronic acids[30] also proved suitable substrates
under inert atmosphere as illustrated with the synthesis of 2-
2q
; 85% (73%)
2p
; 98% (72%)
2o;
27% (25%)
[a] Reactions performed on 0.5 mmol of 1 in 2 mL of DMF.
Yields were determined by 19F NMR of the crude reaction mixture
using fluorobenzene as an internal standard. Isolated yields are
given in parentheses. [b] Yield of gram-scale reaction. [c] Reaction
performed using Pd(PCy3)2 as catalyst in toluene under inert
atmosphere of a glovebox.
Synthetic potential: orthogonal functionalization
As a broader perspective in the cross-coupling reactions of
α,α-difluoroacetamides,
we
conceived
that
N-
(bromodifluoroacetyl)-glutarimide (1e) could possibly serve as
a useful template that would offer orthogonal connective
pathways to α-(hetero)aryl-α,α-difluoroketones by combining
alkylation and acetylation steps through successive C–Br and
C–N bond cleavage processes (Scheme 3a). To evaluate the
feasibility of this design, we selected as first strategic bond
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connecting pathway the photo-induced CF2 radical-based
Page 6 of 10
new
Scheme 3. Orthogonal functionalization as
perspective, and synthetic applications.
a
1
2
3
4
5
6
7
8
approach that will ensure mechanistic discrimination between
the two reactive sites through selective activation of the C–Br
bond. Most delightedly, exploratory experiments indicated that
N-glutarimide-derived bromodifluoroacetamide 1e could be
used as an effective difluoroalkylation reagent of 2,3-
benzofuran and N-methylpyrrole, and most importantly under
base-free conditions.[31] A brief optimization study revealed that
the C–H bond gem-difluoroalkylation of these heteroarenes
with 1e proceeds selectively in DMF as the solvent using either
Ru- or Ir-based photocatalysts (i.e., Ru(bpy)3Cl26H2O; Ir(dF-
CF3-ppy)2(dtbpy)(PF6)) under the illumination of 5W blue
light-emitting diodes (LEDs) to give access to the desired N-(α-
heteroaromatic α,α-difluoroacetyl)-glutarimide derivatives (1g-
h).
a) Connective pathway from N-(bromodifluoroacetyl)-glutarimide:
1st
O
O
(Het)Ar
H
O
O
Br
(Het)Ar
3 mol% Ru(bpy)3Cl26H2O
N
N
F
F
F
F
Blue LEDs (5W)
DMF, rt, 16 h
O
O
1e
1g-h
(Het)Ar =
N
O
Me
9
1g
1h
; 80%
; 55% (64%*)
* yield with Ir(dF-CF3-ppy)2(dtbpy)(PF6)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
(HO)2
B
Ph
TsNHNH2
NH
N
AcONa, EtOH, reflux
O
52%
O
cat Pd
standard conditions
O
F
F
F
F
79%
Further reactivity and synthetic applications of the
difluorinated N-acylglutarimides were then investigated with a
particular focus on target compounds of potential biological
relevance (Scheme 3a). For instance, α-fluorinated α',β'-
unsaturated ketones have recently attracted much interest as
advanced intermediates for the synthesis of fluoroalkyl-
substituted heterocycles, and most notably pyrazole-based
drugs and agrochemicals. However, methods to access these
compounds remain sporadic and often rely on multiple-step
pathways combined with the use of specialized reagents.[32]
Pleasingly, the successful participation of trans-β-styrylboronic
acid in the cross-coupling reaction with 1g through C(acyl)–N
bond activation provides a straightforward access to α,α-
difluorinated enone 3 in good yield. The synthetic interest of 2-
benzofuryl derivative 3 was illustrated by reaction with N-
tosylhydrazine[33] to furnish valuable CF2-linked bis-
heteroarene 4. Notably, bis-(hetero)arene difluoromethane
derivatives are currently being considered as possible
lipophilic, metabolically stable replacements for bis-
(hetero)arene methanes in medicinal chemistry.[34] Importantly,
1g also displayed further interesting reactivity towards catalyst-
free direct transamidation reactions. These methods have
recently emerged as the most attractive, though the most
challenging, for amide synthesis.[35] For instance,
interconversion of glutarimide to L-phenylalanine methyl ester
proceeded smoothly at room temperature under catalyst-free
conditions, to yield difluoroacetyl phenylalanine derivative 5.
Finally, we envisioned that N-(difluoroacetyl)-glutarimide
(1f) could also prove useful as an alternative platform for
orthogonal functionalization through sequential cross-coupling
connective pathways involving here C–H and CN bond
cleavage processes. Indeed, the Pd-catalyzed Buchwald-
Hartwig type α-arylation of α,α-difluoroketones (HCF2COR, 6)
with haloarenes has recently been established as a new method
to access α-aryl-α,α-difluoroketones (2).[36] We reasoned that N-
(α,α-difluoroacetyl)-glutarimide 1f could then serve as a
valuable synthetic precursor of the starting α,α-difluoroketones,
and thereby offer a first catalytic connective pathway toward
bis-arylated difluoroketones via C–N bond cleavage (Scheme
3b). To showcase the feasibility and the potential of this
pathway, the cross-coupling of CF2H-containing amide 1f was
carried out with selected examples of boronic acids, affording
aryl ketones 6, including estrone derivative 6c. This brief survey
represents, to the best of our knowledge, the first demonstration
of a catalytic process allowing transfer of an intact COCF2H
group from a reagent to an (hetero)arene.[37]
4
3
ArCF2-substituted
pyrazole
2nd
N
O
O
O
F
F
O
1g
CO2Me
NH2.HCl
O
Ph
O
N
CO2Me
H
F
F
Et3N, DMF, 20 °C, 16 h
92%
5
Phenylalanine derivative
b) Connective pathway from N-(difluoroacetyl)-glutarimide:
1st
Ar2 Hal
cat Pd
2nd
O
Ar1 B(OH)2
cat Pd
O
O
O
Ar2
H
H
N
Ar1
Ar1
F
F
Qing, ref [36a]
Hartwig, ref [36b]
Standard conditions
F F
F
F
O
2
6
1f
O
O
O
Ar1
=
H
H
H
6b
; 72%
6a
; 68%
6c
; 22%
Estrone derivative
CONCLUSIONS
In summary, we have developed a novel and simple synthetic
access to diversely substituted α,α-difluoroketones based on
palladium-catalyzed cross-coupling of difluoroacetamides with
boronic acids. The mechanism of the reaction has been
thoroughly investigated to gain a clear understanding of the
catalytic cycle. The first step involves C–N bond oxidative
addition of difluoracetamide to give difluoroacyl palladium
intermediates that have been structurally authenticated. Then,
the difluoroacyl palladium-amidate intermediate has been
shown to rapidly undergo base-free transmetallation with
boronic acids, followed by C–C bond reductive elimination to
yield the desired difluoroketone selectively. The reaction
proceeds under mild conditions on the bench top to provide
structurally diverse difluoroketones, including MeCF2-
and HCF2-ketones that are not easily accessible by other
reported methodologies. We also demonstrated the synthetic
potential and complementarity of this protocol by highlighting
orthogonal C–Br and C–N bond functionalization of readily
available α-bromo-α,α-difluoroacetamide substrates, which
bring new opportunities to the field of synthetic organofluorine
chemistry. Current work in our laboratory is seeking to
generalize this methodology to other difluorinated carboxylic
acid derivatives and to investigate the application of this
approach to the development of decarbonylative cross-coupling
of difluorocarbonyl substrates.
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ACS Catalysis
Compounds. Chem. Eur. J. 2017, 23, 14676–14701. (c) Feng, Z.; Xiao,
EXPERIMENTAL SECTION
Y.-L.; Zhang, X. Transition-Metal (Cu, Pd, Ni)-Catalyzed
Difluoroalkylation via Cross-Coupling with Difluoroalkyl Halides.
Acc. Chem. Res. 2018, 51, 2264–2278. For an illustrative example from
our laboratory, see: (e) Prieto, A.; Melot, R.; Bouyssi, D.; Monteiro, N.
Palladium-Catalyzed C(sp2)−H Alkylation of Aldehyde-Derived
Hydrazones with Functionalized Difluoromethyl Bromides. Angew.
Chem. Int. Ed. 2016, 55, 1885–1889.
1
2
3
4
5
6
7
8
Preparation of α-(hetero)aryl-α,α-difluoroketones 2. A
10 mL microwave reaction vial equipped with a magnetic stir
bar was charged with palladium acetate (3 mol%; 0.015 mmol;
3.2 mg), PCy3HBF4 (6 mol%; 0.03 mmol; 11 mg), the selected
N-(-(hetero)aryl--difluoroacetyl)-glutarimide derivative
(1.0 equiv; 0.5 mmol), the selected boronic acid (2.0 equiv; 1.0
mmol), triethylamine (12 mol%; 0.06 mmol; 8 μL) and dry
DMF (2 mL; 0.25 M). The vial was flushed with argon and
capped, and the reaction mixture was stirred for 16 h at 80 °C
(aluminum heating block). The mixture was then cooled to
room temperature, diluted with dichloromethane (10 mL) and
washed with HCl 1N (3 x 10 mL). The organic phase was then
dried over MgSO4, concentrated under vacuum, and the residue
subjected to silica gel flash chromatography to afford the
corresponding -difluoroketone.
(3)
(a) Chatterjee, T.; Iqbal, N.; You, Y.; Cho, E. J. Controlled
Fluoroalkylation Reactions by Visible-Light Photoredox Catalysis.
Acc. Chem. Res. 2016, 49, 2284–2294. (b) Lemos, A.; Lemaire, C.;
Luxen, A. Progress in Difluoroalkylation of Organic Substrates by
Visible Light Photoredox Catalysis. Adv. Synth. Catal. 2019, 361,
1500–1537.
9
10
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4)
Belhomme, M.-C.; Besset, T.; Poisson, T.; Pannecoucke, X.
Recent Progress toward the Introduction of Functionalized
Difluoromethylated Building Blocks onto C(sp2) and C(sp) Centers.
Chem. Eur. J. 2015, 21, 12836–12865.
(5)
For an up-to-date overview of the preparation, use, and
biological activity of α,α-difluoroketones, see: Pattison, G. Methods for
the Synthesis of α,α-Difluoroketones. Eur. J. Org. Chem. 2018, 2018,
3520–3540.
AUTHOR INFORMATION
Corresponding Author
* E-mail: nuno.monteiro@univ-lyon1.fr
* E-mail: abderrahmane.amgoune@univ-lyon1.fr
(6)
For illustrative examples, see: (a) Arlow, S. I.; Hartwig, J. F.
Synthesis of Aryldifluoroamides by Copper-Catalyzed Cross-
Coupling. Angew. Chem. Int. Ed. 2016, 55, 4567–4572. (b) Ge, S.;
Arlow, S. I.; Mormino, M. G.; Hartwig, J. F. Pd-Catalyzed α-Arylation
of Trimethylsilyl Enolates of α,α-Difluoroacetamides. J. Am. Chem.
Soc. 2014, 136, 14401–14404. (c) Arimitsu, S.; Fernández, B.; del
Pozo, C.; Fustero, S.; Hammond, G. B. Concise Preparation of 2,2-
Difluorohomopropargyl Carbonyl Derivatives. Application to the
Synthesis of 4,4-Difluoroisoquinolinone Congeners. J. Org. Chem.
2008, 73, 2656–2661.
Author Contributions
‡Antonio Reina and Tetiana Krachko contributed equally to this
work.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS
Publications website at DOI:
(7)
For selected reviews on C–N and C–O bond activation, see:
(a) Meng, G.; Shi, S.; Szostak, M. Cross-Coupling of Amides by N–C
Bond Activation. Synlett 2016, 27, 2530–2540. (b) Takise, R.; Muto,
K.; Yamaguchi, J. Cross-Coupling of Aromatic Esters and Amides.
Chem. Soc. Rev. 2017, 46, 5864–5888. (c) Dander, J. E.; Garg, N. K.
Breaking Amides Using Nickel Catalysis. ACS Catal. 2017, 7, 1413–
1423. (d) Guo, L.; Rueping, M. Decarbonylative Cross-Couplings:
Nickel Catalyzed Functional Group Interconversion Strategies for the
Construction of Complex Organic Molecules. Acc. Chem. Res. 2018,
51, 1185–1195. (e) Liu, C.; Szostak, M. Decarbonylative Cross-
Coupling of Amides. Org. Biomol. Chem. 2018, 16, 7998–8010. (f) Shi,
S.; Nolan, S. P.; Szostak, M. Well-Defined Palladium(II)–NHC
Precatalysts for Cross-Coupling Reactions of Amides and Esters by
Selective N–C/O–C Cleavage. Acc. Chem. Res. 2018, 51, 2589–2599.
(g) Chaudhari, M. B.; Gnanaprakasam, B. Recent Advances in the
Metal-Catalyzed Activation of Amide Bonds. Chem. Asian J. 2019, 14,
76–93. (h) Bourne-Branchu, Y.; Gosmini, C.; Danoun, G. N -Boc-
Amides in Cross-Coupling Reactions. Chem. Eur. J. 2019, 25, 2663–
2674. For C–F bond activation: (i) Keaveney, S. T.; Schoenebeck, F.
Palladium-Catalyzed Decarbonylative Trifluoromethylation of Acid
Fluorides. Angew. Chem. Int. Ed. 2018, 57, 4073-4077. (j) Blanchard,
N.; Bizet, V. Acid Fluorides in Transition-Metal Catalysis: A Good
Balance between Stability and Reactivity. Angew. Chem. Int. Ed. 2019,
58, 6814–6817.
Experimental procedures, spectral and analytical data
including NMR spectra (PDF)
Crystallographic data for IIb (CIF)
Crystallographic data for IIc (CIF)
ACKNOWLEDGMENT
Financial support from the Université de Lyon, IDEXLYON
project (ANR-16_IDEX-0005) and the Agence Nationale de la
Recherche (ANR-JCJC-2016-CHAUCACAO) is gratefully
acknowledged. We thank A. Baudouin and E. Chefdeville for their
help in setting up and conducting NMR experiments, and C.
Duchamp for mass spectrometry analyses.
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for
Palladium-Catalyzed
Decarbonylative
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(22) See Supporting Information for details.
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(25) NMR data consistent with those of previously reported
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Phosphine)Palladium(II)
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(27) CCDC 1958225 (IIb) and CCDC 1958226 (IIc) contain the
supplementary crystallographic data for this paper. Copies of the data
can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(28) Notably, in these conditions the product of decarbonylative
cross-coupling was detected in 29% spectroscopic yield, see SI.
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Miyaura Coupling of Acid Fluorides. Nature 2018, 563, 100–104. (b)
Ohashi, M.; Saijo, H.; Shibata, M.; Ogoshi, S. Palladium-Catalyzed
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a
previous report on the photo-catalyzed
(hetero)arylation of halodifluoroacetamides, see: Wang, L.; Wei, X.-J.;
Jia, W.-L.; Zhong, J.-J.; Wu, L.-Z.; Liu, Q. Visible-Light-Driven
Difluoroacetamidation of Unactive Arenes and Heteroarenes by Direct
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(37) Another direct, catalytic access to -difluoromethyl aryl
ketones (ArCOCF2H) from arylboronic acids has just been reported,
based on the use of diethyl bromodifluoromethylphosphonate as a
fluorine source: see ref [15].
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Difluoromethylation and Difluoroacetylation. Org. Lett. 2015, 17,
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Vanadium-Catalyzed Coupling of Allenols with Electrophilic Halide
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Abstract:
1
Difluoroacetamides are established as difluoroacetylation reagents through Pd-catalyzed Cacyl–N bond cleavage, and
effectively participate in base-free SM cross-coupling reactions to afford high-value α,α-difluoroketones. Mechanistic studies
allowed the structural characterization of oxidative addition-derived fluoroacyl-PdII intermediates. Insight into possible
applications to orthogonal C–Br and C–N bond functionalization of α-bromodifluoroacetamides is also provided.
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Ar
B(OH)2
O
Catalysis
O
O
R
cat Pd/PCy3
R
N
Ar
F
F
O
No base
F
F
R = (Het)Ar, Alk, H
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Mechanistic studies
X = Cl, OCOCF2Ph
Orthogonal reactivity
O
Ph
O
Cy3P
X
2nd arylation
Pd catalysis
F
F
Br
O
Pd
N
1st arylation
Photoredox
catalysis
ZnCl2 or H3BO3
as additives
F
F
PCy3
O
X-Ray
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