Direct Access to α,α-Difluoroacylated Arenes by Palladium-Catalyzed Carbonylation of (Hetero)Aryl Boronic Acid Derivatives

Article abstract of DOI:10.1002/anie.201604152

A palladium-catalyzed carbonylative coupling of (hetero)aryl boronates or boronic acid salts with carbon monoxide and α-bromo-α,α-difluoroamides and bromo-α,α-difluoroesters is described herein. The method is useful for the synthesis of a diverse selection of (hetero)aryl α,α-difluoro-β-ketoamides and α,α-difluoro-β-ketoesters, which are useful building blocks for the generation of functionalized difluoroacylated and difluoroalkyl arenes. The method could be further extended to a one-pot protocol for the formation of difluoroacetophenones.

Full text of DOI:10.1002/anie.201604152

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International Edition: DOI: 10.1002/anie.201604152
German Edition: DOI: 10.1002/ange.201604152
Cross-Coupling
Direct Access to a,a-Difluoroacylated Arenes by Palladium-Catalyzed
Carbonylation of (Hetero)Aryl Boronic Acid Derivatives
Thomas L. Andersen, Mette W. Frederiksen, Katrine Domino, and Troels Skrydstrup*
Abstract: A palladium-catalyzed carbonylative coupling of
(hetero)aryl boronates or boronic acid salts with carbon
monoxide and a-bromo-a,a-difluoroamides and bromo-a,a-
difluoroesters is described herein. The method is useful for the
synthesis of a diverse selection of (hetero)aryl a,a-difluoro-b-
ketoamides and a,a-difluoro-b-ketoesters, which are useful
building blocks for the generation of functionalized difluoro-
acylated and difluoroalkyl arenes. The method could be further
extended to a one-pot protocol for the formation of difluor-
oacetophenones.
T
he introduction of fluorine atoms as substitutes for hydro-
gen is an important strategy for the modulation of the
biological activity of a pharmaceutically relevant molecules.[1]
Considerable efforts have been devoted to the development
of new synthetic methodologies for accessing fluorinated
compounds. This includes the CF2 group, which can function
as a bioisostere for e.g. -C(CH3)2, an oxygen atom, or
a carbonyl group.[2] In this aspect, the introduction of a,a-
difluorinated carbonyls has attracted much attention, as such
motifs in small building blocks are readily available.[3] For
instance, palladium- or copper-catalyzed a-arylations of aryl
halides with the enolates of a,a-difluorinated acetamides,
phenones, or esters have been reported by the groups of
Hartwig, Qing, and Amii, for accessing a wide range of aryl
a,a-difluoroacetamides, a,a-difluoroketones, and a,a-
difluoroesters (Scheme 1a).[4] Alternatively, similar structures
have been obtained by reversing the polarity of the coupling
partners, for example, the coupling of a-halo-a,a-difluoro-
acetamides with the corresponding aryl zinc or boronic acid
derivatives (Scheme 1b).[5] The latter approach was also
extended to include the formation of gem-difluorinated
amides, esters, and phosphonates, as well as a similar strategy
towards gem-difluoromethylation of (hetero)aryl boronic
acids.[6]
Scheme 1. Recent developments in catalytic difluoroalkylation proto-
cols and novel carbonylative approach. TMS=trimethylsilyl.
tion.[7] Nevertheless, the a,a-difluorinated dicarbonyl moiety
remains an excellent entry point for accessing a variety of
functionalities and ring structures containing fluorine. For
these reasons, we investigated the three-component palla-
dium-catalyzed carbonylative a-arylation of a-silylated-a,a-
difluoroacetamides to deliver structures such as the ketone
1 (Scheme 1c). Whereas preliminary reactions revealed that
this ketone was generated, it was accompanied by the product
from simple protonation of the TMS enolate. In addition,
a compound from enolate addition to 1 was produced, an
event arising from the electron-withdrawing effect exerted by
the fluorine atoms.[8] Attempts to control these unwanted side
reactions were unsuccessful, and instead we resorted to
employing boronic acid derivatives as the nucleophilic
coupling partner, in combination with an a-bromo-a,a-
difluoroacetamide (3) as the electrophile (Scheme 1c). Such
an approach would bypass the issue of product reactivity, as
the boronic ester coupling partner would be less nucleophilic
towards the a,a-difluoroacylated arene products.
So far no efforts have been directed to a carbonylative
version of these transformations to generate a,a-difluoroacy-
lated arenes such as 1 (Scheme 1c). Such structures are not
widely found and their overall absence in the pharmaceutical
portfolio may be related to the challenges in their prepara-
We initially investigated the carbonylative coupling of the
aryl boronic acid neopentylglycol ester 2a and
bromodifluoroacetamide 3a (Table 1). In this setup, CO gas
was generated from COgen in a separate reaction chamber
and in a slight excess (1.6 equiv).[9] After optimization of the
coupling conditions, formation of 1a occurred in the presence
of [Pd(PPh3)4] with Xantphos as a secondary ligand by
heating the reactions to 1008C in toluene with water as
a cosolvent (9:1). CuI was employed as a cocatalyst along with
an excess of K2CO3 (entry 1). The coupling also proceeded by
[*] T. L. Andersen, M. W. Frederiksen, K. Domino, Prof. Dr. T. Skrydstrup
Carbon Dioxide Activation Center (CADIAC), Department of
Chemistry and the Interdisciplinary Nanoscience Center (iNANO),
Aarhus University
Gustav Wieds Vej 14, 8000 Aarhus C (Denmark)
E-mail: ts@chem.au.dk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201604152.
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Table 1: Optimization of the carbonylative assembly of boronic ester 2a
and bromide 3a.
Entry
Deviations from standard cond.
Yield [%][b]
1
2
none
with ArB(OH)2
99
52
3
with ArBF3K
27
4
without Xantphos
37
5
6
7
8
PPh3 instead of Xantphos
P(tBu)3 instead of Xantphos
dppf instead of Xantphos
Pd(OAc)2 instead of [Pd(PPh3)4]
[Pd(PPh3)2Cl2] instead of [Pd(PPh3)4]
without CuI
32
56
58
39
53
75
9
10
11
12
without water as co-solvent
5mol% [Pd(PPh3)4] and 10mol% Xantphos
69
99 [92][c]
[a] CO gas was generated from 9-methyl-9H-fluorene-9-carbonyl chloride
in a separate reaction chamber; see the Supporting Information section.
[b] As determined by 1H NMR spectroscopy using mesitylene as an
internal standard. [c] Yield of isolated product. Bnep=boronic acid
neopentylglycol ester, dppf=1,1’-bis(diphenylphosphanyl)ferrocene,
Xantphos=9,9’-dimethyl-4,5-bis(diphenylphosphino)xanthene.
employing either the corresponding boronic acid or the BF3K
salt, however, in both cases the yields were lower (entries 2
and 3). Similarly, conducting the reaction in the absence of
Xantphos or with additional PPh3 or dppf led to a lower
product formation. Substituting Xantphos for P(tBu)3 pro-
vided full conversion of the starting boronic ester, but resulted
in a more complex product distribution (entries 4–7). Several
palladium sources were also investigated, but led to no
improvement over using [Pd(PPh3)4] (entry 8 and 9). The
omission of CuI led to a decrease in yield, although product
formation was still observed to a large extent. However,
a more reliable and reproducible turnover was observed in
the presence of copper. The same trend was observed when
water was omitted as a cosolvent, thus leading to a lowered
yield (entries 10 and 11). Finally, by increasing the catalyst
loading, 1a could be isolated in a 92% yield in a reproducible
fashion (entry 12).
To establish the applicability of the protocol, a range of
aryl boronic esters were coupled with 3a under similar
reaction conditions. It was found that simple aryl substituents
such as a phenyl or the coupling of a naphthalene derivative
was well tolerated, thus leading to the corresponding b-keto-
a,a-difluoroacetamides (1b and 1g; Scheme 2). The presence
of halogen substituents such as fluoride on the aryl group was
equally well tolerated, thus leading to 1d and 1e in good
yields. As was seen for 1a, it was also possible to employ the
corresponding aryl boronic acid to form 1d, albeit in a lower
yield when compared to that of the boronic ester. Having
a chloride in the para-position led to a drop in the yield of 1c
when compared to that of the fluorine analogue, possibly
because of halogen activation by the transition metal.
However, the yield could be increased to 71% by lowering
Scheme 2. Scope of a,a-difluoro-b-ketoamides. [a] CO gas was gener-
ated from 9-methyl-9H-fluorene-9-carbonyl chloride in a separate reac-
tion chamber. See the Supporting Information section. [b] Average of
two runs. [c] Reaction run at 908C. [d] Reaction run at 808C without
CuI. Bpin=boronic acid pinacol ester.
the reaction temperature to 908C. It is well-known that
heterocyclic boronic acids and ester derivatives are prone to
protodeboronation and dimerization events, which are most
likely accelerated in the presence of heat, base, and metal
catalysts.[10] Therefore, and not surprisingly, attempts to
couple 3-pyridineboronic acid neopentylglycol ester led to
a low yield (30%) of the corresponding a,a-difluorinated b-
ketoamide 1h under unaltered coupling conditions.
However, by employing the more stable 3-pyridinebor-
onic acid pinacol ester and by lowering the reaction temper-
ature to 808C in the absence of CuI, 1h could be isolated in
78% yield in a reproducible fashion (Sceme2). This result
suggests that an intimate relationship is operating between
the boronic ester hydrolysis rate, the rate of alkyl bromide
activation, and transmetallation, and that successful coupling
relies on the fine-tuning of these parameters. Meanwhile,
a range of heteroaromatic boronic acid derivatives could be
coupled with these modified reaction conditions, to give for
example, quinolone and pyridine derivatives 1i (77%) and 1j
(66%), respectively. Furthermore, even notoriously challeng-
ing coupling partners such as 2-thienyl- and 2-benzothienyl
boronic acid esters were viable substrates, thus leading to 1k
2
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and 1l in an 82 and 59% yield, respectively.[11] Useful yields of
1m and 1n could be obtained when 2-boronato derivatives of
nitrogen-containing heterocycles such as an N-substituted
pyrazole or a free indole were employed.[12]
In a similar fashion, we investigated the tolerance for
substitutions on the amide coupling partner. These acet-
amides are readily available in one synthetic step from the
corresponding ethyl ester or carboxylic acid. In general, it was
found that tertiary amides underwent the carbonylative
coupling to give the corresponding b-ketoamides in high
yields (1o and 1p; Scheme 3). Secondary amides could also
Scheme 3. N-Substituted a-bromo-a,a-difluoroacetamides. [a] CO gas
was generated from 9-methyl-9H-fluorene-9-carbonyl chloride in a sepa-
rate reaction chamber; see Supporting Information section. [b] Average
of two runs. [c] Reaction run at 1108C and with 7.5 mol% CuI.
Scheme 4. Synthesis of a,a-difluoro-b-keto esters and a,a-difluoro
acetophenones. [a] CO gas was generated from 9-methyl-9H-fluorene-
9-carbonyl chloride in a separate reaction chamber; see Supporting
Information section. [b] Average of two runs. [c] 10% CuI. [d] Decar-
boxylation conducted on the corresponding ethyl ester 6 without
purification in TFA/H2O (1:1) at 1008C. [e] Decarboxylation occurred
spontaneously after coupling of 4 with ester 8. TFA=trifluoroacetic
acid.
be employed with high yield, even with increasingly sterically
demanding N-substituents (1q–t). Rapid deprotection of the
secondary tert-butyl amide 1r with catalytic MeSO3H pro-
vided a convenient approach to the formation of the primary
a,a-difluorinated-b-ketoamide 1s. Finally, the amino-acid
derivative 1u could be prepared in a high yield from the
corresponding amide.
difluorinated-b-ketoesters 6 f–h in 82, 55, and 79% yield,
respectively.
a-Bromo-a,a-difluorinated esters (5) represent another
interesting motif for this coupling reaction, and an attempt
was made to extend the optimized reaction conditions to
these starting materials (Scheme 4). Unfortunately, direct
translation of such conditions led only to a modest yield
(49%) of the a,a-difluoro-b-ketoester 6a, upon attempted
coupling between the ethyl ester and 4-t-butylphenylboronic
acid neopentylglycol ester. Better results were obtained when
the corresponding potassium trifluoroborate was employed,
thus leading to 6a in a 91% yield upon isolation. This trend
proved to be general and a range of aryl trifluoroborates
could be used to generate the desired compounds 6a–d.[13]
Attention was then turned to the ester coupling partner.
Initially, we found that the isopropyl ester furnished the
desired product 6e in a high yield of 80%. When more bulky
esters were employed, it was beneficial to increase the
amount of copper salt. Under these reaction conditions,
sterically encumbered esters derived from tBuOH, tert-amyl
alcohol, and (À)-borneol provided the corresponding a,a-
Finally, the possibility of performing a one-pot, acid-
mediated decarboxylation of the a,a-difluorinated-b-ketoest-
ers into their corresponding a,a-difluoroacetophenone coun-
terparts was examined. These structures are commonly
obtained from a Friedel–Crafts acylation of arenes with
difluoroacetonitrile (Houben–Hoesch reaction), or by metal-
ation of an aryl halide followed by electrophilic quenching
with, for example, ethyl 2,2-difluoroacetate. In the present
case, we found that filtration and concentration of the crude
mixture from the coupling reaction with the ethyl ester 5 (R =
Et) and subsequent heating in a TFA/H2O (1:1) mixture,
promoted an efficient decarboxylation. This way, the difluoro-
acetophenones 7a–d could be obtained in good to excellent
yields. When ester 8 was examined, the corresponding
difluoroacetophenones 7a and 7e were identified as the
only coupling products, arising from in situ decarboxylation.
Aryl a,a-difluoro-b-ketoamides and a,a-difluoro-b-esters
provide an excellent platform for the synthesis of function-
alized fluoroalkylated arenes. For instance, facile access to the
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fluorinated alcohol 9a could be achieved by reduction of 1b
with NaBH4 (Scheme 5). Alternatively, when the morpholine
amide 1o was employed under similar reaction conditions, the
corresponding a,a-difluorinated diol 12C/H-9b was formed in
Scheme 6. Mechanistic investigations. [a] Standard conditions identi-
cal to Scheme 2. [b] As determined by NMR analysis. A small quantity
of 12a was isolated for the purpose of characterization.
TEMPO=2,2,6,6-tetramethylpiperidinyl-1-oxyl.
Scheme 5. Functionalization of a,a-difluorinated-b-keto amides and
-esters. a) NaBH4 (2 equiv), methanol, 08C–RT. b) NaBH4 (3.5 equiv),
1-propanol, 808C. c) BH3·THF (5 equiv), THF, 0–808C. d) 1. NaBH4
(3.7 equiv), methanol, 08C–RT. 2. PPh3 (1.5 equiv), DIAD (1.5 equiv),
THF, RT. e) 1. NaBH4 (3.5 equiv), 1-propanol, 808C, 2. TsCl (1.1 equiv),
Et3N (2 equiv), CH2Cl2, 08C–RT. 3. nBuLi (1 equiv), ethanol, 0–708C.
f) Hydrazine (1 equiv), ethanol, 808C. DIAD=diisopropyl azodicarbox-
ylate, THF=tetrahydrofuran, Ts=4-toluenesulfonyl.
corresponding TEMPO adduct with no formation of 1a
(Scheme 6).[15] In addition to these observations, it should be
noted that fluoroalkylated toluene isomers such as 10 were
observed as side products under the described reaction
conditions.[16] Employing 11 as the starting material led to
formation of 12a in a low yield (20%).[17] The corresponding
cyclized adduct 12b was not observed, although we cannot
exclude its formation in small quantities. Instead, 12c was
identified as the major side product as determined by NMR
and MS analysis. Taken together, these results suggest that C-
centered radicals are generated by a SET pathway. Recombi-
nation with a palladium(I) species furnishes an oxidative
addition complex which ultimately leads to product forma-
tion. Alternatively, radical addition to the solvent may occur
leading to formation of the toluene isomers 10, or, when 11 is
employed as the substrate, 12c is formed by radical cycliza-
tion followed by H abstraction. The formation of 12a suggests
that recombination of the difluoroalkyl radical with palla-
dium occurs on a timescale comparable to that of the
intramolecular radical cyclization.
In summary, we have reported the development of
a synthetic route to aryl a,a-difluoro-b-ketoamides and a,a-
difluoro-b-esters by carbonylative cross-coupling. The
method relies largely on starting materials, which are either
commercially available or accessible in only few synthetic
steps, and provides access to a variety of fluorinated small
molecules. Furthermore, this chemistry can be extended to
a,a-difluoroacetophenones in a one-pot fashion. Our palla-
dium-catalyzed carbonylation reaction could grant ready
access to a range of privileged structures to aid the drug
discovery processes.
an excellent yield. One advantage of the described approach
to carbonylation is the ease of isotopic labeling of the
carbonyl group introduced by substituting COgen for an
isotope-labeled version. As such the 13C-labeled version of 1o
was obtained by using the normal coupling conditions, and by
reduction with NaBD4, an M + 4 version of the diol 13C/D-9b
could be prepared in a similar yield. When an analogous
morpholine amide was subjected to reduction with BH3·THF,
the corresponding amino alcohol 9c was obtained in good
yield. The a,a-difluorinated dicarbonyls also serve as versatile
precursors for the preparation of heterocyclic structures. By
reaction of the ester 6a with hydrazine, the 4,4-difluorinated
pyrazoline-3-one 9 f could be prepared. Alternatively, easy
access to difluorinated diols could be exploited for the
synthesis of the gem-difluoro oxetane 9e, through sequential
tosylation and base-promoted ring closure of the compound
12C/H-9b. Finally, the b-lactam 9d was prepared from 1q in an
86% overall yield by a two-step sequence involving ketone
reduction followed by a Mitsunobu-type cyclization.
The mechanism for the transition metal catalyzed cou-
pling of fluoroalkyl halides has been proposed in several
cases. In the presence of either copper, palladium, or nickel,
experimental data supports the formation of radicals on the
fluorinated carbon by a single-electron transfer (SET)
pathway.[3f,5b,14] To evaluate the possibility for such a pathway
under our reaction conditions, the coupling of 2a and 3a was
performed in the presence of 1,4-dinitrobenzene as a SET
scavenger. Addition of 20% did not lead to any change in the
yield of 1a, whereas increasing the amount to 2 equivalents
completely suppressed conversion of the starting material.
Addition of TEMPO (2 equiv) led to formation of the
Acknowledgments
We appreciate generous financial support from the Danish
National Research Foundation (grant no. DNRF118), the
4
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[7] The main synthetic routes to access these structures are
Villum Foundation, and the Danish Council for Independent
Research: Technology and Production Science, and Aarhus
University.
generally multistep operations featuring for example, metal-
mediated addition of a-bromo-a,a-dilfuoro acetates to aryl
aldehydes followed by oxidation: see Ref. [3g]; or electrophilic
a-fluorination of a previously assembled 1,3-dicarbonyl or
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2003, 44, 2799 – 2801; b) W. M. Peng, J. N. M. Shreeve, J. Org.
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Gotoh, J. Fluorine Chem. 1992, 58, 71 – 79.
Keywords: carbonylation · cross-coupling · fluorine · palladium ·
synthetic methods
[8] Addition adducts of this type were in several cases isolated as
a sideproduct.
[9] A detailed description of the experimental setup is included in
the Supporting Information section. For example, from our
group see: a) P. Hermange, A. T. Lindhardt, R. H. Taaning, K.
Bjerglund, D. Lupp, T. Skrydstrup, J. Am. Chem. Soc. 2011, 133,
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[12] The main limitations of the enclosed method were found to be
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no conversion was seen when alkyl chlorides were used as
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[13] Aryl trifluoroborates bearing electron-deficient groups led in
general to coupling yields ranging from 30–50%. The same was
observed when the potassium 3-pyridyl trifluoroborate salt was
employed.
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Received: April 28, 2016
Revised: June 3, 2016
Published online: && &&, &&&&
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Cross-Coupling
Yielding to pressure: The title reaction
produces aryl a,a-difluoro-b-ketoamides
and -esters from readily available
difluorinated carboxylic acid derivatives
by employing gaseous carbon monoxide.
The method features low CO pressures
and high functional-group tolerance. The
fluorinated products can be transformed
into a variety fluoroalkylated structures.
T. L. Andersen, M. W. Frederiksen,
K. Domino,
T. Skrydstrup*
&&&& — &&&&
Direct Access to a,a-Difluoroacylated
Arenes by Palladium-Catalyzed
Carbonylation of (Hetero)Aryl Boronic
Acid Derivatives
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!