Pd-Catalyzed Selective Carbonylation of gem-Difluoroalkenes: A Practical Synthesis of Difluoromethylated Esters

Article abstract of DOI:10.1002/anie.201813801

The first catalyst for the alkoxycarbonylation of gem-difluoroalkenes is described. This novel catalytic transformation proceeds in the presence of Pd(acac)₂/1,2-bis((di-tert-butylphosphan-yl)methyl)benzene (btbpx) (L4) and allows for an efficient and straightforward access to a range of difluoromethylated esters in high yields and regioselectivities. The synthetic utility of the protocol is showcased in the practical synthesis of a Cyclandelate analogue using this methodology as the key step.

Full text of DOI:10.1002/anie.201813801

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Accepted Article
Title: Pd-Catalyzed Selective Carbonylation of gem-Difluoroalkenes: A
Practical Synthesis of Difluoromethylated Esters
Authors: Jiawang Liu, Ji Yang, Francesco Ferretti, Ralf Jackstell, and
Matthias Beller
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813801
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10.1002/anie.201813801
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Pd-Catalyzed Selective Carbonylation of gem-Difluoroalkenes: A
Practical Synthesis of Difluoromethylated Esters
Jiawang Liu[a], Ji Yang[a], Francesco Ferretti[a,b], Ralf Jackstell[a], and Matthias Beller[a]*
Abstract: The first catalyst for the alkoxycarbonylation of gem-
approach to this interesting class of products can be achieved
difluoroalkenes is described. This novel catalytic transformation
by carbonylation of gem-difluoroalkenes (Scheme 1, c).
proceeds
in
the
presence
of
Pd(acac)2/1,2-bis((di-tert-
butylphosphan-yl)methyl)benzene (btbpx) (L4) and allows for an
efficient and straightforward access to a range of difluoromethylated
esters in high yields and regioselectivities. The synthetic utility of the
protocol is showcased in the practical synthesis of a Cyclandelate
analogue using this methodology as the key step.
The incorporation of fluorine or fluorinated building blocks into
organic molecules has become an important tool for designing
bioactive compounds and to improve the properties of functional
materials.[1] Thus, in recent years the controlled introduction of
these groups represents one of the most active areas in the
development of novel synthetic methodologies.[2]
Among the various fluorinated moieties, the difluoromethyl group
(CF2H) is a particularly interesting one. Compared with the well-
known CF3 substituent, this group bears a slightly acidic C-H
bond,[3] which is capable of hydrogen-bonding interactions to
improve the binding selectivity to specific receptors.[4] Moreover,
the difluoromethyl group is recognized as being isosteric and
isopolar with alcohols[5] or thiols.[6] Thus, at present there is a
strong interest to replace hydroxyl, amino, or thio substituents by
CF2H groups within lead structures of pharmaceuticals.[7]
Although significant advancements have been made in the direct
introduction of CF2H group into organic compounds,[8] including
Scheme 1. Synthesis of α,α-Difluoroalkyl Carbonyl Compounds and α-
Difluoromethyl Carbonyl Compounds.
As one of the most important processes for producing carboxylic
derivatives, transition metal catalyzed carbonylation reactions
have been extensively investigated and applied in academia and
industry for several decades.[18] In this respect, the
alkoxycarbonylation represents a well-established method for
the transformation of alkenes into the corresponding esters.[19] In
recent years, notable advancements were achieved with respect
to catalyst activity,[20] selectivity,[21] and CO surrogates.[22] To the
best of our knowledge, the direct alkoxycarbonylation of such
functionalized olefins to give difluoromethylated esters has not
been reported yet. Obviously, a key challenge for such process
is to avoid the competitive β-F elimination to form undesired
byproducts.[23] Advantageously, there are many methods and
reagents developed for the synthesis of gem-difluoroalkenes
from aldehydes and ketones.[24]
[9]
[10]
[11]
electrophilic,
nucleophilic,
free-radical,
and
difluorocarbene-involving[12] reactions, the preparation of
functionalized difluoromethyl and α,α-difluoroalkyl carbonyl
compounds is still highly desired.
Today, transition metal catalyzed cross-coupling reactions using
commercially available BrCF2CO2Et or its analogs with
organometallic
regents[13]
and
the
radical-induced
functionalization of alkenes and/or alkynes[14] provide the most
convenient strategies for the synthesis of α,α-difluoroalkyl
carboxylic acid derivatives (Scheme 1, a).[15] Nevertheless, for
the preparation of α-difluoromethyl compounds, few efficient
catalytic reports exist.[16] Notably, in 2016 Jacobsen and co-
workers developed the first catalytic asymmetric geminal
difluorination of β-substituted styrenes to give difluoromethylated
carbonyl compounds with tertiary or quaternary stereocenters
(Scheme 1, b).[17] We thought a complementary practical
Based on our continuous interest in carbonylations, herein we
present the first examples of alkoxycarbonylations to construct
α-difluoromethylated esters. Interestingly, using aliphatic alkenes
a cascade isomerization-alkoxycarbonylation allows for remote
olefin functionalization in high yield and selectivity. [27]
Recently, we demonstrated the advantage of specific phosphine
ligands
with
built-in-base
function
for
Pd-catalyzed
[*] a. Dr. J. Liu, J. Yang, Dr. F. Ferretti, Dr. R. Jackstell, Prof. Dr. M. Beller
Leibniz-Institut für Katalyse an der Universität Rostock, Albert-Einstein-
Straße 29a, 18059, Rostock, Germany
E-mail: matthias.beller@catalysis.de
b. Current address: Department of Chemistry, Università degli Studi di
Milano, Via Golgi 19, 20133 Milano, Italy
alkoxycarbonylations of less-reactive olefins including hindered
tetra-substituted alkenes.[20] Incorporation of tert-butyl and
pyridine substituents on the phosphorous atom of several
bidentate phosphine ligands dramatically improved the rate of
the nucleophilic attack on the intermediate Pd acyl complex,
Supporting information for this article is given via a link at the end of the
document.
[25]
which can be rate-limiting step in these catalytic protocols.
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10.1002/anie.201813801
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Hence, at the start of our studies, we investigated the influence
alkoxycarbonylations of different gem-difluoroalkenes, a variety
of aromatic gem-difluoroalkenes bearing diverse substituents
and heterocycles, are transformed into the corresponding
products in high yields with excellent regioselectivities. More
specifically, gem-difluoroalkenes 1a–k with either electron-
donating (OMe, OBn, OPh) or electron-withdrawing (Cl, Br,
CO2Me) groups on the phenyl ring provided the corresponding
products 2a–k in 85-98%. Notably, in case of bromo-substituted
substrates, which provide useful handles for further synthetic
transformations, no dehalogenation was observed. Furthermore,
substrates 1l-1o with multiple functional groups, also give the
corresponding products 2l-2o in 90-97%. The position of
substituents on the phenyl ring has no influence on the reaction
outcome. Hence, gem-difluoroalkenes 1p-1r afforded 2p-2r in
very good yields and selectivities. Interestingly, heterocycle-
substituted gem-difluoroalkenes based on (benzo)thiophene,
indole and furan proved to be viable substrates and gave the
corresponding products 2s-2v in moderate to excellent yields. It
should be noted that the product 2u was obtained by
carbonylation and deprotection of 1-(3-(2,2-difluorovinyl)-1H-
indol-1-yl)ethan-1-one under standard conditions. Unfortunately,
when other heterocyclic including 2-(2,2-difluorovinyl)benzofuran,
quinoline as well as tetra-substituted difluoroalkenes were used,
no desired product was detected (see SI, Table S8 and S11).
of
these
and
related
standard
ligands
for
the
methoxycarbonylation of 2-(2,2-difluorovinyl)naphthalene 1a
under typical carbonylation conditions for alkenes (Table 1).
Table 1. Pd-Catalyzed Alkoxcarbonylation of 2-(2,2-Difluorovinyl)naphthalene:
Investigation of Reaction Conditionsa
Entry
1
Ligand
L1
Acid (x)
b/lb
Yield (%)b
PTSA·H2O (16)
PTSA·H2O (16)
PTSA·H2O (16)
PTSA·H2O (16)
PTSA·H2O (16)
PTSA·H2O (16)
No acid
98/2
76/24
93/7
>99/1
93/7
>99/1
-/-
18
2
L2
7
3
L3
72
4
L4
92
5
L5
5
Table 2. Substrate Scope with respect to gem-Difluoroalkenesa
6
L6
9
7
L4
0
8
L4
HOAc (16)
-/-
0
5
9
L4
H2SO4 (8)
92/8
>99/1
>99/1
>99/1
10
11
12
L4
HOTf (16)
91
L4
PTSA·H2O (8)
PTSA·H2O (5)
97 (96c)
93
L4
[a] Reaction conditions: 1a (0.5 mmol), Pd(acac)2 (1.0 mol%), L (4.0 mol%)
PTSA·H2O (16.0 mol%), CO (40 atm),120 °C and methanol (2.0 mL). [b] The
ratio of branched/linear (b/l) and yield was determined by GC. [c] Isolated
yield.
Applying 1,1'-ferrocenediyl-bis(tert-butyl(pyridin-2-yl)phosphine)
L1, ester 2a was obtained with excellent regioselectivity albeit in
18% yield. In the presence of 1,3-bis(tert-butyl(pyridin-2-
yl)phosphanyl)propane L2 as the ligand, the yield of the desired
product was even lower. To our delight, using 1,2-bis((tert-
butyl(pyridin-2-yl)phosphanyl)methyl)benzene L3 the desired
product 2a was obtained in 72% yield. Surprisingly, the
commercially
available
1,2-bis((di-tert-butylphosphan-
yl)methyl)benzene (btbpx) ligand L4[26] which has the same
backbone to L3, gave an improved yield of 92% and >99/1
regioselecivity. Other commonly used bidentate phosphine
ligands such as Naphos L5 and Xantphos L6 only afforded the
product in poor yields. No reaction occurred without acid or
weak acid. Even sulfuric acid gave only trace amounts of 2a,
while trifluoromethanesulfonic acid afforded the desired product
in 91 % yield with excellent regioselectivity. Besides, the acid
concentration had a significant influence on the productivity
giving 2a in 93% and 97% in the presence of 5 and 8 mol%
PTSA, respectively.
[a] Reaction conditions: 1 (0.5 mmol), Pd(acac)2 (1.0 mol%), L4 (4.0 mol%)
PTSA·H2O (16.0 mol%), CO (40 atm),120 °C in methanol (2.0 mL). Isolated
yield for all products. The ratio of branched/linear was determined by GC. [b]
3/12/12 mol% of Pd/L4/PTSA·H2O and CO (50 atm).
Next, we evaluated the reactivity of aliphatic gem-
difluoroalkenes, which from the viewpoint of selectivity represent
more demanding substrates as they may undergo additional
isomerization reactions. Nevertheless, alkoxycarbonylations
With optimized reaction conditions established, we examined the
substrate scope of this process. First, we studied the
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proceeded selectively to afford various difluoromethylated esters. nonanol, cyclopropylmethanol, cyclopentylmethanol, and
The linear long chain aliphatic substrates 1w, 1x and 1y without
other functional groups gave the corresponding products 2w-2y
in good to high yields and selectivities. The isomerization
process for those substrates takes place at a faster rate than the
carbonylation in -position explaining the selectivity towards the
linear -ester. Reactions of 1,1-difluoro-4-arylbutenes 1z-1cc
also reacted well leading to the γ-difluoromethylated esters 2z-
2cc in good to high yields and selectivities, albeit at higher
catalyst loading and higher CO pressure.
cyclohexylmethanol, gave the desired products 3a-3f in 84-92%
yield. Similarly, carbonylations with less reactive secondary
alcohols, for instance cyclopentanol, cyclohexanol and cis-3,3,5-
trimethylcyclohexanol proceeded smoothly, providing the
products 3g-3i in 67-94% yield. Moreover, 1,7-heptanediol could
also be used in this reaction to afford selectively the monoester
product 3j. Notably, in case of inexpensive alcohols (see
products 3a, 3b and 3d-3h) the reactions can be easily
performed in neat alcohol. Furthermore, aliphatic and
heterocyclic gem-difluoroalkenes also gave the corresponding
products 3k-3p in 60-80% yield.
Table 3. Substrate Scope with Respect to Alcoholsa
A practical advantage of the presented methodology is the
possibility for easy scale up. Hence, we performed the gram-
scale synthesis of 2a under 0.5 mol% Pd catalysts loading and
the desired product was obtained in 92% yield (Scheme 2).
Obviously, this and related esters present versatile building
blocks which can be straightforwardly converted to interesting
amides, acids, nitriles, alcohols, and so on. To showcase such
possibilities, the reduction of 2a to 4 has been performed. To
explore the stability of the system, we further decreased the
catalyst loading. Keeping the acid concentration constant and
fixing the L4 concentration to 2 mmol/L, at 1a/Pd ratio >10000,
TONs up to 8400 were reached (for more details, see Table S9).
Scheme 2. Gram-Scale Synthesis of 2a
To highlight the usefulness of our protocol further on, we
synthesized the analogue of Cyclandelate, which is a commonly
used drug for claudication, arteriosclerosis and Raynaud's
disease. The desired product 6 was achieved in 83% yield via
direct alkoxycarbonylation of gem-difluoroalkene 5 with 3,3,5-
trimethylcyclohexanol under the optimized reaction conditions.
To the best of our knowledge, this is the first example for the
synthesis of this drug’s analogue.
[a] Reaction conditions: 1 (0.5 mmol), ROH (1.5 mmol), Pd(acac)2 (1.0 mol%),
L4 (4.0 mol%) PTSA·H2O (16.0 mol%), CO (40 atm),120 °C in toluene/MeCN
(1/1). Isolated yield for all products. The ratio of branched/linear was
determined by GC. For 3a-3j, Ar = 2-Naphthyl. [b] 1.0 mL alcohols were used
as solvents.
To demonstrate that this novel transformation can be applied to
wider scope of alcohols, we investigated the alkoxycarbonylation
of 1a with n-butanol as the nucleophile. Hence, different solvents
and conditions were tested using L4 as the ligand, and the yield
and selectivity was optimized to be 94% and 99/1 when a mixed
solvent system of toluene and acetonitrile (v/v = 1/1) was used
(see SI for more details).
Scheme 3. Practical Synthesis of Cyclandelate Analogue
In summary, we have developed the first selective carbonylation
of gem-difluoroalkenes. This catalytic protocol makes use of a
Pd/L4 catalyst and provides a variety of synthetically useful
difluoromethylated esters in high yields and excellent
regioselectivities. Due to availability of starting materials and the
step-economy, this procedure is efficient and easy to scale up.
The straightforward synthesis of a Cyclandelate analogue
demonstrates the synthetic utility of this methodology. It is
expected to provide other valuable difluoromethyl-containing
Under this optimized conditions, the scope of different alcohols
with 2-(2,2-difluorovinyl)naphthalene 1a were examined (Table
3). Gratifyingly, the corresponding esters were obtained in good
to high yields, again with excellent regioselectivities. For
example, primary alcohols, such as ethanol, n-butanol, n-
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Keywords: carbonylation • fluoroalkenes • difluoromethylated
esters • palladium• selectivity
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10.1002/anie.201813801
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Jiawang Liu, Ji Yang, Francesco
Ferretti, Ralf Jackstell, and Matthias
Beller *
Page No. – Page No.
Pd-Catalyzed Selective Carbonylation
of gem-Difluoroalkenes: A Practical
Synthesis of Difluoromethylated
Esters
The first selective carbonylations of gem-difluoroalkenes was developed, providing
a general approach to a variety of synthetically useful difluoromethylated esters in
high yields and excellent regioselectivities.
This article is protected by copyright. All rights reserved.