Deoxygenative trifluoromethylthiolation of carboxylic acids

Article abstract of DOI:10.1039/c9sc03396c

Here we describe a deoxygenative trifluoromethylthiolation method that yields trifluoromethyl thioesters from readily available carboxylic acids. The method is built upon an "umpolung" strategy where triphenylphosphine is used to first activate an electro

Full text of DOI:10.1039/c9sc03396c

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DOI: 10.1039/C9SC03396C
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Deoxygenative Trifluoromethylthiolation of Carboxylic Acids
Received 00th January 20xx,
Accepted 00th January 20xx
Runze Mao,a Srikrishna Bera,a Alexis Cheseaux,a and Xile Hu*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Here we describe
a deoxygenative trifluoromethylthiolation
method that yields trifluoromethyl thioesters from readily
available carboxylic acids. The method is built upon an “umpolung”
strategy where triphenylphosphine is used to first activate an
electrophilic trifluoromethylthiolating reagent and then serves as
an oxygen acceptor for the deoxygenation. The method is mild,
efficient, broad-scope, and tolerant. It can be applied for the late-
stage functionalization of numerous natural products and drug
molecules containing a carboxylic acid group. The trifluoromethyl
thioesters can be converted into trifluoromethyl thioethers by Pd-
catalyzed decarbonylation.
Organofluorine compounds have widespread applications in
medicinal and materials sciences.1-4 Among fluorine-containing
moieties, the trifluoromethylthio group (-SCF3) is of
considerable interest because of its high lipophilic and electron-
withdrawing nature. Significant progress has been made in
direct trifluoromethylthiolation of C-H and C-X moieties.4-19
However, there are still few efficient methods for the synthesis
of trifluoromethyl thioesters. Trifluoromethyl thioesters could
be prepared by reactions of acid chlorides with Hg(SCF3)2,
NMe4SCF3 or (bpy)CuSCF3 (Fig. 1A).17, 20-21 These reactions were
limited by the use of reactive or toxic reagents, or the
generation of a stoichiometric amount of metallic by-products.
The groups of Glorius18 and Shen19 reported elegant methods of
accessing trifluoromethyl thioesters from aldehydes via a
hydrogen atom transfer (HAT) process (Fig. 1A). Nevertheless,
among organic carbonyl compounds aldehydes are relatively
instable and less available. Carboxylic acids, on the other hand,
are abundant, stable, and non-toxic. The deoxygenative
Figure 1. (A) Examples of bio-active compounds containing a C-SCF3 moiety; (B)
Previous methods to synthesize trifluoromethyl thioesters from acid chlorides or
aldehydes; (C) This work: deoxygenative trifluoromethylthiolation of carboxylic
acids
a.Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences
and Engineering, École Polytechnique Fédérale de Lausanne (EPFL), ISIC-LSCI,
Lausanne 1015, Switzerland. E-mail: xile.hu@epfl.ch
desirable approach to the synthesis of trifluoromethyl
thioesters.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Despite its conceptual simplicity, the deoxygenative
trifluoromethylthiolation of carboxylic acids is challenging to
trifluoromethylthiolation of carboxylic acids would represent an
efficient and highly
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Table 2. Scope of the trifluoromethylthiolation of carboxylic acids[a]
achieve. It was reported that in the presence of a carboxylic
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acid, a CF3S- anion would lose an F- to form carbonothioic
Table 1. Summary of the effects of reaction parameters and conditions on the reaction
efficiency[a]
DOI: 10.1039/C9SC03396C
Entry
1
SCF3 reagent
Lewis acid
none
Yield
40%
95%
71%
64%
39%
71%
19%
51%
7%
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2a
2a
2a
2
FeCl3
3
FeCl3·6H2O
BF3·OEt2
AlCl3
4b
5
6
Sc(OTf)3
FeCl3
7
8
FeCl3
9
FeCl3
10
11[c]
12[d]
13[e]
FeCl3
0%
FeCl3
69%
68%
39%
FeCl3
FeCl3
[a]Yield determined by 19F NMR spectroscopy of the crude reaction mixture using
a,a,a-trifluorotoluene as an internal standard. [b]BF3·OEt2 (10 mol%).[c]NaHCO3 (1.0
equiv) as an external base. [d]2,6-lutidine (1.0 equiv) as an external base.
[e]tricyclohexanephosphine (PCy3) in place of PPh3.
difluoride, which further reacted with carboxylic acids to give
eventually an acyl fluoride.10, 22 Inspired by the rich chemistry of
phosphorus reagents and (acyl)oxyphosphonium ions I (Fig. 1B)
in peptide coupling,23 Mitsunobu,24-25 and Appel26 reactions, we
hypothesized that such intermediates could be possibly
transformed into trifluoromethyl thioesters from carboxylic
acids under suitable conditions. Here we describe an
“umpolung” strategy that allows the use of electrophilic
trifluoromethylthiolating
reagents
and
avoids
the
decomposition of CF3S- anion by carboxylic acids (Fig. 1C). The
“umpolung” is achieved with triphenylphosphine (PPh3), which
first captures a CF3S+ cation to form a SCF3-phosphonium salt
(
II), followed by a methathesis reaction with a carboxylate to
give an oxyphosphonium intermediate (III), which is probe to
deoxygenative trifluoromethylthiolation to give
a
trifluoromethyl thioester while eliminating triphenylphosphine
oxide (PPh3=O) (Fig. 1C). This strategy is
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[a]Carboxylic acid (1.0 equiv.), triphenylphosphine (Ph3P, 1.1 equiv.), N-
(trifluoromethylthio)phthalimide (1.3 equiv.), FeCl3 (5 mol%) in THF (0.2 M), room
temperature, 30 min, isolated yield.
carboxylic acids. Reactions of some alcohols, especially primary
alcohols, gave the desired products in low yields, which were
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DOI: 10.1039/C9SC03396C
difficult to isolate amide various side products. Several amino
acids were also used as substrates, however, yields were low
(Table S7), possibly due to the competition of N- and O-
nucleophilic sites.
The direct use of carboxylic acids as substrates makes the
current trifluomethylthiolation method applicable for the rapid,
late-stage modification of carboxylic acid-containing natural
products and drug molecules (Figure 3). Indeed, aromatic
carboxylic acids such as adapalene (6a), probenecid (6b),
applicable for the rapid synthesis of a diverse set of
trifluoromethyl thioesters from readily available aromatic and
aliphatic carboxylic acids, including many natural products and
drugs.
We began our investigation by optimizing the reaction of 4-
phenylbenzoic
acid
(
1a
)
with
N-
(trifluoromethylthio)phthalimide (2a) to give the corresponding
trifluoromethyl thioester (3a). To our delight, the reaction
proceeded in the presence of 1.1 equiv of Ph3P in
tetrahydrofuran (THF,0.2 M) with a yield of 40% (Table 1, entry
1). The reaction was then optimized by varying reaction
parameters (Table SI, S1-S5). A summary of key observations is
shown in Table 1. THF was the best solvent (Table S2). A small
amount of Lewis acid could enhance the reactivity of 2a (Table
1, entries 2-6; Table S3). The binding of a Lewis acid by the
lanosterol
(
6c),
L-menthol
derivative
(
6d
)
were
trifluoromethylthiolated with ease. Moreover, natural-
occurring cinnamic acids such as piperic acid (6e) and caffeic
acid isomer (6f) underwent smooth transformations as well.
Drug molecules and natural products containing an aliphatic
carboxylic acid group such as zaltoprofen (6g), ibuprofen (6h),
ketoprofen (6i), naproxen (6j), gemfibrozil (6k) and abietic acid
(6l) were all easily converted to their corresponding
phthalimide
group
might
polarize
N-
trifluoromethyl thioesters. The successful late-stage
functionalization of these natural products and drugs, many of
which contain sensitive sulfonamide, alkene, carbonyl and
heterocyclic groups, underscores the high chemoselectivity and
functional group tolerance of the current method.
(trifluoromethylthio)phthalimide, facilitating the nucleophilic
attack of PPh3 to N-(trifluoromethylthio)phthalimide and
subsequent generation of the key intermediate SCF3-
phosphonium salt (Figure 1C , II). Anhydrous FeCl3 (5 mol%) was
the best Lewis acid, giving a yield of 95% (Table 1, entry 2).
Among various trifluoromethylthiolating agents,27 2a proved to
be superior than other electrophilic trifluoromethylthiolating
Table 3. Late-Stage trifluoromethylthiolation of natural products and drugs containing a
carboxylic group[a]
reagent 2b-2d (Table 1, entries 7-9). When the nucleophilic
NMe4SCF3 (2e) was used, no product was formed (Table 1, entry
10). Addition of an external base slightly lowered the yields
(Table 1, entries 11-12; Table S4). Further optimization
indicated Ph3P was the best mediator (Table 1, entries 2, 13;
Table S5). It was worthy to note that the reaction completed
within 30 minutes at room temperature.
With the optimized conditions in hand (entry 2, Table 1), we
probed the generality of this transformations (Figure 2). A
myriad of aryl carboxylic acids containing electron-donating
(
3b
coupled to give the corresponding trifluoromethyl thioesters in
moderate to excellent yields. Notable, aryl halides (3g 3m),
including relatively reactive aryl iodides (3j 3m), were tolerated
-3f) and electron-withdrawing (3g-3o) substituents were
-
,
in the reaction. Functional groups such as trifluoromethyl (3n),
ester (3o), (tert-butoxycarbonyl)amino (3p), thiomethyl (3q),
boronic ester (3r), alkene (3s), alkyne (3t), 1,3-benzodioxole
(
3u) and naphthalene (3v) were all compatible. The reactions
also proceeded smoothly with various heteroaryl carboxylic
acids, giving the desired products (3w 3x) in satisfying yields.
−
Importantly, the reactions worked with aliphatic carboxylic
acids as well. Primary, secondary, tertiary carboxylic acids were
all suitable substrates, affording the corresponding
trifluoromethyl thioesters
(4a-4e) in good yields. The
trifluoromethylthiolation was also successful for various
cinnamic acids containing electron-neutral (5a), electron-
withdrawing
(5b-5e, 5h), and electron-donating (5f-5g)
substituents. A variety of alcohols and substituted methyl
benzoates were also tested as substrates (Table S7). Reactions
with methyl benzoates gave no products under the standard
conditions, suggesting a crucial role of the O-nucleophilic site of
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[a]Carboxylic acid (1.0 equiv.), triphenylphosphine (Ph3P, 1.1 equiv.), N-
(trifluoromethylthio)phthalimide (1.3 equiv.), FeCl3 (5 mol%) in THF (0.2 M), room
temperature, 30 min, isolated yield.
The trifluoromethyl thioesters can be converted into
trifluoromethyl thioethers in one step by Pd-catalyzed
decarbonylation.
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DOI: 10.1039/C9SC03396C
To demonstrate the synthetic utility of trifluoromethyl
thioesters, compound 3a was subjected to a Pd-catalyzed
decarbonylation29-30 to give the corresponding trifluoromethyl
thioether 7a in 91% yield (Figure 2). Trifluoromethyl thioethers
are ubiquitous in pharmaceutical and agrochemical
compounds.28 Thus, our method enables the synthesis of
trifluoromethyl thioethers from readily available carboxylic
acids.
Conflicts of interest
The authors declare no conflict of interest
Acknowledgements
This work is supported by the NoNoMeCat Marie Skłodowska-
Curie training network funded by the European Union under the
Horizon 2020 Program (675020-MSCA-ITN-2015-ETN) and the
Swiss National Science Foundation.
Figure 2. Conversion of
a trifluoromethyl thioester (3a) to the corresponding
trifluoromethyl thioether (7a) via a Pd-catalyzed decarbonylation.
Notes and references
Based on results from the control experiments (Table 1, S1-
S5),31 31P NMR study (Figure S51), and previous reports,32-33 we
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(Figure 3). N-
(trifluoromethylthio)phthalimide (2a) coordinates to FeCl3 via
the phthalimide group. This coordination increases the
electrophilicity of the SCF3 group, promoting the nucleophilic
attack
of
PPh3.
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latter
generates
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Conclusions
In summary, by using PPh3 as a mediator to “umpolung” the
electrophilic trifluoromethylthiolating agent 2a, we have
achieved,
for
the
first
time,
deoxygenative
trifluoromethylthiolation of carboxylic acids. The reactions are
rapid and occur at room temperature. They allow the access of
a wide range of trifluoromethyl thioesters from readily available
carboxylic acids. The method can be applied for the late-stage
functionalization of many natural products and drug molecules.
4 | J. Name., 2012, 00, 1-3
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COMMUNICATION
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were not indispensable (Table 1, entries 1-6, Table S3).
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DOI: 10.1039/C9SC03396C
A deoxygenative trifluoromethylthiolation method produces trifluoromethyl thioesters from
readily available carboxylic acids.