Deoxygenative tri- And difluoromethylthiolation of carboxylic acids with benzothiazolium reagents

Article abstract of DOI:10.1021/acs.orglett.0c03328

Deoxygenative syntheses of fluorinated thioesters directly from carboxylic acids have been developed employing benzothiazolium reagents. The process using BT-SCF₃ represents an attractive approach toward these SCF₃containing compounds that avoids the use of metal ^?SCF₃ salts or preactivated acyl electrophiles. Moreover, the in situ activation of BT-SCF₂H allows for an unprecedented nucleophilic difluoromethylthiolation reaction. DFT calculations support a mechanistic scenario involving a four-membered transition state where acyl substitution occurs without the formation of an unstable free ^?SCF₂H anion.

Full text of DOI:10.1021/acs.orglett.0c03328

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Letter
Deoxygenative Tri- and Difluoromethylthiolation of Carboxylic
Acids with Benzothiazolium Reagents
†
†
̈
Matteo Tironi, Lilian M. Maas, Arushi Garg, Stefan Dix, Jan P. Gotze, and Matthew N. Hopkinson*
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ABSTRACT: Deoxygenative syntheses of fluorinated thioesters directly from
carboxylic acids have been developed employing benzothiazolium reagents. The
process using BT-SCF3 represents an attractive approach toward these SCF3-
−
containing compounds that avoids the use of metal SCF3 salts or preactivated
acyl electrophiles. Moreover, the in situ activation of BT-SCF2H allows for an
unprecedented nucleophilic difluoromethylthiolation reaction. DFT calculations
support a mechanistic scenario involving a four-membered transition state where
−
acyl substitution occurs without the formation of an unstable free SCF2H anion.
Having identified BT-SCF3 as a convenient reagent for the
luorinated compounds play an important role in the
1
Fagrochemical and pharmaceutical industry. However, due trifluoromethylthiolation of alcohols, we considered whether
other important classes of fluoroalkylthiolated compounds
could be similarly prepared in a deoxygenative fashion from
readily available substrates. For example, deoxytrifluorome-
thylthiolation of carboxylic acids with BT-SCF3 would provide
facile access to trifluoromethylthioesters. Whereas trifluor-
omethylthioethers have been widely studied, the correspond-
ing esters remain relatively underexplored despite the potential
for applications in pharmaceuticals and agrochemicals.2 Most
reported synthetic routes toward trifluoromethylthioesters
to a scarcity of naturally occurring fluorinated molecules, the
production of fluorinated targets relies heavily on synthetic
organic chemistry. Among the various fluorine-containing
functional groups, fluoroalkylthio groups such as the SCF3
moiety have attracted considerable attention recently due to
their lipophilic yet polar nature and several fluoroalkylthiolated
pharmaceuticals and agrochemicals have been developed.2
The renewed interest in the SCF3 group in particular has
been spurred to a large extent by the development of new
electrophilic trifluoromethylthiolating reagents capable of
operating under mild conditions, which have supplanted the
previously available toxic gases F3CS-Cl and F3CS-SCF3.2b,d,3
In contrast, nucleophilic trifluoromethylthiolation relies on a
few comparatively expensive salts such as AgSCF3, CuSCF3,
and [Me4N]SCF3. In 2019, we reported a new purely organic
reagent for nucleophilic trifluoromethylthiolation suitable for
the deoxygenative functionalization of aliphatic alcohols: the
benzothiazolium salt BT-SCF3.4 This solid reagent can be
easily prepared on a multigram scale in two steps from the
inexpensive starting material 2-mercaptobenzothiazole (MBT)
and is bench stable at least over several months. In the
presence of an alcohol and the amine base NEt(iPr)2, however,
−
involve addition/elimination of SCF3 salts to acid chlorides,
which in addition to employing expensive, relatively unstable,
−
or even toxic SCF3 sources, require preformation of the acyl
electrophile and generate stoichiometric amounts of metal
chloride waste.7 A selection of recent reports have instead
employed electrophilic trifluoromethylthiolating reagents such
as Phth-SCF3 (Phth = phthalimide) or PhSO2SCF3, which
while still expensive, are bench stable and easily handled. The
groups of Glorius,8 Shen,9 and Wang10 have developed radical
methodologies involving SCF3 group transfer onto acyl radicals
generated via hydrogen atom transfer (HAT) from alde-
hydes.11 The only synthesis of trifluoromethylthioesters
directly from carboxylic acids was reported recently by Hu
and co-workers.12 This method uses an umpolung approach
that employs Phth-SCF3 as an electrophilic trifluoromethylth-
iolating reagent together with triphenylphosphine as a
stoichiometric reductant and an iron(III) catalyst.
−
addition/elimination at the C2 carbon releases SCF3, which
then reacts with the intermediate 2-alkoxybenzothiazolium salt
to afford a wide range of trifluoromethylthioethers under mild
conditions.5 This “in situ activation” approach is particularly
attractive for nucleophilic trifluoromethylthiolation as the free
−SCF3 anion is unstable toward β-fluoride elimination.6 Using
BT-SCF3, this anion is generated in a controlled fashion
together with a highly reactive electrophile. As such,
nucleophilic trifluoromethylthiolation is expected to proceed
rapidly while the concentration of −SCF3 in the reaction
mixture remains low (Scheme 1a).
Received: October 6, 2020
© XXXX The Authors. Published
byAmerican Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c03328
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Scheme 1. Previous Direct Syntheses of Tri- and Difluoromethylthioesters and In Situ Activation of BT Reagents
Partially fluorinated difluoromethylthioesters have been even
less studied. In addition to the lipophilic and electron-
withdrawing characteristics typical for fluoroalkylthio groups,
the SCF2H moiety can engage in hydrogen bonding
interactions in biological systems.13 These beneficial properties
have duly led to the development of SCF2H containing
pharmaceuticals and agrochemicals such as flomoxef sodium
and pyriprole. While there are currently no difluoromethylth-
ioester-containing pharmaceuticals, a structurally similar
monofluoromethylthioester motif is found in the corticosteroid
medication fluticasone. Synthetic routes toward SCF2H-
substituted compounds are comparatively limited with most
approaches involving difluoromethylation of a sulfur-contain-
ing substrate. In recent years, a few direct methods for
installing the entire SCF2H group onto organic molecules have
been introduced, employing a selection of mostly electrophilic
or radical difluoromethylthiolating reagents.14 To date,
however, only two methods both involving group transfer
from PhSO2SCF2H onto aldehyde-derived acyl radicals have
been reported for the synthesis of difluoromethylthioesters
(Scheme 1b).9,14
of BT reagents could provide a strategy for conducting
nucleophilic reactions of otherwise unstable fluorinated or
nonfluorinated anions (Scheme 1c).
We began our study by reacting preformed cesium 4-
methylbenzoate with BT-SCF3 (1.25 equiv)4,15 in MeCN.
After 2 h at rt, we were pleased to observe the formation of the
desired trifluoromethylthioester 2a in 39% NMR yield. With
the aim of developing an efficient set of conditions for the
direct deoxyfunctionalization of the free carboxylic acid 1a, a
survey of different bases and solvents was conducted. The
combination of NaH (3 equiv) and THF proved to be
optimum, while dilution to 0.033 M, dropwise addition of the
acid, and a lower reaction temperature of −78 °C suppressed
the formation of side products resulting from nucleophilic
attack of a second carboxylate anion or ring-opening of THF.16
With a set of optimized conditions established, an
investigation into the reaction scope with variously substituted
carboxylic acids 1 was conducted (Scheme 2). A wide range of
aryl derivatives could be successfully converted into the
corresponding thioesters in generally moderate to good yields.
Electronically diverse functional groups such as −OMe and
−NO2 were well tolerated, while halogen-substituted products
that are potentially amenable to further functionalization
through cross-coupling methodologies were efficiently pro-
vided. As demonstrated by Hu and co-workers, aromatic
trifluoromethylthioesters can be converted into the corre-
sponding aryl thioethers via palladium-catalyzed decarbon-
ylation.12,17 As such, the deoxygenative trifluoromethylthiola-
tion could serve as the first part of a facile two-step synthesis of
valuable trifluoromethylthioethers from readily available
carboxylic acids. The standard reaction conditions with BT-
SCF3 could also be applied to a series of alkyl carboxylic acids
with the corresponding thioesters being formed in isolated
yields up to 73%.
Herein, we report a transition metal free methodology for
the direct deoxygenative fluoroalkylthiolation of readily
available carboxylic acids via in situ activation of BT-SRF
reagents. The method using BT-SCF3 provides aryl and alkyl
trifluoromethylthioesters without any additives other than an
inorganic base. The similarly efficient synthesis of difluor-
omethylthioesters using the novel reagent BT-SCF2H is
especially noteworthy. Not only is this method the only
reported approach toward these partially fluorinated com-
pounds from simple carboxylic acids, it also constitutes a rare
example of a formally nucleophilic difluoromethylthiolation
reaction. The success of this method despite the well-known
−
instability of the SCF2H anion suggests that in situ activation
B
https://dx.doi.org/10.1021/acs.orglett.0c03328
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Scheme 2. Scope of Deoxygenative Tri- and Difluoromethylthiolation of Acids Using BT-SCF3 and BT-SCF2H
a
b
c
Isolated yields, 0.5 mmol scale. For full conditions, see the SI. No dropwise addition of acid, 0.1 M concentration, stirred for 2 h at rt. No
dropwise addition of acid, 0.033 M concentration, stirred for 2 h at rt.
Having developed a practical protocol for the deoxytri-
fluoromethylthiolation of carboxylic acids, we next turned our
attention to the deoxygenative synthesis of difluoromethylth-
ioesters. According to the general mechanism outlined in
Scheme 1a, addition of a carboxylate to the C2 carbon of the 2-
difluoromethylthio-substituted benzothiazolium salt BT-
SCF2H groups in transition-metal-mediated cross-coupling
reactions but, to the best of our knowledge, no applications in
direct nucleophilic substitution reactions, including for the
synthesis of difluoromethylthioesters, have been reported.18,19
In order to investigate the feasibility of nucleophilic
difluoromethylthiolation using BT reagents, we first synthe-
sized the new compound BT-SCF2H. As for BT-SCF3, BT-
SCF2H was efficiently prepared in a two-step protocol starting
from MBT. Formal insertion of difluorocarbene obtained from
HCF2OTf into the S−H bond of MBT20 followed by N-
methylation with methyl triflate afforded the desired salt in
high yields on scales up to at least 25 mmol. BT-SCF2H was
obtained as a pale yellow solid and, like BT-SCF3, is bench
stable over at least several months under ambient conditions
(Scheme 3). In a test experiment, 1.25 equiv of BT-SCF2H was
then reacted with octanoic acid and NaH (3 equiv) in THF.
After 2 h at rt, we were delighted to observe clean formation of
the desired difluoromethylthioester 3a in 72% NMR yield. The
−
SCF2H would result in the generation of the SCF2H anion.
Whereas nucleophilic pathways are often employed to install
the SCF3 group, direct difluoromethylthiolation reactions are
almost exclusively electrophilic or radical in character. The
scarcity of nucleophilic methods can be explained by the very
low stability of −SCF2H toward β-fluoride elimination. Despite
many attempts over the years, only one stable −SCF2H salt has
been successfully isolated to date: the N-heterocyclic carbene
(NHC)-stabilized silver complex [SIPrAg(SCF2H)] (SIPr =
1,3-(2,6-diisopropylphenyl)imidazolinylidene). This com-
pound, which was introduced in 2015 by Shen and co-
workers,18 has been employed as a stoichiometric source of
C
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Scheme 3. Synthesis of BT-SCF2H
Scheme 4. Proposed Mechanism via Four-Membered TS
success of this transformation suggests that in situ activation of
BT reagents can enable unprecedented nucleophilic difluor-
omethylthiolation reactions and that BT-SCF2H itself could
serve as a practical formal “−SCF2H” source.
A short optimization study led to the set of conditions
shown in Scheme 2 (conditions B). Preforming the carboxylate
with NaH for 30 min before addition of BT-SCF2H led to the
highest yields of thioesters 3 while, in contrast to the
deoxytrifluoromethylthiolation reaction, cooling of the reaction
mixture to −78 °C was not required. A survey of carboxylic
acid substrates allowed for the facile synthesis of a range of
diverse difluoromethylthioesters in generally good to excellent
yields up to 99%. The method proved to be tolerant of several
commonly encountered functional groups, such as nitro
groups, halogens, heterocycles, and alkoxy groups. The reagent
also proved capable of efficiently converting sterically
encumbered substrates with the thioester of adamantane
carboxylic acid (3g) being afforded in 79% yield. In general,
aliphatic carboxylic acids reacted most smoothly although
aromatic and heteroaromatic substrates could also be
successfully converted in moderate yields.
The scope of both the deoxytrifluoromethylthiolation and
difluoromethylthiolation reactions was then tested further with
a selection of pharmaceuticals, agrochemicals, and natural
products (Scheme 2). CF3- or CF2H-thioesters of several
blockbuster drugs such as ibuprofen or naproxen as well as
naturally occurring species such as linoleic acid could be
obtained directly from the parent compounds in excellent
yields using BT-SCF3 or BT-SCF2H. Moreover, the practical
utility of the deoxyfunctionalization process was demonstrated
by the gram-scale synthesis of ibuprofen derivative 3t in 88%
isolated yield (5 mmol scale).
tion reaction (energy barrier = 12.3 kcalmol−1 cf. 34.1
−
kcalmol−1 for release of SCF2H). Moreover, an albeit more
asynchronous concerted pathway was also predicted for the
analogous trifluoromethylthiolation (see the SI). These results
suggest BT reagents could open up hitherto unfeasible
nucleophilic reaction pathways by circumventing the gen-
eration of an unstable free anion nucleophile.
In conclusion, fluorine-containing benzothiazolium salts
have been employed as efficient reagents for deoxygenative
substitution reactions of unactivated carboxylic acids. A wide
range of trifluoromethylthioesters could be conveniently
prepared using BT-SCF3, while the novel reagent BT-SCF2H
allowed for an unprecedented nucleophilic difluoromethylth-
iolation reaction. The success of this latter transformation can
be explained by the involvement of a four-membered
concerted transition state that avoids the formation of the
−
unstable SCF2H anion. As such, BT reagents could facilitate
otherwise unachievable nucleophilic reaction pathways and
further investigations of this concept for the formal installation
of −SCF2H or other unstable anions are underway in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03328.
Experimental procedures, characterization data, and
computational details (PDF)
The remarkable success of the deoxydifluoromethylthiola-
tion reaction led us to consider the reaction mechanism more
−
closely. Given the well-documented instability of SCF2H, we
AUTHOR INFORMATION
Corresponding Author
■
considered whether an alternative mechanistic scenario to that
outlined in Scheme 1a that avoids the intermediate formation
of a free anion could be operating. In particular, a concerted
process involving a four-membered transition state from
intermediate A (Scheme 4) could provide the thioester
product and thiocarbamate byproduct directly. Similar
concerted mechanisms have been previously proposed in
deoxygenative fluorination reactions of phenols using the
imidazolium-based reagent Phenofluor.21 In order to test this
hypothesis, DFT calculations (B3LYP/def2-SVP)22 were
carried out on model intermediate A (R1 = Et). As predicted,
a concerted mechanism proceeding through the four-
membered transition state TS1 (Scheme 4) was found to be
the most favored pathway for the deoxydifluoromethylthiola-
Matthew N. Hopkinson − Institut fur Chemie und Biochemie,
̈
̈
Freie Universitat Berlin, 14195 Berlin, Germany; orcid.org/
0000-0002-0183-0466; Email: matthew.hopkinson@fu-
berlin.de
Authors
Matteo Tironi − Institut fu
̈
r Chemie und Biochemie, Freie
Universitat Berlin, 14195 Berlin, Germany
Lilian M. Maas − Institut fur Chemie und Biochemie, Freie
Universitat Berlin, 14195 Berlin, Germany
Arushi Garg − Institut fur Chemie und Biochemie, Freie
Universitat Berlin, 14195 Berlin, Germany
̈
̈
̈
̈
̈
D
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Stefan Dix − Institut fu
pubs.acs.org/OrgLett
Letter
Trifluoromethylthiolation. Acc. Chem. Res. 2015, 48, 1227−1236.
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̈
r Chemie und Biochemie, Freie
Universitat Berlin, 14195 Berlin, Germany
̈
̈
̈
Jan P. Gotze − Institut fur Chemie und Biochemie, Freie
̈
Universitat Berlin, 14195 Berlin, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03328
Author Contributions
†M.T. and L.M.M. contributed equally to this work.
Notes
́
Langlois, B. R.; Bacque, E. Trifluoromethanesulfanylamides as Easy-
The authors declare the following competing financial
interest(s): M.N.H. and S.D. are coinventors on a European
and International Patent Application concerning the synthesis
and use of benzothiazolium reagents for installing fluorine-
containing functional groups (EP 3 677 576 A1; WO
2020141195 A1).
to-Handle Equivalents of the Trifluoromethanesulfanyl Cation
(CF3S+): Reaction with Alkenes and Alkynes. Angew. Chem., Int. Ed.
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Q. An Electrophilic Hypervalent Iodine Reagent for Trifluorome-
thylthiolation. Angew. Chem., Int. Ed. 2013, 52, 3457−3460. (d) Yang,
Y.-D.; Azuma, A.; Tokunaga, E.; Yamasaki, M.; Shiro, M.; Shibata, N.
Trifluoromethanesulfonyl Hypervalent Iodonium Ylide for Copper-
Catalyzed Trifluoromethylthiolation of Enamines, Indoles, and β-
Keto Esters. J. Am. Chem. Soc. 2013, 135, 8782−8785. (e) Alazet, S.;
Zimmer, L.; Billard, T. Electrophilic Trifluoromethylthiolation of
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C.; Ma, B.; Shen, Q. N-Trifluoromethylthiosaccharin: An Easily
Accessible, Shelf-Stable, Broadly Applicable Trifluoromethylthiolating
Reagent. Angew. Chem., Int. Ed. 2014, 53, 9316−9320. (g) Zhang, P.;
Li, M.; Xue, X.-S.; Xu, C.; Zhao, Q.; Liu, Y.; Wang, H.; Guo, Y.; Lu,
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Stable, Broadly Applicable Electrophilic Trifluoromethylthiolating
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Milandou, L. J. C.; Carreyre, H.; Alazet, S.; Greco, G.; Martin-
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ACKNOWLEDGMENTS
■
This work is funded by the Dahlem Research School and the
Studienstiftung des deutschen Volkes (scholarship to M.T.).
Financial support from the Daimler und Benz Stiftung (Project
Nr. 32-04/18), the State of Berlin (Elsa Neumann scholarship
to A.G.), the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation), Project-IDs 387284271-SFB
̈
1349 and 393271229 (gefordert durch die Deutsche
Forschungsgemeinschaft (DFG) - Projektnummer 387284271
- SFB 1349 and 393271229), and the Fonds der Chemischen
Industrie (Sachkostenzuschuss) is also gratefully acknowl-
edged. The theoretical calculations were prepared, executed,
and evaluated by QoD Technologies GmbH. We acknowledge
the assistance of the Core Facility BioSupraMol supported by
the DFG.
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For a similar ring-opening process affording trifluoromethylethers,
F
https://dx.doi.org/10.1021/acs.orglett.0c03328
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