Trifluoromethyl Sulfoxides: Reagents for Metal-Free C?H Trifluoromethylthiolation

Article abstract of DOI:10.1002/anie.202005531

Trifluoromethyl sulfoxides are a new class of trifluoromethylthiolating reagent. The sulfoxides engage in metal-free C?H trifluoromethylthiolation with a range of (hetero)arenes. The method is also applicable to the functionalization of important compound classes, such as ligand derivatives and polyaromatics, and in the late-stage trifluoromethylthiolation of medicines and agrochemicals. The isolation and characterization of a sulfonium salt intermediate supports an interrupted Pummerer reaction mechanism.

Full text of DOI:10.1002/anie.202005531

A Journal of the Gesellschaft Deutscher Chemiker
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Chemie
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Accepted Article
Title: Trifluoromethyl sulfoxides: New reagents for metal-free C–H
trifluoromethylthiolation
Authors: Dong Wang, C Grace Carlton, Masanori Tayu, J J.W.
McDouall, Gregory J.P. Perry, and David John Procter
This manuscript has been accepted after peer review and appears as an
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using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202005531
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Trifluoromethyl sulfoxides: New reagents for metal-free C–H
trifluoromethylthiolation
Dong Wang,[a] C. Grace Carlton,[a] Masanori Tayu,[a][b] Joseph J. W. McDouall,[a] Gregory J. P. Perry[a]
and David J. Procter*[a]
[a]
Dr. D. Wang, C. G. Carlton, Dr. M. Tayu, Joseph J. W. McDouall, Dr. G. J. P. Perry, Prof. Dr. D. J. Procter
Department of Chemistry
University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
E-mail: david.j.procter@manchester.ac.uk
[b]
Dr. M. Tayu
Department of Chemistry
Meiji Pharmaceutical University
2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
Supporting information for this article is given via a link at the end of the document.
Abstract: Trifluoromethyl sulfoxides are
a
new class of
sulfide precursors.[9c] Key to these reactions is the in situ
formation of a highly electrophilic sulfonium salt, by activation of
the sulfoxide with an acid anhydride, which is susceptible to
reaction with a range of nucleophiles.
trifluoromethylthiolating reagent. The sulfoxides engage in metal-free
C–H trifluoromethylthiolation with a range of (hetero)arenes. The
method is also applicable to the functionalization of important
compound classes, such as ligand derivatives and polyaromatics,
and in the late-stage trifluoromethylthiolation of medicines and
agrochemicals. The isolation and characterization of a sulfonium salt
intermediate supports an interrupted Pummerer reaction mechanism.
(A)
H
S
[SCF3]
CF3
Ar
Ar
SCF3
[SCF3] =
I
O
I
NAc
OSCF3
N
SCF3
Incorporating fluorine into organic compounds is a useful tool in
drug design and development. The fluoro group is well known to
improve the pharmacokinetic properties of a molecule and
fluorine-18 is an important radioisotope in molecular imaging.[1,2]
Trifluoromethylthio (SCF3) groups are commonly found in drug
X
Me Me
O
X = CO, SO2
R1
N
O
S
O O
S
R2
F3C
Cl
F3C
ONa
SCF3
e.g. R1 = H, R2 = Ph
molecules and veterinary medicines.[3,4] By combining
a
(B)
H
S
O
CF3
fluorinated moiety with a heteroatom, many have turned to the
SCF3 group to impart useful properties, such as high lipophilicity,
to a compound of interest.[5]
Ar
Ar
S
1
R
CF3
• new SCF3 reagent • late-stage trifluoromethylthiolation • tuneable R group
An attractive route for incorporating SCF3 groups into organic
molecules is through the direct, metal-free functionalization of
C–H bonds.[6] Early methods using trifluoromethylsulfenyl
chloride have fallen from favor due to concerns over handling
and toxicity of the reagent.[7] This triggered a push to develop
shelf-stable, easy-to-handle trifluoromethylthiolating agents
(Scheme 1A).[8] Despite the advantages of these reagents, they
are generally limited to the C–H trifluoromethylthiolation of highly
electron-rich (hetero)arenes, such as indoles and phenols,
whereas reactions involving less nucleophilic arenes, such as
anisole and toluene, are scarce.[8d,8o,8p,8ab] Furthermore, few
reports describe the use of these reagents for the late-stage
trifluoromethylthiolation of complex molecules.[8j,8m,8n,8ab]
O
S
O
S
EtOOC
Ph
CF3
CF3
1a
1b
X-ray of 1a
Scheme 1. (A) Current methods for transition metal-free C–H
trifluoromethylthiolation. (B) This work: C–H trifluoromethylthiolation via an
interrupted Pummerer reaction.
We were keen to assess whether underutilized trifluoromethyl
sulfoxides would engage in C–H trifluoromethylthiolation. We
reasoned that trifluoromethylsulfonium salts, generated from
trifluoromethyl sulfoxides via an interrupted Pummerer reaction,
would prove versatile intermediates en route to the incorporation
of SCF3 into nucleophilic arenes. Herein, we present
In recent years, our group[9] and others[10] have explored the so-
called interrupted Pummerer reaction of sulfoxides and its use
for the functionalization of C–H bonds.[11] For example, we have
described the thioarylation of simple arenes using sulfoxides as
trifluoromethyl
sulfoxides
as
novel,
tuneable
trifluoromethylthiolating agents (Scheme 1B). The easy to
prepare, bench-stable and novel trifluoromethyl sulfoxides[12]
1
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10.1002/anie.202005531
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COMMUNICATION
allow SCF3 incorporation into a variety of heteroarenes and
arenes, including drug molecules, at the expense of C–H bonds.
In contrast to current methods for trifluoromethylthiolation, that
involve direct attack of an arene on an electrophilic SCF3
reagent, our unique strategy builds the desired connectivity to
give sulfonium salts that are selectively deconstructed in situ to
deliver trifluoromethylthiolated products.
With
a
novel sulfoxide in hand, we attempted the
trifluoromethylthiolation of indole 2a (Scheme 2). The sulfoxide
was activated using triflic anhydride[9] to give the desired
trifluoromethylthiolated indole 3a in 70% yield. The reaction
tolerated substitution at all positions around the indole motif (C4
(3b, 3f, 3h), C5 (3d, 3e, 3i), C6 (3c, 3g), C7 (3j) and C3 (3k),
including various electron-withdrawing (3b-3g) and electron-
donating (3i-3k) groups. We were pleased to find that functional
groups that are able to undergo subsequent transformations,
such as halides (3b, 3c), nitriles (3d), esters (3e-3g) and
boronate esters (3h), were well tolerated. N-Methyl indoles also
Our first aim was to design and synthesize a sulfoxide suitable
for general and selective trifluoromethylthiolation.[13] Key to our
mechanistic hypothesis for trifluoromethylthiolation is the
selective loss of the R group, rather than the CF3 group, from
worked well in the procedure (3l-3n).
A range of other
sulfoxide
1
(Scheme 1B). As this step likely occurs via
heteroaromatic compounds also underwent efficient C–H
trifluoromethylthiolation, such as benzothiophene (3o),
thiophenes (3p, 3q), benzofuran (3r) and pyrroles (3s, 3t). The
reaction was also executed on a gram scale without severe
detriment to the yield (3a).
nucleophilic substitution in a sulfonium salt intermediate (vide
infra), we identified benzyl-substituted trifluoromethyl sulfoxide
1a as a candidate for enabling trifluoromethylthiolation: the
activating effect of the adjacent π-system, combined with the
inhibitory effect of fluoro groups towards incoming
nucleophiles,[14] would make the benzyl group more susceptible
to removal. We developed a new route for the synthesis of
sulfoxide 1a, which was obtained as a free-flowing, bench-stable,
crystalline solid and has been characterized by X-ray
crystallographic analysis (Scheme 1B).[15]
i) Tf2O (1.5 eq)
-25 °C - RT
H
SCF3
O
S
+
Ar
EtOOC
Ar
CF3
MeNO2 (0.2 M)
ii) Et2NH (3.5 eq), RT
4 (1.0 eq)
1b (1.2 eq)
5
SCF3
SCF3
iPr
SCF3
tBu
SCF3
SCF3
MeO
Me
5b 46% (13:1)b
SCF3
i) Tf2O (1.2 eq)
0 °C, MeCN (0.2 M)
O
S
SCF3
5a 63%
5c 46%
SCF3
5d 50%
5g 70%
Ar
Ar
Ph
+
CF3
ii) Et2NH (2.5 eq)
MeO
MeO
X
X
2 (1.5 eq)
SCF3
1a (1.0 eq)
3
HO
H2N
Br
Br
SCF3
SCF3
SCF3
5e 38%c
5f 0%
NC
SCF3
SCF3
MeO2C
MeO
SCF3
O
O
N
H
N
N
H
N
H
Br
H
MeO
3a 70%
3b 78%
3c 64%
3d 79%
(63%)b
5i 80%
5l 64%
5j 68%
5h 63%d
MeO2C
SCF3
SCF3
SCF3
SCF3 MeO2C
OMe
SCF3
OMe
Me
SCF3
MeO2C
N
N
N
MeO
Me
5m 60%
MeO2C
H
H
H
5k 73% (3.9:1)e
3e 70%
3f 75%
3g 81%
SCF3
Bpin
OMe
Me
SCF3
SCF3
SCF3
O
O
Me
SCF3
SCF3
SCF3
SCF3
N
Br
N
N
N
H
MeO
OMe
MeO
H
H
H
Me
3j 61%
5q 73%c
5n 44%
5o 97%
5p 26% (6.3:1)f
3h 38%
3i 41%
3k 53%
F3CS
SCF3
SCF3
SCF3
Br
MeO
SCF3
OMe
OMe
Me
N
N
N
H
NMe
Me
3l 53%
SCF3
Me
3m 84%
Me
F3CS
3n 59%
5s 53%c
(SCF3-Pyrene)
5t 86%d
(SCF3-Dextromethorphan)
F3CS
5r 28%d
S
SCF3
OMe
Me
S
S
(SCF3-BINOL Derivative)
SCF3
S
S
H
O
SCF3
F3CS
3o 63%
3p 71%
3q 66%
H
H
SCF3
SCF3
N
O
Me
5u 49%d
(SCF3-Pyriproxyfen)
Scheme 3.a Scope of the metal-free C–H trifluoromethylthiolation of arenes.
O
MeO
SCF3
5v 57%d
MeO2C
N
(SCF3-Estradiol Derivative)
N
Ph
3s 93% (1:1)c
O
Me
3t 72%
a
3r 62%
Procedure B, conditions: i) 4 (0.2 mmol, 1.0 eq), 1b (0.24 mmol, 1.2 eq), Tf2O
(0.3 mmol, 1.5 eq), MeNO2 (1.0 mL, 0.2 M) at –25 °C for 10 min, then at RT
for 3 h. ii) Et2NH (0.7 mmol, 3.5 eq) at RT for 15 h. b Numbers in parenthesis
indicate ratio of C4 versus C2 trifluoromethylthiolation. The major regioisomer
is shown. c Procedure A (see Scheme 2). d See Supporting Information for
Scheme 2.a Scope of the metal-free C–H trifluoromethylthiolation of
heteroarenes. a Procedure A, conditions: i) 2 (0.3 mmol, 1.5 eq), 1a (0.2 mmol,
1.0 eq), Tf2O (0.24 mmol, 1.2 eq), MeCN (1.0 mL, 0.2 M) at 0 °C for 1 h. ii)
Et2NH (0.5 mmol, 2.5 eq). Reaction run on a gram scale. Numbers in
parenthesis indicate ratio of C2 versus C3 trifluoromethylthiolation.
b
c
e
modified reaction stoichiometry. Numbers in parenthesis indicate ratio of C4
versus C2 trifluoromethylthiolation. The major regioisomer is shown.
f
2
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Numbers in parenthesis indicate ratio of C1 versus C2 trifluoromethylthiolation.
The major regioisomer is shown.
H
R
(A)
Ar
Tf2O
O
S
OTf
S
S
4
CF3
In comparison to heteroarenes, the trifluoromethylthiolation of
arenes has received less attention.[8d,8o,8p,8ab] Initial results using
Ar
R
CF3
R
CF3
-
-
- CF3SO3
- CF3SO3
1
6
7
sulfoxide
1a
gave
poor
yields
of
the
desired
Et2NH
SCF3
Et2N
8
R = CH2COEt
(detected
R
trifluoromethylthiolated arenes, however, a novel ester derived
trifluoromethyl sulfoxide 1b showed good reactivity (Scheme 3).
This suggests that the structure of the sulfoxide can be tuned for
optimization with a specific class of substrate.[16] With sulfoxide
1b, anisole, phenol and other alkylated arenes were responsive
to trifluoromethylthiolation (5a-5e).[17] Unfortunately, free amines
were not tolerated in this reaction (5f).[18] A range of 1,2- (5g-5j)
1,3- (5k) and 1,4-disubstituted (5l, 5m) arenes, bearing various
functionalities, such as halogens and esters, also performed well
under our conditions. The reaction was also applicable to
trisubstituted arenes (5n, 5o) and naphthalenes (5p, 5q). Finally,
we showcased our method using substrates relevant in catalysis,
materials, medicine and agriculture; we were able to
trifluoromethylthiolate a BINOL derivative (5r), pyrene (5s),
drugs (5t), pesticides (5u), and a natural product derivative (5v).
Me CF3
S
O
OEt
-
CF3SO3
by GC-MS)
Ar
7m
Me
(from 4m and 1b)
X-ray of 7m
5
(B)
TS2
TS2
TS1
TS1
attack at -CH2CO2Et
21.4 kJ mol-1
attack at -CF3
62.2 kJ mol-1
(not observed)
7ma + Et2NH
(observed)
(0.0)
Scheme 4. (A) Proposed mechanism for the trifluoromethylthiolation of
(hetero)arenes using sulfoxides. (B) Computational investigation of the
chemoselective dealkylation. a The process was modelled using the cation of
7m. See the Supporting Information for further details.
A
mechanistic proposal for the trifluoromethylthiolation is
summarized in Scheme 4. The trifluoromethyl sulfoxides 1 are
initially activated through reaction with Tf2O to produce the
electrophilic intermediates 6. The intermediates 6 then undergo
In summary, we have developed a new strategy for the metal-
free C–H trifluoromethylthiolation of (hetero)arenes. In this
process, we utilize the interrupted Pummerer reaction to
the so-called interrupted Pummerer reaction with
(hetero)arene (e.g. 4) to give sulfonium salts 7. Selective
removal of the R-group by Et2NH reveals the
a
establish
trifluoromethyl
sulfoxides
as
novel
trifluoromethylthiolating agents. Our method for incorporating
SCF3 components exploits a build-up/deconstruct strategy and is
mechanistically distinct from current processes. A variety of
trifluoromethylthiolated products (e.g. 5). Experimental and
computational studies provided support for our proposed
mechanism. Firstly, sulfonium salt 7m was isolated from the
reaction between p-xylene 4m and sulfoxide 1b.[15, 19] We then
modelled the dealkylation step using DFT calculations. These
results showed that the transition state for attack of the amine
(Et2NH) at the –CH2CO2Et group lies 40.8 kJ mol–1 lower in
energy than the transition state for attack at the –CF3 group. In
(hetero)aromatic
compounds
underwent
efficient
trifluoromethylthiolation, including drug molecules and natural
products. We expect trifluoromethyl sulfoxides to find application
in other trifluoromethylthiolation reactions in the future.
addition, the expected side-product, Et2NCH2CO2Et 8, was Acknowledgements
detected by GCMS. It is likely that attack at the –CF3 group is
disfavored due to unfavorable electrostatic interactions,[14]
We thank EPSRC (Postdoctoral Fellowship to D. W.
EP/S014128/1; Established Career Fellowship to D.J.P.
–
–
though further studies are required to fully delineate the
intricacies of this mechanism. These studies highlight our unique
strategy for trifluoromethylthiolation; whereas current methods
proceed through direct attack of an arene on an electrophilic
SCF3 reagent,[8] we have introduced alternative reactivity in
which the desired connectivity is built, to give intermediate 7,
before inducing controlled deconstruction and release of the
desired trifluoromethylthiolated products.
EP/M005062/1) and The University of Manchester (Lectureship
to G.J.P.P.) for their generous support.
Keywords: sulfoxide • interrupted Pummerer •
trifluoromethylthiolation • late-stage functionalization • transition
metal-free
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[15] X-ray crystallographic data for 1a and 7m can be found at the
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[16] See the SI for details of the optimization. When reacting indole 2l with
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electrophilic sulfoxide 1a to react. However, further studies are required
to fully understand the differing reactivity.
[17] The reaction with benzene gave only a trace of product.
[18] Preliminary results suggest that some amines, e.g. NPh3, are tolerated.
See the supporting information.
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10.1002/anie.202005531
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
O
S
R
CF3
R = CH2Ph, CH2CO2Et
• novel trifluoromethylthiolating reagents
H
SCF3
O
S
Ar
Ar
R
CF3
• late-stage trifluoromethylthiolation
• tuneable reactivity
May I interrupt?: Taking advantage of the interrupted Pummerer reaction, trifluoromethyl sulfoxides engage in the metal-free C–H
trifluoromethylthiolation of (hetero)arenes, including drug molecules and natural products. This new class of trifluoromethylthiolating
reagent exploits a new strategy for trifluoromethylthiolation in which sulfonium salts are built and selectively deconstructed.
Institute and/or researcher Twitter usernames: @GroupProcter, @UoMChemistry
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