Trifluoromethylthiolation and Trifluoromethylselenolation of α-Diazo Esters Catalyzed by Copper

Article abstract of DOI:10.1002/chem.201602730

α-Diazo esters are smoothly converted into the corresponding trifluoromethyl thio- or selenoethers by reaction with Me₄NSCF₃or Me₄NSeCF₃, respectively, in the presence of catalytic amounts of copper thiocyanate. This straightforward method gives high yields under neutral conditions at room temperature and is applicable to a wide range of functionalized molecules, including diverse α-amino acid derivatives. It is well-suited for the late-stage introduction of trifluoromethylthio or -seleno groups into drug-like molecules.

Full text of DOI:10.1002/chem.201602730

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Accepted Article
Title: Trifluoromethylthiolation and Trifluoromethylselenolation of α-Diazo Esters Ca-
talyzed by Copper
Authors: Christian Matheis; Thilo Krause; Valentina Bragoni; Lukas J Goossen
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To be cited as: Chem. Eur. J. 10.1002/chem.201602730
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COMMUNICATION
Trifluoromethylthiolation and Trifluoromethylselenolation of α-
Diazo Esters Catalyzed by Copper
Christian Matheis, Thilo Krause, Valentina Bragoni and Lukas J. Goossen*[a]
Abstract: α-Diazo esters are smoothly converted into the
corresponding trifluoromethyl thio- or selenoethers by reaction with
Me4NSCF3 or Me4NSeCF3, respectively, in the presence of catalytic
amounts of copper thiocyanate. This straightforward method gives
high yields under neutral conditions at room temperature and is
applicable to a wide range of functionalized molecules, including
diverse α-amino acid derivatives. It is well-suited for the late-stage
introduction of trifluoromethylthio or -seleno groups into drug-like
molecules.
Several
efficient
strategies
for
the
late-stage
trifluoromethylthiolation of organic molecules have recently been
devised.[5] These are based on electrophilic,[6] nucleophilic,[7]
radical,[8] or oxidative processes,[9] usually starting from
arylboronic acids or aryl halides, but also from arenes via C–H
activation.[10] Our contribution to this emerging field includes the
development
of
Sandmeyer
fluoroalkyl-
and
fluoroalkylthiolations.[11] In this context, we have demonstrated
that (hetero-)aromatic amines can conveniently be converted
into aryl trifluoromethylthio ethers by
a
diazotization
/
trifluoromethylthiolation sequence using the bench-stable
reagent Me4NSCF3.[12] This SCF3-source is readily available
from tetramethylammonium fluoride, elemental sulfur and
TMSCF3.[13] Following initial reports by Röschenthaler[14] and
Yagupolskii,[15] it has successfully been employed in
trifluoromethylthiolations of vinyl iodides,[16] boronic acids,[9c] aryl
halides,[7b,17] and triflates[18] mediated by Cu, Ni and Pd catalysts.
Over the past decades, fluorine-containing moieties have
become ubiquitous functionalities in modern bioactive molecules.
They are present in close to 40% of currently marketed
agrochemicals and 25% of pharmaceuticals.[1] Their systematic
evaluation, the so-called “fluorine scan”, is routinely performed
when refining lead structures in drug discovery. Hence, new
methods for the late-stage introduction of fluorinated moieties
into complex, functionalized molecules are highly sought-after.
Originally, research efforts have focused mainly on the
development of methods for the introduction of CF3 groups.[2]
Lately, the SCF3 group has attracted particular attention since it
induces an even higher lipophilicity and membrane permeability
(Hansch constant 1.44 for SCF3 vs. 0.88 for CF3).[3]
Trifluoromethylthio groups are present in an increasing number
of bioactive molecules, including the antibiotic Cefazaflur, a
trifluoromethylthiolated methionine analog with antimalarial
properties, and a ribose derivative with antipneumnonia activity
(Figure 1).[4]
We envisioned that this stable and easy-to-handle reagent
might be the key towards enabling a catalytic trifluoromethylation
of α-diazo esters (Scheme 1). These substrates are easily
accessible in broad structural diversity from amino acids.
Moreover, they can be synthesized from ketones via the
Bamford-Stevens reaction or from acetoacetates via a Regitz
deprotonation/diazo transfer sequence.[19]
Me4NSCF3 / Me4NSeCF3
R'
EW G
R'
EW G
R'
EW G
SeCF3
or
5-10 m ol% Cu-cat.
MeCN, r.t.
N2
SCF3
Scheme 1. Catalytic trifluoromethylthiolation / –selenolation of -diazo esters.
O
O H
N
N
O
N
HO
N
O
O H
SCF3
HO
N
HO
S
O
NH2
SCF3
SCF3
α-Diazo esters have been used as substrates for
dediazotative trifluoromethylations, difluoroolefinations,[20] and
stoichiometric trifluoromethylthiolations. Wang and Hu have
disclosed trifluoromethylthiolation processes based on
stoichiometric amounts of AgSCF3 and Cu salts.[21] In an
analogous synthesis of trifluoromethyl thioethers, Rueping et al.
have used preformed CuSCF3.[22] Gouverneur et al. have
extended this method from α-diazo esters to 1-(diazo-2,2,2-
O
S
N
H
H
Cefazaflur
parenteral cephalosporin
Methionine analog
lead for am oebiasis
antim alarial
antipneum nonia
Figure 1. Biologically active trifluoromethyl thioethers.
trifluoroethyl)-arenes.[20a]
However,
in
all cases, the
stoichiometric use transition metal salts is unavoidable.
[a]
[+]
C. Matheis, T. Krause,+ V. Bragoni,+ Prof. Dr. L. J. Goossen
FB Chemie-Organische Chemie
Technische Universität Kaiserslautern
Erwin-Schrödinger-Str. Geb. 54
67663 Kaiserslautern (Germany)
E-mail: goossen@chemie.uni-kl.de
Homepage: http://www.chemie.uni-kl.de/goossen
These authors contributed equally.
The catalytic use of copper in combination with a stable
trifluoromethylthiolation reagent would vastly improve the
sustainability and practicability of this reaction concept. Making
the decisive transition from stoichiometric reactions based on
preformed transition metal-SCF3 complexes to
a catalytic
trifluoromethylthiolation process would require (a) identifying a
copper precursor that reacts with Me4NSCF3 to form a Cu-SCF3
complex capable of transferring the SCF3 moiety to the substrate,
and (b) sufficiently stabilizing the Cu species liberated during
Supporting information for this article is given via a link at the end of
the document.

Chemistry - A European Journal
10.1002/chem.201602730
COMMUNICATION
product formation to allow regeneration of the initial Cu-SCF3
complex (Scheme 2).
conditions, the copper loading could be reduced to 10 mol%
without impacting the yield, and even at 5 mol%, moderate
yields were obtained (Entries 6-9). This demonstrates that the
reactive CuSCF3 species can indeed be regenerated.
O
O
O
R'
R'
CuI SCF3
OR
OR
SCF3
+
- N2
Table 2. Scope of the trifluoromethylthiolation of α-diazo esters.[a]
N2
Cu
1.5 equiv. Me4NSCF3
O
O
Me4NSCF3
10 m ol% CuSCN
R'
R'
OR
OR
O
15 h, r.t.
MeCN
H+
N2
SCF3
R'
R'
Cu
[Cu]+
+
OR
OR
1
2
SCF3
SCF3
O
O
O
Scheme 2. Proposed mechanism for the Cu-catalyzed trifluoromethylthiolation
of α-diazo esters.
Ph
OR
OR
OR
SCF3
SCF3
SCF3
R
R
=
Et: 2a, 97%
Bn: 2b, 98%
R
= Et: 2c, 93%
R
R
= Et: 2e, 93%
= Bn: 2f, 81%
=
R = Bn: 2d, 84%
O
In order to probe the feasibility of our approach, we
investigated the reaction of phenylalanine α-diazo ester 1a with
Me4NSCF3 in the presence of a range of copper salts under
various conditions (Table 1).
O
O
R'
OBn
HO
OEt
OMe
SCF3
SCF3
2i, 48% [b]
SCF3
R' = i-Bu: 2g, 89% [b]
R' = s-Bu: 2h, 81% [b]
HO
2j, 94%
O
O
O
O
S
BnO
Table 1. Optimization of the reaction conditions.[a]
OEt
OBn
MeO
O Me
SCF3
O
SCF3
SCF3
2l, 83% [b]
Me4NSCF3
2k, 97%
2m , 96% [b]
O
O
Cu-source
Ph
OEt
Ph
OEt
O
O
O
r.t.
solvent
N2
SCF3
OEt
OEt
OEt
SCF3
SCF3
SCF3
1a
2a
N
H
MeO
MeS
2n, 86%
2o, 95%
2p, 98%
Entry
Solvent
Cu-source
Me4NSCF3 [equiv.]
Yield 2a [%]
X
X
O
O
O
1
2
3
MeCN
NMP
DMF
MeCN
1 equiv. CuSCN
1.1
"
"
86
37
63
6
OEt
OEt
OEt
"
"
SCF3
SCF3
SCF3
NC
Cl
=
F: 2s, 79%
Br: 2t, 75%
2q, 81%
2r, 79%
4
1 equiv. Cu
"
I:
2u, 93%
5
6
7
8
"
"
"
"
"
"
"
1 equiv. CuI
1 equiv. CuSCN
50 mol% CuSCN
10 mol% CuSCN
"
1.5
"
"
"
"
"
"
"
24
99
99
99
53
0
64
91
85
87[e]
O
O
O
N
OEt
OEt
Ph
OEt
Ph
SCF3
SCF3
SCF3
9
5 mol% CuSCN
2w , 96%
2v, 89%
O
2x, 93%
10
11[b]
12[c]
13[d]
14
-
10 mol% CuSCN
O
O
O
"
"
"
O
O
O
"
"
O
SCF3
SCF3
"
SCF3
Ph
NO2
2y, 95%
2z, 94%
2aa, 97%
[a] Reaction conditions: 0.5 mmol 1a in 1 mL solvent was added to Me4NSCF3
and the Cu-source in 1 mL solvent, and the mixture stirred for 15 h at room
temperature. Yields were determined by 19F NMR using trifluoroethanol as an
internal standard; [b] 6 h reaction time [c] under air; [d] standard-grade MeCN;
[e] isolated yield on 10 mmol scale.
O
O
O
I
N
O
O
SCF3
SCF3
SCF3
F
2ab, 98%
2ac, 76%
2ad, 42%
O
N
O
O
O
O
Ph
P(O Me)2
OEt
O
SCF3
SCF3
SCF3
2ag, 36% [b]
After 15 h at room temperature, the trifluoromethyl thioether
2a was observed in the presence of stoichiometric amounts of
CuSCN in acetonitrile, which proves that the first critical step,
the generation of a reactive Cu-SCF3 species, is possible
starting from this precursor (Entry 1). Other solvents and copper
sources were less effective in these stoichiometric experiments
(Entries 2-5). Near-quantitative yields of the desired product
were obtained when using 1.5 equiv. of Me4NSCF3 in
combination with CuSCN (Entry 6). Under these optimized
O
2af, 45%
2ae, 87%
[a] Reaction conditions: 1.0 mmol 1a-ag, 1.5 mmol Me4NSCF3 and 0.1 mmol
CuSCN, 4 mL MeCN, 15 h, room temperature. Yields of isolated products. [b]
Yields determined by 19F NMR using trifluoroethanol as standard.

Chemistry - A European Journal
10.1002/chem.201602730
COMMUNICATION
Control experiments confirmed that the reaction does not
proceed without copper (Entry 10) and that several hours of
reaction time are required (Entry 11). It was found that air and
water are tolerated to a certain threshold, so that the reaction
can be performed with standard-grade solvents without special
precautions (Entries 12-13). This is a great advantage over the
stoichiometric reactions reported in the literature, which had to
be set up under rigorous exclusion of air or moisture with freshly
prepared reagents.[20a,21,22] The scalability of the process was
demonstrated by the high-yielding synthesis of 2a on gram scale
(Entry 14).
[a] Reaction conditions: 1.0 mmol 1a-z, 1.5 mmol Me4NSeCF3 and 0.1 mmol
CuSCN, 4 mL MeCN, 15 h, room temperature. Yields of isolated products.
We next probed whether it was possible to extend this
reaction concept to trifluoromethylseleno groups. The SeCF3
moiety should impart similarly beneficial properties as the SCF3
group, but its introduction is less developed,[12,25] and
trifluoromethylselenolations of -diazo esters are unknown to
date. We were pleased to find that by simply replacing
Me4NSCF3
with
Me4NSeCF3,
various
trifluoromethyl
The scope of this straightforward and convenient method for
the trifluoromethylthiolation of α-diazo esters is illustrated by the
examples in Table 2. A large number of diversely substituted α-
diazo esters were smoothly converted into the corresponding
trifluoromethyl thioethers in high yields, with a focus on amino
acid-derived starting materials. Moreover, various other common
functionalities, such as ether, ester, thio, keto, cyano, nitro, and
hydroxy groups, are tolerated. Reactive halide substituents
remain unchanged in the process, which opens up opportunities
for further derivatization. Even α-diazo esters bearing
heterocyclic substituents such as indoles, pyridines, and
phthalimides, were successfully converted. Aryl α-diazo esters
predominantly underwent homo-coupling to the corresponding
olefins under the reaction conditions.[23] Phosphoric acid
derivatives were also converted, albeit in somewhat lower yields.
selenoethers are accessible in high yields from the
corresponding α-diazo esters (Table 3). None of the structures
have previously been synthesized.
In conclusion, the catalytic trifluoromethylthiolation
/
trifluoromethylselenolation process reported herein opens up a
convenient entry to trifluoromethyl thio- and selenoethers from
easily available α-diazo esters. Its key advantages are the
operational simplicity, tolerance to air and moisture, use of
inexpensive, easy-to-store and handle SCF3 / SeCF3 sources,
mild reaction conditions, and exceptional functional group
tolerance. As a result, this method is well-suited for the late-
stage derivatization of drug-like molecules.
Experimental Section
A series of experiments was performed to better understand
the reaction mechanism (Scheme 2). A signal at -28.0 ppm in
the 19F NMR spectrum of a mixture of Me4NSCF3 and CuSCN
gives evidence for the formation of CuSCF3.[12,14] Based on the
findings of Hu and Wang, we excluded a radical pathway.[21] Still,
radical quenchers, such as 2,2,6,6-tetramethylpiperidine-N-oxyl
(TEMPO) or p-benzoquinone, suppressed the reaction but did
not form adducts, pointing to a deactivation of the SCF3
species.[24] It is interesting that the reaction, which is formally an
ipso addition of H-SCF3 to a carbene, does not seem to require
a proton source. Deuterium labeling experiments indicate that
the extra proton in the product originates from the
tetramethylammonium ion and/or traces of water in the reaction
mixture, but not from the solvent (for details see SI).
An oven-dried 20 mL crimp-cap vessel with stirrer bar was charged with
CuSCN (12 mg, 0.10 mmol), Me4NSCF3 (262 mg, 1.50 mmol) and MeCN
(2 mL). The α-diazo ester 1a-ag (1 mmol) in MeCN (2 mL) was then
added. The reaction mixture was stirred for 15 h at room temperature,
then diluted with diethyl ether (20 mL) and washed with water (2 × 10
mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered
and concentrated (700 mbar, 40°C). The residue was purified by flash
chromatography (SiO2, cyclohexane / ethyl acetate gradient), yielding the
trifluoromethyl thioethers 2a-ag.
Acknowledgements
We thank Ann-Katrin Seitz for technical assistance and Jennifer
Mohrbach for ESI-MS measurements.
Table 3. Scope of the trifluoromethylselenolation of α-diazo esters.[a]
1.5 equiv. Me4NSeCF3
O
O
Keywords: copper • diazo compounds • fluorine •
fluoroalkylthiolation • synthetic methods
10 m ol% CuSCN
R'
R'
OR
OR
15 h, r.t.
MeCN
N2
SeCF3
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Chemistry - A European Journal
10.1002/chem.201602730
COMMUNICATION
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Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
10.1002/chem.201602730
Christian Matheis, Thilo Krause,
Valentina Bragoni and Lukas J.
Goossen*
Page No. – Page No.
Trifluoromethylthiolation and
Trifluoromethylselenolation of α-
Diazo Esters Catalyzed by Copper
In the presence of catalytic amounts of copper thiocyanate, α-diazo esters are
smoothly converted into the corresponding trifluoromethyl thio- or selenoethers by
reaction with inexpensive, easy-to-store and handle Me4NSCF3 or Me4NSeCF3,
respectively. This straightforward method gives high yields under neutral conditions
at room temperature and is applicable to a wide range of functionalized molecules.