Metal-free trifluoromethylthiolation of arenediazonium salts with Me4NSCF3

Article abstract of DOI:10.1016/j.jfluchem.2018.03.011

A metal-free entry to the pharmaceutically meaningful substrate class of trifluoromethyl thioethers has been developed starting from widely available arenediazonium salts and commercially available Me₄N⁺SCF₃^?. This reaction proceeds within one hour at 0 °C and is applicable to a wide range of functionalized substrates.

Full text of DOI:10.1016/j.jfluchem.2018.03.011

Accepted Manuscript
Title: Metal-free trifluoromethylthiolation of arenediazonium
salts with Me4NSCF3
Authors: Giulia Bertoli, Benjamin Exner, Mathies V. Evers,
Kristina Tschulik, Lukas J. Gooßen
PII:
S0022-1139(18)30095-2
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.03.011
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Please cite this article as: Bertoli G, Exner B, Evers MV, Tschulik K, Gooßen LJ,
Metal-free trifluoromethylthiolation of arenediazonium salts with Me4NSCF3, Journal
of Fluorine Chemistry (2010), https://doi.org/10.1016/j.jfluchem.2018.03.011
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Metal-free trifluoromethylthiolation of arenediazonium salts with Me4NSCF3
Giulia Bertolia, Benjamin Exnera, Mathies V. Eversb, Kristina Tschulikb and Lukas J. Gooßena,*
a
Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstraße 150, ZEMOS 2.27, 44801
Bochum, Germany.
b
Micro- & Nano-Electrochemistry, Center for Electrochemical Sciences (CES), Ruhr-Universität Bochum,
ZEMOS 1.45, Universitätsstr. 150, 44801, Bochum, Germany.
*E-Mail address: lukas.goossen@rub.de, phone: +49 234 32 19075, fax: +49 234 32 14675
Graphical abstacrt
Highlights

Arenediazonium salts are converted into aryl trifluoromethyl thioethers without the use of any metal
mediators.



The transformation is based on readily available starting materials and tolerates various functional groups.
Cyclic voltammetry was used to elucidate the reaction mechanism.
The aryltrifluoromethyl thioether products are interesting for applications in drug discovery.
Abstract
A metal-free entry to the pharmaceutically meaningful substrate class of trifluoromethyl thioethers has been

developed starting from widely available arenediazonium salts and commercially available Me4N+SCF . This
reaction proceeds within one hour at 0 °C and is applicable to a wide range of functionalized substrates.
Keywords: trifluoromethylthiolations; arenediazonium salts; trifluoromethyl thioethers; radicals;
cyclovoltammetry
1. Introduction
Fluorine-containing molecules are abundant in pharmaceuticals, agrochemicals, material and surface sciences.[1]
Their increased lipophilicity compared to the non-fluorinated analogs allows modulating solubility, bioavailability
and adhesive properties. Hence, powerful methods for the selective introduction of fluorinated residues into
functionalized molecules are constantly sought. In this context, SCF3 groups, which induce particularly high
lipophilicity and membrane permeability[2] have recently received increased attention. Examples of biologically
active compounds containing SCF3 groups include vaniliprole, toltrazuril and tiflorex (Figure 1).

tiflorlex
vaniliprole
toltrazuril
stimulant amphetamine
pesticide
antiprotozoal agent
Figure 1: Biologically active trifluoromethyl thioethers.
Traditional strategies for the preparation of trifluoromethylthiolated compounds are based on waste-intensive,
multistep syntheses involving halogen-fluorine exchange reactions.[3] Trifluoromethylations of sulfur-containing
precursors[4] such as thiols,[5] disulfides,[6] or thiocyanates[7] constitute a viable alternative. However, especially
for applications in drug discovery, it is advantageous to introduce this subgroup as a whole, starting from easily
accessible substrate classes with inexpensive, easily stored and handled reagents. In this context, several processes
involving stoichiometric amounts of nucleophilic silver or copper reagents,[8] electrophilic N–SCF3 reagents,[9]
or oxidative cross-couplings[10] have been described. A particularly straightforward approach is the Sandmeyer-
type copper-catalyzed trifluoromethylthiolation of arenediazonium salts using tetramethylammonium
trifluoromethanethiolate as the SCF3 source.[11] This reagent was first introduced by Röschenthaler[12] and
Yagupolskii,[13]and has meanwhile found numerous applications in the field of trifluoromethylthiolation[14]of
vinyl iodides,[15] boronic acids,[16] and aryl halides[17] catalyzed by Cu, Ni and Pd complexes. Lately, it was
used by Schönebeck et al. for the synthesis of acyl fluorides,[18] thiocyanates[19] and trifluoromethylamines.[20]
The Sandmeyer-type reaction is remarkable in that it is one of the few processes in which substoichiometric
amounts of copper are sufficient to achieve high yields. Still, for pharmaceutical and agrochemical applications, it
would be best if heavy metals could be left out altogether. To the best of our knowledge only one example[21] of
synthesis of arene trifluoromethyl thioethers is reported employing the toxic[22] and arduous to prepare (SCF3)2
as reagent. In the course of the method development leading to the copper-catalyzed trifluoromethylthiolation,[10]
we had performed control experiments without copper and in one case surprisingly observed the formation of the
desired trifluoromethyl thioethers in appreciable amounts. At that time,[10] we could not reproduce this and
attributed the outlying experiment to the presence of copper traces in the apparatus or in the reagents.[23] However,
when we later reinvestigated the reaction under highly optimized conditions using new glassware and stirrers as
well as analytically pure reagents, we consistently detected trifluoromethylthiolation products even in the absence

of copper when treating arenediazonium salts with Me4N+SCF . Similar observations were made also for

Me4N+SeCF .[24] Systematic reaction development led to the discovery of an efficient metal-free
trifluoromethylthiolation process that we present herein.
2. Results and discussion
Preliminary investigations had shown that the reaction of 4-methoxybenzenediazonium tetrafluoroborate (1a) and

Me4N+SCF (2) reproducibly afforded 4-methoxyphenyl trifluoromethyl thioether (3a), thus this was used as a
starting point for reaction optimization (Table 1).

Table 1: Optimization of the reaction conditionsa .
[Me4N][SCF3] 2
solvent
1a
3a
4
Entry
Solvent
Temperature [°C]
2 [equiv.]
Yield 3a [%] b
Yield 4 [%] c
CH3CN
CH3CN
acetone
DMF
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
r.t.
r.t.
r.t.
r.t.
r.t.
50
0
0
0
0
0
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.1
3.0
1.1
1.1
41
40
36
14
-
43
52
48
49
55
66
18
15
20
47
-
16
15
16
16
12
7
1
2 d
3
4
5
6
7
8
9
10 e
11 f
[a] Reaction conditions: 0.5 mmol diazonium salt 1a and Me4NSCF3 2 (0.9 mmol) in 2 mL solvent, 1 h.[b] Yields were
determined by 19F NMR analysis using trifluorotoluene as internal standard [c] Yields were determined by GC analysis
using n-tetradecane as internal standard.[d] 16 h reaction time.[e] 1.3 mL CH3CN.[f] 0.5 mL CH3CN.
Indeed, when simply stirring a mixture of 1a and an excess of 2 in acetonitrile at room temperature, a promising
yield of 41% was obtained (Table1, entry 1). The main side product was anisole (4), resulting from
protodediazotization.[25]The starting material was consumed already within 1 h, and the yield of 3a was equal
when increasing the reaction time to 16 h (Table 1, entry 2). Among the solvents tested, acetonitrile was most
effective. In more polar solvents, such as DMF, the amount of protodediazotization product increased and in
nonpolar solvents such as toluene, there was no conversion, likely due to solubility issues (Table 1, entries 3–5).
The key parameter affecting yield and selectivity was the reaction temperature. Whereas the yield remained
unchanged when increasing the temperature to 50 °C, it increased to 52% at 0 °C (Table 1, entries 6-7). The excess
of 2 could be reduced to 1.1 equivalents (Table 1, entry 8-9). At increased concentrations, higher yields were
obtained and the protodediazotization was suppressed (Table 1, entries 10-11). Under optimal conditions, the
product was obtained in 66% yield along with 7% anisole and small amounts of other byproducts including aryl
trifluoromethyl disulfide, diaryl sulfide and several biaryls (see SI). Having thus identified an effective and reliable
metal-free protocol for the trifluoromethylthiolation of arenediazonium salts, we next investigated its scope (Table

2).
Table 2: Scope of the metal-free trifluoromethylthiolationa.
[Me4N][SCF3] 2
1 h, 0 °C, CH3CN
3
1
[b]
p-Me 3c, 63%
o-Me 3d, 82%
m-Me 3e, 66%
p-OMe 3a, 57%
o-OMe 3b, 51%
[b]
[b]
[b]
3f, 67%
[b]
p-F 3h, 52%
m-F 3i, 47%
p-Cl 3j, 61%
[b]
[b]
[b]
m-Cl 3k, 39%
[e]
3n, 66%
3g, 88%
[b]
p-Br 3l, 51%
p-I 3m, 30%
[b]
[d]
[c]
3p,53 %
3q, 53%
3t, 55%
3o, 66%
3r, 50%
3u, 16%
3s, 42%
3v, 70%
[b]
3w, 20%
[b]
[b]
3y, 32%
3x, 15%
[a] Reaction conditions: 0.5 mmol diazonium salt 1 and Me4NSCF3 (2) (0.55 mmol) in 0.5 mL solvent, 1 h, 0 °C. [b]
Yields were determined by 19F NMR analysis using α,α,α-trifluorotoluene as internal standard. [c] Yield was determined
by 19F NMR analysis using 1,4-difluorobenzene as internal standard. [d] 0.5 mmol diazonium salt 1 and Me4NSCF3 (2)
(0.9 mmol) in 0.5 mL solvent, 1 h, 0 °C. [e] Reaction conditions: 0.5 mmol diazonium salt 1 and Me4NSCF3 (2) (0.9 mmol)
in 2.0 mL solvent, 1 h, 0 °C.
Different arenediazonium salts were converted into the desired products with moderate to high yields. Both
electron-withdrawing and electron-donating groups were converted, and common functional groups including
ester, ether, keto, and cyano groups were tolerated. Expectedly, the yields were low for arenediazonium salts
containing basic amine groups, presumably due to triazene formation.[26] The synthesis of 1-nitro-4-
[(trifluoromethyl)thio]benzene (3g) was successfully scaled up to 4 mmol yielding 759 mg (85%) of the desired
product. 4-fluoro- and 4-iodoarenediazonium salts led to 1,4-disubstituted products, as detected by 19F NMR
spectroscopy and/or GC-MS. The presence of these byproducts suggests a radical reaction mechanism. A signal
at δ= −47.4 ppm in the 19F NMR spectrum suggests the presence of the dimer (SCF3)2, which would be expected
in the termination step by combination of two SCF3 radicals.[12]

2 (1.1 equiv.)
TEMPO (1.5 equiv.)
a)
1h, 0°C, CH3CN
3a, 2%
5, 10%
1a
2 (1.1 equiv.)
b)
1h, 0°C, CH3CN
3ab, 30%
1ab
Scheme 1: Radical capture experiments.
a.
b.
t
Figure 2: Cyclic voltammograms of 1a (a) and 2 (b) in 1 mM concentration, respectively, with 0.1 M Bu4NPF6
in CH3CN. Blue circles: experimental data, red line: simulated curves.
Further evidence for a radical mechanism was obtained by performing the reaction between 1a and 2 in the
presence of the radical scavenger 2,2,6,6-tetramethylpiperidin-1-yl-N-oxyl (TEMPO). Under these conditions, the
TEMPO adduct (5) was formed as the major product along with small quantities of 3a (Scheme 1a). Moreover, a
radical capture experiment with 2-(allyloxy)diazonium tetrafluoroborate (1ab) resulted in the formation of 3ab
(Scheme 1b). The question to answer was how radical formation leading to a SET mechanism takes place in the
absence of metals or radical initiators. The thermodynamics of this transformation was addressed by cyclic
voltammetry studies of 4-methoxybenzenediazonium tetrafluoroborate (1a) and Me4NSCF3 (2) in acetonitrile

using silver as a quasi-reference electrode.[27] As can be seen in Figure 2, the cyclic voltammetric wave shows a
single-electron transfer in both cases. These were fitted to simulated curves using DigiElch® software to extract
the formal potentials and the electron transfer rates (k). The formal potential of arenediazonium salt 1a was
determined as -0.147 V, with k = 0.0025 cm/s, that of Me4NSCF3 (2) as 0.153 V, with k = 1.0·10-6 cm/s (see the
SI). One can thus conclude that the electron transfer from 2 to 1a under the conditions used is endergonic by G
roughly estimated as − z · F ·E = 28.9 kJ/mol and relatively slow. However, under typical experimental conditions,
such a small activation barrier can easily be crossed. It is thus conceivable that the formation of radicals takes
place even in the absence of radical initiators or metal mediators. Once these active species have been formed, the
rest of the reaction can be expected to be energetically downhill. Based on these findings, we propose a mechanism
−
that consists of reduction of the diazonium ion by the SCF3 ion, followed by dediazotization and subsequent
recombination of the two radical species (Scheme 2), in analogy to reports by Studer et al.[28]
.
- N2
.
SET
1 + 2
3
Scheme 2: Proposed radical mechanism of the trifluoromethylthiolation.
3. Conclusions
Overall, this study demonstrates that it is possible to perform trifluoromethylthiolations of arene nucleophiles in
the absence of heavy metal mediators. The reaction times are short, and the conditions mild. This protocol is
beneficial especially for applications in which even ppm quantities of metals need to be avoided. However, it is
also evident from the results that the copper-mediated reaction variants remain of great use whenever near-
quantitative yields are required, or whenever product separation is an issue.
4. Experimental
An oven-dried 20 mL crimp-cap vessel with magnetic stirrer was charged with tetramethylammonium
trifluoromethanethiolate (2, 1.10 mmol) and the aryl diazonium tetrafluoroborate (1, 1.00 mmol). Cold (0 °C),
degassed acetonitrile (1 mL) was added and the reaction mixture was stirred at 0 °C for 1 h. After the reaction, the
mixture was diluted with diethyl ether (20 mL), and aq. sat. NaHCO3 (10 mL) was added. The aqueous layer was
extracted with diethyl ether (2 × 20 mL) and the combined organic layers were washed with water (20 mL) and
brine (20 mL). The organic layer was then dried over MgSO4, filtered and concentrated (700 mbar, 40 °C). The
residue was purified by flash chromatography (SiO2, n-pentane/dichloromethane gradient). The solvent was
removed by slow evaporation through a Vigreux column at ambient pressure, yielding the aryl trifluoromethyl
thioethers. The yields of particularly volatile compounds and of those that could only be obtained in low yields
were determined by 19F NMR, and their identity was confirmed by MS.
Acknowledgments
We thank the DFG (Cluster of Excellence RESOLV, EXC 1069) and BMBF and the state NRW (Center of
Solvation Science ZEMOS) for financial support, and Melania Prado Merini for technical assistance. We thank
Dr. Manfred Rudolph for providing the beta version of DigiElch® software.
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