Sandmeyer-Type Trifluoromethylthiolation and Trifluoromethylselenolation of (Hetero)Aromatic Amines Catalyzed by Copper

Article abstract of DOI:10.1002/chem.201503524

Aromatic and heteroaromatic diazonium salts were efficiently converted into the corresponding trifluoromethylthio- or selenoethers by reaction with Me₄NSCF₃ or Me₄NSeCF₃, respectively, in the presence of catalytic amounts of copper thiocyanate. These Sandmeyer-type reactions proceed within one hour at room temperature, are applicable to a wide range of functionalized molecules, and can optionally be combined with the diazotizations into one-pot protocols.

Full text of DOI:10.1002/chem.201503524

DOI: 10.1002/chem.201503524
Communication
&
Synthetic Methods |Hot Paper|
Sandmeyer-Type Trifluoromethylthiolation and
Trifluoromethylselenolation of (Hetero)Aromatic Amines
Catalyzed by Copper
Christian Matheis, Victoria Wagner, and Lukas J. Goossen*[a]
Abstract: Aromatic and heteroaromatic diazonium salts
were efficiently converted into the corresponding trifluor-
omethylthio- or selenoethers by reaction with Me4NSCF3
or Me4NSeCF3, respectively, in the presence of catalytic
amounts of copper thiocyanate. These Sandmeyer-type re-
actions proceed within one hour at room temperature,
Figure 1. Biologically active trifluoromethyl thioethers.
are applicable to a wide range of functionalized mole-
cules, and can optionally be combined with the diazotiza-
tions into one-pot protocols.
ing from arylboronic acids or aryl halides, or proceed via CÀH
activation.[9,11]
Sandmeyer-type trifluoromethylthiolations are advantageous
alternatives, because they start from inexpensive and broadly
available anilines, use inexpensive copper mediators, and are
usually orthogonal to halide-based cross-coupling reactions.
In the course of our research on Sandmeyer-type fluoroalky-
lations,[12] we have developed a trifluoromethyl thioether syn-
thesis via Sandmeyer thiocyanation followed by Langlois-type
nucleophilic CN/CF3 substitution.[13] Due to its low cost, this
two-step approach, in which the sulfur and the CF3 groups
originate from different reagents, is advantageous particularly
for large-scale applications. However, on laboratory scale,
a Sandmeyer-type trifluoromethylthiolation based on a pre-
Fluorine-containing residues are key functionalities in bioactive
compounds and present in up to 40% of currently marketed
agrochemicals and 25% of pharmaceuticals.[1] Thus, the sys-
tematic introduction of fluorinated groups, so called “fluorine
scans”, has become standard procedure in drug discovery.
Hence, new methods for the late-stage introduction of fluori-
nated moieties into functionalized molecules are highly
sought-after. In the last decade, a particular focus was set on
CF3 groups, and various powerful trifluoromethylation methods
have been developed.[2] The attention has recently shifted to-
wards trifluoromethyl thioethers, because the SCF3 group indu-
ces an even higher lipophilicity (Hansch constant 1.44 for SCF3
vs. 0.88 for CF3) and membrane permeability.[3] Trifluorome-
thylthio groups are key functionalities in several pharmaceuti-
cal and agrochemical products, including tiflorex and toltrazuril
(Figure 1).
formed SCF3 reagent would be
a welcome alternative
(Scheme 1). In this context, Me4NSCF3 appeared to be the re-
Traditional strategies for the introduction of SCF3 groups in-
clude the halogen/fluorine exchange of trihalomethyl thioeth-
ers with HF or SbF3,[4] and the trifluoromethylation of sulfur-
containing precursors, for example, thiols, disulfides, and thio-
cyanates.[5,6] However, these methods are limited by substrate
availability and/or functional group tolerance. Contemporary
trifluoromethylthiolation reactions are based on electrophilic,[7]
nucleophilic,[8] radical,[9] or oxidative processes,[10] usually start-
Scheme 1. Sandmeyer trifluoromethylthiolation of aromatic amines.
[a] C. Matheis, V. Wagner, Prof. Dr. L. J. Goossen
FB Chemie-Organische Chemie
Technische Universität Kaiserslautern
Erwin-Schrçdinger-Strasse, Geb. 54
67663 Kaiserslautern (Germany)
E-mail: goossen@chemie.uni-kl.de
Homepage: http://www.chemie.uni-kl.de/goossen
agent of choice, because it is readily available on preparative
scales from tetramethylammonium fluoride, elemental sulfur,
and TMSCF3, and can easily be stored and handled. It was first
synthesized by Rçschenthaler[14] and Yagupolskii and co-
worker[15] and has successfully been employed in trifluorome-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503524.
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thylthiolations of vinyl iodides,[16] boronic acids,[10c] and aryl hal-
ides[8b,17] catalyzed by Cu, Ni, and Pd complexes.
CuSCN and 1.8 equivalents of Me4NSCF3 in acetonitrile, 3a was
formed in 95% yield (Table 1, entry 13).
The feasibility of such a Sandmeyer-type trifluoromethylation
with catalytic amounts of copper was unclear, since Clark and
co-workers had found that the reaction of arenediazonium
salts with stoichiometric amounts of CuSCF3 gives only moder-
ate yields and has a narrow substrate spectrum.[18] Moreover,
our two-step trifluoromethylthiolation had been shown to pro-
ceed via CuÀSCN rather than CuÀSCF3 intermediates.
Having thus identified an effective and convenient protocol
for a Sandmeyer-type trifluoromethylthiolation, we next inves-
tigated its scope. Diversely substituted aryl trifluoromethyl thi-
oethers were synthesized in high yields from the correspond-
ing arenediazonium tetrafluoroborates (Table 2, Method A).
Table 2. Scope of the Sandmeyer trifluoromethylthiolation.[a]
To probe the viability of the approach sketched in Scheme 1,
we investigated the reaction of 4-methoxybenzenediazonium
tetrafluoroborate (2a) with Me4NSCF3 in the presence of sever-
al copper salts under various conditions (Table 1).[12a] In the
Table 1. Optimization of the reaction conditions.[a]
Entry
Solvent
Cu source
Me4NSCF3 [equiv]
Yield 4 [%]
1
2
3
MeCN
DMF
THF
CuSCN
“
“
1.2
”
”
64
22
0
4
5
6
7
MeCN
Cu
CuOAc
CuI
CuSCN
”
”
”
”
“
”
”
1.5
54
56
18
85
99
99
72
99
0
“
“
“
“
“
“
“
“
“
8
1.8
9[b]
10[c]
11[d]
12
13[e]
“
“
“
”
”
–
CuSCN
95
[a] Reaction conditions: dropwise addition of 0.5 mmol diazonium salt 2a
in 1 mL solvent to Me4NSCF3 and 0.5 mmol copper source in 1 mL sol-
vent, 15 h at room temperature. Yields were determined by 19F NMR anal-
ysis using trifluoroethanol as an internal standard. [b] Cu source
(10 mol%). [c] Cu source (5 mol%). [d] 1 h reaction time. [e] 2a was gen-
erated in situ.
[a] Method A: dropwise addition of 1.0 mmol diazonium salt (2) in 2 mL
MeCN to 1.8 mmol Me4NSCF3 and 0.1 mmol CuSCN in 2 mL MeCN, 1 h at
RT. Method B: 2 was generated in situ from 1.0 mmol aromatic amine,
1.0 mmol tert-butyl nitrite and 1.5 mmol p-TSA in 2 mL MeCN. Yields of
isolated products. [b] Yields were determined by 19F NMR analysis using
trifluoroethanol as standard.
presence of a stoichiometric amount of CuSCN, a promising
yield of 64% was obtained at room temperature in acetonitrile
(Table 1, entry 1). Other solvents were less effective (Table 1,
entries 2 and 3). Of the copper sources tested, CuSCN gave the
best yields (entries 4–6). Further investigations revealed that at
least 1.8 equivalents of Me4NSCF3 are required to push the re-
action to completion (Table 1, entries 7–8). The reaction gave
near-quantitative yields within one hour at room temperature
even when reducing the amount of CuSCN to 10 mol%
(Table 1, entries 9–11). This is remarkable, because most Sand-
meyer protocols call for much higher copper loadings. Control
experiments confirmed that the reaction does not proceed
without copper (Table 1, entry 12).
Both electron-withdrawing and electron-donating substrates
gave similarly high yields. Various common functionalities are
tolerated, such as ether, ester, thio, keto, cyano, amino, nitro,
amido, and acetal groups. The reaction is applicable even to
halides and carboxylic acids, which opens up opportunities for
further derivatization. Heteroarenediazonium salts, including
quinoline, carbazole, thiophene, and phthalimide derivatives,
were also successfully converted. The scalability of this reaction
variant was demonstrated by the synthesis of 3a in 93% on
a gram scale.
The diazonium salt can optionally be generated in situ from
the corresponding anilines. When 4-methoxyaniline (1a) was
treated with p-toluenesulfonic acid and tert-butyl nitrite; and
the resulting mixture was added to a solution of 10 mol%
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The scope of the one-pot diazotization/trifluoromethylthiola-
tion protocol was also investigated with functionalized aromat-
ic and heteroaromatic amines (Table 2, Method B). It was found
to be broadly applicable, but the yields were somewhat lower
than for the two-step process. A series of experiments was per-
formed to shed some light on the reaction mechanism. The
addition of radical quenchers, such as 2,2,6,6-tetramethylpiperi-
dine-N-oxyl (TEMPO) or p-benzoquinone, suppressed the reac-
tion, and with 2-(allyloxy)diazonium tetrafluoroborate (2ac) as
the substrate, the cyclized product 3ac was formed exclusively
(Scheme 2). A signal at d=À28.0 ppm in the 19F NMR spectrum
selenoethers from easily available aromatic amines. The key ad-
vantages of this set of methods are their mild reaction condi-
tions (neutral, 1 h at room temperature), the use of an inex-
pensive copper catalyst, and the exceptional functional group
tolerance. As a result, they are well suited for the late-stage in-
troduction of trifluoromethylthio or -seleno groups into drug-
like molecules.
Experimental Section
An oven-dried crimp-cap vessel (20 mL) with stirrer bar was
charged with CuSCN (12 mg, 0.10 mmol), Me4NSCF3 (315 mg,
1.80 mmol), and MeCN (2 mL). Then, the diazonium salt 2a–ac
(1 mmol) in MeCN (2 mL) was added dropwise, and the reaction
mixture was stirred for 1 h at room temperature. The resulting mix-
ture was diluted with diethyl ether (20 mL), then washed with
water (2”10 mL), and brine (10 mL). The organic layer was dried
over MgSO4, filtered, and concentrated (700 mbar, 408C). The resi-
due was purified by flash chromatography (SiO2, pentane/diethyl
ether gradient), yielding the aryl trifluoromethyl thioethers 3a–ac.
The yields of particularly volatile compounds were determined by
19F NMR spectroscopy, and their identity by MS.
Scheme 2. Radical-capture experiment.
of a mixture of Me4NSCF3 and CuSCN suggests the formation
of CuSCF3.[14] Together, these findings support a classical Sand-
meyer-type single-electron transfer (SET) mechanism involving
aryl radicals (Scheme 1).
Acknowledgements
Next, we probed whether this reaction concept can also be
utilized for the synthesis of trifluoromethyl selenoethers. The
SeCF3 moiety imparts similar properties to the SCF3 group,[19]
but its introduction can be cumbersome.[6d,20] Schoenebeck
and co-workers recently disclosed an effective Pd-catalyzed tri-
fluoromethylselenolation, which is, however, based on expen-
sive aryl iodides.[19a]
We thank KØvin Jouvin for helpful discussions and Nanokat for
financial support.
Keywords: copper
·
fluorine
·
fluoroalkylthiolation
·
Sandmeyer reaction · synthetic methods
We were pleased to find that by simply replacing Me4NSCF3
with Me4NSeCF3, our Sandmeyer protocol can be turned into
an efficient synthesis of trifluoromethyl selenoethers. The
scope of this reaction variant is demonstrated by the examples
given in Table 3, which include diversely functionalized arenes
and heteroarenes.
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[a] Reaction conditions: 1.0 mmol diazonium salt in 2 mL MeCN was
added dropwise to a mixture of 1.8 mmol Me4NSeCF3 and 0.1 mmol
CuSCN in 2 mL MeCN. The reaction mixture was stirred for 1 h at room
temperature. Yields of isolated products are given.
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Received: September 3, 2015
Published online on October 20, 2015
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