Metal-Free Trifluoromethylthiolation of Alkyl Electrophiles via a Cascade of Thiocyanation and Nucleophilic Cyanide-CF3 Substitution

Article abstract of DOI:10.1055/s-0034-1378702

A straightforward synthesis of alkyl trifluoromethyl thioethers was developed that starts from widely available alkyl halides or mesylates and the inexpensive reagents sodium thiocyanate and trimethyl(trifluoromethyl)silane. The alkyl electrophiles are converted in situ into the corresponding thiocyanates, which react with the nucleophilic Ruppert-Prakash reagent to give the corresponding trifluoromethyl thioethers via a Langlois-type CN-CF₃ substitution. This process enables the efficient introduction of the pharmaceutically meaningful trifluoromethylthio groups into functionalized molecules without the need of metal catalysts or expensive preformed trifluoromethylthiolating agents.

Full text of DOI:10.1055/s-0034-1378702

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1628–1632
letter
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C. Matheis et al.
Letter
Synlett
Metal-Free Trifluoromethylthiolation of Alkyl Electrophiles via a
Cascade of Thiocyanation and Nucleophilic Cyanide–CF3 Substitu-
tion
Christian Matheis
NaSCN
– simple and environmentally benign system
– one-pot protocol
– 22 examples in high yields
X
S
Minyan Wang
Thilo Krause
Alk
Alk
CF3
TMSCF3
Cs2CO3
Lukas J. Goossen*
Department of Organic Chemistry, TU Kaiserslautern,
Erwin-Schrödinger-Str. Geb. 54, 67663 Kaiserslautern, Germany
goossen@chemie.uni-kl.de
X = Cl, Br, I, OMs
Received: 10.03.2015
Accepted: 15.04.2015
Published online: 30.04.2015
DOI: 10.1055/s-0034-1378702; Art ID: st-2015-b0170-l
O
OH
N
N
N
N
O
O
N
O
S
SCF3
HO
Me
SCF3
Abstract A straightforward synthesis of alkyl trifluoromethyl thio-
ethers was developed that starts from widely available alkyl halides or
mesylates and the inexpensive reagents sodium thiocyanate and
trimethyl(trifluoromethyl)silane. The alkyl electrophiles are converted
in situ into the corresponding thiocyanates, which react with the nucle-
ophilic Ruppert–Prakash reagent to give the corresponding trifluoro-
methyl thioethers via a Langlois-type CN–CF3 substitution. This process
enables the efficient introduction of the pharmaceutically meaningful
trifluoromethylthio groups into functionalized molecules without the
need of metal catalysts or expensive preformed trifluoromethylthiolat-
ing agents.
S
N
NH2
H
H
cefazaflur
parenteral cephalosporin
methionine analog
lead for amoebiasis
HO
OH
HO
SCF3
O
antimalarial
antipneumnonia
Figure 1 Biologically active alkyl trifluoromethyl thioethers
Key words trifluoromethylthiolation, alkyl halides, fluorine, nucleo-
philes, sulfur
Traditional strategies for the synthesis of trifluorometh-
ylthio groups include halogen–fluorine exchange reactions
of trihalomethyl thioethers,6 as well as the trifluoromethyl-
ation of thiols, disulfides, and related compounds.7 Howev-
er, these methods are limited by substrate availability. Re-
cently, various methods for the introduction of trifluoro-
methylthio groups into aromatic substrates via
electrophilic,8 nucleophilic,9 radical,10 or oxidative methods
have been reported.11 The synthesis of alkyl trifluoromethyl
thioethers is less studied.3e,12 Contemporary syntheses start
from diazo compounds,13 alcohols,14 halides,15 or carboxylic
acids16 or proceed via C–H activation following methods by
Tang, Chen, Rüping, or Qing.17 However, each of these meth-
ods calls for preformation of SCF3 reagents.18
Around 40% of marketed agrochemicals and 25% of
pharmaceuticals contain fluorine atoms. Fluorine-contain-
ing residues are central functionalities in bioactive com-
pounds, because they induce higher lipophilicity and meta-
bolic stability.1 The unique properties of fluorinated groups
have led to the development of a range of sustainable con-
cepts for the late-stage introduction of trifluoromethyl
groups.2 In recent years, the focus has shifted towards the
corresponding trifluoromethylthio groups,3 since these en-
hance the lipophilicity of druglike molecules even more
than their trifluoromethylated analog (Hansch constant
1.44 for SCF3 vs. 0.88 for CF3).4 This property improves the
bioavailability of drug molecules due to their more effective
transport through lipid membranes.3d,e
Efficient methods for the late-stage introduction of tri-
fluoromethylthio groups into functionalized molecules
based on widely available leaving groups and inexpensive,
easy-to-use reagents are still highly sought-after.
The trifluoromethylthio moiety is a key functionality
for example in the antibiotic cefazaflur, in a trifluorometh-
ylthiolated methionine analogue with antimalarial proper-
ties, and in a ribose derivative with antipneumnonia activi-
ty (Figure 1).3b,5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1628–1632

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C. Matheis et al.
Letter
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We envisioned that the nucleophilic displacement of
the CN group in thiocyanates by CF3 using TMSCF3, as origi-
nally reported by Langlois et al., might be the key towards
such a process.7e If this transformation could be combined
in one pot with a straightforward synthesis of the alkyl
thiocyanates from alkyl halides or pseudohalides, the over-
all protocol would allow accessing valuable trifluoromethyl
thioethers without the need for preformed trifluorometh-
ylthiolation reagents (Scheme 1).
Systematic studies revealed that the choice of the base
had a profound effect on the reaction outcome (Table 1, en-
tries 3–5). Using Cs2CO3, near-quantitative yields were
achieved in the stepwise procedure (Table 1, entry 5). Ace-
tonitrile was found to be the optimal solvent with regard to
yield and reaction rate, but DMF and THF can be used as
well (Table 1, entry 6). The amounts of base and trifluoro-
methylation reagent could be reduced to 1.0 equivalent of
Cs2CO3 and 1.2 equivalents of TMSCF3, respectively, without
affecting the reaction outcome (Table 1, entries 7 and 8).
trifluoromethylthiolation approach
Table 1 Optimization of the Reaction Conditionsa
MSCF3
Alk
one-pot thiocyanation–CN substitution approach
TMSCF3
X
Alk SCF3
base
TMSCF3
NaSCN
solvent
Br
SCF3
SCN
solvent
15 h, r.t.
1 h, 60 °C
NaSCN
Cs2CO3
1
2
Alk
X
Alk SCN
Alk SCF3
Langlois-type
trifluoromethylation
nucleophilic
thiocyanation
Entry
Base
TBAF
Solvent
Yield (%)
X = Cl, Br, I, OMs
1
DMF
20
15
76
80
99
99
99
99
99
78
41
2
TBAF
THF
Scheme 1 Strategies to access alkyl trifluoromethyl thioethers
3
CsF
DMF
4
KF
DMF
In the context of our work on di- and trifluoromethyla-
tion methods,19 we discovered that for the synthesis of aryl
di- and trifluoromethyl thioethers the envisioned approach
is viable starting from diazonium salts.20 However, since the
nucleophilic substitution of alkyl halides with thiocyanate
salts requires substantially higher temperatures than do
Sandmeyer processes, it was doubtful whether the sensitive
Ruppert–Prakash reagent would tolerate this initial reac-
tion step.
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
6
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
7b
8b,c
9b–d
10b–e
11b–d,f
In order to probe the viability of our projected ap-
proach, we started with benzyl bromide (1) as a model sub-
strate and investigated its nucleophilic substitution with
sodium thiocyanate, with addition of the trifluoromethyl-
ating agent TMSCF3 following complete formation of the al-
kyl thiocyanate (Table 1). In order to combine both steps to
a true one-pot procedure, it was crucial to identify solvents
and conditions that would be equally effective for both
steps.
a Reaction conditions: benzyl bromide (0.5 mmol) and NaSCN (0.6 mmol)
in solvent (1 mL), 60 °C, 1 h, then addition of base (1.0 mmol) and TMSCF3
(1.0 mmol), 15 h, r.t. Yields were determined by 19F NMR using trifluoroeth-
anol as an internal standard.
b 0.5 mmol Cs2CO3.
c 0.6 mmol TMSCF3.
d All reagents were added at the same time, and the mixture was stirred for
1 h at 60 °C.
e 0.25 mmol Cs2CO3.
f 0.1 mmol Cs2CO3.
The nucleophilic substitution of bromide with sodium
thiocyanate was found to proceed best in polar aprotic sol-
vents such as DMF. GC analysis revealed that full conversion
was reached within one hour at 60 °C. However, when add-
ing TMSCF3 and TBAF, the reagent combination described
by Langlois, the trifluoromethylation proceeded rather
sluggishly and gave an unsatisfactory 20% yield (Table 1, en-
try 1). In THF, reported to be the optimal solvent for trifluo-
romethylations,7e the thiocyanation was slower, and the
yield of the trifluoromethylation remained low (Table 1, en-
try 2). This suggests that the sodium bromide released in
the thiocyanation step may interfere with the trifluoro-
methylation step.
We next probed whether under the optimal conditions
the reagents for both steps could directly be combined. To
our delight, the desired trifluoromethyl thioether 2 formed
in quantitative yield when heating a mixture of 1 with 1.2
equivalents of sodium thiocyanate, 1.0 equivalent of Cs2CO3,
and 1.2 equivalents of TMSCF3 in acetonitrile to 60 °C for
one hour (Table 1, entry 9). The reaction also proceeds with
catalytic amounts of Cs2CO3 (Table 1, entries 10 and 11),
since the released cyanate anions are able to desilylate the
Ruppert–Prakash reagent as proposed by Langlois.7e How-
ever, full conversion was only obtained with equimolar
amounts.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1628–1632

1630
C. Matheis et al.
Letter
Synlett
Having thus found a convenient and highly efficient tri-
fluoromethylthiolation protocol, we went on to investigate
its scope. Diversely substituted alkyl trifluoromethyl thio-
ethers were synthesized in high yields from the corre-
sponding alkyl halides (Scheme 2).22
are well-tolerated. In contrast to most metal-mediated tri-
fluoromethylthiolations, chloro- and bromoarene moieties
remain intact in this transformation, which opens up op-
portunities for further derivatization. Terminal alkynes are
trimethylsilylated under the reaction conditions, but the
TMS group can easily be cleaved by basic workup (19).21
All products were obtained in reasonable purity after
aqueous workup and can be further purified by column
chromatography. Compound 2 was isolated in 91% yield on
a gram scale, demonstrating the scalability of the process.
In conclusion, a metal-free trifluoromethylthiolation of
alkyl electrophiles via a cascade of thiocyanation and nuc-
leophilic CN–CF3 substitution has been developed. The key
advantages of this approach, in which the sulfur and the CF3
moiety originate from different sources, are the mild reac-
tion conditions and the use of inexpensive, ready available
reagents. As a result, this is suitable both for large-scale ap-
plications and late-stage trifluoromethylthiolations in drug
discovery.
NaSCN
Cs2CO3
TMSCF3
Alk
X
Alk SCF3
MeCN
1 h, temp
X = Cl, Br, I, OMs
SCF3 CN
SCF3
2, 98%d
SCF3
SCF3
3, 98%d
4, 93%d
Cl
Br
MeO
SCF3
SCF3
6, 76%c
7, 74%f
5, 83%c
Acknowledgment
O
O
SCF3
We thank NanoKat for financial support.
SCF3
SCF3
8, 82%f
9, 68%f
SCF3
10, 83%f
Supporting Information
O
SCF3
SCF3
Supporting information for this article is available online at
HO
14, 94%d
R
10
http://dx.doi.org/10.1055/s-0034-1378702.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
R = Hex, 11, 97%b,d
Oct, 12, 97%c
13, 87%d
O
References and Notes
SCF3
5
SCF3
SCF3
(MeO)3Si
TMS
O
n-Bu2N
17, 82%f
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16, 96%e
15, 96%d
O
SCF3
SCF3
SCF3
HO
18, 62%b,d
O
19, 93%c
20, 71%b,d
O
SCF3
SCF3
N
SCF3
23, 64%b,f
O
S
21, 94%f
22, 93%d
Scheme 2 Trifluoromethylthiolation of alkyl halides and mesylates.
a Reagents and conditions: alkyl electrophile (1.0 mmol), NaSCN (1.2
mmol), Cs2CO3 (1 mmol), TMSCF3 (1.2 mmol) in MeCN (2 mL), 60–
110 °C, 1 h, isolated yields (see Supporting Information). b Yields were
determined by 19F NMR using trifluoroethanol as an internal standard.
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Thiocyanates Generated in situ
An oven-dried 20 mL crimp-cap vessel with Teflon-coated
stirrer bar was charged with Cs2CO3 (652 mg, 1.00 mmol) and
NaSCN (100 mg, 1.20 mmol). MeCN (2 mL), TMSCF3 (537 mg,
0.60 mL, 1.20 mmol), and the alkyl halide or mesylate (1.00
mmol) were added via syringe. The suspension was heated to
the following temperatures, depending on the leaving group:
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mides and primary chlorides 90 °C, and alkyl mesylates 110 °C.
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[(Trifluoromethyl)thio]methylbenzene [CAS No.: 351-60-0]
(2)
1H NMR (400 MHz, CDCl3): δ = 7.38–7.36 (m, 5 H), 4.15 (s, 2 H)
ppm. 19F NMR (375 MHz, CDCl3): δ = –41.47 ppm. 13C NMR (101
MHz, CDCl3): δ = 135.0, 130.6 [q, 1J(C,F) = 307.0 Hz], 128.9 (2 C),
128.8 (2 C), 128.0, 34.2 [q, 3J(C,F) = 2.7 Hz] ppm. IR (neat): ν =
2922, 2853, 1463, 1378 cm–1. MS (ion trap, EI, 70 eV): m/z (%) =
192 (23) [M+], 91 (100), 69 (13). HRMS (EI-TOF): m/z calcd for
C8H7F3S: 192.0221; found: 192.0224.
11-[(Trifluoromethyl)thio]undecanoic Acid (14)
1H NMR (400 MHz, CDCl3): δ = 2.88 (t, 3J = 7.5 Hz, 2 H), 2.35 (t,
3J = 7.5 Hz, 2 H), 1.72–1.60 (m, 4 H), 1.44–1.29 ppm (m, 12 H)
ppm. 19F NMR (375 MHz, CDCl3): δ = –41.3 ppm. 13C NMR (101
MHz, CDCl3): δ = 180.5, 131.2 [q, 1J(C,F) = 305.2 Hz], 34.1, 29.83
[q, 3J(C,F) = 2.4 Hz], 29.34, 29.27, 29.25, 29.1, 29.0, 28.9, 28.5,
24.6 ppm. IR (neat): ν = 2927, 2856, 1709, 1464, 1414, 1113,
938, 756 cm–1. MS (ion trap, EI, 70 eV): m/z (%) = 287 (12) [M+ +
H], 199 (73), 129 (44), 117 (91), 101 (9), 69 (24). HRMS (EI-
TOF): m/z calcd for: C12H21F3O2S: 286.1214; found: 286.1230.
3-[(Trifluoromethyl)thio]propyltrimethoxysilane (16)
1H NMR (400 MHz, CDCl3): δ = 3.55 (s, 9 H), 2.88 (t, 3J = 7.3 Hz, 2
H), 1.79 (qi, 3J = 7.8 Hz, 2 H), 0.73 (t, 3J = 8.3 Hz, 2 H) ppm. 19F
NMR (375 MHz, CDCl3): δ = –41.2 ppm. 13C NMR (101 MHz,
CDCl3): δ = 131.2 [q, 1J(C,F) = 305.9 Hz], 50.5 (3 H), 32.5 [q,
3J(C,F) = 1.5 Hz], 23.2, 8.3 ppm. IR (neat): ν = 2945, 2843, 1759,
1077, 809, 754 cm–1. MS (ion trap, EI, 70 eV): m/z (%) = 264 (1)
(16) Hu, F.; Shao, X.; Zhu, D.; Lu, L.; Shen, Q. Angew. Chem. Int. Ed.
2014, 53, 6105.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1628–1632

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[M+], 233 (12), 195 (63), 121 (13), 93 (100). HRMS (EI-TOF): m/z
calcd for C7H15O3SiF3S: 264.0463; found: 264.0468.
3J(C,F) = 1.8 Hz], 28.3, 18.6, 0.0 (3 C) ppm. IR (neat): ν = 2960,
2176, 1685, 1432, 1250, 1107, 838, 758, 699 cm–1. MS (ion trap,
EI, 70 eV): m/z (%) = 240 (11) [M+], 171 (97), 129 (100). HRMS
(EI-TOF): m/z calcd for C9H15SiF3S: 240.0616; found: 240.0614.
(1R,5S)-[(Trifluoromethyl)thio]-2-{6,6-dimethylbicyclo[3.1.1]-
hept-2-en-2-yl}ethylene (21)
N-{2-[(Trifluoromethyl)thio]ethyl}-N,N-dibutylamine (17)
1H NMR (400 MHz, CDCl3): δ = 3.30 (t, 3J = 7.1 Hz, 2 H), 2.74 (t, 3J
= 7.0 Hz, 2 H), 2.42 (t, 3J = 7.2 Hz, 4 H), 1.43–1.37 (m, 4 H), 1.34–
1.28 (m, 4 H), 0.92 (t, 3J = 7.3 Hz, 6 H) ppm. 19F NMR (375 MHz,
CDCl3): δ = –41.4 ppm. 13C NMR (101 MHz, CDCl3): δ = 131.6 [q,
1J(C,F) = 306.8 Hz], 53.6 (2 C), 52.8, 29.3 (2 C), 28.8, 20.5 (2 C),
14.0 (2 C) ppm. IR (neat): ν = 2959, 2934, 2874, 1739, 1460,
1366, 1217, 1119, 748 cm–1. MS (ion trap, EI, 70 eV): m/z (%) =
257 (3), 214 (44), 172 (66), 142 (100), 58 (41). HRMS (EI-TOF):
m/z calcd for C11H22NF3S: 257.1425; found: 257.1420.
1-Trimethylsilyl-5-(trifluoromethyl)thiopent-1-yne (19)
1H NMR (400 MHz, CDCl3): δ = 3.01 (t, 3J = 7.1 Hz, 2 H), 2.38 (t,
3J = 6.8 Hz, 2 H), 1.90 (qi, 3J = 7.0 Hz, 2 H), 0.15 (s, 9 H) ppm.
19F NMR (375 MHz, CDCl3): δ = –41.1 ppm. 13C NMR (101 MHz,
CDCl3): δ = 131.0 [q, 1J(C,F) = 306.1 Hz], 104.8, 86.2, 28.7 [q,
1H NMR (400 MHz, CDCl3): δ = 5.31 (m, 1 H), 2.93–2.89 (m, 2 H),
2.41–2.38 (m, 1 H), 2.37–2.32 (m, 2 H), 2.26–2.23 (m, 2 H),
2.11–2.09 (m, 1 H), 2.02–1.99 (m, 1 H), 1.29 (s, 3 H), 1.16 (d, 3J =
8.5 Hz, 1 H), 0.84 (s, 3 H) ppm. 19F NMR (375 MHz, CDCl3): δ =
–41.2 ppm. 13C NMR (101 MHz, CDCl3): δ = 145.2, 132.2 [q,
1J(C,F) = 306.1 Hz], 118.8, 40.6, 38.0, 36.6, 31.6, 31.2, 27.8 [q,
3J(C,F) = 1.8 Hz], 26.2, 21.1 ppm. IR (neat): ν = 2917, 1434, 1366,
1104, 887, 794, 756 cm–1. MS (ion trap, EI, 70 eV): m/z (%) = 250
(14) [M+], 105 (100), 121 (10). HRMS (EI-TOF): m/z calcd for
20
C
12H17F3S: 250.1003; found: 250.0987; [α]D –25.9 (c 1.00,
Et2O).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1628–1632