Synthesis of perfluoroalkyl thioethers from aromatic thiocyanates by iron-catalysed decarboxylative perfluoroalkylation

Article abstract of DOI:10.1016/j.jfluchem.2016.12.006

Easily available aryl and heteroaryl thiocyanates were converted into the corresponding perfluoroalkyl thioethers via decarboxylation of potassium perfluoroalkylcarboxylates, catalysed by the inexpensive and environmentally benign iron(III) chloride.

Full text of DOI:10.1016/j.jfluchem.2016.12.006

Accepted Manuscript
Title: Synthesis of perfluoroalkyl thioethers from aromatic
thiocyanates by iron-catalysed decarboxylative
perfluoroalkylation
Author: Benjamin Exner Bilguun Bayarmagnai Christian
Matheis Lukas J. Goossen
PII:
S0022-1139(16)30423-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.12.006
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28-10-2016
9-12-2016
9-12-2016
Please cite this article as: Benjamin Exner, Bilguun Bayarmagnai, Christian Matheis,
Lukas J.Goossen, Synthesis of perfluoroalkyl thioethers from aromatic thiocyanates
by iron-catalysed decarboxylative perfluoroalkylation, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.12.006
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Synthesis of perfluoroalkyl thioethers from aromatic thiocyanates by iron-catalysed decarboxylative
perfluoroalkylation
Benjamin Exnera, Bilguun Bayarmagnaia, Christian Matheisa, Lukas J. Goossenb,*
a
FB Chemie - Organische Chemie, Technische Universität Kaiserslautern, Erwin-Schrödinger-Strasse Geb. 54,
67663 Kaiserslautern, Germany
b Evonik Chair of Organic Chemistry, Ruhr-Universität Bochum, Universitätsstraße 150, ZEMOS 2.27, 44801
Bochum, Germany
*E-Mail address: lukas.goossen@rub.de, phone: +49 234 32 19075, fax: +49 234 32 14675
Graphical abstract
Highlights


FeCl3 efficiently promotes the decarboxylative perfluoroalkylation of aryl thiocyanates.
The iron catalyst fulfils a dual role as catalyst and as scavenging agent of the cyanide ions, which are
transformed into non-toxic hexacyanoferrate.


The aryl perfluoroalkyl thioether products are interesting for applications in drug discovery.
The high-yielding transformation is based on readily available starting materials and has a good functional
group tolerance.
Abstract
Easily available aryl and heteroaryl thiocyanates were converted into the corresponding perfluoroalkyl thioethers
via decarboxylation of potassium perfluoroalkylcarboxylates, catalysed by the inexpensive and environmentally
benign iron(III) chloride.
Keywords: Iron, perfluoroalkylation, perfluoroalkylthiolation, decarboxylative couplings

1. Introduction
The introduction of fluorine-containing groups into organic molecules is of great interest for the development of
pharmaceuticals, agrochemicals, and functional materials, since these groups enhance properties such as metabolic
stability, lipophilicity and dipole moment.[1–3] Perfluoroalkyl thioethers, in particular, have recently drawn
considerable attention in drug discovery because of their higher lipophilicity and membrane permeability
compared to the perfluoroalkyl analogues.[4]
Traditional trifluoromethylation reactions are usually confined to the beginning of a chemical synthesis due to the
common use of aggressive reagents under often harsh reaction conditions.[5] This has triggered considerable
advances in this field in recent years.[6–9] In contrast, the chemistry of longer-chain substituents such as
pentafluoroethyl groups remains somewhat underdeveloped,[10–18] even though their biological activity is greater
at times.[19–21] Regardless of the chain length, most methods require fluoroalkylating reagents that are costly,
sensitive, waste-intensive and/or arduous to prepare, and that in some cases are banned by the Montreal protocol
because of their ozone-depleting properties. Fluorocarbons, such as fluoroform, offer an alternative that
circumvents most of these issues, and have successfully been employed.[21–27] They are, however, gaseous up
to quite high chain lengths (C4 for linear compounds[28]) and therefore inconvenient for laboratory use.
Furthermore, their immense global warming potentials (GWP, e.g. for CHF3 it is 14,800 times greater than for
CO2 [29]) are certain to lead to restrictions in their use in the coming years.[30] Perfluoroalkylcarboxylate salts,
on the other hand, are solids, easy to store and handle, and release only CO2. This greenhouse gas is problematic
when released in huge quantities by cars and power plants, but in chemical production it is one of the least harmful
byproducts. Decarboxylative perfluoroalkylation reactions have been known for several decades, ever since
Kondo’s pioneering research on the trifluoromethylation of aromatic halides.[31] Several methodologies for the
decarboxylative perfluoroalkylation of various electrophiles have since been developed.[32–37] However, almost
all of the described processes require overstoichiometric amounts of copper and several equivalents of the
corresponding perfluoroalkyl carboxylic acid derivative, exceptions remaining scarce.[38–40]
Based on our experience in fluoroalkylations[41–43] as well as decarboxylative couplings,[44–47] we have
recently developed a Langlois-type[48] decarboxylative trifluoromethylation of organothiocyanates catalysed by
30 mol% of iron(II) chloride with 1.2 equivalents of potassium trifluoroacetate, leading to trifluoromethyl
thioethers.[49] Literature procedures for the synthesis of thioethers bearing longer perfluoroalkyl chains usually
start from thiols or disulfides,[11,16,38,50–52] which is undesirable because of their limited availability. Protocols
starting from simple arenes and aromatic amines using preformed reagents have been published only recently by
Billard[53] and our own group.[54] In continuation of our work on fluoromethyl(thiol)ations,[55–59] we herein
report the synthesis of higher homologues via decarboxylative perfluoroalkylation of aryl thiocyanates accessed
from aromatic amines by Sandmeyer reaction.
2. Results and discussion
We started the investigations with optimized conditions from our decarboxylative trifluoromethylation. Thus, aryl
thiocyanate 1a, 1.2 equivalents of potassium pentafluoropropionate 2a and 30 mol% of iron(II) chloride gave the
desired product 3aa in a promising yield of 67% (Table 1, entry 1). A switch to iron(III) chloride or bromide led
to quantitative yields (entries 2 and 3). Other Lewis acids as well as CuI gave inferior results, and a control reaction
without catalyst also provided substantially lower product yields (entries 4–7). Modifications of the solvent or the
catalyst loading did not improve the outcome (entries 8–11), and performing the reaction at a decreased
temperature of 120 °C led to a substantially lower yield (entry 12). Besides its good catalytic activity, iron(III) has
the additional advantage of capturing the cyanide ion that is released from the thiocyanate as non-toxic
hexacyanoferrate(III). (LD50 2970 mg/kg vs. 5 mg/kg for KCN, oral, rat).

Having thus found the optimal conditions for this reaction, we next investigated its scope (Table 2). Starting
materials bearing various functional groups such as ether, thioether, dimethylamino, ester, keto and cyano were
smoothly converted into their corresponding SC2F5 derivatives (3aa–3kl). Heterocycles including quinolines (3la,
3ma) and carbazoles (3na) were also suitable substrates. The successful conversion of halogeno compounds
including chloro (3pa) and bromo (3qa) derivatives demonstrates that the decarboxylative pentafluoroethylation
may be combined with further coupling reactions. p-Nitrophenyl thiocyanate gave a moderate product yield (3ra),
and poor yields were observed starting from thiophene derivatives (3sa) or compounds with acidic protons (3ta,
3ua). In the latter case, we hypothesised that the protons led to protodecarboxylation, and the resulting product
pentafluoroethane was indeed detected by 19F NMR. This side reaction leaves an insufficient amount of
pentafluoropropionate for full conversion, so that we attempted another decarboxylative pentafluoroethylation of
the phenol derivative 1u using 2.2 equivalents of potassium pentafluoropropionate. Indeed, the yield of 3ua
increased from 35 to 53%. The fact that it still remained lower than for most other substrates may be explained by
the low electrophilicity of the phenolate ion. The successful synthesis of 3aa in 89% yield on a 5 mmol scale
demonstrates the scalability of the process.
Longer-chain perfluoroalkyl groups were investigated next. With n-heptafluorobutyrate, the thioether 3ab was
obtained in 68% yield, along with the corresponding iso-heptafluoropropyl side product in ca. 5% yield
(determined by 19F NMR). This compares favourably by the work of Roques et al. who got only moderate yields
of this product. They rationalized the formation of the unwanted byproduct by a mechanism that involves
–
decarboxylation of the carboxylate to C3F7 , followed by elimination and readdition of fluoride leading to
rearrangement of the n- to the iso-heptafluoropropyl anion (Scheme 1a).[38] A second, cyclic byproduct observed
by Roques, 2,3-difluoro-5-methoxy-3-(trifluoromethyl)-2,3-dihydro-1-benzothiophene (5), was not detected here
(Scheme 1b). Interestingly, extending the perfluoroalkyl chain by another four CF2 units yielded 4-methoxyphenyl
perfluoroheptyl thioether 3ac in 29% yield without any branched side products, as determined by 19F NMR (see
the supporting information).
To elucidate the reaction mechanism, one equivalent of the radical scavenger 3,5-di-tert-butyl-4-hydroxytoluene
(BHT) was added to several reactions using different metal salts as the catalyst. The fact that the reactions were
not completely suppressed speaks against a radical mechanism for all these mediators. In another control
experiment, the decarboxylation was performed in the presence of benzaldehyde leading to the formation of
2,2,3,3,3-pentafluoro-1-phenylpropan-1-ol in a yield of 43%. This supports a pathway via a nucleophilic
perfluoroalkyl species (see SI).[60]
3. Conclusions
The decarboxylative perfluoroalkylation reported herein allows
a Langlois-type synthesis of aryl
perfluoroalkylthioethers from aryl thiocyanates. Its key advantages are the use of readily available, inexpensive
starting materials and an environmentally benign and cheap iron catalyst. Despite the rather high reaction
temperatures, the process shows good functional group tolerance, which makes it suitable for the late-stage
introduction of perfluoroalkyl chains.
4. Experimental
An oven-dried crimp-cap vessel (20 mL) with stir bar was charged with aryl thiocyanate 1a–u (2.0 mmol),
potassium perfluoroalkylcarboxylate 2a–c (2.40 mmol), FeCl3 (77.3 mg, 0.60 mmol), and DMF (6 mL). The
reaction mixture was stirred for 16 h at 140 °C. The resulting mixture was diluted with diethyl ether (20 mL), then
washed with water (20 mL), 20 % (m/m) aqueous LiCl solution (20 mL) and brine (20 mL). The organic layer was
dried over MgSO4, filtered, and concentrated (700 mbar, 40 °C). The residue was purified by flash chromatography
(SiO2, pentane), yielding the perfluoroalkyl thioethers 3aa–3ac. The yields of particularly volatile compounds
were determined by 19F NMR spectroscopy, and their identity by MS.

Acknowledgements
We thank the Heinrich-Böll-Stiftung e.V. (scholarship to B.B.) and the Cluster of Excellence RESOLV (EXC
1069) funded by the Deutsche Forschungsgemeinschaft for financial support.
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(a)
(b)
F
F
F
F
F
F
F–
COO–
F
140 °C, DMF
F
–
CF3
F3C
F3C
–
F3C
–F–
– CO2
F3C
F
F
F
F
S
SX
SC3F7
SCF(CF3)2
n-C3F7COOK
–X–
F
+
+
R
R
R
R
CF3
F
3
4
5
29%
68%
33%
5%
15%
not observed
Roques (R = H, X = SPh):
Our protocol (R = OMe, X = CN):
Scheme 1. (a) Origin of side products in decarboxylative heptafluoropropylation and (b) their distribution in the
product mixture.

Table 1. Optimisation of the reaction conditions[a]
SCN
SC2F5
[M] (30 mol%)
C2F5COOK
+
Solvent, 140 °C,
– CO2
MeO
MeO
1a
2a
3aa
Entry
1
2
3
[M]
Solvent
DMF
DMF
DMF
DMF
3aa [%]
67
99
99
81
FeCl2
FeCl3
FeBr3
CuI
4
5
6
7
Sc(OTf)3
In(OTf)3
–
DMF
DMF
DMF
16
31
31
8
9
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
NMP
97
89
18
89
Me2SO
Propylene carbonate
DMF
10
11[c]
12[d]
DMF
81
[a]
Reaction conditions: 0.30 mmol of 4-methoxyphenyl thiocyanate 1a, 0.36 mmol of potassium
pentafluoropropionate 2a, 0.09 mmol of [M], 1 mL of solvent, 140 °C, 16 h. Yields were determined by 19F
NMR spectroscopy using 2,2,2-trifluoroethanol as an internal standard. [c] Using 0.20 eq. of FeCl3. [d] at 120 °C.
[b]
Table 2.Substrate scope of the decarboxylative perfluoroalkylation of arylthiocyanates[a]
SCN
SCnF2n+1
30 mol% FeCl3
R1
R1
C2F2n+1COOK
+
DMF, 16 h,
140 °C
1a–u
2a–c
3aa–ua, ab, ac
SC2F5
SC2F5
SC2F5
SC2F5
SC2F5
Me
MeO
MeS
PhO
Ph
3ga, 96%
3aa, 97%
o-Me 3da, 87%[b]
m-Me 3ea, 95%
p-Me 3fa, 99%[b]
3ca, 96%
3ba, 98%
SC2F5
SC2F5
SC2F5
SC2F5
SC2F5
N
Ph
MeOOC
3ia, 91%
Me2N
NC
O
3ha, 96%
3ka, 95%
3ja, 97%
SC2F5
3la, 98%
SC2F5
SC2F5
SC2F5
SC2F5
N
X
COOMe
3sa, 32%
O2N
S
N
3ma, 97%
X = F 3oa, 97%[b]
Cl 3pa, 96%
3ra, 68%
Et
3na, 97%
SC2F5
Br 3qa, 98%
SnC7F15
SnC3F7
SC2F5
O
N
H
HO
MeO
MeO
3ab, 68%[d]
3ac, 29%
3ua, 35%
53%[c]
3ta, 23%
[a]
Reaction conditions: 2.0 mmol of organothiocyanate 1, 0.30 mmol of FeCl3, 2.4 mmol of potassium
perfluoroalkylcarboxylate 2, 6.0 mL of DMF, 140 °C, 16 h, isolated yields. The yield was determined by 19F
NMR using 2,2,2-trifluoroethanol as an internal standard. [c] 2.2 eq. of potassium pentafluoropropionate were used.
[d]The product was contaminated with 5% of the corresponding iso-heptafluoropropyl compound as determined by
19F NMR. The yield was adjusted accordingly.
[b]