Iron-Catalyzed Decarboxylation of Trifluoroacetate and Its Application to the Synthesis of Trifluoromethyl Thioethers

Article abstract of DOI:10.1002/chem.201503915

Nucleophilic CF₃ has been generated by decarboxylation of potassium trifluoroacetate, arguably the most easy-to-handle, inexpensive, and sustainable source of trifluoromethyl groups. Simple iron(II) chloride catalyzes the decarboxylation as well as a subsequent trifluoromethylation of organothiocyanates, resulting in a straightforward synthesis of trifluoromethyl thioethers. The KCN byproduct is absorbed by iron(II) with formation of nontoxic potassium hexacyanoferrate. An analogous trifluoromethylation of aldehydes with trifluoroacetate underlines the synthetic potential of such iron-catalyzed decarboxylative trifluoromethylations.

Full text of DOI:10.1002/chem.201503915

DOI: 10.1002/chem.201503915
Communication
&
Synthesis Design
Iron-Catalyzed Decarboxylation of Trifluoroacetate and Its
Application to the Synthesis of Trifluoromethyl Thioethers
Benjamin Exner, Bilguun Bayarmagnai, Fan Jia, and Lukas J. Goossen*[a]
Milestone discoveries in the field of trifluoromethylation
Abstract: Nucleophilic CF3 has been generated by decar-
boxylation of potassium trifluoroacetate, arguably the
most easy-to-handle, inexpensive, and sustainable source
of trifluoromethyl groups. Simple iron(II) chloride catalyzes
the decarboxylation as well as a subsequent trifluorome-
thylation of organothiocyanates, resulting in a straightfor-
ward synthesis of trifluoromethyl thioethers. The KCN by-
product is absorbed by iron(II) with formation of nontoxic
potassium hexacyanoferrate. An analogous trifluoromethy-
lation of aldehydes with trifluoroacetate underlines the
synthetic potential of such iron-catalyzed decarboxylative
trifluoromethylations.
chemistry include catalytic couplings of aryl halides or other
aryl electrophiles with TMSÀCF3, KCF3B(OMe)3, or preformed
copper- or silver-CF3 complexes as well as electrophilic CÀH
functionalizations using the Umemoto or Togni reagents.[4]
The comparatively high cost of these contemporary trifluor-
omethylation reagents has triggered extensive research on po-
tential alternatives. Grushin[5] and Prakash[6] have recently dem-
onstrated that fluoroform, a byproduct of Teflon production,
can be utilized as a source of nucleophilic CF3. Gaseous fluoro-
form might one day become the reagent of choice for industri-
al manufacturing in dedicated plants.
Still, trifluoroacetate salts are the most desirable CF3 source
for other applications, since they are inexpensive (!1 $gÀ1),
stable, and easy-to-handle solids. Kondo, Chambers and others
have shown that trifluoroacetate can be decarboxylated and
the resulting CF3 nucleophile transferred to carbon electro-
philes such as aryl halides,[7] carbonyl compounds,[8] and disul-
fides[9] in the presence of stoichiometric amounts of Cu salts at
ꢀ1608C. Vicic and Buchwald have disclosed contemporary var-
iants of this reaction using NHC complexes or flow reactors.[10]
Beller et al. have successfully reduced the Cu loadings to cata-
lytic quantities (20 mol%) by starting from methyl trifluoroace-
tate.[11] However, these high-temperature reactions have limit-
ed scope and tend to give a wide spectrum of byproducts.
Building on our expertise with catalytic decarboxylative cou-
plings,[12] we intensively searched for alternative, efficient con-
cepts for trifluoroacetate decarboxylation and their application
to trifluoromethylation reactions. One of our main target prod-
ucts are trifluoromethyl thioethers, because these have recent-
ly attracted considerable attention in drug discovery.[1,13] SCF3
groups are key functionalities in several pharmaceutical and
agrochemical products including tiflorex and toltrazuril
(Figure 1), and induce even higher lipophilicity and membrane
permeability than their CF3 analogs (Hansch constants 1.44 for
SCF3 vs. 0.88 for CF3).[14] Traditional syntheses of trifluoromethyl
thioethers usually involve chlorination/Cl–F-exchange reac-
tions.[15] Contemporary methods include Ni-,[16] Cu-,[17] or Pd-
catalyzed[18] trifluoromethylthiolations of aryl halides, organo-
metallic reagents, or arenes with costly AgSCF3, N-(trifluorome-
thylthio)phthalimide, -saccharin, or -succinimide reagents.[19]
Langlois et al. demonstrated that organothiocyanates react
with TMS-CF3 via nucleophilic CN/CF3 exchange.[20]
The development of methods to introduce trifluoromethyl
groups into organic molecules is of great importance due to
their presence in many top-selling pharmaceuticals, agrochem-
icals, and functional materials.[1] Fluoroalkyl groups impart de-
sirable properties to drug-like molecules, such as metabolic
stability, increased lipophilicity, and stronger dipole moments.[2]
Traditional trifluoromethylation methods often suffer from
harsh reaction conditions or the use of aggressive reagents,
which confines them to the beginning of a chemical synthe-
sis.[3] The pressing need for late-stage fluoroalkylations in drug
discovery has triggered rapid advances in method develop-
ment over recent years (Scheme 1).
Scheme 1. Nucleophilic trifluoromethylation: reagents and synthetic targets.
[a] B. Exner,+ B. Bayarmagnai,+ F. Jia, 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
We have recently disclosed a trifluoromethyl thioether syn-
thesis through Sandmeyer thiocyanation with concomitant
Langlois-type nucleophilic trifluoromethylation of the organo-
thiocyanate intermediate.[21] This synthetic entry is straightfor-
[+] These authors contributed equally.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503915.
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Communication
er, at least 20 mol% FeCl2 are needed to ensure high yields
(entry 9). With increasing cyanide concentrations, iron(II) pro-
gressively loses its activity, and K4[Fe(CN)6] is catalytically inac-
tive (entry 10). Further experiments revealed that water and
oxygen hinder the reaction only when present in large quanti-
ties, so that special purification of reagents and solvents is not
required.
Figure 1. Biologically active trifluoromethyl thioethers.
We next investigated the applicability of our iron-catalyzed
decarboxylative trifluoromethyl thioether synthesis. The exam-
ples in Table 2 show that various organothiocyanates, which
are easily accessible from aromatic amines through Sandmeyer
reactions,[24] from arylboronic acids via Chan–Lam reactions,[25]
or from (hetero)arenes by Friedel–Crafts reactions,[26] were
smoothly converted into the corresponding trifluoromethyl thi-
oethers. The decarboxylative trifluoromethylation is applicable
to aliphatic, aromatic and heteroaromatic substrates. Common
functionalities are tolerated, including ester, ether, keto, amino,
hydroxy and even bromo groups. The reaction is particularly
effective for electron-rich thiocyanates; electron-deficient de-
rivatives gave somewhat lower yields. This may indicate that
the substitution reaction proceeds via a transition state with
strongly elongated SÀCN bond and a positive partial charge at
the sulfur atom which is destabilized by electron-withdrawing
substituents. The successful synthesis of 2a in 96% yield on
a multigram scale validates the scalability of the process.
The reaction mechanism was investigated in a series of ex-
periments (Scheme 2). The iron-catalyzed decarboxylative tri-
fluoromethylation of 1a takes place in the presence of radical
scavengers, discounting a radical pathway (1). In contrast, the
non-catalyzed background reaction is strongly affected by radi-
cal scavengers (2). Because disulfides are known substrates for
thermal decarboxylative trifluoromethylations,[19] one might
suspect their intermediacy in the iron-catalyzed process. How-
ever, the reaction of 1a with FeCl2 did not result in the forma-
tion of disulfides (3). Moreover, the decarboxylative trifluoro-
methylation of preformed disulfides was not improved by the
presence of FeCl2, and was strongly affected by radical scav-
engers (4).
ward and relatively inexpensive, but would yet vastly improve
if the CF3 nucleophile could be generated from trifluoroacetate
rather than TMSÀCF3.
In our search for novel decarboxylation catalysts, we used
a model reaction of 4-methoxyphenyl thiocyanate and potassi-
um trifluoroacetate. In the absence of a catalyst, the desired
trifluoromethyl thioether 2a was formed in low quantities by
thermal decarboxylation in DMF at 1408C (Table 1, entry 1). In
the presence of stoichiometric amounts of a standard decar-
boxylation mediator, that is, copper iodide, 2a was obtained in
reasonable yields (entry 2).[8]
Table 1. Optimization of the reaction conditions.[a]
Entry
[M]
2a [%][b]
1
–
CuI
ZnI2
17
73
80
14
48
9
51
98
70
15
2[c]
3
4
5
6
7
MnBr2·4H2O
Fe(OTf)2
Fe(NH4)2(SO4)2·6H2O
FeCl3
FeCl2
FeCl2
8
9[d]
10
K4[Fe(CN)6]
[a] Reaction conditions: 0.5 mmol of 4-methoxyphenyl thiocyanate,
1.5 mL of DMF, 0.6 mmol of KTFA, 0.15 mmol of [M], 1408C, 16 h.
[b] Yields were determined by 19F NMR spectroscopy using 2,2,2-trifluor-
oethanol as an internal standard. [c] 1 equiv of [M]. [d] 20 mol% FeCl2.
KTFA=potassium trifluoroacetate.
Our findings suggest that the iron-catalyzed process pro-
ceeds via two-electron intermediates and is much more effi-
cient than the thermal decarboxylation observed as a back-
ground reaction (Scheme 3). It is not yet clear whether the pro-
cess indeed involves FeCF3 species or whether FeII serves to
stabilize intermediate DMF-CF3À adducts.
If FeII truly functions as a two-electron catalyst, the decar-
boxylative trifluoromethylation will potentially extend to
a broad range of nucleophilic coupling processes. Indeed, the
well-studied thermal trifluoromethylation of aryl aldehydes[8]
was also efficiently promoted by iron chloride. Thus, KCO2CF3
and the highly functionalized aldehyde 4a reacted to the
corresponding a-trifluoromethyl alcohol in the presence of
iron chloride, with yields substantially in excess of those ob-
served for the thermal decarboxylative trifluoromethylation
(Scheme 4).
A systematic survey of other metal salts revealed that some
zinc, manganese and iron salts also display decarboxylation ac-
tivity (entries 3–8, see also the Supporting Information).
Among them, iron(II) chloride is the most effective promoter.
Even when employed in catalytic quantities, complete conver-
sion and near-quantitative yields were obtained (entry 8). This
was an exciting finding, because iron(II) catalysts[22] are inex-
pensive and nontoxic, and in this particular reaction, should
capture the cyanide byproduct with formation of exceedingly
stable, nontoxic potassium hexacyanoferrate(II).[23] Its formation
was confirmed by the intense Prussian blue color observed
upon addition of FeCl3 to the reaction mixture.
Control experiments with high-purity FeCl2 confirmed that
the catalyst is indeed iron(II), rather than a metal contaminant.
Because of its dual function as a catalyst and cyanide scaveng-
In conclusion, FeCl2 strongly promotes the decarboxylation
of trifluoroacetate with formation of CF3 nucleophiles. This was
incorporated as an elemental step into a novel synthesis of val-
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Table 2. Decarboxylative trifluoromethylation of organothiocyanates.[a]
Scheme 4. FeII-catalyzed decarboxylative trifluoromethylation of aldehydes.
uable trifluoromethyl thioethers from easily accessible organo-
thiocyanates, and of a-trifluoromethyl alcohols from aldehydes.
Ongoing research is directed towards utilizing trifluoroacetates
À
as a sustainable CF3 source in other nucleophilic trifluorome-
thylation reactions.
Acknowledgements
We thank D. Bauer for technical assistance and the Heinrich-
Bçll-Stiftung e.V. (scholarship to B.B.), the China Scholarship
Council (fellowship to F.J.) and Nanokat for financial support.
Keywords: decarboxylative couplings
trifluoromethylation · synthesis design
· fluorine · iron ·
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Published online on October 20, 2015
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