Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench-Stable Precursor (Me4N)SCF3

Article abstract of DOI:10.1002/anie.201609480

Reported herein is the one-pot synthesis of trifluoromethylated amines at room temperature using the bench-stable (Me₄N)SCF₃reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF₃with the amine, giving quantitative formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N-CF₃. The mildness and high functional group tolerance render the method highly attractive for the late-stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug molecules.

Full text of DOI:10.1002/anie.201609480

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201609480
German Edition: DOI: 10.1002/ange.201609480
Synthetic Methods
Efficient Synthesis of Trifluoromethyl Amines through a Formal
Umpolung Strategy from the Bench-Stable Precursor (Me4N)SCF3
Thomas Scattolin, Kristina Deckers, and Franziska Schoenebeck*
Abstract: Reported herein is the one-pot synthesis of trifluoro-
methylated amines at room temperature using the bench-stable
(Me4N)SCF3 reagent and AgF. The method is rapid, opera-
tionally simple and highly selective. It proceeds via a formal
umpolung reaction of the SCF3 with the amine, giving
quantitative formation of thiocarbamoyl fluoride intermediates
within minutes that can readily be transformed to N-CF3. The
mildness and high functional group tolerance render the
method highly attractive for the late-stage introduction of
trifluoromethyl groups on amines, as demonstrated herein for
a range of pharmaceutically relevant drug molecules.
F
luorination confers molecules with improved properties
and function, affecting lipophilicity, solubility, conformational
and metabolic stability features that impact numerous
branches of chemistry, including the agrochemical and
pharmaceutical arenas.[1] While up to 40% of all active
compounds feature at least one fluorine atom, nitrogen makes
up for an even greater abundance of 80%.[2] In view of the
widespread dissemination of both elements in pharmaceut-
icals, it is somewhat puzzling that their combined function-
ality, that is, trifluoromethyl amines, are scarcely investigated
to date. This might be a consequence of the lack of safe,
general and high-yielding methodology to access these
compounds as well as encountered difficulties in their
purifications (see Figure 1).[3] The latest advances in the
methodological repertoire include the direct N-trifluorome-
thylation of certain amines, nitriles and azoles with electro-
philic[4] or radical-based reagents,[5] posing continued chal-
lenges in terms of generality and late-stage synthetic appli-
cations to compounds with incompatible additional function-
ality. Alternatively, N-CF3 compounds can be made in a two-
step sequence from free amines via oxidative transformations
of dithiocarbamates.[6] Access to the latter can be non-trivial
however with respect to functional group compatibility, as
their syntheses generally require strong base, alkylating or
toxic reagents.[7]
Figure 1. Overview of methods to access N-CF3 compounds and this
work.
under N-CF3 modification.[8] In addition, our calculations of
selected drug molecules indicate similar conformational
preferences but increased logP values for N-CF3 vs. N-Me.[9]
Moreover, a promising isolated study found the N-CF3
analogue of floxacin to retain similar antibacterial activities
as its methylated counterpart.[10]
We herein demonstrate the rapid and selective formation
of a wide range of trifluoromethylated amines from secondary
amines. The high-yielding, one-pot strategy is based on
a polarity inversion and in situ formation of a thiocarbamoyl
fluoride intermediate using the bench-stable (Me4N)SCF3
reagent.
As part of our ongoing mechanistic and methodological
program[11] that also focusses on the generation of fluorine-
containing compounds,[12] we recently developed metal-cata-
À
lyzed C SCF3 bond formation protocols of aryl (pseudo)-
À
halides,
using
the
bench-stable
“SCF3 ”
source
(Me4N)SCF3.[13,14] During these investigations, we encoun-
tered the unexpected formation of a challenging class of
compounds, that is, a thiocarbamoyl fluoride. The subjection
of one equivalent of (Me4N)SCF3 to N-methylaniline in
toluene at room temperature remarkably gave rise to facile
and quantitative formation of N-methyl-N-phenylthiocarba-
moyl fluoride 1a within minutes without any need for
additional reagents or catalysts (see Scheme 1). Although
thiocarbamoyl chlorides are well known and widely reported,
interestingly, the fluoride equivalent has seen much less
precedence.[15] The few reported syntheses relied on the use of
highly toxic and strongly electrophilic reagents.[16] As such,
our discovery constitutes a considerable advance, being safe,
convenient, rapid and utilizing a bench-stable solid as the sole
reaction partner for quantitative transformation within
minutes. To test the generality, we explored a variety of
A mild, safe and operational simple synthetic route to N-
CF3 compounds would hence be desirable and may enable
numerous avenues in chemical and biomedical research. For
example, the frequently encountered facile oxidation of
amines in metabolic processes should be less pronounced
[*] T. Scattolin, K. Deckers, Prof. Dr. F. Schoenebeck
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: franziska.schoenebeck@rwth-aachen.de
Homepage: http://www.schoenebeck.oc.rwth-aachen.de/
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609480.
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the course of 15 h at room temperature (see Scheme 1,
bottom).
These results clearly indicate that in contrast to estab-
lished transformations to access these and related compound
classes, the nucleophilicity of the to be functionalized
heteroatom is not the decisive reactivity factor, therefore
offering a platform for distinct selectivities and functional
group tolerance in the context of late-stage applications of
this methodology.
That said, we next set out to further transform this
valuable intermediate to trifluoromethyl amines. We antici-
pated that the distinct selectivity imposed in the first reaction
step should ultimately translate to the final N-CF3 com-
pounds.
Building on Tyrraꢀs report that described the AgF-
mediated conversion of a diethylcarbamoyl fluoride to N-
CF3,[21] we subsequently investigated the feasibility of this
protocol to convert a wider range of thiocarbamoyl fluorides,
including those generated in situ under our conditions. Mixing
N-methylaniline in acetonitrile with (Me4N)SCF3 led to the
quantitative formation of the corresponding thiocarbamoyl
fluoride within 10 minutes at room temperature, as judged by
quantitative 19F-NMR analysis of the reaction mixture.
Subsequent direct addition of AgF (3 equiv) to the same
Scheme 1. Generation of thiocarbamoyl fluorides via umpolung (top)
and selectivity in reactivities with alternative nucleophiles (bottom).
additional secondary amines for their reactivities with mixture gave complete conversion to the corresponding
(Me4N)SCF3. Scheme 1 shows two additional examples of trifluoromethylated amine 1 in Table 1 within two hours.
isolated thiocarbamoyl fluorides (and Tables 1 and 2 report The reaction between AgF and the thiocarbamoyl fluoride
their follow-up usage). Notably, through the addition of was found to proceed smoothly at room temperature or
hexane after 10 min reaction time, all side-products are higher temperature (508C).[22] No side-products, for example,
precipitated, allowing facile isolation of the thiocarbamoyl arising from a Ritter-type reaction as commonly observed
fluoride upon filtration, if desired.
under electrophilic trifluoromethylation of amines,[4b] were
Given this intriguing and non-obvious reactivity of two detected.
nucleophiles (R2NH and CF3SÀ) to generate the highly
Notably, the only by-products generated in this one-pot
electrophilic thiocarbamoyl fluoride quantitatively, we set two-step sequence are salts [(Me4N)HF2 and Ag2S]. Those
out to explore this transformation in greater detail. On first can readily be precipitated from the reaction mixture via the
sight, a reasonable scenario would appear to be the in situ addition of low polarity solvents, such as hexane or pentane,
[17]
=
generation of F2C S upon fluoride elimination, which leaving the desired N-CF3 target compound as the only
could then serve as an electrophile to the amine. However, product dissolved in the organic phase (MeCN). Thus, only
=
dissolved (Me4N)SCF3 salt in MeCN neither generated F2C S filtration and solvent removal are required to isolate the
by itself nor under the addition of a small amount of water.[18] desired N-CF3 compounds. For more volatile products, we
=
Furthermore, if generated F2C S were to trigger the observed identified that it is also possible to use the lower boiling
reactivity, we would also expect to see transformation with solvent CH2Cl2 as reaction medium. Although AgF is not
nucleophiles other than secondary amines. However, sub- soluble in CH2Cl2, sonication of the reaction mixture miti-
jection of the (Me4N)SCF3 reagent to tertiary amines or gates this and the trifluoromethylamines are generated
phosphines did not give rise to any reaction,[19] indicating equally effectively.
potential for selectivity which would otherwise not be given
This one-pot protocol therefore presents a convenient,
with standard electrophiles that would preferentially select safe and high-yielding route to trifluoromethylamines, and we
for the most nucleophilic site (Scheme 1). In our case, subsequently set out to investigate its full potential. Table 1
selectivity for the “heteroatom-H” site appears to be given. presents an overview of the studied amines. We found our
We next investigated oxygen-based nucleophiles.[17b] We protocol to be compatible with aromatic as well as aliphatic
observed that the reaction of phenol with (Me4N)SCF3 gives secondary amines, generating the corresponding N-CF3
rapid formation of the thiocarbonate species ROC(S)OR products in excellent yields (98–81%). Electron-poor and
within minutes. Similarly, also rather weakly nucleophilic rich amines were coupled with the same efficiency (see
alcohols, such as 2,2,2-trifluoroethanol (N = 1.11 according to Table 1). Exclusive selectivity for the NH site and a high
Mayrꢀs scale[20]
)
or hexafluoroisopropanol (N = À1.93) functional group tolerance were observed. Halogens (6, 11,
formed the corresponding thiocarbonates upon subjection 18), ester (2, 5, 7, 14, 17), nitrile (4), nitro (3, 15), amide (13),
to (Me4N)SCF3. On the other hand, the arguably more sulfonyl (19), methoxy (12, 16) as well as a heterocycle (18)
nucleophilic 4-(trifluoromethyl)phenoxide did not markedly were all tolerated. Two protected amino acids, that is, the
react with (Me4N)SCF3, showing only traces of product over glycine (7) and proline (2) derivatives, were also successfully
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Table 1: Scope of trifluoromethylation of secondary amines.[a]
Table 2: N-Trifluoromethylation of important drug molecules.[a]
[a] Reaction conditions: Amine (0.2 mmol), (Me4N)SCF3 (46 mg,
0.26 mmol), AgF (76 mg, 0.6 mmol) solvent (1.5 mL).
trifluoromethylation of secondary amines. The readily acces-
sible bench-stable (Me4N)SCF3 salt formally serves as CF3
source via initial reaction between the SCF3-anion and the
amine. Upon umpolung a rarely encountered and valuable
thiocarbamoyl fluoride intermediate is generated quantita-
tively in situ that can subsequently be converted to the
corresponding N-CF3 compounds upon reaction with AgF.
The purification consists solely of precipitation of the salt by-
products with non-polar solvent, followed by filtration. The
umpolung strategy allowed distinct selectivities in trifluoro-
methylation which is not governed by nucleophilicity, but
instead by the availability of an “N-H” unit. As such, the
protocol displays a wide functional group tolerance, and was
demonstrated to be compatible with carbonyl, alkene, alkyne,
tertiary amine, nitrile, nitro, heterocycles as well as protected
amino acids and relevant pharmaceuticals.
[a] Reaction conditions: Amine (0.2 mmol), (Me4N)SCF3 (46 mg,
0.26 mmol), AgF (76 mg, 0.6 mmol) solvent (1.5 mL). [b] Formation of
thiocarbamoyl fluoride in 1 h. [c] Formation of thiocarbamoyl fluoride in
24 h. [d] Filtration and column chromatography performed.
synthesized. As such, the presented methodology constitutes
a significant improvement to previous protocols in terms of
operational simplicity and generality.
As a further test of our newly developed methodology for
pharmaceutical and agrochemical applications, we next
investigated nitrogen-containing drug molecules of greater
complexity. We successfully N-trifluoromethylated tetracaine
20, a widely used anesthetic, in 97% yield (Table 2).[23]
Similarly, there are numerous N-Me containing drugs on the
market, and we therefore also investigated the feasibility to
synthesize their N-CF3 bioisosteres.[24] In this context, we
primarily focused on pharmaceuticals that are listed on the
“WHO Model List of Essential Medicines” (a list containing
the most important medications required in any basic health
system).[25] We prepared the N-CF3 analogue of Sildenafil 21
in high yield (88%), the most widely used drug against
erectile dysfunction (Viagraꢁ),[26] the antifungal agents terbi-
nafine 22 (in 95%),[27] and naftifine 23 (88%) as well as
amitriptyline 24 (98%)[28] that finds use in the treatment of
mental illnesses (see Table 2). We were pleased to obtain high
yields in all cases, demonstrating the scope and applicability
of this protocol in a pharmaceutical context, as heterocycles,
tertiary amines, alkynes and alkenes were well tolerated.
In summary, we reported a convenient, safe and opera-
tionally simple one-pot protocol for the rapid and mild
Acknowledgements
We thank the RWTH Aachen, the MIWF NRW and the
European Research Council (ERC-637993) for funding. We
are grateful to Julia Baums and Tomꢂs de Sousa Aguiar for
their practical assistance.
Conflict of interest
The authors declare no conflict of interest.
Keywords: amines · synthetic methods ·
thiocarbamoyl fluoride · trifluoromethylation
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Manuscript received: September 27, 2016
Revised: October 18, 2016
Final Article published: && &&, &&&&
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Communications
Synthetic Methods
T. Scattolin, K. Deckers,
F. Schoenebeck*
&&&& — &&&&
Efficient Synthesis of Trifluoromethyl
Amines through a Formal Umpolung
Strategy from the Bench-Stable Precursor
(Me4N)SCF3
Straight to the goal: Rapid, simple and
highly selective one-pot synthesis of tri-
fluoromethylated amines at room tem-
perature using the bench-stable reagent
(Me4N)SCF3 and AgF is reported. The
reaction proceeds through a formal
umpolung reaction of the (Me4N)SCF3
with the amine, giving quantitative for-
mation of thiocarbamoyl fluoride inter-
mediates within minutes that can readily
be transformed to N-CF3 products.
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