Synthesis and Use of Trifluoromethylthiolated Ketenimines

Article abstract of DOI:10.1002/chem.202002723

The synthesis of trifluoromethylthiolated ketenimines is herein described. They are easily synthesized from the corresponding α-trifluoromethylthiolated oximes upon activation with triflic anhydride and a base. The presumed nitrilium ion resulting from the Beckmann rearrangement is deprotonated to lead to the key intermediate, whose stability brought by the fluorinated substituent was unforeseeable. The reaction of these new building blocks with a variety of nucleophiles affords a vast array of cyclic and acyclic products bearing the valuable SCF₃ moiety.

Full text of DOI:10.1002/chem.202002723

Accepted Article
Accepted Article
Title: Synthesis and use of trifluoromethylthiolated ketenimines
Authors: Thomas Guérin, Nadiia V. Pikun, Ryutaro Morioka, Armen
Panossian, Gilles Hanquet, and Frédéric R. Leroux
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202002723
Link to VoR: https://doi.org/10.1002/chem.202002723
01/2020

10.1002/chem.202002723
Chemistry - A European Journal
COMMUNICATION
Synthesis and use of trifluoromethylthiolated ketenimines
Thomas Guérin,[a] Nadiia V. Pikun,[b] Ryutaro Morioka,[c] Armen Panossian,[a] Gilles Hanquet*[a] and
Frédéric R. Leroux*[a]
Abstract: The synthesis of trifluoromethylthiolated ketenimines is
herein described. They are easily synthesized from the corresponding
α-trifluoromethylthiolated oximes upon activation with triflic anhydride
and a base. The presumed nitrilium ion resulting from the Beckmann
rearrangement is deprotonated to lead to the key intermediate, whose
stability brought by the fluorinated substituent was unforeseeable. The
reaction of these new building blocks with a variety of nucleophiles
affords a vast array of cyclic and acyclic products bearing the valuable
SCF3 moiety.
A. Ketenimine reactivity
N
R = SiR3 R’ = CF3
N
E
•
R
R'
R
ADDITION of
ELECTROPHILES
E
E
Δ
Nuc
N
N
N
R'
•
R
R'
R
R'
ADDITION of
NUCLEOPHILES
KETENIMINE to
Nuc
NITRILE
REARRANGEMENT
R
PERICYCLIC
REACTIONS
Decades of chemical research have shown that the fluorine atom
and the fluorine-containing motifs profoundly impact the structure,
reactivity and function of organic and inorganic molecules.[1]
Fluorine-containing compounds are nowadays synthesized in
pharmaceuticals, agrochemicals, polymers and electronic
research on a routine basis. As an example, it is well established
that fluorine atom(s) and/or fluoroalkyl group(s) can lead to many
beneficial effects in a biologically active molecule.[2, 3] In the past
decade, fluorine chemistry greatly expanded with insightful
contributions from research groups aiming at developing novel
synthetic methods and reagents for the regio- and stereoselective
introduction of fluorine or fluorine-containing groups into
molecular scaffolds. Indeed, the fluorine chemistry field is still
developing at a rapid pace and one of the current challenges is
the search for Emergent Fluorinated Substituents (EFS) that
would not only give new reactivity and functions to man-made
molecules but also eventually lead to improved biological activity
or even a novel mode of action. Such EFS are based on carbon
(e.g. CHF2), on carbon linked to a heteroatom e.g. (O-CF3, S-CF3),
or based on sulfur (e.g. SF5). From an industrial perspective, it
should be noted that CHF2, OCF3, SF5 and SCF3 groups are quite
rarely encountered and there is an urgent need to develop
academic as well as industrial viable approaches towards
scaffolds substituted by these EFS.[4]
R’
(B)n
R’
R
N
N
R
(B)n
A
A
B. Known fluorinated ketenimines
N
N
•
Ar
CF3
•
Alk
F
N
•
Ar
CF3
CF3
Knunyants, 1965
F
Katagiri, 2009
Wang, 2019
C. This work
Tf2O (1 equiv.)
Base (2 equiv.)
NOH
N
•
Ar
SCF3
SCF3
Ar
■ Access to unprecedented structures
■ Metal free
■ Simple procedure
■ 2-carbon building block
■ New intermediate used in situ
■ NMR, MS, IR characterization
Scheme 1. Context of the present work.
reagents.[5] On the other hand, most fluorinated compounds are
often produced on an industrial scale from simple starting building
blocks.[2a-d] Ketenimines are very versatile intermediates, capable
of undergoing a variety of reactions such as nucleophilic additions
and pericyclic reactions (Scheme 1, A).[6] Among them fluorinated
ketenimines are understudied, most likely as only few synthetic
methods are available to prepare them. As a matter of fact since
The ways of introducing the EFSs are important as they are
clearly cost-determining in a chosen synthetic route. In the early
stage of drug development, the late-stage introduction of
fluorinated moieties in advanced synthetic intermediates is highly
desirable and various methods are now available; however, this
late-stage introduction is tedious and relies on expensive
the
seminal
work
of
Knunyants
in
1965
on
bis(trifluoromethyl)arylketenimines, [7] only the trifluoromethyl and
bis(difluoro) derivatives by, respectively, Katagiri in 2009[8] and
Wang in 2019[9] were reported (Scheme 1, B). The SCF3
substituent has witnessed in recent years a huge interest and
different methods for its direct introduction by means of
electrophilic, nucleophilic as well as radical sources have been
assessed.[10] Therefore, we decided to try to access a ketenimine
bearing the SCF3 moiety to further complete the range of
fluorinated ketenimines available (Scheme 1, C). Access to
ketenimine 1a was envisioned to be possible through the
Beckmann rearrangement of ketoxime 2a. Treatment of 2a with
one equivalent of triflic anhydride in toluene, in the presence of
two equivalents of Hünig’s base led to a stable intermediate
whose mass in GC-MS matched 1a’s. The reaction was highly
[a]
Thomas Guérin, Dr. Armen Panossian, Dr. Gilles Hanquet, Dr.
Frédéric Leroux
Université de Strasbourg, Université de Haute-Alsace, CNRS, UMR
7042-LIMA, ECPM, 25 Rue Becquerel, Strasbourg 67087, France
E-mail: ghanquet@unistra.fr, frederic.leroux@unistra.fr
[b]
[c]
Dr. Nadiia Pikun
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-
1006, Latvia
Ryutaro Morioka
Division of Chemistry, Faculty of Pure and Applied Sciences,
University of Tsukuba, Tsukuba, Ibaraki, 305-8571, Japan
Supporting information for this article is given via a link at the end of
the document
1
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10.1002/chem.202002723
Chemistry - A European Journal
COMMUNICATION
exothermic and, if carried out under air, the major product was
amide 3 (Scheme 2) resulting from water addition onto the
electrophilic sp carbon of 1a. All signs seemed to be strongly
indicating of the effective formation of the desired ketenimine 1a.
Furthermore, the reaction of 1a with picric acid led to amide 4,
presumably through Meisenheimer complex B produced after
intramolecular cyclization of imidate A (Scheme 2). A solution of
1a under argon turned out to be stable for several days as
indicated by GC-MS monitoring, yet any attempt to isolate it failed,
leading to amide 3.
Scheme 3. Spectral data of 1a (13C NMR shifts in blue and 1H in yellow, in ppm,
in C6D6) and a plausible mechanism for its formation.
Next, we submitted various amines to the reaction with
intermediate 1a. We were delighted to observe a very clean GC
chromatogram in each occurrence with only the expected product
obtained in the reaction. After a rapid screening of bases and
oxime activators (see supporting information) we studied the
scope of the reaction (Scheme 4). Primary amines gave modest
yields (products 6-8, 10, 11), comparable to the one obtained with
N,N-dimethylhydrazine (product 9). Secondary amines gave the
corresponding amidines with better yields (12-15), that we
attributed to their increased nucleophilicity. Modifying the aryl
moiety for a p-anisyl group did not really affect the outcome of the
reaction (8, 11) and we thus preferred to focus on the scope of
nucleophiles. To our great pleasure thiols and phosphites react
with 1a to give respectively thioimidate 16 and a-
aminophosphonate 17 (Scheme 4, A). In this last example, we
believe the product forms via elimination of ethylene (Scheme 4,
B).[11] We were also pleased to see that malonitrile could add to
1a to form acrylonitrile 18. Several substrates, however, did not
lead to the expected products. Indole left the ketenimine 1a
unreacted while diethylphosphite led to a complex mixture. Unlike
picric acid (see Scheme 2), aliphatic alcohols did not afford the
corresponding imidates.
Tf2O (1 equiv.)
Hünig’s base
(2 equiv.)
NOH
Stable in solution
under argon
for several days
N
•
Ph
SCF3
SCF3
Toluene, 0 °C, 5 min
Ph
1a
2a
O
H2O
Ph
SCF3
N
H
3, 58%
1a
O2N
NO2
O
≡
SCF3
Picric acid
N
O2N
Ph
4
through
Ph
Ph
H
2
HN
SCF3
O N
SCF3
N
O2N
O
O
A. Scope of nucleophiles
1. 2,4,6-collidine
NO2
NO2
O2N
O2N
NucH
(1.1 equiv.)
(2 equiv.)
A
B
N
N
2. Tf2O (1 equiv.)
•
SCF3
SCF3
2
R
R
Scheme 2. Synthesis of 1a and its reaction with oxygen-centered nucleophiles.
Toluene
25 °C
Toluene
Nuc
0 °C, 5 min
1
Though rather inclined to believe in the ketenimine nature of 1a,
we had to further characterize it. Although less coherent with the
formation of 3 and 4, we could not totally exclude 1a to be actually
azirine 5 produced by a Neber rearrangement, and isomassic to
1a. NMR leaned on the ketenimine side as the upfield proton was
likely vinylic, despite its adjacent carbon being very shielded.
Nevertheless, infrared analysis cleared all remaining doubt by
O
N
N
SCF3
SCF3
N
N
HN
SCF3
N
HN
N
SCF3
SCF3
NHn-Pr
NHPMB
NHBn
O
O
6 | 31 %
7 | 34 %
8 | 39 %
9 | 39 %
10 | 58 %
O
showing a clear band at 2028 cm-1, characteristic of the stretching
[6a]
band νN=C=C
.
Thus we are proposing the mechanism to be as
follows (Scheme 3): first the oxime is converted into its triflic ether
derivative I. I then undergoes a Beckmann rearrangement, the
phenyl group migrates onto the nitrogen as the triflate anion
departs, to form II, a mesomeric form of nitrilium III. II, or III is then
deprotonated by the remaining equivalent of base to form
ketenimine 1a.
N
N
N
SCF3
≡
SCF3
SCF3
O
N
N
HN
O
11 | 34 %
12 | 64 %
13 | 52 %
SCF3
H
N
H
N
spectral analyses
P
N
N
O
SCF3
O
SCF3
2a
SCF3
O
infrared
N
N
O
S
Tf2O
Et2(iPr)N
!
N=C=C = 2028 cm-1
-Et2(iPr)NHOTf ↓
17 | 58 %
(from triethylphosphite)
O
O
NMR
NEBER
CYCLIZATION
14 | 66 %
15 | 47 %
16 | 50 %
137,5
OTf
N
5
N
179,3
SCF3
B. Plausible mechanism for the formation of 17
Ph
SCF3
SCF3
N
Ph
•
SCF3
H
H
SCF3
I
N
4,09
H
HN
NC
18 | 39 %[a]
N
O
H
P(OEt)3
BECKMANN
REARRANGEMENT
SCF3
CN
39,1
Ph
1a
P
O
O
P
O
O
Et2(iPr)N
-Et2(iPr)NHOTf ↓
O
N
N
17
Ph
SCF3
OTf
•
Ph
SCF3
N
Ph
SCF3
OTf
II
1a
III
Scheme 4. Scope of the nucleophiles affording acyclic products. [a] 3 equiv. of
base were used.
2
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10.1002/chem.202002723
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We then envisioned using ambiphilic reagents, bearing both
nucleophilic and electrophilic moieties in order to access the
corresponding heterocyclic compounds after N- or C-
cyclization.[6c] Our first attempts implied diverse salicylaldehydes
derivatives. Although the reaction at room temperature was
irreproducible, microwave conditions gave consistent results. Yet
the isolated yield turned out to be quite poor, indeed product 19
was obtained in only 23 % yield (Scheme 5). However, this
methodology would provide the only alternative to access 3-
trifluoromethylthio coumarins (after hydrolysis) to the one
described in the literature, using expensive AgSCF3.[12] 1a could
react similarly with benzoic or formic hydrazides to form the
corresponding 1,2,4-triazoles 20 and 21 resulting from N-
cyclization.
bond of the ketenimine. Interestingly, the resulting product did not
display the characteristic azide stretching band at ca. 2100 cm-1
in infrared spectroscopy. Our product bearing a CH2SCF3 moiety
according to 1H and 13C NMR, we believe that the distal nitrogen
of TMSN3 acts as any other nucleophile and attacks the sp carbon
of 1 to form 23 and, after N-cyclization, intermediate 24 that
rearomatizes through protodesilylation in the presence of water to
give the corresponding 4H-tetrazoles 25 and 26 (Scheme 7).
R
TMSN3
N
SCF3
(1.1 equiv.)
•
SCF3
N
Toluene, 25 °C, 16 h
R
N
N
N
R = H : 1a
R = Br : 1c
R = H : 25 | 45 %
R = Br : 26 | 84 %
Ar SCF3
Toluene, 150 °C
30 min, microwave
Toluene, 150 °C
30 min, microwave
TMSN3
SCF3
Ar
N
N
N
N
N
H2O
•
Ph
SCF3
Si
N
O
O2N
CHO
OH
N
Si
N
1a
N
NH2
R
N
H
23
24
Scheme 7. Reaction with TMSN3 and cyclization of the presumed imidoyl azide
(1 equiv.)
(1 equiv.)
O2N
intermediate.
SCF3
SCF3
N
O
NPh
≡
N
In conclusion, we have developed a simple method to access
trifluoromethylthiolated ketenimines. We could show that these
unprecedented structures react under metal-free conditions with
a variety of nucleophiles to form acyclic trifluoromethylthiolated
products. When an electrophilic moiety is present on the
nucleophilic reagent, trifluoromethylthiolated heterocycles can be
synthesized, allowing for rapid structure diversification through
the addition of a C-C-SCF3 unit. The reactivity of the ketenimines
in other types of reactions is currently being explored in our
laboratory. These original intermediates should likely prove to be
useful in the synthesis of bioactive compounds.
R
N
19 | 23%
R = Ph : 20 | 33 %
R = H : 21 | 60 %
Scheme 5. Reaction with ambiphilic reagents.
Having established the feasibility to access heterocyclic
compounds through N- or C-cyclization, we wondered whether
the aniline group resulting from the 1,2-phenyl shift could be
eliminated by the condensation of a second nucleophilic position
on the coupling partner. Thus, we used 2-hydrazinopyridine and
could indeed isolate [1,2,4]triazolo[4,3-a]pyridine 22 in 68 % yield
(Scheme 6) from ketenimine 1b.
Acknowledgements
We gratefully acknowledge the French Agence Nationale pour la
Recherche (ANR) (grant number ANR-17-CE07-0008-01, DEFIS),
CNRS and Université de Strasbourg for financial support. T. G. is
much grateful to the French Ministry of Education and Research
for funding. N. P. was supported by the PostDoc project
Nr.1.1.1.2/ VIAA/2/18/373. R. M. received a mobility grant from
the University of Tsukuba. We thank L. Karmazin and C. Bailly
from the Service de radiocristallographie de la Fédération de
Chimie Le Bel FR 2010 for the SCXRD analyses. The French
Fluorine Network (GIS Fluor) is also acknowledged.
NH2
N
N
H
SCF3
N
(1.1 equiv.)
•
SCF3
N
N
Toluene, 25 °C, 16 h
N
R
22
R = H : 1a
R = OMe : 1b
from 1a | 40 %
from 1b | 68 %
N
H
Ar
SCF3
Ar
N
-NH2Ar
NH
SCF3
HN
N
N
N
H
Keywords: ketenimines
• heterocycles • rearrangement •
N
organofluorine compounds • trifluoromethylthioethers
Scheme 6. Reaction with a bisnucleophilic reagent.
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3
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10.1002/chem.202002723
Chemistry - A European Journal
COMMUNICATION
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4
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10.1002/chem.202002723
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COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Amidines
Thomas Guérin, Nadiia V. Pikun,
Tf2O, Base
Aminophosphonate
Thioimidate
NOH
Ryutaro Morioka, Armen Panossian,
Gilles Hanquet* and Frédéric R. Leroux*
Page No. – Page No.
N
•
Ar
SCF3
SCF3
Toluene, 0 °C, 5 min
Ph
Heterocycles
…
■Unprecedented ketenimines
■New SCF3 building block
■Simple procedure
Synthesis and use of
trifluoromethylthiolated ketenimines
We herein disclose the first synthesis of trifluoromethylthiolated ketenimines. They
are quickly and easily formed from α-trifluoromethylthiolated oximes through a
Beckmann rearrangement and deprotonation of the nitrilium intermediate. Their
interest is exemplified by many reactions, such as the direct addition of several C-,
O-, N-, S- and P-centered nucleophiles as well as their incorporation into valuable
heterocycles through cascade reactions.
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