Boron Trifluoride-Mediated Trifluoromethylthiolation of N-Acyliminiums

Article abstract of DOI:10.1002/adsc.201800514

Herein, we describe a hitherto unprecedented trifluoromethylthiolation of N-acyliminiums promoted by boron trifluoride etherate to enable a convenient access to various α-amino trifluoromethylthiolate derivatives in good yields. The reaction proceeds under mild conditions, relying on copper(I) trifluoromethylthiolate as a nucleophilic partner. (Figure presented.).

Full text of DOI:10.1002/adsc.201800514

Title: Boron Trifluoride-Mediated Trifluoromethylthiolation of N-
Acyliminiums
Authors: Julien Maury, Guillaume Force, Benjamin Darses, and david
leboeuf
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800514
Link to VoR: http://dx.doi.org/10.1002/adsc.201800514

Advanced Synthesis & Catalysis
10.1002/adsc.201800514
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Boron Trifluoride-Mediated Trifluoromethylthiolation of N-
Acyliminiums
a
a
b
a
Julien Maury, Guillaume Force, Benjamin Darses and David Lebœuf *
a
Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Univ. Paris-Sud, Université Paris-Saclay,
Bâtiment 420, 91405 Orsay cedex, France. E-mail: david.leboeuf@u-psud.fr
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ. Paris-Sud, Université Paris-Saclay, 1 av. de la
b
Terrasse, 91198 Gif-sur-Yvette, France.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract Text. Herein, we describe
a
hitherto heteroatoms in medicinal chemistry. In this context, it
unprecedented trifluoromethylthiolation of N-acyliminiums appears to be especially appealing to devise a method
promoted by boron trifluoride etherate to enable a for the preparation of valuable fluorinated nitrogen-
convenient
access
to
various
-amino containing compounds as potentially bioactive
trifluoromethylthiolate derivatives in good yields. The
reaction proceeds under mild conditions, relying on
copper(I) trifluoromethylthiolate as a nucleophilic partner.
molecules. Regarding this goal, we thought to use N-
acyliminiums as electrophiles combined with a
nucleophilic source of SCF . The chemistry of N-
3
acyliminiums has been extensively exploited in the
last decades through the addition of manifold
nucleophiles (allylsilanes, alkynylsilanes, silyl enol
ethers, (hetero)arenes, ketones, vinylboronic acids,
Keywords: N-Acyliminium; N,O-Acetal;
Trifluomethylthiolation; Lewis acids; Heterocycles
[9]
etc.) to provide structurally intricate frameworks.
A large majority of fundamental molecules in
medicinal chemistry feature the presence of at least
They can be easily generated via the activation of
N,O-acetals in the presence of Lewis and Brønsted
acids, releasing water as the sole by-product. Of note,
while N,O-acetals have never been employed to
[
1]
one nitrogen atom. However, in the past decade, the
incorporation of fluorine functional groups (F, CF
SCF , SCF H, etc.) on bioactive compounds has
3
,
3
2
introduce the SCF
methods, to date, have been reported for the
dehydroxytrifluomethylthiolation of alcohols
In the present communication, we
3
group, only three synthetic
generated an increasing interest in drug design,
becoming now a parameter that is routinely
[
2]
evaluated. This is mainly due to the enhancement
of biochemical and pharmacological properties of the
corresponding molecules. This phenomenon is
especially true for highly polar compounds because
of their lower ability to cross lipid membranes and,
therefore, their limited bioavailability. Owing to its
[10]
(
Scheme 1).
depict the first trifluoromethylthiolation of N-
acyliminiums assisted by boron trifluoride as a Lewis
acid.
higher lipophilicity when compared to CF
membrane permeability and metabolic stability,[3]
SCF has become an intriguing functional group and
an upsurge in synthetic methods enabling its
3
or F,
3
[
4]
straightforward introduction has been reported.
[
5]
[6]
Currently,
oxidative,
electrophilic
and
[
7]
nucleophilic
trifluoromethylthiolation processes
stand out among the main synthetic strategies, even if
photocatalytic approaches have recently emerged as a
powerful tool to incorporate a SCF
3
group.[8]
However, the direct -trifluomethylthiolation of
amino groups remains still a challenge to address,
which is surprising given that this class of
compounds combines two of the most popular
Scheme 1. Dehydroxytrifluomethylthiolation of alcohols.
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201800514
1
1
1
7
8
9
-
CuSCF
CuSCF
CuSCF
3
(2)
(2)
(2)
MeCN
MeCN
MeCN
-
92
67
Initially, we investigated the reactivity of N-
BF
HBF
3
·OEt
2
(3)
(3)
3
hydroxyisoindolinone 1a in the presence of CuSCF
3
4
·OEt
2
3
(
1
2 equiv), a readily-available source of SCF
). Several Lewis and Brønsted acids, which are
3
(Table
a)
Reaction conditions: 3-hydroxyisoindolinone 1a (1
equiv) and SCF source (2 equiv) in the indicated solvent
0.1 M) in the presence of promoter at rt for 24 h under
3
commonly used to catalytically generate N-
acyliminiums,[ were first surveyed for the direct
trifluoromethylthiolation of 1a (Entries 1-7).
However, in each case, the starting material was fully
recovered, whether the reaction was performed at
room temperature or under reflux. Based on these
(
11]
b)
argon.
dichloroethane.
Reaction performed at 80 C. 1,2-DCE = 1,2-
With the optimized reaction conditions in hand, we
examined the reactivity of a series of N-aryl- and N-
alkyl-substituted 3-hydroxy isoindolinones (Table 2).
To our delight, the reaction was compatible with a
large variety of aryl, propargyl, allyl, benzyl and
results, we turned our attention to BF
3
·OEt , which
2
has already been successfully employed in the
dehydroxytrifluoromethylthiolation of alcohols by
Rueping’s group, while being also a well-established
promoter to trigger the formation of N-
acyliminiums. Thus, in the presence of a catalytic
amount of BF ·OEt (10 mol%), only traces of the
product 2a were observed (Entry 8). On the other
hand, in the presence of 2 equivalents of BF ·OEt
the reaction afforded 2a in 75% yield within 24 h
alkyl
groups,
affording the
corresponding
isoindolinones in good to excellent yields (up to
97%). The reaction was even found to tolerate the
free amide (2k), albeit in lower yield (45%). It is
noteworthy that oxidation of the N,O-acetal moiety
into the corresponding amide was observed in some
cases (2h and 2i, for instance). To prevent this side-
reaction, the reaction had to be conducted in degassed
MeCN, a condition that we then applied to all the
substrates.
[9]
3
2
3
2
,
(
Entry 9). Heating the reaction mixture at 80 C
proved to be detrimental to the transformation,
leading mainly to the decomposition of 1a (Entry 10).
Other solvents (toluene, 1,2-DCE, CH
MeNO ) were also tested without success, resulting
either in the formation of the Friedel-Crafts adduct
Entry 11) or degradation (Entries 12-14). In stark
contrast, other nucleophilic sources of SCF (AgSCF
and Me NSCF ) were rather ineffective for the
transformation (Entries 15-16), implying that the role
of CuSCF is critical in the reaction process with
BF ·OEt (Entry 17). Finally, increasing the promoter
loading (3 equiv) improved the yield to 92% yield
Entry 18). We also found out that the reaction could
be promoted by the corresponding Brønsted acid
HBF ·OEt . However, the reaction was less efficient
67%) when compared to BF ·OEt
2
Cl
2
and
Table 2. Scope of 3-hydroxyisoindolinones.
2
(
3
3
,
4
3
3
3
2
(
4
2
(
3
2
.
Table 1. Optimization of the reaction conditions.a)
SCF
3
source
2a
(yield)
NR
Entry
Promoter (equiv)
Sn(NTf (0.1)
Solvent
MeCN
MeCN
(equiv)
1
2
2
)
4
CuSCF
3
3
(2)
(2)
Ca(NTf
nBu NPF
HNTf (0.1)
Al(OTf)
Bi(OTf)
Cu(OTf)
B(C
BF
BF
BF
BF
BF
BF
BF
BF
BF
2 2
) /
CuSCF
NR
4
6
(0.1)
3
4
5
6
7
8
9
2
CuSCF
CuSCF
CuSCF
CuSCF
CuSCF
CuSCF
CuSCF
CuSCF
CuSCF
CuSCF
CuSCF
CuSCF
3
3
3
3
3
3
3
3
3
3
3
3
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
1,2-DCE
NR
NR
NR
NR
NR
traces
75
ND
-
-
-
3
(0.1)
(0.1)
(0.1)
3
2
6 5 3
F ) (0.1)
Reaction conditions: 3-hydroxyisoindolinones 1a-1k (1
3
·OEt
·OEt
·OEt
·OEt
·OEt
·OEt
·OEt
·OEt
·OEt
2
(0.1)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
equiv) and CuSCF
3
(2 equiv) in MeCN (0.1 M) in the
3
2
2
2
2
2
2
2
2
b)
1
1
1
1
1
1
1
0
1
2
3
4
5
6
3
presence of BF ·OEt (3 equiv) at rt for 24-40 h under
3
2
3
argon.
3
3
CH
2
Cl
2
During the course of our investigations, we explored
3
MeNO
MeCN
MeCN
2
-
40
25
the reactivity of substrate 1l (Equation 1), which can
3
AgSCF
Me NSCF
3
[12]
3
4
3
(2)
be assimilated to a 1,3-bis-N-acyliminium species,
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201800514
in
order
to
access
the
compound
corresponding
2l.
we believe that CuSCF
3
is first transformed into the
bis(trifluoromethylthiolate)
Gratifyingly, the reaction worked as anticipated
giving rise to product 2l in 58% yield.
putative cationic complex 5 in the presence of
[14]
BF
BF
3
·OEt
·OEt
2
.
2
From there, both cationic copper(I) and
could induce the formation of the
3
-
corresponding N-acyliminium, while [BF
3 3
(SCF )]
would be the true nucleophilic species. To support
1
9
11
this hypothesis, F and B NMR experiments were
performed (see Supporting Information). Interestingly,
3
adding BF ·OEt
2
to a solution of CuSCF
3
in CD CN
3
We then extended the reaction to other N-
acyliminium derivatives to provide the corresponding
led to a significant shift of the signal of fluorine from
 = 27.2 ppm to  = 32.6 ppm (with a second
signal at  = 151.6 ppm) and of the signal of boron
from  = 0.48 ppm to  = 0.77 ppm, which seems
in agreement with the formation of 5. Then, substrate
1d was added to this mixture. After 1 h, several
signals were observed by F NMR. Among them, we
detected the same signal at  = 32.6 ppm and
additional ones at  = 38.4 ppm (2d),  = 46.8 ppm

-amido trifluoromethylthiolates with a naphthyl,
perfluoroaryl, cyclohexenyl and norbornenyl
counterpart in yields ranging from 52% to 89%
(
Table 3). On the other hand, substrate 3c failed to
deliver the desired product, which might be explained
by competitive conjugate addition of SCF to the -
1
9
3
unsaturated amide. Indeed, employing a more
hindered precursor produced 4d in 88% yield.
Interestingly, pyrrolidin-2-one 4g and piperidin-2-one
(
characteristic shift of CF
ppm, which could be attributed to a [BF
species. Under these conditions, 2d was isolated in
5% yield. To determine if CF SSCF could be the
true source of SCF , the reaction was carried out
using CF SSCF instead of CuSCF , but little or no
3
SSCF ) and  = 49.1
3
-
3
(OH)]
4
h could also be obtained with a good control of the
[13]
diastereoselectivity.
Disappointingly, no reaction
7
3
3
was observed with sultam 3i, resulting likely from an
unwanted coordination between the sulfonyl group
3
3
3
3
and either BF or Cu.
3
reaction was observed in that case with or without a
copper source. This mechanistic proposal could
provide an explanation about the impossibility to
achieve a catalytic version of this reaction because of
Table 3. Scope of N,O-acetals.a)
[15]
the requirement to initially generate species 5.
a)
Reaction conditions: N,O-acetals 3a-3i (1 equiv) and
CuSCF
BF ·OEt
3
(2 equiv) in MeCN (0.1 M) in the presence of
(3 equiv) at rt for 24-40 h under argon. b)
2
3
Minor diastereoisomer 4’g was isolated in 6% yield.
Regarding the mechanism of this reaction, we were
puzzled by the stumbling block that a catalytic
version represented. And, to account for this
behaviour, mechanistic studies were performed with
substrate 1d (Scheme 2). To rule out a radical
mechanism, the reaction was conducted in the
presence of 2 equivalents of 4-methyl-2,6-di-tert-
butyl phenol (BHT), which did not prevent the
formation of the desired product 2d (49%). In fact,
Scheme
2.
Mechanistic proposal
for the
trifluoromethylthiolation of N,O-acetals.
In conclusion, we have developed a new approach
towards the preparation of
trifluoromethylthiolates from N,O-acetal derivatives,
-amino
using a simple and efficient procedure. It is worth
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201800514
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generate these compounds, paving the way for
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,
CNRS, Université Paris-Sud and Institut de Chimie des
Substances Naturelles for financial support of this work. Dr.
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2
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[
[
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1
3
409). In this case, CHSCF appears as a singlet. On
the other hand, the structure of 4i was determined by
NOESY with a clear cross peak between the vicinal
protons CHSCF and CHOAc.
3
2
016, 22, 4753; c) S. Mukherjee, B. Maji, A. Tlahuext-
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[
14] Unfortunately, our attempts to isolate and
characterize the species 5 have not been successful
because of its instability, which might be the reason
why two equivalents of CuSCF
obtain the full conversion.
3
were necessary to
[15] L. Ma, X.-F. Cheng, Y. Li, X.-S. Wang, Tetrahedron
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[
16] Even if we did not observe such a species by NMR,
we cannot rule out the possibility of a subsequent
[
[
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reaction of 5 with a second equivalent of BF
3 2
·OEt to
give the organoboron difluoride BF SCF , a Lewis acid
2
3
capable of activating the N,O-acetal derivative to
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5
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Boron Trifluoride-Mediated
Trifluoromethylthiolation of N-Acyliminiums
Adv. Synth. Catal. Year, Volume, Page – Page
a
a
Julien Maury, Guillaume Force, Benjamin
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Darses and David Lebœuf *
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