Functionalized S-perfluorinated sulfoximines: Preparation and evaluation in catalytic processes

Article abstract of DOI:10.1016/j.jfluchem.2015.06.020

N-substituted S-perfluoroalkylated sulfoximines were synthesized from the NH sulfoximines either by a copper coupling reaction with aryl halides or by a reaction with electrophilic substrates. The procedure allowed the preparation of N,N′-bridged bis sulf

Full text of DOI:10.1016/j.jfluchem.2015.06.020

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Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Functionalized S-perfluorinated sulfoximines: Preparation
and evaluation in catalytic processes
a
a
b
b
Thanh-Nghi Le a,b, Patrick Diter , Bruce Pegot , Chloee Bournaud , Martial Toffano ,
´
´
Regis Guillot b, Giang Vo-Thanh b, , Yurii Yagupolskii , Emmanuel Magnier
c
*
a,**
a Institut Lavoisier de Versailles (ILV), UMR CNRS 8180, Universite´ de Versailles St Quentin en Yvelines, 45, Avenue des Etats-Unis, 78035 Versailles
Cedex, France
b
´
´
´
´
Laboratoire de Catalyse Moleculaire, Institut de Chimie Moleculaire et des Materiaux d’Orsay (ICMMO), UMR CNRS 8182, Universite Paris-Sud, 91405 Orsay
Cedex, France
c Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmans’ka Str. 5, Kyiv 02094, Ukraine
A R T I C L E I N F O
A B S T R A C T
Article history:
N-substituted S-perfluoroalkylated sulfoximines were synthesized from the NH sulfoximines either by a
copper coupling reaction with aryl halides or by a reaction with electrophilic substrates. The procedure
allowed the preparation of N,N0-bridged bis sulfoximines and of thioureas. The potential of these new
sulfoximines was evaluated in different catalytic processes.
Received 10 June 2015
Received in revised form 17 June 2015
Accepted 20 June 2015
Available online xxx
ß 2015 Elsevier B.V. All rights reserved.
Keywords:
S-Perfluoroalkylated sulfoximines
Copper
Catalyst
Microwaves
Thioureas
1. Introduction
the synthesis of original per-, polyfluoroalkyl substituted sulfox-
imines and present some seminal evaluations of these compounds
The growing interest for the sulfoximines is explained by both
the wide structural variation offered by this original structure and
by their numerous applications in chemistry. They indeed
demonstrated promising potential activities for medicinal chem-
istry [1] or in crop sciences [2]. Sulfoximines were also plentifully
employed as ligands in catalytic reactions or in enantioselective
metal catalysis [3], but surprisingly much more rarely for
organocatalytic transformations.[4] The S-perfluoroalkylated sul-
foximines have recently grown in importance and revealed very
particular properties. They were described as building blocks for
liquid crystals [5], as very powerful electron-withdrawing sub-
stituents and especially as nucleophilic and electrophilic perfluor-
oalkylating reagents [6]. This panel of applications clearly
emphasized the need of new and reliable methods for the
preparation of sulfoximines. In this paper, we herein disclose
in catalytic and organocatalytic processes.
2. Results and discussion
We have previously developed a three-step methodology for
the preparation of NH S-perfluoroalkylated sulfoximines
1
(Scheme 1) [7]. Compared to the previous procedures [7c,8,9],
our method revealed advantages especially concerning the
opportunity to be extended to various per-, polyfluorinated chains.
Practically, we were able to finely-tune the aryl and the
perfluorinated substituents attached to the sulfur atom to give
rise to a wide range of free NH-sulfur (VI) derivatives 1a–e. This
enabled thus the further post-functionalization on this iminosul-
fane group (HN55S). As part as our program [10,11] devoted to the
comprehensive studies of the reactivity of this specific nitrogen
atom, we report now recent developments of this chemistry.
2.1. N-Functionalization by copper catalysis
*
Corresponding author. Tel.: +33 1 69 15 78 91; fax: +33 1 69 15 46 80.
Corresponding author. Tel.: +33 1 39 25 44 66; fax: +33 1 39 25 44 52.
E-mail addresses: giang.vo-thanh@u-psud.fr (G. Vo-Thanh),
**
The copper based catalytic system, initially developed by Bolm
emmanuel.magnier@uvsq.fr (E. Magnier).
et al. [12] was previously adapted by us to S-perfluoroalkylated
http://dx.doi.org/10.1016/j.jfluchem.2015.06.020
0022-1139/ß 2015 Elsevier B.V. All rights reserved.
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Scheme 1. Straightforward synthesis of NH S-perfluoroalkylated sulfoximines 1.
compounds to provide various N-arylated sulfoximines [11]. To
perform this transformation, a substoichiometric amount of
copper salt (50%) was necessary. A reappraisal of this slightly
modified system by the use of microwaves activation allowed a
significant reduction of the reaction time (Table 1). As a typical
example, the coupling between the iodobenzene 2a and the
sulfoximine 1a was finished in 15 min instead of 3 hours without
any erosion of the yield (entry 1). This result stimulated us to gain
into increased molecular diversity. Ortho iodobenzenes 2b–d
reacted smoothly providing an augmentation of the reaction time
(entries 2–4). This transformation was then tolerant to nitro, fluoro
or amino group. The variation of the fluorinated moiety was quite
surprising. Under previous conditions, the reaction with the
S-dibromofluoromethyl sulfoximine 1a was accompanied with
the loss of the bromine atom and compound 3e was isolated (entry
5). Fortunately, a slight decrease of the temperature, counter-
balanced by a longer reaction time, gave rise to the desired
sulfoximine 3f (entry 6). As a next part of this study and inspired by
the seminal work of Bolm et al., we turned our attention toward
the preparation of bis-sulfoximines [13] starting from dibromo- or
diiodobenzene. With stoichiometric amounts of each reagent, the
monosulfoximines 3g and 3h were rationally isolated in good
yields whereas a small amount of the bis-sulfoximine 4a was
nevertheless detected (entries 7–8). A reasonable increase of the
equivalent the sulfoximine as well as the reaction time was
necessary for the isolation of the compound 4a in 71% yield (entries
9–12).
In order to circumvent the use of an excess of the sulfoximine
for the synthesis of the target molecule 4a, a two-step procedure
was envisioned. Starting from 3g or 3h, we were pleased to
perform a second coupling step (Scheme 2). The desired compound
4a was isolated with the same yield with both substrates 3g or
3h. Beyond the good isolated yield without excess of sulfoximines,
another advantage of this two-step sequence was the opportunity
of the preparation of non-symmetrical bridged sulfoximines. This
transformation was also effective when RF = C4F9, delivering
another original molecule 4b.
For each of the products 4a or 4b, we succeeded in the
separation of the two diastereoisomers with the help of the
preparative plate chromatography. In the particular case of 4a,
the two couples were identified by X-ray analysis after crystalli-
zation (Fig. 1).
Table 1
Synthesis of mono and bis adducts (3 and 4) by copper coupling reaction between fluoroalkylated sulfoximines 1a, 1c and aryl halides 2a–g.
X
Y
O
S
CuI (50mol%)
O
O
O
S
RF
DMEDA (100mol%)
NH
+
S
N
Y
+
S
N
N
RF
RF = CF3
PhMe/ K2CO3(2 equiv.)
MW 110°C
.
RF
2a-g
RF
1a
3a-h
4a
CF2Br 1c
n equiv.
1 equiv.
Entry
RF
X
Y
n
Time (min)
Yield (%)a
(3a–h)
4a
1
2
CF3
I
H
1
1
1
1
1
1
1
1
2
5
5
5
15
45
91 (3a)
81 (3b)
90 (3c)
86 (3d)
77 (3e)b
76 (3f)c
92 (3g)
90 (3h)
82 (3h)
56 (3h)
5 (3h)
–
–
CF3
Br
I
NO2
3
CF3
F
60
–
4
CF3
I
NH2
60
–
5
CF2Br
CF2Br
CF3
I
H
H
Br
I
60
–
6
I
240
90
–
7
Br
I
5
8
CF3
90
6
9
CF3
I
I
90
13
27
71
68
10
11d
12d
CF3
I
I
90
CF3
I
I
150
150
CF3
Br
Br
6 (3g)
a
Isolated yield.
b
c
CF2Br reduced to CF2H in 3e, with 21% of 3f (CF2Br).
MW activation at 100 8C, with 18% of 3e.
MW activation at 125 8C.
d
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Scheme 2. Synthesis of N,N-bridged bis S-perfluoroalkylated sulfoximines 4a and 4b.
Fig. 1. ORTEP drawing for crystal structure of the two diastereoisomers of compound 4a.
Scheme 3. Synthesis of thioureas 6–7.
The reactivity of the nitrogen atom toward nucleophiles was
also studied during this work.
good yield. On the other hand, the sulfoximines 7a–b were easily
synthesized from the aniline 3d in almost quantitative yields.
The direct nucleophilic substitution between the substrate 1a
and benzyl halides did not occur. This not surprising failure was
offset thanks to basic conditions, previously described for non
fluoroalkykated NH-sulfoximines [10,15]. This procedure was
easily adapted to these base sensitive compounds and gave rise
to the N-alkylated S-sulfoximines 8a–b with excellent yields
(Scheme 4).
As last example of N-post-functionalization was realized by the
condensation reaction between the sulfoximine 3d and benzalde-
hyde, followed by a reduction. This process, previously described in
non-fluorinated series [3d] afforded the amine 9a in almost
quantitative yield (Scheme 5).
2.2. Sulfoximines as nucleophilic reagents
Urea- and thiourea-based substances were widely studied in
organic synthesis, especially for organocatalytic purposes [14]. We
were then intrigued by the possibility of the synthesis of
‘‘sulfoximines-thioureas’’, previously described by Bolm et al. with
non perfluorinated sulfoximines [4]. The reaction between the
molecule 1a and phenyl isothiocyanate 5a delivered the expected
compound 6a albeit with low yield, due to the tamed nucleophi-
licity of the nitrogen atom induced by the presence of the
trifluoromethyl group of the sulfur (VI) moiety (Scheme 3). The use
of more harsh conditions (DMSO, 150 8C) did not really improve
the yield (32%). The rise of the electrophilicity of the isothiocyanate
partner 5b allowed nevertheless the preparation of urea 6b with a
With these sulfoximines in hand, we turned our attention to
their use as ligand for metal catalysis and also as organocatalysts.
In order to assess the catalytic activity of the perfluoroalkylated
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Scheme 4. N-Alkylation of sulfoximine 1a under basic conditions.
Scheme 5. Reductive amination of aniline 3d with benzaldehyde.
Table 2
HDA reaction catalyzed by copper/bis-sulfoximine 4a complex
10mol% 4
10mol% Cu(OTf)2
O
R
R
O
S N
R
O
S
OEt
+
N
O
DCM, rt
O
CO2Et
R
10
11a-b
12a
12b
4a
4c
R = H
R = CO2Et
R = CF3
R = Me
.
Entry
R
Ligand
Time (h)
Yield (%)
1
2
3
4
H
H
4c
4a
4c
4a
2
48
8
62a
51b
95a
55b
CO2Et
CO2Et
48
a
GC yields.
b
Isolated yields.
Scheme 6. Mukaiyama-type aldol reaction catalyzed by the 9/Cu(OTf)2 complex.
sulfoximines, we settled on model reactions already described
with the non-fluorinated sulfoximine equivalent. However, we
limited firstly the investigation of our ligands to racemic series
in order to focus on the principle possibility of its utilization.
et al. with enantiomerically pure non-fluorinated sulfoximine 4c
(Table 2, entries 1 and 3) [13]. The full comparison between ligands
4a and 4c proved limited as the yield with 4c was determined by
GC analysis in [13]. We were nevertheless quite satisfied to obtain
a somewhat comparable isolated yield of target products 12a–b
with the perfluorinated ligand 4a providing an increase of the
reaction time. To the best of our knowledge, it has been the first
example of the use of S-trifluoromethylated sulfoximine as ligand
in catalysis.
2.3. Applications in catalytic systems
The hetero Diels–Alder reaction (HDA) between the cyclohex-
adiene 10 and the
a-ketoester 11 catalyzed by copper catalyst
was firstly examined [16]. The bis-sulfoximine 4a was used
as ligand. The reaction was performed in dichloromethane at
room temperature using the same conditions described by Bolm
For the next comparison, Mukaiyama-type aldol reaction was
chosen (Scheme 6). The catalytic version of this transformation
was already studied using a chiral copper–ligand complex with the
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Scheme 7. Sulfoximines 7a,b as organocatalyst in Biginelli’s reaction.
Scheme 8. Friedel–Crafts reaction with sulfoximine thiourea 7b as organocatalyst.
sulfoximine 9b [17]. We performed the catalytic preparation of the
molecule 15 with comparable yield to Bolm et al., but only in
racemic series in our example.
model substrates (Scheme 8). The essays with and without the
catalyst 7b clearly demonstrated the catalytic effect of this
molecule (34% yield versus 65%) [24]. The same yield was
obviously obtained with the enantiomerically pure sulfoximine
(R)-(+)-7b [25] but unfortunately without any asymmetric
induction (or no asymmetric induction was observed).
To the best of our knowledge, this has been the first example of
the use of a ‘‘sulfoximine-thiourea’’ function in an organocatalytic
Friedel–Crafts reaction. This result partially validates our initial
hypothesis about the increased of the NH acidity due to the
presence of the perfluoroalkyl chain.
As partial conclusion, the presence of perfluoroalkyl group on
sulfur atom of sulfoximines does not seem to bring dramatical
influence in metal catalytic system. In order to give some clue to
these results, an insight to mechanistical, kinetic and thermody-
namic features should be envisioned but fall down the scope of this
article. We may nevertheless assume the change of basicity of
nitrogen atoms in ligands 4a and 9a can have positive effect in
organocatalytic transformations.
2.4. Applications is organocatalysis
3. Conclusion
Ureas and especially thioureas were widely used as ligands in
catalysis [18] or as templates in organocatalytic systems
[14,19]. They incorporate very often a 3,5-bis (trifluoromethyl)-
phenyl moiety allowing to increase the acidity of double H-
bonding organocatalyst strengthening interactions between
substrates and a catalyst [19b,20]. We postulated that we could
take profit of electron-withdrawing of perfluoroalkylated moiety
for this purpose.
Following the same approach than during the catalytic studies,
we started a comparison between thioureas 7a and 7b with their
non-fluorinated analogs in a Biginelli’s reaction (Scheme 7)
[4]. This one-pot three-component reaction between the benzal-
Original S-perfluoroalkylated sulfoximines have been success-
fully synthesized. They incorporated a range of different function-
alities such as an aromatic bridge, an amine or a thiourea. They
were prepared in good to quantitative yields by using different
strategies such as the nucleophilic substitution, a coupling reaction
with copper salt or the functionalization of aryl sulfoximines.
These new series of per-, polyfluoroalkyl containing sulfoximines
were applied in various catalytic processes. They showed an
interesting potential, especially as organocatalyst, where their
electron-withdrawing effect seems to be a major added value.
Further investigations on the application of these novel fluorinated
sulfoximines ligands are currently underway in our laboratory.
dehyde, the
b-ketoester 14 and the urea 16, using a thiourea as
organocatalyst, was carried out for the synthesis of 3,4-dihydro-
pyrimidin-2(1H)-one 17. The results obtained with sulfoximine
thioureas 7a–b were close to the literature (respectively 49% and
65% compared to 42 and 92% yields) [4]. This demonstrated the
proper activation of the thiourea by the trifluoromethyl group.
Encouraged by the previous results, we finally tested the
efficiency of perfluoroalkyl containing ligands in a process which
has never been, to the best of our knowledge, catalyzed with the
help of sulfoximine. The Friedel–Crafts reaction was extensively
studied using Lewis acids [21], amino compounds [22] and
thioureas [23] as organocatalyst but never described with a
4. Experimental
4.1. General experimental procedures
Each reaction was carried out under argon atmosphere and in a
freshly distilled solvent, unless otherwise notes. All chemicals
were purchased from commercial sources (Sigma–Aldrich, ABCR or
Alfa Aesar) and used without further purification. Organic solvents
were purchased from Sigma–Aldrich and Carlo Erba companies.
Reactions were monitored by thin-layer chromatography on silica
gel 60F254, or by 19F NMR spectroscopy. Unless otherwise notes,
yields refer to materials purified by column chromatography. NMR
sulfoximine. Indole 18 and
b-(E)-nitrostyrene 19 were chosen as
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spectra were collected on a Bruker AC-200 or AC-300 spectrome-
ter. Reported coupling constants and chemicals shifts were based
on a first order analysis. Internal reference was the residual peak of
CHCl3 (7.27 ppm) for 1H (200 or 300 MHz), central peak of CDCl3
(77 ppm) for 13C (75 or 50 MHz) NMR spectra, and CFCl3 (0 ppm) as
internal reference for 19F (188 MHz) NMR spectra. High resolution
mass spectrometry (HRMS) were recorded on a Mass Spectrometer
XEVO-QTOF in Institute Lavoisier of Versailles – University of
Versailles Saint Quentin.
d = 8.20 (d, J = 7.8 Hz, 2H, Har), 7.82–7.77 (m, 1H, Har), 7.69–7.64
(m, 2H, Har), 7.17 (dd, J = 7.8 and 0.9 Hz, 1H, Har), 6.96–6.90 (m, 1H,
Har), 6.78 (dd, J = 6.6 and 1.2 Hz, 1H, Har), 6.67 (m, 1H, Har), 3.69 (bs,
2H, NH2). 13C NMR (75 MHz, CDCl3):
d = 140.9, 135.5, 131.7, 130.6,
129.7, 127.5, 124.8, 123.4, 121.0 (q, 1J = 334.5 Hz, CF3), 118.7,
115.6. HRMS: calculated for C13H12F3N2OS ([MH+]) = 301.0622;
found = 301.0624 (d = 0.7 ppm).
4.2.6. Difluoromethyl-oxo-phenyl-phenylimino-l6-sulfane (3e)
Yield: 103 mg (77%) as a colorless liquid. 19F NMR (188 MHz,
4.2. Synthetic procedures and characterization data
CDCl3):
1H NMR (200 MHz, CDCl3):
7.59 (m, 3H, Har), 7.24–7.13 (m, 4H, Har), 7.05–6.98 (m, 1H, Har),
6.35 (t, 2J = 54 Hz, CF2H). 13C NMR (75 MHz, CDCl3):
= 142.4,
d
= ꢁ116.8 and ꢁ122.2 (AB system, J = 252 and 55 Hz, 2F).
d
= 8.10 (d, J = 6.0 Hz, 2H, Har), 7.79–
4.2.1. General procedure for the microwave assisted copper-catalyst
coupling reaction
d
Under argon atmosphere, in a dried microwave tube was added
sulfoximine 1a (1.0 equiv., 0.5 mmol, 104.5 mg), aryl halide
(1.1 equiv., 0.55 mmol), CuI (0.5 equiv., 0.25 mmol, 48 mg), N,N0-
134.9, 131.6, 131.1, 129.5, 129.3, 123.8, 123.1, 114.70 (t,
1J = 192 Hz, CCF2). HRMS: calculated for C13H12F2NOS ([MH+]) =
268.0608; found = 268.0605 (
d
= ꢁ1.1 ppm).
dimethylethylenediamine (DMEDA) (1.0 equiv., 0.5 mmol, 54
mL),
K2CO3 (2.5 equiv., 1.25 mmol, 172.5 mg) and 3 mL of fresh distilled
toluene. The reaction was irradiated by microwave reactor at
110 8C during the given time. The mixture was then cooled down to
room temperature, diluted with water and neutralized with 10 mL
of 2 M HCl in vigorous stirring condition. The reaction mixture was
then extracted with dichloromethane (3 ꢀ 10 mL). The combined
organic fractions were washed with water, dried over MgSO4 and
the solvent was removed under reduced pressure. The purification
was carried out by flash chromatography on silica gel (pentane/
diethyl ether) to give desired compound.
4.2.7. [Bromo(difluoro)methyl]-oxo-phenyl-phenylimino-l6-sulfane
(3f)
Yield: 130 mg (76%) as a light brown liquid. 19F NMR (188 MHz,
CDCl3):
d
= ꢁ50.2 and ꢁ52.5 (AB system, J = 98.7 and 140 Hz, 2F).
= 8.22 (d, J = 7.6 Hz, 2H, Har), 7.83–
1H NMR (200 MHz, CDCl3):
d
7.76 (m, 1H, Har), 7.70–7.62 (m, 2H, Har), 7.30–7.28 (m, 2H, Har),
7.12–7.06 (t, J = 4.2 Hz, 1H, Har). 13C NMR (75 MHz, CDCl3):
d
= 141.4, 135.1, 131.1, 131.0, 129.4, 129.1, 124.2, 123.7, 121.6
(t, 1J = 357 Hz, CF2Br). HRMS: calculated for C13H11BrF2NOS
([MH+]) = 345.9713; found = 345.9709 (
= ꢁ1.2 ppm).
d
4.2.2. Oxo-phenyl-phenylimino-(trifluoromethyl)-l6-sulfane (3a)
4.2.8. (2-Bromophenyl)imino-oxo-phenyl-(trifluoromethyl)-l6
sulfane (3g)
-
Yield: 130 mg (91%) as a colorless liquid. 19F NMR (188 MHz,
CDCl3):
d
= ꢁ72.59 (s, 3F). 1H NMR (200 MHz, CDCl3):
d
= 8.24 (d,
Yield: 167.5 mg (92%) as light brown solid. Mp = 54–56 8C. 19F
J = 7.6 Hz, 2H, Har), 7.85–7.77 (m, 1H, Har), 7.71–7.63 (m, 2H, Har), 7.35–
7.24 (m, 4H, Har), 7.15–7.06 (m, 1H, Har). 13C NMR (75 MHz, CDCl3):
NMR (188 MHz, CDCl3):
CDCl3): d = 8.36 (d, J = 7.4 Hz, 2H, Har), 7.84–7.77 (m, 1H, Har), 7.71–
d
= ꢁ72.92 (s, 3F). 1H NMR (200 MHz,
d
= 141.1, 135.4, 131.5, 130.5, 129.5, 129.1, 123.9, 121.4 (q, 1J = 337 Hz,
7.60 (m, 3H, Har), 7.50 (d, J = 8.0 Hz, 1H, Har), 7.24 (dt, J = 7.4 and
1.6 Hz, 1H, Har), 6.97 (dt, J = 7.8 and 1.4 Hz, 1H, Har). 13C NMR
(75 MHz, CDCl3): d = 139.9, 135.6, 133.1, 131.3 (d, J = 1.3 Hz),
CF3). MS (pos. ESI): m/z = 308 (MNa+). HRMS: Calculated for
13H10F3NOS ([MNa+]) = 308.0327; Found = 308.0331 (
= 1.2 ppm).
C
d
130.7, 129.6, 127.9, 124.9, 124.1 (d, J = 0.8 Hz), 119.3, 121.3 (q,
1J = 337 Hz, CF3). HRMS: calculated for C13H10BrF3NOS
4.2.3. (2-Nitrophenyl)imino-oxo-phenyl-(trifluoromethyl)-l6
sulfane (3b)
-
([MH+]) = 363.9619; Found = 363.9622 (
d = 0.8 ppm).
Yield: 133.5 mg (81%) as a yellow liquid. 19F NMR (188 MHz,
CDCl3):
d
= ꢁ72.99 (s, 3F). 1H NMR (200 MHz, CDCl3):
d
= 8.27 (d,
4.2.9. (2-Iodophenyl)imino-oxo-phenyl-(trifluoromethyl)-l6-sulfane
(3h)
J = 6.0 Hz, 2H, Har), 7.88–7.80 (m, 2H, Har), 7.74–7.66 (m, 2H, Har),
7.59 (dd, J = 8, 2 and 1.4 Hz, 1H, Har), 7.47 (dt, J = 7.2 and 1.6 Hz, 1H,
Har), 7.18 (m, 1H, Har). 13C NMR (75 MHz, CDCl3):
Yield: 185 mg (90%) as a pale yellow solid. Mp = 68–70 8C. 19F
d
= 144.6, 136.0,
NMR (188 MHz, CDCl3):
CDCl3): d = 8.38 (d, J = 7.7 Hz, 2H, Har), 7.84 (dd, J = 7.9 and 1.3 Hz,
d
= ꢁ72.75 (s, 3F). 1H NMR (200 MHz,
135.5, 133.2, 130.9, 130.7, 130.6, 129.5, 125.3, 125.2, 123.7, 121.3
(q, 1J = 336 Hz, CF3). HRMS: Calculated for C13H10F3N2O3S
1H, Har), 7.81–7.74 (m, 1H, Har), 7.70–7.62 (m, 2H, Har), 7.47 (dd,
([MH+]) = 331.0362; Found = 331.0362 (
d
= 0.0 ppm).
J = 8.1 and 1.4 Hz, 1H, Har), 7.30–7.20 (m, 1H, Har), 6.82 (dt,
J = 7.7 and 1.5 Hz, 1H, Har). 13C NMR (75 MHz, CDCl3):
d = 143.1,
4.2.4. (2-Fluorophenyl)imino-oxo-phenyl-(trifluoromethyl)-l6
sulfane (3c)
-
139.3, 135.7, 131.4, 130.9, 129.6, 129.0, 125.2, 124.0, 122.8, 121.3
(q, 1J = 339 Hz, CF3), 95.4. MS (pos. ESI): m/z = 434 (MNa+). HRMS:
calculated for C13H9F3INOS ([MNa+]) = 433.9294; found =
Yield: 136 mg (90%) as a yellow viscous liquid, turned easily to
solid in the fridge. 19F NMR (188 MHz, CDCl3):
d
= ꢁ73.58 (d,
433.9293 (d = 0.2 ppm).
J = 2.3 Hz, 3F); ꢁ124.5 (m, 1F). 1H NMR (200 MHz, CDCl3):
d = 8.26
(d, J = 7.6 Hz, 2H, Har), 7.83–7.75 (m, 1H, Har), 7.70–7.61 (m, 2H,
4.2.10. General procedure for the preparation of bis-sulfoximines
ligands
Har), 7.40 (m, 1H, Har), 7.08 (m, 3H, Har). 13C NMR (75 MHz, CDCl3):
d
= 156.4 (d, 1J = 245 Hz, Far), 135.6, 131.6 (d, J = 0.5 Hz), 130.6,
A microwave tube with magnetic stirring bar was charged with
sulfoximine halide 3g or 3h (0.5 mmol, 1 equiv., X = Br or I),
sulfoximine 1a (1.1 equiv., 0.55 mmol, 115 mg), K2CO3 (4 equiv.,
2 mmol, 276 mg), CuI (0.5 equiv., 0.25 mmol, 48 mg), DMEDA
129.6, 128.9 (d, J = 12.7 Hz), 125.9, 124.9 (d, J = 7.2 Hz), 124.3 (d,
J = 3.9 Hz), 121.3 (q, 1J = 335 Hz, CF3), 116.1 (d, J = 20 Hz). HRMS:
calculated for C13H10F4NOS ([MH+]) = 304.0419; Found = 304.0420
(
d
= 0.3 ppm).
(1 equiv., 0.5 mmol, 54 mL) and 3 mL toluene. After performing the
reaction under microwave activation at the given temperature
for indicated time, the reaction was diluted with water and
neutralized by 10 mL of 2 M HCl solution in vigorous stirring
condition, then extracted with dichloromethane (3 ꢀ 10 mL). The
combined organic phases were washed with water, dried over
4.2.5. 2-[[Oxo-phenyl-(trifluoromethyl)-l6-sulfanylidene] amino]
aniline (3d)
Yield: 129.5 mg (86%) as a dark brown liquid. 19F NMR
(188 MHz, CDCl3):
d
= ꢁ73.73 (s, 3F). 1H NMR (300 MHz, CDCl3):
Please cite this article in press as: T.-N. Le, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.06.020

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T.-N. Le et al. / Journal of Fluorine Chemistry xxx (2015) xxx–xxx
7
MgSO4. Solvent was removed under reduced pressure. The
purification was carried out by flash chromatography on silica
gel (pentane/diethyl ether = 9/1) to give desired compound as a
white solid.
4.2.16. 1-[2-[[Oxo-phenyl-(trifluoromethyl)-l6
sulfanylidene]amino]phenyl]-3-phenyl-thiourea (7a)
-
Yield: 208.5 mg (96%) as a beige solid. Mp = 136–138 8C. 19F
NMR (188 MHz, CDCl3):
d
= ꢁ73.43 (s, 3F). 1H NMR (300 MHz,
Yield of 4a: 189 mg (77%, X = Br); 184 mg (75%, X = I).
CDCl3): d = 8.22 (s, 1H, NH); 8.1–7.95 (m, 2H, NH and Har), 7.85 (d,
J = 7.8 Hz, 2H, Har), 7.67 (t, J = 7.5 Hz, 1H, Har), 7.49 (t, J = 8.1 Hz, 2H,
4.2.11. Oxo-[2-[[oxo-phenyl-(trifluoromethyl)-l6
-
Har), 7.25 (m, 5H, Har), 7.13 (m, 1H, Har), 7.04 (m, 2H, Har). 13C NMR
sulfanylidene]amino]phenyl]imino-phenyl-(trifluoromethyl)-l6
sulfane (4a)
-
(75 MHz, CDCl3): d = 179.1 (CS), 137.0, 135.8, 134.6, 131.4,
130.7, 130.5, 129.9, 129.6, 126.9, 125.3, 125.0, 124.1, 123.4,
Yield: 189 mg (76%) as a white solid. Mp = 108–110 8C. 19F
121.0 (q, 1J = 334.7 Hz, CF3). HRMS: calculated for C20H17F3N3OS2
NMR (188 MHz, CDCl3):
CDCl3):
d
= ꢁ73.97 (s, 3F). 1H NMR (300 MHz,
([MH+]) = 436.0765; found = 436.0763 (
d
= ꢁ0.5 ppm).
d
= 8.26 (d, J = 7.8 Hz, 4H, Har), 7.79–7.74 (m, 2H, Har),
7.63–7.58 (m, 4H, Har), 7.36–7.32 (m, 2H, Har), 7.00–6.98
(m, 2H, Har). 13C NMR (75 MHz, CDCl3):
= 135.4, 135.3, 132.1,
4.2.17. 1-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-[[oxo-phenyl-
(trifluoromethyl)-l6-sulfanylidene] amino]phenyl]thiourea (7b)
Yield: 277 mg (97%) as a beige solid. Mp = 146–148 8C. 19F NMR
d
130.7, 129.5, 124.4, 121.2 (q, 1J = 335 Hz, CF3). HRMS: calculated
for C20H15F6N2O2S2 ([MH+]) = 493.0479; found = 493.0479 (
0.0 ppm).
d
=
(188 MHz, CDCl3):
d
= ꢁ63.49 (s, 6F, CF3-C), ꢁ72.80 (s, 3F, CF3-S). 1H
NMR (200 MHz, CDCl3):
d = 8.24 (d, J = 7.8 Hz, 2H, Har), 8.09 (s, 1H,
NH), 7.89 (s, 2H, Har), 7.82 (t, J = 7.5 Hz, 1H, Har), 7.78 (s, 1H, Har) 7.67
(t, J = 8.1 Hz, 2H, Har), 7.63 (s, 1H, NH), 7.56 (d, J = 8.1 Hz, 1H, Har),
7.47 (d, J = 7.8 Hz, 1H, Har), 7.34 (dt, J = 7.8 and 1.2 Hz, 1H, Har), 7.21
4.2.12. 1,1,2,2,3,3,4,4,4-Nonafluorobutyl-oxo-[2-[[oxo-pheny l-
(trifluoromethyl)-l6-sulfanylidene]amino]phenyl]imino-phenyl-l6
sulfane (4b)
-
(dt, J = 7.8 and 0.9 Hz, 1H, Har). 13C NMR (75 MHz, CDCl3):
d = 180.3,
Yield: 262.5 mg (81%) as a white solid. Mp = 78–80 8C. 19F NMR
139.8, 137.5, 136.1, 132.1, 131.7, 130.5, 129.9, 129.6, 129.4, 127.2,
125.1, 124.8, 124.7, 124.6, 124.5, 121.4 (q, 1J = 330 Hz, SCF3), 121.1,
119.2 (q, J = 3.9 Hz). HRMS: calculated for C22H15F9N3OS2
(188 MHz, CDCl3):
d
= ꢁ74.32 (s, 3F, SCF3), ꢁ81.24 (t, J = 9.6 Hz, 3F,
CCF3), ꢁ108.2 (AB system, J = 255 and 14.7 Hz, 2F, CF2), ꢁ120.7 (d,
J = 5 Hz, 2F, CF2), ꢁ126.4 (m, 2F,CF2). 1H NMR (300 MHz, CDCl3):
([MH+]) = 572.0513; found = 572.0500 (
d
= ꢁ2.3 ppm).
d
= 8.29 (t, J = 6 Hz, 4H, Har), 7.77 (q, J = 9 Hz, 2H, Har), 7.62 (q,
J = 9 Hz, 4H, Har), 7.36 (m, 2H, Har), 6.99 (m, 1H, Har). 13C NMR
4.2.18. General procedure for nucleophilic substitution of sulfoximines
Sulfoximine (1 equiv., 0.5 mmol), NaH (1.2 equiv., 0.6 mmol)
and a catalytic amount of Bn4NBr (0.05 equiv., 0.025 mmol) were
dissolved in anhydrous DME (5 mL) under argon at room
temperature. The electrophilic species (1.1 equiv., 0.55 mmol)
was then added and the reaction mixture was stirred for 16 h at
room temperature. Subsequently water (10 mL) was added and
the resulting mixture was extracted with dichloromethane
(3 ꢀ 20 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography (pentane/diethyl ether, 7:3) to
give the N-functionalized sulfoximines.
(75 MHz, CDCl3): d = 135.6, 135.4, 135.3, 135.1, 133.5, 132.4, 130.9,
130.7, 129.5, 129.3, 124.5, 124.4, 124.3, 124.3, 121.2 (q, 1J = 335 Hz,
SCF3). HRMS: calculated for C23H15F12N2O2S2 ([MH+]) = 643.0383;
found = 643.0380 (
d
= ꢁ0.5 ppm).
4.2.13. General procedure for preparation of thiourea sulfoximines
To a solution of the sulfoximine (1 equiv., 0.5 mmol) in dried
dichloromethane (2.5 mL), at 0 8C, (3,5-bistrifluoromethyl) phenyl
isothiocyanate (1.2 equiv., 0.6 mmol, 113
mL) was added dropwise.
The solution was then stirred at room temperature for 13 h. The
reaction was monitored by TLC. After evaporation of the solvent
under reduced pressure, the residue was processed directly by
column chromatography (pentane/diethyl ether) to afford desired
product as a pale yellow solid.
4.2.19. Benzylimino-oxo-phenyl-(trifluoromethyl)-l6-sulfane (8a)
Yield: 147 mg (98%) as an oil. 19F NMR (282 MHz, CDCl3) (ppm)
d
= ꢁ73.3 (s, CF3); 1H NMR (300 MHz, CDCl3) (ppm)
d = 8.0 (d,
4.2.14. 1-[Oxo-phenyl-(trifluoromethyl)-l6-sulfanylidene]-3-
phenyl-thiourea (6a)
J = 7.9 Hz, 2H), 7.6 (t, J = 8 Hz, 1H), 7.44 (t, J = 8 Hz, 2H), 7.31 (d,
J = 7.3 Hz, 2H), 7.23 t, J = 7.1 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 4.5 (AB
system, J = 14.6 Hz, 2H, CH2–N); 13C NMR (75 MHz, CDCl3):
Yield: 108 mg (20%) as a yellow solid. Mp = 140–142 8C. 19F
NMR (188 MHz, CDCl3):
d
= ꢁ76.75 and ꢁ76.83 (s, 3F), two
d
= 139.8, 134.9, 132.0, 130.1, 129.2, 128.3, 127.2, 126.9, 121.7
(q, 1J = 338 Hz, CF3), 46.4; HRMS calculated for [MH+]
14H13F3NOS: 300.0670; measured: 300.0674 ( = 1.3 ppm).
isomers. 1H NMR (300 MHz, CDCl3):
d
= 8.96 and 8.57 (s, brs
1H, NH), 8.96 (bs, 1H, NH), 8.01 (m, 2H, Har), 7.81 (m, 1H, Har),
7.71–7.64 (m, 3H, Har), 7.44 (d, J = 8.1 Hz, 1H, Har), 7.36
(t, J = 7.8 Hz, 2H, Har), 7.19 (t, J = 7.2 Hz, 1H, Har). 13C NMR
C
d
4.2.20. Oxo-phenyl-(2-pyridylmethylimino)-(trifluoromethyl)-l6
sulfane (8b)
-
(75 MHz, CDCl3):
d = 184.0 (CS), 138.2, 135.9, 130.5, 130.3,
129.0, 126.1, 125.5, 123.2, 121.8, 119.8 (q, 1J = 321 Hz, CF3).
Yield: 134 mg (90%) as an oil. 19F NMR (282 MHz, CDCl3) (ppm)
HRMS: calculated for C14H12F3N2OS2 ([MH+]) = 345.0343; found
d
: ꢁ73.4 (s, CF3); 1H NMR (300 MHz, CDCl3) (ppm)
d = 8.5 (d,
345.0346 (
d
= 0.9 ppm).
J = 4.8 Hz, 1H), 8.15 (d, J = 7.7 Hz, 2H), 7.5 (m, 5H), 7.15 (t, J = 7 Hz,
1H), 4.6 (AB system, J = 15.8 Hz, 2H, CH2–N); 13C NMR (75 MHz,
CDCl3):
CF3), 48.1; HRMS calculated for [MH+] C13H12F3N2OS: 301.0622;
measured: 301.0619 (
= ꢁ1 ppm).
4.2.15. 1-[3,5-Bis(trifluoromethyl)phenyl]-3-[oxo-phenyl-
(trifluoromethyl)-l6-sulfanylidene]thiourea (6b)
d
= 159.4, 148.7, 136.6, 136.0, 129.3, 121.5 (q, 1J = 336 Hz,
Yield: 350 mg (73%) as a yellow solid. Mp = 137–139 8C. 19F
d
NMR (188 MHz, CDCl3):
SCF3). 1H NMR (300 MHz, CDCl3):
7.97 (s, brs, 2H), 7.88 (t, J = 7.1 Hz, 1H), 7.74 (t, J = 7.8 Hz, 2H), 7.57
(s, 1H), 7.42 (s, 1H). 13C NMR (50 MHz, CDCl3):
= 154.9 (CS),
d
= ꢁ63.54 (s, 6F, 2CF3Ar) and ꢁ74.84 (s, 3F,
d
= 8.12 (d, J = 7.8 Hz, 2H),
4.2.21. N-Benzyl-2-[[oxo-phenyl-(trifluoromethyl)-l6
sulfanylidene]amino]aniline (9a)
round-bottom flask was charged with sulfoximine 3d
(1 equiv., 1 mmol, 300 mg) in 10 mL of MeOH, benzaldehyde
(1.2 equiv., 1.2 mmol, 122 L) and glacial acetic acid (1.0 equiv.,
1 mmol, 57 L). After stirring at room temperature for 3 h, NaBH4
(2.5 equiv., 2.5 mmol, 37 mg) was slowly added in small portions
-
d
A
139.6, 136.5, 132.3 (q, 1J = 33 Hz, CCF3), 130.3, 130.2, 130.1,
123.0 (q, 1J = 271 Hz, SCF3), 118.5 (m, CCF3), 116.8 (m, CCF3).
HRMS: calculated for C16H10F9N2OS2 ([MH+]) = 481.0091; found =
m
m
481.0090 (
d
= ꢁ0.2 ppm).
Please cite this article in press as: T.-N. Le, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.06.020

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at 0 8C and the reaction mixture was additionally stirred for 12 h at
room temperature. The reaction mixture was quenched with
20 mL of 10% aqueous K2CO3 then diluted with CH2Cl2. The
aqueous layer was extracted with CH2Cl2 (3 ꢀ 10 mL) and the
combined organic extracts were dried over MgSO4. After removing
solvent under reduced pressure, the crude product was purified by
flash column chromatography on silica gel (pentane/diethyl
ether = 3/7) to give final product.
CH3CH2). 13C NMR (75 MHz, CDCl3):
128.7, 128.1, 72.6, 47.9, 26.4, 14.0.
d = 198.7, 175.9, 136.3, 133.6,
4.2.26. Ethyl 6-methyl-2-oxo-4-phenyl-3,4-dihydro-1H-pyrimidine-
5-carboxylate (17)
Urea (1 equiv., 0.25 mmol, 15.0 mg), benzaldehyde (1.5 equiv.,
0.38 mmol, 38
mL) and trifluoroacetic acid (0.1 equiv., 0.025 mmol,
1.9 L) were dissolved in dried dichloromethane (10 mL). The
m
Yield: 377 mg (97%) as light green solid. Mp = 133–135 8C. 19F
reaction mixture was stirred at room temperature for 1 h. To
the solution, thiourea sulfoximine 6a (0.1 equiv., 0.025 mmol,
10.9 mg) or 6b (0.1 equiv., 0.025 mmol, 14.3 mg) and ethyl
NMR (188 MHz, CDCl3):
CDCl3):
d
= ꢁ73.67 (s, CF3); 1H NMR (300 MHz,
d
= 8.12 (d, J = 7.8 Hz, 2H, Har), 7.63 (t, J = 8.7 Hz, 1H, Har),
7.59 (t, J = 7.8 Hz, 2H, Har), 7.47–7.31 (m, 5H, Har), 7.23 (dd,
J = 7.5 and 1.2 Hz, 1H, Har), 7.02 (m, 1H, Har), 6.62 (m, 2H, Har),
4.98 (bs, 1H, NH), 4.49 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3):
acetoacetate (3 equiv., 0.75 mmol, 96 mL) were then added, and
stirring condition was continued at ambient temperature. After
5 days, the solvent was evaporated under reduced pressure and
the remaining solid residue was washed with a small amount of
cold ethyl acetate to obtain the final products as white solid.
Yield of 17: 32 mg (49%) with catalyst 6a and 42 mg (65%) with
d
= 141.7, 139.2, 135.5, 134.5, 131.8, 130.6, 129.7, 129.0, 128.6,
127.3, 127.2, 124.9, 122.7, 121.2 (q, 1J = 334.5 Hz, CF3), 117.7,
111.7, 48.4. HRMS: calculated for C20H18F3N2OS ([MH+]) =
391.1092; found = 391.1092 (
d
= 0 ppm).
catalyst 6b. 1H NMR (300 MHz, CDCl3):
d = 9.16 (s, 1H, NH), 7.71 (s,
1H, NH), 7.34 (m, 2H, Har), 7.25 (m, 3H, Har), 5.15 (d, J = 3 Hz, 1H,
CH), 4.00 (qd, J = 7.2 and 1.2 Hz, 2H, CH3CH2), 2.24 (s, 3H, CCH3),
1.09 (t, J = 6.9 Hz, 3H, OCH3CH2). 13C NMR (75 MHz, (CD3)2SO):
4.2.22. General procedure for the HDA cycloaddition
A dried Schlenk-tube under argon atmosphere with a magnetic
stirring bar was charged with Cu(OTf)2 (5 mol%, 0.033 mmol,
11.9 mg), the bis-sulfoximine 4a (5 mol %, 0.033 mmol, 16.2 mg),
d
= 165.3, 152.1, 148.3, 144.8, 128.4, 127.2, 126.2, 99.2, 59.2, 53.9,
17.7, 14.0.
˚
MS 4 A and the 3 mL of fresh distilled dichloromethane. The
mixture was stirred at room temperature for 30 min, then ethyl
4.2.27. 3-(2-Nitro-1-phenyl-ethyl)-1H-indole (20)
glyoxalate (1 equiv., 0.66 mmol, 130
(1 equiv., 0.66 mmol, 100 L) was added followed by the addition
of 1,3-cyclohexadiene (2 equiv., 1.32 mmol, 125 L). Stirring
condition was continued at room temperature until the reaction
was completed (no glyoxalate or ketomalonate could be detected
by TLC). The product was isolated by flash chromatography on
silica gel (pentane/diethyl ether = 7/3) to give desired compound.
m
L) or diethyl ketomalonate
In a dried Schlenk-tube, a solution of trans-beta nitro styrene
(1 equiv., 0.1 mmol, 15 mg) and catalyst 6b (0.2 equiv., 0.02 mmol,
11.5 mg) in 10 mL of dichloromethane were stirred at room
temperature for 30 min. Indole (1.5 equiv., 0.15 mmol, 18 mg) was
then added in one portion. The reaction mixture was continued to
stir for 72 h at room temperature. The crude mixture was purified
by flash column chromatography on silica gel (pentane/diethyl
ether = 7/3 (RF = 0.35)) to give final compound as colorless oil.
m
m
4.2.23. Ethyl 3-oxabicyclo[2.2.2]oct-5-ene-2-carboxylate (12a)
Yield of 20: (19.5 mg, 65%). 1H NMR (200 MHz, CDCl3):
d = 8.09
Yield: 62 mg (51%) as a colorless liquid. 1H NMR (300 MHz,
(bs, 1H, NH), 7.49–7.02 (m, 10H), 5.19 (q, J = 8.0 Hz, 1H, C6H5CH),
5.25–4.90 (m, 3H, CH and CH2), 5.00 (J = 15 and 12.2 Hz, 1H, CH2).
13C NMR (75 MHz, CDCl3):
d = 139.1, 136.4, 128.9, 127.7, 127.6,
CDCl3):
d = 6.57–6.52 (m, 1H), 6.31–6.26 (m, 1H), 4.61–4.58 (m,
1H), 4.32 (d, J = 3 Hz, 1H), 4.16 (q, J = 6 Hz, 2H), 3.12–3.10 (m, 1H),
2.12–2.05 (m, 1H), 1.79–1.73 (m, 1H), 1.37 (m, 1H), 1.25 (m, 4H);
126.0, 122.6, 121.5, 119.9, 118.9, 114.3, 111.3, 79.5, 41.5
13C NMR (75 MHz CDCl3):
33.0, 25.5, 20.7, 14.0.
d = 172.0, 134.5, 130.3, 73.9, 66.2, 60.5,
Acknowledgments
4.2.24. Diethyl 3-oxabicyclo[2.2.2]octane-2,2-dicarboxylate (12b)
Thanh-Nghi Le is grateful to the Vietnamese Government, the
National Institute of Medicinal Materials in Hanoi for a doctoral
fellowship.
Yield: 91.5 mg (55%) as a colorless liquid. 1H NMR (200 MHz,
CDCl3):
3.41–3.39 (m, 1H), 2.21–2.15 (m, 1H), 1.66–1.60 (m, 1H), 1.31–1.21
(m, 8H). 13C NMR (50 MHz, CDCl3):
= 169.5, 168.8, 133.7, 133.4,
d = 6.56–6.43 (m, 2H), 4.69–4.66 (m, H), 4.34–4.07 (m, 4H),
d
82.9, 68.0, 61.9, 61.6, 34.6, 24.5, 17.5, 14.1, 14.0.
Appendix A. Supplementary data
4.2.25. Ethyl 2-hydroxy-2-methyl-4-oxo-4-phenyl-butanoate (15)
A oven-dried Schlenk tube under argon atmosphere was
charged with Cu(OTf)2 (10 mol%, 0.02 mmol, 7.2 mg) and the
sulfoximine 12 (10 mol%, 0.02 mmol, 7.8 mg). Dried THF (4.0 mL)
was added and the green obtained solution was stirred at room
temperature for 30 min. Subsequently, ethyl pyruvate (1 equiv.,
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jfluchem.2015.
06.020.
References
0.2 mmol, 22
18 L) and 1-phenyl-1-trimethyl siloxyethylene (1.1 equiv.,
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mL), 2,2,2-trifluoroethanol (1.2 equiv., 0.24 mmol,
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7.44 (m, 2H, Har), 4.24 (q, J = 7 Hz, 2H, CH3CH2), 3.52 (AB system,
J = 18 Hz, 2H, COCH2), 1.52 (s, 3H, CCH3), 1.26 (t, J = 7.2 Hz, 3H,
Please cite this article in press as: T.-N. Le, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.06.020

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FLUOR-8594; No. of Pages 9
T.-N. Le et al. / Journal of Fluorine Chemistry xxx (2015) xxx–xxx
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