SO2F2-Mediated N-Alkylation of Imino-Thiazolidinones

Article abstract of DOI:10.1021/acs.joc.1c01247

The N-alkylation of ambident and weakly nucleophilic imino-thiazolidinones has been developed via substitution with alkyl fluorosulfonates. These reactive electrophiles are obtained through the transformation of nontoxic, economic, and commercially availa

Full text of DOI:10.1021/acs.joc.1c01247

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SO2F2‑Mediated N‑Alkylation of Imino-Thiazolidinones
Laura Santos, Morgan Donnard, Armen Panossian, Jean-Pierre Vors, Peter Jeschke, David Bernier,
Sergii Pazenok, and Frédéric R. Leroux*
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ABSTRACT: The N-alkylation of ambident and weakly nucleophilic imino-thiazolidinones has been developed via substitution
with alkyl fluorosulfonates. These reactive electrophiles are obtained through the transformation of nontoxic, economic, and
commercially available alcohol derivatives on exposure to SO2F2 gas. The use of electron-withdrawing groups and DMAc as solvent
affords a (Z)- and N-endocyclic selectivity for the easy introduction of a variety of alkyl and polyfluoroalkyl chains.
methylation, two regioselective methods have been developed.
Endocyclic N-methylation can be achieved by intermolecular
condensation of DMF-DMA on the enolic form of imino-
thiazolidinone followed by intramolecular rearrangement.
Though, a dimethylaminomethylene group will thus be
introduced on position 5 of imino-thiazolidinone.16,17 On the
other hand, methylation with dimethyl sulfate can be
regioselective depending on the reaction conditions. Indeed,
a reaction carried out under reflux of acetone favored
endocyclic N-methylation while the one at low temperature
in EtOH favored exocyclic N-methylation (Scheme 1c).18,19
The last method is a Mannich-type reaction between
formaldehyde and secondary amines which allowed formation
of the N-en isomer of the dialkylaminomethylated product
with moderate to excellent yields (Scheme 1d).20 A major
obstacle reported in the literature on alkylation of free NH
imino-thiazolidinone is the lack of diversity on the newly
introduced alkyl chain. Knowing that there is a strong demand
for a handy late-stage introduction of alkyl groups on this type
of scaffold, we decided to turn our attention to the
development of a method that would be simple, economical,
and versatile. For this purpose, we identified an activating
agent that fulfilled all these criteria, namely sulfuryl fluoride
(SO2F2), through the formation of fluorosulfonate intermedi-
INTRODUCTION
■
The imino-thiazolidinone core is arousing widespread interest
due to its presence in diverse synthetic biologically active
compounds.1 Free NH imine and amine tautomers are well
studied and described, and the modulation of their substituents
can provide anticancer, antimicrobial, anti-inflammatory, and
anticonvulsant properties as well as act as hypertensive
agents.1,2 Despite these potent activities, to the best of our
knowledge, very few active compounds of this family bearing a
substituted nitrogen are known, including N-endocyclic
trifluoroethylated species with insecticidal and acaricidal
properties and N-endocyclic alkylated imino-thiazolidinones
which have the potential to reduce local inflammation
(Scheme 1a).3−7 This scarcity could be explained by the
poor nucleophilicity of the nitrogen atoms and the potential
disadvantageous presence of both N-endocyclic and N-
exocyclic regioisomers (hereafter named N-en and N-ex),
which can be a liability for industrialization. To circumvent this
drawback, the main approach is to resort to already N-alkylated
thiourea synthons before ring closure by using chloroacetyl
chloride.3,8 However, introduction of diversity on the nitrogen
atom requires to go two steps backward. Hence, the direct and
regioselective alkylation of free NH imino-thiazolidinone is
challenging. Many attempts using alkyl halides have been made
for the N-alkylation; however, high temperature is required and
the regioselectivity strongly depends on the alkylating species
(Scheme 1b).9−14 Regarding trifluoroethylation using poly-
fluorinated fluorosulfonates, no regioselective transformation
was obtained (Scheme 1b). In addition to the poor atom
economy of this methodology, triflate and perfluorbutane-l-
sulfonate are obtained from an expensive triflic anhydride or by
reaction of sulfolane via electrochemical fluorination.15 For the
Special Issue: Excellence in Industrial Organic Syn-
thesis 2021
Received: May 28, 2021
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© XXXX American Chemical Society
A

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Scheme 1. Alkylation of Imino-Thiazolidinones
RESULTS AND DISCUSSION
■
The synthesis of free NH imino-thiazolidinones was published
via several routes.24−26 The first pathway we applied was the S-
methylation of rhodanine, followed by reaction with a variety
of ortho and para-substituted anilines, to form a library of
aromatic imino-thiazolidinones 1a−l and 1w (Scheme 2,
a
Scheme 2. Free NH Imino-Thiazolidinones Synthesis
a
Reagents and conditions: (i) MeI (1.1 equiv), NaOH, water, 17 h, rt.
(ii) Ar-NH2 (1.1 equiv), AcOH, 9 h, reflux. (iii) PhCOCl (1 equiv),
NH4SCN (1.1 equiv), acetone, 1 h, reflux. (iv) NaOH, H2O, 1 h,
reflux. (v) BrCH2CO2Et (1.1 equiv), NaOAc (1.3 equiv), ACN, 17 h,
rt. (vi) ClCH2COCl (1 equiv), TEA (1.2 equiv), DMF, 2 h, rt. (vii)
NH4SCN (2 equiv), acetone, 3 h, reflux.
pathway A).24,26 Unfortunately, for the imines bearing a
pyridine or a thiazole on the exocyclic nitrogen, the targeted
imino-thiazolidinones were obtained in yields up to only 35%.
As an alternative route, 2-aminopyridine was condensed with
benzoyl isothiocyanate to furnish thiourea 4 in 87% yield
(Scheme 2, pathway B). Then, deprotection with NaOH to
provide 5 followed by a ring closure with ethyl bromoacetate
led to targeted compound 1m in 85% yield.25,27 For the
synthesis of the 2-aminothiazole derivative, in the first step, the
unintended product 6 was obtained through the formation of
an unstable intermediate followed by intramolecular rearrange-
ment.28 The desired imino-thiazolidinone 1n was finally
obtained with 74% yield by reaction of N-(1,3-thiazol-2-yl)-
chloroacetamide 7 with ammonium thiocyanate (Scheme 2,
pathway C).29,30
Once the library of free NH imino-thiazolidinones was
completed, we focused our attention on the optimization of
the reaction conditions for the addition of trifluoroethanol. To
do so, we initiated our investigation with the trifluoroethyla-
tion of ortho-chlorophenylimino-thiazolidinone (1a) using
trifluoroethanol and SO2F2 (Table 1). As a starting point, 1
equiv of 1a and 1 equiv of trifluoroethanol were mixed with 2
equiv of DIPEA as a base in DMAc as solvent. The in situ
generation of trifluoroethyl fluorosulfonate (CF3CH2OSO2F)
was achieved by slow bubbling of SO2F2 in the reaction
mixture. Trifluoroethylation succeeded with a moderate
conversion of 48% and a good regioselectivity of 92:8 for N-
ates (ROSO2F) starting from simple alcohols. Over the past
decade, there has been a growing interest in the use of SO2F2
as fluorosulfonate precursor, since the fluorosulfonyl group can
be involved in reactions as a good leaving group or be
considered as a connecting functionality.21,22 In 2018, Sammis
et al. developed the N-alkylation of rather basic primary and
secondary aliphatic amines with polyfluoroalkyl fluorosulfo-
nates.23 However, in the case of imino-thiazolidinones, the
whole process would probably be rougher due to the poor
nucleophilicity of both nitrogen atoms which are involved in
various mesomeric effects. Indeed, the endocyclic nitrogen can
be expected to exhibit reactivity similar to that of an amide,
while the exocyclic nitrogen similar to that of an aniline.
Herein, we describe a useful method to generate a diverse
library of N-alkylated imino-thiazolidinones from commercially
available and inexpensive alcohols. Atom economic and
affordable SO2F2 was used to generate electrophilic alkyl
fluorosulfonates in situ, which can react with easily accessible
free NH imino-thiazolidinones. Considering the ambident
reactivity of the reactant, an investigation of the N-en
regioselectivity was performed.
B
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Table 1. Optimization of Reaction Conditions for the
Trifluoroethylation of 1a
Scheme 3. Tentative Mechanism and Possible Undesired
Side Reactions
a
entry
base
solvent
temp. (°C) NMR ratio 2a:3a conv. (%)
b
1
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
KF
DBU
DIPEA
DIPEA
DIPEA
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
toluene
ACN
20
20
0
40
20
20
20
20
20
20
92:8
92:8
91:9
92:8
92:8
92:8
92:8
41:59
83:17
60:40
48
quant.
70
quant.
56
63
quant.
93
2
3
4
5
6
7
8
9
10
trifluoroethylation, as shown in Scheme 4. Unfortunately,
protected thiourea 4 was quantitatively alkylated at the sulfur
Scheme 4. Trifluoroethylation of Thioureas and
a
Chloroacetamide Derivatives
76
78
EtOAc
a
Reaction conditions: 1a (0.44 mmol), CF3CH2OH (1.10 mmol),
and base (1.76 mmol) were mixed in the solvent (5 mL), and SO2F2
was bubbled through the mixture. 19F or 1H NMR ratios are reported.
b
With 1 equiv of CF3CH2OH and 2 equiv of DIPEA.
en (2a) and N-ex (3a) products, respectively, after 17 h (Table
1, entry 1). The N-en product (2a) was always isolated as the
Z diastereomer (vide infra).
Pleasingly, the targeted regioisomer 2a was predominantly
obtained. Nonetheless, the amount of trifluoroethanol and
DIPEA were, respectively, increased to 2.5 equiv and 4 equiv
to improve the conversion. Thereupon, 1a was fully converted,
and the regioselectivity was upheld (Table 1, entry 2). By
working at 0 °C, a similar ratio of 91:9 was obtained, although
the conversion slightly decreased (Table 1, entry 3). A
temperature of 40 °C also did not affect the regioselectivity
(Table 1, entry 4). Subsequently, the effect of the base was
investigated. Triethylamine (Table 1, entry 5) and the
inorganic base KF (Table 1, entry 6) lowered the conversion
but still allowed a good regioselectivity of 92:8. The sterically
hindered DBU (Table 1, entry 7) led to the completion of the
reaction in only 2 h with preservation of the ratio. This base
has already been investigated to increase the reaction rate of
alkyl fluorosulfonates with amines.31 As DBU is more
expensive and toxic, DIPEA was used as an alternative for
the alkylation studies. Interestingly, the nature of the solvent
had a significant impact on the regioselectivity as previously
described in the literature.18,19 Nonpolar solvents such as
toluene favored the N-ex regioisomer 3a (Table 1, entry 8),
while more polar ones, such as acetonitrile or ethyl acetate,
gave lower ratios of 83:17 and 60:40, respectively (Table 1,
entries 9 and 10). Finally, the most fruitful outcome was the
use of 2.5 equiv of trifluoroethanol and 4 equiv of DIPEA as a
base in DMAc with a reaction at 20 °C for 17 h (Table 1, entry
2). Interestingly, all along this optimization we never observed
side products coming from competitive nucleophilic attacks of
the free fluoride, of the substrate itself to form the
bis(trifluoroethyl)sulfate,23 or from the solvent (DMAc)32 on
the trifluoroethyl fluorosulfonate intermediate (Scheme 3).
In the quest for regioselective N-alkylation, intermediates
obtained from the synthesis of free NH imino-thiazolidinone
1m and 1n were studied under the best reaction conditions for
a
Yields reported are isolated yields. Ratio and conversions were
calculated with 19F NMR.
atom (8). Likewise, S-alkylation of pyridyl thiourea 5 was
detectable. For the chloroacetamide derivative 7, dimerization
was observed along with a mixture of O- and N-
trifluoroethylation (10). These results finally convinced us to
carry out the late-stage functionalization of easily accessible
free NH imino-thiazolidinones, which occurs regioselectively at
the N-endocyclic amide.
With these optimized conditions in hand, the effect of the
substituent on the aromatic ring R1 attached to the exocyclic
nitrogen was investigated with trifluoroethanol as the alkylating
agent (Scheme 5). The alkylation of the nonsubstituted
phenylimino-thiazolidinone 1b afforded a mixture of re-
gioisomers in a ratio of 85% of N-en product 2b and 15% of
N-ex product 3b with 86% yield. This lower regioselectivity
compared to 1a shows a positive repercussion of the chlorine
atom due to its steric or electronic effect. Besides, ortho
substitution with a methyl group in 2d afforded a ratio similar
to that of phenyl derivative 2b. The ortho-bromo product 2c,
which is more sterically hindered and for which the electron-
withdrawing inductive effect is weaker than for chlorine,
afforded a slightly better ratio of 88:12 in comparison to the
phenyl derivative 2b. These preliminary results suggest that the
electronic effect of chlorine may be responsible for the good
regioselectivity rather than steric hindrance, as evidenced by
the attempt with the chlorine atom in para position. Indeed, 2e
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a
yield. Conversely, a methoxy group as electron-donating group
in the para position (2j) caused a dramatic decrease of the
ratio to 76:24. Surprisingly, in ortho position, the methoxy
group favored the N-ex compound 3k with a ratio of 36:64.
The presence of an additional methoxy group in para position,
in order to further enrich the aromatic ring and enhance the
nucleophilicity of the exocyclic nitrogen, favored even more
the N-ex isomer 3l with a N-en/N-ex ratio of 25:75. As shown
in Table 1, the choice of solvent had a strong influence on
regioselectivity. In toluene, 1l allowed the exocyclic N-
trifluoroalkylation with an excellent regioselectivity of 7:93
with a yield of 42% due to a slow conversion to product 3l. We
also tested the trifluoroethylation of two heterocyclic
derivatives. Pyridine, an electron-poor heterocycle, gave only
regioisomer 2m in 78% yield. Thiazole, a five-membered
electron-rich heterocycle, afforded a ratio of 59:41 with a
quantitative yield of the mixture of 2n and 3n.
Scheme 5. Scope of Alkylation of Imino-Thiazolidinones
Next, we explored the effect of the alcohol with phenyl-
imino-thiazolidinone 1b. Going from trifluoroethanol to the
more fluorinated derivative pentafluoropropanol decreased the
ratio to 81:19 for 2o. While using nonfluorinated ethanol, an
excellent ratio of 96:4 was obtained for 2p. This trend could
presume that the presence of fluorine atoms facilitates the
approach to the exocyclic nitrogen over attack of the
endocyclic one. Accordingly, difluoroethanol provides a better
ratio than trifluoroethanol from 85:15 to 93:7 for 2q.
Unexpectedly, the 2,2,3,3-tetrafluoropropanol derivative 2r
was obtained with an excellent ratio of 95:5 despite the more
heavily fluorinated chain. The good results with polyfluoroalkyl
fluorosulfonates bearing a difluoromethyl group could be due
to the ability of the CHF2 moiety to engage in H-bonding with
the amide.35,36 This interaction may explain the better N-
endocyclic regioselectivity. Isobutyl alcohol with a steric
hindrance similar to the one of trifluoroethanol gave rise to
2s in a ratio of 88:12, proving that steric hindrance also
controls the regioselectivity of the alkylation. Propargyl
alcohol, which can allow postfunctionalization, gave an
excellent yield of 94% of 2t. However, the alkylation was
nonregioselective with a ratio of 48:52. Methylation of 1b
worked with an excellent yield and was fully N-endocyclic
regioselective. To the best of our knowledge, this example
stands for the first regioselective N-methylation of imino-
thiazolidinones under mild conditions.
After understanding the importance of the substituents on
the aromatic ring, we also tested methylimino-thiazolidinone
1v and benzylic derivative 1w. As these derivatives achieved
slow conversion with DIPEA, DBU was used, as it reduces the
reaction time (Table 1, entry 7). By analogy with the
nucleophilicity parameter determined by Mayr et al. for
primary amines in acetonitrile MeNH2(15.19) >
BnNH2(14.29) > PhNH2(12.64),37,38 the methyl derivative
2v afforded an anticipated ratio of 81:19 since the
nucleophilicity of the exocyclic nitrogen is higher. Benzyl
derivatives should also favor more N-ex alkylation. Instead, an
astonishing increase in favor of N-en isomer 2w with a ratio of
87:13 was achieved, proving that steric hindrance of the imine
substituent might after all be important in the alkylation of
imino-thiazolidinones. Notably, a substrate bearing an
unsubstituted imine led only to the formation of a complex
mixture demonstrating that a substituent on the exocyclic
nitrogen is mandatory for a clean and complete reaction.
As imino-thiazolidinones are ambident reagents, two
regioisomers 2 and 3 were always obtained. The elucidation
a
Yields reported are isolated yields of pure mixtures of regioisomers 2
b
and 3. 19F or 1H NMR ratios are reported following 2a−w:3a−w. In
toluene as solvent. With DBU as a base.
c
was obtained with a good regioselectivity of 91:9. Thus, the
electron-withdrawing inductive effect33,34 of halogens results in
a less nucleophilic exocyclic nitrogen and thereby less exocyclic
N-trifluoroethylation. We could have expected that fluorine
would increase this effect due to its strong electronegativity.
Unfortunately, the ratio for 2f was only of 85:15. This can be
explained by the donating resonance effect of fluorine which
can be more important on a phenyl ring.34
In order to corroborate the electronic effect of substituents,
we studied the effect of a trifluoromethyl group as an electron-
withdrawing group in the ortho position (2g) and para position
(2h). Nicely, both afforded excellent ratios up to 96:4. The
strong negative mesomeric effect of the nitro group in para
position gave only the desired N-en regioisomer 2i in 86%
D
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of their structures was achieved via spectroscopy and X-ray
analysis for purified ortho-methoxy derivatives 2k and 3k
(Figure 1). In 13C NMR spectroscopy, the first eluted and
and 1511 cm−1 were found for speculated 2k and 3k,
respectively. Lesyk et al. investigated all the tautomeric forms
of free NH imino-thiazolidinone. In conclusion of these
studies, a characteristic and very strong band for an endocyclic
CN bond was identified at the absorption of 1640 cm−1,39
indicating that the regioisomer that we obtained with the
major band at 1638 cm−1 could be the N-ex form. A contrario,
in a previous manuscript, Lesyk et al. were working on the
synthesis and anti-inflammatory activity of thiazolidinones.40
Their characterization highlighted the presence of three
1
tautomers. According to H NMR and infrared spectroscopy,
the N-en form had higher wavenumbers compared to the N-ex
form, meaning that the regioisomer with a band at 1638 cm−1
could, this time, be the N-en regioisomer. As an unquestion-
able clue, we performed 15N−1H HMBC, which revealed for
the N-ex regioisomer that the exocyclic nitrogen can undergo a
nuclear Overhauser effect (NOE) with an aromatic proton as
well as with the CH2 from the trifluoroethyl chain (Figure 1c).
As a last and irrefutable proof, crystals of both regioisomers
were obtained and analyzed by X-ray diffraction (Figure 1d).
The first isolated regioisomer is thus the N-en form 2k and
the second one the N-ex form 3k. The Z diastereomer was
observed by X-ray diffraction crystallography for compounds
2k and 2h with substituents in ortho and para positions. The
absence of NOE between the −CH2 from the trifluoroalkyl
chain and aromatic protons was a first clue to generalize the Z
configuration of all alkylated imino-thiazolidinones of this
work. Furthermore, according to literature and crystallographic
data, endocyclic N-alkylated species systematically show Z
configuration.3,11,16 Without substituents in ortho position on
the phenyl group, H-bonding has already been observed
between one aromatic −H and the sulfur atom.12 In addition,
we performed DFT calculations on representative products
(i.e., 2j, 2k, 2n, and 2v), and they support the highly
preferential formation of the Z isomer in all cases (the energy
difference between the Z and the E isomer was consistently
between 5 and 10 kcal/mol, see Supporting Information, Table
S1).
CONCLUSIONS
■
In conclusion, we developed a versatile methodology for the N-
alkylation of imino-thiazolidinones from commercially avail-
able, nontoxic, and economic alcohols in a one-pot procedure.
SO2F2 is used as an inexpensive and atom economic reagent
for the formation of alkyl fluorosulfonates. The purpose was to
extend the alkylation to longer chains than methyl and to
perform for the first time the direct polyfluoroalkylation of
iminothiazolidinones with easily accessible fluorinated surro-
gates. As the ambident reactivity of imino-thiazolidinones gives
rise to regioselectivity issues, we showed that the ratio of N-en
and N-ex regioisomers can be modulated via the substituents
on the exocyclic nitrogen. Electron-withdrawing groups
together with polar solvents were required for regioselective
alkylation of the endocyclic nitrogen. Furthermore, the
electrophilic alkyl fluorosulfonate also plays a role, as we
could show that less sterically hindered alcohols or
difluoromethyl surrogates can afford excellent regioselectivity.
This late stage alkylation allows to produce in a simple way a
library of compounds for further biological trials.
Figure 1. Elucidation of ortho-methoxy regioisomers. (a and b) 13C
NMR spectra of both regioisomers 2k and 3k. (c) 15N−1H HMBC of
N-ex form 3k. (d) ORTEP structures of 2k and 3k; ellipsoids at the
50% probability level.
isolated regioisomer by column chromatography showed a
peak at 171 ppm for the carbonyl, and a peak at 154 ppm for
the carbon atom surrounded by both nitrogen atoms (Figure
1a). The second regioisomer possessed signals at 187 and 186
ppm (Figure 1b). The carbonyl of the amide group and the
carbon bearing both nitrogen atoms are expected to be
deshielded for the N-ex form 3. We could therefore
hypothesize that the first regioisomer was the N-en form 2k
and the other one the N-ex form 3k. For infrared spectroscopy,
antithetical publications were found for the determination of
N-en and N-ex regioisomers. In our case, strong bands at 1638
EXPERIMENTAL PROCEDURES
■
General Information. All reactions were carried out under argon
atmosphere. Warning: Sulfuryl fluoride is a toxic gas and must always be
E
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handled with care in a well-ventilated fume hood. Excess sulfuryl fluoride
was quenched by passing it through a basic aqueous medium. All
reagents and solvents were purchased commercially and used without
further purification unless otherwise stated. Diisopropylethylamine
(DIPEA) was distilled and stored over KOH under argon. The SO2F2
gas bottle was purchased from ABCR. Analytical thin-layer
chromatography (TLC) was performed using aluminum plates coated
with silica (0.25 mm, Merck silica gel 60-F254). Flash column
chromatography was performed on VWR silica gel (40−63 μm) using
solution was taken up in water and filtered, yielding 7 as a white solid
(2.5 g, 14.2 mmol, 71%). Mp 158−160 °C.
7 (1 equiv, 2.4 g, 13.5 mmol) and ammonium thiocyanate (2 equiv,
2.1 g, 27.1 mmol) were refluxed in acetone for 3 h. The mixture was
cooled, and the beige precipitate was collected by filtration, washed
with water, and dried under vacuum. 1n was obtained as a beige solid
(2.0 g, 10.0 mmol, 74%). Mp 187−190 °C.
Procedure for the Synthesis of Substrate 1v. N-Methyl-
thiourea (1 equiv, 2.0 g, 22.2 mmol), anhydrous sodium acetate (2
equiv, 3.6 g, 44.4 mmol), and monochloroacetic acid (1 equiv, 1.33
mL, 22.2 mmol) were dissolved in 7 mL of water. The reaction
mixture was refluxed for 45 min. The yellow precipitate obtained
upon cooling was filtered, washed with cold water, and dried under
vacuum. 1v was obtained as a yellow solid (2.0 g, 15.8 mmol, 71%).
General Procedure for the Synthesis of 2a−w. Imino-
thiazolidinone 1 (1 equiv), diisopropylethylamine (4 equiv), and
alkyl alcohol (2.5 equiv) were placed in 15 mL of DMAc. SO2F2,
placed in a balloon, was gently bubbled through the reaction mixture
for 1 h at rt. The solution was stirred for 17 h at rt. After completion
of the reaction, argon was bubbled through to remove SO2F2 gas. The
solution was concentrated under pressure. The obtained brown oil
was diluted with t-butyl methyl ether and washed with water. The
organic layer was dried over MgSO4, filtered, and concentrated.
Purification by flash column chromatography with a gradient of
cyclohexane:EtOAc was used when needed.
1
the indicated solvents. H NMR (400 or 600 MHz), 19F NMR (376
or 565 MHz), and 13C NMR (101 or 151 MHz) spectra were
recorded on Bruker Avance III HD 400 and 600 MHz instruments,
respectively. Chemical shifts are reported as δ values in parts per
million (ppm). The spectra were processed with MestreNova
(Mestrelab) or ACD/Spectrus Processor. If not otherwise noted,
the coupling constants given are either H−H or H−F coupling
constants for proton signals and C−F coupling constants for carbon
signals. High-resolution mass spectrometry (HRMS) analyses were
performed with a Bruker MicroTOF mass analyzer under ESI in
positive ionization mode detection (measurement accuracy ≤15 ppm)
by the analytical facility at the University of Strasbourg. The X-ray
crystallographic structure analyses were performed by the radio-
crystallographic facility at the University of Strasbourg. The analysis
was carried out on a Bruker PHOTON III DUO CPAD
diffractometer equipped with an Oxford Cryosystem liquid N2 device,
using Mo−Kα radiation (λ = 0.71073 Å)
General Procedure for the Synthesis of Substrates 1a−l and
1w. Rhodanine (1 equiv, 3.0 g, 22.5 mmol) was dissolved in a
solution of NaOH (2.2 equiv, 2.0 g, 50.0 mmol) in water (50 mL) at
22 °C. MeI (1.1 equiv, 1.54 mL, 24.8 mmol) was added dropwise to
this solution, and the reaction mixture was stirred at rt for 17 h. The
yellow reaction mixture was diluted with dichloromethane and
washed with cold saturated aq. NaHCO3 and water. The organic
phase was dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash column chromatography from 0 to 60% of
EtOAc in CyH yielding 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazol-4-
one as a yellow solid (2.15 g, 14.6 mmol, 65%).
(2Z)-2-(2-Chlorophenyl)imino-3-(2,2,2-trifluoroethyl)thiazolidin-
4-one (2a). According to the general procedure, 1a (500 mg, 2.2
mmol), DIPEA (1.54 mL, 8.8 mmol), and TFE (0.40 mL, 5.5 mmol)
were used affording the pure mixture of regioisomers 2a and 3a
1
(quantitative yield, 690 mg, ratio 92:8). H NMR (600 MHz, ACN-
d3) δ = 7.50 (dd, J = 1.3, 8.1 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.19
(t, J = 7.8 Hz, 1H), 7.02 (dd, J = 1.5, 7.9 Hz, 1H), 4.57 (q, J = 9.0 Hz,
2H), 3.98 (s, 2H). 13C{1H} NMR (151 MHz, ACN-d3) δ = 172.8,
157.7, 146.1, 131.4, 129.3, 127.3, 127.2, 123.2, 125.1 (q, J = 279.8
Hz), 44.2 (q, J = 35.8 Hz), 34.1. 19F NMR (565 MHz, ACN-d3) δ =
−69.67 (t, J = 9.1 Hz, 3F). HRMS (ESI+) m/z: [M + H]+ calcd for
C11H9N2OF3SCl, 309.0076; found, 309.0077.
2-(Methylsulfanyl)-4,5-dihydro-1,3-thiazol-4-one (1 equiv, 0.50 g,
3.4 mmol) and the desired substituted aniline (1.1 equiv, 3.74 mmol)
were dissolved in acetic acid (20 mL) and refluxed for 9 h. The
reaction mixture was then allowed to cool to rt and the formed
precipitate was filtered off. Recrystallization from AcOH or EtOH
yielded pure aromatic imino-thiazolidinones 1 as powders (yields
from 62 to 88%).
Procedure for the Synthesis of Substrate 1m. Ammonium
thiocyanate (1.1 equiv, 1.8 g, 23.3 mmol) was placed in 20 mL of dry
acetone. Benzoyl chloride (1 equiv, 2.52 mL, 21.6 mmol) was added
dropwise by maintaining the temperature between 20 and 25 °C. The
reaction mixture was refluxed for 30 min and then cooled to rt. 2-
Aminopyridine (1 equiv, 2.0 g, 21.2 mmol) was added gradually to the
solution at rt. The reaction mixture was stirred again at reflux for
further 30 min. The obtained precipitate was filtered, washed with
cold water, and dried, yielding 4 as a white powder (4.8 g, 18.4 mmol,
87%). Mp 128−132 °C.
4 (1 equiv, 4.0 g, 15.5 mmol) was added to a solution of NaOH (4
equiv, 2.5 g, 62.1 mmol) in 25 mL of water. The reaction mixture was
stirred at reflux for 1 h. The solution was filtered yielding 5 as a yellow
powder (1.8 g, 11.6 mmol, 75%). Mp 145−146 °C.
5 (1 equiv, 1.4 g, 9.1 mmol) was placed in 23 mL of acetonitrile,
and ethyl bromoacetate (1.1 equiv, 1.12 mL, 10.0 mmol) was added
dropwise. Then, anhydrous sodium acetate (1.3 equiv, 1.0 g, 11.8
mmol) was added, and the white slurry was stirred at rt for 17 h. The
white solid was filtered, washed with water, and dried under vacuum.
1m was obtained as a white powder (1.5 g, 7.8 mmol, 85%). Mp 258−
259 °C.
(2Z)-2-Phenylimino-3-(2,2,2-trifluoroethyl)thiazolidin-4-one
(2b). According to the general procedure, 1b (500 mg, 2.6 mmol),
DIPEA (1.81 mL, 10.4 mmol), and TFE (0.47 mL, 6.5 mmol) were
used affording the pure mixture of regioisomers 2b and 3b (86% yield,
1
615 mg, ratio 85:15). H NMR (600 MHz, CDCl3) δ = 7.38−7.35
(m, 2H), 7.17 (t, J = 7.5 Hz, 1H), 6.97 (dd, J = 8.3 Hz, 2H), 4.55 (q, J
= 8.5 Hz, 2H), 3.91 (s, 2H). 13C {1H} NMR (151 MHz, CDCl3) δ =
170.8, 152.3, 147.0, 129.3, 125.0, 120.8, 123.2 (q, J = 280.7 Hz), 42.9
(q, J = 36.1 Hz, 1C), 32.4. 19F NMR (565 MHz, CDCl3) δ = −67.83
(t, J = 9.1 Hz, 3F). HRMS (ESI+) m/z: [M + H]+ calcd for
C11H10N2OF3S, 275.0466; found, 275.0466.
(2Z)-2-(2-Bromophenyl)imino-3-(2,2,2-trifluoroethyl)thiazolidin-
4-one (2c). According to the general procedure, 1c (220 mg, 0.8
mmol), DIPEA (0.54 mL, 3.25 mmol), and TFE (0.15 mL, 2.0 mmol)
were used affording the pure mixture of regioisomers 2c and 3c
(quantitative yield, 290 mg, ratio 88:12). 1H NMR (400 MHz,
CDCl3) δ = 7.62 (dd, J = 8.0, 1.4 Hz, 1H), 7.29 (td, J = 7.6, 1.4 Hz,
1H), 7.03 (ddd, J = 8.0, 7.4, 1.6 Hz, 1H), 6.95 (dd, J = 7.9, 1.6 Hz,
1H), 4.58 (q, J = 8.4 Hz, 2H), 3.93 (s, 2H). 13C{1H} NMR (126
MHz, CDCl3) δ = 170.5, 154.5, 145.5, 133.0, 128.0, 125.9, 123.0 (q, J
= 280.6 Hz), 121.2, 115.9, 42.8 (q, J = 36.3 Hz, 3F), 32.4. 19F NMR
(377 MHz, CDCl3) δ = −69.04 (t, J = 8.5 Hz). HRMS (ESI+) m/z:
[M + H]+ calcd for C11H9BrN2OF3S, 352.9566; found, 352.9589.
(2Z)-2-(o-Tolylimino)-3-(2,2,2-trifluoroethyl)thiazolidin-4-one
(2d). According to the general procedure, 1d (500 mg, 2.6 mmol),
DIPEA (1.81 mL, 10.4 mmol), and TFE (0.47 mL, 6.5 mmol) were
used affording the pure mixture of regioisomers 2d and 3d (88% yield,
615 mg, ratio 85:15). 1H NMR (400 MHz, CDCl3) δ = 7.13 (dd, J =
7.2, 1.4 Hz, 1H), 7.10−7.03 (m, 1H), 6.97 (td, J = 7.5, 1.4 Hz, 1H),
6.73 (dd, J = 7.7, 1.4 Hz, 1H), 4.47 (q, J = 8.6 Hz, 2H), 3.83 (s, 2H).
13C{1H} NMR (151 MHz, CDCl3) δ = 170.8, 151.9, 145.7, 130.8,
Procedure for the Synthesis of Substrate 1n. 2-Aminothiazole
(1 equiv, 2.0 g, 20.0 mmol) and triethylamine (1.2 equiv, 3.35 mL,
24.0 mmol) were placed in 40 mL of anhydrous DMF. Chloroacetyl
chloride (1.0 equiv, 1.59 mL, 20.0 mmol) in 10 mL of anh. DMF was
added dropwise. The reaction mixture was stirred at rt for 2 h. The
129.9, 126.5, 125.0, 123.2 (q, J = 280.7 Hz), 119.3, 42.9 (q, J = 36.4
Hz), 32.4, 17.5. 19F NMR (377 MHz, CDCl3) δ = −69.21 (t, J = 8.5
F
https://doi.org/10.1021/acs.joc.1c01247
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Article
Hz, 3F). HRMS (ESI+) m/z: [M + H]+ calcd for C12H12N2OF3S,
289.0617; found, 289.0637.
(s, 3H). 13C{1H} NMR (151 MHz, DMSO-d6) δ = 171.4, 156.3,
153.4, 121.8, 123.7 (q, J = 280.8 Hz), 114.5, 55.1, 42.5 (q, J = 34.9
Hz), 32.2. 19F NMR (565 MHz, CDCl3) δ = −69.68 (t, J = 8.7 Hz,
3F). HRMS (ESI+) m/z: [M + H]+ calcd for C12H12N2O2F3S,
305.0572; found, 305.0560.
(2Z)-2-(2-Methoxyphenyl)imino-3-(2,2,2-trifluoroethyl)-
thiazolidin-4-one (2k). According to the general procedure, 1k (400
mg, 1.8 mmol), DIPEA (1.23 mL, 7.1 mmol), and TFE (0.32 mL, 4.4
mmol) were used affording the pure mixture of regioisomers 2k and
3k (90% yield, 426 mg, ratio 36:64). 1H NMR (400 MHz, CDCl3) δ
= 7.17−7.11 (m, 1H), 6.98−6.91 (m, 2H), 6.90−6.84 (m, 1H), 4.57
(q, J = 8.5 Hz, 2H), 3.88 (s, 2H), 3.81 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ = 171.0, 153.5, 150.6, 136.2, 125.9, 123.3 (q, J =
281.7 Hz), 121.4, 121.0, 112.2, 55.8, 42.9 (q, J = 36.1 Hz), 32.5. 19F
NMR (377 MHz, CDCl3) δ = −69.24 (t, J = 17.0 Hz, 3F). HRMS
(ESI+) m/z: [M + H]+ calcd for C12H12N2O2F3S, 305.0566; found,
305.0583.
(2Z)-2-(4-Chlorophenyl)imino-3-(2,2,2-trifluoroethyl)thiazolidin-
4-one (2e). According to the general procedure, 1e (400 mg, 1.8
mmol), DIPEA (1.23 mL, 7.1 mmol), and TFE (0.32 mL, 4.4 mmol)
were used affording the pure mixture of regioisomers 2e and 3e (78%
1
yield, 426 mg, ratio 91:9). H NMR (600 MHz, CDCl3) δ = 7.34−
7.32 (m, 2H), 6.93−6.89 (m, 2H), 4.53 (q, J = 8.4 Hz, 2H), 3.92 (s,
2H). 13C{1H} NMR (151 MHz, CDCl3) δ = 170.7, 156.9, 151.8,
139.9, 121.8, 123.2 (q, J = 280.7 Hz), 114.4, 55.3, 42.8 (q, J = 36.1
Hz), 32.2. NMR (151 MHz, CDCl3) δ = 170.6, 153.1, 145.5, 130.3,
129.4, 122.2, 123.2 (q, J = 280.7 Hz), 43.0 (q, J = 36.1 Hz), 32.4. 19F
NMR (565 MHz, CDCl3) δ = −67.83 (t, J = 9.1 Hz, 3F). HRMS (ESI
+) m/z: [M + H]+ calcd for C11H9ClN2OF3S, 309.0076; found,
309.0067.
(2Z)-2-(2-Fluorophenyl)imino-3-(2,2,2-trifluoroethyl)thiazolidin-
4-oneone (2f). According to the general procedure, 1f (480 mg, 2.3
mmol), DIPEA (1.67 mL, 9.6 mmol), and TFE (0.43 mL, 5.9 mmol)
were used. Flash column chromatography from 0 to 30% EtOAc in
CyH afforded the pure mixture of regioisomers 2f and 3f (94% yield,
(2Z)-2-(2,4-Di(methoxy)phenyl)imino-3-(2,2,2-trifluoroethyl)-
thiazolidin-4-one (3l). According to the general procedure, 1l (200
mg, 0.8 mmol), DIPEA (0.55 mL, 3.2 mmol), and TFE (0.14 mL, 2.0
mmol) were used. DMAc afforded the pure mixture of regioisomers 2l
and 3l with 74% yield (198 mg, ratio 25:75). Toluene afforded the
pure mixture of regioisomers 2l and 3l with 42% yield (112 mg, ratio
1
626 mg, ratio 85:15). H NMR (600 MHz, CDCl3) δ = 7.16−7.10
(m, 3H), 7.01−6.96 (m, 1H), 4.56 (q, J = 8.3 Hz, 2H), 3.93 (s, 2H).
13C{1H} NMR (151 MHz, CDCl3) δ = 170.6, 154.8, 153.4 (d, J =
1
7:93). H NMR (600 MHz, CDCl3) δ = 7.23 (d, J = 8.7 Hz, 1H),
247.0 Hz), 134.7 (d, J = 12.3 Hz), 126.0 (d, J = 7.5 Hz), 124.5 (d, J =
3.6 Hz), 122.5 (d, J = 1.5 Hz), 123.2 (q, J = 280.7 Hz), 116.4 (d, J =
19.6 Hz), 42.9 (q, J = 36.3 Hz), 32.5. 19F NMR (565 MHz, CDCl3) δ
= −67.87 (t, J = 9.1 Hz, 3F), −125.7 (m, 1F). HRMS (ESI+) m/z:
[M + H]+ calcd for C11H9N2OF4S, 293.0372; found, 293.0364.
(2Z)-3-(2,2,2-Trifluoroethyl)-2-[2-(trifluoromethyl)phenyl]imino-
thiazolidin-4-one (2g). According to the general procedure, 1g (400
mg, 1.8 mmol), DIPEA (1.23 mL, 7.1 mmol), and TFE (0.32 mL, 4.4
mmol) were used affording the pure mixture of regioisomers 2g and
3g (96% yield, 426 mg, ratio 96:4). 1H NMR (400 MHz, CDCl3) δ =
7.71−7.64 (m, 1H), 7.51 (tdd, J = 8.0, 1.5, 0.7 Hz, 1H), 7.26−7.21
(m, 1H), 7.01 (ddd, J = 7.9, 1.3, 0.7 Hz, 1H), 4.53 (q, J = 8.5 Hz,
2H), 3.94 (s, 2H). 19F NMR (377 MHz, CDCl3) δ = −61.96 (3F),
−69.27 (t, J = 8.5 Hz, 3F). 13C{1H} NMR (126 MHz, CDCl3) δ =
170.7, 154.4, 145.3, 132.8, 126.9 (q, J = 5.0 Hz), 124.7, 124.7, 123.2
(q, J = 280.7 Hz), 122.3 (q, J = 30.4 Hz), 121.2, 43.0 (q, J = 36.5 Hz),
32.5. HRMS (ESI+) m/z: [M + H]+ calcd for C12H9N2OF6S,
343.0334; found, 343.0337.
6.56 (d, J = 2.6 Hz, 1H), 6.53 (dd, J = 2.6, 8.7 Hz, 1H), 5.24−5.17
(m, 1H), 4.00−3.94 (m, 1H), 3.91 (q, J = 15.7 Hz, 2H), 3.86 (s, 3H),
3.86 (s, 3H). 13C{1H}NMR (151 MHz, CDCl3) δ = 188.3, 187.5,
162.3, 155.9, 131.2, 123.6 (q, J = 280.3 Hz), 120.6, 104.6, 99.7, 55.8,
55.6, 52.5 (q, J = 34.1 Hz), 41.4. 19F NMR (565 MHz, CDCl3) δ =
−69.45 (t, J = 8.7 Hz, 3F). HRMS (ESI+) m/z: [M + H]+ calcd for
C13H14N2O3F3S, 335.0677; found, 335.0673.
(2Z)-2-(2-Pyridylimino)-3-(2,2,2-trifluoroethyl)thiazolidin-4-one
(2m). According to the general procedure, 1m (500 mg, 2.6 mmol),
DIPEA (1.80 mL, 10.3 mmol), and TFE (0.47 mL, 6.5 mmol) were
used affording pure regioisomer 2m (78% yield, 555 mg, beige solid,
1
mp 110−113 °C). H NMR (600 MHz, DMSO-d6) δ = 8.46−8.38
(m, 1H), 7.88−7.79 (m, 1H), 7.21−7.12 (m, 2H), 4.64 (q, J = 9.1 Hz,
2H), 4.04 (s, 2H). 13C{1H} NMR (151 MHz, DMSO-d6) δ = 171.8,
157.6, 157.2, 146.7, 138.6, 123.7 (q, J = 280.7 Hz), 120.7, 120.3, 42.6
(q, J = 34.9 Hz), 32.6. 19F NMR (565 MHz, DMSO-d6) δ = −67.71
(t, J = 9.1 Hz, 3F). HRMS (ESI+) m/z: [M + H]+ calcd for
C10H9N3OF3S, 276.0418; found, 276.0410.
(2Z)-3-(2,2,2-Trifluoroethyl)-2-[4-(trifluoromethyl)phenyl]imino-
thiazolidin-4-one (2h). According to the general procedure, 1h (400
mg, 1.5 mmol), DIPEA (1.07 mL, 6.1 mmol), and TFE (0.28 mL, 3.8
mmol) were used. Flash column chromatography from 0 to 30%
EtOAc in CyH afforded the pure mixture of regioisomers 2h and 3h
(2Z)-2-Thiazol-2-ylimino-3-(2,2,2-trifluoroethyl)thiazolidin-4-
one (2n). According to the general procedure, 1n (500 mg, 2.5
mmol), DIPEA (1.75 mL, 10.0 mmol), and TFE (0.45 mL, 6.3 mmol)
were used. Flash column chromatography from 0 to 45% EtOAc in
CyH afforded the pure mixture of regioisomers 2n and 3n
(quantitative yield, 745 mg, ratio 59:41, yellow solid, mp 133−139
1
(96% yield, 503 mg, ratio 95:5). H NMR (600 MHz, CDCl3) δ =
7.63 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 4.55 (q, J = 8.5 Hz,
2H), 3.95 (s, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ = 170.5,
153.6, 150.1, 127.1 (q, J = 32.6 Hz), 126.6 (q, J = 3.6 Hz), 124.1 (q, J
= 271.6 Hz), 123.1 (q, J = 280.7 Hz), 121.1, 43.0 (q, J = 36.3 Hz),
32.5. 19F NMR (565 MHz, CDCl3) δ = −62.09 (s, 3F), −69.18 (t, J =
8.2 Hz, 3F). HRMS (ESI+) m/z: [M + H]+ calcd for C12H9N2OF6S,
343.0340; found, 343.0334.
1
°C). H NMR (600 MHz, DMSO-d6) δ = 7.66 (d, J = 3.7 Hz, 1H),
7.50 (d, J = 3.7 Hz, 1H), 4.58 (q, J = 9.2 Hz, 2H), 4.17 (s, 2H).
13C{1H} NMR (151 MHz, DMSO-d6) δ = 171.8, 168.3, 160.1, 140.0,
123.5 (q, J = 280.5 Hz), 117.7, 42.6 (q, J = 34.9 Hz), 33.2. 19F NMR
(565 MHz, DMSO-d6) δ = −67.75 (t, J = 9.1 Hz, 3F). HRMS (ESI+)
m/z: [M + H]+ calcd for C8H7N3OF3S2, 281.9953; found, 281.9977.
(2Z)-3-(2,2,3,3,3-Pentafluoropropyl)-2-phenylimino-thiazolidin-
4-one (2o). According to the general procedure, 1o (400 mg, 2.1
mmol), DIPEA (1.45 mL, 8.3 mmol), and 2,2,3,3,3-pentafluoropro-
panol (0.52 mL, 5.2 mmol) were used. Flash column chromatography
from 0 to 30% EtOAc in CyH afforded the pure mixture of
(2Z)-2-(4-Nitrophenyl)imino-3-(2,2,2-trifluoroethyl)thiazolidin-4-
one (2i). According to the general procedure, 1i (400 mg, 1.7 mmol),
DIPEA (1.17 mL, 6.7 mmol), and TFE (0.31 mL, 4.2 mmol) were
1
used affording pure regioisomers 2i (86% yield, 465 mg). H NMR
(600 MHz, CDCl3) δ = 8.26−8.22 (m, 2H), 7.10−7.05 (m, 2H), 4.54
(q, J = 8.4 Hz, 2H), 3.98 (s, 2H). 13C{1H} NMR (151 MHz, CDCl3)
δ = 170.3, 154.3, 152.9, 144.8, 125.2, 121.5, 123.0 (q, J = 280.7 Hz),
43.0 (q, J = 36.4 Hz), 32.5. 19F NMR (565 MHz, CDCl3) δ = −67.85
(m, 3F). HRMS (ESI+) m/z: [M + H]+ calcd for C11H9N3O3F3S,
320.0317; found, 320.0306.
1
regioisomers 2o and 3o (55% yield, 370 mg, ratio 81:19). H NMR
(600 MHz, DMSO-d6) δ = 7.39 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 7.4
Hz, 1H), 6.92 (d, J = 7.7 Hz, 2H), 4.59 (t, J = 15.1 Hz, 2H), 4.19 (s,
2H). 13C{1H} NMR (151 MHz, DMSO-d6) δ = 171.5, 154.1, 147.2,
129.4, 124.6, 120.6, 118.4 (q, J = 273.5 Hz), 112.6 (dt, J = 37.5, 256.7
Hz), 40.6 (t, J = 24.1 Hz), 32.3. 19F NMR (565 MHz, DMSO-d6) δ =
−83.83 (s, 3F), −117.95 (t, J = 15.2 Hz, 2F). HRMS (ESI+) m/z: [M
+ H]+ calcd for C12H10N2OF5S, 325.0434; found, 325.0432.
(2Z)-3-Ethyl-2-phenylimino-thiazolidin-4-one (2p). According to
the general procedure, 1p (300 mg, 1.6 mmol), DIPEA (1.09 mL, 6.2
mmol), and ethanol (0.23 mL, 3.9 mmol) were used affording the
(2Z)-2-(4-Methoxyphenyl)imino-3-(2,2,2-trifluoroethyl)-
thiazolidin-4-one (2j). According to the general procedure, 1j (500
mg, 2.2 mmol), DIPEA (1.57 mL, 5.6 mmol), and TFE (0.41 mL, 5.6
mmol) were used affording the pure mixture of regioisomers 2j and 3j
1
(77% yield, 524 mg, ratio 76:24). H NMR (600 MHz, CDCl3) δ =
6.94 (q, J = 8.3 Hz, 4H), 4.56 (q, J = 8.3 Hz, 2H), 3.92 (s, 2H), 3.83
G
https://doi.org/10.1021/acs.joc.1c01247
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pure mixture of regioisomers 2p and 3p (58% yield, 200 mg, ratio
96:4). 1H NMR (600 MHz, DMSO-d6) δ = 7.36 (t, J = 7.6 Hz, 2H),
7.13 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.7 Hz, 2H), 4.01 (s, 2H), 3.78−
3.74 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz,
DMSO-d6) δ = 171.6, 154.8, 148.1, 129.2, 124.2, 120.8, 37.3, 32.4,
12.2. HRMS (ESI+) m/z: [M + H]+ calcd for C11H13N2OS,
221.0749; found, 221.0736. These data are in accordance with
previously reported results.41
mg, ratio 81:19). H NMR (600 MHz, ACN-d3) δ = 4.42 (q, J = 9.0
Hz, 2H), 3.98 (s, 2H), 3.23 (s, 3H). 13C{1H} NMR (151 MHz,
ACN-d3) δ = 177.0, 155.7, 125.7 (q, J = 280.4 Hz), 53.7 (q, J = 33.7
Hz), 42.5, 39.4. 19F NMR (565 MHz, ACN-d3) δ = −70.37 (t, J = 9.1
Hz, 3F). HRMS (ESI+) m/z: [M + H]+ calcd for C6H8N2OF3S,
212.0309; found, 212.0297.
(2Z)-2-Benzylimino-3-(2,2,2-trifluoroethyl)thiazolidin-4-one
(2w). According to the general procedure, 1w (100 mg, 0.5 mmol),
DIPEA (0.34 mL, 1.9 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene
(0.15 mL, 1.0 mmol), and TFE (0.09 mL, 1.2 mmol) were used
affording the pure mixture of regioisomers 2w and 3w (68% yield, 95
mg, ratio 87:13). 1H NMR (600 MHz, DMSO-d6) δ = 7.37−7.28 (m,
5H), 4.49 (s, 2H), 4.48 (q, J = 9.2 Hz, 2H), 4.19 (s, 2H). 13C{1H}
NMR (151 MHz, DMSO-d6) δ = 171.3, 152.6, 139.0, 128.2, 127.1,
126.7, 123.7 (q, J = 280.9 Hz), 54.1, 42.3 (q, J = 34.8 Hz), 32.2. 19F
NMR (565 MHz, DMSO-d6) δ = −67.82 (t, J = 9.5 Hz, 3F). HRMS
(ESI+) m/z: [M + H]+ calcd for C12H12N2OF3S, 289.0622; found,
289.0612.
(2Z)-3-(2,2-Difluoroethyl)-2-phenylimino-thiazolidin-4-one (2q).
According to the general procedure, 1q (500 mg, 2.6 mmol), DIPEA
(1.81 mL, 10.4 mmol), and 2,2-difluoroethanol (0.41 mL, 6.5 mmol)
were used affording the pure mixture of regioisomers 2q and 3q (77%
1
yield, 510 mg, ratio 93:7). H NMR (600 MHz, CDCl3) δ = 7.39−
7.35 (m, 2H), 7.20−7.14 (m, 1H), 6.99−6.95 (m, 2H), 6.21 (tt, J =
5.0, 55.8 Hz, 1H), 4.24 (dt, J = 4.7, 13.2 Hz, 2H), 3.88 (s, 2H).
13C{1H} NMR (151 MHz, CDCl3) δ = 171.1, 153.5, 147.1, 129.3,
124.9, 120.8, 111.9 (t, J = 243.2 Hz), 44.2 (t, J = 30.3 Hz), 32.6. 19F
NMR (565 MHz, DMSO-d6) δ = −121.30 (td, J = 14.4, 55.7 Hz, 2F).
HRMS (ESI+) m/z: [M + H]+ calcd for C11H11N2OF2S, 257.0560;
found, 257.0561.
(NZ)-N-[(2-Pyridylamino)-(2,2,2-trifluoroethylsulfanyl)-
methylene]benzamide (8). According to the general procedure, 4
(300 mg, 1.2 mmol), DIPEA (0.81 mL, 4.7 mmol), and TFE (0.21
mL, 2.9 mmol) were used affording pure compound 8 (quantitative
(2Z)-2-Phenylimino-3-(2,2,3,3-tetrafluoropropyl)thiazolidin-4-
one (2r). According to the general procedure, 1r (500 mg, 2.6 mmol),
DIPEA (2.26 mL, 12.9 mmol), and tetrafluoro-1-propanol (0.70 mL,
7.8 mmol) were used affording the pure mixture of regioisomers 2r
1
yield, 428 mg, yellow solid, mp 92−119 °C). H NMR (600 MHz,
CDCl3) δ = 8.43 (dd, J = 1.4, 4.9 Hz, 1H), 8.06 (d, J = 7.3 Hz, 2H),
7.79 (dt, J = 1.9, 7.7 Hz, 1H), 7.66−7.60 (m, 1H), 7.57−7.54 (m,
2H), 7.31 (d, J = 8.0 Hz, 1H), 7.13 (ddd, J = 1.0, 5.0, 7.3 Hz, 1H),
4.07 (q, J = 10.2 Hz, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ =
165.5, 158.8, 154.8, 145.4, 139.0, 133.7, 133.0, 128.9, 128.0, 123.3,
125.4 (q, J = 276.6 Hz), 120.0, 31.9 (q, J = 32.5 Hz). 19F NMR (565
MHz, CDCl3) δ = −64.00 (br t, J = 10.4 Hz, 3F). HRMS (ESI+) m/
z: calcd for C15H13N3F3OS, 340.0731; found, 340.0719.
1
and 3r (quantitative yield, 830 mg, ratio 95:5). H NMR (600 MHz,
DMSO-d6) δ = 7.38 (t, J = 7.6 Hz, 2H), 7.15 (tt, J = 1.3, 7.4 Hz, 1H),
6.93 (d, J = 7.7 Hz, 2H), 6.60 (tt, J = 5.7, 51.3 Hz, 1H), 4.41 (t, J =
14.7 Hz, 2H), 4.14 (s, 2H). 13C{1H} NMR (151 MHz, DMSO-d6) δ
= 171.7, 154.5, 147.4, 129.3, 124.5, 120.7, 114.9 (tt, J = 25.9, 252.2
Hz), 109.4 (tt, J = 32.7, 248.3 Hz), 41.1 (t, J = 25.4 Hz), 32.3. 19F
NMR (565 MHz, DMSO-d6) δ = −120.05 to −120.15 (m, 2F),
−138.26 (td, J = 6.1, 52.0 Hz, 2F). HRMS (ESI+) m/z: [M + H]+
calcd for C12H11N2OF4S, 307.0528; found, 307.0523.
(2Z)-3-Isobutyl-2-phenylimino-thiazolidin-4-one (2s). According
to the general procedure, 1s (500 mg, 2.6 mmol), DIPEA (1.81 mL,
10.4 mmol), and isobutanol (0.60 mL, 6.5 mmol) were used affording
the pure mixture of regioisomers 2s and 3s (85% yield, 546 mg, ratio
88:12). 1H NMR (600 MHz, DMSO-d6) δ = 7.35 (t, J = 7.6 Hz, 2H),
7.12 (tt, J = 1.2, 7.4 Hz, 1H), 6.90 (d, J = 7.8 Hz, 2H), 4.05 (s, 2H),
3.57 (d, J = 7.5 Hz, 2H), 2.20−2.13 (m, J = 6.9, 6.9, 13.8 Hz, 1H),
0.92−0.88 (m, 7H). 13C{1H} NMR (151 MHz, DMSO-d6) δ =
172.1, 155.4, 148.2, 129.2, 124.1, 120.7, 49.2, 32.3, 26.2, 19.9. HRMS
(ESI+) m/z: [M + H]+ calcd for C13H17N2OS, 249.1062; found,
249.1056. These data are in accordance with previously reported
results.41
1-(2-Pyridyl)-2-(2,2,2-trifluoroethyl)isothiourea (9). According to
the general procedure, 5 (221 mg, 1.4 mmol), DIPEA (1.01 mL, 5.8
mmol), and TFE (0.26 mL, 3.6 mmol) were used affording a mixture
1
of 9 and unreacted 5 (56%, 190 mg, ratio 23:77). H NMR (600
MHz, DMSO-d6) δ = 8.27 (dd, J = 2.1, 5.8 Hz, 1H), 7.72 (dt, J = 2.0,
7.7 Hz, 1H), 7.02−6.98 (m, 2H), 4.21 (q, J = 10.3 Hz, 2H). 13C{1H}
NMR (151 MHz, DMSO-d6) δ = 160.1 (br s), 156.8 (br s), 146.3,
138.5, 125.9 (q, J = 275.6 Hz), 120.2, 118.2, 31.0 (q, J = 32.3 Hz). 19F
NMR (565 MHz, DMSO-d6) δ = −65.13 (t, J = 10.8 Hz, 3F). HRMS
(ESI+) m/z: calcd for C8H9N3F3S, 236.0469; found, 236.0459.
2-Chloro-N-thiazol-2-yl-N-(2,2,2-trifluoroethyl)acetamide (10).
According to the general procedure, 7 (500 mg, 2.8 mmol), DIPEA
(1.46 mL, 11.3 mmol), and TFE (0.52 mL, 7.1 mmol) were used
affording a mixture of regioisomers 10 and unreacted 7 (28%, 510 mg,
1
ratio 79:21). H NMR (600 MHz, CDCl3) δ = 7.08−7.05 (m, 1H),
(2Z)-2-Phenylimino-3-prop-2-ynyl-thiazolidin-4-one (2t). Ac-
cording to the general procedure, 1t (500 mg, 2.6 mmol), DIPEA
(1.81 mL, 10.4 mmol), and propargyl alcohol (0.38 mL, 6.5 mmol)
were used affording the pure mixture of regioisomers 2t and 3t (94%
yield, 563 mg, ratio 48:52). 1H NMR (600 MHz, CDCl3) δ = 7.31 (t,
J = 7.8 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.96 (dd, J = 1.0, 8.3 Hz,
2H), 4.57 (d, J = 2.5 Hz, 2H), 3.80 (s, 2H), 2.22 (t, J = 2.5 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ = 170.5, 152.5, 147.3, 129.0,
6.77 (d, J = 4.8 Hz, 1H), 4.87 (q, J = 8.5 Hz, 2H), 4.30 (s, 2H).
13C{1H} NMR (151 MHz, ACN-d3) δ = 175.8, 170.5, 138.3, 124.4
(q, J = 278.6 Hz), 116.9, 48.3 (q, J = 35.2 Hz), 47.2. 19F NMR (565
MHz, ACN-d3) δ = −71.13 (t, J = 8.7 Hz, 3F). HRMS (ESI+) m/z:
calcd for C7H7N2F3SOCl, 258.9841; found, 258.9908.
ASSOCIATED CONTENT
■
124.5, 120.8, 76.9, 71.2, 32.4, 31.8. HRMS (ESI+) m/z: [M + H]+
calcd for C12H11N2OS, 231.0592; found, 231.0585.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01247.
(2Z)-3-Methyl-2-phenylimino-thiazolidin-4-one (2u). According
to the general procedure, 1u (100 mg, 0.5 mmol), DIPEA (0.36 mL,
2.1 mmol), and methanol (0.05 mL, 1.3 mmol) were used affording
pure regioisomer 2u (93% yield, 100 mg). 1H NMR (600 MHz,
CDCl3) δ = 7.35 (t, J = 7.6 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H), 6.97 (d,
J = 7.8 Hz, 2H), 3.81 (s, 2H), 3.32 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ = 171.7, 154.8, 147.9, 129.2, 124.6, 120.9, 32.7, 29.5.
HRMS (ESI+) m/z: [M + H]+ calcd for C10H11N2OS, 207.0592;
found, 207.0587. These data are in accordance with previously
reported results.42
(2Z)-2-Methylimino-3-(2,2,2-trifluoroethyl)thiazolidin-4-one
(2v). According to the general procedure, 1v (84 mg, 0.64 mmol),
DIPEA (0.45 mL, 2.58 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene
(0.19 mL, 1.3 mmol), and TFE (0.12 mL, 1.6 mmol) were used
affording the pure mixture of regioisomers 2v and 3v (29% yield, 40
DFT calculations, X-ray data, experimental procedures,
and characterization data (PDF)
Accession Codes
CCDC2085230, CCDC2085231 and CCDC2097481 contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44
1223 336033
H
https://doi.org/10.1021/acs.joc.1c01247
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(7) Cerezo-Galvez, S.; Marienhagen, C.; Weckwert, H.; Thielert, W.;
John, M. Active Compound Combinations Having Insecticidal/
Acaricidal Properties. EP 3473100 A1, 2019.
AUTHOR INFORMATION
Corresponding Author
Frédéric R. Leroux − University of Strasbourg, University of
Haute-Alsace, CNRS, UMR 7042-LIMA, ECPM, 67087
Strasbourg, France; orcid.org/0000-0001-8900-5753;
Email: frederic.leroux@unistra.fr
■
̀
(8) Ottana, R.; Maccari, R.; Ciurleo, R.; Paoli, P.; Jacomelli, M.;
Manao, G.; Camici, G.; Laggner, C.; Langer, T. 5-Arylidene-2-
Phenylimino-4-Thiazolidinones as PTP1B and LMW-PTP Inhibitors.
Bioorg. Med. Chem. 2009, 17, 1928−1937.
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Synthesis of Thiazolidines via Sequential Hydrolysis/Rearrangement
Reactions of 5-Arylidenethiazolidin-4-Ones at Room Temperature.
Org. Biomol. Chem. 2018, 16, 1932−1938.
(10) Bhandari, S. V.; Bothara, K. G.; Patil, A. A.; Chitre, T. S.;
Sarkate, A. P.; Gore, S. T.; Dangre, S. C.; Khachane, C. V. Design,
Synthesis and Pharmacological Screening of Novel Antihypertensive
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400.
Authors
Laura Santos − University of Strasbourg, University of Haute-
Alsace, CNRS, UMR 7042-LIMA, ECPM, 67087
Strasbourg, France
Morgan Donnard − University of Strasbourg, University of
Haute-Alsace, CNRS, UMR 7042-LIMA, ECPM, 67087
Strasbourg, France; orcid.org/0000-0002-9303-4634
Armen Panossian − University of Strasbourg, University of
Haute-Alsace, CNRS, UMR 7042-LIMA, ECPM, 67087
Strasbourg, France; orcid.org/0000-0003-2317-1200
Jean-Pierre Vors − Bayer S.A.S., 69263 Lyon, France
Peter Jeschke − Bayer CropScience AG, 40789 Monheim,
Germany
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Dean, M.; Debbert, S. L.; Delves, M.; Dennis, A. S. M.; Deroose, F.;
Duffy, S.; Fletcher, S.; Giaever, G.; Hallyburton, I.; Gamo, F.-J.;
Gebbia, M.; Guy, R. K.; Hungerford, Z.; Kirk, K.; Lafuente-
Monasterio, M. J.; Lee, A.; Meister, S.; Nislow, C.; Overington, J.
P.; Papadatos, G.; Patiny, L.; Pham, J.; Ralph, S. A.; Ruecker, A.;
Ryan, E.; Southan, C.; Srivastava, K.; Swain, C.; Tarnowski, M. J.;
Thomson, P.; Turner, P.; Wallace, I. M.; Wells, T. N. C.; White, K.;
White, L.; Willis, P.; Winzeler, E. A.; Wittlin, S.; Todd, M. H. Open
Source Drug Discovery: Highly Potent Antimalarial Compounds
Derived from the Tres Cantos Arylpyrroles. ACS Cent. Sci. 2016, 2,
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David Bernier − Bayer S.A.S., 69263 Lyon, France
Sergii Pazenok − Bayer CropScience AG, 40789 Monheim,
Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01247
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Centre National de la Recherche
Scientifique, France. The authors are grateful to Bayer S.A.S.
for a Ph.D. grant to L.S and to Dr. W. Etzel for analytical
support and structures elucidation. The authors would like to
acknowledge the High-Performance Computing Center of the
University of Strasbourg for supporting this work by providing
scientific support and access to computing resources. Part of
the computing resources were funded by the Equipex Equip@
Meso project (Programme Investissements d’Avenir) and the
CPER Alsacalcul/Big Data. The French Fluorine Network
(GIS-FLUOR) is also acknowledged for its support.
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