One-pot synthesis of 2-imino-4-(trifluoromethyl)thiazolidin-4-ol derivatives in a three-component reaction: Application to structurally diverse scaffolds of biological interest through subsequent reactions

Article abstract of DOI:10.1002/ejoc.201301710

A highly efficient method for the synthesis of 2-imino-4-(trifluoromethyl) thiazolidin-4-ol derivatives has been achieved by the one-pot, three-component reactions of primary amines, aryl isothiocyanates, and 3-bromo-1,1,1- trifluoropropanone. The reactions go via symmetrical and unsymmetrical thiourea intermediates. Subsequent reactions of the products allow the synthesis of various scaffolds, including isoxazoles, triazoles, and propargylamine derivatives. A one-pot, three-component reaction for the synthesis of 2-imino-4-(trifluoromethyl)thiazolidin-4-ol derivatives is described. Subsequent reactions of the products allow the synthesis of various scaffolds, including isoxazoles, triazoles, and propargylamine derivatives. Copyright

Full text of DOI:10.1002/ejoc.201301710

FULL PAPER
DOI: 10.1002/ejoc.201301710
One-Pot Synthesis of 2-Imino-4-(trifluoromethyl)thiazolidin-4-ol Derivatives in
a Three-Component Reaction: Application to Structurally Diverse Scaffolds of
Biological Interest Through Subsequent Reactions
Tulshiram Dalmal,[a] K. Appalanaidu,[a] Umesh B. Kosurkar,[a] N. Jagadeesh Babu,[b] and
Ravindra M. Kumbhare*[a]
Keywords: Medicinal chemistry / Multicomponent reactions / Cyclization / Nitrogen heterocycles / Sulfur heterocycles /
Fluorine
A highly efficient method for the synthesis of 2-imino-4-(tri- propanone. The reactions go via symmetrical and unsymmet-
fluoromethyl)thiazolidin-4-ol derivatives has been achieved
by the one-pot, three-component reactions of primary
amines, aryl isothiocyanates, and 3-bromo-1,1,1-trifluoro-
rical thiourea intermediates. Subsequent reactions of the
products allow the synthesis of various scaffolds, including
isoxazoles, triazoles, and propargylamine derivatives.
hydronaphthalen-1-yl)iminothiazolidine IV (Figure 1) acts
as an antidepressant.[12] 3-Substituted 2-(cyanoimino)-
thiazolidines V (Figure 1) can be used in agriculture, due to
their neonicotinoid insecticidal activity, and thiacloprid (V:
R = H) is a commercially available insecticide released by
Bayer in 2001.[13]
Introduction
There has been increasing interest in the introduction of
fluorine or a fluorinated group into organic compounds,
since this influences the pharmacodynamic and pharmaco-
kinetic properties of a drug.[1] The introduction of a tri-
fluoromethyl group into cyclic compounds, especially at
strategic positions of drug molecules, has become an impor-
tant aspect of pharmaceutical research, owing to the unique
physical and biological properties of fluorine.[2,3] Therefore,
the development of fluorinated potential drugs is a key is-
sue and a challenge for medicinal chemistry and related dis-
ciplines.[4] 2-Imino-1,3-thiazolidines and 2-imino-1,3-thiaz-
olines have emerged as important classes of heterocyclic
compounds, due to their diverse applications in medicinal
chemistry.[5,6] These heterocycles show a wide range of bio-
logical properties, including anti-inflammatory, anodyne,
anti-Alzheimer, antimicrobial, antihistaminic, antihyperten-
sive, anticonvulsant activities, and also as myeloperoxidase
inhibitors etc.[7,8] For example, 4,5-dialkyl-substituted thi-
azolidines I (Figure 1) are reported to be nitric oxide syn-
thase inhibitors.[9] A member of another class of thiazolid-
ines, 3-methylthiazolidine II (Figure 1; R1 = H, R2 = Me),
is a potent inhibitor of indole–ethylamine N-methyltrans-
ferase.[10] β-(Hydroxyethyl)thiazolidines III (Figure 1) are
reported to be effective antihypertensive agents.[11] 2-(Tetra-
Figure 1. Biologically active 2-imino-1,3-thiazolidine motifs.
Furthermore, thiazoline derivatives have applications in
agriculture as pesticides, acaricides, insecticides, and plant-
growth regulators.[14] Consequently, in recent decades, there
has been continuous interest in developing new synthetic
strategies for the synthesis of such attractive target mo-
lecules.
A detailed literature survey revealed the various methods
available for the synthesis of functionalized 2-iminothiazol-
idines and related compounds. These include acid-mediated
intramolecular cyclization of N-(2-hydroxyethyl)thiourea,
ring transformation of 2-(thiocyanomethyl)aziridines, treat-
ment of aziridines with thiocyanuric acid, reaction of 2-vin-
ylaziridine with phenyl isothiocyanate, condensation of α-
halo ketones with thioureas, etc.[15,16] However, methods for
the synthesis of 2-imino-1,3-thiazolidin-4-ol derivatives are
[a] Fluoroorganic Division, Indian Institute of Chemical
Technology, CSIR,
Hyderabad, India
E-mail: kumbhare@iict.res.in, rakumbhare@yahoo.com
http://www.iictindia.org/
[b] Laboratory of X-ray Crystallography, Indian Institute of
Chemical Technology, CSIR,
Hyderabad, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301710.
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Synthesis of 2-Imino-4-(trifluoromethyl)thiazolidin-4-ols
rare in the literature.[17] The known methods use substituted Table 1. Solvent effects on the reaction of furfurylamine, phenyl
isothiocyanate, and 3-bromo-1,1,1-trifluoropropan-2-one.
thioureas as substrates, and have major drawbacks: they re-
quire the use of base and harsh reaction conditions, and the
yields are low. To improve on these limitations, it is impor-
tant to develop a simple and efficient method for the syn-
thesis of 2-imino-thiazolidin-4-ols. Bearing in mind the bio-
logical importance of 2-imino-1,3-thiazolidine derivatives,
we planned to insert a trifluoromethyl group into the
thiazolidine ring to achieve a better biological profile. We
envisioned that the reaction of 3-bromo-1,1,1-trifluoropro-
panone, a primary amine, and an aryl isothiocyanate would
generate a 2-imino-thiazolidin-4-ol by the in situ generation
of thiourea in one pot. To the best of our knowledge, there
are no reports on the one-pot synthesis of 2-imino-4-(tri-
fluoromethyl)thiazolidin-4-ols by such a three-component
reaction.
In a continuation of our research program into the syn-
thesis of new heterocyclic compounds and their biological
evaluation,[18] in this paper, we report a simple, efficient,
catalyst-free, one-pot, three-component method for the syn-
thesis of 2-imino-4-(trifluoromethyl)thiazolidin-4-ol deriva- bromo-1,1,1-trifluoropropanone to give the corresponding
tives. We also describe subsequent reactions of the products, products (i.e., 4h–4j) in good yields (Table 2, entries h–j).
using their free hydroxy group for the synthesis of structur- All the products were characterized by IR spectroscopy, 1H
ally diverse scaffolds.
and 13C NMR spectroscopy, and mass spectrometry. The
structure of 4d (Table 2, entry d) was confirmed by X-ray
crystallography. The X-ray structure of compound 4d shows
the Z-configuration of the imino group (Figure 2).[19]
All the reactions were exothermic at room temperature,
Results and Discussion
As a model reaction, we first attempted the reaction of which suggests that the mechanism involved the in situ gen-
furfurylamine (1b), phenyl isothiocyanate (2b), and 3- eration of thiourea from the primary amine and the phenyl
bromo-1,1,1-trifluoropropan-2-one (3) in N,N-dimethyl- isothiocyanate, followed by reaction with 3-bromo-1,1,1-tri-
formamide (DMF) at room temperature (Table 1, entry 1). fluoropropanone to give product 4. As may be seen in
The reaction proceeded smoothly to give corresponding 2- Table 2, the reactions provided a single regioisomer of 4 as
imino-4-(trifluoromethyl)thiazolidin-4-ol (i.e., 4b) as the the exclusive product in all those cases where reaction pro-
sole product in 98% yield. Later, we studied the same reac- ceeded via an in-situ-generated unsymmetrical thiourea.
tion in DMF/water (1:1), in water alone, and under solvent- The outcome is dependent on the pKa value of the amines.
free conditions to try to optimize the reaction outcome un- It is reported that the amine with the lower pKa of the two
der green conditions (Table 1, entries 2–4). We found that in the thiourea becomes part of the imine group, whereas
when the water content increased, the yield of the product the amine with the higher pKa gives rise to the other hetero-
decreased. Of the solvents tested, DMF seemed to be the cyclic nitrogen.[20]This protocol is simple, efficient, and
best choice. base-free, and it provides the desired products in good to
We went on to investigate this process for various other excellent yields.
primary amines and substituted phenyl isothiocyanates un-
Previous mechanistic studies of the formation of the 2-
der the optimized reaction conditions, and the results are imino thiazolines suggested that after cyclization, the terti-
given in Table 2. Interestingly, several primary amines, in- ary hydroxy group in the intermediate undergoes dehy-
cluding thiophen-2-ylmethylamine, tryptamine, 2-morphol- dration to give the thiazole-2-imine.[15] However, our in-
inoethylamine, 2-(pyridin-2-yl)ethylamine, prop-1-ylamine, vestigations revealed that the dehydration process was not
cyclopropylamine, and 2-methylprop-2-ylamine, and phenyl taking place during the course of our reaction. Even when
isothiocyanates, including 3- or 4-(trifluoromethyl)phenyl the reaction was carried out at 70–80 °C in DMF for
isothiocyanate, and 1-chloro-2-(trifluoromethyl)phenyl iso- 30 min, we still obtained the desired product (i.e., 4) with a
thiocyanate, reacted with 3-bromo-1,1,1-trifluoropro- tertiary hydroxy group. This might be due to the electron-
panone to give the corresponding 2-imino-4-(trifluoro- withdrawing effect of the trifluoromethyl group on same
methyl)thiazolidin-4-ol derivatives (i.e., 4) in good to excel- carbon. The proposed mechanism for the model reaction is
lent yields (Table 2, entries a, c–g, k–o). This method outlined in Scheme 1. The reaction may proceed via thio-
worked effectively not only for aliphatic and heteroaryl pri- urea 5, which is generated in situ from the primary amine
mary amines, but also for aromatic primary amines. For and the phenyl isothiocyanate. This is followed by attack of
instance, aniline, 3-fluoroaniline, and 4-methoxyaniline re- the thiocarbonyl group of thiourea 5 on the bromomethyl
acted smoothly with various phenyl isothiocyanates and 3- group of 3 to produce 6. This compound may then undergo
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Table 2. Synthesis of 2-imino-4-(trifluoromethyl)thiazolidin-4-ol derivatives.
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Synthesis of 2-Imino-4-(trifluoromethyl)thiazolidin-4-ols
allow the synthesis of more attractive molecules with poten-
tially improved biological properties. Isoxazoles and tri-
azoles are important heterocyclic pharmacophores in the
development of antiviral, anticancer, anti-HIV, anti-inflam-
matory, anticonvulsant, anticestoidal, antileprosy, antidia-
betes, and antibiotic agents.[21,22] The Mannich reaction is
also one of the most important multicomponent coupling
reactions of aldehydes, alkynes, and amines in organic
chemistry.[23] Propargylamines are of considerable interest;
they have found applications in the chemical/pharmaceuti-
cal industry, and they also have various biological activi-
ties.[24]
We have used the tertiary hydroxy group in 4 to synthe-
size 2-imino-4-(trifluoromethyl)thiazolidine-tethered isox-
azole and triazole derivatives using 1,3-dipolar cycload-
Figure 2. ORTEP structure of 4d.
rapid cyclization to give the desired product (i.e., 4b). The dition reactions of propargylated 2-imino-4-(trifluoro-
reaction proceeds in regioselective manner because of the methyl)thiazolidin-4-ols. Compounds 4b and 4k were cho-
higher acidity of NH proton flanked by a phenyl group.
sen as model compounds for this study. Base-mediated
Next, we turned our attention to structural diversifica- propargylation of 4b and 4k gave terminal alkynes 7a and
tion of the 2-imino-4-(trifluoromethyl)thiazolidin-4-ols (i.e., 7b, respectively (Scheme 2). 1,3-Dipolar cycloaddition of
4; Table 2). Further reactions of the tertiary hydroxy group alkyne 7a with (E)-4-methoxybenzaldehyde oxime (8a) in
Scheme 1. Plausible reaction mechanism.
Scheme 2. Synthesis of isoxazole, triazole, and propargylamine derivatives of 2-imino-4-(trifluoromethyl)thiazolidinol. Reagents and con-
ditions: (a) propargyl bromide, K2CO3, DMF, room temp.; (b) oxime 8, NaOCl, Et3N, CH2Cl2, 0 °C to room temp.; (c) azide 10, CuI,
dry THF, room temp.; (d) HCHO, sec. amine 12, CuI, THF, room temperature.
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the presence of sodium hypochlorite and triethylamine in reacted well with alkyne 7b to give the respective triazole
dichloromethane gave the corresponding isoxazole deriva- derivatives (i.e., 11b–11e) in good to excellent yields
tive (i.e., 9a) as a single product in 87% yield (Table 3, en- (Table 4, entries b–e).
try a). Interestingly, various other aromatic aldoximes 8b–
In addition, a multicomponent coupling reaction of alk-
8e underwent smooth cycloadditions with alkyne 7a to give yne 7a, formaldehyde, and morpholine (12a) in the presence
the corresponding isoxazole derivatives 9b–9e (Table 3, en- of CuI (10 mol-%) in THF gave the respective propar-
tries b–e) in good yields.
gylamine (i.e., 13a) in 90% yield (Table 5, entry a). Several
Next, the reaction of alkyne 7b with azide 10a in the secondary amines were investigated in this reaction, and the
presence of CuI (5 mol-%) in anhydrous tetrahydrofuran results are summarized in Table 5. Other secondary amines
gave the corresponding triazole derivative (i.e., 11a) in 88% 12b–12e also reacted well under the same conditions to give
yield in a Sharpless click chemistry reaction (Table 4, en- the respective propargylamines (i.e., 13b–13e) in satisfactory
try a). Similarly, other functionalized azides 10a–10e also yields (entries b–e).
Table 3. Synthesis of isoxazole derivatives of 2-imino-4-(trifluoromethyl)thiazolidinol 9a–9e.[a]
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Synthesis of 2-Imino-4-(trifluoromethyl)thiazolidin-4-ols
Table 4. Synthesis of triazole derivatives of 2-imino-4-(trifluoromethyl)thiazolidinol 11a–11e.[a]
ucts for the synthesis of various scaffolds such as isoxazoles,
triazoles, and propargylamine derivatives, which are found
Conclusions
In conclusion, we have developed a simple one-pot protocol in many biological compounds, has been demonstrated.
for the synthesis of 2-imino-4-(trifluoromethyl)thiaz- Since the thiazolidine ring itself has great biological impor-
olidin-4-ol derivatives by the three-component reaction of a tance, the newly synthesized products and their isoxazole,
primary amine, an aryl isothiocyanate, and 3-bromo-1,1,1- triazole, and propargylamine derivatives may find applica-
trifluoropropan-2-one. The reaction uses easily available tions in medicinal chemistry. Biological screening of these
precursors and gives the desired products in excellent to new products is underway, and the results of these investi-
good yields in single-step operation. The utility of the prod- gations will be reported in due course.
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Table 5. Synthesis of propargylamine derivatives of of 2-imino-4-(trifluoromethyl)thiazolidinol 13a–13e.[a]
Procedure for Synthesis of 2-Imino-4-(trifluoromethyl)thiazolidin-4-
ol Derivatives 4a–4l: A solution of primary amine 1 (1 mmol) and
aryl isothiocyanate 2 (1 mmol) in N,N-dimethylformamide (5 mL)
was stirred for 5 min, and then 3-bromo-1,1,1-trifluoropropanone
3 (1 mmol) was added dropwise. The reaction mixture was stirred
at room temperature for 20–30 min. After TLC indicated that the
reaction was complete, the mixture was quenched with saturated
NaHCO3 solution (1 mL), diluted with water, and extracted with
EtOAc (3ϫ 10 mL). The combined organic extracts were washed
with brine solution, dried (Na2SO4), filtered and concentrated. The
resulting crude product was purified by column chromatography
using EtOAc/n-hexane gradients to give pure product 4 (Table 2).
Experimental Section
General Remarks: All solvents were distilled before use. Dry reac-
tions were conducted under a nitrogen atmosphere. Crude products
were purified by column chromatography on silica gel (60–120 or
100–200 mesh). Thin-layer chromatography plates were visualized
by exposure to ultraviolet light, exposure to iodine vapors, and/or
exposure to a methanolic acidic solution of p-anisaldehyde followed
by heating (Ͻ1 min) on a hot plate (ca. 250 °C). IR spectra were
recorded with an FTIR spectrometer. H, 19F, and 13C (proton de-
1
coupled) NMR spectra were recorded in CDCl3 with 300 and
500 MHz NMR spectrometers. Chemical shifts (δ) are reported in
parts per million (ppm) relative to tetramethylsilane, which was
used as an internal standard. Coupling constants (J) are quoted in
Hertz (Hz). High-resolution mass specta (HRMS) were obtained
using electrospray ionization (ESI) and a orbitrap mass analyser.
(Z)-2-(Phenylimino)-3-(thiophen-2-ylmethyl)-4-(trifluoromethyl)-
thiazolidin-4-ol (4a): Solid (347 mg, 96 %), m.p. 126–128 °C. 1H
NMR (CDCl3, 500 MHz): δ = 3.09 (br. s, 1 H), 3.16 (d, J =
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Synthesis of 2-Imino-4-(trifluoromethyl)thiazolidin-4-ols
12.1 Hz, 1 H), 3.53 (d, J = 12.1 Hz, 1 H), 4.72 (d, J = 15.9 Hz, 1
1584, 1494, 1361, 1319, 1183 cm–1. MS (ESI): m/z = 305 [M +
H), 5.38 (d, J = 15.9 Hz, 1 H), 6.93–6.98 (m, 1 H), 7.01–7.07 (m, H]+. HRMS (ESI): calcd. for C13H16ON2F3S 305.0916 [M + H]+;
2 H), 7.08–7.17 (m, 2 H), 7.27–7.38 (m, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 35.1, 41.7, 91.3 (q, J = 32.7 Hz), 121.5,
124.0, 126.2, 127.0, 127.3, 129.0, 140.0, 150.1, 156.4 ppm. IR
found 305.0929.
(Z)-3-Cyclopropyl-2-(phenylimino)-4-(trifluoromethyl)thiazolidin-4-
1
ol (4g): Solid (286 mg, 95%), m.p. 159–161 °C. H NMR (CDCl3,
(KBr): ν = 3063, 2363, 1607, 1584, 1437, 1338, 1303, 1176 cm–1.
˜
500 MHz): δ = 0.79–1.01 (m, 3 H), 1.14–1.25 (m, 1 H), 2.52–2.61
(m, 1 H), 3.16 (d, J = 11.7 Hz, 1 H), 3.51 (d, J = 11.7 Hz, 1 H),
3.61 (s, 1 H), 6.86–6.95 (m, 2 H), 7.06–7.12 (m, 1 H), 7.27–7.34 (m,
2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 5.0, 5.6, 24.8, 32.4,
89.7 (q, J = 31.3 Hz), 116.7, 120.1, 121.8, 124.3, 127.2, 127.4, 149.7,
MS (ESI): m/z = 359 [M + H]+. HRMS (ESI): calcd. for
C15H14ON2F3S2 359.0484 [M + H]+; found 359.0494.
(Z)-3-(Furan-2-ylmethyl)-2-(phenylimino)-4-(trifluoromethyl)-
thiazolidin-4-ol (4b): Solid (335 mg, 98 %), m.p. 105–107 °C. 1H
NMR (CDCl3, 500 MHz): δ = 3.20 (d, J = 12.1 Hz, 1 H), 3.55 (d,
J = 12.1 Hz, 1 H), 3.98 (br. s, 1 H), 4.46 (d, J = 16.2 Hz, 1 H), 5.22
(d, J = 16.2 Hz, 1 H), 6.34–6.39 (m, 1 H), 6.40–6.46 (m, 1 H), 6.85–
6.94 (m, 2 H), 7.02–7.12 (m, 1 H), 7.23–7.34 (m, 2 H), 7.34–7.44
(m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 34.8, 39.6, 90.7
(q, J = 32.4 Hz), 109.8, 110.9, 121.4, 123.8, 125.1, 129.0, 142.0,
150.0, 150.2, 156.0 ppm. 19F NMR (CDCl3, 500 MHz): δ = –78.81
156.0 ppm. IR (KBr): ν = 3103, 2115, 1609, 1586, 1486, 1342,
˜
1163 cm–1. MS (ESI): m/z = 303 [M + H]+. HRMS (ESI): calcd.
for C13H14ON2F3S 303.0765 [M + H]+; found 303.0773.
(Z)-3-Phenyl-2-(phenylimino)-4-(trifluoromethyl)thiazolidin-4-ol
(4h): Solid (310 mg, 92 %), m.p. 152–154 °C. 1H NMR (CDCl3,
500 MHz): δ = 3.31 (d, J = 12.1 Hz, 1 H), 3.62 (br. s, 1 H), 3.71
(d, J = 12.1 Hz, 1 H), 6.84–6.91 (m, 2 H), 7.01–7.09 (m, 1 H), 7.22–
7.30 (m, 2 H), 7.32–7.51 (m, 5 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 34.5, 91.0 (q, J = 31.9 Hz), 120.8, 121.6, 124.0, 124.6,
128.9, 129.3, 130.4, 136.7, 150.6, 159.0 ppm. 19F NMR (CDCl3,
(s, 3 F) ppm. IR (KBr): ν = 3061, 2690, 1605, 1581, 1427, 1331,
˜
1302, 1192, 1153 cm–1. MS (ESI): m/z = 343 [M + H]+. HRMS
(ESI): calcd. for C15H14O2N2F3S 343.0713 [M + H]+; found
343.0722.
500 MHz): δ = –78.24 (s, 3 F) ppm. IR (KBr): ν = 3025, 1619,
˜
1585, 1490, 1324, 1183 cm–1. MS (ESI): m/z = 339 [M + H]+.
HRMS (ESI): calcd. for C16H14ON2F3S 339.0763 [M + H]+; found
339.0773.
(Z)-3-[2-(1H-Indol-3-yl)ethyl]-2-(phenylimino)-4-(trifluoromethyl)-
thiazolidin-4-ol (4c): Solid (360 mg, 89 %), m.p. 128–130 °C. 1H
NMR (CDCl3, 500 MHz): δ = 2.78–2.94 (m, 2 H), 2.95–3.07 (m, 1
H), 3.40–3.60 (m, 2 H), 3.62–3.76 (m, 1 H), 4.01–4.15 (m, 1 H),
6.98–7.28 (m, 6 H), 7.30–7.42 (m, 3 H), 7.68–7.78 (m, 1 H), 8.15
(br. s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 23.0, 34.8, 45.4,
111.4, 113.5, 118.9, 119.9, 121.8, 122.5, 123.8, 125.3, 127.0, 129.0,
136.0, 150.3 ppm. 19F NMR (CDCl3, 500 MHz): δ = –80.45 (s, 3
(Z)-4-(Trifluoromethyl)-3-[3-(trifluoromethyl)phenyl]-2-[3-(trifluoro-
methyl)phenylimino]thiazolidin-4-ol (4i): Solid (369 mg, 78%), m.p.
106–108 °C. 1H NMR (CDCl3, 500 MHz): δ = 3.40 (d, J = 12.1 Hz,
1 H), 3.70 (br. s, 1 H), 3.81 (d, J = 12.1 Hz, 1 H), 7.0 –7.20 (m, 2
H), 7.29–7.46 (m, 2 H), 7.55–7.79 (m, 4 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 35.2, 91.1 (q, J = 32.4 Hz), 118.6, 120.7,
121.7, 124.4, 124.8, 125.3, 125.9, 127.3, 129.5, 129.9, 131.3 (q, J =
32.4 Hz), 131.4 (q, J = 32.4 Hz), 133.9, 137.2, 150.4, 159.0 ppm.
19F NMR (CDCl3, 500 MHz): δ = –62.60 (s, 3 F), –62.70 (s, 3 F),
F) ppm. IR (KBr): ν = 3409, 3062, 2683, 1606, 1585, 1420, 1311,
˜
1182, 1147 cm–1. MS (ESI): m/z = 406 [M + H]+. HRMS (ESI):
calcd. for C20H19ON3F3S 406.1182 [M + H]+; found 406.1195.
(Z)-3-(2-Morpholinoethyl)-2-(phenylimino)-4-(trifluoromethyl)-
thiazolidin-4-ol (4d): Solid (348 mg, 93 %), m.p. 124–126 °C. 1H
NMR (CDCl3, 500 MHz): δ = 2.29–2.39 (m, 1 H), 2.41–2.95 (m, 4
H), 2.98–3.11 (m, 1 H), 3.22 (d, J = 12.0 Hz, 1 H), 3.42–3.55 (m,
2 H), 3.62–3.94 (m, 4 H), 4.19–4.29 (m, 1 H), 6.87–6.96 (m, 2 H),
7.03–7.12 (m, 1 H), 7.24–7.35 (m, 2 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 34.9, 41.1, 53.7, 55.0, 66.0, 89.9 (q, J = 31.2 Hz),
121.5, 123.7, 123.9 (q, J = 288.7 Hz), 129.0, 150.6, 157.3 ppm. IR
–78.22 (s, 3 F) ppm. IR (KBr): ν = 3160, 2660, 1583, 1451, 1334,
˜
1158 cm–1. MS (ESI): m/z = 475 [M + H]+. HRMS (ESI): calcd.
for C18H12ON2F9S 475.0498 [M + H]+; found 475.0497.
(Z)-3-(4-Methoxyphenyl)-4-(trifluoromethyl)-2-[4-(trifluorometh-
yl)phenylimino]thiazolidin-4-ol (4j): Solid (370 mg, 85%), m.p. 154–
1
156 °C. H NMR (CDCl3, 500 MHz): δ = 3.39 (d, J = 12.1 Hz, 1
H), 3.43 (br. s, 1 H), 3.75 (d, J = 12.1 Hz, 1 H), 3.81 (s, 3 H), 6.91–
7.02 (m, 4 H), 7.24–7.32 (m, 2 H), 7.46–7.55 (m, 2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 34.4, 55.3, 91.0 (q, J = 31.8 Hz),
114.8, 120.8, 121.9, 124.6, 126.1, 128.6, 131.4, 153.7, 159.8 ppm.
19F NMR (CDCl3, 500 MHz): δ = –61.82 (s, 3 F), –78.43 (s, 3
(KBr): ν = 3065, 2669, 1619, 1594, 1456, 1356, 1303, 1163 cm–1.
˜
MS (ESI): m/z = 376 [M + H]+. HRMS (ESI): calcd. for
C16H21O2N3F3S 376.1292 [M + H]+; found 376.1301.
(Z)-2-(Phenylimino)-3-[2-(pyridin-2-yl)ethyl]-4-(trifluoromethyl)-
thiazolidin-4-ol (4e): Solid (330 mg, 90 %), m.p. 103–105 °C. 1H
NMR (CDCl3, 500 MHz): δ = 3.18 (d, J = 12.1 Hz, 1 H), 3.21–
3.32 (m, 1 H), 3.42–3.48 (m, 1 H), 3.52 (d, J = 12.1 Hz, 1 H), 3.78–
3.90 (m, 1 H), 4.38–4.51 (m, 1 H), 6.52–6.61 (m, 2 H), 6.95–7.04
(m, 1 H), 7.14–7.36 (m, 4 H), 7.68–7.76 (m, 1 H), 8.41–8.49 (m, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 33.6, 36.0, 41.3, 91.1 (q,
J = 31.3 Hz), 121.5, 121.9, 123.4, 125.1, 125.8, 128.7, 138.0, 146.4,
F) ppm. IR (KBr): ν = 3158, 2847, 1589, 1510, 1462, 1410, 1322,
˜
1160 cm–1. MS (ESI): m/z = 437 [M + H]+. HRMS (ESI): calcd.
for C18H15O2N2F6S 437.0728 [M + H]+; found 437.0752.
(Z)-3-(Furan-2-ylmethyl)-4-(trifluoromethyl)-2-[4-(trifluorometh-
yl)phenylimino]thiazolidin-4-ol (4k): Solid (356 mg, 87%), m.p. 98–
1
100 °C. H NMR (CDCl3, 500 MHz): δ = 3.26 (d, J = 11.76 Hz, 1
H), 3.60 (d, J = 11.76 Hz, 1 H), 3.89 (br. s, 1 H), 4.47 (d, J =
16.3 Hz, 1 H), 5.23 (d, J = 16.3 Hz, 1 H), 6.35–6.45 (m, 2 H), 6.95–
7.00 (m, 2 H), 7.39–7.43 (m, 1 H), 7.51–7.57 (m, 2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 34.9, 39.7, 90.8 (q, J = 32.7 Hz),
110.0, 111.0, 121.7, 123.2 (q, J = 287.9 Hz), 125.8, 126.2, 126.3,
142.2, 149.7, 153.2, 156.4 ppm. 19F NMR (CDCl3, 500 MHz): δ =
150.3, 156.7, 158.6 ppm. IR (KBr): ν = 2989, 2649, 1619, 1588,
˜
1443, 1295, 1248, 1186 cm–1. MS (ESI): m/z = 368 [M + H]+.
HRMS (ESI): calcd. for C17H17ON3F3S 368.1029 [M + H]+; found
368.1038.
(Z)-2-(Phenylimino)-3-propyl-4-(trifluoromethyl)thiazolidin-4-ol
(4f): Solid (279 mg, 92%), m.p. 130–132 °C. 1H NMR (CDCl3,
500 MHz): δ = 0.94 (t, J = 7.6 Hz, 3 H), 1.60–1.93 (m, 2 H), 3.16
(d, J = 12.1 Hz, 1 H), 3.23–3.61 (m, 4 H), 6.89–6.95 (m, 2 H), 7.04–
7.12 (m, 1 H), 7.25–7.34 (m, 2 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 11.3, 21.4, 35.1, 45.8, 90.9 (q, J = 31.9 Hz), 121.6,
–61.84 (s, 3 F), –78.84 (s, 3 F) ppm. IR (KBr): ν = 3431, 2926,
˜
1590, 1427, 1329, 1304, 1166, 1124 cm–1. MS (ESI): m/z = 411 [M
+ H]+. HRMS (ESI): calcd. for C16H13O2N2F6S 411.0582 [M +
H]+; found 411.0596.
(Z)-3-(2-Morpholinoethyl)-4-(trifluoromethyl)-2-[4-(trifluorometh-
yl)phenylimino]thiazolidin-4-ol (4l): Solid (398 mg, 90%), m.p. 92–
123.7, 129.0, 150.6, 156.1 ppm. IR (KBr): ν = 3062, 2658, 1606,
˜
Eur. J. Org. Chem. 2014, 2468–2479
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2475

R. M. Kumbhare et al.
FULL PAPER
1
94 °C. H NMR (CDCl3, 500 MHz): δ = 2.32–2.39 (m, 1 H), 2.41– 75 MHz): δ = 30.3, 40.2, 51.7, 75.1, 78.4, 94.4 (q, J = 31.8 Hz),
2.94 (m, 4 H), 2.96–3.05 (m, 1 H), 3.25 (d, J = 11.9 Hz, 1 H), 3.45– 109.2, 110.4, 121.4, 122.6 (q, J = 287.0 Hz), 123.9, 129.0, 141.6,
3.58 (m, 2 H), 3.64–3.94 (m, 4 H), 4.20–4.28 (m, 1 H), 6.98–7.04
150.2, 150.3, 156.4 ppm. 19F NMR (CDCl3, 500 MHz): δ = –78.10
(m, 2 H), 7.52–7.57 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ (s, 3 F) ppm. IR (Neat): ν = 2927, 1635, 1592, 1321, 1183,
˜
= 34.9, 41.2, 53.3, 55.0, 66.0, 90.0 (q, J = 31.3 Hz), 121.8, 126.2, 1135 cm–1. MS (ESI): m/z = 381 [M + H]+. HRMS (ESI-orbitrap):
126.3, 146.9, 153.6, 158.0 ppm. IR (KBr): ν = 3036, 2687, 1588,
calcd. for C18H16O2N2F3S 381.0866 [M + H]+; found 381.0879.
˜
1541, 1477, 1420, 1320, 1173, 1140 cm–1. MS (ESI): m/z = 444 [M
+ H]+. HRMS (ESI): calcd. for C17H20O2N3F6S 444.1158 [M +
H]+; found 444.1150.
(Z)-N-[3-(Furan-2-ylmethyl)-4-(prop-2-ynyloxy)-4-(trifluorometh-
yl)thiazolidin-2-ylidene]-4-(trifluoromethyl)aniline (7b): Viscous li-
quid (367 mg, 82%). 1H NMR (CDCl3, 500 MHz): δ = 2.51 (t, J
= 2.3 Hz, 1 H), 3.56–3.65 (m, 2 H), 4.11 (dd, J = 15.6, 2.3 Hz, 1
H), 4.24 (dd, J = 15.6, 2.3 Hz, 1 H), 4.72 (d, J = 16.4 Hz, 1 H),
4.84 (d, J = 16.4 Hz, 1 H), 6.31–6.35 (m, 1 H), 6.36–6.41 (m, 1 H),
6.99–7.08 (m, 2 H), 7.33–7.40 (m, 1 H), 7.51–7.60 (m, 2 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 30.2, 40.4, 51.8, 75.3, 78.2, 94.5
(q, J = 32.4 Hz), 109.3, 110.4, 118.6, 120.4, 122.5 (q, J = 287.6 Hz),
124.0 (q, J = 272.8 Hz), 124.9, 129.5, 131.3 (q, J = 31.8 Hz), 141.8,
(Z)-2-[4-Chloro-3-(trifluoromethyl)phenylimino]-3-(thiophen-2-yl-
methyl)-4-(trifluoromethyl)thiazolidin-4-ol (4m): Solid (418 mg,
91%), m.p. 123–125 °C. 1H NMR (CDCl3, 500 MHz): δ = 3.09 (br.
s, 1 H), 3.23 (d, J = 12.3 Hz, 1 H), 3.59 (d, J = 12.3 Hz, 1 H), 4.73
(d, J = 15.8 Hz, 1 H), 5.36 (d, J = 15.8 Hz, 1 H), 6.94–7.02 (m, 1
H), 7.10–7.20 (m, 2 H), 7.28–7.33 (m, 1 H), 7.34–7.39 (m, 1 H),
7.41–7.51 (m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 35.3,
41.8, 121.1, 125.9, 126.4, 127.2, 127.5, 132.0, 139.5, 148.8,
157.8 ppm. 19F NMR (CDCl3, 500 MHz): δ = –62.65 (s, 3 F),
150.0, 150.5, 157.4 ppm. IR (Neat): ν = 2934, 1634, 1442, 1320,
˜
1183, 1129 cm–1. MS (ESI): m/z = 449 [M + H]+. HRMS (ESI-
orbitrap): calcd. for C19H15O2N2F6S 449.0743 [M + H]+; found
449.0752.
–78.44 (s, 3 F) ppm. IR (KBr): ν = 3074, 2704, 1585, 1475, 1415,
˜
1313, 1161 cm–1. MS (ESI): m/z = 461 [M + H]+. HRMS (ESI):
calcd. for C16H12ON2ClF6S2 460.9967 [M + H]+; found 460.9978.
Typical Procedure for the Synthesis of Isoxazole Derivatives 9a–9e
of 2-Imino-4-(trifluoromethyl)thiazolidinol: NaOCl (9–12% aqueous
solution; 1.6 mmol) was slowly added over a period of 1 h to a
stirred solution of alkyne 7a (1 mmol) and triethylamine (1 mmol)
in dichloromethane (5 mL) at 0 °C. Then a solution of oxime 8
(1 mmol) in dichloromethane (2 mL) was added. The reaction mix-
ture was stirred at room temperature for 24 h, and after TLC indi-
cated that the reaction was complete, the dichloromethane was re-
moved under reduced pressure. Water (5 mL) was added, and the
mixture was extracted with ethyl acetate (2ϫ 10 mL). The com-
bined organic extracts were washed with brine, dried (Na2SO4),
filtered, and concentrated. The crude product was purified by col-
umn chromatography using ethyl acetate/n-hexane gradients to give
pure product 9 (Table 3).
(Z)-2-[4-Chloro-3-(trifluoromethyl)phenylimino]-3-[2-(pyridin-2-yl)-
ethyl]-4-(trifluoromethyl)thiazolidin-4-ol (4n): Solid (408 mg, 87%),
m.p. 118–120 °C. 1H NMR (CDCl3, 500 MHz): δ = 3.22 (d, J =
11.5 Hz, 1 H), 3.25–3.33 (m, 1 H), 3.34–3.41 (m, 1 H), 3.56 (d, J
= 11.5 Hz, 1 H), 3.76–3.88 (m, 1 H), 4.38–4.50 (m, 1 H), 6.66–6.78
(m, 2 H), 7.22–7.37 (m, 3 H), 7.69–7.78 (m, 1 H), 8.40–8.48 (m, 1
H), 11.29 (br. s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 33.8,
36.2, 41.6, 91.4 (q, J = 31.3 Hz), 121.3, 122.0, 125.2, 125.7, 131.7,
138.0, 146.6, 149.2, 158.2, 158.5 ppm. IR (KBr): ν = 3031, 2720,
˜
1611, 1587, 1477, 1420, 1343, 1197, 1142 cm–1. MS (ESI): m/z =
470 [M + H]+. HRMS (ESI): calcd. for C18H15ON3ClF6S 470.0505
[M + H]+; found 470.0523.
(Z)-3-tert-Butyl-2-[4-chloro-3-(trifluoromethyl)phenylimino]-4-(tri-
fluoromethyl)thiazolidin-4-ol (4o): Solid (361 mg, 86%), m.p. 80–
(Z)-N-(3-(Furan-2-ylmethyl)-4-{[3-(4-methoxyphenyl)isoxazol-5-
yl]methoxy}-4-(trifluoromethyl)thiazolidin-2-ylidene)aniline (9a): So-
1
82 °C. H NMR (CDCl3, 500 MHz): δ = 0.95 (t, J = 7.0 Hz, 3 H),
1.18–1.44 (m, 3 H), 1.57–1.84 (m, 2 H), 3.23 (d, J = 13.0 Hz, 1 H),
3.45–3.68 (m, 3 H), 7.00–7.06 (m, 1 H), 7.22–7.29 (m, 1 H), 7.36–
7.43 (m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 13.7, 20.2,
30.1, 35.1, 44.2, 91.0 (q, J = 32.4 Hz), 120.9, 121.2, 121.3, 123.0 (q,
J = 287.6 Hz), 124.5, 126.0, 126.4, 131.9, 149.3, 157.6 ppm. IR
1
lid (460 mg, 87%), m.p. 73–75 °C. H NMR (CDCl3, 500 MHz): δ
= 3.41 (d, J = 13.6 Hz, 1 H), 3.67 (d, J = 13.6 Hz, 1 H), 3.85 (s, 3
H), 4.45 (d, J = 12.8 Hz, 1 H), 4.69–4.79 (m, 2 H), 4.96 (d, J =
15.8 Hz, 1 H), 6.29–6.33 (m, 1 H), 6.41–6.45 (m, 1 H), 6.50 (s, 1
H), 6.92–7.02 (m, 4 H), 7.07–7.15 (m, 1 H), 7.28–7.38 (m, 3 H),
7.71–7.78 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 30.7,
40.2, 55.3, 56.8, 94.4 (q, J = 32.4 Hz), 101.1, 109.4, 110.5, 114.3,
121.0, 121.4, 124.0, 124.5, 128.1, 129.0, 130.2, 150.0, 150.1, 156.0,
161.0, 162.0, 167.3 ppm. 19F NMR (CDCl3, 500 MHz): δ = –78.19
(KBr): ν = 3078, 2667, 1607, 1582, 1496, 1350, 1182 cm–1. MS
˜
( ESI) : m/ z = 4 2 1 [ M + H ] + . H R M S ( E S I ) : c a l c d . fo r
C15H16ON2ClF6S 421.0556 [M + H]+; found 421.0570.
Procedure for Propargylation of 2-Imino-4-(trifluoromethyl)thiaz-
olidin-4-ol (7a and 7b): Propargyl bromide (1 mmol) was slowly
added to a stirred solution of 2-imino-4-(trifluoromethyl)thiazolidi-
nol 4b or 4j (1 mmol) and K2CO3 (2 equiv.) in DMF (5 mL), and
the reaction mixture was stirred at ambient temperature for 24 h.
After the reaction was complete, it was quenched with saturated
NaHCO3 solution (3–4 mL), and the mixture was extracted with
EtOAc (2ϫ 15 mL). The combined organic extracts were washed
with brine, dried (Na2SO4), filtered, and concentrated. The crude
product was purified by column chromatography using EtOAc/n-
hexane gradients to give pure product 7a or 7b.
(s, 3 F) ppm. IR (KBr): ν = 2962, 1633, 1593, 1531, 1433, 1256,
˜
1181 cm–1. MS (ESI): m/z = 530 [M + H]+. HRMS (ESI): calcd.
for C26H23O4N3F3S 530.1343 [M + H]+; found 530.1355.
(Z)-N-[3-(Furan-2-ylmethyl)-4-({3-[4-(trifluoromethoxy)phenyl]-
isoxazol-5-yl}methoxy)-4-(trifluoromethyl)thiazolidin-2-ylidene]-
aniline (9b): Viscous liquid (431 mg, 74 %). 1H NMR (CDCl3,
500 MHz): δ = 3.40 (d, J = 13.4 Hz, 1 H), 3.68 (d, J = 13.4 Hz, 1
H), 4.48 (d, J = 13.2 Hz, 1 H), 4.72 (d, J = 15.8 Hz, 1 H), 4.76 (d,
J = 13.2 Hz, 1 H), 4.98 (d, J = 15.8 Hz, 1 H), 6.29–6.34 (m, 1 H),
6.41–6.46 (m, 1 H), 6.55 (s, 1 H), 6.94–7.02 (m, 2 H), 7.07–7.15 (m,
1 H), 7.27–7.37 (m, 4 H), 7.44–7.55 (m, 1 H), 7.64–7.77 (m, 2 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 30.7, 40.0, 56.8, 94.4 (q, J
(Z)-N-[3-(Furan-2-ylmethyl)-4-(prop-2-ynyloxy)-4-(trifluorometh-
yl)thiazolidin-2-ylidene]aniline (7a): Viscous liquid (330 mg, 87%).
1H NMR (CDCl3, 500 MHz): δ = 2.50 (t, J = 2.4 Hz, 1 H), 3.47– = 32.4 Hz), 101.2, 109.4, 110.5, 116.8, 118.6, 119.3, 120.6, 121.3,
3.66 (m, 2 H), 4.09 (dd, J = 16.0, 2.4 Hz, 1 H), 4.24 (dd, J = 16.0,
2.4 Hz, 1 H), 4.72 (d, J = 16.0 Hz, 1 H), 4.85 (d, J = 16.0 Hz, 1
H), 6.28–6.36 (m, 1 H), 6.37–6.45 (m, 1 H), 6.91–7.00 (m, 2 H),
7.05–7.15 (m, 1 H), 7.23–7.40 (m, 3 H) ppm. 13C NMR (CDCl3,
122.0, 122.5, 124.0, 124.5, 125.1, 126.0, 128.3, 129.0, 130.0, 130.4,
141.7, 149.5, 149.9, 150.1, 156.0, 161.2, 168.2 ppm. 19F NMR
(CDCl3, 500 MHz): δ = –57.80 (s, 3 F), –78.12 (s, 3 F) ppm. IR
(Neat): ν = 2926, 1638, 1593, 1448, 1260, 1182 cm–1. MS (ESI): m/z
˜
2476
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2468–2479

Synthesis of 2-Imino-4-(trifluoromethyl)thiazolidin-4-ols
= 584 [M + H]+. HRMS (ESI): calcd. for C26H20O4N3F6S 584.1066
[M + H]+; found 584.1073.
(Z)-N-(3-Chloro-4-fluorophenyl)-2-[4-({3-(furan-2-ylmethyl)-4-(tri-
fluoromethyl)-2-[4-(trifluoromethyl)phenylimino]thiazolidin-4-
yloxy}methyl)-1H-1,2,3-triazol-1-yl]acetamide (11a): Solid (594 mg,
(Z)-N-[3-(Furan-2-ylmethyl)-4-(trifluoromethyl)-4-({3-[4-(trifluoro-
methylthio)phenyl]isoxazol-5-yl}methoxy)thiazolidin-2-ylidene]-
aniline (9c): Viscous liquid (455 mg, 76 %). 1H NMR (CDCl3,
500 MHz): δ = 3.41 (d, J = 13.4 Hz, 1 H), 3.70 (d, J = 13.4 Hz, 1
H), 4.49 (d, J = 13.2 Hz, 1 H), 4.68–4.82 (m, 2 H), 4.99 (d, J =
15.8 Hz, 1 H), 6.29–6.34 (m, 1 H), 6.41–6.46 (m, 1 H), 6.58 (s, 1
H), 6.94–7.01 (m, 2 H), 7.07–7.15 (m, 1 H), 7.28–7.38 (m, 3 H),
7.72–7.80 (m, 2 H), 7.83–7.91 (m, 2 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 30.8, 40.0, 56.8, 101.3, 109.5, 110.5, 121.4, 124.0,
127.7, 128.7, 129.0, 131.0, 136.6, 141.7, 149.9, 150.1, 155.9, 161.3,
168.3 ppm. 19F NMR (CDCl3, 500 MHz): δ = –42.20 (s, 3 F),
1
88%), m.p. 64–66 °C. H NMR (CDCl3, 500 MHz): δ = 3.54 (d, J
= 13.6 Hz, 1 H), 3.70 (d, J = 13.6 Hz, 1 H), 4.55 (d, J = 12.0 Hz,
1 H), 4.71 (d, J = 15.8 Hz, 1 H), 4.79–4.95 (m, 2 H), 5.15–5.29 (m,
2 H), 6.29–6.33 (m, 1 H), 6.36–6.41 (m, 1 H), 7.02–7.12 (m, 3 H),
7.24–7.33 (m, 2 H), 7.54–7.61 (m, 2 H), 7.65–7.71 (m, 1 H), 7.77
(s, 1 H), 8.37 (br. s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
30.6, 40.1, 53.1, 57.2, 94.4 (q, J = 31.8 Hz), 109.4, 110.6, 116.6 (d,
J = 21.9 Hz), 119.8 (d, J = 7.1 Hz), 120.6, 121.7, 122.3, 125.0, 126.3
(d, J = 3.3 Hz), 133.5 (d, J = 2.7 Hz), 141.7, 143.7, 149.9, 153.0,
155.0 (d, J = 247.5 Hz), 157.1, 163.1 ppm. 19F NMR (CDCl3,
500 MHz): δ = –61.70 (s, 3 F), –78.27 (s, 3 F), –118.67 (s, 1 F) ppm.
–78.01 (s, 3 F) ppm. IR (Neat): ν = 2923, 1634, 1592, 1429, 1261,
IR (KBr): ν = 3287, 2956, 1639, 1501, 1260, 1182, 1062 cm–1. MS
˜
˜
1183, 1117, 1085 cm–1. MS (ESI): m/z = 600 [M + H]+. HRMS
(ESI): calcd. for C26H20O3N3F6S2 600.0841 [M + H]+; found
600.0844.
( E S I ) : m/ z = 6 7 7 [ M + H ] + . H R M S ( E S I ) : c a l c d . fo r
C27H21O3N6ClF7S 677.0968 [M + H]+; found 677.0967.
(Z)-N-(4-Fluorophenyl)-2-[4-({3-(furan-2-ylmethyl)-4-(trifluoro-
methyl)-2-[4-(trifluoromethyl)phenylimino]thiazolidin-4-yl-
oxy}methyl)-1H-1,2,3-triazol-1-yl]acetamide (11b): Solid (545 mg,
(Z)-N-(4-{[3-(4-Bromophenyl)isoxazol-5-yl]methoxy}-3-(furan-2-
ylmethyl)-4-(trifluoromethyl)thiazolidin-2-ylidene)aniline (9d): Solid
(473 mg, 82%), m.p. 96–98 °C;1H NMR (CDCl3, 500 MHz): δ =
3.40 (d, J = 13.6 Hz, 1 H), 3.69 (d, J = 13.6 Hz, 1 H), 4.46 (d, J =
13.6 Hz, 1 H), 4.72 (d, J = 15.8 Hz, 1 H), 4.75 (d, J = 13.6 Hz, 1
H), 4.98 (d, J = 15.8 Hz, 1 H), 6.29–6.34 (m, 1 H), 6.41–6.46 (m,
1 H), 6.53 (s, 1 H), 6.94–7.01 (m, 2 H), 7.07–7.16 (m, 1 H), 7.29–
7.37 (m, 3 H), 7.57–7.72 (m, 4 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 30.8, 40.0, 56.8, 94.4 (q, J = 32.4 Hz), 101.1, 109.5,
110.5, 121.4, 124.0, 124.5, 127.5, 128.3, 129.0, 132.2, 141.7, 149.9,
1
85%), m.p. 86–88 °C. H NMR (CDCl3, 500 MHz): δ = 3.55 (d, J
= 13.3 Hz, 1 H), 3.69 (d, J = 13.3 Hz, 1 H), 4.55 (d, J = 12.3 Hz,
1 H), 4.72 (d, J = 16.1 Hz, 1 H), 4.83 (d, J = 12.3 Hz, 1 H), 4.91
(d, J = 16.1 Hz, 1 H), 5.15–5.24 (m, 2 H), 6.28–6.32 (m, 1 H), 6.37–
6.40 (m, 1 H), 6.98–7.08 (m, 4 H), 7.28–7.31 (m, 1 H), 7.40–7.46
(m, 2 H), 7.52–7.58 (m, 2 H), 7.74 (s, 1 H), 8.02 (br. s, 1 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 30.6, 40.2, 53.3, 57.3, 94.4 (q, J
= 31.3 Hz), 109.4, 110.5, 115.8 (d, J = 22.5 Hz), 121.7, 122.0 (d, J
= 8.2 Hz), 124.8, 126.3, 132.7, 141.7, 143.8, 150.0, 153.0, 157.0,
159.8 (d, J = 245.3 Hz), 162.9 ppm. 19F NMR (CDCl3, 500 MHz):
δ = –61.77 (s, 3 F), –78.34 (s, 3 F), –116.15 (s, 1 F) ppm. IR (KBr):
150.1, 156.0, 161.5, 168.0 ppm. IR (KBr): ν = 3139, 3004, 1632,
˜
1592, 1431, 1260, 1180, 696 cm–1. MS (ESI): m/z = 578 [M + H]+.
HRMS (ESI): calcd. for C25H20O3N3BrF3S 578.0353 [M + H]+;
found 578.0355.
ν = 3300, 2929, 1639, 1510, 1259, 1182, 1063 cm–1. MS (ESI): m/z
˜
= 643 [M + H]+. HRMS (ESI): calcd. for C27H22O3N6F7S 643.1345
[M + H]+; found 643.1365.
(Z)-N-(4-{[3-(2-Fluorophenyl)isoxazol-5-yl]methoxy}-3-(furan-2-
ylmethyl)-4-(trifluoromethyl)thiazolidin-2-ylidene)aniline (9e): Solid
1
(413 mg, 80%), m.p. 79–81 °C. H NMR (CDCl3, 500 MHz): δ =
(Z)-N-Cyclohexyl-2-[4-({3-(furan-2-ylmethyl)-4-(trifluoromethyl)-
2-[4-(trifluoromethyl)phenylimino]thiazolidin-4-yloxy}methyl)-1H-
1,2,3-triazol-1-yl]acetamide (11c): (585 mg, 93%). Solid, m.p. 68–
70 °C. 1H NMR (CDCl3, 500 MHz): δ = 1.05–1.22 (m, 2 H), 1.24–
1.41 (m, 2 H), 1.48–1.98 (m, 6 H), 3.57 (d, J = 13.0 Hz, 1 H), 3.68
(d, J = 13.0 Hz, 1 H), 3.72–3.82 (m, 1 H), 4.53 (d, J = 12.0 Hz, 1
H), 4.74 (d, J = 16.0 Hz, 1 H), 4.82 (d, J = 12.0 Hz, 1 H), 4.89 (d,
J = 16.0 Hz, 1 H), 4.96–5.07 (m, 2 H), 5.93 (s, 1 H), 6.30–6.35 (m,
1 H), 6.37–6.44 (m, 1 H), 7.01–7.12 (m, 2 H), 7.30–7.34 (m, 1 H),
7.52–7.63 (m, 2 H), 7.71 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 24.6, 25.2, 30.6, 32.6, 40.1, 48.9, 53.1, 57.5, 94.4 (q, J =
30.7 Hz), 109.3, 110.5, 121.7, 124.3, 126.2, 126.3, 141.7, 143.8,
3.43 (d, J = 13.4 Hz, 1 H), 3.70 (d, J = 13.4 Hz, 1 H), 4.48 (d, J =
13.2 Hz, 1 H), 4.74 (d, J = 15.8 Hz, 1 H), 4.77 (d, J = 13.2 Hz, 1
H), 4.98 (d, J = 15.8 Hz, 1 H), 6.31–6.35 (m, 1 H), 6.42–6.46 (m,
1 H), 6.71 (d, J = 3.6 Hz, 1 H), 6.95–7.00 (m, 2 H), 7.07–7.38 (m,
6 H), 7.40–7.50 (m, 1 H), 7.95–8.03 (m, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 30.8, 40.0, 56.7, 94.5 (q, J = 31.8 Hz), 104.0
(d, J = 9.3 Hz), 109.5, 110.5, 116.4 (d, J = 21.9 Hz), 121.4, 124.0,
124.6 (d, J = 3.8 Hz), 129.0, 131.8 (d, J = 8.8 Hz), 141.7, 150.0,
150.2, 156.1, 157.8, 161.9, 167.3 ppm. 19F NMR (CDCl3,
500 MHz): δ = –78.14 (s, 3 F), –114.31 (s, 1 F) ppm. IR (KBr): ν
˜
= 2926, 1633, 1591, 1470, 1258, 1178 cm–1. MS (ESI): m/z = 518
[M + H]+. HRMS (ESI): calcd. for C25H20O3N3F4S 518.1147 [M
+ H]+; found 518.1156.
150.0, 153.0, 157.0, 163.7 ppm. IR (KBr): ν = 3305, 2935, 1642,
˜
1553, 1257, 1185, 1060 cm–1. MS (ESI): m/z = 631 [M + H]+.
HRMS (ESI): calcd. for C27H28O3N6F6NaS 653.1721 [M + Na]+;
found 653.1740.
Typical Procedure for the Synthesis Triazole Derivatives 11a–11e of
2-Imino-4-(trifluoromethyl)thiazolidinol: CuI (10 mol-%) was added
to a stirred solution of alkyne 7b (1 mmol) in dry tetrahydrofuran
(Z)-2-[4-({3-(Furan-2-ylmethyl)-4-(trifluoromethyl)-2-[4-(trifluoro-
(5 mL). The mixture was stirred for 5–10 min at room temperature methyl)phenylimino]thiazolidin-4-yloxy}methyl)-1H-1,2,3-triazol-1-
under a nitrogen atmosphere, then a solution of azide 10 (1 mmol)
in dry THF (2 mL) was added. Stirring was continued for 24 h at
the same temperature. After TLC indicated that the reaction was
complete, the reaction was quenched with saturated NH4Cl solu-
tion (1–2 mL), then the mixture was diluted with water and ex-
tracted with ethyl acetate (3ϫ 10 mL). The combined organic ex-
tracts were washed with brine, dried (Na2SO4), filtered, and con-
centrated. The crude product was purified by column chromatog-
raphy using ethyl acetate/n-hexane gradients to give triazole deriva-
tive 11 as a pure product (Table 4).
yl]-N-(thiophen-2-ylmethyl)acetamide (11d): Viscous liquid (579 mg,
90%). 1H NMR (CDCl3, 500 MHz): δ = 3.54 (d, J = 13.6 Hz, 1
H), 3.67 (d, J = 13.6 Hz, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.62 (d,
J = 5.3 Hz, 2 H), 4.67–4.95 (m, 3 H), 5.00–5.13 (m, 2 H), 6.28–
6.34 (m, 1 H), 6.37–6.41 (m, 1 H), 6.46 (s, 1 H), 6.90–6.98 (m, 2
H), 7.01–7.11 (m, 2 H), 7.19–7.34 (m, 2 H), 7.52–7.62 (m, 2 H),
7.70 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 30.5, 38.3,
40.1, 52.6, 57.3, 109.2, 110.5, 121.7, 122.5, 124.6, 125.3, 126.3,
126.9, 139.6, 141.6, 143.6, 150.0, 153.0, 157.1, 164.7 ppm. IR
(Neat): ν = 3301, 2932, 1645, 1551, 1250, 1182, 1060 cm–1. MS
˜
Eur. J. Org. Chem. 2014, 2468–2479
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2477

R. M. Kumbhare et al.
FULL PAPER
( ESI) : m/ z = 6 4 5 [ M + H ] + . H R M S ( E S I ) : c a l c d . fo r
(d, J = 15.6 Hz, 1 H), 4.27 (d, J = 15.6 Hz, 1 H), 4.72 (d, J =
16.0 Hz, 1 H), 4.84 (d, J = 16.0 Hz, 1 H), 6.30–6.34 (m, 1 H), 6.38–
6.42 (m, 1 H), 6.59–6.71 (m, 2 H), 6.90–7.01 (m, 2 H), 7.05–7.15
(m, 1 H), 7.24–7.40 (m, 3 H), 7.43–7.54 (m, 1 H), 8.15–8.25 (m, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 30.1, 40.0, 44.7, 46.8,
51.4, 51.9, 80.2, 81.5, 94.2 (q, J = 31.8 Hz), 107.0, 108.9, 110.3,
113.3, 121.3, 122.5 (q, J = 287.6 Hz), 123.2, 123.7, 128.8, 129.5,
137.4, 141.4, 144.4, 147.6, 150.0, 150.2, 156.3, 159.0, 169.0 ppm.
C26H23O3N6F6S2 645.1155 [M + H]+; found 645.1171.
(Z)-2-[4-({3-(Furan-2-ylmethyl)-4-(trifluoromethyl)-2-[4-(trifluoro-
methyl)phenylimino]thiazolidin-4-yloxy}methyl)-1H-1,2,3-triazol-1-
yl]-N-(4-methoxyphenyl)acetamide (11e): Solid (595 mg, 91%), m.p.
1
76–78 °C. H NMR (CDCl3, 500 MHz): δ = 3.54 (d, J = 13.6 Hz,
1 H), 3.68 (d, J = 13.6 Hz, 1 H), 3.77 (s, 3 H), 4.52 (d, J = 12.0 Hz,
1 H), 4.68–4.95 (m, 3 H), 5.12–5.26 (m, 2 H), 6.28–6.32 (m, 1 H),
6.36–6.40 (m, 1 H), 6.80–6.88 (m, 2 H), 7.01–7.10 (m, 2 H), 7.28–
7.42 (m, 3 H), 7.52–7.60 (m, 2 H), 7.78 (s, 1 H), 8.12 (s, 1 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 30.5, 40.1, 53.2, 55.3, 57.3, 94.4
(q, J = 32.5 Hz), 109.3, 110.5, 114.1, 121.7, 122.0, 124.8, 126.3,
129.7, 141.7, 143.7, 150.0, 153.0, 157.0, 157.1, 162.9 ppm. 19F
NMR (CDCl3, 500 MHz): δ = –61.81 (s, 3 F), –78.42 (s, 3 F) ppm.
IR (Neat): ν = 2924, 1632, 1590, 1508, 1457, 1325, 1178, 1136 cm–1.
˜
MS (ESI): m/z = 556 [M + H]+. HRMS (ESI): calcd. for
C28H29O2N5F3S 556.1976 [M + H]+; found 556.1966.
(Z)-N-{3-(Furan-2-ylmethyl)-4-[4-(piperidin-1-yl)but-2-ynyloxy]-4-
(trifluoromethyl)thiazolidin-2-ylidene}aniline (13d): Viscous liquid
1
(424 mg, 89%). H NMR (CDCl3, 500 MHz): δ = 1.47–1.68 (m, 5
IR (KBr): ν = 3291, 2930, 1639, 1552, 1249, 1180, 1062 cm–1
.
˜
H), 2.32–2.55 (m, 5 H), 3.27 (s, 2 H), 3.56 (s, 2 H), 4.13 (d, J =
16.0 Hz, 1 H), 4.26 (d, J = 16.0 Hz, 1 H), 4.73 (d, J = 16.0 Hz, 1
H), 4.82 (d, J = 16.0 Hz, 1 H), 6.29–6.34 (m, 1 H), 6.37–6.42 (m,
1 H), 6.90–7.00 (m, 2 H), 7.04–7.12 (m, 1 H), 7.24–7.39 (m, 3 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 23.7, 25.7, 30.1, 40.1, 47.7,
52.0, 53.3, 79.3, 82.8, 94.3 (q, J = 31.8 Hz), 108.9, 110.3, 121.3,
122.5 (q, J = 287.0 Hz), 123.7, 128.8, 141.4, 150.1, 150.3,
156.3 ppm. 19F NMR (CDCl3, 500 MHz): δ = –78.72 (s, 3 F) ppm.
MS (ESI): m/z = 655 [M + H]+. HRMS (ESI): calcd. for
C28H25O4N6F6S 655.1544 [M + H]+; found 655.1556.
Typical Procedure for the Synthesis of Propargylamine Derivatives
13a–13e of 2-Imino-4-(trifluoromethyl)thiazolidinol: CuI (10 mol-%)
was added to a stirred solution of alkyne 7a (1 mmol) in tetra-
hydrofuran (5 mL). The mixture was stirred for 15–20 min at room
temperature, then formaldehyde (1.5 equiv.) and secondary cyclic
amine 12 (1 mmol) were added. Stirring was continued for 4–6 h at
the same temperature. After TLC indicated that the reaction was
complete, the reaction was quenched with saturated NH4Cl solu-
tion (1–2 mL). The mixture was diluted with water and extracted
with ethyl acetate (2ϫ 15 mL). The combined organic extracts were
washed with brine, dried (Na2SO4), filtered, and concentrated. The
crude product was purified by column chromatography using ethyl
acetate/n-hexane gradients to give propargylamine 13 as a pure
product (Table 5).
IR (Neat): ν = 2925, 1638, 1593, 1496, 1447, 1235, 1182 cm–1. MS
˜
( E S I ) : m/ z = 4 7 8 [ M + H ] + . H R M S ( E S I ) : c a l c d . fo r
C24H27O2N3F3S 478.1755 [M + H]+; found 478.1748.
(Z)-N-(4-{4-[4-(4-Fluorophenyl)piperazin-1-yl]but-2-ynyloxy}-3-
(furan-2-ylmethyl)-4-(trifluoromethyl)thiazolidin-2-ylidene)aniline
(13e): Viscous liquid (491 mg, 86%). 1H NMR (CDCl3, 500 MHz):
δ = 2.66–2.77 (m, 4 H), 3.07–3.20 (m, 4 H), 3.34–3.44 (m, 2 H),
3.49–3.63 (m, 2 H), 4.14 (d, J = 15.8 Hz, 1 H), 4.29 (d, J = 15.8 Hz,
1 H), 4.74 (d, J = 15.8 Hz, 1 H), 4.84 (d, J = 15.8 Hz, 1 H), 6.30–
6.36 (m, 1 H), 6.38–6.44 (m, 1 H), 6.81–7.03 (m, 6 H), 7.05–7.16
(m, 1 H), 7.24–7.42 (m, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 30.1, 40.2, 46.9, 49.8, 51.8, 51.9, 79.9, 81.9, 94.2 (q, J = 31.9 Hz),
108.9, 110.3, 115.3 (d, J = 22.0 Hz), 117.7 (d, J = 7.1 Hz), 121.3,
123.7, 128.8, 141.4, 147.6, 150.0, 150.3, 156.2, 157.0 (d, J =
238.8 Hz) ppm. 19F NMR (CDCl3, 500 MHz): δ = –78.60 (s, 3 F),
(Z)-N-[3-(Furan-2-ylmethyl)-4-(4-morpholinobut-2-ynyloxy)-4-(tri-
fluoromethyl)thiazolidin-2-ylidene]aniline (13e): Viscous liquid
1
(431 mg, 90%). H NMR (CDCl3, 500 MHz): δ = 2.45–2.60 (m, 4
H), 3.29–3.36 (m, 2 H), 3.64–3.77 (m, 6 H), 4.13 (d, J = 15.7 Hz,
1 H), 4.28 (d, J = 15.7 Hz, 1 H), 4.74 (d, J = 15.8 Hz, 1 H), 4.82
(d, J = 15.8 Hz, 1 H), 6.30–6.35 (m, 1 H), 6.38–6.42 (m, 1 H), 6.90–
6.98 (m, 2 H), 7.05–7.12 (m, 1 H), 7.26–7.38 (m, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 30.4, 39.7, 47.3, 51.8, 52.2, 66.8, 79.9,
81.8, 94.3 (q, J = 31.8 Hz), 109.0, 110.3, 121.4, 122.5 (q, J =
287.0 Hz), 123.8, 128.9, 141.5, 150.0, 150.3, 156.3 ppm. IR (Neat):
–124.30 (s, 1 F) ppm. IR (Neat): ν = 2926, 1635, 1592, 1510, 1454,
˜
1320, 1181 cm–1. MS (ESI): m/z = 573 [M + H]+. HRMS (ESI):
calcd. for C29H29O2N4F4S 573.1933 [M + H]+; found 573.1941.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of products 4a–4o, 7a,
7b, 9a–9e, 11a–11e, and 13a–13e; X-ray data of compound 4d are
provided in the CIF file.
ν = 2931, 1630, 1596, 1512, 1451, 1321, 1183, 1130 cm–1. MS (ESI):
˜
m/z = 480 [M + H]+. HRMS (ESI): calcd. for C23H25O3N3F3S
480.1546 [M + H]+; found 480.1563.
(Z)-N-(3-(Furan-2-ylmethyl)-4-{4-[4-(2-methoxyphenyl)piperazin-
1-yl]but-2-ynyloxy}-4-(trifluoromethyl)thiazolidin-2-ylidene)aniline
(13b): Viscous liquid (537 mg, 92%). 1H NMR (CDCl3, 500 MHz):
δ = 2.77 (t, J = 4.5 Hz, 4 H), 3.02–3.20 (m, 4 H), 3.38–3.43 (m, 2
H), 3.54–3.59 (m, 2 H), 3.85 (s, 3 H), 4.14 (d, J = 15.8 Hz, 1 H),
4.29 (d, J = 15.8 Hz, 1 H), 4.74 (d, J = 15.8 Hz, 1 H), 4.84 (d, J =
15.8 Hz, 1 H), 6.31–6.36 (m, 1 H), 6.38–6.43 (m, 1 H), 6.82–7.15
(m, 7 H), 7.24–7.41 (m, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 30.2, 40.2, 47.2, 50.4, 52.1, 52.2, 55.3, 79.9, 82.3, 94.3 (q, J =
31.8 Hz), 109.0, 110.4, 111.0, 118.2, 120.9, 121.5, 123.0, 123.8,
Acknowledgments
The authors are grateful to Dr. J. S. Yadav, Former Director, IICT
for providing facilities. T. D. thanks the University Grants Com-
mitee (UGC), New Delhi, and A. N. and U. K. thank the Council
of Scientific and Industrial Research (CSIR), New Delhi for the
award of fellowships. R. M. K. thanks the Department of Sci-
ence & Technology, SERC, Government of India for financial as-
sistance under the Fast Track Scheme for young scientists (SR/FT/
CS-031/2010).
128.9, 141.0, 141.6, 150.2, 150.4, 152.2, 156.4 ppm. IR (Neat): ν =
˜
2927, 1636, 1590, 1498, 1449, 1239, 1179 cm–1. MS (ESI): m/z =
585 [M + H]+. HRMS (ESI): calcd. for C30H32O3N4F3S 585.2135
[M + H]+; found 585.2141.
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Received: November 13, 2013
Published Online: February 26, 2014
Eur. J. Org. Chem. 2014, 2468–2479
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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