Synthesis of Novel Thiazolidin-4-ones and Thiazinan-4-ones Analogous to Rosiglitazone

Article abstract of DOI:10.1002/jhet.3402

This work reports the synthesis of thiazolidin-4-ones and thiazinan-4-ones analogous to rosiglitazone, a potent antidiabetic drug. The desired compounds were synthesized with moderate to good yields by one-pot reactions between different primary amines, mercaptoacetic or mercaptopropionic acids, and the 4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzaldehyde. The cyclocondensation reactions were carried out for 20?h, and all the products were characterized by ¹H and ¹³C nuclear magnetic resonance spectroscopy, mass spectrometry, and one example by X-ray diffraction.

Full text of DOI:10.1002/jhet.3402

Month 2018
Synthesis of Novel Thiazolidin-4-ones and Thiazinan-4-ones Analogous
to Rosiglitazone
Adriana M. das Neves,a José C. Campos,a
Daniela P. Gouvêa,b Gabriele A. Berwaldt,a Taís B. Goulart,a
a
c
d
a
*
Cinara T. Avila, Pablo Machado, Geórgia C. Zimmer, and Wilson Cunico
aLaQuiABio, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campos
Universitário s/no, 96010-900 Pelotas, RS, Brazil
bMESOLab, Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianopolis, SC, Brazil
cInstituto Nacional de Ciência e Tecnologia em Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul,
90619-900 Porto Alegre, RS, Brazil
dNúcleo de Química de Heterociclos (NUQUIMHE) Department of Chemistry, Federal University of Santa Maria
(UFSM), CEP 97105-900 Santa Maria, RS, Brazil
*E-mail: wjcunico@yahoo.com.br
Received August 3, 2018
DOI 10.1002/jhet.3402
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
This work reports the synthesis of thiazolidin-4-ones and thiazinan-4-ones analogous to rosiglitazone, a
potent antidiabetic drug. The desired compounds were synthesized with moderate to good yields by one-
pot reactions between different primary amines, mercaptoacetic or mercaptopropionic acids, and the 4-(2-
(methyl(pyridin-2-yl)amino)ethoxy)benzaldehyde. The cyclocondensation reactions were carried out for
20 h, and all the products were characterized by 1H and 13C nuclear magnetic resonance spectroscopy, mass
spectrometry, and one example by X-ray diffraction.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
Thiazolidinedione (TZD) is an important class of
heterocycles, because of its unique benefits for the
treatment of insulin resistance and type II diabetes. TZDs
target the nuclear receptor peroxisome proliferator
activated receptor gamma and include rosiglitazone,
pioglitazone, and troglitazone drugs (Fig. 1) [3].
It is reported that TZDs have three important interactions
for the activation of the receptor peroxisome proliferator
activated receptor gamma. Based on the ligand–protein
interactions, different features were assigned to the
rosiglitazone molecule that include (i) two hydrogen
bond acceptor features corresponding to the two
carbonyls of TZD ring and one hydrogen bond donor,
Diabetes is a major health concern, especially in
developing countries. According to the World Health
Organization, more than 180 million people have
diabetes, and this number is expected to reach 366
million in 2030 [1]. The main characteristic of diabetes is
hyperglycemia, and it can be diagnosed as type 1 or type
2. Type-1 diabetes results from chronically low insulin
secretion. Type-2 diabetes is a heterogeneous group of
disorders that are characterized by varying degrees of
insulin resistance, a decrease in insulin secretion, and an
increase in glucose production [2].
© 2018 Wiley Periodicals, Inc.

A. M. das Neves, J. C. Campos, D. P. Gouvêa, G. A. Berwaldt, T. B. Goulart, C. T. Avila,
P. Machado, G. C. Zimmer, and W. Cunico
Vol 000
Figure 1. Chemical structures of antidiabetic drugs pioglitazone, rosiglitazone, and troglitazone and similarity of the chemical structures of the com-
pounds synthesized with the drug rosiglitazone. [Color figure can be viewed at wileyonlinelibrary.com]
related to the –NH of the TZD ring, (ii) a hydrophobic
aromatic feature was assigned to the central aromatic
region, and (iii) a hydrophobic aromatic feature was also
assigned to the pyridine ring in the lipophilic side chain [4].
Rosiglitazone (Avandia, GlaxoSmithKline) was initially
approved in 1999 to treat hyperglycemia in patients with
type-2 diabetes. Original approval was based on the
ability of the drug to lower glycemia and glycosylated
hemoglobin levels. However, this drug was associated
with a significant increase in the risk of myocardial
infarction and increased risk of death from cardiovascular
causes, and for this reason, the Food and Drug
Administration removed rosiglitazone from the market in
2010 [4–6].
inflammatory, antimalarial, and antibacterial agents [10–
14].
Furthermore, some studies reported the synthesis of
analogues of TDZ by performing the changing of TZD
by thiazolidinone nucleus, as shown by Patel et al. [15]
who reported the synthesis of thiazolidinone analogous to
pioglitazone and as shown by Raza et al. [14] that
reported the synthesis of thiazolidinone and thiazinanone
analogous to rosiglitazone with significant anti-
hyperglycemic activity.
The strategy to synthesize thiazinanones is very similar
to the strategy to synthesize thiazolidinones [16]. The
main synthetic route reported in literature involves three
components: an aldehyde,
a primary amine, and
Because of this, continuous efforts are needed to design
and discover new safe drugs for this therapeutic target. In
this context, heterocyclic nucleus have a major role in the
field of medicinal chemistry, and they are a key template
for the genesis of various therapeutic agents. The
majority of drugs in the market have at least one
heterocyclic nucleus in their structures [4,7,8].
mercaptoacetic acid. New derivatives of 4-thiazolidinones
have been obtained by modifications of the 2-position, 3-
position, and 5-position [9,17–20].
In the present work, our aim is to generate novel
thiazolidin-4-ones and novel thiazinan-4-ones analogous
to rosiglitazone, from the reaction of aldehyde
(containing the rosiglitazone scaffold), primary amines,
and mercaptocarboxilic acid. The amines are aromatic or
aliphatic and contain heterocyclic rings (five or six
membered) in their structures. Because thiazolidin-4-ones
and thiazinan-4-ones are similar to TZD, this work
targets the contribution to the limited therapeutic arsenal
for the treatment of type-2 diabetes, searching for new
candidates to drugs (Fig. 1).
The aldehyde precursor was prepared in two steps using
the microwave methodology (MO) according to Gaonkar
et al. [21] as outlined in Scheme 1. In the first step, the
aromatic nucleophilic substitution reaction between 2-
chloropyridine 1 and 2-(N-methylamino)ethanol 2 led to
the 2-(methylpyridin-2-yl)aminoethanol 3. In a second
The TZD heterocycle has a structural similarity to
thiazolidin-4-one and thiazinan-4-one because it contains
nitrogen, sulfur, and
a
carbonyl group. These
heterocycles differ in number of carbonyl groups and ring
size. The thiazolidinone (five-membered heterocycle) is a
versatile scaffold that has occupied a prominent position
in the medicinal chemistry. Numerous studies describe a
wide range of pharmacological properties of
thiazolidinones: anti-HCV, anti-HIV, antitumoral,
antifungal,
tuberculostatic,
and
antioxidant.[9]
Thiazinanones (six-membered heterocycle) are less
common in the literature; however, they also show major
biological properties as immune potentiating, anti-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Thiazolidin-4-ones and Thiazinan-4-ones Analogous
to Rosiglitazone
Scheme 1. Synthesis of 4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzaldehyde 5.
step, compound 3 reacts with 4-fluorobenzaldehyde 4
through the aromatic nucleophilic substitution reaction,
using potassium hydroxide and tetrabutylammonium
hydrogen sulfate as phase transfer catalyst (Scheme 1).
The compound 4-(2-(methyl(pyridin-2-yl)amino)ethoxy)
benzaldehyde 5 was obtained after purification by column
chromatography using silica gel and solution of
hexane/ethyl acetate (7:3) as eluent.
Compounds 3 and 5 were characterized and confirmed by
mass spectrometry and nuclear magnetic resonance (1H
and 13C NMR).
Thus,
4-(2-(methyl(2-pyridinyl)amino)ethoxy)
benzaldehyde 5 was used as precursor to synthesize
thiazolidin-4-ones 9a–l and thiazinan-4-ones 10a–g by
standard thermal heating methodology via one-pot
multicomponent reactions. The syntheses were carried out
by the carbonyl addition/elimination reaction between
aldehyde 5 and different amines 6 followed by a
RESULTS AND DISCUSSION
cyclocondensation
reaction
with
corresponding
mercaptocarboxilic acid 8a or 8b (Scheme 2). The
reactions were monitored by TLC with a solution of
hexane/ethyl acetate (7:3), and after formation of imine
intermediate 7, an excess of mercaptocarboxylic acid 8a
or 8b was added after 2 h to obtain products 9 and 10
through intramolecular cyclization for 18 h. The primary
amines used are aliphatic or aromatic and may contain
rings with heteroatoms. This factor shows the diversity
that the effect of these groups may have on biological
activity. The literature reported that different reaction
times are needed according to amine [22–25]; however,
all compounds were obtained in the same reaction times
in this work (18 h). The thiazolidin-4-ones 9a–l and
thiazinan-4-ones 10–g were purified by column
chromatography using as adsorbent, the silica gel (0.2–
The aldehyde precursor was prepared in two steps using
the microwave methodology (MO) according to Gaonkar
et al. [21] as outlined in Scheme 1. In the first step, the
aromatic nucleophilic substitution reaction between 2-
chloropyridine
produced the 2-(methylpyridin-2-yl)aminoethanol 3. In a
second step, compound reacts with 4-
fluorobenzaldehyde through aromatic nucleophilic
1
and 2-(N-methylamino)ethanol
2
3
4
substitution reaction, using potassium hydroxide and
tetrabutylammonium hydrogen sulfate as phase transfer
catalyst (Scheme 1). Compound 4-(2-(methyl (pyridin-2-
yl)amino)ethoxy)benzaldehyde
5 was obtained after
purification by column chromatography using silica gel
and solution of hexane/ethyl acetate (7:3) as eluent.
Scheme 2. Synthesis of thiazolidin-4-ones 9a–l and thiazinan-4-ones 10–g.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. M. das Neves, J. C. Campos, D. P. Gouvêa, G. A. Berwaldt, T. B. Goulart, C. T. Avila,
P. Machado, G. C. Zimmer, and W. Cunico
Vol 000
0.5 mm) and as eluent, a solution of hexane/ethyl acetate
(8:2 to 1:1), and yields ranged from 18% to 76% and
16% to 84%, respectively. A possible explanation for
some low yields may be the laborious purification step.
Compounds 3, 5, 9a–l, and 10–g were characterized,
and their chemical structures were confirmed by mass
spectrometry and NMR (1H and 13C). The analytical
spectral data for all compounds are in full agreement with
the proposed structure, and in this work, two-dimensional
NMR techniques were used to help assign the signals of
the compounds correctly. Compound 9d was also
characterized by single crystal X-ray diffraction, and the
ORTEP[26] diagram is depicted in Figure 2.
C15, plus C16 for thiazin-4-one. The most deshielded
carbon in the spectrum is the carbonyl group C14
(169.3–171.6 ppm), and asymmetric C13 appears around
61.7–63.9 ppm for both heterocycles. The thiazolidin-4-
one is assigned to C15 in the region of 29.8–33.1 ppm
and thiazinan-4-one in the region of 34.4–34.6 ppm. For
thiazinan-4-one, the C16 appears in the region of 21.9–
21.7 ppm. Other spectral signals of the product belong to
the amines and the aldehyde 5 cores.
Two-dimensional NMR experiments help the correct
assignment of signals for thiazinan-4-ones. In the HMBC
of thiazinan-4-one 10f, the coupling of H13 can only be
verified with C16. In the HSQC, it was possible to verify
the coupling of diastereopic hydrogens H15 and H16
with their corresponding C15 and C16 carbons.
1
In the H NMR spectrum, the signals that confirm the
formation of thiazolidin-4-one and thiazinan-4-one are the
asymmetric carbon –CH and the diastereotopic hydrogens
of heterocyclic rings. Hydrogen H13 appears with
chemical displacement around 5.35–5.85 ppm as singlet or
doublet (4J with H15a). The diastereotopic hydrogens H15a
and H15b appear with doublet (2J), double doublet (2J and
4J), or multiplet signals with chemical displacement around
3.59–3.83 ppm. For thiazinan-4-one ring, the diastereotopics
H15a, H15b, H16a, and H16b appear more shielded as
double doublet or multiplet with chemical displacement
around 2.58–3.82 ppm.
The HRMS was performed for six compounds (9a, 9b,
9f, 10a, 10b, and 10f) and shows interesting results. The
molecular ion was identified in all spectra; however, a
second peak with m/z equal to a half of molecular ion
was also observed for all compounds (see Supporting
Information).
CONCLUSION
1
In the H NMR spectrum, the signals that confirm the
In conclusion, the method was efficient to obtain 12
novel thiazonan-4-one and seven novel thiazinan-4-one
analogues to rosiglitazone. No influence of kind of amine
(aliphatic or aromatic) or mercaptocarboxilic acid was
observed, and the time was the same for all reactions.
The synthesis of aldehyde 5 was a critical step
necessitating a longer reaction time in microwave (1.5 h),
different from that described by Gaonkar et al. [21] The
yields for the thiazolidi-4-ones and thiazinan-4-ones were
moderate to good, because a purification step by
chromatographic column was required.
formation of thiazolidin-4-one and thiazinan-4-one are the
asymmetric carbon –CH and the diastereotopic hydrogens
of heterocyclic rings. Hydrogen H13 appears with
chemical displacement around 5.35–5.85 ppm as singlet or
doublet (4J with H15a). The diastereotopic hydrogens H15a
and H15b appear with doublet (2J), double doublet (2J and
4J), or multiplet signals with chemical displacement around
3.59–3.83 ppm. For thiazinan-4-one ring, the diastereotopics
H15a, H15b, H16a, and H16b appear more shielded as
double doublet or multiplet with chemical displacement
around 2.58–3.82 ppm.
In the 13C NMR spectrum, the characteristic signals of
thiazolidine-4-one and thiazinan-4-one are C13, C14,
EXPERIMENTAL
The microwave device: CEM Discovery-SP with
ActiVent; Model No. 909150; Serial No. DC8141;
Volts: 90/140; Vac Max Cur: 7.3 A; Frequency: 50/60
Hz; Max. PWR.: 725 W; MFG. DATA: 32231; MAG.
Frequency: 2455 MHz; Max. Microwave Power: 300
W; Prod. Tag.: 2118141. The melting points were
determined on a Fisatom machine with three capillary
tubes, model 430, 230 V, 60 Hz, 50 W. The
thermometer was up to 360°C. The characterization of
compounds was performed using NMR techniques and
mass spectrometry. 1H and 13C NMR spectra were
acquired in an Avance (1H 600 MHz and 13C
150 MHz) equipment. The solvent used was deuterated
chloroform (CDCl3) containing tetramethylsilane as an
Figure 2. ORTEP diagram of compound 9d with thermal ellipsoids
drawn at 50% probability level. [Color figure can be viewed at
wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Thiazolidin-4-ones and Thiazinan-4-ones Analogous
to Rosiglitazone
internal standard. Mass spectra were obtained on a
Shimadzu CG 2010-Plus equipment, with GCMS-
QP2010SE automatic injector. Mass spectra were
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-(2-
(pyrrolidin-1-yl)ethyl)thiazolidin-4-one (9a). M.W. 426.58,
1
brown oil (72%), H-NMR (600 MHz, CDCl3): δ = 8.15
(dd, J = 3.7, 1.1 Hz, 1H, H1), 7.44–7.47 (m, 1H, H3),
7.22 (d, J = 8.2 Hz, 2H, H11), 6.89 (d, J = 8.6 Hz, 2H,
H10), 6.56 (dd, J = 6.7, 5.3 Hz, 1H, H2), 6.52 (d,
J = 8.6 Hz, 1H, H4), 5.80 (s, 1H, H13), 4.19 (t,
J = 5.7 Hz, 2H, H8), 3.98 (t, J = 5.6 Hz, 2H, H7), 3.74–
3.79 (m, 2H, H15a, –C(O)NCH2CH2N–(a)), 3.71 (d,
J = 15.4 Hz, 1H, H15b), 3.14 (s, 3H, H6), 2.82–2.86 (m,
1H, –C(O)NCH2CH2N–(b)), 2.66 (dd, J = 12.7, 6.3 Hz,
1H, –C(O)NCH2CH2N–(a)), 2.52 (sl, 4H, pyrrolidinyl),
2.48 (dd, J = 12.4, 6.3 Hz, 1H, –C(O)NCH2CH2N–(b)),
1.76 (sl, 4H, pyrrolidinyl). 13C-NMR (150 MHz, CDCl3):
δ = 171.4 (C14), 159.6, 158.3, 147.9, 137.4, 131.2,
128.7, 115.0, 111.8, 105.8, 66.5, 63.8 (C13), 54.1, 53.0,
49.5, 41.3, 37.9, 33.1 (C15), 23.5. MS (70 eV): m/z
(%) = 292 (1), 253 (1), 207 (2), 151 (1), 133 (2), 120 (1),
84 (100). HRMS: (M + H+): C23H30N4O2S calculated
427.2162; found 427.2132; 214.1106.
obtained for all compounds on
a LTQ Orbitrap
Discovery mass spectrometer (Thermo Fisher Scientific).
This hybrid system meets the LTQ XL linear ion trap
mass spectrometer and an Orbitrap mass analyzer. The
experiments were performed via direct infusion of
sample (flow: 15 μL/min) in the positive-ion mode
using electrospray ionization. Elemental composition
calculations for comparison were executed using the
specific tool included in the Qual Browser module of
Xcalibur (Thermo Fisher Scientific, release 2.0.7)
software. Diffraction measurements of compounds 9d
were performed using a Bruker D8 Venture with a
Photon
monochromatized
100
CMOS
Mo
detector
Kα
with
radiation
graphite
with
λ = 0.71073 Å. Absorption corrections were performed
using multi-scan methods. Anisotropic displacement
parameters for non-hydrogen atoms were applied. The
structure was solved and refined using the WinGX151
software package. The structures were refined based on
the full-matrix least-squares method using the SHELXL
program [27]. The ORTEP projections of the molecular
structures were generated using the ORTEP-3[26]
program. Crystallographic information files for the
studied compounds have been deposited at the
Cambridge Crystallographic Data Centre with the
following identification 1841878. X-ray diffraction data
for compound 9d are listed in Table SX.
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-(2-
(piperidin-1-yl)ethyl)thiazolidin-4-one (9b).
M.W. 440.61,
1
brown oil (28%), H NMR (600 MHz, CDCl3): δ = 8.15
(d, J = 4.0 Hz, 1H, H1), 7.45 (t, J = 7.3 Hz, 1H, H3),
7.20 (d, J = 8.3 Hz, 2H, H11), 6.88 (d, J = 8,3 Hz, 2H,
H10), 6.55 (t, J = 5.9 Hz, 1H, H2), 6.52 (d, J = 8.5 Hz,
1H, H4), 5.82 (s, 1H, H13), 4.19 (t, J = 5.5 Hz, 2H,
H8), 3.98 (t, J = 5.5 Hz, 2H, H7), 3.76–3,71 (m, 2H,
H15a, –C(O)NCH2CH2N–(a)), 3.68 (d, J = 15.4 Hz, 1H,
H15b), 3.14 (s, 3H, H6), 2.81–2.77 (m, 1H, –C(O)
NCH2CH2N–(b)),
2.51–2.47
(m,
2H,
–C(O)
General procedure for thiazolidin-4-ones 9a–l and 1,3-
NCH2CH2N–), 2.32 (sl, 4H, piperidinyl), 1.59–1.54 (m,
4H, piperidinyl), 1.41 (d, J = 4.5 Hz, 2H, piperidinyl).
13C NMR (150 MHz, CDCl3): δ = 171,3 (C14), 159.3,
158.3, 147.8, 137.4, 131.3, 128.9, 114.9, 111.9, 105.8,
66.5, 63.9 (C13), 56.0, 54.5, 49.5, 39.6, 37.9, 33.1
(C15), 25.7, 23.8. MS (70 eV): m/z (%) = 306 (1), 281
(2), 207 (4), 151 (1), 133 (3), 113 (4), 98 (100). HRMS:
(M + H+): C24H32N4O2S calculated 441.2319; found
441.2287; 221.1181.
thiazinan-4-ones
10a–f.
The compounds were
synthesized using toluene (70 mL), amine 6a–l (1 mmol),
and aldehyde 5 (1 mmol). The system was connected to a
Dean-Stark for the removal of water via azeotropic
distillation; the reaction mixture was stirred for 2 h at the
reflux temperature of the solvent (110°C). After
formation
of
the
imine
intermediate
7a–l,
mercaptocarboxylic acid 8a or 8b (3 mmol) was added
and left to react for 18 h. The mixture was washed with
saturated
sodium
hydrogen
carbonate
solution
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-(2-
(3 × 10 mL); the organic phase was dried over
magnesium sulfate and filtered, and the solvent was
removed under reduced pressure. The thiazolidin-4-ones
9a–l and thiazinan-4-ones 10–g were purified by column
chromatography silica gel (0.2–0.5 mm) and as eluents a
solution of hexane/ethyl acetate (8:2 to 1:1).
morpholinoethyl)thiazolidin-4-one (9c).
M.W. 442.58,
brown solid (76%), mp
=
91–93°C, 1H NMR
(600 MHz, CDCl3) δ = 8.15 (d, J = 4.8 Hz, 1H, H1),
7.44–7.47 (m, 1H, H3), 7.20 (d, J = 8.5 Hz, 2H, H11),
6.89 (d, J = 8.5 Hz, 2H, H10), 6.55–6.57 (m, 1H, H2),
6.52 (d, J = 8.6 Hz, 1H, H4), 5.79 (s, 1H, H13), 4.19
(t, J = 5.5 Hz, 2H, H8), 3.99 (t, J = 5.5 Hz, 2H, H7),
3.73–3.78 (m, 2H, H15a, –C(O)NCH2CH2N–(a)), 3.70
(d, J = 15.5 Hz, 1H, H15b), 3.66 (t, J = 4,1 Hz, 4H,
morpholinyl), 3.15 (s, 3H, H6), 2.78 (dt, J = 6.7,
13.9 Hz, 1H, –C(O)NCH2CH2N–(b)), 2.45 (dt, J = 6.4,
12.8 Hz, 1H, –C(O)NCH2CH2N–(a)), 2.33–2.30 (m,
5H, –C(O)NCH2CH2N–(b), morpholinyl). 13C NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. M. das Neves, J. C. Campos, D. P. Gouvêa, G. A. Berwaldt, T. B. Goulart, C. T. Avila,
P. Machado, G. C. Zimmer, and W. Cunico
Vol 000
(150 MHz, CDCl3): δ = 171.4 (C14), 159.6, 158.3,
147.9, 137.4, 131.2, 128.8, 115.0, 111.9, 105.8, 67.0,
66.5, 63.8 (C13), 55.9, 53.5, 49.5, 39.4, 38.0, 33.1
(C15). MS (70 eV): m/z (%) = 308 (1), 281 (1), 207
(2), 151 (1), 133 (3), 113 (8), 100 (100).
6.90 (d, J = 8.5 Hz, 2H, H10), 6.56 (dd, J = 6.6, 5.3 Hz,
1H, H2), 6.52 (d, J = 8.5 Hz, 1H, H4), 5.62 (s, 1H, H13),
4.19 (t, J = 5.6 Hz, 2H, H8), 3.99 (t, J = 5.6 Hz, 2H, H7),
3.78 (dd, J = 1.2, 15.5 Hz, 1H, H15a), 3.68 (d,
J = 15.6 Hz, 1H, H15b), 3.65 (t, J = 4.3 Hz, 4H,
morpholinyl), 3.58–3.63 (m, 1H, –C(O)NCH2CH2CH2N–
(a)), 3.14 (s, 3H, H6), 2.76 (ddd, J = 5.8, 8.3, 14.0 Hz, 1H,
–C(O)NCH2CH2CH2N–(b)), 2.33 (sl, 4H, morpholinyl),
2.28 (dd, J = 6.2, 13.5 Hz, 1H, –C(O)NCH2CH2CH2N–
(a)), 2.20–2.25 (m, 1H, –C(O)NCH2CH2CH2N–(b)), 1.67
(ddd, J = 2.1, 7.8, 13.7 Hz, 1H, –C(O)NCH2CH2CH2N–
3-(Cyclohexylmethyl)-2-(4-(2-(methyl(pyridin-2-yl)amino)
ethoxy)phenyl)thiazolidin-4-one (9d). M.W. 425.59, white
crystal (isopropyl alcohol) (23%), mp = 94–96°C, 1H
NMR (600 MHz, CDCl3): δ = 8.15 (dd, J = 4.8, 1.1 Hz,
1H, H1), 7.45 (ddd, J = 1.9, 7.1, 8.7 Hz, 1H, H3), 7.17
(d, J = 8.6 Hz, 2H, H11), 6.89 (d, J = 8.6 Hz, 2H, H10),
6.55 (dd, J = 5.1, 6.8 Hz, 1H, H2), 6.51 (d, J = 8.6 Hz,
1H, H4), 5.57 (d, J = 1.2 Hz, 1H, H13), 4.19 (t,
J = 5.6 Hz, 2H, H8), 3.99 (t, J = 5.6 Hz, 2H, H7), 3.78
(dd, J = 1.5, 15.4 Hz, 1H, H15a), 3.70 (d, J = 15.4 Hz,
1H, H15b), 3.72 (dd, J = 8.7, 13.7 Hz, 1H, –C(O)
NCH2N–(a)), 3.14 (s, 3H, H6), 2.42 (dd, J = 5.9,
13.7 Hz, 1H, –C(O)NCH2N–(b)), 1.66–1.71 (m, 2H,
cyclohexyl), 1.58–1.63 (m, 2H, cyclohexyl), 1.52–1.54
(m, 2H, cyclohexyl), 1.10–1.19 (m, 3H, cyclohexyl),
0.87–0.92 (m, 2H, cyclohexyl). 13C NMR (150 MHz,
CDCl3): δ = 171.3 (C14), 159.5, 158.3, 147.9, 137.3,
131.4, 128.3, 115.0, 111.8, 105.7, 66.5, 63.7 (C13), 49.4,
48.7, 37.9, 35.4, 32.9 (C15), 31.0, 30.4, 26.3, 25.8, 25.7.
MS (70 eV): m/z (%) = 291 (34), 258 (50), 216 (16), 195
(41), 148 (100), 122 (50), 107 (78).
(a)), 1.56 (td,
J
=
7.2, 14.3 Hz, 1H, –C(O)
NCH2CH2CH2N–(b)). 13C NMR (150 MHz, CDCl3):
δ = 171.1 (C14), 159.6, 158.3, 147.9, 137.4, 131.2, 128.6,
114.9, 111.9, 105.7, 66.9, 66.5, 63.6 (C13), 55.9, 53.4,
49.5, 41.2, 37.9, 33.1 (C15), 23.7. MS (70 eV): m/z
(%) = 322 (3), 236 (1), 206 (1), 151 (1), 129 (10), 114 (4),
100 (100). HRMS: (M + H+): C24H32N4O3S calculated
457.2268; found 457.2234; 229.1154.
3-(Furan-2-ylmethyl)-2-(4-(2-(methyl (pyridin-2-yl)amino)
ethoxy)phenyl)thiazolidin-4-one (9g).
M.W. 409.50, light
1
brown oil (18%), H NMR (600 MHz, CDCl3): δ = 8.15
(dd, J = 4.8, 1.2 Hz, 1H, H1), 7.46 (ddd, J = 8.8, 7.2,
1.8 Hz, 1H, H3), 7.34 (d, J = 1.0 Hz, 1H, furanyl), 7.21
(d, J = 8.6 Hz, 2H, H11), 6.90 (d, J = 8.6 Hz, 2H, H10),
6.56 (dd, J = 6.7, 5.3 Hz, 1H, H2), 6.52 (d, J = 8.6 Hz,
1H, H4), 6.28 (dd, J = 2.9, 1.8 Hz, 1H, furanyl), 6.10 (d,
J = 3.0 Hz, 1H, furanyl), 5.49 (s, 1H, H13), 4.95 (d,
J = 15.4 Hz, 1H, –C(O)NCH2N–(a)), 4.20 (t, J = 5.6 Hz,
2H, H8), 3.99 (t, J = 5.6 Hz, 2H, H7), 3.82 (dd, J = 15.6,
1.2 Hz, 1H, H15a), 3.71 (d, J = 15.6 Hz, 1H, H15b),
3.62 (d, J = 15,4 Hz, 1H, –C(O)NCH2N–(b)), 3.15 (s,
3H, H6). 13C NMR (150 MHz, CDCl3): δ = 171.0 (C14),
159.6, 158.3, 149.1, 147.9, 142.7, 137.4, 130.6, 128.9,
115.0, 111.9, 110.5, 109.2, 105.8, 66.5, 62.9 (C13), 49.5,
38.9, 38.0, 33.1 (C15). MS (70 eV): m/z (%) = 275 (26),
200 (17), 148 (15), 137 (99), 120 (15), 109(27), 81 (100).
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-(3-
(piperidin-1-yl)propyl)thiazolidin-4-one (9e). M.W. 454.63,
light brown oil (54%), 1H NMR (600 MHz, CDCl3):
δ = 8.15 (dd, J = 4.8, 1.2 Hz, 1H, H1), 7.45 (ddd,
J = 1.9, 7.1, 8.8 Hz, 1H, H3), 7.21 (d, J = 8.6 Hz, 2H,
H11), 6.89 (d, J = 8.6 Hz, 2H, H10), 6.55 (dd, J = 6.8,
5.1 Hz, 1H, H2), 6.52 (d, J = 8.6 Hz, 1H, H4), 5.64 (d,
J = 1.2 Hz, 1H, H13), 4.19 (t, J = 5.6 Hz, 2H, H8), 3.98
(t, J = 5.6 Hz, 2H, H7), 3.77 (dd, J = 1.8, 15.4 Hz, 1H,
H15a), 3.68 (d, J = 15.4 Hz, 1H, H15b), 3.58–3.63 (m,
1H, –C(O)NCH2CH2CH2N–(a)), 3.14 (s, 3H, H6), 2.70
(ddd, J = 5.8, 7.9, 13.8 Hz, 1H, –C(O)NCH2CH2CH2N–
(b)), 2.25–2.30 (m, 5H, –C(O)NCH2CH2CH2N–(a),
piperidinyl), 2.18–2.22 (m, 1H, –C(O)NCH2CH2CH2N–
(b)), 1.66–1.69 (m,1H, –C(O)NCH2CH2CH2N–(a)),
1.58–1.62 (m, 1H, –C(O)NCH2CH2CH2N–(b)), 1.54 (dt,
J = 5.4, 11.0 Hz, 4H, piperidinyl), 1.40 (sl, 2H,
piperidinyl). 13C NMR (150 MHz, CDCl3): δ = 171.1
(C14), 159.6, 158.3, 147.9, 137.4, 131.2, 128.6, 114.9,
111.8, 105.8, 66.5, 63.4 (C13), 56.2, 54.4, 49.5, 41.2,
37.9, 33.1 (C15), 25.8, 24.3, 24.0. MS (70 eV): m/z
(%) = 320 (2), 281 (1), 236 (1), 151 (1), 127 (6), 112 (4),
98 (100).
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-
(pyridin-2-ylmethyl)thiazolidin-4-one (9h).
M.W. 420.53,
brown oil (32%), 1H NMR (600 MHz, CDCl3):
δ = 8.51–8.50 (m, 1H, pyridinyl), 8.15 (ddd, J = 5.0,
1.9, 0.7 Hz, 1H, H1), 7.61 (td, J = 1.8, 7.7 Hz, 1H,
pyridinyl), 7.46 (ddd, J = 2.0, 7.1, 8.8 Hz, 1H, H3),
7.20–7.16 (m, 3H, H11, pyridinyl), 7.15–7.13 (m, 1H,
pyridinyl), 6.85 (d, J = 8.7 Hz, 2H, H10), 6.57–6,55 (m,
1H, H2), 6.53 (d, J = 8.6 Hz, 1H, H4), 5.68 (d,
J = 1.2 Hz, 1H, H13), 5.02–4.99 (m, 1H, –C(O)
NCH2N–(a)), 4.18 (t, J = 5.6 Hz, 2H, H8), 3.98 (t,
J = 5.6 Hz, 2H, H7), 3.90–3,86 (m, 1H, H15a), 3.85–
3.84 (m, 1H, –C(O)NCH2N–(b)), 3.78 (d, J = 15.5 Hz,
1H, H15b), 3.14 (s, 3H, H6). 13C NMR (150 MHz,
CDCl3): δ = 171.5 (C14), 159.6, 158.2, 155.5, 149.5,
147.7, 137.5, 136.8, 130.6, 128.9, 122.6, 122.4, 114.9,
111.9, 105.9, 66.5, 63.4 (C13), 49.5, 47.7, 38.0, 33.0
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-(3-
morpholinopropyl)thiazolidin-4-one (9f).
M.W. 456.61,
1
brown solid (38%), mp = 68–70°C, H NMR (600 MHz,
CDCl3): δ = 8.15 (d, J = 4.7 Hz, 1H, H1), 7.46 (dt,
J = 1.6, 6.9 Hz, 1H, H3), 7.21 (d, J = 8.5 Hz, 2H, H11),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Thiazolidin-4-ones and Thiazinan-4-ones Analogous
to Rosiglitazone
(C15). MS (70 eV): m/z (%) = 193 (2), 179 (5), 151 (1),
136 (2), 119 (5), 105 (7), 93 (100).
3-(3-(Diethylamino)propyl)-2-(4-(2-(methyl
(pyridin-2-yl)
amino)ethoxy)phenyl)thiazolidin-4-one (9l). M.W. 442.62,
1
brown oil (55%), H NMR (600 MHz, CDCl3): δ = 8.15
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-
(dd, J = 3.5, 1.3 Hz, 1H, H1), 7.44–7.47 (m, 1H, H3),
7.21 (d, J = 8.6 Hz, 2H, H11), 6.89 (d, J = 8.6 Hz, 2H,
H10), 6.56 (dd, J = 6.9, 5.1 Hz, 1H, H2), 6.52 (d,
J = 8.5 Hz, 1H, H4), 5.62 (s, 1H, H13), 4.19 (t,
J = 5.6 Hz, 2H, H8), 3.99 (t, J = 5.6 Hz, 2H, H7), 3.78
(dd, J = 1.7, 15.5 Hz, 1H, H15a), 3.68 (d, J = 15.4 Hz,
1H, H15b), 3.59 (ddd, J = 6.7, 8.8, 14.0 Hz, 1H, –C(O)
NCH2CH2CH2N–(a)), 3.14 (s, 3H, H6), 2.71 (ddd,
J = 5.4, 8.6, 13.9 Hz, 1H, –C(O)NCH2CH2CH2N–(b)),
2.44 (q, J = 7.1 Hz, 5H, diethylamine), 2.29–2.37 (m,
2H, –C(O)NCH2CH2CH2N–), 1.60–1.66 (m,1H, –C(O)
NCH2CH2CH2N–(a)), 1.50–1.56 (m, 1H, –C(O)
NCH2CH2CH2N–(b)), 0.96 (dd, J = 5.5, 8.7 Hz, 6H,
diethylamine). 13C NMR (150 MHz, CDCl3): δ = 171.1
(C14), 159.6, 158.3, 147.9, 137.4, 131.2, 128.6, 115.0,
111.9, 105.8, 66.5, 63.5 (C13), 50.1, 49.5, 46.6, 41.4,
37.9, 33.1 (C15), 24.4, 11.4. MS (70 eV): m/z (%) = 308
(3), 279 (2), 236 (4), 151 (1), 137 (3), 107 (7), 86 (100).
(pyridin-3-ylmethyl)thiazolidin-4-one (9i).
M.W. 420.53,
yellow solid (29%), mp
=
99–101°C, 1H NMR
(600 MHz, CDCl3): δ = 8.51–8.52 (m, 1H, pyridinyl),
8.27 (d, J = 1.4 Hz, 1H, pyridinyl), 8.15–8.16 (m, 1H,
H1), 7.50 (d, J = 7.8 Hz, 1H, pyridinyl), 7.47 (ddd,
J = 1.8, 7.2, 8.7 Hz, 1H, H3), 7.24 (dd, J = 4.9, 7.5 Hz,
1H, pyridinyl), 7.12 (d, J = 8.6 Hz, 2H, H11), 6.87 (d,
J = 8.6 Hz, 2H, H10), 6.57 (dd, J = 6.7, 5.2 Hz, 1H, H2),
6.53 (d, J = 8.6 Hz, 1H, H4), 5.35 (s, 1H, H13), 4.98 (d,
J = 14.7 Hz, 1H, –C(O)NCH2N–(a)), 4.20 (t, J = 5.3 Hz,
2H, H8), 4.00 (t, J = 5.6 Hz, 2H, H7), 3.86 (d,
J
=
15.7 Hz, 1H, –C(O)NCH2N–(b)), 3.75 (d,
J = 15.7 Hz, 1H, H15a), 3.67 (d, J = 14.9 Hz, 1H,
H15b), 3.16 (s, 3H, H6). 13C NMR (150 MHz, CDCl3):
δ = 171.4 (C14), 159.8, 158.2, 149.6, 149.2, 147.8,
137.4, 136.4, 131.4, 130.0, 128.9, 123.8, 115.1, 111.9,
105.8, 66.5, 62.8 (C13), 49.5, 43.7, 38.0, 33,0 (C15). MS
(70 eV): m/z (%) = 286 (62), 211 (100), 148 (13), 139
(8), 120 (14), 107 (15), 92 (84).
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-
(phenylamino)thiazolidin-4-one (9j). M.W. 420.53, reddish
1
brown oil (32%), H NMR (600 MHz, CDCl3) δ = 8.14
(dd, J = 4.9, 1.1 Hz, 1H, H1), 7.45 (ddd, J = 8.8, 7.1,
1.9 Hz, 1H, H3), 7.22 (d, J = 7.7 Hz, 2H, phenylamine),
7.19 (d, J = 8.5 Hz, 2H, H11), 6.92 (dd, J = 11.5,
4.1 Hz, 1H, phenylamine), 6.87 (d, J = 8.7 Hz, 2H, H10),
6.67 (d, J = 7.7 Hz, 2H, phenylamine), 6.56 (dd,
J = 6.8 Hz, 1H, H2), 6.52 (d, J = 8.5 Hz, 1H, H4), 5.68
(s, 1H, H13), 4.18 (t, J = 5.6 Hz, 2H, H8), 3.98 (t,
J = 5.6 Hz, 2H, H7), 3.83 (dd, J = 15.9, 1.7 Hz, 1H,
H15a), 3.76 (d, J = 15.9 Hz, 1H, H15b), 3.15 (s, 3H,
H6). 13C NMR (150 MHz, CDCl3): δ = 169.6 (C14),
159.8, 158.3, 147.8, 144.7, 137.5, 130.0, 129.5, 128.9,
122.0, 115.1, 114.1, 111.9, 105.9, 66.6, 61.7 (C13), 49.5,
38.0, 29,8 (C15). MS (70 eV): m/z (%) = 286 (100), 212
(43), 139 (54), 120 (51), 105 (36), 93 (50), 77 (94).
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-(2-
(pyrrolidin-1-yl)ethyl)-1,3-thiazinan-4-one (10a).
M.W.
440.61, light brown oil (48%), 1H NMR (600 MHz,
CDCl3): δ = 8.14–8.15 (m, 1H, H1), 7.45 (ddd, J = 8.8,
7.1, 1.9 Hz, 1H, H3), 7.12 (d, J = 8.5 Hz, 2H, H11), 6.88
(d, J = 8.7 Hz, 2H, H10), 6.64–6.56 (m, 1H, H2), 6.52
(d, J = 8.6 Hz, 1H, H4), 5.71 (s, 1H, H13), 4.19 (t,
J = 5.6 Hz, 2H, H8), 4.14–4.17 (m, 1H, –C(O)
NCH2CH2N–(a)), 3.98 (t, J = 5.6 Hz, 2H, H7), 3.15 (s,
3H, H6), 2.74–2.77 (m, 1H, –C(O)NCH2CH2N–(b)),
2.79–2.81 (m, 4H, H16a, H16b, H15a, H15b), 2.60–2.64
(m, 1H, –C(O)NCH2CH2N–(a)), 2.55–2.59 (m, 1H, –
C(O)NCH2CH2N–(b)), 2.47–2.50 (sl, 4H, pyrrolidinyl),
1.73 (t, J = 6.1 Hz, 4H, pyrrolidinyl). 13C NMR
(150 MHz, CDCl3): δ = 169.4 (C14), 158.7, 158.3,
147.9, 137.4, 131.4, 128.8, 114.5, 111.8, 105.8, 66.7,
62.3 (C13), 54.3, 53.8, 49.6, 46.6, 37.9, 35.6 (C15), 23.6,
21.9 (C16). MS (70 eV): m/z (%) = 306 (2), 273 (1), 133
(1), 120 (1), 98 (6), 84 (100), 70 (7). HRMS: (M + H+):
C24H32N4O2S calculated 441.2319; found 441.2286;
221.1181.
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-
phenylthiazolidin-4-one (9k).
M.W. 405.52, white solid
1
(44%), mp = 113–115°C, H NMR (600 MHz, CDCl3):
δ = 8.12 (d, J = 4.8 Hz, 1H, H1), 7.43 (t, J = 7.8 Hz, 1H,
H3), 7.25 (t, J = 7.7 Hz, 2H, phenyl), 7.18 (d, J = 8.5 Hz,
2H, H11), 7.14 (t, J = 7.6 Hz, 1H, phenyl), 7.11 (d,
J = 8.1 Hz, 2H, phenyl), 6.77 (d, J = 8.5 Hz, 2H, H10),
6.54 (m, 1H, H2), 6.48 (d, J = 8.6 Hz, 1H, H4), 6.03 (s,
1H, H13), 4.11 (t, J = 5.6 Hz, 2H, H8), 3.96–3.91 (m, 3H,
H7, H15a), 3.85 (d, J = 15.8 Hz, 1H, H15b), 3.09 (s, 3H,
H6). 13C NMR (150 MHz, CDCl3): δ = 171.1 (C14),
159.2, 158.3, 147.8, 137.5, 137.4, 131.1, 129.1, 128.5,
127.2, 126.0, 114.7, 111.8, 105.8, 66.3, 65.5 (C13), 49.5,
37.9, 33,6 (C15). MS (70 eV): m/z (%) = 271 (37), 196
(66), 148 (67), 151 (64), 124 (60), 107 (29), 77 (100).
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-(2-
(piperidin-1-yl)ethyl)-1,3-thiazinan-4-one
(10b).
M.W.
454.63, light brown solid (84%), mp = 75–77°C, 1H
NMR (600 MHz, CDCl3): δ = 8.14–8.15 (m, 1H, H1);
7.45 (ddd, J = 1.9, 7.1, 8.7 Hz, 1H, H3), 7.13 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. M. das Neves, J. C. Campos, D. P. Gouvêa, G. A. Berwaldt, T. B. Goulart, C. T. Avila,
P. Machado, G. C. Zimmer, and W. Cunico
Vol 000
J = 8.6 Hz, 2H, H11), 6.88 (d, J = 8.7 Hz, 2H, H10), 6.54–
6.56 (m, 1H, H2), 6.52 (d, J = 8.6 Hz, 1H, H4), 5.83 (s, 1H,
H13), 4.19 (t, J = 5.6 Hz, 2H, H8), 4.14 (ddd, J = 4.9, 7.1,
13.4 Hz, 1H, –C(O)NCH2CH2N–(a)), 3.98 (t, J = 5.6, 2H,
H7), 3.15 (s, 3H, H6), 2.79–2.81 (m, 2H, H16a, H15a),
2.74–2.77 (m, 2H, –C(O)NCH2CH2N–(b), H16b), 2.61–
2.63 (m, 1H, H15b). 2.56–2.59 (m, 1H, –C(O)
NCH2CH2N–(a)), 2.43–2.47 (m, 1H, –C(O)NCH2CH2N–
(b)), 2.34–2.39 (m, 4H, piperidinyl), 1.51–1.58 (m, 4H,
piperidinyl), 1.39–1.41 (m, 2H, piperidinyl). 13C NMR
(150 MHz, CDCl3): δ = 169.4 (C14), 158.7, 158.3,
147.9, 137.4, 131.5, 127.8, 114.5, 111.8, 105.8, 66.5,
62.3 (C13), 56.8, 54.8, 49.5, 44.8, 37.9, 34.6 (C15), 26.1,
24.3, 21.8 (C16). MS (70 eV): m/z (%) = 320 (2), 287
(1), 133 (2), 113 (4), 98 (100), 84 (9), 70 (4). HRMS:
(M + H+): C25H34N4O2S calculated 455.2475; found
455.2441; 228.1257.
66.5, 62.5 (C13), 54.2, 49.5, 37.9, 36.4, 34.4 (C15), 31.2,
30.7, 26.4, 25.9, 25.8, 21.7 (C16). MS (70 eV): m/z
(%) = 406 (1), 305 (41), 216 (42), 176 (17), 134 (61),
122 (56), 107 (100).
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-(3-
(piperidin-1-yl)propyl)-1,3-thiazinan-4-one (10e).
M.W.
1
468.66, reddish brown oil (27%), H NMR (600 MHz,
CDCl3): δ = 8.15 (ddd, J = 4.8 Hz, 1H, H1), 7.45 (ddd,
J = 8.8, 7.2, 1.9, Hz, 1H, H3), 7.11 (d, J = 8.6 Hz, 2H,
H11), 6.88 (d, J = 8.6 Hz, 2H, H10), 6.55 (dd, J = 6.7,
5.2 Hz, 1H, H2), 6.52 (d, J = 8.6 Hz, 1H, H4), 5.77 (s,
1H, H13), 4.19 (t, J = 5.6 Hz, 2H, H8), 4.07 (ddd,
J = 13.2, 7.6, 5.3 Hz, 1H, –C(O)NCH2CH2CH2N–(a)),
3.98 (t, J = 5.6 Hz, 2H, H7), 3.15 (s, 3H, H6), 2.74–2.80
(m, 3H, H16a, H15a, –C(O)NCH2CH2CH2N–(b)), 2.65
(dd, J = 13.0, 7.0 Hz, 1H, H16b), 2.59–2.61 (m, 1H,
H15b), 2.36–2.40 (m, 1H, –C(O)NCH2CH2CH2N–(a)),
2.34 (sl, 4H, piperidinyl), 2.21–2.24 (m, 1H, –C(O)
NCH2CH2CH2N–(b)), 1.75–1.84 (m, 2H, –C(O)
NCH2CH2CH2N-), 1.54 (dt, J = 10.9, 5.5 Hz, 4H,
piperidinyl), 1.41 (sl, 2H, piperidinyl). 13C NMR
(150 MHz, CDCl3): δ = 169.3 (C14), 158.7, 158.3,
147.9, 137.3, 131.6, 127.8, 114.5, 111.8, 105.8, 61.8
(C13), 55.8, 54.4, 49.5, 46.2, 37.9, 34.5 (C15), 26.1,
24.8, 24.5, 21.8 (C16). MS (70 eV): m/z (%) = 399 (1),
301 (4), 250(1), 153 (1), 134 (6), 112 (7), 98 (100).
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-(2-
morpholinoethyl)-1,3-thiazinan-4-one (10c). M.W. 456.61,
1
yellow solid (50%), mp = 89–91°C, H NMR (600 MHz,
CDCl3): δ = 8.15 (dd, J = 4.8, 1.1 Hz, 1H, H1), 7.45
(ddd, J = 8.8, 7.2, 1.9 Hz, 1H, H3), 7.14 (d, J = 8.6 Hz,
2H, H11), 6.89 (d, J = 8.6 Hz, 2H, H10), 6.56 (dd,
J = 6.7, 5.2 Hz, 1H, H2), 6.52 (d, J = 8.6 Hz, 1H, H4),
5.77 (s, 1H, H13), 4.19 (t, J = 5.6 Hz, 2H, H8), 4.11
(ddd, J = 13.6, 6.5, 5.3 Hz, 1H, –C(O)NCH2CH2N–(a)),
3.99 (t, J = 5.6 Hz, 2H, H7), 3.66 (dd, J = 8.8, 4.5 Hz,
4H, morpholinyl), 3.15 (s, 3H, H6), 2.82–2.85 (m, 1H,
H16a), 2.80–2.81 (m, 2H, H16b, –C(O)NCH2CH2N–(b)),
2.76 (dd, J = 9.9, 4.8 Hz 1H, H15a), 2.63–2.65 (m, 1H,
H15b), 2.59 (dd, J = 13.3, 6.4 Hz, 1H, –C(O)
NCH2CH2N–(a)), 2.48–2.50 (m, 1H, –C(O)NCH2CH2N–
(b)), 2.41–2.44 (m, 4H, morpholinyl). 13C NMR
(150 MHz, CDCl3): δ = 169.5 (C14), 158.8, 158.3,
147.9, 137.4, 131.3, 127.8, 114.6, 111.9, 105.8, 67.1,
66.5, 62.5 (C13), 56.5, 53.8, 49.5, 44.4, 37.9, 34.6 (C15),
21.9 (C16). MS (70 eV): m/z (%) = 322 (2), 289 (1), 208
(3), 148 (1), 137 (2), 113 (30), 100 (100).
2-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)phenyl)-3-(3-
morpholinopropyl)-1,3-thiazinan-4-one
(10f).
M.W.
470.63, light brown oil (35%), 1H NMR (600 MHz,
CDCl3): δ = 8.15 (dd, J = 4.9, 1.1 Hz, 1H, H1), 7.45
(ddd, J = 8.8, 7.1, 1.9 Hz, 1H, H3), 7.12 (d, J = 8.6 Hz,
2H, H11), 6.89 (d, J = 8.7 Hz, 2H, H10), 6.56 (dd,
J = 6.6, 5.1 Hz, 1H, H2), 6.52 (d, J = 8.6 Hz, 1H, H4),
5.70 (s, 1H, H13), 4.19 (t, J = 5.6 Hz, 2H, H8), 4.07
(ddd, J = 13.4, 7.9, 5.2 Hz, 1H, –C(O)NCH2CH2CH2N–
(a)), 3.99 (t, J = 5.6 Hz, 2H, H7), 3.68 (t, J = 4.4 Hz, 4H,
morpholinyl), 3.15 (s, 3H, H6), 2.75–2.81 (m, 3H, H16a,
H15a, –C(O)NCH2CH2CH2N–(b)), 2.66–2.70 (m, 1H,
H16b), 2.60–2.63 (m, 1H, H15b), 2.60–2.63 (m, 1H,
H16b), 2.39–2.44 (m, 3H, –C(O)NCH2CH2CH2N–(a),
morpholinyl), 2.38 (sl, 2H, morpholinyl), 2.28 (ddd,
J = 12.3, 7.3, 4.9 Hz, 2H, –C(O)NCH2CH2CH2N–(b)),
1.73–1.85 (m, 2H, –C(O)NCH2CH2CH2N–). 13C NMR
(150 MHz, CDCl3): δ = 169.4 (C14), 158.7, 158.3,
147.9, 137.4, 131.5, 127.8, 114.6, 111.9, 105.8, 67.1,
66.6, 62.0 (C13), 55.9, 53.5, 49.7, 46.3, 37.9, 34.5 (C15),
24.3, 21.8 (C16). MS (70 eV): m/z (%) = 336 (4), 303
(4), 208 (3), 134 (12), 114 (7), 107 (14), 100 (100).
HRMS: (M + H+): C25H34N4O3S calculated 471.2424;
found 471.2387; 236.1231.
3-(Cyclohexylmethyl)-2-(4-(2-(methyl (pyridin-2-yl)amino)
ethoxy)phenyl)-1,3-thiazinan-4-one (10d).
M.W. 439.62,
1
brown oil (16%), H NMR (600 MHz, CDCl3): δ = 8.15
(dd, J = 4.8, 1.1 Hz, 1H, H1), 7.45 (ddd, J = 8.7, 7.1,
1.9 Hz, 1H, H3), 7.10 (d, J = 8.6 Hz, 2H, H11), 6.88 (d,
J = 8.6 Hz, 2H, H10), 6.55 (dd, J = 6.8, 5.2 Hz, 1H, H2),
6.52 (d, J = 8.5 Hz, 1H, H4), 5.45 (s, 1H, H13), 4.19 (t,
J = 5.6 Hz, 2H, H7), 4.12 (dd, J = 13.6, 7.1 Hz, 1H, –
C(O)NCH2N–(a)), 3.98 (t, J = 5.6 Hz, 2H, H7), 3.15 (s,
3H, H6), 2.79–2.83 (m, 1H, H16a), 2.73–2.77 (m, 2H,
H15a, H15b), 2.58–2,61 (m, 1H, H16b), 2.25 (dd,
J = 13.6, 7.3 Hz, 1H, –C(O)NCH2N–(b)), 1.64–1.75 (m,
4H, cyclohexyl), 1.18–1.26 (m, 4H, cyclohexyl), 1.12–
1.16 (m, 1H, cyclohexyl), 0.87–0.97 (m, 2H, cyclohexyl).
13C NMR (150 MHz, CDCl3): δ = 169.6 (C14), 158.7,
158.3, 147.9, 137.4, 131.4, 127.8, 114.5, 111.8, 105.8,
3-(Furan-2-ylmethyl)-2-(4-(2-(methyl (pyridin-2-yl)amino)
ethoxy)phenyl)-1,3-thiazinan-4-one (10g).
M.W. 423.53,
light brown oil (16%), 1H NMR (600 MHz, CDCl3):
δ = 8.15 (d, J = 4.2 Hz, 1H, H1), 7.45 (t, J = 7.2 Hz, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Thiazolidin-4-ones and Thiazinan-4-ones Analogous
to Rosiglitazone
[11] Rudrapal, M.; Chetia, D.; Prakash, A. Med Chem Res 2013,
22, 3703.
[12] Mohamed, S. K.; Abdelhamid, A. A.; Omara, W.; Jaber, A. A.
M.; Albayati, M. J Chem Pharm Res 2013, 5, 19.
[13] Bosenbecker, J.; Bareño, V. D. O.; Difabio, R.; Vasconcellos,
F. A.; Dutra, F. S. P.; Oliveira, P. S.; Barschak, A. G.; Stefanello, F. M.;
Cunico, W. J Biochem Mol Toxicol 2014, 28, 425.
[14] Raza, S.; Srivastava, S. P.; Srivastava, D. S.; Srivastava, A. K.;
Haq, W.; Katti, S. B. Eur J Med Chem 2013, 63, 611.
[15] Patel, N. B.; Patel, H. R.; Shaikh, F. M.; Rajani, D. Med Chem
Res 2014, 23, 1360.
[16] Gouvêa, D. P.; Berwaldt, G. A.; Neuenfeldt, P. D.; Nunes, R.
J.; Almeida, W. P.; Cunico, W. J Braz Chem Soc 2016, 27, 1109.
[17] Hassan, A. A.; Mohamed, S. K.; Mohamed, N. K.; El-Shaieb,
K. M. A.; Abdel-Aziz, A. T.; Mague, J. T.; Akkurtd, M. J Heterocyclic
Chem 2017, 54, 2043.
[18] Hassan, A. A.; El-Shaieb, K. M. A.; El-Aal, A. S. A.; Bräse,
S.; Nieger, M. Z.; Naturforsch, B. Chem Sci 2015, 70, 243.
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2018, 55, 1579.
H3), 7.32 (s, 1H, furanyl), 7.12 (d, J = 8.3 Hz, 2H, H11),
6.89 (d, J = 8.3 Hz, 2H, H10), 6.57–6.55 (m, 1H, H2),
6.52 (d, J = 8.3 Hz, 1H, H4), 6.28 (s, 1H, furanyl), 6.19
(d, J = 2.0 Hz, 1H, furanyl), 5.54 (s, 1H, H13), 5.40 (d,
J = 15.5 Hz, 1H, –C(O)NCH2N–(a)), 4.19 (t, J = 5.5 Hz,
2H, H8), 3.99 (t, J = 5.4 Hz, 2H, H7), 3.74 (d,
J = 15.5 Hz, 1H, –C(O)NCH2N–(b)), 3.15 (s, 3H, H6),
2.86 (d, J = 5.2 Hz, 2H, H16a, H16b), 2.81–2.77 (m, 1H,
H15a), 2.65–2.63 (m, 1H, H15b). 13C NMR (150 MHz,
CDCl3): δ = 169.4 (C14), 158.8, 158.3, 150.1, 147.9,
142.5, 137.4, 130.8, 127.8, 114.6, 111.8, 110.4, 109.0,
105.8, 66.5, 61.2 (C13), 49.5, 42.3, 37.9, 34.7 (C15),
22.0 (C16). MS (70 eV): m/z (%) = 289 (11), 182 (42),
137 (11), 122 (17), 107 (11), 96(29), 81 (100).
[20] Sasaki, R.; Nakatsuji, H.; Tanabe, Y. J Heterocyclic Chem
2018, 55, 1112.
[21] Gaonkar, S. L.; Nagashima, I.; Shimizu, H. Org Chem Int
2011, ID 751894, 5.
Acknowledgments. The authors thank CNPq for their financial
support of the research, UFPel and CAPES. We also thank
NUQUIMHE for RMN analysis.
[22] da Silva, D. S.; da Silva, C. E. H.; Soares, M. S. P.; Azambuja,
J. H.; de Carvalho, T. R.; Zimmer, G. C.; Frizzo, C. P.; Braganhol, E.;
Spanevello, R. M.; Cunico, W. Eur J Med Chem 2016, 124, 574.
[23] Gouvea, D. P.; Vasconcellos, F. A.; Berwaldt, G. A.; Neto, A.
C. S.; Fischer, G.; Sakata, R.; Almeida, W. P.; Cunico, W. Eur J Med
Chem 2016, 118, 259.
[24] Neves, A. H.; da Silva, D. S.; Siqueira, G. M.; Gamaro, G. D.;
Cunico, W.; da Silva, A. L. Med Chem Res 2018, 27, 186.
[25] Drawanz, B. B.; Zimmer, G. C.; Rodrigues, L. V.; Nörnberg,
A. B.; Hörner, M.; Frizzo, C. P.; Cunico, W. Synthesis 2018, 49, 5167.
[26] Farrugia, L. J. J Appl Cryst 2012, 45, 849.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet