5,6,7,8-Tetrahydronaphthalen-1-amine as Precursor for Thiazolidi-nones and Benzothiazepinones: Synthesis and Atropisomeric Relationship

Article abstract of DOI:10.1055/s-0036-1590866

The one-pot reaction of 5,6,7,8-tetrahydronaphthalen-1-amine, mercaptoacetic acid, and arenealdehydes having strong and weak electron-withdrawing groups gave the corresponding 1,3-thiazolidin-4-ones (47-70%). When arenealdehydes bearing strong and weak electron-donating groups were used as precursors, the 1,4-benzothiazepin-2-ones were obtained (30-72%) by p -TsOH catalysis. All compounds are unknown and were characterized by GC-MS and NMR techniques, and available crystals by X-ray diffraction studies. The atropisomerism phenomenon was observed in several 1,3-thiazolidin-4-ones as confirmed by VTNMR method. The Tc was established as 332 K and the energy required for the interconversion of one atrop-isomer into another is around 16.8 kcal·mol ^-1. Chemical quantum calculation and NOESY displayed that more stable isomer has the tetrahydro-naphthalene portion below the five-ring plane. Only a small difference between isomers (-0.21 to -0.84 kcal·mol ^-1) was observed by calculated energy.

Full text of DOI:10.1055/s-0036-1590866

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–I
paper
A
en
B. B. Drawanz et al.
Paper
Synthesis
5,6,7,8-Tetrahydronaphthalen-1-amine as Precursor for Thiazolidi-
nones and Benzothiazepinones: Synthesis and Atropisomeric
Relationship
O
Bruna B. Drawanza
Georgia C. Zimmerb
Leticia V. Rodriguesb
Andressa B. Nörnberga
Manfredo Hörnerc
Clarissa P. Frizzob
N
S
O
S
HN
CHO
CHO
EWG
NH2
O
EDG
EWG
HS
+
OH
Wilson Cunico*a
EDG
toluene
reflux, 24 h
47–70%
p-TsOH, toluene
reflux, 24 h
30–72%
O
a LaQuiABio, Centro de Ciências Químicas, Farmacêuticas e
de Alimentos, Universidade Federal de Pelotas, Campus
Universitário s/no, 96010-900, Pelotas, RS, Brazil
wjcunico@yahoo.com.br
b NUQUIMHE, Departamento de Química, Universidade
Federal de Santa Maria, Av. Roraima nº 1000, Cidade
Universitária, 97105-900,Santa Maria, RS, Brazil
c NITRICO, Departamento de Química, Universidade Federal
de Santa Maria, Av. Roraima nº 1000, Cidade Universitária,
97105-900,Santa Maria, RS, Brazil
N
S
9 examples
5 examples
EWG
Atropisomeric
relationship
Received: 09.06.2017
Accepted after revision: 13.07.2017
Published online: 10.08.2017
reaction process: ultrasound irradiation6 or microwave en-
ergy.7 Both methodologies with lower reaction times are
faster than conventional thermal heating.
DOI: 10.1055/s-0036-1590866; Art ID: ss-2017-m0387-op
Benzothiazepinone has the same heteroatoms and a
carbonyl group that are present in thiazolidinone structure,
but in a seven-membered ring fused with benzene. This
heterocycle also shows biological importance, among them:
neuroprotection,8 antioxidant,9 and potential therapeutic
for type II diabetes.10 Nowadays, these heterocycles are in
the pharmaceutical market acting as angina-relieving calci-
um channel blocker (Diltiazem), antihypertensive agent
(Clentiazem), and antidepressant GABBAA blocker (Thiaz-
esim).11 The benzothiazepinones synthesis is reported in
different ways. An approach was developed by the S-alkyla-
tion of mercaptoacetic acid with 2-aminobenzhydrol in
HCl, but longer reaction times were needed (48–72 h).12 Al-
so, extreme conditions (–78 °C and t-BuLi) are required to
promote o-lithiation of Boc-protected p-chloroaniline.8,10
But, simpler procedures are currently being published such
as the use of high potential microwave irradiation in a mul-
ticomponent process9,13 or by cyclization of 2-aminothio-
phenol with cinnamic acid by TBAF catalysis.11
Our research group has explored the synthesis of 1,3-
thiazolidin-4-ones,14 1,3-thiazinan-4-ones,15 and thiazoli-
din-2,4-diones16 in the last years. Originally, the purpose of
this work was the use of 5,6,7,8-tetrahydronaphthalen-1-
amine (1) as precursor in the synthesis of 1,3-thiazolidin-4-
ones, which were expected to be powerful AChE inhibitors
due to the union of heterocyclic thiazolidinone and tetrahy-
dronaphthalene – a tacrine analogue moiety. To our sur-
prise, when arenealdehydes bearing electron-donating
Abstract The one-pot reaction of 5,6,7,8-tetrahydronaphthalen-1-
amine, mercaptoacetic acid, and arenealdehydes having strong and
weak electron-withdrawing groups gave the corresponding 1,3-thiazoli-
din-4-ones (47–70%). When arenealdehydes bearing strong and weak
electron-donating groups were used as precursors, the 1,4-benzothiaz-
epin-2-ones were obtained (30–72%) by p-TsOH catalysis. All com-
pounds are unknown and were characterized by GC-MS and NMR tech-
niques, and available crystals by X-ray diffraction studies. The
atropisomerism phenomenon was observed in several 1,3-thiazolidin-
4-ones as confirmed by VTNMR method. The Tc was established as
332 K and the energy required for the interconversion of one atrop-
isomer into another is around 16.8 kcal·mol–1. Chemical quantum cal-
culation and NOESY displayed that more stable isomer has the
tetrahydronaphthalene portion below the five-ring plane. Only a small
difference between isomers (–0.21 to –0.84 kcal·mol–1) was observed
by calculated energy.
Key words thiazolidinone, atropisomer, benzothiazepinone, chemical
quantum calculation, X-ray
Thiazolidinones and their derivatives are very promis-
ing compounds because of their vast action in biological ac-
tivities, such as antitubercular,1 anticancer,2 anti-inflamma-
tory,3 and as AChE and BChE inhibitors.4 Generally, 1,3-thi-
azolidin-4-one synthesis is a reaction of three components:
a primary amine, aldehyde or ketone, and mercaptoacetic
acid. The synthesis can occur in two-steps or by multicom-
ponent one-pot procedure that can be catalyzed or not.5
Usually, thermal conventional heating is used most of the
times, but alternative sources could also be utilized in the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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B. B. Drawanz et al.
Paper
Synthesis
O
O
O
X
H
R
NH2
HS
OH
N
S
4
X
i
+
R
ii: 5a–c
iii: 5d–i
N
R
1
2a–i
3a–i
b
5a–i
X
47–70%
i: Dean–Stark, toluene, reflux, 30 min
ii: 3 mmol of 4, reflux, 24 h
iii: 6 mmol of 4, reflux, 24 h
a
c
d
H
e
f
g
H
N
h
i
R: 2-NO2 3-NO2 4-NO2
2-Cl 4-Cl
CH
2-F 4-F
CH CH
X: CH CH CH CH CH
Scheme 1 Synthesis of thiazolidinones 5a–i
groups were used, unexpected seven-membered rings
(benzothiazepinones) were obtained. Interestingly, this
heterocycle was not observed in our previously work.17
Then, considering the possibility to obtain this another im-
portant class of heterocycles, the synthesis of 1,4-benzothi-
azepin-2-ones became another goal in this work.
O
O
HN
O
O
H
N
S
SH
S
HN
i
1
+
+
+
ii
5j
7j
OMe
We started the preparation of thiazolidinones 5a–c
from nitrobenzaldehydes 2a–c, 5,6,7,8-tetrahydronaphtha-
len-1-amine (1), and mercaptoacetic acid (4), following the
procedure described by Masteloto et al. (Scheme 1, condi-
tions ii).17c For the synthesis of thiazolidinones 5d–i an op-
timization was necessary, mainly because no total con-
sumption of imine 3d–i was observed. The optimization
was monitored by TLC or GC-MS analysis. During all the
process of evaluation, amine 1 and 4-fluorobenzaldehyde
(2i) were used as model compounds, changing the follow-
ing variables: (a) reactions time (24–48 h); (b) one-pot or
multicomponent procedure; and (c) mercaptoacetic acid (4)
proportion. It was found that a reaction time of 24 hours
was necessary for the formation of thiazolidinones 5d–i by
the one-pot procedure using Dean–Stark apparatus and an
excess of 4 (6 equiv), more than 3 equiv that was generally
indicated in the literature14 (Scheme 1, conditions iii). The
isolation occurs by neutralization of the organic phase with
saturated aqueous NaHCO3. The crude products were puri-
fied by column chromatography using hexane–EtOAc (8:2)
as eluent or recrystallization from ethanol (5c and 5d) to af-
ford pure compounds 5a–i in expected yields from an aro-
matic amine.17
OMe
OMe
2j
6
i: Dean–Stark, toluene, reflux, 30 min
ii: Mercaptoacetic acid 4, reflux, 24 h
Scheme 2 Products identified by reaction with 4-methoxybenzalde-
hyde (2j)
In trying to avoid the formation of amide 6 and improve
the amount of thiazolidinone 5j, the catalyst BF3·MeOH
(50%) was added to the reaction as previously done by Gou-
vea et al.17a GC-MS showed no amide 6, but the presence of
a mixture of isomers of five- (5j) and seven-membered (7j)
rings with a proportion of 1:3, respectively. The non-signif-
icant achievement of thiazolidinone 5j might be attributed
to poor reactivity of carbonyl group in 2j.
The literature reports that in some cases, reactions be-
tween aromatic amines, mercaptoacetic acid, and areneal-
dehydes substituted with electron-donating groups, induce
the benzothiazepinone formation.9,13 Indeed, in our work
this seven-membered heterocycle was observed when 4-
methoxybenzaldehyde (2j) was the reactant, so we began to
focus on specific benzothiazepinone synthesis.
Once catalysis with BF3·MeOH (50%) favored the seven-
membered conversion but mixed with 5j, another acid cat-
alyst was tested. Then, it was found that 1 mmol of p-TsOH
worked well in a one-pot procedure. The p-TsOH was added
together with amine 1 and aldehyde 2j using a Dean–Stark
apparatus. Mercaptoacetic acid (4) was added after reflux-
ing in toluene for 30 minutes and the mixture was refluxed
continuously for more than 24 hours. This condition result-
ed in a conversion of 90% (GC-MS) in 1,4-benzothiazepin-2-
one 7j and the yield after recrystallization from ethanol was
72%. This procedure was followed by reaction with arene-
aldehydes 2f, 2j–m (Scheme 3).
However, monitoring the reaction with 4-methoxy-
benzaldehyde (2j) by GC-MS, formation of three com-
pounds was observed: the amide 6, the expected 1,3-thi-
azolidin-4-one 5j, and another compound with the same
molecular ion of thiazolidinone (Scheme 2). By column
chromatography both compounds were isolated in analyti-
cal quantities. The 1H and 13C NMR spectra revealed charac-
teristic signals corresponding to amide 6 and 1,4-benzothi-
azepin-2-one 7j, according to the literature.13
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B. B. Drawanz et al.
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1,3-thiazolidin-4-ones 5a–i, the signals of the diastereo-
topic hydrogens are more deshielded. H5a resonates in the
range of 3.97–4.09 ppm as a doublet or as a double doublet
(5b) due to spatial H2 coupling and H5b resonates as dou-
blet from 3.76 to 3.95 ppm. The 13C NMR spectrum exhibits
a considerable difference in the asymmetric carbon signal.
The C5 in 1,4-benzothiazepin-2-ones 7f, 7j–m resonates
from 42.8 to 47.1 ppm and C2 in 1,3-thiazolidin-4-ones 5a–i
resonates in the range of 59.9–65.1 ppm.
O
S
O
H
HN
OH
NH2
ii
i
1 +
R
R
(30–72%)
2f, 2j–m
8f, 8j–m
R
7f, 7j–m
i: p-TSOH, Dean–Stark, toluene, reflux, 30 min
ii: Mercaptoacetic acid 4, reflux, 24 h
f
j
k
l
m
R: 4-Cl 4-OMe
3,4-(OMe)2 4-Me 2,6-Cl2
The 1H and 13C NMR spectral data are in full agreement
with the proposed structures; however, an unexpected sig-
nal duplication (Figure 1) were observed in the spectra of
thiazolidinones 5b, 5c, 5d, 5f, 5g, 5h, and 5i. This behavior
can be attributed to the occurrence of atropisomerism phe-
nomenon, as found in 2-allylidenethiazolidin-4-ones re-
ported by Zapol’skii et al.18 Atropisomers are spatial iso-
mers generated by the rotation hindrance of an axis bond
and has to be considered as temperature dependent asym-
metry with a wide rate of energy barrier.19 Authors who
have identified atropisomerism in their compounds cite the
NMR duplication signals as the most common proof of oc-
currence.20,21 In benzothiazepinones 7f, 7j–m, this phe-
nomenon was not observed.
Scheme 3 Synthesis of 1,4-benzothiazepin-2-ones 7f, 7j–m
Tu et al.13 described the synthesis of 1,4-benzothiaze-
pin-2-ones from arenealdehydes with strong electron-do-
nating substituents and weak electron-withdrawing groups
(F, Cl, or Br). In extreme cases, the seven-membered forma-
tion is attributed to the strong electron-donating substitu-
ents in amines that can overcome the electron-withdraw-
ing effect on aldehydes. In another work, Shi et al.9 synthe-
sized benzothiazepinone with the strong electron-
withdrawing NO2, however, the electronic nature effect of
the substituent in the course of the reaction was not dis-
cussed.
When aldehydes 2a–i bearing electron-withdrawing
groups (strong and weak) were used in the presence of p-
TsOH, only a small amount of benzothiazepinone 7 was ob-
served. However, it was possible to isolate the benzothiaze-
pinone 7f in low yield (30%) with 2 equivalents of 2f (4-Cl).
It is supposed that the thiazolidinone 5m (R = 2,6-Cl2)
was not obtained because of the ortho group hindrance and
only imine 3m was identified. In turn, this ortho group does
not affect the reaction between the intermediate 8m and
mercaptoacetic acid (4) leading to the benzothiazepinone
7m formation.
The elucidation of this behavior came from the Variable-
Temperature Nuclear Magnetic Resonance (VTNMR) meth-
od. The coalescence was observed at 332.15 K (TC) and the
free energy of the transition state (ΔG‡) for conformational
interconversion was estimated using the TC and the fre-
quency difference (δv) of the particular resonances of the
two conformers whose coalescence is to be monitored.22
The rate of conversion (kT) at a given temperature (generally
in the coalescence temperature TC) was estimated using
Eyring Equation.22c The data are then analyzed using an
Arrhenius type procedure in order to obtain activation
parameters. Equations and details are given in the Support-
ing Information (SI).
A mechanism for 1,3-thiazolidin-4-one is well elucidat-
ed in literature,5,17c but for benzothiazepinone, a mecha-
nism can be proposed based on the intermediate 8 reported
by Tu et al.13 The mechanism begins with the attack on car-
bonyl group of arenealdehyde by the ortho carbon of aro-
matic amine, affording an amino alcohol intermediate 8,
which leads to the cyclization to a seven-membered ring,
1,4-benzothiazepin-2-one 7. In this study, it was observed
that p-TsOH was necessary in order to improve the yields.
All synthesized compounds are novel. The initial struc-
ture analysis was by GC-MS that exhibits the associated
fragments and molecular ions of the proposed structures.
As an example, the 1H NMR spectrum of compound 5c is
shown in Figure 1 and exhibits peak multiplicity (in a range
of 3.84 to 3.95 ppm for H5B and H5B′; and in a range of 4.10
to 4.20 ppm for H5A and H5A′) as a result of slow to inter-
mediate exchange between conformational isomers (com-
pounds 5c and 5c′). Quantification of the interconversion of
isomers involves the monitoring of the disappearance of
the peak corresponding to the two isomers (i.e., HA and HA′
– HB, and HB') upon heating, these signals broaden, co-
alesce, and finally sharpen as the rate of exchange increases.
1
1
In the H and 13C NMR characterization, the 1,3-thiazolidi-
Thus, through H NMR experiments in DMSO-d6 as part of
nones 5a–i and 1,4-benzothiazepin-2-ones 7f, 7j–m struc-
tures were differentiated by their diastereotopic hydrogens
signals (H3a and H3b for seven-membered, H5a and H5b
for five-membered). For 1,4-benzothiazepin-2-ones 7, the
characteristic H3a appears as a doublet (2J = 12.4–11.8 Hz)
that resonates in the range of 2.98–3.57 ppm and H3b
shows signals at 2.87–2.96 ppm also as a doublet (except for
the coalescence method, we measured the energy barriers
for interconversion of a conformer. Data showed that the
energy required for the interconversion of one isomer into
another is around 16.8 kcal·mol–1 (see Table S1 in the SI).
This energy is high and sufficient to impair the rotation of
axis bond, but low to permit the isolation of isomers at
room temperature.
2
4
H3b of 7m, dd, J = 12.4 and J = 1.4 Hz). In the spectra of
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B. B. Drawanz et al.
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Synthesis
The different energy values (ΔG°) of the individual
products are shown in Table 1. These values indicates a
small energy difference between the isomers, ranging from
–0.21 to –0.84 kcal·mol–1. These data suggest a slight prefer-
ence for the formation of the isomer with the aliphatic por-
tion of tetrahydronaphthalene below the plane of five-
membered heterocycle (isomer II).
Table 1 Energies Calculated by DFT-B3LYP/cc-pVDZ for Isomers I and II
of Compounds 5b, 5c, 5d
Isomer ΔG°
a
(kcal·mol–1
)
O
O
5b
5c
5d
I
0
II
I
–0.84
0
N
S
N
S
II
I
0.44
0
R
R
isomer I
isomer II
II
–0.21
Figure 1 Variable temperature 1H NMR spectra (stacked expansions of
the aliphatic region) of compound 5c
a ΔG = [G(isomer I) – G(isomer II)].
Based on atropisomerism phenomenon in thiazolidi-
nones 5b, 5c, 5d, 5f, 5g, 5h, and 5i, the stability of these iso-
mers was investigated by chemical quantum calculations.
The stability of the isomers was determined from molecu-
lar geometry with the lowest global energy for compounds
5b, 5c, and 5d. The molecular geometry found for the two
isomers are depicted in the Figure 2. The dihedral angle be-
tween tetrahydronaphthalene substituent and five-mem-
bered heterocycle are around 90° in both isomers, and in
the isomer I, the aliphatic portion of tetrahydronaphtha-
lene is positioned above the plane of the five-membered
heterocycle, and in the isomer II, the aliphatic portion of
tetrahydronaphthalene is positioned below the plane.
In addition, molecular geometry revealed by chemical
quantum calculations showed that spatial distance of H7
and H21 in isomer II (2.94, 2.97, 2.82 Å for 5b, 5c, and 5d,
respectively) is shorter than isomer I (5.10, 3.46, 3.56 Å for
5b, 5c, 5d, respectively). Based on this, a NOESY experiment
of 5b was performed to unambiguously characterize the
isomers in solution. Results showed a spatial coupling of
the H7 (tetrahydronaphthyl ring) with the H21 (phenyl
ring) (see SI) indicating that the favored atropisomer in
solution is isomer II, where spatial distance of H7 and H21
is shorter. Absence of spatial coupling of the H7′ with the
H21′ confirmed this result.
Considering that isomer II is favored in solution, results
of chemical quantum calculation are in agreement with the
results observed in the 1H NMR spectrum in CDCl3 at 298 K
where the proportion of isomers identified for isomers II/I
was 64:36 for the compounds 5c and 5d and 62:38 for com-
pound 5b.
Finally, compounds 5a, 5d, and 5e each formed a crystal
available for structure determination by single-crystal X-
ray diffraction. ORTEP views of 5e with thermal ellipsoids
at 50% probability are shown in Figure 3 (a). As we can see,
torsion angle between tetrahydronaphthalene substituent
and five-membered heterocycle is around 90°, which is in
accordance with geometry determined by chemical quan-
tum calculation. However, isomer I was isolated as a crystal
for 5d and isomer II was isolated as a crystal for 5a and 5e.
Structural factors that drove this preferential crystallization
are under investigation in our group and will be published
later.
Figure 2 Representation of isomeric relationship for 5b with aliphatic
portion of tetrahydronaphthalene above (isomer I, left) and below (iso-
mer II, right) the plane of thiazolidinone and the distance (Å) of H7 and
H21
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B. B. Drawanz et al.
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Synthesis
Figure 3 (a) ORTEP views of 5e with thermal ellipsoids at 50% probability (b) ORTEP views of 7j with thermal ellipsoids at 50% probability
Additionally, X-ray crystallography data showed that all
compounds crystallized in spatial groups that have mirror-
symmetry operator (m) indicating that two enantiomers
can be found in the crystalline structure. Thus, the assign-
ment of the absolute stereochemistry of the asymmetric
center in C2 is arbitrary, and this structure may represent
the R- or S-enantiomer. Benzothiazepinone 7j also formed a
crystal available for structure determination by single-
crystal X-ray diffraction. ORTEP views of 7j with thermal el-
lipsoids at 50% probability are shown in Figure 3 (b) con-
firming the benzothiazepinone formation. The crystal data
and details concerning data collection and structure refine-
ment are given in the SI.
The present study reported the synthesis of nine un-
published 2-aryl-3-(5,6,7,8-tetrahydronaphthalen-1-yl)thi-
azolidin-4-ones 5a–i by conventional thermal heating
through a one-pot procedure. By the same one-pot proce-
dure, but innovating through assistance of p-TsOH, a new
way to synthesize 1,4-benzothiazepin-2-ones from arene-
aldehydes substituted with electron-donating groups was
found and five 5-aryl-1,5,8,9,10,11-hexahydronaphtho[1,2-
e][1,4]thiazepin-2(3H)-ones 7f, 7j–m were obtained. All
structural dates are in full agreement with expected for
both heterocyclic structures.
The occurrence of atropisomerism phenomenon in
some 1,3-thiazolidin-4-ones was elucidated by VTNMR and
the energy required for the interconversion of one isomer
into another is around 16.8 kcal·mol–1. The stability of iso-
mers was investigated by chemical quantum calculations
that were confirmed by NOESY and 1H NMR and the isomer
II, with the aliphatic portion of tetrahydronaphthalene be-
low the plane of thiazolidinone ring is more stable. In addi-
tion, isomer II was isolated as a crystal for 5a and 5e, and
isomer I was isolated as a crystal for 5d.
Finally, in this work we have obtained biologically im-
portant compounds: thiazolidinones 5a–i with a similar
fragment of tacrine structure, and benzothiazepinones 7f,
7j–m as benzodiazepine analogues. The next step will be to
evaluate the potential of AChE inhibition and antidepres-
sant activity of these heterocycles.
All common reagents and solvents were used as obtained from com-
mercial suppliers without further purification. Reactions progress
was monitored by TLC (silica gel 60 F253, hexane–EtOAc (3:1), UV
254 nm). The GC-MS spectra were obtained by a Shimadzu GCMS-QP
2010SE mass spectrometer-coupled gas chromatograph (GC-MS)
with an AOC-20i automatic injector and Rtx-5MS 30 m × 0.25 mm ×
0.25 μm column. Melting points were determined using open capil-
laries on a Fisatom model 430 apparatus and are uncorrected. 1H and
13C NMR spectrum of 5g was recorded on a Bruker DRX 400 spec-
trometer (400.14 MHz for 1H and 100.61 MHz for 13C). All other spec-
tra were recorded on a Bruker Avance III 600 (1H at 600.13 MHz and
13C at 150.62 MHz), in CDCl3 or DMSO-d6 containing TMS as an inter-
nal standard also in this equipment the VT-NMR experiments were
recorded in DMSO-d6/TMS. The sample concentration was 0.17 M and
the chemical shifts (δ values) are given in ppm. The experiments
were done in a range of 298–333 K. Free energies of activation were
calculated using the Eyring equation, ΔG≠ = –RTC·ln(kc·h/kBTc), where
kc = (πΔν)/√2 or kc = π√(Δν2 + 6J2)/√2, where R, h, and kB are the gas,
Planck and Boltzmann constants, respectively. The 1H-1H NOESY NMR
experiment of compound 5b was recorded on Bruker Avance III (600
MHz) in CDCl3/TMS solutions at 298 K. The number of scans for
NOESY were 32, the pulse sequence NOESYGPPHPP relaxation delay
1.5, mixture time 0.5, and acquisition time 0.13. The general repro-
ducibility of chemical shift data was estimated to be not greater than
± 0.01 ppm. All spectra were acquired in a 5 mm tube. Chemical shifts
(δ) are given in ppm and J values in Hz.
The diffraction measurements of compounds 5a and 5e were carried
out by graphite monochromatized MoKα radiation with λ = 0.71073 Å
on a Bruker D8 Venture diffractometer. The diffraction measurements
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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B. B. Drawanz et al.
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Synthesis
of compound 5d and 7j was carried out by graphite monochroma-
tized CuKα radiation with λ = 1.54080 Å on a Bruker D8 QUEST dif-
fractometer. Two diffractometers are equipped with goniometer
KAPPA four circles, and with PHOTON II CPAD area detector. The
structures were solved with direct methods using the SHELXS pro-
gram, and refined on F2 by full-matrix least-squares with the SHELXL
package.23 Absorption correction was performed by the Gaussian
method.24 Anisotropic displacement parameters for non-hydrogen at-
oms were applied. The hydrogen atoms were placed at calculated po-
sitions with 0.96 (methyl CH3), 0.97 (methylene CH2), 0.98 (methine
CH), 0.93 (aromatic CH), and 0.82 Å (OH) using a riding model. Hydro-
gen isotropic thermal parameters were kept equal to Uiso(H) = xUeq
(carrier C atom), with x = 1.5 for methyl groups and x = 1.2 otherwise.
The valence angles C–C–H and H–C–H of methyl groups were set to
109.5°, and H atoms were allowed to rotate around the C–C bond.
Graphic projections were constructed using Ortep3 for Windows pro-
gram included in WinGx program package.25 Parameters in CIF format
are available as an electronic supplementary publication.26 The crys-
tal data and details concerning data collection and structure refine-
ment are given in SI.
3.76 (d, J = 15.9 Hz, 1 H, H5b), 2.79–2.75 (m, 2 H, CH2 cyclohexyl),
2.70–2.62 (m, 2 H, CH2 cyclohexyl), 1.88–1.76 (m, 4 H, 2 × CH2 cyclo-
hexyl).
13C NMR (150 MHz, CDCl3): δ = 172.6 (C4), 146.9, 139.8, 136.9, 135.6,
135.1, 134.0, 130.2, 129.3, 127.4, 125.9, 125.5, 125.5, 59.9 (C2), 31.6
(C5), 29.5, 24.9, 22.5, 22.4.
MS (70 eV): m/z (%) = 354 (M+, 8), 337 (63), 264 (35), 217 (50), 186
(85), 159 (100), 130 (89).
2-(3-Nitrophenyl)-3-(5,6,7,8-tetrahydronaphthalen-1-yl)thiazoli-
din-4-one (5b and 5b′)
Yield: 0.198 g (56%); off-white solid; mp 147–149 °C.
1H NMR (600 MHz, CDCl3): δH and δH′ (1 H:0.6 H′) = 8.23 (br, 1 H′,
ArH′), 8.18–8.17 (m, 2 H, ArH), 8.10 (dd, J = 8.1, 1.1 Hz, 1 H′, ArH′),
7.70 (d, J = 7.7 Hz, 1 H, ArH), 7.65 (d, J = 7.7 Hz, 1 H′, ArH′), 7.54 (t, J =
8.3 Hz, 1 H, ArH), 7.42 (t, J = 7.9 Hz, 1 H′ ArH′), 7.09 (t, J = 7.7 Hz, 1 H′,
H8′), 7.03–6.99 (m, 2 H, 1 H, H9 and 1 H′, H7′), 6.95 (d, J = 7.5 Hz, 1 H′,
H9′), 6.86 (t, J = 7.7 Hz, 1 H, H8), 6.31 (d, J = 7.7 Hz, 1 H, H7), 6.20 (s, 1
H, H2′), 5.76 (1 H, d, J = 1.5 Hz, H2), 4.09 (dd, J = 15.9, 1.7 Hz, 1 H, H5a),
4.02 (dd, J = 15.9, 1.5 Hz, 1 H′,H5a′), 3.95 (d, J = 15.9 Hz, 1 H′, H5b′),
3.91 (d, J = 15.9 Hz, 1 H, H5b), 2.79–2.53 (m, 8 H, 2 × CH2 cyclohexyl
and 2 × CH2′ cyclohexyl′), 2.09–1.56 (m, 8 H, 2 × CH2 and 2 × CH2′ cy-
clohexyl′).
13C NMR (150 MHz, CDCl3): δC and δC′ = 170.9 (C4), 169.4 (C4′), 148.3,
148.0, 142.6, 139.9, 139.5, 139.3, 135.9, 135.0, 134.8, 134.7, 134.3,
133.6, 130.2, 129.9, 129.5, 129.4, 126.8, 126.0, 124.1, 124.0, 123.4,
122.6, 122.5, 65.7 (C2′), 63.9 (C2), 33.5 (C5′), 32.4 (C5), 29.4, 29.2,
25.2, 24.8, 22.5, 22.5, 22.3, 22.2.
All theoretical calculations were performed with the Gaussian09
package of programs.27 With the aim to obtain the most stable con-
former of compounds, a scan of the dihedral angle C–N–C=C changing
360° in steps of 10° at the HF/3-21G was performed A scan of the di-
hedral angle C(carbonyl)–N–C(aromatic)–C(aromatic) was performed
for the compounds 5b, 5c, and 5d changing the angle in 360° in steps
of 10° at the HF/3-21G level. The more stable conformers were reopti-
mized at the B3LYP/cc-pVDZ level. All the other geometries of com-
pounds were fully optimized at the B3LYP/cc-pVDZ level of theory
taking into account the effect of the solvent (CHCl3). All geometries
were verified as minima on the potential energy by calculating the
Hessian matrices by harmonic frequency calculations. The atomic co-
ordinates used in theoretical calculations for compounds 5b, 5c, and
5d are given in the SI.
MS (70 eV): m/z (%) = 354 (M+, 43), 321 (3), 279 (53), 252 (12), 187
(27), 159 (100), 131 (35).
2-(4-Nitrophenyl)-3-(5,6,7,8-tetrahydronaphthalen-1-yl)thiazoli-
din-4-one (5c and 5c′)
The general structure of 2-arylthiazolidin-4-ones 5a–i with number-
ing of carbon atoms is presented in Figure 4.
Yield: 0.221 g (60%); yellow solid; mp 191–193 °C.
1H NMR (600 MHz, CDCl3): δH and δH′ (1 H:0.5 H′) = 8.19 (d, J = 8.6 Hz,
2 H, ArH), 8.09 (d, J = 8.6 Hz, 2 H′, ArH), 7.53–7.50 (m, 3 H, 2 H, ArH
and 1 H′, ArH), 7.09 (t, J = 7.7 Hz, 1 H′, H8′), 7.01 (d, J = 7.8 Hz, 1 H, H9
and 1 H′, H7′), 6.96 (d, J = 7.5 Hz, 1 H′, H9′), 6.88 (t, J = 7.7 Hz, 1 H, H8),
6.33 (d, J = 7.8 Hz, 1 H, H7), 6.18 (s, 1 H′, H2′), 5.73 (br, 1 H, H2), 4.07
(d, J = 15.8 Hz, 1 H, H5a), 4.01 (d, J = 15.9 Hz, 1 H′, H5a′), 3.94 (d, J =
15.8 Hz, 1 H′, H5b′), 3.90 (d, J = 15.9 Hz, 1 H, H5b), 2.78–2.52 (m, 8 H,
2 × CH2 cyclohexyl and 2 × CH2′ cyclohexyl′), 2.04–1.96 (m, 8 H, 2 ×
CH2 cyclohexyl and 2 × CH2′ cyclohexyl′).
5b
H
5a
H
15
14
O
12
5
11
8
13
10
N 4 S 1
6
2
3
9
H
16
7
21
17
R
X
20
18
19
5a–i
13C NMR (150 MHz, CDCl3): δC and δC′ = 170.9 (C4), 169.4 (C4′), 148.2,
148.1, 147.4, 144.6, 139.5, 139.3, 135.8, 135.0, 134.9, 134.7, 130.2,
129.6, 129.4, 128.4 (2 C), 126.5, 126.1, 126.0, 124.1 (2 C), 123.5, 122.5,
65.7 (C2′), 63.8 (C2), 33.5 (C5′), 32.3 (C5), 29.4, 29.2, 25.1, 24.8, 22.5,
22.5, 22.3, 22.2.
MS (70 eV): m/z (%) = 354 (M+, 62), 279 (58), 251 (11), 205 (11), 187
(21), 159 (100), 131 (34).
Figure 4 General structure of 2-arylthiazolidin-4-ones 5a–i
1,3-Thiazolidin-4-ones 5a–c, General Procedure
The compounds 5a–c were synthesized according Masteloto et al.17c
but purified by column chromatography using hexane–EtOAc (8:2) as
eluent (for 5a,b) or recrystallization from EtOH (for 5c).
2-(2-Nitrophenyl)-3-(5,6,7,8-tetrahydronaphthalen-1-yl)thiazoli-
din-4-one (5a)
1,3-Thiazolidin-4-ones 5d–i, General Procedure
A mixture of 5,6,7,8-tetrahydronaphthalen-1-amine (1; 0.147 g, 1
mmol) and the corresponding arenealdehyde 2d–i (1 mmol) in tolu-
ene (30 mL) was heated to reflux using a Dean–Stark apparatus for 30
min. Then, mercaptoacetic acid (4; 0.42 mL, 6 mmol) was added and
the mixture was heated until the reaction was complete (24 h). The
organic layer was washed with sat. aq NaHCO3 (3 × 20 mL), dried
(MgSO4), and concentrated under reduced pressure. The crude
Yield: 0.184 g (52%); yellow solid; mp 179–181 °C.
1H NMR (600 MHz, CDCl3): δ = 8.01 (d, J = 7.8 Hz, 1 H, ArH), 7.94 (d, J =
7.8 Hz, 1 H, ArH), 7.79 (t, J = 7.0 Hz, 1 H, ArH), 7.51 (t, J = 7.3 Hz, 1 H,
ArH), 7.04 (d, J = 7.1 Hz, 1 H, H9), 6.93 (t, J = 7.3 Hz, 1 H, H8), 6.64 (d,
J = 7.3 Hz, 1 H, H7), 6.29 (s, 1 H, H2), 3.97 (d, J = 15.9 Hz, 1 H, H5a),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

G
B. B. Drawanz et al.
Paper
Synthesis
compounds 5e–i were purified by column chromatography on silica
gel using hexane–EtOAc (8:2) as eluent. The crude 5d was recrystal-
lized from EtOH.
2-(Pyridin-3-yl)-3-(5,6,7,8-tetrahydronaphthalen-1-yl)thiazoli-
din-4-one (5g and 5g′)
Yield: 0.217 g (70%); orange oil.
1H NMR (400 MHz, CDCl3): δH and δH′ (1 H:0.15 H′) = 8.56 (dd, J = 4.8,
1.5 Hz, 1 H, ArH), 8.49 (dd, J = 4.8, 1.4 Hz, 1 H′, ArH′), 8.46 (d, J = 1.8
Hz, 1 H′, ArH′), 8.44 (d, J = 1.9 Hz, 1 H, ArH), 7.81–7.78 (m, 2 H, ArH),
7.34 (dd, J = 7.9, 4.9 Hz, 1 H, ArH), 7.22 (dd, J = 7.9, 4.9 Hz, 1 H′, ArH′),
7.10 (t, J = 7.6 Hz, 1 H′, H8′), 7.03–6.99 (m, 2 H, H9 and H7′), 6.96 (d,
J = 7.4 Hz, 1 H′, H9′), 6.87 (t, J = 7.7 Hz, 1 H, H8), 6.29 (d, J = 7.7 Hz, 1 H,
H7), 6.10 (s, 1 H′, H2′), 5.71 (d, J = 1.4 Hz, 1 H, H2), 4.08–3.99 (m, 1 H,
H5a and 1 H′, H5a′), 3.95–3.89 (m, 1 H′, H5b′ and 1 H, H5b), 2.77–1.26
(m, 16 H, 4 × CH2 cyclohexyl and 4 × CH2′ cyclohexyl′).
13C NMR (100 MHz, CDCl3): δC and δC′ = 170.9 (C4), 169.4 (C4′), 150.3,
150.2, 149.6, 149.6, 148.7, 139.4, 139.2, 136.2, 135.8, 135.7, 135.5,
134.7, 134.6, 133.1, 130.1, 129.6, 126.9, 126.0, 125.0, 123.7, 123.2,
122.8, 104.9, 64.3 (C2′), 62.3 (C2), 33.5 (C5′), 32.5 (C5), 29.4, 29.2,
24.9, 24.8, 22.5, 22.5, 22.2, 22.1.
2-Phenyl-3-(5,6,7,8-tetrahydronaphthalen-1-yl)thiazolidin-4-one
(5d and 5d′)
Yield: 0.157 g (51%); off-white solid; mp 184–186 °C.
1H NMR (600 MHz, CDCl3): δH and δH′ (1 H:0.6 H′) = 7.32 (br, 5 H, ArH
and 2 H′, ArH′), 7.22–7.21 (m, 3 H′, ArH′), 7.08 (t, J = 7.4 Hz, 1 H′, H8′),
7.01 (d, J = 7.6 Hz, 1 H, H7′), 6.99 (d, J = 7.4 Hz, 1 H, H9), 6.93 (d, J = 7.1
Hz, 1 H′, H9′), 6.84 (t, J = 7.6 Hz, 1 H, H8), 6.33 (d, J = 7.7 Hz, 1 H, H7),
6.07 (s, 1 H′, H2′), 5.64 (s, 1 H, H2), 4.06 (d, J = 15.8 Hz, 1 H, H5a), 4.00
(d, J = 15.7 Hz, 1 H′, H5a′), 3.90 (d, J = 15.8 Hz, 1 H′, H5b′), 3.86 (d, J =
15.7 Hz, 1 H, H5b), 2.77–2.45 (m, 8 H, 2 × CH2 cyclohexyl and 4 H′ 2 ×
CH2′ cyclohexyl′), 2.03–1.22 (m, 8 H, 2 × CH2 cyclohexyl and 2 × CH2′
cyclohexyl′).
13C NMR (150 MHz, CDCl3): δC and δC′ = 171.1 (C4), 169.7 (C4′), 140.2,
139.0, 138.9, 137.3, 136.3, 135.6, 135.4, 134.7, 129.8, 129.2, 129.2,
129.1, 128.7 (2 C), 128.5, 128.2, 127.5 (2 C), 126.8, 125.8, 125.8, 123.0,
67.1 (C2′), 65.1 (C2), 33.7 (C5′), 32.6 (C5), 29.5, 29.3, 24.9, 24.8, 22.7,
22.6, 22.4, 22.2.
MS (70 eV): m/z (%) = 310 (M+, 75), 277 (29), 235 (80), 207 (37), 187
(49), 159 (100), 136 (67).
2-(2-Fluorophenyl)-3-(5,6,7,8-tetrahydronaphthalen-1-yl)thiazo-
lidin-4-one (5h and 5h′)
MS (70 eV): m/z (%) = 309 (M+, 70), 276 (56), 234 (100), 206 (47), 177
(21), 159 (83), 135 (73).
Yield: 0.153 g (47%); off-white solid, mp 142–145 °C.
1H NMR (600 MHz, CDCl3): δH and δH′ (1 H:0.4 H′) = 7.54 (t, J = 7.2 Hz,
1 H′, ArH′), 7.41 (t, J = 7.1 Hz, 1 H, ArH), 7.30–7.27 (m, 1 H, ArH), 7.23–
7.17 (m, 1 H′, ArH′), 7.13 (t, J = 7.5 Hz, 1 H, ArH), 7.07 (d, J = 6.5 Hz, 1
H, ArH), 7.01–6.98 (m, 2 H, H9 and H7′), 6.94 (d, J = 5.4 Hz, 1 H′, H9′),
6.88 (t, J = 7.7 Hz, 1 H, H7), 6.44 (br, 1 H and H2′), 5.94 (s, 1 H, H2),
4.07–4.01 (m, 2 H, H5a and H5a′), 3.88 (d, J = 15.6 Hz, 1 H, H5b′), 3.82
(d, J = 15.6 Hz, 1 H, H5b), 2.78–2.53 (m, 8 H, 2 × CH2 cyclohexyl and 2
× CH2′ cyclohexyl′), 1.85–1.73 (m, 8 H, 2 × CH2 cyclohexyl and 2 × CH2′
cyclohexyl′).
2-(2-Chlorophenyl)-3-(5,6,7,8-tetrahydronaphthalen-1-yl)thiazo-
lidin-4-one (5e)
Yield: 0.195 g (57%); off-white solid; mp 154–156 °C.
1H NMR (600 MHz, CDCl3): δ = 7.75 (br, 1 H, ArH), 7.39–7.17 (m, 4 H,
ArH and CHCl3), 7.02–7.01 (m, 1 H, ArH), 6.91–6.91 (m, 1 H, ArH), 6.55
(d, J = 7.4 Hz, 1 H, H7), 6.25 (br, 1 H, H2), 3.98 (d, J = 15.4 Hz, 1 H, H5a),
3.80 (d, J = 13.7 Hz, 1 H, H5b), 2.78–2.72 (m, 4 H, 2 × CH2 cyclohexyl),
1.84–1.77 (m, 4 H, 2 × CH2 cyclohexyl).
13C NMR (150 MHz, CDCl3): δC and δC′ = 171.2 (C4), 169.5 (C4′), 160.6
(d, 1J = 248.5 Hz, 1 C′), 160.4 (d, 1J = 249.1 Hz, 1 C), 139.1, 138.7, 135.9,
135.2, 134.9, 130.8 (d, 3J = 8.4 Hz, 1 C′), 130.6 (d, 3J = 8.4 Hz, 1 C),
129.9, 129.2, 128.8 (d, 4J = 2.4 Hz, 1 C), 127.5, 127.4, 126.1, 125.8,
124.4, (d, 4J = 3.4 Hz, 1 C), 124.1, 123.0, 116.0 (d, 2J = 21.4 Hz, 1 C),
115.5 (d, 2J = 22.0 Hz, 1 C′), 59.5 (C2′), 58.8 (C2), 33.6 (C5′), 32.5 (C5),
29.4, 29.3, 24.8, 24.7, 22.6, 22.5, 22.3, 22.2.
13C NMR (150 MHz, CDCl3): δ = 171.7 (C4), 139.2, 135.5, 135.1, 135.0,
129.9, 129.7, 127.7, 127.3, 127.2, 126.1, 125.8, 60.6 (C2), 33.7 (C5′),
32.0 (C5), 29.5, 24.9, 22.6, 22.6.
MS (70 eV): m/z (%) = 343 (M+, 70), 308 (36), 268 (59), 234 (31), 186
(22), 159 (100), 135 (63).
2-(4-Chlorophenyl)-3-(5,6,7,8-tetrahydronaphthalen-1-yl)thiazo-
lidin-4-one (5f and 5f′)
MS (70 eV): m/z (%) = 327 (M+, 70), 294 (30), 252 (86), 224 (48), 186
(21), 159 (100), 130 (44).
Yield: 0.185 g (54%); orange oil.
1H NMR (600 MHz, CDCl3): δH and δH′ (1 H:0.7 H′) = 7.29 (d, J = 8.5 Hz,
2 H, ArH), 7.27–7.25 (m, 4 H, 2 × ArH, 2 × ArH′ and CHCl3), 7.19 (d, J =
8.4 Hz, 2 H′, ArH′), 7.07 (t, J = 7.7 Hz, 1 H′, H8′), 7.00–6.97 (m, 2 H, H9
and H7′), 6.95 (d, J = 7.5 Hz, 1 H′, H9′), 6.88 (t, J = 7.7 Hz, 1 H, H8), 6.32
(d, J = 7.7 Hz, 1 H, H7), 6.05 (s, 1 H, H2′), 5.62 (br, 1 H, H2), 4.03 (dd, J =
15.8, 1.5 Hz, 1 H, H5a), 3.96 (d, J = 15.9 Hz, 1 H, H5a), 3.89 (d, J = 16.0
Hz, 1 H, H5b′), 3.86 (d, J = 15.8 Hz, 1 H, H5b), 2.78–2.50 (m, 8 H, 2 ×
CH2 cyclohexyl and 2 × CH2′ cyclohexyl′), 2.05–1.61 (m, 8 H, 2 × CH2
cyclohexyl and 2 × CH2′ cyclohexyl′).
13C NMR (150 MHz, CDCl3): δC and δC′ = 170.9 (C4), 169.5 (C4′), 139.2,
139.1, 138.7, 136.1, 135.8, 135.3, 135.1, 135.0, 134.8, 134.6, 130.0,
129.9, 129.3, 128.9, 128.4, 126.8, 125.9, 125.8, 122.7, 119.6, 66.2 (C2′),
64.3 (C2), 33.6 (C5′), 32.5 (C5), 29.4, 29.3, 24.9, 24.8, 22.6, 22.5, 22.3,
22.2.
2-(4-Fluorophenyl)-3-(5,6,7,8-tetrahydronaphthalen-1-yl)thiazo-
lidin-4-one (5i and 5i′)
Yield: 0.173 g (53%); light orange solid; mp 145–148 °C.
1H NMR (600 MHz, CDCl3): δH and δH′ (1 H:0.7 H′) = 7.33–7.28 (m, 4 H,
2 × ArH and 2 ArH′), 7.08 (t, J = 7.7 Hz, 1 H′, ArH′), 7.01–6.99 (m, 2 H,
ArH′ and H7′), 6.95 (d, J = 7.6 Hz, 1 H′, ArH′), 6.90 (t, J = 8.5 Hz, 1 H,
ArH′), 6.86 (t, J = 7.7 Hz, 1 H, H8), 6.29 (d, J = 7.7 Hz, 1 H, H7), 6.06 (s, 1
H′, H2′), 5.65 (s, 1 H, H2), 4.03 (d, J = 15.8 Hz, 1 H, H5a), 3.97 (d, J =
15.8 Hz, 1 H′, H5a′), 3.91–3.86 (m, 1 H, H5b and 1 H′, H5b′), 2.78–2.46
(m, 8 H, 2 × CH2 cyclohexyl and 2 × CH2′ cyclohexyl′), 2.02–1.25 (m, 8
H, 2 × CH2 cyclohexyl and 2 × CH2′ cyclohexyl′).
13C NMR (150 MHz, CDCl3): δC and δC′ = 171.1 (C4), 169.6 (C4′), 162.9
(d, 1J = 248.8 Hz), 162.8 (d, 1J = 248.6 Hz), 139.1, 139.0, 136.1, 135.8 (d,
4
4J = 3.1 Hz, 1 C), 135.3, 135.1, 134.6, 133.0 (d, J = 2.7 Hz, 1 C′), 130.3
MS (70 eV): m/z (%) = 343 (M+, 46), 310 (8), 268 (60), 240 (23), 187
(21), 159 (100), 135 (62).
(d, 3J = 8.5 Hz, 2 C′), 129.9, 129.5 (d, 3J = 8.2 Hz, 2 C), 129.3, 126.9,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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B. B. Drawanz et al.
Paper
Synthesis
125.8, 125.8, 122.9, 115.7 (d, 2J = 21.9 Hz, 2 C), 115.2 (d, 2J = 21.8 Hz 2
C′), 66.2 (C2′), 64.3 (C2), 33.6 (C5′), 32.6 (C5), 29.4, 29.3, 24.9, 24.8,
22.6, 22.5, 22.3, 22.2.
MS (70 eV): m/z (%) = 339 (M+, 86), 306 (50), 297 (73), 264 (100), 250
(14), 184 (31), 121 (38).
MS (70 eV): m/z (%) = 327 (M+, 67), 294 (54), 252 (83), 224 (47), 187
5-(3,4-Dimethoxyphenyl)-1,5,8,9,10,11-hexahydronaphtho-
[1,2-e][1,4]thiazepin-2(3H)-one (7k)
(18), 159 (100), 130 (45).
Yield 0.258 g (70%); off-white solid; mp 182–185 °C.
1H NMR (600 MHz, CDCl3): δ = 7.72 (s, 1 H, NH), 7.04–7.01 (m, 2 H,
ArH), 6.92 (d, J = 8.0 Hz, 1 H, ArH), 6.86 (d, J = 8.2 Hz, 1 H, ArH), 6.74
(d, J = 8.0 Hz, 1 H, ArH), 5.64 (s, 1 H, H5), 3.88 (s, 3 H, OCH3), 3.85 (s, 3
H, OCH3), 3.26 (d, J = 11.8 Hz, 1 H, H3a), 2.95 (d, J = 10.8 Hz, 1 H, H3b),
2.75–2.60 (m, 4 H, 2 × CH2 cyclohexyl), 1.88–1.71 (m, 4 H, 2 × CH2 cy-
clohexyl).
13C NMR (150 MHz, CDCl3): δ = 170.3 (C2), 148.9, 148.8, 138.0, 134.4,
132.2, 131.3, 129.8, 128.3, 125.2, 121.6, 112.8, 111.2, 55.9 (2 × OCH3),
47.6 (C5), 31.7 (C3), 29.5, 25.3, 22.7, 22.4.
1,4-Benzothiazepin-2-ones 7f and 7j-m; General Procedure
General structure of 5-aryl-1,4-benzothiazepin-2-ones 7f, 7j–m with
numbering of carbon atoms is presented in Figure 5.
15
O
3b
12
1
14
13
H
HN
11
2
H
10
9
6
3a
5
S 4
7
H
8
16
21
17
MS (70 eV): m/z (%) = 369 (M+, 100), 336 (38), 312 (40), 294 (61), 278
(10), 231 (17), 184 (20).
R
18
20
19
7f, 7j–m
5-(p-Tolyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-e][1,4]thiazepin-
2(3H)-one (7l)
Figure 5 General structure of 5-aryl-1,4-benzothiazepin-2-ones 7f, 7j–m
Yield: 0.180 g (56%); beige solid; mp 229–231 °C.
A mixture of 5,6,7,8-tetrahydronaphthalen-1-amine (1; 0.147g, 1
mmol), the corresponding arenealdehyde 2f (0.143 g, 2 mmol) or 2j–
m (1 mmol), and p-TsOH (0.190 g, 1 mmol) in toluene (30 mL) was
heated to reflux using a Dean–Stark apparatus for 30 min. Then, mer-
captoacetic acid (4; 0.21 mL, 3 mmol) was added and the mixture was
heated until the reaction was complete (24 h). The organic layer was
washed with sat. aq NaHCO3 (3 × 20 mL), dried (MgSO4), and concen-
trated under reduced pressure. The crude compounds were purified
by recrystallization from EtOH, except 7l, which was purified by col-
umn chromatography on silica gel using hexane–EtOAc (8:2) as elu-
ent.
1H NMR (600 MHz, CDCl3) δ = 7.87 (s, 1 H, NH), 7.28 (d, J = 7.9 Hz, 2 H,
ArH), 7.10 (d, J = 7.7 Hz, 2 H, ArH), 6.82 (d, J = 8.0 Hz, 1 H, ArH), 6.63
(d, J = 8.0 Hz, 1 H, ArH), 5.58 (s, 1 H, H5), 3.18 (d, J = 11.8 Hz, 1 H, H3a),
2.87 (d, J = 11.5 Hz, 1 H, H3b), 2.66–2.59 (m, 4 H, 2 × CH2 cyclohexyl),
2.28 (s, 3 H, CH3), 1.79–1.63 (m, 4 H, 2 × CH2 cyclohexyl).
13C NMR (150 MHz, CDCl3): δ = 170.4 (C2), 137.9, 137.7, 134.5, 134.4,
132.1, 131.3, 129.3 (2 C), 129.2 (2 C), 128.2, 125.2, 47.5 (C5), 31.7 (C3),
29.5, 25.2, 22.7, 22.4, 21.1 (CH3).
MS (70 eV): m/z (%) = 323 (M+, 100), 336 (38), 312 (40), 294 (61), 278
(10), 231 (17), 184 (20).
5-(4-Chlorophenyl)-1,5,8,9,10,11-hexahydronaphtho-
[1,2-e][1,4]thiazepin-2(3H)-one (7f)
5-(2,6-Dichlorophenyl)-1,5,8,9,10,11-hexahydronaphtho-
[1,2-e][1,4]thiazepin-2(3H)-one (7m)
Yield: 0.102 g (30%); yellowish solid; mp 201–203 °C.
Yield: 0.215 g (57%); off-white solid; mp 232–235 °C.
1H NMR (600 MHz, DMSO-d6): δ = 8.96 (s, 1 H, NH), 7.47–7.43 (m, 4 H,
ArH), 6.95 (d, J = 7.9 Hz, 1 H), 6.71 (d, J = 7.7 Hz, 1 H), 5.54 (s, 1 H, H5),
2.98 (d, J = 12.0 Hz, 1 H, H3a), 2.90 (d, J = 11.9 Hz, 1 H, H3b), 2.70–2.49
(m, 4 H, 2 × CH2 cyclohexyl), 1.72–1.64 (m, 4 H, 2 × CH2 cyclohexyl).
13C NMR (150 MHz, DMSO-d6): δ = 167.6 (C2), 136.9, 134.8, 131.5,
131.4, 130.8, 130.0 (2 C), 127.7 (2 C), 126.9, 124.1, 46.0 (C5), 30.3 (C3),
28.3, 23.9, 21.6, 21.4.
1H NMR (600 MHz, CDCl3): δ = 7.40 (d, J = 8.0 Hz, 2 H, ArH), 7.29 (br, 1
H, NH), 7.24 (t, J = 8.1 Hz, 1 H, ArH), 6.93 (d, J = 8.1 Hz, 1 H, ArH), 6.85
(d, J = 8.1 Hz, 1 H, ArH), 6.73 (s, 1 H, H5), 3.57 (d, J = 12.4 Hz, 1 H, H3a),
2.96 (dd, J = 12.4, 1.4 Hz, 1 H, H3b), 2.77–2.56 (m, 4 H, 2 × CH2 cyclo-
hexyl), 1.94–1.67 (m, 4 H, 2 × CH2 cyclohexyl).
13C NMR (150 MHz, CDCl3): δ = 170.2 (C2), 138.7, 134.9, 132.9, 131.4,
129.7, 127.9, 126.5, 126.1, 42.9 (C5), 31.6 (C3), 29.5, 25.6, 22.7, 22.3.
MS (70 eV): m/z (%) = 343 (M+, 100), 301 (78), 268 (65), 232 (35), 218
(21), 165 (8), 118 (27).
Funding Information
5-(4-Methoxyphenyl)-1,5,8,9,10,11-hexahydronaphtho-
[1,2-e][1,4]thiazepin-2(3H)-one (7j)
CNPq (307330/2012-5).
C
o
nseh
l
o
N
a
ocin
a
l
de
D
ese
n
v
ovmli
e
n
ot
Cecnifoít
e
Te
c
n
oólgcoi
C(
N
P
q)
3(
0
7
3
3
0
2/
0
1
2-5)
Yield 0.244 g (72%); golden colored solid; mp 206–209 °C.
1H NMR (600 MHz, CDCl3): δ = 8.15 (s, 1 H, NH), 7.40 (d, J = 8.5 Hz, 2
H, ArH), 6.91–6.89 (m, 3 H, ArH), 6.70 (d, J = 8.0 Hz, 1 H), 5.65 (s, 1 H,
H5), 3.81 (s, 3 H, OCH3), 3.27 (d, J = 11.8 Hz, 1 H, H3a), 2.94 (d, J = 11.8
Hz, 1 H, H3b), 2.78–2.63 (m, 4 H, 2 × CH2 cyclohexyl), 1.90–1.66 (m, 4
H, 2 × CH2 cyclohexyl).
13C NMR (150 MHz, CDCl3): δ = 170.6 (C2), 159.2, 137.9, 134.4, 132.0,
131.3, 130.5 (2 C), 129.2, 128.2, 125.1, 113.9 (2 C), 55.2 (OCH3), 47.1
(C5), 31.7 (C3), 29.4, 25.2, 22.7, 22.3.
Acknowledgment
The authors thank UFPel, FAPERS and CAPES (B.B.D.)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590866.
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p
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ortiInfogrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

I
B. B. Drawanz et al.
Paper
Synthesis
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