Synthesis of novel 2-Aryl-3-(2-morpholinoethyl)-1,3-thiazinan-4-ones via ultrasound irradiation

Article abstract of DOI:10.5935/0103-5053.20160009

This study describes the synthesis of fourteen thiazinanones from a multicomponent reaction of 2-morpholinoehtylamine (as primary amine), arenealdehydes (as carbonyl compound) and the mercaptopropionic acid using both conventional (thermal heating) and ul

Full text of DOI:10.5935/0103-5053.20160009

http://dx.doi.org/10.5935/0103-5053.20160009
J. Braz. Chem. Soc., Vol. 27, No. 6, 1109-1115, 2016.
Printed in Brazil - ©2016 Sociedade Brasileira de Química
0
103 - 5053 $6.00+0.00
Article
Synthesis of Novel 2-Aryl-3-(2-morpholinoethyl)-1,3-thiazinan-4-ones Via
Ultrasound Irradiation
a
a
b
b
Daniela P. Gouvêa, Gabriele A. Berwaldt, Patrícia D. Neuenfeldt, Ricardo J. Nunes,
c
,a
Wanda P. Almeida and Wilson Cunico*
a
Laboratório de Química Aplicada a Bioativos (LaQuiABio), Universidade Federal de Pelotas
(
UFPel), Campus Universitário, CP 354, 96010-900 Pelotas-RS, Brazil
b
Laboratório Estrutura e Atividade (LEAT), Universidade Federal de Santa Catarina (UFSC),
Campus Trindade, 88040-970 Florianópolis-SC, Brazil
c
Laboratório de Desenvolvimento de Fármacos e Medicamentos (LAFAME), Universidade Estadual
de Campinas (UNICAMP), CP 6154, 13083-970 Campinas-SP, Brazil
This study describes the synthesis of fourteen thiazinanones from a multicomponent reaction
of 2-morpholinoehtylamine (as primary amine), arenealdehydes (as carbonyl compound) and the
mercaptopropionic acid using both conventional (thermal heating) and ultrasound methodologies.
Through thermal heating methodology, the thiazinanones were obtained in 49 to 97% yields for
1
6 hours and through sonochemistry methodology, the reaction time was reduced for 25 minutes
with yields 41 to 88%. The full identification and characterization of unpublished heterocycles were
1
13
achieved by proton ( H) and carbon 13 ( C) nuclear magnetic resonance (NMR) spectroscopy,
mass spectrometry and infrared. Some of them were also characterized by elemental analysis.
Keywords: thiazinanone, 2-morpholinoethylamine, multicomponent reaction, sonochemistry
Introduction
diverse biological activities. Sonochemistry has been also
studied to the synthesis of heterocycles, such as thiazoles,
6
7
8
9
The cleaner ultrasound methodology has been very
effective in organic synthesis, especially in cases where
the reactions take too much time. The effect of cavitation
thiophenes, thiazines and thiadiazines. Our research
group and others recently published the efficient ultrasound
1
10-13
14
synthesis of thiazolidinones
and thiazolidinediones.
promotes the formation, growth and collapse of bubbles
in the irradiated liquid. Consequently, the resulting high
temperature and pressure inside the bubbles enhances mass
transfer and a turbulent flow in the liquid and the reaction
Thiazinanones also belongs to this heterocyclic class and it
is important to note that, to our knowledge, the application
of sonochemistry to the synthesis of thiazinanones has not
been reported in the literature.
2,3
time is reduced.
Six-membered thiazinanones show important biological
properties as antioxidant, anti-inflammatory, anti-diabetic
Multicomponent reaction is a modern and environmental
friendly synthetic strategy, wherein three or more starting
materials are converted into one product. This kind of
reaction has attracted interest in organic synthesis due the
various advantages, such as reduction in reaction times,
economy of the atoms and simplification of the synthetic
procedures. This approach has also been widely exploited
in medicinal chemistry for obtaining bioactive compound
1
5-18
and antimicrobial.
The strategies to the synthesis of
thiazinanones are quite similar to the strategies to the
synthesis of analogue five-membered thiazolidinones.
Thus, thiazinanones could be obtained by a multicomponent
reaction between a primary amine, an aldehyde (or ketone)
1
5,17,19
and the mercaptopropionic acid
or by a reaction
18
between thioureas and β-propylhaloacetic acid. Moreover,
these methods can be applied in two steps, multicomponent
(all reactants together in the beginning of reaction) or one-
pot reactions, under catalysis or not.
4
5
libraries including heterocycles.
Small heterocyclic moieties containing atoms of nitrogen,
sulfur and oxygen have been extensively studied due to their
These observations associated to the crescent interest
in multicomponent reactions encouraged us to evaluate
*e-mail: wjcunico@yahoo.com.br; wilson.cunico@ufpel.edu.br

1
110
Synthesis of Novel 2-Aryl-3-(2-morpholinoethyl)-1,3-thiazinan-4-ones Via Ultrasound Irradiation
J. Braz. Chem. Soc.
the effect of ultrasound on the three component synthesis
of novel thiazinanones from 2-morpholinoehtylamine,
arenealdhydes and mercaptopropionic acid. For comparative
purpose, the reactions were performed in the presence and
in the absence of ultrasonic irradiation, i.e., by conventional
method.
General procedure for the synthesis of 2-(aryl)-3-(2-
morpholinoethyl)-1,3-thiazinan-4-ones
Synthesis of thiazinanones 5a-n by thermal heating
methodology
In a 100 mL flask with a Dean-Stark apparatus, toluene
(
50 mL), 2-morpholinoethylamine [4-(2-aminoethyl)
morpholine] 2 (1 mmol) and corresponding arenealdehyde
a-n (1 mmol) were added and the reaction mixture
Experimental
1
Material and methods
was heated at 110 ºC for 3 h. After this time, the
mercaptopropionic acid 4 (2 mmol) was added and the
mixture was heated for additional 16 h. The reaction
mixture was washed with saturated solution of NaHCO3
Reagents and solvents were purchased from Sigma-
Aldrich (St. Louis, MO, USA) and were used without
additional purification. Reactions in ultrasound were carried
out with a microtip probe (3 mm) connected to a 500 W
SonicsVibra-Cell ultrasonic processor (Sonics & Materials,
Inc., Newtown, CT, USA), operating at 20 kHz (25% of
the maximum power output). Reactions were monitored by
thin layer chromatography (silica gel 60 F253, ultraviolet
(3 × 30 mL), dried with MgSO and concentrated in vacuo
4
to give the expected thiazinanones. When necessary, the
compounds were washed with a hot hexane to furnish the
pure compounds.
Synthesis of thiazinanones 5a-n by ultrasound methodology
A mixture of 2-morpholinoethylamine 2 (1 mmol),
arenealdehyde 1a-n (1 mmol) and mercaptopropionic
acid 4 (3 mmol) in toluene (10 mL) was sonicated for
25 min in an ultrasonic probe with frequency of 20 kHz.
The organic layer was washed with a saturated solution of
NaHCO (3 × 30 mL), dried with MgSO and concentrated
2
54 nm) and gas chromatography, in a gas chromatograph
(
GC) GC-2010 (Shimadzu Corp., Kyoto, Japan) with a
column ID of 0.25 mm and length of 30 m. The analyses
were carried out with a 14 psi column head pressure. The
temperature range was 50 °C (2 min) to 250 °C (10 min)
−
1
with a 16 °C min rate. Temperatures of the injector
and detector were 250 and 270 °C, respectively. Gas
chromatography with mass spectrometer (GC-MS) analyses
was performed on a GC-2010 plus GCMS-QP2010 SE
system AOC-20i auto injector (Shimadzu, Kyoto, Japan).
3
4
in vacuo to generate the products without purification.
Selected data for the thiazinanones 5a-n
1
13
Proton ( H) and carbon 13 ( C) nuclear magnetic resonance
NMR) spectra were recorded on a Bruker DRX 400
(
1
13
spectrometer (400.14 MHz for H and 100.61 MHz for C)
or on a Bruker AVANCE 600 spectrometer (600.17 MHz
1
13
for H and at 150.91 MHz for C) or on a BrukerAC 200 F
1
13
spectrometer ( H at 200.13 MHz and C at 50.32 MHz;
Billerica, MA, USA) in CDCl containing tetramethylsilane
3
1
3
(
TMS) as internal standard. The C NMR spectrum of
Figure 1. Atom-numbering for thiazinanones 5a-n.
compound 5k was recorded on Bruker AVANCE 500
spectrometer (125.75 MHz). The fids were processed in
the MestReC 4.7.0.0 (Mestrelab Research SL, Santiago de
Compostela, Spain) or in the TopSpin (Bruker, Billerica,
MA, USA) softwares. Figure 1 shows the atom-numbering
for thiazinanones 5a-n to the identification of NMR signals.
Infrared (IR) spectra were obtained in attenuated total
reflectance (ATR) on a IVAgilent absorption spectrometer,
model Cary 630 FTIR (Agilent Technologies, Santa
Clara, CA, USA). The elemental analyses (C, H and
N) were used for thiazinanones 5a, 5b, 5c and 5g on a
3-(2-Morpholinoethyl)-2-(2-nitrophenyl)-1,3-thiazinan-4-
one (5a)
−
1
Yellow oil; IR (ATR) νmax / cm : 2951 (C-H stretch),
sp2
2866-2816 (C-Hsp3 stretch), 1615 (C=O stretch), 1528-1462
(aromatic C=C stretch), 1525 and 1357 (NO stretch), 1121
2
1
(C-O stretch); H NMR (400 MHz, J Hz) d 2.45-2.35 (m,
H-H
5H, H-8b,H-9), 2.51-2.54 (m, 2H, H-5b, H-6b), 2.72-2.64
(m, 2H, H-7b, H-8a), 2.79-2.74 (m, 2H, H-5a, H-6a), 3.63
(t, 4H, J 4.6, H-10), 4.16 (dt, 1H, J 13.0, 4.2, H-7a), 6.85
(s, 1H, H-2), 7.19 (d, 1H, J 8.6, Ph-H), 7.44 (td, 1H,J 7.7,
1.2, Ph-H), 7.56 (td, 1H, J 7.6, 1.1, Ph-H), 8.01 (dd, 1H,
2400 Series II CHNS/OAnalyser equipment (PerkinElmer,
13
Waltham, MA, USA). Analyses were consistent within
ca. 0.4 theorical values.
J 8.0, 1.2, Ph-H); C NMR (125 MHz) d 21.5 (C-6), 34.1
(C-5), 44.8 (C-7), 53.9 (2C, C-9), 56.9 (C-8), 58.3 (C-2),

Vol. 27, No. 6, 2016
Gouvêa et al.
1111
6
6.9 (2C, C-10), 126.9, 128.9, 132.7, 135.4, 169.9 (C-4);
J 11.9), 129.68 (d, J 8.3), 159.5 (d, J 248.5), 169.3 (C-4);
GC-MS m/z (%): 324 (M , 1.65), 113 (43.12), 100 (100),
+
anal. calcd. for C H N O S: C, 54.69; H, 6.02; N, 11.96;
16
21
3
4
found: C, 54.98; H, 6.40; N, 12.01; GC-MS m/z (%): 351
86 (5.77), 44 (1.96).
+
(M , 1.5), 113 (42.86), 100 (100), 56 (8).
2
-(3-Fluorophenyl)-3-(2-morpholinoethyl)1,3-thiazinan-4-
3
-(2-Morpholinoethyl)-2-(3-nitrophenyl)-1,3-thiazinan-4-
one (5e)
−1
one (5b)
Yellow oil; IR (ATR) νmax / cm : 2961 (C-H stretch),
2947 and 2929 and 2818 (C-H stretch), 1618 (C=O stretch),
sp2
−1
White oil; IR (ATR) νmax / cm : 3062 (C-H stretch),
sp2
sp3
2
947 and 2816 (C-Hsp3 stretch), 1660 and 1454 (aromatic
1590 and 1402 (aromatic C=C stretch), 1117 (C-O stretch);
H NMR (600 MHz, JH-H Hz) d 2.45-2.34 (m, 5H, H-8b,
1
C=C stretch), 1525 and 1348 (NO stretch), 1663 (C=O
stretch), 1117 (C-O stretch); H NMR (400 MHz, J Hz)
d 2.47-2.30 (m, 8H), 2.79-2.69 (m, 1H), 3.66-3.65 (m, 4H,
H-9), 4,06-3,81 (m, 2H), 5.83 (s, 1H, H-2), 7.57 (m, 2H, Ph-
2
1
H-9), 2.60-2.53 (m, 2H, H-6b, H-8a), 2.81-2.71 (m, 4H,
H-5a, H-6a, H-5b, H-7b), 3.62-3.57 (m, 4H, H-10), 4.07 (dt,
1H, J 13.9, 5.1, H-7a), 5.75 (s, 1H, H-2), 6.98-6.91 (m, 3H,
H-H
13
13
H), 8.13 (q, 2H,J 7.6, Ph-H); C NMR (100 MHz) d 20.1
C-6), 39.6 (C-5), 42.3 (C-7), 53.6 (2C, C-9), 55.7 (C-8),
Ph-H), 7.28 (2d, 1H, J 7.9, 5.8, Ph-H); C NMR (150 MHz,
(
JC-F Hz) d 21.8 (C-6), 34.4 (C-2), 44.6 (C-7), 53.8 (C-8), 55.5
(2C, C-9), 62.2 (C-2), 67.1 (2C, C-10), 113.7 (d, J 22.7),
115.1 ( J 21.2), 122.1 (J 2.8), 130.2 (J 8.4), 142.6 (J 6.5),
162.9 (d, J 247.3), 169.2 (C-4); GC-MS m/z (%): 324 (1.56),
113 (30.74), 100 (100), 86 (5.58), 56 (9.32).
6
1
1.3 (C-2), 66.8 (2C, C-10), 121.9, 123.9, 130.3, 132.7,
41.9, 148.6, 174.2 (C-4); anal. calcd. for C H N O S:
16
21
3
4
C, 54.69; H, 6.02; N, 11.96; found: C, 54.40; H, 5.97; N,
+
11.82; GC-MS m/z (%): 351 (M , 0.98), 113 (32.21), 100
(100), 56 (9.14).
2
-(2-Chlorophenyl)-3-(2-morpholinoethyl)1,3-thiazinan-4-
3
-(2-Morpholinoethyl)-2-(4-nitrophenyl)-1,3-thiazinan-4-
one (5f)
−
1
one (5c)
White oil; IR (ATR) νmax / cm : 2951 (C-H stretch),
2868 and 2818 (C-Hsp3 stretch), 1668 (C=O stretch), 1594
sp2
−1
Brown oil; IR (ATR) νmax / cm : 3065 (C-H stretch),
sp2
2
952-2812 (C-Hsp3 stretch), 1596 and 1456 (aromatic
and 1409 (aromatic C=C stretch), 1113 (C-O stretch);
H NMR (200 MHz, JH-H Hz) d 2.41-2.30 (m, 5H, H-8b,
1
C=C stretch), 1519 and 1348 (NO stretch), 1631 (C=O
stretch), 1119 (C-O stretch); H NMR (400 MHz, J Hz)
d 2.48-2.33 (m, 5H, H-9, H-8b), 2.66-2.60 (m, 3H, H-5b,
H-6b, H-8a), 2.81-2.79 (m, 3H, H-5a, H-6a, H-7a),
2
1
H-9), 2.68-2.51(m, 3H, H-5b, H-6b, H-8a), 2.78-2.70 (m,
1H, H-7b), 2.82-278 (m, 2H, H-5a, H-6a), 3.61 (t, 4H, J 4.7,
H-10), 4.03-4.01 (m, 1H, H-7a), 6.16 (s, 1H, H-2), 7.01
(dt, 1H, J 4.7, 3.1, Ph-H), 7.22 (dt, 2H, J 4.6, 4.4, Ph-H),
H-H
3
5
.61-3.58 (m, 4H, H-10), 4.20 (dt, 1H, J 14.0, 5.6, H-7b),
.90 (s. 1H, H-2), 7.45 (d, 1H, J 8.6, Ph-H), 8.24 (d, 2H,
13
7.39 (dt, 1H, J 4.6, 3.8, Ph-H); C NMR (50 MHz) d 21.1
(C-6), 34.4 (C-5), 44.1(C-7), 53.8 (2C, C-9), 56.9 (C-8),
59.6 (C-2), 67.0 (2C, C-10), 126.5, 126.6, 129.3, 130.27,
1
3
J 8.8, Ph-H); C NMR (100 MHz) d 21.8 (C-6), 34.3
C-2), 44.9 (C-7), 53.6 (2C, C-9), 56.6 (C-8), 62.0 (C-2),
7.0 (2C, C-10), 124.3, 127.3, 130.4, 147.6, 171.8 (C-4);
anal. calcd. for C H N O S: C, 54.69; H, 6,02; N, 11.96;
(
6
+
132.6, 136.3, 169.3 (C4); GC-MS m/z (%): 340 (M , 1.81),
113 (47.70), 100 (100), 56 (9.89).
16
21
3
4
found: C, 54.42; H, 6.10; N, 11.84; GC-MS m/z (%): 351
+
(
M , 1.12), 113 (13.12), 100 (100), 44 (2.02).
2-(3-Chlorophenyl)-3-(2-morpholinoethyl)-1,3-thiazinan-
4
-one (5g)
−1
2
-(2-Fluorophenyl)-3-(2-morpholinoethyl)-1,3-thiazinan-4-
Yellow oil; IR (ATR) νmax / cm : 3050 (C-H stretch),
sp2
one (5d)
2935-2809 (C-Hsp3 stretch), 1619 (C=O stretch), 1597 and
1465 (aromatic C=C stretch), 1109 (C-O stretch); H NMR
−1
1
Yellow oil; IR (ATR) νmax / cm : 2959 (C-H stretch),
sp2
2
1
925 and 2863 (C-Hsp3 stretch), 1650 (C=O stretch), 1584-
422 (aromatic C=C stretch), 1116 (C-O stretch); H NMR
(400 MHz, JH-H Hz) d 2.46-2.33 (m, 4H, H-8b, H-9), 2.61-
1
2.52 ( m, 2H, H-6b, H-8a), 2.81-2.69 (m, 4H, H-5a, H-6a,
3
(
2
400 MHz, JH-H Hz) d 2.44-2.34 (m, 5H, H-9, H-8b),
.60-2.54 (m, 2H, H-5b, H-6b), 2.67 (dt, 1H, J 13.9, 6.1,
H-8a), 2.84-2.74 (m, 3H, H-5a, H-6a, H-7b), 3.62-3.60
m, 4H, H-10), 4.06 (dt, 1H, J 13.8, 5.4, H-7a), 6.10 (s,
H, H-2), 7.00 ( m, 2H, Ph-H), 7.27 (2d, 2H, J 7.2, 6.2,
H-7b, H-5b), 3.60 (q, 4H, J 4.7, H-10), 4.06 (dt, 1H, J 13.9,
5.2, H-7a), 5.73 (s, 1H, H-2), 7.07 (dt, 1H, J 6.6, 1.7, Ph-H),
13
7.23 (dt, 2H, J 7.9, 6.4, Ph-H); C NMR (100 MHz) d 169.3
(C-4), 141.9, 134.7, 129.8, 126.6, 124.6, 67.0 (2C, C-10),
62.2 (C-2), 56.6 (C-8), 53.8 (2C, C-9), 44.6 (C-7), 34.4
(C-5), 21.8 (C-6); anal. calcd. for C H N ClO S: C, 56.38;
(
1
1
3
Ph-H); C NMR (100 MHz, J Hz) d 21.5 (C-6), 34.5
C-F
16 21
2
2
(
6
C-2), 44.0 (C-7), 53.7 (C-8), 56.0 (2C, C-9), 57.0 (C-2),
7.0 (2C, C-10), 116.2 (J 20.9), 126.8 (d, J 2.4), 127.0 (d,
H, 6.21; N, 8.22; found: C, 56.57; H, 6.23; N, 8.35; GC-MS
m/z (%): 340 (M , 1.20), 113 (32.21), 100 (100), 56 (9.14).
+

1
112
Synthesis of Novel 2-Aryl-3-(2-morpholinoethyl)-1,3-thiazinan-4-ones Via Ultrasound Irradiation
J. Braz. Chem. Soc.
2
-(4-Chlorophenyl)-3-(2-morpholinoethyl)1,3-thiazinan-4-
JH-H Hz) d 2.45-2.33 (m, 5H, H-9, H-8b), 2.62-2.50 ( m, 2H,
one (5h)
H-6b, H-8a), 2.78-2.71 (m, 4H, H-7b, H-5, H-6a), 3.6-3.56
−1
White oil; IR (ATR) νmax / cm : 2940 (C-H stretch),
(m, 4H, H-10), 3.74 (s, 3H, OCH ), 4.05 (dt, 1H, J 13.8, 5.3,
sp2
3
2
1
858-2825 (C-Hsp3 stretch), 1508 (C=O stretch), 1576 and
463 (aromatic C=C stretch), 1102 (C-O stretch); H NMR
H-7a), 5.71 (s, 1H, H-2), 6.81 (d, 2H, J 8.7, Ph-H), 7.09 (d,
2H, J 8.7, Ph-H); C NMR (125 MHz) d 21.8 (C-6), 34.5
1
13
(
2
250 MHz, JH-H Hz) d 2.46-2.36 (m, 5H, H-9, H-8b),
.59-2.52 (m, 2H, H-6b, H-8a), 2.79-2.68 (m. 4H, H-5a,
(C-5), 53.8 (2C, C-9), 55.4 (OCH ), 56.4 (C-8), 62.45 (C-2),
3
67.0 (2C, C-10), 114.0, 127.8, 132.3, 159.4, 169.5 (C4);
+
H-5b, H-6a, H-7b), 3.61-3.59 (m, 4H, H-10), 4.08 (dt, 1H,
GC-MS m/z (%): 336 (M , 2.14), 222 (6.70), 113 (36.21),
J 13.7, 5.6, H-7a), 5.75 (s, 1H, H-2), 7.13 (d, 2H, J 8.0,
Ph-H), 7.29 (d, 2H, J 8.3, Ph-H); C NMR (100 MHz)
d 169.3 (C-4), 138.3, 133.9, 128.8, 127.9, 67.0 (2C, C-10),
100 (100), 86 (5.48), 44 (2.70).
13
2-(2-Hydroxyphenyl)-3-(2-morpholinoethyl)1,3-thiazinan-
6
2.2 (C-2), 56.5 (C-8), 53.8 (2C, C-9), 44.5 (C-7), 34.5
4-one (5l)
+
−1
(
(
C-5), 21.3 (C-6); GC-MS m/z (%): 340 (M , 1.14), 113
28.16), 100 (100), 86 (5.83), 56 (8.93).
Brown oil; IR (ATR) νmax / cm : 3344 (OH stretch),
3070 (C-Hsp2 stretch), 2950 and 2899 (C-Hsp3 stretch), 1615
(
C=O stretch), 1591 and 1441 (aromatic C=C stretch), 1115
1
2
4
-(2-Methoxyphenyl)-3-(2-morpholinoethyl)-1,3-thiazinan-
(C-O stretch); H NMR (600 MHz, J Hz) d 2.51-2.42 (m,
H-H
-one (5i)
5H, H-8b, H-9), 2.60-2.54 (m, 2H, H-6b, H-8a), 2.83-2.70
(m, 4H, H5, H-6a, H-7b), 3.62 (q, 4H, J 4.2, H-10), 4.08
(dt, 1H, J 13.8, 5.3, H-7a), 5.65 (s, 1H, H-2), 6.73 (dd,
−1
Yellow oil; IR (ATR) νmax / cm : 2947 (C-H stretch),
sp2
2
1
846-2811 (C-Hsp3 stretch), 1634 (C=O stretch), 1599 and
458 (aromatic C=C stretch), 1110 (C-O stretch); H NMR
1
13
2H, J 7.9, 1.8, Ph-H), 7.00 (d, 2H, J 7.9, Ph-H); C NMR
(
2
600 MHz, JH-H Hz) d 2.42-2.34 (m, 5H, H-8b, H-9),
.58-2.51 (m, 2H, H-6b, H-8a), 2.62 (m, 1H, J 13.9, 5.0,
(150 MHz) d 21.7 (C-6), 34.4 (C-5), 44.4 (C-7), 62.5 (C-2),
53.6 (2C, C-9), 56.1 (C-8), 66.7 (2C, C-10), 115.5, 127.8,
+
H-7b), 2.81-2.76 (m, 3H, H-5, H-6a), 3.62 (q, 4H, J 4.4,
129.8, 156.7, 170.0 (C4); GC-MS m/z (%): 322 (M , 0.50),
H-10), 3.93 (s, 3H, OCH ), 4.03 (dt, 1H, J 13.6, 4.7, H-7a),
113 (43.55), 100 (100), 86 (2.17), 44 (20.68).
3
6
.05 (s, 1H, H-2), 6.87 (q, 2H, J 7.1, Ph-H), 6.92 (dd, 1H,
13
J 7.5, 1.7, Ph-H),7.21 (dt, 1H, J 7.7,1.8, Ph-H); C NMR
150 MHz) d 21.5 (C-6), 34.6 (C-5), 44.2 (C-7), 53.7 (2C,
2-(3-Hydroxyphenyl)-3-(2-morpholinoethyl)1,3-thiazinan-
(
4-one (5m)
−
1
C-9), 56.5 (C-8), 58.6 (C-2), 67.0 (2C, C-10), 111.0, 119.9,
Brown oil; IR (ATR) νmax / cm : 3244 (OH stretch),
2949 (C-Hsp2 stretch), 2944 (OH stretch), 2861 and 2820
(C-Hsp3 stretch), 1605 (C=O stretch), 1526-1456 (aromatic
+
1
26.0, 129.2, 155.9, 169.6 (C4); GC-MS m/z (%): 336 (M ,
3
.71), 222 (6.20), 113 (66.26), 100 (100), 56 (11.51).
1
C=C stretch), 1108 (C-O stretch); H NMR (400 MHz,
2
4
-(3-Methoxyphenyl)-3-(2-morpholinoethyl)1,3-thiazinan-
JH-H Hz) d 2.50-2.38 (m, 5H, H-8b, H-9), 2.60-2.54 (m,
2H, H-6b, H-8a), 2.84-2.72 (m, 4H, H-5, H-6a, H-7a), 3.61
(q, 4H, J 4.2, H10), 4.09 (dt, 1H, J 13.8, 5.3, H7b), 5.69
(s, 1H, H2), 6.62 (d, 1H, J 1.8, Ph-H), 6.71 (dd, 2H, J 7.9,
-one (5j)
−1
Brown oil; IR (ATR) νmax / cm : 2958 (C-H stretch),
sp2
2852-2807 (C-Hsp3 stretch), 1611 (C=O stretch), 1507 and
1
13
1458 (aromatic C=C stretch), 1111 (C-O stretch); H NMR
1.8, Ph-H), 7.24 (d, 2H, J 7.9, Ph-H); C NMR (100 MHz)
(
2
400 MHz, JH-H Hz) d 2.45-2.34 (m, 5H, H-8b, H-9),
.60-2.50 (m, 2H, H-7a, H-8a), 2.79-2.68 (m, 4H, H5, H-6a,
H-7b), 3.61-3.58 (m, 4H, H-10), 3.74 (s, 3H, OCH ), 4.05
d 21.6 (C-6), 34.5 (C-5), 44.8 (C-7), 54.7 (2C, C-9), 57.3
(C-8), 63.6 (C-2), 67.9 (2C, C-10), 114.1, 116.3, 119.5,
+
131.2, 141.9, 157.7, 170.9 (C4); GC-MS m/z (%): 322 (M ,
3
(
dt, 1H, J 13.8, 5.2, H-6b), 5.71 (s, 1H, H-2), 6.91 (dd, 2H,
1.23), 113 (35.67), 100 (100), 86 (6.93), 44 (2.00).
13
J 8.7, 2.0, Ph-H), 7.10 (dd, 1H, J 8.6, 1.7, Ph-H); C NMR
100 MHz) d 21.5 (C-6), 34.6 (C-5), 44.2 (C-7), 53.7 (2C,
C-9), 55.3 (OCH ), 56.3 (C-8), 62.3 (C-2), 66.9 (2C, C-10),
(
2-(4-Hydroxyphenyl)-3-(2-morpholinoethyl)1,3-thiazinan-
4-one (5n)
3
−
1
1
3
14.0, 127.8, 131.3, 159.4, 169.4 (C-4); GC-MS m/z (%):
Yellow oil; IR (ATR) νmax / cm : 3305 (OH stretch),
+
36 (M , 2.55), 222 (1.68), 113 (42.86), 100 (100), 56 (9.69).
3056 (C-Hsp2 stretch), 2970 and 2869 (C-Hsp3 stretch), 1636
(
C=O stretch), 1610 and 1461 (aromatic C=C stretch), 1112
1
2
4
-(4-Methoxyphenyl)-3-(2-morpholinoethyl)1,3-thiazinan-
(C-O stretch); H NMR (600 MHz, J Hz) d 2.50-2.42 (m,
H-H
-one (5k)
5H, H-8b, H-9), 2.60-2.54 (m, 2H, H-6b, H-8a), 2.84-2.70
(m, 4H, H-5, H-6a, H-7b), 3.44 (dt, 1H, J 13.3, 5.7, H-7a),
3.71 (q, H4, J 4.6, H-10), 4.16 (dt, 1H, J 13.7, 5.6, H-6b),
5.74 (s, 1H, H-2), 6.82 (d, 2H, J 8.6, Ph-H), 7.08 (d, 2H,
−1
Yellow oil; IR (ATR) νmax / cm : 2941 (C-H stretch),
sp2
2851 (C-H stretch), 1601 and 1460 (aromatic C=C stretch),
sp3
1
1627 (C=O stretch), 1115 (C-O stretch); H NMR (400 MHz,

Vol. 27, No. 6, 2016
Gouvêa et al.
1113
13
J 8.5, Ph-H); C NMR (150 MHz) d 21.7 (C-6), 34.5 (C-5),
4.4 (C-7), 53.7 (2C, C-9), 56.2 (C-8), 62.5 (C-2), 66.7 (2C,
Sonification effect on the multicomponent synthesis of
thiazinanones
4
C-10), 115.6, 127.9, 156.8, 170.1 (C-4); GC-MS m/z (%):
+
3
22 (M , 1.36), 113 (32.58), 100 (100), 86 (7.14), 44 (3.09).
The six-membered thiazinanone has structural
similarity to the five-membered thiazolidinone, so the
reaction condition using ultrasound was based in such
Results and Discussion
1
2
heterocycle, according to a recent work published by us.
One-pot synthesis of thiazinanones by the conventional
thermal heating method
2-Morpholinoethylamine is an aliphatic amine and the first
experiment was carried out in a multicomponent reaction
of amine 2, 2-nitrobenzaldehyde 1a and mercaptopropionic
acid 4 (3 equivalents) in toluene for 5 min. However, it was
observed the starting material aldehyde in TLC and GC.
The next experiment was monitored by TLC in ten, fifteen,
twenty and twenty-five minutes. The complete formation
of thiazinanone 5a (up to 99% in GC) was observed in
25 min. The product was isolated and all spectrometric and
spectroscopic data are identical to those for thiazinanone
5a prepared by the conventional method. Further, the
proportion of the mercaptopropionic acid 4 was also studied
and no significant difference on yields was found when 1,
2 or 3 equivalents of acid were used.
Found the best condition, the synthesis of all
thiazinanones 5a-n were carried out in a mixture of 1 mmol
of arenaldehydes 1a-n, 1 mmol of amine 2 and 1 mmol of
the mercaptopropionic acid 4 that was sonicated for 25 min
in toluene (Scheme 2). The heterocycles 5a-n were obtained
in a range of 41-88%, without further purification.
To the synthesis of thiazinanones 5a-n, three components
were used as the starting materials: the mercaptoacetic acid,
arenealdehydes bearing electron-withdrawn or electron-
releasing groups, and the 2-morpholinoethylamine. The
choice for 2-morpholinoethylamine as amine core was
due the biological importance of heterocyclic morpholine.
Compounds with this scaffold feature a wide range of
20
biological activities, recently reviewed by Pal´chkov.
Our first purpose was the synthesis of heterocycles by
the conventional thermal heating methodology (Scheme 1).
The expected compounds were synthesized through the
one-pot reaction procedure in toluene refluxing. In this
procedure, the intermediate imine was completely formed
(
(
3 h) before the cyclocondensation step to the thiazinanones
16 h). The water was removed by azeotropic distillation
using a Dean-Stark apparatus and the progresses of all
reactions were monitored by thin layer chromatography
(
TLC) and/or by GC. The heterocycles were obtained
The comparative yields of thiazinanones 5a-n
are summarized in Table 1. The electronic nature of
arenealdehyde substituent did not affect the yields
in moderate to excellent yields after the purification by
washing with hot hexane/ethyl acetate (9:1).
O
O
H
N
S
N
NH2
(ii)
N
(
i)
N
N
R
–H O
2
O
O
O
–
H O
2
R
R
2
1a-n
5
a-n
3
a-n
Scheme 1. (i) Toluene, 110 °C, 3h; (ii) HSCH CH COOH, 110 °C, 16h (49-97%).
2
2
O
O
H
N
S
N
NH2
(i)
)))
N
O
R
O
)
R
1a-n
2
5
a-n
Scheme 2. (i) Toluene, HSCH CH COOH, ultrasound, r.t., 25 min (41-88%).
2
2

1
114
Synthesis of Novel 2-Aryl-3-(2-morpholinoethyl)-1,3-thiazinan-4-ones Via Ultrasound Irradiation
J. Braz. Chem. Soc.
1
3
of products as well the position, with exception for
thiazinanones 5l-n bearing a phenolic group that showed
lower yields. A possible explanation is the polar hydroxyl
group that increase water solubility and an amount of
product might be lost in the extraction procedure.
As we expected, the sonochemisty methodology
afford the pure thiazinanones in lower reaction times than
conventional heating (25 minutes to 19 hours) in quite
similar yields. Other important advantage of ultrasound
methodology is the absence of water remove procedure,
e.g., azeotropic distillation, desiccant agents.
the range of 2.82-2.51 ppm. In C NMR, the C10 and
C9 of morpholine ring appear at 66.7-67.9 ppm and
53.6-56.0 ppm, respectively. The chemical shift of ethylene
carbons shows that C8 is deshilded at 67.9-66.7 ppm and
C7 are shielded at 56.0-53.6 ppm, according to HMQC
spectra. The carbons of thiazinanones are assigned as
174.2-169.2 ppm for the carbonyl (C4), 62.2-57.0 ppm
for the C2, 34.6-34.1 ppm for C5 and 21.8-21.5 ppm for
C6. The HMBC confirm the assignment of C5 and C6.
Conclusions
Table 1. Yields of thiazinanones 5a-n synthesized by ultrasound and
thermal heating methodologies
Therefore, the sonochemistry was efficient as an
attractive strategy to promote the synthesis of thiazinanones
through a multicomponent reaction. The products were
obtained in good yields in shorter reaction times (25 min)
when compared to thermal heating methodology (19 h).
In addition, no water removal was necessary when the
ultrasound was used.
a
Yield / %
entry
R
Thermal heating
Ultrasound
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
2-NO2
3-NO2
4-NO2
2-F
87
79
89
97
74
85
91
64
88
87
84
60
72
49
71
86
73
82
48
46
86
78
85
75
88
53
55
41
Suplemantary Information
3-F
2-Cl
Supplementary information with analytical data (mass,
H and C NMR and infrared spectra) is available free of
1
13
g
h
i
3-Cl
4-Cl
charge at http://jbcs.sbq.org.br as PDF file.
Acknowledgments
2-OCH3
3-OCH3
4-OCH3
2-OH
3-OH
4-OH
j
k
l
Authors thank UFPel and FAPERGS (Process
11/2068-7) for the financial support. W. P.A. is also grateful
m
n
to FAPESP (Process 2013/18203-5) and W. C. is grateful
to CNPq (Process 307330/2012-5).
5
a
Yield of isolated compounds.
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