Three-component one-pot synthetic route to 2-amino-5-alkylidene-thiazol-4-ones

Article abstract of DOI:10.1016/j.tet.2008.10.045

A fast and straightforward three-component reaction to 2-amino-5-alkylidene-thiazol-4-ones is described. The one-pot methodology, reported for the first time, involves Knoevenagel condensation of aromatic aldehydes and rhodanine followed by displacement o

Full text of DOI:10.1016/j.tet.2008.10.045

Tetrahedron 65 (2009) 344–350
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Tetrahedron
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Three-component one-pot synthetic route to 2-amino-5-alkylidene-
thiazol-4-ones
*
ˇ
ˇ
Marko Anderluh , Marko Jukic, Rok Petric
ˇ
ˇ
University of Ljubljana, Department of Medicinal Chemistry, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2008
Received in revised form 1 October 2008
Accepted 16 October 2008
Available online 1 November 2008
A fast and straightforward three-component reaction to 2-amino-5-alkylidene-thiazol-4-ones is de-
scribed. The one-pot methodology, reported for the first time, involves Knoevenagel condensation of
aromatic aldehydes and rhodanine followed by displacement of the thiocarbonyl sulfur with primary or
secondary amines in the same reaction mixture. The reactions were performed using a dedicated mi-
crowave reactor, which enabled short reaction times and easy work-up.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
2-Amino-5-alkylidene-thiazol-4-one
Rhodanine
Knoevenagel condensation
Multi-component reaction
Parallel synthesis
Microwave-assisted organic synthesis
1. Introduction
In the first route the rhodanine thiocarbonyl sulfur is substituted
with the amine, either immediately (3, Route 1) or after activation
Thiazolidinone derivatives have been extensively used in drug
discovery.1 In particular, the biological activities of various 2-
amino-5-alkylidene-thiazol-4-ones (1, Fig. 1) have been reported in
approximately 150 publications, including 80 patents.2 Not sur-
prisingly, numerous synthetic routes have been developed in order
to obtain this heterocyclic core, many of which were recently
reviewed.2
These procedures involve cyclocondensations from acyclic pre-
cursors, and step-wise functionalization of thiazolones or, most
conveniently, from rhodanine (2). We were particularly interested
in synthesis from the latter, where three routes are possible (Fig. 2).
via alkyl thioether (4, Route 2), the resulting aminothiazolone being
condensed with aldehyde via Knoevenagel condensation.2,3
Alternatively, rhodanine is first condensed with an aldehyde and
the resulting alkylidene rhodanine (5) reacted with an amine
(Route 3).3a–c,4 These two procedures involve at least two sub-
sequent steps with lengthy reaction times and sometimes laborious
work-up, which is hardly convenient for a parallel synthesis. This
was partly overcome by Pulici et al. by a traceless two-step solid-
phase synthesis that, however, requires a rather expensive solid
support and still suffers from lengthy reaction times.2 During the
course of our work, Bourahla et al. reported a quite attractive
microwave-assisted synthesis of 2-amino-5-alkylidene-thiazol-4-
ones, which, however, comprises a rather complicated sequence of
reaction steps.4d
O
We are interested in the inhibition of the enzymes involved in
peptidoglycan biosynthesis (see Acknowledgements). The title
compounds and their derivatives have already been reported to
inhibit bacterial growth and/or enzymes involved in this proc-
ess.1b,5–7 To produce a library of 2-amino-5-alkylidene-thiazol-4-
ones for subsequent screening, we sought a rapid and convenient
synthetic route toward 2-amino-5-alkylidene-thiazol-4-ones. As
noted above, none of the previously reported methods appeared to
meet our requirements.
R1
N
S
R3
N
R2
1
Figure 1. 2-Amino-5-alkylidene-thiazol-4-one core.
We have therefore developed a novel, fast, and straightforward
three-component reaction to 2-amino-5-alkylidene-thiazol-4-ones
* Corresponding author. Tel.: þ386 1 47 69 639; fax: þ386 1 42 58 031.
E-mail address: marko.anderluh@ffa.uni-lj.si (M. Anderluh).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.045

M. Anderluh et al. / Tetrahedron 65 (2009) 344–350
345
O
microwave reactor for 45 min at various temperatures. Knoevena-
gel condensation proceeded quantitatively in a few minutes, as
concluded from the 1H NMR spectra of the precipitate formed after
a few minutes in the reaction mixture at room temperature (data
not included). This led us to conclude that the first step of the re-
action is a Knoevenagel condensation followed by addition of the
amine. The one-pot reaction was sufficiently robust to withstand
high temperatures (up to 150 ꢀC). As expected, higher temperatures
led to higher yields. Interestingly, microwave heating for 45 min at
80 ꢀC led to far higher yield than the conventional heating for the
same time at temperature of reflux (approx. 80 ꢀC), and practically
the same yield was obtained only after 5 h. This may be explained
by the specific non-thermal microwave effect, which could accel-
erate thiocarbonyl sulfur displacement.8,9 Thus, the addition–
elimination mechanism proceeds via the bipolar intermediate,
which could selectively absorb microwaves by dielectric heating.
Decreasing the reaction time to 20 min had no influence on the
yield, but after 10 min the conversion was incomplete. The reaction
time was thus reduced to only 20 min. It may be concluded that the
large excess of piperidine that acts as a catalyst in the Knoevenagel
condensation leads to significant reduction of time compared to the
previously reported methods.2,3a–c,4 The maximum yield obtained
by this protocol (8e) was 83%, but other yields were significantly
lower in some cases. We might speculate that the low yields are
also due to the precipitation method of isolation.
The choice of the solvent had a crucial effect on the yield and
ethanol was chosen as the best of those used. However, it should be
noted that the yields relate to the products crystallized from the
reaction mixture and the lower yield may be simply due to higher
solubility of the compounds in some solvents. Interesting yields
were obtained under solvent-free conditions, but the products
obtained were proven, by 1H NMR, not to be sufficiently pure. Since
this solvent-free procedure required additional crystallization, it
was concluded that the use of small quantities of solvent is nec-
essary to obtain pure compounds and that the reaction conditions
of the entry 5 (Table 1) are optimal. In this manner, the work-up
was optimized to a single step of filtration.
N
S
S
R3
N
ROUTE 1
R2
3
O
O
ROUTE 2
O
R1
NH
N
S
S
N
S
R3
N
R2
R4
S
2
ROUTE 3
1
4
O
R1
NH
S
S
5
Figure 2. 2-Amino-5-alkylidene-thiazol-4-one synthesis starting from rhodanine.
(Scheme 1). The one-pot methodology involves Knoevenagel con-
densation of aromatic aldehyde (6) and rhodanine (2) followed by
displacement of the thiocarbonyl sulfur with primary or secondary
amines (7) in the same reaction mixture. The amine acts as the
catalyst in the Knoevenagel condensation and as a nucleophile in
the second step. The reactions were performed using a dedicated
microwave reactor, which enabled short reaction times and easy
work-up, as well as conventional heating. Such a synthesis has not
been published before.
O
O
O
R1
R2
R3
MW
N
NH
N
H
R1
H
various
S
S
conditions
R3
N
S
6
R2
7
2
1
Reagent quantities were optimized (Table 2). Surprisingly, the
larger excess of piperidine (2 molar equivalents) was detrimental to
the yield, as was also observed with the other amines. In contrast,
the same excess of the aldehyde led to higher yields. The latter
could be explained by a competitive Cannizzaro reaction, a typical
reaction for aromatic aldehydes in the basic media that yields ar-
omatic acids and consumes aldehydes in the reaction mixture.10
Another possible cause could be the oxidation of aromatic ade-
hydes to their corresponding acids. Both were shown to be possible,
proven by 1H NMR and also by mass spectra of the crude product
Scheme
synthesis.
1. One-pot
2-amino-5-alkylidene-thiazol-4-one
microwave-assisted
2. Results and discussion
The one-pot synthesis (Scheme 1) was optimized on a model
reaction involving benzaldehyde (6a), rhodanine (2), and piperi-
dine (7a) under a variety of conditions (Table 1). The reaction was
first tried with a large excess (2 equiv) of benzaldehyde in the
Table 1
Optimization of the model one-pot synthesis with benzaldehyde (6a) and piperidine (7a) under different conditions according to the general procedure in Section 4.2.1
Entry
7a (equiv)
6a (equiv)
Heating conditions
Solvent
Reaction time
Temperature (ꢀC)
Yield %a
1
2
3
4
5
6
7
8
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.0
1.1
1.1
1.1
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.2
1.1
MW
MW
MW
MW
MW
MW
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
AcOH
THF
45 min
45 min
45 min
45 min
20 min
10 min
45 min
5 h
20 min
20 min
20 min
20 min
20 min
20 min
80
100
120
150
150
150
Reflux
Reflux
150
150
150
61
69
73
79
83
73
21
66
23
24
25
67
52
92
Conventional heating
Conventional heating
9
MW
MW
MW
MW
MW
MW
10
11
12
13b
14b
2.0
2.0
2.0
1.1
150
150
150
d
d
a
Yields relate to the products crystallized from the solvents in the reaction mixture and are calculated relative to the effective loading of rhodanine.
Yields relate to crude compounds.
b

346
M. Anderluh et al. / Tetrahedron 65 (2009) 344–350
Table 2
and ninhydrin charring. Flash column chromatography was carried
out on Merck silica gel 60 (particle size 0.040–0.063 mm). Melting
points were determined on a Reichert hot stage microscope and are
uncorrected. 1H NMR spectra were recorded on a Bruker AVANCE
DPX300 spectrometer in CDCl3 or DMSO-d6 solution with TMS as
the internal standard. Coupling constants (J) are given in hertz. IR
spectra were obtained on a Perkin–Elmer 1600 FT-IR spectrometer.
Mass spectra were obtained using a VG-Analytical Autospec Q mass
spectrometer.
Microwave-assisted reactions were performed using a focused
microwave reactor (DiscoverÔ, CEM Corporation, Matthews, NC).
The reactor uses a continuous, focused microwave power-delivery
system with an operator-selectable power output of up to 300 W.
Reactions were performed in glass vials (10 mL) sealed with a sep-
tum. The pressure was monitored by a load cell connected to the
septum. The temperature of the reaction mixture was monitored
using a calibrated infrared temperature controller mounted under
the reaction vessel.
One-pot synthesis via Scheme 1 according to the optimized procedure in Section
4.2.2 with benzaldehyde (6a) and different amines
Entry
Amine
Amine equivalents
6a (equiv)
Yield %a
1
2
1.1
2.0
2.0
1.1
83
24
H
N
7a
3
4
1.1
1.1
1.2
2.0
23
55
H
N
7b
5
6
2.0
1.1
1.1
1.2
27
61
O
7
8
1.1
2.0
2.0
1.1
56
14
H
N
7c
9
1.1
1.2
37
4.2. Synthesis
10
11
12
1.1
2.0
1.1
2.0
1.1
1.2
41
11
27
NH2
7d
4.2.1. General procedure for microwave-assisted synthesis of 2-
amino-5-alkylidene-thiazol-4-ones
a
Yields relate to the products crystallized from the solvents in the reaction
mixture and are calculated relative to the effective loading of rhodanine.
To a suspension of rhodanine (1.0 equiv) in dry solvent (3 mL),
aldehyde (1.1–2.0 equiv), amine (1.1–2.0 equiv), and glacial acetic
acid (0.1 equiv) were added. The reactions were also performed
under solvent-free conditions. The reaction mixture was stirred for
half a minute in order to prevent aggregation of solid substances
and then heated with microwave irradiation (20 W of max. power)
to the desired temperature. The pressure limit was set at 20 bar.
Once the desired temperature was reached, heating was continued
for a further period (Table 1) to maintain the temperature. The
reaction vessel was then cooled in an ice bath, the precipitated
crystalline solid was filtered off, washed with ice-cooled solvent, and
dried under vacuum. If performed under solvent-free conditions,
additional recrystallization was needed to obtain pure product.
(Table 1, entry 13), which showed the characteristic peak for ben-
zoic acid (m/z 122 Mþ).
Further reactions were performed according to the optimized
conditions (Table 1, entry 5) with a variety of amines and aromatic
aldehydes. Thus we obtained a focused library of 2-amino-5-alky-
lidene-thiazol-4-ones (Table 3). The described protocol worked
well with the majority of the substrates. In only one case (15) was
flash chromatography necessary to obtain pure product.
The described synthesis could lead to two isomers, E and Z. In all
cases, the 1H NMR spectra revealed only one type of methine
proton at 7.55–7.93 ppm, at lower field values than those expected
for the E-isomers.5 Thus we may conclude that the Knoevenagel
condensation proceeds in a completely regioselective way to give
the thermodynamically more stable Z-isomer, as noted.2,4d,5
4.2.2. The optimized procedure for microwave-assisted synthesis of
2-amino-5-alkylidene-thiazol-4-ones
To a suspension of rhodanine (0.500 g, 3.75 mmol, 1.0 equiv) in
dry ethanol (3 mL), aldehyde (7.50 mmol, 2.0 equiv), amine
3. Conclusion
(4.13 mmol, 1.1 equiv), and glacial acetic acid (21
mL, 0.375 mmol,
0.1 equiv) were added. The reaction mixture was stirred before
heating for half a minute and then heated with microwave irra-
diation (20 W of max. power) to reach 150 ꢀC, the rate not ex-
ceeding 2 ꢀC/s. The pressure limit was set to 20 bar, since H2S
developed during the reaction. Once the desired temperature was
reached, the mixture was heated for a further 20 min at the same
temperature. The reaction vessel was then cooled in an ice bath,
the precipitated crystalline solid was filtered off, washed with
ice-cooled ethanol, and dried under vacuum.
This paper describes for the first time a one-pot, three-compo-
nent reaction to 2-amino-5-alkylidene-thiazol-4-ones, involving
conventional heating or microwave irradiation. The one-pot
methodology was proved to work well with different amines and
aromatic aldehydes and has numerous advantages over the pre-
viously reported methods: a robust reaction that withstands high
temperatures that significantly shorten reaction times, easy work-
up (reactions and work-up performed in one vial, simple filtration
to obtain pure products), no solid support is needed, and reactions
performed well even in solvent-free conditions (shown in a model
reaction). The protocol is thus particularly useful for parallel syn-
thesis with automated microwave synthesis systems. By its use,
a wide variety of target compounds could be reached in a matter of
days.
4.2.3. The reaction performed using conventional heating
To a suspension of rhodanine (0.500 g, 3.75 mmol, 1.0 equiv) in
dry ethanol (3 mL), benzaldehyde (1.042 mL, 7.50 mmol, 2.0 equiv),
piperidine (0.408 mL, 4.13 mmol, 1.1 equiv), and glacial acetic acid
(21 mL, 0.375 mmol, 0.1 equiv) wereadded. Thereactionmixturewas
stirred under reflux in an oil bath for 5 h. The reaction vessel was
then cooled in an ice bath, the precipitated crystalline solid was fil-
tered off, washed with ice-cooled ethanol, and dried under vacuum.
4. Experimental
4.1. General methods and materials
4.3. Analytical and spectroscopic data of the products
Chemicals from Aldrich Chemical Co., Fluka, and Acros Organics
were used without further purification. Analytical TLC was per-
formed on Merck silica gel (60 GF254) plates (0.25 mm) and com-
ponents were visualized with ultraviolet light (254 nm wavelength)
All compounds included were synthesized according to the
optimized procedure for microwave-assisted synthesis of 2-amino-
5-alkylidene-thiazol-4-ones (see Section 4.2.2).

M. Anderluh et al. / Tetrahedron 65 (2009) 344–350
347
Table 3
The one-pot synthesis via Scheme 1 according to the optimized procedure in Section 4.2.2
H
N
H
N
H
N
H
N
NH2
Compound, yield %a
7a
7b
7c
7d
7e
O
O
6a
H
8, 83%
9, 55%
10, 56%
11, 41%
12, 68%
O
H
S
13, 53%
18, 64%
14, 57%
19, 70%
15,b 37%
20, 62%
16, 55%
21, 53%
17, 81%
22, 99%
6b
O
H
6c
NC
O
H
6d
23, 56%
28, 90%
24, 80%
29, 89%
25, 63%
30, 80%
26, 57%
31, 57%
27, 95%
32, 96%
O
H
N
6e
O
H
O
33, 94%
34, 82%
35, 70%
36, 66%
37, 88%
O
H
6f
O
a
Yields relate to the products crystallized from the solvents in the reaction mixture (except 15) and are calculated relative to the effective loading of 2.
The pure compound was obtained after purification with flash chromatography.
b
4.3.1. 5-Benzylidene-2-(piperidin-1-yl)thiazol-4(5H)-one (8)2
Yellow crystalline solid (0.849 g, 83% yield). Mp¼213–215 ꢀC. IR
nmax (KBr): 2939, 1700, 1673, 1612, 1560 cmꢁ1. 1H NMR (300 MHz,
49.2, 50.0, 129.7, 130.4, 130.5, 134.8, 174.2, 180.2 ppm. MS (EI): m/z
286 (Mþ, 73%), 134 (100). HRMS (ESI): calcd for C16H19N2OS
287.1218, found 287.1222.
CDCl3):
d
¼1.78 (6H, br s, –CH2–CH2–CH2–), 3.60 (2H, br s, –CHax
-
Heq–N–CHaxHeq–), 4.03–4.06 (2H, m, –CHaxHeq–N–CHaxHeq–), 7.39–
7.49 (3H, m, CHAr), 7.56 (dd, 2H, dd, J¼1.2, 8.3 Hz, CHAr), 7.82 (1H, s,
CH) ppm. MS (ESI): m/z 273 (MHþ, 100). HRMS (ESI): calcd for
C15H17N2OS 273.1062, found 273.1056.
4.3.4. 2-(Benzylamino)-5-benzylidenethiazol-4(5H)-one (11)2,11
Pale yellow crystalline solid (0.449 g, 41%). Mp¼236–237 ꢀC.
IR nmax (KBr): 3207, 3012, 2363, 1674, 1622, 1492 cmꢁ1 1H NMR
.
(300 MHz, DMSO-d6):
d
¼4.75 (2H, d, J¼5.6 Hz, CH2NH), 7.29–7.64
(11H, m, CHAr, CH), 10.08 (1H, t, J¼5.6 Hz, NH) ppm. MS (ESI) m/z
295 (MHþ). HRMS (ESI) calcd for C17H15N2OS 295.0905, found
295.0908.
4.3.2. 5-Benzylidene-2-morpholinothiazol-4(5H)-one (9)11
Yellow crystalline solid (0.571 g, 55%). Mp¼194–195 ꢀC. IR nmax
(KBr): 3049, 2856, 1630, 1589 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d
¼3.09 (4H, t, J¼4.7 Hz, CH2–N–CH2), 3.82 (4H, t, J¼4.7 Hz, CH2–O–
4.3.5. 5-Benzylidene-2-(pyrrolidin-1-yl)thiazol-4(5H)-one (12)12
Yellow crystalline solid (0.661 g, 68%). Mp¼219–220 ꢀC. IR nmax
(KBr): 2361, 1682, 1616, 1558 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
CH2), 7.48–7.50 (5H, m, CHAr), 7.60 (1H, s, CH) ppm. MS (EI): m/z 274
(Mþ, 13%), 134 (100). HRMS (EI): calcd for C14H14N2O2S 274.077600,
found 274.078250.
d
¼1.96–2.06 (4H, m, –CH2–CH2–), 3.63 (2H, t, J¼6.5 Hz, –CH0H00–
N–CH0H00–), 3.71 (2H, t, J¼6.5 Hz, –CH0H00–N–CH0H00–), 7.42–7.54
(3H, m, CHAr), 7.61–7.64 (3H, m, CHAr, CH) ppm. MS (ESI): m/z 259
(MHþ, 100). HRMS (ESI): calcd for C14H15N2OS 259.0905, found
259.0910.
4.3.3. 5-Benzylidene-2-(4-methylpiperidin-1-yl)thiazol-4(5H)-
one (10)
Light yellow crystalline solid (0.598 g, 56%). Mp¼171 ꢀC. IR nmax
(KBr): 2933, 2364, 1677, 1607, 1577, 1560 cmꢁ1. 1H NMR (300 MHz,
DMSO-d6):
d
¼0.95 (3H, d, J¼6.3 Hz, CH3), 1.12–1.29 (2H, m, CH2),
4.3.6. 2-(Piperidin-1-yl)-5-((thiophen-2-yl)methylene)thiazol-
4(5H)-one (13)13
1.75–1.85 (3H, m, CH2–CH–CH3), 3.25 (1H, dt, J¼2.7, 13.5 Hz, N–
CHax2Heq2), 3.45 (1H, dt, J¼2.1, 13.5 Hz, N–CHax1Heq1), 3.80 (1H, br d,
J¼13.5 Hz, N–CHax2Heq2), 4.60 (1H, br d, J¼13.5 Hz, –N–CHax1Heq1),
7.44–7.55 (3H, m, CHAr), 7.63 (1H, s, CH), 7.62–7.65 (2H, m,
Yellow-green crystalline solid (0.551 g, 53%). Mp¼203 ꢀC. IR nmax
(KBr): 3015, 2938, 2861, 1718, 1700, 1670, 1606, 1560 cmꢁ1. 1H NMR
2CHAr) ppm. 13C NMR (75 MHz, DMSO-d6):
d¼22.0, 30.7, 33.9, 34.5,
(300 MHz, DMSO-d6):
d
¼1.63–1.68 (6H, m, –CH2–CH2–CH2–), 3.61

348
M. Anderluh et al. / Tetrahedron 65 (2009) 344–350
(2H, s, –CHaxHeq–N–CHaxHeq–), 3.88–3.92 (2H, m, –CHaxHeq–N–
CHaxHeq–), 7.26 (1H, dd, J¼1.2, 3.9 Hz, CHAr), 7.59 (1H, d, J¼3.3 Hz,
CHAr), 7.85 (1H, s, CH), 7.90 (1H, d, J¼5.1 Hz, CHAr) ppm. MS (ESI): m/
z 279 (MHþ, 100). HRMS (ESI): calcd for C13H18N2OS2 279.0626,
found 279.0630.
4.3.12. 4-((2-Morpholino-4-oxothiazol-5(4H)-ylidene)-
methyl)benzonitrile (19)
Yellow crystalline solid (0.778 g, 70%). Mp¼271 ꢀC. IR nmax
(KBr)¼2934, 2227, 1701, 1576 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d
¼3.69 (2H, t, J¼3.6 Hz, CHaxHeq–N–CHaxHeq), 3.74–3.78 (4H, m,
–CH2–O–CH2–), 3.95 (2H, t, J¼4.8 Hz, CHaxHeq–N–CHaxHeq), 7.72
4.3.7. 2-Morpholino-5-((thiophen-2-yl)methylene)thiazol-4(5H)-
one (14)13
(1H, s, CH), 7.81 (2H, AA0, J¼8.3 Hz, CHAr), 7.98 (2H, BB0, J¼8.3 Hz,
CHAr) ppm. 13C NMR (75 MHz, DMSO-d6):
d
¼49.7, 66.4, 66.5, 112.4,
Dark yellow crystalline solid (0.599 g, 57%). Mp¼193 ꢀC. IR nmax
119.4, 128.8, 130.9, 132.7, 133.8, 139.3, 174.9, 179.6 ppm. MS (EI): m/z
299 (Mþ, 35%), 159 (100). HRMS (EI): calcd for C15H13N3O2S
299.072849, found 299.073500.
(KBr): 3014, 2857, 1700, 1672, 1602, 1559 cmꢁ1. 1H NMR (300 MHz,
DMSO-d6):
d
¼3.60 (2H, t, J¼4.7 Hz, CHaxHeq–N–CHaxHeq), 3.71–3.78
(4H, m, CH2–O–CH2), 3.90 (2H, t, J¼4.7 Hz, –CHaxHeq–N–CHaxHeq–),
7.26 (1H, dd, J¼3.6, 5.1 Hz, CHAr), 7.60 (1H, AA0, J¼3.6 Hz, CHAr), 7.88
(1H, s, CH), 7.91 (1H, BB0, J¼5.1 Hz, CHAr) ppm. MS (EI): m/z 280 (Mþ,
40%), 140 (100). HRMS (EI): calcd for C12H12N2O2S2 280.034021,
found 280.035000.
4.3.13. 4-((2-(4-Methylpiperidin-1-yl)-4-oxothiazol-5(4H)-ylidene)-
methyl)benzonitrile (20)
Yellow crystalline solid (0.722 g, 62%). Mp¼133–136 ꢀC. IR nmax
(KBr): 3431, 3056, 2952, 2868, 2366, 2344, 2231, 1718, 1683, 1611,
1572 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d
¼0.90 (3H, d, J¼2.3 Hz,
4.3.8. 2-(4-Methylpiperidin-1-yl)-5-((thiophen-2-
yl)methylene)thiazol-4(5H)-one (15)
CH3), 1.15–1.31 (2H, m, –CH2–), 1.77–1.86 (3H, m, CH2–CH), 3.24–
3.40 (1H, m, –N–CHax2Heq2–), 3.43–3.53 (1H, m, –N–CHax1Heq1),
3.81–3.86 (1H, br d, J¼13.5 Hz, –N–CHax2Heq2–), 4.59 (1H, br d,
J¼13.5 Hz, –N–CHax1Heq1–), 7.69 (1H, s, CH), 7.81 (2H, AA0, J¼7.8 Hz,
CHAr), 7.97 (2H, BB0, J¼7.8 Hz, CHAr) ppm. 13C NMR (75 MHz, DMSO-
Yellow solid (0.402 g, 37%). Mp¼164–166 ꢀC. IR nmax (KBr): 2951,
2360, 1677, 1602, 1570 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d¼0.94
(3H, d, J¼6.0 Hz, CH3), 1.12–1.29 (2H, m, –CH2–), 1.74–1.89 (3H, m,
CH2–CH–), 3.24 (1H, br t, J¼12.3 Hz, –N–CHax2Heq2–), 3.44 (1H, br t,
J¼12.6, –N–CHax1Heq1), 3.78 (1H, br d, J¼12.5 Hz, –N–CHax2Heq2),
4.56 (1H, br d, J¼12.5 Hz, –N–CHax1Heq1–), 7.24–7.27 (1H, m, CHAr),
7.59 (1H, d, J¼2.4 Hz, CHAr), 7.85 (1H, s, CH), 7.89 (1H, d, J¼4.8 Hz,
d6):
d
¼22.0, 30.7, 33.5, 34.5, 49.5, 50.1, 112.2, 119.4, 128.3, 130.8,
133.7, 139.4, 173.8, 179.8 ppm. MS (ESI): m/z 312 (MHþ). HRMS
(ESI): calcd for C17H18N3OS 312.1171, found 312.1185.
CHAr) ppm. 13C NMR (75 MHz, DMSO-d6):
49.2, 50.0, 123.5, 127.9, 129.7, 131.9, 133.7, 139.5, 173.2, 179.9 ppm.
MS (ESI): m/z 293 (MHþ). HRMS (ESI): calcd for C14H16N2OS2
293.0782, found 293.0791.
d
¼22.0, 30.7, 33.9, 34.5,
4.3.14. 2-(Benzylamino)-5-benzylidenethiazol-4(5H)-one (21)
Orange crystalline solid (0.641 g, 53%). Mp¼265–269 ꢀC. IR nmax
(KBr): 2228, 1711, 1606, 1436, 1411, 1364, 1341, 1299, 1258, 1218,
1192, 1086, 1062 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d¼4.77 (2H,
d, J¼5.6 Hz, CH2NH), 7.32–7.42 (5H, m, CHAr), 7.69 (1H, s, CH), 7.77
4.3.9. 2-(Benzylamino)-5-((thiophen-2-yl)methylene)thiazol-
4(5H)-one (16)
(2H, AA0, J¼8.4 Hz, CHAr), 7.98 (2H, BB0, J¼8.4 Hz, CHAr), 10.22 (1H, t,
J¼5.6 Hz, NH) ppm. 13C NMR (75 MHz, DMSO-d6):
¼48.9, 112.1,
d
Yellow-green crystalline solid (0.449 g, 55%). Mp¼195–196 ꢀC.
119.4,128.1,128.7,129.5,130.0,131.6,133.2,133.8,137.8,138.2,139.5,
174.3, 180.0 ppm. MS (ESI): m/z 320 (MHþ). HRMS (ESI): calcd for
C18H14N3OS 320.0858, found 320.0870.
IR nmax (KBr): 2365, 1684, 1616, 1589 cmꢁ1 1H NMR (300 MHz,
.
DMSO-d6):
d
¼4.74 (2H, d, J¼5.9 Hz, CH2NH), 7.24–7.27 (1H, m,
CHAr), 7.29–7.39 (5H, m, CHAr), 7.57 (1H, d, J¼3.6 Hz, CHAr), 7.85 (1H,
s, CH), 7.89 (1H, d, J¼4.8 Hz, CHAr), 10.04 (1H, t, J¼5.9 Hz, NH) ppm.
4.3.15. 4-((4-Oxo-2-(pyrrolidin-1-yl)thiazol-5(4H)-ylidene)-
methyl)benzonitrile (22)
13C NMR (75 MHz, DMSO-d6):
d¼48.7, 123.3, 127.9, 128.3, 128.5,
128.6, 129.5, 129.5, 129.7, 131.9, 133.7, 138.0, 139.7, 173.7, 180.2 ppm.
MS (ESI): m/z 301 (MHþ, 100). HRMS (ESI): calcd for C15H12N2OS2
301.0469, found 301.0475.
Orange crystalline solid (1.049 g, 99%). Mp¼256–260 ꢀC. IR nmax
(KBr): 2219, 1686, 1560 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
.
d
¼1.97–2.07 (4H, m, –CH2–CH2–), 3.66 (2H, t, J¼6.6 Hz, –CH0H00–N–
CH0H00–), 3.73 (2H, t, J¼6.3 Hz, –CH0H00–N–CH0H00–), 7.68 (1H, s, CH),
4.3.10. 2-(Pyrrolidin-1-yl)-5-((thiophen-2-yl)methylene)thiazol-
4(5H)-one (17)
7.78–7.83 (2H, m, CHAr), 7.96–7.99 (2H, m, CHAr) ppm. 13C NMR
(75 MHz, DMSO-d6):
d
¼25.4, 25.6, 49.7, 51.7, 113.1, 119.2, 127.4,
Red crystalline solid (0.799 g, 81%). Mp¼184–186 ꢀC. IR nmax
130.8, 133.2, 133.8, 139.4, 148.4, 171.6, 179.1 ppm. MS (ESI) m/z 284
(MHþ, 100). HRMS (ESI): calcd for C15H14N3OS 284.0858, found
284.0850.
(KBr): 3062, 1682, 1603, 1560 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d
¼1.96–2.06 (4H, m, –CH2–CH2–), 3.63 (2H, t, J¼6.3 Hz, –CH0H00–N–
CH0H00–), 3.70 (2H, t, J¼6.6 Hz, –CH0H00–N–CH0H00–), 7.24–7.27 (1H,
m, CHAr), 7.58 (1H, d, J¼3.6 Hz, CHAr), 7.84 (1H, s, CH), 7.89 (1H, d,
4.3.16. 5-(4-(Benzyloxy)benzylidene)-2-(piperidin-1-yl)thiazol-
4(5H)-one (23)
J¼5.1 Hz, CHAr) ppm. 13C NMR (75 MHz, DMSO-d6):
¼25.4, 25.6,
d
49.7, 51.5, 123.6, 128.1, 131.9, 133.8, 139.5, 171.0, 179.3 ppm. MS (ESI)
m/z 265 (MHþ, 100). HRMS (ESI): calcd for C12H13N2OS2 265.0469,
found 265.0470.
Dark yellow crystalline solid (0.795 g, 56%). Mp¼175–177 ꢀC. IR
nmax (KBr): 2363, 1675, 1560, 1508 cmꢁ1. 1H NMR (300 MHz, DMSO-
d6):
d
¼1.67 (6H, br s, –CH2–CH2–CH2–), 3.60 (2H, br s, –CHaxHeq–N–
CHaxHeq–), 3.88–3.90 (2H, m, –CHaxHeq–N–CHaxHeq–), 5.19 (2H, s,
–O–CH2–), 7.15 (2H, AA0, J¼8.7 Hz, CHAr), 7.36–7.40 (5H, m, CHAr),
7.57 (1H, s, CH), 7.58 (2H, BB0, J¼8.7 Hz, CHAr) ppm. 13C NMR
4.3.11. 4-((4-Oxo-2-(piperidin-1-yl)thiazol-5(4H)-ylidene)-
methyl)benzonitrile (18)
Yellow crystalline solid (0.717 g, 64% yield). Mp¼192 ꢀC. IR nmax
(75 MHz, DMSO-d6):
d¼24.3, 26.0, 26.6, 49.9, 50.7, 70.3,116.4, 126.9,
(KBr): 2929, 2219, 1687, 1560 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
127.4, 128.7, 128.9, 129.4, 130.3, 132.2, 137.5, 160.4, 174.1, 180.5 ppm.
MS (ESI): m/z 379 (MHþ, 100). HRMS (ESI): calcd for C22H23N2O2S
379.1480, found 379.1470.
d
¼1.68 (6H, br s, –CH2–CH2–CH2–), 3.64 (2H, br s, –CHaxHeq–N–
CHaxHeq–), 3.91–3.94 (2H, m, –CHaxHeq–N–CHaxHeq–), 7.68 (1H, s,
CH), 7.81 (2H, AA0, J¼8.4 Hz, CHAr), 7.96 (2H, BB0, J¼8.4 Hz,
CHAr) ppm. 13C NMR (75 MHz, DMSO-d6):
d¼24.2, 26.0, 26.6, 50.3,
4.3.17. 5-(4-(Benzyloxy)benzylidene)-2-morpholinothiazol-4(5H)-
one (24)12
50.9, 112.2, 119.4, 128.3, 130.8, 133.2, 133.7, 139.4, 173.8, 179.8 ppm.
MS (ESI): m/z 298 (MHþ, 100). HRMS (ESI): calcd for C16H16N3OS
298.1014, found 298.1025.
Yellow crystalline solid (1.14 g, 80%). Mp¼169–171 ꢀC. IR nmax
(KBr): 1676, 1559, 1508, 1387, 1350, 1240, 1162, 1111 cmꢁ1 1H
.

M. Anderluh et al. / Tetrahedron 65 (2009) 344–350
349
NMR (300 MHz, DMSO-d6):
d
¼3.65–3.68 (2H, m, CHaxHeq–N–
1280, 1223, 1180, 1114, 1020 cmꢁ1
.
1H NMR (300 MHz, DMSO-d6):
CHaxHeq), 3.71–3.77 (4H, m, CH2–O–CH2), 3.90–3.94 (2H, m,
–CHaxHeq–N–CHaxHeq–), 6.12 (2H, s, CH2), 5.19 (2H, s, –O–CH2–),
7.16 (2H, AA0, J¼8.9 Hz, CHAr), 7.34–7.49 (4H, m, CHAr), 7.59 (2H,
BB0, J¼8.9 Hz, CHAr), 7.62 (1H, s, CH) ppm. MS (EI): m/z 380 (Mþ,
100%). HRMS (EI): calcd for C21H20N2O3S 380.119465, found
380.120000.
d
¼3.66–3.67 (2H, m, CHaxHeq–N–CHaxHeq), 3.73–3.77 (4H, m, CH2–
O–CH2), 3.90–3.91 (2H, m, –CHaxHeq–N–CHaxHeq–), 7.17–7.27 (2H,
m, CHAr), 7.50 (1H, d, J¼7.5 Hz, CHAr), 7.74 (1H, d, J¼2.7 Hz, CHAr),
7.86 (1H, d, J¼7.5 Hz, CHAr), 7.93 (1H, s, CH), 12.00 (1H, s, NH) ppm.
13C NMR (75 MHz, DMSO-d6):
d
¼48.8, 49.3, 66.4, 66.5, 111.9, 113.2,
119.2, 121.6, 123.0, 123.1, 127.6, 128.2, 137.2, 174.3, 180.4 ppm. MS
(EI): m/z 313 (Mþ, 22%), 173 (100). HRMS (EI): calcd for C16H15N3O2S
313.088499, found 313.089500.
4.3.18. 5-(4-(Benzyloxy)benzylidene)-2-(4-methylpiperidin-1-
yl)thiazol-4(5H)-one (25)
Orange crystalline solid (0.929 g, 63%). Mp¼165–166 ꢀC. IR nmax
4.3.23. 5-((1H-Indol-3-yl)methylene)-2-(4-methylpiperidin-1-
yl)thiazol-4(5H)-one (30)
(KBr): 2926, 1674, 1598, 1558, 1508 cmꢁ1 1H NMR (300 MHz,
.
DMSO-d6):
d
¼0.94 (3H, d, J¼6.2 Hz, CH3), 1.15–1.28 (2H, m, –CH2–),
Light yellow crystalline solid (0.970 g, 80%). Mp¼235–236 ꢀC. IR
1.74–1.84 (3H, m, CH2–CH–), 3.19–3.27 (1H, m, –N–CHax2Heq2–),
3.38–3.48 (1H, br d, J¼13.4 Hz, –N–CHax1Heq1), 3.81 (1H, br d,
J¼13.4 Hz, –N–CHax2Heq2–), 4.60 (1H, d, J¼13.3 Hz, –N–CHax1Heq1–),
5.18 (2H, s, –O–CH2–), 7.15 (2H, AA0, J¼8.8 Hz, CHAr), 7.32–7.49 (5H,
m, CHAr), 7.58 (1H, s, CH), 7.59 (2H, BB0, J¼8.8 Hz, CHAr) ppm. 13C
nmax (KBr): 3166, 2923, 2868, 2365, 1654, 1603, 1558 cmꢁ1. 1H NMR
(300 MHz, DMSO-d6):
m, –CH2–), 1.75–1.86 (3H, m, CH2–CH), 3.17–3.27 (1H, m, –N–CHax2
d
¼0.96 (3H, d, J¼2.7 Hz, CH3), 1.16–1.26 (2H,
-
Heq2), 3.39–3.49 (1H, m, –N–CHax1Heq1), 3.82 (1H, br d, J¼13.3 Hz,
–N–CHax2Heq2–), 4.6 (1H, br d, J¼13.3 Hz, –N–CHax1Heq1–), 7.15–7.26
(2H, m, CHAr), 7.49 (1H, d, J¼7.8 Hz, CHAr), 7.74 (1H, d, J¼2.4 Hz, CHAr),
7.83(1H, s, CH), 7.85 (1H, d, CHAr) ppm.13C NMR(75 MHz, DMSO-d6):
NMR (75 MHz, CDCl3):
d¼21.8, 31.2, 33.9, 34.5, 49.3, 49.8, 70.5,
115.8, 126.3, 127.6, 127.9, 128.6, 129.1, 131.4, 131.9, 136.8, 160.3, 174.9,
181.7 ppm. MS (ESI): m/z 393 (MHþ, 100). HRMS (ESI): calcd for
C23H25N2O2S 393.1637, found 393.1656.
d
¼19.4, 22.1, 30.8, 34.0, 48.8, 49.7, 111.9, 113.1, 119.1, 121.5, 122.5,
123.6, 123.6, 127.7, 128.1, 137.2, 173.3, 180.6 ppm. MS (ESI): m/z 326
(MHþ, 100). HRMS (ESI) calcd for C18H20N3OS 326.1327, found
326.1329.
4.3.19. 5-(4-(Benzyloxy)benzylidene)-2-(benzylamino)thiazol-
4(5H)-one (26)
Pale orange crystalline solid (0.849 g, 57%). Mp¼182 ꢀC. IR nmax
4.3.24. 5-((1H-Indol-2-yl)methylene)-2-(benzylamino)thiazol-
4(5H)-one (31)
(KBr): 3007, 1685, 1586, 1507 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d
¼4.74 (2H, d, J¼5.4 Hz, CH2NH), 5.15 (2H, d, –O–CH2–), 7.17 (2H,
Orange crystalline solid (0.713 g, 57%). Mp¼271 ꢀC. IR nmax
(KBr): 3265, 3043, 2850, 1681, 1589, 1570, 1512, 1491, 1457, 1436,
AA0, J¼9.0 Hz, CHAr), 7.31–7.61 (12H, m, CHAr, CH), 7.60 (1H, s, CH),
10.00 (1H, t, J¼5.4 Hz, NH) ppm. 13C NMR (75 MHz, DMSO-d6):
1348, 1331, 1292, 1214, 1141, 1086, 1010 cmꢁ1 1H NMR (300 MHz,
.
d
¼48.6, 70.5, 116.5, 123.3, 126.6, 127.5, 128.2, 128.6, 128.8, 129.3,
DMSO-d6):
d
¼4.73 (2H, d, J¼5.7 Hz, CH2NH), 7.19–7.40 (7H, m,
129.5, 132.6, 133.5, 137.5, 138.1, 160.3, 174.5, 180.7 ppm. MS (ESI): m/
z 401 (MHþ, 100). HRMS (ESI): calcd for C24H20N2O2S 401.1324,
found 401.1323.
CHAr), 7.51 (1H, dd, J¼5.0, 7.5 Hz, CHAr), 7.62 (1H, s, CHAr), 7.86 (1H,
d, J¼7.8 Hz, CHAr), 7.93 (1H, s, CH), 9.87 (1H, t, J¼5.7 Hz, NH) ppm.
13C NMR (75 MHz, DMSO-d6):
d¼48.4, 112.0, 113.2, 119.2, 121.4,
122.3, 123.5, 127.6, 127.9, 128.4, 128.6, 129.5, 137.2, 138.4, 173.6,
180.8 ppm. MS (ESI): m/z 334 (MHþ). HRMS (ESI): calcd for
C19H16N3OS 334.1014, found 334.1005.
4.3.20. 5-(4-(Benzyloxy)benzylidene)-2-(pyrrolidin-1-yl)thiazol-
4(5H)-one (27)
Yellow crystalline solid (1.304 g, 95%). Mp¼203–209 ꢀC. IR
nmax (KBr): 1676, 1554, 1508, 1455, 1416, 1371, 1346, 1328, 1287,
4.3.25. 5-((1H-Indol-2-yl)methylene)-2-(pyrrolidin-1-yl)thiazol-
4(5H)-one (32)
1240, 1173 cmꢁ1
.
1H NMR (300 MHz, DMSO-d6):
d
¼1.99–2.04 (4H,
m, –CH2–CH2–), 3.62 (2H, t, J¼6.3 Hz, –CH0H00–N–CH0H00–), 3.70
(2H, t, J¼6.3 Hz, –CH0H00–N–CH0H00–), 5.19 (2H, s, CH2Ph), 7.17 (2H,
AA0, J¼8.9 Hz, CHAr), 7.34–7.48 (6H, m, CHAr), 7.58 (1H, s, CH),
7.58 (2H, BB0, J¼8.9 Hz, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
Orange crystalline solid (0.989 g, 96%). Mp¼333–337 ꢀC. IR nmax
(KBr): 3148, 1654, 1603, 1558, 1452, 1368, 1346, 1311, 1223, 1131,
1017 cmꢁ1
.
1H NMR (300 MHz, DMSO-d6):
d¼1.97–2.06 (4H, m,
–CH2–CH2–), 3.61 (2H, t, J¼6.6 Hz, –CH0H00–N–CH0H00–), 3.69 (2H, t,
J¼6.6 Hz, –CH0H00–N–CH0H00–), 7.17 (1H, dt, J1¼1.2 Hz, J2¼7.8 Hz,
CHAr), 7.23 (1H, dt, J1¼1.5 Hz, J2¼7.4 Hz, CHAr), 7.50 (1H, d, J¼7.8 Hz,
CHAr), 7.72 (1H, s, CHAr), 7.85 (1H, d, J¼7.4 Hz, CHAr), 7.87 (1H, s, CH),
d
¼24.9, 25.2, 48.6, 50.6, 70.0, 115.3, 125.9, 127.0, 127.3, 128.1,
128.6, 131.2, 131.4, 136.3, 159.8, 172.3, 180.5 ppm. MS (ESI) m/z
365 (MHþ, 100). HRMS (ESI): calcd for C21H21N2O2S 365.1324,
found 365.1324.
11.96 (1H, s, NH) ppm. 13C NMR (75 MHz, DMSO-d6):
d
¼25.4, 25.7,
49.5, 51.1, 111.9, 113.2, 119.1, 121.5, 122.6, 123.6, 127.6, 137.6, 171.1,
180.0 ppm. MS (ESI) m/z 298 (MHþ, 100). HRMS (ESI): calcd for
C16H16N3OS 298.1014, found 298.0999.
4.3.21. 5-((1H-Indol-3-yl)methylene)-2-(piperidin-1-yl)thiazol-
4(5H)-one (28)
Dark yellow crystalline solid (1.502 g, 90%). Mp¼245 ꢀC. IR nmax
(KBr): 3172, 2939, 1654, 1604, 1559 cmꢁ1
.
1H NMR (300 MHz,
4.3.26. 5-((Benzo[d][1,3]dioxol-6-yl)methylene)-2-(piperidin-1-
yl)thiazol-4(5H)-one (33)15
DMSO-d6):
d
¼1.68 (6H, br s, –CH2–CH2–CH2–), 3.62 (2H, br s,
–CHaxHeq–N–CHaxHeq–), 3.87–3.91 (2H, m, –CHaxHeq–N–CHaxHeq–),
7.17–7.24 (2H, m, CHAr), 7.49 (1H, d, J¼7.2 Hz, CHAr), 7.74 (1H, d,
J¼3.0 Hz, CHAr), 7.84 (1H, d, J¼8.4 Hz, CHAr), 7.87 (1H, s, CH), 11.97
Yellow crystalline solid (1.119 g, 94%). Mp¼200 ꢀC. IR nmax (KBr):
3404, 2940, 1664, 1611, 1595, 1570, 1507 cmꢁ1. 1H NMR (300 MHz,
DMSO-d6):
d
¼1.67 (6H, br s, –CH2–CH2–CH2–), 3.62 (2H, br s,
(1H, s, NH) ppm. 13C NMR (75 MHz, DMSO-d6):
d¼23.5, 25.1, 25.8,
–CHaxHeq–N–CHaxHeq–), 3.88–3.91 (2H, m, –CHaxHeq–N–CHaxHeq–),
6.12 (2H, s, CH2), 7.06 (1H, d, J¼8.7 Hz, CHAr), 7.17–7.20 (2H, m,
CHAr), 7.56 (1H, s, CH) ppm. MS (ESI): m/z 317 (MHþ, 100). HRMS
(ESI): calcd for C16H17N2O3S 317.0960, found 317.0970.
48.7, 49.7, 111.1, 112.3, 118.3, 121.6, 122.7, 122.8, 126.8, 127.2, 136.4,
172.5, 179.8 ppm. MS (ESI): m/z 312 (MHþ). HRMS (ESI): calcd for
C17H18N3OS 312.1171, found 312.1165.
4.3.22. 5-((1H-Indol-2-yl)methylene)-2-morpholinothiazol-4(5H)-
one (29)
Yellow-green crystalline solid (1.05 g, 89%). Mp¼310–314 ꢀC. IR
nmax (KBr): 3204, 2363, 1661, 1602, 1544, 1458, 1437, 1385, 1351,
4.3.27. 5-((Benzo[d][1,3]dioxol-6-yl)methylene)-2-
morpholinothiazol-4(5H)-one (34)4d
Yellow crystalline solid (0.973 g, 82%). Mp¼268 ꢀC. IR nmax (KBr):
3152, 1734, 1684, 1612, 1564, 1501 cmꢁ1. 1H NMR (300 MHz, DMSO-

350
M. Anderluh et al. / Tetrahedron 65 (2009) 344–350
d6):
d
¼3.67–3.69 (2H, m, CHaxHeq–N–CHaxHeq), 3.71–3.78 (4H, m,
under the thematic priority of Life Sciences, Genomics, and
Biotechnology for Health (http://www.cip.ulg.ac.be/EUR-INTAFAR).
CH2–O–CH2), 3.90–3.92 (2H, m, –CHaxHeq–N–CHaxHeq–), 6.12 (2H, s,
CH2), 7.05–7.08 (1H, m, CHAr), 7.17–7.20 (2H, m, CHAr), 7.59 (1H, s,
CH) ppm. MS (EI): m/z 318 (Mþ, 22%),178 (100). HRMS (EI): calcd for
C15H14N2O4S 318.067429, found 318.068400.
ˇ
ꢀ
Dr. B. Kralj and Dr. D. Zigon (Center for Mass Spectrometry, Jozef
Stefan Institute, Ljubljana, Slovenia) are gratefully acknowledged
ꢀ
for the mass measurements. We thank Dr. Roger Pain and Dr. Jozko
Cesar for careful reading of the manuscript and many useful
suggestions.
4.3.28. 5-((Benzo[d][1,3]dioxol-6-yl)methylene)-2-(4-
methylpiperidin-1-yl)thiazol-4(5H)-one (35)
Yellow crystalline solid (0.871 g, 70%). Mp¼162–167 ꢀC. IR nmax
References and notes
(KBr)¼2928, 2865, 1677, 1611, 1560, 1500 cmꢁ1. 1H NMR (300 MHz,
1. (a) Lee, C. L.; Sim, M. M. Tetrahedron Lett. 2000, 41, 5729–5732; (b) Andres, C. J.;
Bronson, J. J.; D’Andrea, S. V.; Deshpande, M. S.; Falk, P. J.; Grant-Young, K. A.;
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DMSO-d6):
d
¼0.95 (3H, d, J¼5.7 Hz, CH3), 1.15–1.28 (2H, m, –CH2–),
1.74–1.84 (3H, m, CH2–CH), 3.19–3.28 (1H, m, –N–CHax2Heq2–),
3.39–3.48 (1H, m, –N–CHax1Heq1), 3.83 (1H, br d, J¼13.5 Hz, –N–
CHax2Heq2–), 4.57 (1H, br d, J¼13.2 Hz, –N–CHax1Heq1–), 6.11 (2H, s,
–O–CH2–O–), 7.06 (1H, d, J¼8.7 Hz, CHAr), 7.17–7.20 (2H, m, CHAr),
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7.56 (1H, s, CH) ppm. 13C NMR (75 MHz, DMSO-d6):
d¼22.0, 30.7,
33.9, 34.5, 49.1, 49.9, 102.7, 109.6, 109.8, 125.9, 127.4, 129.0, 130.5,
149.0,149.5,174.1,180.4 ppm. MS (ESI): m/z 331 (MHþ). HRMS (ESI):
calcd for C17H19N2O3S 331.1116, found 331.1124.
4.3.29. 5-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-
(benzylamino)thiazol-4(5H)-one (36)14
Yellow-orange crystalline solid (0.841 g, 66%). Mp¼245–246 ꢀC.
IR nmax (KBr): 3243, 1662, 1602, 1542, 1458, 1436, 1385, 1351, 1281,
1223, 1180, 1115, 1020 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d¼4.73
(2H, d, J¼4.8 Hz, CH2NH), 6.13 (2H, s, CH2), 7.08–7.18 (5H, m, CHAr),
7.34–7.39 (2H, m, CHAr), 7.57 (1H, s, CH), 10.01 (1H, t, J¼4.8 Hz,
NH) ppm. MS (ESI): m/z 339 (MHþ). HRMS (ESI): calcd for
C18H15N2O3S 339.0803, found 339.0804.
4.3.30. 5-((Benzo[d][1,3]dioxol-6-yl)methylene)-2-(pyrrolidin-1-
yl)thiazol-4(5H)-one (37)
Yellow crystalline solid (0.989 g, 88%). Mp¼277–279 ꢀC. IR nmax
(KBr): 1687, 1610, 1558 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
.
d
¼1.97–2.06 (4H, m, –CH2–CH2–), 3.62 (2H, t, J¼6.4 Hz, –CH0H00–N–
CH0H00–), 3.70 (2H, t, J¼6.4 Hz, –CH0H00–N–CH0H00–), 6.12 (2H, s, CH2),
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7.06–7.19 (3H, m, CHAr), 7.55 (1H, s, CH) ppm. 13C NMR (75 MHz,
DMSO-d6):
d
¼25.6, 51.4, 103.0, 110.2, 110.4, 123.8, 127.6, 128.1, 132.8,
149.2, 150.6, 170.3, 179.7 ppm. MS (ESI) m/z 303 (MHþ, 100). HRMS
(ESI): calcd for C15H15N2O3S 303.0803, found 303.0810.
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Acknowledgements
This work was supported by the European Union FP6 Integrated
Project EUR-INTAFAR (Project No. LSHM-CT 2004-512138)