Synthesis of some series of 1,3-thiazolidin-4-ones and indoles incorporating furoxan moiety starting with anethole isolated from star anise oil

Article abstract of DOI:10.1002/jhet.939

Some series of 1,3-thiazolidin-4-ones and indoles incorporating furoxan moiety were synthesized from anethole, a main component of star anise oil. The structure of these compounds and the intermediates was examined by elemental and spectral data. Ten compounds were screened against some bacteria and fungi.

Full text of DOI:10.1002/jhet.939

September 2012
Synthesis of Some Series of 1,3-Thiazolidin-4-ones and Indoles
Incorporating Furoxan Moiety Starting with Anethole Isolated
from Star Anise Oil
1077
*
Nguyen Huu Dinh , Nguyen Quang Trung, Nguyen Dang Dat,
and Nguyen Hien
Department of Chemistry, Hanoi National University of Education,
Xuan Thuy, Cau Giay, Hanoi, Vietnam
*
E-mail: nguyenhuudinh1954@yahoo.com
Received January 16, 2011
DOI 10.1002/jhet.939
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
Some series of 1,3-thiazolidin-4-ones and indoles incorporating furoxan moiety were synthesized
from anethole, a main component of star anise oil. The structure of these compounds and the intermedi-
ates was examined by elemental and spectral data. Ten compounds were screened against some bacteria
and fungi.
J. Heterocyclic Chem., 49, 1077 (2012).
INTRODUCTION
uses, for example, as antimalarial [6], antimicrobial
[7, 8] anti-inflammatory [9, 10], and antiviral agents,
especially as anti-HIV agents [11, 12].
As already seen, the investigation of the chemistry of
indoles has been, and continues to be, one of the most
active of heterocyclic chemistry since many natural and
synthetic indoles and related compounds are used as
pharmaceuticals and agrochemicals [13, 14].
During recent years, there is a widespread interest in
several classes of “hybrid” compounds, obtained com-
bining appropriate pharmacophoric groups with NO-
releasing furoxan moiety [15]. A number of them, such
as NO-aspirin [16], NO-steroids [17], and NO-ursodeox-
ycholic acid [18], are now under clinical investigations.
In view of the aforementioned findings, some series of
new compounds containing furoxan ring incorporating
thiazolidinone or indole moieties were synthesized from
anethole and to find out if the resulting compounds have
any biological action.
Anethole, a main component of star anise (Illicium
verum Hook f) oil, is trans-1-methoxy-4-(prop-1-enyl)-
benzene being a flavoring substance of commercial
value. Anethole has potent antimicrobial properties,
against bacteria, yeast, and fungi [1]. Antifungal activity
includes increasing the effectiveness of some other phy-
tochemicals (e.g., polygodial) against Saccharomyces
cerevisiae and Candida albicans, this synergistic effect
has potential medicinal uses [2]. Pharmaceutical drugs
derived from or related to anethole include anisyldi-
thiolthione, anethole dithione (ADT), and anethole trithione
(ATT) [3]. Also, anethole is an inexpensive chemical
precursor for paramethoxyamphetamine (PMA) [4].
In our previous article [5], anethole was treated with ni-
trous acid to give 3-methyl-4-(4-methoxyphenyl)furoxan
which was nitrated and subsequently reduced to 2-
methoxy-5-(3-methylfuroxan-4-yl)phenylamine (1). Com-
pounds 1 exhibit inhibition activity toward P. aeruginosa
at concentration 25 μg/mL. Several imines and azo com-
pounds derived from 1 have antimicrobial properties at
concentrations 12.5–25.0 μg/mL.
RESULTS AND DISCUSSION
2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamine (1) was
prepared from anethole according to the literature method
[5]. Amine 1 was converted into thiazolidin-4-ones 4a–e
by condensation with appropriate aromatic aldehydes and
mercaptoacetic acid, and into 2-methoxy-5-(3-methylfuroxan-
4-yl)phenylhydrazine (2) by diazotization and subsequent
Nowadays, thiazolidinones and their derivatives have
become among the most extensively investigated com-
pounds. They constitute an important group of heterocy-
clic compounds, having valuable biological activities in
the areas of medicine and agriculture. They have found
© 2012 HeteroCorporation

1078
N. H. Dinh, N. Q. Trung, N. D. Dat, and N. Hien
Vol 49
reduction. The condensation of 2 with aromatic aldehydes
gave hydrazones 3a–j, with substituted acetophenones
gave hydrazones 3k–m (Fig. 1, the numeration on these
structures is used specifically for NMR analysis only).
To our knowledge, the 2-methoxy-5-(3-methylfuroxan-
4-yl)phenylhydrazine (2), hydrazones 3a–m, thiazolidin-
4-ones 4a–e, thiazolidin-4-ones 5a–j, and indoles 6a–c
have not been previously reported in the literature, thus
besides elemental and IR spectral data, their 1H-NMR
and 13C-NMR spectra were accurately analyzed on the
basis of chemical shift, spin–spin splitting patterns, and
2D NMR spectra. The IR and 13C-NMR of 2 are similar
In 1H-NMR and 13C-NMR spectra of thiazolidin-4-ones
4a–e beside signals of amine moiety (H3–H10 and C1–
C10) and signals of aldehyde moiety (Hi, H12–H17, and
Ci, C11–C17) there were also signals of CH2 and C=O of
the thiazolidinone ring (Table 2, Experimental). Moreover,
two methylene protons of thiazolidinone ring are unequiva-
lent (denoted Hk, Hk’). Proton Hk gave rise to a doublet of
doublets at 3.99–4.10 ppm with geminal coupling constant
2JHk,Hk’ = 15.5–16 Hz and long-range coupling constant
4JHk,Hi = 1.5 Hz, while Hk’ appeared as a doublet at
3.86–3.93 ppm with 2JHk,Hk’ =16 Hz (4JHk’,Hi = 0). Proton
Hi of thiazolidin-4-ones 4a–e theoretically give rise to a
1
4
to those of 1 (see Experimental). In H-NMR spectrum of
doublet with JHk,Hi ≈ 1.5 Hz but in fact its signal often
1, there is a singlet at 5.06 ppm (2H) associated with
appeared as a singlet, only Hi of 4b appeared as a doublet
1
4
1
the NH2 group but in H-NMR spectrum of 2 beside a
at 6.65 ppm with JHk,Hi = 1.3 Hz (Table 2). In H-NMR
spectrum of mercaptoacetamide 4f beside signals of amine
moiety (H3, H5, H6, H7, and H10), there also were a
singlet at 3.89 ppm (2H) due to the methylene group
(Hk) and another singlet at 3.57 ppm associated with HS
proton. Amide HN proton displayed a singlet at 9.59 ppm
(1H) instead of the singlet at 5.06 ppm (2H) belonging to
NH2 group of amine 1.
singlet at 4.05 ppm (2H) associated with the NH2 group
there is also a singlet at 6.28 ppm (1H) due to NH
group. EI MS of 1 and 2 displayed molecular ion at m/z
221 and 236 which confirmed their molecular weights,
respectively. The 1H-NMR and 13C-NMR spectra of
hydrazones 3a–m displayed the signals of hydrazine moiety:
H3–H10, C1–C10 and signals of carbonyl moiety: Hi or
Hk, H12–H17, Ci, Ck, C11–C17 (Table 1, Experimental).
For example, the resonance of methin proton Hi of aldohydra-
zones 3a–j appeared as a singlet at 8.0–8.6 ppm, and the
resonance methin Ci of these aldohydrazones appeared at
133.6–143.0 ppm.
The main synthetic routes to 1,3-thiazolidin-4-ones
involve three components (an amine, an aldehyde, and
mercaptoacetic acid), either in a one- or two-step process
[19]. The one-pot reaction of 1 equiv of amine 1, 1 equiv
of appropriated aromatic aldehyde with 3 equiv of
mercaptoacetic acid in toluene using a Dean–Stark
trap for 6–8 h, gave the thiazolidinones 4a–e in good
yields. Unfortunately, in the same condition the one-
pot reaction using 4-dimethylaminobenzaldehyde,
4-bromobenzaldehyde or 4-hydroxy-3-methoxyben-
zaldehyde as the carbonyl precursor did not produce
the expected thiazolidin-4-ones, but rather the mer-
captoacetamide 4f (Fig. 2).
Because the one-pot reaction some time could give
unexpected product as mentioned earlier, to prepare
thiazolidin-4-ones 5a–j, the two-step process was used:
aldohydrazones 3a–j which were obtained from hydrazine
2 were refluxed with mercaptoacetic acid in toluene using
a Dean–Stark trap for 6–7 h.
The distinctive features for NMR spectra of thiazolidin-
4-ones 5a–j in comparison to those of the hydrazone
precursor 3a–j are as following. First, it can be seen that
the signals of Hi and HN in 5a–j (Table 3) are shifted by
about 2.0 ppm as compared to those in 3a–j (Table 1).
1
Second, in H-NMR spectra of 5a–j beside the signals of
H3–H10, Hi, and H12–H17, there are also a doublet of
doublets at 3.86–3.92 ppm (1H) with germinal coupling
constant 2JHk,Hk’ = 16 Hz and long-range coupling constant
4JHk,Hi = 1.5 Hz (denoted Hk) and a doublet at 3.70–3.75
2
ppm (1H, denoted Hk’) with JHk,Hk’ =16 Hz (Table 3).
In 13C-NMR spectra of 5a–j beside the signals of
Figure 1. Synthesis of 1,3-thiazolidi-4-ones and indoles from anethole. i: (1) HNO2, 0–5ꢀC, (2) SnCl2/HCl, 0ꢀC; ii: ArCH=O, reflux or
ArCO–CH3, reflux; iii: ArCH=O, HSCH2COOH, reflux; iv: HSCH2COOH, reflux; v: polyphosphoric acid, 120ꢀC.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Synthesis of Some Series of 1,3-Thiazolidin-4-ones and Indoles Incorporating
Furoxan Moiety Starting with Anethole Isolated from Star Anise Oil
1079
Table 1
1H-NMR signals of the hydrazones 3a-j, δ (ppm), J (Hz).
Com.
Ar
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
H3
H5
H6
H7
7.74 d
J: 2
7.15 dd
J: 2; 8.5
7.13 d
J: 8.5
7.77 d
J: 2
7.74 d
J: 2
7.77 d
J: 2
7.76 d
J: 2
7.75 d
J: 2
7.77 d
J: 2
7.73 d
J: 2
7.75 d
J: 2
7.66 d
J: 2
7.15 dd
J: 2; 8.5
7.12 d
J: 8.5
3.93 s
2.32 s
10.00 s
8.39 s
—
7.16 dd
J: 2; 8.5
7.14 d
J: 8.5
3.95 s
2.32 s
9.89 s
8.52 s
—
7.14 dd
J: 2; 8.5
7.12 d
J: 8.5
3.94 s
2.29 s
9.84 s
8.19 s
7.53 d
J: 8
7.17 dd
J: 2; 8.5
7.13d
J: 8.5
3.93s
2.31
10.36 s
8.60 s
—
7.17 dd
J: 2; 8.5
7.14 d
J: 8.5
3.94 s
2.29 s
10.04 s
8.21 s
7.65 d
J: 8.5
7.45 d
J: 8.5
—
7.15 dd
J: 2; 8.5
7.13 d
J: 8.5
3.94 s
2.33 s
9.95 s
8.22 s
7.69 dd
J: 8.5; 5.5
7.24 t
J: 9
7.17 dd
J: 2; 8.5
7.13 d
J: 8.5
3.94 s
2.33 s
9.97 s
8.19 s
7.20 s
7.11 dd
J: 2; 8.5
7.09 d
J: 8.5
3.91 s
2.30 s
9.71 s
8.15 s
7.58 d
J: 8.5
6.96 d
J: 8.5
—
7.14 dd
J: 2; 8.5
7.11 d
J: 8.5
3.93 s
2.34 s
9.66 s
8.11 s
7.26 d
J: 1.5
—
3.94 s
H10 2.33 s
N–H 9.95 s
Hi
8.23 s
H12 7.64 d
J: 7.5
H13 7.41 t
J: 7.5
H14 7.32 t
J: 7.5
H15 7.41 t
J: 7.5
7.20 d
J: 7.5
7.22 t
J: 7.5
7.21 t
J: 7.5
7.78 d
J: 7.5
2.44 s
7.21 d
J: 8
—
7.44 dd
J: 8; 1.5
7.37 t
—
7.21 d
J: 3.5
7.06 t
J: 4
7.48 d
J: 4.5
—
—
6.90 dd
J: 8
HO: 9.21
J: 8
7.21 d
J: 8
7.53 d
J: 8
7.31 td
J: 8; 1.5
8.00 dd
J: 8; 1.5
—
7.45 d
J: 8.5
7.45 d
J: 8.5
—
7.24 t
J: 9
7.69 dd
J: 8.5; 5.5
—
7.21 d
J: 8; 2
7.19 dd
J: 8; 2
3.80 s
6.96 d
J: 8.5
7.58 d
J: 8.5
3.77 s
6.81 d
J: 8
7.01 dd
J: 8; 1.5
3.83 s
H16 7.64 d
J: 7.5
H17
—
2.32
—
C1–C10, Ci, and C11–C17, there are also signals of Ck
(28.5–29.7 ppm) and C=O (169.1–169.9 ppm) associated
with the methylene and carbonyl groups, respectively.
These confirmed the formation of the thiazolidin-4-one
3k–m. The signals of Ck in 3k–m appeared at 12.38,
12.36, 12.39 ppm, but in 6a–c, they appeared at 98.5,
97.76, 97.92 ppm, respectively, the signal of Ci in 6a–c
is upfield shifted by about 5 ppm as compared to those in
3k–m, and so all (see Experimental).
1
ring. The H-NMR spectra of 5a–j differ from those of
4a–e on the presence of the singlet at 7.60–8.02 ppm due
to NH group.
The HMBC spectra of 6a–c clearly demonstrated the
indole cyclization. For example, in Figure 3, proton HN
give rise to not only cross peak b and c with C3 and Ci
but also cross peaks a with Ck; proton Hk give rise to
not only cross peak f with C11 of 4-methylphenyl group
but also cross peaks d and e with C2 and C3 of the indole
ring respectively.
ESI MS of 6a–c shown molecular weights of 321, 335,
337 au corresponding with their molecular formula.
It has been pointed out that furoxans could be undergone
a isomerization to isomeric furoxans under heating
condition and a reduction to furazans by stannous chloride
[20]. Gasco et al. [21] showed that the chemical shift of a
ring methyl group adjacent to the N-oxide oxygen of
furoxans occurs at 2.30–2.33 ppm, while a ring methyl
group remote from it (i.e. in isomeric furoxans) or a ring
methyl group of furazan appears at 2.50–2.53 ppm. The
signal of the ring methyl group (H10) of all examined
compounds appears as a singlet at 2.10–2.34 ppm
(Tables 1–4) indicating that during the reported synthesis
the furoxan ring was not isomerized, and was not reduced
by stannous chloride.
The indoles 6a–c were prepared according to the Fischer
synthesis by heating ketohydrazones 5k–m with polypho-
1
sphoric acid at 120ꢀC for 2 h. H-NMR and 13C-NMR
spectra of indoles 6a–c quite differ from those of the
hydrazone precursors 3k–m (Table 4). Particularly, in
1H-NMR spectra of indoles 6a–c, there was no signal of
H3; proton Hk give rise to a signal at 6.96–7.16 ppm
(1H) instead of the singlet at 2.24–2.32 ppm (3H) in the
spectra of 3k–m; the indole HN proton displayed singlet
at 11.67–11.91 ppm instead of the singlet at 8.26–8.24
ppm belonging to hydrazone NH group in precursors
Figure 2. Mercaptoacetamide derived from amine 1. (i) HSCH2COOH,
4-Me2NPhCH=O (or 4-BrPhCH=O, 4-HO-3-MeOPhCH=O), reflux.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1080
N. H. Dinh, N. Q. Trung, N. D. Dat, and N. Hien
Vol 49
Table 2
1H-NMR signals of 1,3-thiazolidin-4-one 4a-e, δ (ppm), J (Hz).
Com.
4a
4b
4c
4d
4e
Ar
H3
H5
H6
H7
7.43 d J: 2.0
7.61 dd J: 2; 9
7.23 d J: 9
3.88 s
7.64 d J: 2
7.66 dd J: 2; 8.5
7.28 d J: 8
3.88 s
7.54 d J: 2
7.45 d J: 2
7.46 dJ: 2
7.64 dd J: 2; 8.5
7.26 d J: 8.5
3.88 s
7.64 dd J: 2; 8.5
7,25 d J: 8.5
3.87 s
7.61 dd J: 2; 9
7.23 d J: 9
3.88 s
H10
Hi
Hk
Hk’
H12
H13
H14
H15
H16
2.10 s
6.25 s
2.15 s
2.14 s
6.44 s
2.13 s
6.27 s
2.10 s
6.23 s
6.65 d J: 1.3
4.05 dd J: 16; 1.5
3.86 d J: 16
—
8.06 dd J: 8; 1
7.53 td J: 8; 1
7.77 t J: 8
4.01 dd J: 16; 1.5
3.88 d J: 16
7.44 d J: 7
7.28 t J: 7
7.24 t J: 7
7.28 t J: 7
7.44 d J: 7
4.10 dd J: 16; 1.5
3.93 d J: 16
7.76 d J: 8.5
8.13 d J: 8,5
—
4.02 dd J: 16; 1.5
3.90 d J: 16
7.47 d J: 8.5
7.34 d J: 8.5
—
3.99 dd J: 16; 1.5
3.86 d J: 16
6.99 d J: 1.5
H17: 3.69 s
6.78 dd J: 1.5; 8
7.17 t J: 8
8.13 d J: 8,5
7.76 d J: 8.5
7.34 d J: 8.5
7.47 d J: 8.5
7.91 dd J: 8; 1
6,98 d J: 8
Table 3
1H-NMR signals of 1,3-thiazolidin-4-one 5a-j, δ (ppm), J (Hz).
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
Ar
H3
Ph
6.95 d
J: 2
2-MePh
7.01 d
J: 2
4-MePh
6.94 d
J: 2
2-ClPh
7.04 d
J: 2
4-ClPh
6.91 d
J: 2
4-FPh
6.92 d
J: 2
3-MeO-Ph
6.95 d
J: 2
4-MeO-Ph
6.91 d
J: 2
4-HO-3-MeO-Ph
6.94 d
J: 2
2-Thienyl
6.87 d
J: 2
H5
H6
7.13 dd
J: 8.5; 2
7.04 d
J: 8.5
3.82 s
2.27 s
7.71 s
5.88 s
3.91 dd
J:16; 1.5
3.73 d
J: 16
7.16 dd
J: 8.5; 2
7.07 d
J: 8.5
3.84 s
2.29 s
7.79 s
6.12 s
3.82 dd
J:16; 1.5
3.74 d
J: 16
7.13 dd
J: 8.5; 2
7.04 d
J: 8.5
3.83 s
2.27 s
7.64 s
5.83 s
3.89 dd
J:16; 1.5
3.72 d
J: 16
7.19 dd
J: 8.5; 2
7.09 d
J: 8.5
3.85 s
2.29 s
8.02 s
6.17 s
3.86 dd
J:16; 1.5
3.75 d
J: 16
7.14 dd
J: 8.5; 2
7.05 d
J: 8.5
3.83 s
2.27 s
7.64 s
5.90 s
3.92 dd
J:16; 1.5
3.73 d
J: 16
7.17 d
J: 8.5
7.05 d
J: 8.5
3.83 s
2.27 s
7.76 s
5.91 s
3.92 d
J: 16
7.13 dd
J: 8.5; 2
7.05 d
J: 8.5
3.83 s
2.27 s
7.77 s
5.86 s
3.92 d d
J:16; 1.5
3.72 d
J: 16
7.11 dd
J: 8.5; 2
7.03 d
J: 8.5
3.82 s
2.26 s
7.60 s
5.82 s
3.88 d d
J:16; 1.5
3.71 d
J: 16
7.10 dd
J: 8.5; 2
7.03 d
J: 8.5
3.83 s
2.24 s
7.63 s
5.77 s
3.88 d d
J:16; 1.5
3.70 d
J: 16
7.12 dd
J: 8.5; 2
7.05 d
J: 8.5
3.87 s
2.24 s
7.62 s
6.13 s
3.88 d d
J:16; 1.5
3.74 d
J: 16
H7
H10
HN
Hi
Hk
Hk’
3.73 d
J: 16
H12
H13
H14
H15
H16
H17
7.50 d
J: 8
7.34 t
J: 8
7.31 t
J: 8
7.34 t
J: 8
—
7.39 d
J: 8
7.14 d
J: 8
—
7.54 d
J: 8.5
7.40 d
J: 8.5
7.57 m
7.06 d
J: 8
—
7.43 d
J: 9
6.87 d
J: 9
7.06 d
J: 2
—
—
7.15 dd
J: 8.5; 2
7.20 td
J: 8.5; 2
7,21 td
J: 8.5; 2
7.59 dd
J: 8.5; 2
2.29 s
7.47 dd
J: 7.5; 1.5
7.37 td
J: 7.5; 1.5
7.40 td
J: 7.5; 1.5
7.74 dd
J: 7.5; 2
—
7.14 t
J: 9
—
7.24 dd
J: 4; 1
6.93 dd
J: 5; 4
7.54 d
J: 5
—
—
6.87 d d
J: 8; 2
7.24 t
J: 8
7.04 d
J: 8
—
HO:
9.07 s
6.67 d
J: 8.5
6.84 dd
J: 8.5; 2
3.73 s
7.14 d
J: 8
7.39 d
J: 8
7.40 d
J: 8.5
7.54 d
J: 8.5
—
7.14 t
J: 9
7.57 m
6.87 d
J: 9
7.43 d
J: 9
7.50 d
J: 8
—
—
2.29 s
—
3.73 s
3.72 s
—
EXPERIMENTAL
Some reported compounds were tested for their in vitro
antimicrobial activities; the results are listed in Table 5. It
is seen that the examined compounds showed low activi-
ties toward the tested microorganism.
General.
IR spectra were recorded on an IMPACK-410
NICOLET spectrometer in KBr discs at 400–4000 cm−1. The EI
mass spectra of examined compounds were recorded using a
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Synthesis of Some Series of 1,3-Thiazolidin-4-ones and Indoles Incorporating
Furoxan Moiety Starting with Anethole Isolated from Star Anise Oil
1081
Table 4
1H-NMR signals of hydrazone 3k-m and indoles 6a-c, δ (ppm), J (Hz).
Com.
3k
3l
3m
6a
6b
6c
Ar
Ph
4-MePh
4-HOPh
Ph
4-MePh
4-HOPh
H3
H5
H6
H7
7.81 d; J: 2
7.22 dd; J: 8.5; 2
7.17 d; J: 8.5
3.97 s
7.80 d; J: 2
7.19 dd; J: 8.5; 2
7.16 d; J: 8.5
3.96 s
7.76 d; J: 2
7.18 dd; J: 8.5; 2
7.14 d; J: 8.5
3.95 s
—
—
—
7.33 d; J: 8
6.89 d; J: 8
4.05 s
7.31 d; J: 8
6.86 d; J: 8
4.04 s
7.29 d; J: 8
6.82 d; J: 8
4.03 s
H10
N–H
Hk
H12
H13
H14
H15
H16
2.32 s
8.24 s
2.31 s
7.82 d; J: 7.5
7.41 t; J: 7.5
7.34 t; J: 7.5
7.41 t; J: 7.5
7.82 d; J: 7.5
2.32 s
8.18 s
2.32 s
7.71 d; J: 8
7.22 d; J: 8
H17: 2.32 s
7.22 d; J: 8
7.71 d; J: 8
2.32 s
8.06 s
2.24 s
7.65 d; J: 8.5
6.79 d; J: 8.5
HO: 9.62 s
6.79 d; J: 8.5
7.65 d; J: 8.5
2.32 s
11.91 s
2.32 s
11.83 s
2.31 s
11.67 s
6.96 s
7.80 d; J: 8
6.83 d; J: 8
HO: 9.65
6.83 d; J: 8
7.80 d; J: 8
7.16 d; J: 2.5
7.99 d; J: 8
7.44 t; J: 8
7.33 t; J: 8
7.44 t; J: 8
7.99 d; J: 8
7.11 d; J: 2.5
7.88 d; J: 8
7.25 d; J: 8
H17: 2.34 s
7.25 d; J: 8
7.88 d; J: 8
Figure 3. Partial HMBC spectrum of indole 6b (the formula in Fig. 1, compd. 6b, Ar = 4-MePh).
5989B Hewlett–Packard mass spectrometer. ESI mass spectra
were recorded using Agilent LC-MSD-Trap-SL series 1100
Preparation 2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamine
(1) is prepared from anethole according to the literature method
[5, 23]. Light yellow needle crystals, yield 60%, mp 119–120ꢀC.
IR (cm−1): 3468; 3371 (NH); 3075; 2934 (C–H), 1603, 1582
spectrometer. NMR spectra were recorded on
a Bruker
AVANCE 500 MHz spectrometer, in d6-DMSO with TMS as
the internal standard, at 298–300 K. C, H, and N were analyzed
in Analytical Laboratory – Institute of Chemistry of Natural
Compounds (in Hanoi). The anti microbial activities were tested
1
4
(ring). H-NMR, δ(ppm), J (Hz): 7.06 (1H, d, JHH = 1.5, H3),
3
4
3
6.90 (1H, dd, JHH = 8, JHH = 1.5, H5), 6.96 (1H, d, JHH = 8,
H6), 3.83 (3H, s, H7), 2.28 (3H, s, H10), 5.06 (2H, s, NH2). 13C-
NMR, δ (ppm): 148.69 (C1), 138.70 (C2), 111.89 (C3), 119.01
(C4), 116.02 (C5), 110.68 (C6), 55.59 (C7), 157.49 (C8), 112.98
(C9), 9.38 (C10). EI ms, m/z (%) = 221 (M+, 32), 205 (M+- O, 5),
at the Experimental Biological Laboratory
– Institute of
Chemistry of Natural Compounds (in Hanoi), according to the
method described in reference [22].
Table 5
The minimum inhibition concentration (MIC, μg/mL) of examined compounds against some microorganism.
Compounds
E. coli
B. subtillis
S. aureus
4b
4c
4d
5e
5f
5i
5j
6a
6b
6c
32
88.2
>128
>128
88.2
>128
88.2
32
20.3s
88.2
91.5
91.5
88.2
32
64
32
64
64
20.3
91.5
>128
32
>128
50
64
20.3
50
88.2
50
>128
>128
32
>128
91.5
20.3
32
88.2
88.2
32
20.3
88.2
32
P. aeruginosa
C. albicans
>128
64
64
64
64
91.5
91.5
32
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1082
N. H. Dinh, N. Q. Trung, N. D. Dat, and N. Hien
Vol 49
1
161 (M+- 2NO, 56), 146 (M+- 2NO – CH3, 100). Anal. Calcd. for
C10H11N3O3 (M 221.22): C, 54.29; H, 5.01; N, 18.99. Found: C,
54.61; H, 4.88; N, 18.65.
3060; 2968; 2840 (C–H), 1599, 1538, 1500 (ring). H-NMR: see
Table 1. 13C-NMR, δ (ppm): 147.45 (C1), 134.81 (C2), 110.16
(C3), 119.24 (C4), 118.81 (C5), 111.26 (C6), 55.88 (C7), 157.40
(C8), 112.98 (C9), 9.14 (C10), 135.39 (Ci), 131.68 (C11), 132.91
(C12), 125.54 (C13), 129.77 (C14), 126.03 (C15), 127.45 (C16).
Anal. Calcd. for C17H15N4O3Cl (M 358.76): C, 56.91; H, 4.21; N,
13.38. Found: C, 57.25; H, 4.39; N, 13.05.
2-Methoxy-5-(3-methylfuroxan-4-yl)phenylhydrazine (2). At
0–5ꢀC, 12 mL of 1 M NaNO2 solution was slowly added to a
solution of 10 mmol of 1 in 10 mL of 3 M HCl solution. The
resulting solution was cooled to −10ꢀC and a solution of 6.78g
(30 mmol) SnCl2 in 100 mL of concentrated hydrochloric acid
was slowly added over an hours and stirred at −5ꢀC for 2 hours
additional. The precipitate was collected and neutralized with 2 M
NaOH solution. The white solid was filtered out, washed with
water and recrystallized from ethanol/chloroform 3:1 by volume.
White needle crystals, yield 85%, mp 126ꢀC. IR (cm−1): 3447;
3318; 3230 (NH); 3096; 3030; 2931; 2852 (C–H), 1591, 1531
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-(4-
chlorobenzyliden)hydrazine (3e). White crystals, yield 50%, mp
179ꢀC (from EtOH). IR (cm−1): 3301 (NH); 3060; 3024; 2960;
2853 (C–H), 1582, 1548, 1500 (ring). 1H-NMR: see Table 1.
13C-NMR, δ (ppm): 147.24 (C1), 134.87 (C2), 109.98 (C3),
119.16 (C4), 118.40 (C5), 111.10 (C6), 55.77 (C7), 157.29 (C8),
112.76 (C9), 9.01 (C10), 134.45 (Ci), 132.45 (C11), 128.64 (C12/
C16), 127.27 (C13/C15), 138.14 (C14). Anal. Calcd. for
C17H15N4O3Cl (M 358.76): C, 56.91; H, 4.21; N, 13.38. Found:
C, 57.22; H, 4.49; N, 13.09.
4
(ring). 1H-NMR, δ(ppm), J (Hz): 7.39 (1H, d, JHH = 2, H3),
3
3
7.00 (1H, dd, JHH = 8.5, 4JHH = 2, H5), 6.96 (1H, d, JHH = 8.5,
H6), 3.84 (3H, s, H7), 2.31 (3H, s, H10), 6.28 (1H, s, NH), 4.05
(2H, s, NH2). 13C-NMR, δ (ppm): 147.86 (C1), 141.94 (C2),
108.74 (C3), 118.78 (C4), 116.19 (C5), 109.74 (C6), 55.48 (C7),
157.51 (C8), 112.68 (C9), 9.04 (C10). EI ms, m/z (%) = 236 (M+.,
100), 220 (M+.- O, 8), 175 (M+. - 2NO, 83). Anal. Calcd. for
C10H12N4O3 (M 236.23): C, 50.84; H, 5.12; N, 23.72. Found: C,
51.08; H, 5.38; N, 23.47.
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-(4-
fluobenzyliden)hydrazine (3f). White crystals, yield 62%, mp
167–168ꢀC (from EtOH). IR (cm−1): 3317 (NH); 3064; 3040;
2945; 2853 (C–H), 1599, 1540, 1488 (ring). 1H-NMR: see Table 1.
13C-NMR, δ (ppm): 147.28 (C1), 135.09 (C2), 110.44 (C3), 119.25
(C4), 118.67 (C5), 111.18 (C6), 55.02 (C7), 157.34 (C8), 112.86
3
(C9), 9.11 (C10), 138.50 (Ci), 132.17 (C11), 122.75 d ; JFC 8 Hz
The general procedure for the preparation of hydrazones
3a–m. An equimolar solution of hydrazine 2 (1 mmol) and
aromatic aldehyde (1 mmol) or ketone (1 mmol) in dry ethanol
was refluxed over 2–4 h. The reaction mixture was allowed to
stand at room temperature. The resulting precipitate was
collected and recrystallized.
2
1
(C12/C16), 115.70 d ; JFC 22 Hz (C13/C15), 162.08 d ; JFC 245
Hz (C14). Anal. Calcd. for C17H15N4O3F (M 342.31): C, 59.64; H,
4.42; N, 16.37. Found: C, 59.28; H, 4.29; N, 16.08.
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-(3-
methoxybenzyliden)hydrazine (3g). White needle crystals, yield
68%, mp 140ꢀC (from EtOH/dioxan 1:1). IR (cm−1): 3277
(NH); 3080; 3040; 2958; 2840 (C–H), 1587, 1560, 1503 (ring).
1H-NMR: see Table 1. 13C-NMR, δ (ppm): 147.21 (C1), 135.28
(C2), 109.80 (C3), 119.26 (C4), 118.10 (C5), 111.08 (C6), 55.83
(C7), 157.37 (C8), 112.84 (C9), 9.12 (C10), 139.42 (Ci), 137.05
(C11), 110.10 (C12), 159.56 (C13), 114.28 (C14), 129.76 (C15),
118.24 (C16), 55.84 (C17). Anal. Calcd. for C18H18N4O4
(M 354.35): C, 61.04; H, 5.12; N, 15.81. Found: C, 61.42; H,
4.88; N, 15.49.
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-
benzylidenhydrazine (3a). White crystals, yield 65%, mp
138ꢀC (from EtOH). IR (cm−1): 3307 (NH); 3060; 3032; 2932;
2855 (C–H), 1590, 1539, 1500 (ring). 1H-NMR: see Table 1. 13C-
NMR, δ (ppm): 147.78 (C1), 135.66 (C2), 110.44 (C3), 119.74
(C4), 118.77 (C5), 111.62 (C6), 55.36 (C7), 157.95 (C8), 113.45
(C9), 9.66 (C10), 140.14 (Ci), 136.09 (C11), 126.36 (C12/16),
129.23 (C13/15), 128.84 (C14). Anal. Calcd. for C17H16N4O3
(M 324.32): C, 62.95; H, 4.97; N, 17.28. Found: C, 63.29; H,
4.68; N, 17.57.
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-(4-
methoxybenzyliden)hydrazine (3h). Pale orange crystals, yield
75%, mp 184ꢀC (from EtOH). IR (cm−1): 3341 (NH); 3078;
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-(2-
methylbenzyliden)hydrazine (3b). White crystals, yield 77%, mp
175ꢀC (from EtOH). IR (cm−1): 3321 (NH); 3050; 3020; 2979;
2843 (C–H), 1582, 1540, 1511 (ring). 1H-NMR: see Table 1.
13C-NMR, δ (ppm): 147.21 (C1), 135.28 (C2), 109.80 (C3),
119.26 (C4), 118.10 (C5), 111.08 (C6), 55.83 (C7), 157.37 (C8),
112.84 (C9), 9.12 (C10), 135.23 (Ci), 133.45 (C11), 138.95
(C12), 125.40 (C13), 127.97 (C14), 126.04 (C15), 130.74 (C16),
19.50 (C17). Anal. Calcd. for C18H18N4O3 (M 338.35): C, 63.89;
H, 5.36; N, 16.52. Found: C, 63.56; H, 5.68; N, 16.17.
1
3015; 2970; 2852 (C–H), 1603, 1536, 1497 (ring). H-NMR: see
Table 1. 13C-NMR, δ (ppm): 147.18 (C1), 135.43 (C2), 109.67
(C3), 119.22 (C4), 117.85 (C5), 110.92 (C6), 55.19 (C7), 157.45
(C8), 112.94 (C9), 9.16 (C10), 139.79 (Ci), 128.26 (C11), 127.34
(C12/C16), 114.27 (C13/C15), 159.65 (C14), 55.80 (C17). Anal.
Calcd. for C18H18N4O4 (M 354.35): C, 61.04; H, 5.12; N, 15.81.
Found: C, 60.74; H, 5.29; N, 16.05.
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-(4-
hydroxy-3-methoxybenzyliden)-hydrazine (3i). White needle
crystals, yield 88%, mp 209ꢀC (from EtOH). IR (cm−1): 3380
(OH); 3337 (NH); 3060; 3031; 2974; 2845 (C–H), 1586, 1520,
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-(4-
methylbenzyliden)hydrazine (3c). White needle crystals, yield
57%, mp 168–170ꢀC (from EtOH). IR (cm−1): 3313 (NH); 3050;
1
1
3026; 2970; 2855 (C–H), 1582, 1538, 1511 (ring). H-NMR: see
1494 (ring). H-NMR: see Table 1. 13C-NMR, δ (ppm): 147.01
Table 1. 13C-NMR, δ (ppm): 147.18 (C1), 135.23 (C2), 109.78
(C3), 119.18 (C4), 118.03 (C5), 111.01 (C6), 55.79 (C7), 157.42
(C8), 112.90 (C9), 9.11 (C10), 139.81 (Ci), 132.83 (C11), 129.28
(C12/C16), 125.80 (C13/C15), 137.86 (C14), 20.87 (C17). Anal.
Calcd. for C18H18N4O3 (M 338.35): C, 63.89; H, 5.36; N, 16.52.
Found: C, 64.09; H, 5.09; N, 16.21.
(C1), 135.39 (C2), 109.73 (C3), 119.14 (C4), 117.46 (C5), 110.92
(C6), 55.69 (C7), 157.28 (C8), 112.76 (C9), 9.04 (C10), 140.26
(Ci), 127.09 (C11), 108.69 (C12), 147.89 (C13), 147.49 (C14),
115.48 (C15), 120.01 (C16), 55.44 (C17). Anal. Calcd. for
C18H18N4O5 (M 370.35): C, 58.37; H, 4.90; N, 15.13. Found: C,
58.06; H, 4.68; N, 15.45.
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-(2-
chlorobenzyliden)hydrazine (3d). Yellow needle crystals, yield
66%, mp 196ꢀC (from EtOH). IR (cm−1): 3293 (NH); 3095;
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-[(thien-2-
yl)methyliden]hydrazine (3j). Pale orange crystals, yield 89%,
mp 178ꢀC (from EtOH). IR (cm−1): 3321 (NH); 3100; 3050;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Synthesis of Some Series of 1,3-Thiazolidin-4-ones and Indoles Incorporating
Furoxan Moiety Starting with Anethole Isolated from Star Anise Oil
1083
2970; 2836 (C–H), 1595, 1504, 1500 (ring). 1H-NMR: see Table 1.
13C-NMR, δ (ppm): 147.23 (C1), 134.86 (C2), 109.71 (C3), 119.19 (C4),
118.15 (C5), 111.06 (C6), 55.81 (C7), 157.26 (C8), 112.86 (C9),
9.19 (C10), 134.83 (Ci), 140.79 (C12), 127.09 (C13),
126.28 (C14), 127.64 (C15). Anal. Calcd. for C15H14N4O3S
(M 330.35): C, 54.53; H, 4.27; N, 16.96. Found: C, 54.21; H,
4.48; N, 17.27.
118.48 (C4), 128.85 (C5), 113.25 (C6), 56.21 (C7), 156.23 (C8),
112.69 (C9), 8.66 (C10), 57.62 (Ci), 31.18 (Ck), 171.21 (C=O),
134.80 (C11), 147.56 (C12), 124.47 (C13), 129.11 (C14),
134.16 (C15), 129.65 (C16). Anal. Calcd. for C19H16N4O6S
(M 428.42): C, 53.27; H, 3.76; N, 13.08. Found: C, 53.59;
H, 3.48; N, 13.41.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-2-(4-nitrophenyl)-
1,3-thiazolidin-4-one (4c). White crystals, yield 90%, mp 203–204ꢀC
(from EtOH). IR (cm−1): 3086, 2965, 2945, 2859 (C–H); 1692 (C=O);
1605, 1523 (ring). 1H-NMR: see Table 2. 13C-NMR, δ (ppm): 156.80
(C1), 125.83 (C2), 129.07 (C3), 118.50 (C4), 128.86 (C5), 113.36
(C6), 56.23 (C7), 156.15 (C8), 112.66 (C9), 8.67 (C10), 61.91 (Ci),
31.95 (Ck), 170.70 (C=O), 147.05 (C11), 128.77 (C12/C16), 123.66
(C13/C15), 147.45 (C14). +ms, m/z = 429 (M+H+). Anal. Calcd. for
C19H16N4O6S (M 428.42): C, 53.27; H, 3.76; N, 13.08. Found: C,
53.60; H, 3.45; N, 13.38.
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-[1-(phenyl)
ethyliden]hydrazine (3k). White crystals, yield 56%, mp 131ꢀC
(from EtOH). IR (cm−1): 3389 (NH); 3060; 3006; 2980; 2934
1
(C–H), 1591, 1539, 1490 (ring). H-NMR: see Table 4. 13C-NMR,
δ (ppm): 147.75 (C1), 135.35 (C2), 110.65 (C3), 119.20 (C4),
118.85 (C5), 111.02 (C6), 56.01 (C7), 157.38 (C8), 112.88
(C9), 9.12 (C10), 144.76 (Ci), 12.38 (Ck), 138.66 (C11), 125.43
(C12/C16), 128.35 (C13/C15), 128.12 (C14). +ms, m/z = 339
(M+H+). Anal. Calcd. for C18H18N4O3 (M 338.35): C, 63.89; H,
5.36; N, 16.55. Found: C, 64.04; H, 5.09; N, 16.26.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-2-(4-chlorophenyl)-
1,3-thiazolidin-4-one (4d). White crystals, yield 56%, mp 176ꢀC
(from EtOH). IR (cm−1): 3067, 2989, 2931, 2850 (C–H); 1684
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-[1-(4-
methylphenyl)ethyliden]-hydrazine (3l). White crystals, yield 67%,
mp 161–162ꢀC (from EtOH). IR (cm−1): 3382 (NH); 3041; 3000;
1
(C=O); 1606, 1564 (ring). H-NMR: see Table 2. 13C-NMR, δ
1
2949; 2850 (C–H), 1590, 1537, 1497 (ring). H-NMR: see Table
(ppm): 156.85 (C1), 126.05 (C2), 129.02 (C3), 118.40 (C4),
128.94 (C5), 113.26 (C6), 56.19 (C7), 156.20 (C8), 112.67
(C9), 8.63 (C10), 62.37 (Ci), 32.12 (Ck), 170.60 (C=O), 133.25
(C11), 129.54 (C12/C16), 128.46 (C13/C15), 138.33 (C14). Anal.
Calcd. for C19H16N3O4ClS (M 417.85): C, 54.61; H, 3.86; N,
10.06. Found: C, 54.92; H, 3.59; N, 9.78.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-2-(3-
methoxyphenyl)-1,3-thiazolidin-4-one (4e). White crystals, yield
74%, mp 178–179ꢀC (from EtOH). IR (cm−1): 3022, 2970, 2937,
2845 (C–H); 1692 (C=O); 1616, 1520, 1495 (ring). 1H-NMR: see
Table 2. 13C-NMR, δ (ppm): 156.88 (C1), 126.28 (C2), 129.01
(C3), 118.33 (C4), 128.78 (C5), 113.22 (C6), 56.19 (C7), 156.22
(C8), 112.66 (C9), 8.61 (C10), 63.03 (Ci), 32.16 (Ck), 170.70
(C=O), 140.79 (C11), 112.79 (C12), 159.27 (C13), 114.36 (C14),
129.57 (C15), 119.63 (C16), 55.03 (C17). Anal. Calcd. for
C20H19N3O5S (M 413.43): C, 58.10; H, 4.63; N, 10.16. Found: C,
57.82; H, 4.39; N, 10.42.
4. 13C-NMR, δ (ppm): 147.71 (C1), 135.45 (C2), 110.57 (C3),
119.19 (C4), 118.69 (C5), 110.97 (C6), 55.99 (C7), 157.39
(C8), 112.88 (C9), 9.12 (C10), 144.77 (Ci), 12.36 (Ck), 135.93
(C11), 125.37 (C12/C16), 128.95 (C13/C15), 137.59 (C14), 20.72
(C17). EI ms, m/z (%) = 352 (M+., 50), 336 (M+.- O, 10), 292
(M+. - 2NO, 24). Anal. Calcd. for C19H20N4O3 (M 352.37): C,
64.76; H, 5.72; N, 15.90. Found: C, 64.44; H, 5.98; N, 16.21.
N1-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-N2-[1-(4-
hydroxyphenyl)ethyliden]-hydrazine (3m). White needle crystals,
yield 76%, mp 186ꢀC (from EtOH). IR (cm−1): 3363 (NH); 3300
(OH), 3062; 3000; 2970; 2848 (C–H); 1605, 1579, 1514 (ring).
1H-NMR: see Table 4. 13C-NMR, δ (ppm): 147.61 (C1), 135.65
(C2), 110.31 (C3), 119.13 (C4), 118.37 (C5), 110.79 (C6), 55.93
(C7), 157.45 (C8), 112.97 (C9), 9.16 (C10), 145.19 (Ci), 12.39
(Ck), 129.63 (C11), 126.91 (C12/C16), 115.16 (C13/C15), 157.92
(C14). Anal. Calcd. for C18H18N4O4 (M 354.45): C, 61.01; H,
5.12; N, 15.81. Found: C, 61.42; H, 4.98; N, 16.11.
2-Mercaptoacetamido-1-methoxy-4-(3-methylfuroxan-4-yl)
benzene (4f). White crystals, yield 56%, mp 115–117ꢀC (from
EtOH/H2O 1:1). IR (cm−1): 3389, 3277 (NH); 3097, 2928, 2844
(C–H); 1672 (C=O); 1600, 1549 (ring). 1H-NMR, δ(ppm), J
(Hz): 8.50 (1H, d, 4JHH = 1.5, H3), 7.49 (1H, dd, 3JHH = 8.5, 4JHH
The one-pot procedure for the preparation of thiazolidin-4-
ones 4a–e. To a solution of 1 mmol (0.221 g) of amine 1 and 1
mmol of an appropriated aromatic aldehyde in 15 mL dry
toluene 3.5 mmol (2.5 mL) of mercaptoacetic acid was slowly
added. The reaction mixture was fluxed using a Dean–Stark trap
for 8–10 hours. The cooled mixture was neutralized with 0.1 M
NaOH solution and then was evaporated in vacuo. The residue
was recrystallized from suitable solvents.
3
= 1.5, H5), 7.24 (1H, d, JHH = 8.5, H6), 3.91 (3H, s, H7), 2.28
(3H, s, H10), 3.89 (2H, s, Hk). 13C-NMR, δ (ppm): 167.41
(C=O),151.12 (C1), 127.69 (C2), 119.83 (C3), 118.23 (C4),
123.84 (C5), 111.676 (C6), 56.08 (C7), 156.70 (C8), 112.75 (C9),
8.98 (C10), 66.32 (Ck). +ms, m/z = 296 (M+H+). Anal. Calcd. for
C12H13N3O4S (M 295.31): C, 48.81; H, 4.44; N, 14.23. Found: C,
49.52; H, 4.19; N, 13.88.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-2-phenyl-1,3-
thiazolidin-4-one (4a). White crystals, yield 86%, mp 173ꢀC
(from EtOH/H2O 1:1). IR (cm−1): 3070, 3036, 2973, 2924, 2846
1
(C–H); 1688 (C=O); 1598, 1524 (ring). H-NMR: see Table 2.
13C-NMR, δ (ppm): 156.94 (C1), 126.27 (C2), 129.16 (C3),
118.34 (C4), 128.85 (C5), 113.25 (C6), 56.21 (C7), 156.24 (C8),
112.69 (C9), 8.68 (C10), 63.23 (Ci), 32.23 (Ck), 170.77 (C=O),
139.16 (C11), 127.61 (C12/C16), 128.47 (C13/C15), 128.79
(C14). +ms, m/z = 384 (M+H+). Anal. Calcd. for C19H17N3O4S
(M 383.42): C, 59.52; H, 4.47; N, 10.96. Found: C, 59.20; H,
4.24; N, 11.28.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenyl]-2-(2-nitrophenyl)-
1,3-thiazolidin-4-one (4b) White crystals, yield 79%, mp 198–200ꢀC
(from EtOH/H2O 1:1). IR (cm−1): 3097, 3040, 2985, 2935, 2865
(C–H); 1696 (C=O); 1604, 1576, 1522 (ring). 1H-NMR: see Table
2. 13C-NMR, δ (ppm): 156.66 (C1), 125.53 (C2), 129.03 (C3),
The general procedure for the preparation of 1,3-thiazolidin-
4-ones 5a–j. A solution of 1 mmol of the hydrazone (3a-j) and 2
mmol (0.15 mL) of mercaptoacetic acid in 25 mL dry toluene was
fluxed using a Dean–Stark trap for 7–8 hours. The cooled mixture
was treated with 10 mL of 0.1 M NaOH solution. The resulting
precipitate was collected, washed with ethanol and recrystallized.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamino]-2-phenyl-
1,3-thiazolidin-4-one (5a). White crystals, yield 46%, mp 141ꢀC
(from DMF/H2O 1:2). IR (cm−1): 3334 (NH); 3060; 2930; 2859
(C–H), 1691 (C=O), 1600, 1522 (ring). 1H-NMR: see Table 3.
Anal. Calcd. for C19H18N4O4S (M 398.42): C, 55.27; H, 4.55; N,
14.06. Found: C, 54.94; H, 4.69; N, 14.37.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1084
N. H. Dinh, N. Q. Trung, N. D. Dat, and N. Hien
Vol 49
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamino]-2-(2-
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamino]-2-(4-
methoxyphenyl)-1,3-thiazolidin-4-one (5h). White crystals, yield
82%, mp 190–191ꢀC (from DMF/H2O 1:2). IR (cm−1): 3314
(NH); 3090; 3012, 2972; 2845 (C–H), 1703 (C=O), 1591, 1520
methylphenyl)-1,3-thiazolidin-4-one (5b). White crystals, yield
80%, mp 168–170ꢀC (from DMF/H2O 1:2). IR (cm−1): 3295
(NH); 3060; 2960; 2931, 2853 (C–H), 1706 (C=O), 1596, 1530
1
1
(ring). H-NMR: see Table 3. 13C-NMR, δ (ppm): 148.53 (C1),
(ring). H-NMR: see Table 3. 13C-NMR, δ (ppm): 148.86 (C1),
135.73 (C2), 110.06 (C3), 118.63 (C4), 119.39 (C5), 111.08
(C6), 55.65 (C7), 157.23 (C8), 112.91 (C9), 9.02 (C10), 58.62
(Ci), 28.78 (Ck), 169.61 (C=O), 136.84 (C11), 135.82 (C12),
130.42 (C13), 128.11 (C14), 126.27 (C15), 126.59 (C16), 18.48
(C17). Anal. Calcd. for C20H20N4O4S (M 412.44): C, 58.24; H,
4.89; N, 13.58. Found: C, 58.51; H, 4.69; N, 13.27.
136.61 (C2), 110.32 (C3), 119.09 (C4), 119.73 (C5), 111.48
(C6), 56.18 (C7), 157.78 (C8), 113.44 (C9), 9.56 (C10), 62.44
(Ci), 29.70 (Ck), 169.92 (C=O), 131.13 (C11), 129.81 (C12/C16),
114.32 (C13/C15), 160.08 (C14). Anal. Calcd. for C20H20N4O5S
(M 428.44): C, 56.06; H, 4.71; N, 13.08. Found: C, 55.78; H,
4.45; N, 13.40.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamino]-2-(4-
methylphenyl)-1,3-thiazolidin-4-one (5c). White crystals, yield
56%, mp 170–171ꢀC (from DMF/H2O 1:2). IR (cm−1): 3326
(NH); 3060; 3015, 2923; 2858 (C–H), 1697 (C=O), 1600, 1594,
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamino]-2-(4-
hydroxy-3-methoxyphenyl)-1,3-thiazolidin-4-one (5i). White crystals,
yield 90%, mp 212ꢀC (from DMF/H2O 1:2). IR (cm−1): 3440 (OH),
3256 (NH); 3064; 3020, 2960; 2852 (C–H), 1689 (C=O), 1601,
1
1
1520 (ring). H-NMR: see Table 3. 13C-NMR, δ (ppm): 148.34
1513 (ring). H-NMR: see Table 3. 13C-NMR, δ (ppm): 148.28
(C1), 136.00 (C2), 109.77 (C3), 118.56 (C4), 119.21 (C5), 110.96
(C6), 55.61 (C7), 157.23 (C8), 112.89 (C9), 9.02 (C10), 61.98
(Ci), 29.11 (Ck), 169.44 (C=O), 138.09 (C11), 128.97 (C12/C16),
127.66 (C13/C15), 133.70 (C14), 20.66 (C17). Anal. Calcd. for
C20H20N4O4S (M 412.44): C, 58.24; H, 4.89; N, 13.58. Found:
C, 57.94; H, 5.12; N, 13.79.
(C1), 136.15 (C2), 110.88 (C3), 118.50 (C4), 119.06 (C5), 111.38
(C6), 56.62 (C7), 157.18 (C8), 112.86 (C9), 9.00 (C10), 62.50
(Ci), 29.19 (Ck), 169.00 (C=O), 132.90 (C11), 114.84 (C12),
147.54 (C13), 147.09 (C14), 109.68 (C15), 120.77 (C16). Anal.
Calcd. for C20H20N4O6S (M 444.44): C, 54.05; H, 4.54; N, 12.61.
Found: C, 54.32; H, 4.25; N, 12.33.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamino]-2-(2-
chlorophenyl)-1,3-thiazolidin-4-one (5d). White crystals, yield
58%, mp 177ꢀC (from DMF/H2O 1:2). IR (cm−−1): 3311 (NH);
3070, 3040, 2931, 2852 (C–H), 1706 (C=O), 1602, 1528 (ring).
1H-NMR: see Table 3. 13C-NMR, δ (ppm): 148.68 (C1), 135.58
(C2), 109.88 (C3), 118.71 (C4), 119.68 (C5), 111.23 (C6), 55.67
(C7), 157.21 (C8), 112.95 (C9), 9.03 (C10), 58.65 (Ci), 28.55
(Ck), 169.53 (C=O), 136.66 (C11), 131.89 (C12), 129.58 (C13),
129.96 (C14), 127.70 (C15), 128.22 (C16). Anal. Calcd. for
C19H17N4O4ClS (M 432.86): C, 52.72; H, 3.96; N, 12.94. Found:
C, 53.01; H, 4.24; N, 12.65.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamino]-2-(thien-
2-yl)-1,3-thiazolidin-4-one (5j). White crystals, yield 55%, mp
168ꢀC (from DMF/H2O 1:2). IR (cm−1): 3316 (NH); 3081; 3010,
1
2914; 2853 (C–H), 1691 (C=O), 1600, 1532 (ring). H-NMR: see
Table 3. 13C-NMR, δ (ppm): 148.32 (C1), 136.21 (C2), 109.89
(C3), 118.49 (C4), 119.25 (C5), 110.95 (C6), 55.73 (C7), 157.10
(C8), 112.78 (C9), 9.06 (C10), 57.97 (Ci), 29.34 (Ck), 169.14
(C=O), 142.40 (C12), 127.71 (C13), 126.78 (C14), 128.38 (C15).
Anal. Calcd. for C17H16N4O4S2 (M 404.45): C, 50.48; H, 3.99; N,
13.85. Found: C, 50.22; H, 4.14; N, 14.13.
The general procedure for the preparation of indoles 6a–c.
To a stirring solution of 5 mL polyphosphoric acid at 120ꢀC 1 mmol
of an appropriated hydrazone (3 k–m) was slowly added and stirred
for 2 h. The reaction mixture was allowed to cool to room
temperature, and was poured into 40 mL ice-water and then was
neutralized with 1 M NaOH solution. The resulting precipitate
was collected and recrystallized from ethanol/dioxin 4:1 by volume.
7-Methoxy-4-(3-methylfuroxan-4-yl)-2-phenylindole (6a). Dark
brown crystals, yield 57%, mp 164–164ꢀC. IR (cm−1): 3325
(NH); 3074; 3000; 2938, 2852 (C–H), 1598, 1573, 1539 (ring).
1H-NMR: see Table 4. 13C-NMR, δ (ppm): 148.75 (C1), 127.83
(C2), 128.24 (C3), 110.62 (C4), 122.51 (C5), 102.84 (C6), 56.06
(C7), 157.70 (C8), 113.64 (C9), 10.00 (C10), 139.94 (Ci), 100.04
(Ck), 132.10 (C11), 126.26 (C12/C16), 129.27 (C13/C15), 128.31
(C14). -MS, m/z = 320 (M-H+). Anal. Calcd. for C18H15N3O3
(M 321.33): C, 67.28; H, 4.71; N, 13.08. Found: C, 67.54; H,
4.56; N, 12.86.
7-Methoxy-4-(3-methylfuroxan-4-yl)-2-(4-methylphenyl)indole
(6b). Dark brown crystals, yield 62%, mp 186–187ꢀC. IR (cm−1):
3379 (NH); 3070, 3015, 2979, 2852 (C–H), 1601, 1569 (ring).
1H-NMR: see Table 4. 13C-NMR, δ (ppm): 148.13 (C1), 127.11
(C2), 127.80 (C3), 109.95 (C4), 121.84 (C5), 102.13 (C6), 55.48
(C7), 157.16 (C8), 113.03 (C9), 9.43 (C10), 139.58 (Ci), 98.92
(Ck), 128.81 (C11), 125.65 (C12/C16), 129.26 (C13/C15), 137.18
(C14). -MS, m/z = 334 (M-H+). Anal. Calcd. for C19H17N3O3
(M 335.34): C, 68.05; H, 5.11; N, 12.53. Found: C, 67.84; H,
5.28; N, 12.81.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamino]-2-(4-
chlorophenyl)-1,3-thiazolidin-4-one (5e). White crystals, yield
62%, mp 173–174ꢀC (from DMF/H2O 1:2). IR (cm−1): 3335
(NH); 3095; 3060, 2932; 2862 (C–H), 1699 (C=O), 1595,
1
1535 (ring). H-NMR: see Table 3. 13C-NMR, δ (ppm): 148.44
(C1), 135.90 (C2), 109.74 (C3), 118.60 (C4), 119.38 (C5), 111.06
(C6), 55.68 (C7), 157.23 (C8), 112.93 (C9), 9.04 (C10),
61.26 (Ci), 29.01 (Ck), 169.27 (C=O), 138.38 (C11), 128.45
(C12/C16), 129.64 (C13/C15), 133.20 (C14). Anal. Calcd. for
C19H17N4O4ClS (M 432.86): C, 52.72; H, 3.96; N, 12.94. Found:
C, 52.41; H, 4.21; N, 13.25.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamino]-2-(4-
fluophenyl)-1,3-thiazolidin-4-one (5f). White crystals, yield 71%,
mp 165ꢀC (from DMF/H2O 1:2). IR (cm−1): 3326 (NH); 3086;
3022, 2979; 2859 (C–H), 1686 (C=O), 1602, 1540, 1511 (ring).
1H-NMR: see Table 3. 13C-NMR, δ (ppm): 148.40 (C1), 135.96
(C2), 109.76 (C3), 118.58 (C4), 119.32 (C5), 111.02 (C6), 55.66
(C7), 157.23 (C8), 112.92 (C9), 9.04 (C10), 61.34 (Ci), 29.05
(Ck), 169.28 (C=O), 135.37 (C11), 129.98 (3JFC = 9 Hz, C12/
C16), 115.26 (2JFC = 22 Hz, C13/C15), 162.00 (1JFC = 230 Hz,
C14). Anal. Calcd. for C19H17N4O4FS (M 416.41): C, 54.80; H,
4.12; N, 13.46. Found: C, 55.09; H, 4.22; N, 13.12.
3-[2-Methoxy-5-(3-methylfuroxan-4-yl)phenylamino]-2-(3-
methoxyphenyl)-1,3-thiazolidin-4-one (5g). White crystals, yield
71%, mp 165ꢀC (from DMF/H2O 1:2). IR (cm−1): 3302 (NH);
3080, 3020, 2960, 2931, 2853 (C–H), 1706 (C=O), 1598, 1525
(ring). 1H-NMR: see Table 3. Anal. Calcd. for C20H20N4O5S
(M 428.44): C, 56.06; H, 4.71; N, 13.08. Found: C, 56.34; H,
4.39; N, 13.34.
7-Methoxy-4-(3-methylfuroxan-4-yl)-2-(4-hydroxyphenyl)
indole (6c) Dark brown crystals, yield 46%, mp 192ꢀC. IR (cm−1):
3345 (NH); 3250 (OH); 3060, 3020, 2939, 2830 (C–H), 1595, 1571
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Synthesis of Some Series of 1,3-Thiazolidin-4-ones and Indoles Incorporating
Furoxan Moiety Starting with Anethole Isolated from Star Anise Oil
1085
1
(ring). H-NMR: see Table 4. 13C-NMR, δ (ppm): 148.02 (C1),
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126.87 (C2), 128.07 (C3), 109.69 (C4), 121.69 (C5), 101.83
(C6), 55.47 (C7), 157.25 (C8), 113.04 (C9), 9.47 (C10), 140.15
(Ci), 97.76 (Ck), 122.69 (C11), 127.28 (C12/C16), 115.52 (C13/
C15), 157.43 (C14). +ms, m/z = 338 (M+H+). Anal. Calcd. for
C18H15N3O4 (M 337.31): C, 64.09; H, 4.48; N, 12.46. Found: C,
64.34; H, 4.27; N, 12.73.
Acknowledgments. This work was supported by Vietnam National
Foundation for Science and Technology Development (NAFOSTED).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet