Unexpected Synthesis of Novel 3-Allyl-5-(arylidene)-2-thioxo-thiazolidin-4-ones in Reactions of 3-Allylrhodanine with 2-Arylidene-4-methyl-5-oxopyrazolidinium Ylides

Article abstract of DOI:10.1080/00397911.2015.1063655

The reaction of 3-allylrhodanine with 2-arylidene-4-methyl-5-oxopyrazolidinium ylides proceeded unexpectedly to form novel 3-allyl-5-(arylidene)-2-thioxo-thiazolidin-4-ones 6a-k in good yields. All structures have been formulated on the basis of their spe

Full text of DOI:10.1080/00397911.2015.1063655

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Unexpected Synthesis of Novel 3-Allyl-5-(arylidene)-2-
thioxo-thiazolidin-4-ones in Reactions of 3-
Allylrhodanine with 2-Arylidene-4-methyl-5-
oxopyrazolidinium Ylides
Rahhal El Ajlaouia, Amiri Ouafaa, Souad Mojahidia, Lahcen El Ammarib, Mohamed Saadib &
Rakib El Mostaphaa
a Laboratoire de Chimie Organique et Analytiques, Faculté des Sciences et Techniques,
Université Sultan Moulay Slimane, Béni-Mellal, Morocco
b Laboratoire de Chimie du Solide Appliquée, Faculté des Sciences, Université Mohammed V-
Agdal, Rabat, Morocco
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Accepted author version posted online: 22 Jun 2015.
To cite this article: Rahhal El Ajlaoui, Amiri Ouafa, Souad Mojahidi, Lahcen El Ammari, Mohamed Saadi & Rakib El Mostapha
(2015): Unexpected Synthesis of Novel 3-Allyl-5-(arylidene)-2-thioxo-thiazolidin-4-ones in Reactions of 3-Allylrhodanine
with 2-Arylidene-4-methyl-5-oxopyrazolidinium Ylides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1063655
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1063655
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Unexpected Synthesis of Novel 3-Allyl-5-(arylidene)-2-thioxo-thiazolidin-4-ones in
Reactions of 3-Allylrhodanine with 2-Arylidene-4-methyl-5-oxopyrazolidinium
ylides
Rahhal El Ajlaoui1, Amiri Ouafa1, Souad Mojahidi1, Lahcen El Ammari2, Mohamed
Saadi2, Rakib El Mostapha1
1Laboratoire de Chimie Organique et Analytiques, Faculté des Sciences et Techniques,
Université Sultan Moulay Slimane, Béni-Mellal, Morocco, 2Laboratoire de Chimie du
Solide Appliquée, Faculté des Sciences, Université Mohammed V-Agdal, Rabat,
Morocco
Corresponding author. El Mostapha Rakib, E-mail: elmostapha1@ymail.com
Abstract
The reaction of 3-allylrhodanine with 2-arylidene-4-methyl-5-oxopyrazolidinium ylides
proceeded unexpectedly to the formation of novel 3-allyl-5-(arylidene)-2-thioxo-
thiazolidin-4-ones 6a-k in good yields. All structures have been formulated on the basis
of their spectral (IR, NMR, MS) data and elemental analyses. In addition, the structure of
compound 6a was confirmed by means of X-ray crystallographic analysis.
KEYWORDS: 3-allylrhodanine; 2-arylidene-4-methyl-5-oxopyrazolidinium ylides; 3-
allyl-5-(arylidene)-2-thioxo-thiazolidin-4-ones, X-ray diffraction.
INTRODUCTION
1

The 5-arylidene-2-thioxo-1,3-thiazolidinine-4-ones or 5-arylidene rhodanines are
considered as ‘‘privileged scaffolds’’ in the medicinal chemistry community because they
presented a bioactivity in a large range of derivatives [1-5]. For example, these small
molecules have been known to possesses a wide range of biological properties such as
potent and selective inhibitors of the ‘‘atypical’’ dual-specificity phosphatase (DSP)
family member-JNK-stimulating phosphatase-1 (JSP-1) [6], as aldose reductase inhibitor
in diabetic peripheral neuropathy [7], as DDX3 inhibitor for HIV replication [8]. The
unusual biological activities displayed by many rhodanine-based molecules have made
them attractive synthetic targets. Arylidene rhodanines are generally prepared by reacting
[2, 9-14]
aldehydes and rhodanine in organic solvents and in the presence of organic bases
.
In this paper, we report an easy strategy for the syntheses of novel 3-allyl-5-(arylidene)-
2-thioxo-thiazolidin-4-ones by reaction of 3-allylrhodanine 5 with various 4-methyl-3-
oxo-1,2-pyrazolidinium ylides 4a-k.
RESULTS AND DISCUSSION
The cyclic azomethine imine, 3-oxo-1,2-diazetidinium ylide, was recognized as a 1,3-
dipole, it was successfully employed in the reactions with dipolarophiles, such as alkynes
[15] and alkenes (including unsaturated aldehydes [16], unsaturated ketones and esters [17]
and others [18]). In this context, we decided to investigate the reactivity of 3-
allylrhodanine 5 toward various 4-methyl-5-oxo-1,2-pyrazolidinium ylides 4a-k heated
under reflux of THF, but unexpectedly we observed formation of novel 3-allyl-5-
(arylidene)-2-thioxo-thiazolidin-4-ones 6a-k with good yields (68-85%) (Scheme 1,
Table 2). No cycloadduct resulting from the addition of the dipole 4 on the double bonds
2

C=S and C=C was detected under the identical conditions.
The 5-oxo-1,2-pyrazolidinium ylides 4a-k were prepared from methyl methacrylate and
aromatic aldehydes following the literature procedure [19,15h]. Further treatment of methyl
methacrylate 1 with excess of hydrazine hydrate in ethanol at reflux gave the
pyrazolidinone 2 in 80% yields. Acid-catalyzed treatment of pyrazolidinone with various
aromatic aldehyde 3a-k gave the corresponding 2-arylidene-4-methyl-5-oxo-1,2-
pyrazolidinium ylides 4a-k in excellent yields (80-96%, Table 1).
The chemical structures of all the new compounds were confirmed by IR, 1H NMR, 13C
NMR, elemental analysis, and mass spectrometry.
The single crystal X-ray crystallography of product 6a confirmed the structures of
obtained products 6a-k (Figure 1, details see supporting information).
A conceivable mechanism is proposed in Scheme 2. The reaction is initiated by single
deprotonation in methylene group of 3-allylrhodanine by the dipole 4 (step a) to give the
carbanion which upon nucleophilic attack on the iminium carbon atom of (Z)-2-
benzylidene-4-methyl-5-oxopyrazolidin-1-ium molecule (C-C coupling, step b) forms 3-
allyl-5-[(4-methyl -3-oxo-pyrazolidin-1-yl)-phenyl-methyl]-2-thioxo-thiazolidin-4-one as
an intermediate. Abstraction of the second proton from the methylene active fragment by
the amine nitrogen followed by elimination of pyrazolidinone (step c) leads to the
formation of the corresponding 3-allyl-5-(arylidene)-2-thioxo-thiazolidin-4-ones 6a-k. It
3

is noteworthy, that deprotonation of substrate with basic 1,3-dipoles are known in other
cases of the literature [20]
.
CONCLUSION
A practical access to novel 3-allyl-5-(arylidene)-2-thioxo-thiazolidin-4-ones via reaction
of 3-allylrhodanine with 2-arylidene-4-methyl-5-oxo-1,2-pyrazolidinium ylides was
investigated. The desired products were obtained in good yields under conditions without
any catalysts or other additives. To our knowledge, this new approach has never been
reported and may be a completion to those existing in the literature. Further expansion of
the reaction scope and synthetic applications of this methodology on other methylene
active compounds are in progress in our laboratory.
EXPERIMENTAL
Melting points were determined using a Büchi-Tottoli apparatus. 1H and 13C NMR
spectra were recorded in CDCl3 or DMSO-d6 solution (unless otherwise specified) with
TMS as an internal reference using a Bruker AC 300 (1H) or 75MHz (13C) instruments.
Chemical shifts are given in δ parts per million (ppm) downfield from TMS.
Multiplicities of 13C NMR resources were assigned by distortionless enhancement by
polarization transfer (DEPT) experiments. Low-resolution mass spectra (MS) were
recorded on a Perkin-Elmer Sciex API 3000 spectrometer. Column chromatography was
carried out on SiO2 (silica gel 60 Merck 0.063–0.200 mm). Thin-layer chromatography
(TLC) was carried out on SiO2 (silica gel 60, F 254 Merck 0.063–0.200 mm), and the
4

spots were visualized with UV light. Commercial reagents were used without further
purification unless stated.
General Procedures For The Synthesis Of 2-Arylidene-4-Methyl-5-Oxopyrazolidin-
2-Ium-2-Ides (4a-K)
Cooled in an ice bath, methyl methacrylate (0.85 mol, 60 mL) was added to the solution
of hydrazine hydrate (80%) 26 mL in ethanol 240 mL. After addition, the mixture was
refluxed for 12 h. Then the solvent and the volatile components were removed under
reduced pressure. The thick colorless oil, crude 4-methyl pyrazolidin-3-one 2, was
obtained in 80% yield. CF3COOH (1 ml) was added to a stirred mixture of 4-methyl
pyrazolidin-3-one (2; 1.14 g, 10 mmol), substituted aromatic aldehyde 3a-k (10 mmol),
and anhydrous EtOH (40 ml). The mixture was stirred at room temperature for 8-24 h.
Volatile compounds were evaporated, Et2O (30 ml) added to the residue, and the
precipitate collected by filtration and crystallized from ethanol.
(Z)-(4-Methylbenzylidene)-4-methyl-5-oxopyrazolidin-2-ium-1-ide 4b: From 4-
methyl benzaldehyde; Yield: 90 %, mp 160-162 °C; 1H NMR (DMSO, 300 MHz): δ 1.14
(d, 3H, J = 7.2 Hz), 2.35 (s, 3H, CH3), 2.66–2.74 (m, 1H), 4.16 (dd, 1H, J = 7.2 Hz, 13.5
Hz), 4.70 (dd, 1H, J = 9.3 Hz, 13.5 Hz), 7.32 (d, 2H, J = 8.1 Hz), 7.59 (s, 1H), 8.17 (d,
2H, J = 8.1 Hz); 13C NMR (DMSO-d6, 75 MHz): δ 15.9 (CH3), 21.7 (CH3), 35.3 (CH),
64.3 (CH2N), 127.8 (C), 129.8 (2CH), 131.5 (2CH), 132.6 (=CH), 141.8 (C), 187.2 (CO).
5

General Procedures For The Synthesis Of 3-Allyl-5-(Arylidene)-2-Thioxo-
Thiazolidin-4-Ones (6a-K).
To a solution of 3-allylrhodanine (1.15 mmol) in 10 ml of THF, 4-methyl-5-oxo-1,2-
pyrazolidinium ylides (1.38 mmol) was added. The mixture was refluxed for 8-12 h,
monitored by TLC, the reaction completed and a yellow spot (TLC Rf = 0.3, using
hexane/ethyl acetate 1:9) was generated cleanly. The solvent was evaporated under
diminished pressure. The crude product was purified on SiO2 packed column using
hexane: ethyl acetate (1/9) as eluent.
(Z)-3-Allyl-5-(4-methylbenzylidene)-2-thioxothiazolidin-4-one 6b: Yield: 75%, yellow
1
solid, mp 116-118°C; IR (KBr, cm-1): 1690 (CO), 1257 (CS); H NMR (CDCl3, 300
MHz): δ 2.40 (s, 3H, CH3), 4.72-4.75 (m, 2H, NCH2), 5.23-5.32 (m, 2H, =CH2), 5.80-
5.93 (m, 1H, =CH), 7.28 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4 Hz), 7.71 (s, 1H, =CH);
13C NMR (CDCl3, 75 MHz): δ 21.7 (CH3), 46.4 (NCH2), 119.3 (=CH2), 121.7 (C), 129.6
(CH), 130.1 (2CH), 130.7 (2CH), 133.4 (CH), 131.7 (C), 141.7 (C), 167.5 (CO), 193.0
(CS); EI-MS (m/z) = 276 [M+1]+; Anal. Calcd for C14H13NOS2; C, 61.06; H, 4.76; N,
5.09. Found: C, 61.14; H, 4.68; N, 5.15.
ACKNOWLEDGMENTS
We thank the University of Sultan Moulay Slimane, Beni-Mellal for financial support
and the National Centre for Scientific and Technical Research (CNRST), Rabat, for
providing the NMR and X-ray crystallography of our compounds.
6

SUPPLEMENTAL MATERIAL
Full characterization data, 1H and 13C NMR spectra, and x-ray crystallographic materials
for this article can be accessed on the publisher’s website.
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11

Table 1. Yields, melting points and reaction times of compounds 4a-k
Entry
4a[17]
4b
Ar
Time (h)
Mp (°C)
123-125
160-162
143-145
185-187
178-180
187-189
162-164
170-172
178-180
Yield (%)
C6H5
12
8
80
90
84
86
82
75
78
96
94
4-MeC6H4
4-MeOC6H4
4-ClC6H5
4c[17]
4d
8
16
4-(CH3)2NC6H4 12
4e
4f[17]
4g
3-NO2C6H4
3-BrC6H4
2-furyl
24
24
20
20
4h
2-thienyl
4k
12

Table 2. Yields, melting points and reaction times of compounds 6a-k
Entry
6a
Ar
Time (hrs)
Mp (°C)
142-144
116-118
90-92
Yield (%)
C6H5
10
12
12
12
8
68
75
78
72
82
85
76
77
70
4-MeC6H4
4-MeOC6H4
4-ClC6H5
4-(CH3)2NC6H4
3-NO2C6H4
3-BrC6H4
2-furyl
6b
6c
97-99
6d
6e
118-120
140-142
116-118
96-98
8
6f
10
12
12
6g
6h
6k
2-thienyl
129-131
aIsolated yield after separation by flash chromatography
13

Scheme 1. Synthesis of 3-allyl-5-(arylidene)-2-thioxo-thiazolidin-4-ones 6a-k
14

Scheme 2. Proposed mechanism for the formation of compounds 6a-k
15

Figure 1. ORTEP view of the molecular geometry of compound 6a
16