Reactions of 5-aroylmethylene-3-benzyl-4-oxo-2-thioxo-1,3-thiazolidines with nitrile oxides

Article abstract of DOI:10.3390/60600510

E,Z-5-Aroylmethylene-3-benzyl-4-oxo-2-thioxo-1,3-thiazolidines (3a-c) react with 4-methoxy and 4-chlorophenylnitrile oxides (4a and b) in pyridine solution to afford one or more of the following compounds: Z-3, Z-2,4-dioxo analogues 5 and 3,6-diaryl-1,4,2,5-dioxadiazines (6a-b). The interconversion route is discussed and the structures of all of the synthesised compounds are proven by microanalytical and spectral data.

Full text of DOI:10.3390/60600510

Molecules 2001, 6, 510-518
molecules
ISSN 1420-3049
http://www.mdpi.org
Reactions of 5-Aroylmethylene-3-benzyl-4-oxo-2-thioxo-1,3-
thiazolidines with Nitrile Oxides.
Kamal A. Kandeel and Ahmed S. A. Youssef*
Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt.
*Author to whom correspondence should be addressed; e-mail: ahmedy67@hotmail.com
Received: 4 July 2000; in revised form 13 January 2001 / Accepted:30 April 2001 / Published: 31 May
2001
Abstract: E,Z-5-Aroylmethylene-3-benzyl-4-oxo-2-thioxo-1,3-thiazolidines (3a-c) react
with 4-methoxy and 4-chlorophenylnitrile oxides (4a and b) in pyridine solution to afford
one or more of the following compounds: Z-3, Z-2,4-dioxo analogues 5 and 3,6-diaryl-
1,4,2,5-dioxadiazines (6a-b). The interconversion route is discussed and the structures of
all of the synthesised compounds are proven by microanalytical and spectral data.
Keywords: 4-Thiazolidinones; Nitrile Oxides; Isomerisation; Thiazolidinedione;
Cycloaddition; Dimerisation.
Introduction
Several reports on the chemistry of 4-thiazolidinones have been published [1-6], but literature reports
on reactions of 4-oxo-2-thioxo-thiazolidines with dipolar species are rather limited and treat the problem
of alkylation of the 3-unsubstituted derivatives with diazomethane [7,8] and cycloaddition of nitrilimines
to the thiono function of 5-aroyl-methylene-3-phenyl-4-oxo-2-thioxo-1,3-thiazolidine [9]. The intention
of the present work was to study the reactivity of thiono as well as exocylic double bond functions in

Molecules 2001, 6
511
E,Z-5-aroylmethylene-3-benzyl-4-oxo-2-thioxo-1,3-thiazolidines (3a-c) towards 4-methoxyphenyl- and
4-chlorophenylnitrile oxides (4a,b). Thus a series of E,Z-5-aroylmethylene-3-benzyl-4-oxo-2-thioxo-1,3-
thiazolidines (3a-c) has been synthesised and subsequently reacted with 4-methoxyphenyl- and 4-
chlorophenylnitrile oxides (4a,b).
Results and Discussion
Compounds E,Z-3a-c were synthesised by a method similar to that of Nagase [10] by treating 5-(2-
aryl-2-oxoethyl)-4-oxo-2-thioxo-1,3-thiazolidines (2a-c) (obtained in turn by reaction of 3-aroylacrylic
acids (1a-c) with ammonium benzyldithiocarbamate), with bromine as shown in Scheme 1. Omar et al.
[2] studied the stereochemistry of compounds 3 and reported the formation of E- and Z- stereoisomers
with the predominance of the former one.
S
S
Ph
Ph
S
N
Ph
NH
N
COOH
S
H+
+
O
Br2/AcOH
S
H N
S
O
4
H
A
R
O
R
H
R
H
M
O
H
X
O
(E,Z-3)
(1)
(2)
a, R = 4-MeC6H4-
b, R = 4-BrC6H4-
c, R = 4-ClC6H4-
Scheme 1
Our intent was to perform the reactions in pyridine as, on the one hand, it is able to dissolve the
starting thiazolidinones which are sparingly soluble in most organic solvents, and, on the other hand, it
can be used to liberate the required nitrile oxide in situ from stable α-hydroximinobenzyl chlorides
precursors.
Nitrile oxides 4a and 4b, produced in situ upon addition of α-hydroximino-4-methoxy- and α-
hydroximino-4-chlorobenzyl chlorides to pyridine reacted with E,Z-3a-c to afford the Z-isomers of
either of the starting 4-oxo-2-thioxo- compounds Z-3 or the Z-2,4-dioxo- analogues 5, or a mixture of
them, along with the corresponding head to tail dimerised product, namely 3,6-di-(4-methoxyphenyl)-
1,4,2,5-dioxadiazine (6a), in the former case and the 4-chlorophenyl counterpart (6b), in the latter case,
as outlined in Scheme 2. Small amounts of the unreacted starting materials somewhat enriched with Z-
isomers were isolated in all the studied examples. (cf. Table 1).

Molecules 2001, 6
512
The structures of the isomerized 4-oxo-2-thioxo-1,3-thiazolidines (Z-3b and c) and the respective
2,4-dioxo counterparts (Z-5a-c) were deduced from microanalytical, IR, 1H-NMR and MS spectral data
(cf. Tables 2 and 3). All the IR spectra of compounds 5 show the complex carbonyl pattern extending to
1750 cm-1 consistent with the stretching vibrations of coupled carbonyl groups, whereas those of 3 show
the carbonyl absorptions at mostly lower frequency values not exceeding 1715 cm-1. Their EI-mass
spectra exhibit parent peaks at m/e 91, molecular ion peaks and M.+-CS(CO) [A] and M.+-PhCH2NCS(O)
[B] fragments. The structures of 6a and 6b, which were believed to be the head to the tail dimerised
products, was confirmed by comparison (m.p and IR) with authentic samples [11].
Ar
S
Ar
Ph
N
N
O
Pyridine
+
Z-3*
S
O
N
N
O
(E,Z-3a-c)
+
O
+
+
Ar-C N O
R
H
Ar
O
(4) a, Ar = 4-MeOC6H4-
b, Ar = 4-ClC6H4-
(7)
(6)
a, Ar = 4-MeOC6H4-
b, Ar = 4-ClC6H4-
-(Ar-N=C=S)
O
S
Ph
N
O
R
H
O
a, R = 4-MeC H -
(Z-5)
6
4
b, R = 4-BrC6H4-
c, R = 4-ClC6H4-
* isolated in reactions of (E,Z-3c) with (4a) and (E,Z-3b) with (4b)
Scheme 2
Configurational assignments of compounds 3 and 5 were based exclusively on 1H-NMR
spectroscopy by comparing the observed chemical shift values of the olefinic protons with the

Molecules 2001, 6
513
incremented values [12]; the olefinic protons of the Z-isomers are relatively deshielded by the 4-oxo-
groups compared with the E-counterparts. The Z-configuration was assigned to 3b and 3c by comparing
with the starting E-counterparts and to 5a by comparing with a sample previously prepared [1] upon
treating a solution of 2a in glacial acetic acid with bromine.
A role for pyridine alone in the isomerisation process can be ruled out as compounds E,Z-3a-c are
recovered without detectable configurational change upon refluxing in this solvent. The larger
proportions of Z-isomers observed in the compounds prepared as compared to the starting materials
indicates that isomerisation has occured during the reactions. The great stability of the Z-isomers as
compared with the E-counterparts is probably due to steric considerations Although isomerisation may
be explained according to the hypothesis of formation of zwitterionic or biradical intermediates [13], it is
better explained in terms of successive addition and elimination of nitrile oxide at the β-terminus of the
exocyclic α,β-unsatured carbonyl system of compounds 3 as outlined in Scheme 3. The instability of the
hypothetically formed adducts may be attributed to a sterically hindered transition state. The negative
results reported for the reaction of tri- and tetra-alkyl ethylenes with nitrile oxides [14] seem to be in
accordance with our results.
X
X
X
Ph
Ph
N
N
Ph
N
+
Ar-C N O
S
S
O
-
O
S
-
O
H
O
+
H
R
R
+
H
Ar-C N O
R
O N C-Ar
O
O
X = S or O
+
-
Ar-C N O
(Z-3) or (Z-5)
Scheme 3
The formation of the 2,4-dioxo compounds 5 rather than the spiranes 7; which could be produced by
the attack of nitrile oxides at the thiono group of compounds 3 could be rationalised in terms of
decomposition of the 1,4,2-oxathiazole ring of the spirane ring system by expelling 4-chlorophenyl- or 4-
methoxyphenylisothiocyanates. The decomposition has occured most likely via a radical reaction as it
has been reported by Husigen et al [15] that all the 1,4,2-oxathiazoles which are formed via
cycloaddition of nitrile oxides to thiocarbonyl compounds decompose exothermically at 90-150°C to
form isothiocyanates and the oxygen analogues of the thiocarbonyl compounds. The molecular
rearrangement leading to the isothiocyanate probably proceeds concurrently with the ring opening [15]
(Scheme 2). The preference for the nitrile oxides to react with C=S rather than the C=O groups may be

Molecules 2001, 6
514
attributed to the polarizability of the sulfur function which is manifested by the great readiness with
which several thiono containing compounds react with dipolar species [16]. Formation of stable spiranes
is reported upon reacting 2-thioxo-1,3,4-thiadiazole with nitrile imines [16].
Experimental
General
All melting points are uncorrected. IR spectra were measured on a Unicam SP1200 spectrometer as
1
KBr discs. H-NMR spectra were recorded in d6-DMSO on a Varian Gemini 200 MHz instrument with
chemical shifts (δ) expressed in ppm downfield from TMS. Mass spectra were recorded on Shimadzu
GC-MS-Qp 1000 EX instrument operating at 70 ev. Column chromatography and TLC were run on
Silica Gel Woelm, activity 113/30 mm according to Brockmann & Schodder and Silica Gel 60 F254
(Merck) aluminium backed TLC sheets.
Preparation of Starting Materials
3-Benzyl-5-[2-(4-bromophenyl)-2-oxoethyl]-4-oxo-2-thioxo-1,3-thiazolidine (2b).
Ammonium benzyl-dithiocarbamate (2.2 g, 11 mmol) in ethanol (10 mL) was added dropwise to a
stirred solution of 3-(4-bromobenzoyl) propenoic acid [17] (2.55 g, 10 mmol) in ethanol (10 mL) at room
temperature. Concentrated hydrochloric acid (3 mL) was added portionwise to the stirred reaction
mixture after 30 min. and the precipitated solid was filtered and recrystallised from benzene-light
petroleum (b.p. 60-80°C) to give 2b [1,18].
E,Z-3-Benzyl-5-(4-bromobenzoylmethylene)-4-oxo-2-thioxo-1,3-thiazolidine (3b).
Bromine (20 mmol) was added to a solution of 2b (3.4 g, 10 mmol) in glacial acetic acid (20 mL) and
the resulting mixture was warmed on a water bath for 5 min. After cooling the reaction mixture was
poured into cold water and filtered. The crude orange product (3.34 g, 80%) was recrystallised from
glacial acetic acid to give E,Z-3b.
The analogous compounds 3-benzyl-5-[2-(4-methylphenyl)-2-oxoethyl]-4-oxo-2-thioxo-1,3-thiazolidine
(2a) and 3-benzyl-5-[2-(4-chlorophenyl)-2-oxoethyl]-4-oxo-2-thioxo-1,3-thiazolidine (2c) [18] and E,Z-
3-benzyl-5-(4-methylphenylmethylene)-4-oxo-2-thioxo-1,3-thiazolidine (3a) and E,Z-3-benzyl-5-(4-
chlorophenylmethylene)-4-oxo-2-thioxo-1,3-thiazolidine (3c) [1,10] were prepared by the same methods
mentioned above for 2b and E,Z-3b.

Molecules 2001, 6
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Reactions of Compounds E,Z-3a-c with Arylnitrile Oxides 4a and b: General Procedure
Powdered α-hydroximino-4-chlorobenzyl chloride (4a) [19] or the 4-methoxybenzyl counterpart (4b)
[20] (25 mmol) was added to a suspension of each of E,Z-3a-c (10 mmol) in anhydrous pyridine (10
mL) and the whole mixture was refluxed for 10 hrs. during which it acquired a violet colouration. The
solid which precipitated after allowing the reaction mixture to stand at room temperature overnight was
filtered off, washed with small portion of ether and chromatographed or recrystallised from an
appropriate solvent to give Z-3 and/or Z-5 along with starting materials slightly enriched with the Z-
configured isomers E,Z-3.
The crude product (2.82 g, 80%) obtained upon treating E,Z-3a with 4b was crystallized from
dioxane to give E,Z-3a as yellow crystals (0.71 g, 20%), m.p. 210-212°C containing ca. 20% of the Z-
isomer. Dilution of the dioxane mother liquors gave Z-5a as brownish red crystals (1.77 g, 50%), m.p.
179-181°C (from dilute dioxane).
The reaction mixture of E,Z-3b with 4b was concentrated (final volume ca. 5 mL), chromatographed
over silica gel while monitoring by TLC. Elution with light petroleum (b.p. 40-60°C)-ether mixture (4:1
v/v) gave Z-3b (2.3 g, 55%) as red needles (from benzene). Elution with light petroleum (b.p. 40-60°C)-
ether mixture (1:1 v/v) gave Z-5b (0.4 g, 10%) as brownish red crystals (from benzene-methanol).
Elution with pure ether gave E,Z-3b (0.63 g, 15%) containing 30% of the Z- isomer.
The crude product (2.98 g, 80%) which was obtained upon reacting E,Z-3c with 4b was crystallised
from dioxane to give E,Z-3c (0.75 g, 20%) containing 90% of the Z-isomer as orange crystals m.p. 248-
250°C. On leaving the dioxane mother liquor to stand at room temperature for 24 hrs., it precipitated a
yellow solid (1.96 g, 55%) which was recrystallised from benzene-methanol to give Z-5c as yellow
crystals m.p. 226-228°C.
Recrystallisation of the crude product (1.49 g, 40%) obtained from the reaction of E,Z-3c with 4a
from dioxane precipitated successively E,Z-3c (0.6 g, 16%) containing 10% of the Z-isomer and Z-3c
(0.67 g, 18%).
Upon allowing the water diluted original pyridine mother liquors to stand at room temperature for 48
hrs. therefrom precipitated colourless products which were recrystallised from dioxane to give 45% of
3,6-di-(4-methoxyphenyl)-1,4,2,5-dioxadiazine (6a), m.p. 178-180°C, undepressed on admixture with an
authentic sample [11] in all cases when 4a was used and 5-10% of 3,6-di-(4-chlorophenyl)-1,4,2,5-
dioxadiazine (6b), m.p. 222-224°C undepressed on admixture with an authentic sample [11], when 4b
was the reactant.
Action of pyridine on E,Z-3a-c
A suspension of each of E,Z-3a-c (3 mmol) in pyridine (10 mL) was refluxed for 15 hrs. while the
solution acquired a violet colouration. The crude product which precipitated upon leaving the reaction

Molecules 2001, 6
516
mixture to stand at room temperature overnight (90-95%) was recrystallised from dioxane to give 90% of
each E,Z-3a-c with similar E/Z ratios as the starting materials.
Table 1: Reactions of E,Z-3a-c with Nitrile Oxides 4a and 4b
Reactants
Products (% yield)**
(Z)*-3 (Z)*-5
(E,Z)*-3 Nitrile oxide (E,Z)*-3
[Z%]***
6
3c
3a
3b
3c
4a
4b
4b
4b
3c(16)[10] 3c(18) ---
3a(20)[20] ---
3b(15)[30] 3b(55) 5b(10) 6b(5)
3c(20)[90] --- 5c(55) 6b(10)
6a(45)
5a(50) 6b(7)
* configurational assignment is based on 1H-NMR spectroscopy.
** yield of actually isolated compounds
*** % of the Z-isomer in the E,Z-mixture.
Table 2: Some Data of the Newly Synthesised Compounds
1H-NMR Spectral data [δ-values ppm]
Compd.
No.
MP
Olefinic
H
AroylH*
N-CH2Ph
N-CH2Ph
2H
Me
3H
--
(°C)
2Ha
2Hb
5H
128-129
215-217
---
8.020(db) 7.703(db) 7.205(br.s)
5.15 (br s)
2ba [1,18]
E,Z-3a[1]
7.900(sc)
8.265(sc)
8.265(sc)
8.158(se)
8.275(se)
8.274(de)
7.980(dd)
7.350-7.050 (m)
5.300 (br sc) 3.250 (s)
4.835 (br sc) 2.400 (s)
208-210
250-253
8.14(dd)
8.168(df)
7.500-7.050 (m)
4.836 (br s)
2.400 (s)
---
Z-3a
7.713(df)
7.352(br s) 5.274 (br se)
4.870 (br se)
E,Z-3b
188-190
251-252
8.144(de) 7.831(br s) 7.351 (br s) 4.868 (br s)
---
---
Z-3b
E,Z-
8.135(s)
8.257(dg) 7.686 (dg) 7.353(br s) 5.288 (br sc)
3c[10]
8.161(sc)
8.161(s)
8.271(s)
8.280(s)
8.291(s)
5.050 (br sc)
8.255(dg) 7.700(dg) 7.349(br s) 5.050 (br s)
8.108(dg) 7.433(dg) 7.355(br s) 4.862 (br s)
239-240
179-181
226-228
226-228
--
2.420 (s)
---
Z-3c
Z-5a
Z-5b
Z-5c
8.145(dg) 7.832(dg) 7.352(br s)
8.234(df) 7.689(df)
7.352(br s) 4.850 (br s)
4.869(br s)
* Ha and Hb are the protons at the ortho- and meta positions of the aroyl group.

Molecules 2001, 6
517
a
The spectrum shows also the following signals characteristic for AMX system: δ:
5.505 (dd, HA), 4.815 (dd,HM), 3.920(dd,HX), J = 9.0 Hz, J = 3.5 Hz,
HA,HM
HA,HX
J
= 18.0 Hz.
HM,HX
b
c
d
e
f
J = 7.5 Hz.
Characteristic of E- and Z-isomers with integrated proton ratios of 15:1 respectively.
J = 7.2 Hz.
Characteristic of E- and Z-isomers with integrated proton ratios of 9:1, respectively;
J = 8.6 Hz.
J = 8.2 Hz.
g
Table 3: Spectral and Analytical Data of Newly Synthesised compounds
EI-MS m/e(%)
[M.+]
[A]
---
Analysis: Calcd/Found
Compd.
No.
IR (cm-1)
C=O
Formula
(M.W)
[B]
---
C
H
N
1710,1690 ---
C18H14BrNO2S2
(420.37)
51.43/ 3.36/ 3.33/
51.60 3.40 3.39
64.56/ 4.27/ 3.96/
64.43 4.25 4.03
51.68/ 2.89/ 3.35/
51.65 2.96 3.42
51.68/ 2.89/ 3.35/
51.73 3.02 3.50
57.82/ 3.23/ 3.75/
57.91 3.15 5.62
67.64/ 4.48/ 4.15/
67.73 4.39 4.06
53.74/ 3.01/ 3.48/
53.711 3.10 3.52
60.42/ 3.38/ 3.91/
60.56 3.49 3.83
2b
1710,1680 353
(5.1)
309
204
C19H15NO2S2
(353.47)
Z-3a
E,Z-3b
Z-3b
Z-3c
(39.3) (23.9)
1710,1680 ---
---
---
C18H12BrNO2S2
(418.35)
1710,1680 417
373
268
C18H12BrNO2S2
(418.35)
(13.7) (15.8) (12.0)
1715,1690 373
(3.0)
329
(35.7) (22.2)
309 204
(39.3) (23.9)
373 268
(22.0) (12.2)
329 224
(35.7) (22.2)
224
C18H12ClNO2S2
(373.89)
1745,1690 337
(2.0)
C19H15NO3S
(337.40)
Z-5a
Z-5b
Z-5c
1750,1690 401
(3.7)
C18H12BrNO3S
(402.29)
1750,1690 357
(2.1)
C18H12ClNO3S
(357.83)
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Molecules 2001, 6
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Samples Availability: Samples are available from the authors.
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