Synthesis and stereochemistry of thiapyranothiazoles as diels-alder adducts obtained from spirodimers of 1,3-thiazolidines with cinnamic acid and its ester

Article abstract of DOI:10.1080/10426500307800

Thiation of 5-Arylmethylene-3-phenyl-2-thioxo-1,3-thiazolidin-4-ones (1a and b) with either P₄S₁₀¹ or Lawesson's reagent², gave mainly the spirodimers 3′ phenyl-2′-thoxo-1′,3′-thiazolidino[2,3-d]-spiro [6′,7′ di

Full text of DOI:10.1080/10426500307800

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Synthesis and Stereochemistry of Thiapyranothiazoles
as Diels-Alder Adducts Obtained from Spirodimers of
1,3-Thiazolidines with Cinnamic Acid and its Ester
M. T. Omar a , A. El-Khamry a , Ali M. Youssef a & S. Ramadan a
a Ain Shams University , Abbassia, Cairo, Egypt
Published online: 27 Oct 2010.
To cite this article: M. T. Omar , A. El-Khamry , Ali M. Youssef & S. Ramadan (2003) Synthesis and Stereochemistry of
Thiapyranothiazoles as Diels-Alder Adducts Obtained from Spirodimers of 1,3-Thiazolidines with Cinnamic Acid and its Ester,
Phosphorus, Sulfur, and Silicon and the Related Elements, 178:4, 721-735, DOI: 10.1080/10426500307800
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:721–735
C
Copyright 2003 Taylor & Francis
1042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390197931
SYNTHESIS AND STEREOCHEMISTRY OF
THIAPYRANOTHIAZOLES AS DIELS-ALDER
ADDUCTS OBTAINED FROM SPIRODIMERS OF
1,3-THIAZOLIDINES WITH CINNAMIC ACID
AND ITS ESTER
M. T. Omar, A. El-Khamry, Ali M. Youssef, and S. Ramadan
Ain Shams University, Abbassia, Cairo, Egypt
(Received August 7, 2001; accepted January 17, 2002)
Thiation of 5-Arylmethylene-3-phenyl-2-thioxo-1,3-thiazolidin-4-ones
(1a and b) with either P4S110 or Lawesson’s reagent2, gave mainly
the spirodimers 30phenyl-20-thoxo-10,30-thiazolidino[2,3-d]-spiro[60,70
diaryl-5,50-perhydrothiapyrano]-3-phenyl-1,3-thiazolidin-4-thiones (3a
and b) beside, 5-(3-bromo-4-methoxyphenylmethylene)-3-phenyl-1,3-
thiazolidin-2,4-dithione (2b) as a mixture with 3b. 2b was allowed to
react with ethyl cinnamate as a dienophile producing 4b and 5b. More-
over, prolonged heating of either 3b or 3a with ethyl cinnamate gave a
mixture contains 40% of 4b and a mixture of 4a and 5a respectively.
Furthermore, the dimer 3b reacted with cinnamic acid in glacial acetic
acid to give the Diels-Alder-adduct 6b and 7b. Structures and stereo-
chemistry of obtained compounds have been studied.
Keywords: Spiro[thiapyrano-thiazolidines]; thiapyranothiazoles;
thiation of 1,3-thiazolidines
Thiation of 5-phenylmethylene-3-phenyl-(1a), and 5-(3-bromo-4-
methoxyphenylmethylene)-3-phenyl-(1b)-2-thioxo-1,3-thiazolidin-4-
one with either tetraphosphorous decasulfide or Lawesson’s reagent
in xylene yielded the unexpected hitherto unknown spirodimer; 30-
phenyl-20 thioxo-10,30-thiazoldino[2,3-d]-spiro[5,50-perhydro-3-30,60,70-
tetraphenylthia-pyrano]-1,3-thiazolidin-4-thione (3a) as the sole
product in the former case, and in the latter case, 30-phenyl-20-thioxo-10,
30 -thiazolidino[2,3-d]-spiro[6,70 -di-(3-bromo-4-methoxyphenyl)-5,50-
perhydrothiapyrano]-3-phenyl-1,3-thiazolidin-4-thione (3b) which
was mixed with 30% of the expected 5-(3-bromo-4-methoxy-phe-
nylmethylene)-3-phenyl-1,3-thiazolidine-2,4-dithione (2b).
Address correspondence to A. M. Youssef, Chemistry Department, Faculty of Science,
Ain Shams University, Abbassia, Cairo, Egypt. E-mail: Prof Elkhamry@hotmail.com
721

722
M. T. Omar et al.
The structure of 3a and b was deduced from microanalytical as well
as spectroscopic data. The infrared spectroscopic data (Table I) are de-
void of any absorption which could be correlated with a
while, exhibiting stretching vibration absorptions of
group,
H, and
C
C
O
,
C
H
SCSN, which are consistent with the proposed structure.
Apart from the aromatic protons, the 1H-NMR spectra of 3a,b
(Figure 1) shown from low to high field a partially splitted doublet
(H-60) a doublet (H-70, j = 7.6 Hz) and two central peaks of an ABq
(H2C-2) with the integrated proton ratios of 1:1:2 respectively. Exis-
tence of two doublets (j = 6.5 Hz) is in harmony with the presence of
two vicinal protons and location of two central peaks corresponding to
the two protons of ABq at = 5.5 ppm is consistent with a methylene
group substituted with two electron attracting groups.
Existence of the spiro (C-5), C-2, C-60, and C-70 as well as the quater-
nary carbon atoms [C-4, C-20, C3a, and C-70a) is confirmed by 13C-NMR
spectroscopy (Figure 1). Moreover, the easy decomposition of 3a,b to
give fragments [A] and [B] is evidenced by mass spectroscopy. Frag-
ment [A] is the ion radical of 2a, whereas, fragment [B] is analogous to
2a in which a methylene group displaces the C S group at position-2,
Figure 2.
The structure of 2b was confirmed by microanalytical as well as
spectroscopic data. The infrared spectrum of 2b (Table I) lacks any
absorbance to be correlated with a
group, and shows the presence
O
C
TABLE I Infrared Spectroscopic Data of Compounds 3a,b
and 2b
1
TR (cm
)
Comp.
CH
3060
3060
3060
C
H
SCSN
2H
5H
3a
3b
2b
2840, 2920
2860, 2920
2860, 2920
1240
1220
1220
—
810
810
700, 760
700, 760
600, 760

Synthesis and Stereochemistry
723
1
FIGURE 1 13C-NMR spectroscopic data of compound 3a and H-NMR spec-
troscopic data of compounds 3a and 3b.
of SCNS. The 1H-NMR spectrum of 2b exhibits a singlet consistent with
the olefinic proton, aromatic protons and a singlet consistent with the
three protons of the methoxy group (Figure 3). Moreover, the EI-MS of
2b shows the correct molecular ion peak and was fragmented as pre-
sented in Figure 4.
Formation of 2 was expected as reported previously by V’yunov et al.3
Formation of the unexpected spirodimers 3a,b could be understood tak-
ing into consideration the high reactivity of 2 (which is formed first upon
treatment of 1 with either P4S10 or Lawesson’s reagent) as a heterodi-
ene system. Thus, formation of 3a,b could be visualized as represented
in Scheme 1, in which two molecules of 2 interact; one as a heterodiene,
whereas, the other acts as a dienophile either by using the -electrons
of the exocycle double bond or of the 4-thioxo group.

724
M. T. Omar et al.
SCHEME 1 Conversion of the 2,4-dithioxothiazolidines (1a,b) into the respec-
tive dimer products 3a,b.
The dimeric product actually isolated (3a,b), undoubtedly exhibits
the skeleton [X] as it allows for the vicinal couplings observed in the
1H-NMR spectrum. Structures [Y] and [Z], would each have two sin-
glets. There still remains the problem of existence of four tetrahedral
carbon atoms observed in the 13C-NMR spectrum of 3a. As structure
[X] has only three of such carbon atoms (C-5, C-60, C-7) a new sp3 car-
bon atom is expected to be formed through the reaction, most likely via
reduction at the 2-thioxo group to a methylene group.4
As a chemical evidence for the reactivity of 2 as a heterodiene, the
toluene solution of 2b was treated with ethyl cinnamate and a mixture
of ethyl(5S , 6S , 7S )-7-(3-bromo-4-methoxyphenyl)-5,6-dihydro-3,5-
diphenyl-2-thioxo-thiopyranol[2,3-d] thiazolidine-6-carboxylate (4b)
and the (5S , 6S , 7R ) analogue (5b), in 4:1 ratio respectively was
obtained.
The structure of 4b and 5b was deduced from the following spec-
tral evidence. Their infrared spectra (Table II) exhibit
C
,
and
C
H
C
O
S. The 1H-NMR spectra (Figure 5) display, besides the aromatic and
ethoxycarbonyl proton resonances, two doublets (H-5 and H-7) as well

Synthesis and Stereochemistry
725
Fragments m/e (% abundance)
Comp.
[A]
[B]
[C]
[D]
[E]
[F]
3a
3b
313 (83.5) 283 (0.2) 312 (100)
421 (35.2)
178 (8.9)
177 (40.3) 134 (61.6)
39 (0.2) 420 (32.3) 207 (54.5) 206 (45.5) 134 (20.2)
FIGURE 2 Fragmentation pathway of 3a,b.
as an apparent triplet (H-6 of 4b) and a doublet of doublets (H-6 of 5b).
EI-MS of 4a,b and 5a,b are presented in Figure 6.
The reaction is proved to be of high regioselectivity, although minor
amounts of more isomers were detected in the crude reaction mixture by
FIGURE 3 1H-NMR spectroscopic data of compound 2b.

726
M. T. Omar et al.
FIGURE 4 EI-MS fragmentation pattern of 2b.
1H-NMR spectroscopy. The major products obtained are in agreement
with the favorable interaction between the sulphur atom of the hetero-
diene components, C C C S and -carbon atom of the dienophile.5
The problem of configurational assignment of the three chiral cen-
1
ters (C-5, C-6 and C-7) has been solved by H-NMR spectroscopy via
TABLE II Infrared Spectroscopic Data of Compounds 4a,b, 5a,b,
6b, and 7b
1
IR (cm)
Compound
CH
C
H
C
O
C
S
2H
4b, 5b
4a, 5a
6b, 7b
3060
2950 (br)
1735
1735
1700 (br)
1185
1185
1190
820
2900–3009 (br)
700–750a
700–750a
2900–3700 (br)b
aCharacteristic of the bending frequency of aromatic 5-adjacent hydrogens.
bIncluding interbonded
OH of COOH group.

Synthesis and Stereochemistry
727
analyses of the AMX pattern and extracting of the coupling constants.
Table III shows the coupling constants of H-5, H-6, and H-7 of com-
pounds 4b and 5b.
Taking into consideration the fact that the thiapyrene ring acquires
the halfchair conformation and therefore, H-5, H-6, and H-7, must
FIGURE 5 The 1H-NMR spectroscopic data of compounds 4b and 5b in
(CDCl3).

728
M. T. Omar et al.
Fragments (abundance %)
Compd. [M]
[A]
[B]
[C]
[D]
[E]
[F]
[G]
4a, 5a
4b, 5b
489
(30)
597
(9)
313
(35)
421
312
(100)
420
134
(30)
242
176
(29.5) (25)
176
(12)
131
103
(23)
103
77
(30)
77
131
(42.1) (33.4) (59.5)
423 422 244
(50) (39.6) (100)
599
(6.7) (40.2) (52.5) (57.8)
p + 2 peaks
FIGURE 6 EI-MS spectroscopic data of 4a,b and 5a,b.

Synthesis and Stereochemistry
729
acquire pseudoaxial or pseudoequatorial positions and that the coupling
constant between two pseudoaxial protons is 10 Hz and that between
pseudoaxial and pseudoequatorial protons is 5.0 Hz. The measured
coupling constants (Table II) reaveled that, H-5, H-6, and H-7 of 4b ac-
quire the pseudoaxial conformation, but in 5b H-5 and H-6 acquire the
pseudoaxial conformation whereas H-7 acquires the pseudoequatorial
position.
Consulting the computer software program (Alchemy III, 1992) infers
that the energy optimized molecule in which H-5, H-6, and H-7 acquire
the pseudoaxial conformations will have the (5S , 6S , and 7S config-
urations, whereas, the compound having equatorial H-7 must acquire
the (5S , 6S , 7R ) configuration.
The easy decomposition of the dimeric products (3a,b) during
volatilization in the mass spectrometry has prompted us to check
the possibility of participation of these compounds as heterodiene
precursors in Diels-Alder reactions. The results obtained are quite
interesting and worthy to be discussed. Thus, treating 3b with ethyl
cinnamate under the same conditions as applied with 2b produced un-
reacted starting materials. However, refluxing the reactants for 15 h
gave a mixture of products from which the (5S , 6S , 7S ) derivative
(4b) was isolated in 40% yield.
Similar treatment of 3a with ethyl cinnamate gave a mixture of 4a
and 5a in an overall yield of 70% and in the ratio 5:1, respectively,
whose structures were evidenced exclusively by their 1H-NMR spectra,
Figure 7.
Configurational assignments for 4a and 5a are based solely on
1H-NMR spectroscopy and the coupling constants are represented in

730
M. T. Omar et al.
TABLE III 1H-NMR (CDCl3) Coupling Constants of H-5, H-6,
and H-7
Comp.
3J5,6(H-5sx,H-6sx
)
3J6,7(H-6sx, H-7sx
10.6
)
3J6,7(H-6sx, H-7sx
)
4b
5b
4a
5a
6b
7b
10.6
11.6
11.0
11.8
11.0
11.8
5.0
5.5
5.2
10.8
10.6
Table III. According to the data, 4a has pseudoaxial H-5, H-6, H-7,
whereas 5a has H-5, and H-6 pseudoaxial but H-7 is pseudoequatorial.
Formation of compounds 4 and 5 by prolonged heating of 3 with ethyl
cinnamate is visualized to occur through reaction of the fraction of 2,
which is believed to be formed at first via decomposition of 3, with ethyl
cinnamate.
Furthermore, the dimer (3b) reacts with cinnamic acid in glacial
acetic acid solution to afford a mixture of the Diels-Alder adducts 6b
and 7b, in an overall yield of 60% and in the ratio of 2:1, respectively.
The structures of 6b and 7b are deduced from spectral evidence. The
1H-NMR spectra exhibit the pattern of splitting and coupling constants
similar to the respective ester (Figure 8). The mass spectrum (Figure 9)
do not show the molecular ion peak due to easy elimination of CO2.

Synthesis and Stereochemistry
731
FIGURE 7 1H-NMR spectroscopic data of compounds 4a and 5a.
Subsequent elimination of styrene produced the ion radical of 2b. The
base peak is located at m/e 64.
Configurational assignment to C-5, C-6, and C-7 is based exclusively
1
on H-NMR spectral data. The coupling constants, which are repre-
sented in Table III, infer that H-5, H-6, and H-7 protons of 7b ac-
quire pseudoaxial positions, whereas in 8b, H-5 and H-6 acquire the
pseudoaxial conformation whereas H-7 acquires the pseudoequatorial
position.
CONCLUSION
Ethyl cinnamate and cinnamic acid cycloadded to compound 2 and 3
in a regioselective reaction. The reaction most likely occurs via a non-
concerted reaction and rotation around the bond (a) of the zwitterion (8),
which is believed to be formed first, and would lead to configurational
changes at C-7.
FIGURE 8 The 1H-NMR spectroscopic data of 6b and 7b.

732
M. T. Omar et al.
Experimental
Synthesis of 5-Arylmethylene-1,3-thiazolidine-2,4-
dithione(2b) and the Corresponding Spirodimers (3a,b)
General procedure.
Using half mole of thiating agent. A mixture of 1a or b (10 mmol),
tetraphosphorus decasulfide or Lawesson’s reagent (5 mmol) is refluxed
in dry xylene (75 ml) for 2 h. The dark wine red solution is washed suc-
cessively with water, sodium carbonate solution (10%) then with water
and dried (anhydrous sodium sulphate). Xylene is concentrated (25 ml),
treated with 20 ml of light petroleum (b.p. 40–60 ), the precipitated
dark red solid is filtered off, air dried and chromatographed over silica
gel.
The crude product obtained from 1a (3.5 g) is chromatographed
over silica gel and eluted with a mixture of light petroleum (b.p. 60–
80 )/ether (V/V 90:10) to give 3a as lemon yellow needles.
30 -phenyl-20 thioxo-10,30 -thiazoldino[2,3-d]-spiro[5,50-perhy-
drothiapyrano-60-70-diphenyl]3-phenyl-1,3-thiazolidin-4-thione
(3a): m.p. 230–2 C; yield, 83%. Calcd, for C32H24N2S5 (596): C, 64.43;
H, 4.17; N, 4.70. Found: C, 64.25; H, 4.15; N, 4.56.
The crude product obtained from 1b (3.5 g) is chromatographed
over silica gel and eluted with a mixture of light petroleum (b.p.
60–80 )/ether (V/V 95.5) to yield 2b as dark red needles. Further elution

Synthesis and Stereochemistry
733
FIGURE 9 The EI-MS of compounds 6b and 7b.
with a mixture of light petroleum (b.p. 60–80 )/ether (V/V 90:10 pro-
vides 3b).
5-(3-Bromo-4-methoxyphenylmethylene)-1,3-thiazolidine-2,4-
dithione (2b): Ri = 0.68 (eluent: light petroleum b.p. 60–80 /ether
V/V 7/3), m.p. 222–224 C; yield, 65%. Calcd. for C17H12BrNOS3 (422):
C, 48.34; H, 2.84; N, 3.32% Found C, 48.31; H, 2.67; N, 3.21%.
3-phenyl-20 -thioxo-10,30-thiazolidino[2,3-d]-spiro[6,70-di(3-
bromo-4-methoxyphenyl)-5,50-perhydrothiapyrano]-3-phenyl-
1,3-thiazolidin-4-thione (3b): Ri = 0.28 (eluent; light petroleum
b.p. 60–80 /ether V/V 7/3), m.p. 232–234 C; yield 35%. Calcd. for
C34H26Br2N2 O2S5 (814); C, 50.12; H, 3.19: N, 3.44%. Found: C, 50.26;
H, 3.15; N, 3.41%.
Using two moles of thiating agent. Reflux a mixture 1b (10 mmol) and
Lawesson’s reagent (20 mmol) in 75 ml xylene for 5 h. Then the reaction
mixture is worked up as in the previous experiment. The crude product
(3.5 g) is chromatographed over silica gel and eluted successively with
light petroleum (b.p. 60–80 )/ether (V/V 95/5) then with light petroleum
(b.p. 60–80 )/ether (V/V 90/10)to give 2b, m.p. 222–4 C; yield 20% and
3b, m.p. 232–234 C; yield 70% respectively.

734
M. T. Omar et al.
Synthesis of 4b and 5b
General procedure.
Reflux time two hours. Ethyl cinnamate (1.2 mmol) is added to a
solution of 2b (1 mmol) in dry xylene (20 ml) and the whole mix-
ture is refluxed for 2 h during which the red color fades away. The
mixture is concentrated to 10 ml, light petroleum (b.p. 60–80 ) is
added and the precipitated solid (0.3 g), m.p. 110–113 C is filtered off,
air dried, and recrystallized from ethanol to give a mixture of ethyl
(5S , 6S , 7S ) 7-(3-bromo-4-methoxyphenyl)-5,6-dihydro-3,5-diphenyl-
3-thioxo-thiopyrano[2,3-d]thiazolidin-6-carboxylate (4b) and the (5S ,
6S , 7R ) analogue (5b) in the ratio 4:1 respectively.
Working out the reaction mixture obtained from ethyl cinnamate
(1.2 mmol) and 3b (1 mmol) yields 0.4 g of unreacted starting material
(3b), m.p. 232–234 C.
Reflux time 15 h. A mixture of ethyl cinnamate (1.2 mmol) and 3b
or 3a (1.0 mmol) is refluxed in dry xylene (20 ml) for 15 h and
the concentrated xylene solution (10 ml) is treated with 5 ml light
petroleum (b.p. 60–80 ). The precipitated solid is filtered off and
air dried (0.2 g). The crude product obtained from 3b is repeatedly
recrystallized from ethanol to give; ethyl (5S , 6S , 7S ) 7-(3-bromo-
4-methoxyphenyl)-5,6-dihydro-3,5-diphenyl-3-thioxo-thiopyrano[2,3-d]-
thiazolidine-6-carboxylate (4b): m.p. 110–112 C; yield 40%. Calcd for
C28H24BrNO3S3 (598); C, 56.19; H, 4.01; N, 2.34%. Found; C, 56.21, H,
3.95; N, 2.31%.
The crude product obtained from 2a (0.3 g), m.p. 120–130 C is boiled
with 50 ml light petroleum (b.p. 80–100 ) to afford a mixture of 4a
and 5a.
Diels-Alder Reaction of 3b with Cinnamic Acid:
Synthesis of 7b
General procedure. A mixture of 3b (1 mmol) and glacial acetic
acid (15 ml) is refluxed for 15 h. The concentrated reaction mixture
(5 ml) is poured onto ice-cold water (100 ml) and the precipitated
solid is filtered off, air dried (0.35 g), and boiled with 50 ml of light
petroleum (b.p. 80–100 ). The insoluble product (0.23 g) is recrystal-
lized from ethanol to give 6b. The product which is precipitated from
light petroleum (b.p. 80–100 ) is recrystallized from the same solvent
to afford 7b.
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Synthesis and Stereochemistry
735
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