Generation and reactivity of 3-carbethoxy-5-phenyl-5H,7H-thiazolo[3,4-c] oxazol-4-ium-1-olate

Article abstract of DOI:10.1002/jhet.5570410403

3-Carbethoxy-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olate was generated from (2R,4R)-N-ethoxyoxalyl-2-phenylthiazolidine-4-carboxylic acid and its reactivity studied. This muenchnone showed low reactivity as dipole although from the reaction with di

Full text of DOI:10.1002/jhet.5570410403

Jul-Aug 2004
493
Generation and Reactivity of 3-Carbethoxy-5-phenyl-5H,7H-
thiazolo[3,4-c]oxazol-4-ium-1-olate
Teresa M. V. D. Pinho e Melo,a* Clara S. B. Gomes,a Maria I. L. Soares,a
António M. d'A. Rocha Gonsalves,a José A. Paixão,b Ana M. Bejab
and Manuela Ramos Silvab
a
Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-535
Coimbra, Portugal
b
Departamento de Física, Universidade de Coimbra, 3004-516 Coimbra, Portugal
Received May 23, 2003
Received Revised January 16, 2004
3-Carbethoxy-5-phenyl-5H, 7H-thiazolo[3,4-c]oxazol-4-ium-1-olate was generated from (2R, 4R) -N-
ethoxyoxalyl-2-phenylthiazolidine-4-carboxylic acid and its reactivity studied. This münchnone showed
low reactivity as dipole although from the reaction with dimethyl acetylenedicarboxylate the corresponding
(3R)-3-phenyl-1H, 3H-pyrrolo[1, 2-c]thiazole-5,6,7-tricarboxylate could be isolated. The thermolysis of
(2R,4R)-N-ethoxyoxalyl-2-phenylthiazolidine-4-carboxylic acid in refluxing acetic anhydride led to the syn-
thesis of N-(1-ethoxycarbonyl-2-phenylvinyl)-2-phenyl-4-thioxo-1,3-thiazolidine. The structure of methyl
(2R,4R)-N-ethoxyoxalyl-2-phenylthiazolidine-4-carboxylate was determined by X-ray crystallography.
J. Heterocyclic Chem., 41, 493 (2004).
Introduction.
described in the literature for the synthesis of (2R,4R)-N-
carbethoxy-2-phenyl-1,3-thiazolidine-4-carboxylic acid
[3c], the cis derivative 3a (80%) was obtained selectively
by treating with ethyl oxalylchloride the triethylamine salt
of thiazolidine 2a in tetrahydrofuran (Scheme 1).
The study of 1,3-dipolar cycloaddition of münchnones is
a topic of our current research [1].. The main objective is to
broaden the scope of the intramolecular and intermolecular
1,3-dipolar cycloaddition reaction of 5H,7H-thiazolo[3,4-
c]oxazol-4-ium-1-olate derivatives in order to achieve the
synthesis of a range of new chiral pyrrolo[1,2-c]thiazole
derivatives and analogues, compounds with potential bio-
logical activity [2].
In the previous described intermolecular 1,3-dipolar
cycloadditions, münchnones bearing an aryl group or
methyl group at C-3, acted as masked azomethine ylides
on reacting with electron deficient dipolarophiles [1c,1d].
We decided to explore the possibility of generating a 5-
p h e n y l - 5H, 7H-thiazolo[3, 4-c]oxazol-4-ium-1-olate bear-
ing an electron withdrawing group at C-3 (1) in order to
study its reactivity towards dipolarophiles.
Methyl (2R,4R)-N-ethoxyoxalyl-2-phenyl-thiazolidine-
4-carboxylate 3b was also prepared in 75% yield from the
reaction of methyl 2-phenyl-1,3-thiazolidine-4-carboxy-
1
late 2b with ethyl oxalylchloride (Scheme 1). The H
NMR spectrum, recorded at room temperature, showed the
existence of two separate rotamers. The spectrum is sim-
plified at higher temperature as observed with other
N-acylthiazolidines [1a,1c,1d]. We found that the proton
attached to C4 appears as two singlets when the 1H NMR
spectrum of 3b is recorded at room temperature, and it
becomes one singlet when the spectrum is recorded at 70
ºC (in DMSO-d6).
The structure of 3b was determined by X-ray crystallog-
raphy (Figure 1). The absolute configuration of the mole-
cule was established from X-ray crystallography using
Flack's method [4] which unambiguously assigns the R,R
configuration to the two chiral centers C2 and C4 (Flack's
Results and Discussion.
The synthetic strategy for the generation of 5-substi-
t u t e d - 5 H, 7 H- t h i a z o l o [ 3 , 4 - c] o x a z o l - 4 - i u m - 1 - o l a t e s
involves the cyclodehydration of N-acyl-2-phenyl-1,3-thi-
azolidine-4-carboxylic acids. Thus, our first objective was
to prepare (2R,4R)-N-ethoxyoxalyl-2-phenylthiazolidine-
4-carboxylic acid (3a). Using an experimental procedure

494
T. M. V. D. Pinho e Melo, C. S. B. Gomes, M. I. L. Soares,
Vol. 41
A. M. d'A. Rocha Gonsalves, J. A. Paixão, A. M. Beja and M. R. Silva
(dimethyl acetylenedicarboxylate) did not lead to the
expected products. Although no 1,3-dipolar cycloadducts
were obtained, this study led to an interesting result. From
these reactions we could isolate N-(1-ethoxycarbonyl-2-
phenylvinyl)-2-phenyl-4-thioxo-1,3-thiazolidine (4) in
18% yield (Scheme 2).
parameter refined to η = 0.01(4); should be 0 for the cor-
rect, 1 for the inverted structure).
The thiazolidine ring has a twisted conformation with a
local pseudo two-fold axis running through N3 and the
middle of the S1-C5 bond. The two-fold asymmetry [5]
parameter ΔC2[S1-C5] is 5.02(10)º. The ring puckering
parameters [6] q2 and φ2 are 0.508(1) Å, 347.2(1)º, respec-
tively. The phase angle of the pure twisted conformation
is 342º. S1 and C5 are on opposite sides of the plane pass-
ing through C2, N3 and C4 at 0.565(3) Å and
-0.305(3) Å, respectively. The exocyclic angles around
N3 show some asymmetry. However the sum of the
valence angles around N3 is 359.74(8)º, indicating no sig-
nificant pyramidalization of this atom. The methoxycar-
bonyl and oxalyl groups have bisectional and equatorial
positions, respectively, with respect to the thiazolidine ring
and both have unexceptional geometries. The phenyl ring
has an axial position with torsion angles 88.22(8)º [C5-S1-
C2-C8] and -105.06(9)º [C4-N3-C2-C8]. The thiazolidine
and phenyl rings are almost perpendicular, the dihedral
angle between the least-squares planes is 80.79(5)~º
It has been reported that thiobenzophenone and methyl
thiobenzoate combine with 3-methyl-2,4-diphenyloxa-
zolium-5-olate (5) to give N-thiobenzoylenamines (8) and
CO2 [7]. The process involves a 1,3-dipolar cycloaddition
followed by cycloreversion of carbon dioxide giving 7.
This compound undergoes a rearrangement leading to the
N-thiobenzoylenamines 8 (Scheme 3)
The synthesis of compound 4 can be rationalized by a
similar mechanistic sequence (Scheme 4). We propose the
generation of thiobenzaldehyde from thiazolidine 3a
which could participate in the 1,3-dipolar cycloaddition
with 3-carbethoxy-5-phenyl-5H,7H-thiazolo[3,4-c]oxa-
zol-4-ium-1-olate 1 leading to 11. Cycloreversion of car-
bon dioxide followed by rearrangement allows the forma-
tion of N-(1-ethoxycarbonyl-2-phenylvinyl)-2-phenyl-4-
thioxo-1,3-thiazolidine 4.
Attempts were made to make the synthesis of compound
4 more efficient. However, heating at reflux a solution of
(2 R, 4 R)- N-ethoxyoxalyl-2-phenylthiazolidine-4-car -
boxylic acid 3a in acetic anhydride for 15 hours did not
lead to an improvement. The reaction was also carried out
in a sealed tube and a solution of 3a in acetic anhydride
was heated at 200 °C for 2 hours. From this reaction the
only product that could be isolated was ethyl cinnamate 13
in 32% yield (Scheme 5).
Considering that ethyl cinnamate could be the result of N-
(1-ethoxycarbonyl-2-phenylvinyl)-2-phenyl-4-thioxo-1,3-
thiazolidine 4 cleavage we decided to carry out the reaction
of thiazolidine 3a with acetic anhydride using milder reac-
tion conditions. Compound 3a was heated in acetic
Figure 1. ORTEP plot of methyl (2R,4R)-N-ethoxyoxalyl-2-phenylthia-
zolidine-4-carboxylate 3b.with anisotropic displacement ellipsoids
calculated at the 50% probability level.
Ethyl 5-phenyl-5 H,7H-thiazolo[3,4-c]oxazol-4-ium-1-
olate-3-carboxylate 1 was generated, by heating at reflux a
solution of (2R,4R)-N-ethoxyoxalyl-2-phenylthiazolidine-
4-carboxylic acid 3a in acetic anhydride in presence of a
dipolarophile. However, the attempts to promote the 1,3-
dipolar cycloaddition, using this reaction condition, with
electron rich dipolarophiles (ethyl vinyl ether or dihydro-
furan) and also with an electron deficient dipolarophile

Jul-Aug 2004
3-Carbethoxy-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olate
495
This münchnone (1), bearing an electron withdrawing
group at C-3, is less reactive towards dimethyl
acetylenedicarboxylate than the derivatives bearing an aryl
group or methyl group. On the other hand, münchnone 1
was not electron deficient enough to enable the dipolar
cycloaddition with electron rich dipolarophiles.
The thermolysis of (2R, 4 R) - N- e t h o x y o x a l y l - 2 -
phenylthiazolidine-4-carboxylic acid (3a) in acetic anhy-
dride led to the interesting synthesis of N-(1-ethoxycar-
bonyl-2-phenylvinyl)-2-phenyl-4-thioxo-1,3-thiazolidine
(4) via the generation of münchnone 1 as intermediate.
anhydride at 85 ºC for 2 hours. Two products could be
detected by TLC one of which was compound 4. However,
only 4-thioxo-1,3-thiazolidine 4 could be isolated in low
yield (3%). The very low stability of the second product
indicated that it could be 3-carbethoxy-5-phenyl-5H, 7H-thi-
azolo-[3, 4-c]oxazol-4-ium-1-olate 1. In fact, when the same
reaction was carried out in the presence of dimethyl
acetylenedicarboxylate the 1,3-dipolar cycloadduct 14 could
be isolated although in low yield (Scheme 6). With ethyl
vinyl ether no cycloadduct was isolated.
EXPERIMENTAL
General.
1
H NMR spectra were recorded on a Bruker AMX300 instru-
ment operating at 300 MHz. The solvent is deuteriochloroform.
IR spectra were recorded on a Perkin Elmer 1720X FTIR spec-
trometer. Mass spectra were recorded under electron impact at
70 eV on a VG Micromass 7070E instrument. Optical rotations
were measured on an Optical Activity AA-5 electrical polarime-
ter. M.p. were recorded on a Reichert hot stage and are uncor-
rected. Flash column chromatography was performed with
Merck 9385 silica as the stationary phase. Methyl 2-phenylthia-
zolidine-4-carboxylate 2b and 2-phenylthiazolidine-4-carboxylic
acid 2a were prepared using the general procedure described in
the literature and were isolated as mixture of the (2R, 4R) and
(2S,4R) diastereoisomers [8]. In the case of thiazolidine 2a the
compound precipitates from the reaction mixture and was iso-
lated by filtration.
Conclusion.
The (2R,4R) -N-ethoxyoxalyl-2-phenylthiazolidine-4-
carboxylic acid was prepared selectively from a
diastereoisomeric mixture (2 S,4 R )- and (2 R ,4 R ) - 2 -
phenylthiazolidine-4-carboxylic acid and used to generate
3-carbethoxy-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-
ium-1-olate.
General Procedure for the Synthesis of (2R, 4R)- N-Acyl-2-
phenylthiazolidine-4-carboxylic Acid (3a) and Methyl Ester
(3b).
To a stirred solution of the thiazolidine (29.1 mmol) in THF
(60 mL), triethylamine (72.2 mmol) was added dropwise at –10
°C. After 15 minutes at room temperature the solution was

496
T. M. V. D. Pinho e Melo, C. S. B. Gomes, M. I. L. Soares,
Vol. 41
A. M. d'A. Rocha Gonsalves, J. A. Paixão, A. M. Beja and M. R. Silva
evaporated. The triethylamine salt was dissolved in THF (90
mL) and the solution was cooled at –10 °C. The acid chloride
(34.9 mmol) was added dropwise and after stirring at room tem-
perature for 1 hour the solvent was evaporated off. The residue
was treated with water (150 mL) and then with 25% HCl to pH 3
and extracted with ethyl acetate. The organic layer was washed
with water, separated and dried over magnesium sulphate and the
solvent evaporated off.
sealed tube at 200 °C for 2 h. The reaction was cooled to room
temperature and was diluted with CH Cl (50 mL). The organic
2
phase was washed with saturated aqueous solution of NaHCO
2
3
and with water, dried (MgSO ) and evaporated off. The crude
4
product was purified by preparative tlc [hexane-ethyl acetate
1
(5:1)]. Ethyl cinnamate was isolated as an oil in 32% yield. H
nmr: δ 1.34 (3H, t), 4.27 (2H, q), 6.44 (1H, d, J 16 Hz), 7.36-7.40
(2H, m, Ar-H), 7.48-7.55 (3H, m, Ar-H), 7.69 (1H, d, J 16 Hz);
+
m/z 176 (M , 30%), 148 (15), 131 (100), 103 (46) and 77 (28).
(2R, 4R)-N-Ethoxyoxalyl-2-phenylthiazolidine-4-carboxylic
Acid (3a).
5-Ethyl 6,7-Dimethyl (3R) - 3 - P h e n y l - 1H, 3H-pyrrolo[1, 2-c]thia-
zole-5,6,7-tricarboxylate (14).
This compound was obtained in 80% yield, mp 126.5-128 °C
1
(from ethyl ether-hexane). H nmr (two rotamers are detected): δ
(2R,4R) -N-ethoxyoxalyl-2-phenylthiazolidine-4-carboxylic
acid 3a (5 mmol), dimethyl acetylenedicarboxylate (7.5 mmol)
and Ac O (20 mL) were heated at 85 ºC for 2 h. The reaction
2
0.94 and 1.34 (3H, 2xt), 3.43-3.48 (2H, m), 3.69-3.75, 3.86-3.92
and 4.29-4.33 (2H, 3xm), 5.18 and 5.53 (1H, approx. 2xt, J 5.5
Hz and J 6.3 Hz), 6.32 and 6.40 (1H, 2xs), 7.31-7.38 (3H, m, Ar-
H), 7.52-7.61 (2H, m, Ar-H); m/z [the product was treated with
was cooled to room temperature and was diluted with CH Cl
2
(50 mL). The organic phase was washed with saturated aqueous
2
+
solution of NaHCO and with water, dried (MgSO ) and the sol-
diazomethane giving the corresponding methyl ester] 323 (M ,
7%), 264 (11), 237 (57), 222 (100), 162 (40), 121 (53), 77 (31)
3
4
vent evaporated off. The crude product was purified by flash
chromatography [hexane-ethyl acetate (3:1), hexane-ethyl
acetate (2:1) then hexane-ethyl acetate (1:1)] giving 1H, 3H-
25
and 59 (17). [α] = + 40 (c = 0.1, CH Cl ).
2
2
D
Anal. Calcd. for C
Found: C, 54.6; H, 5.0; N, 4.4; S, 10.7.
H NO S: C, 54.4; H, 4.9; N, 4.5; S, 10.4.
14 15 5
1
pyrrolo[1,2-c]thiazole 14 in 1% yield. H nmr: δ 1.16 (3H, t, J 7.1
Hz), 3.85 (3H, s), 3.92 (3H, s), 4.02 (1H, q, J 7.1 Hz), 4.15 (1H,
q, J 7.1 Hz), 4.35 (1H, d, J 16.0 Hz), 4.48 (1H, d, J 16.0 Hz),
Methyl (2R, 4 R)-N-Ethoxyoxalyl-2-phenylthiazolidine-4-car-
boxylate (3b).
+
6.91-6.94 (3H, m), 7.27-7.31 (3H, m); m/z 389 (M , 18%), 311
(18), 222 (11), 121 (100).
This compound was obtained in 75% yield. mp 100.8-101.8
1
°C (from THF-ethyl ether). H nmr (two rotamers are detected): δ
Crystal Data for Methyl (2R,4R)-N-Ethoxyoxalyl-2-phenylthia-
zolidine-4-carboxylate 3b.
0.93 and 1.35 (3H, 2xt), 3.35-3.48 (2H, m), 3.69-3.91 and 4.28-
4.32 (2H, 2xm), 3.80 and 3.87 (3H, 2xs), 5.13 and 5.47 (1H, dd J
4.0 and 6.6 Hz and approx. t, J 6.4 Hz), 6.33 and 6.41 (1H, 2xs),
7.28-7.37 (3H, m, Ar-H), 7.51-7.53 and 7.63-7.66 (2H, m, Ar-H);
C
H NO S. M = 323.36, monoclinic, space group P2 (# 4),
15 17 5 1
a = 8.0421(10), b = 10.8572(11), c = 9.3248(11) Å, β =
3
105.40(10)º V = 784.96(16) Å , Z = 2, D = 1.368 g cm , F
-3
+
=
000
340, µ = 0.229 mm , T = 293 K. Number of independent inten-
m/z 323 (M , 4%), 237 (51), 222 (100), 162 (41), 121 (48), 104
25
c
-1
(41), 86 (26), 77 (21) and 59 (23). [α] = + 189 (c = 0.1,
CH Cl ).
D
sities 4568 (including 2169 Friedel pairs) from colourless, trans-
3
2
Anal. Calcd. for C
2
parent prism, 0.22 x 0.24 x  mm . Empirical absorption cor-
H NO S: C, 55.7; H, 5.3; N, 4.3; S, 9.9.
15 17 5
.
.
rection applied based on 9 ψ-scans, T = 0.962, T
= 0.983,
= 0.971. No significant crystal decay was detected. Structure
Found: C, 56.1; H, 5.6; N, 4.5; S, 9.8.
min
max
T
ave
solution by direct methods using SHELXS97 [9]. R = 0.0249 for
N (1-Ethoxycarbonyl-2-phenylvinyl)-2-phenyl-4-thioxo-1, 3-
thiazolidine (4).
4190 reflections with I>2σ, R = 0.0664 for 4568 reflections
w
used in the refinement and 268 refined parameters. H-atoms were
placed at calculated positions and refined as riding on their parent
atoms. X-ray measurements were performed on a Enraf-Nonius
CAD-4 diffractometer [10] using Mo Kα radiation (λ = 0.71073
.
Å) and -2θ scans up to 30.01º.
A solution of (2R,4R)-N-ethoxyoxalyl-2-phenylthiazolidine-4-
carboxylic acid 3a (5 mmol) in Ac O (20 mL) was heated at
2
reflux for 4 h. The reaction was cooled to room temperature and
was diluted with CH Cl (50 mL). The organic phase was
2
washed with saturated aqueous solution of NaHCO and with
2
3
water, dried (MgSO ) and evaporated off. The crude product
4
Acknowledgement.
was purified by flash chromatography [hexane-ethyl acetate
(3:1), hexane-ethyl acetate (2:1) then hexane-ethyl acetate (1:1)].
A mixture of (2S)-N-(1-ethoxycarbonyl-2-phenylvinyl)-2-
phenyl-4-thioxo-1,3-thiazolidine and (2R)-N-(1-ethoxycarbonyl-
2-phenylvinyl)-2-phenyl-4-thioxo-1,3-thiazolidine was isolated
The authors wish to thank Chymiotechnon and Fundação para
a Ciência e a Te c n o l o g i a (POCTI/36137/QUI/2000 and
SFRH/BD/9123/2002) for financial support.
1
in 18% yield, mp 117-119 ºC (from ethyl ether-hexane). H nmr
(two rotamers are detected): δ 1.18 and 1.38 (3H, 2xt), 4.02-4.60
(4H, m), 5.72 and 6.22 (1H, 2xs), 6.89-7.48 (10H, m, Ar-H),
REFERENCES AND NOTES
[1a] T. M. V. D. Pinho e Melo, D. M. Barbosa, P. J. R. S. Ramos,
A. M. d'A. Rocha Gonsalves, T. L. Gilchrist, A. M. Beja, J. A. Paixão, M.
Ramos Silva and L. Alte da Veiga, J. Chem. Soc. Perkin Trans. I, 1219
(1999); [b] T. M. V. D. Pinho e Melo, M. I.. L. Soares, D. M. Barbosa, A.
M. d'A. Rocha Gonsalves, A. M. Beja, J. A. Paixão, M. Ramos Silva and
L. Alte da Veiga, Tetrahedron, 56, 3419 (2000); [c] T. M. V. D. Pinho e
Melo, M. I. L. Soares, A. M. d'A. Gonsalves, J. A. Paixão, A. M. Beja, M.
Ramos Silva, L. Alte da Veiga and J. Costa Pessoa, J. Org. Chem., 67,
4045 (2002); [d] T. M. V. D. Pinho e Melo, C. S. B. Gomes, A. M. d'A.
+
7.63 (1H, s); m/z 369 (M , 21%), 247 (49), 201 (35), 174 (100),
25
121 (25), 77 (15). [α] = - 152 (c = 0.1, CH Cl ).
2
H NO S : C, 65.0; H, 5.2; N, 3.8.
2
D
Anal. Calcd. For C
Found: C, 65.0; H, 5.3; N, 3.7.
20 19 2 2
Ethyl Cinnamate (13).
A solution of (2R,4R)-N-ethoxyoxalyl-2-phenylthiazolidine-4-
carboxylic acid 3a (5 mmol) in Ac O (20 mL) was heated in a
2

Jul-Aug 2004
3-Carbethoxy-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olate
497
Gonsalves, J. A. Paixão, A. M. Beja, M. Ramos Silva and L. Alte da
Veiga, Tetrahedron, 58, 5093 (2002).
[4] H. D. Flack, Acta Crystallogr. A, 39, 876 (1983).
[5] W. Duax, C. M. Weeks and D. C. Roher in Topics in
Stereochemistry, E. L. Eliel and N. Allinger, ed, Wiley, New York, 1976,
pp 271-383.
[6] D. Cremer and J. A. Pople, J. Am. Chem. Soc. 97, 1354
(1975).
[7] E. Funke, R. Huisgen and F. C. Schaefer, Chem. Ber., 104,
1550 (1971).
[8] T. L. Gilchrist, A. M. d'A. Rocha Gonsalves and T. M. V. D.
Pinho e Melo, Tetrahedron, 50, 13709 (1994).
[2a] W. K. Anderson and R. H. Mach, J. Med. Chem., 30, 2109
(1987); [b] D. Ladurée, J. Lancelot, M. Robba, E. Chenu and G. Mathé, J.
Med. Chem., 32, 456 (1989); [c] D. Lavé, C. James, H. Rajoharison, P. E.
Bost, and I. Cavero, Drugs of the Future, 1 4, 891 (1989); [d] S. K.
Davidsen, J. B. Summers, D. H. Albert, J. H. Holms, H. Robin Heyman,
T. J. Magoc, R. G. Conway, D. A. Rhein and G. W. Carter, J. Med. Chem.,
37, 4423 (1994).
[3a] L. Szilágyi, and Z. Györgydeák, J. Am. Chem. Soc., 101, 427
(1979); [b] Z. Györgydeák, M. Kajtár-Peredy, J. Kajtár and M. Kajtár,
Liebigs Ann. Chem., 927, (1987); [c] F. Benedini, F. Ferrario, A. Sala, L.
Sala and P. A. Soresinetti, J. Heterocyclic Chem., 31, 1343 (1994).
[9] Sheldrick, G.M. SHELXS97, a program for the solution of
crystal structures. University of Göttingen, Germany, 1997.
[10] Enraf Nonius, MACH3 software, Delft Netherlands, 2000.