Cycloaddition reactions of 3-aryl-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates

Article abstract of DOI:10.1016/S0040-4020(02)00463-5

Intermolecular 1,3-dipolar cycloaddition of (5R)- and (5S)-3,5-diphenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates, (5R)- and (5S)-3-(p-methoxyphenyl)-5-phenyl-5H,7H-thiazolo-[3,4-c]oxazol-4-ium-1-olates with a range of dipolarophiles is described. New chiral 5-aryl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazoles with R and S configuration were obtained. The structure of methyl (3R)-3-phenyl-5-(p-methoxyphenyl)-1H,3H-pyrrolo[1,2-c]thiazole-6-carboxylate was determined by X-ray crystallography. The synthesis of 7,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylates was also achieved.

Full text of DOI:10.1016/S0040-4020(02)00463-5

TETRAHEDRON
Pergamon
Tetrahedron 58 52002) 5093±5102
Cycloaddition reactions of
3-aryl-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates
a,p
Teresa M. V. D. Pinho e Melo, Clara S. B. Gomes, Antonio M. d'A. Rocha Gonsalves,
a
a
Â
Jose A. Paixao, Ana M. Beja, Manuela Ramos Silva and Luiz Alte da Veiga
b
b
b
b
Â
Ä
a
 Ã
Departamento de Quõmica, Faculdade de Ciencias e Tecnologia, Universidade de Coimbra, Coimbra 3004-535, Portugal
b
Â
Departamento de Fõsica, Universidade de Coimbra, 3004-516 Coimbra, Portugal
Received 6 February 2002; revised 9 April 2002; accepted 26 April 2002
AbstractÐIntermolecular 1,3-dipolar cycloaddition of 55R)- and 55S)-3,5-diphenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates, 55R)- and
55S)-3-5p-methoxyphenyl)-5-phenyl-5H,7H-thiazolo-[3,4-c]oxazol-4-ium-1-olates with a range of dipolarophiles is described. New chiral
5-aryl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazoles with R and S con®guration were obtained. The structure of methyl 53R)-3-phenyl-5-5p-
methoxyphenyl)-1H,3H-pyrrolo[1,2-c]thiazole-6-carboxylate was determined by X-ray crystallography. The synthesis of 7,7a-dihydro-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylates was also achieved. q 2002 Elsevier Science Ltd. All rights reserved.
1.Introduction
The dipolar cycloaddition of muÈnchnones 5oxazolium-5-
olates) represents a particularly attractive approach to the
synthesis of pyrroles. These mesoionic rings act as masked
cyclic azomethine ylides on reacting with a variety of
double and triple bond dipolarophiles providing an initial
cycloadduct that usually releases carbon dioxide. Bicyclic
mesoionic ring systems provide a route to heterocycles in
which another ring system is annulated to pyrrole.1
We have been interested in the development of this type of
approach for the synthesis of chiral 1H,3H-pyrrolo[1,2-c]-
thiazole derivatives, heterocyclic compounds with potential
biological activity.2,3 The cyclodehydration of N-acylthiazo-
lidine-4-carboxylic acids was used to generate bicyclic
muÈnchnones, 5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates,
which participated in intramolecular and intermolecular
1,3-dipolar addition.3
The study of the reactivity of 5H,7H-thiazolo[3,4-c]oxazol-
4-ium-1-olates containing internal dipolarophiles allowed
us to describe the ®rst examples of intramolecular 1,3-dipo-
lar cycloaddition of this type of muÈnchnones. The synthesis
of chiral pyrrolo[1,2-c]thiazoles 1±4 and an interesting
rearrangement to pyrrolo[1,2-c]-[1,4]thiazine
achieved.3a,c
5
was
The intermolecular dipolar cycloaddition of 55R)-3-methyl-
Keywords: dipolar cycloaddition; muÈnchnones; 1H,3H-pyrrolo[1,2-c]thia-
zoles.
p
Corresponding author. Tel.: 1351-239-85-2080; fax: 1351-239-82-
6068; e-mail: tmelo@ci.uc.pt
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020502)00463-5

5094
T. M. V. D. Pinho e Melo et al. / Tetrahedron 58 12002) 5093±5102
Scheme 1.
Scheme 3.
5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olate led to
a range of new chiral 1H,3H-pyrrolo[1,2-c]thiazole deriva-
tives 56a±6e and 7) and new spiro compounds 58a and 8b)
were also obtained.3b,3c
N-acyl-2-substituted-1,3-thiazolidine-4-carboxylates as pure
stereoisomers with 52R,4R) or 52S,4R) stereochemistry
depending on the reaction conditions.4
In order to obtain N-acyl-2-phenyl-1,3-thiazolidine-4-
carboxylic acids with 52R,4R) stereochemistry we used an
experimental procedure described in the literature for the
synthesis of 52R,4R)-N-carbethoxy-2-phenyl-1,3-thiazo-
lidine-4-carboxylic acid.4c Thus, the cis derivatives 11a
576%) and 11b 550%) were obtained selectively by treating
with the appropriate acid chloride 5benzoyl chloride and
p-methoxybenzoyl chloride) the triethylamine salt of
thiazolidine 10 in tetrahydrofuran 5Scheme 1).
In this paper we describe the generation and reactivity of
55R)-3-aryl-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-
1-olates 59a and 9c) and 55S)-3-aryl-5-phenyl-5H,7H-thia-
zolo-[3,4-c]oxazol-4-ium-1-olates 59b and 9d) towards
dipolarophiles.
Our previous studies indicated that direct acylation of
2-phenylthiazolidine-4-carboxylic acid with acid chlorides
usually leads to a complex mixture of products and more
ef®cient synthesis were obtained promoting the N-acylation
of methyl 2-phenyl-1,3-thiazolidine-4-carboxylate 12 fol-
lowed by its conversion into the corresponding acid by the
reaction with lithium iodide in ethyl acetate and treatment
with aqueous HCl.3a Compound 11a was prepared by this
route, using benzoyl chloride as the acylating agent, but the
overall yield was only 62% 5Scheme 2).
The objective of this work is to broaden the scope of the
muÈnchnones cycloaddition approach to chiral pyrrolo[1,2-c]-
thiazoles and to study the effect of the nature of the meso-
ionic ring substituent at C-3 on the reactivity.
It is known that NMR spectra of N-acylthiazolidines at
ambient temperature are complicated by the existence of
rotamers but the spectrum is simpler at higher tempera-
1
ture.3a,4 In agreement with this we found that the H NMR
2.Results and discussion
spectra of thiazolidines 11a and 13, recorded at room
temperature, showed very broad lines but when recorded
at 508C, showed a single sharp set of signals.
The synthetic strategy we want to explore requires the
synthesis of N-acyl-2-substituted-1,3-thiazolidine-4-carb-
oxylic acids in diastereoisomeric pure form to generate
the bicyclic muÈnchnones which, on reacting with dipolaro-
philes enable the synthesis of chiral pyrrolo[1,2-c]thiazoles.
Attempts were made to synthesise N-benzoyl-2-phenyl-1,3-
thiazolidine-4-carboxylic acid 14a with 52S,4R) stereo-
chemistry treating at 2408C, a solution of thiazolidine 10
in dry pyridine with benzoyl chloride as described in the
literature for the synthesis of 52S,4R)-N-carbethoxy-2-
phenyl-1,3-thiazolidine-4-carboxylic acid.4c Under these
conditions only starting thiazolidine could be recovered.
However, when the addition of the acid chloride was
2-Substituted-1,3-thiazolidine-4-carboxylic acids are obtained
as mixture of the 52S,4R)- and 52R,4R)-diastereoisomers
from the reaction of aldehydes and l-cysteine. The acylation
of the diastereoisomeric mixture with acetic anhydride or
with acid chlorides can lead to the selective synthesis of
Scheme 2.

T. M. V. D. Pinho e Melo et al. / Tetrahedron 58 12002) 5093±5102
5095
Scheme 4.
made at 2108C and the reaction mixture was stirred at
08C for 4 h thiazolidine 14a was obtained selectively in
moderate yield, 44% 5Scheme 3).
5-5p-methoxyphenyl)-1H,3H-pyrrolo[1,2-c]thiazole-6,7-di-
25
carboxylate 15d 5[a]D ˆ2224), enantiomer of 1H,3H-
pyrrolo[1,2-c]thiazole 15c, was also prepared in 92% yield
from the cycloaddition of 55S)-3-aryl-5-phenyl-5H,7H-thia-
zolo[3,4-c]oxazol-4-ium-1-olate 9d.
Using the same reaction conditions N-5p-methoxybenzoyl)-
2-phenylthiazolidine-4-carboxylic acid was obtained as a
mixture of the 52S,4R)- and 52R,4R)-isomers 575%, d.e.
50%). From this, pure 52S,4R)-N-5p-methoxybenzoyl)-2-
phenylthiazolidine-4-carboxylic acid 14b was obtained by
¯ash chromatography 5overall yield 25%).
The dipolar cycloaddition of the bicyclic mesoionic ring
systems 9a±9d with the dipolarophile methyl propiolate
was also investigated 5Scheme 5).
Treatment of carboxylic acid 11a with methyl propiolate
under cycloaddition reaction conditions gave regioisomers
16a and 17a in a 62:38 mixture and 68% yield. 1H,3H-
Pyrrolo[1,2-c]thiazoles 16b and 17b 564:36), were also
obtained from the reaction of 55S)-3-aryl-5-phenyl-5H,7H-
thiazolo[3,4-c]oxazol-4-ium-1-olate 9b with methyl
propiolate in 55% yield. The reaction of muÈnchnone 9c
gave 3-phenyl-5-5p-methoxyphenyl)-1H,3H-pyrrolo[1,2-c]-
thiazole-6-carboxylates 16c and 17c 570:30) in 55% yield.
The new chiral 53S)-3-phenyl-5-5p-methoxyphenyl)-1H,3H-
pyrrolo[1,2-c]thiazole-6-carboxylate 16d and 53S)-3-phenyl-
5-5p-methoxyphenyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carb-
oxylate 17d 579:21) were synthetised from 9d in 47% yield.
In all four cases the major component 516) could be sepa-
rated from the mixture 516/17) by selective crystallisation
with ethyl ether±hexane.
MuÈnchnones 9a±9d were generated and their dipolar
cycloaddition with dimethyl acetylenedicarboxylate studied
by heating a solution of the appropriated N-aroyl-2-
phenylthiazolidine-4-carboxylic acid in acetic anhydride
in the presence of this dipolarophile 5Scheme 4).
The reaction of 55R)-3,5-diphenyl-5H,7H-thiazolo[3,4-
c]oxazol-4-ium-1-olate 9a gave chiral 53R)-3,5-diphenyl-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 15a in
25
90% yield 5[a]D ˆ1201). Starting from 52S,4R)-N-
benzoyl-2-phenyl-1,3-thiazolidine-4-carboxylic acid 514a)
the synthesis of 53S)-3,5-diphenyl-1H,3H-pyrrolo[1,2-c]-
25
thiazole-6,7-dicarboxylate 15b 5[a]D ˆ2209) was
achieved in 83% yield. The CD spectra of 1H,3H-
pyrrolo[1,2-c]thiazole 15a and 15b were recorded con®rm-
ing these compounds as an enantiomeric pair.
5
Gyorgydeak et al. have reported that the 1H NMR
spectra of 1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate
derivatives show the C-3 proton coupled with one of
the C-1 protons. The same type of coupling is observed
in the 1H NMR spectra of compounds 15a±15d
5J,1.6 Hz).
Â
È
The cycloadditions of 55R)-3-5p-methoxybenzoyl)-5-phenyl-
5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olate
9c
with
dimethyl acetylenedicarboxylate gave chiral 53R)-3-phenyl-
5-5p-methoxyphenyl)-1H,3H-pyrrolo[1,2-c]thiazole-6,7-di-
25
carboxylate 15c in 85% yield 5[a]D ˆ1230). 53S)-3-Phenyl-
Scheme 5.

5096
T. M. V. D. Pinho e Melo et al. / Tetrahedron 58 12002) 5093±5102
C-3 5Flack's parameter re®ned to hˆ0.011518); should be 0
for the correct, 1 for the inverted structure). The pyrrole ring
Ê
is planar with a rms deviation of only 0.0025 A from the
least squares plane. The thiazolidine ring has a twisted
conformation with a local pseudo two-fold axis running
through S2 and the middle of the C-8/N-4 bond. The two-
fold asymmetry7 parameter DC2[C-8/N-4] is 0.452)8. The
8
Ê
ring puckering parameters q2 and f2 are 0.11152) A and
88.1511)8, respectively. The phase angle of the pure twisted
conformation is 908. C-8 and N-4 are on opposite sides of
the plane passing through S-2, C-1 and C-3 at distances
Ê
20.07954) and 0.09555) A, respectively. The dihedral
angle between the two phenyl rings is 26.452)8. The
structure features no classical hydrogen bonds.
Coppola et al. have previously reported that cycloadditions
of methyl propiolate with bicyclic mesoionic compounds
with single-tethered substituents is characterised by a
regioselectivity where the b-carbon of the propiolate
combines preferentially with the untethered centre.9 This
was attributed to the ability of the untethered centre of the
muÈnchnone to became more pyramidalised in the transition
state thereby allowing for a greater degree of bond forma-
tion with the b-carbon of the propiolate. Our own obser-
vations indicate that 55R)-3-methyl-5-phenyl-5H,7H-
thiazolo[3,4-c]oxazol-4-ium-1-olate reacts with methyl
propiolate giving exclusively one regioisomer with the
same regioselectivity.3b
Figure 1. X-Ray crystal structure of methyl 53R)-3-phenyl-5-5p-methoxy-
phenyl)-1H,3H-pyrrolo[1,2-c]thiazole-6-carboxylate 16c.
The 1H NMR spectrum of methyl 53R)-3,5-diphenyl-
1H,3H-pyrrolo[1,2-c]thiazole-6-carboxylate
16a
also
shows the H-3 proton coupled with one of the H-1a/H-1b
1
protons. Supported by H±1H COSY spectrum, we could
also conclude that the H-7 proton is coupled with both
H-1a/H-1b protons. The same coupling pattern is observed
in the H NMR spectra of 1H,3H-pyrrolo[1,2-c]thiazoles
In contrast with these facts, the dipolar cycloaddition of
55R)-3-aryl-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-
1-olates 59a and 9c) and 55S)-3-aryl-5-phenyl-5H,7H-thia-
zolo[3,4-c]oxazol-4-ium-1-olates 59b and 9d) with methyl
propiolate led to the formation of the two possible regio-
isomers being the major product the result of a regioselec-
tivity where b-carbon of the propiolate combines with the
tethered centre. These bicyclic muÈnchnones are charac-
terised by having an aryl group at the untethered centre
and this can prevent the pyramidalised of this centre in
the transition state thus explaining the observed regio-
selectivity.
1
1
16b, 16c and 16d. In the H NMR spectra of compounds
17a±17d only the coupling between the H-3 proton with
1
one of the H-1a/H-1b protons could be observed. This H
NMR data is consistent with the assigned regiochemistry.
The structural assignment of compound 16c was also
supported by a NOESY spectrum. The absence of cross
peaks between H-7 and the aromatic protons of the p-meth-
oxyphenyl group and the observed cross peaks between
these aromatic protons and the methyl ester group indicate
that we are in the presence of a 1H,3H-pyrrolo[1,2-c]thia-
zole derivative bearing a carboxylate group at C-6.
In fact the regiochemistry involved in the cycloaddition of
the mesoionic compounds 9a±9d with methyl propiolate is
similar to the one observed in the cycloaddition of this
dipolarophile with monocyclic muÈnchnones which also
gives rise to a mixture of pyrrole regioisomers, the major
product resulting from an interaction where the carbonyl-
substituted terminus of the muÈnchnone combines with the
b-carbon of methyl propiolate.9
This observation was corroborated by the X-ray structure
determination of compound 16c 5Fig. 1). The absolute
con®guration of the molecule was established from the
X-ray diffraction data using Flack's method6 which unam-
biguously assigns the R con®guration to the chiral centre
Scheme 6.

T. M. V. D. Pinho e Melo et al. / Tetrahedron 58 12002) 5093±5102
5097
Scheme 7.
The presence of the p-methoxy group in the mesoionic
aryl substituent at C-3 leads to higher regioselectivity
5Scheme 5). The effect of this group on the selectivity can
be attributed to the reduced pyramidalisation of the C-3
dipole terminus in the transition state due to the contribution
from the quinoid resonance form.
group. On the other hand, no cross peaks were observed
between the methyl ester group and the aromatic protons
of the p-methoxyphenyl group. This suggests that compound
18c is the regioisomer with the acetyl group at C-7.
The results obtained from the dipolar cycloaddition of
muÈnchnones 9a±9d with methyl vinyl ketone and methyl
propiolate suggest that stereoelectronic transition state
interactions between the substituents of the muÈnchnone
and the substituents of the dipolarophile play an important
role in determining the regioselectivity. This observation
is in agreement with the work of Gribble et al. on the
1,3-dipolar cycloaddition of unsymmetrical muÈnchnones
with 2- and 3-nitroindoles.10
The cycloaddition of 5H,7H-thiazolo[3,4-c]oxazol-4-ium-
1-olate 9a±9ab with methyl vinyl ketone was also performed
5Scheme 6). From the reaction of 55R)-3,5-diphenyl-5H,7H-
thiazolo[3,4-c]oxazol-4-ium-1-olate 59a) and 55S)-3,5-di-
phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olate
59b)
only one regioisomer was obtained in each case: chiral
53R)-7-acetyl-3,5-diphenyl-1H,3H-pyrrolo[1,2-c]thiazole
18a was isolated in 37% yield and 53S)-7-acetyl-3,5-di-
phenyl-1H,3H-pyrrolo[1,2-c]thiazole 18b in 24% yield.
52R,4R)-N-Benzoyl-2-phenylthiazolidine-4-carboxylic acid
11a was heated in acetic anhydride in the presence of
dimethyl fumarate giving a 67:33 mixture of diastereo-
isomers 524 and 25) in 36% yield 5Scheme 8). Based on
The cycloaddition of 55R)-3-5p-methoxybenzoyl)-5-phenyl-
5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olate
59c)
with
1
methyl vinyl ketone led to a 88:12 mixture of regioisomers
53R)-7-acetyl-3-phenyl-5-5p-methoxyphenyl)-1H,3H-
pyrrolo[1,2-c]thiazole 18c and 53R)-6-acetyl-3-phenyl-5-5p-
methoxyphenyl)-1H,3H-pyrrolo[1,2-c]thiazole derivative
19 in 5% yield 5Scheme 7).
the H NMR spectrum we could determine the structure of
these compounds as being 3,5-diphenyl-7,7a-dihydro-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylates. This result
shows that the initially formed dipolar cycloadduct does not
lead to the aromatisation to the pyrrole ring. The synthesis
of compounds 24 and 25 can be rationalised as described
in Scheme 8. We have previously reported that the cycload-
dition of 55R)-3-methyl-5-phenyl-5H,7H-thiazolo[3,4-c]-
oxazol-4-ium-1-olate with acrylonitrile leads to 5,6-di-
hydro-1H,3H-pyrrolo[1,2-c]thiazole derivatives.3b In the
present case 7,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazole
derivatives were obtained as a consequence of a different
substitution pattern of the azomethine ylide intermediate.
Based on a comparison of the 1H NMR spectra of
compounds 18a±18c and 19 with those of 1H,3H-
pyrrolo[1,2-c]thiazoles 16a±16d and 17a±17d we could
determine the structure of the acetyl derivatives 5Table 1).
The 1H NMR spectra of 1H,3H-pyrrolo[1,2-c]thiazole
derivatives bearing a carboxylate or an acetyl group at
C-6 are characterised by having the H-3 and H-1 resonances
at a lower chemical shift then the ones observed for the
1H,3H-pyrrolo[1,2-c]thiazoles with a carboxylate or an
acetyl group at C-6.
3.Conclusion
The structural assignment of compound 18c was also based
on a NOESY spectrum. Cross peaks were observed between
H-6 and the aromatic protons of the p-methoxyphenyl
The intermolecular 1,3-dipolar cycloaddition of 55R)-3-
aryl-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates
59a and 9c) and 55S)-3-aryl-5-phenyl-5H,7H-thiazolo-
[3,4-c]oxazol-4-ium-1-olates 59b and 9d) is described.
Table 1. Selected chemical shifts for 1H,3H-pyrrolo[1,2-c]thiazoles
16a±16d, 17a±17d, 18a±18c and 19
The cycloaddition with dimethyl acetylenedicarboxylate led
to the synthesis of 1H,3H-pyrrolo[1,2-c]thiazoles in very
high yield. These reactions proved to be more ef®cient
than the previously reported cycloaddition of 55R)-3-methyl-
5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olate.3b
d 5ppm)
d 5ppm)
H-1a and H-1b H-3 H-7
H-1a and H-1b H-3 H-6
16a 4.12 and 4.36
6.21 6.50 17a 4.41 and 4.54
6.54 6.75
6.54 6.76
6.46 6.67
16b 4.12 and 4.36
16c 4.10 and 4.35
16d 4.10 and 4.35
6.21 6.50 17b 4.42 and 4.55
6.19 6.48 17c 4.40 and 4.53
6.19 6.48 17d
Cycloadditions with other dipolarophiles led to 1H,3H-
pyrrolo[1,2-c]thiazoles in similar yields to the ones obtained
with 55R)-3-methyl-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-
4-ium-1-olate although in some cases different regio-
selectivity was observed. From the reaction of muÈnchnones
18a 4.45 and 4.58
18b 4.43 and 4.56
6.07 6.51 18c 4.44 and 4.56
6.52 6.66
6.50 6.67
6.44 6.60
19
4.10 and 4.36

5098
T. M. V. D. Pinho e Melo et al. / Tetrahedron 58 12002) 5093±5102
Scheme 8.
9a±9d with methyl propiolate the regioisomers 1H,3H-
pyrrolo[1,2-c]thiazole-6-carboxylate and 1H,3H-pyrrolo-
[1,2-c]thiazole-7-carboxylate derivatives were obtained in
each case. The cycloadditions of muÈnchnones 9a and 9b
with methyl vinyl ketone were completely regioselective
5100:0) whereas with 9c both regioisomers were obtained
588:12).
2108C. After 15 min at room temperature the solution was
evaporated. The triethylamine salt was dissolved in THF
590 mL) and the solution was cooled at 2108C. The acid
chloride 534.9 mmol) was added dropwise and after stirring
at room temperature for 1 h the solvent was evaporated off.
The residue was treated with water 5150 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.
The study allowed to broaden the scope of this cycloaddi-
tion strategy to chiral pyrrolo[1,2-c]thiazoles, a class of
compounds with potential biological activity.2 New chiral
1H,3H-pyrrolo[1,2-c]thiazoles with R con®guration 515a,
15c, 16a, 16c, 17a, 17c, 18a, 18c and 19) and with S
con®guration 515b, 15d, 16b, 16d, 17b, 17d and 18b)
were obtained. The synthesis of 7,7a-dihydro-1H,3H-
pyrrolo[1,2-c]tiazole-6,7-dicarboxylates 524 and 25) was
also achieved.
4.1.1. .2R,4R)-N-Benzoyl-2-phenylthiazolidine-4-carb-
oxylic acid 11a. 576%). Mp 153.6±155.38C 5from ethyl
ether±hexane). 5Found: C, 65.2; H, 4.9; N, 4.3; S, 10.4.
C17H15NO3S requires C, 65.2; H, 4.8; N, 4.5; S, 10.2%).
dH 5run at 508C) 3.37 51H, dd, Jˆ12.3 and 7.0 Hz, SCH2±),
3.54 51H, dd, Jˆ12.3 and 7.0 Hz, SCH2±), 5.19 51H,
approx. t, Jˆ7.0 Hz, ±CHCOOH), 6.17 51H, s, ±CHPh)
and 7.19±7.40 510H, m, Ar-H); m/z 313 5M1, 0.1%), 241
25
525), 105 5100), 77 554). [a]D ˆ1147 5cˆ0.1, CH2Cl2).
4.Experimental
4.1.2.
.2R,4R)-N-.p-Methoxybenzoyl)-2-phenylthiazo-
1H NMR spectra were recorded on a Bruker AMX300
instrument operating at 300 MHz or on a Varian Unity-
500 instrument operating at 500 MHz where indicated. 13C
spectra were recorded on a Varian Unity-500 instrument
operating at 125 MHz. The solvent is deuteriochloroform
except where indicated otherwise. IR spectra were recorded
on a Perkin Elmer 1720X FTIR spectrometer. 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 polari-
meter. Mp were recorded on a Reichert hot stage and are
uncorrected. Flash column chromatography was performed
with Merck 9385 silica as the stationary phase. Methyl
2-phenylthiazolidine-4-carboxylate 12 and 2-phenylthiazo-
lidine-4-carboxylic acid 10 were prepared using the general
procedure described in the literature and were isolated as
mixture of the 52R,4R) and 52S,4R) diastereoisomers.11 In
the case of thiazolidine 10 the compound precipitates from
the reaction mixture and was isolated by ®ltration.
lidine-4-carboxylic acid 11b. 550%). Compound 11b was
isolated as foam 5Found: C, 62.5; H, 5.0; N, 3.6.
C18H17NO4S requires C, 63.0; H, 5.0; N, 4.1%). dH 3.37
51H, dd, Jˆ12.3 and 7.0 Hz, SCH2±), 3.48 51H, dd, Jˆ
12.3 and 7.0 Hz, SCH2±), 3.78 53H, s), 5.20 51H, approx.
t, Jˆ7.0 Hz, ±CHCOOH), 6.23 51H, s, ±CHPh), 6.76±6.79
52H, d, Ar-H, Jˆ9.0 Hz) and 7.27±7.38 57H, m, Ar-H); m/z
343 5M1, 0.1%), 271 516), 135 5100) and 77 515).
4.1.3. Methyl .2R,4R)-N-benzoyl-2-phenylthiazolidine-4-
carboxylate 13. 584%). Mp 72.2±73.78C 5from ethyl ether±
hexane). 5Found: C, 65.7; H, 5.3; N, 4.1. C18H17NO3S
requires C, 66.0; H, 5.2; N, 4.3%). H NMR spectrum at
room temperature gives very broad lines; m/z 327 5M1, 1%),
268 55), 241 561), 222 59), 105 5100) and 77 532).
1
4.2. Synthesis of .2R,4R)-N-benzoyl-2-phenylthiazo-
lidine-4-carboxylic acid 11a from methyl .2R,4R)-N-
benzoyl-2-phenylthiazolidine-4-carboxylate 13
4.1. General procedure for the synthesis of .2R,4R)-N-
acyl-2-phenylthiazolidine-4-carboxylic acids and esters
The methyl N-acyl-2-phenylthiazolidine-4-carboxylate
51 mmol) and LiI 54 mmol) were dissolved in ethyl acetate
51.3 mL). The reaction mixture was protected from light and
heated at re¯ux for 6 h. Water was added 55 mL) and the
solution was acidi®ed with HCl 1 M and extracted with
To a stirred solution of the thiazolidine 529.1 mmol) in THF
560 mL), triethylamine 572.2 mmol) was added dropwise at

T. M. V. D. Pinho e Melo et al. / Tetrahedron 58 12002) 5093±5102
5099
ethyl acetate. The organic phase was washed with water and
with saturated aqueous solution of NaCl. The organic
solvent was evaporated off. To the residue a saturated
aqueous solution of NaHCO3 was added and the solution
was washed with DCM. The aqueous solution was acidi®ed
with concentrated HCl and extracted with ethyl acetate. The
organic phase was dried and the solvent was evaporated
off giving 52R,4R)-N-benzoyl-2-phenylthiazolidine-4-carb-
oxylic acid 11a in 74% yield. The product was identi®ed by
comparison with the specimen previously prepared.
4.4.2. Dimethyl .3S)-3,5-diphenyl-1H,3H-pyrrolo[1,2-c]-
thiazole-6,7-dicarboxylate 15b. The titled compound was
prepared by the general procedure from thiazolidine 11a
using dimethylacetylene dicarboxylate as dipolarophile
583%). Compound 15b was isolated as an oil. dH 3.65
53H, s), 3.86 53H, s), 4.42 51H, d, Jˆ15.1 Hz, SCH2±),
4.57 51H, dd, Jˆ15.1 and 1.7 Hz, SCH2±), 6.32 51H,
d, Jˆ1.7 Hz, ±CHPh), 6.71±6.74 52H, m, Ar-H) and
7.01±7.21 58H, m, Ar-H); m/z 393 5M1, 53%), 361 579),
25
272 599), 121 5100) and 77 546). [a]D ˆ2209 5cˆ0.1,
CH2Cl2).
4.3. General procedure for the synthesis of .2S,4R)-N-
acyl-2-phenylthiazolidine-4-carboxylic acids
4.4.3. Dimethyl .3R)-3-phenyl-5-.p-methoxyphenyl)-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 15c. The
titled compound was prepared by the general procedure
from thiazolidine 11b using dimethylacetylene dicarboxyl-
ate as dipolarophile 585%). Mp 94.7±96.48C 5from ethyl
ether±hexane). 5Found: C, 65.0; H, 5.1; N, 3.2; S, 7.4.
C23H21NO5S requires C, 65.2; H, 5.0; N, 3.3; S, 7.6%). dH
3.67 53H, s), 3.75 53H, s), 3.86 53H, s), 4.41 51H, d, Jˆ
15.1 Hz, SCH2±), 4.56 51H, dd, Jˆ15.1 and 1.4 Hz,
SCH2±), 6.28 51H, d, Jˆ1.4 Hz, ±CHPh), 6.69 52H, d,
Jˆ8.5 Hz, Ar-H), 6.72±6.79 52H, m, Ar-H), 6.96 52H, d,
Jˆ8.5 Hz, Ar-H) and 7.11±7.16 53H, m, Ar-H); m/z 423
5M1, 89%), 341 522), 301 5100); 281 561), 207 597) and
To a stirred solution of the thiazolidine 54.88 mmol) in dry
pyridine 512 mL), the acid chloride 59.75 mmol) was added
dropwise at 2108C. After 4 h at 08C, the solution was
treated with water 520 mL) at room temperature 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.
4.3.1. .2S,4R)-N-Benzoyl-2-phenylthiazolidine-4-carb-
oxylic acid 14a. 544%). Compound 11b was isolated as a
foam. 5Found: C, 65.0; H, 5.0; N, 4.8. C17H15NO3S requires
25
1
73 533). [a]D ˆ1230 5cˆ1, CH2Cl2).
C, 65.2; H, 4.8; N, 4.5%). H NMR spectrum at room
temperature gives very broad lines; m/z 313 5M1, 0.1%),
268 50.5), 251 50.6); 241 562), 105 5100) and 77 570).
4.4.4. Dimethyl .3S)-3-phenyl-5-.p-methoxyphenyl)-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 15d. The
titled compound was prepared by the general procedure
from thiazolidine 11b using dimethylacetylene dicarboxyl-
ate as dipolarophile 592%). Mp 91.8±93.68C. 5Found C,
64.8; H, 5.0; N, 3.2; S, 7.8. C23H21NO5S requires C, 65.2;
H, 5.0; N, 3.3; S, 7.6%). dH 3.67 53H, s), 3.75 53H, s), 3.86
53H, s), 4.42 51H, d, Jˆ15.1 Hz, SCH2±), 4.56 51H, dd,
Jˆ15.1 and 1.6 Hz, SCH2±), 6.28 51H, d, Jˆ1.6 Hz,
±CHPh), 6.69 52H, d, Jˆ8.8 Hz, Ar-H), 6.73±6.76 52H,
m, Ar-H), 6.95 52H, d, Jˆ8.8 Hz, Ar-H) and 7.14±7.17
53H, m, Ar-H); m/z 423 5M1, 93%), 301 5100), 286 560),
25
[a]D ˆ2146 5cˆ0.1, CH2Cl2).
4.3.2.
.2S,4R)-N-.p-Methoxybenzoyl)-2-phenylthiazo-
lidine-4-carboxylic acid 14b. 575%, d.e. 50%). Compound
14b was isolated as a foam. Pure 52S,4R)-isomer was
isolated by ¯ash chromatography 525%). 5Found: C, 62.3;
H, 5.0; N, 3.9; S, 9.0. C18H17NO4S requires C, 63.0; H, 5.0;
1
N, 4.1; S, 9.3%). H NMR spectrum at room temperature
gives very broad lines.
4.4. General procedure for the synthesis of 1H,3H-
pyrrolo[1,2-c]thiazoles
25
207 525), 185 518), 135 515) and 77 510). [a]D ˆ2224
5cˆ1, CH2Cl2).
N-Acyl-2-phenylthiazolidine-4-carboxylic acid 55 mmol),
dipolarophile 57.5 mmol) and Ac2O 520 mL) were heated
at re¯ux for 4 h. The reaction was cooled to room tempera-
ture and was diluted with CH2Cl2 550 mL). The organic
phase was washed with saturated aqueous solution of
NaHCO3 and with water, dried 5MgSO4) and evaporated
off. The crude product was puri®ed by ¯ash chromatography
[hexane±ethyl acetate 53:1), hexane±ethyl acetate 52:1)
then hexane±ethyl acetate 51:1)].
4.4.5. Methyl .3R)-3,5-diphenyl-1H,3H-pyrrolo[1,2-c]-
thiazole-6-carboxylate 16a and methyl .3R)-3,5-di-
phenyl-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylate 17a.
The titled compounds were prepared by the general pro-
cedure from thiazolidine 11a using methyl propiolate as
dipolarophile 568%). The crude product was puri®ed by
¯ash chromatography giving a 62:38 mixture of 1H,3H-
pyrrolo[1,2-c]thiazoles: 16a dH 3.64 53H, s), 4.12 51H, dd,
Jˆ13.3 and 0.9 Hz, SCH2±), 4.36 51H, approx. dt, Jˆ13.3
and 1.1 Hz, SCH2±), 6.21 51H, d, Jˆ0.9 Hz, ±CHPh), 6.50
51H, approx. t, Jˆ1.1 Hz), 6.69±6.73 52H, m, Ar-H), 7.01±
7.04 52H, m, Ar-H) and 7.10±7.22 56H, m, Ar-H); 17a 3.86
53H, s), 4.41 51H, d, Jˆ15.0 Hz, SCH2±), 4.54 51H, dd,
Jˆ15.0 and 1.5 Hz, SCH2±), 6.54 51H, bs), 6.75 51H, s),
6.78±6.79 52H, m, Ar-H) and 6.01±6.18 58H, m, Ar-H);
GC±MS: 16a m/z 335 5M1, 70%), 214 5100), 198 553),
182 514) and 121 522); 17a m/z 335 5M1, 81%), 320 525),
214 5100), 182 514), 155 518) and 121 531).
4.4.1. Dimethyl .3R)-3,5-diphenyl-1H,3H-pyrrolo[1,2-c]-
thiazole-6,7-dicarboxylate 15a. The titled compound was
prepared by the general procedure from thiazolidine 11a
using dimethylacetylene dicarboxylate as dipolarophile
590%). Compound 15a was isolated as an oil. dH 3.66
53H, s), 3.87 53H, s), 4.43 51H, d, Jˆ15.1 Hz, SCH2±),
4.57 51H, dd, Jˆ15.1 and 1.7 Hz, SCH2±), 6.32 51H, d,
Jˆ1.7 Hz, ±CHPh), 6.69±6.73 52H, m, Ar-H), 7.02±7.05
52H, m, Ar-H) and 7.09±7.22 56H, m, Ar-H); m/z 393 5M1,
48%), 361 564), 272 573), 240 547), 121 5100) and 77
522); Accurate mass: 393.10375. C22H19NO4S requires
The major component 516a) is separated by selective
crystallisation 5ethyl ether±hexane).
25
393.10349. [a]D ˆ1201 5cˆ0.1, CH2Cl2).

5100
T. M. V. D. Pinho e Melo et al. / Tetrahedron 58 12002) 5093±5102
16a: mp 125.8±127.38C. 5Found: C, 71.7; H, 5.2; N, 4.3.
C20H17NO2S requires C, 71.6; H, 5.1; N, 4.2%). dH 3.64
53H, s), 4.12 51H, dd, Jˆ13.3 and 0.9 Hz, SCH2±), 4.36
51H, approx. dt, Jˆ13.3 and 1.1 Hz, SCH2±), 6.21 51H, d,
Jˆ0.9 Hz, ±CHPh), 6.50 51H, approx. t, Jˆ1.1 Hz), 6.69±
6.73 52H, m, Ar-H), 7.01±7.04 52H, m, Ar-H) and 7.10±
7.22 56H, m, Ar-H) [the assignment was based on a COSY
51H,1H) spectrum]; m/z 335 5M1, 41%), 214 5100), 198 551)
The major component 516c) is separated by selective
crystallisation 5ethyl ether±hexane).
17c: mp 135±1378C 5from ethyl ether). 5Found: C, 69.2; H,
5.4; N, 3.70; S, 9.2%. C21H19NO3S requires C, 69.0; H, 5.2;
N, 3.8; S, 8.8%). dH 3.66 53H, s), 3.76 53H, s), 4.10 51H, dd,
Jˆ13.3 and 0.7 Hz, SCH2±), 4.35 51H, approx. d, Jˆ
13.3 Hz, SCH2±), 6.19 51H, bs, ±CHPh), 6.48 51H, bs),
6.70 52H, d, Jˆ8.7 Hz, Ar-H), 6.69±6.75 52H, m, Ar-H),
6.95 52H, d, Jˆ8.7 Hz, Ar-H), 7.13±7.16 53H, m, Ar-H);
m/z 365 5M1, 57%), 243 578), 228 5100), 212 59), 121 510)
25
and 121 531). [a]D ˆ1348 5cˆ0.1, CH2Cl2).
4.4.6. Methyl .3S)-3,5-diphenyl-1H,3H-pyrrolo[1,2-c]-
thiazole-6-carboxylate 16b and methyl .3S)-3,5-di-
phenyl-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylate 17b.
The titled compounds were prepared by the general pro-
cedure from thiazolidine 14a using methyl propiolate as
dipolarophile 555%). The crude product was puri®ed by
¯ash chromatography giving a 64:36 mixture of 1H,3H-
pyrrolo[1,2-c]thiazoles: 16b dH 3.65 53H, s), 4.12 51H, dd,
Jˆ13.3 and 1.0 Hz, SCH2±), 4.36 51H, approx. dt, Jˆ13.3
and 1.1 Hz, SCH2±), 6.21 51H, d, Jˆ0.9 Hz, ±CHPh), 6.50
51H, approx. t, Jˆ1.1 Hz), 6.69±6.72 52H, m, Ar-H), 7.01±
7.05 52H, m, Ar-H), 7.11±7.20 56H, m, Ar-H); 17b dH 3.87
53H, s), 4.42 51H, d, Jˆ15.1 Hz, SCH2±), 4.55 51H, dd,
Jˆ15.1 and 1.6 Hz, SCH2±), 6.54 51H, d, Jˆ1.6 Hz,
±CHPh), 6.76 51H, s), 6.77±6.81 52H, m, Ar-H),
7.12±7.20 58H, m, Ar-H); GC±MS: 16b m/z 335 5M1,
53%), 283 519), 214 5100), 198 558) and 121 531); 17b
m/z 335 5M1, 81%), 320 525), 214 5100), 155 518) and
121 531).
25
and 77 54). [a]D ˆ1241 5cˆ0.1, CH2Cl2).
4.4.8. Methyl .3S)-3-phenyl-5-.p-methoxyphenyl)-1H,
3H-pyrrolo[1,2-c]thiazole-6-carboxylate 16d and methyl
.3S)-3-phenyl-5-.p-methoxyphenyl)-1H,3H-pyrrolo[1,2-c]-
thiazole-7-carboxylate 17d. The titled compounds were
prepared by the general procedure from thiazolidine 14b
using methyl propiolate as dipolarophile 547%). The crude
product was puri®ed by ¯ash chromatography giving a
79:21 mixture of 1H,3H-pyrrolo[1,2-c]thiazoles: 16d dH
3.66 53H, s), 3.76 53H, s), 4.10 51H, dd, Jˆ13.3 and
1.0 Hz, SCH2±), 4.35 51H, approx. dt, Jˆ13.3 and 1.0 Hz,
SCH2±), 6.19 51H, d, Jˆ1.0 Hz, ±CHPh), 6.48 51H, approx.
t, Jˆ1.0 Hz), 6.70 52H, d, Jˆ8.8 Hz, Ar-H), 6.72±6.75 52H,
m, Ar-H), 6.95 52H, d, Jˆ8.8 Hz, Ar-H) and 7.13±7.16 53H,
m, Ar-H); 17d dH 3.74 53H, s), 3.86 53H, s), 4.40 51H, d,
Jˆ15.0 Hz, SCH2±), 4.52 51H, dd, Jˆ15.0 and 1.5 Hz,
SCH2±), 6.46 51H, d, Jˆ1.5 Hz, ±CHPh), 6.67 51H, s),
6.71 52H, d, Jˆ8.8 Hz, Ar-H), 6.68±6.80 52H, m, Ar-H),
7.04 52H, d, Jˆ8.8 Hz, Ar-H), 7.12±7.18 53H, m, Ar-H);
GC±MS: 16d m/z 365 5M1, 54%), 243 573), 228 5100), 121
53) and 77 53); 17d m/z 365 5M1, 57%), 243 5100), 228 512),
121 510) and 77 53).
The major component 516b) is separated by selective
crystallisation 5ethyl ether±hexane).
16b: mp 118±119.68C. 5Found: C, 71.9; H, 4.8; N, 3.8.
C20H17NO2S requires C, 71.6; H, 5.1; N, 4.2%). dH 3.65
53H, s), 4.12 51H, dd, Jˆ13.3 and 1.0 Hz, SCH2±), 4.36
51H, approx. dt, Jˆ13.3 and 1.1 Hz, SCH2±), 6.21 51H, d,
Jˆ0.9 Hz, ±CHPh), 6.50 51H, approx. t, Jˆ1.1 Hz), 6.69±
6.72 52H, m, Ar-H), 7.01±7.05 52H, m, Ar-H), 7.11±7.20
56H, m, Ar-H); m/z 335 5M1, 53%), 283 519), 214 5100), 198
The major component 516d) is separated by selective
crystallisation 5ethyl ether±hexane).
16d: mp 110±113.58C. 5Found: C, 68.8; H, 5.2; N, 3.4; S,
8.6. C21H19NO3S requires C, 69.0; H, 5.2; N, 3.8; S, 8.8%).
dH 3.66 53H, s), 3.76 53H, s), 4.10 51H, dd, Jˆ13.3 and
1.0 Hz, SCH2±), 4.35 51H, approx. dt, Jˆ13.3 and 1.0 Hz,
SCH2±), 6.19 51H, d, Jˆ1.0 Hz, ±CHPh), 6.48 51H, approx.
t, Jˆ1.0 Hz), 6.70 52H, d, Jˆ8.8 Hz, Ar-H), 6.72±6.75
52H, m, Ar-H), 6.95 52H, d, Jˆ8.8 Hz, Ar-H) and 7.13±
7.16 53H, m, Ar-H); m/z 365 5M1, 65%), 334 55), 243
25
558) and 121 531). [a]D ˆ2310 5cˆ0.1, CH2Cl2).
4.4.7. Methyl .3R)-3-phenyl-5-.p-methoxyphenyl)-1H,
3H-pyrrolo[1,2-c]thiazole-6-carboxylate 16c and methyl
.3R)-3-phenyl-5-.p-methoxyphenyl)-1H,3H-pyrrolo[1,2-c]-
thiazole-7-carboxylate 17c. The titled compounds were
prepared by the general procedure from thiazolidine 11b
using methyl propiolate as dipolarophile 555%). The crude
product was puri®ed by ¯ash chromatography giving a
70:30 mixture of 1H,3H-pyrrolo[1,2-c]thiazoles: 16c dH
3.66 53H, s), 3.76 53H, s), 4.10 51H, dd, Jˆ13.3 and
0.7 Hz, SCH2±), 4.35 51H, approx. d, Jˆ13.3 Hz, SCH2±),
6.19 51H, bs, ±CHPh), 6.48 51H, bs), 6.70 52H, d, Jˆ8.7 Hz,
Ar-H), 6.69±6.75 52H, m, Ar-H), 6.95 52H, d, Jˆ8.7 Hz,
Ar-H), 7.13±7.16 53H, m, Ar-H); 17c dH 3.74 53H, s), 3.86
53H, s), 4.40 51H, d, Jˆ15.0 Hz, SCH2±), 4.53 51H, dd,
Jˆ15.0 and 1.6 Hz, SCH2±), 6.46 51H, d, Jˆ1.6 Hz,
±CHPh), 6.67 51H, s), 6.71 52H, d, Jˆ8.8 Hz, Ar-H),
6.78±6.81 52H, m, Ar-H), 7.04 52H, d, Jˆ8.8 Hz, Ar-H),
7.14±7.119 53H, m, Ar-H); GC±MS: 16c m/z 365 5M1,
57%), 243 578), 228 5100), 212 59), 121 510) and 77 54):
17c m/z 365 5M1, 58%), 243 5100), 228 510), 185 511), 134
510), 121 58) and 77 53).
25
585), 228 5100), 121 512) and 77 55). [a]D ˆ2240
5cˆ0.1, CH2Cl2).
4.4.9. .3R)-7-Acetyl-3,5-diphenyl-1H,3H-pyrrolo-[1,2-c]-
thiazole 18a. The titled compound was prepared by the
general procedure from thiazolidine 11a using methyl
vinyl ketone 525 mmol) as dipolarophile and the reaction
time was 15 h 537%). Compound 18a was isolated as an
oil. dH 2.46 53H, s), 4.45 51H, d, Jˆ15.4 Hz, SCH2±),
4.58 51H, dd, Jˆ15.4 and 1.8 Hz, SCH2±), 6.52 51H,
d, Jˆ1.8 Hz, ±CHPh), 6.66 51H, s), 6.77±6.81 52H, m,
Ar-H), 7.10±7.45 57H, m, Ar-H), 7.72±7.75 51H, m,
Ar-H); m/z 319 5M1, 100%), 198 577), 121 576) and 77
25
538). [a]D ˆ1143 5cˆ0.1, CH2Cl2).
4.4.10. .3S)-7-Acetyl-3,5-diphenyl-1H,3H-pyrrolo[1,2-c]-
thiazole 18b. The titled compound was prepared by the

T. M. V. D. Pinho e Melo et al. / Tetrahedron 58 12002) 5093±5102
5101
general procedure from thiazolidine 14a using methyl vinyl
ketone 525 mmol) as dipolarophile 524%). Compound 18b
was isolated as an oil. dH 2.45 53H, s), 4.43 51H, d,
Jˆ15.4 Hz, SCH2±), 4.56 51H, dd, Jˆ15.4 and 1.8 Hz,
SCH2±), 6.50 51H, d, Jˆ1.8 Hz, ±CHPh), 6.67 51H, s),
6.77±6.78 52H, m, Ar-H), 7.10±7.41 57H, m, Ar-H) and
7.70±7.73 51H, m, Ar-H); m/z 319 5M1, 100%), 286, 520),
F000ˆ384, mˆ1.695 mm21, Tˆ296 K. Number of indepen-
dent intensities 1965 from colourless, transparent prism,
0.35£0.40£0.25 mm3. Empirical absorption correction
applied based on 9 c-scans, Tminˆ0.696, Tmaxˆ0.977,
Taveˆ0.836. No signi®cant crystal decay was detected.
Structure solution by direct methods using SHELXS97.12
Rˆ0.0286 for 1950 re¯ections with I.2s, Rwˆ0.0781 for
1965 re¯ections used in the re®nement and 238 re®ned
parameters. H-atoms were placed at calculated positions
and re®ned as riding on their parent atoms. X-Ray measure-
ments were performed on a Enraf-Nonius MACH3 diffract-
25
198 566), 182 529), 121 530) and 77 59). [a]D ˆ2122
5cˆ0.1, CH2Cl2).
4.4.11. .3R)-7-Acetyl-3-phenyl-5-.p-methoxyphenyl)-1H,
3H-pyrrolo[1,2-c]thiazole 18c and .3R)-6-acetyl-3-phenyl-
5-.p-methoxyphenyl)-1H,3H-pyrrolo[1,2-c]thiazole 19.
The titled compounds were prepared by the general pro-
cedure from thiazolidine 11b using methyl vinyl ketone
525 mmol) as dipolarophile and the reaction time was 15 h
55%). The crude product was puri®ed by ¯ash chroma-
tography giving a 88:12 mixture of 1H,3H-pyrrolo[1,2-c]-
thiazoles 18c and 19 and was isolated as an oil: 18c: dH
5500 MHz) 2.45 53H, s), 3.75 53H, s), 4.44 51H, d, Jˆ
15.4 Hz, SCH2±), 4.56 51H, dd, Jˆ15.4 and 1.7 Hz,
SCH2±), 6.44 51H, d, Jˆ1.7 Hz, ±CHPh), 6.60 51H, s),
6.69±6.75 52H, m, Ar-H), 6.78±6.80 52H, m, Ar-H), 7.03
52H, d, Jˆ8.8 Hz, Ar-H), 7.15±7.17 53H, m, Ar-H); dC
5125 MHz) 27.6, 30.5, 55.2, 65.1, 112.9, 113.8, 125.3,
125.5, 128.4, 128.6, 128.8, 129.3, 131.5, 141.2, 141.3,
159.1, 193.9; 19: dH 5500 MHz) 2.22 53H, s), 3.76 53H, s),
4.10 51H, dd, Jˆ13.4 and 0.9 Hz, SCH2±), 4.36 51H, bd,
Jˆ13.4 Hz, SCH2±), 6.07 51H, bs, ±CHPh), 6.51 51H, bs),
6.69±6.75 54H, m, Ar-H), 6.88 52H, d, Jˆ8.4 Hz, Ar-H),
7.15±7.17 53H, m, Ar-H); GC±MS: 18c: m/z 349 5M1,
62%), 282 55), 227 5100), 212 530), 121 510) and 77 56);
19 m/z 349 5M1, 60%), 281 562), 227 5100), 207 592), 147
520) and 73 548).
ometer13 using Cu Ka radiation 5lˆ1.54184 A) and v22u
Ê
scans up to 72.038.
Acknowledgements
The authors wish to thank Dr Rui M. Brito 5University
of Coimbra) for the COSY and NOESY spectra. We
Ã
also thank Chymiotechnon and FundacËaÄo para a Ciencia e
Tecnologia 5POCTI/36137/QUI/2000) for ®nancial
support.
a
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