Synthesis of chiral pyrrolo[1,2-c]thiazoles via intramolecular dipolar cycloaddition of muenchnones: An interesting rearrangement to pyrrolo[1,2-c]thiazines

Article abstract of DOI:10.1021/jo010807p

Intramolecular dipolar cycloaddition of bicyclic muenchnones, 5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates, derived from cyclodehydration of 2-substituted-N-acylthiazolidine-4-carboxylic acids are reported. A range of new pyrrolo [1,2-c] thiazole derivatives (7, 14, 15, 20, 23, and 26) were obtained as single enantiomers from 2-phenylthiazolidines, 2-benzoylthiazolidines, and 2-methylthiazolidine-4-carboxylates. Pyrrolo[1,2-c][1,4]thiazine derivative 27 was also obtained from pyrrolo[1,2-c]thiazole derivative 26. The structures of methyl (2R,4R)-2-(p-methoxybenzoyl)thiazolidine-4-carboxylate (17a), methyl (2R,4R)-2-(p-methoxybenzoyl)-N-(prop-2- ynyloxyacetyl)thiazolidine-4-carboxylate (18), and 3-oxo-4-phenyl-3,4,6,8-tetrahydro-1H-furo [3′,4′:2,3]pyrrolo[1,2-c][1,4]thiazine (27) were determined by X-ray crystallography. Chirooptical studies of the pyrrolo[1,2-c]thiazoles were done by confirming the absolute configuration at the chiral center C-3.

Full text of DOI:10.1021/jo010807p

J . Org. Chem. 2002, 67, 4045-4054
4045
Syn th esis of Ch ir a l P yr r olo[1,2-c]th ia zoles via In tr a m olecu la r
Dip ola r Cycloa d d ition of Mu1 n ch n on es: An In ter estin g
Rea r r a n gem en t to P yr r olo[1,2-c]th ia zin es
Teresa M. V. D. Pinho e Melo,*,† Maria I. L. Soares,† Anto´nio M. d’A. Rocha Gonsalves,†
J ose´ A. Paixa˜o,‡ Ana M. Beja,‡ Manuela Ramos Silva,‡ Luiz Alte da Veiga,‡ and
J oa˜o Costa Pessoa§
Departamento de Quı´mica, Universidade de Coimbra, 3004-535 Coimbra, Portugal, Departamento de
Fı´sica, Universidade de Coimbra, 3004-516 Coimbra, Portugal, and Centro de Qu´ımica Estrutural,
Instituto Superior Te´cnico, 1049-001 Lisboa, Portugal
tmelo@ci.uc.pt
Received August 9, 2001
Intramolecular dipolar cycloaddition of bicyclic mu¨nchnones, 5H,7H-thiazolo[3,4-c]oxazol-4-ium-
1-olates, derived from cyclodehydration of 2-substituted-N-acylthiazolidine-4-carboxylic acids are
reported. A range of new pyrrolo[1,2-c]thiazole derivatives (7, 14, 15, 20, 23, and 26) were obtained
as single enantiomers from 2-phenylthiazolidines, 2-benzoylthiazolidines, and 2-methylthiazolidine-
4-carboxylates. Pyrrolo[1,2-c][1,4]thiazine derivative 27 was also obtained from pyrrolo[1,2-c]thiazole
derivative 26. The structures of methyl (2R,4R)-2-(p-methoxybenzoyl)thiazolidine-4-carboxylate
(17a ), methyl (2R,4R)-2-(p-methoxybenzoyl)-N-(prop-2-ynyloxyacetyl)thiazolidine- 4-carboxylate (18),
and 3-oxo-4-phenyl-3,4,6,8-tetrahydro-1H-furo[3′,4′:2,3]pyrrolo[1,2-c][1,4]thiazine (27) were deter-
mined by X-ray crystallography. Chirooptical studies of the pyrrolo[1,2-c]thiazoles were done by
confirming the absolute configuration at the chiral center C-3.
Sch em e 1
In tr od u ction
The 1,3-dipolar cycloaddition is the most general
approach to the synthesis of five-membered heterocyclic
compounds. In particular the cycloaddition of oxazolium-
5-oxides (mu¨nchnones) has proved to be a useful method
for the synthesis of pyrroles.1 This mesoionic ring system
acts as cyclic azomethine ylide in the reaction with
alkynes leading to the corresponding cycloadduct, fol-
lowed by cycloreversion of carbon dioxide generating
pyrrole derivatives. Bicyclic mesoionic ring systems
provide a route to heterocycles in which another ring
system is annulated to pyrrole. This type of mu¨nchnone
can be generated by cyclodehydration of cyclic N-acyl-R-
amino acids with reagents such as acetic anhydride or
carbodiimides (Scheme 1).
Thus, N-acylthiazolidine-4-carboxylic acids have been
used to generate bicyclic mu¨nchnones, 5H,7H-thiazolo-
[3,4-c]oxazol-4-ium-1-olates, which give some examples
of intermolecular 1,3-dipolar addition, namely the addi-
tion to dimethyl acetylenedicarboxylate,2 to R-chloroacry-
lonitrile,3 and to imines.4 The products from dimethyl
acetylenedicarboxylate are 1H,3H-pyrrolo[1,2-c]thiazole
derivatives, and this type of heterocyclic compound can
also be obtained from the reaction with R-chloroacryloni-
trile.
In our study the intermolecular dipolar cycloaddition
of 5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates was ex-
tended to other dipolarophiles namely methyl propiolate,
ethyl and methyl vinyl ketone, and acrylonitrile leading
to the synthesis of a range of new chiral 1H,3H-pyrrolo-
[1,2-c]thiazole derivatives and of interesting new spiro
compounds.5 We have also described the first examples
of intramolecular 1,3-dipolar cycloaddition of 5-phenyl-
5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates which led to
the synthesis of new 1H,3H-pyrrolo[1,2-c]thiazole deriva-
tives as single enantiomers (1 and 2).6
(3) (a) Fabre, J . L.; Farge, D.; J ames, C.; Lave´, D. Tetrahedron Lett.
1985, 26, 5447-5450. (b) Lave´, D.; J ames, C.; Rajoharison, H.; Bost,
P. E.; Cavero, I. Drugs Future 1989, 14, 891-898.
(4) (a) Croce, P. D.; Ferraccioli, R.; La Rosa, C. Tetrahedron 1995,
51, 9385-9392. (b) Croce, P. D.; Ferraccioli, R.; La Rosa, R. C.
Tetrahedron 1999, 55, 201-210.
(5) (a) Pinho e Melo, T. M. V. D.; Soares, M. I. L.; Barbosa, D. M.;
Rocha Gonsalves, A. M. d’A.; Matos Beja,; Paixa˜o, J . A.; Ramos Silva,
M.; Alte da Veiga, L. Tetrahedron 2000, 56, 3419-3424. (b) Silva, M.
R.; Matos Beja, A.; Paixa˜o, J . A.; Alte da Veiga, L.; D. M. Barbosa,
Soares, M. I. L.; Pinho e Melo, T. M. V. D.; Rocha Gonsalves, A. M.
d’A. Acta Crystallogr. 1999, C55, 1094-1096.
(6) Pinho e Melo, T. M. V. D.; Barbosa, D. M.; Ramos, P. J . R. S.;
Rocha Gonsalves, A. M. d’A.; Gilchrist, T. L.; Matos Beja, A.; Paixa˜o,
J . A.; Ramos Silva, M.; Alte da Veiga, L. J . Chem. Soc., Perkin Trans.
1 1999, 1219-1223.
† Departamento de Qu´ımica, Universidade de Coimbra.
‡ Departamento de F´ısica, Universidade de Coimbra.
§ Instituto Superior Te´cnico.
(1) (a) Potts, K. T. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley-Interscience: New York, 1984; Vol. 2, p 41. (b) Padwa,
A. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: London, 1991; Vol. 4, p 1069.
(2) (a) Kane, J . M. J . Org. Chem. 1980, 45, 5396-5397. (b) Gyo¨r-
gydea´k, Z.; Szila´gyi, L.; Kajta´r, J .; Argay, G.; Ka´lma´n, A. Monatsh.
Chem. 1994, 125, 189-208. (c) Anderson, W. K.; Mach, R. H. J . Med.
Chem. 1987, 30, 2109-2115. (d) Ladure´e, D.; Lancelot, J .-C.; Robba,
M.; Chenu, E.; Mathe´, G. J . Med. Chem. 1989, 32, 456-461. (e) Padwa,
A.; Fryrell, G. E.; Gasdaska, J . R.; Venkatramanan, M. K.; Wong, G.
S. K. J . Org. Chem. 1989, 54, 644-653.
10.1021/jo010807p CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/17/2002

4046 J . Org. Chem., Vol. 67, No. 12, 2002
Pinho e Melo et al.
Sch em e 2
In this paper we further explore the scope of the
intramolecular 1,3-dipolar cycloaddition of 5H,7H-thia-
zolo[3,4-c]oxazol-4-ium-1-olates thus obtaining new 1H,3H-
pyrrolo[1,2-c]thiazole derivatives, heterocyclic compounds
with potential biological activity.2c,d,3b,7
Resu lts a n d Discu ssion
The synthetic strategy for the generation of 5-substi-
tuted-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates contain-
ing internal dipolarophiles involves the N-acylation of
2-substituted thiazolidine-4-carboxylates with the ap-
propriate acid chloride. The selectivity of this acylation
is crucial since it modulates the stereochemistry of the
final adducts: N-acyl-2-substituted thiazolidine-4-car-
boxylates in diastereoisomeric pure form will lead to
chiral pyrrolo[1,2-c]thiazole derivatives since the chirality
at C-4 of the thiazolidine will be lost and the chirality at
C-2 (C-3 in the product) will be retained.2b,5,6
2-Substituted-1,3-thiazolidine-4-carboxylates are ob-
tained from the reaction of aldehydes and L-cysteine
esters in a process where a new chiral center at C-2
position of the thiazolidine is created leading to a mixture
of the (2S,4R) and (2R,4R) diastereoisomers. The acyla-
tion of the diastereoisomeric mixture with acetic anhy-
dride or with acid chlorides can lead to the selective
synthesis of N-acyl-2-substituted-1,3-thiazolidine-4-car-
boxylates as pure stereoisomers with (2R,4R) or (2S,4R)
stereochemistry depending on the reaction conditions. In
fact 2-substituted-1,3-thiazolidine-4-carboxylates can un-
dergo selective inversion at C-2 through a mechanism
involving the opening of the ring, but the protection with
the acyl group prevents this epimerization and allows the
isolation of pure diastereoisomers.8
described6 to evaluate if the nature of this substituent
would have any influence on its selectivity.
As a first objective we decided to prepare new 5-phenyl-
5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates containing in-
ternal dipolarophiles and promote their cycloaddition.
The synthetic strategy used is outlined in Scheme 2. (But-
3-ynyloxy)acetic acid was prepared from the reaction of
3-butyn-1-ol and chloroacetic acid and converted into the
corresponding acid chloride 4 by the reaction with thionyl
chloride. This acetylenic acid chloride was used to acylate
thiazolidine 3 giving compound 5 as a single stereoisomer
with (2R,4R) stereochemistry, in 68% yield. Thiazolidine
6 was obtained by reacting compound 5 with lithium
iodide in ethyl acetate followed by treatment with aque-
ous HCl. Heating a solution of N-acylthiazolidine 6 in
acetic anhydride led to the generation of the correspond-
ing mesoionic species which underwent an intramolecular
1,3-dipolar cycloaddition with the unactivated terminal
Previous results showed that starting with methyl 1,3-
thiazolidine-4-carboxylate, bearing a phenyl group at C-2,
as a mixture of the (2R,4R) and (2S,4R) diastereoisomers,
N-acylation, using our reaction conditions, lead to the
selective formation of methyl N-acyl-2-phenyl-1,3-thia-
zolidine-4-carboxylate with (2R,4R) stereochemistry.6 The
dehydration of the corresponding N-acyl-2-phenyl-1,3-
thiazolidine-4-carboxylic acids generates 5-phenyl-5H,7H-
thiazolo[3,4-c]oxazol-4-ium-1-olates containing internal
dipolarophiles which undergo cycloaddition giving 1H,3H-
pyrrolo[1,2-c]thiazole derivatives as single enantiomers
and with R configuration (1 and 2).6
This synthetic methodology is now explored to include
the dipolar cycloaddition of new 5-substituted-5H,7H-
thiazolo[3,4-c]oxazol-4-ium-1-olates. N-acylations of thia-
zolidines with phenyl, methyl, and benzoyl groups at C-2
were made using the reaction conditions previously
alkyne. A new chiral 1H,3H-pyrrolo[1,2-c]thiazole deriva-
25
tive having a fused dihydro-2H-pyran ring with [R]D
+148.1 (7) was obtained in 18% yield.
)
Attempts were made to promote this type of intramo-
lecular dipolar cycloaddition using a terminal alkene as
the dipolarophile. (Prop-2-enyloxy)acetic acid was pre-
pared by a known method,9 and its reaction with thionyl
chloride gave the acid chloride 8. N-acylation of thiazo-
lidine 3 with this acid chloride gave compound 9 in 60%
yield, which was converted into the carboxylic acid 10
(46%). However, with heating of compound 10 in acetic
anhydride, no cycloadduct was obtained (Scheme 3). This
indicates the need for dipolarophile activation.
The thiazolidine 11 bearing a methyl group at C-2 was
prepared and isolated as a mixture of the (2S,4R) and
(2R,4R) diastereoisomers. The reaction of this compound
with (prop-2-ynyloxy)acetic acid chloride, prepared from
the reaction of (prop-2-ynyloxy)acetic acid10 with thionyl
1
(7) Davidson, S. K.; Summers, J . B.; Albert, D. H.; Holms, J . H.;
Robin Heyman, H.; Magoc, T. J .; Conway, R. G.; Rhein, D. A.; Carter,
G. W. J . Med. Chem. 1994, 37, 4423-4429.
chloride, gave compound 12 in 63% yield. The H NMR
spectrum of thiazolidine 12 at ambient temperature was
(8) (a) Szila´gyi, L.; Gyo¨rgydea´k, Z. J . Am. Chem. Soc. 1979, 101,
427-432. (b) Gyo¨rgydea´k, Z.; Kajta´r-Peredy, M.; Kajta´r, J .; Kajta´r, M.
Liebigs Ann. Chem. 1987, 927-934. (c) Benedini, F.; Ferrario, F.; Sala,
A.; Sala, L.; Soresinetti, P. A. J . Heterocycl. Chem. 1994, 31, 1343-
1347.
(9) Beckwith, A. L. J .; Bowry, V. W. J . Org. Chem. 1988, 53, 1632-
1641.
(10) Gilchrist, T. L.; Wasson, R. C. J . Chem. Soc., Perkin Trans. 1
1987, 2517-2522.

Chiral Pyrrolo[1,2-c]thiazoles
Sch em e 3
J . Org. Chem., Vol. 67, No. 12, 2002 4047
Sch em e 5
Sch em e 4
lished by X-ray crystallography (see Supporting Infor-
mation). The compound crystallizes in the noncentrossym-
metric P21 space group. The puckering parameters of the
five-membered ring are Q(2) ) 0.357(3)° and φ(2))271.1-
(4)°. The methyl carboxylate substituent bonds to C4 in
an equatorial geometry as shown by the angle between
the C4-C41 bond and the normal to the Cremer and
Pople plane, 63.90(19)°. The p-methoxybenzoyl group
bonds to the ring in a bisecting geometry as shown by
the corresponding angle 52.31(19)°. The conformation is
stabilized by one bifurcated intramolecular hydrogen
bond N3-H3‚‚‚O21, O41 with short distances, 2.680(4)
and 2.724(3) Å, although narrow angles, 107(3) and 102-
(3)°, respectively. The absolute structure was determined
by taking advantage of the sulfur small anomalous
dispersion at the Mo KR wavelength. The Flack param-
eter refined to 0.03(10), confirming the expected R,R
chirality.
complicated by the existence of separated rotamers but
when recorded in DMSO-d6 at 65 °C showed signals for
a single diastereoisomer. Thiazolidine 12 was converted
into the 1H,3H-pyrrolo[1,2-c]thiazole 14 using a synthetic
approach similar to the one described in Scheme 2. This
product (14) was obtained in 26% yield as a single
25
1
enantiomer with R configuration [R]D ) + 75. The
The H NMR spectra of 2-(p-methoxybenzoyl) deriva-
25
acetylated product 15 ([R]D ) + 35) was also isolated
tive 17a are characterized by having the sum of the
coupling constants between geminal protons H(5a), H(5b)
with H(4) larger than the corresponding sum of these
coupling constants for the thiazolidine 17b. This is in
agreement with previous observation that the sum of
J (5a),(4) with J (5b),(4) of the (2R,4R) isomer of 2-substituted
thiazolidine-4-carboxylic acid derivatives is greater than
that of the (2S,4R) isomer.8 The comparison of these
in 12% yield (Scheme 4).
The reaction of phenylglyoxal and L-cysteine methyl
ester gives also a thiazolidine as a mixture of the (2S,4R)
and (2R,4R) diastereoisomers. However, in this case the
two diastereoisomers of methyl 2-benzoylthiazolidine-4-
carboxylate (16a ,b) can be separated by chromatography
proving that the interconversion of these isomers through
a reversible ring opening mechanism is difficult.11
(p-Methoxyphenyl)glyoxal, obtained by oxidation of
4-methoxyacetophenone with aqueous hydrobromic acid
and dimethyl sulfoxide,12 reacts with L-cysteine methyl
ester giving a mixture of diastereoisomeric thiazolidines
(17a ,b), which can also be separated but this time by
selective crystallization.
1
spectra with the H NMR spectra of 16a ,b allowed us to
conclude that 16a is the (2R,4R) isomer and 16b the
(2S,4R) isomer (see Supporting Information).
The unique possibility of isolating pure diastereoiso-
mers of 2-substituted thiazolidines characterized by the
an unfavorable interconversion between the (2R,4R) and
(2S,4R) isomers led us to explore the use of 16a ,b and
17a ,b as precursors of 5H,7H-thiazolo[3,4-c]oxazol-4-ium-
1-olates with internal dipolarophiles and to promote the
dipolar cycloaddition in the hope of retaining the config-
uration of the starting thiazolidine at C-2. This could lead
to chiral dipolar cycloadducts with R and S configura-
tions.
The stereochemistry of the methyl (2R,4R)-2-(p-meth-
oxybenzoyl)thiazolidine-4-carboxylate (17a ) was estab-
The reaction of thiazolidine 17a with (prop-2-ynyloxy)-
acetic acid chloride in the presence of potassium carbon-
ate led to N-acylthiazolidine 18 meaning that retention
of configuration at C-2 has occurred (Scheme 5). This
N-acylthiazolidine showed a positive value for the optical
(11) Gilchrist, T. L..; Rocha Gonsalves, A. M. d’A.; Pinho e Melo, T.
M. V. D. Tetrahedron 1994, 50, 13709-13724.
(12) Brawner Floyd, M.; Du, M. T.; Fabio, P. F.; J acob, L. A.;
J ohnson, B. D. J . Org. Chem. 1985, 50, 5022-5027.
25
rotation ([R]D ) +51.5) which is consistent with the

4048 J . Org. Chem., Vol. 67, No. 12, 2002
Pinho e Melo et al.
Sch em e 6
(2R,4R) stereochemistry. In fact, a positive value for the
optical rotation of 2-substituted N-acyl-1,3-thiazolidine-
4-carboxylates is normally associated with (2R,4R) ster-
eochemistry and a negative value with (2S,4R) stereo-
chemistry.5,6,8a
Meanwhile the structure of thiazolidine 18 was con-
firmed by X-ray crystallography (see Supporting Infor-
mation). The compound crystallizes in the noncentrosym-
metric P212121 space group. The five-membered ring
adopts an envelope conformation on S1 with puckering
parameters Q(2) ) 0.409(3) Å and æ(2) ) 354.3(4)°. The
(prop-2-ynyloxy)acetyl ring substituent bonds to N3 in
an equatorial position as seen by the angle between the
C31-N3 bond and the normal to the Cremer and Pople
plane, 69.1(2)°. The p-methoxybenzoyl and methyl car-
boxylate groups are positioned in axial and bisecting
positions, respectively, as seen by the corresponding
angles, 15.8(2) and 49.7(2)°.
The structure shows no classical hydrogen bonds.
Cohesion is maintained by C-H‚‚‚O and C-H‚‚‚π inter-
molecular bonding. Both terminal methyl groups have
one of their hydrogens atoms directed toward the π cloud
of the benzoyl ring with distances of 2.870 and 2.784 Å
between the hydrogens and the centroid of the ring.
Oxygen atom O21 accepts one proton from C24 [C24-
H24‚‚‚O21i, 3.453(4) Å; i ) -1/2 + x, 3/2 - y, -z]. O31
accepts two protons coming from the same neighbor
molecule [C32-H32A‚‚‚O31ii, 3.293(4) Å; C33-H33A‚‚‚
O31ii, 3.435(4) Å; ii ) 1 - x, -1/2 + y, - z]. O41 accepts
two protons from the (prop-3-ynyloxy)acetyl group of two
neighboring symmetry-related molecules [C26-H26‚‚‚
O41iii, 3.306(4) Å; C35-H35‚‚‚O41iv, 3.313(5) Å; iii ) x,
-1 + y, z; iv ) -x, -1/2 + y, - z].
Sch em e 7
Absolute structure was determined by taking advan-
tage of the small anomalous dispersion of the sulfur atom
at the Mo KR wavelength. The Flack parameter was
refined to 0.01(9), confirming the expected R,R configu-
ration of the C2 and C4 atoms.
Compound 18 reacted with lithium iodide in ethyl
acetate followed by treatment with aqueous HCl, and the
corresponding acid 19 was obtained. This compound was
heated in a solution of acetic anhydride to generate a
mesoionic species which underwent an internal 1,3-
dipolar cycloaddition. The chiral 3-benzoyl-1H,3H-pyr-
rolo[1,2-c]thiazole derivative 20 was obtained with R
25
configuration ([R]D ) + 99.9).
The thiazolidine 21 was obtained from the acylation
of thiazolidine 17b with (prop-2-ynyloxy)acetic acid chlo-
ride (Scheme 6). The compound obtained showed a
negative value for the optical rotation suggesting stere-
ochemistry (2S,4R). Thiazolidine 21 was converted into
-166.7). This observation indicates that the acylation of
thiazolidine 16a occurs with retention of configuration
whereas thiazolidine 16b undergoes inversion of config-
uration at C-2.
the corresponding carboxylic acid 22, which was heated
Compound 24 reacted with lithium iodide in ethyl
acetate followed by treatment with aqueous HCl giving
thiazolidine 25. With heating of N-acylthiazolidine 25 in
acetic anhydride, two products were obtained, the chiral
1H,3H-pyrrolo[1,2-c]thiazole derivative 26 in 17% yield
and compound 27 in 29% yield. The absolute configura-
tion of compound 26 was confirmed by chirooptical
25
in acetic anhydride giving the cycloadduct 23 ([R]D
-96.2), the enantiomer of compound 20.
)
Our study showed that with methyl 2-(p-methoxyben-
zoyl)thiazolidine-4-carboxylates 17a ,b as starting mate-
rial 3-benzoyl-1H,3H-pyrrolo[1,2-c]thiazole derivatives
can be obtained as single enantiomers with retention of
configuration at C-2 of the starting thiazolidine.
25
studies (see below) as being the R configuration ([R]D
) +200.0).
In contrast with the results obtained with 2-(p-meth-
oxybenzoyl)thiazolidines the acylation reaction of 2-ben-
zoylthiazolidines 16a ,b led to products which showed
The structure of the pyrrolo[1,2-c][1,4]thiazine deriva-
tive 27 was established by X-ray crystallography (see
Supporting Information). The unit cell contains a pair of
enantiomeric molecules.
identical 1H NMR (Scheme 7). They both led to the same
25
thiazolidine (24) with R configuration at C-2 ([R]D
)

Chiral Pyrrolo[1,2-c]thiazoles
J . Org. Chem., Vol. 67, No. 12, 2002 4049
Sch em e 8
The furan and pyrrole rings are practically planar; the
largest deviation from the least-squares plane is 0.0145-
(13) Å (atom C3). The thiazine ring has a distorted boat
conformation with puckering parameters Q ) 0.640(2)
Å, θ ) 85.5(2)°, and φ ) 51.81(14)° as defined by Cremer
and Pople. The dihedral angle between the least-squares
planes of the furan and pyrrole rings is 0.30(7)°, and that
between the pyrrole and thiazine rings is 23.86(8)°.
Bond lengths and angles show no unusual values.
There is a significant asymmetry between the two S-C
bond lengths [C5-S1, 1.817(2) Å; C7-S1, 1.749(2) Å],
reflecting the different hybridization of the C5 and C7
atoms. Although there is a large asymmetry between the
valence angles around N1, the sum of these angles adds
up to 359.6(3)°, indicating no significant pyramidal
character of the N1 atom. The environment around the
asymmetric C8 atom is close to tetrahedral, with bond
angles in the range 110.80(14)-112.72(13)°. The phenyl
ring is in an axial position with respect to the thiazine
ring with torsion angles -87.78(16)° [S1-C7-C8-C10]
and 75.32(19)° [C4a-N1-C8-C10]. The dihedral angle
between the least-squares planes of the phenyl and
thiazine rings is 83.78(7)°.
No classical hydrogen bonds are present in the struc-
ture, and cohesion of the crystal is achieved mainly
through van der Waals interactions. The short carbonyl
C7dO71 [1.211(2) Å] bond distance is in agreement with
an O atom not involved in strong hydrogen bonding. An
inspection of the close contact distances shows that C15-
H15‚‚‚N1 [2.843(3) Å] and C11-H11‚‚‚O71 [3.216(3) Å]
are possible weak intramolecular interactions.
The pyrrolo[1,2-c][1,4]thiazine derivative 27 could also
be obtained by heating a solution of 1H,3H-pyrrolo[1,2-
c]thiazole derivative 26 in acetic anhydride. This result
clearly indicates that compound 27 was formed from
pyrrolo[1,2-c]thiazole derivative 26 and not from the
N-acyl-1,3-thiazolidine 25.
The mechanism proposal for the synthesis of the
pyrrolo[1,2-c][1,4]thiazine derivative 27 is outlined in
Scheme 8. The first step is the acetylation of the sulfur
atom with acetic anhydride giving 28. Two possible ways
in which this intermediate could be converted into the
final product are shown in the scheme. Further studies
are underway to clarify the mechanism for the formation
of pyrrolo[1,2-c][1,4]thiazine 27.
contrast the C-3-alkyl-substituted compounds show me-
dium bands. The same applies for the CD spectra,
particularly the bands that originate from the aryl rings.
Among the compounds studied there are three enan-
tiomeric pairs: 20/23, 34a /34b, and 37a /37b. The CD
spectra recorded corroborate the presence of these three
sets of compounds as enantiomers, but the optical purity
is somewhat better for the compounds with the R
configuration at C-3 than for those with S configuration.
The CD spectra in the range 200-330 nm show a
rather complex set of bands with variable intensities. At
least five bands are normally detected. We note that the
sign of the CD bands of the compounds depends, with
few exceptions (see below), on the configuration of the
chiral center C-3.
Isotr op ic UV a n d CD Sp ectr a . The UV isotropic and
CD spectra for some pyrrolo[1,2-c]thiazoles were obtained
(see Supporting Information and Figure 1). The study
includes compounds whose synthesis has been previously
described2b,5,6 (1a ,b, 34a ,b, 35, and 36) and pyrrolo[1,2-
c]thiazoles prepared during this work (14, 15, 20, 23, and
26). Dimethyl (3R)- and (3S)-3,5-dimethyl-1H,3H-pyrrolo-
[1,2-c]thiazole-6,7-dicarboxylate (37a ,b) were also pre-
pared as outlined in Scheme 9 to be used in comparative
CD studies.
Benzene presents bands at 203.5 (K-band) and 254 nm
(B-band), and pyrrole, bands at ∼200 nm.13 It is known
that substitution on the aromatic rings, particularly by
groups that extend conjugation, leads to λmax of bands at
wavelengths longer that those observed for nonsubsti-
tuted aromatic rings.13,14 Therefore we expect that groups
such as -R or -COR (R ) pyrrolo[1,2-c]thiazoles) and
-COOMe will induce a bathochromic effect on these
bands. This affects the type of spectra and the broadness
of the bands; moreover, the Cotton effects observed in
some compounds may overlap and only show up as
shoulders in the CD spectra of other compounds.
The assignment of individual bands was done in
analogy to the similar compounds already studied.2b,8b,15
(13) Williams, D. H.; Fleming, I. Spectroscopic Methods in Organic
Chemistry, 5th ed.; McGraw-Hill: London, 1995; pp 1-27.
(14) Silverstein, R. M.; Bassler, C. C.; Morril, T. C. Spectrometric
Identification of Organic Compounds, 5th ed.; J ohn Wiley & Sons: New
York, 1991; pp 289-315.
(15) Gyo¨rgydea´k, Z.; Kajta´r, J .; Kajta´r, M.; Kajta´r-Peredy, M. Liebigs
Ann. Chem. 1990, 281-286.
Strong bands are found in the UV isotropic spectra of
the C-3-aryl- and C-3-benzoyl-substituted substances. In

4050 J . Org. Chem., Vol. 67, No. 12, 2002
Pinho e Melo et al.
F igu r e 1. CD spectra for chiral C-3 substituted pyrrolo[1,2-c]thiazoles (1a ,b, 14, 15, and 26).
Sch em e 9
mation, the S atom being opposite to the substituent at
C-3 for all compounds except 20, 23, and 26.
Earlier determinations have suggested that the sign
of the Cotton effect associated with band V is related with
the torsion angle N-C-C-S, a negative value corre-
sponding to a negative Cotton effect at 205 nm. In our
molecular mechanics calculations negative torsion angles
N-C-C-S were obtained for compounds with the R
configuration at C-3 and positive angles for the similar
compounds with the S configuration. The same applies
for the torsion angle N-C-S-C, while for the torsion
angle C-N-C-S positive values were found for com-
pounds with R configuration at C-3 and negative values
for the compounds with S configuration at C-3. Com-
pounds 20, 23, and 26 are exceptions to this rule, the
torsion angles N-C-C-S, N-C-S-C, and C-N-C-S
showing signs opposite to those of the other compounds,
the same applying to the sign of the 205 nm band.
Nevertheless, from the results of the molecular mechan-
ics calculations, it may be stated that for all compounds
the relative positions of the atoms of the thiazolidine ring
and of the substituents at C-3, as measured by the signs
of the torsion angles, determine unambiguously the
Cotton effect of band V. In fact, negative values for the
torsion angles N-C-C-S and N-C-S-C and positive
for C-N-C-S always correspond to a negative Cotton
effect for the band at 205 nm.
Compounds containing the carbonyl (ketone) group also
show bands in the 300-330 nm range due to the n f π*
transition of the carbonyl group. The derivatives contain-
ing ester groups (e.g. 34, 35, and 37a ,b) show this band
around 220 nm. As found in these studies,2b,8b,15 the sign
of the 205 nm band (band V) correlates in the spectra of
our compounds with the absolute configuration of the
chiral center C-3: the (3R) derivatives show a negative
Cotton effect at 205 nm. Exceptions to this behavior are
compounds 20, 23, and 26. This band is assigned to a
πfπ* transition of the S-C-N-C(pyrrole) group, the
sign and amplitude of which is determined by the helicity
of the chromophore and the type of group attached to the
C-3 atom.
To better understand the factors that determine the
sign of the Cotton effect associated with the band at ∼205
nm we used the program HyperChem (Polak-Ribiere
optimization) to estimate the structure of the compounds
(therefore the conformation of the thiazolidine ring). The
calculated structures agree reasonably well with those
obtained from single-crystal X-ray diffraction studies,
particularly for 1a , reported earlier.6 Except for the S
atom, all atoms of the thiazolidine pyrrole (and furan)
rings are approximately in the same plane, this corre-
sponding to a rather rigid disposition of atoms. The
thiazolidine rings are obtained with an envelope confor-
Although the methyl-substituted compounds normally
correspond to greater torsion angles, the increased
intensity of the bands of the aryl- or benzoyl- substituted
compounds is explained by the mixing of the transitions
of the aryl (and pyrrole) rings with those of the S-C-N
chromophores.
Summarizing the chirooptical studies of the pyrrolo-
[1,2-c] thiazoles, we confirm that the absolute configu-
ration of the chiral center C-3 can be determined unam-
biguously via the sign of the 205 nm band. The molecular
mechanics studies suggest that this is possible due the
rigidity of the thiazolidine ring that is condensed with
the pyrrole ring, the torsion angles characterizing the
disposition of the most relevant atoms all having the
same sign for the R (or for the S) derivatives. Exceptions
to this general behavior are the compounds with the
benzoyl group at the chiral center C-3, where torsion

Chiral Pyrrolo[1,2-c]thiazoles
J . Org. Chem., Vol. 67, No. 12, 2002 4051
Gen er a l P r oced u r e for t h e Syn t h esis of Th ia zo-
lid in es.11 L-Cysteine methyl ester hydrochloride (3.45 g, 20
mmol) was dissolved in water (15 mL), and potassium hydro-
gen carbonate (2.0 g, 20 mmol) was added following the
addition of a solution of the aldehyde (22 mmol) in ethanol
(15 mL). The reaction mixture was stirred at room temperature
for 30 min. The reaction mixture was diluted with water and
extracted with dichloromethane. The organic extracts were
concentrated, and the residue was purified as stated for each
compound.
angles with opposite signs to those of the other com-
pounds were found in the molecular mechanics calcula-
tions. Accordingly, the sign for the Cotton effect of the
205 nm transition is the opposite in these compounds.
Con clu sion
The reactivity of 5-substituted-5H,7H-thiazolo[3,4-c]-
oxazol-4-ium-1-olates containing internal dipolarophiles
is described. The synthetic strategy involves the N-
acylation of 2-substituted thiazolidine-4-carboxylates
which are used as precursors of the mesoionic species.
Depending on the nature of the substituent at C-2 of the
thiazolidine, N-acyl derivatives with different stereo-
chemistry were obtained. If one starts with methyl
2-phenylthiazolidine-4-carboxylate or methyl 2-meth-
ylthiazolidine-4-carboxylate as a mixture of the (2R,4R)
and (2S,4R) diastereoisomers, a pyrrolo[1,2-c]thiazole
with R configuration was obtained (7, 14, and 15). Using
methyl (2R,4R)-2-(p-methoxybenzoyl)thiazolidine-4-car-
boxylate and methyl (2S,4R)-2-(p-methoxybenzoyl)thi-
azolidine-4-carboxylate in diastereoisomeric pure form,
7-(p-methoxybenzoyl)pyrrolo[1,2-c]thiazole derivatives with
R and S configuration, respectively, were obtained (20
and 23) with retention of configuration at C-2 of the
starting thiazolidine. In the case of 2-benzoylthiazolidines
both diastereoisomers led to the same N-acyl derivative
allowing for the synthesis of compound 26 with R
configuration. An interesting conversion of 1H,3H-pyr-
rolo[1,2-c]thiazole derivative 26 to pyrrolo[1,2-c][1,4]-
thiazine derivative 27 was also achieved. Chirooptical
studies of the pyrrolo[1,2-c]thiazoles were done by con-
firming the absolute configuration at the chiral center
C-3.
Met h yl (2R,4R)- a n d (2S,4R)-2-Met h ylt h ia zolid in e-4-
ca r boxyla te (11). The thiazolidine, obtained in 77% yield, was
purified by flash chromatography [hexanes-ethyl acetate (1:
1)]. The 1H NMR spectrum showed the presence of two
diastereoisomers (ratio 63:37, determined by GC-MS). Major
1
component: H NMR 1.61 (d, 3H, J ) 6.3), 2.35 (s, 1H, NH),
2.94 (dd, 1H, J ) 9.3, 10.5), 3.32 (dd, 1H, J ) 7.2, 10.5), 3.79
(s, 3H), 3.84 (dd, 1H, J ) 7.2, 9.3), and 4.57 (q, 1H, J ) 6.3).
1
Minor component: H NMR 1.50 (d, 3H, J ) 6.3), 2.35 (s, 1H,
NH), 3.13 (dd, 1H, J ) 6.0, 10.6), 3.34 (dd, 1H, J ) 7.2, 10.6),
3.77 (s, 3H), 4.21 (dd, 1H, J ) 6.0, 7.2), and 4.78 (q, 1H, J
6.3).
Meth yl (2R,4R)-2-Ben zoylth ia zolid in e-4-ca r boxyla te
(16a ) a n d Meth yl (2S,4R)-2-Ben zoylth ia zolid in e-4-ca r -
boxyla te (16b). The thiazolidine was obtained in 68% yield.
The 1H NMR spectrum showed the presence of two diastere-
oisomers (ratio 55:45), which were separated by flash chro-
matography [petroleum ether-ethyl acetate (3:1), petroleum
ether-ethyl acetate (1:1), and then ethyl acetate] giving (in
order of elution) the following: methyl (2R,4R)-2-benzoylthi-
azolidine-4-carboxylate (16a ) (the major isomer:) [mp 116.8-
1
119.2 °C (from ethyl ether-hexane); H NMR 2.80 (approxi-
mately t, 1H, J ) 10.2), 3.37 (dd, 1H, J ) 5.8, 10.2), 3.75 and
3.84 (m, 1H), 3.84 (3H), 5.80 (1H, s), 7.47-7.63 (m, 3H, Ar H),
and 7.94-7.99 (m, 2H, Ar H); MS (EI) 251 (M+, 2%), 250 (10),
226 (3), 220 (3), 192 (1), 174 (5) 146 (11), 105 (100), 87 (9),
and 77 (90); HRMS calcd for C12H14NO3S (MH+) 252.0694,
25
found 252.0691; [R]D ) -10.5 (c ) 0.95, CH2Cl2)]; methyl
(2S,4R)-2-benzoylthiazolidine-4-carboxylate (16b) (the minor
isomer) [mp 62.2-64.6 °C (from ethyl ether-hexane); 1H NMR
3.08 (dd, 1H, J ) 6.6, 10.7), 3.40 (dd, 1H, J ) 2.6,10.7), 3.82
(3 H), 4.69 (dd, 1H, J ) 2.6, 6.6), 5.99 (s, 1H), 7.47-7.53 (m,
2H, Ar H), 7.59-7.64 (m, 1H, Ar H), and 7.94-7.98 (m, 2H,
Ar H); MS (EI) 252 (MH+, 24%), 146 (100), 105 (24), 86 (69),
and 77 (27); HRMS calcd for C12H14NO3S (MH+) 252.0694,
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra (300 MHz) were
recorded in CDCl3 as solvent; chemical shifts are expressed
in parts per million related to internal TMS, and coupling
constants (J ) are in Hz. Mass spectra (m/z) were recorded
under electron impact at 70 eV or, where indicated, by
chemical ionization with ammonia (CI). Optical rotations were
recorded at the sodium D line. The circular dichroism spectra
were run on a spectropolarimeter with the UV-vis (170-700
nm) photomultiplier. Flash column chromatography was per-
formed with Merck 9385 silica as the stationary phase.
2-Phenylthiazolidine-4-carboxylate (3) was prepared by a
procedure described earlier, starting from L-cysteine methyl
ester hydrochloride, and was isolated as a mixture of the
(2R,4R) and (2S,4R) diastereoisomers (66:34).11 (Prop-2-yny-
loxy)acetic acid chloride was prepared from the reaction of
(prop-2-ynyloxy)acetic acid with thionyl chloride by a procedure
described in the literature.10
(Bu t-3-yn yloxy)a cetic Acid . This was prepared from
3-butyn-1-ol (10.91 g, 170 mmol) and chloroacetic acid (17.96
g, 190 mmol) by a procedure described in the literature for
the synthesis of (prop-2-ynyloxy)acetic acid:10 1H NMR 2.06
(t, 1H, J ) 2.7), 2.45-2.56 (m, 2H), 3.80 (t, 2H, J ) 6.3), and
4.13 (s, 2H); MS (EI) 129 (MH+, 15%), 83 (19), 79 (100), 61
(48), and 53 (71).
25
found 252.0685; [R]D ) -70.7 (c ) 0.9, CH2Cl2)].
Met h yl (2R,4R)-2-(4-Met h oxyb en zoyl)t h ia zolid in e-4-
ca r boxyla te (17a ) a n d Meth yl (2S,4R)-2-(4-Meth oxyben -
zoyl)th ia zolid in e-4-ca r boxyla te (17b). The thiazolidine was
obtained in 74% yield. The 1H NMR spectrum showed the
presence of two diastereoisomers (ratio 73:27). The major
component is separated by selective crystallization (ethyl
ether). The minor component is purified by flash chromatog-
raphy [petroleum ether-ethyl acetate (1:1) and then ethyl
acetate] giving (in order of elution) the following: methyl
(2R,4R)-2-(4-methoxybenzoyl)thiazolidine-4-carboxylate (17a )
(the major isomer) [mp 157.5-160.3 °C; 1H NMR 2.80 (ap-
proximately t, 1H, J ) 10.4), 3.36 (dd, 1H, J ) 6.0, 10.4), 3.83
(s, 3H), 3.88 (s, 3H), 4.04 (dd, 1H, J ) 6.0, 10.4), 5.75 (s, 1H),
6.97 (d, 2H, J ) 8.8, Ar H), and 7.94 (d, 2H, J ) 8.8, Ar H);
MS (EI) 281 (M+, 1%), 222 (5), 146 (100), 135 (57), and 86 (79);
25
[R]D ) +147.9 (c ) 0.1, CH2Cl2). Anal. Calcd for C13H15
-
NSO4: C, 55.5; H, 5.4; N, 5.0; S, 11.4. Found: C, 55.0; H, 5.4;
N, 5.1; S, 11.4]; methyl (2S,4R)-2-(4-methoxybenzoyl)-thiazo-
lidine-4-carboxylate (17b) (the minor isomer; an oil) [1H NMR
3.06 (dd, 1H, J ) 6.6, 10.6), 3.39 (dd, 1H, J ) 2.2, 10.6), 3.83
(s, 3H), 3.87 (s, 3H), 4.68 (dd, 1H, J ) 2.2, 6.6), 5.93 (s, 1H),
6.95 (d, 2H, J ) 8.8, Ar H), and 7.93 (d, 2H, J ) 8.8, Ar H);
MS (EI) 281 (M+, 1%), 222 (3), 176 (4), 146 (100), 135 (29),
and 86 (48); HRMS calcd for C13H15NO4S 281.0722, found
(P r op -2-en yloxy)a cetic Acid . This was prepared from
prop-2-enyl alcohol (30 mL) and chloroacetic acid (11.7 g, 124
mmol) by a procedure described in the literature.9 This
compound was purified by distillation at 120 °C (0.5 mmHg)
(9.94 g, 68.5%): 1H NMR 4.11-4.15 (m, 4H), 5.24-5.37 (m,
2H), 5.85-5.98 (m, 1H), and 11.27 (s, 1H); MS (CI) 134 [(M +
NH4)+, 100%]. Anal. Calcd for C5H8O3: C, 51.7; H, 6.9.
Found: C, 52.4; H, 7.1.
25
280.9824; [R]D -50.0 (c ) 0.1, CH2Cl2)].
Gen er al P r ocedu r e for th e Syn th esis of Meth yl N-Acyl-
th ia zolid in e-4-ca r boxyla te.
(a ) Acid Ch lor id es 4 a n d 5. Freshly distilled thionyl
chloride (15 mL) was added to (prop-2-enyloxy)acetic acid or

4052 J . Org. Chem., Vol. 67, No. 12, 2002
Pinho e Melo et al.
(but-3-ynyloxy)acetic acid (28.5 mmol). After the solutions were
heated at reflux for 30 min, the solvent was evaporated off.
The residue was dissolved in toluene and the organic solvent
evaporated off giving the corresponding acetylenic acid chlo-
ride, which was used without further purification.
(b) Meth yl N-Acylth ia zolid in e-4-ca r boxyla tes. The thi-
azolidine-4-carboxylate (28.5 mmol) was dissolved in dry
dichloromethane (60 mL). Anhydrous potassium carbonate (6
g, 43.4 mmol) was added followed by a solution of the acid
chloride in dichloromethane (20 mL). The reaction mixture was
stirred under nitrogen at room temperature for 18 h. The
organic solution was washed with water and the solvent
evaporated off. The crude product was purified by flash
chromatography [hexanes-ethyl acetate].
solution of NaHCO3 was added, and the solution was washed
with DCM. The aqueous solution was acidified with concen-
trated HCl and extracted with ethyl acetate. The organic phase
was dried, and the solvent was evaporated giving the N-acyl-
2-phenylthiazolidine-4-carboxylic acid. The following acids
were isolated by this procedure:
(2R,4R)-2-P h en yl-N-(bu t-3-yn yloxya cetyl)th ia zolid in e-
4-ca r boxylic a cid (6): yield 92%, obtained as an oil; 1H NMR
2.38 (m, 1H), 3.27-3.63 (m, 6H), 3.84-4.16 (m, 2H), 4.74 and
5.09 (2 × m, 1H), 6.23 and 6.29 (2 × s, 1H), 7.32-7.47 (m, 3H,
Ar H), and 7.54-7.81 (m, 2H, Ar H); MS (EI) 320 (MH+, 0.7%),
248 (6), 77 (33), and 53 (100); HRMS calcd for C16H18NO4S
(MH+) 320.0957, found 320.0962.
(2R,4R)-2-P h en yl-N-(pr op-2-en yloxyacetyl)th iazolidin e-
4-ca r boxylic a cid (10): yield 46%, obtained as an oil; 1H NMR
3.05-3.57 (m, 2H), 3.75-4.27 (m, 4H), 4.79 (m, 1H), 5.03-
5.26 (m, 2H), 5.69 and 5.87 (2 × m, 1H), 6.18 and 6.35 (2 × s,
1H), 7.30-7.37 (m, 3H, Ar H), and 7.52-7.69 (m, 2H, Ar H);
MS (EI) 307 (M+, 1%), 208 (16), 77 (32), and 41 (100).
(2R,4R)-2-Meth yl-N-(pr op-2-yn yloxyacetyl)th iazolidin e-
4-ca r boxylic a cid (13): yield 59%, obtained as an oil; 1H NMR
1.64 (d, 3H, J 5.7), 2.52 (s, 1H), 3.37-3.47 (m, 2H), 4.19-4.36
(m, 4H), 4.97-5.09 (m, 1H) and 5.32-5.48 (m, 1H); MS (EI)
244 (MH+, 62%), 228 (8), 141 (43), 86 (51), and 69 (100); HRMS
calcd for C10H16NO4S (MH+) 244.0644, found 244.0647.
(2R,4R)-2-(p-Meth oxyben zoyl)-N-(pr op-2-yn yloxyacetyl)-
th ia zolid in e-4-ca r boxylic a cid (19): yield 92%, obtained
as an oil; 1H NMR 2.37-2.56 (m, 1H), 3.44-3.79 (m, 2H), 3.89
and 3.93 (2 × s, 3H), 4.25-4.45 (m, 4H), 4.97-5.36 (m, 1H),
6.48, 6.58, 6.65, and 6.73 (4 × s, 1H, CHCOAr), 6.94-7.03 (m,
2H, Ar H), 7.90-7.95 (m, 1H, Ar H), and 7.98-8.05 (m, 1H,
Ar H); MS (EI) 364 (MH+, 1%), 228 (47), 200 (41), 135 (100),
107 (9), and 69 (41); HRMS calcd for C17H17NO6S (MH+)
364.0855; found 364.0855.
Meth yl (2R,4R)-2-p h en yl-N-(bu t-3-yn yloxya cetyl)th i-
a zolid in e-4-ca r boxyla te (5): yield 68%; 1H NMR 2.35 (m,
1H), 3.20-3.35 (m, 2H), 3.44-3.55 (m, 2H), 3.69-3.82 (m, 2H),
3.85 (s, 3H), 3.93-4.08 (m, 2H), 4.71 and 5.05 (2 × m, 1H),
6.19 and 6.25 (2 × s, 1H), 7.31-7.41 (m, 3H, Ar H) and 7.61-
7.68 (m, 2H, Ar H); MS (EI) 333 (M+, 1%), 274 (28), 222 (32),
77 (27), and 53 (100). Anal. Calcd for C17H19NSO4: C, 61.2; H,
5.7; N, 4.2. Found: C, 59.9; H, 5.6; N, 4.0.
Meth yl (2R,4R)-2-p h en yl-N-(p r op -2-en yloxya cetyl)th i-
a zolid in e-4-ca r boxyla te (9): yield 60%; mp 60.2-62.3 °C;
1H NMR 3.24-3.30 (m, 2H), 3.84 (s, 3H), 3.94-3.99 (m, 4H),
5.04-5.21 (m, 3H), 5.77 (m, 1H), 6.21 (s, 1H), 7.27-7.37 (m,
3H, Ar H), and 7.64-7.66 (m, 2H, Ar H); MS (EI) 321 (M+,
1%), 222 (31), 162 (36), 121 (77), 77 (31), 59 (56) and 41 (100).
Anal. Calcd for C16H19NSO4: C, 59.8; H, 6.0; N, 4.4. Found:
C, 59.7; H, 5.9; N, 4.3.
Meth yl (2R,4R)-2-m eth yl-N-(p r op -2-yn yloxya cetyl)th i-
a zolid in e-4-ca r boxyla te (12): yield 63%, obtained as an oil;
1H NMR 1.61 and 1.66 (d, 3H, J ) 6.3), 2.50 (s, 1H), 3.31-
3.43 (m, 2H), 3.78 and 3.81 (s, 3H), 4.22-4.35 (m, 4H), 4.99-
5.06 (m, 1H), 5.31 and 5.48 (q, 1H, J ) 6.3); MS (EI) 258 (MH+,
43%), 198 (20), 188 (15), 174 (18), 160 (14), and 69 (100). Anal.
Calcd for C11H15NSO4: C, 51.4; H, 5.9; N, 5.4. Found: C, 50.9;
H, 6.0; N, 5.3.
(2S,4R)-2-(p-Meth oxyben zoyl)-N-(pr op-2-yn yloxyacetyl)-
th ia zolid in e-4-ca r b oxylic a cid (22): yield 95%, obtained
as an oil; 1H NMR 2.37-2.55 (m, 1H), 3.16-3.64 (m, 2H), 3.88
and 3.90 (2 × s, 3H), 4.09-4.16 (m, 1H), 4.20-4.31 (m, 3H),
5.31-5.40 (m, 1H), 6.48 and 6.57 (2 × s, 1H, CHCOAr), 6.94-
7.03 (m, 2H, Ar H), and 7.90-7.94 (m, 2H, Ar H); MS (EI) 327
[(M - CH2O2)+, 6%], 228 (28), 200 (32), 135 (100), 86 (30), 77
(40), and 69 (52).
Meth yl (2R,4R)-2-(p-m eth oxyben zoyl)-N-(p r op -2-yn yl-
oxya cetyl)th ia zolid in e-4-ca r boxyla te (18): yield 97%; mp
113.5-114.5 °C (from ethyl acetate-hexane); 1H NMR 2.16-
2.37 (m, 1H), 3.38-3.68 (m, 2H), 3.85-3.90 (m, 6H), 3.94 and
3.96 (m, 1H), 4.22-4.56 (m, 3H), 5.16-5.28 (m, 1H), 6.44 and
6.48 (2 × s, 1H, CHCOAr), 6.93-6.98 (m, 2H, Ar H), and 7.90-
7.95 (m, 2H, Ar H); MS (EI) 378 (MH+, 5%), 242 (86), 214 (85),
184 (32), and 135 (100). Anal. Calcd for C18H19NSO6: C, 57.3;
H, 5.1; N, 3.7; S, 8.5. Found: C, 57.2; H, 5.1; N, 4.0; S, 8.6.
(2R,4R)-2-Ben zoyl-N-(p r op -2-yn yloxya cet yl)t h ia zoli-
d in e-4-ca r boxylic a cid (25): yield 95%; mp 162.8-165.2 °C
(from ethyl ether-hexane); 1H NMR 2.35-2.58 (m, 1H), 3.33-
3.49 (m, 2H), 3.85-3.89 (m, 1H), 4.09-4.34 (m, 3H), 5.32-
5.42 (m, 1H), 6.51 and 6.63 (2 × s, 1H, CHCOMe), 7.43-7.52
(m, 4H, Ar H), and 7.92-7.95 (m, 1H, Ar H); MS (EI) 228 [(M
- COPh)+, 22%], 200 (26), 105 (100), 86 (30), 77 (81), and 69
25
[R]D ) +51.5 (c ) 0.1, CH2Cl2).
Meth yl (2S,4R)-2-(p-m eth oxyben zoyl)-N-(p r op -2-yn yl-
oxya cetyl)th ia zolid in e-4-ca r boxyla te (21): yield 58%, ob-
25
(75); [R]D ) -199.8 (c ) 0.1, CH2Cl2).
1
tained as an oil; H NMR 2.35-2.50 (m, 1H), 3.14-3.61 (m,
Gen er a l P r oced u r e for th e Syn th esis of Ad d u cts 7, 14,
15, 20, 23, 26, a n d 27. The N-acylthiazolidine-4-carboxylic acid
(5 mmol) was dissolved in Ac2O (20 mL), and the solution was
heated at reflux for 6 h. The reaction mixture was cooled to
room temperature and was diluted with CH2Cl2 (50 mL). The
organic phase was washed with a saturated aqueous solution
of NaHCO3 and with water, dried (Na2SO4), and evaporated
off. The crude product was purified by flash chromatography
(hexanes-ethyl acetate).
2H), 3.84 (s, 3H), 3.88 and 3.89 (2 × s, 3H), 3.92-3.94 (m, 1H),
4.05-4.33 (m, 3H), 5.31 (dd, 1H, J ) 6.4, 13.6), 6.45 and 6.58
(2 × s, 1H, CHCOAr), 6.94-6.99 (m, 2H, Ar H), and 7.90-
7.94 (m, 2H, Ar H); MS (EI) 378 (MH+, 3%), 242 (100), 214
(77), 184 (28), 135 (67), and 69 (50); HRMS calcd for C18H20
-
NO6S (MH+) 378.1010, found 378.1011; [R]D ) -107.9 (c )
0.1, CH2Cl2).
25
Met h yl (2R,4R)-2-b en zoyl-N-(p r op -2-yn yloxya cet yl)-
th ia zolid in e-4-ca r boxyla te (24): yield 62%, obtained as an
1
(6R)-6-P h en yl-1,2-d ih yd r o-4H,6H,8H-p yr o[3′,4′:2,3]p yr -
oil; H NMR 2.34-2.51 (m, 1H), 3.14-3.60 (m, 2H), 3.80 and
r olo[1,2-c][1,3]th ia zole (7): yield 18%; mp 100-125 °C (from
3.84 (2 × s, 3H), 3.77-3.89 (m, 1H), 4.01-4.36 (m, 3H), 5.28-
5.36 (m, 1H), 6.47 and 6. 63 (2 × s, 1H, CHCOMe), 7.31-7.64
(m, 4H, Ar H), and 7.92-7.95 (m, 1H, Ar H); MS (EI) 348
1
ethyl ether-hexane); H NMR 2.60-2.62 (m, 2H), 3.68-3.76
(m, 1H), 3.78-3.86 (m, 2H), 4.15 (d, 1H, J ) 12.9), 4.27 (d,
1H, J ) 12.3), 4.31 (d, 1H, J ) 12.9), 5.77 (s, 1H), 6.17 (s, 1H),
7.19-7.35 (m, 5H, Ar H); MS (EI+) 257 (M+, 83%), 136 (94),
121 (100), 105 (94), and 77 (93); HRMS calcd for C15H15NOS
(MH+, 12%), 242 (100), 214 (98), 184 (45), and 105 (45); [R]D
) -166.7 (c ) 0.1, CH2Cl2).
25
Gen er a l P r oced u r e for th e Syn th esis of Th ia zolid in e-
4-ca r boxylic Acid s. The methyl N-acylthiazolidine-4-car-
boxylate (1 mmol) and LiI (4 mmol) were dissolved in ethyl
acetate (1.3 mL). The reaction mixture was protected from
light and heated at reflux for 6 h. Water was added (5 mL),
and the solution was acidified with 1 M HCl and extracted
with ethyl acetate. The organic phase was washed with water
and with a saturated aqueous solution of NaCl. The organic
solvent was evaporated off. To the residue a saturated aqueous
25
257.0874, found 257.0872; [R]D ) +148.1 (c ) 0.1, CH2Cl2).
(7R)-7-Meth yl-1,3-d ih yd r o-5H,7H-fu r o[3′,4′:2,3]p yr r olo-
[1,2-c][1,3]th ia zole (14): yield 26%; mp 54.6-59 °C; 1H NMR
1.66 (d, 3H, J ) 6.0), 4.07 (s, 2H), 4.85-4.89 (m, 4H), 5.37 (q,
1H, J ) 6.0) and 5.67 (s, 1H); MS (EI) 181 (M+, 100%), 122
(54), 93 (50), and 65 (42). Anal. Calcd for C9H11NSO: C, 59.6;
25
H, 6.1; N, 7.7. Found: C, 59.6; H, 6.2; N, 7.7. [R]D ) +75 (c
) 1.0, CH2Cl2).

Chiral Pyrrolo[1,2-c]thiazoles
J . Org. Chem., Vol. 67, No. 12, 2002 4053
(7R )-4-Ac e t y l-7-m e t h y l-1,3-d i h y d r o -5H ,7H -fu r o -
[3′,4′:2,3]p yr r olo[1,2-c][1,3]th ia zole (15): yield 12%; mp
181.8-184.3 °C (from ethyl ether); H NMR 1.68 (d, 3H, J )
(2S,4R)-N-Acetyl-2-m eth ylth iazolidin e-4-car boxylic acid
was prepared from 2-methylthiazolidine-4-carboxylic acid as
described in the literature8a and was obtained as a yellow oil
(90%): 1H NMR 1.58 and 1.63 (2 × d, together 3H, J ) 6.2
and J ) 6.3), 2.10 and 2.25 (2 × s, together 3H), 3.28-3.57
(m, 2H), 4.75-4.98 (m, 1H), 5.16 and 5.39 (2 × q, together
1H, J ) 6.3 and J ) 6.2); MS (EI) (the product was treated
with diazomethane giving the corresponding methyl ester) 203
(M+, 3%), 146 (55), 117 (96), 102 (100), and 86 (31).
1
6.3), 2.26 (s, 3H), 4.30 (d, 1H, J ) 15.3), 4.38 (m, 1H), 4.89-
4.9 (m, 2H), 5.04-5.06 (m, 2H) and 5.41 (q, 1H, J ) 6.3); MS
(EI) 223 (M+, 100%), 208 (60), 136 (19), and 43 (51). Anal. Calcd
for C11H13NSO2: C, 59.2; H, 5.9; N, 6.3. Found: C, 58.8; H,
25
5.9; N, 6.6. [R]D ) +35 (c ) 1.0, CH2Cl2).
(7R)-7-(p -Met h oxyb en zoyl)-1,3-d ih yd r o-5H ,7H -fu r o-
[3′,4′:2,3]p yr r olo[1,2-c][1,3]th ia zole (20) was obtained as a
solid which was washed with ethyl ether (42%): mp 144.5-
145.4 °C; 1H NMR 3.92 (s, 3H), 4.13 (d, 1H, J ) 12.6), 4.22 (d,
1H, J ) 12.6),4.78 (bs, 2H), 4.90-4.95 (m, 2H), 5.82 (s, 1H),
6.28 (s, 1H), 7.01 (d, 2H, J ) 8.9, Ar H), and 7.91 (d, 2H, J )
8.9, Ar H); MS (EI) 301 (M+, 5.4%), 166 (78), 135 (100), 92
Dim eth yl (3R)-3,5-Dim eth yl-1H,3H-p yr r olo[1,2-c]th ia -
zole-6,7-d ica r boxyla te (37a ). (2R,4R)-N-Acetyl-2-methylthi-
azolidine-4-carboxylic acid (0.74 g, 3.9 mmol), DMAD (0.72 mL,
5.9 mmol), and Ac2O (4.5 mL) were heated at 110-120 °C for
3 h. The reaction was cooled to room temperature and was
diluted with CH2Cl2. The organic phase was washed with
saturated aqueous solution of NaHCO3 and with water, dried
(MgSO4), and evaporated off. The crude product was purified
by flash chromatography [hexanes-ethyl acetate (2:1 and 1:1)]
giving compound 37a as a white solid (97%): mp 70.0-72.2
°C (from ethyl ether-hexane); 1H NMR 1.71 (d, 3H, J ) 6.2),
2.39 (s, 3H), 3,79 (s, 3H), 3.84 (s, 3H), 4.18 (d, 1H, J ) 15.0),
4.35 (dd, 1H, J ) 1.7, 15.0), 5.38 (dq, 1H, J ) 1.7, 6.2); MS
(EI) 269 (M+, 42%), 237 (100), 222 (28), 178 (82), and 151 (32).
Anal. Calcd for C12H15NO4S: C, 53.5; H, 5.6; N, 5.2; S, 11.9.
(25), and 77 (31). Anal. Calcd for C16H15NSO3: C, 63.7; H, 5.0;
25
N, 4.7; S, 10.6. Found: C, 63.4; H, 5.0; N, 4.9; S, 11.2. [R]D
+99.9 (c ) 0.1, CH2Cl2).
)
(7S)-7-(p -Me t h oxyb e n zoyl)-1,3-d ih yd r o-5H ,7H -fu r o-
[3′,4′:2,3]p yr r olo[1,2-c][1,3]th ia zole (23) was obtained as a
solid that was washed with ethyl ether (21%): mp 148.2-150.3
1
°C (from ethyl ether); H NMR 3.90 (s, 3H), 4.11 (d, 1H, J )
12.6), 4.20 (d, 1H, J ) 12.6), 4.76 (bs, 2H), 4.88-4.93 (m, 2H),
5.81 (s, 1H), 6.26 (s, 1H), 6.92 (d, 2H, J ) 8.9, Ar H), and 7.89
(d, 2H, J ) 8.9, Ar H); MS (EI) 301 (M+, 8%), 166 (69), 135
25
Found: C, 53.8; H, 5.7; N, 5.5; S, 12.4. [R]D ) +110.0 (c )
1.0, CH2Cl2).
(100), 121 (23) 92 (18), and 77 (22). Anal. Calcd for C16H15
-
Dim eth yl (3S)-3,5-Dim eth yl-1H,3H-p yr r olo[1,2-c]th ia -
zole-6,7-d ica r boxyla te (37b). (2S,4R)-N-Acetyl-2-methylthi-
azolidine-4-carboxylic acid (0.79 g, 4.2 mmol) was dissolved
in toluene (15 mL). DCC (0.86 g, 4.2 mmol) was added followed
by DMAD (0.77 mL, 6.3 mmol). The reaction mixture was
stirred at 100-110 °C for 3 h. The reaction was cooled to room
temperature, and water was added. The organic phase was
separated off, and the aqueous phase was extracted with CH2-
Cl2. The organic phases were joined, dried (MgSO4), and
evaporated off. The product was isolated by flash chromatog-
raphy [hexanes-ethyl acetate (1:1)] giving compound 37b as
a white solid (62%): mp 90.3-92.7 °C (from ethyl ether-
NSO3: C, 63.7; H, 5.0; N, 4.7; S, 10.6. Found: C, 63.5; H, 5.1;
N, 4.8; S, 10.6. [R]D ) -96.2 (c ) 0.1, CH2Cl2).
25
(7R)-7-Ben zoyl-1,3-dih ydr o-5H,7H-fu r o[3′,4′:2,3]pyr r olo-
[1,2-c][1,3]th ia zole (26): yield 17%; mp 167.8-170.3 °C (from
1
ethyl ether); υ (KBr) 1662 and 2856 cm-1; H NMR 4.09 (d,
1H, J ) 12.5), 4.20 (dd, 1H, J ) 1.3, 12.5), 4.76-4.78 (m, 2H),
4.86-4.96 (m, 2H), 5.82 (s, 1H), 6.29 (d, 1H, J 1.3), 7.50-7.54
(m, 2H, Ar H), 7.62-7.67 (m, 1H, Ar H), and 7.89-7.92 (m,
2H, Ar H); MS (EI) 271 (M+, 8%), 166 (100), 122 (30), 105 (35),
94 (28), and 77 (44). Anal. Calcd for C15H13NSO2: C, 66.4; H,
25
4.8; N, 5.2. Found: C, 66.7; H, 4.9; N, 5.2. [R]D ) +200.0 (c
) 0.3, CH2Cl2).
1
hexane); H NMR 1.72 (d, 3H, J ) 6.2), 2.39 (s, 3H), 3,80 (s,
3-Oxo-4-ph en yl-3,4,6,8-tetr a h yd r o-1H-fu r o[3′,4′:2,3]p yr -
r olo[1,2-c][1,4]th ia zin e (27): yield 29%; mp 122.6-124.3 °C
(from ethyl ether); υ (KBr) 1678 and 2873 cm-1; 1H NMR 3.91
(d, 1H, J ) 14.9), 4.17 (dd, 1H, J ) 1.3, 14.9), 4.77-4.83 (m,
2H), 4.93-4.97 (m, 2H), 5.73 (s, 1H), 6.05 (bs, 1H), 7.01-7.08
(m, 2H, Ar H), and 7.37-7.39 (m, 3H, Ar H); MS (EI) 271 (M+,
37%), 211 (100), 182 (30), 121 (23), and 77 (22). Anal. Calcd
for C15H13NSO2: C, 66.4; H, 4.8; N, 5.2. Found: C, 66.7; H,
3H), 3.84 (s, 3H), 4.18 (d, 1H, J ) 15.0), 4.35 (dd, 1H, J ) 1.6,
15.0), 5.38 (dq, 1H, J ) 1.6, 6.2); MS (EI) 269 (M+, 42%), 237
(100), 222 (33), 178 (88), and 151 (29). Anal. Calcd for C12H15
-
NO4S: C, 53.5; H, 5.6; N, 5.2; S, 11.9. Found: C, 53.1; H, 5.6;
25
N, 5.1; S, 11.8. [R]D ) -70.0 (c ) 1.0, CH2Cl2).
Cr ysta l Da ta for Com p ou n d Meth yl (2R,4R)-2-(4-Meth -
oxyben zoyl)th ia zolid in e-4-ca r boxyla te (17a ). X-ray dif-
fraction analysis on compound was carried out on an Enraf-
Nonius CAD-4 diffractometer at room temperature. The
structure of this compound was determined using a transpar-
ent crystal of dimensions 0.34 × 0.20 × 0.12 mm, space group
P21 with unit cell a ) 8.258(3) Å, b ) 9.463(3) Å, c ) 9.063(2)
Å, â ) 108.033(16)°, and V ) 673.5(2) Å3. It contains two
25
5.0; N, 5.3. [R]D ) -0 (c ) 0.3, CH2Cl2).
Syn th esis of Dim eth yl (3R)-3,5-d im eth yl-1H,3H-p yr -
r olo[1,2-c]th ia zole-6,7-d ica r boxyla te (37a ) a n d Dim eth yl
(3S)-3,5-d im eth yl-1H,3H-p yr r olo[1,2-c]th ia zole-6,7-d ica r -
boxyla te (37b).
molecules/unit cell. Dx ) 1.387 g cm-3, and µ ) 0.250 mm-1
.
Th e d ia ster eoisom er ic m ixtu r e (2R,4R)- a n d (2S,4R)-
2-m eth ylth ia zolid in e-4-ca r boxylic a cid was prepared as
described in the literature11 and was obtained as a white solid
(95%): mp 144.0-188.6 °C (from ethyl ether); 1H NMR (minor
isomer) 1.51 (d, 3H, J ) 6.1), 3.16 (dd, 2H, J ) 6.2, 10.5), 4.18
(approximately t, 1H, J ) 6.6), 4.79 (q, 1H, J ) 6.5); 1H NMR
(major isomer) 1.60 (d, 3H, J ) 6.1), 3.36 (dd, 2H, J ) 8.3,
16.5), 3.82 (approximately t, 1H, J ) 8.3), 4.58 (q, 1H, J )
6.1). Anal. Calcd for C5H9NO2S: C, 40.8; H, 6.2; N, 9.5; S, 21.8.
Found: C, 40.9; H, 6.3; N, 9.1; S, 21.7.
(2R,4R)-N-Acetyl-2-m eth ylth iazolidin e-4-car boxylic acid
was prepared from 2-methylthiazolidine-4-carboxylic acid as
described in the literature8a and was obtained as a white solid
(70%): mp 94.5-99.5 °C (from ethyl ether); 1H NMR 1.59 and
1.63 (2 × d, together 3H, J ) 6.2, J ) 6.5), 2.12 and 2.25 (2 ×
s, together 3H), 3.32-3.53 (m, 1H), 3.55-3.79 (m, 1H), 4.78
and 4.96 (dd and approximately t, together 1H, J ) 4.2, 6.9
and J ) 7.8), 5.17 and 5.49 (2 × q, together 1H, J ) 6.5 and
J ) 6.2); MS (EI) (the product was treated with diazomethane
giving the corresponding methyl ester) 203 (M+, 4%), 146 (53),
117 (100), 102 (79), and 86 (26). Anal. Calcd for C7H11NO3S:
C, 44.4; H, 5.9; N, 7.4; S, 16.9. Found: C, 44.0; H, 6.0; N, 7.4;
S, 16.6.
Mo KR radiation was used with λ ) 0.710 73 Å. A total of 2393
reflections were used with I > 2σ(I); Rw ) 0.035.
Cr yst a l Da t a for Com p ou n d Met h yl (2R,4R)-2-(p -
m eth oxyben zoyl)-N-(p r op -2-yn yloxya cetyl)th ia zolid in e-
4-ca r boxyla te (18). X-ray diffraction analysis on compound
18 was carried out on an Enraf-Nonius CAD-4 diffractometer
at room temperature. The structure of this compound was
determined using a prismatic crystal of dimensions 0.49 × 0.49
× 0.10 mm (space group P212121) with unit cell a ) 7.5427-
(10) Å, b ) 9.277(4) Å, c ) 25.805(4) Å, and V ) 1805.7(9) Å3.
It contains four molecules/unit cell. Dx ) 1.388 g cm-3, and µ
) 0.214 mm-1. Mo KR radiation was used (λ ) 0.710 73 Å). A
total of 3010 reflections with I > 2σ(I) were used; R ) 0.033.
Cr ysta l Da ta for 3-Oxo-4-p h en yl-3,4,6,8-tetr a h yd r o-1H-
fu r o[3′,4′:2,3]p yr r olo[1,2-c][1,4]th ia zin e (27). X-ray dif-
fraction analysis on compound 27 was carried out on a Enraf-
Nonius CAD-4 diffractometer at room temperature. The
structure of this compound (C15H13NO2S, Mr ) 271.32 amu)
was determined from a transparent and colorless prismatic
crystal of dimensions 0.15 × 0.25 × 0.41 mm (space group P1h)
with unit cell a ) 8.747(6) Å, b ) 8.903(5) Å, c ) 9.047(3) Å,
R ) 73.27(4)°, â ) 89.55(4)°, γ ) 73.64(5)°, and V ) 645.3(6)

4054 J . Org. Chem., Vol. 67, No. 12, 2002
Pinho e Melo et al.
Å3. It has two molecules/unit cell. Dx ) 1.396 g cm-3, and µ )
0.247 mm-1. Mo KR radiation was used (λ ) 0.710 73 Å). A
total of 2387 unique reflections were collected, with 1978
having I > 2σ(Ι). R (I > 2σ(Ι)) ) 0.0336, and Rw ) 0.0952.
Cir cu la r Dich r oism . The solutions were prepared using
ethanol (Riedel-deHae¨n Spectranal grade). Spectra were run
in either 1 or 0.1 cm quartz cells in concentrations of ca. 10-4
M (1 cm cell) or ca. 10-3 M (0.1 cm cell). Normally at least two
accumulations were made when recording each CD spectrum.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
tables and ORTEP diagrams for compounds 17a , 18, and 27,
CD spectra for the enantiomeric pair 20/23, chemical shifts
and coupling constants for the thiazolidine ring protons of
16a ,b and 17a ,b, CD and UV absorption data for some chiral
C-3 substituted pyrrolo[1,2-c]thiazoles, torsion angles obtained
from structures calculated with the HyperChem program
(Polak-Ribiere optimization), and CD bands for the 3R
enantiomers of pyrrolo[1,2-c]thiazoles. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. The authors wish to thank Chy-
miotechnon and the Fundac¸a˜o para a Cieˆncia e Tecno-
logia (POCTI/36137/QUI/2000) for financial support.
J O010807P