Cycloadditions to pyrrolo[1,2-c]thiazoles and pyrazolo[1,5-c]thiazoles

Article abstract of DOI:10.1016/S0040-4020(00)00956-X

The pyrrolo[1,2-c]thiazole generated by dehydration of dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 2-oxide acts as a thiocarbonyl ylide in its cycloaddition to electron deficient alkenes but as an azomethine ylide with electron deficient alkynes. The analogous pyrazolo[ 1,5-c]thiazole, generated similarly, acts as a thiocarbonyl ylide with both types of dipolarophile. This behaviour is partially explained by Frontier MO theory. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00956-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 10011±10021
Cycloadditions to Pyrrolo[1,2-c]thiazoles and
Pyrazolo[1,5-c]thiazoles
a
b
Oliver B. Sutcliffe,a Richard C. Storr,a, Thomas L. Gilchrist and Paul Rafferty
*
aDepartment of Chemistry, University of Liverpool, P.O. Box 147, Liverpool L69 7BX, UK
bDepartment of Medicinal Chemistry, Knoll Limited, Nottingham, NG1 1GF, UK
Received 9 August 2000; revised 18 September 2000; accepted 5 October 2000
AbstractÐThe pyrrolo[1,2-c]thiazole generated by dehydration of dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate
2-oxide acts as a thiocarbonyl ylide in its cycloaddition to electron de®cient alkenes but as an azomethine ylide with electron de®cient
alkynes. The analogous pyrazolo[1,5-c]thiazole, generated similarly, acts as a thiocarbonyl ylide with both types of dipolarophile. This
behaviour is partially explained by Frontier MO theory. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Several `non-classical' 10p-electron heterocyclic-fused-
[c]thiophenes have been prepared and have been shown to
behave as simple thiocarbonyl ylides in [4p12p] cyclo-
additions to dipolarophiles.1 The presence of bridgehead
nitrogen atoms, as for example in pyrrolo[1,2-c]thiazole 1,
increases the number of resonance forms and raises the
possibility of reaction with dipolarophiles across either
the thiocarbonyl ylide or azomethine ylide portion of the
system.2
Results and Discussion
Several examples of these `non-classical' systems are
known and their participation in [4p12p] cycloadditions
is of interest in the construction of a variety of fused hetero-
We chose to follow Kane's method2 for the generation of 1
and to extend this to produce 2 via Pummerer dehydration of
the corresponding sulfoxides which can be prepared easily
cycles.3 Kane has reported the in situ generation of
compound 1 and its reaction with a limited number of
alkenic and acetylenic dipolarophiles.2 Here we report our
from the parent thiazolidines.
investigations of the range of dipolarophiles which partici-
Thiazolidine 4 was prepared from thiazolidine-4-carboxylic
pate in cycloadditions with 1 and evidence to support the
acid 3 by heating with acetic anhydride in the presence of
transient existence of the previously unreported pyrazolo-
[1,5-c]thiazole 2. Our studies of the pyrrolo- and pyrazolo-
dimethyl acetylenedicarboxylate2 (Scheme 1). Oxidation of
4 with either mCPBA (1.2 equiv.) or sodium periodate
thiazoles 1 and 2 were also prompted by the fact that they
can be considered as `masked' aza- and diazafulvenium
(1.2 equiv.) gave the corresponding sulfoxide 5 in 84 and
95% yields, respectively. TLC analysis [ethyl acetate±
methides which we have recently reported.4a
hexane (1:1)] of the reaction mixtures indicated the
presence of small amounts of the sulfone4 which could be
removed by careful recrystallisation. However, this puri®-
cation was time consuming and led to a reduction in overall
yield and so a cleaner and more selective method of
oxidation was sought.
N-Chlorobenzotriazole5 is inexpensive, readily prepared
Keywords: dipolar cycloaddition; thiocarbonyl ylide; azomethine ylide;
and easily handled and has been employed in the quick
pyrrolo[1,2-c]thiazole; pyrazolo[1,5-c]thiazole; frontier MO theory.
and ef®cient oxidation of sul®des to sulfoxides, without
* Corresponding author. Tel.: 144-151-794-3479; fax: 144-151-794-
3479; e-mail: rcstorr@liv.ac.uk
concomitant formation of sulfones.6 Treatment of sul®de 4
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00956-X

10012
O. B. Sutcliffe et al. / Tetrahedron 56 (2000) 10011±10021
Scheme 1. Reagents and conditions: (i) Ac2O/DMAD/heat; (ii) mCPBA (84%); (iii) NaIO4 (95%); (iv) N-chlorobenzotriazole (98%).
with N-chlorobenzotriazole (1 equiv.) in methanol for 1 h
gave the desired sulfoxide 5 in 98% yield; this was identical
to the sulfoxide 5 reported by Kane.2
went a smooth cycloaddition to give a mixture of 1:1
adducts which after puri®cation were determined to be the
major exo-adduct 6a (72% yield) and the minor endo-adduct
6b (only a trace amount by TLC) (Scheme 2). The 1H NMR
spectrum of the major cycloadduct showed doublet signals
at d 3.48 and d 3.52 corresponding to the imide a-H and
singlets at d 5.50 and d 6.04 corresponding to the sulfur
bridge-H. This is consistent with the data previously
obtained for the exo-cycloadduct by Kane.2 These adducts
are formed by addition of the dipolarophile across the thio-
carbonyl ylide portion of the `non-classical' thiazole 1.
Similar [4p12p] addition across the thiocarbonyl portion
of the betaine 1 by two other substituted maleimides gave
the corresponding cycloadducts 7a±b and 8a±b.
Kane showed that Pummerer-type dehydration of 5 in
boiling acetic anhydride over 3 h led to the transient `non-
classical' pyrrolo[1,2-c]thiazole 1 which could be inter-
cepted with N-phenylmaleimide to give a mixture of 1:1
cycloadducts in 66% yield.2 Chromatographic puri®cation
and subsequent characterisation showed that these adducts
were exo- and endo-adducts 6a and 6b obtained in an exo/
endo ratio of 8.4:1. The exo/endo assignments of major
1
adduct 6a and minor adduct 6b were based on the H
NMR spectra of these products according to the established
procedure of Cava and Potts7 which involved attributing a
larger deshielding effect of the sulfur bridge on the imide
a-protons of the endo-adduct 6b. endo/exo Assignment can
also be inferred from the splitting patterns observed in the
1H NMR spectra. On the basis of models, the dihedral angle
between the a-imide and sulfur bridge hydrogens is less
than 908 in the endo-adduct, and these hydrogens are
coupled giving a double doublet for the a-imide hydrogens
and a doublet for the hydrogens on the sulfur bridge. In the
exo-adduct the dihedral angle between these protons is close
to 908 and as a result only the a-imide hydrogens are
coupled together, giving a doublet for the a-imide hydro-
gens and a singlet for the sulfur bridged hydrogens.
Dehydration of 5 in the presence of dimethyl fumarate
(1.2 equiv.) gave a mixture of products 9 (55%) (Scheme
3). These cycloadducts could not be separated and the
1
complexity of the H NMR spectrum made stereochemical
assignment of this mixture impossible. However, we have
observed that the cycloadducts 6a/6b lose hydrogen sul®de
on treatment with two equivalents of sodium meth-
oxide3a,7b,8 to give the corresponding indolizine 10, the
structure of which was con®rmed by signals at d 2.66 (s,
3H, 6-CH3), 3.97 (s, 3H, ester CH3), 3.98 (s, 3H, ester CH3),
7.51 (s, 5H, N±Ph), 8.51 (s, 1H, Ar-H) and 8.72 ppm (s, 1H,
1
Ar-H) in the H NMR spectrum.
Our own results with pyrrolo[1,2-c]thiazole fully support
and extend those of Kane.2 Thus in our hands pyrrolo-
[1,2-c]thiazole 1, generated from 5 over 4 h in hot acetic
anhydride in the presence of N-phenylmaleimide, under-
Similarly, this mixture of cycloadducts 9 underwent
elimination of hydrogen sul®de on reaction with sodium
methoxide (2 equiv.) to afford indolizine 11, the structure
of which was established by signals at d 2.59 (s, 3H, 5-CH3),
Scheme 2. Reagents and conditions: (i) Ac2O/heat; (ii) N-phenylmaleimide.

O. B. Sutcliffe et al. / Tetrahedron 56 (2000) 10011±10021
10013
Scheme 3. Reagents and conditions: (i) Ac2O/heat; (ii) dimethyl fumarate (55%) or dimethyl maleate (61%); (iii) NaOMe/CH2Cl2 (85 and 79%, respectively).
3.92 (s, 3H, ester CH3), 3.93 (s, 3H, ester CH3), 3.95 (s, 3H,
ester CH3), 3.96 (s, 3H, ester CH3), 8.30 (s, 1H, Ar-H) and
8.47 ppm (s, 1H, Ar-H) in the 1H NMR spectrum. A similar
inseparable mixture of cycloadducts (61%) (which was
cleanly desulfurised to give indolizine 11) was obtained
from reaction of 1 and dimethyl maleate. Surprisingly
other ole®nic dipolarophiles such as maleic anhydride, tetra-
cyanoethylene, norbornadiene and tropone all failed to give
adducts with `non-classical' system 1.
In our hands, sulfoxide 5 was dehydrated in boiling acetic
anhydride in the presence of DMAD (1.2 equiv.) over 4 h to
give a complex mixture. Crystallisation from methanol gave
thiazolo[2,3,4-cd]pyrrolizine 14 as a yellowish powder in an
improved yield of 65%. Structural assignment of 14 was
based on signals at d 1.69 (s, 3H, D3-pyrroline-CH3), 3.78
(s, 12H, ester CH3), 4.99 (s, 1H, 6a-H) and 5.75 ppm (s, 1H,
2-H) which correspond with the data obtained by Kane and
are different from the spectrum obtained for indolizine 11
prepared from aromatisation of the cycloadduct of dimethyl
fumarate and 1. We hoped to extend this reaction to prepare
a number of these interesting heterocyclic compounds.
However, although an analogous reaction occurred with
diethyl acetylenedicarboxylate (1.2 equiv.) to give (13,
RˆCO2Et) (41%), dibenzoyl acetylene and diphenylacetyl-
ene failed to react.
Dehydration of 5 in the presence of activated acetylenes
might have been expected to give indolizines 11 via addition
across the thiocarbonyl ylide portion of the `non-classical'
thiazole 1 and subsequent desulfurisation of the initial
adducts 12. However, Kane2 reported that the reaction of
5 and DMAD in boiling acetic anhydride over 3 h led to a
complex mixture, from which he isolated a colourless solid
in low yield (15%). MS and elemental analysis showed
that the product was a 1:1 adduct of the `non-classical'
thiazole and the acetylene. The structure of the adduct
was established as 14 by the observation of the C-methyl
group at 1.67 ppm, diagnostic of the D3-pyrroline
structure. The corresponding C-methyl in the indolizine
structure is to be expected at ca. 2.6 ppm. Thiazolo[2,3,4-
cd]pyrrolizine 14 results from cycloaddition across the
azomethine ylide portion of the `non-classical' system 1
(Scheme 4).
Although oxidation of 4 with N-chlorobenzotriazole in
methanol for 1 h gave the sulfoxide 5 in high yield, an
interesting reaction was observed when the reaction mixture
was left for a prolonged period (ca. 24 h) before work-up
with aqueous base (Scheme 5). The isolated crystalline
material was not the sulfoxide 5, but the unexpected 1-meth-
1
oxysul®de 16. H NMR spectral analysis con®rmed the
structure of 16 with signals at d 2.38 (s, 3H, 5-CH3), 3.37
(s, 3H, 1-OCH3), 3.82 (s, 6H, ester CH3), 4.83 (d, 1H,
Jˆ10 Hz, 3-H), 5.06 (d, Jˆ10 Hz, 3-H) and 6.23 (s, 1H,
Scheme 4. Reagents and conditions: (i) Ac2O/heat; (ii) DMAD.

10014
O. B. Sutcliffe et al. / Tetrahedron 56 (2000) 10011±10021
Scheme 5. Reagents and conditions: (i) N-chlorobenzotriazole; (ii) benzene/heat; (iii) DMAD.
1-H). Presumably, 16 is formed from the S-chlorosul®de 15
by elimination of HCl and attack by methanol. We antici-
pated that we could generate our desired `non-classical'
thiazole by thermal elimination of methanol from meth-
oxide 16. Indeed when sul®de 16 was heated in benzene
in the presence of DMAD for 2 h, removal of the solvent
in vacuo and puri®cation of the residue afforded the
expected thiazolo[2,3,4-cd]pyrrolizine 14 in 28% yield.
Therefore sul®de 16 offers a novel and milder route to the
`non-classical' thiazole system 1 and may allow more
thermally sensitive dipolarophiles to be trapped in situ.
tographic puri®cation and subsequent characterisation
showed that this adduct was the exo-adduct. This exo assign-
ment was based on comparison with the endo/exo adducts
obtained from cycloaddition of 1 to N-methylmaleimide.
The imide a-protons of adduct 22a were observed to be
simple doublets at d 3.53 and 3.69 ppm, consistent with
the proposed exo-structure.
This adduct arises by addition of the dipolarophile across
the thiocarbonyl portion of 2 in a similar fashion to
pyrrolo[1,2-c]thiazole 1. Similar [4p12p] cycloadditions
were also observed with N-methyl- and N-ethylmaleimide
and with maleic anhydride to give the corresponding exo-
adducts 22b±d (Scheme 7). Dehydration of 21 in the
presence of either dimethyl fumarate or dimethyl maleate
gave a mixture of stereoisomeric products 23 which once
again proved impossible to separate. However, elimination
of hydrogen sul®de from these adducts with sodium
methoxide afforded the expected pyrazolo[1,5-a]pyridine
24 (Scheme 8).
We next turned our attention to the previously unreported
`non-classical' pyrazolo[1,5-a]thiazole 2.
Commercially available thiazolidine-4-carboxylic acid 3
was nitrosated under standard conditions to give N-nitroso-
thiazolidine-4-carboxylic acid 17 (Scheme 6). Treatment of
17 with TFAA in anhydrous ether9 furnished the previously
unreported sydnone 18 in moderate yield. Sydnone 18 is
stable and has a long shelf-life. In agreement with its
expected mesoionic reactivity, 18 underwent a [4p12p]
cycloaddition to DMAD followed by spontaneous extrusion
of carbon dioxide from the initial adduct 19 to give the fused
thiazole 20 in high yield. Finally oxidation of 20 with
sodium periodate under standard conditions afforded the
desired sulfoxide 21 in almost quantitative yield.
Dehydration of 21 in the presence of activated acetylenes,
such as DMAD, was expected to give the tricyclic system 25
(RˆCO2Me) via [4p12p] addition across the azomethine
imine portion of 2 in a similar fashion to that observed by
Kane for 1.2 In the event, the reaction of 21 and DMAD in
boiling acetic anhydride over 4 h led to a complex mixture,
from which a colourless solid was isolated in moderate yield
(Scheme 9). Spectroscopic and elemental analysis of this
adduct established the structure as the pyrazolo[1,5-a]pyri-
dine 24 obtained from cycloaddition across the thiocarbonyl
Pummerer-type dehydration of sulfoxide 21 in boiling
acetic anhydride in the presence of N-phenylmaleimide
gave exclusively adduct 22a after 3 h (Scheme 7). Chroma-
Scheme 6. Reagents and conditions: (i) NaNO2/HCl; (ii) TFAA/Et2O; (iii) xylene/DMAD/heat; (iv) NaIO4.

O. B. Sutcliffe et al. / Tetrahedron 56 (2000) 10011±10021
10015
Scheme 7. Reagents and conditions: (i) Ac2O/heat; (ii) N-phenylmaleimide; (iii) N-methylmaleimide; (iv) N-ethylmaleimide; (v) maleic anhydride.
Scheme 8. Reagents and conditions: (i) Ac2O/heat; (ii) dimethyl fumarate (60%) or dimethyl maleate (adduct not isolated); (iii) NaOMe/CH2Cl2 (76% from
dimethyl fumarate adduct; in the case of dimethyl maleate overall yield of 24 from 22 is 43%).
ylide portion of 2 and subsequent loss of sulfur from the
initial adduct 26 (RˆCO2Me). Similar pyrazolo[1,5-a]pyri-
dines, 27a and 27b, respectively, were also observed in the
cycloadditions of diethyl acetylenedicarboxylate and
dibenzoylacetylene; however, no cycloadduct was observed
in the case of the less reactive diphenylacetylene.
covalent term of the general perturbation equation (Eq.
(1)). The value of Db depends on the nature of the bonds
being formed and is greater for C±C than C±N bonds (i.e.
C±N bonds are weaker than C±C bonds). In the case of 1,
addition via both modes leads to two new carbon±carbon
bonds and the preferred mode is therefore ®nely balanced.
In the case of 2, addition across the thiocarbonyl ylide leads
Using the semi-empirical molecular modeling package
(MOPAC/PM3)10 we calculated the energies of the
HOMO and LUMO in molecules 1 and 2 (Fig. 1). The
relative energies of these orbitals indicate that additions to
activated acetylenes and alkenes should be dipole-HOMO
controlled in both cases.
ꢀ1†
Examination of the amplitudes of the coef®cients in the
HOMO appears to suggest that a mixture of products via
addition across both the thiocarbonyl ylide and the
azomethine ylide or imine portion of 1 and 2, respectively
would result. However, this does not take into account the
contribution of Db (bˆthe resonance integral) to the
Figure 1. MO coef®cients of `non-classical' thiazoles 1 and 2.
Scheme 9. Reagents and conditions: (i) Ac2O/heat; (ii) DMAD; (iii) diethyl acetylenedicarboxylate; (iv) dibenzoyl acetylene.

10016
O. B. Sutcliffe et al. / Tetrahedron 56 (2000) 10011±10021
to two new carbon±carbon bonds, whilst addition across the
azomethine imine portion leads to the formation of a
carbon±carbon and a carbon±nitrogen bond. Hence, the
exclusive formation of the pyrazolo[1,5-a]pyridine adducts
with 2 and the formation of both types of adduct in the case
of 1 is not unexpected. However, why electron de®cient
acetylenes and electron de®cient alkenes add by different
modes to 1 remains unexplained.
Jˆ12 Hz, 3-CH2) and 4.99 (d, 1H, Jˆ12 Hz, 3-CH2); dC
(CDCl3) 11.5 (CH3), 51.5 (CH3 ester), 51.6 (CH3 ester),
53.4 (CH2), 67.8 (CH2), 110.6, 117.2, 131.8, 134.9, 163.5
(CvO ester) and 164.8 (CvO ester); m/z M1 271 (33%),
and 223 (100). Accurate mass: 271.0514, C11H13NO5S
requires 271.0515.
Method B (Oxidation with sodium periodate). Sulfoxide 5
was prepared by adapting the method published by
Nakayama.11 Sodium periodate (12.32 g, 1.2 equiv.,
58 mmol) and dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]-
thiazole-6,7-dicarboxylate 4 (12.28 g, 48 mmol) gave
dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicar-
boxylate 2-oxide (12.40 g, 95%) as colourless ¯akes which
had identical physical and spectroscopic properties to those
of the sulfoxide prepared by method A.
Experimental
1H NMR spectra were recorded on either a Bruker ACE 200
(200 MHz) instrument or a Varian Gemini 300 (300 MHz)
instrument. 13C and 13C DEPT spectra were recorded on the
Varian Gemini 300 (300 MHz) instrument. All spectra were
recorded using tetramethylsilane (TMS) as the internal
reference. Infra-red spectra were recorded in the range of
4000±600 cm21 using a Perkin±Elmer 298 instrument.
Mass spectra were recorded on a VG Analytical 7070E or
a Trio 1000 Quadrapole GC mass spectrometer. Micro-
analyses were performed in the University of Liverpool
Department of Chemistry microanalytical laboratory using
a Carlo Erba elemental analyzer and melting points were
determined using a Gallenkamp melting point apparatus and
are uncorrected. All reagents were of commercial quality
and solvents were dried, where necessary, using standard
procedures.
Method C (Oxidation with N±chlorobenzotriazole). N-
Chlorobenzotriazole (7.37 g, 48 mmol) dissolved in metha-
nol (100 mL) (DO NOT WARM TO EFFECT SOLUTION)
was slowly added to a solution of dimethyl 5-methyl-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 4 (12.28 g,
48 mmol) in methanol (1500 mL) at 2788C. After stirring
for 1 h the almost clear reaction mixture was allowed to
warm to room temperature and 4% (w/v) sodium hydroxide
solution (1000 mL) added. After stirring for ten minutes the
reaction mixture was extracted with dichloromethane
(3£1000 mL), washed with water (500 mL), brine (500
mL) and the combined organic fractions dried over
anhydrous magnesium sulfate. Concentration in vacuo
gave a yellowish oil which crystallised on standing. Recrys-
tallisation of the crude residue from methanol gave dimethyl
5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate
2-oxide (12.79 g, 98%) as colourless ¯akes which had iden-
tical physical and spectroscopic properties to those of the
sulfoxide prepared by method A.
Dimethyl
5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-
dicarboxylate (4). Sul®de 4 was prepared according to
the method published by Kane.2 Thiazolidine-4-carboxylic
acid (5.3 g, 40 mmol) and DMAD (7.4 mL, 1.5 equiv.,
60 mmol) gave dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]-
thiazole-6,7-dicarboxylate as cream coloured needles, mp
1338C, lit.2 131±1328C. (Found: C, 51.8; H, 5.1; N, 5.5.
C11H13NSO4 requires C, 51.8; H, 5.1 and N, 5.5%); nmax
(Nujolw) 2926, 2855, 1718, 1703, 1536, 1449, 1419, 1389,
1376, 1301, 1258, 1208, 1165, 1093, 1050, 972, 886, 800,
781, 768, 741, 724 and 665 cm21; dH (CDCl3) 2.37 (s, 3H,
5-CH3), 3.80 (s, 3H, ester CH3), 3.84 (s, 3H, ester CH3), 4.27
(s, 2H, 1,1-H) and 4.92 (s, 2H, 3,3-H); dC (CDCl3) 11.5
(CH3), 30.2 (CH2), 47.4 (CH2), 51.3 (CH3), 51.5 (CH3),
107.1, 116.6, 130.5, 139.7, 164.0 (CvO) and 165.3
(CvO). m/z M1 255 (24%), 223 (100) 178 (41), 165 (37)
and 137 (42). Accurate mass: 255.0565, C11H13NO4S
requires 255.0565.
Dimethyl
1-methoxy-5-methyl-1H,3H-pyrrolo[1,2-c]-
thiazole-6,7-dicarboxylate (16). N-Chlorobenzotriazole
(1.84 g, 12 mmol) dissolved in methanol (25 mL) (DO
NOT WARM TO EFFECT SOLUTION) was slowly
added to a solution of dimethyl 5-methyl-1H,3H-pyrrolo-
[1,2-c]thiazole-6,7-dicarboxylate (3.07 g, 12 mmol) in
methanol (400 mL) at 2788C. After stirring for 24 h the
almost clear reaction mixture was allowed to warm to
room temperature and 4% (w/v) sodium hydroxide solution
(250 mL) added. After stirring for 10 min the reaction
mixture was extracted with dichloromethane (3£250 mL),
washed with water (150 mL), brine (150 mL) and the
combined organic fractions dried over anhydrous mag-
nesium sulfate. Concentration in vacuo gave a yellowish
oil which crystallised on standing. Recrystallisation of the
crude residue from methanol gave dimethyl 1-methoxy-
5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate
(3.01 g, 88%) as light brown ¯akes, mp 126±1288C.
(Found: C, 50.3; H, 5.3; N, 4.8. C12H15NSO5 requires C,
50.5; H, 5.3 and N, 4.9%); nmax (Nujolw) 2924, 1712,
1539, 1454, 1385, 1298, 1255, 1216, 1168, 1100, 1078,
942, 890, 799, 772 and 728 cm21; dH (CDCl3) 2.38 (s,
3H, 5-CH3), 3.37 (s, 3H, 1-OCH3), 3.82 (s, 6H, 2£ester
CH3), 4.83 (d, 1H, Jˆ10 Hz, 3-H), 5.06 (d, 1H, Jˆ10 Hz,
3-H) and 6.27 (s, 1H, 1-H); dC (CDCl3) 11.2 (CH3), 46.5
(CH2), 51.5 (CH3 ester), 51.5 (CH3 ester), 55.6 (CH3 ether),
Dimethyl
5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-
dicarboxylate 2-oxide (5). Method A (Oxidation with 3-
chloroperoxybenzoic acid). Sulfoxide 5 was prepared
according to the method published by Kane.2 3-Chloro-
peroxybenzoic acid (90%) (4.8 g, 24 mmol) and dimethyl
5-methyl-3-thienyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicar-
boxylate 4 (5.5 g, 22 mmol) gave dimethyl 5-methyl-1H,3H-
pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 2-oxide (4.9 g,
84%) as colourless ¯akes, mp 134±1368C, lit.2 135±
1378C. (Found: C, 48.8; H, 4.8; N, 5.1. C11H13NSO5 requires
C, 48.7; H, 4.8 and N, 5.2%); nmax (Nujolw) 2926, 2856,
1712, 1536, 1455, 1376, 1295, 1208, 1164, 1092, 1056 and
779 cm21; dH (CDCl3) 2.35 (s, 3H, 5-CH3), 3.79 (s, 3H,
ester CH3), 3.83 (s, 3H, ester CH3), 4.24 (d, 1H, Jˆ18 Hz,
1-CH2), 4.39 (d, 1H, Jˆ18 Hz, 1-CH2), 4.78 (d, 1H,

O. B. Sutcliffe et al. / Tetrahedron 56 (2000) 10011±10021
10017
84.8 (CH), 108.9, 117.0, 131.2, 138.0, 163.6 (CvO ester)
and 165.1 (CvO ester); m/z M1 285 (16%), 254 (100) and
222 (28).
7.7%); nmax (Nujolw) 2925, 1726, 1698, 1462, 1377, 1306,
1206, 1154 and 109 cm21; dH (CDCl3) 2.34 (s, 3H, 5-CH3),
2.54 (s, 3H, N±CH3), 3.83 (s, 3H, ester CH3), 3.86 (s, 3H,
ester CH3), 4.00 (dd, 1H, Jˆ4, 7 Hz, imide a-H), 4.02 (dd,
1H, Jˆ4, 7 Hz, imide a-H), 5.44 (d, 1H, Jˆ4 Hz, sulfur
bridge-H), and 6.02 (d, 1H, Jˆ4 Hz, sulfur bridge-H); dC
(CDCl3) 10.9 (CH3), 24.5 (CH3), 50.8 (CH), 51.9 (CH3
ester), 52.1 (CH3 ester), 53.4 (CH), 55.9 (CH), 67.4 (CH),
107.8, 114.3, 132.2, 138.1, 162.8 (CvO ester), 164.9 (CvO
ester), 172.0 (CvO amide) and 174.0 (CvO amide); m/z
M1 364 (34%), 332 (18), 253 (100), 221 (37), 163 (31), 135
(20).
General procedure for generation and trapping of `non-
classical' thiazole (1)
Dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicar-
boxylate 2-oxide 5 (0.27 g, 1.0 mmol) and the appropriate
dipolarophile (1.2 mmol) in acetic anhydride (5 mL) were
heated to re¯ux for 4 h. The reaction mixture was cooled to
room temperature and the solvent removed in vacuo. The
resulting residue was triturated with methanol to give the
cycloadduct which was further puri®ed by ¯ash chroma-
tography and/or recrystallisation from the appropriate
solvent.
Dimethyl 1,3-dioxo-4,9-epithio-2,3,3a,4,9,9a-hexahydro-
2-ethyl-6-methyl-1H-pyrrolo[3,4-f]indolizine-7,8-dicar-
boxylate (8a, exo) and (8b, endo). Dimethyl 5-methyl-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 2-oxide 5
(0.27 g, 1.0 mmol) and N-ethylmaleimide (0.15 g, 1.2
equiv., 1.2 mmol) gave after chromatography [ethyl acetate±
hexane (1:1)] and crystallisation from chloroform±ethanol
(exo-adduct) dimethyl 1,3-dioxo-4,9-epithio-2,3,3a,4,9,9a-
hexahydro-2-ethyl-6-methyl-1H-pyrrolo[3,4-f]indolizine-
7,8-dicarboxylate (0.17 g, 46%) as a colourless powder, mp
212±2138C. (Found: C, 54.0; H, 4.8; N, 7.4. C17H18N2SO6
requires C, 54.0; H, 4.8 and N, 7.4%); nmax (Nujolw) 2926,
1777, 1699, 1533, 1456, 1378, 1348, 1302, 1205, 1153,
1093, 911 and 783 cm21; dH (CDCl3) 1.18 (t, 3H, Jˆ7 Hz,
CH3CH2-N), 2.44 (s, 3H, 5-CH3), 3.29 (d, 1H, Jˆ7 Hz,
imide a-H), 3.32 (d, 1H, Jˆ7 Hz, imide a-H), 3.59 (q,
2H, Jˆ7 Hz, CH3CH2-N), 3.82 (s, 3H, ester CH3), 3.85 (s,
3H, ester CH3), 5.39 (s, 1H, sulfur bridge-H), and 5.93 (s,
1H, sulfur bridge-H); dC (CDCl3) 11.3 (CH3), 12.5 (CH3),
34.5 (CH2), 50.6 (CH), 51.6 (CH3 ester), 51.8 (CH3 ester),
52.0 (CH), 53.3 (CH), 67.1 (CH), 107.8, 114.3, 131.4, 140.4,
163.1 (CvO ester), 164.9 (CvO ester), 173.1 (CvO
amide) and 173.8 (CvO amide); m/z M1 378 (23%), 346
(15), 253 (100), 221 (35), 163 (21), 135 (19), and (endo-
adduct) dimethyl 1,3-dioxo-4,9-epithio-2,3,3a,4,9,9a-hexa-
hydro-2-ethyl-6-methyl-1H-pyrrolo[3,4-f]indolizine-7,8-
dicarboxylate (0.02 g, 6%) as a colourless powder, mp dec.
234±2358C. (Found: C, 53.9; H, 4.7; N, 7.4. C17H18N2SO6
requires C, 54.0; H, 4.8 and N, 7.4%); nmax (Nujolw) 2926,
1778, 1699, 1532, 1456, 1378, 1347, 1302, 1205, 1153,
1093, 910 and 783 cm21; dH (CDCl3) 0.77 (t, 3H, Jˆ7 Hz,
CH3CH2-N), 2.35 (s, 3H, 5-CH3), 3.16 (q, 2H, Jˆ7 Hz,
CH3CH2-N), 3.82 (s, 3H, ester CH3), 3.85 (s, 3H, ester
CH3), 4.01 (dd, 1H, Jˆ4, 7 Hz, imide a-H), 4.06 (d, 1H,
Jˆ4, 7 Hz, imide a-H), 5.44 (d, 1H, Jˆ4 Hz, sulfur bridge-
H), and 6.02 (d, 1H, Jˆ4 Hz, sulfur bridge-H); dC (CDCl3)
10.8 (CH3), 12.0 (CH3), 34.0 (CH2), 50.5 (CH), 51.6 (CH3
ester), 51.7 (CH3 ester), 52.0 (CH), 53.3 (CH), 56.1 (CH),
108.7, 114.4, 132.1, 138.1, 162.9 (CvO ester), 164.7 (CvO
ester), 172.0 (CvO amide) and 173.8 (CvO amide); m/z
M1 378 (33%), 346 (9), 253 (100), 221 (27), 163 (17), 135
(11).
Dimethyl 1,3-dioxo-4,9-epithio-2,3,3a,4,9,9a-hexahydro-
6-methyl-2-phenyl-1H-pyrrolo[3,4-f]indolizine-7,8-dicar-
boxylate (6a). Dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]-
thiazole-6,7-dicarboxylate 2-oxide 5 (0.27 g, 1.0 mmol)
and N-phenylmaleimide gave after recrystallisation from
methanol (exo-adduct) dimethyl 1,3-dioxo-4,9-epithio-
2,3,3a,4,9,9a-hexahydro-6-methyl-2-phenyl-1H-pyrrolo-
[3,4-f]indolizine-7,8-dicarboxylate as a colourless powder,
mp 210±2128C, lit.2 210±2118C. (Found: C, 59.1; H, 4.4; N,
6.5. C21H18N2SO6 requires C, 59.2; H, 4.3 and N, 6.6%);
nmax (Nujolw) 2930, 1714, 1699, 1654, 1595, 1462, 1378,
1308, 1193, 1146, 1093, 919, 843, 785 and 737 cm21; dH
(CDCl3) 2.46 (s, 3H, 5-CH3), 3.48 (d, 1H, Jˆ8 Hz, imide
a-H), 3.51 (d, 1H, Jˆ8 Hz, imide a-H), 3.83 (s, 3H, ester
CH3), 3.86 (s, 3H, ester CH3), 5.50 (s, 1H, sulfur bridge-H),
6.04 (s, 1H, sulfur bridge-H), 7.26±7.28 and 7.44±7.51 (m,
5H, Ar-H); m/z M1 426 (12%), 392 (10), 360 (11), 274
(37), 253 (100), 221 (33), 163 (23), 135 (14).
Dimethyl 1,3-dioxo-4,9-epithio-2,3,3a,4,9,9a-hexahydro-
2,6-dimethyl-1H-pyrrolo[3,4-f]-indolizine-7,8-dicarboxy-
late (7a, exo) and (7b, endo). Dimethyl 5-methyl-1H,3H-
pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 2-oxide 5 (0.27 g,
1.0 mmol), N-methylmaleimide (0.13 g, 1.2 equiv., 1.2
mmol) gave after chromatography [ethyl acetate±hexane
(1:1)] and crystallisation from chloroform±ethanol (exo-
adduct) dimethyl 1,3-dioxo-4,9-epithio-2,3,3a,4,9,9a-hexa-
hydro-2,6-dimethyl-1H-pyrrolo[3,4-f]indolizine-7,8-dicar-
boxylate (0.21 g, 59%) as a colourless powder, mp 190±
1928C. (Found: C, 52.8; H, 4.4; N, 7.7. C16H16N2SO6
requires C, 52.7; H, 4.4 and N, 7.7%); nmax (Nujolw)
2926, 1726, 1699, 1462, 1377, 1307, 1206, 1154 and
1093 cm21; dH (CDCl3) 2.44 (s, 3H, 5-CH3), 3.03 (s, 3H,
N±CH3), 3.33 (d, 1H, Jˆ8 Hz, imide a-H), 3.36 (d, 1H,
Jˆ8 Hz, imide a-H), 3.82 (s, 3H, ester CH3), 3.86 (s, 3H,
ester CH3), 5.39 (s, 1H, sulfur bridge-H), and 5.93 (s, 1H,
sulfur bridge-H); dC (CDCl3) 11.3 (CH3), 25.4 (CH2), 50.8
(CH), 51.6 (CH3 ester), 51.8 (CH3 ester), 51.9 (CH), 53.5
(CH), 67.0 (CH), 107.8, 114.3, 131.4, 140.3, 162.8 (CvO
ester), 164.9 (CvO ester), 173.3 (CvO amide) and 174.0
(CvO amide); m/z M1 364 (26%), 332 (22), 253 (100), 221
(37), 163 (28), 135 (23), and (endo-adduct) dimethyl 1,3-
dioxo-4,9-epithio-2,3,3a,4,9,9a-hexahydro-2,6-dimethyl-1H-
pyrrolo-[3,4-f]indolizine-7,8-dicarboxylate (0.03 g, 9%) as
a colourless powder, mp 206±2088C. Found: C, 52.7; H,
4.3; N, 7.7. C16H16N2SO6 requires C, 52.7; H, 4.4 and N,
Dimethyl 1,3-dioxo-2,3-dihydro-6-methyl-2-phenyl-1H-
pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (10). A solu-
tion of sodium methoxide (0.38 mL, 30% wt. soln.,
2.0 equiv., 2.0 mmol) added slowly to a solution of dimethyl
1,3-dioxo-4,9-epithio-2,3,3a,4,9,9a-hexahydro-6-methyl-2-
phenyl-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate 6a
(0.43 g, 1.0 mmol) dissolved in anhydrous dichloromethane

10018
O. B. Sutcliffe et al. / Tetrahedron 56 (2000) 10011±10021
(10 mL). After stirring for 2 h, the reaction was quenched
with saturated ammonium chloride solution (10 mL). The
dichloromethane layer was separated and dried over anhy-
drous sodium sulfate. The organics were ®ltered and
concentrated in vacuo to give a dark residue. Puri®cation
by ¯ash column chromatography [ethyl acetate±hexane
(1:1)] gave dimethyl 1,3-dioxo-2,3-dihydro-6-methyl-2-
phenyl-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (0.25 g,
63%) as a yellowish powder, mp dec. 210±2118C, lit.2 209±
211. (Found: C, 64.2; H, 4.0; N, 7.1. C21H16N2O6 requires C,
64.3; H, 4.1 and N, 7.1%); nmax (Nujolw) 2926, 2856, 1721,
1699, 1696, 1683, 1654, 1460, 1377, 1240, 1219, 1117, 1072
and 738 cm21; dH (CDCl3) 2.66 (s, 3H, 6-CH3), 3.97 (s, 3H,
ester CH3), 3.98 (s, 3H, ester CH3), 7.51 (s, 5H, N±Ph), 8.51 (s,
1H, Ar-H) and 8.82 (s, 1H, Ar-H). m/z M1 392 (6%), 360 (32),
274 (100), 180 (13), 77 (13).
Tetramethyl 4a,6a-dihydro-4a-methylthiazolo[2,3,4-cd]-
pyrrolizine-3,4,5,6-tetracarboxylate (14). Method A (via
Sulfoxide 5). Dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]thia-
zole-6,7-dicarboxylate 2-oxide 5 (0.27 g, 1.0 mmol) and
dimethyl acetylenedicarboxylate (0.12 mL, 1.2 mmol)
using the general procedure for generation and trapping of
thiazole 1 gave tetramethyl 4a,6a-dihydro-4a-methyl-
thiazolo[2,3,4-cd]pyrrolizine-3,4,5,6-tetracarboxylate (0.26 g,
65%) as a colourless powder, mp 238±2408C, lit.2 239±
2418C. (Found: C, 51.6; H, 4.3; N, 3.6. C17H17NSO8 requires
C, 51.7; H 4.3, and N, 3.5%); nmax (Nujolw) 3440, 2926,
2856, 2358, 1726, 1671, 1641, 1456, 1437, 1377, 1334,
1289, 1222, 1169, 1140, 1127, 1087, 1056, 1018, 960,
940, 859, 827, 803, 784 and 670 cm21; dH (CDCl3) 1.69
(s, 3H, 4a-CH3), 3.78 (s, 12H, ester CH3), 4.99 (s, 1H,
6a-H) and 5.75 (s, 1H, 2-H); dC (CDCl3) 29.3 (5-CH3),
52.2 (2£CH3 ester), 52.6 (2£CH3 ester), 60.6 (CH), 78.7
(CH), 86.4, 94.8, 134.1, 137.6, 141.5, 142.5, 161.9 (CvO
ester), 162.4 (CvO ester), 163.9 (CvO ester) and 164.2
(CvO ester); m/z M1 395 (69%), 304 (100), 253 (33), 221
(19), 163 (21), 135 (17).
Tetramethyl
3-methylpyrrolo[1,2-a]pyridine-1,2,6,7-
tetracarboxylate (11). Method A (via Dimethyl fumarate).
Dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicar-
boxylate 2-oxide (0.54 g, 2.0 mmol), dimethyl fumarate
(0.46 g, 3.2 mmol) and acetic anhydride (10 mL) were
heated to re¯ux for 4 h. The reaction mixture was cooled
to room temperature and the solvent removed in vacuo. The
resulting dark residue was triturated with methanol and the
crude brown mixture of isomers collected by ®ltration
(0.43 g, 55%). The mixture was used without further puri-
®cation. A solution of sodium methoxide (0.38 mL, 30% wt.
soln., 2.0 equiv., 2.0 mmol) was added slowly to a solution
of the crude mixture of isomers (0.40 g, 1.0 mmol)
dissolved in anhydrous dichloromethane (10 mL). After
stirring for 2 h, the reaction was quenched with saturated
ammonium chloride solution (10 mL). The dichloro-
methane layer was separated and dried over anhydrous
sodium sulfate. The organics were ®ltered and concentrated
in vacuo to give a dark residue. Recrystallisation from
benzene-petroleum ether gave tetramethyl 3-methyl-
Method B (via 1-Methoxysul®de 17). Dimethyl 1-methoxy-
5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate
(0.27 g, 1.0 mmol) was suspended in benzene (2 mL) with
dimethyl acetylenedicarboxylate (1.2 mL, 1.2 mmol) and
heated to re¯ux for 2 h. The reaction mixture was cooled
to room temperature and the solvent removed in vacuo. The
resulting dark residue was triturated with methanol and the
crude brown product collected by ®ltration. Recrystalli-
sation from methanol afforded tetramethyl 4a,6a-dihydro-
4a-methylthiazolo[2,3,4-cd]pyrrolizine-3,4,5,6-tetracar-
boxylate (0.11 g, 28%) as a colourless powder which had
identical physical and spectral properties to the material
isolated from the cycloaddition of dimethyl 5-methyl-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 2-oxide
and DMAD.
pyrrolo[1,2-a]pyridine-1,2,6,7-tetracarboxylate
as
a
yellowish powder (0.31 g, 85%), mp 133±1358C. (Found:
C, 56.3; H, 4.7; N, 3.8. C17H17NO8 requires C, 56.2; H, 4.7
and N, 3.9%); nmax (Nujolw) 2930, 1256, 1733, 1709, 1654,
1536, 1462, 1378, 1305, 1279, 1256, 1237, 1193, 1171,
1134, 1082, 1043, 968, 902, 846, 821, 806, 783, 772 and
741 cm21; dH (CDCl3) 2.59 (s, 3H, 5-CH3), 3.92 (s, 3H,
ester CH3), 3.94 (s, 3H, ester CH3), 3.95 (s, 3H, ester
CH3) and 3.96 (s, 3H, ester CH3), 8.29 (s, 1H, Ar-H), 8.47
(s, 1H, Ar-H); dC (CDCl3) 10.1 (5-CH3), 51.7 (CH3 ester),
52.5 (CH3 ester), 52.8 (CH3 ester), 52.9 (CH3 ester), 106.5,
117.6, 122.1 (CH), 122.7, 124.9, 125.4, 125.9 (CH), 132.5,
163.5 (CvO), 165.7 (2£CvO), 166.6 (CvO); m/z M1 363
(37%), 332 (48), 245 (100).
5,6-Diethyl-3,4-dimethyl 4a,6a-dihydro-4a-methylthia-
zolo[2,3,4-cd]pyrrolizine-3,4,5,6-tetracarboxylate (13)
(RˆCO2Et). Dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]thia-
zole-6,7-dicarboxylate-2-oxide 5 (0.27 g, 1.0 mmol) and
diethyl acetylenedicarboxylate (0.19 mL, 1.2 mmol) using
the general procedure for generation and trapping of thia-
zole 1 gave 5,6-diethyl-3,4-dimethyl 4a,6a-dihydro-4a-
methyl-thiazolo[2,3,4-cd]pyrrolizine-3,4,5,6-tetracarboxyl-
ate (0.17 g, 41%) as a yellowish powder, mp 216±2188C.
(Found: C, 53.7; H, 4.9; N, 3.2. C19H21NSO8 requires C,
53.9; H, 5.0 and N, 3.3%); nmax (Nujolw) 2926, 1721,
1683, 1660, 1644, 1462, 1377, 1322, 1262, 1224, 1135,
1108, 1084, 1053, 1018, 858, 840, 800 and 722 cm21; dH
(CDCl3) 1.26±1.32 (m, 6H, 2£CH3CH2CO2±), 1.70 (s, 3H,
4a-CH3), 3.74 (s, 3H, ester CH3), 3.78 (s, 3H, ester CH3),
4.12±4.36 (m, 4H, 2£CH3CH2CO2±), 4.99 (s, 1H, 6a-H)
and 5.76 (s, 1H, 2-H); dC (CDCl3) 13.9 (CH3CH2CO2±),
14.0 (CH3CH2CO2±), 29.3 (5-CH3), 52.2 (2£CH3CO2±),
60.5 (CH), 61.8 (CH2), 61.9 (CH2), 78.8 (CH), 86.5, 94.9,
134.2, 137.7, 141.6, 142.4, 161.31 (CvO ester), 162.8
(CvO ester), 163.9 (2£CvO ester); m/z M1 423 (100%),
364 (38), 332 (75), 253 (84), 221 (51), 163 (43), 135 (37).
Method B (via Dimethyl maleate). Tetramethyl 3-methyl-
pyrrolo[1,2-a]pyridine-1,2,6,7-tetracarboxylate 12 was
prepared from dimethyl maleate using the procedure
detailed in method A. Dimethyl 5-methyl-1H,3H-pyrrolo-
[1,2-c]thiazole-6,7-dicarboxylate 2-oxide
5
(0.54 g,
2.0 mmol) and dimethyl maleate (0.4 mL, 3.2 mmol) gave
after desulfurisation tetramethyl 3-methylpyrrolo[1,2-a]-
pyridine-1,2,6,7-tetracarboxylate (0.35 g, 48% overall
yield from sulfoxide) as a yellowish powder which had
identical physical and spectroscopic properties as the
product prepared by method A.
N-Nitrosothiazolidine-4-carboxylic acid (17). Concen-
trated hydrochloric acid was slowly added dropwise

O. B. Sutcliffe et al. / Tetrahedron 56 (2000) 10011±10021
10019
(CARE!) to a suspension of thiazolidine-4-carboxylic acid
(13.32 g, 0.1 mol) in water (50 mL) until the suspension
dissolved. To the vigorously stirring solution was then
added slowly via a dropping funnel sodium nitrite
(10.35 g, 0.15 mol) dissolved in water (50 mL). Shortly
after the addition was complete a vigorous evolution of
gas (CAUTION!) occurred and the initial red colour faded
to give a pale yellow solution. After stirring for 12 h the
reaction mixture was extracted with ethyl acetate
(3£100 mL) and the combined organic fractions were then
washed with water (100 mL), brine (100 mL) and dried over
anhydrous magnesium sulfate. Concentration in vacuo gave
a yellowish oil which crystallised on trituration with petro-
leum ether to give N-nitrosothiazolidine-4-carboxylic acid
(13.95 g, 86%) as pale yellow crystals, mp 98±998C, lit.12
101±1028C. (Found: C, 29.8; H, 3.7; N, 17.0. C4H6N2SO3
requires C, 29.6; H, 3.7 and N, 17.3%); nmax (Nujolw) 2928,
2855, 2576, 1739, 1462, 1432, 1387, 1345, 1259, 1222, 1201,
1129, 1010, 955, 928, 871, 852, 819, 762, 750, 720 and
693 cm21; m/z M1 162 (1%), 132 (100), 104 (15), and 88 (94).
thiazole-6,7-dicarboxylate (10.23 g, 40 mmol) in methanol
(700 mL) at 08C. The cooling bath was then removed and
the reaction mixture was allowed to warm to room tempera-
ture. After stirring at room temperature for 48 h, the reaction
mixture was ®ltered and the ®ltrate extracted with chloro-
form (3£500 mL). The combined organic fractions were
then washed with water (250 mL), brine (250 mL) and
dried over anhydrous magnesium sulfate. Concentration in
vacuo gave a yellowish oil which crystallised on standing.
Recrystallisation of the crude residue from methanol gave
dimethyl 1H,3H-pyrazolo[1,5-c]thiazole-6,7-dicarboxylate
2-oxide (10.69 g, 98%) as colourless ¯akes, mp 133±
1358C. (Found: C, 41.9; H, 3.9; N, 10.9. C9H10N2SO5
requires C, 41.9; H, 3.9 and N, 10.7%); nmax (Nujolw)
3446, 3006, 2958, 2849, 2352, 2314, 2090, 1730, 1633,
1555, 1488, 1464, 1439, 1397, 1375, 1310, 1231, 1230,
1176, 1134, 1118, 1076, 988, 947, 895, 865, 818, 788,
770, 736, 701, 678, 666 cm21; dH (CDCl3) 3.86 (s, 3H,
ester CH3), 3.96 (s, 3H, ester CH3), 4.28 (d, 1H, Jˆ17 Hz,
3-H), 4.55 (d, 1H, Jˆ17 Hz, 3-H), 5.13 (d, 1H, Jˆ12 Hz,
1-H) and 5.35 (d, 1H, Jˆ12 Hz, 1-H); dC (CDCl3) 52.1 (CH3
ester), 52.4 (CH3 ester), 52.8 (CH2), 71.7 (CH2), 111.1,
145.7, 148.9, 161.3 (CvO ester) and 161.4 (CvO ester);
m/z M1 258 (2%), 226 (30), 196 (37), 151 (100), 59 (30).
4H,6H-Thiazolo[3,4-c][1,2,3]oxadiazolium-3-oxide (18).
Tri¯uoroacetic anhydride (5.37 mL, 38 mmol) was slowly
added to a suspension of N-nitrosothiazolidine-4-carboxylic
acid (6.08 g, 38 mmol) in anhydrous diethyl ether (400 mL)
at 08C. The reaction mixture was stirred at 08C for 6 h and
then allowed to warm to room temperature. After stirring at
room temperature for 24 h the solution was ®ltered and the
crude product was thoroughly washed with cold diethyl
ether (20 mL) to give 4H,6H-thiazolo[3,4-c][1,2,3]oxa-
diazolium-3-oxide (3.51 g, 65%) as colourless crystals, mp
88±908C. (Found: C, 33.4; H, 2.7; N, 19.5. C4H4N2SO2
requires C, 33.3 H, 2.8 and N, 19.4%); nmax (Nujolw)
3439, 2926, 2857, 2352, 1725, 1520, 1456, 1377, 1316,
General procedure for generation and trapping of `non-
classical' thiazole (2)
Dimethyl 5-methyl-1H,3H-pyrazolo[1,5-a]thiazole-6,7-dicar-
boxylate 2-oxide 21 (0.26 g, 1.0 mmol) and the appropriate
dipolarophile (1.2 mmol) in acetic anhydride (5 mL) were
heated to re¯ux for 4 h. The reaction mixture was cooled to
room temperature and the solvent removed in vacuo. The
resulting residue was triturated with methanol to give the
cycloadduct which was further puri®ed by ¯ash chromato-
graphy and/or recrystallisation from the appropriate solvent.
1235, 1187, 1106, 1025, 899, 789, 737, 711 and 62 cm21
;
dH (CDCl3) 4.03 (t, 2H, Jˆ2.0 Hz, CH2) and 5.40 (t, 2H,
Jˆ2.0 Hz, CH2); m/z M1 144 (26%), 114 (100) and 86 (26).
Dimethyl 1,3-dioxo-4,9-epithio-2,3,3a,4,9,9a-hexahydro-
2-phenyl-1H-pyrazolo[1,5-a]pyrrolo[3,4-c]pyridine-7,8-
dicarboxylate (22a). Dimethyl 1H,3H-pyrazolo[1,5-c]thia-
zole-6,7-dicarboxylate 2-oxide 21 (0.26 g, 1.0 mmol), N-
phenylmaleimide (0.21 g, 1.2 mmol) gave after recrystalli-
sation from methanol (exo-adduct) dimethyl 1,3-dioxo-4,9-
epithio-2,3,3a,4,9,9a-hexahydro-2-phenyl-1H-pyrazolo[1,5-a]-
pyrrolo-[3,4-c]pyridine-7,8-dicarboxylate (0.31 g, 75%) as a
colourless powder, mp 202±2038C. (Found: C, 55.3; H, 3.6; N,
10.1. C19H15N3SO6 requires C, 55.2; H, 3.6 and N, 10.2%); nmax
(Nujolw) 2923, 2857, 1757, 1718, 1501, 1460, 1393, 1289,
1193, 1136, 1076 and 889 cm21; dH (CDCl3) 3.53 (d, 1H,
Jˆ6 Hz, imide a-H), 3.69 (d, 1H, Jˆ6 Hz, imide a-H), 3.92
(s, 3H, ester CH3), 3.96 (s, 3H, ester CH3), 5.52 (s, 1H, sulfur
bridge-H) and 6.28 (s, 1H, sulfur bridge-H), 7.23±7.28 and
7.45±7.56 (m, 5H, Ar-H); dC (CDCl3) 50.7 (CH), 51.2 (CH),
52.4 (CH3 ester), 52.8 (CH3 ester and CH), 71.2 (CH), 108.2,
126.4 (2£CH), 129.5 (3£CH), 146.0, 151.3, 161.1 (CvO
ester), 161.4 (CvO ester), 171.4 (CvO amide) and 172.5
(CvO amide); m/z M1 413 (18%), 379 (85), 348 (100), 240
(91), 203 (26), 77 (31), 59 (36).
Dimethyl 1H,3H-pyrazolo[1,5-c]thiazole-6,7-dicarboxyl-
ate (20). 4H,6H-Thiazolo[3,4-c][1,2,3]oxadiazolium-3-
oxide 17 (14.5 g, 0.10 mol) and dimethyl acetylenedi-
carboxylate (19.8 mL, 1.6 equiv., 0.16 mol) in xylene
(60 mL) were heated at re¯ux for 3 h under a positive
¯ow of dry nitrogen. The reaction was cooled to room
temperature and the solvent removed in vacuo to give a
brown crystalline mass which was recrystallised from
methanol to give dimethyl 1H,3H-pyrazolo[1,5-c]thiazole-
6,7-dicarboxylate (18.76 g, 77%) as cream coloured
needles, mp 123±1288C. (Found: C, 44.5; H, 4.2; N, 11.5.
C9H10N2SO4 requires C, 44.6; H, 4.1 and N, 11.6%); nmax
(Nujolw) 3443, 2923, 2857, 1734, 1697, 1550, 1504, 1464,
1377, 1330, 1299, 1231, 1203, 1181, 1149, 1079, 990, 889,
860, 820, 793, 770, 720, 646 cm21; dH (CDCl3) 3.85 (s, 3H,
ester CH3), 3.96 (s, 3H, ester CH3), 4.31 (t, 2H, Jˆ2 Hz,
1-CH2) and 5.25 (t, 2H, Jˆ2 Hz, 3-CH2); dC (CDCl3) 28.3
(CH2), 50.4 (CH2), 51.9 (CH3), 52.6 (CH3), 108.7, 148.3,
149.2, 160.9 (CvO ester) and 161.8 (CvO ester); m/z M1
242 (2%), and 210 (100).
Dimethyl 1H,3H-pyrazolo[1,5-c]thiazole-6,7-dicarboxyl-
ate 2-oxide (21). Sodium periodate (10.23 g, 1.2 equiv.,
48 mmol) dissolved in water (200 mL) was slowly added
to a stirring solution of dimethyl 1H,3H-pyrazolo[1,5-c]-
Dimethyl 1,3-dioxo-4,9-epithio-2,3,3a,4,9,9a-hexahydro-
2-methyl-1H-pyrazolo[1,5-a]pyrrolo[3,4-c]pyridine-7,8-
dicarboxylate (22b). Dimethyl 1H,3H-pyrazolo[1,5-c]thia-
zole-6,7-dicarboxylate 2-oxide 21 (0.26 g, 1.0 mmol) and

10020
O. B. Sutcliffe et al. / Tetrahedron 56 (2000) 10011±10021
N-methylmaleimide (0.14 g, 1.2 mmol) gave after recrystal-
lisation from methanol (exo-adduct) dimethyl 1,3-dioxo-4,9-
epithio-2,3,3a,4,9,9a-hexahydro-2-methyl-1H-pyrazolo-
[1,5-a]pyrrolo-[3,4-c]pyridine-7,8-dicarboxylate (0.22 g,
63%) as a colourless powder, mp 232±2338C. (Found: C,
47.9; H, 3.7; N, 11.9. C14H13N3SO6 requires C, 47.9; H, 3.7
and N, 12.0%); nmax (Nujolw) 2926, 2856, 1779, 1739, 1703,
1699, 1683, 1559, 1462, 1377, 1315, 1211, 1188, 1133,
1072, 973, 888, 830, 805, 795, 776 and 720 cm21; dH
(CDCl3) 3.04 (s, 3H, N±CH3), 3.36 (d, 1H, Jˆ7 Hz, imide
a-H), 3.52 (d, 1H, Jˆ7 Hz, imide a-H), 3.89 (s, 3H, ester
CH3), 3.86 (s, 3H, ester CH3), 5.40 (s, 1H, sulfur bridge-H)
and 6.17 (s, 1H, sulfur bridge-H); dC (CDCl3) 25.5 (CH3),
50.8 (CH), 52.6 (CH), 52.7 (CH3 ester), 52.8 (CH3 ester),
53.0 (CH), 70.9 (CH), 108.1, 131.7, 145.9, 151.3, 160.5
(CvO ester), 161.4 (CvO ester), 172.3 (CvO amide)
and 173.3 (CvO amide); m/z M1 351 (16%), 286 (30),
240 (100), 203 (28), 59 (23).
dride) and 170.6 (CvO anhydride); m/z M1 338 (23%), 307
(18), 240 (100), 234 (33), 203 (60), 59 (44).
Tetramethyl pyrazolo[1,5-a]pyridine-2,3,5,6-tetracar-
boxylate (24). Method A (via Dimethyl fumarate). Dimethyl
1H,3H-pyrazolo[1,5-c]thiazole-6,7-dicarboxylate 2-oxide
21 (0.52 g, 2.0 mmol), dimethyl fumarate (0.34 g, 3.2
mmol) and acetic anhydride (10 mL) were heated to
re¯ux for 4 h. The reaction mixture was cooled to
room temperature and the solvent removed in vacuo.
The resulting dark residue was triturated with methanol
and the crude brown mixture of isomers collected by ®l-
tration (0.42 g, 60%). The mixture was used without further
puri®cation.
A solution of sodium methoxide (0.38 mL, 30% wt. soln.,
2.0 equiv., 2.0 mmol) was added slowly to a solution of the
crude mixture of isomers (0.38 g, 1.0 mmol) dissolved in
anhydrous dichloromethane (10 mL). After stirring for 2 h,
the reaction was quenched with saturated ammonium
chloride solution (10 mL). The dichloromethane layer was
separated and dried over anhydrous sodium sulfate, then
®ltered and concentrated in vacuo to give a dark residue.
Recrystallisation from benzene-petroleum ether gave tetra-
Dimethyl 1,3-dioxo-4,9-epithio-2-ethyl-2,3,3a,4,9,9a-hexa-
hydro-1H-pyrazolo[1,5-a]pyrrolo[3,4-c]pyridine-7,8-
dicarboxylate (22c). Dimethyl 1H,3H-pyrazolo[1,5-c]thia-
zole-6,7-dicarboxylate 2-oxide 21 (0.26 g, 1.0 mmol) and
N-ethylmaleimide (0.16 g, 1.2 mmol) gave after recrystalli-
sation from methanol (exo-adduct) dimethyl 1,3-dioxo-4,9-
epithio-2-ethyl-2,3,3a,4,9,9a-hexahydro-1H-pyrazolo[1,5-a]-
pyrrolo[3,4-c]pyridine-7,8-dicarboxylate (0.26 g, 71%) as a
colourless powder, mp 230±2318C. (Found: C, 49.1; H, 4.0;
N, 11.2. C15H15N3SO6 requires C, 49.3; H, 4.1 and N, 11.5%);
nmax (Nujolw) 3771, 3625, 3369, 2925, 2858, 1777, 1703,
1650, 1576, 1459, 1376, 1302, 1132, 1072, 888, 805,
720 cm21; dH (CDCl3) 1.19 (t, 3H, Jˆ7 Hz, N±CH2CH3),
3.34 (d, 1H, Jˆ7 Hz, imide a-H), 3.50 (d, 1H, Jˆ7 Hz,
imide a-H), 3.61 (q, 2H, Jˆ7 Hz, N±CH2CH3), 3.91 (s, 3H,
ester CH3), 3.95 (s, 3H, ester CH3), 5.42 (s, 1H, sulfur bridge-
H) and 6.18 (s, 1H, sulfur bridge-H); dC (CDCl3) 12.5 (CH3),
34.7 (CH2), 50.6 (CH), 50.7 (CH), 52.3 (CH3 ester), 52.7
(CH3 ester and CH), 70.9 (CH), 108.1, 145.8, 151.4, 161.0
(CvO ester), 161.4 (CvO ester), 172.1 (CvO amide) and
173.1 (CvO amide); m/z M1 365 (16%), 300 (17), 240 (100),
203 (38), 59 (22).
methyl
pyrazolo[1,5-a]pyridine-2,3,5,6-tetracarboxylate
(0.26 g, 76%) as a colourless powder, mp. 133±1358C.
(Found: C, 51.2; H, 3.9; N, 7.8. C15H14N2O8 requires C,
51.4; H, 4.0 and N, 8.0%); nmax (Nujolw) 2925, 2856,
1775, 1728, 1699, 1563, 1529, 1462, 1434, 1377, 1307,
1282, 1251, 1204, 1180, 1154, 1117, 1092, 976, 946, 909,
886, 840, 807, 783, 744 and 710 cm21; dH (CDCl3); 3.96 (s,
3H, ester CH3), 3.97 (s, 3H, ester CH3), 3.98 (s, 3H, ester
CH3), 4.05 (s, 3H, ester CH3), 8.40 (s, 1H, Ar-H) and 9.01 (s,
1H, Ar-H); dC (CDCl3) 52.1 (CH3 ester), 53.2 (3£CH3
ester), 96.6, 118.7, 120.3 (CH), 132.0, 132.1 (CH), 140.8,
149.8, 161.8 (CvO ester), 162.5 (CvO ester), 164.0 (CvO
ester) and 166.2 (CvO ester); m/z M1 350 (55%), 319
(100), 201 (21).
Method B (via Dimethyl maleate). Tetramethyl pyrazolo-
[1,5-a]pyridine-2,3,5,6-tetracarboxylate 27a was prepared
from dimethyl maleate using the procedure detailed in
method A. Dimethyl 1H,3H-pyrazolo[1,5-c]thiazole-6,7-
dicarboxylate 2-oxide 21 (0.52 g, 2.0 mmol) and dimethyl
maleate (0.4 mL, 3.2 mmol) gave after desulfurisation
tetramethyl pyrazolo[1,5-a]pyridine-2,3,5,6-tetracarboxyl-
ate (0.30 g, 43% overall yield from sulfoxide) as a colour-
less powder which had identical physical and spectroscopic
properties as the product prepared by method A.
Dimethyl 1,3-dioxo-4,9-epithio-2-methyl-3a,4,9,9a-tetra-
hydro-1H-pyrazolo[1,5-a]furo[3,4-c]pyridine-7,8-dicar-
boxylate (22d). Dimethyl 1H,3H-pyrazolo[1,5-c]thiazole-
6,7-dicarboxylate 2-oxide 21 (0.26 g, 1.0 mmol) and maleic
anhydride (0.12 g, 1.2 mmol) gave after recrystallisation
from methanol (exo-adduct) dimethyl 1,3-dioxo-4,9-
epithio-2-methyl-3a,4,9,9a-tetrahydro-1H-pyrazolo[1,5-a]-
furo[3,4-c]pyridine-7,8-dicarboxylate (0.11 g, 34%) as a
colourless powder, mp 239±2418C. (Found: C, 46.2; H,
3.0; N, 8.3. C13H10N2SO7 requires C, 46.2; H, 3.0 and N,
8.3%); nmax (Nujolw) 3441, 3058, 3019, 2926, 2856, 2330,
1867, 1846, 1791,1757, 1723, 1551, 1461, 1436, 1415,
1368, 1319, 1298, 1236, 1259, 1229, 1193, 1171, 1130,
1081, 952, 928, 889, 864, 838, 818, 807, 770, 757, 732
and 664 cm21; dH (CDCl3) 3.72 (d, 1H, Jˆ7 Hz, anhydride
a-H), 3.86 (d, 1H, Jˆ7 Hz, anhydride a-H), 3.91 (s, 3H,
ester CH3), 3.95 (s, 3H, ester CH3), 5.53 (s, 1H, sulfur
bridge-H) and 6.28 (s, 1H, sulfur bridge-H); dC (d6
DMSO) 50.7 (CH), 51.6 (CH), 52.0 (CH3 ester), 52.4
(CH3 ester), 53.5 (CH), 71.8 (CH), 106.1, 144.6, 152.3,
161.3 (CvO ester), 162.0 (CvO ester), 170.1 (CvO anhy-
Method C (via Dimethyl acetylenedicarboxylate). Dimethyl
5-methyl-1H,3H-pyrazolo[1,5-c]thiazole-6,7-dicarboxylate
2-oxide (0.26 g, 1.0 mmol) and dimethyl acetylenedicar-
boxylate (0.12 mL, 1.2 mmol) gave after chromatography
[ethyl acetate±hexane (1:1)] and recrystallisation from ben-
zene±petroleum ether tetramethyl pyrazolo[1,5-a]pyridine-
2,3,5,6-tetracarboxylate(0.19 g, 55%) as
a colourless
powder which had identical physical and spectroscopic
properties as the product prepared by method A.
5,6-Diethyl-2,3-dimethyl pyrazolo[1,5-a]pyridine-2,3,5,6-
tetracarboxylate (27a). Dimethyl 5-methyl-1H,3H-pyra-
zolo[1,5-c]thiazole-6,7-dicarboxylate-2-oxide (0.26 g, 1.0

O. B. Sutcliffe et al. / Tetrahedron 56 (2000) 10011±10021
10021
mmol) and diethyl acetylenedicarboxylate (0.19 mL,
References
1.2 mmol) using the general procedure for generation and
trapping of thiazole 2 gave after chromatography [ethyl
acetate±hexane (1:1)] and recrystallisation from benzene±
petroleum ether 5,6-diethyl-2,3-dimethyl pyrazolo[1,5-a]-
pyridine-2,3,5,6-tetracarboxylate (0.19 g, 50%) as a colour-
less powder, mp. dec. 236±2388C. (Found: C, 54.2; H, 4.9;
N, 7.2. C17H18N2O8 requires C, 54.0; H, 4.8 and N, 7.4%);
nmax (Nujolw) 3771, 3695, 3369, 2923, 2859, 1730, 1709,
1659, 1639, 1576, 1458, 1376, 1303, 1259, 1236, 1193,
1171, 1134, 1082, 1052, 1018, 968, 902, 846, 821, 805,
772, 741 and 719 cm21; dH (CDCl3); 1.38±1.43 (m, 6H,
2£CH3CH2CO2±), 3.96 (s, 3H, ester CH3), 4.05 (s, 3H,
ester CH3), 4.39±4.48 (m, 4H, 2£CH3CH2CO2±), 8.39 (s,
1H, Ar-H) and 9.02 (s, 1H, Ar-H); m/z M1 378 (100), 347
(69), 305 (68), 201 (28), 59 (26). Accurate mass: 378.1068,
C17H18N2O8 requires 378.1063.
1. Ramsden, C. A. In Comprehensive Heterocyclic Chemistry,
Katritzky, A. R., Rees, C. W. Eds.; Pergamon: Oxford, 1984;
Vol. 6, pp 1023±1048.
2. Kane, J. M. J. Org. Chem. 1980, 45, 5396.
3. (a) Potts, K. T.; Marshall, J. L. J. Org. Chem. 1976, 41, 129. (b)
Tsuge, O.; Shiraishi, H.; Takata, T. Chem. Lett. 1980, 1369. (c)
Chiuguk, V. A.; Maidannik, A. G. Khim. Geterotsikl. Soedin. 1980,
1695. (d) Tsuge, O.; Shiraishi, H.; Noguchi, M. Chem. Lett. 1981,
213. (e) Shimoharada, H.; Ikeda, S.; Kajigaeshi, S.; Kanemasa, S.
Chem. Lett. 1977, 1237.
4. (a) Sutcliffe, O. B.; Storr, R. C.; Gilchrist, T. L.; Rafferty, P.;
Crew, A. P. A. J. Chem. Soc., Chem. Commun. 2000, 675. (b)
Padwa, A.; Fryxell, G. E.; Gasdaska, J. R.; Venkatramanan, K.;
Wong, G. S. J. Org. Chem. 1989, 54, 644.
5. (a) Rees, C. W.; Storr, R. C. J. Chem. Soc., Chem. Commun.
1968, 1305. (b) Rees, C. W.; Storr, R. C. J. Chem. Soc. C 1969,
1474.
Dimethyl 5,6-dibenzoylpyrazolo[1,5-a]pyridine-2,3-dicar-
boxylate (27b). Dimethyl 5-methyl-1H,3H-pyrazolo[1,5-c]-
thiazole-6,7-dicarboxylate-2-oxide (0.26 g, 1.0 mmol),
dibenzoylacetylene (0.28 g, 1.2 mmol) gave after chroma-
tography [ethyl acetate±hexane (1:1)] and recrystallisation
from methanol dimethyl 5,6-dibenzoylpyrazolo[1,5-a]pyri-
dine-2,3-dicarboxylate (0.26 g, 59%) as a brownish powder,
mp. 168±1708C. (Found: C, 67.9; H, 4.0; N, 6.3.
C25H18N2O6 requires C, 67.9; H, 4.0 and N, 6.3%); nmax
(Nujolw) 2930, 2856, 1740, 1721, 1699, 1673, 1654, 1596,
1524, 1462, 1406, 1377, 1325, 1304, 1230, 1215, 1174,
1071, 980, 886 and 715 cm21; dH (CDCl3); 3.92 (s, 3H,
ester CH3), 4.06 (s, 3H, ester CH3), 7.44±7.50 (m, 4H,
Ar-H), 7.60±7.62 (m, 2H, Ar-H), 7.78±7.85 (m, 4H,
Ar-H), 8.34 (s, 1H, 4-H) and 9.01 (s, 1H, 7-H); m/z M1
442 (40%), 411 (100), 365 (29), 105 (100), 77 (83).
6. Kingsbury, W. D.; Johnson, C. R. J. Chem. Soc, Chem.
Commun. 1969, 365.
7. (a) Cava, M. P.; Behforouz, M.; Husbands, G. E. M.; Srinivasen,
M. J. Am. Chem. Soc. 1973, 95, 2561. (b) Potts, K. T.; McKeough,
D. J. Am. Chem. Soc. 1974, 96, 4298.
8. (a) Potts, K. T.; McKeough, D. J. Am. Chem. Soc. 1974, 96,
4236. (b) Potts, K. T.; Baum J.; Houghton, E. J. Org. Chem. 1974,
39, 3631.
9. Ranganathan, D.; Bamezai, S. Tetrahedron Lett. 1983, 24,
1067.
10. (a) Dewar, M. J. S.; Thiel, W. J. Am. Chem. Soc. 1977, 99,
4899. (b) Stewart, J. P. J. Comput. Chem. 1989, 10, 209.
11. Nakayama, J.; Ishii, A.; Kobayashi, Y.; Hoshino, M. J. Chem.
Soc., Chem. Commun. 1988, 959.
12. Tahira, T.; Tsuda, M.; Wakabayashi, K.; Nagao, M.;
Sugimura, T. Gann. 1984, 75, 889; Chem. Abstr. 1985, 102, 19338.
Acknowledgements
We thank the EPSRC and Knoll Limited for the CASE
Studentship for O. B. S.