Nitrogen-bridged heterocycles via cycloaddition of non-classical heterocyclic-fused-[c]thiazoles

Article abstract of DOI:10.1016/j.tet.2011.08.001

The [4π+2π] cycloaddition of non-classical heterocyclic-fused-[c] thiazoles was explored allowing the synthesis of a range of new nitrogen-bridged bi-, tri- and tetracyclic heterocyclic compounds namely, pyrazolo[1,5-a] pyridines, thiazolo[2,3,4-cd]pyrrol

Full text of DOI:10.1016/j.tet.2011.08.001

Tetrahedron 67 (2011) 8392e8403
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nitrogen-bridged heterocycles via cycloaddition of non-classical
heterocyclic-fused-[c]thiazoles
,
Maria I.L. Soares a, Clara S.B. Gomes b, Teresa M.V.D. Pinho e Melo a
*
a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
b
ꢀ
Centro de Química Estrutural, Instituto Superior Tecnico, Technical University of Lisbon, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2011
Received in revised form 25 July 2011
Accepted 1 August 2011
Available online 22 August 2011
The [4
p
þ2
p] cycloaddition of non-classical heterocyclic-fused-[c]thiazoles was explored allowing the
synthesis of a range of new nitrogen-bridged bi-, tri- and tetracyclic heterocyclic compounds namely,
pyrazolo[1,5-a]pyridines, thiazolo[2,3,4-cd]pyrrolizines and indolizines. For the first time, one non-
classical pyrrolo[1,2-c]thiazole was isolated and its structure determined by X-ray crystallography.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
are slow-channel calcium antagonists6 and others show inhibitory
activity of secretory phospholipases A2,7 phosphatase8 and 15-
Heteropentalene mesomeric betaines are bicyclic 10
heterocycles isoconjugate with the pentalenyl dianion which can-
p
-electron
lipoxygenase.9 On the other hand, indolizine-glyoxylamides
showed cytotoxicity against multidrug resistant cancer cell
lines.10 Pyrazolo[1,5-a]pyridines represent another important class
of N-bridged heterocycles with recognized biological activity.
Compounds incorporating a pyrazolo[1,5-a]pyridine core are highly
selective dopamine D3 and D4 receptor agonists and antagonists
used for the treatment of neurophathological disorders, such as
schizophrenia and Parkinson’s disease.11 Some derivatives were
found to be selective adenosine A1 receptor antagonists with potent
diuretic12 and herpetic activity.13 More recently a 2,3-substituted
pyrazolo[1,5-a]pyridine was identified as a promising p38 kinase
inhibitor.14
ꢀ
not be represented by classic covalent Kekule structures. They can
only be represented by dipolar structures or by structures involving
tetravalent sulfur atoms. Their interesting electronic structure
makes them of interest from both theoretical and synthetic point of
view. These non-classical heteropentalenes are versatile substrates
in cycloaddition reactions for the construction of a variety of fused
heterocycles.1
The non-classical heteropentalenes 2, containing a tetravalent
sulfur atom, can be generated in situ via Pummerer-type de-
hydration of 2-oxo-1H,3H-pyrrolo[1,2-c]thiazole 1a and 2-oxo-
1H,3H-pyrazolo[1,5-c]thiazole 1b, respectively (Scheme 1). These
transient heterocyclic-fused-[c]thiazole systems 2 participate in
In this context, the chemistry of non-classical heterocyclic-fused-
[c]thiazoles was further explored aiming to access a range of new
nitrogen-bridged bicyclic and tricyclic heterocyclic compounds.
[4
p
þ2
p
] cycloadditions to give fused heterocycles.2,3 Hetero-
pentalene 2a reacts as thiocarbonyl ylide in the reaction with
N-substituted maleimides, whereas with acetylene dicarboxylate
intermediate 2a acts as an azomethine ylide. Heteropentalene 2b
reacts with both types of dipolarophiles, giving products resulting
from the addition across the thiocarbonyl ylide moiety.
2. Results and discussion
Initially, we looked again into cycloadditions of heteropentalene
2a with N-phenylmaleimide (NPM) and dimethyl acetylene dicar-
boxylate (DMAD) reported by Kane and Storr (Table 1).2,3
Pummerer-type dehydration of 2-oxo-1H,3H-pyrrolo[1,2-c]thia-
zole 1a in boiling acetic anhydride in the presence of NPM gave
This chemistry allows the synthesis of interesting nitrogen-
bridged bicyclic and tricyclic heterocyclic compounds namely,
pyrazolo[1,5-a]pyridines, thiazolo[2,3,4-cd]pyrrolizines and indo-
lizines. In fact, indolizine is an important structural unit commonly
found in naturally occurring alkaloids and biologically active mol-
ecules, thus representing an important class of heterocycles in drug
discovery. For instance, substituted indolizines have shown anti-
oxidant4 and antimycobacterial properties,5 while some derivatives
a mixture of the exo- and endo-cycloadducts via [4
p
þ2
p] cyclo-
addition across the thiocarbonyl ylide portion of heteropentalene
2a as previously described2,3 (Table 1). Carrying out the reaction for
4 h the exo-cycloadduct 3a was isolated in 54% yield as the major
product together with the synthesis of the endo-cycloadduct 3b in
8% yield (Table 1, entry 1). Longer reaction time led to compound 3a
in low yield, indicating lack of stability of the cycloadducts to these
reaction conditions (Table 1, entry 2). Sealed tube thermolysis at
* Corresponding author. E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.001

M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
8393
CO2Me
CO2Me
CO2Me
CO2Me
O
CO2Me
CO2Me
O
S
R
N
R
N
S
N
N
N
Desulfurization
Me
O
Me
Me
O
MeO2C
CO2Me
Indolizines
N-substituted maleimides
X = CMe
Thiazolo[2,3,4-cd]pyrrolizines
DMAD
DMAD
CO2Me
CO2Me
CO2Me
CO2Me
MeO2C
Ac2O,
S
CO2Me
OS
CO2Me
- H2O
N
N
N
X
X
N
MeO2C
X = N
1a X = CMe
1b X = N
2a X = CMe
2b X = N
Pyrazolo[1,5-a]pyridines
N-substituted maleimides
O
CO2Me
CO2Me
R
N
S
N
N
O
Scheme 1. [4pþ2p] Cycloadditions of non-classical heterocyclic-fused-[c]thiazoles 2.
Subsequently, dehydration of 2-oxo-pyrazolo[1,5-c]thiazole 1b
in the presence of NPM and DMAD was explored (Table 2). In both
cases exclusive formation of cycloadducts resulting from the ad-
dition across the thiocarbonyl ylide moiety of the non-classical
fused-[c]thiazole 2b was observed, as described in the litera-
ture.2,3 The cycloaddition of 2b with N-phenylmaleimide carried
out in boiling acetic anhydride for 4 h gave exo-adduct 5 selectively
in 42% yield (Table 2, entry 1). The yield for the synthesis of com-
pound 5 could be improved to 76% by increasing the reaction time
to 7 h (Table 2, entry 2). The same compound could also be obtained
in good yield under sealed tube thermolysis (Table 2, entries 3 and
4). The microwave induced reaction of heteropentalene 2b with
NPM gave compound 5 in 54% yield (Table 2, entry 5).
Table 1
Cycloaddition of heteropentalene 2a generated from 2-oxo-1H,3H-pyrrolo[1,2-c]
thiazole 1a
CO2Me
O
CO2Me
CO2Me
O
S
CO2Me
Ph
N
S
Ph
N
N
N
O
Me
Me
O
3a
3b
Ac2O, NPM
CO2Me
CO2Me
S
CO2Me
Me
CO2Me
Ac2O
N
CO2Me
OS
N
DMAD
Table 2
MeO2C
Me
1a
4
Cycloaddition of heteropentalene 2b generated from 2-oxo-1H,3H-pyrazolo[1,5-c]
thiazole 1b
Entry
Dipolarophile
Reaction conditions
Products (yield)
CO2Me
O
1
2
3
4
5
6
7
NPM
NPM
NPM
NPM
DMAD
DMAD
DMAD
Reflux, 4 h
Reflux, 7 h
3a (54%)
3a (16%)
3a (58%)
3a (73%)
4 (51%)
4 (35%)
4 (15%)
3b (8%)
d
Ac2O
NPM
S
CO2Me
Ph
N
N
Sealed tube, 140 ꢀC, 4 h
MW, 180 ꢀC, 20 min
Reflux, 4 h
3b (14%)
3b (10%)
N
O
CO2Me
5
Sealed tube, 140 ꢀC, 4 h
MW, 180 ꢀC, 20 min
CO2Me
OS
N
N
1b
CO2Me
CO2Me
140 ꢀC for 4 h gave a good overall yield, the exo-cycloadduct 3a
being again the major product (Table 1, entry 3). It was demon-
strated that heteropentalene 2a can also be generated under mi-
crowave irradiation (MW). The same pattern of reactivity was
observed in the cycloaddition of 2a with NPM carrying out the
microwave irradiation with the temperature set to 180 ꢀC for
20 min, giving exo- and endo-cycloadducts 3 in 83% overall yield
(Table 1, entry 4).
The reaction of 1a and DMAD in boiling acetic anhydride
afforded the 1:1 adduct thiazolo[2,3,4-cd]pyrrolizine 4 in 51% yield
via cycloaddition across the azomethine ylide portion of the non-
classical heterocyclic-fused-[c]thiazole 2a (Table 1, entry 5). Un-
der these reaction conditions a complex mixture was obtained but
crystallization from methanol gave compound 4 in pure form, as
described in the literature.2,3 Carrying out the thermolysis at 140 ꢀC
in a sealed tube for 4 h the tricyclic heterocyclic compound 4 was
obtained in moderate yield (35%), whereas under microwave irra-
diation at 180 ꢀC for 20 min the target molecule 4 could only be
isolated in 15% yield (Table 1, entries 6 and 7). Thus, conventional
thermolysis is the best reaction condition for the synthesis of
heterocycle 4.
MeO2C
MeO2C
Ac2O
N
DMAD
N
6
Entry
Dipolarophile
Reaction conditions
Products (yield)
1
2
3
4
5
6
7
8
9
NPM
NPM
NPM
NPM
Reflux, 4 h
Reflux, 7 h
5 (42%)
5 (76%)
5 (65%)
5 (71%)
5 (54%)
6 (26%)
6 (45%)
6 (45%)
6 (30%)
6 (53%)
Sealed tube, 140 ꢀC, 4 h
Sealed tube, 140 ꢀC, 7 h
MW, 180 ꢀC, 15 min
Reflux, 4 h
NPM
DMAD
DMAD
DMAD
DMAD
DMAD
Reflux, 7 h
Sealed tube, 140 ꢀC, 4 h
MW, 160 ꢀC, 10 min
MW, 180 ꢀC, 15 min
10
The non-classical thiazole 2b reacts with DMAD giving pyrazolo
[1,5-a]pyridine 6 resulting from the initial cycloaddition across the
thiocarbonyl ylide portion of 2b followed by spontaneous loss of
sulfur. Carrying out the reaction in boiling acetic anhydride for 4 h
compound 6 was obtained in only 26% yield but with a longer

8394
M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
Table 3
reaction time the yield could be improved to 45% (Table 2, entries 6
and 7). The same yield was obtained carrying out the sealed tube
thermolysis at 140 ꢀC for 4 h (Table 2, entry 8). The dehydration of
2-oxo-pyrazolo[1,5-c]thiazole 1b and the subsequent cycloaddition
with DMAD was also achieved under microwave irradiation (Table
2, entries 9 and 10). The best reaction conditions, microwave irra-
diation at 180 ꢀC for 15 min, afforded compound 6 in 53% yield.
Semi-empirical calculations reported by Storr et al. indicated
that the cycloaddition of non-classical thiazoles 2 is dipole-HOMO
controlled.3 On the other hand the coefficients in the HOMO
suggest that the addition across both thiocarbonyl ylide and azo-
methine or azomethine imine ylide portion of 2a and 2b, re-
spectively, would be possible. However, exclusive formation of
pyrazolo[1,5-a]pyridine adducts from 2b in contrast with the
synthesis of both types of adducts from 2a can be explained
considering the type of bonds being formed in each case. As
mentioned by the authors, the calculation did not take into ac-
count this fact. In the case of 2a both types of additions lead to two
new carbonecarbon bonds, whereas in the case of 2b addition
across the thiocarbonyl ylide moiety also leads to two new
carbonecarbon bonds but the addition across the azomethine
imine portion would lead to the formation of a carbonecarbon
bond and to a less favourable carbonenitrogen bond.
Generation and cycloaddition of heteropentalene 11
CO2Me
CO2Me
CO2Me
Ac2O
CO2Me
S
OS
Bn
N
N
Me
Me
Bn
8a
11
NPM or
NMM
Ac2O
CO2Me
O
CO2Me
CO2Me
O
S
CO2Me
R
N
S
R
N
11
N
N
Me
O
Me
O
Bn
Bn
10a R = Ph
10b R = Me
9a R = Ph
9b R = Me
Entry
Dipolarophile
Reaction
Products (yield)
conditions
1
2
NPM
NPM
Reflux, 4 h
MW, 160 ꢀC
20 min
9a (22%)
9a (10%)
10a (20%)
10a (23%)
11 (23%)
11 (36%)
3
4
NMM
NMM
Reflux, 4 h
Sealed tube
140 ꢀC, 4 h
MW, 160 ꢀC
20 min
Reflux, 4 h
MW, 160 ꢀC
25 min
9b (10%)
d
10b (39%)
10b (10%)
11 (21%)
11 (16%)
The work was extended to the synthesis and reactivity of new 3-
benzyl and 2-oxo-3-methyl-1H,3H-pyrrolo[1,2-c]thiazoles 8a and
8b in order to evaluate the scope of this approach to nitrogen-
bridged heterocycles (Scheme 2, Tables 3 and 4). 1H,3H-Pyrrolo
[1,2-c]thiazole 7a and 7b were prepared by a known procedure15
and converted into the corresponding sulfoxides 8 by oxidation
with MCPBA (Scheme 2).
5
NMM
9b (6%)
10b (8%)
11 (17%)
6
7
d
d
11 (50%)
11 (33%)
Interestingly, the oxidation of chiral 3-benzyl-1H,3H-pyrrolo
[1,2-c]thiazole 7a gave the corresponding sulfoxide 8a as a 9:1
mixture of diastereoisomers, which could be separated by flash
chromatography to give the optically pure sulfoxides. The major
isomer was isolated in 76% yield and the minor isomer
was obtained in 3% yield. Thus, using an achiral oxidant a diaster-
eoselective reaction was achieved, the stereochemistry of the
sulfoxide being induced by the proximity of the chiral center at the
Table 4
Cycloaddition of the heteropentalene generated from 2-oxo-1H,3H-pyrrolo[1,2-c]
thiazole 8b
CO2Me
CO2Me
OS
Me
N
Me
8b
NPM or
NMM
Ac2O
CO2Me
a
-position of 1H,3H-pyrrolo[1,2-c]thiazole 7a. Chiral sulfoxides are
valuable for asymmetric synthesis due to the high asymmetric in-
duction that can be exerted by the chiral sulfinyl group, making
them interesting target molecules.16
O
CO2Me
CO2Me
O
S
CO2Me
R
N
S
R
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
O
Me
Me
O
Me
Me
MCPBA
13a R = Ph
13b R = Me
12a R = Ph
12b R = Me
S
OS
N
N
Me
Me
R
R
Entry
Dipolarophile
Reaction conditions
Products (yield)
7a R = Bn
7b R = Me
8a R = Bn
8b R = Me
79%
57%
1
2
3
4
5
NPM
NPM
NPM
NMM
NMM
Reflux, 4 h
12a (39%)
12a (36%)
12a (20%)
12b (19%)
12b (20%)
13a (15%)
13a trace
13a trace
13b (23%)
13b (19%)
Sealed tube, 140 ꢀC, 4 h
MW, 140 ꢀC, 20 min
Reflux, 4 h
Scheme 2. Synthesis of 2-oxo-1H,3H-pyrrolo[1,2-c]thiazole 8.
Sealed tube, 140 ꢀC, 4 h
Pummerer-type dehydration of 2-oxo-3-benzyl-1H,3H-pyrrolo
[1,2-c]thiazole 8a in the presence of N-substituted maleimides was
studied (Table 3). Under conventional heating for 4 h the cycload-
dition reaction with N-phenylmaleimide gave a mixture of the exo-
and endo-cycloadducts 9a and 10a in 22% and 20% yield, re-
spectively (Table 3, entry 1). Interestingly, from this reaction the
non-classical thiazole 11 resulting from sulfoxide 8a dehydration,
was also isolated. The structure of heterocycle 11 was established
by X-ray crystallography (Fig. 1). This compound crystallized, in the
monohydrated form, as yellow plates in the monoclinic system
within Cc space group, showing a planar heterocyclic backbone. All
distances and angles are within the expected values for similar
compounds,17 the benzyl substituent making an angle of 33.7ꢀ
with the pyrrolo[1,2-c]thiazole. The carboxylate substituents on
consecutive carbons of the pyrrole fragment, make an angle of 47.0ꢀ
due to the high steric hindrance introduced.
The exo/endo assignments of cycloadducts 9a and 10a were
based on previously described 1H NMR data of similar derivatives,
characterized by a larger deshielding effect of the sulfur bridge on
the imide
a
-protons of the endo-cycloadduct.3,18 The structural
assignment of compound 10a was also supported by two-
dimensional HSQC and NOESY spectra (400 MHz). In the NOESY
spectrum sulfur bridge proton H-9 (5.28 ppm) shows connectivity
with imide a-proton H-9a (3.98 ppm) and aliphatic benzyl protons
(3.78 and 4.38 ppm) are correlated with imide
(3.92 ppm).
a-proton H-3a

M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
8395
successful and led only to the recoveryof the staring material. On the
other hand, reaction with potassium tert-butoxide led to a complex
mixture.
CO2Me
CO2Me
O
R1
N
S
9a/10a R1 = Ph; R2 = Bn
12a/13a R1 = Ph; R2 = Me
12b/13b R1 = R2 = Me
N
Me
O
O
R2
NaOMe or t-BuOK
CO2Me
R1
N
CO2Me
N
Me
O
R2
14a R1 = Ph; R2 = Bn
14b R1 = Ph; R2 = Me
14c R1 = R2 = Me
38%
87%
50%
Fig. 1. ORTEP-3 diagram of compound 11, using 50% probability level ellipsoids. Hy-
drogen atoms have been omitted for clarity.
Scheme 3. Desulfurization of 4,9-epithio-2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-f]
indolizines.
Under microwave irradiation at 160 ꢀC for 20 min compounds
9a, 10a and 11 were obtained, the heteropentalene 11 being the
major product (Table 3, entry 2). The reaction of 2-oxo-3-benzyl-
1H,3H-pyrrolo[1,2-c]thiazole 8a with N-methylmaleimide in boil-
ing acetic anhydride for 4 h gave the expected 1,3-dioxo-2-phenyl-
4,9-epithio-2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizines
9b and 10b together with the formation of heteropentalene 11 in
70% overall yield (Table 3, entry 3). From the sealed tube ther-
molysis only endo-cycloadduct 10b and compound 11 could be
isolated in 10% and 16% yield, respectively (Table 3, entry 4). The
microwave induced reaction of sulfoxide 8a in the presence of
NMM gave compounds 9b, 10b and 11 in low overall yield (Table 3,
entry 5).
In the absence of a dipolarophile the dehydration of 2-oxo-3-
benzyl-1H,3H-pyrrolo[1,2-c]thiazole 8a in boiling acetic anhy-
dride for 4 h gave the non-classical heterocyclic-fused-[c]thiazole
11 in 50% yield, whereas from the microwave induced dehydration
compound 11 was isolated in lower yield (Table 3, entries 6 and 7).
However, attempts to carry out the reaction of non-classical het-
eropentalene 11 with NPM under conventional heating or under
microwave irradiation only led to complex mixtures.
The heteropentalenes derived from 2-oxo-1H,3H-pyrrolo[1,2-c]
thiazoles studied so far were 5-substituted heteropentalene 2a or
3,5-substituted heteropentalenes (compound 11 and the hetero-
pentalene derived from 8b). Only the non-classical thiazole 2a
reacted as thiocarbonyl ylide in the reaction with N-substituted
maleimides and as an azomethine ylide with acetylene dicarbox-
ylate. Therefore, considering that steric effects may play a role in
the observed reactivity, we decided to prepare and explore the
reactivity of new 3,5-unsubstituted heteropentalenes.
3,5-Unsubstituted-1H,3H-pyrrolo[1,2-c]thiazole sulfoxide 18
was prepared as outlined in Scheme 4. Formylation of thiazolidine
15 in high yield was achieved by the reaction with formic acid and
acetic anhydride following a known procedure15 Treatment of the
N-formylthiazolidine 16 with triethylamine and tosyl chloride in
the presence of dimethyl acetylene dicarboxylate afforded pyrrolo
[1,2-c]thiazole 17 in 64% yield. The oxidation of 17 with MCPBA
afforded sulfoxide 18 in 52% yield.
CO2H
CO2H
Although these new disubstituted heteropentalenes showed the
HCO2H
Ac2O
NEt3, TsCl
DMAD
S
N
S
NH
CHO
expected reactivity for the [4
no reaction was observed with acetylene dicarboxylate.
p
þ2
p] cycloaddition with maleimides,
15
16 99%
The chemical behaviour of 2-oxo-3-methyl-1H,3H-pyrrolo[1,2-
c]thiazole 8b under thermolysis in acetic anhydride in the presence
of dipolarophiles was similar to the one observed for sulfoxide 8a.
CO2Me
CO2Me
CO2Me
CO2Me
MCPBA
S
OS
In fact, [4pþ2p] cycloadducts were obtained from the reaction with
N
N
maleimides but no reaction was observed with acetylene dicar-
boxylate (Table 4). However, in this case the heteropentalene
generated in situ from compound 8b could not be isolated. The
reaction of sulfoxide 8b with NPM in boiling acetic anhydride for
4 h gave exo-cycloadduct 12a and endo-cycloadduct 13a in 39% and
15% yield, respectively (Table 4, entry 1). Carrying out the reaction
in a sealed tube at 140 ꢀC for 4 h compound 12a was obtained in
36% yield and only traces of compound 13a could be detected (Table
4, entry 2). Under microwave irradiation compound 12a was iso-
lated in 20% yield (Table 4, entry 3). The reaction of sulfoxide 8a
with N-methylmaleimide in boiling acetic anhydride or under
sealed tube thermolysis gave the expected endo- and exo-cyclo-
adducts 12b and 13b (Table 4, entries 4 and 5).
18 52%
17 64%
Scheme 4. Synthesis of 2-oxo-1H,3H-pyrrolo[1,2-c]thiazole 18.
Dehydration of 2-oxo-1H,3H-pyrrolo[1,2-c]thiazole 18 led to the
target 3,5-unsubstituted heteropentalene, which was trapped with
maleimides leading to products resulting from both additions
across the thiocarbonyl ylide (compounds 19 and 20) and azome-
thine ylide moieties (compound 21) (Table 5). Carrying out the
reaction of sulfoxide 18 in boiling acetic anhydride in the presence
of NPM for 4 h cycloadducts 19a (33%) and 21a (18%) were obtained
(Table 5, entry 1), whereas the sealed tube thermolysis gave com-
pounds 19a, 20a and 21a in 47% overall yield (Table 5, entry 2). The
microwave induced reaction allowed the synthesis of the products
resulting from the cycloaddition across the thiocarbonyl ylide
portion of the in situ generated heteropentalene, the exo-cyclo-
adduct 19a in 55% yield and the endo-cycloadduct 20a in 13% yield
The mixture of exo- and endo-cycloadducts 9a/10a and 12/13
underwent elimination of hydrogen sulfide on treatment with so-
dium methoxide or potassium tert-butoxide to afford indolizines
14 (Scheme 3). Attempts to promote the elimination of hydrogen
sulfide with sodium methoxide from adducts 9b/10b was not

8396
M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
Table 5
Table 6
Cycloaddition of the heteropentalene generated from 2-oxo-1H,3H-pyrrolo[1,2-c]
thiazole 18
Cycloaddition of the heteropentalene generated from 2-oxo-1H,3H-pyrrolo[1,2-c]
thiazole 24
CO2Me
O
CF3
CF3
CF3
S
CO2Me
R
N
S
N
Ac2O
H2O2
Na2WO4
N
S
OS
19a R = Ph
19b R = Me
N
N
O
O
NPM
or
NMM
O
O
N
R
CO2Me
CO2Me
CO2Me
23
24 90%
Ac2O
S
CO2Me
R
N
OS
25
N
N
NPM or NMM
CF3
CF3
O
20a R = Ph
20b R = Me
18
S
H
CO2Me
S
H
N
N
S
CO2Me
N
O
O
O
O
N
R
N
R
H
27a R = Ph
27b R = Me
26a R = Ph
21a R = Ph
21b R = Me
O
O
N
R
Entry
Dipolarophile
Reaction conditions
Products (yield)
1
2
3
4
5
6
NPM
NPM
NPM
NPM
NMM
NMM
Reflux, 4 h
Reflux, 7 h
26a (8%)
26a (11%)
26a (10%)
26a trace
d
27a (13%)
Entry
Dipolarophile
Reaction
conditions
Products (yield)
27a (30%)
27a (26%)
27a trace
27b (50%)
27b (63%)
Sealed tube, 140 ꢀC, 7 h
MW, 140 ꢀC, 20 min
Reflux, 7 h
1
2
NPM
NPM
Reflux, 4 h
Sealed tube
140 ꢀC, 4 h
MW, 180 ꢀC
20 min
19a (33%)
19a (28%)
d
21a (18%)
21a (12%)
20a (7%)
Sealed tube, 140 ꢀC, 7 h
d
3
NPM
19a (55%)
20a (13%)
d
crystallography (Fig. 2). This compound crystallized as colourless
prisms in the triclinic system within Pꢁ1 space group, as a racemic
mixture. All distances and angles are within the expected values for
similar compounds.17 The compound displays an endo configura-
tion, which is attested not only by the torsion angles around
C4aeC4b and C7aeC7b (see Supplementary data), but also from the
angles between planes [C4beC5eN6eC7eC7a] and [C4aeC4be
C7beC7aeN8]; [C4beC5eN6eC7eC7a] and [C2aeC3eC4e
C4aeN8], and [C4aeC4beC7beC7aeN8] and [C2aeC3eC4e
C4aeN8], respectively 64.5, 24.4 and 87.8ꢀ. The thiazole moiety
adopts an envelope conformation characterized by a value of 31.4ꢀ
for the hinge angle that represents the bending at a line defined by
atoms C2 and C7b.
4
5
NMM
NMM
Reflux, 4 h
Sealed tube
140 ꢀC, 4 h
MW, 180 ꢀC
20 min
19b (20%)
19b (19%)
20b (9%)
20b (2%)
21b (27%)
21b (16%)
6
NMM
19b (19%)
20b (8%)
21b (26%)
(Table 5, entry 3). The dehydration of 2-oxo-1H,3H-pyrrolo[1,2-c]
thiazole 18 was also carried out in the presence of NMM under
different reaction conditions (Table 5, entries 4e6). In all cases 19b,
20b and 21b were obtained. Thus, for the first time a pyrrolo[1,2-c]
thiazole heteropentalene reacted with N-substituted maleimides
not only as a thiocarbonyl ylide but also as an azomethine ylide.
The mixture of exo- and endo-cycloadducts 19/20 underwent
elimination of hydrogen sulfide on treatment with potassium tert-
butoxide to afford indolizines 22.
CO2Me
CO2Me
O
R
N
N
22a R = Ph 35%
22b R = Me 38%
O
The work was extended to a new non-classical thiazole derived
from 3,5-unsubstituted-1H,3H-pyrrolo[1,2-c]thiazole sulfoxide 24
(Table 6). Pyrrolo[1,2-c]thiazole 23 bearing only one tri-
fluoromethyl group at C-7 was converted into the corresponding
sulfoxide 24 by catalytic oxidation. By adjustment of an experi-
mental procedure described in the literature for the synthesis of
2,2-dioxo-7-trifluoromethyl-1H,3H-pyrrolo[1,2-c]thiazole20 a 92:8
mixture of sulfoxide 24 and the corresponding sulfone was
obtained as a solid (using 2.4 equiv of hydrogen peroxide). The solid
was washed with diethyl ether giving sulfoxide 24 in pure form in
90% yield, without the need for further purification.
Dehydration of 24 in the presence of NPM led to a mixture of the
exo- and endo-cycloadducts 25 (R¼Ph). Sigmatropic H shift of these
cycloadducts afforded the final products 26a and 27a in moderate
yield either in boiling acetic anhydride or under sealed tube ther-
molysis (Table 6, entries 1e3). However, under microwave irradi-
ation only traces of these products could be detected (Table 6,
entry 4). The structure of heterocycle 27a was determined by X-ray
Fig. 2. ORTEP-3 diagram of 5,7(4bH,6H)-dioxo-6-phenyl-3-(trifluoromethyl)-7a,7b-
dihydro-2H-pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]pyrrolizine 27a, using 50% probability
level ellipsoids. Hydrogen atoms have been omitted for clarity.

M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
8397
The dehydration of sulfoxide 24 in the presence of N-methyl-
meleimide was also explored, which led to the exclusive formation
of the endo-cycloadduct 27b (Table 6). Carrying out the reaction in
boiling acetic anhydride for 7 h compound 27b was obtained in 50%
yield (Table 6, entry 5). The sealed tube thermolysis allowed the
isolation of the same product in 63% yield (Table 6, entry 6).
We could conclude that the heteropentalene derived from 2-
below 25 ꢀC. Acetic anhydride (35.0 mL) was added dropwise to the
solution while maintaining the temperature between 10 and 18 ꢀC.
After stirring for 20 h at a temperature of the order of 20 ꢀC, the
solvent was evaporated off. The compound was obtained as a col-
ourless oil (99%). IR (film) 2934,1736,1665,1384,1216 cmꢁ1.1H NMR
(400 MHz, CDCl3) major isomer:
d 3.29e3.38 (m, 2H), 4.63 (d,
J¼8.8 Hz, 1H), 4.70 (d, J¼8.8 Hz, 1H), 5.09 (approx. t, J¼5.6 and
oxo-1H,3H-pyrrolo[1,2-c]thiazole 24 participates in [4
p
þ2
p] cy-
6.0 Hz, 1H), 7.64 (br s, 1H, OH), 8.35 (s, 1H, CHO); minor isomer:
cloadditions with N-substituted maleimides, but only as an azo-
methine ylide. Thus, steric and electronic factors must be
considered in order to rationalize the observed selectivity.
d
3.29e3.38 (m, 1H), 3.45 (dd, J¼1.6 and 11.6 Hz, 1H), 4.45 (d,
J¼9.6 Hz,1H), 4.76 (d, J¼9.6 Hz,1H), 4.83e4.84 (m,1H), 7.64 (br s,1H,
OH), 8.34 (s, 1H, CHO). MS (EI) m/z 161 (Mþ, 17%), 116 (26), 89 (100).
HRMS (EI-TOF) m/z 161.0151 (Mþ, C5H7NO3S requires 161.0147).
3. Conclusions
4.2.2. Dimethyl 1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate
(17). Triethylamine (5.2 mL, 37.7 mmol) was added to a suspension
of N-formylthiazolidine-4-carboxylic acid 16 (5.52 g, 34.3 mmol) in
dry dichloromethane (15.0 mL). This solution was added dropwise to
a mixture of tosyl chloride (7.34 g, 37.7 mmol) in dichloromethane
(15.0 mL) at 40 ꢀC. Dimethyl acetylene dicarboxylate (4.7 mL,
38.4 mmol) was then added quickly followed by triethylamine
(10.4 mL, 75.4 mmol). The reaction mixturewasmaintainedrefluxing
for 3 h. After cooling to room temperature water was added and the
organic layer was separated. The aqueous phase was extracted with
dichloromethane and the organic extracts are combined, dried over
anhydrous sodium sulfate and the solvent evaporated off. Purification
by flash chromatography [hexane/ethyl acetate (1:1), hexane/ethyl
acetate (1:2), then ethyl acetate] gave 17 as a white solid (64%). Mp
101e103 ꢀC (from ethylactetate/hexane). IR (KBr) 1728, 1708, 1433,
The [4
p
þ2
p] cycloaddition of non-classical heterocyclic-fused-
[c]thiazoles generated by dehydration of 2-oxo-1H,3H-pyrrolo[1,2-
c]thiazoles and 2-oxo-1H,3H-pyrazolo[1,5-c]thiazoles has been in-
vestigated giving access to new nitrogen-bridged bi-, tri- and tet-
racyclic heterocyclic compounds.
The reported results allowed for the definition of a reactivity
pattern of this type of heteropentalenes towards N-substituted mal-
eimides. The cycloaddition of the heteropentalene formed by de-
hydration of 2-oxo-1H,3H-pyrazolo[1,5-c]thiazole-6,7-dicarboxylate
leads to products resulting from the exclusive addition across the
thiocarbonyl ylide moiety. 5-Substituted and 3,5-substituted heter-
opentalenes derived from 2-oxo-1H,3H-pyrrolo[1,2-c]thiazole-6,7-
dicarboxylates also react with N-substituted maleimides as thio-
carbonyl ylide exclusively, whereas the cycloaddition of the 3,5-
unsubstituted derivative led to cycloadducts resulting from both
the addition across the thiocarbonyl and azomethine ylide moieties.
Interestingly, the non-classical heterocyclic-fused-[c]thiazole formed
by dehydration of the 2-oxo-1H,3H-pyrrolo[1,2-c]thiazole bearing
only one trifluoromethyl group at C-7 reacted with N-substituted
maleimides selectively as an azomethine ylide. Therefore, both steric
and electronic factors must be considered in order to rationalize the
observed selectivity.
1285, 1130, 1071 cmꢁ1. 1H NMR (400 MHz, CDCl3)
(s, 3H), 4.27 (s, 2H), 5.04 (s, 2H), 7.19 (s,1H).13C NMR (100 MHz, CDCl3)
d 3.82 (s, 3H), 3.83
d
30.1, 49.1, 51.5, 51.6,107.8,120.5,121.6,142.8,163.6,163.7. MS (EI) m/z
241 (Mþ, 30%), 209 (100),164 (59),151 (46), 134 (25), 123 (36). HRMS
(EI-TOF) m/z 241.0412 (Mþ, C10H11NO4S requires 241.0409).
4.2.3. 2-Oxo-7-trifluoromethyl-1H,3H-pyrrolo[1,2-c]thiazole (24). A
25 mL flask with a solution of 7-trifluoromethyl-1H,3H-pyrrolo[1,2-
c]thiazole 23 (4.03 mmol) in ethyl acetate (12 mL) was charged
For the first time, one non-classical pyrrolo[1,2-c]thiazole was
isolated and its structure determined by X-ray crystallography.
with Na2WO4$H2O (0.05 M in water, 12
(0.05 M in water, 12 L, 0.6 mol), CH3N[(CH2)7CH3]Cl (0.05 M in
methanol, 12 L, 0.6 mol) and 35% H2O2 (4.84 mmol). This mixture
mL, 0.6 mmol), C6H5PO3H2
m
m
4. Experimental
m
m
was vigorously stirred at 35e40 ꢀC. After 3 h, a new load of catalyst
was added and stirred overnight at 35e40 ꢀC. The reaction mixture
was washed with 10% (w/v) aqueous sodium bisulfite and the
aqueous phase was extracted with ethyl acetate. The organic phase
was then dried over anhydrous MgSO4 and the solvent evaporated
off. The crude product of the reaction was washed with ethyl ether
giving compound 24 as a white solid in 90% yield. Mp 101e102 ꢀC.
IR (KBr) 1597, 1486, 1380, 1266, 1161, 1108, 1084, 1031, 979 cmꢁ1. 1H
4.1. General methods
1H NMR spectra were recorded on an instrument operating at
300 or at 400 MHz. 13C NMR spectra were recorded on an in-
strument operating at 100 MHz. Chemical shifts are expressed in
parts per million related to internal TMS, and coupling constants (J)
are in hertz. IR spectra were recorded on a Nicolet 6700 FTIR
spectrometer. Mass spectra were recorded under electron impact
(EI) or electrospray ionization (ESI). HRMS spectra were recorded
on a Finnigan MAT95 S instrument. Melting points were de-
termined in open glass capillary with an Electrothermal melting
point apparatus and are uncorrected. Flash column chromatogra-
phy was performed with Merck 9385 silica as the stationary phase.
Microwave reactions were carried out in a microwave reactor CEM
Focused Synthesis System, Discover S-Class.
NMR (400 MHz, CDCl3)
d
4.10 (d, J¼16.4 Hz, 1H), 4.34 (dd, J¼1.0 and
16.4 Hz, 1H), 4.87 (d, J¼11.6 Hz, 1H), 5.06 (d, J¼11.6 Hz, 1H), 6.48 (d,
J¼2.8 Hz, 1H), 6.70 (d, J¼2.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d
51.6, 69.2, 110.3 (q, JCeCF3¼37.4 Hz), 111.9 (q, JCeCeCF3¼2.8 Hz),
117.4, 123.4 (q, JCeF¼264.4 Hz), 129.3 (q, JCeCeCF3¼4.1 Hz). MS (EI)
m/z 209 (Mþ, 54%), 161 (100), 142 (15), 92 (14). HRMS (EI-TOF) m/z
209.0127 (Mþ, C7H6NOF3S requires 209.0122).
1,3-Thiazolidine-4-carboxylic acid 15,3 1H,3H-pyrrolo[1,2-c]thi-
azoles 715 and 23,20 2-oxo-1H,3H-pyrrolo[1,2-c]thiazole 1a3 and 2-
oxo-1H,3H-pyrazolo[1,5-c]thiazole 1b3 were prepared as described
in the literature.
4.3. General procedure for the synthesis of 2-oxo-1H,3H-
pyrrolo[1,2-c]thiazole-6,7-dicarboxylates
To a stirred ice-cold solution of the appropriate dimethyl pyrrolo
[1,2-c]thiazole-6,7-dicarboxylate (13.0 mmol) in dry dichloro-
methane (70 mL) was added portionwise 3-chloroperoxybenzoic
acid (13.0 mmol) under N2 atmosphere. The cooling bath was re-
moved and the reaction mixture was allowed to warm to room
temperature. After stirring at room temperature for 1 h, the re-
action mixture was washed twice with 10% (w/v) aqueous sodium
4.2. Specific chemical procedures
4.2.1. N-Formylthiazolidine-4-carboxylic acid (16). 1,3-Thiazolidine-
4-carboxylic acid 15 (6.85 g, 51.5 mmol) was added to formic acid
(53.0 mL), the temperature of the reaction medium being kept

8398
M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
bisulfite solution (2ꢂ100 mL) and twice with 10% (w/v) aqueous
sodium bicarbonate solution (2ꢂ100 mL). The organic fraction was
then dried over anhydrous sodium sulfate and the solvent evapo-
rated off. The crude product was purified by flash chromatography
[hexane/ethyl acetate].
dipolarophile (1.22 mmol) in acetic anhydride (5 mL) was heated to
reflux for time indicated in each case. After cooling to room tem-
perature, the solvent was removed in vacuo and the products were
isolated by crystallization and/or flash chromatography.
Method B. A 35 mL sealed tube was charged with the appropriate
2-oxo-1H,3H-pyrrolo[1,2-c]thiazole or 2-oxo-1H,3H-pyrazolo[1,5-
c]thiazole (1.11 mmol), dipolarophile (1.33 mmol) and acetic an-
hydride (5 mL). The reaction mixture was heated at 140 ꢀC for the
time indicated in each case. After cooling to room temperature, the
solvent was removed in vacuo and the products were isolated by
crystallization and/or flash chromatography.
Method C. A solution of the appropriate 2-oxo-1H,3H-pyrrolo
[1,2-c]thiazole or 2-oxo-1H,3H-pyrazolo[1,5-c]thiazole (1.14 mmol)
and dipolarophile (1.36 mmol) in acetic anhydride (2 mL) was ir-
radiated in the microwave reactor with the temperature and time
indicated in each case. After cooling to room temperature, the
solvent was removed in vacuo and the products were isolated by
crystallisation and/or flash chromatography.
4.3.1. Dimethyl 2-oxo-3-benzyl-5-methyl-1H,3H-pyrrolo[1,2-c]thia-
zole-6,7-dicarboxylate (8a). Compound 8a was obtained as a mix-
ture of diastereoisomers, which was separated by flash
chromatography [hexane/ethyl acetate (1:2), ethyl acetate, then
ethyl acetate/methanol (9:1)]. Major isomer was obtained as a white
solid in 76% yield; mp 113e115 ꢀC (from ethyl ether). IR (KBr) 1729,
1684, 1644, 1558, 1451, 1094 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d 2.31
(s, 3H), 3.20 (dd, J¼5.2 and 14.4 Hz, 1H, CH2Ph), 3.28 (dd, J¼4.8 and
14.4 Hz, 1H, CH2Ph), 3.36 (d, J¼17.4 Hz,1H), 3.76 (s, 3H), 3.86 (s, 3H),
3.99 (d, J¼14.4 Hz, 1H), 5.23 (approx. t, J¼5.2 Hz, 1H, CHBn),
6.88e6.89 (m, 2H, ArH), 7.25e7.31 (m, 3H, ArH). 13C NMR (100 MHz,
CDCl3) d 11.4, 37.3, 51.4, 51.6, 51.8, 83.1,110.1,117.8,128.4,129.2,129.3,
131.8, 132.6, 136.6, 163.4, 164.8. MS (EI-TOF) m/z 361 (Mþ, 4%), 311
(38), 254 (37), 222 (100),134 (67). HRMS (EI-TOF) m/z 361.0985 (Mþ,
4.4.1. Dimethyl 1,3-dioxo-6-methyl-2-phenyl-4,9-epithio-2,3,3a,4,9,9a-
hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (3a, exo) and
(3b, endo). Method A (reaction time: 4 h). Trituration of the residue
with methanol followed by purification by flash chromatography
[hexane/ethyl acetate (2:1), then (1:1)] gave, in order of elution, exo-
adduct 3a (54%) and endo-adduct 3b (8%) both as solids.
C18H19NO5S requires 361.0984). ½a D25
þ245 (c 1, CH2Cl2). Minor iso-
ꢃ
mer was obtained as colourless needles in 3% yield; mp 143e144 ꢀC
(from hexane/ethyl acetate). IR (KBr) 1743, 1701, 1445, 1170, 1094,
1068 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
1.66 (s, 3H), 3.06 (dd, J¼9.2
and 14.4 Hz, 1H, CH2Ph), 3.58 (dd, J¼3.6 and 14.4 Hz, 1H, CH2Ph),
3.80 (s, 3H), 3.81 (s, 3H), 3.95 (d, J¼14.8 Hz, 1H), 4.78 (d, J¼14.8 Hz,
1H), 5.23 (dd, J¼4.0 and 9.2 Hz, 1H, CHBn), 7.09e7.10 (m, 2H, ArH),
Method B (reaction time: 4 h). Trituration of the residue with
ethyl acetate followed by purification by flash chromatography
[hexane/ethyl acetate (2:1), then (1:1)] gave, in order of elution,
exo-adduct 3a (58%) and endo-adduct 3b (14%).
7.27e7.32 (m, 3H, ArH). 13C NMR (100 MHz, CDCl3)
d 10.8, 32.8, 48.3,
51.6, 51.7, 71.4, 111.7, 115.7, 127.8, 128.9, 129.2, 129.9, 133.3, 134.5,
163.5, 164.7. MS (EI-TOF) m/z 361 (Mþ, 10%), 329 (38), 312 (65), 280
(100), 249 (73), 222 (57),178 (59). HRMS (EI-TOF) m/z 361.0983 (Mþ,
Method C (temperature set to 180 ꢀC for 20 min). Purification by
flash chromatography [hexane/ethyl acetate (1:1)] gave, in order of
elution, exo-adduct 3a (73%) and endo-adduct 3b (10%).
C18H19NO5S requires 361.0984). ½a D25
þ85 (c 1, CH2Cl2).
ꢃ
4.3.2. Dimethyl
2-oxo-3,5-dimethyl-1H,3H-pyrrolo[1,2-c]thiazole-
4.4.1.1. Dimethyl 1,3-dioxo-6-methyl-2-phenyl-4,9-epithio-2,3,3a,4,
9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate
(3a). Mp 209e211 ꢀC (from ethyl ether), lit. 210e211 ꢀC,2
6,7-dicarboxylate (8b). This compound was prepared in the same
manner described above, except that the reaction was carried at room
temperature for 30 min. The crude product was purified by flash
chromatography [hexane/ethyl acetate (1:1), ethyl acetate, then ethyl
acetate/methanol (9:1)]. Compound 8b was obtained as a white solid
in 74% yield. Mp 104e105 ꢀC (from ethyl ether). IR (KBr) 1733, 1705,
210e212 ꢀC.3 1H NMR (400 MHz, CDCl3)
d
2.46 (s, 3H), 3.48 (d,
-H), 3.84 (s,
J¼8.0 Hz, 1H, imide
a
-H), 3.51 (d, J¼8.0 Hz, 1H, imide
a
3H), 3.87 (s, 3H), 5.49 (s, 1H, sulfur bridge-H), 6.03 (s, 1H, sulfur
bridge-H), 7.25e7.27 (m, 2H, ArH), 7.42e7.52 (m, 3H, ArH).
1306, 1098, 1058 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
1.55 (d, J¼7.1 Hz,
3H), 2.42 (s, 3H), 3.81 (s, 3H), 3.85 (s, 3H), 4.26 (d, J¼17.4 Hz, 1H), 4.34
4.4.1.2. Dimethyl 1,3-dioxo-6-methyl-2-phenyl-4,9-epithio-2,3,3a,
4,9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate
(3b). Mp 244e246 ꢀC (from ethyl ether), lit.3 245e247 ꢀC. 1H NMR
(d, J¼17.4 Hz, 1H), 5.08 (q, J¼7.1 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d
11.2,16.3, 51.0, 51.5, 51.6, 77.8,110.5,117.5,131.5,134.8,163.5,164.8. MS
(EI) m/z 285 (Mþ,14%), 237 (79), 205 (100), 178 (39),147 (42),119 (40).
HRMS (EI-TOF) m/z 285.0675 (Mþ, C12H15NO5S requires 285.0671).
(400 MHz, CDCl3)
(m, 2H, imide
d 2.34 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 4.19e4.26
-H), 5.55 (d, J¼4.0 Hz, 1H, sulfur bridge-H), 6.10 (d,
a
J¼2.4 Hz 1H, sulfur bridge-H), 6.82e6.84 (m, 2H, ArH), 7.33e7.38
4.3.3. Dimethyl 2-oxo-1H,3H-pyrrolo[1,2-c]thiazole-6,7-
dicarboxylate (18). This compound was prepared in the same
manner described above, except that the reaction was carried at
(m, 3H, ArH).
ꢀC for 30 min. The product was obtained as colourless oil, which
4.4.2. Tetramethyl 4a-methyl-4a,6a-dihydrothiazolo[2,3,4-cd]pyrro-
lizine-3,4,5,6-tetracarboxylate (4). Method A (reaction time: 4 h).
Trituration of the residue with methanol followed by re-
crystallization with the same solvent gave compound 4 as a pale
yellow solid (51%).
0
crystallizes with ethyl ether to give a white solid in 45% yield. Mp
133e135 ꢀC. IR (KBr) 1722, 1702, 1438, 1287, 1204, 1126, 1073 cmꢁ1
1H NMR (400 MHz, CDCl3)
3.82 (s, 3H), 3.84 (s, 3H), 4.32 (d,
.
d
J¼17.1 Hz, 1H), 4.42 (d, J¼17.1 Hz, 1H), 4.91 (d, J¼12.1 Hz, 1H), 5.08
(d, J¼12.1 Hz, 1H), 7.28 (s, 1H). 13C NMR (100 MHz, CDCl3)
d 51.6,
Method B (reaction time: 4 h). Trituration of the residue with
methanol followed by recrystallization with the same solvent gave
compound 4 (35%).
51.7, 53.4, 69.6, 111.1, 121.0, 123.0, 138.0, 163.1, 163.2. MS (EI) m/z 257
(Mþ, 33%), 225 (29), 209 (100), 194 (36), 178 (20), 164 (22). HRMS
(EI-TOF) m/z 257.0362 (Mþ, C10H11NO5S requires 257.0358).
Method C (temperature set to 180 ꢀC for 20 min). Trituration of
the residue with methanol followed by recrystallization with the
same solvent gave compound 4 (15%).
4.4. General procedures for generation and trapping of
pyrrolo[1,2-c]thiazole and pyrazolo[1,5-c]thiazole
heteropentalenes
4.4.2.1. Tetramethyl 4a-methyl-4a,6a-dihydrothiazolo[2,3,4-cd]
pyrrolizine-3,4,5,6-tetracarboxylate (4). Mp 238e240 ꢀC lit.
238e240 ꢀC,2 239e241 ꢀC.3 1H NMR (400 MHz, CDCl3)
d 1.69 (s,
Method A. A solution of the appropriate 2-oxo-1H,3H-pyrrolo[1,2-
c]thiazole or 2-oxo-1H,3H-pyrazolo[1,5-c]thiazole (1.02 mmol) and
3H), 3.74 (s, 3H), 3.77 (s, 9H), 4.99 (s, 1H), 5.75 (s, 1H).

M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
8399
4.4.3. Dimethyl
1,3-dioxo-2-phenyl-4,9-epithio-2,3,3a,4,9,9a-hex-
1H), 3.92 (d, J¼8.4 Hz, 1H, imide
1H, imide
a
-H), 3.98 (dd, J¼4.0 and 8.4 Hz,
ahydro-1H-pyrazolo[1,5-a]pyrrolo[3,4-c]pyridine-7,8-dicarboxylate
(5). Method A (reaction time: 7 h). Trituration of the residue with
methanol followed by recrystallization with the same solvent gave
exo-adduct 5 (76%).
a
-H), 4.38 (d, J¼13.6 Hz, 1H), 5.28 (d, J¼4.0 Hz, 1H, sulfur
bridge-H), 6.78e6.80 (m, 2H, ArH), 7.19e7.40 (m, 8H, ArH). 13C NMR
(100 MHz, CDCl3) 10.7, 35.6, 47.6, 50.6, 50.8, 53.3, 54.4, 89.1, 106.5,
d
115.2, 125.6, 127.3, 128.1, 128.2, 129.0, 129.6, 130.7, 133.4, 140.2,
161.8, 164.1, 170.4, 171.0. MS (ESI-TOF) m/z 539 ([MþNa]þ, 100%),
413 (5), 279 (6), 227 (21). HRMS (ESI-TOF) m/z 539.1244 ([MþNa]þ,
C28H24N2O6SNa requires 539.1247).
Method B (reaction time: 7 h). Trituration of the residue with
methanol followed by recrystallization with the same solvent gave
exo-adduct 5 (71%).
Method C (temperature set to 180 ꢀC for 15 min). Trituration of
the residue with methanol followed by recrystallization with the
same solvent gave exo-adduct 5 (54%), which was identified by
comparison with the specimen previously prepared.
4.4.5.3. Dimethyl 1,3-dioxo-4-benzyl-6-methyl-2-phenyl-4,9-
epithio-2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-
dicarboxylate (9a). Pale yellow solid, mp 201e203 ꢀC (from ethyl
ether). IR (KBr) 1710, 1390, 1208, 1173, 1079 cmꢁ1
.
1H NMR
-H),
a-H), 3.84 (s, 3H), 3.87 (s,
4.4.3.1. Dimethyl 1,3-dioxo-2-phenyl-4,9-epithio-2,3,3a,4,9,9a-hex-
ahydro-1H-pyrazolo[1,5-a]pyrrolo[3,4-c]pyridine-7,8-dicarboxylate
(5). White solid, mp 199e201 ꢀC lit.3 202e203 ꢀC. 1H NMR
(400 MHz, CDCl3)
and 6.4 Hz,1H, imide
(400 MHz, CDCl3)
d
2.38 (s, 3H), 3.34 (d, J¼6.4 Hz, 1H, imide
a
3.50 (dd, J¼0.8 and 6.4 Hz, 1H, imide
3H), 4.19 (d, J¼18.0 Hz, 1H), 4.31 (d, J¼18.0 Hz, 1H), 5.44 (br s, 1H,
d
3.53 (d, J¼6.0 Hz, 1H, imide
a-H), 3.68 (dd, J¼1.2
sulfur bridge-H), 7.22e7.32 (m, 8H, ArH), 7.42e7.51 (m, 2H, ArH).
a-H), 3.92 (s, 3H), 3.96 (s, 3H), 5.52 (s,1H, sulfur
13C NMR (100 MHz, CDCl3)
d 11.7, 36.6, 48.6, 51.6, 51.8, 54.4,
bridge-H), 6.28 (s, 1H, sulfur bridge-H), 7.25e7.27 (m, 2H, ArH),
7.45e7.52 (m, 3H, ArH).
55.4, 90.1, 107.5, 116.2, 126.6, 128.4, 129.1, 129.3, 130.0, 130.7,
131.8, 134.4, 141.3, 162.8, 165.1, 171.4, 172.0. MS (ESI-TOF)
m/z 539 ([Mþ1]þ, 100%), 517 (24), 336 (6), 245 (6), 201 (35).
HRMS (ESI-TOF) m/z 517.1419 ([Mþ1]þ, C28H25N2O6S requires
517.1428).
4.4.4. Tetramethyl pyrazolo[1,5-a]pyridine-2,3,5,6-tetracarboxylate
(6). Method A (reaction time: 7 h). Purification by flash chroma-
tography [hexane/ethyl acetate (2:1), then (1:1)] gave compound 6
(45%).
4.4.6. Non-classical dimethyl 3-benzyl-5-methyl-1H,3H-pyrrolo[1,2-
c]thiazole-6,7-dicarboxylate (11), dimethyl 1,3-dioxo-4-benzyl-2,6-
dimethyl-4,9-epithio-2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-f]in-
dolizine-7,8-dicarboxylate (9b, exo) and (10b, endo). Method A (re-
action time: 4 h). Purification by flash chromatography [hexane/
ethyl acetate (2:1), then (1:1)] gave, in order of elution, 11 (21%),
endo-adduct 10b (39%) and exo-adduct 9b (10%).
Method B (reaction time: 7 h). Purification by flash chromatog-
raphy [hexane/ethyl acetate (2:1), then (1:1)] gave compound 6
(45%).
Method C (temperature set to 180 ꢀC for 15 min). Purification by
flash chromatography [hexane/ethyl acetate (2:1), then (1:1)] gave
compound 6 (53%).
Method B (reaction time: 4 h). Purification by flash chromatog-
raphy [hexane/ethyl acetate (2:1), then (1:1)] gave, in order of
elution, 11 (16%) and endo-adduct 10b (10%).
4.4.4.1. Tetramethyl pyrazolo[1,5-a]pyridine-2,3,5,6-
tetracarboxylate (6). Yellow solid, mp 99e101 ꢀC (from ethyl ace-
tate/hexane), lit.19 95e97 ꢀC. 1H NMR (400 MHz, CDCl3)
d
3.96 (s,
Method C (temperature set to 160 ꢀC for 20 min). Purification by
flash chromatography [hexane/ethyl acetate (2:1), then (1:1)] gave,
in order of elution, 11 (17%), endo-adduct 10b (8%) and exo-adduct
9b (6%).
3H), 3.97 (s, 3H), 3.98 (s, 3H), 4.05 (s, 3H), 8.40 (s, 1H), 9.00 (s, 1H).
4.4.5. Non-classical dimethyl 3-benzyl-5-methyl-1H,3H-pyrrolo[1,2-
c]thiazole-6,7-dicarboxylate (11), dimethyl 1,3-dioxo-4-benzyl-6-
methyl-2-phenyl-4,9-epithio-2,3,3a,4,9,9a-hexahydro-1H-pyrrolo
[3,4-f]indolizine-7,8-dicarboxylate (9a, exo) and (10a, endo). Method
A (reaction time: 4 h). Trituration of the residue with methanol
followed by flash chromatography [hexane/ethyl acetate (3:1),
(2:1), then (1:1)] gave, in order of elution,11 (23%), endo-adduct 10a
(20%) and exo-adduct 9a (22%).
Compound 11 was characterized by comparison with a speci-
men previously prepared.
4.4.6.1. Dimethyl 1,3-dioxo-4-benzyl-2,6-dimethyl-4,9-epithio-2,3,
3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate
(10b). Yellow solid, mp 101e103 ꢀC (from ethyl ether). IR (KBr)
1778, 1703, 1434, 1290, 1210, 1123, 1087 cmꢁ1
CDCl3) d 2.47 (s, 3H), 2.57 (s, 3H), 3.77e3.86 (m, 3H, imide a
.
1H NMR (400 MHz,
-H and
-H),
Method C (temperature set to 160 ꢀC for 20 min). Purification by
flash chromatography [hexane/ethyl acetate (3:1), (2:1), then (1:1)]
gave, in order of elution, 11 (36%), endo-adduct 10a (23%) and exo-
adduct 9a (10%).
CH2Ph), 3.80 (s, 3H), 3.83 (s, 3H), 4.40 (d, J¼13.6 Hz, 1H, imide
a
5.25 (d, J¼4.0 Hz, 1H, sulfur bridge-H), 7.36e7.45 (m, 5H, ArH). 13C
NMR (100 MHz, CDCl3)
d 11.6, 24.5, 36.6, 48.5, 51.6, 51.8, 54.0, 55.4,
90.1, 107.6, 116.1, 128.3, 129.0, 130.0, 131.9, 134.5, 141.2, 162.8,
165.1, 172.4, 172.9. MS (EI-TOF) m/z 454 (Mþ, 13%), 422 (100), 336
(86). HRMS (EI-TOF) m/z 454.1198 (Mþ, C23H22N2O6S requires
454.1199).
4.4.5.1. Non-classical dimethyl 3-benzyl-5-methyl-1H,3H-pyrrolo
[1,2-c]thiazole-6,7-dicarboxylate (11). White solid, mp 149e150 ꢀC
(from methanol). IR (KBr) 1702, 1581, 1546, 1445, 1408, 1383, 1229,
1177, 1090 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
2.70 (s, 3H), 3.81 (s,
3H), 3.88 (s, 3H), 4.41 (s, 2H), 6.87 (s, 1H), 7.24e7.27 (m, 1H, ArH),
7.37e7.43 (m, 4H, ArH). 13C NMR (100 MHz, CDCl3)
13.4, 29.3, 51.5,
4.4.6.2. Dimethyl 1,3-dioxo-4-benzyl-2,6-dimethyl-4,9-epithio-
2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-
dicarboxylate (9b). Yellow oil. IR (film) 1701, 1437, 1403, 1384, 1297,
d
52.0, 107.6, 109.4, 119.7, 127.1, 128.0, 128.6, 129.1, 135.4, 136.2, 139.2,
163.6, 165.4. MS (EI) m/z 343 (Mþ, 50%), 311 (98), 225 (34), 134
(100). HRMS (ESI-TOF) m/z 344.0958 ([Mþ1]þ, C18H18NO4S requires
344.0951).
1211, 1121, 1083 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
2.35 (s, 3H), 3.05
(s, 3H), 3.19 (d, J¼6.4 Hz, 1H, imide
a
-H), 3.34e3.36 (m, 1H, imide a-
H), 3.82 (s, 3H), 3.86 (s, 3H), 4.14 (d, J¼18.0 Hz, 1H), 4.28 (d,
J¼18.0 Hz, 1H), 5.34 (br s, 1H, sulfur bridge-H), 7.27e7.30 (m, 5H,
4.4.5.2. Dimethyl 1,3-dioxo-4-benzyl-6-methyl-2-phenyl-4,9-
epithio-2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-
dicarboxylate (10a). Pale yellow solid, mp 238e240 ꢀC (from ethyl
ArH). 13C NMR (100 MHz, CDCl3)
d 11.6, 25.4, 33.3, 49.2, 51.8, 51.9,
53.4, 56.9, 87.2, 106.5, 116.6, 127.5, 128.7, 128.8, 131.3, 135.3, 143.1,
163.2, 165.3, 173.0, 173.8. MS (EI-TOF) m/z 454 (Mþ, 8%), 422 (100),
336 (86). HRMS (EI-TOF) m/z 454.1195 (Mþ, C23H22N2O6S requires
454.1199).
ether). IR (KBr) 1714, 1388, 1207, 1094 cmꢁ1 1H NMR (400 MHz,
.
CDCl3)
d
2.39 (s, 3H), 3.73 (s, 3H), 3.76 (s, 3H), 3.78 (d, J¼13.6 Hz,

8400
M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
4.4.7. Dimethyl 1,3-dioxo-4,6-dimethyl-2-phenyl-4,9-epithio-2,3,3a,
4,9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (12a,
exo) and (13a, endo). Method A (reaction time: 4 h). Trituration of
the residue with methanol followed by purification by flash chro-
matography [hexane/ethyl acetate (2:1), then (1:1)] gave, in order of
elution exo-adduct 12a (39%) and endo-adduct 13a (15%).
Method B (reaction time: 4 h). Purification by flash chromatog-
raphy [hexane/ethyl acetate (2:1), then (1:1)] gave exo-adduct 12a
(36%).
3.66 (d, J¼8.0 Hz, 1H, imide
4.01e4.06 (m, 1H, imide
-H), 5.28 (d, J¼4.0 Hz, 1H, sulfur bridge-
H). 13C NMR (100 MHz, CDCl3)
11.2, 18.1, 24.5, 50.2, 51.6, 51.7,
56.0, 58.7, 84.0, 107.6, 115.6, 132.1, 140.5, 162.9, 165.1, 172.2, 172.4.
MS (EI) m/z 378 (Mþ, 35%), 346 (33), 267 (100), 177 (22), 149 (18).
HRMS (EI-TOF) m/z 378.0886 (Mþ, C17H18N2O6S requires 378.0886).
a-H), 3.71 (s, 3H), 3.75 (s, 3H),
a
d
4.4.9. Dimethyl 1,3-dioxo-2-phenyl-4,9-epithio-2,3,3a,4,9,9a-hexahy-
dro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (19a, exo) and (20a,
endo) and dimethyl 5,7-dioxo-6-phenyl-4b,5,6,7,7a,7b-hexahydro-2H-
pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]pyrrolizine-3,4-dicarboxylate (21a,
endo). Method A (reaction time: 4 h). Trituration of the residue with
methanol followed by purification by flash chromatography [hex-
ane/ethyl acetate (2:1), (1:1), then (1:2)] gave, in order of elution,
exo-adduct 19a (33%) and endo-adduct 21a (18%).
Method C (temperature set to 140 ꢀC for 20 min). Trituration of
the residue with methanol followed by purification by flash chro-
matography [hexane/ethyl acetate (2:1), then (1:1)] gave exo-ad-
duct 12a (20%).
4.4.7.1. Dimethyl 1,3-dioxo-4,6-dimethyl-2-phenyl-4,9-epithio-2,3,
3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate
(12a). White solid, mp 223e225 ꢀC (from ethyl ether). IR (KBr) 1720,
Method B (reaction time: 4 h). Trituration of the residue with
methanol followed by purification by flash chromatography [hex-
ane/ethyl acetate (2:1), (1:1), then (1:2)] gave, in order of elution,
exo-adduct 19a (28%) and a mixture of endo-adduct 20a (7%) and
endo-adduct 21a (12%). The endo-adduct 21a was isolated from the
mixture by selective crystallization with ethyl acetate.
1712, 1692, 1441, 1388, 1200, 1174, 1146, 1078 cmꢁ1 1H NMR
.
(400 MHz, CDCl3)
imide
-H), 3.56 (dd, J¼1.5 and 6.7 Hz, 1H, imide
3.86 (s, 3H), 5.39 (d, J¼1.5 Hz,1H, sulfur bridge-H), 7.25e7.28 (m, 2H,
ArH), 7.46e7.50 (m, 3H, ArH). 13C NMR (100 MHz, CDCl3)
11.8, 17.1,
d
2.41 (s, 3H), 2.50 (s, 3H), 3.28 (d, J¼6.7 Hz, 1H,
a
a
-H), 3.84 (s, 3H),
d
Method C (temperature set to 180 ꢀC for 20 min). Trituration of
the residue with methanol gave exo-adduct 19a (55%). Purification
of the residue by flash chromatography [hexane/ethyl acetate (1:1)]
gave endo-adduct 20a (13%).
50.5, 51.8, 51.9, 53.6, 56.6, 83.4, 106.4, 115.6, 126.4, 129.2, 129.3, 131.1,
131.5, 142.8, 163.2, 165.4, 171.9, 173.1. MS (EI) m/z 440 (Mþ, 38%), 408
(28), 267 (100). HRMS (ESI-TOF) m/z 441.1102 ([Mþ1]þ, C22H21N2O6S
requires 441.1115).
4.4.9.1. Dimethyl 1,3-dioxo-2-phenyl-4,9-epithio-2,3,3a,4,9,9a-hex-
4.4.7.2. Dimethyl 1,3-dioxo-4,6-dimethyl-2-phenyl-4,9-epithio-
2,3,3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-
dicarboxylate (13a). Pale yellow solid, mp 233e235 ꢀC (from
dichloromethane/methanol). IR (KBr) 1780, 1718, 1444, 1389, 1211,
ahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate
solid, mp 207e209 ꢀC (from ethyl ether). IR (KBr) 1737, 1720, 1382,
1284, 1187, 1070 cmꢁ1. 1H NMR (400 MHz, CDCl3)
3.52 (dd, J¼0.8
and 6.8 Hz,1H, imide -H),
(19a). White
d
a
-H), 3.56 (dd, J¼1.2 and 6.8 Hz,1H, imide
a
1144, 1087 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
2.37 (s, 3H), 2.50 (s,
3H), 3.80 (s, 3H), 3.81 (s, 3H), 3.95 (d, J¼8.3 Hz, 1H, imide -H), 4.31
(dd, J¼4.2 and 8.3 Hz, 1H, imide -H), 5.44 (d, J¼4.2 Hz, 1H, sulfur
bridge-H), 6.82e6.86 (m, 2H, ArH), 7.35e7.38 (m, 3H, ArH). 13C NMR
(100 MHz, CDCl3) 11.2, 18.1, 50.3, 51.6, 51.7, 56.0, 59.1, 84.0, 107.6,
3.83 (s, 3H), 3.90 (s, 3H), 5.55 (s, 1H, sulfur bridge-H), 6.01 (s, 1H,
a
sulfur bridge-H), 7.25e7.26 (m, 2H, ArH), 7.36 (s, 1H), 7.44e7.52 (m,
a
3H, ArH). 13C NMR (100 MHz, CDCl3)
d 51.0, 51.8, 52.0, 52.2, 53.5, 69.6,
108.3, 118.0, 121.6, 126.4, 129.3, 129.4, 131.4, 143.1, 162.7, 163.4, 172.2,
172.9. MS (EI) m/z 412 (Mþ) (7), 239 (100), 202 (22). HRMS (EI-TOF)
m/z 412.0724 (Mþ, C20H16N2O6S requires 412.0729).
d
115.7,126.6,129.1,129.2, 130.6, 132.0, 140.6, 162.8, 165.0, 171.2,171.5.
MS (EI) m/z 440 (Mþ, 37%), 408 (26), 267 (100). HRMS (ESI-TOF) m/z
463.0952 ([MþNa]þ, C22H20N2O6SNa requires 463.0934).
4.4.9.2. Dimethyl 5,7-dioxo-6-phenyl-4b,5,6,7,7a,7b-hexahydro-
2H-pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]pyrrolizine-3,4-dicarboxylate
(21a). White solid, mp 248e250 ꢀC. IR (KBr) 1719, 1386, 1301, 1203,
4.4.8. Dimethyl 1,3-dioxo-2,4,6-trimethyl-4,9-epithio-2,3,3a,4,9,9a-
hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (12b, exo)
and (13b, endo). Method A (reaction time: 4 h). Trituration of the
residue with methanol followed by purification by flash chroma-
tography [hexane/ethyl acetate (2:1), then (1:1)] gave, in order of
elution, exo-adduct 12b (19%) and endo-adduct 13b (23%).
1106 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d 3.81 (s, 3H), 3.86 (s, 3H),
4.28 (d, J¼13.6 Hz, 1H, H-2), 4.33 (approx. t, J¼7.6 Hz, 1H, H-7a),
4.78 (d, J¼13.6 Hz, 1H, H-2), 4.89 (d, J¼6.8 Hz, 1H, H-4b), 6.08 (d,
J¼7.6 Hz, 1H, H-7b), 7.19e7.21 (m, 2H, ArH), 7.36e7.46 (m, 3H, ArH).
13C NMR (100 MHz, CDCl3)
d 37.5, 50.8, 51.7, 52.0, 53.2, 60.3, 115.5,
Method B (reaction time: 4 h). Purification by flash chromatog-
raphy [hexane/ethyl acetate (2:1), then (1:1)] gave, in order of
elution, exo-adduct 12b (20%) and endo-adduct 13b (19%).
115.7, 126.3, 129.1, 129.2, 131.0, 131.2, 138.6, 162.7, 163.0, 169.9, 170.6.
MS (EI) m/z 412 (Mþ, 42%), 380 (100), 261 (26), 233 (79), 147 (42).
HRMS (EI-TOF) m/z 412.0730 (Mþ, C20H16N2O6S requires 412.0729).
4.4.8.1. Dimethyl 1,3-dioxo-2,4,6-trimethyl-4,9-epithio-2,3,3a,4,9,
9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate
(12b). Pale yellow solid, mp 186e188 ꢀC (from ethyl acetate/hex-
ane). IR (KBr) 1781, 1711, 1436, 1299, 1203, 1142, 1083 cmꢁ1. 1H NMR
4.4.9.3. Dimethyl 1,3-dioxo-2-phenyl-4,9-epithio-2,3,3a,4,9,9a-hex-
ahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (20a). Yellow oil.
IR (film) 1716, 1499, 1384, 1290, 1186, 1105, 1065 cmꢁ1 1H NMR
.
(400 MHz, CDCl3)
1H, imide
d
3.78(s, 3H), 3.85(s, 3H), 4.22 (dd, J¼2.8 and 8.4 Hz,
(400 MHz, CDCl3)
J¼6.4 Hz, 1H, imide
3.82 (s, 3H), 3.84 (s, 3H), 5.28 (br s, 1H, sulfur bridge-H). 13C NMR
(100 MHz, CDCl3) 11.7, 17.1, 25.3, 50.0, 51.7, 51.8, 53.7, 56.7, 83.0,
d
2.36 (s, 3H), 2.47 (s, 3H), 3.03 (s, 3H), 3.14 (d,
a
-H), 4.27 (dd, J¼4.0 and 8.4 Hz, 1H, imide
a
-H), 5.60 (d,
a
-H), 3.40 (approx. d, J¼6.0 Hz, 1H, imide -H),
a
J¼3.6 Hz, 1H, sulfur bridge-H), 6.10 (d, J¼2.4 Hz, 1H, sulfur bridge-H),
6.81e6.83 (m, 2H, ArH), 7.27 (s, 1H), 7.34e7.36 (m, 3H, ArH). 13C
d
NMR (100 MHz, CDCl3) d 51.7, 51.8, 52.0, 53.6, 56.2, 69.5, 108.9, 118.2,
106.2, 115.4, 131.1, 142.9, 163.2, 165.3, 172.9, 174.0. MS (EI) m/z 378
(Mþ, 34%), 346 (32), 267 (100), 177 (20), 149 (18). HRMS (EI-TOF) m/
z 378.0888 (Mþ, C17H18N2O6S requires 378.0886).
122.4,126.4,129.1,129.2,130.5,140.9,162.3,163.2,171.0,171.2. MS (EI)
m/z 412 (Mþ, 4%), 378 (16), 347 (18), 239 (100), 208 (11), 202 (10).
HRMS (EI-TOF) m/z 412.0727 (Mþ, C20H16N2O6S requires 412.0729).
4.4.8.2. Dimethyl 1,3-dioxo-2,4,6-trimethyl-4,9-epithio-2,3,3a,4,9,
9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate
4.4.10. Dimethyl 1,3-dioxo-2-methyl-4,9-epithio-2,3,3a,4,9,9a-hexahy-
dro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (19b, exo) and (20b,
endo) and dimethyl 5,7-dioxo-6-methyl-4b,5,6,7,7a,7b-hexahydro-2H-
pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]pyrrolizine-3,4-dicarboxylate (21b,
(13b). Yellow oil. IR (film) 1702, 1434, 1402, 1290, 1211, 1090 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d 2.31 (s, 3H), 2.39 (s, 3H), 2.46 (s, 3H),

M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
8401
endo). Method A (reaction time: 4 h). Trituration of the residue with
ethyl acetate gave exo-adduct 19b (20%). Purification of the residue
by flash chromatography [hexane/ethyl acetate (1:1), (1:2), then
ethyl acetate] gave a mixture of endo-adduct 20b (9%) and endo-
adduct 21b (27%). Compound 21b was isolated from the mixture by
selective crystallization with ethyl acetate.
Method B (reaction time: 4 h). Trituration of the residuewith ethyl
acetate gave exo-adduct 19b (19%). Purification of the residue by flash
chromatography [hexane/ethyl acetate (1:1), (1:2), then (1:3)] gave
a mixture of endo-adduct 20b (2%) and endo-adduct 21b (16%).
Method C (temperature set to 180 ꢀC for 20 min). Trituration of
the residue with ethyl acetate gave exo-adduct 19b (19%). Purifi-
cation of the residue by flash chromatography [hexane/ethyl ace-
tate (1:1), (1:2), then (1:3)] gave a mixture of endo-adduct 20b (8%)
and endo-adduct 21b (26%).
(d, J¼5.6 Hz, 1H, H-7b), 6.25 (s, 1H), 7.30e7.32 (m, 2H, ArH),
7.43e7.53 (m, 3H, ArH). 13C NMR (100 MHz, CDCl3)
36.0, 49.6, 57.8,
d
61.9, 107.9 (q, JCeCeCF3¼3.0 Hz), 115.5 (q, JCeCF3¼37.4 Hz), 122.7 (q,
JCeF¼265 Hz), 126.4, 129.2, 129.4, 130.7, 131.2, 134.3 (q,
JCeCeCF3¼4.7 Hz), 171.4, 172.3. MS (ESI-TOF) m/z 365 ([Mþ1]þ,
100%). HRMS (ESI-TOF) m/z 365.0563 ([Mþ1]þ, C17H12N2O2F3S re-
quires 365.0566).
4.4.11.2. 5,7(4bH,6H)-Dioxo-6-phenyl-3-(trifluoromethyl)-7a,7b-
dihydro-2H-pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]pyrrolizine
(27a). White solid, mp 232e233 ꢀC (from ethyl acetate/hexane). IR
(KBr) 1722, 1492, 1376, 1239, 1186, 1101, 1049 cmꢁ1 1H NMR
.
(400 MHz, CDCl3)
d
4.00 (d, J¼13.6 Hz, 1H, H-2), 4.28 (approx. t,
J¼7.2 Hz, 1H, H-7a), 4.72 (d, J¼6.8 Hz, 1H, H-4b), 4.77 (d, J¼13.6 Hz,
1H, H-2), 6.09 (d, J¼7.6 Hz, 1H, H-7b), 6.17 (s, 1H), 7.21e7.23 (m, 2H,
ArH), 7.34e7.48 (m, 3H, ArH). 13C NMR (100 MHz, DMSO-d6)
d 35.2,
4.4.10.1. Dimethyl 1,3-dioxo-2-methyl-4,9-epithio-2,3,3a,4,9,9a-
hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate
(19b). White solid, mp 256e258 ꢀC (from methanol). IR (KBr) 1736,
1692, 1439, 1383, 1288, 1181, 1061 cmꢁ1. 1H NMR (400 MHz, CDCl3)
50.4, 54.1, 59.5, 103.0 (q, JCeCeCF3¼2.7 Hz), 112.4 (q, JCeCF3¼36.8 Hz),
123.1 (q, JCeF¼266 Hz), 126.6, 128.6, 129.0, 131.7, 133.2 (q,
JCeCeCF3¼4.9 Hz), 172.5, 172.9. MS (EI) m/z 364 (Mþ, 100%), 217 (35),
188 (73), 177 (12). HRMS (ESI-TOF) m/z 365.0563 ([Mþ1]þ,
C17H12N2O2F3S requires 365.0566).
d
3.03 (s, 3H), 3.36 (d, J¼6.8 Hz, 1H, imide
1H, imide -H), 3.82 (s, 3H), 3.89 (s, 3H), 5.43 (s, 1H, sulfur bridge-
H), 5.95 (s, 1H, sulfur bridge-H), 7.32 (s, 1H). 13C NMR (100 MHz,
a
-H), 3.40 (d, J¼6.8 Hz,
a
4.4.12. 5,7(4bH,6H)-Dioxo-6-methyl-3-(trifluoromethyl)-7a,7b-dihy-
dro-2H-pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]pyrrolizine (27b, endo).
Method A (reaction time: 7 h). Purification by flash chromatography
[hexane/ethyl acetate (2:1)] gave endo-adduct 27b (50%).
Method B (reaction time: 7 h). Purification by flash chromatog-
raphy [hexane/ethyl acetate (2:1), then (1:1)] gave endo-adduct
27b (63%).
CDCl3)
d 25.4, 51.1, 51.7, 51.8, 52.0, 53.6, 69.2, 108.1, 118.0, 121.5,
143.2, 162.7, 163.4, 173.0, 173.8. MS (EI) m/z 350 (Mþ, 54%), 318
(100), 291 (26), 260 (20), 233 (39), 147 (21). HRMS (EI-TOF) m/z
350.0579 (Mþ, C15H14N2O6S requires 350.0573).
4.4.10.2. Dimethyl 1,3-dioxo-2-methyl-4,9-epithio-2,3,3a,4,9,9a-
hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate
(20b). Yellow oil. IR (film) 1781, 1705, 1435, 1383, 1290, 1208,
4.4.12.1. 5,7(4bH,6H)-Dioxo-6-methyl-3-(trifluoromethyl)-7a,7b-
dihydro-2H-pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]pyrrolizine (27b, en-
do). White solid, mp 189e191 ꢀC (from ethyl ether). IR (KBr) 1711,
1104 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d
2.54 (s, 3H), 3.78 (s, 3H),
3.86 (s, 3H), 4.04 (dd, J¼3.2 and 8.0 Hz, 1H, imide -H), 4.10 (dd,
a
J¼4.0 and 8.0 Hz, 1H, imide
a
-H), 5.49 (d, J¼4.0 Hz, 1H, sulfur
1431, 1376, 1283, 1246, 1226, 1167, 1090 cmꢁ1 1H NMR (400 MHz,
.
bridge-H), 6.03 (d, J¼3.2 Hz, 1H, sulfur bridge-H), 7.21 (s, 1H). 13C
CDCl3)
d
2.99 (s, 3H), 3.97 (d, J¼13.3 Hz, 1H, H-2), 4.13 (approx. t,
NMR (100 MHz, CDCl3)
d
24.6, 51.6, 51.8, 51.9, 53.6, 55.9, 69.4, 108.8,
J¼7.2 Hz, 1H, H-7a), 4.58 (d, J¼6.7 Hz, 1H, H-4b), 4.74 (d, J¼13.3 Hz,
117.9, 122.5, 140.8, 162.4, 163.2, 171.9, 172.0. MS (EI) m/z 350 (Mþ,
57%), 318 (100), 291 (29), 260 (20), 233 (40), 147 (21). HRMS (EI-
TOF) m/z 350.0571 (Mþ, C15H14N2O6S requires 350.0573).
1H, H-2), 6.02 (d, J¼7.5 Hz, 1H, H-7b), 6.09 (s, 1H). 13C NMR
(100 MHz, CDCl3)
d 25.6, 35.9, 50.0, 54.0, 59.6, 105.1 (q,
JCeCeCF3¼3.2 Hz), 115.2 (q, JCeCF3¼37.5 Hz), 122.7 (q, JCeF¼265 Hz),
130.2, 132.2 (q, JCeCeCF3¼4.7 Hz), 172.4, 172.9. MS (EI) m/z 302 (Mþ,
100%), 283 (11), 217 (44), 197 (14), 188 (19), 172 (11), 148 (11). HRMS
(EI-TOF) m/z 302.0335 (Mþ, C12H9N2O2F3S requires 302.0337).
4.4.10.3. Dimethyl 5,7-dioxo-6-methyl-4b,5,6,7,7a,7b-hexahydro-
2H-pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]pyrrolizine-3,4-dicarboxylate
(21b). White solid, mp 222e223 ꢀC. IR (KBr) 1777, 1731, 1697, 1434,
1300, 1119, 1103 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d 2.96 (s, 3H), 3.80
(s, 3H), 3.89 (s, 3H), 4.16 (approx. t, J¼7.6 Hz, 1H, H-7a), 4.24 (d,
4.5. General procedure for the synthesis of dimethyl 1,3-
dioxo-2,3-dihydro-1H-pyrrolo[3,4-f]indolizine-7,8-
dicarboxylates
J¼14.0 Hz, 1H, H-2), 4.73e4.74 (m, 2H, H-2 and H-4b), 6.00 (d,
J¼7.6 Hz, 1H, H-7b). 13C NMR (100 MHz, CDCl3)
d 25.7, 37.4, 50.9,
51.7, 52.0, 53.2, 60.0, 115.3, 115.5, 131.4, 138.2, 162.8, 163.0, 171.0,
171.7. MS (EI) m/z 350 (Mþ, 15%), 319 (9), 239 (100), 208 (14). HRMS
(EI-TOF) m/z 350.0574 (Mþ, C15H14N2O6S requires 350.0573).
Method A. A solution of sodium (11 mg, 0.46 mmol) dissolved in
anhydrous methanol (2 mL) was added slowly to a solution of the
appropriate dimethyl 1,3-dioxo-4,9-epithio-2,3,3a,4,9,9a-hexahy-
dro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (0.23 mmol) in
anhydrous dichloromethane (5 mL). After stirring at room tem-
perature for 1.5 h, the reaction was quenched with saturated
aqueous ammonium chloride solution (5 mL). The organic phase
was separated, dried over anhydrous sodium sulfate and the sol-
vent evaporated off. The crude product was purified by flash
chromatography [hexane/ethyl acetate].
4.4.11. 5,7(4bH,6H)-Dioxo-6-phenyl-3-(trifluoromethyl)-7a,7b-dihy-
dro-2H-pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]pyrrolizine (26a, exo) and
(27a, endo). Method A (reaction time: 7 h). Purification by flash
chromatography [hexane/ethyl acetate (3:1)] gave, in order of
elution, exo-adduct 26a (11%) and endo-adduct 27a (30%).
Method B (reaction time: 7 h). Purification by flash chromatog-
raphy [hexane/ethyl acetate (3:1), then (2:1)] gave, in order of
elution, exo-adduct 26a (10%) and endo-adduct 27a (26%).
Method B.
A solution of potassium tert-butoxide (78 mg,
0.66 mmol) in anhydrous tert-butanol (2 mL) was added slowly to
a solution of the appropriate dimethyl 1,3-dioxo-4,9-epithio-2,3,
3a,4,9,9a-hexahydro-1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate
(0.33 mmol) in anhydrous dichloromethane (8 mL). After stirring at
room temperature for 0.5 h, the reaction was quenched with sat-
urated aqueous ammonium chloride solution (5 mL). The organic
phase was separated, dried over anhydrous sodium sulfate and the
4.4.11.1. 5,7(4bH,6H)-Dioxo-6-phenyl-3-(trifluoromethyl)-7a,7b-
dihydro-2H-pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]pyrrolizine
(26a). Colourless needles, mp 191e193 ꢀC (from ethyl ether). IR
(KBr) 1716, 1392, 1241, 1174, 1109, 1069 cmꢁ1 1H NMR (400 MHz,
.
CDCl3)
d
4.08 (d, J¼13.6 Hz, 1H, H-2), 4.35 (dd, J¼5.6 and 8.4 Hz, 1H,
H-7a), 4.65 (d, J¼8.8 Hz, 1H, H-4b), 4.76 (d, J¼13.6 Hz, 1H, H-2), 5.95

8402
M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
solvent evaporated off. The crude product was purified crystalli-
zation or flash chromatography [hexane/ethyl acetate].
data for both compounds were collected at the IST using graphite
ꢁ
monochromated Mo K
a
radiation (l¼0.71073 A) on a Bruker AXS-
KAPPA APEX II diffractometer equipped with an Oxford Cry-
osystem open-flow nitrogen cryostat, at 150 K. Cell parameters
were retrieved using Bruker SMART software and refined using
Bruker SAINT on all observed reflections. Absorption corrections
were applied using SADABS.21 Structure solution and refinement
were performed using direct methods with the program
SIR200422 included in the package of programs WINGX-Version
1.80.0523 and SHELXL.24 All hydrogen atoms were inserted in
idealized positions and allowed to refine riding on the parent
carbon atom. Figures of the molecular structures were generated
using ORTEP-III.25
4.5.1. Dimethyl 4-benzyl-6-methyl-1,3-dioxo-2-phenyl-2,3-dihydro-
1H-pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (14a). This compound
was prepared by method A and was obtained as a yellow solid
(38%), mp 235e237 ꢀC (from ethyl ether). IR (KBr) 1768, 1713, 1686,
1452, 1398, 1371, 1259, 1164, 1068 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
2.69 (s, 3H), 3.93 (s, 3H), 3.96 (s, 3H), 5.29 (br s, 2H), 6.96e6.99 (m,
2H, ArH), 7.25e7.30 (m, 2H, ArH), 7.40e7.50 (m, 6H, ArH), 8.80 (s,
1H). 13C NMR (100 MHz, CDCl3)
14.5, 32.7, 52.1, 52.8, 109.5, 115.3,
d
116.9, 122.4, 125.8, 126.6, 127.1, 128.4, 128.8, 129.1, 129.4, 131.6,
136.1137.1, 140.7, 163.1, 164.6, 166.0, 166.1. MS (ESI-TOF) m/z 505
([MþNa]þ, 63%), 483 [Mþ1]þ (49), 319 (15), 201 (100). HRMS (ESI-
TOF) m/z 483.1539 ([Mþ1]þ, C28H23N2O6 requires 483.1551).
4.6.1. Crystallographic data for non-classical 3-benzyl-5-methyl-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate
(11). C18H17NO5S,
ꢁ
4.5.2. Dimethyl
4,6-dimethyl-1,3-dioxo-2-phenyl-2,3-dihydro-1H-
M¼359.39, monoclinic, Cc with unit cell, a¼11.8618(19) A,
ꢁ ꢁ
3
pyrrolo[3,4-f]indolizine-7,8-dicarboxylate (14b). This compound
was prepared by method B, except that tert-butanol was replaced
by methanol as solvent. Recrystallization with ethyl acetate/hexane
gave 14b as an orange solid (87%), mp 233e235 ꢀC. IR (KBr) 1763,
1704, 1457, 1397, 1388, 1236, 1094 cmꢁ1. 1H NMR (400 MHz, CDCl3)
b¼21.454(3) A, c¼7.3253(12) A,
a
¼90ꢀ,
b
¼120.633(7)ꢀ,
g
¼90ꢀ,
ꢁ
V¼1604.0(4) A . It contains four molecules/unit cell.
rcalcd¼
1.488 g cmꢁ3
,
Z¼4,
m
¼0.232 mmꢁ1
.
R
[I>2
s
(I)]¼0.0806 and
Rw¼0.2126 for 2171 independent reflections.
d
2.92 (s, 3H), 3.38 (s, 3H), 3.94 (s, 3H), 3.97 (s, 3H), 7.42e7.44 (m,
3H, ArH), 7.50e7.54 (m, 2H, ArH), 8.63 (s, 1H). 13C NMR (100 MHz,
CDCl3) 15.4, 15.9, 52.0, 52.8, 108.9, 113.8, 116.1, 122.9, 125.6, 126.7,
4.6.2. Crystallographic data for 5,7(4bH,6H)-dioxo-6-phenyl-3-(tri-
fluoromethyl)-7a,7b-dihydro-2H-pyrrolo[30,40:5,6]thiazolo[2,3,4-cd]
pyrrolizine (27a). C17H11F3N2O2S, M¼364.34, triclinic, Pꢁ1 with unit
d
¼79.646(4)ꢀ,
ꢁ
ꢁ
ꢁ
128.4, 128.9, 129.1, 131.7, 135.7, 140.6, 163.0, 164.6, 166.1, 166.5. MS
(EI) m/z 406 (Mþ, 44%), 374 (34), 288 (100). HRMS (ESI-TOF) m/z
407.1238 ([Mþ1]þ, C22H19N2O6 requires 407.1238).
cell, a¼8.9513(5) A, b¼9.2025(5) A, c¼9.8159(6) A,
a
3
ꢀ
¼76.155(3)ꢀ,
¼71.164(4) , V¼738.41(7) A . It contains two mole-
g
ꢁ
b
cules/unit cell.
r
calcd¼1.639 g cmꢁ3
,
Z¼2,
m
¼0.269 mmꢁ1
. R
[I>2
s
(I)]¼0.0300 and Rw¼0.0729 for 2652 independent reflections.
4.5.3. Dimethyl
2,4,6-trimethyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo
[3,4-f]indolizine-7,8-dicarboxylate (14c). This compound was pre-
pared by method B, except that tert-butanol was replaced by tetra-
hydrofuran as solvent. Purification by flash chromatographygave 14c
as a yellow solid (50%), mp 210e212 ꢀC (from ethyl ether). IR (KBr)
Acknowledgements
Thanks are due to FCT (Grants: SFRH/BPD/26772/2006 and
SFRH/BPD/64423/2009) and FEDER for financial support. We ac-
knowledge the Nuclear Magnetic Resonance Laboratory of the
Coimbra Chemical Centre (www.nmrccc.uc.pt), University of
Coimbra for obtaining the NMR data. C.S.B.G. would like to
thank Prof. M. Teresa Duarte for valuable discussions on X-ray
crystallography.
1760, 1733, 1706, 1429, 1392, 1291, 1169 cmꢁ1
CDCl3)
8.49 (s, 1H). 13C NMR (100 MHz, CDCl3)
.
1H NMR (400 MHz,
d
2.89 (s, 3H), 3.19 (s, 3H), 3.32 (s, 3H), 3.92 (s, 3H), 3.95 (s, 3H),
15.4, 15.8, 24.4, 51.9, 52.8,
d
108.7, 114.2, 115.4, 123.3, 125.4, 128.8, 135.6, 139.7, 163.1, 165.7, 166.1,
167.5. MS (EI-TOF) m/z 344 (Mþ, 15%), 312 (33), 254 (15), 226 (100).
HRMS (EI-TOF) m/z 344.1005 (Mþ, C17H16N2O6 requires 344.1008).
Supplementary data
4.5.4. Dimethyl 1,3-dioxo-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-f]in-
dolizine-7,8-dicarboxylate (22a). This compound was prepared by
method B. Purification by flash chromatography gave compound
22a as a pale yellow solid (35%), mp 217e219 ꢀC (from ethyl ether).
IR (KBr) 1770, 1721, 1711, 1385, 1240, 1119 cm−1. 1H NMR (400 MHz,
1H and 13C NMR spectra of the new compounds and selected
bond lengths and angles of compounds 11 and 27a determined by
X-ray crystallography. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.tet.2011.08.001.
CDCl3)
d 3.96 (s, 3H), 4.00 (s, 3H), 7.43e7.46 (m, 3H), 7.52e7.56 (m,
2H), 7.94 (s, 1H), 8.61 (s, 1H), 8.72 (s, 1H). MS (EI) m/z 378 (Mþ, 82%),
347 (100), 317 (25), 168 (15). HRMS (ESI-TOF) m/z 407.1238
([Mþ1]þ, C22H19N2O6 requires 407.1238).
References and notes
1. Reviews on non-classical heteropentalene: (a) Moderhack, D. Heterocycles
2008, 75, 1e33; (b) Ramsden, C. A. In Two Fused Five-Membered Heterocyclic
Rings: Non-Classical Systems; Potts, K. T., Katritzky, R. A., Rees, C. W., Eds.;
Comprehensive Heterocyclic Chemistry; Pergamon: Oxford, 1984; Vol. 6;
Chapter 4.37, pp 1027e1048; (c) Ollis, W. D.; Stanforth, S. P. Tetrahedron 1985,
41, 2239e2339.
2. Kane, J. M. J. Org. Chem. 1980, 45, 5396e5397.
3. Sutcliffe, O. B.; Storr, R. C.; Gilchrist, T. L.; Rafferty, P. J. Chem. Soc., Perkin Trans. 1
2001, 1795e1806.
4. Ostby, O. B.; Dalhus, B.; Gundersen, L. L.; Rise, F.; Bast, A.; Haenen, G. R. M. M.
Eur. J. Org. Chem. 2000, 3763e3770.
5. (a) Gundersen, L. L.; Negussie, A. H.; Rise, F.; Ostby, O. B. Arch. Pharm. Pharm.
Med. Chem. 2003, 336, 191e195; (b) Gundersen, L. L.; Charnock, C.; Negussie, A.
H.; Rise, F.; Teklu, S. Eur. J. Pharm. Sci. 2007, 30, 26e35.
4.5.5. Dimethyl
2-methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-f]
indolizine-7,8-dicarboxylate (22b). This compound was prepared by
method B. Purification by flash chromatography gave compound
22b as a white solid (38%), mp 220e222 ꢀC (from ethyl ether). IR
(KBr) 1766, 1736, 1708, 1431, 1210 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
3.22 (s, 3H), 3.94 (s, 3H), 3.97 (s, 3H), 7.88 (s, 1H), 8.49 (s, 1H), 8.60
(s, 1H). 13C NMR (100 MHz, CDCl3)
d
24.6, 52.1, 52.6, 110.5, 117.6,
117.9, 121.2, 123.4, 123.9, 124.3, 134.8, 163.0, 163.6, 165.6, 165.8. MS
(EI) m/z 316 (Mþ, 60%), 298 (44), 285 (95), 255 (43), 240 (23), 212
(100). HRMS (EI) m/z 316.0693 (Mþ, C15H12N2O6 requires 316.0695).
6. Gubin, J.; Luccetti, J.; Mahaux, D.; Nisato, D.; Rosseels, G.; Clinet, M.; Polster, P.;
Chatelain, P. J. Med. Chem. 1992, 35, 981e988.
4.6. Crystal-structure determination of 11 and 27a
7. (a) Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.; Murakami, Y.; Ito, Y.;
Matsuura, T.; Wada, M.; Kato, T.; Ueno, M.; Chikazawa, Y.; Yamada, K.; Ono, T.;
Teshirogi, I.; Ohtani, M. J. Med. Chem. 1996, 39, 3636e3658; (b) Oslund, R. C.;
Cermak, N.; Gelb, G. H. J. Med. Chem. 2008, 51, 4708e4714.
Crystals of compounds 11 and 27a were selected, covered with
polyfluoroether oil, and mounted on a nylon loop. Crystallographic

M.I.L. Soares et al. / Tetrahedron 67 (2011) 8392e8403
8403
~
8. Weide, T.; Arve, L.; Prinz, H.; Waldmann, H.; Kessler, H. Bioorg. Med. Chem. Lett.
2006, 16, 59e63.
9. Teklu, S.; Gundersen, L. L.; Larsen, T.; Malterud, K. E.; Rise, F. Bioorg. Med. Chem.
15. Pinho e Melo, T. M. V. D.; Soares, M. I. L.; Gonsalves, A. M. d’A. R.; Paixao, J. A.;
Beja, A. M.; Silva, M. R. J. Org. Chem. 2005, 70, 6629e6638.
ꢂ
ꢀ
16. (a) Fernandez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651e3705; (b) Wojaczynska,
ꢀ
2005, 13, 3127e3139.
E.; Wojaczynski, J. Chem. Rev. 2010, 110, 4303e4356; (c) Pelissier, H. Tetrahedron
10. James, D. A.; Koya, K.; Li, H.; Liang, G.; Xia, Z.; Ying, W.; Wu, Y.; Sun, L. Bioorg.
Med. Chem. Lett. 2008, 18, 1784e1787.
2006, 62, 5559e5601.
17. Allen, F. H. Acta Crystallogr., Sect. B: Struct. Sci. 2002, 58, 380e388.
18. (a) Cava, M. P.; Behforouz, M.; Husbands, G. E.; Srinivasen, M. J. Am. Chem. Soc.
1973, 95, 2561e2564; (b) Potts, K. T.; McKeough, D. J. Am. Chem. Soc. 1974, 96,
4268e4275.
19. Pinho e Melo, T. M. V. D.; Nunes, C. M.; Soares, M. I. L.; Paixao, J. A.; Beja, A. M.;
Silva, M. R. J. Org. Chem. 2007, 72, 4406e4415.
20. Nunes, C. M.; Silva, M. R.; Beja, A. M.; Fausto, R.; Pinho e Melo, T. M. V. D.
11. (a) Boeckler, F.; Russig, H.; Zhang, W. N.; Lober, S.; Schetz, J.; Hubner, H.; Ferger,
B.; Gmeiner, P.; Feldon, J. Psychopharmacology 2004, 175, 7e17; (b) Lober, S.;
Hubner, H.; Utz, W.; Gmeiner, P. J. Med. Chem. 2001, 44, 2691e2694; (c) Lober,
S.; Hubner, H.; Utz, W.; Gmeiner, P. Bioorg. Med. Chem. Lett. 1999, 9, 97e102; (d)
Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 2002, 12, 2377e2380;
(e) Bettinetti, L.; Schlotter, K.; Hubner, H.; Gmeiner, P. J. Med. Chem. 2002, 45,
4594e4597.
~
Tetrahedron Lett. 2010, 51, 411e414.
12. (a) Kuroda, S.; Akahane, A.; Itani, H.; Nishimura, S.; Durkin, K.; Kinoshita, T.;
Tenda, Y.; Sakane, K. Bioorg. Med. Chem. Lett. 1999, 9, 1979e1984; (b) Akahane,
A.; Katayama, H.; Mitsunaga, T.; Kato, T.; Kinoshita, T.; Kita, Y.; Kusunoki, T.;
Terai, T.; Yoshida, K.; Shiokawa, Y. J. Med. Chem. 1999, 42, 779e783.
13. Johns, B. A.; Gudmundsson, K. S.; Turner, E. M.; Allen, S. H.; Samano, V. A.; Ray,
J. A.; Freeman, G. A.; Boyd, F. L.; Sexton, C. J.; Selleseth, D. W.; Creech, K. L.;
Moniri, K. R. Bioorg. Med. Chem. 2005, 13, 2397e2411.
14. Cheung, M.; Harris, P. A.; Badiang, J. G.; Peckham, G. E.; Chamberlain, S. D.;
Alberti, M. J.; Jung, D. K.; Harris, S. S.; Bramson, N. H.; Epperly, A. H.; Stimpson,
S. A.; Peel, M. R. Bioorg. Med. Chem. Lett. 2008, 18, 5428e5430.
21. Sheldrick, G. M. SADABS, Program for Empirical Absorption Correction; University
€
€
of Gottingen: Gottingen, Germany, 1996.
22. Burla, M. C.; Caliandro, R.; Camalli, M.; Carrozzini, B.; Cascarano, G. L.; De Caro,
L.; Giacovazzo, C.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 2005, 38, 381e388.
23. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837e838.
24. (a) Sheldrick, G. M. SHELX97-Programs for Crystal Structure Analysis (Release
€
€
€
97-2); Institut fur Anorganische Chemie der Universitat: Tammanstrasse 4,
€
D-3400 Gottingen, Germany, 1998; (b) Sheldrick, G. M. Acta Crystallogr. 2008,
A64, 112e122.
25. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, pp 565e565.