Flash vacuum pyrolysis of 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 2-vinyl-1H-pyrroles

Article abstract of DOI:10.1016/j.tet.2008.07.079

The flash vacuum pyrolysis of new 1,1-dimethyl- and 1-methyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides gave penta-substituted 2-vinyl-1H-pyrroles via sigmatropic [1,8]-H shift of the corresponding azafulvenium methide intermediates. In some cases these 1H-pyrroles underwent rearrangement to 2-allyl-1H-pyrroles. Di-substituted 2-vinylpyrroles have also been prepared and their reactivity studied. Under FVP N-benzyl-pyrrol-2-ylpropenoates were converted into 3H-pyrrolizin-3-ones. On the other hand, microwave-assisted reaction of 1-benzyl-2-vinyl-1H-pyrrole gave a 4,5,6,7-tetrahydro-1H-indole derivative.

Full text of DOI:10.1016/j.tet.2008.07.079

Tetrahedron 64 (2008) 9745–9753
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Tetrahedron
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Flash vacuum pyrolysis of 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles
and 2-vinyl-1H-pyrroles
*
Maria I.L. Soares, Susana M.M. Lopes, Pedro F. Cruz, Rui M.M. Brito, Teresa M.V.D. Pinho e Melo
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2008
Received in revised form 15 July 2008
Accepted 18 July 2008
Available online 24 July 2008
The flash vacuum pyrolysis of new 1,1-dimethyl- and 1-methyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-di-
oxides gave penta-substituted 2-vinyl-1H-pyrroles via sigmatropic [1,8]-H shift of the corresponding
azafulvenium methide intermediates. In some cases these 1H-pyrroles underwent rearrangement to
2-allyl-1H-pyrroles. Di-substituted 2-vinylpyrroles have also been prepared and their reactivity studied.
Under FVP N-benzyl-pyrrol-2-ylpropenoates were converted into 3H-pyrrolizin-3-ones. On the other
hand, microwave-assisted reaction of 1-benzyl-2-vinyl-1H-pyrrole gave a 4,5,6,7-tetrahydro-1H-indole
derivative.
Keywords:
Pericyclic reactions
Flash vacuum pyrolysis
Azafulvenium methides
Diazafulvenium methides
2-Allyl-1H-pyrroles
Ó 2008 Elsevier Ltd. All rights reserved.
3H-Pyrrolizin-3-ones
Tetrahydro-1H-indole
Microwave-assisted reactions
1. Introduction
We observed that 7,7-dimethyl-azafulvenium methides (1a–1c),
derived from 1,1-dimethyl-2,2-dioxo-1H,3H-pyrrolo[1,2-c]thi-
The study of pericyclic reactions of transient 8
p
1,7-dipoles
azoles, undergo sigmatropic [1,8]-H shifts to give 2-vinyl-1H-pyr-
roles (2a–2c) even in cases where an alternative pericyclic reaction
could in principle occur (e.g., 7,7-dimethyl-azafulvenium methide
1b). Azafulvenium methide 1d, generated from the corresponding
C-3 unsubstituted 1-methyl-2,2-dioxo-1H,3H-pyrrolo[1,2-c]thi-
azole can only undergo the [1,8]-H shift that leads to the corre-
sponding 2-vinyl-1H-pyrrole (2d). However, the azafulvenium
methide 1e derived from the corresponding 1,3-dimethyl-
2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazole undergoes the two possible
sigmatropic [1,8]-H shifts giving 2-vinyl- and N-vinyl-1H-pyrroles.
Rearrangements of the 2-vinyl-1H-pyrroles under flash vacuum
pyrolysis conditions afford 5-oxo-5H-pyrrolizines (3) or function-
alized 2-allyl-1H-pyrroles (4). The 2-allyl-1H-pyrroles 4 were
obtained directly from the corresponding 2,2-dioxo-1H,3H-pyr-
rolo[1,2-c]thiazoles by FVP although it was established that 2-vinyl-
1H-pyrroles are intermediates in this transformation. In fact, the
FVP of 1-benzyl-2-isopropenyl-5-methyl-1H-pyrrole-3,4-dicarb-
oxylate 2c affords 5-(2-methyl-1-phenylallyl)-1H-pyrrole 4a
(Scheme 1).3
generated by the thermal extrusion of sulfur dioxide from 2,2-dioxo-
1H,3H-pyrrolo[1,2-c]thiazoles and 2,2-dioxo-pyrazolo[1,5-c]thi-
azoles is one of our current research interests.1–4 The intramolecular
trapping of azafulvenium methides in pericyclic reactions, namely
sigmatropic [1,8]-H shifts and 1,7-electrocyclization, allowed the
synthesis of N-vinyl-1H-pyrroles and 2-vinyl-1H-pyrroles, which,
under flash vacuum pyrolysis (FVP) conditions, are converted into
pyrrolizinones, 4-oxo-1,4-dihydro-1-aza-benzo[f]azulenes or 2-al-
lyl-1H-pyrroles.1,3 Diazafulvenium methides unsubstituted at C-7,
generated under conventional solution thermolysis conditions,
participate in [8pþ2p] cycloadditions giving pyrazolo[1,5-a]pyri-
dine derivatives resulting from the addition across the 1,7-position.
1-Methyl- and 7,7-dimethyl-diazafulvenium methides undergo
intramolecular sigmatropic [1,8]-H shifts giving vinylpyrazoles.2
Recently we have reported the generation and reactivity of aza-
fulvenium methides and diazafulvenium methides under micro-
wave irradiation.4 Particularly interesting was to observe that under
these reaction conditions both aza- and diazafulvenium methides
participate in [8
p
þ2
p
] cycloadditions.
The structural feature of the penta-substituted pyrroles, which
allows the rearrangement into the 2-allyl-1H-pyrroles appears to
be the presence of a group of the type –CH2R (with R¼Ph or Me) at
N-1 since N-methyl-2-isopropenyl-1H-pyrrole 2a and N-methyl-
2-ethenyl-1H-pyrrole 2d rearrange by a different pathway giving
* Corresponding author. Tel.: þ351 239 854475.
E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.079

9746
M.I.L. Soares et al. / Tetrahedron 64 (2008) 9745–9753
CO2Me
R1
R2
CO2Me
Me
O2S
N
R2
MeO2C
R1
O
Me
Flash Vacuum Pyrolysis
- SO2
R1
N
Me
MeO2C
R1
3a R1 = Me; R2 = H
3b R1 = R2 = Me
3c R1 = R2 = H
CO2Me
Me
CO2Me
CO2Me
H
N
N
Sigmatropic [1,8]H
MeO2C
R2
CO2Me
Me
R2
Me
R2
Flash Vacuum Pyrolysis
1a R1 = Me; R2 = H
1b
2a R1 = Me; R2 = H
N
H
R
1 = R2 = Me
2b R1 = R2 = Me
2c
R1
1c R1 = Me; R2 = Ph
1d R1 = R2 = H
R
1 = Me; R2 = Ph
2d R1 = R2 = H
4a R1 = Me; R2 = Ph
1e R1 = H; R2 = Me
2e
R
1 = H; R2 = Me
4b R1 = H; R2 = Me
Scheme 1.
5-oxo-5H-pyrrolizines. However, in the case of N-ethyl-1H-pyrroles
another structural requirement appears to be needed, the presence
of the ethenyl substituent at C-2. In fact, 1H-pyrrole 2e is converted
into the 2-allyl-1H-pyrrole whereas N-ethyl-2-isopropenyl-1H-
pyrrole 2b affords 5-oxo-5H-pyrrolizines on FVP.
The work has now been extended to the thermolysis of
new 1,1-dimethyl- and 1-methyl-1H,3H-pyrrolo[1,2-c]thiazole-
2,2-dioxides aiming to get further knowledge on the interesting
rearrangement of 2-vinyl-1H-pyrroles to 2-allylpyrroles. Di-
substituted 2-vinylpyrroles have also been prepared and their
reactivity studied.
2. Results and discussion
The 1,1-dimethyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides (8
and 10) were prepared from 2,5,5-trimethyl-1,3-thiazolidine-4-
carboxylic acid3 (5) as outlined in Scheme 2. The N-acylation of the
starting thiazolidine with the appropriated acid chloride was car-
ried out following a general procedure previously reported.5
Heating a solution of the N-benzoyl-1,3-thiazolidine-4-carboxylic
acid 6 in acetic anhydride in the presence of dimethyl acetylene
dicarboxylate afforded the corresponding 1,1,3-trimethyl-1H,3H-
pyrrolo[1,2-c]thiazoles (7) in high yield (60–93%) via the
CO2Me
CO2Me
MCPBA
CO2Me
CO2Me
Me
Me
Me
Me
CO2H
O
Me
CO2H
ArCOCl
Py or NEt3
Me
Me
O2S
DMAD
Ac2O,
S
N
S
NH
Me
S
N
N
Ar
Ar
Ar
Me
Me
Me
6a Ar = C6H4F-p 66%
7a Ar = C6H4F-p 93%
8a Ar = C6H4F-p 97%
5
8b Ar = Ph
51%
7b Ar = Ph
97%
6b Ar = Ph
85%
Ph
Ph
Me
Me
Me
7
Me
CO2H
O
7a
6
5
CO2Et
Me
CO2Et
Me
1
EtO2C
Ph
MCPBA
S
N
S
N
O2S
N
2
Ac2O,
4
3
Me
Me
Me
10 61%
6a
9 67%
F
F
F
CO2Me
CO2Me
Me
Me
Me
Me
Me
CO2H
Me
CO2H
Me
CO2Me
Me
O2S
CO2Me
MCPBA
DMAD
Ac2O,
PhCOCl
NEt3
O
S
N
S
N
S
NH
N
Ph
Ph
Ph
11
12 83%
14 75%
13 88%
CO2Me
CO2Me
CO2Me
CO2Me
Me
O2S
N
i) LHMDS
ii) MeI
O2S
N
R2
R2
R1
R1
15a R1 = Bn; R2 = Me
16a R1 = Bn; R2 = Me 66%
16b R1 = Me; R2 = Ph 24%
15b R1 = Me; R2 = Ph
Scheme 2.

M.I.L. Soares et al. / Tetrahedron 64 (2008) 9745–9753
9747
Table 1
intermolecular dipolar cycloaddition of the in situ generated
FVP of compounds 8 and 18/19
5,7,7-trimethyl-3-aryl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olates.
Oxidation of the pyrrolo[1,2-c]thiazoles 7 with MCPBA afforded
sulfones 8.
Pyrrolo[1,2-c]thiazole 9 was regioselectively prepared by the 1,3-
dipolar cycloaddition of the thiazolo[3,4-c]oxazol-4-ium-1-olate,
generated from 3-(4-fluorophenylcarbonyl)-2,5,5-trimethylthi-
azolidine-4-carboxylic acid 6a, with phenyl propiolate (Scheme 2).
The exclusive formation of 9 is the result of a regioselectivity
Reagents
Conditions
Products (ratio)
Yield (%)
8a
8a
8b
8b
8b
8b
8b
600 ꢀC, 3.5ꢁ10ꢂ2 mbar
700 ꢀC, 5.0ꢁ10ꢂ2 mbar
500 ꢀC, 2.7ꢁ10ꢂ2 mbar
550 ꢀC, 2.7ꢁ10ꢂ2 mbar
600 ꢀC, 2.0ꢁ10ꢂ2 mbar
650 ꢀC, 2.0ꢁ10ꢂ2 mbar
700 ꢀC, 2.7ꢁ10ꢂ2 mbar
650 ꢀC, 2.0ꢁ10ꢂ2 mbar
600 ꢀC, 2.0ꢁ10ꢂ2 mbar
700 ꢀC, 2.7ꢁ10ꢂ2 mbar
18a/19a (57:43)
18a/19a (79:21)
18b/19b (49:51)
18b/19b (42:58)
18b/19b (62:38)
18b/19b (56:44)
18b/19b (78:22)
18a/19a (67:33)
18b/19b (60:40)
18b/19b (83:17)
81
29
10a
8b
75
54
45
90
84
22
18a/19a (57:43)
18b/19b (56:44)
18b/19b (60:40)
where the b-carbon of the propiolate combines with the tethered
centre of the bicyclic mu¨nchnones. The structural assignment of
pyrrolo[1,2-c]thiazole 9 was based on a NOESY experiment. In fact,
in the NOESY spectrum of compound 9, methyl protons at C-3 show
connectivity with the fluorophenyl protons but no connectivity with
phenyl protons. On the other hand, the two methyl protons at C-1
show connectivity with the phenyl protons but no correlation was
observed with the fluorophenyl protons. Sulfone 10 was also
obtained by oxidation of compound 9 with MCPBA.
a
Obtained together with 8b (48%).
Obtained together with 8b (23%).
b
2-allyl-1H-pyrrole 21 in 23% yield (Scheme 4). In this case the
products could be easily separated. Thus, the presence of two
carboxylate groups in the starting 1H-pyrrole is not a requirement
for the conversion of 2-vinyl-1H-pyrroles into 2-allyl-1H-pyrroles.
The 1,1-dimethyl-5-phenyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-
dioxide 14 was also prepared from 5,5-trimethyl-1,3-thiazolidine-
4-carboxylic acid3 (11) in good yield. 1-Methylpyrrolo[1,2-c]-
thiazole-2,2-dioxides 16 were prepared from sulfones 151b by an
alkylation procedure,6 metallation with LiHMDS and subsequent
reaction with iodomethane gave derivatives 16 (Scheme 2).
The FVP of 1,1-dimethyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-di-
oxide 8a leads to the synthesis of 2-vinyl-1H-pyrrole 18a and 2-
allyl-1H-pyrrole 19a obtained as a mixture that could only be
separated by GC techniques. The best result was obtained by car-
rying out the pyrolysis at 600 ꢀC/3.5ꢁ10ꢂ2 mbar, which gave the
products in 81% overall yield (Scheme 3, Table 1). New 2-vinyl-1H-
pyrrole 18b and 2-allyl-1H-pyrrole 19b were also obtained as
a mixture on FVP of sulfone 8b. The FVP of the mixture of pyrroles,
either 18a/19a or 18b/19b, led only to recovery of the starting
material. However, the mixture is enriched with the 2-vinyl-1H-
pyrrole indicating the lower stability of the allyl-1H-pyrrole de-
rivatives. At higher temperature decomposition of allylpyrrole 19b
occurs (Scheme 3, Table 1). No products could be isolated from the
solution thermolysis of sulfones 8 in a sealed tube (255–260 ꢀC).
Nevertheless, the results obtained indicate that 2-isopropenyl-1H-
pyrroles require the presence of an aryl substituent at C-5 or
a benzyl group at N-1 in order to rearrange to the corresponding 2-
allyl-1H-pyrroles.
Ph
CO2Et
Me
N
Et
Ph
F
Me
Me
O2S
CO2Et
20 40%
FVP
N
+
- SO2
Ph
CO2Et
Me
10
Me
Me
F
N
H
F
21 23%
Scheme 4.
The thermolysis of sulfone 14, unsubstituted at C-3, was also
studied. This compound should lead to a 2-vinyl-1H-pyrrole
without the substituent of the nitrogen of the type CH2R. However,
we decide to determine if the presence of a phenyl group at C-5
would make possible the rearrangement of 22 to the corresponding
2-allyl-1H-pyrrole. It was observed that under FVP (700 ꢀC,
2.0ꢁ10ꢂ2 mbar) sulfone 14 is converted into 2-isopropenyl-1H-
pyrrole 22 in high yield (Scheme 5). These FVP conditions also allow
the synthesis of 2-isopropenyl-1H-pyrrole 2a (70%) from the sul-
fone analogues to 14 but bearing a methyl group instead of the
phenyl group at C-5, although a 5-oxo-5H-pyrrolizine derivative is
also obtained (5%). Thus, the presence of the phenyl substituent
allows the more efficient synthesis of the corresponding 2-vinyl-
1H-pyrrole derivative. Attempts to carry out the rearrangement of
22 via FVP (700 ꢀC, 2.0ꢁ10ꢂ2 mbar and 800 ꢀC, 2.0ꢁ10ꢂ2 mbar) led
only to sublimation of the starting 1H-pyrrole.
On flash vacuum pyrolysis conditions (600 ꢀC/3.0ꢁ10ꢂ2 mbar)
sulfone 10 undergoes SO2 extrusion to give 2-vinyl-1H-pyrrole 20
as the major product in 40% yield together with the formation of
CO2Me
CO2Me
CO2Me
Me
Me
Me
O2S
CO2Me
FVP
- SO2
N
N
H
Me
Me
R
17a R = F
17b R = H
R
8a R = F
8b R = H
CO2Me
Me
MeO2C
Ph
CO2Me
Me
FVP
Me
O2S
CO2Me
700 °C, 2.0 x 10-2 mbar
N
- SO2
N
Me
Ph
MeO2C
Me
CO2Me
MeO2C
Me
CO2Me
14
22 95%
N
H
N
Et
Scheme 5.
R
R
Me
18a R = F
18b R = H
19a R = F
19b R = H
The FVP of 1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides 16, pre-
cursors of 2-ethenyl-1H-pyrroles, was also studied (Scheme 6).
From 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazole 16a the only isolable
Scheme 3.

9748
M.I.L. Soares et al. / Tetrahedron 64 (2008) 9745–9753
products were vinyl-1H-pyrroles 23 and 24 obtained in very low
yield. In contrast with this result, the flash vacuum pyrolysis of 2,2-
dioxo-1H,3H-pyrrolo[1,2-c]thiazole 16b bearing a phenyl group at
C-5 leads to 2-allyl-1H-pyrrole 26 in 54% yield as the only product.
As previously mentioned, in the case of 2-ethenyl-1H-pyrroles the
presence of a phenyl group at C-5 is not a structural requirement in
order to rearrange to the 2-allyl-1H-pyrroles since 1H-pyrrole 2e
can be converted into 4b. However, these results show that the
presence of the phenyl group at C-5 allows the selective synthesis
of the corresponding 2-allyl-1H-pyrrole.
27 following a known general synthetic procedure.7a The Wittig
reaction of N-benzylpyrrole-2-carbaldehyde 28a with the phos-
phorus ylides generated in situ from ethyl- or methyl-
triphenylphosphonium bromide in the presence of sodium hydride
afforded the 2-vinyl-1H-pyrroles 29.8a The reaction of 28a with
triphenylphosphoranylideneacetates gave the corresponding
N-substituted-pyrrol-2-ylpropenoates 30.8b N-Benzyl-2-isopropenyl-
1H-pyrrole 33 was prepared from 2-acetylpyrrole (31) via N-al-
kylation with benzylbromide followed by the appropriated Wittig
reaction.8c,d
MeO2C
Et
CO2Me MeO2C
++
CO2Me
Me
CO2Me
CO2Me
CHO
N
Me
H
27
Me
N
N
O2S
N
- SO2
KOH/R1Br
Me
Bn
24
CO2R2
Bn
16a
Br Ph3(Me)P
Ph
or
Br Ph3(Et)P
NaH
23
PPh3
CHO
N
FVP
R1
600 °C, 2.0 x 10-2 mbar
650 °C, 2.0 x 10-2 mbar
700 °C, 2.0 x 10-2 mbar
a(23% of 16a); b(13% of 16a)
6%
5%
---
7%a
7%b
---
28a R1 = Bn 88%
28b R1 = Et 91%
N
N
R1
CO2R2
R1
R2
CO2Me
30a R1 = R2 = Bn
80%
29a R1 = Bn; R2 = H 68%
MeO2C
Me
CO2Me
Ph
MeO2C
Me
CO2Me
Ph
Me
30b R1 = Bn; R2 = Me 71%
CO2Me
29b R1 = Bn; R2 = Me 63%a
a(cis/trans)
30c R1 = Et; R2 = Bn
54%
O2S
N
+
N
N
H
- SO2
Ph
Me
16b
FVP
Me
Me
Me
25
26
KOH
N
Br Ph3(Me)P
N
Bn
N
H
BnBr
NaH
Bn
O
O
600 °C, 2.0 x 10-2 mbar
650 °C, 2.7 x 10-2 mbar
---
4%
54%
20%
31
32 92%
Scheme 8.
33 88%
Scheme 6.
Flash vacuum pyrolysis of N-substituted-pyrrol-2-ylprope-
noates 30 led to the synthesis of products with an intense red
colour typical of pyrrolizinone derivatives (Scheme 9 and Table 2).
The same product (34a) was obtained in yields ranging from 19 to
21% starting either from 1H-pyrrole 30a or 1H-pyrrole 30b. From
the reaction of N-ethyl-pyrrol-2-ylpropenoate 30c, 5-ethyl-3H-
pyrrolizin-3-one 34b was obtained in 21% yield.
The rearrangement of vinylpyrroles to give functionalised
allylpyrroles can be explained by a sequence of sigmatropic shifts as
shown in Scheme 7. Overall the rearrangement can be regarded as
a formal insertion of the R2CH group in the C–C
s
bond involving
the pyrrole C-2 carbon and the carbon of the vinylic group.
R3
R3
R4
R5
R4
R5
R1
[1,5] shift
R1
[1,5] shift
FVP
N
N
N
N
R1
CO2R2
R2
R1
R1
O
R2
30a R1 = R2 = Bn
34a R1 = Bn
R3
R3
N
30b R1 = Bn; R2 = Me
30c R1= Et; R2= Bn
34b R1 = Et
R4
R5
R1
R4
R5
[1,3]H
H
Scheme 9.
N
H
R2
R2
1H NMR and 13C NMR data of pyrrolizinone 34b are collected in
Table 3. The assignment was supported by two-dimensional COSY,
HMQC and HMBC spectra (400 MHz). In the 13C NMR spectrum two
quaternary carbons are observed at 136.1 and 141.2 ppm besides
the signal at 166.9 ppm corresponding to the carbon of the carbonyl
group. In the HMBC spectrum the carbon with the chemical shift
136.1 ppm shows connectivity with H-1, H-2, H-6 and H-7. Thus,
this signal was assigned to carbon C-7a. The second quaternary
carbon shows connectivity with H-6, H-7, H-8 and H-9 corre-
sponding to carbon C-5. Therefore, the pyrrolizin-3-one must have
the ethyl substituent at C-5.
R3
R4
R5
R3
H
R4
R5
R2
R1
[1,5]H
[1,6] shift
R2
R1
N
H
N
Scheme 7.
We decided to evaluate the possibility of using simple N-
substituted 2-vinyl-1H-pyrroles (29, 30 and 33) for carrying out this
rearrangement of 2-vinylpyrroles to 2-allyl-1H-pyrroles (Scheme
The thermal rearrangement of 1-arylpyrroles to 2-arylpyrroles
by sequential [1,5] shifts is known.9 In fact, under FVP (1000 ꢀC,
0.01 Torr) 1-phenylpyrrole rearranges to 2- and 3-phenylpyrrole.9a
8). N-Benzyl- (28a7a–c
)
and N-ethylpyrrole-2-carbaldehyde
(28b7c,d) were obtained in high yield from pyrrole-2-carbaldehyde

M.I.L. Soares et al. / Tetrahedron 64 (2008) 9745–9753
9749
Table 2
FVP of compounds 30
N
Bn
4
Reagents
Conditions
Products
Yield (%)
5
3a
MW (30 min)
260 °C, 1,2,4-TCB
3
2
1
600 ꢀC, 2ꢁ10ꢂ2 mbar
700 ꢀC, 2.7ꢁ10ꢂ2 mbar
800 ꢀC, 4.0ꢁ10ꢂ2 mbar
700 ꢀC, 2.0ꢁ10ꢂ2 mbar
700 ꢀC, 2.0ꢁ10ꢂ2 mbar
750 ꢀC, 2.0ꢁ10ꢂ2 mbar
800 ꢀC, 2.0ꢁ10ꢂ2 mbar
30a
34a
34a
34a
30c
34b
34b
da
21
19
20
da
21
9
6
N
Bn
30a
30a
30a
30b
30c
30c
30c
N
Bn
39 48%
7a
7
29a
Scheme 11.
a
Sublimation of the starting material.
limited to 3-(1-phenylpyrrol-2-yl)propenoates, and N-ethyl and
N-benzyl derivatives undergo a similar conversion to the corre-
sponding pyrrolizin-3-ones (Scheme 10).
Table 3
1H NMR and 13C NMR data for pyrrolo[1,2-c]pyrimidine 34b
Attempts to carry out the FVP of pyrroles 29a, 29b and 33 did not
lead to isolable products. Under microwave irradiation, although
a similar result was obtained from 29b and 33, the reaction of 29a
led to an interesting outcome. In fact, microwave irradiation of
1-benzyl-2-vinyl-1H-pyrrole 29a in 1,2,4-trichlorobenzene for
30 min afforded 4-(1-benzyl-1H-pyrrol-2-yl)-4,5,6,7-tetrahydro-
1H-indole 39 in 48% yield. This heterocycle is the result of a Diels–
Alder reaction where 1H-pyrrole 29a acts both as a diene and as
a dienophile (Scheme 11).
The structural assignment of 1H-pyrrole 39 was supported by
two-dimensional COSY, HMQC and HMBC spectra (400 MHz). In the
COSY spectrum, H-4 (3.93–3.95 ppm) shows connectivity with
protons H-5 (1.57–1.68 ppm), these protons show connectivity
with H-6 (1.85–1.91 ppm) and finally protons H-6 are correlated
with protons H-7 (2.39–2.42 ppm).
7
1
7a
2
6
N
4
3
O
5
8
9
C
1H NMR
13C NMR
C-8
C-9
C-2
C-6
C-7
C-7a
C-1
C-5
C-3
1.23 (3H, t, J¼7.5 Hz, Et)
2.70 (2H, q, J¼7.5 Hz, Et)
5.61 (1H, d, J¼5.7 Hz)
5.67–5.69 (1H, m)
5.91 (1H, d, J¼3.0 Hz)
d
11.5
20.0
120.9
111.4
112.1
136.1
137.9
141.2
166.9
7.04 (1H, d, J¼5.7 Hz)
d
d
3. Conclusion
On the other hand, benzannelated pyrrolizin-3-ones have been
prepared from the FVP (925 ꢀC, 0.001 Torr) of 1-(2-methoxy-
carbonylphenyl)pyrrole by a cascade process involving rate de-
termining 1,5-aryl migration, elimination of methanol and
electrocyclization of the ketene intermediate.9b MacNab et al. also
described that methyl 3-(1-phenylpyrrol-2-yl)propenoate un-
dergoes a 1,5-sigmatropic shift of the phenyl group regiospecifically
to the 5-position followed by the conversion into 5-phenyl-
pyrrolizin-3-one in 38% yield.9c
The synthesis of pyrrolizin-3-ones 34 can also be explained by
the initial rearrangement of 1-substituted pyrroles 30 to 5-
substituted derivatives 35 via regiospecific benzyl (R1¼Bn) or ethyl
(R1¼Et) 1,5-sigmatropic shift to the 5-position. These compounds
undergo concerted elimination of alcohol (methanol or benzyl al-
cohol) giving pyrrol-2-ylideneketene 38 followed by electro-
cyclisation to the pyrrolizin-3-ones. Therefore, the synthesis of
pyrrolizin-3-ones 34 demonstrate that this cascade process is not
In this report we have presented new examples of the rear-
rangement of 2-vinyl-1H-pyrroles to 2-allyl-1H-pyrroles. The stud-
ied compounds are penta-substituted 1H-pyrroles formed by the
sigmatropic [1,8]-H shifts of 7,7-dimethyl-azafulvenium methides
and 7-methyl-azafulvenium methides, derived from 1,1-dimethyl-
2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 1-methyl-2,2-dioxo-1H,
3H-pyrrolo[1,2-c]thiazoles, respectively. The structural requirement
that allows the rearrangement of the penta-substituted pyrroles
into 2-allyl-1H-pyrroles is the presence of a group of the type
–CH2R (with R¼Ph or Me) at N-1. We could conclude that 2-iso-
propenyl-1H-pyrroles require the presence of an aryl substituent at
C-5 or a benzyl group at N-1 in order to rearrange to the corre-
sponding 2-allyl-1H-pyrroles. This is not the case for the 2-ethenyl-
1H-pyrroles, although the presence of a phenyl group at C-5 allows
the selective synthesis of the corresponding 2-allyl-1H-pyrrole. It
was also demonstrated that the presence of two carboxylate groups
in the starting pyrrole (at C-4 and C5) is not a requirement for
carrying out the rearrangement since 1-ethyl-2-(4-fluorophenyl)-
5-isopropenyl-4-phenyl-1H-pyrrole-3-carboxylate is converted into
the corresponding 2-(4-fluorophenyl)-5-(3-methylbut-3-en-2-yl)-
4-phenyl-1H-pyrrole-3-carboxylate.
[1,5]H
R1
H
[1,5] shift
R1
N
N
N
H
CO2R2
R1
CO2R2
CO2R2
30
35
36
No evidence for the rearrangement of 2-vinyl-1H-pyrroles to 2-
allyl-1H-pyrroles starting with di-substituted pyrroles, N-benzyl or
N-ethyl-2-vinyl-1H-pyrroles. However, under FVP N-benzyl-pyrrol-
2-ylpropenoates are converted into 3H-pyrrolizin-3-ones. On the
other hand, microwave-assisted reaction of 1-benzyl-2-vinyl-1H-
pyrrole gave the corresponding Diels–Alder cycloadduct, the 4-(1-
benzyl-1H-pyrrol-2-yl)-4,5,6,7-tetrahydro-1H-indole.
-R2OH
R1
R1
N
N
H
R2O2C
O
38
37
electrocyclisation
4. Experimental
4.1. General
N
R1
O
1H NMR spectra were recorded on an instrument operating at
300 MHz or at 400 MHz. 13C NMR spectra were recorded on an
34
Scheme 10.

9750
M.I.L. Soares et al. / Tetrahedron 64 (2008) 9745–9753
instrument operating at 75.5 MHz or at 100 MHz. The solvent is
deuteriochloroform except where indicated otherwise; chemical
shifts are expressed in parts per million related to internal TMS, and
coupling constants (J) are in hertz. Microanalyses were performed
using an EA 1108-HNS-O Fisons instrument. Mass spectra were
recorded under electron impact (EI) at 70 eV. Thiazolidines 53 and
113 and 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylates
15a1b and 15b1b were prepared following procedures described in
the literature.
105.6 ꢀC (from ethyl acetate/hexane). IR (KBr) 1736, 1698, 1440,
1168, 1089 cmꢂ1; 1H NMR (300 MHz) 1.90 (6H, s), 3.71 (3H, s), 3.82
(3H, s), 4.93 (2H, s), 7.42–7.43 (5H, m, Ar-H); 13C NMR (100 MHz)
29.6, 47.3, 51.6, 52.0, 52.9, 106.2, 119.0, 128.5, 128.8, 129.4, 129.6,
146.6, 164.1, 165.7.
4.3. General procedure for the synthesis of 2,2-dioxo-1H,3H-
pyrrolo[1,2-c]thiazoles
To a stirred ice-cold solution of the appropriate 1H,3H-pyr-
rolo[1,2-c]thiazole-6,7-dicarboxylate (1.0 mmol) in dry dichloro-
methane (7 mL) was added portionwise 3-chloroperoxybenzoic
acid (3.0 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 3 h, the re-
action mixture was washed twice with 10% (w/v) aqueous sodium
bisulfite solution (2ꢁ20 mL) and twice with 10% (w/v) aqueous
sodium bicarbonate solution (2ꢁ20 mL). The organic fraction was
then dried over anhydrous MgSO4 and the solvent evaporated off.
The crude product was purified by flash chromatography [hexane/
ethyl acetate].
4.2. General procedure for the synthesis of 1H,3H-pyrrolo-
[1,2-c]thiazoles
The appropriate 1,3-thiazolidine-4-carboxylic acid (5 mmol),
dimethyl acetylene dicarboxylate or phenyl propiolate (0.9 mL,
7.5 mmol) and acetic anhydride (20 mL) were heated at 110–120 ꢀC
for 4 h. The reaction mixture was cooled to room temperature and
was diluted with CH2Cl2 (50 mL). The organic phase was washed
with a saturated aqueous solution of NaHCO3 and water, dried
(MgSO4) and the solvent evaporated off. The crude product was
purified by flash chromatography [hexane/ethyl acetate].
4.2.1. Dimethyl 1,1,3-trimethyl-5-(4-fluorophenyl)-1H,3H-
pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 7a
4.3.1. Dimethyl 1,1,3-trimethyl-2,2-dioxo-5-(4-fluorophenyl)-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 8a
Compound 7a was purified by flash chromatography [ethyl ac-
etate/hexane (1:4)] and obtained as a white solid (1.8 g, 93%), mp
134.3–135.7 ꢀC (from ethyl acetate/hexane). IR (KBr) 1710 cmꢂ1; 1H
NMR (300 MHz) 1.27 (3H, d, J¼6.2), 1.89 (3H, s), 1.94 (3H, s), 3.69
(3H, s), 3.82 (3H, s), 5.55 (1H, q, J¼6.2), 7.09–7.16 (2H, m, Ar-H),
7.39–7.44 (2H, m, Ar-H); 13C NMR (75.5 MHz) 25.9, 30.1, 32.3, 51.5,
51.9, 52.2, 58.6, 105.7, 115.8 (d, J¼21.5), 120.3, 125.9, 126.0, 127.9,
131.3, 131.4, 146.6, 162.8 (d, J¼247.9), 164.1, 165.6; MS (EI) m/z 377
(Mþ, 51%), 362 (27), 330 (100), 285 (65), 254 (26) and 227 (10);
HRMS (EI) m/z 377.1096 (C19H20FNO4S [Mþ], 377.1097).
Compound 8a was purified by flash chromatography [ethyl ac-
etate/hexane (1:2)] and obtained as a white solid (0.39 g, 97%), mp
121.9–123.2 ꢀC (from ethyl acetate/hexane). IR (KBr) 1734, 1699,
1327, 1162 cmꢂ1; 1H NMR (300 MHz) 1.32 (3H, d, J¼6.8),1.83 (3H, s),
1.87 (3H, s), 3.69 (3H, s), 3.87 (3H, s), 5.02 (1H, q, J¼6.8), 7.14–7.19
(2H, m, Ar-H), 7.37–7.41 (2H, m, Ar-H); 13C NMR (75.5 MHz) 17.4,
20.7, 23.5, 51.9, 52.1, 61.4, 69.4, 11.3, 116.1 (d, J¼21.6), 118.4, 124.8,
124.9, 131.4, 131.5, 131.6, 136.9, 163.3 (d, J¼249.2), 163.5, 164.8; MS
(EI) m/z 409 (Mþ, 22%), 378 (18), 345 (68), 314 (55), 298 (51), 227
(100) and 212 (26). Anal. Calcd for C19H20FNO6S: C, 55.74; H, 4.92;
N, 3.42%. Found: C, 55.62; H, 4.92; N, 3.64%.
4.2.2. Dimethyl 1,1,3-trimethyl-5-phenyl-1H,3H-pyrrolo-
[1,2-c]thiazole-6,7-dicarboxylate 7b
4.3.2. Dimethyl 1,1,3-trimethyl-2,2-dioxo-5-phenyl-1H,3H-
pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 8b
Compound 7b was purified by crystallization with diethyl ether/
hexane and obtained as a white solid (5.67 g, 97%), mp 91.3–92.8 ꢀC
(from diethyl ether/hexane). IR (KBr) 1717, 1441, 1242, 1201,
1170 cmꢂ1; 1H NMR (300 MHz) 1.25 (3H, d, J¼6.3), 1.90 (3H, s), 1.95
(3H, s), 3.69 (3H, s), 3.82 (3H, s), 5.61 (1H, q, J¼6.3), 7.42–7.43 (5H,
m, Ar-H); 13C NMR (75.5 MHz) 26.0, 30.0, 32.3, 51.5, 51.9, 52.2, 58.7,
105.6, 120.2, 128.6, 128.7, 128.8, 129.2, 129.9, 146.7, 164.0, 165.8; MS
(EI) m/z 359 (Mþ, 46%), 344 (30), 312 (100), 267 (38) and 236 (20).
Anal. Calcd for C19H21NO4S: C, 63.49; H, 5.89; N, 3.90. Found: C,
63.26; H, 5.57; N, 3.68.
This was prepared in the same manner described above, except
that 4 equiv of 3-chloroperoxybenzoic acid were used and the re-
action was carried at room temperature for 6 h. Compound 8b was
purified by flash chromatography [ethyl acetate/hexane (1:2)] and
obtained as a white solid (1.92 g, 51%), mp 148.6–150.0 ꢀC (from
diethyl ether). IR (KBr) 1720, 1439, 1321, 1259, 1207, 1169 cmꢂ1; 1H
NMR (300 MHz) 1.29 (3H, d, J¼6.7), 1.83 (3H, s), 1.87 (3H, s), 3.69
(3H, s), 3.86 (3H, s), 5.09 (1H, q, J¼6.7), 7.37–7.48 (5H, m, Ar-H); 13
C
NMR (75.5 MHz) 13.4, 20.6, 23.5, 51.9, 52.1, 61.4, 69.5, 111.1, 118.2,
128.9, 129.4, 129.5, 130.2, 133.7, 136.9, 163.6, 165.1; MS (EI) m/z 391
(Mþ, 33%), 360 (26), 327 (100), 295 (79), 280 (54) and 209 (94).
Anal. Calcd for C19H21NO6S: C, 58.39; H, 5.41; N, 3.58. Found: C,
57.91; H, 5.02; N, 3.29.
4.2.3. Ethyl 1,1,3-trimethyl-5-(4-fluorophenyl)-7-phenyl-
1H,3H-pyrrolo[1,2-c]thiazole-6-carboxylate 9
Compound 9 was purified by flash chromatography [ethyl ace-
tate/hexane (1:6), ethyl acetate/hexane (1:7) and then ethyl ace-
tate/hexane (1:8)] and obtained as oil (1.37 g, 67%). IR (KBr)
4.3.3. Ethyl 1,1,3-trimethyl-2,2-dioxo-5-(4-fluorophenyl)-7-phenyl-
1H,3H-pyrrolo[1,2-c]thiazole-6-carboxylate 10
1706 cmꢂ1
;
1H NMR (300 MHz) 0.74 (3H, t, J¼7.1), 1.35 (3H, d,
J¼6.2), 1.49 (3H, s), 1.69 (3H, s), 3.82 (2H, q, J¼7.1), 5.51 (1H, q,
J¼6.2), 7.10–7.16 (2H, m, Ar-H), 7.25–7.34 (5H, m, Ar-H); 13C NMR
(75.5 MHz) 13.9, 26.2, 31.8, 34.6, 51.3, 58.2, 59.5, 115.7 (d, J¼21.5),
117.7, 118.1, 127.1, 127.8, 128.3, 128.4, 130.8, 131.2, 132.4, 132.5, 135.5,
139.9, 163.1 (d, J¼246.6), 164.9; MS (EI) m/z 409 (Mþ, 47%), 394
(100), 302 (16), 276 (10) and 261 (11); HRMS (EI) m/z 409.15109
(C24H24FNO2S [Mþ], 409.15117).
Compound 10 was purified by flash chromatography [ethyl ac-
etate/hexane (1:6) and ethyl acetate/hexane (1:4)] and obtained as
a white solid (0.27 g, 61%), mp 139.6–142.3 ꢀC (from ethyl acetate/
hexane). IR (KBr) 1703, 1318, 1180 cmꢂ1 1H NMR (300 MHz) 0.76
;
(3H, t, J¼7.1), 1.40 (3H, d, J¼6.7), 1.46 (3H, s), 1.58 (3H, s), 3.84–3.87
(2H, m), 5.01 (1H, q, J¼6.7), 7.14–7.26 (2H, m, Ar-H), 7.30–7.46 (7H,
m, Ar-H); 13C NMR (75.5 MHz) 13.4, 17.2, 22.1, 25.0, 59.6, 60.4, 69.2,
115.6 (d, J¼21.6), 116.3, 122.4, 126.8, 126.9, 127.3, 127.7, 129.8, 130.5,
132.0, 132.1, 133.7, 133.9, 163.1 (d, J¼248.1), 163.8; MS (EI) m/z 441
(Mþ, 16%), 377 (54), 330 (94), 316 (100), 289 (28), 275 (21) and 261
(14). Anal. Calcd for C24H24FNO4S: C, 65.29; H, 5.48; N, 3.17%. Found:
C, 65.23; H, 5.53; N, 3.39%.
4.2.4. Dimethyl 1,1-dimethyl-5-phenyl-1H,3H-pyrrolo-
[1,2-c]thiazole-6,7-dicarboxylate 13
Compound 13 was purified by crystallization with ethyl acetate/
hexane and obtained as a white solid (2.83 g, 88%), mp 104.5–

M.I.L. Soares et al. / Tetrahedron 64 (2008) 9745–9753
9751
4.3.4. Dimethyl 1,1-dimethyl-2,2-dioxo-5-phenyl-1H,3H-
4.5.1. Dimethyl 1-ethyl-2-(4-fluorophenyl)-5-isopropenyl-1H-
pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 14
pyrrole-3,4-dicarboxylate 18a and dimethyl 2-(4-fluorophenyl)-5-
(3-methylbut-3-en-2-yl)-1H-pyrrole-3,4-dicarboxylate 19a from 8a
[600 ꢀC/3.5ꢁ10ꢂ2 mbar]
Compound 14 was purified by crystallization with diethyl ether
and obtained as a white solid (2.03 g, 75%), mp 152.9–154.8 ꢀC
(from diethyl ether). IR (KBr) 1735, 1708, 1441, 1327, 1167, 1114,
The crude product was purified by flash chromatography [ethyl
acetate/hexane (1:2)] to give a mixture of compounds 18a and 19a
(ratio 57:43) as an oil (0.10 g, 81%). IR (film) 1725, 1643 cmꢂ1. Major
component: 1H NMR (300 MHz) 1.00 (3H, t, J¼7.2), 2.11 (3H, s), 3.80
(3H, s), 3.86 (3H, s), 5.13 (1H, t, J¼1.5), 5.47 (1H, dd, J¼1.5), 7.10–7.16
(2H, m, Ar-H), 7.39–7.46 (2H, m, Ar-H). Minor component: 1H NMR
(300 MHz) 1.40 (3H, d, J¼7.1), 1.73 (3H, s), 3.78 (3H, s), 3.79 (3H, s),
4.11 (1H, q, J¼7.1), 5.01 (1H, app. s), 5.04 (1H, app. d, J¼1.0), 7.10–
7.16 (2H, m, Ar-H), 7.39–7.46 (2H, m, Ar-H), 8.17 (1H, br s). Major
component: MS (EI) m/z 345 (Mþ, 88%), 314 (86), 298 (60), 227
(100), 212 (28). Minor component: MS (EI) m/z 345 (Mþ, 31%), 313
(100), 298 (42), 282 (30), 254 (29).
1087 cmꢂ1 1H NMR (400 MHz) 1.83 (6H, s), 3.72 (3H, s), 3.87 (3H,
;
s), 4.82 (2H, s), 7.39–7.41 (2H, m, Ar-H), 7.45–7.46 (3H, m, Ar-H); 13
C
NMR (100 MHz) 20.8, 52.0, 52.2, 61.3, 62.6, 112.3, 117.1, 128.6, 128.8,
129.4, 129.6, 133.1, 137.2, 163.6, 165.0.
4.4. General procedure for the alkylation of 2,2-dioxo-
pyrrolo[1,2-c]thiazole-2,2-dioxides 15a and 15b
LiHMDS (11.0 mL, 1.0 M in hexanes, 11.0 mmol) was slowly
added to a solution of the 2,2-dioxo-1H,3H-pyrrolo[1,2-c][1,3]thi-
azole-2,2-dioxide (11.0 mmol) in anhydrous THF (230 mL) at
ꢂ78 ꢀC and the mixture stirred for 1 h. A solution of iodomethane
(6.9 mL, 2.0 M, 13.8 mmol, 1.25 equiv) was added slowly and the
reaction mixture stirred for 1 h. The reaction mixture was then
allowed to warm to room temperature and quenched with satu-
rated aqueous ammonium chloride solution (640 mL). The organic
phase was extracted with ethyl acetate, washed with water and
brine (50 mL), and dried over anhydrous Na2SO4. The solvent was
removed in vacuo and the crude was purified by flash chroma-
tography [hexane/ethyl acetate].
4.5.2. Dimethyl 1-ethyl-2-isopropenyl-5-phenyl-1H-pyrrole-3,4-
dicarboxylate 18b and dimethyl 2-(1,2-dimethyl-allyl)-5-phenyl-
1H-pyrrole-3,4-dicarboxylate 19b from 8b [600 ꢀC/2.0ꢁ10ꢂ2 mbar]
The crude product was purified by flash chromatography
[ethyl acetate/hexane (1:2)] to give a mixture of compounds 18b
and 19b (ratio 62:38) as an oil (102 mg, 75%). IR (film) 3302,
2949, 1712, 1443, 1212, 766, 700 cmꢂ1. Major component: 1H NMR
(300 MHz) 1.00 (3H, t, J¼7.1), 2.12 (3H, br s), 3.62 (3H, s), 3.80
(3H, s), 3.78–3.86 (2H, m), 5.13–5.14 (1H, m), 5.47–5.49 (1H, m),
7.38–7.44 (5H, m, Ar-H). Minor component: 1H NMR (300 MHz)
1.40 (3H, d, J¼7.1), 1.73 (3H, br s), 3.81 (3H, s), 3.84 (3H, s), 4.22
(1H, q, J¼7.1), 5.01–5.02 (1H, m), 5.03–5.04 (1H, m), 7.38–7.44
(5H, m, Ar-H), 8.21 (1H, br s). Major component: MS (EI) m/z 327
(Mþ, 29%), 295 (100), 280 (39), 264 (28) and 236 (24). Minor
component: MS (EI) m/z 327 (Mþ, 100%), 296 (94), 280 (43), 236
(21) and 209 (84); HRMS (EI) m/z 327.1471 (C19H21NO4 [Mþ],
327.1471).
4.4.1. Dimethyl 3-benzyl-1,5-dimethyl-2,2-dioxo-1H,3H-
pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 16a
Compound 16a was obtained as a white solid (348 mg, 66%), mp
109.2–110.4 ꢀC (from diethyl ether). IR (KBr) 1740, 1706, 1456, 1332,
1308, 1130, 1091 cmꢂ1; 1H NMR (300 MHz) 1.42 (3H, d, J¼7.3), 1.94
(3H, s), 3.10 (1H, dd, J¼7.0 and 14.8), 3.63 (1H, dd, J¼5.3 and 14.8),
3.82 (3H, s), 3.85 (3H, s), 4.54 (1H, q, J¼7.3), 5.07 (1H, dd, J¼5.3 and
7.0), 7.06–7.09 (2H, m, Ar-H), 7.30–7.32 (3H, m, Ar-H); 13C NMR
(75.5 MHz) 11.1, 16.6, 39.1, 51.7, 51.8, 57.7, 73.3, 112.0, 115.9, 128.1,
129.2, 129.8, 133.0, 133.1, 133.2, 163.1, 169.4; MS (EI) m/z 391 (Mþ,
28%), 327 (50), 295 (100), 209 (31), 191 (26) and 104 (33). HRMS (EI)
m/z 391.1090 (C19H21NO6S [Mþ], 391.1090).
4.5.3. Ethyl 1-ethyl-2-(4-fluorophenyl)-5-isopropenyl-4-phenyl-
1H-pyrrole-3-carboxylate 20 and ethyl 2-(4-fluorophenyl)-5-
(3-methylbut-3-en-2-yl)-4-phenyl-1H-pyrrole-3-carboxylate
21 from 10 [600 ꢀC/3.5ꢁ10ꢂ2 mbar]
The crude product was purified by preparative thin chroma-
tography [ethyl acetate/hexane (1:1)] to give, in order of elution,
ethyl 1-ethyl-2-(4-fluorophenyl)-5-isopropenyl-4-phenyl-1H-pyr-
role-3-carboxylate 20 (35 mg, 40%) and ethyl 5-(1,2-dimethylprop-
2-en-1-yl)-2-(4-fluorophenyl)-4-phenyl-1H-pyrrole-3-carboxylate
21 (20 mg, 23%), both as solids. Ethyl 1-ethyl-2-(4-fluorophenyl)-
5-isopropenyl-4-phenyl-1H-pyrrole-3-carboxylate 20. Mp 118.8–
4.4.2. Dimethyl 1,3-dimethyl-2,2-dioxo-5-phenyl-1H,3H-
pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 16b
Compound 16b was obtained as a white solid (1.00 g, 24%), mp
171.2–173.1 ꢀC (from diethyl ether). IR (KBr) 1724, 1704, 1443, 1327,
1249, 1215, 1178, 1138 cmꢂ1; Minor isomer: 1H NMR (300 MHz) 1.25
(3H, d, J¼6.5), 1.79 (3H, d, J¼7.1), 3.72 (3H, s), 3.83 (3H, s), 4.63 (1H,
q, J¼7.1), 5.04 (1H, q, J¼6.5), 7.39–7.48 (5H, m, Ar-H). Major isomer:
1H NMR (300 MHz) 1.36 (3H, d, J¼7.0), 1.74 (3H, d, J¼7.4), 3.71 (3H,
s), 3.82 (3H, s), 4.71 (1H, q, J¼7.4), 5.04 (1H, q, J¼7.0), 7.39–7.48 (5H,
m, Ar-H); 13C NMR (75.5 MHz) 14.1, 14.2, 51.9, 52.2, 55.6, 69.5, 111.5,
118.1, 128.8, 128.9, 129.3, 129.5, 133.0, 133.7, 163.1, 165.0. MS (EI) m/z
377 (Mþ, 18%), 313 (100), 280 (67) and 195 (41); HRMS (EI) m/z
377.0932 (C18H19NO6S [Mþ], 377.0933).
121.3 ꢀC (from ethyl acetate/hexane). IR (KBr) 1700 cmꢂ1 1H NMR
;
(300 MHz) 0.79 (3H, t, J¼7.1), 1.04 (3H, t, J¼7.1), 1.76 (3H, s), 3.81–
3.88 (4H, m), 5.11 (1H, d, J¼0.81), 5.38 (1H, t, J¼1.6), 7.11–7.17
(2H, m, Ar-H), 7.27–7.43 (7H, m, Ar-H); 13C NMR (75.5 MHz) 13.5,
16.7, 24.1, 39.6, 59.16, 112.9, 115.0 (d, J¼21.4), 120.8, 122.8, 126.1,
127.2, 128.7, 128.8, 130.1, 132.4, 132.5, 132.7, 135.7, 136.2, 136.5,
162.6 (d, J¼246.1), 164.9; MS (EI) m/z 377 (Mþ, 77%), 330 (100),
316 (100), 304 (54), 289 (32), 275 (27) and 261 (16); HRMS (EI)
m/z 377.1791 (C24H24FNO2 [Mþ], 377.1791). Ethyl 2-(4-fluoro-
phenyl)-5-(3-methylbut-3-en-2-yl)-4-phenyl-1H-pyrrole-3-carboxy-
late 21. Mp 106.1–108.0 ꢀC (from ethyl acetate/hexane). IR (KBr)
4.5. General procedure for the flash vacuum pyrolysis of
1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides
Pyrolysis of the appropriate 1H,3H-pyrrolo[1,2-c]thiazole-2,2-
dioxide (0.30–0.90 mmol) or vinyl-1H-pyrrole (0.20–0.35 mmol) at
500–700 ꢀC/2ꢁ10ꢂ2 to 5ꢁ10ꢂ2 mbar onto a surface cooled at
ꢂ196 ꢀC over a period of 0.7–1 h gave a yellowish pyrolysate [the
rate of volatilisation of the starting material was controlled by the
use of a Kugelrohr oven, which heated the sample at 100–250 ꢀC].
After cooling to room temperature the pyrolysate was removed
from the cold finger with dichloromethane and the solvent was
removed in vacuo.
1675 cmꢂ1
;
1H NMR 0.88 (3H, t, J¼7.1), 1.31 (3H, d, J¼7.1), 1.66
(3H, s), 3.40 (1H, q), 3.96 (2H, q, J¼7.1), 4.91 (2H, dd, J¼3.0 and
1.2), 7.07–7.13 (2H, m, Ar-H), 7.26–7.39 (5H, m, Ar-H), 7.52–7.56
(2H, m, Ar-H), 7.92 (1H, sl, –NH); 13C NMR 13.6, 19.5, 22.5, 36.7,
59.5, 110.3, 111.9, 115.2 (d, J¼21.4), 123.9, 126.4, 127.6, 128.6, 130.2,
130.6, 130.7, 132.3, 134.1, 135.7, 147.9, 162.6 (d, J¼246.2), 165.3; MS
(EI) m/z 377 (Mþ, 100%), 362 (40), 336 (18), 316 (58), 288 (18),
274 (13) and 262 (12); HRMS (EI) m/z 377.1795 (C24H24FNO2 [Mþ],
377.1791).

9752
M.I.L. Soares et al. / Tetrahedron 64 (2008) 9745–9753
4.5.4. Dimethyl 5-isopropenyl-1-methyl-2-phenyl-1H-pyrrole-3,4-
dicarboxylate 22 from 14 [600 ꢀC/2.0ꢁ10ꢂ2 mbar]
(81 mg, 54%), which was identified by comparison with the speci-
men previously prepared.
Compound 22 was obtained as a white solid (129 mg, 95%), mp
75.0–76.8 ꢀC (from diethyl ether/hexane). IR (KBr) 2951, 1713, 1218,
1194, 1171 cmꢂ1; 1H NMR (300 MHz) 2.09 (3H, s), 3.33 (3H, s), 3.65
(3H, s), 3.80 (3H, s), 5.12–5.13 (1H, m), 5.48–5.49 (1H, m), 7.36–7.44
(5H, m, Ar-H); 13C NMR (100 MHz) 23.5, 32.6, 51.6, 51.7, 112.3, 114.0,
120.4, 127.2, 128.2, 128.7, 130.4, 130.6, 135.9, 138.8, 165.3, 165.7.
4.6. General procedure for the flash vacuum pyrolysis of
3-(1-substituted-1H-pyrrol-2-yl)-acrylates
Pyrolysis of the appropriate 3-(1-substituted-1Hꢂ-p2yrrol-2-yl)-
acrylates (0.95–1.26 mmol) at 700–750 ꢀC/2ꢁ10
to 2.7ꢁ
10ꢂ2 mbar onto a surface cooled at ꢂ196 ꢀC over a period of 0.7–1 h
gave a red pyrolysate [the rate of volatilisation of the starting
material was controlled by the use of a Kugelrohr oven, which
heated the sample at 100–230 ꢀC]. After cooling to room temper-
ature the pyrolysate was removed from the cold finger with
dichloromethane and the solvent was removed in vacuo.
4.5.5. Dimethyl 2-ethyl-5-methyl-1-styryl-1H-pyrrole-3,4-
dicarboxylate 23 and dimethyl 2-methyl-1-phenylethyl-5-vinyl-1H-
pyrrole-3,4-dicarboxylate 24 from 16a [600 ꢀC/2.0ꢁ10ꢂ2 mbar]
The crude product was purified by flash chromatography [ethyl
acetate/hexane (1:3), then ethyl acetate/hexane (1:2)] to give, in
order of elution, dimethyl 2-ethyl-5-methyl-1-styryl-1H-pyrrole-
3,4-dicarboxylate 23 (9 mg, 6%) as a white solid and dimethyl
2-methyl-1-phenylethyl-5-vinyl-1H-pyrrole-3,4-dicarboxylate 24
(11 mg, 7%) as an oil. Dimethyl 2-ethyl-5-methyl-1-styryl-1H-pyr-
role-3,4-dicarboxylate 23. Mp 114.8–116.6 ꢀC (from diethyl ether). IR
4.6.1. 5-Benzyl-pyrrolizin-3-one 34a from 30b
[700 ꢀC/2.0ꢁ10ꢂ2 mbar]
The crude product was purified by flash chromatography [ethyl
acetate/hexane (1:8), then ethyl acetate/hexane (1:3)] to give 34a
as an intense red oil (61 mg, 20%). IR (KBr) 1728, 1509, 1400,
1238 cmꢂ1; 1H NMR (300 MHz) 4.01 (2H, s), 5.56–5.58 (1H, m), 5.61
(1H, d, J¼5.7), 5.90 (1H, d, J¼3.1), 7.04 (1H, d, J¼5.7), 7.23–7.31 (5H,
m, Ar-H); 13C NMR (75.5 MHz) 32.7, 111.8, 113.5, 121.2, 126.6, 128.4,
129.0, 136.3, 137.4, 137.7, 137.8, 166.5; MS (EI) m/z 209 (Mþ, 100%),
180 (79), 154 (15) and 132 (41). HRMS (EI) m/z 209.0841 (C14H11NO
[Mþ], 209.0841).
(KBr) 2943, 1690, 1548, 1440, 1218 cmꢂ1 1H NMR (300 MHz) 1.16
;
(3H, t, J¼7.5), 2.40 (3H, s), 2.83 (2H, q, J¼7.5), 3.82 (6H, s), 6.66 (1H,
d, J¼14.3), 7.00 (1H, d, J¼14.3), 7.36–7.48 (5H, m, Ar-H); 13C NMR
(75.5 MHz) 12.2, 14.1, 18.9, 51.5, 112.0, 113.0, 122.0, 126.7, 129.0,
132.2, 133.7, 133.8, 139.8, 165.8, 165.9; MS (EI) m/z 327 (Mþ, 56%),
295 (100), 280 (91), 263 (59), 209 (43) and 77 (22); HRMS (EI) m/z
327.1472 (C19H21NO4 [Mþ], 327.1471). Dimethyl 2-methyl-1-phenyl-
ethyl-5-vinyl-1H-pyrrole-3,4-dicarboxylate 24. IR (film) 2949, 1705,
1443, 1218, 1162 cmꢂ1 1H NMR (300 MHz) 2.29 (3H, s), 2.88–2.93
;
(2H, m), 3.78 (3H, s), 3.84 (3H, s), 4.04–4.09 (2H, m), 5.38 (1H, dd,
J¼1.1 and 11.7), 5.61 (1H, dd, J¼1.1 and 17.6), 6.55 (1H, dd, J¼11.7
and 17.6), 7.06–7.09 (2H, m, Ar-H), 7.25–7.30 (3H, m, Ar-H); 13C NMR
(75.5 MHz) 10.8, 36.7, 45.6, 51.3, 52.1, 111.3, 115.1, 118.9, 124.1, 127.1,
128.7, 128.8, 130.3, 135.6, 137.2, 165.0, 167.2; MS (EI) m/z 327 (Mþ,
100%), 295 (100), 236 (27), 209 (55), 191 (58) and 104 (75); HRMS
(EI) m/z 327.1469 (C19H21NO4 [Mþ], 327.1471).
4.6.2. 5-Benzyl-pyrrolizin-3-one 34a from 30a
[700 ꢀC/2.7ꢁ10ꢂ2 mbar]
The crude product was purified by preparative thin layer chro-
matography [ethyl acetate/hexane (1:8)] to give 34a as an intense
red oil (41 mg, 21%). Compound 34a was identified by comparison
with the specimen previously prepared.
4.6.3. 5-Ethyl-pyrrolizin-3-one 34b from 30c
4.5.6. Dimethyl 2-ethyl-5-phenyl-1-vinyl-1H-pyrrole-3,4-
[750 ꢀC/2.0ꢁ10ꢂ2 mbar]
dicarboxylate 25 and dimethyl 2-(1-methyl-allyl)-5-phenyl-1H-
pyrrole-3,4-dicarboxylate 26 from 16b [600 ꢀC/4.0ꢁ10ꢂ2 mbar]
The crude product was purified by preparative thin layer chro-
matography [ethyl acetate/hexane (1:1)] to give, in order of elution,
dimethyl 2-ethyl-5-phenyl-1-vinyl-1H-pyrrole-3,4-dicarboxylate
25 (7 mg, 4%) and dimethyl 2-(1-methyl-allyl)-5-phenyl-1H-pyr-
role-3,4-dicarboxylate 26 (51 mg, 32%), both as oils. Dimethyl 2-
ethyl-5-phenyl-1-vinyl-1H-pyrrole-3,4-dicarboxylate 25. IR (film)
The crude product was purified by flash chromatography [ethyl
acetate/hexane (1:5)] to give 34b as an intense red oil (31 mg, 21%).
IR (film) 2970, 1730, 1518, 1240, 799 cmꢂ1; 1H NMR (300 MHz) 1.23
(3H, t, J¼7.5), 2.70 (2H, q, J¼7.5), 5.61 (1H, d, J¼5.7), 5.67–5.69 (1H,
m), 5.92 (1H, d, J¼3.0), 7.04 (1H, d, J¼5.7); 13C NMR (75.5 MHz) 11.5,
20.0, 111.3, 112.0, 121.0, 136.0, 137.7, 141.0, 166.7; MS (EI) m/z 147
(Mþ, 53%),132 (100) and 104 (19); HRMS (EI) m/z 147.0685 (C9H9NO
[Mþ], 147.0684).
3302, 2950, 1709, 1444, 1203, 766, 699 cmꢂ1 1H NMR (300 MHz)
;
1.23 (3H, t, J¼7.4), 2.97 (2H, q, J¼7.4), 3.70 (3H, s), 3.83 (3H, s), 4.98
(1H, dd, J¼0.7 and 15.9), 5.18 (1H, dd, J¼0.7 and 8.5), 6.54 (1H, dd,
J¼8.5 and 15.9), 7.33–7.37 (5H, m, Ar-H); 13C NMR (75.5 MHz) 14.0,
18.9, 51.4, 51.9, 111.6, 114.6, 116.1, 128.0, 128.3, 129.9, 130.4, 130.6,
133.6, 141.2, 165.0, 166.3; MS (EI) m/z 313 (Mþ, 69%), 281 (97), 266
(100), 194 (45) and 180 (18); HRMS (EI) m/z 313.1309 (C18H19NO4
[Mþ], 313.1314). Dimethyl 2-(1-methyl-allyl)-5-phenyl-1H-pyrrole-
3,4-dicarboxylate 26. IR (film) 3298, 1707, 1456, 1217 cmꢂ1; 1H NMR
(300 MHz) 1.40 (3H, d, J¼7.1), 3.80 (3H, s), 3.82 (3H, s), 4.32–4.37
(1H, m), 5.20–5.26 (2H, m), 6.01–6.12 (1H, m), 7.31–7.47 (5H, m, Ar-
H), 8.34 (1H, br s); 13C NMR (75.5 MHz) 18.5, 34.0, 51.3, 52.1, 114.4,
115.6, 124.4, 127.2, 128.2, 128.7, 130.4, 130.8, 139.2, 141.1, 164.7,
166.9; MS (EI) m/z 313 (Mþ, 24%), 281 (100), 266 (23), 250 (28), 222
(28), 194 (21) and 180 (17); HRMS (EI) m/z 313.1308 (C18H19NO4
[Mþ], 313.1314).
4.6.4. 1-Benzyl-4-(1-benzyl-1H-pyrrol-2-yl)-4,5,6,7-tetrahydro-
1H-indole 39
A solution of 1-benzyl-2-vinyl-1H-pyrrole (0.18 g, 0.98 mmol)
in 1,2,4-trichlorobenzene (1.2 mL) was irradiated in the micro-
wave reactor with the temperature set to 260 ꢀC for 30 min. After
cooling to room temperature, the crude product was purified by
flash chromatography in aluminium oxide [hexane] to remove
1,2,4-trichlorobenzene followed by elution with ethyl acetate/
hexane (1:8) to give 39 as a colourless oil (84 mg, 47%). IR (film)
3029, 2931, 1495, 1453, 1290, 705 cmꢂ1 1H NMR (400 MHz) 1.57–
;
1.68 (2H, m), 1.85–1.91 (2H, m), 2.39–2.42 (2H, m), 3.93–3.95 (1H,
m), 4.96 (2H, s), 5.13–5.14 (2H, m), 5.84–5.86 (2H, m), 6.12 (1H,
dd, J¼2.8 and 3.4), 6.54 (1H, d, J¼2.8), 6.60 (1H, dd, J¼2.8 and
2.0), 6.99–7.02 (4H, m), 7.20–7.37 (6H, m); 13C NMR (100 MHz)
21.4, 21.6, 31.2, 32.4, 50.0, 50.2, 106.6, 106.8, 106.9, 119.7, 120.0,
120.8, 126.3, 126.4, 127.1, 127.2, 128.2, 128.6, 128.7, 137.9, 138.6,
139.0; MS (EI) m/z 366 (Mþ, 88%), 338 (42), 275 (25), 247 (17),
209 (33) and 91 (100); HRMS (EI) m/z 366.2092 (C26H26N2 [Mþ],
366.2096).
4.5.7. Dimethyl 2-(1-methyl-allyl)-5-phenyl-1H-pyrrole-3,4-
dicarboxylate 26 from 16b [600 ꢀC/2.0ꢁ10ꢂ2 mbar]
The crude product was purified by preparative thin layer chro-
matography [ethyl acetate/hexane (1:2)] to give compound 26

M.I.L. Soares et al. / Tetrahedron 64 (2008) 9745–9753
9753
Soares, M. I. L.; Paixa˜o, J. A.; Matos Beja, A.; Ramos Silva, M. J. Org. Chem. 2007, 72,
4406–4415.
Acknowledgements
3. Pinho e Melo, T. M. V. D.; Soares, M. I. L.; Nunes, C. M. Tetrahedron 2007, 63, 1833–
1841.
4. Soares, M. I. L.; Pinho e Melo, T. M. V. D. Tetrahedron Lett. 2008, 49, 4889–4893.
5. Pinho e Melo, T. M. V. D.; Gomes, C. S. B.; Rocha Gonsalves, A. M. d’A.; Paixa˜o,
J. A.; Beja, A. M.; Ramos Silva, M.; Alte da Veiga, L. Tetrahedron 2002, 58, 5093–
5102.
Thanks are due to FCT (Project PTDC/QUI/64470/2006; Grant
SFRH/BPD/26772/2006) and FEDER for financial support.
Supplementary data
6. Sutcliffe, O. B.; Storr, R. C.; Gilchrist, T. L.; Rafferty, P. J. Chem. Soc., Perkin Trans. 1
2001, 1795–1806.
Data regarding the synthesis of compounds 6, 12, 28, 29, 30, 32
and 33 are provided. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.tet.2008.07.079.
7. (a) Heaney, H.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1973, 499–500; (b) Downie,
I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F. Tetrahedron 1993, 49, 4015–4034;
(c) Candy, C. F.; Jones, R. A.; Wright, P. H. J. Chem. Soc. C 1970, 18, 2563–2567; (d)
Stoll, M.; Winter, M.; Gautschi, F.; Flament, I.; Willhalm, B. Helv. Chim. Acta 1967,
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References and notes
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