Reactivity of sarcosine and 1,3-thiazolidine-4-carboxylic acid towards salicylaldehyde-derived alkynes and allenes

Article abstract of DOI:10.1016/j.tet.2013.09.052

The reaction of sarcosine and 1,3-thiazolidine-4-carboxylic acid with salicylaldehyde-derived alkynes and allenes opened the way to new chromeno[4,3-b]pyrrole and chromeno[2,3-b]pyrrole derivatives. Tetrahydro-chromeno[4,3-b]pyrroles were obtained from th

Full text of DOI:10.1016/j.tet.2013.09.052

Tetrahedron xxx (2013) 1e10
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Reactivity of sarcosine and 1,3-thiazolidine-4-carboxylic acid
towards salicylaldehyde-derived alkynes and allenes
a
b
a,
*
Fernanda M. Ribeiro Laia , Clara S.B. Gomes , Teresa M.V.D. Pinho e Melo
a
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
Centro de Química Estrutural, Departamento de Engenharia Química, Instituto Superior T ꢀe cnico, University of Lisbon, 1049-001 Lisboa, Portugal
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2013
Received in revised form 10 September 2013
Accepted 17 September 2013
Available online xxx
The reaction of sarcosine and 1,3-thiazolidine-4-carboxylic acid with salicylaldehyde-derived alkynes
and allenes opened the way to new chromeno[4,3-b]pyrrole and chromeno[2,3-b]pyrrole derivatives.
Tetrahydro-chromeno[4,3-b]pyrroles were obtained from the reaction of these secondary amino acids
with O-propargylsalicylaldehyde. Interestingly, sarcosine reacted with ethyl 4-(2-formylphenoxy)but-2-
ynoate to give a monocyclic pyrrole resulting from rearrangement of the initially formed 1,3-dipolar
cycloadduct. Decarboxylative condensation of ethyl 4-(2-formylphenoxy)but-2-ynoate with 1,3-
thiazolidine-4-carboxylic acid afforded in a stereoselective fashion the expected chromeno-pyrrolo
Keywords:
Cycloaddition
[
1
1,2-c]thiazole, which structure was unambiguously established by X-ray crystallography. However, the
H,3H-pyrrolo[1,2-c]thiazole resulting from the opening of the pyran ring was also isolated. The reaction
Azomethine ylides
Chromeno[4,3-b]pyrroles
Chromeno-pyrrolo[1,2-c]thiazoles
Chromeno[2,3-b]pyrrole
Pyrroles
Allenes
Sarcosine
Thiazolidine
with O-buta-2,3-dienyl salicylaldehyde afforded 3-methylene-hexahydrochromeno[4,3-b]pyrrole. O-Al-
lenyl salicylaldehyde reacted with sarcosine and 1,3-thiazolidine-4-carboxylic acid to give a new type of
chromeno-pyrroles. A mechanism proposal for the synthesis of these chromeno[2,3-b]pyrroles has been
presented.
Ó 2013 Published by Elsevier Ltd.
1. Introduction
salicylaldehydes is known.5 On the other hand, it has been dem-
onstrated that the reaction of imines derived from O-alkenyl sali-
Chromene and chromane substructures are frequently found in
naturally occurring compounds, many of which exhibit useful bi-
ological activity.1 This led to the search for new compounds in-
spired on these structural motifs in order to obtain molecules with
relevance in medicinal chemistry. In this context, hetero-annulated
chromene and chromane derivatives, namely chromeno[4,3-b]
pyrrole derivatives, are important target molecules. Reports on the
construction of the chromeno[4,3-b]pyrrole ring system include
the condensation of alkenyl and alkynyl ethers of salicylaldehydes
cylaldehydes and acid chlorides mediated by PhP(2-catechyl) leads
to chromeno[4,3-b]pyrrole derivatives via intramolecular cycload-
6
dition of phosphorus-containing 1,3-dipoles.
Despite the existing methods for the synthesis of chromeno[4,3-
b]pyrrole derivatives, there still is demand for strategies to achieve
wider structural diversity. Our approach was to study the reactivity
of sarcosine and 1,3-thiazolidine-4-carboxylic acid with a variety of
salicylaldehydes bearing internal dipolarophiles, including de-
rivatives with an allenic moiety, which could give access to new
types of tetrahydrochromeno-pyrrole derivatives.
with either a-amino acid esters or secondary amino acids followed
by intramolecular 1,3-dipolar cycloaddition of the in situ generated
azomethine ylides.2 Intramolecular cycloaddition of mesoionic 2-
[2-(prop-2-ynyloxy)phenyl]oxazolium-5-olates prepared from the
2. Results and discussion
corresponding N-acylamino acids is an alternative approach to
chromeno[4,3-b]pyrroles. 2-Fluorochromeno[4,3-b]pyrroles have
also been prepared by intramolecular cycloaddition of azomethine
3
O-Propargylsalicylaldehyde (2) was efficiently obtained from
the reaction of salicylaldehyde with propargyl bromine in refluxing
ethanol in the presence of potassium carbonate. The Crabb
eꢀ ho-
ylides generated from the reaction of difluorocarbenes with imines
4
derived from alkenyl and alkynyl ethers of salicylaldehydes.
A
mologation of terminal alkynes was applied to the synthesis of O-
7
similar approach involving the generation of azomethine ylides
from ethoxycarbonylcarbenoids and Schiff bases of O-alkynyl
buta-2,3-dienyl salicylaldehyde (3). Thus, the copper(I) bromide
mediated reaction of salicylaldehyde
2
with formaldehyde
0
and N,N -diisopropylamine in refluxing dioxane afforded the cor-
responding allenic derivative 3 in 70% yield. The protection of the
aldehyde functionality of compound 2 was achieved by treatment
*
Corresponding author. E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
0
040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.09.052
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F.M. Ribeiro Laia et al. / Tetrahedron xxx (2013) 1e10
with a 5:1 methanoletrimethyl orthoformate solution in the
presence of p-toluenesulfonic acid following previously reported
We extended the study to the reactivity of sarcosine towards
salicylaldehyde 5, bearing an activated alkyne (Table 1). Carrying
out the reaction in refluxing toluene for 1 h, the corresponding
1,2,4,9b-tetrahydrochromeno[4,3-b]pyrrole was not formed and
instead pyrrole 10 was isolated in 16% yield (entry 1). The
structural assignment of this compound was based on one-
8
general procedures. The acetal protected salicylaldehyde 4 reacted
ꢀ
with potassium tert-butoxide in tert-butanol at 60 C to give the
aryloxyallene derivative after 1.5 h, as described for other aryl
9
propargyl ethers. The acetal group was smoothly hydrolyzed with
8
a
1
13
1
M HCl to afford O-allenyl salicylaldehyde (6) in good yield. At-
dimensional H and C NMR spectra and confirmed by two-
1
tempts to prepare aldehyde 6 from O-propargylsalicylaldehyde (2)
without resorting to aldehyde protection, following a reported
methodology,10 were not successful. The functionalization of ter-
minal alkyne 4 with a carboxylate group was carried out by reacting
it with butyllithium followed by the reaction with ethyl chlor-
oformate.11 Deprotection of the acetal group gave the target O-
propargylsalicylaldehyde 5 in 85% overall yield (Scheme 1).
Initially, we looked again into the reaction of O-prop-
dimensional HMQC spectrum. The H NMR spectrum showed
a signal with a chemical shift of 2.14 ppm corresponding to
methyl protons. In the HMQC spectrum,
a proton having
a chemical shift of 7.40 ppm showed connectivity with the carbon
with the chemical shift 128.9 ppm, which was assigned to carbon
C-2. On the other hand, no connectivity was observed for a proton
with the chemical shift of 5.32 ppm confirming that it belongs to
the hydroxyl group.
8a
Scheme 1. Synthesis of O-propargylic, O-allenyl and O-buta-2,3-dienyl salicylaldehyde derivatives.
argylsalicylaldehyde (2) with sarcosine (Scheme 2). Under the re-
Table 1
2
i
ported reaction conditions, condensation of aldehyde 2 with
sarcosine (2 equiv) in toluene at reflux for 4 h, the expected tetra-
hydro-chromeno[4,3-b]pyrroles 7 was obtained in 70% yield. In-
creasing the reaction time to 16 h gave 1,2,4,9b-tetrahydrochromeno
Synthesis of chromeno[4,3-b]pyrrole 9 and pyrrole 10 from salicylaldehyde 5 and
sarcosine
[4,3-b]pyrrole 7 in 73% yield together with the formation of the
corresponding aromatized derivative 8 obtained in low yield (11%).
Oxidation of compound 7, using Pd/C in refluxing ethyl acetate for
24 h, afforded 1,4-dihydrochromeno[4,3-b]pyrrole 8 in 75% yield.
Entry
Reaction conditions
Isolated yield 9 (%)
Isolated yield 10 (%)
a
1
2
3
4
5
6
7
Reflux, 1 h
d
16
75
81
81
15
d
a
b
Reflux, 2 h
<5
<1
<3
<3
d
a
b
Reflux, 4 h
a
b
Reflux, 15.5 h
ꢀ
c
b
95 C, 4 h
ꢀ
MW, 120 C, 5 min
MW, 150 C, 15 min
ꢀ
b
<3
52
a
DeaneStark apparatus was used.
b
c
Scheme 2. Synthesis of tetrahydrochromeno[4,3-b]pyrrole 7 and dihydrochromeno
4,3-b]pyrrole 8 from O-propargylsalicylaldehyde (2) and sarcosine.
Compound 9 could not be isolated in pure form.
ꢁ
[
Molecular sieves (4 A).
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F.M. Ribeiro Laia et al. / Tetrahedron xxx (2013) 1e10
3
The conventional thermolysis of aldehyde 5 in toluene in the
presence of sarcosine was performed using different reaction times
Table 1). Refluxing for 2 h gave pyrrole 10 in 75% yield, together
with the formation of 1,4-dihydrochromeno[4,3-b]pyrrole 9 in low
yield (entry 2). Increasing the reaction time to 4 h afforded pyrrole
0 in 81% yield (entry 3). The formation of compound 9 in very low
yield was again observed. However, a longer reaction time did not
lead to improvements (entry 4). On the other hand, the use of
milder reaction conditions did not favour the formation of chro-
meno[4,3-b]pyrrole 9 (entry 5).
However, an unexpected result was obtained. In fact, the re-
action of O-allenyl salicylaldehyde (6) with sarcosine afforded
chromeno[2,3-b]pyrrole 16 instead of the chromeno[4,3-b]pyrrole
15 (Table 2). Carrying out the reaction in refluxing toluene for 3 h
chromeno[2,3-b]pyrrole 16 was obtained in 62% yield (Table 2,
entry 1). A slight improvement of the yield was achieved when the
reaction time was increased to 4 h (entry 2). Compound 16 was also
obtained in good yield under microwave-induced reaction condi-
tions (entry 3).
(
1
The synthesis of pyrrole 10 was also achieved under microwave-
induced reaction conditions (Table 1). Irradiation at 120 C for
Table 2
ꢀ
Synthesis of 1-methyl-1,2,3,9a-tetrahydrochromeno[2,3-b]pyrrole (16) from O-al-
lenyl salicylaldehyde (6) and sarcosine
5
min did not lead to any products (entry 6) but setting the tem-
ꢀ
perature to 150 C for 15 min allowed the isolation of pyrrole 10 in
5
2% yield (entry 7).
The synthesis of the monocyclic pyrrole 10 can be rationalized
as outlined in Scheme 3. The initially formed 1,3-dipolar cyclo-
adduct 12 undergoes opening of the pyran ring to give intermediate
13, which is converted into the final product by prototropy.
Entry
Reaction conditions
Isolated yield, 16 (%)
a
1
2
3
Reflux, 3 h
62
66
59
a
Reflux, 4 h
ꢀ
MW, 150 C, 15 min
a
DeaneStark apparatus was used.
The assignment of the structure of compound 16 was supported
by two-dimensional HMQC and HMBC spectra (400 MHz). From
HMQC spectrum, it was established that the carbon with the
chemical shift 117.2 ppm corresponds to C-4 since it shows con-
nectivity with the vinylic proton having a chemical shift of
6.24 ppm. The carbon with the chemical shift 93.8 ppm was
assigned to C-9a since it shows connectivity with the proton
chemical shift 4.92 ppm. On the other hand, protons of the two
1
methylene groups, observed in the H NMR spectrum at 2.66 ppm
and 2.97 ppm, show connectivity with carbons with chemical shift
25.6 ppm (C-3) and 51.3 ppm (C-2), respectively. In the HMBC
spectrum, methyl protons correlate with carbon C-2 (51.3 ppm) and
carbon C-9a (93.8). On the other hand, proton H-4 correlates with
carbons C-3 (25.6 ppm) and C-9a (93.8 ppm), C-8a (151.6 ppm) and
with the aromatic carbon observed at 125.2 ppm (Fig. 1). From the
HMBC spectrum, it was also established that the quaternary car-
bons with the chemical shift 123.3 ppm and 135.5 ppm correspond
to C-4a and C-3a, respectively, since connectivity was observed
between carbon C-4a and the protons H-6 and H-5 but no corre-
lation was observed between these protons and carbon C-3a. In
addition, the values of the chemical shift observed for C-4
Scheme 3. Mechanism proposal for the synthesis of pyrrole 10.
The reactivity of sarcosine towards the salicylaldehyde-derived
allene derivative 6 was also studied. It was expected that the
decarboxylative condensation of salicylaldehyde-derived allene
derivative 6 with sarcosine would lead to tetrahydrochromeno[4,3-
b]pyrrole 15 in a process where the
b,g-carbonecarbon double
bond of the allene would act as dipolarophile on reacting with the
in situ generated azomethine ylide 14 (Scheme 4).
(117.2 ppm) and C-3a (135.5 ppm) confirmed the structural as-
signment and ruled out the alternative isomeric structure 15.
Fig. 1. Main connectivities found in the HMBC spectrum of 1-methyl-1,2,3,9a-tetra-
hydrochromeno[2,3-b]pyrrole 16.
The reaction of sarcosine with O-buta-2,3-dienyl salicylalde-
hyde (3) was also explored under conventional thermolysis and
under microwave irradiation (Table 3). The best result was achieved
carrying out the reaction in refluxing toluene for 27 h giving 3-
methylene-hexahydrochromeno[4,3-b]pyrrole 17 in 58% yield.
Scheme 4. The expected outcome of the reaction of O-allenyl salicylaldehyde (6) with
sarcosine.
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4
F.M. Ribeiro Laia et al. / Tetrahedron xxx (2013) 1e10
The synthesis of this compound can be explained considering the
generation of the expected azomethine ylide, which participates in
Table 4
Synthesis of chromeno-pyrrolo[1,2-c]thiazoles from O-propargylsalicylaldehyde (2)
and 1,3-thiazolidine-4-carboxylic acid (18)
intramolecular 1,3-dipolar cycloaddition with the
a,b-carbon-
ecarbon double bond of the allenic moiety. The stereochemistry of
the ring fusion was assigned considering that the benzylic methine
proton was observed as a doublet with a coupling constant of
5
.2 Hz, which is the value expected for a cis relationship. On the
other hand, in the NOESY spectrum cross-peaks were observed
between protons H-9b and H-3a.
Table 3
Synthesis of 1-methyl-3-methylene-1,2,3,3a,4,9b-hexahydrochromeno[4,3-b]pyr-
role (17) from O-buta-2,3-dienyl salicylaldehyde (3) and sarcosine
Entry
Reaction conditions
Isolated yield, 17 (%)
Entry
Reaction conditions
Isolated yield 20 (%)
Isolated yield 21 (%)
a
a
1
2
3
4
5
Reflux, 4 h
28
31
56
58
6
1
2
3
4
Reflux, 17 h
36
37
40
16
18
16
a
a
Reflux, 6 h
Reflux, 7 h
Reflux, 4 h
a
a
Reflux, 19.5 h
Reflux, 27 h
MW, 150 C, 15 min
a
ꢀ
b
b
MW, 150 C, 15 min
19
6
ꢀ
a
DeaneStark apparatus was used.
Compound 22 was also isolated in <10%.
a
b
DeaneStark apparatus was used.
The structure of this chromeno[4,3-b]pyrrole derivative is of
particular interest since the presence of the methylene group al-
lows further elaboration.
In recent past, we have been interested in exploring the in-
termolecular cycloaddition of nonstabilized ylides generated via
the decarboxylative condensation of 1,3-thiazolidine-4-carboxylic
acids with aldehydes.12 On the other hand, the reaction of O-
propargylsalicylaldehyde (2) with 1,3-thiazolidine-4-carboxylic
connectivity with the proton observed as
a multiplet at
4.60e4.61 ppm. The carbon at 123.7 ppm corresponds to C-7 since
it shows connectivity with the vinylic proton (5.65 ppm). In the
HMBC spectrum, H-7 correlates with carbons C-7a (76.3 ppm), C-6a
(136.4 ppm) and C-11a (67.3 ppm) and protons H-6 correlate with
carbons C-7 (123.7 ppm), C-6a (136.4 ppm), C-4a (153.2 ppm) and
C-11a (67.3 ppm). From the HMBC spectrum, it was also established
that the quaternary carbons with the chemical shift 127.3 ppm and
136.4 ppm correspond to C-11b and C-6a, respectively, since con-
nectivity was observed between carbon C-11b and two aromatic
protons but no correlation was observed between these protons
and carbon C-6a. In the NOESY spectrum of compound 20, no
connectivity was observed between H-7a and H-11a. The same
spectroscopy analysis was carried out for derivative 21. In this case,
connectivity between H-7a and H-11a was observed in the NOESY
spectrum.
2
d
acid (18) has been reported. The authors reported that carrying
ꢀ
out the reaction in toluene at 100 C for 17 h, chromeno-pyrrolo
[1,2-c]thiazole 20 was obtained in 37% yield via the anti-dipole but
no product resulting from the cycloaddition of the syn-dipole was
detected. In this context, we decided to look into this reaction and
to extend the study to the reaction of 1,3-thiazolidine-4-carboxylic
acid with other salicylaldehyde-derived alkynes and allenes.
Carrying out the reaction of O-propargylsalicylaldehyde (2) with
1
,3-thiazolidine-4-carboxylic acid using conditions similar to those
2b
previously described did not lead to the same outcome (Table 4,
entry 1). In fact, chromeno-pyrrolo[1,2-c]thiazole 20 was isolated in
3
6% yield as previously reported, but the chromeno-pyrrolo[1,2-c]
thiazole 21, derived from the cycloaddition of the syn-dipole, was
also obtained in 16% yield. Performing the reaction with a shorter
reaction time (7 h or 4 h) also afforded compound 20 (37e40%) as
the major product together with the formation of the stereoisomer
We have previously described quantum-chemistry calculations,
which were carried out in order to explain the anti/syn selectivity of
the decarboxylative condensation of 1,3-thiazolidine-4-carboxylic
acid with aldehydes. Based on the gas-phase calculations the anti
1,3-dipole was expected to be more stable than the syn form by ca.
21 (16e18%) (entries 2 and 3). The microwave-induced condensa-
tion of O-propargylsalicylaldehyde (2) with 1,3-thiazolidine-4-
carboxylic acid led to chromeno-pyrrolo[1,2-c]thiazoles 20 and 21
in lower yields and the aromatized derivative 22 was also isolated
ꢁ1
17 kJ mol for R¼Ph. Moreover, according to the calculations, the
barrier height for syneanti interconversion is low. This suggests
that, once produced, the syn and anti-dipoles exist in equilibrium.
The theoretical calculations predicted that the produced amount of
syn 1,3-dipole should be significantly higher (ca. 92%) than that of
the anti 1,3-dipole (ca. 8%). However, after being formed in a com-
paratively larger amount, the syn 1,3-dipole is expected to partially
(
entry 4).
The assignment of the structure of compounds 20 and 21 was
supported by two-dimensional NOESY, HMQC and HMBC spectra
400 MHz). From the HMQC spectrum of compound 20, it was
(
established that the carbon with 67.3 ppm chemical shift corre-
sponds to C-11a since it shows connectivity with the proton having
a chemical shift of 4.69 ppm. On the other hand, the carbon with
12
convert to the anti form. These observations are also in agreement
with selective formation of chromeno-pyrrolo[1,2-c]thiazole 20
resulting from the cycloaddition of the anti 1,3-dipole 19a
76.3 ppm chemical shift corresponds to C-7a since it shows
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F.M. Ribeiro Laia et al. / Tetrahedron xxx (2013) 1e10
5
generated from O-propargylsalicylaldehyde (2) and 1,3-
thiazolidine-4-carboxylic acid (18).
The work was then extended to the study of the reactivity of 1,3-
thiazolidine-4-carboxylic acid (18) towards salicylaldehyde 5 (Table
5
). Carrying out the reaction in refluxing toluene a mixture of
chromeno-pyrrolo[1,2-c]thiazoles 23 and 24 and pyrrolo[1,2-c]
thiazole 25 were isolated (entries 1e3). The best result was ach-
ieved when the thiazolidine and salicylaldehyde 5 were left to react
for 7 h giving a 94:6 mixture of compounds 23 and 24 in 73% yield
and pyrrolo[1,2-c]thiazole 25 in 12% yield (entry 2). Interestingly,
selective crystallization of the mixture of 23 and 24 with ethyl
acetate/hexane afforded 23 as a white crystalline solid, whereas
compound 24 was obtained as a yellow solid by crystallization with
ethyl acetate/petroleum ether. The synthesis of 1H,3H-pyrrolo[1,2-
c]thiazole 25 can be explained considering a similar pathway to the
one leading to pyrrole 10 (see Scheme 3) although in this case the
process is less favoured, which is an indication of the higher sta-
bility of the initially formed cycloadduct. The reaction was also
Fig. 2. ORTEP-3 diagram of compound 23, using 50% probability level ellipsoids. For
clarity reasons, only one of the molecules present in the asymmetric unit is shown.
ꢀ
carried out at 95 C for 30 h with the aim of favouring the formation
0 0
chromeno[3 ,2 :4,5]pyrrolo[1,2-c]thiazole 26 instead of the ex-
of chromeno-pyrrolo[1,2-c]thiazoles 23 (entry 4). However, under
these reaction conditions an 80:20 mixture of compounds 23
and 24 was obtained in only 62% yield and 1H,3H-pyrrolo[1,2-c]
0
0
pected 7a,8,10,11a-tetrahydro-7H-chromeno[3 ,4 :4,5]pyrrolo[1,2-
c]thiazole, which would be formed via the generation of the cor-
responding azomethine ylide followed by the addition to the b,g-
carbonecarbon double bond of the allene. Thus, the chemical be-
haviour of salicylaldehyde 6 towards sarcosine was also observed in
the reaction of this compound with 1,3-thiazolidine 18.
Table 5
Decarboxylative condensation of salicylaldehyde
carboxylic acid (18)
5
with 1,3-thiazolidine-4-
Table 6
Synthesis of chromeno-pyrrolo[1,2-c]thiazole 26 from salicylaldehyde 6 and 1,3-
thiazolidine-4-carboxylic acid (18)
Entry
Reaction conditions
Isolated yield, 26 (%)
a
1
2
3
Reflux, 17 h
42
42
9
a
Reflux, 7 h
ꢀ
MW, 150 C, 15 min
Entry
Reaction conditions
Isolated yield (23/24)c
Isolated yield 25 (%)
a
DeaneStark apparatus was used.
1
2
3
4
5
Reflux, 16 ha
58% (96:4)
73% (94:6)
51% (96:4)
62% (80:20)
42% (86:14)
10
12
7
4
15
Reflux, 7 ha
a
Reflux, 5 h
The reaction carried out in refluxing toluene for 17 h resulted in
the chromeno-pyrrolo[1,2-c]thiazole 26 on 42% yield isolated as
single stereoisomer (Table 6, entry 1). The same yield was obtained
heating the reaction mixture for a shorter period (Table 6, entry 2).
Under microwave irradiation compound 26 was isolated in very
low yield (Table 6, entry 3).
ꢀ
b
95 C, 30 h
ꢀ
MW, 150 C, 15 min
a
DeaneStark apparatus was used.
Molecular sieves were used.
b
c
Ratio of isomers determined by 1H NMR.
The assignment of the structure of chromeno-pyrrolo[1,2-c]
thiazole 26 was supported by two-dimensional NOESY, HMQC and
HMBC spectra (400 MHz). From the HMQC spectrum, it was
established that the carbon with 119.5 ppm chemical shift was
assigned to C-10 since it shows connectivity with the vinylic proton
observed at 6.30 ppm. The carbon with chemical shift 33.3 ppm
corresponds to methylene group of pyrrolidine ring (C-11) since it
shows connectivity with two protons with different chemical shifts,
thiazole 25 in 4%. The microwave-induced reaction was less effi-
cient (entry 5).
The structure of chromeno-pyrrolo[1,2-c]thiazole 23 was un-
ambiguously established by X-ray crystallography (Fig. 2). Two
molecules of opposite chirality were present in the crystal struc-
ture. There are two chirogenic centres, C-11a and C-7a, in each
molecule. The hydrogen atoms bonded to these carbons are placed
on opposite faces of the 3-pyrroline ring. The results described
above show that selective formation of the product resulting from
the cycloaddition of the anti-dipole was again observed.
The reactivity of 1,3-thiazolidine-4-carboxylic acid (18) towards
salicylaldehyde-derived allene 6 was also explored (Table 6). We
were please to find that this reaction leads to tetrahydro-1H-
2.50e2.55 ppm and 3.03e3.09 ppm. In the HMBC spectrum, proton
H-10 correlates with carbons C-11 (33.3 ppm) and C-4a (93.5 ppm),
C-5a (152.4 ppm) and with the aromatic carbon observed at
1
(
26.4 ppm. The protons H-1 correlate with carbons C-11
33.3 ppm), C-11a (66.8 ppm) and C-3 (58.1 ppm). On the other
hand, protons H-11 correlate with carbons C-1 (38.7 ppm), C-11a
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6
F.M. Ribeiro Laia et al. / Tetrahedron xxx (2013) 1e10
(
66.8 ppm), C-10 (119.5 ppm) and C-10a (134.6 ppm). From the
3. Conclusions
HMBC spectrum, it was also established that the quaternary car-
bons with the chemical shift 123.5 ppm and 134.6 ppm correspond
to C-9a and C-10a, respectively, since connectivity was observed
between carbon C-9a and two aromatic protons but no correlation
was observed between these protons and carbon C-10a. Thus,
similar spectroscopic features were observed between chromeno
The reactivity of sarcosine and 1,3-thiazolidine-4-carboxylic acid
towards salicylaldehyde-derived alkynes and allenes was explored
as a strategy to obtain new chromeno[4,3-b]pyrrole derivatives.
The decarboxylative condensation of sarcosine and 1,3-
thiazolidine-4-carboxylic acid with O-propargylsalicylaldehyde
led to the synthesis of the corresponding tetrahydrochromeno[4,3-
b]pyrroles. Stereoselectivity was observed in the reaction with the
1,3-thiazolidine with the formation of the cycloadduct resulting
from the anti-dipole as the major product.
A different outcome was observed from the reaction of sarcosine
with ethyl 4-(2-formylphenoxy)but-2-ynoate. In this case, the ini-
tially formed 1,3-dipolar cycloadduct undergoes opening of the
pyran ring followed by prototropy to give a monocyclic pyrrole.
Decarboxylative condensation of ethyl 4-(2-formylphenoxy)but-2-
ynoate with 1,3-thiazolidine-4-carboxylic acid afforded the ex-
pected chromeno-pyrrolo[1,2-c]thiazole with the selective forma-
tion of the product derived from the anti-dipole, which structure
[2,3-b]pyrrole 16 and chromeno-pyrrolo[1,2-c]thiazole 26. In the
NOESY spectrum no connectivity was observed between H-11a and
H-4a, which is in agreement with the stereochemistry assignment.
A mechanism proposal for the synthesis of chromeno[2,3-b]
pyrrole 16 and chromeno-pyrrolo[1,2-c]thiazole 26 is outlined in
Scheme 5. The initial cyclization of O-allenyl salicylaldehyde (6)
affords intermediate 27, which undergoes nucleophilic addition on
reacting with the secondary amino acid to give 28. Opening of the
dihydro-pyran ring, followed by the elimination of carbon dioxide
gives azomethine ylide 31 bearing an allene moiety. The sub-
sequent 1,3-dipolar cycloaddition, with the internal addition to the
allene b,g-carbonecarbon, leads to the final product.
Scheme 5. Mechanism proposal for the synthesis of chromeno[2,3-b]pyrrole 16 and chromeno-pyrrolo[1,2-c]thiazole 26.
Interestingly, 3-methyl-4H-chromen-4-one (33)13 was formed
in low yield (4e9%) as byproduct from the reaction of the salicy-
laldehyde 6 with 1,3-thiazolidine-4-carboxylic acid (18). This ob-
servation reinforces the mechanism proposal for the synthesis of
chromeno-pyrrolo[1,2-c]thiazole 26 since 4H-chromen-4-one 33
derives from the postulated intermediate 27 (Scheme 6).
was unambiguously established by X-ray crystallography. However,
the 1H,3H-pyrrolo[1,2-c]thiazole resulting from the opening of the
pyran ring was also isolated.
A 3-methylene-hexahydrochromeno[4,3-b]pyrrole derivative was
obtained from the reaction of O-buta-2,3-dienyl salicylaldehyde and
sarcosine via intramolecular 1,3-dipolar cycloaddition of the expected
dipole with the a,b-carbonecarbon double bond of the allenic moiety.
The synthesis of a new type of chromeno-pyrrole derivatives was
also achieved from the reaction of O-allenyl salicylaldehyde with
secondary amino acids. O-Allenyl salicylaldehyde reacted with sar-
cosine and 1,3-thiazolidine-4-carboxylic acid to afford 1-methyl-
1
,2,3,9a-tetrahydrochromeno[2,3-b]pyrrole and 3,4a,11,11a-tetrahy-
0
0
dro-1H-chromeno[3 ,2 :4,5]pyrrolo[1,2-c]thiazole, respectively.
Scheme 6. 3-Methyl-4H-chromen-4-one (33) formed as byproduct of the synthesis of
chromeno-pyrrolo[1,2-c]thiazole 26.
4
4
. Experimental section
.1. General
Attempts to carry out the decarboxylative condensation of 1,3-
thiazolidine-4-carboxylic acid with O-buta-2,3-dienyl salicylalde-
hyde (3) led to complex mixtures.
Microwave reactions were carried out in a microwave reactor
CEM Focused Synthesis System Discover S-Class. Flash column
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F.M. Ribeiro Laia et al. / Tetrahedron xxx (2013) 1e10
7
þ
chromatography was performed with silica gel 60 as the stationary
70.4, 51.0, 48.3; HRMS (ESI): calculated C12
229.0835. Found: 229.0832.
H
14NaO
3
[M þNa]:
1
phase. H NMR spectra were recorded on an instrument operating at
4
00 MHz and 13C NMR at 100 MHz. Chemical shifts are expressed in
parts per million relatively to internal tetramethylsilane (TMS), and
coupling constants (J) are in hertz. IR spectra were recorded on
a Fourier Transform spectrometer. HRMS spectrawere obtained on an
electron impact (EI) or electrospray (ESI) TOF mass spectrometer.
Melting points were determined in open glass capillaries and are
uncorrected. Sarcosine was purchased from Aldrich.1,3-Thiazolidine-
4.2.4. Ethyl 4-(2-formylphenoxy)but-2-ynoate (5).8a,11 A solution of
ꢀ
acetal 4 (1.63 g, 7.90 mmol) in dry THF (42 mL) was stirred at ꢁ78 C
for 10 min under nitrogen atmosphere. Butyllithium (2.5 M in
hexane) (4.74 mL, 11.85 mmol) was slowly added to the reaction
mixture over 40 min and the resulting solution was stirred for
30 min at the same temperature. Ethyl chloroformate (1.28 mL,
13.43 mmol) was slowly added to the reaction mixture and stirred
4
-carboxylic acid was prepared by a literature procedure.14
ꢀ
another 40 min at ꢁ78 C. After warming to room temperature, the
4
reaction mixture was quenched with saturated aqueous NH Cl
4
.2. Procedures for the synthesis of salicylaldehyde
solution (80 mL) and diluted with ethyl acetate (200 mL). The or-
derivatives
ganic layer was washed with water (3ꢂ200 mL), brine (2ꢂ40 mL),
2 4
dried over Na SO and the solvent was removed in vacuum. The
4
.2.1. 2-(Prop-2-ynyloxy)benzaldehyde (2). Benzaldehyde
2
was
crude product was dissolved in acetone (25 mL), the solution
cooled to 0 C, followed by the dropwise addition of a HCl aqueous
11
ꢀ
prepared by modifying a literature procedure. To a solution of
salicylaldehyde (11.13 mL, 100 mmol) in ethanol (60 mL) anhydrous
K
solution (1 M, 56.40 mL) and the resulting solution was stirred at
ꢀ
CO
2 3
(15.20 g, 110 mmol) was added and the resulting mixture was
0
C for 5 min. The reaction mixture was treated with saturated
stirred for 5 min at room temperature. After the formation of a yel-
low solid, propargyl bromide (80% in toluene, 11.85 mL, 110 mmol)
was added and the reaction mixture was heated at reflux for 4 h
aqueous NaHCO
dried over Na SO
sure and the crude product was purified by flash chromatography
[ethyl acetate/hexane (1:5)] to give compound 5 (1.55 g, 85%) as
3
solution, extracted with dichloromethane and
4
. The solvent was removed under reduced pres-
2
under N
added, the aqueous layer was extracted with diethyl ether, dried
over anhydrous Na SO and the solvent was removed under reduced
pressure. Recrystallization from diethyl ether afforded 2 (14.36 g,
2
atmosphere. After cooling to room temperature, water was
ꢀ
11
ꢀ
pale white solid. Mp 49e51 C (lit. 50e52 C) (from ethyl acetate/
1
2
4
hexane); H NMR (CDCl
AreH), 7.57e7.60 (1H, m, AreH), 7.06e7.14 (2H, m, AreH), 4.96 (2H,
s, OCH CH CH ), 1.31 (3H, t,
C^C), 4.25 (2H, q, J¼6.8 Hz, CO
J¼6.8 Hz, CO CH CH ).
3
) 10.47 (1H, s, CHO), 7.86e7.88 (1H, m,
ꢀ
11
ꢀ
9
0%) as a white solid. Mp 71e73 C (lit. 64e66 C) (from diethyl
2
2
2
3
1
ether). H NMR (CDCl
AreH), 7.55e7.59 (1H, m, AreH), 7.07e7.13 (2H, m, AreH), 4.83 (2H,
d, J¼2.0 Hz, OCH C^CH), 2.58 (1H, t, J¼2.0 Hz, OCH C^CH).
3
) 10.49 (1H, s, CHO), 7.86 (1H, dd, J¼7.6, 1.2 Hz,
2
2
3
2
2
4.2.5. 2-(Propa-1,2-dienyloxy)benzaldehyde (6). Allene 6 was pre-
8
a,9
pared by modifying a literature procedure.
(2.50 g, 12.10 mmol) in tert-butyl alcohol (7.0 mL) was added
dropwise to solution of potassium tert-butoxide (0.54 g,
A solution of acetal 4
4
.2.2. 2-(Buta-2,3-dienyloxy)benzaldehyde (3). Benzaldehyde 3 was
7
prepared according to a literature procedure. A mixture of sali-
a
cylaldehyde derivative 2 (2.50 g, 15.62 mmol), paraformaldehyde
4.80 mmol) in tert-butyl alcohol (2.5 mL). The resulting mixture
was heated at 60 C for 1.5 h. After cooling to room temperature,
0
ꢀ
(
1.17 g, 39.05 mmol), N,N -di-isopropylamine (4.38 mL, 31.24 mmol)
and anhydrous cuprous bromide (1.12 g, 7.81 mmol) in dioxane
25 mL) was heated at reflux for 75 min. After cooling to room
water was added to the reaction mixture and the aqueous layer was
extracted with diethyl ether, dried over Na SO and the solvent
2 4
(
temperature, saturated aqueous NaCl solution was added to the
reaction mixture, the aqueous layer was extracted with diethyl
removed in vacuum. The crude product was dissolved in acetone
(30 mL), the solution cooled to 0 C, followed by the dropwise
ꢀ
ether, dried over anhydrous Na
under reduced pressure. The crude product was purified by flash
chromatography [ethyl acetate/hexane (1:6)] to give allene 3
2
SO
4
and the solvent was removed
addition of a HCl aqueous solution (1 M, 116.0 mL) and the resulting
mixture was stirred at 0 C for 5 min. The reaction mixture was
ꢀ
3
treated with saturated aqueous NaHCO solution, extracted with
ꢁ1
1
(
1.90 g, 70%) as a yellow liquid. IR (film, cm ): 1957, 1689, 1238; H
NMR (CDCl ) 10.51 (1H, s, CHO), 7.82e7.85 (1H, m, AreH), 7.51e7.55
1H, m, AreH), 6.98e7.05 (2H, m, AreH), 5.38e5.45 (1H, m,
dichloromethane and dried over Na SO . The solvent was removed
2
4
3
under reduce pressure and the crude product was purified by flash
chromatography [ethyl acetate/hexane (1:5)] to give compound 6
(
ꢁ
1
OCH
2
CH]C]CH
2
), 4.88e4.91 (2H, m, OCH
2
CH]C]CH
2
),
(1.32 g, 68%) as pale yellow liquid. IR (film, cm ): 1964, 1691, 1230;
); 13C NMR (CDCl
) 209.5,
1
H NMR (CDCl
AreH), 7.54e7.59 (1H, m, AreH), 7.13e7.21(2H, m, AreH), 6.91 (1H,
);
) 10.47 (1H, s, CHO), 7.87 (1H, dd, J¼7.6, 1.2 Hz,
4
.68e4.69 (2H, m, OCH
2
CH]C]CH
2
3
3
189.8, 160.8, 135.7, 128.4, 125.3, 120.9, 113.1, 86.6, 77.1, 66.2; HRMS
þ
(
ESI): calculated C11
H
11
O
2
[MþH ] 175.07536. Found: 175.07484.
t, J¼6.0 Hz, OCH]C]CH
2
), 5.49 (2H, d, J¼6.0 Hz, OCH]C]CH
2
13
C NMR (CDCl
3
) 202.6, 189.2, 159.4, 135.6, 128.4, 126.2, 123.1, 118.0,
þ
4.2.3. 1-(Dimethoxymethyl)-2-(prop-2-ynyloxy)benzene (4). Acetal
116.7, 90.6; HRMS (ESI): calculated
183.04165. Found: 183.04100.
C
10
H
8
NaO
2
[M þNa]:
8
4
was prepared according to a literature procedure. A mixture of
salicylaldehyde derivative 2 (5.00 g, 31.24 mmol) and trimethyl
orthoformate (20.50 mL, 187 mmol) in 100 mL of dry methanol was
cooled to 0 C under nitrogen atmosphere. p-Toluenesulfonic acid
4.3. General procedures for the synthesis of chromeno-
pyrroles and pyrrole derivatives 10 and 25
ꢀ
(
0.30 g, 1.56 mmol) was added and the resulting mixture was stir-
ꢀ
red at 0 C for 40 min. The reaction mixture was treated with sat-
Method A: A solution of the appropriated aldehyde and sarcosine
or 1,3-thiazolidine-4-carboxilic acid in toluene (10 mL) was heated
at reflux, using a DeaneStark apparatus, except where indicated
otherwise, for the time indicated in each case. The reaction was
monitored by TLC. After the reaction was complete, the solvent was
removed under reduced pressure and the crude product was dis-
solved in dichloromethane. The organic layer was washed several
urated aqueous K
with ethyl acetate, washed with water and dried over anhydrous
Na SO . The solvent was removed under reduced pressure to give
the pure product. Compound 4 (5.96 g, 94%) was obtained as a low
2 3
CO solution, the aqueous layer was extracted
2
4
ꢁ1
1
3
melting solid. IR (film, cm ): 2120, 1222; H NMR (CDCl )
7.54e7.57 (1H, m, AreH), 7.28e7.32 (1H, m, AreH), 7.00e7.04 (2H,
m, AreH), 5.68 (1H, s, CH(OMe)
2
), 4.73 (2H, d, J¼2.4 Hz,
C^CH);
) 149.8, 124.2, 122.2, 121.8, 116.0, 107.3, 93.7, 73.4,
2 4
times with water and dried over Na SO . The solvent was removed
under reduced pressure and the crude product was purified by flash
chromatography.
OCH
2
C^CH), 3.37 (6H, s, OMe), 2.51 (1H, t, J¼2.4 Hz, OCH
2
13
C NMR (CDCl
3
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8
F.M. Ribeiro Laia et al. / Tetrahedron xxx (2013) 1e10
Method B: A solution of the appropriate aldehyde and sarco-
sine or 1,3-thiazolidine-4-carboxylic acid in toluene (1e1.5 mL)
2), 7.33 (1H, t, J¼8.0, 7.6 Hz, AreH), 7.12 (1H, d, J¼7.2 Hz, AreH), 7.02
(1H, d, J¼8.0 Hz, AreH), 6.98 (1H, t, J¼7.6, 7.2 Hz, AreH), 5.32 (1H, s,
was irradiated in the microwave reactor for 15 min with the
OH), 4.28 (2H, q, J¼7.2 Hz, CO
2 2 3
CH CH ), 3.41 (3H, s, NeMe), 2.14
ꢀ
13
temperature set to 150 C. The solvent was removed under re-
(3H, s, CeMe), 1.35 (3H, t, J¼7.2 Hz, CO
2 2 3 3
CH CH ); C NMR (CDCl )
duced pressure and the crude product was dissolved in
dichloromethane. The organic layer was washed several times
with water and dried over Na SO . The solvent was removed
2 4
165.2, 154.6, 132.0, 130.6, 128.9, 126.1, 121.1, 120.4, 117.3, 115.6, 114.2,
þ
59.4, 34.8, 14.5, 11.1; HRMS (EI): calculated C15
259.1208. Found: 259.1206.
H17NO
3
[M ]
under reduced pressure and the crude product was purified by
flash chromatography.
4.3.3. 1-Methyl-1,2,3,9a-tetrahydrochromeno[2,3-b]pyrrole
16). Prepared by method A from aldehyde 6 (237 mg, 1.48 mmol)
(
4
1
.3.1. 1-Methyl-1,2,4,9b-tetrahydrochromeno[4,3-b]pyrrole (7) and
-methyl-1,4-dihydrochromeno[4,3-b]pyrrole (8). Prepared by
and sarcosine (264 mg, 2.96 mmol). The reaction mixture was
stirred for 4 h and evaporation of the solvent under reduced
pressure afforded 16 (184 mg, 66%) as a red oil. Compound 16 was
also prepared by method B in 59% yield (165 mg) from aldehyde 6
(237 mg, 1.48 mmol) and sarcosine (264 mg, 2.96 mmol). Com-
method A from aldehyde 2 (160 mg, 1.00 mmol) and sarcosine
ꢁ
(
178 mg, 2.00 mmol) using 4 A molecular sieves instead of the
DeaneStark apparatus. The reaction mixture was stirred for 16 h
and solvent was removed under reduced pressure. Purification by
flash chromatography [ethyl acetate/hexane (1:2) to ethyl acetate/
hexane (2:1), then ethyl acetate] afforded, in order of elution,
compound 8 (21 mg, 11%) and compound 7 (137 mg, 73%) as white
solids.
ꢁ1
1
3
pound 16: IR (film, cm ): 1229, 1207; H NMR (CDCl ) 7.08 (1H, t,
J¼8.0, 7.2 Hz, AreH), 7.01 (1H, d, J¼7.2 Hz, AreH), 6.91 (1H, d,
J¼7.6 Hz, AreH), 6.88 (1H, t, J¼8.0, 7.6 Hz, AreH), 6.24 (1H, br s, H-
4), 4.92 (1H, br s, H-9a), 2.97 (2H, m, H-2), 2.66e2.67 (2H, m, H-3),
13
3
2.64 (3H, s, NeMe); C NMR (CDCl ) 151.6, 135.5, 127.1, 125.2, 123.3,
1
C
20.6, 117.2, 115.3, 93.8, 51.3, 37.9, 25.6; HRMS (ESI): calculated
þ
4
.3.1.1. 1-Methyl-1,4-dihydrochromeno[4,3-b]pyrrole
(8). Mp
12
H14NO [M þH]: 188.10699. Found: 188.10694.
ꢀ
ꢁ1
6
2e64 C (from ethyl acetate/hexane); IR (KBr, cm ): 1224, 1185;
1
H NMR (CDCl
3
) 7.43 (1H, d, J¼7.6 Hz, AreH), 7.05e7.09 (1H, m,
4.3.4. 1-Methyl-3-methylene-1,2,3,3a,4,9b-hexahydrochromeno[4,3-
b]pyrrole (17). Prepared by method A from aldehyde 3 (270 mg,
1.56 mmol) and sarcosine (278 mg, 3.12 mmol). The reaction mix-
ture was stirred for 27 h and purification by flash chromatography
[ethyl acetate/hexane (1:6)] afforded 17 (181 mg, 58%) as an orange
AreH), 6.93e6.97 (2H, m, AreH), 6.60 (1H, d, J¼2.0 Hz, H-2), 5.95
13
(
1H, d, J¼2.0 Hz, H-3), 5.21 (2H, s, H-4), 3.89 (3H, s, NeMe);
C
NMR (CDCl
3
) 153.1, 126.6, 125.0, 123.9, 121.5, 120.2, 119.9, 117.3,
þ
1
1
16.6, 103.1, 66.2, 36.7; HRMS (ESI): calculated C12
86.09134. Found: 186.09178.
H
12NO [M þH]:
ꢁ1
1
oil. IR (film, cm ): 1261, 1231; H NMR (CDCl
AreH), 6.88e6.91 (2H, m, AreH), 5.06 (1H, br s, C]CH
br s, C]CH
) 3.94e4.05 (2H, m, H-4), 3.66 (1H, d, J¼14.0 Hz, H-2),
3.13 (1H, d, J¼5.2 Hz, H-9b), 3.02 (1H, br d, J¼14.0 Hz, H-2),
3
) 7.18e7.25 (2H, m,
2
), 5.03 (1H,
4
.3.1.2. 1-Methyl-1,2,4,9b-tetrahydrochromeno[4,3-b]pyrrole
2
ꢀ
ꢁ1
(7). Mp 63e65 C (from ethyl acetate/hexane); IR (KBr, cm ):
1
13
1
235, 1222; H NMR (CDCl
3
) 7.37 (1H, d, J¼7.6 Hz, AreH), 7.12e7.15
3
2.84e2.90 (1H, m, H-3a), 2.47 (3H, s, NeMe); C NMR (CDCl )
(
1H, m, AreH), 6.93e6.96 (1H, m, AreH), 6.83 (1H, d, J¼8.4 Hz,
154.9, 146.5, 131.5, 129.0, 120.4, 119.9, 117.1, 107.1, 66.3, 62.6, 60.3,
þ
AreH), 5.71 (1H, br s, H-3), 4.74 (1H, d, J¼12.8 Hz, H-4), 4.64e4.68
41.2, 39.9; HRMS (ESI): calculated C13
Found: 202.12247.
H
16NO [M þH]: 202.12264.
(
1H, m, H-4), 4.43 (1H, br s, H-9b), 4.04e4.07 (1H, m, H-2),
13
3
1
3
.48e3.51 (1H, m, H-2), 2.81 (3H, s, NeMe); C NMR (CDCl ) 153.8,
35.7, 128.3, 127.5, 126.2, 121.6, 121.4, 117.3, 67.1, 65.0, 64.3, 44.0;
0 0
4.3.5. 7a,8,10,11a-Tetrahydro-6H-chromeno[3 ,4 :4,5]pyrrolo[1,2-c]
þ
0
0
HRMS (ESI): calculated C12
1
H
14NO [M þH]: 188.10699. Found:
thiazole (20), 7a,8,10,11a-tetrahydro-6H-chromeno[3 ,4 :4,5]pyrrolo
0
0
88.10642.
[1,2-c]thiazole (21) and 8,10-dihydro-6H-chromeno[3 ,4 :4,5]pyrrolo
1,2-c]thiazole (22). Prepared by method A from aldehyde
[
2
4
.3.2. Ethyl 1-methyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-
(120 mg, 0.75 mmol) and 1,3-thiazolidine-4-carboxylic acid
(200 mg, 1.5 mmol) in toluene (10 mL) was heated at reflux for 7 h,
using a DeaneStark apparatus. Purification of the crude product by
flash chromatography [ethyl acetate/hexane (1:4), then ethyl ace-
tate/hexane (1:2) to ethyl acetate/hexane (2:1), then ethyl acetate]
afforded, in order of elution, compound 20 (65 mg, 37%) as pale
yellow solid and compound 21 (30 mg, 18%) as orange oil.
Prepared by method B from aldehyde 2 (120 mg, 0.75 mmol) and
1,3-thiazolidine-4-carboxylic acid (200 mg, 1.5 mmol) in toluene
(1 mL). Purification of the crude product by flash chromatography
[ethyl acetate/hexane (1:4), then ethyl acetate/hexane (1:2) to ethyl
acetate/hexane (2:1), then ethyl acetate] afforded in order of elu-
tion, compound 22 (<10%) as orange oil, compound 20 (32.5 mg,
19%) and compound 21 (10 mg, 6%).
carboxylate (9) and ethyl 5-(2-hydroxyphenyl)-1,4-dimethyl-1H-
pyrrole-3-carboxylate (10). Prepared by method A from aldehyde 5
(
(
232 mg, 1.00 mmol) and sarcosine (178 mg, 2.00 mmol) in toluene
10 mL) was heated at reflux, using a DeaneStark apparatus, for 4 h.
Purification of the crude product by flash chromatography [ethyl
acetate/hexane (1:4)] afforded, in order of elution, compound 9
(
<1%) as a yellow oil and compound 10 (211 mg, 81%) as a white
solid.
Prepared by method B from aldehyde 5 (116 mg, 0.50 mmol) and
sarcosine (89 mg, 1.00 mmol) in toluene (1 mL). Purification of the
crude product by flash chromatography [ethyl acetate/hexane
(
1:4)] afforded in order of elution, compound 9 (<3%) and com-
pound 10 (68 mg, 52%).
0
0
4
.3.2.1. Ethyl 1-methyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-
4.3.5.1. 7a,8,10,11a-Tetrahydro-6H-chromeno[3 ,4 :4,5]pyrrolo
1
ꢀ
carboxylate (9). H NMR (CDCl
1H, s, H-2), 7.08e7.12 (1H, m, AreH), 6.92e6.97 (2H, m, AreH),
3
) 7.40e7.42 (1H, m, AreH), 7.23
[1,2-c]thiazole (20). Mp 87e89 C (from diethyl ether/petroleum
ether); IR (film, cm ): 1223, 1109, 754; H NMR (CDCl ) 7.37 (1H, d,
3
ꢁ1
1
(
5
.45 (2H, s, H-4), 4.26 (2H, q, J¼7.2 Hz, CO
2
CH
2
CH
3
), 3.90 (1H, s,
J¼7.6 Hz, AreH), 7.14 (1H, pseudo-t, J¼7.6 Hz, AreH), 6.97 (1H,
pseudo-t, J¼7.2 Hz, AreH), 6.82 (1H, d, J¼8.4 Hz, AreH), 5.65 (1H, br
s, H-7), 4.79 (1H, d, J¼13.2 Hz, H-6), 4.74 (1H, d, J¼13.2 Hz, H-6),
NeMe), 1.34 (3H, t, J¼7.2 Hz, CO
2 2 3
CH CH ); HRMS (EI): calculated
þ
C
15
H
15NO
3
[M ] 257.1052. Found: 257.1063.
4
.69 (1H, br s, H-11a), 4.60e4.61 (1H, m, H-7a), 4.42 (1H, d,
4
.3.2.2. Ethyl 5-(2-hydroxyphenyl)-1,4-dimethyl-1H-pyrrole-3-
J¼10.8 Hz, H-10), 4.33 (1H, d, J¼10.8 Hz, H-10), 3.08 (1H, dd, J¼11.2,
ꢀ
13
carboxylate (10). Mp 130e132 C (from ethyl acetate/hexane); IR
8.0 Hz, H-8), 2.85 (1H, dd, J¼11.2, 2.4 Hz, H-8); C NMR (CDCl
153.2, 136.4, 128.3, 127.3, 126.0, 123.7, 121.3, 117.0, 76.3, 67.3, 64.5,
Please cite this article in press as: Ribeiro Laia, F. M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.09.052
3
)
ꢁ1
1
(
KBr, cm ): 3342, 1691, 1252, 1233; H NMR (CDCl
3
) 7.40 (1H, s, H-

F.M. Ribeiro Laia et al. / Tetrahedron xxx (2013) 1e10
9
þ
6
2
2.9, 39.1; HRMS (EI): calculated C13
31.0717.
H
13NOS [M ] 231.0718. Found:
4.3.6.3. Ethyl 5-(2-hydroxyphenyl)-6-methyl-1H,3H-pyrrolo[1,2-
ꢀ
c]thiazole-7-carboxylate (25). Mp 175e177 C (from ethyl acetate/
ꢁ1
1
3
hexane); IR (film, cm ): 3390, 1682, 1108, 757; H NMR (CDCl )
0
0
4
.3.5.2. 7a,8,10,11a-Tetrahydro-6H-chromeno[3 ,4 :4,5]pyrrolo
1,2-c]thiazole (21). IR (film, cm ): 1224, 1112, 759; H NMR
7.30 (1H, pseudo-t, J¼7.2 Hz, AreH), 7.15 (1H, d, J¼6.8 Hz, AreH),
6.95e7.01 (2H, m, AreH), 5.62 (1H, br s), 4.88 (1H, d, J¼8.4 Hz), 4.78
(1H d, J¼8.4 Hz), 4.35e4.40 (2H, m), 4.28 (2H, q, J¼7.2 Hz), 2.17 (3H,
ꢁ1
1
[
(
CDCl
3
) 7.40 (1H, d, J¼7.6 Hz, AreH), 7.18 (1H, pseudo-t, J¼7.6 Hz,
1
3
AreH), 6.98 (1H, pseudo-t, J¼7.2 Hz, AreH), 6.87 (1H, d, J¼8.4 Hz,
AreH), 5.69 (1H, br s, H-7), 5.15 (1H, br s, H-11a), 4.83 (1H, d,
J¼12.4 Hz, H-6), 4.75e4.78 (1H, m, H-7a), 4.55e4.59 (1H, m, H-6),
s), 1.34 (3H, t, J¼7.2 Hz); C NMR (CDCl
3
) 165.0, 154.2, 141.8, 131.4,
130.5, 124.8, 121.5, 120.6, 117.2, 115.9, 107.5, 59.6, 48.5, 31.2, 14.6,
11.8; HRMS (EI): calculated C16
303.0931.
þ
H17NO
3
S [M ] 303.0929. Found:
3
.65 (1H, d, J¼8.6 Hz, H-10), 3.58 (1H, d, J¼8.6 Hz, H-10), 3.32 (1H,
13
dd, J¼11.2, 7.6 Hz, H-8), 3.08 (1H, dd, J¼11.2, 2.8 Hz, H-8); C NMR
0
0
(
CDCl
3
) 154.6,136.1,128.6,127.8,125.6,120.5,120.2,116.7, 72.8, 63.5,
4.3.7. 3,4a,11,11a-Tetrahydro-1H-chromeno[3 ,2 :4,5]pyrrolo[1,2-c]
thiazole (26). Prepared by method A from aldehyde 6 (120 mg,
0.75 mmol) and 1,3-thiazolidine-4-carboxylic acid (200 mg,
þ
6
3.3, 52.2, 33.8; HRMS (EI): calculated C13
H
13NOS [M ] 231.0718.
Found: 231.0720.
1
.5 mmol) in toluene (10 mL) was heated at reflux for 7 h, using
0
0
4
.3.5.3. 8,10-Dihydro-6H-chromeno[3 ,4 :4,5]pyrrolo[1,2-c]thia-
a DeaneStark apparatus. Purification of the crude product by flash
chromatography [ethyl acetate/hexane (1:4)] afforded compound
26 (73 mg, 42%) as a yellow oil.
Prepared by method B from aldehyde 6 (120 mg, 0.75 mmol) and
1,3-thiazolidine-4-carboxylic acid (200 mg, 1.5 mmol) in toluene
1
3
zole (22). H NMR (CDCl ) 7.21e7.23 (1H, m, AreH), 7.02e7.05 (1H,
m, AreH), 6.89e6.92 (2H, m, AreH), 5.73 (1H, s), 5.23 (2H, s), 5.22
2H, s), 4.07 (2H, s); HRMS (EI): calculated C13
þ
(
2
H
11NOS [M ]
29.0561. Found: 229.0561.
(
1 mL). Purification of the crude product by flash chromatography
0
0
4.3.6. Ethyl
7a,8,10,11a-tetrahydro-6H-chromeno[3 ,4 :4,5]pyrrolo
[ethyl acetate/hexane (1:4)] afforded compound 26 (17 mg, 9%).
[
[
1,2-c]thiazole-7-carboxylate (23), ethyl 8,10-dihydro-6H-chromeno
3 ,4 :4,5]pyrrolo[1,2-c]thiazole-7-carboxylate (24) and ethyl 5-(2-
0
0
0 0
4.3.7.1. 3,4a,11,11a-Tetrahydro-1H-chromeno[3 ,2 :4,5]pyrrolo
ꢁ1
1
hydroxyphenyl)-6-methyl-1H,3H-pyrrolo[1,2-c]thiazole-7-
carboxylate (25). Prepared by method A from aldehyde 5 (174 mg,
0
1
a DeaneStark apparatus. Purification of the crude product by flash
chromatography [ethyl acetate/hexane (1:4)] afforded, in order of
elution, a 94:6 mixture of the compounds 23 and 24 (166 mg, 73%)
and 1H,3H-pyrrolo[1,2-c]thiazole 25 (27 mg, 12%) as a white solid.
Selective crystallization of the mixture of 23 and 24 with ethyl
acetate/hexane afforded 23 as a white crystalline solid, whereas
compound 24 was obtained as a yellow solid by crystallization with
ethyl acetate/petroleum ether.
[1,2-c]thiazole (26). IR (film, cm ): 1230, 1204, 755; H NMR
(CDCl
3
) 7.10 (1H, pseudo-t, J¼7.6 Hz, AreH), 7.01 (1H, d, J¼7.2 Hz,
.75 mmol) and 1,3-thiazolidine-4-carboxylic acid (200 mg,
.5 mmol) in toluene (10 mL) was heated at reflux for 7 h, using
AreH), 6.88e6.92 (2H, m, AreH), 6.30 (1H, br s, H-10), 5.34 (1H, br
s, H-4a), 4.42 (1H, d, J¼10.4 Hz, H-3), 4.31 (1H, d, J¼10.4 Hz, H-3),
3.96e4.02 (1H, m, H-11a), 3.14 (1H, dd, J¼11.2, 7.0 Hz, H-1),
3.03e3.09 (1H, m, H-11), 2.62 (1H, dd, J¼11.2, 6.0 Hz, H-1),
13
3
2.50e2.55 (1H, m, H-11); C NMR (CDCl ) 152.4, 134.6, 128.6, 126.4,
123.5, 121.8, 119.5, 116.4, 93.5, 66.8, 58.1, 38.7, 33.3; HRMS (EI):
þ
calculated C13
H
13NOS [M ] 231.0718. Found: 231.0719.
4.4. 1-Methyl-1,4-dihydrochromeno[4,3-b]pyrrole (8)
Prepared by method B from aldehyde 5 (174 mg, 0.75 mmol) and
1
,3-thiazolidine-4-carboxylic acid (200 mg, 1.5 mmol) in toluene
To a solution of compound 7 (135 mg, 0.72 mmol) in ethyl ac-
etate (10 mL) Pd/C 10% (14 mg, 10 wt %) was added. The resulting
solution was heated at reflux for 24 h. After cooling to room tem-
perature, the reaction mixture was filtered on Celite to remove the
oxidant and the solvent was concentrated under reduced pressure.
Purification of the crude product by flash chromatography [ethyl
acetate/hexane (1:2)] afforded 8 (100 mg, 75%) as a white solid.
Compound 8 was identified by comparison with the specimen
previous prepared (see above).
(
[
1 mL). Purification of the crude product by flash chromatography
ethyl acetate/hexane (1:4)] afforded in order of elution, a 86:14
mixture of the compound 23 and the corresponding aromatized
derivative 24 (96.5 mg, 42%) and 1H,3H-pyrrolo[1,2-c]thiazole 25
(
35 mg, 15%).
0
0
4
.3.6.1. Ethyl 7a,8,10,11a-tetrahydro-6H-chromeno[3 ,4 :4,5]pyr-
ꢀ
rolo[1,2-c]thiazole-7-carboxylate (23). Mp 84e86 C (from ethyl
ꢁ1
1
acetate/hexane); IR (KBr, cm ): 1707, 1216, 1125, 771; H NMR
CDCl
(
3
) 7.43 (1H, d, J¼7.2 Hz, AreH), 7.21 (1H, pseudo-t, J¼7.6 Hz,
AreH), 7.07 (1H, pseudo-t, J¼7.4 Hz, AreH), 6.95 (1H, d, J¼8.0 Hz,
4.5. X-ray diffraction
AreH), 5.11 (2H, s, H-6), 4.86 (1H, br s, H-11a), 4.76 (1H, m, H-7a),
4
4
3
.32 (1H, d, J¼10.8 Hz, H-10), 4.28 (1H, d. J¼10.8 Hz, H-10),
.18e4.26 (2H, m, CO CH CH
), 3.24 (1H, dd, J¼11.6, 8.0 Hz, H-8),
.08 (1H, dd, J¼11.6, 2.4 Hz, H-8), 1.30 (3H, t, J¼7.2 Hz, CO CH CH );
) 163.1, 153.5, 152.4, 128.4, 128.3, 124.6, 122.7, 117.4,
A crystal of compound 23 was selected, covered with poly-
fluoroether oil and mounted on a nylon loop. Crystallographic data
for this compound was collected at the IST using graphite mono-
2
2
3
2
2
3
13
ꢁ
C NMR (CDCl
3
chromated Mo K
a
radiation (
l
¼0.71073 A) on a Bruker AXS-KAPPA
7
5.5, 69.1, 66.6, 61.9, 60.8, 39.3, 14.3; HRMS (EI): calculated
APEX II diffractometer equipped with an Oxford Cryosystem 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
þ
C
16
H
17NO
3
S [M ] 303.0929. Found: 303.0915.
0
0
4
.3.6.2. Ethyl 8,10-dihydro-6H-chromeno[3 ,4 :4,5]pyrrolo[1,2-c]
ꢀ
14
thiazole-7-carboxylate (24). Mp 143e145 C (from ethyl acetate/
SADABS. Structure solution and refinement were performed using
ꢁ1
1
15
petroleum ether); IR (KBr, cm ): 1690, 1227, 1139, 767; H NMR
CDCl
) 7.19 (1H, d, J¼7.6 Hz, AreH), 7.08 (1H, pseudo-t, J¼7.4 Hz,
AreH), 6.87e6.91 (2H, m, AreH), 5.46 (2H, s), 5.26 (2H, s), 4.31 (2H,
direct methods with the program SIR2004 included in the pack-
1
6
17
(
3
age of programs WINGX-Version 1.80.05 and SHELXL. All hy-
drogen atoms were inserted in idealized positions and allowed to
refine riding on the parent carbon atom, with CeH distances of
13
s), 4.26 (2H, q, J¼7.2 Hz), 1.34 (3H, t, J¼7.2 Hz); C NMR (CDCl
3
)
ꢁ
ꢁ
ꢁ
ꢁ
1
6
3
64.1, 152.7, 142.8, 127.7, 121.4, 121.0, 120.1, 119.2, 117.6, 117.1, 104.7,
5.5, 59.9, 49.1, 29.4, 14.5; HRMS (EI): calculated C16
01.0773. Found: 301.0775.
0.95 A, 0.98 A, 0.99 A and 1.0 A for aromatic, methyl, methylene and
þ
H15NO
3
S [M ]
methine H atoms, respectively, and with Uiso(H)¼1.2 Ueq(C). The
18
figure of the molecular structure was generated using ORTEP-III.
Please cite this article in press as: Ribeiro Laia, F. M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.09.052

10
F.M. Ribeiro Laia et al. / Tetrahedron xxx (2013) 1e10
4
.5.1. Crystallographic data for 3,4a,11,11a-tetrahydro-1H-chromeno
ndrakumar, S. Tetrahedron 1988, 44, 4953e4966; (e) Kanemasa, S.; Sakamoto,
0
0
K.; Tsuge, O. Bull. Chem. Soc. Jpn. 1989, 62, 1960e1968; (f) Najdi, S.; Park, K.-H.;
Olmstead, M. M.; Kurth, M. J. Tetrahedron Lett. 1998, 39, 1685e1688; (g) Gong,
Y.-D.; Najdi, S.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63, 3081e3086;
(h) Bolognesi, M. L.; Andrisano, V.; Bartolini, M.; Minarini, A.; Rosini, M.; Tu-
miatti, V.; Melchiorre, C. J. Med. Chem. 2001, 44, 105e109; (i) Bashiardes, G.;
Safir, I.; Barbot, F.; Laduranty, J. Tetrahedron Lett. 2003, 44, 8417e8420; (j)
Bakthadoss, M.; Sivakumar, N.; Sivakumar, G.; Murugan, G. Tetrahedron Lett.
[3 ,2 :4,5]pyrrolo[1,2-c]thiazole 23. C16
H
17NO
3
S, M¼303.38, ortho-
ꢁ ꢁ
rhombic, Pca 2
1
ꢁ
with unit cell, a¼23.4004(6) A, b¼6.9636(2) A,
ꢀ
ꢀ
ꢀ
ꢁ
3
c¼17.3619(4) A,
a
¼90 ,
b
¼90 ,
g
¼90 , V¼2829.14(13) A .
3
ꢁ1
r
calcd¼1.424 Mg/m , Z¼8,
m
¼0.239 mm . R [I>2
s(I)]¼0.0366 and
Rw¼0.0860 for 8484 independent reflections.
2
1
2
008, 49, 820e823; (k) Ramesh, E.; Raghunathan, R. Tetrahedron Lett. 2008, 49,
125e1128; (l) Kim, I.; Na, H.-K.; Kim, K. R.; Kim, S. G.; Lee, G. H. Synlett 2008,
069e2071; (m) Purushothaman, S.; Prasanna, R.; Niranjana, P.; Raghunathan,
Acknowledgements
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Arumugam, N.; Raghunathan, R.; Almansour, A. I.; Karama, U. Bioorg. Med.
Chem. Lett. 2012, 22, 1375e1379; (o) Kathiravan, S.; Raghunathan, R. Synth.
Commun. 2012, 42, 3068e3076.
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4. Novikov, M. S.; Khlebnikov, A. F.; Besedina, O. V.; Kostikov, R. R. Tetrahedron Lett.
Thanks are due to Funda c¸ ~a o para a Ci e^ ncia e a Tecnologia (SFRH/
BD/69941/2010, SFRH/BPD/64623/2009, RECI/QEQ-QIN70189/
012, PEst-C/QUI/UI0313/2011 and PEst-OE/QUI/UI0100/2013) for
financial support. We acknowledge the Nuclear Magnetic Reso-
nance Laboratory of the Coimbra Chemistry Center
www.nmrccc.uc.pt), University of Coimbra for obtaining the NMR
spectroscopic data. C.S.B.G. thanks Prof. M. Teresa Duarte for valu-
able discussions on X-ray crystallography.
2
2
001, 41, 533e535.
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(
4
7
teros, A.; Su ꢀa rez-Sobrino, A. L.; Gonzalez, J. M. Chem.dEur. J. 2010, 16,
ꢀ
ꢀ
1
1827e11831.
Supplementary data
8
. (a) Sakakibara, N.; Nakatsubo, T.; Suzuki, S.; Shibata, D.; Shimada, M.; Ume-
zawa, T. Org. Biomol. Chem. 2007, 5, 802e815; (b) Corey, E. J.; Su, W.-G. J. Am.
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1H NMR, 13C NMR, HMQC, HMBC and NOESY spectra for selected
compounds. Crystallographic data of compound 23. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.09.052.
9
1
1
. Boerresen, S.; Crandall, J. K. J. Org. Chem. 1976, 41, 678e681.
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Please cite this article in press as: Ribeiro Laia, F. M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.09.052