Reaction of chromone-3-carbaldehyde with α-amino acids-syntheses of 3- and 4-(2-hydroxybenzoyl)pyrroles

Article abstract of DOI:10.1016/j.tet.2006.11.034

Azomethine ylides generated from the reaction of chromone-3-carbaldehyde with α-amino acids undergo 1,5-electrocyclization reactions to afford 3- and 4-(2-hydroxybenzoyl)pyrroles. These ylides can be trapped with dipolarophiles in 1,3-dipolar cycloadditio

Full text of DOI:10.1016/j.tet.2006.11.034

Tetrahedron 63 (2007) 910–917
Reaction of chromone-3-carbaldehyde with a-amino
acids—syntheses of 3- and 4-(2-hydroxybenzoyl)pyrroles
*
Andrea G. P. R. Figueiredo, Augusto C. Tome, Artur M. S. Silva and Jose A. S. Cavaleiro
ꢀ
ꢀ
Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Received 18 October 2006; revised 8 November 2006; accepted 10 November 2006
Available online 4 December 2006
Abstract—Azomethine ylides generated from the reaction of chromone-3-carbaldehyde with a-amino acids undergo 1,5-electrocyclization
reactions to afford 3- and 4-(2-hydroxybenzoyl)pyrroles. These ylides can be trapped with dipolarophiles in 1,3-dipolar cycloaddition reac-
tions to yield chromonyl pyrrolidines. The reaction of chromone-3-carbaldehyde with methyl glycinate gives a mixture of pyrrole, pyridine,
and 3-aza-9-xanthenone derivatives.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Chromone-3-carbaldehyde has been extensively used in the
synthesis of various heterocyclic systems since its conve-
nient synthesis was reported in the 1970s. The synthesis and
reactivity of this versatile compound have been reviewed.1–4
Much of the synthetic utilities of this compound are derived
from the reactivity of its electron-deficient centers at C-2,
C-4, and formyl group.2 Chromone-3-carbaldehyde can give
access to compounds where the chromone ring is retained or
to 2-hydroxybenzoyl derivatives resulting from the opening
of the pyran-4-one ring.
Recently, we described the synthesis of the fullerene–
chromone dyad 3 from the 1,3-dipolar cycloaddition of
chromone-azomethine ylide 2 with C60 (Scheme 1).9 Since
the azomethine ylide 2 can be easily generated in situ from
chromone-3-carbaldehyde and N-methylglycine, we thought
that it could be a useful intermediate in the synthesis of
other chromonyl pyrrolidines. We decided then to study the
reaction of 2 with various dipolarophiles in order to obtain
a range of novel chromonyl pyrrolidines just by changing
the dipolarophile. As expected, when the azomethine ylide
2 was generated in the presence of N-phenylmaleimide the
cycloadducts 4a and 4b were obtained (60% yield, as a mix-
ture of cis/trans diastereoisomers). In this reaction, the 3-(2-
hydroxybenzoyl)pyrrole 5 was also formed in 27% yield.
Surprisingly, when we used dimethyl fumarate, 1,4-naphtho-
quinone or dimethyl acetylenedicarboxylate as dipolaro-
philes the expected cycloadducts were not obtained; in all
cases pyrrole 5 was the isolated product. In the absence of
any dipolarophile, pyrrole 5 was obtained in 80% yield
just by refluxing a toluene solution of chromone 1 and N-
methylglycine (2.5 equiv), under nitrogen atmosphere. It is
well known that N-methylglycine reacts with aldehydes
and ketones generating azomethine ylides.13 In that way,
the formation of pyrrole 5 probably involves the 1,5-electro-
cyclization14 of dipole 2 followed by the opening of the
pyran-4-one ring (Scheme 2).15 The reaction of chromone
1 with N-methylglycine has already been described, but dif-
ferent experimental conditions were used. Clarke et al.16
obtained pyrrole 5 in 72% yield by heating at reflux, for
6 h, a toluene solution of equimolar quantities of the two
reagents in the presence of a catalytic amount of p-toluene-
sulfonic acid and using a Dean–Stark water trap. These
Chromone-3-carbaldehyde has been used to prepare 1,3-di-
polar compounds, namely, nitrones,5,6 nitrile imines,7 nitrile
oxides,8 and azomethine ylides.9 The utility of these dipolar
species in 1,3-dipolar cycloadditions has already been dem-
onstrated. Here we describe the generation of azomethine
ylides from the reaction of chromone 1 with various a-amino
acids and one a-amino ester. This study allowed us to find
that these dipoles give mainly 1,5-electrocyclizations, af-
fording 3- and 4-(2-hydroxybenzoyl)pyrroles. It is known
that benzoylpyrroles show antibacterial10 and anti-inflam-
matory activity11 and act as aldose reductase inhibitors.11
In that way, the pyrrole derivatives described here are poten-
tial biologically active agents. Considering that pyrroles have
found many applications in medicine and in technology,12
novel synthesis for these type of compounds is, therefore,
of interest.
Keywords: Azomethine ylides; Benzoylpyrroles; 1,5-Electrocyclizations;
1,3-Dipolar cycloadditions; Chromones.
* Corresponding author. Tel.: +351 234 370 714; fax: +351 234 370 084;
e-mail: arturs@dq.ua.pt
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.034

A. G. P. R. Figueiredo et al. / Tetrahedron 63 (2007) 910–917
911
O
Me
O
O
N
O
CHO
1
3
C60
MeNHCH2CO2H
ref. 9
toluene,
reflux
8'
5'
9'
O
4'
O
O
O
7'
6'
2' Me
Me
N
N 5
N
O
O
4
10'
3'
6
Me
O
+
3a
3
5
O
6a
+
N
CH2
O
O
O
O
1
N
N
H
4b
4a
2
6"
5"
2"
3"
absence of a
dipolarophile
4"
1
8'
5'
O
Me
2'
7'
6'
2
N
5"
1
5
2
3
4
6"
1"
4"
3"
3'
N
Me
9a
3a
+
O
1'
3
O 4
O
2"
9
OH
O
5
6
8
5
6
7
Scheme 1.
authors postulated a completely different mechanism for this
reaction, suggesting that pyrrole 5 ‘arises via attack of
the secondary amine (with ring-opening) at the chromone
2-position. Subsequent cyclization of the resulting enamine
then leads to the pyrrole-2-carboxylic acid, which is readily
decarboxylated to the observed product.’16
each). The all-cis configuration of compound 6, resulting
from an endo transition state, was deduced by 2D NMR
experiments (vide infra).
The reaction of aldehyde 1 with N-benzylglycine, L-proline,
L-phenylalanine, and glycine was also studied in order
to find if the corresponding azomethine ylides generated
also undergo 1,5-electrocyclization (Scheme 4). The reac-
tion between aldehyde 1 and N-benzylglycine hydrochloride
(2.5 equiv) was carried out in refluxing dry 1,4-dioxane (5 h)
in the presence of potassium carbonate (2.5 equiv) and af-
forded the N-benzylpyrrole 7 in 87% yield. The reaction of
aldehyde 1 with L-proline or with L-phenylalanine, in reflux-
ing toluene, afforded complex product mixtures from which
the corresponding pyrroles 8 and 9 were isolated in 22% and
27% yields, respectively. The reaction between aldehyde 1
and glycine (5 equiv), in refluxing toluene (17 h), afforded
pyrroles 10 and 1119 in 46% and 2% yields, respectively.
A probable mechanism for the formation of the minor
We have also isolated from the reaction of chromone 1 with
N-methylglycine a minor product which incorporates two
units of chromone. This product, identified as 6 (vide infra),
presumably results from the 1,3-dipolar cycloaddition of
dipole 2 to another molecule of chromone 117 followed by
deformylation18 of the resulting cycloadduct, as indicated in
Scheme 3. The yield of compound 6 was increased to 50%
by reacting chromone 1 with N-methylglycine in a 10:1
proportion (pyrrole 5 was obtained in 22% yield in this
experiment). It is worth to note that this ‘dimerization’ is
simultaneously regio- and stereoselective, although other
two isomers of compound 6 were also isolated (ca. 3% yield
H
H
O
O
O
CH2
N
Me
N
Me
N
Me
OH
O
O
2
5
Scheme 2.
O
O
Me
OHC
N
O
Me
O
O
6
N
OHC
O
+
CH2
O
O
H
2
1
Scheme 3.

912
A. G. P. R. Figueiredo et al. / Tetrahedron 63 (2007) 910–917
HCl.BnNHCH2CO2H
in the regioselectivity is the stabilization of the intermediate
azomethine ylide 20 by intramolecular hydrogen bonding;
this type of stabilization is not possible in the azomethine
ylide 2.
N
Bn
K2CO3, 1,4-dioxane, reflux
OH
O
7
H
1
N
2
3
8
CO2H
O
O
The reaction of aldehyde 1 with ethyl glycinate, and with
other a-amino esters, gives typically a mixture of pyridine
and pyrrole derivatives.16,20 We decided to re-examine the
reaction of aldehyde 1 with methyl glycinate and found
that the outcome is highly dependent on the reaction condi-
tions. For instance, the reaction of 1 with methyl glycinate
hydrochloride (5 equiv) and potassium carbonate (5 equiv)
in refluxing toluene afforded two main products: the ex-
pected pyrrole 12 (37% yield) and the pyridine derivative
13 (6% yield) (Scheme 6).20,21 When only 1 equiv of methyl
glycinate hydrochloride and 0.5 equiv of potassium carbon-
ate were used, pyrrole 12 was obtained in only 8% yield and
compound 13 was the main product (21% yield). In this case,
a new product was also isolated, which was identified as
3-aza-9-xanthenone 14 (12% yield). When these reactions
were carried out in 1,4-dioxane the pyrrole 12 was obtained
in much higher yield. For instance, when a mixture of 1,
methyl glycinate hydrochloride (5 equiv), and potassium
carbonate (5 equiv) in dry 1,4-dioxane was refluxed for
4 h, pyrrole 12 was obtained in 54% yield. In this case,
compounds 13 and 14 were not formed.
7
N4
1'
toluene, reflux
CHO
5
OH
O
8
1
H2NCHCO2H
Bn
toluene,
reflux
H2NCH2CO2H
Bn
toluene, reflux
NH
O
O
OH
O
2'
9
NH
+
3
O
OH
3'
2'''
OH
O
10
N
1''
H
1
5
11
Scheme 4.
pyrrole 11 is shown in Scheme 5. The structure of 11 is
unexpected since it corresponds to the inversion in the regio-
chemistry of the cycloaddition observed when N-methyl-
glycine is used. A plausible explanation for this inversion
A probable mechanism for the formation of compounds 13
and 14 is indicated in Scheme 7.22 It is possible that di-
hydro-3-aza-9-xanthenone 15 is a common intermediate for
both compounds: isomerization with ring-opening leads to
13 while dehydrogenation affords 14.
CHO
O
O
O
O
H
N
O
O
+
H
CH2
N
H
H
CH2
1
2'
2.1. Structural characterization of the new compounds
All new compounds were characterized by 1H and 13C NMR,
MS, and elemental analysis or HRMS. As said above, com-
pounds 5, 11, 12, and a derivative of 13 were previously
synthesized by other approaches.16,21,20 Since the earlier
structural characterization of these compounds was not com-
plete, a detailed NMR characterization of these compounds
was also included here.
O
O
O
H
H
N
N
CHO
O
OHC
O
O
O
O
1
In the H NMR spectra of cycloadducts 4a and 4b (see
Section 4) the resonance of the N-methyl group appears as
a singlet at ca. d 2.3 ppm. In the spectrum of diastereoisomer
4a, the resonances of the two unequivalent protons H-6 ap-
pear at d 2.71 and 3.70 ppm, respectively, as a double doublet
and as a doublet. For the isomer 4b these signals appear at
d 2.97 and 3.51 ppm, both as double doublets. In compound
4a proton H-4 appears at d 3.98 ppm as a doublet with
J¼8.4 Hz, which is consistent with a cis relationship with
H-3a. For the same compound, protons H-3a and H-6a appear
asdouble doublets (J3a,4¼8.4 Hz,J3a,6a¼7.9 Hz, J6a,6¼7.4 Hz)
at d 3.87 and 3.43 ppm, respectively. From these data it is
clear that, in compound 4a, protons H-4, H-3a, and H-6a
are all co-planar (all-cis configuration). These data were cor-
roborated by NOESYexperiments. For isomer 4b the signals
corresponding to protons H-4, H-3a, and H-6a appear within
multiplets, preventingthedeterminationofcouplingconstants.
H
H
N
N
CHO
O
or
O
O
HO
O
H
N
O
O
O
H
N
HO
11'
O
O
OH
11
The resonances of the protons and carbons in the chromone
moiety of compounds 4 were identified by their 2D COSY,
Scheme 5.

A. G. P. R. Figueiredo et al. / Tetrahedron 63 (2007) 910–917
913
O
CHO
O
1
HCl.H2NCH2CO2Me
K2CO3, toluene, reflux
HO
O
8
7
5
O
8a
CO2Me
N
8'
5'
8'
5'
6
9'
9'
O
O
O
O
9a
9
1
5
2'
3'
2'
7'
6'
7'
6'
10a
H
3
O
+
+
4a
6
3'
10'
10
10'
N
N
1
3
CO2Me
CO2Me
OH
O
12
13
14
Scheme 6.
O
O
O
OHC
OHC
OHC
O
CO2Me
O
O
O
O
O
O
O
O
K2CO3
H
CO2Me
CO2Me
C
H
N
C
H
N
C
H
N
H
O
O
HO
H
13
isom.
oxid.
O
O
O
O
O
- H2O
N
N
14
O
CO2Me
CO2Me
15
Scheme 7.
HSQC, and HMBC spectra, and also by comparison with our
previous work.23 The resonance of H-20 in 4b appears at
d 7.93 ppm as a singlet while in 4a it appears at 7.79 ppm as
H-1, H-9a, and H-3a was deduced from the NOESY spec-
trum. The regiochemistry of the compound was deduced
from the HMBC spectrum, which shows the connectivities
of H-1 with C-20, C-30, C-40, and C-9a and of H-9a with
C-9, C-8a, and C-1, which are only compatible with the
structure depicted in Scheme 1 and Figure 2.
0
adoublet, duetolong-rangecouplingwithH-4(J2 ,4¼0.8 Hz).
In both isomers, the resonance of H-50 appears as a doublet
0
0
0
0
of doublets at ca. d 8.2 ppm with J5 ,6 ¼8.0 Hz and J5 ,7 ¼1.6
or 1.7 Hz; H-70 appears at ca. 7.7 ppm as a double doublet of
doublets (for 4a and 4b).
1
The H NMR spectrum of pyrrole 5 shows two distinctive
singlets: one at d 3.74 ppm correspondingto the N–Me group,
and the other at 12.22 ppm corresponding to the hydroxyl
group. The resonance corresponding to the pyrrolic proton
H-2appears atd 7.28 ppm, while H-4and H-5giveamultiplet
at 6.65–6.69 ppm. The signals corresponding to the remain-
ing protons show the expected chemical shifts and multipli-
cities. The 13C NMR spectrum of pyrrole 5 shows three
distinctive signals: one at d 36.7 ppm corresponding to the
N–Me group, one at 162.2 ppm corresponding to C-200 and
one at 193.6 ppm corresponding to the carbonyl group. The
remaining signals appear in the range d 111.3–134.8 ppm.
In the 13C NMR spectra of compounds 4, the resonance of
the N-methyl group appears at d 38–40 ppm. The signals
corresponding to carbons C-4 and C-6 appear, respectively,
at ca. d 64–66 and 58–59 ppm, while the signals correspond-
ing to C-3a and C-6a appear at ca. d 48–50 and 44–45 ppm,
respectively. The resonances of the three carbonyl groups
appear at d 175–178 ppm.
The connectivities found in the HMBC spectra of com-
pounds 4 allowed the assignment of the quaternary carbon
resonances; some of the most important connectivities for
dyad 4a are shown in Figure 1.
O
2'
Me
3'
H
H
H
N
The 1H NMR spectrum of compound 6 is similar to that of
compound 4a; the main difference is the position of the sig-
nals corresponding to protons H-1 (doublet at d 4.42 ppm)
and H-3a (multiplet centered at d 5.1 ppm). The 13C NMR
spectrum of cycloadduct 6 shows, among others, peaks cor-
responding to five sp3 carbons and two carbonyl carbons (d
177.0 and 190.0 ppm). The all-cis configuration of protons
4
3a
6
6aH
O
H
3
1
O
O
N
Ph
Figure 1. Main connectivities observed in the HMBC spectrum of com-
pound 4a.

914
A. G. P. R. Figueiredo et al. / Tetrahedron 63 (2007) 910–917
H
H
O
4. Experimental section
2'
Me
N
H
4'
H
3H
O
1
4.1. General
3a
9a
H
O
O
Melting points were measured on a Reichert Thermovar
apparatus fitted with a microscope and are uncorrected.
1H and 13C solution NMR spectra were recorded in CDCl3
solutions (unless otherwise stated), on a Bruker Avance 300
spectrometer (except compounds 11 and 14, which were
recorded on a Bruker Avance 500). TMS was used as an
internal reference and the solvent is indicated in each case;
the chemical shifts are expressed in d (ppm) and the coupling
constants (J) in hertz (Hz). 1H assignments were made using
2D gCOSY and NOESY (mixing time of 800 ms) experi-
ments, while 13C assignments were made on the basis of
2D gHSQC and gHMBC experiments (delay for long-range
J C/H couplings were optimized for 7 Hz).
8a
Figure 2. Main connectivities observed in the HMBC spectrum of com-
pound 6.
As expected, the 1H NMR spectra of pyrroles 7–10, and 12
show similar features to that of the spectrum of pyrrole 5.
The signal of the NH proton, for compounds 9, 10, and 12,
appears as a broad singlet at d 8.47, 8.76, and 9.72 ppm,
respectively.
The 1H NMR spectrum of pyrrole 11 shows, simultaneously,
features corresponding to a chromonyl group and to a 2-hy-
droxybenzoyl moiety. The resonances of protons H-3 and
H-5 were identified as two doublet of doublets centered at
d 7.01 (J¼2.3 and 1.6 Hz) and 7.52 ppm (J¼3.0 and
1.6 Hz), respectively. The signal of the NH proton appears
as a broad singlet at 11.50 ppm, which indicates that it is
involved in hydrogen bonding with the chromone carbonyl
group. The NOESY spectrum of this compound shows close
proximity between H-20 (8.52 ppm) and H-3, indicating that
it must have the structure (and conformation) shown in
Scheme 4. The broad singlet at 12.15 ppm was attributed
to the 2000-hydroxyl proton.
Mass spectra and HRMS were recorded on VG AutoSpec
Q and M mass spectrometers using CHCl3 as solvent and
NBA as matrix. Elemental analyses were performed in a
Leco 932 CHNS analyser. Column chromatography was
carried out using silica gel (Merck, 35–70 mesh). Analytical
TLC was carried out on precoated sheets with silica gel
(Merck 60, 0.2 mm thick).
4.1.1. 1,3-Dipolar cycloaddition of azomethine ylide 2
with N-phenylmaleimide. A toluene (30 mL) solution of
chromone-3-carbaldehyde (1) (129 mg, 0.739 mmol),
N-methylglycine (129 mg, 1.44 mmol), and N-phenylmale-
imide (200 mg, 1.15 mmol) was refluxed for 7 h under nitro-
gen atmosphere. The solvent was removed under vacuum
and the mixture was purified by flash chromatography (sil-
ica) using a gradient of CH2Cl2 to CH2Cl2/ethyl acetate
(50:50) as an eluent. The first fraction was the unchanged
N-phenylmaleimide and the next one was pyrrole 5
(40 mg, 27% yield). The next fraction was adduct 4a (isomer
with cis configuration), which was further purified by
preparative TLC using toluene/ethyl acetate (90:10) as an
eluent. Compound 4a was crystallized from 1-chlorobutane
to afford white crystals (91.3 mg, 33% yield) with mp 242–
243 ꢀC. The last fraction was adduct 4b (isomer with trans
configuration), which was crystallized from 1-chlorobutane
to afford white crystals (75.3 mg, 27% yield) with mp
272–274 ꢀC.
The 1H NMR spectrum of pyridine 13 shows signals typical
of the chromonyl group and of the 2-hydroxybenzoyl moi-
ety. The resonances of protons H-20 and H-50 appear, respec-
tively, as a singlet at d 9.08 ppm and as a doublet of doublets
centered at 8.32 ppm; the resonance of the hydroxyl proton
appears at 11.82 ppm. It also displays double doublets
(J¼1.5 Hz) centered at d 8.27 and 8.88 ppm, which were
assigned, respectively, to the pyridine protons H-5 and
H-3. The resonance of the methyl ester group appears at
4.06 ppm. The 13C NMR spectrum shows the resonances
of three carbonyl groups at 165 (CO2Me), 176 (C-40), and
199 ppm (4-COAr). The substituted carbons from the pyri-
dine nucleus appear at 152.0 (C-6), 148.1 (C-4), and 146.3
(C-2) ppm; carbons C-5 and C-3 appear at 122.6 and
125.9 ppm, respectively.
4.1.1.1. rel-(3aS,4R,6aS)-5-Methyl-4-(4-oxo-4H-chro-
men-3-yl)-2-phenyl-3a,4,6,6a-tetrahydropyrrolo[3,4-c]-
pyrrole-1,3-dione, 4a. 1H NMR (300.13 MHz, CDCl3):
d¼8.25 (dd, J¼8.0, 1.7 Hz, 1H, H-50), 7.79 (d, J¼0.8 Hz,
1H, H-20), 7.65 (ddd, J¼8.6, 7.0, 1.7 Hz, 1H, H-70), 7.34–
7.44 (m, 5H, H-60,80,300,400,500), 7.18–7.21 (m, 2H,
H-200,600), 3.98 (br d, J¼8.4 Hz, 1H, H-4), 3.87 (dd, J¼8.4,
7.9 Hz, 1H, H-3a), 3.70 (d, J¼9.8 Hz, 1H, H-6), 3.43 (dd,
J¼7.9, 7.4 Hz, 1H, H-6a), 2.71 (dd, J¼9.8, 7.4 Hz, 1H,
H-6), 2.33 (s, 3H, CH3). 13C NMR (75.47 MHz, CDCl3):
d¼178.0 (C-1), 177.4 (C-40), 174.8 (C-3), 156.4 (C-90),
153.2 (C-20), 133.7 (C-70), 131.8 (C-100), 129.1 (C-300,500),
128.5 (C-400), 126.3 (C-200,600), 125.8 (C-50), 125.2 (C-80),
123.5 (C-100), 120.4 (C-30), 118.2 (C-60), 63.9 (C-4), 58.9
(C-6), 48.2 (C-3a), 43.7 (C-6a), 40.2 (CH3). MS (EI) m/z
The 1H NMR spectrum of compound 14 is similar to that of
13, except the absence of the signals corresponding to the
hydroxyl proton and to H-3.
3. Conclusions
Chromone-3-carbaldehyde reacts with amino acids to gener-
ate chromone-azomethine ylides, which undergo 1,5-electro-
cyclization to yield 3- or 4-(2-hydroxybenzoyl)pyrrole. In
the presence of a dipolarophile, these ylides can participate
in 1,3-dipolar cycloaddition reactions to yield chromonyl
pyrrolidines. The reaction of chromone-3-carbaldehyde with
methyl glycinate gives a mixture of pyrrole, pyridine, and
3-aza-9-xanthenone derivatives. The regio- and stereochem-
istry of the products were established by 1D and 2D NMR
studies.
ꢁ
(%): 374 (M+ , 15.5), 359 (100), 345 (0.6), 329 (0.6), 252
(4.3), 238 (12.0), 226 (11.9), 212 (28), 200 (6.0), 186

A. G. P. R. Figueiredo et al. / Tetrahedron 63 (2007) 910–917
915
(2.8), 172 (4.2), 159 (2.9), 141 (0.7), 128 (2.9), 121 (7.3),
114 (3.9), 106 (4.8), 91 (9.9), 84 (6.9), 77 (13.0), 65 (7.1),
57 (1.0), 51 (5.6). Anal. Calcd for C22H18N2O4: C, 70.58;
N, 7.48; H, 4.85. Found: C, 70.53; N, 7.39; H, 4.90.
H-5), 7.43 (ddd, J¼8.4, 7.0, 1.7 Hz, 1H, H-7), 7.37 (ddd,
J¼8.0, 7.1, 1.0 Hz, 1H, H-60), 7.31 (d, J¼8.5 Hz, 1H, H-
80), 6.97 (dd, J¼8.4, 1.0 Hz, H-8), 6.86 (ddd, J¼8.0, 7.0,
1.0 Hz, 1H, H-6), 5.09–5.11 (m, 1H, H-3a), 4.42 (d,
J¼10.8 Hz, 1H, H-1), 3.61 (d, J¼10.8 Hz, 1H, H-3), 3.60
(dd, J¼10.8, 6.2 Hz, 1H, H-9a), 2.83 (dd, J¼10.8, 3.5 Hz,
1H, H-3), 2.39 (s, 3H, CH3). 13C NMR (75.47 MHz,
CDCl3): d¼190.0 (C-9), 177.0 (C-40), 160.7 (C-4a), 156.1
(C-90), 155.1 (C-20), 136.2 (C-7), 133.4 (C-70), 126.7 (C-
5), 126.2 (C-50), 125.0 (C-60), 123.5 (C-100), 121.5 (C-30),
121.4 (C-6), 120.7 (C-8a), 117.9 and 117.9 (C-80 and C-8),
79.4 (C-3a), 62.4 (C-1), 62.2 (C-3), 52.4 (C-9a), 40.6
4.1.1.2. rel-(3aS,4S,6aS)-5-Methyl-4-(4-oxo-4H-chro-
men-3-yl)-2-phenyl-3a,4,6,6a-tetrahydropyrrolo[3,4-c]-
pyrrole-1,3-dione, 4b. 1H NMR (300.13 MHz, CDCl3):
d¼8.23 (dd, J¼8.0, 1.6 Hz, 1H, H-50), 7.93 (s, 1H, H-20),
7.71 (ddd, J¼8.5, 7.0, 1.6 Hz, 1H, H-70), 7.33–7.51 (m,
7H, H-60,80, H–Ph), 3.82–3.88 (m, 3H, H-3a,4,6a), 3.51
(dd, J¼9.7, 7.6 Hz, 1H, H-6), 2.97 (dd, 1H, J¼9.7, 4.1 Hz,
H-6), 2.25 (s, 3H, CH3). 13C NMR (75.47 MHz, CDCl3):
d¼177.9 (C-1), 177.4 (C-3), 177.2 (C-40), 156.2 (C-90),
155.3 (C-20), 134.0 (C-70), 131.9 (C-100), 129.1 (C-300,500),
128.6 (C-400), 126.5 (C-200,600), 126.0 (C-50), 125.6 (C-60),
124.3 (C-100), 120.7 (C-30), 118.1 (C-80), 66.0 (C-4), 57.8
(C-6), 50.5 (C-3a), 45.4 (C-6a), 38.1 (CH3). MS (EI) m/z
ꢁ
(CH3). MS (EI) m/z (%): 347 (M+ , 32), 332 (23.5), 315
(3), 304 (6), 287 (2), 252 (1.5), 238 (1.5), 226 (100), 212
(66.5), 201 (12.5), 184 (9), 171 (7), 156 (4), 149 (6.5), 131
(7), 121 (49.5), 106 (9), 92 (16), 81 (36), 69 (10), 57
ꢁ
(16.5). HRMS (EI) m/z calculated for C21H17NO4 (M+ )
347.1158, found 347.1152. Anal. Calcd for C21H17NO4: C,
72.61; N, 4.03; H, 4.93. Found: C, 72.96; N, 4.09; H, 4.89.
ꢁ
(%): 374 (M+ , 15), 359 (100), 345 (0.5), 329 (0.2), 291
(0.3), 274 (0.3), 252 (1.7), 238 (5.9), 226 (6.5), 212 (14.5),
199 (9.8), 184 (1.9), 171 (7.4), 160 (3.0), 128 (2.7), 121
(4.8), 114 (3.8), 106 (2.6), 92 (4.7), 84 (16.5), 65 (3.8), 57
(0.8). Anal. Calcd for C22H18N2O4: C, 70.58; N, 7.48; H,
4.85. Found: C, 70.58; N, 7.38; H, 4.88.
4.1.3. Reaction of chromone-3-carbaldehyde with gly-
cine. A solution of chromone-3-carbaldehyde (98.5 mg,
0.56 mmol) and glycine (222.0 mg, 2.96 mmol) in toluene
(50 mL) was refluxed for 17 h under N2. Part of the solvent
was removed under vacuum and the mixture was purified by
flash chromatography using toluene as an eluent. The first
fraction to be eluted was pyrrole 11, which was crystallized
from 1-chlorobutane to afford white crystals (1.7 mg, 2%
yield) with mp 254–255 ꢀC (lit.,16 242–243 ꢀC). The second
fraction was the pyrrole 10, which was crystallized from
ethanol to afford yellow crystals (48.7 mg, 46% yield)
with mp 128–129 ꢀC.
4.1.2. Reaction of chromone-3-carbaldehyde with N-
methylglycine. The best procedure to synthesize pyrrole 5
was the following: a solution of chromone-3-carbaldehyde
1 (50.9 mg, 0.29 mmol) and N-methylglycine (64.6 mg,
0.73 mmol) in toluene (25 mL) was heated at reflux under
N2 for 7:30 h. Part of the solvent was removed under vacuum
and the mixture was purified by flash chromatography using
toluene as an eluent. The first fraction to be collected was
pyrrole 5; it was crystallized from ethanol to afford yellow
crystals (46.9 mg, 80% yield) with mp 76–77 ꢀC (lit.,16
83–84 ꢀC). A minor fraction of pyrrolidine 6 was also iso-
lated. The yield of compound 6 could be increased to 50%
by reacting chromone 1 with N-methylglycine in a 10:1 pro-
portion. In this case the pyrrole 5 was obtained in 22% yield.
Pyrrolidine 6 was crystallized from ethanol to afford yellow
crystals with mp 166–169 ꢀC.
4.1.3.1. 3-(2-Hydroxybenzoyl)pyrrole, 10. 1H NMR
(300.13 MHz, CDCl3): d¼12.20 (s, 1H, 200-OH), 8.76 (br
s, 1H, NH), 7.96 (dd, J¼8.0, 1.7 Hz, 1H, H-600), 7.44–7.50
(m, 1H, H-400), 7.46 (t, J¼3.3 Hz, 1H, H-2), 7.04 (dd,
J¼8.3, 1.1 Hz, 1H, H-300), 6.91 (ddd, J¼8.0, 7.1, 1.1 Hz,
1H, H-500), 6.87–6.89 (m, 1H, H-5), 6.76–6.79 (m, 1H,
H-4). 13C NMR (75.47 MHz, CDCl3): d¼194.3 (C]O),
162.3 (C-200), 135.1 (C-400), 131.9 (C-600), 124.7 (C-2),
123.9 (C-3), 120.5 (C-100), 119.3 (C-5), 118.5 (C-500), 118.1
ꢁ
1
4.1.2.1. 3-(2-Hydroxybenzoyl)-1-methylpyrrole, 5. H
(C-300), 110.8 (C-4). MS (EI) m/z (%): 187 (M+ , 100), 170
NMR (300.13 MHz, CDCl3): d¼12.22 (s, 1H, 200-OH),
7.94 (dd, J¼8.0, 1.7 Hz, 1H, H-600), 7.44 (ddd, J¼8.4, 7.1,
1.7 Hz, 1H, H-400), 7.28 (t, J¼1.9 Hz, 1H, H-2), 7.02
(dd, J¼8.4, 1.1 Hz, 1H, H-300), 6.90 (ddd, J¼8.0, 7.1,
1.1 Hz, 1H, H-500), 6.65–6.69 (m, 2H, H-4,5), 3.74 (s, 3H,
N–CH3). 13C NMR (75.47 MHz, CDCl3): d¼193.6
(C]O), 162.2 (C-200), 134.8 (C-400), 131.7 (C-600), 128.3
(C-2), 123.6 (C-3), 123.3 (C-5), 120.5 (C-100), 118.4
(C-500), 118.0 (C-300), 111.3 (C-4), 36.7 (N–CH3). MS (EI)
(4), 159 (2.5), 130 (6.5), 121 (50), 115 (2), 103 (5), 94
(67.5), 77 (11), 67 (76), 53 (7). Anal. Calcd for C11H9NO2:
C, 70.58; N, 7.48; H, 4.85. Found: C, 70.34; N, 7.50; H, 4.92.
4.1.3.2. 2-(4-Oxo-4H-chromen-3-yl)-4-(2-hydroxy-
benzoyl)pyrrole, 11. 1H NMR (500.13 MHz, CDCl3):
d¼12.15 (s, 1H, 2000-OH), 11.50 (br s, 1H, NH), 8.52 (s,
1H, H-20), 8.33 (dd, J¼8.0, 1.6 Hz, 1H, H-50), 7.99 (dd,
J¼7.8, 1.6 Hz, 1H, H-6000), 7.75 (ddd, J¼8.5, 7.1, 1.6 Hz,
1H, H-70), 7.56 (d, J¼8.5 Hz, 1H, H-80), 7.52 (dd, J¼3.0,
1.6 Hz, 1H, H-5), 7.47–7.51 (m, 2H, H-4000,60), 7.05 (dd,
J¼8.3, 0.9 Hz, 1H, H-3000), 7.01 (dd, J¼2.3, 1.6 Hz, 1H,
H-3), 6.94 (ddd, J¼7.8, 7.6, 0.9 Hz, 1H, H-5000). 13C NMR
(125.77 MHz, CDCl3): d¼194.0 (C-100), 177.0 (C-40),
162.3 (C-2000), 155.8 (C-90), 151.7 (C-20), 135.1 (C-4000),
134.2 (C-70), 131.7 (C-6000), 126.3 (C-2), 126.0 (C-50),
125.7 (C-60), 124.8 (C-5), 123.9 and 123.8 (C-100 and
C-4), 120.5 (C-1000), 118.6 (C-5000), 118.3 (C-80), 118.2
(C-3000), 115.3 (C-30), 105.0 (C-3). MS (EI) m/z (%): 331
ꢁ
m/z (%): 201 (M+ , 87), 184 (9.5), 173 (2), 159 (2), 149
(4), 131 (2), 121 (10), 115 (2), 108 (41), 104 (1.5), 100
(3.5), 92 (5), 81 (100), 65 (8), 53 (9). Anal. Calcd for
C12H11NO2: C, 71.63; N, 6.96; H, 5.51. Found: C, 71.49;
N, 6.58; H, 5.76.
4.1.2.2. rel-(1R,3aR,9aR)-2-Methyl-1-(4-oxo-4H-chro-
men-3-yl)-1,3,3a,9a-tetrahydro-1H-chromeno[2,3-c]pyr-
1
rol-9-one, 6. H NMR (300.13 MHz, CDCl3): d¼8.24 (dd,
J¼8.0, 1.7 Hz, 1H, H-50), 7.83 (s, 1H, H-20), 7.60 (ddd,
J¼8.5, 7.1, 1.7 Hz, 1H, H-70), 7.56 (dd, J¼8.0, 1.7 Hz, 1H,
ꢁ
(M+ , 62.5), 303 (3.5), 238 (14), 226 (1), 211 (100), 198

916
A. G. P. R. Figueiredo et al. / Tetrahedron 63 (2007) 910–917
(1.5), 183 (6), 172 (3), 154 (5.5), 138 (1.5), 127 (3.5), 121
(9.5), 105 (3.5), 91 (19.5), 77 (7), 65 (8). Anal. Calcd for
C20H13NO4: C, 72.50; N, 4.23; H, 3.95. Found: C, 72.50;
N, 4.17; H, 4.01.
solvent was removed under vacuum and the mixture was pu-
rified by flash chromatography using a gradient of CH2Cl2
to CH2Cl2/ethyl acetate as an eluent. Pyrrole 9 (43.0 mg,
27%) was obtained as yellow oil.
1
4.1.4. Reaction of chromone-3-carbaldehyde with N-benz-
ylglycine. A solution of chromone-3-carbaldehyde (99.9 mg,
0.57 mmol), N-benzylglycine hydrochloride (296.8 mg,
1.47 mmol) and potassium carbonate (209.1 mg, 1.51 mmol)
in dry 1,4-dioxane (25 mL) was refluxed for 5 h. After cooling
to room temperature the reaction mixture was filtered and the
solvent was removed under vacuum. The residue was dis-
solved in toluene and the product was purified by flash chro-
matography (silica) using toluene as an eluent. Evaporation of
the solvent under vacuum afforded pure pyrrole 7 (138.2 mg,
87% yield) as a yellow oil.
4.1.6.1. 2-Benzyl-4-(2-hydroxybenzoyl)pyrrole, 9. H
NMR (300.13 MHz, CDCl3): d¼12.21 (s, 1H, 200-OH), 8.47
(br s, 1H, NH), 7.94 (dd, J¼8.0, 1.7 Hz, 1H, H-600), 7.44
(ddd, J¼8.4, 7.1, 1.7 Hz, 1H, H-400), 7.21–7.34 (m, 5H,
CH2C6H5), 7.28 (dd, J¼2.8, 1.7 Hz, 1H, H-5), 7.01 (dd,
J¼8.4, 1.1 Hz, 1H, H-300), 6.89 (ddd, J¼8.0, 7.1, 1.1 Hz,
1H, H-500), 6.52 (br s, 1H, H-3), 3.99 (s, 2H, 2ꢂH-1000). 13
C
NMR (125.77 MHz, CDCl3): d¼194.1 (C]O), 162.2 (C-200),
138.1 (Bn-C-1), 134.9 (C-400), 132.6 (C-2), 131.8 (C-600),
128.8 (Bn-C-3,5), 128.7 (Bn-C-2,6), 126.9 (Bn-C-4), 124.7
(C-5), 123.9 (C-4), 120.5 (C-100), 118.5 (C-500), 118.0
(C-300), 108.5 (C-3), 33.7 (CH2Ph). MS (EI) m/z (%): 277
ꢁ
1
4.1.4.1. 1-Benzyl-3-(2-hydroxybenzoyl)pyrrole, 7. H
(M+ , 100), 260 (9), 249 (4), 231 (3), 211 (1), 198 (3), 186
NMR (300.13 MHz, CDCl3): d¼12.20 (s, 1H, 200-OH), 7.93
(dd, J¼8.0, 1.7 Hz, 1H, H-600), 7.44 (ddd, J¼8.4, 7.1, 1.7 Hz,
1H, H-400), 7.32–7.37 (m, 4H, H-2 and Bn-H-3,4,5), 7.16–
7.19 (m, 2H, Bn-H-2,6), 7.01 (dd, J¼8.4, 1.1 Hz, 1H, H-300),
6.88 (ddd, J¼8.0, 7.1, 1.1 Hz, 1H, H-500), 6.71–6.74 (m, 2H,
H-4,5), 5.12 (s, 2H, N-CH2Ph). 13C NMR (75.47 MHz,
CDCl3): d¼193.7 (C]O), 162.3 (C-200), 136.2 (Bn-C-1),
134.9 (C-400), 131.7 (C-600), 129.0 (Bn-C-3,5), 128.3 (Bn-
C-4), 127.7 (C-2), 127.2 (Bn-C-2,6), 123.8 (C-3), 122.7
(C-5), 120.5 (C-100), 118.5 (C-500), 118.0 (C-300), 111.5
(22), 172 (5), 157 (92), 139 (1), 128 (11), 121 (26), 115 (7),
106 (24), 91 (29), 80 (36), 65 (65), 57 (3). HRMS (EI) m/z
ꢁ
calculated for C18H15NO2 (M+ ) 277.1103, found 277.1103.
4.1.7. Reaction of chromone-3-carbaldehyde with methyl
glycinate. A solution of methyl glycinate hydrochloride
(355.3 mg, 2.83 mmol) and potassium carbonate (398.6 mg,
2.88 mmol), in toluene (60 mL), was stirred at room temper-
ature during 15–30 min. Then chromone-3-carbaldehyde
(99.9 mg, 0.57 mmol) was added and the mixture heated at
reflux for 10 h under N2 atmosphere. The reaction mixture
was filtered and part of the solvent was removed under
vacuum. The mixture was purified by flash chromatography
using toluene as an eluent. The first fraction was pyridine 13,
which was crystallized from 1-chlorobutane to afford light
yellow crystals (7 mg, 6% yield) with mp 200–202 ꢀC. The
second fraction was pyrrole 12, which was crystallized
from ethanol to afford yellow crystals (51.5 mg, 37%) with
mp 149 ꢀC (lit.,21 149–150 ꢀC). Compound 14 was obtained
in a similar experiment but using 1 equiv of methyl glycinate
hydrochloride (72.3 mg, 0.58 mmol) and 0.5 equiv of potas-
sium carbonate (40.7 mg, 0.29 mmol). Compound 14, which
has a lower Rf value than 12 and 13, was crystallized from
1-chlorobutane to afford white crystals (13.6 mg, 12% yield)
with mp >300 ꢀC.
ꢁ
(C-4), 53.9 (N-CH2Ph). MS (EI) m/z (%): 277 (M+ , 86),
260 (5), 186 (7), 172 (6), 157 (63), 131 (4), 121 (5), 103 (3),
91 (100), 83 (1), 77 (6), 65 (26). HRMS (EI) m/z calculated
ꢁ
for C18H15NO2 (M+ ) 277.1103, found 277.1104.
4.1.5. Reaction of chromone-3-carbaldehyde with L-pro-
line. A solution of chromone-3-carbaldehyde (100 mg,
0.57 mmol) and L-proline (329.6 mg, 2.86 mmol) in toluene
(50 mL) was refluxed for 4 h under N2. Part of the solvent
was removed under vacuum and the mixture was purified
by flash chromatography using toluene as an eluent. Pyrrole
8 (28.5 mg, 22% yield) was obtained as a yellow oil. This
compound decomposes slowly at room temperature.
4.1.5.1. 6-(2-Hydroxybenzoyl)-2,3-dihydro-1H-pyrro-
1
lizine, 8. H NMR (300.13 MHz, CDCl3): d¼12.24 (s, 1H,
200-OH), 7.95 (dd, J¼8.0, 1.7 Hz, 1H, H-600), 7.44 (ddd,
J¼8.5, 7.2, 1.7 Hz, 1H, H-400), 7.27 (d, J¼1.2 Hz, 1H, H-
5), 7.01 (dd, J¼8.5, 1.0 Hz, 1H, H-300), 6.89 (ddd, J¼8.0,
7.2, 1.0 Hz, 1H, H-500), 6.37 (q, J¼1.2 Hz, 1H, H-7), 4.03
(t, J¼7.2 Hz, 2H, H-3), 2.88 (dt, J¼7.2, 1.2 Hz, 2H, H-1),
2.55 (qui, J¼7.2 Hz, 2H, H-2). 13C NMR (75.47 MHz,
CDCl3): d¼193.8 (C-10), 162.2 (C-200), 138.7 (C-8), 134.6
(C-400), 131.8 (C-600), 127.7 (C-6), 121.2 (C-5), 120.7 (C-
100), 118.3 (C-500), 117.9 (C-300), 102.0 (C-7), 46.7 (C-3),
4.1.7.1. Methyl 4-(2-hydroxybenzoyl)pyrrole-2-car-
1
boxylate, 12. H NMR (300.13 MHz, CDCl3): d¼12.04 (s,
1H, 200-OH), 9.72 (br s, 1H, NH), 7.90 (dd, J¼8.0, 1.7 Hz,
1H, H-600), 7.61 (dd, J¼3.3, 1.6 Hz, 1H, H-3), 7.50 (ddd,
J¼8.4, 7.1, 1.7 Hz, 1H, H-400), 7.37 (dd, J¼2.4, 1.6 Hz, 1H,
H-5), 7.05 (dd, J¼8.4, 1.1 Hz, 1H, H-300), 6.94 (ddd, J¼8.0,
7.1, 1.1 Hz, 1H, H-500), 3.92 (s, 3H, CO2CH3). 13C NMR
(75.47 MHz, CDCl3): d¼193.6 (C-10), 162.5 (C-200), 161.2
(CO2CH3), 135.7 (C-400), 131.7 (C-600), 127.6 (C-3), 125.1
(C-2), 123.8 (C-4), 120.0 (C-100), 118.8 (C-500), 118.3
(C-300), 116.5 (C-5), 52.0 (CO2CH3). MS (EI) m/z (%): 245
ꢁ
27.8 (C-2), 23.9 (C-1). MS (EI) m/z (%): 227 (M+ , 80.5),
210 (11), 198 (8), 186 (7.5), 170 (3.5), 159 (3.5), 147
(2.5), 134 (28), 121 (10), 115 (6), 107 (100), 93 (5.5), 81
(1), 77 (15.5), 65 (18.5). HRMS (EI) m/z calculated for
ꢁ
(M+ , 71.5), 212 (7), 196 (1), 186 (14), 159 (4), 152 (7),
140 (1), 130 (3), 125 (46), 120 (100), 115 (1.5), 107 (2), 92
(26), 77 (6), 65 (27), 53 (7). Anal. Calcd for C13H11NO4:
C, 63.67; N, 5.71; H, 4.52. Found: C, 63.29; N, 5.62; H, 4.76.
ꢁ
C14H13NO2 (M+ ): 227.0946; found: 227.0948.
4.1.6. Reaction of chromone-3-carbaldehyde with L-phe-
nylalanine. A solution of chromone-3-carbaldehyde (99.3 mg,
0.57 mmol) and L-phenylalanine (96.7 mg, 0.58 mmol) in
toluene (25 mL) was refluxed for 3 h under N2. Part of the
4.1.7.2. Methyl 4-(2-hydroxybenzoyl)-6-(4-oxo-4H-chro-
men-3-yl)pyridine-2-carboxylate, 13. 1H NMR (300.13 MHz,
CDCl3): d¼11.82 (s, 1H, 200-OH), 9.08 (s, 1H, H-20), 8.88

A. G. P. R. Figueiredo et al. / Tetrahedron 63 (2007) 910–917
917
(d, J¼1.5 Hz, 1H, H-3), 8.32 (dd, J¼8.0, 1.7 Hz, 1H, H-50),
8.27 (d, J¼1.5 Hz, 1H, H-5), 7.75 (ddd, J¼8.6, 7.0, 1.7 Hz,
1H, H-70), 7.56–7.61 (m, 3H, H-400,600,80), 7.49 (ddd, J¼8.0,
7.0, 1.1 Hz, 1H, H-60), 7.12 (dd, J¼8.8, 1.1 Hz, 1H, H-300),
6.96 (ddd, J¼8.0, 7.1, 1.1 Hz, 1H, H-500), 4.06 (s, 3H,
CO2CH3). 13C NMR (75.47 MHz, CDCl3): d¼199.0 (C]O),
175.9 (C-40), 164.9 (CO2CH3), 163.6 (C-200), 158.4 (C-20),
156.0 (C-90), 152.0 (C-6), 148.1 (C-4), 146.3 (C-2), 137.6
(C-400), 134.1 (C-70), 133.2 (C-600), 126.3 (C-50), 125.9 (C-
3,60), 124.6 (C-100), 122.6 (C-5), 121.1 (C-30), 119.4 (C-500),
118.8 (C-300), 118.3 (C-80), 118.3 (C-100), 53.1 (CO2CH3). MS
6. Ishar, M. P. S.; Kumar, K.; Singh, R. Tetrahedron Lett. 1998, 39,
6547–6550.
7. Baruah, A. K.; Prajapati, D.; Sandhu, J. S. Tetrahedron 1988,
44, 1241–1246.
8. Xie, Z.; Liu, F.; Hui, Y.; Liu, C.; Sun, Y. J. Heterocycl. Chem.
2005, 42, 695–697.
ꢀ
9. De la Torre, M. D. L.; Rodrigues, A. G. P.; Tome, A. C.; Silva,
A. M. S.; Cavaleiro, J. A. S. Tetrahedron 2004, 60, 3581–3592.
10. Laatsch, H.; Renneberg, B.; Hanefeld, U.; Kellner, M.;
Pudleiner, H.; Hamprecht, G.; Kraemer, H.-P.; Anke, H.
Chem. Pharm. Bull. 1995, 43, 537–546.
11. Demopoulos, V. J.; Rekka, E. J. Pharm. Sci. 1995, 84, 79–82.
12. Pyrroles; Jones, R. A., Ed.; Wiley: New York, NY, 1990; Part I.
13. Rizzi, G. P. J. Org. Chem. 1970, 35, 2069–2072.
14. For other examples of 1,5-electrocyclization reactions of
azomethine ylides to afford pyrroles, see: Romashin, Y. N.;
Liu, M. T. H.; Ma, W.; Moss, R. A. Tetrahedron Lett. 1999,
40, 7163–7165; For other examples of 1,5-electrocyclization
reactions of azomethine ylides, see: (a) Seyferth, D.; Shih, H.
J. Org. Chem. 1974, 39, 2336–2341; (b) Silva, A. M. G.;
ꢁ
(EI) m/z (%): 401 (M+ , 100), 386 (15), 372 (98.5), 358 (30),
341 (23), 331 (50), 317 (82), 312 (88), 302 (5.5), 286 (9),
258 (35), 245 (8), 238 (9), 224 (19), 211 (79), 197 (55.5),
171 (12), 165 (37), 147 (19), 138 (33), 121 (70), 111 (10), 92
(37), 83 (17.5), 65 (47), 57 (39). Anal. Calcd for C23H15NO6:
C, 68.83; N, 3.49; H, 3.77. Found: C, 69.27; N, 3.49; H, 3.81.
4.1.7.3. Methyl 9-oxo-2-(4-oxo-4H-chromen-3-yl)-9H-
3-azaxanthene-4-carboxylate, 14. 1H NMR (500.13 MHz,
CDCl3): d¼9.04 (s, 1H, H-1), 8.37 (s, 1H, H-20), 8.35 (dd,
J¼8.0, 1.6 Hz, 1H, H-8), 8.34 (dd, J¼7.7, 1.7 Hz, 1H, H-50),
7.78 (ddd, J¼8.5, 7.3, 1.7 Hz, 1H, H-70), 7.77 (ddd, J¼8.5,
7.1, 1.6 Hz, 1H, H-6), 7.61 (dd, J¼8.5, 0.9 Hz, 1H, H-80),
7.53 (ddd, J¼7.7, 7.3, 0.9 Hz, 1H, H-60), 7.45–7.48 (m, 1H,
H-7), 7.44 (d, J¼8.5 Hz, 1H, H-5), 4.06 (s, 3H, CO2CH3).
13C NMR (125.77 MHz, CDCl3): d¼175.8 (C-9), 174.6
(C-40), 164.6 (CO2CH3), 156.34 (C-90), 156.29 (C-20), 155.6
(C-10a), 152.1 (C-4a), 145.2 (C-4), 142.0 (C-2), 136.2 (C-6),
134.2 (C-70), 126.9 (C-9a), 126.8 (C-8), 126.3 (C-50), 125.8
(C-60), 125.4 (C-7), 124.4 (C-100), 122.5 (C-30), 122.2 (C-1),
121.9 (C-8a), 118.8 (C-5), 118.3 (C-80), 53.1 (CO2CH3). MS
ꢀ
Faustino, M. A. F.; Tome, A. C.; Neves, M. G. P. M. S.;
Silva, A. M. S.; Cavaleiro, J. A. S. J. Chem. Soc., Perkin
Trans. 1 2001, 2752–2753.
15. A N-phenylnitrone derivative of 1 rearranges to other chromone
derivatives presumably via a common intermediate resulted
from a 1,5-electrocyclization reaction.6
16. Clarke, P. D.; Fitton, A. O.; Kosmirak, M.; Suschitzky, H.;
Suschitzky, J. J. Chem. Soc., Perkin Trans. 1 1985, 1747–1756.
17. For the reaction of chromone 1 with other 1,3-dipoles,
namely diazomethane, see: Ghosh, C. K.; Bhattacharyya, A.;
Ghoshdastidar, P. P. Indian J. Chem. 1987, 26B, 423–426.
18. The deformylation of other derivatives of chromone 1 has
already been reported. (a) Cremins, P. J.; Saengchantara,
S. T.; Wallace, T. W. Tetrahedron 1987, 43, 3075–3082; (b)
Kumar, K.; Kapoor, R.; Kapur, A.; Ishar, M. P. S. Org. Lett.
2000, 2, 2023–2025; (c) Sandulache, A.; Silva, A. M. S.;
Cavaleiro, J. A. S. Tetrahedron 2002, 58, 105–114.
19. Pyrrole 11 was previously obtained from the reaction of 1 with
alanine ethyl ester or with ethyl 2-amino-2-phenylethanoate in
44% and 39% yield, respectively.16
ꢁ
(IE) m/z (%): 399 (M+ , 37), 341 (100), 322 (4.5), 312 (1.8),
293 (1.4), 220 (0.7), 164 (4.5), 149 (1.5), 120 (7), 92 (28), 76
(2.2), 63 (7), 57 (3.6). HRMS (EI) m/z calculated for
ꢁ
C23H13NO6 (M+ ) 399.0743, found 399.0732.
Acknowledgements
~
^
Thanks are due to the Fundac¸ao para a Ciencia e a Tecnologia
(Portugal) and POCI 2010 (FEDER) for funding the Organic
Chemistry Research Unit. A.G.P.R.F. thanks FCT for the
grant BD/18387/2004.
20. Fitton, A. O.; Kosmirak, M.; Suschitzky, H. Tetrahedron Lett.
1982, 23, 3953–3956.
21. Pyrrole 12 was previously prepared in two steps, in 30%
global yield, from the reaction of 1 with N-benzoylglycine
(hippuric acid), followed by treatment of the resulting
azlactone with methanolic sodium carbonate. Fitton, A. O.;
Frost, J. R.; Suschitzky, H.; Houghoton, P. G. Synthesis 1977,
133–135.
22. Completely different mechanisms have been proposed for the
formation of these compounds.16
23. Sandulache, A.; Silva, A. M. S.; Pinto, D. C. G. A.; Almeida,
L. M. P. M.; Cavaleiro, J. A. S. New J. Chem. 2003, 27,
1592–1598.
References and notes
1. Ghosh, C. K. J. Heterocycl. Chem. 1983, 20, 1437–1445.
2. Sabitha, G. Aldrichimica Acta 1996, 29, 15–25.
3. Ghosh, C. K. Indian J. Chem. 1997, 36B, 968–980.
4. Ghosh, C. K. Heterocycles 2004, 63, 2875–2898.
5. Baruah, A. K.; Prajapati, D.; Sandhu, J. S. J. Chem. Soc., Perkin
Trans. 1 1987, 1995–1998.