Furo[3,4-b]chromones, and not pyrano[3,4-b]chromones, are obtained by the reaction of 3-formylchromones with isocyanides

Article abstract of DOI:10.1055/s-0032-1317032

The reaction of formylchromones with alkyl isocyanides was reinvestigated. In earlier reports from other research groups, two different structures were proposed for the products of this reaction. Herein, we provide unambiguous evidence that these products

Full text of DOI:10.1055/s-0032-1317032

LETTER
▌2227
letter
Furo[3,4-b]chromones, and not Pyrano[3,4-b]chromones, are Obtained by the
Reaction of 3-Formylchromones with Isocyanides
Furo[3,4-b]chromones from 3-Formylchromones and Isocyanides
Ana G. Neo,a Leda Garrido,a Jesús Díaz,a Stefano Marcaccini,b Carlos F. Marcos*a
a
Laboratorio de Química Orgánica y Bioorgánica (L.O.B.O.), Departamento de Química Orgánica e Inorgánica, Facultad de Veterinaria,
Universidad de Extremadura, 10071 Cáceres, Spain
Fax +34(927)257110; E-mail: cfernan@unex.es
b
Dipartimento di Chimica ‘Ugo Schiff’, Università di Firenze, 50019 Sesto Fiorentino FI, Italy
Received: 14.06.2012; Accepted after revision: 13.07.2012
same reaction, claiming that the products are pyrano[3,4-
Abstract: The reaction of formylchromones with alkyl isocyanides
b]chromones (4; Scheme 1).13 In both reports,12,13 the au-
was reinvestigated. In earlier reports from other research groups,
thors make use of mechanistic rationales and conventional
two different structures were proposed for the products of this reac-
tion. Herein, we provide unambiguous evidence that these products
IR, 1H NMR, 13C NMR, and mass spectrometric analyses
are chromenylmethylene furochromenones and not pyrano- to elucidate the structure of the products. However, al-
chromones. Our structure assignment is based on X-ray diffraction
analysis and two-dimensional NMR methods. The knowledge of the
correct structure of these compounds is essential for the design of
firming that analogous compounds were obtained in both
derivatives with potential applications as bioactive molecules or
fluorescent biomarkers.
though the spectroscopic data of the products obtained by
Bandyopadhyay and Teimouri are virtually identical, con-
cases, they arrive at different structures. Indeed, simple
spectroscopic data do not allow the two alternative struc-
Key words: cycloaddition reactions, furans, fused-ring systems,
tures to be discriminated. Furthermore, Teimouri was ap-
multicomponent reactions, heterocycles, natural products
parently unaware of the previous report by
Bandyopadhyay, and gave no unequivocal arguments in
favour of the proposed structure.
In the last years, the preparation of natural-product-like
libraries has become a foremost strategy for the discovery
O
of new drugs.1 Polycyclic benzopyrones are privileged
O
O
O
O
Y
structures that are present in a large number of natural
products possessing diverse biological activities and,
hence, constitute an important synthetic target.2 In partic-
ular, the furo[3,4-b]chromone scaffold is found in ergot
pigments ergoflavin, ergochrysin A, and ergoxanthin;3
cytotoxic rotenoid amorphispironone;4 and the biflavo-
noids daphnodorins and genkwanols, isolated from Daph-
ne species,5 which have shown antitumour6 and chymase
inhibitory7 activities. The discovery of new bioactive
analogues of these compounds with increased potency
and selectivity relies, to a large extent, on the availability
of efficient methods for the synthesis of furo[3,4-b]chro-
mones. However, only a few syntheses have been reported
in the literature. Most of the synthetic approaches are
based on the cyclisation of chromone-2-carboxylates8 or
2-(hydroxymethyl)chromones9 containing electrophilic
substituents on the 3-position, oxidation,10 or photo-
isomerisation reactions.11 These procedures often involve
multistep reactions or low yields, and do not allow an easy
diversification of the substituents.
Y
Y
O
R
O
O
N
1
4
Y
+
O
+
N
R
C–
O
O
2
O
Y
O
N
R
3
Scheme 1 Two possible structures for the products of the reaction of
formylchromones (1) and isocyanides (2)
Shortly before these two papers were published, as a part
of a program dealing with the use of isocyanides for the
preparation of natural-product-like heterocycles,14 we
were also working to develop a convenient synthesis of
furo[3,4-b]chromones by the cycloaddition of isocyanides
(2) and 3-formylchromones (1), and we arrived at similar
products to those obtained by Bandyopadhyay and
Teimouri.15 As we are interested in the study of their bio-
logical and fluorescent properties, we required an un-
equivocal structure assignation. Hence, the synthesis was
carried out by heating a solution of two equivalents of for-
mylchromone (1a–d) and one equivalent of isocyanide
(2a–g) in tetrahydrofuran (THF). The reactions with alkyl
In a recent work,12 Teimouri reports an experimentally
simple reaction of 3-formylchromones with alkyl iso-
cyanides in anhydrous dichloromethane to allegedly give
furo[3,4-b]chromones (3). Interestingly, in a previous pa-
per, Bandyopadhyay and co-workers report virtually the
SYNLETT 2012, 23, 2227–2230
Advanced online publication: 24.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317032; Art ID: ST-2012-D0513-L
© Georg Thieme Verlag Stuttgart · New York

2228
A. G. Neo et al.
LETTER
isocyanides gave, in each case, a single new product (3a– analysis of the HSQC and 1H–13C HMBC spectra. This al-
j), which was isolated by column chromatography lowed us to easily assign all the 13C NMR signals except
(Scheme 1 and Table 1, entries 1–5 and 8–12).15,16 Unfor- signals at δ = 148.2 (s) and 143.9 (s) ppm, attributable to
tunately, when the reaction was performed with less reac- sp2 quaternary carbon atoms. A more detailed analysis of
tive aryl isocyanides, only starting materials were the HMBC spectrum permitted the connections of these
recovered. We then performed a careful spectroscopic two carbons with the other functional groups to be estab-
analysis of the product obtained from 6-methyl-3-formyl- lished. Thus, the signals at δ = 143.9 and 148.2 ppm must
chromone (1b) and pentyl isocyanide (2a). The resulting correspond, respectively, to an sp2 carbon directly at-
data (see below) led us to provisionally assign furo[3,4-b]- tached to C-9′ by a trisubstituted double bond, and to a
chromone structure 3f to this compound, in agreement carbon directly attached to the nitrogen by a double bond,
with Teimouri’s paper.12
i.e., an imine moiety (Figure 1).
The structure of compound 3f was therefore concluded by
linking the above mentioned sp2 quaternary carbons (C-1
and C-3) by an oxygen atom to form a five-membered het-
erocycle. Thus, the elucidated structure 3f is consistent
with a chromenylmethylene furo[3,4-b]chromenone, in
agreement with all the spectral data (Figure 1) and with
the structure proposed by Teimouri.
Table 1 Cycloaddition of Isocyanides with 3-Formylchromonesa
R1
6'
O
5'
7'
8'
4a'
4'
3'
8a'
THF
9'
O
1O'
2'
1a–d + 2a–g
R1
reflux
9
8
5
1
8a 9a
7
6
2
O
4a 3a
3
4
O
H
H
R2
N
H
H
3a–j
H
Entry Chromone R1
R2NC R2
Adduct Yield
(%)
H
O
δH 7.13
O
H
δC1 143.9
δC3 148.2
δC3a 152.6
δC9a 119.9
H
1
2
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
C5H11
3a
3b
3c
3d
55
O
1
3
NOE
O
H
9a
3a
H
H
c-C6H11
t-Bu
75
δH 3.72
H
N
H
H
O
H
3
54
H
H
H
H
H
4
PhCH2
56
H
H
H
H
10–30b
nrc
nrc
61
H
5
t-BuO2CCH2 3e
Figure 1 MM+ minimised geometry of compound 3f showing se-
lected 1H–13C HMBC (solid arrows) and NOESY (dashed arrow) cor-
relations
6
2,6-Me2C6H4
4-ClC6H4
C5H11
–
7
2g
2a
2b
2b
2d
2b
–
8
Me
Me
Cl
3f
3g
3h
3i
3j
On the other hand, although Teimouri claims the reaction
of isocyanides and 3-formylchromones is stereoselective,
and assigns the stereochemistry of the corresponding
products to be 1Z, he does not give any arguments that
support this assignation.12 All the spectroscopic data dis-
cussed above are, in principle, compatible with the four
possible geometric isomers of 7-methyl-1-[(4-oxo-4H-
chromen-3-yl)methylene]-3-(pentylimino)-1H-furo[3,4-
b]chromen-9(3H)-one. Thus, in order to elucidate the ac-
tual geometry of both C=C and C=N exocyclic double
bonds, we performed a NOESY experiment. The correla-
tion observed in the spectrum of 3f between the signals at
δ = 8.69 ppm (H-2′) and δ = 3.72 ppm (H-1′′, pentyl
group) defined the stereochemistry as 1Z,3Z. The resolved
structure of compound 3f is shown in Figure 1.
9
c-C6H11
c-C6H11
PhCH2
59
10
11
12
69
Cl
55
Br
c-C6H11
60
a Experimental procedure and representative data are given in the
references16,17 Yields correspond to the isolated pure products.
b Compound 3e decomposed in the reaction mixture, although it is sta-
ble in the solid form.
c nr: no reaction after heating to reflux for 24 h.
Mass spectroscopic analysis17 suggested that two mole-
cules of chromone 1b reacted with one molecule of isocy-
anide 2a with the loss of a molecule of water. This was
supported by the H NMR spectrum, which showed sig-
nals corresponding to both a 2,3-disubstituted 6-methyl-
To unambiguously confirm this structure, we also per-
formed a single crystal X-ray diffraction analysis of com-
pound 3a. Suitable crystals were obtained from a solution
of 3a in a mixture of hexanes and ethyl acetate. The re-
solved structure from X-ray diffraction data of one of
these crystals corresponds to (1Z,3Z)-1-[(4-oxo-4H-
chromen-3-yl)methylene]-3-(pentylimino)-1H-furo[3,4-
1
chromone and
a
3-substituted 6-methylchromone
(Figure 1). As these data could, in principle, be compati-
ble with both furo[3,4-b]chromone 3 and pyrano[3,4-
b]chromone 4 (Scheme 1), we carried out a systematic
Synlett 2012, 23, 2227–2230
© Georg Thieme Verlag Stuttgart · New York

LETTER
Furo[3,4-b]chromones from 3-Formylchromones and Isocyanides
2229
should also be revised. Hence, we carried out the hydroly-
sis of formylchromone 3a by treatment with conc. HCl in
ethanol. We found that the reaction is optimally per-
formed under microwave heating at 110 °C for just one
minute. Under these conditions, we could isolate a prod-
uct to which, on the basis of spectroscopic data and the
confirmed structure of the starting material, we assigned
the structure of pyrrolochromenone 10. Furthermore,
when the reaction was performed under milder conditions,
i.e., 10% HCl in refluxing ethanol, intermediate ketone 8
was cleanly obtained. A plausible mechanism for this
transformation involves the acidic hydrolysis of 3, fol-
lowed by recyclisation and dehydration to afford the final
pyrrolochromenone 10 (Scheme 3). Hence, the correct
structure of these hydrolysis products corresponds to 1,2-
dihydrochromeno[2,3-c]pyrrole-3,9-diones (10) and not
to 1H-chromeno[2,3-c]pyridine-1,5(2H)-diones (9), as
claimed by Bandyopadhyay.
Figure 2 ORTEP diagram of the structure of 3a obtained by X-ray
diffraction analysis18
b]chromen-9(3H)-one (Figure 2), which fully confirms
the previous spectroscopic assignation.18
As we anticipated, furochromones 3 were probably
formed by a [4+1]-cycloaddition reaction of 3-formyl-
chromone (1) and isocyanide (2) and subsequent reaction
of the resulting electron-rich aminofuran 6 with a second
molecule of formylchromone (1; Scheme 2). This mecha-
nism is consistent with the known instability of amino-
furans, as recently demonstrated by Quai and
collaborators,19 who reported their rapid oxidation by trip-
let oxygen. Here, aminofurochromenone 6 adds to the
very reactive aldehyde group of chromone (1) present in
the reaction medium, as also suggested by Teimouri.12 In
contrast, the mechanism proposed by Bandyopadhyay and
co-workers seems less likely.13 Particularly, transforma-
tion of the nitrilium intermediate either by deprotonation
to give a ketenimine, or by nucleophilic addition of an al-
dehyde is, in our view, rather improbable.
O
O
O
H2O
H+
O
O
O
O
O
– H2O
O
O
O
N
R
HN
3
R
O
8
O
N
O
O
O
O
O
O
not
N
R
R
O
O
10
9
O
O
O
Scheme 3 Proposed mechanism for the acid-catalysed transforma-
tion of furochromenones 3 into pyrrolochromenones 10
O
O
O
O
O
O
C
1
NR
RHN
1-Substituted-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-
diones have been identified through virtual screening
methods and biochemical testing as tyrosyl-DNA phos-
phodiesterase inhibitors,20 influenza virus endonuclease
inhibitors,21 Hsp90 inhibitors,22 and estrogen receptor li-
gands.23 Hence, the correct structural assignment of these
compounds is crucial for the development of new biolog-
ically active compounds.
5
6
RN
2
1
O
O
O
O
HO
O
O
O
– H2O
O
O
O
In summary, we have unequivocally assigned the struc-
ture of chromenylmethylene furo[3,4-b]chromenones (3)
to the products of the reaction of formylchromones (1)
and alkyl isocyanides (2). Accordingly, this reaction con-
stitutes a useful synthesis of natural-product-like furo[3,4-
b]chromenones. Furthermore, microwave-assisted hydro-
lysis of these furochromenones (3) affords a straightfor-
ward method for the synthesis of pharmacologically
relevant 1,2-dihydrochromeno[2,3-c]pyrrole-3,9-diones
(10).
N
N
R
R
3
7
Scheme 2 Proposed mechanism for the reaction of formylchro-
mones and isocyanides
Bandyopadhyay and co-workers report further transfor-
mations of the alleged pyrano[3,4-b]chromone (4) to lactam
analogues (9) of naturally occurring rotenoid 6-oxo-
dehydrodeguelin. Clearly, the structures of these products
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2227–2230

2230
A. G. Neo et al.
LETTER
Torroba, T. J. Heterocycl. Chem. 2000, 37, 1501. (i) Bossio,
R.; Marcaccini, S.; Pepino, R.; Marcos, C. F. J. Chem. Educ.
2000, 77, 382. (j) Bossio, R.; Marcos, C. F.; Marcaccini, S.;
Pepino, R. Synthesis 1997, 1389. (k) Bossio, R.; Marcos, C.
F.; Marcaccini, S.; Pepino, R. Heterocycles 1997, 45, 1589.
(l) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R.
Tetrahedron Lett. 1997, 38, 2519.
Acknowledgment
For financial support we thank the Instituto de Salud Carlos III
(PI081234), Junta de Extremadura and FEDER.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(15) (a) Díaz-Álvarez, J.; Carrillo, R. M.; Garrido, L.; Neo, A. G.;
Delgado, J.; Jover, A.; Marcaccini, S.; Marcos, C. F.; Book
of Abstracts, 16th European Symposium on Organic
Chemistry (ESOC 2009), Prague, Czech Republic, 2009;
170; ISBN: 978-80-02-02160-5. (b) Díaz-Álvarez, J.; Neo,
A. G.; Carrillo, R. M.; Garrido, L.; Delgado, J.; Marcos, C.
F.; Book of Abstracts, 1st Portuguese Young Chemist
Meeting (1stPYCheM), Lisbon, Portugal, 2008; 79.
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synlett and can be
cited using the following DOI:DyarmaPtirDayr
1
Chemyrtsi
(16) General procedure for the cycloaddition of formyl-
chromones and isocyanides: Isocyanide 2 (2.5 mmol) was
added to a solution of formyl chromone 1 (5 mmol) in
anhydrous THF (5 mL). The resulting solution was heated at
reflux under N2 for 5–8 h, and cooled to 0 °C. The precipitate
was collected by filtration. An additional amount of product
was recovered by concentration of the filtrate and
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Synlett 2012, 23, 2227–2230
© Georg Thieme Verlag Stuttgart · New York