One-pot approach to the synthesis of novel 12H-chromeno[2′,3′:4,5]imidazo[1,2-a]pyridines in aqueous media

Article abstract of DOI:10.1016/j.tet.2010.04.059

The chromeno-imidazo[1,2-a]pyridine scaffold was generated in an one pot condensation/cyclization reaction involving a salicylaldehyde and 1-(cyanomethyl)pyridinium chloride, in aqueous sodium carbonate solution. These novel compounds were isolated in 47-71% yield. The reaction pathway was followed by ¹H NMR spectroscopy allowing a clear understanding of the side reactions involved in the process. Different mono-substituted pyridinium chlorides were synthesized and reacted with mono-substituted salicylaldehydes and a detailed discussion of the scope of the synthetic method is also presented.

Full text of DOI:10.1016/j.tet.2010.04.059

Tetrahedron 66 (2010) 4542e4550
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Tetrahedron
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One-pot approach to the synthesis of novel 12H-chromeno[20,30:4,5]imidazo-
[1,2-a]pyridines in aqueous media
*
M. Fernanda Proença , Marta Costa
Department of Chemistry, University of Minho, Campos de Gualtar 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The chromeno-imidazo[1,2-a]pyridine scaffold was generated in an one pot condensation/cyclization
reaction involving a salicylaldehyde and 1-(cyanomethyl)pyridinium chloride, in aqueous sodium car-
bonate solution. These novel compounds were isolated in 47e71% yield. The reaction pathway was
followed by 1H NMR spectroscopy allowing a clear understanding of the side reactions involved in the
process.
Received 11 March 2010
Received in revised form 12 April 2010
Accepted 13 April 2010
Available online 24 April 2010
Different mono-substituted pyridinium chlorides were synthesized and reacted with mono-substituted
salicylaldehydes and a detailed discussion of the scope of the synthetic method is also presented.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Salicylaldehyde
Pyridinium chloride
Chromene
Imidazo[1,2-a]pyridine
Cascade reaction
1. Introduction
O
Chromene derivatives are an important class of compounds,
considering their diverse biological properties and therapeutic
applications.1 Structural modifications of this core unit led to
new drug candidates for the treatment of psychiatric and
neurological disorders, a research area of recent interest for our
research group. Substituted chromenes can bind to 5HT re-
ceptors, acting as antagonists,2 and were also reported as MAO
N
O
O
N
N
S
N
N
Zolimidine
Zolpidem
Figure 1. Representative examples of bioactive molecules containing the imidazo[1,2-
a]pyridine scaffold.
inhibitors3 and human
b
-secretase inhibitors.4 The imidazo
[1,2-a]pyridine nucleus is also an important scaffold in the
preparation of a diversity of biologically active compounds.
Molecules incorporating this core unit showed antibacterial,5
anti-inflammatory,6,7 analgesic,6,7 antipyretic,6 anticonvulsant,6
hypnoselective,8 and anxioselective8 activities. The antiulcer
agent zolimidine and the hypnotic drug zolpidem are bioactive
molecules already on the market (Fig. 1).
Different synthetic pathways have been used to prepare
substituted imidazo[1,2-a]pyridines, either from the imidazole or
from the pyridine nucleus.9 To the best of our knowledge, the
association of this moiety with the chromene unit has never been
reported. The combination of these two important scaffolds may
lead to new and alternative drug candidates with improved phar-
macological profile.
2. Results and discussion
Our previous studies on the synthesis of chromene derivatives
by the Knoevenagel condensation of salicylaldehydes with N-
substituted cyanoacetamides showed that the reaction occurs in
aqueous base, under mild conditions, leading to 2-imino and 2-oxo-
3-carboxamido-chromenes in excellent yield.10 The substituent in
position 3 of the chromene ring is a crucial element for biological
activity3d and the present work was initially aimed at the synthesis
of 2-imino and 2-oxo-chromenes bearing a good leaving-group in
the 3-position. The pyridinium ion was considered a good candi-
date and the commercially available 1-(cyanomethyl)pyridinium
chloride 1a was reacted with salicylaldehyde 2a using a similar
synthetic approach.
Compound 4a was expected as the major product, from the
Knoevenagel condensation of carbon acid 1 with the aldehyde,
* Corresponding author. Fax: þ351 253 604382; e-mail address:fproenca@
quimica.uminho.pt (M.F. Proença).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.059

M.F. Proença, M. Costa / Tetrahedron 66 (2010) 4542e4550
4543
followed by intramolecular cyclization of intermediate 3a, as is
represented in Scheme 1. When a 1.1:1 M ratio of reagents 1a and
2a were combined in an aqueous 0.05 M sodium carbonate solu-
tion, and stirred in a water bath at 60 ꢀC for 16 h, the solid that
precipitated from the reaction mixture was fully characterized and
identified as the tetracyclic product 6a (Scheme 1). In aqueous base,
the reaction of 4a proceeds with nucleophilic attack of the imine
nitrogen to C-2 of the activated pyridinium ring. The neutral species
5a rapidly tautomerizes to the isolated product 6a.
Nucleophilic attack of a primary amine to C-2 of a N-aryl pyr-
idinium salt, known as the Zincke reaction11 leads to ring opening
of the pyridinium moiety followed by ring closure to generate
a new pyridinium salt incorporating the primary amine.12 In this
work, the unprecedented evolution of the N-heteroaryl pyridinium
chloride is primarily due to the presence of a nucleophilic imino
nitrogen in the chromene moiety, conveniently located in the
vicinity of the pyridinium ring. The evolution of intermediate 5a to
generate the stable tautomer 6a was considered a key feature for
the success of this cascade reaction. The aldehyde was combined
with the pyridinium salt under different temperature conditions
(rt, 60 and 80 ꢀC) using aqueous 0.05 M sodium carbonate or
sodium hydrogen carbonate solution and varying the reaction time.
Compound 6a was always the only product isolated in a yield that
never exceeded 62% (Table 1).
O
O
H
N
N
H
H
+
N
Cl
CN
- H2O
C
O
OCH3
OH
OCH3
O
Na
OCH3
3a(B)
2a(A)
2a(B)
1a
Table 1
Synthesis of substituted 1-(cyanomethyl)pyridinium chlorides 1
Cl
H
H
Compd
Reaction conditions
Yield (%)
N
N
N
N
N
1a
1b
1c
10aþ11 (2 equiv), CH3CN, reflux, 7.5 h
10bþ11 (2 equiv), CH3CN, reflux, 7 h
10cþ11 (1 equiv), rt, 1 day
85a
95a
5
A)
- HCl
H
O
OCH3
O
OCH3
4a
O
OCH3
6a
NH
10cþbromoacetonitrile (1 equiv) rt, 17.5 h
10dþ11 (2 equiv), CH3CN, reflux, 1.5 h
10eþ11 (2 equiv), CH3CN, reflux, 40 min
10fþ11 (3.2 equiv), CH3CN, reflux, 6 h
10gþ11 (4.5 equiv), CH3CN, reflux, 3 days
10hþ11 (4 equiv), CH3CN, reflux, 1 day
10cþ11 (6.2 equiv), CH3CN, reflux, 3 days
58b
93
95
92c
77
77
89
1d
1e
1f
1g
1h
1i
5a
Cl
Cl
H
H
H
N
N
N
O
N
CONH2
B)
a
Cl
Commercially available.
Isolated as the bromide salt.
Ref. 13.
C
b
c
OH
OCH3
3a(A)
-NH3
O
OCH3
8a
OH
OCH3
7a
H
Although the reaction of salicylaldehyde 2a with the pyridinium
N
chloride 1a in aqueous sodium carbonate proceeds directly to the
tetracyclic product 6, the use of ethanol/acetone (1:3 volume ratio)
and one molar equivalent of N-methylpiperazine allowed the
isolation of the intermediate 2-iminochromene 4a. The product
precipitated from solution and was isolated in 78% yield after
30 min in an ice bath. A similar synthetic approach was used to
prepare compounds 4bed, isolated in 45e86% yield and fully
characterized. When 4a was solubilized in aqueous 0.05 M sodium
hydrogen carbonate, and the mixture was stirred at 60 ꢀC for 5 h,
the same product 6a was isolated in 54% yield, supporting the
proposed reaction pathway.
COO
OH
OCH3
9a
Scheme 1. Proposed mechanism for the reaction of 1-(cyanomethyl)pyridinium
chloride 1a with 3-methoxysalicylaldehyde 2a. (A) Intramolecular cyclization by nu-
cleophilic substitution on the pyridinium ring. (B) Hydrolysis of the cyano group due to
a prolonged contact with the aqueous basic medium.
The 1H NMR spectrum of this compound showed a singlet at
4.28 ppm integrating for two protons assigned to C-11
22.4 ppm). The HMBC and HMQC spectra confirmed the
This reaction was also followed by 1H NMR, at room tempera-
ture. Salicylaldehyde 2a, pyridinium salt 1a and sodium carbonate
were combined in D2O, inside the NMR tube. The first spectrum,
registered immediately after addition of the solvent, shows that
2-iminochromene 4a is the only new compound present in solution
(34%) besides the aldehyde (26%) and the pyridinium chloride
d
(
d
neighboring carbon atoms through the two- three- and four-
bonds correlations (Fig. 2). A doublet at 8.31 ppm, assigned to
the proton on C-10 ( 124.6 ppm), allowed the identification of
C-10b ( 98.5 ppm), C-6a ( 139.0 ppm), C-7 ( 114.9 ppm), C-8
125.0 ppm), and C-9 ( 112.8 ppm). Elemental analysis con-
d
d
d
d
d
(
d
d
(40%). The aldehyde proton, around
d 9.9 ppm, confirms the pres-
firmed the empirical formula and IR spectroscopy showed the
absence of OH/NH signals, supporting the novel structure
assigned to the compound.
ence of this functional group, but the aromatic protons are
considerably shifted to higher field. This indicates that the shielding
effect of the electron-donating oxygen atom is enhanced by the
formation of the anion (2a(B)). The chemical shift of the adjacent
methoxyl group is also affected, shifting from
d 3.89 ppm (in the
phenolic aldehyde) to 3.69 ppm. The concentration of compound
d
H
10
N
4a gradually increases in solution. This study indicates that only
part of the iminochromene 4a evolves to 6a. The presence of base
facilitates ring opening to generate the anion 3a(B) or the corre-
sponding phenolic species 3a(A), where the cyano group is
susceptible to hydrolysis (Scheme 1). The extent of this process
increases with time and temperature and a delicate balance is
required to optimize the yield of the chromeno-imidazo[1,2-a]
pyridine 6.
H
H
2
3
11
7
N
O
OCH3
4
Figure 2. Structural information obtained by NMR correlation studies (HMBC and
HMQC) on a DMSO-d6 solution of compound 6a.

4544
M.F. Proença, M. Costa / Tetrahedron 66 (2010) 4542e4550
After approximately 2 h at room temperature, traces of a com-
R
O
R
pound identified as 7a were detected in solution. The signals for 6a
were always absent in the spectrum, as this compound is com-
pletely insoluble in water and gradually precipitates from solution.
The solid suspension was not visible during the first eight hours at
room temperature. After 12 days, no noticeable evolution was
detected in the reaction mixture and the solid was separated from
solution. Both crops were studied by 1H and 13C NMR using
correlation techniques (HMBC and HMQC). The major product in
solution was compound 7a, generated by hydrolysis of the cyano
group due to a long contact with aqueous base. The solid, solubi-
lized in deuterated DMSO, was a mixture of compounds 6a and 9a
(1:1.6 M ratio).
Cl
CN
H
+
N
11
Cl
CN
N
OH
R1
10a
, R=H
1a, R=H
1b
2a
, R1=3-OCH3
10b, R=3-CONH2
10c
, R=3-CONH2
2b, R1=H
, R=3-COOCH3
1c
, R=3-COOCH3
2c
, R1=3-OH
10d, R=3-NH2
1d, R=3-NH2
2d, R1=5-OCH3
2e, R1=5-Cl
10e, R=4-NH2
1e
, R=4-NH2
10f
, R=4-CH3
1f, R=4-CH3
10g, R=4-CONH2
10h
1g
, R=4-CONH2
, R=4-NHCOOCH2CH3
1h
, R=4-NHCOOCH2CH3
10i, R=4-CONH(CH2)2OH
1i, R=4-CONH(CH2)2OH
Compound 8a was always isolated from the mother liquor, in
the synthesis of compound 6a, and probably arises from intra-
molecular cyclization of 7a, with elimination of ammonia, also
identified in the NMR spectrum. Compound 8a could be gener-
ated directly from 4a in ethanol and aqueous HCl solution. The
product precipitated from solution and was isolated in 64% yield
after two days at room temperature and a further four days
standing at 0 ꢀC.
Other substituted pyridines were converted to N-cyanomethyl
pyridinium chlorides 1bei upon reaction with chloroacetonitrile
(Table 1). The reaction usually requires reflux conditions in aceto-
nitrile and the use of an excess of alkyl halide (2e6.2 M equiv).
Pyridine 10c (R¼3-COOCH3) is unstable at temperatures above
40 ꢀC, and the neat liquid reagents were combined at room tem-
perature. The reaction was very slow, and only 5% of the solid
product was isolated after one day. The use of bromoacetonitrile
under similar experimental conditions (neat mixture, at room
temperature) led to the corresponding pyridinium bromide in 58%
yield.
R
Cl
H
R
N
N
N
O
R1
NH
O
R1
6a, R=H, R1=4-OCH3
4a, R=H, R1=8-OCH3
4b, R=H, R1=H
6b
, R=H, R1=H
6c
, R=H, R1=4-OH
4c
, R=H, R1=8-OH
6d, R=H, R1=2-OCH3
4d, R=H, R1=6-OCH3
6e
, R=H, R1=2-Cl
6f, R=(7/9)-CONH2, R1=4-OCH3
6g
, R=(7/9)-CONH2, R1=H
6h
, R=(7/9)-CONH2, R1=4-OH
6i, R=(7/9)-CONH2, R1=2-OCH3
6j
, R=4-CONH2, R1=4-OCH3
6k, R=4-CONH(CH2)2OH, R1=4-OCH3
Scheme 2. Reaction sequence for the preparation of chromeno-imidazo[1,2-a]pyri-
dines 6.
Aldehydes 2bed were reacted with the pyridinium salt 1b, 1g,
and 1i under similar reaction conditions as those used for the
preparation of compound 6a (Table 2).
O
O
Cl
+
NC
N
H
N
H
H
O
N
Cl
Cl
Cl
CN
OH
Table 2
O
H
O
H
Synthesis of chromeno-imidazo[1,2-a]pyridines 6
1a
2e
3e
9e
Compd
Reaction conditionsa
Yield (%)
Scheme 3. Proposed mechanism for the formation of compound 9e.
6a
6b
6c
6d
6e
6f
6g
6h
6i
2aþ1a (1.1 equiv), 60 ꢀC, 16 h
62
49
58
47
2bþ1a (1.1 equiv), 80 ꢀC, 7 h
2cþ1a (1.1 equiv), 80 ꢀC, 14.5 h
2dþ1a (1.1 equiv), 80 ꢀC, 13.5 h and 60 ꢀC 19 h
2eþ1a (1.1 equiv), reflux, 1 h 40 min
2aþ1b (1 equiv), 60 ꢀC, 16 h
The reaction was repeated using reflux conditions, leading to
compound 6e (50%) after 1 h 40 min. Prolonged heating in aqueous
base leads to hydrolysis of the cyano group in intermediate 3e,
preventing intramolecular cyclization to 4e. The formation of
a carboxylate function and the vicinity of the acidic proton to the
chlorine atom on C-5 of the aromatic ring constitute a plausible
driving force for nucleophilic substitution of the halogen, under the
experimental conditions that were used (Scheme 3).
The new pyridinium chlorides prepared, with electron donating
(NH2, NHCOOCH2CH3, CH3) and electron withdrawing (CONH2,
COOCH3, CONH(CH2)2OH) substituents in the 3- and 4- position
of the heteroaromatic ring, were reacted with 3-methoxy-
salicylaldehyde 2a. Compounds 1b, 1g, and 1i were combined with
2a in aqueous base and heated at 60 ꢀC for 16e19 h leading to the
corresponding chromeno-imidazo[1,2-a]pyridines 6f, 6j, and 6k in
55e67% yield (Table 2). The 3-substituted pyridinium chloride 1b
generated a mixture of isomers 6f(A) and 6f(B) in a 1:1.9 M ratio, by
1H NMR (Fig. 3). This indicates that the steric hindrance of the
carbamoyl substituent has a moderate effect on the final cyclization
step, resulting from nucleophilic attack of the imine nitrogen to the
pyridinium ring.
50b
55c
61c
71c
52c
67
2bþ1b (1.1 equiv), 60 ꢀC, 16 h
2cþ1b (1.1 equiv), 60 ꢀC, 16 h
2dþ1b (1.1 equiv), 60 ꢀC, 16 h
2aþ1g (1.1 equiv), 60 ꢀC, 19 h
2aþ1i (1.1 equiv), 60 ꢀC, 19 h
6j
6k
58
a
All reactions were carried out in aqueous 0.05 M Na2CO3 or NaHCO3 solution.
The product was slightly contaminated with 9e.
Yield of the isolated mixture of 6fei(A) and 6fei(B) (approximately 1:1.6 ratio
b
c
by 1H NMR).
The corresponding chromeno-imidazo[1,2-a]pyridines 6 were
isolated after 24e29 h at room temperature (6bed and f) or in
a water bath (60/80 ꢀC) for 7e19 h (6bek). The yellow solid pre-
cipitates from the reaction medium on cooling and requires no
further purification (Scheme 2).
The low solubility of aldehyde 2e (R¼5-Cl) in aqueous base, at
room temperature, resulted in a very slow reaction with 1a. The
suspension was heated at 40 ꢀC for 11 h, followed by 18 h at 80 ꢀC,
leading to a solid product identified as a mixture of 6e and 9e (1:1.3
ratio by 1H NMR) (Scheme 3). A second crop was isolated, corre-
sponding to the pure compound 9e (23%).
Attempts to improve selectivity by performing the reaction at
room temperature (17.5 h) led to a similar isomer ratio by 1H NMR
(6f(A)/6f(B), 1:1.5). These two compounds could be separated using

M.F. Proença, M. Costa / Tetrahedron 66 (2010) 4542e4550
4545
the hydrochloride salt 14 (86%). Addition of concentrated HCl
(3 M equiv) at room temperature resulted in hydrolysis of the imine
to generate the 2-oxochromene 15 (83%). The tetracyclic product 6l
was isolated in 41% yield after refluxing the reagents in water for
2 h. Compound 16 (13%) was collected from the mother liquor, after
a further 9 h of reflux.
O
NH2
N
N
N
N
O
O
OCH3
O
H2N
OCH3
6f (B)
6f (A)
3. Conclusions
Figure 3. Isomers formed in the reaction of 1-(cyanomethyl)pyridinium chloride 1b
with 3-methoxysalicylaldehyde 2a.
In conclusion, we developed an environmentally benign one-
pot procedure for the synthesis of 12H-chromeno[20,30:4,5]imi-
dazo[1,2-a]pyridines 6, through an unprecedented cascade con-
preparative chromatography and a mixture of dichloromethane
and ethanol (9:1 ratio) as eluent.
No further reactions were carried out using 3-substituted pyr-
idinium salts due to the absence of selectivity in the formation of
the tetracyclic product.
Reaction of salicylaldehyde 2a with pyridinium salt 1f (R¼4-
CH3) in aqueous solution resulted in extensive degradation, with
the formation of dark polymeric materials and was not investigated
further.
The reaction of pyridinium salt 1e (R¼4-NH2) with salicylalde-
hydes 2aec (Scheme 4), led to the formation of imino-chromenes
12aec, insoluble in aqueous base at room temperature.
densation/cyclisation approach from
a salicylaldehyde and
1-(cyanomethyl)pyridinium chloride. The products are isolated
in a high purity form by simple filtration from the aqueous
solution. Following the reaction by 1H NMR allowed a clear
understanding of the major pathway and of the side-reactions
that are responsible for a product yield that never exceeded 70%.
4-Substituted pyridinium chlorides were also used in this
reaction. The presence of an amine substituent prevents the
imidazo-pyridine formation, as the positive charge of the imino-
chromene intermediate is preferentially transferred to the exo-
cyclic nitrogen atom. The presence of an acidic NeH in the
4-position of the pyridinium chloride moiety was also a source of
alternative pathways, but refluxing the reagents in water proved
to be the appropriate medium for the formation of the tetracyclic
product. 3-Substituted pyridinium chlorides present no such
problems, but no selectivity was achieved in the final intra-
molecular cyclization step. A mixture of two isomeric tetracyclic
products was formed, but they can easily be separated by chro-
matographic techniques. 12H-Chromeno[20,30:4,5]imidazo[1,2-a]
pyridines 6, prepared in aqueous base from simple starting
materials, can be considered important new scaffolds for the
preparation of biologically significant molecules.
NH2
NH2
Cl
O
H
O
N
Na2CO3 aq (0.05M)
rt
H
+
N
Cl
CN
, R=4-NH2
OH
NH
R1
R1
1e
2a, R1=3-OCH3
12a, R1=8-OCH3, 100%
2b
12b
, R1=H
, R1=H, 65%
12c, R1=8-OH, 32%
2c, R1=3-OH
Scheme 4. Reaction of 4-amino-1-(cyanomethyl)pyridinium chloride 1e with salicy-
laldehydes 2aec.
Under these experimental conditions, intramolecular cycliza-
tion was never observed. The formation of isomer 12 was associ-
ated with the basicity of the amino substituent in the 4-position of
the pyridine moiety. Protection of the amino group as a carbamate
and synthesis of the corresponding pyridinium chloride 1h allowed
studies on the reaction with salicylaldehyde 2a, in aqueous media
(Scheme 5).
4. Experimental section
4.1. General
All compounds were fully characterized by elemental analysis
and spectroscopic data. The NMR spectra were recorded at room
temperature, on a Varian Unity Plus (1H: 300 MHz, 13C: 75 MHz)
and Bruker Avance 3400 (1H: 400 MHz, 13C: 100 MHz), including
the 1He13C correlation spectra (HMQC and HMBC) and deuter-
ated DMSO was used as solvent. The peak patterns are indicated
as follows: s, singlet; d, doublet; t, triplet; m, multiplet; q, quartet
and br, broad. The coupling constants, J, are reported in hertz
(Hz). IR spectra were recorded on a FT-IR Bomem MB 104 using
Nujol mulls and NaCl cells. The reactions were monitored by thin
layer chromatography (TLC) using silica gel 60 F254 (Merck). The
melting points were determined on a Stuart SMP3 melting point
apparatus and are uncorrected. Elemental analysis were per-
formed on a LECO CHNS-932 instrument. High resolution mass
spectra (HRMS) were obtained from the C.A.C.T.I.dUniversidade
de Vigo.
NH
NH2
Cl
N
O
N
N
O
H2O
Reflux, 2 h
Mother-liquor
Reflux, 9 h
O
O
OCH3
O
OCH3
O
6l, 41%
16, 13%
HN
O
N
CHO
N
O
+
O
N
Na2CO3 aq (0.05M)
60 ºC, 7 min
OH
OCH3
2a
NH
O
OCH3
Cl
CN
1h
13, 93%
Cl
Cl
NH
H2O
60 ºC, 1 h
NH
N
N
O
O
O
O
H2O, HCl
rt, 2.5 h
O
NH
O
OCH3
O
OCH3
15, 83%
14, 86%
4.2. General procedure for the synthesis of 1-(cyanomethyl)
pyridinium chlorides 1
Scheme 5. Isomers formed in the reaction of pyridinium chloride 1h with 3-me-
thoxysalicylaldehyde 2a.
2-Chloroacetonitrile 11 (5.0e31.0 mmol) was added to a solu-
tion of pyridine 10 (5.0 mmol) in acetonitrile (6 mL) and the
reaction mixture was refluxed (40 min to 3 days). After a few
minutes the solid started to precipitate from solution. The solid was
filtered and washed with acetonitrile leading to the pure product 1.
In aqueous base (Na2CO3, 0.05 M), product 13 was isolated in
93% yield after 7 min at 60 ꢀC. When the reagents were combined in
water, at 60 ꢀC, the same 2-iminochromene was formed, isolated as

4546
M.F. Proença, M. Costa / Tetrahedron 66 (2010) 4542e4550
4.2.1. 1-(Cyanomethyl)pyridinium chloride (1a). Brown solid. 1H
NMR (300 MHz, DMSO-d6):
2H), 8.73 (td, J¼1.5, 1.2 Hz, 1H), 9.24 (d, J¼6.2, 2H) ppm.
(t, J¼6.9 Hz, 3H), 4.24 (q, J¼7.2 Hz, 2H), 5.90 (s, 2H), 8.08
(d, J¼7.5 Hz, 2H), 8.90 (d, J¼7.8 Hz, 2H), 11.86 (s, 1H) ppm; 13C NMR
d
6.07 (s, 2H), 8.26 (td, J¼6.9, 1.8 Hz,
(75 MHz, DMSO-d6) d 14.1, 45.6, 62.3, 114.2 (2C), 114.8, 145.4 (2C),
154.3, 152.7 ppm; IR (Nujol mull):
n 3470e1800 (br, fringed), 1743,
4.2.2. 3-Carbamoyl-1-(cyanomethyl)pyridinium chloride (1b). Yel-
1638, 1590, 1532, 1519, 1467 cmꢁ1. Anal. Calcd for C10H12N3O2Cl: C,
49.67; H, 4.97; N, 17.39, found: C, 49.40; H, 5.10; N, 17.38.
low solid: 1H NMR (300 MHz, DMSO-d6):
d 6.10 (s, 2H), 8.22 (s, 1H),
8.36 (t, J¼7.2 Hz, 1H), 8.86 (s, 1H), 9.17 (d, J¼8.1 Hz, 1H), 9.36 (d,
J¼6.6 Hz, 1H), 9.73 (s, 1H) ppm.
4.2.9. 1-(Cyanomethyl)-4-(2-hydroxyethylcarbamoyl)pyridinium
chloride (1i). Yellow solid. Mp 211e213 ꢀC; 1H NMR (300 MHz,
4.2.3. 1-(Cyanomethyl)-3-(methoxycarbonyl)pyridinium bromide
DMSO-d6):
d
3.38 (q, J¼5.7 Hz, 2H), 3.56 (t, J¼6.3 Hz, 2H), 3.60e4.80
(1c). Yellow solid. Mp 146e148 ꢀC; 1H NMR (300 MHz, DMSO-d6):
(br s, 1H), 6.14 (s, 2H), 8.63 (d, J¼6.6 Hz, 2H), 9.40 (d, J¼6.9 Hz, 2H),
d
3.99 (s, 3H), 6.12 (s, 2H), 8.40 (td, J¼6.9, 1.5 Hz, 1H), 9.10 (dt, J¼8.1,
9.67 (t, J¼5.4 Hz, 1H) ppm; 13C NMR (75 MHz, DMSO-d6):
d 43.0,
2.1 Hz, 1H), 9.45 (dt, J¼6.0, 1.5 Hz, 1H), 9.78 (t, J¼1.5 Hz, 1H); 13C
47.6, 59.1, 114.2, 126.3 (2C), 146.4 (2C), 149.7, 161.6 ppm; IR (Nujol
NMR (75 MHz, DMSO-d6):
d
47.9, 53.7, 114.1, 128.8, 129.9, 146.97,
mull): n 3310e1740 (br, fringed), 1662, 1606, 1550, 1462, 1409, 1330,
147.04, 148.5, 161.8 ppm; IR (Nujol mull):
n
3500e1800 (br, fringed),
1313, 1283, 1236, 1223, 1154, 1094, 1055, 1040, 1002 cmꢁ1. Anal.
Calcd for C10H11N3O2Cl: C, 49.69; H, 4.97; N, 17.39, found: C, 49.34;
H, 4.96; N, 17.60.
1749,1730, 1691, 1641, 1588, 1498, 1463, 1443, 1411, 1400 cmꢁ1. Anal.
Calcd for C9H9N2O2Br$0.2H2O: C, 41.44; H, 3.61; N, 10.74, found: C,
41.45; H, 3.53; N, 10.80.
4.3. General procedure for the synthesis of 1-(2-Imino-2H-
4.2.4. 3-Amino-1-(cyanomethyl)pyridinium chloride (1d). White
chromen-3-yl)pyridinium chlorides 4
solid. Mp 163e165 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
6.04 (s, 2H);
7.16 (s, 2H); 7.72e7.80 (m, 2H); 8.28e8.32 (m, 2H) ppm; 13C NMR
(75 MHz, DMSO-d6): 47.2, 114.6, 127.8, 128.3, 128.8, 131.4,
1-(Cyanomethyl)pyridinium chloride 1 (1.0 mmol) was added to
a yellow solution of salicylaldehyde 2 (1.0 mmol) and 1-methyl-
piperazine (0.90 mmol) in EtOH/acetone (0.4 mL:1.2 mL). The
reaction mixture was stirred in an ice bath (30 min to 1 h). A solid
started to precipitate after 15 min. The solid was filtered and
washed with acetone leading to the pure product 4.
d
149.2 ppm; IR (Nujol mull):
n 3500e1700 (br, fringed), 1640, 1618,
1585, 1502, 1459 cmꢁ1. Anal. Calcd for C7H8N3Cl$0.2H2O: C, 48.53;
H, 4.85; N, 24.26, found: C, 48.42; H, 4.74; N, 24.39.
4.2.5. 4-Amino-1-(cyanomethyl)pyridinium chloride (1e). Yellow
solid. Mp 270e272 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
5.59 (s, 2H),
4.3.1. 1-(2-Imino-8-methoxy-2H-chromen-3-yl)pyridinium chloride
6.98 (d, J¼7.5 Hz, 2H), 8.29 (d, J¼7.5 Hz, 2H), 8.86 (s, 2H) ppm; 13C
(4a). Yellow solid, 78%. Mp 132e134 ꢀC; 1H NMR (300 MHz,
NMR (75 MHz, DMSO-d6):
d
n
43.8, 109.7 (2C), 115.4, 142.8 (2C),
DMSO-d6):
d
3.91 (s, 3H), 7.21 (dd, J¼7.8, 2.1 Hz, 1H), 7.27 (t,
159.4 ppm; IR (Nujol mull):
3500e1800 (br, fringed), 1727, 1706,
J¼7.8 Hz, 1H), 7.36 (dd, J¼7.8, 1.8 Hz, 1H), 8.23 (s, 1H), 8.34 (td,
J¼7.5, 0.9 Hz, 2H), 8.82 (td, J¼7.5, 1.8 Hz, 1H), 9.12 (s, 1H), 9.30
1667, 1644, 1544, 1519, 1463, 1410 cmꢁ1. Anal. Calcd for C7H8N3Cl: C,
49.56; H, 4.72; N, 24.78, found: C, 49.48; H, 4.75; N, 24.86.
(dd, J¼6.8, 1.2 Hz, 2H) ppm; 13C NMR (75 MHz, DMSO-d6):
d 56.2,
115.8, 118.2, 120.8, 124.5, 127.8 (2C), 131.1, 134.3, 142.4, 146.1 (2C),
4.2.6. 1-(Cyanomethyl)-4-methylpyridinium chloride (1f). Brown
146.2, 148.0, 151.0 ppm; IR (Nujol mull): n 3600e1700 (br,
solid. 1H NMR (300 MHz, DMSO-d6):
d
2.64 (s, 3H), 6.02 (s, 2H), 8.08
fringed), 1663, 1626, 1605, 1580, 1482 cmꢁ1. Anal. Calcd for
C15H13N2O2Cl.H2O.0.2NH4Cl: C, 56.74; H, 4.98; N, 9.71, found: C,
57.10; H, 4.98; N, 9.79.
(d, J¼6.6 Hz, 2H), 9.09 (d, J¼6.9 Hz, 2H).
4.2.7. 4-Carbamoyl-1-(cyanomethyl)pyridinium chloride (1g). Yel-
low solid. Mp 218e220 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
6.24
4.3.2. 1-(2-Imino-2H-chromen-3-yl)pyridinium chloride (4b). Yel-
low solid, 45%. Mp 251e253 ꢀC; 1H NMR (400 MHz, DMSO-d6):
(s, 2H), 8.35 (s, 1H), 8.62 (d, J¼7.2 Hz, 2H), 9.06 (s, 1H), 9.46
(d, J¼7.2 Hz, 2H) ppm; 13C NMR (75 MHz, DMSO-d6):
d
47.5, 114.2,
d
7.30e7.35 (m, 2H), 7.63 (td, J¼6, 1.6 Hz, 1H), 7.68 (dd, J¼7.6, 1.6 Hz
126.4 (2C), 146.5 (2C), 149.7, 163.1 ppm; IR (Nujol mull):
n
1H), 8.28 (s, 1H), 8.35 (td, J¼6.4, 1.6 Hz, 2H), 8.83 (tt, J¼7.6, 1.6 Hz,
3400e1800 (br, fringed), 1693, 1675, 1627, 1568, 1459, 1422 cmꢁ1
.
1H), 9.02 (br s, 1H), 9.32 (dt, J¼5.6, 1.6 Hz, 2H) ppm; 13C NMR
Anal. Calcd for C8H8N3OCl.0.3H2O contaminated with 5% of
C6H7N2OCl: C, 47.16; H, 4.25; N, 20.54, found: C, 47.43; H, 4.04; N,
20.14.
(100 MHz, DMSO-d6): d 115.4, 117.6, 124.5, 127.8 (2C), 129.8, 130.9,
133.2, 134.2, 146.1 (2C), 148.0, 151.5, 153.2 ppm; IR (Nujol mull):
n
3600e1700 (br, fringed), 1673, 1620, 1600, 1568, 1462 cmꢁ1. Anal.
Calcd for C14H12N2OCl$1.2H2O.0.2NH4Cl: C, 57.77; H, 4.88; N, 10.59,
found: C, 57.77; H, 4.69; N, 10.50.
4.2.8. 1-(Cyanomethyl)-4-(ethoxycarbonylamino)pyridinium chloride
(1h). Protection of the amino group in 4-amino-1-(cyanomethyl)
pyridinium chloride 1e was carried out in two steps. First, ethyl
4.3.3. 1-(8-Hydroxy-2-imino-2H-chromen-3-yl)pyridinium chloride
chloroformate (0.80 g, 7.41 mmol, 720
m
L) and DBU (0.94 g,
(4c). Yellow solid, 86%. Mp 242e244 ꢀC; 1H NMR (400 MHz, DMSO-
6.16 mmol, 930 L) were added to a solution of pyridin-4-amine
m
d6):
d
7.05 (dd, J¼7.6, 1.6 Hz, 1H), 7.11 (t, J¼7.6 Hz, 1H), 7.27
(0.58 g, 6.17 mmol) in acetonitrile (3 mL). The reaction mixture was
refluxed for 1 h and then the solvent was removed under reduced
pressure. The reaction mixture was purified by flash chromatog-
raphy, using dichloromethane (15 mLþ10 mL) as eluent. The yellow
solution was concentrated to dryness under reduced pressure and
then acetonitrile (4 mL) was added to the oil. 2-Chloroacetonitrile
(dd, J¼8.0, 1.6 Hz 1H), 8.19 (s, 1H), 8.33 (td, J¼6.4, 1.6 Hz, 2H), 8.82
(tt, J¼7.6, 1.6 Hz, 1H), 8.87 (s, 1H), 9.30 (dt, J¼6.0, 1.6 Hz, 2H), 10.59
(s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
d 118.4, 119.4, 119.7,
124.3, 127.7 (2C), 130.9, 134.6, 141.6, 144.6, 146.2 (2C), 147.9,
151.5 ppm; IR (Nujol mull): 3500e1700 (br, fringed), 1665, 1628,
1615, 1580, 1519, 1480, 1466 cmꢁ1
Anal. Calcd for
n
.
11 (1.86 g, 24.70 mmol, 1600
m
L) was added to the solution and the
C14H11N2O2Cl.0.75H2O.0.1NH4Cl: C, 57.27; H, 4.40; N, 10.02, found:
C, 56.93; H, 4.62; N, 10.00.
reaction mixture was refluxed for 1 day and then concentrated
under reduced pressure and kept at 0 ꢀC for 2 days. A white solid
started to precipitate from solution. The solid was filtered and
washed with acetonitrile leading to the pure product 1h (1.14 g,
4.3.4. 1-(2-Imino-6-methoxy-2H-chromen-3-yl)pyridinium chloride
(4d). Yellow solid, 46%. Mp 177e179 ꢀC; 1H NMR (400 MHz, DMSO-
4.71 mmol). Mp 186e188 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
1.27
d6):
d
3.80 (s, 3H), 7.21 (dd, J¼9.0, 2.8 Hz, 1H), 7.24 (d, J¼2.8 Hz, 1H),

M.F. Proença, M. Costa / Tetrahedron 66 (2010) 4542e4550
4547
7.27 (d, J¼8.8 Hz, 1H), 8.21 (s, 1H), 8.34 (td, J¼6.6, 1.6 Hz, 2H), 8.83
(tt, J¼7.6, 1.6 Hz, 1H), 8.91 (s, 1H), 9.31 (dd, J¼6.8, 1.6 Hz, 2H) ppm;
13C NMR (100 MHz, DMSO-d6):
55.8, 112.7, 116.5, 118.1, 119.6, 127.8
(2C), 131.3, 134.1, 146.1 (2C), 147.5, 148.0, 151.8, 155.4 ppm; IR (Nujol
(75 MHz, DMSO-d6):
d
22.4, 97.7, 112.2, 115.6, 119.3, 120.7, 124.1,
124.3, 127.1, 128.0, 130.1, 139.9, 150.1, 150.8 ppm; IR (Nujol mull):
n
d
1648, 1630, 1603, 1566, 1504, 1465, 1434 cmꢁ1. Anal. Calcd for
C14H9N2OCl.0.8H2O: C, 62.02; H, 3.91; N, 10.34, found: C, 62.02; H,
3.57; N, 10.20.
mull):
n 3600e1700 (br, fringed), 1667, 1627, 1581, 1493, 1460,
1432 cmꢁ1. Anal. Calcd for C15H13N2O2Cl.2H2O$0.2NH4Cl: C, 53.70;
H, 5.31; N, 9.19, found: C, 53.77; H, 5.34; N, 9.12.
4.4.6. 4-Methoxy-12H-chromeno[20,30:4,5]imidazo[1,2-a]pyridine-7-
carboxamide (6f(A)). Yellow solid. 1H NMR (400 MHz, DMSO-d6):
4.4. General procedure for the synthesis of 12H-chromeno
[20,30:4,5]imidazo[1,2-a]pyridines 6
d
3.86 (s, 3H), 4.34 (s, 2H), 6.95 (d, J¼7.6 Hz, 1H), 7.02 (d, J¼7.6 Hz,
1H), 7.11 (t, J¼8.0 Hz,1H), 7.19 (t, J¼6.8 Hz,1H), 7.98 (s,1H), 8.02 (dd,
J¼7.4, 1.2 Hz, 1H), 8.50 (dd, J¼5.4, 1.2 Hz, 1H), 9.02 (s, 1H) ppm; 13C
1-(Cyanomethyl)pyridinium chloride 1 (0.81 mmol) was added
to a yellow solution of salicylaldehyde 2 (0.75 mmol) in aqueous
Na2CO3 (0.05 M, 2 mL) or NaHCO3 (0.05 M, 2 mL). The reaction
mixture was stirred at 60/80 ꢀC (1 h and 40 min to 19 h). A solid
started to precipitate after a few minutes. The suspension was
cooled to room temperature in an ice bath and the yellow solid was
filtered and washed with water leading to the pure product 6.
NMR (100 MHz, DMSO-d6): d 22.50, 55.82, 99.18, 110.92, 111.94,
119.00, 119.19, 121.71, 123.70, 126.70, 127.52, 138.06, 140.57, 148.45,
150.21, 163.72 ppm.
4.4.7. 4-Methoxy-12H-chromeno[20,30:4,5]imidazo[1,2-a]pyridine-9-
carboxamide (6f(B)). Yellow solid. 1H NMR (400 MHz, DMSO-d6):
d
3.86 (s, 3H), 4.34 (s, 2H), 6.95 (d, J¼7.6 Hz, 1H), 7.01 (d, J¼7.4 Hz,
1H), 7.10 (t, J¼8.0 Hz, 1H), 7.52 (s, 1H), 7.55 (dd, J¼9.6, 0.4 Hz, 1H),
4.4.1. 4-Methoxy-12H-chromeno[20,30:4,5]imidazo[1,2-a]pyridine
7.72 (dd, J¼9.2, 1.6 Hz, 1H), 8.07 (s, 1H), 8.84 (s, 1H) ppm; 13C NMR
(6a). Yellow solid. Mp 155e157 ꢀC; 1H NMR (400 MHz, DMSO-d6):
(100 MHz, DMSO-d6): d 22.44, 55.80, 99.16, 110.85, 114.49, 118.98,
d
3.85 (s, 3H), 4.28 (s, 2H), 6.92 (dd, J¼7.0, 1.2 Hz, 1H), 6.99 (dd,
119.33, 121.78, 122.69, 123.50, 125.49, 140.26, 140.70, 148.44, 151.83,
165.68 ppm. Anal. Calcd for C16H13N3O3.0,75H2O: C, 62.24; H, 4.70;
N, 13.61, found: C, 62.19; H, 4.32; N, 13.70.
J¼7.4, 1.2 Hz, 1H), 7.05e7.10 (m, 2H), 7.36 (td, J¼7.6, 0.8 Hz, 1H), 7.56
(d, J¼8.8 Hz, 1H), 8.31 (d, J¼6.8 Hz, 1H) ppm; 13C NMR (100 MHz,
DMSO-d6):
d 22.4, 55.8, 98.5, 110.8, 112.8, 114.9, 119.0, 121.7, 123.6,
124.6, 125.0, 139.0, 140.6, 148.4, 149.6 ppm; IR (Nujol mull):
n
1652,
4.4.8. Mixture of 12H-chromeno[20,30:4,5]imidazo[1,2-a]pyridine-7-
carboxamide (6g(A)) and 12H-chromeno[20,30:4,5]imidazo[1,2-a]-
pyridine-9-carboxamide (6g(B)). Yellow solid. 1H NMR (400 MHz,
1604, 1501, 1573, 1480, 1465, 1431 cmꢁ1
.
Anal. Calcd for
C15H12N2O2.0.4H2O: C, 69.44; H, 4.94; N, 10.80, found: C, 69.48; H,
4.67; N, 10.46.
DMSO-d6):
d 4.33 (s, 2H), 4.35 (s, 2H), 7.16e7.19 (m, 3H), 7.21 (dd,
J¼8.2, 1.2 Hz, 1H), 7.28e7.32 (m, 2H), 7.41 (d, J¼7.6 Hz, 2H), 7.54 (dd,
J¼9.6, 0.8 Hz, 2H), 7.73 (dd, J¼9.4, 1.6 Hz, 1H), 7.98 (br s, 1H), 8.02
(dd, J¼7.6, 1.2 Hz, 1H), 8.08 (s, 1H), 8.43 (dd, J¼6.8, 1.2 Hz, 1H), 8.84
4.4.2. 12H-Chromeno[20,30:4,5]imidazo[1,2-a]pyridine (6b). Yellow
solid. Mp 211e213 ꢀC; 1H NMR (400 MHz, DMSO-d6):
d 4.29 (s, 2H),
6.96 (td, J¼5.8, 0.8 Hz, 1H), 7.14 (td, J¼7.6, 0.9 Hz, 1H), 7.19
(dd, J¼8.0, 1.2 Hz, 1H), 7.24e7.32 (m, 2H), 7.38 (d, J¼7.6 Hz, 1H), 7.51
(d, J¼8.8 Hz, 1H), 8.26 (d, J¼6.4 Hz, 1H) ppm; 13C NMR (100 MHz,
(s, 1H), 9.01 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
d 22.31,
22.36, 99.20 (2C), 111.97, 114.49, 117.53, 117.58, 118.29 (2C), 119.19,
119.39, 122.72, 123.80, 123.98, 125.46, 126.67, 127.48, 128.20, 128.26,
130.72, 130.77, 138.04, 140.26 (2C), 150.25, 150.89, 151.03, 151.88,
163.74, 165.71 ppm. Anal. Calcd for C15H11N3O2.0.4H2O: C, 66.13; H,
4.34; N, 15.43, found: C, 66.17; H, 4.18; N, 15.30.
DMSO-d6):
d 22.4, 98.1, 112.0, 115.4, 117.5, 118.4, 123.6, 123.8, 124.2,
128.1, 130.7, 139.8, 151.0, 151.2 ppm; IR (Nujol mull):
n 1651, 1606,
1570, 1504, 1484, 1465, 1456 cmꢁ1. Anal. Calcd for C14H10N2O: C,
75.68; H, 4.50; N, 12.61, found: C, 75.53; H, 4.20; N, 12.31.
4.4.9. Mixture of 4-hydroxy-12H-chromeno[20,30:4,5]imidazo[1,2-a]pyr-
idine-7-carboxamide (6h(A)) and 4-hydroxy-12H-chromeno[20,30:4,5]
imidazo[1,2-a]pyridine-9-carboxamide (6h(B)). Yellow solid. 1H NMR
4.4.3. 4-Hydroxy-12H-chromeno[20,30:4,5]imidazo[1,2-a]pyridine
(6c). Yellow solid. Mp 279e281 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
4.26 (s, 2H), 6.77 (dd, J¼8.0, 1.5 Hz, 1H), 6.81 (dd, J¼8.1, 1.5 Hz, 1H),
(300 MHz, DMSO-d6):
d
4.30 (s, 2H), 4.32 (s, 2H), 6.80 (dd, J¼8.6,
6.92 (t, J¼7.8 Hz, 1H), 6.98 (td, J¼6.8, 1.2 Hz, 1H), 7.26 (td, J¼7.2,
1.2 Hz, 1H), 7.51 (d, J¼9.0 Hz, 1H), 8.25 (d, J¼6.6 Hz, 1H), 9.64 (br s,
1.5 Hz, 2H), 6.82 (dd, J¼8.4, 1.2 Hz, 2H), 6.95 (t, J¼7.5 Hz, 1H), 6.97
(t, J¼7.5 Hz, 1H), 7.18 (t, J¼6.6 Hz, 1H), 7.55 (dd, J¼9.4, 0.9 Hz, 2H),
7.73 (dd, J¼9.6, 1.8 Hz, 1H), 8.02 (dd, J¼7.5, 1.2 Hz, 2H), 8.09 (s, 1H),
8.49 (dd, J¼6.9, 1.2 Hz, 1H), 8.85 (d, J¼0.6 Hz, 1H), 9.06 (d, J¼2.1 Hz,
1H), 9.20e10.20 (br s, 2H) ppm; 13C NMR (75 MHz, DMSO-d6):
1H) ppm; 13C NMR (75 MHz, DMSO-d6):
d 22.5, 98.2, 112.0, 114.8,
115.5, 119.2, 120.2, 123.3, 123.8, 124.2, 139.8, 140.2, 146.3, 151.1 ppm;
IR (Nujol mull):
n
3181 (br), 1650, 1612, 1583, 1503, 1470, 1432 cmꢁ1
.
Anal. Calcd for C14H10N2O2.0.4H2O: C, 68.52; H, 4.40; N, 11.42,
found: C, 68.65; H, 4.30; N, 11.05.
d 22.45 (2C), 99.35, 99.37, 111.94, 114.44, 114.94 (2C), 119.13 (2C),
119.39 (2C), 120.22, 120.29 (2C), 122.82, 123.56, 123.72, 125.53,
126.64, 127.53, 138.04, 139.90, 140.03, 140.17, 146.37 (2C), 150.30,
151.81, 163.83, 165.75 ppm. Anal. Calcd for C15H11N3O3.1.3H2O: C,
59.13; H, 4.47; N, 13.80, found: C, 59.11; H, 4.38; N, 13.40.
4.4.4. 2-Methoxy-12H-chromeno[20,30:4,5]imidazo[1,2-a]pyridine
(6d). Yellow solid. Mp 176e178 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
3.75 (s, 3H), 4.25 (s, 2H), 6.84e6.92 (m, 2H), 6.98 (td, J¼6.9, 0.9 Hz,
1H), 7.13 (d, J¼8.7 Hz, 1H), 7.26 (t, J¼7.5 Hz, 1H), 7.49 (d, J¼8.7 Hz,
4.4.10. Mixture of 2-methoxy-12H-chromeno[20,30:4,5]imidazo[1,2-a]-
pyridine-7-carboxamide (6i(A)) and 2-methoxy-12H-chromeno[20,30:-
4,5]imidazo[1,2-a]pyridine-9-carboxamide (6i(B)). Yellow solid. 1H
1H), 8.23 (d, J¼6.6 Hz, 1H) ppm; 13C NMR (75 MHz, DMSO-d6):
d
22.7, 55.4, 97.7, 112.0, 114.1, 114.5, 115.4, 118.3, 119.0, 123.7, 124.1,
139.8, 145.1, 151.3, 155.1 ppm; IR (Nujol mull):
n
1650, 1610, 1581,
NMR (400 MHz, DMSO-d6): d 3.77 (s, 6H), 4.31 (s, 2H), 4.32 (s, 2H),
1493, 1466 cmꢁ1. Anal. Calcd for C15H12N2O2.0.25H2O: C, 70.18; H,
4.87; N, 10.92, found: C, 70.19; H, 4.61; N, 10.59.
6.88e6.92 (m, 2H), 6.94 (d, J¼2.8 Hz, 2H), 7.17 (d, J¼8.8 Hz, 2H), 7.18
(t, J¼6.8 Hz, 1H), 7.53 (dd, J¼9.2, 0.8 Hz, 2H), 7.72 (dd, J¼9.2, 2.0 Hz,
1H), 7.97 (d, J¼1.6 Hz, 1H), 8.02 (dd, J¼7.2, 1.2 Hz, 1H), 8.08 (s, 1H),
8.48 (dd, J¼6.8, 1.2 Hz, 1H), 8.81 (dd, J¼1.4, 0.8 Hz, 1H), 9.02 (s, 1H)
4.4.5. 2-Chloro-12H-chromeno[20,30:4,5]imidazo[1,2-a]pyridine
(6e). Yellow solid. Mp 222e224 ꢀC; 1H NMR (300 MHz, DMSO-d6):
ppm; 13C NMR (100 MHz, DMSO-d6):
d 22.60, 22.65, 55.48 (2C),
d
4.31 (s, 2H), 7.01 (td, J¼6.6, 0.9 Hz, 1H), 7.24 (d, J¼8.7 Hz, 1H), 7.28
98.77 (2C), 111.88, 114.10, 114.21, 114.36, 114.58, 114.68, 118.31,
118.34, 119.00 (2C), 119.08, 119.29, 122.63, 125.39, 126.58, 127.41,
138.05, 140.26, 144.77, 144.92, 150.55, 152.17, 155.21, 155.32, 163.75,
(t, J¼7.2 Hz, 1H), 7.35 (dd, J¼9.0 Hz, 2.4 Hz, 1H), 7.47 (d, J¼2.4 Hz,
1H), 7.51 (d, J¼9.3 Hz, 1H), 8.26 (d, J¼6.6 Hz, 1H) ppm; 13C NMR

4548
M.F. Proença, M. Costa / Tetrahedron 66 (2010) 4542e4550
165.72 ppm. Anal. Calcd for C16H13N3O3.0.3H2O: C, 63.92; H, 4.53;
N, 13.98, found: C, 64.06; H, 4.51; N, 13.59.
(td, J¼6.4, 1.6 Hz, 2H), 8.60 (td, J¼7.6, 1.2 Hz, 1H), 9.05 (dd, J¼6.8,
1.2 Hz, 2H) ppm; 13C NMR (100 MHz, DMSO-d6):
56.1, 113.5, 119.0,
121.8, 124.4, 127.4 (2C), 130.0, 140.8, 145.4 (2C), 146.0, 146.8, 150.0,
163.5 ppm ( under the signal for compound 6a).
d
4.4.11. 4-Methoxy-12H-chromeno[20,30:4,5]imidazo[1,2-a]pyridine-
*
8-carboxamide (6j). Cream solid. Mp higher than 300 ꢀC; 1H NMR
(400 MHz, DMSO-d6):
d
3.85 (s, 3H), 4.35 (s, 2H), 6.93 (d, J¼7.6 Hz,
4.8. Procedure for the synthesis of 3-(2-hydroxyphenyl)-2-
(pyridinium-1-yl)prop-2-enoate 9e
1H), 7.01 (dd, J¼8.0, 1.2 Hz, 1H), 7.09 (t, J¼8.0 Hz, 1H), 7.45 (dd,
J¼7.0, 2.0 Hz,1H), 7.51 (s,1H), 8.11 (s,1H), 8.12 (d, J¼0.8 Hz,1H), 8.33
(d, J¼7.2 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
d
22.5, 55.8,
1-(Cyanomethyl)pyridinium chloride 1a (0.12 g, 0.76 mmol) was
added to a white suspension of 5-chlorosalicylaldehyde 2e (0.11 g,
0.70 mmol) in aqueous Na2CO3 (0.05 M, 3 mL). The reaction mix-
ture was heated at 40 ꢀC for 11 h, followed by 18 h at 80 ꢀC. The
yellow suspension was cooled to room temperature in an ice bath
and the yellow solid (0.08 g) was filtered and washed with water.
The solid product was identified as a mixture of 6e and 9e (1:1.3
ratio by 1H NMR). A second crop was isolated from the mother
liquor. The yellow-brownish solid was filtered and washed with
water leading to the pure product 9e (0.02 g, 0.17 mmol). Mp
100.0,110.6,110.9,114.6,118.9,121.7,123.5, 123.7, 128.8,138.9, 140.6,
148.4, 152.2, 166.3 ppm; IR (Nujol mull):
n 3386, 3177, 1675, 1652,
1625, 1601, 1569, 1513, 1458 cmꢁ1; HRMSeFAB (m/z): [MþH]þ calcd
for C16H14N3O3 296.10362, found: 296.10297.
4.4.12. N-(2-Hydroxyethyl)-4-methoxy-12H-chromeno[20,30:4,5]imi-
dazo[1,2-a]pyridine-8-carboxamide
(6k). Cream
solid.
Mp
251e252 ꢀC; 1H NMR (400 MHz, DMSO-d6):
d
3.32e3.38 (m, 2H),
3.53 (t, J¼6.0 Hz, 2H), 3.86 (s, 3H), 4.30e4.70 (br s, 1H), 4.33 (s, 2H),
6.93 (dd, J¼7.8, 1.2 Hz, 1H), 7.01 (dd, J¼8.2, 1.6 Hz, 1H), 7.09 (t,
J¼8.0 Hz, 1H), 7.44 (dd, J¼7.0, 1.6 Hz, 1H), 8.08 (dd, J¼0.8 Hz, 1H),
8.33 (d, J¼6.6 Hz, 1H), 8.61 (t, J¼5.6 Hz, 1H) ppm; 13C NMR
180e182 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
6.83 (td, J¼7.2, 1.2 Hz,
1H), 6.87 (d, J¼7.6 Hz, 1H), 7.22 (s, 1H), 7.26 (td, J¼7.8, 1.6 Hz, 1H),
7.42 (dd, J¼7.6, 1.6 Hz, 1H), 8.12 (t, J¼5.1 Hz, 2H), 8.62 (t, J¼6.0 Hz,
1H), 9.12 (d, J¼4.2 Hz, 2H), 13.25 (s, 1H) ppm; 13C NMR (75 MHz,
(100 MHz, DMSO-d6):
d 22.6, 42.4, 55.8, 59.7, 100.0, 110.5, 110.9,
114.3, 118.9, 121.7, 123.5, 123.8, 129.0, 138.9, 140.7, 148.4, 152.2,
DMSO-d6): d 118.6, 119.6, 121.4, 126.9 (2C), 131.3, 131.7, 133.4, 140.0,
164.7 ppm; IR (Nujol mull):
n
3500e3200 (br), 1633, 1604, 1573,
145.5 (2C), 145.6, 157.8, 162.8 ppm; IR (Nujol mull): n 3536, 3403,
1547, 1515, 1481, 1458 cmꢁ1; HRMSeFAB (m/z): [MþH]þ calcd for
1638, 1610, 1572, 1460 cmꢁ1. HRMSeFAB (m/z): [MþH]þ calcd for
C18H18N3O4 340.12984, found: 340.12918.
C14H12NO3 242.08176, found: 242.08117.
4.5. 2-[3-Amino-3-oxo-2-pyridinium-1-ylprop-1-en-1-yl]-6-
methoxybenzenolate 7a
4.9. General procedure for the synthesis of 1-(2-imino-2H-
chromen-3-yl)pyridin-4(1H)-iminium chloride 12
1H NMR (400 MHz, D2O):
d
3.87 (s, 3H), 6.85 (t, J¼8.0 Hz, 1H),
4-Amino-1-(cyanomethyl)pyridinium chloride 1e (0.69 mmol)
was added to a yellow solution of salicylaldehyde 2 (0.59 mmol) in
aqueous Na2CO3 (0.05 M, 4 mL). The reaction mixture was stirred at
room temperature (1 h and 30 min to 17 h and 30 min). A yellow
solid started to precipitate after a few minutes. The solid was
filtered and washed with water leading to the pure product 12. For
12a and b: the mother liquor was stirred at 10 ꢀC for 16 h and a solid
was filtered. This product was identified by 1H NMR as a second
crop of pure compound 12.
7.04 (dd, J¼8.0, 1.2 Hz, 1H), 7.11 (dd, J¼8.0, 1.2 Hz, 1H), 7.38 (s, 1H),
8.15 (t, J¼7.2 Hz, 2H), 8.66 (td, J¼6.6, 1.2 Hz, 1H), 8.93 (dd, J¼6.6,
1.2 Hz, 2H) ppm; 13C NMR (100 MHz, D2O):
d 56.1, 113.7, 118.7, 120.1,
122.0, 127.8 (2C), 131.0, 138.9, 144.3 (2C), 146.4, 147.4, 148.4,
167.2 ppm.
4.6. Procedure for the synthesis of 1-(8-Methoxy-2-oxo-2H-
chromen-3-yl)pyridinium chloride 8a
Concentrated HCl (0.05 g, 1.50 mmol, 124
m
L) was added to
4.9.1. 1-(2-Imino-8-methoxy-2H-chromen-3-yl)pyridin-4(1H)-imi-
a yellow suspension of 1-(2-imino-8-methoxy-2H-chromen-3-yl)
pyridinium chloride 4a (0.14 g, 0.50 mmol) in EtOH (2 mL). The
reaction mixture was stirred at room temperature for 49 h and then
kept at 0 ꢀC for 4 days. A yellow solid precipitated from solution and
was filtered and washed with EtOH (cold) leading to the pure
product 8a (0.05 g, 0.17 mmol). The mother liquor was kept at 0 ꢀC
for 14 days and the yellow solid was filtered (0.04 g, 0.15 mmol).
This product was identified by 1H NMR as a second crop of the pure
compound 8a (0.09 g, 0.32 mmol). Mp 132e134 ꢀC; 1H NMR
nium chloride (12a). Green solid. Mp 276e278 ꢀC; 1H NMR
(300 MHz, DMSO-d6):
d
3.88 (s, 3H), 6.98 (d, J¼7.8 Hz, 2H), 7.14
(dd, J¼7.8, 1.5 Hz, 1H), 7.21 (t, J¼7.8 Hz, 1H), 7.27 (dd, J¼8.1, 1.8 Hz,
1H), 7.94 (d, J¼1.8 Hz, 1H), 8.29 (d, J¼7.2 Hz, 2H), 8.82 (s, 2H), 8.96
(d, J¼1.8 Hz, 1H) ppm; 13C NMR (75 MHz, DMSO-d6):
d 56.1, 108.6
(2C), 115.0, 118.7, 120.4, 124.2, 130.6, 132.4, 142.0, 143.4 (2C), 146.1,
151.5, 159.6 ppm; IR (Nujol mull):
n
3347, 3267, 3227, 2726,
Anal. Calcd for
1661, 1608, 1581, 1522, 1479, 1462 cmꢁ1
.
C15H14N3O2Cl.2H2O: C, 53.02; H, 5.30; N, 12.37, found: C, 52.80; H,
5.37; N, 12.46.
(300 MHz, DMSO-d6):
d
3.91 (s, 3H), 7.21 (dd, J¼7.8, 2.1 Hz, 1H), 7.27
(t, J¼7.8 Hz, 1H), 7.36 (dd, J¼7.8, 1.8 Hz, 1H), 8.23 (s, 1H), 8.34
(td, J¼7.5, 0.9 Hz, 2H), 8.82 (td, J¼7.5, 1.8 Hz, 1H), 9.12 (s, 1H), 9.30
4.9.2. 1-(2-Imino-2H-chromen-3-yl)pyridin-4(1H)-iminium chloride
(dd, J¼6.8, 1.2 Hz, 2H) ppm; 13C NMR (75 MHz, DMSO-d6):
d
56.2,
(12b). White solid. Mp 293e295 ꢀC; 1H NMR (300 MHz, DMSO-d6):
115.8, 118.2, 120.8, 124.5, 127.8 (2C), 131.1, 134.3, 142.4, 146.1 (2C),
d
6.96 (d, J¼7.5 Hz, 2H), 7.22e7.31 (m, 2H), 7.51e7.62 (m, 2H), 7.96
146.2, 148.0, 151.0 ppm; IR (Nujol mull):
n
3600e1700 (br, fringed),
(d, J¼1.5 Hz, 1H), 8.30 (d, J¼7.2 Hz, 2H), 8.72 (s, 2H), 8.88
1663, 1626, 1605, 1580, 1482 cmꢁ1. Anal. Calcd for C15H13N2O2Cl.
H2O.0.2NH4Cl: C, 56.74; H, 4.98; N, 9.71, found: C, 57.10; H, 4.98; N,
9.79.
(d, J¼1.8 Hz, 1H) ppm; 13C NMR (75 MHz, DMSO-d6):
d 108.6 (2C),
115.2, 118.1, 124.2, 129.2, 130.4, 132.3 (2C), 143.4 (2C), 151.9, 152.9,
159.6 ppm; IR (Nujol mull):
n 3449, 3318, 3288, 3268, 1657, 1624,
1598, 1539, 1458 cmꢁ1. Anal. Calcd for C14H12N3OCl: C, 61.43; H,
4.39; N, 15.36, found: C, 61.10; H, 4.44; N, 15.15.
4.7. 3-(2-Hydroxy-3-methoxyphenyl)-2-(pyridinium-1-yl)
prop-2-enoate 9a
4.9.3. 1-(8-Hydroxy-2-Imino-2H-chromen-3-yl)pyridin-4(1H)-imi-
Identified in the mixture with 6a in a ratio of 9a/6a¼1:1.6 by 1H
nium chloride (12c). Cream solid. Mp 270e272 ꢀC; 1H NMR
NMR. 1H NMR (400 MHz, DMSO-d6):
d
3.75 (s, 3H), 6.78 (t, J¼8.0 Hz,
(400 MHz, DMSO-d6):
d 4.00e6.00 (br s, 3H), 6.92e6.97 (m, 3H),
1H), 6.94e7.02 (m
*
, 1H), 7.10 (dd, J¼7.8, 1.2 Hz, 1H), 7.14 (s, 1H), 8.09
7.04 (t, J¼7.6 Hz, 1H), 7.10 (dd, J¼8.0, 1.6 Hz, 1H), 7.87 (s, 1H), 8.29

M.F. Proença, M. Costa / Tetrahedron 66 (2010) 4542e4550
4549
(d, J¼7.6 Hz, 2H), 8.64 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
140.0, 142.3, 145.6 (2C), 146.6, 152.6, 154.7, 156.4 ppm; IR (Nujol
d
108.6, 108.9, 118.5, 118.8, 119.0, 124.1, 130.2, 132.8, 141.4, 143.2,
mull): n 3700e1800 (br, fringed), 1748, 1717, 1682, 1643, 1611, 1581,
143.5, 144.9, 152.1, 159.5 ppm; IR (Nujol mull):
n
3375, 3291, 3234,
1525, 1483, 1469 cmꢁ1. Anal. Calcd for C18H17N2O5Cl.0.8H2O: C,
55.26; H, 4.76; N, 7.16, found: C, 55.25; H, 4.62; N, 7.35.
3188, 3078, 1682, 1657, 1649, 1628, 1615, 1580, 1546, 1528, 1475,
1463 cmꢁ1
254.09306, found: 254.09240.
;
HRMSeFAB (m/z): [MþH]þ calcd for C14H12N3O2
4.13. Procedure for the synthesis of ethyl (4-methoxy-12H-
chromeno[20,30:4,5]imidazo[1,2-a]pyridin-8-yl)carbamate 6l
and 1-(8-methoxy-2-oxo-2H-chromen-3-yl)pyridin-4(1H)-
iminium chloride 16
4.10. Procedure for the synthesis of ethyl [1-(2-imino-8-
methoxy-2H-chromen-3-yl)pyridin-4(1H)-ylidene]carbamate 13
1-(Cyanomethyl)-4-(ethoxycarbonylamino)pyridinium chlo-
ride 1h (0.13 g, 0.55 mmol) was added to a yellow solution of
3-methoxysalicylaldehyde 2a (0.09 g, 0.56 mmol) in aqueous
Na2CO3 (0.05 M, 5 mL). The reaction mixture was stirred at 60 ꢀC
for 7 min. A yellow solid started to precipitate after 2 min. The
solid was filtered and washed with water leading to the pure
product 13 (0.16 g, 0.49 mmol). Mp 134e136 ꢀC; 1H NMR
1-(Cyanomethyl)-4-(ethoxycarbonylamino)pyridinium chloride
1h (0.40 g, 1.64 mmol) was added to
a yellow solution of
3-methoxysalicylaldehyde 2a (0.23 g, 1.51 mmol) in water (2.5 mL).
The reaction mixture was refluxed for 2 h. A yellow solid started to
precipitate after 20 min. The yellow solid was filtered and washed
with water leading to the pure product 6l (0.21 g, 0.62 mmol). Mp
282e284 ꢀC; 1H NMR (400 MHz, DMSO-d6):
d
1.26 (t, J¼5.4 Hz, 3H),
(400 MHz, DMSO-d6):
d
1.21 (t, J¼7.2 Hz, 3H), 3.82 (s, 3H), 4.07 (q,
3.84 (s, 3H), 4.16 (q, J¼5.4 Hz, 2H), 4.23 (s, 2H), 6.90 (dd, J¼7.6,
1.6 Hz, 1H), 6.98 (dd, J¼7.6, 1.6 Hz, 1H), 7.05 (d, J¼7.6 Hz, 1H), 7.06
(t, J¼7.2 Hz, 1H), 7.63 (d, J¼1.6 Hz, 1H), 8.15 (dd, J¼7.2, 0.4 Hz, 1H),
J¼7.2 Hz, 2H), 7.14 (dd, J¼7.6, 1.6 Hz, 1H), 7.20 (t, J¼7.6 Hz, 1H),
7.26 (dd, J¼8.0, 1.6 Hz, 1H), 7.35 (d, J¼7.6 Hz, 2H), 7.90 (s, 1H),
8.26 (d, J¼7.2 Hz, 2H), 8.94 (s, 1H) ppm; 13C NMR (100 MHz,
9.93 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
d 14.4, 22.53, 55.8,
DMSO-d6):
d 14.4, 56.0, 60.4, 114.0 (2C), 114.9, 118.8, 120.3, 124.2,
60.6, 96.5, 100.5, 105.6, 110.7, 119.1, 121.8, 123.2, 124.5, 136.1, 140.6,
130.7, 132.0, 142.0, 142.3 (2C), 146.0, 151.4, 159.3, 161.2 ppm; IR
140.9, 148.4, 151.1, 153.4 ppm; IR (Nujol mull):
n 3220, 3122, 1721,
1660, 1609, 1592, 1573, 1508, 1491, 1482, 1456, 1426 cmꢁ1. Anal.
Calcd for C18H17N3O4$0.2H2O: C, 63.05; H, 5.08; N, 12.26, found: C,
62.87; H, 4.80; N, 12.17.
(Nujol mull):
n 3575, 3320, 3272, 3220, 1676, 1657, 1631, 1623,
1607, 1578, 1538, 1526, 1464, 1411, 1405 cmꢁ1. Anal. Calcd for
C18H17N3O4.1.4H2O: C, 59.31; H, 5.44; N, 11.53, found: C, 59.41; H,
5.25; N, 11.25.
The mother liquor was refluxed for a further 9 h. After cooling
the yellow-greenish solution in an ice-bath, a yellow solid started to
precipitate. The solid was filtered and washed with water leading to
the pure product 16 (0.05 g, 0.18 mmol). Mp higher than 300 ꢀC; 1H
4.11. Procedure for the synthesis of ethoxy-N-[1-(2-imino-8-
methoxy-2H-chromen-3-yl)pyridin-4(1H)-ylidene]
oxomethanaminium chloride 14
NMR (300 MHz, DMSO-d6):
d
3.95 (s, 3H), 7.01 (d, J¼7.2 Hz, 2H),
7.35 (dd, J¼7.4, 2.1 Hz, 1H), 7.41 (t, J¼8.1 Hz, 1H), 7.46 (d, J¼6.3 Hz,
1H), 8.28 (d, J¼7.2 Hz, 2H), 8.53 (s, 1H), 8.84 (s, 2H) ppm; 13C NMR
1-(Cyanomethyl)-4-(ethoxycarbonylamino)pyridinium chloride
1h (0.29 g, 1.19 mmol) was added to
a yellow solution of
(75 MHz, DMSO-d6):
d 56.5, 109.0 (2C), 115.5, 118.7, 120.4, 125.5,
3-methoxysalicylaldehyde 2a (0.17 g, 1.12 mmol) in water (5 mL).
The reaction mixture was stirred at 60 ꢀC for 1 h. A yellow solid
started to precipitate after 25 min. The solid was filtered and
washed with water leading to the pure product 14 (0.36 g,
128.5, 138.9, 142.0, 143.1 (2C), 146.5, 156.8, 159.6 ppm; IR (Nujol
mull): n 3800e2000 (br, fringed), 1707, 1681, 1664, 1609, 1580, 1548,
1531, 1465, 1481, 1442 cmꢁ1. Anal. Calcd for C15H13N2O3Cl.0.5H2O:
C, 57.42; H, 4.46; N, 8.93, found: C, 57.43; H, 4.32; N, 8.73.
0.95 mmol). Mp 172e173 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d 1.28
(t, J¼7.2 Hz, 3H), 3.89 (s, 3H), 4.25 (q, J¼7.2 Hz, 2H), 7.16e7.26
(m, 2H), 7.31 (dd, J¼7.8, 1.8 Hz, 1H), 8.09 (d, J¼7.5 Hz, 2H), 8.90
(d, J¼7.5 Hz, 2H), 9.05 (s, 1H), 11.20e12.40 (br s, 1H) ppm; 13C NMR
Acknowledgements
We gratefully acknowledge the financial support from Fundação
para a Ciência e a Tecnologia through project PPCDT/QUI/59356/
2004 and a Ph.D. grant awarded to M.C. (SFRH/BD/31531/2006). We
also thank Dr. Elisa Pinto for careful NMR studies.
(75 MHz, DMSO-d6): d 14.3, 56.1, 62.3, 113.2 (2C), 115.5, 118.4, 120.7,
124.4, 130.5, 133.5, 142.3, 145.8 (2C), 146.1, 151.1, 152.9, 154.8 ppm;
IR (Nujol mull):
n 3400e1700 (br, fringed), 1656, 1641, 1605, 1578,
1530, 1462 cmꢁ1. Anal. Calcd for C18H18N3O4Cl$2.2H2O: C, 52.03; H,
5.39; N, 10.12, found: C, 52.05; H, 5.08; N, 10.11.
Supplementary data
4.12. Procedure for the synthesis of ethoxy-N-[1-(8-methoxy-
2-oxo-2H-chromen-3-yl)pyridin-4(1H)-ylidene]
oxomethanaminium chloride 15
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.059.
References and notes
Concentrated HCl (0.04 g, 1.05 mmol, 187
mL) was added to
a
yellow suspension of ethoxy-N-[1-(2-imino-8-methoxy-2H-
1. For recent examples of biologically active chromene derivatives see: (a)
Robert, S.; Bertolla, C.; Masereel, B.; Dogné, J.; Pochet, L. J. Med. Chem.
2008, 51, 3077e3080; (b) Abrunhosa, L.; Costa, M.; Areias, F.; Venâncio, A.;
Proença, F. J. Ind. Microbiol. Biotechnol. 2007, 34, 787e792; (c) Chimenti, F.;
Bizzarri, B.; Bolasco, A.; Secci, D.; Chimenti, P.; Carradori, S.; Granese, A.;
Rivanera, D.; Lilli, D.; Zicari, A.; Scaltrito, M.; Sisto, F. Bioorg. Med. Chem.
Lett. 2007, 17, 3065e3071; (d) Kostova, I. Mini Rev. Med. Chem. 2006, 6,
365e374; (e) Nayyar, A.; Jain, R. Curr. Med. Chem. 2005, 12, 1873e1886; (f)
Fylaktakidou, K.; Hadjipavlou-Litina, K.; Litinas, K.; Nicolaides, D. Curr.
Pharm. Des. 2004, 10, 3813e3833; (g) Asres, K.; Seyoum, A.; Veeresham, C.;
Bucar, F.; Gibbons, S.; Wilson, W.; Boykin, D. Phytother. Res. 2005, 19,
557e581; (h) Jain, N.; Kanojia, R.; Xu, J.; Jian-Zhong, G.; Pacia, E.; Lai, M.;
Du, F.; Musto, A.; Allan, G.; Hahn, D.; Lundeen, S.; Sui, Z. J. Med. Chem.
2006, 49, 3056e3059; (i) Frédérick, R.; Robert, S.; Charlier, C.; Ruyck, J.;
Wouters, J.; Pirotte, B.; Masereel, B.; Pochet, L. J. Med. Chem. 2005, 48,
7592e7603.
chromen-3-yl)pyridin-4(1H)-ylidene]oxomethanaminium chloride
14 (0.13 g, 0.34 mmol) in water (1.6 mL). The reaction mixture was
stirred at room temperature and after 2 min a homogeneous
solution was obtained. A yellow solid started to precipitate after
3 min. The suspension was kept stirring for a further 2 h and
25 min. The yellow solid was filtered and washed with water
leading to the pure product 15 (0.10 g, 0.26 mmol). Mp 241e243 ꢀC;
1H NMR (300 MHz, DMSO-d6):
d
1.31 (t, J¼7.2 Hz, 3H), 3.97 (s, 3H),
4.28 (q, J¼6.9 Hz, 2H), 7.40 (dd, J¼7.6, 1.8 Hz, 1H), 7.45 (t, J¼7.8 Hz,
1H), 7.50 (dd, J¼8.0, 1.8 Hz, 1H), 8.14 (d, J¼7.2 Hz, 2H), 8.69 (s, 1H),
8.89 (d, J¼7.2 Hz, 2H), 11.89 (s, 1H) ppm; 13C NMR (75 MHz, DMSO-
d6):
d 14.1, 56.4, 62.4, 113.4 (2C), 116.1, 118.4, 120.7, 125.7, 128.6,

4550
M.F. Proença, M. Costa / Tetrahedron 66 (2010) 4542e4550
2. (a) Garino, C.; Tomita, T.; Pietrancosta, N.; Laras, Y.; Rosas, R.; Herbette, G.; Mai-
gret, B.; Quéléver, G.; Iwatsubo, T.; Kraus, J. J. Med. Chem. 2006, 49, 4275e4285; (b)
Garino, C.; Tomita, T.; Pietrancosta, N.; Laras, Y.; Rosas, R.; Herbette, G.; Maigret,
B.; Quéléver, G.; Iwatsubo, T.; Kraus, J. Bioorg. Med. Chem. 2006, 16, 1995e1999.
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