Synthesis of 3-aminochromenes: The Zincke reaction revisited

Article abstract of DOI:10.1016/j.tet.2014.05.074

3-Aminocoumarines and 2-iminochromen-3-amines were efficiently prepared from the Zincke-ring-opening reaction of the corresponding 2H-chromen-3- pyridinium chlorides using N-methylpiperazine. This methodology unravels the marked potential of pyridinium salts as protective groups for primary amines. These scaffolds can be considered important building blocks for new novobiocin analogues and heterocyclic compounds.

Full text of DOI:10.1016/j.tet.2014.05.074

Tetrahedron 70 (2014) 4869e4875
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 3-aminochromenes: the Zincke reaction revisited
*
Marta Costa, Ana I. Rodrigues, Fernanda Proenc¸ a
Department of Chemistry, University of Minho, Campus 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:
Received 14 April 2014
Received in revised form 15 May 2014
Accepted 20 May 2014
Available online 29 May 2014
3-Aminocoumarines and 2-iminochromen-3-amines were efficiently prepared from the Zincke-ring-
opening reaction of the corresponding 2H-chromen-3-pyridinium chlorides using N-methylpiperazine.
This methodology unravels the marked potential of pyridinium salts as protective groups for primary
amines.
These scaffolds can be considered important building blocks for new novobiocin analogues and het-
erocyclic compounds.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
3-Aminochromenes
Protecting groups
Pyridinium salt
N-Methylpiperazine
Zincke reaction
1. Introduction
antibiotics bearing this core unit, isolated from several Strepto-
myces strains.4 Novobiocin, an inhibitor of DNA gyrase,5 binds to
The chromene nucleus is present in a wide range of natural
products1 and can be considered an important scaffold in medicinal
chemistry.2 The 3-aminocoumarine core, in particular, has attracted
considerable interest since this molecule can be used as an in-
termediate in the preparation of bioactive compounds.3 Novobio-
cin, clorobiocin and coumermycin A1 (Fig.1) are naturally occurring
heat shock protein 90 at the C-terminal nucleotide-binding region
and leads to a decrease on hsp90 client protein in various cancer
cell lines.6 Analogues have been studied as anticancer agents,
inhibiting hsp90,7 a target that has attracted the attention of both
industrial and academic laboratories for cancer chemotherapeutics.
A scarce number of methods are available for the preparation of
3-aminocoumarin. The first reported synthesis, by F. Linch,8a dates
back over a century and several attempts have been made to im-
prove this synthetic route.7a,8b Experimental procedures described
in the literature often lead to satisfactory yields but the pathway
implies multiple steps, the use of environmentally harmful re-
agents and solvents and several purifications steps. Furthermore
only a limited selection of substituents in the aromatic ring allowed
the successful isolation of the product.
2. Results and discussion
Herein, inspired by the Zincke-ring-opening of pyridinium salts,
we anticipated that the pyridinium ion could be used as a protect-
ing group for the amine function in the C3 position of 1-(2-imino-
2H-chromen-3-yl)pyridinium chlorides 3 and 1-(2-oxo-2H-chro-
men-3-yl)pyridinium chlorides 4. Compounds 3aed and 4a were
previously prepared in our group from the base-catalyzed Knoe-
venagel condensation of salicylaldehydes 1 and 1-(cyanomethyl)
pyridinium chloride 2 (Scheme 1).9
Fig. 1. Natural antibiotics bearing the 3-aminocoumarin nucleus.
Initial deprotecting assays were performed using the reaction of
2-methoxyethylamine with 1-(8-methoxy-2-oxo-2H-chromen-3-
* Corresponding author. Tel.: þ351 253 604379; fax: þ351 253 604383; e-mail
address: fproenca@quimica.uminho.pt (F. Proenc¸ a).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.074

4870
M. Costa et al. / Tetrahedron 70 (2014) 4869e4875
These were the only products identified in the spectrum in a 1:1
molar ratio, after 24 h. The ammonium chloride, present as a con-
tamination in the starting material, was also identified. This study
confirmed that the reaction followed the usual pathway for the
0
Zincke reaction: nucleophilic attack of the primary amine to C2 of
the pyridinium salt moiety of chromene 4a leading to ring opening
followed by ring closure to generate pyridinium salt
corporating the primary amine (Scheme 2).
7 in-
The contamination with ammonium chloride was not affecting
the reaction, as ammonia did not compete with the primary amine
for nucleophilic attack.
This reaction was also repeated in the absence of solvent, using
5 M equiv of 2-methoxyethylamine. Heating the reaction mixture at
60 ꢀC for 17 h followed by addition of water resulted in a solid
product, identified as 8-methoxy-3-((2-methoxyethyl)amino)-2H-
chromen-2-one 8 (31% yield, Scheme 2). The same product was
isolated, although in a lower yield (12%), when chromene 4a was
reacted with 5 M equiv of 2-methoxyethylamine at room temper-
ature for 1 day. This transformation may proceed through nucleo-
philic attack of the primary amine to the electron deficient carbon
C3, releasing pyridinium chloride.
Scheme 1. Previous work: reaction of salicylaldehyde derivatives 1 with 1-(cyano-
methyl)pyridinium chloride 2.
yl)pyridinium chloride 4a. The use of a primary amine, mimicking
the conditions normally used for the Zincke reaction, was expected
to release the amine unit in the 3-position of the chromene ring,
0
0
upon nucleophilic attack at C2 and C6 .
Compound 5a (Scheme 2) was indeed isolated when the re-
agents were combined in ethanol in a 1:1 molar ratio, and the red
suspension was stirred at 10 ꢀC for 22 h. The product was isolated in
a modest yield (27%) and analysis of the reaction mixture by 1H
NMR evidenced that the starting material 4a and the imine 6 were
also present, together with other non-identified components
(Scheme 2).
The poor selectivity in the reaction of the primary amine with
chromen-3-yl-pyridinium chloride 4 was assigned to the presence
0
0
of several electron deficient carbon atoms (C2, C3, C4, C2 and C6 )
resulting in the formation of different products by nucleophilic
attack on these positions, depending basically on the reaction
conditions.
In order to overcome this lack of selectivity and improve the
yield in the synthesis of the 3-aminocoumarins, a secondary amine
was used. Although the Zincke reaction is generally associated with
the reaction of primary amines with pyridinium salts, the reaction
of chromen-3-yl-pyridinium chloride 4a (contaminated with
0.6 M equiv of NH4Cl) was performed with 2 M equiv of N-meth-
ylpiperazine in acetone, at room temperature. The formation of
compound 5a was confirmed by TLC and removal of the solvent in
the rotary evaporator after ca. 20 h, followed by addition of water
and ethanol, allowed the isolation of this product. A second crop
was collected by flash chromatography of the mother liquor but the
total yield did not exceed 39%. In an attempt to improve the yield,
the reaction was repeated under the same experimental conditions
but using 5 M equiv of N-methylpiperazine. After stirring the
mixture at room temperature for 1 day, the solvent was removed
and the red oil was purified by flash chromatography using ethyl
acetate as eluent. 3-Aminocoumarin 5a was isolated an excellent
yield of 99% after removal of the solvent. Other substituted 1-(2-
imino-2H-chromen-3-yl)pyridinium chlorides 3 were prepared
according to our previously reported procedure9 and further con-
verted into the corresponding 1-(2-oxo-2H-chromen-3-yl)pyr-
idinium chlorides 4, after addition of 3 M equiv of concentrated HCl
(37%) to an aqueous solution of 3 and heating for a 2e3 h (Table 1).
The optimal reaction conditions for the synthesis of 3-
aminocoumarins 5 were applied to the remaining chromen-3-yl-
pyridinium chlorides 4 and the desired products 5 were isolated
(Scheme 3).
For chromenes 4c,eeg, bearing a hydroxyl group in the aromatic
ring, the reaction conditions had to be adapted due to the lower
solubility of these compounds in acetone. A small amount of water
and heating conditions were applied and the products were iso-
lated in good yield (70e98%).
The successful and efficient release of the amino group by nu-
cleophilic attack of the secondary amine to the pyridinium ion at C3
of the chromene unit in 2-oxochromene 4, encouraged the appli-
cation of this methodology to 2-iminochromenes 3. In general, 2-
imino-2H-chromenes are more delicate to handle due to the
presence of the NH group in the C2 position that allows a facile
Scheme 2. Reaction of 2-oxo-2H-chromen-3-yl-pyridinium chloride 4a with 2-
methoxyethylamine.
When the reaction was repeated at room temperature, 1H NMR
on the resulting oil indicated the formation of 3-aminocoumarin
5a, accompanied by unreacted starting material 4a and imine 6 in
an equally complex mixture.
The reaction was performed in water, at 60 ꢀC for 26 h, leading to
a complex mixture. Imine 6 was the only product isolated in
a modest yield, after dry flash chromatography (Scheme 2).
The reaction was also performed using 2 M equiv of the amine,
although in this case chromene 4a was contaminated with am-
monium chloride (1 M equiv). Ethyl acetate and ethanol (2:1) were
used as solvents and the reaction mixture was kept at 60 ꢀC for 25 h.
The solid product that precipitated after appropriate work-up, was
identified as the desired product, the 3-aminocoumarin 5a (49%
yield). The mother liquor, analyzed by 1H NMR after removal of the
solvent in the rotary evaporator, showed that a complex mixture
had also been formed.
The reaction of 4a (contaminated with ammonium chloride)
and 2-methoxyethylamine (1 M equiv) was followed by 1H NMR in
deuterated dimethylsulfoxide. A clean progression to chromene 5a
and pyridinium salt 7 was observed under these dilute conditions.
0
0
intramolecular nucleophilic attack to C2 /C6 of the pyridinium ion.

M. Costa et al. / Tetrahedron 70 (2014) 4869e4875
4871
Table 1
Preparation of 2-imino and 2-oxo-2H-chromenes 3 and 4
Entry
1
1
2
Yield (%)
78a
3
Yield (%)
83a
1a
2
3
1b
1c
45a
86a
69
75
Scheme 3. Synthesis of 3-aminocoumarin derivatives 5aeg.
4
5
6
1d
1e
1f
69a
78
53
74
91
64
Scheme 4. Evolution of 2-imino-2H-chromene-3-yl-pyridinium chloride 3a in the
presence of N-methylpiperazine.
7
1g
1h
64
34
94
8
d
d
a
Previously reported by our group.9
This reaction was previously observed by our group,9 and compe-
tition with N-methylpiperazine was to be expected. The reaction
of 2-imino-2H-chromen-3-yl-pyridinium chloride 3a with 5 equiv
of N-methylpiperazine was performed in acetone, at room
temperature.
The solvent was removed in the rotary evaporator after 1 day,
and analysis of the red oil by 1H and 13C NMR spectroscopy showed
the presence of chromene 9a and salt 10, contaminated with N-
methylpiperazine (Scheme 4).
The formation of compound 10 confirmed that the Zincke re-
action involves 2 equiv of the secondary amine leading to an in-
teresting symmetrically substituted conjugated system. This salt
was never isolated before although the formation of an analogous
structure was reported 60 years ago. The compound was only
characterized by elemental analysis and melting point data.10
Flash chromatography was used to isolate the pure 2-imino-2H-
chromen-3-amine derivative 9a (56% yield). When the same re-
action was performed in acetonitrile, the desired product 9a was
isolated in a higher yield (70%). Chromene derivatives 9beg were
synthesized using the reaction conditions presented in Scheme 5.
The synthesis of chromene derivatives 9c,e and f, bearing hy-
droxyl groups, resulted in modest yields. Again, the poor solubility
Scheme 5. Synthesis of 2-imino-2H-chromen-3-amines 9aeg.
of the corresponding reagents 3 in acetone or acetonitrile may be
the source of the problem. In this case, water could not be added to
the reaction mixture in order to enhance solubility as evolution to
the 2-oxo-chromene 4 was detected. Heating the reaction mixture

4872
M. Costa et al. / Tetrahedron 70 (2014) 4869e4875
was also impracticable, as the 2-imino-chromenes 3 evolved to
a tetracyclic product under heating conditions in the presence of
base. This work was previously reported and the product results
from intramolecular cyclization of the imino group to the carbon of
the pyridine moiety, without ring opening.9 The evolution of
chromene derivative 3c in the presence of N-methylpiperazine
resulted in a suspension and in this case the solid was filtered and
identified as a mixture of 2-imino-2H-chromen-3-amine derivative
9c and piperazinium chloride 10, in a 1:1 ratio, by 1H NMR.
Compounds 2 and 5b were synthesized in the laboratory but are
commercially available. Chromene derivatives 3aed and 4a were
previously reported by our research group and synthesized
according to the established experimental procedures (3aed) or by
new methodologies (4a).9
4.2. Synthesis of 1-(cyanomethyl)pyridinium chloride 2
Pyridine (0.77 g, 9.73 mmol; 800
ml) was added to a solution of
This mixture was separated by flash chromatography, and ethyl
acetate allowed the isolation of chromene 9c while a mixture of
dichloromethane and methanol (12e20%) resulted in the isolation of
the pure piperazinium chloride 10 as viscous orange oil. The highly
conjugated structure of compound 10, where the positive charge
bounces between the two piperazine nitrogen atoms, is corroborated
by the 1H and 13C NMR data. The linear carbon chain displays
a symmetrical and alternating electron density leading to three sig-
a chloroacetonitrile (0.47 g, 6.22 mmol, 400
m
l) in acetonitrile (1 ml)
and the mixture was kept under reflux conditions. After 5 min
a beige solid started to precipitate and after 10 min heating was
stopped. The suspensionwas cooled in an ice bath for a few minutes.
The beige solid was filtered and washed with acetonitrile leading to
1-(cyanomethyl)pyridinium chloride (0.82 g, 5.30 mmol, 85.2%), by
1H NMR (300 MHz, DMSO-d6):
2H), 8.73 (td, J¼1.5, 1.2 Hz, 1H), 9.24 (d, J¼6.2 Hz, 2H) ppm.
d
6.07 (s, 2H), 8.26 (td, J¼6.9, 1.8 Hz,
nals in the 13C NMR spectrum: C1 andC5 at
d
0
0
0 0
160.0 ppm, C2 and C4 at
0
d
102.5 ppm and C3 at
d
163.0 ppm. The associated proton coupling
4.3. General procedure for the synthesis of 1-(2-imino-2H-
chromen-3-yl)pyridinium chlorides 3
constant in the 1H NMR spectrum, around J¼12 Hz, indicates that the
trans isomer is stable in DMSO, under the NMR conditions.
N-Methylpiperazine (0.90 mmol) was added to a suspension of
salicylaldehyde derivative 1 (1.0 mmol) and 1-(cyanomethyl)pyr-
idinium chloride 2 (1.0 mmol) in ethanol (0.4 ml) and acetone
(1.2 ml). A red solution was obtained and stirred in an ice bath. After
a few minutes a red suspension was formed and after 30e60 min
the product was filtered and washed with acetone leading to 1-(2-
imino-2H-chromen-3-yl)pyridinium chloride 3.
3. Conclusion
In conclusion, the Zincke-ring-opening reaction of chromen-3-
yl-pyridinium salts induced by N-methylpiperazine led to a series
of 3-aminochromenes in excellent yield. Preliminary studies using
a primary amine (2-methoxyethylamine) resulted in poor selec-
tivity and lower isolated yields of the product, even when different
experimental conditions were assayed. The use of a secondary
amine to perform the Zincke reaction may unravel a versatile per-
spective regarding pyridinium salts as surrogates for the amino
group. The primary amine could be released by excess of N-meth-
ylpiperazine, at room temperature or under mild heating, and
solvents, such as acetone, acetonitrile or water were well tolerated
in the process. The success of this methodology, now applied to
chromen-3-yl-pyridinium salts, where competition for nucleo-
philic attack on the chromene moiety could be a serious drawback,
suggests that this may be used as a general protocol for amino
group protection/deprotection. 3-Aminocoumarines 5 with differ-
ent substituents in the aromatic moiety were efficiently prepared
by this method, paving the way for the preparation of novobiocin
analogues. Novel 2-iminochromen-3-amines 9 were also isolated
and the amino/imino functionality can be considered an important
building block for the new fused heterocycles incorporating the
chromene moiety.
4.3.1. 1-(2-Imino-8-methoxy-2H-chromen-3-yl)pyridinium chloride
3a.9 Yellow solid, 78%. 1H NMR (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 (dd, J¼6.8, 1.2 Hz, 2H) ppm.
4.3.2. 1-(2-Imino-2H-chromen-3-yl)pyridinium chloride 3b.9 Yellow
solid, 45%. 1H NMR (400 MHz, DMSO-d6):
d 7.30e7.35 (m, 2H), 7.63
(td, J¼7.6, 1.6 Hz, 1H), 7.68 (dd, J¼7.6, 1.6 Hz 1H), 8.28 (s, 1H), 8.35
(td, J¼6.4, 1.6 Hz, 2H), 8.83 (tt, J¼7.6, 1.6 Hz, 1H), 9.02 (br s, 1H), 9.32
(dt, J¼5.6, 1.6 Hz, 2H) ppm.
4.3.3. 1-(8-Hydroxy-2-imino-2H-chromen-3-yl)pyridinium chloride
3c.9 Yellow solid, 86%. 1H NMR (400 MHz, DMSO-d6):
d 7.05 (dd,
J¼7.6, 1.6 Hz, 1H), 7.11 (t, J¼7.6 Hz, 1H), 7.27 (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.
4. Experimental section
4.1. General
4.3.4. 1-(2-Imino-6-methoxy-2H-chromen-3-yl)pyridinium chloride
3d.9 Yellow solid, 69%. 1H NMR (400 MHz, DMSO-d6):
d 3.80 (s, 3H),
7.21 (dd, J¼9.0, 2.8 Hz, 1H), 7.24 (d, J¼2.8 Hz, 1H), 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.
All compounds were fully characterized by elemental analysis
and spectroscopic data. The NMR spectra were recorded on a Varian
Unity Plus at 300 MHz for 1H and 75 MHz for 13C or on a Bruker
Avance 3400 at 400 MHz for 1H and 100 MHz for 13C, including the
1He13C correlation spectra (HMQC and HMBC). Deuterated DMSO
4.3.5. 1-(2-Imino-6-hydroxy-2H-chromen-3-yl)pyridinium chloride
3e. Brown solid, 78%. Mp 205e207 ꢀC; IR (Nujol mull)
n
3600e1700
1H NMR (400 MHz,
7.05e7.10 (m, 2H), 7.14 (d, J¼8.8 Hz, 1H), 8.16 (s, 1H),
8.32 (t, J¼6.8 Hz, 2H), 8.74e8.83 (m, 2H), 9.29 (dd, J¼6.8,1.2 Hz, 2H),
10.06 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
114.2, 116.2,
(br, fringed), 1663, 1623, 1612, 1577 cmꢁ1
DMSO-d6):
;
was used as solvent. The chemical shifts are expressed in
d
(ppm)
d
and the coupling constants (J) in hertz (Hz). The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet
and br, broad. IR spectra were recorded on an FT-IR Bomem MB
using Nujol mulls and NaCl cells. The reactions were monitored by
thin layer chromatography using silica gel 60 F254 (Merck and
MachereyeNagel). The melting points were determined on a Stuart
SMP3 melting point apparatus. Elemental analyses were performed
on a LECO CHNS-932 instrument or obtained from C.A.C.T.I. (Uni-
versidade de Vigo) using Carlo Erba 1108.
d
118.0, 120.4, 127.7 (2C), 131.1, 134.3, 146.2 (2C), 146.4, 147.9, 151.8,
153.9 ppm; Anal. Calcd for C14H11N2O2Cl$0.25NH4Cl: C, 58.36; H,
4.17; N, 10.94. Found: C, 58.48; H, 4.47; N, 11.13.
4.3.6. 1-(2-Imino-7-hydroxy-2H-chromen-3-yl)pyridinium chloride
3f. Yellow solid, 64%. Mp 207e208 ꢀC; IR (Nujol mull)
n
3287, 3119,
1667, 1630, 1614, 1582 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d
6.74

M. Costa et al. / Tetrahedron 70 (2014) 4869e4875
4873
(s, 1H), 6.78 (d, J¼8.8 Hz, 1H), 7.45 (d, J¼8.8 Hz, 1H), 8.11 (s, 1H), 8.30
(t, J¼7.6 Hz, 2H), 8.72 (s, 1H), 8.78 (td, J¼7.6, 1.6 Hz, 1H), 9.26 (d,
J¼7.6, Hz, 2H), 11.10 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
148.2, 156.6 ppm; Anal. Calcd for C14H10NO3Cl: C, 60.98; H, 3.63; N,
5.08. Found: C, 60.75; H, 3.91; N, 5.13.
d
101.9, 109.2, 112.8, 127.4, 127.7 (2C), 130.9, 134.4, 146.3 (2C), 147.5,
4.4.4. 1-(2-Oxo-6-methoxy-2H-chromen-3-yl)pyridinium
4d. Yellow solid, 53%; Mp 275e277 ꢀC; IR (Nujol mull)
3600e1700 (br, fringed), 1690, 1628, 1575, 1496, 1456 cmꢁ1
NMR (400 MHz, DMSO-d6):
chloride
151.6, 155.0, 162.6 ppm; Anal. Calcd for C14H11N2O2Cl$0.15H2O: C,
60.61; H, 4.08; N, 10.10. Found: C, 60.61; H, 4.42; N, 10.09.
n
1H
;
d
3.90 (s, 3H), 7.42e7.46 (m, 2H), 7.60
4.3.7. 1-(2-Imino-7-hydroxy-8-methyl-2H-chromen-3-yl)pyridinium
(d, J¼10.0 Hz, 1H), 8.40 (td, J¼6.4, 1.2 Hz, 2H), 8.78 (s, 1H), 8.88 (tt,
chloride 3g. Orange solid, 64%. Mp 255e256 ꢀC; IR (Nujol mull)
n
J¼8.0, 1.2 Hz, 1H), 9.28 (dd, J¼6.8, 1.2 Hz, 2H) ppm. 13C NMR
3600e1700 (br, fringed), 1661, 1607, 1462 cmꢁ1; 1H NMR (400 MHz,
DMSO-d6):
(100 MHz, DMSO-d6): d 112.0, 117.9, 118.1, 121.8, 128.0 (2C), 129.4,
140.5, 146.0, 147.6 (2C), 148.3, 156.3, 156.5 ppm; Anal. Calcd for
C15H12NO3Cl$2H2O: C, 55.30; H, 4.92; N, 4.30. Found: C, 55.31; H,
d
2.15 (s, 3H), 6.93 (d, J¼8.4 Hz, 1H), 7.31 (d, J¼8.4 Hz,
1H), 8.08 (s, 1H), 8.29 (t, J¼7.6 Hz, 2H), 8.72 (s, 1H), 8.78 (tt, J¼7.6,
1.2 Hz, 1H), 9.26 (d, J¼6.4, Hz, 2H), 11.00 (s, 1H) ppm; 13C NMR
5.01; N, 4.37.
(100 MHz, DMSO-d6):
d 7.9, 109.3, 110.7, 111.7, 127.0, 127.67, 127.74,
134.8, 146.3 (2C), 147.5, 152.5, 152.8, 160.5 ppm; Anal. Calcd for
15H13N2O2Cl: C, 55.56; H, 4.01; N, 8.64. Found: C, 55.55; H, 4.12; N,
4.4.5. 1-(2-Oxo-6-hydroxy-2H-chromen-3-yl)pyridinium
chloride
C
4e. Brown solid, 74%; Mp higher than 300 ꢀC; IR (Nujol mull)
n
8.71.
3600e1700 (br, fringed), 1720, 1687, 1623, 1633, 1570, 1486,
1463 cmꢁ1; 1H NMR (300 MHz, DMSO-d6):
d
7.26 (d, J¼2.7 Hz, 1H),
4.3.8. 1-(2-Imino-6-chloro-2H-chromen-3-yl)pyridinium
chloride
3600e1700
7.30 (dd, J¼9.0, 2.7 Hz, 1H), 7.48 (d, J¼9.0 Hz, 1H), 8.38 (td, J¼7.2,
1.2 Hz, 2H), 8.76 (s, 1H), 8.86 (td, J¼7.2, 1.2 Hz, 1H), 9.27 (dd, J¼6.9,
3h. Beige solid, 34%. Mp 229e230 ꢀC; IR (Nujol mull)
n
(br, fringed), 1666, 1461 cmꢁ1; 1H NMR (300 MHz, DMSO-d6):
d
7.35
1.2 Hz, 2H),10.38 (s,1H) ppm; 13C NMR (75 MHz, DMSO-d6):
d 113.7,
(d, J¼9.0 Hz, 1H), 7.66 (dd, J¼9.0, 2.7 Hz, 1H), 7.82 (d, J¼2.7 Hz, 1H),
117.6, 118.1, 122.4, 128.0 (2C), 129.1, 140.8, 146.0 (2C), 148.2, 154.8,
156.6 ppm; Anal. Calcd for C14H10NO3Cl: C, 60.98; H, 3.63; N, 5.08.
Found: C, 60.79; H, 3.91; N, 5.15.
8.22 (s, 1H), 8.35 (t, J¼7.8 Hz, 2H), 8.84 (tt, J¼7.8, 1.2 Hz, 1H), 9.29
(dd, J¼6.8, 1.2 Hz, 2H) ppm. 13C NMR (75 MHz, DMSO-d6):
d 117.4,
119.3, 127.9, 128.0, 128.7, 131.9, 132.6, 133.0, 146.1 (2C), 148.2, 150.9,
152.0 ppm; Anal. Calcd for C14H10N2OCl2: C, 57.34; H, 3.41; N, 9.56.
Found: C, 57.32; H, 3.42; N, 9.66.
4.4.6. 1-(2-Oxo-7-hydroxy-2H-chromen-3-yl)pyridinium
4f. Yellow solid, 91%; Mp higher than 300 ꢀC; IR (Nujol mull)
3600e1700 (br, fringed), 1717, 1695, 1608, 1460 cmꢁ1 1H NMR
(400 MHz, DMSO-d6):
chloride
n
;
d
7.01e7.06 (m, 2H), 7.72 (d, J¼8.4 Hz, 1H),
4.4. General procedure for the synthesis of 1-(2-oxo-2H-
chromen-3-yl)pyridinium chlorides 4
8.35 (td, J¼6.8, 1.2 Hz, 2H), 8.71 (s, 1H), 8.83 (tt, J¼7.6, 1.2 Hz, 1H),
9.25 (dd, J¼6.8, 1.2 Hz, 2H), 11.52 (s, 1H) ppm; 13C NMR (100 MHz,
DMSO-d6):
d 102.5, 109.7, 114.8, 124.9, 127.8 (2C), 131.6, 141.2, 146.1
Concentrated HCl (1.8 mmol, 3 M equiv) was added to a solution
(2C), 147.8, 155.4, 156.8, 163.9 ppm; Anal. Calcd for C14H10NO3Cl: C,
60.98; H, 3.63; N, 5.08. Found: C, 60.91; H, 3.72; N, 5.06.
of
1-(2-imino-2H-chromen-3-yl)pyridinium
chloride
3
(0.60 mmol) in water (3 ml) and the reaction mixture was stirred in
a water bath at 80 ꢀC. After 2e3 h the solvent was removed in the
rotary evaporator and acetone was added to the crude mixture to
precipitate a solid that was filtered and washed with acetone. The
solid was identified as 1-(2-oxo-2H-cromen-3-yl)pyridinium chlo-
ride 4, in some cases contaminated with NH4Cl in variable ratios
(calculated by 1H NMR). For characterization purposes, compounds
4 were recrystallized in ethanol, whenever the presence of NH4Cl
was detected.
4.4.7. 1-(2-Oxo-8-hydroxy-7-methyl-2H-chromen-3-yl)pyridinium
chloride 4g. Yellow solid, 94%; Mp higher than 300 ꢀC; IR (Nujol
mull)
NMR (300 MHz, DMSO-d6):
n ;
3600e1700 (br, fringed), 1720, 1678, 1580, 1461 cmꢁ1 1H
d
2.22 (s, 3H), 7.15 (d, J¼8.4 Hz,1H), 7.58
(d J¼8.4 Hz, 1H), 8.36 (td, J¼6.6, 1.2 Hz, 2H), 8.58 (s, 1H), 8.83 (tt,
J¼7.8, 1.2 Hz, 1H), 9.25 (dd, J¼6.8, 1.2 Hz, 2H), 11.40 (s, 1H) ppm; 13
C
NMR (75 MHz, DMSO-d6):
d 7.92, 109.8, 111.2, 113.6, 124.6, 128.0
(2C), 128.5, 141.6, 146.1 (2C), 147.8, 153.3, 157.0, 161.8 ppm; Anal.
Calcd for C15H12NO3Cl: C, 62.17; H, 4.14; N, 4.86. Found: C, 59.99; H,
0.17; N, 4.85.
4.4.1. 1-(2-Oxo-8-methoxy-2H-chromen-3-yl)pyridinium
4a.9 Yellow solid, 83%; 1H NMR (300 MHz, DMSO-d6):
chloride
3.98 (s, 3H),
d
7.43e7.51 (m, 2H), 7.55 (d, J¼7.1, 2.4 Hz, 1H), 8.41 (td, J¼6.3, 1.8 Hz,
4.5. General procedure for the synthesis of 3-amino-2H-
chromen-2-ones 5
2H), 8.85e8.92 (m, 2H), 9.31 (dd, J¼7.1, 1.5 Hz, 2H) ppm.
4.4.2. 1-(2-Oxo-2H-chromen-3-yl)pyridinium chloride 4b. Beige solid,
N-Methylpiperazine (10 mmol, 5 M equiv) was added to a sus-
69%; Mp higher than 300 ꢀC; IR (Nujol mull)
n
3600e1700 (br,
1H NMR (300 MHz,
7.54(t, J¼6.9Hz,1H), 7.62(d, J¼8.4Hz,1H), 7.85(td,J¼7.9,
1.5 Hz,1H), 7.93 (dd, J¼7.9,1.2Hz,1H), 8.41 (t, J¼6.6Hz, 2H), 8.86e8.92
(m, 2H), 9.31 (s,1H) ppm. 13C NMR (75 MHz, DMSO-d6):
116.7, 117.6,
pension of 1-(2-oxo-2H-cromen-3-yl)pyridinium chloride
4
fringed), 1710, 1696, 1628, 1610, 1461 cmꢁ1
DMSO-d6):
;
(2 mmol, contaminated with NH4Cl) in acetone (50 ml) and an
orange/red suspension was formed and stirred at room tempera-
ture. After 2e3 h a red solution was obtained and after a further
18e24 h the solvent was removed in the rotary evaporator leading
to a red oil. Flash chromatography was performed using ethyl ac-
etate as eluent. Several crops were isolated, all containing the pure
product by TLC. The crops were combined and the solvent was
removed in the rotary evaporator. The solid was collected and
identified as 3-amino-2H-chromen-2-one derivative 5.
d
d
125.8, 128.0 (2C), 129.0, 130.2, 134.4, 140.8, 146.0 (2C), 148.4, 153.2,
156.5 ppm; Anal. Calcd for C14H10NO2Cl$0.1NH4Cl$0.8H2O: C, 60.16;
H, 4.30; N, 5.52. Found: C, 59.82; H, 4.17; N, 5.29.
4.4.3. 1-(2-Oxo-8-hydroxy-2H-chromen-3-yl)pyridinium
4c. Yellow solid, 75%; Mp 242e244 ꢀC; IR (Nujol mull)
(br, fringed), 1718, 1618, 1572, 1463 cmꢁ1
DMSO-d6):
chloride
n
3600e1700
;
1H NMR (300 MHz,
4.5.1. 3-Amino-8-methoxy-2H-chromen-2-one 5a.11 Orange solid,
d
7.26e7.35 (m, 2H), 7.43 (dd, J¼7.6, 2.4 Hz, 1H), 8.39 (td,
99% yield. Mp 128e129 ꢀC; IR (Nujol mull)
n
3453, 3362, 1706, 1635,
J¼6.3, 1.5 Hz, 2H), 8.78 (s, 1H), 8.87 (tt, J¼7.8, 1.2 Hz, 1H), 9.28 (dd,
1612, 1573, 1461 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d
3.85 (s, 3H),
J¼6.6, 1.2 Hz, 2H), 10.88 (s, 1H) ppm; 13C NMR (75 MHz, DMSO-d6):
5.68 (s, 2H), 6.67 (s, 1H), 6.91 (dd, J¼8.2, 1.2 Hz, 1H), 6.96 (dd, J¼7.6,
d
118.5, 119.7, 120.5, 125.8, 128.0 (2C), 129.0, 141.7, 145.1, 146.0 (2C),
1.2 Hz, 1H), 7.12 (t, J¼8.0 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-

4874
M. Costa et al. / Tetrahedron 70 (2014) 4869e4875
d6):
d
55.8, 107.7, 108.2, 116.6, 122.4, 124.4, 133.5, 136.9, 146.2,
1609, 1556, 1460 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
; d 5.22 (s,
158.3 ppm; Anal. Calcd for C10H9NO3: C, 62.83; H, 4.71; N, 7.33.
Found: C, 62.81; H, 4.95; N, 7.05.
2H), 6.63e6.69 (m, 3H), 7.22 (d, J¼8.7 Hz, 1H), 9.80 (s, 1H) ppm; 13
C
NMR (75 MHz, DMSO-d6):
d 101.8, 109.8, 113.0, 113.5, 125.7, 130.2,
149.3, 156.1, 159.0 ppm; Anal. Calcd for C9H7NO3: C, 61.02; H, 3.95;
N, 7.91. Found: C, 61.31; H, 4.23; N, 8.12.
4.5.2. 3-Amino-2H-chromen-2-one 5b. Yellow solid, 98% yield. 1H
NMR (400 MHz, DMSO-d6): d 5.68 (s, 2H), 6.70 (s, 1H), 7.18e7.40 (m,
3H), 7.39 (d, J¼7.8 Hz, 1H) ppm.
4.5.7. 3-Amino-7-hydroxy-8-methyl-2H-chromen-2-one
5g. N-
Methylpiperazine (0.36 g, 3.61 mmol, 409 l, 5 equiv) was added to
m
4.5.3. 3-Amino-8-hydroxy-2H-chromen-2-one 5c. N-Methylpiper-
a suspension of 1-(2-oxo-8-hydroxy-7-methyl-2H-cromen-3-yl)
pyridinium chloride 4g (0.21 g, 0.72 mmol) in acetone (30 ml) and
water (0.6 ml). The reaction mixture was heated at 70 ꢀC and after
3 h a red solution was obtained. The solvent was removed in the
rotary evaporator after 19 h. Flash chromatography was performed
using ethyl acetate (150 ml) as eluent. The solvent was removed in
the rotary evaporator and a red solid was collected and identified as
3-amino-8-hydroxy-7methyl-2H-chromen-2-one 5g (0.084 g,
azine (0.41 g, 4.05 mmol, 458
ml, 7.2 equiv) was added to a sus-
pension of 1-(2-oxo-8-hydroxy-2H-cromen-3-yl)pyridinium
chloride 4c, contaminated with NH4Cl in a 1:1 ratio (0.19 g,
0.58 mmol) in acetone (25 ml) and water (0.5 ml). The reaction
mixture was heated at 70 ꢀC and after 4 h a red solution was ob-
tained. The reaction mixture was heated for a further 5 h and the
solvent was removed in the rotary evaporator. Flash chromatog-
raphy was performed using ethyl acetate (90 ml) as eluent. The
solvent was removed in the rotary evaporator and a red solid was
collected and identified as 3-amino-8-hydroxy-2H-chromen-2-one
0.44 mmol, 61% yield). Mp 213e214 ꢀC; IR (Nujol mull)
n 3443,
3380, 3254, 1679, 1633, 1604, 1568, 1461 cmꢁ1; 1H NMR (300 MHz,
DMSO-d6):
d
2.13 (s, 3H), 5.17 (s, 2H), 6.68 (s, 1H), 6.73 (d, J¼8.4 Hz,
(87.8 mg, 0.50 mmol, 86% yield). Mp 192e192 ꢀC; IR (Nujol mull)
3454, 3439, 3365, 1706, 1634, 1594, 1567, 1460 cmꢁ1 1H NMR
(300 MHz, DMSO-d6):
5.61 (s, 2H), 6.65 (s, 1H), 6.72 (dd, J¼7.8,
1.5 Hz, 1H), 6.80 (dd, J¼7.8, 1.5 Hz, 1H), 6.97 (t, J¼7.8 Hz, 1H), 9.85 (s,
1H) ppm; 13C NMR (75 MHz, DMSO-d6):
108.2, 112.4, 115.1, 122.7,
n
1H), 7.05 (d, J¼8.4 Hz, 1H), 9.71 (s, 1H) ppm; 13C NMR (75 MHz,
;
DMSO-d6): d 8.1, 110.3, 110.5, 112.1, 113.5, 122.4, 129.8, 147.7, 154.1,
d
159.3 ppm; Anal. Calcd for C10H9NO3: C, 62.83; H, 4.71; N, 7.33.
Found: C, 62.95; H, 4.74; N, 7.46.
d
124.4, 133.2, 136.6, 144.2, 158.5 ppm; Anal. Calcd for C9H7NO3: C,
61.02; H, 3.95; N, 7.91. Found: C, 61.15; H, 4.09; N, 7.98.
4.6. General procedure for the synthesis of 2-imino-2H-
chromen-3-amines 9
4.5.4. 3-Amino-6-methoxy-2H-chromen-2-one 5d.12 Yellow solid,
N-Methylpiperazine (1.5 mmol, 5 equiv) was added to a sus-
pension of 1-(2-imino-2H-chromen-3-yl)pyridinium chloride de-
rivatives 3 (0.30 mmol) in acetonitrile or acetone (12 ml) and a red
solution/suspension was obtained and stirred at room temperature.
After 17e48 h the solvent was removed in the rotary evaporator
leading to a red oil. Flash chromatography was performed using
ethyl acetate as eluent to separate the product and the solvent was
removed in the rotary evaporator. The orange solid was collected
and identified as 2-imino-2H-chromen-3-amine 9.
93% yield. Mp 130e131 ꢀC; IR (Nujol mull)
n
3428, 3311, 1710, 1638,
1612,1573,1462 cmꢁ1; 1H NMR (300 MHz, DMSO-d6):
d
3.75 (s, 3H),
5.71 (s, 2H), 6.66 (s, 1H), 6.78 (dd, J¼8.8, 3.0 Hz, 1H), 6.95 (d,
J¼3.0 Hz, 1H), 7.18 (t, J¼8.7 Hz, 1H) ppm; 13C NMR (75 MHz, DMSO-
d6):
d 55.5, 107.50, 107.54, 112.4, 116.3, 122.5, 133.6, 142.3, 155.9,
158.7 ppm; Anal. Calcd for C10H9NO3: C, 62.83; H, 4.71; N, 7.33.
Found: C, 63.19; H, 5.04; N, 7.39.
4.5.5. 3-Amino-6-hydroxy-2H-chromen-2-one
erazine (0.29 g, 2.92 mmol, 330 l, 7 equiv) was added to a sus-
5e.11 N-Methylpip
m
4.6.1. 2-Imino-8-methoxy-2H-chromen-3-amine 9a. Orange solid,
pension of 1-(2-oxo-6-hydroxy-2H-cromen-3-yl)pyridinium chlo-
ride 4e, contaminated with NH4Cl in a 1:1 ratio (0.14 g, 0.41 mmol)
in acetone (22 ml) and water (0.5 ml). The reaction mixture was
heated at 70 ꢀC and after a few minutes a red solution was obtained.
After 9 h the solvent was removed in the rotary evaporator and
flash chromatography was performed using ethyl acetate (80 ml) as
eluent. The solvent was removed in the rotary evaporator and an
orange solid was collected and identified as 3-amino-6-hydroxy-
2H-chromen-2-one 5e (52.2 mg, 0.30 mmol, 71% yield). Mp
70% yield. Mp 115e117 ꢀC; IR (Nujol mull)
n
3422, 3291, 3235e3078
(br), 1645, 1620, 1557, 1450 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6):
d
3.81 (s, 3H), 5.43 (s, 2H), 6.18 (s, 1H), 6.74e6.79 (m, 2H), 6.95 (t,
J¼8.1 Hz, 1H), 8.30 (s, 1H) ppm; 13C NMR (75 MHz, DMSO-d6):
d
55.5,100.9,107.8, 116.3, 123.0, 123.1,134.8,137.2, 145.8,153.4 ppm;
Anal. Calcd for C10H10N2O2: C, 63.16; H, 5.26; N, 14.74. Found: C,
63.20; H, 5.27; N, 14.74.
4.6.2. 2-Imino-2H-chromen-3-amine 9b. Orange solid, 42% yield.
213e214 ꢀC; IR (Nujol mull)
n
3465, 3390, 3347, 1683, 1630, 1561,
5.59 (s, 2H), 6.59 (s,
Mp 116e118 ꢀC; IR (Nujol mull)
n
3429, 3366e3120 (br), 1644, 1626,
1588, 1451 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
5.45 (s, 2H), 6.22
(s, 1H), 7.00e7.05 (m, 3H), 7.17 (d, J¼8.0 Hz, 1H), 8.27 (s, 1H) ppm;
13C NMR (100 MHz, DMSO-d6):
101.1, 114.2, 122.3, 123.3, 124.1,
1461 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
d
d
1H), 6.63 (dd, J¼8.8, 2.8 Hz, 1H), 6.70 (d, J¼2.8 Hz, 1H), 7.08 (d,
J¼8.8 Hz, 1H), 9.37 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
d
d
107.7,109.2,113.2,116.2,122.4,133.3,141.5,153.9,158.8 ppm; Anal.
124.4, 134.4, 148.3, 154.1 ppm; Anal. Calcd for C9H8N2O: C, 67.50; H,
5.00; N, 17.50. Found: C, 67.51; H, 5.06; N, 17.64.
Calcd for C9H7NO3: C, 61.02; H, 3.95; N, 7.91. Found: C, 61.34; H,
4.34; N, 7.83.
4.6.3. 2-Imino-8-hydroxy-2H-chromen-3-amine 9c and 4-methyl-1-
(5-(4-methylpiperazin-1-yl)penta-2,4-dien-1-ylidene)piperazin-1-
4.5.6. 3-Amino-7-hydroxy-2H-chromen-2-one 5f.13 N-Methylpiper-
azine (0.29 g, 2.92 mmol, 330
ml, 5 equiv) was added to a suspension
ium chloride 10. N-Methylpiperazine (0.62 g, 6.18 mmol, 700 ml,
of 1-(2-oxo-7-hydroxy-2H-cromen-3-yl)pyridinium chloride 4f,
contaminated with NH4Cl in a 1:0.7 ratio (0.18 g, 0.58 mmol) in
acetone (25 ml) and water (0.5 ml). The reaction mixture was
refluxed for 9 h. The solvent was removed in the rotary evaporator
and flash chromatography was performed using ethyl acetate
(30 ml) as eluent. The solvent was removed in the rotary evapo-
rator, resulting in an orange solid, collected and identified as 3-
amino-7-hydroxy-2H-chromen-2-one 5f (0.10 g, 0.57 mmol, 98%
7 equiv) was added to a suspension of 1-(2-imino-8-hydroxy-
2H-chromen-3-yl)pyridinium chloride (0.24 g, 0.89 mmol) in
acetone (40 ml) and an orange suspension was obtained and
stirred at room temperature. After 2 days the yellow solid was
filtered and washed with ethyl acetate, leading to a mixture of
2-imino-8-hydroxy-2H-chromen-3-amine
and
piperazinium
chloride 10 (1:1 ratio), by 1H NMR. Flash chromatography of the
isolated mixture was performed using a mixture of DCM and
MeOH 4e10% (150 ml) as eluent. The solvents of this orange
yield). Mp 244e245 ꢀC; IR (Nujol mull)
n 3438, 3347, 3173, 1680,

M. Costa et al. / Tetrahedron 70 (2014) 4869e4875
4875
solution were removed in the rotary evaporator and the orange
solid was collected and identified as 2-imino-8-hydroxy-2H-
chromen-3-amine 9c (52.9 mg, 0.30 mmol, 47% yield). Mp
124.4, 127.1, 135.7, 146.7, 153.0 ppm; Anal. Calcd for C9H7N2OCl: C,
55.53; H, 3.60; N, 14.40. Found: C, 55.56; H, 3.65; N, 14.51.
168e170 ꢀC; IR (Nujol mull)
n
3485e3091 (br), 1658, 1626, 1563,
5.36 (s, 2H), 6.16 (s,
Acknowledgements
1457 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
d
1H), 6.59 (dd, J¼7.8, 1.2 Hz, 1H), 6.61 (dd, J¼7.8, 1.2 Hz, 1H), 6.80
We gratefully acknowledge the financial support from Univer-
sity of Minho. The ‘Foundation for Science and Technology’ provide
the financial support for the Portuguese NMR network (RNRMN),
the Project F-COMP-01-0124-FEDER-022716 (ref. FCT PEst-C/QUI/
UI0686/2013) and the Post-Doc grant awarded to M.C.(SFRH/BPD/
79609/2011).
(t, J¼8.8 Hz, 1H), 8.00 (s, 1H), 9.51 (s, 1H) ppm; 13C NMR
(100 MHz, DMSO-d6):
d 108.2, 112.4, 115.1, 122.7, 124.4, 133.2,
136.5, 144.2, 158.5 ppm; Anal. Calcd for C9H8N2O2: C, 61.36; H,
4.54; N, 15.91. Found: C, 61.54; H, 4.52; N, 15.95.
Flash chromatography was continued using a mixture of DCM
and MeOH 12e20% (150 ml) as eluent and the solvent of this
orange solution was removed in the rotary evaporator. An or-
ange oil was obtained and identified as piperazinium chloride 9c
(44.4 mg, 0.145 mmol). Silica from the flash chromatography
was stirred, at room temperature, in 100 ml of a mixture of
DCM and MeOH 20% for 17 h. The silica was filtered off and the
solvent of the yellow solution was removed in the rotary
evaporator. An orange oil was obtained and identified as a sec-
ond crop of piperazinium chloride (11.2 mg, 0.04 mmol). 4-
Methyl-1-(5-(4-methylpiperazin-1-yl)penta-2,4-dien-1-ylidene)
piperazin-1-ium chloride 10 was isolated as an orange oil and in
a total yield of 21% (0.56 g, 0.18 mmol). 1H NMR (400 MHz,
Supplementary data
Copies of 1H NMR and 13C NMR spectra of all intermediates and
final products. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2014.05.074.
References and notes
1. Selected examples: (a) Maes, D.; Vervisch, S.; Debenedetti, S.; Davio, C.; Man-
gelinckx, S.; Giubellina, N.; De Kimpe, N. Tetrahedron 2005, 61, 2505e2511; (b)
Gutierrez, M.; Parry, M.; Tena, M.; Jorrin, J.; Edwards, R. Phytochemistry 1995, 38,
1185e1191; (c) Chiang, C.; Cheng, M.; Huang, H.; Chang, H.; Wang, C.; Cheng, I. J.
DMSO-d6):
d
2.23 (s, 6H), 2.43e2.50 (m, 8H), 3.57 (t, J¼4.8 Hz,
ꢀ
Nat. Prod. 2010, 73, 1718e1722; (d) Guilet, D.; Seraphin, D.; Rondeau, D.; Ri-
4H), 3.62 (t, J¼4.8 Hz, 4H), 5.94 (t, J¼12.0 Hz, 2H), 7.48 (t,
chomme, P.; Bruneton, J. Phytochemistry 2001, 58, 571e575; (e) Liang, D.; Luo,
H.; Liu, Y.; Hao, Z.; Wang, Y.; Zhang, C.; Zhang, Q.; Chen, R.; Yu, D. Tetrahedron
2013, 69, 2093e2097; (f) Ribeiro, A.; Abdelnur, P.; Garcia, C.; Belini, A.; Severino,
V.; Silva, F.; Fernandes, J.; Vieira, P.; Carvalho, S.; Souza, A.; Machado, M. J. Agric.
Food Chem. 2008, 56, 7815e7822.
J¼12.4 Hz, 1H), 7.84 (d, J¼12.0 Hz, 2H) ppm; 13C NMR (100 MHz,
DMSO-d6):
d 45.0 (2C), 45.7 (2C), 53.4 (2C), 54.4 (2C), 102.7 (2C),
160.1 (2C), 163.1 ppm.
2. Selected examples: (a) Dong, Y.; Morris-Natschke, S.; Lee, K. Nat. Prod. Rep. 2011,
ꢀ
ꢀ
ꢀ
4.6.4. 2-Imino-6-methoxy-2H-chromen-3-amine 9d. Orange solid,
28, 529e542; (b) Lopez-Perez, J.; Olmedo, D.; Olmo, E.; Vasquez, Y.; Solís, P.;
Gupta, M.; Feliciano, A. J. Nat. Prod. 2005, 68, 369e373; (c) Meepagala, K.;
Schrader, K.; Burandt, C.; Wedge, D.; Duke, S. J. Agric. Food Chem. 2010, 58,
9476e9482; (d) Oketch-Rabah, H.; Lemmich, E.; Dossaji, S.; Theander, T.; Olsen,
C.; Cornett, C.; Kharazmi, A.; Christensen, S. J. Nat. Prod. 1997, 60, 458e461; (e)
Cheng, S.; Huang, K.; Wang, S.; Wen, Z.; Chen, P.; Duh, C. J. Nat. Prod. 2010, 73,
771e775; (f) Wang, J.; Chung, K.; Park, J.; Cho, M.; Seo, J.; Song, D.; Yoon, H.;
Park, C.; Joe, B.; Choi, J.; Kim, M.; Han, G. Bioorg. Med. Chem. 2010, 18,
60% yield. Mp 136e138 ꢀC; IR (Nujol mull)
n
3453, 3322, 3272, 1644,
1620, 1601, 1563, 1488, 1451 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6):
d
3.71 (s, 3H), 5.48 (s, 2H), 6.19 (s, 1H), 6.61 (dd, J¼8.8, 2.8 Hz, 1H),
6.75 (d, J¼2.8 Hz, 1H), 6.94 (d, J¼8.8 Hz, 1H), 8.14 (s, 1H) ppm; 13C
NMR (100 MHz, DMSO-d6):
d 55.3, 101.1, 107.9, 110.6, 114.8, 123.0,
134.9, 142.6, 154.5, 155.1 ppm; Anal. Calcd for C10H10N2O2: C, 63.16;
H, 5.26; N, 14.74. Found: C, 63.18; H, 5.16; N, 14.75.
^
8618e8629; (g) Ducharme, Y.; Blouin, M.; Brideau, C.; Chateauneuf, A.; Gareau,
Y.; Grimm, E.; Juteau, H.; Laliberte, S.; Mackay, B.; Masse, F.; Ouellet, M.; Salem,
M.; Sthyler, A.; Friesen, R. ACS Med. Chem. Lett. 2010, 1, 170e174.
ꢀ
ꢀ
3. Selected examples: (a) Shyamala, B.; Ananthalakshmi, P.; Raju, V.; Rao, P.;
Reddy, P. Biometals 1992, 5, 23e27; (b) Kokotos, G.; Theodorou, V.; Tzougraki,
C.; Deforce, D.; Van den Eeckhout, E. Bioorg. Med. Chem. Lett. 1997, 7,
2165e2168; (c) Alt, S.; Burkard, N.; Kulik, A.; Grond, S.; Heide, L. Chem. Biol.
2011, 18, 304e313; (d) Matos, M.; Vilar, S.; Gonzalez-Franco, R.; Uriarte, E.;
Santana, L.; Friedman, C.; Tatonetti, N.; Vina, D.; Fontenla, J. Eur. J. Med. Chem.
2013, 63, 151e161.
4. Heide, L. Nat. Prod. Rep. 2009, 26, 1241e1250.
5. Hoper, D.; Wolfson, J.; McHugh, G.; Winters, M.; Swarz, M. Antimicrob. Agents
Chemother. 1982, 22, 662e671.
4.6.5. 2-Imino-6-hydroxy-2H-chromen-3-amine 9e. Orange solid,
52% yield. Mp 200 ꢀC (decomp.); IR (Nujol mull)
n
3397, 3297,
3247e3097 (br), 1638, 1607, 1563, 1488, 1457 cmꢁ1 1H NMR
(400 MHz, DMSO-d6):
5.39 (s, 2H), 6.12 (s, 1H), 6.46 (dd, J¼8.8,
2.8 Hz,1H), 6.52 (d, J¼2.8 Hz,1H), 6.84 (d, J¼8.8 Hz,1H), 8.06 (s,1H),
9.10 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
101.3, 109.3,
;
d
~
d
111.6, 114.7, 122.8, 134.6, 141.7, 153.0, 154.6 ppm; Anal. Calcd for
C9H8N2O2: C, 61.36; H, 4.54; N, 15.91. Found: C, 61.36; H, 4.58; N,
15.99.
6. (a) Marcu, M.; Chadli, A.; Bouhouche, I.; Catelli, M.; Neckers, L. J. Biol. Chem.
2000, 275, 37181e37186; (b) Marcu, M.; Schulte, T.; Neckers, L. J. Natl. Cancer
Inst. 2000, 92, 242e248.
7. Selected examples: (a) Burlison, J.; Neckers, L.; Smith, A.; Maxwell, A.; Blagg, B.
J. Am. Chem. Soc. 2006, 128, 15529e15536; (b) Le Bras, G.; Radanyi, C.; Peyrat, J.;
Brion, J.; Alami, M.; Marsaud, V.; Stella, B.; Renoir, J. J. Med. Chem. 2007, 50,
6189e6200; (c) Donnelly, A.; Mays, J.; Burlison, J.; Nelson, J.; Vielhauer, G.;
Holzbeierlein, J.; Blagg, B. J. Org. Chem. 2008, 73, 8901e8920; (d) Radanyi, C.; Le
Bras, G.; Messaoudi, S.; Bouclier, C.; Peyrat, J.; Brion, J.; Marsaud, V.; Renoir, J.;
Alami, M. Bioorg. Med. Chem. Lett. 2008, 18, 2495e2498; (e) Kusuma, B.;
Duerfeldt, A.; Blagg, B. Bioorg. Med. Chem. Lett. 2011, 21, 7170e7174; (f) Kusuma,
B.; Peterson, L.; Zhao, H.; Vielhauer, G.; Holzbeierlein, J.; Blagg, B. J. Med. Chem.
2011, 54, 6234e6253; (g) Kamal, G.; Gunaherath, B.; Marron, M.; Wijeratne, E.;
Whitesell, L.; Gunatilaka, A. Bioorg. Med. Chem. 2013, 18, 5118e5129.
8. (a) Linch, F. J. Chem. Soc., Trans. 1912, 101, 1758e1765; (b) Kudale, A.; Kendall, J.;
Warford, C.; Wilkins, N.; Bodwell, G. Tetrahedron Lett. 2007, 48, 5077e5080.
9. Proenc¸ a, M.; Costa, M. Tetrahedron 2010, 66, 4542e4550.
4.6.6. 2-Imino-7-hydroxy-2H-chromen-3-amine 9f. Orange solid,
61% yield. Mp 178 ꢀC (decomp.); IR (Nujol mull)
n
3435, 3353e3065
(br), 1632, 1607, 1556, 1500, 1457 cmꢁ1; 1H NMR (400 MHz, DMSO-
d6):
d
5.03 (s, 2H), 6.18 (s, 1H), 6.45 (d, J¼2.4 Hz, 1H), 6.49 (dd, J¼8.4,
2.4 Hz, 1H), 6.99 (d, J¼8.4 Hz, 1H), 8.08 (s, 1H), 9.51 (s, 1H) ppm; 13
C
NMR (100 MHz, DMSO-d6):
d 101.3, 102.8, 111.1, 113.8, 124.9, 131.5,
149.4, 155.3 (2C) ppm; Anal. Calcd for C9H8N2O2: C, 61.36; H, 4.54;
N, 15.91. Found: C, 61.37; H, 4.58; N, 16.02.
4.6.7. 2-Imino-6-hydroxy-2H-chromen-3-amine 9g. Orange solid,
54% yield. Mp 176e178 ꢀC; IR (Nujol mull)
n
3441, 3322, 3285, 1644,
1H NMR (400 MHz, DMSO-d6):
5.64 (s, 2H), 6.18 (s, 1H), 6.90e7.05 (m, 2H), 7.28 (s, 1H), 8.40 (s,
1H) ppm; 13C NMR (100 MHz, DMSO-d6):
99.3, 115.7, 123.0, 123.4,
€
ꢀ
10. (a) Krohnke, F.; Vogt, I. Liebigs Ann. Chem. 1954, 589, 26e44; (b) Dickore, K.;
€
1626, 1588, 1557, 1469, 1457 cmꢁ1
;
Krohnke, F. Chem. Ber 1960, 93, 2479e2485.
11. Khoo, L. Synth. Commun. 1999, 29, 2533e2538.
12. Connor, D. U.S. Patent, 126, 287, 1981.
13. Rodighiero, G.; Antonello, C. Boll. Chim. Farm. 1958, 97, 592e601.
d
d