2-Aryl-1,9-dihydrochromeno[3,2-d]imidazoles: A facile synthesis from salicylaldehydes and arylideneaminoacetonitrile

Article abstract of DOI:10.1016/j.tet.2011.01.035

2-Aryl-1,9-dihydrochromeno[3,2-d]imidazoles were prepared by a one-pot cascade reaction involving salicylaldehydes and arylideneaminoacetonitriles. These novel compounds were isolated in 11-95% yield after reflux in ethanol and triethylamine. A dimeric st

Full text of DOI:10.1016/j.tet.2011.01.035

Tetrahedron 67 (2011) 1799e1804
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2-Aryl-1,9-dihydrochromeno[3,2-d]imidazoles: a facile synthesis from
salicylaldehydes and arylideneaminoacetonitrile
*
Marta Costa, Fernanda Proenc¸ a
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:
2-Aryl-1,9-dihydrochromeno[3,2-d]imidazoles were prepared by a one-pot cascade reaction involving
salicylaldehydes and arylideneaminoacetonitriles. These novel compounds were isolated in 11e95% yield
after reflux in ethanol and triethylamine. A dimeric structure was also identified and partially evolved to
the tricyclic product in DMSO solution, according to an evolution study by 1H NMR spectroscopy.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 3 November 2010
Received in revised form 5 January 2011
Accepted 13 January 2011
Available online 19 January 2011
Keywords:
Salicylaldehyde
Arylideneaminoacetonitrile
Chromene
2-Arylimidazole
Cascade reaction
1. Introduction
(Table 1, compounds 3aek). The reaction was performed in meth-
anol and using an excess of sodium acetate as base. Stirring at room
The chromene scaffold is present in a diversity of natural and
synthetic products and a considerable number of molecules is
known for their potent biological activity.1 Chromene derivatives
temperature resulted in a suspension of the product (for 3a, 3c, 3f
and 3g) that was filtered and used directly without further purifi-
cation. Compounds 3b, 3d, 3e and 3hek were soluble in the re-
action mixture and the pure product was isolated after dry flash
chromatography.
were reported namely as MAO inhibitors,2 human
b-secretase in-
hibitors,3 antagonists at 5-HT receptors,4 and acetylcholinesterase
inhibitors.5 2-Arylimidazoles have been prepared for over a cen-
tury6 and are important building blocks, present in many bioactive
compounds. Some recent examples include anticancer,7 antiviral,8
antibacterial,9 antiinflammatory,10 anticonvulsant,11 and antihy-
pertensive12 activity. The association of these two important scaf-
folds in a single molecule was never reported in the literature.
These new fused tricyclic systems combining the chromene and the
2-aryl imidazole can be considered alternative drug candidates
with improved pharmacological properties.
Table 1
Synthesis of arylideneaminoacetonitriles 3
N
CN
MeOH
NaOAc
rt (2 h)
CHO
R1
H
+
H2N
CN.HCl
R1
R
R
2
1
3
Entry
Aldehyde
R1
R
Product 3
Yield (%)
2. Results and discussion
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
3-OCH3
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
99
97
97
95
65
90
96
97
93
88
98
As part of our research work on the synthesis of chromene de-
rivatives under ecologically benign conditions, salicylaldehydes 1
were combined with a selection of arylideneaminoacetonitriles 3.
These compounds were prepared from the reaction of aromatic
aldehydes 1aek with the hydrochloride salt of aminoacetonitrile
5-Cl
3-OH
5-OH
5-Br
3-OCH3, 5-Br
5-OCH3
4-N(CH2CH3)2
3-Cl
4-Cl
9
10
11
1j
1k
3j
3k
* Corresponding author. Tel.: þ351 253604379; fax: þ351 253 604383; e-mail
H
address: fproenca@quimica.uminho.pt (F. Proenc¸ a).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.035

1800
M. Costa, F. Proenc¸ a / Tetrahedron 67 (2011) 1799e1804
The reaction of these compounds with salicylaldehydes was
reactions where the ratio of compounds 1c and 3c was varied from
1.9:1 to 1:1.8 and 1:3. A threefold excess of arylideneaminoaceto-
nitrile resulted in 95% yield of 4c, and these conditions were used to
perform all reactions.
When aldehydes 1aec, feh were combined with 3 M equiv of
the corresponding (arylideneamino)acetonitrile 3aec, feh and the
ethanolic solution was refluxed for 4 h in the presence of triethyl-
amine, chromeno-imidazophenols 4aec, eeg were isolated in
67e95% yield (Table 3).
initially carried out in 0.05 M aqueous sodium carbonate solution.
These experimental conditions had been successfully used in the
eco-friendly synthesis of 2-iminochromenes from salicylaldehydes
and cyanoacetamides.13 When 3-methoxysalicylaldehyde 1a and 3-
methoxybenzylideneamino-acetonitrile 3a were combined in
aqueous base, extensive darkening of the reaction mixture was
detected after 19 h at room temperature.
Analysis by TLC indicated the complete consumption of com-
pound 3a and the presence of unreacted aldehyde. Hydrolysis of
the imine was considered a possible cause for the unsuccess of this
reaction and different organic bases were used in ethanol and
acetonitrile.
The optimized reaction conditions were selected from a study
using 5-chlorosalicylaldehyde 1c and the corresponding arylide-
neaminoacetonitrile 3c. These reagents were combined in a 1:1 M
ratio using acetonitrile as solvent and DBU, 1-methylpiperazine or
triethylamine as catalyst (Table 2).
Table 3
Synthesis of compounds 4, using 3 M equiv of arylideneamineacetonitrile 3, NEt3
catalysis and reflux in ethanol
N
CN
EtOH, NEt3 (cat.)
ref lux
(4h - 7h)
R1
CHO
R1
R
N
H
+
N
H
O
R1
R
R
R
1
4
3
Entry
Aldehyde 1
Compound 3
Product
Yield (%)
Table 2
1
2
3
4
5
6
9
1a
1b
1c
1c
1f
3a
3b
3c
3k
3f
4a
4b
4c
4d
4e
4f
80
68
95
11
94
67
94
Optimization of the reaction conditions for the synthesis of 4-chloro-2-(7-chloro-
3,9-dihydrochromeno[3,2-d]imidazol-2-yl)phenol 4c
N
CN
O
Cl
H
N
Cl
Cl
Cl
H
H
+
1g
1h
3g
3h
N
4g
O
OH
OH
HO
3c
4c
1c
An experiment was carried out combining 2 M equiv of 2-(4-
chlorobenzylideneamino)acetonitrile 3k with 5-chlorosalicylal-
dehyde 1cinethanol and triethylamine(Table 3, entry4). Thereaction
mixture was refluxed for 5 h and 40 min leading to a solid material
identified by 1H NMR as a mixture of 4c and 4d in a 1:3 M ratio
(Scheme 1). A pure sample of 4d was isolated from the solution in 11%
yield.
Equiv
3c/1c
Solvent
Catalyst
Reaction conditions
Product,
yield (%)
1:1
1:1
CH3CN
CH3CN
DBU
DBU
rt, 23 h
4cþ5a
4c, 29
1. rt, 2 h
2. Reflux,b 15 min
1. rt, 1 h 10 min
1:1
CH3CN
CH3CN
1-Methyl
-piperazine
4cþ5c
4c, 29
2. 10 ꢀC, 2 h 15 min
1. rt, 1 h 15 min
2. Reflux,b 30 min
3. 80 ꢀC, 21 h
1:1.1
NEt3
N
CN
O
H
N
Cl
Cl
EtOH
H
H
+
Cl
2.2:1
CH3CN
NEt3
4c, 24
1. rt, 28 h
2. Reflux,b 1 h 20 min
Reflux, 4 h 15 min
1. 80 ꢀC, 20 min
2. 80 ꢀC,d 35 min
rt, 22 h
Reflux, 4 h 15 min
Reflux, 4 h 30 min
Reflux, 4 h
N
Cl
O
OH
3k
1c
4d
2:1
1:2.2
CH3CN
CH3CN
NEt3
NEt3
4c, 71
4c, 38e
+
Cl
H
N
Cl
1:1
1:1
1:1.9
1.8:1
3:1
EtOH
EtOH
EtOH
EtOH
EtOH
Piperidine
NEt3
NEt3
NEt3
NEt3
4c, 11
4c, 50
4c, 53
4c, 74
4c, 95
EtO
O
N
O
OEt
Cl
HO
4c
H
H
+
H2N
CN +
Cl
OH
Reflux, 4 h 20 min
1c
a
In a 4:1 ratio, by 1H NMR.
b
c
Reflux of the solid isolated in step 1, using acetonitrile.
In a 1:2.6 ratio by 1H NMR; traces of 1c were also present.
d
Step 1 led to a first crop of 4c and the mother liquor was heated at 80 ꢀC, leading
N
CN
to a second crop of the same product.
Cl
H
e
Yield after combining the first and second crops.
OH
3c
A poor isolated yield of 4c (29%) or the formation of a dimeric
structure identified as 5 (Scheme 2) in part of the experiments led
to the selection of different combinations of compounds 1c and 3c,
with triethylamine catalysis and room temperature or reflux con-
ditions. When these compounds were combined in a 1:2 ratio and
refluxed in acetonitrile for approximately 4 h, the product was
isolated in 71% yield.
The reaction of 4-chloroacetonitrile 1c and the corresponding
arylideneaminoacetonitrile 3c was also performed using ethanol as
solvent (Table 2). When these reagents were combined in a 1:1 M
ratio, using piperidine as catalyst, only 11% of the fused tricyclic
product 4c was isolated after 22 h at room temperature. The yield
was improved (50%) with triethylamine catalysis and under reflux
conditions for 4 h. These conditions were selected for a set of
Scheme 1. Products 4c and 4d isolated in the reaction of 2-(4-chloro-benzylidenea-
mino)acetonitrile 3k with 4-chlorosalicylaldehyde 1c.
The products isolated in this reaction indicate that reflux in
ethanol and base can induce cleavage of the imine moiety in the
(arylideneamino)acetonitrile 3 to generate the acetal and amino-
acetonitrile. A competing reaction with aldehyde 1c leads to 3c, the
precursor of the tricyclic product 4c upon reaction with 5-chlor-
osalicylaldehyde. It is possible that the absence of an hydroxyl
group in the 2-position of the aromatic ring of 3k will be re-
sponsible for the poor reactivity of this compound in the reaction
with salicylaldehyde. A longer reflux time will lead to a larger ex-
tent of alcoholysis, facilitating the corresponding reaction.

M. Costa, F. Proenc¸ a / Tetrahedron 67 (2011) 1799e1804
1801
The formation of compound 5 in acetonitrile and base was also
studied under different reaction conditions (Table 4). The pure solid
could be isolated in 45% yield when a threefold excess of compound
3c was combined with salicylaldehyde 1c and the acetonitrile so-
lution was stirred at room temperature for 3 h, in the presence of
triethylamine.
equilibrium. In DMSO solution, oxidation is also a possible competing
process, leading to the formation of 6. After 3 days at room temper-
ature, the solution contained approximately 20% of the dimer 5,
a similar amount of 6 and 60% of the chromeno-imidazole 4c.
This study supports the reaction mechanism presented in
Scheme 2 for the formation of chromeno[3,2-d]imidazoles 4 from
the reaction of (arylideneamino)acetonitrile and salicylaldehydes.
Table 4
Optimization of the reaction conditions for the synthesis of compound 5
Equiv 3c:1c
Solvent
Catalyst
Reaction conditions
Product, yield (%)
H
H
HO
CN
N
H
H
O
N
CN
O
O
1:1
2.2:1
3.2:1
CH3CN
CH3CN
CH3CN
NEt3
NEt3
NEt3
rt, 1 h 15 min
rt, 1 h 45 min
rt, 3 h
5, 25
5, 42
5, 45
Cl
Cl
Cl
Cl
H
H
+
H
OH
OH
Cl
1c
3c
7
The structure assigned to this compound was mainly based on the
NMR data, including HeC correlation spectra (HMQC and HMBC).
Only one set of bands was observed in the 1H and 13C NMR spectrum,
reflecting the symmetrical nature of the molecule. The signal for C2 -
H (a singlet at
C1 and C3. The proton on C5 (a doublet at
constant of 1.6 Hz) correlated with C11 , C12 and C7 . It was also pos-
sible to identify the 2-bond correlation of the NeH proton (
-H2O
HO
HO
H
H
0
Cl
N
N
N
00
0
d
6.62 ppm) showed a 3-bond correlationwith C5 , C12
,
Cl
Cl
0
H
C
H
d
5.62 ppm with a coupling
O
O
H
NH
0
0
0
9
8
d
Cl
0
0
0
8.05 ppm) to C2 and C12 and also the 3-bond correlation to C4 .
A mixture containing compound 4c and dimer 5 (in a 1:4 M
Cl
H
ratio) was solubilized in DMSO-d6 (5 mg in 650 m
L) and the 1H NMR
O
NH
N
H
HO
a
N
O
spectrum was registered daily during 3 days.
The NeH and CeH signals (
compound 5 and the CH2 signal for compound 4c (
a
5´´
N
Cl
6
H
HO
H
HO
H
H
d
8.06, 6.62 and 5.62 ppm) for
OH
7´
5´
1
a
Cl
N
Cl
6´
N
H
4´ 2´
8´
9´
d
4.15 ppm) were
d 4.86 ppm pro-
Dimerization
5
b
11´
2
N
N
H
H
12´
O
O
used to quantify these compounds. A singlet at
3
4
Cl
10´
H
b
Cl
Cl
gressively increasing with time indicated the formation of a new
molecule in a noticeable amount. Considering that oxidation is also
a possible competing process in DMSO, attempts were made to
prepare and fully characterize this minor product.
In a separate experiment, dimer 5 was combined with manga-
nese dioxide (1.6 M equiv), in THF. The mixture was stirred at room
temperature until the presence of the starting material was no
longer detected by TLC. The NMR of the first solid crop isolated from
10
5
b: Tautomerism
Dedimerization
H
H
Cl
Cl
H
N
O
Cl
Cl
H
N
N
6´´
5´´
5´
N
4´´
Cl
O
OH
7´
HO
1
6
HO
Cl
6´
4´
N
11
2´
8´
9´
5
4
Cl
2
N
H
11´ O
12´
3
the reaction mixture showed a singlet at
d 4.86 ppm and two sin-
10´
glets at 12.09 and 11.45 ppm, together with signals for two
d
Cl
6
H
H
H
N
substituted aromatic rings.
These signals were identical to those assigned to the minor
compound, in the NMR study on the evolution of dimer 5. This new
compound was fully characterized by elemental analysis and spec-
troscopic techniques, including CeH correlation NMR spectra
(HMQC and HMBC). Structure 6 was assigned to the compound
N
O
HO
4c
Scheme 2. Proposed mechanism for the reaction of aldehyde 1c with ar-
ylideneaminoacetonitrile 3c.
considering thatonlyone setofbands was observedin the 1Hand 13
C
The reaction starts with nucleophilic attack of the methylene
carbon atom to the carbonyl group of salicylaldehyde. A cascade
cyclization process is initiated after dehydration of intermediate 7,
leading to betaine 10. This molecule can dimerize to compound 5,
isolated due to the poor solubility of this high molecular weight
structure in acetonitrile.
Tautomeric equilibrium in compound 10 is a competing process
assisted by the use of ethanol as solvent and leads directly to
monomer 4, usually isolated as the major product. The formation of
4 also occurs from dimer 5 upon proton transfer and CeN bond
cleavage. Oxidation of dimer 5 to generate 6 was a minor competing
process, detected when a DMSO solution of compound 5 was kept
at room temperature. The formation of 6 was negligible when the
reaction was performed under heating conditions.
0
NMR spectrum and that the proton on C5
(
dH 4.86 ppm, dC 42.8 ppm)
0
0
0
00
00
showed an intense 3-bond correlation with C7 , C11 , C12 , C4 and C6
A decisive observation was that the proton at 4.88 ppm showed
42.8 ppm, suggesting a 2-
.
d
a faint correlation with the carbon at
d
0
00
bond correlation between C5 -H and C5 -H (and vice-versa).
The evolution registered in Fig. 1 confirmed that compound 5
evolves to the monomeric species 4c as a result of tautomeric
3. Conclusion
A simple and mild procedure was developed for the synthesis of
2-aryl-1,9-dihydrochromeno[3,2-d]imidazoles through a one-pot
cascade reaction initiated by the condensation of a salicylaldehyde
Fig. 1. Evolution of a mixture containing compound 4c and dimer 5 (in a 1:4 M ratio)
in DMSO-d6 at room temperature for 3 days.

1802
M. Costa, F. Proenc¸ a / Tetrahedron 67 (2011) 1799e1804
with an arylideneaminoacetonitrile. This synthetic approach re-
quires reflux conditions in ethanol and triethylamine as catalyst.
Different aromatic substituents in the salicylaldehyde and in the
nitrile led to a mixture of products due to imine alcoholysis and the
formation of two different arylideneaminoacetonitrile derivatives.
A good yield of the tricyclic product 4 was obtained when the same
aromatic moiety was present in both reagents.
1.8 Hz, 1H), 8.70 (t, J¼1.5 Hz, 1H), 11.97 (s, 1H); 13C NMR (75 MHz,
DMSO-d6)
d 44.4, 116.5, 117.1, 118.8, 119.2, 131.4, 133.3, 159.5, 168.0.
Anal. Calcd for C9H8N2O: C, 67.50; H, 5.00; N, 17.50. Found: C, 67.19;
H, 4.79; N, 17.40.
4.2.3. (2-Hydroxy-5-chlorobenzylideneamino) acetonitrile (3c). Ye-
llow-greyish solid. Mp 129e130 ꢀC; IR (Nujol mull) 3500e3200
(br), 3071, 2240, 1641, 1621, 1577, 1514, 1466, 1415; 1H NMR
4. Experimental section
4.1. General
(400 MHz, DMSO-d6)
7.40 (dd, J¼8.8 , 2.8 Hz, 1H), 7.64 (d, J¼2.8 Hz, 1H), 8.69 (t, J¼1.6 Hz,
1H), 11.85 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
44.5, 116.9, 118.5,
d
4.86 (d, J¼1.6 Hz, 2H), 6.96 (d, J¼8.8 Hz, 1H),
d
120.4, 122.7, 129.5, 132.7, 157.9, 165.6. Anal. Calcd for C9H7N2OCl: C,
55.53; H, 3.60; N, 14.40. Found: C, 55.90; H, 3.71; N, 14.56.
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 deuterated
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 an 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 analyses were performed on a LECO
CHNS-932 instrument.
4.2.4. (2,3-Dihydroxy-benzylideneamino) acetonitrile (3d). Yellow
solid. Mp 138e140 ꢀC; IR (Nujol mull) 3500e3200 (br), 2263, 1635,
1595, 1466, 1410; 1H NMR (400 MHz, DMSO-d6)
d
4.84 (d, J¼1.2 Hz,
2H), 6.75 (t, J¼7.6 Hz, 1H), 6.92 (dd, J¼7.6 , 1.6 Hz, 1H), 6.99 (dd,
J¼8.0 , 1.6 Hz, 1H), 8.65 (s, 1H), 8.90e9.60 (br s, 1H), 11.60e12.20 (br
s,1H); 13C NMR (100 MHz, DMSO-d6)
d 44.3,117.1, 118.8, 118.9, 119.0,
122.7, 146.1,148.4,168.8. Anal. Calcd for C9H8N2O2: C, 61.36; H, 4.54;
N, 15.91. Found: C, 61.22; H, 4.41; N, 15.93.
4.2.5. (2,5-Dihydroxy-benzylideneamino) acetonitrile (3e). Yellow
solid. Mp 169e171 ꢀC; IR (Nujol mull) 3400e3300 (br), 2265, 1645,
1597, 1502, 1459, 1409; 1H NMR (400 MHz, DMSO-d6)
d 4.80 (d,
J¼1.6 Hz, 2H), 6.75 (d, J¼8.8 Hz, 1H), 6.82 (dd, J¼8.6 , 2.8 Hz, 1H),
4.2. General procedure for the synthesis of (arylideneamino)
acetonitriles 3
6.94 (d, J¼2.8 Hz, 1H), 8.61 (t, J¼1.2 Hz, 1H), 9.05 (s, 1H), 11.08 (s,
1H); 13C NMR (100 MHz, DMSO-d6)
d 44.6, 116.0, 117.2 (2C), 118.9,
121.0, 149.7, 152.1, 167.1. Anal. Calcd for C9H8N2O2: C, 61.36; H, 4.54;
N, 15.91. Found: C, 60.99; H, 4.36; N, 15.78.
2-Aminoacetonitrile hydrochloride 2 (7.0 mmol) and sodium
acetate (8.0 mmol) were dissolved in 35 mL of methanol. Aldehyde 1
(7.0 mmol) was added to the grey solution, and the reaction mixture
was stirred at room temperature. A solid suspension was formed
after a few minutes (for compounds 3a, 3c, 3f and 3g). The suspen-
sion was stirred for 2 h and the solid filtered and washed with cold
methanol, leading to the pure product 3. A second crop was isolated
from the mother liquor after complete removal of methanol in the
rotary evaporator, addition of dichloromethane (40 mL) and dry
flash chromatography of the solution using dichloromethane
(4ꢁ10 mL) as eluent. The solution was concentrated in the rotary
evaporator and the yellow oil was kept at 0 ꢀC leading to the product
3 that was filtered and washed with cold diethyl ether. For com-
pounds 3b, 3d, 3e and 3hek, the reaction mixture was stirred at
room temperature for 2 h. The solvent was removed in the rotary
evaporator and dichloromethane (40 mL) was added to the mixture.
Dry flash chromatography of this mixture was performed using
20 mL of dichloromethane as eluent. The solvent was removed in the
rotary evaporator leading to a solid product. Cold diethyl ether was
added to the suspension, kept for a few minutes in an ice bath. The
solid was filtered and washed with cold diethyl ether, leading to the
pure (arylideneamino)acetonitrile 3.
4.2.6. (2-Hydroxy-5-bromobenzylideneamino) acetonitrile (3f). Grey
solid. Mp 122e124 ꢀC; IR (Nujol mull) 3500e3000 (br), 2238, 1644,
1619, 1567, 1505, 1465; 1H NMR (400 MHz, DMSO-d6)
d 4.86 (d,
J¼1.2 Hz, 2H), 6.91 (d, J¼8.8 Hz, 1H), 7.51 (dd, J¼8.8 , 2.4 Hz, 1H),
7.79 (d, J¼2.8 Hz, 1H), 8.68 (t, J¼1.2 Hz, 1H), 11.86 (s, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 44.5, 116.9, 119.0, 110.1, 121.0, 132.4, 135.5,
158.3, 165.4. Anal. Calcd for C9H7N2OBr$0.2H2O: C, 44.52; H, 3.05;
N, 11.54. Found: C, 44.38; H, 2.98; N, 11.60.
4.2.7. (2-Hydroxy-3-methoxy-5-bromobenzylideneamino)acetoni-
trile (3g). Beige solid. Mp 165e167 ꢀC; IR (Nujol mull) 3500e3100
(br), 2244, 1646, 1631, 1573, 1467, 1415; 1H NMR (400 MHz, DMSO-
d6)
d
3.82 (s, 3H), 4.86 (d, J¼1.6 Hz, 2H), 7.23 (d, J¼2.4 Hz, 1H), 7.38
(dd, J¼2.4 Hz, 1H), 8.67 (t, J¼1.6 Hz, 1H), 11.77 (s, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 44.4, 56.2, 109.7, 116.9, 117.6, 120.2, 123.6,
148.7, 149.1, 165.8. Anal. Calcd for C10H9N2O2Br: C, 44.61; H, 3.35; N,
10.41. Found: C, 44.51; H, 3.43; N, 10.32.
4.2.8. (2-Hydroxy-5-methoxybenzylideneamino) acetonitrile (3h). Ye-
llow solid. Mp 102e104 ꢀC; IR (Nujol mull) 3500e3000 (br), 2257,
1636, 1621, 1588, 1487, 1456, 1409; 1H NMR (300 MHz, DMSO-d6)
4.2.1. (2-Hydroxy-3-methoxybenzylideneamino) acetonitrile (3a). Ye-
llow solid. Mp 118e120 ꢀC; IR (Nujol mull) 3500e3200 (br), 2201,
d
3.71 (s, 3H), 4.85 (d, J¼1.5 Hz, 2H), 6.86 (d, J¼9.3 Hz, 1H), 6.96 (dd,
J¼9.2 , 3.3 Hz, 1H), 7.17 (d, J¼3.0 Hz, 1H), 8.68 (s, 1H), 11.28 (s, 1H);
13C NMR (75 MHz, DMSO-d6)
44.5, 55.5, 113.7, 117.5, 118.8, 120.4,
1643, 1585, 1461, 1407; 1H NMR (300 MHz, DMSO-d6)
d
3.80 (s, 3H),
d
4.85 (d, J¼1.5 Hz, 2H), 6.87 (t, J¼8.1 Hz, 1H), 7.11 (dd, J¼8.1 , 1.5 Hz,
151.9, 153.4, 166.8. Anal. Calcd for C10H10N2O2: C, 63.16; H, 5.26; N,
14.74. Found: C, 62.98; H, 5.32; N, 14.59.
1H), 7.15 (dd, J¼7.5 , 1.5 Hz, 1H), 8.70 (t, J¼1.5 Hz, 1H), 11.89 (s, 1H);
13C NMR (75 MHz, DMSO-d6)
d 44.4, 55.8, 115.4, 117.1, 118.8 (2C),
122.6, 147.8, 149.5, 168.1. Anal. Calcd for C10H10N2O2: C, 63.16; H,
5.26; N, 14.74. Found: C, 63.11; H, 5.39; N, 14.76.
4.2.9. (4-Diethylamino-2-hydroxybenzylideneamino) acetonitrile
(3i). Yellow solid. Mp 73e75 ꢀC; IR (Nujol mull) 3500e3000 (br),
2252, 1634, 1560, 1523, 1459, 1420; 1H NMR (300 MHz, DMSO-d6)
4.2.2. (2-Hydroxy-benzylideneamino)acetonitrile (3b). Yellow solid.
Mp 51e53 ꢀC; IR (Nujol mull) 3500e3200 (br), 2244, 1638, 1582,
d
1.09 (t, J¼6.9 Hz, 6H), 3.35 (q, J¼6.9 Hz, 4H), 4.68 (d, J¼0.9 Hz, 2H),
6.04 (d, J¼2.1 Hz, 1H), 6.25 (dd, J¼8.4 , 2.4 Hz, 1H), 7.21 (d, J¼9.0 Hz,
1H), 8.38 (s, 1H), 12.39 (s, 1H); 13C NMR (75 MHz, DMSO-d6)
12.5
(2C), 43.7, 43.8 (2C), 96.8, 103.5, 107.4, 117.7, 133.4, 151.3, 162.1, 167.7.
1462, 1420, 1404; 1H NMR (300 MHz, DMSO-d6)
d
4.85 (d, J¼1.8 Hz,
d
2H), 6.90e6.96 (m, 2H), 7.38 (td, J¼8.1 , 1.8 Hz, 1H), 7.57 (dd, J¼8.1 ,

M. Costa, F. Proenc¸ a / Tetrahedron 67 (2011) 1799e1804
1803
Anal. Calcd for C13H17N3O: C, 67.53; H, 7.36; N, 18.18. Found: C,
67.56; H, 7.31; N, 18.07.
zole 4c and 4-chloro-2-(7-chloro-3,9-dihydrochromeno[3,2-d]
imidazol-2-yl)phenol 4d (28.40 mg) in a 3:1 ratio, by 1H NMR. The
mother liquor was concentrated in the rotary evaporator and kept
at 0 ꢀC for 12 h. An orange solid precipitated and was filtered and
washed with ethanol, leading to the pure 7-chloro-2-(4-chlor-
ophenyl)-3,9-dihydrochromeno[3,2-d]imidazole 4d (0.06 mmol,
4.2.10. 2-(3-Chlorobenzylideneamino)acetonitrile (3j). White solid.
Mp 51e53 ꢀC; IR (Nujol mull) 3061, 2245, 1651, 1645, 1621, 1584,
1568, 1538, 1466, 1434, 1409; 1H NMR (300 MHz, DMSO-d6)
d 4.83
(d, J¼1.8 Hz, 2H), 7.52 (d, J¼8.1 Hz, 1H), 7.59 (dt, J¼8.4 Hz, 1H), 7.76
11%): 1H NMR (400 MHz, DMSO-d6)
d
4.33 (s, 2H), 7.13 (d, J¼8.8 Hz,
(d, J¼7.8 Hz, 1H), 7.83 (t, J¼1.5 Hz, 1H), 8.48 (t, J¼1.5 Hz, 1H); 13C
1H), 7.29 (dd, J¼8.6 , 2.8 Hz, 1H), 7.42 (d, J¼2.8 Hz, 1H), 7.50 (dd,
NMR (75 MHz, DMSO-d6)
d 45.4, 117.3, 127.0, 127.6, 130.8, 131.3,
J¼6.8 , 2.0 Hz, 2H), 7.85 (dd, J¼6.8 , 2.0 Hz, 2H), 12.58 (s, 1H); 13C
133.7, 137.0, 163.9. Anal. Calcd for C9H7N2Cl$0.1H2O: C, 59.83; H,
NMR (100 MHz, DMSO-d6) d 23.4, 103.9, 119.1, 121.0, 125.9 (2C),
4.00; N, 15.51. Found: C, 60.07; H, 3.86; N, 15.18.
126.5, 127.7, 128.8 (2C), 129.2, 130.1, 132.3, 138.8, 148.1, 150.4. Anal.
Calcd for C16H10N2OCl2$0.6H2O: C, 58.57; H, 3.42; N, 8.54. Found: C,
58.70; H, 3.50; N, 8.38. Due to the small amount of solid isolated,
the melting point and IR spectrum could not be obtained.
4.2.11. 2-(4-Chlorobenzylideneamino)acetonitrile (3k). White solid.
Mp 79e81 ꢀC; IR (Nujol mull) 1653, 1594, 1569, 1459, 1413, 1404; 1H
NMR (300 MHz, DMSO-d6)
d
4.81 (d, J¼1.5 Hz, 2H), 7.54 (dd, J¼6.6 ,
1.8 Hz, 2H), 7.81 (dd, J¼7.1 , 1.5 Hz, 2H), 8.48 (s, 1H); 13C NMR
4.3.5. 4-Bromo-2-(7-bromo-3,9-dihydrochromeno [3,2-d]imidazol-
2-yl)phenol (4e). Beige solid. Mp 298e300 ꢀC; IR (Nujol mull) 3332,
1650, 1625, 1603, 1579, 1566, 1531, 1473, 1460, 1409; 1H NMR
(75 MHz, DMSO-d6) d 45.4, 117.4, 129.0 (2C), 129.9 (2C), 133.8, 136.3,
164.0. Anal. Calcd for C9H7N2Cl$0.02H2O: C, 60.38; H, 3.94; N, 15.65.
Found: C, 60.38; H, 3.67; N, 15.25.
(300 MHz, DMSO-d6)
d
4.16 (s, 2H), 6.90 (d, J¼8.7 Hz, 1H), 7.09 (d,
J¼8.4 Hz, 1H), 7.33 (dd, J¼8.6 , 2.4 Hz, 1H), 7.42 (dd, J¼8.7 , 2.4 Hz,
4.3. General procedure for the synthesis of chromeno([2,3-d]
imidazol-2-yl)phenol 4
1H), 7.56 (d, J¼2.4 Hz, 1H), 8.00 (d, J¼2.4 Hz, 1H), 11.0e13.0 (br s,
2H); 13C NMR (75 MHz, DMSO-d6)
d 23.1, 103.5, 110.1, 114.4, 115.8,
118.7, 119.2, 121.2, 126.6, 130.4, 131.5, 132.7, 137.8, 145.7, 150.4, 154.2.
Anal. Calcd for C16H10N2O2Br2: C, 45.50; H, 2.37; N, 6.64. Found: C,
45.26; H, 2.48; N, 6.76.
Salicylaldehyde 1 (0.40 mmol) was added to a yellow solution of
arylideneaminoacetonitrile 3 (1.20 mmol) in ethanol (15 mL) and
triethylamine (0.08 mmol) and the reaction mixture was refluxed
for 4e7 h. A solid gradually precipitated from solution and was
filtered and washed with ethanol, leading to the pure product 4.
4.3.6. 4-Bromo-2-(7-bromo-5-methoxy-3,9-dihydrochromeno[2,3-d]
imidazol-2-yl)-6-methoxyphenol (4f). Beige solid. Mp 274e276 ꢀC;
IR (Nujol mull) 3550e3000 (br), 1654, 1604, 1573, 1527, 1463, 1418;
4.3.1. 2-Methoxy-6-(5-methoxy-3,9-dihydrochromeno[2,3-d]imida-
zol-2-yl)phenol (4a). Yellow solid. Mp 238e239 ꢀC; IR (Nujol mull)
3258, 1648, 1622, 1600, 1575, 1534, 1463, 1438, 1419; 1H NMR
1H NMR (400 MHz, DMSO-d6)
d 3.81 (s, 3H), 3.85 (s, 3H), 4.11 (s,
2H), 7.05 (d, J¼2.0 Hz, 1H), 7.11 (d, J¼11.4 Hz, 1H), 7.60 (d, J¼2.4 Hz,
1H), 11.72 (s, 1H), 12.74 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
(400 MHz, DMSO-d6)
d
3.79 (s, 3H), 3.82 (s, 3H), 4.14 (s, 2H), 6.88 (d,
d 23.2, 56.0, 52.2, 103.6, 110.0, 113.6, 114.4, 114.5, 114.9, 118.1, 121.2,
J¼6.0 Hz,1H), 6.85 (t, J¼8.0 Hz,1H), 6.93 (dd, J¼8.2 ,1.6 Hz,1H), 6.96
124.0, 138.2, 140.2, 144.6, 145.2, 149.1, 149.4. Anal. Calcd for
C18H14N2O4Br2$2.5H2O: C, 40.99; H, 3.61; N, 5.31. Found: C, 41.03;
H, 3.54; N, 5.48.
(dd, J¼8.0 , 1.2 Hz, 1H), 7.03 (t, J¼7.6 Hz, 1H), 7.40 (dd, J¼7.8 , 1.6 Hz,
1H),10.5e13.5 (br s, 2H); 13C NMR (100 MHz, DMSO-d6)
d 23.5, 55.6,
55.7, 103.2, 110.5, 112.0, 113.6, 115.9, 118.7, 119.3, 121.8, 123.0, 139.6,
140.9, 145.3, 145.5, 148.3, 148.4. Anal. Calcd for C18H16N2O4$0.2H2O:
C, 65.93; H, 5.01; N, 8.55. Found: C, 65.78; H, 5.22; N, 8.42.
4.3.7. 4-Methoxy-2-(7-methoxy-3,9-dihydrochromeno[2,3-d]imida-
zol-2-yl)phenol (4g). Yellow solid. Mp 274e276 ꢀC; IR (Nujol mull)
3204, 3168, 1650, 1635, 1596, 1536, 1490, 1465; 1H NMR (400 MHz,
4.3.2. 2-(3,9-Dihydrochromeno[3,2-d]imidazol-2-yl)phenol
(4b). Orange solid. Mp 270e272 ꢀC; IR (Nujol mull) 3208, 3176,
1655, 1622, 1590, 1575, 1536, 1493, 1484, 1465, 1458, 1408; 1H NMR
DMSO-d6)
6.90 (d, J¼3.2 Hz, 1H), 7.06 (d, J¼8.8 Hz, 1H), 7.41 (d, J¼2.4 Hz, 1H),
11.24 (s, 1H), 12.59 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
23.6,
d 3.74 (s, 3H), 3.73 (s, 3H), 4.13 (s, 2H), 6.79e6.87 (m, 3H),
d
(400 MHz, DMSO-d6)
d
4.16 (s, 2H), 6.88e6.95 (m, 2H), 7.08e7.15
55.4, 55.5, 102.7, 108.4, 113.6, 114.1, 114.4, 116.1, 117.5, 118.1, 119.3,
139.3, 145.1, 146.0, 149.4, 152.1, 154.9. Anal. Calcd for
C18H16N2O4$0.1H2O: C, 66.30; H, 4.97; N, 8.59. Found: C, 66.24; H,
4.98; N, 8.68.
(m, 2H), 7.21 (td, J¼8.0 , 1.6 Hz, 1H), 7.27 (td, J¼7.6 , 1.6 Hz, 1H), 7.34
(dd, J¼7.6 , 1.2 Hz, 1H), 7.82 (dd, J¼7.8 , 1.2 Hz, 1H), 11.70 (s, 1H),
12.63 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 23.4, 103.1, 113.7,
116.7, 119.2, 117.3, 118.6, 123.3, 124.4, 127.9, 129.5, 130.7, 139.4, 145.6,
151.2, 155.3. Anal. Calcd for C16H12N2O2$0.1H2O: C, 72.23; H, 4.59;
N, 10.53. Found: C, 72.10; H, 4.64; N, 10.25.
4.4. Synthesis of 2,20-(3,10-dichloro-6,11b,12,13-tetrahydro-
4bH,5H-7,14-dioxa-4c,6,11c,13-tetraazadibenzo[e,l] cyclopenta
[h,i]aceanthrylene-5,12-diyl)bis(4-chlorophenol) 5
4.3.3. 4-Chloro-2-(7-chloro-3,9-dihydrochromeno[3,2-d]imidazol-2-
yl)phenol (4c). Beige solid. Mp 290e292 ꢀC; IR (Nujol mull) 3316,
1650, 1629, 1609, 1572, 1536, 1478, 1463, 1415; 1H NMR (300 MHz,
5-Clorosalicylaldehyde 1c (0.06 g, 0.38 mmol) was added to
a solution of (5-chloro-2-hydroxybenzylideneamino)acetonitrile 3c
(0.24 g, 1.23 mmol) in acetonitrile (5 mL) and triethylamine (0.01 g,
DMSO-d6)
d
4.15 (s, 2H), 6.95 (d, J¼8.7 Hz,1H), 7.15 (d, J¼8.7 Hz,1H),
7.21 (dd, J¼8.7 , 2.7 Hz, 1H), 7.30 (dd, J¼8.8 , 2.7 Hz, 1H), 7.42 (d,
0.08 mmol, 14.0 mL), and the yellow solution was stirred at room
J¼2.4 Hz, 1H), 7.87 (d, J¼2.4 Hz, 1H), 11.0e13.0 (br s, 2H); 13C NMR
temperature. After 10 min a yellow solid started to precipitate. The
reaction mixture was stirred for a further 2 h and 50 min and the
yellow solid was filtered and washed with acetonitrile, leading to
the pure product 5 (0.06 g, 0.17 mmol, 45%): mp higher then
300 ꢀC; IR (Nujol mull) 3332, 3312, 3101, 1644, 1609, 1595, 1565,
(75 MHz, DMSO-d6)
d 23.2, 103.4, 115.2, 118.2, 118.8, 120.7, 122.7,
123.7, 126.6, 127.5, 128.6, 129.9, 137.9, 145.6, 149.9, 153.8. Anal. Calcd
for C16H10N2O2Cl2: C, 57.66; H, 3.00; N, 8.41. Found: C, 57.51; H,
3.31; N, 8.26.
1479, 1463, 1415 cmꢂ1 1H NMR (400 MHz, DMSO-d6)
; d 5.62 (d,
4.3.4. 7-Chloro-2-(4-chlorophenyl)-3,9-dihydrochromeno[3,2-d]im-
idazole (4d). After refluxing for 5 h and 40 min a yellow solid was
isolated from the reaction mixture and identified as a mixture of
7-chloro-2-(4-chlorophenyl)-3,9-dihydrochromeno[3,2-d]imida-
J¼1.6 Hz, 2H), 6.62 (s, 2H), 6.87 (d, J¼8.8 Hz, 2H), 6.98 (dd, J¼8.6 ,
2.8 Hz, 2H), 7.06 (d, J¼2.8 Hz, 2H), 7.10 (d, J¼8.4 Hz, 2H), 7.17 (dd,
J¼8.4 , 2.8 Hz, 2H), 7.21 (d, J¼2.4 Hz, 2H), 8.04 (s, 2H), 10.13 (s, 2H);
13C NMR (100 MHz, DMSO-d6)
d 77.8 (2C), 87.7 (2C), 117.0 (2C), 117.1

1804
M. Costa, F. Proenc¸ a / Tetrahedron 67 (2011) 1799e1804
Chem. 2009, 17, 2842e2851; (e) Erichsen, M.; Huynh, T.; Abrahamsen, B.; Bas-
tlund, J.; Bundgaard, C.; Monrad, O.; Bekker-Jensen, A.; Nielsen, C.; Frydenvang,
K.; Jensen, A.; Bunch, L. J. Med. Chem. 2010, 53, 7180e7191; (f) Jain, N.; Xu, J.;
Kanojia, R.; Du, F.; Jian-Zhong, G.; Pacia, E.; Lai, M.; Musto, A.; Allan, G.; Reuman,
M.; Li, X.; Hahn, D.; Cousineau, M.; Peng, S.; Ritchie, D.; Russell, R.; Lundeen, S.;
Sui, Z. J. Med. Chem. 2009, 52, 7544e7569; (g) Endo, S.; Matsunaga, T.; Kuwata,
K.; Zhao, H.; El-Kabbani, O.; Kitade, Y.; Hara, A. Bioorg. Med. Chem. 2010, 18,
2485e2490; (h) Tang, J.; Qian, K.; Zhang, B.; Chen, Y.; Xia, P.; Yu, D.; Xia, Y.;
Yang, Z.; Chen, C.; Morris-Natschke, S.; Lee, K. Bioorg. Med. Chem. 2010, 18,
4363e4373; (i) Conti, C.; Desideri, N. Bioorg. Med. Chem. 2010, 6480e6488.
(2C), 122.4 (2C), 122.7 (2C), 123.1 (2C), 126.2 (2C), 126.8 (2C), 128.2
(2C), 128.5 (2C), 128.7 (2C), 138.0 (2C), 146.0 (2C), 153.7 (2C), 162.8
(2C). Anal. Calcd for C32H20N4O4Cl4: C, 57.66; H, 3.00; N, 8.41.
Found: C, 57.28; H, 2.96; N, 8.56.
4.5. Synthesis of 2,20-(7,70-dichloro-3,30,9,90-tetrahydro-9,90-
bichromeno[2,3-d]imidazole-2,20-diyl)bis(4-chlorophenol) 6
ꢀ
ꢀ
2. (a) Santana, L.; Uriarte, E.; Gonzalez-Dıaz, H.; Zagotto, G.; Soto-Otero, R.;
Manganese dioxide (15.72 mg, 0.18 mmol) was added to a yellow
solution of dimer 5 (0.07 g, 0.11 mmol) in THF (60 mL). The reaction
mixture was stirred at room temperature for 4.5 h. Flash chroma-
tography using THF (4ꢁ10 mL) as eluent was performed and the
yellowsolutionwas concentrated in the rotaryevaporator leading to
a yellow solid. The suspension was kept in an ice bath for a few
minutes and the solid was filtered and washed with THF, leading to
the pure product 6 (13.10 mg, 0.02 mmol, 18%). The mother liquor
was concentrated in the rotary evaporator leading to a second crop
of a yellow solid, identified as a complex mixture containing com-
pound 6, by 1H NMR. Mp 285e287 ꢀC; IR (Nujol mull) 3296, 1636,
ꢀ
ꢀ
Medez-Alvarez, E. J. Med. Chem. 2006, 49, 1149e1156; (b) Catto, M.; Nicolotti,
ꢀ
ꢀ
O.; Leonetti, F.; Carotti, A.; Favia, A.; Soto-Otero, R.; Mendez-Alvarez, E.; Carotti,
A. J. Med. Chem. 2006, 49, 4912e4925; (c) Bruhlmann, C.; Ooms, F.; Carrupt, P.;
}
Testa, B.; Catto, M.; Leonetti, F.; Altomare, C.; Carotti, A. J. Med. Chem. 2001, 44,
3195e3198; (d) Chimenti, F.; Secci, D.; Bolasco, A.; Chimenti, P.; Bizzarri, B.;
ꢀ
Granese, A.; Carradori, S.; Yanez, M.; Orallo, F.; Ortuso, F.; Alcaro, S. J. Med.
Chem. 2009, 52, 1935e1942.
3. Maier, D.; Briner, C.; Ding, M.; Powell, M.; Jiang, Q.; Hill, G.; Heys, J.; Elmore, C.;
Pierson, M.; Mrzljak, L. J. Pharmacol. Exp. Ther. 2009, 330, 342e351.
4. (a) Garino, C.; Tomita, T.; Pietrancosta, N.; Laras, Y.; Rosas, R.; Herbette, G.;
ꢀ ꢀ
Maigret, B.; Quelever, 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.; Quelever, G.; Iwatsubo, T.; Kraus, J. Bioorg. Med. Chem.
2006, 16, 1995e1999.
5. Zhou, X.; Wang, X.; Wang, T.; Kong, L. Bioorg. Med. Chem. 2008, 16, 8011e8021.
6. Radziszewski, B. Ber. 1882, 15, 2706e2709.
1585, 1558, 1536; 1H NMR (400 MHz, DMSO-d6)
d 4.86 (s, 2H), 6.95
(br s, 2H), 6.99 (d, J¼8.8 Hz, 2H), 7.06 (d, J¼8.8 Hz, 2H), 7.25 (dd,
7. (a) Tong, Y.; Bouska, J. J.; Ellis, P. A.; Johnson, E. F.; Leverson, J.; Liu, X.; Marcotte,
P. A.; Olson, A. M.; Osterling, D. J.; Przytulinska, M.; Rodriguez, L. E.; Shi, Y.; Soni,
N.; Stavropoulos, J.; Thomas, S.; Donawho, C. K.; Frost, D. J.; Luo, Y.; Giranda, V.
L.; Penning, T. D. J. Med. Chem. 2009, 52, 6803e6813; (b) Niculescu-Duvaz, D.;
J¼8.8 , 2.4 Hz, 2H), 7.33 (dd, J¼8.8 , 2.4 Hz, 2H), 7.83 (d, J¼2.4 Hz, 2H),
10.45 (s, 2H),12.09 (s, 2H); 13C NMR (100 MHz, DMSO-d6)
d 42.8 (2C),
104.4 (2C), 116.0 (2C), 118.47 (2C), 118.50 (2C), 122.2 (2C), 122.9 (2C),
124.6 (2C), 126.7 (2C), 128.4 (2C), 128.8 (2C), 129.0 (2C), 138.9 (2C),
147.5 (2C), 151.2 (2C), 153.8 (2C). Anal. Calcd for C32H18N4O4Cl4: C,
57.83; H, 2.71; N, 8.43. Found: C, 57.63; H, 2.78; N, 8.18.
ꢀ
Niculescu-Duvaz, I.; Suijkerbuijk, B. M. J. M.; Menard, D.; Zambon, A.; Nourry,
A.; Davies, L.; Manne, H. A.; Friedlos, F.; Ogilvie, L.; Hedley, D.; Takle, A. K.;
Wilson, D. M.; Pons, J.-F.; Coulter, T.; Kirk, R.; Cantarino, N.; Whittaker, S.;
Marais, R.; Springer, C. J. Bioorg. Med. Chem. 2010, 18, 6934e6952; (c) Lee, J.;
Kim, H.; Yu, H.; Chung, J. Y.; Oh, C.-H.; Yoo, K. H.; Sim, T.; Hah, J.-M. Bioorg. Med.
Chem. Lett. 2010, 20, 1573e1577; (d) Bressi, J. C.; Jong, R.; Wu, Y.; Jennings, A. J.;
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Gangloff, A. R. Bioorg. Med. Chem. Lett. 2010, 20, 3138e3141; (e) Potter, A.;
Oldfield, V.; Nunns, C.; Fromont, C.; Ray, S.; Northfield, C. J.; Bryant, C. J.; Scrace,
S. F.; Robinson, D.; Matossova, N.; Baker, L.; Dokurno, P.; Surgenor, A. E.; Davis,
B.; Richardson, C. M.; Murray, J. B.; Moore, J. D. Bioorg. Med. Chem. Lett. 2010, 20,
6483e6488.
Acknowledgements
~
We graˇ tefully acknowledge the financial support from Fundac¸ ao
para a Ciencia e a Tecnologia and a Ph.D. grant awarded to M.C.
(SFRH/BD/31531/2006).
8. (a) Banie, H.; Sinha, A.; Thomas, R. J.; Sircar, J. C.; Richards, M. L. J. Med. Chem.
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Loddo, R.; Colla, P. Bioorg. Med. Chem. Lett. 2010, 18, 2937e2953.
Supplementary data
9. Keurulainen, L.; Salin, O.; Siiskonen, A.; Kern, J. M.; Alvesalo, J.; Kiuru, P.; Maass,
M.; Yli-Kauhaluoma, J.; Vuorela, P. J. Med. Chem. 2010, 53, 7664e7674.
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