A one-pot rearrangement of 2-(N-Alkyl-N-aryl)aminochromone-3-carbaldehyde to N-Alkyl-3-salicyloyl-2-quinolone - An antileishmanial agent

Article abstract of DOI:10.1055/s-0030-1260977

2-(N-Aryl)aminochromone-3-carbaldehyde does not show any change on heating in acetic acid, but under the same reaction conditions 2-(N-alkyl-N-aryl) aminochromone-3-carbaldehyde rearranges to 3-salicyloyl-2-quinolones, which exhibits antileishmanial activ

Full text of DOI:10.1055/s-0030-1260977

LETTER
2001
A One-Pot Rearrangement of 2-(N-Alkyl-N-aryl)aminochromone-3-
carbaldehyde to N-Alkyl-3-salicyloyl-2-quinolone – An Antileishmanial Agent
Synthesis of
3o
u-quinolones
r
–
A
n
A
n
a
tileishmani
v
a
l
A
gent Maiti,a Suvadip Mallick,b Suman Kalyan Panja,a Chiranjib Pal,b Chandrakanta Bandyopadhyay*a
a
Department of Chemistry, R. K. Mission Vivekananda Centenary College, Rahara, Kolkata 700 118, West Bengal, India
E-mail: kantachandra@rediffmail.com
b
Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University,
Barasat, West Bengal, India
Received 1 April 2011
reaction18 and for domino Knoevenagel–hetero Diels–
Alder reaction.19
Abstract: 2-(N-Aryl)aminochromone-3-carbaldehyde does not
show any change on heating in acetic acid, but under the same reac-
tion conditions 2-(N-alkyl-N-aryl)aminochromone-3-carbaldehyde
rearranges to 3-salicyloyl-2-quinolones, which exhibits antileish-
manial activity.
Different methods for the synthesis of the 2-quinolone
moiety have been reported.20 Some recent reports include
the use of a pseudo-domino Heck–Buchwald–Hartwig
reaction,21 reaction of anilines with Meldrum’s acid,22
Wadsworth–Emmons olefination,23 and trifluoroacetic
anhydride induced cyclization of N-methyl cyanoacetanil-
ide.24 We report herein the synthesis of 3-salicyloyl-2-qui-
nolones by a one-pot rearrangement of 2-(N-alkyl-N-
aryl)aminochromone-3-carbaldehyde 4.
Key words: 3-formylchromone, 1-benzopyran, 2-quinolone, 2-
amino-3-formylchromone, molecular rearrangement, heterocycles
The 2-quinolone moiety is widely distributed in the field
of natural products1 and has found diverse applications in
medicinal chemistry. 2-Quinolones having appropriate
substitution at their 3-position exhibit antibacterial,2 anti-
inflamatory,3 antithyroid,4 and antitumor activities.5
Recently, 4-anilino-8-methyl-6-methanesulphonyl-2-quino-
lone-3-carboxamide have been patented as inhibitors of
phosphodiesterase.6 3-Aminoquinolin-2-one acts as an
antiparasitic, antituberculosis, and antiangiogenic agent.7
Atanine, a naturally occurring compound possesses anti-
parasitic activity.8 7-Amino-2-quinolones have been used
as laser dyes with blue-green emission9a and a recent re-
port describes that N-methyl-2-quinolone helps switching
electrical conductivities by its photodimerization mecha-
nism.9b
O
O
O–
Ar
ArNO2
+
N
R1
Zn/NH4Cl
R1
CHO
O
O
2
1
EtOH, heat 2 h
Ar
N
O
O
N
R5
R4
H2SO4
O
or
H
O
R2NH
R1
R1
R3
O
5
AcOH
5 h
no
reaction
3
R2X
K2CO3, NaI
MeCN, reflux
7 h
3-Formylchromone (1), beside its biological activities,10
has proved itself to be a very good substrate for the syn-
thesis of chromone-fused or chromone-linked hetero-
cycles.11 2-Arylaminochromone-3-carbaldehyde (3) has
been synthesized from 1 via the nitrone 212 or by directly
treating 1 with nitro compounds.13 Compound 3 can be
converted into a tertiary amine 4 followed by substitution
with various nucleophiles.14 Latterly, we have utilized 3
for the synthesis of bischromones involving a deformyla-
tive Mannich reaction,15 to prepare chromeno[2,3-b]-
pyridines with varying substituents at their 3-position.16 2-
(N-allyl-N-aryl)aminochromone-3-carbaldehyde has also
been used for intramolecular [3+2]-nitrone cycloaddition
reaction at low temperature involving N-methylhydroxyl-
amine,17 while we have utilized the same compound for
intramolecular [3+2]-azomethine ylide cycloaddition
R1
R2
R2
N
R5
R4
O
R5
R4
O
O
N
7
AcOH–H2O
heat, 2 h
1
3
5
R1
CHO
R3
O
R3
O
4
H
6
Scheme 1
Sulfuric acid induced cyclization of 3 produced
chromenoquinoline 5 (Scheme 1).12,13 Similar cyclization
was also accomplished by using secondary amines.15 It
was of interest to study how 3 would behave towards gla-
cial acetic acid but, on heating 3 in glacial acetic acid for
5 hours, no change was observed. It was assumed that, un-
like H2SO4, acetic acid does not protonate the carbonyl
oxygen of 3, which is engaged in hydrogen bonding with
the NH at C-2. Under this hydrogen-bonded condition the
phenyl group fails to achieve the correct orientation for
cyclization. To verify this assumption, compound 3 was
alkylated to 4 by heating 3 with alkyl halide (R2X) in the
presence of K2CO3 and NaI in MeCN for 7 hours
SYNLETT 2011, No. 14, pp 2001–2004
x
x
.x
x
.2
0
1
1
Advanced online publication: 03.08.2011
DOI: 10.1055/s-0030-1260977; Art ID: D10111ST
© Georg Thieme Verlag Stuttgart · New York

2002
S. Maiti et al.
LETTER
(Scheme 1). In the absence of H bonding in 4, the possi- The appropriate choice of substitution on the nitroarene,
bility of the aromatic ring achieving the correct orienta- employed for the synthesis of 3 (Scheme 1) and suitable
tion for cyclization involving the formyl function of 4 choice of alkyl halide (R2X) provide a means of introduc-
increases. Indeed, on heating 4 in glacial acetic acid for 5 ing suitable substituents on the phenyl ring and on nitro-
hours, the reaction mixture produced quinolone 6 in ex- gen atom, respectively, of the quinolone moiety.
cellent yield (Table 1).25 The structure of compound 6 was Nitrobenzenes having varying substituents were em-
established on the basis of full spectroscopic analysis. ployed for the synthesis of 3, which on subsequent meth-
Formation of 6 was rationalized by considering the acid- ylation (→ 4a–e) and rearrangement by heating in acetic
induced cyclization involving the phenyl ring and the acid containing a few drops of water produced 6a–e in ex-
formyl function of 4 to form 8 via 7 (Scheme 2). Acid-cat- cellent yields (Table 1, entries 1–5). Alkylation was also
alyzed rearrangement of 8 produces 9, which tautomerizes performed using allyl or crotyl bromide to obtain N-ally-
to quinolone 6. The proposed mechanism demands the lated products 4f–h,18,19 which, on subsequent heating in
presence of water in the reaction mixture. Indeed, when acetic acid, produced 6f–h (entries 6–8). Functional-
the above reaction was performed in glacial acetic acid group tolerance was tested using ester, nitro, or methoxy
containing a few drops of water, the reaction was com- substituents, and the mode of cyclization was tested using
plete within 2 hours.
a wide range of electron-donating and electron-withdraw-
ing groups at the meta position of the N-aryl moiety in 4.
On heating 4i (R3 or R5 = CO2Et) in aqueous acetic acid
for 2 hours, the reaction mixture yielded a mixture of 6i
(R3 = CO2Et) and 6j (R5 = CO2Et) in a 1:2 molar ratio,
which were separated by column chromatography (entries
9, 10). The difference in product population was initially
assumed to be due to steric effects but, on carrying out the
rearrangement with 4k (R3 or R5 = Me), a single product
6k (R3 = Me) was obtained (entry 11), which clearly ruled
out the steric effects and so electronic factors are pre-
sumed to be responsible. Electron-donating groups at the
meta position appear to favor 5-substituted quinolones;
whereas electron-withdrawing groups favor 7-substituted
quinolones. To verify this a stronger electron-withdraw-
ing group (NO2) was introduced into the substrate. On
heating 4l (R3 or R5 = NO2), it produced 6l (R5 = NO2) as
the only isolated product (entry 12). Similarly, a substrate
with stronger electron-donating group 4m (R3 or
R5 = OMe) produced only 6m (R3 = OMe, entry 13). Sub-
strates having weakly ortho/para-orienting groups 4n (R3
or R5 = Cl) produced a mixture of 6n (R3 = Cl) and 6o
(R5 = Cl) with the latter predominating (entries 14 and
15).
R2
N+
R2
N
R5
R4
O
R5
R4
O
H+
4
R1
R1
H
O
OH
R3
O
OH R3
7
8
H+/H2O
H
R2
N
O
O
O
R5
R4
6
R1
R3
9
Scheme 2
To estimate the strength of external acid required to pro-
tonate the intramolecular H-bonded formyl function of 3,
reactions were carried out under different acidic condi-
tions, heating 3 in methanol in the presence of concentrat-
ed HCl, in MeOH in the presence of p-toluenesulfonic
acid, in chloroacetic acid, in trifluoroacetic acid, in
HCOOH, but none of the these attempts produced 5.
Table 1 Synthesis of 6 by the Rearrangement of 4 Having Various Substituents
Entry
R1
H
R2
R3
H
H
H
H
H
H
H
H
Ea
H
R4
H
R5
H
H
H
H
H
H
H
H
H
Ea
Compd
4a
Mp (°C)
188–190
188–190
162–164
164–166
182–184
162–164
136–138
164–166
184–186
184–186
Yield (%) Compd Mp (°C)
Yield (%)
1
2
Me
87
85
86
85
81
75
82
80
84
84
6a
6b
6c
6d
6e
6f
182–184
222–224
224–226
190–192
216–217
136–138
158–160
160–162
174–176
246–248
86
85
88
90
93
80
70
95
30
60
Me
Me
H
Me
H
4b
4c
3
Me
Me
Me
Cl
H
4
Me
4d
4e
5
H
Me
6
Me
Me
Me
H
Allyl
Crotyl
Allyl
Me
4f
7
H
4g
6g
6h
6i
8
Me
H
4h
4i
9
10
H
Me
H
4i
6j
Synlett 2011, No. 14, 2001–2004 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Salicyloyl-2-quinolones – An Antileishmanial Agent
2003
Table 1 Synthesis of 6 by the Rearrangement of 4 Having Various Substituents (continued)
Entry
11
R1
H
H
H
H
H
R2
R3
R4
H
H
H
H
H
R5
H
Compd
4k
Mp (°C)
108–110
192–194
153–154
155–156
155–156
Yield (%) Compd Mp (°C)
Yield (%)
Me
Me
Me
Me
Me
Me
H
65
45
82
75
75
6k
6l
184–186
194–196
202–203
157–158
218–219
85
65
80
35
50
12
NO2
H
4l
13
OMe
Cl
4m
4n
6m
6n
6o
14
H
15
H
Cl
4n
a E = CO2Me.
A preliminary investigation on the antiproliferative effect effect of substituents on the nitroarene showed that elec-
of 2-quinolones (6) on L. donovani promastigotes were tron-withdrawing groups (CO2Me, NO2) at the meta posi-
carried out. L. donovani promastigotes were incubated tion favored the formation of 7-substituted-2-quinolones,
with miltefosine26 (a promising drug under clinical trial) whereas electron-donating groups (Me, OMe) at the meta
and graded concentrations of quinolone derivatives 6 (2 position yielded 5-substituted-2-quinolones as the pre-
mg/mL; 5 mg/mL and 10 mg/mL) and the antiproliferative ferred product. Some of the synthesized quinolones exhib-
effect was determined at three different time points (2 d, 4 it significant antileishmanial activity.
d, and 6 d). Of the different compounds tested, compound
6a, 6h and 6k were found to inhibit the growth in a dose
Supporting Information for this article is available online at
dependent manner (Figure 1). At high doses of10.0 mg/
http://www.thieme-connect.com/ejournals/toc/synlett.
mL, 6h and 6k were highly effective and inhibited by ap-
proximately 91.64% (P <0.01 vs. DMSO control) and
78.36% (P <0.02 vs. DMSO control), respectively, on the
fourth day of culture. Highest activity was found on the
sixth day using 10.0 mg/mL of 6h and 6k (inhibited by
96.00% and 87.77%, respectively) and statistically signif-
icant (P <0.003 vs. DMSO control for each experiment).
A detailed investigation on the antileishmanial activity of
6 is in progress.
Acknowledgment
Financial assistance from the Department of Biotechnology (DBT),
India (No. BT/PR8217/Med/14/1239/2006) is gratefully acknowl-
edged. We also gratefully acknowledge IICB and IACS, Jadavpur
for spectral analysis and the college authorities for providing re-
search facilities.
References and Notes
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nolone system from aromatic nitro compounds using 3-
formylchromone as a three-carbon donor. Studies of the
Synlett 2011, No. 14, 2001–2004 © Thieme Stuttgart · New York

2004
S. Maiti et al.
LETTER
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of 2-(N-Methyl-N-phenyl)aminochromone-3-carbox-
aldehyde (4a)
Compound 4a (0.14 g, 0.5 mmol) was heated under reflux in
AcOH (3 mL) containing 4 drops of H2O for 2 h when the
absence of 4a was observed by TLC. The reaction mixture
was cooled to r.t. and poured into ice-cold water. The
resultant acidic mixture was neutralized with NaHCO3 when
a solid began to precipitate. The precipitated solid was
filtered, dried in air, and crystallized from benzene–light PE
(2:1) to give pale yellow crystalline solid 6a.
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Yield 0.12 g (86%); mp 182–184 °C. IR (KBr): 3036, 1645,
1626, 1589 cm–1. 1H NMR (300 MHz, CDCl3): d = 3.78 (s,
3 H, NCH3), 6.81–6.87 (m, 1 H, 5¢-H), 7.04 (br d, J = 8.1 Hz,
1 H, 3¢-H), 7.28–7.34 (m, 1 H, ArH), 7.42–7.47 (m, 1 H,
ArH), 7.49–7.54 (m, 2 H, ArH), 7.63–7.71 (m, 2 H, ArH),
7.86 (s, 1 H, 4-H), 11.96 (s, exchangeable, 1 H, OH). 13
NMR (75 MHz, CDCl3): d = 29.6, 114.3, 118.2, 118.9,
119.2, 119.4, 122.7, 129.8, 130.6, 132.3, 132.9, 136.9,
C
139.1, 140.5, 159.4, 162.9, 199.0. MS: m/z = 280 [M + H+],
302 [M + Na+]. Anal. Calcd for C17H13NO3: C, 73.11; H,
4.69; N, 5.02. Found: C, 72.92; H, 4.60; N, 4.97.
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