Triton B catalyzed three-component, one-pot synthesis of 2-amino-2-chromenes at ambient temperature

Article abstract of DOI:10.1002/jhet.544

A one-pot, three-component synthesis of 2-amino-2-chromenes is described at ambient temperature by the reaction of an aldehyde and malononitrile or ethyl cyanoacetate with α-naphthol or β-naphthol in ethanol in presence of a catalytic amount of Triton B.

Full text of DOI:10.1002/jhet.544

March 2011
Triton B Catalyzed Three-Component, One-Pot Synthesis of
2-Amino-2-chromenes at Ambient Temperature
267
Gowravaram Sabitha,* M. Bhikshapathi, Sambit Nayak, R. Srinivas,
and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
*E-mail: gowravaramsr@yahoo.com
Received February 15, 2010
DOI 10.1002/jhet.544
Published online 19 November 2010 in Wiley Online Library (wileyonlinelibrary.com).
A one-pot, three-component synthesis of 2-amino-2-chromenes is described at ambient temperature
by the reaction of an aldehyde and malononitrile or ethyl cyanoacetate with a-naphthol or b-naphthol in
ethanol in presence of a catalytic amount of Triton B.
J. Heterocyclic Chem., 48, 267 (2011).
INTRODUCTION
opment of an effective catalyst for the synthesis of 2-
aminochromenes, which equally works with a-and b-
naphthol.
Multicomponent reactions are gaining importance
both in academia and industry [1–4] due to their atom
economy, simple procedure, selectivity, time and energy
saving as well as environmental friendliness. 2-amino-
chromenes are widely employed as pigments [5], cos-
metics, and potential biodegradable agrochemicals [6]
and represent an important class of compounds being
the main components of many natural products. These
compounds have been of interest to the medicinal chem-
ist for many years [7]. Fused chromenes are biologically
active compounds with a wide spectrum of activities
such as antimicrobial [8a], mutagenicitical [8b], antiviral
[9,10] antiproliferative [11] sex pheromonal [12], antitu-
mora [13], and central nervous system activities [14].
The most straight forward synthesis of this heterocyclic
nucleus involves the multicomponent reactions of an
aldehyde, malononitrile and an activated phenol in the
presence of piperidine [15] using acetonitrile or ethanol
as solvent. Several methods with modified procedures
have been reported [16] but, most of the reported meth-
ods require prolonged reaction times at reflux tempera-
ture, reagents in stoichiometric amounts, works only
with a-naphthol, and generate moderate yields of the
product. Therefore there is a still demand for the devel-
Initially we tried the reaction of aromatic aldehyde
with malononitrile and a-naphthol using proline as a
catalyst in aq. ethanol, but trace amounts of the product
was isolated at reflux temperature. Then we screened
other catalysts such as CeCl3.7H2O/NaI, PMA/SiO2,
which were failed to give the desired products.
Benzyltrimethylammonium hydroxide (Triton B) has
been used in the preparation of dithiocarbamates using
alcoholic tosylates [17], dihydroxy-dithioethers [18] and
in alkylation of mono Michael products [19].
RESULTS AND DISCUSSION
When p-nitro benzaldehyde 1b, ethyl cyanoacetate 2,
a-naphthol 3, and 10 mol % Triton B were added to-
gether and stirred at ambient temperature in EtOH, the
reaction proceeded rapidly and was complete within 1 h
to give the corresponding product 4b in 92% yield
(Scheme 1).
The structure of the product was confirmed by spec-
tral data and compared with the authentic sample. To
study the generality of this method the optimized
C
V
2010 HeteroCorporation

268
G. Sabitha, M. Bhikshapathi, S. Nayak, R. Srinivas, and J. S. Yadav
Vol 48
Scheme 1
lyzed three component coupling of a- or b-naphthol, ar-
omatic aldehyde and malononitrile or ethyl
cyanoacetate.
EXPERIMENTAL
All reactions were monitored by thin layer chromatography
(TLC) using silica-coated plates. Evaporation of solvents was
performed at reduced pressure, using a Buchi rotary evapora-
tor. 1H NMR spectra were recorded on Varian FT-200 MHz
(Gemini) and Bruker UXNMR FT-300 MHz (Avance) in
CDCl3. Chemical shift values were reported in parts per mil-
lion (d) relative to tetramethylsilane (d 0.0) as an internal
standard. Mass spectra were recorded under electron impact at
70eV on LC-MSD (Agilent Technologies). Column chroma-
tography was performed on silica gel (60–120 mesh) supplied
by Acme Chemical, India. Thin-layer chromatography was
performed on Merck 60 F-254 silica gel plates.
General procedure. A mixture of aldehyde (1.0 mmol),
ethyl cyanoacetate /malononitrile (1.0 mmol) and a-naphthol/
b-naphthol (1.0 mmol) and Triton B (10 mol %) stirred in
EtOH at room temperature for specified time (tables). Precipi-
tated solid was filtered and recrystallized from MeOH.
procedure was used for the synthesis of a variety of 2-
amino-2-chromenes. Aromatic aldehydes having elec-
tron-withdrawing groups reacted fast with malononitrile
and a-naphthol giving high yields of products when
compared to aldehydes containing electron-donating
groups. It should be noted that under similar conditions,
ethyl cyanoacetate also found to give better yields (Ta-
ble 1, entries a-e). Encouraged by these results, we car-
ried out the reaction of aromatic aldehyde and malono-
nitrile with b-naphthol, which was found to react
equally as a-naphthol giving high yields of products.
The results of the study are shown in Table 2. The
Spectral data. Ethyl 2-amino-4-(3-nitrophenyl)-4H-ben-
zo[h]chromene-3-arboxylate (4c). Yellow solid, mp: 198–
200ꢀC; IR (KBr): 3416.0, 3289.9, 3084.4, 2924.3, 2854.7,
1
1
1672.4, 1603.6 and 1522.8 cmꢁ1; H NMR (CDCl3, 300MHz)
structures of all compounds were confirmed by IR, H
1
NMR and mass spectroscopy. The H NMR of 4 dis-
played a singlet at d 5.20 (H-4) and a broad singlet due
to ANH2 at d 6.40 (D2O exchangeable). Signals at d 40
(C-4) and at 160 (C-2) in the 13C NMR spectrum con-
firmed the formation of the product.
d: 8.26-8.22 (m, 2H, Ar-H), 8.03 (dd, J ¼ 8.3, 2.2 Hz, 1H,
Ar-H), 7.78 (d, J ¼ 8.3 Hz, 1H, Ar-H), 7.61-7.48 (m, 4H, Ar-
H), 7.38 (t, J ¼ 8.3 Hz, 1H, Ar-H), 7.09 (d, J ¼ 8.3 Hz, 1H,
Ar-H), 6.52 (brs, 2H, -NH2), 5.20 (s, 1H, -CH-), 4.12 (m, 2H,
-OCH2-), 1.23 (t, J ¼ 6.8 Hz, 3H, -CH3); 13C NMR (CDCl3,
100MHz) d: 168.8, 159.9, 149.5, 147.9, 143.3, 134.2, 133.1,
129.0, 127.6, 126.6, 126.5, 126.1, 124.4, 123.2, 122.9, 121.3,
120.8, 118.9, 78.1, 59.7, 40.8, 14.4.; ESMS m/z: 413.0; HRMS
m/z calc.: 413.1113; found: 413.1099 (MþþNa).
The change in mol% of Triton B did not much alter
the yield of product. Also, when the reaction was run in
EtOH/H2O mixture, at room temperature the intermedi-
ate was isolated and at 100ꢀC a 30% yield of the prod-
uct formation was observed. The present reaction was
studied with other catalysts such as ammonium molyb-
date and amberlite 400. The reaction using ammonium
molybdate as catalyst in different media gives low
yields of products and requires longer reaction time.
However using amberlite 400, the reaction does not pro-
ceed at r. t., but gives low yield of product at higher
temperature and results are shown in Table 3.
Ethyl 2-amino-4-(4-fluorophenyl)-4H-benzo[h]chromene-3-
carboxylate (4d). Pale yellow solid, mp: 206–208ꢀC.; IR
(KBr): 3385.5, 3288.7, 3050.8, 2980.3, 2904.9, 1671.3, 1603.1
1
and 1505.1 cmꢁ1.; H NMR (CDCl3, 300MHz) d: 8.17 (d, J ¼
8.0 Hz, 1H, Ar-H), 7.72 (dd, J ¼ 7.3, 2.2 Hz, 1H, Ar-H),
7.55-7.39 (m, 3H, Ar-H), 7.24-7.14 (m, 2H, Ar-H), 7.07 (d, J
¼ 8.8 Hz, 1H, Ar-H), 6.86 (t, J ¼ 8.8 Hz, 2H, Ar-H), 6.45
(brs, 2H, -NH2), 5.00 (s, 1H, -CH-), 4.08 (dq, J ¼ 6.6, 2.2 Hz,
2H, -OCH2-), 1.18 (t, J ¼ 6.6 Hz, 3H, -CH3).; 13C NMR
(CDCl3, 75MHz) d: 162.9, 159.9, 159.6, 143.4, 143.3, 143.1,
132.9, 129.4, 129.3, 127.6, 126.5, 126.3, 124.1, 123.3, 120.7,
120.4, 115.0, 114.7, 79.0, 59.5, 40.1, 14.3.; ESMS m/z: 386.0;
HRMS m/z calc.: 386.1168; found: 386.1172 (MþþNa).
Mechanism of the reaction. As the mechanism for
the formation of the product is well known that it repre-
sents a cascade reaction in which the benzylidene malo-
nonitrile is produced by Knoevenagel condensation of
malononitrile to the aromatic aldehyde by loss of water.
The second step requires a catalyst which involves the
phenol ortho C-alkylation by reaction with the electro-
philic C¼¼C double bond and the nucleophilic addition
of the phenolic OH group on the CN moiety [16l].
In conclusion, we have developed a highly efficient
reaction protocol at room temperature for the synthesis
of a variety of 2-amino-2-chromenes via Triton B cata-
Ethyl 3-amino-1-phenyl-1H-benzo[f]chromene-2-carboxy-
late (5a). Pale yellow solid, mp: 166–168ꢀC.; IR (KBr):
3402.3, 3295.5, 3052.9, 2991.8, 2963.2, 1671.5 and 1616.7
cmꢁ1.; 1H NMR (CDCl3, 200MHz) d: 7.98 (d, J ¼ 8.0 Hz,
1H, Ar-H), 7.76-7.67 (m, 2H, Ar-H), 7.46-6.98 (m, 8H, Ar-
H), 6.30 (brs, 2H, -NH2), 5.53 (s, 1H, -CH-), 4.30-4.12 (m,
2H, -OCH2-), 1.37 (t, J ¼ 7.3 Hz, 3H, -CH3).; 13C NMR
(CDCl3, 75MHz) d: 169.1, 160.0, 159.9, 147.1, 146.4, 131.1,
131.0, 128.6, 128.3, 128.0, 127.9, 126.8, 126.1, 124.6, 123.5,
119.2, 119.1, 116.6, 80.3, 59.6, 37.1, 14.5.; ESMS m/z: 368.0;
HRMS m/z calc.: 368.1262; found: 368.1260 (MþþNa).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Table 1
Triton B catalyzed synthesis of 2-amino-2-chromenes.a,b,c
Entry
a
Aldehyde 3
R
Product 4
Time (h)
1.50
Yield (%)
88
CO2Et
b
CO2Et
1.00
92
c
CO2Et
1.00
1.25
92
90
d
CO2Et
e
CO2Et
3.00
80
f
CN
CN
1.25
1.00
87[16c]
g
90[16j]
h
CN
3.00
80[16j]
i
CN
1.25
90[16l]
a New products were characterized by IR, 1H NMR, 13C and mass spectral data.
b Known products were compared with authentic samples.
c Isolated pure products.

270
G. Sabitha, M. Bhikshapathi, S. Nayak, R. Srinivas, and J. S. Yadav
Vol 48
Table 2
Triton B catalyzed synthesis of 2-amino-2-chromenes.a,b,c
Entry
Aldehyde 3
R
Product 5
Time (h)
1.50
Yield (%)
87
a
b
c
d
CO2Et
CO2Et
1.00
1.00
3.00
92
CN
90
CN
80[16d]
a New products were characterized by IR, 1H NMR, 13C and mass spectral data.
b Known compounds were compared with authentic samples.
c Isolated pure products.
Table 3
Comparsion of various catalysts at various temperature.
Entry
Catalyst
Solvent
Temp.
Time (h)
Yield (%)
92
a
b
c
d
e
f
Triton B(10 mol%)
’’
EtOH
EtOH:H2O (1:1)
r. t.
r. t.
100ꢀC
r. t.
r. t.
100ꢀC
’’
1.0
6.0
3.0
3.0
6.0
0.5
3.0
12.0
12.0
3.0
2.0
6.0
6.0
3.0
b
–
’’
(NH4)2MoO4(10 mol %)
’’
EtOH
30
85
a
’’
’’
EtOH:H2O (1:1)
–
’’b
H2Ob
’’
88
62
g
h
i
’’
a
’’
’’
r. t.
’’
100ꢀC
–
DMF
’’
PEG 400
’’
EtOH
’’
10
30
74
35
j
k
l
m
n
’’
’’
’’
’’
r. t.
’’
100ꢀC
a
Amberlite 400 (10 mol %)
’’
–
68
a Intermediate was formed.
b Catalytic amount of TBAI was used.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Triton B Catalyzed Three-Component, One-Pot Synthesis of 2-Amino-2-chromenes
at Ambient Temperature
271
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1
1523.4 cm-1.; H NMR (CDCl3, 300MHz) d: 8.28 (s, 1H, Ar-
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H), 7.94 (dd, J ¼ 8.3, 1.5 Hz, 1H, Ar-H), 7.85 (d, J ¼ 8.3 Hz,
1H, Ar-H), 7.76 (d, J ¼ 9.0 Hz, 2H, Ar-H), 7.48-7.24 (m, 5H,
Ar-H), 6.37 (brs, 2H, -NH2), 5.66 (s, 1H, -CH-), 4.30-4.14 (m,
2H, -OCH2-), 1.40 (t, J ¼ 7.5 Hz, 3H, -CH3).; 13C NMR
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nide (5c). Yellow solid, mp: 202–204ꢀC; IR (KBr): 3410.3,
3302.5, 2924.0, 2853.7, 2187.5, 1655.2 cmꢁ1.; 1H NMR
(CDCl3, 200MHz) d: 7.85-7.76 (m, 2H, Ar-H), 7.68-7.61 (m,
2H, Ar-H), 7.42-7.34 (m, 2H, Ar-H), 7.31-7.17 (m, 2H, Ar-
H), 7.15-7.06 (m, 2H, Ar-H), 6.32 (s, 2H, -NH2), 5.18 (s, 1H,
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126.2, 126.0, 124.2, 123.3, 120.8, 119.8, 59.5, 40.7.; ESMS m/
z: 355.0; HRMS m/z calc.: 355.0614; found: 355.0609
(MþþNa).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet