A rapid and efficient access to 4-substituted 2-amino-4 H -chromenes catalyzed by InCl3

Article abstract of DOI:10.1055/s-0030-1260563

A series of 4-substituted 2-amino-4H-chromenes was synthesized via a simple and efficient one-pot synthesis from salicylaldehyde, malononitrile, and a few cyclic nucleophiles using indium trichloride as a catalyst. The methodology affords high yields of p

Full text of DOI:10.1055/s-0030-1260563

LETTER
1389
A Rapid and Efficient Access to 4-Substituted 2-Amino-4H-chromenes
Catalyzed by InCl3
A
ccess to 4-Substi
e
tute
d
2-A
m
e
ino-4
H
-chr
l
omenesakandan Vidhya Lakshmi, Selvarangam E. Kiruthika, Paramasivan T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 17 February 2011
report a simple and facile one-pot procedure for the syn-
thesis of 2-amino-4H-chromene derivatives from 2-hy-
droxybenzaldehydes and a range of cyclic nucleophiles
catalyzed by InCl3 in ethanol at room temperature. To the
best of our knowledge, this is the first report on 3-methyl-
1-phenyl-1H-pyrazol-5(4H)-one, oxindole, and 5,5-dime-
thylcyclohexan-1,3-dione employed as Michael donors
with iminocoumarins to synthesize functionalized
chromenes.
Abstract: A series of 4-substituted 2-amino-4H-chromenes was
synthesized via a simple and efficient one-pot synthesis from sali-
cylaldehyde, malononitrile, and a few cyclic nucleophiles using in-
dium trichloride as a catalyst. The methodology affords high yields
of products in short reaction times.
Key words: chromenes, salicylaldehyde, indium(III) chloride,
malononitrile, three-component
Densely functionalized complex molecules bearing a six-
membered oxygen-containing heterocyclic architecture
are of great value in the design and discovery of new bio-
logically active compounds.1 An efficient method for gen-
erating oxygen-containing heterocycles is by multi-
component reactions (MCR) which are high-yielding
pathways with subsequent transformations that further in-
crease molecular complexity and diversity, requiring a
minimum time, labor, cost, and waste disposal.2 There-
fore, the development of novel MCR for the synthesis of
biologically active compounds has attracted great atten-
tion over the past decades.
Initial studies were carried out by mixing salicylaldehyde
1a, malononitrile (2), and 3-methyl-1-phenyl-1H-pyra-
zol-5(4H)-one (3) in different solvent systems such as
methanol, ethanol, and acetonitrile in the presence of var-
ious Lewis acids and bases at room temperature to afford
2-amino-4-pyrazol-4-yl-4H-chromene 4a (Scheme 1).
Ph
N
N
OH
CN
Ph
N
N
CHO
CN
O
InCl3
+
X
+
X
EtOH, r.t.
CN
OH
O
NH2
Among the oxygen-containing heterocycles, chromene
derivatives are of great importance due to a number of
drugs containing this motif also found in pigments, cos-
metics, and agrochemicals.3 Much attention has been paid
to 4H-chromenes since they have widespread applications
in pharmaceutical and mechanistic studies of biochemical
processes.4 Several 4H-chromenes have been proven to be
efficient DNA polymerase b inhibitors,1c apoptosis induc-
ers,5a antitrypanosomal agents,4a and antibacterial
agents.5b Fused chromenes have various biological activi-
ties such as antimicrobial, antiviral,6 mutagenic, antipro-
liferative, sex pheromone, antitumor,7 and central nervous
system agents. Hence, an easy access to 2-amino-4H-
chromene derivatives is highly desirable as they possess
unique pharmacological properties.
1a–h
2
3
4a–h
Scheme 1 Synthesis of 2-amino-4-pyrazol-4-yl-4H-chromenes 4a–h
Among the Lewis acids and bases (Table 1, entry 1–7),
InCl3 catalyzed the reaction in the shortest reaction time
with highest yield. The best results were obtained using
ethanol as solvent at room temperature in presence of 20
mol% of InCl3.
Table 1 Screening of Various Lewis Acids and Bases in Ethanol
Entry
Lewis acid or base
Yield
(%)a,b
1
2
3
4
5
6
7
SnCl2·2H2O
AlCl3
52
26
85
38
21
74
83
Recently, the synthetic utility of indium(III) Lewis acids8
in organic synthesis has received a great attention due to
their relatively low toxicity, stability in air, water, and re-
cyclability. In the context of our ongoing efforts to devel-
op new methodologies for 2-amino-4H-chromenes,9 use
InCl3
K2CO3
NaOH
pyridine
Et3N
of green chemical techniques10–12 and the application of
13–15
InCl3
in organic synthesis through MCR, herein, we
SYNLETT 2011, No. 10, pp 1389–1394
Advanced online publication: 13.05.2011
DOI: 10.1055/s-0030-1260563; Art ID: D05311ST
x
x
.x
x
.2
0
1
1
a Reactions carried out with 20 mol% of Lewis acid or base at r.t.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York

1390
N. V. Lakshmi et al.
LETTER
InCl3
+
O
CN
CN
NH
CN
CN
H
EtOH, r.t.
··
N
OH
··
OH
O
InCl3
2b
1a
2
2a
Ph
Ph
N
N
N
N
H
InCl3
O
OH
CN
CN
N
N
O
+
CN
··
H
N
O
Ph
InCl3
O
NH2
O
NH2
3
4a
3a
Scheme 2 Plausible mechanism for the synthesis of 2-amino-4-pyrazol-4-yl-4H-chromene
Table 2 Synthesis of New 2-Amino-4-pyrazol-4-yl-4H-chromene
Derivatives 4a–h (continued)
On the basis of the above results, a tentative mechanistic
interpretation to explain the formation of 2-amino-4-pyra-
zol-4-yl-4H-chromene 4a is proposed (Scheme 2). Initial-
ly, salicylaldehyde (1a) undergoes a simple Knoevenagel
condensation with malononitrile (2) to form the interme-
diate iminocoumarin 2b in the presence of InCl3. The in-
termediate 2b undergoes Michael addition with 3-methyl-
1-phenyl-1H-pyrazol-5(4H)-one (3) to give 3a which
enolizes to yield the 2-amino-4-pyrazol-4-yl-4H-
chromene 4a.
Entry Salicylaldehyde 1 Product 4a
Time Yield
(min) (%)b
Br
Br
CHO
OH
4
5
6
60 79
60 82
75 83
N
N
O
Ph
1d
H2N
CN
HO
The scope of the reaction was further studied with various
substituted salicylaldehyde derivatives (including those
containing halogens and alkoxy groups) under the opti-
mized conditions. All the reactions proceeded smoothly to
provide 2-amino-4-pyrazol-4-yl-4H-chromenes 4b–h in
good yields (79–85%). The results are given in Table 2.
4d
Br
Br
CHO
OH
Br
N
O
N
Br
Ph
Table 2 Synthesis of New 2-Amino-4-pyrazol-4-yl-4H-chromene
Derivatives 4a–h
1e
HO
CN
H2N
4e
Entry Salicylaldehyde 1 Product 4a
Time Yield
(min) (%)b
I
I
CHO
I
N
OH
O
H2N
CHO
N
I
Ph
N
N
1
2
30 85
O
1f
CN
HO
OH
Ph
4f
1a
1b
H2N
CN
HO
Cl
4a
Cl
CHO
Cl
EtO
CHO
OH
7
8
60 82
N
N
OH
O
N
N
60 83
O
Cl
Ph
Ph
1g
CN HO
H2N
OEt
H2N
CN
HO
4g
4b
Cl
MeO
CHO
N
Cl
CHO
OH
60 81
O
OH
N
3
60 80
N
N
Ph
OMe
O
H2N
CN
HO
h
Ph
1c
4h
H2N
CN
HO
a The products were characterized by IR, NMR, MS, and elemental
analysis.
4c
b Isolated yield after recrystallization.
Synlett 2011, No. 10, 1389–1394 © Thieme Stuttgart · New York

LETTER
Access to 4-Substituted 2-Amino-4H-chromenes
1391
X
The structures of compounds 4a–h were confirmed by IR,
1H NMR, 13C NMR spectroscopy and elemental analysis.
The IR spectrum of compound 4a showed absorptions at
3418, 3328, 2185 cm–1 indicating the presence of OH,
NH2, and CN groups, respectively. In the 1H NMR spec-
trum, the methyl group was observed as a singlet at d =
1.94 ppm and the OH proton (D2O exchangeable) ap-
peared as a singlet at d = 2.04 ppm. The two characteristic
singlets at d = 4.78 and 6.78 ppm correspond to methyne
proton and NH2 protons (D2O exchangeable), respective-
ly. In the 13C NMR spectrum, the methyl carbon atom res-
onated at d = 29.2 ppm and also the signal at d = 160.7
ppm (C-2) provided further evidence for the formation of
the product.16
H1
H
O
N
H2
CN
6a–h
(or)
NH
O
H2N
O
CHO
5
(or)
CN
InCl3
+
X
+
EtOH, r.t.
O
CN
X
OH
1a–h
2
O
H1
O
O
7
H2
H2N
CN
O
Encouraged by these results, we extended the protocol to
synthesize a series of chromene derivatives 6a–h and 8a–
h using cyclic nucleophiles such as oxindole (5), 5,5-di-
methylcyclohexan-1,3-dione (7) (Scheme 3, Table 3 and
Table 4), and also fused 2-aminochromenes 10–12 from
2-napthol-1-carbaldehyde (9) under the same optimized
conditions in good yields ( Scheme 4).
Scheme 3 Synthesis of 2-amino-4H-chromenes 6a–h and 8a–h
broad singlet at d = 7.61 ppm for the NH2 protons (D2O
exchangeable). The methyne protons appeared as two
doublets at d = 3.95 and 4.50 ppm corresponding to the
5,5-dimethylcyclohexan-1,3-dione and chromene proton,
respectively. The 13C NMR spectrum showed a signal at
d = 160.3 ppm for the C-2 carbon atom.18
The structures of compounds 6a–h, 8a–h, and 10–12 were
confirmed by IR, 1H NMR, 13C NMR spectroscopy and el-
emental analysis. The IR spectrum of compound 6b
showed absorptions at 3189, 2183 cm–1 indicating the
presence of NH2 and CN groups, respectively. In 1H NMR
spectrum, the methyne protons of chromene and oxindole
rings appeared as two distinct doublets at d = 3.58 and
4.19 ppm. The characteristic singlets at d = 7.06 and 10.39
ppm correspond to the NH2 protons of the chromene ring
and NH proton of the oxindole ring (D2O exchangeable),
respectively. In the 13C NMR spectrum, the signal at d =
162.4 ppm corresponds to the C-2 carbon atom.17
This method offers several advantages, including milder
reaction conditions, shorter time for completion, high
yields, and simple experimental and isolation procedures
making an efficient route for the synthesis of 2-amino-4H-
chromenes. This protocol is simple and requires no purifi-
cation by column chromatography.
In summary, we have demonstrated a new, one-pot, three-
component reaction that offers a simple method for the
synthesis of new 2-amino-4H-chromenes from salicylal-
dehyde, malononitrile, and a range of cyclic nucleophiles
catalyzed by indium trichloride. Further studies to delin-
eate the scope and limitations of the present methodology
are under way.
In the IR spectrum of compound 8h, absorptions at 3169
and 2209 cm–1 showed the presence of NH2 and CN peaks,
1
respectively. The H NMR spectrum of 8h exhibited a
Ph
N
N
NH
H2
OH
CN
O
H1
CN
(or)
(or)
O
NH2
O
NH2
CHO
OH
CN
(82%)
(81%)
10
11
InCl3
(or)
(or)
7
+
+
3
5
EtOH, r.t.
CN
9
2
O
H1
O
H2
O
H2N
CN
Scheme 4 Synthesis of fused 2-amino-4H-chromenes
Synlett 2011, No. 10, 1389–1394 © Thieme Stuttgart · New York

1392
N. V. Lakshmi et al.
LETTER
Table 3 Synthesis of 2-Amino-4-(2-oxoindolin-3-yl)-4H-
chromene Derivatives 6a–h
Table 3 Synthesis of 2-Amino-4-(2-oxoindolin-3-yl)-4H-
chromene Derivatives 6a–h (continued)
Entry Salicylaldehyde 1 Product 6a
Time Yield
Entry Salicylaldehyde 1 Product 6a
Time Yield
(min) (%)b
(min) (%)b
MeO
CHO
OH
CHO
H1
H2
H1
H2
1
30 85
8
60 81
O
O
NH
NH
OH
OMe
O
1a
1b
H2N
O
CN
H2N
CN
1h
6a
6h
a The products were characterized by IR, NMR, MS, and elemental
analysis.
CHO
OH
EtO
H1
H2
2
3
60 83
b Isolated yield after recrystallization.
O
NH
OEt
O
H2N
CN
Table 4 Synthesis of 2-Amino-4-(4,4-dimethyl-2,6-dioxocyclo-
hexyl)-4H-chromene Derivatives 8a–h
6b
Cl
Entry Salicylaldehyde 1 Product 8a
Time Yield
(min) (%)b
Cl
CHO
OH
H1
H2
60 80
O
O
H1
NH
CHO
1c
O
H2N
CN
1
2
20
30
84
83
O
6c
OH
H2
Br
O
CN
1a
1b
H2N
8a
Br
CHO
OH
H1
H2
4
5
6
7
60 79
60 82
75 83
60 82
O
CHO
OH
EtO
O
H1
NH
O
1d
O
H2N
CN
H2
CN
OEt
6d
O
H2N
Br
8b
Br
CHO
OH
Cl
Br
H1
Cl
CHO
OH
O
H1
O
NH
3
4
5
40
40
60
80
84
82
Br
H2
O
O
H2N
CN
1e
H2
1c
6e
O
CN
H2N
I
8c
I
CHO
Br
I
H1
H2
Br
CHO
OH
O
H1
OH
O
H2N
NH
I
O
O
1f
CN
H2
1d
6f
O
CN
H2N
Cl
8d
Cl
CHO
Br
Cl
Br
CHO
OH
H1
H2
O
H1
Br
OH
O
NH
Cl
O
1g
O
H2N
CN
Br
H2
CN
6g
O
1e
H2N
8e
Synlett 2011, No. 10, 1389–1394 © Thieme Stuttgart · New York

LETTER
Access to 4-Substituted 2-Amino-4H-chromenes
1393
Table 4 Synthesis of 2-Amino-4-(4,4-dimethyl-2,6-dioxocyclo-
hexyl)-4H-chromene Derivatives 8a–h (continued)
Singh, V. K.; Bhunia, D. C.; Yadav, J. S. Tetrahedron Lett.
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Entry Salicylaldehyde 1 Product 8a
Time Yield
(min) (%)b
I
Voravuthikkunchai, S. P.; Maarten von Dijl, J.; Kayser, O.
Phytomedicine 2009, 16, 645. (b) Bowers, W. S.; Ohta, T.;
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I
CHO
OH
O
H1
I
6
60
85
O
I
H2
O
O
CN
1f
H2N
8f
(6) Hiramoto, J.; Nasuhara, A.; Michiloshi, K.; Kato, T.;
Kikugawa, K. Mutat. Res. 1997, 395, 47.
Cl
Cl
CHO
(7) Bianchi, G.; Tava, A. Agric. Biol. Chem. 1987, 51, 20.
(8) For reviews on indium Lewis acids, see: (a) Frost, C. G.;
Chauhan, K. K. J. Chem. Soc., Perkin Trans. 1 2000, 3015.
(b) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Curr.
Org. Chem. 2003, 7, 1661. (c) Frost, C. G.; Hartley, J. P.
Mini-Rev. Org. Chem. 2004, 1, 1.
(9) (a) Jayashree, P.; Shanthi, G.; Perumal, P. T. Synlett 2009,
917. (b) Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2007,
48, 6785. (c) Babu, T. H.; Perumal, P. T. Synlett 2011, 341.
(d) Shanthi, G.; Perumal, P. T. Synlett 2008, 2791.
(10) (a) Thirumurugan, P.; Perumal, P. T. Tetrahedron Lett.
2009, 50, 4145. (b) Thirumurugan, P.; Nandakumar, A.;
Muralidharan, D.; Perumal, P. T. J. Comb. Chem. 2010, 12,
161.
Cl
H1
7
8
60
60
83
84
OH
O
Cl
H2
CN
O
1g
H2N
8g
CHO
O
H1
MeO
O
OH
H2
OMe
O
CN
H2N
1h
8h
a The products were characterized by IR, NMR, MS, and elemental
analysis.
(11) Lakshmi, N. V.; Thirumurugan, P.; Perumal, P. T.
Tetrahedron Lett. 2010, 51, 1064.
(12) Lakshmi, N. V.; Thirumurugan, P.; Jayakumar, C.; Perumal,
P. T. Synlett 2010, 955.
b Isolated yield after recrystallization.
(13) (a) Thirumurugan, P.; Perumal, P. T. Tetrahedron 2009, 65,
7620. (b) Praveen, C.; Karthikeyan, K.; Perumal, P. T.
Tetrahedron 2009, 65, 9244.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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Acknowledgment
One of the authors (N.V.) thanks the Council of Scientific and Indu-
strial Research, New Delhi, India for a research fellowship.
References and Notes
(16) Experimental Procedure for the Synthesis of 2-Amino-
4H-chromene 4a (Table 2, Entry 1)
(1) (a) Batt, D. G. WO 2010009069, 2010. (b) Tjoeng, F. S.;
Carter, J.; Springer, J. R.; Zupec, M. E. WO 2006040676A1,
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To a stirred mixture of salicylaldehyde 1 (1 mmol) and
malononitrile (2, 1 mmol) in EtOH, 3-methyl-1-phenyl-1H-
pyrazol-5 (4H)-one (3, 1 mmol) and InCl3 (20 mol%) were
added. The reaction mixture was stirred until complete
conversion of the product as indicated by TLC (Table 2).
The solid formed was filtered, dried, and recrystallized from
EtOH to obtain the pure product in good yield (85%) 4a.
2-Amino-4-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-
4-yl)-4H-chromene-3-carbonitrile (4a, Table 2, Entry 1)
White solid; mp 150–152 °C. IR (KBr): nmax = 3418, 3328,
3072, 2185, 1587 cm–1. 1H NMR (500 MHz, DMSO-d6): d =
1.94 (s, 3 H), 2.04 (s, 1 H, OH, D2O exchangeable), 4.78 (s,
1 H), 6.78 (s, 2 H, NH2, D2O exchangeable), 6.96 (d, 1 H,
J = 8.4 Hz), 7.01–7.06 (m, 2 H), 7.14–7.17 (m, 2 H), 7.38 (t,
2 H, J = 8.0 Hz), 7.68 (d, 2 H, J = 8.4 Hz). 13C NMR (125
MHz, DMSO-d6): d = 29.2, 31.2, 54.6, 115.8, 116.1, 119.1,
119.5, 121.2, 121.4, 123.2, 125.2, 125.5, 128.5, 129.4,
147.5, 149.1, 160.9. MS: m/z = 344.5 [M+]. Anal. Calcd (%)
for C20H16N4O2: C, 69.76; H, 4.68; N, 16.27. Found: C,
69.70; H, 4.72; N, 16.23.
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Synlett 2011, No. 10, 1389–1394 © Thieme Stuttgart · New York

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N. V. Lakshmi et al.
LETTER
(17) 2-Amino-8-ethoxy-4-(2-oxo indolin-3-yl)-4H-chromene-
3-carbonitrile (6b, Table 3, Entry 2)
C20H17N3O3: C, 69.15; H, 4.93; N, 12.10. Found: C, 69.13;
H, 4.90; N, 12.08.
White solid; mp 178–180 °C. IR (KBr): nmax = 3614, 3189,
2183, 1698, 1583, 1476, 1422, 1334, 1269, 1217, 1076, 751
cm–1. 1H NMR (500 MHz, DMSO-d6): d = 1.20 (t, 3 H,
6.9Hz), 3.58 (d, 1 H, 3.1 Hz), 3.86–3.93 (m, 2 H), 4.19 (d, 1
H, J = 3.1 Hz), 6.58 (d, 1 H, J = 7.7 Hz), 6.66 (d, 1 H, J = 7.7
Hz), 6.76 (d, 1 H, J = 8.4 Hz), 6.81 (t, 1 H, J = 6.9 Hz), 6.86
(t, 1 H, J = 7.7 Hz), 7.01 (t, 1 H, J = 7.7 Hz), 7.06 (s, 2 H,
NH2, D2O exchangeable), 7.13 (d, 1 H, J = 7.7 Hz), 10.39 (s,
1 H, NH, D2O exchangeable). 13C NMR (125 MHz, DMSO-
d6): d = 15.03, 37.8, 52.9, 53.3, 64.7, 109.65, 113.3, 119.5,
121.2, 121.7, 124.2, 127.2, 128.6, 139.8, 143.5, 146.3,
162.4, 177.2. MS: m/z = 347.2 [M+]. Anal. Calcd (%) for
(18) 2-Amino-8-methoxy-4-(4,4-dimethyl-2,6-dioxocyclo-
hexyl)-4H-chromene-3-carbonitrile (8h, Table 4, Entry 8)
White solid; mp 150–152 °C. IR (KBr): nmax = 3336, 3162,
2209, 1704, 1635, 1508, 1390, 1028 cm–1. 1H NMR (500
MHz, DMSO-d6): d = 1.05 (s, 3 H), 1.06 (s, 3 H), 2.48 (s, 2
H), 2.52 (s, 2 H), 3.72 (s, 3 H), 3.95 (d, 1 H, J = 3.1 Hz), 4.50
(d, 1 H, J = 3.1 Hz), 6.70–6.73 (m, 2 H), 7.17–7.19 (m, 1 H),
7.61 (s, 2 H, NH2, D2O exchangeable). 13C NMR (125 MHz,
DMSO-d6): d = 26.6, 27.0, 32.3, 55.9, 101.9, 109.2, 111.8,
112.2, 113.8, 117.5, 130.6, 151.6, 152.0, 160.3, 165.6,
168.4, 197.0. MS: m/z = 340.1 [M+]. Anal. Calcd (%) for
C19H20N2O4: C, 67.05; H, 5.92; N, 8.23. Found: C, 67.03; H,
5.86; N, 8.27.
Synlett 2011, No. 10, 1389–1394 © Thieme Stuttgart · New York