Catalyst-free cascade synthesis of densely functionalized chromenes in water

Article abstract of DOI:10.14233/ajchem.2019.22191

An expeditious and environmental friendly, general protocol has been developed for the synthesis of 2-amino-3-cyano-4H-chromenes via cascade Knoevenagel-Michael-intramolecular cyclization in water. Pure solid products were obtained by simple filtration technique. The aqueous catalyst-free reactions lead to high product yield at room temperature.

Full text of DOI:10.14233/ajchem.2019.22191

Asian Journal of Chemistry; Vol. 31, No. 11 (2019), 2532-2536
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.22191
Catalyst-Free Cascade Synthesis of Densely Functionalized Chromenes in Water
SUBRAHMANYA ISHWAR BHAT
Department of Chemistry, N.M.A.M. Institute of Technology, Nitte, Karkala-574110, India
Corresponding author: E-mail: subrahmanya@nitte.edu.in
Received: 10 May 2019;
Accepted: 11 June 2019;
Published online: 28 September 2019;
AJC-19582
An expeditious and environmental friendly, general protocol has been developed for the synthesis of 2-amino-3-cyano-4H-chromenes via
cascade Knoevenagel-Michael-intramolecular cyclization in water. Pure solid products were obtained by simple filtration technique. The
aqueous catalyst-free reactions lead to high product yield at room temperature.
Keywords: Green Synthesis, Cascade reaction, Water media, Knoevenagel condensation, Chromenes.
activation [19], microwave irradiation [20,21], ultrasound activ-
ation [22] and under ionic liquids [23], deep eutectic solvents
[24], aqueous media [25-28] and under solvent-free catalyst
free conditions [29,30]. Despite satisfactory results, most of
these methods need to overcome from limitations such as harsh
reaction conditions, tedious work-up and purification procedures,
lack of substrate generality and thus, the development of an
efficient environmental friendly protocol with more general
applicability is of great importance from the synthetic organic
and Green Chemistry viewpoint.
With the aim to develop greener methodology for organic
transformations, the present contribution focuses on a general
protocol for the synthesis of densely functionalized chromenes
via Cascade Knoevenagel-Michael addition-intramolecular
cyclization reaction.
INTRODUCTION
Complete elimination of hazardous solvents or replace-
ment with innocuous solvent is one of the main aspect of Green
Chemistry [1].Among various solvents used as reaction media,
water is the primary choice because of its advantageous
properties such as naturally occurring, economically cheaper,
non-flammable and innocuous nature [2-4]. Further, significant
enhancement in the rate of several reactions was observed in
water, owing to hydrophobic interactions that induce favour-
able aggregation of polar components [5]. In addition to this,
the use of water as a solvent allows simple isolation of products
by filtration, extraction and distillation processes [6].
The cascade reactions involve two or more sequential
bond-formation that occurs without modification of reaction
conditions, to obtain complex molecular structures starting
from simple building blocks [7,8]. Hence, these reactions have
gained increasing interest in greener chemical synthesis, because
they introduce elegance and efficiency to synthetic strategies
[9]. Chromenes are significant fused heterocycles, present in broad
range of natural products and pharmaceuticals [10,11]. Function-
alized chromene scaffolds are known to display potent pharma-
cological activities, such as antioxidant, antifungal, antimicro-
bial, antiviral, antitubercular, antiproliferative and anticancer
properties [12,13]. Owing to their importance, a wide range
of synthetic protocols have been developed for the synthesis
of chromene derivatives using catalysis [14-18], photochemical
EXPERIMENTAL
All chemicals were procured from commercial suppliers
and used without further purification. Melting points were
recorded on Stuart SMP3 melting point apparatus and are uncor-
rected. NMR spectra were recorded as a solution in DMSO-d6
at 400 MHz instrument with tetramethylsilane as an internal
standard. Chemical shifts (δ) are given in parts per million and
coupling constant J-values are given in Hz. Elemental analysis
was performed using a Perkin Elmer, Series II, 2400 analyzer.
Thin Layer Chromatography (TLC) was performed on silica
gel 60 F254 (Merck).
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Vol. 31, No. 11 (2019)
Catalyst-Free Cascade Synthesis of Densely Functionalized Chromenes in Water 2533
General procedure for the synthesis of compounds 4a-i:
A mixture of salicylaldehyde (1 mmol) and malononitrile (2
mmol) was taken in a 25 mL round-bottomed flask containing
water (5 mL). The suspension formed was stirred at room tempe-
rature for a suitable time (Table-1). The formed precipitate
was then filtered and washed with 3 × 10 mL water and dried
under vacuum to obtain pure product. Purity and structure of
all the products are supported by TLC analysis, melting point
determination and NMR characterization (Scheme-I).
2-(2-Amino-3-cyano-4H-chromen-4-yl)malononitrile
(4a): Colour: white solid; Anal. calcd. (found) % for C13H8N4O:
C, 66.10 (65.94); H, 3.41 (3.37); N, 23.72 (23.66). 1H NMR
(DMSO-d6) δ: 4.61 (d, 1H, J = 4 Hz), 5.11 (1H, d, J = 4 Hz),
7.16 (1H, d, J = 8Hz), 7.31 (1H, t, J = 7.5 Hz), 7.45-7.49 (m, 2H),
7.55 (s, 2H); 13C NMR (DMSO-d6) δ: 32.3, 38.2, 49.6, 112.5,
112.8, 116.8, 117.9, 119.3, 125.2, 130.0, 130.3, 150.4, 163.9.
(2-Amino-3-cyano-8-methoxy-4H-chromen-4-yl)malono-
nitrile (4b): Colour: white solid; Anal. calcd. (found) % for
C14H10N4O2: C, 63.15 (63.27); H, 3.79 (3.72); N, 21.04 (20.92).
1H NMR (DMSO-d6) δ: 3.88 (s, 3H), 4.60 (d, 1H, J = 2.5 Hz),
5.05 (d, 1H, 2.5 Hz), 7.02 (d, 1H, J = 7.5 Hz), 7.10 (d, 1H, J =
8 Hz), 7.19-7.23 (m, 1H), 7.53 (s, 2H); 13C NMR (DMSO-d6)
δ: 32.6, 37.4, 48.9, 55.9, 112.9, 113.1, 113.3, 118.9, 119.6,
119.9, 125.1, 139.3, 147.3, 163.7.
C13H7N4OCl: C, 57.69 (57.77); H, 2.61 (2.54); N, 20.70 (20.58).
1H NMR (DMSO-d6) δ: 4.62 (d, 1H, J = 4 Hz), 5.15 (d, 1H, J
= 3.5 Hz), 7.19 (d, 1H, J = 8.5Hz), 7.47 (d, 1H, J = 8.5 Hz),
7.59 (s, 3H); 13C NMR (DMSO-d6) δ: 32.8, 37.3, 48.9, 113.2,
113.4, 118.8, 119.6, 120.4, 128.9, 129.0, 130.5, 149.1, 163.7.
2-(2-Amino-3-cyano-6-nitro-4H-chromen-4-yl)malo-
nonitrile (4e): Colour: pale brownish solid; Anal. calcd. (found)
% for C13H7N5O3: C, 55.52 (55.60); H, 2.51 (2.39); N, 24.90
(24.76). 1H NMR (DMSO-d6) δ: 4.81 (d, 1H, J = 4 Hz), 5.23 (d,
1H, J = 3.5 Hz), 7.40 (d, 1H, J = 9 Hz), 7.81 (s, 2H), 8.30 (d, 1H,
J= 8.5 Hz), 8.53 (s, 1H); 13C NMR (DMSO-d6) δ: 32.9, 37.2, 49.0,
113.1, 113.2, 118.4, 119.2, 119.7, 125.7, 126.3, 144.3, 154.6, 163.2.
2-(2-Amino-3-cyano-8-methoxy-6-nitro-4H-chromen-
4-yl)malononitrile (4f): Colour: pale brownish solid; Anal.
calcd. (found) % for C14H9N5O4: C, 54.02 (54.16); H, 2.91 (2.78);
N, 22.50 (22.41). 1H NMR (DMSO-d6) δ: 4.00 (s, 3H), 4.77
(d, 1H, J = 4Hz), 5.21 (d, 1H, J = 3.5Hz), 7.82 (s, 2H), 7.91 (s,
1H), 8.10 (s, 1H); 13C NMR (DMSO-d6) δ: 32.6, 37.4, 49.1,
57.2, 108.3, 113.1, 113.2, 116.5, 119.2, 119.8, 144.2, 144.4,
148.2, 163.3.
2-(2-Amino-8-bromo-6-chloro-3-cyano-4H-chromene-
4-yl)malononitrile (4g): Colour: pale yellowish solid; Anal.
calcd. (found) % for C13H6N4OBrCl:C, 44.67 (44.74); H, 1.73
(1.66); N, 16.03 (15.90). 1H NMR (DMSO-d6) δ: 4.67 (d, 1H,
J = 4 Hz), 5.15 (d, 1H, J = 3.5 Hz), 7.60 (s, 1H), 7.75 (s, 2H),
7.92 (s, 1H); 13C NMR (DMSO-d6) δ: 32.7, 37.7, 49.4, 111.1,
113.2, 119.2, 121.8, 128.6, 129.4, 133.3, 146.3, 163.4.
2-(2-Amino-6-bromo-3-cyano-4H-chromene-4-yl)malo-
nonitrile (4h): Colour: White solid; Anal. calcd. (found) % for
C14H9BrN4O2: C, 48.72 (48.66); H, 2.63 (2.55); N, 16.23 (16.08).
1H NMR (DMSO-d6) δ: 4.61 (d, 1H, J = 3.5 Hz), 5.13 (d, 1H, J
= 4 Hz), 7.13 (d, 1H, J = 9.0 Hz), 7.53-7.59 (m, 3H), 7.72 (s,
2-(2-Amino-3-cyano-7-methoxy-4H-chromen-4-yl)-
malononitrile (4c): Colour: pale yellow solid; Anal. calcd.
(found) % for C14H10N4O2: C, 63.15 (63.29); H, 3.79 (3.68);
N, 21.04 (20.90). 1H NMR (DMSO-d6) δ: 3.80 (s, 3H), 4.52
(d, 1H, J = 4Hz), 5.04 (d, 1H, J = 3.5 Hz), 6.70 (d, 1H, J= 2.4 Hz),
6.90 (d, 1H, J = 8.5 Hz), 7.41 (d, 1H, J = 8 Hz), 7.49 (s, 2H);
13C NMR (DMSO-d6) δ: 34.5, 38.9, 57.2, 103.3, 111.5, 113.7,
114.7, 115.3, 121.1, 131.7, 152.8, 162.3, 165.3.
13
2-(2-Amino-6-chloro-3-cyano-4H-chromen-4-yl)malo-
nonitrile (4d): Colour: white solid; Anal. calcd. (found) % for
1H); C NMR (DMSO-d6) δ: 32.4, 36.7, 48.4, 112.7, 112.9,
116.4, 118.6, 119.1, 120.3, 131.4, 131.9, 149.0, 163.2.
TABLE-1
SYNTHESIS OF 2-AMINO-3-CYANO-4H-CHROMENES (4a-I)
m.p. (°C)
Reaction time
Compound
R1
R2
Yieldb (%)
(min)a
Found
152
161
150
154
179
190
174
160
198
Lit.
150-153 [[3311]]
161 [[3300]]
150 [[3300]]
151-154 [26]
[26]
180-181 [26]
[26]
190 [30]
[30]
174 [3300]]
160-162 [32]
[32]
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
H
H
H
10
10
25
10
10
10
10
10
10
94
91
88
96
89
90
91
86
88
8-OCH3
7-OCH3
6-Cl
6-NO2
6-NO2
6-Cl
8-OCH3
8-Br
8-OCH3
8-I
6-Br
6-I
198 [[3300]]
aReactions were monitored by TLC; bIsolated yield.
R1
n
O
O
X
CN
NC
CN
CN
NH2
R2
R1
R2
O
O
O
CN
CN
R1
R2
CN
n
CN
NH2
O
water
Catalyst-free
O
water
Catalyst-free
O
X = H, OH
n = 0, 1
5a-l
4a-i
Scheme-I: Cascade synthesis of 2-amino-3-cyano-4H-chromene derivatives involved in the current work

2534 Bhat
Asian J. Chem.
TABLE-2
SYNTHESIS OF 2-AMINO-3-CYANO-4H-CHROMENE DERIVATIVES (5a-i)
Reaction timea
m.p. (°C)
Entry
R1
Yieldc (%)
(A+B) (min)b
Found
230
214
215
206
200
213
177
196
–
Reported
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
4-CH3
2-Cl
20+10
45+20
30+20
10+10
75+30
10+10
10+10
10+10
120
91
86
87
94
90
93
88
92
Trace
226-228 [3333]]
209-211 [3333]]
212-213 [3344]]
202-203 [3333]]
4-Cl
[33]
4-OCH3
3-NO2
4-NO2
4-F
197-199 [33]
212-215 [1188]]
175-176 [1177]]
198-200 [3355]]
–
4-OH
aReactions were monitored by TLC; bReaction time before the addition of dimedone (A) and that for completion of the reaction after the addition of
dimedone (B); cIsolated yield.
2-(2-Amino-3-cyano-6,8-diiodo-4H-chromen-4-yl)malo-
nonitrile (4i): Colour: Brownish solid; Anal. calcd. (found) %
for C13H6N4OI2:C, 31.99 (32.08); H, 1.24 (1.18); N, 11.48 (11.37).
1H NMR (DMSO-d6) δ: 4.54 (d, 1H, J = 4 Hz), 5.09 ( d, 1H, J =
3.5 Hz), 7.71 (s, 2H), 7.82 (s, 1H), 8.2 (s, 1H); 13C NMR (DMSO-
d6) δ: 32.8, 37.4, 49.5, 87.7, 90.2, 113.3, 119.2, 121.5, 137.8,
146.9, 150.2.
General procedure for the synthesis of compounds 5a-l:
A mixture of benzaldehyde/arylglyoxal (1 mmol) and malono-
nitrile (1 mmol) was taken in a 25 mL round bottomed flask
containing water (5 mL). The suspension formed was stirred
at room temperature for a suitable time given in Tables 2 and 3.
Further, dimedone (2 mmol) was added and continued stirring
for a suitable time. Formed precipitate was then filtered and
washed with 3 × 10 mL water and dried under vacuum to obtain
pure product. Purity and structure of all the products are supp-
orted by TLC analysis, melting point determination and NMR
characterization (Scheme-I).
29.3, 31.0, 34.0, 51.6, 54.3, 118.0, 124.8, 127.6, 128.5, 128.7,
140.1, 156.8, 176.2, 190.4.
2-Amino-7,7-dimethyl-5-oxo-4-(p-tolyl)-5,6,7,8-tetra-
hydro-4H-chromene-3-carbonitrile (5b): Colour:White solid;
Anal. calcd. (found) % for C19H20N2O2: C, 74.00 (73.89); H, 6.54
(6.40); N, 9.08 (8.93). 1H NMR (DMSO-d6) δ: 0.1.01 (s, 3H),
1.11 (s, 3H), 2.14-2.19 (m, 2H), 2.29 (s, 3H), 2.48 (s, 2H), 4.32
(s, 1H), 5.63 (s, 2H), 7.02-7.10 (m, 4H); 13C NMR (DMSO-d6)
δ: 20.3, 27.1, 28.7, 32.1, 35.6, 50.6, 58.7, 113.1, 120.3, 127.2,
129.5, 136.1, 142.3, 158.8, 162.6, 182.3, 196.1.
2-Amino-4-(2-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,
8-tetrahydro-4H-chromene-3-carbonitrile (5c): Colour:
White solid;Anal. calcd. (found) % for C18H17N2O2Cl: C, 65.75
(65.69); H, 5.21 (5.11); N, 8.52 (8.44). 1H NMR (DMSO-d6)
δ: 0.98 (s, 3H), 1.12 (s, 3H), 2.13-2.24 (m, 2H), 2.56 (s, 2H), 4.67
(s, 1H), 7.08 (s, 2H), 7.13-7.34 (m, 4H); 13C NMR (DMSO-d6)
δ: 27.2, 28.3, 32.2, 35.1, 50.4, 58.4, 113.7, 115.1, 115.6, 119.9,
129.3, 129.4, 140.5, 141.2, 158.8, 160.0, 162.2, 196.1.
2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,
8-tetrahydro-4H-chromene-3-carbonitrile (5d): Colour:
White solid;Anal. calcd. (found) % for C18H17N2O2Cl: C, 65.75
(65.66); H, 5.21 (5.09); N, 8.52 (8.40). 1H NMR (DMSO-d6)
δ: 0.92 (s, 3H), 1.03 (s, 3H), 2.07-2.29 (m, 4H), 4.19 (s, 1H),
TABLE-3
SYNTHESIS OF 2-AMINO-3-CYANO-4H-
CHROMENE DERIVATIVES (5j-l)
O
R1
13
O
7.08 (s, 2H), 7.15-7.17 (d, 2H), 7.33-7.36 (d, 2H); C NMR
O
O
(DMSO-d6) δ: 27.0, 28.3, 31.8, 35.6, 50.2, 58.0, 112.8, 119.9,
128.8, 129.2, 131.6, 144.4, 158.6, 162.9, 196.1.
O
CN
O
CN
CN
R1
water
2-Amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7,7-
dimethyl-5-oxo-4H-chromene-3-carbonitrile (5e): Colour:
White solid; Anal. calcd. (found) % for C19H20N2O3: C, 70.35
(70.24); H, 6.21 (6.06); N, 8.64 (8.52). 1H NMR (DMSO-d6) δ:
1.04 (s, 3H), 1.13 (s, 3H), 2.16-2.22 (m, 2H), 2.47 (s, 2H ),
3.77 (s, 3H), 4.30 (s, 1H), 5.60 (s, 2H), 6.84 (d, 2H, J = 8Hz),
7.14 (d, 2H, J = 8 Hz).
2-Amino-7,7-dimethyl-4-(3-nitrophenyl)-5-oxo-5,6,7,
8-tetrahydro-4H-chromene-3-carbonitrile (5f): Colour:
White solid; Anal. calcd. (found) % for C18H17N3O4: C, 63.71
(63.56); H, 5.05 (4.91); N, 12.38 (12.26). 1H NMR (DMSO-d6)
δ: 1.05 (s, 3H), 1.11 (s, 3H), 2.20-2.25 (m, 2H), 2.47 (s, 2H), 4.49
(s, 1H), 6.24 (s, 2H), 7.47-7.66 (m, 2H), 8.06-8.11 (m, 2H).
2-Amino-6,6,8,8-tetrahydro-7,7-dimethyl-4-(4-nitro-
phenyl)-5-oxo-4H-chromene-3-carbonitrile (5g): Colour:
Pale brownish solid; Anal. calcd. (found) % for C18H17N3O4:
C, 63.71 (63.58); H, 5.05 (4.89); N, 12.38 (12.23).1H NMR
O
NH2
Catalyst-free
5j-l
Yieldc (%) m.p. (°C)
Reaction timea
(A + B) (min)b
Entry
R1
5j
5k
5l
4-CH3
4-Cl
4-F
60 + 40
45 + 30
45 + 30
68
76
74
176
184
188
aReactions were monitored by TLC; bReaction time before the addition
of dimedone (A) and that for completion of the reaction after the
addition of dimedone (B); cIsolated yield
2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetra-
hydro-4H-chromene-3-carbonitrile (5a): Colour: White
solid; Anal. calcd. (found) % for C18H18N2O2: C, 73.45 (73.35);
H, 6.16 (6.02); N, 9.52 (9.38). 1H NMR (DMSO-d6) δ: 0.96 (s,
3H), 1.10 (s, 3H), 2.06-2.30 (m, 4H), 4.25 (s, 1H), 6.41 (s, 2H),
7.13-7.43 (m, 5H); 13C NMR (100 MHz, DMSO-d6) δ: 28.0,

Vol. 31, No. 11 (2019)
Catalyst-Free Cascade Synthesis of Densely Functionalized Chromenes in Water 2535
(DMSO-d6) δ: 0.95 (s, 3H), 1.08 (s, 3H), 2.13-2.27 (m, 4H),
4.29 (s, 1H), 6.61 (s, 2H), 7.17-7.41 (m, 4H); 13C NMR (DMSO-
d6) δ: 28.8, 33.8, 39.6, 40.9, 51.5, 53.9, 118.5, 123.2, 124.8,
129.0, 145.9, 149.3, 156.9, 178.1, 190.5.
2-Amino-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo-5,6,7,
8-tetrahydro-4H-chromene-3-carbonitrile (5h): Colour:
White solid;Anal. calcd. (found) % for C18H17N2O2F: C, 69.22
(69.04); H, 5.49 (5.41); N, 8.97 (8.86).1H NMR (DMSO-d6)
δ: 0.93 (s, 3H), 1.16 (s, 3H), 1.96-2.32 (m, 4H), 4.22 (s, 1H),
6.91 (s, 2H), 7.11-7.42 (m, 4H); 13C NMR (DMSO-d6) δ: 28.8,
33.7, 39.6, 40.8, 51.5, 54.4, 114.0, 118.3, 124.8, 129.7, 136.1,
156.7, 162.2, 176.2, 190.4.
2-Amino-7,7-dimethyl-4-(4-methylbenzoyl)-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (5j):White
solid. Anal. calcd. (found) % for C20H20N2O3: C, 71.41 (71.29);
H, 5.99 (6.07); N, 8.33 (8.21). 1H NMR (DMSO-d6) δ: 1.02
(s, 3H), 1.11(s, 3H), 2.13-2.26 (m, 2H), 2.42 (s, 3H), 2.46-2.58
(m, 2H), 4.91 (s, 1H), 7.25 (br. s, 2H), 7.37 (d, 2H, J = 7.5 Hz),
8.00 (d, 2H, J = 7.8 Hz). 13C NMR (DMSO-d6) δ: 21.7, 26.8,
29.2, 32.9, 36.0, 50.1, 52.7, 111.2, 119.6, 129.6, 129.7, 133.6,
144.5, 160.5, 164.4, 196.5, 198.4.
of reactants in water turned to white precipitate within 10 min
of stirring. Thin layer chromatography using 30 % ethyl acetate
in petroleum ether confirmed completion of the reaction. The
pure solid product was obtained by simple filtration of reaction
mixture, followed by washing with water without any further
purification. The product was identified by spectroscopic tech-
niques and by comparison with an authentic sample.As expected,
the reactants underwent a series of bond forming reactions to
yield product 4a. With the intention to compare the efficiency
of the current heterogeneous protocol with homogeneous
solution reaction, the exemplary reaction was carried out in
solution state using numerous solvents viz. ethanol, methanol,
tetrahydrofuran, ethyl acetate and dichloromethane. Interes-
tingly, it was found that the reaction proceeds very slowly to
give trace amount of products in organic solvents, which form
homogeneous solution.
With the aim to explore the scope of the following protocol,
a series of salicylaldehyde derivatives were reacted with 1:2
moles of malononitrile in water to obtain chromene derivatives.
The results are summarized in Table-1. It was found that salicyl-
aldehydes attached to functional groups with electron donating
and withdrawal effects underwent smooth reaction to yield
desired products with high conversion rate within few minutes
of stirring.
In order to expand the generality of the current uncatalyzed
cascade Knoevenagel-Michael-intramolecular cyclization
protocol, the aqueous reaction of benzaldehyde with malon-
onitrile and dimedone was revisited. Initially, the reaction was
carried out through one-pot three-component addition of reactants
and monitored by TLC. Upon completion of the reaction, the
pure products were obtained using column chromatography.
Only trace amount of desired chromene was formed (9 %),
(which is in agreement with the reported literature [17,34]),
with the formation of benzylidene malononitrile (20 %)
and 2,2′-(phenylmethylene)bis(3-hydroxycyclohex-2-enone)
(30 %) as major products. Further, the attempt to obtain
compound 5a was successful by treating benzylidene malon-
onitrile with dimedone in water. Thus, with the aim to obtain
desired product, sequential addition of aldehyde and malono-
nitrile followed by dimedone was attempted in water.The desired
product was obtained in 91 % yield by simple filtration of the
precipitate without further purification. Encouraged by this
successful result, synthesis of diverse 2-amino-3-cyano-4H-
2-Amino-4-(4-chlorobenzoyl)-7,7-dimethyl-5-oxo-5,6,-
7,8-tetrahydro-4H-chromene-3-carbonitrile (5k): White
solid.Anal. calcd. (found) % for C19H17N2O3Cl: C, 63.96 (63.80);
H, 4.80 (4.91); N, 7.85 (7.76). 1H NMR (DMSO-d6) δ: 1.05
(s, 3H), 1.12 (s, 3H), 2.13-2.29 (m, 2H), 2.44-2.53 (m, 2H), 5.02
(s, 1H), 7.22 (br. s, 2H), 7.62 (d, 2H, J = 7.5Hz), 8.13 (d, 2H, J =
13
8 Hz); C NMR (DMSO-d6) δ: 26.6, 29.2, 32.9, 36.3, 49.9,
52.4, 110.9, 119.5, 129.4, 131.3, 139.0, 160.5, 164.6, 196.6, 198.2.
2-Amino-4-(4-fluorobenzoyl)-7,7-dimethyl-5-oxo-5,6,
7,8-tetrahydro-4H-chromene-3-carbonitrile (5l):White solid.
Anal. calcd. (found) % for C19H17N2O3F: C, 67.05 (66.92); H,
5.03 (4.90); N, 8.23 (8.09). 1H NMR (DMSO-d6) δ: 1.02 (s,
3H), 1.09 (s, 3H), 2.14-2.28 (m, 2H), 2.49-2.60 (m, 2H), 5.01
(s, 1H), 7.27 (br. s, 2H), 7.40 (d, 2H, J = 7.5 Hz), 8.22 (d, 2H, J
= 8.0 Hz); 13C NMR (DMSO-d6) δ: 26.9, 29.1, 32.9, 36.2, 50.0,
52.4, 111.1, 116.2, 119.6, 132.5, 132.9, 132.9, 160.6, 164.5,
196.6, 197.7.
RESULTS AND DISCUSSION
At the outset, 1:2 molar reaction of salicylaldehyde and
malononitrile was investigated as a probe reaction by stirring
the reactants in water at ambient temperature. The suspension
NC
CN
CN
NC
CN
CN
CN
CN
A
Intramolecular
Cyclization
CN
OH
X = OH
O
NH2
Knoevenagel
condensation
CHO
XH
CN
CN
CN
CN
Michael Addition
water, RT
X
O
X = H
O
I
O
CN
CN
Intramolecular
Cyclization
CN
O
NH2
O
B
O
Scheme-II: Proposed mechanism of current cascade protocol

2536 Bhat
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chromenes (5a-i) was undertaken in water at room temperature
and the results are presented in Table-2. The aromatic aldehydes
bearing both electron withdrawing and electron donating groups
were found to undergo smooth transformation to yield the desired
chromene derivatives in high percentage of conversion.
Furthermore, the applicability of current protocol was
extended to the synthesis of functionalized chromenes through
the sequential reaction of arylglyoxals with malononitrile
followed by dimedone in one-pot. The products were obtained
in moderate yield in aqueous media at ambient temperature
(Table-3).
Based on the experimental results and available literature,
plausible mechanism depicting the series of events for current
cascade reaction is proposed in Scheme-II. The condensation
of aldehyde and malononitrile lead to formation of correspon-
ding benzylidenemalononitrile (I), which act as an electron
deficient Michael acceptor.Another molecule of malononitrile
(path A) or dimedone (path B) attacks the electron deficient
(I) to give Michael addition product, which undergoes simul-
taneous intramolecular cyclization reaction to produce corres-
ponding chromene derivative.
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Conclusion
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An efficient, environmental friendly, one-pot approach
for the synthesis of 2-amino-3-cyano-4H-chromenes has been
developed using water as a reaction medium. High percentage
of conversion of reactants to (2-amino-3-cyano-4H-chromene-
4-yl)malononitrile derivatives were achieved through single
step addition. Further, synthesis of 2-amino-7,7-dimethyl-5-
oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
derivatives and 2-amino-4-(benzoyl)-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile derivatives
were achieved through sequential addition of reactants in one-
pot. The current uncatalyzed cascade Knoevenagel-Michael-
Intramolecular cyclization approach circumvents several
limitations accompanying with previously reported catalytic
protocols.
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CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
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