Ca(OH)2-mediated efficient synthesis of 2-amino-5-hydroxy-4H- chromene derivatives with various substituents

Article abstract of DOI:10.1016/j.tet.2011.08.086

A variety of novel 2-amino-5-hydroxy-4H-chromene derivatives with various substituents on the 4H-chromene ring were efficiently synthesized by one-pot reactions of substituted resorcinols and various 2-benzylidenemalononitriles in the presence of calcium hydroxide in methanol at room temperature. This simple method provided 2-amino-5-hydroxy-4H-chromenes with high yields under mild reaction conditions.

Full text of DOI:10.1016/j.tet.2011.08.086

Tetrahedron 67 (2011) 8271e8275
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ca(OH)2-mediated efficient synthesis of 2-amino-5-hydroxy-4H-chromene
derivatives with various substituents
*
Srinivasa Rao Kolla, Yong Rok Lee
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2011
Received in revised form 27 August 2011
Accepted 29 August 2011
Available online 3 September 2011
A variety of novel 2-amino-5-hydroxy-4H-chromene derivatives with various substituents on the 4H-
chromene ring were efficiently synthesized by one-pot reactions of substituted resorcinols and various
2-benzylidenemalononitriles in the presence of calcium hydroxide in methanol at room temperature.
This simple method provided 2-amino-5-hydroxy-4H-chromenes with high yields under mild reaction
conditions.
Ó 2011 Published by Elsevier Ltd.
Keywords:
Resorcinols
2-Benzylidenemalononitriles
2-Amino-5-hydroxy-4H-chromene
Calcium hydroxide
R1
1. Introduction
CHO
2-Amino-4H-chromenes are important heterocyclic com-
pounds1 with a number of biological and pharmacological prop-
erties including anti-microbial,2 anti-viral,3,4 anti-proliferative,5
anti-tumor,6 and anti-cancer7 activities. They have also been
widely employed as cosmetics, pigments,8 and potent biodegrad-
able agrochemicals.9 In particular, derivatives, such as HA 14-1 and
MX58151, with proapoptotic activity, are being developed as anti-
cancer agents.10,11
2-Amino-4H-chromenes are generally synthesized by reactions
of phenol or resorcinol with malononitrile and arylaldehydes
(Scheme 1). Basic alumina,12 piperidine,13 morpholine,14 cetyl-
trimethylammonium chloride,15 [bmim]OH,16 K2CO3/microwave,17
DBU/microwave,18 and chitosan19 have been used for these re-
actions as catalytic and stoichiometric reagents. Interestingly, re-
actions of resorcinol with malononitrile and arylaldehydes afforded
2-amino-7-hydroxy-4H-chromene derivatives as sole products
without requiring isolation of expected 2-amino-5-hydroxy-4H-
chromene derivatives. In these cases, resorcinol reacted with
malononitrile and arylaldehydes at the position 6 rather than at the
position 2 under above described conditions and further cyclized to
give 2-amino-7-hydroxy-4H-chromenes regioselectively, probably
due to steric hindrance between two hydroxyl groups in a meta-
disubstituted compound.
CN
CN
CN
+
+
R1
R
OH
R
O
NH2
R=H, OH
Scheme 1.
Although several syntheses of 2-amino-4H-chromenes from
phenol or resorcinol have been described, reactions employing
substituted resorcinols have not previously been reported. This
work reports reactions between resorcinols with various sub-
stituents and 2-benzylidenemalononitriles in the presence of sev-
eral bases (Scheme 2). A variety of 2-amino-5-hydroxy-4H-
chromene derivatives with various substituents on the 4H-chro-
mene ring were easily and efficiently synthesized.
R3
OH
OH
R1
R2
CN
bases
R1
R2
CN
R3
+
CN
OH
O
NH2
Scheme 2.
2. Results and discussion
Togiveavarietyof2-amino-5-hydroxy-4H-chromenederivatives,
reactions of readily available resorcinols with substituents of
* Corresponding author. Tel.: þ82 53 810 2529; fax: þ82 53 810 4631; e-mail
address: yrlee@yu.ac.kr (Y.R. Lee).
0040-4020/$ e see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.08.086

8272
S.R. Kolla, Y.R. Lee / Tetrahedron 67 (2011) 8271e8275
electron-withdrawing groups were investigated. The reaction of 2,4-
dihydroxy acetophenone (1a) with 2-benzylidenemalononitrile 2a
under several bases was first attempted based on reported reactions
of resorcinol with malononitrile and benzaldehyde in the presence of
several bases (Table 1). 1 equiv of triethylamine, piperidine, mor-
pholine, ethylenediamine, or DBU as organic bases for 12 h in
methanol at room temperature did not result in the desired products
(entries 1e5). Using KOH as an inorganic base resulted in no products
(entry 6). Ca(OH)2 in several solvents resulted in the desired product
3a. Reaction using 20 mo% of Ca(OH)2 in methanol at room temper-
ature for 20 h produced 3a in 55% yield (entry 7). Interestingly, de-
spite low solubility of Ca(OH)2 in alcohol, 1 equiv of Ca(OH)2 in
methanolatroomtemperaturefor3 hincreased theyieldof3ato80%
(entry 8). It has been reported by other group that Ca(OH)2 is an
important metal reagent and a useful promoter in the aldol-type
reaction of phenolic enolates of resorcinols with benzaldehyde in
methanol.20 Other polar solvents, EtOH and H2O, produced 3a in 61
and 51% yield, respectively (entries 9 and 10). Importantly, in these
reactions, only 3awas formed and the expected 2-amino-7-hydroxy-
4H-chromene as a regioisomer was not produced. The structure of
compound 3a was determined by 1H NMR analysis. The spectrum of
3a showed a characteristic peak of methine on the chromene ring at
reaction quickly produced 2-amino-5-hydroxy-4H-chromene de-
rivatives 3bek with various substituents on the benzene ring.
Unsubstituted resorcinol 1f produced 3l in 90% yield (entry 11).
The formation of product 3a can be explained by comparing
with previously described mechanism as shown in Scheme 3.21 The
regioselectivity of 3a may be determined by the deactivation of the
o-hydroxy group of 1a by intramolecular hydrogen bonding to
neighboring carbonyl group. The more reactive proton of the 4-
hydroxy group of 1a was extracted by calcium hydroxide to form
an intermediate 4, which reacted with 2-benzylidenemalononitrile
(2a) to give 5. Tautomerism of the intermediate 5 gave intermediate
6, which was deprotonated by Ca(OH)2 to produce 7. Intramolecular
nucleophilic addition of phenoxide to the cyano group of 7, fol-
lowed by protonation and isomerization produced 3a.
In summary, a one-pot, two-component condensation reaction
of various resorcinols and substituted 2-benzylidenemalononitriles
was successfully accomplished to give 2-amino-5-hydroxy-4H-
chromene derivatives. This methodology has advantages of mild
reaction conditions, simple experimentation, and high yields.
3. Experimental
3.1. General
d
4.65 as a singlet and a methyl peak of an acetyl group appeared at
d
2.58 as a singlet. The compound was further identified by AB cou-
pling constants of aromatic protons on the 4H-chromene ring at
All experiments were carried out in the methanol. Pre-coated
silica gel plates (Merck, Art. 5554) with a fluorescent indicator
were used for analytical TLC. Flash column chromatography was
performed using silica gel 9385 (Merck). 1H and 13C NMR spectra
d
7.90 (J¼8.7 Hz) and
d
6.72 (J¼8.7 Hz). The 13C NMR spectrum
showed a characteristic tertiary carbon peak with a methine proton
at d 36.1 and a carbonyl carbon peak at d 204.4.
Table 1
Reaction of 2,4-dihydroxy acetophenone with 2-benzylidenemalononitrile under several bases
O
OH
O
OH
CN
CN
CN
bases
+
solvent
rt
OH
O
3a
NH2
1a
2a
Entry
1
Base
Solvent
MeOH
Time (h)
12
Yield (%)
0
Entry
6
Base
Solvent
MeOH
Time (h)
12
Yield (%)
0
KOH (1 equiv)
N
(1 eq)
2
3
MeOH
MeOH
12
12
0
0
7
8
Ca(OH)2 (0.2 equiv)
Ca(OH)2 (1 equiv)
MeOH
MeOH
20
3
55
80
N
H
(1 eq)
(1 eq)
O
N
H
H2N
NH2
(1 eq)
4
5
MeOH
MeOH
12
12
0
0
9
Ca(OH)2 (1 equiv)
Ca(OH)2 (1 equiv)
EtOH
H2O
4
6
61
51
DBU (1 equiv)
10
To explore the generality and scope of this methodology, addi-
tional reactions of various substituted resorcinols and 2-
benzylidenemalononitriles were attempted under the optimized
conditions (Table 2). Reactions of 2,4-dihydroxy acetophenone (1a)
and 2-benzylidenemalononitriles 2bee, with electron-withdrawing
groupson the benzene ring, at room temperature for2e4 h produced
3bee in 81e87% yield (entries 1e4). Electron-donating group on the
2-benzylidenemalononitriles resulted in 3f and 3g in 74 and 73%
yield, respectively, after reaction for 10e12 h at room temperature
(entries 5 and 6). Other resorcinols, 1b and 1c produced 3h and 3i in
82 and 79%, respectively (entries 7 and 8). Resorcinols with ester
groups on the benzene ring produced the expected cycloadducts 3j
and 3k in 84 and 81% yield, respectively (entries 9 and 10). Each
were recorded on a Varian Model VNS spectrometer in DMSO-d6
and CD3OD. IR spectra were recorded on a Jasco FTIR 5300 spec-
trophotometer. HRMS spectra were recorded at the Korea Basic
Science Institute on a Jeol JMS-700 spectrometer.
3.2. General procedure for the preparation of 2-amino-3-
cyano-6-acetoxy-5-hydroxy-4H-chromene derivatives 3ael
A mixture of various resorcinols (1.0 mmol), substituted 2-
benzylidenemalononitrile (1.5 mmol), and calcium hydroxide
(1.0 mmol) in MeOH (5 mL) was stirred at room temperature until
the completion of the reaction, as indicated by TLC (ethyl acetate/n-
hexane). The reaction mixture was filtered through sintered funnel

S.R. Kolla, Y.R. Lee / Tetrahedron 67 (2011) 8271e8275
8273
Table 2
Additional reactions for the synthesis of 2-amino-5-hydroxy-4H-chromene derivatives in the presence of Ca(OH)2
malononitrile
Product
Entry
resorcinol
Time (h)
Yield (%)
82
NO2
CN
2
1
2
Br
CN
3b
O
OH
O2N
Br
2b
CN
3c
CN
O
OH
4
2
87
81
O
NH2
CN
CN
2c
Cl
O
F
NH2
CN
O
OH
3
4
5
CN
3d
2d
Cl
F
O
OH
CN
OH
1a
CN
3e
3
O
OH
O
O
O
NH2
85
74
CN
CN
2e
O
NH2
CN
3f
10
12
O
OH
CN
OCH3
2f
CN
NH2
CN
6
3g
73
82
O
OH
CN
CN
H3CO
2g
O
OH
O
NH2
CN
CN
O
OH
7
8
9
5
5
CN
1b
OH
OH
2a
3h
O
NH2
3i
O
OH
CN
CN
CN
79
84
1c
OH
2a
O
NH2
O
OH
O
O
OH
CN
CN
2a
CN
CN
3j
CN
5
OH
O
1d
O
OH
3k
O
NH2
O
O
OH
O
CN
10
11
3
5
OH
81
O
NH2
1e
2a
CN
CN
OH
CN
3l
90
OH
HO
O
NH2
2a
1f
and the solid was washed with ethyl acetate (10 mL) to remove
excess 2-benzylidenemalononitrile. The solid containing product
was dissolved in THF (30 mL) and filtered to remove remaining
Ca(OH)2. The THF layer was evaporated under reduced pressure and
finally recrystallization with ethanol give pure white solid.
H
H
CN
H+
H
O
O
O
O
O
O
H
CN
CN
Ca (OH)2
-H+
2a
C
N
O-
OH
O
1a
4
5
3.2.1. 6-Acetyl-2-amino-5-hydroxy-4-phenyl-4H-chromene-3-
carbonitrile (3a). A mixture of 2,4-dihydroxy acetophenone 1a
(152 mg, 1.0 mmol), 2-benzylidenemalononitrile 2a (231 mg,
1.5 mmol), and Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of methanol was
stirred at roomtemperature for 3 h. Aftercompletion of the reaction,
recrystallization with ethanol gave product 3a (245 mg, 80%) as
a white solid: charred at 290 ꢀC; 1H NMR (300 MHz, DMSO-d6)
H
H
H
O
O
O
O
O
O
H
Ca (OH)2
CN
CN
NH
CN
C
OH
N
C
N
H+
O-
O
6
8
7
H
O
O
CN
NH2
d
12.95 (1H, s), 7.90 (1H, d, J¼8.7 Hz), 7.30e7.25 (2H, m), 7.20e7.11
(3H, m), 7.08 (2H, s,), 6.72 (1H, d, J¼8.7 Hz), 4.65 (1H, s), 2.58 (3H, s);
13C NMR (75 MHz, DMSO-d6)
204.4,160.1,159.4,153.8,144.7,131.8,
128.4, 127.1, 126.6, 120.0, 115.9, 111.7, 107.3, 57.2, 36.1, 26.6; IR (KBr)
O
3a
d
Scheme 3.

8274
S.R. Kolla, Y.R. Lee / Tetrahedron 67 (2011) 8271e8275
3438, 3317, 3200, 2881, 2195, 1660, 1414, 1251, 1076, 824 cmꢁ1
;
(237 mg, 74%) as a solid: mp 280e282 ꢀC; 1H NMR (300 MHz, DMSO-
HRMS m/z (Mþ) calcd for C18H14N2O3: 306.1004. Found: 306.1008.
d6)
d
12.89 (1H, s), 7.80 (1H, d, J¼8.7 Hz), 7.02e6.94 (6H, m), 6.63 (1H,
d, J¼8.7 Hz), 4.54 (1H, s), 2.50 (3H, s), 2.16 (3H, s); 13C NMR (75 MHz,
3.2.2. 6-Acetyl-2-amino-5-hydroxy-4-(4-nitrophenyl)-4H-chro-
mene-3-carbonitrile (3b). A mixture of 2,4-dihydroxy acetophe-
none 1a (152 mg, 1.0 mmol), 2-(4-nitrobenzylidene) malononitrile
2b (300 mg, 1.5 mmol), and Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of
methanol was stirred at room temperature for 2 h. After comple-
tion of the reaction, recrystallization with ethanol gave product 3b
(288 mg, 82%) as a solid: mp 246e248 ꢀC; 1H NMR (300 MHz,
DMSO-d6) d 204.4,160.1, 159.4, 153.8, 141.8, 135.8, 131.7, 128.9, 127.0,
120.0, 115.9, 111.9, 107.3, 57.4, 35.7, 26.5, 20.5; IR (KBr) 3627, 3427,
3330, 3213, 2955, 2194, 1653, 1415, 1251, 1129, 1069, 814 cmꢁ1
;
HRMS m/z (Mþ) calcd for C19H16N2O3: 320.1161. Found: 320.1164.
3.2.7. 6-Acetyl-2-amino-5-hydroxy-4-(4-methoxyphenyl)-4H-chro-
mene-3-carbonitrile (3g). A mixture of 2,4-dihydroxy acetophenone
1a (152 mg, 1.0 mmol), 2-(4-methoxybenzylidene) malononitrile 2g
(276 mg, 1.5 mmol), and Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of meth-
anol was stirred at room temperature for 12 h. After completion of the
reaction, recrystallizationwith ethanol gave product 3g (245 mg, 73%)
DMSO-d6)
J¼9.0 Hz), 7.41 (2H, d, J¼8.7 Hz), 7.21 (2H, s), 6.75 (1H, d, J¼9.0 Hz),
4.86 (1H, s), 2.58 (3H, s); 13C NMR (75 MHz, DMSO-d6)
204.6,
d
12.96 (1H, s), 8.16 (2H, d, J¼8.7 Hz), 7.94 (1H, d,
d
160.1, 159.5, 153.7, 152.1, 146.3, 132.4, 128.6, 123.8, 119.7, 116.0, 110.3,
107.5, 55.9, 36.1, 26.6; IR (KBr) 3439, 3337, 3209, 2935, 2193, 1654,
1520, 1409, 1348, 1253, 820 cmꢁ1; HRMS m/z (Mþ) calcd for
C18H13N3O5: 351.0855. Found: 351.0856.
as a solid: mp 248e250 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 12.96 (1H,
s), 7.88(1H, d, J¼8.7 Hz), 7.06e7.03(4H, m), 6.83(2H, d, J¼8.4 Hz), 6.70
(1H, d, J¼8.7 Hz), 4.60 (1H, s), 3.70 (3H, s), 2.57 (3H, s); 13C NMR
(75 MHz, DMSO-d6)
d 204.4, 160.1, 159.4, 158.0, 153.7, 136.8, 131.7,
3.2.3. 6-Acetyl-2-amino-4-(4-bromophenyl)-5-hydroxy-4H-chro-
mene-3-carbonitrile (3c). A mixture of 2,4-dihydroxy acetophenone
1a (152 mg, 1.0 mmol), 2-(4-bromobenzylidene) malononitrile 2c
(350 mg, 1.5 mmol), and Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of
methanolwas stirredatroom temperaturefor4 h. Aftercompletionof
the reaction, recrystallization with ethanol gave product 3c (335 mg,
128.2, 120.1, 115.9, 113.7, 112.1, 107.3, 57.5, 55.0, 30.4, 26.5; IR (KBr)
3433, 3324, 3203, 2950, 2194,1655, 1509, 1410, 1252,1068, 823 cmꢁ1
;
HRMS m/z (Mþ) calcd for C19H16N2O4: 336.1110. Found: 336.1111.
3.2.8. 2-Amino-5-hydroxy-4-phenyl-6-propionyl-4H-chromene-3-
carbonitrile (3h). A mixture of 1-(2,4-dihydroxyphenyl)propan-1-one
1b (166 mg, 1.0 mmol), 2-benzylidenemalononitrile 2a (231 mg,
1.5 mmol), and Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of methanol was
stirred at room temperature for 5 h. After completion of the reaction,
recrystallizationwith ethanol gave product 3h (263 mg, 82%) as a solid:
87%)asa solid:mp 283e285 ꢀC;1H NMR (300 MHz, DMSO-d6)
d 12.94
(1H, s), 7.87 (1H, d, J¼8.7 Hz), 7.45 (2H, d, J¼8.1 Hz), 7.08 (2H, s), 7.07
(2H, d, J¼8.1 Hz), 6.66 (1H, d, J¼8.7 Hz), 4.64 (1H, s), 2.55 (3H, s); 13C
NMR (150 MHz, DMSO-d6)
d 204.6, 160.5, 159.7, 153.9, 144.4, 132.3,
131.5, 129.6, 120.0, 119.9, 116.3, 111.4, 107.5, 56.9, 35.9, 26.9; IR (KBr)
mp268e270 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d12.99(1H, s), 7.92 (1H,
3442, 3327, 3205, 2967, 2197, 1661, 1485, 1410, 1253, 1075, 820 cmꢁ1
;
d, J¼9.0 Hz), 7.30e7.25 (2H, m), 7.20e7.11 (3H, m), 7.07 (2H, s), 6.71 (1H,
HRMS m/z (Mþ) calcd for C18H13BrN2O3: 384.0110. Found: 384.0113.
d, J¼9.0 Hz), 4.65 (1H, s), 3.05 (2H, q, J¼7.2 Hz), 1.05 (3H, t, J¼7.2 Hz);
13C NMR (75 MHz, DMSO-d6)
d 206.7, 160.0, 159.5, 153.7, 144.7, 130.8,
3.2.4. 6-Acetyl-2-amino-4-(4-chlorophenyl)-5-hydroxy-4H-chro-
mene-3-carbonitrile (3d). A mixture of 2,4-dihydroxy acetophenone
1a (152 mg, 1.0 mmol), 2-(4-chlorobenzylidene) malononitrile 2d
(282 mg, 1.5 mmol), and Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of
methanolwas stirredatroom temperaturefor2 h. Aftercompletionof
the reaction, recrystallization with ethanol gave product 3d (276 mg,
128.4, 127.1, 126.6, 120.0, 115.4, 111.8, 107.3, 57.2, 36.1, 30.9, 7.9; IR (KBr)
3430, 3331, 3217, 2980, 2194, 1651, 1409, 1260, 1081, 835 cmꢁ1; HRMS
m/z (Mþ) calcd for C19H16N2O3: 320.1161. Found: 320.1161.
3.2.9. 2-Amino-6-benzoyl-5-hydroxy-4-phenyl-4H-chromene-3-
carbonitrile (3i). A mixture of 2,4-dihydroxybenzophenone 1c (214
mg, 1.0 mmol), 2-benzylidenemalononitrile 2a (231 mg, 1.5 mmol), and
Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of methanol was stirred at room
temperature for 5 h. After completion of the reaction, recrystallization
with ethanol gave product 3i (291 mg, 79%) as a solid: mp 280e282 ꢀC;
81%)asa solid:mp 288e290 ꢀC;1H NMR (300 MHz, DMSO-d6)
d 12.95
(1H, s), 7.89 (H, d, J¼8.7 Hz), 7.32 (2H, d, J¼8.1 Hz), 7.13 (2H, d,
J¼8.1 Hz), 7.12 (2H, s), 6.69 (1H, d, J¼8.7 Hz), 4.66 (1H, s), 2.56 (3H, s);
13C NMR (75 MHz, DMSO-d6)
d 204.4, 160.1, 159.4, 153.7, 143.7, 132.0,
131.2, 129.0, 128.4, 119.8, 115.9, 111.1, 107.4, 56.7, 35.6, 26.5; IR (KBr)
1H NMR (300 MHz, DMSO-d6)
d 12.40 (1H, s), 7.65e7.62 (3H, m),
3440, 3328, 3210, 2928, 2200,1662,1487,1412,1251,1080, 821 cmꢁ1
;
7.56e7.54 (2H, m), 7.50 (1H, d, J¼8.4 Hz), 7.31e7.28 (2H, m), 7.23e7.17
HRMS m/z (Mþ) calcd for C18H13ClN2O3: 340.0615. Found: 340.0616.
(3H,m),7.11(2H,s),6.73(1H,d,J¼8.4 Hz), 4.73 (1H, s); 13CNMR(75 MHz,
DMSO-d6)
d 199.6, 178.5, 160.4, 159.5, 153.8, 144.7, 137.1, 133.4, 132.1,
3.2.5. 6-Acetyl-2-amino-4-(4-fluorophenyl)-5-hydroxy-4H-chro-
mene-3-carbonitrile (3e). A mixture of 2,4-dihydroxy acetophenone
1a (152 mg, 1.0 mmol), 2-(4-fluorobenzylidene) malononitrile 2e
(260 mg, 1.5 mmol), and Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of
methanol was stirred at room temperature for 3 h. After completion
of the reaction, recrystallization with ethanol gave product 3e
(275 mg, 85%) as a solid: mp 275e277 ꢀC; 1H NMR (300 MHz, DMSO-
128.8, 128.4, 127.2, 126.7, 120.0, 115.9, 112.4, 107.6, 57.2, 36.2; IR (KBr)
3431, 3323, 2187, 1650, 1599, 1404, 1342, 1254, 1081, 832, 705 cmꢁ1
;
HRMS m/z (Mþ) calcd for C23H16N2O3: 368.1161. Found: 368.1157.
3.2.10. Methyl 2-amino-3-cyano-5-hydroxy-4-phenyl-4H-chromene-
6-carboxylate (3j). A mixture of methyl 2,4-dihydroxybenzoate 1d
(168 mg, 1.0 mmol), 2-benzylidenemalononitrile 2a (231 mg,
1.5 mmol), and Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of methanol was
stirred at room temperature for 5 h. After completion of the reaction,
recrystallization with ethanol gave product 3j (271 mg, 84%) as
d6)
d
12.97 (1H, s), 7.91 (1H, d, J¼8.7 Hz), 7.19e7.07 (6H, m), 6.71 (1H,
d, J¼8.7 Hz), 4.68 (1H, s), 2.58 (3H, s); 13C NMR (75 MHz, DMSO-d6)
d
204.4, 162.5, 160.2, 159.4, 153.7, 141.0, 131.9, 129.0 (d, JCF¼8.3 Hz),
119.9,116.0,115.1 (d, JCF¼21.4 Hz),111.5,107.3, 57.1, 35.4, 26.6; IR (KBr)
a solid: mp275e277 ꢀC; 1HNMR (300 MHz, DMSO-d6)
d 10.99(1H, s),
3431, 3331, 3214, 2878, 2198, 1663, 1505, 1414,1247, 1078, 818 cmꢁ1
;
7.73 (1H, d, J¼9.0 Hz), 7.28e7.23 (2H, m), 7.19e7.08 (3H, m), 7.04 (2H,
HRMS m/z (Mþ) calcd for C18H13FN2O3: 324.0910. Found: 324.0908.
s), 6.69 (1H, d, J¼9.0 Hz), 4.64 (1H, s), 3.82 (3H, s); 13C NMR (75 MHz.
DMSO-d6) d 169.2, 159.6, 158.7, 153.6, 144.8, 129.7, 128.4, 127.1, 126.6,
3.2.6. 6-Acetyl-2-amino-5-hydroxy-4-p-tolyl-4H-chromene-3-
carbonitrile (3f). A mixture of 2,4-dihydroxy acetophenone 1a
(152 mg, 1.0 mmol), 2-(4-methylbenzylidene) malononitrile 2f
(252 mg, 1.5 mmol), and Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of
methanol was stirred at room temperature for 10 h. After comple-
tion of the reaction, recrystallization with ethanol gave product 3f
120.1, 111.9, 108.4, 107.7, 57.2, 52.6, 36.3; IR (KBr) 3428, 3332, 3216,
3071, 2957, 2875, 2197,1664,1408,1338,1262,1075, 782 cmꢁ1; HRMS
m/z (Mþ) calcd for C18H14N2O4: 322.0954. Found: 322.0958.
3.2.11. Ethyl
2-amino-3-cyano-5-hydroxy-7-methyl-4-phenyl-4H-
chromene-6-carboxylate (3k). A mixture of ethyl 2,4-dihydroxy-6-

S.R. Kolla, Y.R. Lee / Tetrahedron 67 (2011) 8271e8275
8275
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methylbenzoate 1e (196 mg, 1.0 mmol), 2-benzylidenemalononitrile
2a (231 mg, 1.5 mmol), and Ca(OH)2 (74 mg, 1.0 mmol) in 5 mL of
methanol was stirred at room temperature for 3 h. After completion of
the reaction, recrystallization with ethanol gave product 3k (284 mg,
81%) as a solid: mp 268e270 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 11.09
(1H, s), 7.29e7.24 (2H, m), 7.20e7.09 (3H, m), 6.98 (2H, s), 6.55 (1H, s),
4.62 (1H, s), 4.28 (2H, q, J¼7.2 Hz), 2.40 (3H, s),1.28 (3H, t, J¼7.2 Hz); 13C
NMR (150 MHz, DMSO-d6)d169.7,159.9,157.9,151.8,145.3,140.3,128.6,
127.3, 126.7, 120.4, 111.7, 110.2, 110.1, 61.7, 57.6, 36.6, 22.4, 14.1; IR (KBr)
3427, 3325, 3213, 2978, 2198, 1661, 1404, 1273, 1172, 1022, 818 cmꢁ1
;
HRMS m/z (Mþ) calcd for C20H18N2O4: 350.1267. Found: 350.1267.
3.2.12. 2-Amino-7-hydroxy-4-phenyl-4H-chromene-3-carbonitrile
(3l). A mixture of resorcinol 1f (110 mg, 1.0 mmol), 2-benzylidene-
malononitrile 2a (231 mg,1.5 mmol), and Ca(OH)2 (74 mg,1.0 mmol)
in 5 mL of methanol was stirred at room temperature for 5 h. After
completion of the reaction, recrystallization with ethanol gave
product 3l (238 mg, 90%) as a solid: mp 233e235 ꢀC; 1H NMR
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Blais, C.; Lamothe, S.; Attardo, G.; Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S.
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W.; Drewe, J.; Jiang, S.; Zhang, H.; Crogan-Grundy, C.; Labreque, D.; Bubenick,
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Cai, S. X. J. Med. Chem. 2008, 51, 417.
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2297.
13. Kemnitzer, W.; Kasibhatla, S.; Jiang, S.; Zhang, H.; Zhao, J.; Jia, S.; Xu, L.; Crogan-
Grundy, C.; Denis, R.; Barriault, N.; Vaillancourt, L.; Charron, S.; Dodd, J.; At-
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(300 MHz, DMSO-d6)
m), 6.85 (2H, s), 6.80 (1H, d, J¼8.4 Hz), 6.47 (1H, d, J¼8.4 Hz), 6.41 (s,
1H), 4.61 (1H, s); 13C NMR (75 MHz, CD3OD)
162.4, 158.6, 150.8,
d 9.68 (1H, s), 7.32e7.27 (2H, m), 7.22e7.15 (3H,
d
147.5, 131.3, 129.7, 128.9, 128.0, 122.1, 115.5, 113.6, 103.7, 58.6, 42.1; IR
(KBr) 3494, 3426, 3336, 2189,1645,1506,1406,1155,1050, 853 cmꢁ1
;
HRMS m/z (Mþ) calcd for C16H12N2O2: 264.0899. Found: 264.0898.
Acknowledgements
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This work was supported by grant No. RTI04-01-04 from the
Regional Technology Innovation Program of the Ministry of
Knowledge Economy (MKE).
References and notes
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