A novel synthesis of diverse 2-amino-5-hydroxy-4H-chromene derivatives with a spirooxindole nucleus by Ca(OH)2-mediated three-component reactions of substituted resorcinols with isatins and malononitrile

Article abstract of DOI:10.1016/j.tet.2013.09.021

An efficient and facile one-pot synthesis is described for the preparation of novel 2-amino-5-hydroxy-4H-chromene derivatives with a spirooxindole nucleus using Ca(OH)₂-mediated three-component reactions of substituted resorcinols with isatins and malononitrile. This simple method provided a variety of biologically interesting diverse 2-amino-5-hydroxy-4H-chromene derivatives in moderate yields under mild reaction conditions.

Full text of DOI:10.1016/j.tet.2013.09.021

Tetrahedron xxx (2013) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel synthesis of diverse 2-amino-5-hydroxy-4H-chromene
derivatives with a spirooxindole nucleus by Ca(OH)2-mediated
three-component reactions of substituted resorcinols with isatins
and malononitrile
,
b
Ji Hyang Park a, Yong Rok Lee a , Sung Hong Kim
*
a School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea
b Analysis Research Division, Daegu Center, Korea Basic Science Institute, Daegu 702-701, 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 31 May 2013
Received in revised form 6 September 2013
Accepted 7 September 2013
Available online xxx
An efficient and facile one-pot synthesis is described for the preparation of novel 2-amino-5-hydroxy-
4H-chromene derivatives with a spirooxindole nucleus using Ca(OH)2-mediated three-component re-
actions of substituted resorcinols with isatins and malononitrile. This simple method provided a variety
of biologically interesting diverse 2-amino-5-hydroxy-4H-chromene derivatives in moderate yields un-
der mild reaction conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Multi-component reaction
One-pot synthesis
Resorcinols
Isatin
Malononitrile
Calcium hydroxide
1. Introduction
hydroxy-4H-chromene derivatives is not required.19 In addition,
reactions of naphthols with arylaldehydes and malononitrile in the
20
2-Aminochromenes are important heterocyclic compounds
with a number of biological and pharmacological properties.1 For
example, they are known to possess potent antimicrobial,2 antivi-
ral,3 anticonvulsant,4 antiproliferative,5 antitumor,6 anti-cancer,7
and central nervous system activities,8a and are widely employed
as cosmetics, pigments,9 and potent biodegradable agrochemi-
cals.10 Furthermore, their derivatives, such as, HA 14-1 and
MX58151, which have proapoptotic effects, are being developed as
anti-cancer agents.11 2-Amino-4H-chromenes are generally syn-
thesized by reactions of phenol or resorcinol, arylaldehydes, and
malononitrile (Scheme 1). Basic alumina,12 piperidine,13 morpho-
line,14 cetyltrimethylammonium chloride,8b [bmim]OH,15 K2CO3/
microwave,16 DBU/microwave,17 and chitosan18 have been used in
these reactions as catalytic and stoichiometric reagents. In-
terestingly, all known reactions of resorcinol, arylaldehydes, and
malononitrile afford 2-amino-7-hydroxy-4H-chromene derivatives
as sole products, and thus, isolation of the expected 2-amino-5-
presence of Na2CaP2O7 or ceric ammonium nitrate21 have been
described to afford 2-aminochromene derivatives. Interestingly,
resorcinol reacts with arylaldehydes and malononitrile at position
6 rather than at position 2 under the above-described conditions to
give 2-amino-7-hydroxy-4H-chromenes regioselectively, probably
due to steric hindrance between two hydroxyl groups in the meta-
disubstituted compound.19
Spirooxindole derivatives also represent an important class of
naturally occurring substances with pronounced biological activi-
ties and properties.22 The spirooxindole unit is a core structure of
many pharmacological agents and alkaloids.23 Furthermore, mol-
ecules bearing a spirooxindole moiety have been shown to possess
a number of important and interesting biological activities.24
In view of these important characteristics, our current research
focus has been targeted toward the facile synthesis of 2-amino-5-
hydroxy-chromenes and spirooxindoles. The unique structural ar-
ray and highly prominent pharmacological activities of these en-
tities stimulated interest in their syntheses, and in particular, the
development of new, simple one-pot synthetic methods for the
preparation of both 2-amino-5-hydroxy-chromenes and spiroox-
indole derivatives has become an interesting challenge.
* 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 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.021
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J.H. Park et al. / Tetrahedron xxx (2013) 1e8
Scheme 1.
Recently, several synthetic methods have been reported for the
malononitrile (3) were first examined in the presence of several
catalysts and bases (Table 1). Using 20 mol % of InCl3 and Yb(OTf)3
as Lewis acids, no products were produced (entries 1 and 2). When
20 mol % of ethylenediamine diacetate (EDDA) was used as an
organocatalyst, no products were isolated (entry 3). In addition, the
use of 1 equiv of DBU and K2CO3 as bases in refluxing methanol for
12 h did not produce the desired products (entries 4 and 5). In-
terestingly, reactions using 1.0 equiv of Ca(OH)2 in refluxing toluene
or acetonitrile for 12 h gave no products (entries 6 and 7), but re-
actions in refluxing ethanol or methanol provided the desired
product 4a at yields of 40 and 60%, respectively (entries 8 and 9).
Two equivalent of Ca(OH)2 in refluxing methanol for 5 h increased
the yield of 4a to 75% (entry 10). The use of H2O as a solvent
resulted in the production of 4a in only 5% yield (entry 11). Im-
portantly, in these reactions, only 4a was formed and other possible
synthesis of 4H-pyrans and 4H-benzo[h]chromenes bearing the
spirooxindole moiety based on multi-component reactions of 1,3-
dicarbonyl compound or 1-naphthol with isatins and malononi-
trile (Scheme 2). A variety of catalysts and reagents, such as,
Al2O3,25 MgO,26 InCl3,27 NiCl2,28 KAl(SO4)2$12H2O,29 p-MeC6H4
-
SO3H,30 ammonium salt,31 Bu4Nþ$Brꢀ,32 Me(CH2)16COꢀ2 $Naþ
(disodium carbonate),33 [BMlm]BF4,34 HOCH2CH2OH polymer,35
beta-cyclodextrin,36 and lipase37 have been studied in the con-
texts of these reactions, which provide rapid synthetic methods to
the production of 2-amino-4H-pyrans and 2-amino-4H-benzo[h]
chromene derivatives bearing the spirooxindole moiety. Further-
more, reactions of substituted resorcinols with isatins and malo-
nonitrile to afford a variety of 6-acyl-2-amino-5-hydroxy-4H-
chromenes bearing various spirooxindoles have not been reported.
Scheme 2.
Recently, we developed a method for synthesizing 2-amino-5-
hydroxy-4H-chromene derivatives based on two-component
regioisomers were not produced. The structure of 4a was de-
termined by 1H NMR, which showed AB aromatic protons on the
reactions
between
2,4-dihydroxyacetophenone
and
2-
4H-chromene ring at
and two methyl peaks at
methyl and an acyl group. The 13C NMR spectrum of 4a contained
d
6.71 (J¼8.6 Hz) and
d
7.90 (J¼8.6 Hz) ppm
benzylidenemalononitriles in methanol in the presence of base
(path a, Scheme 3).38 As part of our ongoing studies on the syn-
theses of novel types of 2-aminochromene derivatives, we exam-
ined three-component reactions of substituted resorcinols with
various isatins and malononitrile in the presence of different cat-
alysts and other reagents. Here, we describe a one-pot synthesis of
biologically interesting diverse 2-amino-5-hydroxy-4H-chromene
derivatives using Ca(OH)2-mediated three-component reactions of
substituted resorcinols with isatins and malononitrile (path b,
Scheme 3).
d
3.15 and 2.50 ppm attributed to a N-
a characteristic quaternary carbon peak at
rooxindole moiety.
d 47.3 ppm due to a spi-
To explore the generality and scope of this method, additional
reactions of substituted resorcinols containing electron-donating or
-withdrawing groups on the benzene ring with malononitrile and
isatins were attempted under optimized conditions. The results are
summarized in Table 2. Reaction of 2,4-dihydroxyacetophenone (1a),
with isatin (2b) and malononitrile (3) in the presence of 2 equiv of
Scheme 3.
2. Results and discussion
Ca(OH)2 in refluxing methanol for 4 h provided compound 4b in 60%
yield (entry 1). When 5-methylisatin with an electron-donating
group on the benzene ring was used, product 4c was produced in
68% yield (entry 2). When 5-bromoisatin, 5-chloroisatin, 7-
chloroisatin, and 5-nitroisatin with electron-withdrawing groups
To afford 2-amino-5-hydroxy-4H-chromenes bearing the spi-
rooxindole moiety, three-component reactions of 2,4-
dihydroxyacetophenone (1a) with 1-methylisatin (2a) and
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J.H. Park et al. / Tetrahedron xxx (2013) 1e8
3
Table 1
3.1. General procedure for the synthesis of spirooxindoles
(4aeu)
Three-component reactions of 2,4-dihydroxyacetophenone (1a) with isatin (2a) and
malononitrile (3) under several conditions
To a solution of substituted isatin (1.0 mmol) in methanol (5 mL)
was added various resorcinols (1.0 mmol), malononitrile
(1.0 mmol), and Ca(OH)2 (2.0 mmol). The mixture was stirred at
reflux until the completion of the reaction, as indicated by TLC
(ethyl acetate/n-hexane). Then the reaction mixture was quenched
with NH4Cl solution (50 mL) and extracted with ethyl acetate
(50 mLꢁ3). The organic layer was washed with water (50 mL), dried
(MgSO4), and evaporated under reduced pressure to give the res-
idue. Chromatography on silica gel using ethyl acetate/n-hexane
(1:1) afforded the desired products.
Entry
Catalyst/reagent
Solvent
Condition
Yield (%)
1
2
3
4
5
6
7
8
InCl3 (0.2 equiv)
MeOH
CH3CN
MeOH
MeOH
MeOH
Toluene
CH3CN
EtOH
Reflux, 12 h
Reflux, 12 h
Reflux, 12 h
Reflux, 12 h
Reflux, 12 h
Reflux, 12 h
Reflux, 12 h
Reflux, 8 h
Reflux, 5 h
Reflux, 5 h
Reflux, 12 h
0
0
0
0
0
0
0
40
60
75
5
Yb (OTf)3 (0.2 equiv)
EDDA (0.2 equiv)
DBU (1.0 equiv)
K2CO3 (1.0 equiv)
Ca(OH)2 (1.0 equiv)
Ca(OH)2 (1.0 equiv)
Ca(OH)2 (1.0 equiv)
Ca(OH)2 (1.0 equiv)
Ca(OH)2 (2.0 equiv)
Ca(OH)2 (2.0 equiv)
3.1.1. 6-Acetyl-2-amino-5-hydroxy-10-methyl-20-oxospiro[chromene-
4,30-indoline]-3-carbonitrile (4a). Yield: 270 mg (75%) as a solid; mp
274e276 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 12.84 (1H, s), 7.90 (1H,
9
10
11
MeOH
MeOH
H2O
d, J¼8.6 Hz), 7.32e7.03 (3H, m), 7.01e6.80 (3H, m), 6.71 (1H, d,
J¼8.6 Hz), 3.15 (3H, s), 2.50 (3H, s); 13C NMR (75 MHz, DMSO-d6)
d
204.7, 176.2, 160.3, 159.4, 154.1, 143.5, 133.5, 132.7, 128.6, 123.2,
122.6, 117.4, 115.8, 108.2, 107.6, 56.2, 54.8, 47.3, 26.4; IR (KBr) 3421,
3324, 3178, 2196, 1710, 1655, 1611, 1489, 1472, 1398, 1368, 1327,
1256, 1127, 1081, 1026, 808, 753 cmꢀ1; HRMS m/z (Mþ) calcd for
on the benzene ring were used, the desired products 4deg were
obtained in 57e70% yield (entries 3e6). When 1-phenylisatin was
used, 4h was produced in 69% yield (entry 7). For other resorcinols,
reactions of 2,4-dihydroxypropiophenone (1b) and 20,40-dihydroxy-
2-phenylacetophenone (1c) afforded the desired products 4ies in
45e75% yield (entries 8e18). Similarly, reactions of 2,4-
dihydroxybenzophenone (1d) were also successful. Reaction of 1d
with isatin and malononitrile in refluxing methanol for 6 h provided
4t in 55% yield, whereas that of 5-chloroisatin afforded 4u in 40%
yield. These reactions provided a rapid means of synthesizing a vari-
ety of 2-amino-5-hydroxy-4H-chromene derivatives 4beu contain-
ingvariousspirooxindolemoieties.Toconfirmthestructuresof4aeu,
the structure of 4i was determined by X-ray crystallography (Fig.1).39
The formation of 4a can be explained by the mechanism shown in
Scheme 4. 2,4-Dihydroxyacetophenone (1a) first gives the phenox-
ide intermediate 5 in the presence of base, which attacks the 2-(1-
methyl-2-oxoindolin-3-ylidene)malononitrile (6) formed by Knoe-
venagel condensation between 1-methylisatin (2a) and malononi-
trile (3), to give intermediate 7. As an evidence of this reaction
pathway, intermediate 6 was isolated and identified by comparison
with spectral data of the reported compound.40 The attack of 5 to 6 at
more crowded 3-position on the benzene ring in comparison with 5-
position may due to higher electron density at the 3-position.41
Tautomerism of 7 followed by intramolecular nucleophilic addition
of oxygen to the cyano group and protonation provides 8, which
undergoes isomerization to give 4a. The regioselective ring closure of
7 to 8 may be determined by the deactivation of the O-hydroxy group
by intramolecular hydrogen bonding to the neighboring carbonyl.
In summary, we describe the efficient and general one-pot syn-
thesis of biologically interesting 2-amino-5-hydroxy-4H-chromene
derivatives bearing spirooxindole skeletons via a Ca(OH)2-mediated
three-component reaction of substituted resorcinols with isatins and
malononitrile. This method has advantages of requiring mild reaction
conditions, ease of handling, and the use of an effective reagent.
C20H15N3O4: 361.1063; found: 361.1067.
3.1.2. 6-Acetyl-2-amino-5-hydroxy-20-oxospiro[chromene-4,30-indo-
line]-3-carbonitrile (4b). Yield: 208 mg (60%) as a solid; mp 290 ꢂC
(decomp.); 1H NMR (300 MHz, DMSO-d6)
d 13.05 (1H, s), 10.59 (1H,
s), 7.94 (1H, d, J¼8.9 Hz), 7.31e7.10 (3H, m), 6.99e6.80 (3H, m), 6.74
(1H, d, J¼8.9 Hz), 2.56 (3H, s); 13C NMR (75 MHz, DMSO-d6)
d 204.9,
177.9, 160.7, 159.4, 154.3, 142.0, 134.5, 132.8, 128.5, 123.6, 122.0,
117.7, 115.8, 109.4, 108.4, 107.6, 56.5, 47.7, 26.6; IR (KBr) 3316, 3176,
2194, 1711, 1651, 1475, 1401, 1326, 1255, 1129, 1079, 808, 752 cmꢀ1
;
HRMS m/z (Mþ) calcd for C19H13N3O4: 347.0906; found: 347.0903.
3.1.3. 6-Acetyl-2-amino-5-hydroxy-50-methyl-20-oxospiro[chro-
mene-4,30-indoline]-3-carbonitrile (4c). Yield: 245 mg (68%) as
a solid; mp 205e207 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 13.04 (1H,
s), 10.45 (1H, s), 7.94 (1H, d, J¼8.7 Hz), 7.17 (2H, br s), 6.97 (1H, d,
J¼7.5 Hz), 6.80e6.63 (3H, m), 2.56 (3H, s), 2.16 (3H, s); 13C NMR
(75 MHz, DMSO-d6)
d 204.6, 177.6, 160.6, 159.2, 154.2, 139.5, 134.4,
132.4, 130.7, 128.6, 123.9, 117.4, 115.7, 109.0, 108.5, 107.4, 56.9, 47.6,
26.3, 20.4; IR (KBr) 3331, 3198, 2197, 1719, 1655, 1492, 1398, 1324,
1255, 1132, 1079, 810 cmꢀ1; HRMS m/z (Mþ) calcd for C20H15N3O4:
361.1063; found: 361.1059.
3.1.4. 6-Acetyl-2-amino-50-bromo-5-hydroxy-20-oxospiro[chromene-
4,30-indoline]-3-carbonitrile (4d). Yield: 243 mg (57%) as a solid;
mp 279 ꢂC (decomp.); 1H NMR (300 MHz, DMSO-d6)
d 13.07 (1H,
s), 10.71 (1H, s), 7.96 (1H, d, J¼9.0 Hz), 7.36 (1H, d, J¼8.3 Hz), 7.28
(2H, br s), 7.16 (1H, br s), 6.84 (1H, d, J¼8.3 Hz), 6.75 (1H, d,
J¼9.0 Hz), 2.56 (3H, s); 13C NMR (75 MHz, DMSO-d6)
d 204.9,
177.6, 160.5, 159.5, 154.3, 141.4, 136.7, 132.9, 131.3, 126.5, 117.6,
115.8, 113.7, 111.4, 107.7, 107.7, 55.7, 47.9, 26.6; IR (KBr) 3318, 3180,
2197, 1718, 1653, 1475, 1401, 1325, 1254, 1127, 1079, 807, 632 cmꢀ1
;
HRMS m/z (Mþ) calcd for C19H12BrN3O4: 425.0011; found:
3. Experimental section
425.0009.
All experiments were carried out in a nitrogen atmosphere.
Merck pre-coated silica gel plates (Art. 5554) and a fluorescent in-
dicator were used for analytical TLC. Flash column chromatography
was performed using silica gel 9385 (Merck).1H and 13C NMR spectra
were recorded on a Bruker Model ARX (300 and 75 MHz, re-
spectively) spectrometer in DMSO-d6. IR spectra were recorded on
a JASCO FTIR 5300 spectrophotometer. HRMS was carried out at the
Korea Basic Science Institute (Daegu) on a Jeol JMS 700 spectrometer.
3.1.5. 6-Acetyl-2-amino-50-chloro-5-hydroxy-20-oxospiro[chromene-
4,30-indoline]-3-carbonitrile(4e). Yield: 218 mg (57%) as a solid; mp
280 ꢂC (decomp.); 1H NMR (300 MHz, DMSO-d6)
d 12.38 (1H, s),
10.05 (1H, s), 7.26 (1H, d, J¼8.7 Hz), 6.64 (2H, s), 6.53 (1H, d,
J¼8.0 Hz), 6.37 (1H, s), 6.17 (1H, d, J¼8.0 Hz), 6.05 (1H, d, J¼8.7 Hz),
1.86 (3H, s); 13C NMR (75 MHz, DMSO-d6)
d 205.1,177.9,160.8,159.8,
154.6, 141.3, 136.6, 133.2, 128.7, 126.2, 124.1, 117.8, 116.1, 111.1, 108.0,
56.1, 48.2, 26.8; IR (KBr) 3389, 3323, 3178, 2197, 1707, 1654, 1477,
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J.H. Park et al. / Tetrahedron xxx (2013) 1e8
Table 2
Additional reactions for the synthesis of a variety of 2-amino-5-hydroxy-4H-chromenes bearing spirooxindole moieties in the presence of Ca(OH)2
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J.H. Park et al. / Tetrahedron xxx (2013) 1e8
5
Table 2. (continued)
(75 MHz, DMSO-d6)
d
204.6, 177.4, 160.4, 159.4, 154.2, 140.9, 136.2,
132.7, 128.2, 125.8, 123.6, 117.3, 115.8, 110.7, 107.6, 107.5, 55.9, 47.9,
26.4; IR (KBr) 3390, 3319, 3175, 2197, 1707, 1653, 1478, 1405, 1325,
1254, 1127, 1079, 809, 633 cmꢀ1; HRMS m/z (Mþ) calcd for
C19H12ClN3O4: 381.0516; found: 381.0514.
3.1.7. 6-Acetyl-2-amino-5-hydroxy-50-nitro-20-oxospiro[chromene-
4,30-indoline]-3-carbonitrile (4g). Yield: 239 mg (61%) as a solid; mp
260 ꢂC (decomp.); 1H NMR (300 MHz, DMSO-d6)
d 13.08 (1H, s),
11.37 (1H, s), 8.17 (1H, d, J¼8.3 Hz), 7.97 (1H, d, J¼9.0 Hz), 7.92 (1H,
s), 7.45 (2H, s), 7.08 (1H, d, J¼8.3 Hz), 6.77 (1H, d, J¼9.0 Hz), 2.54
(3H, s); 13C NMR (75 MHz, DMSO-d6)
d 205.1, 178.7, 160.6, 160.0,
154.6, 148.8, 143.0, 135.6, 133.5, 126.3, 119.7, 117.7, 116.2, 110.0, 108.2,
107.3, 55.2, 48.1, 26.8; IR (KBr) 3442, 3364, 3276, 2197, 1731, 1652,
1484, 1404, 1333, 1254, 1079, 809, 632 cmꢀ1; HRMS m/z (Mþ) calcd
for C19H12N4O6: 392.0757; found: 392.0759.
Fig. 1. The X-ray structure of compound 4i.
1404, 1325, 1255, 1126, 1079, 809, 633 cmꢀ1; HRMS m/z (Mþ) calcd
for C19H12ClN3O4: 381.0516; found: 381.0518.
3.1.8. 6-Acetyl-2-amino-5-hydroxy-20-oxo-10-phenylspiro[chromene-
4,30-indoline]-3-carbonitrile (4h). Yield: 292 mg (69%) as a solid;
mp 254e256 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 13.08 (1H, s), 8.00
3.1.6. 6-Acetyl-2-amino-70-chloro-5-hydroxy-20-oxospiro[chromene-
(1H, d, J¼9.0 Hz), 7.78e7.56 (2H, m), 7.55e7.40 (3H, m), 7.36 (2H, s),
4,30-indoline]-3-carbonitrile (4f). Yield: 267 mg (70%) as a solid; mp
7.22 (1H, t, J¼7.5 Hz), 7.13e6.96 (2H, m), 6.80 (1H, d, J¼9.0 Hz), 6.71
(1H, d, J¼7.8 Hz), 2.58 (3H, s); 13C NMR (75 MHz, DMSO-d6)
d 204.5,
269 ꢂC (decomp.); 1H NMR (300 MHz, DMSO-d6)
d 12.97 (1H, s),
175.7, 160.2,159.2,154.1,143.1,134.5,133.2,132.7,129.6,128.5,128.1,
126.6, 123.7, 123.1, 117.3, 115.9, 108.5, 108.1, 107.5, 56.4, 47.4, 26.4; IR
10.60 (1H, s), 7.90 (1H, d, J¼8.9 Hz), 7.23e7.03 (3H, m), 6.98 (1H, s),
6.82 (1H, d, J¼8.4 Hz), 6.68 (1H, d, J¼8.9 Hz), 2.50 (3H, s); 13C NMR
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6
J.H. Park et al. / Tetrahedron xxx (2013) 1e8
Scheme 4. Plausible mechanism for the formation of 4a.
(KBr) 3463, 3318, 3192, 2196, 1722, 1657, 1609, 1498, 1369, 1327,
a solid; mp >300 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 13.08 (1H, s),
1254, 1077, 810, 749, 700, 625 cmꢀ1; HRMS m/z (Mþ) calcd for
10.68 (1H, s), 7.98 (1H, d, J¼8.7 Hz), 7.29e7.17 (3H, m), 7.03 (1H, s),
C
25H17N3O4: 423.1219; found: 423.1217.
6.88 (1H, d, J¼8.1 Hz), 6.74 (1H, d, J¼8.7 Hz), 3.03 (2H, q, J¼6.6 Hz),
1.04 (3H, t, J¼6.6 Hz); 13C NMR (75 MHz, DMSO-d6)
d 207.0, 177.5,
3.1.9. 2-Amino-5-hydroxy-10-methyl-20-oxo-6-propionylspiro[chro-
160.4,159.4,154.0,141.0,136.3,131.9,128.3,125.8,123.6,117.4,115.3,
110.7, 107.7, 107.5, 55.9, 47.9, 30.9, 7.9; IR (KBr) 3475, 3305, 3180,
2196, 1724, 1654, 1473, 1395, 1302, 1238, 1119, 807 cmꢀ1; HRMS m/z
(Mþ) calcd for C20H14ClN3O4: 395.0673; found: 395.0677.
mene-4,30-indoline]-3-carbonitrile (4i). Yield: 195 mg (52%) as
a solid; mp 270e272 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 13.00 (1H,
s), 7.97 (1H, d, J¼9.0 Hz), 7.32e7.19 (3H, m), 7.09e6.91 (3H, m), 6.76
(1H, d, J¼9.0 Hz), 3.21 (3H, s), 3.02 (2H, q, J¼7.5 Hz), 1.03 (3H, t,
J¼7.5 Hz); 13C NMR (75 MHz, DMSO-d6)
d
207.3, 176.5, 160.6, 159.7,
3.1.14. 2-Amino-5-hydroxy-50-nitro-20-oxo-6-propionylspiro[chro-
154.2,143.8,133.8,132.1,128.8,123.5,122.9,117.7,115.5,108.6,108.5,
107.8, 56.4, 47.6, 31.2, 26.7, 8.2; IR (KBr) 3385, 3309, 3198, 2194,
1718,1655,1468, 1367, 1236, 1120, 1080, 1023, 803, 748 cmꢀ1; HRMS
m/z (Mþ) calcd for C21H17N3O4: 375.1219; found: 375.1217.
mene-4,30-indoline]-3-carbonitrile (4n). Yield: 187 mg (46%) as
a solid; mp >300 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 13.10 (1H, s),
11.32 (1H, s), 8.18 (1H, d, J¼8.7 Hz), 8.00 (1H, d, J¼9.0 Hz), 7.89 (1H,
s), 7.37 (2H, s), 7.09 (1H, d, J¼8.7 Hz), 6.77 (1H, d, J¼9.0 Hz), 3.02
(2H, q, J¼7.2 Hz),1.02 (3H, t, J¼7.2 Hz); 13C NMR (75 MHz, DMSO-d6)
3.1.10. 2-Amino-5-hydroxy-20-oxo-6-propionylspiro[chromene-4,30-
d 207.0, 178.3, 160.2, 159.6, 154.1, 148.5, 142.6, 135.3, 132.2, 125.9,
indoline]-3-carbonitrile (4j). Yield: 191 mg (53%) as a solid; mp
119.2, 117.3, 115.4, 109.6, 107.7, 107.1, 55.0, 47.8, 30.9, 7.8; IR (KBr)
3421, 3306, 3182, 2195, 1725, 1653, 1524, 1479, 1406, 1340, 1232,
1118, 1077, 833, 690 cmꢀ1; HRMS m/z (Mþ) calcd for C20H14N4O6:
406.0913; found: 406.0910.
289 ꢂC (decomp.); 1H NMR (300 MHz, DMSO-d6)
d 13.08 (1H, s),
10.57 (1H, s), 7.96 (1H, d, J¼8.9 Hz), 7.25e7.12 (3H, m), 6.94e6.81
(3H, m), 6.74 (1H, d, J¼8.9 Hz), 3.02 (2H, q, J¼6.9 Hz), 1.04 (3H, t,
J¼6.9 Hz); 13C NMR (75 MHz, DMSO-d6)
d 207.1, 177.8, 160.5, 159.3,
154.1, 142.0, 134.4, 131.7, 128.4, 123.5, 121.9, 117.6, 115.3, 109.3, 108.5,
107.5, 56.6, 47.7, 31.0, 8.0; IR (KBr) 3472, 3332, 3193, 2197, 1721,
1655, 1469, 1393, 1299, 1236, 1119, 1076, 808, 747 cmꢀ1; HRMS m/z
(Mþ) calcd for C20H15N3O4: 361.1063; found: 361.1060.
3.1.15. 2-Amino-70-chloro-5-hydroxy-20-oxo-6-propionylspiro[chro-
mene-4,30-indoline]-3-carbonitrile (4o). Yield: 234 mg (59%) as
a solid; mp >300 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 13.11 (1H, s),
10.97 (1H, s), 7.98 (1H, d, J¼8.7 Hz), 7.31e7.18 (3H, m), 6.95e6.86
(2H, m), 6.74 (1H, d, J¼8.7 Hz), 3.02 (2H, q, J¼7.1 Hz), 1.04 (3H, t,
3.1.11. 2-Amino-5-hydroxy-50-methyl-20-oxo-6-propionylspiro[chro-
J¼7.1 Hz); 13C NMR (75 MHz, DMSO-d6)
d 207.0, 177.7, 160.3, 159.3,
mene-4,30-indoline]-3-carbonitrile (4k). Yield: 169 mg (45%) as
153.8, 139.7, 136.0, 131.9, 128.3, 123.1, 122.1, 117.3, 115.3, 113.5, 107.9,
107.5, 56.0, 48.5, 30.9, 7.8; IR (KBr) 3413, 3326, 3199, 2197, 1729,
1649, 1466, 1400, 1239, 1124, 1088, 800, 751 cmꢀ1; HRMS m/z (Mþ)
calcd for C20H14ClN3O4: 395.0673; found: 395.0676.
a solid; mp >300 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 13.06 (1H, s),
10.42 (1H, s), 7.98 (1H, d, J¼9.0 Hz), 7.14 (2H, br s), 6.98 (1H, d,
J¼7.8 Hz), 6.78e6.67 (3H, m), 3.04 (2H, q, J¼7.1 Hz), 2.18 (3H, s), 1.07
(3H, t, J¼7.1 Hz); 13C NMR (75 MHz, DMSO-d6)
d 207.2, 177.9, 160.6,
159.3, 154.1, 139.6, 134.6, 131.8, 130.9, 128.8, 124.1, 117.8, 115.3, 109.2,
108.6, 107.6, 56.7, 47.7, 31.1, 20.6, 8.0; IR (KBr) 3472, 3322, 3185,
2197, 1719, 1655, 1491, 1393, 1305, 1239, 1131,1110, 809 cmꢀ1; HRMS
m/z (Mþ) calcd for C21H17N3O4: 375.1219; found: 375.1219.
3.1.16. 2-Amino-5-hydroxy-10-methyl-20-oxo-6-(2-phenylacetyl)
spiro[chromene-4,30-indoline]-3-carbonitrile (4p). Yield: 317 mg
(75%) as a solid; mp >300 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 12.91
(1H, s), 10.53 (1H, s), 8.14 (1H, d, J¼8.7 Hz), 7.35e7.09 (8H, m),
6.95e6.70 (4H, m), 4.36 (2H, s); 13C NMR (75 MHz, DMSO-d6)
3.1.12. 2-Amino-50-bromo-5-hydroxy-20-oxo-6-propionylspiro[chro-
d 203.9, 177.6, 160.9, 159.2, 154.2, 141.9, 134.3, 134.2, 132.3, 129.5,
mene-4,30-indoline]-3-carbonitrile (4l). Yield: 268 mg (61%) as
128.3, 128.2, 126.7, 123.4, 121.8, 117.4, 115.1, 109.2, 108.6, 107.5, 56.6,
47.6, 44.1; IR (KBr) 3432, 3289, 3181, 2198, 1716, 1650, 1478, 1404,
1345, 1255, 1109, 1040, 804, 746 cmꢀ1; HRMS m/z (Mþ) calcd for
a solid; mp 188e190 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 13.10 (1H, s),
10.70 (1H, s), 7.98 (1H, d, J¼8.6 Hz), 7.36 (1H, d, J¼8.1 Hz), 7.26 (2H, s),
7.15 (1H, s), 6.83 (1H, d, J¼8.1 Hz), 6.74 (1H, d, J¼8.6 Hz), 3.03 (2H, q,
C25H17N3O4: 423.1219; found: 423.1216.
J¼6.6 Hz),1.05 (3H, t, J¼6.6 Hz); 13C NMR (75 MHz, DMSO-d6)
d 207.0,
177.3, 160.3, 159.4, 154.0, 141.4, 136.7, 131.9, 131.1, 126.3, 117.4, 115.3,
113.5, 111.2, 107.7, 107.5, 55.8, 47.8, 30.9, 7.9; IR (KBr) 3476, 3309,
3.1.17. 2-Amino-50-bromo-5-hydroxy-20-oxo-6-(2-phenylacetyl)spiro
[chromene-4,30-indoline]-3-carbonitrile (4q). Yield: 246 mg (49%) as
3182, 2197, 1722, 1655, 1472, 1396, 1303, 1239, 1119, 1080, 807 cmꢀ1
;
a solid; mp >300 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d
12.94 (1H, s),
10.69 (1H, s), 8.15 (1H, d, J¼8.7 Hz), 7.40e7.12 (9H, m), 6.89e6.71
(2H, m), 4.36 (2H, s); 13C NMR (75 MHz, DMSO-d6)
203.9, 177.3,
HRMS m/z (Mþ) calcd for C20H14BrN3O4: 439.0168; found: 439.0171.
d
3.1.13. 2-Amino-50-chloro-5-hydroxy-20-oxo-6-propionylspiro[chro-
mene-4,30-indoline]-3-carbonitrile (4m). Yield: 198 mg (50%) as
160.8, 159.3, 154.3, 141.3, 136.6, 134.2, 132.5, 131.1, 129.6, 128.3,
126.7, 126.3, 117.4, 115.2, 113.5, 111.2, 107.9, 107.6, 55.9, 47.8, 44.2; IR
Please cite this article in press as: Park, J. H.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.09.021

J.H. Park et al. / Tetrahedron xxx (2013) 1e8
7
Feducovich, S. K.; Belyakov, P. A.; Nikishin, G. I. Adv. Synth. Catal. 2008, 350, 591
and references cited therein.
2. Khafagy, M. M.; Abd El-Wahab, A. H. F.; Eid, F. A.; El-Agrody, A. M. Farmaco
(KBr) 3359, 3170, 2195, 1724, 1649, 1475, 1401, 1349, 1258, 1111,
1036, 806, 696 cmꢀ1; HRMS m/z (Mþ) calcd for C25H16BrN3O4:
501.0324; found: 501.0325.
2002, 57, 715.
3. (a) Smith, P. W.; Sollis, S. L.; Howes, P. D.; Cherry, P. C.; Starkey, I. D.; Cobley, K.
N.; Weston, H.; Scicinski, J.; Merritt, A.; Whittington, A.; Wyatt, P.; Taylor, N.;
Green, D.; Bethell, R.; Madar, S.; Fenton, R. J.; Morley, P. J.; Pateman, T.; Be-
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Med. Chem. Lett. 1997, 7, 3165.
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5. Bianchi, G.; Tava, A. Agric. Biol. Chem. 1987, 51, 2001.
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S.; Sambandam, A.; Snider, P. A.; Masih, L. Bioorg. Med. Chem. Lett. 2005, 15,
1587; (b) Skommer, J.; Wlodkowic, D.; Matto, M.; Eray, M.; Pelkonen, J. Leu-
kemia Res. 2006, 30, 322 and references cited therein; (c) Wang, J. L.; Liu, D.;
Zhang, Z. J.; Shan, S.; Han, X.; Srinvasula, S. M.; Croce, C. M.; Alnemri, E. S.;
Huang, Z. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7124.
3.1.18. 2-Amino-50-chloro-5-hydroxy-20-oxo-6-(2-phenylacetyl)spiro
[chromene-4,30-indoline]-3-carbonitrile (4r). Yield: 252 mg, (55%)
as a solid; mp >300 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 12.96 (1H,
s), 10.71 (1H, s), 8.17 (1H, d, J¼8.7 Hz), 7.36e7.16 (8H, m), 7.07 (1H,
s), 6.87 (1H, d, J¼8.1 Hz), 6.78 (1H, d, J¼8.7 Hz), 4.38 (2H, s); 13C
NMR (75 MHz, DMSO-d6)
d 203.9, 177.4, 160.8, 159.3, 154.3, 140.9,
136.2, 134.2, 132.5, 129.6, 128.3, 128.2, 126.7, 125.8, 123.6, 117.3,
115.1, 110.7, 107.8, 107.7, 55.9, 47.9, 44.2; IR (KBr) 3357, 3169, 2196,
1724, 1648, 1478, 1401, 1349, 1257, 1111, 1037, 806, 698 cmꢀ1; HRMS
m/z (Mþ) calcd for C25H16ClN3O4: 457.0829; found: 457.0831.
8. (a) Erichsen, M. N.; Huynh, T. H. V.; Abrahamsen, B.; Bastlund, J. F.; Bundgaard,
C.; Monrad, O.; Bekker-Jensen, A.; Nielsen, C. W.; Frydenvang, K.; Jensen, A. A.;
Bunch, L. J. Med. Chem. 2010, 53, 7180; (b) Ballini, R.; Bosica, G.; Conforti, M. L.;
Maggi, R.; Mazzacanni, A.; Righi, P.; Sartori, G. Tetrahedron 2001, 57, 1395.
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Chromones; Weissberger, A., Taylor, E. C., Eds.; John Wiley: New York, NY, 1977;
Chapter II, pp 11e139.
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Heterocycles 1987, 26, 903; (b) Abdel-Galil, F. M.; Riad, B. Y.; Sherif, S. M.; El-
nagdi, M. H. Chem. Lett. 1982, 1123; (c) Sofan, M. A.; El-Taweel, F. M.; Elagamey,
A. G. A.; Elnagdi, M. H. Liebigs Ann. Chem. 1989, 935.
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Drewe, J.; Jiang, S.; Zhang, H.; Wang, Y.; Zhao, J.; Jia, S.; Herich, J.; Labreque, D.;
Storer, R.; Meerovitch, K.; Bouffard, D.; Rej, R.; Denis, R.; Blais, C.; Lamothe, S.;
Attardo, G.; Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S. X. J. Med. Chem. 2004,
47, 6299; (c) Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Zhao, J.; Crogan-
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51, 417.
12. Maggi, R.; Ballini, R.; Sartori, G.; Sartorio, R. Tetrahedron Lett. 2004, 45, 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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3.1.19. 2-Amino-70-chloro-5-hydroxy-20-oxo-6-(2-phenylacetyl)spiro
[chromene-4,30-indoline]-3-carbonitrile (4s). Yield: 229 mg (50%) as
a solid; mp 177e179 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 12.95 (1H,
s), 10.98 (1H, s), 8.17 (1H, d, J¼8.9 Hz), 7.40e7.16 (8H, m), 6.93 (2H,
br s), 6.78 (1H, d, J¼8.9 Hz), 4.38 (2H, s); 13C NMR (75 MHz, DMSO-
d6) d 203.9, 177.6, 161.3, 160.8, 159.3, 154.1, 139.7, 136.0, 134.2, 132.5,
129.6, 128.3, 126.7, 123.1, 122.1, 117.3, 115.2, 113.5, 108.0, 107.6, 56.0,
48.4, 44.1; IR (KBr) 3338, 3200, 2197, 1730, 1650, 1469, 1402, 1360,
1255, 1114, 1041, 800, 741, 717 cmꢀ1; HRMS m/z (Mþ) calcd for
C
25H16ClN3O4: 457.0829; found: 457.0829.
3.1.20. 2-Amino-6-benzoyl-5-hydroxy-20-oxospiro[chromene-4,30-
indoline]-3-carbonitrile (4t). Yield: 225 mg (55%) as a solid; mp
>300 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 12.54 (1H, s), 10.61 (1H, s),
7.67e7.45 (6H, m), 7.29e7.12 (3H, m), 7.02e6.82 (3H, m), 6.75 (1H,
d, J¼8.1 Hz); 13C NMR (75 MHz, DMSO-d6)
d 199.7, 177.8, 161.0,
159.3, 154.2, 142.0, 136.9, 134.4, 134.2, 132.2, 128.8, 128.5, 128.4,
123.6,122.0, 117.6, 115.7, 109.3, 109.0, 107.6, 56.6, 47.8; IR (KBr) 3421,
3319, 3187, 2193, 1713, 1648, 1478, 1397, 1343, 1256, 1093, 1019, 802,
754, 704 cmꢀ1; HRMS m/z (Mþ) calcd for C24H15N3O4: 409.1063;
found: 409.1065.
14. Klokol, G. V.; Sharanina, L. G.; Nesterov, V. N.; Shklover, V. E.; Sharanin, Y. A.;
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2008, 288.
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Zahouily, M. Green. Chem. 2010, 12, 2261.
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3.1.21. 2-Amino-6-benzoyl-50-chloro-5-hydroxy-20-oxospiro[chro-
mene-4,30-indoline]-3-carbonitrile (4u). Yield: 178 mg (40%) as
a solid; mp >300 ꢂC; 1H NMR (300 MHz, DMSO-d6)
d 12.54 (1H, s),
10.74 (1H, s), 7.70e7.68 (3H, m), 7.68e7.46 (3H, m), 7.31 (2H, s), 7.24
(1H, d, J¼8.3 Hz), 7.12 (1H, s), 6.88 (1H, d, J¼8.3 Hz), 6.75 (1H,
J¼7.2 Hz); 13C NMR (75 MHz, DMSO-d6)
d 199.5, 177.5, 160.7, 159.4,
154.1,141.0,136.9,136.3,134.2,132.1,128.7,128.4,128.2,125.8,123.7,
117.4, 115.8, 110.7, 108.2, 107.6, 55.9, 48.0; IR (KBr) 3352, 3309, 3183,
2195, 1714, 1648, 1628, 1478, 1401, 1342, 1254, 1092, 803, 698 cmꢀ1
;
HRMS m/z (Mþ) calcd for C24H14ClN3O4: 443.0673; found:
443.0670.
Acknowledgements
This research was supported by the Nano Material Technology
Development Program of the Korean National Research Foundation
(NRF) funded by the Korean Ministry of Education, Science, and
Technology (2012M3A7B4049675).
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.09.021.
References and notes
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8
J.H. Park et al. / Tetrahedron xxx (2013) 1e8
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Please cite this article in press as: Park, J. H.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.09.021