Synthesis of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes

Article abstract of DOI:10.1016/j.tet.2011.08.045

A combinatorial library of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes was synthesized in high yield by C4-SMe substitution in N-alkyl/phenyl 4-(methylthio)-3-nitro-4H-chromen-2-amines with a variety of phenols. The reaction always provided C2 substitution in

Full text of DOI:10.1016/j.tet.2011.08.045

Tetrahedron 67 (2011) 8146e8154
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Synthesis of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes
*
H. Surya Prakash Rao , K. Geetha, M. Kamalraj
Department of Chemistry, School of Physical, Chemical and Applied Sciences, Pondicherry University, Pondicherry 605 014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2011
Received in revised form 14 August 2011
Accepted 17 August 2011
Available online 24 August 2011
A combinatorial library of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes was synthesized in high yield by
C4-SMe substitution in N-alkyl/phenyl 4-(methylthio)-3-nitro-4H-chromen-2-amines with a variety of
phenols. The reaction always provided C2 substitution in the phenol ring, dictated by hydrogen bond
interactions between the phenolic hydroxyl group and the nitro group in 3-nitro-4H-chromenes.
Reduction of the nitro group with concomitant hydrolysis of the enamine in 4-(2-hydroxyaryl)-3-nitro-
4H-chromenes with Zn, Ac2O in AcOH furnished hybrid amino-acid lactone incorporating ortho-tyrosine
and phenyl alanine moieties.
Keywords:
Nitroketene
Electrophlic substitution
4-Aryl-4H-chromenes
Hybrid amino acid
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
replacing C4-SMe in 2 with phenols 4 to generate a combinatorial
library of 4-aryl-4H-chromenes, e.g., 6a. In this method there is
The 4-aryl-4H-chromenes are potent apoptosis (controlled cell
death) inducing agents.1 Since cancer cells grow faster, apoptosis
inducing agents act on cancer cells to restrict their abnormal cell
division and thus act as anti-cancer drugs. 4-Aryl-4H-chromenes,
e.g., 1 inhibit tubulin polymerization and in the process induce
apoptosis.2 In addition to being anti-cancer agents, a few 4-aryl-4H-
chromenes, particularly those derived from 2-naphthol exhibit for
antibacterial activity.3 Generally, 4-aryl-4H-chromenes were syn-
thesized by three-component condensation involving a phenol, an
aromatic aldehyde and malononitrile. This method, however, is
limited to electron rich phenols and electron poor aromatic alde-
hydes and is not suitable for the synthesis of 4-aryl-4H-chromenes
emanating from electron poor phenols and electron rich aldehydes.
We have recently disclosed a facile, high yielding and convenient
synthesis of a combinatorial library of N-alkyl/aryl 4-(methylthio)-
3-nitro-4H-chromen-2-amines like 2 from readily available nitro-
ketene N,S-acetals and 2-hydoxybenzaldehydes.4 We have also
demonstrated that the C4 methylthio group (C4-SMe) in 2 is labile
owing to electron donating ability of oxygen and availability of
conjugation. C4-SMe in 2 can be replaced through SN1 reaction
pathway with nucleophiles like thiols or electron rich aromatic
rings. For example, heating 2 with thiophenol provided N-methyl-
a possibility of variation at three sites of 4-aryl-4H-chromenes
namely chromene ring, C2-amine and C4-phenol.
Three pathways are possible in the reaction of C4-methylthio-
4H-chromene 2 with phenol 4a as shown in Scheme 1. Path 1 leads
to ether 5 where SN1 type substitution takes place on phenolic
oxygen, similar to the reaction of 2 with thiophenol to provide
thioether 3. On the other hand, paths 2 and 3 furnish aromatic
electrophilic substitution products of phenol 4a, at ortho and para
positions, leading to products 6a and 7, respectively. In reality and
OH
OH
O
O
SMe
OH
NO2
NO2
NO2
4a
4a
Path 1
Path 2
NHMe
O
NHMe
O
NHMe
2
5
6a
Path3
OH
OH
4a
3-nitro-4-(phenylthio)-4H-chromen-2-amine
yield. In continuation of this work, we explored the possibility of
3 in quantitative
NO2
O
NHMe
7
* Corresponding author. Tel.: þ91413 2654411 (office), þ914132252080 (residence),
þ919443264222 (mobile); fax: þ914132656230; e-mail addresses: hspr@yahoo.com,
hspr.che@pondiuni.edu.in.
Scheme 1. Three possible paths in the reaction of 4-methylthio-4H-chromene 2 with
phenols 4.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.045

H. Surya Prakash Rao et al. / Tetrahedron 67 (2011) 8146e8154
8147
R3
R4
R2
OH
SMe
R2
OH
NO2
EtOH, reflux,
NO2
R3
+
12-29 h, 40-88%
R4
O
NHR1
O
NHR1
2a-d
4a-e
6a-n
2a: R1 = Me;
4a: R2 = R3 = R4 = H;
6a: R1 = Me, R2 = R3 = R4 = H;
6b: R1 = Me, R2 = R3 = H, R4 = Me;
6c: R1 = Me, R2 = R3 = H, R4 = Cl;
6d: R1 = n-Bu, R2 = R3 = R4 = H;
6e: R1 = n-Bu, R2 = R3 = H, R4 = Me;
6f: R1 = n-Bu, R2 = R3 = H, R4 = Cl;
6g: R1 = Ph, R2 = R3 = R4 = H;
2b: R1 = n-Bu;
2c: R1 = Ph;
2d: R1 = Bn.
4b: R2 = R3 = H, R4 = Me;
4c: R2 = R3 = H, R4 = Cl;
4d: R2 = R4 = H, R3 = Me;
4e: R2 = Me, R3 = R4 = H.
6h: R1
= Ph, R2 = R3 = H, R4 = Me;
6i: R1 = Ph, R2 = R3 = H, R4 = Cl;
6j: R1 = Bn, R2 = R3 = R4 = H;
6k: R1 = Bn, R2 = R3 = H, R4 = Me;
6l: R1 = Bn, R2 = R3 = H, R4 = Cl;
6m: R1 = Me, R2 = R4 = H, R3 = Me;
6n: R1 = R2 = Me, R3 = R4 = H.
Scheme 2. Synthesis of a combinatorial library of 4-aryl-4H-chrmenes 6aen.
in contrast to the reaction of 2 with thiophenol, the reaction with
phenol 4a furnished the regioselective electrophilic aromatic ring
substitution product 6a exclusively (Scheme 2). There was no trace
of O-substitution product 5 or para-substitution product 7. We have
now explored the scope of this reaction for the synthesis of
a combinatorial library of 4-aryl-4H-chromenes. In addition, we
have unmasked the enamine and nitro groups present in 6a for the
synthesis of the lactone of a non-natural hybrid amino acid in-
corporating phenyl alanine and ortho-tyrosine.
indicating the decisive role of the phenolic hydroxyl group in the
formation of 6a. We have conducted severalexperimentsto find out if
one-pot three-component condensation of 2-hydroxybenzldehyde,
N-methyl-1-(methylthio)-2-nitroethenamine and phenol takes place
to provide 6a directly, that is, without isolating 2a. All attempts,
however, were mostly unsuccessful. In one case, under microwave
irradiation for 2 min in a mono-mode microwave oven, the three-
component domino condensation between 2-hydroxybenzldehyde,
N-methyl-1-(methylthio)-2-nitroethenamine and phenol provided
51% yield of 4-aryl-4H-chromene 6a. However, the reaction was not
clean and purification required subjecting crude product to column
chromatography. Even though the present procedure is a two-step
process to 4-(2-hydroxyphenyl)-4H-chromene 6a both the steps are
high yielding and the products crystallize out of the reaction mixture
in excellent yield, obliviating the need for column chromatographic
purification.
2. Results and discussion
When a mixture of 4H-chromene 2a and phenol 4a was heated
to reflux in EtOH for 12 h, 2-(2-(methylamino)-3-nitro-4H-chro-
men-4-yl) phenol 6a precipitated in quantitative yield. Simple fil-
tration was sufficient to furnish the clean product. Although
reaction was faster (2 h) in the presence of 1 equiv of NaOAc, the
reaction was cleaner without it. Conducting the reaction in pres-
ence of NaH in THF or K2CO3 in CH3COCH3 or NaOMe in MeOH
lowered the yield of 6a. In all the cases, however, there was no trace
of para-substitution product 7. The assigned structure 6a was
established by analysis of 1H and 13C NMR spectra. The 1H NMR
OMe
Br
OMe
CN
SMe
S
3
4
spectrum displayed a characteristic singlet for C4-H at
d 5.4 ppm. In
N
O2
N
2
O2
Me
addition there was a doublet at 6.8 ppm for 1Hdrather than for
d
N
O
NH2
1
2Hdassignable to aromatic hydrogen next to phenolic hydroxyl
group, which indicated that substitution had taken place on C20
carbon ortho to phenolic hydroxyl. In the 13C NMR spectrum six
signals for the aromatic ring with phenolic hydroxyl group were
discernable. This data also confirmed the substitution taking place
at C2 rather than C4 of phenol 4a. The 13C NMR spectrum exhibited
a quaternary carbon at 124.7 ppm. In comparison, the C2 quater-
nary carbon in 2-methylphenol occurs at 124.0 ppm. Further un-
equivocal confirmation of the structure came from single crystal X-
ray structure determination of the acetyl derivative of 4H-chro-
mene 6a (Fig. 1; see Experimental section).5
O
O
Me
NHMe
NHMe
1
2
3
Fig. 1. 4H-Chromenes 1e3.
To test generality of above transformation, we subjected three
phenols 4aec to reaction with four N-substituted 3-nitro-4H-
chromenes 2aed to furnish 4-(2-hydroxyaryl)-4H-chromenes 6ael
(Scheme 1 and Table 1). In each case, a single C20 substituted
regioisomer of 6 was obtained exclusively. We have, thus, prepared
a combinatorial library of 12 4-aryl-3-nitro-4H-chromenes 6ael
without any event. Electron donating (C4-Me, 4b) or electron
withdrawing (C4-Cl, 4c) groups on phenol 4 did not affect outcome
of the reaction in a perceptible manner. Other than three phenols
4aec, we subjected ortho-cresol 4d and meta-cresol 4e to reaction
Exclusive formation of 6a can be traced to hydrogen bonding in-
teraction of phenolic hydroxyl in 4a with the nitro group in 2a, which
directs the substitutiontotakeplace atC2position. Substitutionon 2a
did not take place with anisole or with catechol dimethyl ether

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H. Surya Prakash Rao et al. / Tetrahedron 67 (2011) 8146e8154
Table 1
Combinatorial library of 4-aryl-3-nitro-4H-chromenes 6aen prepared from 4-methylsulfanyl-4H-chromenes 2aed and phenols 4aee
with the parent 3-nitro-4H-chromenes 2a to yield two isomeric 4-
aryl-3-nitro-4H-chromenes 6men in good yield.
HMBC correlations between C4-H and quaternary C20 carbon, that
is, the carbon next to aryl OH. It is interesting to note the regio-
chemical outcome of the reaction of 2a with 1-naphthol 4f. Aro-
matic electrophilic substitution on 1-naphthol 4f takes place both
at C2 and C4, generally yielding a mixture of products.6 Isolation of
a single regioisomer 6o, however, shows that the substitution is
highly influenced by hydrogen bonding interaction of phenolic OH
in 4f with NO2 in 2a.
After demonstrating facile aromatic substitution of phenols in
their reaction with 4H-chromenes 2 to provide 4-aryl-4H-chro-
menes 6, we turned our attention toward the synthesis of bis-
chromenes by reaction of 2a with 1,2-, 1,3- and 1,4-
dihydroxybenzenes 8aec. The reaction of parent 4H-chromene 2a
(2.0 equiv), 1,2-dihydroxybenzene (catechol, 1.0 equiv) provided
two products (Scheme 4). A major product (30%; higher Rf value in
Interestingly, some of the phenol substituted 4H-chromenes
e.g., 6c and 6m exhibit atropisomerism due to restricted rotation
around C4eC20 single bond possibly due to strong hydrogen
bonding stabilization between the hydroxyl and the nitro group of
the chromene moiety. The operation of atropisomerism was evi-
denced by observation of two sets of equal intensity peaks in 1H
and 13C spectra of 4H-chromenes.
Parent 4H-chromene 2a was subjected to substitution of C4-
SMe with 1-naphthol 4f, 2-naphthol 4g, and 8-hydroxyquinoline
4h in ethanol reflux to furnish 4-aryl-3-nitro-4H-chromenes
6oeq, respectively, in very good yields (Scheme 3). In each case,
only one regioselective C20-substitution product was formed. The
structure of 4-aryl-3-nitro-4H-chromenes 6oeq was confirmed by

H. Surya Prakash Rao et al. / Tetrahedron 67 (2011) 8146e8154
8149
OH
N
OH
N
SMe
4h
4g
OH
NO2
NO2
OH
NO2
EtOH, reflux
12 h, 92%
EtOH, reflux
12 h, 89%
O
NHMe
O
NHMe
OH 2a
O
NHMe
6p
EtOH, reflux
8 h, 74%
6q
4f
OH
NO2
O
NHMe
6o
Scheme 3. Substitution of C4-SMe in 2a with 1-napthol 4f, 2-naphthol 4g and 8-hydroxyquinoline 4h to furnish 4-ayl-4H-chromenes 6oeq.
silica gel TLC) is the mono-substitution product 6r and the minor
OH
(25%) being bis-chromene 6s. Formation of bis-chromene 6s was
confirmed on the basis of ESI-MS, which exhibited anticipated MþH
signal at 519.1526. The 1H and 13C NMR spectra of 6s matched well
with 4-aryl-4H-chromene 6r. Several attempts to increase yields of
bis-chromene by changing reaction conditions like use of excess
4H-chromene 2a or higher boiling solvents like isopropanol or
using NaOAc did not help.
NHMe
NO2
O
O
OH
HO
OH
SMe
O
9
NHMe
NO2
N
O2
HO
OH
NaOAc
EtOH reflux
NHMe
N
O2
MeHN
O
2a
6v
NHM
e
O
Scheme 6. Anticipated reaction of 1,3,5-trihydroxybenzene 9 with 2a.
H
O
N
O
O2
H
H
H
O
SMe
OH
Attempted substation of C4-SMe in 2a with marginally elec-
tron rich aromatic compounds like anisole, 1,3-dimethoxy ben-
zene and o, p-directing chlorobenzene also did not provide
substitution products, indicating that electron rich nature of ar-
omatic ring and the hydrogen bonding interaction of OH with
nitro group are required for the aromatic electrophilic sub-
stitution reaction.
8a
NO2
O
H
O2
O
N
+
NO2
EtOH reflux, 7 h
NHM
O
e
NHMe
O
NHMe
)
O
)
2a
6r (31%
6s (25
%
Scheme 4. Reaction of 1,2-dihydroxybenzene 8a with 2a to provide 6r and 6s.
Reaction of 1,3-dihydroxybenzene (resorcinol), 1,4-dihydroxy-
benzene (quinol) in presence or absence of NaOAc provided only
a mono-substitution product 6t and 6u, respectively (Scheme 5).
Even though TLC and 13C NMR spectrum of the crude product
indicated presence of bis-chromenes in minor quantities (less
than 3%) they could not be purified and characterized.
2.1. Synthesis of non-natural hybrid amino acid 11
The 4H-chromene like 6a has all the structural features of
a masked amino acid. Reduction of the nitro group in 6a to primary
amine and hydrolysis of the enamine should reveal the amino acid
having structural features of ortho-tyrosine lactone. ortho-Tyrosine
H
O
H
O
H
O
H
O
H
O
SMe
O
H
O
8b
8c
N
H
O2
O2
O
N
H
O2
O
N
NaOAc
NaOAc
EtOH reflux,
4 h, 81%
EtOH reflux,
7 h, 74%
NHMe
O
NHMe
O
6t
NHMe
2a
6u
Scheme 5. Synthesis of 4-aryl-4H-chromenes 6res by the reaction of 2a with 1,3-dihydroxybenzene 8b and 1,4-dihydroxybenzene 8c.
The reaction of 4H-chromene 2a with 1,3,5-trihydroxybenzene
(phloroglucinol) 9 did not yield desirable tris-4-aryl-4H-chro-
mene 6v (Scheme 6) but provided unintractable products in EtOH
reflux with or without NaOAc.
lactone and other such non-essential amino acids possess enormous
potential to be used as therapeutic agents.7 As an example, levels of
ortho-tyrosine lactone can indicate onset of diabetes or some dis-
eases due to malfunctioning of kidneys.8 Reduction of the nitro

8150
H. Surya Prakash Rao et al. / Tetrahedron 67 (2011) 8146e8154
group to amino with concomitant hydrolysis of the enamine in 6a
should deliver hybrid amino acid incorporating two units of ortho-
tyrosine. After unsuccessfully screening several reducing agents like
H2/Pd/C, H2/Pt, LiAlH4, NaBH4/NiCl2 all of which have been used for
reduction of the nitro group, we were gratified to find that Zn/AcOH
delivered enamine 10 in good yield (Scheme 7). However, reduction
with Zn/AcOH/Ac2O system provided required protected hybrid
amino-acid lactone 11 in good yield (Scheme 7).9 From 13C NMR
spectrum we concluded both cis- and trans-isomers were formed in
about 6:5 ratio. Interestingly, the cis-isomer 11 crystallized out
during fractional crystallization and its structure was confirmed by
single crystal X-ray analysis (Fig. 2; see Experimental section).
(SRL, India) or silica gel GF-254 (E-Merck) using hexanes/ethyl ac-
etate as eluent and the spots were visualized by short exposure to
iodine vapor or UV light. Column chromatography was carried on
silica gel (100e200 mesh, Acme Synthetic Chemicals, India) using
increasing percentage of ethyl acetate in hexanes. Melting points
were recorded using Gallenkamp melting point apparatus and
were uncorrected. IR spectra were recorded as KBr pellets using
Bomem MB104 spectrometer. UV spectra were recorded using
Hitachi ratio-beam spectrometer. The 1H NMR (500 MHz, 400 MHz,
300 MHz) and 13C NMR (100 MHz or 75 MHz) and DEPT spectra
were recorded in CDCl3, DMSO-d6 or CDCl3/DMSO-d6 (1:1) with
Bruker 400 MHz, Bruker 300 MHz, JEOL 400 MHz with TMS (0 ppm)
Zn, Ac2O
AcOH
110 oC, 1 h
62%
Zn, AcOH
110 oC, 1 h
40%
OH
NH2
H
O2
H
O
NHAc
O
N
NHMe
O
10
O
O
6a
O
11
O
Scheme 7. Conversion of 6a into hybrid amino-acid lactones 10 and 11.
as internal standard. Mass spectra (HRMS) were recorded on HP
MS-engine S989A (EI¼Electron Impact, 70eV). Elemental analysis
was carried out in NCL, Pune, India on a PerkineElmer 2400 Series II
CHNS/O Elemental Analyzer.
4.2. Representative procedure for preparation of 4-(2-
hydroxyaryl)-4H-chromenes. 2-[2-(methylamino)-3-nitro-4H-
4-chromenyl]phenol 6a
A solution of 4H-chromene 2a (0.5 g, 2.0 mmol) and phenol 4a
(0.56 g, 5.9 mmol) in ethanol (15 mL) was heated to reflux for 12 h by
which time the reaction was completed (TLC). The reaction mixture
was cooled to room temperature and kept aside for 3 h. The com-
pound that crystallized out was separated by filtration with the help
of cold ethanol (5 mL) to yield title compound 6a (0.52 g, 88%) as
a colorless solid; mp >220 ꢀC (EtOH); Rf (60% hexanes/EtOAc) 0.4; UV
(MeOH) lmax 349 nm(log
3
¼3.9), 277 nm(log
3
¼3.5); nmax 3184,1644,
1600,1469,1349,1249,1062, 755, 704 cmꢁ1
;
dH (300 MHz, DMSO-d6)
10.46 (br q, J¼5.1 Hz,1H), 9.5 (s,1H), 7.3e7.0 (m, 5H), 6.69 (t, J¼7.2 Hz,
2H), 5.51 (s, 1H), 3.16 (d, J¼5.1 Hz, 3H); dC (75 MHz, DMSO-d6) 159.5
(C), 154.5 (C), 147.4 (C), 130.2 (C), 129.1 (CH), 129.0 (CH), 127.9 (CH),
127.7 (CH), 125.2 (CH), 124.7 (C), 118.8 (CH), 115.8 (CH), 115.6 (CH),
106.8 (C), 37.1 (CH), 28.0 (NHMe). Anal. Calcd for C16H14N2O4: C,
64.42; H, 4.73; N, 9.30; Found: C, 64.48; H, 4.84; N, 9.38.
Fig. 2. The single crystal X-ray structure of 2-[2-(methylamino)-3-nitro-4H-4-
chromenyl]phenyl acetate. (deposited with CCDC; deposition No. 647163).
3. Conclusion
4.2.1. 2-[2-(Methylamino)-3-nitro-4H-4-chromenyl]phenyl
aceta-
te. To a well stirred mixture of 2-[2-(methylamino)-3-nitro-4H-4-
chromenyl]phenol 6a (0.5 g, 1.7 mmol) and Ac2O (0.53 g, 0.5 mL,
5.2 mmol), pyridine (0.16 g, 0.02 mL, 0.2 mmol) was added at room
temperature. The reaction mixture was stirred thoroughly for 16 h.
Excess pyridine was quenched with 0.01N HCl (6 mL) and then
extracted with dichloromethane (DCM; 30 mL). Separated organic
layer was washed with water and brine solution. Evaporation of
DCM afforded 2-[2-(methylamino)-3-nitro-4H-4-chromenyl]phe-
nyl acetate (57%) as a pale yellow solid. Single crystals were grown
by slow evaporation of 20% DCM in hexanes; mp >200 ꢀC (EtOH); Rf
In conclusion, we have reported a facile synthesis of 4-(2-
hydroxyaryl)-3-nitro-4H-chromenes
6 from by C4-SMe sub-
stitution in 4H-chromene 2. This effort leads to a combinatorial
library of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes with structural
variations in phenol and N-alkyl groups. Reduction of the nitro
group in 4-aryl-2-alkylamino-3-nitro-4H-chromene 6a with Zn/
AcOH favored the formation of enamine 10. On the other hand, its
reduction with Zn/Ac2O/AcOH provided hybrid amino-acid lactone
11 incorporating phenyl alanine and ortho-tyrosine units.
(80% hexanes/EtOAc) 0.6; UV (MeOH) lmax 351 nm (log
261 nm (log ¼4.7); nmax 3202, 3059, 1767,
¼4.5), 229 nm (log
1648, 1609, 1478, 1402, 1368, 1211, 1059, 758 cmꢁ1
dH (300 MHz,
CDCl3/DMSO-d6) 10.50 (br s, 1H), 7.45e6.80 (m, 8H), 5.53 (s, 1H),
3.27 (d, J¼5.1 Hz, 3H), 2.48 (s, 3H); dC (75 MHz, CDCl3/DMSO-d6)
168.1 (C), 158.6 (C), 147.8 (C), 146.7 (C), 134.1 (C), 130.4 (CH), 129.2
(CH), 127.9 (CH), 127.4 (CH), 125.4 (CH), 125.2 (CH), 123.0 (CH), 122.7
3
¼4.8),
4. Experimental section
4.1. General
3
3
;
All reagents and solvents were purchased from SigmaeAldrich,
E-Merck or SRL, India. The TLC was performed with silica gel-G

H. Surya Prakash Rao et al. / Tetrahedron 67 (2011) 8146e8154
8151
(C), 115.3 (CH), 107.2 (CH), 37.4 (CH), 27.4 (Me), 20.4 (CH3). Anal.
Calcd for C18H16N2O5: C, 63.52; H, 4.74; N, 8.23. Found: C, 63.48; H,
4.82; N, 8.19.
(C), 130.0 and 129.8 (C), 129.4 and 129.0 (CH), 128.4 and 128.1 (CH),
127.9 and 127.7 (CH), 127.7 and 127.1 (CH), 125.2 (CH), 124.7 and
124.3 (C), 118.7 (CH), 115.7 and 115.5 (CH), 106.9 and 106.8 (C), 40.5
(CH2NH), 37.4 and 37.2 (CH), 31.5 (CH2), 20.3 and 20.2 (CH3), 19.4
(CH2), 13.6 (CH3). Anal. Calcd for C20H22N2O4: C, 67.78; H, 6.26; N,
7.90. Found: C, 67.71; H, 6.34; N, 7.82.
4.2.2. 4-Methyl-2-[2-(methylamino)-3-nitro-4H-4-chromenyl]phe-
nol 6b. Following the representative procedure described pre-
viously for preparation of 6a, a solution of 4H-chromene 2a (0.5 g,
2.0 mmol) and p-cresol 4b (0.64 g, 5.9 mmol) in EtOH (10 mL) reflux
for 19 h provided title compound 6b (0.45 g, 73%) as yellow color
crystals; mp >200 ꢀC (EtOH); Rf (50% hexanes/EtOAc) 0.5; UV
4.2.6. 2-[2-(Butylamino)-3-nitro-4H-4-chromenyl]-4-chlorophenol
6f. Following the representative procedure described previously
for preparation of 6a, a solution of 4H-chromene 2b (0.5 g,
5.1 mmol) and 4-chlorophenol 4c (0.66 g, 3.4 mmol) in EtOH
(10 mL) reflux for 13 h furnished the title compound 6f (0.27 g, 43%)
as yellow color crystals; mp 200 ꢀC (EtOH); Rf (60% hexanes/EtOAc)
(MeOH) lmax 349 nm (log
3
¼4.1), 277 nm (log
3
¼3.6); nmax 3269,
1644, 1600, 1472, 1395, 1202, 1063, 812, 756, 701, 637 cmꢁ1
;
dH
(300 MHz, CDCl3/DMSO-d6) 10.5 (br s, 1H), 9.35 (s, 1H), 7.3e6.5 (m,
7H), 5.48 (s, 1H), 3.2 (d, J¼4.8 Hz, 3H), 2.19 (s, 3H); dC (75 MHz,
CDCl3 : DMSO-d6) 159.1 (C), 154.1 (C), 145.0 (C), 133.7 (C), 129.7
(CH), 128.6 (CH), 128.5 (CH), 127.7 (CH), 127.0 (CH), 123.9 (CH), 118.3
(CH), 115.2 (CH), 114.8 (CH), 106.7 (C), 36.7 (CH), 27.3 (NHMe), 19.9
(CH3). Anal. Calcd for C17H16N2O4: C, 65.38; H, 5.16; N, 8.97. Found:
C, 65.33; H, 5.18; N, 8.88.
0.5; UV (MeOH) lmax 349 nm (log
3177, 1636, 1609, 1479, 1422, 1345, 1250, 1210, 1168, 1068, 828, 756,
668 cmꢁ1
dH (300 MHz, DMSO-d6) 10.62 (br s,1H), 9.80 and 9.56 (s,
3 ¼3.6), 282 nm (log
3 ¼3.1); nmax
;
1H), 7.3e7.0 (m, 6H), 6.68 (br d, J¼8.4 Hz, 1H), 5.47 and 5.45 (s, 1H),
3.61 (br q, J¼7.0 Hz, 2H), 1.66 (pentet, J¼7.2 Hz, 2H), 1.35 (septet,
J¼7.2 Hz, 2H), 0.94 (t, J¼7.2 Hz, 3H); dC (75 MHz, DMSO-d6) 159.0
(C), 153.7 (C), 147.5 (C), 131.9 (C), 129.0 (CH), 129.0 (CH), 128.2 (CH),
127.4 (CH), 125.2 (CH), 123.6 (C), 122.1 (C), 117.2 (CH), 115.7 (CH),
106.2 (C), 40.7 (CH2), 37.6 (CH), 31.5 (CH2), 19.4 (CH2), 13.5 (CH3).
Anal. Calcd for C19H19ClN2O4: C, 60.88; H, 5.11; N, 7.47. Found: C,
60.93; H, 5.05; N, 7.42.
4.2.3. 4-Chloro-2-[2-(methylamino)-3-nitro-4H-4-chromenyl]phenol
6c. Following the representative procedure described previously
for preparation of 6a, a solution of 4H-chromene 2a (0.5 g,
1.9 mmol) and 4-chlorophenol 4c (0.76 g, 5.9 mmol) in EtOH
(10 mL) reflux for 29 h provided title compound 6c (0.33 g, 51%) as
yellow color crystals; mp 204e206 ꢀC (EtOH); Rf (40% hexanes/
4.2.7. 2-(2-Anilino-3-nitro-4H-4-chromenyl)phenol 6g. Following
the representative procedure described previously for preparation
of 6a, a solution of 4H-chromene 2c (0.5 g, 1.6 mmol) and phenol 4a
(0.449 g, 4.8 mmol) in EtOH (10 mL) reflux for 14 h provided the
title compound 6g (0.26 g, 45%) as a yellow color solid; mp >200 ꢀC
(EtOH); Rf (60% hexanes/EtOAc) 0.5; UV (MeOH) lmax 347 nm
EtOAc) 0.5; UV (MeOH) lmax 350 nm (log
(log
¼3.4); nmax 3228,1734, 1646, 1601, 1476,1400,1337, 1231, 1061,
766, 655, 578 cmꢁ1
dH (300 MHz, CDCl3/DMSO-d6) 10.49 (br s, 1H),
3 ¼3.8), 282 nm
3
;
9.67 and 9.46 (s,1H), 7.3e6.68 (m, 7H), 5.53 and 5.49 (s,1H), 3.23 (d,
J¼2.1 Hz, 3H); dC (75 MHz, CDCl3/CCl4/DMSO-d6 6:3:1) 159.1 (C),
153.4 (C),147.3 (C),131.8 (C),128.8 (CH),128.4 (CH),127.7 (CH),127.0
(CH),124.9 (CH),123.7 (C),122.4 (C),117.0 (CH),115.4 (CH),106.3 (C),
37.0 (CH), 27.7 (NHMe). Anal. Calcd for C16H13ClN2O4: C, 57.75; H,
3.94; N, 8.42; Found: C, 57.69; H, 408; N, 8.34.
(log
3
¼3.0), 280 nm (log
3
¼3.5); nmax 3209, 1636, 1575, 1458, 1417,
1352, 1205, 1168, 1068, 749 cmꢁ1
;
dH (300 MHz, DMSO-d6) 12.12 (s,
1H), 9.57 (s, 1H), 7.59e6.97 (m, 11H), 6.67 (br d, J¼7.2 Hz, 2H), 5.58
(s, 1H); dC (75 MHz, DMSO-d6) 156.9 (C), 154.7 (C), 147.3 (C), 135.3
(C), 129.6 (C), 129.5 (CH), 129.2 (2ꢂ CH), 129.1 (2ꢂ CH), 128.0 (CH),
127.9 (CH), 126.2 (CH), 124.5 (CH), 124.4 (C), 123.8 (2ꢂ CH), 118.8
(CH), 115.7 (CH), 108.2 (C), 37.4 (CH). Anal. Calcd for C21H16N2O4: C,
69.99; H, 4.48; N, 7.77. Found: C, 69.89; H, 4.52; N, 7.84.
4.2.4. 2-[2-(Butylamino)-3-nitro-4H-4-chromenyl]phenol 6d. Follo-
wing the representative procedure described previously for prep-
aration of 6a, a solution of 4H-chromene 2b (0.5 g, 1.7 mmol) and
phenol 4a (0.480 g, 5.1 mmol) in EtOH (10 mL) reflux for 12 h
provided title compound 6d (0.36 g, 63%) as yellow color crystals
after recrystallization; mp 200 ꢀC (EtOH); Rf (60% hexanes/EtOAc)
4.2.8. 2-(2-Anilino-3-nitro-4H-4-chromenyl)-4-methylphenol 6h.
Following the representative procedure described previously for
preparation of 6a, a solution of 4H-chromene 2c (0.5 g, 1.6 mmol)
and p-cresol 4b (0.52 g, 4.8 mmol) in EtOH (10 mL) reflux for 14 h
provided the title compound 6h (0.38 g, 64%) as yellow color
crystals; mp 202e204 ꢀC (EtOH); Rf (60% hexanes/EtOAc) 0.6; UV
0.5; UV (MeOH) lmax 351 nm (log
3
¼4.3), 275 nm (log
3
¼4.0); nmax
3460, 2955, 1637, 1600, 1458, 1417, 1350, 1248, 1065, 755 cmꢁ1
;
dH
(300 MHz, CDCl3) 10.79 (br s, 1H), 7.64 (s, 1H), 7.29e6.67 (m, 8H),
5.77 (s, 1H), 3.6 (m, 2H), 1.7 (pentet, J¼7.2 Hz, 2H), 0.99 (t, J¼7.2 Hz,
3H); dC (75 MHz, CDCl3) 159.9 (C), 153.6 (C), 148.3 (C), 130.2 (C),
129.9 (CH), 129.2 (CH), 128.5 (CH), 128.4 (CH), 126.4 (CH), 125.0 (C),
121.2 (CH), 118.1 (CH), 115.7 (CH), 106.8 (C), 41.5 (CH2), 35.5
(CH2NH), 31.5 (CH2), 20.0 (CH2), 13.6 (CH3). Anal. Calcd for
C19H20N2O4: C, 67.05; H, 5.92; N, 8.23. Found: C, 67.05; H, 6.02; N,
8.20.
(MeOH) lmax 367 nm (log
3
¼3.7), 261 nm (log
3
¼3.3); nmax 3492,
1635, 1581, 1461, 1362, 1212, 1149, 1065, 742 cmꢁ1
;
dH (300 MHz,
DMSO-d6) 12.16 (s, 1H), 9.57 and 9.34 (s, 1H), 7.5e6.6 (m, 12H), 5.53
and 5.51 (s, 1H), 2.16 (s, 3H); dC (75 MHz, DMSO-d6) 157.0 and 156.9
(C), 154.7 and 152.4 (C), 147.2 and 145.4 (C), 135.3 and 134.6 (C),
129.8 and 129.6 (CH),129.2 (2ꢂ CH),129.1 and 129.0 (CH),128.6 and
128.3 (CH), 128.0 (CH), 127.2 (C), 126.2 and 125.5 (CH), 124.4 (C),
124.0 (C), 123.7 (CH) 118.9 (CH), 115.7 (2ꢂ CH), 115.6 and 115.4 (CH),
108.3 (C), 37.6 and 37.4 (CH), 20.3 and 20.2 (CH3). Anal. Calcd for
C22H18N2O4: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.52; H, 4.71; N,
7.37.
4.2.5. 2-[2-(Butylamino)-3-nitro-4H-4-chromenyl]-4-methylphenol
6e. Following the representative procedure described previously
for preparation of 6a, a solution of 4H-chromene 2b (0.5 g,
1.7 mmol) and p-cresol 4b (0.55 g, 5.1 mmol) in EtOH (10 mL) reflux
for 12 h provided title compound 6e (0.44 g, 73%) as yellow color
crystals; mp 158 ꢀC (EtOH); Rf (50% hexanes/EtOAc) 0.5; UV
4.2.9. 2-(2-Anilino-3-nitro-4H-4-chromenyl)-4-chlorophenol 6i. Fo-
llowing the representative procedure described previously for
preparation of 6a, a solution of 4H-chromene 2c (0.5 g, 1.6 mmol)
and 4-chlorophenol 4c (0.61 g, 4.8 mmol) in EtOH (10 mL) reflux for
16 h provided the title compound 6i (0.25 g, 40%) as yellow color
crystals; mp >200 ꢀC (EtOH); Rf (60% hexanes/EtOAc) 0.6; UV
(MeOH): lmax 351 nm (log
3190, 2957, 2866,1636,1502,1456,1370,1249,1212,1162,1065, 941,
817, 755, 704 cmꢁ1
dH (300 MHz, DMSO-d6) 10.6 (s, 1H) 9.45 and
3 ¼4.1), 277 nm (log
3 ¼3.9); nmax 3473,
;
9.24 (s, 1H), 7.3e6.5 (m, 7H), 5.46e5.43 (s, 1H), 3.61 (br t, J¼7.5 Hz,
2H), 2.17 and 2.13 (s, 3H), 1.65 (br pentet, J¼7.5 Hz, 2H), 1.38 (br
sextet, J¼7.5 Hz, 2H), 0.94 (t, J¼7.5 Hz, 3H); dC (75 MHz, DMSO-d6)
159.2 and 159.1 (C), 154.6 and 152.3 (C), 147.4 and 145.5 (C), 134.3
(MeOH) lmax 318 nm (log
3
¼4.2), 240 nm (log
3
¼4.0); nmax 3209,
1635, 1579, 1483, 1417, 1347, 1161, 1068, 824, 755, 686 cmꢁ1
;
dH

8152
H. Surya Prakash Rao et al. / Tetrahedron 67 (2011) 8146e8154
(300 MHz, CDCl3/DMSO-d6 9:1) 12.3 (br s, 1H) 9.69 (br s, 1H),
7.9e6.7 (m, 12H), 5.56 (s, 1H); dC (75 MHz, CDCl3 : DMSO-d6 5:1)
156.6 (C), 153.3 (C), 147.1 (C), 134.8 (C), 130.9 (C), 128.9 (2ꢂ CH),
127.7 (CH),127.2 (CH),125.9 (CH), 125.2 (CH),123.2 (CH),123.0 (CH),
122.9 (C), 122.5 (C), 116.9 (CH), 115.2 (CH), 107.7 (C), 37.4 (CH). Anal.
Calcd for C21H15ClN2O4: C, 57.75; H, 3.94; N, 8.42. Found: C, 57.821;
H, 3.87; N, 8.39.
color crystals; mp >200 ꢀC (EtOH); Rf (50% hexanes/EtOAc) 0.5; UV
(MeOH) lmax 351 nm (log ¼4.2); nmax 3266,
¼4.5), 273 nm (log
1647, 1619, 1469, 1400, 1362, 1250, 1168, 1056, 943, 755 cmꢁ1
dH
(400 MHz, DMSO-d6) 10.46 (s,1H), 9.46 and 9.37 (s, 1H), 7.2e6.9 (m,
5H), 6.68 and 6.49 (s, 1H), 5.46 (s, 1H), 3.17 (s, 3H), 2.25 and 2.12 (s,
3H); dC (100 MHz, DMSO-d) 159.4, 159.3 (C), 154.4, 154.2 (C), 147.3,
147.1 (C), 137.6, 136.8 (C), 130.3, 128.9 (CH), 128.8, 128.5 (CH), 127.7,
127.5 (CH), 127.3, 125.9 (CH), 125.0, 124.8 (CH), 121.6, 119.3 (C), 118.7,
116.1 (C), 115.8, 115.6(CH), 115.5 (CH), 106.9 (C), 36.7 (CH), 27.8
(NHMe), 20.6, 20.3 (CH3). Anal. Calcd for C17H16N2O4: C, 65.36; H,
5.16; N, 8.97. Found: C, 65.28; H, 5.22; N, 9.07.
3
3
;
4.2.10. 2-[2-(Benzylamino)-3-nitro-4H-4-chromenyl]phenol 6j. Fol-
lowing the representative procedure described previously for
preparation of 6a, a solution of 4H-chromene 2d (0.5 g, 1.5 mmol)
and phenol 4a (0.43 g, 4.6 mmol) in EtOH (10 mL) reflux for 12 h
provided the title compound 6j (0.5 g, 87%) as a yellow color solid;
mp >200 ꢀC (EtOH); Rf (50% hexanes/EtOAc) 0.5; UV (MeOH) lmax
4.2.14. 2-Methyl-6-[2-(methylamino)-3-nitro-4H-4-chromenyl]phe-
nol 6n. Following the representative procedure described pre-
viously for preparation of 6a, a solution of 4H-chromene 2a (0.5 g,
2.0 mmol) and o-cresol 4e (0.64 g, 5.9 mmol) in EtOH (10 mL) reflux
for 16 h provided the title compound 6n (0.54 g, 88%) as yellow
color crystals; mp >200 ꢀC (EtOH); Rf (50% hexanes/EtOAc) 0.5; UV
303 nm (log
3
¼4.6), 230 nm (log
3
¼4.3); nmax 3569, 3215,1634,1601,
1471, 1368, 1212, 1168, 1056, 756, 698, 623 cmꢁ1
;
dH (300 MHz,
DMSO-d6) 10.94 and 10.82 (s, 1H), 9.55 and 9.32 (s, 1H), 7.5e6.9 (m,
11H), 6.72 (t, J¼5.2 Hz, 1H), 6.65 (d, J¼9.0 Hz, 1H), 5.49 and 5.28 (s,
1H), 4.82 (br s, 2H); dC (75 MHz, DMSO6) 158.9 and 158.5 (C), 156.2
and 154.6 (C),147.4 (C),134.8 and 138.1 (C),130.0 (C),129.2 and 129.1
(CH), 128.9 (CH), 128.7 (2ꢂ CH), 128.1 (CH), 127.9 and 127.8 (CH),
127.6 (2ꢂ CH),127.4 (CH),125.7 and 125.2 (CH),124.7 (C),118.8 (CH),
116.0 and 115.7 (CH), 115.6 and 115.2 (CH), 108.2 and 107.1 (C), 44.7
and 44.6 (CH2), 37.2 (CH). Anal. Calcd for C22H18N2O4: C, 70.58; H,
4.85; N, 7.48. Found: C, 70.62; H, 4.77; N, 7.55.
(MeOH) lmax 350 nm (log
3
¼5.9), 273 nm (log
3
¼4.0); nmax 3472,
1645, 1614, 1460, 1369, 1268, 1187, 1087, 1031, 786, 586 cmꢁ1
;
dH
(400 MHz, DMSO-d6) 10.42 (br s, 1H), 9.5 (s, 1H), 7.16e7.10 (m, 3H),
6.97 (m, 2H), 6.70e6.68 (m, 2H), 5.53 (s, 1H) 3.20 (s, 3H) 2.33 (s,
3H); dC (100 MHz, DMSO-d6) 159.3 (C), 154.4 (C), 145.8 (C), 130.4 (C),
129.0 (CH), 128.8 (CH), 127.5 (CH), 126.4 (CH), 124.8 (CH), 124.6
(CH), 124.5 (CH), 118.8 (CH), 115.5 (CH), 106.9 (C), 36.9 (CH), 28.0
(NHMe), 15.4 (CH3). Anal. Calcd for C17H16N2O4: C, 65.36; H, 5.16; N,
8.97. Found: C, 65.41; H, 5.06; N, 9.02.
4.2.11. 2-[2-(Benzylamino)-3-nitro-4H-4-chromenyl]-4-methylphe-
nol 6k. Following the representative procedure described pre-
viously for preparation of 6a, a solution of 4H-chromene 2d (0.5 g,
1.5 mmol) and p-cresol 4b (0.49 g, 4.6 mmol) in EtOH (10 mL) reflux
for 16 h provided the title compound 6k (0.27 g, 46%) as yellow color
crystals; mp 126 ꢀC (EtOH); Rf (50% hexanes/EtOAc) 0.5; UV (MeOH)
4.2.15. 2-[2-(Methylamino)-3-nitro-4H-4-chromenyl]-1-naphthol
6o. Following the representative procedure described previously
for preparation of 6a, a solution of 4H-chromene 2a (0.5 g,
2.0 mmol) and 1-naphthol 4f (0.86 g, 6.0 mmol) in EtOH (10 mL) on
8 h reflux provided the title compound 6o (0.51 g, 74%) as a yellow
color solid after recrystallization; mp >200 ꢀC (EtOH); Rf (50%
lmax 351 nm (log
3
¼3.7), 276 nm (log
3
¼3.2); nmax 3592, 3178, 1631,
1606, 1462, 1370, 1205,1063, 805, 753, 692, 521 cmꢁ1
;
dH (300 MHz,
DMSO-d6) 10.91 (br s,1H), 9.49 and 9.29 (s, 1H), 7.45e6.59 (m,12H),
5.46 and 5.0 (s, 1H), 4.81 and 4.79 (br s, 2H), 2.14 and 2.10 (s, 3H); dC
(75 MHz, DMSO-d6) 159.0 (C), 154.6 and 152.2 (C), 147.3 and 145.4
(C), 138.2 (C), 134.4 (C) 130.0 and 129.9 (CH), 129.1 (CH), 128.6 (2ꢂ
CH), 128.4 and 128.1 (CH), 127.9 and 127.7 (CH), 127.6 and 127.4 (2ꢂ
CH), 127.1 (CH), 125.3 (CH), 124.9 (C), 124.3 (C), 118.8 and 115.7 (CH),
115.6 and 115.4 (CH), 107.2 and 107.1 (C), 44.5 (CH2), 37.2 and 36.8
(CH), 20.3 and 20.2 (CH3). Anal. Calcd for C23H20N2O4: C, 71.12; H,
5.19; N, 7.21. Found: C, 71.02; H, 5.11; N, 7.17.
hexanes/EtOAc) 0.4; UV (MeOH) lmax 352 nm (log
(log ¼4.0); nmax 3178, 1628, 1456, 1381, 1262,
¼3.2), 227 nm (log
1174, 1093, 1018, 955, 750, 692 cmꢁ1
dH (300 MHz, DMSO-d6) 10.53
3
¼3.5), 279 nm
3
3
;
(br q, J¼4.8 Hz, 1H), 9.5 (s, 1H), 8.2 (d, J¼8.1 Hz, 1H), 7.89 (d,
J¼7.8 Hz,1H), 7.7e7.5 (m, 2H), 7.4e7.2 (m, 2H), 6.96 (t, J¼7.5 Hz,1H),
6.7e6.6 (m, 2H), 5.61 (s, 1H), 3.35 (d, J¼4.8 Hz, 3H); dC (75 MHz,
DMSO-d6) 159.2 (C), 154.7 (C), 141.6 (C), 132.6 (C), 129.9 (C), 129.5
(CH), 127.8 (2ꢂ CH), 127.0 (CH), 126.7 (CH), 125.9 (CH), 124.6 (CH),
122.4 (C), 120.4 (CH), 119.6 (C), 118.9 (CH), 115.6 (CH), 107.0 (C), 37.6
(CH), 28.2 (Me). Anal. Calcd for C20H16N2O4: C, 68.96; H, 4.63; N,
8.04. Found: C, 68.84; H, 4.71; N, 7.97.
4.2.12. 2-[2-(Benzylamino)-3-nitro-4H-4-chromenyl]-4-chlorophe-
nol 6l. Following the representative procedure described pre-
viously for preparation of 6a, a solution of 4H-chromene 2d (0.5 g,
1.5 mmol) and 4-chlorophenol 4c (0.59 g, 4.6 mmol) in EtOH
(10 mL) reflux for 22 h provided the title compound 6l (0.44 g, 70%)
as yellow color crystals; mp 190e192 ꢀC (EtOH); Rf (60% hexanes/
4.2.16. 1-[2-(Methylamino)-3-nitro-4H-4-chromenyl]-2-naphthol
6p. Following the representative procedure described previously
for preparation of 6a, a solution of 4H-chromene 2a (0.5 g,
2.0 mmol) and 2-naphthol 4g (0.86 g, 6.0 mmol) in EtOH (10 mL) on
12 h reflux provided the title compound 6p (0.61 g, 89%) as yellow
color crystals; mp >200 ꢀC (EtOH); Rf (50% hexanes/EtOAc) 0.4; UV
EtOAc) 0.5; UV (MeOH) lmax 303 nm (log
(log
¼4.2); nmax 3078, 1634, 1607, 1469, 1419, 1354, 1246, 1179,
1062, 819, 755, 686 cmꢁ1
dH (300 MHz, CDCl3/DMSO-d6) 10.9 (br s,
3 ¼4.5), 237 nm
3
;
(MeOH) lmax 354 nm (log
(log
¼4.1); nmax 3234, 1644, 1596, 1456, 1396, 1274, 1212, 1174,
1062, 817, 755, 695 cmꢁ1
dH (400 MHz, DMSO-d6) 10.39 (s, 1H),
3
¼3.9), 268 nm (log ¼3.2), 226 nm
3
1H), 9.62 and 9.42 (s,1H), 7.5e6.7 (m,12H), 5.55 and 5.2 (s,1H), 4.86
and 4.84 (s, 2H); dC (75 MHz, CDCl3/DMSO-d6 5:1) 158.7 (C), 153.3
(C), 147.2 (C), 137.3 (C), 131.4 (C), 128.8 (CH), 128.4 (2ꢂ CH), 127.7
(CH), 127.2 (3ꢂ CH), 127.1 (CH), 125.0 (CH), 123.6 (C), 122.5 (C), 118.7
(CH), 116.9 (CH), 115.6 and 115.3 (CH), 106.7 (C), 44.5 (CH), 37.1 (CH).
Anal. Calcd for C22H17ClN2O4: C, 64.63; H, 4.19; N, 6.85. Found: C,
64.54; H, 4.21; N, 6.87.
3
;
9.58 (s, 1H), 8.31e8.29 (m, 1H), 7.90e7.88 (m, 2H), 7.50e7.36 (m,
4H), 6.93 (m, 1H), 6.69e6.62 (m, 2H), 6.0 (s, 1H), 3.22 (s, 3H); dC
(100 MHz, DMSO-d6) 158.7 (C), 154.6 (C), 145.6 (C), 131.2 (CH), 130.8
(C), 130.3 (C), 128.9 (CH), 128.4 (CH), 128.2 (C), 127.6 (CH), 127.0
(CH), 125.0 (CH), 123.5 (CH), 118.5 (CH), 117.1 (C), 116.3 (CH), 115.7
(CH), 107.8 (C), 34.9 (CH), 27.9 (Me). Anal. Calcd for C20H16N2O4: C,
68.96; H, 4.63; N, 8.04. Found: C, 68.85; H, 4.75; N, 7.92.
4.2.13. 5-Methyl-2-[2-(methylamino)-3-nitro-4H-4-chromenyl]phe-
nol 6m. Following the representative procedure described pre-
viously for preparation of 6a, a solution of 4H-chromene 2a (0.5 g,
2.0 mmol) and m-cresol 4d (0.64 g, 5.9 mmol) in EtOH (10 mL)
reflux 16 h provided the title compound 6m (0.5 g, 80%) as yellow
4.2.17. 7-[2-(Methylamino)-3-nitro-4H-4-chromenyl]-8-quinolinol
6q. Following the representative procedure described previously
for preparation of 6a, a solution of 4H-chromene 2a (0.5 g,

H. Surya Prakash Rao et al. / Tetrahedron 67 (2011) 8146e8154
8153
2.0 mmol) and 8-quinolinol 4h (0.863 g, 5.9 mmol) in EtOH (10 mL)
on 12 h reflux provided the title compound 6q (0.638 g, 92%) as
yellow color crystals after recrystallization; mp >200 ꢀC (EtOH); Rf
2.0 mmol) and hydroquinone 8c (0.65 g, 5.9 mmol) in EtOH (10 mL)
on 7 h reflux provided the title compound 6u (0.46 g, 74%) as yellow
color crystals; mp >200 ꢀC (EtOH); Rf (50% hexanes/EtOAc) 0.4; UV
(70% hexanes/EtOAc) 0.4; UV (MeOH) lmax 347 nm (log
248 nm (log ¼4.0); nmax 3200,1638,1607,1463,
¼4.3), 210 nm (log
1400, 1356, 1212, 1168, 1062, 893, 824, 743, 680 cmꢁ1
dH (300 MHz,
3
¼3.9),
(MeOH) lmax 351 nm (log
(log
¼4.5); nmax 3522, 3159,1649,1612,1481,1312,1249,1193,1070,
816, 754, 703, 648 cmꢁ1
dH (400 MHz, CCl4/DMSO-d6) 10.44e10.40
3
¼4.5), 281 nm (log
3
¼4.2), 224 nm
3
3
3
;
;
DMSO-d6) 10.51 (br q, J¼5.1 Hz,1H), 9.90 (br s,1H), 8.25 (d, J¼6.9 Hz,
1H), 8.81 (d, J¼2.7 Hz, 1H), 7.5e7.0 (m, 7H), 5.86 (s, 1H), 3.28 (d,
J¼5.1 Hz, 3H); dC (75 MHz, DMSO-d6) 159.3 (C),149.6 (C),148.2 (CH),
147.2 (C), 138.3 (C), 135.9 (CH), 129.0 (CH), 128.1 (CH), 127.8 (CH),
127.4 (C),126.8 (C), 125.4 (CH),124.4 (C),121.5 (CH),117.2 (CH), 116.0
(CH), 106.6 (C), 36.7 (CH), 28.1 (Me). Anal. Calcd for C19H15N3O4: C,
65.32; H, 4.33; N, 12.03. Found: C, 65.27; H, 4.38; N, 12.12.
(m, 1H), 9.44 (s, 1H), 9.28 (s, 1H), 7.18e6.93 (m, 3H), 6.73e6.57 (m,
4H), 5.48 (s, 1H), 2.50e2.49 (m, 3H); dC (100 MHz, CCl4:DMSO-d6)
159.5 (C), 154.3 (C), 154.3 (C), 140.2 (C), 130.4 (C), 128.4 (CH), 127.3
(CH), 125.5 (C), 118.6 (CH), 116.3 (CH), 115.4 (CH), 114.5 (CH), 114.2
(CH), 106.8 (C), 36.7 (CH), 27.7 (Me). Anal. Calcd for C16H14N2O5: C,
61.14; H, 4.49; N, 8.91. Found: C, 61.05; H, 4.39; N, 9.01.
4.2.22. 3-Amino-4-(2-hydroxyphenyl)-2H-2-chromenone
10. A
4.2.18. 3-[2-(Methylamino)-3-nitro-4H-4-chromenyl]-1,2-benzenedi
ol 6r. Following the representative procedure described previously
for preparation of 6a, a solution of 4H-chromene 2a (0.5 g,
2.0 mmol) and pyrocatechol 8a (0.65 g, 5.9 mmol) in EtOH (10 mL)
on 7 h reflux provided the title compound 6r (0.192 g, 31%) as
yellow color crystals after recrystallization; mp >200 ꢀC (EtOH); Rf
mixture of 2-[2-(methylamino)-3-nitro-4H-4-chromenyl]phenol 6a
(0.5 g,1.7 mmol) and zinc powder (1.58 g, 0.017 mol) in AcOH (9.4 g,
9 mL) medium was heated at 110 ꢀC for 1 h by which time reduction
was complete (TLC). Filtration of undissolved solids and removal of
AcOH under reduced pressure followed bycolumn chromatographic
purification with EtOAc (20%e50%) in hexanes furnished the title
compound 10 (0.17 g, 40%) as an orange color solid; mp 170 ꢀC
(EtOH); Rf (50% hexanes/EtOAc) 0.6; UV (MeOH) lmax 326 nm
(50% hexanes/EtOAc) 0.4; UV (MeOH) lmax 352 nm (log
274 nm (log
¼3.6); nmax 3478, 1644, 1612, 1460, 1402, 1368, 1281,
1212, 1168, 1062, 761 cmꢁ1
dH (300 MHz, DMSO-d6) 10.46 (br s,
3
¼4.1),
3
;
(log
3
¼4.1), 284 nm (log
3
¼3.8), 243 nm (log
3
¼4.0); nmax 3415, 3334,
1H), 9.49 (s, 1H), 7.4e6.4 (m, 7H), 5.97 and 5.50 (s, 1H), 3.2 (s, 3H);
dC (75 MHz, DMSO-d6) 159.4 (C), 154.5 (C), 144.9 (C), 136.4 (C), 130.4
(C), 128.9 (CH), 127.5 (CH), 125.0 (CH), 126.0 (C), 118.8 (CH), 118.5
(CH), 115.6 (CH), 114.6 (CH), 106.9 (C), 37.1 (CH), 28.1 (Me). Anal.
Calcd for C16H14N2O5: C, 61.14; H, 4.49; N, 8.91. Found: C, 61.24; H,
4.53; N, 8.87.
1673,1600,1494,1451,1341,1283,1194,1112, 841, 759, 598 cmꢁ1
;
dH
(300 MHz, DMSO-d6) 9.53 (br s, 1H), 7.37e7.10 (m, 5H), 7.04 (d,
J¼8.1 Hz,1H), 6.97 (t, J¼7.5 Hz, 2H), 6.83 (d, J¼7.5 Hz,1H), 4.90(s, 2H);
dC (75 MHz, DMSO-d6) 158.6 (C),154.9 (C),147.6 (C),130.8 (CH),130.0
(C), 129.9 (CH), 125.8 (CH), 124.3 (CH), 123.9 (CH), 122.0 (CH), 119.8
(CH),119.2 (CH),117.6 (C), 116.5 (CH), 115.7 (CH); HRMS (ESIþ): calcd
for C15H11NO3 (MHþ), 254.0818, (MNaþ) 276.0637, (MKþ) 292.1722;
found, (MHþ), 254.0817, (MNaþ), 276.0639, (MKþ) 292.1720 (Fig. 3).
4.2.19. 3,6-Di[2-(methylamino)-3-nitro-4H-4-chromenyl]-1,2-
benzenediol 6s. Following the representative procedure described
previously for preparationof 6a, a solution of 4H-chromene 2a (0.5 g,
2.0 mmol) and pyrocatechol 8a (0.65 g, 5.9 mmol) in EtOH (10 mL) on
7 h reflux furnished the title compound 6s (0.26 g, 25%) as yellow
color crystals; mp >200 ꢀC (EtOH); Rf (50% hexanes/EtOAc) 0.2; UV
(MeOH) lmax 353 nm (log
3
¼4.0), 263 nm (log
3
¼3.5); nmax 3202,
1644, 1464, 1368, 1249, 1212, 1172, 1062, 755 cmꢁ1
;
dH (300 MHz,
DMSO-d6) 10.47 (br s, 1H), 9.43 (s, 1H), 9.34 9s, 1H0, 7.24e6.49 (m,
10H), 5.75, 5.52, and 5.43 (s, 2H), 3.23 and 3.18 (d, J¼5.1 Hz, 3H); dC
(DEPT-135, DMSO-d6) 129.1 (CH), 128.1 (CH), 127.5 (CH), 126.0 (CH),
125.3 (CH),118.6 (CH),115.6 (CH), 37.0 (CH), 28.0 (Me); HRMS (ESIþ):
calcd for C26H22N4O8 (MHþ), 519.1517; found, (MHþ), 519.1521. Anal.
Calcd for C26H22N4O8: C, 60.23; H, 4.28; N, 10.81. Found: C, 60.31; H,
4.17; N, 10.77.
4.2.20. 4-[2-(Methylamino)-3-nitro-4H-4-chromenyl]-1,3-
benzenediol 6t. Following the representative procedure described
previously for preparation of 6a, a solution of 4H-chromene 2a
(1.37 g, 5.4 mmol) and resorcinol 8b (0.3 g, 2.7 mmol) in the
presence of NaOAc (0.45 g, 5.4 mmol) using EtOH (10 mL) on 4 h
reflux provided the title compound 6t (0.231 g, 81%) as yellow color
crystals after recrystallization; mp >200 ꢀC (EtOH); Rf (50% hex-
Fig. 3. Single crystal XRD structure of N1-[4-(2-hydroxyphenyl)-2-oxo-3, 4-dihydro-
2H-3-chromenyl]acetamide 11 (deposited with CCDC; deposition No. 698176).
anes/EtOAc) 0.4; UV (MeOH) lmax 351 nm (log
(log
¼3.3); nmax 3272, 1646, 1475, 1375, 1237, 1055, 974, 866,
759 cmꢁ1
dH (500 MHz, DMSO-d6) 10.5 (br s, 1H), 9.09 (br s, 1H),
7.29e6.49 (m, 5H), 6.19 (s, 1H), 6.1 (d, J¼9.0 Hz, 3H), 5.4 (s, 1H), 3.2
(d, J¼4.5 Hz, 3H); dC (125 MHz, DMSO-d6) 160.1 (C), 157.4 (C), 147.8
(C), 131.0 (C), 129.7 (CH), 127.6 (CH), 125.8 (C), 125.3 (CH), 116.1 (C),
113.3 (CH), 107.9 (C), 107.35 (CH), 102.5 (CH), 36.9 (CH), 22.8 (Me).
Anal. Calcd for C16H14N2O5: C, 61.14; H, 4.49; N, 8.91. Found: C,
61.17; H, 4.37; N, 8.85.
3
¼4.2), 279 nm
3
4.2.23. N1-[4-(2-Hydroxyphenyl)-2-oxo-3,4-dihydro-2H-3-chrom-
enyl]acetamide 11. Following the above procedure, on heating
a mixture of 2-[2-(methylamino)-3-nitro-4H-4-chromenyl]phenol
6a (0.5 g, 1.7 mmol) and zinc dust (2.2 g, 34 mmol) in Ac2O (9.72 g,
9 mL, 95 mmol) and AcOH (1.0 g, 1 mL, 17 mmol) for 1 h at 110 ꢀC
provided the title compound 11 (0.31 g, 62%) as a colorless solid;
mp 192e194 ꢀC (EtOH); Rf (20% hexanes/EtOAc) 0.5; nmax 3316,
;
1763, 1650, 1532, 1369, 1225, 1143, 755 cmꢁ1
; dH (300 MHz, CDCl3)
9.5 (br s, 1H), 7.2e6.6 (m, 8H), 5.18 (d, J¼6.8 Hz, 1H), 4.87 (d,
J¼6.8 Hz, 1H), 1.87 (s, 3H); dC (75 MHz, CDCl3) 169.8 (C), 166.7 (C),
155.3 (C), 150.5 (C), 128.9 (CH), 128.3 (CH), 128.2 (CH), 124.8 (2ꢂ C),
124.3 (CH), 124.1 (CH), 118.9 (CH), 116.1 (CH), 115.3 (CH), 51.2 (CH),
4.2.21. 2-[2-(Methylamino)-3-nitro-4H-4-chromenyl]-1,4-benzene-
diol 6u. Following the representative procedure described pre-
viously for preparation of 6a, a solution of 4H-chromene 2a (0.5 g,

8154
H. Surya Prakash Rao et al. / Tetrahedron 67 (2011) 8146e8154
Drewe, J.;labrecque, D.;Kasibhatla, S.; Tseng, B. Mol. Cancer Ther. 2004, 3,1375e1384;
(c) Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Wang, Y.; Zhao, J.; Jia, S.; Herich, J.;
Labrecque, D.; Storer, R.; Meerovitch, K.; Bouffard, D.; Rej, R.; Denis, R.; Blais, C.; La-
mothe, S.; Attardo, G.; Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S. X. J. Med. Chem.
2004, 47, 6299e6310; (d) Kemnitzer, W.; Kasibhatla, S.; Drewe, J.; Jiang, S.; Zhang, H.;
Wang, Y.; Zhao, J.; Jia, S.; Xu, L.; Crogan-Grundy, C.; Denis, R.; Brriault, N.; Vaillancourt,
L.; Charron,S.; Dodd,J.; Attardo,G.;Labreque, D.;Lamothe,S.;Gourdeau, H.; Tseng, B.;
Drew, J.; Cai, S. X. Bioorg. Med. Chem. Lett. 2005, 15, 4745e4751.
38.8 (CH), 22.1 (CH3). Anal. Calcd for C17H15NO4: C, 68.68; H, 5.09;
N, 4.71; Found: C, 68.71; H, 5.14; N, 4.69.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.08.045.
3. Kidwai, M.; Saxena, S.; Khan, K. R.; Thukral, S. S. Bioorg. Med. Chem. Lett. 2005, 15,
4295e4298.
4. Rao, H. S. P.; Geetha, K. Tetrahedron Lett. 2009, 50, 3836e3839.
5. Gayathri, D.; Velmurugan, D.; Ravikumar, K.; Geetha, K.; Rao, H. S. P. Acta Crys-
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