A versatile route to 2-alkyl-/aryl-amino-3-formyl- and hetero-annelated-chromones, through a facile nucleophilic substitution at C2 in 2-(N-methylanilino)-3-formylchromones

Article abstract of DOI:10.1016/S0040-4020(02)00128-X

The N-methylanilino group in 2-(N-methylanilino)-3-formylchromones, obtained in high yield by rearrangement of C(4-oxo-4H[1]-benzopyran-3-yl)-N-phenylnitrones to 2-anilino-3-formyl-chromones followed by N-methylation, undergoes facile nucleophilic substitution by a variety of nitrogen nucleophiles, thereby paving the way for synthesis of a variety of novel 2-substituted-3-formylchromone derivatives as well as hetero-annelated chromones.

Full text of DOI:10.1016/S0040-4020(02)00128-X

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 2471±2480
A versatile route to 2-alkyl-/aryl-amino-3-formyl- and hetero-
annelated-chromones, through a facile nucleophilic substitution
at C2 in 2-(N-methylanilino)-3-formylchromones
Gurmit Singh, Rajinder Singh, Navdeep K. Girdhar and M. P. S. Isharp
Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India
Received 2 November 2001;revised 2 January 2002;accepted 31 January 2002
AbstractÐThe N-methylanilino group in 2-(N-methylanilino)-3-formylchromones, obtained in high yield by rearrangement of C(4-oxo-
4H[1]-benzopyran-3-yl)-N-phenylnitrones to 2-anilino-3-formyl-chromones followed by N-methylation, undergoes facile nucleophilic
substitution by a variety of nitrogen nucleophiles, thereby paving the way for synthesis of a variety of novel 2-substituted-3-formylchromone
derivatives as well as hetero-annelated chromones. q 2002 Published by Elsevier Science Ltd.
1.Introduction
ration of the chromone moiety5 and attempts are being made
to develop its solid supported synthetic equivalents.5g
However, it has been observed that nucleophilic attack at
C2 in 3-formylchromone or its derivatives, results in either
pyrone ring opening or loss of the C2±C3± p bond, thereby,
limiting its synthetic applications.2,3,5 This facile pyrone
ring opening has also attracted the attention of theo-
reticians.6 We had earlier observed7 that C-(4-oxo-4H[1]-
benzopyran-3-yl)-N-phenylnitrones (1, RˆH, Me, Cl)
undergo intramolecular rearrangement to yield 2-anilino-
3-formylchromones (2, 70±90%) and 3-phenylimino-
methyl-enechromone-2,4-diones (3, 10±25%, Scheme 1).
Besides forming the basic nucleus of an entire class of
natural products, i.e. ¯avones,1 the chromone moiety is
also part of a large number of molecules of medicinal sig-
ni®cance.2 Consequently, considerable attention is being
devoted to isolation from natural resources, chemistry and
synthesis of chromone derivatives, and evaluation of their
biological activity with stress on their potential medicinal
applications.2±4 Some of the biological activities recently
ascribed to chromone derivatives include cytotoxic (anti-
cancer),4a±c P-glycoprotein binding (to overcome multi-drug
resistance, anticancer),4d neuroprotective,4e HIV-inhibitory,4f
antimicrobial,4g,h cyclin-dependent kinase inhibitory (anti-
cancer),4i antifungal4j and antioxidant activity.4k 3-Formyl-
chromone has emerged as a valuable synthon for incorpo-
We report herein that N-methylation of 2 yields 2-(N-methyl-
anilino)-3-formylchromone (4) in high yield (.95%) and
the 2-N-methylanilino group in the latter undergoes facile
Scheme 1.
Keywords: chromones;substitution;addition elimination;diazepines;heterocycles.
Corresponding author. Tel.: 191-183-258802p3321;fax: 191-183-258819-20;e-mail: mpsishar@angel®re.com
p
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)00128-X

2472
G. Singh et al. / Tetrahedron 58 (2002) 2471±2480
Scheme 2.
Table 1. Reaction times, yields (%) and melting points of the products (5a±n) for reactions of 2-(N-methylanilino)-3-formyl-chromones (4a,b) with various
primary amines in aqueous-acetonitrile
Entry
X
R
Reaction time (h)
Product (% yield)
Melting point (8C)
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
Benzyl
n-Butyl
p-Anisyl
p-Tolyl
2-Naphthyl
o-Anisyl
p-Chloro
Benzyl
n-Butyl
p-Anisyl
p-Tolyl
1
1
3
4
4
7
5
1
1
3
4
4
7
5
5a (90)
5b (89)
5c (94)
5d (91)
5e (86)
5f (92)
5g (84)
5h (91)
5i (88)
5j (94)
5k (88)
5l (84)
5m (91)
5n (82)
156±157
91±92
175±176
149±150
191±192
219±220
217±218
152±153
89±90
173±174
142±143
186±187
205±206
211±212
9
10
11
12
13
14
2-Naphthyl
o-Anisyl
p-Chloro
H
H
substitution by various nitrogen nucleophiles, paving the
way for the preparation of a large number of novel 2-substi-
tuted-3-formylchromones and heteroannelated-chromones.
To further enhance the synthetic potential of this approach,
taking cognizance of a literature report on the acid promoted
cyclization of 3-formylchromone-oxime,3l the yield of 2 has
been improved to 96% by re¯uxing the nitrone 1 in dry
benzene in the presence of a catalytic amount of acetic
acid (Scheme 1);the product obtained can be directly
methylated (without any separation from 3) to 4, which is
crystallized out.
2.Results and discussion
Initially, the reactions of 4b (XˆCl) were carried out
with 1 molar equiv. of primary aromatic/aliphatic amines
(benzylamine, n-butylamine and p-ansidine) in dry aceto-
nitrile, which afforded, the 2-substituted product (5a±c) in
23±29% yield, along with 2-arylamino-3-(N-arylimino-
methyl)chromones (6a±c, 30±36%);the rest of 4 was
recovered unreacted. On the other hand, when the reaction
was carried out with 2 molar equiv. of the above amines
the yields of (6a±c) were more than 90%. However, when
the reactions were carried out in re¯uxing aqueous-aceto-
nitrile (CH3CN±H2O 65:35), 5 were obtained as the only
product;the latter reaction has been extended to o-ansidine,
p-toluidine, p-chloroaniline and b-naphthylamine (Scheme
2, Table 1).
The reaction has been extended to some cyclic-amines like
pyrrolidine, piperidine, morpholine and N-methylpiperazine,
Scheme 3.
Table 2. Reaction times, yields (%) and melting points of the products (7a±h) for reactions of 4a,b with cyclic-amines in dry-acetonitrile
Entry
X
Amine reacted
Reaction time (min)
Product (% yield)
Melting point (8C)
1
2
3
4
5
6
7
8
Cl
Cl
Cl
H
H
H
Piperidine
Morpholine
N-Methylpiperazine
Piperidine
Morpholine
N-Methylpiperazine
Pyrrolidine
Pyrrolidine
30
30
30
30
30
30
45
45
7a (90)
7b (92)
7c (92)
7d (91)
7e (94)
7f (91)
7g (91)
7h (90)
157±158
177±178
155±156
160±161
180±181
152±153
188±189
190±191
Cl
H

G. Singh et al. / Tetrahedron 58 (2002) 2471±2480
2473
Scheme 4.
Table 3. Reaction times, yields (%) and melting points of products (8a±l) from cyclization of 2-N-arylamino-3-formylchromones
Entry
X
Ar
Reaction time (h)
Product (% yield)
Melting point (8C)
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
Phenyl
p-Tolyl
p-Anisyl
o-Anisyl
p-Cl-Phenyl
Phenyl
6
6
5
5
6
5
5
5
5
6
5
5
8a (96)
8b (94)
8c (95)
8d (96)
8e (91)
8f (94)
8g (96)
8h (95)
8i (98)
8j (90)
8k (97)
8l (94)
211±212
218±219
221±223
251±252
221±222
217±218
209±210
245±246
243±244
214±215
252±253
241±243
p-Tolyl
p-Anisyl
o-Anisyl
p-Cl-Phenyl
2-Naphthyl
2-Naphthyl
9
10
11
12
Cl
H
Scheme 5.
which react with 4 under anhydrous conditions, in aceto-
nitrile, to afford 2-substituted-3-formyl chromones (7a±h)
in high yields (Scheme 3, Table 2). The assigned structures
of the products are based on detailed spectroscopic analysis
and microanalytical data.
spectroscopic analysis. The H-11 resonance in the 1H
NMR spectra of 8a±j appeared as a singlet (1H) at ,d
9.1 and the corresponding resonance of H-13 in 8k,l was
located at ,d 10.0. The orientation of cyclization in
5e,l leading to 8k,l is based on the presence of a 1H doublet
1
in the H NMR spectra of the latter at d 8.8, which is
attributed to H-12 and also there is present only one singlet
Hetero-annulated chromones have been particularly
targeted due to their medicinal signi®cance.2,8 Therefore,
to demonstrate the usefulness of present approach,
compounds 5c±g and 5j±n have been cyclized to chro-
1
in the H NMR of 8k (H-13), whereas three singlets are
anticipated for the alternative linear structure. It may be
mentioned here that these compounds ¯uoresce even in
the solid state and display strong ¯uorescence bands in the
region 420±570 nm (CH3CN solvent, excited at 350 and
390 nm).
²
manoquinolines (8a±l, Scheme 4, Table 3); valuable
pharmacological activities have been attributed to such
compounds.8
The products (8a±l) have been characterized by rigorous
Investigations have also been extended to reactions of 4a
with diamines i.e. o-phenylenediamine and hydrazine to
afford chromone annelated heterocyclic systems (9,10,
Scheme 5);best yields of products ( 9,10) are obtained in
aqueous-acetonitrile (80:20) and use of anhydrous solvent
²
The presently described method of cyclization employing sulfuric acid is
a marked improvement over the AlCl3 effected cyclization of 5 (ArˆPh)
reported by us earlier.7a

2474
G. Singh et al. / Tetrahedron 58 (2002) 2471±2480
led only to a highly insoluble product which could not be
investigated further.
potassium carbonate (1.5 g), and dried methyl iodide
(5 mL, excess) were added. The contents were re¯uxed
with stirring and the reaction was monitored by TLC.
After completion of reaction (8 h) the K2CO3 was ®ltered-
off, and residue was washed with a little acetone and the
solvent from ®ltrate was evaporated under vacuum. The
resulting solid was suspended in 10 mL of acetonitrile,
®ltered and washed with acetonitrile (2 mL) to obtain 4a
(3.1 g, ,98%). The obtained product is utilized as such
for further reactions and an analytical sample was obtained
by re-crystallization from acetonitrile. Faint yellow solid,
mp 168±1698C;(Found: C, 72.88;H, 4.86;N, 4.93.
C17H13NO3 requires C, 73.11;H, 4.69;N, 5.02%); lmax
(MeOH): 325, 286, 248 nm; nmax (KBr): 1670, 1631,
1621, 1518 cm21; dH (200 MHz, CDCl3): 3.56 (s, 3H,
N±CH3), 7.10±7.60 (m, 8H, arom.-Hs), 8.18 (br d, 1H,
Jˆ7.8 Hz, C5±H), 10.09 (s, 1H, CHO); dC (50 MHz,
CDCl3): 42.97 (N±CH3), 102.63 (C3), 116.71 (C8),
123.14 (C4a), 124.98 (CH), 125.41 (CH), 126.07
(CH), 127.43 (CH), 129.55 (CH), 133.69 (C7), 143.99
(quat. Arom.), 153.34 (C8a), 163.70 (C2), 178.65 (C4),
186.7 (CHO); m/z (%): 279 (M1, 21), 278 (100), 250 (29),
91 (78).
The structures of various products have been again
established by rigorous spectroscopic analysis (UV, IR, H
1
and 13C NMR, Mass) and microanalytical data, and com-
parison of the spectroscopic data with related systems.3n,4f,9
Mechanistically, the substitution reaction at C2 can be best
described as a conjugate-addition±elimination;the high
nucleofugality of N-methylanilino group completely
prevents any chromone ring opening The reaction not
only provides an easy access to a large number of novel
2-substituted-chromone derivatives, but also has a lot of
other interesting applications. For instance, the reaction
can be utilized to introduce other moieties at C2 to obtain
biologically active molecules. The reaction can also
be utilized to obtain chromano-diaza-heterocycles (like 9
and 10) as well as macrocycles bearing intact chro-
mone moieties on the periphery, i.e. by reacting 4 with
a,v-diamino compounds, combining nucleophilic substi-
tution at C2 with condensation with the C3-formyl group;
recently chromone based macrocycles have found some
interesting applications.10
3.1.3. 6-Chloro-2-(N-methylanilino)-3-formylchromone
(4b). It was obtained by reacting 2-anilino-6-chloro-3-
formylchromone (2b, 3.0 g, 10.0 mmol) with methyliodide
(5 mL, excess) in presence of anhyd. K2CO3 (1.5 g) in
re¯uxing dry acetone (175 mL) according to method
described above, as a cream colored solid (CH3CN, 3.1 g,
99%), mp 174±1768C;(Found C, 65.32;H, 3.97;N, 4.27.
C17H12NClO3 requires C, 65.08;H, 3.86;N, 4.46%); lmax
(MeOH): 328, 292, 260 nm; nmax (KBr): 1675, 1634, 1531,
1446 cm21; dH (200 MHz, CDCl3): 3.54 (s, 3H, N±Me),
7.03 (d, 1H, Jˆ8.64 Hz, C8±H), 7.51±7.25 (m, 6H,
arom.-Hs), 8.13 (d, 1H, Jˆ2.4 Hz, C5±H), 10.09 (s, 1H,
±CHvO); dC (CDCl3, 50 MHz): 43.27 (N±Me), 102.33
(C3), 118.21 (C8), 125.04 (CH), 125.59 (CH), 126.5
(CH), 127.61 (CH), 129.05 (CH), 131.24 (C6), 133.46
(C7), 143.55 (quat. arom.), 151.5 (C8a), 163.35 (C2),
177.09 (C4), 186.28 (CHvO); m/z (%) 315 (M112, 22),
313 (M1, 61), 284 (63), 91 (100).
3.Experimental
3.1. General
NMR spectra ware recorded on Bruker 200, 300 and
400 MHz FT NMR spectrometers, using TMS as internal
standard and CDCl3/DMSO-d6 as solvents. Chemical shifts
are reported in ppm as down ®eld displacements from tetra-
methylsilane used as internal standard. Mass spectra were
recorded on Shimadzu GCMS-QP-2000A spectrometer.
The microanalytical data were collected on a Perkin±
Elmer 240C elemental analyzer. IR spectra were recorded
on a Shimadzu DR 2001 IR spectrophotometer in CHCl3
solution or as pellets with KBr and are reported in wave
numbers (cm21). All melting points are uncorrected and
measured in open glass-capillaries. Column chroma-
tography was conducted using silica gel 60±120 mesh
(Acme, India). Solvents, starting materials and reagents
were purchased from commercial suppliers and used
after puri®cation (crystallization/distillation). 3-Formyl-
chromones were purchased from Aldrich and used as such.
3.2. General procedure for reactions of 4b with primary-
amines in dry acetonitrile leading to 5a±c and 6a±c
6-Chloro-2-(N-methylanilino)-3-formylchromone (4b, 313
mg, 1.0 mmol) was dissolved in dry acetonitrile (60 mL)
and a solution of amine (1.0 mmol) in acetonitrile (3 mL)
was added to it. The contents were re¯uxed under an
anhydrous setup and progress of the reaction was monitored
by TLC. After completion of reaction (1±4 h, TLC), the
solvent was distilled off and the products were separated
by column chromatography over silica gel column packed
in hexane, eluted with 6% EtOAc/hexane.
3.1.1. Conversion of nitrone 1 to 2-anilino-3-formylchro-
mone (2). Nitrone (1a,b, 5.0 g, 18.8 and 16.72 mmol,
respectively) were taken in dry benzene (100 mL) and a few
drops of acetic acid added to it. The contents were re¯uxed
for 6 h. The solvent was evaporated under vacuum and the
resulting compounds were directly crystallized in methanol
to afford products (2a,b) as yellow crystalline solids.
7a
3.2.1. Reaction of 4b with benzylamine in dry aceto-
nitrile. Reaction of 4b (313 mg, 1 mmol) with benzylamine
(107 mg, 1 mmol) afforded 2-benzylamino-6-chloro-3-
formylchromone (5a, 91 mg, 29%) as white crystalline
solid (hexane±CHCl3, 4:1);(Found: C, 64.91;H, 3.97;N,
4.37. C17O3H12NCl requires C, 65.08;H, 3.86;N, 4.46%);
2a: yield: 4.8 g (96%): mp 156±1578C;Lit.
mp 156±
7c
1588C; 2b: yield: 4.85 g (97%): mp 159±1608C;Lit. mp
158±1598C.
3.1.2. 2-(N-Methylanilino)-3-formylchromone (4a). 2-Ani-
lino-3-formylchromone (2a, 3.0 g, 11.3 mmol) was dis-
solved in dry acetone (160 mL) and anhydrous (fused)
l
max (MeOH): 325, 273, 247 nm; nmax (CHCl3): 3175, 2925,

G. Singh et al. / Tetrahedron 58 (2002) 2471±2480
2475
1671, 1640.9, 1576.8, 1495, 1465 cm21; dH (200 MHz,
CDCl3): 4.75 (d, 2H, Jˆ6.2 Hz, benzylic-Hs), 7.22 (d, 1H,
Jˆ8.8 Hz, C8±H), 7.30±7.42 (m, 5H, arom.-Hs), 7.53 (dd,
1H, Jˆ8.8, 2.6 Hz, C7±H), 8.15 (d, 1H, Jˆ2.6 Hz, C5±H),
10.20 (s, 1H, HCvO), 10.96 (bs, 1H, N±H); dC (50 MHz,
CDCl3): 44.93 (benzylic-C), 99.21 (C3), 118.01 (C8),
124.05 (C4a), 125.91 (CH), 126.38 (C5), 127.28 (CH),
129.08 (CH), 131.67 (C6), 133.40 (C7), 135.44
(quat.arom.), 151.41 (C8a), 164.08 (C2), 174.1 (C4),
189.25 (CHvO); m/z (%) 315 (M112, 18), 314 (M11, 9),
313 (M1, 50), 284 (58), 91 (100). 2-Benzylamino-6-chloro-
3-(N-benzyliminomethyl)chromone (6a, 121 mg, 30%) as
cream colored solid (hexane±CHCl3, 4:1);mp 118±
1198C;(Found: C, 71.72;H, 4.93;N, 6.83. C 24H19ClN2O2
requires C, 71.55;H, 4.75;N, 6.95%); lmax (MeOH): 386,
349, 328, 278, 247 nm; nmax (CHCl3): 3225, 1669.8, 1623.8,
1576.8, 1465.7 cm21; dH (200 MHz, CDCl3): 4.66 (br d, 4H,
benzylic-Hs,), 7.09±7.28 (m, 11H, arom.-Hs), 7.41 (dd, 1H,
Jˆ8.9, 2.3 Hz, C7±H), 8.07 (d, 1H, Jˆ2.3 Hz, C5±H), 8.73
(s, 1H, imino-H), 10.97 (broad, 1H, N±H); dC (75 MHz,
CDCl3): 47.00 (benzlylic-C), 59.19 (benzylic-C), 96.01
(C3), 117.82 (C8), 123.16 (C4a), 125.91 (CH), 126.29
(CH), 127.19 (CH), 127.33 (CH), 128.35 (CH), 129.58
(CH), 129.97 (CH), 132.87 (C6), 133.43 (C7), 137.88
(quat.arom.), 138.63 (quat.arom.), 152.29 (C8a), 157.19
(CHvN), 158.42 (C2), 174.38 (C4); m/z (%) 402 (M1,
32), 311 (12), 284 (14), 91 (100).
3.2.3. Reaction of 4b with p-anisidine. Reaction of (4b,
313 mg, 1 mmol) with p-anisidine (123 mg, 1 mmol)
afforded 2-(p-anisylamino)-6-chloro-3-formylchromone (5c,
69 mg, 21%) as a pale-yellow solid (hexane±CHCl3, 3:1);
(Found: C, 61.95;H, 3.79;N, 4.14. C 17H12NO4Cl requires
C, 61.92;H, 3.67;N, 4.25%);
lmax(MeOH): 323, 288.5,
247 nm; nmax (KBr): 3210, 2925, 1670, 1625, 1612, 1502,
1451 cm21; dH (300 MHz, CDCl3): 3.70 (s, 3H, OCH3),
6.98 (d, 2H, Jˆ6.7 Hz, arom.-Hs), 7.22 (d, 1H, Jˆ6.8 Hz,
C8±H), 7.36 (d, 2H, Jˆ6.7 Hz, arom.Hs), 7.55 (dd, 1H,
Jˆ8.8, 2.5 Hz, C7±H), 8.20 (d, 1H, Jˆ2.5 Hz, C±5H),
10.29 (s, 1H, HCvO), 12.31 (broad, 1H, N±H); dC
(50 MHz, CDCl3): 55.66 (OCH3), 99.43 (C3), 114.85
(CH), 116.49 (C8), 122.17 (C4a), 125.03 (C5), 126.00
(CH), 131.96 (C6), 133.62 (C7), 135.14 (quat. arom.),
151.9 (C8a), 158.60 (quat. arom.), 162.7 (C2), 174.6 (C4),
189.67 (HCvO); m/z (%): 330 (52, M111), 329 (M1, 100),
328 (98), 300 (96), 284 (20). 2-(p-Anisylamino)-6-chloro-3-
(N-p-anisyliminomethyl)-chromone (6c, 156 mg, 36%) as
light-yellow solid (hexane±CHCl3, 4:1);mp 185±186 8C;
(Found: C, 66.41;H, 4.53;N, 6.31. C 24H19N2O4Cl requires
C, 66.29;H, 4.40;N, 6.44%); lmax (MeOH): 370, 317.5,
285.5 nm; nmax (KBr): 3300, 3040, 1660, 1622, 1580, 1511,
1449 cm21; dH (200 MHz, CDCl3): 3.70 (s, 3H, OCH3),
3.72 (s, 3H, OCH3), 6.78 (broad d, 4H, Jˆ8.7 Hz,
arom.-Hs), 6.96 (d, 1H, Jˆ8.7 Hz, C8±H), 7.09±7.16 (m,
4H), 7.32 (dd, 1H, Jˆ8.8, 2.4 Hz, C7±H), 7.95 (d, 1H,
Jˆ2.4 Hz, C5±H), 8.82 (broad s, 1H, HCvN), 13.92
(broad, 1H, N±H); dC (50 MHz, CDCl3): 55.35 (OCH3),
55.29 (OCH3), 97.58 (C3), 114.13 (CH), 114.82 (CH),
117.97 (C8), 120.17 (CH), 122.62 (C4a), 124.39 (CH),
125.91 (C5), 129.80 (C6), 133.19 (C7), 134.79 (quat.
arom.), 135.32 (quat. arom.), 149.57 (CHvN), 152.46
(C8a), 154.42 (quat. arom.), 156.72 (quat. arom.), 158.07
(C2), 173.97 (C4); m/z (%) 435 (M112, 40), 434 (M111,
52), 433 (M1, 61), 171 (60), 58 (100).
3.2.2. Reaction of 4b with n-butylamine in dry aceto-
nitrile. Reaction of (4b, 313 mg, 1 mmol) with n-butyl-
amine (73 mg, 1 mmol) afforded 2-(n-butylamino)-6-
chloro-3-formylchromone (5b, 75 mg, 27%) as an off-
white solid (hexane±CHCl3, 4:1);(Found: C, 59.97;H,
5.19;N, 4.90. C 14H14NO3Cl requires C, 60.11;H, 5.04;N,
5.01%); lmax (MeOH): 322.5, 292.5, 247 nm; nmax (CHCl3):
3190, 2917, 1676.8, 1632.4, 1581.1, 1495.6 cm21; dH
(300 MHz, CDCl3): 1.00 (t, 3H, Jˆ7.7 Hz, CH3), 1.41±
1.54 (m, 2H, CH2), 1.67±1.77 (m, 2H, CH2), 3.59 (dt, 2H,
Jˆ6.9, 6.1 Hz, N±CH2), 7.26 (d, 1H, Jˆ8.7 Hz, C8±H),
7.55 (dd, 1H, Jˆ8.7, 2.6 Hz, C7±H), 8.77 (d, 1H, Jˆ
2.6 Hz, C5±H), 10.20 (s, 1H, HCvO), 10.63 (broad, 1H,
N±H); dC (75 MHz, CDCl3): 13.57 (CH3), 19.95 (CH2),
31.28 (CH2), 40.62 (N±CH2), 99.11 (C3), 118.16 (C8),
124.1 (C4a), 125.77 (C5), 131.5 (C7), 133.41 (C7), 151.55
(C8a), 164.12 (C2), 174.24 (C4), 189.03 (HCvO); m/z (%)
280 (M111, 19), 279 (M185), 250 (100), 91 (60). 2-(n-
Butylamino)-6-chloro-3-(N-n-butyliminomethyl)chromone
(6b, 107 mg, 32%) as pale-yellow solid (hexane±CHCl3,
4:1);mp 84±85 8C;(Found C, 64.41;H, 7.03;N, 8.32.
C18H23N2O2Cl requires C, 64.57;H, 6.92;N, 8.37%); lmax
(MeOH): 330, 278.5, 269.5, 247 nm; nmax (CHCl3): 3161,
1666.6, 1628.1, 1572.8, 1461.4 cm21; dH (300 MHz,
CDCl3): 1.00 (overlapping ts, 6H, 2£CH3), 1.37±1.52 (m,
4H, 2£CH2), 1.58±1.79 (m, 4H, 2£CH2), 3.50±3.60 (m,
4H), 7.14 (dd, 1H, Jˆ8.8 Hz, C±8H), 7.45 (dd, 1H, Jˆ
8.8, 2.5 Hz, C7±H), 8.11 (d, 1H, Jˆ2.5 Hz, C5±H), 8.65
(bs, 1H, CHvN), 11.98 (broad, 1H, N±H); dC (75 MHz,
CDCl3): 13.69 (2£CH3), 20.08 (CH2), 20.33 (CH2), 32.31
(CH2), 33.09 (CH2), 42.30 (NH±CH2), 55.27 (vNCH2),
95.54 (C3), 117.77 (C8), 123.26 (C4a), 125.64 (C5),
129.62 (C6), 132.54 (C7), 152.27 (C8a), 156.41 (C2),
158.62 (CvN), 174.15 (C4); m/z (%): 336 (M112, 14),
334 (M1, 40), 319 (26), 317 (77), 291 (71), 58 (100).
3.3. General procedure for reaction of 2-(N-methyl-
anilino)-3-formylchromones (4a,b) with primary amines
in aqueous-acetonitrile
2-(N-Methylanilino)-3-formylchromones (4a,b, 1.0 mmol)
were dissolved in re¯uxing aqueous-acetonitrile (60 mL)
and a solution of an amine (1.0 mmol) in acetonitrile
(3 mL) was added to it. The contents were re¯uxed and
the progress of reaction was monitored by TLC. After
completion of reaction (1±4 h, TLC), the solvent was
distilled off and the traces were removed under vacuum
and the compounds were puri®ed by column chroma-
tography over silica gel using 6% ethyl acetate/hexane as
eluent.
3.3.1. 2-Benzylamino-6-chloro-3-formylchromone (5a).
Reaction of 4a (313 mg, 1 mmol) with benzylamine (107
mg, 1 mmol) afforded the title compound (5a, 282 mg).
3.3.2. 2-(n-Butylamino)-6-chloro-3-formylchromone (5b).
Reaction of 4a (313 mg, 1 mmol) with n-butylamine
(73 mg, 1 mmol) afforded the title compound (5b, 248 mg).
3.3.3. 2-(p-Anisylamino)-6-chloro-3-formylchromone (5c).
Reaction of 4a (313 mg, 1 mmol) with p-ansidine (123 mg,
1 mmol) afforded the title compound (5c, 309 mg).

2476
G. Singh et al. / Tetrahedron 58 (2002) 2471±2480
3.3.4. 6-Chloro-2-(p-tolylamino)-3-formylchromone (5d).
Reaction of 4a (313 mg, 1 mmol) with p-toluidine (107 mg,
1 mmol) afforded the title compound (5d, 285 mg) as
yellowish solid (hexane±CHCl3 3:1);(Found: C, 64.92;H,
3.99;N, 4.33. C 17H12NO3Cl requires C, 65.08;H, 3.86;N,
4.46%); lmax (MeOH): 324, 292, 252 nm; nmax (KBr): 3230,
1665, 1632, 1618, 1582 cm21; dH (CDCl3 300 MHz): 2.41
(s, 3H, CH3), 7.21±7.58 (m, 6H, arom.-Hs), 8.20 (d, 1H,
Jˆ2.6 Hz, C5±H), 10.28 (s, 1H, CHO), 12.37 (bs, 1H,
NH); m/z (%) 313 (M1, 2), 302 (6), 169 (85), 112 (27),
111 (48), 91 (100).
10.15 (s, 1H, CHO), 10.88 (bs, 1H, NH); m/z (%) 280
(M111, 11), 279 (M1, 52), 251 (24), 250 (100).
3.3.9. 2-n-Butylamino-3-formylchromone (5i). Reaction
of 4a (279 mg, 1 mmol) with n-butylamine (73 mg,
1 mmol) afforded the title compound (5i, 216 mg) as
cream colored solid (hexane±CHCl3 3:1);(Found: C,
68.69;H, 6.02;N, 5.87. C 14H15NO3 requires C, 68.56;H,
6.16;N, 5.71%); lmax (MeOH): 320, 268, 247 nm; nmax
(KBr): 3225, 2944, 1672, 1635, 1608, 1575, 1455 cm21
;
dH (300 MHz, CDCl3): 1.00 (t, 3H, Jˆ7.4 Hz, CH3),
1.42±1.54 (m, 2H, CH2), 1.67±1.77 (m, 2H, CH2), 3.57±
3.63 (m, 2H, N±CH2), 7.29 (d, 1H, Jˆ7.9 Hz, C8±H), 7.38
(distorted triplet, 1H, Jˆ7.8 Hz, C6±H), 7.61 (split triplet,
1H, Jˆ7.6, 2.3 Hz, C7±H), 8.21 (dd, 1H, Jˆ7.9, 2.3 Hz,
C5±H), 10.23 (s, 1H, CHO), 10.60 (bs, 1H, N±H); m/z
(%) 246 (16, M111), 245 (M1, 95), 217 (69), 216 (32),
188 (28), 121 (100).
3.3.5. 6-Chloro-2-(b-naphthylamino)-3-formylchromone
(5e). Reaction of 4a (313 mg, 1 mmol) with b-naphthyl-
amine (143 mg, 1 mmol) afforded the title compound (5e,
301 mg) as yellow solid (hexane±CHCl3 3:1);(Found: C,
68.59;H, 3.53;N, 3.84. C 20H12NO3Cl requires C, 68.68;H,
3.46;N, 4.00%); lmax (MeOH): 323, 282, 245 nm; nmax
(KBr): 3210, 2925, 1673, 1632, 1587, 1465, 1308 cm21
;
dH (200 MHz, CDCl3): 7.26±7.30 (m, 2H, arom.-Hs),
7.46±7.60 (m, 4H, arom.-Hs), 7.85±7.95 (m, 3H,
arom.-Hs), 8.21 (d, 1H, Jˆ2.5 Hz, C5±H), 10.33 (s, 1H,
CHO), 12.62 (bs, 1H, NH); m/z (%) 350 (M112, 4), 349
(M1, 18), 348 (7), 331 (45), 171 (22), 58 (100).
3.3.10. 2-(p-Anisylamino)-3-formylchromone (5j). Reac-
tion of 4a (279 mg, 1 mmol) with p-ansidine (123 mg,
1 mmol) afforded the title compound (5j, 277 mg) as yellow
solid (hexane±CHCl3 3:1);(Found: C, 68.93;H, 4.57;N,
4.87. C17H13NO4 requires C, 69.15;H, 4.44;N, 4.74%);
lmax (MeOH): 324, 291, 248 nm; nmax (KBr): 3330. 3150,
2940, 1668, 1635, 1575, 1455 cm21; dH (300 MHz, CDCl3):
3.84 (s, 3H, OCH3), 6.98 (d, 2H, Jˆ6.8, arom.-Hs), 7.00±
7.30 (m, 2H, arom.-Hs), 7.36±7.43 (m, 2H, C6 and C8±Hs),
7.58±7.64 (m, 1H, C7±H), 8.24 (dd, 1H, Jˆ8.1, 2.5 Hz,
C5±H), 10.35 (s, 1H, CHO), 12.66 (bs, 1H, NH); m/z (%)
295 (M1, 16), 294 (24), 279 (60), 266 (26), 167 (31), 149
(90), 58 (100).
3.3.6. 6-Chloro-2-(o-anisylamino)-3-formylchromone (5f).
Reaction of 4b (313 mg, 1 mmol) with p-chloroaniline
(123 mg, 1 mmol) afforded the title compound (5f,
303 mg) as a faint-yellow solid (hexane±CHCl3, 3:1);
(Found: C, 61.95;H, 3.79;N, 4.44. C 17H12NO4Cl requires
C, 61.92;H, 3.67;N, 4.25%);
lmax(CHCl3): 301, 287,
248 nm; nmax (KBr): 3260, 3048, 1676, 1648, 1578,
1463 cm21; dH (200 MHz, CDCl3): 3.93 (s, 3H, OCH3),
6.99±6.91 (m, 2H, C30 and C8±Hs), 7.12±7.26 (m, 2H,
C40, C50 ±Hs), 7.49 (dd, 1H, Jˆ8.8, 2.5 Hz, C7±H), 7.70
(dd, 1H, Jˆ7.2, 1.4 Hz, C60 ±H), 8.14 (d, 1H, Jˆ2.5 Hz,
C5±H), 10.23 (s, 1H, HCvO), 12.56 (broad, 1H, N±H);
m/z (%) 329 (M1, 12), 328 (24), 169 (100).
3.3.11. 2-(p-Tolylamino)-3-formylchromone (5k). Reac-
tion of 4a (279 mg, 1 mmol) with p-toluidine (107 mg,
1 mmol) afforded the title compound (5k, 246 mg) as
yellow solid (hexane±CHCl3 3:1);(Found: C, 73.19;H,
4.74;N, 4.91. C 17H13NO3 requires C, 73.11;H, 4.69;N,
5.02%); lmax (MeOH): 371, 321, 285 nm; nmax (KBr):
3350, 3140, 2940, 1670, 1620, 1462 cm21; dH (300 MHz,
CDCl3): 2.41 (s, 3H, CH3), 7.17±7.48 (m, 6H, arom.-Hs),
7.59 (split triplet, 1H, Jˆ7.9, 1.3 Hz, C7±H), 8.23 (br d, 1H,
Jˆ7.7 Hz, C5±H), 10.29 (s, 1H, CHO), 12.38 (bs, 1H, NH);
m/z: 279 (M1, 20), 278 (33), 171 (25), 149 (20), 58 (100).
3.3.7. 6-Chloro-2-(p-chloroanilino)-3-formylchromone
(5g). Reaction of 4b (313 mg, 1 mmol) with p-chloroaniline
(117 mg, 1 mmol) afforded the title compound (5g, 280 mg)
as a yellow crystalline solid (hexane±CHCl3 3:1);(Found:
C, 57.57;H, 2.84;N, 4.17. C 16H9NO3Cl2 requires C, 57.51;
H, 2.71;N, 4.19%); lmax(CHCl3): 218.5, 291.5, 246 nm;
nmax (KBr): 3230, 3100, 1681, 1627, 1583, 1452 cm21; dH
(200 MHz, CDCl3): 6.95 (d, 1H, Jˆ8.8 Hz, C8±H),
7.16±7.35 (m, 2H, arom.-Hs), 7.49±7.57 (m, 2H,
arom.-Hs), 7.65 (dd, 1H, Jˆ8.8, 2.5 Hz, C7±H), 8.17 (d,
1H, Jˆ2.5 Hz, C5±H), 10.26 (s, 1H, CHvO), 12.28 (bs,
1H, NH); m/z (%) 335 (M112, 3), 333 (M1, 9), 169 (100),
112 (29), 11 (46), 94 (21), 89 (29), 84 (32), 83 (48).
3.3.12. 2-(b-Naphthylamino)-3-formylchromone (5l).
Reaction of 4a (279 mg, 1 mmol) with b-naphthylamine
(143 mg, 1 mmol) afforded the title compound (5l,
264 mg) as a yellow solid (hexane±CHCl3 3:1);(Found:
C, 76.06;H, 4.23;N, 4.35. C 20H13NO3 requires C, 76.18;
H, 4.16;N, 4.44%); lmax (MeOH): 332, 318, 287, 250 nm;
nmax (KBr): 3290, 3210, 2940, 1672, 1638, 1608,
1577, 1472; dH (200 MHz, CDCl3): 7.25±7.95 (m, 10H,
arom.-Hs), 8.08 (d, 1H, Jˆ8.0 Hz, C5±H), 10.35 (s, 1H,
CHO), 12.61 (bs, 1H, NH); m/z (%) 315 (M1, 3.7), 269
(4.5), 240 (20), 117 (38), 58 (100).
3.3.8. 2-Benzylamino-3-formylchromone (5h). Reaction
of 4b (279 mg, 1 mmol) with benzylamine (107 mg,
1 mmol) afforded the title compound (5h, 254 mg) as a
white crystalline solid (hexane±CHCl3 3:1);(Found: C,
72.93;H, 4.73;N, 4.92. C 17H13NO3 requires C, 73.11;H,
4.69;N, 5.02%); lmax (MeOH): 318, 270, 228 nm; nmax
(KBr): 3276, 2930, 1670, 1636, 1586, 1499 cm21; dH
(200 MHz, CDCl3): 4.69 (d, 2H, Jˆ6.0 Hz, benzylic Hs),
7.19±7.35 (m, 7H, arom.-Hs), 7.53 (distorted t, 1H,
Jˆ7.0 Hz, C7±H), 8.13 (dd, 1H, Jˆ8.4, 1.6 Hz, C5±H),
3.3.13. 2-(o-Anisylamino)-3-formylchromone (5m).
Reaction of 4a (279 mg, 1 mmol) with o-ansidine
(123 mg, 1 mmol) afforded the title compound (5m,
268 mg) as a yellow solid (hexane±CHCl3 3:1);(Found:
C, 69.16;H, 4.47;N, 4.69. C 17H13NO4 requires C, 69.15;
H, 4.44;N, 4.74%); lmax (CHCl3): 318, 288, 248 nm; nmax

G. Singh et al. / Tetrahedron 58 (2002) 2471±2480
2477
(KBr): 3330, 3050, 1660, 1636, 1582, 1480; dH (200 MHz,
CDCl3): 3.93 (s, 3H, OCH3), 6.91±6.99 (m, 2H, C30, C8±
Hs), 7.11±7.19 (m, 1H, C6±H), 7.25±7.36 (m, 2H, C40 and
C50 ±Hs), 7.51±7.55 (m, 1H, C7±H), 7.76 (dd, 1H, Jˆ7.9,
1.4 Hz, C60 ±H), 8.18 (dd, 1H, Jˆ7.8, 1.7 Hz, C5±H), 10.24
(s, 1H, HCvO), 12.56 (broad, 1H, N±H); m/z (%) 295 (M1,
32), 294 (69), 284 (20), 169 (100).
133.64 (C7), 151.39 (C8a), 162.64 (C2), 177.53 (C4),
186.59 (HCvO); m/z (%) 295 (M112, 9), 294 (M111,
5), 293 (M1, 24), 169 (100), 112 (26).
3.4.3. 6-Chloro-2-4N-methylpiprazino-3-formylchromone
(7c). Reaction of 4b (313 mg, 1 mmol) with N-methyl-
piperazine (110 mg, 1.1 mmol) afforded 7c as yellow
solid (282 mg);(Found: C, 58.82;H, 5.01;N, 9.36.
C15H15N2O3Cl requires C, 58.73;H, 4.93;N, 9.13%); lmax
(MeOH): 365, 320, 284.5, 228 nm; nmax (KBr): 1673, 1631,
1615, 1544 cm21; dH (300 MHz, CDCl3,): 2.37 (s, 3H,
N±Me), 2.63 (dist.t, 4H, Jˆ5.7 Hz, 2£CH2), 3.72 (dist.t,
4H, J,5.7 Hz, 2£CH2), 7.25 (d, 1H, Jˆ8.8 Hz, C8±H),
7.55 (dd, 1H, Jˆ8.8, 2.5 Hz, C7±H), 8.10 (d, 1H, Jˆ
2.5 Hz, C5±H), 10.11 (s, 1H, HCvO); dC (75 MHz,
CDCl3): 45.85 (NCH3), 49.57 (CH2), 54.78 (CH2), 101.68
(C3), 118.17 (C8), 124.07 (C4a), 125.81 (C5), 131.33 (C6),
133.79 (C7), 151.43 (C8a), 162.51 (C2), 177.72 (C4),
186.53 (CHO); m/z (%) 307 (M1, 4), 283 (15), 169 (94),
112 (26), 111 (46), 71 (100).
3.3.14. 2-(p-Chloroanilino)-3-formylchromone (5n).
Reaction of 4a (279 mg, 1 mmol) with p-chloroaniline
(127 mg, 1 mmol) afforded the title compound (5n,
246 mg) as a yellow solid (hexane±CHCl3 3:1);(Found:
C, 64.18;H, 3.47;N, 4.83. C 16H10NO3Cl requires C,
64.12;H, 3.36;N, 4.67%); lmax (CHCl3): 389.5, 281.5,
248.5 nm; nmax (KBr): 3440, 3082, 1677, 1612, 1461,
1321 cm21; dH (200 MHz, CDCl3): 7.23±7.74 (m, 7H,
arom.-Hs), 8.25 (dd, 1H, Jˆ7.8, 2.4 Hz, C5±H), 10.30 (s,
1H, CHvO), 12.44 (bs, 1H, NH); m/z (%) 300 (M111, 1),
299 (M1, 3), 169 (100), 112 (29), 111 (43), 94 (22).
3.4. General procedure for reactions of 2-(N-methyl-
anilino)-3-formylchromones (4a,b) with sec-cyclic-amines
leading to 2-sec-cyclic-amino-3-formylchromones (7a±h)
3.4.4. 2-Piperidino-3-formylchromone (7d). 4a (279 mg,
1 mmol) was reacted with piperidine (92 mg, 1.08 mmol) to
obtain the title compound (7d) as creamy solid (234 mg);
(Found: C, 69.84;H, 5.76;N, 5.67. C 15H15NO3 requires C,
70.02;H, 5.88;N, 5.44%); lmax (MeOH): 322, 281, 232 nm;
nmax (KBr): 1672, 1638, 1590, 1572, 1515, 1465 cm21; dH
(300 MHz, CDCl3): 1.80 (broad multiplet, 6H, 3£CH2),
3.65 (bm, 4H, 2£CH2), 7.15 (d, 1H, Jˆ8.3 Hz, C8±H),
7.25±7.63 (m, 2H, C6±H and C7±H), 8.20 (dd, 1H, Jˆ
7.7, 1.4 Hz, C5±H), 10.12 (s, 1H, CHO); m/z (%) 257
(M1, 8), 255 (18), 241 (32), 214 (72), 169 (76), 11934),
94 (20), 83 (35), 70 (100).
2-(N-Methylanilino)-3-formylchromones (4a,b, 1.0 mmol)
were dissolved in dry acetonitrile (50 mL) and to the stirred
solution, at 80±908C bath temperature, was added, drop-
wise, the solution of an amine (1±1.2 mmol) in dry aceto-
nitrile (5 mL). After completion of reaction (30±45 min,
TLC), the solvent was distilled off so as to concentrate the
reaction mixture to ,1/7 of its original volume and the
concentrate was ice-cooled in a refrigerator for 2 h, when
the crystalline products separated out, which were ®ltered,
and re-crystallized from acetonitrile.
3.4.5. 2-Morpholino-3-formylchromone (7e). Reacting 4a
(279 mg, 1 mmol) with morpholine (94 mg, 1.08 mmol)
afforded 7e as creamy solid. (243 mg);(Found: C, 64.71;
H, 5.22;N, 5.22. C 14H13NO4 requires C, 64.86;H, 5.05;N,
5.40%); lmax (MeOH): 318, 280, 234 nm; nmax (KBr): 1671,
1640, 1615, 1590, 1560, 1462 cm21; dH (300 MHz, CDCl3):
3.71 (dist.t, 4H, Jˆ5.3 Hz, 2£CH2), 3.92 (dist.t, 4H,
Jˆ5.3 Hz, 2£±CH2), 7.27 (d, 1H, Jˆ7.5 Hz, C8±H), 7.39
(dis t, 1H, Jˆ8.0 Hz, C6±H), 7.63 (dis t, 1H, Jˆ7.5 Hz,
C7±H), 8.19 (dd, 1H, Jˆ8.0, 1.1 Hz, C5±H), 10.15 (s,
1H, CHO); m/z (%) 260 (17, M111), 259 (M1, 54), 243
(10), 242 (10), 201 (10), 174 (36), 171 (37), 83 (22), 71 (53),
58 (100).
3.4.1. 6-Chloro-2-piperidino-3-formylchromone (7a).
Obtained by reacting 4b (313 mg, 1 mmol) with piperidine
(92 mg, 1.08 mmol) as cream-colored solid (7a, 262 mg);
(Found: C, 61.63;H, 4.96;N, 4.71. C 15H14NO3Cl requires
C, 61.76;H, 4.84;N, 4.80%); lmax (MeOH): 367, 324,
284.4, 227 nm; nmax (KBr): 1670, 1620, 1542, 1443,
1416 cm21; dH (300 MHz, CDCl3): 1.79 (broad m, 6H,
3£CH2), 3.64 (broad m, 4H), 7.22 (d, 1H, Jˆ8.8 Hz, C8±
H), 7.54 (dd, 1H, Jˆ8.8, 2.4 Hz, C7±H), 8.13 (d, 1H,
Jˆ2.4 Hz, C5±H), 10.11 (s, 1H, HCvO); dC (75 MHz,
CDCl3): 23.65 (CH2), 26.07 (CH2), 50.86 (CH2), 101.49
(C3), 118.15 (C8), 125.53 (C4a), 126.61 (C5), 130.92
(C6), 133.53 (C7), 151.35 (C8a), 162.36 (C2), 177.65
(C4), 186.28 (CHO); m/z (%) 293 (M112, 11) 292 (30),
291 (M1, 30), 167 (25), 149 (79), 71 (58), 70 (47), 58 (100).
3.4.6. 2-4N-Methylpiperazino-3-formylchromone (7f).
Reacting 4a (279 mg, 1 mmol) and N-methylpiperizine
(110 mg, 1.1 mmol) afforded 7f as creamish-yellow solid.
(248 mg);(Found: C, 66.03;H, 5.82;N, 10.51. C 15H16N2O3
requires C, 66.16;H, 5.92;N, 10.29%); lmax (MeOH): 357,
322, 280, 225 nm; nmax (KBr): 1674, 1634, 1612, 1545,
1470, 1430 cm21; dH (300 MHz, CDCl3): 2.36 (bs,
3H, N±CH3), 2.63 (bm, 4H, 2£±CH2), 3.72 (bm, 4H,
2£±CH2), 7.27±7.36 (m, 2H, arom.-Hs), 7.59±7.64 (m,
1H, C7±H), 8.12 (br d, 1H, Jˆ7.8 Hz, C5±H), 10.13 (s,
1H, CHO); m/z (%) 272 (M1,10), 270 (17), 269 (45), 267
(10), 169 (95), 111 (48), 97 (22), 94 (39), 83 (43), 71 (100).
3.4.2. 6-Chloro-2-morpholino-3-formylchromone (7b).
Obtained by reacting 4b (313 mg, 1 mmol) with morpholine
(94 mg, 1.08 mmol) as light-yellow solid (7b, 271 mg);
(Found: C;57.45;H, 4.21;N, 4.89. C 14H12NO4Cl requires
C, 57.28;H, 4.12;N, 4.77%); lmax (MeOH): 365.2, 327,
285.6, 230.8 nm; nmax (KBr): 1672, 1639, 1619, 1542,
1434 cm21; dH (300 MHz, CDCl3): 3.69 (dist.t, 4H, Jˆ
5.1 Hz), 3.91 (dist. t, 4H, Jˆ5.1 Hz), 7.22 (d, 1H, Jˆ
8.8 Hz, C8±H), 7.55 (dd, 1H, Jˆ8.8, 2.5 Hz, C7±H), 8.26
(d, 1H, Jˆ2.5 Hz, C5±H), 10.11 (s, 1H, HCvO); dC
(75 MHz, CDCl3): 49.93 (CH2), 66.6 (CH2), 101.69 (C3),
116.16 (C8), 120.17 (C4a), 124.04 (C5), 131.44 (C6),
3.4.7. 6-Chloro-2-pyrrolidino-3-formylchromone (7g).
Obtained by reacting 4b (313 mg, 1 mmol) with pyrrolidine

2478
G. Singh et al. / Tetrahedron 58 (2002) 2471±2480
(85 mg, 1.19 mmol) as pale-yellow solid (7g, 252 mg);
(Found: C, 60.39;H, 4.49;N, 4.93. C 14H12NO3Cl requires
C, 60.55;H, 4.36;N, 5.04%); lmax (MeOH): 317, 278,
(CvO); m/z (%) 261 (M1, 11), 169 (100), 111 (46), 84
(37), 83 (47).
227 nm; nmax (KBr): 1674, 1638, 1624, 1545, 1440 cm21
;
3.5.3. 9-Methoxy-quinolino[2,3-b]chroman-12-one (8c).
The title compound (8c) was obtained by treating 5j
(295 mg, 1 mmol) with sulfuric acid, as creamy green
solid (265 mg);(Found: C, 73.87;H, 4.07;N, 4.94.
C17H11NO3 requires C, 73.64;H, 4.00;N, 5.05%); lmax
(CH3CN): 404, 317.5, 306, 259, 212 nm; nmax (KBr):
1659, 1601, 1560, 1497, 1462 cm21; dH (400 MHz,
CDCl3): 3.95 (s, 3H, OMe), 7.26 (dist. t, 1H, Jˆ2.7 Hz,
C10±H), 7.40 (dt, 1H, Jˆ7.5, 7.1, 1.0 Hz, arom.-H), 7.54
(dd, 1H, Jˆ9.3, 2.8 Hz), 7.60 (dd, 1H, Jˆ8.4, 0.6 Hz, 1H),
7.78 (ddd, 1H, Jˆ7.8, 7.7, 1.7 Hz), 7.97 (d, 1H Jˆ9.3 Hz,
C7±H), 8.32 (dd, 1H, Jˆ7.9, 1.7 Hz), 9.12 (s, 1H, C11±H);
dC (100 MHz, CDCl3): 55.72 (OCH3);105.76 (C10), 116.42
(C11a), 118.44 (CH), 121.00 (C12a), 124.19 (CH), 126.93
(CH), 127.17 (CH), 129.47 (CH), 135.92 (CH), 137.84
(CH), 145.66 (C6a), 156.24 (C4a), 156.26 (C9), 157.64
(C5a), 178.17 (CvO); m/z (%) 277 (M1, 12), 169 (95),
112 (31), 11 (44), 94 (23), 89 (32), 84 (32), 83 (46), 71
(98), 70 (79), 69 (100).
dH (300 MHz, CDCl3): 2.06 (broad, 4H, 2£CH2), 3.67
(broad, 4H, 2£CH2), 7.19 (d, 1H, Jˆ8.7 Hz, C8±H), 7.49
(dd, 1H, Jˆ8.7, 2.6 Hz, C7±H), 8.18 (bs, 1H, C5±H), 10.19
(s, 1H, CHvO); dC (75 MHz, CDCl3): 25.16 (CH2), 51.27
(N±CH2), 101.5 (C3), 118.04 (C8), 120.12 (C4a), 125.59
(C5), 129.59 (C6), 133.37 (C7), 151.48 (C8a), 161.19 (C2),
176.88 (C4), 187.02 (HCvO); m/z (%) 279 (M112, 12),
278 (M111, 14), 277 (M1, 21), 249 (65), 241 (41), 221
(100).
3.4.8. 2-Pyrolidino-3-formylchromone (7h). The title
compound (7h) was obtained by reacting 4a (279 mg,
1 mmol) with pyrrolidine (85 mg, 1.19 mmol) as cream
colored solid. (219 mg);(Found: C, 69.39;H, 5.24;N,
5.61. C14H13NO3 requires C, 69.11;H, 5.39;N, 5.76%);
lmax (MeOH): 318, 277, 229 nm; nmax (KBr): 1672, 1636,
1610, 1580, 1534 cm21; dH (300 MHz, CDCl3): 2.05 (broad,
4H, 2£±CH2), 3.69 (broad, 4H, 2£±CH2), 7.26 (d, 1H,
Jˆ8.2 Hz, C8±H), 7.35 (distorted triplet, 1H, Jˆ7.3 Hz,
C6±H), 7.59 (split triplet, 1H, Jˆ7.7, 1.6 Hz, C7±H), 8.18
(dd, 1H, Jˆ7.9, 1.6 Hz, C5±H), 10.25 (s, 1H, CHO); m/z
(%) 244 (M111, 2), 243 (M1, 12), 215 (12), 187 (13), 171
(28), 160 (14), 83 (34), 58 (100).
3.5.4. 7-Methoxy-quinolino[2,3-b]chroman-12-one (8d).
The title compound (8d) was obtained by treating 5m
(295 mg, 1 mmol) with sulfuric acid, as light green solid
(271 mg);(Found: C, 73.81;H, 4.25;N, 5.32. C 17H11NO3
requires C, 73.64;H, 4.00;N, 5.05%);
lmax (CH3CN):
375, 320, 269, 227 nm; nmax (KBr): 1663, 1605, 1519,
1498, 1396 cm21; dH (200 MHz, CDCl3): 4.05 (s, 3H,
OCH3), 7.58±7.10 (m, 5H, arom.-Hs), 7.70±7.60 (m, 1H,
arom.-H), 8.25 (bd, 1H, Jˆ8.0 Hz, C1±H), 9.16 (s, 1H,
C11±H); m/z (%) 277 (M1, 9), 169 (100), 154 (50), 153
(55), 112 (34), 111 (46), 98 (31), 97 (39), 96 (40), 84
(48), 83 (65), 71 (48), 70 (84), 69 (75).
3.5. General method of preparation of quinilino[2,3-b]-
chromones (8a±l)
2-Arylamino-3-formylchromones (2a,b, 5c±g and 5j±n,
1.0 mmol) were stirred with concentrated sulfuric acid
(1 mL) to make a paste, which was allowed to stand at
room temperature for 5±6 h. It was treated with ice-
cold water (100 mL), stirred and extracted with chloro-
form (2£100 mL). The chloroform extract was washed
thoroughly with water and dried over anhyd. sodium-
sulfate, ®ltered and the solvent was distilled off. The
obtained solid products (.95% pure, 1H NMR) were
re-crystallized from chloroform±pet. ether (4:1).
3.5.5. 9-Chloro-quinolino[2,3-b]chroman-12-one (8e).
The title compound (8e) was obtained by treating 5n
(299 mg, 1 mmol) with sulfuric acid, as yellow crystalline
solid (253 mg);(Found: C, 68.06;H, 2.99;N, 5.04.
C16H8NO2Cl requires C, 68.22;H, 2.86;N, 4.97%); lmax
(CH3CN): 376.5, 317.5, 290.5, 248 nm; nmax(KBr): 1658,
1605, 1578, 1493, 1472, 1448, 1410, 1300 cm21; dH
(200 MHz, CDCl3): 7.43±7.25 (m, 4H, arom.-Hs), 7.68 (d,
2H, Jˆ8.8 Hz, arom.Hs), 8.25 (dd, 1H, Jˆ7.8, 1.3 Hz,
C1±H), 9.05 (s, 1H, C11±H); m/z (%) 281 (M1, 22), 169
(100), 112 (61), 111 (90), 94 (64), 84 (64), 83 (92), 71 (99),
69 (91).
3.5.1. Quinolino[2,3-b]chroman-12-one (8a). The title
compound was obtained by treating 2a (265 mg, 1 mmol)
with sulfuric acid (1 mL) as white solid. (237 mg);mp
211±2128C, Lit.7a mp 210±2118C.
3.5.2. 9-Methyl-quinolino[2,3-b]chroman-12-one (8b).
The title compound (8b) was obtained by treating 5k
(279 mg, 1 mmol) with sulfuric acid as light green solid,
(251 mg);(Found: C, 78.06;H, 4.37;N, 5.51. C 17H11NO2
3.5.6. 2-Chloro-quinolino[2,3-b]chroman-12-one (8f). It
was obtained by treating 5d (299 mg, 1 mmol) with sulfuric
acid, as colorless crystals (8f, 264 mg);(Found: C, 68.48;H,
2.96;N, 5.07. C 16H8NO2Cl requires C, 68.32;H, 2.84;N,
4.98%); nmax (KBr): 1668, 1628, 1601, 1575, 1495,
1470 cm21; dH (200 MHz, CDCl3): 7.40 (d, 1H, Jˆ
6.9 Hz, arom.-Hs), 7.49±7.75 (m, 2H, arom.-Hs), 7.92 (m,
1H, arom.-Hs), 8.09 (dd, 1H, Jˆ7.0, 2.5 Hz, C3±H), 8.28
(d, 1H, Jˆ2.5 Hz, C1±H), 9.28 (s, 1H, C11±H); dC
(50 MHz, CDCl3): 116.82 (C11a), 118.52 (C4), 121.97
(C12a), 125.60 (CH), 126.61 (C10a), 127.17 (CH), 128.34
(CH), 129.04 (C2), 129.96 (CH), 133.69 (CH), 135.99 (C3),
140.24 (C11), 149.25 (C6a), 155.11 (C4a), 162.95 (C5a),
176.29 (C12); m/z (%) 283 (M112, 65), 281 (M1, 100).
requires C, 78.15;H, 4.24;N, 5.36%);
lmax (CH3CN):
377.5, 321.5, 308, 256.5, 29.5 nm; nmax: 1670, 1602,
1497, 1461, 1435, 1382 cm21; dH (400 MHz, CDCl3):
2.54 (s, 3H, ±CH3), 7.39 (ddd, 1H, Jˆ7.5, 7.4, 0.7 Hz),
7.59 (d, 1H, Jˆ8.3, arom.-H), 7.68 (dd, 1H, Jˆ8.7, 1.8,
arom.-H), 7.75±7.79 (m, 2H, arom.-Hs), 7.95 (d, 1H, Jˆ
8.7 Hz, arom.-H), 8.30 (dd, 1H, Jˆ7.9, 1.6 Hz, C5±H), 9.12
(s, 1H, C11±H); dC (100 MHz, CDCl3): 21.46 (CH3);
116.33 (C11a), 118.39 (C4), 120.95 (C12a), 124.22 (CH),
126.23 (C10a), 126.92 (CH), 127.76 (CH) 128.01 (CH),
135.92 (CH), 135.96 (C9), 136.36 (C3), 138.96 (C11),
147.94 (C6a), 156.18 (C4a), 157.04 (C5a), 178.11

G. Singh et al. / Tetrahedron 58 (2002) 2471±2480
2479
3.5.7. 2-Chloro-9-methyl-quinolino[2,3-b]chroman-12-
one (8g). The title compound (8g) was obtained by treating
5d (313 mg, 1 mmol) with sulfuric acid as light green solid
(277 mg);(Found: C, 69.23;H, 3.53;N, 4.90. C 17H10NO2Cl
requires C, 69.05;H, 3.41;N, 4.74%); lmax (CH3CN): 385,
372, 317, 250, 207 nm; nmax (KBr): 1655, 1600, 1508,
1470 cm21; dH (200 MHz, CDCl3): 2.61 (s, 3H, CH3),
7.57 (d, 1H, Jˆ8.8 Hz), 7.72 (bd, 2H, Jˆ8.8 Hz), 7.83 (s,
1H, C10±H), 7.99 (d, 1H, Jˆ8.6 Hz, C3±H), 8.27 (d, 1H,
Jˆ2.5 Hz, C5±H), 9.16 (s, 1H, C11±H); m/z (%) 297
(M112, 0.2), 296 (M111, 0.3), 295 (M1, 3), 169 (100),
112 (29), 111 (41), 94 (22), 89 (31), 84 (35), 83 (46), 69
(48).
Jˆ8.2, 9.2 Hz, C9±H, C8±H), 8.16 (d, 1H, Jˆ9.2 Hz,
C7±H), 8.40 (dd, 1H, Jˆ8.0, 1.5 Hz, C1±H), 8.80 (br
d, 1H, Jˆ8.2 Hz, C12±H), 10.00 (s, 1H, C13±H); dC
(100 MHz, CDCl3): 115.37 (C13a), 118.53 (C4), 121.37
(C14a), 123.14 (CH), 123.83 (C12a0), 124.52 (CH),
126.77 (CH), 126.98 (CH), 127.86 (CH), 128.47 (CH),
129.15 (CH), 130.07 and 131.16 (C8a and C12a), 133.60
(CH), 135.67 (CH), 135.88 (CH), 150.93 (C6a), 156.11
(C4a), 158.25 (C5a), 178.08 (C14); m/z (%) 298 (M111,
1), 297 (M1, 5), 169 (100), 112 (30), 111 (41), 97 (29), 94
(28), 85 (25), 84 (35), 83 (48).
3.5.12. 2-Chlorobenzo( f )quinolino[2,3-b]chroman-14-
one (8l). The title compound (8l) was obtained by treating
5e (348 mg, 1 mmol) with sulfuric acid as golden yellow
solid. (323 mg);(Found: C, 72.56;H, 3.24;N, 4.34.
C20H10NO2Cl requires C, 72.41;H, 3.04;N, 4.22%); lmax
(CH3CN): 386.5, 367, 348.5, 290, 247 nm; nmax (KBr):
1656, 1604, 1480, 1465, 1410, 1381 cm21; dH (200 MHz,
CDCl3): 7.64±7.82 (m, 4H, arom.-Hs), 7.82±7.96 (m, 2H,
arom.-Hs), 8.16 (d, 1H, Jˆ9.2 Hz, arom.-H, C7±H), 8.34 (d,
1H, Jˆ1.5 Hz, C1±H), 8.78 (d, 1H, Jˆ8.0 Hz, C12±H),
9.96 (s, 1H, C13±H); m/z (%) 333 (M112, 7), 332
(M111, 4), 331 (M1, 10), 169 (100), 112 (28), 111 (46),
94 (22), 89 (31), 84 (33), 83 (46).
3.5.8. 2-Chloro-9-methoxy-quinolino[2,3-b]chroman-12-
one (8h). The title compound (8h) was obtained by
treating 5c (329 mg, 1 mmol) with sulfuric acid as light
green solid. (295 mg);(Found: C, 65.69;H, 3.37;N, 4.43.
C17H10NO3Cl requires C, 65.50;H, 3.23;N, 4.49%); lmax
(CH3CN): 400.5, 315, 307, 255, 211 nm; nmax (KBr):
1658 (sharp), 1602, 1560, 1509, 1470 cm21; dH (200
MHz, CDCl3): 3.91 (s, 3H, OCH3), 7.16±7.22 (m, 1H,
arom.-Hs), 7.53±7.48 (m, 2H, arom.-Hs), 7.66±7.62 (m,
1H, arom.-Hs), 7.92 (d, 1H, Jˆ8.5 Hz, C3±H), 8.22 (bs,
1H, C1±H), 9.08 (s, 1H, C11±H); m/z (%) 311 (M1, (2)),
169 (98), 112 (31), 111 (45), 94 (22), 89 (29), 70 (69), 69
(48), 59 (100).
3.5.13. 6-Chloro-1H-[1]-benzopyrano[2,3-c]pyrazole-4-
one (9). 6-Chloro-2-N-methylanilino-3-formyl-chromone
(4b, 313 mg, 1 mmol) was dissolved in hot aqueous aceto-
nitrile (80:20, 60 mL) and the hydrazine hydrate (50 mg,
1 mmol) was added to the above solution, and the contents
stirred overnight at room temperature. A yellow solid
(110 mg), practically insoluble in any solvent, separated
out, which was ®ltered off. The ®ltrate was concentrated
under vacuum to ,1/5 of its original volume and kept at
room temperature, when the title compound (9) separated
out as a white crystalline solid in a day, and was re-crystal-
lized from acetone (99 mg, 45%);mp 241±242 8C;(Found:
C, 54.26;H, 2.39;N, 12.93. C 10H5N2O2Cl requires C, 54.44;
H, 2.28;N, 12.70%); lmax (MeOH): 322, 265, 223 nm; nmax
(KBr): 3274, 1649, 1636, 1586, 1465 cm21; dH (300 MHz,
DMSO-d6): 7.49 (d, 1H, Jˆ8.9 Hz, C8±H), 7.64 (dd, 1H,
Jˆ8.9, 2.73 Hz, C7±H), 8.20 (d, 1H, Jˆ2.7 Hz, C5±H),
8.24 (s, 1H, C3±H), 13.57 (b, 1H, N±H); dC(75 MHz,
DMSO-d6): 105.30 (C3), 119.35 (C8), 123.01 (C4a),
125.59 (C5), 127.95 (C10), 128.33 (C6), 133.70 (C7),
153.80 (C8a), 161 (C2), 173 (C4); m/z (%) 222 (M112,
18), 221 (M111, 9), 220 (M1, 45), 171 (10), 167 (29),
149 (72), 112 (15), 83 (77), 71 (58), 58 (100).
3.5.9. 2-Chloro-7-methoxy-quinolino[2,3-b]chroman-12-
one (8i). The title compound (8i) was obtained by treating
5f (329 mg, 1 mmol) with sulfuric acid as light green solid
(299 mg);(Found: C, 65.66;H, 3.37;N, 4.56. C 17H10NO3Cl
requires C, 65.50;H, 3.23;N, 4.49%);
lmax (CH3CN):
392.5, 347.5, 317.5, 272, 235 nm; nmax (KBr): 1661, 1605,
1558, 1519, 1498, 1477 cm21; dH (200 MHz, CDCl3): 4.07
(s, 3H, OCH3), 7.12±7.19 (m, 1H, arom.-H), 7.42±7.68 (m,
4H, arom.-Hs), 8.22 (d, 1H, 2.8 Hz, C1±H), 9.17 (s, 1H,
C11±H); m/z (%) 312 (M111, 19), 311 (M1, 48), 169
(100), 112 (31), 111 (47), 89 (29), 84 (32), 83 (47), 69 (44).
3.5.10.
2,9-Dichloro-quinolino[2,3-b]chroman-12-one
(8j). The title compound (8j) was obtained by treating 5g
(333 mg, 1 mmol) with sulfuric acid, as light green solid.
(286 mg);(Found: C, 60.93;H, 2.41;N, 4.28. C 16H7NO2Cl2
requires C, 60.79;H, 2.23;N, 4.43%);
lmax (CH3CN):
370.5, 313, 304, 252, 207.5 nm; nmax (KBr): 1645, 1604,
1588, 1551, 1451, 1404, 1297 cm21; dH (200 MHz,
CDCl3): 7.36±7.21 (m, 2H, arom.-Hs), 7.52±7.41 (m, 3H,
arom.-Hs), 8.25 (d, 1H, Jˆ2.6 Hz, C1±H), 9.11 (s, 1H,
C11±H); m/z (%) 316 (M111, 1), 315 (M1, 2), 169 (92),
112 (29), 11 (45), 94 (22), 89 (29), 84 (36), 58 (100).
3.5.14. 3-Chloro-12H-[1]-benzopyrano[2,3-e]-1,5-benzo-
diazepine (10). Chromone (4b, 313 mg, 1 mmol) was
dissolved in re¯uxing aqueous acetonitrile (80:20) and the
solution of o-phenylenediamine (108 mg, 1 mmol) in aceto-
nitrile (4 mL) was added to the above re¯uxing solution.
The contents were re¯uxed for 6 h and cooled. A yellow
crystalline solid which separated out was ®ltered and
washed with little cold acetonitrile and re-crystallized
from hexane±CHCl3 (3:1), to obtain the title compound
(10, 278 mg, 94%);mp 273±274 8C;(Found: C, 64.89;H,
2.95;N, 9.32. C 16H9N2O2Cl requires C, 64.77;H, 3.06;N,
9.44%); lmax (MeOH): 406, 340, 302, 247 nm; nmax (KBr):
3315, 2960, 1663, 1641, 1602, 1581, 1564, 1499 cm21; dH
3.5.11. Benzo( f )quinolino[2,3-b]chroman-14-one (8k).
The title compound (8k) was obtained by treating 5l
(314 mg, 1 mmol) with sulfuric acid, as golden yellow
solid. (279 mg);(Found: C, 80.93;H, 3.62;N, 4.94.
C20H11NO2 requires C, 80.80;H, 3.73;N, 4.71%); lmax
(CH3CN): 384, 364.5, 346, 286, 278, 247.5, 219.5 nm;
nmax (KBr): 1664, 1645, 1610, 1445, 1404, 1310 cm21; dH
(400 MHz, CDCl3): 7.46 (ddd, 1H, Jˆ8.0, 7.4, 1.1 Hz,
C2±H), 7.67 (dd, 1H, Jˆ8.4, 1.1 Hz, C4±H), 7.71 (ddd,
1H, Jˆ8.4, 7.4, 1.5 Hz, C3±H), 7.80±7.84 (m, 2H, C10±
H, C11±H), 7.98 and 7.96 (overlapping doublets, 2H,

2480
G. Singh et al. / Tetrahedron 58 (2002) 2471±2480
B. M.;Coles, S. J.;Hursthouse, M. B. J. Chem. Soc., Perkin
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Chem. 1999, 64, 8736. (m) Eiden, F.;Berndl, K. Arch. Pharm.
1986, 319, 347 and references cited therein. (n) Ghosh, C.;
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Schuler, E.;Michelotti, E. Tetrahedron Lett. 2001, 42, 5331.
(p) Wang, Y.;Tan, W.;Li, W. Z.;Li, Y. J. Nat. Prod. 2001,
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(200 MHz, CDCl3): 7.24±7.31 (m, 2H, arom.-Hs), 7.54±
7.59 (m, 2H, arom.-Hs), 7.66±7.74 (m, 2H, arom.-Hs),
8.31 (d, 1H, Jˆ2.47 Hz, C4±H), 9.32 (s, 1H, C6±H),
11.67 (bs, 1H, NH); m/z (%) 298 (M112, 4.1), 297
(M111, 3.2), 296 (M1, 10), 283 (4), 183 (16), 171 (22),
149 (15), 112 (20), 71 (48), 58 (100).
Acknowledgements
We thank Dr Patrick Perlmutter, Monash University,
Clayton, Australia for recording NMR spectra of some
samples.
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