2-(N-Methylanilino)-3-formylchromone - A versatile synthon for incorporation of chromone moiety in a variety of heterocyclic systems and macrocycles through reactions with bifunctional nucleophiles

Article abstract of DOI:10.1016/S0040-4020(02)00908-0

Reactions of 2-(N-methylanilino)-3-formylchromones with a number of bifunctional nucleophiles, involving substitution of N-methylanilino moiety and/or condensations with 3-formyl function have provided an easy access to a variety of potentially biologically active hetero-annelated chromones, novel macrocycles, and tetradentate ligands having intact chromone moiety.

Full text of DOI:10.1016/S0040-4020(02)00908-0

Tetrahedron 58 (2002) 7883–7890
2-(N-Methylanilino)-3-formylchromone—a versatile synthon for
incorporation of chromone moiety in a variety of heterocyclic
systems and macrocycles through reactions with
bifunctional nucleophiles
*
Gurmit Singh, Lakhwinder Singh and M. P. S. Ishar
Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India
Received 13 May 2002; revised 1 July 2002; accepted 25 July 2002
Abstract—Reactions of 2-(N-methylanilino)-3-formylchromones with a number of bifunctional nucleophiles, involving substitution of
N-methylanilino moiety and/or condensations with 3-formyl function have provided an easy access to a variety of potentially biologically
active hetero-annelated chromones, novel macrocycles, and tetradentate ligands having intact chromone moiety. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
number of chromano-heterocycles, and 2-alky/arylamino-
chromones (Scheme 1); the latter are highly sought after on
account of their valuable biological activities such as
antiplatelet, antiproliferative and antidepressant.7 Herein we
describe the further utilization of 2-(N-methylanilino)-3-
formylchromones through reactions with a number of
bifunctional nucleophiles to obtain a variety of chromano-
heterocycles, novel macrocycles having an intact chromone
moiety at the periphery and some novel tetradentate ligands
having an intact chromone moiety with potential appli-
cations as fluorescent sensors.
The chromone moiety forms the important component of
pharmacophores of a number of biologically active
molecules of synthetic as well as natural origin and many
of them have useful medicinal applications.1 Consequently,
chromone chemistry continues to draw considerable interest
of synthetic organic and medicinal chemists.2 Though,
3-formylchromone has emerged as a valuable synthon for
incorporation of the chromone moiety into a number of
molecular frameworks,3 its synthetic utility is limited due to
facile opening of the chromone ring3,4 and strategies are
being developed to circumvent it.5
2. Results and discussion
Recently, we have reported6 a facile conversion of C-(4-
oxo-4H[1]benzopyran3-yl)-N-phenylnitrones (1) to 2-(N-
methylanilino)-3-formylchromones (3) and the latter’s
utilization, by easy displacement of its N-methylanilino
moiety with a variety of nitrogen-nucleophiles, to obtain a
Earlier6 we had reported the reaction of 3b with o-phenyl-
enediamine leading to chromano-azepine (5b) in high
yield. We have now carried out, besides the reaction of
3a with o-phenylenediamine, the reactions of 3a,b with
Scheme 1.
Keywords: chromones; addition–elimination; condensation; chromano-azepines; chromano-oxazepines; chromano-thiazapine; chromanopyrazoles;
chromanopyrole; chromano-quinolines; macrocycles.
*
Corresponding author. Tel.: þ91-183-258808-Ã3321; fax: þ91-183-258819-20; e-mail: mpsishar@angelfire.com
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00908-0

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G. Singh et al. / Tetrahedron 58 (2002) 7883–7890
hydrate in aqueous-acetonitrile (80:20), affords chromano-
pyrazole (6a, 45%).6 Now the reactions of 3a,b have been
carried out with phenylhydrazine in refluxing dry aceto-
nitrile leading to chromano-pyrazoles (6b,c), derived from
an initial condensation of phenylhydrazine with the formyl
group followed by nucleophilic substitution at C2. How-
ever, in the reaction of 3a (X¼H) with phenylhydrazine,
another product (6b0) derived from initial substitution at C2
followed by condensation with the formyl group was also
formed (Scheme 3). The structures of the products are again
1
based on spectroscopic analysis. In the H NMR of 6b the
C3–H appeared as a singlet at d 8.58 and C5–H at d 8.29
(dd, 1H), while in case of 6b0, the C5–H appeared at d 8.36
(dd, 1H) and C3–H at d 8.25 (s, 1H); these structural
conclusions are supported by a comparison of the NMR
spectral data of 6b, 6b0 and 6c and corroborated by 13C
NMR as well as mass spectral data.
Scheme 2.
ortho-substituted anilines such as o-aminophenol, and
o-amino-thiophenol, leading to chromano-heterocyclic
systems (5a–e, Scheme 2). In the case of reaction with
o-phenylenediamine, the best yield of diazepine (5a) was
obtained when reaction was carried out in aqueous-
acetonitrile (80:20). The use of anhydrous solvents led
only to highly insoluble products, which could not be
investigated further. The corresponding reactions with
o-aminophenol and o-aminothiophenol were carried out in
refluxing xylene and afforded chromano-oxazepines
(5c,d), and chromano-thiazepine (5e), respectively, in high
yields.
It has been reported3h that reaction of 3-formylchromone
with ethyl glycinate affords products, which are derived
from opening of the chromone ring. Presently, we have
reacted 3a with methyl glycinate-hydrochloride by refluxing
in aqueous-acetonitrile, in the presence of triethylamine,
which led to isolation of the C2 substituted product (7,
Scheme 4) in 91% yield; the latter has been characterized
spectroscopically. Its 1H NMR revealed, inter alia,
aldehydic proton resonance at d 10.27 along with a 2H
doublet at d 4.37 and a 3H singlet at d 3.87.9 However, when
potassium carbonate was used instead of triethylamine, the
in situ formed 7 underwent intramolecular cyclization to
chromano-pyrrole (8). Refluxing of 7 in aqueous-aceto-
nitrile in the presence of potassium carbonate also led to
formation of 8. The structure of 8 has been assigned based
on spectroscopic analyses. The characteristic features of its
1H NMR spectrum being a broad singlet at d 9.56 (C3–H)
and a 3H singlet d 3.75 (–OCH3); the doublet at d 4.37
observed in the case of 7, disappears in the 1H NMR
spectrum of 8. The mass spectrum of 8 was also in
consonance with the assigned structure.
The structures have been arrived at by detailed spectro-
scopic analysis and comparison of the spectroscopic data
with the data reported for related systems.8 The C12–H in
1
the H NMR of oxazepine (5c) appeared at d 8.89 (1H
singlet) and C1–H as a broad doublet at d 8.37; all other
proton resonances were in the aromatic region. The 13C
NMR spectrum of 5c revealed, inter alia, the C13 resonance
at d 172.81, which was in consonance with an intact
chromone ring;6 assigned structures are also corroborated
by IR, microanalytical and mass spectral data.
We had reported earlier that reaction of 6-chloro-2-N-
methylanilino-3-formylchromones (3b) with hydrazine-
Scheme 3.
Scheme 4.

G. Singh et al. / Tetrahedron 58 (2002) 7883–7890
7885
Scheme 5.
chromone moiety is intact;6 the FAB-mass spectrum
[(MþH)þ at m/z 481.3] also corroborated the structure.
Compound 9 on treatment with one molar equivalent of
m-xylene-diamine in dry-acetonitrile afforded the 2þ2
‘head to head’ macrocycle (10, Scheme 5) in high yield,
whose formation has been confirmed by FAB-mass
spectrum through (MþH)þ ion at 581.3.
On the other hand reaction of 3a with m-aminophenol in
refluxing xylene led to 3þ3-macrocycle (11) in high yield
(Scheme 6). The formation of the macrocycle (11) has been
established, inter alia, by FAB-mass spectrum [(MþH)þ at
792.4) and comparison of NMR spectral data with that of
5c,d.
Scheme 6.
Recently, some interesting applications such as a receptor
for hydroxycarboxylates have been reported for a chromone
based macrocycle.10 However, attempts at obtaining
macrocycles by reacting 3-formylchromone with diamines
had led to only ring-opened products.3i A lot of attention is
being drawn towards the development of fluorescent metal
sensors, mainly based on the common design that a
modulation of fluorescence occurs whenever a fluorophore
interacts directly with the nonbonding electrons of a metal-
chelating group.11 Therefore, a facile route to macrocycles
involving a 2-amino/oxygen-substituted chromone moiety
was a highly desired objective. Towards this end, it was
decided to react 3 with a,v-diamines. When equivalent
amounts of 3a and m-xylene-diamine were refluxed in dry-
acetonitrile, the product obtained was a white solid having
very low solubility. It appeared to be a 2þ2 macrocycle
from its FAB-mass and IR spectra; the latter did not reveal
presence of a band due to a formyl group, anticipated around
1670–1690 cm21, however, its exact structure (head to
head or head to tail) could not be established. Alternatively,
when half molar equivalent of amine was refluxed with 3a in
aqueous-acetonitrile, the disubstituted product (9) with
intact chromone moiety was obtained in high yield, which
As a variation, compound 3a was reacted with dipiperidine-
hydrochloride (half molar equivalent), by stirring in dry-
acetonitrile at 708C, in presence of anhydrous-potassium
carbonate, which resulted in the disubstituted product (12,
Scheme 7) in high yield (95%). The structure of 12 has been
established spectroscopically. However, attempted conden-
sation of 12 with aliphatic diamines such as 1,3-diamino-
propane and 1,4-diaminobutane did not yield any
macrocycle as nucleophilic substitution by amines at C2
predominated.
However, when m-phenylenediamine was reacted with 3a
by refluxing in xylene, it led to formation of only oligomeric
materials and no characterizable product was isolated. On
the contrary refluxing equimolar aqueous-acetonitrile
(80:20) solutions of m-phenylenediamine and 3a,b led to
chromano-quinolines (13a,b) in good yield, which are
derived from intramolecular cyclization of the C2 sub-
stituted intermediate (B, Scheme 8). The structures of 13a,b
have been established by detailed spectroscopic analysis.
1
The H NMR of 13b revealed two singlets (1H each) at d
9.03 and d 7.08, three doublets (1H each) at d 8.26, d 7.84,
and d 7.54, and two (1H) double doublets (d 7.67 and d
6.99). The assigned structures are also supported by the
respective mass spectra. It may be mentioned here that such
chromano-tetracycles have been ascribed a number of
useful biological activities.12
1
was characterized spectroscopically. Its H NMR spectrum
showed a broad singlet (2H) at d 11.00 due to N–Hs and
aldehydic proton resonances at d 10.23 (bs, 2H). Appear-
ance of C5–H at d 8.22 as a broad doublet indicated that the
Scheme 7.

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G. Singh et al. / Tetrahedron 58 (2002) 7883–7890
Scheme 8.
Scheme 9.
In addition to the macrocyclic fluorescent receptors, a
number of non-cyclic fluorescent ligands based on the same
general approach discussed above are also finding valuable
application.11 Presently, we have utilized 2a to obtain non-
cyclic ligands (14, Scheme 9) containing intact fluorescent
chromone moiety. These have been characterized spectro-
scopically. The NH protons in these molecules (14) appear
in the region d 12–14 and it is anticipated that these NH
groups will be deprotonated during complexation with
metal ions. The 2-anilino moieties in 14 can be replaced by
other arylamino or sec·amino groups6 and this can be
utilized to modulate the spectral properties of these ligands.
The investigations on complexation of these ligands with
metal ions are in progress and shall be reported elsewhere.
All melting points are uncorrected and measures in open
glass-capillaries. Column chromatography was conducted
using silica gel 60–120 mesh (Acme, India). Solvents,
starting materials and reagents were purchased from
commercial suppliers and used after purification (crystal-
lization/distillation). 3-Formylchromones were purchased
from Aldrich and used as supplied.
3.1.1. 6H-[1]-Benzopyrano[2,3-b][1,5]-benzodiazepine-
13-one (5a). 2-(N-Methylanilino)-3-formylchromone 3a
(279 mg, 1 mmol) was dissolved in refluxing aqueous-
acetonitrile (80:20) and the solution of o-phenylenediamine
(108 mg, 1 mmol) in acetonitrile (4 mL) added to it, and the
contents were refluxed for 6 h and cooled. Yellow crystal-
line solid (5a), which separated out was filtered and washed
with little acetonitrile and re-crystallized from hexane–
CHCl3 (3:1), (Yield 241 mg, 0.92 mmol, 92%), mp 268–
2698C (hexane–CHCl3 3:1); lmax (MeOH): 312.4, 285.8,
247 nm; nmax (KBr): 3230 (b), 1642, 1626, 1581, 1533,
The reactions of 2-(N-methylanilino)-3-formylchromones
with various bifunctional nucleophiles have, thus, provided
an easy access to a large number potentially biological
active heteroannulated-chromones and macrocycles having
an intact chromone moiety at the periphery. The reaction
with m-phenylenediamine, however, results in an amino-
substituted chromanoquinoline and such chromane based
polycyclic molecules are known to display useful biological
activities.12 Macrocycles as well as synthesized noncyclic
ligands having intact fluorescent chromone moieties on the
periphery can be useful as fluorescent sensors.
1
1461, 1404, 1378 cm21; H NMR (200 MHz, CDCl3): d
11.78 (bs, 1H, NH), 9.33 (s, 1H, C12–H), 8.32 (bd, 1H,
J¼8.36 Hz, C1–H), 7.81–7.74 (m, 2H, arom-Hs), 7.62–
7.49 (m, 3H, arom-Hs), 7.30–7.25 (m, 2H, arom-Hs); mass
m/z: 263 (Mþþ1, 8), 262 (Mþ, 26), 171 (86), 71 (100). Anal.
calcd for C16H10N2O2: C, 73.27; H, 3.84; N, 10.68%; found:
C, 73.65; H, 3.65; N, 10.81.
3.1.2. [1]Benzopyrano[2,3-b][1,5]-benzoxazepin-13-one
(5c). A solution of 2-(N-methylanilino)-3-formylchromone
(3a, 279 mg, 1 mmol) and o-aminophenol (109 mg,
1 mmol) in xylene (50 mL) was refluxed, and the progress
of the reaction was monitored by tlc. After the completion of
reaction (20 h), the solvent was evaporated under vacuum.
Crystallization of the residue from acetonitrile (5 mL)
afforded the title compound (5c, 234 mg, 0.89 mmol, 89%)
as a reddish-crystalline solid, mp 140–418C (hexane–
CHCl3 3:1); lmax (MeOH): 342, 306, 260 nm; nmax (KBr):
1663, 1621, 1573, 1527, 1512, 1428, 1338, 1302, 1262,
3. Experimental
3.1. General information
NMR spectra were recorded on Bruker 200 MHz FT NMR
spectrometer, CDCl3/DMSO-d6/D2O as solvents. Chemical
shifts are reported in ppm as down field displacements from
tetramethylsilane used as internal standard. Mass spectra
were recorded on a Shimadzu GCMS-QP-2000A spec-
trometer. The microanalytical data were collected on a
Perkin–Elmer 240C elemental analyzer. IR spectra were
recorded on a Shimadzu DR 2001 IR spectrophotometer as
pellets with KBr and are reported in wave numbers (cm21).
1
1208, 1085, 1041 cm21; H NMR (200 MHz, CDCl3): d
8.89 (s, 1H, C12–H), 8.37 (bd, 1H, J¼7.56 Hz, C1–H),
7.77–7.69 (m, 2H, arom-Hs), 7.62–7.44 (m, 3H, arom-Hs),

G. Singh et al. / Tetrahedron 58 (2002) 7883–7890
7887
7.36–7.24 (m, 2H, arom-Hs); 13C NMR (50 MHz, CDCl3):
d 172.81 (C13), 158.36 (C12), 157.53 (C5a), 155.66 (C4a),
150.39 (C6a), 141.20 (C10a), 134.14 (CH), 126.69 (CH),
126.16 (CH), 125.29 (CH), 124.66 (C13a), 124.56 (CH),
120.20 (CH), 118.11 (C4), 113.96 (C12a), 110.78 (CH);
mass m/z: 264 (Mþþ1, 8), 263 (Mþ, 40), 169 (70), 111 (44),
83 (49), 71 (100). Anal. calcd for C16H9NO3: C, 73.00; H,
3.45; N 5.32%; found: C, 72.79; H, 3.42; N, 5.41.
1.24 Hz, C5–H in 6b), 8.25 (s, 1H, C3–H in 6b0), 7.90 (d,
2H, J¼7.92 Hz, arom-Hs), 7.79–7.67 (m, 2H, arom-Hs),
7.66–7.25 (m, 4H, arom-Hs); 13C NMR (50 MHz, CDCl3):
d 174.56 (C4 in 6b), 172.60 (C4 in 6b0), 162.06 (C9a in 6b),
155.63 (C8a in 6b), 154.37 (C9a in 6b0), 152.70 (C8a in
6b0), 138.96 (q), 137.00 (q), 136.74 (C3 in 6b), 134.49 (C7
in 6b), 133.95 (CH), 129.69 (CH), 129.43 (CH), 128.12
(CH), 127.71 (CH), 127.07 (CH), 126.82 (CH), 125.32
(CH), 125.15 (CH), 124.04 (C3 in 6b0), 122.99 (C4a in 6b0),
122.27 (C4a in 6b), 121.36 (CH), 119.61 (CH), 118.08 (C8
in 6b), 117.63 (C8 in 6b0), 106.73 (C3a in 6b0), 106.53 (C3a
in 6b); mass m/z: 263 (Mþþ1, 18), 262 (Mþ, 100). Anal.
calcd for C16H10N2O2: C, 73.27; H, 3.84; N, 10.68%; found:
C, 73.43; H, 3.72; N, 10.57.
3.1.3. 2-Chloro-[1]benzopyrano[2,3-b][1,5]-benzoxaze-
pin-13-one (5d). A solution of 6-chloro-2-(N-methyl-
anilino)-3-formylchromone (3b, 313 mg, 1 mmol) and
o-aminophenol (109 mg, 1 mmol) in xylene (50 mL) was
refluxed for 20 h. Removal of solvent under vacuum and
crystallization of the residue from acetonitrile afforded the
title compound (5d, 270 mg, 0.91 mmol, ,91%) as a
brownish-crystalline solid, mp 181–828C (hexane–CHCl3
3:1); lmax (CHCl3): 304.2, 282.6, 246.2 nm; nmax (KBr):
1660, 1623, 1596, 1573, 1522, 1503, 1456, 1387, 1365,
3.1.6. 6-Chloro-1-phenyl-[1]-benzopyrano[2,3-c]pyra-
zole-4-one (6c). Reaction of 6-chloro-2-(N-methyl-
anilino)-3-formylchromone (3b, 313 mg, 1 mmol) with
phenylhydrazine (108 mg, 1 mmol) according to the
procedure described above, afforded 6c (267 mg,
0.90 mmol, 90%) as a light yellow crystalline solid, mp
281–828C (acetonitrile); lmax (MeOH): 344, 297.5,
245 nm; nmax (KBr): 1641, 1576, 1558, 1535, 1452, 1420,
1324, 1292, 1231, 1181, 1168, 1142 cm21 1H NMR
;
(200 MHz, CDCl3): d 8.89 (s, 1H, C12–H), 8.32 (d, 1H,
J¼2.20 Hz, C1–H), 7.81–7.59 (m, 2H, arom-Hs), 7.50 (d,
1H, J¼8.85 Hz, arom-H), 7.38–6.71 (m, 3H, arom-Hs);
mass m/z: 299 (Mþþ2, 8), 297 (Mþ, 51), 273 (32), 169
(100). Anal. calcd for C16H8NO3Cl: C, 64.55; H, 2.71; N,
4.71%; found: C, 64.71; H, 2.94; N, 4.99.
;
1410, 1255, 1188, 1095 cm21 1H NMR (200 MHz,
CDCl3): d 8.59 (s, 1H, C3–H), 8.29 (bs, 1H, C5–H), 7.80
(bd, 2H, J¼7.65 Hz, arom-Hs), 7.68–7.43 (m, 5H, arom-
Hs); mass m/z: 298 (Mþþ2, 19), 297 (Mþþ1, 10), 296 (Mþ,
49), 169 (80), 111 (47), 83 (49), 71 (100). Anal. calcd for
C16H9N2O2Cl: C, 64.77; H, 3.06; N, 9.44%; found: C,
64.99; H, 2.92; N, 9.12.
3.1.4. 2-Chloro-[1]benzopyrano[2,3-b][1,5]-benzothiaze-
pin-13-one (5e). A solution of 6-chloro-2-(N-methyl-
anilino)-3-formylchromone (3b, 313 mg, 1 mmol) and
o-aminothiophenol (125 mg, 1 mmol) in xylene (50 mL)
was refluxed for 13 h and the solvent was evaporated under
vacuum. The crude product was directly crystallized from
acetonitrile (20 mL) to afford (5a, 298 mg, 0.95 mmol,
95%) as a light yellow crystalline solid, mp 291–928C
(acetonitrile); lmax (MeOH): 326, 279, 247.5, 226 nm; nmax
(KBr): 1647, 1621, 1571, 1517, 1482, 1460, 1408, 1320,
3.1.7. 2-Methoxycarbonylmethylamino-3-formyl-
chromone (7). 2-(N-Methylanilino)-3-formylchromone
(3a, 279 mg, 1 mmol) was dissolved in refluxing aqueous-
acetonitrile (80:20) and a solution of methyl glycinate-
hydrochloride (126 mg, 1 mmol) in water (4 mL) and a few
drops of triethylamine were added to the above solution.
The contents were refluxed for 3 h. The solvent was distilled
off and the traces were evaporated under vacuum. The crude
product was directly crystallized from methanol to afford 7
(238 mg, 0.91 mmol, 91%) as a cream-colored solid; mp
192–1938C (decomposes); lmax (CHCl3): 270.2, 243 nm;
1
1288, 1140 cm21; H NMR (200 MHz, CDCl3): d 9.31 (s,
1H, C12–H), 8.37 (d, 1H, J¼2.51 Hz, C1–H), 8.06–8.02
(m, 2H, arom-Hs), 7.81–7.55 (m, 4H, arom-Hs); mass m/z:
315 (Mþþ2, 29), 314 (Mþþ1, 8), 313 (Mþ, 60), 169 (92),
111 (49), 71 (100). Anal. calcd for C16H8NO2SCl: C, 61.25;
H, 2.57; N, 4.46%; found: C, 60.96; H, 2.69; N, 4.55.
n
max (KBr): 3400 (b), 2897, 1724, 1686, 1616, 1578, 1504,
;
1481, 1472, 1438, 1406, 1394, 1331 cm21 1H NMR
3.1.5. Reaction of 2-(N-methylanilino)-3-formyl-
chromone (3a) with phenylhydrazine. Phenylhydrazine
(108 mg, 1 mmol) in acetonitrile (10 mL) was added to a
solution of 3a (279 mg, 1 mmol) in refluxing dry-aceto-
nitrile (50 mL) and the contents were refluxed until the
reaction completed (9 h, tlc). The solvent was then
evaporated under vacuum to 1/5 of its original volume
and the solution was kept in a refrigerator. The crystals
appeared in 2 h were filtered and washed with cold
acetonitrile (1 mL) to obtain a crystalline solid, which was
recrystallized from acetonitrile to obtain light yellow
crystals (250 mg, 95%), which melted at 218–2198C, but
were revealed to be a mixture (7:1, 1H NMR) of two closely
related compounds characterized as 6b and 6b0; lmax
(CHCl3): 327, 331, 297.4, 247.6, 293.6, 261, 244 nm; nmax
(KBr): 1689, 1639, 1632, 1614, 1600, 1575, 1558, 1506,
(200 MHz, CDCl3): d 10.97 (bs, 1H, NH), 10.27 (s, 1H,
CHO), 8.24 (bd, 1H, J¼7.53 Hz, C5–H), 7.62 (distorted t,
1H, J¼7.51 Hz, C7–H), 7.48–7.27 (m, 2H, arom-Hs), 4.37
(d, 2H, J¼5.80 Hz, N–CH2), 3.87 (s, 3H, OMe); mass m/z:
262 (Mþþ1, 44), 261 (Mþ, 91), 260 (45), 171 (84), 71
(100). Anal. calcd for C13H11NO5: C, 59.77; H, 4.24; N,
5.36%; found: C, 60.00; H, 4.23; N, 5.52.
3.1.8. 2-Methoxycarbonyl[1]benzopyrano[2,3-b]pyrrole-
4-one (8). 2-(N-Methylanilino)-3-formylchromone (3a,
279 mg, 1 mmol) was dissolved in refluxing aqueous-
acetonitrile (80:20, 50 mL) and a solution of methyl
glycinate-hydrochloride in water (5 mL) was added to the
above solution, followed by potassium carbonate (276 mg,
2 mmol), and the contents were refluxed with stirring for 2 h
when a cream-colored crystalline compound separated out,
which was filtered, and washed with acetonitrile. (Yield
228 mg, 0.94 mmol, 94%); mp 271–728C decomposes
(water); lmax (MeOH): 262.5, 291 nm; nmax (KBr): 3040
1478, 1438, 1412, 1255, 1190, 1095 cm21 1H NMR
;
(200 MHz, CDCl3): d 8.58 (s, 1H, C3–H in 6b), 8.36 (dd,
1H, J¼8.04, 1.24 Hz, C5–H in 6b0), 8.29 (dd, 1H, J¼8.04,

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G. Singh et al. / Tetrahedron 58 (2002) 7883–7890
1
(b), 1715, 1656, 1631, 1582, 1511, 1485, 1420 cm21; H
NMR (200 MHz, D2O): d 9.56 (s, 1H, C3–H), 7.62 (bd, 1H,
J¼7.51 Hz, C5–H), 7.42 (dist. t, 1H, J¼7.52 Hz, C7–H),
7.17–7.04 (m, 2H, arom-Hs), 3.75 (s, 3H, OMe); mass m/z:
243 (Mþ, 11), 242 (Mþ21, 13), 241 (45), 227 (21), 207
(23), 171 (92), 71 (100). Anal. calcd for C13H9NO4: C,
64.20; H, 3.73; N, 5.76%; found: C, 63.99; H, 3.97; N, 5.92.
(10 mL) was added to the above solution. The contents were
refluxed with stirring and the progress of the reaction was
monitored with tlc. After 20 h the solvent was evaporated to
1/4 of its original volume when a dark brown crystalline
solid (11) separated out, which was filtered and washed with
a little cold xylene and recrystallized from acetone. Yield
248 mg, 0.313 mmol, 94%, mp .2758C (acetone); lmax
(CHCl3): 348.6, 268.6, 245 nm; nmax (KBr): 1671, 1616,
1538, 1492, 1428, 1387, 1374, 1313, 1276, 1241, 1230,
1164 cm21; 1H NMR (200 MHz, DMSO-d6–CDCl3, 1:1): d
9.16 (s, 3H, HCvN£3), 8.22 (bd, 3H, J¼7.85 Hz, C5–
H£3), 8.10–8.06 (m, 6H, arom-Hs), 7.86–7.82 (m, 3H,
arom-Hs), 7.64–7.60 (m, 3H, arom-Hs), 7.50–7.42 (m, 6H,
arom-Hs), 7.26–7.21 (m, 3H, arom-Hs); 13C NMR
(50 MHz, DMSO-d6–CDCl3, 1:1): d 176.54 (CvO),
162.40 (CvN), 157.08 (C2), 154.93 (C8a), 150.65 (q),
138.29 (q), 135.24 (CH), 131.06 (CH), 125.66 (CH), 123.65
(CH), 120.16 (CH), 120.10 (C4a), 119.30 (C8), 117.48
(CH), 112.57 (C3), 107.92 (CH); mass (FAB) m/z: 792.4
[(MþH]þþ2, 21], 790.3 [(MþH]þ, 76], 624.6 (100). Anal.
calcd for C48H27N3O9: C, 73.00; H, 3.45; N, 5.32%; found:
C, 73.39; H, 3.79; N, 5.20.
3.2. Conversion of 2-methoxycarbonylmethylamino-3-
formylchromone (7) to 2-methoxy-carbonyl[1]benzo-
pyrano[2,3-b]pyrrole-4-one (8)
2-Methoxycarbonylmethylamino-3-formylchromone (7,
131 mg, 0.5 mmol) was dissolved in aqueous-acetonitrile
(80:20) and anhydrous potassium-carbonate (100 mg) was
added to it. The contents were refluxed with stirring for 3 h,
when cream colored crystals of 2-methoxycarbonyl[1]ben-
zopyrano[2,3-b]pyrrole-4-one (8) separated were filtered
and washed with acetonitrile (yield 115 mg, 0.47 mmol,
95%).
3.2.1. N,N0-Bis(4-oxo-3-formyl-4H[1]benzopyran-2-yl)-
m-xylenediamine (9). 2-(N-Methylanilino)-3-formyl-
chromone (3a, 279 mg, 1 mmol) was dissolved in refluxing
aqueous-acetonitrile (80:20, 50 mL) and a solution of
m-xylenediamine (68 mg, 0.5 mmol) in acetonitrile (4 mL)
was added to it. The contents were refluxed for 3 h and the
solvent was distilled off under vacuum. The obtained
product was directly crystallized from methanol to obtain
the title compound as a white crystalline solid (226 mg,
0.47 mmol, 94%), mp 266–2678C (methanol); lmax
(CHCl3): 357.2, 305.4, 298.4, 272.2, 245.2 nm; nmax
(KBr): 3210 (b), 1682, 1674, 1632, 1585, 1494, 1468,
3.2.4. 1,10-Bis(4-oxo-3-formyl-4H[1]benzopyran-2-yl)-
4,40-bipiperidine (12). 2-(N-Methylanilino)-3-formyl-
chromone (3a, 279 mg, 1 mmol) was dissolved in dry-
acetonitrile (200 mL) and to the stirred solution were adde0d
anhydrous potassium carbonate (276 mg, 2 mmol), and 4,4 -
bipiperidine-dihydrochloride (121 mg, 0.5 mmol). The con-
tents were stirred at 808C until the completion of reaction
(6 h, tlc). The solvent was distilled off and the solid mass
was dissolved in chloroform (200 mL), filtered and the
solvent was distilled off to afford the title compound as a
white crystalline solid (233 mg, 0.455 mmol, 91%), mp
273–2748C (chloroform–hexane 1:3); lmax (CHCl3): 321,
283.6, 243.4 nm; nmax (KBr): 1673, 1618, 1546, 1462, 1424,
1413, 1338 cm21; 1H NMR (200 MHz, CDCl3): d 10.14 (s,
2H, 2£CHO), 8.18 (bd, 2H, J¼7.82 Hz, 2£C5–H), 7.61
(dist. t, 2H, J¼7.22 Hz, 2£C7–H), 7.41–7.26 (m, 4H,
arom-Hs), 4.10 (d, 4H, J¼12.74 Hz, C20-Hs-axial), 3.24
(unresolved t, 4H, C20-Hs-equitorial), 2.00–1.93 (m, 4H,
C30-Hs-axial), 1.60–1.54 (m, 40H, C30-Hs-equatorial),
1.24–1.20 (m, 2H, C4–H and C4 –H); mass (FAB) m/z:
514.3 [(MþH)þþ1, 40], 513.3 [(MþH)þ, 100], 485.3 (8),
360.4 (13), 341.3 (14), 338.5 (11). Anal. calcd for
C30H28N2O6: C, 70.30; H, 5.51; N, 5.47%; found: C,
70.09; H, 5.23; N, 5.62.
1
1440, 1376, 1358, 1324, 1228 cm21; H NMR (200 MHz,
CDCl3): d 11.00 (bs, 2H, NH£2), 10.23 (s, 2H, 2£CHO),
8.22 (bd, 2H, J¼7.88 Hz, C5–H£2), 7.60 (unresolved t, 2H,
J,7.12 Hz, C7–H£2), 7.43–7.26 (m, 8H, arom-Hs), 4.78
(d, 4H, J¼5.96 Hz, benzylic-Hs); mass (FAB) m/z: 482.3
[(MþH)þþ1, 40], 481.3 [(MþH)þ, 100], 291.3 (8), 279.1
(8). Anal. calcd for C28H20N2O6: C, 69.99; H, 4.20; N,
5.83%; found: C, 69.60; H, 4.46; N, 5.59.
3.2.2. Reaction of N,N0-bis(4-oxo-3-formyl-4H[1]benzo-
pyran-2-yl)-m-xylenediamine (10) with m-xylenedi-
amine. N,N0-Bis(4-oxo-3-formyl-4H[1]benzopyran-2-yl)-
m-xylenediamine (9, 120 mg, 0.25 mmol) was dissolved in
a mixture of acetonitrile-dichloromethane (2:1, 50 mL) and
a solution of m-xylenediamine (34 mg, 0.25 mmol) in
acetonitrile (5 mL) was added to the above stirred solution.
The contents were stirred overnight at room temperature. A
white solid (10), which separated out was filtered and was
found to be practically insoluble in any solvent. Yield
139 mg, 0.24 mmol, 96%, mp 251–528C; nmax (KBr): 3320
(b), 1645, 1590, 1539, 1469, 1452, 1422, 1340, 1247, 1232,
1195, 1128, 1105, 1087 cm21; mass (FAB) m/z: 583.3
[(MþH)þþ2, 9], 582.3 [(MþH)þþ1, 41], 581.3 [(MþH)þ,
100], 291.3 (6). Anal. calcd for C36H28N4O4: C, 74.47; H,
4.86; N, 9.65%; found: C, 74.12; H, 4.81; N, 9.77.
3.3. General procedure for the reaction of 3a,b with 1,3-
diaminobenzene in aqueous-acetonitrile
Compounds (3a,b, 1 mmol) were dissolved in refluxing
aqueous-acetonitrile (50 mL) and solutions of m-phenyl-
enediamine (108 mg, 1 mmol) in acetonitrile (10 mL) were
added to the above solutions. The contents were refluxed
with stirring for 6 h after which the solvent was evaporated
and the crude was purified over silica gel column (60–
120 mesh) using hexane–ethyl acetate (9:1) as eluent. The
products (13a,b) were recrystallized from acetonitrile.
3.2.3. Reaction of 3a with m-aminophenol leading to
macrocycle (11). 2-(N-Methylanilino)-3-formylchromone
(3a, 279 mg, 1 mmol) was dissolved in xylene (50 mL) and
a solution of m-aminophenol (109 mg, 1 mmol) in xylene
3.3.1. 8-Amino-quinolino[2,3-b]chroman-12-one (13a).
2-(N-Methylanilino)-3-formylchromone (3a, 279 mg,
1 mmol) was treated with m-phenylene-diamine (108 mg,

G. Singh et al. / Tetrahedron 58 (2002) 7883–7890
7889
1 mmol) to afford the title compound (13a, 176 mg,
compound as
a
crystalline yellow solid (266 mg,
0.67 mmol, 67%) as a dark brown solid, mp 267–688C
(acetonitrile); nmax (KBr): 3350 (b), 3134 (b), 1622 (w),
1614 (w), 1577, 1552, 1535, 1467, 1432, 1347, 1331, 1290,
0.48 mmol, 96%), mp 211–2128C (acetonitrile); nmax
(KBr): 3100 (b), 2980 (b), 1650 (s), 1605 (s), 1581 (s),
1487, 1444, 1393, 1346, 1290, 1251, 1213 cm21; lmax
(CHCl3): 368, 319.5, 286.5, 246.5 nm; 1H NMR (200 MHz,
CDCl3): d 12.40 (bs, 2H, N–Hs), 8.64 (s, 2H, HCvN), 8.14
(d, 2H, J¼7.52 Hz, C5–Hs), 7.47 (dis. t, 2H, J¼7.24 Hz,
C7–Hs), 7.24–6.91 (m, 14H, arom-Hs), 3.69 (s, 4H,
–CH2–£2); 13C NMR (50 MHz, CDCl3): 176.31 (CvO),
157.68 (CvN), 153.51 (C2), 152.1 (C8a), 141.2 (q), 133.55
(CH), 128.55 (CH), 126.19 (CH), 123.99 (CH), 122.99
(CH), 121.31 (C4a), 116.54 (C8), 96.94 (C3), 53.61 (CH2).
Anal. calcd for C34H26N4O4: C, 75.63; H, 4.73; N, 10.10%;
found: C, 75.49; H, 4.41; N, 9.81.
1262, 1189, 1120, 1100 cm21
;
1H NMR (200 MHz,
CDCl3): d 9.05 (s, 1H, C11–H), 8.27 (dd, 1H, J¼7.81,
2.60 Hz, C1–H), 7.85 (d, 1H, J¼8.80 Hz, C10–H), 7.68
(split t, 1H, J,7.65, 2.60 Hz, C3–H), 7.54 (dd, 1H, J¼7.60,
2.31 Hz, C4–H), 7.32 (m, 1H, C2–H), 7.09 (bs, 1H, C7–
H), 7.00 (dd, 1H, J¼8.80, 2.32 Hz, C9–H), 4.52 (bs, 2H,
exchangeable with D2O, NH2); mass m/z: 263 (Mþþ1, 21),
262 (Mþ, 81), 171 (76), 121 (82), 71 (100). Anal. calcd for
C16H10N2O2: C, 73.27; H, 3.84; N, 10.68%; found: C,
73.02; H, 3.97; N, 10.97.
3.3.2. 2-Chloro-8-amino-quinolino[2,3-b]chroman-12-
one
3.4.3. Reaction of 2a with m-phenylenediamine leading
to ligand 14c. Compound (2a, 265 mg, 1 mmol) was treated
with m-phenylenediamines (108 mg, 1 mmol) to afford the
title compound as a crystalline brownish solid (283 mg,
0.47 mmol, 94%), mp 244–468C decomposes (acetonitrile);
nmax (KBr): 3060 (b), 1662 (Sh), 1621 (Sh), 1567, 1476,
(13b).
6-Chloro-2-(N-methylanilino)-3-formyl-
chromone (3b, 313 mg, 1 mmol) was treated with m-phenyl-
enediamine (108 mg, 1 mmol) to obtain the title compound
(13b, 214 mg, 0.72 mmol, 72%) as a dark brown solid, mp
274–2758C (acetonitrile); lmax (MeOH): 418.5, 241.5,
225 nm; 1H NMR (300 MHz, CDCl3): d 9.03 (s, 1H,
C11–H), 8.26 (d, 1H, J¼2.59 Hz, C1–H), 7.84 (d, 1H,
J¼8.84 Hz, C10–H), 7.67 (dd, 1H, J¼7.60, 2.59 Hz, C3–
H), 7.54 (d, 1H, J¼7.6 Hz, C4–H), 7.08 (bs, 1H, C7–H),
6.99 (dd, 1H, J¼8.84, 2.32 Hz, C9–H), 4.51 (bs, 2H,
exchangeable with D2O, NH2); mass m/z: 298 (Mþþ1, 13),
297 (Mþ, 10), 296 (Mþ21, 45), 171 (84), 71 (100). Anal.
calcd for C16H9N2O2Cl: C, 64.77; H, 3.06; N, 9.44%; found:
C, 64.49; H, 3.31; N, 9.97.
1448, 1302 cm21
; lmax (CHCl3): 397, 248.5, 319,
1
290.5 nm; H NMR (200 MHz, CDCl3): d 13.84 (bs, 2H,
N–H), 9.10 (bs, 2H, HCvN), 8.14 (d, 2H, J¼7.90 Hz, C5–
H), 7.55–7.10 (m, 20H, arom-Hs). Anal. calcd for
C38H26N4O4: C, 75.73; H, 4.35; N, 9.30%; found: C,
75.59; H, 4.13; N, 9.77.
Acknowledgements
3.4. General procedure for the preparation of tetra-
dentate ligands
We are thankful to Dr Patrick Perlmutter, Monash
University, Clayton Campus, Victoria, Australia, for
obtaining FAB mass spectra of some compounds.
To solutions of compound (2a, 1 mmol) in refluxing dry-
acetonitrile (50 mL) were added solutions of corresponding
diamines (1 mmol) in acetonitrile (10 mL), after which the
contents were cooled and stirred at room temperature for
12 h. Yellow colored crystalline solids separated out, were
filtered and the second crop was recovered by concentrating
the filtrates to 1/5 of their original volume and cooling.
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0.485 mmol, 97%), mp 284–2858C (acetonitrile); nmax
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1580 (s), 1481, 1448, 1341, 1213 cm21; lmax (CHCl3): 368,
1
301.5, 287.5, 246.5 nm; H NMR (200 MHz, CDCl3): d
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