Synthesis of 2,2′-diaminobischromones using a modified procedure for the rearrangement of 5-(2-hydroxyphenyl)isoxazole to 2-aminochromone

Article abstract of DOI:10.1055/s-2005-869965

A modified procedure for the rearrangement of 5-(2-hydroxyphenyl)isoxazoles 6a-e to 2-aminochromones 8a-e was developed and this procedure was utilised in the synthesis of hitherto unreported bischromones 3a-c. The isoxazoles 6a-e were prepared regioselec

Full text of DOI:10.1055/s-2005-869965

PAPER
1845
Synthesis of 2,2¢-Diaminobischromones Using a Modified Procedure for the
Rearrangement of 5-(2-Hydroxyphenyl)isoxazole to 2-Aminochromone
D
iaminobischro
a
mones usin
r
g
a
R
ear
u
rangement
o
n
f
5-(2-Hydroxyphe
G
nyl)isoxazole hosh, Satyajit Saha, Chandrakanta Bandyopadhyay*
Department of Chemistry, R. K. Mission Vivekananda Centenary College, Rahara, Kolkata 700 118, West Bengal, India
E-mail: kantachandra@rediffmail.com
Received 1 December 2004; revised 8 February 2005
only;5 (ii) Curtius rearrangement of chromone 2-acid
Abstract: A modified procedure for the rearrangement of 5-(2-hy-
droxyphenyl)isoxazoles 6a–e to 2-aminochromones 8a–e was de-
veloped and this procedure was utilised in the synthesis of hitherto
unreported bischromones 3a–c. The isoxazoles 6a–e were prepared
regioselectively from aminovinylketones 5.
azide to 2-aminochromone via chromone 2-isocyanate;6
(iii) thermal cyclisation of 2-hydroxybenzoylacetonitrile
(7);7 and (iv) tandem rearrangement and cyclisation of 5-
(2-hydroxyphenyl)isoxazole (6) or its 3-carboxy deriva-
tive either by heating above their mps8 or by heating in
quinoline at 200 °C.9 Considering the effect of base and
heat in the conversion of 5-(2-hydroxyphenyl)isoxazole
(6) to 8, we intended to carry out this transformation under
milder conditions by heating the isoxazole 6 in the pres-
ence of a suitable base and solvent.
Key words: heterocycles, chromones, regioselectivity, rearrange-
ments, isoxazoles
Bischromones 1 and 2 having ester or carboxylic acid
functionalities at their 2 and 2¢-positions (Figure 1) are ca-
pable of exhibiting various biological activities. They are
inhibitors of certain types of antigen–antibody reactions,
they are antiallergic and antiasthmatic and can cure hay
fever, urticaria and viral infections. They can be com-
pounded with bronchodilators when used in inhalation
preparations.1 Although a considerable amount of work
has been done for the synthesis of bischromones having
ester or acid functionalities at the 2- and 2¢-positions,2 lit-
tle attention has been given to the synthesis of bis-
chromones containing other functionalities.
With regards to the synthesis of isoxazole 6, different
groups have studied the reaction of hydroxylamine with
chromone under different conditions.10 In most of the cas-
es, a mixture of isomeric isoxazoles along with other
products were found to form. Most of these processes
could not be considered as a preparative process to isox-
azole 6 because of poor yield and separation problems.
Synthesis of isoxazole from chalcones 5 (Ar in place of
NMe2) leads to 3-(2-hydroxyphenyl)isoxazole, a regiomer
of 6.11 Dialkylaminovinyl ketones are found to be very
good substrates for the regioselective synthesis of isox-
azole.12 Here dialkylaminovinyl ketone 5, obtained from
4, was utilized for the synthesis of the desired isoxazole 6
(Scheme 1). 1-(2-Hydroxyphenyl)-3-N,N-dimethylami-
nopropenone (5),13 obtained from o-hydroxyacetophe-
none (4) and dimethylformamide dimethyl acetal
(DMFDA), was heated with NH2OH·HCl in ethanol under
reflux for 30 min. The desired isoxazole 6 was obtained in
moderate yield (60–70%). Conversion of 5-(2-hydroxy-
phenyl)isoxazole (6) to 2-aminochromone (8) consists of
two steps: (i) base catalysed rearrangement of 6 to 2-hy-
droxybenzoylacetonitrile (7); and (ii) thermal cyclisation
of 7 to 8 (Scheme 1). In order to accomplish these two
steps under mild conditions, we attempted with various
bases and solvents to optimize the reaction conditions
(Table 1). Comparing different bases such as NH3, pyri-
dine, Et3N, DABCO and solvents such as EtOH, dioxane
or DMF, it was observed that heating 6 in DMF under re-
flux in the presence of Et3N for ca. 8 h is the most effective
and convenient method for the preparation of 8 (entries
13–17). This reaction can also be carried out at relatively
lower temperature by heating under reflux in EtOH in the
presence of Et3N, but it takes around 20–25 h for comple-
tion (entries 3, 10–12). Although DABCO in place of
Et3N can effect this transformation in lower yield (entry
7), pyridine fails to effect this transformation (entries 4–
6).
The 2-aminochromone class of compounds are important
for their antiplatelet activity.3 Our present interest in the
field of 2-aminochromone system4 gave us an impetus to
synthesise 2,2¢-diaminobischromones 3 (Figure 1).
Figure 1
The different synthetic routes to 2-aminochromone in-
clude: (i) condensation of methyl salicylate with alkyl ni-
trile in the presence of NaNH2 in liquid ammonia, where
2-aminochromone was assigned as its tautomer 4-hy-
droxyiminocoumarin on the basis of elemental analysis
SYNTHESIS 2005, No. 11, pp 1845–1849
x
x.
x
x
.
2
0
0
5
Advanced online publication: 20.06.2005
DOI: 10.1055/s-2005-869965; Art ID: T14704SS
© Georg Thieme Verlag Stuttgart · New York

1846
T. Ghosh et al.
PAPER
er pharmaceutical potency than other linkages.2 Bis(2-
hydroxyacetophenone) 12 was obtained by heating a mix-
ture of 2,5-dihydroxyacetophenone, a,w-dibromoalkane,
anhydrous K2CO3 and a catalytic amount of NaI in ace-
tone under reflux for 72 h with stirring.1 The enamino ke-
tone 13, obtained by treating 12 with DMFDA at 80–
90 °C, was heated with NH2OH·HCl in EtOH for 2 h to
get isoxazole 14, which on heating under reflux with Et3N
in DMF for 8 h produced bischromone 3 in good to excel-
lent yields (Scheme 3).
Scheme 1
Recently, we have synthesised 4H-1-benzopyrano[3,4-
d]isoxazol-4-one (9) from 3-(N-alkylaminomethyl-
ene)chroman-2,4-dione.14 In an endeavour to synthesise
4-hydroxy-2-oxo-2H-1-benzopyran-3-carbonitrile (10)
from 9 (Scheme 2, Path a) by a base-catalysed isoxazole
ring-opening process, 9 was heated with Et3N in DMF un-
der reflux for 8 h. Surprisingly, the product obtained was
2-aminochromone 8 in good yield (70–75%) instead of
our expected product 10. A plausible mechanism is de-
picted in Scheme 2. Of the two rings between coumarin or
isoxazole, the one which opens first could not be predicted
firmly; however, the facile decarboxylation of 11 may be
considered more favourable entropically over pyran ring
closure (Scheme 2).
Scheme 3
One noticeable thing in the 1H NMR spectra of 13, 14 and
3 is that the methylene protons in compounds 13b, 14b
and 3b (having a 4-carbon chain) appear as singlets al-
though those in compounds 12a–c, 13a,c, 14a,c, and 3a,c
they appear with their usual multiplicities.
The recorded mps are uncorrected. IR spectra were recorded in KBr
on a Beckman IR 20a and NMR spectra in DMSO-d6 on a 300 MHz
spectrometer. Light petroleum refers to the fraction with bp 60–
80 °C unless stated otherwise. All chemicals used are of commer-
cial grade and are used as such.
5-(2-Hydroxyphenyl)isoxazoles (6a–e); General Procedure
To an EtOH solution (15 mL) of enamino ketone 5 (1 mmol),
NH2OH·HCl (105 mg, 1.5 mmol) was added. The reaction mixture
was heated under reflux. Within 5 min, the yellow colour of the
enamino ketone 5 disappeared. The reaction mixture was heated for
30 min. Solvent was removed under reduced pressure. Ice-cold H2O
(10 mL) was added to the residue, the precipitated white solid was
filtered off, washed with H2O, dried in air and recrystallised
(EtOAc–light petroleum) to afford white fine crystalline solids 6.
Scheme 2
The convenient one-pot transformation of isoxazole 6 to
2-aminochromone 8 was then utilised in the synthesis of
bischromone 3 having amine functionalities at its 2,2¢-po-
sitions. Compound 12 containing two molecules of 2,5-di-
hydroxyacetophenone moieties tethered by an alkyl chain
through ethereal linkage was the substrate of our choice.
Compound 6a
Yield: 110 mg (68%); mp 182–184 °C (Lit.10a 181 °C).
IR: 3250, 1625, 1575, 1135 cm–1.
1H NMR: d = 6.95 (d, J = 1.5 Hz, 1 H, 4-H), 7.15–7.30 (m, 3 H, 3¢-
Linkage through the 5-position of 2,5-dihydroxyace- H, 4¢-H, 5¢-H), 7.70 (dd, J = 8.2, 2.0 Hz, 1 H, 6¢-H), 8.45 (d, J = 1.5
Hz, 1 H, 3-H), 10.38 (s, exchangeable, 1 H, OH).
tophenone leads to 6,6¢-bischromone, which shows great-
Synthesis 2005, No. 11, 1845–1849 © Thieme Stuttgart · New York

PAPER
Diaminobischromones Using a Rearrangement of 5-(2-Hydroxyphenyl)isoxazole
1847
Table 1 2-Aminochromones 8 from Isoxazoles 6 by Heating in Various Solvents in the Presence of Various Bases
Entry
1
Isoxazole
6a
R1
H
R2
H
Solvent
EtOH
EtOH
EtOH
EtOH
Pyridine
Dioxane
EtOH
Dioxane
Dioxane
EtOH
EtOH
EtOH
DMF
Base
Time (h)
Product
No reaction
8a
Yield (%) Mp (°C)
NH3
10
10
25
22
10
22
20
30
20
25
22
25
7
2
6a
H
H
NH3 + Et3N
Et3N
25
45
270a
274a
3
6a
H
H
8a
4
6c
Cl
H
H
Pyridine
–
No reaction
No reaction
No reaction
8a
5
6a
H
6
6c
Cl
H
H
Pyridine
DABCO
DABCO
Et3N
7
6a
H
20
272a
8
6a
H
H
Could not be isolated
9
6a
H
H
8a
8b
8c
8d
8a
8b
8c
8d
8e
30
55
57
67
72
75
77
81
78
274a
320b
10
11
12
13
14
15
16
17
6b
6c
Me
Cl
H
H
Et3N
H
Et3N
>325
6d
6a
Me
H
Et3N
300–302c
272–274a
320–322b
>325
H
Et3N
6b
6c
Me
Cl
H
H
DMF
Et3N
8
H
DMF
Et3N
8
6d
Me
H
DMF
Et3N
8
302–304c
>325
6e
Br
DMF
Et3N
8
a Lit.5 mp 275 °C.
b Lit.9 mp 323–325 °C.
c Lit.9 mp 304–306 °C.
Compound 6b
Compound 6e
Yield: 175 mg (72%); mp 208–210 °C.
IR: 3151, 1606, 1473, 1407, 1299 cm–1.
1H NMR: d = 6.92 (d, J = 1.8 Hz, 1 H, 4-H), 7.01 (d, J = 8.7 Hz, 1
H, 3¢-H), 7.47 (dd, J = 8.7, 2.5 Hz, 1 H, 4¢-H), 7.86 (d, J = 2.5 Hz,
1 H, 6¢-H), 8.64 (d, J = 1.8 Hz, 1 H, 3-H), 10.96 (s, exchangeable, 1
H, OH).
Yield: 110 mg (65%); mp 172–174 °C (Lit.9 double mp 171–172 °C
and 324–26 °C).
IR: 3125, 1625, 1590, 1120 cm–1.
1H NMR: d = 2.38 (s, 3 H, CH3), 6.94 (d, J = 1.4 Hz, 1 H, 4-H),
7.13–7.30 (m, 2 H, 3¢-H and 4¢-H), 7.71 (d, J = 2.0 Hz, 1 H, 6¢-H),
8.66 (d, J = 1.4 Hz, 1 H, 3-H), 10.40 (s, exchangeable, 1 H, OH).
Anal. Calcd for C9H6NBrO2: C, 45.02; H, 2.51; N, 5.83. Found: C,
44.70; H, 2.77; N, 5.83.
Compound 6c
Yield: 135 mg (70%); mp 196–198 °C.
IR: 3240, 1637, 1550, 1148 cm–1.
2-Amino-4H-1-benzopyran-4-ones (8a–e); General Procedure
Et3N (200 mg, 2 mmol) was added to a solution of isoxazole 6a–e
(1 mmol) in DMF (10 mL). The reaction mixture was heated in an
oil bath maintaining the bath temperature at 140–150 °C for 8 h.
DMF was removed under reduced pressure and ice-cold H2O was
added to the residue. The separated solid was filtered off and recrys-
tallised from MeOH to get faintly yellow crystalline compounds 8.
1H NMR: d = 6.92 (d, J = 1.6 Hz, 1 H, 4-H), 7.30–7.55 (m, 2 H, 3¢-
H, 4¢-H), 7.91 (d, J = 1.9 Hz, 1 H, 6¢-H), 8.65 (d, J = 1.6 Hz, 1 H, 3-
H), 10.42 (s, exchangeable, 1 H, OH).
Anal. Calcd for C9H6NClO2: C, 55.26; H, 3.09; N, 7.16. Found: C,
55.30; H, 3.12; N, 7.20.
Compound 6d
Compound 8a
Yield: 105 mg (60%); mp 187–189 °C (Lit.9 double mp 189–190 °C
and 303–306 °C).
Yield: 115 mg (72%); mp 272–274 °C (Lit.5 275 °C).
IR: 3303, 3098, 1644, 1609, 1546, 1276, 755 cm–1.
IR: 3210, 1630, 1585, 1125 cm–1.
1H NMR: d = 5.19 (s, 1 H, 3-H), 7.32–7.38 (m, 2 H, 6-H, 8-H), 7.53
(s, exchangeable, 2 H, NH2), 7.57–7.63 (m, 1 H, 7-H), 7.90 (dd,
J = 7.7, 1.4 Hz, 1 H, 5-H).
1H NMR: d = 2.32 (s, 3 H, CH3), 6.90 (d, J = 1.5 Hz, 1 H, 4-H),
7.00–7.20 (m, 2 H, 3¢-H and 5¢-H), 7.72 (d, J = 8.1 Hz, 1 H, 6¢-H),
8.55 (d, J = 1.5 Hz, 1 H, 3-H), 10.45 (s, exchangeable, 1 H, OH).
Synthesis 2005, No. 11, 1845–1849 © Thieme Stuttgart · New York

1848
T. Ghosh et al.
PAPER
Compound 8b
Anal. Calcd for C25H30N2O6: C, 66.06; H, 6.65; N, 6.16. Found: C,
66.01; H, 6.61; N, 6.10.
Yield: 130 mg (75%); mp 320–322 °C (Lit.9 323–325 °C).
IR: 3283, 3059, 1655, 1613, 1557, 1276, 809 cm–1.
Compound 13b
Yield: 400 mg (85%); mp 212–214 °C.
IR: 3300, 2940, 2870, 1636, 1533, 1285 cm–1.
1H NMR: d = 2.37 (s, 3 H, CH3), 5.15 (s, 1 H, 3-H), 7.25 (d, J = 8.2
Hz, 1 H, 8-H), 7.41 (dd, J = 8.2, 1.0 Hz, 1 H, 7-H), 7.45 (s, ex-
changeable, 2 H, NH2), 7.69 (d, J = 1.0 Hz, 1 H, 5-H).
1H NMR: d = 1.97 (s, 4 H, 2 CH2), 2.93 (s, 6 H, 2 NMe), 3.19 (s, 6
H, 2 NMe), 4.03 (s, 4 H, 2 OCH2), 5.67 (d, J = 11.1 Hz, 2 H,
2 CH=CHNMe2), 6.87 (d, J = 8.9 Hz, 2 H, 2 3-H), 7.00 (dd, J = 8.9,
2.6 Hz, 2 H, 2 4-H), 7.19 (d, J = 2.6 Hz, 2 H, 2 6-H), 7.86 (d,
J = 11.3 Hz, 2 H, 2 CH=CHNMe2), 11.82 (s, exchangeable, 2 H,
2 OH).
Compound 8c
Yield: 150 mg (77%); mp >325 °C.
IR: 3280, 3060, 1660, 1615, 1550, 1265, 810 cm–1.
1H NMR: d = 5.20 (s, 1 H, 3-H), 7.42 (d, J = 8.8 Hz, 1 H, 8-H), 7.64
(dd, J = 8.8, 2.5 Hz, 1 H, 7-H), 7.68 (s, exchangeable, 2 H, NH2),
7.82 (d, J = 2.5 Hz, 1 H, 5-H).
Anal. Calcd for C26H32N2O6: C, 66.65; H, 6.88; N, 5.98. Found: C,
66.58; H, 6.90; N, 5.90.
Anal. Calcd for C9H6NClO2: C, 55.26; H, 3.09; N, 7.16. Found: C,
55.28; H, 3.12; N, 7.21.
Compound 13c
Yield: 450 mg (93%); mp 168 °C.
IR: 3250, 2938, 2872, 1638, 1534, 1280 cm–1.
Compound 8d
Yield: 140 mg (81%); mp 302–304 °C (Lit.9 304–306 °C).
1H NMR: d = 1.64–1.72 (m, 2 H, CH2), 1.81–1.90 (m, 4 H, 2 CH2),
2.94 (s, 6 H, 2 NMe), 3.18 (s, 6 H, 2 NMe), 3.97 (t, J = 6.2 Hz, 4 H,
2 OCH2), 5.69 (d, J = 11.6 Hz, 2 H, 2 CH=CHNMe2), 6.86 (d,
J = 8.9 Hz, 2 H, 2 3-H), 6.99 (dd, J = 8.9, 2.9 Hz, 2 H, 2 4-H), 7.19
(d, J = 2.9 Hz, 2 H, 2 6-H), 7.87 (d, J = 11.6 Hz, 2 H,
2 CH=CHNMe2), 11.80 (s, exchangeable, 2 H, 2 OH).
IR: 3273, 3055, 1658, 1610, 1545, 1260, 812 cm–1.
1H NMR: d = 2.46 (s, 3 H, CH3), 5.16 (s, 1 H, 3-H), 7.12 (dd,
J = 8.2, 1.0 Hz, 1 H, 6-H), 7.15 (d, J = 1.0 Hz, 1 H, 8-H), 7.46 (s,
exchangeable, 2 H, NH2), 7.75 (d, J = 8.2 Hz, 1 H, 5-H).
Compound 8e
Yield: 190 mg (78%); mp >325 °C.
IR: 3265, 3128, 1653, 1543, 1284, 817 cm–1.
Anal. Calcd for C27H34N2O6: C, 67.20; H, 7.10; N, 5.80. Found: C,
67.25; H, 7.14; N, 5.90.
1H NMR: d = 5.19 (s, 1 H, 3-H), 7.37 (d, J = 8.7 Hz, 1 H, 8-H), 7.70
(s, exchangeable, 2 H, NH2), 7.75 (dd, J = 8.7, 2.4 Hz, 1 H, 7-H),
7.95 (d, J = 2.4 Hz, 1 H, 5-H).
5,5¢-{(a,w-Alkanediol)bis[oxy(4-hydroxyphen)-3-yl]}bisisox-
azoles (14a–c); General Procedure
To a suspension of aminovinyl ketone 13 (1 mmol) in EtOH (20
mL), NH2OH·HCl (210 mg, 3 mmol) was added and the reaction
mixture was heated under reflux. Within 5 min, a clear solution was
obtained and after 30 min a white solid began to separate. Heating
was continued for 2 h under these conditions. The separated solid
was filtered off, washed with H2O, dried in air and recrystallised
(EtOAc–MeOH, 1:1) to afford white solids 14.
Anal. Calcd for C9H6NBrO2: C, 45.02; H, 2.51; N, 5.83. Found: C,
45.01; H, 2.76; N, 5.77.
Treatment of 4H-1-Benzopyrano[3,4-d]isoxazol-4-ones (9a–b)
with Et3N in DMF
To a solution of 1-benzopyranoisoxazole 9a–b (0.5 mmol) in DMF
(5 mL), Et3N (100 mg, 1 mmol) was added and the resultant solution
was heated under reflux for 8 h. Solvent from the reaction mixture
was removed under reduced pressure. Cold H2O (10 mL) was added
to the residue. The precipitated solid was filtered off, washed with
H2O, dried in air and recrystallised (MeOH) to afford faint yellow
crystalline compounds 8a–b, identical in all respects to those pro-
duced from 6a,b, respectively.
Compound 14a
Yield: 250 mg (63%); mp 210–212 °C.
IR: 3135, 2965, 2890, 1575, 1516, 1480, 1210 cm–1.
1H NMR: d = 2.13–2.17 (m, 2 H, CH2), 4.13 (t, J = 6.0 Hz, 4 H,
2 OCH2), 6.88 (d, J = 1.7 Hz, 2 H, 2 4-H), 6.97–7.00 [m, 4 H, 2 (3¢-
H + 4¢ H)], 7.32 (d, J = 1.0 Hz, 2 H, 2 6¢-H), 8.59 (d, J = 1.7 Hz, 2
H, 2 3-H), 10.17 (s, exchangeable, 2 H, 2 OH).
1,1¢-{(a,w-Alkanediol)bis[oxy(4-hydroxyphen)-3-yl]}bis(3-N,N-
dimethylaminopropenones) (13a–c); General Procedure
Anal. Calcd for C21H18N2O6: C, 63.96; H, 4.60; N, 7.10. Found: C,
63.90; H, 4.55; N, 7.00.
A suspension of bis(2-hydroxyacetophenone) 12 (1 mmol) in
DMFDA (2 mL) was stirred at 80–90 °C. A clear solution was ob-
served after 15 min. Within 30 min, a yellow precipitate began to
appear. After stirring for 2 h in these conditions, the reaction mix-
ture was filtered, washed with light petroleum and dried. The solid
was recrystallised from CHCl3 to afford bright yellow solids 13.
Compound 14b
Yield: 285 mg (70%); mp 232–234 °C.
IR: 3136, 2959, 2886, 1574, 1516, 1477, 1209 cm–1.
1H NMR: d = 2.50 (s, 4 H, 2 CH2), 4.03 (s, 4 H, 2 OCH2), 6.88 (d,
J = 1.5 Hz, 2 H, 2 4-H), 6.94–6.96 [m, 4 H, 2 (3¢-H + 4¢ H)], 7.30
(d, J = 1.0 Hz, 2 H, 2 6¢-H), 8.60 (d, J = 1.5 Hz, 2 H, 2 3-H), 10.13
(s, exchangeable, 2 H, 2 OH).
Compound 13a
Yield: 410 mg (90%); mp 202–204 °C.
IR: 3280, 2950, 2870, 1640, 1535, 1285 cm–1.
1H NMR: d = 2.23 (quin, J = 6.0 Hz, 2 H, CH2), 2.93 (s, 6 H,
2 NMe), 3.18 (s, 6 H, 2 NMe), 4.15 (t, J = 6.0 Hz, 4 H, 2 OCH2),
5.67 (d, J = 11.3 Hz, 2 H, 2 CH=CHNMe2), 6.87 (d, J = 8.9 Hz, 2
H, 2 3-H), 7.02 (dd, J = 8.9, 2.8 Hz, 2 H, 2 4-H), 7.21 (d, J = 2.8 Hz,
2 H, 2 6-H), 7.87 (d, J = 11.3 Hz, 2 H, 2 CH=CHNMe2), 11.85 (s,
exchangeable, 2 H, 2 OH).
Anal. Calcd for C22H20N2O6: C, 64.70; H, 4.94; N, 6.86. Found: C,
64.66; H, 4.90; N, 6.80.
Compound 14c
Yield: 275 mg (65%); mp 210–212 °C.
IR: 3130, 2955, 2880, 1570, 1520, 1480, 1210 cm–1.
1H NMR: d = 1.58–1.63 (m, 2 H, CH2), 1.74–1.80 (m, 4 H, 2 CH2),
3.98 (t, J = 6.2 Hz, 4 H, 2 OCH2), 6.88 (d, J = 1.8 Hz, 2 H, 2 4-H),
Synthesis 2005, No. 11, 1845–1849 © Thieme Stuttgart · New York

PAPER
Diaminobischromones Using a Rearrangement of 5-(2-Hydroxyphenyl)isoxazole
1849
6.93–6.95 [m, 4 H, 2 (3¢-H + 4¢ H)], 7.28 (d, J = 1.2 Hz, 2 H, 2 6¢-
H), 8.59 (d, J = 1.8 Hz, 2 H, 2 3-H), 10.13 (s, exchangeable, 2 H,
2 OH).
J = 8.9, 2.9 Hz, 2 H, 2 7-H), 7.28 (d, J = 8.9 Hz, 2 H, 2 8-H), 7.33
(d, J = 2.9 Hz, 2 H, 2 5-H), 7.44 (s, exchangeable, 4 H, 2 NH2).
MS (positive ion electrospray): m/z = 445 (M + Na+).
Anal. Calcd for C23H22N2O6: C, 65.39; H, 5.25; N, 6.63. Found: C,
65.42; H, 5.30; N, 6.60.
Anal. Calcd for C23H22N2O6: C, 65.39; H, 5.25; N, 6.63. Found: C,
65.20; H, 5.10; N, 6.55.
6,6¢-[(a,w-Alkanediol)bis(oxy)]bis(2-amino-4H-1-benzopyran-
4-ones) (3a–c); General Procedure
Excess of Et3N (1 mL, ca. 7 mmol) was added to a solution of bis-
isoxazole 14 (1 mmol) in DMF (10 mL). The reaction mixture was
heated under reflux in an oil bath at 140–150 °C for 8 h. The sepa-
rated solid was filtered off and recrystallised (EtOAc–MeOH, 1:1)
to afford faint yellow solids 3.
Acknowledgement:
We gratefully acknowledge U. G. C., New Delhi for financial assi-
stance; IICB, Jadavpur for 1H NMR and mass spectral analysis and
finally the college authority for providing research facilities.
References
Compound 3a
Yield: 340 mg (86%); mp 322–324 °C.
IR: 3300, 3075, 2935, 1650, 1610, 1560, 1455, 1280 cm–1.
1H NMR: d = 2.21–2.23 (m, 2 H, CH2), 4.20 (t, J = 5.6 Hz, 4 H,
2 OCH2), 5.17 (s, 2 H, 2 3-H), 7.20 (dd, J = 8.7, 2.2 Hz, 2 H, 2 7-
H), 7.31 (d, J = 8.7 Hz, 2 H, 2 8-H), 7.37 (d, J = 2.2 Hz, 2 H, 2 5-
H), 7.46 (s, exchangeable, 4 H, 2 NH2).
(1) (a) Fisons Pharmaceuticals Ltd, Neth. Patent 6603997,
1966; Chem. Abstr. 1967, 67, 100002. (b) Fitzmaurice, C.;
Lee, T. B.; Altounyan, R. E. C. Brit. Patent 1144905, 1969;
Chem. Abstr. 1969, 71, 91309.
(2) Ellis, G. P. Heterocyclic Compounds, Vol. 31; Weissberger,
A., Ed.; Interscience: New York, 1977, Chap. XXI, 1043;
and references therein.
(3) (a) Gamill, R. B.; Judge, T. M.; Morris, J. WO 90/06921,
1990. (b) Mazzei, M.; Balbi, R.; Roma, G.; Braccio, M. D.;
Leoncini, G.; Buzzi, E.; Maresca, M. Eur. J. Med. Chem.
1988, 23, 237. (c) Morris, J.; Wishka, D. G.; Fang, Y.
J. Org. Chem. 1992, 57, 6502. (d) Morris, J.; Wishka, D. G.;
Fang, Y. Synth. Commun. 1994, 24, 849.
(4) Bandyopadhyay, C.; Sur, K. R.; Patra, R.; Banerjee, S. J.
Chem. Res., Synop. 2003, 459; J. Chem. Res. (M), 2003, 847.
(5) Kawase, Y.; Sakashita, K. Bull. Chem. Soc. Jpn. 1962, 35,
1869.
MS (positive ion electrospray): m/z = 417 (M + Na+).
Anal. Calcd for C21H18N2O6: C, 63.96; H, 4.60; N, 7.10. Found: C,
63.99; H, 4.65; N, 7.15.
Acetate of 3a
Mp 298–300 °C.
1H NMR: d = 2.14 (s, 6 H, 2 CH3), 2.22–2.24 (m, 2 H, CH2), 4.25
(t, J = 5.0 Hz, 4 H, 2 OCH2), 6.76 (s, 2 H, 2 3-H), 7.36–7.48 [m, 6
H, 2 (5-H + 7-H + 8-H)], 11.22 (br s, exchangeable, 2 H, 2 NHCO).
(6) Zagorevski, Z. A.; Vinokurov, V. G.; Glozman, S. M. Khim.
Geterotsikl. Soedin. 1970, 171.
Compound 3b
Yield: 390 mg (96%); mp >325 °C.
IR: 3298, 3084, 2937, 1649, 1610, 1558, 1456, 1278 cm–1.
1H NMR: d = 1.91 (s, 4 H, 2 CH2), 4.09 (s, 4 H, 2 OCH2), 5.16 (s, 2
H, 2 3-H), 7.17 (dd, J = 8.9, 2.7 Hz, 2 H, 2 7-H), 7.31 (d, J = 8.9 Hz,
2 H, 2 8-H), 7.35 (d, J = 2.7 Hz, 2 H, 2 5-H), 7.44 (s, exchangeable,
4 H, 2 NH2).
(7) Checchi, S.; Pecori, V. L. Gazz. Chim. Ital. 1966, 96, 874.
(8) Basinski, W. Rocz. Chem. 1977, 51, 2283.
(9) Basinski, W. Polish J. Chem. 1995, 69, 376.
(10) (a) Beugelmans, R.; Morin, C. J. Org. Chem. 1977, 42,
1356. (b) Szabo, V.; Borbely, J.; Theisz, E.; Borda, J.;
Janzso, G. Tetrahedron 1984, 40, 413. (c) Szabo, V.;
Borbely, J.; Theisz, E.; Nagy, S. Tetrahedron 1986, 42,
4215. (d) Khilya, V.-P.; Ishchenko, V. V. Chem. Heterocycl.
Compd. (N.Y., N.Y.) 2002, 38, 883.
(11) (a) Shenoi, R. B.; Shah, R. S.; Wheeler, T. S. J. Chem. Soc.
1940, 247. (b) Maib, P.; Basinski, W. Polish J. Chem. 1981,
55, 1527.
(12) (a) Kochetkov, N. K. Izv. Akad. Nauk SSSR, Ser. Khim.
1954, 47. (b) Lin, Y.-I.; Lang, S. A. Jr. J. Heterocycl. Chem.
1977, 14, 345.
MS (positive ion electrospray): m/z = 431 (M + Na)+.
Anal. Calcd for C22H20N2O6: C, 64.70; H, 4.94; N, 6.86. Found: C,
64.65; H, 4.90; N, 6.90.
Compound 3c
Yield: 340 mg (80%); mp >325 °C.
IR: 3300, 3070, 2933, 1651, 1612, 1556, 1456, 1278 cm–1.
1H NMR: d = 1.58–1.62 (m, 2 H, CH2), 1.77–1.83 (m, 4 H, 2 CH2),
4.02 (t, J = 6.2 Hz, 4 H, 2 OCH2), 5.17 (s, 2 H, 2 3-H), 7.13 (dd,
(13) Gamill, R. B. Synthesis 1979, 901.
(14) Ghosh, T.; Bandyopadhyay, C. Tetrahedron Lett. 2004, 45,
6169.
Synthesis 2005, No. 11, 1845–1849 © Thieme Stuttgart · New York