May 2009
Synthesis and In Vitro Study of a New Class of
Methylene-bis-4,6-diarylbenzo[d]isoxazoles as Potential Antifungal Agents
501
ArH), 6.82 (2H, s, ArH), 7.00 (2H, d, J ¼ 9.2 Hz, ArH), 7.10–
7.14 (10H, m, ArH); 13C NMR (DMSO-d6): d 31.0, 38.9, 42.0,
47.5, 116.1, 122.6, 124.5, 126.2, 127.4, 127.8, 128.5, 131.2,
132.3, 140.5, 150.1, 155.2, 198.0; IR (KBr): t 3357, 3025, 2932,
1687, 1596 cmꢁ1; MS: m/z 541 (Mþ þ1). The other compounds
5b–i were also prepared by the similar procedure.
117.0, 125.4, 127.0, 127.9, 128.3, 130.0, 133.2, 134.7, 137.4,
144.9, 145.2, 150.4, 151.2, 153.6, 159.3, 171.4; IR (KBr): t
3344, 3062, 2972, 1609, 1470, 1030 cmꢁ1; MS: m/z 586 (Mþ).
Anal. calcd. for C39H26N2O4: C, 79.85; H, 4.47; N, 4.78.
Found: C, 79.90; H, 4.39; N, 4.71. The other compounds 8b–i
were also prepared by the similar procedure.
5-[2-Hydroxy-5-(4-hydroxy-3-{6-[(Z)-1-hydroxymethyli-
dene]-5-oxo-3-phenyl-3-cyclohexenyl}benzyl)phenyl]-6-[(Z)-
1-hydroxymethylidene]-3-phenyl-2-cyclohexen-1-one (6a). In
a solution of 10% sodium methoxide (10 mL) in benzene (25
mL), ethylformate (2.24 mL, 0.03 mol) was added and then
compound 5a (5.4 g, 0.01 mol), dissolved in benzene (10 mL),
was added over 30 min. The resulting solution was stirred for
10 h at room temperature and allowed to stand overnight, then
evaporated to dryness. The suspension obtained was mixed
with cold water, acidified with dil HCl (20 mL), and extracted
three times with ether (40 mL). The organic layer was dried
over MgSO4, evaporated in vacuo to give solid, and purified
by crystallization in ethanol to afford pure 6a (81% yield) as
yellow solid; mp 143–145ꢂC; 1H NMR (DMSO-d6): d 3.22
(4H, d, CH2), 3.72 (2H, s, CH2), 4.12 (2H, t, CH), 5.67 (2H, s,
CH), 6.40–6.49 (4H, m, ArH), 6.80 (2H, s, ArH), 7.10–7.14
(10H, m, ArH), 7.92 (2H, s, CH), 8.97 (2H, s, OH); 13C NMR
(DMSO-d6):d 37.8, 42.0, 44.1, 115.5, 116.7, 126.2, 127.6,
127.9, 128.0, 128.9, 130.2, 130.6, 131.1, 142.0, 149.7, 156.1,
167.6, 191.3; IR (KBr): t 3320, 3028, 2952, 1662, 1620, 1597
cmꢁ1; MS: m/z 596 (Mþ). The other compounds 6b–i were
also prepared by the similar procedure.
4-[4-Hydroxy-3-(6-phenyl-4,5-dihydrobenzo[d]isoxazol-4-
yl)benzyl]-2-(6-phenyl-4,5-dihydrobenzo[d]isoxazol-4-yl)phe-
nol (7a). To a solution of 6a (5.9 g, 0.01 mol) in glacial acetic
acid (50 mL), hydroxylamine hydrochloride (2.0 g, 0.03 mol)
was added. After stirring at 80ꢂC for 10 h, the mixture was
concentrated in vacuo. To the residue was added water and
twice extracted with ether. The organic layer was washed with
saturated NaHCO3 solution, subsequently with water and birne,
dried over MgSO4 and evaporated to dryness. The residue was
recrystallized from ethanol to afford 7a (79% yield) as brown
solid; mp 123–125ꢂC; 1H NMR (DMSO-d6): d 2.82 (4H, d,
CH2), 3.72 (2H, s, CH2), 4.22 (2H, t, CH), 4.62 (2H, s, OH),
6.70 (2H, s, ArH), 6.73 (2H, d, J ¼ 9.0 Hz, ArH), 6.84 (2H, d,
J ¼ 9.1 Hz, ArH), 6.99 (4H, m, ArH), 7.00 (2H, s, ArH), 7.21
(2H, s, ArH), 7.32 (4H, d, J ¼ 9.2 Hz, ArH); 13C NMR
(DMSO-d6): d 38.1, 39.3, 42.1, 110.5, 117.2, 118.7, 125.4,
126.5, 127.8, 128.0, 128.9, 130.0, 132.0, 132.8, 140.3, 143.4,
156.2, 161.7; IR (KBr): 3390, 3037, 2972, 1609, 1470, 1030
cmꢁ1; MS: m/z 590 (Mþ). The other compounds 7b–i were
also prepared by the similar procedure.
2-[6-(4-Bromophenyl)benzo[d]isoxazol-4-yl]-4-3-[6-(4-bro-
mophenyl)benzo[d]isoxazol-4-yl]-4-hydroxybenzylphenol
(8b). This compound was obtained as brown solid; yield 84%;
mp 171–172ꢂC; 1H NMR (DMSO-d6): d 4.00 (2H, s, CH2),
4.65 (2H, s, OH), 6.90 (2H, s, ArH), 7.00 (2H, d, J ¼ 8.9 Hz,
ArH), 7.29 (2H, d, J ¼ 8.9 Hz, ArH), 7.40–7.45 (8H, m,
ArH), 7.90 (2H, s, ArH), 8.20 (2H, s, ArH), 8.60 (2H, s, ArH);
13C NMR (DMSO-d6): d 40.7, 115.0, 117.1, 122.1, 125.4,
130.0, 130.6, 132.3, 133.1, 134.6, 137.3, 141.3, 144.9, 147.1,
151.3, 153.6, 159.4, 171.4; IR (KBr): t 3390, 3065, 2995,
1609, 1470, 1030, 586 cmꢁ1; MS: m/z 742/744/746 (Mþ).
Anal. calcd. for C39H24Br2N2O4: C, 62.92; H, 3.25; N, 3.76.
Found: C, 62.85; H, 3.30; N, 3.70.
2-[6-(4-Aminophenyl)benzo[d]isoxazol-4-yl]-4-3-[6-(4-ami-
nophenyl)benzo[d]isoxazol-4-yl]-4-hydroxybenzylphenol
(8c). This compound was obtained as brown solid; yield 79%;
mp 158–160ꢂC; 1H NMR (DMSO-d6): d 4.06 (2H, s, CH2),
4.65 (2H, s, OH), 6.68 (4H, d, J ¼ 8.5 Hz, ArH), 6.90 (2H, s,
ArH), 7.00 (2H, d, J ¼ 8.9 Hz, ArH), 7.31 (2H, d, J ¼ 8.9
Hz, ArH), 7.52 (4H, d, J ¼ 8.5 Hz, ArH), 7.90 (2H, s, ArH),
8.20 (2H, s, ArH), 8.60 (2H, s, ArH); 13C NMR (DMSO-d6): d
40.7, 115.9, 116.7, 125.3, 127.3, 128.5, 130.1, 133.0, 134.1,
134.7, 137.5, 139.6, 144.5, 146.3, 151.2, 153.4, 159.2, 171.3;
IR (KBr): t 3390, 3065, 2972, 1612, 1469, 1028 cmꢁ1; MS:
m/z 616 (Mþ). Anal. calcd. for C39H28N4O4: C, 75.96; H,
4.58; N, 9.09. Found: C, 75.85; H, 4.60; N, 9.03.
2-[6-(4-Chlorophenyl)benzo[d]isoxazol-4-yl]-4-3-[6-(4-chlor-
ophenyl)benzo[d]isoxazol-4-yl]-4-hydroxybenzylphenol (8d). This
compound was obtained as yellow solid; yield 86%; mp 144–
146ꢂC; 1H NMR (DMSO-d6): d 4.02 (2H, s, CH2), 4.68 (2H,
s, OH), 6.90 (2H, s, ArH), 7.00 (2H, d, J ¼ 8.9 Hz, ArH),
7.31 (2H, d, J ¼ 8.9 Hz, ArH), 7.39 (4H, d, J ¼ 8.1 Hz,
ArH), 7.83 (4H, d, J ¼ 8.1 Hz, ArH), 7.90 (2H, s, ArH), 8.22
(2H, s, ArH), 8.51 (2H, s, ArH); 13C NMR (DMSO-d6): d
40.7, 115.7, 117.2, 125.4, 127.3, 128.5, 130.1, 133.0, 134.1,
134.7, 137.5, 139.6, 144.5, 146.3, 151.2, 153.4, 159.2, 171.3;
IR (KBr): t 3384, 3062, 2968, 1605, 1470, 1028, 782 cmꢁ1
;
MS: m/z 654/656/658 (Mþ). Anal. calcd. for C39H24Cl2N2O4:
C, 71.46; H, 3.69; N, 4.27. Found: C, 71.42; H, 3.61; N, 4.31.
4-4-Hydroxy-3-[6-(4-methoxyphenyl)benzo[d]isoxazol-4-
yl]benzyl-2-[6-(4-methoxyphenyl)benzo[d]isoxazol-4-yl]phenol
(8e). This compound was obtained as yellow solid; yield 77%;
mp 135–137ꢂC; 1H NMR (DMSO-d6): d 3.81 (6H, s, OMe), 4.02
(2H, s, CH2), 4.70 (2H, s, OH), 6.90 (2H, s, ArH), 6.96 (4H, d, J
¼ 8.4 Hz, ArH), 7.00 (2H, d, J ¼ 8.9 Hz, ArH), 7.32 (2H, d, J ¼
8.9 Hz, ArH), 7.34 (4H, d, J ¼ 8.4 Hz, ArH), 7.90 (2H, s, ArH),
8.22 (2H, s, ArH), 8.51 (2H, s, ArH); 13C NMR (DMSO-d6): d
40.5, 54.7, 115.0, 112.1, 117.0, 125.0, 129.5, 130.1, 133.1,
134.1, 137.3, 139.5, 144.3, 147.2, 151.1, 153.5, 159.1, 160.7,
4-[4-Hydroxy-3-(6-phenylbenzo[d]isoxazol-4-yl)benzyl]-2-
(6-phenylbenzo[d]isoxazol-4-yl)phenol (8a). To a solution of
7a (5.9 g, 0.01 mol) in dry benzene (20 mL), DDQ (6.81 g,
0.03 mol), dissolved in dry benzene (20 mL), was added in
portions. The mixture was heated to reflux and stirred for 5 h
under nitrogen atmosphere. The precipitated DDQ-H2 was fil-
tered off and the filtrate was subjected to column chromatogra-
phy on silica gel (60–120 mesh) to afford pure 8a (78% yield)
172.1; IR (KBr): t 3384, 3062, 2968, 1605, 1470, 1240 cmꢁ1
;
1
as orange solid; mp 158–160ꢂC; H NMR (DMSO-d6): d 3.99
MS: m/z 646 (Mþ). Anal. calcd. for C41H30N2O6: C, 76.15; H,
4.68; N, 4.33. Found: C, 76.21; H, 4.61; N, 4.35.
(2H, s, CH2), 4.65 (2H, s, OH), 6.90 (2H, s, ArH), 6.99 (2H,
d, J ¼ 8.9 Hz, ArH), 7.29 (2H, d, J ¼ 8.9 Hz, ArH), 7.44–
7.50 (10H, m, ArH), 7.90 (2H, s, ArH), 8.20 (2H, s, ArH),
8.60 (2H, s, ArH); 13C NMR (DMSO-d6): d 40.7, 115.1,
2-[6-(2-Furyl)benzo[d]isoxazol-4-yl]-4-3-[6-(2-furyl)benzo-
[d]isoxazol-4-yl]-4-hydroxybenzylphenol (8f). This compound
was obtained as black solid; yield 80%; mp 162–163ꢂC; 1H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet