March 2009
Bis(enaminones): Key Intermediates for Novel a,x-Bis(pyrazolylphenoxy),
Bis(pyranylphenoxy), and Bis(benzo[b]furanylphenoxy) Alkanes
345
C21H20N4O2 Calcd: C, 69.98; H, 5.59; N, 15.54. Found: C,
69.62; H, 5.74; N, 15.30%.
1,4-Bis[4-(1H-pyrazol-3-yl)phenoxy]butane (12b). Colorless
(OH), 1658 (C¼¼O); 1H NMR (DMSO-d6) d 2.25 (m, 2H,
OCH2CH2CH2O), 4.28 (m, 4H, OCH2CH2CH2O), 6.83–6.88
(m, 2H, ArH), 7.05–7.15 (m, 5H, ArH), 7.45–7.52 (m, 2H,
ArH), 7.87–7.94 (m, 5H, ArH), 8.54 (s, 2H, 2 furan-2-CH),
9.44 (brs, 2H, 2 OH, D2O-exchangeable); 13C NMR (DMSO-
d6): d 28.4, 64.6, 106.5, 111.9, 114.3, 114.5, 119.9, 125.9,
130.4, 131.02, 148.9, 153.4, 154.6, 162.03, 187.9; MS: m/z
(%) 548 (Mþ, 50), 161 (100), 121 (26.8), 105 (36.2), 93
(26.1), 76 (25.4), 51 (24.6). Anal. for C33H24O8 Calcd: C,
72.26; H, 4.41. Found: C, 72.63; H, 4.27%.
1,4-Bis[4-(5-hydroxybenzo[b]furan-3-ylcarbonyl)pheno-
xy]butane (20b). Yield: method A/method B (79/47%); pale
yellow powder, mp 283–285ꢁC; IR (KBr) mmax/cmꢀ1 3277
(OH), 1662 (C¼¼O); 1H NMR (DMSO-d6) d 1.94 (m, 4H,
OCH2CH2CH2CH2O), 4.15 (m, 4H, OCH2CH2CH2CH2O),
6.84–7.09 (m, 6H, ArH), 7.45–7.52 (m, 4H, ArH), 7.85–7.92
(m, 4H, ArH), 8.53 (s, 2H, 2 furan-2-CH), 9.38 (brs, 2H, 2
OH, D2O-exchangeable); MS: m/z (%) 562 (Mþ, 35.2), 428
(60.2), 309 (25), 254 (25.8), 161 (100), 121 (64.8), 76 (32), 55
(65.6). Anal. for C34H26O8 Calcd: C, 72.59; H, 4.66. Found:
C, 72.44; H, 4.84%.
powder, mp 227–229ꢁC; IR (KBr) mmax/cmꢀ1 3186 (NH),
1612 (C¼¼N); 1H NMR (DMSO-d6)
d 1.91 (s, 4H,
OCH2CH2CH2CH2O), 3.3 (brs, 2H, 2 NH, D2O-exchangeable),
4.07 (s, 4H, OCH2CH2CH2CH2O), 6.59 (d, J ¼ 2.1 Hz, 2H, 2
pyrazole-4-CH), 6.98 (d, J ¼ 8.4 Hz, 4H, ArH), 7.64 (d, J ¼
1.8 Hz, 2H, 2 pyrazole-5-CH), 7.70 (d, J ¼ 8.4 Hz, 4H, ArH);
MS: m/z (%) 374 (Mþ, 17.7), 215 (100), 173 (55.5), 160
(31.2), 131 (27.1), 77 (22.2), 55 (28.3). Anal. for C22H22N4O2
Calcd: C, 70.57; H, 5.92; N, 14.96. Found: C, 70.94; H, 5.78;
N, 14.86%.
Synthesis of the bis(pyran-2-one) derivatives 17a,b Method
A: General procedure. A solution of the bis(enaminones) 5a,b
(1 mmol) and N-benzoylglycine (13) (0.36 g, 2 mmol) in ace-
tic anhydride (20 mL) was heated under reflux for 1 h then
left to cool to room temperature. The solid product that formed
upon cooling was collected by filtration and recrystallized
from DMF/water to give the bis(pyran-2-one) derivatives
17a,b, in 74 and 77% yields, respectively.
Method B: General procedure. The reactions were carried
out under the same experimental conditions mentioned in
method A earlier using the piperidyl derivatives 9a,b instead
of the enaminones 5a,b to afford the bis(pyran-2-one) deriva-
tives 17a,b in 45 and 52% yields, respectively.
1,3-Bis[4-(3-benzoylamino-2-oxo-2H-pyran-6-yl)phenoxy]-
propane (17a). Orange-colored powder, mp 250–252ꢁC; IR
(KBr) mmax/cmꢀ1 3405 (NH), 1705, 1671 (C¼¼O); 1H NMR
(DMSO-d6) d 2.24 (m, 2H, OCH2CH2CH2O), 4.25 (m, 4H,
OCH2CH2CH2O), 7.03 (d, J ¼ 7.2 Hz, 2H, 2 pyranone-5-CH),
7.1–7.96 (m, 18H, ArH), 8.16 (d, J ¼ 7.2 Hz, 2H, 2 pyranone-
4-CH), 9.50 (brs, 2H, 2 NH, D2O-exchangeable); MS: m/z (%)
654 (Mþ, 48.5), 105 (100), 77 (23.1), 50 (16.4). Anal. for
C39H30N2O8 Calcd: C, 71.55; H, 4.62; N, 4.28. Found: C,
71.86; H, 4.43; N, 4.21%.
1,3-Bis[4-(5-hydroxynaphtho[1,2-b]furan-3-ylcarbonyl)-
phenoxy]propane (20c). Yield: method A/method
B (61/
31%); pale yellow powder, mp 258–260ꢁC; IR (KBr) mmax
/
cmꢀ1 3224 (OH), 1672 (C¼¼O); 1H NMR (DMSO-d6) d 2.24
(m, 2H, OCH2CH2CH2O), 4.26 (m, 4H, OCH2CH2CH2O),
7.04–7.16 (m, 6H, ArH), 7.55–7.95 (m, 10H, ArH), 8.18–8.28
(m, 2H, ArH), 8.62 (s, 2H, 2 furan-2-CH), 10.17 (s, 2H, 2 OH,
D2O-exchangeable); 13C NMR (DMSO-d6): d 28.4, 64.6,
114.3, 114.5, 119.3, 120.8, 121.1, 121.5, 123.3, 123.5, 124.9,
127.4, 130.5, 131.2, 144.5, 150.8, 151.7, 162.3, 188.2. Anal.
for C41H28O8 Calcd: C, 75.92; H, 4.35. Found: C, 76.22; H,
4.29%.
1,4-Bis[4-(5-hydroxynaphtho[1,2-b]furan-3-ylcarbonyl)-
phenoxy]butane (20d). Yield: method A/method B (74/40%);
pale yellow powder, mp > 300ꢁC; IR (KBr) mmax/cmꢀ1 3213
(OH), 1706 (C¼¼O); 1H NMR (DMSO-d6) d 1.93 (m, 4H,
OCH2CH2CH2CH2O), 4.12 (m, 4H, OCH2CH2CH2CH2OA),
7.09–7.13 (m, 6H, ArH), 7.54–7.96 (m, 10H, ArH), 8.18–8.28
(m, 2H, ArH), 8.64 (s, 2H, 2 furan-2-CH), 10.25 (brs, 2H, 2
OH, D2O-exchangeable); 13C NMR (DMSO-d6): d 25.3, 67.6,
114.0, 114.3, 119.3, 120.7, 121, 121.4, 123.3, 123.5, 124.9,
127.3, 129.1, 131.1, 144.5, 150.7, 151.5, 162.3, 188.2. Anal. for
C42H30O8 Calcd: C, 76.12; H, 4.56. Found: C, 76.00; H, 4.44%.
1,4-Bis[4-(3-benzoylamino-2-oxo-2H-pyran-6-yl)phenoxy]-
butane (17b). Orange-colored powder, mp > 300ꢁC; IR (KBr)
1
m
max/cmꢀ1 3403 (NH), 1698, 1637 (C¼¼O); H NMR (DMSO-
d6) d 1.91 (m, 4H, OCH2CH2CH2CH2O), 4.14 (m, 4H,
OCH2CH2CH2CH2O), 7.03–7.13 (m, 20H, ArH, 2 pyranone-5-
CH), 8.16 (d, J ¼ 7.5 Hz, 2H, 2 pyranone-4-CH), 9.56 (brs, 2H,
2 NH, D2O-exchangeable); Anal. for C40H32N2O8 Calcd: C,
71.85; H, 4.82; N, 4.19. Found: C, 72.11; H, 4.65; N, 4.38%.
Synthesis of the bis(benzofurans) 20a,b and bis(naphtho-
furans) 20c,d Method A: General procedure. To a stirred
solution of the bis(enaminones) 5a,b (2 mmol) in acetic acid
(20 mL), p-benzoquinone (18a) or 1,4-naphthoquinone (18b)
(4 mmol) was added and the reaction mixture was stirred over-
night at room temperature. The solid product formed was col-
lected by filtration, washed with water and ethanol, dried, and
finally recrystallized from EtOH/DMF to give the correspond-
ing bis(benzofurans) 20a,b and bis(naphthofurans) 20c,d,
respectively.
REFERENCES AND NOTES
[1] Present address: Ibn Sina National College, P. O. Box
31906, Jeddah 21418.
[2] Prakash, O.; Kumar, R.; Parkash, V. Eur J Med Chem
2008, 43, 435.
[3] Farag, A. M.; Mayhoub, A. S.; Barakat, S. E.; Bayomi, A.
H. Bioorg Med Chem 2008, 16, 881.
[4] Ochi, T.; Jobo-Magari, K.; Yonezawa, A.; Matsumori, K.;
Fujii, T. Eur J Pharmacol 1999, 365, 259.
Method B: General procedure. This method is similar to
method A except that the enaminone derivatives 9a,b were
used instead of 5a,b to afford the corresponding bis(benzofur-
ans) 20a,b and bis(naphthofuran) derivatives 20c,d but in
lower yields compared to that obtained in method A.
[5] Milano, J.; Oliveira, S. M.; Rossato, M. F.; Sauzem, P. D.;
Machado, P.; Beck, P.; Zanatta, N.; Martins, M. A. P.; Mello, C. F.;
Rubin, M. A.; Ferreira, J.; Bonacorso, H. G. Eur J Pharmacol 2008,
581, 86.
1,3-Bis[4-(5-hydroxybenzo[b]furan-3-ylcarbonyl)pheno-
xy]propane (20a). Yield: method A/method B (66/43%); pale
yellow powder, mp 190–192ꢁC; IR (KBr) mmax/cmꢀ1 3258
[6] Reddy, M. V. R.; Billa, V. K.; Pallela, V. R.; Mallireddi-
gari, M. R.; Boominathan, R.; Gabriel, J. L.; Reddy, E. P. Bioorg Med
Chem 2008, 16, 3907.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet