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S.E. Bariamis et al. / European Journal of Medicinal Chemistry 60 (2013) 155e169
125.4, 124.8, 118.6, 114.9 (2C), 106.6, 61.2; MS (ESI, 30 eV): m/z 309.5
(M þ Na)þ, 287.1 (M þ H)þ.
4.1.2.9.2. From bromide 12. To a solution (ꢁ10 ꢀC) of boronate
TDBBA (0.11 g, 0.44 mmol) and bromide 12 (0.1 g, 0.34 mmol) in
anhydrous THF (3 mL), K2CO3 (0.09 g, 0.68 mmol) was added and
the resulting mixture was degassed. Then, PdCl2(dppf) (0.02 g,
0.02 mmol) was added and the resulting mixture was redegassed.
The resulting reaction mixture was heated at 67 ꢀC for 1 d. After the
completion of the reaction, the mixture was acidified with 2 N aq.
HCl solution to pH 1 and passed through a short pad of celite. The
filtrate was evaporated to dryness and the residue was subjected to
flash column chromatography to give pure product, which was
crystallized upon addition of Et2O. The thus obtained acid 22 had
identical physical data with the sample obtained from 21.
4.1.2.8.2. E-3-(5-Methoxypsoralen-8-yl)propenoic
acid
(23).
Reaction time 2 h; yield: 90% (0.062 g of white solid); mp 229 ꢀC
(dec.); Rf ¼ 0.27 (E); IR (KBr, cmꢁ1):
n 3700e3250, 1738, 1694, 1622,
1574; found C, 62.78; H, 3.63. Calc. for C15H10O6: C, 62.94; H, 3.52%;
1H NMR (DMSO-d6,
d
): 8.24 (1H, d, J ¼ 9.8 Hz), 8.21 (1H, d,
J ¼ 2.4 Hz), 8.01 (1H, d, J ¼ 16.2 Hz), 7.65 (1H, d, J ¼ 2.4 Hz), 6.96 (1H,
d, J ¼ 16.2 Hz), 6.41 (1H, d, J ¼ 9.8 Hz), 4.34 (3H, s); 13C NMR (DMSO-
d6, d): 166.5, 158.6, 148.5 (2C), 142.4, 140.9, 136.4, 132.4, 124.9 (2C),
118.0, 114.4 (2C), 106.2, 60.6; MS (ESI, 30 eV): m/z 309.5 (M þ Na)þ,
287.1 (M þ H)þ.
4.1.2.8.3. E-3-[4-(8-Methoxypsoralen-5-yl)phenyl]propenoic acid
(29). Reaction time 1 h; yield: 81% (0.07 g of white solid); mp
4.1.2.10. General procedure for the preparation of esters 6, 18e20 and
34. To an ice-cold (0 ꢀC) suspension or solution of acids 4, 16 or 31
(0.1 mmol), the corresponding alcohol (0.15 mmol) and TPP
213 ꢀC (dec.); Rf ¼ 0.31 (E); IR (KBr, cmꢁ1):
n 3600e3250, 1707,
1685, 1626, 1557; found C, 69.49; H, 4.01. Calc. for C21H14O6: C,
69.61; H, 3.89%; 1H NMR (DMSO-d6,
d
): 12.49 (1H, br s), 8.16 (1H,
(0.032 g, 0.12 mmol) in freshly distilled THF (0.34 mL), DIAD (24 mL,
d, J ¼ 2.4 Hz), 7.90 (2H, d, J ¼ 8.0 Hz), 7.82 (1H, d, J ¼ 9.8 Hz), 7.71
(1H, d, J ¼ 16.0 Hz), 7.49 (2H, d, J ¼ 8.0 Hz), 6.81 (1H, d,
J ¼ 2.4 Hz), 6.65 (1H, d, J ¼ 16.0 Hz), 6.41 (1H, d, J ¼ 9.8 Hz), 4.23
0.12 mmol) was added. The reaction mixtures were stirred at room
temperature for 1e2 h. The anticipated esters 6, 18e20 and 34 were
obtained pure after FCC purification.
(3H, s); 13C NMR (DMSO-d6,
d
): 167.9, 159.8, 148.8, 146.8, 143.6,
4.1.2.10.1. Ethyl (E)-3-(trioxsalen-40-yl)propenoate (6). Reaction
time: 2 h; yield: 92% (0.05 g of white solid); mp 191e192 ꢀC; Rf ¼ 0.31
143.5, 143.0, 137.1, 134.6, 132.0, 131.3 (2C), 129.1 (2C), 126.2, 125.8,
120.5, 114.9, 114.3, 106.7, 61.6; MS (ESI, 30 eV): m/z 363.6
(M þ H)þ.
(B); IR (KBr, cmꢁ1):
n 1738, 1712, 1636, 1570, 1160, 752; found C, 69.81;
H, 5.68. Calc. for C19H18O5: C, 69.93; H, 5.56%; 1H NMR (DMSO-d6,
d):
4.1.2.8.4. E-3-[4-(5-Methoxypsoralen-8-yl)phenyl]propenoic acid
(34). Reaction time 1 h; yield: 82% (0.07 g of white solid); mp
7.92 (1H, d, J ¼ 16.0 Hz), 7.89 (1H, s), 6.87 (1H, d, J ¼ 16.0 Hz), 6.29 (1H,
s), 4.24 (2H, q, J ¼ 7.2 Hz), 2.63 (3H, s), 2.46 (3H, s), 2.37 (3H, s), 1.29
238 ꢀC (dec.); Rf ¼ 0.34 (E); IR (KBr, cmꢁ1):
n
3600e3400, 1739,
(3H, t, J ¼ 7.2 Hz); 13C NMR (DMSO-d6,
d); 164.4, 163.9, 163.4, 155.2,
1693, 16.22, 1579; found C, 69.53; H, 3.99. C21H14O6: C, 69.61; H,
154.8,149.9,140.2,121.9,117.6,115.0,113.6,113.2,111.5,109.4, 61.6,19.9,
14.5, 13.7, 9.1; GCeMS (EI, 20 eV): tR ¼ 13.95 min, m/z 326 (Mþ, 100%),
297 (MꢁC2H5, 13), 281 (MꢁOC2H5, 10), 252 (MꢁHCO2C2H5, 19).
4.1.2.10.2. Ethyl E-3-(8-methoxypsoralen-5-yl)propenoate (18).
Reaction time: 1.5 h; yield: 89% (0.028 g of white solid); mp 129e
3.89%; 1H NMR (DMSO-d6,
d): 12.44 (1H, br s), 8.11 (1H, d,
J ¼ 2.4 Hz), 7.94 (1H, d, J ¼ 9.8 Hz), 7.84 (2H, d, J ¼ 8.0 Hz), 7.65 (1H,
d, J ¼ 16.0 Hz), 7.44 (2H, d, J ¼ 8.0 Hz), 6.76 (1H, d, J ¼ 2.4 Hz), 6.60
(1H, d, J ¼ 16.0 Hz), 6.36 (1H, d, J ¼ 9.8 Hz), 4.18 (3H, s); 13C NMR
(DMSO-d6,
d
): 167.4, 161.8, 157.1, 150.0, 149.9, 146.0, 144.2 (2C),
132 ꢀC; Rf ¼ 0.26 (B); IR (KBr, cmꢁ1):
n 1728, 1636, 1576, 1164,
140.4, 135.2 (2C), 131.9 (2C), 129.0 (2C), 125.2, 121.5, 113.9, 113.7,
106.2, 61.4; MS (ESI, 30 eV): 762.9 (2M þ K)þ, 746.9 (2M þ Na)þ,
400.9 (M þ K)þ, 385.2 (M þ Na)þ.
752; found C, 64.82; H, 4.56. Calc. for C17H14O6: C, 64.97; H, 4.49%;
1H NMR (DMSO-d6,
d
): 8.38 (1H, d, J ¼ 10.0 Hz), 8.23 (1H, d,
J ¼ 2.4 Hz), 8.16 (1H, d, J ¼ 16.0 Hz), 7.36 (1H, d, J ¼ 2.4 Hz), 6.51 (1H,
d, J ¼ 16.0 Hz), 6.49 (1H, d, J ¼ 10.0 Hz), 4.25 (2H, q, J ¼ 7.2 Hz), 4.24
4.1.2.9. General procedure for the preparation of acids 22 and 33
4.1.2.9.1. From aldehydes 21 and 32. To a suspension of aldehyde
21 or 32 (0.04 g, 0.11 mmol) in DMF (1 mL), OxoneÒ (0.21 g,
0.33 mmol) was added and the resulting mixtures were stirred at
25 ꢀC (21) or at 60 ꢀC (32) for 2e3 d. After completion of the
reaction, the resulting mixtures were subjected to FCC to give the
corresponding acids.
(3H, s), 1.30 (3H, t, J ¼ 7.2 Hz); 13C NMR (DMSO-d6,
d): 165.8, 159.1,
149.0, 146.3, 142.9, 141.4, 137.4, 133.1, 125.0, 124.2, 118.3, 115.0 (2C),
106.6, 61.2, 60.5, 14.2; MS (ESI, 30 eV): m/z 667.1 (2M þ K)þ, 651.1
(2M þ Na)þ, 353.2 (M þ K)þ, 337.2 (M þ Na)þ.
4.1.2.10.3. n-Butyl E-3-(8-methoxypsoralen-5-yl)propenoate (19).
Reaction time: 1 h; yield: 85% (0.03 g of white solid); mp 120e
123 ꢀC; Rf ¼ 0.34 (B); IR (KBr, cmꢁ1):
n 1724, 1630, 1572, 1144,
4.1.2.9.1.1. 4-(8-Methoxypsoralen-5-yl)benzoic acid (22). Reaction
1044, 750; found C, 66.85; H, 5.14. Calc. for C19H18O6: C, 66.66; H,
time 3 d; yield: 43% (0.016 g of white solid); mp 220 ꢀC (dec.);
5.30%; 1H NMR (CDCl3,
d): 8.15 (1H, d, J ¼ 16.0 Hz), 8.14 (1H, d,
Rf ¼ 0.12 (D); IR (KBr, cmꢁ1):
n
3180e2500, 1735, 1698; found C, 67.92;
): 12.70 (1H,
J ¼ 10.0 Hz), 7.76 (1H, d, J ¼ 2.4 Hz), 7.07 (1H, d, J ¼ 2.4 Hz), 6.45 (1H,
d, J ¼ 10.0 Hz), 6.44 (1H, d, J ¼ 16.0 Hz), 4.34 (3H, s), 4.26 (2H, t,
J ¼ 6.4 Hz), 1.72 (2H, quint., J ¼ 7.2 Hz), 1.45 (2H, sext., J ¼ 7.6 Hz),
H, 3.41. C19H12O6: C, 67.86; H, 3.60%; 1H NMR (DMSO-d6,
d
br s), 8.17 (1H, d, J ¼ 2.4 Hz), 8.12 (2H, d, J ¼ 8.2 Hz), 7.80
(1H, d, J ¼ 9.8 Hz), 7.57 (2H, d, J ¼ 8.2 Hz), 6.81 (1H, d, J ¼ 2.4 Hz),
0.98 (3H, t, J ¼ 7.2 Hz); 13C NMR (CDCl3,
d): 166.1, 159.9, 147.7 (2C),
6.42 (1H, d, J ¼ 9.8 Hz), 4.23 (3H, s); 13C NMR (DMSO-d6,
d
):
147.2, 143.6, 140.5, 134.1, 125.5, 124.6, 118.5, 115.6, 115.4, 106.6, 65.1,
61.6, 31.0, 19.4, 14.0; MS (ESI, 30 eV): m/z 723.1 (2M þ K)þ, 707.1
(2M þ Na)þ.
168.9, 160.8, 149.8, 147.8, 144.6, 144.5, 144.0, 138.1, 135.6, 133.0,
132.3 (2C), 130.1 (2C), 126.8, 121.5, 115.9, 107.7, 62.6; MS (ESI, 30 eV):
m/z 711.1 (2M þ K)þ, 695.4 (2M þ Na), 375.5 (M þ K)þ, 359.6
(M þ Na)þ.
4.1.2.10.4. 3-Phenoxybenzyl E-3-(8-methoxypsoralen-5-yl)prope-
noate (20). Reaction time: 2 h; yield: 92% (0.042 g of colorless oil);
4.1.2.9.1.2. 4-(5-Methoxypsoralen-8-yl)benzoic acid (33). Reaction
time 2 d; yield: 38% (0.014 g of white solid); mp 228 ꢀC (dec.);
Rf ¼ 0.48 (B); IR (neat, cmꢁ1):
n 1724, 1630, 1572, 744; found C,
71.69; H, 4.50. Calc. for C28H20O7: C, 71.79; H, 4.30%; 1H NMR (CDCl3,
Rf ¼ 0.33 (E); IR (KBr, cmꢁ1):
n
3600e3380, 1737, 1691, 1610, 1594,
d
): 8.20 (1H, d, J ¼ 15.8 Hz), 8.13 (1H, d, J ¼ 10.0 Hz), 7.76 (1H, d,
1104; found C, 67.83; H, 3.48. C19H12O6: C, 67.86; H, 3.60%; 1H NMR
J ¼ 2.2 Hz), 7.35e7.29 (4H, m), 7.14e7.08 (3H, m), 7.06 (1H, d,
J ¼ 2.2 Hz), 7.03e6.98 (2H, m), 6.49 (1H, d, J ¼ 15.8 Hz), 6.45 (1H, d,
(DMSO-d6,
d
): 7.78 (1H, d, J ¼ 9.8 Hz), 7.68 (1H, d, J ¼ 2.0 Hz), 7.62
(2H, d, J ¼ 8.0 Hz), 7.40 (2H, d, J ¼ 8.0 Hz), 6.66 (1H, d, J ¼ 2.0 Hz), 6.32
J ¼ 10.0 Hz), 5.27 (2H, s), 4.36 (3H, s); 13C NMR (CDCl3,
d): 157.8,
(1H, d, J ¼ 9.8 Hz), 4.34 (3H, s); 13C NMR (DMSO-d6,
d): 167.6, 162.0,
157.2, 147.7 (2C), 143.1 (2C), 140.4, 138.6, 137.9, 130.2, 130.1, 130.0,
129.9 (2C), 123.9, 123.8, 123.6, 123.1, 121.7, 119.3 (2C), 118.1, 117.3,
115.7, 115.5, 106.6, 66.5, 61.6; HRMS-ESI (m/z): [M þ Na]þ. Calc. for
C28H20NaO7, 491.11012; found, 491.11058.
157.3, 146.2 (2C), 144.4 (2C), 140.6 (2C), 135.4 (2C), 132.1 (2C), 129.2
(2C), 121.7, 113.9, 106.4, 61.5; MS (ESI, 30 eV): m/z 375.5 (M þ K)þ,
359.5 (M þ Na)þ, 291.7 (MꢁCOOH)þ.