K. Harada et al. / European Journal of Medicinal Chemistry 148 (2018) 86e94
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4.1.7. 1-(4-Benzyloxy-3-methoxyphenyl)propan-1-one (4a)
4.1.12. 1-(benzo[d][1,3]dioxol-5-yl)-4-(4-benzyloxy-3-
To a solution of 4-benyloxy-3-methoxybenzaldehyde (3, 5.00 g,
20.6 mmol) in THF (206 mL) was added EtMgBr (30.0 mL, 1.0 M
solution in THF) at 0 ꢁC. After being stirred for 16 h, the reaction was
quenched with saturated NH4Cl. The aqueous layer was extracted
with ether. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, and concentrated in vacuo. To the
residue was added Dess-Martin periodinane (11.3 g, 30.1 mmol) in
DCM (103 mL). After being stirred for 12 h, the mixture was added
to excess ether and filtered through Celite, and the filtrate was
concentrated in vacuo. The residue was purified by column chro-
matography (hexane:EtOAc ¼ 3:1) to afford 4a (5.51 g, 99%) as a
methoxyphenyl)-2,3-dimethylbutane-1,4-dione (7a)
To a solution of 6a (1.00 g, 5.58 mmol) in DMF (35.0 mL) was
added KHMDS (13.4 mL, 0.5 M solution in toluene) at ꢀ45 ꢁC. After
being stirred for 1 h, a solution of 5a (1.95 g, 5.58 mmol) in DMF
(35.0 mL) was added to the reaction mixture at the same temper-
ature. After being stirred overnight, the reaction was quenched
with saturated NH4Cl. The aqueous layer was extracted with ether.
The combined organic layers were washed with brine, dried over
anhydrous MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (hexane:ether ¼ 1:1) to afford
7a (2.15 g, 86%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3)
d 7.63
colorless oil. 1H NMR (200 MHz, CDCl3)
d
7.56e7.33 (7H, m), 6.89
(1H, dd, J ¼ 8.4, 1.5 Hz), 7.61 (1H, dd, J ¼ 8.4, 1.8 Hz), 7.50 (1H, d,
J ¼ 1.8 Hz), 7.44e7.32 (6H, m), 6.90 (1H, d, J ¼ 8.4 Hz), 6.86 (1H, d,
J ¼ 8.4 Hz), 6.02 (2H, s), 5.23 (2H, s), 3.90 (3H, s), 3.90e3.85 (2H, m),
1.27 (3H, d, J ¼ 6.6 Hz), 1.26 (3H, d, J ¼ 6.6 Hz). 13C NMR (100 MHz,
(1H, d, J ¼ 8.4 Hz), 5.23 (2H, s), 3.94 (3H, s), 2.94 (2H, q, J ¼ 7.3 Hz),
1.21 (3H, t, J ¼ 7.3 Hz). 13C NMR (75 MHz, CDCl3)
d 199.5,152.1,149.4,
136.3, 130.3, 128.6, 128.1, 127.1, 122.3, 112.1, 110.5, 70.7, 56.0, 31.3,
8.6. IR (ATR) 2972, 2935, 1671, 1584, 1510, 1453, 1416, 1340 cmꢀ1
.
CDCl3) d 202.9, 202.5, 152.4, 151.7, 149.5, 148.2, 136.4, 131.0, 129.4,
HRMS (EI) m/z: calcd. for C17H18O3 [M]þ 270.1256, found 270.1252.
128.7, 128.1, 127.2, 124.7, 122.9, 112.3, 111.1, 108.4, 108.0, 101.8, 70.8,
56.0, 43.5, 43.4, 16.0, 15.8. IR (ATR) 3018, 2974, 1665, 1594, 1505,
1454, 1246 cmꢀ1. HRMS (EI) m/z: calcd. for C27H26O6 [M]þ 446.1730,
found 446.1717.
4.1.8. 1-(4-Benzyloxy-3-methoxyphenyl)-2-bromopropan-1-one
(5a)
To a solution of 4a (3.90 g, 14.4 mmol) in CHCl3 (100 mL) was
added Br2 (741
m
L,14.4 mmol) in CHCl3 (45.0 mL) at 0 ꢁC. After being
4.1.13. 1,4-bis(benzo[d][1,3]dioxol-5-yl)-2,3-dimethylbutane-1,4-
dione (7b)
stirred overnight, saturated NaHCO3 solution was added and
extracted with DCM. The organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chro-
matography (hexane:EtOAc ¼ 88:12) to afford 5a (3.93 g, 78%) as a
Compound 7b was prepared in the same manner as compound
7a using
(66.6 mg, 48%) was obtained as a pale yellow oil. 1H NMR (300 MHz,
CDCl3)
7.63 (2H, dd, J ¼ 8.3, 1.8 Hz), 7.42 (2H, d, J ¼ 1.8 Hz), 6.86
a-bromoketone 4b (100 mg, 389 mmol). The product 7b
colorless oil. 1H NMR (300 MHz, CDCl3)
d
7.59 (1H, brs), 7.58 (1H,
d
brd, J ¼ 8.2 Hz), 7.44e7.31 (5H, m), 6.90 (1H, d, J ¼ 8.2 Hz), 5.25 (1H,
(2H, d, J ¼ 8.3 Hz), 6.03 (4H, s), 3.84e3.78 (2H, m), 1.27 (6H, d,
q, J ¼ 6.6 Hz), 5.23 (2H, s), 3.94 (3H, s), 1.87 (3H, d, J ¼ 6.6 Hz). 13
C
J ¼ 7.0 Hz). 13C NMR (75 MHz, CDCl3)
d 202.4, 151.7, 148.2, 130.8,
NMR (75 MHz, CDCl3)
d
192.1, 152.9, 149.7, 136.1, 128.7, 128.2, 127.2,
124.7, 108.4, 108.0, 101.8, 43.5, 15.9. IR (ATR) 2956, 1667, 1440, 1244,
1038 cmꢀ1. HRMS (EI) m/z: calcd. for C20H18O6 [M]þ 354.1103, found
354.1099.
123.2, 112.0, 111.5, 70.8, 56.1, 41.2, 20.4. IR (ATR) 2933, 2358, 1671,
1591, 1453, 1376, 1260 cmꢀ1. HRMS (EI) m/z: calcd. for C17H17O3Br
[M]þ 348.0362, found 348.0356.
4.1.14. 1,4-bis(4-methoxyphenyl)-2,3-dimethylbutane-1,4-dione
(7c)
4.1.9. 1-(benzo[d][1,3]dioxol-5-yl)-2-bromopropan-1-one (5b)
Compound 5b was prepared in the same manner as compound
5a using ketone 4b (9.00 g, 50.0 mmol). The product 5b (11.3 g, 87%)
Compound 7c was prepared in the same manner as compound
7a using
a-bromoketone 4c (2.05 g, 8.47 mmol). The product 7c
was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3)
d 7.64
(1.66 g, 60%) was obtained as a pale yellow oil. 1H NMR (200 MHz,
(1H, dd, J ¼ 8.1, 1.8 Hz), 7.50 (1H, d, J ¼ 1.8 Hz), 6.88 (1H, d,
CDCl3)
d
7.97 (4H, d, J ¼ 8.7 Hz), 6.93 (4H, d, J ¼ 8.7 Hz), 3.95e3.90
J ¼ 8.1 Hz), 6.07 (2H, s), 5.22 (1H, q, J ¼ 6.6 Hz), 1.88 (3H, d,
(2H, m), 3.86 (6H, s), 1.28 (6H, d, J ¼ 6.7 Hz). 13C NMR (75 MHz,
J ¼ 6.6 Hz). 13C NMR (75 MHz, CDCl3)
d
191.6, 152.3, 148.4, 128.6,
CDCl3) d 202.9, 163.4, 130.8, 129.1, 113.7, 55.5, 43.2, 15.8. IR (ATR)
125.3, 108.7, 108.1, 102.1, 41.3, 20.3. IR (ATR) 2953, 1683, 1443, 1245,
1039 cmꢀ1. HRMS (EI) m/z: calcd. for C10H9O3Br [M]þ 257.9867,
found 257.9899.
2971, 1667, 1597, 1168, 968 cmꢀ1. HRMS (EI) m/z: calcd. for C20H22O4
[M]þ 326.1518, found 326.1508.
4.1.15. 2,3-Dimethyl-1,4-di-p-tolylbutane-1,4-dione (7d)
4.1.10. 2-Bromo-1-(4-methoxyphenyl)propan-1-one (5c)
Compound 7d was prepared in the same manner as compound
Compound 5c was prepared in the same manner as compound
5a using ketone 4c (2.00 g, 12.2 mmol). The product 5c (2.45 g, 83%)
7a using
a-bromoketone 4d (400 mg, 1.78 mmol). The product 7d
(472 mg, 90%) was obtained as a pale yellow oil. 1H NMR (200 MHz,
was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3)
d
8.01
CDCl3)
d
7.89 (4H, d, J ¼ 8.2 Hz), 7.26 (4H, d, J ¼ 8.2 Hz), 3.98e3.90
(2H, d, J ¼ 9.3 Hz), 6.95 (2H, d, J ¼ 9.3 Hz), 5.26 (1H, q, J ¼ 6.6 Hz),
(2H, m), 2.41 (6H, s), 1.27 (6H, d, J ¼ 6.7 Hz). 13C NMR (75 MHz,
3.88 (3H, s), 1.89 (3H, d, J ¼ 6.6 Hz). 13C NMR (75 MHz, CDCl3)
CDCl3)
d 203.9, 143.6, 133.6, 129.2, 128.6, 43.4, 21.6, 15.5. IR (ATR)
d
191.9, 163.9, 131.3, 126.8, 113.9, 55.5, 41.4, 20.2. IR (ATR) 2933,
2963,1666,1541, 966 cmꢀ1. HRMS (EI) m/z: calcd. for C20H22O2 [M]þ
1674, 1597, 1238, 1157, 840 cmꢀ1. HRMS (EI) m/z: calcd. for
10H11O2Br [M]þ 241.9942, found 241.9950.
294.1620, found 294.1619.
C
4.1.16. 1,4-bis(4-benzyloxy-3-methoxyphenyl)-2,3-dimethylbutane-
1,4-dione (7e)
4.1.11. 2-Bromo-1-(p-tolyl)propan-1-one (5d)
Compound 5d was prepared in the same manner as compound
5a using ketone 4d (2.01 mL, 13.5 mmol). The product 5d (2.05 g,
67%) was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3)
Compound 7e was prepared in the same manner as compound
7a using
(137 mg, 59%) was obtained as a pale yellow oil. 1H NMR (300 MHz,
CDCl3)
a-bromoketone 4e (150 mg, 431 mmol). The product 7e
d
7.92 (2H, d, J ¼ 8.4 Hz), 7.28 (2H, d, J ¼ 8.4 Hz), 5.28 (1H, q,
d
7.61 (2H, dd, J ¼ 8.7, 2.0 Hz), 7.49 (2H, d, J ¼ 2.0 Hz),
J ¼ 6.5 Hz), 2.43 (3H, s), 1.89 (3H, d, J ¼ 6.5 Hz). 13C NMR (75 MHz,
7.44e7.31 (10H, m), 6.90 (2H, d, J ¼ 8.7 Hz), 5.23 (4H, m), 3.97e3.87
CDCl3)
d 193.1, 144.8, 131.5, 129.5, 129.1, 41.6, 21.8, 20.2. IR (ATR)
(2H, m), 3.89 (6H, s), 1.27 (6H, d, J ¼ 6.5 Hz). 13C NMR (75 MHz,
2973, 1667, 1440, 1245, 1037 cmꢀ1. HRMS (EI) m/z: calcd. for
10H11OBr [M]þ 225.9993, found 226.0007.
CDCl3) d 203.0, 152.3, 149.5, 136.4, 129.4, 128.7, 128.1, 127.2, 122.9,
C
112.2, 111.1, 70.8, 56.0, 43.2, 16.0. IR (ATR) 2972, 1666, 1593, 1511,