M.Á. Castro et al. / European Journal of Medicinal Chemistry 67 (2013) 19e27
25
828. HRMS (ES, M þ 1): calcd: 362.1756, found: 362,1736. (b)
102 mg (30%) of 15a/15b (1:1 ratio). (c) 21 mg (6%) of 15b as a
4.1.8.2. 3-Chloro-2-ethylamino-5,5(8,8)-dimethyl-5,6,7,8-
tetrahydroanthracene-1,4-diones 19a (19b). Following the above
procedure, treatment of 17 with ethylamine for 7 days at 80 ꢂC and
2 more weeks at 100 ꢂC, gave out, after column chromatography
(eluent: Hex/EtOAc 8:2), the 1:1 mixture of regioisomers 19a/19b
viscous oil. 1H NMR (CDCl3)
d: 1.35 (s, 6H, H-11,12), 1.70e1.83 (m,
4H, H-6,7), 2.88 (t, 2H, J ¼ 6.4, H-5), 6.16 (s, 1H, H-3), 7.75 (s, 1H, H-
10), 8.06 (s, 1H, H-9)), 3.82 (s, 3H, OMe), 6.93, 7.19 (AB system,
J ¼ 8.8, Ph-NH). 13C NMR
d
: 19.2 (C6), 31.5 (C5), 31.6 (C-11,12), 34.5
(viscous oil, 30%). 1H NMR (CDCl3)
d
: 1.31 (s, 6H, H-11,12), 1.68e1.80
(m, 4H, H-6,7), 2.82 (m, 2H, H-8), 7.66/7.96 (s, 1H, H-9), 8.06/7.77 (s,
1H, H-10), 1.30 (m, 3H, Et-NH), 3.88 (m, 2H, Et-NH). 13C NMR
: 19.1
(C8), 38.7 (C7), 102.4 (C3), 125.4 (C9), 127.1 (C10), 128.4 (C9a), 130.4
(C4a), 144.7 (C10a), 145.9 (C2), 150.9 (C8a), 182.1 (C1), 184.3 (C4),
d
55.6 (OMe), 114.9, 124.9, 130.4, 157.6 (Ph-NH). IR (
n
, cmꢁ1): 3318,
(C7/6), 30.9 (C8/5), 31.5 (C-11,12), 34.5 (C5/8), 39.9 (C6/7), 125.7
(C10/9), 126.9 (C9a), 127.8 (C9/10), 130.9/126.8 (C4a), 141.5/151.1
(C8a),144.2 (C3) 154.2/144.8 (C10a),177.2 (C1),180.4 (C4),16.4, 38.6
1672, 1596, 1559, 1515, 1341, 1246, 828. HRMS (ES, M þ 1): calcd:
362.1756, found: 362.1736.
(Et-NH). IR (n
, cmꢁ1): 1673, 1595, 1561, 1513, 1337, 1294,1255.
4.1.7. 2-(4-Acetoxyanilino)-5,5(8,8)-dimethyl-5,6,7,8-
tetrahydroanthracene-1,4-diones 16a (16b)
4.1.8.3. 3-Chloro-2-(3,4-dimethylanilino)-5,5(8,8)-dimethyl-5,6,7,8-
tetrahydroanthracene-1,4-diones 20a (20b). Following the above
procedure, treatment of 17 with 3,4-dimethylaniline for 24 h under
reflux, gave the 1:1 mixture of regioisomers 20a/20b (viscous oil,
Following the procedure described above, treatment of 12 with
p-hydroxyaniline in methanol gave a reaction product that was
treated with acetic anhydride and pyridine for 20 h. The acetylated
product afforded, after column chromatography, quinone 16
(viscous oil, 20%) as a 1:1 mixture of 16a/16b regioisomers. 1H NMR
84%). 1H NMR (CDCl3)
d: 1.32 (s, 6H, H-11,12), 1.66e1.82 (m, 4H, H-
6,7), 2.82 (m, 2H, H-5, 8), 7.70/8.08 (s, 1H, H-9), 8.09/7.78 (s, 1H, H-
10), 2.21 (s, 6H, Me-Ph), 6.78 (m, 1H, Ph-NH), 6.82 (bs, 1H, Ph-NH),
(CDCl3) d: 1.34 (s, 6H, H-11,12), 1.70-1.83 (m, 4H, H-6,7), 2.88 (t, 2H,
J ¼ 6.4, H-5,8), 6.32/6.30 (s, 1H, H-3), 7.77/8.06 (s, 1H, H-9), 8.04/
7.03 (d, 1H, J ¼ 7.7, Ph-NH). 13C NMR
d: 19.1 (C7/6), 30.9 (C8/5), 31.4
7.75 (s, 1H, H-10)), 2.31 (s, 3H, Ac), 7.13/7.12, 7.26/7.75 (AB system,
(C-11,12), 34.6/30.9 (C5), 38.6 (C6/7), 127.0/129.7 (C9a), 128.0 (C9),
129.4 (C10),130.5/129.7 (C4a),142.1/151.7 (C8a),154.3/144.9 (C10a),
177.8 (C4), 180.6 (C1), 19.4, 113.5, 121.7, 125.4, 125.9, 134.1, 135.3,
J ¼ 8.8, Ph-NH). 13C NMR
d: 19.2 (C7/6), 31.4/34.5 (C8), 31.5 (C-11,12),
34.9/31.4 (C5), 38.6 (C6/7), 103.4 (C3), 125.4/127.2 (C10), 127.6/124.9
(C9), 141.5(C9a/4a),145.0 (C4a/9a), 144.8/145.0 (C2), 151.1 (C8a/10a),
154.2 (C10a/8a), 181.8 (C1), 184.3 (C4), 21.1 and 169.4 (Ac), 122.8,
136.7, 141.6, 141.9 (C2, C3, Ph-NH). IR (n
, cmꢁ1): 3307, 1669, 1593,
1561, 1510, 1337, 1287, 1253, 877. HRMS (ES, M þ H): calcd:
123.6, 131.1/130.3, 135.3 (Ph-NH). IR (
1612, 1598, 1192, 921, 755.
n
, cmꢁ1): 3318, 1766, 1678,
394.1568, found: 394.1588.
4.1.8.4. 3-Chloro-2-(4-methoxyanilino)-5,5(8,8)-dimethyl-5,6,7,8-
tetrahydroanthracene-1,4-diones 21a (21b). Following the above
procedure, treatment of 17 with 4-methoxyaniline for 24 h under
reflux, gave the 1:1 mixture of regioisomers 21a/21b (viscous oil,
4.1.8. General procedure for the preparation of compounds 18e24
A mixture of naphthoquinone 17 (0.90 mmol) and the corre-
sponding amine (0.90 mmol) in ethanol (10 mL) was stirred at room
temperature until compound 17 disappeared by TLC control. Then,
the solvent was vacuum-evaporated and the residue was redis-
solved in ethyl acetate. The organic layer was washed with 2 N HCl
and brine, dried over Na2SO4, filtered and evaporated till dryness,
affording a crude product, which was purified through column
chromatography over silica gel.
91%). 1H NMR (CDCl3)
d: 1.33 (s, 6H, H-11,12), 1.75e1.84 (m, 4H, H-
6,7), 2.86 (m, 2H, H-5, 8), 7.75/8.04 (s, 1H, H-9), 8.10/7.81 (s, 1H, H-
10), 3.82 (s, 3H, MeO-Ph), 6.85, 7.03 (AB system, J ¼ 8.6, Ph-NH). 13
C
NMR d: 19.1 (C7/6), 30.9 (C8/5), 31.3 (C-11,12), 34.9/30.9 (C5), 38.5
(C6/7), 125.7 (C10), 126.9/127.7 (C9a), 128.0 (C9), 130.4/129.6 (C4a),
142.0/151.5 (C8a), 154.1/144.8 (C10a), 177.5 (C4), 180.3 (C1), 55.4 (s,
3H, MeO-Ph), 113.5, 126.2, 130.6, 142.0, 157.3 (C2, C3, Ph-NH). IR (n,
4.1.8.1. 2-Acetamido-3-chloro-5,5(8,8)-dimethyl-5,6,7,8-tetrahydroa
nthracene-1,4-diones 18a (18b). Following the above procedure,
treatment of 17 with 30% NH4OH for 1 h, gave a reaction product
which was acetylated at 0 ꢂC with Ac2OeH2SO4 (6 mL taken from a
previously solution prepared with 50 mL of Ac2O and 0.15 mL of
H2SO4) for 30 min. The reaction was quenched with ice and
extracted with EtOAc. The organic layer was washed with satd aq
NaHCO3, and brine, dried over anhydrous Na2SO4 and vacuum-
evaporated yielding a crude product, which was purified by col-
umn chromatography (eluent: Hex/EtOAc 8:2) to afford: (a) 10 mg
cmꢁ1): 3306, 1670, 1593, 1513, 1337, 1289, 1245, 1036, 895. HRMS
(ES, M þ Na): calcd: 418.1180, found: 418.1176.
4.1.8.5. 3-Chloro-2-(3,4-dimethoxyanilino)-5,5(8,8)-dimethyl-
5,6,7,8-tetrahydroanthracene-1,4-diones 22a (22b). Following the
above procedure, treatment of 17 with 3,4-dimethoxyaniline for
24 h under reflux, gave the 1:1 mixture of regioisomers 22a/22b
(viscous oil, 95%). 1H NMR (CDCl3)
d: 1.33 (s, 6H, H-11,12), 1.68e1.84
(m, 4H, H-6,7), 2.87 (m, 2H, H-5, 8), 7.75/8.04 (s, 1H, H-9), 8.11/7.81
(s, 1H, H-10), 3.85(s, 3H, MeO-Ph), 3.88 (s, 3H, MeO-Ph), 6.63/6.64
(8%) of 18a. M.p. 75e80 ꢂC. 1H NMR (CDCl3)
1.70e1.83 (m, 4H, H-6,7), 2.89 (t, 2H, J ¼ 6.2, H-8), 7.82 (s, 1H, H-
10), 8.05 (s, 1H, H-9), 2.29 (s, 3H, Ac). 13C NMR
: 19.1 (C7), 31.1
d
: 1.33 (s, 6H, H-11,12),
(s, 1H, Ph-NH), 6.65 (m, 1H, Ph-NH), 6.80 (d, 1H, J ¼ 8.1, Ph-NH). 13
C
NMR d: 19.0 (C7/6), 30.1/34.5 (C8), 31.4 (C-11,12), 34.8/30.8 (C5),
d
38.5 (C6/7), 125.8 (C10/9), 126.8/127.6 (C9a), 128.0 (C9/10), 130.4/
129.6 (C4a), 142.0/151.6 (C8a), 154.3/144.9 (C10a), 177.7 (C4), 180.4
(C1), 55.9 (MeO-Ph), 109.0/109.1, 110.4, 113.7, 116.9/117.0, 130.7,
(C8), 31.4 (C-11,12), 34.9 (C5), 38.4 (C6), 126.4 (C10), 127.3 (C4a),
128.1 (C9), 129.4 (C9a), 138.8 (C2), 143.8 (C8a) 154.2 (C10a), 177.8
(C1), 180.0 (C4), 24.2 and 166.7 (Ac). IR (
1558, 1516, 1344, 1248, 828. IR (
, cmꢁ1): 3319, 1673, 1597, 1493,
1336, 1291, 750. (b) 34 mg (30%) of 18a/18b. (c) 6 mg (5%) of 18b.
M.p. 140e144 ꢂC. 1H NMR (CDCl3)
: 1.33 (s, 6H, H-11,12), 1.70e1.83
(m, 4H, H-6,7), 2.88 (t, 2H, J ¼ 6.2, H-5), 7.76 (s, 1H, H-9), 8.11 (s,
1H, H-10), 2.28 (s, 3H, Ac). 13C NMR
: 19.1 (C6), 31.2 (C5), 31.4 (C-
n
, cmꢁ1): 3319, 1669, 1597,
141.8, 147.1, 148.5 (C2, C3, Ph-NH). IR (n
, cmꢁ1): 3307, 1669, 1593,
n
1512, 1461, 1337, 1238, 1028, 870. HRMS (ES, M þ H): calcd:
426.1466, found: 426.1480.
d
4.1.8.6. 3-Chloro-2-(3,4,5-trimethoxyanilino)-5,5(8,8)-dimethyl-
5,6,7,8-tetrahydroanthracene-1,4-diones 23a (23b). A 3:1 mixture of
13a/13b (0.29 mmol) was treated with 3,4,5-trimethoxyaniline
(0.31 mmol) in dioxane (10 mL) for 4 days at 120 ꢂC. Treatment of
the reaction mixture as described in the general procedure afforded
a reaction product that gave, after column chromatography (eluent:
Cl2CH2/EtOAc 97:3), (a) 42% of unreacted 13a/13b mixture, (b) 18%
d
11,12), 34.8 (C8), 38.4 (C7), 124.1 (C4a), 125.9 (C9), 128.6 (C9a,10),
133.4 (C3), 139.0 (C2), 144,7 (C10a) 154.3 (C8a), 177.8 (C1), 180.0
(C4), 24.2 and 166.6 (Ac). IR (n
, cmꢁ1): 3323, 1673, 1597, 1488,
1335, 1295, 1230, 745. HRMS (ES, M þ Na): calcd: 354.0867, found:
354.0853.