Substituted naphthazarins
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
99
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Methylation of mompain (2,5,7,8-tetrahydroxy-1,4-naph-
thoquinone, 2a) afforded 2,5,8-trihydroxy-7-methoxy-1,4-naph-
thoquinone (4a) in a yield of 25 mg (35%), Rf 0.28,
m.p. 225227 °C (cf. lit. data:7 m.p. 240241 °C). IR (CDCl3),
ν/cm1: 3525 m, 3422 m (β-OH), 1661 w, 1629 m, 1606 s
(C=O), 1585 sh.w (C=C). 1H NMR (CDCl3), δ: 3.97 (s, 3 H,
OCH3); 6.48 and 6.53 (both s, 1 H each, H(6), H(3)); 12.08
and 13.11 (both s, 1 H each, C(8)OH, C(5)OH). MS (EI,
18 eV), m/z (Irel (%)): 236 [M]+ (100), 223 (9), 218 (22), 208
(13), 206 (17), 205 (11), 193 (15), 190 (14). In addition to
product 4a, 5,8-dihydroxy-2,7-dimethoxy-1,4-naphthoquinone
(10) was isolated from the reaction mixture in a yield of
46 mg (61%), Rf 0.34, m.p. 270272 °C (cf. lit. data:7
m.p. 273275 °C). 1H NMR (CDCl3), δ: 3.96 (s, 6 H,
2 OCH3); 6.40 (s, 2 H, H(6) and H(3)); 12.73 and 13.15
(both s, 1 H each, C(8)OH, C(5)OH).
Methylation of 3-ethyl-2,5,7,8-tetrahydroxy-1,4-naphtho-
quinone (2b) afforded 3-ethyl-2,5,8-trihydroxy-7-methoxy-1,4-
naphthoquinone (cristazarin, 4b) in a yield of 54 mg (68%),
Rf 0.40, m.p. 230232 °C (cf. lit. data:5 m.p. 154157 °C, lit.
data:7 m.p. 230232 °C). IR (CDCl3), ν/cm1: 3526 w, 3424 m
(β-OH), 1654 w, 1629 m, 1599 s (C=O), 1577 sh.m (C=C).
1H NMR (CDCl3), δ: 1.16 (t, 3 H, CH3, J = 7.6 Hz); 2.64 (q,
2 H, CH2, J = 7.6 Hz); 3.96 (s, 3 H, OCH3); 6.57 (s, 1 H,
H(6)); 7.13 (br.s, 1 H, β-OH); 12.04 and 13.34 (both s,
1 H each, C(8)OH, C(5)OH). 1H NMR (DMSO-d6),
δ: 1.05 (t, 3 H, CH3, J = 7.6 Hz); 2.50 (q, 2 H, CH2,
J = 7.6 Hz); 3.91 (s, 3 H, OCH3); 6.76 (s, 1 H, H(6)); 11.11
(br.s, 1 H, β-OH); 12.27 and 13.50 (both s, 1 H each,
C(8)OH, C(5)OH). MS (EI, 18 eV), m/z (Irel (%)):
264 [M]+ (100). In addition to product 4b, 3-ethyl-5,8-
dihydroxy-2,7-dimethoxy-1,4-naphthoquinone was isolated from
the reaction mixture in a yield of 27 mg (32%), Rf 0.45,
m.p. 146149 °C (cf. lit. data:4,7,14 m.p. 145147 °C). 1H NMR
(CDCl3), δ: 1.16 (t, 3 H, CH3, J = 7.6 Hz); 2.73 (q, 2 H, CH2,
J = 7.6 Hz); 3.94 and 4.06 (both s, 3 H each, OCH3); 6.26 (s,
1 H, H(6)); 12.80 and 13.31 (both s, 1 H each, C(8)OH,
C(5)OH). MS (EI, 18 eV), m/z (Irel (%)): 278 [M]+ (100).
Methylation of 3-chloro-2,5,7,8-tetrahydroxy-1,4-naphtho-
quinone (2ñ) afforded 6-chloro-2,5,8-trihydroxy-7-methoxy-
1,4-naphthoquinone (4c) in a yield of 50 mg (62%), Rf 0.32,
m.p. 234235 °C. IR (CDCl3), ν/cm1: 3520 m, 3418 m
(β-OH), 1663 w, 1620 m, 1606 s (C=O), 1575 m (C=C).
1H NMR (CDCl3), δ: 4.15 (s, 3 H, OCH3); 6.45 (s, 1 H, H(3));
11.97 and 13.37 (both s, 1 H each, C(8)OH, C(5)OH). MS
(EI, 18 eV), m/z (Irel (%)): 270/272 [M]+ (100), 269/271
[M 1]+ (36). In addition to product 4c, 6-chloro-5,8-
dihydroxy-2,7-dimethoxy-1,4-naphthoquinone was isolated from
the reaction mixture in a yield of 25 mg (29%), Rf 0.40,
m.p. 195197 °C. 1H NMR (CDCl3), δ: 3.97 and 4.19 (both s,
3 H each, OCH3); 6.35 (s, 1 H, H(3)); 12.69 and 13.27
(both s, 1 H each, C(8)OH, C(5)OH). MS (EI, 18 eV),
m/z (Irel (%)): 284/286 [M]+ (100), 283/285 [M 1]+ (89),
256 (57).
21 mg (22%), Rf 0.59, m.p. 129131 °C. H NMR (CDCl3),
δ: 1.15 (t, 3 H, CH3, J = 7.5 Hz), 2.70 (q, 2 H, CH2,
J = 7.5 Hz); 4.10 and 4.21 (both s, 3 H each, OCH3); 12.82 and
13.33 (both s, 1 H each, C(8)OH, C(5)OH). MS (EI,
70 eV), m/z (Irel (%)): 312/314 [M]+ (100), 311/313 [M 1]+
(70), 297/299 (27), 296/298 (30), 278 (12), 223 (16).
Methylation of 3,6-diethyl-2,5,7,8-tetrahydroxy-1,4-naph-
thoquinone (2e) afforded 3,6-diethyl-2,5,8-trihydroxy-7-
methoxy-1,4-naphthoquinone (4e) in a yield of 32 mg (36%),
Rf 0.50, m.p. 115117 °C. IR (CDCl3), ν/cm1: 3519 m,
3417 m (β-OH), 1623 m, 1600 s (C=O), 1575 sh.m (C=C).
1H NMR (CDCl3), δ: 1.15 and 1.18 (both t, 3 H each, CH3,
J = 7.6 Hz); 2.62 and 2.76 (both q, 2 H each, CH2, J = 7.6 Hz);
4.03 (s, 3 H, OCH3); 12.01 and 13.54 (both s, 1 H each,
C(8)OH, C(5)OH). MS (EI, 18 eV), m/z (Irel (%)):
292 [M]+ (17), 291 [M 1]+ (16), 258 (37), 256 (100), 255
(15). In addition to product 4e, 3,6-diethyl-2,5,7-trihydroxy-8-
methoxy-1,4-naphthoquinone (14) was isolated from the reaction
mixture in a yield of 27 mg (31%), Rf 0.38, m.p. 180185 °C.
1H NMR (CDCl3), δ: 1.14 and 1.18 (both t, 3 H each, CH3,
J = 7.6); 2.58 and 2.77 (both q, 2 H each, CH2, J = 7.6 Hz);
3.94 (s, 3 H, OCH3); 6.62 and 7.53 (both s, 1 H each, β-OH);
13.72 (s, 1 H, C(5)OH). MS (EI, 18 eV), m/z (Irel (%)):
293 [M + 1]+ (17), 292 [M]+ (100), 291 [M 1]+ (97), 278
(18), 277 (24).
5,8-Dihydroxy-2,7-dimethoxy-3-methyl-1,4-naphthoquinone
(9). A solution of acetyl peroxide in ether15 was added
portionwise to a boiling solution of substrate 10 (175 mg,
0.7 mmol), which was prepared from compound 2a according
to the above-described procedure, in ButOH (70 mL). The
course of the reaction was monitored by TLC. The reaction was
terminated when the degree of conversion reached ∼60%. The
mixture was concentrated. Chromatography of the residue by
preparative TLC afforded product 9 in a yield of 68 mg (37%),
Rf 0.42, m.p. 193195 °C. 1H NMR (CDCl3), δ: 2.22 (s, 3 H,
CH3); 3.94 and 4.04 (both s, 3 H each, OCH3); 6.26 (s, 1 H,
H(6)); 12.78 and 13.29 (both s, 1 H each, α-OH). MS (EI,
70 eV), m/z (Irel (%)): 264 [M]+ (100), 263 [M 1]+ (86), 250
(22), 249 (13), 234 (11). In addition to product 9, 5,8-dihydroxy-
2,7-dimethoxy-3,6-dimethyl-1,4-naphthoquinone (12) was iso-
lated from the reaction mixture in a yield of 53 mg (27%),
Rf 0.66, m.p. 168171 °C. 1H NMR (CDCl3), δ: 2.19 (s, 6 H,
2 CH3); 4.06 (s, 6 H, 2 OCH3); 12.86 and 13.39 (both s,
1 H each, α-OH). MS (EI, 18 eV), m/z (Irel (%)): 278 [M]+
(75), 277 [M 1]+ (100), 263 (53), 262 (52), 235 (36).
2,5,8-Trihydroxy-7-methoxy-6-methyl-1,4-naphthoquinone
(13). Concentrated HCl (30 mL) was added dropwise to a
boiling solution of dimethyl ether 9 (53 mg, 0.2 mmol) in
methanol (30 mL) during 3 min. The reaction mixture was
refluxed for 60 min, cooled, diluted with H2O (50 mL), ex-
tracted with chloroform (2½20 mL), washed with a saturated
solution of NaCl (2½20 mL), dried with anhydrous Na2SO4,
and concentrated. Separation by preparative TLC afforded com-
pound 13 in a yield of 20 mg (40%), Rf 0.39, m.p. 228233 °C.
1H NMR (CDCl3), δ: 2.25 (s, 3 H, CH3); 4.02 (s, 3 H, OCH3);
6.38 (s, 1 H, H(3)); 7.29 (br.s, 1 H, β-OH); 13.04 and 13.37
(both s, 1 H each, α-OH). MS (EI, 70 eV), m/z (Irel (%)):
250 [M]+ (100), 249 [M 1]+ (97), 235 (36), 234 (40), 207
(27), 206 (35).
Methylation of 6-chloro-3-ethyl-2,5,7,8-tetrahydroxy-1,4-
naphthoquinone (2d) afforded 6-chloro-3-ethyl-2,5,8-tri-
hydroxy-7-methoxy-1,4-naphthoquinone (4d) in a yield of 68 mg
(76%), Rf 0.42, m.p. 172176 °C. IR (CDCl3), ν/cm1: 3524 w,
3421 m (β-OH), 1654 w, 1626 m, 1603 s (C=O), 1566 sh.m
(C=C). 1H NMR (CDCl3), δ: 1.15 (t, 3 H, CH3, J = 7.5 Hz);
2.63 (q, 2 H, CH2, J = 7.5 Hz); 4.12 (s, 3 H, OCH3); 11.91 and
13.64 (both s, 1 H each, C(8)OH, C(5)OH). MS (EI,
18 eV), m/z (Irel (%)): 298/300 [M]+ (100), 297/299 [M 1]+
(84), 283/285 (45), 282/284 (37). In addition to product 4d,
6-chloro-3-ethyl-5,8-dihydroxy-2,7-dimethoxy-1,4-naphtho-
quinone was isolated from the reaction mixture in a yield of
3-Ethyl-2,5,8-trihydroxy-7-methoxy-6-methyl-1,4-naphtho-
quinone (6-methylcristazarin, 7). Free-radical C-ethylation of
substrate 13 (13 mg, 0.05 mmol) in ButOH (2 mL) under the
action of an ethereal solution of propionyl peroxide15 according
to the procedure used for 9 afforded 6-methylcristazarin 7 in a
yield of 6 mg (44%), Rf 0.90, m.p. 152155 °C (cf. lit. data:5
m.p. 148151 °C). IR (CHCl3), ν/cm1: 3518 w, 3417 m