Chemistry of naphthazarin derivatives 8. Determination of structures of substituted 2-hydroxy-6(7)-methoxynaphthazarins and 7(8)-hydroxypyranonaphthazarins by IR spectroscopy

Article abstract of DOI:10.1023/A:1009533403588

A set of substituted 2-hydroxy-6(7)-methoxynaphthazarins and 7(8)-hydroxypyranonaphthazarins were synthesized. The IR spectra of 2-hydroxy-6-methoxynaphthazarins and 7-hydroxypyranonaphthazarins, on the one hand, and of 2-hydroxy-7-methoxynaphthazarins an

Full text of DOI:10.1023/A:1009533403588

Russian Chemical Bulletin, International Edition, Vol. 50, No. 1, pp. 95—100, January, 2001
95
Chemistry of naphthazarin derivatives
8.* Determination of structures of substituted 2-hydroxy-6(7)-methoxynaphthazarins
and 7(8)-hydroxypyranonaphthazarins by IR spectroscopy
V. P. Glazunov,a A. Ya. Tchizhova,a O. P. Shestak,a G. I. Sopel´nyak,b and V. Ph. Anufrieva«
aPacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Sciences,
159 prosp. 100-letiya Vladivostoka, 690022 Vladivostok, Russian Federation.
Fax: +7 (423 2) 31 4050. E-mail: piboc@stl.ru
bInstitute of Chemistry and Applied Ecology, Far Eastern State University,
27 ul. Octyabr'skaya, 690600 Vladivostok, Russian Federation.
Fax: +7 (423 2) 25 7609
A set of substituted 2-hydroxy-6(7)-methoxynaphthazarins and 7(8)-hydroxypyrano-
naphthazarins were synthesized. The IR spectra of 2-hydroxy-6-methoxynaphthazarins and
7-hydroxypyranonaphthazarins, on the one hand, and of 2-hydroxy-7-methoxynaphthazarins
and 8-hydroxypyranonaphthazarins, on the other hand, have the characteristic nonoverlapping
intervals of stretching vibration frequencies of the β-hydroxy groups. These regularities confirm
the structures of cristazarin and 6-methylcristazarin, which are metabolites of lichen Cladonia
cristatella.
Key words: 5,8-dihydroxy-1,4-naphthoquinone, naphthazarin; 2,5,8-trihydroxy-6(7)-
methoxy-1,4-naphthoquinone; 5,7(8),10-trihydroxy-2-methyl-2-(4-methyl-3-penten-1-yl)-2H-
naphtho[2,3-b]pyran-6,9-dione; 3-ethyl-2,5,8-trihydroxy-7-methoxy-1,4-naphthoquinone,
cristazarin, 3-ethyl-2,5,8-trihydroxy-7-methoxy-6-methyl-1,4-naphthoquinone, 6-methyl-
cristazarin, stretching vibration frequencies of the β-hydroxy group; IR spectra of
hydroxynaphthazarins, Cladonia cristatella.
The determination of the relative arrangement of the
β-hydroxy groups in substituted 2,6(7)-dihydroxy-
napthazarins (2,5,6(7),8-tetrahydroxy-1,4-naphthoquino-
nes) presents serious difficulties.1 With the aim of over-
coming these difficulties, we synthesized a set of substi-
tuted 2,6-dihydroxy- (1a—e) and 2,7-dihydroxynapth-
azarins (2a—e) and demonstrated that the stretching
vibration frequencies ν(OH) of the β-hydroxy groups of
the quinoid and aromatic moieties of the molecules are
observed in the characteristic nonoverlapping intervals
of the IR spectra. As a result of the present investigation,
the structure of cuculoquinone, which has been identi-
fied previously as 7,7´-bis(3-ethyl-2,5,6,8-tetrahydr-
oxynaphthalene-1,4-dione),2 was revised. We established
that this compound has the structure of 6,6´-bis(3-ethyl-
2,5,7,8-tetrahydroxynaphthalene-1,4-dione).3,4
Analysis of the structures of monomethyl ethers of
substituted 2,6(7)-dihydroxynapthazarins presents prob-
lems analogous to those that emerge in determining the
structures of their O-demethylated analogs because the
available physicochemical methods do not allow unam-
biguous conclusions about the relative arrangement of
the substituents at the C(2), C(3), C(6), and C(7) atoms.
The development of new procedures for investigation of
the structures of monoalkyl ethers of 2,6(7)-dihydroxy-
naphthazarins is also of great importance in connection
with the discovery of these compounds in nature.3,5 To
solve this problem, we synthesized several pairs of sub-
stituted 2-hydroxy-6(7)-methoxynaphthazarins 3a—d and
4a—e and 7(8)-hydroxypyranonaphthazarins 5a and 5b.
Methylation of 2,6-dihydroxynapthazarins (1a—d)
and 2,7-dihydroxynapthazarins (2a—e) with diazo-
methane under controlled conditions afforded the corre-
sponding 2-hydroxy-6-methoxy (3a—d) and 2-hydroxy-
7-methoxy derivatives (4a—e). The direction of methy-
lation of 2,6-dihydroxy- (1c,d) and 2,7-dihydroxy-
naphthazarins (2c,d) at position 2 is affected by the
chlorine atom at the C(3) atom, which increases the
acidity of the corresponding β-hydroxy group (products
3c,d and 4c,d, respectively).6 The reaction is accompa-
nied by the formation of substantial amounts of dimethyl
ethers (see Experimental). In the case of isomompain 1a
and mompain 2a, these ethers predominate due to the
tautomerism resulting in the equalization of the acidity
OH Oν 3392—3373
OH Oν 3431—3413
ν 3533—3523
R2
2
OH
HO
7
2
OH
6
HO
ν 3512—3508 OH
R1
R2
R1
O
OH
O
1a—e
2a—e
d e
a
b
c
R1
R2
H
H
Et
H
Cl
H
Et
Cl
Et
Et
* For Part 7, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 92—97, January, 2001.
1066-5285/00/5001-0095 $25.00 © 2001 Plenum Publishing Corporation

96
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
Glazunov et al.
1
2
OH
O
OH
O
R2
7
6
2
3
OH
R1
MeO
R2
7
6
2
3
OH
R1
MeO
–1
3450
3400
3350 ν/cm
OH
O
OH
O
Fig. 1. Ranges of stretching vibration frequencies of the
β-hydroxy group in the IR spectra of chloroform solutions of
2-hydroxy-6-methoxynaphthazarins 3a—d (1) and 2-hydroxy-
7-methoxynaphthazarins 4a—e, 7, and 8 (2).
3a—d
4a—e
OH
O
O
1
O
intensity (the intensity is approximately 3—4 times
3
7
OH
–1
smaller than that of the band at 3422 cm ) broad
–1
OH
5a
diffuse absorption band at 3400—2200 cm
with the
maximum at ∼3000 cm–1 belongs to the stretching vibra-
tion of the α-hydroxy group.1*
OH
OH
O
1
O
8
OH
Scheme 1
3
O
O
HO
HO
OH
OH
O
O
β
β
OH
R
OH
R
O
5b
a
b
c
d
e
R1
R2
H
H
Et
H
H
Et
Cl
Et
Et
Cl
A
B
6: R = H, 4à: R = OMe
of the β-hydroxy groups in the quinoid and aromatic
moieties in the case of the identical spatial environment
about these groups.7 Hydroxypyranonaphthazarins 5a
and 5b were prepared by the acid-catalyzed reactions of
dihydroxynaphthazarins 1a and 2a, respectively, with
citral.8 The resulting compounds were studied by IR
spectroscopy in chloroform solutions. In the IR spectra
(KBr), the absorption region for the β-hydroxy groups of
More detailed examination of the IR spectra of
2-hydroxy-6(7)-methoxynaphthazarins (3a—d and 4a—e)
revealed the dependence of the stretching vibration fre-
quency of the β-hydroxy group in the quinoid moiety of
the molecule on the position (6 or 7) of the methoxy
group in the aromatic nucleus. Thus, the ν(OH) fre-
quencies of the β-hydroxy group in 2-hydroxy-6-
–1
the compounds under study (3300—3600 cm ) is poorly
–1
–1
methoxynaphthazarins 3a (3392 cm ), 3b (3397 cm ),
informative.1
–1
and 3d (3381 cm ) (Fig. 1, Table 1) confirm that these
It is known that naphthazarins in solutions undergo
rather rapid prototropic tautomerism.9 The β-hydroxy
group in substituted hydroxynaphthazarins has a pro-
nounced effect on the tautomeric equilibrium by shifting
it to the isomer containing the OH group in the quinoid
moiety10 (Scheme 1). This fact was also confirmed by IR
spectral data. Thus, the IR spectrum of naphthopurpurin
6 in CHCl3 has a ν(OH) stretching absorption band at
compounds are derivatives of 2,6-dihydroxynaphthazarins
–1
1a—e (3394 cm ≥ ν(OH) ≥ 3373 cm–1 for the quinoid
β-hydroxy group).1 In the spectrum of monomethyl
ether of chloromompain 3c, the stretching vibration
–1
frequency of the β-hydroxy group (3409 cm ) is shifted
–1
by 15 cm to the high-frequency region, but this band
also does not overlap with the region of the ν(OH)
frequencies for 2-hydroxy-7-methoxynaphthazarins
4a—e. However, the IR spectra of 2-hydroxy-7-methoxy-
naphthazarins 4a—e have the absorption bands of the
β-hydroxy groups in the region of 3424—3417 cm–1 and
the ν(OH) frequencies fall totally in the corresponding
range found previously for the initial 2,7-dihydroxy-
–1
3412 cm belonging to the β-hydroxy group linked to
the carbonyl group at the C(1) atom (structure 6(B))
through an intramolecular hydrogen bond.1 In the IR
spectrum of monomethyl ether of mompain 4a in CHCl3,
the ν(OH) absorption band of the β-hydroxy group is
–1
also observed in the "quinoid" region (at 3422 cm ).
–1
–1
naphthazarins 2a—e (3431 cm ≥ ν(OH) ≥ 3413 cm
The spectra in chloroform solutions measured at differ-
for the quinoid β-hydroxy group).1
The stretching vibration frequencies of the β-hydroxy
groups in the IR spectra of hydroxypyranonaphthazarins
–2
–3
–1
ent concentrations (from 4•10
to 2•10
mol L )
and the results of the change of the polar solvent CHCl3
for nonpolar CCl4 demonstrated that this band at
–1
3422 cm belongs to the β-hydroxy group linked to the
* This poorly informative absorption band is observed in the IR
spectra of all compounds under study and is not reported in the
Experimental section.
carbonyl group at the C(1) atom (structure 4a(B))
through an intramolecular hydrogen bond. The low-

Substituted naphthazarins
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
97
of the standard product.5 Our investigation demon-
strated that the absorption band of the β-hydroxy group
in the IR spectrum of a chloroform solution of com-
pound 7 is observed at 3417 cm , which is typical of
2-hydroxy-7-methoxynaphthazarin derivatives. The
Table 1. Stretching vibration frequencies of the β-OH groups in
the IR spectra of the compounds synthesized
–1
–1
–1
Com-
pound
ν/cm
Com-
pound
ν/cm
stretching vibration frequency of the β-hydroxy group in
3a
3b
3c
3d
4a
4b
4c
3392
3397
3409
3381
3422
3424
3418
4d
4e
5a
5b
7
3421
3417
3395
3414
3417
3419
–1
the IR spectrum of compound 8 (3419 cm ) also falls
in the range found for derivatives of monomethyl ether
of mompain 4a—e. We synthesized 6-methylcristazarin
7 and its homolog 8 starting from mompain 2a accord-
ing to Scheme 2.11
8
Of two paths presented in Scheme 2 (a and b), which
give rise to the key substrate 9 in the synthesis of
pigment 7, the first path proved to be practically more
convenient due to the fact that the purification of inter-
mediates of conversion 2a→10→9 is less a problem than
that associated with the purification of intermediates of
conversion 2a→11→9, the total yield of the target prod-
uct 9 being the same (∼25%). Free-radical C-methyla-
tion of dimethoxynaphthazarin 10 with acetyl peroxide
gave rise to product 12 along with compound 9. Under
particular conditions, the former compound was ob-
tained as the major product. Mild acid hydrolysis of
dimethyl ethers 9 and 12 afforded 2-hydroxy-7-
methoxynaphthazarin (13) and its methyl analog 8, re-
spectively. Pigment 7 was prepared by free-radical
C-ethylation of hydroxynaphthazarin 13 under the ac-
tion of propionyl peroxide.
The IR spectra of the resulting compounds always
have the stretching absorption band of the β-hydroxy
group in the benzoid region1 along with the stretching
absorption band of the β-hydroxy group adjacent to the
carbonyl quinoid group, which indicates that the tauto-
meric equilibrium actually occurs (see Scheme 1). In the
spectra of different compounds, the intensity of the
absorption band of the β-hydroxy group in the benzoid
fragment changes from weak (∼5%) to strong (∼35%)
with respect to that of the quinoid fragment. Investiga-
are also in good agreement with the ranges of the
corresponding values found for the series of 2,6- and
2,7-dihydroxynaphthazarins and their monomethyl
ethers. Thus, the ν(OH) absorption band of the
β-hydroxy group in pyranonaphthazarin 5a is observed
–1
at 3395 cm , which indicates that this compound be-
longs to 2,6-dihydroxynaphthazarin derivatives. The IR
spectrum of pyranonaphthazarin 5b, which is an isomer
of compound 5a, has the stretching absorption band of
–1
the β-hydroxy group at 3414 cm (see Table 1), which
indicates that this compound belongs to 2,7-dihydroxy-
naphthazarin derivatives.
The regularity revealed for the stretching vibration
frequencies of the β-hydroxy group in the IR spectra
allows one to unambiguously identify substituted 6- and
7-alkoxy-2-hydroxynaphthazarins. In addition to crist-
azarin 4b, this possibility was demonstrated using an-
other pigment of lichen Cladonia cristatella, viz.,
6-methylcristazarin 7, and its homolog 8 as examples
(see Fig. 1, Table 1). It should be mentioned that
compound 7 has been previously assigned to the series of
2,7-dihydroxynaphthazarin derivatives based on the bio-
synthesis of 6-methylcristazarin enriched with 13C atoms
and on a comparison of its 13C NMR spectrum with that
Scheme 2
OH
O
O
OH
O
O
OH
O
O
MeO
OMe
MeO
OH
MeO
Me
OH
Et
(EtCO2)2
(MeCO2)2
Me
OH
OH
OH
OH
OH
O
O
[H]+
a
CH2N2
10
13
7
MeO
OMe
Me
2a
(MeCO2)2
(MeCO2)2
b
OH
O
O
OH
O
O
OH
O
O
CH2N2
9
HO
OH
Me
MeO
Me
OMe
Me
MeO
Me
OH
Me
[H]+
OH
11
OH
OH
12
8

98
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
Glazunov et al.
6.41 and 6.47 (both s, 1 H each, H(7), H(3)); 12.25 and 13.30
(both s, 1 H each, C(8)—OH, C(5)—OH). MS (EI, 18 eV),
m/z (Irel (%)): 236 [M]+ (100), 222 (57), 218 (16), 207 (32),
194 (16). In addition to product 3a, 5,8-dihydroxy-2,6-
dimethoxy-1,4-naphthoquinone was isolated from the reaction
mixture in a yield of 44 mg (58%), Rf 0.34, m.p. 275—280 °C
(cf. lit. data:7 m.p. 295—296 °C). 1H NMR (CDCl3), δ: 3.98 (s,
6 H, 2 OCH3); 6.37 (s, 2 H, H(3), H(7)); 13.09 (s, 2 H,
C(8)—OH, C(5)—OH).
tion of this interesting phenomenon is beyond the scope
of the present study and will be reported elsewhere.
Unlike the IR spectra of 2-hydroxy-6(7)-methoxy-
naphthazarins 3a—d, 4a—e, 7, and 8, the spectrum of
the 8-methoxy derivative of 2,7-dihydroxynaphthazarin
14, which is one of the
products of methylation of
OMe O
substrate 2e with diazo-
Methylation of 3-ethyl-2,5,6,8-tetrahydroxy-1,4-naphtho-
quinone (1b) afforded 3-ethyl-2,5,8-trihydroxy-6-methoxy-1,4-
naphthoquinone (3b) in a yield of 51 mg (65%), Rf 0.40,
m.p. 198—201 °C. IR (CDCl3), ν/cm–1: 3515 w, 3397 m
methane, has the stretching
absorption bands of the
β-hydroxy groups at the
C(2) and C(7) atoms at
3385 and 3498 cm , re-
spectively. Their ν(OH) fre-
quencies fall in the ranges,
which overlap with those found for the stretching ab-
sorption bands of the β-hydroxy group in the spectra of
2-hydroxy-6-methoxynaphthazarin derivatives 3a—d. The
determination of the structures of products of type 14
occurring in nature3,12 by IR spectroscopy requires in-
vestigation of the corresponding series of model com-
pounds.
HO
Et
7
2
OH
Et
1
(β-OH), 1629 m, 1596 s (C=O), 1580 sh.m (C=C). H NMR
–1
OH
14
O
(CDCl3), δ: 1.15 (t, 3 H, CH3, J = 7.9 Hz); 2.62 (q, 2 H, CH2,
J = 7.9 Hz); 3.99 (s, 3 H, OCH3); 6.50 (s, 1 H, H(7)); 7.46
(br.s, 1 H, β-OH); 12.09 and 13.60 (both s, 1 H each, α-OH).
1H NMR (DMSO-d6), δ: 1.03 (t, 3 H, CH3, J = 7.9 Hz); 2.51
(q, 2 H, CH2, J = 7.9 Hz); 3.93 (s, 3 H, OCH3); 6.74 (s, 1 H,
H(7)); 12.62 and 13.52 (both s, 1 H each, α-OH). MS (EI,
18 eV), m/z (Irel (%)): 265 [M + 1]+ (17), 264 [M]+ (100), 250
(9), 249 (22). In addition to product 3b, 3-ethyl-5,8-dihydroxy-
2,6-dimethoxy-1,4-naphthoquinone was isolated from the reaction
mixture in a yield of 18 mg (22%), Rf 0.45, m.p. 139—142 °C.
1H NMR (CDCl3), δ: 1.15 (t, 3 H, CH3, J = 7.6 Hz); 2.70 (q,
2 H, CH2, J = 7.6 Hz); 3.95 and 4.12 (both s, 3 H each,
OCH3); 6.25 (s, 1 H, H(7)); 13.10 and 13.22 (both s, 1 H each,
C(8)—OH, C(5)—OH). MS (EI, 18 eV), m/z (Irel (%)):
279 [M + 1]+ (20), 278 [M]+ (100), 264 (17), 263 (37).
Experimental
The melting points were determined on a Boetius heating
stage and were not corrected. The IR spectra were measured on
a Bruker Vector 22 Fourier spectrometer (the resolution was
2.0 cm–1) in CDCl3 and CHCl3 using cells with CaF2 windows
and polyethylene gaskets (the thickness of the layer was
0.40—1.50 mm). The stretching vibration frequencies of the
β-hydroxy groups were measured after "leveling" of the spec-
trum. The reproducibility of the results of measurements was
not worse than ±0.5 cm–1. The concentrations of solu-
tions of compounds 3a—d, 4a—e, 5a,b, 7, and 8 were
(2—5)•10–3 mol L–1. The 1H NMR spectra were recorded on a
Bruker AC-250 spectrometer (250.13 MHz) in CDCl3,
DMSO-d6, and acetone-d6 (Me4Si as the internal standard).
The mass spectra (EI) were obtained on an LKB-9000S instru-
ment with direct introduction of the samples; the energies of
ionizing electrons were 18 and 70 eV. The course of the
reactions and the purities of the compounds were monitored by
TLC on Merñk 60F-254 plates using the 2 : 1 hexane—acetone
system as the eluent. The individual compounds were isolated
from mixtures of the reaction products by preparative TLC on
plates (20½20 cm) with a nonfixed silica gel layer (H+ form;11
5—40 µm) in the 2 : 1 hexane—acetone system. The yields of
the resulting compounds were not optimized. Compounds 1a
and 2a were prepared according to a procedure reported
previously.11 Compounds 1b—d and 2b—e were synthesized
according to a known procedure.1
2-Hydroxy-6(7)-methoxynaphthazarins 3a—d and 4a—e.
The compounds were prepared by treatment of an ethereal
solution of the corresponding 2,6(7)-dihydroxynaphthazarin
(0.3 mmol) with a solution of diazomethane in diethyl ether.13
The course of the reaction was monitored by TLC.
Methylation of isomompain (2,5,6,8-tetrahydroxy-1,4-naph-
thoquinone, 1a) afforded 2,5,8-trihydroxy-6-methoxy-1,4-naph-
thoquinone (3a) in a yield of 11 mg (16%), Rf 0.28,
m.p. 224—226 °C (cf. lit. data:7 m.p. 265—267 °C). IR (CDCl3),
ν/cm–1: 3512 m, 3392 m (β-OH), 1628 m, 1602 s (C=O),
1582 sh.s (C=C). 1H NMR (CDCl3), δ: 4.00 (s, 3 H, OCH3);
Methylation of 3-chloro-2,5,6,8-tetrahydroxy-1,4-naphtho-
quinone (1c) afforded 7-chloro-2,5,8-trihydroxy-6-methoxy-
1,4-naphthoquinone (3c) in a yield of 47 mg (58%), Rf 0.41,
m.p. 200—204 °C. IR (CDCl3), ν/cm–1: 3515 m, 3409 m
(β-OH), 1661 w, 1624 sh.m, 1607 s (C=O), 1580 m, 1567 m
1
(C=C). H NMR (CDCl3), δ: 4.26 (s, 3 H, OCH3); 6.44 (s,
1 H, H(3)); 12.32 and 13.24 (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]+ (20), 252/254 (39), 241/243 (35), 235
(22), 224/226 (22). In addition to product 3c, 7-chloro-5,8-
dihydroxy-2,6-dimethoxy-1,4-naphthoquinone was isolated from
the reaction mixture in a yield of 32 mg (38%), Rf 0.43,
m.p. 190—194 °C. 1H NMR (CDCl3), δ: 3.97 and 4.26 (both s,
3 H each, OCH3); 6.35 (s, 1 H, H(3)); 13.03 and 13.10
(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]+ (92),
266/268 (25), 255 (19), 249 (12), 236 (9).
Methylation of 7-chloro-3-ethyl-2,5,6,8-tetrahydroxy-1,4-
naphthoquinone (1d) afforded 7-chloro-3-ethyl-2,5,8-tri-
hydroxy-6-methoxy-1,4-naphthoquinone (3d) in a yield of 54 mg
(60%), Rf 0.45, m.p. 137—139 °C. IR (CDCl3), ν/cm–1: 3503 w,
3381 m (β-OH), 1662 w, 1649 m, 1626 m, 1602 s (C=O),
1
1573 sh.m (C=C). H NMR (CDCl3), δ: 1.16 (t, 3 H, CH3,
J = 7.5 Hz); 2.73 (q, 2 H, CH2, J = 7.5 Hz); 4.12 (s,
3 H, OCH3); 7.82 (br.s, 1 H, β-OH); 12.15 and 13.20
(both s, 1 H each, C(8)—OH, C(5)—OH). MS (EI, 18 eV),
m/z (Irel (%)): 298/300 [M]+ (61), 297/299 [M – 1]+ (100),
283/285 (19), 282/284 (23), 280 (8), 279 (9), 213 (10). In
addition to product 3d, 7-chloro-3-ethyl-5,8-dihydroxy-2,6-
dimethoxy-1,4-naphthoquinone was isolated from the reaction
mixture in a yield of 19 mg (20%), Rf 0.61, m.p. 136—138 °C
(from acetone). 1H NMR (CDCl3), δ: 1.15 (t, 3 H, CH3,
J = 7.5 Hz); 2.69 (q, 2 H, CH2, J = 7.5 Hz); 4.12 and 4.25
(both s, 3 H each, OCH3); 13.10 and 13.15 (both s, 1 H each,
α-OH). MS (EI, 18 eV), m/z (Irel (%)): 312/314 [M]+ (100),
311/313 [M – 1]+ (92), 297/299 (12), 296/298 (25), 294 (10),
293 (11), 256 (9).

Substituted naphthazarins
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
99
1
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. 225—227 °C (cf. lit. data:7 m.p. 240—241 °C). IR (CDCl3),
ν/cm–1: 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. 270—272 °C (cf. lit. data:7
m.p. 273—275 °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. 230—232 °C (cf. lit. data:5 m.p. 154—157 °C, lit.
data:7 m.p. 230—232 °C). IR (CDCl3), ν/cm–1: 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. 146—149 °C (cf. lit. data:4,7,14 m.p. 145—147 °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. 234—235 °C. IR (CDCl3), ν/cm–1: 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. 195—197 °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. 129—131 °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. 115—117 °C. IR (CDCl3), ν/cm–1: 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. 180—185 °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. 193—195 °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. 168—171 °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. 228—233 °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. 172—176 °C. IR (CDCl3), ν/cm–1: 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. 152—155 °C (cf. lit. data:5
m.p. 148—151 °C). IR (CHCl3), ν/cm–1: 3518 w, 3417 m

100
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
Glazunov et al.
(β-OH), 1658 w, 1623 m, 1598 s (C=O), 1577 sh.m (C=C).
1H NMR (CDCl3), δ: 1.14 (t, 3 H, CH3, J = 7.8 Hz); 2.25 (s,
3 H, CH3); 2.62 (q, 2 H, CH2, J = 7.8 Hz); 3.99 (s, 3 H,
OCH3); 11.97 and 13.52 (both s, 1 H each, α-OH). 1H NMR
(DMSO-d6), δ: 1.03 (t, 3 H, CH3, J = 7.7 Hz); 2.14 (s, 3 H,
CH3); 2.48 (q, 2 H, CH2, J = 7.7 Hz); 3.91 (s, 3 H, OCH3);
11.28 (br.s, 1 H, β-OH); 12.27 (br.s, 1 H, α-OH); 13.64 (s,
1 H, α-OH). MS (EI, 70 eV), m/z (Irel (%)): 278 [M]+ (53),
277 [M – 1]+(100), 252 (15), 251 (28), 250 (22), 224 (18), 223
(77), 222 (67).
(β-OH), 1663 m, 1602 s (C=O), 1560 sh.m (C=C). 1H NMR
(CDCl3), δ: 1.52 (s, 3 H, C(2)—CH3); 1.56 and 1.69 (both br.s,
3 H each, C(4)—CH3); 1.68—1.78 (m, 1 H, HaC(1)); 1.84—1.99
(m, 1 H, HbC(1)); 2.06—2.20 (m, 2 H, H(2)); 5.09 (br.t, 1 H,
H(3), J = 6.3 Hz); 5.75 (d, 1 H, H(3), J = 10.2 Hz); 6.40 (s,
1 H, H(7)); 6.76 (d, 1 H, H(4), J = 10.2 Hz); 7.14 (br.signal,
1 H, β-OH); 12.00 and 13.36 (both s, 1 H each, C(10)—OH,
C(5)—OH). MS (EI, 70 eV), m/z (Irel (%)): 356 (34) [M]+, 273
(100), 272 (46).
This work was partially supported by the Russian
Foundation for Basic Research (Project No. 96-15-
97316), the USA Civilian Research and Development
Foundation (Grant REC-003), and the Ministry of Edu-
cation of the Russian Federation.
2,5,7,8-Tetrahydro-3-methyl-1,4-naphthoquinone (11).
Free-radical C-methylation of mompain 2a (100 mg, 0.45 mmol)
in ButOH (50 mL) under the action of acetyl peroxide afforded
2,5,7,8-tetrahydroxy-3-methyl-1,4-naphthoquinone (11) in a
1
yield of 46 mg (43%), Rf 0.32, m.p. 238—241 °C. H NMR
(acetone-d6), δ: 2.15 (s, 3 H, CH3); 6.66 (s, 1 H, H(6)); 10.03
(br.s, 1 H, β-OH); 12.15 (br.s, 1 H, OH); 13.40 (s, 1 H, OH).
MS (EI, 70 eV), m/z (Irel (%)): [M]+ (100), [M – 1]+ (86).
Methylation of 3-methylmompain 11 (45 mg, 0.19 mmol)
with a solution of diazomethane gave rise to dimethyl ether 9 in
a yield of 45 mg (89%).
References
1. V. P. Glazunov, A. Ya. Tchizhova, M. I. Shuvalova, and
V. F. Anufriev, Izv. Akad. Nauk, Ser. Khim., 2001, 85 [Russ.
Chem. Bull., Int. Ed., 2001, 50, 88].
2,5,8-Trihydroxy-7-methoxy-3,6-dimethyl-1,4-naphtho-
quinone (8). Partial hydrolysis of dimethyl ether 12 (36 mg,
0.13 mmol) under the above-described conditions gave rise to
2,5,8-trihydroxy-7-methoxy-3,6-dimethyl-1,4-naphthoquinone
(8) in a yield of 9 mg (25%), Rf 0.47, m.p. 206—210 °C. IR
(CDCl3), ν/cm–1: 3523 w, 3419 m (β-OH), 1662 w, 1623 m,
2. O. E. Krivoschekova, O. B. Maximov, L. S. Stepanenko,
and N. P. Mishchenko, Phytochemistry, 1982, 21, 193.
3. R. H. Thomson, Naturally Occurring Quinones, 3d Ed.,
Chapman and Hall, London—New York, 1987, 734 pp.
4. L. S. Stepanenko, O. E. Krivoshchekova, P. S. Dmitrenok,
and O. B. Maximov, Phytochemistry, 1997, 46, 565.
5. Y. Yamamoto, H. Matsubara, Y. Kinoshita, K. Kinoshita,
K. Koyama, K. Takahashi, V. Ahmadjiam, T. Kurokawa,
and I. Yoshimura, Phytochemistry, 1996, 43, 1239.
6. V. Ph. Anufriev, V. L. Novikov, G. V. Malinovskaya, and
V. P. Glazunov, Synth. Commun., 1997, 27, 119.
7. R. E. Moore, H. Singh, C. W. J. Chang, and P. J. Scheuer,
Tetrahedron, 1967, 23, 3271.
8. A. Ya. Tchizhova, V. F. Anufriev, and V. L. Novikov,
Zh. Org. Khim., 1995, 31, 237 [Russ. J. Org. Chem., 1995,
31 (Engl. Transl.)].
9. J. R. De la Vega, J. H. Busch, J. H. Schauble, K. L. Kunze,
and B. E. Haggert, J. Am. Chem. Soc., 1982, 104, 3295.
10. R. E. Moore and P. J. Scheuer, J. Org. Chem., 1966,
31, 3272.
11. G. V. Malinovskaya, A. Ya. Tchizhova, and V. F. Anufriev,
Izv. Akad. Nauk, Ser. Khim., 1999, 1019 [Russ. Chem. Bull.,
1999, 48, 1010 (Engl. Transl.)].
12. (a) A. G. Medentsev and V. K. Akimenko, Prikl. Biokhim.
Mikrobiol. [Applied Biochem. Microbiology], 1996, 32, 10 (in
Russian); (b) A. G. Medentsev and V. K. Akimenko, Phy-
tochemistry, 1998, 47, 935.
13. W. Bachmann and W. Struve, in Organic Reactions, Eds.
R. Adams and W. Bachmann, J. Wiley and Sons, New York,
1942, No. 1.
14. R. E. Moore, H. Singh, C. W. J. Chang, and P. J. Scheuer,
J. Org. Chem., 1966, 31, 3638.
1
1599 s (C=O), 1577 sh.m (C=C). H NMR (CDCl3), δ: 2.10
and 2.25 (both s, 3 H each, CH3); 4.01 (s, 3 H, OCH3); 7.25
(br.s, 1 H, β-OH); 11.98 and 13.49 (both s, 1 H each, α-OH).
MS (EI, 70 eV), m/z (Irel (%)): 264 [M]+ (100), 263 [M – 1]+
(98), 249 (30), 248 (28), 234 (13), 233 (13), 221 (16), 220 (14),
218 (18), 217 (17).
5,7,10-Trihydroxy-2-methyl-2-(4-methyl-3-penten-1-yl)-
2H-naphtho[2,3-b]pyran-6,9-dione (5a). A solution of isomom-
pain 1a (0.3 mmol), freshly distilled citral (0.3 mmol), and
MeNH2•HCl (0.4 mmol) in ethanol (10 mL) was kept at
∼20 °C for 2 days. The reaction mixture was concentrated to
1—2 mL in vacuo at ∼20 °C. Then H2O (10 mL) was added and
the mixture was extracted with diethyl ether (3½5 mL). The
combined extracts were washed with H2O and dried with
Na2SO4. The solvent was removed and the residue was thor-
oughly dried in vacuo. Isolation by preparative TLC with the
3 : 1 hexane—acetone system as the eluent afforded compound
–1
5a in a yield of 33 mg (32%), Rf 0.38. IR (CDCl3), ν/cm
:
3520 m, 3395 m (β-OH), 1667 m, 1642 m, 1615 sh.s, 1596 s
(C=O), 1560 sh.m (C=C). 1H NMR (CDCl3), δ: 1.54 (s, 3 H,
C(2)—CH3); 1.56 and 1.69 (both br.s, 3 H each, C(4)—CH3);
1.68—1.78 (m, 1 H, HaC(1)); 1.84—2.01 (m, 1 H, HbC(1));
2.06—2.23 (m, 2 H, H(2)); 5.09 (br.t, 1 H, H(3), J = 6.3 Hz);
5.69 (d, 1 H, H(3), J = 10.2 Hz); 6.35 (s, 1 H, H(8)); 6.71 (d,
1 H, H(4), J = 10.2 Hz); 12.39 and 13.20 (both s, 1 H each,
C(5)—OH, C(10)—OH).
5,8,10-Trihydroxy-2-methyl-2-(4-methyl-3-penten-1-yl)-
2H-naphtho[2,3-b]pyran-6,9-dione (5b). A solution of mompain
2a (0.3 mmol), freshly distilled citral (0.3 mmol), and
MeNH2•HCl (0.4 mmol) in ethanol (10 mL) was kept at
∼20 °C for 2 days. The reaction mixture was worked up as
described for compound 5a. Product 5b was obtained in a yield
of 36 mg (34%), Rf 0.40. IR (CDCl3), ν/cm–1: 3523 m, 3413 m
15. V. Karnojitzki, Les Peroxides Organiques, Hermann,
Paris, 1958.
Received June 15, 2000;
in revised form August 4, 2000