Chemistry of naphthazarin derivatives 11. Trisubstituted hydroquinone derivatives in the preparative synthesis of naphthazarins

Article abstract of DOI:10.1023/B:RUCB.0000011886.03785.bd

The Friedel-Crafts acylation of trimethylhydroquinone, 3,5-diethyl-2- hydroxyhydroquinone, and 3,5-diethyl-1,2,4-triniethoxybenzene with dichloromaleic or citraconic anhydride in an AlCl₃-NaCl melt is accompanied by o-C-dealkylation to afford f

Full text of DOI:10.1023/B:RUCB.0000011886.03785.bd

Russian Chemical Bulletin, International Edition, Vol. 52, No. 10, pp. 2247—2250, October, 2003
2247
Chemistry of naphthazarin derivatives
11.* Trisubstituted hydroquinone derivatives in the preparative synthesis of naphthazarins
V. Ph. Anufriev,ꢀ S. G. Polonik, N. D. Pokhilo, and N. N. Balanyova
Pacific Institute of Bioorganic Chemistry, FarꢀEastern Branch of the Russian Academy of Sciences,
159 prosp. 100ꢀletiya Vladivostoka, 690022 Vladivostok, Russian Federation.
Fax: +7 (423 2) 31 4050. Eꢀmail: anufriev@piboc.dvo.ru
The Friedel—Crafts acylation of trimethylhydroquinone, 3,5ꢀdiethylꢀ2ꢀhydroxyhydroꢀ
quinone, and 3,5ꢀdiethylꢀ1,2,4ꢀtrimethoxybenzene with dichloromaleic or citraconic anhyꢀ
dride in an AlCl3—NaCl melt is accompanied by oꢀCꢀdealkylation to afford functionally
substituted naphthazarins.
Key words: hydroquinone derivatives; dichloromaleic anhydride, citraconic anhydride;
5,8ꢀdihydroxyꢀ1,4ꢀnaphthoquinone, naphthazarin; the Friedel—Crafts reaction; dealkylation.
Scheme 1
Cycloacylation of 2,3ꢀdisubstituted hydroquinone
ethers of the type 1 with dichloromaleic anhydride (2) is a
simple and efficient method for the formation of strucꢀ
tures related to naphthazarin (5,8ꢀdihydroxyꢀ1,4ꢀnaphꢀ
thoquinone) 3 (Scheme 1).2,3 The reaction is accompaꢀ
nied by Oꢀdealkylation to liberate hydroxy groups in the
product formed. This is caused, first, by drastic condiꢀ
tions of the process and, second, the possibility to form a
thermodynamically favorable naphthazarin structure.**
The reductive dehalogenation of dichloronaphthazarins of
the type 3 5 can produce a series of natural naphthazarins6
and helpful byꢀproducts in the synthesis of antibiotics.7—10
This reaction is also the basis of an approach to the synꢀ
thesis of pharmacologically active polyhydroxynaphthazaꢀ
rins, viz., sea urchin metabolites and their analogs.11,12
It is noteworthy that most of 2,3ꢀdisubstituted hydroꢀ
quinones used are not commercially available compounds.
For example, O,2,3ꢀtrimethylhydroquinone was syntheꢀ
sized from dimethylanisole by the Vilsmeier formylation13
followed by the oxidative cleavage of 4ꢀmethoxyꢀ2,3ꢀ
dimethylbenzaldehyde formed by hydrogen peroxide in
an acidic medium.14
1: R1, R2 = H, Alk, OMe; R3 = H, Me
3: R1, R2 = H, Alk, OH
tion.15 Evidently, the efficiency of this cycloacylation deꢀ
pends on the easiness of migration (elimination) of the
alkyl substituent from position 5 of the substrate used. We
performed comparative studies of the reactivities of hydroꢀ
quinone derivatives 4 and 5a,b in the reactions with
dichloromaleic (2) and citraconic (6) anhydrides.
The condensation of compound 2 with thymohydroꢀ
quinone (4) affords dichloro(methyl)naphthazarin (3a)
in high yield. The absence of even trace amounts of alterꢀ
native dichloro(isopropyl)naphthazarin 3b under the reꢀ
action conditions is related to the higher proneness of the
isopropyl group to undergo elimination compared to the
methyl group. Under the same conditions, the condensaꢀ
tion of 2,3,5ꢀtrimethylhydroquinone (5a) with comꢀ
In the present work, we showed that the target
naphthazarin structures can also be prepared from more
accessible 2,5ꢀdiꢀ and 2,3,5ꢀtrialkylhydroquinones.***
This is associated with the fact that Cꢀdealkylation can
occur under the conditions of the Friedel—Craft acylaꢀ
* For Part 10, see Ref. 1.
** Hereafter, as well as in Ref. 4, methyl ether of substituted
hydroquinones are shown to give higher yields of the desired
products in this reaction than nonmethylated substrates.
*** For example, 2,3,5ꢀtrimethylhydroquinone (5a), unlike
O,2,3ꢀtrimethylhydroquinone, is a commercially available prodꢀ
uct (Fluka).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2128—2131, October, 2003.
1066ꢀ5285/03/5210ꢀ2247 $25.00 © 2003 Plenum Publishing Corporation

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Anufriev et al.
approach based on the use of the Diels—Alder reaction in
the synthesis of compound 8.16
The practical application of the developed approach is
the preparative synthesis of 6,7ꢀdichloroꢀ3ꢀethylꢀ2,5,8ꢀ
trihydroxyꢀ1,4ꢀnaphthoquinone (9),17 which is the key
byꢀproduct in the synthesis of one of the sea urchin pigꢀ
ments, being the active principle of a drug Hystoꢀ
chromeтм.18 Two schemes of the synthesis of compound 9
have been described previously.11,12 One of them is based12
on the cycloacylation of 3ꢀethylꢀ1,2,4ꢀtrimethoxybenzene
(10), which can be synthesized, in turn, by the lithiation
of 1,2,4ꢀtrimethoxybenzene (11) followed by ethylation
of lithium derivative 12 with diethyl sulfate (Scheme 3).
Scheme 3
3: R1 = H, R2 = Me (a); R1 = Pri, R2 = H (b); R1 = R2 = Me (c)
5: R = H (a), Me (b)
pound 2 gave dichloro(dimethyl)naphthazarin 3c (75%)
(Scheme 2).
Scheme 2
Durohydroquinone (5b) was not involved in cycloꢀ
acylation, indicating that, first, the reaction always begins
from the electrophilic attack of the acylating substrate on
the unsubstituted carbon atom of the benzene ring and,
second, the acylating agent formed from compound 2
cannot directly substitute the alkyl group. The latter is
eliminated only in the second step of cycloacylation
(7 → 3c) (see Scheme 2).
Citraconic anhydride (6) also turned out to be an effiꢀ
cient cycloacylating agent with respect to 2,3,5ꢀtriꢀ
methylhydroquinone (5а), which made it possible to synꢀ
thesize trimethylnaphthazarin (8) in 82% yield (see
Scheme 2). This reaction is a good alternative to the
Reactants and conditions: i. BuLi, THF, –30 °C, 2 h;
ii. Et2SO4, 0 °C, then ∼20 °C., 2 h;
iii. 2, AlCl3—NaCl, 190 °C, 5 min;
iv. Zn/Hg, HCl, refluxing, 2 h; v. Me2SO4, NaOH.
We have shown that 3,5ꢀdiethylꢀ1,2,4ꢀtrimethoxyꢀ
benzene (13) can be used as an equivalent of synthon 10.
Compound 13 is readily synthesized by reduction of
diacetyltrihydroxybenzene 14 followed by methylation of
diethyltrihydroxybenzene 15 formed with dimethyl sulꢀ
fate (see Scheme 3). The condensation of derivative 13
with compound 2 afforded the desirable product 9 in 59%
yield. The cycloacylation of trihydroxyꢀsubstituted deꢀ

Synthesis of naphthazarins
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2249
H(7), J = 1.0 Hz); 12.79, 13.12 (both s, 1 Н each, ОН).
MS (18 eV), m/z (Irel (%)): 233 [M + 1]+ (14); 232 [M]+ (100).
3,5ꢀDiethylꢀ1,2,4ꢀtrihydroxybenzene (15). Solid zinc amalꢀ
gam21 (600 g), 3,5ꢀdiacetylꢀ1,2,4ꢀtrihydroxybenzene (14)22
(31.5 g, 0.15 mol), and concentrated HCl (375 mL) were placed
in a 3ꢀL flask. The reaction mixture was heated to boiling with
vigorous stirring. After 30 min, compound 14 (31.5 g, 0.15 mol)
and concentrated HCl (375 mL) were added portionwise. The
mixture was refluxed with stirring for 3 h, and the hot solution
was decanted and left for 12 h. A solid layer formed on the
solution surface and a precipitate formed were separated, washed
with iceꢀcold water (30 mL), and dried to a constant weight.
Crude 3,5ꢀdiethylꢀ1,2,4ꢀtrihydroxybenzene (15) was obtained
(58 g), the content of the main substance was 80% (1Н NMR).
1Н NMR, δ: 1.18, 1.20 (both t, 3 Н each, Me, J = 7.8 Hz);
2.52, 2.68 (both q, 2 Н each, СН2, J = 7.8 Hz); 4.35, 4.54,
5.15 (all br.s, 1 H each, ОH); 6.56 (s, 1 H, Н arom.). The
product was used for the synthesis of 3,5ꢀdiethylꢀ1,2,4ꢀtriꢀ
methoxybenzene (13) without purification.
rivative 15, unlike trimethyl ether 13, occurred less effiꢀ
ciently: product 9 was obtained in 35% yield only.
Thus, the reactions of 2,5ꢀdiꢀ and 2,3,5ꢀtrisubstituted
hydroquinone derivatives with cyclic anhydrides in an
AlCl3—NaCl melt afford cycloacylation products, viz.,
functionally substituted naphthazarins. The use of accesꢀ
sible trisubstituted hydroquinone derivatives substantially
simplifies the general scheme of synthesis of the imporꢀ
tant representatives of this class of compounds.
Experimental
Melting points were determined on a Boetius heating stage
and are uncorrected. IR spectra were recorded on a Bruker
1
Vector 22 spectrophotometer in CHCl3. Н NMR spectra were
obtained on a Bruker ACꢀ250 spectrometer (250.13 MHz) in
CDCl3 using Me4Si as the internal standard. Mass spectra (EI)
were obtained on an LKBꢀ9000S instrument with a direct inlet
at energies of ionizing electrons of 18 and 70 eV. The course of
reactions and purity of synthesized compounds were monitored
by TLC on Silufolꢀ254 plates in a hexane—acetone (2 : 1) mixꢀ
ture. The yields of synthesized compounds were not optimized.
Compounds 2, 5а, and 6 are commercially available (Aldrich,
Fluka). Thymohydroquinone (4)19 and durohydroquinone (5b)20
were synthesized according to known procedures.
Cycloacylation of hydroquinone derivatives 4 and 5а with anꢀ
hydrides 2 and 6 (general procedure). A mixture of a substituted
hydroquinone (5 mmol) and anhydride (10 mmol) was introꢀ
duced with stirring at 160—170 °С into a melt of anhydrous
AlCl3 (26.7 g, 0.2 mol) and NaCl (5.85 g, 0.1 mol). The temꢀ
perature was increased to 207—210 °С, and the melt was addiꢀ
tionally stirred for 3—4 min. The reaction mixture was cooled,
5% HCl (400 mL) was added, and left for 12 h. The precipitated
product was separated, washed with hot water, and dried to a
constant weight.
3,5ꢀDiethylꢀ1,2,4ꢀtrimethoxybenzene (13). Crude diethyltriꢀ
hydroxybenzene 15 (56.9 g) was treated with 10% NaOH
(400 mL) with vigorous stirring under nitrogen with Me2SO4
(94.5 g, 0.75 mL), maintaining the temperature of the mixture
not above 40 °С. After Me2SO4 was added, the reaction mixture
was heated for 30 min in a boiling water bath. After the mixture
was cooled, the organic layer was separated, and the aqueous
layer was extracted with benzene. The combined organic layers
were washed with 5% NaOH and water and dried with anhyꢀ
drous CaCl2. The solvent was removed under reduced pressure.
The residue was fractionated in vacuo. The fraction with
b.p. 133—139 °С (7 Torr) was 3,5ꢀdiethylꢀ1,2,4ꢀtrimethoxyꢀ
1
benzene (13), the yield being 45.9 g (82%). Н NMR, δ: 1.19,
1.24 (both t, 3 Н each, Ме, J = 7.8 Hz); 2.64, 2.66 (both q,
2 Н each, СН2, J = 7.8 Hz); 3.71, 3.82, 3.83 (both s, 3 H each,
ОМе); 6.60 (s, 1 H, Н arom.).
6,7ꢀDichloroꢀ3ꢀethylꢀ2,5,8ꢀtrihydroxyꢀ1,4ꢀnaphthoquinone
(9). A mixture of 3,5ꢀdiethylꢀ1,2,4ꢀtrimethoxybenzene (13)
(44.8 g, 0.2 mol) and anhydride 2 (76.8 g, 0.46 mol) was added
at 140 °С with vigorous stirring to a melt of anhydrous AlCl3
(410 g, 3.07 mol) and NaCl (80.8 g, 1.38 mol). The temperature
of the mixture was increased to 195 °С, and the melt was stirred
for 5 min. The reaction mixture was cooled and hydrolyzed with
a solution of concentrated HCl (300 mL) in Н2О (4.0 L). After
12 h, a precipitate was separated, washed with hot water (2.0 L),
and dried. Product 9 was isolated by the extraction with
hot chloroform and recrystallized from an EtOH—H2O mixꢀ
ture. Compound 9 was obtained in 59% yield (36.0 g), m.p.
6,7ꢀDichloroꢀ5,8ꢀdihydroxyꢀ2ꢀmethylꢀ1,4ꢀnaphthoquinone
(3a) was synthesized from hydroquinone 4 and anhydride 2. The
yield was 77%, m.p. 147—149 °С (from light petroleum) (cf.
Ref. 2: m.p. 148—150 °С). IR (СНСl3), ν/cm–1: 3500—2200
(αꢀОН); 1618 (С=О); 1578 (С=С); 1562, 1443, 1406, 1342,
1
1300, 1276, 1078, 1024. Н NMR, δ: 2.34 (d, 3 Н, Ме, J =
1.2 Hz); 7.11 (dq, 1 Н, Н(7), J = 1.2 Hz, J = 0.5 Hz); 12.56 (s, 1
Н, ОН); 12.88 (d, 1 Н, ОН, J = 0.5 Hz).
6,7ꢀDichloroꢀ5,8ꢀdihydroxyꢀ2,3ꢀdimethylꢀ1,4ꢀnaphthoꢀ
quinone (3c) was synthesized from hydroquinone 5а and anhyꢀ
dride 2. The yield was 75%, red needles, m.p. 238—240 °С (from
1
156—158 °С (cf. Ref. 12: m.p. 156—158 °С). Н NMR, δ: 1.18
(t, 3 Н, Ме, J = 7.7 Hz); 2.66 (q, 2 Н, СН2, J = 7.7 Hz); 7.42
(br.s, 1 Н, βꢀОН); 12.07 (br.s, 1 H, αꢀOH); 13.60 (s, 1 H,
αꢀOH). MS, m/z (Irel (%)): 302/304/306 [M]+ (100).
toluene) (cf. Ref. 4: m.p. 235—236 °С). IR (СНСl3), ν/cm–1
:
3600—2300 (αꢀОН); 1608 (С=О); 1562 (С=С); 1448, 1393,
1
1291, 1275, 1203, 1109. Н NMR, δ: 2.28 (s, 6 Н, 2 Me); 13.20
(s, 2 Н, 2 ОН). MS (18 eV), m/z (Irel (%)): 286/288/290 [M]+
(100), 285/287/289 [M – 1]+ (41).
This work was carried out in the framework of the
State Program of Support of Leading Scientific Schools
of the Russian Federation (Grant NSh 1237.2003.3) and
the Interdisciplinary Integration Project of the Novosibirsk
Institute of Organic Chemistry (Siberian Branch of the
Russian Academy of Sciences) and the Pacific Institute of
Bioorganic Chemistry (FarꢀEastern Branch of the Rusꢀ
sian Academy of Sciences) (Project No. 03ꢀ2ꢀ0ꢀ00ꢀ002).
5,8ꢀDihydroxyꢀ2,3,6ꢀtrimethylꢀ1,4ꢀnaphthoquinone (8) was
synthesized from hydroquinone 5а and anhydride 6. The yield
was 83%, red needles, m.p. 167—170 °С (sublim.) (cf. Ref. 16:
m.p. 165 °С (sublim.)). IR (СНСl3), ν/cm–1: 3600—2300
(αꢀОН); 1601 (С=О); 1576 (С=С); 1456, 1439, 1403, 1380,
1
1364, 1305, 1283, 1192, 1129, 1108, 1067, 1011. Н NMR, δ:
2.20 (s, 6 Н, 2 Ме); 2.29 (d, 3 Н, Ме, J = 1.0 Hz); 7.01 (q, 1 Н,

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Anufriev et al.
A. V. Shvilkin, N. I. Afonskaya, M. Ya. Ruda, and N. M.
Cherpachenko, Bioorg. Med. Chem. Lett., 1998, 8, 587.
12. A. Ya. Tchizhova, T. Yu. Kochergina, V. Ph. Anufriev, V. A.
Denisenko, and V. P. Glazunov, Izv. Akad. Nauk, Ser. Khim.,
1999, 947 [Russ. Chem. Bull., 1999, 48, 938 (Engl. Transl.)].
13. M. Godfrey and M. V. Sargent, J. Chem. Soc., Perkin
Trans. 1, 1974, 1353.
14. M. Matsumoto, H. Kobayashi, and Y. Hotta, J. Org. Chem.,
1984, 49, 4740.
15. G. A. Olah, FriedelꢀCrafts and Related Reactions. III. Acylaꢀ
tion and Related Reactions, Part I, Interscience Publishers,
New York—London—Sydney, 1964, 910 pp.
16. J.ꢀG. Rodriguez, A. De Pablo, P. SmithꢀVerdier,
F. Florencio, and S. GarciaꢀBlanco, Bull. Chem. Soc. Jpn.,
1986, 59, 3957.
17. Patent of RF No. 2193550; Byul. Izobret. [Invention Bulleꢀ
tin], 2002, 33 (in Russian).
18. N. P. Mishchenko, S. A. Fedoreev, and V. L. Bagirova,
Khim.ꢀFarm. Zh., 2003, 37, 49 [Pharm. Chem. J., 2003, 37
(Engl. Transl.)].
19. A. A. Svishchuk and M. M. Visotskii, Farm. Zh. (Kiev),
1970, 25, 74; Chem. Abstrs., 1971, 75, 35333m.
20. S. Fujita and K. Sano, Tetrahedron Lett., 1975, 1695.
21. Yu. V. Karyakin and I. I. Angelov, Chistye khimicheskie
veshchestva [Pure Chemical Substances], Khimiya, Moscow,
1974, p. 398 (in Russian).
References
1. V. P. Glazunov, N. D. Pokhilo, N. V. Bochinskaya, A. Ya.
Yakubovskaya, and V. Ph. Anufriev, Izv. Akad. Nauk, Ser.
Khim., 2003, 1544 [Russ. Chem. Bull., Int. Ed., 2003,
52, 1629].
2. R. Huot and P. Brassard, Canad. J. Chem., 1974, 54, 838.
3. I. Singh, R. E. Moore, C. W. J. Chang, R. T. Ogata, and
P. J. Scheuer, Tetrahedron, 1968, 24, 2969.
4. V. Ph. Anufriev, N. N. Balanyova, A. Ya. Tchizhova, V. L.
Novikov, and G. B. Elyakov, Atsilirovanie rezortsinov,
paraꢀzameshchennykh fenolov, gidrokhinonov, ikh atsetatov i
metilovykh efirov dikhlormaleinovym angidridom [Acylation of
Resorcinols, 4ꢀSubstituted Phenols, Hydroquinones, their
Acetates and Methyl Ethers with Dichloromaleic Anhydride],
Vladivostok, 1988, 23 pp.; Available from VINITI 7.06.88,
6275ꢀVꢀ88 (in Russian).
5. V. Ph. Anufriev, G. V. Malinovskaya, V. L. Novikov, N. N.
Balanyova, and S. G. Polonik, Synth. Commun., 1998,
28, 2149.
6. R. H. Thomson, Naturally Occurring Quinones, 2nd ed.,
Academic Press, London—New York, 1971; 3rd ed.,
Chapman & Hall, London—New York, 1987.
7. C. J. Burns, M. Gill, and S. Saubern, Aust. J. Chem., 1991,
44, 1427.
8. V. L. Novikov, N. N. Balanyova, A. M. Moiseenkov, and
G. B. Elyakov, Izv. Akad. Nauk, Ser. Khim., 1992, 1901
[Bull. Russ. Acad. Sci., Div. Chem. Sci., 1992, 41, 1485 (Engl.
Transl.)].
22. R. D. Desai and C. K. Mavani, J. Sci. Ind. Res. (India),
1953, 12B, 236.
9. C. J. Burns and M. Gill, Aust. J. Chem., 1991, 44, 1447.
10. D. S. Larsen and R. T. Stoodley, Tetrahedron, 1990, 46, 4711.
11. V. Ph. Anufriev, V. L. Novikov, O. B. Maximov, G. B.
Elyakov, D. O. Levitsky, A. V. Lebedev, S. M. Sadretdinov,
Received May 19, 2003;
in revised form September 3, 2003