An original one-pot synthesis of dialkyl-substituted anthraquinones

Article abstract of DOI:10.1055/s-1998-1863

2,3-Bis(chloromethyl)-1,4-naphthoquinone reacts with primary nitroalkanes in a one-pot synthesis to give a series of anthraquinones bearing two n-alkyl substituents at C-2 and C-3 in good yields. The reaction is shown to proceed by two consecutive S_RN1 processes followed by base-promoted nitrous acid elimination, electrocyclic ring-closure and dehydrogenation. In comparison with the classical Diels-Alder reaction, the advantage of this route is the simplicity of starting-material preparation.

Full text of DOI:10.1055/s-1998-1863

October 1998
SYNLETT
1067
An Original One-Pot Synthesis of Dialkyl-Substituted Anthraquinones
a
a
a
b
c*
Patrice Vanelle, * Thierry Terme, José Maldonado, Michel P. Crozet and Luc Giraud
a
Laboratoire de Chimie Organique, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
Fax (33) 04 91 79 46 77; E-mail : patrice.vanelle@pharmacie.univ-mrs.fr
b
LCMO UMR 6517, CNRS-Universités d’Aix-Marseille I et III, B.P. 562, 13397 Marseille Cedex 20, France
c
Institut de Chimie Organique, Université de Fribourg, Pérolles, CH-1700 Fribourg, Suisse
Fax +41 (026) 300 87 79; E-mail : anne.giraud@unifr.ch
Received 7 July 1998
Abstract: 2,3-Bis(chloromethyl)-1,4-naphthoquinone reacts with
primary nitroalkanes in a one-pot synthesis to give a series of
anthraquinones bearing two n-alkyl substituents at C-2 and C-3 in good
yields. The reaction is shown to proceed by two consecutive S
1
RN
processes followed by base-promoted nitrous acid elimination,
electrocyclic ring-closure and dehydrogenation. In comparison with the
classical Diels-Alder reaction, the advantage of this route is the
simplicity of starting-material preparation.
Due to the presence of the quinone ring in numerous biologically active
1,2
compounds as well as to their use as auxiliaries in organic synthesis
3,4
and in dye industry, quinonoid compounds continue to attract interest.
Quinones, and particularly anthracyclines such as adriamycin and
daunorubicin, are effective in the palliative management of a wide
variety of human malignancies. However, intrinsic and acquired drug
resistance as well as undesired effects such as cumulative dose-
5
dependent cardiotoxicity
limit their clinical utilization. As
bioreductible agents, they constitute potential substrates for the radical
6
nucleophilic substitution (S 1 reaction). In the anthraquinone series,
RN
2,3-dialkylanthraquinone 5. Use of nitroethane under the standard
experimental conditions during 0.5 h with a 2:1 nitronate anion to
bis-chloride ratio, allowed isolation of the bis-C-alkylation product 2a
the method of choice for the synthesis of dialkyl-substituted
compounds is the Diels-Alder reaction between 1,4-naphthoquinone
7,8
and a 1,3-diene, followed by dehydrogenation of the obtained primary
17
in 32% yield along with 35 % of remaining starting material.
9
tricyclic adduct. However, the limitation of this method was the
Treatment of 2a in the presence of the appropriate nitronate anion (2
eq.) under the same experimental conditions during 24 h gave the
required 2,3-dimethylanthraquinone (5a) in 65 % yield. A similar yield
difficult preparation of 2,3-dialkyl-1,3-butadienes, which are usually
synthesized by alkylation of the dianion of 2,3-dimethyl-1,3-butadiene
7
with 1-halo-alkanes. Indeed, Bates has reported the formation of this
18
was observed in the presence of classical inhibitors (p-dinitrobenzene,
dianion by deprotonation of 2,3-dimethyl-1,3-butadiene with a mixture
TEMPO or bubbling dioxygen) which indicates the absence of
10
of n-butyllithium and potassium tert-butoxide in pentane. To optimize
19
intramolecular SET reaction for the transformation of 2a into 5a.
the yield of Diels-Alder reaction, the resulting dienes must be purified
by distillation.7
In connection with our program directed toward the development of
novel synthetic quinone congeners as anticancer agents, we report here a
new and easy one-pot preparative method to produce dialkyl-substituted
anthraquinones.
2,3-Bis(chloromethyl)-1,4-naphthoquinone (1) was prepared by
saturating a cooled solution of 1,4-naphthoquinone and aqueous
formaldehyde in glacial acetic acid with dry hydrogen chloride, for 2 h,
11
according to Thomson's procedure. Nitroalkanes were commercially
available or easily obtained in excellent yields (70-80 %) from primary
amines by oxidation with m-chloroperbenzoic acid in refluxing 1,2-
12
dichloroethane.
Treatment of the bis-chloride 1 (1 equiv) with the primary nitroalkanes
(4 equiv) during 48 h, under standard S 1 reaction conditions (inert
RN
13
atmosphere, photostimulation) and in a phase-transfer system (40 %
tetrabutylammonium hydroxide in water and toluene), furnished 2,3-
14
dialkylanthraquinones 5 in 52-70 % good yield.
15
As reported previously, two consecutive S 1 processes led to the bis-
RN
C-alkylation product 2, which, in the presence of an anion excess,
underwent double nitrous acid elimination to give the non-isolated bis-
ethylenic product 3. Electrocyclic ring-closure of the latter produced
In conclusion, compared to the published methods, this route is clearly
the shortest and the most efficient known. It appears to be promising for
the synthesis of dialkyl-substituted anthraquinones.
16
dihydroanthraquinone 4 that, after dehydrogenation, gave the expected

1068
LETTERS
SYNLETT
References and Notes
7.5, 4H, CH ); 7.77 (m, 2H, 6-H, 7-H); 8.10 (s, 2H, 1-H, 4-H);
2
13
8.29 (m, 2H, 5-H, 8-H). C NMR (CDCl ) δ : 183.37 (CO);
(1) Lin, A. J.; Cosby, L. A.; Shansky, C. W.; Sartorelli, A. C. J. Med.
Chem. 1972, 15, 1247.
3
149.15 (C-2, C-3); 133.84 (C-8a, C-10a); 133.69 (C-6, C-7);
131.51 (C-4a, C-9a); 127.06 (C-1, C-4); 126.98 (C-5, C-8); 25.80
(2) Moore, H. W. Science 1977, 197, 527.
(CH ); 14.64 (CH ). Anal. calcd for C
H O (264.32) : C,
18 16 2
2
3
(3) Nair, V.; Kumar, S. Synlett 1996, 1143.
81.79; H, 6.10. Found : C, 81.57; H, 6.05.
(4) Gallagher, P. T. Contemporary Organic Synthesis 1996, 3, 433.
1
5g, orange solid, mp 66 °C, H NMR (CDCl ) δ : 0.88 (t, J = 6.0,
3
(5) Matsuda, F.; Matsumoto, T.; Ohsaki, M.; Terashima, S.
6H, CH ); 1.28 (m, 32H, CH ); 1.66 (m, 4H, CH CH ); 2.76 (t, J
3
2
2
3
Tetrahedron Lett. 1989, 30, 4259.
= 7.6, 4H, benzylic CH ); 7.76 (m, 2H, 6-H, 7-H); 8.07 (s, 2H, 1-
2
13
(6) Murguia, M. C.; Rossi, R. A. Tetrahedron Lett. 1997, 38, 1355.
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H, 4-H); 8.30 (m, 2H, 5-H, 8-H). C NMR (CDCl ) δ : 183.37
3
(CO); 148.14 (C-2, C-3); 133.82 (C-8a, C-10a); 133.74 (C-6, C-
7); 131.32 (C-4a, C-9a); 127.83 (C-1, C-4); 127.05 (C-5, C-8);
32.99, 31.90, 30.77, 29.70, 29.65, 29.62, 29.55, 29.47, 29.34,
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22.67 (CH ); 14.10 (CH ). Anal. calcd for C
H O (516.81) : C,
36 52 2
2
3
(9) Wassermann, A. Diels-Alder Reactions; Elsevier Publishing Co.:
83.67; H, 10.14. Found : C, 83.35; H, 10.34.
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nitroethane (0.293 g, 3.90 mmol). Orange solid, mp 106 °C
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1
(isopropanol), H NMR (CDCl ) δ : 1.69 (d, J = 6.6, 6H, CH );
3
3
Tetrahedron Lett. 1977, 3063.
3.13 (m, 4H, benzylic CH ); 4.89 (m, 2H, CH); 7.75 (m, 2H, 6-H,
2
(14) Typical procedure for the formation of 5. Under nitrogen
atmosphere, a solution of tetrabutylammonium hydroxide (1.6 M/
water, 5.00 mL, 7.8 mmol) was treated with a nitroalkane (7.8
mmol) for 1 h. A solution of 2,3-bis (chloromethyl)-1,4-
naphthoquinone (1) (0.5 g, 1.95 mmol) in toluene (20 ml) was
added and the mixture was irradiated with a 300 W sun lamp for
48 h at r.t. under an inert atmosphere. The organic layer was
separated and the aqueous layer was extracted with toluene (3 x 10
ml). The combined organic layers were washed twice with water
7-H); 8.08 (m, 2H, 5-H, 8-H). Anal. calcd for C
H N O
16 16 2 6
(332.31) : C, 57.83; H, 4.85; N, 8.43. Found : C, 57.83; H, 4.80;
N, 8.45.
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(20 ml), dried over MgSO and removed under reduced pressure.
4
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Purification by chromatography on silica gel eluting with
dichloromethane and recrystallization from ethanol gave 2,3-
dialkylanthraquinone 5. New products: 5b, orange solid, mp 126
1
°C, H NMR (CDCl ) δ : 1.32 (t, J = 7.5, 6H, CH ); 2.81 (q, J =
3
3