An Original One-Pot Synthesis of Dialkyl-Substituted Anthraquinones

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 RN 1 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 compounds 1,2 as well as to their use as auxiliaries in organic synthesis and in dye industry, 3,4 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 dosedependent cardiotoxicity 5 limit their clinical utilization. As bioreductible agents, they constitute potential substrates for the radical nucleophilic substitution (S RN 1 reaction). 6 In the anthraquinone series, the method of choice for the synthesis of dialkyl-substituted compounds 7,8 is the Diels-Alder reaction between 1,4-naphthoquinone and a 1,3-diene, followed by dehydrogenation of the obtained primary tricyclic adduct. 9 However, the limitation of this method was the 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 with 1-halo-alkanes. 7 Indeed, Bates has reported the formation of this dianion by deprotonation of 2,3-dimethyl-1,3-butadiene with a mixture of n-butyllithium and potassium tert-butoxide in pentane. 10 To optimize the yield of Diels-Alder reaction, the resulting dienes must be purified by distillation. 7In 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, according to Thomson's procedure. 11 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-dichloroethane. 12 Treatment of the bis-chloride 1 (1 equiv) with the primary nitroalkanes (4 equiv) during 48 h, under standard S RN 1 reaction conditions (inert atmosphere, photostimulation) and in a phase-transfer system 13 (40 % tetrabutylammonium hydroxide in water and toluene), furnished 2,3-dialkylanthraquinones 5 in 52-70 % good yield. 14 As reported previously, 15 two consecutive S RN 1 processes led to the bis-C-alkylation product 2, which, in the presence of an anion excess, underwent double nitrous acid elimin...

Nucleophilic Substitution Reactions by Electron Transfer

“…Under these conditions, the Me group in the substitution product is deprotonated, yielding a good Michael acceptor, which in the presence of an excess of anion gives the bis-C-alkylated compound. As indicated previously, , after oxidation, nitrous acid elimination, electrocyclization, and dehydrogenation, the corresponding dialkylanthraquinones are obtained.

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“…The reaction of 2,3-bis(chloromethyl)-1,4-naphthoquinone with the - CMe 2 NO 2 ion proceeds by two consecutive S RN 1 reactions leading to a bis-C-alkylated product, which after ring closure gives a 2,3-dihydro-9,10-anthracenedione derivative . A novel and very interesting one-pot synthesis of dialkyl-substituted anthraquinones was performed by this procedure, which consists of two consecutive S RN 1 processes followed by base-promoted nitrous acid elimination, electrocyclic ring closure, and dehydrogenation . The advantage of this procedure, in comparison with the classical Diels−Alder reaction, is the simplicity of the preparation of the starting material.…”

“…The iodo-monosubstituted compound is not an intermediate in these reactions. 244 Two [245][246][247][248] and four 231 consecutive S RN 1 substitutions have been achieved in the reactions of nitronate ions with di-and tetrabenzylic type chlorides bearing a quinone as EWG. Low yields of disubstitution are formed in the reaction of an allylic dichloride with a 5-nitroimidazole ring at the alkene terminus; in this reaction the monochloro-substituted product is an intermediate.…”

Strategies in Synthetic Radical Organic Chemistry. Recent Advances on Cyclization and SRN1 Reactions

“…Other related examples are known [159]. The reaction of 2,3-bis (chloromethyl)-1,4-naphtoquinone with -CMe 2 NO 2 anions proceeds by two consecutive S RN 1 reactions leading to a bis-C-alkylated product, which after ring closure affords a 2,3-dihydro-9,10-anthracenedione derivative [160].…”

Spectral investigations on 2‐methyl‐3‐chloromethyl‐1,4‐naphthoquinone and 2,3‐bis(chloromethyl)‐1,4‐naphthoquinone under laser excitation

“…9,10 2,3-Bis(chloromethyl)-1,4-naphthoquinone 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, according to Thomson's procedure. 9,11 Silver sol was prepared according to the literature. 12 For solvent effects on 2-methyl-3-chloromethyl-1,4-naphthoquinone (1) and 2,3-bis(chloromethyl)-1,4-naphthoquinone (2), carbon tetrachloride, dichloromethane, propan-2-ol, methanol and acetonitrile from Sisco Laboratory with 99% purity were used without further purification.…”