The Directed Lithiation Route to 2-Amino-3-alkylquinones: Highly Regioselective Introduction of Electrophiles at the C-7 Position of 2(1H)-Quinolinones

Abstract

An ortho-directed lithiation strategy starting from 2-amino-1,4-dimethoxybenzene derivatives allowed the efficient preparation of 2-amino-3-alkylbenzoquinone derivatives. This method was also successful in the case of 6-pivaloylamino-4-methyl-5,8-dimethoxycarbostyril derivatives, in spite of the fact that two other modes of lithiation are possible, and allowed the preparation of derivatives containing alkyl chains or functional groups at the highly hindered C-7 position. A reaction starting from 4-methyl-5,8-dimethoxy-2-pivaloyloxyquinoline was regioselectively directed to the C-4 methyl group.A number of natural heterocyclic quinones with antitumor properties, most notably some members of the mitomycin family, contain a 2-amino-3-alkyl-1,4-benzoquinone fragment (1, Figure 1). Compounds with this structure can also be considered as useful potential synthons for the preparation of other biologically active natural products like the sebastianins, 2 a group of cytotoxic marine alkaloids belonging to the pyridoacridine family. 3 Figure 1Previous work related to the synthesis of structures 1 has normally involved the construction of 2-methoxy-3-aminobenzoquinone moieties, followed by the displacement of the methoxy group by ammonia, but the preparation of these starting materials involves lengthy routes. 4 We describe in this communication some results related to the development of a directed-metalation-based strategy 5 for the synthesis of compounds 1, as summarized in Scheme 1. This strategy is simpler, and therefore potentially more efficient than previous methods in that it avoids the difficulties associated with the preparation of 1,2,3,4-tetrasubstituted benzene derivatives as starting materials. It also avoids issues of regioselectivity at the oxidation stage due to the presence of a 2-methoxy group, which facilitates ortho-quinone synthesis. In connection with this strategy, we report here our results on the preparation of a simple quinone containing the desired substitution pattern and the subsequent application of the directed lithiation strategy to 4-methylcarbostyril, a challenging system where two additional modes of lithiation are possible. Scheme 1Our initial studies were aimed at the preparation of the 3-methyl-5,6-unsubstituted compound 5, an acyl derivative of the simplest possible compound with structure 1, namely the benzoquinone derivative. As shown in Scheme 2, directed ortho-lithiation of 2,5-dimethoxy-N-pivaloylaniline 2 proceeded very efficiently by its treatment with 2.5 equivalents of BuLi to give the nonisolated dilithio species 3, which was trapped with methyl iodide to afford compound 4 in 94% yield. 6 Oxidative demethylation of 4 to 5 was carried out in 45% yield under standard conditions, by treatment of 4 with ceric ammonium nitrate in acetonitrile-water at room temperature. 7Having proved the feasibility of the ortho-metalation strategy, we decided to test its scope by applying it to a more complex case. We chose the 2(1H)-quinolinone (carbostyril) system to this effect, prompted by t...