Synthesis of Isatins by I2/TBHP Mediated Oxidation of Indoles

A novel palladium-catalyzed C-H double carbonylation introduces two adjacent carbonyl groups for the synthesis of isatins from readily available anilines. The reaction proceeds under atmospheric pressure of CO with high regioselectivity and without any additives. Density functional theory investigations indicate that the palladium-catalyzed double carbonylation catalytic cycle is plausible.

From Anilines to Isatins: Oxidative Palladium‐Catalyzed Double Carbonylation of C ? H Bonds

Syntheses and antiproliferative evaluation of oxyphenisatin derivatives.

The synthesis of bisisoindigo, a near IR absorbing electron acceptor in which two isoindigo units are ring-fused along the 6 and 7 positions, is reported. An electron-deficient bisisatin was first synthesized using the Martinet isatin synthesis, after which two concurrent aldol condensations with 1-alkyl-2-oxindole yielded the ring-fused isoindigo dimer. The ring fusion significantly extends the conjugation length of the molecule relative to the isoindigo parent compound. The bisisoindigo sub-unit was then coupled to 2,2′-bithiophene, yielding a new organic semiconductor with a donor–acceptor structure. Both bisisoindigo and the donor–acceptor compound absorb light well into the near IR; the donor–acceptor compound features an absorption edge of almost 1000 nm in the solid state. Both compounds were employed in prototype organic photovoltaic devices alongside common electron donors and acceptors.

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Bisisoindigo: using a ring-fusion approach to extend the conjugation length of isoindigo

Mefloquine has been one of the more valuable antimalarial drugs but has never reached its full clinical potential due to concerns about its neurologic side effects, its greater expense than that of other antimalarials, and the emergence of resistance. The commercial development of mefloquine superseded that of another quinolinyl methanol, WR030090, which was used as an experimental antimalarial drug by the U.S. Army in the 1970s. We evaluated a series of related 2-phenyl-substituted alkylaminoquinolinyl methanols (AAQMs) for their potential as mefloquine replacement drugs based on a series of appropriate in vitro and in vivo efficacy and toxicology screens and the theoretical cost of goods. Generally, the AAQMs were less neurotoxic and exhibited greater antimalarial potency, and they are potentially cheaper than mefloquine, but they showed poorer metabolic stability and pharmacokinetics and the potential for phototoxicity. These differences in physiochemical and biological properties are attributable to the “opening” of the piperidine ring of the 4-position side chain. Modification of the most promising compound, WR069878, by substitution of an appropriate N functionality at the 4 position, optimization of quinoline ring substituents at the 6 and 7 positions, and deconjugation of quinoline and phenyl ring systems is anticipated to yield a valuable new antimalarial drug.

Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs

Nine alpha-dibutylaminomethylbenzo[h]quinoline-4-methanols were synthesized from the corresponding 1-amino-naphthalenes by the following sequence: 1-aminonaphthalene leads to 1H-benz[g]indole-2,3-dione leads to benzo[h]quinoline-4-carboxylic acid leads to acid chloride leads to bromomethyl ketone leads to epoxide leads to benzo[h]quinoline-4-methanol. Several acid chlorides substituted in the 3 position reacted incompletely with ethereal diazomethane but were efficiently converted, without isolation of the intermediates, to the bromomethyl ketones by reaction with ethoxymagnesium diethylmalonate, bromination, hydrolysis, and decarboxylation. Several compounds prepared, especially alpha-dibutylaminomethyl-2-(2',4'-dimethylphenyl)-3-methyl-6-chlorobenzo[h]quinoline-4-methanol, showed significant antimalarial activity against Plasmodium berghei in infected mice but were moderately phototoxic.

T. J. Rauls

Papers

Synthesis, antimalarial activity, and phototoxicity of some benzo(h)quinoline-4-methanols.

Synthesis, antimalarial activity, and phototoxicity of some benzo(h)quinoline-4-methanols