RESUMO
Rubazonic acids are a class of dyes that are long-known, but studies on their syntheses and uses are rare. We now describe an experimentally simple and highly practical one-pot procedure for their synthesis starting from easily accessible 1H-pyrazol-5(4H)-ones. This protocol provides direct access to a broad range of the desired rubazonic acid derivatives through oxidative diazidation combined with a reductive work-up, without the need to isolate the potentially hazardous diazido compounds generated en route the target compounds. We also show how more challenging variants of rubazonic acid are efficiently prepared using an alternative two-step procedure and controlled hydrogenation conditions.
Assuntos
HidrogenaçãoRESUMO
A new synthetic route toward the tetrazole core is described, which is based on a general fragmentation pattern that was found in a range of compounds featuring geminal diazido units. Through a simple two-step procedure, the synthesis of structurally diverse target compounds containing a tetrazole, such as tetrazoloquinoxalinones, benzoylaryltetrazoles, tetrazolotriazinones, and tetrazoloazepinones, was easily accomplished, starting from broadly accessible substrates (i.e., oxindoles, diarylethanones, pyrazolones, and phenanthrols). The initial oxidative diazidation reaction with iodine and sodium azide under mild conditions is followed by the thermal fragmentation under microwave irradiation, leading to the tetrazole products. Noteworthy, an experimental solution is presented in which the potentially hazardous diazide intermediates are not isolated and the concentration of crude reaction mixtures containing diazides is not required to achieve the tetrazoles in good yields.
RESUMO
The synthesis of previously unknown 3,3-diazidooxindoles as synthetically useful derivatives of isatins was accomplished through the direct oxidative diazidation of 2-oxindoles. The method yielded the diazido compounds from the starting oxindoles under mild and simple conditions with NaN3 and iodine, in good yields. The notable reactivity of this new class of compounds toward primary and secondary nucleophilic amines is also described, which gives access to either 4-imino-3,4-dihydroquinazolin-2(1 H)-one derivatives or cyanophenylureas.
RESUMO
The degradation of geminal diazides is described. We show that diazido acetates are converted into tetrazoles through the treatment with bases. The reaction of dichloro ketones with azide anions provides acyl azides, through in situ formation of diazido ketones. We present experimental and theoretical evidence that both fragmentations may involve the generation of acyl cyanide intermediates. The controlled degradation of terminal alkynes into amides (by loss of one carbon) or ureas (by loss of two carbons) is also shown.
RESUMO
Despite the troubling psychiatric side-effects it causes in some patients, mefloquine (MQ) has been used for malaria prophylaxis and therapy, due to its activity against all Plasmodium species, its ease of dosing, and its relative safety in children and pregnant women. Yet at present there is no consensus on the mechanism of antimalarial action of MQ. Two leading hypotheses for the mechanism of MQ are inhibition of heme crystallization and inhibition of host cell hemoglobin endocytosis. In this report we show that MQ is a potent and rapid inhibitor of amino acid efflux from intact parasitized erythrocytes, which is a measure of the in vivo rate of host hemoglobin endocytosis and catabolism. To further explore the mechanism of action of MQ, we have compared the effects of MQ and 18 non-piperidine analogs on amino acid efflux and parasite growth. Among these closely related compounds, an excellent correlation over nearly 4 log units is seen for 50% inhibition concentration (IC50) values for parasite growth and leucine efflux. These data and other observations are consistent with the hypothesis that the antimalarial action of these compounds derives from inhibition of hemoglobin endocytosis.
