New Adducts of Lapachol with Primary Amines

Abstract

A reação do lapachol à temperatura ambiente, com aminas alifáticas primárias forneceu novos adutos identificados como derivados do núcleo fenazina. Os produtos foram obtidos em rendimentos bons a razoáveis (52 a 88%), a temperatura ambiente e sem o uso de solvente, a partir da reação com alquilaminas funcionalizadas, como n-butilamina, etanolamina, 3-propanolamina, 2-metoxi-etilamina, 3-metoxi-propilamina e 2-feniletilamina.New adducts of lapachol with neat primary aliphatic amines were obtained in a solvent-free reaction in good to reasonable yields (52 to 88%), at room temperature. The new compounds containing a phenazine moiety were obtained from suitable functionalized aminoalkyl compounds, including ethanolamine, 3-propanolamine, 2-methoxy-ethylamine, 3-methoxy-propylamine, n-butylamine and 2-phenetylamine. Keywords: phenazines, lapachol, nitrogen adducts, quinones, 1,4-naphthoquinone IntroductionMolecules containing a quinone moiety as a structural component constitute an important class of compounds in organic chemistry. The conjugated 1,4-dicarbonyl or 1,2-dicarbonyl moiety is responsible for a characteristic reactivity behavior, yielding a somewhat particular chemistry repertoire for these compounds. These functional groups are also involved in numerous biological activities, mostly cytotoxic ones. The wide range of biological activities includes anticancer, 1 inhibitors of topoisomerase II, 2 highlighting their use as valuable candidates in neglected tropical diseases, including leishmaniasis, 3 tuberculosis 4 and tripanosomiasis. 5 Among the naturally occurring naphthoquinones in Tabebuia spp, lapachol, a-lapachone and b-lapachone and xyloidones are the most abundant and studied compounds in these and related species.6 b-Lapachone, in particular, showed a more defined and impressive biological profile in antitumor screenings than the regioisomer a-lapachone or lapachol. 7,8 The molecular mechanism involved in the observed antitumoral and cytotoxic activities of these compounds seems to be mainly related to the ability of the quinone nucleus in participating in redox processes, in which the cascade of one-electron radical enzymaticmediated reactions results in the formation of superoxide radical anions, responsible for cellular damage in living media. 9 In a continuing work concerning the reactivity of lapachol and related quinones, 10,11 we now present our results concerning the reaction of lapachol with primary aliphatic amines. This smooth reaction conduced to new adducts with a cyclic structure consisting of a phenazine nucleus.12 Our initial observation, unlike previous reports, 13 is that lapachol 1 is almost entirely consumed when mixed with primary amines, like n-butylamine, ethanolamine, 3-hydroxypropylamine, 2-methoxyethylamine, 3-methoxypropylamine, and 2-phenylethylamine. The reaction of some few secondary cyclic amines with lapachol have also been described previously, with some unusual spectroscopic data found. 14 Results and DiscussionThe products were formed in reactions at room tempera...

Synthesis of New 2-N,N' ­ dialkylamino-1,4-naphthoquinone Derivatives: Concerning the Reactivity of Lapachol with Secondary Amines

“…The absence of HMBC correlation between the carbon chain of amine with C-2 further compromises the conclusions put forward by these authors. In this case, as we previously stated, 15 we expect that the amines used 27,28 deprotonates the 2-hydroxy group of lapachol (or hydroxyquinones), 29 according to Scheme 4. The resulting salt of lapachol has a characteristic dark-reddish coloration as described by both Oliveira et al (2002) 27 and Wenceslau et al (2006), 28 and also noticed by us.…”

“…The resulting salt of lapachol has a characteristic dark-reddish coloration as described by both Oliveira et al (2002) 27 and Wenceslau et al (2006), 28 and also noticed by us. 15 As far as we know, there is no precedent in the literature for a direct displacement of a hydroxyl-attached to a quinone nucleus by amines. 12,13,[30][31][32] To prove this conclusion, we repeated the procedure described, 27,28 with lapachol and nor-lapachol and morpholine.…”

“…[9][10][11][12][13] In our group, we have been found facile acess to lapachol (1) by extraction from Brazilian Tabebuia sp (ipê) heartwood, 14 allowed us to observe that (1) reacts with neat primary amines to yield phenazines 15 (2) (Scheme 1), in the so called Strecker degradation oxidation. 16 This behavior contrasts with other previously direct substitution procedure explored by our group 12,17,18 which the 2-methoxy derivative of (1a) or synthetic nor-lapachol (5) smoothly afford the formation of 2-aminoalkyl derivatives and some other interesting unexpected cyclization products (Scheme 1).…”

Tautomerism in quinoxalines derived from the 1,4-naphthoquinone nucleus: acid mediated synthesis, X-ray molecular structure of 5-chlorobenzo[f]quinoxalin-6-ol and density functional theory calculations

“…23 Unusual dimeric phenazines h have been synthesized in high yields by reacting lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone) with neat alkylamines. 24 The reactions of ethylene diamines or 1,2-cyclohexyldiamine 34 with 1,4-naphthoquinone (R = H), 2,3-dibromo or dichloro-1,4-naphthoquinone (R = Cl or Br), 2,3-phthalimido-1,4-naphthoquinone (R = NHAc, NH 2 ) 29 and 2-alkyl or 2-aryl,3-halogen-1,4-naphthoquinones, in CH 2 Cl 2 / ethanol, 26 have yielded the dihydrobenzoquinoxalines shown in Figure 1b.…”

“…23 Unusual dimeric phenazines h have been synthesized in high yields by reacting lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone) with neat alkylamines. 24 The reactions of ethylene diamines or 1,2-cyclohexyldiamine 34 with 1,4-naphthoquinone (R = H), 2,3-dibromo or dichloro-1,4-naphthoquinone (R = Cl or Br), 2,3-phthalimido-1,4-naphthoquinone (R = NHAc, NH 2 ) 29 and 2-alkyl or 2-aryl,3-halogen-1,4-naphthoquinones, in CH 2 Cl 2 / ethanol, 26 have yielded the dihydrobenzoquinoxalines shown in Figure 1b.Following our continuing interest in aminonaphthoquinones [35][36][37][38] and their metal complexes 39-41 as potential antimicrobial and anticancer agents, our group has investigated the possibility of synthesizing molecular hybrids from 2,3-dichloro-1,4-naphthoquinone and N-Boc-monoprotected diamines (NH 2 (CH 2 ) n NHBoc), whose deprotection would be followed by further extension of the diamine chain with nitrogen or oxygen containing fragments for coordination with metal ions. This tactic has proven successful for the diamines with a linear carbon chain longer than n = 3, 42 and the results will be reported elsewhere.…”