1-Naphthols, 1,4-dihydro- from

Table 2 summarizes pK measurements for the simplest protonated aromatic hydrocarbons. The columns to the right and left of the benzenonium ion correspond to benzoannelation of ions subject to protonation at the 2- and 4-positions of the benzene ring, respectively. In the parent ion the two positions correspond to resonance forms (one of which has been rotated through 120° in the table). The naphthalenonium ion 17 is shown as being formed from the 1,4-water adduct (hydrate) of naphthalene. It may also be formed from the isomeric 2,1 hydrate (l,2-dihydro-2-naphthol) with pAR = -6.7 and pAn2o = 13.7. 

The first synthesis of (R)-4,5-dihydro-37/-dinaphtho[2,l-f l, 2 -i ]selenepin oxide 110 has been achieved from (R)-(+)-l,l -bi-2-naphthol, which in turn was obtained by resolution of raol,l -bi-2-naphthol. Palladium-catalyzed alkoxy carbonylation of the alcohol 108 gave a dimethyl ester which was then reduced by LiAlfLi, and the resultant diol converted to key intermediate chloride 109. Cyclization with sodium selenide gave a novel enantiomerically pure selenide, which upon oxidation yielded the desired selenoxide 110 <2000SC2975>. 

Pyrolysis of the Mannich base (109) derived from 2-naphthol leads to generation of a quinone methide which when trapped with an aromatic amine leads to benz[a]acridines (0. Bilgic and D.W. Young, J. chem. Soc. Perkin I, 1980, 1233). Thus, aniline yields the parent compound together with 7,12-dihydrobenz[a]acridine. Formation of the dihydro compound appears to be variable for whereas /7-metlylaniline and o-anisidine yield only... 

Owing to its widespread practical application, the metabolism of carbaryl has been investigated extensively. In the human organism it is converted partly hydrolytically to 1-naphthol, and partly oxidatively to 4-hydroxycarbaryl (4) and 5,6-dihydro-5,6-dihydroxycarbaryl (5) (Knaak et al., 1968 Leeling and Casida, 1966 Camp and Arthur, 1967). These metabolites are eliminated from the organism mainly as glucuronides or sulfates. 

By this process 2-naphthol, for example, affords l,2-dihydro-2-[3/-methyl-2/-(l///)benzo-thiazolidinylidene]-2-naphthalenone (crude yield 1.4 g, 88% m.p. 237°), which on recrystallization from chlorobenzene forms fine red needles, m.p. 243-244°. 

Touring studies at NIH, it was discovered that enzymatic hydroxyla-tion of (deuterated or tritiated) substrates leads to a novel and mechanistically important shift of the deuterium or tritium from the point of substitution by oxygen to an adjacent position in the aromatic ring (12). [It has been found recently that arene oxides are likely intermediates in the metabolism of aromatic compounds. They rearrange to phenols with concomitant NIH Shift, and they are enzymatically converted to dihydrodiols and premercapturic acids. In addition, naphthalene oxide has now been demonstrated as an intermediate in the conversion of naphthalene to a-naphthol, frari5-l,2-dihydro-I,2-dihydroxynaphthalene, and... 

These include the SSA-catalyzed synthesis of heterocyclic compounds such as xanthenes, coumarins, oxazoles, and so on. Xanthenes are of great therapeutic and biological interest on account of their many biological activities such as anti-inflanunatory, antiviral, antibacterial properties, and so on. Seyyed Hamzeh et al. (2008) carried out the SSA-catalyzed synthesis of aryl-14 f-dibenzo[fl,y]xanthenes from aldehydes and P-naphthol and 1,8-dioxo-octahydro-xanthenes from aldehydes and 1,3-dicarbonyl componnd such as dimedone under solvent-free conditions (Schemes 5.25, 5.26). Reactions were carried out at 80°C. Nazeruddin et al. (2011) documented an effective method for 9,10-dihydro-12-aryl-8 f-benzo[a]xanthenes-ll(12 f)-one derivatives in excellent yield and short reaction time using SSA under solvent-free conditions (Scheme 5.27). 

A number of instances can be cited from the literature wherein the isosteres had similar transformations. Bacterial dioxygenase-catalyzed ci5-dihydroxylation of the tetracyclic arene benzo[c]phenanthrene was found to occur exclusively at fjord region (cavity region) bonds. The isosteric compounds benzo[b]naphthol [l,2-d]furan and benzo[b]naphthol[l,2-d]thiophene were also similarly ci5-dihydroxylated at the fjord region bonds by bacterial dioxygenases (Boyd et al., 2001) (see Fig. 4.3). The isosteres 1,2-dihydronaphthalene, 2,3-dihydrobenzothiophene, and 2,3-dihydro-benzofuran gave similar corresponding diol products on incubation with Pseudomonas putida UV4. Microbes that possess the metabolic pathways to metabolize benzene, when substituted by... 

Perumal has described a four-component sequential protocol that allows the synthesis in good yields of antitubercular 2-aryl-5-methyl-2,3-dihydro-l/f-3-pyrazolones 18 from atylhydrazines, methyl acetoacetate, aromatic aldehydes and 5-naphthol in the presence of / -TSA in water under reflux conditions [13], The reaction proceeds by an initial acid-catalyzed cyclocondensation of the hydrazine and dicarbonyl components to give pyrazolinone 19. A parallel acid-catalyzed condensation between p-naphthol and the aromatic aldehyde affords the intermediate quinone methide 20, and Michael addition of the enol form of 19 onto the exocyclic double bond of 20 furnishes the final product (Scheme 1.9). 

R = H, OMe) have been prepared from l-aminomethyl-2-naphthols and 3,4-dihydro-isoquinolines. The predominant diastereomer is trans- (at the 7a- and 15-positions), (g) but a surprising inversion at nitrogen can be observed by NMR (nuclear magnetic resonance). Computations support ring-opening at the C(7a)-oxygen bond, giving an iminium-phenolate intermediate. 

ARQ 501 is a fully synthetic version of B-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b] pyran-5,6-dione) and has shown promising anticancer activity in multiple Phase II clinical trials. Recently, we disclosed the identification and characterization of the phase I metabolites of ARQ 501 from human blood. In continuation of our studies on the metabolism of ARQ 501, we studied the phase II metabolites in vivo. The sulfate and glucuronidate conjugates were identified as the two major metabolites formed in vivo. In this presentation, we will discuss the synthesis and structural elucidation of these sulfate and glucuronidate conjugates of ARQ 501. 

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