84498-34-0Relevant academic research and scientific papers
Directed ortho -Metalation and Anionic ortho -Fries Rearrangement of Polycyclic Aromatic O -Carbamates: Regioselective Synthesis of Substituted Chrysenes
Kancherla, Sindhu,Lorentzen, Marianne,Snieckus, Victor,J?rgensen, Kare B.
, p. 3590 - 3598 (2018)
A general method for the regioselective synthesis of a series of ortho-substituted chrysenyl N,N-diethyl-O-carbamates by the directed ortho-metalation (DoM) strategy is reported. The starting O-carbamates were prepared from the corresponding chrysenols, available by oxidative photochemical cyclization or directed remote metalation tactics. Chrysen-1-yl and chrysene-3-yl ring site selectivity of directed ortho-metalation (DoM) and anionic ortho-Fries rearrangement (AoF) protocols, with s-BuLi/TMEDA, followed by electrophilic quench using a selection of electrophiles, were observed, leading to new chrysenyl derivatives. 5-Chrysenyl N,N-diethyl-O-carbamate underwent instant AoF rearrangement even at -100 °C to furnish chrysenyl o-hydroxycarboxamide. Iterative DoM reactions were carried out to gain insight into the regioselectivity factors.
Synthesis of 13C4-labelled oxidized metabolites of the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene
Wu, Anhui,Xu, Daiwang,Lu, Ding,Penning, Trevor M.,Blair, Ian A.,Harvey, Ronald G.
, p. 7217 - 7233 (2012/09/05)
Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are ubiquitous environmental contaminants that are implicated in causing lung cancer. BaP is a component of tobacco smoke that is transformed enzymatically to active forms that interact with DNA. We reported previously development of a sensitive stable isotope dilution LC/MS method for analysis of BaP metabolites. We now report efficient syntheses of 13C4-BaP and the complete set of its 13C4-labelled oxidized metabolites needed as internal standards They include the metabolites not involved in carcinogenesis (Group A) and the metabolites implicated in initiation of cancer (Group B). The synthetic approach is novel, entailing use of Pd-catalyzed Suzuki, Sonogashira, and Hartwig cross-coupling reactions combined with PtCl2-catalyzed cyclization of acetylenic compounds. This synthetic method requires fewer steps, employs milder conditions, and product isolation is simpler than conventional methods of PAH synthesis. The syntheses of 13C4-BaP and 13C4-BaP-8-ol each require only four steps, and the 13C-atoms are all introduced in a single step. 13C4-BaP-8-ol serves as the synthetic precursor of all the oxidized metabolites of 13C-BaP implicated in initiation of cancer. The isotopic purities of the synthetic 13C 4-BaP metabolites were estimated to be ≥99.9%.
Acid-catalyzed rearrangement of K-region arene oxides: Observation of ketone intermediates and a sterically induced change in rate-determining step
Nashed, Nashaat T.,Sayer, Jane M.,Jerina, Donald M.
, p. 1723 - 1730 (2007/10/02)
K-region arene oxides rearrange to phenols in acetonitrile in two acid-catalyzed steps: rapid rearrangement of the arene oxide to positionally isomeric keto tautomers of K-region phenols, followed by slow enolization. Accumulation of the ketones, proposed intermediates in the acid-catalyzed solvolyses of arene oxides in aqueous solution, allowed their direct spectroscopic observation and characterization for the first time under solvolytic conditions. Rate constants and products are reported for the K-region arene oxides of benz[a]anthracene, its 1-, 4-, 7-, 11-, 12-methyl, and 7,12-dimethyl substituted derivatives, benzo[a]pyrene, benzo[c]phenanthrene, 3-bromophenanthrene, chrysene, dibenz[a,h]anthracene, phenanthrene, and pyrene. No primary kinetic isotope effect is observed for ketone formation from phenanthrene 9,10-oxide. A linear correlation with a slope of 1.07 is observed between the logarithm of the second-order rate constants for acid-catalyzed reaction of the arene oxide at each K-region position in acetonitrile (first step) and in methanol (where ketone does not accumulate). Negative deviations from this correlation are observed for the formation of ketones in which the carbonyl oxygen is peri to a methyl substituent. These results are discussed in terms of a mechanism in which pseudoaxial opening of the epoxide gives an initial carbocation that must undergo conformational isomerization in order to produce phenolic products by migration of a pseudoaxial hydrogen. For compounds that follow the correlation, the rate-determining step in both methanol and acetonitrile is formation of the carbocation. For those compounds that deviate from the correlation and whose carbocations have their hydroxyl group in a peri position to a methyl ring substituent, the rate-determining step changes from formation of the carbocation (methanol) to its conformational inversion (acetonitrile). With few exceptions, NMR and kinetic evidence show that the regioisomeric K-region keto tautomers from a given arene oxide enolize with very similar rates (kslow). Rates of enolization are decreased by electron withdrawing groups and by steric factors that favor nonplanarity of the ring system. A large primary kinetic isotope effect (kH/kD = 4.4) is observed for the acid-catalyzed enolization of the K-region ketone derived from phenanthrene. Slow abstraction of a proton by the solvent acetonitrile from the α-methylene group of the O-protonated ketone is proposed to account for these results and for the fact that ketone does not accumulate in more basic solvents. The major driving force for enolization (kslow) is development of aromaticity in the phenol. For unsubstituted keto tautomers, a linear relationship, log kslow = 31.8-39.2 (X), is observed, where X is the Hu?ckel π-bond character for the K-region bond of the parent hydrocarbon.
Methanolysis of K-region arene oxides: Comparison between acid-catalyzed and methoxide ion addition reactions
Nashed, Nashaat T.,Bax, Ad,Loncharich, Richard J.,Sayer, Jane M.,Jerina, Donald M.
, p. 1711 - 1722 (2007/10/02)
Reactions of K-region arene oxides of benz[a]anthracene (BA-O) and its 1-(1-MBA-O), 4- (4-MBA-O), 7-(7-MBA-O), 11- (11-MBA-O), 12-methyl- (12-MBA-O), 7,12-dimethyl-(DMBA-O), and 7-bromo- (7-BrBA-O) substituted derivatives, benzo[a]pyrene (BaP-O), benzo[c]phenanthrene (BcP-O), benzo[e]pyrene (BeP-O), benzo[g]chrysene (BgC-O), chrysene (Chr-O), dibenz[a,h]anthracene (DBA-O), phenanthrene (Phe-O), 3-bromophenanthrene (3-BrPhe-O), and pyrene (Pyr-O) with acid and methoxide ion in methanol, are compared. For the acid-catalyzed reaction, products consist of cis- and trans-methanol adducts and phenols. There is no isotope effect on the ratio of phenols to solvent adducts produced from Phe-O or BcP-O when deuterium is substituted for the hydrogen that migrates. This observation is consistent with a mechanism in which product distribution in acid is determined by the relative rates of solvent capture and conformational inversion of a carbocation intermediate. As expected, only trans-methanol adducts, consisting of regioisomeric mixtures for unsymmetrical arene oxides, are formed from the reaction of methoxide ion with K-region arene oxides. The use of methanol permits the identification of products formed at each benzylic position of unsymmetrical arene oxides. Rate data for reactivity at each position could be fitted to the equation log kMeO/kMeOPhe-O = m(log kH/kHPhe-O) + b, where kMeO and kH are the second-order rate constants of the methoxide ion addition and acid-catalyzed reaction, respectively, and kMeOPhe-O and kHPhe-O are the corresponding rate constants for the reference compound phenanthrene oxide. A plot of log kMeO/kMeOPhe-O vs log kH/kHPhe-O for the reaction of 1-MBA-O, 12-MBA-O, DMBA-O, BcP-O, and BgC-O, which have either a methyl substituent in the bay region or a sterically crowded fjord region which affects the planarity of the molecules, defined one line (m = 0.31 ± 0.02, b = 0.67 ± 0.09), whereas a plot of the data for the reaction of the nearly planar arene oxides BA-O, 4-MBA-O, 7-MBA-O, 11-MBA-O, BaP-O, BeP-O, Chr-O, DBA-O, Phe-O, and Pyr-O defined a different line (m = 0.33 ± 0.07, b = -0.05 ± 0.05). The nonzero intercept for the sterically crowded, nonplanar arene oxides indicates a steric acceleration of their rates of methoxide ion addition. The positive slopes of both lines are consistent with an SN2 mechanism with an unsymmetrical transition state in which the epoxide C-O bond breaking is more advanced than the formation of the new C-O bond to methoxide ion, such that a partial positive charge is developed on the aromatic moiety.
