Pd-Catalyzed Chemoselective O-Benzylation of Ambident 2-Quinolinone Nucleophiles

Abstract

We have discovered and developed a highly chemoselective O-benzylation of ambident 2-quinolinone nucleophiles via Pd-catalysis. Detailed reaction analysis using direct-injection high resolution mass spectrometry (DI-HRMS) combined with in situ 31P NMR implicate a phosphine mono-oxide Pd­(II) η1-benzyl complex as a key intermediate on the catalytic cycle. Extrapolation of this method to selectively O-alkylate a series of substituted 2-quinolinones using several benzylic electrophiles is demonstrated providing 2-benzyloxy quinolines in good yields and high O:N selectivities (up to 100:1) utilizing as little as 1 mol % Pd-catalyst to achieve these results.

Synthesis of N-Alkyl-3-[2-oxoquinolin-1(2H)-yl]propanoic Acid Derivatives and Related Compounds: Cytotoxicity and EGFR Inhibition of Some Propanamide Derivatives

“…Thus, quinolin-2-one selectively gave the N-substituted quinolin-2-one by the reaction with electrophiles; alkyl halides, aroyl halides in the presence of bases; potassium carbonate, sodium hydride, KOH, and cesium carbonate at room temperature to 80 °C in DMF and, in some cases, under inert atmosphere. − Alkylation using unsaturated compounds afforded the N-substituted quinolone in 7% yield by the reaction with N -(quinolin-6-yl) acrylamide in the presence of palladium diacetate in acetonitrile at 120 °C for 24 h in a sealed tube . However, the reaction of quinolin-2-one with substituted benzyl chloride derivatives in the presence of dichloro [9,9-dimethyl-4,5-bis­(diphenylphosphino)­xanthene]­palladium­(II); potassium carbonate in toluene at 100 °C afforded either the O-substituted quinolone or a mixture of both O- and N-substituted quinolone derivatives . Chemoselective reactions of heterocyclic amides with electrophiles were extensively investigated by our research group to afford either N-substituted, O-substituted, or a mixture of both.…”

“… 21 However, the reaction of quinolin-2-one with substituted benzyl chloride derivatives in the presence of dichloro [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II); potassium carbonate in toluene at 100 °C afforded either the O-substituted quinolone or a mixture of both O- and N-substituted quinolone derivatives. 22 Chemoselective reactions of heterocyclic amides with electrophiles were extensively investigated by our research group to afford either N-substituted, O-substituted, or a mixture of both. These results were used to structure and modify several heterocyclic systems and were supported by theoretical DFT calculations to predict the site of alkylation.…”

Deciphering the Differences in Ambident Reactivity between the Cyanate, Thiocyanate Ions, and their P‐ and As‐Containing Analogues

“…[1][2][3][4][5] Investigations aiming for a deeper understanding of ambident reactivity are crucial for developing and controlling new regioselective or even regiospecific reactions. [6][7][8][9][10][11][12][13][14] Unquestionably, the cyanate [NCO] À and thiocyanate [NCS] À anions are among the most known textbook examples of ambident nucleophiles, [15][16][17] and their ambident behaviours can be well represented by two leading resonance structures (Figure 1A). Their Se-containing analogue, the selenocyanate, [NCSe] À anion, is also known but lesser explored.…”

“…Ambident nucleophiles, species that can undergo the same type of chemical transformations at two (or more) reacting sites with the same electrophile, have an unquestionably important role in several aspects of organic synthesis [1–5] . Investigations aiming for a deeper understanding of ambident reactivity are crucial for developing and controlling new regioselective or even regiospecific reactions [6–14] …”