Selective Functionalization of Benzo‐Fused N‐Heterocycles by Using In Situ Trapping Metalations

Abstract

We have prepared some benzo-fused N-heterocycles derivatives by regioselective metalation of quinoline, isoquinoline, quinoxaline, and quinazoline with LiTMP in the presence of zinc chloride. Applying this strategy to synthesize an analog of the antitumor verubulin illustrates its relevance for medicinal chemistry. Computational calculations of the pK a values of the aromatic hydrogens have helped us to rationalize substrate reactivity and metalation regioselectivity by the complexinduced proximity effect concept.

Regioselective Functionalization of Ester-, Amide-, Carbonate-, and Carbamate-Substituted 2-Phenyl-2-oxazolines with Mixed Lithium–Magnesium Amides

“…DFT calculations have been used to investigate how substrate complexation with metal amides and salts affects the regioselectivity and deprotonation rates. , Here, we employed DFT calculations to investigate how oxazoline group coordination with both LiCl and TMPMgCl influenced the acidity of the aromatic hydrogens of substrates 1a – c (see Experimental Section). While the acidity of the hydrogens that are in the vicinity of the 2-oxazoline group that coordinates to both reagents (LiCl and TMPMgCl) clearly increased, coordination of the substrates with TMPMgCl appeared to generate more stable complexes and to affect the p K a values more significantly.…”

Synthesis of 7-Chloroquinoline Derivatives Using Mixed Lithium-Magnesium Reagents

“…We computed the p K a values by employing hypothetical reactions between the heterocycle and pyridine (reference) in THF, as described in the literature. , As expected, H-8 was the most acidic (p K a : 34.8), being much more acidic than H-3 (p K a : 38.4). Moreover, coordination of the quinoline nitrogen with ZnCl 2 should significantly affect the p K a of the adjacent hydrogens, favoring selective deprotonation of H-8 (See the SI).…”

“…67,68 As expected, H-8 was the most acidic (pK a : 34.8), being much more acidic than H-3 (pK a : 38.4). Moreover, coordination of the quinoline nitrogen with ZnCl 2 should significantly affect the pK a of the adjacent hydrogens, 69 favoring selective deprotonation of H-8 (See the SI).…”

Efficient N-arylation of 4-chloroquinazolines en route to novel 4-anilinoquinazolines as potential anticancer agents

“…Surprisingly, further reaction of 4-chloro-8-iodoquinazoline with 4-methoxy-N-methylaniline was not efficient under various reaction conditions and afforded the desired product in low yields even in basic medium (AcONa). To address this issue, we investigated a microwave-mediated base-free amination strategy involving a mixture of THF and water (1:1) as solvent system, which furnished the desired verubulin analog in 87% yield (Scheme 2) [27].…”