Synthesis of 3-Alkylbenzoxazolones fromN-Alkyl-N-arylhydroxylamines by ContiguousO-Trichloroacetylation, Trichloroacetoxyortho-Shift, and Cyclization Sequence

Abstract

Benzoxazolone pharmacophore is present in clinical pharmaceuticals, drug candidates, and many compounds having a wide spectrum of biological activities. The methods available for the synthesis of benzoxazolones have limited diversity due to problems in accessibility and air-sensitivity of diversely substituted o-aminophenols from which they are generally prepared by cyclocarbonylation with phosgene or its equivalents. The present paper describes a mild method for the synthesis of 3-alkylbenzoxazolones from easily accessible and air-stable nitroarenes. Nitroarenes were converted to N-alkyl-N-arylhydroxylamines in two steps involving partial reduction to arylhydroxylamines followed by selective N-alkylation. Treatment of N-alkyl-N-arylhydroxylamines with trichloroacetyl chloride and triethylamine afforded 3-alkylbenzoxazolones generally in good yields through an uninterrupted three-step sequence involving O-trichloroacetylation, N→C(ortho) trichloroacetoxy shift, and cyclization in a single pot at ambient temperatures. The present method is mild, wide in scope, economical, and regioselective. Many sensitive groups like alkyl and aryl esters, amide, cyano, and the carbon-carbon double bond survive the reaction.

The Photocatalyzed Aza-Henry Reaction of N-Aryltetrahydroisoquinolines: Comprehensive Mechanism, H•- versus H+-Abstraction, and Background Reactions

“…The carbon atom at position C3 is shifted upfield from 48.0 ppm @280 K (THIQ 1) to 46.1 ppm @280 K (intermediate 10). Compared to literature values [14][15][16][17] the C3 carbon is expected to be shifted [18] corroborate our assignment. 2 Further, a ring closure between 15 N12 and N2 would result in a 3 J NH coupling of N12 and H3 which in analogy to the product should be detectable in the 1 H, 15 N-hmbc and a 2 J CN coupling of N12 and C3, which should be detectable in the proton decoupled 13 C spectra.…”

“…For analysis Bruker Avance 400 ( 1 H: 400 MHz, 13 C: 101 MHz, T = 300 K) or Bruker Avance 300 ( 1 H: 300 MHz, 13 C: 75 MHz, T = 295 K) spectrometer were used. Tetramethylsilane (δ = 0 ppm) or the solvent residual peak (NO 2 Me-d 3 : 1 H δ = 4.33 ppm; 13 C δ = 63.0 ppm; 15 N δ = 380.9 ppm (280 K); CDCl3: 1 H δ = 7.26 ppm; 13 C δ = 77.0 ppm) was used as reference. The data were processed with Brukers Topspin 3.2.…”

“…The integral (1H) and carbon chemical shift at C1 hint towards a double bond at this position. The coupling between the nitrogen atom N12 and C1 was proven by 15 N labeled nitromethane, showing 1 H, 15 N-hmbc cross peaks between N12-H1 and N12-H13 (see Figure S6). The cross peak detected in the 1 H, 13 C-hmbc between C1 and C13 is due to a 3 J CH coupling, because a 2 J CH coupling would imply a 3 J HH coupling between H1 and H13, what is not the case.…”

“…By phase sensitive 1 H, 13 C-hsqc spectra a cross peak between 2.61 and 41.5 ppm (CH or CH 3 group) was detected. Additionally, this CH/CH 3 -groupe is bound to a nitrogen atom, as 1 H, 15 N-hmbc spectra revealed a cross peak between 2.61 and 118.3 ppm. The amine and hydroxyl proton could not be observed due to fast exchange in water.…”

“…The intermediates were characterized and assigned by NMR in the reaction mixture. The intermediate species 10 was assigned by 1D ( 1 H, 13 C) and 2D ( 1 H, 1 H-noesy, 1 H, 1 H-cosy, 1 H, 1 Htocsy 1 H, 13 C-hmbc, 1 H, 13 C-hsqc, 1 H, 15 detectable for all other THIQ specieshints towards a spin barrier between C1 and C3, which can occur because of a ring opening or insertion of a nitrogen or oxygen atom between position C1 and N2, as the C3-C9a coupling is not affected (Figure S5). The carbon atom at position C3 is shifted upfield from 48.0 ppm @280 K (THIQ 1) to 46.1 ppm @280 K (intermediate 10).…”