Strong deshielding in aromatic isoxazolines

Abstract

Very strong proton deshielding was found in di/tri-aromatic isoxazoline regioisomers prepared from acridin-4-yl dipolarophiles and stable benzonitrile oxides (BNO). Three alkenes, (acridin-4-yl)-CH=CH-R (R = COOCH3, Ph, and CONH2), reacted with three BNO dipoles (2,4,6-trimethoxy, 2,4,6-trimethyl, 2,6-dichloro) to give pairs of target isoxazolines with acridine bound to C-4 or C-5 carbon of the isoxazoline (denoted as 4-Acr or 5-Acr). Regioselectivity was dependent on both the dipolarophile and dipole character. The ester and amide dipolarophile displayed variable regioselectivity in cycloadditions whereas the styrene one afforded prevailing 4-Acr regioisomers. 2,4,6-Trimethoxy-BNO was most prone to form 5-Acr isoxazolines while mesitonitrile oxide gave major 4-Acr isoxazolines. Basic hydrolysis of the amide cycloadduct led to an unexpected isoxazolone product. The structure of the target compounds was studied by NMR, MS, and X-ray crystallography.

Prediction by 13C NMR of regioselectivity in 1,3‐dipolar cycloadditions of acridin‐9‐yl dipolarophiles

“…The coupling constant 16.4 Hz confirmed the trans ( E ) configuration on the CHCH bond in both 4 and 5 – none cis ( Z ) isomers were detected in the crude reaction mixtures. Owing to a shielding effect of the close symmetrical acridin‐9‐yl moiety, both alkene proton signals of (acridin‐9‐yl)alkenes 4 and 5 were shifted by Δ∆ δ = −0.45 – −0.82 ppm more upfield than in (acridin‐4‐yl)alkenes, methyl 3‐(acridin‐4‐yl)propenoate ( 4 *) and 4‐(2‐styryl)acridine ( 5 *) (Table ). Concerning polarization of the CHCH bond expressed via 1 H chemical shifts of olefinic protons in the esters 4 , 4 *, and 3‐(acridin‐4‐yl)propenamide ( 6 *), β protons vicinal to acridine were, as expected, more deshielded by 1.56–2.06 ppm than α protons owing to the − M effect of the ester (amide) moiety.…”

“…1,3‐Dipolar cycloadditions of methyl 3‐(acridin‐9‐yl)propenoate ( 4 ) with nitrile oxides 6a–c were studied in the same conditions as recently in a molar ratio 1:3 at room temperature in dry chloroform (Scheme ). They proceeded slowly despite a triple excess of the dipole had been used.…”

“…In our previous study we have shown that acridine isoxazolines, which combine favorable chemical and biological properties of both building blocks, show unusually high 1 H NMR chemical shifts of isoxazoline skeletal protons resulting from a confined arrangement of two or three aromatic species within these molecules. Here we present a new observation that regioselectivity in dipolar cycloadditions affording the title compounds can be successfully predicted from 13 C chemical shifts of a CHCH bond in starting (acridin‐9(4)‐yl) dipolarophiles.…”

“…As model compounds for this study, two alkene dipolarophiles possessing an acridin‐9‐yl substituent have been chosen, the reactions and NMR characteristics of which we wanted to compare with our dipolar cycloadditions of three acridin‐4‐yl dipolarophiles with the same BNOs . The motif for that choice was a distinct dissimilarity of electronic and steric effects of acridin‐9‐yl versus acridin‐4‐yl cores on the alkene attached—acridine nitrogen in acridin‐9‐yl dipolarophiles (N‐10′) elicits a significant withdrawing effect on the bound 9‐alkene, while in acridin‐4‐yl dipolarophiles the acridine flanking ring and alkene substituent on C‐4 compose an aromate‐alkenoate/aromate‐alkene system similar to cinnamate/stilbene, respectively.…”

“…To examine substituent effects on the reaction course, two starting acridin‐9‐yl‐alkene dipolarophiles with COOCH 3 or phenyl substituent on the other alkenic carbon were prepared. As the dipoles, the same three nitrile oxides (BNO), 2,4,6‐trimethoxybenzonitrile oxide ( 6a ), mesitonitrile oxide ( 6b ), and 2,6‐dichlorobenzonitrile oxide ( 6c ) as before were used in this work.…”