Switchable highly regioselective synthesis of 3,4-dihydroquinoxalin-2(1H)ones from o-phenylenediamines and aroylpyruvates

Abstract

3-Acylmethylidene-3,4-dihydroquinoxalin-2(1H)-ones are compounds which possess a wide range of physical and pharmaceutical applications. These compounds can be easily prepared by cyclocondensation of o-phenylenediamines and aroylpyruvates. Unsymmetrically substituted o-phenylenediamines can be obtained form regioisomeric mixtures of 3,4-dihydroquinoxalin-2(1H)-ones. It is often quite difficult to get a pure regioisomer and determine its structure without controlling the reaction selectivity and exploitation of complex NMR techniques (HSQC, NOESY, HMBC). This article examines the regioselectivity of the cyclocondensation between six monosubstituted o-phenylenediamines (-OMe, -F, -Cl, -COOH, -CN, -NO2) and the derivatives of p-chlorobenzoylpyruvate (ester or acid) which we studied. Six regioisomeric 3,4-dihydroquinoxalin-2(1H)-one pairs were selectively prepared and characterised. Based on our experiences, a simplified methodology for determining the structure of the regioisomers was proposed. We developed two general and highly selective methodologies starting from the same o-phenylenediamines and activated 4-chlorobenzoylpyruvates (ester or acid) enabling switching of 3,4-dihydroquinoxalin-2(1H)-one regioselectivity in a predictable manner. For comparison, all regioselective cyclocondensations were performed with the same standardized conditions (DMF, rt, 3 days), differing only by the additives p-TsOH or HOBt/DIC (hydroxybenzotriazole/N,N’-diisopropylcarbodiimide). Both selected methods are simple, general and highly regioselective (72–97%). A mechanism for the regioselectivity was also proposed and discussed. This study can be used as a guide when choosing the most optimal reaction conditions for the synthesis of the desired 3,4-dihydroquinoxalin-2(1H)-one regioisomers with the best selectivity. The demonstrated methodologies in this article may also be applied to differently substituted 3,4-dihydroquinoxalin-2(1H)-ones in general, which could expand the synthetic impact of our results.

Synthesis of 1,4-benzothiazinones from acylpyruvic acids or furan-2,3-diones and o-aminothiophenol

“…To develop an approach to target the BTAs III, we analyzed the general synthetic methods to enaminones I and II, which involve the reaction of the acylpyruvic acids or their esters IV, 5-arylfuran-2,3-diones V, and acetylenedicarboxylates VI with o-aminophenols or o-phenylenediamines (Scheme 3) [1][2][3][4][5][6].…”

“…These two approaches could be used as interchangeable in the synthesis of BTAs 3. The furandione-based approach gave less side products, but the yield of the BTA 3 was lower and, sometimes, furandiones 5 were difficult to be synthesized [2]. The acylpyruvic acid-based approach gave higher yields of the target compounds 3, involved available reagents, but produced more waste.…”

“…Enaminones fused to the 1,4-benzoxazine-2-one I or quinoxaline-2(1H)-one II moiety ( Figure 1) represent an intensively investigated class of enamines. Undying interest in these compounds is due to the simplicity of their synthesis and purification, the availability of starting materials and the possibility of their synthesis under mild green conditions [1][2][3][4][5][6]. Because of their availability in gram-scale quantities, these compounds were thoroughly investigated for the possibility of practical use.…”

Facile Synthesis of Regioisomeric N‐Alkyl Substituted 3‐Methylene‐3,4‐dihydroquinoxalin‐2(1H)‐ones

“…Installation of different substituents in QOs molecules is crucial for their pharmacological evaluation. Set up by these circumstances, regioselective strategies towards QOs from monosubstituted at benzene ring o ‐phenylenediamines were thoroughly developed …”