Reaction of esters of 2-arylcyclo-propanecarboxylic acids with nitrous acid. Synthesis of aryl-substituted 3-ethoxycarbonyl-4,5-dihydroisoxazoles and 3-ethoxycarbonylisoxazoles

Abstract

Esters of 2-arylcyclopropanecarboxylic acids react with nitrous acid generated in situ with regioselective insertion of the nitrosyl cation into the cyclopropane ring. Depending on the substrate/nitrosylating agent ratio, the reaction proceeds with the formation of either aryl-substituted 3-ethoxycarbonyl-4,5-dihydroisoxazoles or the corresponding isoxazoles. The nature and position of the substituents in the aromatic ring of the starting 2-arylcyclopropanecarboxylic acid esters affect the reaction rate but have no effect on the regioselectivity of the attack by the nitrosyl cation on the three-membered ring. A dependence of the reactivity of isomeric substrates on their stereochemistry and position of the nitro group in the aromatic ring is noted for 2-and 4-nitrophenyl derivatives of esters of cis-and trans-2-arylcyclopropanecarboxylic acids.Keywords: 5-aryl-3-ethoxycarbonyl-4,5-dihydroisoxazoles, 5-aryl-3-ethoxycarbonylisoxazoles, ethyl esters of 2-arylcyclopropanecarboxylic acids, insertion of the nitrosyl cation into the cyclopropane ring.The reaction of arylcyclopropanes with nitrosylating agents, which proceeds through insertion of the nitrosyl cation or nitrosyl radical into the cyclopropane ring, may be seen as one of the most efficient methods for the synthesis of aryl-substituted 4,5-dihydroisoxazoles and isoxazoles, which are potential pharmaceutical agents and important precursors for the preparation of biologically-active compounds, including natural products [1][2][3][4][5][6].

Heterocyclization of trans-1,2,3-triphenyl-cyclopropane using nitrous acid

“…This result shows that triphenylcyclopropanes can be used successfully in the synthesis of the corresponding isoxazolines. We have previously reported that dihydroisoxazoles prepared from phenylcyclopropanes using an equivalent of HNO 2 can be oxidized to the corresponding isoxazoles using one equivalent of this reagent [4]. These same arylisoxazoles can also be directly formed from arylcyclopropanes if two equivalents of nitrous acid are used [4,5].…”

“…We have previously reported that dihydroisoxazoles prepared from phenylcyclopropanes using an equivalent of HNO 2 can be oxidized to the corresponding isoxazoles using one equivalent of this reagent [4]. These same arylisoxazoles can also be directly formed from arylcyclopropanes if two equivalents of nitrous acid are used [4,5]. It was found that reaction of hydrocarbon 1 with two equivalents of HNO 2 does not give rise to 3,4,5-triphenylisoxazole but, in this case, yields isoxazoline 2 (81%) and trans-3,5-diphenyl-4-(4-nitrophenyl)-4,5-dihydroisoxazole (3) (14%).…”

“…under nitrous acid oxidation conditions when compared with monophenylated analogs. It was interesting that treatment of the nitrophenylisoxazoline 3 with one equivalent of HNO 2 or of the hydrocarbon 1 with three equivalents of HNO 2 gave, in both cases, a high yield of the 4-(4-nitrophenyl)-3,5-diphenylisoxazole (4).…”

Nitration of aryl cyclopropyl ketones using HNO2

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Arylcyclopropanes containing electron-acceptor substituents in both the benzene and the small ring react with in situ generated nitrous acid with the insertion of an N=O fragment into the three-carbon ring resulting in the formation of substituted isoxazoles and isoxazolines [1][2][3]. We have proposed that aryl cyclopropyl ketones containing an electron-donor type aryl fragment can also be converted to the corresponding heterocycles in the presence of the indicated nitrosylating agent.

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“…Calculated, %: C 59.73; H 5.01; N 6.33. 5-Cyclopropylcarbonyl-2-nitrothiophene (4) was prepared from the cyclopropyl 2-thienyl ketone(2). Yield 93% (based on the starting material undergoing the reaction); mp 104-105ºC (hexane).…”