Synthesis of 5-(ethoxymethyl)-4-nitroso-1H-pyrazoles

Abstract

SHORT COMMUNICATIONSIn recent time, interest in new nitrosopyrazole derivatives has increased. Naphthyl-substituted nitrosopyrazoles have recently been synthesized by condensation of naphthyl-substituted 2-(hydroxyimino)-1,3-diketones with alkylhydrazines [1,2]. We continued studies in the field of cycloaromatization of derivatives of β-dicarbonyl compounds with the goal of obtaining nitrosopyrazoles containing an ethoxymethyl group. Such derivatives attract interest since transformation of a hydroxy or carboxy group in medicinal agents into ether or ester moiety is known to change the polarity of their molecules and improve their pharmacological activity [3].To achieve our goal, ethyl ethoxyacetate was reacted with acetone and acetophenone in the presence of sodium ethoxide in anhydrous diethyl ether according to the procedure described in [4]. As a result, we isolated 1-ethoxypentane-2,4-dione (1a) [4] and previously unknown diketone 1b. Nitrosation of diketones 1a and 1b with sodium nitrite in acid medium gave oximes 2a [5] and 2b, and the latter were treated with hydrazine hydrate in aqueous alkali. New nitrosopyrazoles 3a and 3b containing an ethoxymethyl group were isolated as green crystalline substances with sharp melting points.4-Ethoxy-1-phenylbutane-1,3-dione (1b). A mixture of 14.35 g (108 mmol) of ethyl ethoxyacetate and 13.04 g (108 mmol) of acetophenone in 100 mL of anhydrous diethyl ether was added to a flask charged with 100 mL of anhydrous diethyl ether and freshly prepared sodium ethoxide [from 2.5 g (108 mmol) of sodium and 50 mL of ethanol, followed by evaporation to dryness under reduced pressure]. The mixture was heated on a water bath, sodium ethoxide rapidly dissolved, and the mixture was heated for 40 min more. The mixture was then treated with 100 mL of water, and the aqueous layer was extracted with diethyl ether. The diethyl ether layer was separated, and the aqueous layer was acidified with sulfuric acid to a weakly acidic reaction (litmus) and extracted with diethyl ether (4 × 25 mL). The extract was dried over anhydrous sodium sulfate and evaporated on a water bath, and the residue was distilled under reduced pressure. Yield 3 g (15%), bp 186°C (12 mm). 1 H NMR spectrum, δ, ppm: 1.13 t (3H, CH 3 , J = 7.0 Hz), 3.5 q (2H, CH 2 , J = 6.8 Hz), 4.76 s (2H, CH 2 ), 7.59 t (2H, H arom , J = 7.7 Hz), 7.74 t (1H, H arom , J = 7.4 Hz), 7.82 d (2H, H arom , J = 7.4 Hz), 13.12 s (1H, OH, enol). Mass spectrum, m/z (I rel , %): 206 (7) [M] + , 105 (100), 77 (68), 59 (62), 189 (13), 106 (9), 131 (7). Found, %: C 69.98; H 6.79. C 12 H 14 O 3 . Calculated, %: C 69.88; H 6.84. M 206.24. 4-Ethoxy-3-(hydroxyimino)-1-phenylbutane-1,3dione (2b). A solution of 1.06 g (15 mmol) of sodium R = Me (a), Ph (b).

Experimental and theoretical study of the acylation reaction of aminopyrazoles with aryl and methoxymethyl substituents

“…Earlier, we reported the synthesis of new derivatives of alkoxymethylnitrosopyrazoles [20], their reduction to aminopyrazoles [21] and their acylation [22]. The present work is devoted to the preparation of previously unknown 4-nitroso-1H-pyrazole derivative with methoxymethyl and 2naphthyl substituents, its reduction to amine with further acylation by acetic anhydride or chloroacetyl chloride.…”