Synthesis of 3-aminomethyl-substituted pyrazoles and isoxazoles

Abstract

A series of new 3-(aminomethyl)pyrazoles and 3-(aminomethyl)isoxazoles was synthesized along a route involving the formation as key intermediates of esters of 5-substituted 1Н-pyrazole-3-carboxylic and 1Н-isoxazole-3-carboxylic acids. All compounds obtained were characterized by physicochemical constants, IR, 1 Н, 13 С NMR, and mass spectra.Many functionally substituted pyrazoles and isoxazoles possess a wide range of pharmacologic activity [1-3]. For instance, 3-pyrazole-and 3-isoxazolecarboxylic acids А and B having alkyl or aryl substituents in the positions 4 and (or) 5 are antagonists of niacinic receptors and analogs of nicotinic acid C (niacin) and of acipimox D used in the medical praxis in the atherosclerosis treatment [4][5][6].Pyrazoles and isoxazoles with substituent of the basic character of E and F type are far less understood. They underlie the synthesis of selective inhibitors of enzymes, like factor Xa, and blood anticoagulants [7]. At the same time the known procedures for the preparation of compounds of E and F type apply diffi cultly available reagents [3,8] or unstable compounds like azides [9] or organometallic derivatives [7]. Therefore the search for more convenient synthetic methods for their preparation is urgent.In this study we performed the synthesis of aminomethyl derivatives of heterocycles of E and F type along a scheme involving the condensation of various ketons I with diethyl oxalate (Claisen reaction) followed by the cyclocondensation of the intermediate α,γ-diketone II with hydrazine or hydroxylamine [1-6].As a result substituted in the ring esters of 3-pyrazoleor 3-isoxazolecarboxylic acids III and IV were obtained. Therewith the cyclocondensation of diketones IIe and IIf with the hydroxylamine proceeded regioslectively. In event of diketones IIa and IIb alongside the 3-ethoxycarbonyl derivatives also 5-ethoxycarbonyl-substituted isoxazoles were obtained in a ratio 9:1. Further compounds III, VI were subjected to ammonolysis or aminolysis with methylamine with the subsequent reduction of amides IV, VII into the corresponding amines V, VIII. Amides IV of the substituted 3-pyrazolecarboxylic acids were reduced with LiAlH 4 , and amides VII of the substituted 3-isoxazolecarboxylic acid, with the help of BH 3 obtained in situ from NaBH 4 and BF 3 ·Et 2 O. The latter procedure was required for the reaction of amides VII with LiAlH 4 occurred nonselectively with the formation of a large number of side products. In both cases THF was used as solvent.

Visible Light-Induced Coupling Cyclization Reaction of α-Diazosulfonium Triflates with α-Oxocarboxylic Acids or Alkynes

“…Following the general procedure, 5n was isolated by flash chromatography on silica (EtOAc/PE = 2/5) as a yellow solid (24.4 mg, 55% yield); 1 H NMR (600 MHz, CDCl 3 ): δ 11.55 (s, 1H), 7.37 (d, J = 3.5 Hz, 1H), 7.80–7.01 (m, 1H), 7.30 (d, J = 5.0 Hz, 1H), 7.01 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13 C­{ 1 H} NMR (151 MHz, CDCl 3 ): δ 160.1, 145.6, 137.7, 134.0, 127.6, 125.4, 124.6, 105.5, 61.4, 14.1; HRMS­(ESI-TOF): [M + Na] + calculated for C 10 H 10 N 2 NaO 2 S + : 245.0355, found: 245.0362. The NMR data are consistent with the reported values …”

“…Following the general procedure, 5m was isolated by flash chromatography on silica (EtOAc/PE = 2/5) as a yellow oil (20.0 mg, 40% yield); 1 H NMR (500 MHz, CDCl 3 ): δ 12.22 (s, 1H), 7.71−7.69 (m, 1H), 7.47−7.45 (m, 1H), 7.31−7.28 (m, 2H), 7.26 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13 Ethyl 5-(Thiophen-2-yl)-1H-pyrazole-3-carboxylate (5n). Following the general procedure, 5n was isolated by flash chromatography on silica (EtOAc/PE = 2/5) as a yellow solid (24.4 mg, 55% yield); 1 H NMR (600 MHz, CDCl 3 ): δ 11.55 (s, 1H), 7.37 (d, J = 3.5 Hz, 1H), 7.80−7.01 (m, 1H), 7.30 (d, J = 5.0 Hz, 1H), 7.01 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13 32 Ethyl 5-(Thiophen-3-yl)-1H-pyrazole-3-carboxylate (5o). Following the general procedure, 5o was isolated by flash chromatography on silica (EtOAc/PE = 2/5) as a yellow solid (20.0 mg, 45% yield); mp 165−166 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 11.52 (s, 1H), 7.62−7.61 (m, 1H), 7.44 (m, 1H), 7.39 (m, 1H), 6.99 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); 13…”

The First Example of Azole-Fused Cyclic Anhydride Reacting in the Castagnoli–Cushman Way

“…Ethyl 3-(thiophen-2-yl)-1H-pyrazole-5-carboxylate (9d). 4 Yield 8.9 g (40%) after recrystallization. 1 H NMR (400 MHz, CDCl 3 +DMSO-d 6 (5:1)) δ 7.33 (dd, J = 3.6, 1.0 Hz, 1H), 7.21 (dd, J = 5.1, 1.0 Hz, 1H), 6.99 (dd, J = 5.1, 3.6 Hz, 1H), 6.85 (s, 1H), 5.90 (br.s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).…”

“…Ethyl 3-(tert-butyl)-1H-pyrazole-5-carboxylate (9e). 4 Yield 11.0 g (59%). 1 H NMR (400 MHz, CDCl 3 ) δ 6.67 (s, 1H), 6.28 (br.s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.37 (s, 9H).…”