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.
Different synthetic approaches to functionally substituted benzylamines were examined: reductive amination of alkyl aryl ketones and reduction of aromatic aldehyde oximes. The most efficient procedures were used to prepare a series of previously unknown hydroxy-, alkoxy-, and halogen-substituted benzylamines.Benzylamines are widely used in the synthesis of enzyme inhibitors [1][2][3][4][5] and compounds exhibiting analgesic [3], antithrombotic [2], antibacterial [6], fungicidal [7], and other kinds of biological activity. Benzylamines are usually prepared by reductive amination of carbonyl compounds [8-12] and reduction of the corresponding oximes, nitriles, or azines. Oximes can be reduced with sodium amalgam [13], metallic sodium in liquid ammonia [14, 15], Mg-HCOONH 4 -MeOH [16], Raney nickel-EtOH-base [17-19], LiAlH 4 [10], NaBH 4 -TiCl 4 [20], and NaBH 4 -LiCl-Amberlyst [21]. Oxime ethers, nitriles, and azines were also reduced in the presence of Pd/C [19,22,23]. However, despite diversity of methods for the preparation of benzylamines, there are very limited published data on the synthesis of benzylamines with hydroxy and alkoxy groups in the aromatic ring [11,13,[16][17][18]21].In the present work we examined different synthetic approaches to functionally substituted benzylamines, primarily to those containing hydroxy and alkoxy substituents. In particular, such standard procedures as hydride reduction of aldehyde and ketone oximes with LiAlH 4 , reduction of ketone oximes with sodium in liquid ammonia, and reductive amination of ketones according to Leuckart-Wallach were studied.In the first step of our study we examined the possibility for synthesizing functionally substituted 1-phenylalkan-1-amines by reduction of the corresponding aromatic ketone oximes with LiAlH 4 ; as model substrates we used acetophenone oxime and its O-methyl ether. Both these substrates were completely reduced in boiling THF in 3 h, but the reactions were not selective: apart from the target 1-phenylethanamine, secondary N-ethylaniline was formed as a result of side Beckmann rearrangement followed by reduction of intermediate acetanilide. In the reaction with acetophenone oxime the ratio 1-phenylethanamine-N-ethylaniline was 1 : 1.5, and in the reduction of acetophenone O-methyloxime both products were formed in equimolar amounts. The reduction of acetophenone oxime with the system LiAlH 4 -Me 3 SiCl was more selective, and the ratio of 1-phenylethanamine and N-ethylaniline was 3 : 1. With a view to obtain functionally substituted benzylamine, 1-(4-hydroxyphenyl)ethanamine, the corresponding oxime was reduced with sodium in liquid ammonia. This reaction was not accompanied by side Beckmann rearrangement, and the target product was formed in high yield. As far as we known, we were the first to apply this procedure for the reduction of an aromatic ketone oxime having a hydroxy group in the aromatic ring. However, the use of sodium in liquid ammonia for the reduction of ketone oximes is strongly limited. For example, alkoxy-substitu...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.