Introduction

Substituted isoxazolo[5,4-b]pyridines and their condensed derivatives are compounds with high biological potential. They are characterized by a wide range of pharmacological activity, including antitumor activity.1 The promising nature of this group of compounds is confirmed by the high potential of isoxazolo[5,4-b]pyridines in the field of agrochemistry: many derivatives have pronounced pesticidal activity and are also herbicide antidotes.2 This microreview presents the most significant publications on the methods of synthesis of the isoxazolo[5,4-b]pyridine system over the 2016–2020 period.

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Syntheses based on reactions of 5-aminoisoxazoles with 1,3-dielectrophiles

5-Amino-3-methylisoxazole (1) is the most accessible and versatile starting material for the preparation of isoxazolo-[5,4-b]pyridines. Review articles3 considered earlier examples of the preparation of isoxazolopyridines based on heterocyclization reactions of 5-aminoisoxazole with 1,3-electrophilic agents. Among the newest approaches, a simple method for the preparation of substituted isoxazolopyridines from compound 1 and Mannich bases 2 in pyridine under reflux is notable.4 The resulting products 3 exhibit antitumor activity.

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4-Acyl-1H-pyrrole-2,3-diones 4 undergo recyclization upon treatment with isoxazole 1 to form α-ketoamides 5 in good yields.5

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Functionalization of the isoxazolopyridine system at position 6 can be achieved by introducing isoxazole 1 into the reaction with keto esters 6. Compounds 7 were obtained in moderate yields upon heating, while under milder conditions, partially hydrogenated analogs, for example, compounds 8, can be isolated.6

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Ludmila Vsevolodovna Dyadyuchenko defended her PhD thesis in Chemistry in 1989. At present, she is Head of the Laboratory of plant growth regulators at the All-Russian Research Institute of Biological Plant Protection. Her research interests: chemistry of nitrogen-containing heterocycles, synthesis of biologically active substances.

Victor Victorovich Dotsenko was born in Voroshilovgrad (Lugansk) in 1976, Doctor of Sciences in Chemical Sciences (2015). His research interests: chemistry of O,S,Se,N-heterocycles, chemistry of active methylene nitriles and thioamides, cascade reactions.

Syntheses based on reactions of 5-aminoisoxazoles with 1,3-dielectrophiles (continued)

The domino reaction of chromone-3-carboxylic acids 9 with 5-aminoisoxazoles 1 yielded a series of polynuclear heterocyclic compounds 10 exhibiting fluorescence and the ability to inhibit the activity of the enzyme ecto-5'-nucleotidase.7

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Syntheses based on hydroxylamine

Condensation of hydroxylamine with the available 2-substituted nicotinonitriles is a convenient alternative to the above-considered aminoisoxazole-based methods.8,9 Some of the limitations of this approach to the preparation of isoxazolo[5,4-b]pyridines include the difficult to predict dependence of the regiodirectivity of the reaction on the reaction conditions. Thus, nicotinonitrile 11 reacts with NH2OH in anhydrous MeOH to form the target product 12, whereas a mixture of the corresponding amidoxime 13 and nicotinamide 14 is formed in an aqueous ethanol solution.8

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At the same time, the reaction of nicotinonitriles 15 with acetohydroxamic acid in DMF leads to, along with the expected isoxazolopyridines 17, hydrolysis products 16; in an aqueous medium, the target products 17 were obtained in 80–93% yields.10

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Isoxazolo[5,4-b]pyridines 19 were synthesized in low yields by the reaction of chloroximes 18 with malononitrile dimer in the presence of a strong base.11

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Multicomponent syntheses of isoxazolo[5,4- b ]pyridines

An analysis of various strategies for multicomponent synthesis of heterocyclic systems (including isoxazolo[5,4-b]pyridines) based on the Michael and Hantzsch reactions is presented in reviews.3b,12 In recent publications, multicomponent synthesis of isoxazolo[5,4-b]pyridines is represented by a wide range of examples, where the key reagent is 5-aminoisoxazole, whereas aldehydes, dicarbonyl compounds, isatins, etc. are used as the other heterocyclization components. Thus, the three-component reaction of isoxazole 1 with aromatic aldehydes and ketoamide 20 makes it possible to obtain isoxazolo[5,4-b]-pyridines 21 which exhibit antitumor activity.13

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Condensation of arylglyoxal hydrate 22, 4-hydroxycoumarin (23), and isoxazole 1 under the conditions of microwave activation leads to the formation of annulated isoxazolo[5,4-b]pyridines 24 in high yields.14

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A detailed analysis of the three-component reaction of 5-amino-3-methylisoxazole (1) with aromatic aldehydes and Meldrum’s acid (25) is presented in a study.15 It was shown that under irradiation by ultrasound in EtOH, the reaction leads to the formation of spirocycles 26, while during reflux in n-BuOH, the products are compounds 27. According to the authors of the study,15 compounds 26 are the reaction products formed under kinetic control, while compounds 27 are formed under thermodynamic control conditions. The yields of spirocycles 26 predictably increase when 2 equiv of the aldehyde is used.

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Multicomponent syntheses of isoxazolo[5,4- b ]pyridines (continued)

Isatins are often used for the synthesis of spiroisoxazolo[5,4-b]pyridines via multicomponent reactions.16,17,18 Thus, the three-component condensation of 5-amino-3-methylisoxazole (1), isatins 28, and cyclic 1,3-dicarbonyl compounds 29 produced a series of isoxazolo[5,4-b]pyridines 30 exhibiting antitumor effects.16

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The reaction of enolizable cyclic 1,3-diketones 29 with isoxazole 1 and aromatic aldehydes under the conditions of brief microwave irradiation leads to the formation of annulated isoxazolo[5,4-b]pyridines 31 with changing yields.19

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A pseudo-five-component domino reaction with the participation of acetonitrile dimer, hydroxylamine hydrochloride, aldehydes, and barbituric acids 32 leading to spirocycles 33 in high yields was described.20 The formation of the key component (5-amino-3-methylisoxazole (1)) occurred in situ by condensation of acetonitrile dimer with hydroxylamine. It is noted that the reaction is regioselective and is not accompanied by the formation of the [3,4-b]-isomers.

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Instead of 1,3-dicarbonyl compounds, other active metylene reagents can be used in condensation with isoxazole 1 and carbonyl components. Thus, β-ketonitriles 34 react with isatins 28 and isoxazole 1 to form spirocyclic isoxazolopyridines 35.21 It is noted that the maximum yields of products 35 (up to 89%) are achieved with prolonged heating of the reagents in PhMe under reflux in the presence of an acid catalyst.

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