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Synthesis of 3,5-Disubstituted Isoxazoles and Isoxazolines In Page 1 of 27 ACS Sustainable Chemistry & Engineering 1 2 3 4 5 6 7 8 Synthesis of 3,5-Disubstituted Isoxazoles and 9 10 11 12 Isoxazolines in Deep Eutectic Solvents 13 14 15 16 a a 17 Juana M. Pérez and Diego J. Ramón * 18 19 20 aInstituto de Síntesis Orgánica (ISO), and Departamento de Química Orgánica, Facultad de 21 22 Ciencias, Universidad de Alicante, Apdo. 99, E-03080-Alicante, Spain. 23 24 25 26 E-mail: [email protected] 27 28 29 KEYWORDS: Deep Eutectic Solvent, metal free, isoxazoles, isoxazolines, recyclable. 30 31 32 33 34 35 36 ABSTRACT: The synthesis of different 3,5-disubstituted isoxazoles and related isoxazolines 37 38 using choline chloride:urea as deep eutectic solvent (DES) in a one-pot three step reaction has 39 40 been accomplished successfully. The use of highly nucleophilic functionalized DES did not 41 42 43 affect the process where highly electrophilic reagents or intermediates are involved. The 44 45 presence of DES showed to be essential since the reaction in absence of this media did not 46 47 proceed. The DES media could be reused up to five times without a detrimental effect on the 48 49 50 yield of the reaction. To exemplify the synthetic potential of this methodology, the reaction was 51 52 scaled up to gram scale without any noticeable problem. Finally, different isoxazoles were easily 53 54 transformed into β-aminoenones. 55 56 57 58 59 60 ACS Paragon Plus Environment 1 ACS Sustainable Chemistry & Engineering Page 2 of 27 1 2 3 4 5 6 7 INTRODUCTION 8 9 10 Isoxazoles and related 4,5-dihydroisoxazoles, are a valuable and well established 1-4 class of 11 12 5 6-7 13 heterocyclic compounds with broad applications, including pharmaceutical and agricultural 14 8-11 15 activities. 16 17 18 Numerous synthetic approaches for the construction of the isoxazole and 4,5-dihydroisoxazole 19 20 21 framework have been reported. There are two main methodologies: The first approach involves 22 23 the condensation of hydroxylamine with 1,3-dicarbonyl compounds, or their three-carbon 1,3- 24 25 electrophilic variants, such as α,β-unsaturated ketones, enamino ketones, β-alkylthioenones and 26 27 28 ynones. The second one is the 1,3-dipolar cycloaddition reaction between alkynes or alkenes 29 30 with nitrile oxides, generated in situ from aldoximes or nitroalkanes. 12-23 In turn, these 31 32 24 33 heterocycles can be transformed into β-functionalizes carbonylic compounds, by cleavage of 34 35 the labile N-O heterocyclic bond. 36 37 38 Different metallic derivatives have been used to perform the regioselective cycloaddition 39 40 25 26-27 28 29-36 41 reaction, including aluminum, magtrieve (CrO 2), cobalt and copper complexes, 42 37 38 39 43 AgBF 4, SnPh 4, triscetylpyridiniumtetrakis(oxodiperoxotungsto) phosphate, gold 44 45 compounds 40 and Pb(OAc) .41 Conversely, in the case of cyclopentadienyl ruthenium 46 2 47 42 48 derivatives, the regioselective formation of the related 4,5-disubstituted heterocycles was 49 50 observed. It should be pointed out that for many applications the use of toxic transition metals is 51 52 undesirable, if not prohibited. Therefore, there is a clear necessity for metal-free protocols. This 53 54 43-44 45-47 55 green approach has been conducted by different oxidative reagents such as oxone, iodine, 56 57 iodobenzene trifluoroacetate, 48 iodobenzene diacetate, 49-51 tert -butyl hypoiodite 52 or chloramine- 58 59 60 ACS Paragon Plus Environment 2 Page 3 of 27 ACS Sustainable Chemistry & Engineering 1 2 3 T. 53 However, these new protocols have several inconveniencies such as stability, price and 4 5 6 manipulation of reagents. The importance of the used solvent has been recently addressed by the 7 8 use of aqueous biphasic protocols, 54-55 ionic liquid, 56 and aqueous polyethylene glycol. 57 9 10 11 12 Within the framework of green chemistry, solvents occupy a strategic place. To be qualified as a 13 14 green medium, the components of this solvent have to meet different criteria such as availability, 15 16 non-toxicity, biodegradability, recyclability, inflammability, renewability and low price, among 17 18 58-61 19 others. Deep eutectic solvents (DES) are an environmentally benign alternative to hazardous 20 21 (organic) solvents and, in many cases, might replace them. DESs are liquid systems formed from 22 23 a eutectic mixture of solid Lewis or Brønsted acids and bases which can contain a variety of 24 25 62 26 anionic and/or cationic species. These two components are capable of self-association, often 27 63-66 28 through a strong bond interaction, to form an eutectic mixture with a melting point lower 29 30 than that of each individual component. The typical green characteristic properties of a solvent, 31 32 33 such as conductivity, viscosity, vapor pressure and thermal stability can be fine-tuned by the 34 35 appropriate choosing of the mixture components, with the large-scale preparation being feasible. 36 37 38 39 The applications of DES in organic synthesis have notable advantages. As most of the 40 41 components are soluble in water, addition of water to the reaction mixture dissolves the reaction 42 43 medium, and the organic products either form a separate layer or precipitate. Moreover, the 44 45 46 solvent and the catalyst may be recycled by the adequate quenching of the reaction. 47 48 49 DES have been used as ideal medium in biocatalyzed,67 organocatalyzed 68 reactions, as well as in 50 51 reactions using homogeneous 69 and heterogeneous 70 catalysts. Although there are several 52 53 54 misconceptions about their uses in Organic Synthesis due to the high reactivity of intermediate, 55 56 this kind of eutectic mixture has a promising future. 57 58 59 60 ACS Paragon Plus Environment 3 ACS Sustainable Chemistry & Engineering Page 4 of 27 1 2 3 Herein we report an experimentally and environmentally convenient one-pot three-component 4 5 6 process for the regioselective synthesis of 3,5-disubstituted isoxazoles and the related 3,5- 7 8 disubstituted-4,5-dihydroisoxazoles from aldehydes and alkynes or alkenes using choline 9 10 11 chloride (ChCl):urea as biorenewable DES. The protocol permitted the simple use of highly 12 13 reactive reagents, such as NCS, even the presence of highly electrophilic intermediate, such as 14 15 imidoil chlorides. 16 17 18 19 EXPERIMENTAL 20 21 22 General Procedure for the DES preparation. A mixture of choline chloride (6.98 g, 50 mmol) 23 24 or acetylcholine chloride (9.08 g, 50 mmol) and urea (6.00 g, 100 mmol) was added in a round 25 26 27 bottom flask under inert atmosphere. The mixture was stirred during 60 minutes at 75 or 50 ºC 28 29 for ChCl:urea or AcChCl:urea, respectively, obtaining the corresponding DES. 30 31 32 33 General Procedure for the formation of 3,5-disubstituted isoxazoles. To a stirred solution of 34 35 the corresponding aldehyde ( 1, 2 mmol) in ChCl:urea 1:2 (1 mL) were added hydroxylamine 36 37 (138 mg, 2 mmol) and sodium hydroxide (80 mg, 2 mmol). The resulting mixture was stirred at 38 39 40 50 ºC during one hour. After that, N-chlorosuccinimide (400 mg, 3 mmol) was added to the 41 42 mixture and it reacted during three hours at 50ºC. Then, the corresponding alkyne ( 2, 2 mmol) 43 44 was added and the mixture reacted during four hours at 50ºC, after this time the reaction was 45 46 47 quenched with water and extracted with AcOEt (3x5 mL). The organic phases were dried over 48 49 MgSO 4, followed by evaporation under reduced pressure to remove the solvent. The product was 50 51 usually purified by column chromatography on silica gel (hexane/ethyl acetate) to give the 52 53 54 corresponding products 3. 55 56 57 58 59 60 ACS Paragon Plus Environment 4 Page 5 of 27 ACS Sustainable Chemistry & Engineering 1 2 3 General Procedure for the formation of 3,5-disubstituted-4,5-dihydroisoxazoles. To a stirred 4 5 6 solution of the corresponding aldehyde ( 1, 2 mmol) in ChCl:urea 1:2 (1 mL) were added 7 8 hydroxylamine (138 mg, 2 mmol) and sodium hydroxide (80 mg, 2 mmol). The resulting mixture 9 10 11 was stirred at 50 ºC during one hour. After that N-chlorosuccinimide (400 mg, 3 mmol) was 12 13 added to the mixture and it reacted during three hours at 50ºC. Then, the corresponding alkene 14 15 (4, 2 mmol) was added and the mixture reacted during four hours at 50ºC, after this time the 16 17 18 reaction was quenched with water and extracted with AcOEt (3x5 mL). The organic phases were 19 20 dried over MgSO 4, followed by evaporation under reduced pressure to remove the solvent. The 21 22 product was usually purified by column chromatography on silica gel (hexane/ethyl acetate) to 23 24 25 give the corresponding products 5. 26 27 28 General Procedure for the formation of β-amino enones. A solution of isoxazole ( 3, 1 mmol), 29 30 water (1 mmol), and Mo(CO) (0.5 mmol) in acetonitrile (20 mL) was refluxed during 4h. After 31 6 32 33 this time, 30 mL of hexane was added and the reaction mixture was filtered through Celite. The 34 35 filtrate was concentrated and the residue was purified by column chromatrography on silica gel 36 37 38 (hexane/ethyl acetate) to give the corresponding products 6. 39 40 41 General Procedure for the formation of 3,5-disubstituted isoxazoles.
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