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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 28 through a strong bond interaction, to form an eutectic mixture with a melting point lower 63 66 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. To a stirred solution of 42 43 ethyl 2 nitroacetate (7a , 1mmol) in AcChCl:urea 1:2 (1 mL) was added the corresponding alkyne 44 45 46 (2, 0.5 mmol) and the reaction was stirred at 100ºC during 4h. After this time, the reaction was 47 48 quenched with water and extracted with AcOEt (3x5 mL). The organic phases were dried over 49 50 MgSO , followed by evaporation under reduced pressure to remove the solvent. The product was 51 4 52 53 purified by chromatography on silica gel (hexane/ethyl acetate) to give the corresponding 54 55 products 8. 56 57 58 59 60 ACS Paragon Plus Environment 5 ACS Sustainable Chemistry & Engineering Page 6 of 27
1 2 3 RESULTS AND DISCUSSION 4 5 6 7 To start our study we decided to examine the three step one pot synthesis of 3,5 disubstituted 8 9 isoxazoles using benzaldehyde (1a) and phenylacetylene (2a) as the starting materials. After 10 11 12 dissolving reagents in DES, hydroxylamine and solid NaOH were added, which should led to the 13 14 formation of the corresponding oxime. Then NCS was added to the basic reaction mixture, which 15 16 should result in formation of hydroxyiminoyl chloride, which should enter the reaction with 17 18 19 present phenylacetylene (Table 1). Initially, the effect of DES in the reaction was examined 20 21 (entries 1 6). In first place, the reaction was performed in the deep eutectic solvent formed by 22 23 ChCl:glycerol and although the yield was not satisfactory, it proved that the concept may work 24 25 26 (entry 1). Then, other DESs were examined as medium for the reaction, finding that DES 27 28 containing urea gave better results. The mixture ChCl:urea (1:2) reached the best yield (entry 6). 29 30 31 32 It should be pointed out that this renewable solvent is a good medium for different reactions 33 34 including the deprotonation of aromatic hydroxylammonium chloride with solid sodium 35 36 hydroxide, condensation of amine derivative with benzaldehyde, chlorination of the formed 37 38 39 oxime with N chlorosuccinimide to give the corresponding hydroximinoyl chloride, which is 40 41 stable enough into the highly functionalized medium, to permit the final [3+2] cycloaddition by 42 43 slow HCl elimination. Then, the reaction time was evaluated for the last cycloaddition step 44 45 46 (entries 6 9), finding that after 4h the increase of the yield was marginal. The reaction was scaled 47 48 up to grams using 10 mL of DES (entry 9, footnote c), and after completion of the reaction 10 49 50 mL of NaOH 1M and 10 mL of hexane was added. The resulting mixture was stirred during 30 51 52 53 minutes and after that, the obtained solid was filtrated obtaining the corresponding pure product 54 55 with good yield. This purification protocol is easier and greener than that employed in mg scale. 56 57 58 59 60 ACS Paragon Plus Environment 6 Page 7 of 27 ACS Sustainable Chemistry & Engineering
1 2 3 Table 1. Optimization of the Reaction Conditions for the Multi Step Approach. a 4 5 6 7 8 9 10 11 12 13 14 b 15 entry DES (molar ratio) t (h) yield (%) 16 17 18 1 ChCl:glycerol (1:2) 8 20 19 20 21 2 ChCl:trifluoroacetamide (1:2.5) 8 0 22 23 24 25 3 ChCl:ethylene glycol (1:2) 8 0 26 27 28 + – 4 Ph 3P MeBr :glycerol (1:2) 8 0 29 30 31 32 5 AcChCl:urea (1:2) 8 40 33 34 35 6 ChCl:urea (1:2) 8 71 36 37 38 7 ChCl:urea (1:2) 1 46 39 40 41 42 8 ChCl:urea (1:2) 2 64 43 44 45 9 ChCl:urea (1:2) 4 73 (70) c 46 47 48 d 49 10 THF 8 4 50 51 52 11 d THF (urea) e 8 13 53 54 55 12 d THF (ChCl) e 8 11 56 57 58 59 60 ACS Paragon Plus Environment 7 ACS Sustainable Chemistry & Engineering Page 8 of 27
1 2 3 13 Urea f 8 34 4 5 6 f 7 14 ChCl 8 15 8 9 10 a Reaction carried out using compounds 1a (203 L, 2mmol), NH 2OH·HCl (138 mg, 2 mmol), 11 NaOH (80 mg, 2 mmol), NCS (400 mg, 3 mmol) and 2a (110 L, 2 mmol) in 1mL of DES. 12 b c 13 Isolated yield after column chromatography. Reaction carried out using compounds 1a (2.03 14 mL, 20 mmol), NH 2OH·HCl (1,38 g, 20 mmol), NaOH (800 mg, 20 mmol), NCS (4g, 30 mmol) d e 15 and 2a (2.2 mL, 20 mmol) in 10 mL of DES. Reaction performed using 1 mL of THF. 2 16 Equivalents of additive was added. fReaction carried out in absence of solvent using 2 17 equivalents of additive. 18 19 20 21 22 23 In order to clarify the role of different components of the solvent, the reaction was performed in 24 25 THF adding 2 equivalents of urea or choline chloride (Table 1, entries 10 12), obtaining slightly 26 27 28 better results using additives. When the reaction was repeated in absence of solvent but in the 29 30 presence of the aforementioned additives (Table 1, entries 13 14), the best result was obtained in 31 32 the presence of urea. These facts highlight the beneficial role of urea in the reaction mechanism, 33 34 35 probably by stabilizing the ionic intermediates through hydrogen bonds. 36 37 38 With the best conditions in hand, the scope of the reaction was evaluated (Table 2). The reaction 39 40 41 gave excellent results for substituted benzaldehydes independently of the nature of the 42 43 substituent on the aromatic ring of the aldehyde (entries 1 3) as well as of the relative position 44 45 (compare entries 3 and 4). The reaction was tested using aliphatic (entry 5) and heterocyclic 46 47 48 (entries 6 and 7) aldehydes obtaining good yields. 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 8 Page 9 of 27 ACS Sustainable Chemistry & Engineering
1 2 3 Table 2. Preparation of Isoxazoles a 4 5 6 7 8 9 10 11 12 13 14 entry R1 R2 Isoxazole yield (%) b 15 16 17 18 1 Ph Ph 3a 73 19 20 21 2 4 ClC 6H4 Ph 3b 83 22 23 24 25 3 4 MeC 6H4 Ph 3c 96 26 27 28 4 2 MeC 6H4 Ph 3d 81 29 30 31 5 C H Ph 3e 86 32 6 11 33 34 35 6 2 Quinolyl Ph 3f 82 36 37 38 7 2 Thienyl Ph 3g 86 39 40 41 42 8 Ph 3 ClC 6H4 3h 80 43 44 45 9 Ph 4 MeOC 6H4 3i 76 46 47 48 10 Ph 2 Pyridyl 3j 63 49 50 51 52 11 Ph C6H11 3k 84 53 54 55 12 4 MeC 6H4 4 MeOC 6H4 3j 70 56 57 58 59 60 ACS Paragon Plus Environment 9 ACS Sustainable Chemistry & Engineering Page 10 of 27
1 2 3 a Reaction carried out using compounds 1 (2mmol), NH 2OH·HCl (138 mg, 2 mmol), NaOH (80 4 b 5 mg, 2 mmol), NCS (400 mg, 3 mmol) and 2(2 mmol) in 1mL of ChCl:urea (1:2). Isolated yield 6 after column chromatography. 7 8 9 10 11 The reaction was also accomplished with different substituted ethynylbenzenes, using electron 12 13 14 donating substituents as well as electron withdrawing groups obtaining good yields (entries 8 15 16 and 9). Heterocyclic (entry 10) and aliphatic (entry 11) alkynes were also tested reaching the 17 18 previous results. The combination of substituted aldehydes and alkynes was not problematic 19 20 21 obtaining the corresponding product with a similar good yield (entry 12). 22 23 24 The recycling of ChCl:urea medium was evaluated once the compound 3a was obtained. The 25 26 27 simple decantation of DES mixture with toluene permitted the partial isolation of all organic 28 29 products and by products. The lower DES layer was reused in a second cycle, but the yield 30 31 decreased from 73 to 32%. The high solubility of initial reagents (NH 2OH·HCl, NaOH, NCS), as 32 33 34 well as the stoichiometric by product formed (H 2O and succinimide) presented in the second 35 36 cycle might modify the initial DES structure, decreasing the initial beneficial solvent effect. 37 38 39 Once the study of this reaction was finished, a similar process was performed but using alkenes 71 40 41 42 (Table 3). The yields were similar to the previously obtained with alkynes allowing either the use 43 44 of aromatic (entry 1 3) and heterocyclic (entry 4) aldehydes or the use of aromatic (entry 5), 45 46 47 heterocyclic (entry 6) and aliphatic (entries 7 and 8) alkenes. The combination of aromatic 48 49 aldehydes and aliphatic alkenes gave the corresponding product with moderate yield (entries 9). 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 10 Page 11 of 27 ACS Sustainable Chemistry & Engineering
1 2 3 Table 3. Preparation of Isoxazolines a 4 5 6 7 8 9 10 11 12 13 14 entry R1 R2 Isoxazoline yield (%) b 15 16 17 18 1 Ph Ph 5a 54 19 20 21 2 4 ClC 6H4 Ph 5b 91 22 23 24 25 3 4 MeC 6H4 Ph 5c 51 26 27 28 4 2 Thienyl Ph 5d 79 29 30 31 5 Ph 4 ClC H 5e 70 32 6 4 33 34 35 6 Ph 2 Pyridyl 5f 84 36 37 38 7 Ph C6H13 5g 74 39 40 41 42 8 Ph 4 MeOC 6H4CH 2 5h 47 43 44 45 9 4 NO 2C6H4 CH 2Br 5i 42 46 47 48 a Reaction carried out using compounds 1 (2mmol), NH 2OH·HCl (138 mg, 2 mmol), NaOH (80 49 b 50 mg, 2 mmol), NCS (400 mg, 3 mmol) and 4 (2 mmol) in 1mL of DES. Isolated yield after 51 column chromatography. 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 11 ACS Sustainable Chemistry & Engineering Page 12 of 27
1 2 3 Once the scope of the reaction was studied, a ring opening reaction 72 79 was carried out using 0.5 4 5 6 equivalents of Mo(CO) 6 and starting from the previously obtained isoxazoles 3 (Table 4). The 7 8 reaction took place with good yields when the substituents of the isoxazole were aromatic, 9 10 11 independently of the electronic nature of the substituents in these rings (entries 1 3). However, 12 13 when the reaction was performed with aliphatic substituents, the yield decreased (entry 4). 14 15 16 Table 4. Synthesis of β amino enones a 17 18 19 20 21 22 23 24 25 26 27 entry R1 R2 β amino enones yield (%) b 28 29 30 31 1 Ph Ph 6a 90 32 33 34 2 4 ClC 6H4 Ph 6b 92 35 36 37 38 3 Ph 4 MeOC 6H4 6c 89 39 40 41 4 Ph C6H13 6d 55 42 43 44 a Reaction carried out using compound 3 (1 mmol), H 2O (1 mmol), Mo(CO) 6 (0.5 mmol) in 20 45 b 46 mL of CH 3CN. Isolated yield after column chromatography. 47 48 49 50 51 Our next goal was to examine if similar dipolar cycloaddition would go also with activated 52 53 nitroalkenes. So, the simple approach for the synthesis of ethyl 5 substituted isoxazole 3 54 55 56 carboxylates by reaction of the corresponding nitrocompounds using a DES was tested (Table 5). 57 58 59 60 ACS Paragon Plus Environment 12 Page 13 of 27 ACS Sustainable Chemistry & Engineering
1 2 3 Ethyl 2 nitroacetate ( 7) and phenylacetylene ( 2a) were selected as the model for the optimization 4 5 6 of the reaction conditions. Initially, the effect of different DES was examined (entries 1 5). The 7 8 reaction was performed in some of the previously tested DES, only those containing urea gave 9 10 11 the expected product 8a. With these results in hand, the reaction was repeated increasing the 12 13 temperature (entries 6 and 7) observing that in acetyl choline chloride (AcChCl):urea the 14 15 reaction took place in good yield after 24h. The reaction was tested using 2 equivalents of 16 17 18 compound 7, obtaining a good yield after only 4h of reaction (entry 8), with the yield not being 19 20 improved by an increase in the reaction time. To prove the beneficial effect of the DES media the 21 22 reaction was repeated in absence of solvent, under the best reaction conditions, and the starting 23 24 25 material was recovered unchanged (entry 9). 26 27 28 Table 5. Optimization of the Reaction Conditions a 29 30 31 32 33 34 35 36 37 38 39 b 40 entry DES (molar ratio) T (ºC) t (h) yield (%) 41 42 43 1 ChCl:glycerol (1:2) 50 48 0 44 45 46 47 2 ChCl:ethylene glycol (1:2) 50 48 0 48 49 + – 50 3 Ph 3P MeBr :glycerol (1:2) 50 48 0 51 52 53 4 AcChCl:urea (1:2) 50 48 42 54 55 56 57 58 59 60 ACS Paragon Plus Environment 13 ACS Sustainable Chemistry & Engineering Page 14 of 27
1 2 3 5 ChCl:urea (1:2) 50 48 35 4 5 6 7 6 ChCl:urea (1:2) 100 24 40 8 9 10 7 AcChCl:urea (1:2) 100 24 85 11 12 13 c d 14 8 AcChCl:urea (1:2) 100 4 79 (80) 15 16 17 9 100 24 0 18 19 20 aReaction carried out using compounds 7 (0.5 mmol) and 2a (0.5 mmol) in 1mL of DES. 21 bIsolated yield after column chromatography. cReaction carried out using compounds 7 (1 22 d 23 mmol) and 2a (0.5 mmol) in 1mL of AcChCl:urea. After 8h of reaction. 24 25 26 27 28 Once the optimization was performed and with the best conditions in hands, the scope of the 29 30 31 reaction was evaluated using AcChCl:urea (1:2) at 100 ºC (Table 6). The reaction gave excellent 32 33 results with different substituted ethynylbenzenes 2 independently of the relative position or the 34 35 electron nature of the substituent. However, the reaction with the related aliphatic alkyne gave 36 37 38 the expected product 8e with a slight decrease in the yield (entry 5). 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 14 Page 15 of 27 ACS Sustainable Chemistry & Engineering
1 2 3 Table 6. Preparation of Isoxazoles a 4 5 6 7 8 9 10 11 12 13 14 15 b 16 entry R Isoxazole yield (%) 17 18 19 1 Ph 8a 79 20 21 22 2 3 ClC 6H4 8b 91 23 24 25 26 3 3 MeC 6H4 8c 85 27 28 29 4 4 MeOC 6H4 8d 78 30 31 32 33 5 C6H13 8e 63 34 35 a b 36 Reaction carried out using compounds 7 (1 mmol) and 2 (0.5 mmol) in 1mL of DES. Isolated 37 yield after column chromatography. 38 39 40 41 42 43 Once the positive effect of the DES on the reaction was proved, the recycling of the media was 44 45 evaluated. After performing the reaction and generating compound 8a in AcChCl:urea the 46 47 product was isolated by extraction with toluene and the DES media was reused for the next 48 49 50 process (Figure 1). The DES solvent could be reused five times obtaining similar yields to the 51 52 freshly prepared one. 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 15 ACS Sustainable Chemistry & Engineering Page 16 of 27
1 2 3 4 5 6 100 7 90 8 9 80 10 70
11 8a 12 60 13 50 14 15 40 16 Yield (%) (%) of Yield 17 30 18 20 19 20 10 21 0 22 23 1 2 3 4 5 24 Cycle 25 26 Figure1. Yields obtained with recycled DES (AcChCl:urea). 27 28 29 30 31 32 33 Finally, a possible picture of the hypothetic mechanism is described in Scheme 1. In both 34 35 36 protocols, only DES containing urea gave product in a reasonable yield. This fact might be due 37 38 to the high hydrogen bond donating character of this component. In the first approach, we 39 40 believe that urea favors the release of chloride from the imidoyl chloride. In fact, this interaction 41 42 43 is the responsible for the formation of DES. In the second approach, a similar interaction would 44 45 favor the nitro tautomerization. Finally, the nitrile oxide intermediate formed in both cases could 46 47 be stabilized by both component of DES, through hydrogen bonding with urea and through 48 49 50 electronic interaction with the choline derivative. 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 16 Page 17 of 27 ACS Sustainable Chemistry & Engineering
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Scheme 1. Possible mechanism pathway. 17 18 19 20 21 22 23 CONCLUSIONS 24 25 26 27 In conclusion, we have demonstrated that the appropriate DES is a good solvent to perform the 28 29 one pot three step reaction to obtain isoxazoles and isoxazolines under mild reaction conditions, 30 31 using highly reactive reagents and through excellent electrophiles, with the different nucleophilic 32 33 34 functionalities of the DES media not interfering in the reaction process and not affecting into the 35 36 high obtained yield. This reaction is the first one pot multistep process described using a highly 37 38 functionalized DES as medium, which is a non toxic, biodegradable and green solvent compared 39 40 41 to usual Volatile Organic Compounds (VOC). The reaction could be scaled up to gram scale with 42 43 no negative effect, favouring the isolation of product by crystallization. Moreover, the DES 44 45 could be easily recovered by the addition of a non protonated and a polar solvent to solve the 46 47 48 product, recycling the DES up to five times, by simple decantation, without any decrease in the 49 50 reaction yields. 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 17 ACS Sustainable Chemistry & Engineering Page 18 of 27
1 2 3 ASSOCIATED CONTENT 4 5 6 7 Supporting Information . General information, analytical data for products and NMR spectra of 8 9 products. 10 11 12 13 AUTHOR INFORMATION 14 15 Corresponding Author 16 17 18 * E mail: [email protected] 19 20 21 22 23 24 ACKNOWLEDGMENT 25 26 This work was supported by the Spanish Ministerio de Economía y Competitividad (MICINN; 27 28 29 CTQ2011 24151) and University of Alicante. J.M.P. thanks the MICINN (FPI program) for her 30 31 fellowship 32 33 34 35 36 37 38 39 40 41 42 ABBREVIATIONS 43 44 45 DES, Deep Eutectic Solvent; ChCl, choline chloride; AcChCl, Acetyl choline chloride; VOC, 46 47 Volatile Organic Compounds. 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 18 Page 19 of 27 ACS Sustainable Chemistry & Engineering
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1 2 3 4 5 6 7 8 9 10 11 12 For Table of Contents Use Only 13 14 15 16 17 18 19 20 Synthesis of 3,5 Disubstituted Isoxazoles and Isoxazolines in Deep Eutectic Solvents 21 22 23 Juana M. Pérez and Diego J. Ramón* 24 25 26 27 28 29 30 31 32 33 34 35 The synthesis of different 3,5 disubstituted isoxazoles and related isoxazolines using choline 36 37 chloride:urea as deep eutectic solvent (DES) in a one pot three step reaction has been 38 39 40 accomplished successfully. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 27