HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 6, 2014, pp. 1473-1482
Received, 13th March, 2014, Accepted, 16th April, 2014, Published online, 25th April, 2014.
DOI: 10.3987/COM-14-12979

■ A Convenient Synthetic Method of Isoxazole Derivatives Using Copper(II) Nitrate

Ken-ichi Itoh,* Tadashi Aoyama, Hiroaki Satoh, Kenta Hasegawa, Natsumi Meguro, Akira C. Horiuchi, Toshio Takido, and Mitsuo Kodomari

Department of Liberal Arts and Science, College of Science and Technology, Nihon University, 7-24-1 Narashinodai, Funabashi-shi, Chiba 274-8501, Japan

Abstract

3-Acetylisoxazoles were synthesized by the reaction of alkenes or alkynes in acetone as solvent with copper(II) nitrate and formic acid. In the case of ethyl acetate as solvent, 3-benzoylisoxazoles were yielded by the reaction of alkynes and acetophenone with copper(II) nitrate and nitric acid. This synthetic method provides a convenient production of isoxazole derivatives.

Isoxazole derivatives, five-membered nitrogen-containing heterocycles, are an important class of heterocyclic compounds. They can be converted into a number of useful synthetic units by the reductive ring cleavage, such as β-hydroxy ketones1 or γ-amino alcohols.2 Moreover, many compounds bearing the isoxazole moieties show relevant biological activity: very late antigen-4 (VLA-4) antagonist3 and cyclooxygenase-1 (COX-1) inhibitor.4 Isoxazole derivatives are synthesized according to an intermolecular [3+2] cycloaddition reaction between alkenes (or alkynes) and nitrile oxides.5 Nitrile oxides are generally prepared from aldoximes by following two steps: halogenation of aldoxime (into hydroximoyl halide) and dehydrohalogenation using base.6
We have recently reported that a newly synthetic method of isoxazole derivatives using ammonium cerium nitrate (CAN)7 or iron(III) nitrate.8 3-Acetyl- and 3-benzoylisoxazoles were synthesized by the reaction of alkenes (or alkynes) with acetone or acetophenone as solvent in the presence of CAN or iron(III) nitrate involving the nitrile oxide intermediate generated from ketones. Although the reaction using CAN proceeded, the reaction using iron(III) nitrate was inexpensive and non-toxic synthetic method of isoxazole derivatives. The synthetic method using iron(III) nitrate is a simple production of isoxazole derivatives, however, the use of iron(III) nitrate has drawbacks: the resulting brown color of iron salts after the reaction was made difficult to isolate the product from reaction mixture. In addition, since ketone was employed as solvent, it was necessary to remove ketone from the reaction mixture. Here, we wish to report a convenient method for the synthesis of 3-acetyl- and 3-acylisoxazoles using copper(II) nitrate rather than the reaction using CAN or iron(III) nitrate. Copper(II) nitrate is inexpensive and non-toxic reagent compared with CAN, and the resulting dark green color of copper salts after the reaction was easily dissolved by the addition of dilute hydrochloric acid. Moreover, since the quantity of ketone was limited to the amount of substrate by the use of ethyl acetate as solvent, 3-benzoylisoxazoles were obtained from the reaction of alkynes and acetophenone as substrate with copper(II) nitrate and nitric acid in ethyl acetate. The present method is afforded to a simple and efficient synthesis of isoxazole derivatives.

At first, the reaction of 1-octene 1a (R1 = n-C6H13) with copper(II) nitrate in acetone 2a under reflux for 24 h was carried out (Scheme 1 and Table 1).

3-Acetyl-5-hexyl-4,5-dihydroisxoazole 3a was obtained in low yield (about 20-30% yields). It seems that the production of isoxazole derivative was inhibited by the formation of copper complex from copper and reaction intermediate. In order to improve the yield of 3a, we further examined the reactions adding several carboxylic acids (Table 2).

The yields of 3a increased into about 50-80% yields. In particular, when the reaction adding 7.5 molar equivalent of formic acid was carried out, 3a was obtained in 80% GLC yield (Table 2, entry 3). Although the reaction using sulfuric acid gave 3a in about 60% yield (Entries 16 and 17), it was clearly that the formation of 3a effectively proceeded by the addition of formic acid.
Therefore, the reaction of several alkenes in the presence of copper(II) nitrate and formic acid was performed in acetone under reflux. The results were summarized in Table 3.

In addition, the reaction of disubstituted alkenes was carried out. In the case of cyclohexene 1j, the corresponding 4,5-disubstituted isoxazole derivative 3j was obtained in 19% yield (Scheme 2).

The reaction of 2-ethyl-1-butene 1k and methylenecyclohexane 1l as 1,1-disubstituted alkenes gave the corresponding 5,5-disubstituted isoxazole derivatives 3k and 3l in 13 and 13% yields, respectively (Scheme 3).

The yield of the product from disubstituted alkenes was lowered compared with the reaction of terminal alkenes. We further examined the reaction of several alkynes in the presence of copper(II) nitrate and formic acid in acetone (Scheme 4 and Table 4).

The present method is a simple and convenient synthesis of 3-acetylisoxazoles, however, since ketone was employed as solvent, it was difficult to apply to the reaction by the use of high boiling ketones. In order to solve the problem, we investigated the reaction using several solvent: chloroform, acetic anhydride, tetrahydrofuran, 1,4-dioxane, ethyl acetate, pyridine, and dimethyl sulfoxide (Scheme 5, Table 5). Among them, it was found that the reaction of 1-octyne 4a and acetophenone 2b (R5 = Ph) in the presence of copper(II) nitrate in ethyl acetate afforded to 3-benzoyl-5-hexylisoxazole 6a (Table 3, Entry 6).

In the literature,7,8 we proposed the reaction mechanism: the corresponding nitrile oxide was transformed from α-nitro ketone via the nitration of ketone. On the basis of our studies, we tried to the reaction adding nitric acid (Table 6).

The addition of nitric acid was improved the yield of the product into 24% GLC yield (Table 6, entry 1). Furthermore, it was found that 6a was obtained in 45% GLC yield under optimum reaction condition (Entry 4).
From the results, we carried out the reaction of alkynes and ketones in the presence of copper(II) nitrate and nitric acid in ethyl acetate (Table 7).

In conclusion, we developed a simple and efficient synthesis of 3-acetylisoxazoles by the use of copper(II) nitrate. Moreover, we have succeeded the improvement of the synthesis of 3-benzoylisoxazoles by the use of ethyl acetate as solvent. These synthetic methods provide a convenient production of isoxazole derivatives.

EXPERIMENTAL
Melting points were determined on a Yanako Micro melting point apparatus. The IR spectra were recorded using a Thermo Electron Nicolet 380 spectrometer. The 1H and 13C NMR spectra were measured using a JEOL JNM-GX400 spectrometer. Tetramethylsilane (δ=0) was used as an internal standard for 1H NMR. Mass analysis was performed on an Agilent G1969LC/MDS TOF. All chemicals were purchased from Tokyo Chemical Industry Co., Ltd, and Wako Pure Chemical Industries, Ltd.
Typical Procedure for the Preparation of 3-Acetylisoxazoles
A mixture of alkenes (or alkynes) (0.5 mmol), copper(II) nitrate trihydrate (0.5 mmol) and formic acid (7.5 mol. equiv.; 3.75 mmol) in acetone (5 mL) was stirred under reflux for 18 h. The reaction mixture was extracted with EtOAc (30 mL) and washed with 1 mol/L HCl (3 mL), aq. NaHCO3 solution (2x3 mL), saturated aq. sodium chloride solution (3 mL) and water (3 mL). The extract was dried over sodium sulfate and was concentrated in vacuo after the filtration. The residue was chromatographed with EtOAc and n-hexane on silica gel (Merck silica gel 60: 0.063-0.200 mm).
3-Acetyl-5-octyl-4,5-dihydroisoxazole (3b): a pale yellow oil; IR (neat) 2925, 2855, 1573 cm-1; 1H NMR δ 0.88 (t, J = 6.8 Hz, 3H), 1.27-1.43 (m, 12H), 1.53-1.59 (m, 1H), 1.70-1.79 (m, 1H), 2.49 (s, 3H), 2.75 (dd, J = 8.2, 17.4 Hz, 1H), 3.15 (dd, J = 10.9, 17.4 Hz, 1H), 4.78 (m, 1H); 13C NMR δ 14.0, 22.6, 25.1, 26.6, 29.1, 29.2, 29.3, 31.7, 35.1, 36.6, 84.8, 158.2, 193.4; HRMS (TOF-Cl) calcd for C13H24NO2 (MH+): 226.1807. Found: 226.1817.
3-Acetyl-5-decyl-4,5-dihydroisoxazole (3c): a white solid; mp 34.1-34.3 °C; IR (neat) 2917, 2848, 1691, 1585 cm-1; 1H NMR δ 0.88 (t, J = 6.8 Hz, 3H), 1.26-1.43 (m, 16H), 1.53-1.59 (m, 1H), 1.70-1.79 (m, 1H), 2.49 (s, 3H), 2.75 (dd, J = 8.2, 17.4 Hz, 1H), 3.15 (dd, J = 10.9, 17.4 Hz, 1H), 4.78 (m, 1H); 13C NMR δ 14.0, 22.7, 25.1, 26.6, 29.3, 29.4, 29.5, 29.6, 29.6, 31.9, 35.1, 36.7, 84.9, 158.2, 193.4; HRMS (TOF-Cl) calcd for C15H28NO2 (MH+): 254.2120. Found: 254.2119.
3-Acetyl-5-t-butyl-4,5-dihydroisoxazole (3d): a pale yellow oil; IR (neat) 2961, 1689, 1578 cm-1; 1H NMR δ 0.93 (s, 9H), 2.48 (s, 3H), 2.88 (dd, J = 9.1, 17.9 Hz, 1H), 2.98 (dd, J = 11.5, 17.9 Hz, 1H), 4.50 (dd, J = 9.1, 11.5 Hz, 1H); 13C NMR δ 24.7, 26.5, 32.3, 34.1, 92.6, 158.2, 193.4; HRMS (TOF-Cl) calcd for C9H16NO2 (MH+): 170.1181. Found: 170.1180.
3-Acetyl-5-cyano-4,5-dihydroisoxazole (3e): a pale brown oil; IR (neat) 3001, 1698, 1592 cm-1; 1H NMR δ 2.55 (s, 3H), 3.55 (d, J = 9.2, 2H), 5.37 (t, J = 9.2 Hz, 1H); 13C NMR δ 27.0, 38.6, 68.3, 115.9, 157.0, 191.3; HRMS (TOF-Cl) calcd for C6H6N2O2 (MH+): 138.0429. Found: 138.0426.
3-Acetyl-5-cyclohexyl-4,5-dihydroisoxazole (3g): a yellow oil; IR (neat) 2927, 2854, 1688, 1575 cm-1; 1H NMR δ 0.99-1.27 (m, 5H), 1.54-1.99 (m, 6H), 2.84 (dd, J = 9.2, 17.6 Hz, 1H), 3.05 (dd, J = 11.2, 17.6 Hz, 1H), 4.53 (m, 1H); 13C NMR δ 25.5, 25.6, 26.1, 26.5, 28.0, 28.2, 34.1, 42.2, 89.0, 158.2, 193.4; HRMS (TOF-Cl) calcd for C11H18NO2 (MH+): 196.1337. Found: 196.1345.
3-Acetyl-5-chloromethyl-4,5-dihydroisoxazole (3h): a pale yellow oil; IR (neat) 1693, 1583 cm-1; 1H NMR δ 2.51 (s, 3H), 3.11 (dd, J = 3.2, 18.2 Hz, 1H), 3.27 (dd, J = 11.2, 18.2 Hz, 1H), 3.44 (dd, J = 6.8, 10.8 Hz, 1H), 3.53 (dd, J = 4.0, 10.8 Hz, 1H), 5.05 (m, 1H); 13C NMR δ 26.4, 35.1, 44.5, 82.1, 157.6, 192.4; HRMS (TOF-Cl) calcd for C6H9NO2Cl (MH+): 162.0321. Found: 162.0319.
3-Acetyl-5-bromomethyl-4,5-dihydroisoxazole (3i): a pale yellow oil; IR (neat) 1692, 1583 cm-1; 1H NMR δ 2.50 (s, 3H), 3.11 (dd, J = 3.2, 18.2 Hz, 1H), 3.27 (dd, J = 11.2, 18.2 Hz, 1H), 3.44 (dd, J = 6.8, 10.8 Hz, 1H), 3.53 (dd, J = 4.0, 10.8 Hz, 1H), 5.05 (m, 1H); 13C NMR δ 26.4, 35.1, 44.5, 82.1, 157.6, 192.4; HRMS (TOF-Cl) calcd for C6H9NO2Br (MH+): 205.9816. Found: 205.9823.
3-Acetyl-5,5-diethyl-4-hydroisoxazole (3k): a colorless oil; IR (neat) 2925, 1716, 1689, 1577 cm-1; 1H NMR δ 0.91 (t, J = 7.3 Hz, 6H), 1.70 (q, J = 7.3 Hz, 4H), 2.48 (s, 3H), 2.84 (s, 2H); 13C NMR δ 7.7, 26.3, 30.6, 38.5, 94.9, 157.9, 193.7; HRMS (TOF-Cl) calcd for C9H16NO2 (MH+): 170.1181. Found: 170.1184.
3-Acetyl-5,5-spirohexyl-4-hydroisoxazole (3l): a yellow oil; IR (neat) 2936, 2859, 1688, 1574 cm-1; 1H NMR δ 1.29-1.50 (m, 4H), 1.60-1.65 (m, 2H), 1.75-1.82 (m, 4H), 2.48 (s, 3H), 2.82 (s, 2H); 13C NMR δ 23.1, 24.7, 26.3, 36.3, 41.6, 91.5, 157.9, 193.8; HRMS (TOF-Cl) calcd for C10H16NO2 (MH+): 182.1181. Found: 182.1184.
3-Acetyl-5-octylisoxazole (5b): a colorless oil; IR (neat) 2928, 2858, 1707, 1593 cm-1; 1H NMR δ 0.88 (t, J = 7.3 Hz, 3H), 1.27-1.36 (m, 10H), 1.70 (quint., J = 7.3 Hz, 2H), 2.63 (s, 3H), 2.78 (t, J = 7.8 Hz, 2H), 6.35 (s, 1H); 13C NMR δ 14.1, 22.6, 26.6, 27.2, 27.3, 28.9, 29.0, 29.1, 31.7, 99.1, 162.1, 175.6, 192.4; HRMS (TOF-Cl) calcd for C13H22NO2 (MH+): 224.1650. Found: 224.1660.
3-Acetyl-5-trimethylsilylisoxazole (5e): a yellow oil; IR (neat) 2962, 1705 cm-1; 1H NMR δ 0.36 (s, 9H), 2.68 (s, 3H), 6.81 (s, 1H); 13C NMR δ -2.0, 27.8, 110.9, 160.6, 180.4, 192.4; HRMS (TOF-Cl) calcd for C8H14NO2Si(MH+): 184.0793. Found:184.0799.
3-Acetyl-5-chloromethylisoxazole (5f): a yellow oil; IR (neat) 3141, 2361, 1707, 1600 cm-1; 1H NMR δ 2.66 (s, 3H), 4.66 (s, 2H), 6.70 (s, 1H); 13C NMR δ 27.0, 33.8, 102.0, 161.9, 169.0, 191.3; HRMS (TOF-Cl) calcd for C6H7NO2Cl (MH+): 160.0165. Found: 160.0174.
3-Acetyl-5-bromomethylisoxazole (5g): a yellow oil; IR (neat) 2360, 2341, 1704, 1595 cm-1; 1H NMR δ 2.65 (s, 3H), 4.50 (s, 2H), 6.68 (s, 1H); 13C NMR δ 17.8, 27.2, 102.1, 162.2, 169.1, 191.5; HRMS (TOF-Cl) calcd for C6H7NO2Br (MH+): 203.9660. Found: 203.9667.
3-Acetyl-5-(1-hydroxy-1-methylethyl)-isoxazole (5h): a yellow oil; IR (neat) 3440, 2984, 2924, 1705, 1582 cm-1; 1H NMR δ 1.65 (s, 6H), 2.54 (brs., 1H), 2.64 (s, 3H), 6.53 (s, 1H); 13C NMR δ 27.2, 28.9, 69.0, 97.8, 161.8, 179.6, 192.2; HRMS (TOF-Cl) calcd for C8H12NO3 (MH+): 170.0817. Found: 170.0824.
Typical Procedure for the Preparation of 3-benzoylisoxazoles
A mixture of alkynes (2.5 mmol), acetophenone (0.5 mmol), copper(II) nitrate trihydrate (0.5 mmol) and nitric acid (10.0 mmol) in EtOAc (5 mL) was stirred at 60 °C for 24 h. The reaction mixture was extracted with EtOAc (30 mL) and washed with 1 mol/L HCl (3 mL), aq. NaHCO3 solution (2x3 mL), saturated aq. sodium chloride solution (3 mL) and water (3 mL). The extract was dried over sodium sulfate and was concentrated in vacuo after the filtration. The residue was chromatographed with EtOAc and n-hexane on silica gel (Merck silica gel 60: 0.063-0.200 mm).
3-Benzoyl-5-methoxycarbonylisoxazole (6d): a pale yellow solid; mp 82.6-83.5 °C; IR (neat) 3144, 1729, 1655, 1596 cm-1; 1H NMR δ 4.02 (s, 3H), 7.44 (s, 1H), 7.53-7.70 (m, 3H), 8.31-8.33 (m, 2H); 13C NMR δ 53.1, 110.2, 128.7, 130.7, 134.4, 135.1, 156.6, 160.7, 162.1, 184.4; HRMS (TOF-Cl) calcd for C12H10NO4 (MH+): 232.0604. Found: 232.0609.
3-(4-Methylbenzoyl)-5-hexylisoxazole (7a): a yellow oil; IR (neat) 2954, 2933, 1653, 1606 cm-1; 1H NMR δ 0.90 (t, J = 7.3 Hz, 3H), 1.30-1.42 (m, 6H), 1.75 (quint., J = 7.3 Hz, 2H), 2.44 (s, 3H), 2.83 (t, J = 7.3 Hz, 2H), 6.50 (s, 1H), 7.31 (d, J = 8.2 Hz, 2H), 8.20 (d, J = 8.2 Hz, 2H); 13C NMR δ 14.0, 21.7, 22.4, 26.6, 27.3, 28.6, 31.3, 101.5, 129.2, 130.7, 133.3, 144.9, 161.9, 174.5, 185.7; HRMS (TOF-Cl) calcd for C17H22NO2 (MH+): 272.1645. Found: 272.1653.
3-(4-Fluorobenzoyl)-5-hexylisoxazole (8a): a yellow oil; IR (neat) 2956, 2931, 1666, 1599 cm-1; 1H NMR δ 0.90 (t, J = 7.3 Hz, 3H), 1.30-1.42 (m, 6H), 1.75 (quint., J = 7.3 Hz, 2H), 2.84 (t, J = 7.3 Hz, 2H), 6.52 (s, 1H), 7.17-7.21 (m, 2H), 8.37-8.40 (m, 2H); 13C NMR δ 14.0, 22.5, 26.6, 27.4, 28.6, 31.4, 101.6, 115.6, 115.8, 133.4, 133.5, 161.8, 174.9, 184.4; HRMS (TOF-Cl) calcd for C16H19NO2F (MH+): 276.1394. Found: 276.1397.
3-(2-Thienylcarbonyl)-5-hexylisoxazole (9a): a yellow oil; IR (neat) 2954, 2929, 1685, 1644, 762, 725, 680, 630 cm-1; 1H NMR δ 0.89 (t, J = 7.3 Hz, 3H), 1.25-1.43 (m, 6H), 1.74 (quint., J = 7.3 Hz, 2H), 2.83 (t, J = 7.3 Hz, 2H), 6.52 (s, 1H), 7.20-7.22 (m, 1H), 7.78-7.79 (m, 1H), 8.43-8.45 (m, 1H); 13C NMR δ 13.9, 22.4, 26.5, 27.3, 28.6, 31.3, 101.0, 128.4, 135.8, 136.5, 141.6, 161.5, 174.9, 177.3; HRMS (TOF-Cl) calcd for C14H18NO2S (MH+): 264.1052. Found: 264.1051.

ACKNOWLEDGEMENTS
This work was financially supported by the Nihon University College of Science and Technology Grants-in-Aid for Fundamental Science Research.

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