A Facile Approach to the Synthesis of 3-Acylisoxazole Derivatives with Reusable Solid Acid Catalysts

Key words

isoxazoles - nitrile oxide - solid acid - supported reagents - acidic polymer - facile synthesis

The heterogeneous reaction with solid acid catalysts has been used for many kinds of the organic synthesis in the field of green chemistry,[1] because this catalyst has some merits of low cost, ease of preparation, ease of handling, and easy separation of the catalyst from the products. In general, zeolite, acidic solid-supported reagents, and ion-exchange resins have been used as solid acid catalyst. Among them, we have reported various organic transformations using silica gel-supported sodium hydrogen sulfate (NaHSO₄/SiO₂). For instance, direct alkylation of aromatics using alcohols,[2] cross-coupling of two different alcohols,[3] Ritter reaction from alcohols and nitriles,[4] C–C bond cleavage of 1,3-diketones,[5] and the formation of chroman ring from benzylic and aliphatic alcohols[6] were reported.

Recently, we have reported that α-nitro ketones were converted into the corresponding nitrile oxides using acidic silica gel-supported reagents, followed by the synthesis of 3-benzoylisoxazoles on reaction with alkynes in the presence of silica gel-supported polyphosphoric acid (PPA/SiO₂).[7] N-Alkoxyacyimidoyl halides were synthesized by the reaction of alkyl halides with nitrile oxides in the presence of NaHSO₄/SiO₂ [8] (Scheme [1a]). Among the products, isoxazole and related 4,5-dihydroisoxazole (isoxazoline) derivatives as five-membered nitrogen-containing heterocycles are useful organic compounds.

Scheme 1 A facile approach to the synthesis of isoxazole derivatives

The isoxazole ring units are a key structure in many of natural products or biologically and pharmaceutically active compounds[9] (Figure [1]), such as muscimol [3-hydroxy-5-aminomethylisoxazole, γ-aminobutyric acid-A receptor (GABA_A) agonist],[10] and ibotenic acid [α-amino-3-hydroxy-5-isoxazoleacetic acid, N-methyl-d-aspartate receptor (NMDA) agonist],[11] or isocarboxazid [1-benzyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine, monoamine oxidase inhibitors (MAOIs)],[12] leflunomide {5-methyl-N-[4-(trifluoromethyl)phenyl]isoxazole-4-carboxamide, an immunosuppressive agents for rheumatoid arthritis},[13] and valdecoxib [4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfoamide, cyclooxygenase-2 inhibitor].[14] Nitrile oxides are versatile intermediates prepared from aldoximes or nitroalkanes, affording isoxazole or isoxazoline derivatives by intermolecular [3+2] cycloaddition with dipolarophiles (alkynes or alkenes).[15]

Figure 1 Biologically and pharmaceutically active isoxazoles

The heterocycles isoxazoles and isoxazolines are building blocks and available synthons in synthetic chemistry, and they can be converted into β-enamino ketones (from isoxazoles),[16] β-hydroxy ketones, or γ-amino alcohols (from isoxazolines)[17] via the reductive ring cleavage of the N–O heterocyclic bond. Concerning the synthesis of isoxazole derivatives from α-nitro ketones as substrate, the corresponding nitrile oxides are prepared by the action of strong acid (sulfuric acid or p-toluenesulfonic acid)[18] or base [1,4-diazabicyclo[2.2.2]octane (DABCO) or copper(II) acetate/ N-methylpiperidine (NMP)] on α-nitro ketones.[19] In this paper, we report on the facile synthesis of 3-acylisoxazoles[20] from α-nitro ketones and alkynes in the presence of NaHSO_­4/SiO₂ (Scheme [1b]). The use of NaHSO₄/SiO₂ is more excellent due to the low cost, preparation and handling (viscosity, calculation of the equivalent, and so on) compared with PPA/SiO₂. In addition, we would like to report the convenient synthetic method for isoxazole derivatives using Amberlyst 15 as a solid acid catalyst. Amberlyst 15, based on styrene-divinylbenzene polymer including a sulfo group, is a strong acidic catalyst in several organic reactions.[21] Also, we have investigated the reusability of these catalysts in the present synthetic methods.

At first, the reaction of benzoylnitromethane (1a) and 1-octyne (2a) in the presence of NaHSO₄/SiO₂ was performed in toluene under reflux. The results in the amount of catalyst used are summarized in Table [1].

Table 1 Effect of the Amount of Catalyst on the Synthesis of 3aa ^a

Entry	Amount (g) of NaHSO4/SiO2	Yield (%)b of 3aa
1 2 3 4	0.025 0.050 0.075 0.25	53, 1a (45)c 73, 1a (18)c 86 89

^a Reaction conditions: 1a (0.50 mmol), 2a (0.60 mmol), NaHSO₄/SiO₂ (2.1 mmol g^–1) in toluene (5.0 mL) under reflux for 6 h.

^b The yields are based on 1a as determined by GLC.

^c Yield of recovered 1a.

Since the reaction using NaHSO₄/SiO₂ (0.25 g, 2.1 mmol g^–1) gave 3-benzoyl-5-hexylisoxazole (3aa) in the highest yield (Table [1], entry 4), this condition was considered as the optimum.

This synthetic method is a heterogeneous reaction, and the separation of NaHSO₄/SiO₂ from the reaction mixture by filtration is simple. The recovered catalyst is reused in the next reaction after washing and drying. Therefore, we attempted the recycling reaction of NaHSO₄/SiO₂ (Table [2]).

Table 2 The Reusability of Recovered Catalyst on the Reaction of 1a and 2a ^a

Entry	Number of uses	Yield (%)b of 3aa
1 2 3 4 5 6 7 8 9 10	1 2 3 4 5 6 7 8 9 10	89 97 99 91 98 89 88 79, 1a (14)c 78, 1a (8)c 82, 1a (16)c

^a Reaction conditions: 1a (0.50 mmol), 2a (0.60 mmol), NaHSO₄/SiO₂ (0.25 g, 2.1 mmol g^–1) in toluene (5.0 mL) under reflux for 6 h.

^b The yields are based on 1a as determined by GLC.

^c Yield of recovered 1a.

From the results, it can be seen that this catalyst was recycled ten times (Table [2], entries 1–10), and 3aa was obtained in sufficient yield.

Also, the previous several reports indicated that the transformation of 1a to 3aa using acidic solid-supported reagents proceeded through the corresponding nitrile oxide, and the nitrile oxide was dimerized into the corresponding furoxan 4a. Then, we tested the reaction of 1a in the presence of NaHSO₄/SiO₂ to confirm the reaction pathway (Scheme [2]). When the reaction of 1a (0.50 mmol) was conducted in the presence of NaHSO₄/SiO₂ (0.25 g, 2.1 mmol g^–1) in toluene (5.0 mL) under reflux for 6 h, the corresponding furoxan 4a was formed in 11% isolated yield via dimerization of nitrile oxide formed by dehydration from 1a.

Scheme 2 Formation of furoxan 4a from 1a

Then, the reaction of 1a with several alkynes 2 in the presence of NaHSO₄/SiO₂ was carried out (Table [3]). In the reaction using terminal alkynes (Table [3], entries 1–13), 5-substituted 3-benzoylisoxazoles were obtained in good yields expect from ethynylbenzene (2l). The reaction using 2l afforded a low yield of 3al (36%, entry 11). Besides, in the case of internal alkynes, 4,5-disubstituted 3-benzoylisoxazoles were obtained in moderately yields (entries 14 and 15).

Table 3 Reaction of 1a and Alkynes 2 in the Presence of NaHSO₄/SiO₂ ^a

Entry	Alkyne 2	Product 3 Yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15	2b (R2 = H, R3 = C3H7) 2c (R2 = H, R3 = C4H9) 2d (R2 = H, R3 = C5H11) 2e (R2 = H, R3 = C7H15) 2f (R2 = H, R3 = C8H17) 2g (R2 = H, R3 = CH2Cl) 2h (R2 = H, R3 = CH2Br) 2i (R2 = H, R3 = CHMe2) 2j (R2 = H, R3 = CMe3) 2k (R2 = H, R3 = SiMe3) 2l (R2 = H, R3 = Ph) 2m (R2 = H, R3 = CO2Me) 2n (R2 = H, R3 = CO2Et) 2o (R2 = R3 = CO2Me) 2p (R2 = R3 = CO2Et)	3ab (86) 3ac (80) 3ad (84) 3ae (84) 3af (92) 3ag (82) 3ah (93) 3ai (73) 3aj (66) 3ak (97) 3al (36) 3am (90) 3an (91) 3ao (66) 3ap (69)

^a Reaction conditions: 1a (0.50 mmol), 2 (0.60 mmol), NaHSO₄/SiO₂ (0.25 g, 2.1 mmol g^–1) in toluene (5.0 mL) under reflux for 6 h.

^b Isolated yield based on 1a.

In addition, we tested the reaction using 1-octene (5a) as one example about the use of alkenes to compare with the synthetic method using PPA/SiO₂.[7] When 1a (0.50 mmol) was reacted with 1-octene (5a; 0.60 mmol) in the presence of NaHSO₄/SiO₂ (0.25 g, 2.1 mmol g^–1) in toluene (5 mL) under reflux for 6 hours, the corresponding 3-benzoyl-5-hexyl-4,5-dihydroisoxazole (6aa) was obtained in 89% isolated yield (Scheme [3]).

Scheme 3 Reaction of 1a and 5a in the presence of NaHSO₄/SiO₂

Also, the reaction of α-nitro ketones 1b–e with alkynes 2 in the presence of NaHSO₄/SiO₂ was carried out (Table [4]).

Table 4 The Reaction of α-Nitro Ketones 1b–e and Alkynes 2 in the Presence of NaHSO₄/SiO₂ ^a

Entry	α-Nitro ketone 1	Alkyne 2	Product 3 Yield (%)b
1 2 3 4 5 6 7 8 9 10 11	1b, R1 = 4-MeC6H4 1c, R1 = 2-Thienyl 1d, R1 = Et 1e, R1 = C10H21 1b 1c 1d 1e 1b 1c 1e	2a 2a 2a 2a 2h 2h 2h 2h 2p 2p 2p	3ba (96) 3ca (81) 3da (75) 3ea (70) 3bh (91) 3ch (84) 3dh (75) 3eh (70) 3bp (85) 3cp (68) 3ep (61)

^a Reaction conditions: 1 (0.50 mmol), 2 (0.60 mmol), NaHSO₄/SiO₂ (0.25 g, 2.1 mmol g^–1) in toluene (5.0 mL) under reflux for 6 h.

^b Isolated yield based on 1.

In the case of 1 containing aromatic ring, 3-acylisoxazoles were obtained in good yields (Table [4], entries 1, 2, 5, 6, 9, and 10). However, the reaction of 1d–e substituted with alkyl group gave the corresponding isoxazoles in moderate yields (entries 3, 4, 7, 8, and 11).

Among the α-nitro ketones, the reaction of ethyl nitroacetate (1f; R¹ = OEt) with 2a gave the corresponding isoxazole derivative 3fa in low yield (27% yield, Table [5], entry 1). However, the reaction using o-dichlorobenzene as solvent instead of toluene increased the yield of 3fa (entry 2), namely, it was necessary to use a higher temperature to transform 1f into the corresponding nitrile oxide. The results using other alkynes are shown in Table [5].

Table 5 Reaction of 1f with Alkynes 2 in the Presence of NaHSO₄/SiO₂ ^a

Entry	Alkyne 2	Solvent	Product 3 Yield (%)b
1 2 3 4	2a 2a 2h 2p	Toluene o-Dichlorobenzene o-Dichlorobenzene o-Dichlorobenzene	3fa (27) 3fa (51) 3fh (42) 3fp (66)

^a Reaction conditions: 1f (0.50 mmol), 2 (0.60 mmol), NaHSO₄/SiO₂ (0.25 g, 2.1 mmol g^–1) in solvent (5.0 mL) under reflux for 6 h.

^b Isolated yield based on 1f.

On the other hand, we also investigated using Amberlyst 15 to change the supported reagent in the synthesis of 3aa from 1a and 2a. We first examined the reaction using several solvents (Table [6]), and it became clear that the use of toluene as solvent gave the highest yield compared with other solvents (Table [6], entry 5).

Table 6 Effect of Solvent on the Reaction of 1a with 2a ^a

Entry	Solvent	Yield (%)b of 3aa
1 2 3 4 5 6 7	MeOH H2O CH2Cl2 MeCN Toluene DMSO DMF	Trace N.D. 4 20 94 8 N.D.

^a Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), Amberlyst 15 (0.030 g) in solvent (2.0 mL) at 80 °C for 12 h.

^b GLC yield based on 1a. N.D.: Not detected.

Besides, we tried to the explore the optimized reaction conditions, and the results are shown in Table [7]. When the reaction of 1a and 2a in the presence of Amberlyst 15 (0.020 g) was carried out in toluene at 80 °C for 9 hours, 3aa was obtained in high yield (99%, Table [7], entry 10).

Table 7 Optimization of the Reaction Conditions Using 1a and 2a in the Presence of Amberlyst 15^a

Entry	Amberlyst 15 (g)	Temp (°C)	Time (h)	Yield (%)b of 3aa
1 2 3 4 5 6 7 8 9 10	0.005 0.010 0.020 0.030 0.020 0.020 0.020 0.020 0.020 0.020	80 80 80 80 rt 60 reflux 80 80 80	12 12 12 12 12 12 12 3 6 9	50 83 90 88 Trace 75 70 90 97 99

^a Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), Amberlyst 15 in toluene (2.0 mL).

^b GLC yield based on 1a.

We then tested the recycling reaction using Amberlyst 15 (Table [8]). After the reaction, Amberlyst 15 was recovered by filtration, and washed with methanol three times.

Table 8 The Reusability of Recovered Catalyst by Filtration on the Reaction of 1a and 2a ^a

Entry	Number of uses	Recovered catalyst (%)b	Yield (%)c of 3aa
1 2 3 4 5 6d 7 8d 9d 10d 11d 12d 13d 14d	1 2 3 4 5 6 7 1 2 3 4 5 6 7	100 100 100 74 67 52 47 100 95 91 69 43 38 32	89 95 81 59 51 75 63 85 89 96 83 85 71 39

^a Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), Amberlyst 15 (0.020 g) in toluene (2.0 mL) at 80 °C for 9 h.

^b Based on the amount of Amberlyst 15 at the first reaction.

^c GLC yield based on 1a.

^d Recovered Amberlyst 15 was regenerated by HCl (1 mol L^–1).

The typical advantage of Amberlyst 15 is the ability of its regeneration, in other words, the sulfo group was easily regenerated by treating with acid solution, especially with aqueous HCl (1 mol L^–1). The yields of 3aa and the amounts of recovered catalyst were decreased gradually in accordance with the number of uses (Table [8], entries 1–5). Then, the reaction using acid regenerated catalyst (HCl 1 mol L^–1) before the 6th reaction gave 3aa in improved yield (entries 5 and 6). However, since the amount of catalyst was decreased to 47% in the 7th reaction, the yield of 3aa was lowered (entry 7). In the case of renewable reactions by aqueous HCl in every time, these trends have continued (entries 8–14). Mostly, the shape of purchased Amberlyst 15 has a spherical structure (Figure [2]). Before the reaction Amberlyst 15 was steeped in and washed with methanol, continuously desiccated under reduced pressure, but the shape was hardly changed. Also, when the number of uses were increased, the recovery of catalyst would be difficult because it had decomposed into a fine powder. The surface of Amberlyst 15, which was kept as a spherical structure after the reaction, was gradually coarse as the number of reactions progress (Figure [2a,b]). Therefore, we tried to improve the recovered method by using decantation instead of filtration to increase the recovered amount of catalyst (Table [9]).

Figure 2 The SEM images of Amberlyst 15 (Left: whole, Right: enlargement)

Table 9 The Reusability of Recovered Catalyst by Decantation^a

Entry	Number of uses	Recovered catalyst (%)b	Yield (%)c of 3aa
1 2 3 4 5	1 2 3 4 5	100 100 99 97 97	94 96 93 88 86

^a Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), Amberlyst 15 (0.020 g) in toluene (2.0 mL) at 80 °C for 9 h.

^b Based on the amount of Amberlyst 15 at the first reaction.

^c GLC yield based on 1a.

In this method, the reaction mixture was collected from the vessel by decantation, and then Amberlyst 15 was steeped in and washed with methanol. Continuously, methanol in the vessel was removed by decantation. After this process was conducted three times, Amberlyst 15 was dried under decompression by evaporation. In the regeneration section, aqueous HCl (1 mol L^–1, 1.0 mL) was added to the vessel containing the catalyst, and this mixture was stirred for 0.5 hour. After the treatment, HCl solution was removed, and Amberlyst 15 was washed each with water and methanol three times. All the cleaning solvents were removed by decantation. Finally, Amberlyst 15 was dried under decompression by evaporation and used in the next reaction. From the results, the recovered amount of catalyst had been improved and 3aa was obtained in a satisfactory yield in the 5th reuse of the reaction (Table [9], entry 5).

Furthermore, the formation of 4a was confirmed in the reaction of 1a using Amberlyst 15 as with NaHSO₄/SiO₂.

Finally, the reaction of α-nitro ketones 1 with alkynes 2 in the presence of Amberlyst 15 was carried out. These results are summarized in Table [10]. In all the reactions, the corresponding 3-acylisoxazoles were obtained, and then the similar tendency of product yield could also be seen concerning acid solid-supported reagent.

Table 10 The Reaction of α-Nitro Ketones 1 and Alkynes 2 in the Presence of Amberlyst 15^a

Entry	α-Nitro ketone 1	Alkyne 2	Product 3 Yield (%)b
1 2 3 4 5 6 7	1a 1a 1a 1a 1c 1c 1c	2h 2l 2n 2p 2a 2h 2p	3ah (85) 3al (40) 3an (79) 3ap (80, 95/93/93/90)c 3ca (82, 97/91/98/96)c 3ch (81) 3cp (64)

^a Reaction conditions: 1 (0.30 mmol), 2 (0.36 mmol), Amberlyst 15 (0.020 g) in toluene (2.0 mL) at 80 °C for 9 h.

^b Isolated yield based on 1.

^c GLC yield based on 1 in the recycling and regenerative reactions (1st/2nd/3rd/4th reaction).

Moreover, in the synthesis of 3ap and 3ca, when the recycling reactions were performed at the 4th time, the products were obtained in excellent yields (Table [10], entries 4 and 5).

Likewise, in the reaction using 1a and 2l, it was found that acetophenone 7 was obtained as a by-product in 78% GLC yield based on 2l. Therefore, we investigated the time course of this reaction (Table [11]).

Table 11 The Time Course of Reaction Using 1a and 2l ^a

Entry	Time (h)	Yield (%)b of 2l	Yield (%)c of 3al	Yield (%)d of 7
1 2 3 4 5 6	0.5 1 2 4 6 9	3 1 N.D. N.D. N.D. N.D.	21 24 27 27 30 36	69 69 69 73 77 78

^a Reaction conditions: 1a (0.30 mmol), 2l (0.36 mmol), Amberlyst 15 (0.020 g) in toluene (2.0 mL) at 80 °C for 9 h.

^b GLC yield based on 2l. N.D.: Not detected.

^c GLC yield based on 1a.

^d GLC yield based on 2l.

Since it was known that hydration of alkynes gave the corresponding carbonyl compounds under acidic condition, it seems that the formations of 3al via the cycloaddition and 7 via the hydration concertedly proceeded in this reaction (Scheme [4]). From the results in the time course, it seems that the reaction rate of hydration is faster than cycloaddition because Amberlyst 15 directly react with 2l. Besides, even in the reaction using 1a and 2a, 2-octanone (8) was obtained via the hydration of 2a in 0.50 (reaction time: 1 h), 9.5 (2 h), 24 (4 h) and 26% (6 h) GLC yields, respectively. From the results, since the hydration of 2a by Amberlyst 15 is slower than 2l in the reaction rate, 3aa was formed in high yield in the reaction of 1a and 2a.

Scheme 4 Reaction mechanism for the formation of 3al and 7

In conclusion, we have proposed a facile and reusable synthetic method of 3-acylisoxazole derivatives using NaHSO­₄/SiO₂, or Amberlyst 15 as solid acid catalyst. In the application of solid-supported reagent, isoxazole derivatives were obtained at a lower price and to make experimental procedure easier compared with the use of PPA/SiO₂. Also, the use of acidic ion-exchange resin afforded isoxazole derivatives in a small-scale, easy handling, and renewable reaction. These catalysts can be used for different purposes as required with the effective production of isoxazole derivatives.

All reagents were purchased from commercial source. Melting points were determined on Büchi Melting Point B-540, or Mettler Toledo MP70 Melting Point System. NMR spectra were recorded on a JEOL ECX 400 spectrometer, TMS (δ = 0) was used as an internal standard for ¹H NMR and CDCl₃ (δ = 77.0) for ¹³C NMR spectroscopy. IR spectra were recorded using a Jasco FT/IR 6100 spectrometer. Mass analyses were performed on a Xevo G2-5 QTof (Waters) or a JEOL GCMate spectrometer. GC analyses were performed using GC column (DB-1, 25 m) equipped with a Shimazu GC-2014. Scanning electron microscope (SEM) of Amberlyst 15 was performed on a Hitachi SU-1510 SEM.

NaHSO₄/SiO₂

Silica gel (SiO₂, Wakogel C-200, 10 g) was added to a solution of NaHSO­₄·H₂O (4.14 g, 30 mmol) in distilled H₂O, and the mixture was stirred at rt for 0.5 h. H₂O was removed by rotary evaporator under reduced pressure, and the resulting reagent was dried in vacuo at 120 °C/10 Torr for 5 h.

3-Acylisoxazoles Using NaHSO₄/SiO₂; General Procedure

A mixture of α-nitro ketone 1 [22] (0.50 mmol), alkyne 2 (0.60 mmol), and NaHSO₄/SiO₂ (0.25 g, 2.1 mmol g^–1) was stirred in toluene (5.0 mL) under reflux for 6 h. After completion of the reaction, the mixture was filtered, and the recovered supported reagent was washed with small amounts of toluene and EtOAc. The solvent was removed from the filtrate by evaporation and the obtained crude product was purified by column chromatography (hexane/EtOAc). The GLC yield of 3-acylisoxazole was determined using 2,7-dimethoxynaphthalene as an internal standard. In the recycling reaction, after the reaction, recovered NaHSO₄/SiO₂ was washed with toluene, and dried at 180 °C for 2 h; consecutively dried catalyst was used in the next reaction.

3-Acylisoxazoles Using Amberlyst 15; General Procedure

A mixture of α-nitro ketone 1 [22] (0.30 mmol), alkyne 2 (0.36 mmol), and Amberlyst 15 (0.020 g) was stirred in toluene (2.0 mL) at 80 °C for 9 h. After completion of the reaction, the mixture was filtered, and the recovered Amberlyst 15 was washed with MeOH. The solvent was removed from the filtrate by evaporation and the obtained crude product was purified by column chromatography (hexane/EtOAc). The GLC yield of 3-acylisoxazoles were obtained using n-dodecane as an internal standard. In the recycling reaction, after the reaction, Amberlyst 15 was washed and regenerated to comply with the procedure.

The analytical and spectral data of newly prepared 3-acylisoxazoles are listed below.

3-Benzoyl-5-heptylisoxazole (3ae)

White solid; yield: 0.114 g (84%); mp 42–43 °C.

IR (neat): 3131, 2951, 2927, 2850, 1657, 1593 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 0.89 (t, J = 6.8 Hz, 3 H), 1.27–1.42 (m, 8 H), 1.76 (quint, J = 7.6 Hz, 2 H), 2.84 (t, J = 7.6 Hz, 2 H), 6.52 (s, 1 H), 7.26–7.53 (m, 2 H), 7.61–7.65 (m, 1 H), 8.28–8.31 (m, 2 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 14.0, 22.6, 26.6, 27.4, 28.8, 29.0, 31.6, 101.6, 128.5, 130.6, 133.9, 135.8, 161.8, 174.7, 186.1.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₁₇H₂₂NO₂: 272.1650; found: 272.1626.

3-Benzoyl-5-octylisoxazole (3af)

Pale-yellow oil; yield: 0.131 g (92%).

IR (neat): 2927, 2855, 1662, 1597 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 0.89 (t, J = 7.2 Hz, 3 H), 1.28–1.42 (m, 10 H), 1.75 (quint, J = 7.2 Hz, 2 H), 2.84 (t, J = 7.6 Hz, 2 H), 6.52 (s, 1 H), 7.49–7.54 (m, 2 H), 7.61–7.66 (m, 1 H), 8.28–8.31 (m, 2 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 14.1, 22.6, 26.6, 27.4, 29.0, 29.1, 29.1, 31.8, 101.6, 128.5, 130.6, 133.8, 135.9, 161.8, 174.7, 186.1.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₁₈H₂₄NO₂: 286.1807; found: 286.1769.

3-Benzoyl-4,5-diethoxycarbonylisoxazole (3ap)

White solid; yield: 0.109 g (69%); mp 44–45 °C.

IR (neat): 2986, 2936, 1747, 1732, 1669, 1597 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 1.29 (t, J = 7.2 Hz, 3 H), 1.44 (t, J = 7.2 Hz, 3 H), 4.37 (q, J = 7.2 Hz, 2 H), 4.50 (q, J = 7.2 Hz, 2 H), 7.52–7.56 (m, 2 H), 7.66–7.71 (m, 1 H), 8.15–8.18 (m, 2 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 13.8, 14.0, 62.5, 63.2, 117.6, 128.8, 130.5, 134.8, 134.9, 155.8, 159.3, 159.7, 159.9, 183.9.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₁₆H₁₆NO₆: 318.0977; found: 318.0949.

3-(4-Methylbenzoyl)-5-bromomethylisoxazole (3bh)

White solid; yield: 0.127 g (91%); mp 76–78 °C.

IR (neat): 3137, 1642, 1597, 1170, 889, 754 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 2.45 (s, 3 H), 4.55 (s, 2 H), 6.84 (s, 1 H), 7.32–7.34 (m, 2 H), 8.20–8.22 (m, 2 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 18.0, 21.8, 104.7, 129.4, 130.8, 132.9, 145.4, 162.2, 168.2, 184.7.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₁₂H₁₁BrNO₂: 279.9973; found: 279.9975.

3-(4-Methylbenzoyl)-4,5-diethoxycarbonylisoxazole (3bp)

Pale yellow oil; yield: 0.141 g (85%).

IR (neat): 2992, 1738, 1279, 1181, 1092, 1014, 899 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 1.30 (t, J = 7.2 Hz, 3 H), 1.44 (t, J = 7.2 Hz, 3 H), 2.46 (s, 3 H), 4.37 (q, J = 7.2 Hz, 2 H), 4.49 (q, J = 7.6 Hz, 2 H), 7.32–7.34 (m, 2 H), 8.05–8.08 (m, 2 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 13.8, 14.0, 21.9, 62.5, 63.2, 117.6, 129.6, 130.6, 132.5, 146.1, 155.5, 159.1, 159.8, 160.0, 183.4.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₁₇H₁₈NO₆: 332.1134; found: 332.1128.

3-(2-Thienylcarbonyl)-5-bromomethylisoxazole (3ch)

White solid; yield: 0.114 g (84%); mp 78 °C.

IR (neat): 3035, 1628, 1396, 1220, 859, 809, 723 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 4.54 (s, 2 H), 6.85 (s, 1 H), 7.21–7.24 (m, 1 H), 7.81–7.82 (m, 1 H), 8.45–8.46 (m, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 17.9, 104.2, 128.7, 136.3, 136.8, 141.3, 161.9, 168.5, 176.4.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₉H₇BrNO₂S: 271.9380; found: 271.9379.

3-Propanoyl-5-hexylisoxazole (3da)

Pale-yellow oil; yield: 0.078 g (75%).

IR (neat): 2930, 2864, 1704, 1451, 921 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 0.89 (t, J = 7.2 Hz, 3 H), 1.21 (t, J = 7.2 Hz, 3 H), 1.28–1.39 (m, 6 H), 1.71 (quint, J = 7.2 Hz, 2 H), 2.78 (t, J = 7.2 Hz, 2 H), 3.06 (q, J = 7.2 Hz, 2 H), 6.35 (s, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 7.5, 14.0, 22.4, 26.6, 27.4, 28.6, 31.3, 33.1, 99.3, 161.7, 175.4, 195.6.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₁₂H₂₀NO₂: 210.1494; found: 210.1495.

3-Propanoyl-5-bromomethylisoxazole (3dh)

Pale-yellow oil; yield: 0.081 g (75%).

IR (neat): 2981, 1704, 1450, 1148, 923 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 1.22 (t, J = 7.2 Hz, 3 H), 3.08 (q, J = 7.2 Hz, 2 H), 4.50 (s, 2 H), 6.69 (s, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 7.4, 17.9, 33.2, 102.3, 161.8, 169.0, 194.7.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₇H₁₀BrNO₂: 217.9816; found: 217.9812.

3-Undecanoyl-5-hexylisoxazole (3ea)

Pale yellow oil, yield: 0.112 g (70%).

IR (neat): 2925, 2857, 1703, 1454, 935 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 0.86–0.91 (m, 6 H), 1.26–1.38 (m, 19 H), 1.67–1.76 (m, 4 H), 2.78 (t, J = 7.6 Hz, 2 H), 3.02 (t, J = 7.2 Hz, 2 H), 6.35 (s, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 14.0, 14.1, 22.4, 22.7, 23.7, 26.6, 27.3, 28.6, 29.1, 29.3, 29.3, 29.4, 29.5, 31.3, 31.9, 39.9, 99.3, 161.9, 175.4, 195.3.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₁₆H₃₅NO₂: 322.2740; found: 322.2740.

3-Undecanoyl-5-bromomethylisoxazole (3eh)

White solid; yield: 0.115 g (70%); mp 57 °C.

IR (neat): 2919, 2852, 1701, 1456, 1144, 943 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 0.88 (t, J = 7.2 Hz, 3 H), 1.22–1.38 (m, 14 H), 1.73 (quint, J = 7.2 Hz, 2 H), 3.03 (t, J = 7.2 Hz, 2 H), 4.50 (s, 2 H), 6.68 (s, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 14.1, 17.9, 22.6, 23.6, 29.1, 29.2, 29.3, 29.4, 29.5, 31.8, 39.9, 102.3, 162.0, 168.9, 194.3.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₁₅H₂₅BrNO₂: 330.1068; found: 330.1071

3-Undecanoyl-4,5-diethoxycarbonylisoxazole (3ep)

Pale-yellow oil; yield: 0.116 g (61%).

IR (neat): 2925, 2857, 1744, 1267, 1187, 1105, 1013 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 0.88 (t, J = 7.2 Hz, 3 H), 1.26–1.34 (m, 14 H), 1.39 (t, J = 7.2 Hz, 3 H), 1.40 (t, J = 7.2 Hz, 3 H), 1.69–1.77 (m, 2 H), 3.06 (t, J = 7.2 Hz, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 4.45 (q, J = 7.2 Hz, 2 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 13.9, 14.0, 14.1, 22.7, 23.3, 29.0, 29.3, 29.4, 29.5, 31.9, 40.4, 62.7, 63.1, 116.9, 155.3, 158.6, 159.1, 160.3, 192.8.

HRMS (TOF-Cl): m/z [MH⁺] calcd for C₂₀H₃₂NO₆: 382.2229; found: 382.2222

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