Regioselective Synthesis of 3,4-Disubstituted Isoxazoles by Using a Chalcone-Rearrangement Strategy

Abstract

We have developed a regioselective synthesis of 3,4-disubstituted isoxazoles by using a chalcone-rearrangement strategy. The reaction of β-ketoacetals with hydroxylamine hydrochloride and pyridine afforded the corresponding 3,4-disubstituted isoxazoles via isoxazolines or oximes. Depending on the substrate, another disubstituted isomer was also obtained under our optimized conditions, and a reaction mechanism for each transformation is proposed.

Isoxazoles are a class of important heterocyclic frameworks with multiple applications in biological and pharmacological science.[1] There has been recent interest in functionalized isoxazoles,[2] and the synthesis of isoxazole derivatives is attractive; numerous methods have been reported.[3]

Our research focuses on the development of methods for synthesizing various heterocycles by using β-ketoacetals,[4] which are easily obtained by the rearrangement of chalcones.[5] We have reported methods for synthesizing 3-acylindoles[6] and for the highly selective synthesis of two benzofuran isomers.[7] In this study, we investigated the synthesis of isoxazoles by using a chalcone-rearrangement strategy. With this heterocyclic synthesis approach, 4,5-disubstituted isoxazoles were selectively synthesized in two different ways (Scheme [1]). Kamal and co-workers synthesized 4,5-diarylisoxazoles by using the corresponding chalcones via ditosylate intermediates (Scheme [1a]).[8] The Semenov group’s method involved the construction of 4,5-disubstituted isoxazoles through the reaction of hydroxylamine with β-ketoacetals (Scheme [1b]).[9] Although there are several methods for synthesizing 3,4-disubstituted isoxazoles,[10] a method starting from chalcones has not been developed, and different sources are needed to supply regioisomers. Consequently, 3,4-disubstituted isoxazoles had to be synthesized from nitrostilbenes in the Semenov group’s biological investigation (Scheme [1c]).[9c] [11]

However, 3,4-disubstituted isoxazoles were obtained when hydroxylamine reacted with the carbonyl group instead of the acetal moiety in β-ketoacetals (Scheme [1d]). The selective synthesis of regioisomers from chalcones would simplify the supply of isoxazole derivatives. We therefore examined the reaction conditions needed to control the selective synthesis of 3,4-disubstituted isoxazoles, and we achieved conversion via two groups of intermediates (oximes or isoxazolines), followed by a cyclization reaction.[12]

We began to investigate the conditions required to form 3,4-disubstituted isoxazoles by using the β-ketoacetal 1a, which is easily obtained by the oxidative rearrangement of the corresponding chalcone, as the substrate (Table [1]). Initially, we used hydroxylamine hydrochloride and sodium acetate in EtOH under reflux conditions as general conditions for oxime formation, but only a trace of the target 3,4-disubstituted isoxazole 2a was obtained, and 1a was recovered (Table [1], entry 1). When LiOH, a stronger base, was used, decomposition occurred, although small amounts of 2a and 3a were isolated (entry 2). The reaction became complicated when K₂CO₃ was used (entry 3). Isoxazoles were not detected with pyridine, but a precursor of 2a, the isoxazoline 4a, was isolated in 20% yield (entry 4). When the reaction was performed with excess pyridine, 4a was obtained as the major product (entry 5). After screening the reagent amount and solvent concentration, 4a was finally obtained in 92% yield by using 1.5 equivalents of hydroxylamine hydrochloride and 3.0 equivalents of pyridine in 0.5 M MeOH (entry 6).

Table 1 Optimization of reaction conditions

Entry	Base (equiv)	ROH (M)	Temp (°C)	Time (h)	Yielda (%)
					2a	3a	4a
1	AcONa (2.0)	EtOH (0.1)	80	24	trace	–	–
2	LiOH·H2O (2.0)	MeOH (0.1)	60	10	12	8	–
3	K2CO3 (2.0)	MeOH (0.1)	80	4	–	–	–
4	pyridine (2.0)	MeOH (0.1)	80	24	–	–	20
5	pyridine (6.0)	MeOH (0.1)	80	24	10	–	75
6	pyridine (3.0)	MeOH (0.5)	80	24	trace	–	92

^a Isolated yield.

We next examined the conditions required for the formation of isoxazole 2a (Table [2]). The reaction did not occur in the presence of pyridine or K₂CO₃, even under reflux conditions, and 4a was recovered completely (Table [2], entries 1 and 2). When 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used in EtOH with heating, 2a was isolated in 92% yield (entry 3). The conversion also proceeded with NaH, and afforded 2a in 95% yield (entry 4). We conducted additional experiments under acidic conditions. Aromatization did not proceed using TsOH at room temperature, but 2a was obtained in 84% yield on increasing the temperature to 80 °C (entry 5). TFA, a weaker acid, was ineffective for the conversion of 4a (entry 6).

Table 2 Survey of reaction conditions for the aromatization^a

Entry	Reagent	Solvent	Temp (°C)	Time (h)	Yieldb (%)
1	pyridine	THF	65	24	–
2	K2CO3	THF	65	24	–
3	DBU	EtOH	80	3	92
4	NaH	THF	rt	1	95
5	TsOH	toluene	80	7	79
6	TFA	toluene	80	24	–

^a Reaction conditions: 4a (0.1 mmol), solvent (1.0 mL).

^b Isolated yield.

After optimizing the formation of 3,4-disubstituted isoxazoles, we investigated the substrate scope of the β-ketoacetal 1 (Table [3]). For β-ketoacetals with two electron-rich aromatic rings (1b and 1c), the cyclization reaction worked well, affording isoxazolines 4b and 4c in yields of 71 and 53%, respectively (Table [3], entries 1 and 2). When halogens or electron-withdrawing groups were attached to the aromatic rings (1d–h), isoxazolines 4d–h and oximes 5d–h were obtained in moderate yields (entries 3–7). Substrates carrying an alkyl group, 1i and 1j, gave the corresponding isoxazolines 4i and 4j in yields of 69 and 79%, respectively (entries 8 and 9).

Table 3 Substrate scope of β-ketoacetals 1

Entry	Substrate	R	Ar	Yield (%)a of 4	Yield (%)a of 5
1	1b	4-MeOC6H4	4-MeOC6H4	71	–
2	1c	4-MeOC6H4	1-naphthyl	53	–
3	1d	4-O2NC6H4	4-MeOC6H4	57	18
4	1e	4-MeOC6H4	4-ClC6H4	29	51
5	1f	4-ClC6H4	4-MeOC6H4	32	43
6	1g	4-BrC6H4	4-MeC6H4	42	38
7	1h	4-IC6H4	4-MeOC6H4	30	41
8	1i	cyclohexyl	4-MeOC6H4	69	–
9	1j	Et	4-MeOC6H4	79	–

^a Isolated yield.

We next examined the substrate scope of 3,4-isoxazole formation under basic and acidic conditions (Scheme [2]). First, we examined the reaction to give isoxazoline 4 as the major product (Table [3]). Isoxazolines 4b and 4c reacted smoothly under basic conditions, affording isoxazoles 2b and 2c, respectively, in yields of 99 and 97%. Whereas some decomposition occurred in the conversion of 4i and 4j under basic conditions, the yields of both 2i and 2j increased significantly under acidic conditions.

We also evaluated the conversion of oximes 5, and we found that isoxazoles formed smoothly compared with the conversion from the isoxazolines 4 (Scheme [3]). When one equivalent of TsOH was used, the reaction of oxime 5d at room temperature gave isoxazole 2d in 30 minutes. Under these conditions, all the oximes 5e–h were efficiently converted into the corresponding isoxazoles 2e–h in high yields.

Another isoxazole isomer was obtained when screening some β-ketoacetals 1. The reaction of β-ketoacetal 1k bearing an ortho-substituent on the benzene ring gave the 4,5-disubstituted isoxazole 3k as the major product (52%) (Scheme [4]). The reaction of isoxazoline 4k gave the 3,4-disubstituted isoxazole 2k under aromatization conditions, thus confirming that the main isoxazole obtained from 1k was the regioisomer 3k. Other β-ketoacetals showed similar regioselectivities, and 1l gave isoxazole 3l in 55% yield. In comparison, the presence of a bromo or nitro group tended to increase the yields of 4,5-disubstituted isoxazoles (3m: 97% yield; 3n: 72% yield).

To gain insight into the formation of 4,5-disubstituted isoxazoles, we next performed a control experiment by using enone 6, prepared from β-ketoacetal 1a (Scheme [5]). The reaction of 6 with NH₂OH·HCl and pyridine under our optimized conditions led to the 4,5-disubstituted product 3a in 69% yield. Because 3a was isolated directly from 1a only when a relatively strong base was used (Table [1], entry 2), an enone might be an intermediate in the formation of 3.

Based on our investigation, possible pathways for isoxazole formation depending on the nature of the β-ketoacetal 1 are outlined in Scheme [6]. For the synthesis of 3,4-disubstituted isoxazole 2, hydroxylamine preferentially undergoes a 1,2-addition reaction with the carbonyl group in 1. The transformation then proceeds by different pathways, via either the isoxazoline 4 or the oxime 5. As shown in path A, isoxazoline 4 might be generated by cyclization followed by dehydration. The resulting 4 is aromatized to isoxazole 2 under acidic or basic conditions. In contrast, 4 was not detected in the transformation of oxime 5, and isoxazole 2 was formed under acidic conditions without heating, suggesting that the conversion of 5 into 2 does not occur via 4. The presumed reaction mechanism is that the geometric isomer of 4, the cis-form 4′,[13] is formed as a result of cyclization from oxime 5. Methanol elimination occurs quickly due to the steric hindrance between the adjacent methoxy group and the aromatic ring (path B). The results in Table [3] suggest that two pathways compete in the reactions of 1d–h, and that stable intermediates 4 or 5 were isolated from each pathway. In the presence of an ortho-substituent on the benzene ring, Michael-type addition of the hydroxylamine generates a hemiaminal intermediate that transforms into the 4,5-disubstituted isoxazole 3 through a sequence of cyclization and aromatization (path C).

In summary, we investigated the synthesis of isoxazoles by using a chalcone-rearrangement strategy and we obtained 3,4-disubstituted isoxazoles, unlike the regioisomers obtained from reported chalcone transformations.[14] Under our optimized conditions, β-ketoacetals were converted into isoxazolines or oximes, whereas 4,5-disubstituted isoxazoles were formed directly from β-ketoacetals with steric hindrance at positions adjacent to the carbonyl group.[15] Combining this study with reported isoxazole syntheses will permit a more diverse range of isoxazoles to be obtained from chalcones.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank the Kindai University Joint Research Center for use of their facilities.

• References and Notes

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• 3a Hu F, Szostak M. Adv. Synth. Catal. 2015; 357: 2583
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• 3b Das S, Chanda K. RSC Adv. 2021; 11: 32680
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• 4a Miki Y, Kobayashi S, Ogawa N, Hachiken H. Synlett 1994; 1001
  Thieme Connect
• 4b Miki Y, Fujita R, Matsushita K. J. Chem. Soc., Perkin Trans. 1 1998; 2533
  Crossref
• 4c Nakamura A, Takane R, Tanaka J, Morimoto J, Maegawa T. Heterocycles 2018; 97: 785
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• 5 Moriarty RM, Khosrowshahi JS, Prakash O. Tetrahedron Lett. 1985; 26: 2961
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• 6 Nakamura A, Tanaka S, Imamiya A, Takane R, Ohta C, Fujimura K, Maegawa T, Miki Y. Org. Biomol. Chem. 2017; 15: 6702
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• 7 Nakamura A, Imamiya A, Ikegami Y, Rao F, Yuguchi H, Miki Y, Maegawa T. RSC Adv. 2022; 12: 30426
  CrossrefPubMedSearch in Google Scholar
• 8 Kamal R, Sharma D, Wadhwa D, Prakash O. Synlett 2012; 93
  Thieme Connect
• 9a Tsyganov DV, Semenova MN, Konyushkin LD, Ushkarov VI, Raihstat MM, Semenov VV. Mendeleev Commun. 2019; 29: 163
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• 9b Stroylov VS, Svitanko IV, Maksimenko AS, Kislyi VP, Semenova MN, Semenov VV. Bioorg. Med. Chem. Lett. 2020; 30: 127608
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• 9c Silyanova EA, Ushkarov VI, Samet AV, Maksimenko AS, Koblov IA, Kislyi VP, Semenovac MN, Semenov VV. Mendeleev Commun. 2022; 32: 120
  CrossrefSearch in Google Scholar
• 10a Kim HJ, Lee JH, Olmstead MM, Kurth MJ. J. Org. Chem. 1992; 57: 6513
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• 10b Grecian S, Fokin VV. Angew. Chem. Int. Ed. 2008; 47: 8285
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• 10c Brahma S, Ray JK. J. Heterocycl. Chem. 2008; 45: 311
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• 10d Schmitt DC, Lam L, Johnson JS. Org. Lett. 2011; 13: 5136
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• 10e Dissanayake AA, Odom AL. Tetrahedron 2012; 68: 807
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• 10f Jia Q, Benjamin PM. S, Huang J, Du Z, Zheng X, Zhang K, Conney AH, Wang J. Synlett 2013; 24: 79
  Search in Google Scholar
• 11 Chernysheva NB, Maksimenko AS, Andreyanov FA, Kislyi VP, Strelenko YA, Khrustalev VN, Semenova MN, Semenov VV. Eur. J. Med. Chem. 2018; 146: 511
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For other reports on syntheses of disubstituted isoxazole from chalcones, see:
• 12a Wei X, Fang J, Hu Y, Hu H. Synthesis 1992; 1205
  Thieme Connect
• 12b Desai VG, Tilve SG. Synth. Commun. 1999; 29: 3017
  CrossrefSearch in Google Scholar
• 12c Kurangi RF, Kawthankar R, Sawal S, Desai VG, Tilve SG. Synth. Commun. 2007; 37: 585
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• 12d Tang S, He J, Sun Y, He L, She X. Org. Lett. 2009; 11: 3982
  CrossrefPubMedSearch in Google Scholar
• 12e Bhatt A, Singh RK, Kant R. Synth. Commun. 2019; 49: 1083
  CrossrefSearch in Google Scholar
• 12f Bhatt A, Singh RK, Kant R. Tetrahedron Lett. 2019; 60: 1143
  CrossrefSearch in Google Scholar
• 13 The trans-relationship between the aromatic ring and the methoxy group was confirmed by X-ray crystallographic analysis of 4a. See the Supporting Information for the details of the X-ray analysis.
• 14 Isoxazoles; General Procedure NaH (2.0 equiv) was added to a solution of the appropriate isoxazoline (1.0 equiv) in THF (0.1 M), and the mixture was stirred at r.t. until the reaction was complete. The reaction was then quenched with aq NH₄Cl and the organic layer was extracted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (10:1)]. 3-(4-Methoxyphenyl)-4-(p-tolyl)isoxazole (2a) White solid; yield: 95%; mp 141–142 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.45 (s, 1 H), 8.45 (d, J = 8.8 Hz, 2 H), 7.16 (s, 4 H), 6.89 (d, J = 8.8 Hz, 2 H), 3.83 (s, 3 H), 2.37 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 160.8, 160.0, 156.2, 138.0, 130.2, 129.6, 128.9, 126.3, 121.1, 120.2, 114.2, 55.4, 21.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₆NO₂: 266.1181; found: 266.1168.
• 15 4,5-Disubstituted Isoxazoles; General Procedure NH₂OH·HCl (1.5 equiv) and pyridine (3.0 equiv) were added to a solution of the appropriate β-ketoacetal 1 (1.0 equiv) in MeOH (0.5 M), and the mixture was stirred at 80 °C for 24 h, then cooled to r.t. The reaction was then quenched with aq NH₄Cl, and the organic layer was extracted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (10:1)]. 5-(2-Methoxyphenyl)-4-(p-tolyl)isoxazole (3k) Pale-yellow oil; yield: 98%. ¹H NMR (400 MHz, CDCl₃): δ = 8.48 (s, 1 H), 7.48–7.43 (m, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 2 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 3.54 (s, 3 H), 2.33 (s, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 162.4, 157.2, 150.7, 137.2, 131.8, 131.1, 129.3, 127.8, 127.2, 120.8, 117.8, 117.4, 111.7, 55.4, 21.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₆NO₂: 266.1176; found: 266.1174.

Corresponding Author

Publication History

Received: 07 January 2023

Accepted after revision: 06 February 2023

Accepted Manuscript online:
06 February 2023

Article published online:
01 March 2023

© 2023. Thieme. All rights reserved

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• References and Notes

• 1 Arya GC, Kaur K, Jaitak V. Eur. J. Med. Chem. 2021; 221: 113511
  CrossrefPubMedSearch in Google Scholar
• 2a Morita T, Yugandar S, Fuse S, Nakamura H. Tetrahedron Lett. 2018; 59: 1159
  CrossrefPubMedSearch in Google Scholar
• 2b Bondarenko OB, Zyk NV. Chem. Heterocycl. Compd. 2020; 56: 1523
  CrossrefSearch in Google Scholar
• 3a Hu F, Szostak M. Adv. Synth. Catal. 2015; 357: 2583
  CrossrefSearch in Google Scholar
• 3b Das S, Chanda K. RSC Adv. 2021; 11: 32680
  CrossrefPubMedSearch in Google Scholar
• 4a Miki Y, Kobayashi S, Ogawa N, Hachiken H. Synlett 1994; 1001
  Thieme Connect
• 4b Miki Y, Fujita R, Matsushita K. J. Chem. Soc., Perkin Trans. 1 1998; 2533
  Crossref
• 4c Nakamura A, Takane R, Tanaka J, Morimoto J, Maegawa T. Heterocycles 2018; 97: 785
  CrossrefSearch in Google Scholar
• 5 Moriarty RM, Khosrowshahi JS, Prakash O. Tetrahedron Lett. 1985; 26: 2961
  CrossrefPubMedSearch in Google Scholar
• 6 Nakamura A, Tanaka S, Imamiya A, Takane R, Ohta C, Fujimura K, Maegawa T, Miki Y. Org. Biomol. Chem. 2017; 15: 6702
  CrossrefPubMedSearch in Google Scholar
• 7 Nakamura A, Imamiya A, Ikegami Y, Rao F, Yuguchi H, Miki Y, Maegawa T. RSC Adv. 2022; 12: 30426
  CrossrefPubMedSearch in Google Scholar
• 8 Kamal R, Sharma D, Wadhwa D, Prakash O. Synlett 2012; 93
  Thieme Connect
• 9a Tsyganov DV, Semenova MN, Konyushkin LD, Ushkarov VI, Raihstat MM, Semenov VV. Mendeleev Commun. 2019; 29: 163
  CrossrefSearch in Google Scholar
• 9b Stroylov VS, Svitanko IV, Maksimenko AS, Kislyi VP, Semenova MN, Semenov VV. Bioorg. Med. Chem. Lett. 2020; 30: 127608
  CrossrefPubMedSearch in Google Scholar
• 9c Silyanova EA, Ushkarov VI, Samet AV, Maksimenko AS, Koblov IA, Kislyi VP, Semenovac MN, Semenov VV. Mendeleev Commun. 2022; 32: 120
  CrossrefSearch in Google Scholar
• 10a Kim HJ, Lee JH, Olmstead MM, Kurth MJ. J. Org. Chem. 1992; 57: 6513
  CrossrefSearch in Google Scholar
• 10b Grecian S, Fokin VV. Angew. Chem. Int. Ed. 2008; 47: 8285
  CrossrefPubMedSearch in Google Scholar
• 10c Brahma S, Ray JK. J. Heterocycl. Chem. 2008; 45: 311
  CrossrefSearch in Google Scholar
• 10d Schmitt DC, Lam L, Johnson JS. Org. Lett. 2011; 13: 5136
  CrossrefPubMedSearch in Google Scholar
• 10e Dissanayake AA, Odom AL. Tetrahedron 2012; 68: 807
  CrossrefSearch in Google Scholar
• 10f Jia Q, Benjamin PM. S, Huang J, Du Z, Zheng X, Zhang K, Conney AH, Wang J. Synlett 2013; 24: 79
  Search in Google Scholar
• 11 Chernysheva NB, Maksimenko AS, Andreyanov FA, Kislyi VP, Strelenko YA, Khrustalev VN, Semenova MN, Semenov VV. Eur. J. Med. Chem. 2018; 146: 511
  CrossrefPubMedSearch in Google Scholar

For other reports on syntheses of disubstituted isoxazole from chalcones, see:
• 12a Wei X, Fang J, Hu Y, Hu H. Synthesis 1992; 1205
  Thieme Connect
• 12b Desai VG, Tilve SG. Synth. Commun. 1999; 29: 3017
  CrossrefSearch in Google Scholar
• 12c Kurangi RF, Kawthankar R, Sawal S, Desai VG, Tilve SG. Synth. Commun. 2007; 37: 585
  CrossrefSearch in Google Scholar
• 12d Tang S, He J, Sun Y, He L, She X. Org. Lett. 2009; 11: 3982
  CrossrefPubMedSearch in Google Scholar
• 12e Bhatt A, Singh RK, Kant R. Synth. Commun. 2019; 49: 1083
  CrossrefSearch in Google Scholar
• 12f Bhatt A, Singh RK, Kant R. Tetrahedron Lett. 2019; 60: 1143
  CrossrefSearch in Google Scholar
• 13 The trans-relationship between the aromatic ring and the methoxy group was confirmed by X-ray crystallographic analysis of 4a. See the Supporting Information for the details of the X-ray analysis.
• 14 Isoxazoles; General Procedure NaH (2.0 equiv) was added to a solution of the appropriate isoxazoline (1.0 equiv) in THF (0.1 M), and the mixture was stirred at r.t. until the reaction was complete. The reaction was then quenched with aq NH₄Cl and the organic layer was extracted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (10:1)]. 3-(4-Methoxyphenyl)-4-(p-tolyl)isoxazole (2a) White solid; yield: 95%; mp 141–142 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.45 (s, 1 H), 8.45 (d, J = 8.8 Hz, 2 H), 7.16 (s, 4 H), 6.89 (d, J = 8.8 Hz, 2 H), 3.83 (s, 3 H), 2.37 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 160.8, 160.0, 156.2, 138.0, 130.2, 129.6, 128.9, 126.3, 121.1, 120.2, 114.2, 55.4, 21.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₆NO₂: 266.1181; found: 266.1168.
• 15 4,5-Disubstituted Isoxazoles; General Procedure NH₂OH·HCl (1.5 equiv) and pyridine (3.0 equiv) were added to a solution of the appropriate β-ketoacetal 1 (1.0 equiv) in MeOH (0.5 M), and the mixture was stirred at 80 °C for 24 h, then cooled to r.t. The reaction was then quenched with aq NH₄Cl, and the organic layer was extracted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (10:1)]. 5-(2-Methoxyphenyl)-4-(p-tolyl)isoxazole (3k) Pale-yellow oil; yield: 98%. ¹H NMR (400 MHz, CDCl₃): δ = 8.48 (s, 1 H), 7.48–7.43 (m, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 2 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 3.54 (s, 3 H), 2.33 (s, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 162.4, 157.2, 150.7, 137.2, 131.8, 131.1, 129.3, 127.8, 127.2, 120.8, 117.8, 117.4, 111.7, 55.4, 21.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₆NO₂: 266.1176; found: 266.1174.

• Supplementary Material