INTRODUCTION

Isoxazoles are a very important class of heterocyclic compounds, because they exhibit broad-spectrum biological activity [1–4]. Based on this, several commercially available isoxazole drugs of different categories have been developed [1‒4]. In particular, a number of molecular hybrids [5‒10] containing an isoxazole moiety have been created as a result of efforts to develop new therapeutic agents. Thus, selective acetylcholinesterase inhibitors have been found among isoxazole–piperazine [6], isoxazole–tacrine [7], isoxazole–chromenone [8], and isoxazole–benzylpyridinium hybrids [8], useful for treating Alzheimer’s disease [6‒10]. Isoxazole–oxazol-5-one [11], isoxazole–oxazole–1,3,4-oxadiazole [12], indole–isoxazole [13], tetrahydroquinoline–isoxazole [14], and spirooxindole–cyclopentene–isoxazole hybrids [15] showed antitumor properties. Isoxazole–1,2,4-oxadiazole hybrids demonstrated anti-HIV activity [16]. Isoxazole–mercaptobenzimidazole hybrids are analgesic and anti-inflammatory agents [17]. Thus, the search for new synthetic approaches to molecular heterocyclic hybrids with an isoxazole fragment is of undoubted interest, and it has been significantly intensified in recent years [6–20]. Although isoxazole–oxazole hybrids showed useful biological activity, the structural diversity of available compounds is still quite limited [11, 12, 20]. Taking into account that the reaction of alkyl 2-diazo-2-heterocyclylacetates with nitriles, leading to 4-heterocyclyl-5-methoxyoxazoles, is only known for methyl 2-diazo-2-(1H-tetrazol-5-yl)acetate [21, 22] (Scheme 1, reaction (1)), we suggested that the reaction of the recently synthesized methyl 2-diazo-2-(isoxazol-5-yl)acetates [23] with nitriles might provide isoxazole–oxazole hybrids, specifically substituted 5-(5-methoxyoxazol-4-yl)isoxazoles [Scheme 1, reaction (2)]. Such approach could be useful not only due to the potential bioactivity of isoxazole–oxazole hybrids [11, 12, 20], but also because 5-alkoxyoxazole, being a versatile building block in (bio)organic synthesis [24], opens the way to the preparation of new heterocyclic hybrids containing the isoxazole core. As part of our ongoing project devoted to the synthesis of heterocycles based on isoxazoles [23, 25‒33], we report here the synthesis of variously substituted isoxazole–oxazole hybrids and some their transformations.

Scheme
scheme 1

1.

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RESULTS AND DISCUSSION

Taking into account that the intermediate nitrile ylide 5 formed from nitrile and isoxazolyl-substituted singlet carbene 4 can cyclize in several ways (to compounds 3, 6, or 7, Scheme 2), to assess the possibilities for the proposed synthesis of isoxazole–oxazole hybrides 3, we performed DFT calculations (at the DFT B3LYP-D3/6-311+G(d,p) level with SMD model for MeCN) of the energy profile of the thermolysis of diazo compound 1a in MeCN (Scheme 2, for details of the calculations, see Supplementary information). As seen from the obtained results (Scheme 2), the formation of isoxazole–oxazole hybrid 3а via the 1a+2a-TS1→4a+2a+N2-TS2→ 5a-TS4→5′a-TS5→3a route is the most favorable both from the kinetic and thermodynamic points of view. Therefore, we proceeded with the optimization of the reaction conditions for preparing oxazolylisoxazole 3b (Table 1).

Scheme
scheme 2

2.

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Since Rh2(OAc)4 is commonly used as a catalyst for the synthesis of oxazoles by the reaction of nitriles with diazo compounds bearing two electron-acceptor groups [34–36], we started optimization by reacting compound 1b with MeCN in the presence of this catalyst. However, the reaction of rhodium carbene derived from 1b in CF3Ph and DCE resulted in quite a low yield of oxazolylisoxazole 3b, and the reaction in pure MeCN gave a complex mixture of products (Table 1, entries 1–3). Therefore, we turned to the thermolytic and photolytic decomposition of diazo compound 1b in MeCN (Table 1, entries 4–8). The best result was obtained with the thermal decomposition of compound 1b at 100°C, where the yield of compound 3b for the gram-scale reaction reached 81% in 1 h (Table 1, entry 6). Photolysis required higher dilution and gave a lower product yield.

Table 1. Optimization of the reaction conditions
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Having determined the optimal reaction conditions, we explored the substrate scope of the reaction using alkyl-, aryl-, and hetaryl-substituted methyl 2-diazo-2-(isoxazol-5-yl)acetates 1b–1j and alkyl and aryl cyanides 2a–2h (Scheme 3). All new compounds were characterized by 1H and 13C NMR and HRMS. The structure of compound 3e was also confirmed by single-crystal X-ray diffraction (XRD) analysis (Fig. 1). The reaction allows the synthesis of variously substituted isoxazole–oxazole hybrids in yields of 22‒81%. The use of α,α-disubstituted acetonitrile 2b and ortho-substituted benzonitrile 2h reduces the reaction yields, most likely for steric reasons. The reaction with malononitrile 2f gave the lowest yield (22%), possibly due to nonselective cycloaddition to two CN groups, although no diadduct formation was detected. At the same time, the reaction of methyl 2-diazo-2-[(3-isoquinolin-2-yl)isoxazol-5-yl]acetate (1g) with MeCN gives isoquinoline–isoxazole–oxazole hybrid 3k in a fairly good yield.

Fig. 1.
figure 1

X-ray structure of isoxazole-oxazole hybrid 3e.

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Scheme
scheme 3

3.

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The reaction with acrylonitrile 2i proceeds in a different way to form, instead of the expected vinyl-substituted oxazole 3p, a mixture of products of the cyclopropanation of the acrylonitrile C=C bond c-8b and t-8b (Scheme 4). It is assumed that the metal-catalyzed cyclopropanation of acrylonitrile involves a metal carbene [37‒40] or a metal radical [41, 42], while metal-free cyclopropanation involves the addition of a singlet carbene to the C=C bond [43] or the decomposition of an intermediate pyrazoline resulting from the (2+3)-cycloaddition of a diazo compound to the C=C bond [48], with N2 evolution [44‒47].

Scheme
scheme 4

4.

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To shed some light on the reaction mechanism and the reasons for the absence of hybrid 3p and pyrazolines 9b and 10b among the products of the reaction of diazo compound 1b with acrylonitrile 2i, we performed DFT calculations of the energy profile of possible reactions of diazo compound 1a with acrylonitrile 2i (Scheme 5; for details of the calculations, see Supplementary information).

Scheme
scheme 5

5.

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According to the calculations, the barrier to formation of oxazole 3q is higher (TS10) compared to cyclopropanes c-8a and t-8a (TS8 and TS9), which explains the absence of hybrid 3p among the products of the reaction of diazo compound 1b with acrylonitrile 2i. Surprisingly, the formation of pyrazolines 9a and 10a via the (3+2) cycloaddition of the reagents requires overcoming rather higher barriers of 33.4‒35.6 kcal/mol (TS14‒TS17), which is appreciably higher than the barrier to the decomposition of the diazo compound to carbene 4a. From this it follows that the formation of carbene 4 followed by cyclopropanation is a preferred route to cyclopropanes 8.

Due to the high reactivity of the 5-alkoxyoxazole fragment [24] of hybrids 3, they can be used to obtain another class of isoxazole-containing heterocyclic hybrids, isoxazole–pyridines 12 with a 3-hydroxypyridine fragment which is present in biologically active compounds [24]. Actually, the hetero-Diels–Alder reaction of oxazole 3d with acrylic acid at 120°C gave isonicotinic acid derivative 12a, through the intermediate formation of an oxabicyclic intermediate followed by aromatization of the latter with elimination of MeOH (Scheme 6). The reaction of oxazole 3b with acrylic acid at 120°C gave an inseparable mixture of products, among which compound 12′b (R = CO2H) and its decarboxylation product 12b (R = H) were detected by NMR. However, the reaction carried out at 145°C provided a mixture, from which we were able to isolate decarboxylation product 12b in a yield of 26%. The hetero-Diels–Alder reaction of oxazole 3b with dimethyl fumarate, too, proceeded at a higher temperature to form decarboxylation product 12c, albeit in a low yield (Scheme 6).

Scheme
scheme 6

6.

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CONCLUSIONS

The synthesis of various substituted isoxazole–oxazole hybrids by the noncatalytic reaction of methyl 2-diazo-2-(alkyl/aryl/hetarylisoxazol-5-yl)acetates with alkyl and aryl cyanides has been reported. According to DFT calculations, the reaction proceeds through the intermediate formation of a nitrile ylide and its subsequent cyclization on the carbonyl oxygen. The reaction with acrylonitrile with methyl 2-diazo-2-(isoxazol-5-yl)acetate proceeds quite differently and leads to a mixture of cis- and trans-cyclopropanes, which, according to DFT calculations, are formed by the cycloaddition of a diazo-derived carbene to the C=C bond of acrylonitrile. The hetero-Diels–Alder reaction of the 5-alkoxyoxazole moiety of isoxazole–oxazole hybrids with electron-deficient alkenes makes it possible to obtain isoxazole–pyridine hybrids, albeit in a low yield.

EXPERIMENTAL

The melting points were determined on a Stewart SMP30 melting point apparatus. The 1H (400 MHz) and 13C (100 MHz) spectra were recorded on a Bruker AVANCE 400 spectrometer in CDCl3 or DMSO-d6. The chemical shifts (δ) are reported in ppm downfield from TMS (δ 0.00 ppm). The 1H NMR spectra were calibrated according to the residual peak of CDCl3 (7.26 ppm) and DMSO-d6 (2.50 ppm). For all new compounds, 13C{1H} and 13C DEPT-135 spectra were recorded and calibrated according to the peak of CDCl3 (77.00 ppm) and DMSO-d6 (39.51 ppm). Electrospray ionization (ESI) positive mode, mass spectra were measured on a Bruker MaXis mass spectrometer, HRMS-ESI-QTOF. Single-crystal X-ray data were collected by means of a diffractometer. The crystals of 3e were measured at temperature 100 K, using monochromated CuKα radiation. Crystallographic data for the structure 3e (CCDC 2258620) has been deposited with the Cambridge Crystallographic Data Centre. Thin-layer chromatography (TLC) was conducted on aluminum sheets with 0.2 mm silica gel with a fluorescent indicator. Physical and spectral data of methyl 2-diazo-[3-(p-tolyl)isoxazol-5-yl]acetate 1c [9], methyl 2-diazo-[3-(4-fluorophenyl)isoxazol-5-yl]acetate 1d [9], methyl 2-diazo-[3-(4-chloro)isoxazol-5-yl]acetate 1e [9], 3-(4-nitrophenyl)-5-isoxazoleacetic acid 13f [49], methyl 2-[3-(4-(tert-butyl)phenyl)-4-iodoisoxazol-5-yl]acetate 15j [27], methyl 2-[3-(4-methoxyphenyl)isoxazol-5-yl]acetate 14b [27], methyl 2-[3-(quinolin-2-yl)isoxazol-5-yl]acetate 14g [50], methyl 2-(3-benzylisoxazol-5-yl)acetate 14h [50] and methyl 2-(3-heptylisoxazol-5-yl)acetate 14i [50] were consistent with previously reported values.

Methyl 2-[3-(4-nitrophenyl)isoxazol-5-yl]acetate (14f) was prepared according published procedure [9] from 2-[3-(4-nitrophenyl)isoxazol-5-yl]acetic acid 13f (320 mg, 1.3 mmol) in THF (5 mL) and freshly prepared diazomethane [40% KOH water solution (2.2 mL), NMU (670 mg, 6.5 mmol)] in ether (30 mL) in 246 mg (73% yield), after a column chromatography on silica [light petroleum/ethyl acetate, 10 : 1, (v/v)], as a colorless solid, mp 122–123°C (light petroleum–ethyl acetate), Rf 0.32 [light petroleum–ethyl acetate, 3 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 8.34–8.30 m (2H), 8.01–7.98 m (2H), 6.70 s (1H), 3.93 s (2H), 3.80 s (3H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 167.7 (C), 166.7 (C), 160.9 (C), 148.7 (C), 135.0 (C), 127.7 (CH), 124.2 (CH), 101.7 (CH), 52.8 (CH3), 32.5 (CH2). Mass spectrum (ESI-HRMS): m/z: 285.0476 [M + Na]+ (calcd for C12H10N2NaO5+: 285.0482).

Methyl 2-[3-(4-(tert-butyl)phenyl)-4-(4-fluorophenyl)isoxazol-5-yl]acetate (14j was prepared according published procedure [27] from methyl 2-[3-(4-(tert-butyl)phenyl)-4-iodoisoxazol-5-yl]acetate 15j (227 mg, 0.57 mmol) and 4-fluoroboronic acid (96 mg, 0.69 mmol), NaHCO3 (143 mg, 1.71 mmol) and Pd(dppf)Cl2 (20.8 mg, 0.028 mmol) in dioxane (6 mL) and water (2 mL) in 128 mg (61% yield) after column chromatography on silica [light petroleum/ethyl acetate, 20 : 1, (v/v)] as a light yellow oil, Rf = 0.51 [light petroleum/ethyl acetate, 5 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.38–7.32 m (4H), 7.24–7.20 m (2H), 7.12–7.06 m (2H), 3.77 s (2H), 3.74 s (3H), 1.30 s (9H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 168.1 (C), 162.6 d (C, J = 248.1 Hz), 162.1 (C), 161.0 (C), 152.8 (C), 131.7 d (CH, J = 7.8 Hz), 127.9 (CH), 125.63 d (C, J = 3.2 Hz), 125.55 (C), 125.50 (CH), 117.1 (C), 116.0 d (CH, J = 21.6 Hz), 52.3 (CH3), 34.7 (C), 31.8 (CH2), 31.2 (CH3). Mass spectrum (ESI-HRMS): m/z 390.1476 [M + Na]+ (calcd for C22H22FNNaO+: 390.1482).

Methyl 2-diazo-2-[3-(4-methoxyphenyl)isoxazol-5-yl]acetate (1b) was prepared according published procedure [9] from methyl 2-[3-(4-methoxyphenyl)isoxazol-5-yl]acetate 14b (512 mg, 2.07 mmol), 3-(chlorosulfonyl)benzoic acid (609 mg, 2.76 mmol), NaN3 (269 mg, 4.14 mmol), K2CO3 (763 mg, 5.52 mmol) in MeCN (7 mL) and water (5.5 mL). After 2 d additional 3-(chlorosulfonyl)benzoic acid (609 mg, 2.76 mmol), NaN3 (269 mg, 4.14 mmol), K2CO3 (763 mg, 5.52 mmol), water (5.5 mL) and MeCN (12 mL) were added and reaction mixture was stirred for 3 d, to give product in 514 mg (91% yield), as a yellow solid: mp 118‒119°C (DCM), Rf = 0.22 [light petroleum/ethyl acetate, 10 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.78–7.74 m (2H), 6.99-6.96 m (2H), 6.79 s (1H), 3.92 s (3H), 3.86 s (3H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 162.9 (C), 161.1 (C), 156.2 (C), 128.3 (CH), 121.1 (C), 114.3 (CH), 98.8 (CH), 55.3 (CH3), 52.7 (CH3). Mass spectrum (ESI-HRMS): m/z 274.0822 [M + H]+ (calcd for C13H12N3O4+: 274.0824).

Methyl 2-diazo-2-[3-(4-nitrophenyl)isoxazol-5-yl]acetate (1f) was prepared according published procedure [9] from methyl 2-[3-(4-nitrophenyl)isoxazol-5-yl]acetate 14f (246 mg, 0.94 mmol), 3-(chlorosulfonyl)benzoic acid (277 mg, 1.25 mmol), NaN3 (163 mg, 2.5 mmol), K2CO3 (260 mg, 1.88 mmol) in MeCN (13 mL) and water (2 mL) to give product in 230 mg (80% yield) after 4 d, as a yellow solid: mp 158‒159°C (DCM), Rf = 0.20 [light petroleum/ethyl acetate, 10 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 8.35‒8.31 m (2H), 8.02–7.99 m (2H), 6.92 s (1H), 3.95 s (3H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 162.5 (C), 161.5 (C), 158.0 (C), 148.8 (C), 134.7 (C), 127.8 (CH), 124.2 (CH), 98.8 (CH), 52.9 (CH3). Mass spectrum (ESI-HRMS): m/z 289.0567 [M + H]+ (calcd for C12H9N4O5+: 289.0581.

Methyl 2-diazo-2-[3-(quinolin-2-yl)isoxazol-5-yl]acetate (1g) was prepared according published procedure [9] from methyl 2-[3-(quinolin-2-yl)isoxazol-5-yl]acetate 14g (134 mg, 0.5 mmol), 3-(chlorosulfonyl)benzoic acid (147 mg, 0.67 mmol), NaN3 (65 mg, 1 mmol), K2CO3 (184 mg, 1.33 mmol) in MeCN (5 mL) and water (2 mL). After 2 d additional 3-(chlorosulfonyl)benzoic acid (117 mg, 0.53 mmol), NaN3 (52 mg, 0.8 mmol), K2CO3 (147 mg, 1.06 mmol), water (1 mL) and MeCN (3 mL) were added and reaction mixture was stirred for 3 d to give product in 128 mg (88% yield), as a yellow solid: mp 129‒130°C (DCM), Rf = 0.24 [light petroleum/ethyl acetate, 10 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 8.25 d (1H, J = 8.5 Hz), 8.17 d (1H, J = 8.9 Hz), 8.14 d (1H, J = 8.5 Hz), 7.86 d. d (1H, J = 8.2, 1.4 Hz), 7.76 d. d. d (1H, J = 8.4, 6.9, 1.5 Hz), 7.59 d. d. d (1H, J = 8.1, 6.9, 1.2 Hz), 7.35 s (1H), 3.96 s (3H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 164.4 (C), 156.8 (C), 148.1 (C), 148.1 (C), 136.9 (CH), 129.90 (CH), 129.89 (CH), 128.4 (C), 127.6 (CH), 127.4 (CH), 119.1 (C), 100.2 (CH), 52.8 (CH3). Mass spectrum (ESI-HRMS): m/z 317.0645 [M + Na]+ (calcd for C15H10N4NaO3+: 317.0649.

Methyl 2-(3-benzylisoxazol-5-yl)-2-diazoacetate (1h) was prepared according published procedure [9] from methyl 2-(3-benzylisoxazol-5-yl)acetate 14h (500 mg, 2.16 mmol), 3-(chlorosulfonyl)benzoic acid (636 mg, 2.88 mmol), NaN3 (281 mg, 4.32 mmol), K2CO3 (797 mg, 5.77 mmol) in MeCN (10 mL) and water (6 mL) to give product in 340 mg (61% yield), after a column chromatography on silica [light petroleum/ethyl acetate, 20 : 1, (v/v)], as a yellow oil, Rf = 0.40 [light petroleum/ethyl acetate, 10 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.33–7.23 m (5H), 6.30 s (1H), 3.99 s (2H), 3.86 (s 3H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 163.9 (C), 156.0 (C), 136.9 (C), 128.8 (CH), 128.7 (CH), 126.9 (CH), 100.9 (CH), 52.6 (CH3), 32.3 (CH2). Mass spectrum (ESI-HRMS): m/z 280.0693 [M + Na]+ (calcd for C13H11N3NaO3+: 280.0699).

Methyl 2-diazo-2-(3-heptylisoxazol-5-yl)acetate (1i) was prepared according published procedure [9] from methyl 2-(3-heptylisoxazol-5-yl)acetate 14i (600 mg, 2.5 mmol), 3-(chlorosulfonyl)benzoic acid (738 mg, 3.34 mmol), NaN3 (326 mg, 5 mmol), K2CO3 (924 mg, 6.69 mmol) in MeCN (8 mL) and water (7 mL). After 3 d additional 3-(chlorosulfonyl)benzoic acid (369 mg, 1.67 mmol), NaN3 (163 mg, 2.5 mmol), K2CO3 (382 mg, 2.73 mmol), water (3 mL) and MeCN (8 mL) were added and reaction mixture was stirred for 4 d and then additional 3-(chlorosulfonyl)benzoic acid (294 mg, 1.33 mmol), NaN3 (130 mg, 2 mmol), K2CO3 (368 mg, 2.66 mmol), water (5 mL) and MeCN (7 mL) were added and reaction mixture was stirred for 14 d to give product in 333 mg (50% yield), after a column chromatography on silica [light petroleum/MTBE, 80 : 1, (v/v)], as a yellow oil, Rf = 0.37 [light petroleum/ethyl acetate, 20 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 6.38 s (1H), 3.89 (s 3H), 2.64 t (2H, J = 7.6 Hz), 1.66 p (2H, J = 7.5 Hz), 1.35‒1.26 m (8H), 0.88 t (3H, J = 6.5 Hz). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 165.1 (C), 155.5 (C), 100.6 (CH), 52.6 (CH3), 31.7 (CH2), 29.1 (CH2), 28.9 (CH2), 28.1 (CH2), 25.9 (CH2), 22.6 (CH2), 14.0 (CH3). Mass spectrum (ESI-HRMS): m/z 288.1319 [M + Na]+ (calcd for C13H19N3NaO3+: 288.1324).

Methyl 2-[3-(4-(tert-butyl)phenyl)-4-(4-fluorophenyl)isoxazol-5-yl]-2-diazoacetate (1j) was prepared according published procedure [50] from methyl 2-[3-(4-(tert-butyl)phenyl)-4-(4-fluorophenyl)isoxazol-5-yl]acetate 14j (180 mg, 0.49 mmol), TsN3 (164 mg, 0.83 mmol) and NEt3 (0.2 mL, 0.98 mmol) in MeCN (6 mL) for 3 d in 119 mg (62% yield) after column chromatography on silica [light petroleum/ethyl acetate, 50 : 1, (v/v)] as a yellow solid: mp 97–98°C (light petroleum/ethyl acetate), Rf = 0.38 [light petroleum/ethyl acetate, 10 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.35–7.34 m (4H), 7.24–7.19 m (2H), 7.12–7.06 m (2H), 3.73 s (3H), 1.31 s (9H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 163.3 (C), 162.6 d (C, J = 248.3 Hz), 161.7 (C), 153.2 (C), 153.1 (C), 131.5 d (CH, J = 8.4 Hz), 128.0 (CH), 125.6 (CH), 125.3 (C), 125.2 d (C, J = 3.3 Hz), 116.8 (C), 116.0 d (CH, J = 21.7 Hz), 52.7 (CH3), 34.8 (C), 31.2 (CH3). Mass spectrum (ESI-HRMS): m/z 416.1381 [M + Na]+ (calcd for C22H20FN3NaO3+: 416.1388).

General procedure A for the synthesis of compounds 3. Diazo compound 1 (1 mmol) in nitrile 2 (4–7.mL for aliphatic nitriles, 20 mmol for aromatic nitriles) in screw-cap tube was heated at 100°C (oil bath temperature) for 1‒5.5 h (TLC control). The nitrile was evaporated if possible and the residue was purified on silica gel by silica gel chromatography (light petroleum ether/ethyl acetate). After evaporation of the solvents the product was washed with pentane.

5-(5-Methoxy-2-methyloxazol-4-yl)-3-(4-methoxyphenyl)isoxazole (3b) was prepared according to the general procedure A from diazoacetate 1b (274 mg, 1 mmol) and acetonitrile 2a (7 mL) for 3 h to give product in 171 mg (60% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 3 : 1, (v/v)], as a beige solid: mp 112‒113°C (light petroleum/ethyl acetate). Compound 3b was also prepared according to the general procedure A from diazoacetate 1b (1.506 g, 5.5 mmol) and acetonitrile 2a (63 mL) for 4.5 h. After evaporation of solvent product was washed with MTBE to give compound 3b in 738 mg (47% yield). Additional compound 3b was isolated from the washings by chromatography on silica [light petroleum ether/ethyl acetate, 3 : 1, (v/v)] (540 mg (34% yield)), Rf = 0.44 [light petroleum/ethyl acetate, 1 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.77–7.74 m (2H), 7.00‒6.96 m (2H), 6.79 s (1H), 3.93 s (3H), 3.86 s (3H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 162.9 (C), 162.0 (C), 160.9 (C), 156.1 (C), 152.5 (C), 128.2 (CH), 121.6 (C), 114.2 (CH), 105.3 (C), 97.0 (CH), 60.3 (CH3), 55.3 (CH3), 14.0 (CH3). Mass spectrum (ESI-HRMS): m/z 287.1026 [M + H]+ (calcd for C15H15N2O4+: 287.1027).

5-(2-Isopropyl-5-methoxyoxazol-4-yl)-3-(4-methoxyphenyl)isoxazole (3c) was prepared according to the general procedure A from diazoacetate 1b (274 mg, 1 mmol) and isobutyronitrile 2b (9 mL) for 3 h to give product in 138 mg (44% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 10 : 1, (v/v)], as a beige solid: mp 53‒54°C (light petroleum/ethyl acetate), Rf = 0.35 [light petroleum/ethyl acetate, 5 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.80–7.76 m (2H), 6.99‒6.95 m (2H), 6.65 s (1H), 4.14 s (3H), 3.85 s (3H), 3.04 hept (1H, J = 7.0 Hz), 1.36 d (6H, J = 7.0 Hz). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 163.1 (C), 161.9 (C), 160.9 (C), 160.0 (C), 155.9 (C), 128.2 (CH) (C), 121.7 (C), 114.2 (CH), 105.0 (C), 97.2 (CH), 60.3 (CH3), 55.3 (CH3), 28.6 (CH), 20.1 (CH3). Mass spectrum (ESI-HRMS): m/z 315.1339 [M + H]+ (calcd for C17H19N2O4+: 315.1345).

5-(5-Methoxy-2-phenyloxazol-4-yl)-3-(4-methoxyphenyl)isoxazole (3d) was prepared according to the general procedure A from diazoacetate 1b (137 mg, 0.5 mmol) and benzonitrile 2c (1.086 g, 10.5 mmol) for 3 h to give product in 60 mg (34% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 10 : 1, (v/v)], as a beige solid: mp 116‒117°C (light petroleum/ethyl acetate), Rf = 0.38 [light petroleum/ethyl acetate, 5 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 8.02–7.99 m (2H), 7.83–7.80 m (2H), 7.48–7.45 m (3H), 7.01-6.97 m (2H), 6.75 s (1H), 4.26 s (3H), 3.86 s (3H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 162.9 (C), 162.1 (C), 160.9 (C), 156.3 (C), 152.6 (C), 130.3 (CH), 128.8 (CH), 128.3 (CH), 126.7 (C), 125.8 (CH), 121.6 (C), 114.2 (CH), 106.9 (C), 97.6 (CH), 60.4 (CH3), 55.3 (CH3). Mass spectrum (ESI-HRMS): m/z 349.1183 [M + H]+ (calcd for C20H17N2O4+: 349.1185).

5-(2-Ethyl-5-methoxyoxazol-4-yl)-3-(p-tolyl)isoxazole (3e) was prepared according to the general procedure A from diazoacetate 1c (209 mg, 0.8 mmol) and propionitrile 2d (6 mL) for 2 h to give product in 134 mg (59% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 10 : 1, (v/v)], as a beige solid: mp 118‒119°C (light petroleum/ethyl acetate), Rf = 0.64 [light petroleum/ethyl acetate, 5 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.75–7.23 m (2H), 7.26 d (2H, J = 7.9 Hz), 6.67 s (1H), 4.14 s (3H), 2.75 q (2H, J = 7.6 Hz), 2.40 s (3H), 1.35 t (3H, J = 7.6 Hz). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 163.1 (C), 162.3 (C), 156.9 (C), 156.0 (C), 139.9 (C), 129.5 (CH), 126.7 (CH), 126.3 (C), 105.2 (C), 97.3 (CH), 60.3 (CH3), 21.8 (CH2), 21.4 (CH3), 10.9 (CH3). Mass spectrum (ESI-HRMS): m/z 285.1234 [M + H]+ (calcd for C16H17N2O3+: 285.1238).

5-(2-Benzyl-5-methoxyoxazol-4-yl)-3-(p-tolyl)isoxazole (3f) was prepared according to the general procedure A from diazoacetate 1c (258 mg, 1 mmol) and 2-phenylacetonitrile 2e (6 g, 51 mmol) for 3 h to give product in 113 mg (33% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 100 : 1 ‒ 15 : 1, (v/v)], as a beige solid: mp 106‒107°C (light petroleum/ethyl acetate), Rf = 0.47 [light petroleum/ethyl acetate, 5 : 1, (v/v)]. 1H NMR spectrum (DMSO-d6, 400 MHz), δ, ppm: 7.80 d (2H, J = 7.7 Hz), 7.38–7.27 m (6H), 6.99 s (1H), 4.12 s (2H), 4.11 s (3H), 2.36 s (3H). 13C{1H} NMR spectrum (DMSO-d6, 100 MHz), δ, ppm: 162.7 (C), 161.9 (C), 156.2 (C), 154.1 (C), 139.9 (C), 135.2 (C), 129.6 (CH), 128.8 (CH), 128.7 (CH), 127.0 (CH), 126.6 (CH), 125.6 (C), 104.2 (C), 97.4 (CH), 60.7 (CH3), 33.7 (CH2), 21.0 (CH3). Mass spectrum (ESI-HRMS): m/z 347.1390 [M + H]+ (calcd for C21H19N2O3+: 347.1394).

3-(4-Fluorophenyl)-5-(5-methoxy-2-methyloxazol-4-yl)isoxazole (3g) was prepared according to the general procedure A from diazoacetate 1d (260 mg, 1 mmol) and acetonitrile 2a (7 mL) for 4 h to give product in 178 mg (65% yield), after a column chromatography on silica [light petroleum/ethyl acetate;3 : 1, (v/v)], as a beige solid: mp 106‒107°C (light petroleum/ethyl acetate), Rf = 0.27 [light petroleum/ethyl acetate, 3 : 1, (v/v)]. 1H NMR spectrum (DMSO-d6, 400 MHz), δ, ppm: 7.84–7.81 m (2H), 7.16–7.12 m (2H), 6.65 s (1H), 4.14 s (3H), 2.44 s (3H). 13C{1H} NMR spectrum (DMSO-d6, 100 MHz), δ, ppm: 163.7 d (C, J = 249.7 Hz), 163.3 (C), 161.5 (C), 156.2 (C), 152.6 (C), 128.7 d (CH, J = 8.5 Hz), 125.3 d (C, J = 3.2 Hz), 115.9 d (CH, J = 21.6 Hz), 105.1 (C), 97.1 (CH), 60.3 (CH3), 14.0 (CH3). Mass spectrum (ESI-HRMS): m/z 297.0646 [M + Na]+ (calcd for C14H11FN2NaO3+: 297.0652).

2-(4-(3-(4-Fluorophenyl)isoxazol-5-yl)-5-methoxyoxazol-2-yl)acetonitrile (3h) was prepared according to the general procedure A from diazoacetate 1d (261 mg, 1 mmol) and malononitrile 2f (990 mg, 20 mmol) for 4 h to give product in 67 mg (22% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 20 : 1–2 : 1, (v/v)], as a beige solid: mp 159‒160°C (light petroleum/ethyl acetate), Rf = 0.29 [light petroleum/ethyl acetate, 2 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.85–7.81 m (2H), 7.18–7.13 m (2H), 6.68 s (1H), 4.21 s (3H), 3.92 s (2H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 163.8 d (C, J = 250.5 Hz), 162.3 (C), 161.6 (C), 156.9 (C), 143.8 (C), 128.8 d (CH, J = 8.5 Hz), 125.0 d (C, J = 3.1 Hz), 116.0 d (CH, J = 22.2 Hz), 112.8 (C), 106.1 (C), 97.9 (CH), 60.7 (CH3), 18.4 (CH2). Mass spectrum (ESI-HRMS): m/z 322.0598 [M + Na]+ (calcd for C15H10FN3NaO3+: 322.0604).

3-(4-Chlorophenyl)-5-(5-methoxy-2-(p-tolyl)oxazol-4-yl)isoxazole (3i). Compound 3i was prepared according to the general procedure A from diazoacetate 1e (278 mg, 1 mmol) and 4-methylbenzonitrile 2g (2.34 g, 20 mmol) for 4 h to give product in 112 mg (30% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 20 : 1–5 : 1, (v/v)], as a beige solid: mp 151‒152°C (light petroleum/ethyl acetate), Rf = 0.30 [light petroleum/ethyl acetate, 10 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.89–7.87 m (2H), 7.82–7.79 m (2H), 7.46–7.42 m (2H), 7.28–7.26 m (2H), 6.75 s (1H), 4.26 s (3H), 2.41 s (3H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 163.5 (C), 161.5 (C), 156.2 (C), 152.9 (C), 140.7 (C), 135.9 (C), 129.5 (CH), 129.1 (CH), 128.1 (CH), 127.6, 125.7 (CH), 123.9 (C), 106.4 (C), 97.1 (CH), 60.3 (CH3), 21.5 (CH3). Mass spectrum (ESI-HRMS): m/z 389.0663 [M + Na]+ (calcd for C20H15ClN2NaO3+: 389.0666).

5-(5-Methoxy-2-phenyloxazol-4-yl)-3-(4-nitrophenyl)isoxazole (3j) was prepared according to the general procedure A from diazoacetate 1f (50 mg, 0.17 mmol) and benzonitrile 2c (358 mg, 3.47 mmol) for 5.5 h to give product in 30 mg (48% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 10 : 1, (v/v)], as a beige solid: mp 207–208°C (light petroleum/ethyl acetate), Rf = 0.66 [light petroleum/ethyl acetate, 5 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 8.33 d (2H, J = 8.4 Hz), 8.05 d (2H, J = 8.4 Hz), 8.01–7.99 m (2H), 7.50–7.47 m (3H), 6.85 s (1H), 4.29 s (3H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 164.2 (C), 160.6 (C), 156.6 (C), 152.7 (C), 148.6 (C), 135.3 (C), 130.5 (CH), 128.9 (CH), 127.7 (CH), 126.5 (C), 125.8 (CH), 124.1 (CH), 106.2 (C), 97.5 (CH), 60.3 (CH3). Mass spectrum (ESI-HRMS): m/z 386.0747 [M + Na]+ (calcd for C19H13N3NaO5+: 386.0744).

5-(5-Methoxy-2-methyloxazol-4-yl)-3-(quinolin-2-yl)isoxazole (3k). Compound 3k was prepared according to the general procedure A from diazoacetate 1g (100 mg, 0.34 mmol) and acetonitrile 2a (3 mL) for 7 h to give product in 73 mg (70% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 10 : 1‒4 : 1, (v/v)], as a light green solid: mp 132‒133°C (light petroleum/ethyl acetate), Rf = 0.21 [light petroleum/ethyl acetate, 3 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 8.25 d (1H, J = 8.6 Hz), 8.22 d (1H, J = 8.5 Hz), 8.17 d (1H, J = 8.4 Hz), 7.86 d. d (1H, J = 8.1, 1.4 Hz), 7.75 d. d. d (1H, J = 8.4, 6.9, 1.5 Hz), 7.58 d. d. d (1H, J = 8.0, 6.8, 1.2 Hz), 7.21 s (1H), 4.16 s (3H), 2.46 s (3H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 163.7 (C), 163.2 (C), 156.2 (C), 152.5 (C), 148.7 (C), 148.0 (C), 136.7 (CH), 129.8 (CH), 129.8 (CH), 128.3 (C), 127.6 (CH), 127.2 (CH), 119.3 (CH), 105.2 (C), 98.3 (CH), 60.2 (CH3), 14.1 (CH3). Mass spectrum (ESI-HRMS): m/z 308.1030 [M + H]+ (calcd for C17H14N3O3+: 308.1040).

3-Benzyl-5-(2-ethyl-5-methoxyoxazol-4-yl)isoxazole (3l) was prepared according to the general procedure A from diazoacetate 1h (100 mg, 0.39 mmol) and propionitrile 2d (6.4 mL) for 4 h to give product in 67 mg (61% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 8 : 1, (v/v)], as a light yellow oil, Rf = 0.34 [light petroleum/ethyl acetate, 5 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.33–7.23 m (5H), 6.13 s (1H), 4.08 s (3H), 4.02 s (2H), 2.71 q (2H, J = 7.6 Hz), 1.31 t (3H, J = 7.6 Hz). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 163.1 (C), 162.8 (C), 156.8 (C), 155.9 (C), 137.4 (C), 128.9 (CH), 128.7 (CH), 126.8 (CH), 99.3 (CH), 60.2 (CH3), 32.4 (CH2), 21.8 (CH2), 10.9 (CH3). Mass spectrum (ESI-HRMS): m/z 307.1053 [M + H]+ (calcd for C16H16N2NaO3+: 307.1047).

3-Benzyl-5-(2-(2-fluorophenyl)-5-methoxyoxazol-4-yl)isoxazole (3m) was prepared according to the general procedure A from diazoacetate 1h (167 mg, 0.65 mmol) and o-fluorobenzonitrile 2h (1.58 g, 13 mmol) for 3.5 h to give product in 53 mg (23% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 15 : 1–5 : 1, (v/v)], as beige solid: mp 116‒117°C (light petroleum/ethyl acetate), Rf = 0.69 [light petroleum/ethyl acetate, 3 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 8.01–7.97 m (1H), 7.45–7.39 m (1H), 7.34–7.21 m (6H), 7.20–7.15 m (1H), 6.25 s (1H), 4.21 s (3H), 4.05 s (2H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 163.1 (C), 162.4 (C), 159.7 d (C, J = 256.9 Hz), 156.3 (C), 148.9 d (C, J = 3.8 Hz), 137.3 (C), 131.9 d (CH, J = 8.5 Hz), 129.0 (CH, J = 1.2 Hz), 128.8 (CH), 128.7 (CH), 126.8 (CH), 124.4 d (CH, J = 3.8 Hz), 116.8 d (CH, J = 20.9 Hz), 115.0 (C), 106.5 (C), 99.8 (CH), 60.2 (CH3), 32.3 (CH2) . Mass spectrum (ESI-HRMS): m/z 373.0959 [M + Na]+ (calcd for C20H15FN2NaO3+: 373.0951).

3-Heptyl-5-(5-methoxy-2-phenyloxazol-4-yl)isoxazole (3n) was prepared according to the general procedure A from diazoacetate 1i (153 mg, 0.58 mmol) and benzonitrile 2c (1.5 g, 14.5 mmol) for 3 h to give product in 95 mg (48% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 10 : 1, (v/v)], as beige solid: mp 54-55°C (light petroleum/ethyl acetate), Rf = 0.29 [light petroleum/ethyl acetate, 10 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 8.00–7.97 m (2H), 7.49–7.42 m (3H, 6.35 s (1H), 4.23 s (3H), 2.70 t (2H, J = 7.6 Hz), 1.70 p (2H, J = 7.5 Hz), 0.88 t (3H, J = 6.7 Hz), 1.39‒1.27 m (8H) ; 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 164.2 (C), 162.2 (C), 156.1 (C), 152.5 (C), 130.3 (CH), 128.8 (CH), 126.7 (C), 125.7 (CH), 107.1 (C), 99.5 (CH), 60.4 (CH3), 31.7 (CH2), 29.1 (CH2), 29.0 (CH2), 28.4 (CH2), 25.9 (CH2), 22.6 (CH2), 14.0 (CH3). Mass spectrum (ESI-HRMS): m/z 330.0849 [M + Na]+ (calcd for C17H13N3NaO3+: 330.0852).

3-(4-(tert-Butyl)phenyl)-4-(4-fluorophenyl)-5-(5-methoxy-2-methyloxazol-4-yl)isoxazole (3o) was prepared according to the general procedure A from diazoacetate 1j (100 mg, 0.25 mmol) and acetonitrile 2a (5 mL) for 3 h to give product in 54 mg (53% yield), after a column chromatography on silica [light petroleum/ethyl acetate; 10 : 1, (v/v)], as a beige solid: mp 134‒136°C (light petroleum/ethyl acetate), Rf = 0.40 [light petroleum/ethyl acetate, 5 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.37–7.31 m (4H), 7.27–7.24 m (2H), 7.06–7.01 m (2H), 3.79 s (3H), 2.36 s (3H), 1.30 s (9H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 162.4 d (C, J = 246.8 Hz), 161.4 (C), 159.1 (C), 156.4 (C), 152.6 (C), 152.5 (C), 132.3 d (CH, J = 7.9 Hz), 128.1 (CH), 126.1 d (CH, J = 3.5 Hz), 125.8 (C), 125.4 (CH), 115.2 d (CH, J = 21.6 Hz), 114.6 (C), 104.5 (C), 60.0 (CH3), 34.7 (C), 31.2 (CH3), 14.1 (CH3). Mass spectrum (ESI-HRMS): m/z 429.1585 [M + Na]+ (calcd for C24H23FN2NaO3+: 429.1574).

Methyl (1RS,2SR)-2-cyano-1-[3-(4-methoxyphenyl)isoxazol-5-yl]cyclopropane-1-carboxylate (c-8b) and methyl (1RS,2RS)-2-cyano-1-[3-(4-methoxyphenyl)isoxazol-5-yl]cyclopropane-1-carboxylate (t-8b) were prepared according to the general procedure A from diazoacetate 1b (273 mg, 1 mmol) and acrylonitrile 2i (7 mL) for 2 h to give compound c-8b in 121 mg (41% yield, 1st fraction) and compound t-8b in 124 mg (42% yield, 2nd fraction), after a column chromatography on silica [light petroleum/ethyl acetate; 7 : 1–4 : 1, (v/v)].

Compound c-8b: a dark rose oil, Rf = 0.43 (light petroleum/ethyl acetate, 3 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.75–7.71 m (2H), 7.00‒6.96 m (2H), 6.86 s (1H), 3.91 s (3H), 3.86 s (3H), 2.49 d. d (1H, J = 9.3, 7.4 Hz), 2.42 d. d (1H, J = 7.4, 5.1 Hz), 2.15 d. d (1H, J = 9.3, 5.1 Hz). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 166.3 (C), 165.1 (C), 162.6 (C), 161.3 (C), 128.2 (CH), 120.8 (C), 116.0 (C), 114.4 (CH), 103.0 (CH), 55.3 (CH3), 53.5 (CH3), 28.6 (C), 20.9 (CH2), 15.1 (CH). Mass spectrum (ESI-HRMS): m/z 299.1026 [M + H]+ (calcd for C16H15N2O4+: 299.1029).

Compound t-8b: colorless solid, mp 77–7.°C (light petroleum/ethyl acetate), Rf = 0.21 [light petroleum/ethyl acetate, 3 : 1, (v/v)]. 1H NMR spectrum (CDCl3, 400 MHz), δ, ppm: 7.78–7.74 m (2H), 6.99‒6.96 m (2H), 6.78 s (1H), 3.86 s (3H), 3.75 s (3H), 2.66 d. d (1H, J = 8.8, 7.6 Hz), 2.18-2.14 m (2H). 13C{1H} NMR spectrum (CDCl3, 100 MHz), δ, ppm: 168.2 (C), 164.0 (C), 162.4 (C), 161.2 (C), 128.3 (CH), 121.0 (C), 116.3 (C), 114.3 (CH), 103.7 (CH), 55.3 (CH3), 53.8 (CH3), 27.3 (C), 20.9 (CH2), 14.6 (CH). Mass spectrum (ESI-HRMS): m/z 299.1026 [M + H]+ (calcd for C16H15N2O4+: 299.1030).

General procedure B for the synthesis of compounds 12. A mixture of oxazole 3 and acrylic acid or dimethyl fumarate in screw-cap tube was heated at 120‒150°C (oil bath temperature) for 2–3 h (TLC control). Purification conditions are indicated for each substance below.

3-Hydroxy-2-(3-(4-methoxyphenyl)isoxazol-5-yl)-6-phenylisonicotinic acid (12a). Compound 12a was prepared according to the general procedure B from oxazole 3d (40 mg, 0.12 mmol) and acrylic acid (1 mL) at 120°C for 2h After evaporation of acid product was washed with MTBE to give compound 12a in 14.4 mg (32% yield) as a beige solid: mp 240°C (dec., acrylic acid), Rf = 0.55 [light petroleum/ethyl acetate, 1 : 1, (v/v)]. 1H NMR spectrum (DMSO-d6, 400 MHz), δ, ppm: 11.44 (br. s, 1H), 8.10 d (2H, J = 7.7 Hz, 1H), 7.97 d (1H, J = 8.6 Hz), 7.92 d (2H, J = 8.3 Hz), 7.55 d (1H, J = 8.6 Hz), 7.52–7.48 m (3H), 7.41 t (1H, J = 7.3 Hz), 7.09 d (2H, J = 8.3 Hz), 3.84 s (3H). 13C{1H} NMR spectrum (DMSO-d6, 100 MHz), δ, ppm: 173.4 (C), 166.4 (C), 161.8 (C), 160.7 (C), 151.3 (C), 147.1 (C), 138.1 (C), 132.8 (C), 128.7 (CH), 128.3 (CH), 128.2 (CH), 126.0 (CH), 125.2 (CH), 122.4 (CH), 121.2 (C), 114.5 (CH), 102.5, 55.3 (CH3). Mass spectrum (ESI-HRMS): m/z 411.0951 [M + Na]+ (calcd for C22H16N2NaO5+: 411.0947).

2-(3-(4-Methoxyphenyl)isoxazol-5-yl)-6-methylpyridin-3-ol (12b). Compound 12b was prepared according to the general procedure B from oxazole 3b (89 mg, 0.31 mmol) and acrylic acid (1 mL) at 145°C for 3 h. After evaporation of acid product was washed with MTBE to give compound 12b in 23 mg (26% yield) as an yellow solid: mp 270°C (dec., acrylic acid), Rf = 0.40 [light petroleum/ethyl acetate, 1 : 1, (v/v)]. 1H NMR spectrum (DMSO-d6, 400 MHz), δ, ppm: 10.72 s (1H), 7.89 d (2H, J = 8.3 Hz), 7.37 s (1H), 7.36 d (1H, J = 8.4 Hz), 7.23 d (1H, J = 8.4 Hz), 7.07 d (2H, J = 8.3 Hz), 3.83 s (3H), 2.45 s (3H). 13C{1H} NMR spectrum (DMSO-d6, 100 MHz), δ, ppm: 166.4 (C), 161.7 (C), 160.6 (C), 149.8 (C), 148.4 (C), 132.1 (C), 128.1 (CH), 125.4 (CH), 124.7 (CH), 121.2 (C), 114.5 (CH), 102.1 (CH), 55.3 (CH3), 23.0 (CH3). Mass spectrum (ESI-HRMS): m/z 305.0897 [M + Na]+ (calcd for C16H14N2NaO3+: 305.0899).

Methyl 5-hydroxy-6-(3-(4-methoxyphenyl)isoxazol-5-yl)-2-methylnicotinate (12c). Compound 12c was prepared according to the general procedure B from oxazole 3b (100 mg, 0.35 mmol) and dimethyl fumarate (1 g, 7 mmol) at 150°C for 2.5 h. Product was isolated with column chromatography on silica (light petroleum/ethyl acetate; 7 : 1–0 : 1, (v/v)]. After evaporation of solvents product was washed with MeOH to give compound 12c in 18 mg (13% yield) as a colorless solid: mp 238°C (dec., ethyl acetate), Rf = 0.55 [light petroleum/ethyl acetate, 1 : 1, (v/v)]. 1H NMR spectrum (DMSO-d6, 400 MHz), δ, ppm: 11.20 (br. s, 1H), 7.91–7.89 m (2H), 7.87 s (1H), 7.52 s (1H), 7.10–7.07 m (2H), 3.88 s (3H), 3.83 s (3H), 2.68 s (3H). 13C{1H} NMR spectrum (DMSO-d6, 100 MHz), δ, ppm: 165.8 (C), 165.3 (C), 161.9 (C), 160.8 (C), 149.5 (C), 148.8 (C), 134.7 (C), 128.2 (CH), 125.9 (C), 125.8 (CH), 120.9 (C), 114.5 (CH), 103.7 (CH), 55.3 (CH3), 52.4 (CH3), 23.5 (CH3). Mass spectrum (ESI-HRMS): m/z 363.0951 [M + Na]+ (calcd for C18H16N2NaO5+: 363.0948).