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Feb 15, 2018 - Institute of Chemistry, Saint Petersburg State University, 7/9 Universitetskaya nab., St. Petersburg 199034, Russia. •S Supporting In...
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Cite This: J. Org. Chem. 2018, 83, 3177−3187

Fe(II)-Catalyzed Isomerization of 5‑Chloroisoxazoles to 2H‑Azirine-2carbonyl Chlorides as a Key Stage in the Synthesis of Pyrazole− Nitrogen Heterocycle Dyads Kirill I. Mikhailov, Ekaterina E. Galenko, Alexey V. Galenko, Mikhail S. Novikov, Alexander Yu. Ivanov, Galina L. Starova, and Alexander F. Khlebnikov* Institute of Chemistry, Saint Petersburg State University, 7/9 Universitetskaya nab., St. Petersburg 199034, Russia S Supporting Information *

ABSTRACT: 2-(1H-Pyrazol-1-ylcarbonyl)-2H-azirines were synthesized by in situ trapping of 2H-azirine-2-carbonyl chlorides, generated by Fe(II)catalyzed isomerization of 5-chloroisoxazoles, with pyrazoles. According to DFT calculations, the selectivity of nucleophilic substitution at the carbonyl group of 2H-azirine-2-carbonyl chloride by a pyrazole nucleophile, which is a mixture of two tautomers, is controlled by thermodynamic factors. 2-(1H-Pyrazol-1-ylcarbonyl)-2H-azirines are excellent precursors for the preparation of two other pyrazole−nitrogen heterocycle dyads: 5-(1H-pyrazol-1-yl)oxazoles by photolysis and 1-(1Hpyrrol-2-ylcarbonyl)-1H-pyrazoles by a Ni(II)-catalyzed reaction with 1,3dicarbonyl compounds. 5-(1H-Pyrazol-1-yl)oxazoles show strong emission in acetonitrile at 360−410 nm with high quantum yields.

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INTRODUCTION Many drugs, including the best-selling ones, are ensembles of two or more heterocycles from the list of so-called privileged structures of medical chemistry. 1,2 There are various approaches to the construction of such molecules. Among the most used are the formation of the second heterocycle using functionalized substituents on the first and combining heterocycles via metal-catalyzed cross-coupling reactions.1,3 The isomerization used to form heterocyclic ensembles is relatively rare, despite the fact that it is a 100% atom-economical reaction.4 We assumed that metal-catalyzed isomerization of an isoxazole-azirine5 could be a good starting point for the creation of facile synthetic approaches to obtain pyrazole−nitrogen heterocycle dyads, consisting of a pyrazole unit as one of the privilege structure6 and a series of other heterocyclic moieties such as azirine, pyrrole, and oxazole7 (Scheme 1). Target compounds 5−7 could be interesting, not only as potentially bioactive molecules but also as polydentate ligands for metal complexes and fluorophores.8

Scheme 1. Retrosynthetic Scheme for the Synthesis of Pyrazole−Nitrogen Heterocycle Dyads

RESULTS AND DISCUSSION We assumed that azirines 5, an unknown class of azirine derivatives, can be key intermediates on the way to dyads 6 and 7. One can imagine two routes for the synthesis of these compounds: (1) Fe(II)-catalyzed isomerization of 5-(1Hpyrazol-1-yl)isoxazoles 3; (2) trapping of 2H-azirine-2-carbonyl chloride 4, formed by isomerization of 5-chloroizoxazole 1, by the pyrazole nucleophile. To test the first route, substituted 5-(1H-pyrazol-1-yl)-3phenylisoxazoles 3a−c were synthesized in 60−75% yield by

heating 5-chloroisoxazole 1a with pyrazoles 2a−c in DMF in the presence of potassium carbonate (Scheme 2). Compounds 3a−c were characterized by 1H and 13C NMR and mass spectrometry. The structure of 3a was additionally confirmed by XRD analysis (see Supporting Information). It has been shown that Fe(II) salts9 and rhodium acetates9e are good catalysts for the isomerization of isoxazoles with 5-NRR′

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© 2018 American Chemical Society

Received: January 9, 2018 Published: February 15, 2018 3177

DOI: 10.1021/acs.joc.8b00069 J. Org. Chem. 2018, 83, 3177−3187

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The Journal of Organic Chemistry Scheme 2. Synthesis of 2-(1H-Pyrazol-1-ylcarbonyl)-2H-azirines 5a−c

substituents to 2-(aminocarbonyl)-2H-azirines. The substituents on NRR′ were comprised of dialkylamino, alkylarylamino, or saturated nitrogen heterocycles such as pyrrolidine and piperidine. Isomerization of 5-pyrazolylisoxazoles 3a−c under conditions that were usually used for the isomerization of 5NRR′ isoxazoles (rt, 10 mol % FeCl2·4H2O)9a proceeded too slowly; consequently, the loading of the catalyst was increased from 40 to 80 mol %. However, even under these conditions, the reaction was relatively successful only with compound 3a, which contained the unsubstituted pyrazole moiety. Compounds 5b and 5c were obtained in 5−14% yields (4−10% on two steps) (Scheme 2) with 80 mol % catalyst after 2 weeks. DFT computations of the Fe(II)-catalyzed isomerizations of isoxazoles 3 were performed to understand the possible reasons for the observed slowing of the isomerization of isoxazoles with a pyrazolyl substituent in comparison with the 5-chloroizoxazole 1a (Figure 1). Complexes 8−10 were chosen as the

Scheme 3. Model Complexes 8−10 for Calculations

Although the replacement of Cl or MeO by the pyrazolyl substituent leads to an increase in the barrier of the ratedetermining step, the magnitude of this change cannot account for the dramatic deceleration of the reaction rate and the need for a 16-fold increase in catalyst loading.9a Therefore, the most probable reason for the observed decrease in reactivity of 5-pyrazolylisoxazoles is their complexation as an N,N′-chelating ligand with the Fe(II) catalyst.11 Taking these results into account, the second route to 2-(1Hpyrazol-1-ylcarbonyl)-2H-azirines via 5-chloroisoxazole-azirine2-carbonyl chloride isomerization, followed by the acylation of pyrazole, looks much more attractive since the isomerization of 5-chloroizoxazole 1 in the presence of Fe(II) chloride should not be complicated by a deactivation of the catalyst. A test reaction between isoxazole 1a and pyrazole 2b using FeCl2·4H2O as a catalyst and pyridine as a base gave compound 5b in 39% yield under mild conditions (rt, 12 h). This prompted us to optimize the reaction conditions (Table 1). Reactions without any base or with the use of Et3N or DMAP instead of pyridine were ineffective (entries 1−3). However, the addition of DMAP (5 mol %) as an acylation catalyst12 improved the yield (entry 6). In an experiment without catalyst (entry 7), neither 5b nor 3b was detected, indicating that the formation of 5b proceeds via acyl chloride 4a. The use of Fe(NTf)2 as an anhydrous catalyst was ineffective (entry 5), whereas the use of anhydrous FeCl2 improved the yield by 10%, likely due to the prevention of partial hydrolysis of acyl chloride 4a with water from the hydrated catalyst FeCl2·4H2O. Using the optimized procedure, azirines 5a−m were synthesized from isoxazoles 1a−e and pyrazoles 2a−h in moderate to good yields (Table 2). All new compounds were fully characterized by spectroscopic methods (1H and 13C NMR and mass spectrometry). The structure of 5l was additionally confirmed by XRD analysis (see Supporting Information). HMBC 1H−15N NMR spectroscopy and a selective HSQMBC IPAP 1H−15N experiment were used to establish the structure of compound 5k (see Supporting Information). Variously substituted 3-aryl/hetaryl-5-chloroisoxazoles 1a−e were used as starting materials. The reaction tolerates MeO, Cl, and Br substituents on the phenyl group.

Figure 1. Energy profiles for the transformations of complexes 8−10. Relative Gibbs free energies (in kcal mol−1, 298 K, PCM model for MeCN) computed at the DFT B3LYP/6-31G(d){CHNOCl}/SDD{Fe} level. For details of the calculations, see the Supporting Information.

model compounds for the calculations (Scheme 3) based on the results of previous calculations for the Fe(II)-catalyzed isomerization of substituted 5-methoxy-4-vinylisoxazoles.9b The transformation pathways of 8 to 10 were computed in the quintet state since for such Fe(II) complexes the quintet state is usually the thermodynamically most stable in solution.9b,10 According to the calculations, 5-pyrazolylisoxazole Fe(II) complexes 8c and 8d have higher barriers for ring opening to vinylnitrene Fe(II)-complexes 9c and d by 1.2−1.8 kcal mol−1 in comparison with chloro- and methoxy-analogues 8a and 8b. Ring opening is the rate-determining step of the isomerization since the transition states for ring closing of 9 into azirine complexes 10 have lower Gibbs free energies (Figure 1). 3178

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observed when indazole 2g and tetrahydroindazole 2h were used as azole components in the reaction. The results of performed experiments show that the acylation of 3-monosubstituted pyrazoles 2b−e and 3,4-disubstituted pyrazole 2h with acyl chloride intermediates 4 occurs regioselectively to give 1,3-disubstituted and 1,3,4-trisubstituted pyrazoles 5, respectively. Although the yields of the products are not quantitative, NMR analysis of the reaction mixtures showed the absence of the second possible isomer, 1,5-di- or 1,4,5-trisubstituted pyrazole 5′, in all cases. To explain the regioselectivity of the nucleophilic substitution at the carbonyl group of 4a, reaction pathways involving the nucleophilic sp2 nitrogen of 3-phenyl-1H-pyrazole 2b and 5-phenyl-1H-pyrazole 2′b were calculated at the B3LYP/6-31+G(d,p) level of theory with the PCM solvent model for MeCN (Figure 2). According

Table 1. Optimization of Reaction Conditions for the Synthesis of 2H-Azirines 5a

entry 1 2 3 4 5 6

catalyst (mol %) FeCl2·4H2O (10) FeCl2·4H2O (10) FeCl2·4H2O (10) FeCl2·4H2O (10) Fe(NTf)2 (10) FeCl2·4H2O (10)

7 8 9 10 a

FeCl2·4H2O (20) FeCl2 (20) FeCl2(20)

base (equiv)

yieldb 5b, %

no base

0

Et3N (1)

0

DMAP (1)

0

pyridine (1/1.5/2/3)

39/44/46c/40

pyridine (1.5) pyridine (1.5) + DMAP (1/5/10 mol %) pyridine (1.5) + DMAP (5 mol %) pyridine (1.5) + DMAP (5 mol %) pyridine (1.5) pyridine (1.5) + DMAP (5 mol %)

2c 41c/55c/31 0 64c 69 79

MeCN, rt, overnight. bIsolated yield. cAnalytical yield.

Table 2. Synthesis of 2H-Azirines 5a−m

Figure 2. Energy profiles for the reaction of 3-phenyl-2H-azirine-2carbonyl chloride 4 with 3-phenyl-1H-pyrazole 2b and 5-phenyl-1Hpyrazole 2′b. Relative Gibbs free energies (in kcal mol−1, 298 K, PCM model for MeCN) computed at the DFT B3LYP/6-31+G(d,p) level.

to the calculations, 3-phenyl-1H-pyrazole 2b is more stable (0.8 kcal mol−1, 2b/2′b is ∼8/2 at 298 K in MeCN) than 5-phenyl1H-pyrazole 2′b. Equilibria 2b/2′b were earlier studied by NMR in solution with HMPA-d18, a solvent known to slow the annular prototropic equilibria, and 72/28 (253 K)13 and 65/35 (300 K)14 ratios of 2b/2′b were found. According to the calculations, the acylation of minor isomer 2′b should lead to isolated product 5b, while the substitution at the carbonyl group of major isomer 2b should provide nonforming isomer 5′b. Intramolecular acyl-shift 5b → 5′b has an extremely high barrier (39.3 kcal mol−1), and interconversion of these compounds can occur only via the reverse reaction of pyrazole 2b formation, followed by tautomerization and acylation. The formation of both isomers 5b and 5′b occurs under thermodynamic control, and the high regioselectivity of the reaction is due to the greater stability of 1,3-disubstituted acylpyrazole 5b, with a difference of 6.3 kcal mol−1 compared to that of the 1,5-disubstituted acylpyrazole 5′b. The reactions of 3-phenyl-2H-azirine-2-carbonyl chloride 4a with indazole 2g proceeded regioselectively, leading to the (1Hindazol-1-yl)(3-phenyl-2H-azirin-2-yl)methanone isomer 5k. NMR analysis of the reaction mixture showed the absence of the second possible isomer, (2H-indazol-2-yl)(3-phenyl-2Hazirin-2-yl)methanone 5′k. According to the calculations

Unsubstituted 1H-pyrazole 2a and 1H-pyrazoles with 3-(4-Rphenyl)-substituents (R = H, Br, MeO, NO2) 2b−e selectively afford the corresponding (3-(4-R-phenyl)-1H-pyrazol-1-yl)(3phenyl-2H-azirin-2-yl)methanones. 4-Phenyl-1H-pyrazole 2f gives (3-(4-bromophenyl)-1H-pyrazol-1-yl)(3-phenyl-2H-azirin-2-yl)methanone 5f in 83% yield. A decrease in yields was 3179

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The Journal of Organic Chemistry (Figure 3), 1H-indazole 2g is more stable (4.0 kcal mol−1, 298 K, MeCN) than 2H-indazole 2′g, which is in agreement with

Figure 4. Energy profiles for the reaction of 3-phenyl-2H-azirine-2carbonyl chloride 4 with 4,5,6,7-tetrahydro-1H/2H-indazole 2h. Relative Gibbs free energies (in kcal mol−1, 298 K, PCM model for MeCN) computed at the DFT B3LYP/6-31+G(d,p) level. Figure 3. Energy profiles for the reaction of 3-phenyl-2H-azirine-2carbonyl chloride 4 with 1H/2H-indazole 2g. Relative Gibbs free energies (in kcal mol−1, 298 K, PCM model for MeCN) computed at the DFT B3LYP/6-31+G(d,p) level.

acetylacetone in toluene at 120 °C with NiCl2·6H2O as a catalyst affords pyrrole 6a in 87% yield. Under these conditions, a series of pyrrole and pyrazole containing dyads (6) were prepared in moderate to good yields (Table 3). Compounds 6a−k were characterized by 1H and 13C NMR and mass spectrometry. The structure of compound 6d was

the literature data.15 Nucleophilic substitution at the carbonyl group by minor 2′g leads to the isolated product 5k, and substitution at the carbonyl group by major 2g would result in the nonforming isomer 5′k. The transition state for substitution at the carbonyl group of 2H-indazole 2′g (TS2′g) has a higher Gibbs free energy compered to 1H-indazole 2g (TS2g) by 3.0 kcal mol−1, but isomer 5k is much more stable than isomer 5′k (by 7.3 kcal mol−1). Therefore, in this case, 5k is the thermodynamic product. The intramolecular isomerization of 5k to 5′k does not occur due to too high of an energy barrier. The reactions of 3-phenyl-2H-azirine-2-carbonyl chloride 4a with 4,5,6,7-tetrahydroindazole 2h proceeded regioselectively, leading to (3-phenyl-2H-azirin-2-yl)(4,5,6,7-tetrahydro-2H-indazol-2-yl)methanone isomer 5l. NMR analysis of the reaction mixture showed the absence of the second possible isomer, (3phenyl-2H-azirin-2-yl)(4,5,6,7-tetrahydro-1H-indazol-1-yl)methanone 5′l. According to the calculations (Figure 4), 4,5,6,7-tetrahydro-1H-indazole 2h is only a little more stable (0.2 kcal mol−1, 298 K, MeCN) than 4,5,6,7-tetrahydro-2Hindazole 2′h. Nucleophilic substitution at the carbonyl group by 2h leads to the isolated product 5l, and substitution at the carbonyl group by 2′h would result in the nondetected isomer 5′l. The transition state for substitution at the carbonyl group of 2h (TS2h) has a slightly lower Gibbs free energy compered to 2′h (TS2′h) by 0.8 kcal mol−1, and isomer 5l is more stable than isomer 5′l (by 1.8 kcal mol−1, 5l/5′l is 95:5 at 298 K). Thus, we can conclude that in all the reactions investigated the regiochemistry is controlled by thermodynamic factors. The obtained azirines (5) are potential precursors of pyrroles with pyrazolylcarbonyl substituents formed via reactions of azirines with 1,3-dicarbonyl compounds.7a,c,9h,16 However, azirine 5a with an amide-type C2 substituent does not react with acetylacetone under the conditions used earlier for the Nicatalyzed reaction of 1,3-dicarbonyl compounds with 2-phenyland 2-methoxycarbonyl-substituted analogs (MeCN or acetone, 20−40 °C).9h,16 We found that heating azirine 5a and

Table 3. Synthesis of Pyrrole and Pyrazole-Containing Dyads (6).

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decomposition of the product when using a Hg lamp. Therefore, these conditions were used for the isomerization of azirines 5a,b,d−f,j−l into oxazoles 7a−h in 48−84% yields (Table 4). Attempts to isomerize compound 5c with a NO2 substituent into the corresponding oxazole were unsuccessful. Photolysis proceeded with intense tarring of the reaction mixture.

additionally confirmed by 2D NOESY NMR and compound 6e by XRD analysis (see Supporting Information). Only a few examples of isomerizations of 2-carbonyl-2Hazirines to oxazoles under UV irradiation are known.7a The photobehavior of 2-carbonyl-2H-azirines depends strongly on the wavelength of the light used. For example, 2-benzoyl-3phenyl-2H-azirine under irradiation at 313 nm transforms to 2,5-diphenyloxazole, whereas at 334 nm it rearranges to 3,5diphenylisoxazole.17 According to calculations, the carbonyl n → π∗ transition induces a cleavage of the C−N single bond in 2-formyl-2H-azirine to yield β-formylvinylnitrene, whereas the n → π∗ excitation of the imine chromophore results in a cleavage of the C−C single bond, producing a nitrile ylide intermediate. The latter is easily transformed into oxazole.18 Photoisomerization of 2-(azolylcarbonyl)-2H-azirines to the corresponding oxazoles is unknown. Therefore, we decided to find conditions for such a potentially useful transformation for the preparation of oxazol−azol dyads. Irradiation of a dilute solution of 5b (0.012 M in MeOH−CH3CN) using light from a mercury lamp with a wide spectrum and a Pyrex filter (light >310 nm) did not lead to the formation of oxazole 7a. However, when a quartz filter was used (light >220 nm), oxazole 7a was isolated in 49% yield. As can be seen from the UV−vis spectra, azirine 5b has an intensive absorption in the range of 230−280 nm and oxazole 7a has an intensive band with λmax 310 nm (Figure 5). Calculations of the absorption

Table 4. Synthesis of Oxazole and Pyrazole-Containing Dyads (7)

Compounds 7a−h were characterized by 1H and 13C NMR and mass spectrometry. The structure of 7d was additionally confirmed by XRD analysis (see Supporting Information). The resulting oxazole-pyrazole dyads 7a−h are luminescent in solutions of MeCN with high quantum yields (36−84%), which potentially make them interesting ligands for the preparation of luminescent complexes. Photophysical data are listed in Table 5, excitation and emission spectra are given in Figures 6 and 7, and absorption spectra are presented in the Supporting Information. Typically, small values of Stokes shifts indicate that the emission observed originates from the singlet excited state, i.e., fluorescence.

Figure 5. UV−vis absorption spectra of azirine 5b and oxazole 7a in CH3CN.

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spectrum by TD-DFT at B3LYP/6-31+G(d,p)/M062X/631+G(d,p) level with a PCM model for MeCN gave main absorption bands with λmax 266 nm f 0.84 and 237 nm f 0.51 for 5b and a band with λmax 308 nm f 1.27 for 7a, which is in good accordance with the experiment. There is an observable contribution of the n → π∗ excitation of the imine chromophore into the 266 nm band of 5b; therefore, the use of light with this wavelength should lead to the isomerization of azirine to oxazole. Using a laser with a wavelength of 266 nm, despite the fact that irradiation was monochromatic close to the maximum in the azirine absorption and far from the maximum of the product absorption, the reaction afforded a 70% analytical yield of 7a. Several additional experiments on further optimization lead to a 74% isolated yield of 7a by using a Hg lamp with a quartz filter (λmax 254 nm) and a diluted solution of 5b (0.015 M in MeOH−CH3CN, 5:1) in an argon atmosphere. Comparison of the results obtained with laser light and a Hg lamp with a quartz filter shows that there is no noticeable

CONCLUSIONS 2-(1H-Pyrazol-1-ylcarbonyl)-2H-azirines were synthesized by in situ trapping of 2H-azirine-2-carbonyl chlorides and generated by Fe(II)-catalyzed isomerization of 5-chloroisoxazoles with pyrazole or indazole derivatives. According to DFT calculations, the regioselectivity of the acylation of pyrazoles, which are a mixture of two tautomers, by 2H-azirine-2-carbonyl chloride is controlled by thermodynamic factors. An alternative route to 2(1H-pyrazol-1-ylcarbonyl)-2H-azirines via Fe(II)-catalyzed isomerization of 5-pyrazolylisoxazoles is not effective, probably due to complexation of the catalyst with starting material as the N,N′-chelating ligand. 2-(1H-Pyrazol-1-ylcarbonyl)-2H-azirines were shown to be useful starting materials for the synthesis of pyrazole−oxazole and pyrazole−pyrrole dyads. Thus, these azirine derivatives were effectively transformed to highquantum-yield fluorescent 5-(1H-pyrazol-1-yl)oxazoles by photolysis. Heating 2-(1H-pyrazol-1-ylcarbonyl)-2H-azirines 3181

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The Journal of Organic Chemistry Table 5. Photophysical Characteristics of 7a−h in Acetonitrile Solutions at Room Temperature compound

absorbance, λmax, nm (ε, 103·M−1·cm−1)

7a 7b 7c 7d 7e 7f 7g 7h

310 309 293 312 316 307 321 328

emission, λmax, nm

excitation, λmax, nm

quantum yield, %

373 373 359 374 380 374 408 402

311 312 294 314 320 310 295 329

69.3 66.1 64.5 48.4 84.1 73.8 35.8 54.7

(40.1) (32.3) (20.5) (33.2) (35.1) (30.5) (21.9) (35.5)

mode. Single-crystal X-ray data were collected by means of a diffractometer at 100 K using monochromated Cu Kα radiation. Crystallographic data for structures 3a, 5l, 6e, and 7d have been deposited with the Cambridge Crystallographic Data Centre (CCDC 3a 1544861, 5l 1544898, 6e 1549061, 7e 1549067). All the photophysical measurements in solution were carried out in freshly distilled dry acetonitrile. UV/vis spectra were recorded on a spectrophotometer. The emission and excitation spectra in solutions were measured with a spectrofluorimeter. The absolute emission quantum yields of the solutions were determined by a comparative method at room temperature with an integrating sphere. Thin-layer chromatography (TLC) was conducted on aluminum sheets with 0.2 mm silica gel with a fluorescent indicator. The mercury lamp used for photolysis has an emission power of 40 mW/cm2 at 15 cm and the following emission spectrum: 254, 265, 296, 302, 313, 334, 365, and 406 nm. A solid-state pulsed Nd:YAG diode pumped laser with a wavelength of 266 nm and an emission power of 50 mW/cm2 was used for laser photolysis experiments. Chloroisoxazoles 1a−d were prepared by the reported procedure.19 3-(Benzo[b]thiophen-2-yl)-5-chloroisoxazole (1e). Triethylamine (253 mg, 2.5 mmol, 0.35 mL) was added dropwise at 0 °C to a stirring suspension of 3-(benzo[b]thiophen-2-yl)isoxazol-5(4H)-one9f (651 mg, 3 mmol) in POCl3 (4 mL). The mixture was stirred at 90 °C for 27 h, poured into ice (300 g), carefully basified to a pH of 6−7 by 10% aq KOH, and extracted with DCM. The organic layer was dried over Na2SO4 and filtered off. The solvent was evaporated, and the product was purified by column chromatography (light petroleum (LP)/ EtOAc, 10:1) to give chloroisoxazole 1e (475 mg, 67%) as a lightyellow solid, mp 135−138 °C (LP/EtOAc). 1H NMR (CDCl3, 400 MHz): δ 6.54 (s, 1H), 7.35−7.46 (m, 2H), 7.68 (s, 1H), 7.80−7.85 (m, 1H), 7.85−7.93 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 99.8 (CH), 122.6 (CH), 124.4 (CH), 124.95 (CH), 125.00 (CH), 126.0 (CH), 129.9 (C), 139.1 (C), 140.3 (C), 155.6 (C), 159.8 (C). HRMS (ESI−TOF) (m/z): [M + Ag]+ calcd for C11H6AgClNOS+, 341.8904; found, 341.8921. General Procedure A for the Synthesis of 5-Pyrazolylisoxazoles 3. A mixture of 5-chloroisoxazole 1 (0.5−1.0 mmol, 1 equiv), pyrazole (0.52−1.05 mmol, 1.05 equiv), and K2CO3 (1.5−3.0 mmol, 3 equiv) in dry DMF (1−2 mL) was held at 120−160 °C under stirring for 2−4 h (TLC monitoring, LP/EtOAc 4:1). The mixture was poured into water (10−20 mL), and the precipitated solid was filtered, washed with water and aq MeOH (v/v, 1:1), and dried on air. 3-Phenyl-5-(1H-pyrazol-1-yl)isoxazole (3a). Compound 3a was prepared from isoxazole 1a (135 mg, 0.75 mmol), pyrazole 2a (102 mg, 1.5 mmol), and K2CO3 (311 mg, 2.25 mmol) in DMF (2 mL) for 4 h at 160 °C according to general procedure A to afford a colorless solid, mp 91−93 °C (DMF/water), yield 95 mg (60%). 1H NMR (CDCl3, 400 MHz): δ 6.54 (dd, J = 2.7, 1.7 Hz, 1H), 6.65 (s, 1H), 7.46−7.55 (m, 3H), 7.79−7.91 (m, 3H), 8.11 (d, J = 2.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 86.8 (CH), 108.9 (CH), 126.8 (CH), 128.2 (CH), 128.5 (C), 129.0 (CH), 130.5 (CH), 143.5 (CH), 162.1 (C), 164.0 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C12H10N3O+ [M + H]+, 212.0818; found, 212.0825. 3-Phenyl-5-(3-phenyl-1H-pyrazol-1-yl)isoxazole (3b). Compound 3b was prepared from isoxazole 1a (63 mg, 0.35 mmol), pyrazole 2b (53 mg, 0.37 mmol), and K2CO3 (152 mg, 1.10 mmol) in DMF (1 mL) for 4 h at 160 °C according to general procedure A to afford a

Figure 6. Excitation and emission spectra of oxazoles 7a−d in CH3CN.

Figure 7. Excitation and emission spectra of oxazoles 7e−h in CH3CN.

with 1,3-dicarbonyl compounds under Ni(II) catalysis affords derivatives of 1-(1H-pyrrol-2-ylcarbonyl)-1H-pyrazole.

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EXPERIMENTAL SECTION

General Information and Methods. Melting points were determined on a melting-point apparatus. 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on an NMR spectrometer in CDCl3. Chemical shifts (δ) are reported in parts per million downfield from tetramethylsilane (TMS δ = 0.00). 1H NMR spectra were calibrated according to the residual peak of CDCl3 (7.26 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). Electrospray ionization (ESI) mass spectra were recorded on a mass spectrometer, HRMS−ESI−QTOF, electrospray ionization, positive 3182

DOI: 10.1021/acs.joc.8b00069 J. Org. Chem. 2018, 83, 3177−3187

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The Journal of Organic Chemistry colorless solid, mp 125−128 °C (DMF/water), yield 75 mg (75%). 1H NMR (CDCl3, 400 MHz): δ 6.72 (s, 1H), 6.84 (d, J = 2.7 Hz, 1H), 7.37−7.43 (m, 1H), 7.44−7.57 (m, 5H), 7.83−7.94 (m, 4H), 8.14 (d, J = 2.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 86.7 (CH), 106.6 (CH), 126.2 (CH), 126.8 (CH), 128.6 (C), 128.8 (CH), 129.0 (CH), 129.5 (CH), 130.5 (CH), 131.8 (C), 155.3 (C), 162.1 (C), 164.1 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C18H14N3O+, 288.1131; found, 288.1144. 5-(3-(4-Nitrophenyl)-1H-pyrazol-1-yl)-3-phenylisoxazole (3c). Compound 3c was prepared from isoxazole 1a (54 mg, 0.30 mmol), pyrazole 2c (60 mg, 0.32 mmol), and K2CO3 (132 mg, 0.96 mmol) in DMF (1 mL) for 2 h at 120 °C according to general procedure A to afford a colorless solid, mp 164−167 °C (DMF/water), yield 73 mg (73%). 1H NMR (CDCl3, 400 MHz): δ 6.76 (s, 1H), 6.93 (d, J = 2.7 Hz, 1H), 7.47−7.57 (m, 3H), 7.82−7.94 (m, 2H), 8.08 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 2.7 Hz, 1H), 8.33 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 87.6 (CH), 107.1 (CH), 124.2 (CH), 126.87 (CH), 126.89 (CH), 128.5 (C), 129.1 (CH), 130.2 (CH), 130.6 (CH), 138.0 (C), 148.2 (C), 153.0 (C), 161.8 (C), 164.2 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C18H13N4O3+, 333.0982; found, 333.0992. General Procedure B for the Domino Synthesis of 2HAzirines 5 from 5-Chloroisoxazoles 1 and Pyrazoles 2. To a stirred mixture of 5-chloroisoxazole 1 (2−3 mmol, 1 equiv) and pyrazole 2 (2−3.3 mmol, 1.0−1.1 equiv) in dry CH3CN (6 mL) (unless otherwise indicated) a solution of pyridine (3−4.5 mmol, 1.5 equiv) and DMAP (0.1−0.15 mmol, 5 mol %) in dry CH3CN (4 mL) was added, followed by the addition of anhydrous FeCl2 (0.4−0.6 mmol, 20 mol %) in an Ar atmosphere. The mixture was stirred overnight at ambient temperature, the solvent was evaporated, and azirine 5 was isolated by column chromatography on silica (LP/ EtOAc, 20:1). The product was recrystallized from LP/DCM. (3-Phenyl-2H-azirin-2-yl)(1H-pyrazol-1-yl)methanone (5a). Compound 5a was prepared from isoxazole 1a (393 mg, 2.19 mmol), pyrazole 2a (164 mg, 2.41 mmol), pyridine (260 mg, 3.28 mmol), DMAP (13.5 mg, 0.11 mmol), and FeCl2 (56 mg, 0.44 mmol) according to general procedure B to afford a light-yellow solid, mp 59−62 °C (LP/DCM), yield 262 mg (57%). 1H NMR (CDCl3, 400 MHz): δ 4.30 (s, 1H), 6.48−6.59 (m, 1H), 7.53−7.62 (m, 2H), 7.61− 7.70 (m, 1H), 7.80−7.90 (m, 2H), 7.89−8.09 (m, 1H), 8.25−8.39 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 29.2 (CH), 109.8 (CH), 121.8 (C), 128.6 (CH), 129.3 (CH), 130.7 (CH), 134.0 (CH), 144.7 (CH), 156.6 (C), 169.5 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C12H10N3O+, 212.0818; found, 212.0800. (3-Phenyl-1H-pyrazol-1-yl)(3-phenyl-2H-azirin-2-yl)methanone (5b). Compound 5b was prepared from isoxazole 1a (368 mg, 2.05 mmol), pyrazole 2b (295 mg, 2.05 mmol), pyridine (243 mg, 3.07 mmol), DMAP (12.5 mg, 0.10 mmol), and FeCl2 (52 mg, 0.41 mmol) in CH3CN according to general procedure B to afford a light-yellow solid, mp 113−115 °C (LP/DCM), yield 466 mg (79%). 1H NMR (CDCl3, 400 MHz): δ 4.41 (s, 1H), 6.87 (d, J = 2.8 Hz, 1H), 7.38− 7.52 (m, 3H), 7.54−7.63 (m, 2H), 7.62−7.70 (m, 1H), 7.86−8.01 (m, 4H), 8.34 (d, J = 2.8 Hz, 1H). 13C NMR (100 MHz, CDCl3), δ (ppm): 29.3 (CH), 107.7 (CH), 121.9 (C), 126.4 (CH), 128.8 (CH), 129.3 (CH), 129.8 (CH), 130.8 (C), 131.7 (CH), 134.0 (CH), 156.2 (C), 156.9 (C), 169.5 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C18H14N3O+, 88.1131; found, 288.1141. (3-(4-Nitrophenyl)-1H-pyrazol-1-yl)(3-phenyl-2H-azirin-2-yl)methanone (5c). Compound 5c was prepared from isoxazole 1a (368 mg, 2.05 mmol), pyrazole 2c (580 mg, 3.07 mmol), pyridine (243 mg, 3.07 mmol), DMAP (12.5 mg, 0.10 mmol), and FeCl2 (78 mg, 0.61 mmol) according to general procedure B to afford a colorless solid, mp 154−156 °C (LP/EtOAc), yield 365 mg (54%). 1H NMR (CDCl3, 400 MHz): δ 4.36 (s, 1H), 6.94 (d, J = 2.8 Hz, 1H), 7.54−7.63 (m, 2H), 7.65−7.72 (m, 1H), 7.91−8.02 (m, 2H), 8.08 (d, J = 8.8 Hz, 2H), 8.31 (d, J = 8.8 Hz, 2H), 8.39 (d, J = 2.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 29.2 (CH), 107.9 (CH), 121.7 (C), 124.1 (CH), 127.0 (CH), 129.4 (CH), 130.4 (CH), 130.8 (CH), 134.2 (CH), 137.8 (C), 148.1 (C), 153.7 (C), 156.6 (C), 169.5 (C). HRMS (ESI− TOF) (m/z): [M + Na]+ calcd for C18H12N4NaO3+, 355.0802; found, 355.0798.

(3-(4-Bromophenyl)-1H-pyrazol-1-yl)(3-phenyl-2H-azirin-2-yl)methanone (5d). Compound 5d was prepared from isoxazole 1a (424 mg, 2.36 mmol), pyrazole 2d (547 mg, 2.45 mmol), pyridine (280 mg, 3.54 mmol), DMAP (14.4 mg, 0.12 mmol), and FeCl2 (60 mg, 0.47 mmol) according to general procedure B to afford a colorless solid, mp 130−132 °C (LP/DCM), yield 520 mg (60%). 1H NMR (CDCl3, 400 MHz): δ 4.36 (s, 1H), 6.83 (d, J = 2.8 Hz, 1H), 7.54−7.63 (m, 4H), 7.62−7.71 (m, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.89−8.04 (m, 2H), 8.34 (d, J = 2.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 29.3 (CH), 107.4 (CH), 121.9 (C), 123.5 (C), 127.9 (CH), 129.5 (CH), 130.0 (CH), 130.65 (C), 130.75 (CH), 132.0 (CH), 134.0 (CH). 155.0 (C), 156.8 (C), 169.5 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C18H12BrN3NaO+, 388.0056; found, 388.0045. (3-(4-Methoxyphenyl)-1H-pyrazol-1-yl)(3-phenyl-2H-azirin-2-yl)methanone (5e). Compound 5e was prepared from isoxazole 1a (318 mg, 1.77 mmol), pyrazole 2e (320 mg, 1.84 mmol), pyridine (210 mg, 2.66 mmol), DMAP (10.8 mg, 0.09 mmol), and FeCl2 (45 mg, 0.35 mmol) according to general procedure B to afford a colorless solid, mp 122−124 °C (LP/DCM), yield 360 mg (64%). 1H NMR (CDCl3, 400 MHz): δ 3.87 (s, 3H), 4.39 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 7.53− 7.62 (m, 2H), 7.61−7.70 (m, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.92−7.99 (m, 2H), 8.31 (d, J = 2.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 29.4 (CH), 55.3 (CH3), 107.4 (CH), 114.2 (CH), 122.0 (C), 124.4 (C), 127.7 (C), 129.3 (CH), 129.8 (CH), 130.8 (CH), 134.0 (CH), 155.0 (C), 157.0 (C), 160.6 (C), 169.5 (C). HRMS (ESI−TOF) (m/ z): [M + Na]+ calcd for C19H15N3NaO2+, 340.1056; found, 340.1068. (4-Phenyl-1H-pyrazol-1-yl)(3-phenyl-2H-azirin-2-yl)methanone (5f). Compound 5f was prepared from isoxazole 1a (438 mg, 2.44 mmol), 4-phenyl-1H-pyrazole 2f (387 mg, 2.69 mmol), pyridine (294 mg, 3.66 mmol), DMAP (15 mg, 0.12 mmol), and FeCl2 (62 mg, 0.49 mmol) in a mixture of dry DMF (6 mL) and CH3CN (5 mL) according to general procedure B to afford a colorless solid, mp 103− 105 °C (LP/EtOAc), yield 584 mg (83%). 1H NMR (CDCl3, 400 MHz): δ 4.31 (s, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.54−7.62 (m, 4H), 7.63−7.73 (m, 1H), 7.89−8.01 (m, 2H), 8.14 (s, 1H), 8.53 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 29.1 (CH), 121.8 (C), 124.2 (CH), 126.1 (CH), 126.6 (C), 127.9 (CH), 129.1 (CH), 129.4 (CH), 130.4 (C), 130.8 (CH), 134.1 (CH), 142.9 (CH), 156.6 (C), 169.4 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C18H13N3NaO+, 310.0951; found, 310.0964. (3-(4-Chlorophenyl)-2H-azirin-2-yl)(3-phenyl-1H-pyrazol-1yl)methanone (5g). Compound 5g was prepared from isoxazole 1b (189 mg, 0.88 mmol), pyrazole 2b (140 mg, 0.97 mmol), pyridine (105 mg, 1.32 mmol), DMAP (5 mg, 0.04 mmol), and FeCl2 (22 mg, 0.18 mmol) according to general procedure B to afford a colorless solid, mp 101−102 °C (LP/EtOAc), yield 201 mg (71%). 1H NMR (CDCl3, 400 MHz): δ 4.41 (s, 1H), 6.87 (d, J = 2.9 Hz, 1H), 7.41−7.50 (m, 3H), 7.57 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.5 Hz, 2H), 7.91−7.94 (m, 2H), 8.34 (d, J = 2.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 29.5 (CH), 107.8 (CH), 120.5 (C), 126.4 (CH), 128.8 (CH), 129.4 (CH), 129.85 (CH), 129.88 (CH), 131.6 (C), 131.9 (CH), 140.5 (C), 156.28 (C), 156.34 (C), 169.3 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C18H13ClN3O+, 322.0742; found, 322.0745. (3-(4-Bromophenyl)-2H-azirin-2-yl)(3-phenyl-1H-pyrazol-1yl)methanone (5h). Compound 5h was prepared from isoxazole 1c (207 mg, 0.80 mmol), pyrazole 2b (127 mg, 0.88 mmol), pyridine (95 mg, 1.20 mmol), DMAP (5 mg, 0.04 mmol), and FeCl2 (20 mg, 0.16 mmol) according to general procedure B to afford a colorless solid, mp 108−109 °C (LP/EtOAc), yield 229 mg (78%). 1H NMR (CDCl3, 400 MHz): δ 4.41 (s, 1H), 6.87 (d, J = 2.9 Hz, 1H), 7.41−7.50 (m, 3H), 7.73 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.91−7.93 (m, 2H), 8.33 (d, J = 2.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 29.5 (CH), 107.8 (CH), 120.9 (C), 126.4 (CH), 128.8 (CH), 129.2 (C), 129.4 (CH), 129.9 (CH), 131.6 (C), 131.9 (CH), 132.8 (CH), 156.3 (C), 156.6 (C), 169.3 (C). HRMS (ESI−TOF) (m/z): [M + H]+, calcd for C18H13BrN3O+, 366.0237; found, 366.0247. (3-(4-Methoxyphenyl)-2H-azirin-2-yl)(3-phenyl-1H-pyrazol-1yl)methanone (5i). Compound 5i was prepared from isoxazole 1d (210 mg, 1.00 mmol), pyrazole 2b (159 mg, 1.10 mmol), pyridine (119 mg, 1.50 mmol), DMAP (6 mg, 0.05 mmol), and FeCl2 (25 mg, 0.20 3183

DOI: 10.1021/acs.joc.8b00069 J. Org. Chem. 2018, 83, 3177−3187

Article

The Journal of Organic Chemistry mmol) according to general procedure B to afford a colorless solid, mp 82−83 °C (LP/EtOAc), yield 252 mg (79%). 1H NMR (CDCl3, 400 MHz): δ 3.89 (s, 3H), 4.35 (s, 1H), 6.86 (d, J = 2.6 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 7.42−7.49 (m, 3H), 7.89 (d, J = 8.6 Hz, 2H), 7.93− 7.95 (m, 2H), 8.34 (d, J = 2.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 29.1 (CH), 55.6 (CH3), 107.5 (CH), 114.1 (C), 114.9 (CH), 126.4 (CH), 128.8 (CH), 129.3 (CH), 129.8 (CH), 131.8 (C), 132.9 (CH), 155.4 (C), 156.1 (C), 164.2 (C), 169.9 (C). HRMS (ESI−TOF) (m/ z): [M + H]+, calcd for C19H16N3O2+ 318.1237; found, 318.1247. (3-(Benzo[b]thiophen-2-yl)-2H-azirin-2-yl)(3-phenyl-1H-pyrazol1-yl)methanone (5j). Compound 5j was prepared from isoxazole 1e (117 mg, 0.50 mmol), pyrazole 2b (79 mg, 0.55 mmol), pyridine (60 mg, 0.75 mmol), DMAP (3 mg, 0.03 mmol), and FeCl2 (13 mg, 0.10 mmol) in mixture of dry 1,4-dioxane (3 mL) and acetonitrile (4 mL) according to general procedure B to afford a colorless solid, mp 139− 141°C (LP/DCM), yield 71 mg (41%). 1H NMR (CDCl3, 400 MHz): δ 4.52 (s, 1H), 6.89 (d, J = 2.9 Hz, 1H), 7.40−7.56 (m, 5H), 7.88− 8.02 (m, 5H), 8.36 (d, J = 2.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 30.6 (CH), 107.8 (CH), 122.9 (CH), 123.9 (C), 125.5 (CH), 125.8 (CH), 126.4 (CH), 127.7 (CH), 128.8 (CH), 129.4 (CH), 129.9 (CH), 131.6 (C), 133.7 (CH), 138.2 (C), 143.6 (C), 151.7 (C), 156.3 (C), 168.9 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C20H14N3OS+, 344.0852; found, 344.0843. (1H-Indazol-1-yl)(3-phenyl-2H-azirin-2-yl)methanone (5k). Compound 5k was prepared from isoxazole 1a (180 mg, 1.00 mmol), 1Hindazole 2g (236 mg, 2.00 mmol), pyridine (119 mg, 1.50 mmol), DMAP (6.1 mg, 0.05 mmol), and FeCl2 (26 mg, 0.20 mmol) according to general procedure B to afford a colorless solid, mp 111− 113 °C (LP/DCM), yield 103 mg (39%). 1H NMR (CDCl3, 400 MHz): δ 4.38 (s, 1H), 7.35−7.43 (m, 1H), 7.51−7.60 (m, 3H), 7.59− 7.68 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.90−8.08 (m, 2H), 8.28 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 29.9 (CH), 115.6 (CH), 120.9 (CH), 122.2 (C), 124.8 (CH), 126.1 (C), 129.3 (CH), 129.6 (CH), 130.7 (CH), 133.9 (CH), 139.2 (C), 140.7 (CH), 157.2 (C), 170.6 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C16H11N3NaO+, 284.0794; found, 284.0806. (3-Phenyl-2H-azirin-2-yl)(4,5,6,7-tetrahydro-2H-indazol-2-yl)methanone (5l). Compound 5l was prepared from isoxazole 1a (404 mg, 2.25 mmol), tetrahydroindazole 2h (302 mg, 2.48 mmol), pyridine (267 mg, 3.38 mmol), DMAP (14 mg, 0.11 mmol), and FeCl2 (57 mg, 0.45 mmol) according to general procedure B to afford a colorless solid, mp 116−118 °C (LP/DCM), yield 220 mg (37%). 1H NMR (CDCl3, 400 MHz): δ 1.74−1.84 (m, 2H), 1.83−1.94 (m, 2H), 2.63 (t, J = 6.0 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 4.22 (s, 1H), 7.45− 7.60 (m, 2H), 7.59−7.67 (m, 1H), 7.88−7.94 (m, 1H), 7.92−7.94 (m, 1H), 7.97 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 20.6 (CH2), 22.96 (CH2), 22.99 (CH2), 23.8 (CH2), 29.2 (CH), 121.2 (C), 122.1 (C), 124.9 (CH), 129.2 (CH), 130.7 (CH), 133.9 (CH), 156 (C), 157.0 (C), 169.1 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C16H16N3O+, 266.1288; found, 266.1291. (3-(4-Bromophenyl)-2H-azirin-2-yl)(4,5,6,7-tetrahydro-1H-indazol-1yl)methanone (5m). Compound 5m was prepared from isoxazole 1c (207 mg, 0.80 mmol), tetrahydroindazole 2h (108 mg, 0.88 mmol), pyridine (95 mg, 1.20 mmol), DMAP (5 mg, 0.04 mmol), and FeCl2 (20 mg, 0.16 mmol) according to general procedure B to afford a colorless solid, mp 135−136 °C (LP/EtOAc), yield 67 mg (24%). 1H NMR (CDCl3, 400 MHz): δ 1.76−1.81 (m, 2H), 1.85− 1.91 (m, 2H), 2.61−2.64 (m, 2H), 2.77−2.80 (m, 2H), 4.23 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.96 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 20.6 (CH2), 22.95 (CH2), 22.98 (CH2), 23.8 (CH2), 29.4 (CH), 121.1 (C), 121.3 (C), 125.0 (CH), 129.0 (C), 131.9 (CH), 132.8 (CH), 156.2 (C), 156.7 (C), 168.8 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C16H14BrN3NaO+, 366.0212; found, 366.0223. General Procedure C for the Synthesis of 2H-Azirines 5 from 5-Pyrazolylsoxazoles 3. Anhydrous FeCl2 (0.05−0.08 mmol, 20−40 mol %) was added to a stirring solution of 5-pyrazolylisoxazole 3 (0.2− 0.3 mmol) in dry CH3CN or in a mixture CH3CN/1,4-dioxane (4−6 mL) in an inert atmosphere and stirred at ambient temperature for 3− 4 days (TLC monitoring, LP/EtOAc, 4:1). If the reaction was not

complete then an additional amount of FeCl2 (20−40 mol %) was added and the reaction was stirred for several days more. After completion of the reaction, solvents were evaporated and azirine 5 was isolated by column chromatography (LP/EtOAc, 10:1). (3-Phenyl-2H-azirin-2-yl)(1H-pyrazol-1-yl)methanone (5a). Compound 5a was prepared from isoxazole 3a (46 mg, 0.22 mmol) and FeCl2 (10 mg, 0.08 mmol, 36 mol %) in CH3CN (4 mL) for 3 days according to general procedure C to yield 24 mg (52%). (3-Phenyl-1H-pyrazol-1-yl)(3-phenyl-2H-azirin-2-yl)methanone (5b). Compound 5b was prepared from isoxazole 3b (50 mg, 0.17 mmol) and FeCl2 (18 mg, 0.14 mmol, 82 mol %) in a mixture of CH3CN (4 mL) and 1,4-dioxane (2 mL) for 5 days according to general procedure C to yield 7 mg (14%). (3-(4-Nitrophenyl)-1H-pyrazol-1-yl)(3-phenyl-2H-azirin-2-yl)methanone (5c). Compound 5c was prepared from isoxazole 3c (50 mg, 0.15 mmol) and FeCl2 (15 mg, 0.12 mmol, 80 mol %) in a mixture of CH3CN (2 mL) and 1,4-dioxane (3 mL) for 14 days according to general procedure C to yield 4 mg (5%). General Procedure D for the Synthesis of Pyrroles 6. A mixture of azirine 5 (0.1−0.3 mmol, 1 equiv), 1,3-dicarbonyl compound 11 (0.2−0.6 mmol, 2 equiv), and NiCl2·6H2O (10 mol %) in toluene (3−5 mL) was held at 120 °C under stirring for 2−4 h in a thick-wall tube (15 mL) with a screw cap. After the reaction was complete (TLC monitoring, LP/EtOAc, 4:1), the solvent was evaporated and the residue was purified with column chromatography (LP/EtOAc, 10:1−4:1) to give pyrrole 6. 1-(2-Methyl-4-phenyl-5-(3-phenyl-1H-pyrazole-1-carbonyl)-1Hpyrrol-3-yl)ethanone (6a). Compound 6a was prepared from azirine 5b (50 mg, 0.17 mmol), acetylacetone 11a (35 mg, 0.34 mmol), and NiCl2·6H2O (4 mg, 0.014 mmol) for 4 h according to general procedure D to afford a colorless solid, mp 184−187 °C (LP/EtOAc), yield 56 mg (87%). 1H NMR (CDCl3, 400 MHz): δ 1.85 (s, 3H), 2.70 (s, 3H), 6.76 (d, J = 2.9 Hz, 1H), 7.35−7.42 (m, 2H), 7.41−7.57 (m, 6H), 7.77−7.93 (s, 2H), 8.37 (d, J = 2.9 Hz, 1H), 12.29 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 15.3 (CH3), 30.8 (CH3), 106.1 (CH), 117.8 (C), 124.2 (C), 126.3 (CH), 127.9 (CH), 128.2 (CH), 129.0 (CH), 129.4 (CH), 129.5 (CH), 131.4 (C), 131.8 (CH), 135.5 (C), 139.5 (C), 139.9 (C), 153.6 (C), 155.5 (C), 196.5 (C). HRMS (ESI− TOF) (m/z): [M + Na]+ calcd for C23H19N3NaO2+, 392.1369; found, 392.1369. 1-(5-(3-(4-Bromophenyl)-1H-pyrazole-1-carbonyl)-2-methyl-4phenyl-1H-pyrrol-3-yl)ethanone (6b). Compound 6b was prepared from azirine 5d (100 mg, 0.27 mmol), acetylacetone 11a (55 mg, 0.54 mmol), and NiCl2·6H2O (7 mg, 0.03 mmol) for 4 h according to general procedure D to afford a colorless solid, mp 172−175 °C (LP/ EtOAc), yield 106 mg (87%). 1H NMR (CDCl3, 400 MHz): δ 1.84 (s, 3H), 2.69 (s, 3H), 6.73 (d, J = 2.9 Hz, 1H), 7.33−7.41 (m, 2H), 7.41− 7.52 (m, 3H), 7.64 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 8.37 (d, J = 2.9 Hz, 1H), 12.14 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 15.3 (CH3), 30.8 (CH3), 106.0 (CH), 117.6 (C), 123.7 (C), 124.3 (C), 127.8 (CH), 127.9 (CH), 128.2 (CH), 129.3 (CH), 130.4 (C), 132.0 (CH), 132.3 (CH), 135.4 (C), 139.7 (C), 140.0 (C), 153.4 (C), 154.5 (C), 196.4 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C23H18N3NaO2Br+, 470.0475; found, 470.0486. (4-Benzoyl-3,5-diphenyl-1H-pyrrol-2-yl)(1H-pyrazol-1-yl)methanone (6c). Compound 6c was prepared from azirine 5a (30 mg, 0.14 mmol), dibenzoylmethane 11b (64 mg, 0.28 mmol), and NiCl2· 6H2O (4 mg, 0.014 mmol) for 2 h according to general procedure D to afford a colorless solid, mp 172−175 °C (LP/EtOAc), yield 28 mg (48%). 1H NMR (CDCl3, 400 MHz): δ 6.50 (dd, J = 2.9, 1.6 Hz, 1H), 7.14−7.27 (m, 5H), 7.28−7.41 (m, 6H), 7.51−7.57 (m, 2H), 7.64− 7.72 (m, 2H), 7.86 (dd, J = 1.7, 0.8 Hz, 1H), 8.44 (dd, J = 2.9, 0.8 Hz, 1H), 12.61 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 108.3 (CH), 118.8 (C), 124.0 (C), 127.52 (CH), 127.55 (CH), 127.8 (CH), 127.9 (CH), 128.89 (CH), 128.95 (CH), 129.7 (CH), 130.0 (CH), 130.48 (C), 130.56 (CH), 132.7 (CH), 133.2 (C), 137.9 (C), 138.1 (C), 139.5 (C), 143.7 (CH), 153.9 (C), 194.0 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C27H19N3NaO2+, 440.1369; found, 440.1350. 3184

DOI: 10.1021/acs.joc.8b00069 J. Org. Chem. 2018, 83, 3177−3187

Article

The Journal of Organic Chemistry Ethyl 2-methyl-4-phenyl-5-(3-phenyl-1H-pyrazole-1-carbonyl)1H-pyrrole-3-carboxylate (6d). Compound 6d was prepared from azirine 5b (50 mg, 0.17 mmol), ethyl acetoacetate 11c (45 mg, 0.35 mmol), and NiCl2·6H2O (4 mg, 0.014 mmol) for 5 h according to general procedure D to afford a colorless solid, mp 168−170 °C (LP/ EtOAc), yield 28 mg (41%). 1H NMR (CDCl3, 400 MHz): δ 0.98 (t, J = 7.1 Hz, 3H), 2.72 (s, 3H), 4.06 (q, J = 7.1 Hz, 2H), 6.76 (d, J = 2.9 Hz, 1H), 7.29−7.46 (m, 5H), 7.42−7.57 (m, 3H), 7.81−7.89 (m, 2H), 8.38 (d, J = 2.9 Hz, 1H), 12.26 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 13.7 (CH3), 14.6 (CH3), 59.6 (CH2), 106.0 (CH), 114.9 (C), 118.1 (C), 126.3 (CH), 127.1 (CH), 127.3 (CH), 129.0 (CH), 129.2 (CH), 129.5 (CH), 131.5 (C), 131.8 (CH), 135.3 (C), 140.0 (C), 140.7(C), 153.5 (C), 155.4 (C), 164.5 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C24H21N3NaO3+, 422.1475; found, 422.1462. Ethyl 2-methyl-4-phenyl-5-(1H-pyrazole-1-carbonyl)-1H-pyrrole3-carboxylate (6e). Compound 6e was prepared from azirine 5a (50 mg, 0.24 mmol), ethyl acetoacetate 11c (62 mg, 0.48 mmol), and NiCl2·6H2O (6 mg, 0.024 mmol) for 1.5 h according to general procedure D to afford a colorless solid, mp 104−105 °C (LP/EtOAc), yield 33 mg (42%). 1H NMR (CDCl3, 400 MHz): δ 0.97 (t, J = 7.1 Hz, 3H), 2.68 (s, 3H), 4.04 (q, J = 7.1 Hz, 2H), 6.44 (dd, J = 2.9, 1.7 Hz, 1H), 7.29−7.34 (m, 2H), 7.34−7.46 (m, 3H), 7.80 (dd, J = 1.6, 0.8 Hz, 1H), 8.34 (dd, J = 2.9, 0.7 Hz, 1H), 12.11 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 13.7 (CH3), 14.4 (CH3), 59.6 (CH2), 108.1 (CH), 114.9 (C), 118.1 (C), 127.1 (CH), 127.3 (CH), 129.2 (CH), 130.5 (CH), 135.3 (C), 140.2 (C), 140.8 (C), 143.5 (CH), 153.5 (C), 164.6 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C18H17N3NaO3+, 346.1162; found, 346.1160. 1-(4-(4-Bromophenyl)-2-methyl-5-(3-phenyl-1H-pyrazole-1-carbonyl)-1H-pyrrol-3-yl)ethanone (6f). Compound 6f was prepared from azirine 5h (92 mg, 0.25 mmol), acetylacetone 11a (50 mg, 0.50 mmol), and NiCl2·6H2O (6 mg, 0.025 mmol) for 3 h according to general procedure D to afford a colorless solid, mp 228−229 °C (LP/ EtOAc), yield 103 mg (92%). 1H NMR (CDCl3, 400 MHz): δ 1.88 (s, 3H), 2.69 (s, 3H), 6.77 (d, J = 2.9 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.45−7.54 (m, 3H), 7.60 (d, J = 8.3 Hz, 2H), 7.84−7.86 (m, 2H), 8.37 (d, J = 2.9 Hz, 1H), 12.31 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 15.3 (CH3), 31.0 (CH3), 106.3 (CH), 117.8 (C), 122.2 (C), 124.1 (C), 126.3 (CH), 129.1 (CH), 129.6 (CH), 131.1 (CH), 131.3 (C), 131.5 (CH), 131.7 (CH), 134.5 (C), 137.9 (C), 140.0 (C), 153.6 (C), 155.7 (C), 196.0 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C23H19BrN3O2+, 448.0655; found, 448.0673. (4-Benzoyl-3-(4-bromophenyl)-5-phenyl-1H-pyrrol-2-yl)(4,5,6,7tetrahydro-1H-indazol-1yl)methanone (6g). Compound 6g was prepared from azirine 5m (38 mg, 0.11 mmol), dibenzoylmethane 11b (49 mg, 0.22 mmol), and NiCl2·6H2O (3 mg, 0.011 mmol) for 4 h according to general procedure D to afford a colorless solid, mp 215−216 °C (LP/EtOAc), yield 29 mg (48%). 1H NMR (CDCl3, 400 MHz): δ 1.78−1.82 (m, 2H), 1.86−1.92 (m, 2H), 2.61−2.64 (m, 2H), 2.78−2.81 (m, 2H), 7.18−7.24 (m, 4H), 7.31−7.37 (m, 6H), 7.47− 7.49 (m, 2H), 7.66−7.68 (m, 2H), 8.06 (s, 1H), 12.75 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 20.5 (CH2), 22.86 (CH2), 22.93 (CH2), 23.8 (CH2), 119.5 (C), 119.6 (C), 121.7 (C), 123.5 (C), 126.8 (CH), 127.7 (CH), 128.1 (CH), 128.8 (CH), 128.9 (CH), 129.7 (CH), 130.6 (C), 130.7 (CH), 131.7 (CH), 132.5 (C), 132.8 (CH), 137.1 (C), 137.3 (C), 138.1 (C), 154.1 (C), 155.4 (C), 193.9 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C31H25BrN3O2+, 550.1125; found, 550.1145. (4-Benzoyl-3-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl)(3-phenyl-1H-pyrazol-1-yl)methanone (6h). Compound 6h was prepared from azirine 5i (60 mg, 0.19 mmol), dibenzoylmethane 11b (85 mg, 0.38 mmol), and NiCl2·6H2O (5 mg, 0.020 mmol) for 2 h according to general procedure D to afford a colorless solid, mp 199−200 °C (LP/EtOAc), yield 91 mg (92%). 1H NMR (CDCl3, 400 MHz): δ 3.75 (s, 3H), 6.78−6.80 (m, 2H), 6.82 (d, J = 2.9 Hz, 1H), 7.20−7.24 (m, 2H), 7.33−7.40 (m, 6H), 7.44−7.53 (m, 3H), 7.58−7.60 (m, 2H), 7.72−7.74 (m, 2H), 7.89−7.91 (m, 2H), 8.48(d, J = 2.9 Hz, 1H), 12.94 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 55.1 (CH3), 106.0 (CH), 113.1 (CH), 118.8 (C), 123.8 (C), 125.4 (C), 126.3 (CH),

127.5 (CH), 128.0 (CH), 128.9 (CH), 129.01 (CH), 129.04 (CH), 129.5 (CH), 129.8 (CH), 130.7 (C), 131.3 (CH), 131.4 (C), 131.9 (CH), 132.8 (CH), 137.5 (C), 138.1 (C), 139.3 (C), 153.9 (C), 155.4 (C), 159.0 (C), 194.3 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C34H26N3O3+, 524.1969; found, 524.1985. 1-(4-(4-Methoxyphenyl)-2-methyl-5-(3-phenyl-1H-pyrazole-1carbonyl)-1H-pyrrol-3-yl)ethanone (6i). Compound 6i was prepared from azirine 5i (60 mg, 0.19 mmol), acetylacetone 11a (38 mg, 0.38 mmol), and NiCl2·6H2O (5 mg, 0.020 mmol) for 3 h according to general procedure D to afford a colorless solid, mp 201−202 °C (LP/ EtOAc), yield 64 mg (85%). 1H NMR (CDCl3, 400 MHz): δ 1.88 (s, 3H), 2.69 (s, 3H), 3.87 (s, 3H), 6.76 (d, J = 2.9 Hz, 1H), 7.01 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 7.46−7.53 (m, 3H), 7.84−7.86 (m, 2H), 8.38 (d, J = 2.9 Hz, 1H), 12.28 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 15.2 (CH3), 30.8 (CH3), 55.2 (CH3), 106.0 (CH), 113.7 (CH), 117.8 (C), 124.4 (C), 126.3 (CH), 127.4 (C), 129.0 (CH), 129.5 (CH), 130.6 (CH), 131.4 (C), 131.7 (CH), 139.4 (C), 139.8 (C), 153.6 (C), 155.5 (C), 159.3 (C), 196.7 (C). HRMS (ESI− TOF) (m/z): [M + H]+ calcd for C24H22N3O3+, 400.1656; found, 400.1671. 6,6-Dimethyl-3-phenyl-2-(3-phenyl-1H-pyrazole-1-carbonyl)-6,7dihydro-1H-indol-4(5H)-one (6j). Compound 6j was prepared from azirine 5b (50 mg, 0.17 mmol), dimedone 11d (49 mg, 0.35 mmol), and NiCl2·6H2O (4 mg, 0.017 mmol) for 8 h according to general procedure D to afford a light-yellow solid, mp 192−194 °C (LP/ EtOAc), yield 31 mg (44%). 1H NMR (CDCl3, 400 MHz): δ 1.20 (s, 6H), 2.41 (s, 2H), 2.88 (s, 2H), 6.78 (d, J = 2.9 Hz, 1H), 7.33−7.59 (m, 8H), 7.79−7.92 (m, 2H), 8.41 (d, J = 2.9 Hz, 1H), 12.26 (s, 1H). 13 C NMR (100 MHz, CDCl3): δ 28.5 (CH3), 35.2 (C), 37.5 (CH2), 53.3 (CH2), 106.3 (CH), 119.0 (C), 119.7 (C), 126.4 (CH), 127.4 (CH), 127.8 (CH), 129.0 (CH), 129.6 (CH), 129.8 (CH), 131.4 (C), 131.9 (CH), 133.1 (C), 137.9 (C), 145.2 (C), 154.0 (C), 155.6 (C), 192.5 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C26H23N3NaO2+, 432.1682; found, 432.1686. 3-(4-Chlorophenyl)-6,6-dimethyl-2-(3-phenyl-1H-pyrazole-1-carbonyl)-6,7-dihydro-1H-indol-4(5H)-one (6k). Compound 6k was prepared from azirine 5g (96 mg, 0.30 mmol), dimedone 11d (84 mg, 0.60 mmol), and NiCl2·6H2O (7 mg, 0.030 mmol) for 20 h according to general procedure D to afford a colorless solid, mp 221− 222 °C (LP/EtOAc), yield 54 mg (41%). 1H NMR (CDCl3, 400 MHz): δ 1.20 (s, 6H), 2.41 (s, 2H), 2.88 (s, 2H), 6.79 (d, J = 2.9 Hz, 1H), 7.37−7.43 (m, 4H), 7.47−7.56 (m, 3H), 7.84−7.86 (m, 2H), 8.41 (d, J = 2.9 Hz, 1H), 12.30 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 28.5 (CH3), 35.2 (C), 37.5 (CH2), 53.2 (CH2), 106.5 (CH), 118.8 (C), 119.8 (C), 126.4 (CH), 127.6 (CH), 129.1 (CH), 129.7 (CH), 131.3 (C), 131.41 (CH), 131.44 (C), 131.9 (CH), 133.4 (C), 145.4 (C), 154.0 (C), 155.8 (C), 192.7 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C26H23ClN3O2+, 444.1473; found, 444.1491. General Procedure E for the Synthesis of Oxazoles 7. A solution of azirine 5 (0.15−0.25 mmol) in a mixture of CH3CN (2 mL), MeOH (10 mL), and water (0.05 mL) in a quartz tube was irradiated under an Ar atmosphere using a mercury lamp for 100−150 min (TLC monitoring, LP/EtOAc, 4:1). The mixture was cooled, the solvents were evaporated, and a crude product was purified by column chromatography (LP/EtOAc, 10:1) to give oxazole 7. 2-Phenyl-5-(3-phenyl-1H-pyrazol-1-yl)oxazole (7a). Compound 7a was prepared from azirine 5b (50 mg, 0.17 mmol) for 150 min according to general procedure E to afford a light-yellow solid, mp 172−174 °C (MeOH/CH3CN), yield 37 mg (74%). 1H NMR (CDCl3, 400 MHz): δ 6.82 (d, J = 2.6 Hz, 1H), 7.28 (s, 1H), 7.34− 7.41 (m, 1H), 7.42−7.55 (m, 5H), 7.86−7.97 (m, 3H), 8.04−8.13 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 105.5 (CH), 114.3 (CH), 126.1 (CH), 126.2 (CH), 126.8 (C), 128.67 (CH), 128.75 (CH), 128.9 (CH), 130.2 (CH), 130.6 (CH), 132.1 (C), 146.2 (C), 154.6 (C), 157.5 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C18H14N3O+, 288.1131; found, 288.1121. 2-Phenyl-5-(4-phenyl-1H-pyrazol-1-yl)oxazole (7b). Compound 7b was prepared from azirine 5f (40 mg, 0.14 mmol) for 100 min according to general procedure E to afford a light-yellow solid, mp 3185

DOI: 10.1021/acs.joc.8b00069 J. Org. Chem. 2018, 83, 3177−3187

Article

The Journal of Organic Chemistry 119−121 °C (LP/EtOAc), yield 29 mg (73%). 1H NMR (CDCl3, 400 MHz): δ 7.26 (s, 1H), 7.27−7.36 (m, 1H), 7.39−7.46 (m, 2H), 7.45− 7.54 (m, 3H), 7.54−7.63 (m, 2H), 8.03−8.12 (m, 3H), 8.12 (s, 1H). 13 C NMR (100 MHz, CDCl3): δ 114.2 (CH), 125.0 (CH), 125.3 (C), 125.9 (CH), 126.2 (CH), 126.7 (C), 127.4 (CH), 128.9 (CH), 129.0 (CH), 130.7 (CH), 131.0 (C), 140.5 (CH), 146.0 (C), 157.6 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C18H14N3O+, 288.1131; found, 288.1124. 2-Phenyl-5-(1H-pyrazol-1-yl)oxazole (7c). Compound 7c was prepared from azirine 5a (50 mg, 0.24 mmol) for 150 min according to general procedure E to afford a light-yellow solid, mp 62−63 °C (PE-DCM), yield 24 mg (48%). 1H NMR (CDCl3, 400 MHz): δ 6.52 (dd, J = 2.6, 1.8 Hz, 1H), 7.22 (s, 1H), 7.43−7.53 (m, 3H), 7.80 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 2.6 Hz, 1H), 8.00−8.11 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 107.9 (CH), 114.3 (CH), 126.1 (CH), 126.7 (C), 128.8 (CH), 128.9 (CH), 130.6 (CH), 142.6 (CH), 146.1 (C), 157.6 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C12H9N3NaO+, 234.0638; found, 234.0647. 5-(3-(4-Bromophenyl)-1H-pyrazol-1-yl)-2-phenyloxazole (7d). Compound 7d was prepared from azirine 5d (50 mg, 0.14 mmol) for 150 min according to general procedure E to afford a light-yellow solid, mp 177−179 °C (MeOH/CH3CN), yield 34 mg (68%). 1H NMR (CDCl3, 400 MHz): δ 6.79 (d, J = 2.6 Hz, 1H), 7.27 (s, 1H), 7.44−7.53 (m, 3H), 7.57 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 2.6 Hz, 1H), 8.01−8.12 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 105.4 (CH), 114.4 (CH), 122.7 (C), 126.2 (CH), 126.7 (C), 127.6 (CH), 128.9 (CH), 130.4, 130.7 (CH), 131.1 (C), 131.9 (CH), 146.0 (C), 153.5 (C), 157.6 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C18H12BrN3NaO+, 388.0056; found, 388.0051. 5-(3-(4-Methoxyphenyl)-1H-pyrazol-1-yl)-2-phenyloxazole (7e). Compound 7e was prepared from azirine 5e (50 mg, 0.16 mmol) for 150 min according to general procedure E to afford a light-yellow solid, mp 159−162 °C (MeOH/CH3CN), yield 28 mg (56%). 1H NMR (CDCl3, 400 MHz): δ 3.86 (s, 3H), 6.74 (d, J = 2.6 Hz, 1H), 6.93−7.03 (m, 2H), 7.25 (s, 1H), 7.42−7.57 (m, 3H), 7.79−7.87 (m, 2H), 7.90 (d, J = 2.6 Hz, 1H), 8.02−8.12 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 55.3 (CH3), 105.1 (CH), 114.1 (CH), 114.2 (CH), 124.9 (C), 126.2 (CH), 126.8 (C), 127.4 (CH), 128.9 (CH), 130.1 (CH), 130.5 (CH), 146.3 (C), 154.4 (C), 157.4 (C), 160.1 (C). HRMS (ESI−TOF) (m/z): [M + Na]+ calcd for C19H15N3NaO2+, 340.1056; found, 340.1050. 2-Phenyl-5-(4,5,6,7-tetrahydro-2H-indazol-2-yl)oxazole (7f). Compound 7f was prepared from azirine 5l (50 mg, 0.19 mmol) for 100 min according to general procedure E to afford a light-yellow solid, mp 97−99 °C (CHCl3), yield 42 mg (84%). 1H NMR (CDCl3, 400 MHz): δ 1.76−1.86 (m, 2H), 1.84−1.96 (m, 2H), 2.66 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 6.3 Hz, 2H), 7.43−7.52 (m, 3H), 7.59 (s, 1H), 7.94−8.12 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 20.5 (CH2), 23.1 (CH2), 23.4 (CH2), 112.9 (CH), 118.7 (C), 125.6 (CH), 126.0 (CH), 126.9 (C), 128.8 (CH), 130.3 (CH), 146.6 (C), 153.2 (C), 157.0 (C). HRMS (ESI−TOF) (m/z): [M + Ag]+ calcd for C16H15AgN3O+, 372.0261; found, 372.0266. 5-(1H-Indazol-1-yl)-2-phenyloxazole (7g). Compound 7g was prepared from azirine 5k (50 mg, 0.19 mmol) for 90 min according to general procedure E to afford a light-yellow solid, mp 88−92 °C (LP/EtOAc), yield 24 mg (48%). 1H NMR (CDCl3, 400 MHz): δ 7.28−7.37 (m, 2H), 7.46−7.60 (m, 4H), 7.74−7.81 (m, 2H), 7.79− 7.87 (m, 2H), 8.06−8.16 (m, 2H), 8.28 (d, J = 1.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 110.5 (CH), 116.3 (CH), 121.5 (CH), 122.8 (CH), 124.8 (C), 126.2 (CH), 127.0 (C), 128.4 (CH), 128.9 (CH), 130.6 (CH), 137.9 (CH), 139.7 (C), 145.5 (C), 158.2 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C16H12N3O+, 262.0975; found, 262.0975; yield 24 mg (48%). 2-(Benzo[b]thiophen-2-yl)-5-(3-phenyl-1H-pyrazol-1-yl)oxazole (7h). Compound 7h was prepared from azirine 5j (50 mg, 0.15 mmol) for 100 min according to general procedure E to afford a light-yellow solid, mp 164−166 °C (LP/EtOAc), yield 31 mg (62%). 1H NMR (400 MHz, CDCl3): δ 6.83 (d, J = 2.6 Hz, 1H), 7.29 (s, 1H), 7.33− 7.59 (m, 5H), 7.81−8.06 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 105.7 (CH), 114.3 (CH), 122.5 (CH), 124.5 (CH), 124.6 (CH),

125.1 (CH), 126.09 (CH), 126.11 (CH), 128.76 (CH), 128.78 (CH), 130.2 (CH), 132.0 (C), 139.4 (C), 140.5 (C), 146.2 (C), 153.6 (C), 154.8 (C). HRMS (ESI−TOF) (m/z): [M + H]+ calcd for C20H14N3OS+, 344.0852; found, 344.0867. Synthesis of Oxazole 7b under Laser Irradiation. A solution of azirine 5b (20.5 mg, 0.07 mmol) in CH3CN (3 mL) in a quartz cuvette was irradiated using laser light with a wavelength of 266 nm and an emission power of 50 mW/cm2 for 150 min. After the reaction was complete (TLC monitoring, LP/EtOAc, 4:1), 2-methylnaphtalene (10.8 mg, 0.07 mmol) was added to the reaction mixture as an internal standard, the solvent was evaporated, and the yield of oxazole 7a (70%) was determined by 1H NMR analysis.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00069. X-ray diffraction experiments, NMR spectra for all new compounds, computation details, and energies of compounds and their Cartesian coordinates (PDF) Crystallographic data for 3a (CIF) Crystallographic data for 5l (CIF) Crystallographic data for 6e (CIF) Crystallographic data for 7d (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kirill I. Mikhailov: 0000-0001-8368-4468 Ekaterina E. Galenko: 0000-0001-5021-7142 Alexey V. Galenko: 0000-0003-3980-8798 Mikhail S. Novikov: 0000-0001-5106-4723 Alexander F. Khlebnikov: 0000-0002-6100-0309 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the financial support of the Russian Science Foundation (grant no. 16-13-10036). This research was carried out using the resources of the X-ray Diffraction Centre, the Centre for Magnetic Resonance, the Computer Centre, the Centre for Chemical Analysis and Materials, and the Centre for Optical and Laser Materials Research of St. Petersburg State University.

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REFERENCES

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DOI: 10.1021/acs.joc.8b00069 J. Org. Chem. 2018, 83, 3177−3187

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DOI: 10.1021/acs.joc.8b00069 J. Org. Chem. 2018, 83, 3177−3187