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Article

Isomerization of 5-(2H-Azirin-2-yl)oxazoles: An Atom-Economic Approach to 4H-Pyrrolo[2,3-d]oxazoles

by
Timur O. Zanakhov
,
Ekaterina E. Galenko
,
Mariya A. Kryukova
,
Mikhail S. Novikov
and
Alexander A. Khlebnikov
*
Institute of Chemistry, St. Petersburg State University, 7/9 Universitetskaya nab., 199034 St. Petersburg, Russia
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(7), 1881; https://doi.org/10.3390/molecules26071881
Submission received: 28 February 2021 / Revised: 19 March 2021 / Accepted: 23 March 2021 / Published: 26 March 2021
(This article belongs to the Special Issue Diazo Chemistry)
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Versions Notes

Abstract

:
An atom economical method for the preparation of variously substituted 4H-pyrrolo[2,3-d]oxazoles was developed on the basis of thermal isomerization of 5-(2H-azirin-2-yl)oxazoles. The latter were prepared by Rh2(oct)4 catalyzed reaction of 2-(3-aryl/heteroaryl)-2-diazoacetyl-2H-azirines with a set of substituted acetonitriles, benzonitriles, acrylonitrile and fumaronitrile. According to DFT calculations the transformation of 5-(2H-azirin-2-yl)oxazole to 4H-pyrrolo[2,3-d]oxazole occurs through the nitrenoid-like transition state to give a 3aH-pyrrolo[2,3-d]oxazole intermediate, followed by 1,5-H-shift.

1. Introduction

Intramolecular ring-to-ring isomerization, while having 100% atom economy [1], appears to be a very attractive synthetic approach. Such isomerization of substituted azirines, which occurs easily due to the high strain of the three-membered ring under thermolysis, photolysis or catalysis, is widely used for the synthesis of various heterocycles [2,3,4]. 2-Carbonyl-substituted 2H-azirines can be isomerized to isoxazoles [2,3,4,5,6,7,8] or oxazoles [2,3,4,5,8], 2-vinyl-2H-azirines to pyrroles [9,10,11,12], and 2-(hydrazonomethyl) and 2-(iminomethyl)-2H-azirines to pyrazoles [13,14]. The isomerization can lead also to six-membered rings, thus, variously substituted pyridines were prepared from 2-propargyl [15,16,17,18], 2-allyl [19] or 2-vinyl-substituted 2H-azirines [10]. 5,6-Bicyclic heterocycles are also available via isomerization of azirines. Various indoles [2,3,4,20,21] and pyrazolo[1,5-a]pyridines [22,23,24,25] were synthesized by thermal or catalytic isomerization of 2-aryl- and 2-(pyrid-2-yl)-2H-azirines, respectively. Meanwhile, this isomerization has been used less for the preparation of 5,5-heterobicyclic systems. Single representatives of 6H-thieno[2,3-b]pyrrole [20,26], 4H-thieno[3,2-b]pyrrole [21,25,26], 4H-furo[3,2-b]pyrrole [26], 1,4-dihydropyrrolo[3,2-b]pyrrole [26] have been synthesized by rearrangement of vinyl azides or isoxazole, which presumably proceeds via the intermediate formation of the corresponding 2H-azirines followed by their isomerization (Scheme 1).
5,5-Heterobicyclic systems with three and more heteroatoms in the bicyclic framework, as far as we know, have not been prepared by using the azirine methodology. This is not least due to the difficulties in the synthesis of polyheteroatomic azoles bearing an azirin-2-yl substituent. One of the possible solutions to this problem could be the use of 2-diazoacetylazirine building blocks 1, the convenient synthesis of which we have recently reported [27,28]. Preliminary results on the Rh(II)-catalyzed reaction of 2-diazoacetylazirines with acetonitrile demonstrated the principal utility of this protocol for the preparation of 5-(2H-azirin-2-yl)oxazoles 2 [27]. We hypothesized that oxazoles 2 can be isomerized to 4H-pyrrolo[2,3-d]oxazoles 3 (Scheme 2), which have not yet been characterized in the literature. Only one compound of this class, 4H-pyrrolo[2,3-d]oxazole-5-carboxylic acid, was mentioned in connection with the study of D-amino acid oxidase inhibition, however, its synthesis, physical and spectral data were not published [29]. Here, we report the synthesis of a series of variously substituted 5-(2H-azirin-2-yl)oxazoles 2, their conversion to 4H-pyrrolo[2,3-d]oxazoles 3 and full characterization of the latter, including X-ray structural study.

2. Results and Discussion

A series of 5-(2H-azirin-2-yl)oxazoles 2 was synthesized from 2-(3-aryl/heteroaryl)-2-diazoacetyl-2H-azirines 1 [28] by Rh2(oct)4 catalyzed reaction [27] with a set of substituted acetonitriles, benzonitriles, acrylonitrile and fumaronitrile in a 15–73% yield (Figure 1).
Intramolecular ring-to-ring isomerization of azirines with the formation of five-membered nitrogen heterocyles most often occurs under conditions of metal catalysis or thermolysis at high temperatures [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Using azirine 2a as a test compound, various isomerization conditions (catalysts, solvents, temperatures) were tested to achieve maximum yield of 4H-pyrrolo[2,3-d]oxazole 3a. First of all, iron-containing catalysts, which successfully have been used for isomerization of different azirines, were tested. However, the use of FeCl2·4H2O (20 mol%) at various temperatures in acetonitrile (85 °C), 1,4-dioxane (110 °C), mesitylene (170 °C), DMSO (170 °C), anhydrous FeCl2 (20 mol%) in acetonitrile (85 °C), 1,4-dioxane (110 °C), mesitylene (150 °C), DMSO (150 °C) and anhydrous FeCl3 (20 mol%) in acetonitrile (85 °C), 1,4-dioxane (110 °C), toluene (110 °C), THF (66 °C) resulted in complete resinification of the reaction mixtures. Similar results were obtained when Co(acac)2·(20 mol%), Co(acac)3·(20 mol%) were tried as catalysts. The use of ZnBr2 (20 mol%), CuOAc (20 mol%), [(MeCN)4Cu]BF4 (20 mol%), Cu(tfacac)2 (20 mol%), Yb(Tf)3 (20 mol%) in acetonitrile (85 °C), 1,4-dioxane (110 °C), toluene (110 °C), DMF (110 °C) also resulted in complete resinification of the reaction mixtures. Heating of azirine 2a in the presence of NiCl2·6H2O (20 mol%) in acetonitrile (85 °C), 1,4-dioxane (110 °C), toluene (110 °C) gave only traces of pyrrolooxazole 3a. It was suggested that the failure of these experiments is due to the non-selective interaction of the catalysts with the polyheteroatomic substrate. Therefore, in the further experiments, it was decided to carry out the thermolysis in the absence of catalysts in an inert solvent. Heating azirine 2a in mesitylene at 170 °C for 3 h afforded pyrrolooxazole 3a in 70% yield. An increase in temperature to 180 °C reduced the reaction time to 1 h. These reaction conditions were used for the isomerization of 5-(2H-azirin-2-yl)oxazoles 2b-q to 4H-pyrrolo[2,3-d]oxazoles 2b-q (Figure 2).
The reaction tolerates a variety of substituted aryl and alkyl groups at the 3 position (R1) in azirine fragment and at the 2 position (R2) in oxazole fragment of starting compounds 2 and affords the desired products 3 in generally good yields (30–77%). Whereas heating compounds 2r and 2s with vinyl and chloromethyl substituents resulted in complete resinification of the reaction mixtures. All new compounds were characterized by 1H, 13C-NMR and HRMS methods. Moreover, the structure of 3d was also confirmed by single-crystal X-ray diffraction analysis (Figure 3). Pyrrolooxazoles 3a-q are non-hygroscopic crystalline solids, which are stable under an air atmosphere for at least 3 months at rt.
To shed some light on the mechanism for the isomerization of azirines 2 into pyrrolooxazoles 3, the DFT calculations of the transformation 2a→3a was performed at the DFT B3LYP-D3/6-311+G(d,p) level of theory with SMD model for mesitylene (Scheme 3, for details of the calculations see the Supplementary Materials).
According to the calculations, the transformation of the azirine ring of 2a occurs through the nitrenoid-like transition state TS2a-3′a with high relative Gibbs free energy. However, this activation barrier (38.3 kcal/mol) can be overcome under the harsh experimental conditions to give 2-methyl-5-phenyl-3aH-pyrrolo[2,3-d]oxazole 3′a. The intermediate 3′a can be further aromatized to final product 3′a by 1,5-H-shift (TS3′a-3a) through the surmountable activation barrier under the experimental conditions. An intermolecular 1,2-prototropic shift at the last stage also cannot be excluded if it has a lower energy barrier.
The pyrrole nitrogen of 4H-pyrrolo[2,3-d]oxazoles 3 can be protected by acylation. Thus, the reaction of compound 3a,h with p-toluoyl chloride mediated with NaH/15-crown-5 afforded compounds 4a,b in moderate-to-good yield (Scheme 4).

3. Materials and Methods

3.1. General Instrumentation

Melting points were determined on a melting point apparatus SMP30 (Research Park, Saint Petersburg State University, Saint Petersburg, Russia). 1H-NMR (400 MHz) and 13C-NMR (100 MHz) spectra were recorded on a Bruker AVANCE 400 spectrometer (Research Park, Saint Petersburg State University, Saint Petersburg, Russia) in CDCl3 or DMSO-d6. 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) 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 (Research Park, Saint Petersburg State University, Saint Petersburg, Russia). Single-crystal X-ray data were collected by means of a HyPix diffractometer (Research Park, Saint Petersburg State University, Saint Petersburg, Russia). The crystal of 3d was measured at a temperature of 100(2) K, using monochromated CuKα radiation. Crystallographic data for the structure 3d (CCDC 2064882) have been deposited with the Cambridge Crystallographic Data Centre. Thin-layer chromatography (TLC) was conducted on aluminum sheets precoated with SiO2 ALUGRAM SIL G/UV254. Column chromatography was performed on Macherey-Nagel silica gel 60M (Research Park, Saint Petersburg State University, Saint Petersburg, Russia) (0.04–0.063 mm). 1,2-Dichloroethane was washed with concentrated H2SO4 and water, then with saturated aq. NaHCO3 and dried over CaCl2, then distilled from P2O5, then from CaH2, and stored over anhydrous K2CO3. Acetonitrile and propionitrile were distilled from P2O5, then distilled from anhydrous K2CO3, and stored over 3Å sieves. Other nitriles were recrystallized or distilled prior to use. 3-Aryl/heteryl-5-chloroisoxazoles 5 and diazoacetylazirines 1 were prepared according to the published procedures [28,30].

3.2. General Experimental Procedures

3.2.1. General Procedure A (GP-A) for the Synthesis of 5-(2H-azirin-2-yl)oxazoles 2

Compound 2 was prepared following the slightly modified published procedure [27]. A portion of Rh2(oct)4 (1 mol%) was added to a mixture of azirine 1 (1 mmol) and appropriate nitrile (50–200 mmol) in DCE (500 mL per 1 mmol. of azirine). The resulting mixture was refluxed under argon for 10 min. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel.

3.2.2. General Procedure B (GP-B) for the Synthesis of 4H-pyrrolo[2,3-d]oxazoles 3

A solution of azirine 2 (0.1 mmol) in mesitylene (0.5 mL per 0.1 mmol of 2) in a thick-wall tube with screw cap at 180 °C (bath temperature) for 1 h (TLC control).

3.2.3. General Procedure C (GP-C) for the Synthesis of 4H-pyrrolo[2,3-d]oxazol-4-yl)(p-tolyl)methanones 4

A mixture of 4H-pyrrolo[2,3-d]oxazole 3 (0.1 mmol) and 15-crown-5 (0.1 mmol) in THF was added to a suspension of NaH (60% in mineral oil, 0.15 mmol, 1.5 eq.) in THF. After stirring for 0.5 h, a solution of 4-methylbenzoyl chloride (0.2 mmol) in THF was added dropwise to the resulting mixture. The reaction mixture was stirred for 3 h at room temperature, then poured into cold water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel.

3.2.4. Specific Procedures and Characterization

2-Methyl-5-(3-phenyl-2H-azirin-2-yl)oxazole (2a). Compound 2a [27] was prepared following the general procedure GP-A from azirine 1a (463 mg, 2.5 mmol), acetonitrile (26 mL, 500 mmol) and Rh2(oct)4 (19.5 mg, 0.025 mmol) in DCE (250 mL) in 365 mg (73% yield, after column chromatography on silica (light petroleum/ethyl acetate, 4:1 (v/v)) as a light brown oil. 1H-NMR (CDCl3, 400 MHz): δ 2.36 (s, 3H), 3.25 (s, 1H), 6.84 (s, 1H), 7.56–7.62 (m, 2H), 7.63–7.67 (m, 1H), 7.90–7.93 (m, 2H).
2-Methyl-5-(3-(4-bromophenyl)-2H-azirin-2-yl)oxazole (2b). Compound 2b was prepared following the general procedure GP-A from azirine 1b (264 mg, 1 mmol), acetonitrile (10.4 g, 200 mmol) and Rh2(oct)4 (8 mg, 0.01 mmol) in DCE (150 mL) in 135 mg (49% yield, after column chromatography on silica (light petroleum/ethyl acetate, 7:1–4:1 (v/v)) as a brown oil. 1H-NMR (CDCl3, 400 MHz): δ 2.36 (s, 3H), 3.27 (s, 1H), 6.85 (s, 1H), 7.73–7.79 (m, 4H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 13.9 (CH3), 25.3 (CH), 122.6 (C), 124.5 (CH), 128.6 (C), 131.1 (CH), 132.8 (CH), 150.7 (C), 160.9 (C), 162.1 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C12H10BrN2O+ 276.9971; found 276.9974. IR (KBr, cm−1): ν 1571, 1743, 2925.
5-(3-(Adamantan-1-yl)-2H-azirin-2-yl)-2-methyloxazole (2c). Compound 2c was prepared following the general procedure GP-A from azirine 1c (100 mg, 0.41 mmol), acetonitrile (4.3 mL, 82 mmol) and Rh2(oct)4 (3 mg, 0.0041 mmol) in DCE (100 mL) in 63 mg (61% yield, after column chromatography on silica (light petroleum/ethyl acetate, 10:1 (v/v)) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 1.77–1.85 (m, 6H), 1.95–1.98 (m, 6H), 2.10–2.13 (m, 3H), 2.38 (s, 3H), 2.81 (s, 1H), 6.75 (s, 1H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 13.9 (CH3), 24.0 (CH), 27.5 (CH), 35.6 (C), 36.4 (CH2), 38.2 (CH2), 123.6 (CH), 152.0 (C), 160.2 (C), 170.7 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C16H20N2NaO+ 279.1468; found 279.1458. IR (KBr, cm−1): ν 1574, 1697, 2851, 2907.
2-Ethyl-5-(3-phenyl-2H-azirin-2-yl)oxazole (2d). Compound 2d was prepared following the general procedure GP-A from azirine 1a (185 mg, 1 mmol), propionitrile (14.3 mL, 200 mmol) and Rh2(oct)4 (8 mg, 0.01 mmol) in DCE (200 mL) in 121 mg (57% yield, after column chromatography on silica (light petroleum/ethyl acetate, 11:1–7:1 (v/v)) as a light brown oil. 1H-NMR (CDCl3, 400 MHz): δ 1.26 (t, 3H, J = 7.6 Hz), 2.69 (q, 2H, J = 7.6 Hz), 3.26 (s, 1H), 6.83 (s, 1H), 7.56–7.66 (m, 3H), 7.90–7.93 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 11.1 (CH3), 21.7 (CH2), 25.1 (CH), 123.8 (C), 124.1 (CH), 129.3 (C), 129.9 (CH), 133.6 (CH), 151.0 (C), 162.5 (C), 165.2 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C13H12N2O+ 213.1022; found 213.1027. IR (KBr, cm−1): ν 1566, 1599, 1691, 1745, 2981.
2-Ethyl-5-(3-(4-methoxyphenyl)-2H-azirin-2-yl)oxazole (2e). Compound 2e was prepared following the general procedure GP-A from azirine 1d (215 mg, 1 mmol), propionitrile (14.3 mL, 200 mmol) and Rh2(oct)4 (8 mg, 0.01 mmol) in DCE (200 mL) in 117 mg (48% yield, after column chromatography on silica (light petroleum/ethyl acetate, 4:1 (v/v)) as a brown oil. 1H-NMR (CDCl3, 400 MHz): δ 1.26 (t, 3H, J = 7.6 Hz), 2.69 (q, 2H, J = 7.6 Hz), 3.19 (s, 1H), 3.91 (s, 3H), 6.80 (s, 1H), 7.06–7.09 (m, 2H), 7.84–7.87 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 11.0 (CH3), 21.7 (CH2), 24.7 (CH), 55.6 (CH3), 114.9 (CH), 116.1 (C), 123.8 (CH), 131.9 (CH), 151.3 (C), 161.1 (C), 163.8 (C), 165.02 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C14H15N2O2+ 243.1128; found 243.1131. IR (KBr, cm−1): ν 1509, 1567, 1605, 1679, 1745, 2939, 2980.
5-(3-(tert-Butyl)-2H-azirin-2-yl)-2-ethyloxazole (2f). Compound 2f was prepared following the general procedure GP-A from azirine 1e (150 mg, 0.91 mmol), propionitrile (9.7 mL, 136 mmol) and Rh2(oct)4 (7 mg, 0.0091 mmol) in DCE (150 mL) in 67 mg (38% yield, after column chromatography on silica (light petroleum/ethyl acetate, 6:1 (v/v)) as an orange oil. 1H-NMR (CDCl3, 400 MHz): δ 1.27 (t, 3H, J = 7.6 Hz), 1.34 (s, 9H), 2.70 (q, 2H, J = 7.6 Hz), 2.90 (s, 1H), 6.80 (s, 1H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 11.0 (CH3), 21.6 (CH2), 24.5 (CH), 26.0 (CH3), 33.3 (C), 123.6 (CH), 151.4 (C), 164.7 (C), 171.8 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C11H17N2O+ 193.1335; found 193.1328. IR (KBr, cm−1): ν 1568, 1700, 2971.
2-Benzyl-5-(3-(4-bromophenyl)-2H-azirin-2-yl)oxazole (2g). Compound 2g was prepared following the general procedure GP-A from azirine 1d (200 mg, 0.76 mmol), benzyl cyanide (12.9 g, 110 mmol) and Rh2(oct)4 (6 mg, 0.0076 mmol) in DCE (200 mL) in 94 mg (35% yield, after column chromatography on silica (toluene/light petroleum/ethyl acetate, 20:1 + 0.5% triethylamine (v/v)) as a brown oil. 1H-NMR (CDCl3, 400 MHz): δ 3.30 (s, 1H), 4.06 (s, 2H), 6.89 (s, 1H), 7.26–7.35 (m, 5H), 7.75–7.81 (m, 4H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 25.3 (CH), 34.6 (CH2), 122.6 (C), 124.5 (CH), 127.1 (CH), 128.7 (CH), 128.8 (C), 131.1 (CH), 132.8 (CH), 135.3 (C), 151.3 (C), 161.9 (C), 161.9 (C), 162.5 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C18H14BrN2O+ 353.0284; found 353.0288. IR (KBr, cm−1): ν 1670, 2924.
2-Phenyl-5-(3-phenyl-2H-azirin-2-yl)oxazole (2h). Compound 2h [27] was prepared following the general procedure GP-A from azirine 1a (500 mg, 2.7 mmol), benzonitrile (29 mL, 284 mmol) and Rh2(oct)4 (2.1 mg, 0.027 mmol) in DCE (250 mL) in 302 mg (43% yield, after column chromatography on silica (light petroleum/ethyl acetate, 7:1 (v/v)) as a brown oil. 1H-NMR (CDCl3, 400 MHz): δ 3.37 (s, 1H), 7.06 (s, 1H), 7.38–7.42 (m, 3H), 7.59–7.67 (m, 3H), 7.92–7.98 (m, 4H).
5-(3-(4-Fluorophenyl)-2H-azirin-2-yl)-2-phenyloxazole (2i). Compound 2i was prepared following the general procedure GP-A from azirine 1f (102 mg, 0.5 mmol), benzonitrile (10.4 mL, 100 mmol) and Rh2(oct)4 (4 mg, 0.005 mmol) in DCE (200 mL) in 78 mg (56% yield, after column chromatography on silica (light petroleum/ethyl acetate, 1:0–11:1–6:1 (v/v)) as a brown oil. 1H-NMR (CDCl3, 400 MHz): δ 3.38 (s, 1H), 7.07 (s, 1H), 7.28–7.33 (m, 2H), 7.38–7.42 (m, 3H), 7.91–7.94 (m, 2H), 7.96–8.00 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 25.4 (CH), 117.0 (d, CH, J = 22.4 Hz,), 119.9 (d, C, J = 3.2 Hz,), 125.8 (CH), 126.2 (CH), 127.3 (C), 128.7 (CH), 130.2 (CH), 132.3 (d, CH, J = 9.3 Hz), 136.0 (CH), 151.4 (C), 161.3 (C), 165.9 (d, C, J = 256.6 Hz). HRMS (ESI) m/z: [M + H]+ calcd. for C17H12FN2O+ 279.0928; found 279.0925. IR (KBr, cm−1): ν 1505, 1543, 1600, 1745, 3059.
5-(3-(tert-Butyl)-2H-azirin-2-yl)-2-phenyloxazole (2j). Compound 2j was prepared following the general procedure GP-A from azirine 1e (150 mg, 0.91 mmol), benzonitrile (14 mL, 137 mmol) and Rh2(oct)4 (7 mg, 0.0091 mmol) in DCE (150 mL) in 111 mg (51% yield, after column chromatography on silica (light petroleum/ethyl acetate, 9:1 (v/v)) as an orange oil. 1H-NMR (CDCl3, 400 MHz): δ 1.40 (s, 9H), 3.02 (s, 1H), 7.06 (s, 1H), 7.41–7.43 (m, 3H), 7.93–7.96 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 25.6 (CH), 26.1 (CH3), 33.6 (C), 125.5 (CH), 126.1 (CH), 127.4 (C), 128.7 (CH), 130.1 (CH), 152.1 (C), 160.6 (C), 171.6 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C15H16N2NaO+ 263.1155; found 263.1144. IR (KBr, cm−1): ν 1547, 1590, 2933, 2970.
5-(3-(Adamantan-1-yl)-2H-azirin-2-yl)-2-phenyloxazole (2k). Compound 2k was prepared following the general procedure GP-A from azirine 1c (150 mg, 0.62 mmol), benzonitrile (9.5 mL, 93 mmol) and Rh2(oct)4 (5 mg, 0.0062 mmol) in DCE (130 mL) in 84 mg (43% yield, after column chromatography on silica (light petroleum/ethyl acetate, 7:1 (v/v)) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 1.79–1.87 (m, 6H), 1.99–2.07 (m, 6H), 2.12–2.16 (m, 3H), 2.93 (s, 1H), 7.01 (s, 1H), 7.41–7.45 (m, 3H), 7.93–7.96 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 24.1 (CH), 27.5 (CH), 35.7 (C), 36.4 (CH2), 38.3 (CH2), 125.2 (CH), 126.1 (CH), 127.5 (C), 128.8 (CH), 130.1 (CH), 152.4 (C), 160.5 (C), 170.5 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C21H22N2NaO+ 341.1624; found 341.1621. IR (KBr, cm−1): ν 1580, 1756, 2855, 2911.
5-(3-(4-Methoxyphenyl)-2H-azirin-2-yl)-2-(p-tolyl)oxazole (2l). Compound 2l was prepared following the general procedure GP-A from azirine 1d (200 mg, 0.93 mmol), p-toluonitrile (7 g, 60 mmol) and Rh2(oct)4 (7 mg, 0.0093 mmol) in DCE (200 mL) in 58 mg (27% yield, after column chromatography on silica (light petroleum/ethyl acetate, 1:0–8:1–4:1 (v/v)) as a brown oil. 1H-NMR (CDCl3, 400 MHz): δ 2.37 (s, 3H), 3.31 (s, 1H), 3.92 (s, 3H), 7.02 (s, 1H), 7.08–7.10 (m, 2H), 7.19–7.21 (m, 2H), 7.82–7.84 (m, 2H), 7.88–7.92 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 21.4 (CH3), 24.9 (CH), 55.6 (CH3), 114.9 (CH), 115.9 (C), 124.7 (C), 125.4 (CH), 126.2 (CH), 129.3 (CH), 132.0 (CH), 140.4 (C), 151.7 (C), 160.9 (C), 161.2 (C), 163.9 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C19H17N2O2+ 305.1285; found 305.1296. IR (KBr, cm−1): ν 1509, 1605, 1676, 1724, 2853, 2924.
5-(3-(4-Chlorophenyl)-2H-azirin-2-yl)-2-(p-tolyl)oxazole (2m). Compound 2m was prepared following the general procedure GP-A from azirine 1g (200 mg, 0.91 mmol), p-toluonitrile (10.6 g, 91 mmol) and Rh2(oct)4 (7 mg, 0.0091 mmol) in DCE (150 mL) in 95 mg (34% yield, after column chromatography on silica (light petroleum/ethyl acetate, 1:0–7:1 (v/v)) as a brown oil. 1H-NMR (CDCl3, 400 MHz): δ 2.37 (s, 3H), 3.37 (s, 1H), 7.04 (s, 1H), 7.19–7.21 (m, 2H), 7.58–7.60 (m, 2H), 7.79–7.81 (m, 2H), 7.89–7.91 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 21.5 (CH3), 25.5 (CH), 122.1 (C), 124.6 (C), 125.8 (CH), 126.2 (CH), 129.4 (CH), 129.9 (CH), 131.1 (CH), 140.1 (C), 140.6 (C), 150.9 (C), 161.3 (C), 161.8 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C18H14ClN2O2+ 309.0789; found 309.0792. IR (KBr, cm−1): ν 1590, 1675, 1741, 2924.
5-(3-(Adamantan-1-yl)-2H-azirin-2-yl)-2-(p-tolyl)oxazole (2n). Compound 2n was prepared following the general procedure GP-A from azirine 1c (100 mg, 0.41 mmol), p-toluonitrile (5.2 g, 41 mmol) and Rh2(oct)4 (3 mg, 0.0041 mmol) in DCE (100 mL) in 63 mg (46% yield, after column chromatography on silica (light petroleum/ethyl acetate, 1:0–10:1 (v/v)) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 1.79–1.87 (m, 6H), 1.98–2.07 (m, 6H), 2.12–2.15 (m, 3H), 2.39 (s, 3H), 2.92 (s, 1H), 6.99 (s, 1H), 7.23–7.25 (m, 2H), 7.82–7.84 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 21.5 (CH3), 24.2 (CH), 27.5 (CH), 35.7 (C), 36.4 (CH2), 38.3 (CH2), 124.8 (C), 125.1 (CH), 126.0 (CH), 129.5 (CH), 140.4 (C), 152.1 (C), 160.7 (C), 170.6 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C22H25N2O+ 333.1961; found 333.1964. IR (KBr, cm−1): ν 1590, 1758, 2856, 2903.
2-(4-Bromophenyl)-5-(3-phenyl-2H-azirin-2-yl)oxazole (2o). Compound 2o was prepared following the general procedure GP-A from azirine 1a (185 mg, 1 mmol), 4-bromobenzonitrile (25 g, 200 mmol) and Rh2(oct)4 (8 mg, 0.01 mmol) in DCE (200 mL) in 51 mg (15% yield, after column chromatographies on silica (toluene/light petroleum/ethyl acetate, 100:0:0–100:1:1–0:12:1 (v/v); hexanes/methyl acetate, 20:1 (v/v) + 0.5% NEt3) as a brown oil. The low yield of compound 2o is associated with its significant losses during chromatographic isolation due to the low solubility of the starting 4-bromobenzonitrile, which is used in a large excess in the reaction. 1H-NMR (CDCl3, 400 MHz): δ 3.36 (s, 1H), 7.05 (s, 1H), 7.52–7.55 (m, 2H), 7.59–7.63 (m, 2H), 7.65–7.69 (m, 1H), 7.77–7.81 (m, 2H), 7.94–7.971 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 25.2 (CH), 123.4 (C), 124.6 (C), 125.8 (CH), 126.3 (C), 127.7 (CH), 129.4 (CH), 130.0 (CH), 132.0 (CH), 133.8 (CH), 152.02 (C), 160.1 (C), 162.2 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C17H12N2O+ 339.0128; found 339.0128. IR (KBr, cm−1): ν 1599, 1675, 1728, 1741.
2-(4-Bromophenyl)-5-(3-(tert-butyl)-2H-azirin-2-yl)oxazole (2p). Compound 2p was prepared following the general procedure GP-A from azirine 1e (150 mg, 0.91 mmol), 4-bromobenzonitrile (14 g, 77 mmol) and Rh2(oct)4 (7 mg, 0.0091 mmol) in DCE (150 mL) in 89 mg (31% yield, after column chromatography on silica (light petroleum/ethyl acetate, 9:1–8:1 (v/v)) as a red oil. 1H-NMR (CDCl3, 400 MHz): δ 1.39 (s, 9H), 3.00 (s, 1H), 7.04 (s, 1H), 7.55–7.57 (m, 2H), 7.78-7.80 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 25.5 (CH), 26.1 (CH3), 33.6 (C), 124.6 (C), 125.5 (CH), 126.3 (C), 127.5 (CH), 132.0 (CH), 152.5 (C), 159.7 (C), 171.4 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C15H15BrN2NaO+ 341.0260; found 341.0251. IR (KBr, cm−1): ν 1573, 1754, 2971.
(E)-3-(5-(3-phenyl-2H-azirin-2-yl)oxazol-2-yl)acrylonitrile (2q). Compound 2q was prepared following the general procedure GP-A from azirine 1a (100 mg, 0.54 mmol), fumaronitrile (4.2 g, 54 mmol) and Rh2(oct)4 (4 mg, 0.0054 mmol) in DCE (150 mL) in 38 mg (30% yield, after column chromatography on silica (light petroleum/ethyl acetate, 1:0–30:1 (v/v)) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 3.30 (s, 1H), 6.10 (d, 1H, J = 16.5 Hz), 7.08 (d, 1H, J = 16.5 Hz), 7.13 (s, 1H), 7.59–7.63 (m, 2H), 7.66–7.70 (m, 1H), 7.90–7.93 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 24.9 (CH), 102.4 (CH), 116.5 (C), 122.8 (C), 127. (CH), 129.5 (CH), 130.0 (CH), 133.8 (CH), 134.0 (CH), 154.2 (C), 157.0 (C), 161.3 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C14H9N3NaO+ 258.0638; found 258.0638. IR (KBr, cm−1): ν 1516, 1746, 2217, 2854, 2924, 3062.
5-(3-Phenyl-2H-azirin-2-yl)-2-vinyloxazole (2r). Compound 2r was prepared following the general procedure GP-A from azirine 1a (222 mg, 1.2 mmol), acrylonitrile (15.7 mL, 240 mmol) and Rh2(oct)4 (10 mg, 0.012 mmol) in DCE (200 mL) in 106 mg (38% yield, after column chromatography on silica (light petroleum/ethyl acetate, 5:1 (v/v)) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 3.30 (s, 1H), 5.53 (dd, 1H, J = 11.3, 1.1 Hz), 6.04 (dd, 1H, J = 17.7, 1.1 Hz), 6.51 (dd, 1H, J = 17.7, 11.3 Hz), 6.97 (s, 1H), 7.58–7.67 (m, 3H), 7.92–7.95 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 25.1 (CH), 121.4 (CH2), 123.2 (CH), 123.5 (C), 125.4 (CH), 129.4 (CH), 129.9 (CH), 133.7 (CH), 151.4 (C), 160.4 (C), 162.2 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C13H10N2NaO+ 233.0685; found 233.0677. IR (KBr, cm−1): ν 1519, 1597, 1696, 1745, 3061.
2-(Chloromethyl)-5-(3-phenyl-2H-azirin-2-yl)oxazole (2s). Compound 2s was prepared following the general procedure GP-A from azirine 1a (200 mg, 1.1 mmol), chloroacetonitrile (13.8 mL, 220 mmol) and Rh2(oct)4 (8 mg, 0.01 mmol) in DCE (150 mL) in 67 mg (26% yield, after column chromatography on silica (light petroleum/ethyl acetate, 5:1 (v/v)) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 3.29 (s, 1H), 4.53 (d, 2H, J = 0.8 Hz), 6.93 (s, 1H), 7.58–7.63 (m, 2H), 7.65–7.69 (m, 1H), 7.91–7.94 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 24.9 (CH), 35.8 (CH2), 123.3 (C), 124.8 (CH), 129.4 (CH), 130.0 (CH), 133.8 (CH), 153.3 (C), 158.2 (C), 161.8 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C12H10ClN2O+ 213.0476; found 233.0476. IR (KBr, cm−1): ν 1526, 1598, 1689, 2854, 2926, 3035, 3143.
2-Methyl-5-phenyl-4H-pyrrolo[2,3-d]oxazole (3a). Compound 3a was prepared following the general procedure GP-B from azirine 2a (100 mg, 0.5 mmol) in mesitylene (1.0 mL) in 74 mg (74% yield, after column chromatography on silica (chloroform/methanol, 0:1–100:1 (v/v)) as a light brown solid: mp 194–195 °C (chloroform). 1H-NMR (DMSO-d6, 400 MHz): δ 2.52 (s, 3H), 6.60 (d, 1H, J = 1.7 Hz), 7.15–7.19 (m, 1H), 7.33–7.37 (m, 2H), 7.64–7.67 (m, 2H), 11.60 (s, 1H). 13C{1H}-NMR (DMSO-d6, 100 MHz): δ 14.8 (CH3), 87.7 (CH), 123.4 (CH), 125.9 (CH), 128.7 (CH), 131.1 (C), 133.4 (C), 139.0 (C), 140.9 (C), 162.6 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C12H11N2O+ 199.0866; found 199.0873. IR (KBr, cm−1): ν 1509, 1556, 1606, 3167, 3205.
2-Methyl-5-(4-bromophenyl)-4H-pyrrolo[2,3-d]oxazole (3b). Compound 3b was prepared following the general procedure GP-B from azirine 2b (98 mg, 0.35 mmol) in mesitylene (1.5 mL) in 52 mg (53% yield, after evaporation of solvent and washing with cold ether) as a brown solid: mp 274–276 °C (mesitylene). 1H-NMR (DMSO-d6, 400 MHz): δ 2.52 (s, 3H), 6.66 (d, J = 1.6 Hz, 1H), 7.52–7.55 (m, 2H), 7.60–7.63 (m, 2H), 11.68 (s, 1H). 13C{1H}-NMR (DMSO-d6, 100 MHz): δ 14.8 (CH3), 88.3 (CH), 118.4 (C), 125.3 (CH), 129.8 (C), 131.6 (CH), 132.7 (C), 139.4 (C), 140.9 (C), 162.0 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C12H10BrN2O+ 276.9971; found 276.9965. IR (KBr, cm−1): ν 1558, 3131, 3214.
5-(Adamantan-1-yl)-2-methyl-4H-pyrrolo[2,3-d]oxazole (3c). Compound 3c was prepared following the general procedure GP-B from azirine 2c (56 mg, 0.22 mmol) in mesitylene (1.0 mL) in 35 mg (70% yield, after column chromatography on silica (light petroleum/ethyl acetate, 7:1 (v/v)) as a light brown solid: mp 204–206 °C (light petroleum/ethyl acetate). 1H-NMR (CDCl3, 400 MHz): δ 1.73–1.86 (m, 6H), 1.94–1.95 (m, 6H), 2.07–2.09 (m, 3H), 2.55 (s, 3H), 5.83 (d, 1H, J = 1.8 Hz), 8.96 (s, 1H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 15.0 (CH3), 27.5 (CH), 28.5 (CH), 34.2 (C), 36.7 (CH2), 43.0 (CH2), 85.6 (CH), 136.1 (C), 140.7 (C), 143.0 (C), 160.5 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C16H21N2O+ 257.1648; found 257.1647. IR (KBr, cm−1): ν 1552, 1663, 1714, 2847, 2905, 3211.
2-Ethyl-5-phenyl-4H-pyrrolo[2,3-d]oxazole (3d). Compound 3d was prepared following the general procedure GP-B from azirine 2d (75 mg, 0.35 mmol) in mesitylene (1.0 mL) in 52 mg (69% yield, after column chromatography on silica (toluene/chloroform, 100:1 (v/v)) as a light brown solid: mp 155–157 °C (toluene). 1H-NMR (CDCl3, 400 MHz): δ 1.43 (t, 3H, J = 7.6 Hz), 2.97 (q, 2H, J = 7.6 Hz), 6.45 (d, 1H, J = 1.6 Hz), 7.21-7.26 (s, 1H), 7.37–7.40 (m, 2H), 7.52–7.55 (m, 2H), 9.26 (s, 1H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 11.8 (CH3), 23.1 (CH2), 88.4 (CH), 124.0 (CH), 126.5 (CH), 128.9 (CH), 132.2 (C), 133.6 (C), 138.7 (C), 141.9 (C), 166.74 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C13H13N2O+ 213.1022; found 213.1015. IR (KBr, cm−1): ν 1508, 1551, 1604, 3204.
2-Ethyl-5-(4-methoxyphenyl)-4H-pyrrolo[2,3-d]oxazole (3e). Compound 3e was prepared following the general procedure GP-B from azirine 2e (82 mg, 0.34 mmol) in mesitylene (1.5 mL) in 40 mg (49% yield, after column chromatography on silica (light petroleum/ethyl acetate, 5:1 + 5% chloroform (v/v)) as a brown solid: mp 214–216 °C (light petroleum/ethyl acetate). 1H-NMR (DMSO-d6, 400 MHz): δ 1.40 (t, 3H, J = 7.6 Hz), 2.92 (q, 2H, J = 7.6 Hz), 3.84 (s, 3H), 6.30 (d, 1H, J = 1.6 Hz), 6.92–6.95 (m, 2H), 7.44–7.47 (m, 2H), 9.03 (s, 1H). 13C{1H}-NMR (DMSO-d6, 100 MHz): δ 11.9 (CH3), 22.6 (CH2), 55.6 (CH3), 87.1 (CH), 114.7 (CH), 125.4 (CH), 126.7 (C), 131.8 (C), 138.7 (C), 141.3 (C), 158.2 (C), 165.8 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C14H15N2O2+ 243.1128; found 243.1122. IR (KBr, cm−1): ν 1517, 1551, 1613, 2959, 3233.
5-(tert-Butyl)-2-ethyl-4H-pyrrolo[2,3-d]oxazole (3f). Compound 3f was prepared following the general procedure GP-B from azirine 2f (59 mg, 0.31 mmol) in mesitylene (1.5 mL) in 39 mg (67% yield, after column chromatography on silica (light petroleum/ethyl acetate, 7:1 (v/v)) as a light brown solid: mp 151–154 °C (light petroleum/ethyl acetate). 1H-NMR (CDCl3, 400 MHz): δ 1.35 (s, 9H), 1.37 (t, 3H, J = 7.5 Hz), 2.87 (q, 2H, J = 7.5 Hz,), 5.86 (d, 1H, J = 1.7 Hz), 8.82 (s, 1H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 11.8 (CH3), 22.8 (CH2), 30.6 (CH3), 32.4 (C), 86.0 (CH), 136.4 (C), 140.4 (C), 142.4 (C), 165.3 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C11H17N2O+ 193.1335; found 193.1333. IR (KBr, cm−1): ν 1525, 1550, 1584, 2867, 2963, 3236.
2-Benzyl-5-(4-bromophenyl)-4H-pyrrolo[2,3-d]oxazole (3g). Compound 3g was prepared following the general procedure GP-B from azirine 2g (94 mg, 0.27 mmol) in mesitylene (1.5 mL) in 56 mg (60% yield, after column chromatography on silica (light petroleum/ethyl acetate, 4:1 + 5% chloroform (v/v)) as a brown solid: mp 227–230 °C (light petroleum/ethyl acetate). 1H-NMR (DMSO-d6, 400 MHz): δ 4.22 (s, 2H), 6.66 (d, 1H, J = 1.7 Hz), 7.26–7.29 (m, 1H), 7.32–7.37 (m, 4H), 7.53–7.56 (m, 2H), 7.60–7.63 (m, 2H), 11.72 (s, 1H). 13C{1H}-NMR (DMSO-d6, 100 MHz): δ 34.9 (CH2), 88.4 (CH), 118.6 (C), 125.4 (CH), 126.8 (CH), 128.6 (CH), 128.7 (CH), 130.3 (C), 131.6 (CH), 132.5 (C), 136.1 (C), 139.3 (C), 141.2 (C), 163.5 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C18H14BrN2O+ 353.0284; found 353.0284. IR (KBr, cm−1): ν 1506, 3210.
2,5-Diphenyl-4H-pyrrolo[2,3-d]oxazole (3h). Compound 3h was prepared following the general procedure GP-B from azirine 2h (85 mg, 0.33 mmol) in mesitylene (1.0 mL) in 64 mg (75% yield, after column chromatography on silica (toluene/chloroform, 100:1 (v/v)) as a light brown solid: mp 246–247 °C (toluene). 1H-NMR (DMSO-d6, 400 MHz): δ 6.75 (d, 1H, J = 1.6 Hz), 7.21–7.25 (m, 1H), 7.38–7.42 (m, 2H), 7.48–7.50 (m, 1H), 7.51–7.56 (m, 2H), 7.72–7.74 (m, 2H), 8.01–8.04 (m, 2H), 11.86 (s, 1H). 13C{1H}-NMR (DMSO-d6, 100 MHz): δ 87.9 (CH), 123.8 (CH), 125.3 (CH), 126.4 (CH), 128.1 (C), 128.8 (CH), 129.1 (CH), 129.8 (CH), 133.0 (C), 133.4 (C), 140.3 (C), 141.7 (C), 160.8 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C17H13N2O+ 261.1022; found 261.1015. IR (KBr, cm−1): ν 1467, 1600, 3256.
5-(4-Fluorophenyl)-2-phenyl-4H-pyrrolo[2,3-d]oxazole (3i). Compound 3i was prepared following the general procedure GP-B from azirine 2i (120 mg, 0.43 mmol) in mesitylene (1.5 mL) in 43 mg (36% yield, after evaporation of solvent and washing with acetonitrile) as a brown solid: mp 248–251 °C (mesitylene). 1H-NMR (DMSO-d6, 400 MHz): δ 6.72 (d, 1H, J = 1.6 Hz), 7.23–7.28 (m, 2H), 7.46–7.50 (m, 1H), 7.51–7.56 (m, 2H), 7.74–7.77 (m, 2H), 8.00–8.03 (m, 2H), 11.86 (s, 1H). 13C{1H}-NMR (DMSO-d6, 100 MHz): δ 88.5 (CH), 116.2 (d, CH, J = 21.6 Hz), 125.8 (CH), 126.2 (d, CH, J = 7.8 Hz), 128.5 (C), 129.6 (CH), 130.2 (d, C, J = 3.2 Hz), 130.3 (CH), 132.9 (C), 140.7 (C), 142.1 (C), 161.2 (C), 161.4 (d, C, J = 243.7 Hz). HRMS (ESI) m/z: [M + H]+ calcd. for C17H12FN2O+ 279.0928; found 279.0932. IR (KBr, cm−1): ν 1513, 1563, 3252.
5-(tert-Butyl)-2-phenyl-4H-pyrrolo[2,3-d]oxazole (3j). Compound 3j was prepared following the general procedure GP-B from azirine 2j (87 mg, 0.36 mmol) in mesitylene (1.5 mL) in 67 mg (77% yield, after column chromatography on silica (light petroleum/ethyl acetate, 9:1 (v/v)) as a light brown solid: mp 119–121 °C (light petroleum/ethyl acetate). 1H-NMR (CDCl3, 400 MHz): δ 1.35 (s, 9H), 5.96 (d, 1H, J = 1.7 Hz), 7.35–7.39 (m, 1H), 7.41–7.46 (m, 2H), 8.03–8.05 (m, 2H), 8.19 (s, 1H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 30.5 (CH3), 32.6 (C), 86.5 (CH), 125.7 (CH), 128.7 (CH), 129.0 (C), 129.2 (CH), 138.0 (C), 141.2 (C), 144.2 (C), 160.8 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C15H17N2O+ 241.1335; found 241.1337. IR (KBr, cm−1): ν 1541, 1571, 1605, 2963, 3134, 3215.
5-(Adamantan-1-yl)-2-phenyl-4H-pyrrolo[2,3-d]oxazole (3k). Compound 3k was prepared following the general procedure GP-B from azirine 2k (50 mg, 0.15 mmol) in mesitylene (1.0 mL) in 31 mg (62% yield, after column chromatography on silica (light petroleum/ethyl acetate, 10:1 (v/v)) as a light grey solid: mp 205–207 °C (light petroleum/ethyl acetate). 1H-NMR (CDCl3, 400 MHz): δ 1.69–1.79 (m, 6H), 1.92–1.93 (m, 6H), 2.04–2.06 (m, 3H), 5.93 (d, 1H, J = 1.7 Hz), 7.35–7.39 (m, 1H), 7.41–7.45 (m, 2H), 8.03–8.06 (m, 2H), 8.34 (s, 1H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 28.5 (CH), 34.4 (C), 36.6 (CH2), 42.8 (CH2), 85.9 (CH), 125.7 (CH), 128.7 (CH), 129.0 (C), 129.2 (CH), 137.7 (C), 141.3 (C), 144.9 (C), 160.7 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C21H22N2NaO+ 341.1624; found 341.1627. IR (KBr, cm−1): ν 1569, 2848, 2900, 3264.
5-(4-Methoxyphenyl)-2-(p-tolyl)-4H-pyrrolo[2,3-d]oxazole (3l). Compound 3l was prepared following the general procedure GP-B from azirine 2l (58 mg, 0.19 mmol) in mesitylene (1.0 mL) in 18 mg (31% yield, after column chromatography on silica (light petroleum/ethyl acetate, 1:0–4:1 (v/v)) as a light brown solid: mp 217–219 °C (light petroleum/ethyl acetate). 1H-NMR (DMSO-d6, 400 MHz): δ 2.37 (s, 3H), 3.78 (s, 3H), 6.58 (d, 1H, J = 1.6 Hz), 6.96–6.98 (m, 2H), 7.32–7.34 (m, 2H), 7.63–6.65 (m, 2H), 7.87–7.89 (m, 2H), 11.65 (s, 1H). 13C{1H}-NMR (DMSO-d6, 400 MHz): δ 21.5 (CH3), 55.6 (CH3), 87.3 (CH), 114.8 (CH), 125.6 (CH), 125.7 (CH), 126.0 (C), 126.3 (C), 130.2 (CH), 133.7 (C), 139.9 (C), 140.1 (C), 142.0 (C), 158.5 (C), 161.0 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C19H17N2O2+ 305.1285; found 305.1296. IR (KBr, cm−1): ν 1604, 1661, 3252.
5-(4-Chlorophenyl)-2-(p-tolyl)-4H-pyrrolo[2,3-d]oxazole (3m). Compound 3m was prepared following the general procedure GP-B from azirine 2m (76 mg, 0.25 mmol) in mesitylene (1.5 mL) in 47 mg (61% yield, after evaporation of solvent and washing with cold ether) as a light brown solid: mp 237–239 °C (mesitylene). 1H-NMR (DMSO-d6, 400 MHz): δ 2.38 (s, 3H), 6.78 (d, 1H, J = 1.5 Hz), 7.34–7.36 (m, 2H), 7.44–7.46 (m, 2H), 7.72–7.74 (m, 2H), 7.90–7.92 (m, 2H), 11.89 (s, 1H). 13C{1H}-NMR (DMSO-d6, 400 MHz): δ 21.5 (CH3), 89.0 (CH), 125.7 (CH), 125.8 (C), 125.9 (CH), 129.3 (CH), 130.2 (CH), 131.0 (C), 132.2 (C), 132.5 (C), 140.3 (C), 141.0 (C), 141.9 (C), 161.9 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C18H14ClN2O+ 309.0789; found 309.0777. IR (KBr, cm−1): ν 1551, 3247.
5-(Adamantan-1-yl)-2-(p-tolyl)-4H-pyrrolo[2,3-d]oxazole (3n). Compound 3n was prepared following the general procedure GP-B from azirine 2n (60 mg, 0.18 mmol) in mesitylene (1.0 mL) in 21 mg (35% yield, after column chromatography on silica (light petroleum/ethyl acetate, 7:1 (v/v)) as a light brown solid: mp 198–201 °C (light petroleum/ethyl acetate). 1H-NMR (CDCl3, 400 MHz): δ 1.70–1.79 (m, 6H), 1.92–1.93 (m, 6H), 2.06 (s, 3H), 2.39 (s, 3H), 5.92 (s, 1H), 7.23–7.25 (m, 2H), 7.92–7.94 (m, 2H), 8.31 (s, 1H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 21.4 (CH), 28.5 (CH), 34.4 (C), 36.7 (CH2), 42.9 (CH2), 85.8 (CH), 125.7 (CH), 126.3 (C), 129.4 (CH), 137.6 (C), 139.3 (C), 141.0 (C), 144.6 (C), 161.0 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C22H24N2NaO+ 355.1781; found 355.1781. IR (KBr, cm−1): ν 1551, 1570, 2847, 2908, 3261.
2-(4-Bromophenyl)-5-phenyl-4H-pyrrolo[2,3-d]oxazole (3o). Compound 3o was prepared following the general procedure GP-B from azirine 2o (48 mg, 0.14 mmol) in mesitylene (0.5 mL) in 26 mg (54% yield, after evaporation of solvent and washing with cold ether) as a light brown solid: mp 244–245 °C (mesitylene). 1H-NMR (DMSO-d6, 400 MHz): δ 6.74 (d, 1H, J = 1.5 Hz), 7.21–7.24 (m, 1H), 7.37–7.41 (m, 2H), 7.70–7.73 (m, 4H), 7.92–7.94 (m, 2H), 11.89 (s, 1H). 13C{1H}-NMR (DMSO-d6, 100 MHz): δ 87.9 (CH), 123.0 (C), 123.8 (CH), 126.5 (CH), 127.1 (CH), 127.2 (C), 128.8 (CH), 132.2 (CH), 132.9 (C), 133.8 (C), 140.3 (C), 141.9 (C), 159.8 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C17H12N2O+ 339.0128; found 339.0131. IR (KBr, cm−1): ν 1597, 3262.
2-(4-Bromophenyl)-5-(tert-butyl)-4H-pyrrolo[2,3-d]oxazole (3p). Compound 3p was prepared following the general procedure GP-B from azirine 2p (91 mg, 0.29 mmol) in mesitylene (1.5 mL) in 44 mg (47% yield, after column chromatography on silica (light petroleum/ethyl acetate, 10:1 (v/v)) as a light brown solid: mp 181–183 °C (light petroleum/ethyl acetate). 1H-NMR (CDCl3, 400 MHz): δ 1.35 (s, 9H), 5.95 (d, 1H, J = 1.7 Hz), 7.54–7.56 (m, 2H), 7.87-7.89 (m, 2H), 8.07 (s, 1H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 30.5 (CH3), 32.6 (C), 86.5 (CH), 123.3 (C), 127.0 (CH), 127.9 (C), 131.9 (CH), 138.0 (C), 141.4 (C), 144.7 (C), 159.7 (C). HRMS (ESI) m/z: [M + H]+ calcd. for C15H16BrN2O+ 319.0441; found 319.0434. IR (KBr, cm−1): ν 1534, 1566, 2955, 3225.
(E)-3-(5-phenyl-4H-pyrrolo[2,3-d]oxazol-2-yl)acrylonitrile (3q). Compound 3q was prepared following the general procedure GP-B from azirine 2q (84 mg, 0.36 mmol) in mesitylene (1.0 mL) in 25 mg (30% yield, after evaporation of solvent and washing with cold ether) as a yellow solid: mp 251–253 °C (mesitylene). 1H-NMR (DMSO-d6, 400 MHz): δ 6.46 (d, 1H, J = 16.3 Hz), 6.78 (d, 1H, J = 1.5 Hz), 7.27–7.31 (m, 1H), 7.41–7.45 (m, 2H), 7.55 (d, 1H, J = 16.3 Hz), 7.76–7.78 (m, 2H), 12.12 (s, 1H). 13C{1H}-NMR (DMSO-d6, 100 MHz): δ 88.2 (CH), 99.3 (CH), 118.7 (C), 124.8 (CH), 127.8 (CH), 129.4 (CH), 132.7 (C), 135.1 (CH), 138.0 (C), 141.8 (C), 143.7 (C), 158.2 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C14H9N3NaO+ 258.0638; found 258.0643. IR (KBr, cm−1): ν 1555, 1603, 1628, 1744, 2218, 2924, 3212.
(2-Methyl-5-phenyl-4H-pyrrolo[2,3-d]oxazol-4-yl)(p-tolyl)methanone (4a). Compound 4a was prepared following the general procedure GP-C from 4H-pyrrolo[2,3-d]oxazole 3a (100 mg, 0.51 mmol), NaH (30 mg, 0.76 mmol), 15-crown-5 (112 mg, 0.51 mmol), 4-methylbenzoyl chloride (154 mg, 1.0 mmol) in tetrahydrofuran (5.0 mL) in 132 mg (83% yield, after column chromatography on silica (light petroleum/ethyl acetate, 10:1 (v/v)) as a yellow solid: mp 121–124 °C (light petroleum/ethyl acetate). 1H-NMR (CDCl3, 400 MHz): δ 2.44 (s, 3H), 2.52 (s, 3H), 6.43 (s, 1H), 7.21–7.25 (m, 2H), 7.27–7.234 (m, 5H), 7.85–7.87 (m, 2H). 13C{1H}-NMR (CDCl3, 100 MHz): δ 15.1 (CH3), 21.8 (CH3), 98.2 (CH), 127.2 (CH), 127.8 (CH), 128.3 (CH), 129.1 (CH), 130.0 (C), 131.2 (CH), 133.3 (C), 136.5 (C), 140.9 (C), 141.0 (C), 144.7 (C), 162.4 (C), 166.7 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C20H16N2NaO+ 339.1104; found 339.1104. IR (KBr, cm−1): ν 1611, 1705, 2919.
(2,5-Diphenyl-4H-pyrrolo[2,3-d]oxazol-4-yl)(p-tolyl)methanone (4b). Compound 4b was prepared following the general procedure GP-C from 4H-pyrrolo[2,3-d]oxazole 3h (58 mg, 0.22 mmol), NaH (14 mg, 0.33 mmol), 15-crown-5 (49 mg, 0.55 mmol), 4-methylbenzoyl chloride (68 mg, 0.44 mmol) in tetrahydrofuran (3.0 mL) in 46 mg (55% yield, after column chromatography on silica (light petroleum/ethyl acetate, 20:1 (v/v)) as a yellow solid: mp 156–158 °C (light petroleum/ethyl acetate). 1H-NMR (CDCl3, 400 MHz): δ 2.47 (s, 3H), 6.53 (s, 1H), 7.25–7.34 (m, 5H), 7.36–7.43 (m, 5H), 7.90–7.92 (m, 2H), 7.97–8.00 (m, 2H). 13C{1H}-NMR (CDCl3, 400 MHz): δ 21.8 (CH3), 98.1 (CH), 126.2 (CH), 127.4 (CH), 127.8 (CH), 128.1 (C), 128.3 (CH), 128.7 (CH), 129.0 (CH), 129.95 (C), 129.99 (CH), 131.4 (CH), 133.2 (C), 137.8 (C), 141.4 (C), 142.3 (C), 144.7 (C), 162.2 (C), 166.8 (C). HRMS (ESI) m/z: [M + Na]+ calcd. for C25H18N2NaO+ 401.1260; found 401.1262. IR (KBr, cm−1): ν 1609, 1699, 2854, 2924.

4. Conclusions

A series of variously substituted 4H-pyrrolo[2,3-d]oxazoles was synthesized by thermally induced isomerization of 5-(2H-azirin-2-yl)oxazoles in mesitylene at 180 °C. The reaction tolerates a variety of substituted aryl and alkyl groups at the 3 position in the azirine fragment and at the 2 position in the oxazole fragment of starting compounds. Whereas heating 5-(3-phenyl-2H-azirin-2-yl)-2-vinyl/(chloromethyl)oxazoles resulted in complete resinification of the reaction mixtures. Starting 5-(2H-azirin-2-yl)oxazoles were prepared by Rh2(oct)4 catalyzed reaction of 2-(3-aryl/heteroaryl)-2-diazoacetyl-2H-azirines with a set of substituted acetonitriles, benzonitriles, acrylonitrile and fumaronitrile. According to DFT calculations at the DFT B3LYP-D3/6-311+G(d,p) level of theory with SMD model for mesitylene, the transformation of 5-(2H-azirin-2-yl)oxazole to 4H-pyrrolo[2,3-d]oxazole occurs through the nitrenoid-like transition state to give 3aH-pyrrolo[2,3-d]oxazole intermediate, followed by either by 1,5-H-shift or a pathway involving intermolecular 1,2-prototropic shift.

Supplementary Materials

The following are available online, X-Ray diffraction experiments; NMR spectra of compounds 2–4; Computational Details.

Author Contributions

Methodology, A.A.K., E.E.G.; synthesis, T.O.Z.; diffraction experiments, M.A.K.; computation, A.A.K., M.S.N.; writing, A.A.K., E.E.G., M.S.N.; funding acquisition, A.A.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Russian Science Foundation, grant number 19-13-00039.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Acknowledgments

This research was carried out using resources of the Centre for Magnetic Resonance, the Research Centre for X-ray Diffraction Studies, the Centre for Chemical Analysis and Materials, and the Computer Centre of the Science Park of Saint Petersburg State University.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 2–4 are available from the authors.

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Molecules 26 01881 sch001 550
Scheme 1. Synthesis of 5,5-heterobicyclic systems via isomerization of 2H-azirines.
Scheme 1. Synthesis of 5,5-heterobicyclic systems via isomerization of 2H-azirines.
Molecules 26 01881 sch001
Molecules 26 01881 sch002 550
Scheme 2. Approach for the synthesis of 4H-pyrrolo[2,3-d]oxazoles 3.
Scheme 2. Approach for the synthesis of 4H-pyrrolo[2,3-d]oxazoles 3.
Molecules 26 01881 sch002
Molecules 26 01881 g001 550
Figure 1. Synthesis of 5-(2H-azirin-2-yl)oxazoles 2.
Figure 1. Synthesis of 5-(2H-azirin-2-yl)oxazoles 2.
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Molecules 26 01881 g002 550
Figure 2. Synthesis of 4H-pyrrolo[2,3-d]oxazoles 3.
Figure 2. Synthesis of 4H-pyrrolo[2,3-d]oxazoles 3.
Molecules 26 01881 g002
Molecules 26 01881 g003 550
Figure 3. Perspective view of compounds 3d showing thermal ellipsoids at 50% probability level.
Figure 3. Perspective view of compounds 3d showing thermal ellipsoids at 50% probability level.
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Molecules 26 01881 sch003 550
Scheme 3. Relative Gibbs free energies for the energy profile of compound 2a thermolysis in mesitylene (in kcal/mol, 398 K, DFT B3LYP-D3/6-311+G(d,p) level with SMD model for mesitylene).
Scheme 3. Relative Gibbs free energies for the energy profile of compound 2a thermolysis in mesitylene (in kcal/mol, 398 K, DFT B3LYP-D3/6-311+G(d,p) level with SMD model for mesitylene).
Molecules 26 01881 sch003
Molecules 26 01881 sch004 550
Scheme 4. Acylation of compounds 3a,h.
Scheme 4. Acylation of compounds 3a,h.
Molecules 26 01881 sch004
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Zanakhov, T.O.; Galenko, E.E.; Kryukova, M.A.; Novikov, M.S.; Khlebnikov, A.A. Isomerization of 5-(2H-Azirin-2-yl)oxazoles: An Atom-Economic Approach to 4H-Pyrrolo[2,3-d]oxazoles. Molecules 2021, 26, 1881. https://doi.org/10.3390/molecules26071881

AMA Style

Zanakhov TO, Galenko EE, Kryukova MA, Novikov MS, Khlebnikov AA. Isomerization of 5-(2H-Azirin-2-yl)oxazoles: An Atom-Economic Approach to 4H-Pyrrolo[2,3-d]oxazoles. Molecules. 2021; 26(7):1881. https://doi.org/10.3390/molecules26071881

Chicago/Turabian Style

Zanakhov, Timur O., Ekaterina E. Galenko, Mariya A. Kryukova, Mikhail S. Novikov, and Alexander A. Khlebnikov. 2021. "Isomerization of 5-(2H-Azirin-2-yl)oxazoles: An Atom-Economic Approach to 4H-Pyrrolo[2,3-d]oxazoles" Molecules 26, no. 7: 1881. https://doi.org/10.3390/molecules26071881

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