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Synlett 2010(14): 2106-2108  
DOI: 10.1055/s-0030-1258516
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Improved Diastereoselective Synthesis of Spiroazoles Using Multi­component Domino Transformations

Elisa Altieri, Massimiliano Cordaro, Giovanni Grassi, Francesco Risitano*, Angela Scala
Dipartimento di Chimica Organica e Biologica, Università, Vill. S. Agata, 98166 Messina, Italy
Fax: +39(090)393897; e-Mail: frisitano@unime.it;
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Publication History

Received 11 May 2010
Publication Date:
22 July 2010 (online)

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Abstract

Spiroisoxazole and spiropyrazole derivatives were obtained in a four-component reaction of active isoxazol- or pyrazol-5-ones with aromatic aldehydes, phenacyl chloride and AcOH-AcONH4 mixture. The reaction sequence is highly chemo- and ­diastereoselective affording good yields of spiroisoxazoles in refluxing ethanol, while efficient formation of spiropyrazoles is closely related to the use of a microwave-assisted protocol.

Key words

spirans - multicomponent reactions - cyclizations - ­microwave - diastereoselectivity

    References and Notes

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  • In contrast with previous findings, the above spirocyclization is promoted by the regiospecific gem-C-C bond formation at the 4-position of the azolone rings. See:
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5

In comparison with our previous study, the observed contracted ring size seems to be due to the substitution of a 1,3-dielectrophilic compound, such as α,β-unsaturated carbonylic compounds (ref. 4), with phenacyl chloride 3, whose electrophilic centers are in 1,2-position.

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Method A; Typical Procedure: To a stirred solution of isoxazol-5-one 1 (4.2 mmol) in EtOH (20 mL), containing
4 Å molecular sieves and an excess of AcOH-AcONH4, aldehyde 4 (8.5 mmol) and phenacyl chloride 3 (4.2 mmol) were added. The solution was heated at reflux for 2 h. After cooling, the reaction mixture was filtered to remove molecular sieves and the solvent was evaporated. The resulting residue was washed with cool H2O and the aqueous suspension was then extracted with Et2O (3 × 30 mL). The combined organic layer was washed with H2O, dried over anhyd Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by recrystallization from MeOH or by column chromatography on SiO2 (CHCl3) to afford 5. The use of pyrazolin-5-one 2 in place of isoxazol-5-one 1 provided 6 and 7.

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Bridgehead aziridines 7 were generated from 4 and 3 in the presence of the AcOH-AcONH4 mixture, as reported in ref. 4.

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Typical Procedure: A mixture of pyrazolin-5-one 2 (4.2 mmol), aldehyde 4 (8.5 mmol) and phenacyl chloride 3 (4.2 mmol) in n-PrOH (30 mL) containing an excess of AcOH-AcONH4 and 4 Å molecular sieves was heated by MW irradiation at 95 ˚C for 5-15 min. After cooling the reaction to r.t., filtration and evaporation of the solvent afforded a solid residue which was worked up as mentioned above. The crude product was purified by recrystallization from CHCl3-MeOH or by column chromatography on neutral Al2O3 (CHCl3) to give 8 as colorless crystals.

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Selected Data for 8a-h: 8a: yield: 79%; mp 194-195 ˚C. IR (Nujol): 1716 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 5.91 (s, 1 H), 6.79-7.25 (m, arom., 10 H), 7.32 (s, 1 H), 7.34-8.24 (m, arom., 15 H). ¹³C NMR (75 MHz, CDCl3): δ = 68.3, 119.9-142.5, 156.6, 171.7, 175. Anal. Calcd for C37H27N3O: C, 83.91; H, 5.14; N, 7.93. Found: C, 84.13; H, 5.16; N, 8.02. 8b: yield: 85%; mp 108-110 ˚C. IR (Nujol): 1708 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 2.14 (s, 3 H), 2.17 (s, 3 H), 5.91 (s, 1 H), 6.73-7.24 (m, arom., 10 H), 7.33 (s, 1 H), 7.35-7.95 (m, arom., 13 H). ¹³C NMR (75 MHz, CDCl3): δ = 21.0, 21.1, 68.3, 119.8-141.7, 157.2, 171.4, 174.8. Anal. Calcd for C39H31N3O: C, 83.99; H, 5.60; N, 7.53. Found: C, 83.81; H, 5.51; N, 7.49. 8c: yield: 84%; mp 106-108 ˚C. IR (Nujol): 1713 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 3.65 (s, 3 H), 3.73 (s, 3 H), 5.92 (s, 1 H), 6.51-7.25 (m, arom., 10 H), 7.30 (s, 1 H), 7.35-7.95 (m, arom., 13 H). ¹³C NMR (75 MHz, CDCl3): δ = 55.2, 55.4, 68.6, 119.5-140.7, 157.4, 159.8, 160.0, 171.4, 174.6. Anal. Calcd for C39H31N3O3: C, 79.44; H, 5.30; N, 7.13. Found: C, 79.28; H, 5.20; N, 7.05. 8d: yield: 78%; mp 124-125 ˚C. IR (Nujol): 1712 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 5.93 (s, 1 H), 6.70-7.24 (m, arom., 10 H), 7.32 (s, 1 H), 7.35-7.96 (m, arom., 13 H). ¹³C NMR (75 MHz, CDCl3): δ = 68.5, 119.3-143.0, 156.5, 170.5, 174.5. Anal. Calcd for C37H25N3OCl2: C, 74.25; H, 4.21; N, 7.02. Found: C, 74.09; H, 4.16; N, 6.95. 8e: yield: 65%; mp 175-177 ˚C. IR (Nujol): 1714 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.64 (s, 3 H), 2.01 (s, 3 H), 6.39 (s, 1 H), 6.72-7.25 (m, arom., 10 H), 7.31 (s, 1 H), 7.33-7.95 (m, 13 H). ¹³C NMR (75 MHz, CDCl3): δ = 19.4, 19.5, 67.2, 119.5-143.2, 157.2, 172.3, 174.2. Anal. Calcd for C39H31N3O: C, 83.99; H, 5.60; N, 7.53. Found: C, 84.21; H, 5.61; N, 7.59. 8f: yield: 63%; mp 129-130 ˚C. IR (Nujol): 1714 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 3.21 (s, 3 H), 3.31 (s, 3 H), 6.31 (s, 1 H), 6.40-7.24 (m, arom., 10 H), 7.33 (s, 1 H), 7.35-7.99 (m, arom., 13 H). ¹³C NMR (75 MHz, CDCl3): δ = 55.1, 55.5, 67.2, 118.3-143.2, 156.0, 157.2, 158.1, 172.5, 175.0. Anal. Calcd for C39H31N3O3: C, 79.44; H, 5.30; N, 7.13. Found: C, 79.32; H, 5.17; N, 7.03. 8g: yield: 84%; mp 140-141 ˚C. IR (Nujol): 1710 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.95 (s, 3 H), 2.20 (s, 3 H), 5.91 (s, 1 H), 6.61-7.25 (m, arom, 10 H), 7.30 (s, 1 H), 7.34-7.96 (m, arom., 13 H). ¹³C NMR (75 MHz, CDCl3): δ = 20.2, 20.3, 68.3, 119.6-142.4, 157.2, 171.8, 174.5. Anal. Calcd for C39H31N3O: C, 83.99; H, 5.60; N, 7.53. Found: C, 83.85; H, 5.49; N, 7.46. 8h: yield: 81%; mp 136-138 ˚C. IR (Nujol): 1709 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 3.37 (s, 3 H), 3.66 (s, 3 H), 5.89 (s, 1 H), 6.64-7.25 (m, arom. 10 H), 7.32 (s, 1 H), 7.36-7.95 (m, arom., 13 H). ¹³C NMR (75 MHz, CDCl3): δ = 55.1, 55.4, 68.5, 118.9-141.9, 156.7, 158.5, 159.1, 171.9, 174.8. Anal. Calcd for C39H31N3O3: C, 79.44; H, 5.30; N, 7.13. Found: C, 79.58; H, 5.31; N, 7.19.

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X-ray data to be submitted to Acta Crystallogr.