An Improved Diastereoselective Synthesis of Spiroazoles Using Multi­component Domino Transformations

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.

Multicomponent reactions (MCRs) continue to emerge as valuable tools in the development of new synthetic strategies to generate in few steps highly functionalized heterocyclic molecules from commercially available starting materials. [¹]

Recently, [²] we reported the synthesis of tetrahydrospiropyridines using a MCR that exploited a Michael addition of 1,2-azol-5-ones to α,β-unsaturated carbonyl compounds in the presence of arylaldehydes and NH₃, generated in situ by the AcOH-AcONH₄ mixture. [³]

In continuation of the above investigation, a concise route to bridged aziridines was recently developed in our laboratories through a multicomponent domino process involving phenacyl chloride both as 1,2-dielectrophile and as pronucleophile. [4]

In the present study, with the intention of further expanding the scope of this methodology, we explored the use of phenacyl chloride as selective agent for the construction of spiroheterocycles of different ring size. Thus, the procedure involving 3 instead of α,β-unsaturated carbonylic compounds [5] was applied to azolin-5-ones 1 and 2 (Scheme  [¹] ).

Reactions of 3-phenylisoxazolin-5-ones 1 with equimolar quantities of 3 and arylaldehyde 4 in refluxing ethanol in the presence of AcOH-AcONH₄ (method A) gave spiro derivatives 5 (Scheme  [¹] , X = O) [6] as single diastereomers with high yield. The efficiency of the new synthetic protocol (method A) is highly improved when compared with our previous procedure (method B; [7] Table  [¹] ).

No reaction occurred with enolizable aldehydes or with phenacyl halogenides substituted on carbon bearing the halogen or with aliphatic α-halogen ketones.

Conversely, analogous 1,3-diphenylpyrazolin-5-one 2 did not give comparable results (Scheme  [¹] , X = NPh). Under the above conditions, in fact, bisderivatives 6 and diaza­bicycles 7 were isolated as the only reaction products. Instantaneous formation of the slightly soluble 6 likely removes azolone 2 from the reaction mixture, thus favoring the formation of fused aziridines 7. [8]

The isolated products were identified by direct comparison with authentic samples. [4] [7]

As a result of these findings, we decided to examine the reactivity of the pyrazolin-5-one 2 in a one-pot microwave-assisted reaction. Under these conditions, the irradiation of the described mixture in n-propanol gave spiro derivatives 8 in good yield as single diastereomers (Scheme  [²] ). [9]

In the light of these results, the MCR with isoxazolin-5-one 1 was repeated under the new conditions but no compound of interest was isolated.

The structure of spirans 8 was assigned on the basis of analytical and spectroscopic data [¹0] and by comparing the ^¹H NMR spectra with the corresponding known spirans 5. The configuration assignment was based on a NOE experiment carried out on compounds 8a and 8b. As for 5, these have E,5R*,6R* configuration, which was confirmed by X-ray crystal structure analysis of compound 8d. [¹¹]

A likely mechanism for the formation of these spiroazoles is shown in Scheme  [³] .

A Mannich reaction between the azolones 1 or 2 and the aldimine salt 9, meanwhile formed from the aldehyde 4 and ammonium salt, seems initially to occur leading regiospecifically to the nonisolated Mannich base 10. This is intercepted by phenacyl chloride 3 to give 11, which rapidly cyclizes through 5-exo-tet process, providing 12 as a single diastereomer. Finally, immediate and inevitable condensation of 12 with aldehyde 4 gives 5 or 8.

In conclusion, we have devised a novel strategy for the synthesis of spiroazole derivatives that proceeds with high chemo- and diastereoselectivity. The reaction process employs the AcOH-AcONH₄ mixture as the basic catalyst and nitrogen atom provider and involves a domino double nucleophilic addition-cyclization-aldolic condensation sequence. Further exploration of the domino strategy and their applications in the synthesis of other types of spirocycles are in progress.

References and Notes

• For reviews, see:
• 1a Posner GH. Chem. Rev.  1986,  86:  831 
  Search in Google Scholar
• 1b Armstrong RW. Combs AP. Tempest PA. Brown SD. Keating TA. Acc. Chem. Res.  1996,  29:  123 
  Search in Google Scholar
• 1c Tietze LF. Modi A. Med. Res. Rev.  2000,  20:  304 
  Search in Google Scholar
• 1d Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
  Search in Google Scholar
• 1e Ramon DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 
  Search in Google Scholar
• 2 Risitano F. Grassi G. Foti F. Romeo R. Synthesis  2002,  116 
  Thieme Connect
• 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:
• 3a Tietze LF. Hippe T. Steinmetz A. Synlett  1996,  1043 
• 3b Tietze LF. Evers H. Töpken E. Angew. Chem. Int. Ed.  2001,  40:  903 
  Search in Google Scholar
• 4a Risitano F. Grassi G. Foti F. Moraci S. Synlett  2005,  1633 
• 4b Bruno G. Rotondo A. Nicolò F. Risitano F. Grassi G. Foti F. Helv. Chim. Acta  2006,  89:  190 
  Search in Google Scholar
• 7 Risitano F. Grassi G. Foti F. Bilardo C. Tetrahedron  2000,  56:  9669 
  CrossrefSearch in Google Scholar

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.

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.

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

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.

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.

X-ray data to be submitted to Acta Crystallogr.

References and Notes

• For reviews, see:
• 1a Posner GH. Chem. Rev.  1986,  86:  831 
  Search in Google Scholar
• 1b Armstrong RW. Combs AP. Tempest PA. Brown SD. Keating TA. Acc. Chem. Res.  1996,  29:  123 
  Search in Google Scholar
• 1c Tietze LF. Modi A. Med. Res. Rev.  2000,  20:  304 
  Search in Google Scholar
• 1d Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
  Search in Google Scholar
• 1e Ramon DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 
  Search in Google Scholar
• 2 Risitano F. Grassi G. Foti F. Romeo R. Synthesis  2002,  116 
  Thieme Connect
• 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:
• 3a Tietze LF. Hippe T. Steinmetz A. Synlett  1996,  1043 
• 3b Tietze LF. Evers H. Töpken E. Angew. Chem. Int. Ed.  2001,  40:  903 
  Search in Google Scholar
• 4a Risitano F. Grassi G. Foti F. Moraci S. Synlett  2005,  1633 
• 4b Bruno G. Rotondo A. Nicolò F. Risitano F. Grassi G. Foti F. Helv. Chim. Acta  2006,  89:  190 
  Search in Google Scholar
• 7 Risitano F. Grassi G. Foti F. Bilardo C. Tetrahedron  2000,  56:  9669 
  CrossrefSearch in Google Scholar

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.

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.

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

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.

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.

X-ray data to be submitted to Acta Crystallogr.