Acid-Mediated Denitrogenation/Rearrangement/Coupling of ­Benzyl Azides with Triazolyl-Substituted Cycloalkanones

Abstract

Organic molecules containing α-triazolyl or β-amino cyclic ketone fragments have been individually proven to show good bioactivities and to be useful in asymmetric and pharmaceutical syntheses. A triflic acid-promoted simple and efficient method for the synthesis of unsymmetrical α-triazolyl-α′-(aminomethyl)cycloalkanones from benzyl azides and α-triazolylcycloalkanones has been developed. A series of unsymmetrical α,α′-disubstituted cycloalkanones were obtained with high syn-diastereoselectivity and up to 82% yield. Examination of the reaction mechanism showed that the benzyl azides undergo protonation, nitrogen elimination, rearrangement, and electrophilic attack by the enol forms of the cyclic ketones.

Key words

amino ketones - benzyl azides - denitrogenation - rearrangement - azido-Mannich reaction

• References and Notes

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• 22 Acid-Mediated Denitrogenation/Rearrangement/Coupling of Benzyl Azides with Triazolyl-Substituted Cycloalkanones; General Procedure A dried 50 mL round-bottomed flask was charged with CH₂Cl₂ (2 mL) and placed in an ice bath. The appropriate triazolyl-substituted cycloalkanone (0.1 mmol) and benzylic azide (0.2 mmol) were added, and the mixture was stirred for 2–3 min. TfOH (0.5 mmol) was added dropwise, and the mixture was stirred at ice-bath temperature for 5 min, then allowed to warm to r.t. for 20 h. NaHCO₃ (0.2 g) and CH₂Cl₂ (5 mL) were added, and the CH₂Cl₂ phase was extracted with distilled H₂O (3 × 10 mL). The organic phase was purified by column chromatography [silica gel, EtOAc–PE (1:1)]. 2-[(Phenylamino)methyl]-6-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexanone (3a) Pale-yellow solid; yield: 26.6 mg (77%); mp 129–132 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.86–7.83 (m, 3 H), δ 7.42 (t, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H), 7.17 (t, J = 7.8 Hz, 2 H), 6.71 (t, J = 7.4 Hz, 1 H), 6.57 (d, J = 8.2 Hz, 2 H), 5.43 (dd, J = 13.4, 5.8 Hz, 1 H), 3.53 (dd, J = 14.0, 4.2 Hz, 1 H), 3.24 (dd, J = 14.2, 4.6 Hz, 1 H), 2.91 (td, J = 12.6, 5.6 Hz, 1 H), 2.63–2.66 (m, 1 H), 2.34–2.30 (m, 1 H), 2.21–2.28 (m, 1 H), 2.14–2.13 (m, 1 H), 1.96–2.04 (m, 1 H), 1.62–1.69 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 204.6, 147.7, 147.5, 130.8, 129.4, 128.8, 128.1, 125.7, 119.6, 117.7, 112.8, 67.8, 49.7, 43.1, 35.3, 32.0, 23.7. HRMS (ESI, CH₃CN/CH₃OH): m/z [M + H]⁺ calcd for C₂₁H₂₃N₄O: 347.1866; found: 347.1858
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