Ti(Oi-Pr)₄-Promoted Regio- and Stereoselective Aminolysis of 2,3-Epoxy Amides

Abstract

A mild and inexpensive Ti(Oi-Pr)₄-mediated aminolysis of 2,3-epoxy amides has been developed. The reaction proceeds with excellent regioselectivity, regardless of the steric hindrance of the substituents on the heterocyclic ring, providing vicinal amino alcohols that are very suitable for synthetic applications.

Key words

amides - diastereoselectivity - epoxides - regioselectivity - ring opening

• References and Notes

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• 13 HPLC analysis was performed with a VYDAC reverse-phase C18 column (25 cm by 4.6 mm); MeCN–H₂O containing 0.1% TFA, 25:75 to 35:65; flow rate: 1.0 mL; UV detection: 254 nm
• 14 General procedure: A mixture of 2,3-epoxy amide (1 mmol), amine (excess, 1 mL), and Ti(Oi-Pr)₄ (1.5 mmol) was stirred at the required temperature for 12 h. After this time, EtOAc was added and the organic phase was washed with aqueous tartaric acid solution (0.5 M), dried over Na₂SO₄, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH₂Cl₂–MeOH, 95:5, 0.2% NH₄OH). Compound 3: ¹H NMR (300 MHz, CDCl₃): δ = 0.80–0.95 (m, 9 H), 1.15–1.65 (m, 12 H), 2.21–2.67 (m, 4 H), 2.74–2.85 (m, 1 H), 3.76–3.85 (m, 2 H), 3.89 (d, J = 7.1 Hz, 1 H), 4.59 (br s, 1 H), 5.04–5.20 (m, 2 H), 5.69–5.85 (m, 1 H), 7.80 (br s, 1 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 13.9, 20.5, 21.2, 27.5, 31.4, 41.5, 51.1, 63.6, 68.8, 116.5, 133.9, 173.4. Compound 8: ¹H NMR (300 MHz, CDCl₃): δ = 0.83 (t, J = 6.6 Hz, 3 H), 1.11–1.81 (m, 10 H), 2.34–2.51 (m, 2 H), 2.54–2.76 (m, 3 H), 3.76–3.84 (m, 2 H), 3.88 (d, J = 7.1 Hz, 1 H), 4.30 (br s, 1 H), 5.01–5.22 (m, 2 H), 5.67–5.86 (m, 1 H), 8.10 (br s, 1 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 14.1, 21.2, 24.3, 26.5, 27.8, 41.3, 50.5, 67.4, 68.6, 116.1, 133.9, 173.48. Compound 9: ¹H NMR (300 MHz, CDCl₃): δ = 0.85 (t, J = 7.1 Hz, 3 H), 1.31–1.81 (m, 4 H), 2.53–2.63 (m, 2 H), 2.64–2.76 (m, 3 H), 3.57–3.76 (m, 5 H), 3.86–3.91 (m, 2 H), 4.11 (d, J = 7.15 Hz, 1 H), 5.10–5.23 (m, 2 H), 5.74–5.91 (m, 1 H), 7.65 (br s, 1 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 14.2, 20.9, 27.8, 41.5, 50.0, 66.8, 67.4, 69.1, 116.5, 133.8, 173.4. Compound 10: ¹H NMR (300 MHz, CDCl₃): δ = 0.85–0.97 (m, 6 H), 1.21–1.65 (m, 12 H), 2.21–2.67 (m, 3 H), 2.91–3.05 (m, 1 H), 3.78–3.85 (m, 2 H), 4.01 (d, J = 7.2 Hz, 1 H), 4.21 (br s, 1 H), 5.04–5.20 (m, 2 H), 5.69–5.85 (m, 1 H), 7.69 (br s, 1 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 13.9, 17.9, 20.3, 21.2, 23.1, 27.5, 31.0, 41.2, 53.1, 56.8, 69.8, 116.3, 133.9, 172.4. Compound 11: ¹H NMR (300 MHz, CDCl₃): δ = 0.74–2.02 (m, 17 H), 2.41–2.56 (m, 1 H), 3.06–3.22 (m, 2 H), 3.79–3.98 (m, 2 H), 4.01–4.07 (m, 1 H), 5.06–5.24 (m, 2 H), 5.73–5.87 (m, 1 H), 7.21 (br s, 1 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 13.9, 19.1, 24.9, 25.0, 31.0, 33.5, 34.3, 41.0, 53.9, 56.4, 71.3, 116.1, 133.9, 172.1. Compound 12: ¹H NMR (300 MHz, CDCl₃): δ = 0.87 (t, J = 7.1 Hz, 3 H), 1.24–1.57 (m, 4 H), 3.72–3.99 (m, 4 H), 4.28 (d, J = 1.6 Hz, 1 H), 5.04–5.27 (m, 2 H), 5.66–5.88 (m, 1 H), 6.57–6.78 (m, 3 H), 6.93–7.07 (br s, 1 H), 7.07–7.21 (m, 3 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 14.2, 19.7, 31.6, 33.9, 41.3, 41.6, 55.5, 72.3, 113.8, 116.8, 117.5, 129.6, 133.9, 147.3, 172.7. Compound 13: ¹H NMR (300 MHz, CDCl₃): δ = 0.85–0.95 (m, 9 H), 1.21–1.65 (m, 12 H), 2.20–2.65 (m, 4 H), 2.79 (d, J = 2.1 Hz, 3 H), 2.81–2.95 (m, 2 H), 3.91 (d, J = 7.2 Hz, 1 H), 6.09 (br s, 1 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 13.9, 20.4, 21.1, 25.7, 27.4, 31.4, 41.5, 63.6, 68.8, 173.4. Compound 14: ¹H NMR (300 MHz, CDCl₃): δ = 0.82–0.95 (m, 9 H), 1.15–1.67 (m, 12 H), 2.23–2.65 (m, 4 H), 2.73–2.83 (m, 1 H), 3.91 (d, J = 7.1 Hz, 1 H), 4.39 (d, J = 14.5 Hz, 1 H), 4.42 (d, J = 14.5 Hz, 1 H), 4.62 (br s, 1 H), 6.39 (br s, 1 H), 7.05–7.37 (m, 5 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 13.9, 20.5, 21.2, 27.5, 31.4, 41.5, 55.4, 63.6, 68.8, 139.7, 128.5, 128.1, 126.8, 168.2. Compound 20: ¹H NMR (300 MHz, CDCl₃): δ = 0.84–1.97 (m, 13 H), 3.10–3.24 (m, 1 H), 3.76–4.12 (m, 4 H), 4.65 (d, J = 5.6 Hz, 1 H), 5.05–5.33 (m, 2 H), 5.76–5.94 (m, 1 H), 6.76 (br s, 1 H), 7.08–7.68 (m, 5 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 26.0, 26.2, 28.4, 29.5, 30.2, 41.3, 47.1, 51.4, 63.9, 70.2, 116.3, 126.8, 128.1, 128.4, 130.6, 134.3, 175.0