Organocatalytic Asymmetric Synthesis of 1,2,4-Trisubstituted Azetidines by Reductive Cyclization of Aza-Michael Adducts of Enones

Abstract

An efficient and highly enantioselective organocatalytic aza-Michael addition of N-substituted phosphoramidates to enones generates aza-Michael adducts which undergo intramolecular reductive cyclization with (R)-alpine borane to afford 1,2,4-trisubstituted azetidines in a one-pot procedure. These optically active products are obtained in good to high yields (67–93%) with excellent stereocontrol (78–96% ee) from a vast variety of enones.

Key words

asymmetric organocatalysis - conjugate addition, enones - reductive cyclization - chiral azetidines - phosphoramidates

• References and Notes


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• 19 General Procedure for the Synthesis of Representative Diethyl N,N-Disubstituted Phosphoramidates 3h,j Reactions were carried out in undistilled toluene without any precaution to exclude water. The aforementioned catalytic salt A (0.04 mmol) was prepared from 9-amino-(9-deoxy)-epi-hydroquinine (0.04 mmol, 13.0 mg) and 0.08 mmol (20 mg) of d-N-Boc-phenylglycine in toluene (2 mL) as reported in the literature.^14a After addition of α,β-unsaturated ketone 1 (0.2 mmol) to it, the mixture was stirred at 60 °C for 10 min. Then a solution of phosphoramidate 2 (0.2 mmol) was added to the reaction mixture slowly with stirring at 60 °C, and stirring was continued for 12–24 h which resulted in the formation of aza-Michael adduct 3h,j as monitored by TLC. The resulting mixture was diluted with toluene and filtered on neutral Al₂O₃. The solvent was evaporated under reduced pressure, and the product was purified by flash chroma-tography on neutral Al₂O₃ (PE–CH₂Cl₂ = 6:4) to obtain pure phosphoramidates 3h,j as white solids. Enantiomeric purity of adducts were checked by chiral HPLC with a 250 × 4.6 mm, 5μ chiral Eurocel column. Characterization Data of Representative Compounds Compound 3h (R¹ = R² = Et, R³ = o-tolyl): white solid; yield 85%; mp 195–197 °C. IR (KBr): ν_max = 3060, 2889, 1690, 1609, 1565, 1455, 1353, 1272, 1115, 742 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.83 (t, J = 7.4 Hz, 3 H), 1.14 (q, J = 7.4 Hz, 2 H), 1.20 (t, J = 7.5 Hz, 6 H), 1.52 (m, 2 H), 2.35 (s, 3 H), 2.50 (t, J = 7.2 Hz, 3 H), 2.96 (dd, J = 12.9, 8.5 Hz, 1 H), 3.16 (dd, J = 12.9, 3.5 Hz, 1 H), 4.06 (q, J = 7.5 Hz, 4 H), 4.09 (m, 1 H), 6.61 (d, J = 8.1 Hz, 1 H _ortho ), 6.68–7.06 (m, 3 H_arom). ¹³C NMR (100 MHz, CDCl₃): δ = 9.4, 10.4, 14.5, 16.0, 30.0, 40.1, 46.2, 54.0, 62.6, 113.4, 117.5, 126.9, 127.8, 130.5, 144.0, 219.5 ppm. MS (EI): m/z = 355 [M⁺]. Anal. Calcd for C₁₈H₃₀NO₄P: C, 60.83; H, 8.51; N, 3.94. Found: C, 60.57; H, 8.63; N, 4.27. [α]_D ²⁵ –115 (c 1, CHCl₃). The ee was determined to be 80% by HPLC on a chiral Eurocel column [(250 × 4.6 mm, 5μ), λ = 225 nm, (i-PrOH–hexane = 10:90), 1 mL/min]; t _R (minor) = 12.4 min, t _R (major) = 14.2 min. Compound 3j (R¹ = Bn, R² = Et, R³ = Ts): white solid; yield 92%; mp 178–179 °C. IR (KBr): ν_max = 3054, 2992, 1692, 1605, 1580, 1455, 1372, 1337, 1263, 1154, 1130, 855 cm^—1. ¹H NMR (400 MHz, CDCl₃): δ = 0.78 (t, J = 7.4 Hz, 3 H), 1.23 (t, J = 7.5 Hz, 6 H), 2.37 (s, 3 H), 2.05 (q, J = 7.4 Hz, 2 H), 2.49 (dd, J = 12.9, 8.5 Hz, 1 H), 2.58 (dd, J = 12.9, 3.5 Hz, 1 H), 2.75 (dd, J = 13.4, 10.5 Hz, 1 H), 2.83 (dd, J = 13.4, 3.9 Hz, 1 H), 3.24 (m, 1 H), 4.16 (q, J = 7.5 Hz, 4 H), 7.08–7.43 (m, 9 H_arom). ¹³C NMR (100 MHz, CDCl₃): δ = 8.4, 15.6, 23.3, 28.4, 35.8, 42.6, 44.7, 62.9, 124.4, 126.3, 128.2, 129.0, 129.9, 136.7, 138.0, 143.9, 218.9 ppm. MS (EI): m/z = 481 [M⁺]. Anal. Calcd for C₂₃H₃₂NO₆PS: C, 57.37; H, 6.70; N, 2.91. Found: C, 57.57; H, 6.97; N, 3.25. [a]_D ²⁵ –120 (c 1, CHCl₃). The ee was determined to be 82% by HPLC on a chiral Eurocel column [(250 × 4.6 mm, 5μ), λ = 225 nm, (i-PrOH–hexane = 10:90), 1 mL/min]; t _R (minor) = 10.9 min, t _R (major) = 13.4 min
• 20 General Procedure for the Synthesis of Azetidines 4h,j To a solution of adduct 3h or 3j (0.2 mmol) in THF was added (R)-alpine borane (0.2 mmol), and the reaction mixture was stirred at 60 °C for 42–48 h. A sat. aq NH₄Cl solution (4 mL) was added, and the resulting mixture was extracted once with Et₂O (5 mL) and then with CH₂Cl₂ (2 × 5 mL), dried over anhyd MgSO₄, filtered, and evaporated to dryness. The crude product thus obtained was purified by flash chromatography using a gradient mixture of EtOAc–hexane as eluent to afford an analytically pure sample of 4h (yield 69%) or 4j (yield 73%). Characterization data were in good agreement with those given in ref. 21
• 21 General Procedure for the One-Pot Synthesis of Azetidines 4 Reactions were carried out in undistilled toluene without any precaution to exclude water. The catalytic salt A (0.04 mmol) was prepared as described above (ref. 19) following the literature method.^14a After addition of α,β-unsaturated ketone 1 (0.2 mmol) to it, the mixture was stirred at 60 °C for 10 min. Then a solution of phosphoramidate 2 (0.2 mmol) was added to the reaction mixture slowly with stirring at 60 °C, and stirring was continued for next 12–24 h which resulted in the formation of aza-Michael adduct 3 as monitored by TLC. The reaction mixture was cooled to r.t. followed by addition of (R)-alpine borane (0.2 mmol), and stirring at r.t. for another 42–48 h. A sat. aq NH₄Cl solution (4 mL) was added, and the resulting mixture was extracted once with Et₂O (5 mL) and then with CH₂Cl₂ (2 × 5 mL), dried over anhyd MgSO₄, filtered, and evaporated to dryness. The crude product thus obtained was purified by flash chromatography using a gradient mixture of EtOAc–hexane as eluent to afford an analytically pure sample of 4. Characterization Data for Representative Compounds Compound 4h: colorless oil; yield 67%. ¹H NMR (400 MHz, CDCl₃): δ = 0.83 (t, J = 7.4 Hz, 6 H), 1.33–1.52 (m, 4 H), 2.02 (t, J = 6.1 Hz, 2 H), 2.12 (s, 3 H), 4.07 (m, 2 H), 6.62 (d, J = 8.1 Hz, 1 H _ortho ), 6.76–7.11 (m, 3 H_arom). ¹³C NMR (100 MHz, CDCl₃): δ = 9.0, 19.2, 26.0, 27.8, 61.8, 114.0, 119.4, 126.1, 130.8 ppm. MS (EI): m/z = 203 [M⁺]. Anal. Calcd for C₁₄H₂₁N: C, 82.70; H, 10.41; N, 6.89. Found: C, 83.06; H, 10.49; N, 6.82. [α]_D ²⁵ –193 (c 1, CHCl₃). The ee was determined to be 81% by HPLC on a chiral Eurocel column [(250 × 4.6 mm, 5μ), λ = 225 nm, (i-PrOH–hexane = 10:90), 1 mL/min]; t _R (minor) = 19.4 min, t _R (major) = 20.5 min. Compound 4j: colorless oil; yield 70%. ¹H NMR (400 MHz, CDCl₃): δ = 0.67 (t, J = 7.6 Hz, 3 H), 1.35–1.43 (m, 1 H), 1.66–1.72 (m, 1 H), 1.86–1.97 (m, 2 H), 2.35 (s, 3 H), 2.70 (dd, J = 13.4, 10.5 Hz, 1 H), 3.29 (dd, J = 13.4, 3.9 Hz, 1 H), 4.04–4.08 (m, 1 H), 4.30–4.33 (m, 1 H), 7.06–7.25 (m, 7 H), 7.69 (d, J = 8.3 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 8.3, 21.5, 26.5, 27.2, 40.2, 62.8, 63.6, 126.6, 127.4, 128.5, 129.3, 129.6, 136.7, 137.9, 143.1 ppm. MS (EI): m/z = 329 [M⁺]. Anal. Calcd for C₁₉H₂₃NO₂S: C, 69.27; H, 7.04; N, 4.25. Found: C, 69.35; H, 7.40; N, 4.50. [α]_D ²⁵ +79 (c 1, CHCl₃). The ee was determined to be 78% by HPLC on a chiral Eurocel column [(250 × 4.6 mm, 5μ), λ = 225 nm, (i-PrOH–hexane = 10:90), 1 mL/min]; t _R (minor) = 21.3 min, t _R (major) = 22.4 min