Michael Addition of Manganese Enolates to Nitroolefins

Abstract

The Michael addition to nitroolefins of manganese enolates derived from an array of ketones is reported. The desired 1,4-adducts are obtained in high yield and excellent diastereo- and regioselectivity, the sole kinetic adduct being obtained in the case of nonsymmetrical ketones. The effect of a thiourea-type organocatalyst on the addition of several representative nitroolefins to the kinetic manganese enolate derived from isopropyl ethyl ketone is also reported.

Key words

Michael addition - manganese - enolates - nitroolefins - selectivity

References and Notes

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16

General Procedure for the Preparation of Enolates via Manganese Enamides: To a suspension of LiBr (417 mg, 4.8 mmol) in freshly distilled THF (6 mL) in a 3-necked 25-mL round-bottomed flask under argon, MnBr₂ (516 mg, 2.4 mmol) was introduced and the solution was stirred until complete dissolution (transparent pale yellow solution). After addition of n-butylaniline (380 µL, 2.4 mmol) the temperature was cooled to -20 °C and methyllithium (3 mL, 4.8 mmol) was introduced dropwise. On keeping the temperature under 0 °C, the solution became limpid and red-dark colored after 10 min. The desired ketone (2 mmol) was then slowly added keeping the temperature between -10 °C and 10 °C. All the Mn enolates were formed in 30 min at this temperature.
General Procedure for Michael Addition of Manganese Enolates to Nitroalkenes: The nitroalkenes (1.15 equiv) were added to the enolate solution at the required temperature without previous dissolution. The consumption of the nitroalkenes was monitored by TLC. The reactions were quenched with 1 M HCl (5 mL). The mixture was extracted with Et₂O (3 × 10 mL), and the organic phase was washed with brine. The organic layers were combined, dried over Mg₂SO₄, and concentrated in vacuo. The resulting orange or green oil was purified by flash chromatography.
Michael Additions with Catalytic Amounts of Catalyst A: The experimental protocol was the same as described previously with addition of thiourea A (5 mol%) immediately after the nitroolefin had been introduced. Representative characterizations are given here.
Compound 1d: syn-isomer; R _f 0.42 (PE-EtOAc, 9:1); white solid; mp 98 °C; yield: 74%; dr (syn/anti) = 78:22. ¹H NMR (300 MHz, CDCl₃): δ = 0.75 (d, J = 6.9 Hz, 3 H), 1.04 (d, J = 6.9 Hz, 3 H), 1.27 (d, J = 6.6 Hz, 3 H), 2.45 (sept, J = 6.9 Hz, 1 H), 3.22 (dq, J ₁ = 6.6 Hz, J ₂ = 2.4 Hz, 1 H), 3.90 (ddd, J ₁ = 10.2 Hz, J ₂ = 9.6 Hz, J ₃ = 2.4 Hz, 1 H), 2.85 (dd, J ₁ = 12.6 Hz, J ₂ = 10.2 Hz, 1 H), 2.95 (dd, J ₁ = 12.6 Hz, J ₂ = 9.6 Hz, 1 H), 7.33 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 15.7, 17.3, 17.5, 41.0, 46.0, 48.2, 77.6, 106.6, 127.9, 128.9, 213.9. IR: 1379, 1467 (Ph, C=C), 1557 (NO₂), 1712 (C=O), 2974, 3016 (Ph, CH) cm^-1. GC-MS: t _R = 8.34 min. MS: m/z = 199, 159, 131, 91, 71, 43. Anal. Calcd for C₁₄H₁₉NO₃ (249.1365): C, 67.45; H, 7.68. Found: C, 66.51; H, 7.72.
Compound 2a: syn-isomer; R _f 0.21 (PE-EtOAc, 9:1); oil; yield: 74%; dr (syn/anti) = 86:14. ¹H NMR (300 MHz, CDCl₃): δ = 0.60 (d, J = 6.9 Hz, 3 H), 0.85 (d, J = 6.9 Hz, 3 H), 1.05 (d, J = 6.9 Hz, 3 H), 2.40 (sept, J = 6.9 Hz, 1 H), 3.35 (m, 1 H), 3.85 (s, 3 H), 3.95 (ddd, J ₁ = 9.6 Hz, J ₂ = 6.9 Hz, J ₃ = 5.1 Hz, 1 H), 4.75 (dd, J ₁ = 12.6 Hz, J ₂ = 5.0 Hz, 1 H), 4.85 (dd, J ₁ = 12.6 Hz, J ₂ = 9.6 Hz, 1 H), 6.80 (m, 2 H), 7.00-7.10 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.5, 17.3, 17.9, 40.6, 42.7, 45.0, 55.4, 76.1, 111.1, 120.8, 126.0, 129.0, 130.5, 157.2, 216.1. GC-MS: t _R = 9.14 min. MS: m/z = 279, 189, 161, 134, 91, 71, 43. HRMS (EI): m/z [M⁺] calcd for C₁₅H₂₁NO₄: 279.147059; found: 279.14722.
Compound 3b: syn-isomer; R _f 0.42 (PE-EtOAc, 9:1); translucent oil; yield: 70%; dr (syn/anti) = 70:30. With catalyst: yield: 78%; dr (syn/anti) >99:1. ¹H NMR (300 MHz, CDCl₃): δ = 0.95 (d, J = 6.9 Hz, 3 H), 1.10 (d, J = 7.2 Hz, 6 H), 1.20-1.30 (d, J = 6.9 Hz, 6 H), 1.80 (m, 1 H), 2.65 (m, 1 H), 2.90 (sept, J = 6.9 Hz, 1 H), 3.10 (dqd, J ₁ = 7.2 Hz, J ₂ = 1.8 Hz, 1 H), 4.30 (dd, J ₁ = 13.8 Hz, J ₂ = 6.3 Hz, 1 H), 4.40 (dd, J ₁ = 13.8 Hz, J ₂ = 5.1 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 12.6, 18.3, 18.8, 19.1, 20.7, 29.9, 40.0, 43.8, 44.0, 75.91, 216.6. IR: 1220, 1559 (NO₂), 1703 (C=O), 2976 cm^-1. GC-MS: t _R = 6.32 min. MS: m/z = 172, 144, 100, 97, 71, 43. ESI-MS: m/z = 216 [M + 1]⁺, 238 [M + Na]⁺, 254 [M + K]⁺.
Compound 4a: R _f 0.7 (PE-EtOAc, 9:1); yellowish oil; yield: 65%; dr (syn/anti) = 82:12. With catalyst: yield: 67%; dr (syn/anti) >99:1. ¹H NMR (300 MHz, CDCl₃): δ = 0.90 (t, J = 6.9 Hz, 3 H), 0.95 (d, J = 7.2 Hz, 3 H), 1.10 (d, J = 6.9 Hz, 6 H), 1.20-1.40 (m, 8 H), 1.80 (m, 1 H), 2.65 (m, 1 H), 2.8 (sept, J = 6.9 Hz, 1 H), 4.40 (dd, J ₁ = 12.6 Hz, J ₂ = 4.5 Hz, 1 H), 4.60 (dd, J ₁ = 12.6 Hz, J ₂ = 7.2 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): = 12.9, 14.1, 18.0, 18.5, 22.6, 26.8, 30.3, 31.7, 39.0, 39.9, 44.8, 76.6, 215.3. IR: 1225, 1556 (NO₂), 1706 (C=O), 2976 cm^-1. GC-MS: t _R = 7.38 min. MS: m/z = 201, 172, 125, 97, 83, 71, 43. ESI-MS (+ve mode): m/z = 244 [M + 1]⁺, 266 [M + Na]⁺, 282 [M + K]⁺.
Compound 5a: R _f 0.13 (PE-EtOAc, 9:1); crystal; mp 129 °C; yield: 65%; dr (syn/anti) = 75:25. With catalyst: yield: 82%; dr (syn/anti) >99:1. ¹H NMR (300 MHz, CDCl₃): δ = 1.15 (d, J = 6.9 Hz, 6 H), 1.20 (d, J = 6.6 Hz, 3 H), 2.90 (sept, J = 6.9 Hz, 1 H), 3.30 (m, 1 H), 3.40 (dd, J ₁ = 17.9 Hz, J ₂ = 5.8 Hz, 1 H), 3.50 (dd, J ₁ = 17.9 Hz, J ₂ = 0.5 Hz, 1 H), 4.40 (dt, J ₁ = 10.5 Hz, J ₂ = 0.5 Hz, 1 H), 5.20 (dd, J ₁ = 5.8 Hz, J ₂ = 0.5 Hz, 1 H), 6.70-7.20 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.5, 17.3, 17.9, 40.6 (C7), 42.7, 45.1, 55.4, 78.1, 117.0, 117.9, 122.2, 128.0, 129.0, 153.8, 215.4. IR: 1226 (CO), 1460, 1492 (Ph, C=C), 1554 (NO₂), 1715 (C=O), 2976, 3023 (Ph, CH) cm^-1. GC-MS: t _R = 9.65 min. MS: m/z = 277, 227, 184, 159, 131, 71, 43. Anal. Calcd for C₁₅H₁₉NO₄ (277.1314): C, 64.97; H, 9.91; N, 5.05. Found: C, 65.02; H, 7.02; N, 5.03.
Compound 6a: R _f 0.55 (PE-EtOAc, 9:1); red oil; yield: 79%; dr (syn/anti) = 95:5. ¹H NMR (300 MHz, CDCl₃): δ = 1.10 (d, J = 6.9 Hz, 3 H), 1.2 (d, J = 6.9 Hz, 3 H), 1.60 (d, J = 7.2 Hz, 3 H), 2.9 (sept, J = 6.9 Hz, 1 H), 4.7 (qd, J = 7.2 Hz, 1 H), 7.60 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.0, 18.3, 18.7, 40.5 (C2), 45.1, 127.4, 130.6, 135.4, 141.3, 144.1, 148.3, 211.6. GC-MS: t _R = 8.87 min. MS: m/z = 249, 234, 210, 114, 71. ESI-MS: 298 [M + H]⁺, 320 [M + Na]⁺, 336 [M + K]⁺. ESI-MS (-ve mode): m/z = 296 [M - H]⁺.
General Procedure for the Preparation of Pyrrolidines: A mixture of nitroketone (38 mg, 0.15 mmol) and 10% Pd(OH)₂ on carbon in anhyd MeOH (7.4 mL) was hydrogenated at 60 psi for 50 h using a Parr apparatus. The crude product was dissolved in CH₂Cl₂ (2 mL), cooled to 0 °C and treated with Et₃N (3 equiv) followed by p-toluene-sulfonyl chloride (1.1 equiv) for 60 h. After aqueous workup, the organic phase was dried on MgSO₄ and concentrated in vacuo. The product was purified by flash chromatography (hexane-EtOAc, 90:10).
Compound 7: brown oil; yield: 65%. ¹H NMR (300 MHz, CDCl₃): δ = 0.69 (t, J = 7.8 Hz, 3 H), 0.92 (t, J = 9.0 Hz, 3 H), 0.95-1.05 (m, 1 H), 1.05-1.22 (m, 2 H), 1.29-1.47 (m, 2 H), 1.70-1.84 (m, 1 H), 1.88-2.00 (m, 1 H), 2.45 (s, 3 H), 3.08 (q, J ₁ = 15.2 Hz, J ₂ = 6.7 Hz, 1 H), 3.62-3.79 (m, 3 H), 7.13-7.38 (m, 7 H), 7.77 (d, J = 8.9 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 13.4, 14.1, 18.7, 20.6, 21.5, 33.2, 45.8, 48.2, 52.7, 63.9, 126.7, 127.3, 128.1, 128.6, 129.7, 134.6, 139.3, 143.8. ESI-MS: m/z = 394 [M + Na]⁺.
Compound 8: brown oil; yield: 70%. ¹H NMR (300 MHz, CDCl₃): δ = 0.70 (d, J = 7.3 Hz, 3 H), 1.10 (d, J = 7.0 Hz, 6 H), 1.29-1.41 (m, 1 H), 2.30-2.50 (m, 5 H), 3.54 (t, J = 6.3 Hz, 1 H), 3.69-3.86 (m, 2 H), 6.96 (d, J = 6.3 Hz, 2 H), 7.13-7.36 (m, 5 H), 7.75 (d, J = 7.5 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 11.3, 14.1, 19.3, 22.6, 29.4, 31.6, 51.0, 69.7, 126.7, 127.7, 127.8, 128.3, 129.7, 138.1, 142.4, 143.4. ESI-MS: m/z = 380 [M + Na]⁺.