Allenyl Ketones as Versatile Michael Acceptors for the Addition of Chelated Enolates

Simon Lucas; Uli Kazmaier

doi:10.1055/s-2005-923591

LETTER

Allenyl Ketones as Versatile Michael Acceptors for the Addition of Chelated Enolates

Simon Lucas, Uli Kazmaier*
Institut für Organische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax: +49(681)3022409; e-Mail: u.kazmaier@mx.uni-saarland.de;

Abstract

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Abstract

Chelated amino acid ester enolates undergo clean 1,4-addition towards allenyl ketones 9, giving rise to unsaturated δ-keto amino acid esters 12 at low temperature. If the reaction is allowed to warm to room temperature, the enolate intermediates A undergo cyclization towards the corresponding α-pyrones 13.

Key words

amino acids - chelates - enolates - Michael addition - MIRC

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References

References and Notes

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Reviews:

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NMR Spectroscopic Data of Allenylketones 9.
Compound 9a: ¹H NMR (500 MHz, CDCl₃): δ = 3.90 (s, 2 H, 5-H), 5.27 (d, ⁴ J _1,3 = 6.6 Hz, 2 H, 1-H), 5.81 (t, ⁴ J _3,1 = 6.6 Hz, 1 H, 3-H), 7.21-7.32 (m, 5 H, 7-H, 8-H, 9-H). ¹³C NMR (125 MHz, CDCl₃): δ = 45.9 (t, C-5), 79.8 (t, C-1), 95.4 (d, C-3), 126.8 (d, C-9), 128.4 (d, C-7), 129.4 (d, C-8), 134.5 (s, C-6), 197.5 (s, C-4), 217.1 (s, C-2).
Compound 9b: ¹H NMR (500 MHz, CDCl₃): δ = 5.24 (d, ⁴ J _1,3 = 6.6 Hz, 2 H, 1-H), 6.43 (t, ⁴ J _3,1 = 6.6 Hz, 1 H, 3-H), 7.44 (m, 2 H, 7-H), 7.54 (m, 1 H, 8-H), 7.88 (dd, ³ J _6,7 = 8.2 Hz, ⁴ J _6,8 = 1.3 Hz, 2 H, 6-H). ¹³C NMR (125 MHz, CDCl₃): δ = 79.2 (t, C-1), 93.2 (d, C-3), 128.6 (d, C-6), 128.7 (d, C-7), 132.8 (d, C-8), 137.5 (s, C-5), 191.0 (s, C-4), 217.1 (s, C-2).
Compound 9c: ¹H NMR (500 MHz, CDCl₃): δ = 5.07 (d, ⁴ J _1,3 = 6.6 Hz, 2 H, 1-H), 6.13 (t, ⁴ J _3,1 = 6.6 Hz, 1 H, 3-H), 7.23 (m, 1 H, 8-H), 7.51 (m, 1 H, 7-H), 7.45 (m, 1 H, 9-H), 7.54 (m, 1 H, 6-H). ¹³C NMR (125 MHz, CDCl₃): δ = 79.9 (t, C-1), 96.8 (d, C-3), 119.0 (s, C-10), 126.9 (d, C-8), 128.7 (d, C-6), 131.1 (d, C-7), 133.1 (d, C-9), 140.5 (s, C-5), 194.4 (s, C-4), 218.8 (s, C-2).

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Kazmaier, U.; Lucas, S.; Klein, M. Adv. Synth. Catal. 2005, submitted.

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NMR Spectroscopic Data of Aldol Product 11aa.
¹H NMR (500 MHz, CDCl₃): δ = 1.54 (s, 9 H, 15-H), 2.74 (s, 1 H, OH), 2.96 (d, ² J _8,8 _′ = 13.6 Hz, 1 H, 8-H), 3.12 (d, ² J ₈ _′ _,8 = 13.6 Hz, 1 H, 8′-H), 4.58 (d, ³ J _3,NH = 9.2 Hz, 1 H, 3-H), 4.75 (dd, ² J _7,7 _′ = 11.4 Hz, ⁴ J _7,5 = 6.6 Hz, 1 H, 7-H), 4.89 (dd, ² J ₇ _′ _,7 = 11.4 Hz, ⁴ J ₇ _′ _,5 = 6.9 Hz, 1 H, 7′-H), 5.17 (dd, ⁴ J _5,7 = 6.6 Hz, ⁴ J _5,7 _′ = 6.9 Hz, 1 H, 5-H), 7.00 (d, ³ J _NH,3 = 9.2 Hz, 1 H, NH), 7.17-7.32 (m, 5 H, 10-H, 11-H, 12-H). ¹³C NMR (125 MHz, CDCl₃): δ = 28.0 (q, C-15), 44.4 (t, C-8), 58.8 (d, C-3), 75.2 (t, C-7), 80.2 (s, C-14), 84.3 (s, C-4), 94.8 (d, C-5), 127.1 (d, C-12), 128.2 (d, C-11), 130.9 (d, C-10), 135.0 (s, C-9), 167.7 (s, C-13), 206.3 (s, C-6). Signals of the TFA protecting group are not detectable.

General Procedure for Michael Additions of Chelated Enolates. Hexamethyldisilazane (280 mg, 1.73 mmol) was diluted in a Schlenk tube under argon with THF (1.5 mL). The solution was cooled to -20 °C before a solution of n-BuLi (1 mL, 1.6 M, 1.6 mmol) was added slowly. Stirring was continued for further 20 min, before the cooling bath was removed and the mixture allowed to warm to r.t. In another Schlenk flask a solution of the protected amino acid ester (0.63 mmol) in THF (3 mL) was cooled to -78 °C, before the fresh prepared LHMDS solution was added slowly via syringe. After stirring for 15 min at -78 °C a solution of ZnCl₂ (94 mg, 0.69 mmol) in THF (1 mL) was added and stirring was continued for further 45 min, before a solution of the allenyl ketone 9 (0.5 mmol) in THF (1 mL) was added. The progress of the reaction was monitored by TLC, and after complete consumption of the ketone (2-3 h) the reaction mixture was diluted with Et₂O and hydrolyzed with 1 N KHSO₄ giving rise to the expected ketone 12. [18] The aqueous layer was extracted twice with CH₂Cl₂, the combined organic layers were dried (Na₂SO₄) and the solvent was evaporated in vacuo. The crude product was purified by flash chromato-graphy or crystallization. To obtain the α-pyrones 13 [19] the reaction mixture was allowed to warm to r.t. before work-up.
Analytical Data of Michael Addition Products 12. Compound 12aa: ¹H NMR (500 MHz, CDCl₃): δ = 1.42 (s, 9 H, 15-H), 3.28 (d, ² J _5,5 _′ = 17.0 Hz, 1 H, 5-H), 3.34 (d, ² J ₅ _′ _,5 = 17.0 Hz, 1 H, 5′-H), 3.75 (s, 2 H, 7-H), 4.85 (d, ³ J _3,NH = 6.6 Hz, 1 H, 3-H), 5.10 (s, 1 H, 12-H_trans), 5.34 (s, 1 H, 12-H_cis), 7.19 (dd, ³ J _9,10 = 8.2 Hz, ⁴ J _9,11 = 1.3 Hz, 2 H, 9-H), 7.27 (tt, ³ J _11,10 = 7.3 Hz, ⁴ J _11,9 = 1.3 Hz, 1 H, 11-H), 7.33 (m, 2 H, 10-H), 7.87 (d, ³ J _NH,3 = 6.6 Hz, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ = 27.7 (q, C-15), 49.1 (t, C-5), 49.8 (t, C-7), 58.1 (d, C-3), 83.6 (s, C-14), 115.7 (q, ¹ J _1,F = 287.9 Hz, C-1), 121.6 (t, C-12), 127.3 (d, C-11), 128.9 (d, C-10), 129.4 (d, C-9), 133.4 (s, C-4), 135.6 (s, C-8), 156.6 (q, ² J _2,F = 38.4 Hz, C-2), 167.5 (s, C-13), 206.5 (s, C-6). HRMS (CI): m/z calcd for C₁₉H₂₃F₃NO₄ [M + H]⁺: 386.1498; found: 386.1539.
Compound 12ab: ¹H NMR (500 MHz, CDCl₃): δ = 3.28 (d, ² J _5,5 _′ = 17.3 Hz, 1 H, 5-H), 3.37 (d, ² J ₅ _′ _,5 = 17.3 Hz, 1 H, 5′-H), 3.70 (s, 3 H, 14-H), 3.72 (s, 2 H, 7-H), 5.00 (d, ³ J _3,NH = 6.6 Hz, 1 H, 3-H), 5.11 (s, 1 H, 12-H_trans), 5.36 (s, 1 H, 12-H_cis), 7.19 (dd, ³ J _9,10 = 8.2 Hz, ⁴ J _9,11 = 1.3 Hz, 2 H, 9-H), 7.28 (tt, ³ J _11,10 = 7.3 Hz, ⁴ J _11,9 = 1.3 Hz, 1 H, 11-H), 7.34 (m, 2 H, 10-H), 8.01 (d, ³ J _NH,3 = 6.6 Hz, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ = 46.0 (t, C-5), 49.8 (t, C-7), 53.0 (q, C-14), 57.5 (d, C-3), 115.6 (q, ¹ J _1,F = 287.9 Hz, C-1), 122.4 (t, C-12), 127.4 (d, C-11), 128.9 (d, C-10), 129.4 (d, C-9), 133.2 (s, C-4), 134.9 (s, C-8), 156.7 (q, ² J _2,F = 37.4 Hz, C-2), 169.0 (s, C-13), 206.8 (s, C-6). HRMS (CI): m/z calcd for C₁₆H₁₇F₃NO₄ [M + H]⁺: 343.1130; found: 344.1120. Compound 12bb: ¹H NMR (500 MHz, CDCl₃): δ = 3.75 (s, 3 H, 13-H), 3.82 (d, ² J _5,5 _′ = 17.4 Hz, 1 H, 5-H), 3.94 (d, ² J ₅ _′ _,5 = 17.4 Hz, 1 H, 5′-H), 5.12 (d, ³ J _3,NH = 6.4 Hz, 1 H, 3-H), 5.29 (s, 1 H, 11-H_trans), 5.48 (s, 1 H, 11-H_cis), 7.48 (m, 2 H, 9-H), 7.60 (tt, ³ J _10,9 = 7.6 Hz, ⁴ J _10,8 = 1.2 Hz, 1 H, 10-H), 7.95 (dd, ³ J _8,9 = 8.5 Hz, ⁴ J _8,10 = 1.2 Hz, 2 H, 8-H), 8.19 (br s, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ = 43.1 (t, C-5), 53.1 (q, C-13), 57.9 (d, C-3), 115.6 (q, ¹ J _1,F = 286.9 Hz, C-1), 122.9 (t, C-11), 128.4 (d, C-8), 128.8 (d, C-9), 133.9 (d, C-10), 135.4 (s, C-4), 135.9 (s, C-7), 156.8 (q, ² J _2,F = 37.6 Hz, C-2), 169.1 (s, C-12), 198.4 (s, C-6). HRMS (CI): m/z calcd for C₁₅H₁₄F₃NO₄ [M]⁺: 329.0837; found: 329.0856.
Compound 12cb: ¹H NMR (500 MHz, CDCl₃): δ = 3.77 (s, 3 H, 15-H), 3.78 (d, ² J _5,5 _′ = 17.8 Hz, 1 H, 5-H), 3.86 (d, ² J ₅ _′ _,5 = 17.8 Hz, 1 H, 5′-H), 5.12 (d, ³ J _3,NH = 6.7 Hz, 1 H, 3-H), 5.32 (s, 1 H, 13-H_trans), 5.46 (s, 1 H, 13-H_cis), 7.29-7.40 (m, 3 H, 9-H, 10-H, 11-H), 7.59 (d, ³ J _8,9 = 7.9 Hz, 1 H, 8-H), 7.93 (br s, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ = 46.7 (t, C-5), 53.2 (q, C-15), 57.6 (d, C-3), 115.5 (q, ¹ J _1,F = 287.9 Hz, C-1), 118.6 (s, C-12), 122.9 (t, C-13), 127.5 (d, C-8), 128.7 (d, C-9), 132.2 (d, C-10), 133.8 (d, C-11), 134.6 (s, C-4), 140.5 (s, C-7), 156.7 (q, ² J _2,F = 37.6 Hz, C-2), 169.0 (s, C-14), 201.9 (s, C-6). HRMS (CI): m/z calcd for C₁₅H₁₄ ⁷⁹BrF₃NO₄ [M + H]⁺: 408.0074; found: 408.0066.

Analytical Data of α-Pyrones 13.
Compound 13a: ¹H NMR (500 MHz, CDCl₃): δ = 2.04 (s, 3 H, 13-H), 3.78 (s, 2 H, 8-H), 5.84 (s, 1 H, 6-H), 7.23 (dd, ³ J _10,11 = 6.9 Hz, ⁴ J _10,12 = 1.6 Hz, 2 H, 10-H), 7.29 (tt, ³ J _12,11 = 7.3 Hz, ⁴ J _12,10 = 1.6 Hz, 1 H, 12-H), 7.34 (dd, ³ J _11,12 = 7.3 Hz, ⁴ J _11,10 = 6.9 Hz, 2 H, 11-H), 8.38 (br s, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ = 19.2 (q, C-13), 39.6 (t, C-8), 107.5 (d, C-6), 115.6 (q, ¹ J _C,F = 287.9 Hz, C-1), 115.9 (s, C-5), 127.6 (d, C-10), 128.9 (d, C-12), 129.2 (d, C-11), 134.5 (s, C-9), 150.1 (s, C-4), 155.5 (q, ² J _C,F = 37.4 Hz, C-2), 160.4 (s, C-7), 161.6 (s, C-3). Anal. Calcd for C₁₅H₁₂F₃NO₃ (311.26): C, 57.88; H, 4.50; N, 3.89. Found: C, 57.53; H, 4.44; N, 3.93. HRMS (CI): m/z calcd for C₁₅H₁₃F₃NO₃ [M + H]⁺: 312.0774; found: 312.0811.
Compound 13b: ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.14 (s, 3 H, 12-H), 7.16 (s, 1 H, 6-H), 7.53 (m, 3 H, 10-H, 11-H), 7.87 (m, 2 H, 9-H), 11.01 (br s, 1 H, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 17.8 (q, C-12), 104.9 (d, C-6), 115.8 (q, ¹ J _1,F = 287.9 Hz, C-1), 116.8 (s, C-5), 125.5 (d, C-10), 129.2 (d, C-11), 130.4 (d, C-9), 131.0 (s, C-8), 152.3 (s, C-4), 155.3 (q, ² J _2,F = 36.5 Hz, C-2), 156.9 (s, C-7), 158.1 (s, C-3). HRMS (CI): m/z calcd for C₁₄H₁₀F₃NO₃ [M]⁺: 297.0595; found: 297.0604.
Compound 13c: ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.14 (s, 3 H, 14-H), 6.76 (s, 1 H, 6-H), 7.47 (m, 1 H, 10-H), 7.54 (m, 1 H, 11-H), 7.65 (dd, ³ J _12,11 = 7.6 Hz, ⁴ J _12,10 = 1.9 Hz, 1 H, 12-H), 7.80 (dd, ³ J _9,10 = 7.9 Hz, ⁴ J _9,11 = 1.0 Hz, 1 H, 9-H), 11.04 (br s, 1 H, NH). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 17.7 (q, C-14), 109.7 (d, C-6), 115.8 (q, ¹ J _1,F = 287.9 Hz, C-1), 117.5 (s, C-5), 121.0 (s, C-13), 128.2 (d, C-10), 131.4 (d, C-9), 132.4 (d, C-12), 132.6 (d, C-11), 133.6 (s, C-8), 151.8 (s, C-4), 157.0 (s, C-7), 158.1 (s, C-3). C-2 was not detectable. HRMS (CI): m/z calcd for C₁₅H₉ ⁷⁹BrF₃NO₃ [M]⁺: 374.9718; found: 374.9709.