Synlett 2006(2): 255-258  
DOI: 10.1055/s-2005-923591
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
Further Information

Publication History

Received 17 November 2005
Publication Date:
23 December 2005 (online)

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.

12

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).

15

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

17

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.

18

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.

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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.