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Synlett 2003(10): 1439-1442
DOI: 10.1055/s-2003-40823
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Alternate Route to Substituted 1,4-Pentanedienes through Acetates of Baylis-Hillman Adducts in Aqueous Medium [1]

Rashmi Saxena, Arundhati Patra, Sanjay Batra*
Medicinal Chemistry Division, Central Drug Research Institute,, PO Box 173, Lucknow 226 001, India
Fax: +91(522)2223405; e-Mail: batra_san@yahoo.co.uk;
Further Information

Publication History

Received 6 May 2003
Publication Date:
24 July 2003 (online)

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Abstract

The acylated Baylis-Hillman adducts have been reacted with α,β-unsaturated ketones, esters and nitriles in the presence of DABCO under aqueous condition as an alternate route towards the synthesis of substituted 1,4-pentanedienes. The plausible mechanism for the course of this reaction has been discussed.

Key words

Baylis-Hillman reaction - acetates - 1,4-pentanedienes - DABCO - aqueous medium

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CDRI Communication no. 6404.

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CDRI Communication no. 6404.

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General Procedure: To the solution of appropriate acetate (0.001 mol) in a mixture of THF:H2O (4 mL, 50:50) was added DABCO (112 mg, 0.001 mol) under stirring at r.t. In another vessel a solution of appropriate activated alkene (0.002 mmol) and DABCO (112 mg, 0.001 mol) in 1mL of THF was stirred at r.t. After 15 min of onset of the reaction, the contents of both vessels were mixed and the reaction mixture was allowed to stir at r.t. for required time (Table [1] ). Thereafter, the reaction was quenched with 10% aq HCl solution and extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried (Na2SO4) and evaporated to obtain an oily residue. This residue upon column chromatography on silica gel (230-400 mesh) using a linear gradient of 100:0 to 75:25 of hexanes:EtOAc furnished the desired products as oils.
2,4-Dimethylene-3-(3-nitro-phenyl)-pentanedioic Acid Dimethyl Ester (entry 1): 1H NMR (200 MHz, CDCl3): δ = 3.74 (s, 6 H), 5.38 (s, 2 H), 5.43 (s, 1 H), 6.48 (s, 2 H), 7.47-7.53 (m, 2 H), 8.03-8.15 (m, 2 H). 13C NMR (50.32 MHz, CDCl3): δ = 47.83, 52.70, 122.71, 124.03, 128.30, 129.95, 134.39, 139.59, 141.15, 142.03, 166.69. Anal. Calcd for C15H15NO6: C, 59.01; H, 4.95; N, 4.59. Found: C, 58.82; H, 4.91; N, 4.34%.
4-Acetyl-2-methylene-3-(3-nitro-phenyl)-pent-4-enoic Acid Methyl Ester (entry 2): 1H NMR (200 MHz, CDCl3): δ = 2.39 (s, 3 H), 3.73 (s, 3 H), 5.30 (s, 1 H), 5.50 (s, 1 H), 5.66 (s, 1 H), 6.37 (s, 1 H), 6.46 (s, 1 H), 7.50-7.72 (m, 2 H), 8.10-8.30 (m, 2 H). Anal. Calcd for C15H15NO5: C, 62.28; H, 5.23; N, 4.84. Found: C, 61.97; H, 5.50; N, 5.00%.
3,5-Dimethylene-4-(3-nitro-phenyl)-heptane-2,6-dione (entry 3): 1H NMR (200 MHz, CDCl3): δ = 2.37 (s, 6 H), 5.53 (s, 2 H), 5.83 (s, 1 H), 6.31 (s, 2 H), 6.46 (s, 1 H),
7.47-7.52 (m, 2 H), 8.07-8.16 (m, 2 H). Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C, 66.01; H, 5.60; N, 4.99%.
4-Acetyl-2-methylene-3-(4-trifluoromethyl-phenyl)-pent-4-enoic Acid Butyl Ester (entry 4): 1H NMR (200 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 7.2 Hz), 1.22-1.33 (m, 2 H) 1.53-1.60 (m, 2 H), 2.37 (s, 3 H), 4.10 (t, 2 H, J = 6.4 Hz, CH2), 5.24 (s, 1 H), 5.44 (s, 1 H), 5.61 (s, 1 H), 6.31 (s, 1 H), 6.41 (s, 1 H), 7.25, 7.28 (d, 2 H, J = 8.0 Hz), 7.54, 7.58 (d, 2 H, J = 8.0 Hz). Anal. Calcd for C19H21F3O3: C, 64.40; H, 5.97. Found: C, 64.38; H, 6.09%.
2,4-Dimethylene-3-(3-phenyl-isoxazol-5-yl)-pentanedioic Acid Dimethyl Ester (entry 5): 1H NMR (200 MHz, CDCl3): δ = 3.77 (s, 6 H), 5.55 (s, 1 H), 5.64 (s, 2 H), 6.36 (s, 1 H), 6.51 (s, 2 H), 7.42-7.45 (m, 3 H), 7.62-7.80 (m, 2 H). 13C NMR (50.32 MHz, CDCl3): δ = 40.96, 52.77, 101.96, 127.16, 128.42, 129.28, 130.44, 138.57, 162.76, 166.26, 171.60. Anal. Calcd for C18H17NO5˙H2O: C, 62.60; H, 5.55; N, 4.06. Found: C, 62.93; H, 5.54; N, 4.03%.
2,4-Dimethylene-3-(3-phenyl-isoxazol-5-yl)-pentanedioic Acid Ethyl Ester Methyl Ester (entry 6): 1H NMR (200 MHz, CDCl3): δ = 1.27 (t, 3 H, J = 7.2 Hz), 3.77 (s, 3 H), 4.22 (q, 2 H, J = 7.0 Hz), 5.38 (s, 1 H), 5.55-5.65 (m, 2 H), 6.36 (s, 1 H), 6.50-6.53 (s, 2 H), 7.42-7.45 (m, 3 H), 7.76-7.80 (m, 2 H). Anal. Calcd for C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found: C, 67.11; H, 5.76; N, 4.34%.
4-Acetyl-2-methylene-3-(3-phenyl-isoxazol-5-yl)-pent-4-enoic Acid Methyl Ester (entry 7): 1H NMR (200 MHz, CDCl3): δ = 2.41 (s, 3 H), 3.76 (s, 3 H), 5.60 (s, 1 H), 5.62 (s, 1 H), 5.89 (s, 1 H), 6.34 (s, 1 H), 6.36 (s, 1 H), 6.47 (s, 1 H), 6.78 (s, 1 H), 7.42-7.44 (m, 3 H), 7.76-7.78 (m, 2 H). Anal. Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.66; H, 5.55; N, 4.70%.
2,4-Dimethylene-3-(3- p -tolyl-isoxazol-5-yl)-pentanedioic Acid Dimethyl Ester (entry 8)
1H NMR (200 MHz, CDCl3): δ = 3.76 (s, 6 H), 5.21 (s, 1 H, CH), 5.37 (s, 2 H), 6.10 (s, 1 H), 6.51 (s, 2 H), 7.23-7.27 (d, 2 H, J = 8.0 Hz), 7.66-7.70 (d, 2 H, J = 8.0 Hz). Anal. Calcd for C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found: C, 69.12; H, 5.60; N, 4.30%.
4-Cyano-4-methyl-2-methylene-3-(3- p -tolyl-isoxazol-5-yl)-but-3-enoic Acid Methyl Ester (entry 9): 1H NMR (200 MHz, CDCl3): δ = 2.41 (s, 3 H), 2.45 (s, 3 H), 3.77 (s, 3 H), 6.12 (s, 1 H), 6.56 (s, 1 H), 6.80 (s, 1 H), 7.26, 7.30 (d, 2 H, J = 8.0 Hz), 7.66, 7.70 (d, 2 H, J = 8.0 Hz). 13C NMR (50.32 MHz, CDCl3): δ = 19.29, 21.82, 53.12, 105.73, 114.65, 119.03, 125.61, 127.11, 130.14, 133.69, 137.51, 141.15, 162.90, 165.00, 166.80. Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.19; N, 9.09. Found: C, 70.48; H, 5.84; N, 9.12%.
4-Cyano-4-methyl-2-methylene-3-(3- p -tolyl-isoxazol-5-yl)-but-3-enoic Acid Ethyl Ester (entry 10): 1H NMR (200 MHz, CDCl3): δ = 1.23 (t, 3 H, J = 7.2 Hz), 2.40 (s, 3 H), 2.44 (s, 3 H), 4.22 (q, 2 H, J = 7.0 Hz), 6.11 (s, 1 H), 6.56 (s, 1 H), 6.79 (s, 1 H), 7.26, 7.30 (d, 2 H, J = 8.0 Hz), 7.65, 7.69 (d, 2 H, J = 8.0 Hz). Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.98; H, 5.66; N, 9.01%.
3-[3-(2,4-Dichloro-phenyl)-isoxazol-5-yl]-2,4-dimethylene-pentanedioic Acid Dimethyl Ester (entry 11): 1H NMR (200 MHz, CDCl3): δ = 3.74 (s, 6 H), 5.24 (s, 3 H), 5.39 (s, 1 H), 5.65 (s, 2 H), 6.12 (s, 1 H), 6.53 (s, 1 H), 6.69 (s, 1 H), 7.32, 7.35 (dd, 1 H, J 1 = 2.0 Hz, J 2 = 8.0 Hz), 7.50, 7.51 (s, 1 H, J = 2.0 Hz), 7.67, 7.71 (d, 1 H, J = 8.0 Hz). Anal. Calcd for C18H15Cl2NO5: C, 54.56; H, 3.82; N, 3.54. Found: C, 54.88; H, 4.09; N, 3.70%.
4-Acetyl-3-[3-(2,4-dichloro-phenyl)-isoxazol-5-yl]-2-methylene-pent-4-enoic Acid Methyl Ester (entry 12): 1H NMR (200 MHz, CDCl3): δ = 2.41 (s, 3 H), 3.76 (s, 3 H), 5.60 (s, 1 H), 5.64 (s, 1 H), 5.90 (s, 1 H), 6.37 (s, 1 H), 6.48 (s, 2 H), 6.49 (s, 2 H), 7.31, 7.35 (dd, 1 H, J 1 = 2.0 Hz, J 2 = 8.0 Hz), 7.49, 7.50 (d, 1 H, J = 2.0 Hz), 7.66, 7.70 (d, 2 H, J = 8.0 Hz). 13C NMR (50.32 MHz, CDCl3): δ = 26.16, 39.52, 52.73, 104.85, 126.51, 127.92, 128.21, 128.41, 130.63, 132.07, 133.96, 138.86, 146.65, 160.49, 166.24 (C), 171.49 (C), 197.19. Anal. Calcd for C18H15Cl2NO4: C, 56.86; H, 3.98; N, 3.68. Found: C, 57.12; H, 3.92; N, 3.51%.

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Characterization Data for Acetates ( 5): The stereochemistry of the acetates was confirmed through NOE studies.
R = 3-Nitro phenyl, EWG = CO2Me. Yield 94% as pale yellow oil (from Et3N). IR(neat): 1728 (br, CO2Me and Ac) cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.14 (s, 3 H), 3.88 (s, 3 H), 4.89 (s, 2 H), 6.87 (s, 1 H), 7.57-7.71 (m, 1 H), 7.99 (s, 1 H), 8.20-8.30 (m, 2 H). Mass (FAB-MS+): m/z = 280 [M+ + 1]. Anal. Calcd for C13H13NO6: C, 55.91; H, 4.69; N, 5.02. Found: C, 56.20; H, 4.86; N, 4.85%.
R = 3-Phenylisoxazol-5-yl, EWG = CO2Me. Yield 92% as white solid (from Et3N), mp 114-116 °C. IR (KBr): 1723 (br, CO2Me and Ac) cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.09 (s, 3 H), 3.89 (s, 3 H), 5.26 (s, 2 H), 6.87 (s, 1 H), 7.47-7.50 (m, 3 H), 7.70 (s, 1 H), 7.81-7.83 (m, 2 H). Mass (FAB+): m/z = 302 [M+ + 1]. Anal. Calcd for C16H15NO5: C, 63.78; H, 5.02; N, 4.65. Found: C, 63.80; H, 4.76; N, 4.55%.
R = 3-(p-Tolyl) isoxazol-5-yl, EWG = CN. Yield 68% as yellow oil (from Et3N). IR(neat): 1730 (Ac), 2230 (CN)
cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.18 (s, 3 H), 2.41 (s, 3 H), 4.86 (s, 2 H), 6.78 (s, 1 H), 7.27, 7.31 (d, 2 H, J = 8.0 Hz), 7.67 (s, 1 H), 7.71, 7.75 (d, 2 H, J = 8.0 Hz). Mass (FAB+): m/z = 283 [M+ + 1]. Anal. Calcd for C16H14N2O3: C, 68.07; H, 4.99; N, 9.92. Found C, 68.17; H, 5.20; N, 10.00%.
R = 3-(2,4-Dichlorophenyl) isoxazol-5-yl, EWG = CO2Me. Yield 90% as white solid (from DABCO), mp 90-92 °C. IR (KBr): 1724 (CO2Me and Ac) cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.08 (s, 3 H), 3.89 (s, 3 H), 5.23 (s, 2 H), 7.05 (s, 1 H), 7.35, 7.39 (dd, 1 H, J 1 = 2.0 Hz, J 2 = 8.0 Hz), 7.54, 7.55 (d, 1 H, J = 2.0 Hz), 7.72, 7.76 (d, 3 H, J = 8.0 Hz). Mass (FAB-MS+): m/z = 370 [M+ + 1]. Anal. Calcd for C16H13Cl2NO5: C, 51.91; H, 3.54; N, 3.78. Found: C, 52.04; H, 3.81; N, 4.02%.

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In a few cases carried out in our lab we have been able to isolate and characterize the intermediate I. Unpublished results.