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

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.

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

References

1

CDRI Communication no. 6404.

2 Basavaiah D. Jaganmohan Rao A. Satyanarayana T. Chem. Rev.  2003,  103:  811 

3a Patra A. Batra S. Kundu B. Joshi BS. Roy R. Bhaduri AP. Synthesis  2001,  276 

3b Patra A. Roy AK. Joshi BS. Roy R. Batra S. Bhaduri AP. Tetrahedron  2003,  59:  663 

3c Patra A. Roy AK. Batra S. Bhaduri AP. Synlett  2002,  1819 

4

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 C₁₈H₁₅C_l2NO₅: 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 C₁₈H₁₅C_l2NO₄: C, 56.86; H, 3.98; N, 3.68. Found: C, 57.12; H, 3.92; N, 3.51%.

5

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%.

6a Basavaiah D. Kumaragurubaran N. Sharada DS. Tetrahedron Lett.  2001,  42:  85 

6b Basavaiah D. Sharada DS. Kumaragurubaran N. Reddy RM. J. Org. Chem.  2002,  67:  7135 

7

In a few cases carried out in our lab we have been able to isolate and characterize the intermediate I. Unpublished results.

8 Mason PH. Emslie ND. Tetrahedron  1994,  50:  12001