Baylis-Hillman Chemistry in Aqueous Media: A Fast and Practical Approach to the Azides of Baylis-Hillman Adducts in Solution and on Solid Phase [1]

Abstract

Fast and practical access to azides of Baylis-Hillman adducts, from the corresponding acetates in aqueous media and in excellent yields is described. The solution phase methodology has been successfully translated to the solid phase for applications toward combinatorial synthesis.

Baylis-Hillman reaction - 5-isoxazolecarboxaldehyde - isoxazole - DABCO - sodium azide - azides - aqueous medium - solid phase

References

1

CDRI Communication no 6322.

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14

General Procedure: To the appropriate acetate (1.6 mmol) in THF:H₂O (4 mL, 1:1, v/v) was added DABCO (1.6 mmol, 180 mg) and the reaction was stirred at r.t. for 10 min. Thereafter NaN₃ (2.4 mmol, 156 mg) was added under stirring. After 5 min the reaction was extracted with ethyl acetate (2 × 20 mL), the organic layers were combined, dried and evaporated to obtain a residue. This residue was either triturated with hexanes in the case of solid products or passed through a small band of silica gel using hexanes:ethyl acetate (98:2, v/v) as eluent to obtain oils.
R = 3-NO₂C₆H₄, EWG = CO₂Me. ¹H NMR (CDCl₃, 200 MHz): δ = 3.92 (s, 3 H, CO₂CH₃), 4.16 (s, 2 H, CH₂), 7.62 (t, 1 H, J = 8.0 Hz, Ar-H), 7.76 (d, 1 H, J = 7.7 Hz, Ar-H), 7.96 (s, 1 H, =CH), 8.23-8.30 (m, 2 H, Ar-H). ¹³C NMR (CDCl₃, 75.4 MHz): δ = 46.5 (CH₂), 52.6 (CH₃), 124.0 (CH), 124.01 (CH), 129.3 (C), 129.8 (CH), 135.0 (CH), 135.5 (C), 141.2 (CH), 148.3 (C), 166.7 (C). Anal. Calcd for C₁₁H₁₀N₄O₄: C, 50.38; H, 3.84; N, 21.36. Found: C, 50.61; H, 4.02; N, 21.08%.
R = 4-NO₂C₆H₄, EWG = CO₂Et. ¹H NMR (CDCl₃, 200 MHz): δ = 1.40 (t, 3 H, J = 7.2 Hz, CH₃), 4.13 (s, 2 H, CH₂), 4.37 (q, 2 H, J = 7.2 Hz, CH₂), 7.59 (d, 2 H, J = 8.8 Hz, Ar-H), 7.95 (s, 1 H, =CH), 8.28 (d, 2 H, J = 8.8 Hz, Ar-H). Anal. Calcd for C₁₂H₁₂N₄O₄: C, 52.17; H, 4.37; N, 20.28. Found: C, 52.00; H, 4.43; N, 19.94%.
R = 4-NO₂C₆H₄, EWG = CO₂-n-Bu. ¹H NMR (CDCl₃, 200 MHz): δ = 0.98 (t, 3 H, J = 7.3 Hz, CH₃), 1.41-1.56 (m, 2 H, CH₂), 1.68-1.82 (m, 2 H, CH₂), 4.13 (s, 2 H, CH₂), 4.31 (t, 2 H, J = 6.6 Hz, CH₂), 7.59 (d, 2 H, J = 8.6 Hz, Ar-H), 7.94 (s, 1 H, =CH), 8.28 (d, 2 H, J = 8.6 Hz, Ar-H). ¹³C NMR (CDCl₃, 75.4 MHz): δ = 13.6 (CH₃), 19.1 (CH₂), 30.5 (CH₂), 46.6 (CH₂), 65.8 (CH₂), 123.8 (2 × CH), 130.2 (2 × CH), 130.3 (C), 140.4 (C), 141.2 (CH), 147.9 (C), 166.2 (C). Anal. Calcd for C₁₄H₁₆N₄O₄: C, 55.25; H, 5.30; N, 18.41. Found: C, 55.17; H, 5.25; N, 18.11%.
R = 4-CF₃C₆H₄, EWG = CO₂-n-Bu. ¹H NMR (CDCl₃, 200 MHz): δ = 0.98 (t, 3 H, J = 7.3 Hz, CH₃), 1.41-1.52 (m, 2 H, CH₂), 1.68-1.79 (m, 2 H, CH₂), 4.13 (s, 2 H, CH₂), 4.30 (t, 2 H, J = 6.6 Hz, CH₂), 7.53 (d, 2 H, J = 8.2 Hz, Ar-H), 7.68 (d, 2 H, J = 8.2 Hz, Ar-H), 7.95 (s, 1 H, =CH). Anal. Calcd for C₁₅H₁₆F₃N₄O₄: C, 55.04; H, 4.92; N, 12.83. Found: C, 55.10; H, 5.03; N, 12.98%.
R = 3-(4-Methylphenyl)isoxazol-5-yl, EWG = CO₂Et. ¹H NMR (CDCl₃, 200 MHz): δ = 1.39 (t, 3 H, J = 7.0 Hz, CH₃), 2.41 (s, 3 H, Ar-CH₃), 4.36 (q, 2 H, J = 7.0 Hz, CH₂), 4.51 (s, 2 H, CH₂), 6.84 (s, 1 H, =CH), 7.28 (d, 2 H, J = 8.0 Hz, Ar-H), 7.35 (s, 1 H, =CH), 7.71 (d, 2 H, J = 8.0 Hz, Ar-H). ¹³C NMR (CDCl₃, 75.4 MHz): δ = 14.1 (CH₃), 21.3 (CH₃), 46.7 (CH₂), 62.0 (CH₂), 106.6 (CH), 125.1 (C), 125.6 (CH), 126.6 (2 × CH), 129.6 (2 × CH), 130.4 (C), 140.6 (CH), 162.7 (C), 165.1 (C), 165.8 (C). Anal. Calcd for C₁₆H₁₆N₄O₃: C, 61.52; H, 5.16; N, 17.93. Found: C, 61.48; H, 5.33; N, 17.64%.
R = 3-(2-Chlorophenyl)isoxazol-5-yl, EWG = CO₂-t-Bu. ¹H NMR (CDCl₃, 200 MHz): δ = 1.58 [s, 9 H, CO₂(CH₃)₃], 4.46 (s, 2 H, CH₂), 7.02 (s, 1 H, =CH), 7.37-7.41 (m, 3 H, Ar-H), 7.62 (s, 1 H, =CH), 7.69-7.78 (m, 1 H, Ar-H). Anal. Calcd for C₁₇H₁₇N₄O₃: C, 56.59; H, 4.74; N, 15.52. Found: C, 56.42; H, 4.57; N, 15.88%.

15

General Procedure for Reduction of Azide: To the appropriate solution of azide derivative (1.01 mmol, Table [1] entry 4 or 12) in THF (5 mL) was added Ph₃P (1.31 mmol, 345 mg) under stirring at r.t. After 1 h water (40 µL) was added and the reaction was allowed to proceed for 16 h. Thereafter, on completion, the reaction mixture was subjected to acid (5% HCl) and base (5% NaOH) work up. The residue obtained after washing(water), drying (Na₂SO₄) and evaporation was passed through a small band of basic alumina using CHCl₃:MeOH (99.7:0.3, v/v) to obtain pure amine.
R = 3-NO₂C₆H₄, EWG = CO₂-t-Bu (amine from entry 4, Table [1] ). Yield: 75%.; Mp oil. IR (neat): 3340 (NH₂), 1709 (CO₂-t-Bu) cm^-1. ¹H NMR (CDCl₃, 200 MHz): δ = 1.57 [s, 9 H, CO₂(CH₃)₃], 3.60 (s, 2 H, CH₂), 7.45-7.71 (m, 3 H, 2 Ar-H and =CH), 8.17-8.33 (m, 2 H, Ar-H). ¹³C NMR (CDCl₃, 75.4 MHz): δ = 28.0 (3 × CH₃), 38.5 (CH₂), 81.5 (CH), 122.2 (CH), 124.0 (CH), 129.4 (C), 129.7 (CH), 131.9 (CH), 134.3 (CH), 136.3 (CH), 148.2 (C), 166.2 (C). Mass (FABMS+): 279 (M⁺ + 1). Anal. Calcd for C₁₄H₁₈N₂O₄: C, 60.42; H, 6.52; N, 10.07. Found: C, 60.22; H, 6.89; N, 9.91%.
R = 3-Phenylisoxazol-5-yl, EWG = CO₂Me (amine from entry 12, Table [1] ). Yield: 67%. Mp 84-86 °C. IR(neat): 3428 (NH₂), 1711 (CO₂Me) cm^-1. ¹H NMR (CDCl₃, 200 MHz): δ = 3.88 (s, 3 H, CO₂CH₃), 3.96 (s, 2 H, CH₂), 6.81 (s, 1 H, =CH), 7.47-7.49 (m, 3 H, 2 Ar-H and =CH), 7.80-7.85 (m, 2 H, Ar-H). Mass (FABMS+): 259 (M⁺ + 1). Anal. Calcd for C₁₄H₁₄N₂O₃: C, 65.11; H, 5.46; N, 10.85. Found: C, 65.42; H, 5.59; N, 10.68%.

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18

General Procedure for Solid Phase: To Wang acrylate resin (100 mg, 1.13 mmol/g, Novabiochem) in 800 µL DMSO was added 3 equiv of DABCO followed by 5 equiv of substituted 5-isoxazolecarboxaldehyde solution in 300 µL of DMSO after 20 min. The resulting mixture was shaken at 600 rpm for 8 h. Subsequently, the resin was washed with DMF (4 mL × 6), MeOH (4 mL × 6) and DCM (4 mL × 3). To this resin suspended in 700 µL of DCM was added 12 equiv of DIEA. After 5 min a solution of 10 equiv of acetyl chloride in 800 µL was added dropwise through syringe and reaction was shaken for 18 h. Thereafter the resin was washed thoroughly as described above. To this was then added 1.5 mL of THF:H₂O (9:1, v/v) followed by 3 equiv of DABCO. After 20 min of shaking, 10 equiv of sodium azide were added and the reaction was continued for 1 h further. Then the resin was washed with THF (4 mL × 6), MeOH (4 mL × 6), DCM (4 mL × 3) and Et₂O (4 mL × 2). After drying the resin was cleaved with TFA:DCM (50:50, v/v) for 1 h, filtered and the filtrate was evaporated to obtain a residue which was lyophilized using tert-butanol:H₂O (4:1, v/v). For the reduction to amine, the dried resin (50 mg) was suspended in THF (700 µL) and to it 15 equiv of triphenyl phosphine was added under shaking at r.t. After 2 h, 30 µL of water was added and the shaking was continued for 24 h. The resin was subsequently washed, dried and cleaved as described above.
Azide: R = 3-(4-Methylphenyl)-isoxazol-5-yl. Yield: 72%. Mp 162-164 °C. IR (KBr): 2109 (N₃), 1670 (CO₂H) cm^-1. ¹H NMR (CDCl₃, 200 MHz): δ = 2.42 (s, 3 H, CH₃), 4.54 (s, 2 H, CH₂), 6.89 (s, 1 H, =CH), 7.28 (d, 2 H, J = 8.6 Hz, Ar-H), 7.70 (s, 1 H, =CH), 7.76 (d, 2 H, J = 8.6 Hz, Ar-H). ¹³C NMR (CDCl₃, 75.4 MHz): δ = 21.1 (CH₃), 46.4 (CH₂), 106.3 (CH), 125.3 (CH), 126.4 (2 × CH and C merged), 129.4 (2 × CH), 130.7 (C), 140.3 (CH), 162.4 (C), 165.2 (C), 167.6 (C). Mass (FABMS+): 285 (M⁺ + 1). Anal. Calcd for C₁₄H₁₂N₄O₃: C, 59.15; H, 4.25; N, 19.71. Found: C, 59.48; H, 4.39; N, 19.94%.