A Novel Liquid-Phase Synthesis of Baylis-Hillman Products Using PEG-Supported α-Phenylselenopropionate Ester

Shou-Ri Sheng; Qiong Wang; Qiu-Ying Wang; Lei Guo; Xiao-Ling Liu; Xian Huang

doi:10.1055/s-2006-947341

LETTER

A Novel Liquid-Phase Synthesis of Baylis-Hillman Products Using PEG-Supported α-Phenylselenopropionate Ester

Shou-Ri Sheng*^a, Qiong Wang^a, Qiu-Ying Wang^a, Lei Guo^a, Xiao-Ling Liu^a, Xian Huang^a,b
^a Institutes of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330027, P. R. of China
^b Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. of China
Fax: +86(791)8120380; e-Mail: shengsr@jxnu.edu.cn;

Abstract

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Abstract

Treatment of the lithio derivative of novel PEG-supported α-phenylselenopropionate ester with aldehydes and subsequent cleavage from the PEG support by oxidative elimination with 30% hydrogen peroxide efficiently afforded Baylis-Hillman products in good yields and high purities.

Key words

liquid-phase organic synthesis - PEG-supported α-selenopropanoate ester - Baylis-Hillman products

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References

References and Notes

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PEG-Bound α-Phenylselenopropionate Ester 2: To a stirred solution of PEG (5.0 g, 2.5 mmol) in CH₂Cl₂ (20 mL) were added α-phenylselenopropanoic acid (1.72 g, 7.5 mol), DCC (2.06 g, 10 mol), and DMAP (0.305 g, 2.5 mol). After the mixture was stirred at r.t. for 24 h, the precipitate was removed by filtration, and the polymer was precipitated by addition of Et₂O (200 mL) to the filtrate. To allow complete precipitation, the suspension was left at 0 °C for 30 min. The precipitate was collected and washed with Et₂O (3 × 30 mL), and dried in vacuo to afford the PEG-bound ester 2 as a pale yellow solid. IR (KBr): 2886, 1728, 1644, 1455, 1350, 1252, 1146, 950, 849 cm^-1. ¹H NMR (CDCl₃): δ = 7.61-7.59 (m, 2 H), 7.31-7.29 (m, 3 H), 4.18 (t, J = 4.98 Hz, 2 H, PEG-OCH₂CH ₂OCO), 4.08 (q, J = 6.8 Hz, 1 H), 3.46-3.81 (m, PEG CH₂), 1.54 (d, J = 6.8 Hz, 3 H).

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Liquid-Phase Synthesis of Target Molecules 5a-k; General Procedure. To a stirred solution of LDA [2.0 mmol; from i-Pr₂NH (2.2 mmol) and n-BuLi (2.0 mmol)] in anhyd THF (10 mL) at -78 °C under a nitrogen atmosphere was added PEG-bound ester 2 (1.0 mmol). After stirring at -78 °C for 30 min, the neat aldehyde (2.0 mmol) in THF (5 mL) was added dropwise over ca. 15 min. After 20 min the reaction mixture was warmed to 0 °C and glacial AcOH (0.5 mL) and 30% aqueous H₂O₂ (1.0 mL, 11.6 mmol) were added. After 30 min, the ice bath was removed and the mixture was allowed to stir at r.t. for 1-2 h. After completion of the reaction, the reaction mixture was cooled and Et₂O (100 mL) was added to allow the precipitation of resin 4, which was collected by filtration and washed with Et₂O (3 × 30 mL). Resin 4 was stirred at r.t. for 8 h with 0.1 N NaOEt in EtOH (10 mL), then Et₂O (40 mL) and H₂O were added to the mixture, and the organic phase was separated. The organic extracts were dried over anhyd Na₂SO₄ and concentrated to afford BH crude products 5a-k, which were further purified by passing the crude product through a silica gel column (EtOAc-hexane, 1:9→1.5:8.5), if necessary. The products were characterized from their spectra (¹H NMR and IR) and by comparison with authentic samples. 5a: IR (neat): 3468, 1720, 1630 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.43-7.41 (m, 2 H), 7.21-7.19 (m, 3 H), 6.31 (s, 1 H), 5.90 (s, 1 H), 5.51 (s, 1 H), 3.70 (s, 3 H), 2.83 (br s, 1 H). 5b: IR (neat): 3448, 1722, 1629 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.28 (d, J = 8.8 Hz, 2 H), 6.70 (d, J = 8.8 Hz, 2 H), 6.34 (s, 1 H), 6.30 (s, 1 H), 5.10 (s, 1 H), 3.78 (s, 3 H), 3.74 (s, 3 H), 2.85 (br s, 1 H). 5c: IR (neat): 3448, 1716, 1630 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.33 (d, J = 7.6 Hz, 2 H), 7.20 (d, J = 7.6 Hz, 2 H), 6.32 (s, 1 H), 5.80 (s, 1 H), 5.49 (s, 1 H), 3.74 (s, 3 H), 2.59 (br s, 1 H). 5d: IR (neat): 3445, 1718, 1631 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.65 (d, J = 7.8 Hz, 1 H), 7.39-7.26 (m, 3 H), 6.33 (s, 1 H), 5.81 (s, 1 H), 5.50 (s, 1 H), 3.75 (s, 3 H), 2.62 (br s, 1 H). 5e: IR (neat): 3446, 1718, 1626 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.30-7.36 (m, 2 H), 6.98-7.05 (m, 2 H), 6.32 (s, 1 H), 5.80 (s, 1 H), 5.53 (s, 1 H), 3.71 (s, 3 H), 2.57 (br s, 1 H). 5f: IR (neat): 3450, 1721, 1628 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.49 (s, 1 H), 7.24-7.36 (m, 2 H), 6.30 (s, 1 H), 5.90 (s, 1 H), 5.55 (s, 1 H), 3.76 (s, 3 H), 2.97 (br s, OH). 5g: IR (neat): 3473, 1689, 1630, 1520 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.18 (d, J = 8.8 Hz, 2 H), 7.55 (d, J = 8.8 Hz, 2 H), 6.37 (s, 1 H), 5.86 (s, 1 H), 5.60 (s, 1 H), 3.73 (s, 3 H), 2.93 (br s, 1 H). 5h: IR (neat): 3498, 1715, 1620 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.24 (s, 1 H), 5.85 (s, 1 H), 4.41 (t, J = 6.5 Hz, 1 H), 3.78 (s, 3 H), 2.72 (br s, 1 H), 1.71-1.62 (m, 2 H), 1.39-1.25 (m, 2 H), 0.92 (t, J = 7.0 Hz, 3 H). 5i: IR (neat): 3440, 1721, 1633 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.35 (s, 1 H), 6.36 (s, 1 H), 6.24-6.35 (m, 2 H), 5.92 (s, 1 H), 5.57 (s, 1 H), 3.74 (s, 3 H), 2.87 (br s, 1 H). 5j: IR (neat): 3450, 1718, 1626 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.35 (s, 1 H), 8.25 (d, J = 3.6 Hz, 1 H), 7.64 (d, J = 7.8 Hz, 1 H), 7.17 (dd, J = 4.8, 8.1 Hz, 1 H), 6.31 (s, 1 H), 5.98 (s, 1 H), 5.20 (s, 1 H), 5.17 (br s, 1 H), 3.60 (s, 3 H). 5k: IR (neat): 3445, 1718, 1634 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.91-7.30 (m, 7 H), 6.36 (s, 1 H), 6.31 (s, 1 H), 5.18-5.19 (m, 1 H), 3.75 (s, 3 H), 2.58 (br s, 1 H).

<A NAME="RW08306ST-13">13</A> Guo H.-C. Ding K.-L. Tetrahedron Lett. 2003, 44: 7103

Compound 6a: IR (neat): 3330, 1690, 1628 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.42-7.40 (m, 2 H), 7.22-7.19 (m, 3 H), 6.43 (s, 1 H), 6.02 (s, 1 H), 5.70 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.5, 140.6, 139.8, 128.7, 127.6, 127.2, 126.1, 69.2.

Liquid-Phase Synthesis of Methyl ( E )-3-Phenyl-2-bromomethyl-2-propenoate ( 8a).
To a stirred solution of resin 4a (2.3 g, approximate loading 0.45 mmol/g) and Ph₃P (2.7 g, 10 mmol) in anhyd CH₂Cl₂ (15 mL) at -50 °C under a nitrogen atmosphere was added NBS (1.79 g, 10 mmol) in CH₂Cl₂ (5 mL) dropwise. After warming to r.t. overnight, the resin 7a was precipitated by adding Et₂O (100 mL) to the reaction mixture. The sus-pension was kept at 0 °C for a further 30 min to ensure complete precipitation and finally the polymer was filtered, washed with Et₂O (3 × 30 mL), and dried in vacuo. The cleavage step for 8a was performed according to the above procedure. IR (neat): 1715, 1641, 1440, 1387, 1356 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.81 (s, 1 H), 7.46-7.44 (m, 2 H), 7.31-7.29 (m, 3 H), 4.23 (s, 2 H), 3.89 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.5, 146.2, 131.8, 129.7, 128.2, 127.4, 120.7, 52.1, 20.4.

Compound 8b: IR (neat): 1715, 1641, 1440, 1387, 1356 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (s, 1 H), 7.45-7.43 (m, 2 H), 7.30-7.27 (m, 3 H), 4.25 (s, 2 H), 3.88 (s, 3 H), 3.23 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.3, 145.9, 131.3, 129.3, 128.8, 127.1, 121.0, 57.1, 52.2, 20.7.