Synthesis of 4-Substituted Phosphacoumarins via Cross-Coupling of 4-Tosylphosphacoumarins with Organozinc Reagents

Xueshu Li; Feng Shen; Hua Fu; Yuyang Jiang; Yufen Zhao

doi:10.1055/s-2006-926245

LETTER

Synthesis of 4-Substituted Phosphacoumarins via Cross-Coupling of 4-Tosylphosphacoumarins with Organozinc Reagents

Xueshu Li^a, Feng Shen^a, Hua Fu*^a, Yuyang Jiang^a,b, Yufen Zhao^a
^a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. of China
^b Key Laboratory of Chemical Biology, Guangdong Province, College of Shenzhen, Tsinghua University, Shenzhen 518057, P. R. of China
Fax: +86(10)62781695; e-Mail: fuhua@mail.tsinghua.edu.cn;

Abstract

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Abstract

A series of 4-subsituted phosphacoumarin derivatives with potential biological and pharmacological activity has been synthesized through Negishi-type cross-coupling reactions of 4-tosylphosphacoumarins with organozinc reagents.

Key words

phosphacoumarin - Negishi-type cross-coupling - organozinc reagents

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References and Notes

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Analytical data of 4-benzyl-2-ethoxy-3-phenylphospha-coumarin (4a) and 4-allyl-3-(4′-chlorophenyl)-2-ethoxy-phosphacoumarin (4g) (Figure [1] ).
4a White foam; yield: 72%. ¹H NMR (300 MHz, CDCl₃): δ = 1.17 (t, ³ J = 7.2 Hz, 3 H, CH₂CH₃), 4.07 (m, 4 H, CH₂CH₃, PhCH₂), 7.12-7.40 (m, 14 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 16.4 (d, ³ J _P-C = 5.7 Hz, POCH₂CH₃), 36.0 (d, ³ J _P-C = 15.1 Hz, PhCH₂), 63.9 (d, ² J _P-C = 6.5 Hz, POCH₂CH₃), 119.4-138.4 (ArC), 146.6 (C-4), 150.9 (d, ² J _P-C = 7.2 Hz, C-8a). ³¹P NMR (125 MHz, CDCl₃): δ = 8.57. HRMS: m/z calcd for C₂₃H₂₂PO₃ [M + H]⁺, 377.1307; found: 377.1304.
4g Yellowish viscous oil; yield: 85%. ¹H NMR (300 MHz, CDCl₃): δ = 1.17 (t, ³ J = 7.2 Hz, 3 H, CH₂CH₃), 3.32 (m, 2 H, CH₂=CHCH₂), 4.08 (m, 2 H, OCH₂CH₃), 4.95-5.12 (dd, 2 H, CH₂=CHCH₂), 5.84 (m, 1 H, CH₂=CHCH₂), 7.18-7.57 (m, 8 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 16.4 (d, ³ J _P-C = 6.5 Hz, POCH₂CH₃), 34.2 (d, ³ J _P-C = 15.10 Hz, CH₂=CHCH₂), 63.8 (d, ² J _P-C = 6.5 Hz, POCH₂CH₃), 117.8-134.5 (ArC, CH₂=CH), 147.2 (C-4), 150.8 (C-8a). ³¹P NMR (125 MHz, CDCl₃): δ = 8.13. HRMS: m/z calcd for C₁₉H₁₉PO₃Cl [M + H]⁺: 361.0760; found: 361.0753.
Organozinc Reagents; General Procedure Zn powder was treated with 1 M HCl for 10 min, washed with acetone and then dried under vacuum before use. A mixture of Zn powder (3.0 mmol) and TMSCl (0.5 mL) in THF (10 mL) was stirred under a nitrogen atmosphere at r.t. for 20 min, and then heated to 55-65 °C (Table [1] ). Alkyl or aryl halide (3, 2.0 mmol) in anhyd THF (2 mL) was added dropwise, and the reaction was maintained at this temperature for 10-24 h. The resulting solution was cooled to r.t., and the clear liquid could be directly used for the following reaction.
Negishi Cross-Coupling Reaction of Organozinc Reagents with 4-Tosylphosphacoumarins General Procedure A mixture of 4-tosylphosphacoumarin (1) (1.0 mmol), Pd(PPh₃)₄ (0.05 mmol), PPh₃ (0.05 mmol) and the organozinc reagent prepared above in anhyd THF (10 mL) was heated to 55 °C under a nitrogen atmosphere. After 2-8 h, the reaction mixture was cooled to r.t. After the solvent was removed under reduced pressure, H₂O (10 mL) was added to the residue, the solution was extracted with CH₂Cl₂ (3 × 5 mL), and the combined organic phase was dried over anhyd Na₂SO₄. After removal of the solvent, the residue was purified by column chromatography on silica gel (PE-EtOAc, 2:1) to give product 2.