Palladium(0)-Catalyzed Benzylation
of H-Phosphonate Diesters: An Efficient Entry to Benzylphosphonates

Gaston Lavén; Jacek Stawinski

doi:10.1055/s-0028-1087522

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Synlett 2009(2): 225-228
DOI: 10.1055/s-0028-1087522

LETTER

Palladium(0)-Catalyzed Benzylation of H-Phosphonate Diesters: An Efficient Entry to Benzylphosphonates

Gaston Lavén^a, Jacek Stawinski*^a,b
^a Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 10691 Stockholm, Sweden
e-Mail: js@organ.su.se;
^b Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61704 Poznan, Poland

Further Information

Publication History

Received 24 September 2008
Publication Date:
15 January 2009 (online)

Abstract
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Abstract

A new, efficient method for the synthesis of benzylphosphonate diesters via a palladium(0)-catalyzed cross-coupling reaction between benzyl halides and H-phosphonate diesters, using Pd(OAc)₂ as a palladium source and Xantphos as a supporting ligand, has been developed.

Key words

benzylphosphonates - palladium cross-coupling - H-phosphonates - C-phosphonates

References and Notes

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29

Presence of water in the reaction mixture facilitated reduction of palladium(II) acetate and resulted in improved reproducibility of the reactions.

38

Typical Procedure for the Preparation of Dinucleoside Benzylphosphonates 2: Pd(OAc)₂ (0.05 mmol), Xantphos (0.1 mmol), and N,N-diisopropylethylamine (mmol), were refluxed for ca. 3 h in degassed THF (5 mL) containing H₂O (0.025 mmol). To this, separate diastereomers of dinucleoside H-phosphonate 1 (1a or 1b; 0.5 mmol), [³7] and benzyl bromide (0.75 mmol), dissolved in THF (2 mL), were added and the mixture was heated under reflux for 3 h. After concentration and partition of the reaction mixture between sat. aq NaHCO₃ and CH₂Cl₂, the product was purified by silica gel column chromatography using a stepwise gradient of ethanol (0-5%) in CH₂Cl₂ containing triethylamine (0.02%). Compounds 2 were obtained as off-white solids (purity >98%, ^¹H NMR spectroscopy). Compound 2a: 83% yield from 1a (probably R _P diastereomer). HRMS: m/z [M + Na]⁺ calcd for C₅₄H₆₅N₄NaO₁₃PSi⁺: 1059.3947; found: 1059.3908. Compound 2b: 84% yield from 1b (probably S _P diastereomer). HRMS: m/z [M + Na]⁺ calcd for C₅₄H₆₅N₄NaO₁₃PSi⁺: 1059.3947; found: 1059.3941.
Benzylphosphonates (Table [²] ) prepared from benzyl chlorides vs. benzyl bromides were spectrally indistinguishable, and were obtained as yellowish oils (purity >98%, ^¹H NMR spectroscopy). Diethyl benzylphosphonate: HRMS: m/z [M + Na]⁺ calcd for C₁₁H₁₇NaO₃P⁺: 251.0808; found: 251.0818. Diethyl 4-methyl-benzylphosphonate: HRMS: m/z [M + Na]⁺ calcd for C₁₁H₁₇NaO₃P⁺: 265.0964; found: 265.0975. Diethyl
4-methoxybenzylphosphonate: HRMS: m/z [M + Na]⁺ calcd for C₁₂H₁₉NaO₄P⁺: 281.0913; found: 281.0907. Diethyl 4-fluorobenzylphosphonate: HRMS: m/z [M + Na]⁺ calcd for C₁₁H₁₆FNaO₃P⁺: 269.0713; found: 269.0727. Diethyl 4-chlorobenzylphosphonate: HRMS: m/z [M + Na]⁺ calcd for C₁₁H₁₆ClNaO₃P⁺: 285.0418; found: 285.0394. Diisopropyl benzylphosphonate: HRMS: m/z [M + Na]⁺ calcd for C₁₃H₂₁NaO₃P⁺: 279.1121; found: 279.1127. Diphenyl benzylphosphonate: HRMS: m/z [M + Na]⁺ calcd for C₁₉H₁₇NaO₃P⁺: 347.0808; found: 347.0798.
The benzylphosphonate diesters synthesized were characterized by ^¹H NMR, ^¹³C NMR, and ^³¹P NMR spectroscopy.