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DOI: 10.1055/s-0028-1087522
Palladium(0)-Catalyzed Benzylation of H-Phosphonate Diesters: An Efficient Entry to Benzylphosphonates
Publication History
Publication Date:
15 January 2009 (online)
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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
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References and Notes
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.