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

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.

Although phosphorus compounds containing the P-C bond are not particularly abundant in nature, [¹] they have attracted considerable interest as isosteric analogues of phosphate esters. [²-4] Due to the presence of the P-C bond, these compounds are usually resistant to enzymatic hydrolysis and exhibit a vast array of biological activity. [²] [³] [5] This constitutes a primary rationale of using C-phosphonates analogues as target-specific modulators of variety of biological processes, e.g. as pesticides and therapeutics. [²] [5]

For the formation of the P-C(sp^³) bond the most common approaches are probably those involving the Michaelis-Arbuzov [6] [7] and Michaelis-Becker [8] reactions. Although quite general in scope, these methods suffer from important drawbacks.

For the Michaelis-Arbuzov reaction [6] [7] (a reaction of trialkyl phosphites with alkyl halides), the formation of alkylphosphonates is exothermic, [9] but the activation energy is usually high, and this necessitates a prolonged heating at high temperature. [7] [¹0] Since during the course of the reaction a new alkyl halide is formed, this has to be less reactive than the one used as a substrate, or it has to be removed from the reaction media. [¹¹] Some problems may arise for P-chiral phosphites due to regioselectivity of the dealkylation process, [7] and in addition, a stereochemical outcome of the reaction (retention of configuration or epimerization) may depend on the reaction conditions and the kind of a nucleophile used. [¹²] As to the Michaelis-Becker reaction [8] (a reaction of alkali metal salts of dialkyl phosphites with alkyl halides), this usually occurs under milder reaction conditions, but it requires strong bases [¹³] and, due to high reactivity of the generated phosphite anions, complex reaction mixture can be formed (SET mechanism), [¹³] [¹4] especially with substrates having a pseudohalide character. [¹5]

The above drawbacks of the Michaelis-Arbuzov and the Michaelis-Becker reactions usually become apparent during synthesis of more complex structures e.g. those that can be interesting from biological point of view. [²] To alleviate these problems, in such instances the formation of the P-C bond has to be carried out at the early stages of the synthesis, [¹6] or dedicated reagents with the preformed P-C linkages, [¹7] have to be used. For example, in the synthesis of antisense benzylphosphonate-modified oligonucleotides, that show potent in vivo and in vitro inhibitory effects against hepatitis C virus, [¹8] benzylphosphonous dichloride was used as a starting material. [¹9] This lessened some inconveniences of the Michaelis-Arbuzov and the Michaelis-Becker reactions, but introduced new problems, e.g. scrambling of the substituents at phosphorus due to fast ligand exchange in the tervalent P(III) precursors used. In addition, since such methods are based on dedicated phosphonylating reagents, the whole synthetic sequence has to be repeated for each new benzylphosphonate analogue synthesized. [¹9]

Inspired by potent biological activity of various benzylphosphonate derivatives, on one hand, and mild reaction conditions provided by transition metal chemistry for the synthesis of nucleoside aryl- [²0] [²¹] and vinylphosphonates, [²²] on the other one, we set out to develop a new, general method for a palladium-catalyzed formation of benzylphosphonate diesters. Although benzylpalladium(II) complexes were prepared for the first time some 40 years ago, [²³] activation and functionalization of benzylic derivatives by palladium catalysts is by far less common [²4] than that of aromatic and olefinic compounds. [²5] This is particularly true for cross-coupling reactions with phosphorus nucleophiles, for which only a few examples of a P-C(sp^³) bond formation using benzyl halides have been reported so far. [²6]

As a model reaction for our studies, a cross-coupling of diethyl H-phosphonate with benzyl bromide, catalyzed by palladium(0), was investigated using different palladium sources and monodentate or bidentate ligands (Table  [¹] ). The experiments were carried out in THF, at 66 ºC, in the presence of N,N-diisopropylethylamine (DIPEA) as a base, and the extent of conversion into diethyl benzylphosphonate was estimated after 20 hours by ^³¹P NMR spectroscopy.

Attempted synthesis of diethyl benzylphosphonate using 10 mol% of Pd(dba)₂ as a catalyst was unsuccessful, as no the product formation could be detected after 20 hours by the ^³¹P NMR spectroscopy. With 10 mol% of Pd(PPh₃)₄ [the prevalent catalyst for the P-C(sp^²) bond formation [²7] ] ca. 22% of the desired diethyl benzylphosphonate was formed, but the yield was not improved upon prolonged heating.

With Pd(OAc)₂ and monodentate ligands, namely, with an electron-deficient tris(p-chlorophenyl)phosphine [P(4-C₆H₄Cl)₃], the conversion into benzylphosphonate increased to 71%, but with a trialkylphosphine, tris(cyclohexyl)phosphine (PCy₃), it was lower than that for PPh₃ (Table  [¹] ). We also screened several bisphosphines as possible supporting ligands (Figure  [¹] ). Unfortunately, most of them, e.g. 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), and 1,4-bis(diphenylphosphino)butane (dppb), and also those frequently used in cross-coupling reactions with heteroatom nucleophiles (including H-phosphonates), [²5] [²8] [e.g. 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP, racemic) and 1,1-bis(diphenylphosphino)ferrocene (dppf)], turned out to be rather inefficient (Table  [¹] , entries 4-8).

Table 1 Efficiency of Different Ligands in the Cross-Coupling ­Reaction between Diethyl H-Phosphonate and Benzyl Bromide

Entry	Ligand	Conversion (%)a
1	PPh3 b	22
2	P(4-C6H4Cl)3	71
3	PCy3	15
4	dppe	0
5	dppp	5
6	dppb	21
7	BINAP	14
8	dppf	19
9	DPEphos	86
10	Xantphos	99
Reaction conditions: (EtO)2P(O)H (0.1 mmol), Pd(OAc)2 (0.1 equiv), ligand [monodentate (0.4 equiv) or bidentate (0.2 equiv)], N,N-diisopropylethylamine (1.2 equiv), benzyl bromide (1.5 equiv), THF [1 mL; containing H2O (0.05 equiv)], [²9] 66 ˚C in a sealed tube, 20 h. a Conversion into the product was determined by ³¹P NMR. b Pd(PPh3)4 was used.

Since Stockland et al. [³0] reported that reductive elimination from metalphosphonate complexes is significantly accelerated in the presence of large bite angle phosphine ligands, we investigated DPEphos and its more rigid counterpart, Xanthpos [³¹] (Figure  [¹] ) as possible bidentate ligands for our reaction. To our delight, there was a sharp increase in the yield of benzylphosphonate diesters formation in the reaction with DPEphos, and for Xantphos, the cross-coupling of diethyl H-phosphonate with benzyl bromide was virtually quantitative (Table  [¹] , entries 9 and 10). Monitoring progress of the reaction using ^³¹P NMR spectroscopy revealed that the cross-coupling in the presence of Xantphos as a supporting ligand went to completion within three hours at 50 ˚C.

Having found an efficient catalytic system for the formation of diethyl benzylphosphonate, we carried out similar experiments with different H-phosphonate diesters and various benzyl halide derivatives (Table  [²] ).

Table 2 Reaction of Different H-Phosphonate Diesters with ­Various Benzyl Halide Derivatives

Entry	R	Y	X	Time	Isolated yield
1	Et	H	Br	3 h	95%
2	Et	H	Cl	3 h	94%
3	Et	Me	Br	2 h	91%
4	Et	MeO	Br	2 h	94%
5	Et	F	Br	4 h	98%
6	Et	Cl	Cl	4 h	86%
7	i-Pr	H	Br	4 h	94%
8	i-Pr	H	Cl	4 h	93%
9	Ph	H	Br	2 h	74%
10	Ph	H	Cl	2 h	71%
11	Bn	F	Br	2 h	89%
Reaction conditions: (RO)2P(O)H (1 mmol), Pd(OAc)2 (0.1 equiv), Xantphos (0.2 equiv), benzyl halide (1.5 equiv), N,N-diisopropyl­ethylamine (1.3 equiv), THF [10 mL; containing H2O (0.05 equiv)], [²9] reflux under inert atmosphere.

As apparent from data in Table  [²] , the reactions investigated were only slightly sensitive to the kind of benzyl halides and the H-phosphonate diesters used. They were somewhat faster for the electron-rich benzyl halides (Table  [²] , entries 3 and 4), while the presence of electron-withdrawing substituents in the aromatic ring, slightly slowed down the reaction (Table  [²] , entries 5 and 6).

On the H-phosphonate part, there was a small decrease in the reaction rates when going from diethyl to diisopropyl H-phosphonates (Table  [²] , entries 1 and 2 vs. 7 and 8), and a small shortening of the reaction time was observed for diphenyl H-phosphonate (Table  [²] , entries 9 and 10). [³²] It is worth noticing here that there were no significant differences in the reaction times when the corresponding benzyl chlorides vs. bromides were used as substrates.

Assuming that the reactions investigated followed a standard three-step Pd-catalytic cycle [³³] (Scheme  [¹] ), the observed trends in reactivity can be explained in the following way.

The fact that benzyl chlorides and benzyl bromides displayed similar reactivity indicated that the oxidative addition was probably not the rate-determining step. This conclusion was additionally supported by the finding that electron-deficient benzyl halides reacted slower than the electron-rich ones, since the opposite order of reactivity would be expected when the oxidative addition were kinetically significant. [³4] [³5] Thus, it seemed likely that the slowest step of the catalytic cycle was probably the reductive elimination (step C, Scheme  [¹] ). Such an assumption was justified by two reaction features: (i) a higher reactivity of the electron-rich [³5] [³6] benzyl derivatives in the cross-coupling reaction, and (ii) a significant increase in the reaction rate when large bite angle phosphine ligands [³0] were used. Of course, one cannot exclude a kinetic participation of some additional factors in the mechanistic pathway. Since more acidic diphenyl H-phosphonate reacted faster than diethyl H-phosphonate, it is possible that the ligand substitution process may, at least to some extent, affect the reaction rate.

As a final stage of these investigations, we checked the efficacy of the developed synthetic protocol by reacting dinucleoside H-phosphonates 1 (a diastereomeric mixture, ca. 1:1) with benzyl bromide in THF in the presence of Pd (OAc)₂, N,N-diisopropylethylamine, and Xantphos (Scheme  [²] ).

The reaction was complete within three hours and produced the expected dinucleoside benzylphosphonate 2 (ca. 1:1 mixture of the diastereomers) quantitatively (^³¹P NMR spectroscopy). As for simple dialkyl H-phosphonates, also dinucleoside derivative 1 reacted readily with benzyl chloride to afford the desired product 2 in a comparable yield.

To have some insight into the stereochemistry of this palladium(0)-catalyzed cross-coupling, the reaction with benzyl bromide was repeated using separate diastereo­mers of dinucleoside H-phosphonate 1 (1a and 1b). [³7] It was found that the P-C bond formation was completely stereospecific (most likely retention of configuration) as the R _P diastereomer 1a (δ_P = 6.9 ppm) afforded exclusively the diastereomer 2a, (δ_P = 27.4 ppm), while the S _P dia­stereomer 1b (δ_P = 8.6 ppm) produced the other diastereomer of benzylphosphonate 2b (δ_P = 28.4 ppm). [³8]

In conclusion, we have developed a new, general method for efficient preparation of benzylphosphonate diesters via the Pd(0)-catalyzed cross-coupling reaction of benzyl chlorides or bromides with H-phosphonate diesters. Several ligands have been evaluated for their ability to catalyze this P-C(sp^³) bond formation, and the most efficient catalytic system was found to consist of Pd(OAc)₂ as a palladium source and Xantphos as a supporting ligand. The reaction is stereospecific (most likely retention of configuration at the phosphorus centre [²0] [³9] ), proceeds under mild conditions, and permits preparation of various benzylphosphonate derivatives from a common precursor. Since the underlying chemistry of the method is different from that of the Michaelis-Arbuzov and the Michaelis-Becker reactions, this new protocol expands the range of synthetic methods available for the preparation of biologically important C-phosphate analogues.

Acknowledgment

Financial support from the Swedish Research Council is gratefully acknowledged.

References and Notes

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

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.

References and Notes

• 1a Kittredge JS. Roberts E. Science  1969,  164:  37 
  Search in Google Scholar
• 1b White AK. Metcalf WW. Annu. Rev. Microbiol.  2007,  61:  379 
  Search in Google Scholar
• 2 Engel R. Chem. Rev.  1977,  77:  349 
  CrossrefSearch in Google Scholar
• 3 Kafarski P. Lejczak B. Phosphorus, Sulfur Silicon  1991,  63:  193 
  CrossrefSearch in Google Scholar
• 4 Huang JM. Chen RY. Heteroatom. Chem.  2000,  11:  480 
  CrossrefSearch in Google Scholar
• 5 Engel R. In Handbook of Organophosphorus Chemistry   Engel R. Marcel Dekker; New York: 1992.  p.559 
• 6a Michaelis A. Kaehne R. Chem. Ber.  1898,  31:  1048 
  Search in Google Scholar
• 6b Methoden der organischen Chemie (Houben-Weyl)   Vol. XII/1:  Müller E. George Thieme Verlag; Stuttgart: 1964.  p.433 
• 7 Bhattacharya AK. Thyagarajan G. Chem. Rev.  1981,  81:  415 
  CrossrefSearch in Google Scholar
• 8a Michaelis A. Becker T. Chem. Ber.  1897,  30:  1003 
  Search in Google Scholar
• 8b Methoden der organischen Chemie (Houben-Weyl)   Vol. XII/1:  Müller E. George Thieme Verlag; Stuttgart: 1964.  p.446 
• 8c Waschbüsch R. Carran J. Marinetti A. Savignac P. Synthesis  1997,  727 
• 9 Brill TB. Landon SJ. Chem. Rev.  1984,  84:  577 
  CrossrefSearch in Google Scholar
• 10 Harizi A. Zantour H. Phosphorus, Sulfur Silicon  2004,  179:  1883 
  CrossrefSearch in Google Scholar
• 11 Saady M. Lebeau L. Mioskowski C. Helv. Chim. Acta  1995,  78:  670 
  CrossrefSearch in Google Scholar
• 12 DeBruin KE. Chandrasekaran S. J. Am. Chem. Soc.  1973,  95:  974 
  CrossrefSearch in Google Scholar
• 13 Kers A. Stawinski J. Dembkowski L. Kraszewski A. Tetrahedron  1997,  53:  12691 
  CrossrefSearch in Google Scholar
• 14a Witt D. Rachon J. Phosphorus, Sulfur Silicon  1995,  107:  33 
  Search in Google Scholar
• 14b Witt D. Rachon J. Heteroatom. Chem.  1996,  7:  359 
  Search in Google Scholar
• 15a Birckenbach L. Kellermann K. Chem. Ber.  1925,  58:  786 
  Search in Google Scholar
• 15b Michalski J. Skowronska A. Lopusinski A. Phosphorus, Sulfur Silicon  1991,  58:  61 
  Search in Google Scholar
• 16a Yao Z.-J. Gao Y. Burke TR. Tetrahedron: Asymmetry  1997,  10:  3727 
  Search in Google Scholar
• 16b Li P. Zhang M. Peach ML. Liu H. Yang D. Roller PP. Org. Lett.  2003,  5:  3095 
  Search in Google Scholar
• 17 Löschner T. Engels JW. Nucleic Acids Res.  1990,  18:  5083 
  CrossrefSearch in Google Scholar
• 18a Alt M. Eisenhardt S. Serwe M. Renz R. Engels JW. Caselmann WH. Eur. J. Clin. Invest.  1999,  29:  868 
  Search in Google Scholar
• 18b Lehman TJ. Engels JW. Bioorg. Med. Chem.  2001,  9:  1827 
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• 19 Amberg S. Engels JW. Helv. Chim. Acta  2002,  85:  2503 
  CrossrefSearch in Google Scholar
• 20 Johansson T. Stawinski J. Chem. Commun.  2001,  2564 
  Crossref
• 21 Lavén G. Stawinski J. Coll. Symposium Series  2005,  7:  195 
  Search in Google Scholar
• 22 Abbas S. Hayes CJ. Synlett  1999,  1124 
  Thieme Connect
• 23 Fitton P. McKeon JE. Ream BC. J. Chem. Soc., Chem. Commun.  1969,  370 
• 24 Liegault B. Renaud J.-L. Bruneau C. Chem. Soc. Rev.  2008,  36:  290 
  Search in Google Scholar
• 25 Prim D. Campagne J.-M. Joseph D. Andrioletti B. Tetrahedron  2002,  58:  2041 
  CrossrefSearch in Google Scholar
• 26 Bravo-Altamirano K. Huang ZH. Montchamp JL. Tetrahedron  2005,  61:  6315 
  Search in Google Scholar
• 27 Schwan AL. Chem. Soc. Rev.  2004,  33:  218 
  CrossrefPubMedSearch in Google Scholar
• 28 Abbas S. Hayes CJ. Worden S. Tetrahedron Lett.  2000,  41:  3215 
  CrossrefSearch in Google Scholar
• 30 Stockland RA. Levine AM. Giovine MT. Guzei IA. Cannistra JC. Organometallics  2004,  23:  647 
  CrossrefSearch in Google Scholar
• 31 Klingensmith LM. Strieter ER. Barder TE. Buchwald SL. Organometallics  2006,  25:  82 
  CrossrefSearch in Google Scholar
• 32 Lower yields of diphenyl benzylphosphonate for the reactions of diphenyl H-phosphonate (Table 2, entries 9 and 10) were due to partial hydrolysis of the starting H-phosphonate under the reaction conditions
• 33 Kalek M. Stawinski J. Organometallics  2007,  26:  5840 
  CrossrefSearch in Google Scholar
• 34 Stille JK. Lau KSY. Acc. Chem. Res.  1977,  10:  434 
  CrossrefSearch in Google Scholar
• 35 Amatore C. Jutand A. J. Organomet. Chem.  1999,  576:  254 
  CrossrefSearch in Google Scholar
• 36 Hartwig JF. Acc. Chem. Res.  1998,  31:  852 
  CrossrefSearch in Google Scholar
• 37 Stawinski J. Strömberg R. Zain R. Tetrahedron Lett.  1992,  33:  3185 
  CrossrefSearch in Google Scholar
• 39a Xu Y. Zhang J. J. Chem. Soc., Chem. Commun.  1986,  1606 
• 39b Zhang J. Xu Y. Huang G. Guo H. Tetrahedron Lett.  1988,  29:  1955 
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Presence of water in the reaction mixture facilitated reduction of palladium(II) acetate and resulted in improved reproducibility of the reactions.

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.