Improved Synthetic Route to Heteroleptic Alkylphosphine Oxides

Abstract

A new method for the synthesis of heteroleptic alkylphosphine oxides (R 2 R 1 PO, where R ≠ R 1 ) from secondary phosphine oxides (or SPOs, R 2 HPO) is presented. These reactions were fast at room temperature, sterically selective, high yielding, and >95% pure after an aqueous wash. Deprotonation of an SPO generates a phosphinite anion ([R 2 P− O] − ) that was found to be highly selective for nucleophilic P−C bond formation (as opposed to O−C bond formation) with alkyl halides. Surprisingly, most strong organometallic bases failed to deprotonate SPOs to their respective phosphinite anions (pK a s for most SPOs are <27). Only sodium bis(trimethylsilyl)amide (NaHMDS) cleanly formed the phosphinite anion, which was stable in solution (0.1 M, 23 °C in THF) for over 24 h. The need for a very specific base to deprotonate suggests that both ion pairing and the conjugate acid play a role in stabilizing the phosphinite anion. Phosphinite anion reactivity followed the expected trend for an S N 2 mechanism on reaction with alkyl halides; elimination products were never observed. A wide variety of heteroleptic alkylphosphine oxides were isolated in near-quantitative yield with only an aqueous wash as purification. This methodology was then used to make new bis(phosphine oxide)alkanes and unsymmetrical α,ω-bis(phosphine oxide)alkanes (R 2 P(O)(CH 2 ) 3 P(O)R 12 ) on the benchtop with unprecedented ease.

Synthesis of Unsymmetrical Bis(phosphine) Oxides and Their Phosphines via Secondary Phosphine Oxide Precursors

“…(Similar disubstituted products were also found in every other reaction of a phosphinite anion with 1-bromo-3-choropropane.) Substitution of the chloride is contrary to the observations in our previous study [32], which suggested little to no substitution would occur at the chloride position in the time it would take to substitute the bromide. The comparable rates of reaction observed in the current study may be due to the presence of the phosphonyl group near the alkyl chloride, which could stabilize the transition state by interacting with the Na + counterion (Figure 2A).…”

“…In prior work [32], we showed that the phosphinite anions displayed reactivity suggestive of an SN2-like mechanism, as indicated by their sensitivity to steric constraints and by their reactivity with alkyl halides following the trend RI > RBr > RCl. The observed regioselectivity allowed for isolation of (Me)2P(O)(CH2)3-5Cl species and subsequent reaction to form unsymmetrical bis(phosphine) oxides (Me)2P(O)(CH2)3-5P(O)(t-Bu)2 [32], Scheme 2. intermediates. In order to demonstrate the coordination chemistry of these ligands, two X-ray crystal structures of the metal complexes with unsymmetrical ligands were obtained.…”

“…(Note that addition of the phosphinite anion to the reaction solution is opposite to the procedure in our previous work [32]. Addition of the phosphinite to the 1-bromo-3-chloro propane led to respectable increases in the yields, Table 1.)…”

“…The development of synthetic routes to tertiary phosphines via air-stable intermediates and easier workups has been of great interest to our research group [31,32]. In this work, we demonstrate the synthesis of unsymmetric bidentate phosphines utilizing air-stable phosphine oxide starting materials and intermediates.…”

“…In this work, we demonstrate the synthesis of unsymmetric bidentate phosphines utilizing air-stable phosphine oxide starting materials and intermediates. The synthetic route [32] employs nucleophilic phosphinite anions, generated by deprotonation of secondary phosphine oxides (SPOs) with sodium hexamethyldisilazide (NaHMDS), followed by the alkylation of the anions with alkyl halides to form tertiary phosphine oxides, Scheme 1 [32].…”