Article pubs.acs.org/Organometallics
Direct Conversion of Phosphonates to Phosphine Oxides: An Improved Synthetic Route to Phosphines Including the First Synthesis of Methyl JohnPhos Alexander J. Kendall, Chase A. Salazar, Patrick F. Martino, and David R. Tyler* Department of Chemistry & Biochemistry, University of Oregon, 1253 University of Oregon, Eugene, Oregon 97403, United States S Supporting Information *
ABSTRACT: The synthesis of tertiary phosphine oxides from phosphonates was achieved reliably and in good to excellent yields using stoichiometric amounts of alkyl or aryl Grignard reagents and sodium trifluoromethanesulfonate (NaOTf). In the absence of the NaOTf additive, covalent coordination oligomers of magnesium and phosphorus species dominate the reaction, producing very low yields of phosphine oxide, but high conversions of the phosphonate starting material. Mechanistic studies revealed that a five-coordinate phosphorus speciesnot a phosphinateis the reaction intermediate. A diverse array of phosphonates was converted to phosphine oxides using a variety of Grignard reagents for direct carbon− phosphorus functionalization. This new methodology especially simplifies the synthesis of dimethylphosphino (RPMe2)-type phosphines by using air-, water-, and silica-stable intermediates. To highlight this reaction, a new Buchwald-type ligand ([1,1′-biphenyl]-2-yldimethylphosphine, or methyl JohnPhos) and a classic bidentate phosphine, bis(diphenylphosphino)propane (dppp), were synthesized in excellent yields.
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INTRODUCTION The use of heteroleptic phosphine ligandsin particular Buchwald-type phosphines (Figure 1)has enjoyed great success for a diverse array of catalytic transformations.1,2 The synthesis of heteroleptic phosphines, however, is laborious and requires air- and water-free techniques for most of their multistep syntheses.3−5 The intermediates can be difficult to purify due to their instability on silica (e.g., P−Cl bonds) or the exceptional volatility of primary, secondary, and alkyl phosphines. In addition, commercially available sources of phosphine precursor compounds can be prohibitively expensive for preparatory-scale chemistry. For these reasons, traditional syntheses are limited to bulky groups on phosphorus and are plagued by low yields. Heteroleptic phosphines incorporating methyl moieties (RPMe2) are exceptionally rare due to the harsh reaction
conditions and difficult purification and handling necessary to access both potential precursors: chlorodimethylphosphine6 and RPCl2 species from either PCl3 or ClP(NEt2)2.7−9 This problem becomes especially prevalent during exploratory chemistry in which reactions are poorly optimized, ultimately limiting phosphine ligand design and development. A more common motif for modern ligand design is the inclusion of a diphenylphosphino, di-tert-butylphosphino, or dicyclohexylphosphino moiety. This is best demonstrated by Buchwald-type ligands, which have a diverse array of biaryl structures, but all share a narrow set of phosphine functionalization (Figure 1, typically R = Ph, t-Bu, Cy).10 The precursors for these phosphines are commercially avaliable11 and easier to handle (i.e., higher boiling points or melting points), and the resulting phosphines are relatively air stable.12 Synthetically this choice is convenient but can be unfavorable because, as ligands, smaller alkyl phosphines remain better electron donors and form considerably shorter phosphine− metal bonds.13−16 For instance, dimethyl Buchwlad-type ligands (e.g., methyl Johnphos, Figure 1, R = Me, R1 = H) have never been synthesized, even though as ligands they would be excellent at stabilizing high oxidation states of metals and would impart greater catalytic activity in many cases.17,18 The synthesis of phosphines from phosphonates is an alternative to traditional phosphine syntheses. However, current routes rely on molecules with P−Cl or P−H bonds
Figure 1. Buchwald-type phosphine.
Received: August 22, 2014 Published: October 22, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/om500854u | Organometallics 2014, 33, 6171−6178
Organometallics
Article
Grignard reagents are widely commercially available as well as easy to synthesize and handle, providing convenient methods for preparation. Lewis acid additives were screened in the expectation that they would increase the electrophilicity of the phosphonate through coordination, analogous to Lewis acid catalyzed nucleophilic ester substitution. Similar work by Hays suggested the viability of this approach.22 After a rigorous Lewis acid screening (see SI Table S3), the highest yield achieved was 54% of phosphine oxide when using lutetium triflate (Lu(OTf)3). Although this yield was promising, it was still lower than desired. The phosphonate was completely consumed in the reaction, demonstrating a substantial side reaction was the major reason for the low yields. To determine if activating the phosphonate was truly a viable strategy for increasing the phosphine oxide yields, the cyclic phosphonate 2-phenyl-1,3,2-dioxaphospholane 2-oxide (Table 1, entry 6) was synthesized. The ring strain (estimated 5.2 kcal/ mol) of this phosphonate has been shown to increase the rate of hydration compared with an acyclic analogue.23 Assuming the ring strain would increase the rate of nucleophilic substitution, we reacted this cyclic phosphonate with MeMgBr. The cyclic phosphonate was unable to outcompete the side reaction (Table 1, entry 6), suggesting a side reaction and not phosphonate activation is the major problem in optimizing the reaction. Identifying the Side Reaction. While studying the reaction of MeMgBr with PhP(O)(OMe)2, a 23% yield of PhP(O)Me2 was obtained; however, 77% of the starting material in the reaction was unaccounted for by gas chromatography (SI Figure S2). These results suggested a nonvolatile byproduct is responsible for the low yields in the reaction. NMR spectroscopy was used to observe the reaction in solution over time in a sealed NMR tube affixed with a J. Young valve. Surprisingly, as many as seven phosphorus species (converting into two discrete peaks) were observed by 31P NMR spectroscopy over the course of 24 h (SI Figure S6). These final species observed in the NMR spectra are likely the phosphine oxide and another thermodynamic byproduct of the reaction. 1H NMR spectroscopy revealed a considerable accumulation of C2H6 (1H NMR, δ = 0.85 ppm in THF-d8, Figure 2b) in addition to MeBr (1H NMR, δ = 2.65 ppm in THF-d8) transiently appearing in solution when MeMgBr was used. The C2H6 generation had a clear induction period and increased proportionally to the loss of both MeBr and MeMgBr. The production of MeBr in situ would logically be followed by the production of C2H6 from reaction with active MeMgBr. To confirm the identity of these assignments, the experiment was repeated with MeMgCl in the expectation that MeCl would be observed (Figure 2a). Indeed, the reaction yielded traces of MeCl (1H NMR, δ = 3.02 ppm in THF-d8), no observable peak at 2.65 ppm, and again a buildup of C2H6. Mikulski and co-workers observed that phosphonates under nearly the same conditions used for this study reacted with metal halides to cause an Arbuzov-like decomposition of the phosphonates into alkyl halides and metal−phosphonate salts and oligomers.26 Our observations corroborate this mechanism (Scheme 2). This side reaction accounts for the low yields of phosphine oxide with high conversion of starting material, as well as the inability to characterize the side products of the reaction by GC. To test if the side reaction (Scheme 2) could be prevented, PhP(O)(OPh)2 was reacted with MeMgBr with
(Scheme 1, top and bottom routes). The synthesis of phosphine oxides from phosphonates in a single step (Scheme Scheme 1. Synthetic Routes from Phosphonates to Heteroleptic Phosphines
1, middle route) offers a tantalizingly simple and selective pathway because of its respective air, water, and silica stability. In addition, phosphonates can be easily synthesized from alkyl or aryl halides using the Arbuzov reaction19 or H-phosphonate cross-coupling reactions.20 Despite this, phosphine oxide synthesis from phosphonates (Scheme 1, middle route) is a low-yielding (typically
