Review
Applications of 31P NMR spectroscopy in development of M(Duphos)-catalyzed asymmetric synthesis of P-stereogenic phosphines (M = Pt or Pd)

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Abstract

This perspective describes the use of 31P NMR spectroscopy in an ongoing research project on enantioselective P−C bond formation catalyzed by platinum and palladium Duphos complexes. This technique was used to characterize catalyst precursors, intermediates and products, to determine equilibrium and rate constants, and to measure the enantiomeric excess (ee) of the P-stereogenic phosphine products. Applications of 31P NMR spectroscopy in problem-solving and identifying unexpected products, as well as the analysis of an unusual and esthetically pleasing spectrum, are also discussed.

Introduction

Chiral phosphines are widely used ligands in metal-catalyzed asymmetric reactions [1]. They are commonly prepared by resolution or by using a stoichiometric amount of a chiral auxiliary [2]. Using a catalytic amount of chiral material could be more efficient [3], so we have been developing metal-catalyzed reactions for enantioselective preparation of phosphorus–carbon bonds [4]. The targets were P-stereogenic phosphines like DiPAMP (Chart 1); although its synthesis and application in asymmetric hydrogenation earned Knowles the Nobel Prize in 2001 [5], development of related ligands with chirality at the phosphorus center has been slow [6]. Instead, phosphines featuring different elements of chirality, like BINAP and Duphos, have been more popular [7].

Phosphines (PR3) undergo pyramidal inversion slowly [8], but inversion in metal phosphido complexes (M–PR2) is fast, often occurring on the NMR time scale [9]. Therefore, phosphido complexes containing a chiral ligand (M(L*)(PRR’)) are mixtures of rapidly interconverting diastereomers [10]. These observations suggested a general method for metal-catalyzed asymmetric synthesis of P-stereogenic phosphines (Scheme 1) [4].

The key intermediates, phosphido complexes 1, would be formed from a catalyst precursor and the substrate, racemic secondary phosphine 2. We hypothesized that inversion, which interconverts diastereomers 1R and 1S, would be much faster than their reactions with an electrophile to yield tertiary phosphines 3, in which the substituent E comes from the electrophile. If so, P-stereogenic phosphines could be formed enantioselectively; the product ratio (enantiomeric excess) would depend on the equilibrium constant (Keq = [1S]/[1R]) and the rate constants for P–C bond formation involving these diastereomers (kS and kR, Scheme 1) [11].

Displacement of the chiral ligand L* by the excess of phosphines present must be avoided, so we chose the rigid, preorganized chelate alkylphosphine Duphos, and developed enantioselective syntheses of P-stereogenic phosphines via Pt-catalyzed hydrophosphination of activated alkenes, Pd-catalyzed phosphination (cross-coupling of secondary phosphines and aryl iodides) and Pt-catalyzed asymmetric alkylation of secondary phosphines (Scheme 2) [4].

Scheme 3 shows proposed mechanisms for the reactions, with the phosphido intermediates highlighted; specific intermediates in the coupling of the secondary phosphine PHMe(Is) (Is = 2,4,6-(i-Pr)3C6H2) with phenyl iodide or benzyl bromide are illustrated, with more generic structures in the hydrophosphination mechanism. In all cases, the interplay of P inversion and P–C bond formation as in Scheme 1 was suggested to be responsible for enantioselection. As summarized in Scheme 2, Pd phosphido complexes underwent P–C reductive elimination [12], while the phosphido ligand in analogous Pt intermediates acted as a nucleophile to attack benzyl bromide substrates [13]. The details of P–C bond formation in hydrophosphination were less clear and appeared to be substrate-dependent; it might occur via zwitterionic intermediates after nucleophilic attack of the Pt-phosphido group on an activated alkene, or by olefin insertion into the Pt–P bond [14].

Section snippets

Applications of 31P NMR spectroscopy in M(Duphos)-catalyzed enantioselective P–C bond formation

31P NMR spectroscopy is routinely used to study reactions catalyzed by metal–phosphine complexes, such as hydrogenation or hydroformylation [15]. When the substrates are phosphines, this technique becomes even more valuable for monitoring reactions and characterizing catalytic intermediates and products. This perspective describes how 31P NMR spectroscopy contributed to each step of this continuing research project. It provided information on structure and bonding in diastereomeric phosphido

Conclusions

31P NMR spectroscopy, a commonly used technique in studies of the chemistry of metal–phosphine complexes and their role in catalysis, becomes even more valuable for catalysis involving phosphine substrates. This perspective has provided some examples from our research on asymmetric synthesis of P-stereogenic phosphines catalyzed by Pt and Pd Duphos complexes, which continues to be guided and enriched by 31P NMR spectroscopy.

Acknowledgments

This research was carried out by many outstanding coworkers, whose names are included in the references. Among them, I especially thank Corina Scriban, Tim Brunker and Ivan Kovacik, who obtained the spectra illustrated in Figures. We thank the National Science Foundation, the American Chemical Society Petroleum Research Fund, Union Carbide, DuPont, Exxon Education Foundation, and Cytec Canada for support.

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