Synthesis of New BINAP-Based Aminophosphines and Their 31P-NMR Spectroscopy

BINAP aminophosphines are prevalent N,P-bidentate, chiral ligands for asymmetric catalysis. While modification via the BINAP-nitrogen linkage is well explored and has provided a diverse body of derivatives, modification of the other substituents of the phosphorous center is another avenue in generating new congeners of this important class of chiral ligands. Herein reported are new BINAP aryl aminophosphines with electron rich or deficient substituents on the aryl rings. This scalable synthesis converted readily available starting material, (S)-BINOL, to a key intermediate (S)-NOBIN, from which the final chiral aminophosphines were prepared via a palladium-catalyzed, phosphonylation reaction. The aryl substituents are able to modify the electronic properties of the phosphorous center as indicated by the range of 31P-NMR shifts of these new ligands. A computational analysis was performed to linearly quantitate contributions to the 31P-NMR shifts from both resonance and field effects of the substituents. This correlation may be useful for designing and preparing other related aminophosphines with varying ligand properties.

Herein we report a synthesis of new congeners of the MAP class of BINAP aminophosphines 11b, 11c, and 11d. The diphenyl substituents of MAP in this class are replaced with aryl substituents bearing electron rich or deficient groups. These phosphines exhibit a range of 31 P-NMR chemical shifts. These new BINAP-based bidentate aminophosphines will lead to expanded applications in transition metal-complex formation and asymmetric catalysis.

Synthesis of Phosphine Oxides 1-3
Secondary phosphine oxides are important precursors to phosphine ligands. They are either commercially available or readily prepared. The typical strategy for the synthesis of secondary phosphine oxides, such as 1-3, is via substitution of diethyl phosphonate by alkyl or aryl Grignard reagents, as demonstrated by the groups of Busacca [25] and Hays [26] (Scheme 1). For the preparation of 3, the procedure by Hays' proceeded in 44% yield. Although Hays' procedure was used here for the preparation of 2 and resulted in a low yield of 16%, Busacca and coworkers reported a gram-scale synthesis of 2 with 80% yield. The Busacca procedure was also used to prepare 1 in 83% yield at gram-scale.

Synthesis of Aminophosphines 11a-d
The bidentate, BINAP aminophosphine compounds 11a-d were synthesized from the key intermediate (S)-NOBIN using conditions previously described by Kocovsky [27]. Whilst (S)-NOBIN is commercially available, it is relatively expensive (on average up to $250 per gram). Therefore a scalable synthesis of this key intermediate was performed from the much cheaper (S)-BINOL (approximately $1 per gram), using a modified procedure by Sälinger and Brückner [28] as we have previously reported (Scheme 2) [29]. It was found that the reduction of 5 at 10 mol% Pd on carbon for 2 h at 45 °C eliminated the over-reduction problem which occurred when the reduction was performed at 5% Pd on carbon for 7 h at 60 °C. This process consistently produced batches of (S)-NOBIN in good yields from (S)-BINOL at 10-20 mmol scale. Scheme 2. Synthesis of (S)-NOBIN from (S)-BINOL. With (S)-NOBIN in hand, triflate 8 was synthesized in three steps as the key precursor to generating various aminophosphine derivatives via a palladium-catalyzed, phosphonylation reaction with the corresponding phosphine oxides (Scheme 3). The reaction with acetyl chloride proceeded with both N-and O-acetylation, and the undesired O-acetylation product was removed by mild hydrolysis to give 7 in excellent yield. From triflate 8, the synthesis of N-acetylaminophosphine oxides 9a-d proceeded smoothly in good yields (72-85%) under conditions reported by Kocovsky, with the exception of aminophosphine oxide 9b. In this case, conditions reported by Maxwell and coworkers were required, which involve the coupling between bis(3,5-difluorophenyl)phosphine oxide and an aryl triflate using a 24-fold excess of Hünig's base. Further, it was also found that an increased loading of palladium and dppb at 20-30 mol% or more was required for coupling to occur in moderate yield (54%). The N-acetylated phosphine oxides 9a-d were converted by refluxing in ethanol/HCl into the free aminophosphine oxides 10a-d, which were in turn converted to the corresponding aminophosphines 11a-d via reduction in neat phenyl silane, which provided cleaner reduction products compared to those obtained by trichloro silane reduction.

Phosphine NMR Spectroscopy and Computational Analysis of Aminophosphines 11a-d
The 31 P-NMR shifts were recorded for aminophosphines 11a-d (Table 1). In general, all aminophosphines displayed shifts upfield to that of the reference compound (H 3 PO 4 ) with 31 P chemical shifts ranging from −7.3 to −14.2 ppm. The substituent effects on the electronic properties of the phosphorous center have been investigated continuously since the work by Streuli and co-workers [30], who correlated the Brønsted basicity of phosphines to the sum of the Taft constant *. The difficulty of correlating 31 P-NMR shifts with σ* has been recognized very early [31]. The * constant is essentially correlated to the inductive effect and it is clear from our work that the 31 P chemical shift of 11c is closer to 11d than 11a, suggesting that hyperconjugation (resonance effect) of the phenyl ring with the phosphorous 3d orbitals is more important than induction [32]. Kabachnik and co-workers developed a Taft constant ( ph ) specifically for organophosphorus compounds based on the ionization constants for about 150 phosphorus acids [33]. They reported that this constant gave a better fit for the pK a and reactivity of phosphines than *. For compounds 11a-d, we attempted to correlate the 31 P chemical shift to the Taft constants * and  I as well as eight other Hammett sigmas including  ph ,  m ,  p , °, ′,  + ,  − ,  • and the Taft steric parameter (E S ), MR and . The electronic parameters were found to dominate, as the aminophosphines considered here are arylphosphines with very similar steric parameters. The best correlation (R 2 = 0.9418) was found with  − indicating that electronic factors, including the ability to stabilize a negative charge, are the most important factors in predicting the 31 P chemical shift of simple triaryl phosphines. It should be noted that significant correlations were also found for ( p +  m ) and  + but no correlation was found with the other parameters. Clearly induction is of minor importance because the 31 P chemical shift of 11c (strongly electron withdrawing by induction) is closer to that of 11d than was expected. Swain and Lupton [34] showed that these different sigma values are just linear combinations of resonance (R) and field/induction (F) parameters, which they calculated.   Given that no simple method of predicting the chemical shift of phosphines has been reported we looked into this possibility a little more closely. Looking at the phosphorus chemical shifts reported by Maier et al. [35] we looked at their correlation to R and F. Surprisingly, for para-substituted triaryl phosphines (n = 23) the 31 P chemical shift correlated with R, and ortho-substituted phosphines correlated best with 0.4F + 0.6 R ( Figures 1A and B). No correlation was found with the meta-substituted triarylphosphines suggesting possibly other effects are at play here. Using these data, we looked at the correlation between R and F and the chemical shift of our para-substituted MAP analogs. A strongly linear correlation (R 2 = 0.9998) was observed with R for the para-substituted MAP analogs (data not shown). Inclusion of any F component only made the correlation worse. Inclusion of 11b with the Field parameter resulted in a linear regression (R 2 = 0.9997) where the 31 P chemical shift is proportional to R p + 0.85F m . Our data, albeit with a small dataset, suggests that the 31 P chemical shifts of MAP analogs is related to the Swain and Lupton resonance and field parameters and that only the resonance parameter is important for para-substitution and only the field (induction) parameter is important in meta-substitution. To add weight to these finding, we used the 31 P chemical shifts for para-and meta-substituted simple triarylphosphines [35] and plotted these against R p + 0.85F m and obtained a reasonable fit (R 2 = 0.7473). This linear correlation, though totally empirical, may be useful when designing and preparing other congeners of this class of aminophosphines in the future with tunable electronic properties at the phosphine center.

General
Linear regressions were carried out in GraphPad Prism v 5. (S)-BINOL, palladium acetate, palladium on carbon and dppb were purchased from Combi-Blocks, Inc. (San Diego, CA, USA). Diphenylphosphine oxide was purchased from Digital Specialty Chemicals (Toronto, Canada). Trifluoromethane sulfonic anhydride was purchased from Oakwood Products Inc. (West Columbia, Anaheim, CA, USA). 3,5-Difluorobromobenzene was purchased from AK Scientific. All other reagents were purchased from Sigma-Aldrich (Castle Hill, New South Wales, Australia). Unless specified, all commercially available reagents were used without further purification. Dichloromethane was distilled from calcium hydride. Tetrahydrofuran and toluene were distilled from sodium/benzophenone ketal. Diisopropylethylamine and pyridine were distilled from potassium hydroxide. Trifluoromethane-sulfonic anhydride was distilled from phosphorous pentoxide. All air and moisture sensitive reactions were performed under a nitrogen atmosphere. Reactions were magnetically stirred and monitored by thin-layer chromatography (TLC) using silica gel 60 F254 aluminium pre-coated plates (0.25 mm, Merck, Darmstadt, Germany). Flash column chromatography was performed on DAVISIL silica gel. All 1 H, and 13 C-NMR experiments were performed on a Bruker Avance DPX 400 MHz spectrometer. Chemical shifts were reported in ppm using CHCl 3 ( H ; 7.26 ppm, ( C ; 77.5 ppm) as an internal reference. 31 P-NMR spectroscopy was performed on a Bruker Avance DPX 400 MHz spectrometer at 298 K calibrated to H 3 PO 4 (0 ppm). All spectra were processed using Bruker TOPSPIN (3). Infrared spectra were taken on a Thermo Fisher Scientific Inc. Nicolet iS10 smart iTR spectrometer and processed using OMNIC software, version 8.1. High resolution mass analysis was provided by University of Illinois, Urban-Champaign, IL, USA.

Preparations of Phosphinoxides 1-3
Bis(3,5-difluorophenyl)phosphine oxide (1). Compound 1 was prepared as described by Busacca [25]. A flame dried 3-neck 250 mL round bottom flask equipped with a magnetic stirrer and 100 mL addition funnel was charged with aryl halide (17.3 mmol) and THF (10 mL) under N 2 gas. The clear solution was cooled to −10 °C on an ice salt bath and the addition funnel was charged with i-PrMgCl (9.1 mL, 18.2 mmol) which was added to the cooled solution dropwise over a period of 8 min and then left to stir at 0 °C for 1 h. The reaction was re-cooled to −10 °C whereby the addition funnel was charged with diethylphosphite (675 μL, 5.24 mmol), and this reagent was added dropwise to the cooled solution over a period of 5 min, after which the reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction was cooled to 0 °C and quenched with careful addition of 3N HCl (10 mL). The mixture was extracted with methyl tert-butyl ether (3 × 10 mL) and the combined organic layers were dried (MgSO 4 ) and concentrated. The oil was dried under high vacuum (0.01 mm Hg) overnight to yield the phosphine oxide as a white solid (1.2g, 83%) without further purification. 1 (2) and bis(4-methoxy)phosphine oxide (3) were prepared as described by Hays [26]. Magnesium turnings (85.1 mmol) in THF (20 mL) was stirred at 40 °C under argon for 1 h. To this Mg/THF slurry was added 4-bromoanisole (77.6 mmol) dropwise over 20 min. The mixture was then cooled to 0 °C and diethylphosphite (38.8 mmol) was added dropwise over 10 min and then stirred at 45 °C for 4 h. The reaction was carefully quenched with water and the resultant white mixture was diluted with ethyl acetate (EtOAc) and 10% HCl solution and stirred at room temperature for 30 min until the residual magnesium had disappeared. The product was extracted three times with EtOAc and the organic layer was washed with 2% HCl, brine and dried (MgSO 4 ). Removal of solvent in vacuo afforded a pale yellow powder which was purified using flash chromatography (EtOAc/hexanes, 60% to 100%) to give the final phosphine oxide product.  (4). To a solution of (S)-BINOL (5.02 g, 17.5 mmol) and diisopropylethylamine (3.05 mL, 17.5 mmol) in dichloromethane (90 mL) was slowly added triflic anhydride (2.94 mL, 17.5 mmol) at 0 °C under nitrogen. After stirring at room temperature for 1 h, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude triflate was dissolved in tetrahydrofuran (80 mL) under nitrogen and cooled to 0 °C whereby sodium hydride (505 mg, 21 mmol) was added portionwise. After stirring for 15 min at 0 °C chloromethylmethyl ether (1.60 mL, 21 mmol) was added dropwise and the mixture was left to stir at room temperature for 2 h. The reaction was carefully quenched with water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel, hexane:dichloromethane (2:1) to yield 4 (6.84 g, 84%) as large white crystals. 1 (6). A suspension of 5 (4.51 g, 10.8 mmol) and palladium acetate (10% on carbon, 1.10 g, 1.08 mmol) in ethyl acetate (25 mL) was heated under hydrogen gas (1 atm) at 45 °C for 3 h. After filtration through Celite, the solvent was evaporated under reduced pressure to afford 6 (3.42 g, 96%) as a slightly yellow solid, which was used without further purification. 1  (S)-NOBIN. To a solution of 6 (3.31 g, 10.1 mmol) in methanol (25 mL) and dichloromethane (25 mL) was added concentrated sulfuric acid (1.6 mL). After refluxing for 5 h, the reaction was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (pH 8-9) and extracted three times with dichloromethane. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford (S)-NOBIN (2.71 g, 94%) as a white solid which was used without further purification or recrystallized from benzene for spectroscopy. 1  3.3.2. Synthesis of (S)-2-N-Acetyl-2′-hydroxy-1,1′-binaphthyl (7) To a solution of (S)-NOBIN (4.94 g, 17.2 mmol) in pyridine (70 mL) was slowly added acetyl chloride (2.7 mL, 37.8 mmol) at 0 °C under nitrogen. After stirring at room temperature for 3 h, the reaction mixture was carefully poured onto ice cold water and extracted 3 times with dichloromethane. The extracts were washed twice with 5% aqueous hydrochloric acid, twice with water, twice with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford the crude N,O-diacetate. To a solution of crude diacetate in methanol (450 mL) was added sodium methoxide (140 L, 25% in methanol). After stirring at room temperature for 1 h, the solvent was evaporated under reduced pressure and the residue redissolved in dichloromethane. The organic layer was washed twice with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 7 (5.3 g, 94%) as an off-white solid that was used without further purification. 1

Synthesis of Aminophosphine Oxides 10a-d
To a solution of 7 (5.15 g, 15.7 mmol) and pyridine (3.82 mL, 47.1 mmol) in dichloromethane (80 mL) was slowly added triflic anhydride (2.91 mL, 17.3 mmol) at 0 °C under nitrogen. After stirring at room temperature for 3 h, the reaction was diluted with dichloromethane (80 mL). The organic layer was washed with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford the crude (S)-2-Nacetyl-2′-(trifluoromethanesulfonyloxy)1,1′-binaphthyl (8) which was used immediately for the phosphonylation reactions without further purification or characterization. To a suspension of the crude triflate (1.0 equiv.), phosphine oxide (2.1 equiv.), 1,4-bis(diphenylphosphino)butane (0.2 equiv.), palladium acetate (0.2 equiv.) in DMSO, 0.156 mmol/mL) was added diisopropylethylamine (3.7 equiv.). The reaction mixture was heated under nitrogen at 120 °C. After 12 h the reaction was cooled to room temperature, diluted with dichloromethane and the dark organic solution was washed twice with 5% aqueous hydrochloric acid, twice with water, saturated sodium bicarbonate, brine and dried (MgSO 4 ). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel to afford the purified N-acetylphosphine oxide compounds 9a-d which were used as intermediates to the aminophosphine compounds 10a-d.
(S)-2-Amino-2′-(diphenylphosphinoyl)-1,1′-binaphthyl (10a). A solution of phosphine oxide (700 mg, 1.37 mmol) in ethanol (14 mL) was added 5M hydrochloric acid (3.5 mL) was heated to reflux. After 6 h, the reaction was worked up according to the general procedure to afford aminophosphine 10a (623 mg, 97%) as an off white solid. 1  The corresponding phosphine oxide 10a-d was dissolved in neat phenyl silane and heated at 120 °C for 24 h. The dark reaction was dried down under a gentle stream of N 2 gas to remove most of the phenyl silane, and the crude residue was purified by flash chromatography on silica gel to afford the purified aminophosphine compounds 11a-d.