A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions

Detailed mechanistic studies of a Pd-catalyzed asymmetric C–N coupling led to a rational design of a new series of bis-phosphine mono-oxides ligated Pd(ii) pre-catalysts that allow for reliable and complete catalyst activation.


Complex C: catalyst robustness
The temporal concentration of 1 at the beginning of reaction (red hollow circles) is identical to a reaction with a higher starting concentration running for ca. 11 min (blue circles) (Fig. S11). Comparison of these two reaction profiles from a point of identical substrate concentration is possible by shifting the curve with hollow red circles in time, as shown by the red arrows to give the adjusted curve shown in red circles. The overlay between the two kinetic profiles from the time-adjusted point is a good indicator of high catalyst stability.

First order kinetics in [C]
Having demonstrated catalyst robustness, the catalyst order was determined by using the normalized time scale method. 1 The two plots of [1] against a normalized time scale, t[cat] T n , for two reactions carried out at different catalyst loadings showed overlay for n = 1.

Saturation kinetics in [1]
Using 5 mol % of complex C, the reaction showed saturation kinetics in [1], the initial rates matched up to 20% conversion for the two reactions that differed on their initial concentrations by half.    S-20

Buchwald G3/G4 type pre-catalyst with QuinoxP*(O)
Buchwald G3/G4 type pre-catalysts with BPMO have been prepared as shown in the scheme below: Both pre-catalysts resulted inactive in the current system, which further emphasizes the utility of catalyst type K-3. atmosphere. After 16 hours, the mixture was cooled to ambient temperature and slowly added to isopropanol (500 mL) cooled in an ice/water bath over the course of 20 min. The resulting slurry was diluted by adding water (125 mL) over 10 min. After aging for 30 min in the ice/water bath, the mixture was filtered and the solid was washed with 4:1 isopropanol/water (50 mL).
The solid was dried under vacuum to provide compound 5 (20.14 g, 53.3 mmol, 80% yield) as a

Synthesis of 1•CD 2 from 1
To a solution of 1 (1.0 g, 1.95 mmol) in 10 mL of THF-d 8  extracted with 40 mL of CH 2 Cl 2 . The organic layer was dried over Na 2 SO 4, treated with 2.0 g of Na 2 CO 3 , and stirred for 5 min. The solids were filtered and the organic solvent was concentrated. CH 3 CN (10 mL) was added to the oil and then evaporated. The resulted solid was then suspended in CH 3 CN (10 mL) and stirred at ambient temperature for 10 min.      14. X-ray crystallography data

Crystal data and structure refinement for complex D (CCDC 1512973)
A single crystal grown from toluene by slow evaporation was selected for single crystal X-ray analysis. The crystal was a small yellow plate with dimensions of 0.20 mm x 0.15 mm x 0.04 mm.
Data collection was performed on a Bruker Apex II system at 100 K. The unit cell was determined to be orthorhombic in space group P2 1 2 1 2 1 . The complex crystallized as a monotoluene solvate, with the toluene solvate found to be positionally disordered, with two orientations observed (56:44 occupancy ratio). Crystallographic data is summarized in Table 1.

Absolute configuration was established by anomalous-dispersion effects in diffraction
measurements on the crystal and confirmed that the stereochemistry was as shown in the scheme below. Fig. S16 shows a thermal ellipsoid representation of complex D toluene solvate with thermal ellipsoids set at the 50% probability level.

Crystal data and structure refinement for complex E (CCDC 1512974)
A single crystal grown from dichloromethane and toluene by slow evaporation was selected for single crystal X-ray analysis. The crystal was a small yellow plate with dimensions of 0.05 mm x 0.05 mm x 0.01 mm. Data collection was performed on a Bruker Apex II system at 100 K. The unit cell was determined to be orthorhombic in space group P2 1 2 1 2 1 . The complex crystallized as an anhydrous form with one molecule in the crystallographic asymmetric unit.
Crystallographic data is summarized in Table 2. Absolute configuration was established by anomalous-dispersion effects in diffraction measurements on the crystal and confirmed that the stereochemistry was as shown in the scheme below. Fig. S18 shows a thermal ellipsoid representation of complex E, with thermal ellipsoids set at the 50% probability level.

Crystal data and structure refinement for pre-cataylst K3 (CCDC 1512975)
A single crystal grown from toluene by slow evaporation was selected for single crystal X-ray analysis. The crystal was a pale yellow block with dimensions of 0.3 mm x 0.2 mm x 0.1 mm.
Data collection was performed on a Bruker Apex II system at 100 K. The unit cell was determined to be monoclinic in space group C2. The complex crystallized as an anhydrous form with one molecule in the asymmetric unit. Crystallographic data is summarized in Table 3.
Absolute configuration was established by anomalous-dispersion effects in diffraction measurements on the crystal and confirmed that the stereochemistry was as shown in the scheme below. Fig. S19 shows a thermal ellipsoid representation of pre-catalyst J3, with thermal ellipsoids set at the 50% probability level.             After determination of the favorable conformation and configuration of D-I, the phenyl group was replaced with a 2-cyclopropylthiazole (C). Again, the relative energy of the (R) configuration of the substrate was more favorable compared to the complex binding the (S) configuration for all substitution patterns (Fig. S33). The configuration of the 2-cyclopropylthiazole corresponding to C-III was not pursued. The crystal structure of D was determined (MDK052) and is depicted in to be ~0.5 kcal/mol higher in energy than the lowest energy conformation seen in conformer type A. This slight variation in computationally modeled rotamer and crystallographically observed rotamer is attributed to stacking interactions in the crystal lattice (Fig. S35).

Calculations on oxidative addition transition states and deprotonation pathways
Choice of the optimal density functional and basis set for modeling this reaction pathway was made by comparing results from geometry optimization of catalytic complex D with the X-ray crystal structure. Minimal variation was observed for the functionals and basis sets tested, with M06/6-31G*:SDD 11 , 12 demonstrating good correlation to the bond distances and dihedrals observed experimentally (Table S5). Coordinates of minima are provided in the SI zip file.