P,S-Bidentate Phosphoramidites with (Ra)-BINOL Core in Palladium-Catalyzed Asymmetric Allylic Substitution

New P,S-bidentate phosphoramidite ligands, including these having a stereogenic phosphorus atom in the 1,3,2-dioxaphosphepine ring, have been synthesized on the basis of (Ra)-BINOL and its adamantanyl derivatives. With their participation in the Pd-catalyzed asymmetric allylic alkylation of (E)-1,3-diphenylallyl acetate with dimethyl malonate and the amination with pyrrolidine involving these ligands have afforded selectivity up to 84 and 75% ee, respectively.


DOI: 10.1134/S1070363222120088
Synthesis of novel, available, and efficient phosphoruscontaining chirality inducers for the use in metal complex catalysis is a topical issue [1][2][3][4][5][6][7]. The C 1 -symmetrical P,S-bidentate ligands of significant interest. They possess high affinity of the thioether sulfur atom to soft complex forming ions. The Р-and S-donor sites different in the nature (the phosphorus exhibits good π-acceptor and σ-donor ability, whereas the sulfur is a weak σ-donor and weak π-acceptor) exhibit different trans-effect. The steric requirements of the Р-and S-donor sites are also different: the sulfide atom of sulfur bearing two substituents imparts less spatial hindering in comparison with the phosphorus atom bearing three substituents. Let us note that the sulfur atom turns asymmetrical upon the complex formation with a metal atom. The mentioned factors positively affect the activity and stereoselectivity of the catalytic transformations [8][9][10][11][12].
The molecules of known P,S-bidentate ligands L A-C include sufficiently complex sulfur-containing substituents, and the corresponding starting compounds have been prepared in several sophisticated stages [17,18]. In this study, we describe the preparation of novel P,S-bidentate phosphoramidites L1a-L1c with the (R a )-BINOL fragment, containing small achiral exocyclic substituent, and their use in palladium asymmetric catalysis. The Pd-catalyzed reactions of enantioselective allyl alkylation and amination, which form an effective toolkit to assess the efficiency of novel chirality inducers and have been widely used in asymmetric synthesis of valuable engineering and biologically important compounds [7,[20][21][22][23][24], were used as the catalytic processes to test the obtained ligands.
Condensation of diols 1a-1c with PCl 3 in the presence of a catalytic amount of N-methylpyrrolidone (NMP) afforded the corresponding intermediate chlorophosphites which were further reacted with N-methyl-2-(methylthio)ethane-1-amine in toluene in the presence of Et 3 N as base, to give the P,S-bidentate phosphoramidites L1a-L1c (Scheme 2). Upon the purification by flash chromatography, those ligands were white solid substances, readily soluble in organic solvent, sufficiently stable in air, and prone to prolonged storage in dry atmosphere.
Structure of compounds L1a-L1c was confirmed by the data of 1 Н, 13 С{ 1 H}, and 31 Р{ 1 H} NMR spectroscopy as well as elemental analysis. Detailed investigation of a solution of the L1a ligand in CDCl 3 by means of two-dimensional NMR spectroscopy ( 1 H-1 H COSY, 1 H-13 C HSQC, and 1 H-13 C HMBC) allowed complete assignment of its signals in the 1 Н and 13 С{ 1 H} NMR spectra (Scheme 3).
The L1c ligand bearing a P* chiral center was an individual stereoisomer, as compared by the presence of a narrow singlet signal at 147.44 ppm in its 31 [25,26], in which structurally different intermediates contributing to the asymmetry inducing prevailed depending on the L : Pd ratio. Probably, the intermediate compounds with a single P,S-chelated ligand (P-Pd-S) prevailed at L : Pd = 1, whereas the complexes with two P-monodentate phosphoramidites (SP-Pd-PS) were predominantly formed in the L : Pd formulation. Moreover, the fraction of the SP-Pd-PS intermediates in the equilibrium mixture depended on the solvent nature, To verify that hypothesis, ligand L1b was additionally tested towards alkylation of substrate 2 by dimethyl malonate at other L : Pd ratios in the CH 2 Cl 2 medium. The efficiency of the systems with L : Pd = 0.5 and 1 turned out to be the same, whereas the increase in the L : Pd molar ratio from 2 to 3 led to the increase in the enantioselectivity, due to additional shift of the equilibrium towards the SP-Pd-PS species (Table 1, Exp. 7 and 8, 10 and 11; Fig. 1). Comparison of the catalytic formulations with L : Pd = 1, 1.5, and 2 ( Table 1, Exp. 8-10; Fig. 1) showed that the intermediate ee value was observed in Exp. 9 (L : Pd = 1.5), due to the predominant contribution of the SP-Pd-PS intermediates into the asymmetry inducing.
At the same time, the (R)-3 product was obtained with 78-84% ее in the presence of the 2,9,14-tri(adamant-1-yl)substituted phosphoramidite L1c, almost irrespectively of the L : Pd molar ratio and the solvent nature. That fact could be related either with close enantioselectivity of the P-Pd-S and SP-Pd-PS catalytically active species produced from that ligand or with prevailing of the same intermediate independently of the reaction conditions. Since the L1c was sterically bulky, prevailing of the P-Pd-S intermediate with a single ligand in the coordination sphere of palladium could be expected.
Using pyrrolidine as the N-nucleophile and the palladium catalysts based on ligands L1a and L1b, the (R)-4 product was formed with the enantioselectivity not exceeding 17% ee (Scheme 4; Table 2, Exp. 1-8). On the contrary, the (S)-4 amine was formed with enantiomeric excess up to 75% using the chirality inducer L1c. The best results were observed when the reaction was performed in CH 2 Cl 2 at the molar ratio L : Pd = 2 (Exp. 9-12).
In summary, the prepared novel P,S-bidentate phosphoramidite ligands exhibited high sensitivity to the nature of the nucleophile and the solvent. In a model reaction of palladium-catalyzed enantioselective allyl alkylation of (E)-1,3 diphenylallyl acetate with dimethyl malonate, they were found significantly advantageous over the P,S-bidentate stereoselectors based on BINOL enantiomers bearing additional chiral elements yet affording the stereoselectivity as low as 26% ee [17]. Moreover, one of the prepared ligands afforded the stereoselectivity of up to 75% ee in that reaction, its P-monodentate ligand (R a )-Monophos affording only 25%  ee [32]. The latter example confirmed positive influence of the sulfide donor site on the asymmetric induction. In the case of the allyl alkylation in the presence of ligands L1a and L1b, inversion of the absolute configuration of the major enantiomer of the reaction product (from R to S) occurred with the increase in the L : Pd molar ratio from 1 to 2, likely due to the formation of structurally different catalytic intermediates. EXPERIMENTAL 31 Р{ 1 Н}, 1 H, and 13 С{ 1 Н} NMR spectra were recorded using a Varian Inova 500 instrument (202.4, 499.9, and 125.7 MHz) relative to 85% Н 3 РО 4 in D 2 О ( 31 Р{ 1 Н}) or residual protons of the solvents ( 1 H and 13 С{ 1 Н}). Assignment of the signals in the 1 H and 13 С{ 1 Н} NMR spectra was performed using the APT, 1 H-1 H COSY, 1 H-13 C HSQC, and 1 H-13 C HMBC methods. Enantiomer analysis of the products of the catalytic reactions was performed using a Staier HPL chromatograph. Elemental analysis was performed using a Carlo Erba EA1108 CHNS-O microanalyzer.
The  2 pre-catalyst were prepared as described elsewhere [33][34][35]. Catalytic reactions of asymmetric alkylation of compound 2 with dimethyl malonate and its amination with pyrrolidine as well as determination of conversion of substrate 2 and enantiomeric excess of products 3 and 4 were performed according to the earlier published procedures [27,34].
General procedure for preparation of ligands L1a-1c. N-Methylpyrrolidone (0.01 g, 0.1 mmol) was added to a vigorously stirred suspension of compound 1a-1c (2 mmol) in PCl 3 (4 mL, 45.5 mmol). The obtained mixture was boiled during 5 min until complete homogenization, and then excess of PCl 3
Asymmetric amination of (E)-1,3-diphenylallyl acetate 2 with pyrrolidine. A solution of [Pd(allyl)Cl] 2 (0.001 g, 0.0025 mmol) and the corresponding ligand L1a-c (0.005 or 0.01 mmol) in 1.5 mL of the corresponding solvent was stirred during 40 min. (E)-1,3-Diphenylallyl acetate (0.05 mL, 0.25 mmol) was added, and the solution was stirred during 15 min; freshly distilled pyrrolidine (0.06 mL, 0.75 mmol) was then added. The reaction mixture was stirred during 24 h, diluted with 2 mL of CH 2 Cl 2 or THF, and filtered through a thin layer of SiO 2 . The solvent was removed under reduced pressure (40 Torr); the residue containing (E)-1-(1,3-diphenylallyl) pyrrolidine 4 [38,39] was dried in vacuum (10 Torr, 12 h). To determine the conversion of substrate 2 and enantiomeric excess of the product 4, the obtained residue was dissolved in the corresponding eluent (8 mL) and sampled to perform the HPLC analysis on a chiral stationary phase.