Synthesis of novel, available, and efficient phosphorus-containing chirality inducers for the use in metal complex catalysis is a topical issue [1–7]. The C1-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 [8–12].

The phosphoramidites form a favored class of phosphite-type chiral ligands characterized by universality, availability, and high efficiency in a wide range of catalytic processes [13–16]. Selected examples of phosphoramidites based on the BINOL enantiomers {(Ra)- and/or (Sa)-[1,1′-binaphthyl]-2,2′-diol} are shown in Scheme 1 [13, 17–19].

Scheme
scheme 1

1.

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The molecules of known P,S-bidentate ligands LA–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 (Ra)-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, 20–24], were used as the catalytic processes to test the obtained ligands.

Condensation of diols 1a–1c with PCl3 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 Et3N 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.

Scheme
scheme 2

2.

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Structure of compounds L1a–L1c was confirmed by the data of 1Н, 13С{1H}, and 31Р{1H} NMR spectroscopy as well as elemental analysis. Detailed investigation of a solution of the L1a ligand in CDCl3 by means of two-dimensional NMR spectroscopy (1H–1H COSY, 1H–13C HSQC, and 1H–13C HMBC) allowed complete assignment of its signals in the 1Н and 13С{1H} NMR spectra (Scheme 3).

Scheme
scheme 3

3.

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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 31Р{1H} NMR spectrum in CDCl3.

Two model reactions of Pd­catalyzed enantioselective allyl substitution involving (E)-1,3-diphenylallyl acetate 2 were utilized for the catalytic investigation of novel chirality inducers; [Pd(allyl)Cl]2 was chosen as the palladium precursor (Scheme 4). In the case of allyl alkylation of (E)-1,3-diphenylallyl acetate 2 with dimethyl malonate (the C-nucleophile) in the presence of BSA–KOAc as combined base [BSA = N,O-bis(trimethylsilyl)acetamide] and compounds L1a–L1c as ligands, stereoselectivity of the reactions at quantitative conversion was 75, 70, and 84% ee, respectively (Table 1, Exp. 3, 5, and 12). Ligand L1a containing unsubstituted aromatic ring and 9,14-di(adamant-1-yl)-substituted ligand L1b revealed similar behavior during the allyl alkylation catalysis. The increase in the L : Pd molar ratio from 1 to 2 led to inversion of the absolute configuration of the major enantiomer of product 3 (Table 1, Exp. 1 and 2, 3 and 4, 5 and 6, 8 and 10), possibly resulting from dynamic nature of the catalytic systems formed in situ [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, being more prominent in CH2Cl2 than in THF (Table 1, Exp. 2 and 4, 6 and 10).

Scheme
scheme 4

4.

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Table 1. Data on the Pd-catalyzed alkylation of substrate 2 with dimethyl malonate
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To verify that hypothesis, ligand L1b was additionally tested towards alkylation of substrate 2 by dimethyl malonate at other L : Pd ratios in the CH2Cl2 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.

Fig. 1.
figure 1

Enantioselectivity of the catalytic compositions at different molar ratio L1b/Pd towards the Pd-catalyzed alkylation of substrate 2 with dimethyl malonate.

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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 CH2Cl2 at the molar ratio L : Pd = 2 (Exp. 9–12).

Table 2. Data on the Pd-catalyzed amination of substrate 2 with pyrrolidine
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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)-1,3­diphenylallyl 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 (Ra)-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

31Р{1Н}, 1H, and 13С{1Н} NMR spectra were recorded using a Varian Inova 500 instrument (202.4, 499.9, and 125.7 MHz) relative to 85% Н3РО4 in D2О (31Р{1Н}) or residual protons of the solvents (1H and 13С{1Н}). Assignment of the signals in the 1H and 13С{1Н} NMR spectra was performed using the APT, 1H–1H COSY, 1H–13C HSQC, and 1H–13C 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 reactions were performed in anhydrous solvents under inert atmosphere. Dimethyl malonate, BSA, pyrrolidine, triethylamine, and (Ra)-BINOL 1a were commercial chemicals (Fluka and Aldrich). (Ra)-6,6′-Di(adamant-1-yl)-[1,1′-binaphthyl]-2,2′-diol 1b, (Ra)-3,6,6′-tri(adamant-1-yl)-[1,1′-binaphthyl]-2,2′-diol 1c, N-methyl-2-(methylthio)ethane-1-amine, (E)-1,3-diphenylallyl acetate 2, and the [Pd(allyl)Cl]2 pre-catalyst were prepared as described elsewhere [33–35]. 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 PCl3 (4 mL, 45.5 mmol). The obtained mixture was boiled during 5 min until complete homogenization, and then excess of PCl3 was removed in vacuum (40 Torr). The residue was dried in vacuum (30 min, 10–3 Torr) to remove the traces of PCl3 and dissolved in 15 mL of toluene. Et3N (0.56 mL, 4 mmol) and N-methyl-2-(methylthio)ethane-1-amine (0.21 g, 2 mmol) were added to the obtained solution with vigorous stirring at 20°C (or –73°C during the synthesis of ligand L1c). The reaction mixture was stirred during 24 h at 20°C and filtered through a short column with SiO2/Al2O3 dried under vacuum. The filtrate was concentrated in vacuum (40 Torr); the obtained products were purified by column chromatography on silica gel [eluent: toluene–hexane (1 : 1) in the case of L1a; toluene in the case of L1b and L1c] and then dried under vacuum (10–3 Torr).

(Ra)-4-[N-Methyl-N-(2-methylthioethyl)amino]dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphenin (L1a). Yield 0.73 g (87%), white powder, mp 139–140°C. 1H NMR spectrum (CDCl3, 25°C), δ, ppm: 1.97 s (3H, CH3), 2.38 d (3H, CH3, 3JHP 6.0 Hz), 2.57–2.67 m (2H, CH2), 3.07–3.16 m (1H, CH2), 3.25–3.33 m (1H, CH2), 7.21–7.24 m [1H, CH(Ar)], 7.22–7.26 m [1H, CH(Ar)], 7.32 d [1H, CH(Ar), 3JHH 8.4 Hz], 7.38–7.40 m [3H, CH(Ar)], 7.41 d [1H, CH(Ar), 3JHH 8.7 Hz], 7.49 d [1H, CH(Ar), 3JHH 8.8 Hz], 7.89 d [1H, CH(Ar), 3JHH 8.7 Hz], 7.88–7.90 m [2H, CH(Ar)], 7.94 d [1H, CH(Ar), 3JHH 8.8 Hz]. 13C{1H} NMR spectrum (CDCl3, 25°C), δС, ppm: 15.32 d (CH3, 5JCP 1.0 Hz), 32.56 d (CH3, 2JCP 8.0 Hz), 33.14 d (CH2, 3JCP 3.3 Hz), 48.99 d (CH2, 2JCP 32.8 Hz), 122.10 d [CH(Ar), 3JCP 1.8 Hz], 122.19 [CH(Ar)], 122.93 d [C(Ar), 3JCP 2.2 Hz], 124.11 d [C(Ar), 3JCP 5.0 Hz], 124.94 [CH(Ar)], 124.96 [CH(Ar)], 126.23 [CH(Ar)], 126.24 [CH(Ar)], 127.07 [CH(Ar)], 127.17 [CH(Ar)], 128.40 [CH(Ar)], 128.47 [CH(Ar)], 130.16 [CH(Ar)], 130.40 [CH(Ar)], 130.97 [C(Ar)], 131.60 [C(Ar)], 132.87 [C(Ar)], 133.06 d [C(Ar), 4JCP 1.5 Hz], 149.65 d [C(Ar), 2JCP 1.0 Hz], 150.09 d [C(Ar), 2JCP 5.1 Hz]. 31P{1H} NMR spectrum (CDCl3, 20°C): δР 148.83 ppm. Found, %: C 68.88; H 5.34; N 3.28. C24H22NO2PS. Calculated, %: C 68.72; H 5.29; N 3.34.

(Ra)-9,14-Di(adamant-1-yl)-4-[N-methyl-N-(2-methylthioethyl)amino]dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphenin (L1b). Yield 1.13 g (82%), viscous milk-white oil solidifying during storage, bp 188–190°C. 1H NMR spectrum (CDCl3, 25°C), δ, ppm: 1.75–1.81 m [12H, CH2(Ad)], 1.96 s (3H, CH3), 1.98–1.99 m [12H, CH2(Ad)], 2.10 br. s [6H, CH(Ad)], 2.37 d (3H, CH3, 3JHP 5.8 Hz), 2.56–2.66 m (2H, CH2), 3.07–3.15 m (1H, CH2), 3.24–3.32 m (1H, CH2), 7.31–7.39 m [5H, CH(Ar)], 7.43 d [1H, CH(Ar), 3JHH 8.8 Hz], 7.74–7.75 m [2H, CH(Ar)], 7.82 d [1H, CH(Ar), 3JHH 8.7 Hz], 7.89 d [1H, CH(Ar), 3JHH 8.8 Hz]. 13C{1H} NMR spectrum (CDCl3, 25°C), δC, ppm: 15.31 d (CH3, 5JCP 0.6 Hz), 29.20 [CH(Ad)], 32.61 d (CH3, 2JCP 7.5 Hz), 33.14 d (CH2, 3JCP 3.4 Hz), 36.39 [С(Ad)], 37.08 [CH2(Ad)], 43.30 [CH2(Ad)], 43.32 [CH2(Ad)], 49.06 d (CH2, 2JCP 33.3 Hz), 121.81 d [CH(Ar), 3JCP 1.5 Hz], 121.89 [CH(Ar)], 122.72 d [C(Ar), 3JCP 2.0 Hz], 123.28 [CH(Ar)], 123.37 [CH(Ar)], 123.97 d [C(Ar), 3JCP 4.9 Hz], 124.40 [CH(Ar)], 124.43 [CH(Ar)], 126.87 [CH(Ar)], 126.97 [CH(Ar)], 130.04 [CH(Ar)], 130.29 [CH(Ar)], 131.06 [C(Ar)], 131.09 d [C(Ar), 4JCP 0.6 Hz], 131.30 d [C(Ar), 4JCP 1.4 Hz], 131.69 [C(Ar)], 147.53 [C(Ar)], 147.77 [C(Ar)], 149.07 d [C(Ar), 2JCP 0.7 Hz], 149.54 d [C(Ar), 2JCP 5.2 Hz]. 31P{1H} NMR spectrum (CDCl3, 20°C): δP 148.50 ppm. Found, %: C 77.02; H 7.40; N 2.13. C44H50NO2PS. Calculated, %: C 76.82; H 7.33; N 2.04.

(Ra)-2,9,14-Tri(adamant-1-yl)-4-[N-methyl-N-(2-methylthioethyl)amino]dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphenin (L1c). Yield 1.32 g (80%), white powder, mp 224–225°C. 1H NMR spectrum (CDCl3, 25°C), δ, ppm: 1.77–1.82 m [18H, CH2(Ad)], 1.94 s (3H, CH3), 2.00 br. s [12H, CH2(Ad)], 2.12 br. s [9H, CH(Ad)], 2.31 br. s [6H, CH2(Ad)], 2.45 d (3H, CH3, 3JHP 6.7 Hz), 2.56–2.67 m (2H, CH2), 3.09–3.18 m (1H, CH2), 3.19–3.27 m (1H, CH2), 7.13–7.31 m [4H, CH(Ar)], 7.35 d [1H, CH(Ar), 3JHH 8.7 Hz), 7.75–7.77 m [2H, CH(Ar)], 7.83–7.87 m [2H, CH(Ar)]. 13C{1H} NMR spectrum (CDCl3, 25°C), δC, ppm: 15.18 (CH3), 29.07 [CH(Ad)], 29.10 [CH(Ad)], 29.32 [CH(Ad)], 32.77 d (CH3, 2JCP 11.1 Hz), 33.15 d (CH2, 3JCP 3.7 Hz), 36.22 [С(Ad)], 36.25 [С(Ad)], 36.95 [CH2(Ad)], 36.98 [CH2(Ad)], 37.21 [CH2(Ad)], 37.85 [С(Ad)], 42.09 d [CH2(Ad), 5JCP 5.4 Hz], 43.18 [CH2(Ad)], 43.24 [CH2(Ad)], 48.54 d (CH2, 2JCP 30.9 Hz), 121.40 [CH(Ar)], 123.13 [CH(Ar)], 123.15 [CH(Ar)], 123.49 d [C(Ar), 3JCP 2.2 Hz], 123.68 [CH(Ar)], 124.13 [CH(Ar)], 124.21 d [C(Ar), 3JCP 4.9 Hz], 126.35 [CH(Ar)], 126.69 [CH(Ar)], 127.10 [CH(Ar)], 129.70 [CH(Ar)], 129.97 [C(Ar)], 130.88 [C(Ar)], 130.93 [C(Ar)], 131.39 [C(Ar)], 141.57 d [C(Ar), 3JCP 2.5 Hz], 147.18 [C(Ar)], 147.50 [C(Ar)], 148.92 d [C(Ar), 2JCP 3.9 Hz], 148.98 [C(Ar)]. 31P{1H} NMR spectrum (CDCl3, 20°C): δP 147.44 ppm. Found, %: C 79.18; H 7.95; N 1.55. C54H64NO2PS. Calculated, %: C 78.89; H 7.85; N 1.70.

Asymmetric alkylation of (E)-1,3-diphenylallyl acetate 2 with dimethyl malonate. A solution of [Pd(allyl)Cl]2 (0.001 g, 0.0025 mmol) and the corresponding ligand L1a, L1c (0.005 or 0.01 mmol) or L1b (0.0025– 0.015 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; dimethyl malonate (0.05 mL, 0.44 mmol), BSA (0.11 mL, 0.44 mmol), and potassium acetate (0.002 g) were then added. The reaction mixture was stirred during 24 h, diluted with 2 mL of CH2Cl2 or THF, and filtered through a thin layer of SiO2. The solvent was removed under reduced pressure (40 Torr); the residue containing (E)-dimethyl-2-(1,3-diphenylallyl) malonate 3 [36, 37] was dried in vacuum (10 Torr, 12 h). To determine the conversion of substrate 2 and enantiomeric excess of the product 3, the obtained residue was dissolved in the corresponding eluent (8 mL) and sampled to perform the HPLC analysis on a chiral stationary phase.

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 CH2Cl2 or THF, and filtered through a thin layer of SiO2. 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.