Computationally Guided Design of a Readily Assembled Phosphite–Thioether Ligand for a Broad Range of Pd-Catalyzed Asymmetric Allylic Substitutions

Abstract

A modular approach employing indene as common starting material, has enabled the straightforward preparation in three reaction steps of P-thioether ligands for the Pd-catalyzed asymmetric allylic substitution. The analysis of a starting library of Pthioether ligands based on rational design and theoretical calculations has led to the discovery of an optimized anthracenethiol derivative with excellent behavior in the reaction of choice. Improving most approaches reported to date, this ligand presents a broad substrate and nucleophile scope. Excellent enantioselectivities have been achieved for a range of linear and cyclic allylic substrates using a large number of C-, N-and O-nucleophiles (40 compounds in total). The species responsible for the catalytic activity have been further investigated by NMR in order to clearly establish the origin of the enantioselectivity. The resulting products have been derivatized by means of ring-closing metathesis or Pauson-Khand reactions to further prove the synthetic versatility of the methodology for preparing enantiopure complex structures. Scheme 1. Three-step synthesis of phosphite/phosphinite-thioether ligands L1-L7a-g from indene. (i) (R,R)-Mn-salen catalyst, 4-PPNO, aq. NaClO, CH2Cl2; 10 (ii) RSH, NaOH, dioxane/H2O (10:1); 11 (iii) ClP(OR 1 R 2 )2; (OR 1 R 2 )2= a-c, Py, toluene and (iv) ClPR 3 2; R 3 = d-g, NEt3, toluene.All ligands were characterized by 31 P{ 1 H}, 1 H and 13 C{ 1 H} NMR spectroscopy and HRMS. All data were in agreement with assigned structures. 13 See experimental section for purification and characterization details.

Indene Derived Phosphorus‐Thioether Ligands for the Ir‐Catalyzed Asymmetric Hydrogenation of Olefins with Diverse Substitution Patterns and Different Functional Groups

“…Phosphorochloridites are easily prepared in one step from the corresponding biaryls [29] . Phosphite/phosphinite‐thioether ligands L1 ‐ L8a ‐ f were prepared as previously reported [16] . Substrates S1 , [30] S2 , [12e] S3 – S4 , [30] S5 – S7 , [12g] S8 , [31] S9 – S10 , [32] S11 , [33] S12 , [32] S13 , [33] S14 , [34] S15 – S18 , [13b] S19 , [35] S20 , [13a] S21 , [36] S22 , [37] S28 , [6g] S29 , [38] S30 – S37 , [6g] S38 , [39] S39 – S43 , [22b] S44 , [40] S45 – S46 , [27j] S47 , [41] S48 , [27j] S49 , [27i] S50 [27a] were prepared following the reported procedures.…”

“…To continue the improvement of Ir‐catalysts with air‐stable and readily available ligands, we would like to disclose here the study of a simple but modular P,S‐ligand family (Figure 2, ligands L1 ‐ L8a ‐ f ) for the AH of olefins. These ligands are easily synthesized in only three steps from unexpensive indene [16] . The substrates studied cover different substitution patterns with different functional groups, ranging from unfunctionalized olefins, through olefins with poorly coordinative groups to olefins with a coordinative functional group that can also anchor the substrate to the metal.…”

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications

“…Later, it was found that the adaptable furanoside backbone in ligand L98 was not needed to induce high ee values and that a simpler and modular indene backbone could be used (e.g., ligand L99 ). 303 The modular structure of indene derivatives facilitated an iterative optimization of the ligand to adapt the size of the chiral cavity to a specific substrate type. In addition, the simple backbone simplified the NMR spectra, which facilitated studies of intermediates and accelerated DFT calculations.…”

“…One of them comprises P-thioether ligands L99 derived from indene ( Figure 7 ). 303 Within this family, the use of DFT studies was crucial to identifying the optimal phosphite-thioether ligand L99 , which provided excellent enantioselectivities for 40 substrates including linear and cyclic allylic esters and a broad range C-, N-, and O-nucleophiles. These studies also showed that in the case of linear substrates the enantioselectivity is mainly governed by the different reactivity of the endo and exo Pd allyl intermediates toward the nucleophile, rather than the population of the endo and exo isomers, as it was found for cyclic substrates.…”

Pd/Phosphoramidite Thioether Complex-Catalyzed Asymmetric N-Allylic Alkylation of Hydrazones with Allylic Acetates

“…With the development of catalytic asymmetric synthesis, Ir- and Pd-catalyzed asymmetric allylic alkylation (AAA) reactions with nitrogen-centered nucleophiles have recently been established as one of the most powerful methods for chemo-, regio-, and stereoselective formation of various C–N bonds . In this context, representative nitrogen nucleophiles include ammonia, alkyl and aromatic amines, azides, amides and sulfonamides, imides, heterocycles, and so on (Scheme a) . The Wang group recently disclosed the first example of organocatalytic asymmetric N -allylic alkylation of hydrazones using Morita–Baylis–Hillman carbonates, giving the corresponding N -alkylated hydrazones with excellent regio- and enantioselectivity (Scheme b) .…”