Enantioselective Heck/Tsuji-Trost reaction of flexible vinylic halides with 1,3-dienes

Abstract

The enantioselective domino Heck/cross-coupling has emerged as a powerful tool in modern chemical synthesis for decades. Despite significant progress in relative rigid skeleton substrates, the implementation of asymmetric Heck/cross-coupling cascades of highly flexible haloalkene substrates remains a challenging and and long-standing goal. Here we report an efficient asymmetric domino Heck/Tsuji-Trost reaction of highly flexible vinylic halides with 1,3-dienes enabled by palladium catalysis. Specifically, the Heck insertion as stereodetermining step to form ƞ³ allyl palladium complex and in situ trapping with nucleophiles enable efficient Heck/etherification in a formal (4 + 2) cycloaddition manner. Engineering the Sadphos bearing androgynous non-C₂-symmetric chiral sulfinamide phosphine ligands are vital component in achieving excellent catalytic reactivity and enantioselectivity. This strategy offers a general, modular and divergent platform for rapidly upgrading feedstock flexible vinylic halides and dienes to various value-added molecules and is expected to inspire the development of other challenging enantioselective domino Heck/cross-couplings.

Fig. 1. Catalytic asymmetric domino Heck/Tsuji−Trost reactions.

a Asymmetric domino Heck/cross-coupling of rigid & flexible substrates. b Asymmetric domino Heck/Tsuji−Trost reactions with 1,3-dienes. c Asymmetric protocol for the highly flexible haloalkenes.

Fig. 2. Ligand enabled catalytic asymmetric domino Heck/Tsuji−Trost reaction of flexible vinylic halides with 1,3-Dienes.^[a-d].

a Natural product featuring a cyclic isoprenoid skeleton. b Preliminary attempt. c Screening of chiral ligands. [a] 1a (0.1 mmol), 2a (0.4 mmol), palladium catalyst (10 mol%), ligand (20 mol%), silver salt (0.6 equiv), solvent (0.2 M), Ar, 70 °C, 48 h. [b] Yields are determined by GC analysis using anisole as an internal standard. [c] Isolated yield after flash-column chromatography. [d] Determined by HPLC analysis.

Fig. 3. Scope of the asymmetric domino Heck/Tsuji-Trost reaction of 1 with cyclohexadienes 2.

The yields reported represent single runs and have not been reproduced in this work.^[a] [a] 1 (0.2 mmol), 2 (0.8 mmol), Pd(CO₂^tBu)₂ (10 mol %), (Sc,Rs)-Xu3 (20 mol%), Ag₂SO₄ (0.6 equiv), DMAc (1 mL), Ar, 70 °C, 48 h.

Fig. 4. Variation of conjugated cyclohexadiene 2.

The yields reported represent single runs and have not been reproduced in this work.^[a] [a] 1 (0.2 mmol), 2 (0.8 mmol), Pd(CO₂^tBu)₂ (10 mol %), (Sc,Rs)-Xu3 (20 mol%), Ag₂SO₄ (0.6 equiv), DMAc (1 mL), Ar, 70 °C, 48 h.

Fig. 5. Synthetic transformations and plausible mechanism.

a Gram-scale reaction and Functional transformations. b Plausible asymmetric induction model.