NHC-Ni catalyzed enantioselective synthesis of 1,4-dienes by cross-hydroalkenylation of cyclic 1,3-dienes and heterosubstituted terminal olefins

Enantioenriched 1,4-dienes are versatile building blocks in asymmetric synthesis, therefore their efficient synthesis directly from chemical feedstock is highly sought after. Here, we show an enantioselective cross-hydroalkenylation of cyclic 1,3-diene and hetero-substituted terminal olefin by using a chiral [NHC-Ni(allyl)]BArF catalyst. Using a structurally flexible chiral C2 NHC-Ni design is key to access a broad scope of chiral 1,4-diene 3 or 3′ with high enantioselectivity. This study also offers insights on how to regulate chiral C2 NHC-Ni(II) 1,3-allylic shift on cyclic diene 1 and to build sterically more hindered endocyclic chiral allylic structures on demand.


Supplementary Figure 3 Synthesis of 2-alkyl cyclic 1,3-diene
Target compound was synthesized as same as the literature. 38
General procedure for the enantioselective cross-hydroalkenylation reaction:

Supplementary Figure 6 General expression of the cross-hydroalkenylation reaction
In situ generation of [chiral NHC-Ni(allyl)]BAr F catalyst. In a glove box, the [chiral NHC-Ni(allyl)Cl] complex solution was filtered to another oven-dried test tube with 0.05 mmol NaBAr F , and the residue was rinsed by toluene (3*0.2 ml). After 0.2 mmol 1-octene was added (for NiH or its equiv. generation) [11][12][13][14] , the mixture was stirred at r.t. for 1 hr before use.
General cross-hydroalkenylation procedure. In a glove box, a toluene solution of cyclic 1,3-diene and terminal olefin (1:3, 2 ml) were added into the indicated catalyst. This solution was allowed to stir for 6 hrs at r.t., except otherwise indicated.
General workup procedure. After stirring for the indicated time at r.t., the reaction mixture was added a spatula of K2CO3(s), diluted with 4 mL of hexane, and was stirred in open air for 1 hr. The mixture was 13 then filtered through a short plug of silica gel and rinsed with 75 mL EA/hexane (3: 2, buffered with 0.5 mol% NEt3). The solvent was removed carefully on rotary evaporation at below 30 °C.
General procedure for product analysis. The residue was then subjected to 1 H NMR analysis (d1 = 10s) by using nitromethane as standard. Product structure was confirmed by chromatography isolation on silica gel (0.5% EA/Hex as eluent, buffered with 0.5% NEt3) and NMR spectra. Ee was determined by HPLC (HPLC condition was described under specific compound). Optical rotation was measured by a Rudolph Autopol I Polarimeter at the sodium D line in chloroform.
The absolute configuration of the product was determined by comparison with relevant literature. [41][42][43][44] Supplementary   reaction was quenched with H2O and then hexanes was added. After extraction, the organic phase was collected, and the aqueous phase was extracted twice with hexanes. Then, the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.

Supplementary Figure 12 Deprotection of methyl enol ether for ketone synthesis
General Deprotection Method IV. 46 An oven-dried 25 ml round bottom flask equipped with a magnetic stir bar, was sealed with a rubber septum and then evacuated and backfilled with nitrogen (3 cycles). The flask was charged with a solution of the cross-hydroalkenylation product (0.1 mmol, 1.0 equiv) in anhydrous THF (2 ml) and then warm to 40 °C. Pd(CH3CN)2Cl2 (2 mol%) was added, stirring was continued for 2 hrs at 40 °C at which time TLC indicated complete consumption of the crosshydroalkenylation product. The reaction was quenched with saturated NH4Cl solution and then hexanes was added. After extraction, the organic phase was collected, and the aqueous phase was extracted twice with hexanes. Then, the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5% EA/hexane) to get the corresponding ketone.