Background and Originality Content
The remarkable modification ability of α -chiral allylic alcohols has attracted extensive attentions of researchers, and has demonstrated fascinating functionalities in the field of natural product synthesis as well as polymer and material science.[1] As one of the most direct and efficient strategies, asymmetric 1,2-reduction of readily available α,β-unsaturated ketones was adopt by many researchers to synthesize α-chiral allylic alcohols with various chiral catalyst systems, such as Ru,[2]Ir,[3] Cu,[4]etc.[5] However, there were relatively few reports involving fertile metallic nickel. In 2017, Zhu’s group reported the first nickel-catalyzed chemoselective 1,2-reduction of α,β-unsaturated ketones with oxazoline-pyrimidine ligand with central chirality, affording the allylic alcohols with excellent reactivity and enantioselectivity.[6] Until now, there were no other type ligands applied in this catalytic system. Therefore, it is extremely attractive to exploit a novel type of chiral ligands to achieve nickel-catalyzed enantioseletive 1,2-reduction of α,β-unsaturated ketones with high enantioselectivity.
In recent years, planar-chiral ligands have been widely applied as a class of unique and significant ligands in asymmetric catalysis. Planar-chiral ligands mainly include ferrocenes, metal carbonyl- complexes, paracyclophane units, etc.[7] Among them, the skeleton of [2.2]paracyclophane has the advantages of stable properties, rigid structure and large steric hindrance.[8] Considering the characteristics of this skeleton, our group has been committed to design and synthesis of various kinds of [2.2]paracyclophane-derived ligands with planar chirality, such as chiral oxzole-pyridine ligands and tridentate PNO ligands.[9] Inspired by the excellent performance of the [2.2]paracyclophane skeleton, a series of [2.2] paracyclophane-derived oxazole-pyrimidine ligands containing planar chirality (abbreviated as PYMCOX) were designed, synthesized, and successfully applied in nickel-catalyzed asymmetric 1,2-reduction of α,β-unsaturated ketones with up to 99% yield and 99% ee. Furthermore, the reduction could be conducted at gram-scale without loss of activity, and the oxazole-pyrimidine ligand could be also recovered by flash column chromatography.
Scheme 1 Metal-catalyzed asymmetric 1,2-reduction of α,β-unsaturated ketones
Results and Discussion
At the beginning, the paracyclophane-derived chiral N,N -ligands PYMCOX (R p)-L1-10 were synthesized from the known [2,2]paracyclophane-derived chiral aminophenol (R p)-1 through two approaches according to the known similar procedures (see Supporting Information). Method A: 2-cyanopyrimidines 2 under- went the nucleophilic addition with methanol to give the intermediates methyl ester of imino-pyrimidine acid derivatives.[10] Then, the intermediates underwent the condensation reaction with paracyclophane-derived aminophenol (R p)-1 to afford the chiral PYMCOX ligands (R p)-L1-9 . Method B: 2-cyanopyrimidine 2 underwent the hydrolysis to give the carboxylic acid 3 .[11] Then, two step condensation/cyclization reactions between chiral aminophenol (R p)-1 and carboxylic acid 3were conducted to provide the chiral PYMCOX ligand (R p)-L10 .[12]
Scheme 2 The synthesis of chiral PYMCOX ligands
With the chiral PYMCOX ligands in hand, we began our investigation with (E )-4-phenylbut-3-en-2-one (4a ) as model substrate. Ni(COD)2 (2.0 mol %) and PYMCOX L1 (2.4 mol %) were employed in the presence of 1.2 equivalent of pinacolborane (HBpin), 1.5 equivalent of 1,4-diazobicyclo[2.2.2]octane (DABCO) and toluene at -25 °C for 1 hour. To our delight, the chemoselective reduction underwent smoothly to afford the desired allylic alcohol5a (entry 1, 92% yield, 97% ee), and the product of 1,4-reduction was not detected. The other parameters were summarized as follows: (a) Ni precursors such as nickel triflate and nickel acetate were completely inefficient (entries 2, 3). (b) The base is of utmost importance, in which DABCO was optimum. Others like DBU and DIPEA, the target product was obtained with lower yield or enantioselectivity (entries 4, 5). (c) While the reductant HBpin was a competent hydrogen source, both catcholborane (CB) and Ph2SiH2 were ineffective (entries 6, 7). (d) The activity and enantio- selectivity were also affected by the changes in solvents. It was found that the solvents like dichloromethane (DCM), ethyl acetate (EA) and diethyl ether were superior to polar aprotic and protic alternatives (entries 8-11). Encouraged by these results, compared with different chiral ligands ((R p)-L1 to (R p)-L10 ), the oxazole-pyrimidine ligandL2 bearing 4-methylpyrimidine motif povided the highest 99% of yield and 98% of enantioselectivity.
Table 1 Optimization of reaction parameters.a