Reaction optimization of the C1-selective reaction. To determine the suitable conditions for C1-selective allylic alkylation of α-CF3 ketone 1, we first studied the reaction of dihydroindenone 1a and MBH ester 2a (1.2 equiv.) in the presence of Pd2dba3 (5 mol%) with a survey of chiral ligand (12 mol%) in THF at room temperature (Table 1). Spiro type ligand (L1) afforded the products in a total of 85% yield, in which the C1-adduct 3a was only 7% with 50% ee (entry 1). When using BINAP (L2) and Phoxphos (L3-L5), low region- and enantioselectivities for 3a were obtained (entries 2-5). The reverse of the absolute configuration was obtained with L6 (entry 6). When switching to mono-dentate binaphthol-derived phosphoramidite L7,37,38 increased ratio of the C1 adduct 3a was observed (entry 7, 35:65). SIPHOS L8 resulted in a good regioselectivity (85:15) and 97% ee (entry 8).
Further optimization with L8 showed that using dichloromethane as the solvent did not improve the reaction yield (entry 9). With toluene, the yield increased to 92% (entry 10). By adding 2 equivalents of Et3N, both reaction yields and selectivities were simultaneously (entry 11). The best results were obtained with DIPEA (entry 12, 96%, 95:5 for 3a, >20:1 d.r., 99% ee). Thus, the optimized conditions were selected for further investigation of the C1-selective AAA reaction.
Substrate scope of C1-alkylation. The reaction scope of C1-alkylation was explored using CF3-ketones 1a and different MBH esters 2 (Table 2). Phenyls bearing both electron-withdrawing and electron-donating groups could be readily added to 1a to fur nish the CF3-ketones in high yields with excellent distereoselectivities and enantioselectivities (3b-3l). Furan, thiophene and naphthyl-derived MBH esters were tolerated (3n & 3o). Various substituted indenones on benzene ring could also afford the corresponding the C1-adducts (3p-3x).
Reaction optimization of the C3-selective reaction. For the optimization of C3-selective adduct, we slightly modified the reaction conditions for substrate 1a and MBH ester 2b (LG = OBoc). With L1 and L4, low ee’s were obtained. For L3 and L7, moderate regioselectivity and distereoselectivity were achieved. L5 gave high regioselectivity (96:4) and 60% ee (entry 6). Switching the leaving to -10 °C and -30 °C further improved the distereoselectivity, affording the C3-selective adduct in 85% ee and 95% ee, respectively.However, the reaction yields decreased significantly (entries 8 & 9).By adding bases such as Na3PO4, K2CO3 and NaOAc, the reaction yields were improved and the enantioselectivities remain high. KOH is found to be detrimental both to the reaction efficiency and distereoselectivity.
Substrate scope of C3-alkylation. The reaction scope of asymmetric allylic alkylation is further extended to a range of MBH esters with L5 to generate C3-selective adducts (Scheme 2). MBH esters 2 with -OAc leaving group and phenyls bearing both electron-withdrawing and electron-donating groups could readily furnish the CF3-ketones in good yields with high d.r. and ee’s (4a-4j). Napthalene-derived MBH esters were also tolerated (4k). Using CF3-substituted tetralones, the corresponding adducts were also formed with equally high distereoselectivity (4l-4o).
Theoretical calculation study. To gain insight into the regioselectivity, DFT calculation was carried out with M06L/6-311++G(2d,p)-SDD-SMD(THF)//B3LYP/6-31G(d)-LANL2DZ-SMD (THF). For the Pd/L5 system,39 calculation suggests an outer-sphere SN2 type attack is 3.6 kcal/mol lower than that for C1 attack, consistent with the experimental regioselectivity (Fig. 2a). Interestingly, the calculated ΔΔG‡ value of the nucleophilic addition TS parallels the calculated ΔΔG‡ of their corresponding π-allyl-Pd precursor (Fig. 2b) with 2.4 kcal/mol energy difference. Thus, the relative stability of the π-allyl-Pd complexes preserved in thesubsequent nucleophilic addition TSs and thus dictates the regioselectivity of the Pd/L5 system. A closer look at Pd-allyl complexes reveals longer C-Pd distances in C1-attack precursor, indicating a looser Pd-allyl binding. This is likely the result of the trans-influence of phosphine on the PHOX ligand as well as the delocalization of positive charges on C1 by the conjugated phenyl group. As shown in Fig. 2c, the back-donation interaction involving d orbital of Pd-center and n-π orbital of allyl moiety favors C3-attack precursor (-5.90 eV vs -5.79 eV on HOMOs).In order to disclose the regio- and stereo-effects of the CF3 group for the AAA reaction, further calculations on the trifluoromethyl and the methyl ester analogue have been performed. The free energy difference between C1 and C3 attack for the -CO2Me substrate is only 1.3 kcal, much smaller than that of CF3 substrate (3.6 kcal). Thus, poor regioselectivity is expected. The bond lengths between Pd center and allyl group in each transition state for CF3 and CO2Me substituted ketones remain no change. For the three centers involved in SN2 type reactions, there are obvious differences between the breaking Pd-C bond length and the forming C-C bond length. This is because trifluoromethyl group is close to a spherical structure compared with the planar structure of methyl ester. Therefore, the repulsion of allylic spherical hindrance and repulsion is greater than that of CO2Me group, which makes the transition state C-C bond longer than that of CO2Me in the reaction intermediate. Meanwhile, in the transition state of C3 attack, it was found that two substituents have obvious differences in the weak interaction between allylic group and ligands. For spherical trifluoromethyl moiety, multiple C-H···F interactions can be observed. This weak interaction can stabilize the transition state of C3 attack and reduce the energy of transition state, which enhances the reaction regioselectivity. While in the unfluorinated system, this effect was not identified (Fig. 3).
The plausible reaction pathways that based on previous reports40-42 and computational studies are illustrated in Fig. 4. The AAA process was initiated by the coordination of Pd-L* complex to the MBH ester followed by oxidative addition to generate Pd-πallyl species. Subsequent nucleophilic addition of α-CF3 enolate to Pd-π allyl species at C1 or C3-position afforded trifluoromethylated ketones depending on the ligand-regulated process. The final decomlexation releases the corresponding product 3/4 and regenerate palladium catalysts. The key selectivity deviation is originated from each catalytic pathway using bidentate or monodentate ligand. For the bidentate Phoxphos L5, complextion of A with MBH ester and oxidative addition generated Pd-π allyl specie B. Because B is stable enough and ligand exchange with L5 is not likely to occur. Hence, nucleophilic addition of CF3-enolate to B from outer-sphere affords C3-selective intermediate D. For the monodentate SIPHOS ligand L8, only one phosphoramidite ligand can coordinate to the metal center of the allylpalladium complexes.43-45 Thus, similar oxidative addition process occurs first. The following decarboxylation of the Boc group releases tBuO‑ and the Pd-tBuO‑ complex F is obtained.46 Here, an equilibrium of ligand exchange between the CF3-enolate and tBuO‑ controls the regioselectivity of the product. Configuration G with less steric hindrance against the Ar group of MBH ester is more favorable than H, which explains the C1 selectivity for SIPHOS L8.