Highly Enantioselective Construction of Trifluoromethylated All-Carbon Quaternary Stereocenters via Nickel-Catalyzed Friedel–Crafts Alkylation Reaction

Abstract

A highly enantioselective Friedel-Crafts alkylation reaction of indoles with β-CF(3)-β-disubstituted nitroalkenes was achieved using a Ni(ClO(4))(2)-bisoxazoline complex as a catalyst, which afforded indole-bearing chiral compounds with trifluoromethylated all-carbon quaternary stereocenters in good yields with excellent enantioselectivities (up to 97% ee). The transformation of one of the products into first a trifluoromethylated tryptamine and then a trifluoromethylated tetrahydro-β-carboline by sequential nitro reduction and Pictet-Spengler cyclization were realized with complete preservation of enantiopurity.

Chiral‐at‐Metal Octahedral Iridium Catalyst for the Asymmetric Construction of an All‐Carbon Quaternary Stereocenter

“…[5] We recently demonstrated the use of chiral-atmetal octahedral complexes for the tailored design of a highly efficient asymmetric noncovalent catalyst that requires low catalyst loading by reporting an inert iridium(III)-based catalyst for the conjugate asymmetric transfer hydrogenation of b,b-disubstituted nitroalkenes. Nevertheless, Hoveyda and co-workers introduced a Cu-catalyzed dialkylzinc conjugate addition, [9] Arai and co-workers reported a Cu-catalyzed addition of indoles to isatin-derived nitroalkenes, [10] Jia and co-workers disclosed a Ni-catalyzed addition of indoles to b-CF 3 -b-disubstituted nitroalkenes, [11] Ricci and co-workers reported a phase-transfer asymmetric organocatalytic conjugate addition of cyanide to b,b-disubstituted nitroalkenes, albeit with only modest enantioselectivities, [12] Melchiorre and co-workers introduced the asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes catalyzed by natural cinchona alkaloids, including one reaction using a b,b-disubstituted nitroalkene, [13] and finally Kastl and Wennemers introduced a proline-peptide-catalyzed asymmetric addition of aldehydes to b,b-disubstituted nitroalkenes under formation of g-nitroaldehydes. In this respect, the asymmetric conjugate addition of carbon nucleophiles to b,b-disubstituted nitroalkenes constitutes a highly attractive reaction as it permits the construction of a stereogenic carbon atom bound to four other carbon substituents (all-carbon quaternary stereocenter).…”

Catalytic Nucleophilic Addition of 3, 5-Dialkyl-4-nitroisoxazoles to Trifluoromethyl Ketones on Water

“…After washing with water and brine, the organic phase was separated and dried over anhydrous MgSO 4 . The solvent was removed under vacuum and the residue was purified with flash chromatography on silica gel, eluting with ethyl acetate/petroleum ether (V∶V＝1 ∶ 20), to afford (E)-3-methyl-4-nitro-5-(3,3,3-trifluoro-2-phenyl-prop-1-en-1-yl)-isoxazole (5), [22] pale yellow solid, 86% yield. Z∶E＝3∶97, m. 131.3, 130.5, 130.0, 128.7, 128.6, 122.3 (q, J C -F ＝ 273.4 Hz), 116.0 (q, J C -F ＝6.4 Hz), 11.4; 19 F NMR (376 MHz, CDCl 3 ) δ: -67.14 (s, 3F); IR (KBr) ν: 2967,2922,1659,1578,1520,1416,1379,1359,1266,1171,1131,962,828,720,696 …”

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

“…Jia et al reported and example of PSR into their report on the enantioselective Friedel-Crafts alkylation of indoles with β-CF3-β-disubstituted nitroalkenes. Actually, (R)-3-(1,1,1-trifluoro3-nitro-2-phenylpropan-2-yl)-1H-indole (96% ee) was reduced and then cyclized with benzaldehyde under TFA catalysis, in 78% yield, but only a 67:33 diastereomeric ratio was achieved although the enantiomeric excess of both isomers reflected that of the starting material [76]. Arai and co-workers set up a four-step synthetic route to fully substituted chiral tetrahydro-β-carbolines [75].…”

“…Actually, (R)-3-(1,1,1-trifluoro3-nitro-2-phenylpropan-2-yl)-1H-indole (96% ee) was reduced and then cyclized with benzaldehyde under TFA catalysis, in 78% yield, but only a 67:33 diastereomeric ratio was achieved although the enantiomeric excess of both isomers reflected that of the starting material [76].…”