Highly Enantioselective Synthesis of β‐Heteroaryl‐Substituted Dihydrochalcones Through Friedel–Crafts Alkylation of Indoles and Pyrrole

Abstract

A highly enantioselective Friedel-Crafts (F-C) alkylation of indoles and pyrrole with chalcone derivatives catalyzed by a chiral N,N'-dioxide-Sc(OTf)(3) complex has been developed that tolerates a wide range of substrates. The reaction proceeds in moderate to excellent yields and high enantioselectivities (85-92 % enantiomeric excess) using 2 mol % (for indole) or 0.5 mol % (for pyrrole) catalyst loading, which showed the potential value of the catalyst system. Meanwhile, a strong positive nonlinear effect was observed. On the basis of the experimental results and previous reports, a possible working model is proposed to explain the origin of the activation and asymmetric induction.

Palladium-catalyzed oxidative annulation of in situ generated enones to pyrroles: a concise route to functionalized indoles

“…In 2006, Gaunt, et al reported palladiumcatalyzed olefination of simple pyrroles by acrylates through Nprotecting groups differentiating in steric and electronic 55 properties, 14a and later Yao lab achieved palladium-catalyzed solvent-controlled switchable olefination of 3,4-disubstituted pyrroles with electron-deficient olefins 14b (Scheme 1a). Under acid, 15 iodine, 16 or organo-catalysis 17 conditions pyrrole substrates usually underwent Friedel-Crafts alkylation with α,β-60 unsaturated ketones (enones) (Scheme 1b). Intrigued by the advantages of using in-situ generated enones as the olefin sources for carbon-carbon bond formation, [18][19][20][21] we reasonably envisioned the oxidative annulation reactions of β-chloroalkyl ketones to pyrroles.…”

“…A combination of additives 10 tetra-butyl ammonium bromide (TBAB) and pivalic acid (PivOH) enhanced the yield of 3a to 70% (Table 1, entries 7-9). With a lower loading of the oxidant (4 equiv) at a higher temperature (130 C) the target product was also obtained in a decent yield (68%), while varying the temperature around 130 C was 15 detrimental to the reaction efficiency (Table 1, entries 10-13). Various palladium sources and bases were also investigated, and Pd(OAc) 2 and NaOAc were shown to be the most efficient catalyst and base for the desired reaction, respectively (see the Supporting Information).…”

“…In conclusion, palladium-catalyzed oxidative annulation of 3chloropropiophenones and their analogues to N-substituted simple pyrroles has been successfully achieved to synthesize functionalized indoles. The synthetic protocol features 15 construction of a substituted benzene ring onto a pyrrole backbone through the in-situ generated enones. A domino dehydrochlorination/C-H olefination/Diels-Alder cycloaddition/ dehydrogenative aromatization sequence was established as the reaction pathway.…”

“…) N-Substituent 14a and solvent-controlled 14b olefination of pyrroles (b) Friedel-Crafts alkylation of pyrroles with enones[15][16][17] …”

Asymmetric Bromoamination of Chalcones with a Privileged N,N′‐Dioxide/Scandium(III) Catalyst

“…Feng and co-workers addressed the issue of regioselectivity by using the Lewis acid Sc(OTf) 3 as the promoter; 4 molecular sieves significantly accelerated the reaction, and the desired compound was obtained as the major product in 70 % yield. [15] Under the optimized reaction conditions, the reaction of 31 chalcone derivatives having various structures, including fused-ring, multisubstituted, and heteroaryl-substituted chalcones and even rigid enones, proceeded efficiently with a catalyst loading of 0.05 mol %; the corresponding a-bromo-bamino ketone derivatives were obtained in 80-99 % yield with 90-99 % ee and > 99:1 d.r. The Sc(OTf) 3 complex of (S)-pipecolic acid derived N,N'-dioxide L3 (10 mol %) turned out to be the most effective catalyst.…”