Sidearm Effect:  Improvement of the Enantiomeric Excess in the Asymmetric Michael Addition of Indoles to Alkylidene Malonates

Abstract

A pseudo-C3-trisoxazoline was designed and synthesized. The improvement of the traditional bisoxazoline into a novel trisoxazoline by a sidearm approach resulted in highly catalytic enantioselective Michael addition of indoles to alkylidene malonates. Excellent catalytic reactivity and enantioselectivity (up to 99% yield and 93% ee) were achieved.

C-2/C-3 Annulation and C-2 Alkylation of Indoles with 2-Alkoxycyclopropanoate Esters

“…Recent examples of indole functionalization include asymmetric C-3 Friedel-Craft reactions, 1,2,3 allylations, 4,5 radical couplings, 6 arylations, 7,8,9 Michael-additions, 10 C-H activation, 11 and N-arylations. 12 Indoles containing a fused 5-membered ring at the C-2 and C-3 positions are well represented in nature, and include the penitrems 13 and kopsane 14 alkaloids.…”

Enantioselective Intramolecular Aza‐Michael Additions of Indoles Catalyzed by Chiral Phosphoric Acids

“…Therefore, considerable attention has been paid to the asymmetric C3 alkylation of indole. [3] Recently, the enantioselective C2 alkylation of indole was realized through an asymmetric Pictet-Spengler reaction, [4] alkylation of 2-indolyl trifluoroborate salts, [5] and Friedel-Crafts alkylation of 4,7-dihydroindoles.…”

Highly Enantioselective Friedel–Crafts Reaction of Indole with Alkylidenemalonates Catalyzed by Heteroarylidene Malonate‐Derived Bis(oxazoline) Copper(II) Complexes

“…Such a phenomenon was basically in agreement with reports on Tangs tris-A C H T U N G T R E N N U N G (oxazoline) and Reisers aza-BOX that the Cu(II) complexes of oxazoline with an isopropyl substituent usually result in the highest ee values. [5,6] Surprisingly, under the same conditions 1c and 2c with a benzyl group on the oxazoline ring also afforded excellent ee values (98.7 and 99.3%, entries 3 and 7). To the best of our knowledge, this is the first report to find that the Cu(II) complex of an oxazoline ligand bearing a benzyl substituent gives such excellent results in this type of reaction.…”

“…The desired adducts were obtained in excellent yields with up to 93% ee in isobutyl alcohol, while in 1,1,2,2-tetrachloroethane the opposite enantiomer of the product was formed with up to 89% ee. [5] The enantioselectivity of the model reaction of indole with diethyl benzylidenemalonate was further improved to > 99% ee by Reiser et al by using aza-BOX-Cu(II) complexes. The fine control of the ratio of chiral ligand to copper proved to be a critical factor.…”