Asymmetric Organocatalytic Friedel-Crafts Alkylation-Cyclization Cascade Reaction of Indoles with o-Hydroxyaromatic α,β-Unsaturated Aldehydes

Sung-Hyuk Gwon, Shin-Ae Kim, Sung-Gon Kim
2011 Bulletin of the Korean Chemical Society (Print)  
The indole molecular scaffold is the most widely distributed heterocycle found in nature. 1 In addition, substituted indoles are important in drug discovery because of their presence in numerous biologically active natural products and their high-affinity binding to many receptors. 2 Functionalization of indole rings is therefore an important branch of organic chemistry and various synthetic approaches have been reported. 3 Friedel-Crafts alkylation is one of the most powerful methods for the
more » ... l methods for the construction of substituted indole ring especially when applied to catalytic asymmetric transformations. 4 Nowadays, asymmetric organocatalysis has been new paradigm for the catalytic enantioselective Friedel-Crafts alkylation of indoles. 5 As part of our continuing interest in exploring the organocatalytic reaction using o-hydroxyaromatic α,β-unsaturated aldehydes as an electrophile, 6 we recently discovered that imidazolidinone organocatalysts are efficient for the Friedel-Crafts alkylation of indoles with o-hydroxyaromatic α,βunsaturated aldehydes. During this reaction, the indole reacts through conjugate addition with o-hydroxyaromatic α,βunsaturated aldehyde to give a chiral β-substituted aldehyde, which can be hemiacetalized to a chiral 4-substituted chroman-2-ol (Scheme 1). Here we report our preliminary results from this discovery. The obtained chroman-2-ol can easily be transform to chroman and derivatives that are ubiquitously found in numerous biologically active natural products. Molecules containing chroman scaffolds exhibit a broad range of biological functions, such as antiviral, antitumor, and antimicrobial activities. 7 Their importance has led to many methods being developed for their synthesis. 8 We initially investigated the reaction of N-methylindole (2a) with o-hydroxycinnamaldehyde (3a) in the presence of readily available diphenylprolinol trimethylsilyl ether (1a, 20 mol %) in CH 2 Cl 2 at 0 o C (Table 1) . 9 However, the reaction did not produced corresponding chroman-2-ol 4a, despite the starting material 3a being completely disappeared (entry 1). Next, we examined MacMillan imidazolidinone catalysts, 10 which have been used in many Friedel-Crafts alkylations of α,β-unsaturated aldehydes, in this reaction. Imidazolidinone catalyst 1b with CF 3 CO 2 H additive pro-Scheme 1. Organocatalytic Friedel-Crafts alkylation-cyclization cascade reactions of indoles with o-hydroxyaromatic α,β-unsaturated aldehydes. Table 1. Asymmetric Friedel-Crafts alkylation of N-methylindole (2a) with o-hydroxycinnamaldehyde (3a) by organocatalyst a Entry Catalyst Additive Solvent Time (h) Yield b (%) er c a Unless otherwise specified, the reaction was carried out in solvent (0.3 M) with 1.3 equiv of N-methylindole (2a) relative to the o-hydroxycinnamaldehyde (3a) in the presence of 20 mol % catalyst and additive. b Isolated yield after chromatographic purification. c Determined by HPLC using chiral column AD-H after oxidation. d The desired product was not obtained.
doi:10.5012/bkcs.2011.32.12.4163 fatcat:hghip4nhzrezxov2roy5czjbyu