Gold‐Catalyzed C‐3‐Alkylation of 7‐Azaindoles Through Michael‐Type Addition to α,β‐Enones

Abstract

The AuIII‐catalyzed reactions of 7‐azaindole derivatives with α,β‐enones are described. Factors that can direct the C‐3‐ versus N‐1‐alkylation reaction on the 7‐azaindole nucleus are explored. The AuIII‐catalyzed reaction of 7‐azaindole with β‐unsubstituted α,β‐enones afforded 1‐substituted7‐azaindoles through an aza‐Michael‐type reaction. Incontrast, 6‐substituted 7‐azaindoles underwent regioselective C‐3‐alkylation through a Na[AuCl4]·2H2O‐catalyzed conjugate addition‐type reaction. Analogously, the Na[AuCl4]·2H2O‐catalyzed reaction of 7‐azaindole derivatives with β‐aryl‐substituted α,β‐enones gave 3‐substituted 7‐azaindoles in moderate‐to‐satisfactory yields. Moreover, the Na[AuCl4]·2H2O‐catalyzed reaction of 1‐substituted 7‐azaindoles with α,β‐enones allowed an easy entry to 1,3‐disubstituted 7‐azaindoles in moderate‐to‐high yields. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Gold Catalysis

“…The concept of the direct auration of electron‐rich arenes was confirmed by Shi and He15 when they investigated the gold(III)‐catalyzed reaction of sulfonated primary alcohols with donor‐substituted benezenes (a related investigation describes the intramolecular reactions of arenes with epoxides) 324. Pyrroles are so nucleophilic that the reactions are difficult to control—a twofold addition often dominates in an unselective reaction; indoles on the other hand give a highly selective mono‐hydroarylation 325–327. The same is true for 7‐azaindoles,327 and benzofurans have also been investigated 307.…”

“…Pyrroles are so nucleophilic that the reactions are difficult to control—a twofold addition often dominates in an unselective reaction; indoles on the other hand give a highly selective mono‐hydroarylation 325–327. The same is true for 7‐azaindoles,327 and benzofurans have also been investigated 307. Kobayashi et al328 discovered that AuCl 3 is the most active catalyst for the aza‐Michael reaction of enones with carbamates.…”

Addition Reactions: Polar Addition

“…In analogy, the Na[AuCl 4 ].2H 2 Ocatalysed reaction of 7-azaindole derivatives with β-aryl-substituted α,β-enones gave 3-substituted 7-azaindoles in moderate to satisfactory yields and the reaction of 1-substituted 7-azaindoles with α,β-enones allowed an easy entry to 1,3-disubstituted 7-azaindoles in moderate to high yields. 165 Simple bis(oxazoline) ligands, especially azabis(oxazolines), can catalyse the addition of indoles to benzylidene malonates in up to 99% ee, provided that excess of the chiral ligand is avoided. 166 The paradigm followed in many asymmetric catalytic ee reactions that an excess of the chiral ligand with respect to the metal should improve enantioselectivity because the background reaction catalysed by a free metal is suppressed, was shown not to be applicable here, 166 which might call for revisiting some of the many copper(II)-bis(oxazoline)-catalysed processes known.…”

“…The first examples of its application involve hydroxyacetophenones (157) as donors in the asymmetric Michael addition to nitroalkene acceptors (158); the best stereocontrol was observed with a zinc-ee magnesium dinuclear complex, where enantiomeric excesses ranged up to 92% for the major anti diastereoisomer (159 The chiral quaternary ammonium bifluoride (162) has been shown to catalyse a de highly diastereo-and enantio-selective conjugate addition of silyl nitronates (160) to nitroalkenes, giving rise to 1,3-dinitro compounds (161) (76-96% ee). 213 ee Direct nucleophilic acylation of nitroalkenes (164), promoted by a combination of de fluoride anion and thiourea catalyst (165), has been developed, using the thiazolium derivative (163) as the umpolung reagent (≤20:1 dr; 74% ee). 214 ee Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of N -heterocycles, such as benztriazole, to nitroalkenes in moderate to high ee enantioselectivities (≤94% ee).…”

Catalysis

“…However selectivity increases if the substrates are indoles, 7-aza-indoles, benzofuranes or benzopyrroles [75][76][77]. …”