Efficient Synthesis of 3H-Indoles Enabled by the Lead-Mediated α-Arylation of β-Ketoesters or γ-Lactams Using Aryl Azides

Abstract

The development of a lead-mediated α-arylation reaction between aryl azides and β-ketoesters or γ-lactams that facilitates the formation of 3H-indoles is disclosed. Twenty-five examples are included which demonstrate the generality of this reaction to access aryl azides bearing tetrasubstituted o-alkyl substituents. When paired with a Staudinger reduction, this reaction streamlines the synthesis of functionalized 3H-indoles.

Regioselective Synthesis of 2‐Arylindoles via Palladium‐Catalyzed Cyclization of Phenylglyoxal and 2‐Anilinoacetophenones with Anilines

“…5‐Chloro‐2‐phenyl‐1H‐indole (3c): [2k] Colorless solid; 175.9 mg; yield 80 %. 1 H NMR (300 MHz, CDCl 3 ) δ 8.28 (br, 1H, N‐H), 7.63–7.47 (m, 3H), 7.40–7.35 (m, 2H), 7.32–7.16 (m, 2H), 7.06 (dd, J = 8.6 Hz, J = 2.1 Hz, 1H), 6.68 (d, J = 2.2 Hz, 1H).…”

“…5‐Fluoro‐2‐phenyl‐1H‐indole (4c): [2l] Colorless oil, 173.3 mg; yield 82 %. 1 H NMR (300 MHz, CDCl 3 ) δ 8.22 (br, 1H, N‐H), 7.58–7.54 (m, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 (d, J = 7.3 Hz, 1H), 7.24–7.16 (m, 2H), 6.85 (td, J = 6.85 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H).…”

“…Mixture of isomers, 6‐methyl‐2‐phenyl‐1H‐indole (5c) [2k] and 4‐methyl‐2‐phenyl‐1H‐indole (5c′): [2f] Colorless solid mixture (Ratio: 39:61), 145.6 mg; yield 88 %. 1 H NMR [300 MHz, CDCl 3 ] δ 8.15 (br, 1H, N‐H), 8.01 (br, 1H, N‐H), 7.55–7.48 (m, 3H), 7.42–7.40 (m, 1H), 7.35–7.28 (m, 3H), 7.23–7.19 (m, 2H), 7.12–7.10 (m, 1H), 7.03–7.01 (m, 2H), 6.88–6.82 (m, 2H), 6.75 (s, 1H), 6.67 (s, 1H), 2.49 (s, 3H), 2.36 (s, 3H).…”

“…The indoles are recognized as fundamental structural motifs in numerous natural products and synthetic compounds that display remarkable biological activity Because of their versatile therapeutic properties, numerous approaches have been developed using a wide range of substrates, for example: γ‐lactams,[2a] epoxides,[2b] N ‐alkyl enamines,[2c] nitrovinylarenes,[2d] dibromovinylphenylamines,[2e] and ammonia/alkynylbromoarenes, among others. In particular, 2‐arylindoles exhibit favorable biological activity and pharmaceutical significance.…”

Recent Developments in Inter- and Intramolecular Enolate Arylation

“…33 A series of b-ketoesters were examined to determine the scope of this process, observing, for instance, that the ring size of the b-ketoester could be modified without affecting the yield of the a-arylation reaction, and even, acyclic b-ketoesters could be transformed into the desired product. The effect of the composition of the b-ketoester was tested using indanone, 4-tetrahydropyranone, 4-aminocyclohexanone, and even g-lactam moieties, all of which were arylated to produce the expected aryl azides in good yields.…”