Palladium-catalyzed synthesis of indoles via ammonia cross-coupling–alkyne cyclization

Abstract

The synthesis of indoles via the metal-catalyzed cross-coupling of ammonia is reported for the first time; the developed protocol also allows for the unprecedented use of methylamine or hydrazine as coupling partners. These Pd/Josiphos-catalyzed reactions proceed under relatively mild conditions for a range of 2-alkynylbromoarenes.

Palladium‐Catalyzed Aromatic Carbon–Nitrogen Bond Formation

“…A particularly useful application of this methodology was presented by Stradiotto et al [79] for the Pd-catalyzed domino C-N coupling/5-endo-dig cyclization to obtain indole derivatives in only one step from alkynylaryl bromides and ammonia (Scheme 13.22) [80].…”

A practical Cu(I)-catalyzed domino approach to 1,2-disubstituted indoles and its application for the assembly of indolophenanthridines

“…[17][18][19] In spite of these remarkable progresses, many of the previous methods require expensive and/or sensitive catalysts (such as Pd and Au salts) or special substrates such as 1-or 2-substituted indoles and o-(gem-dihalovinyl)anilines. The annulation of N-substituted 2-alkynylanilines [20][21][22] and the coupling/cyclization of 2-alkynyl halobenzenes with primary amines [23][24][25] can also generate 1,2-disubstituted indoles. Katz's group utilized the tandem substitution/cyclization to furnish 2-substituted N-arylindoles, but the protocol was limited to the reactions of 2-alkynylfluorobenzenes.…”

CHAPTER 5. Ancillary Ligand Design in the Development of Palladium Catalysts for Challenging Selective Monoarylation Reactions

“…can be conducted in air. It is worthy of mention that this ammonia monoarylation chemistry involving 2-halo(hetero)arylacetylenes does not exhibit the substrate scope limitations encountered when using Pd(cinnamyl)Cl] 2 / L1 ( Figure 5.3), 35 in that 2-chloro(hetero)arylacetylenes and substrates featuring sp 3 substituents at the alkynyl terminus were successfully transformed in the presence of [Pd(cinnamyl)Cl] 2 /L2 catalyst mixtures. 36 Biarylmonophosphine ligands developed by Buchwald and co-workers have played a central role in the advancement of BHA chemistry, 10,14 and their application in the selective monoarylation of ammonia has been examined.…”

“…Encouraged by the seminal work of Vo and Hartwig in applying L1 in palladium-catalyzed ammonia monoarylation, Stradiotto and co-workers demonstrated subsequently that [Pd(cinnamyl)Cl] 2 /L1 precatalyst mixtures could be applied successfully in analogous reactions employing functionalized 2-bromoarylacetylenes, 35 whereby KOtBu-catalyzed hydroamination of the putative 2-aminoarylacetylene intermediates affords NH-indoles by way of a one-pot process ( Figure 5.3). The establishment of this protocol is significant in that it represented the first reported synthesis of the biologically important indole framework directly from ammonia employing metal-catalyzed cross-coupling.…”

“…57 The successful application of [Pd(cinnamyl)Cl] 2 /L1 catalyst mixtures in the BHA of hydrazine with 2-alkynylbromoarenes to afford N-aminoindoles and indazoles was reported by Stradiotto and co-workers ( Figure 5.11). 35 Although in all cases the N-aminoindole product was favored, the formation of appreciable quantities of the analogous indazole serves to limit the synthetic utility of this protocol; efforts to achieve greater selectivity by altering the base or solvent or by including additives (e.g., CuCl 2 or Ag 2 CO 3 ) were unsuccessful. It is interesting that despite the efficacy of palladium catalysts featuring L10 in the selective monoarylation of hydrazine ( Figure 5.9), 57 [Pd(cinnamyl)Cl] 2 /L10 catalyst mixtures performed poorly in comparison with L1-based palladium catalysts in these tandem BHA-hydroamination processes.…”