Azido‐Alkynes in Gold(I)‐Catalyzed Indole Syntheses

Abstract

The exploitation of nitrogen-functionalized reactive intermediates plays an important role in the synthesis of biologically relevant scaffolds in the field of pharmaceutical sciences. Those based on gold carbenes carry a strong potential for the design of highly efficient cascade processes toward the synthesis of compounds containing a fused indole core structure. This personal account gives a detailed explanation of our contribution to this sector, and embraces the reaction development of efficient gold-catalyzed cascade processes based on diversely functionalized azido-alkynes. Challenging cyclizations and their subsequent application in the synthesis of pharmaceutically relevant scaffolds and natural products conducted in an intra-or intermolecular fashion are key features of our research.

Steric, Electronic and Conformational Synergistic Effects in the Au(I)-catalyzed alpha-C-H Bond Functionalization of Tertiary Amines

“…We started our investigations by studying the reactivity of ortho-alkynyl phenylazides of type 15 in an attempt to validate our approach (Scheme 2, part A). 10,13,14 In the expected scenario, the -imino Au-carbene 16, intermediately produced from 15 under electrophilic gold catalysis, would react with the C-H bond  to the nitrogen atom to ultimately produce polycyclic indoles 17. The choice of homo-propargylamines as substrates instead of propargylamines was made on the basis of geometrical considerations, presuming that the hypothetic 1,6-hydride transfer would more likely proceed in the presence of a two-carbon linker.…”

Gold(I)-Catalyzed Benzylic C(sp3)-H Functionalizations: Product Bifurcation towards Indole[a]- and [b]-Fused Polycycles

“…31 This concept was further extended by Gagosz and Zhang to cascade cyclizations, 32,33 in which an umpolung reactivity for indole was established for unusual nucleophilic functionalizations at the C3 position. Based upon this reactivity, multiple polycyclic indole syntheses have been reported by the groups of Zhang, 32 Ye, [34][35][36][37][38] Xu, 39 and Hashmi, 40,41 and by our group [42][43][44][45][46][47][48] (Scheme 1A). 49 Although the involvement of C-H functionalization via a 1,5-hydride shift-based internal redox process has been observed for gold complexes with keteniminium, 50 furyl, 51 allenyl, 52,53 alkynyl, [54][55][56][57] vinyl cation, 58 unfunctionalized carbene, 59 and oxo carbene species, 60 these processes are unprecedented among -imino gold carbenes.…”

“…In our ongoing endeavors in reaction development using gold catalysis, [42][43][44][45][46][47][48]65,66 we previously reported the synthesis of acenaphthenes 2, which can be rationalized by a 1,5-hydride shift on a vinyl cationic gold complex A generated from allenynes 1 (Scheme 1B). 65 From this vantage point, we envisioned that a 1,5-hydride shift leading to electrophilic -imino gold carbene functionalization should also be conceivable in gold-catalyzed electrophilic C-H functionalization, leading to fused indoles such as 4 (Scheme 1C), which often exhibit biologically intriguing properties.…”

Gold(I)-Catalyzed Benzylic C(sp3)-H Functionalizations: Product Bifurcation towards Indole[a]- and [b]-Fused Polycycles

“…[31] This concept was further extended by Gagosz and Zhang to cascade cyclizations, [32,33] in which an umpolung reactivity for indole was established for unusual nucleophilic functionalizations at the C3 position. Based upon this reactivity, multiple polycyclic indole syntheses have been reported by the groups of Ye, [34][35][36][37][38] Xu, [39] Hashmi, [40,41] and by our group [42][43][44][45][46][47] (Scheme 1A). [48] Although the involvement of C-H functionalization via a 1,5-hydride shift-based internal redox process has been observed for gold complexes with keteniminium, [49] furyl, [50] allenyl, [51,52] alkynyl, [53][54][55][56] vinyl cation, [57] unfunctionalized carbene, [58] and oxo carbene species, [59] these processes are unprecedented among α-imino gold carbenes.…”

“…[60][61][62] The occurrence of 1,5-migrations onto gold carbene centers remains disproportionately rare compared with the occurrence of 1,2-migrations. [63] In our ongoing endeavors in reaction development using gold catalysis, [42][43][44][45][46][47] we previously reported the synthesis of acenaphthenes 2, which can be rationalized by a 1,5-hydride shift on a vinyl cationic gold complex A generated from allenynes 1 (Scheme 1B). [64,65] From this vantage point, we envisioned that a 1,5-hydride shift leading to electrophilic α-imino gold carbene functionalization should also be conceivable in gold-catalyzed electrophilic C-H functionalization, leading to fused indoles such as 4 (Scheme 1C), which often exhibit biologically intriguing properties.…”