Access to Indole‐Fused Benzannulated Medium‐Sized Rings through a Gold(I)‐Catalyzed Cascade Cyclization of Azido‐Alkynes

Abstract

Because benzannulated and indole-fused mediumsized rings are found in many bioactive compounds, combining these fragments might lead to unexplored areas of biologically relevant and uncovered chemical space. Herein is shown that α-imino gold carbene chemistry can play an important role in solving the difficulty in the formation of medium-sized rings. Namely, phenylene-tethered azido-alkynes undergo arylative cyclization through the formation of a gold carbene intermediate to afford benzannulated indolefused medium-sized tetracycles. The reactions allow a range of different aryl substitution patterns and efficient access to these otherwise difficult-to-obtain medium-sized rings. This study also demonstrates the feasibility of the semihollowshaped C-dtbm ligand for the construction of a ninemembered ring.

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

“…[12a] These backgrounds inspired us to construct sp 3 -enriched benzannulated mediumsized-fused indoles 71 through α-imino gold(I)-carbene A generated from azido-alkynes 70 (Scheme 19). [28] The requisite azido-alkynes 70 were easily prepared from amines in a straightforward manner. Typically, protected (2aryl)ethylamines 72 were converted to 70 via propargylation, Sonogashira-coupling, and azidation (Scheme 20).…”

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.…”

Gold(I)‐Catalyzed Benzylic C(sp3)−H Functionalizations: Divergent Synthesis of 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 CÀ 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 αimino gold carbene functionalization should also be conceivable in gold-catalyzed electrophilic CÀ H functionalization, leading to fused indoles such as 4 (Scheme 1C), which often exhibit biologically intriguing properties.…”