Gold-Catalyzed Cyclization of Yndiamides with Isoxazoles via α-Imino Gold Fischer Carbenes

Abstract

Gold catalysis is an important method for alkyne functionalization. Here we report the gold-catalyzed formal [3+2] aminative cyclization of yndiamides and isoxazoles in a direct synthesis of polysubstituted diaminopyrroles, which are important motifs in drug discovery. Key to this process is the formation, and subsequent cyclization, of an α-imino gold Fischer carbene, which represents a new type of gold carbene intermediate. The reaction proceeds rapidly under mild conditions, with high regioselectivity being achieved by introducing a subtle steric bias between the nitrogen substituents on the yndiamide. DFT calculations revealed that the key to this regioselectivity was the interconversion of isomeric gold keteniminiun ions via a low-barrier π-complex transition state, which establishes a Curtin-Hammett scenario for isoxazole addition. By using benzisoxazoles as substrates, the reaction outcome could be switched to a formal [5+2] cyclization, leading to 1,4-oxazepines.

Keywords: carbene; cyclization; gold catalysis; pyrrole; yndiamide.

Scheme 1

a Previous work: gold‐catalyzed oxidative functionalization of yndiamides with pyridine N‐oxides; b This work: Yndiamide activation via α‐imino gold Fischer carbenes; c Polysubstituted pyrroles in medicinal chemistry.

Figure 1

Isoxazole scope for Au(I)‐catalyzed yndiamide cyclization. Unless otherwise stated all reactions were performed on 0.1 mmol scale at room temperature with [1 a]=0.5 M; Yields refer to isolated yields. [a] Reaction treated with HCl (1.0 M in Et₂O, 1.0 eq.) for 30 min after full conversion of 2 a as indicated by TLC. [b] Reaction performed on 1.0 mmol scale and reached completion after 3 h. [c] Reaction performed at 80 °C. [d] Reaction reached completion after 4 h.

Scheme 2

Regioselectivity in the gold‐catalyzed functionalization of unsymmetrical yndiamides with isoxazoles. Reactions were carried out using (ArO)₃PAuNTf₂ (5 mol%) in DCE (0.5 M) with 3 Å M.S. at room temperature for 2 h on 0.1 mmol scale. Yields are isolated yields of both regioisomers; r.r. determined by ¹H NMR spectroscopic analysis of the isolated mixture of regioisomers. The identity of the major regioisomer was assigned by NOESY experiments. [a] Reaction reached completion after 24 h.

Scheme 3

a Proposed catalytic cycle for symmetric yndiamide. PG=Benzenesulfonyl. b Reaction energy profiles of regioselectivity determining steps for unsymmetric yndiamide. PG=Benzenesulfonyl. Relative Gibbs free energies (ΔGsol, in kcal mol‐1) of key intermediates and transition states were computed at CPCM(1,2‐dichloroethane)‐DLPNO‐CCSD(T)/def2‐TZVPP//IEFPCM(1,2‐dichloroethane)‐M06/6‐31+g(d)+SDD(Au) level of theory at 298 K.

Scheme 4

Reactivity of yndiamides with a benzisoxazoles and b anthranil. Standard conditions: (ArO)₃PAuNTf₂ (5 mmol%), DCE (0.5 M), 3 Å M.S., room temperature, 2 h, 0.10 mmol scale; yields refer to isolated yields. c 2,3‐Diaminopyrrole derivatizations.