Nucleophilic arylation with tetraarylphosphonium salts

Abstract

Organic phosphonium salts have served as important intermediates in synthetic chemistry. But the use of a substituent on the positive phosphorus as a nucleophile to construct C-C bond remains a significant challenge. Here we report an efficient transition-metal-free protocol for the direct nucleophilic arylation of carbonyls and imines with tetraarylphosphonium salts in the presence of caesium carbonate. The aryl nucleophile generated from phosphonium salt shows low basicity and good nucleophilicity, as evidenced by the successful conversion of enolizable aldehydes and ketones. The reaction is not particularly sensitive to water, shows wide substrate scope, and is compatible with a variety of functional groups including cyano and ester groups. Compared with the arylmetallic reagents that are usually moisture sensitive, the phosphonium salts are shelf-stable and can be easily handled.

Figure 1. Design of arylation reaction with phosphonium salt.

An aryl substituent on phosphorus can act as a nucleophile to realize the nucleophilic arylation of carbonyls and imines.

Figure 2. Mechanistic experiments.

(1) The use of Ph₃P/PhI system instead of salt 2a failed to convert aldehyde 1a into product 3aa. (2) Neither radical scavenger TEMPO nor single-electron-transfer inhibitor p-dinitrobenzene can obviously suppress the phenylation reaction. ^aIsolated yields.

Figure 3. Evidence to support the path via alkaline hydrolysis.

(1) Ph₃PO was isolated as a by-product for phenylation reaction. ^aIsolated yield based on 1a; ^bIsolated yield based on 2a; (2) An equilibrium between Cs₂CO₃ and CsOH may be established under the reaction conditions. (3) The presence of H₂¹⁸O led to the formation of Ph₃P¹⁸O. ^cIsolated yield. (4) CsOH can also initiate the phenylation reaction.

Figure 4. Evidence to support the Cs₂CO₃ promoted arylation without water.

The more Cs₂CO₃ was used for the reaction of Ph₄P⁺ I⁻ with Cs₂CO₃ for the same period of time, the more Ph₃PO was produced, ^ayields were determined by ³¹P NMR.

Figure 5. Proposed nucleophilic arylation mechanism.

The reaction should be predominantly initiated by Cs₂CO₃ (path I), and may also be promoted by CsOH due to the trace amount of water present in the reaction system (path II).