Carbene-Catalyzed Alkylation of Carboxylic Esters via Direct Photoexcitation of Acyl Azolium Intermediates

Abstract

A carbene-catalyzed reductive coupling reaction of carboxylic esters and substituted Hantzsch esters is disclosed. Key steps of this reaction include one-electron reduction of a carbene catalyst-bound acyl azolium intermediate to generate the corresponding radical intermediate for subsequent alkylation reactions. The reaction is promoted by irradiation with visible light without the involvement of transition-metal photocatalysts. Mechanistic studies suggest that direct photoexcitation of the in situ formed acyl azolium intermediate is likely responsible for this light-induced one-electron-reduction process. Photoexcitation converts the acyl azolium intermediate to a single-electron oxidant, enabling single-electron oxidation of Hantzsch esters to generate radical intermediates. Our reactions work well for a broad range of aryl carboxylic ester and Hantzsch ester substrates. Sophisticated structures, including those present in medicines, can be incorporated into ketone molecules using our approach via very mild conditions that tolerate various functional groups.

Aryl radical-mediated N-heterocyclic carbene catalysis

“…Thus, the enolate form of the Breslow intermediate can serve as a single electron donor and an acyl radical equivalent. Since this report, a series of NHC-catalyzed radical cross-coupling reactions have been developed by us and other groups [21][22][23][24][25][26][27][28][29][30][31][32][33] . However, these reported examples have been limited to catalysis mediated by C(sp 3 )-centered radicals.…”

Critical Assessment of the Reducing Ability of Breslow‐type Derivatives and Implications for Carbene‐Catalyzed Radical Reactions**

“…Note that we have not observed any side‐product stemming from the reaction of NaH with the solvent [24] . Importantly, purifications involve aqueous work‐ups, indicating that acyl thiazolium salts are not as sensitive to moisture as previously suggested [8f] . We also applied this procedure to the synthesis of acyl azoliums 7 – 8 + , starting from precursors of C TN [25] and C MIC , [26] respectively.…”

Carbene and Photocatalyst-Catalyzed Decarboxylative Radical Coupling of Carboxylic Acids and Acyl Imidazoles to Form Ketones

“…43 Hong reported that Breslow intermediate can also be oxidized by Katritzky pyridinium salts followed by deaminative cross-coupling to forge ketones. 49 Very recently, studies from Scheidt, [51][52][53] Studer, [54][55][56][57] and our laboratories 58 found that NHC-derived azolium ester intermediates (int. II) can undergo singleelectron-reduction to generate radical intermediates for further couplings to form ketones (Figure 1b, bottom).…”

“…II) can undergo singleelectron-reduction to generate radical intermediates for further couplings to form ketones (Figure 1b, bottom). Scheidt [51][52] and our group 58 used Hantzsch esters as precursors of the other transient radical intermediates to furnish two-component coupling reactions (Figure 1c). Studer reported a tri uoromethyl radical initiated three-component coupling for the synthesis of b-Tri uoromethylated ketones (Figure 1d).…”

“…bring undesired operations and pose limitations on substrate scopes. 70 In addition, despite the seminal work achieved in NHC and photocatalyst cocatalyzed ketone synthesis, [51][52][53][54][55][56][57][58] three-component radical relay coupling that involves various carbon radicals is still limited. 70 Here we disclose a new and operationally simple strategy for coupling of acyl imidazoles and carboxylic acids to form ketones (Figure 1e, right), in which the carboxylic acids were directly used as radical precursors.…”