Room Temperature, Reductive Alkylation of Activated Methylene Compounds: Carbon–Carbon Bond Formation Driven by the Rhodium-Catalyzed Water–Gas Shift Reaction

Abstract

The rhodium-catalyzed water−gas shift reaction has been demonstrated to drive the reductive alkylation of several classes of activated methylene compounds at room temperature. Under catalysis by rhodium trichloride (2−3 mol %), carbon monoxide (10 bar), water (2−50 equiv), and triethylamine (2.5−7 equiv), the scope has been successfully expanded to cover a wide range of alkylating agents, including aliphatic and aromatic aldehydes, as well as cyclic ketones, in moderate to high yields. This method is comparable to, and for certain aspects, surpasses the established reductive alkylation protocols.

Palladium/Rhodium Cooperative Catalysis for the Production of Aryl Aldehydes and Their Deuterated Analogues Using the Water–Gas Shift Reaction

“…TheW GSR-driven reductive alkylation of activated methylene compounds can be performed at room temperature as reported earlier by our group; [16] however, ah igher temperature was required to produce the deuterated product 2d owing to the kinetic isotope effect. Thec onditions for reductive alkylation can be applied to provide amines that are selectively deuterated at the a-position even with electron-rich benzylic amines 3d,w hich are challenging to synthesize with radical-based H/D exchange methods.…”

“…Eliminating the possibility of formate ions and molecular hydrogen acting as hydride shuttles between the two metals led us to propose direct reduction of the palladium aroyl intermediate with ar hodium hydride as the predominant mechanism by which these two metals cooperate to affect the desired transformation ( Figure 3). Thef ormation of ar hodium hydride under basic WGSR conditions has been proposed earlier, [12,15,16] and is believed to proceed through nucleophilic attack of the hydroxide ion on the metal carbonyl to form am etal formate that undergoes b-hydride elimination on the Rh center to form carbon dioxide and ar hodium hydride.I nt he proposed mechanism, TMEDAi s required to neutralize the acidity of the hydrogen iodide byproduct and to maintain the concentration of the hydrox-Scheme 2. Doubly deuteratedp roducts from D-formyla ldehydes using D 2 Oa nd WGSR.…”

“…Thereaction was found to proceed with higher efficiency in polar solvents,f or example,a cetonitrile and dimethyl sulfoxide,than in the less polar ones,that is,1,4-dioxane and toluene (entries [14][15][16][17]. Attempting the reaction in dimethylformamide in the absence of aligand led to adrastic decrease in the yield of 1b (entry 18).…”

Palladium/Rhodium Cooperative Catalysis for the Production of Aryl Aldehydes and Their Deuterated Analogues Using the Water–Gas Shift Reaction

“…The formation of a rhodium hydride under basic WGSR conditions has been proposed earlier, [12,15,16] and is believed to proceed through nucleophilic attack of the hydroxide ion on the metal carbonyl to form a metal formate that undergoes b-hydride elimination on the Rh center to form carbon dioxide and a rhodium hydride. In the proposed mechanism, TMEDA is required to neutralize the acidity of the hydrogen iodide byproduct and to maintain the concentration of the hydrox ide/formate ions throughout the reaction, which explains the need for two equivalents of the dibasic amine to achieve complete conversion.…”

“…The WGSR-driven reductive alkylation of activated methylene compounds can be performed at room temperature as reported earlier by our group; [16] however, a higher temperature was required to produce the deuterated product 2d owing to the kinetic isotope effect. The conditions for reductive alkylation can be applied to provide amines that are selectively deuter ated at the a-position even with electron-rich benzylic amines 3d , which are challenging to synthesize with radical-based H/D exchange methods.…”