Visible-light-induced coupling of carboxylic acids with alcohols/amines via a phosphorous linchpin strategy

Abstract

The combination of activated carboxylic acids and alcohols/amines to access esters and amides, respectively, is a cornerstone of organic chemistry and has been well developed over the past century. These dehydrations are extensively used in medicinal chemistry and natural product synthesis due to the prevalence of these functional groups in bioactive molecules. Here, we report a divergent process from the expected ester/amide outcomes through a light-induced coupling of activated carboxylic acids and alcohols/amines to efficiently prepare α-hydroxy/amino ketones or β-ketophosphonates via single-electron chemistry. A phosphorus linchpin strategy allows for the combination of these simple reagents through an intramolecular triplet state radical process, thereby enabling new carbon-carbon bond formation.

Keywords: alcohols/amines; carboxylic acids; posphorous linchpin; α-functionalized carbonyl compounds.

Figure 1.. Approaches to α-hydroxy/amino ketones

A) α-Hydroxy/Amino ketones in bioactive molecules. B) Overview of general routes to α-hydroxy/aminoketones. C) New light-induced phosphorus linchpin-enabled radical coupling reaction.

Figure 2.. Substrate scope of α-hydroxy/amino ketones.

^[a] Conditions: 1 (0.40 mmol, 1.0 equiv), triethyl phosphite (1.05 equiv), CH₂Cl₂ (4.0 mL), 25 oC, 2 h; then DABCO (10 mol %) was added and the reaction was stirred under Blue LEDs (456 nm) for 20 hours. ^[b] Phosphonate as starting material. ^[c] Violet LEDs (390 nm) were used, and the dr was detected by 1H NMR spectroscopy of unpurified reaction mixture. ^[d] Carboxylic acid as starting material. ^[e] Blue LEDs (427 nm) were used. ^[f] Phosphonate as starting material, blue LEDs (465 nm) were used, 40 h; then hydrolysis by AcOH/H₂O (1/9, v/v), 2 h. ^[g] AcCl (1.5 equiv) was added after hydrolysis. See the Supplementary Materials for experimental details.

Figure 3.. Substrate scope of β-ketophosphonates

^[a] Conditions: acyl chloride (0.20 mmol, 1.0 equiv), phosphite (1.05 equiv), CH₂Cl₂ (2.0 mL), Blue LEDs (456 nm) for 20 hours. ^[b] TMSCHN₂ (10.0 equiv) and MeOH (0.5 mL) were added. ^[c] Violet LEDs (390 nm) were used. ^[d] Phosphonate as starting material. ^[e] TMSBr (10.0 equiv) was added. See the Supplementary Materials for experimental details.

Figure 4.. Mechanistic experiments

A) Shift order experiments reveal that secondary and benzyl radical are favored over primary and secondary radical, respectively; tertial radical is favored than secondary radical. B) Crossover experiments indicate the [1,5]-HAT process is an intramolecular process. C) Parallel KIE studies show that the 1,5-HAT process is the rate-determining step of this reaction. D) Proposed mechanism. Condition A: DABCO (10 mol %), CH₂Cl₂ (0.1 M), Blue LEDs (456 nm); Condition B: CDCl₃ (0.1 M), Blue LEDs (456 nm); Condition C: DABCO (10 mol %), CD₂Cl₂ (0.1 M), Blue LEDs (456 nm); See the Supplementary Materials for experimental details.

Figure 5.. DFT calculation

See the Supplementary Materials for experimental details.