α-Amino acids serve as the fundamental building blocks of peptides and proteins while also functioning as precursors for natural products and catalysts. Synthesizing unnatural amino acids through chemical methods remains an active area of research, with visible-light photocatalysis emerging as an attractive approach due to its mild conditions and practical advantages. Carbon dioxide represents an abundant, inexpensive, and renewable C1 building block, yet its thermodynamic stability and kinetic inertness make it challenging to incorporate into organic molecules. Direct activation of C–H bonds followed by carboxylation with CO2 offers an elegant route to α-amino acids, but homogeneous photocatalytic systems capable of this transformation under visible light have remained elusive.
A team of researchers at Nankai University, led by Professor Baiquan Wang, published in Organic Letters, developed a visible-light-driven method for converting benzylamines directly into substituted arylglycines through C(sp3)–H bond carboxylation with CO2. The optimized system employs 4CzIPN as the organic photocatalyst, diisopropylethylamine as the reductant, and magnesium chloride as an additive in DMSO under atmospheric CO2 pressure. Blue LED irradiation at 410 nm drives the reaction at room temperature, requiring no transition metal catalysts.
Abstract Figure
Systematic optimization revealed that each component plays an essential role. Alternative photocatalysts such as 3DPAFIPN gave reduced yields, while iridium-based catalysts produced only trace product. The choice of reductant proved critical, with DIPEA outperforming triethylamine and cesium carbonate. Magnesium chloride likely functions as a Lewis acid to activate both the substrate and CO2 while stabilizing radical and anionic intermediates. Control experiments confirmed that omitting any single component eliminated product formation. The protecting group on nitrogen also influenced reactivity significantly. N-benzoyl substrates performed well, though switching to a 4-trifluoromethoxybenzoyl group boosted yields to 95% through fine-tuning of electronic effects. The substrate scope proved broad, with para-, meta-, and ortho-substituted benzylamines all delivering products in 66–97% yields. Electron-donating substituents gave slightly higher yields than electron-withdrawing groups. The reaction tolerated valuable functional groups including fluoro, chloro, and pyrazolyl substituents. Fused aromatic systems such as naphthalene and heterocycles including furan also participated effectively. Gram-scale reactions proceeded smoothly in a one-pot, three-step sequence, delivering free α-amino acids in 42–64% yields and demonstrating practical synthetic utility.
Mechanistic studies illuminated the reaction pathway. Adding the radical scavenger BHT suppressed the reaction, and mass spectrometry detected a benzyl radical adduct, confirming radical involvement. Deuterium incorporation experiments under nitrogen atmosphere indicated that a benzyl carbanion intermediate also participates. Kinetic isotope effect measurements of 2.36–2.85 established that C–H bond cleavage occurs during the rate-determining step. Stern–Volmer quenching studies showed that excited 4CzIPN transfers an electron to DIPEA through oxidative quenching. The proposed mechanism involves consecutive photoinduced electron transfer: the reduced photocatalyst and an amine-derived carbon radical perform hydrogen atom transfer from the substrate, generating an α-amino radical that accepts another electron to form a nucleophilic carbanion. This carbanion then attacks CO2 to forge the new carbon-carbon bond. This transition-metal-free approach offers a sustainable route to phenylglycine derivatives under exceptionally mild conditions, expanding the synthetic toolkit for unnatural amino acid preparation.
