Synthesis of alcohols: streamlined C1 to C n hydroxyalkylation through photoredox catalysis

Abstract

Naturally occurring and readily available α-hydroxy carboxylic acids (AHAs) are utilized as platforms for visible light-mediated oxidative CO₂-extrusion furnishing α-hydroxy radicals proved to be versatile C1 to Cn hydroxyalkylating agents. The direct decarboxylative Giese reaction (DDGR) is operationally simple, not requiring activator or sacrificial oxidants, and enables the synthesis of a diverse range of hydroxylated products, introducing connectivity typically precluded from conventional polar domains. Notably, the methodology has been extended to widely used glycolic acid resulting in a highly efficient and unprecedented C1 hydroxyhomologation tactic. The use of flow technology further facilitates scalability and adds green credentials to this synthetic methodology.

Fig. 1. A) Examples of therapeutic agents containing hydroxyalkyl motifs. Overview of the main approaches for incorporating an α hydroxyalkyl motif in both polar (B) and radical (C) domains. (D) This work unlocks the utilisation of α-hydroxy acids as a synthetic platform for radical hydroxyalkylations.

Fig. 2. Reaction development. (A) Design plan for the direct generation of a ketyl radical from α-hydroxy acids. SET, single-electron transfer. ^aOxidation potentials measured by cyclic voltammetry in a 0.1 M solution of NBu₄PF₆ in MeCN at 25 °C with 100 mV s⁻¹ scan rate and reported vs. SCE. Carboxylates generated in situ through the addition of a solution of NBu₄OH. Here, the potentials at half the peak (E_p/2) are reported. See the ESI for further experimental details. ^bLiterature values vs. SCE. (B) Computational studies on the addition of the ketyl radicals to unsaturated acceptors. ^cValues calculated at the SMD(DMSO)-M06-2X/ma-def2-TZVP//ωB97X-D3/def2-SVP level of theory (298.15 K, 1 M). ^dValues calculated at the SMD(DMSO)-ωB97X-D3/def2-TZVP//ωB97X-D3/def2-SVP level of theory (298.15 K, 1 M).

Fig. 3. Optimization of radical hydroxyalkylation involving ketyl radicals. Yields were determined by proton NMR spectroscopy using dibromomethane as an internal standard. ^aReaction performed using 40 W and a reaction time of 16 hours. ^bReaction performed using 128 W and a reaction time of 16 hours. Abbreviations: Me, methyl; Ph, phenyl; equiv., equivalents; DABCO, 1,4-diazabicyclo[2.2.2]octane; 4CzIPN, 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene; ppy, 2-phenylpyridyl; dtbbpy, 4,4'-di-tert-butyl-2,2'-bipyridyl; DMSO, dimethyl sulfoxide; DMF, N,N′-dimethylformamide; 2-MeTHF, 2-methyltetrahydrofuran; DCM, dichloromethane; M, molarity; h, hours; W, watt.

Scheme 1. Scope for radical hydroxyalkylation from AHAs. ^aReaction performed under optimized reaction conditions: unsaturated acceptor (0.23 mmol, 1 equiv.), α-hydroxy acid (1.3 equiv.), K₃PO₄ (1.3 equiv.), and 4CzIPN (2.5 mol%) in DMSO (0.46 M) as the solvent. The mixture was irradiated with 457 nm light (40 W) for 3 h unless otherwise specified. Isolated yields are reported. ^bOxidation potentials measured by cyclic voltammetry. Refer to the ESI for further details. ^cA reaction time of 16 hours was used instead of 3 hours. ^dReaction performed using a concentration of 0.15 M instead of 0.46 M. ^eReaction performed using 128 W instead of 40 W. Abbreviations: Ph, phenyl; Me, methyl; iPr, isopropyl; Et, ethyl.

Scheme 2. Scope of the radical hydroxymethylation protocol. ^aReaction performed under optimized reaction conditions: unsaturated acceptor (0.23 mmol, 1 equiv.), glycolic acid (1.3 equiv.), K₃PO₄ (1.3 equiv.), and 4CzIPN (2.5 mol%) in DMSO (0.15 M) as the solvent. The mixture was irradiated with 457 nm light (40 W) for 3 h unless otherwise specified. Isolated yields are reported. ^bOxidation potentials measured by cyclic voltammetry. Refer to the ESI for further details. ^cValues calculated at the SMD(DMSO)-M06-2X/ma-def2-TZVP//ωB97X-D3/def2-SVP level of theory (298.15 K, 1 M). ^dA reaction time of 16 hours was used instead of 3 hours. ^eReaction performed using 128 W instead of 40 W. Abbreviations: Me, methyl; Et, ethyl; Bu, butyl; Hex, hexyl; Bn, benzyl; Ph, phenyl; Tf, triflyl.

Scheme 3. Radical hydroxyalkylation in continuous flow. ^aReaction performed under optimized reaction conditions: unsaturated acceptor (0.23 mmol, 1 equiv.), α-hydroxy acid (1.3 equiv.), KOtBu (1.3 equiv.), and 4CzIPN (2.5 mol%) in DMSO (0.46 M) as the solvent. The mixture was irradiated with 457 nm light (128 W) using a residence time of 0.5 hours unless otherwise specified. Isolated yields are reported. ^bThe reaction was performed by premixing the hydroxy acid and the base before adding the photocatalyst (see the ESI for further details). A concentration of 0.08 M was used. ^cReaction performed using 40 W instead of 128 W. ^dA residence time of 3 hours was used.

Fig. 4. A) Radical trapping experiment using 2,6-bis(1,1-dimethylethyl)-4-methylphenol (BHT) or (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). (B) Light on–off cycles. (C) Stern–Volmer quenching studies of the *4CzIPN excited state by using the carboxylate of acid 1a and methyl acrylate.