Photochemical phosphorus-enabled scaffold remodeling of carboxylic acids

Abstract

The excitation of carbonyl compounds by light to generate radical intermediates has historically been restricted to ketones and aldehydes; carboxylic acids have been overlooked because of high energy requirements and low quantum efficiency. A successful activation strategy would necessitate a bathochromic shift in the absorbance profile, an increase in triplet diradical lifetime, and ease of further functionalization. We present a single-flask transformation of carboxylic acids to acyl phosphonates that can access synthetically useful triplet diradicals under visible light or near-ultraviolet irradiation. The use of phosphorus circumvents unproductive Norrish type I processes, promoting selectivity that enables hydrogen-atom transfer reactivity. Use of this strategy promotes the efficient scaffold remodeling of carboxylic acids through various annulation, contraction, and expansion manifolds.

Fig. 1.. Carboxylic acid scaffold remodeling concept at visible wavelengths

A) Photoexcitation of ketones and aldehydes. B) The challenges and opportunities for photoexcitation of carboxylic acids. C) The phosphorus-promoter enabled diverse scaffold remodeling of carboxylic acids. D) The α-hydroxyl/amino phosphonates in bioactive molecules.

Fig. 2.. Reaction development*.

A) The scaffold remodeling mechanisms for β/γ-amino acids, α-prolines, and pipecolic acids. B) β-amino acid scaffold remodeling reaction optimization table. *0.10 mmol scale, acyl phosphonate as starting material, yield determined by ¹H NMR using 1,3,5-trimethoxybenzene as internal standard, diastereomeric ratios determined by ¹H NMR analysis of unpurified reaction mixtures, major diastereomer assigned by x-ray crystallography; ^†10.0 mmol scale, yield after recrystallization from toluene and dichloromethane (20:1, v/v); ^‡Carboxylic acids as starting materials. ^§Control experiments: 0.10 mmol, acyl phosphonate 1d as starting material; no irradiation; 2.0 equivalents of TEMPO; under oxygen atmosphere; 10.0 equivalents of water added

Fig. 3.. Substrate scope for β/γ-amino acid annulation via [1,6]/[1,7]-HAT process*.

^. *Reactions were conducted at 0.20 mmol scale, with carboxylic acid as starting material; isolated yields are reported; diastereomeric ratios were determined by ¹H NMR spectroscopic analysis of unpurified reaction mixtures. ^†456 nm LEDs were used. ^‡MeCN was solvent. ^§2a (0.10 mmol), LiHMDS (1.05 equiv.), MeCN (0.1 M), −30 °C, 10 min. ^¶3b (0.10 mmol), K₂CO₃ (3.0 equiv.), MVK (methyl vinyl ketone, 3.0 equiv.), MeCN (0.1 M), 40 °C, 6 h.

Fig. 4.. Substrate scope for cyclo-α-amino acid ring contraction/expansion via [1,5]-HAT process*.

*Reactions were conducted at 0.20 mmol scale, carboxylic acid used as starting material, isolated yields reported, diastereomeric ratios determined by ¹H NMR analysis of unpurified reaction mixtures. ^†0.10 equivalent of diphenyl phosphate was added. ^‡1.0 equivalent of DBU was added when treated with nucleophile. ^§MeCN was solvent.

Fig. 5.. Mechanism study.

A) Photophysical properties. (Left) Ultraviolet-visible spectra: 0.1 mM of S1–3a, S1–3b, S1–3c, and S1–3d in toluene. (middle) Transient absorption data for S1–3d in degassed toluene excited at 414 nm. (right) Femtosecond time-resolved absorption spectra of S1–3a in toluene for 355 nm excitation in the 0.8 ns–300 μs temporal window, S1–3d in toluene for 414 nm excitation in the 0.8 ps–300 μs temporal window. B) Proposed mechanism supported by computational studies. Calculated free Gibbs energies [CPCM(toluene) uB3LYP-D3/def2-svp] are given in kcal/mol.