Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of N-Aryl Azacycle Photomediated Ring Contractions

Abstract

Under mild blue-light irradiation, α-acylated saturated heterocycles undergo a photomediated one-atom ring contraction that extrudes a heteroatom from the cyclic core. However, for nitrogenous heterocycles, this powerful skeletal edit has been limited to substrates bearing electron-withdrawing substituents on nitrogen. Moreover, the mechanism and wavelength-dependent efficiency of this transformation have remained unclear. In this work, we increased the electron richness of nitrogen in saturated azacycles to improve light absorption and strengthen critical intramolecular hydrogen bonding while enabling the direct installation of the photoreactive handle. As a result, a broadly expanded substrate scope, including underexplored electron-rich substrates and previously unsuccessful heterocycles, has now been achieved. The significantly improved yields and diastereoselectivities have facilitated reaction rate, kinetic isotope effect (KIE), and quenching studies, in addition to the determination of quantum yields. Guided by these studies, we propose a revised ET/PT mechanism for the ring contraction, which is additionally corroborated by computational characterization of the lowest-energy excited states of α-acylated substrates through time-dependent DFT. The efficiency of the ring contraction at wavelengths longer than those strongly absorbed by the substrates was investigated through wavelength-dependent rate measurements, which revealed a red shift of the photochemical action plot relative to substrate absorbance. The elucidated mechanistic and photophysical details effectively rationalize empirical observations, including additive effects, that were previously poorly understood. Our findings not only demonstrate enhanced synthetic utility of the photomediated ring contraction and shed light on mechanistic details but may also offer valuable guidance for understanding wavelength-dependent reactivity for related photochemical systems.

Figure 1.

(a) Single-atom skeletal editing vs peripheral editing. (b) An abbreviated summary of previous work on the photomediated ring contractions of saturated heterocycles. *3-cyanoumbelliferone (30 mol %) added. ^†Med. pressure Hg lamp for 24 h. (c) Conceptual outline of this work.

Figure 2.

Synthetic strategies for substrate preparation. (a) Conceptual outline of peripheral to skeletal editing strategy. (b) Conceptual outline of α-functionalization strategies for N-aryl piperidines. (c) Photomediated α-aroylation from Xu and co-workers.

Figure 3.

(a) Ring contraction scope. Reactions were performed on a 0.1 mmol scale. Isolated yields are reported, and relative stereochemistry is shown. Diastereomeric ratios were determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude. *Irradiated with a medium-pressure mercury lamp in a quartz tube for 6 (30) or 7 (29) hours. (b) One-pot aroylation and ring contraction. Reaction performed on a 0.1 mmol scale. NMR yield against Ph₃CH internal standard reported.

Figure 4.

Demonstration of control over diastereoselectivity by the choice of reaction conditions and associated mechanistic probe.

Figure 5.

Molar extinction coefficients for N–Ph and N–SO₂Ph substrates 15 and 55 from 300–450 nm with λ_max values for the $n\to {\pi }^{\ast }$ absorbance band of interest. ε was calculated from five UV–Vis absorption spectra of different concentrations for each substrate.

Figure 6.

Comparison of the H-bonding interaction in Mannich ring-closing transition states for N–SO₂Tol (56) and N–Ph (15) substrates.

Figure 7.

Mechanistic experiments. (a) The reaction order in substrate was obtained using the method of initial rates and determined to be zeroth order. (b) KIE was obtained by parallel measurement of initial rates for separate reactions. (c) No triplet quenching was observed with 1,3-cyclohexadiene (0.05 M). (d) Linear dependence of the reaction rate on the wattage of the light source for the contraction of 15 at standard 50 mM concentration.

Figure 8.

Proposed mechanism depicting both 1,5-HAT and ET/PT pathways.

Figure 9.

Optimized structures for S0 (ground electronic state), S1 (lowest singlet excited state), and T1 (lowest triplet excited state) of 15, with HOMO and LUMO surfaces depicted for S0 and the most significantly contributing NTO hole-particle pairs depicted for the excited states.

Figure 10.

Characterization of wavelength-dependent reactivity. Initial rates of the photomediated ring contraction as a function of wavelength are plotted over the molar extinction spectrum of 15 in the reaction solvent (THF).

Figure 11.

Molar extinction spectra of N–Ph substrate 15, product 16, and their difference (substrate minus product) across wavelengths of interest.