7 research outputs found
Synthesis of Bridged Bicyclic Amines by Intramolecular Amination of Remote C-H Bonds: Synergistic Activation by Light and Heat.
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Photomediated ring contraction of saturated heterocycles
Saturated heterocycles are found in numerous therapeutics and bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework. Herein, we describe a visible light-mediated ring contraction of α-acylated saturated heterocycles. This unconventional transformation is orthogonal to traditional ring contractions, challenging the paradigm for diversification of heterocycles including piperidine, morpholine, thiane, tetrahydropyran, and tetrahydroisoquinoline derivatives. The success of this Norrish type II variant rests on reactivity differences between photoreactive ketone groups in specific chemical environments. This strategy was applied to late-stage remodeling of pharmaceutical derivatives, peptides, and sugars
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Synthesis of Bridged Bicyclic Amines by Intramolecular Amination of Remote C-H Bonds: Synergistic Activation by Light and Heat.
The construction of complex aza-cycles is of interest to drug discovery due to the prevalence of nitrogen-containing heterocycles in pharmaceutical agents. Herein we report an intramolecular C-H amination approach to afford value-added and complexity-enriched bridged bicyclic amines. Guided by density functional theory and nuclear magnetic resonance investigations, we determined the unique roles of light and heat activation in the bicyclization mechanism. We applied both light and heat activation in a synergistic fashion, achieving gram-scale bridged aza-cycle synthesis
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Synthesis of Bridged Bicyclic Amines by Intramolecular Amination of Remote C-H Bonds: Synergistic Activation by Light and Heat.
The construction of complex aza-cycles is of interest to drug discovery due to the prevalence of nitrogen-containing heterocycles in pharmaceutical agents. Herein we report an intramolecular C-H amination approach to afford value-added and complexity-enriched bridged bicyclic amines. Guided by density functional theory and nuclear magnetic resonance investigations, we determined the unique roles of light and heat activation in the bicyclization mechanism. We applied both light and heat activation in a synergistic fashion, achieving gram-scale bridged aza-cycle synthesis
Synthesis of Bridged Bicyclic Amines by Intramolecular Amination of Remote CH Bonds: Synergistic Activation by Light and Heat
Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of <i>N</i>–Aryl Azacycle Photomediated Ring Contractions
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