3 research outputs found
Unprotected Indazoles Are Resilient to Ring-Opening Isomerization: A Case Study on Catalytic C–S Couplings in the Presence of Strong Base
Indazoles represent a privileged
scaffold in medicinal chemistry.
In the presence of strong base, however, N-protected indazoles are
prone to an undesirable ring-opening reaction to liberate <i>o</i>-aminobenzonitriles. By employing unprotected indazoles
with a free N–H bond, isomerization is averted because the
heterocycle is deprotonated in situ. We herein report functional group-tolerant
and robust C–S couplings of bromoindazoles with thiols of varying
electronic nature in the presence of lithium bisÂ(trimethylsilyl)Âamide
at elevated temperatures
Unprotected Indazoles Are Resilient to Ring-Opening Isomerization: A Case Study on Catalytic C–S Couplings in the Presence of Strong Base
Indazoles represent a privileged
scaffold in medicinal chemistry.
In the presence of strong base, however, N-protected indazoles are
prone to an undesirable ring-opening reaction to liberate <i>o</i>-aminobenzonitriles. By employing unprotected indazoles
with a free N–H bond, isomerization is averted because the
heterocycle is deprotonated in situ. We herein report functional group-tolerant
and robust C–S couplings of bromoindazoles with thiols of varying
electronic nature in the presence of lithium bisÂ(trimethylsilyl)Âamide
at elevated temperatures
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