The
substitution of hydrogen atoms with fluorine in bioactive molecules
can greatly impact physicochemical, pharmacokinetic, and pharmacodynamic
properties. However, current synthetic methods cannot readily access
many fluorinated motifs, which impedes utilization of these groups.
Thus, the development of new methods to introduce fluorinated functional
groups is critical for developing the next generation of biological
probes and therapeutic agents. The synthesis of one such substructure,
the α,α-difluoroalkylthioether, typically requires specialized
conditions that necessitate early-stage installation. A late-stage
and convergent approach to access α,α-difluoroalkylthioethers
could involve nucleophilic addition of thiols across gem-difluorostyrenes. Unfortunately, under basic conditions, nucleophilic
addition to gem-difluorostyrenes generates an anionic
intermediate that can undergo facile elimination of fluoride to generate
α-fluorovinylthioethers. To overcome this decomposition, we
herein exploit an acid-based catalyst system to facilitate simultaneous
nucleophilic addition and protonation of the unstable intermediate.
Ultimately, the optimized mild conditions afford the desired α,α-difluoroalkylthioethers
in high selectivity and moderate to excellent yields. These α,α-difluoroalkylthioethers
are less nucleophilic and more oxidatively stable relative to nonfluorinated
thioethers, suggesting the potential application of this unexplored
functional group in biological probes and therapeutic agents.
A practical and convenient procedure for the nucleophilic aromatic substitution of aryl fluorides and chlorides with dimethylamine was developed using a hydroxide assisted, thermal decomposition of N,N-dimethylforamide. These conditions are tolerant of nitro, nitrile, aldehyde, ketone, and amide groups but will undergo acyl substitution to form amides for methyl esters and acyl chlorides. Isolated yields of the products range from 44 – 98%, with the majority being greater than 70% for seventeen examples.
gem-Difluoroalkenes
represent valuable synthetic
handles for organofluorine chemistry; however, most reactions of this
substructure proceed through reactive intermediates prone to eliminate
a fluorine atom and generate monofluorinated products. Taking advantage
of the distinct reactivity of gem-difluoroalkenes,
we present a cobalt-catalyzed regioselective unsymmetrical dioxygenation
of gem-difluoroalkenes using phenols and molecular
oxygen, which retains both fluorine atoms and provides β-phenoxy-β,β-difluorobenzyl
alcohols. Mechanistic studies suggest that the reaction operates through
a radical chain process initiated by Co(II)/O2/phenol and
quenched by the Co-based catalyst. This mechanism enables the retention
of both fluorine atoms, which contrasts most transition-metal-catalyzed
reactions of gem-difluoroalkenes that typically involve
defluorination.
gem-Difluoroalkenes are readily available fluorinated building blocks, and the fluorine-induced electronic perturbations of the alkenes enables a wide array of selective functionalization reactions. However, many reactions of gem-difluoroalkenes result in a net C–F functionalization to generate monofluorovinyl products or addition of F to generate trifluoromethyl-containing products. In contrast, fluorine-retentive strategies for the functionalization of gem-difluoroalkenes remain less generally developed, and is now becoming a rapidly developing area. This review will present the development of fluorine-retentive strategies including electrophilic, nucleophilic, radical, and transition metal catalytic strategies with an emphasis on key physical organic and mechanistic aspects that enable reactivities.
We report the conversion
of aryl methyl ethers and phenols into
six fluoroalkyl analogues through late-stage functionalization of
a natural product-derived FDA-approved therapeutic. This series of
short synthetic sequences exploits a combination of both modern and
traditional methods and demonstrates that some recently reported methods
do not always work as well as desired on a natural product-like scaffold.
Nonetheless, reaction optimization can deliver sufficient quantities
of each target analogue for medicinal chemistry purposes. In some
cases, classical reactions and synthetic sequences still outcompete
modern organofluorine transformations, which should encourage the
continued search for improved reactions. Overall, the project provides
a valuable synthetic roadmap for medicinal chemists to access a range
of fluorinated therapeutic candidates with distinct physicochemical
properties relative to the original O-based analogue.
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