α,α‐Difluoroketones are valuable compounds and can be used as synthetic intermediates for the synthesis of fluorinated molecules, but they also have a direct application in medicinal chemistry, particularly as inhibitors for hydrolytic enzymes. This Microreview will summarize the major methods currently available for the synthesis of α,α‐difluoroketones, highlighting methods involving direct C–F bond formation, as well as those using pre‐difluorinated building blocks.
In the presence of a rhodium complex containing a newly developed chiral diene ligand, alkenes activated by a range of π-deficient or π-excessive heteroarenes engage in highly enantioselective conjugate additions with various arylboronic acids.
Regioselective α,α-difunctionalization adjacent to a ketone is a significant synthetic challenge. Here, we present a solution to this problem through the transition-metal-free coupling of esters with geminal bis(boron) compounds. This forms an α,α-bis(enolate) equivalent which can be trapped with electrophiles including alkyl halides and fluorinating agents. This presents an efficient, convergent synthetic strategy for the synthesis of unsymmetrical blocked ketones.
The
replacement of oxygenated functionality (hydroxy and alkoxy)
with a fluorine atom is a commonly used bioisosteric replacement in
medicinal chemistry. In this paper, we use molecular matched-pair
analysis to better understand the effects of this replacement on lipophilicity.
It seems that the reduced log P of the oxygenated
compound is normally dominant in determining the size of this difference.
We observe that the presence of additional electron-donating groups
on an aromatic ring generally increases the difference in lipophilicity
between an oxygenated compound and its fluorinated analogue, while
electron-withdrawing groups lead to smaller differences. Ortho-substituted compounds generally display a reduced difference in log P compared to para- and meta-substituted compounds, particularly if an ortho-substituent can form an intramolecular hydrogen bond. Hydrogen-bond
acceptors remote to an aromatic ring containing fluorine/oxygen can
also reduce the difference in log P between oxygen-
and fluorine-substituted compounds.
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