Mild and practical: Trifluoromethylation of (hetero)aromatic aldehyde N,N‐dialkylhydrazones was achieved at room temperature by using Togni's trifluoromethylation reagent under CuCl catalysis (see scheme). This simple reaction is believed to occur by a CF3‐radical‐transfer mechanism and yields useful trifluoromethylated building blocks.
This
study describes the development and understanding of a palladium-catalyzed
cross-coupling of fluoroacetamides with boronic acids, under base-free
conditions, to selectively give valuable α,α-difluoroketone
derivatives. Detailed mechanistic studies were conducted to assess
the feasibility of each elementary step, that is, C(acyl)–N
bond oxidative addition, followed by base-free transmetallation and
reductive elimination. These investigations allowed the structural
characterization of palladium(II)fluoroacyl intermediates derived
from C–N bond oxidative addition of an amide electrophile.
They also revealed the high reactivity of these intermediates for
transmetallation with boronic acids without exogenous base. The mechanistic
studies also provided a platform to design a practical catalytic protocol
for the synthesis of a diversity of α,α-difluoroketones,
including CF2H–ketones. Finally, the synthetic potential
of this fluoroacylation methodology is highlighted in sequential,
orthogonal C–Br and C–N bond functionalization of an
α-bromo-α,α-difluoroacetamide with a focus on compounds
of potential biological relevance.
In the late 1980's, a new process based on an intramolecular palladium-mediated cyclisation coupled with a carbon-carbon bond forming reaction appeared in the literature. Since the first report, many novel ring systems have been synthesized using this methodology. The aim of this present review article is to summarise a number of synthetic applications of this new process developed over the last fifteen years.
The Cu-catalyzed direct difluoroalkylation
of aldehyde hydrazones
with functionalized difluoromethyl bromides is described. The reaction
yields stereodefined α,α–difluoro-β-keto
hydrazones under mild conditions and can be carried out at a scale
that opens up the possibility of practical applications.
[reaction: see text] An efficient new method for constructing the 4a-methyltetrahydrofluorene skeleton was achieved via Friedel-Crafts intramolecular cyclization of 1,3-bis-exocyclic dienes. This strategy offers a simple and promising method for accessing complex structures.
Recent advances in electrophilic trifluoromethylation reactions of carbonyl compounds and their usual surrogates are highlighted with particular focus on copper-catalysed (or mediated) C-CF3 bond forming reactions. Ketones and aldehydes (notably via their enol ether and enamine derivatives) enable electrophilic trifluoromethylation at the α-carbon of the carbonyl compounds, whereas aldehyde N,N-disubstituted hydrazones undergo electrophilic attack of the cationic or radical CF3 species at the azomethine carbon, thus providing an umpolung alternative to nucleophilic trifluoromethylation of carbonyl compounds. A reversal in reactivity is also observed for conjugated systems. While α,β-unsaturated ketones regioselectively incorporate the CF3 moiety at the α-position of the enones, trifluoromethylation occurs preferentially at the olefinic β-carbon of the corresponding hydrazones.
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