Chemistry Reference
In-Depth Information
5.3.3 Summary
The successful development of palladium-catalyzed protocols for the selective
monoarylation of hydrazine represents a significant advance in BHA chemistry,
providing a new route to (hetero)arylhydrazines that can be employed directly
in the construction of sought-after nitrogen heterocycles. Whereas the initial
development of this reactivity involved batch reactions, follow-on studies con-
firmed that palladium-catalyzed hydrazine monoarylation can be conducted
under continuous flow conditions at room temperature, thereby providing a
means of mitigating the potential hazards associated with the use of hydrazine
under BHA conditions. Although a report of a copper-based catalyst system that
is capable of promoting the selective monoarylation of hydrazine has ap-
peared,
60
this chemistry involves the use of hydrazine hydrate as a co-solvent
and is limited to selected aryl bromides and iodides; in this regard, palladium
catalysts exhibit superior reactivity. Several of the ligands that were shown to
perform well in the palladium-catalyzed monoarylation of ammonia also
proved to be effective in hydrazine monoarylation, suggesting that these lig-
ands may have use in the selective monoarylation of other substrates that are
inherently prone to polyarylation, including acetone in a-arylation chemistry.
5.4 Selective Monoarylation of Acetone
Despite significant progress with regard to the establishment of effective
metal-catalyzed protocols for the a-arylation of carbonyl compounds, the
development of catalysts that exhibit high levels of monoarylation selectivity
with sterically unbiased (hetero)aryl electrophiles has proven chal-
lenging.
11,12
As mentioned in Section 5.1.2, the diculties associated with
achieving high levels of monoarylation selectivity in such transformations
can be attributed in part to the fact that the initially formed a-arylation
product possesses a-CH protons that are more acidic than those in the
starting carbonyl compound, resulting in more facile enolate formation; for
most catalysts, this scenario results in low monoarylation selectivity. Al-
though examples of the palladium-catalyzed selective monoarylation of
methyl carbonyl compounds started to appear at the time of the initial
discovery of palladium-catalyzed a-arylation chemistry in 1997,
11,12,61-63
such transformations involving acetone,
19
the structurally simplest ketone,
remained unknown for more than a decade thereafter. As was described in
the preceding sections regarding the successful development of palladium-
catalyzed protocols for the selective monoarylation of ammonia and hydra-
zine, the judicious choice of ancillary ligand proved important in achieving
monoarylation selectivity in the a-arylation of acetone.
5.4.1 Development of Palladium-Catalyzed Acetone
Monoarylation
The diculties associated with accommodating acetone in a-arylation
chemistry have been circumvented in part through the use of stannyl or silyl
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