A NiH-catalyzed thioether-directed
cyclometalation strategy is
developed to enable remote methylene C–H bond amidation of
unactivated alkenes. Due to the preference for five-membered nickelacycle
formation, the chain-walking isomerization initiated by the NiH insertion
to an alkene can be terminated at the γ-methylene site remote
from the alkene moiety. By employing 2,9-dibutyl-1,10-phenanthroline
(L4) as the ligand and dioxazolones as the reagent, the
amidation occurs at the γ-C(sp3)–H bonds to
afford the amide products in up to 90% yield (>40 examples) with
remarkable
regioselectivity (up to 24:1 rr).
Pd(II)-catalyzed site-selective β-
and γ-C(sp3)–H arylation of primary aldehydes
is developed by rational
design of L,X-type transient directing groups (TDG). External 2-pyridone
ligands are identified to be crucial for the observed reactivity.
By minimizing the loading of acid additives, the ligand effect is
enhanced to achieve high reactivities of the challenging primary aldehyde
substrates. Site selectivity can be switched from the proximate to
the relatively remote position by changing the bite angle of TDG to
match the desired palladacycle size. Experimental and computational
investigations support this rationale for designing TDG to potentially
achieve remote site-selective C(sp3)–H functionalizations.
Pd(II)-catalyzed γ-C(sp 3 )−H (hetero)arylation of aliphatic ketones is developed using α-amino acids as transient directing groups (TDG). A variety of aliphatic ketones were (hetero)arylated at the γ-position via a 5,6-membered fused cyclopalladation intermediate to afford the remotely arylated products in up to 88% yield. The crucial ligand effect of 2pyridone is further enhanced by reducing the loading of acid additives. Consequentially, the improved reactivity of this catalytic system has also made possible the cyclic γ-methylene C(sp 3 )−H arylation of ketones. Mechanistic investigation and comparison to the γ-C−H arylation of aldehydes revealed a structural insight for designing site-selective TDG.
The addition of a nitrogen-based functional group to alkenes via a direct catalytic method is an attractive way of synthesizing value-added amides. The regioselective hydroamidation of unactivated alkenes is considered one of the easiest ways to achieve this goal. Herein, we report the NiH-catalyzed anti-Markovnikov intermolecular hydroamidation of unactivated alkenes enabled by using 2,9-dibutylphenathroline (diBuphen) as the ligand. This protocol provides a platform for the direct synthesis of over 90 structurally diverse N-alkyl amides using dioxazolones, which can be easily derived from abundant carboxylic acid feedstocks. This method succeeds for both terminal and internal unactivated alkenes and some natural products. Mechanistic studies including DFT calculations reveal an initial reversible insertion/elimination of the [NiH] to the alkene, followed by the irreversible amidation to furnish the N-alkyl amides. By crossover experiments and deuterium labeling studies, the observed anti-Markovnikov regioselectivities are suggested to be controlled by the sterical environment of the coupling reaction.
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