A palladium-catalyzed carbonylative coupling of (hetero)aryl boronates or boronic acid salts with carbon monoxide and α-bromo-α,α-difluoroamides and bromo-α,α-difluoroesters is described herein. The method is useful for the synthesis of a diverse selection of (hetero)aryl α,α-difluoro-β-ketoamides and α,α-difluoro-β-ketoesters, which are useful building blocks for the generation of functionalized difluoroacylated and difluoroalkyl arenes. The method could be further extended to a one-pot protocol for the formation of difluoroacetophenones.
A palladium-catalyzed carbonylative approach for the direct conversion of (hetero)aryl bromides into their α,α-bis(trifluoromethyl)carbinols is described, and it employs only stoichiometric amounts of carbon monoxide and trifluoromethyltrimethylsilane. In addition, aryl fluorosulfates proved highly compatible with these reaction conditions. The method is tolerant of a diverse set of functional groups, and it is adaptable to late-stage carbon-isotope labeling.
A catalytic
protocol for the preparation of α,α-difluoro-β-alkyl-β-ketoamides
is developed employing a Pd-mediated carbonylative Suzuki coupling
between alkylboron reagents and bromodifluoroacetamides with COgen
as the CO source. The reaction reveals good functional group tolerance
providing a broad selection of α,α-difluoro-β-alkyl-β-ketoamides
in moderate to good yields, which represent useful precursors for
further synthetic manipulation. Finally, the methodology is amenable
to 13C-isotope labeling at the ketone carbon applying 13C-COgen.
We have performed a series of stoichiometric
studies in order to
identify viable steps for a hypothetical catalytic cycle for the palladium-mediated
carbonylative coupling of an aryl bromide with TMSCF3.
Our work revealed that benzoyl Pd(II) complexes bearing Xantphos or tBu3P as the phosphine ligands, which are generated
from the corresponding PdII(Ph)Br complexes exposed to
stoichiometric 13CO from 13COgen, were unable
to undergo transmetalation and reductive elimination to trifluoroacetophenone.
Instead, in the presence of base and additional CO, these organometallic
complexes readily underwent reductive elimination to the acid fluoride.
Attempts to determine whether the acid fluoride could represent an
intermediate for acetophenone production were unrewarding. Only in
the presence of a boronic ester did we observe some formation of the
desired product, although the efficiency of transformation was still
low. Finally, we investigated the reactivity of four phosphine-ligated
PdII(Ph)CF3 complexes (Xantphos, DtBPF, tBu3P, and triphenylphosphine) with
carbon monoxide. With the exception of the tBu3P-ligated complex, all other metal complexes led to the facile
formation of trifluoroacetophenone. We also determined in the case
of triphenylphosphine that CO insertion occurred into the Pd–Ar
bond, as trapping of this complex with n-hexylamine
led to the formation of n-hexylbenzamide.
A palladium‐catalyzed carbonylative coupling of (hetero)aryl boronates or boronic acid salts with carbon monoxide and α‐bromo‐α,α‐difluoroamides and bromo‐α,α‐difluoroesters is described herein. The method is useful for the synthesis of a diverse selection of (hetero)aryl α,α‐difluoro‐β‐ketoamides and α,α‐difluoro‐β‐ketoesters, which are useful building blocks for the generation of functionalized difluoroacylated and difluoroalkyl arenes. The method could be further extended to a one‐pot protocol for the formation of difluoroacetophenones.
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