Although
the past 15 years have witnessed the development of sterically bulky
and electron-rich alkylphosphine ligands for palladium-catalyzed cross-couplings
with aryl chlorides, examples of palladium catalysts based on either triarylphosphine or bidentate phosphine ligands for efficient room temperature cross-coupling
reactions with unactivated aryl chlorides are rare. Herein we report
a palladium catalyst based on NiXantphos, a deprotonatable
chelating aryldiphosphine ligand, to oxidatively add unactivated
aryl chlorides at room temperature. Surprisingly, comparison of an
extensive array of ligands revealed that under the basic reaction
conditions the resultant heterobimetallic Pd–NiXantphos catalyst
system outperformed all the other mono- and bidentate ligands in a
deprotonative cross-coupling process (DCCP) with aryl chlorides. The
DCCP with aryl chlorides affords a variety of triarylmethane products,
a class of compounds with various applications and interesting biological
activity. Additionally, the DCCP exhibits remarkable chemoselectivity
in the presence of aryl chloride substrates bearing heteroaryl groups
and sensitive functional groups that are known to undergo 1,2-addition,
aldol reaction, and O-, N-, enolate-α-,
and C(sp2)–H arylations. The advantages and importance
of the Pd–NiXantphos catalyst system outlined herein make it
a valuable contribution for applications in Pd-catalyzed arylation
reactions with aryl chlorides.
Although metal-catalyzed direct arylation reactions of non- or weakly acidic C-H bonds have recently received much attention, chemists have relied heavily on substrates with appropriately placed directing groups to steer reactivity. To date, examples of intermolecular arylation of unactivated C(sp(3))-H bonds in the absence of a directing group remain scarce. We report herein the first general, high-yielding, and scalable method for palladium-catalyzed C(sp(3))-H arylation of simple diarylmethane derivatives with aryl bromides at room temperature. This method facilitates access to a variety of sterically and electronically diverse hetero- and nonheteroaryl-containing triarylmethanes, a class of compounds with various applications and interesting biological activity. Key to the success of this approach is an in situ metalation of the substrate via C-H deprotonation under catalytic cross-coupling conditions, which is referred to as a deprotonative-cross-coupling process (DCCP). Base and catalyst identification were performed by high-throughput experimentation (HTE) and led to a unique base/catalyst combination [KN(SiMe(3))(2)/Pd-NiXantphos] that proved to efficiently promote the room-temperature DCCP of diarylmethanes. Additionally, the DCCP exhibits remarkable chemoselectivity in the presence of substrates that are known to undergo O-, N-, enolate-, and C(sp(2))-H arylation.
The palladium-catalyzed α-arylation of unactivated sulfoxides has been developed. The weakly acidic α-protons of sulfoxides are reversibly deprotonated by LiOtBu, and a palladium phosphine complex facilitates the arylation. A variety of aryl methyl sulfoxides were coupled with aryl bromides. More challenging coupling partners, such as alkyl methyl sulfoxides (including dimethyl sulfoxide) and aryl chlorides proved to be suitable under the optimized conditions. This method was utilized to synthesize bioactive benzyl sulfoxide intermediates.
Palladium-catalyzed cross-coupling reactions have become one of the most useful tools in modern organic chemistry. Current methods to achieve direct functionalization of sp 3 C-H bonds of arenes and heteroarenes often employ substrates with appropriately placed directing groups to enable reactivity.Examples of intermolecular arylation methods of weakly acidic sp 3 C-H bonds in the absence of directing groups, however, are still limited. We describe herein a study on the use of additives in Pd-catalyzed deprotonative-cross-coupling processes (DCCP) of sp 3 C-H bonds of diarylmethanes with aryl bromides at room temperature. These studies resulted in development of four new efficient Pd-catalyzed DCCP using additives that enabled the generation of a range of sterically and electronically diverse aryl-and heteroaryl containing triarylmethanes in good to excellent yields. Additive identification and optimization of all reaction conditions (additive loading, solvent and temperature) were performed using high-throughput experimentation (HTE). The approach outlined herein is expected to be generalizable to other C-H functionalization reactions involving the deprotonation of weakly acidic C-H bonds.Scheme 1 Palladium-catalyzed sp 3 C-H arylation approaches developed by our group.
The reactivity of a representative set of 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross-coupling reactions was evaluated by high-throughput experimentation protocols. The high-fidelity scaleup of successful reactions in parallel enabled the isolation of sufficient material for biological testing, thus demonstrating the high value of these new solid zinc reagents in a drug-discovery setting and potentially for many other applications in chemistry. Principal component analysis (PCA) clearly defined the independent roles of the zincates and the informers toward druggable-space coverage.
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