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.
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 Tsuji-Trost allylic substitution reaction provides a useful and efficient approach to construct C-C bonds between sp3-hybridized carbons. The widely accepted paradigm for classifying the mode of attack of nucleophiles on palladium π-allyl intermediates in the Tsuji-Trost reaction is based on the pKa of the pronucleophile: (1) stabilized or “soft” carbon nucleophiles and heteroatom nucleophiles (e.g., pronucleophiles with pKa’s < 25), and (2) unstabilized or “hard” nucleophiles (those from pronucleophiles with pKa’s > 25). One of the keys to the continuing development of allylic substitution processes remains broadening the scope of “soft” nucleophiles. Herein we report a general method for the room temperature Pd-catalyzed allylic substitution with diarylmethane derivatives (pKa’s up to 32). The synthetic significance of the method is that it provides a rapid access to products containing allylated diarylmethyl motifs. The method is general for a wide range of nucleophiles derived from diarylmethanes and heterocyclic derivatives. A procedure for the Pd-catalyzed allylic substitutions to afford diallylation products with quaternary centers is also described. With triarylmethanes and, alkylated diarylmethanes the corresponding allylated products are isolated. We anticipate that the described method will be a valuable complement to the existing arsenal of nucleophiles in Pd-catalyzed allylic substitutions. Mechanistic studies show that the nucleophile derived from diphenylmethane undergoes external attack on π-allyl palladium species under our reaction conditions. This unexpected observation indicates that diarylmethane derivatives behave as “soft” or stabilized nucleophiles. The results of this study indicate that the cutoff between “soft” and “hard” nucleophiles should be raised from a pronucleophile pKa of 25 to at least 32.
Scheme 1. Dual catalyst cycle for the asymmetric benzylic functionalization process.Scheme 2. Tricarbonylchromium-assisted synthesis of achiral and racemic polyarylmethanes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.