Efficient Palladium-Catalyzed Cross-Coupling of Highly Acidic Substrates, Nitroacetates

Palladium-catalyzed cross-coupling conditions were developed that efficiently afford 2-aryl-2-nitroacetates from aryl bromides and the very acidic nitroacetates

Palladium-Catalyzed C(sp³)–H Arylation of Diarylmethanes at Room Temperature: Synthesis of Triarylmethanes via Deprotonative-Cross-Coupling Processes

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(sp³)–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(sp³)–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(SiMe₃)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(sp²)–H arylation

P₂Et Phosphazene: A Mild, Functional Group Tolerant Base for Soluble, Room Temperature Pd-Catalyzed C–N, C–O, and C–C Cross-Coupling Reactions

The non-nucleophilic organic superbase P₂Et phosphazene can enable a broad range of palladium-catalyzed cross-coupling reactions, including C–C, C–N, and C–O couplings of aryl chlorides, bromides, and iodides at room temperature. The mildness and substrate compatibility of this chemistry can deliver immediate synthetic utility for the preparation of complex molecules

Scope of the Palladium-Catalyzed Aryl Borylation Utilizing Bis-Boronic Acid

The Suzuki-Miyaura reaction has become one of the more useful tools for synthetic organic chemists. Until recently, there did not exist a direct way to make the most important component in the coupling reaction, namely the boronic acid. Current methods to make boronic acids often employ harsh or wasteful reagents to prepare boronic acid derivatives and require additional steps to afford the desired boronic acid. The scope of the previously reported palladium-catalyzed, direct boronic acid synthesis is unveiled, which includes a wide array of synthetically useful aryl electrophiles. It makes use of the newly available second generation Buchwald XPhos preformed palladium catalyst and bis-boronic acid. For ease of isolation and to preserve the often sensitive C–B bond, all boronic acids were readily converted to their more stable trifluoroborate counterparts

Palladium-Catalyzed Allylic Substitution with (η⁶-Arene–CH₂Z)Cr(CO)₃-Based Nucleophiles

Although the palladium-catalyzed Tsuji–Trost allylic substitution reaction has been intensively studied, there is a lack of general methods to employ simple benzylic nucleophiles. Such a method would facilitate access to “α-2-propenyl benzyl” motifs, which are common structural motifs in bioactive compounds and natural products. We report herein the palladium-catalyzed allylation reaction of toluene-derived pronucleophiles activated by tricarbonylchromium. A variety of cyclic and acyclic allylic electrophiles can be employed with in situ generated (η⁶-C₆H₅CHLiR)Cr(CO)₃ nucleophiles. Catalyst identification was performed by high throughput experimentation (HTE) and led to the Xantphos/palladium hit, which proved to be a general catalyst for this class of reactions. In addition to η⁶-toluene complexes, benzyl amine and ether derivatives (η⁶-C₆H₅CH₂Z)Cr(CO)₃ (Z = NR₂, OR) are also viable pronucleophiles, allowing C–C bond-formation α to heteroatoms with excellent yields. Finally, a tandem allylic substitution/demetalation procedure is described that affords the corresponding metal-free allylic substitution products. This method will be a valuable complement to the existing arsenal of nucleophiles with applications in allylic substitution reactions

NiXantphos: A Deprotonatable Ligand for Room-Temperature Palladium-Catalyzed Cross-Couplings of Aryl Chlorides

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 <i>triarylphosphine</i> or <i>bidentate phosphine</i> ligands for efficient <i>room temperature</i> cross-coupling reactions with unactivated aryl chlorides are rare. Herein we report a palladium catalyst based on NiXantphos, a <i>deprotonatable chelating aryldiphosphine</i> 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 <i>O</i>-, <i>N</i>-, 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

Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl‑1<i>H</i>‑benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging S_<i>N</i>Ar reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure–activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1