A P,N‐Ligand for Palladium‐Catalyzed Ammonia Arylation: Coupling of Deactivated Aryl Chlorides, Chemoselective Arylations, and Room Temperature Reactions

Abstract

Ammonia is an abundant and inexpensive nitrogen source that represents an ideal reagent for amine synthesis. Despite its tremendous potential to provide more direct and economical routes to nitrogen-containing molecules, the use of ammonia in transition-metal-catalyzed reactions has only very recently begun to be realized.[1] The copper-or palladium-catalyzed cross-coupling of aryl halides and amines is a well-established and important method for the synthesis of arylamines in both academic and industrial settings, [2] and recent advances in catalyst design have enabled the use of ammonia as a coupling partner to generate primary arylamines. [3][4][5][6][7] Despite the success of these initial reports, a number of serious limitations regarding the scope and utility of metal-catalyzed cross-couplings of aryl halides and ammonia still exist and must be addressed before this method can be considered a viable alternative to more traditional aniline syntheses. In the case of copper, high loadings of metal and ligand are typically required (10-50 mol %) and less reactive but more economically attractive aryl chlorides, [8] or more readily accessible pseudohalides derived from phenols, are poor reaction partners.[3] Limitations regarding the palladium-catalyzed cross-coupling of ammonia [4][5][6][7] include the coupling of electron-rich, sterically unbiased aryl chlorides as well as the selective coupling of ammonia in the presence of additional amine functionality (chemoselectivity).[9] In addition, currently known systems require catalyst loading of 0.5-5 mol % of palladium as well as elevated temperatures (70-120 8C) to maintain reasonable activity for even simple aryl chloride substrates. The slow rate of oxidative addition of electron-rich aryl chlorides, combined with a lower tendency for such species lacking ortho-substitution to undergo reductive elimination [10] from the requisite [L n Pd(Ar)amido] species, can provide a rationale for the difficulties posed by such reaction partners and the elevated reaction temperatures required for catalyst turnover. Herein, we report the preparation of a suitably designed P,N-ligand that addresses several of the above-described challenges in ammonia cross-coupling, including highly chemoselective transformations and the first report of aryl chloride and aryl tosylate coupling with ammonia at room temperature.Recently, we initiated a research program employing P,Nligands as alternatives to more traditional archetypes in C À N coupling reactions. We envisioned that easily prepared and tunable ligands of this type might provide a useful middle ground in Buchwald-Hartwig aminations between strongly chelating bisphosphanes [2a] and biarylmonophosphanes [2b] that feature only weak secondary metal-ligand interactions.We have found L1 (Me-DalPhos) to be a broadly useful ligand for the palladium-catalyzed cross-coupling of aryl chlorides and amines (including ammonia); however, modestly electron-rich substrates lacking ortho-substitution gave very poor results, requiring harsh re...

Palladium‐Catalyzed Mono‐α‐arylation of Acetone at Room Temperature

“…As such, the identification of alternative catalysts that are capable of promoting such transformations at room temperature would represent an important advance. Indeed, it is worthy of mention that while progress has been made with regardt ot he development of myriad palladium-catalyzed room temperature transformations using relatively inexpensive and abundant (hetero)aryl chloride reaction partners, [15,20] relatede xamples of room temperature ketone mono-a-arylation chemistry are limited to four table entries involving( IPr)Pd-catalyzed transformationso fp ropriophenone (41-75 %). [21] Herein, we report the first examples of acetone mono-a-arylation chemistry conducted at room temperature, which is achieved through use of ap alladium catalysts ystem featuring the JosiPhos [22] ligand variant CyPF-tBu depicted in Figure 1.…”

“…Thesea nd other factors make the use of acetone, the most structurally simple ketone, aformidable challenge for most catalyst systems, [12] despite the fact that the palladium-catalyzed mono-a-arylation of alternative methyl carbonyl compounds was established during the initial development of the field nearlyt wenty years ago. [13] The selective mono-a-arylation of acetone wasf irst reported by our group in 2011, [14] employing a[ Pd(cinnamyl)Cl] 2 /MorDalPhos [15] catalystsystem (X = Cl, Br,I,tosylate, mesylate);aselectiono fo ther palladium catalysts featuring either closely related ortho-phenylene P, N-ligands (X = Cl, Br), [16] or XantPhos (X = imidazolylsulfonate), [17] have subsequently proven capable of promoting such transformations (Figure1). Very recently we demonstratedt hat the mono-a-arylation of acetoneu sing the [Pd(cinnamyl)Cl] 2 /Mor-DalPhosc atalyst systemc an be incorpo- Figure 1.…”

CHAPTER 5. Ancillary Ligand Design in the Development of Palladium Catalysts for Challenging Selective Monoarylation Reactions

“…45 Subsequent ligand optimization gave rise to the Mor-DalPhos ligand (L10), which was shown to be highly effective for the palladium-catalyzed cross-coupling of ammonia with aryl chlorides and tosylates, including those lacking ortho substitution; included in this report are the first examples of room temperature BHA chemistry involving ammonia. 46 Reactions employing [Pd(cinnamyl)Cl] 2 /L10 catalyst mixtures proceeded with high monoarylation selectivity, generally at low catalyst loadings and under mild reaction conditions without the need for high pressures of ammonia ( Figure 5.7). Aryl chlorides bearing electrondonating groups at the para or meta positions that have proven to be particularly challenging in ammonia monoarylation chemistry were effectively cross-coupled, as were substrates containing N, O, F or S heteroatoms.…”

“…46 Reactions of aryl chlorides featuring secondary aryl/alkyl-, diaryl-or dialkylamine addenda each afforded good to excellent isolated yields (64-98%) of the ammonia-derived monoarylation product. Perhaps even more remarkable was the ability of [Pd(cinnamyl)Cl] 2 /L10 to promote selectively the selective monoarylation of ammonia in the presence of aryl chlorides featuring contending primary aryl-or alkylamino substituents.…”

“…45,46 In an initial report, 45 Me-DalPhos (L9) was shown to be effective in BHA chemistry involving a wide range of (hetero)aryl chlorides and NH-containing substrates, including ammonia. However, whereas L9 was observed to afford high conversions and good monoarylation selectivities in the cross-coupling of ammonia with orthosubstituted aryl chlorides, the use of alternative aryl chlorides lacking steric bias resulted in diminished monoarylation selectivity.…”