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...

Utilizing Mor‐DalPhos/Palladium‐Catalyzed Monoarylation in the Multicomponent One‐Pot Synthesis of Indoles

“…All coupling constants (J) are reported in Hertz (Hz). In some cases fewer than expected independent 13 C NMR resonances were observed despite prolonged acquisition times. Mass spectra were obtained using ion trap (ESI) instruments operating in positive mode, and GC data were obtained on an instrument equipped with a SGE BP-5 column (30 m, 0.25 mm i.d.…”

“…Preparatory thin layer chromatography was carried out using Silicycle (TLG-R1001B-341) glass backed TLC plates (extra hard layer, 60 , 1 mm thickness, indicator F-254). All 1 H NMR (500.1 MHz) and 13 C NMR (125.8 MHz) spectra were recorded at 300 K in CDCl 3 . Chemical shifts are expressed in parts per million (ppm) using the solvent signal CHCl 3 ( 1 H 7.26 ppm, 13 C 71.4 ppm) as an internal reference.…”

“…All 1 H NMR (500.1 MHz) and 13 C NMR (125.8 MHz) spectra were recorded at 300 K in CDCl 3 . Chemical shifts are expressed in parts per million (ppm) using the solvent signal CHCl 3 ( 1 H 7.26 ppm, 13 C 71.4 ppm) as an internal reference. Splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.…”

“…Toluene was deoxygenated by sparging with dinitrogen followed by passage through an mBraun double column solvent purification system packed with alumina and copper-Q5 reactant and storage over activated 4 molecular sieves. Mor-DalPhos [13] and (Mor-DalPhos)Pd(h 1 -cinnamyl)Cl (A) [20] were prepared according to literature procedures; all other reagents, solvents and materials were used as received from commercial sources. Column chromatography was carried out using neutral alumina (150 mesh; Brockmann-III; activated).…”

“…[13][14][15][16][17][18][19][20][21] Encouraged by these observations, we envisioned that these two classes of transformations (Buchwald-Hartwig amination [22][23][24][25][26] and ketone monoa-arylation [27][28][29][30] ) could be combined in the development of a new and synthetically useful one-pot, multicomponent indole synthesis starting from commercially available ortho-dihaloarenes, alkyl ketones, and primary amines; one possible reaction sequence of this type is outlined in Scheme 1. Scheme 1.…”