A Bulky and Electron-Rich N-Heterocyclic Carbene–Palladium Complex (SIPr)^Ph₂Pd(cin)Cl: Highly Efficient and Versatile for the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides with (Hetero)aryl Amines at Room Temperature

Abstract

A bulky and electron-rich N-heterocyclic carbene–palladium complex (SIPr)Ph2 Pd­(cin)Cl was synthesized and characterized. It was found to be highly efficient and versatile for the coupling of different (hetero)­aryl chlorides with various (hetero)­aryl amines at room temperature, especially for the challenging amination of five- or six-membered ring heteroaryl chlorides with five- or six-membered ring heteroaryl amines. It was also successfully applied with high yields to the synthesis of various commercial pharmaceuticals and candidate drugs or compounds with potential pharmacological activities. All of these demonstrate its excellent catalytic efficacy in Buchwald–Hartwig amination and broad application prospects in relevant pharmaceutical preparations. DFT calculations suggest that the steric-induced electronic interaction makes the ligand more electron-donating, and the steric effect effectively regulates the rotation of the iPr-Ph-iPr group in the catalyzed system due to the introduction of the diphenyl skeleton. Considering the electronic effect and the steric effect together, the oxidative addition activation barriers of the (SIPr)Ph2 and (SIPr) ligands are close to each other. Reductive elimination is the rate-determining step of the (SIPr)Ph2 Pd­(cin)­Cl-catalyzed system in the catalytic cycle, and the appropriate steric hindrance of the (SIPr)Ph2 ligand greatly reduces the energy barrier of this step. The perfect combination of the electron-donating and steric hindrance abilities of the ligand significantly improves the catalytic activity.

In Situ Formation of Cationic π-Allylpalladium Precatalysts in Alcoholic Solvents: Application to C–N Bond Formation

“…31 Using this system, we screened a series of simple alcohols (Table 1, entries 1-7). All the primary alcohols (MeOH, EtOH, n-PrOH, and n-BuOH) afforded compound 3a in quantitative yields after 4 h at 50°C, whereas secondary alcohols such as i-PrOH (entry 4) and s-BuOH (entry 6) led to lower yields (29% and 48%, respectively), 26 and in alcoholic solvents (this work) and only 7% yield was obtained with the tertiary alcohol t-BuOH (entry 7).…”

“…[8][9][10][11] According to D. G. Brown and J. Bostro, the Buchwald-Hartwig reaction was used at least once in about 10% of all medicinal chemistry papers published in 2014 and was one of the top-20 most used reactions in the pharmaceutical industry. 11,12 Over the last two decades, considerable efforts have been made to develop more efficient reaction conditions, 6,7,[13][14][15][16][17][18][19][20][21][22][23][24][25][26] notably through the development of several generations of catalysts and ligands. In terms of solvents, the Buchwald-Hartwig crosscoupling reaction classically occurs in hydrocarbon solvents (most frequently toluene) or in cyclic ethers such as THF or 1,4-dioxane.…”

“…Over the last two decades, considerable efforts have been made to develop more efficient reaction conditions, ,,− notably through the development of several generations of catalysts and ligands. In terms of solvents, the Buchwald–Hartwig cross-coupling reaction classically occurs in hydrocarbon solvents (most frequently toluene) or in cyclic ethers such as THF or 1,4-dioxane .…”

C(acyl)–C(sp2) and C(sp2)–C(sp2) Suzuki–Miyaura cross-coupling reactions using nitrile-functionalized NHC palladium complexes

“… 30 Pd–PEPPSI–IPr complexes have also been good alternatives to classical Pd–PEPPSI–NHC complexes in C–C and C–N bond formation reactions. 31 The steric affects of IPr ligands would improve the efficiency of reductive elimination step. NHC ligands are an influencing factor in determining which step in the cycle is rate limiting.…”

A General C–N Cross-Coupling to Synthesize Heteroaryl Amines Using a Palladacyclic N-Heterocyclic Carbene Precatalyst

“…7 Recently, Qiu and co-workers presented an interesting example of Pd-mediated amination of (hetero)aryl chlorides with (hetero)aryl amines at room temperature. 8 In contrast to a previous report based on phosphine-ligated palladacycles, 9 the key to success was the utilization of a bulky, electron-rich NHC-Pd complex possessing diphenyl groups in the imidazol-2-ylidene framework. In this way, the precatalyst exhibited a densely crowded environment around the Pd center, which favored the reductive elimination process.…”