Amination Reactions of Aryl Halides with Nitrogen-Containing Reagents Mediated by Palladium/Imidazolium Salt Systems

Abstract

Nucleophilic N-heterocyclic carbenes have been conveniently used as catalyst modifiers in amination reactions involving aryl chlorides, aryl bromides, and aryl iodides with various nitrogen-containing substrates. The scope of a coupling process using a Pd(0) or Pd(II) source and an imidazolium salt in the presence of a base, KO(t)Bu or NaOH, was tested using various substrates. The Pd(2)(dba)(3)/IPr.HCl (1, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) system presents the highest activity with respect to electron-neutral and electron-rich aryl chlorides. The ligand is also effective for the synthesis of benzophenone imines, which can be easily converted to the corresponding primary amines by acid hydrolysis. Less reactive indoles were converted to N-aryl-substituted indoles using as supporting ligand the more donating SIPr.HCl (5, SIPr = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene). The Pd(OAc)(2)/SIPr.HCl/NaOH system is efficient for the N-arylation of diverse indoles with aryl bromides. The general protocol developed has been applied successfully to the synthesis of a key intermediate in the synthesis of an important new antibiotic. Mechanistically, palladium-to-ligand ratio studies strongly support an active species bearing one nucleophilic carbene ligand.

Palladium‐Catalyzed CN and CO Coupling–A Practical Guide from an Industrial Vantage Point†

“…[16,64,65] When carbenes are used as ligands, the base also serves as the deprotonating agent for the imdazolium salt precursor, which often requires the use of a strong base. [22,75] LHMDS proved to be especially useful for the coupling of amines with aryl halides containing hydroxy, amide or enolizable keto groups in conjunction with bulky biphenyl-based ligands at least in catalytic amounts.…”

“…So far mainly the simpler cases, for example, coupling with electron neutral anilines proceeded well with the Buchwald ligand system, [15] the TAP ligands [32,33] and with carbenes. [22,88] Cyclic secondary amines as coupling partners could also be utilized by using the same ligand systems, in some cases also the coupling with primary amines is described. [15] Last but not least, pyridyl triflates as starting materials were also described in the literature.…”

“…Carbene ligands showed their potential as low temperature ligands for aryl bromides, aryl chlorides and aryl iodides. [20,22,23] Specifically, halopyridines proved to be good starting materials with carbenes as ligands for the amination reaction. [20] Even broader applicability and generally higher catalytic activity can be attributed to Buchwalds biphenylphosphine family, which allows for room temperature reactions using aryl chlorides, bromides or iodides, but also for the use of nonaflates and triflates.…”

Highly Reactive, General and Long-Lived Catalysts for Palladium-Catalyzed Amination of Heteroaryl and Aryl Chlorides, Bromides, and Iodides: Scope and Structure–Activity Relationships

“…These factors have limited the use of the coupling of amines to produce less expensive intermediates and commodity building blocks. 6,7 (1) Three general classes of reagents react slowly and require high loading of catalyst, even with most of the most recently developed systems: 8 (1) primary alkylamines, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] which form substantial amounts of product from diarylation in the absence of an ortho substituent on the haloarene reagent or an excess of the primary amines; (2) heteroaryl halides, 11,12,15,17,19,[24][25][26][27][28][29][30][31][32] which are important for medicinal chemistry applications, but have reacted more slowly, with narrower scope, and with higher catalyst loadings than aryl halides; and (3) aryl iodides, which react more slowly and provide lower yields than aryl bromides in couplings with amine nucleophiles, 15,17,[33][34][35][36][37][38][39][40][41][42]…”

Mechanistic Aspects of Metal‐Catalyzed C—C and C—X Bond‐Forming Reactions

“…Interestingly, while with isolated [Pd(P(tBu) 3 to be performed at room temperature [66d, 89,[90][91][92]. Remarkably, under these conditions, aryl chlorides coupled in preference to aryl triflates [90].…”