Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds Carolin Fischer and Burkhard Koenig* Review Address: Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, D-93053 Regensburg, Germany Open Access Beilstein J. Org. Chem. 2011, 7, 59–74. doi:10.3762/bjoc.7.10 Email: Burkhard Koenig* - Received: 14 October 2010 Accepted: 14 December 2010 Published: 14 January 2011 * Corresponding author Dedicated to Prof. Henning Hopf on the occasion of his 70th birthday. Keywords: biologically active compounds; boronic acid; copper; N-arylation; palladium Associate Editor: I. Marek © 2011 Fischer and Koenig; licensee Beilstein-Institut. License and terms: see end of document. Abstract N-Arylated aliphatic and aromatic amines are important substituents in many biologically active compounds. In the last few years, transition-metal-mediated N-aryl bond formation has become a standard procedure for the introduction of amines into aromatic systems. While N-arylation of simple aromatic halides by simple amines works with many of the described methods in high yield, the reactions may require detailed optimization if applied to the synthesis of complex molecules with additional functional groups, such as natural products or drugs. We discuss and compare in this review the three main N-arylation methods in their application to the synthesis of biologically active compounds: Palladium-catalysed Buchwald–Hartwig-type reactions, copper-mediated Ullmanntype and Chan–Lam-type N-arylation reactions. The discussed examples show that palladium-catalysed reactions are favoured for large-scale applications and tolerate sterically demanding substituents on the coupling partners better than Chan–Lam reactions. Chan–Lam N-arylations are particularly mild and do not require additional ligands, which facilitates the work-up. However, reaction times can be very long. Ullmann- and Buchwald–Hartwig-type methods have been used in intramolecular reactions, giving access to complex ring structures. All three N-arylation methods have specific advantages and disadvantages that should be considered when selecting the reaction conditions for a desired C–N bond formation in the course of a total synthesis or drug synthesis. Introduction Palladium- and copper-mediated N-arylations are important tools in organic synthesis. Due to the widespread importance of aryl-N bond formation, many synthetic methods have emerged over the years. Besides the traditional Ullmann [1,2] and Goldberg [3-5] procedures, the palladium-catalysed reaction discov- ered by Buchwald [6,7] and Hartwig [8,9] has been a major breakthrough in this field. More recently, Chan [10] and Lam [11,12] introduced the copper-mediated arylation of N-nucleophiles using stoichiometric copper(II) acetate and boronic acids. Collman improved the procedure using catalytic amounts of 59 Beilstein J. Org. Chem. 2011, 7, 59–74. [Cu(OH)TMEDA]2Cl2, omitting the base and working at room temperature [13,14]. Besides palladium and copper, nickel catalysis also allows the arylation of primary and secondary amines [15,16]. However, the three methods (Ullmann–Goldberg, Buchwald–Hartwig and Chan–Lam) have become standard procedures for N-aryl bond formation, and many examples illustrate their wide application in organic synthesis. The chelating phosphines BINAP, DPPF [17] and DtBPF [18], commonly used for the Buchwald–Hartwig amination, were recently displaced by the biaryl-(dialkyl)phosphine or arylphosphinepyrrole ligands [18-20]. Industrial scale-up of these methods has already been applied on the 100 kg scale for arylpiperazines and different diarylamines [21]. In addition, Nolan et al. and Organ et al. have reported Pd-N-heterocyclic carbene (NHC)-catalysed Buchwald–Hartwig amination protocols that provide access to a range of hindered and functionalized aryl amines [22-24]. Aryl bromides are most frequently applied as substrates for the coupling of primary and cyclic secondary amines [17]. In the presence of a weak base such as caesium carbonate, many functional groups are tolerated, while NaOt-Bu has limitations when base-labile functional groups are present. Electron-neutral and electron-poor aryl bromides are suitable substrates [17], and ortho-substituents on the aryl halide are tolerated. In contrast, electron-rich aryl bromides give only poor results. Recently, the modular synthesis of indoles by a palladium-catalysed cascade process provided an efficient entry to substituted indoles [25]. Although copper is less toxic and less expensive than palladium, the required harsh conditions, the limited range of suitable substrates and moderate yields prevented the use of Ullmann-type reaction from reaching its full potential for a long time. Aryl halides activated by electron-withdrawing groups can only be converted at high temperatures (210 °C) using stoichiometric amounts of copper. The discovery of efficient copper/ ligand systems enabled the use of catalytic amounts of metal under milder conditions (90–100 °C) and resulted in good yields [4,26]. Copper-diamine-catalysed N-arylation facilitated the arylation of pyrroles, pyrazoles, indazoles, imidazoles, triazoles, benzimidazoles and indoles [27-29]. Besides aryl halides as the aryl donor, arylsiloxanes [30], arylstannanes [31], iodonium salts [32], aryl lead(IV) triacetates [33] and pentavalent organobismuth reagents [34] have also been used as aryl donors for copper-mediated C–N couplings. Further improvement of N-arylation conditions was achieved by the use of arylboronic acids. The reagents are not sensitive to air; the reaction proceeds at room temperature [35,36] and in aqueous solution [37]. However, the reactions are very slow and require several hours or even days for completion [38]. In general, there are a wide variety of protocols describing the metal-mediated arylation of amines [17,37,39], amides [38], imides [38], imidazoles [14,37,40], benzimidazoles [40,41], sulfonamides [38], pyrroles [42] and lactams [43]. The three typical methods for N-arylation have been extensively reviewed concerning scope and limitation of these reactions [4,44-48]. However, the application of palladium- and copper-mediated N-arylation reactions in the synthesis of complex molecules such as natural products or drugs is, in comparison to standard small-molecule N-arylation, not always straightforward and requires specially optimized conditions. Since amine- and amide-substituted aromatics and heteroaromatics are typical structures in medicinal chemistry and natural product synthesis, a broad application of catalytic C–N-arylation is highly desirable. Evano et al. recently reviewed copper-mediated C–N-arylation reactions in natural product syntheses and discussed different examples from total synthesis using the arylation of alkylamines, amides, carbamates, N-heterocycles, enamines and intramolecular N-arylation reactions [45]. We (...truncated)