First selective direct mono-arylation of piperidines using ruthenium-catalyzed C–H activation

ABSTRACT: A Ru-catalyzed mono-arylation in α-position of saturated cyclic amines is reported employing a C–H activation protocol. Substitution of the pyridine directing group with a bulky group, e.g., trifluoromethyl in the 3-position, proved to be crucial to avoid bis-arylation. This highly selective transformation can be performed with different amines and arylboronate esters. Additionally, the directing group can be cleaved, taking advantage of an unprecedented detrifluoromethylation reaction. GRAPHICAL ABSTRACT: [Image: see text

Transition metal-catalyzed C-H bond functionalization of sp3-carbon centers

Zsfassung in dt. SpracheHauptaufgabe der hier vorgelegten Arbeit war die Entwicklung neuer Übergangsmetall katalysierten Arylierungen an sp3 C-H Bindungen cyclischer und acyclischer Verbindungen. Die regioselective Funktionalisierung nicht aktivierter C-H Bindungen kann durch Cyclometallierung erreicht werden. Eine entscheidende Herausforderung ist die Einführung einer geeigneten dirigierenden Gruppe, die anschließend spaltbar ist. Im Rahmen dieser Arbeit wurden verschiedene dirigierende Gruppen sowie unterschiedliche katalytische Methoden für die direkte Arylierung benzylischer Verbindungen untersucht. Pyridin, welches in Position 3 substituiert ist, stellte sich dabei als beste DG heraus. Es wurden drei unterschiedliche Methoden für die direkte Funktionalisierung entdeckt. Die C-H Aktivierung konnte sowohl mit Arylboronsäureestern als auch mit Arylbromiden und Arylchloriden erfolgreich durchgeführt werden. Zum besseren Verständnis wurde eine Reihe an mechanistischen Experimenten durchgeführt. Die generelle Anwendbarkeit dieser DG konnte außerdem anhand der spezifisch einseitigen Arylierung von Piperidinen dargelegt werden.The task of the presented PhD thesis was the development of new transition-metal catalyzed arylation methods for sp3 C-H bonds of cyclic and acyclic amines. The regioselective C-H activation of the unactivated bond can be achieved by cyclometalation. One of the key steps for this transformation was the introduction of a suitable directing group which can be cleaved after the transformation. Different directing groups as well as different catalytic methods for the direct arylation of benzylic amines were investigated. After intensive screenings, 3-substituted pyridines were found to be the best directing groups. Three different protocols could be established for the direct transformation of benzylic amines. The C-H bond functionalization could be performed with arylboronic acid esters, aryl bromides, and aryl chlorides. Furthermore, mechanistic studies were conducted to obtain a better understanding of the transformation. Finally, the general applicability of this directing group was also demonstrated for the selective mono arylation of piperidines.1

Ruthenium(II)-Catalyzed sp³ C–H Bond Arylation of Benzylic Amines Using Aryl Halides

A ruthenium(II)-catalyzed protocol for the direct arylation of benzylic amines was developed. Employing 3-substituted pyridines as directing groups, arylation was achieved using aryl bromides or aryl iodides as the aryl source. Potassium pivalate proved to be an important additive in this transformation. The arylation took place selectively in the benzylic sp3 position, and no significant competitive sp2 arylation was obsd. Arylated imines were obsd. as byproducts in minor amts. Addnl., reaction conditions for cleaving the pyridine group were established, enabling access to bis-arylated methylamines

Palladium(II)-Catalyzed Regioselective Ortho Arylation of sp2 C-H Bonds of N-Aryl-2-amino Pyridine Derivatives

The direct arylation of N-(2-pyridyl) substituted anilines is described. Arylation takes place in ortho position to the amine functionality and is directed by the pyridine N-substituent. Remarkably, N-arylation was never obsd. as a competing process even though conditions also suitable for Buchwald-Hartwig reactions were applied. The scope of the reaction was investigated in terms of aryl donors as well as the electronic nature of the substrate. Good yields were obtained for most examples through an operationally simple procedure, which did not require inert conditions or even glove box techniques. Pd(OAc)2 was applied as a cheap catalyst and boronic acids as readily available aryl donors. To obtain full conversion, 1,4-benzoquinone and a silver salt (e.g., Ag2O) were required as additives and reacted at relatively mild temps. (e.g., 80 °C). Addnl., the pyridine-directing group was cleaved after the reaction to give ortho-arylated aniline derivs

Ruthenium(0)-Catalyzed sp³ C–H Bond Arylation of Benzylic Amines Using Arylboronates

A Ru-catalyzed direct arylation of benzylic sp³ carbons of acyclic amines with arylboronates is reported. This highly regioselective and efficient transformation can be performed with various combinations of <i>N</i>-(2-pyridyl) substituted benzylamines and arylboronates. Substitution of the pyridine directing group in the 3-position proved to be crucial in order to achieve high arylation yields. Furthermore, the pyridine directing group can be removed in high yields via a two-step protocol