Investigations into the Kinetic Modeling of the Direct Alkylation of Benzylic Amines: Dissolution of K₂CO₃ Is Responsible for the Observation of an Induction Period

Investigations into the kinetics of a Rh­(I)-catalyzed direct C–H alkylation of benzylic amines with alkenes revealed that K₂CO₃, which is effectively insoluble in the reaction mixture, is only needed in the beginning of the reaction. During the concomitant induction period, K₂CO₃ is proposed to dissolve to a vanishingly small extent and the Rh-precatalyst irreversibly reacts with dissolved K₂CO₃ to form the active catalyst. The duration of this induction period is dependent on the molar loading, the specific surface, the H₂O content of K₂CO₃, and agitation, and these dependences can be rationalized based on a detailed kinetic model

Quaternary Ammonium Salts as Alkylating Reagents in C–H Activation Chemistry

A rhodium­(I)-catalyzed alkylation reaction of benzylic amines via C­(sp³)–H activation using quaternary ammonium salts as alkyl source is described. The reaction proceeds via <i>in situ</i> formation of an olefin via Hofmann elimination, which is the actual alkylating reagent. This represents an operationally simple method for substituting gaseous and liquid olefins with solid quaternary ammonium salts as alkylating reagents, which is transferable to other C–H activation protocols as well

Direct Functionalization of (Un)protected Tetrahydroisoquinoline and Isochroman under Iron and Copper Catalysis: Two Metals, Two Mechanisms

A highly facile, straightforward synthesis of 1-(3-indolyl)-tetrahydroisoquinolines was developed using either simple copper or iron catalysts. N-protected and unprotected tetrahydroisoquinolines (THIQ) could be used as starting materials. Extension of the substrate scope of the pronucleophile from indoles to pyrroles and electron-rich arenes was realized. Additionally, methoxyphenylation is not limited to THIQ but can be carried out on isochroman as well, again employing iron and copper catalysis

Selective Ru(0)-Catalyzed Deuteration of Electron-Rich and Electron-Poor Nitrogen-Containing Heterocycles

A highly selective Ru₃(CO)₁₂-catalyzed deuteration method using <i>t</i>-BuOD as deuterium source is reported. Electron-rich and electron-poor N-heteroarenes such as indoles, azaindoles, deazapurines, benzimidazole, quinolines, isoquinolines, and pyridines were efficiently deuterated at specific positions with high selectivity; in most cases, deuterium incorporation was close to the theoretically possible values. To further increase deuteration degrees, several cycles of the reaction protocol can be carried out which gave superior deuteration degrees employing a much lower excess of deuterating agent compared to established protocols. It was proved that the same protocol can in principle be applied to tritiation reactions important for radioactive labeling of bioactive molecules

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 observed. Arylated imines were observed as byproducts in minor amounts. Additionally, reaction conditions for cleaving the pyridine group were established, enabling access to bis-arylated methylamines

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

Monoselective N‑Methylation of Amides, Indoles, and Related Structures Using Quaternary Ammonium Salts as Solid Methylating Agents

We herein report the use of phenyl trimethylammonium iodide (PhMe3NI) as a safe, nontoxic, and easy-to-handle reagent for an absolutely monoselective N-methylation of amides and related compounds as well as for the N-methylation of indoles. In addition, we expanded the method to N-ethylation using PhEt3NI. The ease of operational setup, high yields of ≤99%, high functional group tolerance, and especially the excellent monoselectivity for amides make this method attractive for late-stage methylation of bioactive compounds

Mechanistic Investigations and Substrate Scope Evaluation of Ruthenium-Catalyzed Direct sp³ Arylation of Benzylic Positions Directed by 3‑Substituted Pyridines

A highly efficient direct arylation process of benzylic amines with arylboronates was developed that employs Ru catalysis. The arylation takes place with greatest efficiency at the benzylic sp³ carbon. If the distance to the activating aryl ring is increased, arylation is still possible but the yield drops significantly. Efficiency of the CH activation was found to be significantly increased by use of 3-substituted pyridines as directing groups, which can be removed after the transformation in high yield. Calculation of the energy profile of different rotamers of the substrate revealed that presence of a substituent in the 3-position favors a conformation with the CH₂ group adopting a position in closer proximity to the directing group and facilitating C–H insertion. This operationally simple reaction can be carried out in argon atmosphere as well as in air and under neutral reaction conditions, displaying a remarkable functional group tolerance. Mechanistic studies were carried out and critically compared to mechanistic reports of related transformations

Mechanistic and Kinetic Studies of the Direct Alkylation of Benzylic Amines: A Formal C(sp³)–H Activation Proceeds Actually via a C(sp²)–H Activation Pathway

Mechanistic investigations of a Rh­(I)-catalyzed direct C–H alkylation of benzylic amines with alkenes, formally an C­(sp³)–H activation, reveal this reaction to proceed via imine intermediates and, hence, via C­(sp²)–H activation. The reaction shows a primary kinetic isotope effect of 4.3 at the benzylic C–H position together with a reversible H–D exchange at the same position, which indicates that there are at least two distinct steps in which the corresponding C–H bonds are broken. The imine intermediates are shown to be converted to the final product under the reaction conditions, and a time course analysis of the alkylated imine intermediate shows that it is formed before the final amine product in the course of the reaction

Continuous Formation of Limonene Carbonates in Supercritical Carbon Dioxide

We present a continuous flow method for the conversion of bioderived limonene oxide and limonene dioxide to limonene carbonates using carbon dioxide in its supercritical state as a reagent and sole solvent. Various ammonium- and imidazolium-based ionic liquids were initially investigated in batch mode. For applying the best-performing and selective catalyst tetrabutylammonium chloride in continuous flow, the ionic liquid was physisorbed on mesoporous silica. In addition to the analysis of surface area and pore size distribution of the best-performing supported ionic liquid phase (SILP) catalysts via nitrogen physisorption, SILPs were characterized by diffuse reflectance infrared Fourier transform spectroscopy and thermogravimetric analysis and served as heterogeneous catalysts in continuous flow. Initially, the continuous flow conversion was optimized in short-term experiments resulting in the desired constant product outputs. Under these conditions, the long-term behavior of the SILP system was studied for a period of 48 h; no leaching of catalyst from the supporting material was observed in the case of limonene oxide and resulted in a yield of 16%. For limonene dioxide, just traces of leached catalysts were detected after reducing the catalyst loading from 30 to 15 wt %, thus enabling a constant product output in 17% yield over time