The Role of the Alcohol and Carboxylic Acid in Directed Ruthenium‐Catalyzed C(sp³)H α‐Alkylation of Cyclic Amines

Abstract

A general directed Ru-catalyzed C(sp(3))-H α-alkylation protocol for piperidines (less-reactive substrates than the corresponding five-membered cyclic amines) has been developed. The use of a hindered alcohol (2,4-dimethyl-3-pentanol) as the solvent and catalyst activator, and a catalytic amount of trans-1,2-cyclohexanedicarboxylic acid is necessary to achieve a high conversion to product. This protocol was used to effectively synthesize a number of 2-hexyl- and 2,6-dihexyl piperidines, as well as the alkaloid (±)-solenopsin A. Kinetic studies have revealed that the carboxylic acid additive has a significant effect on catalyst initiation, catalyst longevity, and reverses the reaction selectivity compared with the acid-free reaction (promotes alkylation versus competing alkene reduction).

Ruthenium-Catalyzed Transfer Hydrogenation for C–C Bond Formation: Hydrohydroxyalkylation and Hydroaminoalkylation via Reactant Redox Pairs

“…[92][93][94] Indeed, with the exception of the present authors work, [95][96][97][98][99] all other late transition metal catalyzed hydroaminoalkylations require pyridyl directing groups in combination with mono-olefin reactants. [100][101][102][103][104][105][106][107][108] In a significant departure from prior art, it was found that ruthenium catalyzed hydrogen transfer from 4-aminobutanol to 1-substituted-1,3-dienes results in the generation of dihydropyrrole-allylruthenium pairs, which combine to form products of hydroaminoalkylation with good to complete control of anti-diastereoselectivity (Scheme 18). 95 As corroborated by deuterium labeling experiments, kinetically preferred hydrometalation of the terminal olefin of the 1-substituted-1,3-diene delivers a 1,1-disubstituted π-allylruthenium complex that isomerizes to the more stable monosubstituted π-allylruthenium complex.…”

Übergangsmetallkatalysierte C‐C‐Kupplungen mit Ethylen im Labormaßstab

“…Die Spaltung nichtaktivierter C sp 3-H-Bindungen stellt wegen ihrer thermodynamischen und kinetischen Inertheit eine große Herausforderung dar. [50] Hierbei sind C sp 3-H-Bindungen mit benachbarten Heteroatomen reaktiver als solche mit benachbarten Kohlenstoffatomen. Vor diesem Hintergrund beschrieben Murai und Mitarbeiter 1997 eine dehydrierende [Rh 4 (CO) 12 ]-katalysierte Dreikomponenten-Acylierungsreaktion, die an einer C-H-Bindung in a-Stellung zu einem Piperazin-Stickstoffatom mit einer dirigierenden Pyridingruppe als Substituent abläuf [Gl.…”

Ruthenium‐Catalyzed α‐(Hetero)Arylation of Saturated Cyclic Amines: Reaction Scope and Mechanism

“…However, when we applied the described alkylation protocol to other alkenes (for example, 1-hexene) and less reactive substrates (for example, piperidine and substituted derivatives thereof), we failed to isolate the anticipated C2-functionalized products in synthetically useful yields. [15] This is due to the chair conformation of the sixmembered piperidine ring being inherently less reactive than the five-membered ring counterpart. [16] Only recently, our group has succeeded in developing novel reaction conditions that allow the efficient ruthenium-catalyzed sp 3 C À H alkylation of piperidines that is not possible under the original conditions of Murai and co-workers.…”

“…[16] Only recently, our group has succeeded in developing novel reaction conditions that allow the efficient ruthenium-catalyzed sp 3 C À H alkylation of piperidines that is not possible under the original conditions of Murai and co-workers. [15] The first direct arylation reaction of saturated cyclic amines through transition-metal-catalyzed sp 3 CÀH activation was disclosed by Sames and co-workers in 2006. [13] The protocol is based upon the direct arylation of aromatic ketones developed by Kakiuchi et al [17] Pyrrolidines were successfully arylated adjacent to the nitrogen atom by using a Ru-catalyzed C À H activation process and employing arylboronic esters as the coupling partners.…”

“…With ethene as the alkene, the substrate scope of the reaction could also be extended to six‐ and seven‐membered cyclic amines. However, when we applied the described alkylation protocol to other alkenes (for example, 1‐hexene) and less reactive substrates (for example, piperidine and substituted derivatives thereof), we failed to isolate the anticipated C2‐functionalized products in synthetically useful yields 15. This is due to the chair conformation of the six‐membered piperidine ring being inherently less reactive than the five‐membered ring counterpart 16.…”