3466-80-6

Usage

Chemical Properties

Colorless liquid

Synthesis Reference(s)

Synthetic Communications, 25, p. 3789, 1995 DOI: 10.1080/00397919508011452Chemical and Pharmaceutical Bulletin, 43, p. 1422, 1995 DOI: 10.1248/cpb.43.1422

InChI:InChI=1/C11H15N/c1-2-6-10(7-3-1)11-8-4-5-9-12-11/h1-3,6-7,11-12H,4-5,8-9H2

Upstream product

• 30091-51-1 5-benzoyl-2-phenylpyridine 
• 10413-00-0 5-oxo-5-phenylpentanenitrile 
• 136667-30-6 2-phenyl-pyridine; hydrochloride 
• 505-18-0 2,3,4,5-tetrahydropyridine 
• 109-72-8 n-butyllithium 
• 108-86-1 bromobenzene 
• 71602-40-9 2-phenyl-1-piperidinecarboxaldehyde 
• 122333-71-5 trans-5-phenyl-4-penten-1-amine 
• 3146-87-0 1-hydroxy-2-phenylpiperidine 
• 110-89-4 piperidine 
• 591-51-5 phenyllithium 
• 57050-07-4 2-phenyl-3,4,5,6-tetrahydropyridine 
• 675-20-7 piperidin-2-one 
• 2905-25-1 o-bromobenzenesulfonyl chloride 

Downstream Products

• 98817-10-8 N-(etossimetil)-2-fenilpiperidina 
• 139881-90-6 (E)-α-(2-phenylpiperidin-1-yl)acetophenone oxime 
• 82902-45-2 1-benzoyl-2-phenylpiperidine 
• 111422-83-4 2-Phenyl-piperidine-1-carboxylic acid phenylamide 
• 131248-97-0 2-Phenyl-piperidine-1-carbothioic acid phenylamide 
• 137965-16-3 cis/trans-1,3,4,6,7,11b-Hexahydro-7-phenyl-2H-benzoquinolizin-6-one 
• 139881-95-1 (Z)-O-Benzoyl-1-phenyl-2-(2-phenylpiperidino)-ethanonoxim 
• 118087-36-8 2-Phenyl-1-trimethylsilanylmethyl-piperidine 
• 177948-45-7 1-(tert-butyloxycarbonyl)4-(2-phenylpiperidin-1-yl)piperidine 
• 36939-28-3 N-methyl-2-phenylpiperidine 
• 1179524-58-3 3-(2-Phenyl-piperidine-1-carbonyl)-piperidine-1-carboxylic acid tert.-butyl ester 
• 1086420-42-9 2-(2-phenylpiperidin-1-yl)-1H-benzoimidazole 
• 1224733-20-3 N-(2-iodobenzyl)-2-phenylpiperidine 
• 1227150-02-8 C₁₇H₁₈ClNO₂S 

Relevant academic research and scientific papers

Rapid Synthesis of α-Chiral Piperidines via a Highly Diastereoselective Continuous Flow Protocol

A practical continuous flow protocol has been developed using readily accessible N-(tert-butylsulfinyl)-bromoimine and Grignard reagents, providing various functionalized piperidines (34 examples) in superior results (typically >80% yield and with >90:10 dr) within minutes. The high-performance scale-up is smoothly carried out, and efficient synthesis of the drug precursor further showcases its utility. This flow process offers rapid and scalable access to enantioenriched α-substituted piperidines.

Zinc-Catalyzed Asymmetric Hydrosilylation of Cyclic Imines: Synthesis of Chiral 2-Aryl-Substituted Pyrrolidines as Pharmaceutical Building Blocks

The first successful enantioselective hydrosilylation of cyclic imines promoted by a chiral zinc complex is reported. In situ generated zinc-ProPhenol complex with silane afforded pharmaceutically relevant enantioenriched 2-aryl-substituted pyrrolidines in high yields and with excellent enantioselectivities (up to 99% ee). The synthetic utility of presented methodology is demonstrated in an efficient synthesis of the corresponding chiral cyclic amines, being pharmaceutical drug precursors to the Aticaprant and Larotrectinib. (Figure presented.).

Borane-Catalyzed Reduction of Pyridines via a Hydroboration/Hydrogenation Cascade

We have developed a method for a B(C6F5)3-catalyzed hydroboration/hydrogenation cascade reduction of pyridines. The method was particularly effective for 2,3-disubstituted pyridines, which generated piperidines in high yields with high cis selectivity. Mechanistic studies indicated that the pyridine substrates and the piperidine products sequentially acted as bases in cooperation with B(C6F5)3to split H2. The broad functional group tolerance of the method allowed its use for the synthesis of some biologically active molecules.

Borenium-Catalyzed Reduction of Pyridines through the Combined Action of Hydrogen and Hydrosilane

Mesoionic carbene-stabilized borenium ions efficiently reduce substituted pyridines to piperidines in the presence of a hydrosilane and a hydrogen atmosphere. Control experiments and deuterium labeling studies demonstrate reversible hydrosilylation of the pyridine, enabling full reduction of the N-heterocycle under milder conditions. The silane is a critical reaction component to prevent adduct formation between the piperidine product and the borenium catalyst.

H2 Activation by Non-Transition-Metal Systems: Hydrogenation of Aldimines and Ketimines with LiN(SiMe3)2

In recent years, H2 activation at non-transition-metal centers has met with increasing attention. Here, a system in which H2 is activated and transferred to aldimines and ketimines using substoichiometric amounts of lithium bis(trimethylsilyl)amide is reported. Notably, the reaction tolerates the presence of acidic protons in the α-position. Mechanistic investigations indicated that the reaction proceeds via a lithium hydride intermediate as the actual reductant.

Enantioselective Synthesis of 2-Substituted Pyrrolidines via Intramolecular Reductive Amination

Catalyzed by the complex generated in situ from iridium and the chiral ferrocene ligand, tert -butyl (4-oxo-4-arylbutyl)carbamate substrates were deprotected and then reductively cyclised to form 2-substituted arylpyrrolidines in a one-pot manner, in which the intramolecular reductive amination was the key step. A range of chiral 2-substituted arylpyrrolidines were synthesised in up to 98percent yield and 92percent ee.

α-Functionalization of Cyclic Secondary Amines: Lewis Acid Promoted Addition of Organometallics to Transient Imines

Cyclic imines, generated in situ from their corresponding N-lithiated amines and a ketone hydride acceptor, undergo reactions with a range of organometallic nucleophiles to generate α-functionalized amines in a single operation. Activation of the transient imines by Lewis acids that are compatible with the presence of lithium alkoxides was found to be crucial to accommodate a broad range of nucleophiles including lithium acetylides, Grignard reagents, and aryllithiums with attenuated reactivities.

Hydrogenation of N-Heteroarenes Using Rhodium Precatalysts: Reductive Elimination Leads to Formation of Multimetallic Clusters

A rhodium-catalyzed method for the hydrogenation of N-heteroarenes is described. A diverse array of unsubstituted N-heteroarenes including pyridine, pyrrole, and pyrazine, traditionally challenging substrates for hydrogenation, were successfully hydrogenated using the organometallic precatalysts, [(η5-C5Me5)Rh(N-C)H] (N-C = 2-phenylpyridinyl (ppy) or benzo[h]quinolinyl (bq)). In addition, the hydrogenation of polyaromatic N-heteroarenes exhibited uncommon chemoselectivity. Studies into catalyst activation revealed that photochemical or thermal activation of [(η5-C5Me5)Rh(bq)H] induced C(sp2)-H reductive elimination and generated the bimetallic complex, [(η5-C5Me5)Rh(μ2,η2-bq)Rh(η5-C5Me5)H]. In the presence of H2, both of the [(η5-C5Me5)Rh(N-C)H] precursors and [(η5-C5Me5)Rh(μ2,η2-bq)Rh(η5-C5Me5)H] converted to a pentametallic rhodium hydride cluster, [(η5-C5Me5)4Rh5H7], the structure of which was established by NMR spectroscopy, X-ray diffraction, and neutron diffraction. Kinetic studies on pyridine hydrogenation were conducted with each of the isolated rhodium complexes to identify catalytically relevant species. The data are most consistent with hydrogenation catalysis prompted by an unobserved multimetallic cluster with formation of [(η5-C5Me5)4Rh5H7] serving as a deactivation pathway.

Direct α-C-H bond functionalization of unprotected cyclic amines

Cyclic amines are ubiquitous core structures of bioactive natural products and pharmaceutical drugs. Although the site-selective abstraction of C-H bonds is an attractive strategy for preparing valuable functionalized amines from their readily available parent heterocycles, this approach has largely been limited to substrates that require protection of the amine nitrogen atom. In addition, most methods rely on transition metals and are incompatible with the presence of amine N-H bonds. Here we introduce a protecting-group-free approach for the α-functionalization of cyclic secondary amines. An operationally simple one-pot procedure generates products via a process that involves intermolecular hydride transfer to generate an imine intermediate that is subsequently captured by a nucleophile, such as an alkyl or aryl lithium compound. Reactions are regioselective and stereospecific and enable the rapid preparation of bioactive amines, as exemplified by the facile synthesis of anabasine and (-)-solenopsin A.

Chemoenzymatic Synthesis of Substituted Azepanes by Sequential Biocatalytic Reduction and Organolithium-Mediated Rearrangement

Enantioenriched 2-aryl azepanes and 2-arylbenzazepines were generated biocatalytically by asymmetric reductive amination using imine reductases or by deracemization using monoamine oxidases. The amines were converted to the corresponding N′-aryl ureas, which rearranged on treatment with base with stereospecific transfer of the aryl substituent to the 2-position of the heterocycle via a configurationally stable benzyllithium intermediate. The products are previously inaccessible enantioenriched 2,2-disubstituted azepanes and benzazepines.