22232-64-0Relevant articles and documents
Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-Disubstituted 2-Piperidinones
Chamorro-Arenas, Delfino,Nolasco-Hernández, Alejandro A.,Fuentes, Lilia,Quintero, Leticia,Sartillo-Piscil, Fernando
supporting information, p. 4671 - 4676 (2020/03/10)
Remote and multiple functionalization of piperidines without the use of transition-metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two-step protocol that enables the multiple functionalization of piperidines to either 4-substituted or trans-3,4-disubstituted 2-piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent-radical form, a novel multiple C(sp3)-H oxidation of piperidines to α,β-unsaturated 2-piperidones was developed. Second, the intrinsic low reactivity of the unsaturated piperidones toward conjugated Grignard additions was overcome by using trimethylsilyl chloride (TMSCl) as Lewis acid. Subsequently, conjugated Grignard addition/electrophilic trapping protocol provided substituted 2-piperidone intermediates, some of which were then transformed into pharmaceutical alkaloids.
Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: A stereo- and regio- selective study
Boyd, Derek R.,Sharma, Narain D.,Belhocine, Tayeb,Malone, John F.,McGregor, Stuart T.,Atchison, Jordan,McIntyre, Peter A. B.,Stevenson, Paul J.
, p. 997 - 1008 (2014/01/06)
The reactions of enantiopure cyclohexene epoxides and trans-1,2- bromoacetates, derived from the corresponding substituted benzene cis-dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2-aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms. Allylic trans-1,2-azidohydrins were prepared by Lewis acid-catalysed ring-opening of cyclic vinyl epoxides with sodium azide via an SN2 mechanism. On heating, these trans-1,2-azidohydrins isomerized to the corresponding trans-1,4-azidohydrins via a suprafacial allyl azide [3,3]-sigmatropic rearrangement mechanism. Conversion of a 1,2-azidohydrin to a 1,2-azidoacetate moved the equilibrium position in favour of the 1,4-substitution product. Allylic trans-1,2- bromoacetates reacted with sodium azide at room temperature to give C-2 and C-4 substituted products. A clean inversion of configuration at C-2 was found, as expected, from a concerted SN2-pathway. However, substitution at C-4 was not stereoselective and resulted in mixtures of 1,4-cis and 1,4-trans products. This observation can be rationalized in terms of competitive S N2 and SN2′ reactions allied to a [3,3]-sigmatropic rearrangement. cis-1,2-Azidohydrins and cis-1,2-azidoacetates were much more prone to rearrange than the corresponding trans-isomers. Reaction of the softer tosamide nucleophile with trans-1,2-bromoacetates resulted, predominantly, in C-4 substitution via a syn-SN2′ mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans-1,2-aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an SN2 mechanism. Copyright 2013 John Wiley & Sons, Ltd. Multiple reaction pathways including SN2, S N2′, and [3,3]-sigmatropic rearrangement mechanisms are required to rationalize the formation of products obtained from the reaction of cyclohexene epoxides and trans-bromoacetates with azide and other nitrogen nucleophiles. Copyright
In vitro characterization of radioiodinated (+)-2-[4-(4-iodophenyl) piperidino]cyclohexanol [(+)-pIV] as a sigma-1 receptor ligand
Shiba, Kazuhiro,Ogawa, Kazuma,Mori, Hirofumi
, p. 1095 - 1099 (2007/10/03)
We investigated the binding characteristics of a (+)-enantiomer of radioiodinated 2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[ 125I]pIV], radioiodinated at the para-position of the 4-phenylpiperidine moiety, to sigma receptors (σ-1, σ-2) and to vesicular acetylcholine transporters (VAChT) in membranes of the rat brain and liver. In competitive inhibition studies, (+)-pIV (Ki = 1.30 nM) had more than 10 times higher affinity to the sigma-1 (σ-1) receptor than (+)-pentazocine (Ki = 19.9 nM) or haloperidol (Ki = 13.5 nM) known as sigma ligands. Also, the binding affinity of (+)-pIV for the σ-1 receptor (Ki = 1.30 nM), was about 16 times higher than the sigma-2 (σ-2) receptor (Ki = 20.4 nM). (+)-pIV (Ki = 1260 nM) had a much lower affinity for VAChT than (-)-vesamicol (Ki = 13.0 nM) or (-)-pIV (Ki = 412 nM). (+)-[125I]pIV had low affinity for the dopamine, serotonin, adrenaline, and acetylcholine receptors. Furthermore, in a saturation binding study, (+)-[125I]pIV exhibited a Kd of 6.96 nM with a Bmax of 799 fmol/mg of protein. These results showed that (+)-pIV binds to the σ-1 receptor with greater affinity than sigma receptor ligands such as (+)-pentazocine or haloperidol, and that radioiodinated (+)-pIV is suitable as radiotracer for σ-1 receptor studies in vitro.
