Piperidines, 1-aryl

Diastereomeric oxazolidines 88 and 89 (Scheme 8.4.27) were available via 1,4-reduction and cyclization of Zincke product 87, with 88 being the kinetic product under the reaction conditions and 89 (X-ray) the thermodynamically favored isomer in CDCI3 solution. Iterative reductive oxazolidine opening provided 3-aryl piperidine 91, which was readily advanced to (-)-PPP (92), a selective dopaminergic receptor antagonist. ... 

Scheme 16 The neophylic rearrangement in the synthesis of 3-aryl piperidines...

FIuorobutyrophenone derivatives of 4-aryl piperidines are well-known antipsychotic agents. It is thus interesting to note that the piperidine can in fact be fused onto an... 

Alkyl- und 1-Aryl-piperidine erhalt man auch durch eine andere Zweistufen-Re-aktion, bei welcher man ein primares Amin mit Benzotriazol in Wassser mischt, nach 10 min Pentandial zugibt und das nach 1-2 h erhaltene 1-Alkyl- bzw. l-Aryl-2,6-bis-[lH-benzotriazolyl]-piperidin mit Natrium-boranat reduktiv zerlegt (Weg )3. Wenn man das Zwischenprodukt jedoch anstelle der Reduktion mit Alkyl-magnesiumbromiden umsetzt, erhalt man 1,2,6-trisubstituierte Piperidine (Weg )3. 

Die direkte, reduktive Aminierung von Pentandial mit primaren, aliphatischen oder aro-matischen Aminen und Kalium-(hydrido-tetracarbonyl-ferrat) ergibt 1-Alkyl-piperidine in mittleren Ausbeuten bzw. 1 -Benzyl- und 1 -Aryl-piperidine in guten Ausbeuten1. 

Ifenprodil (= l-Methyl-2-hydroxy-2-(4-hydroxyphenyl) ethyl-1 -(4-benzyl-piperidine)] -(aryl piperidine) [at(/o-3-(Indol-2-yl)-8-methyl-8-azabicyclo-[3.2.1] octane] (indolotropane) [Kynurenic acid (= 4-Hydroxy-2-quinolinecarboxylic acid)] (quinoline carboxylic acid) [Memantine (= 1-Amino-3,5 dimethyladamantane)] (amino adamantane, amino cyclic aliphatic) [Methadone (= 6-Dimethylamino-4,4-diphenyl-3-heptanone)] (aryl tertiary amine) [em/o-3-(l -Methylindol-2-yl)-8-methyl-8-azabicyclo-[3.2.1] octane(indolotropane) exo- 3-( 1 -Methylindol-2-yl)-8-methyl-8-... 

Donepezil (= Aricept)] (aryl piperidine) Synthetic AChE [1 nM] [nootropic]... 

The reactions were conducted with catalytic Cul (10 mol%) and Na2C03 (2 equivalents) in CH2C12 at room temperature. Moderate to good yields (65-83%) of the IV-arylated piperidines and anilines were obtained in less than 6 h (Figure 21). 

In fhe T2 variant (Scheme 64), the diazonium salt is first formed on fhe solid support and is fhen reacted with an amine. If the amine is a secondary one, then the cleavage of the triazene formed again yields a secondary amine. As such, these systems represent a linker for secondary amines. This has been exemplified in the synthesis of a set of 3-aIkyloxy-4-aryl piperidines [159]. 

R = H, alkyl, aryl R = aryl, piperidine, pyrrolidine, morpholine, alkynyl... 

SCHEME 3.6 Bicyclic aryl piperidine protecting groups and nitration. 

SCHEME 3.8 Conversion of dinitrated bicyclic aryl piperidine 8 to varenicline (1). 

To overcome these obstacles, we turned our attention to novel approaches to benzazepine 6 that did not involve benzonorbomadiene and obviated the problems presented by cyclopentadiene generation and oxidative cleavage chemistry (Figure 3.8). Both the Mazzocchi and discovery syntheses generated 1,3-indane dicarbonyl intermediates that were converted to the bicyclic aryl piperidine nucleus. We therefore focused on alternative indane syntheses to access this functionality, targeting readily available synthetic precursors. 

Coe, J.W. Brooks, P.R. Wirtz, M.C., et al. 3,5-Bicyclic aryl piperidines a novel class of a4P2 neuronal nicotinic acetylcholine receptor partial agonists for smoking cessation. Bioorg. Med. Chem. Lett. 2005, 15, 4889 897. 

El Kaim and Grimaud also used cyclic imines as starting materials for the Ugi-Smiles coupling [103]. Cyclic imines were obtained by oxidation with A-chlorosuccinimide (NCS) followed by elimination of HCl with a base (DBU). Then, the imine reacted with isocyanides and electrodeficient phenols to afford A-aryl piperidines 114 and pyrrolidines in good yields (Scheme 7.46). 

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