Preparations of piperidines

The application of olefin metathesis to the synthesis of piperidines continues to be widely employed. The use of ring closing metathesis (RCM) in the synthesis of fluorovinyl-containing a,P-unsaturated lactams 148 and cyclic amino acid derivatives 149 is shown below. A key improvement in these reactions is the addition of the Grubbs 2nd generation catalyst (G2) in small portions during the reaction to compensate for catalyst decomposition that occurs at elevated reaction temperatures 06EJOl 166 . 

Two RCM reactions were employed in a new and efficient route to a key chiral intermediate, isoquinuclidine 150, in the synthesis of alkaloid (-F)-catharanthine 06AG(I)5334 . The first RCM makes use of chiral enone 151, derived from L-serine, to generate a chiral dihydropyridinone 152. Intramolecular alkene metathesis of dialkenyl piperidine 153 generates 150, which represents the first example of the use of RCM in the generation of an azabicyclo[2.2.2]alkene system. 

Another form of olefin metathesis widely used for piperidine formation is ring-rearrangement metathesis (RRM), as shown below. The versatility of this reaction can be seen in its ability 

A new approach to piperidines via cyclization of dienes, such as 158, employs a phosphorus hydride mediated radical addition/cyclization reaction 06JOC3656 . This reaction proceeds with complete regioselectivity to create the 6-exo-trig product 159, although as an inseparable mixture of two of the four possible diastereomers. 

Other radical cyclization approaches to the synthesis of piperidines include a CAN-mediated stereoselective cyclization of epoxypropyl cinnamyl amines 06TL705 and a cyclization of (-trimethylsilylmethylamine radical cation, generated via a photoinduced electron transfer reaction to a tethered -functionality 06JOC8481 . 

Harrity and co-workers have developed strategies for piperidine synthesis based on [3+3] cycloaddition reactions and have published a perspective on their and the work of other groups 05OBC1349 . The construction of 6-membered nitrogen heterocycles was included in a review of the [3+3] cycloaddition approach to natural product synthesis by Hsimg and coworkers 05EJO23 . 

A Yb(OTf)3-catalyzed three-component aza Diels-Alder reaction of a diene with aldehydes and benzhydrylamine to provide 2,5-disubstituted 2,3-dihydro-4-pyridones has been developed 05SL1018, 05T9594 . A catalytic asymmetric aza Diels-Alder reaction of acylhydrazones 183 

These were converted to several target structures including all four isomers of 3,4,5-trihydroxypiperidine 05JOC5207 . 

The chiral Betti base 250, as a salt with L-(+)-tartaric acid, reacted with pentane-1,5-dial and benzotriazole to form diasteieopure 251 in 92% yield. Sequential replaeement of the Bt and aryloxy substituents of the piperidine ring with Grignard reagents, followed by hydrogenolytic removal of the chiral auxiliary, gave optieally pure 252 (Seheme 75) 05JOC1897 . 

This protocol was used in the synthesis of both (2S, 3R)-3-hydroxypipecolic acid 281 and (2S, 3S)-3-hydroxypipecolic acid 282 from D-serine 05JOC10182  

Olefin metathesis, in particular ring closing metathesis (RCM), remains a popular route to the synthesis of piperidines. This is exemplified in the following references which employed an RCM reaction utilizing Grubbs first generation catalyst (benzyl - 

Of particular interest was the development of a one-pot enantioselective synthesis of a piperidine appended benzimidazole 147 utilizing a new chiral allylchlorosilane 148. The reaction proceeds via allylation of ketimine 149 followed by RCM in the presence of the G2 catalyst 07OL3699 . 

Also noteworthy was the use of the RCM reaction as the key step in a concise route to spirocyclic tetrahydropiperidine derivatives such as 150 and 151 07T10486 . 

A novel domino metathesis reaction of nitroso Diels-Alder cycloadduct 152 has been developed by Calvet et al. 07OL1485 . This reaction uses favorable thermodynamics to rearrange a strained unsaturated bicycle to access a rare lactam-containing scaffold, isoxazolo[2,3-a]pyridine-7-ones 153. 

New this year, Brummond et al. extended the scope of the rhodium(I)-catalyzed allenic Alder-ene carbocyclization to the preparation of S-lactams with rapid reaction times (on the order of 15 minutes) and in yields ranging from 45% to 92% 07OL347 . 

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The preparation of piperidines by cycloaddition can use either an imino (Scheme 13) or azadiene (Scheme 14) substrate. Highly functionalized tetrahydropiperidines were prepared by a high-pressure aza-Diels-Alder reaction <99TL1877>. The hetero [4+2] cycloaddition of vinyl... 

Rudolf, K., Eberlein, W., Dreyer, A., Muller, S.G., Doods, H., Bauer, E. (Boehringer IngelheimJ Preparation of piperidine-substituted amino-acids for use in treatment of CGRP-mediated disorders, W01049676 (2001). 

These methods parallel the synthesis just described for the five-membered rings. As indicated in structures (42)—(49), standard reactions of aliphatic chemistry can be extended to the preparation of piperidines, tetrahydropyrans and pentamethylene sulfides (44 Z = N, O, S) glutarimides, glutaric anhydrides and glutaric thioanhydrides (46 Z = N, O, S) and 8-lactams, 8-lactones and 8-thiolactones (49 Z = N, O, S). 

Tandem radical additions have been used in the preparation of piperidines. Substituted nitrogen containing heterocycles with ring sizes ranging from 5-8 have been synthesized by radical methods [95JCS(P1)19]. Addition of sulfur radicals to 225 occurs selectively at the enamide portion followed by an intramolecular 6-exo cyclization to produce a diastereomeric mixture of 226 in good yield. 

Preparation of piperidine derivates required the conversion of the auxiliary s amine into an imine function. Subsequent Lewis acid promoted Mannich-Michael reaction with Danishefsky s diene gave aliphatic, resin-bound dehydropiperidi-nones 5. After cleavage, the yields of the obtained enaminones 6 ranged between 13 and 90% (Scheme 12.4). The diastereomeric ratios varied from 78 22 to 99 1. The authors reported that aliphatic substituted enaminones were formed with lower diastereoselectivity than aromatic products. 

Ladenburg s preparation of piperidine from pyridine14 will be described as an example Pyridine (20 g) in anhydrous ethanol (150 g) is placed in a round-bottomed flask under a reflux condenser and warmed on the water-bath. Then sodium pieces (75 g) are added not too slowly. As soon as the reaction slackens or sodium ethoxide separates, more ethanol is added and the reaction is brought to conclusion as fast as possible. When all the sodium has been consumed, the mixture is allowed to cool, treated with an equal volume of water, and distilled in steam. The distillate is neutralized with hydrochloric acid and evaporated to dryness. Piperidine hydrochloride is obtained as residue in almost quantitative yield and can be recrystallized from ethanol. 

USE Preparation of piperidine compounds as NMDA receptor antagonists for treatment of dementia [7973]. 

More recently, Pagenkopf and coworkers have extended the scope of this reaction to produce alkoxy substituted tetrahydropyrans [17], and also by using imines as the substrate to give piperidines [18]. This latter reaction provides a useful route to an important nitrogen heterocycle in good yield and excellent stereocontrol. The same trick of preparing the cyclobutane in situ can also be employed, and this provides a robust method for the one-pot preparation of piperidines. 

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