Piperidine ring formation

Other routes to piperidines involving 1,4-addition reactions include the incorporation of a Michael addition reaction as the piperidine ring formation step in the total synthesis of Histrionicotoxin <06JA12656> and the use of an intramolecular 1,4-addition, 6-endo-dig ring... 

The enantiopure tricarbonyl(dienal)iron complex 61 suitably transfers chirality in the piperidine ring formation. Condensation to the Schiff base is followed by the intramolecular Mannich reaction catalyzed with p-TSA. The piperidine was converted to dienomycin C (62) in five additional steps <99EJOC1517>. 

A total synthesis for 3,14-dihydroxy isomorphinans from 4a-(2-aminoethyl)-l,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene (34, Scheme 3.5) has been published/116) The urethane epoxide (116) was given upon treatment of 34 with ethyl chloroformate-triethylamine, followed by m-chloroperbenzoic acid oxidation. During base treatment, regioselective opening of the epoxide occurred with concomitant piperidine ring formation to 117. 

Piperidine Ring Formation from Concluding Remarks 369... 

Piperidine Ring Formation via Amidomercu ration 365 References 370... 

PIPERIDINE RING FORMATION VIA INTRAMOLECULAR NUCLEOPHILIC ATTACK... 

PIPERIDINE RING FORMATION BY INTRAMOLECULAR NUCLEOPHILIC DISPLACEMENT... 

PIPERIDINE RING FORMATION FROM FURAN DERIVATIVES... 

Here the alcoholic hydroxyl is first protonated and then eliminated as water. The allylcarbenium ion (2) is initially stabilized by elimination of the proton at C-14. Then the ether link is opened after protonation of the ring oxygen with the formation of carbenium ion (3), whereby the neighboring C-C bond of the piperidine ring is cleaved with aromatization of the C ring. The carbenium ion (4) formed is stabilized by elimination of a proton and ring closure to apomorphine (5). 

Formation of the central piperidine ring of 418 has been achieved by Decroix following generation of the iminium ion via dehydration of 417 and subsequent cyclization (Equation 112) <1997T2495>. 

The resulting derivatives (269) can be considered as strategically important intermediates in the synthesis of glycosidase inhibitors and carbocyclic nucleosides (150). A new approach to the stereoselective synthesis of the piperidine ring with the use of [4+ 2] [3+ 2]-cycloaddition from specially prepared substrates is also very interesting (431)b, c. In the context of this problem, the conditions for the formation of systems containing quaternary vicinal stereocenters were found. 

Scheme 41 Enantioselective formation of a piperidine ring system...

Fig. 5.26. Metabolism of the piperidine ring according to the mechanism in Fig. 5.23. Diphen-idol (5.97) and DN-9893 (5.73) yield both amino acid and lactam metabolites [177], Phencyclidine (5.98) yields only the amino acid derivative steric hindrance at the N-atom appears to impede formation of the lactam metabolite [190].

A free radical cyclization of oxime ethers tethered to an aldehyde has been used in the synthesis of azepine derivatives . For example, oxime ether 389 is cyclized to azepine 390 by reaction with Sml2 in HMPA and f-BuOH at —78°C (equation 170) . Similar free radical cyclization of oxime ethers can be carried out also in the presence of Bu3SnH/AIBN in benzene . Oxime 0-methyl ether 391 underwent thermal cyclization in refluxing o-dichlorobenzene (ODCB) leading to the mixture of two products 392 and 393 in ratio 69 31 in overall yield of 91% (equation 171) °. Rearrangement of oxime 0-tosylates in the presence of piperidine also leads to azepine ring formation . ... 

The rare reports of quinolizidine formation by a nitrone cycloaddition strategy include the racemic total synthesis of lasubine II (58), one of a series of related alkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme 1.14) (104). While these alkaloids were previously accessed by infennolecular nitrone cycloaddition reactions, this more recent report uses an intramolecular approach to form the desired piperidine ring. Thus, cycloaddition of nitrone 59 affords predominantly the desired bridged adduct 60 along with two related... 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

Iminium salts (182) were starting materials in reactions with enamines (93CB133 94CB1437), which proceed by two different pathways with the formation of bicyclic ketones (183) and with the formation of substituted pyridines. The authors assume that the reaction takes place by a double electrophilic attack of the salt (182) in the /3-positions of the enamine and the resulting immonium cations undergo a retro-Mannich type of reaction with the opening of one of the piperidine rings. 

Quinuclidine ring formation starting from piperidine derivatives is carried out usually by (a) intramolecular alkylation or acylation or (b) intramolecular Dieckmann condensation. 

Piperidine ring-expansion methodology and aziridinium ion intermediate formation has been demonstrated to provide good regio- and stereochemical control in the synthesis of substituted azepanes. Reaction of 298 with azide ion afforded 300 from preferential attack from behind by the azide ion at the methine carbon in the intermediate 299 (Scheme 38) <2002J(P1)2080>. 

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