Piperidine synthesis

FeX3 was also found to be an excellent promoter in the classical Prins cycliza-tion (Scheme 10, route H), with the observation of a satisfactory reaction between 3-buten-l-ol and several aldehydes, affording the corresponding c/s-4-halo-2-alkyl tetrahydrop3Tans in good yields [Eq. (1) in Scheme 32] [35], In a similar manner, the methodology can be extended to the piperidine synthesis through an aza-Prins cyclization [Eq. (2), Scheme 32] [41],... 

The excellent reducing properties of potassium tetracarbonylhydrido-ferrate have been used to good effect in providing an efficient general piperidine synthesis from alkyl and aryl amines and glutaraldehyde210 (Scheme 138). The reaction probably proceeds via reduction of intermediate Schiff bases and cyclization via the iminium salt. 

A review was published this year covering the literature of saturated nitrogen heterocycles over 1998 with a section devoted to piperidine synthesis <99JCS(P1)2553>. 

For examples of piperidine synthesis see a) Doemyei, G., Incze, M., Moldvai,... 

Piperidine synthesis.3 The important glycohydrolase inhibitor 1-deoxynojiri-mycin (3) can be prepared in two steps from 5-keto-D-glucose (1). Thus 1 on treatment with benzhydrylamine and sodium cyanoborohydride in CH3OH at 0° undergoes double reductive amination to form essentially only one product (2), which on deprotection provides the piperidine 3. The high stereoselectivity is attributed to hydroxyl-directed hydride delivery. 

Diastereoselectivity in functionalized piperidine synthesis has also been reported using chiral sulfinimines (Scheme 18) <2003OL3855>. It was postulated that the observed selectivity arose from an intermediate alkoxy aluminium species shielding one face of the imine during reduction. 

Cross metathesis (CM) reactions can also be used as the key step in a piperidine synthesis (Scheme 40) <2004TL1167> or in sequence with ring-rearrangement metathesis, for example, in the synthesis of (—)-lasubine (Scheme 41) <2004T9629>. 

Table 9 Piperidine synthesis by ring expansion (Scheme 119)...

The addition of lithium (.Sj-iV-allyl-A -o -methylbenzylamide to unsaturated esters was shown to be an effective method for producing RCM precursors <02SL1146> for piperidine synthesis, as was the addition of allylamine to the enantiomerically-enriched allylic epoxide 37 <02TL779> (Scheme 20). 

Grignard addition-cyclization reaction for piperidine synthesis... 

Laschat, S. Dicker, T. Stereoselective Synthesis of Piperidines, Synthesis 2000, 1781-1813. 

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>. 

In the first total synthesis of pseudodistomin D 261, the 1,2-diamine 262 of known absolute configuration was prepared and cychzed to 263 by sequential hydroamination and in situ imiue reduction. The absence of any pyrrolidine product formation was rationalized mechanistically (Scheme 79) <05OL823>. A high-yield intramolecular hydroamination protocol has been developed for sulfonyl-protected primary aminoalkynes and application to piperidine synthesis... 

The techniques of hindered piperidine synthesis are constantly improving. Take, for example the method of 2,2,6,6-... 

Trost, B.M., Pinkerton, A.B. and Kremzow, D. (2000) A ruthenium-catalyzed pyrrolidine and piperidine synthesis, Journal of the American Chemical Society, 122 12007-12008. 

Piperidine Synthesis Oxidative Cleavage/Reductive Amination.31... 

Piperidine Synthesis Oxidative Cleavace/Reductive Amination... 

Metal-mediated cyclizations have been applied to piperidine synthesis (Scheme 16). Ring closing metathesis catalyzed by Ru catalysts is used to prepare chiral piperidines <97TL677, 97AG(E)3036>. Similarly to the cyclization to 37 is Ti-(II)-mediated intramolecular cyclization of optically active enyne precursors for preparing chiral piperidines <97TL8351>. 

A novel strategy for piperidine synthesis has been developed by Harrity and co-workers <01SL1596>. A variety of piperidines were synthesized in yields ranging from 63-82% by employing a [3+3] cycloaddition reaction between enantiomcrically pure aziridines 100 (generated from amino acids) and palladium trimcthylenemethane complexes (99). The efficiency of the methodology was demonstrated through a 4-step synthesis of (-)-pseudoconhydrine (101). 

Kornet, M. J. and Thio, A. P. 1976. Oxindole-3-spiropyrrolidines and -piperidines. Synthesis and local anesthetic activity. J. Med. Chem. 19 892-898. 

Mitich W (1998) Poison-hemlock (Conium maculatum L.). Weed Technol 12 194—197 Moody CJ, Lightfoot AP, Gallagher PT (1997) Asymmetric synthesis of 2-substituted piperidines. Synthesis of the alkaloids (—)-coniine and ( )-pseudoconhydrine. J Org Chem 62 746-748... 

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