Synthesis 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>. 

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>. 

The following two schemes exemplify the synthesis of piperidines via 1,4-addition of amines. In the first scheme below, a one-pot Stille coupling/double Michael addition, starting from readily available vinyl stannanes, is used to generate piperidinones 174 <06SL547>. An example of the reduction of piperidinone 174 to piperidine 175 is also highlighted. 

A review was published covering recent progress in the stereoselective synthesis of piperidines <00S1781>. Routes described in detail include those derived from the chiral-pool, chiral auxiliaries, and catalytic asymmetric methodology. 

Several examples of transition metal catalysis for the synthesis of piperidines appeared this year. Palladium catalyzed intramolecular urethane cyclization onto an unactivated allylic alcohol was described as the key step in the stereoselective synthesis of the azasugar 1-deoxymannojirimycin . A new synthetic entry into the 2-azabicyclo[3.3.1]nonane framework was accomplished through a palladium mediated intramolecular coupling of amine tethered vinyl halides and ketone enolates in moderate yields . A palladium catalyzed decarboxylative carbonylation of 5-vinyl... 

Piperidines. Grieco et al. have described a general synthesis of piperidines by reaction of the acid salt of a primary amine with an allylsilane and 2 equiv. of formaldehyde in water. The reaction involves reaction of iminium ion (a), derived from the amine and formaldehyde, with the allylsilane to form a homoallylamine (b), which can form a second iminium ion (c), which cyclizes with capture of water to the piperidine. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

Andrews, D.M., Stokes, E.S.E., Carr, G.R., Matusiak, Z.S., Roberts, C.A., Waring, M.J. et al. (2008) Design and campaign synthesis of piperidine- andfhiazole-based histone deacetylase inhibitors. Bioorganic ej Medicinal Chemistry Letters, 18, 2580-2584. 

Ojima and coworkers have developed a similar approach to the synthesis of piperidine and related ring systems, which they describe as cyclohydrocarbonylation. In this approach, carbamate-protected allylglydnes (for example, 32) are subjected to rho-dium(I)-catalyzed hydroformylation in an alcohol solvent (Scheme 5.13) [17]. 6-Alkoxy-pipecolates 33 are isolated in good yield and were shown to be amenable to further stereoselective transformations. This methodology has recently been expanded to include fully intramolecular variants that can form two rings in a single reaction. Thus, alkenes 34 are subjected to the cyclohydrocarbonylation conditions to provide azabicy-clo[4.4.0]aUcane amino acids 35 which can serve as conformationaUy restricted dipeptide surrogates and /9-turn mimetics [18]. 

M. Ruiz, T. M. Ruanova, O. Blanco, F. Nunez, C. Pato, and V. Ojea, Diastereoselective synthesis of piperidine imino sugars using aldol additions of metalated bislactim ethers to threose and erythrose acetonides, J. Org. Chem., 73 (2008) 2240-2255. 

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>. 

Other cycloadditions were reported. The intramolecular cycloaddition of alkenylnitrones was 2q>phed to the synthesis of piperidines <99TL1397, 99JCS(P1)185>. Cycloaddition of an alkenyl azide afforded piperidines after reduction of the bicyclo triazole <99T1043, 99EJOC1407>. Similar to the cyclization of the diazo imide 2 in section 6.1.2.1, isomiinchnone intermediates can rearrange to functionalized piperidines <99JOCS56>. 

Deprotonation of the 9-azabicyclo 3.3.11nonan-3-one derivative 1 with chiral lithium amides in tetrahdyrofuran at low temperatures in the presence of chlorotrimethylsilane (internal quench) gives the trimethylsilyl enol ether (lS,5/ )-2 in high yield with high enantiomeric excess. The absolute configuration and enantiomeric excess of 2 are based on chemical correlation and HPLC on a chiral Daicel OJ column, respectively38. The 2,2-dimethylpropyl- and 4-methyl-l-piperazinyl- substituted lithium amide is, as noted in other cases, superior. The bicyclic trimethylsilyl enol ether 2 serves as intermediate in the synthesis of piperidine alkaloids. 

The production of pyridine and its wide use as a solvent and as an intermediate in the synthesis of piperidine and a wide variety of drugs, insecticides and herbicides and chemicals used in rubber vulcanization may result in its release into the environment (Jori et al., 1983 Agency for Toxic Substances Disease Registry, 1992 Environmental Protection Agency, 1999). Pyridine occurs in the environment as a by-product of coal gasification (Stuermer et al., 1982). 

Nitrogen based heterocycles are present in an array natural products, thousands of which have been mentioned in clinical or preclinical studies.1 Thus, the synthesis of piperidine-2 and pyrrolidine-3 derivatives have attracted much attention from the modem day organic chemists. Of particular interest are strategies that lead to chiral heterocyclic derivatives.4... 

This chapter deals with applying ruthenium catalysed olefin metathesis to the synthesis of piperidine and pyrrolidine containing compounds. 

RRM has been implemented in the synthesis of fused carbocycles9 as well as a number of polycyclic ethers.10 This has been extended to the synthesis of piperidines and pyrrolidines via ROM-RCM or RCM-ROM-RCM combinations (Figure 3). 

Organolanthanide-catalyzed silylation has recently been developed and is a significant new strategy for the synthesis of piperidines. For example, the diallyl compound 37 was cyclized in 83% yield with 5mol% catalyst in the presence of a suitable silyl terminator (Equation 85) <2005T2631>. 

The insertion of carbon fragments is another common strategy for the synthesis of piperidines. Hydroformylation of an allyl-substituted aminoallylboronate in the presence of a rhodium catalyst produces a reasonable yield of piperidine (Equation 107) <2000H(52)121>. Aldehydes have also been used in the cyclization of imines in a one-pot multistep synthesis of piperidines that allowed further functionalization to take place (Scheme 51) <2003TL8249>. 

Palladium-mediated intramolecular aminations onto an allylic alcohol <1998TL5971> or allene <1998TL5421> are reported for the synthesis of piperidines. An intermolecular version of the allene-based reactions has been reported in the synthesis of spiropiperidines (Equation 167) <1998JOC2154>. 

Termination of cyclic carbopalladation of alkynes using carbonylative lactamization can be achieved with alkenyl or aryl halides containing an w-carboxamido or tu-sulfonamido group and can be used in the synthesis of piperidines (Equation 173) <1996T11529>. 

The often potent biological properties of piperidine derivatives underlie their vast use in pharmaceuticals, agrochemicals, and natural products. It is for this reason that there exists a myriad of synthetic routes to variously functionalized and substituted piperidine derivatives, which will be highlighted in the subsequent section. In the past year there have been two reviews highlighting two approaches to the synthesis of piperidines. One review focused on the use of aziridines in parallel and solid-phase synthesis of substituted piperidine derivatives as well as other scaffolds <07EJO1717>. The other review covered the synthesis of 3-arylpiperidines by radical 1,4- and 1,2-aryl migration <07T7187>. 

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 -... 

Intramolecular Mannich reactions have also been used in the synthesis of piperidines. An intramolecular Mannich reaction was applied as the key step in the synthesis of the piperidine A ring of cylindrospermopsin <07SL1446> and in the high yielding diastereoselective conversion of 3-amino acids to 2,6-yy -disubstituted piperidinones <07JOC10287>. 

Z. Chen, W.S. Miller, S. Shan and K.J. Valenzano, Design and parallel synthesis of piperidine libraries targeting the nociceptin (N/OFQ) receptor, Bioorg. Med. Chem. Lett, 2003,13(19), 3247. 

As an approach to the synthesis of piperidines with stereocontrol, multiple functionality, and flexibility, the authors employed a [3+3] cycloaddition reaction of a silylpropenyl acetate with aziridines in the presence of a palladium catalyst. The key intermediate is a palladium-trimethylenemethane (Pd-TMM) complex <03JOC4286>. Optically active aziridines gave enantiomerically pure piperidines. 

A three-component Diels-Alder reaction has been reported. Depending on the chiral auxiliary on the nitrogen end of the l-aza-4-borono-1,3-butadiene, diastereomeric excesses can exceed 95% in moderate yield. The method was applied to solid-phase synthesis of piperidine derivatives with acceptable results <03MI466>. 

Anodic oxidation in the synthesis of piperidine alkaloids 90YGK814. Antitumor sesbanimides, total synthesis of 87YGK983. l-Azaspiro[5.5]undecane system of histrionicotoxines, syntheses of 89BSF370. 

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

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