Functionalized piperidines

A functionalized piperidine system 204, on deprotection of the BOC group followed by treatment of the resulting amine with Me3Al, afforded a 4 1 mixture of trans- and cis- 4,6-disubstituted quinolizidines 205 and 206 (Scheme 39) <1999T15209>. 

Hydroamination of olefins has received considerable attention this year as a route to functionalized piperidines and spiropiperidines, particularly in regard to the investigation of new catalysts. In the synthesis of spiro-piperidines, two new mild and more general intramolecular hydroamination protocols were developed this year. One protocol uses a cationic gold-phosphine complex (Au[P(fBu)2(o-biphenyl)]Cl) as the catalyst... 

Perhydrooxazolo[3,2- ]pyridines 338 are excellent precursors of iminium ions 339 obtained after treatment of the oxazolidine with either a Bronsted or Lewis acid. Trapping of these intermediate iminium ions with nucleophiles then allows for substitution at the C-8a position together with ring opening, yielding functionalized piperidines 340 (Scheme 93). 

Scheme 24 BDMS-catalyzed multicomponent access to functionalized piperidines...

A vast array of piperidine containing cores, both natural and synthetic, are of biological and medicinal interest. These heterocyclic scaffolds have been the subjects of considerable synthetic efforts, especially for the construction of optically active compounds. In this context, Khan et al. reported a catalytic bromodi-methylsulfonium bromide (BDMS) three-component reaction of 1,3-dicarbonyls with aromatic aldehydes and aromatic amines for a facile access to highly functionalized piperidines (Scheme 24) [104]. This strategy is an interesting illustration of... 

Khan AT, Parvin T, Choudhury LH (2008) Effects of Substituents in the beta-Position of 1,3-dicarbonyl compounds in bromodimethylsulfonium bromide-catalyzed multicomponent reactions a facile access to functionalized piperidines. J Org Chem 73 8398-8402... 

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>. 

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. 

Tetrahydro-2-pyridones are also produced by a [4+2] cycloaddition of l-aza-2-siloxydiene with simple dienes in a Lewis acid-catalyzed reaction (Equation 142) <2004S2222>. In an analogous manner, hydrazone derivatives have been in aza-[4+2] cycloadditions with reactive dienophiles which can be trapped with aldehydes to form highly functionalized piperidines (Scheme 88) <2004AGE2001, 2004JOC8429>. 

Novel methods for functionalizing piperidines at the 3- and 4-positions were also introduced. Mete and co-worker synthesized 3-diazo-piperidin-2-one and characterized its reactivity in transition-metal catalyzed reactions, particularly H-X insertion reactions and cyclopropanation reactions <02T3137>. Christoffers and co-workers developed an asymmetric Michael addition reaction with a chirally modified 4-piperidone-enamine. They were able to create a quaternary carbon center in >95% de and elaborate the compound on through classical means to the functionalized piperidine 107 (Scheme 21) <02EJ01505>. 

Functionalized piperidines 165 and 166 for the synthesis of enantiopure homokainoids have been generated in excellent yields via a Rh-catalyzed cyclohydrocarbonylation reaction on both homoallylic amines 167 and homopropargylic amines 168 <07JOC9418>. 

Highly-functionalized piperidines are available from readily-available pyrazinones by way of Diels-Alder cyclization and acid-catalyzed methanolysis. Products are reported as single stereoisomers <03T5047>. 

As an extension, the same laboratory demonstrated the possibility of performing one-pot oxidative decarboxylations with concomitant iodina-tion when excess iodine was used (Scheme 16) [23]. As illustrated with the pipecolinic carbonate 26, this sequence can be performed followed by trapping of the iminium ion intermediate with 2-hexen-l-ol leading to the functionalized piperidine 27 in 71% yield. Subsequently, a 5-exo cyclization can be performed to give the bicyclic M,0-acetal 28, thus illustrating the potential of preparing complex systems in few steps. 

As mentioned above, acetals are much more reactive acceptors in la-catalyzed ally-lation than aldehydes or ketones. Intramolecular allylation has been examined for the synthesis of highly functionalized piperidine derivatives [50]. Catalytic use of la effects cyclization of nitrogen-containing acetal 23 bearing an allylic silane to give piperidine 24 with moderate selectivity (Sch. 19). 

Khim and Mariano have used the same strategy for the synthesis of several functionalized piperidines (Scheme 62) [309]. 

In addition, functionalized piperidines (68) have been generated by the a ition of organometallic reagents to S,6-dihydropyridinium salts (67 equation 11). ... 

The synthesis of novel DNA topoisomerase II (topo II) inhibitors was undertaken in the laboratory of T.L. MacdonaldJ" Their research program dealt with the synthesis of piperidin-3-one derivatives, which were needed as synthetic intermediates for a variety of potential topo ll-directed agents. The key step in their approach was the Amadori reaction for the preparation of highly functionalized piperidin-3-ones under mild conditions. Upon treatment with a catalytic amount of p-toluenesulfonic acid in toluene at reflux, the desired rearrangement took place in high yield. 

A stereoselective synthesis of 2,3,5,6-tetra- and 2,3,4,5,6-penta-substituted piperidines was achieved from oxidative cleavage of 2-azabicyclo[2.2.2]octane Diels-Alder adducts 176 derived from dihydropyridine 177. Appropriate functional group interconversions of the amidine and ester functionalities in 176 ultimately gave densely functionalized piperidines such as 178 <05OL5773> (Scheme 51). 

Benzenesulfonylaldimines 289 underwent 3-hydroxyquinuclidine-catalyzed Morita-Bayhs-Hillman reaction with diene 290 to give adducts 291 as an E/Z mixture. The E-isomers cyclized to functionalized piperidines 292 on treatment with base, while the Z-isomers did not. However, simultaneous irradiation with UV light at 300 nm effected photoisomerization to afford high yields of 292 from the 291 mixture (Scheme 88) <05OL2377>. 

A second 5-exo-trig cyclization of an intermediate occurred with the enamide 187 to give 188 <04X8181>. The tributyltin hydride-promoted ring expansion of 189 to 190 demonstrates the key step in a novel protocol for the conversion of electron deficient pyrroles to functionalized piperidines <04CC1422>. 

Finally, the use of stoichiometric amounts of transition metal complexes can play an important role in the synthesis of functionalized piperidines. <01H14.39> Liebeskind and coworkers have developed a chiral transition metal complex and have used it in the synthesis of (-)-indolizidine 209B <01JA12477>. A lipase mediated allylic alcohol resolution provides access to both antipodes of enantiomerically pure allyl acetates (115) which can be used to form an ri -allyl molybdenum complex (116), Hydride abstraction followed by methoxide quench yields a reactive species 117 which may be further functionalized through reactions with Grignard reagents. The eventual products 119 arc 2,3,6-trisubstituted piperidines in enantiomerically pure form. 

Lashkari M, Maghsoodlou MT, Hazeri N, Habibi-Khraassani SM, Sajadikhah SS, Doostmohamadi R. Synthesis of highly functionalized piperidines via one-pot, five-component reactions in the presence of acetic acid solvent. Synthetic Comm 2013 43(5) 635. ... 

Enantioselective synthesis of brefeldin A was achieved by utilizing [3 + 2] cycloaddition of 263 with the chiral butenolide 268 to provide 269 as a key reaction [99]. Less basic triisopropyl phosphite was used as a suitable ligand. Functionalized piperidine 271 was prepared in an enantiomerically pure form by [3 + 3] cycloaddition of enantiomerically pure aziridine 270 with 263 and the total synthesis of (—)-pseudoconhydrine has been achieved [100]. 

Piperidine and pyridine ring systems are the key structural elements in a vast array of natural products as well as in a large class of biologically active natural products. They are also often embedded within scaffolds as privileged structures by medicinal chemists. Indeed, over 12000 piperidine derivatives have been mentioned in clinical or preclinical studies during the last ten years. The development of new methods for the synthesis of multi-functionalized piperidines and pyridines is therefore of considerable importance. ... 

Metal bis(oxazoline) catalysts are also highly efficient at promoting asymmetric Diels-Alder reactions. Ishira developed a highly selective copper bis(oxazoline) catalyst for use in standard intermolecular Diels-Alder reactions. Arrayas and Carretero used a nickel bis(oxazoline) catalyst in inverse electron demand hetero Diels-Alder reactions of 1-azadienes for the production of functionalized piperidines. bis(oxazoline) catalysts in reactions pyrazolidinone dienophiles and determined that copper and palladium catalysts were most efficient. Sibi applied a copper bis(oxazoline) catalyst in a kinetic resolution experiment in which one enantiomer of dienophile 46 reacts selectively with cyclopentadiene to yield cycloadduct 48 and 98% ee... 

Khan et al. [131] reported a simple and convenient one-pot multicomponent reaction (MCR) for the synthesis of highly functionalized piperidines 87,88, and 89 using molecular iodine as a catalyst. This strategy demonstrated the five-component reaction of 1,3-dicaiboityl compounds, amines, and aromatic aldehydes in... 

Khan AT, Khan MM, Bannuru KKR (2010) Iodine catalyzed one-pot five-component reactions for direct synthesis of densely functionalized piperidines. Tetrahedron 66 7762-7772... 

Keywords Aromatic aldehydes, p-keto esters, amines, bismuth nitrate, ethanol, room temperature, homogeneous catalysis, tandem reaction, one-pot synthesis, multicomponent reaction (MCR), Mannich reaction, functionalized piperidines... 

---