Tetrahydropyridines => alkenes

Secondary amines can be added to certain nonactivated alkenes if palladium(II) complexes are used as catalysts The complexation lowers the electron density of the double bond, facilitating nucleophilic attack. Markovnikov orientation is observed and the addition is anti An intramolecular addition to an alkyne unit in the presence of a palladium compound, generated a tetrahydropyridine, and a related addition to an allene is known.Amines add to allenes in the presence of a catalytic amount of CuBr " or palladium compounds.Molybdenum complexes have also been used in the addition of aniline to alkenes. Reduction of nitro compounds in the presence of rhodium catalysts, in the presence of alkenes, CO and H2, leads to an amine unit adding to the alkene moiety. An intramolecular addition of an amine unit to an alkene to form a pyrrolidine was reported using a lanthanide reagent. 

Attempts to liberate l-methyl-l-aza-2,3-cyclohexadiene (329) from 3-bromo-l-methyl-l,2,5,6-tetrahydropyridine (326) by KOtBu in the presence of [18]crown-6 and furan or styrene did not lead to products that could have been ascribed to the intermediacy of 329 (Scheme 6.70) [156], Even if there is no doubt as to the allene nature of 329 on the basis of the calculations on the isopyridine 179 and 3d2-lH-quinoline (257), it is conceivable that the zwitterion 329-Za is only a few kcal mol-1 less stable than 329. This relationship could foster the reactivity of 329 towards the tert-butoxide ion to an extent that cycloadditions to activated alkenes would be too slow to compete. On the other hand, the ultimate product of the trapping of 329 by KOtBu could have been an N,0-acetal or a vinylogous N,0-acetal, which might not have survived the workup (see, for example, the sensitivity of the N,0-acetal 262 [14], Scheme 6.57). 

Electron-rich alkenes like an enol ether react with N-allenylsulfonamides to assist a 1,3-shift of the sulfonyl group, eventually furnishing formal [4+2]-cycloaddition products, tetrahydropyridine derivatives. The sulfonyl group migrates from the nitrogen to the central allenyl carbon atom [25b, 195]... 

Electron transfer reduction of pyridines in both acid and alkaline solution generates the protonated radical-anion. This rapidly accepts a further electron and a proton to give a mixture of dihydropyridines. Enamine structures in these dihydro-pyridines can tautomerise to the imine, which is more readily reduced than the original pyridine molecule. Further reaction of the 1,4-dihydropyridine leads to piperidine while reduction of the t, 2-dihydropyridine leads to a tetrahydropyridine in which the alkene group cannot tautomerise to the imine and which is not therefore reduced to the piperidine stage. The reaction sequence is illustrated for 2,6-dimethyl-pyridine 18 which yields the thermodynamically favoured cis-2,6-dimethylpiperidine in which the two alkyl substituents occupy equatorial conformations. 

Electron-rich bifunctional vinyl ethers (e.g. ethylene glycol divinyl ether) react with electron-poor alkenes (e.g. TCNE) to produce cyclobutanes in good yields via tetramethylene zwitterion intermediates. In some cases, cyclobutanes reacted with the solvent (MeCN) to yield tetrahydropyridines.9 Trifluoromethanesulfonimide is an... 

There has been extensive research into electrophilic additions to 3-substituted-l,4-dihydropyridines, such as N-methyl-3-cyano-l,4-dihydropyridine 138, which readily undergoes addition across the more reactive enamine-like 5,6-alkene to give 2,3,5-trisubstituted-l,2,3,4-tetrahydropyridines (Scheme 38) <1998JOC2728, 2000CEJ1763, 2003TL8449>. In an unusual example, the reaction with sulfinyl chlorides and triethylamine results in the formation of the 1,4-dihydropyridine sulfoxide 139, where in the absence of an additional nucleophile, the iminium intermediate is deprotonated to yield the monosubstituted 1,4-dihydropyridine product 139. 

When comparing the chemistry of the three tetrahydropyridine isomers, the reactivities of 1,2,3,4- and 2,3,4,5-tetrahydropyridines are similar and these two isomers are often interconvertable. The chemistry of 1,2,3,6-tetrahy-dropyridines is somewhat different, and in particular the influence of the nitrogen atom has the least effect on the reactivity of the alkene, which behaves more like an alkene in a nonheterocyclic system. 

Treatment of 2-alkyl-l,4-bis(4-tolylsulfonyl)-l,2,3,4-tetrahydropyridines 196 with nucleophilic Lewis-acidic orga-nometallic reagents results in addition of the nucleophile at the 6-position and elimination of the 4-tosyl group with concomitant isomerization of the alkene to give 2,6-.sy -disubstituted-l,2,3,6-tetrahydropyridines 202 (Equation 17) <1998SL55, 2001JOM380>. 

Cycloadditions on 1,2,3,4-tetrahydropyridines are usually limited to those bearing an electron-withdrawing group at the 5-position or with a 4-oxo group to activate the enamine-like alkene. For example, di-l,2,3,4-tetrahydropyridine 220 in which one of the two 1,2,3,4-tetrahydropyridine units has a 4-oxo group undergoes [2+2] photocycloaddition... 

These oxygenated piperidines, or aza-sugars, are of considerable interest due to their wide-ranging biological activities. Diequatorial hydroxylation of the alkene of 1,2,3,6-tetrahydropyridines has also been achieved by... 

The vast majority of the reactions of piperidines occur either at nitrogen or at the a-carbons to the nitrogen atom. With no ring alkene, the types of manipulations that can be carried out upon piperidines are fewer than those of the dihydro- and tetrahydropyridines. 

Azine approach. Bicyclic isoxazolines can be prepared by 1,3-dipolar cycloaddition of nitrile oxides to heterocyclic alkenes such as the iV-acetyl tetrahydropyridine (92) (68CPB117). 

Tietze and Schuffenhauer explored the intermolecular hetero Diels-Alder reaction of ethyl vinyl ether and sulfinimine 204 and found that at high pressures (11 kbar) and long reaction times (48 h at room temperature), tetrahydropyridines 205 and 206 were obtained in 96% yield and in a ratio of 1.7 1.107 The exo-adducts were not observed. Phenyl vinyl sulfide reacts similarly, but simple alkenes failed. Theoretical calculations and the experimental results suggest that while the cycloaddition is concerted, it is highly asynchronous. 

Recent work has shown that the carbamate reaction shows no regioselectivity in the rather demanding case of 1,2,3,6-tetrahydropyridines 1,2-dihydropyridines react at the 5,6 double bond, but with no selectivity in the N,0 orientation. The regioselectivities of the Sharpless oxyaminations have been rationalize, and the reaction has recently been studied from the point of view of the inorganic chemist. These procedures and 3ther cis hydroxyaminations below produce stereochemistry complementary to that provided by ring o ming of the epoxidized alkene. ... 

Hydroxy-l,2,3,4-tetrahydropyridines (161) are obtained on irradiation of enamine carbaldehydes (162) in the presence of a wide range of alkenes (163) the cycloaddition proceeds with high regioselectivity and in almost... 

Sc(OTf)3-catalyzed three-component coupling reactions of aldehydes, amines, and dienes have been examined. In the presence of 10 mol % Sc(OTf)3 and magnesium sulfate, benzaldehyde was treated with aniline and Danishefsky s diene. The desired three-component reaction proceeded smoothly to afford the corresponding tetrahydropyridine derivative in 83 % yield (Eq. 9) [24b]. Under the same reaetion conditions, cyclopentadiene was used instead of Danishefsky s diene to afford the corresponding tetrahydroquinoline derivative (Eq. 10). Different combinations of aldehydes, amines, and alkenes are possible in these reactions, and afford diverse tetrahydroquinoline derivatives in high yields. 

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