Efficient Solution‐Phase Parallel Synthesis of 4‐Substituted N‐Protected Piperidines

Abstract

Practical conditions for the synthesis of 4‐substituted N‐protected piperidines through CuCN·2LiBr‐catalyzed organozinc additions to 1‐acylpyridinium salts and subsequent hydrogen‐transfer hydrogenation have been established. The reaction sequence is performed at room temperature and provides 4‐substituted N‐protected piperidines in excellent overall yields without the isolation of intermediate dihydropyridines. In those cases in which the organozinc addition results in mixtures of 2‐ and 4‐substituted dihydropyridines, the 2‐substituted isomers are efficiently scavenged with maleic anhydride and subsequently removed by a mild extractive workup with NaHCO3 (sat.). The N‐acyl group can conveniently be exchanged from N‐phenoxycarbonyl to N‐tBoc, thus allowing orthogonal deprotection strategies. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Reactions between Grignard reagents and heterocyclic N-oxides: Stereoselective synthesis of substituted pyridines, piperidines, and piperazines

“…In a collaborative effort, our laboratories recently started to look at the potential of using pyridine N-oxides as starting material for the synthesis of 2-substituted piperidines. 6 We confirmed previous results reported on dienal-oxime formation, and in addition found that a fast addition rate of the Grignard reagent to the pyridine Noxide dissolved in THF was important for achieving high yields of the dienal-oximes. 7 Further studies showed that the reaction was compatible with a variety of differently substituted pyridine N-oxides and Grignard reagents (Scheme 1).…”

“…When 4-substituted products are desired, a practical solution is to remove the undesired conjugated 2-regioisomer by trapping it via a Diels-Alder reaction. 6 (1) Nevertheless, the strategy of using activated pyridines is attractive, and additional methods using activated pyridine derivatives with directing groups have been reported. In 2001 Charette and co-workers presented a method for the synthesis of substituted pyridines and piperidines.…”

“…3b In the synthesis of a range of different piperidine containing alkaloids, Comins and co-workers used 4-dihydropyridones 15 as common intermediates, formed from the addition of Grignard reagents to N-acyl-4-methoxypyridinium salts 14 (eqn ( 6)). (6) Probably because of the earlier reports that confirm that pyridine N-oxides 1 undergo ring-opening when reacted with Grignard reagents, pyridine N-oxides have never been used as precursors to piperidines. However, during our studies of the previously discussed ortho metalation reaction, PhMgCl was reacted with pyridine N-oxide (1a) at -40 • C, followed by the addition of MeOD.…”

Reissert‐Type Acylation with Acylzirconocene Chloride Complexes

“…Since α‐ketols 12 were obtained in 4–9 % yields in the Reissert‐type acylation of quinolines by Cu I /CH 2 Cl 2 catalytic systems, the acyl Cu species might be involved in these preferred 1,4‐addition reactions. Such a preferential formation of 1,4 adducts has been reported in Reissert‐type transformations of quinolines and pyridines by using organocopper compounds8a–8c or organometallic compounds with Cu I additives 5e,6d,8d,8e. Although details about the solvent effect22 and the role of the cationic Rh I catalyst23 for the regioselectivity remain uncertain at present, the cationic Rh I catalyst might take part in promoting the generation of N ‐acylquinolinium intermediates 13 24…”

Pyridylic anions are soft nucleophiles in the palladium-catalyzed C(sp3)–H allylation of 4-alkylpyridines

“…3-Alkylpyridines also form the corresponding pyridinium salts, however deprotonation is not possible with mild base because the resulting 3-pyridylic anion would not be resonance-stabilized by the pyridine nitrogen. The heterobenzylic position in 2-alkylpyridines is inherently activated by the ring, and these substrates also form the required pyridinium salts readily, 19 however they cannot be deprotonated with mild base. The reasons for this are unclear at present but may reflect an orthogonal relationship between the heterocycle and the alkoxycarbonyl group in the pyridinium salt or developing allylic strain during the necessary deprotonation step.…”