Synthesis of piperidones

Attempts to apply Rh(II)-catalysis conditions similar to those in the synthesis of piperidones 164 (n = 1) to substrates 163 ( = 2, 3 R = Ph) with one or two additional methylene units in the linker met with little success [164 (n = 2 R = Ph) 35% yield, (/i = 3 R = Ph) 0% yield]. Intramolecular C —H insertion to give cyclopentanones appeared to be the major pathway in these cases. Use of Cu(acac)2-catalyzed decomposition of 163 (n = 2, 3 R = Ph) furnishes 164 ( = 2, 3 R = Ph) in 61 and 58% yield, suggesting a remarkably efficient and selective capture of the copper carbenoid by the amine to give a medium-size cyclic ylide in preference to other carbenoid pathways (94JOC6892). 

Recent advances in the synthesis of piperidones and piperidines 03T2953. 

By the same principle a synthesis of piperidones is achieved in one step. 

Dieckmann synthesis of piperidones by a 6-exo-trig reaction (favored)... 

SCHEME 87 Synthesis of piperidone-grafted pyridopyrimidines using [BMIM][Br]. 

A variety of l,2,3,4-tetrahydro-j8-carbolines have been prepared from 3-piperidone phenylhydrazone derivatives. Used initially to obtain pentacyclic derivatives (35) related to the yohimbe alkaloids, this route was later extended to the synthesis of tetracyclic compounds (36). l-Methyl-5,6,7,8-tetrahydro-j8-carboline (37) was prepared in low yield by heating cyclohexanone 2-methyl-3-pyridylhydrazone with zinc chloride, a synthesis probably based on the similar preparation of the tetracyclic compound 38 starting from the corresponding quinolylhydrazine. Abramovitch and Adams extended this approach to the cyclization of cyclohexanone 3-pyri-dylhydrazone (39) itself. The main product was 6,7,8,9-tetrahydro-8-carboline (40), a smaller amount of the j8-isomer (41) also being obtained. This provides a convenient and readily reproducible route to the otherwise difficultly accessible 8-carboline ring system. The favored attack at carbon-2 over carbon-4 of the pyridine nucleus... 

A one-pot, four-component process involving the in situ formation of an azadiene followed by an intermolecular or intramolecular Diels-Alder reaction for the synthesis of highly functionalized piperidone scaffolds has been reported [81]. The compounds were obtained in good yields and diastereoselectivities (Figure 5). 

Klumpp, D. A. Garza, M. Jones, A. Mendoza, S. Synthesis of Aryl-Substituted Piperidines by Superacid Activation of Piperidones. J. Org. Chem. 1999,64,6702-6705. 

The first publications on the successful stereospecific synthesis of uleine (7a) and epiuleine (31) appeared in 1971 (71JA2492). Using 31 as an example, the key step lies in the formation of transoid piperidone 37, whose conformational stability allows the subsequent transformations to be carried out stereoselectively (Scheme 6). 

Padwa and co-workers (60,106,107) have been highly active in using carbonyl ylides for the synthesis of a number of bioactive alkaloids (Scheme 4.51). In an approach to the aspidosperma alkaloids, a push-pull carbonyl ylide was used to generate a bicyclic ylide containing a tethered indole moiety. This strategy ultimately allowed for the synthesis of the dehydrovindorosin skeleton (108). Starting from a quaternary substimted piperidone (200), elaboration of the 3-carboxylic acid provided p-ketoester amide 201. Addition of the indole tethered side chain provided a very rapid and efficient method to generate the cycloaddition precursor 203. 

A very popular route to piperid-4-ones is by a Dieckmann or Thorpe cyclization of appropriate diesters or dinitriles. In most cases the nitrogen atom is tertiary, to avoid the formation of amides as by-products. A simple example is provided by the synthesis of the piperidone ester (129) which, after hydrolysis and decarboxylation, gives the piperid-4-one (130) (45JOC277). The diesters are available by addition of amines to acrylates and so the two ester fragments can be different. For the production of AT-benzoylpiperid-4-one (132) the whole operation from benzamide and ethyl acrylate to the ester (131) can be achieved... 

Substituted-3-aryl[l,6]naphthyridin-2-amines and 7-substituted-3-aryl[l,6]naphthyridin-2(l//)-ones have been prepared by diazotization of 3-aryl[l,6]naphthyridine-2,7-diamines, themselves obtained by the condensation cycli-zation of 4,6-diaminonicotinaldehyde and phenylacetonitrile <2000J(P1)1843>. Derivatives of cyanoacetic acid have rarely been used in the synthesis of naphthyridines, although a recent study has shown that they may be reacted with 4-piperidone derivatives to give [l,6]naphthyridines <2000CHE496>. 

A similar vinylogous Mannich reaction has been used by Martin in the total syntheses of the heteroyohimboid alkaloids (—)-ajmalicine and (—)-tetrahydroalstonine <1995JOC3236>. An attempted synthesis of an opioid analgesic 2,4-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one-l,5-dicarboxylate (piperidone) by a double Mannich reaction of oxoglutarate, 2 equiv of phenylacetaldehyde, and methylamine did not give the expected product but instead gave rise to an unexpected [l,6]naphthyridine derivative (Scheme 57) <1998PHA442>. 

D. Synthesis of Reduced Pyrazolo[3,4-c]pyridines 1. From 3-Piperidones... 

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