2-Piperidone ring system

Heinrich et al. 167) studied the reaction of (132) with the model compound N-acetyl-tryptophan amide at a constant pH of 4.7. At least ten different reaction products could be detected some of them were expected on the basis of the results obtained by previous workers. However, in the case of N-acetyl-tryptophan amide, the most stable and abundant product was found to be a compound (134) bearing a 2-piperidone ring system, which could arise from a cyclization of the presumed intermediate (133) in the reaction. 

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 new route has been developed for the efficient formation of the variably substituted indolo[2,3-a]quinolizine ring system, starting from a properly substituted 2-piperidone (103, 104). For the preparation of octahydroindolo-quinolizine (1), the unsubstituted 2-piperidone 139 was treated with triethox-onium tetrafluoroborate. Then the corresponding lactim ether 140 was alkylated with 3-chloroacetylindole followed by a subsequent two-step reduction process and Bischler-Napieralski ring closure. Finally, reduction of the C=N bond afforded ( )-l (104). 

Systems which can react by either 5-exo or 6-endo cyclization normally produce the five-membered ring system. Exceptions result when equilibration of the initially formed five-membered ring is facile and substitution electronically favors the 6-endo mode of cyclization. Several examples have been found in amidoselenation reactions.41158 216 216 232 For example, halocyclization of thioimidate (17) produced only the pyrrolidone product,217b 217c 233 while selenocyclization of amide (18) produced only the piperi-done product.232 Note that the cyclization of (18) to a piperidone also involves regioselectivity in the cyclization of an amide functionality to a lactam rather than an imidate. Both the ring size and type of product can be explained by equilibration. 

A derivative of the almost fully reduced imidazo[4,5-c]pyridine ring system, 3,3a,4,5,6,7-hexa-hydro-2//-imidazo[4,5-c]pyridine (357) has been prepared (Equation (29)) <88IZV409>. Cyclization of l-hydroxy-3-hydroxyamino-2,2,6,6-tetramethyl-4-piperidone oxime acetate (356) with benz-aldehyde or formalin at — 20°C for 3 d gave the reduced bicyclic compound (357). 

Perhydro-oxazolo[3,4- ]pyridines have long been prepared by condensation between the appropriate piperidyl-2-carbinol and an aldehyde or ketone. For example, the antidepressant spiropiperidine derivative (135) is obtained by the reaction between a-phenyl-2-piperidine methanol and N-benzyl-4-piperidone (81USP4260623). Perhydro-oxazolo[3,4-a]pyridin-3-one (136) is obtained by phosgenation of 2-(hydroxymethyl)piperidinium p-toluene sulfonate followed by cyclization of the resultant chloroformate salt by treatment with triethylamine in dichloromethane. This ring system... 

The reaction of thiosalicylic acids with A,A-dialkylacetamides with an electron withdrawing group at the 2-position leads to 2-dialkylamino-3-substituted thiochromones. The use of A-alkylated piperidones produces the benzothiopyrano[2,3-Z)]pyridine ring system <05AJC864>. Cyclisation of alkyl 2-mercaptophenyl ketones, prepared from thiosalicylic... 

Pyrolysis and smoke studies of amino acids indicate that they are potential precursors of several nitrogen heterocyclic ring systems found in tobacco smoke. Proline has been shown to be efficiently converted to pyrrole upon pyrolysis (3219, 3724) and in addition has been proposed as a possible precursor of pyrocoll (2593, 4336). y-Amino acids and dicarboxy-lic amino acids are capable, under pyrolytic conditions, of forming 2-pyrrolidones (1967, 3079) and by a similar mechanism, A-amino acids can form 2-piperidones (1967, 3079). A side effect of the pyrolysis of amino acids is the formation of hydrogen cyanide. 

Many ringed systems are included in the Howell-Walles patent,including a wide range of nitrogen-containing systems such as piperidones, oxazinidinone, oxa-zolidinone, morpholinone, caprolactam, succinimid, imidazolidinone, cyanuric acid, and hydantoin. 

N-Methyl-2-phenyl-A2-tetraJiydropyridine and similar compounds have previously been prepared by the hydrolysis and decarboxylation of a-benzoyl-N-methyl-2-piperidone3 and by the addition of phenyl Grignard reagents to N-methyl-2-piperidone followed by dehydration.4 Both of these methods require that a heterocyclic ring already be present in the system. In contrast, this procedure offers a new flexible route to the construction of five- or six-membered heterocyclic rings which may easily be incorporated into a larger polycyclic product. Several examples of this process that can be cited to demonstrate this utility are... 

Lactams are named in several ways. They are named as alkanolactams by the IUPAC substitutive system, such as 3-propanolactam, 4-butanolactam, 5-pentanolactam, and 6-hexano-lactam, respectively, for the 4-, 5-, 6-, and 7-membered rings, respectively. An alternate IUPAC method, the specialist heterocyclic nomenclature system, names these lactams as 2-azetidinone, 2-pyrrolidinone, 2-piperidinone, and hexahydro-2f/-azepi n-2-one, respectively. These lactams are also known by the trivial names fl-propiolactam, a-pyrrolidone (y-butyrolactam), a-piperidone (8-valerolactam), and e-caprolactam, respectively. 

The Chemical Development Drug Evaluation branch of Johnson Johnson Pharmaceutical Research Development LLC in Raritan, USA, investigated the ring-expansion reaction of N-Boc-4-piperidone with ethyl diazoacetate in a microreactor system as an example of processing hazardous substances [34],... 

For 2-piperidone, quaternary salts and alkaline salts were investigated as polymerization initiators, and the rate of polymerization was related to the dissociation constant. A novel polyamide, poly(tetrahydropyran-2,6-diyalaminocarbonyl) has been reported and was prepared in THF or DMSO at or below room temperature by ring-opening of the bicyclic oxalactam 8-oxa-6-azabicyclo[3.2.]]octam-7-one. No activator system was required. 

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