Tetrahydropyridines, formation

Alkyl-1,4-dihydropyridines on reaction with peracids undergo either extensive decomposition or biomimetic oxidation to A-alkylpyridinum salts (98JOC10001). However, A-methoxycarbonyl derivatives of 1,4- and 1,2-dihydro-pyridines (74) and (8a) react with m-CPBA to give the methyl tmns-2- 2>-chlorobenzoyloxy)-3-hydroxy-1,2,3,4-tetrahydropyridine-l-carboxylate (75) and methyl rran.s-2-(3-chlorobenzoyloxy)-3-hydroxy-l,2,3,6-tetrahydropyridine-l-carboxylate (76) in 65% and 66% yield, respectively (nonbiomimetic oxidation). The reaction is related to the interaction of peracids with enol ethers and involves the initial formation of an aminoepoxide, which is opened in situ by m-chlorobenzoic acid regio- and stereoselectively (57JA3234, 93JA7593). 

The intramolecular cycloaddition has proven to be the method of choice for the preparation of steroids. A diastereomeric mixture of 204, prepared from 191 and tosylate 203 has been cleanly converted to dl-estra-1,3,5(10)-trien-17-one (205) in 85% yield (equation 130). A second example of the intramolecular cycloaddition reaction is the formation of the cycloadduct (209), the key intermediate in a synthesis of the As-pidosperma alkaloid aspidospermine, upon heating 208 at 600 °C (equation 131)124. The sulfone 208 can be prepared by reaction of 3-ethyl-3,4,5,6-tetrahydropyridine (206) with the acid chloride 207. 

Radical cyclizations of tetrahydropyridine scaffolds have been used to access diverse skeletal frameworks.An example of tandem radical cyclizations with two C-C bond formation is shown in Reaction (82). Treatment... 

Some cases are known in which Diels-Alder reactions of electron-deficient allenes and dienes compete with [2 + 2]-cycloadditions (see also Section 7.3.7) [12, 151, 335, 336]. Recently, a phosphane-catalyzed [4 + 2]-annulation starting from allenic ester 337 and N-tosylaldimines 338 was published [337]. However, the formation of the tetrahydropyridines 339 isolated in excellent yields is explained by a multi-step mechanism and only resembles a Diels-Alder reaction. 

Enol ethers 268a-c reacted with N-tosy]-4-vinylidene-l,3-oxazolidin-2-ones to give bicyclic tetrahydropyridine derivatives 269a-c (Table 12.12). Methyl /Tmcthoxyacry-late afforded 269c without formation of the [2 + 2] adduct. 

More recently, Menendez et al. reported a closely related four-component access to tetrahydropyridines, the amino alcohol being replaced by a primary amine and an alcohol. Thus, the cerium(IV) ammonium nitrate (CAN)-catalyzed reaction between primary aliphatic amines, 1,3-dicarbonyls, cx,p-unsaturated aldehydes, and alcohols resulted in the formation of 6-aUcoxy-2-methyl-l,4,5,6-tetrahydropyridines with... 

Inhibition mechanisms by A/-cyclopropyl MPTP analogues are also discussed in terms of two catalytic pathways, one of which is based on an initial SET step from the nitrogen lone pair, as proposed by Silverman, and the second is based on an initial a-carbon hydrogen atom transfer (HAT) step, as proposed by Edmondson, leading to a radical and dihydropyridinium product formation. The observation that MAO B catalyzes the efficient oxidation of certain 1-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridines to the corresponding dihydropyridinium metabolites suggests that the catalytic pathway for these cyclic tertiary allylamines may not proceed via the putative SET-generated aminyl radical cations [122], Further studies will be necessary to clarify all the facets of the mechanism of inhibition of MAO by cyclopropylamines. 

Perhaps one of the best known syntheses of a heterocyclic polymer via the modification method is the generation of nitrogen-containing ladder polymers by pyrolysis of polyacrylonitrile) (77MI11109). The thermolysis is known to take place in discrete steps. The first step in the sequence, which can take place with explosive violence if the heating rate is not sufficiently slow, occurs at about 150 °C and can be detected by the onset of intense color formation. The product of this reaction (Scheme 101) is the cyclic tetrahydropyridine ladder structure (209). The next step, which is conducted in the presence of air at ca. 250 °C, involves the thermooxidation of polymer (209) to form what is best described as terpolymer (210) containing dihydropyridine, pyridone and pyridine units. 

JOC2691). Analogously, in the reaction of chalcone (145) with the enaminonitrile 146, the intermediate dihydropyridine (147) can be detected only in trace amounts because it undergoes disproportionation with the formation of tetrahydropyridine (148) and pyridine derivatives (149) (92JOC7352). Fused 5,6-dihydropyridines (150) were obtained from cyclic... 

The photochemistry of certain A-substituted heterocycles has also been studied. As part of a continuing investigation of the photolysis of A-nitroso compounds in solution, the conversion of A-nitroso-3-azabicyclo[3.2.2]nonane (65) into the oxime (66) by photolysis in the presence of acid was reported.58 N-Nitrosopyrrolidine is similarly transformed. The mechanism of this reaction is said58 to involve elimination of NOH with the formation of an imine as intermediate, and, in fact, in the photolysis of 2-ethyl-A-nitrosopiperidine (67), the tetrahydropyridine (68) is the major product. This mechanism certainly does not operate in the photolysis of iV-nitroso-2-azacyclo-octanone, which can be rationalized on the basis of an intramolecular hydrogen transfer [Eq. (16)].59 Acyclic iV-nitrosoamides behave in a similar fashion to IV-nitrosoamines.60... 

Accepting the enthalpies of formation given by Jackman and Packam150 for all three imines results in a value of 40 14 kJ mol 1, considerably lower than experiment148. In principle, clarification of this discrepancy could be achieved by related studies on other 1-azacycloalkenes. However, except for an unsuccessful attempt148 for the corresponding 1-azacyclohexene (alternatively, A1-piperideine or 3,4,5,6-tetrahydropyridine) 65—its trimer fails to monomerize—we do not know of any such study. 

Amino-3,4,5,6-tetrahydropyridines were usually reacted with /3-oxo esters in the absence or presence of a base to give 6,7,8,9-tetrahydro-4//-pyrido[ 1,2-a ]pyrimidin-4-ones [83JHC393 85EUP132375, 85JOC166 88JCS(P1)2653]. In these cases the formation of the isomeric 6,7,8,9-tetrahydro-2Z/-pyrido[ 1,2-a]pyrimidin-2-one must also be considered (see Section II, C). 

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