1.2.3.6- Tetrahydropyridines

Amines undergo aminopalladation to alkynes. The intramolecular addition of amines to alkynes yields cyclic imines. The 3-alkynylamine 273 was cyclized to the 1-pyrroline 274, and the 5-alkynylamine 275 was converted into the 2,3,4,5-tetrahydropyridine 276[137]. Cyclization of o-(l-hexynyl)aniline (277)... 

A2acyclobutenes have been used to generate l-a2abutadienes, which are intramolecularly as weU as intermolecularly cycli2ed to give tetrahydropyridines, eg, hexahydroquinoli2in-4-one [87842-80-6] (64,65). In the following, FVP = flash vacuum pyrolysis. 

Sixty-two novel experimental carboxamides of 1,2,3,6-tetrahydropyridine have been tested as repellents of German cockroaches, and five provided 100% repeUency for 17 d in a stringent test (48). 

Some of the partially and fully reduced heterocyclic six-membered rings are sufficiently important to have trivial names with which the reader should be familiar. Thus hexahy-dropyridine (38) is known as piperidine, and tetrahydro-l,4-oxazine (39) is morpholine. Tetrahydropyridines are also sometimes referred to as piperideines, with the position of the double bond denoted by a A, but this system is obsolescent (at the least). 

The results so far recorded are those upon which Ladenburg chiefly based his formulae representing tropine and tropidine as A-methyl-J -tetrahydropyridines, substituted in position 2 by the residues. CHa. CH OH (or. CHOH. CH3) for tropine (XIV) and, CH CH for tropidine (XV) thus ... 

The separation of mixtures involving N-methyl-JLtetrahydropyridines into their pure components by means of gas-liquid chromatography was discussed in a report by Holik et al. (87). They found that, using tris(/3-cyanoethoxymethyl)-y-picoline as the stationary phase, the primary factors involved in the specific retention volumes of these enamines is the electronic effect of a methyl substituent and the nitrogen atom on the carbon-carbon double bond. It was observed that 1,3-dimethyl-Zl -tetrahydropyridine (141) has a smaller specific retention volume and, hence, is eluted before... 

When a pyridinium salt such as (27) is treated with sodium borohydride, the final product is the tetrahydropyridine (30). The mechanism for this reaction was proposed by Katritzky (65) and experimentally verified by Anderson and Lyle (66-68). The sequence is visualized as reduction of the... 

Lithium aluminum hydride reduction of pyridinium salts is very similar to sodium horohydride reduction and gives similar products, but the ratio of 1,2- and 1,4-dihydro- or tetrahydropyridines differs considerably (5). Isoquinolinium salts are reduced hy sodium borohydride or lithium aluminum hydride in a manner identical to pyridinium salts (5). Quino-linium salts are reduced by sodium borohydride to give primarily tetra-hydroquinolines (72) as shown by the conversion of 33 to 34 and 35. When lithium aluminum hydride is used, the product is usually the dihydroquinoline (73) as shown in the conversion of 36 to 37 and 38. 

Partial hydrogenation of pyrrole derivatives and partial dehydrogenation of pyrrolidines afford /I -pyrrolines (80-82). However, because of the complex nature of the reaction, it is of little preparative value. The same is true for isomerization of /) -pyrrolines to /) -pyrrolines (83). A photodehydrogenation of 2,6-dimethylpiperidine (26) has been observed recently, affording 2,6-dimethyl-3,4,5,6-tetrahydropyridine (27) in a good yield (84)-... 

Hofmann degradation of l,l-dimethyl-2-methylenepyrrolidinium hydroxide furnishes dimethylamine and dimethyl-3-pentynylamine 198). 1,1,4,4-Tetramethyltetrahydropyridinium hydroxide was obtained from l-dimethylamino-4,5-dibromopentane by means of silver oxide. Hofmann degradation of the product gives I,4,4-trimethyl-/j -tetrahydropyridine 199). 

Dihydro- and 1,4-dihydro derivatives are formed as intermediates in the reduction of quaternary pyridine salts and their homologues with sodium borohydride or formic acid. A proton is added to the present enamine grouping and the formed immonium salts are reduced to the l-methyl-l,2,5,6-tetrahydropyridine derivatives (157) and to completely saturated compounds (158) (254) (Scheme 14). 

Partial hydrogenation of the quaternary pyridinium salts in the presence of triethylamine on palladium in methanol has been used for the synthesis of a large number of alkaloids. The tetrahydropyridine derivatives thus formed undergo various cyclization reactions in acidic media (89). 

Fluorophenyl)-4-methoxy-1,2,5,6-tetrahydropyridine, mesitylenesul-fonic acid or TFA, CH2CI2, 76-91% yield." "... 

With Af-acyl or Af-sulfonyl hydrazines as nucleophiles, Zincke salts serve as sources of iminopyridinium ylides and ylide precursors.Reaction of the nicotinamide-derived Zincke salt 8 with ethyl hydrazino urethane 42 provided salt 43, while the tosyl hydrazine gave ylide 44 (Scheme 8.4.14). ° Benzoyl hydrazines have also been used in reactions with Zincke salts under similar conditions.Af-amino-1,2,3,6-tetrahydropyridine derivatives such as 47 (Scheme 8.4.15), which showed antiinflammatory activity, are also accessible via this route, with borohydride reduction of the initially formed ylide 46. ... 

Eda and Kurth applied a similar solid-phase combinatorial strategy for synthesis of pyridinium, tetrahydropyridine, and piperidine frameworks as potential inhibitors of vesicular acetylcholine transporter. One member of the small library produced was prepared from amino-functionalized trityl resin reacting with a 4-phenyl Zincke salt to give resin-bound product 62 (Scheme 8.4.21). After ion exchange and cleavage from the resin, pyridinium 63 was isolated. Alternatively, borohydride reduction of 62 led to the 1,2,3,6-tetrahydropyridine 64, which could be hydrogenated to the corresponding piperidine 65. 

Marazano and co-workers have used the Zincke reaction extensively to prepare chiral templates for elaboration to substituted piperidine and tetrahydropyridine natural products and medicinal agents. For example, 3-picoline was converted to Zincke salt 40 by reaction with 2,4-dinitrochlorobenzene in refluxing acetone, and treatment with R- -)-phenylglycinol in refluxing n-butanol generated the chiral pyridinium 77. Reduction to... 

Direct addition of Grignard reagents to Zincke-derived chiral pyridinium salts such as 99, meanwhile, allowed subsequent reduction to 1,2,3,6-tetrahydropyridines (e.g., 100, Scheme 8.4.32). This strategy provided entry to asymmetric syntheses of (-)-lupetidin and (+)-solenopsin. Tetrahydropyridines prepared by reduction of chiral... 

Quatemization of pyridine derivatives 271 with methyl iodide in acetone gave salts, which were reduced with sodium borohydride to tetrahydropyridines 272... 

When the pyridinyl substituted furazan 285 was treated with methyl iodide in acetone, the quaternary salt was formed. Reduction with sodium borohydride affords tetrahydropyridine derivative 286 (Scheme 187 see also Scheme 176) (92W003430). 

Stereocontrolled Additions to Dihydropyridines and Tetrahydropyridines Access to N-Heterocyclic Compounds Related to Natural Products... 

A number of dihydropyridines and tetrahydropyridines undergo cycloaddition reactions. 

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