Tetrahydropyridines reduction

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. 

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). 

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... 

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). 

The [2 + 2] cycloaddition reaction of A -benzyl-l,4-dihydropyridine 34b with acrylonitrile, followed by catalytic reduction gave two pairs of diastereoisomeric amides 36 and 37 with a low diastereomeric excess, probably due to the large distance between the asymmetric center and the site of acrylonitrile attack. Compounds 36 and 37 were resolved into the four individual diastereoisomers (ca 5% for compound 36 and 15% for 37) [97JCR(M)321], Irradiation of 1,4-dibenzyl-1,4,5,6-tetrahydropyridine 38 in the presence of 29 gave two stereoisomers. 

The synthetic utility of radical cyclization was used as the key step in a four-step synthesis of the natural product (d,0-epilupinine (134b, a quinolizidine alkaloid) (75CB1043) from methyl nicotinate (146). Thus, l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (140), obtained from methyl nicotinate (146), was cyclized to 141 (43%), which on reduction with LiAlH4 in THF provided 134b in 95% yield (89T5269). 

Alkylation of the tetrahydropyridine, 52 (obtained by reaction of a suitable protected derivative of 4-piperidone followed by dehydration and deprotection), with chloroacetonitrile affords 53, Reduction of the cyano group gives the diamine (54). Reaction of this intermediate with the S-methyl ether of thiourea affords guancycline (55). 

Secondary amines can be added to certain nonactivated alkenes if palladium(II) complexes are used as catalysts The complexation lowers the electron density of the double bond, facilitating nucleophilic attack. Markovnikov orientation is observed and the addition is anti An intramolecular addition to an alkyne unit in the presence of a palladium compound, generated a tetrahydropyridine, and a related addition to an allene is known.Amines add to allenes in the presence of a catalytic amount of CuBr " or palladium compounds.Molybdenum complexes have also been used in the addition of aniline to alkenes. Reduction of nitro compounds in the presence of rhodium catalysts, in the presence of alkenes, CO and H2, leads to an amine unit adding to the alkene moiety. An intramolecular addition of an amine unit to an alkene to form a pyrrolidine was reported using a lanthanide reagent. 

Dihydroxybenzoic acid (DHB) is also a commonly used tool to measure the pharmacological effects of HIF-la stabilization via PHD inhibition. Recently, it was shown that mice pretreated with DHB (100 mg/kg, i.p.) showed a marked resistance to the neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) via protection of dopaminergic cell loss and striatal denervation. Importantly, this protection was seen to coincide with HIF-la stabilization, and the prevention of the MPTP-induced loss of ferroportin and striatal iron. Additionally, in these studies, DHB was also observed to block MPTP-induced reduction in mitochondrial pyruvate dehydrogenase, at both the mRNA level and through the measurement of enzyme activity in midbrain substantia nigra [26]. 

The reduction of 1,2,5,6-tetrahydropyridine (THPY) with D2 in the presence of [Rh(NCMe)3Cp ]2+, yielding exclusive deuterium incorporation in the C3 and C4 carbon atoms, and the independent synthesis of [Rhfz/ fNJ-THPYfNC-Me)2Cp ]2+ showed that 1) (NJ-THPY complexes are not intermediate to piperidine production and 2) partially hydrogenated N-heterocycles are easily dehydrogenated to their aromatic precursors [55]. 

According to another approach, treatment of A-[2-(indol-3-yl)ethyl]-l,2,5,6-tetrahydropyridine (137), obtained from the corresponding pyridinium salt 136 by borohydride reduction, first with potassium rerf-butoxide, and then with acetic acid, led to ( )-l via key intermediate 135 in 78% yield (102). 

A stereoselective total synthesis of ( )-hirsutine has been developed by Brown et al. (179). Catalytic hydrogenation of hydroxycyclopentenone 327, prepared previously (180), afforded a mixture of isomeric diols 328, which were quantitatively cleaved by sodium periodate to supply 329. Reductive amination of 329 with tryptamine resulted in tetrahydropyridine 330, which upon treatment with aqueous methanol in the presence of hydrochloric acid gave indolo-[2,3-a]quinolizine 321 with pseudo stereochemistry. Conversion of 321 to ( )-hirsutine was accomplished in a similar manner by Wenkert et al. (161) via selective reduction with diisobutylaluminum hydride and methylation with methanol (179). 

Pyridine and its homologs can be reduced completely to hexahydro derivatives, or partially to dihydro- and tetrahydropyridines. Catalytic hydrogenation is faster than with the corresponding benzene derivatives and gives only completely hydrogenated products. Partial reduction can be achieved by different methods (pp. 55, 56). 

If the quaternary nitrogen is a member of a ring, the ring is cleaved. 3-Benzyl-2-phenyl-A, A -dimethylpyrrolidinium chloride was cleaved by hydrogenation over Raney nickel at 20-25° almost quantitatively to 2-benzyl-4-dimethylamino-l-phenylbutane [722]. Reduction of methylpyridinium iodide (and its methyl homologs) with sodium aluminum hydride gave 24-89% yields of 5-methylamino-l,3-pentadiene (and its methyl homologs) in addition to A -methyl dihydro- and tetrahydropyridine [448]. 

Electrolytic reduction using a lead cathode in 20% sulfuric acid converted pyridine a-carboxaldehyde to a mixture of 41% of a-picoline, 25% of a-pipecoline and 11% of 2-methyl-1,2,3,6-tetrahydropyridine [443]. 

Electron transfer reduction of pyridines in both acid and alkaline solution generates the protonated radical-anion. This rapidly accepts a further electron and a proton to give a mixture of dihydropyridines. Enamine structures in these dihydro-pyridines can tautomerise to the imine, which is more readily reduced than the original pyridine molecule. Further reaction of the 1,4-dihydropyridine leads to piperidine while reduction of the t, 2-dihydropyridine leads to a tetrahydropyridine in which the alkene group cannot tautomerise to the imine and which is not therefore reduced to the piperidine stage. The reaction sequence is illustrated for 2,6-dimethyl-pyridine 18 which yields the thermodynamically favoured cis-2,6-dimethylpiperidine in which the two alkyl substituents occupy equatorial conformations. 

In this case the aqueous conditions permit protonation at C-5 after the first hydride addition, thereby setting up the next hydride transfer. The reduction stops before the ring is fully saturated, however, as the lone pair electrons on the N atom of the 1,2,5,6-tetrahydropyridine are not conjugated with the C=C double bond i.e. further activation by protonation is not possible). 

Reduction of 1,2,5,6-tetrahydropyridines to A-alkylpiperidines requires catalytic hydrogenation. 

Treatment of (16-3) with sodium borohydride leads to the selective reduction of the enamine bond to lead to the tetrahydropyridine (16-4). This intermediate undergoes ring closure with a strong acid to give the benzomorphan (16-5) in direct analogy to the more complex morphinans. The product consists predominantly of the isomer that bears the equatorial secondary methyl group [18],... 

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