Nicotine reduction products

Phenyl-1-pyrroline is useful for various purposes.10 11 In particular, its reduction product, 2-phenylpyrrolidine, is important in the synthesis of pyrroloisoquinoline antidepressants,20 12 and can be a starting point in alkaloid synthesis.13 The overall reaction sequence described here has been used to prepare nicotine derivatives such as myosmine.2a b... 

In early work Stockman (8,9) had obtained an alkaloid preparation from khat which he called cathidine, and mass spectrometric examination of an old preparation led Luftmann and Spiteller (44) to the view that it was a mixture based on a reduction product of the evonine sesquiterpene core esterified with acetic, benzoic, trimethoxybenzoic, nicotinic, and evoninic acids. Ginsburg and colleagues (45) also examined cathidine which they had reisolated from khat and found that it contained at least four compounds. One of these, cathidine D, was studied in some detail and formulated as being either 28 or 29 (45). 

Nicotine replacement products have relatively few side effects. Nausea and light-headedness are possible signs of nicotine overdose that warrant a reduction of the nicotine dose. 

The production of metanicotine explains the formation of two reduction products from nicotine. Hexahydronicotine is 3, 2-piperidyl-iV-methylpyrrolidine, whereas hydrogenolysis of the pyrrolidine nucleus is involved in the formation of octahydrometanicotine, i.e., 4-0-piperidyl)-1-methylaminobutane, C5H10N - CH2 CH2 CH2 CH2 NH CH,. Hexahydrometanicotine is prepared by the reduction of metanicotine with sodium in alcohol (355) it is an optically inactive oil, b.p. 251-252°. Dihydrometanicotine is converted to octahydrometanicotine by reduction with sodium in alcohol (356). 

The reactions of anabasine have been studied for many years by Russian chemists. Hydrogenation of 1-anabasine with Raney nickel in aqueous suspension gives dZ-a, -dipiperidyl in alkaline suspension the product is l-a,(8 -dipiperidyl 103). With hydrogen peroxide in acetic acid at 60° A-methylanabasine gives the A,A -dioxide which is reduced by sulfur dioxide to the py-A-oxide, in a manner analogous to nicotine. Reduction of the A,A -dioxide with zinc and hydrochloric acid gives back A-methylanabasine 104). 

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). 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

Several total syntheses of antirhine (11) and 18,19-dihydroantirhine (14) have been developed during the last decade. Wenkert et al. (136) employed a facile route to ( )-18,19-dihydroantirhine, using lactone 196 as a key building block. Base-catalyzed condensation of methyl 4-methylnicotinate (193) with methyl oxalate, followed by hydrolysis, oxidative decarboxylation with alkaline hydrogen peroxide, and final esterification, resulted in methyl 4-(methoxycar-bonylmethyl)nicotinate (194). Condensation of 194 with acetaldehyde and subsequent reduction afforded nicotinic ester derivative 195, which was reduced with lithium aluminum hydride, and the diol product obtained was oxidized with manganese dioxide to yield the desired lactone 196. Alkylation of 196 with tryptophyl bromide (197) resulted in a pyridinium salt whose catalytic reduction... 

When the reduction is performed without control of the potential, a mixture of products results. Thus, reduction in sulfuric acid at lead or mercury cathodes of the pyridine carboxylic acids leads to a mixture of picolines andtetra- and hexahydropyridine derivatives.284-287 Derivatives of nicotinic acid are more apt to be reduced in the ring than the 2- and 4-carboxypyridines. Reduction of the corresponding pyridylcarbinoles under identical conditions produces a similar reaction mixture.287... 

That worked rather well Though reduction is needed to get the enamine, the final product must The same reduction of pyridinium be oxidized back to a pyridine again so there is no overall oxidation or reduction. Let s try adding s lts to tetrahydropyridines with a the same enamine to nicotinic acid as an electrophile. Now we need decarboxylation of both rings, oxidation of the left-hand ring, and reduction of the right-hand ring, all easily achieved with imines or enamines. 

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