Quinuclidine

Quinuclidines — see also l-Azabicyclo[2.2.2]octanes electron diffraction, 2, 117 microwave spectrum, 2, 107 NMR, 2, 121... 

Quinuclidine (l-azabicyclo[2.2.2]octane) 10.95. Crystd from diethyl ether. 

It has already been shown that both the laevorotatory and dextrorotatory cinchona alkaloids on degradation yield scission products from the quinuclidine nucleus, which are structurally and optically identical, for example, meroquinenine, [a] -f- 27 6° d-/3-cincholoiponic acid. 

These changes have been experimentally demonstrated only for quinine and quinidine, but in view of the optical identity of the quinuclidine degradation products from the principal cinchona alkaloids, it may be assumed that in all of them the total dextrorotatory effect at C and C is made up of a dextrorotatory effect at C exceeding a laevorotatory effect at C. ... 

The cinchona alkaloids on degradation break down into derivatives of (1) quinoline and (2) quinuclidine and the synthesis of any one of them involves the preparation of each of these two halves in a form suitable for combination. 

Much interesting work has been done in the last ten years on the bridging of pyrrole and piperidine rings. Early in their work on this subject Clemo and Metcalfe (1937) prepared quinuclidine (V) by the reduction of 3-ketoquinuclidine (IV), the latter resulting from the hydrolysis and decarboxylation of the product (III) of a Dieckmann internal alkylation, applied to ethyl piperidine-l-acetate-4-carboxylate (II), itself made by condensing ethyl piperidine-4-carboxylate (I) with ethyl chloroacetate. 

This synthesis came shortly after one by Prelog, Kohlberg, Cerkovnikov, Rezek and Piantanida (1937) based on a series of reactions which, with modifications and extensions. Prelog and his colleagues have applied to the syntheses of bridged heterocyclic nuclei, of which this is an example. 4-Hydroxymethyltetrahydropyran (VI R =. OH) is converted via the bromo-compound (VI R = Br) and the nitrile (VI R = CN) into tetrahydropyran-4-acetic acid of which the ethyl ester (VII) is reduced to 4-()3-hydroxyethyl)-tetrahydropyTan (VIII). This is converted by fuming hydrobromic acid into 3-(2-bromoethyl)-l 5-dibromopentane (IX) which with ammonia in methyl alcohol yields quinuclidine (V). 

Work also prepared a series of carbinolamines and polyamines without a quinoline nucleus but, in other respects, conforming in type and range of molecular weight, with quinoline compounds known to possess plasmocidal activity. As none of these were active, it seems clear that the quinoline nucleus in the cinchona alkaloids and in certain synthetic anti-malarials is a potent factor in the production of plasmocidal action. Later the same author made (1942) a series of lepidylamine derivatives of the form R. Q. CHj. NH[CH2] . NEtj, which were found to be inactive, in spite of their similarity to the active examples of the type R. Q. NH[CH2] . NEt2 prepared by Magidson and Rubtzow. Rubtzow (1939) has also shown that an isomeride of dihydroquinine (II) with the quinuclidine nucleus attached via the carbinol group at C in the quinoline nucleus was inactive in an infection of Plasmodium prcecox in finches. 

The alkyl ethers of dihydrocupreine (II) are known to exhibit local anassthetic action, which appears to be at a maximum at woamyldihydro-cupreine, but local anassthetic action in this group does not depend on the intact quinuclidine nucleus, since woamyldihydrocupreicine (VII) is more potent than isoamyldihydrocupreine (II), producing local anassthesia in the cornea of the rabbit at 1 in 2,000 compared with cocaine at 1 in 50. ... 

Quinolylpiperidylcarbinols, syntheses, 460 Quinolylquinuclidine alkaloids, 418 Quinotoxine, 425. See also Quinicine. /3-isoQuinotoxine, 444, 454 Quinovatine, 466. See also Aricine. Quinuclidine, 436, 443... 

The fluoraza reagents consist of two types of compounds one in which a fluorine atom is bound to the nitrogen atom of an amide or, more often, a sulfonamide and one in which a fluorine atom is bound to the nitrogen atom of a tertiary amine such as pyridine, quinuclidine, or triethylenediamine 1,4-diaza-bicyclo[2 2.2]octane. The positive charge on the nitrogen is counterbalanced by a non-nucleophilic anion such as triflate or tetrafluoroborate. 

This apparent characteristic enhancement in the basicity has been used quite frequently for the determination of the position of a double bond with respect to the nitrogen atom in unsaturated amines. The cases such as neostrychnine (134) and dehydroquinuclidine (139) in which the protonation at the 8-carbon atom cannot occur due to the lack of overlap between the electron pair on the nitrogen atom and the tt electrons of the double bond, since this would involve the formation of a double bond at the bridgehead— a violation of Bredt s rule—show a decrease in basicity. For instance the basicities of quinuclidine (140) and dehydroquinuclidine (139) have been shown by Grob et al. (82), to differ by 1.13 pK units in aqueous solution at 25. This decrease in basicity has been attributed to the electron-withdrawing inductive effect of the double bond. 

The simplest examples of this type of compound are enamines derived from the quinuclidine skeleton (67). The formulation of enamines of qflmuclidine in a inesomeric form would violate Bredt s rule. Actually, the ultraviolet spectrum of 2,3-benzoquinuclidine shows that there exists no interaction of aromatic ring tt electrons and the nitrogen-free electron pair (160,169). The overlap of the olefinic tt orbital and the lone pair orbital on nitrogen is precluded. 

Some enamines with special structural features are those derived from ammonia (19 ) and the quinuclidine enamines (19J). Aminocyclobutenes... 

Quinuclidine, toluene, reflux. In dibenzyl phosphates, only one benzyl group is removed. 

The following picture shows electron density surfaces for ammonia, trimethylamine and quinuclidine. The surfaces are qualitatively very similar to the space-filling models. 

Together with a shift of the proton from the a-carbon to the alkoxide oxygen, the tertiary amine is eliminated from the addition product to yield the unsaturated product 3. Early examples of the Baylis-Hillman reaction posed the problem of low conversions and slow reaction kinetics, which could not be improved with the use of simple tertiary amines. The search for catalytically active substances led to more properly adjusted, often highly specific compounds, with shorter reaction times." Suitable catalysts are, for example, the nucleophilic, sterically less hindered bases diazabicyclo[2.2.2]octane (DABCO) 6, quinuclidin-3-one 7 and quinuclidin-3-ol (3-QDL) 8. The latter compound can stabilize the zwitterionic intermediate through hydrogen bonding. ... 

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

The 3-chloromelhyl-quinuclidine hydrochloride used as starling material in this process can be obtained as described by Grob and coll., Helv. Chim. Acta, 37 (1954), 1689. 

Chinchona alkaloids, such as quinine, are readily available quinuclidine chiral bases which have been used extensively in catalytic Michael additions239 243. Methy 1-2,3-dihydro-1-oxo-l/f-in-dene-2-carboxylate (1) is most frequently used as the Michael donor in these studies. Enantiose-lectivities as high as 76% are reached in the additions to 3-buten-2-one. Modest enantioselec-tivities (< 67%) were also obtained with ethyl 2-oxo-l-cyclohexanecarboxylate and methyl l,3-dihydto-3-oxo-l-isobcnzol urancarboxylate244 245. 

Europium, tris(2,2,6,6-tetramethyl-3,5-heptanedione-quinuclidine)-stereochemistry, 1, 81 Europium complexes... 

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