Quinuclidin-3-ones

Interesting chemical properties were discovered in such bicyclic amides as quinuclidin-2-one (3).43-46 In this type of compound the axis of the nitrogen p electrons is orthogonal to the w electrons of the carbonyl group. As a result the necessary condition for conjugation, i.e., parallel axes of n and p electrons with maximum overlap, is not observed. This is why the conjugation of type... 

These structural peculiarities make some properties of quinuclidin-2-ones closer to those of aminoketones than of amides. The nitrogen of quinuclidin-2-one is easily protonated (common amides and lactams are O-protonated) and can be methylated. They are very basic (pK 5.33-5.6)44 compared with other amides (e.g., A-acetyl-piperidine, pK 0.4). 

Carbonyl group frequencies for quinuclidin-2-ones are on the average 80 cm-1 higher than for common lactams, and integral intensities of the same absorptions are nearly half those of quinuclidin-2-ones. Ultraviolet (UV) absorption maxima for quinuclidin-2-ones are midway between those for amides and ketones. On account of the lack of amide mesomerism quinuclidin-2-ones gain in reactivity. This is shown by the rather high rates of hydrolysis of such compounds... 

Intramolecular acylation in piperidines also is used to build up a quinuclidine ring. By this method Yakhontov and Rubtsov,43 and later Pracejus,44,45,101 synthesized quinuclidin-2-one (3) and its 6,6-dimethyl and 6,6,7-trimethyl derivatives, starting from the corresponding acid chlorides, by the action of potassium carbonate or tertiary amines. 

Quinuclidin-3-one is the most easily accessible of the keto derivatives of quinuclidine. Quinuclidin-2-ones have been investigated less and at the present time are not much used as starting compounds for synthetic work. 

Rotation about bonds which increases the dihedral angle between p-orbitals on adjacent atoms does decrease resonance interaction. For example, the increased basicity of the quinuclidin-2-one [25] may be attributed to decreased amide resonance. Similarly, the energy barrier to rotation about... 

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. 

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). 

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. 

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

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 ... 

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. 

Treatment of GaH3(quin) (quin = quinuclidine) with 1 equivalent of the sterically bulky formamidine as shown in Scheme 40 resulted in formation of a monomeric amido-gallane complex containing a monodentate amidinate ligand. Reaction of this species with a second equivalent of the amidine led to displacement of the quinuclidine ligand and formation of a five-coordinate monohydride complex, which could also be prepared directly by a one-pot reaction of GaHsfquin) with the free amidine in a molar ratio of 1 2 ... 

We have compared, the rate acceleration effect induced either by the CD and different moieties originated from CD, i.e quinuclidine and quinoline. These experiments were carried out in ethanol If the relative rate of racemic hydrogenation is equal to one the following relative rates has been measured quinoline = 2, quinuclidine = 3, cinchonidine = 40. In the presence of quinoline a short induction period was needed to observe the rate acceleration. It is suggested that during this period quinoline was partly hydrogenated. Other tertiary nitrogen bases, such as triethylamine, triethylenediamine, etc. resulted also rate acceleration with relative rate = 2-4. 

This new process has one unexpected benefit the rates and turnover numbers are increased substantially with the result that the amount of the toxic and expensive 0s04 is considerably reduced (usually 0.002 mole %). The rate acceleration is attributed to formation of an Os04-alkaloid complex, which is more reactive than free osmium tetroxide. Increasing the concentration of 1 or 2 beyond that of 0s04 produces only negligible increase in the enantiomeric excess of the diol. In contrast quinuclidine itself substantially retards the catalytic reaction, probably because it binds too strongly to osmium tetroxide and inhibits the initial osmylation. Other chelating tertiary amines as well as pyridine also inhibit the catalytic process. 

Recently, Vayner and coworkers [239] have revisited the model proposed by Augustine et al. [34] which is based on the assumption that the QN can make a nucleophilic attack to an activated carbonyl. According to this model the two possible zwitterionic intermediates that can thus be formed have different energies, which leads to the selective formation of one of the two intermediates, and, therefore, to e.s. after hydrogenolysis by surface hydrogen. This model nevertheless does not explain the e.d. of nonbasic modifiers, such as the one reported by Marinas and coworkers [240], which have no quinuclidine moiety and no nitrogen atom, and thus no possibility to form zwitterionic intermediates. Furthermore, in situ spectroscopic evidence for hydrogen bond formation between the quinuclidine moiety of cinchonidine and the ketopantolactone has been provided recently [241], which supports the hypothesis of the role of weak bond formation rather than the formation of intermediates such as those proposed by Vayner and coworkers. 

One of the possible ways to stabilize the amine-halonium complexes is to increase the basicity of the amine, bearing in mind that an appropriate one must also not have easily removable P-hydrogens which will lead to oxidation of the amine and formation of an imine. Quinuclidine (pKa of quinuclidinium ion is 11.3 (55)) is 105-106-fold more basic than the pyridines and both the bromonium (10 (36)) and iodonium (11 (57)) BF4 salts have been made and characterized by X-ray crystallography. Interestingly, although the reaction must generally occur as outlined in Figure 7, neither of these ions shows any observable reaction... 

An elecrophilic Br+ or I+ can be successfully transferred to hydroquinidine (13) and two of its commercially available derivatives (4-chlorobenzoate and 9-phenanthryl ether hydroquinidines) simply by mixing two equivalents of the hydroquinidine with one equivalent of sym(co d ne)2-X+ perchlorate in methylene chloride or acetonitrile. H NMR studies (31) showed that the iodonium ion was associated with the nitrogen at the quinuclidine portion of the hydroquinidine instead of the aromatic nitrogen and also that all of the sym-collidines were removed from the X+ since only free collidine and no collidine-I+ peaks were observed. The (hydroquinidine)2-halonium ion is stable in solution for more than 30 minutes at room temperature these ions (and their parent amines) are more soluble in methylene chloride than in acetonitrile, and having R group other than hydrogen also improves the solubility. 

One aspect of asymmetric catalysis has become clear. Every part of the molecule seems to fulfill a role in the process, just as in enzymic catalysis. Whereas many of us have been used to simple acid or base catalysis, in which protonation or proton abstraction is the key step, bifunctional or even multifunctional catalysis is the rule in the processes discussed in this chapter.Thus it is not only the increase in nucleophilicity of the nucleophile by the quinine base (see Figures 6 and 19), nor only the increase in the electrophilicity of the electrophile caused by hydrogen bonding to the secondary alcohol function of the quinine, but also the many steric (i.e., van der Waals) interactions between the quinoline and quinuclidine portions of the molecule that exert the overall powerful guidance needed to effect high stereoselection. Important charge-transfer interactions between the quinoline portion of the molecule and aromatic substrates cannot be excluded. 

The notable mode of stereoselectivity of Cinchona alkaloids is presented by its psendoenantiomeric pairs which can be employed to generate either enantiomer of chiral prodnct. Key moieties that are central to Cinchona alkaloids are the quinuclidine nitrogen and the adjacent C(9)-OH (the N-C(8)-C(9)-OH moiety) (Fig. 2). In psendoentiomeric alkaloids in the natural open conformation, the torsion angle N-C(8)-C(9)-0 are opposite in sign Q and CD are (-), and thereby induce selectivity for one enantiomer, whereas QD and C are (-I-) and afford the other enantiomer [28, 29],... 

The chair conformation of l-hydroxy-2,2,6,6-tetramethylpiperidin-4-one at 120 °C has been confirmed by ED (74ACS(A)67l). In the corresponding free radical at 125 °C the chair form is slightly flattened (74ACS(A)675), and is in the twisted boat form in the solid state (see Section 2.04.2.2). ED measurements on quinuclidine are also available (80JST(65)297). 

A novel approach to the synthesis of a 1,5-naphthyridine starts from quinuclidin-3-one (143), which is first converted to the 2-arylidene derivative and then reacted with phenacyl-pyridinium bromides and ammonium acetate to give l,4-ethano-3,4-dihydro-2//-l,5-naph-thyridines (144) (82S27). 

Functionalization of the double bond of 2-azabicyclo[2.2.2]oct-5-ene derivatives has been shown to be remarkably regjoselective. Thus, oxymercuration [112] and selenohalogenation [113] lead to adducts which are convenient precursors of iso-quinuclidin-5-one and -6-one, respectively. This means an excellent control of the polarity at the double bond termini by the nitrogen atom (Note that simple allylic urethanes also undergo regioselective oxymercuration). 

The carbamate was converted to 2 using a stoichiometric amount of NaH (which is associated with safety concerns) and (J )-quinuclidin-3-ol. Despite using more than one equivalent of the expensive (J )-quinuclidin-3-ol, the transformation was found to be low yielding, as a substantial amount of unreacted starhng material was recovered and the isolation became cumbersome. Thus the process cannot be regarded as green, and the development of an eco-friendly and catalytic synthesis for solefinacin (2) is warranted. 

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