3- hydroxy-quinuclidine

Leonard and Elkin s08 cyclodehydration of 4-(/3-hydro xyethyl)-piperidine (43) in the gas phase can be considered as an intramolecular alkylation. The same method was used for synthesis of 3-hydroxy-quinuclidine (44) from 4-piperidylethane-l,2-diol (45).00... 

In the course of investigations on allylic and acetylene-allene rearrangements of 3-substituted quinuclidines, it was found that by oxidation and ozonolysis of compounds with functional groups at positions allylic to the double bond, not only the double bonds but also the adjacent carbon-carbon bonds are broken. For example, in the oxidation of 3-hydroxy-3-vinylquinuclidine (119), with potassium permanganate under mild conditions, and in its ozonolysis, qui-nuclidin-3-one (2) is formed along with 3-hydroxy quinuclidine-3-carboxylic acid.161 The positions of double bonds in such systems can be firmly established by NMR spectroscopy, but not by oxidative methods.101... 

Historically, the most effective N-based organic catalysts were nucleophilic unhindered tertiary amines such as DABCO (diazabicyclo[2.2.2]octane, 1) [23], qui-nuclidine (2), 3-hydroxy quinuclidine (3-HDQ, 3), 3-quinuclidone (4) and indoli-zine (5) (Fig. 5.1) [24]. A direct correlation has been found between pKa and the activity of the quinuclidine-based catalysts the higher the pKa, the faster the rate [25]. More recently, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 6), considered as a hindered and non-nucleophilic base, was shown to be a better catalyst than DABCO, or 3-HDQ [26]. The reason for the increased reactivity for this catalyst was attributed to stabilization of the zwitterionic enolate by delocalization of the positive charge. Other N-based catalysts such as N,N-(dimethylamino)pyridine... 

We chose 2-chlorotrityl chloride resin for the attachment of acrylic acid, because in solution-phase chemistry the best results have been obtained by using aryl acrylates or (erf-butyl acrylates [21], In addition to DABCO (1,4-diazabicyclo [2.2.2]octane) - the most common tertiary cyclic amine for this type of reaction - we also used the more reactive 3-quinuclidinol (3-hydroxy-quinuclidine, 3-HQN) for the Baylis-Hillman reaction with aldehydes. We used 26 different aldehydes and obtained good to excellent purities, as determined by analytical HPLC. 

To find the structure-activity relationships in this series esters of both non-substituted 3-hydroxyquinuclidine and 3-hydroxyquinuclidines having various substituents in the 3-, 6- and other positions have been synthesized. Esters of homologous aminoalcohols 3-hydroxymethyl- and 3-(j8-hydroxyethyl)-qui-nuchdines, esters of isomeric and homologous 1-azabicycloalkanols - 1-aza-bicyclo(3,2,l)-octanol-6 and l-azabicyclo(3,3,2)-nonanole-4 and also esters containing the opened 3-hydroxy-quinuclidine structure, e.g. AT-alkyl-3-hy-... 

In this group the following compounds have been studied four 3-hydroxy-quinuclidine esters with phenylaliphatic acids, i.e. the phenylacetic (IVi), phenylpropionic (IV k), phenoxyacetic (IV1) and cinnamic (IVm) esters, and two esters of 3-hydroxyquinuclidine with diphenylaliphatic acids, i.e. the diphenylpropionic (IVo) and benzilic esters (IVp). 

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 cursory examination of the Cinchona catalysts used in O Donnell-type alkylation [90] of methyl (diphenylimino)glycinate (Appendix 7.A) reveals that only minor modifications to the Cinchona scaffold are required for the synthesis of a catalyst the 8-substituent on the quinuclidine core may either be a vinyl group (as in the parent alkaloids, quinine and quinidine) or can be an ethyl substituent, introduced by hydrogenation. The quinoline system at the 2-position ofthe quinuclidine ring can be unsubstituted if the catalyst is derived from quinine or quinidine, but can contain a 6-methoxy group ifit is derived from cinchonine or cinchonidine. The 3-position ofthe quinuclidine ring may contain either a hydroxy group or else a vinyloxy or benzyloxy... 

Cinchona alkaloids, naturally ubiquitous /3-hydroxy tertiary-amines, are characterized by a basic quinuclidine nitrogen surrounded by a highly asymmetric environment (12). Wynberg discovered that such alkaloids effect highly enantioselective hetero-[2 -I- 2] addition of ketene and chloral to produce /3-lactones, as shown in Scheme 4 (13). The reaction occurs catalytically in quantitative yield in toluene at — 50°C. Quinidine and quinine afford the antipodal products by leading, after hydrolysis, to (S)- and (/ )-malic acid, respectively. The presence of a /3-hydroxyl group in the catalyst amines is not crucial. The reaction appears to occur... 

In the reaction of the hydroxy ester (87) with methylmagnesium iodide the process stops at the ketone (91) stage. The pinacols were investigated under various pinacolone rearrangement conditions.144 By a Grignard reaction of 2-cyanoquinuclidine (92), 2-benzoyl-quinuclidine (93) has been prepared.49... 

Selective reduction of 3-ethynyl-3-hydroxyquinuclidine (118, R = H) yields 3-hydroxy-3-vinylquinuclidine (119).130 This was also synthesized directly from quinuclidin-3-one (2) and vinylmagnesium bromide.161... 

Various reactions of quinuclidin-3-one have led to the synthesis of two series of geometrical isomers of 3-substituted quinuclidines with semicyclic double bonds 3-ethylidene,130-157> 102 3-()9-hydroxy-ethylidene)-,136 157 and 3-(j8-chloroethylidene)-quinuclidines157 (Scheme 4). Some inter con versions of compounds within each series were realized157 and-the configurations of each compound were established by NMR spectroscopy.16 157.103... 

EtOH), were first isolated in 1872 and 1877, respectively (14). Quin-amine was observed to give indole color reactions (7, 15), and 2,3-dimethylindole was a result of zinc dust distillation of the alkaloid (15). With chromic acid (9), the quinuclidine carboxylic acid (III) was obtained, and with nitric acid 3,6,8-trinitro-4-hydroxyquinoline was isolated (15, 16). This quinoline is a consequence of fission of the indole and recyclization, with nitration preceding and following these steps [cf. ozonolysis of yohimbine to furnish a 2,3-disubstituted 4-hydroxy-quinoline (17)]. 

A transition-state model of the Orito reaction is presented at the end of the section although various models have been proposed on many occasions, the structure shown in Figure 10.2 is currently the most reliable. The CD is adsorbed onto the catalyst surface with the quinoline ring facing against the surface, while the hydroxy group stays near the surface. In this conformation (the so-called Open-3 ), the ammonium proton at the quinuclidine interacts with the carbonyl and is reduced. 

The photolysis of the Cinchona alkaloids in neutral solution results in cleavage of the bond between the aromatic ring and the carbon atom (C-9) carrying the secondary hydroxy-group quinidine (272), for example, gives 6-methoxyquinoline and the quinuclidine aldehyde (273) in moderately good yield (50—60%) (Scheme 45). This contrasts with photolysis in acid solution, which is reported to result simply in the formation of 9-deoxy-derivatives. 

The tertiary alcohols necessary for these syntheses were obtained by interacting quinuchdon-3 with Grignard reagents. Subsequent dehydratation of 3-hydroxy-3-alkyl(aryl)-quinuclidines afforded 3-aryl-Zl -dehydroquinuclidines and 3-alkylidenequinuclidines, the reduction of the double bonds of which gave 3-alkyl(aryl)-quinuclidines [108, 37]. 

When quinamine was refluxed in dilute acetic acid for a prolonged period it afforded the ketoamine, quinamicine, which may have been the result of a direct loss of water or more likely an allylic rearrangement of the tertiary hydroxyl group in the hydroxy-methyleneindoline form then elimination (the hydroxyl cannot be lost to form the iminium ion because of the bridgehead position of the quinuclidine nitrogen). The formulation of quinamicine is the only reaction of these compounds which has any parallel in... 

An alternative approach entails the formation of an epoxide and then simultaneous formation of the quinuclidine ring and introduction of the hydroxy-group. Unfortunately all four possible diastereomers were obtained (Scheme 61). 

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