Quinuclidine carboxylic acids

Koenigs method for quinuclidine ring closure was applied by Rubtsov90,91 and Grob 92,93 to the intramolecular alkylation of a-halogeno acids and esters of piperidines. Rubtsov and Dorokhova 90 developed a simple five-step method for the synthesis of quinuclidine-2-carboxylic acid (39). 

Condensation of y-picoline with mesoxalic ester yielded 4-(j8,j8-diethoxycarbonylvinyl)pyridine (35). The unsaturated ester (35) was hydrogenated with platinum catalyst to form 36 which was treated with bromine. 4-(j8-Bromo-j8,j8-diethoxycarbonylethyl)-piperidine (37) was obtained and was cyclized with pyridine to 2,2-die th 0 xycarbony 1 quinuclidine (38). Hydrolysis of 38 and partial decarboxylation gave quinuclidine-2-carboxylic acid (39). 

The above method of cyclization of a-halogenoesters of the piperidine series was widely used for the preparation of various 2,3-and 2,5-disubstituted quinuclidines 3-carboxymethylquinuclidine-2-carboxylic acid (40),04 3-methylquinuclidine-2-carboxylic acid (41),05 5-(/ -hydro xyethyl and /3-methoxyethyl)quinuclidine-2-carboxylic acids (42).98,07... 

These methods were used for the preparation of quinuclidine,301114 117 2-,23,24 g 24 ancj 4-alkylquinuclidines,25 and quinuclidine-2-carboxylic acid.118 Prelog s attempts to prepare quinine analogs by quinuclidine ring closure starting from the tribromoalkyl derivative (57) failed.119... 

However, the preparation of quinuclidine derivatives starting from tribromoalkanes and dibromoalkylamines may be difficult because the starting compounds require multistage syntheses resulting in poor yields. Prelog s scheme is also less useful for the formation of quinuclidine derivatives with functional groups, e.g., quinuclidine-2-carboxylic acid (39),118 which requires twelve steps with overall yield of only 4%. In the five-step synthesis starting from y-picoline the yield is 30%.00... 

For this reason reactive groups are usually introduced before quinuclidine ring closure and various transformations are effected afterward. The carboxyl and carbonyl derivatives, e.g., quinuclidine-2-carboxylic acid, quinuclidin-3-one, and so on, are useful compounds containing such functional groups. Nearly all substituted quinuclidines were obtained from their carboxylic acids and carbonyl derivatives by common synthetic methods. 

At the present time quinuclidine 2-,90,118 3-,121 122 and 4-mono-carboxylic acids 97,100 are known as well as quinuclidine-2- carboxylic acids with various substituents at positions 395,108 or 5 99,110 and quinuclidine-3-carboxylic acids substituted at positions 2123 or 6.U1 Only one compound with two carboxylic groups in the quinuclidine ring, the 2,3-dicarboxylic acid, has been described.109 Homologs of many quinuclidinecarboxylic acids have been prepared, among which quinuclidine-3-acetic124-127 and 3-carboxymethylquinuclidine-2-carboxylic acids94 are interesting for subsequent transformations. 

Scheme 12.17 Synthesis of enantiopure 5-quinuclidine-2-carboxylic acid ester. Reagents and conditions (a) 1. B0C2O, 2. DMSO, (COCI)2, Et3N, rt (b) NaCN, HCI, H20 (c) MsCI, Et3N, CH2CI2 (d) 1. F3CC02H, CH2CI2, 2. Et3N (e) (+(-tartaric acid, EtOH, H + (f) 1. (COCI)2, 2. MeOH, 3. Ba(OH)2.

To our knowledge, one alternative route to simple enantiopure quinuclidine-2-carboxylic acid has recently been described by Corey who assembled target molecule 68 whereas racemic 68 was first synthesized several decades ago by Prelog and [44]. Parent quinuclidine-2-carboxylic acid ester 68 that is structurally related to proline and pipecolinic acid was obtained from commercial 4-(2-hydroxyethyl)-piperidine in six chemical steps including one tartaric acid-mediated resolution (Scheme 12.17) [45]. A cyanoactivated intramolecular SN2 reaction delivered the strained [2.2.2]bicyclic system. The cyano group serves as a handle of further functionality and elaboration. 

A wide-ranging investigation of quinuclidine derivatives was started in 1953 by M. V. Rubtsov who in collaboration with M. I. Dorokhova devised a simple method for preparation of quinuclidine-2-carboxylic acid [62]. The synthesis is basically condensation of y-picoline with mezoxalic esters followed by reduction of the unsaturated diester (IX) to a piperidine compound (X) and cyclization of the bromoderivative thereof (XI) to 2,2-diethoxycarbonylquinuclidine (XII). Hydrolysis and partial decarboxylation of compound XII yield quinuclidine-2-carboxylic acid (XIII), a key substance in the synthesis of the various 2-sub-... 

Dickmann intramolecular cyclization was later used for the synthesis of other quinucHdine derivatives containing reactive functional groups i.e. 5-keto-quinuclidine-2-carboxylic acid, 6-methyl- and 6,7-dimethylquinuclid-3-ons [78-80]. The development of practical synthetic processes for making jS-keto-and a-carboxyquinuclidine derivatives, the first of which were for quinuclidon-3. 

Research work by Soviet scientists has an important place in this work [1, 63, 64]. Devising a practical process for quinuclidine-2-carboxylic acid production provided a basis for the production of a variety of 2-substituted quinuclidines the first of which were alkaminoesters, amides and hydrazides of quinuclidine-2-carboxylic acid [90-93]. Analogous compounds were also synthesized starting from 3-methoxycarbonyl-quinuclidine-2-carboxylic acid, 5-keto-quinuclidine-2-carboxylic acid and other quinuclidine-2-carfeoxylic acids substituted in the quinuclidine ring [66-68, 76, 78]. 

An attempted synthesis of 3-carboxymethyl quinuclidine-2-carboxylic acid anhydride in the presence of acetic anhydride and sodium acetate yielded unexpectedly a tricyclic /8-diketone (XVIII) [94]. The latter in the course of interaction with substances having a labile hydrogen atom (water, alcohols, amines) opened readily to form derivatives of 2-acetvlquinuclidine-3-acetic acid [94]. 

By selective saponification of carboalkoxyl groups in the a- and other positions of the quinuclidine molecule it was possible to obtain for example a monoester (XX), e.g. by treatment of the diethylester of 3-carboxymethyl-quinuclidine-2-carboxylic acid (XIX) with water at room temperature. The same method was used in the S3mthesis of compounds containing other functional groups in positions 2 and 3 [95]. 

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)]. 

Stearoyloxyethyl) - 2 - (N - piperidinomethyl)quinuclidine (66) was converted by Kraft s reaction into an unsaturated compound (67) which formed 2-Ar-piperidinomethylquinuclidine-3-carboxylic acid (68) by oxidation with potassium permanganate.123... 

Formation of quinuclidine-3-carboxylic acid derivatives (68) from these reactions was conclusive proof of saponification of the ethoxy-carbonyl group at position 2 of the diester (61). A similar reaction takes place with diethyl quinuclidine-2,3-dicarboxylate.100 This is in agreement with the known principle of easier saponification of a- than j8-amino acid esters. Some 3-(j8-acyloxyethyl)-2-diethylaminomethyl-quinuclidines (69, 70)123 on distillation at atmospheric pressure cyclize with loss of ester and formation of a new tricyclic system, quinuclidino[2,3-c]piperidine (72). The same reaction takes place by heating the corresponding amino alcohol (71) with phthalic anhydride in the presence of benzenesulfonic acid.123... 

For example, 2-bromoquinuclidine (80) does not form Grignard reagents and 2-aminoquinuclidine is so unstable that on hydrolysis of its urethans (81) under mild conditions ammonia is lost and polymers of dehydroquinuclidine are formed. The synthesis of 2-bromoquinuclidine (80) was achieved by the Borodin reaction,90 and the urethans (81) were obtained from quinuclidine-2-carboxhydrazide (82) by the Curtius reactions.142 The Curtius reaction with quinucli-dine-4-carboxylic acid derivatives gave 4-aminoquinuclidine (83).143 This compound (83) was also synthesized directly from quinuclidine-4-carboxylic acid by the Schmidt reaction. However, the first method is better, in spite of having more steps. 

By hydrolysis and dehydration of quinuclidin-3-one cyanhydrin (108), 3-alkoxycarbonyl-Zl2-dehydroquinuclidines (109) were obtained, which can be reduced and saponified to quinuclidine-3-carboxylic acid (110).121,122 Quinuclidine-2,3-dicarboxylic acid (112) was similarly prepared from 2-ethoxycarbonylquinuclidin-3-one cyanohydrin (111).109... 

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... 

Pyridine V-oxides may be deprotonated to give ylides which react with electrophiles such as carbon dioxide and ketones. For example, 4-chloropyridine /V-oxide reacts with butyllithium at -65 °C followed by quenching with carbon dioxide to give 4-chloropyridine A -oxide 2-carboxylic acid in 49% yield. Quinuclidine yV-oxide can be deprotonated with r-butyllithium to give the anion which can be trai ied with deuterium oxide or benzaldehyde. ... 

The requirements for secondary sources are the same as those given previously for the reference set with the exception of the requirement that the set permit the o/ constants to be properly scaled. The p/iTaS of bicyclooctane carboxylic acids and of quinuclidines meet these requirements fairly well. The data available in the literature does not permit the evaluation of o/ for many additional substituents. The greatest potential source of additional aj values consists of >Ka values of acetic acids. To use the acetic acid system as a secondary source for the evaluation of U/ constants it must be shown that steric effects and resonance effects are absent. To establish that this is indeed the case, pAToS of substituted acids in water at 25° were correlated with the extended Hammett equation (Eq. 19) using primary (7/ constants (Table 7) obtained from Equation 58 and an constants obtained from Equation 40. Only those substituents for... 

The same principle, i.e. cyclizing a-haloidesters of the piperidine series, was also applied in the synthesis of various 2,3- and 2,5-disubstituted quinuchdines 3-carboxymethylquinuclidine-2-carboxylic acid (XIV), 3-methylquinuchdine-2-carboxylic acid (XV) and 5-(d-hvdroxv(methoxv)ethyl)-quinuclidine-2-carb-oxylic acids (XVI) [63-69]. 

Most of the substituted quinuclidines known at present have been obtained from their carboxyl or carbonyl derivatives and primarily from quinuchdine-2-carboxylic acid, quinuclidon-3 and their derivatives [1]. 

Formation of a quinuclidine-3-carboxylic acid derivative as a result of these reactions proved convincingly that saponification of the ethoxycarbonyl-group had occurred at position 2 of diethyl 3-carboxy-methylquinuclidine-2-carboxy-late (XIX) [94, 96]. 

Claisen condensation of ethyl quinuclidine-2-carboxylate (73) with ethyl acetate yields ethyl j8-oxo-j8-(2-quinuclidyl)propionate (84). This was transformed into j8-amino-j3-(2-quinuclidyl)propionic acid (85)108 and 2-acetylquinuclidine (86).43... 

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