Quinuclidine carboxylic acids derivatives

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. 

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]. 

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. 

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. 

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]. 

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]. 

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