Reactions of Pyrrolizidine and Its Derivatives

The configurations of the isomeric 3-methylpyrrolizidines have been determined by quaternization experiments.From models, the endo-isomer (143a) should quaternize readily with alkyl halides, whereas considerable deformation would be required with the exo-form (143b). Using 

Sadritdinov, 1. Khamdamov, and B. Rustamov, Dokl. Akad. Nauk Uzb. SSR 31, 22 

Many esters, both naturally occurring and semisynthetic, have been prepared by esterification of hydroxy-substituted pyrrolizidine bases. Mattocks synthesized a range of retronecine diesters by heating retronecine (127) hydrochloride with acid chlorides.Mattocks also converted retronecine into the corresponding amine, retronamine, from which amide analogs of pyrrolizidine esters were prepared [Eq. (35)]. 

Hoskins and Crout have synthesized C-9 monoesters of retronecine (127) in reasonable yields by using iV,N -dicyclohexylcarbodiimide as the coupling reagent.The use of AT,JV -carbonyldiimidazole, with prior formation of the acylimidazole, was necessary with aj8-unsaturated acids and bulky a-trisubstituted acids. Subsequent esterification at C-7 of the retronecine ester with a suitable acid chloride produced unsymmetrical diesters of retronecine. 

Much effort has been expended in developing mild routes for the oxidation of the sensitive allylic alcohols, such as retronecine (127) to the corresponding carbonyl compounds. Mattocks has recently converted retronecine into the aldehyde (145) in 30% yield using specially prepared manganese dioxide under controlled conditions. This aldehyde (145) is probably an intermediate in the formation of the dihydropyrrolizines (see Section V,D). 

The compound in this category which has been most widely studied is 3,5-dioxopyrrolizidine (130). It shows the typical properties expected of a dilactam structure, and it is a useful intermediate in the preparation of 

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Note It is reported that the use of chlorobenzene as solvent is essential when the reagent is to be used to detect aromatic amines [1]. In the case of steroids, penicillins, diuretics and alkaloids the reaction should be accelerated and intensified by spraying afterwards with dimethylsulfoxide (DMSO) or dimethylformamide (DMF), indeed this step makes it possible to detect some substances when this would not otherwise be possible [5,9-11] this latter treatment can, like heating, cause color changes [5,9]. Penicillins and diuretics only exhibit weak reactions if not treated afterwards with DMF [10, 11]. Steroids alone also yield colored derivatives with DMSO [9]. Tlreatment afterwards with diluted sulfuric acid (c = 2 mol/L) also leads to an improvement in detection sensitivity in the case of a range of alkaloids. In the case of pyrrolizidine alkaloids it is possible to use o-chloranil as an alternative detection reagent however, in this case it is recommended that the plate be treated afterwards with a solution of 2 g 4-(dimethyl-amino)-benzaldehyde and 2 ml boron trifluoride etherate in 100 ml anhydrous ethanol because otherwise the colors initially produced with o-chloranil rapidly fade [12]. 

Pyrrolizidine (1) and its derivatives have attracted the attention of chemists during the last two or three decades because this bicyclic system occurs in a number of alkaloids from various families of Compositae, Boraginaceae, Leguminosae, etc. Structural analysis of these substances, study of their reactions, and attempted syntheses have afforded considerable information concerning the chemistry of this class of compounds. Although the field has been covered by a... 

Dioxopyrrolizidine was widely used by Micheel et al33,118 as starting compound in the syntheses of some pyrrolizidine derivatives. Its reaction with phosphorus pentasulfide gave rise to pyrrolizidine-3,5-dithione, and it was converted via a Reformatsky reaction into ethyl 3-oxo-5-hydroxypyrrolizidine-5-acetate (165) and ethyl 3-oxo-pyrrolizylidene-5-acetate (166). Condensation with organomagnesium... 

By using a sequence involving regio and diastereoselective reduction of the adducts (it only affects the carbonyl far away from the sulfinyl group, yielding y-oxygenated lactones), stereoselective AT-acyliminium addition, and retro Diels-Alder reactions as the main key steps, Koizumi et al. have synthesized chirally functionalized pyrrolidines [96, 97], pyrrolizidines [98], and indolizidines [98-100], depicted in Scheme 56. The milder conditions required for the evolution of the adducts derived from furan preserve the chirality of the substrates. 

Coleman and Goheen409 found it better to use iV-chloro amines rather than the A-bromo compounds for synthesis of pyrrolidines and in this way achieved yields of around 75% of substituted pyrrolidines. The method has also proved valuable for synthesis of bicyclic tertiary amines.410"412 Schmitz413 applied it to N,N-dibromo derivatives of primary amines from iV,JV-dibromo-l-propylbutylamine he obtained pyrrolizidine in 35% yield,414 the best yields being obtained here, as in other cases,412 415 416 when the reaction is carried out with irradiation in ultraviolet light. Recently ring closure was also achieved with JV-monochloro derivatives of primary amines 417 pyrrolidine (70%) was obtained from butylamine, 2-methylpyrrolidine (80%) from pentylamine, and 2-propylpyrrolidine (50% and 70%, respectively) from heptylamine or 1-pro-pylbutylamine.417 The mechanism of the Hofmann-Loffler reaction has been discussed by Wawzonek and Culbertson.416... 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

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