Forming pyrrolizines

Cycloaddition of the tetrahydropyrrolopyridine-2-carbaldehyde 153 with electron-depleted alkenes in the presence of a base leads to products, the 111 NMR spectra of which are consistent with their formulation as 154 rather than 155. In the case of the acrylonitrile adduct, the initially formed pyrrolizine reacts with another molecule of acrylonitrile to give a cyanoethyl-substituted derivative <1998CHE1418> (Scheme 43). 

The 977-pyrido[3,4- ]pyrrolizin-9-one 145 has been prepared for its photochemical properties. The preparation involves an intramolecular Friedel-Crafts acylation of the acid chloride formed from 3-(l-pyrrolyl)pyridine-4-carboxy-late (Scheme 40). The product is a photosensitizer, which absorbs visible light its absorption spectra are pH, solvent, and concentration dependent <1994SAA57>. 

Dimethyl-3/7-indole reacts with diethyl oxaloacetate in acetic acid to give the pyrrolizine 157. Upon reaction of this product with guanidine for extended periods of time, the tetracyclic product 158 is formed in low yield <1988J(P1)451> (Scheme 46). 

Pyranopyrrolothiazoles can be prepared in a similar way to certain pyrano- and thiopyrano-pyrrolizines and pyrrolizinopyridines as discussed earlier. Thus, thiazolidine-4-carboxylic acid reacts with the aldehyde 179 to give a 2 1 mixture of 180 and 181 (Equation 16). This reaction is a 1,3-dipolar cycloaddition of the alkene to the 1,3-dipole formed from reaction of the amino acid amine with the aldehyde <1988T4953, 1990T2213>. The alkyne analogue of 179 is similarly converted into 182 (Equation 17). 

In this section, whatever the saturation level of the aza-bicyclic compound considered, we will focus only on the bond-formation step which leads to the azabicyclic skeleton of pyrrolizines and their derivatives. The reported routes will be classified according to the number of atoms in the newly formed bond, as already done in CHEC-II(1996) <1996CHEC-II(8)12> and shown in Figure 1. Not all of these modes were equally employed the most popular are 1,8- 1,2- 2,3- 3,4- 1,8 2,3- 1,2 3,4- and 1,8 3,4-bond formations. Each of these modes will be described in this section all other bond-formation modes will be discussed in Section 11.01.9. 

Most of the methods of forming cycl[3,2,2]azine derivatives involve indolizines. Other precursors are 3//-pyrrolizines and pyridines. 

The 3-methyl group of nitrile 2b selectively activates C-2 for intramolecular electrophilic substitution so that only one isomer [3b (30%)]18 is formed. Cydization of nitrile esters 4 in the presence of hydrogen chloride did not lead to the expected ketenimmonium chlorides, l-amino-3//-pyrrolizines (5) being formed instead. This may be caused by conjugation of the 1-amino and the 2-alkoxycarbonyl groups on the 1,2-double bond. The dihydropyrrolizinone (6a) could be obtained from compound 5 (R = Me)19 only under drastic conditions.20... 

A new metabolite from Streptomyces olivaceus has been shown to be (2S)-1-oxo-2,3-dihydropyrrolizine-3-carboxylic acid (15b) by total synthesis. The pyrrolizine ring was formed from the pyrrole (14) by stereoselective cyclization with phosphorus pentoxide in toluene in 37% yield. Partial racemization occurred during the hydrolysis of ester 15a.21... 

Friedel-Crafts reactions have found application to form the 1,2-bond of pyrrolizines. Treatment of anhydride 78 with aluminum chloride gave 93% of acid 79, which on heating in the presence of copper gave a 91% yield of 2,3-benzo-1 H-pyrrolizin-1 -one (17).55 Benzopyrrolizinones (81) have been obtained from acid chlorides (80) by a similar route.56,57 Houben-Hoesch cyclization of nitrile 82 gave 2,3-benzo-lf/-pyrrolizin-l-one (17) in a reaction that resembles the formation of 17 from 16a.58... 

Pyrrolizin-3-one (94a) is formed in 98% yield by flash thermolysis of 96, which was obtained from 2-formylpyrrole and Meldrum s acid. A possible ketene intermediate then reacts in an intramolecular acylation.66... 

Vinylphosphonium salts accept nucleophiles by addition in a Michael reaction to form phosphoranes, which may subsequently react with a carbonyl group to form an alkene (see Scheme 10). This reaction, discovered by E. E. Schweizer in 1964,80 was developed into a widely applicable cycliza-tion method.81 The reaction of 2-formyIpyrrole with vinyltriphenylphos-phonium bromide to give 87% of 3/f-pyrrolizine (1) is among the first to... 

The l-amino-3H-pyrrolizines are potentially tautomeric. Whereas the 1-isopropylamino derivative 227 is reported to have the 3-imino structure, the 1-benzyl derivative is said to favor the 3-amino form (228).67... 

The only reaction reported between 3//-pyrrolizine (1) and a carbene (or carbenoid) is that involving n-butyllithium and dichloromethane.135 One of the products is formed by cycloaddition (Section III,B,6), one by ring opening (Section III,B,7), and the third according to Eq. (4). The latter two products are viewed as derived from the carbenoid 272, and the proposed route to indolizine (273) is shown in Eq. (4). 

Components 2 5 and 1 2 were first detected in wort, which was heated above 140 °C. Beer, produced by this process, possessed a bitter aftertaste. Compound 3. was recently identified as a reactive intermediate, which decomposed very soon even by storage at -20 °C. On heating L-proline and monosaccharides at 150 °C for 1.5 h all compounds increased ten to fiftyfold and 2,3-dihydro-1H-pyrrolizines and di- and tetrahydro-1H-azepines were characterized as major components. On roasting L-proline and monosaccharides (or sucrose) pyrrolidines and azepinones predominate among the Maillard products. These compounds were also formed by heating pyrrolidine and glucose at 100 "C. Azepinones and certain pyrrolin-derivatives possess extreme bitter taste and thresholds of 5 - 10 ppm ( 3, 5 ). ... 

Response Surface Methodology (RSM) was used to investigate the effects of temperature, pH and relative concentration on the quantity of selected volatiles produced from rhamnose and proline. These quantities were expressed as descriptive mathematical models, computed via regression analysis, in the form of the reaction condition variables. The prevalence and importance of variable interaction terms to the computed models was assessed. Interaction terms were not important for models of compounds such as 2,5-dimethyl-4-hydroxy-3(2H)-furanone which are formed and degraded through simple mechanistic pathways. The explaining power of mathematical models for compounds formed by more complex routes such as 2,3-dihydro-(lH)-pyrrolizines suffered when variable interaction terms were not included. 

Figure 2 illustrates the formation of 5-acetyl-7-methyl-[iv], 5-acetyl-6-methyl-[v], 7-formyl-5-methyl-[vi] and [vii] 7-acetyl-5-methyl-2,3-dihydro-(lH)-pyrrolizines after Tressl et al. (5). The 2,3-dihydro-(lH)-pyrrolizines require both carbohydrate fragmentation products and proline for their formation. Both the 5-acetyl- pyrrolizines [iv] and [v] increased in quantity as the reaction temperature increased while [vi] and [vii] were found at maximum quantity at 152.5°C. The first pair are formed through an iminium carboxylate intermediate which is decarboxylated into an exocyclic iminium ion which then undergoes an aldol... 

The 7-formyl- and 7-acetyl- pyrrolizines are formed by an iminium carboxylate intermediate followed by decarboxylation to the cyclic iminium ion which underwent nucleophilic addition followed by aldol ring closure. This pathway accounts for the 7-formyl-5-methyl [vi] and 7-acetyl-5-methyl [vii] depending if the iminium addition is by OHCCH2OH or CH3COCH2O. 

Variable interaction terms do not aid in the understanding of DMHF content within the experimental space studied because the primary variable effects are very strong. This is reasonable for a compound which is both easily formed and readily degraded. Variable interaction terms are more important in understanding the formation of 2,3-dihydro-lH-pyrrolizines. These compounds are formed through more complicated mechanistic pathways. Where the interaction terms are important, a 17% and 35% improvement in model fit as expressed by R-Square value was obtained when the interaction terms are considered. 

H. Shigematsu, S. Shibata, T. Kurata, H. Sato, and M. Fujimaki, 5-Acetyl-2,3-hydro-1H-pyrrolizines and 5,6,7,8- terahydroindolizin-8-ones, odor constituents formed on heating proline with D-glucose, J. Agric. Food Chem., 1975, 23, 233-237. 

Crystal structures for a number of bimanes (see Scheme 6) have been reported (81JOC1666). The formation from 3-(l-pyrrolidinyl)thiophenes and dimethyl acetylenedicar-boxylate (DMAD) of 6,7,7a,8-tetrahydro-5IT-thieno[2,3-6]pyrrolizines (226) always occurs stereospecifically, as shown by the X-ray structure of (226) (81JOC424). It is also shown that in l,3a,6,6a-tetrahydropyrrolo[3,4-c]pyrazoles (see equation 70), both of the cw-fused five-membered rings are in the envelope form with six peripheral side groups directly bonded to them (81BCJ41). 

Quaternary anilinium salts (240), obtained from reaction of (pyrrol-l-yl)methanol and the appropriate aniline with trioctylphosphine, react in polar solvents via the azonia-fulvene ion (241) with enamines through a Mannich-type reaction followed by cyclization to give pyrrolizidines 242 and 243124. The ratio between the pyrrolizidines formed varies considerably with ring size of the enamine employed (equation 50). Pyrrolizines have also been obtained by reaction of pyrrole with two equivalents of enamine125 or condensation of some ketones with L-sodium or L-ethyl prolinate126. 

The course of the reaction of pyrrolidinostilbene with dimethyl acetylenedicarboxylate is solvent-dependent in apolar solvents, such as ether or toluene, the dienamine 57 is formed by ring-opening of an intermediate cyclobutene, whereas in methanol the pyrrolizine 59 is the main product. The pyrrolizine is thought to arise from an initial betaine which rearranges to the ylide 58 by a proton shift. Cyclization then gives the pyrrolizine (equation 31)53. 

When pyrrole 987 was subjected to the usual reaction conditions, l-(2,3-dihydro-17/-pyrrolizin-5-yl)-l-ethanone 988 was obtained as the major product. The desired diketone 989 was isolated in very low yield together with a small amount of the unexpected sulfone 984 (Equation 234). This compound is formed by alkyl radical addition at C-5, and subsequent aromatization by the loss of an acetyl radical. When pyrrole 987 was reacted with BusSnH/AIBN in the absence of CO, dihydropyrrolizines 988 and 984 were isolated in 74% and 23% yields, respectively <2000TL3035>. 

Compound 1295 undergoes a smooth reaction in boiling THE to produce triphenylphosphine oxide and l-(tri-fluoromethyl)-3/f-pyrrolizines 1296 that may be considered as a product of an intramolecular Wittig reaction (Scheme 247) <2006ARK55>. The tautomeric l//-pyrrolizine 1297 was not formed. When phosphorus ylides containing the trichloromethyl group 1298 were heated in THE the expected pyrrolizine 1299 was not formed, and the 2,2,2-trichloro-l-(l//-pyrrol-2-yl)ethanone 1300, dialkyl 2-butynedioate and triphenylphosphine were obtained instead (Scheme 248). 

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