2.3- dihydro-lH-pyrrolizines

Benzoyl-2,3-dihydro-lH-pyrrolizine-l-cai boxylic acid (ketorolac, L ) and 2-(3-benzoyl-phenyl)propionic acid (ketoprofen, L ) ai e biologically activ ligands used in medicine as non-steroidal anti-inflammatory dmgs. 

A solution of 4-chloro-N-methyl-N-phenyl-2-(2-pyrrolyl)butanamide in toluene was added dropwise at 85°C over 40 min to 1 hour to a stirred suspension of ALIQUAT 336 (phase transfer catalyst, 2 mol % with respect to pyrrolylbutanamide) and granular sodium hydroxide (3 equivalents) in toluene (50 mL). After the addition was complete, the suspension was stirred under a nitrogen atmosphere at a temperature of 85°C for 30 min, then cooled to 35°C. Cooled water (200 mL) was rapidly added to the mixture and stirred for 15 min at 25°C. The solution was rinsed with water and the layers were separated. The organic layer was washed with water, then distilled under atmospheric pressure to recover the toluene and water. The resultant solution was cooled to 50°C and allowed to crystallize after the addition of hexane and a seed crystal. The suspension was cooled to 5°C and stirred for 15 minutes. The resultant precipitate was filtered, washed with 100 mL of hexane, and dried under vacuum at 25°C to yield approximately 38 g (63%) N-methyl-N-phenyl-2,3-dihydro-lH-pyrrolizine-l-carboxamide. This solid was recrystallized from toluene to yield colorless crystals of N-methyl-N-phenyl-2,3-dihydro-lH-pyrrolizine-l-carboxamide, melting point 112-112.5°C. 

N-Methyl-N-phenyl-2,3-dihydro-lH-pyrrolizine-l-carboxamide (480 mmol) and toluene (100 mL) were added to a mixture of benzoylpiperidine (1.05 eq.) and phosphorus oxychloride (0.96 eq.), which had been stirred at 25°C for 1 hour. An additional 100 mL toluene was added. The suspension was heated to at 40-45°C for 4 hours. The resulting syrup was transferred into a rapidly stirring solution of sodium hydroxide (4.5 mol), piperidine (1.0 mL), and water (650 mL) at 25-35°C and the mixture was stirred for 1 hour. A mixture of toluene (100 mL), water (50 mL), and sodium hydroxide (12 g, 300 mmol) was added to the reaction flask, and the reaction mixture was stirred at 25°C for 1 hour. The suspension was then heated to 75°C and the layers were separated. The organic layer was cooled to 60°C and hexane (100 mL) was slowly added, and the solution slowly stirred and cooled to -15°C. The precipitate was filtered, washed with toluene/hexane (2 1) and then with hexane, and dried under vacuum at 25°C to yield 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-lH-pyrrolizine-l-carboxamide (83.5% yield). 

A mixture of 34.4 g (100 mmol) 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-lH-pyrrolizine-l-carboxamide, 25 g sodium hydroxide in 25 mL water, and 80 mL methanol was refluxed for 5 hours. The mixture was cooled to room temperature, stirred under nitrogen for sixteen hours, and then diluted with 80 mL of water. The mixture was extracted with toluene, and the aqueous and organic phases were separated. The aqueous phase was acidified with 6 N hydrochloric acid. The resulting precipitate was extracted with dichloromethane. The combined extract was treated with activated clay decolorizing agent (4.5 g) for 30 minutes, filtered, and concentrated by... 

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. 

Rhamnose and proline were reacted under a wide range of reaction conditions with the expectation of producing volatiles of differing type and ratio. Such large differences were desired to give the best opportunity for the empirical models to account for and explain the variation. If valid, the model terms would be expected to account for differences in product composition and perhaps provide insight into the reaction pathways. Some of the 23 volatiles modeled including 2,3-dimethyl-4-hydroxy-3(2H)-furanone (DMHF), 2-acetoxy-3-pentanone, and four 2,3-dihydro-(lH)-pyrrolizines will be discussed below. 

The 2-3-dihydro-(lH)-pyrrolizines have two responses to reaction temperature increasing with rising temperature or reaching a maxima at 152.5°C. These are compounds in which proline plays a structural as well as a catalytic role. The concentration of these compounds do not follow proline content as would be expected if the structural role of proline was determining. It appears that the concentration of carbohydrate fragments determines the pyrrolizine content. 

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... 

Figure 1. Temperature/pH response surface at 0.033 m rhamnose and 0.167 m proline. Graphical representation of the quantity (ppm) of 6-methyl-2,3-dihydro-(lH)-pyrrolizine.

Figure 2. Formation of 5-acetyl-7-methyl, 5-acetyl-6-me[]lvi methyl-2,3-dihydro-(lH)-pyrrolizines. (Modified from ref 1)...

Interaction terms were found to be very important for volatiles whose formation precursors were limited due to competition for precursor, stability of precursor, or because the designed experiments purposefully limited selected precursors. The 2,3-dihydro-(lH)-pyrrolizines fall into this category. 

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. 

A good example of the effect of pH98 is that observed on a xylose-lysine model system (1 M each, refluxed 1 h with diethyl ether in a Likens and Nickerson apparatus, initial pH 4.9, either kept at pH 5 with NaOH additions or left, when the final pH is 2.6) 54 and 28 volatiles were identified, respectively, 2-furaldehyde dominating with 52.2 and 99.9% (w/w). Total yield and number of nitrogen-containing compounds were greater at higher pH values of the former system, and monocyclic pyrroles, pyridines, and 2,3-dihydro-lH-pyrrolizines were identified only in that system. 

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

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