2.5- Dialkyl-1-pyrrolines

Both possible isomers of the 2,5-dialkyl-1-pyrrolines have been identified in the venoms of Solenopsis and Monomorium species. These compounds generally accompany the corresponding dialkylpyrrolidines as venom constituents. The venom of 3. punctaticeps, an African species, contains both 61- and -pyrrolines (VII) (j3) as do the venoms of three North American Monomorium species (12 ). The latter dialkylpyrrolines (VIII) are distinguished by the presence of two terminally unsaturated side chains. The pyrrolines in the venom of M. latinode are distinctive in constituting the only 5-pyrrolines (IX) in ant venoms that are not accompanied by the 1-pyrrolines (6). 

Pyrroline is a desirable starting material for alkylation of heterocycles. 1-(Methoxycarbonyl)-3-pyrroline2 has been used to prepare 2,5-dialkylated pyrrolines,3 which resulted in the synthesis of the Pharaoh ant trail pheromone43 and gephyrotoxin 2 2 3.4b Alkylation of 3-pyrrolines has also led to the synthesis of 12-azaprostaglandins.5 The submitters have used a formamidine derived from 3-pyrroline to provide access to 2-substituted pyrrolines and pyrrolidines,6 which has led to the synthesis of the unnatural (+)-anisomycin.7... 

The use of primary amines instead of ammonia affords l,2-dialkyl-/l -pyrrolines or l,2-dialkyl-/l -piperideines. Amino ketones with a primary amino group are intermediates in the reduction of y-nitropropylalkyl ketones (14,15) or S-nitrobutylalkyl ketones (16-18) by catalytic hydrogenation over Raney nickel or with zinc and hydrochloric acid (Scheme 1). 

Lukes studied the reaction of N-methyl lactams with Grignard reagents. With the five- (39-42) and six-membered (43-47) rings, 2,2-dialkylated bases (16, = 1,2) are formed as by-products in addition to the l-methyl-2-alkyl pyrrolines (15, = 1) or l-methyl-2-alkyl piperideines (15, =2). Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors (48,49). Separation of enamines and 2,2-dialkylated amines from each other can be easily achieved since the perchlorates of the enamines and the picrates of 2,2-dialkylated bases crystallize readily. Therefore enamines can be isolated as crystalline perchlorates and the 2,2-dialkylated bases as crystalline picrates. Some authors who repeated the reactions isolated only pyrrolines (50,57) or, by contrast, 2,2-dialkylated bases (52). This can be explained by use of unsuitable isolation techniques by the authors. 

Lukes [62] and Craig [63] first reported that JV-methyl lactams with five- and six-membered rings react with Grignard reagents to yield l-methyl-2-alkyl-pyrrolines (n = 1) and l-methyl-2-alkylpiperideines (n = 2) In some cases, some 2,2-dialkylated bases are formed as by-products. This method provides... 

The seco-phenanthroindolizidine alkaloid septicine has been synthesized by a nitrone route. A cycloaddition of 1-pyrroline 1-oxide with 2,3-bis-(3,4-dimethoxyphenyl)butadiene gives two stereoisomeric isoxazolidines, one of which is converted into ( ) septicine.10 ( )-Tylophorine and 5-coniceine have been prepared by a new route that makes use of an intramolecular imino-Diels-Alder reaction.11 A stereoselective synthesis of 3,5-dialkyl-indolizidines has been applied to the synthesis of a stereoisomer of the trail pheromone of the Pharaoh ant and to a stereoisomer of gephyrotoxin 223.12 A stereoselective total synthesis of ( )-perhydrogephyrotoxin (21)13 and a simple synthesis of ( )-gephyran14 have been reported. 

If the amino group forms part of the ketone, as it does with y-87, 88 and 8-amino-ketones,89,90 heterocyclic enamines are obtained. 1,2-Dialkyl-J2-pyrrolines and 1,2-dialkyl-J2-piperideines (15) are formed from secondary amino groups, whereas primary amino groups 91 lead to 2-alkyl-J pyrrolines and 2-alkyl-J -piperideines. Gabriel90 used the suitably substituted phthalimidoketone for the synthesis of the alkaloid y-coniceine (15 R = H, R = n-Pr, n = 2). 

The venom of the fire ant, Solenopsis punctaticeps, contains several 2,5-dialkyl-pyrrolidines and -pyrrolines their structures have been settled by combined g.c-m.s., and confirmed by syntheses employing the Hofmann-Loffler reaction on the corresponding primary amines.7 A new synthesis of 2,5-dialkyl-pyrrolidines via lithiated iV-nitrosopyrrolidine and two stages of alkylation, followed by removal of the nitroso-group, should be applicable to the synthesis of the venom components. The major products are trans in stereochemistry.8... 

Lukes and coworkers " developed a very simple and useful method for the preparation of heterocyclic enamines. A-M ethyl lactams with five- and six-membered rings (104, n = 1,2) give, with Grignard reagents, l-methyl-2-alkyI(aryl)-2-pyrrolines (105, n = 1) and l-methyl-2-alkyl(aryl)-2-piperideines (105, n = 2), respectively. 2,2-Dialky-lated bases (106, n = 1,2) are by-products of this reaction. Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors " ". Some authors who repeated the reactions isolated only pyrrolines or, in other cases, 2,2-dialkylated bases . This can be ascribed to the use of unsuitable isolation technique by the authors. The reaction was also carried out with various substituted and non-methylated lactams . ... 

The Eschenmoser reaction was applied a second time as one of the methods to introduce the -butyl appendage. The alkylated a-amino ester (97) was oxidized to the monosubstituted thiolactam (98), and introduction of the butyl side chain, via sulfide contraction as described above, yielded a mixture of vinylogous carbamates (99). Treatment of the carbamates (99) under transfer hydrogenolysis conditions yielded the optically pure dialkylpyrroline (100), another component of the ant trail pheromone. Subsequent reduction of the pyrroline with platinum afforded the optically pure ds-2,5-dialkyl-substituted pyrrolidine (101). Other pyrrolidine-containing alkaloids have been prepared by similar approaches involving the Eschenmoser reaction. ... 

Condensation of addehydes with N-acyl-V -alkylhydrazines affords an incipient azomethineimine capable of cycloaddition to suitable double bonds. The value of the synthesis is indicated by reactions in Scheme 16. Reaction with benzaldehyde shows a marked regioselectivity. Other interesting dipolar additions are shown in Scheme 17. The interm iacy of a diazacyclopenta-dienone in the decomposition of (59) is clearly shown by the trapping experiments. Also reported are adducts of tetracyanoethylene with 3,6-dialkyl-azepines and the Cope rearrangement of the pyrroline oxide (60) to give... 

Highly substituted 3-pyrrolin-2-ones, especially congeners-containing substitution at C-3 and/or C-4, are often prepared utilizing intramolecular aldol-like condensations of a-amidoketones 122 (Scheme 21). Jacobi and coworkers prepared a 3,4-dialkyl-3-pyrrolin-2-one (Scheme 21 R, = CH2CH2SeAr = Me) by treating an a-amidoketone 122 with i-BuOK this was a key step in a synthesis of the pyrromethenone moiety... 

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