Pyrrolidines ring closure

Closure of 5-halo-amines by nucleophilic displacements of halogen, is complemented by the conversion of iV-chloro-pent-4-enylamines into 3-chloropiperidines by exposure to tetra-n-butylammonium iodide. The process is believed to involve conversion to an A -iodo-amine, which serves as an electrophilic source of iodine, cyclisation to a 2-(iodomethyl)-pyrrolidine, ring closure to a bicyclic aziridinium ion and ring opening via attack by chloride to produce the six-membered heterocycle. 

To build the central ABC core present in 1, two main synthetic strategies have been used Diels-Alder reactions and asymmetric synthesis. This tricyclic subunit was chosen as the first synthetic target because it contains all five stereogenic carbons. A central pyrrolo-isoquinoline skeleton (ABC) was initially synthesized by the high-pressure Diels-Alder reaction of 3-alkyl-5,6-dihydro-2-pyridones with Danishefsky s diene, followed by deprotection and spontaneous pyrrolidine ring closure (see Scheme 16) [77]. 

Loffler-Freytag pyrrolidine ring closure, with prim, amines, s. 17, 565... 

Sulfuric acidjferrous salt Pyrrolidines from N-halogenamines Ldffler-Freytag pyrrolidine ring closure... 

Reductive pyrrolidine ring closure Prim, amines from nitriles N-Decarbobenzoxy lation... 

Reductive pyrrolidine ring closure with N-decarbobenzoxylation... 

Hofmann-Loifler-Freytag pyrrolidine ring closure... 

The converse situation in which ring closure is initiated by the attack of a carbon-based radical on the heteroatom has been employed only infrequently (Scheme 18c) (66JA4096). The example in Scheme 18d begins with an intramolecular carbene attack on sulfur followed by rearrangement (75BCJ1490). The formation of pyrrolidines by intramolecular attack of an amino radical on a carbon-carbon double bond is exemplified in Scheme 19. In the third example, where cyclization is catalyzed by a metal ion (Ti, Cu, Fe, Co " ), the stereospecificity of the reaction depends upon the choice of metal ion. 

A novel ring closure was discovered by Stork (6) in which the pyrrolidine enamine of a cycloalkanone reacts with acrolein. The scheme illustrates the sequence in the case of 1-pyrrolidino-l-cyclohexene, and the cyclopentane compound was found to undergo the reaction analogously. The procedure details the preparation of the bicyclo adduct and its cleavage to 4-cyclooctenecarboxylic acid. 

The transformation proceeds with excellent stereoselectivity by kinetic formation of the 2,5-trans-disubstituted pyrrolidine 2-328 [182]. The tertiary amine can now initiate a nucleophilic backside displacement of the vicinal iodide in 2-328, leading to an aziridinium salt 2-329 [183]. This event ensures a net retention of the stereochemistry at C-13 in the following attack of the ester carbonyl in the butyrolactone ring closure to give 2-330. 

When the reaction is conducted in the presence of added fumarate, the yield of pyrrolidine (130) increases at the expense of the aziridine. Jacobsen suggests that the aziridines and pyrrolidines arise from a common intermediate, azo-methine ylide (132), Scheme 6, which may also be partly responsible for the poor levels of asymmetric induction in this reaction. Electrocyclic ring closure of the azo-methine while still within the coordination sphere of the metal (131) may provide aziridine with some induction, while decomplexation (132) will lead to the formation of racemic aziridine and pyrrolidine. 

A-Benzylimines have also been reported to react with acrylonitriles under solidrliquid conditions in which the initial anionic intermediate undeigoes an intramolecular nucleophilic ring closure to produce a diastereoisomeric mixture of the pyrrolidine (Scheme 6.23) [30-32], Similar cyclized products have been reported for the reaction of benzylidene-protected a-amino esters and vinyl ketones [33, 34],... 

The approach, which differs from other recent syntheses (3,4,5), is outlined in Scheme 1. Three points may be noted (i) in the Grignard addition to 2,3-0-isopropylidene-D-ribose (2) the D-allo configuration in (3 is in accordance with the Felkin-Anh model (0 and is to be expected from our earlier work (1 ) (ii) methane-sulfonylation of the oxime ( ) serves not only to dehydrate the oxime but to introduce a leaving group for ring closure at the next step (iii) the intramolecular displacement to form the pyrrolidine ring (( ) ] proceeds cleanly and with complete inversion of... 

In the reaction of 4-diazotriazoles with morpholine, pyrrolidine [83DIS(B)(43)2557], and several other secondary amines (66JMC733), the corresponding triazenes 247 were obtained. Also, in the case of 4-diazo-l,2,3-triazole-5-carboxamide, these compounds could easily be obtained in organic solvents despite the competing intramolecular ring closure to 2,8-diazahypoxanthine. In aqueous media, the intermolecular coupling... 

Miscellaneous Compounds. A saturated spirocychc pyrrohdine serves as the nucleus for a diamine that has been described as a hypohpemic agent. Treatment of the carbanion of the substituted cylcohexane carboxyhc ester (20-1) with methyl bromoacetate leads to the alkylation and formation of the diester (20-2). Saponification of the ester groups followed by reaction with acetic anhydride leads to ring closure of the succinic anhydride (20-3). Condensation with ammonia leads to the succinimide (20-4). The side chain is then added by alkylation of the anion on nitrogen with l-bromo-4-dimethylaminobutane (20-5). Reaction of this last intermediate with lithium aluminum hydride leads to the reduction of the carbonyl groups to methylene. This affords the pyrrolidine (20-6) atiprimod [22]. 

The perfect diastereocontrol of ring closures of substituted homoallylic glycines1760 (e.g. 162) and bishomoallylic glycines1766 (e.g. 164) has been also reported, leading to substituted pyrrolidines 163 or piperidines 165 (equations 83 and 84). 

Pyrrolidines piperidines.7 Reaction with benzeneselenenyl chloride converts A4-and As-unsaturatcd ethyl urethanes into phcnylseleno-substituted pyrrolidines and piperidines, respectively. Yields are considerably improved by the presence of silica gel, which presumably facilitates the ring closure subsequent to addition of the reagent to the double bond (equation I). 

N-Methyl-2-hydroxypyrroIidine (246) is derived biosynthetically from ornithine (245). It functions as a source of the N- methylpyrrolinium ion (247), which in turn functions as a precursor of alkaloids such as tropine (248). The pyrrolidine enamine of cyclopentanone undergoes an interesting ring closure reaction with DMAD, resulting in the formation of a pyrrolizine (Scheme 92) (78TL1351). 

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