A/- pyrrolidine

Enamines are not easily formed from 17-ketones. A pyrrolidine enam-ine is obtained by acid catalysis accompanied by azeotropic removal of water whereas the morpholine and piperidine enamines do not form under these forcing conditions. 

The selective bromination of a ketone in the presence of another susceptible functional group was achieved in a diterpene synthesis 240). A competing bromination of an anisole ring could be avoided here through the use of a pyrrolidine enamine derivative for activation of the methylene group adjacent to the carbonyl function. 

This sulfonate, prepared from B0CNHCH2CH2C(CH3)2CH20H and the sulfonyl chloride (Pyr, 100% yield) is cleaved by initial BOC cleavage to release the free amine after pH adjustment to 7-8. Intramolecular displacement occurs to release the sulfonate and a pyrrolidine. ... 

Cyclization of the thiazolidine methylidinemalonate 684 with PPA gave thiazoloquinoline 3-carboxylate which upon hydrolysis afforded 685 and reaction with A-methylpiperazine or a pyrrolidine derivative gave 686 as antibacterial agent (82EP58392, 85USP4550104) (Scheme 116). 

Secondary amines can be added to certain nonactivated alkenes if palladium(II) complexes are used as catalysts The complexation lowers the electron density of the double bond, facilitating nucleophilic attack. Markovnikov orientation is observed and the addition is anti An intramolecular addition to an alkyne unit in the presence of a palladium compound, generated a tetrahydropyridine, and a related addition to an allene is known.Amines add to allenes in the presence of a catalytic amount of CuBr " or palladium compounds.Molybdenum complexes have also been used in the addition of aniline to alkenes. Reduction of nitro compounds in the presence of rhodium catalysts, in the presence of alkenes, CO and H2, leads to an amine unit adding to the alkene moiety. An intramolecular addition of an amine unit to an alkene to form a pyrrolidine was reported using a lanthanide reagent. 

Bressanelli S, Tomei L, Rey FA, De Francesco R (2002) Stmctural analysis of the hepatitis C vims RNA polymerase in complex with ribonucleotides. J Virol 76 3482-3492 Burton G, Ku TW, Carr TJ, Kiesow T, Sarisky RT, Lin-Goerke J, Baker A, Eamshaw DL, Hofmann GA, Keenan RM, Dhanak D (2005) Identification of small molecule inhibitors of the hepatitis C vims RNA-dependent RNA polymerase from a pyrrolidine combinatorial mixture. Bioorg Med Chem Lett 15 1553-1556... 

An enzyme that catalyzes the reduction of A -piperidein-2-carboxylate to piperidine-2-car-boxylate (r-pipecolate) in the catabolism of o-lysine by Pseudomonas putida ATCC12633 is an NADPH-dependent representative of a large family of reductases that are distributed among bacteria and archaea (Muramatsu et al. 2005). It also catalyzes the reduction of A -pyrrolidine-2-carboxylate to L-proline. 

In 1998, Ruiz et al. reported the synthesis of new chiral dithioether ligands based on a pyrrolidine backbone from (+ )-L-tartaric acid. Their corresponding cationic iridium complexes were further evaluated as catalysts for the asymmetric hydrogenation of prochiral dehydroamino acid derivatives and itaconic acid, providing enantioselectivities of up to 68% ee, as shown in Scheme 8.18. 

Scheme 8.18 Hydrogenations of olefins with iridium complexes containing dithio-ether ligands with a pyrrolidine backbone.

Molecules whose sole heterocyclic moiety consists of a pyrrolidine ring are dealt with elsewhere in this book. There is a wealth of evidence to indicate that N-alkylpyrrolidine is usually a surrogate for a tertiary amine. 

The N-N bond in a pyrrolidine ring was hydrogenolyzed on Ra-Ni with the assistance of ultrasound (Scheme 4.150).553... 

An interesting modification of such a reaction, wherein the reactivity of the excited chromophore is increased by protonation is outlined in the following example whereby a pyrrolenine derivative is photocyclized to a pyrrolidine derivative (4.75) 488). 

All four bases consist of two units a pyrrolidine and a flavonoid (or flavan), and their spectra present characteristics of both parts. Thus the UV and IR spectra resemble the spectra of the parent flavonoid (chrysine for 61 and 62, hispidulin for 64, and 4, 5-dihydroxy-7-methoxyflavan for 63). The mass spectra of 61, 62, and 63 do not easily give a molecular ion but rather show fragments pertaining to the flavonoid and to the pyrrolidine parts [m/e 84 and 83 (61 and... 

The presence of a pyrrolidine unit in complex systems such as the azabicy-clo[2.1.1]hexane unit of 2,4-methanoproline (56) lends itself to synthesis pertaining to the 1,3-disubstituted cyclobutane part of the molecule. Thus two syntheses of 56 have been published, relying on the [2 + 2] photochemical synthesis of cyclobutanes. A nontrivial problem of the synthesis of these compounds is liberation of the target molecule from its protective groups (Scheme... 

The ring-closing metathesis (RCM) approach is useful for the synthesis of indolizidinone derivatives. The procedures published are based on the use of compound 103, an amide of a pyrrolidine derivative bearing on C-l the second unsaturated branch ready for the cyclization. The reaction proceeded smoothly with high yields in both examples (Scheme 27) <2001JOC9056, 2004JOC3968>. 

Pyrrolo[l,2-c][l,3]oxazin-l-one 248 has been obtained by reaction of allylsilanes with a pyrrolidine-lV-acyliminium ion 247 (Scheme 32), formed by addition of a Lewis acid on compound 244. The /3-silyl carbocation formed by the reaction with allylsilane 246 reacted with the oxygen of the N-15OC group followed by the loss of 2-methylpropene. The reaction was not very stereoselective when trimethylsilane was used, whereas with larger group on the silicon the selectivity was increased <1997J(P1)2163>. 

Pyrrolines. This diene undergoes a [4 + ljannelation with primary amines to form a pyrrolidine 2 that can be converted to a 3-(3-phenylsulfonyl)pyrroline (3) in high yield. These pyrrolines are oxidized by DDQ to pyrroles (4), which can be converted readily to 2,3-disubstituted pyrroles (5). 

FIGURE 7.23 Decomposition of a Boc-amino-acid /V-carboxyanhydnde by tertiary amine. Two molecules combine with the release of two molecules of C02 to form a pyrrolidine-2,4-dione. 

A comparable reaction was seen decades ago in the metabolism of methadone [173 - 175]. This well-known synthetic opiate undergoes A-demeth-ylation as a major metabolic reaction in humans and laboratory animals. The resulting secondary amine (11.168, Fig. 11.21) has never been isolated, as it undergoes practically instantaneous cyclization. The reaction is believed to proceed via the carbinolamine with formation of metabolite 11.169 as the major urinary metabolite in humans. This structurally intriguing basic compound is, in its neutral form, a pyrrolidine with an exocyclic C=C bond,... 

Fig. 6.52. El mass spectra of tetrahydrofuran (a), pyrrolidine (b), tetrahydropyran (c), and piperidine (d). Spectra used by permission of NIST. NIST 2002.

In connection with the synthesis of cytohalasin B, a pyrrole derivative 13 was prepared from methyl (5)-3-aminophenylbutyrate (78JA7775). In connection with the synthesis of l,2,4-triazolo[4,3-a]pyrazine derivatives with human Renin inhibitor activity, a /3,y-diamino acid derivative was transformed into a pyrrolidin-2-one (91JMC151). 

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