2- Pyrrolines metallation

Pyrrole can be reduced catalyticaHy to pyrroHdine over a variety of metal catalysts, ie, Pt, Pd, Rh, and Ni. Of these, rhodium on alumina is one of the most active. Less active reducing agents have been used to produce the intermediate 3-pyrroline (36). The 2-pyrrolines are ordinarily obtained by ring-closure reactions. Nonaromatic pyrrolines can be reduced easily with to pyrroHdines. 

Additionally, it was found that the double reductive alkylation of the 2,5-diester 66 could be achieved under Birch conditions (Li/NH3) to produce the 3-pyrroline 67. On the basis of a mechanistic postulate that such reductions do not involve transfer of a proton from ammonia, the authors discovered that the same reduction could be performed in THF (no ammonia) with lithium metal and catalytic amounts of naphthalene as an electron shuttle, thereby making this reaction more practicable on a large scale <00TL1327>. 

The lithiation of 2,3-pyrrolines has received only moderate attention, but two different nitrogen protection systems have been found acceptable. Thus the terf-butylformamidine derivative metalates readily with either n-or t-butyllithium, and after reaction with a variety of electrophiles the formamidine group can be removed with hydrazine to give 2-substituted... 

Seven-membered azaheterocycles such as azepines have received much less attention than their five- or six-membered counterparts, although, as with the related 2,3-pyrroline and 1,2,3,4-tetrahydropyridine compounds, the tm-butylformamidine derivative of azepine has been a-metalated with... 

Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction 132,412), the metal hydride reduction of pyrrolines 413,414), the a-alkylation of N-nitro-sopyrrolidine 412,415), the catalytic hydrogenation of pyrroles 133), the reductive amination of 1,4-diketones 25,138), the direct alkylation of 1-methoxy-carbonyl-3-pyrroline 416), the versatile synthesis from the Lukes-Sorm dilac-... 

Thus, N-metalated azomethine ylides of the cyano-stabilized type are important in the stereoselective synthesis of pyrrolines. These reactive intermediates are regarded as synthetic equivalents of nonstabilized nitrile ylides. 

Further reduction of the pyrrolines to pyrrolidines is relatively easy both by catalytic hydrogenation and by metal-acid reduction (see Section 3.05.1.5). In contrast, further hydrogenation of the indolines can only be effected under extreme pressures and temperature to give the octahydroindole, and chemical reduction with hydriodic acid and phosphorus results in cleavage of the five-membered ring (72HC(25-l)i). 

Both 2H- and 3f/-pyrrolium isomers are moderately susceptible to nucleophilic addition at the iminium carbon. Their reactivity, however, is greatly reduced by 7t-backbonding effects of the metal to the point that they resist hydrolysis, even in aqueous solution. Dihapto-coordinated 2-and 3-pyrroline complexes can be synthesized in good yields by reduction of 3H- and 2f/-pyrrolium complexes, respectively (Figure 14).12b Hydride reduction of the 3/f-pyrrolium isomers of 1-methylpyrrole (28),... 

In addition to the high regiochemistry observed, the bulky osmium pentaammine metal center also effectively blocks one face of the pyrrole ring from attack. This directs each transformation carried out on the complex to occur on the same face of the pyrrole ring. For example, in the synthesis of 3-pyrroline complex 74, both protonation and hydride addition occur from the same face of the pyrrole ring, producing 74 exclusively as the c/s-isomer. This feature is also illustrated in the synthesis of pyrrolizinone 109 vide infra), where a stereoselective hydride reduction allows the preparation of 109 as only one diastereomer. 

In summary, the metal can be readily removed from both 1//-pyrrole and 3-pyrroline (including azanorbomene) complexes to give a wide variety of highly functionalized molecules not readily obtained from the aromatic precursors without the use of osmium. The inherent instability of 2-pyrrolines prevents clean decomplexation unless quatemization or acylation of the nitrogen is carried out prior to oxidation of the metal. 

X-ray data for coordination compounds of metals with anion ligands based on nitroxyl radicals, derivatives of imidazoline, piperidine, pyrrolidine, and pyrroline 93ZSK119. 

Benzyl isocyanide is a useful precursor of compounds containing the ot-benzylamino moiety. Substituted styrenes, vinyl isocyanides, 2-oxa-zolines, 1-pyrrolines, imidazoles, and a-amino acids and ketones can be obtained by metalation of isocyanides with butyllithium12 or copper salts,13 and subsequent reaction with various electrophiles.12... 

Metalation of the amine substrate 184, followed by annulation promoted by tetramethylethylenediamine (TMEDA), gave the intermediate 185, which could thereafter be converted to the fused 3-pyrroline system 186 (Scheme 22). Subsequent dehydrogenation with DDQ gave the corresponding fused pyrrole. This methodology was used for preparation of an extended set of related pyrroles, as well as a series of indole derivatives, which were accessed by lithiation of iV-bromoallyl-2-bromoanilines <2001CEJ2896>. 

The final series of five procedures presents optimized preparations of a variety of useful organic compounds. The first procedure in this group describes the preparation of 3-BROMO-2(H)-PYRAN-2-ONE, a heterodiene useful for (4+2] cycloaddition reactions. An optimized large scale preparation of 1,3,5-CYCLOOCTATRIENE, another diene useful for [4+2] cycloaddition, is detailed from the readily available 1,5-cyclooctadiene. Previously, the availability of this material has depended on the commercial availability of cyclooctatetraene at reasonable cost. A simple large scale procedure for the preparation of 3-PYRROLINE is then presented via initial alkylation of hexamethylenetetramine with (Z)-1,4-dichloro-2-butene. This material serves as an intermediate for the preparation of 2,5-disubstituted pyrroles and pyrrolidines via heteroatom-directed metalation and alkylation of suitable derivatives. The preparation of extremely acid- and base-sensitive materials by use of the retro Diels-Alder reaction is illustrated in the preparation of 2-CYCLOHEXENE-1.4-DIONE, a useful reactive dienophile and substrate for photochemical [2+2] cycloadditions. Functionalized ferrocene derivatives... 

Photochemical rearrangements have also been reported, as shown in equation (53). " Transition metal catalyzed rearrangement [palladium(O)] of a dienylaziridine has been reported in one case, and a radical opening of a dienylaziridine led to pyrroline formation under the conditions of radical initiation with AIBN/PhsSnH (equation 54). For those vinylaziridines that contain additional unsaturation, the corresponding aza equivalent of a divinylcyclopropane Cope rearrangement is the usual pathwayThe subject of heterodivinylcyclopropane Cope rearrangement is covered in detail elsewhere." The... 

---