Pyrrolidines, generation by radical

New cyclizations via photochemically generated aminyl radicals have been reported, including further examples of the Hofmann-Loeffler-Freytag reaction.313 Intramolecular addition of an aminyl radical, generated by photochemically induced nitrogen chlorine bond homoysis, is also accompanied by cyclization as illustrated by the conversion of the unsaturated N-chloroamide 378 to the pyrrolidine 379.314 Piperidine formation can also... 

Neutral aminyl radicals generated by anodic oxidation of lithium alkenyl amides undergo a stereoselective cyclization to cis-l-methyl-2,5-disubstituted pyrrolidines [249]. 

An interesting application of PET-generated amine radical cations has been shown [87,99] to produce a-amino radicals by efficient desilylation of a-methyl silylamine 99. High yields of both pyrrolidines and piperidines (101) are... 

Neutral aminyl radicals were generated by the anodic oxidation of lithium 4-pentenylamides and underwent regioselective and stereoselective cyclization to 1 -methyl-2,5-c/. -disubstituted pyrrolidines 123 25. 

In this protocol the pyridine- and the pyrrolidine-ring of 1 are built up in a one-pot radical domino reaction." Photolysis of iodopyridone 11 in the presence of hexamethylditin provides radical 56, which attacks the reactive isonitrile 15. The resulting radical 57 reacts with the alkyne group in a 5-exo-dig cyclization (see Chapter 11). Next, the newly formed vinyl radical 58 cyclizes onto the aryl ring generating speeies 59. Final oxidation via a so far unknown mechanism yields 1 with 31 % yield. For the generation of radical 56 by photolysis two ways (A and B) are possible. 

Comparable results are obtained in radical additions to several C2-symmetric fumaric bisamidcs. 2,5-Dimcthylpyrrolidine14,15,2°, 2,5-bis(methoxymethyl)pyrrolidine and 1,3 4,6-di-0-benzylidene-2,5-dideoxy-2,5-imino-L-idit21 are used as chiral auxiliaries. Reactions with cyclohexyl or tort-butyl radicals, generated by the mercury or the tin method, respectively, proceed with high levels of asymmetric induction, yielding essentially only one of the two possible products. 

Radicals normally do not occur in peptides but they can be generated by irradiation at low temperature with UV, electrons or X-rays, usually at the a-carbon atom, and then can be recognized by ESR. There are some radicals that are stable at ambient temperature, for instance N-oxides with the structural element C-NO-C. In biochemistry, e.g. derivatives of 2,2,5,5-tetramethyl-pyrrolidine-l-oxide are being used as spin labels, conjugated to bioactive compounds. In this way ESR can localize the position of possible receptor sites. For instance, in hormone research the distances in the neurophysin complex between spin-labeled small peptides, models of oxytocin, have been determined [27]. 

One of the best methods for the controlled generation of alkenaminyl radicals is via PTOC carbamates (Section II,E). These precursors react in efficient radical chain reactions with hydrogen atom donors to form amines and pyrrolidines. They are stable to anhydrous acids and, therefore, are suitable precursors for aminium radicals produced by protonation of the first-formed neutral aminyl radical. 

Heating or photolytic treatment of A,A-dialkyl-A-haloamine in sulfuric acid or trifluoroacetic acid, followed by neutralization with a base, generates a pyrrolidine or piperidine skeleton. This is the Hofmann-Loffler-Frey tag reaction, and the reaction comprises of the formation of an electrophilic aminium radical, 1,5-H shift (6-membered transition state) or 1,6-H shift (7-membered transition state), formation of 4-haloalkyl ammonium or 5-haloalkyl ammonium, and its polar cyclization by neutralization with a base. Eq. 6.16 shows the formation of A-alkyl pyrrolidine (31) from A-chloro-A-alkyl-A-butylamine (30) in sulfuric acid [46, 47]. 

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