Radicals pyrrolidine formation from

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]. 

HeterocycUzation. Captodative radicals are generated from a-heterosubstituted a-chloroacetic esters by treatment with CuCl bipy. Such a radical can be trapped in-tramolecularly by an alkene (e.g., a 3-butenyl group) attached to the a-heteroatom. Formation of five-membered ring heterocycles is a favorable process. Thus methyl 3-chloromethyltetrahydrofuran-2-carboxylate has been obtained in 75% yield as a mixture of cis and trans isomers (ratio 64 36). The glycine analog gives both pyrrolidine and piperidine derivatives. ... 

The reaction of carboxylic acids with the PhI(OAc)2-iodine system may result in a decarboxylation ieading to the intermediate formation of a carbon-centered radical, which can be further oxidized to a carbocation and trapped by a nucleophile. This process has been utilized in several syntheses [97, 615,616, 617]. In a typical example, the oxidative decarboxylation of uronic acid derivatives 568 in acetonitrile under mild conditions affords acetates 569 in good yields (Scheme 3.225) [615]. A similar oxidative decarboxylation has been be used for the synthesis of 2-substituted pyrrolidines 571 from the cyclic amino acid derivatives 570 [616,617]. 

The synthesis of pyrrolidines by the free radical transformation of (V-chloroamines, the Hofmann-Loeffler-Freytag reaction, is of preparative significance. The key step is the formation of a radical cation which abstracts hydrogen intramolecularly to form a carbon-based radical (Scheme 21(a)). This species then abstracts chlorine from another TV-chloroamine (60JA1657, 50JA2118). The observed positional selectivity for hydrogen abstraction is a consequence of the preferred adoption of a six-membered transition state. A typical conversion achieved is indicated in Scheme 21(b). 

Although this strategy had solved the problem of pyrrolidine ring formation, the unexpected incorporation of the oxygen functions in both products presented a new one. Strenuous measures to eliminate air from the reaction mixture failed to avoid this complication, suggesting that the reaction intermediates (which may be either zwitterionic or radical in nature) were remarkably efficient scavengers of O2. Thus, faced with additional steps required to manipulate these groups in a productive way and the already poor yield of the dipolar cycloaddition, this approach was abandoned. 

Aminyl radicals can also be generated from amide bases and organic oxidants via an electron transfer process. The utility of /V-lithio-Af-butyl-5-methyl-l-hex-4-enamine (10) as a mechanistic probe for such a process was studied (Scheme 2) (88JA6528). The formation of cyclic pyrrolidine... 

Aminyl radicals also can be generated via electrochemical oxidation of amide bases or O-substituted hydroxylamines. Suginome has studied radical cyclizations involving oxidations of lithium alkenylamides as a route to ccs-l-methyl-2,5-disubstituted pyrrolidines (85TL6085). Electrolysis of lithium alkenylamide 17a, generated from the amine and butyllithium at - 78°C, led to the formation of 18a, exclusively cis, in 52% yield (Scheme 4). The reactions require 0.25 M UC104 in THF HMPA (30 1) as the supporting electrolyte. A variety of 2-substituted amines were studied. 

Functionalization of the carbon radical resulting from cyclization of an aminium radical is an important step for synthetic chemists in order to obtain the desired product directly or to provide a handle for further transformations. Radical reactions of A-chloroalkenylamines (Section III,B) lead to /3-chloro pyrrolidines, which are prone to rearrangement to give piperidines. Reactions of N-nitroso alkenylamines lead to 8-nitroso pyrrolidines and, if an a-hydrogen is present, ultimately to oximes of aldehydes or ketones. Advantages of the latter transformation are the formation of stable substituted pyrrolidines and the utility of the oxime moiety in regard to further transformations. 

Hydrogen abstraction under conditions similar to those in Section 3.8.1 may occur also from nitrogen compounds, with formation of amidyl free radicals. The results vary, depending on the substrate for example, 6-amino derivatives of steroids were converted into TV-substituted pyrrolidines [127], Medium-sized lactams underwent transannular cyclization to bicyclic lactams [128], and bicyclic carbinolamides afforded mainly -fragmentation products (Table 3.7). 

The efficient desilylation from amine radical cation in media favouring SSIP formation has also been used [104] for the sequential double desilylation reaction of amine 110 to generate azomethine ylide 111 which upon cycloaddition with a different dipolarophile gives a stereoselective pyrrolidine ring system 112 as depicted in Scheme 20. 

Loss of ethene from 67 leads to the enamine 68 which loses either a propyl radical (m/z 56) or, more easily, a methyl radical probably after pyrrolidine ring formation (cf 19 in Scheme 12) (Scheme 37). 

Most interestingly, also C-H bonds at a-positions of aliphatic amines can be activated by iron(III) catalysts and subjected to C-C bond formation reactions with Grignard or organozinc reagents (Scheme 4-251). As a catalyst, tris(acetylacetonato)iron is employed. The reaction requires an iodoarene substituent in appropriate distance to the amine. A mechanistic proposal involves the formation of an aryl radical by a reduced iron species, hydrogen abstraction from the a-position of the amine, ligation of the alkyl radical to the iron complex, and subsequent reductive elimination to provide the substituted pyrrolidine. ... 

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