Hofmann-Loeffler reaction

Steps similar to the Hofmann-Loeffler reaction are also involved in cyclization of iV-alkylmethanesulfonamides by oxidation with Na2S204 in the presence of cupric ion.373... 

B. Cyclization of Halogen-Containing Compounds 1. The Hofmann-Loeffler Reaction... 

The cyclization of V-halogenated amines to pyrrolidines, the Hofmann-Loeffler reaction,869 can be effected by irradiation in sulfuric acid, followed by treatment with base. The initial step in the conversion870 of V-chlorodibutylamine to 1-butylpyrrolidine [Eq. (96)] is photochemically induced homolytic cleavage of the nitrogen-... 

In contrast to the cyclization of jV-halogeno-4-(oxoalkyl)-piperidines, closure of the quinuclidine ring starting from 4-alkyl-JV-halogenopiperidines met with difficulties. Application of the Hofmann-Loeffler reaction to 4-alkyl-i r-chloropiperidines by Wawzonek, LukeS, Ferles, and co-workers 83-88 led to a mixture of... 

Scheme 3. Synthesis of conanine derivative by the Hofmann-Loeffler reaction [24]...

The remote halogenation is believed to proceed by a chain mechanism analogous to the Hofmann-Loeffler reaction in both the iodoamide and bromoamide reactions. 

HOFMANN - LOEFFLER FREYTAG Pyrrolidine Synthesis Synthesis of pyrrolidines or piperidines from N-haloamlnes (free radical reaction). 

The so-called Hofmann-Loeffler-Freytag reaction" " of TV-chloroamines 9 proceeds by a similar mechanism, and is for example used for the synthesis of pyrrolidines 11 ... 

The Hofmann-Loeffler-Freytag reaction has been described with A-chloro-as well as A-bromoamines—the former however usually give better yields. A-chlorinated primary amines react well in the presence of Fe-(II) ions. Just like the Barton reaction, the Hofmann-Loeffler-Freytag reaction has been applied mainly in steroid chemistry. An interesting example from alkaloid chemistry is the synthesis of nicotine 12 by Loeffler ... 

One example of this type of reaction is the photolytically initiated decomposition of (V-chloroamines in acidic solution, which is known as the Hofmann-Loeffler-Freytag reaction 11 The initial products are 8-chloroamines, but these are usually converted to pyrrolidines by intramolecular nucleophilic substitution. 

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... 

The Hofmann-Loeffler photolytic rearrangement of chloroamines has been used in early syntheses of ant pyrrolidines (Scheme 26) (129, 164). This reaction, however, suffers from lack of stereo- and regioselectivity. 

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). 

Another synthesis of a quaternary salt (8) was developed by Meyer and Sapianchiay for the purpose of studying the steric course of formation of the pyrrolizidine system.9 Photolysis of the N-chloroamine (9) in a Hofmann-Loeffler-Freytag reaction [Eq. (4)], gave an intermediate that yielded the pyrrolizidine salt (8) in an intramolecular N-alkylation. The product was the cis-isomer, reflecting the greater degree of strain in the trans-fusion of two five-membered rings. 

Hofmann-Loeffler rearrangement has a variety of forms, and a number of related reactions are known. Among these is the inter-molecular chlorination of alkyl chlorides and esters shown in (158)... 

A re-investigation " of the early work on the total synthesis of quinine (116a) has provided more efficient methods. In particular, and following earlier work, Uskokovic has prepared the requisite vinylpiperidine intermediate by introducing unsaturation into an ethyl-precursor using the Hofmann-Loeffler-Freytag reaction. Other improvements are the addition of the quinoline ring " "... 

---