The Barton Reaction

This reaction has been extensively utilized in the functionalizations of steroids and other bioactive organic compounds. For example, 11-hydroxycorticosterone acetate 2 was converted into aldosterone-21-acetate 3 [4]. 

In steroid 4, 6-hydrogen abstraction takes place from C(19)-methyl instead of C (18)-methyl to give oxime 5 [5]. 

Other important applications of Barton reaction are in the synthesis of alkaloids and terpenoids. For example, the photolysis of nitrite 6 was used in a crucial step in the synthesis of alkaloid perhydrohistrionicotoxin 7 [6]. The oxime 8, formed in about 20 % yield, gives the spirolactam ring of the alkaloid 7 on Beckmann rearrangement. 

The Barton reaction (BR) is also used in key steps in the synthesis of tetracyclic triterpenoid, azadiradione 9 [7] and 3(a-hydroxyethyl)-quinuclidine 10 for synthesis of cinchona alkaloids [8]. 

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Nitrous acid esters 1 can be converted to 3-nitroso alcohols 2 by irradiation with ultraviolet light. This conversion is called the Barton reaction. ... 

There is quite some evidence for a mechanism as formulated above,especially for the six-membered transition state—the Barton reaction is observed only with starting materials of appropriate structure and geometry, while the photolysis of nitrite esters in general seldom leads to useful products formed by fragmentation, disproportionation or unselective intermolecular hydrogen abstraction. 

The Barton reaction is usually carried out by irradiation of a nitrite ester 1 dissolved in a hydroxyl-free solvent under nitrogen atmosphere. Possible side-reactions can be decomposition reactions and intermolecular reactions sometimes the disproportionation may even predominate ... 

The required nitrite esters 1 can easily be obtained by reaction of an appropriate alcohol with nitrosyl chloride (NOCl). The 3-nitroso alcohols 2 formed by the Barton reaction are useful intermediates for further synthetic transformations, and might for example be converted into carbonyl compounds or amines. The most important application for the Barton reaction is its use for the transformation of a non-activated C-H group into a functional group. This has for example been applied for the functionalisation of the non-activated methyl groups C-18 and C-19 in the synthesis of certain steroids. ... 

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 ... 

A radical approach to asymmetnc iildol synthesis, which is based on the radical addition of a chiral hydroxyalkyl radical equivalent to a tutroalkene, has been reported, as shown in Eq 4 93 The radical precursor is prepared from the corresponding carboxyhc acid by the Barton reaction, which has been used for synthesis of new fi-lactams ... 

Scheme 19. Nitrite ester photolysis the Barton reaction.

Scheme 21. The Barton reaction in Magnus s synthesis of grandisol (117).

Another related reaction is the Barton reaction, by which a methyl group in the 0 position to an OH group can be oxidized to a CHO group. The alcohol is first converted to the nitrite ester. Photolysis of the nitrite results in conversion of the nitrite group to the OH group and nitrosation of the methyl group. Hydrolysis of the oxime tautomer gives the aldehyde, for example,... 

Other synthetic applications of the Barton reaction in the steroid field follow[Pg.263]

Photolysis of 2-propylnitrite, in which intramolecular hydrogen abstraction cannot occur via a six-membered transition state, results in a 30% yield of 2-propanone. As we shall see, this intramolecular hydrogen abstraction has been extensively applied to steroid syntheses by D. H. R. Barton and hence is commonly referred to as the Barton reaction. 

Radical migration of hydrogen is also known, though only over longer distances than 1,2-shifts, e.g. a 1,5-shift to oxygen via a 6-membered cyclic T.S. in the photolysis of the nitrite ester (129)—an example of the Barton reaction ... 

An alternative method in the synthesis of alkaloids, photochemical rearrangement of endocyclic nitrones into bicyclic lactams has drawn special attention. Analyses of photochemical rearrangement and application of modified conditions of the Barton reaction testify to the comparability of results obtained in these approaches (Scheme 2.89) (460). 

Some examples of radical nonchain reactions are shown in Figure 4.8. In the Barton reaction (hrst example in Fig. 4.8), photolysis of a nitrite ester gives an... 

The Barton reaction [102], A photochemical exchange process between a nitrite group and a proximate nonactivated hydrogen has been called the Barton reaction. The process appears to be limited to aliphatic compounds (Eq. 52). 

In the case of cycloheptyl nitrite and cyclooctyl nitrite, the 4-nitroso-l-cyclic alcohol dimers expected from the Barton reaction are isolated. 

Another related reaction is the Barton Reaction,613 by which a methyl group in the 8 position to an OH group can be oxidized to a CHO group. The alcohol is first converted... 

Photolysis of primary, secondary, and tertiary alkyl nitrites in benzene indicated that a minimum chain length of five carbon atoms attached to the nitrite grouping is required for appreciable yields of secondary nitroso dimers via the Barton reaction. In the case of primary and secondary nitrites, a chain of length of four carbon atoms or more attached to the nitrite grouping is required for formation of the six-membered intermediate (e.g., A) involved in the Barton reaction.139140... 

One of the prerequisites for the Barton reaction is the availability of a six-membered, cyclic transition state... 

To date, the major synthetic achievements in the application of the Barton reaction have been in the steroid field, particularly with compounds involving functionalization of Cw and C19. In principle, Ci can be attacked from an alkoxy radical at C20, C , Cu, or Cu and Cu from an alkoxy radical at Cn, C6, C4, or C2 (six-membered transition-state requirement). 

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