Nitrite esters, Barton reaction

The first step in the mechanism is the homolysis of the 0-N bond to form an oxygen-centered radical and a nitrogen-centered free radical. Next, the highly reactive alkoxyl radical abstracts a hydrogen atom from the 5-position (5-position) via a quasi chair-like six-atom transition state to generate a new carbon-centered radical that is captured by the initially formed NO free radical. If a competing radical source such as iodine is present, the reaction leads to an iodohydrin, which can cyclize to form a tetrahydrofuran derivative. Occasionally, tetrahydropyran derivatives are obtained in low yields. 

In the partial synthesis of myriceric acid A by T. Konoike and co-workers, the Barton nitrite ester reaction was utilized in a large-scale preparation of one of the intermediates  

Cephalosporins are important (f-lactams, but a number of pathogenic microorganisms have developed resistance to these antibiotic compounds. In order to prepare novel antibiotic cephalosporin analogs, I. Chao and co-workers synthesized 1-dethia-3-aza-1-carba-2-oxacephem, which is not a substrate of the inducible 3-lactamase enzyme. The key step of the synthetic sequence was the Barton nitrite ester reaction in which regioisomeric oximino 3-lactams were generated and transformed into the desired product.  

The Barton reaction was utilized during the synthesis of various terpenes and has played a crucial role in the elucidation of terpene structures. The Barton nitrite ester reaction was a key step in E.J. Corey s synthesis of azadiradione and perhydrohistrionicotoxin . Even though the yields were low, other ways to access the same intermediates would have been tedious, and afforded lower overall yields than in the applied Barton reactions. 

The Barton reaction does not always afford only a single major product. J. Sejbal and co-workers isolated two products in a Barton reaction on triterpene substrates. In this example, reaction at either (or both) the C4 and C10 methyl groups was expected, but oxidation of the C8 methyl group was not. This remote functionalization occured via 

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Related reactions Barton nitrite ester reaction ... 

Intra-Molecular y-Hydroxy Oxime Formation (Barton Nitrite Ester Reaction)... 

Addition of radical trapping agents can extend the functionality of the Barton nitrite ester reaction. The Cekovic group added Michael acceptors to the reaction, and the carbon-centered radical adds to the Michael acceptor to form a chain elongated product 10. A large excess of Michael acceptor is necessary for yields to be practical. 

The Barton nitrite ester photolysis is undeniably one of the most popular and useful reactions in radical chemistry for the functionalization of remote and inactivated positions within steroids (Scheme 19). Photolysis of nitrite esters gives nitric oxide and an alkoxyl radical that abstracts an ideally positioned hydrogen atom (1,5-hydrogen atom abstraction). The resulting alkyl radical reacts with nitric oxide in a solvent cage to afford the nitroso-alcohol derivative that is finally isolated as an oxime [53]. Related cyclizations of alkoxyl radicals have been reported by Surzur photolysis of y,(5-alkenyl nitrite esters leads to alkoxyl radicals that undergo subsequent tandem 5-exo cyclization followed by NO-trapping [54, 55]. 

The Barton nitrite photolysis reaction involves the conversion of a nitrite ester 1 to a y-oximino-alcohol 3 by photolysis involving the homolytic cleavage of a nitrogen oxygen bond followed by hydrogen abstraction. ... 

A recent patent application disclosed a method for making polyurethanes made from nitrite esters and di/poly-isocyanates with the help of UV-irradiation for use as coatings. The application disclosed polymerizable and curable compositions and processes of polymerizing and curing polyurethanes involving an isocyante compound and a nitrite ester compound. Irradiation of the nitrite ester compound with UV generates an active hydrogen compound by the Barton nitrite photolysis reaction that reacts with an isocyanate compound to produce and/or crosslink a polyurethane. 

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. ... 

Scheme 19. Nitrite ester photolysis the Barton reaction.

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,... 

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 ... 

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... 

Alkoxyl radicals can be generated by a variety of methods including peroxide reduction, nitrite ester photolysis, hypohalite thermolysis, and fragmentation of epoxyalkyl radicals (for additional examples of alkoxyl radical generation, see Section 4.2.S.2). Hypohalites are excellent halogen atom donors to carbon-centered radicals, and a recent example of this type of cyclization from the work of Kraus is illustrated in Scheme 43.182 Oxidation of the hemiketal (57) presumably forms an intermediate hypoiodite, which spontaneously cyclizes to (58) by an atom transfer mechanism. Unfortunately, the direct application of the Barton method for the generation of alkoxyl radicals fails because the intermediate pyridine-thione carbonates are sensitive to hydrolytic reactions. However, in a very important recent development, Beckwith and Hay have shown that alkoxyl radicals are formed from N-alkoxypyridinethiones.183 Al-... 

H. Suginome, Remote functionalization hy alkoxyl radicals generated hy the photolysis of nitrite esters The Barton reaction and related reactions of nitrite esters in CR. Handbook of Organic Photochemistry and Photobiology, 2nd Edition,... 

A functionalization that converts C—H bonds to C— NO bonds occurs when nitrite esters are photo-lyzed (the Barton reaction Scheme 4). Again an alkoxyl radical abstracts a 8-hydrogen, and the resulting carbon radical picks up NO. The product nitroso compounds convert easily to oximes. Particularly valuable examples have bMn studied in the steroid field. If the photolysis is performed in the presence of copperfll) acetate the intermediate carbon radical can be oxidized to an alkene, rather than capture NO. If the alcohol whose nitrite ester is photolyzed is part of a cyanohydrin, then the Heusler-Kalvoda reaction occurs, and the product is a ketone with a migrated cyano group (Scheme 5) ... 

When a free radical is formed and held tightly within a molecule, reactions of quite high site specificity (regioselectivity) may be observed. The free radical may be generated from another functional group in the molecule, but the result is the substitution at a centre that in a formal sense has the characteristics of a hydrocarbon. Such reactions are observed in the photolysis of nitrite esters (RONO) (the Barton reaction), the... 

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