Nitrite photolysis the Barton reaction

The last important steroidal hormone of the adrenal cortex to be characterized was aldosterone la. This substance was only available in minute amounts from natural sources and the determination of structure by Reichstein and his colleagues1-2 was a masterpiece of collaboration between University (Basel) and Industry (Ciba-Geigy). The masked aldehyde group at C18 is an unusual feature for a steroidal molecule and at once posed interesting problems of synthesis. There are very few natural steroids which are substituted at C18, so a partial synthesis did not, at first, seem very practical. 

Aldosterone controls the electrolyte balance of mammalian systems, and so there was tremendous interest in obtaining enough aldosterone to examine in detail its biological proper- 

My mind was prepared from my knowledge of the pyrolysis of chlorinated hydrocarbons (Chapter 1) and related subjects. The work of the late Professor E. W. R. Steacie, who eventually became Director of the National Research Council of Canada, had showed that the pyrolysis of alkyl nitrites in the gas phase gave NO and an alkoxy radical in a unimolecular reaction. The temperatures required for this reaction were much too high for 

In reality, it required only a few weeks to convert 3 into aldosterone acetate lb.5-7 The acetate is a biological equivalent to aldosterone and easier to handle and store. The overall yield of crystalline acetate was about 15%. However, this was satisfactory for the preparation of 60 g of aldosterone acetate 

The relatively poor overall yield was due principally to the partitioning of the 11/f-alkoxy radical between the 18 and 19 methyl groups. Neglecting conformation effects due to the 4(5)- 

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The book explores the invention of new chemical reactions for use in the synthesis of biologically and economically important compounds. It begins with a mechanistic study of the industrial importance of the pyrolysis of chlorinated alkanes. It continues with a theory on the biosynthesis of phenolate derived alkaloids involving phenolate radical coupling. Included in the book is a description of the work on nitrite photolysis (the Barton Reaction) which involved the invention of new radical chemistry leading to a simple synthesis of the hormone, aldosterone. In two final chapters Dr Shyamal Parekh views Professor Barton s pioneering work from the modern perspective, with a review of recent applications in industry and research. 

Scheme 19. Nitrite ester photolysis the Barton reaction.

The involvement of an intramolecular hydrogen abstraction in the Barton reaction is not necessarily limited to those molecules with rigid stereochemistry. In fact, simple aliphatic nitrites undergo the Barton reaction with equal ease. Thus, the principal product obtained from the photolysis of ra-octyl nitrite20 in benzene solution is the dimer of 4-nitroso-l-octanol however, photolysis of n-octyl nitrite in n-heptane20 produced a mixture of 7/-nitroso heptanes in addition to 4-nitroso-l-octanol in the ratio l 4.5,f respectively. The formation of y-nitroso heptane obviously results from an attack of the intermediate alkoxy radical on the solvent molecule. The intermediate alkyl radical then collapses, according to eq. 2. For the sake of convenience we have indi-... 

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,... 

Suginome, H., Remote Functionalization by Alkoxyl Radicals Generated by the Photolysis of Nitrite Esters the Barton Reaction and Related Reactions of Nitrite Esters. In Horspool, W. M., Lenci, F. (eds), CRC Handbook of Organic Photochemistry and Photobiology, 2nd edn, CRC Press LLC, Boca Raton, FL, 2004, Chapter 102, pp. 1 16. 

Remote Functionalization by Alkoxyl Radicals Generated by the Photolysis of Nitrite Esters The Barton Reaction and Related Reactions of Nitrite Esters... 

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. 

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... 

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... 

In a similar manner, 11/3-nitrites, on photolysis, attack Ci to furnish the corresponding oximes which, upon nitrous acid treatment, gave 18-oxygenated steroids. The most spectacular application of the Barton reaction has been a three-step synthesis of aldosterone.12 Irradiation of corticosterone-11-nitrite (27, R = NO), followed by nitrous acid treatment, gave aldosterone (29) in 15% overall yield. Comparable conversions of 11/3-hydroxyprogesterone to 21-desoxyaldosterone12 and A1-corticosterone to A aldosterone14 have also been achieved. 

Similarly, the products derived from the photolysis of steroidal nitrites (60 and 11/8) in toluene were mainly the result of intramolecular hydrogen abstraction (the Barton reaction). Kxothermicity calculations23 predict intermolecular hydrogen abstraction process (AH = 25 kcal./mole) to predominate over intramolecular hydrogen abstraction (AH = —3 to 5 kcal./mole). 

To explain the high chemical yield in the transformation A - D, coupled with the fact that the quantum yield for the photodecomposition of nitrites is less than unity, it was suggested that the Barton reaction might take place through a radical "cage mechanism.2 However, recent studies at the Institute on the mechanism of nitrite photolysis have shown this not to be so. Photolysis of an equimolecular mixture of 3/3-acetoxy-androstan-6/8-yl nitrite (102) and 3/8-acetoxy-cholestan-6/8-yf nitrite containing 98% of nitrogen as N16 (103) in iso-octane or toluene... 

The photolysis of organic nitrites of appropriate constitution and conformation in solvents such as benzene or acetonitrile transforms them into A-nitroso alcohols via the sequence (1) a homolytic fission of the O-N bond of their nitrosoxy group (2) an intramolecular d-hydrogen abstraction of the resulting alkoxyl radicals to generate a d-carbon radical and (3) formation of d-nitroso alcohols by combining of the d-carbon radical with the generated nitric oxide. The nitroso alcohols are isolated as d-hydroxyimino alcohols as a result of spontaneous thermal isomerization or as nitroso-dimers [1] (Scheme 1). This transformation has been named the Barton reaction [2, 3],... 

Schemes 5 and 6 outline the functionalization of a 10/1-Me by a steroidal 6/f-ol [1] and a 2/3-61 nitrite [6], Functionalization of 13/i-Me by a 20a-ol nitrite [7] and functionalization in the terpenoid field [8] are outlined in Schemes 7 and 8. The last example involves a 7-membered cyclic transition state that seldom occurs. Scheme 9 outlines a recent application of the Barton reaction in the synthesis of a biologically active carbacepham [9]. The photolysis of acyclic 5-phenyl-1-pentanol nitrite gives, preferentially, a nitroso dimer arising as a result of the abstraction of a hydrogen attached to the d-carbon, rather than the e-carbon from which the better stabilized benzyl radical can be generated (Scheme 10) [10].

Barton reaction In the Barton reaction " a methyl group in the 7 -position to an OH group is converted into an oxime group. For example, corticosterone acetate (2.45) on reaction with nitrosyl chloride (NOCl) in pyridine forms its 1 l -nitrite 2.46, which on photolysis in toluene gives aldosterone acetate oxime (2.47) in 21% yield. Treatment of 2.47 with nitrous acid (HNO2) gives aldosterone acetate (2.48) (Scheme 2.40). 

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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