Barton reaction synthesis

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

Nitro-aldols, which are readily available (see Henry reaction Section 3.1), are converted into olefins via conversion of the hydroxyl group to the corresponding phenyl thiocarbonate ester and treatment with tin radical.158 The yield was not reported. Because the radical deoxygenation via thiocarbonate (Barton reaction) proceeds in good yield, the elimination of Eq. 7.115 might be good choice for olefin synthesis.159... 

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). 

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. 

Barton-Kellogg Reaction (Barton Olefin Synthesis)... 

The oxygen atom of the activated alkoxy radical and the hydrogen to be abstracted and subsequently replaced by X, form two adjacent corners of the six-membered transition state. The major application of the Barton reaction have been in the synthesis of steroids particularly with compounds involving functionalization of Clg and C,9 which is difficult to achieve in other ways. 

The introduction of functional groups in nonactivated positions of the steroid nucleus poses a problem of considerable difficulty and importance particularly in the synthesis of C-18 oxygenated steroids such as aldosterone. The Barton reaction provides an excellent solution to many problems in the introduction of functional groups in nonactivated sites in the steroid nucleus. 

Intramolecular hydrogen abstraction is an important synthetic reaction because it provides a method of introducing a functional group at a saturated carbon bonded to only hydrogen and other carbons, a difficult task to accomplish by other means.196 The abstracting radical need not be carbon the Barton reaction (Scheme 15) is a standard method in which the abstracting radical is oxygen.197 This technique has been used extensively for selective introduction of functionality in steroid synthesis.198... 

In addition to Scheme 20, the synthesis of (5,(5 -substituted pyrroles has also been achieved through a Zard-Barton reaction (1985JCS(CC)1098, 1990T7587, 1991SL127). Likewise, Hayashi et al. (03OL2845, 03IC7345)... 

See Section 3 for a discussion of the photochemical synthesis of an endothelin receptor antagonist 199 using the Barton reaction and the synthesis of a precursor to (-)-rose oxide 200 which is of industrial interest to fragrance manufacturers. 

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].

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. 

Aprotic Solvents, in J. F. Coetzee and C. D. Ritchie (eds.) Solute-Solvent Interactions, Dekker, New York, London, 1969, Vol. 1, p. 219ff. [95] H. Liebig Prdparative Chemie in aprotonischen Ldsungsmitteln, Chemiker-Ztg. 95, 301 (1971). [96] E. S. Amis and J. F. Hinton Solvent Effects on Chemical Phenomena, Academic Press, New York, London, 1973, Vol. 1, p. 271ff. [97] P. K. Kadaba Role of Protic and Dipolar Aprotic Solvents in Heterocyclic Syntheses via 1,3-Dipolar Cycloaddition Reactions, Synthesis 1973, 71. [98] J. H. Hildebrand and R. L. Scott The Solubility of Nonelectrolytes, 3 ed., Reinhold, New York, 1950 Dover, New York, 1964 J. H. Hildebrand and R. L. Scott Regular Solutions, Prentice-Hall, Englewood Cliffs/New Jersey, 1962 J. H. Hildebrand, J. M. Prausnitz, and R. L. Scott Regular and Related Solutions, Van Nostrand-Reinhold, Princeton/New Jersey, 1970. [99] A. E. M. Barton Handbook of Solubility Parameters and other Cohesion Parameters, CRC Press, Boca Raton/Elorida, 1983. [100] M. R. J. Dack, Aust. J. Chem. 28, 1643 (1975). 

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. 

In a second example, Ryu and co-workers [87, 88] demonstrated the nitrite photolysis (Barton reaction) of the steroidal substrate 157 to afford 158 (Scheme 6.41), a key intermediate in the synthesis of an endothelin receptor antagonist, using a 300 W high-pressure mercury lamp. Maintaining a gap of 7.5 cm between the stainless-steel/glass reactor [channel dimensions = 1000 pm (width) x 107 pm (depth) x 2.2 m (length)] and the light source, an acetone solution of the nitrite... 

Remote functionalization of the angular methyl group in santonin derivatives has also been accomplished using the Barton reaction. For example a key step in the previously reported synthesis of the norsesquiterpenoid rishitin (450) from tetrahydro-a-santonin (443) involves photochemical transformation of the nitrite ester (447) to the oxime (448) (c/. Scheme 46). Rishitin (450) is a well known antifungal phytoalexin produced by diseased potato tubers and recent studies... 

Figure 4. Regioselective Oxidative Coupling The final step for the completion of the pentacyclic ring system of the morphine alkaloids involves the closure of the C4-C5 ether bridge. Synthetic salutaridine has been transformed in vivo to thebaine, codeine, and morphine in Papaver sominiferum. Reduction of the dienone was proposed,30 and indeed, hydride reduction of salutaridine produces a mixture of two epimeric alcohols. However, upon feeding 7-3H labelled salutaridinol epimers to Papaver somniferum, only the S-isomer was converted into thebaine an indication that the reaction is enzyme mediated.31 >32 This finding contradicted earlier work by Barton in which the configuration of the alcohol was assigned as R (See description of Barton s synthesis, ref. 50).

A classic example of the Barton reaction is the key step in a synthesis of the acetate 24 of aldosterone, a hormone of the adrenal cortex (4.24). Photolysis of the nitrite 22 provided the oxime 23, which on hydrolysis with nitrous acid gave aldosterone-21-acetate direetly. In this case the yield is limited in part by competing... 

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