Barton esters, photolysis

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,... 

Examples of radical-mediated C-alkylations are listed in Table 5.4. In these examples, radicals are formed by halogen abstraction with tin radicals (Entries 1 and 2), by photolysis of Barton esters (Entry 3), and by the reduction of organomercury compounds (Entry 4). Carbohydrate-derived, polystyrene-bound a-haloesters undergo radical allylation with allyltributyltin with high diastereoselectivity (97% de [41]). Cleavage from supports by homolytic bond fission with simultaneous formation of C-H or C-C bonds is considered in Section 3.16. 

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-... 

The photolysis of Barton esters (N-hydroxy-2-thiopyridone esters, 43) proved to be an efficient method for generating carbon-centered radicals that are exploited for the regioselective alkylation of electron-deficient olefins a thiopyridyl unit is likewise incorporated into the end products. In a recent application, Barton esters were found useful in the synthesis of natural and unnatural disubstituted maleimides or maleic anhydrides by way of two consecutive radical addition steps, as described in Scheme 3.27 [72]. 

Musso has reported the synthesis of diasterane (tricyclo-[3.1.1.I2 4]octane) 15. For this first member of the series of asteranes, the decarboxylation of 16b -> 16c was best achieved via the photolysis of the Barton ester of 16a in the presence of BuSH, as shown in Scheme 5.14 Fukumoto has accomplished asymmetric total synthesis of atisine 17, where the bridged pentacyclic intermediate 18, a precursor for atisine, was synthesized via an intramolecular double Michael reaction starting with 19, Scheme 6.15 Barton protocol was favored during the late stages of the synthesis and the presence of various functionalities was easily accommodated. 

Barton Esterification Reductive Decarboxylation. O-Acyl thiohydroxamates or Barton esters are useful precursors of carbon-centered radicals via thermolysis or photolysis. Several different methods are available for converting carboxylic acids into Barton esters (eq 1). These reactions generally proceed via the attack of a 2-mercaptopyridine-N-oxide salt on an activated carboxylic acid that has either been preformed (acid chloride, mixed anhydride) or generated in situ (with 1,3-dicyclohexylcarbodiimide or tri-n-butylphosphine + 2,2 -dithiodipyridine-l,r-dioxide). However, HOTT has the distinct advantages of (1) being easy to prepare and handle without the need for any special precautions, (2) facilitates efficient Barton esterification of carboxylic acids, and (3) simplifies subsequent work-up and purifications by avoiding the need to remove by-products like 1,3-dicyclohexylurea. 

Akhtar, M., Barton, D. H. R., Sammes, P. G. Some radical exchange reactions during nitrite ester photolysis. J. Am. Chem. Soc. 1965, 87,... 

The classical demonstration of the real existence of a solvent-equilibrated intermediate was finally performed with the radical Ph-CHX-C (OMe)Me, which was generated by flash photolysis of the Barton esters in tetrahydrofu-ran. The loss of monitored by the change of UV absorbance at 20 °C loss of... 

The Barton reaction (photolysis of a nitrite ester ) has been employed to attack C-4 methyl substituents in 4,4-dimethyl-5a-steroids. Nitrites of the 6a-and 6)3-alcohols (714) afforded alkoxyl radical species, which attacked the 4a-and 4/ -methyl groups respectively, giving the corresponding aldoximes e.g. 715). Yields were quite high (56—60%) from the 6a-ol and the 19-nor-6 -ol, but attack... 

Barton and Crich reported the first examples of the uses of 2-substituted allylic sulfur compounds [53]. Their initial experiments with additions of simple alkyl radicals to allyl sulfides, sulfoxides and sulfones were relatively unsuccessful. This failure was largely due to the fact that the nucleophilic alkyl radicals, which were generated by photolysis of the corresponding Barton ester, underwent addition to a second equivalent of Barton ester faster than they added to the allyl transfer agent. Reactions were much more successful with the electron-deficient acrylate reagent 93 (Fig. 4). Crich was later able to show that this same reagent underwent addition reactions with an acyl radical derived from an acyl phenyl telluride [54]. 

An excellent alternative to the classical Hunsdiecker reaction and its variants, which totally avoids the use of heavy metal salts and potent electrophilic reagents, consists of the simple photolysis or thermolysis of Barton esters in refluxing bromotri-chloromethane for the bromides or tetrachloromethane for the chlorides [4], The analogous decarboxylative iodination can also be achieved using iodoform as the reagent in a benzene/cyclohexene solvent system (Scheme 5). For the cases of vinylic and aromatic acids, where the usual problems of chain efficiency are encountered, the addition of azobisisobutyronitrile (AIBN) is also required [10]. Nevertheless, since this method can operate on both electron-rich and electron-poor aromatic systems, and moreover does not suffer from the competitive electrophilic aromatic bromination found with electron rich aromatics under normal Hunsdiecker conditions, this route to synthetically useful aryl iodides and bromides should find widespread application. 

The use of a protonated heterocyclic base as the radical trap has also proven to be a very useful extension of O-acyl thiohydroxamate chemistry and is typically carried out by photolysis of the Barton ester in a dichloromethane solution containing the camphorsulfonate salt of the heterocycle [41]. Two examples of this approach are shown in Scheme 38. 

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]. 

O-Acyl esters (Barton esters) of A hydrox3q)yridine-2-thione are excellent precursors of carbon-centered radicals through the rapid decarboxylation of the acyloxyl radicals formed, under mild reaction conditions (photolysis with a tungsten lamp at room temperature, or refluxing in benzene or toluene). Carbon-centered radicals formed in this manner can be used for various types of functional group conversions and C-C bond formations (Figure 1). ... 

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. 

Remote Oxidation.—Remote oxidation reactions generally involve intramolecular hydrogen abstraction. The best known example is the Barton reaction (photolysis of nitrite esters). "- One of the most important applications of this reaction was to the synthesis of aldosterone acetate. The yield of this reaction has been substantially improved (55%) by irradiating the dienone nitrite ester (172) in which the extended conjugation ensures that sufficient separation between C-19 and the 11/3-oxygen atom exists to suppress functionalization at C-19 in favour of attack at C-18. Another recent application of the Barton reaction occurred in the synthesis of perhydrohistrionicotoxin (175), where the key step was the stereoselective formation of the oxime (174) from the nitrite ester (173). °... 

Tin Hydride-Mediated Reaction Allyltin Method Photochemical Fragmentation of Barton Esters Direct Photolysis of Cobaloximes Direct Photolysis of Organotellurium Compounds Miscellaneous... 

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. 

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