Thiohydroxamic esters

In more recent studies, the Barton group has shown that 0-acyl thiohydroxamates (thiohydroxamate esters) are convenient sources of alkyl radicals.490,51,52 Barton s thiohydroxamate ester chemistry is mild and easily executed, and the intermediate organic radicals are amenable to a wide variety of useful transformations. A thiohydroxamate ester of the type 125 (see Scheme 23) can be formed... 

Scheme 23. Barton s thiohydroxamate ester chemistry synthesis of alkyl pyridyl sulfides (127).

If the reaction just described is conducted in the presence of a suitable hydrogen atom donor such as tri-n-butyltin hydride or tert-butyl hydrosulfide, reductive decarboxylation occurs via a radical chain mechanism to give an alkane (see 125—>128, Scheme 24). Carboxylic acids can thus be decarboxylated through the intermediacy of their corresponding thiohydroxamate esters in two easily executed steps. In this reducjtive process, one carbon atom, the carbonyl carbon, is smoothly excised... 

The scope of Barton s thiohydroxamate ester chemistry has been significantly expanded by the finding that the intermediate alkyl radicals (R ) can be intercepted by a host of neutral molecules (see Scheme 25).42b 49c,52>53 Several different classes of compounds can thus be prepared from a common thiohydroxamate ester precursor. 

These thiohydroxamic esters have seen use in grafting of PAN onto PE,iM of PS, PAM and I MPAM onto cellulose127128 and of PS, PMMA, PVP and PAM onto poly(arylene ether sulfone).12 7 The process involves derivitization of a parent carboxy functional polymer to form the thiohydoxamic ester 82 (R=polvmcr) which then behaves as a polymeric transfer agent and/or radical generator. 

Decarboxylativehalogenation (12,417). The Hunsdiecker reaction is not useful for aromatic acids, but decarboxylative halogenation of these acids can be effected in useful yield by radical bromination or iodination of the thiohydroxamic esters, as reported earlier for aliphatic acids.1 Thus when the esters 2 are heated at 100° in the presence of AIBN, carbon dioxide is evolved and the resulting radical is trapped by BrCCl3 to provide bromoarenes (3). Decarboxylative iodination is effected with iodoform or methylene iodide as the iodine donor. 

Dauben et al. found that the CCI3 radical produced by sonolysis of carbon tetrachloride can be used in a decarboxylation-halogenation sequence (Scheme 3.5) [43]. Sonication of a thiohydroxamic ester at 33 °C for 10 - 50 min in carbon tetrachloride leads to the corresponding chloride in high yield. In the presence of bromotrichloromethane or iodoform, bromides and iodides are formed in yields > 80 %. This reaction can be successfully applied to primary, secondary, or tertiary esters and offers an interesting variant to the usual Hunsdiecker procedure. 

In a non-electrolytic reaction, which is limited to R = primary alkyl, the thiohydroxamic esters 24 give dimers when irradiated at -64°C in an argon atmosphere 435... 

An alternative method is the deoxygenation of the anomeric carboxylic acid 52, producing 55 [27], The functionalized precursor, in particular the O-acyl-thiohydroxamate ester 54, which is formed in situ after exposure of the carboxylic acid 52 to the salt 53, is decarboxylated by the Barton method. 

Scheme 44 summarizes an addition reaction by the Barton method. Thiohydroxamate esters (32) are readily prepared and isolated, but, more typically, they are generated in situ. Experimental procedures have been described in detail148151 and often entail the slow addition of an acid chloride to a refluxing chlorobenzene solution of the readily available sodium salt (31), dimethylaminopyridine (DMAP, to catalyze the esterification), and excess alkene. The products are usually isolated by standard aqueous work-up and chromatographic purification. 

The basic transformation that underlies the Barton method is outlined in Scheme 45, steps 1 and 2.152 Thermolysis in refluxing toluene or photolysis with a sunlamp rapidly converts a thiohydroxamate ester (32) to the decarboxylated pyridyl sulfide (33). This pyridyl sulfide is formed by addition of an alkyl radical R to the thiohydroxamate (32) followed by fragmentation of (34) as indicated. In the planning of addition reactions by the Barton method, it is usually assumed that the addition step 1 is rate limiting. However, there is now evidence that step 1 may sometimes be reversible and step 2 may be rate limiting.153... 

Another way that has potential for the generation of perfluoroalkyl radicals from carboxylic acids is the use of Barton esters. However, unlike the situation for their hydrocarbon analogs, fluorinated thiohydroxamate esters have thus far only been able to be prepared in situ [65]. 

O-Acyl derivatives of thiohydroxamic esters (Barton esters) react with benzynes to afford a tricyclic thiophene ring system thus the pyridine derivative 30 gives benzo[4,5]thieno[2,3-A pyridines 31 (Scheme 14) <2002JOC3409, CHEC-III(3.11.3.3)900>. 

In an attempt to prepare selenopane 1, 7-(benzylseleno)heptanoic acid 126 was converted to the corresponding yellow thiohydroxamic ester 127 in the usual way (Scheme 11). In an NMR experiment, the thiohydroxamic ester 127 was irradiated and converted into selenopane in ca. 50% yield. When the preparation of selenopane 1 was repeated on a preparative scale, extensive formation of a white precipitate was observed. Attempted isolation of 1,1-dibromoseleno-pane yielded no product. Selenopane is known to polymerize readily <1993TL2557>. 

Barton, D.H.R., Bridon, D., Fernandez-Picot, 1., and Zard, S.Z. 1987. The invention of radical reactions Part XV Some mechanistic aspects of the decarboxylative rearrangement of thiohydroxamic esters. Tetrahedron 43, 2733-2740. 

In the second step a thiohydroxamate ester is formed with NaNHTP, which is called a Barton ester. 

The initiation step is the homolytic cleavage of the C-Br bond upon light irradiation. The resulting trichloromethyl radical starts the radical chain process by attacking the sulfur atom of the thiohydroxamate ester. Next, radical fragmentation occurs, and the released alkyl radical abstracts the bromine atom of a solvent molecule, generating another trichloromethyl radical. 

Conversion of a carboxylic acid to a thiohydroxamate ester, followed by heating the product in the presence of a suitable hydrogen donor such as tri-n-butyltin hydride, produces a reductive decarboxylation. This sequence of reactions is called the Barton decarboxylation reaction and may be used to remove a carboxylic acid and replace it with other functional groups. 

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