Barton reaction thiohydroxamate esters

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... 

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. 

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. 

Barton, D. H. R., Crich, D., Motherwell, W. B. The invention of new radical chain reactions. Part VIII. Radical chemistry of thiohydroxamic esters a new method for the generation of carbon radicals from carboxylic acids. Tetrahedron 1985, 41,3901-3924. 

Chiral auxiliaries have also been applied to the radicals themselves in the formation of chiral hydroxyalkyl radical equivalents [59]. Once again, stereocontrol is accessed through the use of chiral acetals, which are readily available in the form of sugars. Typical reactions of this type are shown in Eq. (13.47). First, the thiohydroxamate ester 148 is prepared so that radical intermediate 149 can be formed photolytically via Barton s radical decarboxylation protocol [60]. The chiral radical 149 can then be trapped by methyl acrylate in a 61% yield with an 11 1 diastereomeric preference for y-substituted 150. 

By the reaction between Bi(SPh)3 and a carbon-centered radical R, generated by decarboxylation of thiohydroxamate esters (the Barton reaction), an organylbismuth dithiolate can be prepared a 1 2 mixture of 3-(3,3-diphenyl-... 

The last, but certainly not the least, is the Barton modification to the Hunsdiecker reaction.24-26 It involves decomposition of thiohydroxamate esters in halogen donor solvents such as CCU, BrCCh, CHI3, or CH2I2 promoted by a source of radical initiation, which could be radical initiator (e.g., 18—>20),24 thermal (e.g., 21—>22),25 or photolytic26 conditions. The Barton modification is highly compatible with most functional groups. For example, under photolytic conditions, acid 23 was converted to acid chloride 24, which, without isolation, was treated with the sodium salt of Z/-hydroxypyridine-2-thione (19) with bromotrichloromethane as solvent to give alkyl bromide 25 in 90% yield.26... 

Thiohydroxamic esters, such as V-hydrox5q)5nidine-2-thione, were first used as free radical precursors by Barton. " The decomposition of such esters by heat or visible light yields acyloxy radicals and pyridine thiol radicals. However, on irradiation at low-temperature, the chain reaction is essentially suppressed. 

The difficulties inherent in the original Hunsdiecker reaction and its modifications stimulated the development of an additional halo-decarboxylation method that involves treatment of thiohydroxamic esters of carboxylic acids with BrCCls, ICH3 or CH2I2 in the presence of a radical initiator (Route 3, Barton reaction, Figure 10.23). 

Phenylselenyl radicals are also formed when benzeneselenol is used as a reducing agent. These radicals are usually unable to propagate chain reactions since they dimerize rapidly. Two important exceptions are known the propagation with acyl thiohydroxamates ( Barton esters ) and the use of polarity reversal catalysis. 

The decarboxylation of carboxylic acid via thiohydroxamate derivatives (often called Barton esters ) is an efficient procedure for the generation of radicals. When this reaction is performed in the presence of diphenyl diselenide, the corresponding selenides are obtained in excellent yield [Eq. (42)] [104]. For example, this reaction has been used for the preparation of AT,Se-acetals from a-aminoacids [105,106]. 

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. 

In terms of generation and manipulation of O-acyl thiohydroxamates it is important to recognize that, in the absence of any other reagents, decarboxylative rearrangement to alkyl-2-pyridyl sulfides can occur (Scheme 7). This is the simplest free-radical reaction of Barton esters and is of preparative utility in its own right. A series of crossover experiments demonstrated that the only mechanism which oper-... 

O-acyl thiohydroxamates was initially thwarted by competing ionic reactions but eventually culminated in the introduction of 3-bromo or 3-(trifluoromethyl)-3-phenyl diazirine as extremely effective reagents [27]. In contrast to almost all of the other reactions of Barton esters described in this chapter, however, the reaction sequence does not involve a chain process. Thus, as outlined in Scheme 25, capture of the alkyl radical by the diazirine is followed by dimerization and subsequent loss of nitrogen to give the product imine from which the desired amide or amine is easily liberated by mild hydrolysis. Some typical yields are shown in the Scheme 26. 

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