Barton esters preparation

Barton esters prepared with 2,2 -dipyridyl disulfide-jV,A -dio-xide and tributylphosphine have been used for the determination of the rate constants for the 5-evo-tr(g ring-closure of TV allyl amide radicals and for the ring-opening of cyclopropylmethyl radicals (eq 8). ... 

Thioethers have also been prepared on cross-linked polystyrene by radical addition of thiols to support-bound alkenes and by reaction of support-bound carbon radicals (generated by addition of carbon radicals to resin-bound acrylates) with esters of l-hydroxy-l,2-dihydro-2-pyridinethione ( Barton esters Entry 6, Table 8.5). Additional methods include the reaction of metallated supports with symmetric disulfides (Entries 7-9, Table 8.5) and the alkylation of polystyrene-bound, a-lithiated thioani-sole [65],... 

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]. 

Taddei [7] has studied the use of the Barton decarboxylation reaction in solid-phase chemistry. FeasibiUty studies began with the preparation of simple immobihzed Barton ester 37 from Wang resin-derived acid 36 (Scheme 8). Irradiation of 37 followed by acid cleavage gave 38 in good overall yield. Attempts to prepare bromide 39 by interception of the intermediate radical... 

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]. 

The radical substitution at selenium is efficient when the leaving radical is stabilized (e.g. benzyl, tert-butyl). This reaction has been used for the preparation of selenium containing heterocycles [117]. In Eq. 50, the conversion of the Barton ester 156 to the tetrahydroselenophene derivative 157 is described [118, 119]. Mechanistic studies and ab initio calculations indicate that the substitution does not involve hypervalent selenium derivatives. 

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. 

The di-O-tosylates (prepared by action of tosyl chloride in pyridine) are reduced with zinc (Nal/Zn route e Tipson-Cohen reaction) [13]. Cyclic ortho-esters (prepared by reaction of the diol with ethyl orthoformate) are transformed into olefins by simple heating in the presence of acids (Eastwood reaction, route b) [14]. Cyclic thiocarbonates (obtained by reaction of a diol with thiophosgene or (V,(V -thiocarbonyl-di-imidazole) are reduced to olefin with trimethyl phosphite (Corey-Winter method, route c) [15]. Finally, reduction of vicinal di-xanthates with tri- -butyltin hydride according to the Barton procedure [16] affords olefins via a reductive elimination process route a). The Corey-Winter, Garegg, and Tipson-Cohen methods are most commonly applied for deoxygenation of sugar diols. 

The introduction of 0-acyl thiohydroxamates (mixed anhydrides of carboxylic acids with thiohydroxamic acids) by the Barton group in 1983 [1] has provided one of the mildest and most convenient and versatile sources of carbon-centered radicals which fulfill the above criteria, and can hence, in Sir Derek s own words, be described as disciplined . Since their preparation from carboxylic acids is extremely straightforward, and since they have demonstrated a rapacious radicophilicity in a wide variety of very useful transformations, it is no surprise that these derivatives are commonly named either as Barton esters or by the acronym PTOC (pyridine thiocarbonyl) esters. The ongoing development of this chemistry has been summarized over the years in several useful reviews [2], and some of the tried and tested experimental procedures have also been collated [3]. 

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-... 

As anticipated, by analogy with the chemistry of Barton esters, the same mixed oxalate esters can be used to prepare tertiary alkyl chlorides, simply by refluxing in carbon tetrachloride [47], and also for the creation of quaternary carbon centers through selection of either a Michael acceptor [46] or 2-(carboethoxy) allyl tert-butyl sulfide [46] as the radicophile. 

New innovations incorporated in the sequences shown in Eqs. (25) and (26) are an improved method for Barton ester formation by the use of a thiouronium derivative of Barton s reagent 42 [41] and new auxiliary groups 43 bearing a tertiary C-6 substituent, which can be prepared in either enantiomeric form. These new auxiliaries give product as a mixture of diastereomers in a ratio of 7 1 to 10 1. The fact that both enantiomers of 43 are available permits one to dial in the configuration of each stereogenic center produced in a complex product. 

It is a useful reagent for deoxygenating phosphine oxides to phosphines, and will redueed chiral phosphine oxides to chiral phosphines with retention of eonfiguration [Marsi J Org Chem 39 265 1974]. It is a reducing agent in radical reactions [Perez et al. J Org Chem 52 5570 1967], and deoxygenates primary and seeondaty alcohols via their xanthate or thionocarbonate esters (prepared from aryl-OCSCl and an inhibitor, e.g benzoyl peroxide) in 60-100 minutes in >87% yields [Barton et al. Synlett 435 7997]. [Beilstein 16 III 1198,16 IV 1360.]... 

The natural product tyromycin was prepared in a good yield by the photolytic treatment of the double Barton ester of a di-carboxylic acid with a tungsten lamp (500 W) in the presence of citranic anhydride (eq 9). ... 

A decade later. Barton and coworkers reported the alkylation of biologically active molecules by photo-induced decomposition of Barton esters (Scheme 15,16) [28]. Afterward, a similar photo-induced protocol was used to prepare an analogous of abiraterone (17), which is applied in the treatment of prostate cancer (Scheme 16) [29]. 

Interestingly, alkyl radicals can be generated along the polymer backbone in the presence of monomer and nitroxide via a bimolecular process. The preparation of polypropylene (PP) functionalized by hydroperoxide by means of y-irradiation was reported. The resulting macroperoxide was then heated up to 125 °C in the presence of styrene or a styrene/butyl methacrylate mixture to produce the desired PP-g-PS or PP-g-P(S-co-BMA), respectively. Daly et a . and Daly and Evenson used esters of N-hydroxypyridine-2-thione or Barton esters to produce radicals on a polymer backbone under UV irradiation. This was successfully applied to poly (arylene ether sulfone) or hydroxypropyl cellulose backbones. ... 

Structure and Reactivity PTOC Esters Related Thiohydroxamate Systems Preparation of Barton Esters 67-1... 

In addition to the general usefulness of this class of compounds, the popularity of this chemistry is largely due to the facile preparation of the starting materials (Scheme 7). The most straightforward method of preparation of Barton esters of types I to IV is acylation by activation of the corresponding carboxylic acid (paths A and B). Accordingly, the hydroxamic acid sodium salt can be O-acylated with the acyl chlorides or, alternatively, the free hydroxamic acid can be condensed with primary carboxylic acids in the presence of N,W -dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP). Likewise, condensation of the free thiohydroxamic acid or the corresponding sodium salt with the mixed anhydride formed from the acid and isobutyl chloroformate in the presence of N-methylmorpholine has proven to... 

Such artificial photonucleases can be generated by UV excitation of N-hydroxypyridinethiones (N-HTP) 1 and 6 (R = H) and N-aroyloxypyridine-2-thiones (1, R = ArCOj), which can photocleave DNA through release of hydroxyl or aryloyloxyl radicals, repectively. " " Some more complex structures based on Barton esters were also prepared. Recent efforts are focused on combining these highly efficient DNA-cleaving families with an intercalative moiety (Scheme 20). ... 

Free radicals generated under photochemical conditions from thiohydroxamates add readily to the NN double bond of diaziridines and in particular to the 3-bromo or 3-trifluoromethyl-3-phenyldiazirine to produce diaziridinyl radicals (Scheme 25) these intermediates undergo dimerization and fragmentation to yield the corresponding imines, which can be hydrolyzed to the corresponding amines. Barton esters can also be used for the direct preparation of nitroso compounds. From a synthetic standpoint, the yields are moderate and the method is limited to primary and secondary carboxylic acids, which form dimers as an end product. Tertiary nitroso compounds do not dimerize and further react with the radical present under the reaction conditions. 

Barton, D. H. R. and Samadi, M., The invention of radical reactions. 25. A convenient method for the synthesis of the acyl derivatives of N-hydroxypyridine-2-thione, Tetrahedron, 48, 7083,1992. Garner, R, Anderson, J. T. and Dey, S., S-(l-oxido-2-pytidinyl)-l,l,3,3-tetramethylthiouronium hexafluorophosphate a new reagent for preparing hindered barton esters,/. Org. Chem., 63,5732,1998. Prabhakar, S., Lobo, A. M., and Santos, A., A, Convenient method for the synthesis of N-hydroxy thiobenzamides (C-arylthiohydroxamic acids). Synthesis, 829,1984. 

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. 

Pyrroles prepared by the Barton-Zard reaction are very important as precursors of porphyrins and also of conducting polymers. The ester group at the 2-position is readily removed on heating with KOH in ethylene glycol at 170 °C to give a-free pyrroles, which are useful for preparing porphyrins (Eq. 10.42)47 or polypyrroles (Eq. 10.43).38a,4S... 

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