A-hydroxy-2-thiopyridone

Protected L-Asp reacted with cyclohexyl bromide and was converted into an A-hydroxy-2-thiopyridone derivative. Photolysis at room temperature afforded a mixture of cyclic stereoisomers (Scheme 45), the stereochemistry of which was determined by NMR and X-ray analysis (87TL1413). 

Barton Decarboxylation Reaction with A/-Hydroxy-2-thiopyridone... 

One great advantage of the decarboxylative halogenation with O-acyl esters of A-hydroxy-2-thiopyridone is that the reaction does not require any heavy metal such as Ag or Hg, unlike the Hunsdiecker reaction [24, 25]. Moreover, decarboxylative bromination of p-methoxybenzoic acid can be also carried out in good yield, while it does not proceed with the Hunsdiecker reaction instead, electrophilic bromination on the aromatic ring occurs. 

A mixture of O-acyl ester (1 mmol) of A-hydroxy-2-thiopyridone and benzoquinone (5-7 mmol) in degassed dichloromethane (20 ml) was irradiated with a 300 W tungsten lamp for 30 min. under a nitrogen atmosphere at 0 °C. After the reaction, the solvent was removed and the residue was chromatographed on silica gel to give 1,2-disubstituted benzoquinone [63]. 

The reactions based on A-hydroxy-2-thiopyridone derivatives are clearly radical chain reactions. In a recent paper,91 we have reported quantum yield measurements for a number of reactions based on iV-hydroxy-2-thiopyridone. Most of the reactions had quantum yields of 10-30. Synthesis of the N-hydroxyquinazolin-4-thione 139 (Ar = Ph, An, 1-Naph) by an improved route gave thiohydroxamic acids which were more sensitive to light than iV-hydroxy-2-thiopyridone. The quantum yield for bromination was in the range 30-60. More important, while the JV-hydroxy-2-thiopyridone system at — 30 °C, makes21 radicals only in a non-chain fashion, the derivatives of 139 continue radical chain reactions even at — 60 °C. 

It was discovered that the acetyl derivalive of A-hydroxy-2-thiopyridone is especially suitable as a source of methyl radicals, being photolysed by irradiation with a simple tungsten lamp. On this basis, and because of the high radicophilicity of tellurides (especially anisyl tellurides), a radical exchange occurs when the reagent is irradiated in the presence of an... 

A covalent bond is generally cleaved to its radical fragments at temperatures higher than 800 °C. Covalent bonds that can be cleaved at <150°C are limited to weak bonds whose dissociation energies are under 30-40 kcal/mol [1]. Azo compounds, peroxides, nitrite esters, ester of A-hydroxy-2-thiopyridone etc. fit into this group... 

Barton and coworkers have thoroughly investigated the radical chemistry of acyl derivatives of A-hydroxy-2-thiopyridone (Eq. 9) [29]. In the presence of Bu3SnH a smooth reaction takes place involving the addition of tin radicals to the thio-carbonyl moiety followed by a decarboxylation to generate R radicals. This process provides an efficient route for reductive decarboxylation (Volume 1, Chapter 1.7). 

Thiols have successfully replaced BuaSnH as reducing agents for the decarboxylation of acid via the acyl derivatives of A -hydroxy-2-thiopyridone (cf. Eq. 9) [29]. 

Radical decarboxylation of A-hydroxy-2-thiopyridone esters in the presence of an olefin results in the formation of a carbon-carbon bond. The monoester 5 is not prone to jS-elim-ination, and the faces of the dioxolane ring are encumbered by the methyl ester, so radical trapping occurs preferentially from the side opposite the methyl ester. This results in overall retention of configuration at the reacting carbon. Irradiation of ester 11 in the presence of methyl acrylate affords the tmns-eAkQm 12 after appropriate isolation. Once the first carboxylic acid has been modified, the second can be reacted similarly, whereby the stereochemistry of the first substitution controls the stereochemistry of the second. In this way the resulting product is obtained with overall double retention [11]. 

Fundamentally, O-esters of N-hydroxy-2-thiopyridone are photo-lyzed in the presence of an excess of white phosphorus in a methylene chloride/carbon disulfide medium. On solvent removal, hydrolysis, and oxidation with hydrogen peroxide, good yields of phosphonic acids (Figure 2.10) bearing the carbon functionality of the parent acid are isolated. 

Scheme 5-5. Reagents and conditions a NaOCE Ph, THF/DMF 5 1, — 10°C to room temperature, b LiAlELt, Et20, reflux, c AC2O, Py. d (1) Cat. RuCh/NaKTt, CCI4/ MeCN/H20 1 1 1.5, room temperature. (2) LiOH, THF/H20 5 4, 0°C. (3) 2N HC1, Et20, 0°C to room temperature, e (1) IV-methylmorpholine, isobutylchloroformate, N-hydroxy-2-thiopyridone, THF, NEt3, TFIF, — 15°C, (2) t-butyl mercaptan, irradiation, THF, room temperature, f H2, 10% Pd/C, EtOFI. g Cat. ( -Pr)4NRu04, NMO, 4 A MS, CH2CI2, room temperature.

From the practical point of view, alkylation of heteroaromatics with Barton decarboxylation of A-acyloxy-2-thiopyridones (17), prepared from carboxylic acids and Af-hydroxy-2-thiopyridone, is very useful, since it can be used for various kinds of carboxylic acids such as sugars and nucleosides [23-26]. This reaction comprises of the initial homolytic cleavage of the N-0 bond in A-acyloxy-2-thiopyridone to form an acyloxyl radical and PyS , (3-cleavage of the acyloxyl radical to generate an alkyl radical and C02, addition to the electron-deficient position of heteroaromatics by the alkyl radical to form the adduct, and finally, abstraction of a hydrogen atom from the adduct by PyS , as shown in eq. 5.10. 

To a solution of Af-hydroxy-2-thiopyridone (140 mg, 1.1 mmol) and pyridine (0.1 ml) in toluene (10 ml) was added a solution of 3(3-acetoxy-ll-ketobisnorallocholanic acid... 

The same reaction can be carried out by the dropwise addition of 3p-acetoxy-ll-ketobisnorallocholanic acid chloride (1 mmol) in toluene (5 ml) to a refluxing solution of dried sodium salt of V-hydroxy-2-thiopyridone (1.2 mmol), 4-(dimethylamino)pyridine (0.1 mmol), and tert-BuSH (4.5 mmol) in toluene (20 ml), over 15 min [1]. 

A solution of sulfur (S8, 74 mg, 0.29 mmol) and adamantanecarboxylate ester of N-hydroxy-2-thiopyridone (290 mg, 1 mmol) in dichloromethane (15 ml) was irradiated with a tungsten lamp for 1 h under a nitrogen atmosphere at 0 °C. After the reaction, a solution of NaBH4 (20 mmol) in methanol (10 ml) was added drop wise over 15 min to the reaction mixture at room temperature, and the mixture was stirred for one hour. After the reaction, 1 M sulfuric acid (60 ml) was added to the mixture, and then the solution was extracted with dichloromethane (4 X 20 ml), and dried over Na2S04. After removal of the solvent, the residue was purified by column chromatography on silica gel (eluent hexane/ethyl acetate = 97/3) to provide adamantanethiol in 88% yield [33]. 

To a solution of P,p-diphenylpropionic acid (2 mmol) in CHC13 (8 ml) were added oxalyl chloride (1.5 g) and DMF (one drop). After stirring for 1 h, the solvent and excess oxalyl chloride were removed. The residue was dissolved in CHC13 (6 ml) and then Af-hydroxy-2-thiopyridone (2.2 mmol) was added to the mixture under a nitrogen atmosphere at 0 °C. 

Carbonate and carbamate derivatives, prepared from the reaction of alcohols and amines with phosgene and /V-hydroxy-2-thiopyridone, provide the corresponding alkoxyl radicals and aminyl radicals respectively, via radical decarboxylation [71-81]. For example, photolytic treatment of carbamate (57) derived from 4-pentenylamine generates the corresponding 4-pentenylaminyl radical, as shown in eq. 8.24. Under neutral conditions in the presence of tert-BuSH, a direct reduction product (A) of 4-pentenylaminyl radical is formed, while, in acidic conditions, cyclized product (C), pyrrolidine, via 5-exo-trig manner from 4-pentenylaminyl radical is formed. Under the latter conditions, the real reactive species is an electrophilic 4-pentenylaminium radical which rapidly cyclized via 5-exo-trig manner. 

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]. 

Many important natural products are (formerly) derived by chain elongation at position 5 of pentoses, or at position 6 of hexoses. Uronic acids, which are easily prepared, can be converted into the 4 radical 90 by chemistry based on the thiohydroxamate 6.77 We postulated that, if the hindrance on the a-side of the molecule was great enough, the carbon-carbon bond formed by reaction of 90 with a suitable radicophilic olefin would be the natural / -bond. In fact, even a dimethyl-ketal as in 90 (B = natural base or protected derivative thereof) was sufficient to direct the bond formation very largely to the desired face.77 The diacetone ketal of glucuronic acid 91 upon conversion to its iV-hydroxy-2-thiopyridone derivative 92 and then photolysis in the usual way in the presence of methyl acrylate gave the expected derivative 93 as a mixture of... 

Barton, D. H. R., Jaszberenyi, J. C., Morrell, A. I. The generation and reactivity of oxygen centered radicals from the photolysis of derivatives of N-hydroxy-2-thiopyridone. Tetrahedron Lett. 1991,32, 311-314. 

C-Glycopyranosides may be obtained from glycopyranosyl halides via intermolecular addition of glycopyranosyl radicals [129]. In a more useful example, the a-aminoacrylate 192 was used as the radical acceptor for preparation of C-glycosyl amino acids 193 and 194 [130] (Scheme 66). In a concise synthesis of showdomycin (197), Barton utilized the trigger reaction of the 7V-hydroxy-2-thiopyridone derivative and the exceptional radicophilicity of tellurides in concocting the conditions for the conversion from the anisyl telluride 195 to the intermediate 196 after oxidative elimination [131] (Scheme 67). In Keck s synthesis of (-t-)-pseudomonic acid C (201), the intermediate 200 was prepared via stereocontrolled intermolecular addition of the radical generated from the iodide 198 to the allylic sulfone 199 [132] (Scheme 68). 

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