Thiopyridones

Pyridone (333) is allylated with allylic carbonates on the nitrogen atom rather than on the oxygen atom, but 2-thiopyridone (334) is allylated on the sulfur atom[204]. 

In another version of this method, the radical generated by radical exchange from the aryl telluride carbohydrate 83 and the N-acetoxy-2-thiopyridone affords, after intramolecular cyclization and desulfanylation, the polyhydroxylated and phosphorylated pseudo sugar 84 [54] (Scheme 23). 

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.

It was discovered that the acetyl derivalive of iV-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... 

In accordance with the following scheme the hydroxyaldehyde A was submitted to a Wittig olefmation followed by the mesylation of the hydroxyl group to give the a,)3-unsat-urated compound B which was in turn converted into the telluride C by treatment with the appropriate aryltellurolate. Irradiation of C in the presence of iV-acetoxy-2-thiopyridone gave rise to the cyclic compound D. 

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). 

A similar procedure has successfiiUy generated aminyl radicals by treating the iV-carbamates of Ar-hydroxyl-2-thiopyridones (40) with radical initiators such as RS- and RsSi-. The aminyl radical generated abstracts a proton or adds intramolecularly to the double bond to result in the cycli-zation products shown in Scheme 26 (87JA3163). 

Alkylation of 2-thiopyridone and of 2-thiobenzoxazolone has been described by Dou et al.195 Yields are good, and only S-alkylation is detected. In a later study, A4-thiazoline-2-thione, thiazolidine-2-thione (130) and benzothiazoline-2-thione have been alkylated, using the phase transfer technique.196... 

The released 2-thiopyridone was quantified by UV spectroscopy (343 rnn) to determine the amount of immobilized moenomycin A. 

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. 

A solution of A-adamantanecarbonyloxy-2-thiopyridone (145 mg, 0.5 mmol), cam-phorsulfonate salt of lepidine (1.23 g, 3.27 mmol), and dichloromethane (6 ml) was irradiated with a tungsten lamp (200 W, W-hv) under nitrogen atmosphere at the range of 20 25 °C for 1 h. After the reaction, the reaction mixture was poured into... 

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

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]. 

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 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. 

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]. 

Unlike Af-hydroxy-2-thiopyridone, TV-hydroxy-2-selenopyridone is rather unstable and is easily oxidized. However, once photolytic treatment of O-acyl ester (53) of AMiydroxy-2-selenopyridone is carried out, the formed 2-pyridyl selenide is very useful. Thus, elimination of the selenoxides, formed from the oxidation of the selenide with mCPBA or ozone, proceeds effectively at low temperature. For example, eq. 8.23 shows the preparation of (l)-vinylglycine (56) from (L)-glutamic acid without racemization at all [70]. 

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. 

Since Barton decarboxylation can be performed under mild conditions, thermal or photolytic treatment of the Barton ester (13) of propionic acid with TV-hydroxy-2-thiopyridone in the presence of chiral menthyl acrylates generates addition products (14). However, diastereoselectivity is rather poor, since the chiral menthyl center is too far away from the C-C bond-forming position, as shown in eq. 10.7. When the chiral center is adjacent to the reaction position, stereocontrol is significantly affected, as shown in eq. 10.8 [9-12]. 

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... 

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