[1121-30-8]  · C5H5NOS  · N-Hydroxypyridine-2-thione  · (MW 127.18)

(reaction with a carboxylic acid or acid chloride leads to the corresponding O-acyl thiohydroxamate; treatment of these intermediates with a radical source leads to alkyl or aryl radicals [R&bdot;], the fate of which depends on the precise reactions conditions1)

Alternate Name: 1-hydroxy-2-(1H)-pyridinethione; the tautomeric N-oxide form [1121-31-9], although the minor component, is often the source of alternate names for this compound, which include 2-pyridinethiol 1-oxide, 2-mercaptopyridine N-oxide, 2-mercaptopyridine 1-oxide, and the abbreviated form pyrithione.

Physical Data: mp 70-72 °C.

Form Supplied in: both the pyridinethione and the corresponding sodium salt (sometimes as the hydrate) are commercially available. A 40% aqueous solution of the sodium salt is also available and cheaper (also referred to as sodium omadine). The free thione can be obtained from this by acidification to neutrality using concentrated aq HCl, filtration of the crude product, and crystallization from EtOH. Alternatively, evaporation of the aqueous solution (<50 °C) and crystallization of the residue from ethanol provides the sodium salt, mp 285-290 °C, after slow crystallization from ethanol and drying at 50 °C under vacuum.3

Preparative Methods: prepared from 2-bromopyridine by oxidation to the N-oxide using either Perbenzoic Acid or Peracetic Acid, followed by displacement of bromide using either Sodium Dithionite or Sodium Sulfide and Sodium Hydroxide.2 An alternative is to treat the N-oxide with Thiourea and then hydrolyze the resulting thiouronium salt.

Handling, Storage, and Precautions: all operations in this area should be carried out with due regard to both the thermal and photochemical sensitivity of the reagents and intermediate O-acyl thiohydroxamates.

Preparation of O-Acyl Thiohydroxamates.

There are three commonly used options available for the preparation of O-acyl thiohydroxamates, outlined in eqs 1-3.1,4 Firstly, the carboxylic acid can be activated by conversion into a mixed anhydride from Isobutyl Chloroformate and then coupled directly with the pyridinethione (1). Alternatively, O-acyl thiohydroxamates (2) can be obtained using the DCC (1,3-Dicyclohexylcarbodiimide) coupling method (eq 1). If acid chlorides are used, these are best converted into the hydroxamates (2) by reaction with the sodium salt (3) in the presence of 4-Dimethylaminopyridine (eq 2). A further option is to activate the pyridinethione component by formation of the bicyclic system (4) from the parent and Phosgene and then react this with the triethylammonium salt of the carboxylic acid (eq 3). Compound (4) is commercially available as 1-oxa-2-oxo-3-thiaindolizinium chloride (2-oxo-[1.4.2]oxathiazolo[2,3-a]pyridinium chloride).1,4b The latter two methods appear to be the most favored; the sensitive esters are used promptly with little purification, often just filtration through a short silica column.3


Perhaps the best-known application of this type of pyridinethione derivative in synthesis is in the overall, radical-mediated decarboxylation of carboxylic acids, i.e. RCO2H -> RH (eq 4).1,4b The transformation is of a wide generality and usually proceeds in good to excellent yields. The chain carrier and hydrogen radical source is either Tri-n-butylstannane or a tertiary thiol, most often t-butanethiol (but see Barton and Crich6), and the reactions are generally triggered thermally when tin hydride is employed, or photolytically (tungsten lamp suffices) when a thiol is used.5 The latter method offers considerable advantages in terms of product purification; for details of this aspect as well as sound advice on how to conduct these and related radical reactions in general, consult Motherwell and Crich.1

A wide variety of functionality can be incorporated into the substrate acids, such as in the decarboxylation of a-amino acid derivatives which leads to amines (eq 5).4d Application of this methodology to the appropriate aspartate and glutamate derivatives provides access to the useful radicals (5) which can be trapped in many ways, such as by halides (overall, a Hunsdiecker reaction),4d as can many other radical species obtained using this chemistry (see below).

Alcohol Deoxygenation.

A limitation of the useful Barton-McCombie procedure for the deoxygenation of alcohols is its application to tertiary alcohols because of difficulties in preparing the required xanthate or other derivatives. A solution to this is to first form a monoester with Oxalyl Chloride and then react the remaining acyl chloride function with the sodium salt (3) (eq 6).6 In these reactions, although t-butanethiol is suitable as the chain carrier, in some cases 3-ethyl-3-pentanethiol gives superior yields (50-90%). The intermediate tertiary radicals can be trapped by powerful Michael acceptors such as 1,2-dicyanoethylene.

Decarboxylative Rearrangement.

When O-acyl thiohydroxamates are simply heated or photolyzed alone, a decarboxylative rearrangement occurs to give 71-92% yields of 2-thiopyridines (eq 7).4b,7 While the thermal process involves some contribution from a cage recombination mechanism, the photolytic reaction is a purely radical chain process.

Formation of Sulfides, Selenides, Tellurides, and Selenocyanates.

When O-acyl thiohydroxamates are decomposed in the presence of disulfides, diselenides, or ditellurides, mixed sulfides, selenides, or tellurides are formed, respectively (eq 8).8 If the reactions are triggered thermally, a large excess of the disulfide etc. has to be used to avoid competition from decarboxylative rearrangement (see above); however, light-induced reactions proceed at lower temperatures and, in such cases, only a slight excess of the trap is required. When the trapping agent is dicyanogen triselenide then selenocyanates, RSeCN, are produced.

Decarboxylative Sulfonation.

When a solution of an O-acyl thiohydroxamate in CH2Cl2 containing excess SO2 is photolyzed at -10 °C, the initially formed radicals are intercepted by the latter before decarboxylative rearrangement can take place. The resulting radicals (RSO2&bdot;) then react with a second molecule of the O-acyl thiohydroxamate to give an S-pyridyl alkylthiosulfonate (38-91%) and the radical R&bdot; (eq 9).9 The products are useful as precursors to unsymmetrical sulfones and sulfonamides, significantly by a nonoxidative procedure.

The Hunsdiecker Reaction.

The classical Hunsdiecker reaction is somewhat restricted due to the relatively harsh conditions required. In the Barton version, alkyl radicals generated from O-acyl thiohydroxamates, under either thermal or photolytic conditions, are efficiently trapped either by Cl3C-X (X = Cl or Br; Cl3C&bdot; is the chain carrier) or by Iodoform.1,4b,10 The method is applicable to sensitive substrates for which the classical methods are unsuitable,4d,11 thus allowing the preparation of a wide range of alkyl chlorides, bromides, and iodides by the one-carbon degradation of a carboxylic acid. Similar reactions of aromatic acid derivatives tend to require an additional radical initiator (e.g. Azobisisobutyronitrile), if high yields (55-85%) are to be obtained.12

Decarboxylative Hydroxylation.

A close relative of the foregoing degradation, the transformation RCO2H -> ROH can be carried out in two ways. Perhaps the most practical version consists of thermolysis or photolysis of an O-acyl thiohydroxamate, typically in oxygen-saturated toluene, followed by reduction of the initial hydroperoxide (eq 10).4b,13 In similar fashion to decarboxylative sulfonation (see above), the intermediate radicals are trapped much faster (~104) by oxygen than by H-abstraction from the thiol chain carrier. As an alternative, the initial hydroperoxides can be O-tosylated in pyridine to give the corresponding nor-aldehyde or ketone (53-62%). The alternative, mechanistically more convoluted but still efficient and simple procedure (82-93%), has tris(phenylthio)antimony, (PhS)3Sb, as the radical trap in the presence of both oxygen and water (in practice, wet air).14

Decarboxylative Phosphorylation.

In similar fashion to the foregoing, radicals generated by decomposition of an O-acyl thiohydroxamate can be trapped by tris(phenylthio)phosphine (eq 11).15 In some cases, the use of alternative thiohydroxamates may be advantageous.

Michael Additions and Other Radical Reactions.

As decomposition of O-acyl thiohydroxamates provides radicals, these can subsequently participate in a variety of other reactions, the most common of which are Michael additions to electron-deficient alkenes. The most commonly successful pathway (eq 12) involves reaction of the intermediate carbon-centered radical adjacent to the electron-withdrawing group with a second molecule of the thiohydroxamate, rather than hydrogen abstraction, to give an a-S-pyridyl derivative,1,6,7b which can subsequently be manipulated in a variety of ways.16 Other thiohydroxamates can lead to higher yields; the mildness and potential of this methodology is illustrated in eq 13.17

Similar reactions, but using nitroalkenes as traps, lead to the corresponding a-pyridylthio nitroalkanes, which are useful as precursors to the one-carbon homologated carboxylic acids, aldehydes, or the related ketones, by starting with an a-substituted nitroalkene (eq 14).7b,18

Radicals derived from decarboxylation of perfluorocarboxylic acids will undergo addition to ethyl vinyl ether to provide the expected homologs in ~60% yields (eq 15).19

Protonated pyridines can also be used as acceptors of carbon radicals generated from thiohydroxamates in general.20 A useful extension of the Michael addition reactions is to incorporate an additional t-butylthio substituent into the acceptor component (eq 16).18b,21 Tandem reactions are also possible, as exemplified by the conversion of a cyclopentenecarboxylic acid into a bicyclo[2.2.1]heptane (eq 17).22

Carbon radicals obtained from thiohydroxamates can also be trapped intramolecularly by unactivated alkene functions especially in the 5-exo-trig mode,7b,23 as can aminyl radicals generated in the same way; better yields of cyclic products are obtained in the presence of a weak acid which presumably protonates the N-centered radical prior to cyclization (eq 18).24

1. For an excellent overview of this area, including practical examples, see Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic Synthesis, Academic: London, 1992.
2. Shaw, E.; Bernstein, J.; Losee, K.; Lott, W. A. JACS 1950, 72, 4362.
3. Barton, D. H. R.; Bridon, D.; Fernandez-Picot, I.; Zard, S. Z. T 1987, 43, 2733.
4. (a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. CC 1983, 939. (b) Barton, D. H. R.; Crich, D.; Motherwell, W. B. T 1985, 41, 3901. (c) Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J. CC 1984, 1298. (d) Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J. T 1988, 44, 5479.
5. See, for example: Della, E. W.; Tsanaktsidis, J. AJC 1986, 39, 2061; Ihara, M.; Suzuki, M.; Fukumoto, K.; Kametani, T.; Kabuto, C. JACS 1988, 110, 1963; Crich, D.; Ritchie, T. J. CC 1988, 1461; Braeckman, J. C.; Daloze, D.; Kaisin, M.; Moussiaux, B. T 1985, 41, 4603; Campopiano, O.; Little, R. D.; Petersen, J. L. JACS 1985, 107, 3721; Otterbach, A.; Musso, H. AG(E) 1987, 26, 554; Winkler, J. D.; Sridar, V. JACS 1986, 108, 1708; Winkler, J. D.; Hey, J. P.; Williard, P. G. JACS 1986, 108, 6425; Winkler, J. D.; Henegar, K. F.; Williard, P. G. JACS 1987, 109, 2850.
6. Barton, D. H. R.; Crich, D. JCS(P1) 1986, 1603.
7. (a) Barton, D. H. R.; Crich, D.; Potier, P. TL 1985, 26, 5943. (b) Barton, D. H. R.; Crich, D.; Kretzschmar, G. JCS(P1) 1986, 39.
8. Barton, D. H. R.; Bridon, D.; Zard, S. Z. TL 1984, 25, 5777; H 1987, 25, 449; Barton, D. H. R.; Bridon, D.; Herve, Y.; Potier, P.; Thierry, J.; Zard, S. Z. T 1986, 42, 4983.
9. Barton, D. H. R.; Lacher, B.; Misterkiewicz, B.; Zard, S. Z. T 1988, 44, 1153.
10. Barton, D. H. R.; Crich, D.; Motherwell, W. B. TL 1983, 24, 4979.
11. See, for example: Fleet, G. W. J.; Son, J. C.; Peach, J. M.; Hamor, T. A. TL 1988, 29, 1449; Rosslein, L.; Tamm, C. HCA 1988, 71, 47; Kamiyama, K.; Kobayashi, S.; Ohno, M. CL 1987, 29.
12. Vogel, E.; Schieb, T.; Schulz, W. H.; Schmidt, K.; Schmickler, H.; Lex, J. AG(E) 1986, 25, 723; Barton, D. H. R.; Lacher, B.; Zard, S. Z. TL 1985, 26, 5939; T 1987, 43, 4321.
13. Barton, D. H. R.; Crich, D.; Motherwell, W. B. CC 1984, 242.
14. Barton, D. H. R.; Bridon, D.; Zard, S. Z. CC 1985, 1066.
15. Barton, D. H. R.; Bridon, D.; Zard, S. Z. TL 1986, 27, 4309.
16. See, for example: Ahmad-Junan, S. A.; Walkington, A. J.; Whiting, D. A. JCS(P1) 1992, 2313.
17. Barton, D. H. R.; Gateau-Olesker, A.; Gero, S. D.; Lacher, B.; Tachdjian, C.; Zard, S. Z. CC 1987, 1790.
18. (a) Barton, D. H. R.; Togo, H.; Zard, S. Z. TL 1985, 26, 6349; (b) T 1985, 41, 5507. (c) Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J. T 1987, 43, 4297.
19. Barton, D. H. R.; Lacher, B.; Zard, S. Z. T 1986, 42, 2325.
20. Barton, D. H. R.; Garcia, B.; Togo, H.; Zard, S. Z. TL 1986, 27, 1327.
21. Barton, D. H. R.; Crich, D. JCS(P1) 1986, 1613.
22. Barton, D. H. R.; da Silva, E.; Zard, S. Z. CC 1988, 285.
23. See, for example: Green, S. P.; Whiting, D. A. CC 1992, 1754.
24. Newcomb, M.; Deeb, T. M. JACS 1987, 109, 3163.

David W. Knight

Nottingham University, UK

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