2,2-Dipyridyl Disulfide1

[2127-03-9]  · C10H8N2S2  · 2,2-Dipyridyl Disulfide  · (MW 220.34)

(macrolactonization of o-hydroxy acids,6 acylation of pyrroles,22 couplings at anomeric centers27)

Alternate Names: 2,2-dithiopyridine.

Physical Data: mp 57-58 °C.

Solubility: benzene, THF, CH2Cl2, MeCN, DMF.

Form Supplied in: white (colorless) crystalline solid.

Preparative Methods: although 2,2-dipyridyl disulfide is commercially available, it can be readily prepared from 2-pyridinethione by oxidation with a number of reagents.2

Purification: recrystallization from hexane at 30 mL g-1 concentration.3

Handling, Storage, and Precautions: the solid is irritating to eyes, mucus membranes, and respiratory tract, and physical contact should be avoided. Combustion produces toxic byproducts including nitrogen oxides. Cold storage in air-tight containers is recommended. Use in a fume hood.

Macrolactonization.4

When a carboxylic acid is treated with 2,2-dipyridyl disulfide in the presence of Triphenylphosphine, the corresponding 2-pyridinethiol ester is formed.5 Corey and Nicolaou have developed an efficient method for the synthesis of macrocyclic lactones based on these 2-pyridinethiol esters.6 When an o-hydroxy thiolester is heated in refluxing xylene under high dilution conditions (10-5 M, typically accomplished with syringe pump techniques), macrolactonization occurs, liberating triphenylphosphine oxide and pyridinethione. The reaction is quite general and is believed to proceed by a double activation mechanism in which the basic 2-pyridinethiol ester simultaneously activates both the hydroxy and the carboxylic acid moieties with a single proton transfer. It has been shown that the cyclization rate is not affected by the presence of acids, bases, or any of the possible reaction contaminants.7

This method is mild, highly efficient for the preparation of medium to large rings (7-16,6 12-217), and has been applied to the synthesis of a number of important macrocyclic targets including monensin,8 brefeldin A (eq 1) and erythronolide B,9 (±)-11-hydroxy-trans-8-dodecenoic acid lactone,10 (±)-vermiculine,11 enterobactin,12 and prostaglandins.8,13

In an effort to develop an even milder lactonization protocol, other diaryl disulfides were explored, the most promising being imidazole derivatives (1) and (2).14 The formation of dilides (dimers of macrocyclic lactones) is occasionally a problem, necessitating the use of other cyclization methods.4,15 A variation of Corey's method using silver salts has been developed.3,16

If an o-aminopyridinethiol ester is used, macrolactamization occurs.17 A method for the synthesis of b-lactams from b-amino acids has also been developed where the use of MeCN has been found to be critical (eq 2).18 The intermolecular version of this reaction is a powerful peptide coupling method.19,20

Related Reactions of 2-Pyridinethiol Esters.

In the absence of an internal nucleophile, the thiopyridyl esters generated by the reaction of carboxylic acids with 2,2-dipyridyl disulfide and triphenylphosphine exhibit other reactivities. Thiolesters are potent acylating agents, reacting with Grignard reagents to yield ketones instead of tertiary alcohols.21,22 This activity has been exploited for the synthesis of 2-acylpyrroles using pyrrylmagnesium salts as the nucleophilic species. Nicolaou and co-workers have exploited 2-pyridinethiol esters in the synthesis of a number of complex 2-acylpyrroles (eq 3).23 In certain troublesome cases, the use of stoichiometric Copper(I) Iodide has been found to significantly improve yields.24

2-Pyridinethiol esters are readily reduced with Sodium Borohydride in the presence of isopropanol.25 Activation of 2-pyridinethiol esters with Iodomethane allows for mild trapping with alcohols or benzenethiol, yielding esters or thiolesters.26 In these cases the use of iodomethane avoids the need for thiophilic silver or mercury salts and allows for transthiolesterification.

Disaccharide Formation.

Treatment of glycoside (3) with 2,2-dipyridyl disulfide and Tri-n-butylphosphine in CH2Cl2 rapidly yields thiopyridyl derivative (4) as a mixture of anomers. Activation of (4) with iodomethane, followed by treatment with glycoside acceptor (5), affords the disaccharide fragment of avermectin (6),27 exclusively a-linked in 78% yield (eq 4).28 Although other methods are available, this protocol offers advantages in practicality and stereoselectivity.

Carbon-carbon bonds can be similarly formed at the anomeric center of carbohydrates. Oxonium ions, formed by the treatment of 1-(2-thiopyridyl)glycosides with Silver(I) Trifluoromethanesulfonate, can be trapped with silyl enol ethers, silyl ketene acetals, and reactive aromatic compounds, where the stereoselectivity of the addition is determined by solvent and nucleophile choice.29 The intramolecular version of this process has also been examined (eq 5).30 Similarly, bicyclic piperazinediones are available by the intramolecular trapping of iminium ions, generated from the appropriate thiopyridyl derivatives with PhHgClO4 (eq 6).31

Alkene Formation.

The elimination of pyridinethione or 2-pyridylsulfenic acid forms the basis of a number of alkene syntheses. For example, treatment of dithioacetal anions with 2,2-dipyridyl disulfide affords the a-thiopyridyl derivative, which undergoes elimination at below room temperature to give ketene dithioacetals.32 Ester enolates have been similarly treated, although m-Chloroperbenzoic Acid is first used to generate the sulfoxide which reacts further to yield an a,b-unsaturated ester.33 This methodology has been applied to the synthesis of methyl dehydrojasmonate (7) (eq 7).34

Other Reactions.

Treatment of an active hydroxy compound with 2,2-dipyridyl disulfide and n-Bu3P yields the corresponding thiopyridyl derivative. This methodology has been applied to the preparation of 5-arylthio-5-deoxyribonucleosides (eq 8).35 Monophosphate esters [ROP(O)(OH)2] will react similarly to form the activated triphenylphosphonium adduct, which, in the absence of an added external nucleophile, dimerizes yielding a pyrophosphate.36 N-Methylimidazole has been found to catalyze this transformation. The addition of alcohols or amines, however, traps the phosphoryloxyphosphonium salt as the mixed diphosphate ester or mixed ester/amide, respectively (eq 9).37 Chlorotrimethylsilane and (pyS)2 have also been reported to facilitate the oxidation of phosphites to phosphates.38

General Reactions of Diaryl Disulfides.1

2,2-Dipyridyl disulfide reacts with a variety of carbon nucleophiles, yielding the corresponding thiopyridyl derivatives. These include phosphonate stabilized anions,39 bromouridine derivatives,40 indole anions,41 and heterocyclic stabilized anions.42


1. (a) Capozzi, G.; Modena, G. The Chemistry of the Thiol Group; Patai, S.; Ed.; Wiley: New York, 1974; Part 2, pp 785-839. (b) Jocelyn, P. C. The Chemistry of the SH Group; Academic: New York, 1972.
2. (a) NaOH/KI3: Marckwald, W.; Klemm, W.; Trabert, H. CB 1900, 33, 1556. (b) Nickel peroxide: Nakagawa, K.; Shiba, S.; Horikawa, M.; Sato, K.; Nakamura, H.; Harada, N.; Harada, F. SC 1980, 10, 305. (c) I2: McAllan, D. T.; Cullum, T. V.; Dean, R. A.; Fidler, F. A. JACS 1951, 73, 3627. (d) Zn(BiO3)2: Firouzabadi, H.; Mohammadpour-Baltork, I. BCJ 1992, 65, 1131. (e) (NH4)2Ce(NO3)6 (CAN): Dhar, D. N.; Bag, A. K. IJC(B) 1984, 23B, 974. (f) Bromodimethylsulfonium bromide: Olah, G. A.; Arvanaghi, M.; Vankar, Y. D. S 1979, 721. (g) NaBO3: McKillop, A.; Koyunçu, D. TL 1990, 31, 5007. (h) Diethyl bromomalonate: Kato, E.; Oya, M.; Iso, T.; Iwao, J.-I. CPB 1986, 34, 486. (i) FeCl3-Bu3SnOMe: Sato, T.; Otera, J.; Nozaki, H. TL 1990, 31, 3591.
3. Thalmann, A.; Oertle, K.; Gerlach, H. OSC 1990, 7, 470.
4. Reviews: (a) Nicolaou, K. C. T 1977, 33, 683. (b) Back, T. G. T 1977, 33, 3041. (c) Ogliaruso, M. A.; Wolfe, J. A. In Synthesis of Lactones and Lactams; Patai, S.; Rappaport, Z.; Eds.; Wiley: New York, 1993.
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13. Bundy, G. L.; Peterson, D. C.; Cornette, J. C.; Miller, W. L.; Spilman, C. H.; Wilks, J. W. JMC 1983, 26, 1089.
14. Corey, E. J.; Brunelle, D. J. TL 1976, 3409.
15. (a) Karim, M. R.; Sampson, P. JOC 1990, 55, 598. (b) Justus, K.; Steglich, W. TL 1991, 32, 5781.
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18. (a) Ohno, M.; Kobayashi, S.; Iimori, T.; Wang. Y.-F.; Izawa, T. JACS 1981, 103, 2405. (b) Ohno, M.; Kobayashi, S.; Iimori, T.; Wang. Y.-F.; Izawa, T. JACS 1981, 103, 2406.
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22. For other recent methods for the synthesis of 2-acylpyrroles, see: (a) Review: Patterson, J. M. S 1976, 281. (b) Kozikowski, A. P.; Ames, A. JACS 1980, 102, 860. (c) Martinez, G. R.; Grieco, P. A.; Srinivasan, C. V. JOC 1981, 46, 3760. (d) Edwards, M. P.; Ley, S. V.; Lister, S. G.; Palmer, B. D. CC 1983, 630.
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25. Nicolaou, K. C.; Maligres, P.; Suzuki, T.; Wendeborn, S. V.; Dai, W.-M.; Chadha, R. K. JACS 1992, 114, 8890.
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27. Springer, J. P.; Arison, B. H.; Hirshfield, J. M.; Hoogsteen, K. JACS 1981, 103, 4221.
28. (a) Mereyala, H. B.; Kulkarni, V. R.; Ravi, D.; Sharma, G. V. M.; Rao, B. V.; Reddy, G. B. T 1992, 48, 545. (b) Ravi, D.; Kulkarni, V. R.; Mereyala, H. B. TL 1989, 30, 4287. (c) for mechanistic details see: Mereyala, H. B.; Reddy, G. V. T 1991, 47, 6435.
29. Williams, R. M.; Stewart, A. O. TL 1983, 24, 2715.
30. Craig, D.; Munasinghe, V. R. N. TL 1992, 33, 663.
31. Williams, R. M.; Dung, J.-S.; Josey, J.; Armstrong, R. W.; Meyers, H. JACS 1983, 105, 3214.
32. Nagao, Y.; Seno, K.; Fujita, E. TL 1979, 4403.
33. Nagao, Y.; Takao, S.; Miyasaka, T.; Fujita, E. CC 1981, 286.
34. Dubs, P.; Stüssi, R. HCA 1978, 61, 998.
35. (a) Nakagawa, I.; Hata. T. TL 1975, 1409. (b) Nakagawa, I.; Aki, K.; Hata, T. JCS(P1) 1983, 1315.
36. Kanavorioti, A.; Lu, J.; Rosenbach, M. T.; Hurley, T. B. TL 1991, 32, 6065.
37. Mukaiyama, T.; Hashimoto, M. BCJ 1971, 44, 196.
38. Hata, T.; Sekine, M. TL 1974, 3943.
39. Ebertino, F. H.; Degenhart, C. R.; Jamieson, L. A.; Burdsall, D. C. H 1990, 30, 855.
40. Hirota, K.; Tomishi, T.; Maki, Y. H 1987, 26, 3089.
41. Atkinson, J. G.; Hanel, P.; Girard, Y. S 1988, 480.
42. Mirazaei, Y. R.; Simpson, B. M.; Triggle, D. J.; Natale, N. R. JOC 1992, 57, 6271.

Eric J. Stoner

Abbott Laboratories, North Chicago, IL, USA



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