2-Thiopyridyl Chloroformate1

[73371-99-0]  · C6H4ClNOS  · 2-Thiopyridyl Chloroformate  · (MW 173.63)

(convenient preparation of 2-pyridylthiol esters;2 subsequent transformation into lactones,3 peptides,4 and ketones5)

Physical Data: 1H NMR (CDCl3) d 8.64 m (1H), 7.75 m (2H), 7.38 m (1H).

Solubility: sol CH2Cl2, ether.

Form Supplied in: colorless oil; main impurity is bis(thiopyridyl) carbonate; not commercially available.

Analysis of Reagent Purity: IR (CH2Cl2) 1765 cm-1 (C=O); main impurity: IR (CH2Cl2) 1715 cm-1 (C=O).

Preparative Method: Phosgene (5 equiv) in toluene and CH2Cl2 is cooled to 0 °C. Dropwise addition (5 min) of a CH2Cl2 solution of Triethylamine (slight excess) and 2-Pyridinethiol is followed by stirring for 10 min. After removal of excess phosgene and CH2Cl2 in vacuo, hexane is added and the resulting precipitate is filtered. After concentration of the combined filtrates, the colorless oil (96%) is dissolved in CH2Cl2 and stored at -25 °C.

Handling, Storage, and Precautions: very unstable to water and silica gel; however, it can be handled in air. It is stable for one month if stored at -25 °C. Since phosgene is used in preparing this reagent, preparation should be in a working fume hood and extreme caution is required.

Preparation of 2-Pyridylthiol Esters.

2-Pyridylthiol esters are formed by treating a carboxylic acid with 2-thiopyridyl chloroformate under extremely mild conditions (eq 1).2 The Et3N.HCl is removed by filtration or by washing with cold aqueous acid and base. After thorough drying, the thiol esters are generally pure enough to use in many synthetic applications.

There are several other reagents for preparing 2-pyridylthiol esters. 1,3-Dicyclohexylcarbodiimide4 generally gives lower yields of the thiol ester and removal of the dicyclohexylurea can be difficult. Treating an acid chloride with thallium(I) 2-pyridinethiolate6 has been used, but thallium salts are toxic. The method used most frequently before the introduction of 2-thiopyridyl chloroformate involves reacting a carboxylic acid with Triphenylphosphine and 2,2-Dipyridyl Disulfide.7 This procedure suffers from the necessity of removing 2-pyridinethiol and triphenylphosphine oxide by chromatography, which precludes preparing large batches of the thiol esters since there can be a loss of product by reaction with the silica gel. 2-Thiopyridyl chloroformate provides access to many reported synthetic transformations. In some of these reports, the thiol ester has been prepared by other methods. However, use of 2-thiopyridyl chloroformate should make these transformations even more accessible.

Lactone Formation.

There are several examples of the synthesis of lactones with 2-pyridylthiol esters.3 Since this is a facile reaction, reasonable yields of complex macrocycles are obtained (eq 2).8 The pyridine nitrogen may provide anchimeric assistance for the approaching nucleophile, thus facilitating the acylation.3

Ester Formation.

2-Pyridylthiol esters acylate lysophosphatidylcholines rapidly when catalyzed by silver ion, giving mixed-chain phosphatidylcholines in high yields and isomeric purity (eq 3).9 The main advantages of this procedure over the usual 4-Dimethylaminopyridine catalyzed acylation with acid anhydrides10 are that less acylating reagent is required to give high yields and rearrangement of the fatty acids is minimized. The main disadvantage is the sensitivity of the 2-pyridylthiol ester to water.

Peptide Coupling.

These thiol esters have been used in the synthesis of several dipeptides. Many of the examples involve highly sterically hindered amino acids and result in very good yields and high optical purity (eq 4).4 There are many useful active esters for peptide coupling, such as Pentafluorophenol, p-Nitrophenol, and N-Hydroxysuccinimide. However, these do not work as well with the hindered amino acids shown in eq 4. Additionally, there are many direct coupling procedures; therefore the 2-pyridylthiol esters have not been used frequently.

Ketones.

Reaction of 2-pyridylthiol esters with Grignard reagents occurs rapidly to give ketones in almost quantitative yields (eq 5).5 In all studies, less than 1% of the tertiary alcohol is observed. This procedure works reasonably well with a suitably protected amino acid to give the ketone (eq 6).11 Phthaloyl protection of the amine is required since esters with amide NH groups decompose when treated with Grignard reagents.11

Preparation of thiol esters of highly elaborated phosphoranes with thiopyridyl chloroformate has been reported. Treatment of the thiol ester with an aryl Grignard reagent gives the corresponding ketone without epimerization of the chiral centers (eq 7).12 There are many procedures for reacting Grignard reagents with activated carboxylic acids to give ketones. Other reagents used with varying degrees of success include acid chlorides, nitriles, acid anhydrides, and N-acylimidazolides (e.g. N,N-Carbonyldiimidazole, 1,1-Thionylimidazole).13 Many of these give higher yields of the tertiary alcohol. However, treating acid chlorides with Grignard reagents at -78 °C gives better results,14 so this may be an alternative to the thiol esters.


1. Haslam, E. T 1980, 36, 2409.
2. Corey, E. J.; Clark, D. A. TL 1979, 31, 2875.
3. Corey, E. J.; Nicolaou, K. C. JACS 1974, 96, 5614.
4. Lloyd, K.; Young, G. T. JCS(C) 1971, 2890.
5. Mukaiyama, T.; Araki, M.; Takei, H. JACS 1973, 95, 4763.
6. Masamune, S.; Kamata, S.; Diakur, J.; Sugihara, Y.; Bates, G. S. CJC 1975, 53, 3693.
7. Mukaiyama, T.; Matsueda, R.; Suzuki, M. TL 1970, 1901.
8. Le Drian, C.; Greene, A. E. JACS 1982, 104, 5473.
9. Nicholas, A. W.; Khouri, L. G.; Ellington, J. C., Jr.; Porter, N. A. Lipids 1983, 18, 434.
10. Gupta, C. M.; Radhakrishran, R.; Khorana, H. G. PNA 1977, 74, 4315.
11. Almquist, R. G.; Chao, W.-R.; Ellis, M. E.; Johnson, H. L. JMC 1980, 23, 1392.
12. Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods, M. F.; Salzmann, T. N.; Christensen, B. G. JMC 1987, 30, 871.
13. (a) Shirley, D. A. OR 1954, 8, 28. (b) Posner, G.; Witten, C. E. TL 1970, 4647. (c) Staab, H. A.; Jost, E. LA 1962, 655, 90.
14. Sato, F.; Inoue, M.; Oguro, K.; Sato, M. TL 1979, 4303.

Richard S. Pottorf

Marion Merrell Dow Research Institute, Cincinnati, OH, USA



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