Triphenylphosphine-N-Bromosuccinimide1

(Ph3P)

[603-35-0]  · C18H15P  · Triphenylphosphine-N-Bromosuccinimide  · (MW 262.30) (NBS)

[128-08-5]  · C4H4BrNO2  · Triphenylphosphine-N-Bromosuccinimide  · (MW 177.99) (NCS)

[128-09-6]  · C4H4ClNO2  · Triphenylphosphine-N-Chlorosuccinimide  · (MW 133.54) (NIS)

[516-12-1]  · C4H4INO2  · Triphenylphosphine-N-Iodosuccinimide  · (MW 224.99)

(conversion of primary alcohols to alkyl halides)

Physical Data: See Triphenylphosphine, N-Bromosuccinimide, N-Chlorosuccinimide, and N-Iodosuccinimide.

Preparative Methods: the mixed reagent is prepared in situ as needed by combining triphenylphosphine, the alcohol, and N-halosuccinimide in a suitable solvent (usually DMF) and heating.

Handling, Storage, and Precautions: precautions in handling should be made as described for the individual reagents. This mixed reagent is not appropriate for storage. Recrystallization of the triphenylphosphine and N-halosuccinimide is necessary to achieve the most efficient halogenation reaction. In addition, the use of anhydrous solvent is important for the success of the reaction.

Introduction.

The combination of triphenylphosphine and N-halosuccinimide was applied by Hanessian2 to the preparation of primary halides from carbohydrate precursors. This method is related to a number of other methods for hydroxyl substitution via oxyphosphonium salts as described in a comprehensive review.1

Conversion of Alcohols to Alkyl Halides.

The typical procedure2 as applied to the preparation of methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-b-D-ribofuranose (eq 1) involves the addition of 2 equiv of N-iodosuccinimide followed by 2 equiv of triphenylphosphine to a cooled solution of the alcohol in anhydrous DMF and heating the mixture to 50 °C for 20 min. Methyl alcohol is added to destroy excess reagent, followed by n-butanol to aid in the removal of DMF under reduced pressure. After concentration, the product is purified from the byproducts (succinimide and triphenylphosphine oxide) by addition of ether and aqueous extraction followed by column chromatography. Isolated yields of 70-85% are regularly obtained using this procedure for the preparation of chlorides, bromides, and iodides. In addition, the reaction conditions allow the preparation of primary halides in the presence of many functional groups used in carbohydrate chemistry, including the ester, amide, lactone, benzylidene acetal, and acetonide groups (eq 2). In fact, moderate yields (49-82%) of a number of primary halides are obtained using this procedure on sugars containing one or more free secondary hydroxyl groups (eq 3).2-4

Other examples of the use of this method include the preparation of tetrahydrofurfuryl bromide,5 3a-cholestanyl bromide (using THF as solvent, 85% yield),6 and intermediates toward the syntheses of alkaloids (eqs 4 and 5).7 The reaction of the reagent with DMF alone generates the formamidinium salt which can ultimately result in the isolation of the formate ester derivative of the alcohol substrate (eq 6).1,8 It is therefore important that the N-halosuccinimide is added last for the preparation of alkyl halides. Other solvents used for this reaction include CH2Cl2 (which can facilitate the workup of the reaction products) and HMPA.9

The standard procedure has often been found to be unsatisfactory for substrates which are prone to acid-catalyzed rearrangements (including migration of acetonide protecting groups) and cleavage and is also not suitable for substrates containing labile protecting groups such as THP ethers.10,11 In some cases this problem has been circumvented by the addition of various bases such as BaCO3 (eq 7),12 Pyridine, and Imidazole. A recent study has achieved the preparation of 3-bromo-3-deoxy-1,2:5,6-di-O-isopropylidene-a-D-allofuranose by addition of 2 equiv of N-halosuccinimide to a refluxing solution of the secondary alcohol and 2 equiv each of PPh3 and imidazole in toluene or chlorobenzene (eq 8). Previous applications of PPh3 and N-halosuccinimide alone afforded only the primary halide products resulting from acetonide migration. The use of pyridine and imidazole have also been found to play an essential role in the conversion of carbohydrates to halides using the reagents Triphenylphosphine-Iodine and Triphenylphosphine-Carbon Tetrachloride, respectively.13


1. Castro, B. R. OR 1983, 29, 1.
2. (a) Ponpipom, M. M.; Hanessian, S. Carbohydr. Res. 1971, 18, 342. (b) Hanessian, S.; Ponpipom, M. M.; Lavallee, P. Carbohydr. Res. 1972, 24, 45.
3. (a) Nakane, M.; Hutchinson, C. R.; Gollman, H. TL 1980, 21, 1213. (b) Aspinall, G. O.; Carpenter, R. C.; Khondo, L. Carbohydr. Res. 1987, 165, 281.
4. Hasegawa, A.; Morita, M.; Ishida, H.; Kiso, M. J. Carbohydr. Chem. 1989, 8, 579.
5. Schweizer, E. E.; Creasy, W. S.; Light, K. K.; Shaffer, E. T. JOC 1969, 34, 212.
6. Bose, A. K.; Lal, B. TL 1973, 3937.
7. (a) Birkinshaw, T. N.; Holmes, A. B. TL 1987, 28, 813. (b) Comins, D. L.; Myoung, Y. C. JOC 1990, 55, 292.
8. Hodosi, G.; Podányi, B.; Kuszmann, J. Carbohydr. Res. 1992, 230, 327.
9. Baker, C. W.; Whistler, R. L. Carbohydr. Res. 1975, 45, 237.
10. Yunker, M. B.; Tam, S. Y.-K.; Hicks, D. R.; Fraser-Reid, B. CJC 1976, 54, 2411.
11. Gensler, W. J.; Marshall, J. P.; Langone, J. J.; Chen, J. C. JOC 1977, 42, 118.
12. Jäger, V.; Häfele, B. S 1987, 801.
13. (a) Garegg, P. J.; Johansson, R.; Samuelsson, B. S 1984, 168. (b) Whistler, R. L.; Anisuzzaman, A. K. M. Methods Carbohydr. Chem. 1980, 8, 227.

Scott C. Virgil

Massachusetts Institute of Technology, Cambridge, MA, USA



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