[57320-65-7]  · C12H7Cl2N3O3S  · 6-Chloro-1-(p-chlorobenzenesulfonyloxy)benzotriazole  · (MW 344.17)

(reagent for active ester formation;1 synthesis of amides,1 esters,2 thiol esters3 from carboxylic acids; peptide synthesis1)

Physical Data: mp 125-127 °C.

Preparative Method: prepared by reaction of 6-chloro-1-hydroxybenzotriazole with p-chlorobenzenesulfonyl chloride in 1M aqueous NaOH/ether.

Purification: recrystallization from benzene/petroleum ether.

Handling, Storage, and Precautions: stable for long periods in the absence of moisture and light.

Active Ester Formation.

6-Chloro-1-(p-chlorobenzenesulfonyloxy)benzotriazole (1) converts carboxylic acids to the 1-acyloxybenzotriazole derivatives (2) in good yield (eq 1).1 A study of several related reagents found (1) to be most suitable based on overall considerations of reactivity, stability, and accessibility. The reaction occurs rapidly (usually less than 1 h) in the presence of one equivalent of Triethylamine in CHCl3 or EtOAc; the more polar solvent MeCN is required if Pyridine is used as base. The active esters (2) can generally be isolated as stable, crystalline solids.

The active esters (2) react readily in the presence of base with amines,1 alcohols,2 and certain thiols3 to provide amides, esters, and thioesters, respectively (eq 2). Aminolysis is generally rapid, as is reaction with primary alcohols; use of secondary alcohols such as i-propanol requires higher temperature (boiling CHCl3), while no reaction is observed between (2) and t-butanol.

Ester formation may also be achieved without isolation of (2) by mixing a carboxylic acid and an alcohol with (1) in the presence of two equivalents of base (eq 3).2 Formation of the 1-alkoxy-6-chlorobenzotriazole as byproduct is suppressed by the use of ether as solvent rather than CHCl3; use of pyridine in MeCN is also suitable.

Similarly, one-pot amide synthesis is possible;1 formation of sulfonamide by direct reaction of (1) with amine is avoided by using N-methylmorpholine or pyridine as base instead of Et3N.1a

Peptide Synthesis.

This method of amide bond formation has been used for peptide synthesis; the active ester is usually reacted with the amino component in situ (eq 4).1

These reaction conditions have advantages over the popular 1,3-Dicyclohexylcarbodiimide (DCC) method, not least that the sulfonic acid and hydroxybenzotriazole co-products can be washed out with aqueous sodium bicarbonate. In the coupling of N-protected L-asparagine or L-glutamine with amino components, no dehydration of the side-chain amide (to the nitrile) was observed. Free hydroxy or imino groups do not cause problems, as shown by the successful preparation of serine-, tyrosine- and histidine-containing peptides.

Using the coupling of Cbz-Phe-Ile-OH with H-Pro-OBn in DMF as a test, the degree of racemization using (1) with various bases was compared with other methods; less racemization occurred using (1) than with DCC.1b A more extensive comparison of degree of racemization has also been reported.4

1. (a) Itoh, M.; Nojima, H.; Notani, J.; Hagiwara, D.; Takai, K. TL 1974, 3089. (b) Itoh, M.; Nojima, H.; Notani, J.; Hagiwara, D.; Takai, K. BCJ 1978, 51, 3320.
2. Itoh, M.; Hagiwara, D.; Notani, J. S 1975, 456.
3. Horiki, K. SC 1977, 7, 251.
4. Kitada, C.; Fujino, M. CPB 1978, 26, 585.

Alan Armstrong

University of Bath, UK

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.