N-Ethylbenzisoxazolium Tetrafluoroborate

[4611-62-5]  · C9H10BF4NO  · N-Ethylbenzisoxazolium Tetrafluoroborate  · (MW 234.99)

(peptide-coupling reagent;1 reacts with a wide range of nucleophiles to give o-hydroxy-N-ethylbenzamido derivatives2)

Physical Data: mp 109.5-110.2 °C.

Solubility: sol acetonitrile; slightly sol dichloromethane; sol aqueous acid (unstable above pH 4).

Form Supplied in: crystalline solid; commercially available.

Preparative Methods: ethylation of benzisoxazole with purified Triethyloxonium Tetrafluoroborate.2

Handling, Storage, and Precautions: the salt is reported not to be hygroscopic, although it etches glass on long exposure to moist air; should be protected from light; reported to be an irritant.

Peptide Coupling.

N-Ethylbenzisoxazolium tetrafluoroborate (EBF) is used to couple amines and carboxylic acids in a two-stage procedure. Firstly, EBF reacts with the carboxylic acid to form an active phenolic ester. Secondly, the active ester reacts with the amine to form the peptide linkage (eq 1).3 The procedure for the formation of the active ester employs a carefully buffered aqueous solution of the Cbz-protected aminoacid (or oligopeptide), to which an equal volume of ethyl acetate or dichloromethane is added, followed by 1.1 equiv of finely powdered EBF. The acylsalicylamide ester is isolated from the organic solvent and may be recrystallized. This product is stable to storage. This procedure does not suffer when used with the sterically demanding valine or proline residues. The active ester cleanly reacts with peptide amines in dipolar aprotic solvents, yielding the amide and N-ethylsalicylamide, which can be removed with alkali or carbon tetrachloride. The second step is, however, very slow, taking ca. 48 h at room temperature (roughly 20 times slower than the rate of p-nitrophenyl ester couplings4), and suffers from unwanted side-reactions (Brenner rearrangements5) in the presence of strongly basic amines such as triethylamine. More seriously, significant amounts (up to 1-2%) of epimerization may occur.6

EBF has been used to prepare peptide cyclodimers in yields which compare favorably with other procedures.1 For this method, intermediate Cbz-protected acylsalicylamide esters were hydrogenolyzed to form the free amines which then yielded the cyclodimers (eqs 2 and 3).

Peptide cyclotrimers have also been prepared in this manner.7,8 After deblocking at nitrogen, a highly dilute solution of the resulting free amine in dry pyridine was stirred for 65 h at room temperature to give the cyclotrimer in an impressive 90% yield (eq 4).

Detailed mechanistic studies indicate that the N-ethylbenzisoxazolium cation readily undergoes base-catalyzed elimination to form a transitory N-ethylbenzoketoketenimine (eq 5).9

In the case of reactions with carboxylic acids (X = RCO2), the initial addition product then rapidly rearranges to the active ester (eq 6).

Several hydroxy-,10 nitro-,3 and chloro-substituted11 N-ethylbenzisoxazolium cations have been studied in attempts to vary the reactivity of the intermediate active ester (see 2-Ethyl-7-hydroxybenzisoxazolium Tetrafluoroborate).

Reactions with Nucleophiles.

The N-ethylbenzisoxazolium cation reacts rapidly in aqueous solution with a range of nucleophiles, yielding o-hydroxy-N-ethylbenzimido derivatives. Hydrolysis proceeds smoothly in mild acid, but at pH above 7, polymeric material is obtained (eq 7).2

Treatment of EBF with aqueous solutions of simple nucleophiles (HS-, F-, CN-) or with methanolic methoxide gives high yields of the benzimido derivatives (eq 8).

Reaction of EBF with cyanate, thiocyanate, and thiourea generates initial adducts which can undergo internal rearrangements. For example, the adduct of cyanate to EBF yields a cyclic urethane (eq 9); reaction with thiocyanate yields the analogous thiourethane.2

1. Rajappa, S.; Akerkar, A. S. TL 1966, 25, 2893.
2. Kemp, D. S.; Woodward, R. B. T 1965, 21, 3019.
3. Kemp, D. S.; Wang, S.-W.; Mollan, R. C.; Hsia, S.-L.; Confalone, P. N. T 1974, 30, 3677.
4. Kemp, D. S.; Wang, S.-W. JACS 1967, 89, 2745.
5. Kemp, D. S.; Duclos, J. M.; Bernstein, Z.; Welch, W. M. JOC 1971, 36, 157.
6. Kemp, D. S.; Wang, S.-W.; Busby, G., III; Hugel, G. JACS 1970, 92, 1043.
7. Kemp, D. S.; McNamara, P. TL 1981, 22, 4571.
8. Kemp, D. S.; McNamara, P. JOC 1985, 50, 5834.
9. Kemp, D. S. T 1967, 23, 2001.
10. Kemp, D. S.; Chien, S.-W. JACS 1967, 89, 2743.
11. Rajappa, S.; Akerkar, A. S. CC 1966, 826.

Ross P. McGeary

University of Cambridge, UK

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