(Z)-N-Methyl-N-phenylbenzohydrazonyl Bromide

[59259-48-2]  · C14H13BrN2  · (Z)-N-Methyl-N-phenylbenzohydrazonyl Bromide  · (MW 289.19)

(coupling mediator in peptide synthesis)

Physical Data: bp 82-85 °C/0.5 mmHg.

Solubility: usually used in polar solvents (acetone).

Analysis of Reagent Purity: satisfactory microanalytical data reported.1

Preparative Method: from the corresponding hydrazide using either Phosphorus(V) Chloride in dry benzene or Triphenylphosphine-Carbon Tetrabromide in acetonitrile for 2 h.1 The solid material resulting is extracted four times with ether and the resulting organic layer is concentrated to yield the crude product. Distillation provides the pure compound as exclusively the (Z)-isomer.

General Discussion.

Imidoyl halide reagents such as (1) have been utilized as coupling mediators in peptide synthesis.2 This reactivity is based on the instability of (1) in polar media, in which rapid unimolecular ionization occurs to give nitrilium ions (2) (eq 1).3 These ions exhibit unusual reactivity, being more reactive with carboxylate ions than with simple amines; thus in the presence of equal amounts of acetic acid and morpholine, the major product is the O-acyl isoamide (3) rather than the amidine (eq 2). This situation is enhanced by pH control so that, when trapping of the nitrilium ion is carried out at pH 6 (i.e. >2 pH units below the pKa of the amine), the isoamide (3) is the exclusive product. Furthermore, (2) will discriminate between carboxylate and water as nucleophile and thus the reaction can be carried out in aqueous media. Addition of an amine to (3) results in formation of amides in good yields. Use of N-protected a-amino acids in reaction with (1) gives isoamides (4) (eq 3), whose reaction with a-amino esters allows efficient preparation of peptides (eq 4). No racemization occurs during the reaction (as shown by the Anderson4 method). Base hydrolysis of the crude reaction mixture gives N-protected peptides in 80% overall yield. No acyl migration occurs in the reaction.

The unusual reactivity and concomitant pronounced selectivity of (1) allows peptides to be synthesized with a minimum number of protecting groups. Indeed, completely unprotected amino acids may be coupled using the above protocol, but best results are obtained when there is a protection of the nitrogen of the first amino acid to be coupled (Table 1). This facilitates separation of the product and subsequent manipulation is simplified.

1. Wolkoff, P. CJC 1975, 53, 1333.
2. Hegarty, A. F.; McCarthy, D. G. JACS 1980, 102, 4539.
3. McCormack, M. T.; Hegarty, A. F. JCS(P1) 1976, 1701.
4. Anderson, G. W.; Callahan, F. M. JACS 1958, 80, 2902.

Joseph Sweeney

University of Bristol, UK

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