[67543-08-2]  · C9H14N2O  · 4-(4-Methyl-1-piperazinyl)-3-butyn-2-one  · (MW 166.25)

(peptide coupling)

Physical Data: colorless crystals; mp 18-19 °C.

Preparative Method: can be made in multigram quantities in three steps from commercially available 4-Methoxy-3-buten-2-one in 54% overall yield (eq 1).1 The intermediates (2) and (3) are purified by recrystallization or distillation. No chromatography is involved. The final product can be purified by distillation under reduced pressure.

Handling, Storage, and Precautions: stable for a period of hours at rt. It should be stored at refrigerator/freezer temperatures to prolong its shelf life.

Peptide Coupling.

This push-pull alkyne reagent has found use in the production of amides from carboxylic acids and amines (eq 2).2 Typically, the carboxylic acid is added to a solution of the ynone in THF at 0 °C and stirred for 30 min. The amine is added at -20 °C and the reaction is allowed to warm to rt. It has been confirmed by isolation that enol esters such as (7) are intermediates in the process, which is thought to proceed as shown in (5) -> (8). A variety of saturated and unsaturated carboxylic acids can be combined with primary and secondary amines to give amides in 73-95% yields.

Because of the near-neutral conditions of the coupling process, the reagent is excellent in the formation of peptides (eq 3).3 Because (4) reacts quickly with carboxylic acids to form (5), peptide fragments containing unprotected and potentially nucleophilic groups can be used in the coupling process. For example, unprotected serine, methionine, hydroxyproline, tyrosine, and histidine react only at the primary amino group (eq 3). Yields are excellent and little or no racemization is observed.

1. Lienhard, U.; Fahrni, H.-P.; Neuenschwander, M. HCA 1978, 61, 1609.
2. (a) Neuenschwander, M.; Lienhard, U.; Fahrni, H.-P.; Hurni, B. HCA 1978, 61, 2428. (b) Neuenschwander, M.; Lienhard, U.; Fahrni, H.-P.; Hurni, B. C 1978, 32, 212.
3. (a) Neuenschwander, M.; Fahrni, H.-P.; Lienhard, U. HCA 1978, 61, 2437. (b) Neuenschwander, M.; Fahrni, H.-P.; Lienhard, U. C 1978, 32, 214.

Kim F. Albizati

University of California, San Diego, CA, USA

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