From the wide range of different chemical transformations used in the pharmaceutical industry, amide and peptide couplings belong to the most important and widely applied. This is due to the relevance of the amide moiety in pharmaceutical compounds. Unfortunately, traditional amidation reaction conditions require hazardous reagents and organic solvents which generate significant amounts of waste. Therefore, finding greener alternatives that are transferrable to industrial applications on a large scale is an important area of process research and development. This approach is essential for increasing sustainability in the pharmaceutical and chemical industries. In this article, we describe our efforts to develop a sustainable, practical, and scalable protocol for amide and peptide couplings. Our approach is based on pivaloyl chloride as an inexpensive and readily obtainable coupling reagent in water as the main reaction media. The conditions developed were applied to the synthesis of a range of amides and peptides. We then investigated the scope of the transformation and the effect of the surfactant TPGS-750-M by comparing the outcome and the selectivity of reactions carried out in an aqueous solution containing 2 wt % of surfactant and solely in aqueous media.
Orthoamides. L. Contribution to the Chemistry of Propiolaldehydaminales – Synthesis and Transformations to Push–Pull‐substituted Buta‐1,3‐dienes, Cyclobutanes, Vinylogous Amidinium Salts and 1,2,3‐Triazoles
Tert‐butylaminalester 5 reacts with terminal alkynes to give aminals of substituted propiolaldehydes 3c, d. The aminal 3a is accessible from N,N,N′,N′‐tetramethylformamidinium chloride (7b) and sodium acetylide. The aminals 3b,c can also be prepared from bis(dimethylamino)acetonitrile 8 and terminal alkynes in the presence of sodium hydride. The nitrile 8 is also useful for the preparation of the bis‐aminal of acetylenedialdehyde 6. The aminal 3e can be transaminated by heating with secondary amines to give the aminals 3f–i. The aminals 3a–i react with strong CH2‐acidic compounds (pKa between 9 and 14) to give the 1‐dialkylamino‐1,3‐butadienes 10. The isomeric 1‐dialkylamino‐butadienes 18 can be obtained from the condensation of the CH‐acidic cinnamic acid derivatives 19 with dimethylformamidedimethylacetal. CH and NH‐acidic compounds as cyanacetamide react with the aminals 3c,e exclusively with the acidic methylene group to produce the enamines 10h,t. The acylformamidine 21 can be obtained from 10t and tert‐butylaminalester 5. The pyridone 22 is accessible from the condensation product 10h by thermal cyclization. The pyrido[2,3‐d]pyrimidine 26 is formed in the reaction of the 6‐amino‐uracile 23 with the aminal 3a. In an unexpected reaction the 1,2‐bis(cyano‐dialkylaminomethylene)‐cyclobutanes 28a–d result from the action of trimethylsilylcyanide on the aminals 3e–h. The corresponding reaction with trimethylsilylisothiocyanate affords the vinylogous amidinium thiocyanates 34a, b. In the reaction of trimethylsilylazide and the aminals 3 are produced the 4‐(dialkylaminomethylene)‐4H‐1,2,3‐triazoles 38.
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