Department of Chemistry and Chemical Biology, Rutgers-The State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA.
Department of Chemistry and Biochemistry, Swarthmore College, 500 College Avenue, Swarthmore, PA 19081, USA.
Molecules. 2021 Dec 23;27(1):66. doi: 10.3390/molecules27010066.
The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed.
四氢异喹啉-1-酮-4-羧酸的酰胺化反应是抗疟药物 SJ733 的多公斤规模制备的关键步骤，目前处于 2 期临床试验阶段。在研究 THIQ 酰胺化反应的过程中，我们发现丙磷酰基三嗪（T3P）是一种有效的试剂，尽管收率和副产物随碱的性质和用量而变化。作为对照，在没有胺的情况下进行了 3-(2-噻吩基）THIQ 的 T3P 反应，并对产物进行了表征：其中有三个二聚烯丙基和两个二聚内酯。受微妙的空间和立体电子效应影响的亲核试剂促进的酮烯二聚化过程解释了它们的形成。还分离出两种新型单体产物，即脱羧异喹啉和紫色稠合芳基酮，并提出了它们从烯酮中间体形成的机制。
