Progress In The Development Of Multicomponent Reactions
Multicomponent reactions (MCRs) are processes in which three or more reactants are combined in one pot to form products that display structural features from each reactant. For this reason, MCRs provide rapid access to chemically diverse structures in an operationally simple manner. MCRs that produce drug-like structures are particularly useful in pharmaceutical development. As part of our ongoing effort to improve and expand synthetically useful MCRs, tert-butylisonitrile was developed as an inexpensive, efficient, and readily available "convertible isonitrile", one whose post-condensation product (typically a carboxamide) can be converted to a variety of new functionalities. The process, which occurred under mild nonaqueous conditions, left carboxylic esters unaffected and transformed MCR amides into useful carboxylic acids for further synthetic elaboration. We further showed that n-butylisonitrile may provide a viable alternative to other convertible isonitriles for amide-to-ester transformations in Ugi reactions. In another project, a simple and general synthesis of carbonimidic dichlorides from isonitriles was developed using sulfuryl choride at low temperature. Carbonimidic dihalides are found in several natural products and have been used as protecting groups for isonitriles. The method, which suppressed free radical chlorination, rapidly and selectively furnished the corresponding carbonimidic dichlorides in excellent yields without further purification. Published reports on the reaction of nitronates with thiols under strongly basic conditions to form thiohydroximate esters led to an investigation on the analogous reaction of nitronates with amines to afford the corresponding amidoximes, an important family of medicinally active compounds. During this investigation, the first example of an amidoxime-to-amidine transformation by nucleophilic addition of an amine and elimination of NH2OH was discovered. The effect of metallating agent and amine substitution was also studied. Two generally useful sets of conditions were developed and applied to the preparation of a representative family of amidoximes. This thesis also describes attempts to replace the intermediate iminium electrophile in the Ugi reaction with a thionium electrophile. In the course of that study, a rapid and gentle catalytic oxidation of isonitriles to isocyanates was serendipitously discovered. The new method proved to be simple and easy to use. It generated only volatile and innocuous byproducts, and represented a very mild, rapid, and environmentally acceptable procedure for preparing isocyanates from isonitriles.
Schroeder, Frank; Dichtel, William Robert
Chemistry and Chemical Biology
Ph. D., Chemistry and Chemical Biology
Doctor of Philosophy
dissertation or thesis