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The Washington Research Foundation Fellowship
Jeremy Housekeeper, Chemistry
Jeremy Housekeeper is a senior studying Chemistry and Biochemistry.
Mentor: Christine Luscombe, Materials Science & Engineering
Project Title: Heterocycle Synthesis through a C-H Activation Cascade Reaction
Abstract: Until recently, little research has been done on C-S bond formation in transition-metal catalyzed transformations compared to other carbon-heteroatom bonds such as C-N, C-O, and C-P. As sulfur-based coupling partners (thiol and disulfide for example) tend to poison transition-metal catalysts, development of C-S bond formation has been slow. However, a recent nickel-catalyzed system shed new light on this difficult transformation. In this context, C-H functionalization is a sustainable and straightforward approach to sulfur-containing heteroaromatic production. C-H activation is a process whereby a carbon-hydrogen bond is cleaved, thereby allowing the exposed carbon atom to form new bonds. Thus, in order to expand the above research of C-S bond formation toward development of short synthesis for fused thiophene systems, focus was placed on a palladium catalyzed cascade-type reaction system. C-H activation reactions can and have been manipulated to work in a cascade-type fashion. By combining cascade-type methodology with the reduced environmental impact of C-H activation, these fused thiophenes can be synthesized cleanly and efficiently. The test substrates in this work are O,O-diethyl S-phenyl phosphorothioate and 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane. Both substrates were chosen because they contain sulfur, thereby aiding the C-H activation process. By effecting a C-H activation with a palladium catalyst at one of the ortho carbons of the phenyl ring with the boronic ester of the thiophene, the first C-C bond will be formed. In the time immediately after this first transformation, the now-changed palladium complex is able to insert into the S-P bond of the phenyl-based compound. This step sets up the second reaction, whereby the phosphorothioate directing group is cleaved along the S-P bond and the resulting thiol is coupled to a carbon atom to close the ring. This molecule is known as benzo[b]thieno[2,3-d]thiophene.