Transition metal-catalyzed reactions have risen to the forefront of synthetic organic chemistry and are often the method of choice when trying to construct a plethora of C-C, C-N, and C-0 bond types. Palladium is often the metal of choice for a variety of these reactions which are routinely carried out on scales ranging from milligrams to tons. Although a large number of catalyst/ligand systems are known, it is often the case that they work for only certain substrates in certain reaction classes. That is to say a truly general cross- coupling catalyst has yet to be discovered. One likely reason is that it is difficult to envision a catalyst that is optimal for each step of the catalytic cycle (oxidative addition, transmetilation, reductive elimination) since each of these fundamental organometallic reactions have different preferences in the electronics of the metal center and the steric demands of the ligands. An unorthodox approach to ligand design would be a ligand whose properties (electron donor ability and steric demands) could change throughout catalysis thus promoting individual steps differently. Carbocyclic groups, capable of undergoing unimolecular pericyclic reactions will be attached to phosphine groups as a means to achieve these goals. Three novel ligand classes, each of which possesses unique chemical properties, are introduced as well as their application to currently challenging problems in cross-coupling reactions as well as aryl fluorination. Although the Suzuki coupling is a routine synthetic procedure, significant challenges can still be encountered when trying to use certain substrate classes. Couplings involving electron deficient boron compounds, particularly 2-pyridyl boronic acids are an example. The ability of uniquely designed shape-shifting ligands to promote such reactions will be investigated. The metal-catalyzed synthesis of aryl fluorides using Pd(0)/Pd(ll) catalysis has proven difficult to date. The use of size changing ligands to promote aryl fluoride reductive elimination from Pd(ll) (which is currently the troublesome step) will be investigated. The relevance of this research to public health is simple: fluorine containing compound appear in numerous medicines and their syntheses are currently difficult and often dangerous. One measure of the importance of fluorination in medicine is the fact that of the 20 top selling brand-name drugs sold in 2007, nine contained fluorine and five possessed an aryl fluoride motif. In addition, cross coupling reactions have revolutionized the pharmaceutical industry, and in particular the Suzuki coupling has become a staple in medicinal chemistry. Thus the entire proposal seeks to use novel insight in ligand design to address problems that are of real significance to public health and therapeutics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04A-L (20))
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Marino, Pamela
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Milner, Phillip J; Maimone, Thomas J; Su, Mingjuan et al. (2012) Investigating the dearomative rearrangement of biaryl phosphine-ligated Pd(II) complexes. J Am Chem Soc 134:19922-34
Noel, Timothy; Maimone, Thomas J; Buchwald, Stephen L (2011) Accelerating palladium-catalyzed C-F bond formation: use of a microflow packed-bed reactor. Angew Chem Int Ed Engl 50:8900-3
Maimone, Thomas J; Milner, Phillip J; Kinzel, Tom et al. (2011) Evidence for in situ catalyst modification during the Pd-catalyzed conversion of aryl triflates to aryl fluorides. J Am Chem Soc 133:18106-9
Maimone, Thomas J; Buchwald, Stephen L (2010) Pd-catalyzed O-arylation of ethyl acetohydroximate: synthesis of O-arylhydroxylamines and substituted benzofurans. J Am Chem Soc 132:9990-1