Copper(II) Catalyzed Aminomethylation of Alkanes with Amine N-Oxides via C-H Bond Activation Matthew Cipolla Honors Undergraduate Research Conference University of Rhode Island April 30, 2009

Outline Example Target Molecules Desired Method Current Methods Bioactive molecules containing amines Desired Method Double (sp3)C-H activation Current Methods Double (sp2)C-H activation Results Aminomethylation of cyclohexane with Me3NO Friedel-Crafts acetylation of toluene with TFA Future Work

Synthetic Appeal of Molecules Containing Amines

Desired Synthesis Method Bufotenin Ephedrine

Why is this important? Double C-H bond activation by transition metal complexes is very challenging. Functionalization of saturated alkanes is difficult, since they are unreactive to most methods. Very high BDE (> 100 kcal/mol)

Previous Methods Daugulis, JACS 2008, 129, 12404. Itahara, Heterocycles 1986, 24, 2557. King, JOC 2007, 72, 2279.

Previous Methods (cont.) Mori, OL 2005, 7, 5083. Lu, Organometallics 2006, 25, 5973. Fagnou, Science 2007, 316, 1172.

DeBoef Work 1 2 3 Dwight, et al., Org. Lett., 2007, 9, 3137-9.

Double Activation of (sp3)C-H Bonds Fujiwara, J. Organomet. Chem. 1995, 704, 137. Fujiwara, Catal. Today 1997, 36, 86.

Aminomethylation of Cyclohexane with Me3NO

Reaction of Toluene with Me3NO Expected Aminomethylation Observed Friedel-Crafts Acetylation Benzylic C-H bond should be easier to activate (BDE ~ 85 kcal/mol) Toluene is a slightly more functional substrate

Prevent Friedel-Crafts Acetylation Use Electron Poor Arenes Nitrotoluene Use Inorganic Acids HCl

Functional Molecules Synthesize more functional molecules Design new molecules Use more functional substrates than cyclohexane

Reaction Rates Observe reaction rate competitions between substrates Use substrate with lowest rate as solvent for all future reactions

Stereoselective Reactions Synthesis of Ephedrine Will require the use of chiral ligands for the Cu(II) catalyst

Summary Double C-H activation is very important, but rare. There is currently only one example of double (sp3)C-H activation. Double (sp3)C-H activation with cyclohexane was successful. Desire to prevent Friedel-Crafts acetylation Desire to synthesize more functional molecules and design new molecules by using more functional substrates Desire to observe reaction rate competitions between substrates Desire to perform stereoselective reactions

Acknowledgments Brenton DeBoef, Ph.D. Gregory Naumiec Shathaverdhan Potavathri Kyle Pereira