1. 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

2. 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

3. Synthetic Appeal of Molecules Containing Amines

4. Desired Synthesis Method
Bufotenin
Ephedrine

5. 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)

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

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

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

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

10. Aminomethylation of Cyclohexane with Me3NO

11. 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

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

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

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

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

16. 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

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