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Teresa Phan Dr. Buonora California State University, Long Beach

Effects of Varying Acidic Conditions on Ring Closure of acyliminium Ion Intermediates in the Synthesis of Aryl-substituted bicyclic lactams: Finding Optimal Conditions for Increasing Yields. Teresa Phan Dr. Buonora California State University, Long Beach. Brief Overview. Introduction

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Teresa Phan Dr. Buonora California State University, Long Beach

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  1. Effects of Varying Acidic Conditions on Ring Closure of acyliminium Ion Intermediates in the Synthesis of Aryl-substituted bicyclic lactams: Finding Optimal Conditions for Increasing Yields. Teresa Phan Dr. Buonora California State University, Long Beach

  2. Brief Overview • Introduction • Bicyclic Lactams • Making Bicyclic Lactam • Experiment: Varying pH on Ring Closure • Anticipated Results • Concluding Remarks

  3. Introduction • Libraries of dihydropyridazinones and hydroxamic acids as potential pharmaceutical uses and advancement in organic synthesis • Ex: inodilators and phosphodiesterase inhibitors • Find conditions to optimize yields of each reaction to increase efficiency • Bicyclic Lactams are important starting materials

  4. Introducing Bicyclic lactams • 1-aza-8-oxo-4-oxa-[3.3.0]bicyclooctanes These α-hydrogens can be replaced and more functional groups added • Vehicles for the construction of natural and unnatural products containing quaternary carbon centers

  5. Cyclodehydration Process • Bicyclic lactams from cyclodehydration of amino alcohols and dicarbonyl compounds • One synthetic step, limited only by availability of ketoacid • Limitation on the angular position

  6. Bicyclic Lactams Through N-Acyliminium Species Part One ~ Cyclic Anhydride and Amino Alcohol Yields an Imide ~ In this case, succinic anhydride and ethanolamine where heated to form ethanol succinimide.

  7. Bicyclic Lactams Through N-Acyliminium Species Part Two ~ Imide and Grignard (or Hydride) Yields Carbinolamine, Which Under Acidic Conditions Results in Ring Closure to Form Bicyclic Lactams ~ In this case, the ethanol succinimide was reacted with two molar equivalences of an aryl-substituted Grignard Reagent and then refluxed overnight with an acid catalyst.

  8. Why We Chose to Work With the Latter Method (2-step synthesis involving N-acyliminium species) • Grignard reagents can add a greater variety of R groups at the angular position • Better yields than the respective cyclodehydration route • Previous studies indicate that reagent stoichiometry and solution pH during ring closure may directly affect yields

  9. Grignard Reactions • Uses Grignard Reagents: RMgBr • Grignard Reagents are Very Reactive Nucleophiles • Concentration Deteriorate With Time, Moisture and Air • True Concentrations Found by Direct Titration Using sec-Butanol in Xylene and 1,10-Phenanthroline as Indicator • Grignard Reagents Should be Titrated Once a Month

  10. Closing the Ring... • Remove water as it forms to push reaction forward • Azeotropic removal of water with Dean-Stark Trap • Minimum-boiling azeotropes: azeotrope comes off the liquid first • Heptane instead of toluene LG-16002 http://www.lab-glass.com/html/nf/DSTA-LG-16002.html

  11. Bicyclic Lactam Purification and Isolation • Run TLC, visualize with vanillin solution • Push through silica gel plug • Radial Chromatography (Chromatotron) • Collect Fractions in Tubes • Run TLC to Combine Tubes • Evaporate off Solvent Via Rotary Evaporator • Analyze by NMR • Find Percent Yield by Weight of Purified Product

  12. Identifying Compound Compound and purity were identified by NMR spectra. Also by IR, C-13 NMR, and TLC spotting. 1H NMR of Phenyl-substituted Bicyclic Lactam

  13. Experiment Vary the pH upon ring closure of Bicyclic lactams. Correlation between yields and pH? Yes No Ring closure is not affected by pH. There is an optimal pH. Use the optimal pH and vary reagent stoichiometry. Vary reagent stoichiometry.

  14. Examples of Possible Buffers List acidic buffers of different strengths and pH Record the yields Find a relationship between acidic conditions and yields

  15. Results If there is a correlation between pH and ring closure: • There would be an optimal pH. • Closer to pH of 6 or near 7. • Very Strong acids will cause unwanted chemistry

  16. Conclusion • We will find out if pH affects the yields by looking for peaked yields at a specific pH • It may be that the pH does not matter as much as the type of acid used • If we can’t get yields to increase to >90%, then we have to look at reaction preferences as well as reagent stoichiometry

  17. Future Experiments • Vary the reagent stoichiometry • Vary the R groups on the angular position: • Aromatic vs. Allyl • Alkyl: Straight Chain vs. Branched

  18. Industrial Size Distillation Column • Future Applications: • Dihydropyridazinone and Hydroxamic Acid derivatives • Medicine • Safer Insecticides • Natural and Unnatural Products with Quaternary Carbon Centers http://www.aut.ee.ethz.ch/~disti/

  19. Acknowledgements • California State University, Long Beach (Department of Chemistry and Biochemistry and the Department of Biological Sciences) • Dr. Paul Buonora • Dr. Mason and Dr. Archie • The Howard Hughes Medical Institute

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