Effects of Varying Acidic Conditions on Ring Closure

q Introduction q Bicyclic Lactams q Making Bicyclic Lactam q Experiment: Varying p. H

Ø Libraries of dihydropyridazinones and hydroxamic acids as potential pharmaceutical uses and advancement in

Ø 1 -aza-8 -oxo-4 -oxa-[3. 3. 0]bicyclooctanes These α-hydrogens can be replaced and more

Ø Bicyclic lactams from cyclodehydration of amino alcohols and dicarbonyl compounds Ø One synthetic

~ Cyclic Anhydride and Amino Alcohol Yields an Imide ~ In this case, succinic

~ Imide and Grignard (or Hydride) Yields Carbinolamine, Which Under Acidic Conditions Results in

(2 -step synthesis involving N-acyliminium species) • Grignard reagents can add a greater variety

v Uses Grignard Reagents: RMg. Br v Grignard Reagents are Very Reactive Nucleophiles v

Ø Remove water as it forms to push reaction forward ØAzeotropic removal of water

Ø Run TLC, visualize with vanillin solution Ø Push through silica gel plug Ø

Compound and purity were identified by NMR spectra. Also by IR, C-13 NMR, and

Vary the p. H upon ring closure of Bicyclic lactams. Correlation between yields and

List acidic buffers of different strengths and p. H Record the yields Find a

If there is a correlation between p. H and ring closure: Ø There would

Ø We will find out if p. H affects the yields by looking for

ü Vary the reagent stoichiometry ü Vary the R groups on the angular position:

Industrial Size Distillation Column Ø Future Applications: • Dihydropyridazinone and Hydroxamic Acid derivatives •

ØCalifornia State University, Long Beach (Department of Chemistry and Biochemistry and the Department of

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

q Introduction q Bicyclic Lactams q Making Bicyclic Lactam q Experiment: Varying p. H on Ring Closure q Anticipated Results q Concluding Remarks

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

Ø 1 -aza-8 -oxo-4 -oxa-[3. 3. 0]bicyclooctanes These α-hydrogens can be replaced and more functional groups added Ø Vehicles for the construction of natural and unnatural products containing quaternary carbon centers

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

~ Cyclic Anhydride and Amino Alcohol Yields an Imide ~ In this case, succinic anhydride and ethanolamine where heated to form ethanol succinimide.

~ 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.

(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 p. H during closure may directly affect yields

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

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

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

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

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

List acidic buffers of different strengths and p. H Record the yields Find a relationship between acidic conditions and yields

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

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

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

Industrial Size Distillation Column Ø 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/

ØCalifornia State University, Long Beach (Department of Chemistry and Biochemistry and the Department of Biological Sciences) ØDr. Paul Buonora ØDr. Mason and Dr. Archie ØThe Howard Hughes Medical Institute