University of Puget Sound Sound Ideas

Summer Research

Summer 2015

Developing Catalysts for Improving Direct Amide Formation

Courtney Carley

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Recommended Citation Carley, Courtney, "Developing Catalysts for Improving Direct Amide Formation" (2015). Summer Research. 235. https://soundideas.pugetsound.edu/summer_research/235

This Article is brought to you for free and open access by Sound Ideas. It has been accepted for inclusion in Summer Research by an authorized administrator of Sound Ideas. For more information, please contact [email protected]. Developing Catalysts for Improving Direct Amide Formation Courtney Carley*, Luc Boisvert University of Puget Sound, Department of Chemistry, Summer 2015

BACKGROUND CATALYST FORMATION CATALYTIC TESTING RESULTS

• Over the last two decades, the development of more sustainable and • Target catalysts will be formed by condensing the thiourea catalyst intermediate • The pair of 1H NMR spectra below show the progress of the reaction greener chemical processes has become a global focus.1 12 with various aldehydes to form imines (13). shown using catalyst 31 under the previously mentioned conditions, • 25% of all pharmaceuticals contain the amide functional group.2 illustrating the growth of the amide product over time. • Amides are usually formed from carboxylic acids and amines. • Current methods of amide formation use toxic reagents and produce large amounts of harmful byproducts.3

• Aldehyde 14 is commercially available. 0 hours

• The synthesis of aldehyde 16 as an intermediate to the final aldehyde 18 was • Direct amide formation would be highly desirable as no toxic reagents repeatedly attempted.5 are needed and water is the only byproduct. 1,4-dioxane amine (standard) acid amide amide 40.5 hours

• However, direct amide formation generally does not proceed without a • However the water-sensitive property of the reaction led to inconsistent results, catalyst. including failure to react at all, or not proceeding to completion. • Commercially available boron-based catalysts for direct amide • Excessive formation of the undesired side product 17 also indicates the need for formation are not active enough to be widely useful.3 optimization. • The plot below compares the reactivity of these catalysts, and shows the effect that adding molecular sieves has on the reactions. • Arsenic-based catalysts previously developed in the Boisvert • The synthesis of aldehyde 23 involves the formation of dibromo intermediate 22.6 laboratory proved to be less active than the boron-based catalysts. • The thiourea catalysts have promising reactivity in comparison to known catalysts. • Both previous and target catalysts aim to activate the carboxylic acid: • These catalysts represent the first successful application of thioureas in direct amidation reactions! 45 o The main mode of activation for previously developed catalysts 40 (e.g., boron, arsenic) is to • Compound 22 was successfully synthesized after 11 sets of conditions were transform the hydroxyl group into a tested over a year. 35 better leaving group: • The last step to form the final aldehyde 23 is currently being tested.6 30

25 o The targeted catalysts will attempt to activate the carbonyl group by making 20 it a better electrophile: CATALYST TESTING Summer 2015

Conversion (%) Conversion 15 o Thioureas achieve this kind of activation With mol. sieves: Without mol. sieves: 4 : catalyst 28 : catalyst 28 of the carbonyl group through dual H-bonding. • Commercially available thioureas 28-30, catalyst 31 (based on aldehyde 14), and 10 catalyst 32 (a side-product of the formation of 12) were tested as catalysts in : catalyst 29 : catalyst 32 direct amide formation. 5 : catalyst 30 : iPr2PhAsO • New bifunctional catalysts will be designed to achieve the double • Catalyst testing reactions were run in J. Young NMR tubes with toluene-d as the : catalyst 31 : boric acid activation of the carboxylic acid and of the hydroxyl group: 8 0 solvent, using carboxylic acid 24 and amines 26 and 27. 0 10 20 30 40 50 60 70 80 90 Reaction Time (Hours) FUTURE WORK

• Optimize the synthesis of aldehydes 18 and 23. • Synthesize catalysts derived from aldehydes 18 and 23. • 1,4-dioxane was added to each NMR sample, and was used as an integration • Continue catalytic testing with same procedure and comparison of standard to monitor the progress of each reaction. data to determine relative efficiency of target catalysts. • No reaction at room temperature: the reactions proceeded only when the tubes RESEARCH OBJECTIVES were in a 90 °C water bath, allowing for more precise monitoring of reaction time. • 4 Å molecular sieves were added at the beginning of the reactions to remove ACKNOWLEDGEMENTS water as it was formed to push the reactions further than in prior catalyst testing. • Synthesize bifunctional thiourea-based catalysts that utilize the double I would like to extend my gratitude to Professor Boisvert for his help and activation strategy and optimize all synthetic steps involved. guidance throughout this research experience. I would also like to thank the University of Puget Sound for providing financial support for this project. • Test the efficiency of the catalysts for amide formation reactions on standard substrates and monitor reaction progress by 1H NMR spectroscopy. REFERENCES

1) Sheldon, R. A. Fundamental of Green Chemistry: Efficiency in Reaction Design. Chem. Soc. Rev. 2012, 41, 1437-1451. • Compare the thiourea catalysts to amidation catalysts previously 2) Monks, B. M.; Whiting, A. Direct Amide Formation Avoiding Poor Atom Economy Reagents. In Sustainable Catalysis: Challenges and formed in the Boisvert laboratory, and to other commercially available Practices for the Pharmaceutical and Fine Chemical Industries; Dunn, P. J.; Hii, K. K.; Krische, M. J.; Williams, M. T., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, 2013; Chapter 5, pp 89-110. thioureas. 3) Charville, H.; Jackson, D.; Hodges, G.; Whiting, A. The Thermal and Boron-Catalysed Direct Amide Formation Reactions: Mechanistically Understudied Yet Important Processes. Chem. Commun. 2010, 46, 1813-1823. 4) Doyle, A. G.; Jacobsen, E. N. Small-Molecule H-Bond Donors in Asymmetric Catalysis. Chem. Rev. 2007, 107, 5713-5743. 5) Trécourt, F.; Mallet, M.; Marsais, F.; Quéguiner, G. Catalyzed Metalation Applied to 2-Methoxypyridine. J. Org. Chem. 1988, 53, 1367- 1371. 6) Arun, V.; Robinson, P. P.; Manju, S.; Leeju, P.; Varsha, G.; Digna, V.; Yusuff, K. K. M. A Novel Fluorescent Bisazomethine Dye Derived from 3-hydroxyquinoxaline-2-carboxaldehyde and 2,3-diaminomaleonitrile. Dyes and Pigments 2009, 82, 268-275.