Chain ExtensionMannich Reactions with Sulfonyl Imines Brittney Hutchinson

Chain Extension-Mannich Reactions with Sulfonyl Imines Brittney Hutchinson, Dr. Charles Zercher bsl 28@wildcats. unh. edu; Parsons Hall, 23 Academic Way, Durham NH 03824 Introduction Investigation into tandem chain extended- Mannich reactions have provided insight into some organic synthesis pathways. Researchers have looked into the demonstration of functional groups and their ability to stabilize intermediates. Zinc organometallic intermediates are common in the Zercher tandem chain-extension research. The zinc-enolates formed in this process have shown the ability to stabilize the intermediates. 5 The Jacobe Mannich Variation focused on trapping of the chain extension intermediate with different activated imines. Jacobe used imines that were activated with either a phosphoryl group or a carbamate (Boc) group. Although yields were low, this proved that Mannich reactions could be carried out much like aldol reactions. 2 Future Work • Synthesize the chain extension-Mannich reaction product using the sulfonyl imine Scheme 1: Synthesis of (E)-N-Benzylidene-4 -methylbenzenesulfonamide 3 • Raise reaction yields • Experimentation on the activated imine. • Further investigation into the applications of the sulfonyl imine Scheme 2: Synthesis of Methyl-4 -4 -dimethyl-3 -oxopentanoate 4 Scheme 3: Synthesis of chain extension with sulfone activated imine Compared to the Jacobe study done on phosphoryl imines, the sulfonyl imine activated group allowed the reaction to proceed at a faster rate. The rate was decreased from 48 hours (phosphoryl imine) to 34 hours (sulfonyl imine). The reaction is hypothesized to proceed quicker with the sulfonyl imine because of the electron withdrawing abilities of sulfur. Results and Discussion Zinc- Carbenoid Mediated Chain Extension Figure 1 demonstrates the proposed mechanism of a chain extension reaction. This mechanism is supported through computational work done by Zercher, Egar, and Williams. 1 Pathway B shows conversion to the chain extended material by a direct conversion to the chain extended organometallic intermediate. Pathway A proceeds via a donor-acceptor cyclopropane formation and is found to be the lower energy conversion. Conclusions The synthesis of the sulfonyl activated imine was successful with a 70. 5% yield. However, for the other two reactions the outcome wasn’t the same. Synthesis 2 has proven to be difficult for a number of reasons. The synthesis has worked once, and chain extension reaction was completed. However, the chain extended material was then lost during column purification. Figure 2: 1 H NMR of Methyl-4 -4 -dimethyl-3 oxopentanoate Acknowledgments This work would not have been possible without the help of Dr. Zercher, Deepthi Bhogadhi, Rekha Chhetri, and Kaushik Bala for their help and support in lab. I would also like to thank the Department of Chemistry, UNH, for funding. References 1. Egar, W. ; Zercher, C. K. ; Williams, C. M. A Mechanistic Investigation into the Zinc Carbenoidmediated Homologation Reaction by DFT methods: Is a Classical Donor-Acceptor Cyclopropane Intermediate Involved? J. Org. Chem. 2010, 75, 7322 -7331. 2. Jacobine, A. M. ; Puchlopek, A. L. A. ; Zercher, C. K. , Briggs, J. B. ; Jasinski, J. P. ; Butcher, R. J. Tandem Chain Extension-Mannich Reaction: An Approach to β-proline Derivatives. Tetrahedron 2012, 68, 7799 -7805. 3. Lu, K. ; Ohyum, K. ; Phosphine-Catalyzed [2+4] Annulation: Synthesis of Ethyl 6 -Phenyl-1 -Tosyl 1, 2, 5, 6 -Tetrahydropyridine-3 -Carboxylate. Org. Synth, 2009, 86, 212 -224. 4. Mazzone, J. R. Ph. D. Dissertation, University of New Hampshire, 2011. 5. Spencer, C. Ph. D. Dissertation, University of New Hampshire, 2013. Figure 1: Proposed mechanism of Zinc mediated chain extension 5 Figure 3: 1 H NMR of (E)-N-Benzylidene-4 methylbenzenesulfonamide