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A Green Approach to Nitrogen Heterocycles: Application to Biologically Active Compounds Name: Josephine Dimbleby Department: Chemistry Supervisor: Andy.

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Presentation on theme: "A Green Approach to Nitrogen Heterocycles: Application to Biologically Active Compounds Name: Josephine Dimbleby Department: Chemistry Supervisor: Andy."— Presentation transcript:

1 A Green Approach to Nitrogen Heterocycles: Application to Biologically Active Compounds Name: Josephine Dimbleby Department: Chemistry Supervisor: Andy Clark Background  Copper catalysed atom transfer radical cyclisation (ATRC) was carried out for nitrogen heterocyclic synthesis.  Two precursors were synthesized 3a-b from amine 2 to test their ability to undergo ATRC.  Various ligands were selected in combination with copper (II) sulphate and KBH 4 to determine the effect of different conditions on their efficiencies. Methodology Formation of Precursors 3a-b and Cyclisation– Scheme 1 Compounds 3a-b were prepared by benzylation of allylamine to give 1 followed by the addition of either acid bromide 2a or acid chloride 2b to give the target amides. The initial ligand chosen for the cyclisation of 3a-b was tripyridyl amine (TPA). Both compounds 3a-b have free rotation around the central nitrogen atom and two conformational isomers were identified at room temperature with broad peaks observed in their 400MHz 1H NMR. These peaks were sharpened at low temperature. Control igand for ATRC TPA – Tripyridylmethamine (TPA) was prepared and used as a ligand [(L) in Scheme 2]. This gave 100% conversion to product 3a to 4a and so was used as a control to compare the effect of different ligands (L). Control igand for ATRC TPA – Tripyridylmethamine (TPA) was prepared and used as a ligand [(L) in Scheme 2]. This gave 100% conversion to product 3a to 4a and so was used as a control to compare the effect of different ligands (L). Results Additional Product Discovered during ATRC of 3a ATRC was proven feasible with each of the four ligands (L) tested. The best conversions were those obtained when the ligand contained a nitrogen atom (e.g. the control ligand, TPA and 6). Lower conversions were obtained for ligands containing a bidentate phosphorous ligand 7 or two equivalents of a monodentate ligand PPh 3 However, the use of other ligands other than the conventional TPA led to the formation of two different compounds4a and 5a lowering the yield of the desired product.. The ligands used were also either relatively expensive or had to be synthesized in a separate preliminary step which immediately added extra time and cost to the overall synthesis. We can conclude that (TPA) is the best ligand system for this reaction. The spectrum below contains the final product obtained following ATRC using PPh 3 as ligand instead of TPA. References and Acknowledgements Figure 5. COSY NMR of the additional product showing coupling between additional proton present on the carbon where bromine atom should be. Figure 6. NMR obtained before flash chromatography took place. Additional alkyl peaks present from additional product. Conclusion 1. A. J. Clark, G. M. Battle, A. M. Heming, M. Haddleton, A. Bridge, R. R. South, and E. R. M, Tetrahedron Lett, Xs, 2005, 42, 2003– A. J. Clark, D. J. Duncalf, R. P. Filik, D. M. Haddleton, G. H. Thomas, and H. Wongtap, Tetrahedron Lett, 1999, 40, 3807– A. J. Clark and P. Wilson, Tetrahedron Lett, 2008, 49, 4848– A. J. Clark, A. E. C. Collis, D. J. Fox, L. L. Halliwell, N. James, R. K. O’Reilly, H. Parekh, A. Ross, A. B. Sellars, H. Willcock, and P. Wilson, The Journal of organic chemistry, 2012, 77, 6778–88. I would like to thank the Clark group for assisting me with my research throughout the project. Figure 3. Illustrates NMR spectrum of TPA Figure 8. illustrates the structures of ligand 6 and 7 respectively. Ligand Conversi on (%) 12-(2-(diphenylphosphine)ethyl)) pyridine Ethylene bis(diphenylphosphine 744 3PPh TPA100 The table below (table 1) illustrates the conversion values obtained for 4 different ligand at a molar concentration of 20%.  The reducing agent, KBH 4 reduces the copper based catalyst Cu(II)(TPA)SO 4 to its ‘active’ form Cu(I)(TPA)BH 4. The active species has the ability to catalyse the ATRC through abstracting a halogen atom from the precursor, (Scheme 2).  During cyclisation, the catalyst is oxidized back to the inactive Cu(II) form. This allows the transfer of the abstracted halogen atom to the newly cyclised compound via inner sphere electron transfer.  The presence of KBH 4 prevents the need for high catalyst loading concentrations, as it reduce the deactivated Cu(II) species back to its activated Cu(I) form in situ.  A number of different ligands (L) based around phosphorous were used instead of TPA to determine if P based ligands could catalyse the process. However a second product was detected when the reaction was carried out with PPh 3 Analysis of the NMR spectrum containing the crude mixture of 3a indicated an additional product which had the same molecular structure as 3a but had a proton substituted for the bromine 5a atom. Scheme 1. Synthesis of cyclisation percursors 3a-b Scheme 2. ATRC of compound 3a using CuSO 4


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