Optimization of Negishi Cross-Coupling Reactions of Oxime Ethers Sarju Adhikari, Jane Moore, Debra D. Dolliver, Kevin Shaughnessy

Introduction Named after Ei-ichi Negishi who received the 2010 Nobel Prize in Chemistry. Palladium catalyzed cross-coupling reactions. Couple organohalides and organozinc reagents. Create a new carbon-carbon covalent bond.

General Scheme X = Cl, Br or I M = Palladium Ln = Ligand

Negishi Mechanism A simplified route for the reaction of cross coupling of an organozinc halide with an aryl halide is shown the reaction in general proceeds through an oxidative addition step of the organic halide which is the increase in the oxidation state and co-ordination no. of metal center..followed by transmetalation with the zinc compound where there is exhange of ligands and then reductive elimination: to give the coupling product

Scheme Followed X = Cl, Br or I M = Palladium Ln = Ligand While the negishi coupling has been widely used, there has not been many comprehensive studies concerning cross-coupling of imidoyl halides. Herein we report a study of the first palladium catalyzed cross-coupling reactions between N-alkoxybenzimidoyl haludes and organozinc regeants

Synthesis of imidoyl iodide

Reaction GC trace : presence of coupling product along with byproduct as benzonitrile. Product / nitrile / unreacted iodide: 38 / 62 / 0 We did one of the negishi coupling based upon the procedures on a literature where we used …. The success of our reaction was gauged by the ratio of ……………….a failry high yield of the the byproduct

Optimization Yield & byproduct formation . Optimization Metal source, Temperature, Concentration, Ligands, Additives and Imidoyl halides.

Effect of Metal Source and Ligand Entry Metal Source Ligand T/oC Time/hr Product/ nitrile/unreacted iodide 1 No metal source No ligand rt 24 0 / 10 / 90 Our results are based upon the ratio of product ,nitrile, unreacted iodide

Effect of Metal Source and Ligand Entry Metal Source Ligand T/oC Time/hr Product/ nitrile/unreacted iodide 1 No metal source No ligand rt 24 0 / 10 / 90 2 Pd2(dba)3 dppf 11 / 89 / 0 3 P(t-Bu)3HBF4 25 / 75 / 0 4 S-Phos 6 / 94 / 0 5 5 / 95 / 0 6 PPh3 26 / 74 / 0

Effect of Metal Source and Ligand Entry Metal Source Ligand T/oC Time/hr Product/ nitrile/unreacted iodide 1 No metal source No ligand rt 24 0 / 10 / 90 2 Pd2(dba)3 dppf 11 / 89 / 0 3 P(t-Bu)3HBF4 25 / 75 / 0 4 S-Phos 6 / 94 / 0 5 5 / 95 / 0 6 PPh3 26 / 74 / 0 7 50 28 / 72 / 0 8 80 38 / 62 / 0 9 100 52 / 48 / 0

Effect of Metal Source and Ligand Entry Metal Source Ligand T/oC Time/hr Product/ nitrile/unreacted iodide 1 No metal source No ligand rt 24 0 / 10 / 90 2 Pd2(dba)3 dppf 11 / 89 / 0 3 P(t-Bu)3HBF4 25 / 75 / 0 4 S-Phos 6 / 94 / 0 5 5 / 95 / 0 6 PPh3 26 / 74 / 0 7 50 28 / 72 / 0 8 80 38 / 62 / 0 9 100 52 / 48 / 0 10 PdCl2(CNCH3)2 63 / 37 / 0

Effect of Temperature The next thing that we tried was to look for the effect of the temperature. In doing so we found….Diasspointely the ratio of product to nitrile is almost the same as before It was found that even decreasing the reaction temperature to room temperature and reaction period to an hour led to the completion of the coupling reaction It

Effect of Concentration of Metal Source and Ligand

Effect of Additives It is accepted that the primary influece of ligands is towards the oxudative addition and reductive eliminations steps and an addition of additives can influence the transmetalation step of the catalytic coupling cycle..so these additives had little effect on the product / nitrile ratio. Additionally, N,N,NI,NI – tetramethylethylenediamine (TMEDA), which has been used to facilitate some Zn-mediated cross-couplings reactions7, appeared to slow down the reaction, as there was a significant amount of unreacted starting material when the reaction was sampled (entry 3, Table 4)

Effect of ligand We then tried to switch our ligand to a more electron rich phosphine like tris(p-methoxyphenyl) phosphine (Table 5). Unfortunately, this only increased the amount of nitrile formed during the reaction.

Effect of Halides zinc coordinating with the iodide and helping in its elimination to make the nitrile. Since, iodide is easier to remove than other halogens, we thought working with N-alkoxyimidoyl bromide or chloride could slow down the process of nitrile formation.

Effect of Halides Entry Imidoyl Halide T/oC Time/hr Product/ nitrile/Unreacted iodide 1 X = I , Y = CH3 rt 66 / 34 / 0

Effect of Halides Entry Imidoyl Halide T/oC Time/hr Product/ nitrile/Unreacted iodide 1 X = I , Y = CH3 rt 66 / 34 / 0 2 X = Br , Y = H 69 / 16 / 15

Effect of Halides Entry Imidoyl Halide T/oC Time/hr Product/ nitrile/Unreacted iodide 1 X = I , Y = CH3 rt 66 / 34 / 0 2 X = Br , Y = H 69 / 16 / 15 3 X = Cl , Y = H 16 / 7 / 77 4 24 43 / 27 / 30

Conclusion Formation of coupling product and byproduct. Reaction completed within an hour at room temperature. Imidoyl bromide gave the highest product yield. Additional studies are underway to get higher yields on the desired coupling product.

Acknowledgement Dr. Debra Dolliver Dr. Kevin Shaughnessy Bijay Tilak Bhattarai Arjun Pandey Dr. Steven Raders Jane Moore Shaughnessy group NSF-REU University of Alabama NSF-RUI U.A. / SeLU PRF Grant SeLU

Questions Would like to thanks for their supervision, support and comments on the research NSF-REU University of Alabama NSF-RUI U.A. / SLU PRF Grant SLU