41263-B1
Methodological Studies into the Synthetic Preparation of Novel 1,3-Difluoroaromatics using Asymmetric Cyclobutenes
PRF Report
2007-2008
����������� Work in the laboratory on the grant �Methodological Studies� continued with both students and the PI tackling a number of multi-step syntheses to produce a variety of asymmetric substituted cyclobutenes.� These asymmetric substituted cyclobutenes are to be used in reactions with difluorocarbene to see if they too will produce a 1,3-difluorobenzene product. Asymmetric cyclobutenes either synthesized or under synthesis during this past year include 1-phenylcyclobutene, 1-hexylcyclobutene, 1-methyl-2-pentylcyclobutene, 1-methyl-2-phenylcyclobutene, 3-phenylcyclobutene, 3-hexylcyclobutene, and 3-methyl-3-pentylcyclobutene.
����������� This past year Jennifer Bonn (junior undergraduate) worked on making bicyclo[4.2.0]oct-7-ene.� This compound was prepared by adapting the procedure of Baldwin (Scheme 1).1� Once made, the alkene compound was� brominated (due to volatility of the alkene and lack of a prep-GC) purified and characterized.
����������� In 100 mg samples the dibromo compound was debrominated using Zn in acetic acid.� Once done, benzene was added and the acetic acid washed out with water and 10% NaHCO3.� Reactions of the alkene with Ph-Hg-CF3 showed that a new difluorobenzene was in fact produced.� Full characterization of the new molecule is underway.� Further experiments on bicyclo[4.2.0]oct-7-ene with NaCF2ClCO2 are also under way as well.
����������� On other projects Tracy Nichol worked on the synthesis of 1-methyl-2-pentylcyclobutene.� She worked during the past academic year and during the summer of 2008.� Adapting the procedure of Negishi, this molecule has successfully been made in sufficient quantity to allow for reactions with difluorocarbene (Scheme 2)2.� The additional step of bromination, purification of the dibromide and debromination has also been employed with this molecule.� Preliminary results with this molecule (GC-MS and 19F NMR) indicate that another new difluorobenzene has been produced.� Full characterization awaits a sufficient quantity of material.
����������� The PI worked this past summer on the synthesis of phenyl cyclobutene.� Previously, a former student has made this desired molecule in a small scale.� However, yields were low.� The literature procedure was followed to the point of making 1-penyl-1-cyclobutane.3� However, the literature procedure used a very aggressive method of dehydrating the alcohol and ultimately produced only a 5% yield.
����������� Following production of the desired cyclobutanol by addition of phenyl Grignard to cyclobutanone, the alcohol was dehydrated in benzene with p-touenesulfonic acid.� The compound was isolated by a careful vacuum distillation with a glass bead filled column.� The molecule was columned on silica using pentane with the pentane carefully removed using the same glass bead filled column under reduced pressure.� This procedure afforded a 48% yield of the desired phenyl cyclobutene.
1. Baldwin, J. E.; Belfield, K. D. J. Org. Chem. 1987, 52, 4772.
2. Negishi, E. I.; Liu, F.Choueiry, D.; Mohamud, M. M. J. Org. Chem. 1996, 61, 8325.
3. Celebi, S.; Leyva, S.; Modarelli, D. A.; Platz, M. S. J. Am. Chem. Soc. 1993, 115, 8613.
