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.
