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41263-B1
Methodological Studies into the Synthetic Preparation of Novel 1,3-Difluoroaromatics using Asymmetric Cyclobutenes
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.
During this past year, the synthesis of 1-hexylcyclobutene was completed by Chris Kane (now a graduate student at the University of North Carolina at Charlotte). Reactions of this compound with difluorocarbene produced approximately a 70:30 mixture of two different difluorobenzenes. The asymmetric compound (compound 2) was determined to be the major product by 19F NMR integrations. Examination of the proposed mechanism leads one to believe that this product ratio is driven by a difference in the steric hindrance encountered by fluoride when removing a proton from the intermediate cyclopentylcation. These two compounds await purification and complete characterization.
The synthesis of 1-phenylcyclobutene was also completed as well By Don Davidson (now in medical school at the Medical College of Virginia). After much effort was expended to synthesis this compound by a ring closing method, it was finally produced starting from cyclobutanone. Phenyl Grignard was added to the cyclobutanone and the resulting alcohol dehydrated with acid. It was determined that stirring a solution of the alcohol in pentane over a mildly acidic water solution was enough to effect the dehydration.
Reactions of this cyclobutene with difluorocarbene generated from Ph-Hg-CF3 produced a total of three compounds with the desired mass to be difluorobenzenes as seen in the mass spectrometer. Further study of this reaction and full characterization of the products is underway.
The majority of the effort by the PI focused on the synthesis of 3-methyl-3-pentylcyclobutene. This compound is important, as it stands to potentially produce a 2-fluorocyclopentadiene when reacted with difluorocarbene. For some time now, we have postulated that just such a fluorocyclopentadiene is an intermediate on the pathway to 1,3-difluorobenzenes produced form substituted cyclobutenes and difluorocarbene. This particular substituted cyclobutene would give us the opportunity to isolate the 2-fluorocyclopentadiene.
The compound 3-methyl-3-pentylcyclobutene was successfully produced adapting a scheme by Baldwin.1 The synthesis began with a reaction between 2-methyl-1-heptene and trichloroacetyl chloride. This produced 2,2-dichloro-3-methyl-3-pentylcyclo- butanone in over 91% yield. Being a new compound, it was fully characterized by 1H, 13C, DEPT, HETCORE and HRMS.
The ketone was then subjected to reduction using lithium aluminum hydride to produce an approximate 50:50 mixture of two diastereomers in 81.4% after column chromatography. The mixture of alcohols was converted under standard conditions to the corresponding mesylates. The mesylate was then reduced to the desired cyclobutene with a sodium in liquid ammonia reaction.
The 3-methyl-3-pentylcyclobutene proved very volatile and as such difficult to purify. It was immediately converted the 1,2-dibromo derivative for purification purposes. Once cleaned, the bromines were removed with a zinc/acetic acid mixture with the cyclobutene being drawn up into a pentane layer. Reactions of this cyclobutene with Ph-Hg-CF3 are pending.
