Wednesday, November 6, 2013

Process Wednesday: when a dilute reaction is better

Credit: Fishman, A. et al. Org. Process. Res. Dev., 2000, 77.
From Organometallics in Process Chemistry [1], an interesting reaction setup to generate a desired
product in a dilute fashion
They found the intramolecular cyclopropanation proceeded best when run at low concentration. To accomplish this while maintaining good process throughput, they slowly added the starting material from a dilution feed tank while distilling the solvent from the reaction mixture to maintain a constant volume. In this manner, [(R)-2] was maintained at low concentration during the cyclization reaction while the volume yield of the process was a reasonable 60 g/L... Halogenated hydrocarbons gave the highest selectivity for the desired reaction, while a temperature above 80°C was needed to effect good conversion in a reasonable time. Rarely used as a solvent, dibromomethane was selected as the optimate balance of these factors. 
This reaction was run at 21 gram scale of diazoacetate with 200 mL of dibromomethane in the original paper [2]; I wonder if scale-up was ever tried? I'd be concerned about maintaining the concentration of the reaction on large scale (apart from the safety concerns with heating a perchlorate salt.)

1. DelMonte, A.J.; Dowdy, E.D.; Watson, D.J. "Development of Transition Metal-Mediated Cyclopropanation Reactions." Topics Organomet. Chem. 2004, 6, 97-122.
2. Fishman, A.; Kellner, D.; Ioffe, D.; Shapiro, E. "Practical Chemo-Enzymatic Process for the Preparation of (1R,cis)-2-(2,2-Dihaloethenyl)-3,3-dimethylcyclopropane Carboxylic Acids." Org. Process Res. Dev. 2000, 4, 77. 

1 comment:

  1. Heating a perchlorate and using a diazo compounds is enough for me to avoid any attempt to scale up such reaction. Not to mention the brominated solvent, a thing that will not earn you any applause from any environmental agency (at least in EU).