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. 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).

  2. Products listed on our website are either in stock or can be resynthesized within a reasonable time frame. 1-dodecyl-2,3-methylimidazolium perchlorate


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