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MRT - Synthesis with Aryllithium Intermediates

By: Matthias Junkers, Aldrich ChemFiles 2009, 9.4, 16.

Aldrich ChemFiles 2009, 9.4, 16.

Benefit from MRT & Flow Chemistry: cost savings & scaleindependent metal organic chemistry at room temperature.

Organo lithiums formed by the metal halogen exchange reaction of butyllithium with organic halides, are extremely powerful intermediates for the synthesis of a plethora of products. Performed as a batch synthesis, the lithium bromine exchange reaction requires thorough dry ice cooling and extended dosing times. If the exothermic reaction is allowed to heat the batch reactor greater than -60 °C, undesired side reactions like the Wurtz coupling or double lithiation become predominant. This makes scaling up this process very difficult and expensive. Exceedingly cost-intensive cryogenic vessels are needed which are not even available at all in many kilo-lab facilities. Conversion of the process into microfluidics makes it more reliable and scale-independent (Scheme 10).1-4

Scheme 10: Direct conversion of Lithium-organic intermediates in a 2-stage MRT system (403229)

A two-stage set-up with two sequential microreactors is required (Figure 20). In the first microreactor the bromine lithium exchange takes place and the aryllithium intermediate formed is fed directly into a second microreactor where it its coupled to the desired electrophile, e.g. CF3CO2Et as illustrated in Scheme 10. Interestingly, particular cooling is no longer necessary for this reaction sequence as a microfluidic process, as simple wet ice cooling completely suffices. The fast transport of the lithium intermediate from its formation in the first microreactor to the follow-up reaction in the second microreactor effectively protects it from undesired side reactions. Depending on the substrates it is even recommended to carry out one of the reactions at room temperature, to avoid clogging of the micro channels. The procedure described here affords up to 1 kg product in about 8 hours of operation time of the microreactor system.

Figure 20: Two-stage assembly of two Sigma-Aldrich glass microreactors

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  1. Nagaki, A.; Takizawa, E.; Yoshida, J.-I. J. Am. Chem. Soc. 2009, 131, 1654.
  2. Nagaki, A.;Tomida, Y.; Usutani, H.; Kim, H.; Takabayashi, N.; Nokami, T.; Okamoto, H.; Yoshida, J.-I. Chem. Asian J. 2007, 2, 1513.
  3. Gross, T.; Chou, S.; Bonneville, D.; Gross, R.; Wang, P.; Campopiano, O.; Quellette, M.; Zook, S.; Reddy, J.; Moree, W.; Jovic, F.; Chopade, S. Org. Process Res. Dev. 2008, 12, 929-939.
  4. Schwalbe, T.; Autze, V.; Hohmann, M.; Stirner, W. Org. Process Res. Dev. 2004, 8, 440.

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