(102c) Dirhodium Immobilized Hollow Fiber Flow Reactor for Scalable and Sustainable C–H Functionalization in Continuous Flow

Authors: 
Yoo, C. J., Georgia Institute of Technology
Jones, C. W., Georgia Institute of Technology
Hoyt, C., Georgia Institute of Technology
Rackl, D., Emory University
Liu, W., Emory University
Pimentel, B. R., Georgia Institute of Technology
Lively, R., Georgia Institute of Technology
Davies, H. M. L., Emory University
Dirhodium immobilized hollow fiber reactor for scalable and sustainable C-H functionalization in continuous flow

Chun-Jae Yoo,[a] Daniel Rackl,[b] Wenbin Liu,[b] Caroline B. Hoyt,[a] Brian Pimentel,[a] Ryan P. Lively,[a] Huw M. L. Davies[b] and Christopher W. Jones[a]

aGeorgia Institute of Technology, School of Chemical & Biomolecular Engineering, 311 Ferst Drive NW, Atlanta, GA 30332, USA

bEmory University, Department of Organic Chemistry, 1515 Dickey Drive, Atlanta, GA 30322, USA

C−H functionalization has become an exciting new synthetic strategy that has brought significant innovation into total synthesis and new methodologies for drug development. [1] One particularly useful C−H functionalization procedure has been the C−H insertion chemistry of transition metal carbenes, typically generated from diazo compounds. [2] In recent years, rhodium-stabilized donor/acceptor carbenes have proven to be effective in a wide range of intermolecular C−H functionalization reactions, in which the site selectivity and stereoselectivity are dominated by catalyst control. [3-5] However, there are several critical drawbacks for this chemistry that present potential barriers to application in the pharmaceutical industry at scale. First, the metal carbenes are created by using relatively reactive and unstable diazo compounds, which are potentially explosive and highly toxic. Thus, such reactive compounds are ideally not stored in large quantities on site, and just-in-time syntheses are preferred. [6] The price of the soluble dirhodium catalysts (Rh2L4, L= ligand) is another barrier for industrial applications. Rhodium is a very expensive noble metal and the cost for the synthesis of the ligands for these catalysts also cannot be ignored. To recycle the homogenous dirhodium catalysts, additional separation steps are required and the catalytic activities are often not maintained after recovery and recycle. Thus, new methodologies for maximizing catalyst turnover number (TON) and recovering Rh for reprocessing are needed; one such approach involves immobilizing these catalysts on a support material. [7] In this research, we have developed tandem flow reactors where the reactive donor/acceptor-substituted diazo compounds are synthesized in flow from hydrazones, and immediately convert the diazo compounds in a second, downstream polymeric hollow fiber flow reactor containing supported asymmetric dirhodium catalysts. Enantioselective cyclopropanation and C-H functionalizations are described, giving similar performance as conventional batch reactions.

References

  1. Davies, H. M. L. and Manning J. R., Nature, 2008, 451, 417
  2. Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, R.; McKervey, M. A. Chem. Rev. 2015, 115, 9981
  3. Qin, C.; Davies, H. M. L. Am. Chem. Soc. 2014, 136, 9792.
  4. Guptill, D. M.; Davies, H. M. L. Am. Chem. Soc. 2014, 136, 17718.
  5. Liao, K.; Negretti, S.; Musaev, D. G.; Bacsa, J.; Davies, H. L. Nature 2016, 533, 230.
  6. Rackl, D.; Yoo, C.-J.; Jones, C. W.; Davies, H. M. L.; Lett. 2017, 19 (12), 3055.
  7. Moschetta, E. G., Negretti, S., Chepiga, K. M., Brunelli, N. A., Labreche, Y., Feng, Y., Rezaei, F., Lively, R. P., Koros, W. J., Davies, H. M. L., and Jones C. W. Chem. Int. Ed., 2015, 54, 6470
Topics: