Diazo compounds in continuous flow technology

Doctoral thesis English OPEN
Mueller, Simon T. R.
  • Subject: QD

Diazo compounds are highly reactive carbene precursors which can be used to generate molecular complexity rapidly. However, diazo compounds are highly energetic and dangerous\ud compounds and therefore, their use in large-scale applications remains rare.\ud In this work, the use of continuous flow technology for the safe, efficient and scalable use of diazo compounds is described. By using flow chemistry, diazo compounds were safely generated within small diameter devices and directly used in subsequent reactions without a hazardous isolation of the diazo reagents. This thesis describes five new protocols for the use of diazo compounds. In the first project, ethyl diazoacetate (EDA) was generated safely in flow and used in subsequent aldol addition reactions to aldehydes with high yields (right). The preparation of the organometallic ethyl lithiodiazoacetate species in flow was achieved in the second project and used for the addition to ketones (left).\ud Detailed kinetic and thermal studies on aryl diazoacetates were performed in the third project which yielded a new, multistep continuous flow protocol for the use of donor / acceptor carbenes. Rapid reaction optimisation was achieved using in-line infrared spectroscopy.\ud Purification of the diazo species was performed in flow using in-line liquid / liquid extraction methodology.\ud The fourth protocol entails the rapid assembly of complex lactone-cyclopropane structures of biological interest from diazo compounds in a combination of flow and batch technologies (left). In the final project, the stereoselective preparation of indolines using diazo compounds is discussed (right).
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