Enabling organometallic libraries by flow: a tale of two metals

We herein describe our experience with developing flow methods for generating organometallics for their use in C(sp 2 )-C(sp 3 ) couplings in library synthesis. Recent publications have demonstrated that zinc and magnesium organometallics can be generated 'on-demand' using flow chemistry protocols. Our work focussed on extending this capability to sequentially generate varying organometallic reagents which were then immediately telescoped into a coupling step. We present, to our knowledge, the first library synthesised from on-demand Grignard reagents: a 76-member library. We also present a matrix library of 21 Negishi products, both libraries giving a success rate of >90% at the organometallic step. We demonstrate a phenomenon of retention of the organohalide substrates on the surface of the metal. In slug flow this became apparent and needed to be compensated for to achieve success in telescoping of the organometallics with coupling reactions. We also demonstrate here that our efforts to maintain the activity of magnesium in particular, led us to a protocol that can be re-activated from a 'cold start'. This finding itself could have huge utility in maintaining a protocol for the generation of Grignard reagents on-demand. We present, to our knowledge, the first library synthesised from on-demand Grignard reagents: a 76-member library. We also present a matrix library of 21 Negishi products, both libraries giving a success rate of >90% at the organometallic step.