HFO‐1234yf as a CF3‐Building Block: Synthesis and Chemistry of CF3‐Ynones

Reaction of low cost, readily available 4th generation refrigerant gas 2,3,3,3‐tetrafluoropropene (HFO‐1234yf) with lithium diisopropylamide (LDA) leads to formation of lithium 3,3,3‐trifluoropropynide, addition of which to a range of aldehydes formed CF3‐alkynyl alcohol derivatives on multigram scale, which were oxidised using Dess–Martin periodinane (DMP) to give substituted CF3‐ynones with minimal purification required. Michael‐type additions of alcohol and amine nucleophiles to CF3‐ynones are rapid and selective, affording a range of CF3‐enone ethers and enaminones in excellent yields with high stereoselectivity for the Z‐isomer. By analogous reactions with difunctional nucleophiles, a wide range of CF3‐substituted pharmaceutically relevant heterocyclic structures can be accessed, exemplified in the simple synthesis of the anti‐arthritis drug celecoxib from HFO‐1234yf in just three steps. Reaction of the inexpensive refrigerant gas HFO‐1234yf with strong base leads to elimination of HF to give an alkynide that can be trapped to form CF3‐ynones, which are highly reactive electrophiles for rapid and clean Michael‐type additions. With dinucleophiles, various CF3‐heterocycles can be synthesised including the blockbuster drug celecoxib.