|Credit: Campbell et al., Org. Process Res. Dev.|
Second, the ketone deoxygenation step, which utilized trifluoroacetic acid (TFA) and triethylsilane, was a liability from a waste disposal perspective. Incineration of fluoride-containing waste is known to corrode waste incinerators and reduces the useful life of incinerator refractory brick. Silicon dioxide which results from triethylsilane incineration leads to particulate agglomeration on the heat transfer media of regenerative thermal oxidizers.If I interpret that correctly, I believe they're saying, "If we decided to scale this reaction up, we wouldn't be able to find anybody to take our waste." A problem, that.
Rather than forming the key imidazopyridazine with the ketone intact and reducing it off, the authors decided to attempt a direct benzylation. After they found that the C3 carboxylate would not couple with 10, they were able to use 4N sulfuric acid to decarboxylate the ethyl ester to arrive at 13, which they subjected to direct benzylation conditions. After a number of attempts at optimization, the authors note that the original conditions were pretty much the best ones, providing them with a 50% isolated yield on 235 gram scale.
I wonder if this is the largest "modern" C-H activation yet performed? I am excited to see more and different examples, as much as I hope that we're still going to be making boronic acids on ton scale for Suzuki reactions for ages to come. All in all, a pretty neat example by the Lilly team -- congratulations to them.
 Campbell, A.N.; Cole, K.P.; Martinelli, J.R.; May, S.A.; Mitchell, D.; Pollock, P.M.; Sullivan, K.A. Org. Process Res. Dev. ASAP. doi: 10.1021/op300344m