I'm confronting a difficult problem and I'm reaching out for help. I am trying to get to sulfonamide (1). Eventually I'd like to try other functional groups on the sulfur side, but tosyl or benzene seems a good place to start
I am starting with 2-Hydroxy-4-nitrobenzaldehyde. Ive done several approaches trying to mildly reduce the nitro without touching the aldehyde, but I think it has been either reduced, not reacted, or oligomerized (unsurprisingly).
The scheme I am attempting now involving a simultaneous diemethyl acetal protection of the aldehyde along with the reduction of the nitro in one step as seen using phoshomolybdic acid in dry methanol, followed by NaBH4 in the same pot in this paper http://www.sciencedirect.com/science/article/pii/0021951789902674
(Joshi et al. Journal of Catalysis 1989). I decided to try to basically "trap" the amine with the tosyl chloride, knowing that the workup would be tough for the intermediate, especially since if I deprotected the aldehyde with acid in the presence of the amine I could get Schiff base oligomers, and that I would be working with a pretty water soluble intermediate in my aminophenol.
I ended up with the acetal protected sulfonate ester with the nitro still intact (rather pure). I only did the reduction for 30 minutes, rotovapped the methanol, added THF and tosyl chloride and letting that stir overnight. Even if I push the nitro to better conversion, I don't feel confident in trying to separate sulfonamide and sulfonate ester without a column (not feasible industrially).
I've tried again, letting the nitro reduction step go for two days and pulled some aliquots, and I can't get much into my organic phase. I'm trying to figure how I can react the tosyl chloride at the amine while leaving the acetal intact so I don't get Schiff base side reaction. Just to be clear, in the end this pretty much has to be a one-pot-ish reaction from start to finish for it to be commercially viable. If anyone sees another, better pathway for this, I'm all ears. Sulfonyl chlorides react with anilines extremely readily in an almost "click" like fashion, so they can handle almost anything else in the pot aside from another very good nucleophile like phenolate. I also would be OK with exploring the sulfonyl being on the benzaldehyde side instead, but I couldn't find a starting material that contributed to that pathway.