[Dan]

I was wondering whether the sulfonamide activates it. The sulfonyl side is definitely electron withdrawing, I'm not sure how I would characterize the nitrogen side

According to this review (a handy resource), σ_p = 0.01 for -NHSO₂Ph (Table 1, entry 428).

So it shouldn't activate or deactivate the phenol (much).

[wildfyr]

So what do you guys think of this pathway then:

Excess 4-aminophenol+tosyl chloride with 1.1 eq TEA in THF, wash with weak acid to get unreacted aminophenol and TEA out, wash with bicarb to get any tosic acid out.

Take sulfonamide product and Do a Duff reaction. Add to 2 equivalents of hexmethylenetetramine in refluxing acetic acid for a few hours. Lower temp to 70°C, Add aqueous 6M sulfuric acid, and get it back up to reflux for a few more hours. Cool down, add EtOAc and extract. If some starting material is left I can use the bisulfite trick to push it back and forth between the water and organic layers to purify. I don't expect to get any bi-substituted materials since the first aldehyde should sufficiently deactivated the ring.

[rolnor]

I would check with TLC or LC/MS if the Duff reaction is working before workup, othervise sounds good. Perhaps you can find any recipe in the literature also as guide.

[Dan]

Excess 4-aminophenol

Start with 3-aminophenol!

[Dan]

Also, I would not be very confident about the Ts group surviving refluxing 6M sulfuric acid. I remember now a colleague who struggled with a formylation reaction via Duff and Vilsmeier-Haak but eventually got nice results with Reiche formylation. Not sure how practical that would be on scale or the substrate scope, but maybe worth a look.

[wildfyr]

Why would you go with 3-aminophenol? the 4 allows me to block the para position and ensure the best regioselectivity.

[Dan]

Why would you go with 3-aminophenol? the 4 allows me to block the para position and ensure the best regioselectivity.

Because the N and O are meta to each other in the product, not para - wouldn't 4-aminophenol give you 2-hydroxy-5-(sulfonamide) benzaldehyde (i.e. not your target)? Or have I misunderstood something?

[wildfyr]

I actually don't care too much at this point about the substitution pattern. It could be something worth investigating, but this is for an application in a polymeric material where I don't think it will matter. I'd rather block the para position and simplify synthesis. My first pathway was just based on the starting material I had.

[phth]

Hey guys,
I've made and isolated the dimethylacetal protected 2-hydroxy-5-nitrobenzaldehyde. I've tried reducing it with Na₂S₂O₄ in ethanol/water at 55°C. Within minutes the solution turns bright red. At the end, I get red solid only soluble in water (perhaps sparingly soluble in highly polar organics), and nothing in the organic layer of an EtOAc extraction. NMR shows a little aryl junk, and IR isn't very helpful either. I'm suspicious that I'm basically making a diazo dye of some kind, but I wouldn't expect it to be only water soluble. Any ideas what I'm making, and perhaps another neutral or basic way to reduce nitrobenzene derivs to anilines?

Yes, it is a water soluble diazo dye that is an pH indicator (yellow low pH, red neutral).  The reducing agent being too weak/slow is the problem.  The dyes are suppressible, but not wen the concentration of the nitrosyl is too high.

[wildfyr]

I am going to try to go with the hydroxyl benzene (tosyl) sulfonamide, then formylate it with the Rieche conditions (TiCl4, dichloromethyl methyl ether). Seems to be the most mild and modern condition of those I've found.

[phth]

I am going to try to go with the hydroxyl benzene (tosyl) sulfonamide, then formylate it with the Rieche conditions (TiCl4, dichloromethyl methyl ether). Seems to be the most mild and modern condition of those I've found.

Well, Im sorry I couldn't help you. That nitro reduction is a motherf*#$&@ of a reaction best avioded.  Good luck Wildfyr.

[wildfyr]

@Phth
No sweat, if I didn't produce some piles of brown junk, would I even be doing synthesis?