Synthesis of 4'-acetylacetanilide

So for my organic chemistry lab project this semester, my professor gave me acetanilide as a starting material to synthesise p-acetylacetanilide. While the first step was to attempt a Freidel-Craft's acetylation, it obviously didn't work because the AlCl4 complex created with the molecule as an intermediate would deactivate the ring moreso than it already is.

After that fucked up, I got blazed and worked out a series of steps to eventually end up with my product:

acetanilide -->p-nitroacetanilide --> p-aminoacetanilide --> I'm not sure the name of this one, but I'm changing the amino group to an N2 + group --> p-cyanoacetanilide --> using methyl grinard and something else add a methyl group the the C of the cyano and replace the N with an O for the final product

So my professor liked the idea and let me give it a shot. At this point I've definitely made the nitroacetanilide and I'm pretty sure I have my aminoacetanilide from it (I've got to run an IR and mass spec still yet, but the GC showed the reaction went through almost completely). I'm stuck though on the next step. While the organic book gives basic reagents to use for each of the various reactions in this process, I've been using the sci-finder database (scifinder.cas.org) to get specific reaction conditions and reagents for each of the steps so far for journal articles. After looking up the conversion of the amino group to an N2 + group, however, I can't find a specific reaction for the conversion from aminoacetanilide (though I've found reactions for the conversion of the functional group on similar molecules). Anybody who hasn't had the class probably have no idea what I'm talking about, but is anybody a chemist or have any lab experience that could help me out (or some specific journal articles will work as well)? I've put in enough effort that I'm going to get a good grade anyhow, but just for pride I actually want to get this shit to work.

I'm not sure the name of this one, but I'm changing the amino group to an N2 + group

Are you talking about 2,4-diaminoacetanilide? I don't see dinitrogen-acetanilide happening, but maybe I'm wrong?

Edited by Candamile, 14 April 2012 - 11:18 AM.

I was going to try for a 4'-diazoacetanilide salt, and while I THINK it could probably be produced, after looking up the properties of aryl diazonium salts, I think I may go with some other intermediate. Any ideas on how to produce 4'-cyanoacetanilide from 4'-nitro or 4'-amino acetanilide without producing explosive intermediates (or acetanilide, but preferably the other two as I have a nice sample of them left)?

I cant really help you as I'm pretty ignorant in the ways of chemistry but if you don't get your answer here you could try the forums over at Shroomery.org. They have a pretty good chemistry section with a lot of knowledgeable people that could probably help you.

Well I'm not able to really help too much, I have little experience with aromatics as my limited experience has been primarily indole based. But if someone asked me how to acylate an aromatic, I would immediately say Friedel Crafts. If someone then said, but it's a deactivated aromatic!! I'd say, get a better catalyst....

Such as this. These guys do a direct acylation of anilide using Ga(OTf)3 in a mixture of MeNO2-LiCl4, to afford your product, in 93% yield. One step in excellent yield beats doing however many steps you plan on doing, that don't actually sound all that feasible (Grignard not an option! I'm not sure about that diazo chemistry you're toying with, either). Not to say that it's not respectable that you are thinking right out of the box on this one.. just remember that limiting the steps in the reaction is a primary interest in formulating a strategy.

Catalytic Friedel-Crafts Acylation of Aniline Derivatives - Kobayashi - 2001 - Advanced Synthesis & Catalysis - Wiley Online Library


One other idea that I have, is doing a Fries rearrangement of your acetanilide to para-amino acetophenone. You could then acylate the amine with acetic anhydride or acetyl chloride, whatever works best. That's two steps, and I don't see why it wouldn't work. But again, benzene chemistry is not my forte... I don't have a paper to link you to because this is just me speculating, but I'm willing to bet if you do a little bit of google search you will see that this reaction has already been done before.

Well I'm not able to really help too much, I have little experience with aromatics as my limited experience has been primarily indole based. But if someone asked me how to acylate an aromatic, I would immediately say Friedel Crafts. If someone then said, but it's a deactivated aromatic!! I'd say, get a better catalyst....

Such as this. These guys do a direct acylation of anilide using Ga(OTf)3 in a mixture of MeNO2-LiCl4, to afford your product, in 93% yield. One step in excellent yield beats doing however many steps you plan on doing, that don't actually sound all that feasible (Grignard not an option! I'm not sure about that diazo chemistry you're toying with, either). Not to say that it's not respectable that you are thinking right out of the box on this one.. just remember that limiting the steps in the reaction is a primary interest in formulating a strategy.

Catalytic Friedel-Crafts Acylation of Aniline Derivatives - Kobayashi - 2001 - Advanced Synthesis & Catalysis - Wiley Online Library


One other idea that I have, is doing a Fries rearrangement of your acetanilide to para-amino acetophenone. You could then acylate the amine with acetic anhydride or acetyl chloride, whatever works best. That's two steps, and I don't see why it wouldn't work. But again, benzene chemistry is not my forte... I don't have a paper to link you to because this is just me speculating, but I'm willing to bet if you do a little bit of google search you will see that this reaction has already been done before.

I think I'm gonna look a few things up on it and try that Fries rearrangement idea. I had ran across the synthesis of acetaminophen when doing early research for the project but didn't want to 'cheat' and ask for aniline to start with instead of acetanilide. I've got 2 weeks, but if I can find enough on the Fries rearragement with I'll probably be able to get it done.
I had read that same article about the catalytic acetylation when I first started the project, but my professor won't let us work with Li compounds because they (or at least in the case of organic lithium compounds) can blow up rather easily.

I think I'm gonna look a few things up on it and try that Fries rearrangement idea. I had ran across the synthesis of acetaminophen when doing early research for the project but didn't want to 'cheat' and ask for aniline to start with instead of acetanilide. I've got 2 weeks, but if I can find enough on the Fries rearragement with I'll probably be able to get it done.
I had read that same article about the catalytic acetylation when I first started the project, but my professor won't let us work with Li compounds because they (or at least in the case of organic lithium compounds) can blow up rather easily.

You may encounter difficulties doing the Fries rearrangement due to, again, the deactivated aromatic ring. If you have access to a microwave, you may want to consider using it.. Only other problem is that you might get a lot of ortho product as well. So read up on the reaction and find out the best way, good luck!

Lithium has a bad name but it's really nothing that a basic understanding of safety protocol can't handle. I simply could not do chemistry without lithium-based reagents. I guess it's your professors call, though. I would tend to think he just doesn't want to have to buy obscure catalysts

If you could start from aniline, which anyone else would (beyond just buying the material you're trying to make) it would be a walk in the park. That's what made me consider the Fries idea because you're essentially going back to aniline from the amide, and also installing the acetyl group. But I assume that the whole point of this project is to find a way around the deactivation issue. I wouldn't worry too much if you can't make it in two weeks.

Yeah I'm not really to worried about it. From my professor's reaction to what I've done so far, I'm pretty sure he'll give me an A for lab this semester. Still, I want to actually finish it just for pride's sake. At the beginning of the semester he came and asked "(Insert my name here), using this starting material, I've never had a student get past the first step (producing a substituted acetophenone from a substituted benzene reagent to react with a benzealdehyde to produce a substituted chalcone) of the project, but of anyone in lab I think you're the most likely person in here to get it done. You want to take the challenge or try starting from another material?"