[Bru]

I don't understand, aren't carboxylic acids and alcohols already reactive? They form esters, no?

So I'm guessing this wouldn't work, then?

[clarkstill]

I think the more reliable disconnection would be to alkylate a phenylacetic acid derivative with ethyl iodide... the chemistry you are trying to use is "umpolung" for the carbonyl group, i.e. trying to make a carbonyl group electrophilic at the alpha position when it's natural reactivity is to be nucleophilic at this position via the enolate.

[kriggy]

I think if we already found out how tomake the α-bromo acid its easier to alkylate with this. By esterification with diol you run to high possibility of having esterification raction on the other -OH group too.

Since diethylamine is available at Sigma-Aldrich so there is no need to make it from amonia. So you can alkylate the diethylamine witch such compound, which will make the ethanoldiethylamine you want. Why did you chose the acid and then reduction?

[Bru]

Sorry about that accidental reduction, I just forgot to add the C=O by accident.

So, this is what I have, but how do I get my final two "reactants" to form my target molecule through alkylizing the carboxylic acid?

[Rutherford]

Why do you use ethanediol to form the amine? Oxirane would be better.
Don't make the ethyl ester of the acid. The alkyl moiety is too stable. You need something more reactive.

[Bru]

Why do you use ethanediol to form the amine? Oxirane would be better.
Don't make the ethyl ester of the acid. The alkyl moiety is too stable. You need something more reactive.

Sorry, I wasn't sure which compound was being referred to to react with the amine. Coincidentally, we just started learning about amine reactions in class today.

I thought about the ethyl ester of the acid too, it didn't make sense to me to form that.

If I can't do anything more with an ethyl ester, but I still need two more carbons, can't I add ethanediol to my diethylaminethanol (via acid-catalyzed condensation) to form the two extra carbons I need, then react that product with an acyl chloride (I could turn the carboxylic acid into a acyl chloride) like this?:

edit: hold on, I messed up the acyl chloride.

[discodermolide]

I apologise if this scheme has already been suggested:
You need to figure out protecting groups, such as make the phenyl acetic acid ester and alkylate it!

[AlphaScent]

and Disco for the win....

The Hell-Volhard-Zylinski chemistry is in fact not the best way.  A simple enolate addition to ethylhalide is the way to go.  I was stuck in thinking too hard about how to accomplish Friedel-Crafts.

Disco, Clark and Raderford all have better points than I. 

Also, just in principle, Friedel-Crafts will over alkylate too. 

[kriggy]

The over alkylation might be problem. Why Hell-Volhard-Zylinski reaction is not a good idea?

My thought:

I think the raction with oxirade migh be done in one step if excess of oxirane is used. Or not?

[AlphaScent]

As Clarkstill mentioned, may be difficult to have the the alpha carbon center act electophilically.  Since friedel-crafts is electrophilic aromatic substiution.  That is where the umpolung chemistry comes in.  The alpha carbon is acting electrophilically instead nuclephilically, which is its preferred method of reacting being next to a carbonyl and aromatic system.  It has to do with polarization of the molecule.

http://en.wikipedia.org/wiki/Umpolung

It is a concept that I was not completely familiar with until I read more today. 

You may have problems doing that in one step with a base being needed to deprotonate the hydroxy group to again react with oxirane.  Oxirane will react with the hydroxide base in, according to wiipedia, is another example of umpolung chemistry.

The final step needs to be done with the acid chloride of the carboxylic acid.  React it with thionyl chloride.  then you can couple those two quite easily. 

Acid catalyzed esterification may work well here, but acid chlorides just work great.

[Bru]

Alright, after talking to my professor, this is what I have as the final retrosynthesis:



My professor said that I should add the fact that I need to protect the 2-bromoethanol so that it doesn't react with itself, and that I needed to add the deprotonation step  so that the reaction works.

Is there anything else I should be concerned about? If you're curious, I actually used a Grignard reaction with CO₂ to create the carboxylic acid, thanks to my professor's help (He said that creating it the way I had it before was wrong).

[Rutherford]

The over alkylation might be problem. Why Hell-Volhard-Zylinski reaction is not a good idea?

My thought:

I think the raction with oxirade migh be done in one step if excess of oxirane is used. Or not?

I think that excess of oxirane could lead to 1,4-dioxane formation.

[Dan]

Is there anything else I should be concerned about? If you're curious, I actually used a Grignard reaction with CO₂ to create the carboxylic acid, thanks to my professor's help (He said that creating it the way I had it before was wrong).

Your F-C alkylation is unlikely to go smoothly because propyl benzene is much more reactive than benzene - you will get overalkylation of benzene. I think malonate chemistry is a much better (more reliable) avenue to explore for this section of the molecule.

The other side looks ok - I would go for reductive amination of glyoxal with diethylamine though. Also, 2-bromoethanol is cheaper than oxirane - so better to buy rather than synthesise (oxirane is in fact often generated from 2-haloethanols in the presence of base).