[Orgoslave69]

starting with ethyl 3-oxopentanoate, ethyne, benzene, methanol, and any inorganic reagents that you need, please synthesize : 2-methyl-1-phenylpentan-3-one

Ok I have a huge orgo final coming up, and I'm stuck on this synthesis in my practice homework.

Part of the hint for this question says to use the acetoacetic ester synthesis.

Now I have the mechanism for that synthesis in front of me, but I just can't put it all together.

I took the ethyne, added H2/Ni to make into ethene, then used H2O and heat to make it into ethanol, then NaOH to make it into the ethoxide ion which is needed for the ester synthesis. Also, I figured I could just add HBr to the methanol making it into a methoxide, however, can I now just have that attack the starting ester at the most acidic proton (in between the two carbonyls) then simply brominate the benzene (Br2/FeBr3) and use the benzene as the alkyl halide in my acetoacetic ester synthesis?

Help??

[Orgoslave69]

Actually what if I used HBr with a second mole of methanol, making it into CH3Br, then took that and used it with FeBr3 to methylate the benzene, then used Br2 and light to brominate the methyl group?

[frisbee]

The ethyl 3-oxopentanoate is very much like the acetoacetic ester (ethyl 3-oxobutanoate). I think that is what the hint is pointing out. Don't forget that with those syntheses there is usually a step at the end involving H₃O⁺, heat which causes hydrolysis of the ester and decarboxylation.

Your ideas to make methyl bromide and benzyl bromide are good.

"just add HBr to the methanol making it into a methoxide" doesn't make sense - right? That would form CH₃OH₂⁺ not CH₃O^-. If you need to make sodium ethoxide (or methoxide) use the alcohol and sodium metal.

[Dan]

The sequence:

PhH -> PhMe -> BnBr

Logical disconnection for the target, but making toluene from a FC alkylation of benzene is going to be tricky since toluene is so much more reactive than benzene.

Why not go for a FC formylation, with a formyl reagent derived from MeOH, to give benzaldehyde. PhCHO could be a precursor to BnBr or used for a Knoevenagel.

I am struggling to find a use for ethyne - making ethanol to use as a solvent is unnecessary as you have access to methanol. The ethyl ester will transesterify to a methyl ester if methanol is used as a solvent, but that is no problem.

[Orgoslave69]

Well in my notes for acetoacetic ester synthesis, I need 1 equivalent of the leaving group of the ester (In this case ethoxide, which is why I had to synthesize ethoxide ion). Then I also need an R-X, R being the new R group I want attached to make my substituted acetone, and X just a good leaving halide. What I wanna add onto this is a methyl benzene, which is why I used H3PO4 to methylate the benzene, then I'm gonna use the Br2 and light to add one Br atom to the CH3 end, and this is my R-X

[Dan]

Well in my notes for acetoacetic ester synthesis, I need 1 equivalent of the leaving group of the ester (In this case ethoxide, which is why I had to synthesize ethoxide ion).

You don't need ethoxide, you can use any alkoxide in an alcoholic solvent - if the solvent alcohol doesn't match the ester (in this case ethanol would be the matching solvent) then you will notice a transesterification as well as the condensation reaction. It will still work.

Then I also need an R-X, R being the new R group I want attached to make my substituted acetone, and X just a good leaving halide.

Yes I understand the chemistry you are trying to do, I am just suggesting an alternative approach to the target using the Knoevenagel reaction.

What I wanna add onto this is a methyl benzene, which is why I used H3PO4 to methylate the benzene,

There is no carbon in phosphoric acid, how do you propose to methylate benzene with it?

[Orgoslave69]

Whoops, meant to say use MeOH with H3PO4 to methylate the benzene, and while I'm sure the knovenagle reaction would work, I'm required to perform this synthesis via the acetoacetic ester synthesis, and I'm supposed to do it using the reagents given for any carbon chains.

[frisbee]

I think that for this academic exercise the Friedel-Crafts alkylation of benzene using methyl bromide is acceptable (even though in practice you would get some over alkylation). You will need methyl bromide anyway for the second alkylation. As Dan said, there's no problem using sodium methoxide to form enolate since whatever ester you have is going to be gone in the final product anyway.

[asa029]

I love doing synthesis, so I have a solution suggestion (this is not using the acetoacetic pathway, though) and i know this is a LATE posting.

1) Reduction using sodiumborhyrdride (ketone to alcohol)
2) Hydrolysis of ester (base-catalyzed) to acid salt and formation of enol (0n C-2)
3) Conversion of methanol to bromomethane (using either HBr og NaBr/H2SO4)
4) Addition of bromomethane (made in 3) to enole
5) Ester formation (acetic acid, phosphorous acid) to protect the alcohol at C-3
6) Conversion of benzene to bromobenzene (using 1 eq. bromine and iron(III)bromine).
7) bromobenzene to magnesiumbromobenzene (Mg and dry ether or THF)
Reduction of acid (C-1) to aldehyde and treatment of the Grignard reagent (made in 7)
9) Elimination of alcohol at C-1 (either through protonation or through bromo intermediate) to yield conjugated alkene.
10) Reduction of alkene (C-1) to alkane and acetic ester to alcohol.
11) Oxidation of alcohol at C-3 to ketone.