[combatwombat]

All carbons must come from benzene or acetaldehyde

[nielsgeode]

All carbons must come from benzene or acetaldehyde

I count 3 carbon's that do not come from benzene
Acetaldehyde has only 2....

[azmanam]

how efficient does the synthesis need to be?  Is this homework?  Any reagent restrictons (besides sources of carbon)?

I can do it in 8 steps.

[combatwombat]

I count 3 carbon's that do not come from benzene
Acetaldehyde has only 2....

No reagent restrictions, though we are doing aldol reactions right now so that's probably involved.

I started by Friedel-Crafts'ing acetyl chloride to benzene, then hitting it with KMnO4 to make benzaldehyde.

Then, I made acetaldehyde into a Grignard reagent by reducing it with NaBH4 then changing the OH into a Br with PBr3, then treating it with magnesium in /\o/\

Finally, I then reacted that with the benzaldehyde, remade the ketone with PCC, and then eliminated a beta-hydrogen with NaOEt. If I am correct, you'd have this:



Assuming the benzene ring was an appropriate nucleophile to react with the beta carbon, it would react with itself and you'd get the desired product.

Does this sound OK? If so, could I have used H2CrO4 instead of PCC? (my professor always wants us to use the cheaper reagents, and I guess PCC is pretty costly - but I am not sure if it cleaves carbon chains like KMnO4 does).

How did you do it?

[azmanam]

hitting it with KMnO4 to make benzaldehyde.

Aldehydes are way more reactive than just about anything.  KMnO₄ will oxidize it all the way to the acid.

http://www.cem.msu.edu/~reusch/VirtTxtJml/benzrx2.htm#benz9a

eliminated a beta-hydrogen with NaOEt

NaOEt will not eliminate a beta-hydrogen atom.  You'd need a better leaving group than hydride to get to the unsaturation.

we are doing aldol reactions right now

yup, mine involves an aldol condensation.

Assuming the benzene ring was an appropriate nucleophile

Benzene's a pretty poor nucleophile.  The only reason it works in EAS is because you generate such a hot electrophile in situ (R⁺, acylium ion, etc).  The final step will not spontaneously react.

could I have used H2CrO4 instead of PCC

In theory, yes.  But I don't think you have a workable synthesis at this point.

I started with F.C. acylation, too, though.  My 2nd step was also conversion to benzoic acid, but I used the iodoform reaction instead of KMnO₄ (http://www.cem.msu.edu/~reusch/VirtTxtJml/suppmnt3.htm#halfm).  From there we differ.  you're off to a good start, imho.

[James Newby]

I'm very interested in this style of chemistry so i thought id have a go! Some of the reactions will give a poor yield but i think it should work in principle:

1) Benzene to toluene via freidel-crafts alkylation with CH3Cl, AlCl3.
2) Toluene brominated on methyl group using Br2 in UV
3) Acetaldeyde to acetic acid using Cr2O7 then to acyl chloride using SOCl2.
4) Friedel Crafts acylation on brominated toluene should substitute in the ortho and para positions
5) SiMe3Cl in a suitable base to form the enol equivalent.  Removal of the SiMe3 group from the oxygen can produce the 5 membered ring via the alkene and SN2 elimination on the bromine.

So...

Benzene to toluene.
Toluene to phenyl bromide
Acetaldeyde to carboxylic acid then to acyl chloride

friedel crafts acylation of acyl chloride onto ortho position of benzene ring
enol formation using SiMe3Cl or another suitable reagent.
Lone pair on oxygen reforms the ketone, double bond attacks the methyl group eliminating the bromine via SN2.

Potential Problems:

Toluene to phenyl bromide could over substitute
friedel crafts acylation could affect the bromine-carbon bond and give the para product.
The base required in forming the enol equivilent could substitute with the bromine

[azmanam]

Interesting route.  Some notes:

freidel-crafts alkylation with CH3Cl

We are restricted to only using Acetaldehyde as our carbon source.  Can't use methyl chloride.

Friedel Crafts acylation on brominated toluene

We also have an alkyl halide (benzyl bromide). That can also be converted to an electrophile upon treatment with AlCl₃.  Benzyl bromide will likely react with itself.

SiMe3Cl in a suitable base to form the enol equivalent.

I see where you're going with this, and there's nothing academically wrong with the step.  However, there's no need to trap the enolate as the silyl enol ether.  Deprotonation with base is really all that would be needed.


The synthesis looks ok.  The only problem step I see is the F.C. acylation in the presence of a potent F.C. alkylation electrophile.

As to your potential problems, the oversubstitution is likely.  and as long as you use a non-nucleophilic base (LDA), you'll probably be ok in the final step.

[James Newby]

Quote: We also have an alkyl halide (benzyl bromide). That can also be converted to an electrophile upon treatment with AlCl3.  Benzyl bromide will likely react with itself.

This is the step i struggled with. I also thought about a Palladium cross coupling reactioon by having a benzene-halogen bond and adding it to an alkene but couldnt get the number of carbons right.  Could a hydroxyl group be used in place of the benzene, do the friedel crafts acylation, then convert the hydroxyl group to a bromine group via the Appel reaction (PPh3, Br2 or NBS)? This could then self condense with LDA forming the 5 membered ring.

As for making toluene from benzene and acetaldehyde, im stumped! Azmanam could you PM your route to me please?

[combatwombat]

Ugh, I can't believe I tried to use H- as a leaving group. That's what I get for trying to do syntheses while watching the simpsons.

If I make this, could I cleave off the last carbon with KMnO4 (leaving the 3rd carbon as RCOOH)? Or would that only work if it were closer to the aromatic ring?

[nj_bartel]

Pretty sure that'll just take you to ketone.

[macman104]

Chewing off an alkyl group with KMnO4 and hot alkaline solutions to leave a carboxylic acid only works with groups that have a benzylic hydrogen.

[combatwombat]

So, going back to this compound:



Is there no way this could react to form the 3-membered ring? This is the one step I'm not sure about

[aldoxime_amine]

So, going back to this compound:



Is there no way this could react to form the 3-membered ring? This is the one step I'm not sure about

Adding catalytic amount of acid may give it in low yield. Most probably (always?) the resonance stabilised carbocation will form, so formation of a highly strained cyclobutane ring may take place.


My synthesis uses 8 steps, the carbon reduction step being the haloform reaction.

[nj_bartel]

What about chlorinating, then acylating benzene with that substituent you have in your picture, then nitrating, then hydroboration/oxidation, then PBr₃, then Mg, which would hopefully lead to NAS of the chloride.

[azmanam]

convert the hydroxyl group to a bromine group via the Appel reaction (PPh3, Br2 or NBS)?

probably not on an aryl alcohol (a phenol).  The Appel is really only useful for alkyl alcohols.

As for making toluene from benzene and acetaldehyde, im stumped!

My route (not that it's the best or the only way to do it) does not go through toluene.  Hint: I have benzaldehyde as an intermediate in my route.

then PBr3, then Mg, which would hopefully lead to NAS of the chloride.

if I'm following correctly, you add Mg to the alkyl bromide in the presence of the aryl chloride?  You'll likely get insertion without selectivity - that is, you'll get the aryl Grignard as well as the alkyl Grignard.