Sciencemadness Discussion Board - ethylacetoacetate + bromobenzene = ?

ethylacetoacetate + bromobenzene = ?

joe_aldehyde - 4-8-2005 at 11:53

would a methylene arylation with bromobenzene work on ethylacetoacetate, which yields phenylacetone upon decarboxylation with dilute NaOH?

praseodym - 4-8-2005 at 23:21

Is your main purpose to get phenylacetone?

joe_aldehyde - 5-8-2005 at 00:40

not really, i just wonder if arylation is possible at all (since i'm preparing for a written exam which features retrosynthesis, where compounds with a phenethylamine backbone are often to be synthesized). i've seen a ref. on wiley interscience which says that acetoacetates can be arylated with a palladium catalyst, but i have no access to interscience articles.
anyways, if it was possible, it would be quite a cheap way to ring substituted phenylacetones.

Sandmeyer - 5-8-2005 at 06:17

It is possible via SRN1 mechanism, radical initiators such as UV-light and certain transition metals promote this mechanism. I have been very interested in this route for some time. Using a beta-keto ester followed by decarboxylation is my opinion much better than using enol equivalents as it is usually done in the litterature.

[Edited on 5-8-2005 by Sandmeyer]

sparkgap - 5-8-2005 at 06:22

Wasn't phenobarbital first made through the arylation of a malonic ester before condensing with urea? I can't recall the synthesis offhand, but I think it's similar to what you want...

(edit) My bad, so it wasn't a malonate functionalization synthesis. Thanks, Sandmeyer.

sparky (^_^)

[Edited on 5-8-2005 by sparkgap]

Sandmeyer - 5-8-2005 at 06:39

No, this chemistry was not known back then. They make it from diethyl phenylmalonate (made from benzylcyanide and ethyl carbonate). It is funny you mantion barbiturates, it was so i 'discovered' this route, by thinking if the concepts of Ullmann ether synthesis could be applied to enolates as nucleophiles, then I read it was allready known -- albeit very rescently in my opinion (late 70-ies).

Sergei_Eisenstein - 5-8-2005 at 08:03

Quote:

Originally posted by joe_aldehyde
would a methylene arylation with bromobenzene work on ethylacetoacetate, which yields phenylacetone upon decarboxylation with dilute NaOH?

The "standard alkylation" of ethyl acetoacetate is an SN2 reaction, which already should answer much of your question. Primary alkyl halides work best, secondary tend to give lower yields and tertiary undergo elimination.

I have seen a few references where the alkylation was achieved by using iodoarenes and an appropriate Cu-salt in a polar aprotic solvent. Yields are not superb but OK. The reaction mechanism is different from the SN2 though. Addition of Cu-salts usually make me think that radicals are involved in one way or the other.

Don't ask your teacher. He'll say it isn't possible to arylate ethyl acetoacetate

sparkgap - 5-8-2005 at 08:09

"...Don't ask your teacher. He'll say it isn't possible to arylate ethyl acetoacetate..."

LOL, that was funny but true, Comrade Sergei.

I've had a grand time reading in JOC and JACS about syntheses my Chemistry teachers told me was difficult or impossible. Pretty nifty mechs too.

sparky (~_~)

joe_aldehyde - 11-8-2005 at 23:55

hehe...well, i already made an idiot out of myself in front of the lecture audience by calling a cyano alcohol a cyanhydrine - in the LAST lecture before the exam! you can be sure i got all eyes on me

Sandmeyer - 22-9-2005 at 05:41

Quote:

Originally posted by Sandmeyer
It is possible via SRN1 mechanism, radical initiators such as UV-light and certain transition metals promote this mechanism.

I want to (sort of) correct myself. I said this type of coupling proceeds via SRN1 mechanism, but this mechanism has only been demonstrated to be catalysed by UV light and iron(ii) salts. A pioneering chemist in this area was Bunnett, and in one paper (among many) published on the subject, namely in J. Org. Chem. 1984, 49, 3041-3042. enolate equivalent of acetone is reacted with bromobenzene to give P2P with FeSO4 as catalyst. In my opinion the most interesting part of the paper is that CuCl (which catalyze aromatic nucleophilic substitution between for example diethylmalonate and iodobenzene) was ineffective. So I can speculate that when harder carbanion-nucleophiles are used FeSO4 is a good catalyst, whereas beta-keto esters and other compounds whose carbanion can be stablised by 2 adjecent 'electron-withdrawing' groups (softer nucleophile) the good catalyst is palladium ligands and/or CuI and in that case the mecahnism is not likely to be SRN1.

solo - 22-9-2005 at 08:33

Quote:

13-12 Arylation at a Carbon Containing an Active Hydrogen
BIS(ETHOXYCARBONYL)METHYL-DE-HALOGENATION, AND SO ON

ArBr + Z-CH-Z'------> Z-CH-Z'Ar

The arylation of compounds of the form ZCH2Z' is analogous to 10-104, and Z is as
defined there. Activated aryl halides generally give good results.'8S Even unactivated
aryl halides can be employed if the reaction is carried out in the presence of a strong
base such as NaNH2
186 or LDA. Compounds of the form ZCH2Z' and even simple
ketones187 and carboxylic esters have been arylated in this manner. The reaction
with unactivated halides proceeds by the benzyne mechanism and represents a
method for extending the malonic ester (and similar) syntheses to aromatic
compounds.

........March 5th ed. pg.869

here is the book.....

http://rapidshare.de/files/965524/March_5th_ocr.rar.html

this might be a good refresher as well as a good review for the procedure in question ........solo

[Edited on 22-9-2005 by solo]

Sandmeyer - 22-9-2005 at 08:55

Here is a review I requested rescently on copper catalysed nucleophilic substitution of aryl halogen, on page 1443 carbon nucleophiles are discussed: http://rapidshare.de/files/4359048/tetrahedron163.pdf.html
( thanks to KidCurry for retrieval

)

Eclectic - 22-9-2005 at 12:00

Calcium and magnesium ions are supposed to stabilize the enolate form of ethyl acetoacetate and have some yield improvements over using sodium ethoxide.
( sorry I don't have the reference handy)

Sandmeyer - 22-9-2005 at 13:00

Yes, such measure is nescessery if you want to do for example a C-acylation of enolates since it is likely to occur at oxygen too. Hence, using magneziumalkoxide (rather than Na, Li, K) as a base to deprotonate say 1,3-dicabonyl compound gives only C-acylation. The magnesium enolates are only nucleophilic at carbon as magnesium bonds so well to oxygens rendering them non-nucleophilic by neutralizing the negative charge and oxygen anion nucleophilicity is driven by charge rather than homo-lumo overlap. But to use Mg-enolates for C-copuling is only nescessery with hard electrophiles (e.g acid chlorides/anhydrides) and I don't think it will improve the yield in aromatic nucleophilic substitution as 'side products' resulting from the substitution by oxygen have not been reported in the papers i have read. I like Cu a lot, it is poor mans palladium, and it works for some couplings where palladium fails due to poisioning.

[Edited on 23-9-2005 by Sandmeyer]