[UbikPkd]

hi

having some trouble with a synthesis and hoping someone could lend me a hand, or rather a CH2....(sorry!  )

i'm not sure if the names are right....

ethyl 2-oxocyclohexanecarboxylate ----> ethyl 2-(2-oxocyclohexyl)acetate

basically i've got -COOEt attatched ortho on oxocyclohexane and i want to make it -CH2-COOEt instead. ie, slip in a CH2

A friend came to me with this problem and it has me rattled

thanks

[Dan]

Hmmm. Not sure this is the most efficient way, but the first thing that springs to mind is:

(i) H₃O⁺, heat (hydrolysis of ester and decarboxylation)

(ii) HONO - (to give alpha-keto oxime)

(iii) Hydrolyse - (to give the 1,2-diketone)

(iv) Wittig reaction - (with R₃P=CHCOOEt) - I guess there may be issues here with only reacting at one ketone, but a ketone alpha to another ketone should be more electrophilic than the Wittig product, so perhaps in theory as long as you use 1 eq of the ylid you'll be OK.

(v) Hydrogenation

That's pretty lengthy though...

Maybe you could treat with base, say 1 eq NaH, to form the enolate then drop in Ethyl alpha-bromoacetate. Not sure if your enolate will be too hindered to do this Sn2 though. After that you could hydrolyse your esters/decarboxylate. From here re-esterification would give the desired product.

eg

(i) Base, then BrCH₂COOEt
(ii) H₃O⁺, heat
(iii) EtOH, H⁺

I think that approach might be better.

[sjb]

Why not saponify, carefully, as you have a beta-ketoacid floating around, then Arndt-Eistert and realkylate?

http://www.organic-chemistry.org/namedreactions/arndt-eistert-synthesis.shtm

[Dan]

Neat, nice one!

[UbikPkd]

thanks! 

dan, we were thinking the same as your second idea, but we weren't convinced that it was feasable. sjb, that Arndt-Eistert looks pretty neat, thanks!

[sjb]

To be completely honest, I've not convinced my idea would work in vitro. I'd rather try something a bit more reliable first like Dan's idea to at least get some of the material through - the decarboxylation of the keto-acid looks fairly easy to my mind. But, if you're happy with chemistry en papier, it ought to be reasonably OK.

You may be able to miss out the HNO₂ / hydrolysis step and directly oxidise with SeO₂ or similar, but maybe the diketone exists as a enone, especially with the intramolecular hydrogen bond stabilising it..?

S