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I asked a similar question yesterday. They ask us to suggest a retrosynthesis for 4-ethyl-2,2,5,5-tetramethyl-1,3-dioxane

target molecule

I found this slide in our lecture where a dioxane is synthesized.

another dioxane ring synthesis

If I understand correctly, we could start with diethyl malonate ($\ce{EtOOC-CH2-COOEt}$), then use formaldehyde ($\ce{H2C=O}$) to create the dioxane ring. To add the 4-ethyl group, it seems obvious that we can use a Grignard reagent, so in this case ethyl magnesium bromide ($\ce{C2H5MgBr}$).

What I'm less sure about is how to add the different methyl groups. We could add them by using the same Grignard reagent twice, but I'm unsure if that's what they expect, because the methyl groups won't necessarily be added at the 2,2 and 5,5 positions, right? Is there another way to add the methyl groups or am I missing something? If you have any hint or suggestion, I would really appreciate it

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    $\begingroup$ There are certain pattern you should become familiar with, like a cyclic acetal used to protect a carbonyl, or like here, a dioxane to protect a 1,3 diol. If you can find some retrosynthesis exercises that are challenging but doable for you, you might pick up these patterns. $\endgroup$
    – Karsten
    Commented May 19 at 18:18

2 Answers 2

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We can start the retrosynthesis by disconnecting the two $\ce{C-O}$ bonds of the acetal. This takes us to a diol that can be formed by reduction of a 1,3-dicarbonyl. A methyl group can be added by deprotonation of a 1,3-dicarbonyl at the most acidic site followed my methylation with methyl iodide. In the final step of the retrosynthesis we can disconnect the two extra methyl groups to arrive at the commercially available acetoacetic ester.

Retrosynthesis

Now for the forward synthesis we can form the acetoacetic ester dianion with 2 equivalents of strong base followed by 2 equivalents of methyl iodide. The product can be deprotonated easily by a relatively strong base such as $\ce{NaOEt}$ in ethanol, then the enolate can be methylated at the alpha carbon. The product of this step can be reduced to a diol by a strong reducing agent such as $\ce{LiAlH4}$ ($\ce{LiBH4}$ also works in this case). Finally the target molecule can be obtained by condensation with acetone (under acid catalysis) with the removal of water.

Synthesis

Of course there are a lot of ways to do this, the synthesis above is just one of them

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Start with the commercially available methyl 3-oxo-valerate, also called ethyl propionylacetate vendor here

Dimethylate with potassium carbonate and MeI in refluxing acetonitrile or acetone.

Reduce with LiAlH4 to the diol.

Form the dimethyl dioxane with acetone under PTSA catalysis in Toluene under Dean-Stark reflux.

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