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I am having some trouble finding a proper synthesis route for the following product.

2-(3-azido-3-oxopropoxy)ethyl 2-methylprop-2-enoate

Originally, I was thinking of reacting methacrylic acid with a large excess of ethylene glycol (along with an acid catalyst), in accordance with Fischer esterification, to obtain the following structure.

2-hydroxyethyl 2-methylprop-2-enoate

I subsequently thought of reacting a base such as sodium hydride, NaH, with the alcohol group (removing its 'H') in the hopes of connecting it to the other fragment, which I thought would contain an alkyl halide. However, I was unsure how realistic this step might be due to the following concern: couldn't the hydride ion, which is a very strong base, attack the ester group instead of the alcohol (despite the alcohol having the lower pKa of the two groups)?

To get around this, I attempted a synthesis, pictured below, starting from ethylene glycol. My main concern with this, however, is the potential for intramolecular Fischer esterification instead of, as depicted, the esterification taking place through methacrylic acid and the acid catalyst (e.g., HCl). How valid is this concern? Additionally, please identify any mistakes I may have made in my synthesis and suggest improvements, even if you have a different synthesis route in mind.

enter image description here

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  • $\begingroup$ Your esterification reaction on the second line with methacrylic acid will give an intractable mixture if you don't protect the acid of the propionate group. There will be no selectivity over which group gets esterified $\endgroup$
    – Waylander
    Jul 19, 2020 at 6:40
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    $\begingroup$ Also acyl azide tends to be unstable and rearranges to isocyanate on heating. So, note the temperature. $\endgroup$
    – Nilay Ghosh
    Jul 19, 2020 at 6:55
  • $\begingroup$ here's how you make an acyl azide orgsyn.org/demo.aspx?prep=CV3P0846 $\endgroup$
    – Waylander
    Jul 19, 2020 at 7:25

1 Answer 1

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You're going need a protection strategy to make this work. Here is one possible route:

  1. Start with 2-Chloro/bromo ethanol and protect the OH with a silyl ether, $\ce{SiMe3}$ will do, but requires anhydrous workup.
  2. React the protected haloethanol with the anion of 3-hydroxypropionate-t-butyl ester (commercially available) ($\ce{NaH, NaI, DMF}$) then deprotect the product (mild acidic work up for $\ce{Me3SiO}$ or $\ce{F-}$ for others).
  3. React this product with the acid chloride of methacrylic acid (commercially available). Isolate and purify the product.
  4. Remove the t-butyl ester with $\ce{TFA/CH2Cl2}$, concentrate to dry and form the acyl chloride ($\ce{SOCl2}$, cat DMF). React this with sodium azide to give the product following the first part of this prep (Org. Syn.).
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  • $\begingroup$ For "Step 2" of your answer, I am guessing (correct me if I am wrong) that NaH would react with 3-hydroxypropionate-t-butyl ester to produce the anion; however, it is unclear to me what purposes NaI and DMF would serve and/or how they might come into play. Could you please clarify? $\endgroup$
    – Jonathan G
    Jul 20, 2020 at 1:23
  • $\begingroup$ NaI does an in situ exchange with the halide of the haloethanol to make the alkylation go better, you only need a catalytic amount. DMF is the reaction solvent; as a polar aprotic it is frequently used with NaH $\endgroup$
    – Waylander
    Jul 20, 2020 at 6:18
  • $\begingroup$ Could DMF also be used effectively with NaI for the halide exchange stage? I found out that acetone is often used with NaI for the Finkelstein reaction, but I would like to minimize the number of solvents used. $\endgroup$
    – Jonathan G
    Jul 21, 2020 at 4:20
  • $\begingroup$ It can all be done in DMF. There is no separate step with NaI. $\endgroup$
    – Waylander
    Jul 21, 2020 at 4:32

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