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I am trying to design a proper synthesis route for phenylpiracetam.

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I am thinking a good starting material would be styrene or benzaldehyde. Here is my proposed route.

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Is there a better method? Please identify any mistakes I may have made in my synthesis and suggest improvements, even if you have a different synthesis route in mind.

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This is a reasonably sound route. I have some observations:

The prep of nitrostyrene from benzaldehyde is well known, it is best to use freshly distilled benzaldehyde. Here are the conditions from org syn prep.

The sidechain can be added by treatment of the phenylpyrrolidine with $\ce{NaOMe/MeOH}$/Methyl chloroacetate then heating with $\ce{NH3/MeOH}$ (patent).

You are better off reducing the nitro group at the diester stage as it will spontaneously cyclise to the pyrrolidine. On hydrolysis it will then decarboxylate. In my experience, hydrogenation of alkyl nitro compounds does not give good yields. $\ce{Al/Hg}$ amalgam is better. Sodium hypophosphite /phosphinic acid with cat. 5% Pd/C in water/THF and ultrasound was recently reported here as an efficient method for reduction of alkyl nitro, and the paper contains an example of spontaneous cyclisation of the product amine onto a methyl ester.

A synthesis of phenylpiracetam is described here in this patent.

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  • $\begingroup$ May I add the Al-Hg "as is", or should water and/or a solvent such as THF be present alongside Al-Hg before the amalgam is reacted with the nitro compound (after the Michael addition of dimethyl malonate)? $\endgroup$
    – Jonathan G
    Jul 25 '20 at 23:56
  • $\begingroup$ Additionally, after the cyclization, how would the H₃O⁺/Δ step only affect the ester but not the amide in the ring? If this would necessitate a lengthy answer on your end, I can start a new thread with this question. Also, isn't an application of heat (Δ) or water required for the spontaneous cyclization to occur? I did some research and apparently esters can react with amines in, e.g., water, heat, and NH4Cl/Δ (though I am not sure what the side products would be for the third example). $\endgroup$
    – Jonathan G
    Jul 26 '20 at 4:14
  • $\begingroup$ Al/Hg needs a protic solvent, EtOH is good. Cyclic amides are difficult to hydrolyse under acid conditions so I think you will achieve adequate selectivity over the methyl ester. Intramolecular cyclisations to form amides go readily, heating the reaction mixture after the Al/Hg reduction will make sure. $\endgroup$
    – Waylander
    Jul 26 '20 at 7:02
  • $\begingroup$ Would using Zn, Sn, or Fe with an acid (e.g., HCl), instead of Al/Hg amalgam, be a valid option too? $\endgroup$
    – Jonathan G
    Jul 27 '20 at 3:00
  • $\begingroup$ Zn/acid reduction of aliphatic nitro gives the hydroxylamine. I have not seen Sn or Fe used effectively. Pyridine zinc borohydride is reported as a good method, but I have not used it. onlinelibrary.wiley.com/doi/abs/10.1002/jccs.200300040. Sodium hypophosphite/phosphinic acid and 5%Pd/C in water/THF looks like a good method pubs.rsc.org/en/content/articlelanding/2013/gc/… $\endgroup$
    – Waylander
    Jul 27 '20 at 6:52

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