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I know the malonic ester is probably used to make propanoic acid or some carboxylic acid, and then joined to the methylnitrobenzene. But I just can't figure out what glues to the methyl. I know the nitro can be reduced to amine and bonded to a carboxylic acid, but then what about the ends?

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    $\begingroup$ What are we missing? What other reagents are specified? How many steps? $\endgroup$ – Waylander May 5 '18 at 12:23
  • $\begingroup$ @Waylander It's just another synthetic route question in which reagents provided on the left hand side must be used to synthesize the compound on the right. $\endgroup$ – Carlson Miller May 5 '18 at 12:56
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This is a challenging question as we have so few details.

One method would be to convert the orthonitrotoluene into the benzyl bromide with NBS or another free radical bromination reagent. Then you could react the dimethyl malonate with sodium methoxide in methanol. Next react the sodium salt of dimethyl malonate with 2-nitrobenzyl bromide.

Then filter off the sodium bromide thus formed, next stir it with the product of reacting Merifield's resin with tris-2-aminoethyl amine to scavenge anyunreacted nitrobenzyl bromide. Next subject the mixture to hydrogenation with a palladium on carbon cataylst. This will convert the nitro group into an amine.

Next evapourate it down to form a oil, heat this to make the amine react with the methyl ester to form methanol and an amide. When you are done with this step. Then react it with dilute sodium hydroxide to convert the remaining methyl ester into the sodium carboxylate. Make it acidic again and it will decarboxylate to give you a cyclic amide.

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For the next step I would convert the amide to a thioamide with Lawesson's reagent and then treat the thioamide with rainey nickel to convert it into am amine. Between some of the steps it would be a good idea to purify the intermidates, but this is how I would (off the top of my head) try to make the conversion. I suspect that there will be cheaper ways of making the final product.

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  • $\begingroup$ LiAlH4 or Borane.DMS will reduce the amide. Conditions for the bromination here: patents.google.com/patent/US5092971 $\endgroup$ – Waylander May 5 '18 at 13:06
  • $\begingroup$ Are you sure about the LiAlH4, I am a little wary of it. Have you got a good refernece for it working. Also what do you think of the thioamide route ? $\endgroup$ – Nuclear Chemist May 5 '18 at 13:14
  • $\begingroup$ Yes, I've used LiAlH4 many times to reduce amides to amines. I prefer Borane.dms as the workup is easier. The thioamide route will work but is an extra step $\endgroup$ – Waylander May 5 '18 at 13:51
  • $\begingroup$ Tet. Letts (1999) vol40 3673 for a reduction using 9-BBN $\endgroup$ – Waylander May 5 '18 at 14:03
  • $\begingroup$ Well I tend to be a bit careful about LiAlH4, one of my classmates had a nasty near miss with it. He managed to start a rather nasty fire with it. The thioamide method involves some smelly and toxic things, but it is a bit harder to burn the lab down with Lawessons's reagent. I would also like to use not true raniey nickel but the nickel boron material obtained from NiCl2 and NaBH4. $\endgroup$ – Nuclear Chemist May 5 '18 at 14:07

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