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I am trying to synthesize 1-(2-amino-4-chlorophenyl)ethan-1-one from benzene. The answer I came up with is that the benzene must undergo nitration first, then halogenation, then hydration for $\ce{NO2}$ to be $\ce{NH2}$, then acylation. But from the readings I've made acylation cannot happen with $\ce{NH2}$. Is there another way to synthesize this to benzene?

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  • $\begingroup$ @Mithoron, sigmaaldrich.com/catalog/product/aldrich/… $\endgroup$ – orthocresol Oct 31 '18 at 21:44
  • $\begingroup$ Well, I overstated it, but even if you get aminoketone, it may react with itself, here two or more molecules could condense especially if catalyst is present. $\endgroup$ – Mithoron Oct 31 '18 at 22:48
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You can synthesize your desired compound from Benzene in the following way.

First, you can synthesize m-dinitrobenzene, and perform selective reduction to have 3-nitroaniline. Now, you can acylate the ring by first protecting the amine group. After acylation you can convert the amide to amine by acidic hydrolysis, diazotize the amine group and perform Sandmeyer's reaction. Then just reduce the remaining nitro group to amine to have your product.

The synthetic scheme is given below,
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  • $\begingroup$ is the acylation of the benzene ring possible with the presence of NO2? $\endgroup$ – hsf Nov 1 '18 at 23:03
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You are correct that acylation will be trouble with the amine there as similar reagents acylate benzene and amines.

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Could this not be used in your favor? Once converted to an amide, the $\ce{NH2}$ is no longer trouble, and it is still an ortho-para director. In this regard the amide is acting as something of a protecting group: it prevents the amine from misbehaving. Hydrolysis to the amine requires strong acid or base are higher temperatures and concentrations. enter image description here There are better amides out there than the acetyl amide for this purpose. The tert-butyloxycarbonyl (BOC) group can be removed with dilute acid. enter image description here

However, if this is more than an academic exercise, please note Mithoron's comment. Amines and ketones react to form imines under the conditions of some of these reactions, so oligomerization of your target compound is likely.

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  • $\begingroup$ I would like to clarify based on what I have understood in your reply. So, benzene must go through nitration first, then halogenation, then hydration to form NH2. Then NH2 must be converted to amide (by what type of reaction?). Then it will be able to undergo acylation then lastly hydrolysis (?) to convert amide back to NH2. Am I correct? Thank you. $\endgroup$ – hsf Oct 31 '18 at 3:58
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    $\begingroup$ Note - your BOC group is removed by Lewis acids such as AlCl3 $\endgroup$ – Waylander Oct 31 '18 at 8:25
  • $\begingroup$ @Ben Norris, When you are doing the acylation in the ring, isn't it preferable for the $\ce{-CO-CH3}$ group to go to the para of $\ce{NHCOCH3}$ moiety (ortho to $\ce{Cl}$) as there is too much steric repulsion. Won't the para product be majorly formed ? $\endgroup$ – Soumik Das Oct 31 '18 at 9:39
  • $\begingroup$ @SoumikDas - You are right! Good catch. I see you have submitted an answer that addresses this issue. $\endgroup$ – Ben Norris Oct 31 '18 at 11:12

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