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I am attempting to form a synthetic route to a tetrasubstituted benzene compound. In the scheme, there is a step that requires the formation of a carbon–carbon bond in the C-6 position of a methoxy group in a trisubstituted benzene ring (there is a silyl protected phenol in the 3 position and an alkyl group in the 4 position). Instead of the actual structure I may not disclose, below, I drew a structural prototype in the conversion intended:

enter image description here

I would like to complete the transformation via a Friedel–Crafts acylation because I have heard that anisoles, though not phenols, are suitable for performing Friedel–Crafts reactions. However I have also read that aluminum chloride can be used to demethylate anisole derivatives. I would like to know if I need to worry about demethylating the methoxy group and, more interestingly, if I do not, why?

Buttonwood
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user114654
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    A picture would greatly help. – orthocresol Aug 03 '21 at 16:34
  • One of the advantages of organic chemistry is that we've formulae to depict what is going on / is planned to happen. While the reaction inserted is a mere place holder for to have some idea about the substitution pattern already installed, please adjust the drawing to the structures actually in mind. Learn how to use a sketcher (a survey), or use a service like this, or insert a drawing by hand (in decreasing preference for chemistry.se). – Buttonwood Aug 03 '21 at 17:15
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    This is a very activated aromatic system so you don't need as strong a F-C catalyst as AlCl3. ZnCl2 or TiCl4 are milder and will not demethylate your anisole. – Waylander Aug 03 '21 at 17:20
  • Thank you for the replies, and I am sorry for not providing a picture in the original post. – user114654 Aug 03 '21 at 17:26
  • @user114654 If there not patent application or publication of said structure intended, replace the drawing with one which depicts the situation better. Or camouflage the structure a well enough (different alkyl group, other protecting group, etc) to depict the principle. By the way, $\ce{SnCl4}$ would be an other, less strong Lewis acid for such an activated electron rich system. – Buttonwood Aug 03 '21 at 17:41
  • Hello buttonwood, I believe that the current drawing is satisfactory for my purposes. The only other functional groups present are silyl ethers on the acid chloride. My professor told me that the compounds should be kept secret, so I was vague in my description. I hope you understand. – user114654 Aug 03 '21 at 18:07
  • @ Waylander: At refluxing temperature in toluene, anisole polymer has been demethylated quantitatively according to here. – Mathew Mahindaratne Aug 03 '21 at 18:38
  • If you do not need demethylation, you cannot use $\ce{AlCl3}$ in this reaction. Anisole with o-electron withdrawing substituent will demethylate at room temperature (see here). – Mathew Mahindaratne Aug 03 '21 at 19:07
  • @user114654 If you cannot find suitable F-C conditions I would suggest iodinating. Iodination should occur in the 6 position. You can then do a low temperature Li-Hal exchange and quench with acetyl Weinreb amide to give the required product – Waylander Aug 03 '21 at 19:24
  • @user114654 Fair argument, I slightly edited the question to account for this. – Buttonwood Aug 03 '21 at 20:01
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    Why worry about demethylation; remethylate. If you have access to the free phenol, consider a Fries rearrangement followed by methylation. – user55119 Aug 03 '21 at 20:50

1 Answers1

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I think it is clear that you want to acylate a trisubstituted benzene compound. It is also clear that the ring consists of two oxygen atoms, one of which is methoxy group. That makes the acylation easy because two oxygen atoms make the benzene nucleus more active. Same time, it makes the acylation difficult with $\ce{AlCl3}$, a strong Lewis acid, which is known to demethylate methoxy groups on the ring under special circumstances even at room temperature (Ref.1 and 2). Thus I urge you that you should not use the common and convenient $\ce{AlCl3}$ catalyst in this Friedel-Crafts reaction.

However, there are milder conditions available for convenient acylation of aryl nucleus. One such condition is use of Rare Earth metal trifluoromethanesulfonates (triflates) such as $\ce{Sc(OTf)3}$ and $\ce{Y(OTf)3}$ (Ref.3 and Ref.4). For instance, when 1,3-dimethoxybenzene is reacted with two equivalents of acetic anhydride in the presence $0.2$ equivalent of $\ce{Sc(OTf)3}$ in nitromethane, 2,4-dimethoxyacetophenone is obtained in 89% yield at $\pu{50 ^\circ C}$ within $\pu{4 h}$ (this is awfully similar to your compound, 2-methoxy-5-methyl-4-trisopropylsilylacetophenone).

References:

  1. Zhen-Ting Du, Jing Lu, Hong-Rui Yu, Yan Zu, and An-Pai Li, "A Facile Demethylation of Ortho Substituted Aryl Methyl Ethers Promoted by $\ce{AlCl3}$," Journal of Chemical Research 2010, 34(4), 222–227 (DOI: https://doi.org/10.3184/030823410X12708998015900).
  2. Doo-Jin Byun, Kil-Yeong Choi, and Sang Youl Kim, "Synthesis of Phenol Group Containing Polyethylenes via Metallocene Catalyzed Ethylene-Allylanisole Copolymerization," Macromol. Chem. Phys. 2001, 202(7), 992-997 (DOI: https://doi.org/10.3184/030823410X12708998015900).
  3. Atsushi Kawada, Shuichi Mitamura, Jun-ichi Matsuo, Takehiro Tsuchiya, and Shu Kobayashi, "Friedel-Crafts Reactions Catalyzed by Rare Earth Metal Trifluoromethanesulfonates," * Bulletin of the Chemical Society of Japan* 2000, 73(10), 2325-2333 (DOI: https://doi.org/10.1246/bcsj.73.2325).
  4. Shu Kobayashi, "Method of friedel-crafts acylation of anilides," European Patent Office 2007, EP 1 359 141 B1 (Application number: 02715709.8; International application number: PCT/JP2002/000020; International publication number: WO 2002/055483).
Waylander
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Mathew Mahindaratne
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