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Topic: Acid-resistant protecting group for phenol?  (Read 625 times)

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Offline cdeewo

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Acid-resistant protecting group for phenol?
« on: February 14, 2020, 02:54:02 AM »
Hi everyone,
I am trying to perform a Friedel-Crafts acylation on a phenolic compound, and usual reaction conditions involve high temperature (150-230C) in the presence of strong acid. The reaction does not work well with the free phenolic compound so I am now trying to protect the phenol group to see if the reaction proceeds more efficiently. I am therefore looking for a phenol protecting group that could resist harsh acid conditions upon heating. I already tried Bn but the reaction didn't work either, and I am now trying a methyl ether but I was wondering if anyone on this forum had an alternative suggestion?
Thank you!

Offline rolnor

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Re: Acid-resistant protecting group for phenol?
« Reply #1 on: February 14, 2020, 07:54:44 AM »
Can you post the structure?

Offline cdeewo

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Re: Acid-resistant protecting group for phenol?
« Reply #2 on: February 14, 2020, 10:30:03 AM »
The starting material is 3,3'-(dimethylsilanediyl)diphenol. Trying to make some kind of siliconfluorescein derivatives.
My guess is the Si group deactivates the aromatic too much, so maybe protecting the phenol could help...
Happy to hear your thoughts about this!

Offline pgk

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Re: Acid-resistant protecting group for phenol?
« Reply #3 on: February 14, 2020, 01:51:24 PM »
Take a look at these articles below, because it seems that an alkylsilyl group is a very slightly activating substituent on the benzene ring but has essentially no directing effect. Besides, alkylsilanes are not very resistant against strong acids.
Deprotonative Friedel–Crafts alkylation of arylsilanes with α-chlorosulfides, J. Chem. Soc., Perkin Trans. 1, (15), 1953-1957, (1992)
https://pubs.rsc.org/en/content/articlelanding/1992/p1/p19920001953
Cleavage of alkylsilanes by strong acids, Journal of Organometallic Chemistry, 21(2), 321-328, (1970)
https://www.sciencedirect.com/science/article/pii/S0022328X0083630X

Offline pgk

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Re: Acid-resistant protecting group for phenol?
« Reply #4 on: February 14, 2020, 01:51:49 PM »
Why don’t you try a classical, Lewis acid catalyzed Fries rearrangement of the corresponding diphenol diester and try to obtain the desired regioselectivity by temperature control?
In Fries rearangement, the reaction and substituent orientation mechanisms are somehow different than the Friedel-Crafts ones.
« Last Edit: February 14, 2020, 02:28:31 PM by pgk »

Offline rolnor

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Re: Acid-resistant protecting group for phenol?
« Reply #5 on: February 14, 2020, 04:41:58 PM »
Yes, the silane has limited stability. If you protect the phenol it will be less activating? If you halogenate the p-position you can use Pd-chemistry to get the acyl-derivative.
« Last Edit: February 14, 2020, 05:10:26 PM by rolnor »

Offline cdeewo

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Re: Acid-resistant protecting group for phenol?
« Reply #6 on: February 14, 2020, 10:00:30 PM »
Besides, alkylsilanes are not very resistant against strong acids.

I have definitely observed some desylilation depending on acid/temperature, but I did not think the alkylsilane group would be the main issue as the reaction seems to work for making siliconrhodamines:
A general approach to spirolactonized Sirhodamines, Chem. Commun., 2014,50, 14374-14377  https://pubs.rsc.org/en/content/articlelanding/2014/cc/c4cc06178k#!divAbstract
Additionally, the acid-catalyzed method doesn't work either for making carbofluorescein (Si replaced by C).

Why don’t you try a classical, Lewis acid catalyzed Fries rearrangement of the corresponding diphenol diester and try to obtain the desired regioselectivity by temperature control?
In Fries rearangement, the reaction and substituent orientation mechanisms are somehow different than the Friedel-Crafts ones.
If you halogenate the p-position you can use Pd-chemistry to get the acyl-derivative.

Thanks, these are good suggestion for mono-acylation, however making siliconfluorescein requires a double reaction with both aromatic rings, so I'm not sure that the second step would proceed with these methods? I'm unfamiliar with the Fries.
The current best synthetic approach to siliconfluorescein/rhodamines involves di-bromination and lithiation before reacting with anhydride derivatives:
General Synthetic Method for Si-Fluoresceins and Si-Rhodamines, ACS Cent. Sci. 2017, 3, 9, 975-985
https://pubs.acs.org/doi/full/10.1021/acscentsci.7b00247
However this approach limits the nature of functionalizable groups that can be introduced easily, which is why I'm looking for alternative strategies.

Offline rolnor

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Re: Acid-resistant protecting group for phenol?
« Reply #7 on: February 15, 2020, 01:32:27 PM »
Where do you want further substituents? If you can have a protected hydroxy group in this position you can deprotect it after the ringclosure, transform it into a triflate and then apply Pd-chemistry.

Offline cdeewo

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Re: Acid-resistant protecting group for phenol?
« Reply #8 on: February 17, 2020, 02:00:09 AM »
Thanks rolnor, I'm trying to have multiple carboxylic acids on the bottom ring for further functionalization. Sorry, attaching the structure to clarify!

Offline rolnor

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Re: Acid-resistant protecting group for phenol?
« Reply #9 on: February 17, 2020, 04:56:10 AM »
What you are trying to do is not easy. Just the steric hindrance for the tricarboxylic acid makes this difficult. I think the published method with lithiation and reaction with a anhydride is the best way but I am not sure how to get all these carboxylic groups on the aromatic ring. If you try to make them from the tribromoderivative the steric hindrance will be extreme for the first step with the anhydride. How much time do you have?

Offline cdeewo

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Re: Acid-resistant protecting group for phenol?
« Reply #10 on: February 17, 2020, 05:12:40 AM »
I have time, this is kinda my long term side project...
The analogue compound with O instead of Si(Me)2 can be made very easily thought the Friedel Crafts approach. I guess my best shot for making this would be to try the orthoester protection, as was done for introducing two CO2H on siliconfluorescein (General Synthetic Method for Si-Fluoresceins and Si-Rhodamines, ACS Cent. Sci. 2017, 3, 9, 975-985). But more than making specifically this coumpound, I'm generally looking for better approaches for making siliconfluorescein and siliconrhodamine derivatives that would be more tolerant of substitution for further functionalization and not require that many steps... even with this more recent method, the synthesis of derivatives is still quite tedious.

Offline rolnor

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Re: Acid-resistant protecting group for phenol?
« Reply #11 on: February 17, 2020, 01:21:39 PM »
I doubt that there are any "easy" ways to do this, its many functional groups.
I can be wrong.

Offline phth

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Re: Acid-resistant protecting group for phenol?
« Reply #12 on: February 17, 2020, 02:44:58 PM »
I doubt that there are any "easy" ways to do this, its many functional groups.
I can be wrong.

Yeah, it's not easy but it has been done. : the chemoselectivity of requiring 1/4 carboxylates to react is a different story
 https://patents.google.com/patent/US4053517A/en

"Stage A of the process of the invention can for example be carried out by suspending one mole of phloroglucinol and from 1.5 to 2 moles of anhydrous aluminum chloride in ten times the amount of dichloromethane, adding from 1.5 to 2 moles of nitromethane drop by drop while stirring and cooling, and heating the mixture for 5 minutes at from 35° to 40° C, which entails intensive generation of HCl. 1 mole of acid chloride is then added drop by drop and the mixture boiled with reflux for 10 minutes. Decomposition of the resulting complex with ice/HCl, distilling off the methylene chloride and nitromethane, and recyrstallization of the resulting product from water enable the desired product to be obtained in a yield between 70 and 95%, on the average higher than 80%. When straight-chain acid chlorides are used, the yields are generally above 90%."

Offline pgk

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Re: Acid-resistant protecting group for phenol?
« Reply #13 on: February 17, 2020, 03:24:12 PM »
I am afraid that when using strong acids (e.g. methanesulfonic acid), the steric hindrance of the 2-(6-) carboxylic group may inhibit the formation of the intermediate aryl methanesulfonate and/or similar ester. See:
Preparation of 5- and 6-Carboxyfluorescein, Synthesis, (15), 2591-2593, (2004)
https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-2004-829194

Which is not a big problem when using Lewis acid catalysis:
Synthesis of fluorescein from resorcinol and phthalic anhydride
https://labmonk.com/synthesis-of-fluorescein-from-resorcinol-and-phthalic-anhydride

You can rather easily prepare the desired cyclic anhydride from the corresponding benzene polycarboxylic acid:
Facile and Efficient Synthesis of Cyclic Anhydrides from Dicarboxylic Acids, ACS Catalysis, 4(10), 3586-3589, (2014)
https://pubs.acs.org/doi/pdf/10.1021/cs501237p
 
Note that significant amounts of side polymerization byproducts, are not expected because formation of a cyclic anhydride is favored towards an acyclic one:
Preparation of trimellitic anhydride, US Patent 2887497, (1959)
Process for producing trimellitic anhydride, US Patent 3829451, (1974)

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