Sciencemadness Discussion Board

Ketalization of Phenol

Illegal Parkinson - 17-4-2021 at 07:32

Based of your theory of organic chemistry,

is it possible to trap the ketal of Phenol using Dean-Stark trap,

e.g. 1,4-Dioxaspiro[4.5]deca-6,8-diene [23783-59-7]

Then this can participate in a cheletropic reaction.

Alternatively, it might be possible to use 3,4-Difluorostyrene (or m,p-Dichloro) with N-Boc Pyrrole directly.

njl - 17-4-2021 at 09:51


is it possible to trap the ketal of Phenol using Dean-Stark trap,

e.g. 1,4-Dioxaspiro[4.5]deca-6,8-diene [23783-59-7]

Probably not. The closest thing I can think of would be the ketal of cyclohexadienone, if that is possible to form.


Then this can participate in a cheletropic reaction.

Alternatively, it might be possible to use 3,4-Difluorostyrene (or m,p-Dichloro) with N-Boc Pyrrole directly.

No idea. Maybe I am out of the loop but what are you referencing?

Illegal Parkinson - 19-4-2021 at 23:02

In the Pfizer patent, he uses an altogether different procedure to arrive at the same compound.

CID:9859681 i.e. U.S. Patent 20,030,236,405.

Illegal Parkinson - 21-4-2021 at 00:39

Apparently, the professor is only just developing the technology very recently.

Deepankeaw, N., Maihom, T., Probst, M., Prasertsab, A., Homlamai, K., Sittiwong, J., & Limtrakul, J. (2019). Phenol Tautomerization Catalyzed by Acid-Base Pairs in Lewis Acidic Beta Zeolites: A Computational Study. ChemPhysChem. doi:10.1002/cphc.201900377

Alternatively, N-Boc Pyrrole & a ketene lamp should work?

zed - 21-4-2021 at 01:18

Haven't really thought of it.

Phloroglucinol can behave like a Ketone.

It can actually be converted to a tri-oxime.

Dean Stark trap? Dunno. Wouldn't think so.

Probably some way to make the material. Why?

Do you have a use for it?

It would have been nice if you provided a direct link.

Pinnick - 21-4-2021 at 11:26

Quote: Originally posted by Illegal Parkinson  
Based of your theory of organic chemistry,

is it possible to trap the ketal of Phenol using Dean-Stark trap,

A dean stark actually only traps byproducts and removes them to make a reversible reaction irreverisble by interfering in an equilibrium. The product in this case has a higher boiling point then water and you want to make a ketal, wich releases water. So the dean stark will trap water, brought over by forming an azeotrope with your solvent and therefore drives the reaction forward.

Quote: Originally posted by Illegal Parkinson  
e.g. 1,4-Dioxaspiro[4.5]deca-6,8-diene [23783-59-7]

I don't think that it is possible to get the ketal from phenol. In general the ketal is formed from the corresponding Aldehyde/Ketone. Depending on the keto enol equilibrium you are able to predict the reactivity of the carbonyl group. Unfortunatly the aromatic system is just too stable, there wont be any ketone present, only the enole form and it therefore won't react with any diol to form the Ketal.

Another problem is the extra stabilization from the ring. Lets just imagine there would be a part of the phenol wich is present as ketone. The way the mechanism works is that an acid will protonate the oxygen of the carbonyl group, resulting in an electron deficiant oxygen and therefore polarizing the carbonyl bond to make a nucleophilic attack on the carbon more easy for the diol. The positive charge can be stabilized by the ring and make the targeted carbon less reactive. The more mesomeric states you can draw the more stable is your compound and you can draw at least 4 in this case. So it seems to be pretty stable on paper. In general, aromatic systems like to be attacked by electrophiles and not nucleophiles.

I really like you Idea on getting a diene to do a cheleotropic reaction, but I think this is not the way to go.

Quote: Originally posted by Illegal Parkinson  

Alternatively, it might be possible to use 3,4-Difluorostyrene (or m,p-Dichloro) with N-Boc Pyrrole directly.

I have no experience with this specific preperation but using pyrrole seems to be rather hard. It is an aromatic system and not just a diene. Doing this reaction in an acidic environment might protonate the pyrrole and will result in the diene by temporarily removing the aromatic system and making the compound more reactive for your desired cyclisation. Acidifying your reaction mixture will destroy the boc group though. Good luck anyways with whatever you plan on doing!

Illegal Parkinson - 21-4-2021 at 18:18

In terms of the actual use for it, I have provided a direct path through to Epibatidine.


It's very easy to set-up using the brand new technology.

zed - 21-4-2021 at 22:21

You are kinda leaving us without background.

Looks like you are exploring the synthesis of some unique analgesics, bearing ring structures similar to Cocaine and/or Fentanyl. Tropinone-like.

Sometimes it is easier to build the new ring, than it is to modify an existing ring.

See the cat; see the cradle.,4-Benzoquinone

If the common di-ketone Benzoquinone could be "bridged" by an amino group, it would put you in the ball-park.

The 5-membered Prolyl-type structure brought to mind another drug of great interest from yesteryear. Worked great! But, I guess somehow the numbers didn't "crunch". PLG AKA MIF1.
Really great at relieving Parkinson's symtoms. But, not orally active. Had to inject it, or perhaps snort it.

[Edited on 22-4-2021 by zed]

[Edited on 22-4-2021 by zed]

njl - 22-4-2021 at 07:02

For clarity, no you can't trap the ketal of phenol with a dean-stark trap for several reasons. First, phenol doesn't have a carbonyl and is incapable of forming a ketal*. Second, the keto form of phenol doesn't exist in significant enough quantities to be useful here. Third, even if it did, that wouldn't have the same properties as phenol.

Now, this makes more sense since you've clarified that you're trying to perform a diels-alder reaction with a 5 membered heterocycle and the styrene (3,4-Difluorostyrene (or m,p-Dichloro) with N-Boc Pyrrole), but what does that have to do with the "ketal" of phenol?

zed - 22-4-2021 at 09:16

Back to Phenol. Phenol is already in "its Enol form", if you were to consider phenol to be a wayward ketone.

Being aromatic in character, we don't think of it that way.

But if you were to react Ketene with Cyclohexanone, you could trap cyclo-hexanone in its Enol form.

In fact, such a molecule exists, free of ketene, as an impurity in commercial Cyclohexanone.

The double bond is shifted away from the Carbonyl function, in some cases.

Fella wrote a pretty extensive paper on 2,5-hexadienols....

[Edited on 22-4-2021 by zed]

[Edited on 22-4-2021 by zed]

zed - 30-4-2021 at 13:13

On further thought, a Cyclohexanone could be "ketalized", in a manner analogous to that sometimes used to produce acetals. Via a halide.

Reaction of the cyclohexanone with Phosphorus Pentachloride, might convert it to a di-halide plus POCl3.

The dihalide is then reacted with 2 parts Sodium Ethoxide, to yield the Ketal.

I'm sure everyone has moved on from this, but I stumbled across an example somewhere in the library.

Might as well mention it.

njl - 30-4-2021 at 15:00

Cyclohexanone is just a regular ketone, it will form a ketal under the conditions commonly used for other ketones (diol/heat/removal of H2O). No need for chlorination.

clearly_not_atara - 30-4-2021 at 15:24

What you can do is a Birch reduction of phenol to alpha-cyclohexenone. This might then form a ketal in ethylene glycol. Then various methods may dehydrogenate the cyclohexene, such as bromination/dehydrohalogenation, allylic bromination/dehydrohalogenation or Hofmann elimination, SeO2 / SOCl2+NEt3, etc.

Illegal Parkinson - 1-5-2021 at 03:16

The only problem with using Phloroglucinol as the starting material is that it is made from trinitrobenzene, a high explosive.

Even assuming that one does find a pathway through to

1,4-Dioxaspiro[4.5]deca-6,8-diene [23783-59-7]

Assuming that this is reacted with

Tert-Butyl Azidoformate; [1070-19-5]

Can this partake in a chelotropic reaction to form the 7-Azanorborn-2-one framework?

Illegal Parkinson - 1-5-2021 at 03:36

E.g. Wu, Q., Hu, J., Ren, X., & Zhou, J. S. (2011). An Efficient, Overall [4+1] Cycloadditon of 1,3-Dienes and Nitrene Precursors. Chemistry - A European Journal, 17(41), 11553–11558. doi:10.1002/chem.201101630

Although, you still have an olefin, as well as 2x protecting groups.

zed - 1-5-2021 at 18:03

7-Azanorborn-2-one framework.

Illegal Parkinson - 4-5-2021 at 00:36

Anyway, I got to the bottom of it now anyway.

After reading Zhang & Trudell's article again: Doi: 10.1021/jo9608681.

Methyl ortho-Bromo-Benzoate is reacted with 2 equivalents of NaOMe to give the ketal.

A cheletropic [4 + 1] reaction is attempted with a suitable nitrene.

Hydrogenation of the olefin to prevent retro-D.A reaction.

Hydrolysis of the ketal to the ketone, & saponification of the ester.

Then lastly, a Decarboxylation step.

Alternatively, I found another procedure to the published methods using ketene technology: Doi: 10.1021/jo01270a009.

That is not necessarily obvious if you aren't provided the answers beforehand.

njl - 4-5-2021 at 04:45

Ok, so you want something like intermediate 5 from scheme 1?


Methyl ortho-Bromo-Benzoate is reacted with 2 equivalents of NaOMe to give the ketal.

This won't happen to a useful extent in an aromatic system.

Illegal Parkinson - 4-5-2021 at 09:09

Yeah but you have 2 strong electron withdrawing groups which would disrupt the aromaticity. Come to think of it, this structure is close to oil of wintergreen.

The same thing happens with Pyrrole is too aromatic, whereas N-Boc Pyrrole can react with suitable dienophiles since the Boc group withdraws electron density causing the pyrrole to behave as a diene.

I wrote to both Trudell as well as Kozikowski to inform them of this new method.

Illegal Parkinson - 4-5-2021 at 09:32

The benzoquinone is another interesting method.

If you form a thioketal, if the olefin tautomerizes to the enol so it is in conjugation with the other olefin.

If it is able to do the TsN: [4 + 1] cycloaddition.

Then the enol should revert back to the ketone carbonyl.

Removal of the thioketal protecting group by catalytic hydrogenation would also work.

Until the brand-new technology it was not formally this easy to make 7-Azanorbornone.

Illegal Parkinson - 4-5-2021 at 10:22

Even supposing the whole thing is bogus, one last attempt is 1,3-Cyclohexadiene [4 + 1] Nitrene cycloaddition gives a 7-Azanorbornene.

Then either a coupling reaction to make epibatidine (see proc for Homoepibatidine),

or some kind of IBX oxidation or a Wacker oxidation gives a ketone.

zed - 4-5-2021 at 16:05

Well, there must be another approach to forming that ring.

Were it a tropane ring, the way is well known.

The Robinson Synthesis, Double Mannich

Succindialdehyde, an Amine, and some form of Acetone Dicarboxylic Acid.

The ring sort of manufactures itself.

Can this perhaps be replicated with Maleic Anhydride or some such material?

There is no Ketone present to activate, or promote decarboxylation, but an anhydride ain't bad.

Succinic Anhydride?

[Edited on 5-5-2021 by zed]

[Edited on 5-5-2021 by zed]

[Edited on 5-5-2021 by zed]

[Edited on 5-5-2021 by zed]

[Edited on 5-5-2021 by zed]

clearly_not_atara - 5-5-2021 at 03:55

Hm, wait. The Birch reduction of phenol or anisole gives the 3-cyclohexenone, not 2-cyclohexenone or it's enol methyl ether. The latter should be easier to ketalize.

So from the Birch reduction of anisole you can ketalize with ethylene glycol, allylic brominate (NBS/hv, conditions) and dehydrohalogenation gives your target.

Alternatively, salicylic acids can be converted to o-quinone monoketals as described in eg:

Illegal Parkinson - 5-5-2021 at 09:27

I found online evidence that salicylic acid can be made to exist in the tautomeric keto form under certain conditions, then it can be trapped as the ketal.

Oil of wintergreen in almost the same.
[4+1] Nitrene Cycloaddition, reduce olefin, saponification & deketalization, decarboxylation.

Illegal Parkinson - 6-5-2021 at 11:05

I found this also, if anybody interested:

Doi: 10.1021/cr0306900

Dr. Thomas R. R. Pettus knows a lot about it. According to him you need to use an oxidant, the tautomerization does not happen using the logic that is used to form a normal regular ketal.

[Edited on 7-5-2021 by Illegal Parkinson]