Illegal Parkinson
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Ketalization of Phenol
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.
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njl
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| Quote: |
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]
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Probably not. The closest thing I can think of would be the ketal of cyclohexadienone, if that is possible to form.
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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.
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No idea. Maybe I am out of the loop but what are you referencing?
Reflux condenser?? I barely know her!
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Illegal Parkinson
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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.
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Illegal Parkinson
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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?
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zed
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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.
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Pinnick
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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.
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.
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!
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Illegal Parkinson
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In terms of the actual use for it, I have provided a direct path through to Epibatidine.
WO1999061443A1
It's very easy to set-up using the brand new technology.
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zed
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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.
https://en.wikipedia.org/wiki/1,4-Benzoquinone
https://en.wikipedia.org/wiki/Pyrrolidine
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.
https://en.wikipedia.org/wiki/Melanocyte-inhibiting_factor
[Edited on 22-4-2021 by zed]
[Edited on 22-4-2021 by zed]
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njl
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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?
Reflux condenser?? I barely know her!
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zed
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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.
https://www.sigmaaldrich.com/catalog/product/aldrich/c102652...
Fella wrote a pretty extensive paper on 2,5-hexadienols....
https://core.ac.uk/download/pdf/76357598.pdf
[Edited on 22-4-2021 by zed]
[Edited on 22-4-2021 by zed]
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zed
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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.
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njl
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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.
Reflux condenser?? I barely know her!
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clearly_not_atara
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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.
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Illegal Parkinson
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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?
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Illegal Parkinson
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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.
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zed
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7-Azanorborn-2-one framework. https://pubchem.ncbi.nlm.nih.gov/compound/7-Azanorbornene
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Illegal Parkinson
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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.
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njl
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Ok, so you want something like intermediate 5 from scheme 1?
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Methyl ortho-Bromo-Benzoate is reacted with 2 equivalents of NaOMe to give the ketal.
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This won't happen to a useful extent in an aromatic system.
Reflux condenser?? I barely know her!
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Illegal Parkinson
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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.
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Illegal Parkinson
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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.
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Illegal Parkinson
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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.
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zed
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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.
https://en.wikipedia.org/wiki/Tropinone
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.
https://en.wikipedia.org/wiki/Maleic_anhydride
Succinic Anhydride?
https://en.wikipedia.org/wiki/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]
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clearly_not_atara
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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:
https://pubs.acs.org/doi/full/10.1021/ja982125y
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Illegal Parkinson
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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.
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Illegal Parkinson
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I found this also, if anybody interested:
https://de.wikipedia.org/wiki/Cyclohexadienone
http://orgsyn.org/demo.aspx?prep=cv5p1092
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]
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