Trauma
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Raspberry Ketone Synthesis
Hello! First time poster here. I've been interested in the synthesis of raspberry ketone (https://en.wikipedia.org/wiki/Raspberry_ketone) from an OTC precursor for a while, and one intermediate I'm looking to make is 4-hydroxybenzyl
alcohol, a.k.a. Gastrodigenin. (https://en.wikipedia.org/wiki/Gastrodigenin)
An idea I recently had was to start with methylparaben, (https://en.wikipedia.org/wiki/Methylparaben)
and reduce it to 4-hydroxybenzyl alcohol using a Bouvealt-Blanc Reduction
(http://www.organic-chemistry.org/namedreactions/bouveault-bl...)
I have heard this particular reaction has been called "messy" on this website. Is this because of low yields / side reactions?
The organic chemistry portal listing for the reaction states that this reaction is similar to a Birch reduction. Does this mean that Lithium could
potentially work in place of sodium for this reaction?
Thank You! Alternatively, if there are better ideas for arriving at 4-hydroxybenzyl alcohol, I would be more than happy to hear them.
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HeYBrO
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probably just easier just to buy 4-hydroxybenzaldehyde from eBay than to try and make and then oxidise the alcohol if thats the route you are going to
try.
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myristicinaldehyde
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I found this, which sounds easier (for 4-hydroxybenzyl alcohol)
30 g of phenol are dissolved in 150 ml (a slight excess) of 10% sodium hydroxide; 35 g (excess) of 40% formaldehyde solution are added, and the
whole allowed to remain at room temperature for 6 days. Then it is neutralized with hydrochloric acid, extracted repeatedly with ether, and the
latter removed on a water bath. If necessary, the residue is steam distilled to remove unchange phenol, and the obtained mixture of ortho and para
benzyl alcohols is shaken with cold benzene until nothing further dissolves. The ortho compound, which is much the more soluble, is thus separated
from the para-isomer. Yield including both compods, 80% theoretical (32 g). o-Hydroxybenzyl alcohol (saligen) forms colorless crystals; m.p
82° C; the p-hydroxybenzyl alcohol (4-hydroxybenzyl alcohol) melts at 112° C.
Systematic organic chemistry, by W. M. Cumming, 72, 1937.
The problem is the wait time.
[Edited on 2016-6-19 by myristicinaldehyde]
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CuReUS
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IIRC,if you do a reimer-tiemann reaction on phenol along with a complexing agent like PEG,you will get the Para formylated compound as the major
product.Then you can reduce that to benzy alcohol like this - http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201200437/ab... - (99% yield)
another way to make p-hydroxy benzylalcohol from phenol ( 70% yield) - "Journal of Chemical Research - Part S, , # 4 p. 200 - 203"
high yielding (98%) reduction of methylparaben-http://www.tandfonline.com/doi/abs/10.1080/00397910008087061
also see this -https://www.sciencemadness.org/whisper/viewthread.php?tid=97...
[Edited on 19-6-2016 by CuReUS]
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CRUSTY
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As HeYBrO said, it would be pretty easy if you just bought p-hydroxybenzaldehyde and then reduced the aldehyde.
Another possible route to 4-hydroxybenzyl alcohol is to synthesize 4-hydroxybenzoic acid via the Kolbe-Schmitt reaction using potassium hydroxide
instead of the traditional sodium hydroxide. It does require a bit of pressure to complete, but I've seen it as low as 2.7 atm (~40 psi),
which wouldn't be too difficult to compensate for if you can rig up the right setup. More info on that here under "p-Hydroxybenzoic acid": http://chempedia.info/page/145214243004003046136048230017255...
After producing the 4-hydroxybenzoic acid, you could use LAH or another reducing agent to reduce the carboxyl of the 4-hydroxybenzoic acid to yield
4-hydroxybenzyl alcohol.
[Edited on 19-6-2016 by CRUSTY]
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Trauma
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Thank you all for your replies! After making the 4-hydroxybenzyl alcohol, I actually would want to oxidize it to the aldehyde for the next step in the
synthesis, so the p-formylation of phenol seems like the ideal reaction to perform here, since it would make things a bit more simple.
The reaction route I am proposing is:
1) aldol condensation of 4-hydroxybenzaldehyde with acetone
2) hydrogenation of the resulting enone to form raspberry ketone
It looks like a reimer-tiemann reaction that forms p-formylated products would be perfect, thank you CuReUS, I'll do a little more research on that.
Even better, it looks like the reaction can be performed using mostly OTC reagents! Spot on!
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morsagh
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How you want to OTC hydrogenate only double bond and don´t reduce ketone? Because ways like urushibara nickel or Zn/AcOH aren´t selective in this
way...
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NitreRat
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The ketone could be converted to an acetal then you could hydrogenate the double bond under basic conditions like a PdCl2/KHCO2 transfer hydrogenation
or possibly NaBH4/MeOH/CuCl reduction.
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Crowfjord
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There is a good writeup in prepublication, here. Also this thread.
One can also analogously make zingerone (a product of ginger) by substituting vanillin for p-hydroxybenzaldehyde.
[Edited on 20-6-2016 by Crowfjord]
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CuReUS
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Quote: Originally posted by Trauma  |
The reaction route I am proposing is:
1) aldol condensation of 4-hydroxybenzaldehyde with acetone
2) hydrogenation of the resulting enone to form raspberry ketone |
one pot method from p-hydroxybenzaldehyde and acetone-http://onlinelibrary.wiley.com/doi/10.1002/adsc.200900902/ab...
| Quote: | | It looks like a reimer-tiemann reaction that forms p-formylated products would be perfect, thank you CuReUS, I'll do a little more research on that.
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I think this was it-https://www.researchgate.net/publication/244564541_Increased...
| Quote: | | Even better, it looks like the reaction can be performed using mostly OTC reagents! Spot on! |
that's true. PEG is sold as a laxative  | Quote: Originally posted by morsagh | | How you want to OTC hydrogenate only double bond and don´t reduce ketone? Because ways like urushibara nickel or Zn/AcOH aren´t selective in this
way... |
http://www.sciencemadness.org/talk/viewthread.php?tid=66545
[Edited on 25-6-2016 by CuReUS]
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Trauma
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I'd really love to give that PEG paper a read, how would I get access to it though? I can't seem to get access through my university.
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Crowfjord
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Here you go:
Attachment: Para-selective Reimer-Tiemann.pdf (124kB)
This file has been downloaded 588 times
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