Sciencemadness Discussion Board

Synthesis of Phenylacetylcarbinol by Alkyne Hydration and Subsequent Enamine formation

Dope Amine - 2-2-2016 at 04:11

Input on the following is greatly appreciated... ;)

1. Firstly, in the hypothetical hydration of 1-Phenyl-2-propyn-1-ol (H2SO4, HgSO4) it is hoped that the yielded product would be 1-hydroxy-1-phenyl-propan-2-one (phenylacetylcarbinol, PAC). BUT, the concern is that given this product is an alpha-ketol it might possibly isomerize to 2-hydroxypropiophenone (2-HPP) in the acidic reaction solution IF 2-HPP happens to be the more thermodynamically favored alpha-ketol arrangement. If this is the case then heating the hydration reaction would increase the isomerization to the thermodynamically favorable product while running the reaction cold (if possible) would hopefully reduce isomerization...

2. The next item of interest would be to react PAC with a secondary amine such as piperidine in order to form an enamine (likely with the help of mol. sieves or azeotroping). But this product would then be an enol so it would likely have to rearrange to the keto tautomer. No, I'm not researching cathinone analogues (especially not one that would be a pharmacological dud). Before anyone gets excited about any other N-substituted cathinones they should realize that condensation with ammonia or a primary amine will make an imine which wouldn't set up the enol situation as outlined here. Besides, the starting material is too expensive to be worth bothering with anyway. Assuming things went as proposed, my next step would be to reduce the ketone to a racemic phenylpropanolamine analogue (again just a coincidence).



Intelligent input is greatly appreciated! THANKS!!!

phenylacetylcarbinol-enamine2.jpg - 68kB

zed - 2-2-2016 at 14:29

Ummm. Yesterday, I saw a mention of producing ephedrines directly, by the action of an amine upon a propenylbenzene epoxide. No reference to yield.

The epoxide is not especially difficult to produce. Alas, propenylbenzene....doesn't seem to occur in nature.

Skilving - 25-2-2016 at 17:16

HPP will definitely be your major product pretty much no matter what you do due to resonance stabilization. But you should be able to go from HPP to your desired product by performing an alkylation and pushing product towards water formation (acetic anhydride?).

CuReUS - 26-2-2016 at 03:45

Quote: Originally posted by Dope Amine  

BUT, the concern is that given this product is an alpha-ketol it might possibly isomerize to 2-hydroxypropiophenone (2-HPP) in the acidic reaction solution

actually,you should be more worried of this rearrangement,temperature control won't stop this
https://en.wikipedia.org/wiki/Meyer%E2%80%93Schuster_rearran...
the alpha ketol rearrangement is acid,base or heat induced.Because of this reason and the rearrangement mentioned above,the only way left is that you have to protect the OH,and making the benzyl ether is the only amateur friendly way,IMHO
the protecting group can be removed later by reduction
Quote:
Can anyone please comment on the typical reaction temperature for hydrations of alkynes (H2SO4 + HgSO4)?

different books tell different tempertures.One book says 57'C while another says 60-65'C
Quote:
Which alpha-ketol is more thermodynamically favorable, PAC or 2-HPP?

i would say 2-HPP
Quote:
The next item of interest would be to react PAC with a secondary amine such as piperidine in order to form an enamine (likely with the help of mol. sieves or azeotroping). But this product would then be an enol so it would likely have to rearrange to the keto tautomer

Hmmm,there is a chance that a keto-enol tautomerisation might occur,all the more reason to use a protecting group ;)

[Edited on 26-2-2016 by CuReUS]

clearly_not_atara - 26-2-2016 at 04:19

There are unconventional catalysts that will accomplish this reaction without acid:

http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01... (gold)
http://pubs.acs.org/doi/abs/10.1021/ja310282t (cobalt)
http://onlinelibrary.wiley.com/doi/10.1002/cctc.201400071/fu... (cobalt * salen, particularly nice)

Salen is a not-too-difficult introduction to ligands for someone who doesn't have much experience with them. Ethylenediamine is here:

http://www.sciencemadness.org/talk/viewthread.php?tid=4282

and salicylaldehyde is a classic.

CuReUS - 26-2-2016 at 05:52

sorry to rain on your parade atara,but I don't think you read my post carefully, alpha ketol rearrangement is HEAT INDUCED
keeping that in mind , your cobalt-porphyrin and cobalt-salen will not work because both need 50-80'C for quite sometime (5-20 hours).Also the salen method needs H2SO4 as co-catalyst and acidic conditions are required in the Co-porphyrin method in some cases

the gold reference is the only promising one out of the three,but I have a feeling that there might be a reaction between the R-AuCl and the OH group unless the OH is protected.

while doing research on the meyer schuster rearrangement,I realised that it could be catalysed by base as well.
In that case,my previous suggestion of using benzyl ether will not work since it uses base in the protection step.Even if NaH did not cause the rearrangement,using benzyl bromide is going to release HBr ,which would.
in fact no protection group that I know of fulfills the requirements (no acid or base in the protection or deprotection step,no acidic or basic side products during protection) to prevent the MS rearrangement.
This is quite a difficult problem :(

[Edited on 27-2-2016 by CuReUS]

Dope Amine - 27-2-2016 at 05:06

Wow! I so appreciate all of the great replies. For what it's worth, all of my subsequent reading has indicated that PAC is more thermodynamically favored over 2-HPP. In addition to information indicating this, there's also an Alpha-ketol rearrangement wikipedia page which discusses the rules for acyloin rearrangements and the applicable rules all point to PAC being preferred. The main concern in industry is the isomerization of L-PAC to D-PAC, but that's got nothing to do with my goals.

CuReUS, I didn't even think about the Meyer–Schuster rearrangement being an issue. Thanks! I would love to know exactly how acidic and vigorous the conditions are typically for that because it doesn't seem to be a clearly selective reaction. Check out this abstract from Org. Biomol. Chem., 2009,7, 4149-4158 and I think you'll get the gist. Getting hands on the actual article would be key though:

"The Meyer–Schuster rearrangement is the conversion of propargyl alcohols into α,β-unsaturated carbonyl compounds via a formal 1,3-hydroxyl shift and tautomerization. The major challenge associated with the Meyer–Schuster reaction is that of selectively promoting the desired rearrangement over the myriad other reaction pathways available to propargyl alcohols. This Perspective Article features recent advances in the Meyer–Schuster reaction, including several demonstrated techniques for improving the scope. Strengths and weaknesses of each technique are discussed, and outstanding problems that warrant further study are highlighted. The primary motivation for research and development of the Meyer–Schuster rearrangement is as a means of preparing α,β-unsaturated carbonyl compounds as part of a two-stage olefination strategy."

The 3 most common alkyne hydrations (non-exotic catalysts, etc.) are purely sulfuric acid which requires elevated temps, sulfuric and HgSO4 catalyst which likely requires no heat, and lastly formic acid, which may need heating or possibly not. Maybe using a weaker acid such as acetic acid and just a drop of sulfuric acid could be helpful by creating and protonated acetic acid species which might be more selective in action. But my bet is on using the mercury catalyst with with a minimal amount of sulfuric, hoping that the mercury will help facilitate my desired reaction over the others.

Thanks for everybodys kind help on this mental excursion! If I could figure out some good identification spot tests then maybe I'd just run some small test batches. The nMR testing would make things a bit pricey though...

CuReUS - 28-2-2016 at 03:29

Quote: Originally posted by Dope Amine  
all of my subsequent reading has indicated that PAC is more thermodynamically favored over 2-HPP.

that is very surprising :o, could you explain how ?
Quote:
The 3 most common alkyne hydrations (non-exotic catalysts, etc.) are purely sulfuric acid which requires elevated temps, sulfuric and HgSO4 catalyst which likely requires no heat, and lastly formic acid, which may need heating or possibly not

just H2SO4 ? I thought the Hg catalyst was essential in this reaction . The HgSO4 method needs 60-65'C to run
could you post the reference for using formic acid ?

Dope Amine - 29-2-2016 at 00:02

Originally alkyne hydrations were just sulfuric acid. It was later discovered that mercury could catalyze the reaction.


Alpha-ketol rearrangements: According to the "Favorskii rule," an empirical guideline with numerous exceptions, products with the carbonyl group adjacent to a methyl group or distal to a phenyl group are favored over the corresponding isomers. PAC is the product with the carbonyl group adjacent to a methyl AND distal to a phenyl group, and therefore favored over 2-HPP. Colard, P.; Elphimoff-Felkin, I.; Verrier, M. Bull. Soc. Chim. Fr. 1961, 516.



With regard to formic acid:
The researchers found that dry formic acid hydrated alkynes at room temperature without any need for a transition metal catalyst. It supplies H2O and gives off CO.

http://pubs.acs.org/doi/abs/10.1021/jo00008a058

http://pubs.acs.org/doi/abs/10.1021/jo00078a023

They say that oxygenated alkynes are resistant and do require a catalyst though. When they say "oxygenated" do they mean ketones, alcohols, ethers... all of the above? I wish I could see the subsequent pages for examples.

halogen - 29-2-2016 at 01:32

Not maybe relevant, but your phrasing "It was later discovered that mercury could catalyze the reaction." made me think what else could, and lept to mind the thought 'why can't silver?'

http://onlinelibrary.wiley.com/doi/10.1002/aoc.2918/abstract

The silver catalysis towards the hydration of terminal alkynes is explored using Silver(I) triflate (AgOTf). The reaction leads to the formation of only Markovnikov addition product with excellent yield.

So there you go. Not everybody wants a cumulative neurotoxin.

CuReUS - 29-2-2016 at 06:01

Quote: Originally posted by Dope Amine  

Alpha-ketol rearrangements: According to the "Favorskii rule," an empirical guideline with numerous exceptions, products with the carbonyl group adjacent to a methyl group or distal to a phenyl group are favored over the corresponding isomers. PAC is the product with the carbonyl group adjacent to a methyl AND distal to a phenyl group, and therefore favored over 2-HPP.

wow,then this must be the biggest trick question of the decade.I asked a lot of people which one they thought was more stable and everyone said is was 2-HPP.

good references for the formic acid hydration
Quote: Originally posted by Dope Amine  

They say that oxygenated alkynes are resistant and do require a catalyst though. When they say "oxygenated" do they mean ketones, alcohols, ethers... all of the above? I wish I could see the subsequent pages for examples.

yes,and unfortunately your alcohol is similar to those examples,so you would have to use a Ru catalyst,which completely spoils the beauty of the formic acid method :(

but what about which protecting group to use ? the thought of it is giving me heartburn :(

[Edited on 29-2-2016 by CuReUS]

CuReUS - 1-3-2016 at 06:23

the formic acid method is amazing.I wonder why no one mentioned it before
I was thinking about it and a thought entered my mind
what would happen if instead of formic acid, formamide was used along with a reducing agent like NaBH3CN or the formamide was itself used to do a one pot reduction of the enamine formed ? (If the enamine or the imine forms at all,that is).It might not be possible to use NaBH4 as it ignites spontaneously when it comes in contact with DMF,so it might do the same with formamide.
https://en.wikipedia.org/wiki/Sodium_borohydride#Safety
(I hope others don't take this in a bad way,I just want to discuss the chemistry since its so interesting ,and drugs are not the only amines out there.)
A method already exists to convert terminal alkynes to amines,(they use NaBH3CN to reduce the imine formed) but it needs a titanium catalyst.If this works ,it could be an easy way to convert alkynes directly to amines.
http://pubs.acs.org/doi/abs/10.1021/ol035653%2B

[Edited on 1-3-2016 by CuReUS]

Dope Amine - 12-1-2018 at 10:32

halogen, I never thanked you for providing that silver triflate idea and paper. I was thrilled to try a reaction that didn't warrant such paranoia upon work-up. Unfortunately, it doesn't work with propargyl alcohols like 1-Phenyl-2-propyn-1-ol because it generates a Meyer-Shuster rearrangement product and other crap. For whatever reason the HgSO4/H2SO4 reaction doesn't have that problem.

I should also mention (in response to CuReUS's comment) that phenylacetylcarbinol is actually the more stable structure. 2-HPP rearranges to PAC (see this PAPER for proof).

[Edited on 12-1-2018 by Dope Amine]

Sigmatropic - 12-1-2018 at 11:30

You might be interested in this method. Slightly different starting materials, similar products. http://www.organic-chemistry.org/abstracts/lit4/214.shtm

Dope Amine - 12-1-2018 at 11:36

Quote: Originally posted by Sigmatropic  
You might be interested in this method. Slightly different starting materials, similar products. http://www.organic-chemistry.org/abstracts/lit4/214.shtm


Thanks. I actually just posted that paper in another thread here.

clearly_not_atara - 12-1-2018 at 12:04

Quote:
sorry to rain on your parade atara,but I don't think you read my post carefully, alpha ketol rearrangement is HEAT INDUCED


Forgot to mention, alpha-ketol rearrangement is irrelevant on this substrate because phenylacetylcarbinol is the more stable isomer than benzoylmethylcarbinol. See:

http://digitool.library.mcgill.ca/webclient/StreamGate?folde...

"Considerable work has been done on rearrangements of the two isomeric ketols, phenylacetyl carbinol (LXXIX) and benzoyl methyl carbinol (LXXX).
[image]
Favorskii (130) heated (LXXX) with a few drops of concentrated sulfuric acid in a sealed tube at 120-130° and obtained the isomer (LXXIX). "

The reference, 130, is Favorskii, Bull. Soc. Chim., 39, 216 (1926), if you want more details.

[Edited on 12-1-2018 by clearly_not_atara]