Author Topic: Improving the yield of the "Akabori Reaction"  (Read 794 times)

Quantum Dude

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Improving the yield of the "Akabori Reaction"
« on: December 23, 2009, 07:32:51 AM »
Im pretty sure you guys heard of it but I was wondering if anybody has actually tried it. It was reported in this Japanese article that an Oxazolidine intermediate is formed and further hydrolysis is required in order to maximize yield of amino-alcohol. Refluxing the final mixture with a mixture of acetic acid, benzene and methanol seems to be used but it isnt clear.They report a yield of 47 % racemic ephedrine using N-methylalanine. Not bad at all. The interpretation of the authors has received some criticism though.

Question is has anybody tried it in order to obtain greater yields of racemic PPA ?

Heres a rough translation of the experimental protocol and discussion:


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Amino acid is the useful synthetic raw materials as a cheap asymmetrical source. But, after for solubilizing to the control and the organic solvent of the side reaction, protecting amino acid, the fact that it does the conversion reaction was common sense. We discovered character and the reaction whose amino acid is new the unprotected amino acid which, is almost not examined so far as the synthetic raw materials by using, shortly showed the fact that also synthesis of natural ones with the distance which does not need the distance of 1 and protection and deviation from protection is possible. Because 2 this time we the carbon which accompanies the decarboxylation of unprotected amino acid - developed the practical synthesis method of the amino alcohol which utilizes the carbon connection formation reaction, it reports.

As for Akabori and the like, it is low the N-[mechiru] alanine (1) and in pyridine heating benzaldehyde it reported that by (2) in 1942, yield (16%) you can obtain the ephedrine (3) with one distance (Scheme 1). As for 3 these reactions accompanying the decarboxylation in on the asymmetric carbon of amino acid, because the unique reaction type that [A] is, carbon - it causes carbon connection, after that, with the tall tree and Emoto etc from 1951 extending through 1961 in detail inspection Attacking/questioning it was done, but it did not succeed in the improvement of yield. As for 4 these reactions, because from unprotected amino acid you can obtain the amino alcohol which is included mainly as a basic framework of the medical supply with one distance, the possibility of becoming the useful synthesis reaction is concealed

We from the viewpoint of the reaction of unprotected amino acid reexamination did to this reaction with interest, (Scheme 2). The N-[mechiru] alanine (1) and benzaldehyde (4, R=H) with the non solvent 130? and 1hr when it heats, the ephedrine (6, R=H) it was obtained same as Akabori and the like report low at only yield, but when the reaction blend is scrutinized, the Oxazolidine body (5), it became clear from the measurement of NMR to have formed. This chemical compound (5), being unstable, from the fact that isolation is difficult, when adding water it disassembled the reaction liquid directly with the AcOH aqueous solution, improved yield substantially and could obtain 6 at 48% yield as a blend of diastereoisomer. Furthermore this reaction, when it goes with the benzaldehyde which possesses the various substituents, the yield where the benzaldehyde which possesses the electron donating group is better was given, maximum of 87% yield improved (Table and Run 6).The Oxazolidine body (5) formation the Schiff base (7) has suggested formation strongly as a intermediate field. Namely, the decarboxylation happens the Schiff base (7) formation as a trigger, Zwitter Ion 8 occurs, continuously, after the reaction of the aldol type of benzaldehyde, the cyclization reaction inside the molecule of 9 where it forms happens, 5 forming is thought, (Scheme 3). In announcement, the amino acid other than the N-[mechiru] alanine is used when and, it is the schedule which also examination of the solvent and the result etc when the optically active substance is used report together

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We, from the viewpoint of development of the synthesis reaction of the unprotected amino acid which examines so far, observed to this reaction and reexamination did.

N-Methylalanine (2) with 6 equivalent aromatic aldehydes (4) with the non solvent 130? and 1hr when it heats, same as Akabori and the like report, from water layer, the ephedrine was obtained low at only yield. But, when organic layer is scrutinized the [okisazorijin] body (5) it was found that it has formed in large quantities. This without being isolated when adding water it disassembled with the 5%AcOH aqueous solution, the amino alcoholic body (6) diastereoisomer almost 1: It was obtained at 48% yield, as 1 blends (the right figure). Namely, with Akabori and the like experiment, because the [okisazorijin] body (5) the fact that it has formed, is overlooked in organic layer, it is thought as the thing whose yield is bad. Furthermore, this reaction when it goes with various substitution benzaldehyde, about those where the electron donating group is attached yield improved, was obtained at maximum of 87% yield.

In addition, the [okisazorijin] body (5) formation gives very regarding reaction mechanism important information. Namely, amino acid (2) with aldehyde (4), in minium salt (7) it forms, that becomes the trigger and the decarboxylation happens, Zwitter Ion 8 occurs. The aldehyde of the monad (4) reacting with this 8 already, 9 where it occurs cyclizing, it is thought that the [okisazorijin] body (5) it formed. This [okizazorijin] body (5), being relatively unstable, when it heats with the acetic acid aqueous solution, hydrolysis happens, gives the amino alcoholic body.

I feel that the original reaction which has been buried to this, Japan, has concealed big possibility not only being connected to the development of the organic chemistry where the amino acid which you are proud in the world 'as the Akabori reaction' is new, as a practical synthesis method of the medical supply.



http://www.mnc.toho-u.ac.jp/v-lab/yuuki/amino/amino-5-1.html
« Last Edit: December 23, 2009, 07:40:29 AM by Quantum Dude »

jon

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Re: Improving the yield of the "Akabori Reaction"
« Reply #1 on: December 23, 2009, 08:44:39 AM »
no need for complexity this only holds true in the case of n-methylalanine the cylzation product is really a condensation product in the case of alanine a shiff's base would result.

Quantum Dude

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Re: Improving the yield of the "Akabori Reaction"
« Reply #2 on: December 23, 2009, 09:31:36 AM »
no need for complexity this only holds true in the case of n-methylalanine the cylzation product is really a condensation product in the case of alanine a shiff's base would result.

You have a ref for that ? Really not following what youre saying either as a condensation product and a Shiff's base is obtained as some point in both cases.

jon

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Re: Improving the yield of the "Akabori Reaction"
« Reply #3 on: December 23, 2009, 09:51:02 AM »
that's got to be the dumbest question i've been asked all week.
well here's a stupid answer you can't tell that that ring is nothing more than a condensation product of ephedrine and benzaldehyde?
where did you attend school?
you don't need a "ref" just some common sense.
« Last Edit: December 23, 2009, 09:58:26 AM by jon »

no1uno

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Re: Improving the yield of the "Akabori Reaction"
« Reply #4 on: December 23, 2009, 11:33:56 AM »
Settle - the arguments (and they ARE ongoing) about the paper in question (which I seem to remember being the first to find ::)) are irrelevant to what QD is asking... With unmethylated alanine apparently dimers and other byproducts are the problem, which significantly decrease yield. N-Methylalanine is going to be a fucking whole lot easier to make if people just look at how alanine is synthesized - either a-Halopropionic acid is used to N-alkylate methylamine in ethanol or you could do a reductive amination of pyruvic acid (dry distillation of tartaric acid would be an obvious route for small scale synthesis) with methylamine and reduction of the imine. In either case, you'd probably be able to save yourself the resolution as the product, if the azlactone does in fact form, will be racemic regardless of which isomer of alanine you start with...
"...     "A little learning is a dang'rous thing;
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    There shallow draughts intoxicate the brain,
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Quantum Dude

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Re: Improving the yield of the "Akabori Reaction"
« Reply #5 on: December 23, 2009, 06:15:51 PM »
that's got to be the dumbest question i've been asked all week.
well here's a stupid answer you can't tell that that ring is nothing more than a condensation product of ephedrine and benzaldehyde?
where did you attend school?
you don't need a "ref" just some common sense.

Thats gotta be the dumbest answer I ever witnessed indeed but not for the reasons you intended to be. I dont even know why I am bothering replying to you as you obviously dont even know what a condensation of phenylpropanolamine and benzaldehyde would look like!

Seriously are you just some kind of village idiot that lurks around here posting drunken nonsense and attacking people on their academic curriculum because they ask more than ligitimitate questions and youre too chicken shit and ignorant to respond appropriately? If that is so, youre pretty cute. Sorry fella but just because Nicodem says so is not enough for me, I like to have actual data...you know... science and all that ?



In all honesty no1uno I didnt knew you were the first to report it as I didnt get this information form here or ScienceMadness. I appreciate your input and concur that a shift from a primary to a secondary amine might be more than just a detail.
« Last Edit: December 23, 2009, 07:00:02 PM by Quantum Dude »

jon

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Re: Improving the yield of the "Akabori Reaction"
« Reply #6 on: December 23, 2009, 07:16:45 PM »
well for one account for the mechanisn i did and spotted some flaws in thier propsed mechanism, remember a mechanism must acount for formal charges and all the elements must be balanced find the discrepancy i won't tell you what it is.
i'm not going to get into longwinded arguments over this; but, i will admit i ws a bit of an ass in that previous post and, so i apologize, it was rude.
« Last Edit: December 23, 2009, 07:30:04 PM by jon »

Quantum Dude

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Re: Improving the yield of the "Akabori Reaction"
« Reply #7 on: December 23, 2009, 08:11:32 PM »
Now dont get me wrong Im all for the idea that the Oxazolidine is obtained by further condensation of the end product with benzaldehyde. Although if it is obtained for the N-methylalanine case, it has to be accepted for alanine as well.



« Last Edit: December 23, 2009, 08:19:11 PM by Quantum Dude »

jon

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Re: Improving the yield of the "Akabori Reaction"
« Reply #8 on: December 23, 2009, 08:19:58 PM »
well we can argue theory all damn day the only way to proove or disproove is to get in the lab and run the expiriment.
bu that proposed mechanisn seems correct everything (element) is accounted for and the formal charges are in the correct places.
« Last Edit: December 23, 2009, 08:24:13 PM by jon »

Quantum Dude

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Re: Improving the yield of the "Akabori Reaction"
« Reply #9 on: December 23, 2009, 08:24:48 PM »
well we can argue theory all damn day the only way to proove or disproove is to get in the lab and run the expiriment.


Hence the start of this thread...so again...

Has anybody tried it in order to obtain greater yields of racemic PPA ?

jon

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Re: Improving the yield of the "Akabori Reaction"
« Reply #10 on: December 24, 2009, 08:41:12 PM »
i think were really splitting hairs here because during the workup the nonpolar phase is extracted into 10 % hydrochloric acid. does the same thing 5% acetic acid would do.
just stick to convention.

Quantum Dude

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Re: Improving the yield of the "Akabori Reaction"
« Reply #11 on: December 24, 2009, 10:35:15 PM »
i think were really splitting hairs here because during the workup the nonpolar phase is extracted into 10 % hydrochloric acid. does the same thing 5% acetic acid would do.
just stick to convention.
Yeah but you need to give the hydrolysis reaction a little boost before it actually happens. Hence the reason the whole mixture is refluxed for some time. Also glacial acetic acid is soluble in hot benzene (most probably in toluene as well). This argument doesnt explain the use of only 5 % aqueous acetic acid though.

The standard convention sucks ! Some other areas of workup needs to be further analyzed, thats how (potential) progress happens.
« Last Edit: December 24, 2009, 11:50:57 PM by Quantum Dude »

jon

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Re: Improving the yield of the "Akabori Reaction"
« Reply #12 on: December 25, 2009, 08:38:52 PM »
This argument doesnt explain the use of only 5 % aqueous acetic acid though.

hydrolysis means addition of water so, glacial acetic in benzene won't help you

Quantum Dude

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Re: Improving the yield of the "Akabori Reaction"
« Reply #13 on: December 25, 2009, 10:30:33 PM »
This argument doesnt explain the use of only 5 % aqueous acetic acid though.

hydrolysis means addition of water so, glacial acetic in benzene won't help you

If you look again, carefully this time, youll notice the usage of only.

Couldnt hurt to increase the % of AA, thats what I meant.
« Last Edit: December 25, 2009, 10:35:23 PM by Quantum Dude »

jon

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Re: Improving the yield of the "Akabori Reaction"
« Reply #14 on: December 30, 2009, 07:11:34 AM »
i got to hand it to you you have some good points you're a smartie for sure

jon

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Re: Improving the yield of the "Akabori Reaction"
« Reply #15 on: December 30, 2009, 07:14:53 AM »
won't need a two phase system throgh jsut good stirinng and heat will sufiice.
i don't think toulene is going to remove any products becuase they are protonated ntirogen and will stay in the Aq phase.

Quantum Dude

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Re: Improving the yield of the "Akabori Reaction"
« Reply #16 on: December 30, 2009, 07:17:32 AM »
i got to hand it to you you have some good points you're a smartie for sure

What is your stand on Nicodem's argument regarding the formation of an alanine salt of PPA after the decarboxylation ? If you notice, in all write-ups peopls are discarding the solids as it is regarded as "excess undreacted alanine". The latter is washed with toluene but its never kept. Nicodem's arguments was that PPA might react with the carboxylic moeity of alanine to yield PPA alaninate (a surely insoluble salt in toluene). I never saw any info regarding that.
« Last Edit: December 30, 2009, 07:20:58 AM by Quantum Dude »

Naf1

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Re: Improving the yield of the "Akabori Reaction"
« Reply #17 on: December 31, 2009, 02:12:34 AM »
"formation of an alanine salt of PPA after the decarboxylation"

Well there is only one decarboxylation and after that there is no PPA to form an ester with alanine, and the resulting alaninate of the zwitterion formed after decarboxylation would be completely useless (its structure not similar to PPA, a  mere by product) and prone to hydrolysis to the parent compounds in the 3 hours 10% AA reflux.

Product of esterification of Alanine and decarboxylated Schiff Base;


"i got to hand it to you you have some good points you're a smartie for sure"

Lets face it Jon you can be a bit untactful sometimes, but you are no dummy either. Sorry for missing the fun I have been busy elsewhere, I wanted to chime in last week but did not get a chance with Xmas and all.

"hydrolysis means addition of water so.."

Lysis refers to the separation of bonds and is an ancient Greek word, whenever used as a suffix in chemistry it refers to the breaking of bonds!!

http://en.wikipedia.org/wiki/Lysis

Hydro'lysis' refers to chemical reaction where molecules of water are split into hydrogen and hydroxide anions, catalyzed by acids or bases!

http://en.wikipedia.org/wiki/Hydrolysis

I would suggest 10% AA was used to try and make the conditions as mild as possible while still pushing forward the ring opening(hydrolysis), also if one used more the esterification talked about above may actually be possible!(PPA alanine esterification). If you made the mistake of choosing to use sulfuric acid or any strong acid for that matter (Hydrogen chloride, 98% Sulfuric acid etc) instead of an aqueous 10% acetic acid, it would be inevitable any alanine present would take part in esterification with the PPA formed as those strong acids especially sulfuric acid are catalysts for such reactions. Also it can be done with sodium acetate in glacial acetic acid so a good enough reason to keep conc low, also dont forget the formed ester would also be prone to the reverse reaction (hydrolysis to the parent compounds in hot dilute acetic acid!!). The amphetamine ester of alanine, amphetamine alaninate (formed from PPA and Alanine) would not be formed in significant quanities in 10% acetic acid in the second phase of this reaction (as there is a big excess of aldehyde, so the alanine should be very close to completely reacted (in that first step anyway) leaving not really enough alanine in solution after the initial reflux to worry about, then the fact that dilute monoprotic acetic acid is used will negate that issue (as if it does occur, it would be trivial amounts).

I will run this soon! Jon did bring up an excellent point about the N-alkyl group being a neccessity for oxazolidine formation and yielding anything beyond the 16% of the original Akabori style addition, as there is a slight hint at it in this bad translation from the paper;

"When I use an amino acid except the N-methyl alanine in the announcement, I am unpleasant and I match the results when I used the examination of the solvent optical active material and am going to report it."

That was from a babylon translation of a section copied and pasted in from the japanese Akabori paper. I am still looking forward to the results though, as I have a few references for precipitating amino acids from solution so it should not be too hard to N-alkylate.
« Last Edit: December 31, 2009, 02:20:46 AM by Naf1 »

Quantum Dude

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Re: Improving the yield of the "Akabori Reaction"
« Reply #18 on: December 31, 2009, 02:24:29 AM »
"formation of an alanine salt of PPA after the decarboxylation"

Well there is only one decarboxylation and after that there is no PPA to form an ester with alanine, and the resulting alaninate of the zwitterion formed after decarboxylation would be completely useless (its structure not similar to PPA, a  mere by product) and prone to hydrolysis to the parent compounds in the 3 hours 10% AA reflux.

Product of esterification of Alanine and decarboxylated Schiff Base;



Sorry Naf1, I think you misunderstood what I meant. The free amine on PPA would react with the carboxylic acid on alanine to yield an alaninate salt. The latter would def be insoluble in benzaldehyde and therefore crash at the bottom of the flask. Here it is:



Heres a proposal for an upcoming work-up:

Once the reaction is done, equal volume of 10 % HCl is added and the whole mixture is refluxed for 3 hours. This will take care of any Oxazolidine (obtained by condensation of PPA and benzaldehyde) and at the same time will dissolve any PPA*Alaninate present as well. Once done, aqueous layer is separated from tars and excess benzaldehyde. It is then washed and standard work-up afterwards.
« Last Edit: December 31, 2009, 02:32:10 AM by Quantum Dude »

jon

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Re: Improving the yield of the "Akabori Reaction"
« Reply #19 on: December 31, 2009, 04:20:53 AM »
naf and quanttum dude i like your intellect you guys synergize on another.
this is good stuff keep it coming i'll spluge and run the reaction