hydantoins from alpha amino acids (Phenylalanine) and more

java · Consumer

I've included a thread from over at WD to see if any furthering of the thread can occur here as it seems to have died for lack of interest.......however I present it to you for your consideration and input on the sticky points of hydrolysis of the hydantoin and from there decarboxylation to the desired aromatic amino alkane.
I will post some info on the hydrolysis as this is a very interesting approach to the -----amine, an d also ning introduced a second method as a bonus.
Not to attempt to hostage the thread as I have only the interest to develop the interesting approaches presented on this thread............java
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ning
The One-Pot King

Posted - Apr 11 2005 : 11:05:19 PM
And it's not the kolbe, this time...

All the talk of amino acids in the akabori thread got me thinking. And then a fairy appeared, and an idea came.
I couldn't believe it would work, it couldn't bee so easy. So I looked up the chemistry. Surely enough, somebody had done something like it, in one form or another. ---- direct from phenylalanine. Interested? Read on.

So, amino acids, as we can see in the other thread, can be alkylated at carbon. In the case of phenylalanine, we need a methylation, like so:

Ph-CH2-CH(COOH)NH2 --> Ph-CH2-C(CH3)(COOH)NH2

Then we need an N-methylation (unless amphetamine is enough for you...)

Ph-CH2-C(CH3)(COOH)NH-CH3

Finally a decarboxylation

Ph-CH2-CH(CH3)NH-CH3

Ah, you say, but ning, this is obvious. How do you intend to achieve this transformation in an easy, OTC manner?

Well, my friends, I propose two different ways.

First, my original idea. When an amino acid is heated with urea, a common fertilizer, it forms a funny ring called a hydantoin. It goes like this:

Ph-CH2-CH(-CONH-CO-NH-)
yeah, that's a ring in the parentheses.

You can see, that this hydantoin covers the carboxyl group, and the amine.

Now imagine what would happen if an excess of methylating agent, like methyl iodide or dimethyl sulfate, was introduced in the presence of a strong base. The two amide nitrogens would methylate first. Then, if the base was strong enough, the activated alpha-carbon would react once too. Then the molecule would react no more. The final hydantoin would look like this:

Ph-CH2-C(CH3)(-CON(CH3)CON(CH3)-)

A fairly vigorous hydrolysis would break open the hydantoin ring, regenerating the amino acid in a strangely different form:

Ph-CH2-C(CH3)(COOH)NHCH3

Uh-oh! What is this? It seems to be alpha-carboxy methedrine! Well quick, somebody decarboxylate that poor sap!

Ph-CH2-C(CH3)NHCH3

And that is what we came here for.

Bill of materials:
- 3 units methylating agent (dimethyl sulfate?)
- 1 unit phenylalanine
- 4 units strong base, or PTC-boosted weak base
- 2 units urea

The methylating agent is obnoxious to get ahold of, I admit, but compared to making p2p ---- from scratch, I'd say it's a pretty good deal.

Onwards! To method 2.

If the hydantoin method doesn't work well for some reason, there is an alternate way to do the same thing, using slightly more standard methodology.

1. esterify phenylalanine, to methyl or ethyl ester.
2. form a benzylidene derivative by reaction with benzaldehyde or some less-precious aromatic aldehyde (don't worry, you'll get it back)
3. With base, allow 1 equiv methylating agent to react. This will alkylate the carbon.
4. remove base and heat strongly with 1 more equiv methylating agent. This N-alkylates the benzylimine to a quaternary salt.
5. workup with base, hydrolyze acyl group. Recover benzaldehyde.
6. decarboxylate to ---- freebase.

Suddenly, a third way appeared to my mind. What is a pre-esterified source of phenylalanine? Sounds like aspartame, AKA nutrasweet. And what could be sweeter and more nutritious than honey?
Well, maybe there is something there....

Could any smart bee clue me in on the stereochemistry of the resulting product in this synthesis? D or L ?

Peace to all....
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sony
New Dreamer

Posted - Apr 12 2005 : 06:16:04 AM Reply Link
That seems to be a nice idea Ning!

Do you perhaps have any refs or could you elaborate on the reaction details for the hydrolysis of the hydantoin ring.

How strong of a base would you expect to be required? sodium ethoxide? or would NaOH be sufficient

As for the methylating agents what about the friendly dimethylcarbonate? Of course the not so userfriendly methyliodide would be a nice OTC option but one would definately want a fumehood when working with it.

hippler
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WizardX
Wizard Master

Posted - Apr 12 2005 : 06:30:23 AM Reply Link
Urech Hydantoin Synthesis http://themerckindex.cambridgesoft.com/TheMerckIndex/NameReactions/ONR406.htm

http://www.ajinomoto.co.jp/amino/e_aminoscience/bc/amino_13.html
Phenylalanine when heated in 5N sodium hydroxide at 110~115° for 5 hours, it decomposes forming benzaldehyde.

quote:
Could any smart bee clue me in on the stereochemistry of the resulting product in this synthesis? D or L ?

L-Phenylalanine hydantoin : mp 183°C

http://www3.interscience.wiley.com/cgi-bin/abstract/107585346/ABSTRACT

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WhoMe
Exalted Extractor

Posted - Apr 12 2005 : 10:39:24 AM Reply Link
Where can SWIHM sign up for the ning fan club. Dude you rock! Can't wait to see some real world test results. Hmmm better start putting some Phenylalanine away for a rainy day.

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ning
The One-Pot King

Posted - Apr 12 2005 : 10:58:20 AM Reply Link
Well flip my ring, that sounds like a nice way to obtain benzaldehyde.

One would need a rather strong base to alkylate the carbon. Currently it looks like PTCs will be necessary, however a shot with ethoxide or whatnot might be worth a try.
If DMC will be used, a mixture of KOH and K2CO3, probably with a PEG, heated to refluxing temp. of DMC is probably necessary. Conditions will probably be rather touchy.

As I remember, a strong acid solution will hydrolyze the hydantoin. If forcing conditions are used, maybe it will even cause decarboxylation.

I have a few refs, though not on the hydantoin hydrolysis...it's so common. I'll look something up. Probably methyl iodide will be the better starting way, because it surely will not require very rough conditions.

Here's some examples: (chirality 2002, 144)
1.94 mmol LDA in 10 mL THF was chilled to -78 C and 1.78 mmol protected hydantoin was added. Then 2.53 mmol MeI was added and soln. stirred for awhile to yield 75% monomethylated hydantoin.
- Note, they preformed the enolate here, so that's what you'd expect.

in 13 ml THF, 2.7 mmol LDA and 2.7 mmol 5-methyl hydantoin (see above) were stirred at -78 C with 2.68 mmol 3,4-dimethoxy benzyl chloride. Yield 95% 5-(3,4-dimethoxybenzyl),5-methylhydantoin.

hydrolysis:

1 mmol of the above hydantoin was sealed in an ampule with 5 ml of 57% HI and heated to 110 C for 48 h (!!!), then ion-exchanged on Dowex 50W. Amino acids were recovered in >90% yield.
- obviously this workup would be improved.

----gotta go, I do have more refs, especially relating to PTC alkylation.

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jftraptor
New Dreamer

Posted - Apr 13 2005 : 11:31:21 AM Reply Link
ning, man you rock! thanks so much for all the effort you put into helping all of us here! ive learned so much from your posts!

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java
Doctor Who

Posted - Apr 13 2005 : 12:27:46 PM Reply Link
Here is a post from MK-1 over at synthetikal on the subject.........java

------------------------------------------------------------------------------------------------------------------------Topic: Phenylalanine to alkane-amine

thought id drop by and contribute my little part :
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Efficient Procedure for the Reduction of -Amino Acids to Enantiomerically Pure -Methylamines
Dominick A. Quagliato, Patrick M. Andrae, and Edward M. Matelan
J. Org. Chem.; 2000; 65(16) pp 5037 - 5042
DOI: 10.1021/jo000242h
pdf

"Prefiero morir de pie que vivir siempre arrodillado"..............Emiliano Zapata....................(UH)
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hest
Dreamer

Posted - Apr 13 2005 : 12:51:06 PM Reply Link
Overall yield 45%

From NH2-COOH => Boc-NH-COOH => BocNH-COH => BocNH-C-I => Boc-NH-CH3 => NH2-CH3
Interesting, but it will yield some damm expensive amph.

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ning
The One-Pot King

Posted - Apr 13 2005 : 10:41:03 PM Reply Link
heh, yah

I like my idea because theoretically it will produce actual ---- and not just amphetamine.

I'm still wondering about the stereochemistry here. (my weakest point of chem knowledge, boo hoo)
If one were to use L-phenylalanine, since it becomes alkylated across from the carboxyl group, would that mean it yields pure D----- when decarboxylated? Or pure L-----? Or would it become racemized?
An important matter, indeed....

*thanks for all the love and contributions, guys ^_^ *

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java
Doctor Who

Posted - Apr 13 2005 : 11:24:15 PM Reply Link
Why not run some d-phenylalanine and then some L phenylalanine and observe both yields for change of rotation .....or just run dl-phenylalanine and at least get 50% yield d----- ............java

"Prefiero morir de pie que vivir siempre arrodillado"..............Emiliano Zapata....................(UH)
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WizardX
Wizard Master

Posted - Apr 13 2005 : 11:39:49 PM Reply Link
I would like to clarify the topic name as Ning named, "phenylalanine to ----, direct!". Ning's theoretic method is NOT a one-step synthesis of phenylalanine to amphetamine. Please do not take this the wrong way, just want to be scientifically correct.

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ning
The One-Pot King

Posted - Apr 14 2005 : 10:03:04 PM Reply Link
True...not one step. I guess I called it direct because it didn't involve intensive functional group transformation, like reduction or oxidation. And compared to the other ways, it is direct Wink

Ug. Java, you may be right...experiment is king. I have to learn more on stereochem, then will speculate.

more papers soon, promise...

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MiNdBaBY
Tamer of the Brew

Posted - Apr 23 2005 : 6:01:51 PM Reply Link
As far as Swim can find this hasn't been touched on by dreamers yet and swim feels it' could be of value...

though makes for an nice addition to your superb thread java, ning, Wiz, and others..

swim is thinking, use of one of the microbiological grp 3 decarboxylase Enzymes, [swim himself will likey choose Lysine over Orn. & Arg.] such as Lysine to cleave that carboxylic group..

Heres some links with some ref material on the decarboxylases':
http://www.ebi.ac.uk/interpro/DisplayIproEntry?ac=IPR000310
http://www.biochemj.org/bj/344/0633/bj3440633.htm
http://www.rlc.dcccd.edu/mathsci/reynolds/micro/lab_manual/decarb_deam.html

Swim sums up his thought all nice n pretty with following picture.

With the only hurdle being obtaining the decarboxylase.

Edited by - MiNdBaBY on Apr 23 2005 6:07:04 PM
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ning
The One-Pot King

Posted - Apr 23 2005 : 6:14:48 PM Reply Link
Not to mention, that most of those enzymes are _STEREOSELECTIVE_

Find the right one, and you've got pure D-----. Or any ratio of L----- to D----- you like.

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java
Doctor Who

Posted - Jul 01 2005 : 12:19:47 AM Reply Link
The idea of forming hydantoins from alpha amino acids sounds very interesting , it reminds me of dakin west reaction in the sense that both the active ends of the acids are reacted , in the case of dakin west a ketone and an amide are formed, for which I think it´s a excellent way to work towards ----, but this hydantoin reaction interests me as it´s written thae reacting thr aminoacid with potassium cyanate in an aqueous solution and heating the salt of the intermediate in 25% HCl.......as stated in Merck, now the method to the hydrolysis of the hydantoin , would be interesting to study and see what happens and the yields.......will look into this but ning perhaps you can provide some insight......as I'm interested, I also found soe mor info onthe dakin west which I will add to that post.........java

"Prefiero morir de pie que vivir siempre arrodillado"..............Emiliano Zapata....................(UH)