dormouse
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04-19-00 06:12
No 122776
      Alkylation of amino acids under PTC conditions! -Labrat
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Author  Topic:   Alkylation of amino acids under PTC conditions! 
Labrat
Member   posted 12-06-98 09:52 AM          
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Forget LDA, BuLi, HMDMS and other exotic bases, the only thing we need is sodium hydroxide! Even bicarbonate works as a base!
Yes, my partners in crime, you heard it well, alkylation of amino acids can be done by anybody with household-chemicals like alanine, benzyl chloride, NaOH and a phase-transfer catalyst. This latter substance can be bought from chem suppliers, but it can also be found in shampoo's. I'd just order the stuff if I were you. It's not that expensive. And the catalyst can be reused, so you only have to buy enough once!

Now I'm making it look easier then it is maybe. I spose you'll have to use the esterified amino acid, but this may not be necessary. Then this esterified amino acid is condensed with an aldehyde/ketone to form the Schiff base (not optional!). Next, the Schiff base is dumped into neat benzyl chloride, the sodium hydroxide is added and a little PTC. Stirring is started and after several hours at room temp, you'll have you alkylated product in good yields.

For those who have the luxury of having access to a chemistry library, check these articles on this method:

JOC 43: 4682 ('78)
TL 4625('78)+ 2641('78)+ 4259('82)+ 4255('82) + 3067('85)
TETRAHEDRON:Asymmetry 3: 591 ('92)
SYNTHESIS 313 ('84)
SYNTH.COMM. 19: 1157 ('89)
CHEM.ENG.NEWS 25 (april 10 '89)
JACS 111: 2353 ('89)

The yields in this procedure are usually 80-90%. Combine this with a ~80-90% yield of decarboxylated product and you'll have to admit, this looks good! Lr/


 
Lilienthal
Member   posted 12-07-98 02:58 AM          
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Hey Labrat, you're the king bee!
See also: Tetrahedron 44, 5343 1988
99% optimized reaction yield of benzylated alanine aldimine under catalytic solid liquid PTC conditions .
 
Labrat
Member   posted 12-07-98 10:30 AM          
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One step ahead of you, my dear Watson! I have been roaming the library and found even more refs (including the one you mention, Lili):
Tetrahedron 5343('88) + 5389('88)
JACS 110:8520('88)
SYNTHESIS 26('79) + 763('84) + 465('90)

It's pretty strange that the yield of wanted product here tends to depend on the base used in the PTC-rxn. A mixture of NaOH/K2CO3 (1:2) seems to work best. That Tetrahedron article is really interesting! Lr/


 
Lilienthal
Member   posted 12-07-98 12:03 PM          
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Don't call me Lili!!!
The reason for using the ester is to prevent the formation of the carboxylate salt under that alkaline conditions. This negative charge would strongly deactivate the alpha-C. So unfortunately the use of the ester seems to be essential.
One reason why K2CO3 works better than conc. NaOH is the competing reaction of ester saponification to the above mentioned unreactive carboxylate. Some groups used -CN instead of an ester with good results.
 
drone 342
Member   posted 12-07-98 03:20 PM          
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LR,
Now I haven't looked that stuff up yet, but iif you're right, I shall dub thee MACK-DADDY CHEMICAL PIMP OF THE MONTH, if you are correct. Howver, I have some concerns.

I've been spreading the word for months now about my own personal N-alkylation process that uses the same ingrediants that you listed. I know it works for alkylating tryptamine into dialkyltrypamines, but how do you envision protecting the nitrogen from alyklation under these coniditions? I thought about this myself, but the only protecting group I could think of would be to make the amide, but I thought the amide would be readily chewed up onder these conditions. Please tell me where I went astray?

-drone #342


Lilienthal
Member   posted 12-08-98 04:23 AM          
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Drone: pleeeease give us your PTC tryptamine alkylation method. You would be the hero of our recently founded tryptamine fan club.
The amino group is protected as an imine = Schiff base. This also acidifies the alpha-C hydrogen. Using an extremly strong base (or a moderately strong base under PTC), you abstract this proton and get the (-)CR3 anion which is strongly nucleophilic. For the PTC mechanism in this reaction look into the mentioned Tetrahedron article.


Labrat
Member   posted 12-08-98 10:00 AM          
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Sorry, Mr Lilienthal for abbreviating your name!
I thought that using that amino ester was necessary, but can you envisage that the carboxylate salt is benzylated with benzyl-Br under the PTC conditions, creating the phenyl ester? I sure can! Then this ester can be alpha-benzylated without probs. So using at least 2 equivalents of benzyl bromide would allow benzylidene alanine to be esterified and alkylated in one step, I hope.

Under the anhydrous conditions used in the solid-liquid PTC it's hard to hydrolyse that ester. It goes a lot faster in a liquid-liquid PTC, but that's not the preferred embodiment of this procedure. And if my chemical guess is correct, the carboxylate will be esterified immediately under the PTC conditions. Using a cyanide protecting group is nice, but an ester is easier to synthesize.

Drone, I guess you can call me MACK-DADDY CHEMICAL PIMP OF THE MONTH, cuz this procedure really does work! Just check the refs, you'll be more then pleased!

I thought that the N-alkylation under PTC conditions was performed on the straight amine, not the imine. That imine is the protecting group for the amine, you know that! An amine is a stronger nucleophile then the imine derivate. Under the PTC conditions, the alpha-hydrogen will have a high acidity (pKa 17-23), thus the anion will be created, which is a lot stronger nucleophile then the imine. Thus the imine won't be alkylated, but the anion at the alpha-carbon.

But I see a good thing here too. If you have the chems to do the N-alkylation thing under PTC conditions, you only have to buy a few chems to be able to do the alkylation thing of your favorite amino acid. I thank the chemgods for PTC! Lr/


 
Rhodium
Administrator   posted 12-08-98 11:25 AM          
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Lilienthal: Drone's alkylation can be found in a thread called "boosting psilocin's octane numbers" initiated by him. It is available at the following URL: Post 108423 (dormouse: "MDP-2-P  -capacitor", Novel Discourse) 
If the URL to the thread was wrong, it is easily found using the search engine.


Beagle
Member   posted 12-08-98 01:17 PM          
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Lat time I went looking for that procedure I had a hard time finding it. The actual URL is http://hive.lycaeum.org/ubb_board/Forum1/HTML/000631.html 
 
Rhodium
Administrator   posted 12-08-98 02:07 PM          
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Uh, but the thread I linked above ALSO contains refs on the dialkylation of primary amines... A lot of Beilstein refs, that is. But thanks for your link to the thread with the actual procedure included.
 
drone 342
Member   posted 12-08-98 05:11 PM          
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LR,
I'm a little confused here. You're protecting still with the imine? What are you using as the ketone/aldehyde in forming this, and what procedure are you thinking about using to make it?

If not the imine, are you thinking of using an amide to protect it? All these ideas! I gotta get to the library and check those ref's out!

-drone #342


Rhodium
Administrator   posted 12-08-98 06:02 PM          
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Drone: What is the ref for the alkylation of tryptamine to DMT in the procedure you posted in the thread linked by Beagle above?
And I assume that "tryptophan" is a typo for "tryptamine" in what you wrote, right?


 
drone 342
Member   posted 12-08-98 07:54 PM          
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Rh,
You're right about that typo. It should read "tryptamine". If you could be so kind, could you archive that on your page, with the corrective spelling? There have been a great deal of people looking for it in a number of threads, and your page seems to currently be Grand Central Station for practical clandestine procedures right now, aside from The Hive. Puting it there would save a lot of time.

There is no ref for this. You won't find one. This is *my* creation, and it works! True, its based on a procedure found in the literature, but honestly, I cannot divulge my source. This is one instance where you may not, under any circunstances, know where it came from. Period. Sorry. I know this goes against the scientific method, but sometimes other forces come into play.

This is "the drone method", and forever shall it bear that name. Developed by drone #342, and tested by others, who shall remain equally nameless.

Still, I'm not trying to cop out regarding my reliability. This is cheap enough and interesting enough that plenty of people have and will try it. Do so yourself, and you'll see. In case there are any misunderstandings, 5 grams of tryptamine ( 0.03125 moles) is what is meant, an excess of twice the molar amount of tryptamine is used as the amount of alkyl halide (in this case, 11 grams of MeI ( 0.075 moles) is used), and the reaction is tested via TLC for completion.

The reaction is not without parallels that I can describe, however. One of the methods of DMT synthesis listed by Dr. Shulgin in TiHKAL I believe is essentially the same, but using slightly different conditions (mine are better, and give higher yields.)

Sorry for being so eleusive, but this hits close to home.


drone 342
Member   posted 12-08-98 08:06 PM          
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Sooo, we're back to trying to find a convenient way of making the imine of amino acids again, are we? I'll go back to my sources, and see what we can come up with.
 
drone 342
Member   posted 12-08-98 08:43 PM          
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So what we need is a method for making the imine or the ester of the imine of an alkpha amino acid. Here's some things I dug up that may be of help.
glycine forms an imine with acetoacetic acid:
Anal.Chem.; EN; 65; 14; 1993; 1903-1909;

valine with pivaldehyde:
Tetrahedron Lett.; EN; 34; 1; 1993; 63-66;

another pivaldehyde ref:
Helv.Chim.Acta; GE; 71; 1988; 224-236;

methyl ester of cystine with acetone:
Fermentforschung; 13; 1931/1933; 107;

ethyl ester of glycine with acetone or with MEK:
Indian J.Chem.; EN; 11; 1973; 1205-1206;

2-oxo-propionic acid ethyl ester reacts with alanine methyl ester hydrochloride (very interesting reaction conditions!!!):
Bull.Chem.Soc.Jpn.; EN; 57; 5; 1984; 1367-1370;

Really messed-up looking ketone wiuth glycine HCl (kinda interesting conditions, though):
Indian J.Chem.Sect.B; EN; 21; 4; 1982; 372-374;

isopropyl methyl ketone with valine methyl ester or valine ethyl ester:Ref. 1 21260; Journal; Takahashi,H.; Otomasu,H.; CPBTAL; Chem.Pharm.Bull.; EN; 26; 1978; 466-471;

Leucine methyl ester reacting with acetaldehyde (VERY attractive conditions):
J.Med.Chem.; EN; 37; 1; 1994; 158-169;

Serine methyl ester with acetalydehyde:
J.Chem.Soc.Chem.Commun.; EN; 18; 1990; 1275-1277;
J.Amer.Chem.Soc.; EN; 115; 17; 1993; 7593-7611;

alanine ethyl ether with methyl phenyl ketone:
Chem.Pharm.Bull.; EN; 31; 3; 1983; 887-894;

alanine t-butyl ester with (heaven forbid!) phenylacetone:
Chem.Pharm.Bull.; EN; 31; 3; 1983; 887-894;

Lr,

I believe you mentioned somewhere that you had ref's for esterification of amino acids my mere refluxing in methanol? This certainly would save a lot of precious alkyl halide in certain cases. What were the ref's, or should I get them?

-drone #342


Labrat
Member   posted 12-10-98 10:04 AM          
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Drone, I'll put a stop to that confusion! Yes, you'll have to protect the amine in the amino acid, otherwise it'll react with the electrophile. I'm thinking about making benzaldehyde from benzyl alcohol and using this aldehyde to protect the -NH2. Do you know any good and easy methods to do this?
The imine can be made easily, check the literature I gave on this. I think that you'll need an aromatic aldehyde to form the imine. The imines from benzaldehydes are more stable then from alkylaldehydes, so the former will have a higher acidity, which is necessary in the PTC (15The best article on the alkylation is prolly Tetrahedron 5343('88). Don't miss that one!
You can prolly do a Fisher esterification on the amino acids, since they won't decarboxylate at the reflux temp of e.g. methanol or ethanol. The amine won't react too under these conditions. Thus, the esters are made by refluxing the amino acid in methanol/ethanol with a little HCl added. In the Phenylalanine->amphetamine, again thread I gave a ref on this, there's a ref on this method.

BTW, thanks for the BioMedSearch Citations! I'll copy the refs right away! Lr/


Lilienthal
Member   posted 12-10-98 12:46 PM          
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One reason against the in situ esterification of amino acids is their extremely low solubility in the organic solvents used.
But why not preparing the PTC in situ? You only have to add a trialkylamine (triethylamine should do it). The benzylhalogenide is allready in the reaction.
 
Labrat
Member   posted 12-11-98 10:17 AM          
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After reading some more articles, I'm not so convinced anymore that you can use the free amino acid. Transesterification under these conditions was possible, but only thru rxn of benzyl halide with KOH, forming benzyl alcohol, which after deprotonation can react with the esterified amino acid.
But making the esterified amino acid is a breeze, just reflux in methanol or ethanol with a little HCl added and evaporate the methanol to get the amino ester.

I've thought about making the PTC too, until I discovered that the PTC is optional. Useful yields of product are obtained by simply refluxing the alanine ester, K2CO3, benzyl bromide in acetonitrile. But you're right, the catalyst could be made in situ. Lr/


drone 342
Member   posted 12-11-98 03:57 PM          
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Besides, PTC's are cheap, plentiful, and unwatched. There are also lots and lots of examples of facile esterifications of amino acids in the literature, so this is hardly a problem.
-drone #342


Lilienthal
Member   posted 12-21-98 07:55 AM          
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Labrat, my source (Tet. 17, 5343 1988, this paper is an absolutely must!) gives 2% yield for this reaction in CH2Cl2 without the PT-catalyst, so the catalyst seems to be essential. Was it a mistake or do you have other sources?
 
Labrat
Member   posted 12-21-98 10:00 AM          
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Lilienthal, I can't tell you right now what ref alkylated the amino acid without PTC. I'd have to check that out at home (I always work on a public server).
I do remember that the conditions were a little different: the benzylidene amino ester was dissolved in CH3CN and K2CO3 and benzyl bromide were added. The mix was then refluxed and ~70% yield of wanted product was obtained. This is a lot better then the yields in your ref. The article I mean is in one of the refs I gave earlier. Should I look it up again? Lr/


drone 342
Member   posted 12-21-98 08:01 PM          
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PTC's are innocuous and dirt-cheap, why all the fuss of leaving them out of the equation?
 
Labrat
Member   posted 12-23-98 09:16 AM          
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Drone, I just wanted to point out that the PTC is not absolutely necessary. That doesn't mean that we're not going to use them! Yes, ofcourse we'll use them, they're cheap and make the rxn go faster and make higher yields possible. Lr/
 
drone 342
Member   posted 12-23-98 03:41 PM          
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Ah, point taken.
Seeing that there are several steps, perhaps we ought to delegate tasks: I could compile one part, you the other, etc. Maybe this might make things go faster.

-drone #342


Labrat
Member   posted 12-24-98 09:31 AM          
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Yes, it would be a good idea to delegate tasks here, but don't forget that it has got to be tested before submitting anything!
I'd like to do the PTC alkylation and aldol condensation part. Could you take care of the esterification, the imination and the decarboxylation?

And please, send me more Beilstein abstracts (not in *.prn format!). I doubt I got all the pertinent refs on amino acid alkylation and aldol condensation. What happened? Didn't you get my posts? You got fed up with it, what? I'd like to know what's up? Lr/


drone 342
Member   posted 12-24-98 10:44 AM          
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Lr,
Sorry 'bout dropping out like that for a while. My access to making "good" Beilstein files is limited right now. I can send them now, if you like. Can't remeber what exactly you were loking for, so I guess I'll surprise you.

-drone #342


Cherrie Baby
Member   posted 10-31-1999 02:12 AM          
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I have a couple of interesting references from the book "Phase-Transfer Catalysis - Mechanisms and Syntheses", ed by Marc Halpern, ACS 1997.
Chapter 10: Amino Acid and Peptide Synthesis Using Phase-Transfer Catalysis. pages 124-135

Chapter 16: Microwave-Irradiated Alkylations of Active Methylenes Under Solid-Liquid Phase-Transfer Conditions. pages 203-213.

Chapter 16, by some Chinese guys, discusses the use of microwaves to make the reaction work for a subst-benzyl chloride (rather than bromide). Yeh I know they only tried it on 'active methylene groups' [glycine ester imine] but..

Chapter 10 is a review by Martin O'Donnell et al.


 
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