Author Topic: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids] (Read 1290 times)

Naf1 · « **Reply #20 on:** August 04, 2009, 12:28:02 AM »

That is incorrect;
They just used that as a representive of the enolate. For example in patent;6043376, example 2 of the patent they use Lithium bis(trimethylsilyl)amide [C6H18LiNSi2] as strong base that forms a metal enolate (Li-enolate). Like below;

While I have ChemOffice out, lets get this stereochemistry straight. The first image is of the Cis-oxazolidinone note both bonds on the same side. After adding a strong base, the enolate is formed followed quickly by the metal enolate where the original stereogenic center from the amino acid has been destroyed. Now when the alkyl halide attaches to the ring, it is sterically favorable for it to do so trans to the chiral center at 'R'. Trans isomers are generally more stable than Cis, and it holds true for this case also.

zzhuchila_clocker · « **Reply #21 on:** August 04, 2009, 08:45:10 AM »

Thanks, Naf1! Aspartam nation will never forget your impact to amphetamine s?nthesis now )) (aspartam contains phenylalanine if someone didn't know).
some clarifications to the diagrams again: alkylhalide + C=C-OLi = alkyl-C-C=O + Li halide, that is more correct

Naf1 · « **Reply #22 on:** August 04, 2009, 11:27:09 PM »

Man your good!

I would have changed it but I cant modify the message anymore.

Sedit · « **Reply #23 on:** August 05, 2009, 12:01:02 AM »

You both are putting me to shame so im just sitting back watching the show and jammin a little knowledge into Sedits brain.

2bfrank · « **Reply #24 on:** August 05, 2009, 07:29:59 AM »

"That is incorrect"

Yes, my explanation didnt go into the details of what usually happens when a base removes a hydrogen in such a position with respect to the oxygen.(the electrons have to go somewhere, if possible) That movement that includes its brief return to that depicted carbon with 5 bonds, and onward attack, is fast, and obviously the lithium ion is somewhat stabilizing the oxygen when its non bonding orbital gets filled.

To be honest I haven't given that patent much of a look, I think I will, their choice of reagants is pretty cool.

It is good to have what one says scrutinized. I balls things up, and its okay to be learning.
Ill think Ill make the time to work through this mechanism myself, rather than agreeing/disagreeing to bits and pieces.

It is good that their are others here who value this aspect of chem.,people who I can learn from, and also share with others what I have learnt.

2b

[:::POST MERGED:::]

I just read what I wrote and perhaps wasn't clear, So for clarity, etc,

the proton is removed, the electrons wont want to sit on that carbon and as well they are attracted to the oxidised 2+ carbonyl carbon, this forms the depicted carbon w five bonds, It doesnt really, but that it the direction that the patent was conveying I feel, anyway the pi bond of the carbonyl is broken and those electrons move into the oxygens non-bonding orbital, and thus foruming an anion, or enolate, and this is likely to be stabalised with the lithium cation. Anyway due to thermodynamics, or perhaps kinetic factors, the non bonding electrons move back, into the pi orbital, and at the same time the alkene double bond is attacking the alkyl halide, this movement happens quickly and together. Is wonderful, and a common movement in chem I believe.

I just went into this detail, as I think it is important to get this stuff right, and if not, hear from others, etc.

2b

Also the ozidised 2+ carbonyl carbon, is just a way that lots of people view ox/red in organic, but in one way it is delta change, as electron density being drawn from the carbon due to the more electronegative oxygen, and not an actual loss of electons as such.

Naf1 · « **Reply #25 on:** August 05, 2009, 11:01:00 PM »

Sorry 2B;

"Thats IS incorrect"

I was actually agreeing with Enkidu's and your comments, as in yes that enolate diagram with a carbon with 5 bonds is not technically correct. That is incorrect was definitely not aimed at your post! I will definitely be more clear next time. I actually agree with your first post, and enjoyed reading the above so am glad you ended up posting it anyway.

Sorry for that! $:-\$ \

2bfrank · « **Reply #26 on:** August 06, 2009, 01:25:38 AM »

Naf1,

all good, I did think you were refering to what 2b stated, I thought you may of felt that I was stating that the proton or hydrogen being removed would create that carbon/5 bond representation, and from their attack the alkyl halide, and not the rest as described.( enolate formation etc) I didn't go into that detail, and saw briefly what you stated, and thought It best I do. I haven't got a problem at all, getting confused with things, and appreciate learning when I have. I just hate being misunderstood, or feeling that I have, when I do in fact feel very clear on something.

All in all, this thread is a doozy. I think, it was good that I go into that detail for something somewhat standard, perhaps someone who is really new to this may pick something up, I picked up a few things from yourself, and zz-chuzila and will be going into this from start to finish and refer to what you guys discussed.

Like alot of chemical reactions, if you look hard enough it usually contains everything. This reaction in particular, does this, and in short is awesome.

2b

Happyman · « **Reply #27 on:** September 10, 2009, 05:39:18 AM »

Is there an problem with methylating tryptamine to alpha-methyltryptamine? If so got any good suggestions? Would some of the methylations in Phenylpropanolamine to Ephedrine?

Sedit · « **Reply #28 on:** September 24, 2009, 04:04:52 PM »

I have an idea that im kind of annoyed it never struck me before. Would decarboxylation of Ethylenediamine-tetraacetate(EDTA) work?
Im thinking of a reflux of EDTA with acetone to afford the decarboxylated product Ethylene Diamine. A useful ligand for creating metal complexes amongst other valuable uses. EDTA is highly avalible in large amounts so low yeilds are not really a problem as long as a usable amount is fine.

Naf1 · « **Reply #29 on:** September 25, 2009, 12:16:41 AM »

@Happyman

The methylations used for phenylpropanolamines to ephedrines are N-methylations, where the methyl group is attaching to the N (nitrogen) of the amine, thus a N-methylation.

Alpha methylation refers to placing a methyl group at the alpha carbon of the alkyl chain.

@Sedit, simple hydrolysis will afford the parent amine!

procedure from this patent;
http://www.freepatentsonline.com/3994966.html

"Step IV: Hydrolysis of N,N'-diacetyl 1-p-nitrophenylethylenediamine

A solution of 2.65 gm of N,N'-diacetyl 1-p-nitrophenylethylenediamine in 12 ml acetic acid, 2 ml water, and 18 ml conc. hydrochloric acid was heated at reflux for 20 hr., cooled in ice, filtered, made strongly basic, and extracted with methylene chloride. The organic phase was dried with anhydrous magnesium sulfate and dry hydrogen chloride was introduced. The resulting solid was combined with the original precipitate (if any) and washed with methanol. The yield was 1.68 gm (66%) of 1-p-nitrophenylethylenediamine-2HCl, m.p. 220°-241° (decomp.)."

Purification of laboratory chemicals
http://books.google.com.au/books?id=SYzm1tx2z3QC&pg=PA58&lpg=PA58&dq=alkaline+hydrolysis+acetyl+derivatives+amines&source=bl&ots=qBQVjJ2D_I&sig=EKMbwD_aOdjcexd3dRoGgL2i354&hl=en&ei=ofu7SoqPAY6gswP7i9XcBQ&sa=X&oi=book_result&ct=result&resnum=1#v=onepage&q=alkaline%20hydrolysis%20acetyl%20derivatives%20amines&f=false

no1uno · « **Reply #30 on:** September 25, 2009, 03:02:31 AM »

Naf1, instead of going via a-methylation of phenylalanine - why not just look at those papers from Belokon, et al (and MANY others) on the a-alkylation of alanine using benzyl halides... They use PTC (actually they use chiral PTC for high ee's), but that shouldn't be too fucking hard, considering benzyl halides and the ever so easily acquired Quinine would form a chiral PTC too (actually, quite a well known one).

Quote

Generation 2: Cinchona alkaloids[/u]

The most intensely studied group of catalysts has been those prepared by quaternization of cinchona alkaloids (Figure 4 and Table 1 – see p. 10). Cinchona alkaloids are readily available and relatively inexpensive, they are easily quaternized and they exist in diastereomeric pairs. N-Benzyl quininium chloride (“QUIBEC”) was prepared very easily by mixing quinine and benzyl chloride in benzene-ethanol at room temperature for 26 hours. Quinine has long been used as a chiral resolving agent and has been used as a catalyst itself for asymmetric reactions as long ago as 1912. (footnotes omitted)

Taken from here (Page 8/17)

Given that O'Donnell used this "type" of catalyst to a-alkylate Glycine (IIRC) and Belokon etc. have used this, or a variant, to do so with Alanine and of course given the ease of preparing Benzyl Chloride (rather more so than benzaldehyde at any rate), you'd have to expect this to be better known than it is... Anyway, this is a little collection on the subject.

But why is PTC necessary? Surely the N-benzylidene-amino acid (or preferably the benzophenone/ketone [NB seriously thinking acetone here] variant) could be in the form of an ester? Surely that would be soluble in the NP phase?

On top of that, would it be possible to decarboxylate the N,a-dimethylphenylalanine to meth in one pot? Cos Dalopon (2,2-dichloropropionic acid - grass killer) is transformed on hydrolysis to pyruvic acid, that with methylamine gives N-methylalanine... If not - Strecker deg of the a-methylphenylalanine will give P2P in one hit.

I can't see simple hydrolysis of EDTA working, be interesting to see what would happen if you formed amides from all four carboxylic acid ends then hit it with hypochlorite but:P

2bfrank · « **Reply #31 on:** September 28, 2009, 03:00:32 PM »

Interesting, and acetone would be a likely possibility..here's some data that looks at acidities of a Glycine Schiff base, as well as some Product Studies in the Alkylation of Schiff Base Esters of
Alanine by Different Phase-Transfer (PT) Methods - which includes hydrolysis.

Abstract: Equilibrium acidities in Me2S0 are reported for six ketimines of the type Ph2C=NCH(R)C02Et and five aldimines,ArCH=NCH(R)C02Et. Changing R in the ketimine from H to Ph increased the pKa by 2.2 units. This surprising acidity decrease for Ph substitution points to a substantial increase in steric effect,
as do the increases in pKa of 3.8 and 4.2 units observed for the replacement of hydrogen by Me and PhCH,, respectively. Phase-transfer alkylation of the Ph2C=NCH2C02Et ketimine gave over 90% of monoalkylate whereas, under similar conditions, the aldimine 4-ClC6H4CH=NCH2C02Et gave a
mixture of mono- and dialkylate. The difference is that the pKa of the monoalkylated aldimine is essentially the same as that of the parent, which leads to rapid equilibration with the parent anion
and consequent dialkylation. The rates of alkylation in Me2S0 of these parent and monoalkylated anions did not differ greatly, showing that the relative pKHa's of the parent acid and its monoalkyl derivative, rather than the relative rates of the mono- and dialkylation reactions, is the principal factor that
determines the extent of the competition between monoalkylation and dialkylation.

woops, just seen the link to papers on this..I wont remove in case the acidic data is of use.

I also think it might be possible to use a base other than NaOH hence ptc, but one that is not nucleophilic, perhaps stericaly hindered so it doesn't fuck with the ester. Their must be something OTC that could do this. I also haven't done much with PTC's and starting to see enourmous benefits...and also if I am reading this paper correctly, p-chlorobenzaldehyde as the carbonyl for the schiff base gives much better yields, due to an increase in acidity..so something that is not symetrical perhaps..be good if MEK was possible, but an aldehyde may be the prime contender..yep that fits with the asymmetrical paper posted. just had a better look..Interesting..

Naf1 · « **Reply #32 on:** September 29, 2009, 05:09:38 AM »

It definitely has merit, I was initially attracted to phenylalanine because it is so easy to get. Benzyl chloride would be the sticking point though, I know it can be acquired but is most certainly watched (from way before the days of cold pills). If I did have everything to do it, I think it would be easier than any of the a-methylations of phenylalanine I have encountered so far.

"On top of that, would it be possible to decarboxylate the N,a-dimethylphenylalanine to meth in one pot? Cos Dalopon (2,2-dichloropropionic acid - grass killer) is transformed on hydrolysis to pyruvic acid, that with methylamine gives N-methylalanine... If not - Strecker deg of the a-methylphenylalanine will give P2P in one hit."

Now that is a question! I have come across examples of oxidative decarboxylation of N-protected amino acids, and decarboxylations of amino acids having an electron withdrawing group at the alpha position are decarboxylated under mild conditions. It should work!

pyruvic acid and methylamine is a good idea!!

The strecker has been gone over, so has degradation of phenylalanine to phenylacetaldehyde. I am still interested in producing phenylacetaldehyde from phenylalanine, it can be done easily and phenylacetaldehyde is valuble! As that too can be reacted with methylamine then a grignard produces meth.

no1uno · « **Reply #33 on:** September 29, 2009, 12:15:59 PM »

Hmmmmm, 2bfrank - what about our everyday favorite benzaldehyde - vanillin? Of course we are going to waste one equivalent of BnCl alkylating that vacant OH but that shouldn't be too hard to work around?

Shame benzophenone won't work, wonder how acetophenone would work (given that it is used as a benzyl substitute in the a-phenethylamine route to stereospecific transamination - ie removable by hydrogenation - would it form a pseudo-benzylidene? Without the massive steric effects?)

The other real issue is that I have not yet seen anything that says the N,a-dimethylphenylalanine is able to be decarboxylated in any decent sort of yield.

PS Naf1, I have done the l-Phe to Phenylethanal, you need commercial bleach (work out the ratio), at least 2-2.5 equiv's of bleach or you'll see the prettiest red tar ever (turns brown and frustrating over about 5 minutes and is a CUNT to get off glass). The smell of the yellow product when done right is hard to describe, overpowering, floral, sickeningly sweet and somehow cough medicine like (done in a glass using a knife to stir it).

Naf1 · « **Reply #34 on:** September 29, 2009, 11:26:49 PM »

"is a CUNT to get off glass"

LOL, I am sorry no1uno, but I have been pinned elsewhere. Are you Australian? You sound like an aussie!

"I have done the l-Phe to Phenylethanal, you need commercial bleach (work out the ratio), at least 2-2.5 equiv's of bleach or you'll see the prettiest red tar ever"

Well done! Where you able to work up a reasonably pure aldehyde for yield determination? As I would be very interested in the yield returned from that procedure, to work out whether it is an economically feasible way to produce phenylacetaldehyde.

"The other real issue is that I have not yet seen anything that says the N,a-dimethylphenylalanine is able to be decarboxylated in any decent sort of yield."

You wont! try looking for ; N-methyl-a-methylphenylalanine. And you still wont find that compound in the literature (on Google anyway). I will also look into that! i.e decarboxylation of alpha methyl amino acids, if that is possible(which I am sure it is!). Then the N-methyl is not really important, if it does great a one pot shot, if not just N-methylate the amphetamine produced no great problem.

edit; The pure phenylathanal should be colorless to pale yellow oily liquid, the red tar is over oxidized product along with what sounds like polymerization of the formed phenylacetaldehyde along with some by products. After working up, you should have a thin pale yellow oil. You may have to distill the phenylacetaldehyde out, using thermolysis to cleave the polymer back to monomer. In future use something like (oxalic, citric acid) as stated here;
Method for stabilizing phenylacetaldehyde
http://www.freepatentsonline.com/6624330.html

quote from;
Synthesis of Phenyl-2-Propanone (P2P) by Rhodium
http://designer-drugs.com/pte/12.162.180.114/dcd/chemistry/phenylacetone.html#phenylacetaldehyde
"Note 1: The phenylacetaldehyde will polymerise on standing. This polymer is degraded to the monomer on distillation. For this preparation it also needs to be as dry as possible"

no1uno · « **Reply #35 on:** September 30, 2009, 12:55:05 AM »

Didn't work it up, just did it to check the procedure (was busy translating Langheld's paper naturiumwasser, etc. was doing my head in:P)....

I think Java came up with a couple of papers on oxidising the Phenethanal to Phenylacetic acid a while back

Also, the phenylacetaldehyde from this would be great for forming the N-methylphenethylamine for the isoquinoline syntheses;)

Naf1 · « **Reply #36 on:** September 30, 2009, 01:08:12 AM »

I stay of the opinion that the phenylacetaldehyde gassed with methylamine gas, then added to a methyl grignard to produce racemic methamphetamine! or if methylamine could not be acquired, ammonia could be used to produce amphetamine.
http://www.erowid.org/archive/rhodium/chemistry/meth.phenylacetaldehyde.html

"Also, the phenylacetaldehyde from this would be great for forming the N-methylphenethylamine for the isoquinoline syntheses;)"

The phenylalanine would be better, no? As you could just easily decarboxylate to phenethylamine, as per the paper quoted in the first post. Then a simple means to N-methylate with formaldehyde and zinc, working up the amine should not be a problem opposed to the nightmares encountered trying to work up the amino acid.

no1uno · « **Reply #37 on:** October 06, 2009, 09:29:27 AM »

Here is a nice paper - seems ketones aren't necessary at all

Quote

20 gm. of tyrosine were mixed with 120 cc. of pure distilled diphenylmethane and 120 gm. of diphenylamine in a liter round bottom Pyrex flask, fitted with an air condenser, and the mixture was carefully heated with a Bunsen flame, care being taken to prevent local superheating or charring. At 260'C carbon dioxide began to be liberated and in a few minutes the evolution of this gas was copious; and at the end of 40 minutes heating at a temperature of 260-265'C, the reaction was apparently completed, the hydrocarbon->amine solution. presenting a clear yellow appearance without any indication of carbonization. Although the melting point of tyrosine is about 295'C our decarboxylation had been effected in this medium at 260'C. The clear yellow solution was allowed to cool to 60” when the mass became [table - LEFT OUT FOR CLARITY] quite cloudy. At this point 100cc. of benzene were added to prevent tyramine from adhering to the walls of the flask, and the contents agitated to cause thorough mixing of the benzene. 1 hour cooling in an ice bath caused the tyramine to deposit as a fine yellow powder which was filtered off by suction and washed several times with warm benzene to remove the solvent mixture. What tyramine adhered to the walls of the reaction flask was recovered by conversion to the hydrochloride and extracted with water.

From 140 gm. of tyrosine thus treated in seven runs of 20 gm. each, there were obtained 86 gm. of crude tyramine and 18.5 gm. of crude tyramine hydrochloride, equivalent to 14.6 gm. of the base, giving a total of 100.6 gm. of crude tyramine. .A quantitative yield of tyramine from tyrosine is 105.98 gm. Therefore, our yield of tyramine is equivalent to 95 per cent of the theoretical, a result which establishes this method of preparation as the most productive and practical of any hitherto described.

Enkidu · « **Reply #38 on:** October 06, 2009, 07:27:06 PM »

Thanks for that ref. All that the decarboxylation needs is a solvent with a high boiling point (>210*C) but that is also a liquid at room temperature. Any ideas for an otc solvent that meets those requirements?

Sedit · « **Reply #39 on:** October 06, 2009, 10:34:42 PM »

Several types of silicone oil seem like the perfect thing but im unsure about there solvating properties which honestly may not really matter much. Melting and boiling points with the wide range of -100 mp/550C bp would make them pretty useful. I doubt they would be all that reactive either being polymerized Siloxanes which if I recall correctly are not the most reactive species in the world.

Author Topic: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids] (Read 1290 times)

Naf1

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

zzhuchila_clocker

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Naf1

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Sedit

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

2bfrank

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Naf1

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

2bfrank

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Happyman

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Sedit

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Naf1

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

no1uno

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

2bfrank

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Naf1

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

no1uno

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Naf1

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

no1uno

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Naf1

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

no1uno

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Enkidu

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]

Sedit

Re: Tools for the Synthetic Chemist [Decarboxylation of a-Amino Acids]