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Production of 2-Methyl-3-phenylserine.
There are various methods of synthesizing PPA. Perhaps the most straight forward is the reaction of nitroethane with benzaldehyde however the difficulty in aquiring or synthesis of nitroethane, for some, is a major shortcoming. The akabori reaction, where an aldehyde is condensed with an amino acid is an alternative method to the production of PPA. Several abstracts describing the Akabori reaction have been brought to the attention of the hive. Seemingly attractive are the methods where PPA is produced directly from the akabori condensation of alanine and benzaldehyde. Though this appears simple, it does not afford good yields. An alternate route to PPA is the formation of a alpha-methyl phenylserine derivative then its decarboxylation. This idea was put forward by Aurelius and D thinks this is genious and it would be even more genious if D could get it to work but I guess every method starts out this way!. The alpha-methyl phenylserine can be produced in good yields and theoretically can be decarboxylated through heating to form PPA. Below is D’s experimental for the formation of 2-Methyl-3-phenylserine (the desired phenylserine that will give PPA when decarboxylated) according to a Patent put forth by Aurelius (see references and link Post 423224 (missing)
(Aurelius: "US Patent 4501919 (Akabori)", Stimulants), D put the abstract in the post so that it could be easily compared to). It should be added that the patent describes the use of glycine however the patent mentioned that alanine (isomer not specified) would work as well.
Experimental:
1) 0.4 mole of benzaldehyde and 0.02 mole of hexadecyl trimethyl ammonium bromide (HTAB) in 200ml of dichloromethane was cooled to 0 deg C.
2) 0.2 mole of dl-alanine and 0.22 mole of sodium hydroxide was dissolved in 30 ml of water and cooled to 0 deg C.
3) The basic alanine solution was dropped into the dichloromethane phase over 4.5 hrs with good stirring. The temperature of the dichloromethane phase was kept at 2-4 deg C by use of a ice bath. The mixture had no colour.
4) After all of the basic alanine solution had been added, the mixture was allowed to stir for another 3 hrs. The mixture did not take on any colour.
5) 35ml of 1 M HCl in 200ml of water was added to the mixture (homogenous) and the solution was heated to 35 deg C for 30 minutes and then cooled to 20 deg C. The two phases separate out when the mixture cools to 20 deg C. The aqueous and the dichloromethane phase are separated with a sep funnel. The aqueous is concentrated such that 200ml of distillate are collected.
6) The residue was cooled to 5 deg C for two hours by placing the residue in a fridge at 4 deg C. At this point the phenylserine is supposed to crystallize. And a bright white precipitate (ppt) DID form and he was quite excited but when he went to “cold” vacuum filter it, it clogged the filter paper immensely and took about 1hr to filter (no longer “cold”). And what seemed to be initially a large volume of ppt became a thin film on the filter paper that shined and would not dry out. A portion of the ppt film was taken between two fingers and it bubbled. Driven concluded that this was the HTAB and wondered all along how it would be removed from the reaction in the workup. Figuring the product was in the filtrate Driven put it the fridge and yet again another crop of HTAB precipitated out (there was a lot of HTAB added initially so this made sence). So Driven kept filtering and crashing what he believed to be HTAB. After doing this about 5 times Driven gave up and figured that something had gone wrong as the original abstract says that the phenylserine is supposed to ppt NOT the phase transfer catalyst. But there isn’t much to screw up in this procedure. Perhapse the HCL wasn’t concentrated enough?
Does anyone have any thoughts on what could of went wrong? How could the phase transfer catalyst be kept from interfereing?
Thanks everyone!
DRIVEN :)
References:
From US Patent 4501919
Example 1:
60.4 g (0.4 mole) of p-nitrobenzaldehyde and 4.8 g (0.02 mole) of methyltributylammonium chloride in 200 ml of CH.sub.2 Cl.sub.2 are cooled to 5.degree.-7.degree. C. 15 g (0.2 mole) of glycine and 8.8 g (0.22 mole) of sodium hydroxide are dissolved in 30 ml of water and the obtained solution is dropped into the stirred methylene chloride phase in 4 hours. Stirring at 5.degree.-7.degree. C. is continued for further three hours then 35 ml of concentrated hydrochloric acid and 200 ml of water are added. The mixture is heated to 35.degree. C. for 30 minutes and then cooled to 20.degree. C. The two phases are separated and the aqueous one is concentrated by distilling out a volume of 200 g of water. The residue is cooled to 5.degree. C. for 2 hours and the crystalline precipitate which forms is recovered by filtration and dried under vacuum. Yield 42.2 g of threo-(p-nitrophenyl)serine hydrochloride. Considering that the CH.sub.2 Cl.sub.2 phase contains 34 g of p-nitrobenzaldehyde (as determined by G.L.C. analysis) which is recycled, the percent yield in threo-(p-nitrophenyl)serine hydrochloride is 92% calculated on the p-nitrobenzaldehyde. Further 1.6 g of threo-(p-nitrophenyl)serine hydrochloride and 1.5 g of the erithro form may be obtained from the mother liquors deriving from the filtration.
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try doing an extraction of your serine from the mixture and then fractional vacuum distillation. Once you've done this, you should be able to crystallize your product (the catalyst won't come over with it).
After this, you can perform the decarboxylation reaction.
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Thank Aurelius,
By extraction I presume you mean to basify the aqueous to stronly basic then extract with DCM. HTAB, being a PTC will come over into the DCM but during fractional distillation the residual HTAB is separated from the phenylserine.
Aurelius do you have any boiling point data on this particular phenylserine? , all D could find in the literature was melting points.
For the decarboxylation should the phenylserine be as a freebase or its corresponding HCl salt prior to spontaneous decarboxylation from its heating to 150*C+ (up to 200*C).
Cool.
DRIVEN :)
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I'd just leave it as the salt. However, several decarboxylation syntheses I've seen involve the use of the freebase. I don't really think it makes a huge difference as the product will be much more stable regardless how you get there. Try it both ways and report which gives the higher yields on the ~2g starting scale.
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QUESTION
Serine is the synonym for CH2(OH)CH(NH2)COOH
and Phenylserine for Ph CH(OH)CH(NH2)COOH (from benzaldehyde and glycine)
But I think the Akabori Reaction:
PhCHO + CH(NH2)CHCOOH - CO2 (heating) = PhCH(OH)CH2(NH2)
is not running over an intermediate phenylserine, because the alpha (C) atom of glycine will form the bond.
The synthesis of phenylserine was first published in 1895
( Ann. 1895 p. 36 )
Akabori was born in the year 1900
What is the way for the real Akabori Synthesis ?
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I've put all this crap together in a nice little package in the Ephedrine Compilation, I don't see why reading the articles is so hard. The ENTIRE MECHANISM is right there.
It's a two step process in one pot. the two steps toghether comprise the Akabori named reaction. the condensation and then decarboxylation.
(sorry, getting cranky 'cause it's getting late)
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I need the following Akabori literature from the merck index:
http://themerckindex.cambridgesoft.com/TheMerckIndex/NameReactions/ONR3.htm (http://themerckindex.cambridgesoft.com/TheMerckIndex/NameReactions/ONR3.htm)
Ber. 66, 143, 151 (1933)
Ber. 90, 1251 (1957)
and
J. Chem. Soc. 64,608 (1943)
J. Chem. Soc 1955, 1695
J. Chem. Soc. 1956, 303
anyone can publish these literature in the forum ?
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are those not listed in my compilation? (I don't doubt that the text is missing b/c I can't read german and have troubles finding many ref and the time with which to retrieve them)
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If I want to synthesize Phenylserine (the alanin analog), there are a lot of literature,patents pp.
But for the Dacarboxylation I found no successfull prozedure. There are only yields from about 12 or 15%
anyone knows a successful decarboxalation method for the alanin derivat ?
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Driven has been a good researcher for this method so far, I am thankful to be working with him on the literature in this area.
Driven has found a reference (don't remember which one it was) that stated the kinetics of spontaneous amino acid decarboxylation and that it found that addition of acid or base drastically reduced the rate of reaction. A buffer is used to keep the pH around the pKa to keep the molecule in its zwitterionic state. At this point, the decarboxylation proceeds much more quickly/smoothly.
They used a phophate buffer (for pH 7.4) in the example, but I propose find a buffer closer to the pKa of phenylserine. Does anybody have the information necessary for phenylserine?
Thanks again to Driven for his work.
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The article that Aurelius is referring to is Mark J. Snider and Richard Wolfenden. The Rate of Spontaneous Decarboxylation of Amino Acids J. Am. Chem. Soc. 2000, 122, 11507-11508.
It’s a really nice article. I dug it up while searching the literature for optimal conditions in which to decarboxylate 2-methyl-3-phenylserine. As a side note, the authors formed methylamine from the decarboxylation of glycine which is pretty cool. Though the authors concentrated on the basic amino acids like glycine and alanine (and others), they didn’t look at the decarboxylation of 2-methyl-3-phenylserine directly. Nonetheless their work sheds light on the nature of various factors that influence decarboxylation and comments on reaction rates within a biological context. Below I will paraphrase the interesting points.
Start paraphrase. The authors are interested in determining quantitative information about the susceptibility of amino acids to spontaneous decarboxylation in neutral solution. Glycine (0.05 M) in potassium phosphate buffer (0.1 M, pH 6.8) was heated for various time intervals in quartz tubes that had been sealed under vacuum to remove oxygen, over the temperature range between 170 and 260 °C. After the tubes had cooled, the concentrations of glycine and methylamine were determined by comparing the integrated intensities of their proton magnetic resonances in D2O to which pyrazine had been added as an integration standard. The spontaneous decarboxylation of glycine, present almost entirely as the zwitterion at pH 6.8, to yield methylamine was found to proceed to completion following first-order kinetics. The rate of decarboxylation of glycine did not vary significantly in phosphate buffers in the pH range(measured at room temperature) between pH 5.8 to 7.8. However, decarboxylation proceeded approximately 10 times more slowly in solutions in which 0.91 equiv of HCl or 0.91 equiv of KOH had been mixed with the zwitterionic amino acid. Thus, the anionic and cationic forms of glycine appear to be at least 10-fold less reactive than the zwitterion. Decarboxylation was found to be retarded by increasing ionic strength (KCl), as expected for a reaction involving charge dispersal in the transition state. Methyl substitution on glycine produced only a modest effect on the rate of decarboxylation of glycine: thus, rate constants observed for glycine, alanine, sarcosine, and N,N-dimethylglycine were 3.6X10^-6 , 4.7X10^-6 ,17X10 -6 , and 2.0X10 ^-6 s -1 , respectively, at 200 °C.
They determined first-order rate constants for glycine decarboxylation obtained in potassium phosphate buffer (0.1 M, pH 6.8), over the temperature range from 170 to 260 °C. This yielded a linear Arrhenius plot that could be extrapolated to yield a rate constant of 2 X10^-17 s -1 at 25 °C, with an enthalpy of activation of 2 kcal/mol. The half-time for this reaction at 25 °C in neutral.End paraphrase.
So what can we draw from this that pertains to the decarboxylation of 2-methyl-3-phenylserine? Well we learned that it would be optimal to maintain the amino acid in the zwitterionic state, to keep the reaction mixture from becoming to extremely basic or acidic, and to avoid a high ionic strength. To achieve pH control, a buffer system would have to be employed, however we all know that an aqueous system will not permit temperatures of 170-200 deg C to be reached by reflux at atmospheric pressure (perhaps alternatively the reaction could be heated in a bomb of sorts). A challenge will be to derive a buffer system that operates in a high boiling point solvent.
As well it is important to know the pKa of the amino acid to be decarboxylated so that the right buffer system could be chosen. I have yet to find the pKa for 2-methyl-3-phenylserine (that task is on the top of my list) and if anyone has it, please divulge! The next best thing perhaps would be to consider the pKa of serine which is 2-methyl-3-phenylserine minus the 3-phenyl and 2-methyl groups. These groups are not ionizable and are unlikely to affect the pKa AFAIK. There are titration experiments which have reported the average pKa of serine to be 9.02.
Aurelius has helped me immensely with both the technical and theoretical aspects of this experimental. As it stands, the working decarboxylation method (yet to be employed) is to first form zwitterionic state of the phenylserine by basifying it to pKa (as close as possible to the approximated 9.02). This will render the molecule neutral overall and permit its migration into the organic solvent. For convenience the solvent used will be mixed xylenes which has a boiling point range of 136-140 deg C. If D can conveniently find a higher BP solvent, and a buffer system, it will be employed. The solution will be heated to 200 deg C where a slight crackling noise will be heard. Heat will be applied such that the bubbles are maintained. When the bubbling tapers off, heat will be increased but not to ever exceed 220 deg C.
The following is DRIVEN's proposed clean up method (critisms are welcome!) The post reaction will be washed with stongly basic aqueous (remaining phenylserine will be rendered negatively charged and will migrate into aqueous and PPA will be kept nonpolar and will be retained in the xylenes). The xylenes will be extracted with acidic aqueous (PPA will become charge and migrate into aqueous). At this point I'm not sure whether I should crystallize the PPA or form its freebase and distill it. Distilling it will tell me the bp and thus the isomer(s) which is very informative so perhaps that is the way to go.
DRIVEN :)
PS: Amino Acids are fun.
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Thanks for the extra information in that article, I will include it in the akabori section of my digest for additional information for those out there seeking to optimize this procedure. Again, thanks for doing research in this area.
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The Preparation of Hydroxyphenylserines from Benzyloxybenzaldehydes and Glycine1
William A. Bolhofer
JACS, 76, 1322, (1954)
Abstract:
Threo-beta-meta-Hydroxyphenylserine (X), threo-beta-p-hydroxyphenylserine (XI) and both diastereoisomers of beta-3,4-dihydroxyphenylserine (XII) have been prepared. Glycine, when allowed to react with m-benzyloxybenzaldehyde (I) in alcoholic potassium hydroxide, yielded threo-beta-m-hydroxyphenylserine (X) after acidification and hydrogenolysis of the intermediate N-benzylidene potassium salt. Likewise, from glycine and p-benzyloxybenzaldehyde (II), threo-beta-p-hydroxyphenylserine (XI) was prepared. The condensation of 3,4-dibenzyloxybenzaldehyde (III) with glycine yielded beta-3,4-dibenzyloxyphenylserine (IX) as a mixture of diasteroisomers after acidification of the intermediate N-benzylidene potassium salt. These isomers were separated by fractional crystallization and hydrogenolyzed to yield both pure diasteroisomers of beta-3,4-dihydroxyphenylserine (XII).
The involved, indirect procedure required for the preparation of erythro-beta-p-hydroxylphenylserine from ethyl-p-benzyloxybenzylacetate2 and the fact that the threo isomer was not obtained at all indicated that any attempt to extend this method of synthesis to the preparation of even one of the diastereoisomers of beta-3,4-dihydroxyphenylserine would meet with failure. It could be expected that the intermediates in the 3,4-dihydroxy series would be even less stable than those in the p-hydroxy series. For these reasons, a modification of the original Erlenmeyer3 synthesis was examined for its applicability to the preparation of various beta-benzyloxyphenylserines which, on hydrogenolysis, would yield the desired beta-hydroxyphenylserines. In this modification, the aqueous alkali used by Erlenmeyer for the condensation of the aldehyde with glycine, is replaced by alcoholic alkali. Such substituted serines as beta-(2-thienyl)-serine,4 beta-(2-furyl)-serine,5 and beta-3,4-methylenedioxyphenylserine6 have been synthesized by this modified procedure.
In this laboratory, benzyloxybenaldehydes were found to react rapidly with glycine in alcoholic potassium hydroxide to give N-benzylidene-beta-benzyloxyphenylserines. Acidification and hydrogenolysis yielded the desired beta-hydroxyphenylserines. Initial experiments were carried out in the m-hydroxyl series because of the ease of identification of the diastereoisomeric beta-m-hydroxyphenylserines by MP alone.2
The condensation of two moles of m-benzyloxybenzaldehyde (I) with one mole of glycine was brought about in an alcoholic potassium hydroxide solution. A solid, crystalline potassium salt (IV) could be isolated, but a better over-all yield was obtained when the entire mixture was acidified. Acidification of the benzylidene compound (IV) caused the regeneration of approximately half of the starting m-benzyloxybenzaldehyde (I) with the simultaneous formation of beta-m-benzyloxyphenylserine (VII). This compound appeared to be a single diastereoisomer and its melting point did not change after a number of recrystallizations. Although no evidence of the presence of other diastereoisomer was obtained, this does not constitute absolute proof that the reaction proceeds to yield only one isomer. Debenzylation of the beta-m-benzyloxyphetnylserine (VII) was achieved by catalytic hydrogenolysis and the product was identified by its melting point as threo-beta-m-hydroxyphenylserine (X).
Threo-beta-p-hydroxyphenylserine (XI) was prepared from p-benzyloxybenzaldehyde (II) in a similar manner. Two moles of (II) were condensed with one mole of glycine and the resulting potassium benzylidene salt (V) was isolated as a crystalline solid in good yield. Acidification of the salt (V) gave beta-p-benzyloxyphenylserine (VIII) which appeared to be a single isomer. Catalytic hydrogenolysis removed the benzyl group and threo-beta-p-hydroxyphenylserine (XI) was obtained. The threo configuration was assigned to the product by analogy with the m-hydroxy series. The decomposition point of the beta-p-hydoxyphenylserine prepared by this method is 15*C lower than that reported by this laboratory for the erythro isomer.2 Holland, Jenkins and Nayler7 have recently reported the preparation of threo-beta-p-hydroxyphenylserine (MP: 188*C) from threo-beta-p-nitrophenylserine.
When 3,4-dibenzyloxybenzaldehyde (III) was allowed to react with glycine in alcoholic potassium hydroxide, the potassium salt of the N-benzylidene-beta-phenylserine (VI) separated from the alcohol solution as a heavy oil. After acidification and removal of 3,4-dibenzyloxybenzaldehyde, the beta-3,4-dibenzyloxyphenylserine (IX) was obtained as a powder. This product proved to be a mixture of two diasteroisomers which could be separated by fractional crystallization to give a high-melting and a low-melting isomer. The high-melting and a low-melting isomer. The high-melting isomer was debenzylated in 50% methanol by catalytic hydrogenolysis. The product, the low-melting more-soluble isomer of beta-3,4-dihydroxyphenylserine (XII), was obtained as a hydrate when the solution was concentrated. 8 The low-melting isomer of beta-3,4-dibenzyloxyphenylserine (IX) was obtained as a hydrate. It was debenzylated in dilute alkali and the high-melting isomer of beta-3,4-dihydroxyphenylserine (XII) was obtained. This isomer appears to be identical with the beta-3,4-dihydroxyphenylserine reported by Rosenmund and Dornsaft9 and Dalgliesh and Mann.10
The infrared absorption spectra of DL-threonine,11 DL-allothreonine11 and the racemic diastereoisomers of beta-phenylserine,12 beta-m-hydroxyphenylserine,2 beta-p-hydroxyphenylserine2 and beta-3,4-dihydroxyphenylserine were determined in Nujol. The absorption curves are not absolutely conclusive in themselves, but the data can be used in conjunction with chemical evidence as an indication of stereochemical structure. Comparison of the spectra of substances of proven structure (threonine and allothreonine and threo- and erythro-beta-phenylserine) shows that a band occurs regularly at 11.90-11.95 mu for those substances having the erythro- configuration. This band was not observed in the spectra of compounds possessing the threo configuration. A band at 11.90 mu appeared also in the absorption spectrum of the beta-m-hydroxyphenylserine assigned the erythro structure on the basis of chemical evidence alone. Likewise, examination of the spectra of the beta-p-hydroxyphenylserines indicates that the configuration assigned each diastereoisomer is correct. The presence of a band at 11.95 mu in the spectrum of the beta-3,4-dihydroxyphenylserine (MP: 199-200*C) indicates that is has the erythro structure. This band is missing from the spectrum of its isomer melting at 220-225*C, which can therefore be assigned the threo configuration.
Experimental13:
Example 1:
threo-beta-m-benzyloxyphenylserine (VII)
To a solution of 5.61g (0.1 mole) of potassium hydroxide and 3.75g (0.05mol) of glycine in 75ml of absolute alcohol, there was added a solution of 21.2g (0.2mole) of m-benzyloxybenzaldehyde14 in 25ml of absolute alcohol. The mixture was warmed until it was clear and the solution was allowed to stand at RT. A brown oil separated which crystallized slowly, MP: 125-130*C. However, it was unnecessary to obtain a crystalline product at this point. After standing overnight, the alcohol was decanted and the residual oil was dissolved in a mixture of 200ml of 2N HCl and 50ml benzene. The benzene was separated and the aqueous solution was again extracted with 50 ml of benzene. (from these benzene extracts approximately half of the starting material was recovered) The aqueous solution was concentrated ammonia and, after standing overnight at 0*C, crystalline threo-beta-m-benzyloxyphenyserine (9.0g, 62.7%) was obtained. After two recrystallizations from methanol, the product melted with decomposition at 185*C.
Example 2:
threo-beta-m-hydroxyphenylserine (X)
A solution of 14.37g (0.05mol) of the product from Example 1in 50ml of 2N ammonium hydroxide and 25ml of methanol was hydrogenated at 1atm using 1.0g of 5% Pd/C. After 24 hours, the theoretical amount of hydrogen had been absorbed and the catalyst was removed by filtration. Water (100ml) was added and the solution was concentrated to a small volume. The mixture was neutral and 7.9g (79.7%) of threo-beta-m-hydroxyphenylserine had crystallized, MP: 215*C with decomposition. After two precipitations from alkali (with acid), the product melted with decomposition at 225*C. This compared well with the literature. The threo isomer was obtained almost exclusively.
Example 3:
threo-beta-p-benzyloxyphenylserine (VIII)
To a solution of 5.61g (0.1mol) of potassium hydroxide and 3.75g (0.05mol) of glycine in 75ml of absolute alcohol, there was added a solution 21.2g (0.1mol) of p-benzyloxybenzaldehyde15 in 50ml of alcohol. The mixture was warmed until it was absolutely clear. (ca. 60) and the solution was allowed to stand at RT. A crystalline solid precipitated which was filtered after 5 hours and washed thoroughly with alcohol and ether. This product was the potassium salt of N-p-benzyloxybenzylidene-beta-p-benzyloxyphenylserine and it was obtained in 95% yield, MP: 161-163*C.
The potassium salt (41.6g, 0.08mol) was stirred vigorously with 400ml of 1N HCl acid and the mix was filtered immediately. The solid p-benzyloxybenzaldehyde was washed with 200ml of 0.5N HCl acid and then with water. It weighed 19.7g (theory 17g) and probably contained some beta-p-benzyloxyphenylserine. The acid filtrates were combined and, on neutralization, beta-p-benzyloxyphenylserine crystallized, 17.7g (77%). A sample, recrystallized from a mixture of alcohol (6 parts), water (2 parts) and DMF (2 parts) melted at 190-192*C.
Example 4:
threo-beta-p-hydroxyphenylserine (XI)
To 100ml of 0.5N sodium hydroxide there was added 4.0g of threo-beta-p-benzyloxyphenylserine and 0.25g of 5% Pd/C catalyst. The benzyloxy compound did not dissolve completely. The mixture was hydrogenated at 1atm and, when absorption of hydrogen ceased (305ml, theory 330ml), there was no undissolved material present except the catalyst. After removal of the catalyst by filtration, the filtrate was neutralized with HCl and then concentrated under reduced pressure to 30ml. On cooling, a crystalline product weighing 1.8g (65.5%) was obtained. This product was recrystallized from water and washed until chloride free, MP: 195-205*C/w/decomp.
Example 5:
beta-3,4-dibenzyloxyphenylserine (IX)
A warm (70*C) solution of 89.0g (0.28mol) of 3,4-dibenzyloxybenzaldehyde16 was added to a solution of 15.7g (0.28mol) of potassium hydoxide and 10.5g (0.14mol) of glycine in 140ml of alcohol. A crystalline solid formed rapidly but this soon dissolved and an oil separated from solution. After standing overnight at 0*C, the alcohol was decanted from the viscous oil.
The oil was dissolved in 350ml of carbon tetrachloride and the clear solution was acidified with 15 ml of glacial acetic acid. Potassium acetate was removed by filtration and the filtrate was stirred vigorously with 500ml of water for 2hours. The water was decanted and the carbon tetrachloride was washed 4x500ml of water. The carbon tetrachloride slurry was allowed to evaporate in a flat tray and a dry yellow powder remained. After extraction of the powder with three portions of 500ml of ether, 30.5g (55.4%) of insoluble beta-3,4-dibenzyloxyphenylserine remained. Evaporation of the ether solution yielded 51g of 3,4-dibenzyloxybenzaldehyde.
The beta-3,4-dibenzyloxyphenylserine obtained by this method was a mixture of stereoisomers which were separated by fractional crystallization from 50% t-butyl alcohol. The high-melting (180-185*C) isomer was the more insoluble substance and it could be obtained in almost pure state by eluting the more-soluble, low-melting (146-147*C) isomer from the mixture with minimal quantities of boiling 50% t-butyl alcohol. Fairly pure isomer melting at 146-147*C could be recovered by cooling the hot t-butyl alcohol extracts to RT. The original crude mixture consists of about 30% of isomer melting at 146-147*C. The high-melting isomer was obtained pure by recrystallizing it from 50% t-butyl alcohol (1 L. for 8g), MP: 180-185g.
Example 6:
beta-3,4-dihydroxyphenylserine (XII)
from High-melting beta-3,4-dibenzyloxyphenylserine
A suspension of 3.94g (0.01mol) of beta-3,4-dibenzyloxyphenylserine (MP: 180*C) in 50ml of 50% methanol was hydrogenated at 1 atm using 0.2g of 5% Pd/C. In the course of the reduction, it was necessary to add 0.2g of fresh catalyst. After eight hours, 465ml of hydrogen had been absorbed (theory 480ml) and the reduction was stopped. Product had crystallized but it redissolved on warming and the catalyst was removed by filtration. The alcohol was removed by vacuum concentration and the aqueous solution was treated with acid-washed Darco. The almost colorless filtrate was concentrated to 5ml and 15ml of ethyl alcohol was added slowly. After standing at –20*C for 18hours, the crystalline product was collected and washed with 50% alcohol. It weighed 1.83g (85.9%) and melted with decomposition at 199-200*C. Analyses showed that the compound was hydrated.
Example 7:
from Low-melting beta-3,4-dibenzyloxyphenylserine
A solution 12.22g (0.03mol) of beta-3,4-dibenzyloxyphenylserine monohydrate (MP: 146*C) in a mixture of 30ml of water, 30ml of ethanol and 15ml of 2N LiOH was hydrogenated at 1 atm using 2.0g of 5% Pd/C. After 1490ml of hydrogen had been absorbed (1470ml theory). the reduction ceased and 6ml of conc. HCl acid was added to the reaction mix. After filtration through acid-washed Darco, the light yellow filtrate was neutralized with 2N LiOH (22ml). Crystallization was rapid and after cooling the mix at 0*C for 24hours, 5.94g (93%) of product was obtained. Due to the insolubility of the compound, it was purified by dissolving it in alkali and then reprecipitating by the addition of acid. The product had a gray tinge and melted with decomposition at 220-225*C.
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References:
(1)Presented at the Miniature Meeting of the Philadelphia Section of the American Chemical Society, Jan, 29, (1953)
(2)W.A. Bolhofer, THIS JOURNAL, 75, 4469, (1953)
(3)E. Erlenmeyer, Ber., 25, 3445, (1953)
(4)M.E. Dullaghan and F.F. Nord, THIS JOURNAL, 73, 5455, (1951)
(5)K. Hayes and G. Gever, JOC, 16, 269, (1951)
(6)S. Kanao and K Shinozuka, J. Pharm. Soc. Japan, 67, 218, (1947)
(7)D.O. Holland, P.A. Jenkins and J.H.C. Nayler J. Chem. Soc., 273, (1953)
(8)This isomer has presumably been prepared by G. Fodor and J. Kiss (Acta Univ. Szeged, Chem. et Phys., 3, 26, (1950)), who isolated it as a non-crystalline hydrochloride.
(9)K.W. Rosenmund and H. Dornsaft, Ber., 52, 1734, (1919)
(10)C.E. Dalgliesh and F.G. Mann, J.Chem. Soc., 658, (1947)
(11)Commercial Sample
(12)W.A. Bolhofer, THIS JOURNAL, 74, 5459, (1952)
(13)The microanalyses were carried out by Mr. Kermit Streeter and his staff. All melting points are uncorrected. The infrared spectra were determined by the Microanalytical Laboratory of the Massachusetts Institute of Technology.
(14)W.S. Rapson and R. Robinson, J. Chem. Soc., 1533, (1935)
(15)E. Worner, Ber., 29, 142, (1896)
(16)H.S. Mahal, H.S. Rai and K. Venkataraman, J. Chem. Soc., 866, (1935)
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Lately, we see a LOT of damm interesting purely chemistry based posts, by some very dedicated members, we are all VERY thankfull for all the hard work in the background from you ALL!
What I am missing however more and more, is some fundamental good info on metabolic effects of the described compounds.
Our damm good board was once ALSO a very good source for those effects, described by various daring non chemist users. This task is as much of importance, if not more, for the intention of this board, to be a safe haven for CHEMISTS and USERS. It has become less posted, perhaps out of some kind of shiness to post in obvious skillfull chemists threads.
Don't be shy, it's a greatly appreciated other kind of important info!
Appropriate addended bio-assay info, be it from scientific sources as f.ex. Shulgins books or good medicine journals sources, or from streetsmart users, or synthesists who also dare to take their own products, all as reliable as possible, should be included in these novel synthing threads, to complete these threads to the full extend of their importance.
If not, these threads will loose a lot of the Thang to the majority of our users, the psychonauts of the future.
Thanks in advance for any additional info on bio assays. LT/
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The goal lately has been to determine the optimal conditions for the decarboxylation of 2-methyl-3-phenylserine. Ideally, it would be nice to have access reports which specifically describe the kinetics and conditions for optimal decarboxylation of this phenylserine however, such reports have eluded me. The next best thing is likely to predict the conditions based on work that has been done.
In previous work, where the decarboxylation kinetics of aliphatic amino acids such as glycine and alanine in aqueous solutions at various pH's were investigated, it was found that the zwitterionic state of the amino acid was optimal for decarboxylation 1. At this point, it had apparently made sence to run with these findings and apply them to the decarboxylation conditions of 2-methyl-3-phenylserine but then D dug up a recent paper where the stability of decarboxylation of amino acids with different functional substituted sidechains like serine and phenylalanine were explored 2. The authors also studied various pH environments and found that the optimal pH for decarboxylation of serine and phenylalanine was not in the range of their pKa but rather at a low pH (2-2.5). The following is a summary of this work and how it applies to the current goal. Focus will be placed on serine (Ser) and phenylalanine (Phe)because they have side chains most similar to the phenylserine we want to decarboxylate
Ser and Phe was dissolved in water and adjusted to various pH’s by titrating with HCl or NaOH. The solution was passed through a flow FT-IR spectroscopy cell and the concentration of CO2 was measured which was then used to determine the kinetics of the reaction and respective Arhhenius plot. The pH range that was examine was from 1.5 to 8.5. The authors didn’t go above pH 8.5 because under these conditions, the solubility of the amino acid was too low and CO2 hydrolyzed. As well they conducted the reactions at 270 bar and at various temperatures (270-300 deg C).
The kinetics for Ser and Phe were both first order. The optimal pH for decarboxylation of Ser and Phe was 2 and 2.5 respectively. There was little change in reaction rate of these amino acids within their pKa range. Note that this is in contrast to what was reported for alanine and glycine but this shouldn’t be surprising since its becoming evident that the nature of the side chain has drastic effects on the stability of decarboxylation. What was really interesting was that they found that both electronic and steric effects influence decarboxylation but the electrical component was found to be most significant. Though Ser and Phe have similar optimal pH’s of decarboxylation, it would seem that Ser is the best amino acid candidate at this point to approximate the phenylserine of interest since it’s hydroxyl group is an electrical component. Furthermore, out of all the amino acids tested, Ser was only second to threonine for the highest rate of decarboxylation (25 times greater than alanine). As well it was mentioned that side chains containing the hydroxyl group are subject to spontaneous decarboxylation.
The authors believe that mechanism for decarboxylation is similar for all amino acids, despite their differences in side chains and that the mechanism for decarboxylation proceeds through a H2O stabilized intermediate. The authors will discuss the actual mechanism of amino acid decarboxylation in their next paper 3.
Taken together, these results suggest that for serine, decarboxylation should be conducted in an aqueous environment with a pH of 2. Furthermore, the authors use a pressure of 275 bar and a temperature of 270-300 deg C. For driven, it is unclear as how to attain these conditions from a clandestine perspective. Maybe a pressure cooker could be used? As always, comments are much appreciated!
DRIVEN :)
References
1 Mark J. Snider and Richard Wolfenden. The Rate of Spontaneous Decarboxylation of Amino Acids. J. Am. Chem. Soc. 2000, 122, 11507-11508.
2 Jun Li and Thomas B. Brill. Spectroscopy of Hydrothermal Reactions 25: Kinetics of the Decarboxylation of Protein Amino Acids and the Effect of Side Chains on Hydrothermal Stability. J. Phys. Chem. A, 2003, A-F.
3 Li, J,:Brill, T.B. to be submitted for publication.
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Some may bee wondering what happend to the phenylserine that was produced in the first post of this thread. D didn't expect the HTAB to crystallize with the amino acid and this definitely wasn't mentioned in the orginal paper.
There are several possible ways to separate the HTAB from the phenyserine. One yet very expensive option, could be to run the residue through a column designed to trap detergents. These can be found in the catalogs of several biotechnology suppliers.
Aurelius had a good idea where the zwitterion of the phenylserine (rendered neutral)is made and the solution is extracted with a with non polar. Some of the PTC will come along but it can be removed in the next step. The phenyserine is converted back to its salt and a continuous extraction is performed on this solution with any non-polar solvent that the catalyst has high solubility in. This will cause the catalyst to be extracted, leaving behind the very polar and non-soluble product, which can later be acidfied to bring it back to the zwitterionic nature (state) for decarboxylation. The only difficulty here is that the pKa of the phenylserine isn't really known (yet estimated to be 9) but required to get the phenylserine into a non-polar.
Another method would bee to crystallize the phenylserine in a solvent where the HTAB has a high solublity in. Methods of amino acid crystallization have been described 1 What follows is an excerpt from the experimental where the post reaction is being worked up to isolate DL-beta-Phenylalanine.
The residue is then taken up in 30-40 cc. of boiling water, and the pH of the solution is adjusted until it is basic to Congo red, but still acid to litmus, by careful addition of concentrated ammonia and acetic acid (Note 6). Then two volumes of 95 per cent alcohol is added to aid in the separation of the phenylalanine. The mixture is placed in the refrigerator for a day, after which the product is transferred to a Buchner funnel, and washed first with three 25-cc. portions of ice-cold water and then with alcohol. The yield is 14.5 g. The filtrate is evaporated to dryness under reduced pressure on the water bath, and the residue is extracted with about 70 cc. of ice-cold water in three or four portions. The insoluble material, after washing with 95 per cent alcohol, is added to the main fraction of phenylalanine. The total yield is 16 g.
Conveniently, HTAB is soluble in 95% ethanol at -20 deg C. To crystallize the phenylserine the phenylserine/HTAB residue was combined with 2 volumes of 95% ethanol and brough to a light boil for a couple minutes. Very little solid was insoluble (1/4 of a tsp). This was filtered and the filtrate was allowed to cool to room temp after which it was placed in the fridge (the beaker was scratched with stir rod). After a day in the fridge a fluffy white precipitate formed on the bottom of the beaker and crystals were forming on the walls of the beaker. D is confident that this is the phenyserine because HTAB is a very fine solid and remains suspended in solution and doesn't settle. The solution was then placed in the freezer. It has been about 4 days now and it the solution is still crystallizing. IE. when the walls are cleared of crystals with a stir rod, more are formed the next day and the bed of crystals at the bottom of the beaker is getting deeper (looks to be still only about 2g). D thought that this process could be sped up by adding acetone. As a test 0.5ml of the solution was transferred to a test tube and a drop of actone was added. There formed a white fine cloudy precipitate that resembled HTAB and wouldn't settle. We don't want this so I guess patience is the way to go with this one!
Once the phenyserine has been completely crystallized and dried, the pKa will be emperically determined by dissolving known and small amounts of the product in vaious pH environments and extracting with a nonpolar. The pH that results in the most amount (if not all) of product being extracted into the nonpolar will bee the magical pH.
Driven :)
References:
1. H. B. Gillespie and H. R. Snyder. Preparation of DL-beta-Phenylalanine. www.orgsyn.org.
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I learned a lot from this thread.
But what was Akaboris idea and way for decarboxylation ?
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1) The Akabori Reaction (from
Post 226730 (https://www.thevespiary.org/talk/index.php?topic=7382.msg22673000#msg22673000)
(joyman: "Re: P2P - 100% OTC !?!", Chemistry Discourse)):
http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/akabori2.htm (http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/akabori2.htm)
2) Akabori's way for decarboxylation:
See the extensive Akabori compilation by Aurelius where the reaction conditions are described.
D :)
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12g of the 2-methyl-3-phenylserine HCL was produced from this procedure. The yield seemed quite low.
The inital run where all the BzH used was fresh, resulted in a botched workup. Swid didn't have much BzH left (~25g) but figured that since there "should" be about 35g left in the DCM, another run could be performed by just recycling the DCM but adding the ~25g fresh BzH. This was done and the reaction went without any hitches. The post reaction was concentrated to about 100ml and added to 400ml of 95% EtOH. This was brought to a gentle boil and filtered. Only about 1/2 tsp of solids were filtered out. The mix was allowed to crystallize over 2 weeks. The crystals were flakey and pure white. Yield of first crop was 10g.
The mix was concentrated to 75 ml and combined with 100ml 95% etoh and another 2g of phenylserine crystallized out. The filtrate was concentrated again and allowed to cool to RT at which point the PTC crashed out. This was added to EtOH once again and no phenylserine crystallized out.
So Swid is wondering where the other 2/3 of the yield went. Perhaps, recycling is not a good idea. Dispite this it would be nice to move onto the decarboxylation.
For decarboxylation, it was decided the solvent would be DMF and a pH of 2 would be experimented with first. 1 gram of the phenylserine was dissolved in a 0.5 ml of water and added to 100ml of DMF, the mix was pH'd to 2 with HCl. It was previously found that if the phenylserine is added directly to the DMF it doesn't dissolve but when it is added to water prior, it does. The mixture was placed in a 250 ml RBF with 5 boiling stones and heated. Once all the water had evaporated, a condenser was added and the heat turned up for a strong reflux. When the temperature of the liquid climbed to 120 deg C the mixture began boiling. There were both fine bubbles and intermittent bumping at 150 deg C howvever cracking sounds that would indicate decarboxylation were absent. The reflux was continued for another hour.
When the mixture cooled, a white precipitate formed. There looked to be about 1 gram.
Driven is not sure if decarboxylation occured but by the same token, D isn't sure what to expect and raises many questions:
1) It seems the the ppt is unreacted phenylserine but if decarboxylation did occur then could it be PPA-HCL?
2) Does anyone know of the solublity of PPA-HCL in DMF?
D is thinking about forming the phenylserine freebase prior to decarboxylation and seeng what happens then. Any advice is much appreciated!
Thanks everyone,
DRIVEN :)
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As requested in
Post 448664 (https://www.thevespiary.org/talk/index.php?topic=9709.msg44866400#msg44866400)
(roger2003: "Akabori literature", Methods Discourse). I believe that the last one is wrong, and deals with the Akabori Reduction (amino acids to amino aldehydes), rather than the Akabori Reaction (benzaldehyde/amino acid condensation) we are interested in.
So - roger2003 and others, better check your references in the fduture so that you know that the articles are dealing with the correct transformation.
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000448052-file_x2lk.gif)
The Akabori Amino Acid Reduction
Synthese von Imidazol-Derivaten aus (https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000448052-file_lwwo.gif)-Amino-säuren
1. Mitteilung: Eine neue Synthese von Desaminohistidin und ein Beitrag zur Kenntnis der Konstitution des Ergothioneins.
Shiro Akabori
Chem. Ber. 66, 151-158 (1933) (https://www.thevespiary.org/rhodium/Rhodium/pdf/akabori-1933.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/akabori-1933.pdf)
Eine Neue Darstellungsweise Von Aminen Aus (https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000448052-file_lwwo.gif)-Aminocarbonsäuren
Klaus Dose
Chem. Ber. 90, 1251-1258 (1957) (https://www.thevespiary.org/rhodium/Rhodium/pdf/akabori-1957.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/akabori-1957.pdf)
Abstract
Eine Methode zur Darstellung von Aminen aus (https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000448052-file_lwwo.gif)-Aminocarbonsäuren durch Decarboxylierung bei Gegenwart aromatischer Aldehyde wird beschrieben und der Mechanismus dieser Reaktion elektronentheoretisch gedeutet. Die Reaktionsgemische werden durch Hochspannungspherographie im mikropräparativen und analytischen Maßstab aufgetrennt und u.a. mit Hilfe kolorimetrischer Methoden bestimmt.
2-Mercaptoglyoxalines. Part IX. The Preparation of 1,5-Disubstituted 2-Mercaptoglyoxalines from (https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000448052-file_lwwo.gif)-Amino-acids
A. Lawson & H.V. Morley
J. Chem. Soc. 1695-1698 (1955) (https://www.thevespiary.org/rhodium/Rhodium/pdf/akabori-1955.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/akabori-1955.pdf)
Abstract
The reduction of (https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000448052-file_lwwo.gif)-amino-acid esters by the Akabori procedure and condensation of the resulting carbonyl compounds with thiocyanate at pH 4 gives 1,5-disubstituted 2-mercaptoglyoxalines (III). The constitution of these compounds is proved by synthesis of the derivative (IV, R = H, R' = Me, R" = Propyl) obtained by Wolff-Kishner reduction of (III, R = Me). These ketones (III) have been converted into thiazolo(3',2'-1,2)glyoxalines (IX) by ring closure.
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Blasted German!!!!!!!!
Would somebody please translate and type the first two articles in Rhodium's post?
(And BTW, in the General Discourse Forum, I've got a request for another german article to be translated and typed. It's about Psilocybin and Psilocin in Mushrooms. I can only get a VERY vague picture of what's in that article- It's in this thread:
Post 450823 (missing)
(Aurelius: "Cland Drug Labs J. For Sci 15,1, 51-64 (1970)", General Discourse)
Please, somebee, do this favor for (ahem-me-ahem) the Hive... For the love of bees, please?)
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Experiments were conducted to answer the question about the identity of the ppt that formed after the decarboxylation.
It was reasoned that if the ppt was PPA-HCl, it would turn into an oil when the mixuture is basified strongly. The entire post reaction was basified. There was difficulty in determining the pH of the DMF mixuture using pH paper as the solution acted very much like xylene, specifically in the way that it's pH can't be reliably tested with pH paper. Dispite this an excess of 40% NaOH was added that exceeded at least the known molarity of the phenylserine. The ppt did not dissolve. The DMF was thought to be interfering with the process so the ppt was filtered out. The filtrate (DMF) was saved. About 100 ml of water ws added to the isolated ppt, it did not dissolve, the pH was very basic. At this point it was suspected that the ppt was phenylserine sodium salt because, at this pH the phenylserine has negative charges on the carboxyic acid group and the alcohol group giving it a total negative charge where if it was the PPA free base, it would be an oil.
Decarboxylation attempt #2 will involve dissolving the salt in DMSO and heating to 190 deg C.
This is based on some important points that have recently come to light.
a) The phenylserine will be charged at any pH, therefore it will always bee ionized and have limited solubility in non polar solvents. Therefore the choice of solvent for decarboxylation will be limited to the polar spectrum.
b) It is likely that the decarboxylation of this phenylserine will require more heat than what can be offered by the boling temperature of DMF (~150).
DMSO is both polar and of high BP so its next in line. Aurelius, now I know what you were getting at with recommending DMSO ::) ....)
DRIVEN :)
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you notice in the akabori reaction a 2 fold excess of aldehyde is used?
Well it has a carbonyl group that forms a shiff's base with the amino acid, this shiff's base may abstract a proton from the carboxylic acid causing it to form a leaving group.
This mechanism applies to alpha amino acids (those seperated by one carbon)
In this case it's a beta amino acid so I don't know if the same holds true.
Looking at DMSO you see the carbonyl group in the middle?
with it's high B.P., polarity and carbonyl group capable of forming the shiff's base I would react the "serine" in the free acid form with the proton dangling from that carboxyl group, as opposed to it's sodium or potassium salt as this effect can not take place in this instance.
who knows it might just work! :)
for instance you could just use the classical akabori reaction by heating benzaldehyde and alanine in DMSO.
this would serve both as a solvent and a decarboxylation promoter, we'll see.'
allow me to correct myself, It would seem wiser to first form the alanine bezaldehyde serine derivative and then decarboxylate using a high boiling polar solvent with a sulfonyl (not carbonyl) function (like dmso)
I fear using dmso as a sovent in a straight akabori condensation/decarboxylation reaction might interfere.
The advantage here is that you can form this shiff's base intermediate which will facilitate the decarboxylation of the COOH+ group by proton abstraction to the shiff's base.
but the interatomic distance in a alpha VS beta amino acid (like the one you are referring too) may cause this not to work.
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Hey fellow beez,
Driven is unable to continue the experimental on this project. Yes, D is feeling the pain... All these hypothesis and no way to test. Argh.
Are there any takers? Common, it's a lot of fun ;D .
DRIVEN
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letbee get this right: the desire is to first create the serine derivitive of bzH and Alanine, then react the derivitive with another mole of BzH in DMSO?
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ahgreich, your half way there,
1) React dl-alanine with BzH to form the 2-methyl-3-phenylserine. D (among others) showed this to work.
2) Decarboxylate the phenylserine to form phenylpropanolamine. Has yet to be done.
Driven
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Is it really possible to abstract and generalize from amino acid decarboxylation literature to derive a procedure for decarboxying 2-methyl3phenylserine? - here you have another methyl group hanging off the carbon where the carboxylic and amino groups are - that has to change change many factors.?
maybe use hypochlorite to get to PAC (phenylacetylcarbinol or hydroxy-p2p) - aka streker degradation with aqueous hypochlorite.
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i just purveyed a cold medicine expired 07/2001 it contains, acetylsalicylic acid, chlorphenerimine maleate, and phenylpropranolamine bitartrate.
perhaps a trip to Mexico is in order?
I am inaware of any laws prohibiting the importation of otc cold medicine from Mexico, especially otc cold remedies.
BTW: the decarboxylation worked on a beta amino acid with the classic akabori reaction, why not in this case???
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no man, not questioning that it *can* be decarboxylated only that maybe much of detail in the literature *may* not be relevant.., like ph or buffers or solvent. another alternative might be heating with a cyclic ketone,
https://www.thevespiary.org/rhodium/Rhodium/chemistry/decarboxpha.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/decarboxpha.html)
there is some suggestion that the Akabori works much better when the amine is secondary rather than primary - dont know if this is referable to the aldol condensation or decarboxylation. anybee know if its possible to methylate alanine with formaldehyde forming the imine then Al/Hg to reduce? - would be cleaner than using methyl iodide.