Sciencemadness Discussion Board - lefetamine - Powered by XMB 1.9.11 (Debug Mode)

...a theoretical synthesis to this compound from easily available chemicals. not for illicit purposes, simply because of the chalange and enjoyment of reaching the theoroetical goal.

...anything producing a reasonable amount will be adiquete.

...if there is a hurdle that maybe a little to hard to jump in this synthesis that can be overcome by changing the end product into something similar with equal or greater value...

Let me see if I get this right... You want us to help you come up with a synthesis of an illicit compound, produced in reasonable quantity, using OTC materials, and if thats not possible you want something similar of equal or greater value? I'm skeptical...

Not only that, you appear to have a lack of chemical knowledge, and seeing as your "theoretical synthesis" could entail some toxic chemicals (e.g. Mercury and/or its compounds) then I would be worried that your "theoretical product" might end up killing your "theoretical customers"... But what the hell do I know...

entropy51 - 17-1-2010 at 09:11

Quote:

a paper discussing the original synthesis has not been found by me

Have you just not looked? They are for sure out there. Oh, I see: you just want to be spoonfed a recipe.

Arrhenius - 17-1-2010 at 10:06

Let me offer a few suggestions, because I don't really care what you want this compound for (it's probably nothing magnificent anyhow). I'd rather you learn some chemistry.

1.) Friedel-crafts reactions are a textbook favorite, and otherwise a pretty big pain in the ass (unless you're working with highly active subtrates or intramolecular reaction). So scrap that idea. You simply won't get a clean enough product, and if you're fixated on OTC then you probably don't have the means to purify liquid products.

2.) I urge you to move beyond Shulgin. The Al/Hg reduction is neat, but there are excellent reductive amination reactions which are anhydrous and will not hydrolyse the imine back to the ketone. Please look into NaBH4 reduction of pre-formed imines, and also hydrogenation of imines formed in situ.

3.) Dimethylamine + formaldehyde... no. You need to learn about oxidation states. If an alkane is considered to be in the "zero" oxidation state and an alcohol considered "+1", then formaldehyde and any other aldehyde is "+2" (carboxylic acids +3, ureas +4) then the reaction of methylamine (0) with formaldehyde (+2) must undergo a net reduction to get to dimethylamine (0). Reduction Is Gain (of electrons).

4.) Stop researching chemistry in patents. Patents are garbage and poorly descriptive (i.e. difficult to learn from). What you need to do is buy some elementary and intermediate organic chemistry books, and ready primary literature (scientific journals) for procedures.
An excellent elementary textbook
An excellent intermediate textbook

5.) Which of your proposed routes would be realistic? None. Here's how to do it easily. Grignard addition of benzylmagnesium bromide to benzaldehyde. Oxidation of the resultant alcohol to the ketone (pick your favorite oxidation.. PDC or PCC is damn easy. bleach is possible). This gives you "deoxybenzoin" (if want to sound naive) or 2-phenylacetophenone (if you want to sound like a chemist). If you don't know how to name compounds, draw the structure in the search engine at Sigma Aldrich (Here). Reductive amination with dimethylammonium chloride in a buffered reaction or formation of the imine from dimethylammonium acetate and subsequent reduction with NaBH4 will yield racemic product

6.) Reductive amination will give a pair of enantiomers. Knowledge is respectable, so try to learn the lingo. It's important because then you'll recognize that enantiomers have identical physical properties. You might, however, be able to separate these enantiomers with a fractional crystallization (lactic or tartaric acid to form a diastereomeric salt).

P.S. Another possible route - condensation of benzaldehyde with dimethylammonium salt to give the iminium ion followed by reaction with benzyl grignard. 2 steps to racemic product.

P.P.S. Chemistry gets a lot more fun if you move beyond the fixation with OTC. There are plenty of safe ways to buy chemicals, and they're perfectly lawful. My main concern is that you store them properly at your 'lab' (house), so please ask if you need help.

[Edited on 17-1-2010 by Arrhenius]

Nicodem - 17-1-2010 at 11:23

so what am i missing?

You are missing the point of this forum, which is not to spoonfeed those who are so lazy as to open a thread without providing one single reference where needed and then arrogantly asking others for information about making some drug that might even be illegal where you live. You even go as far as saying that you found no paper on the synthesis of lefetamine, which makes it obvious to everyone that you never ever ventured into a library. Most members here would even pass over your petty criminal intents if you at least show a decent interest in chemistry and some minimum effort, but your discourse shows anything but that.

The simplest synthesis of lefetamine is also what is probably its first synthesis. Made by Stevens using the Stevens rearrangement. I will make just as much effort as you did in providing any reference - that is none.

Quote:

i understand that open discussion of these sort of compounds are looked down upon here. for that reason i really would like to keep this thread on topic and ask everyone to leave out any and all BS.

You should have done so in the first place by using a scientific discourse. Now that you miserably failed in doing so you invited others to continue at the same BS level.

turd - 17-1-2010 at 12:37

3.) Dimethylamine + formaldehyde... no. You need to learn about oxidation states. If an alkane is considered to be in the "zero" oxidation state and an alcohol considered "+1", then formaldehyde and any other aldehyde is "+2" (carboxylic acids +3, ureas +4) then the reaction of methylamine (0) with formaldehyde (+2) must undergo a net reduction to get to dimethylamine (0). Reduction Is Gain (of electrons).

I think he was talking about making dimethylamine via the well known (and annoyingly low yielding) NH4Cl + CH2O route.

P.P.S. Chemistry gets a lot more fun if you move beyond the fixation with OTC. There are plenty of safe ways to buy chemicals, and they're perfectly lawful. My main concern is that you store them properly at your 'lab' (house), so please ask if you need help.

Oh yes, "desoxybenzoin" is probably not any more suspicious than the various precursor to either desoxybenzoin or the Stevens rearrangement (very interesting - never heard of that!) reactant.

Vogelzang - 17-1-2010 at 12:58

How about

1) benzoin + hydroxylamine -> oxime
2) reduce the oxime to the amine
3) methylate the amine to the tertiary amine using paraformaldehyde and oxalic acid (with microwave treatment) or use the Eschweiler-Clarke reaction
4) reduce the OH group using I2 and H2S (with plenty of ventilation for the H2S), or you can use red phosphorus in place of H2S if its available.

According to some things I found in Google books, H2S can be made by heating sulfur and a hydrocarbon such as mineral oil or paraffin wax.

DJF90 - 17-1-2010 at 15:07

Arrhenius: FC-reactions work fine under reasonable conditions. So long as you have a site that is almost certain to react in your ring (i.e. stereoelectronically favoured) then FC-reactions are fine. Acylation is obviously superior if you want mono-substitution but alkylation can work reasonably well in some cases. Reduction of the phenyl ketone that results is relatively easy, and I believe it can be effected by the use of H2/Pd under acidic conditions (e.g. in glacial acetic acid). Sodium borohydride also works in acidic conditions, as do a few/many other reagents.

You've completely lost me on point 3... It appears you've made a mistake regarding what Kafka actually wrote, but even then what you've written does not make sense. As I see it, methylamine is on the oxidation level 1.

You also say that reductive amination yields a racemic product. This may indeed be true, but I would at least expect a small enatiomeric excess, even with boohydride. LiAlH(OtBu)3 would give a much better enatiomeric excess, and from my mental working it looks like it would even favour the enantiomer given on the Lefetamine wikipedia page (which I am assuming to be the required isomer).

Arrhenius - 17-1-2010 at 17:05

turd: Howdy. I don't think anything except methylamine is suspicious here. I don't even think benzaldehyde is (it's OTC anyway). Benzyl bromide?? if you're THAT concerned (I wish folks wouldn't be) then make it from benzyl alcohol, which is not suspicious at all.

DJF90: yes, +1 on methylamine, pardon me. Please draw me a reaction mechanism for the reaction of formaldehyde and methylamine that does not involve a two electron reduction. And I'm sorry, but any reductive amination here will give a racemate. Even lithium tri-tBuO aluminum hydride or L-selectride will give a racemate. There is no thermodynamic or kinetic preference for one face of the imine over the other. Please draw a transition state that is more thermodynamically favorable for one face if you believe you're correct. An enantiomeric excess *might* be achieved using the CBS reduction, but I don't know if this works for imines... I found a paper on it, but I'm busy in the lab right now.. will read it later. Unless you've run a hydrogenation to reduce a benzyl ketone, I wouldn't make the claim that it's facile. Try it.

[Edited on 18-1-2010 by Arrhenius]

entropy51 - 17-1-2010 at 18:38

I don't think anything except methylamine is suspicious here. I don't even think benzaldehyde is (it's OTC anyway).

See number 22

Arrhenius - 17-1-2010 at 21:30

Nevermind this comment... waste your time being paranoid while I do chemistry.

[Edited on 18-1-2010 by Arrhenius]

DJF90 - 17-1-2010 at 23:13

Arrhenius: The reason I suggest the lack of a racemate is due to Cram's rules. Draw a newman projection and check it out. Or go read about Cram's rules. Obviously the larger the nucleophile, the more pronounced the effect will be. And I didnt claim the reduction of the benzyl ketone to be facile, I said phenyl ketone, which is a different matter altogether and from the literature I've seen, it is facile

And yes, reductive amination/alkylation using formaldehyde is a reductive process, but that wasn't what my quarm was about.

[Edited on 18-1-2010 by DJF90]

Paddywhacker - 18-1-2010 at 00:06

Quote: Originally posted by entropy51

I don't think anything except methylamine is suspicious here. I don't even think benzaldehyde is (it's OTC anyway).

See number 22

mmmm... I only have two of the chemicals from list 1 in stock, but I have nine out of eleven from list two, and I have absolutely no interest in making illicit drugs. That says more about the lists, I think, than it says about me.

[Edited on 18-1-2010 by Paddywhacker]

turd - 18-1-2010 at 00:09

turd: Howdy. I don't think anything except methylamine is suspicious here. I don't even think benzaldehyde is (it's OTC anyway). Benzyl bromide?? if you're THAT concerned (I wish folks wouldn't be) then make it from benzyl alcohol, which is not suspicious at all.

Yes, I should have said just as unsuspicious instead of not any more suspicious. The Stevens rearrangement sounds like a really nice project, just the pharmacology seems to be bleak...

Quote:

The reason I suggest the lack of a racemate is due to Cram's rules. Draw a newman projection and check it out. Or go read about Cram's rules.

I read the wikipedia article and I don't get it. Can you explain to the uninitiated by which magic a symmetric (by mirroring) molecule can give an enantiomeric excess. Is there some weird diastereomer involved?

Quote:

if there is a hurdle that maybe a little to hard to jump in this synthesis that can be overcome by changing the end product into something similar with equal or greater value... point it out.

Please define the evaluation function.

kmno4 - 18-1-2010 at 01:06

Back to main topic.
Synthetic references can be found via Google:
http://www.chemsynthesis.com/base/chemical-structure-6716.ht...
The best starting point for amateur seems to be desoxybenzoin.
It can be prepared from easily available benzoin by simple reduction (without LAH or borohydrides, see references given in OS for desoxybenzoin)
Next: desoxybenzoin-> its oxime -> reduction -> methylation (in this case very good would be formalin/formic acid way) -> racemic shit.
A little cheaper and easier way than suggested by Vogelzang.

Nicodem - 18-1-2010 at 02:42

Quote: Originally posted by DJF90

You also say that reductive amination yields a racemic product. This may indeed be true, but I would at least expect a small enatiomeric excess, even with boohydride. LiAlH(OtBu)3 would give a much better enatiomeric excess, and from my mental working it looks like it would even favour the enantiomer given on the Lefetamine wikipedia page (which I am assuming to be the required isomer).

You can not have asymmetry in a reaction if every component and media is symmetric. An asymmetric induction is only possible where you already have a chiral centre in the substrate, reagent or catalyst in which case already the transition states are in diastereomeric relationship, thus having different thermodinamic stability, and consequently different activation energies exist for these transition states (hence the induction). Since in this specific case none of the possible substrates (BnCOPh or its enamine with Me2NH) have a chiral centre there can be no asymmetry induction unless a chiral reagent or catalyst with enantimeric excess is used.

The most rational approach would be to use chiral catalysts like in the example of asymmetric reduction of the BnC(=NH)Ph imine described in EP1191030 or in the assymetric alfa-benzylation of the Bn2C=NBn imine (Tetrahedron: Asymmetry, 6, 1225-1228). Chiral auxiliaries can also be used, but that is not that rational any more (for one example see Synthetic Communications, 19, 1423-1430). The product of all these reductions, one or the other enantiomer of PhCH2CH(NH2)Ph, needs to be N-dimethylated to give lefetamine or its enantiomer.

An asymmetric reduction of the PhCH=C(NMe2)Ph enamine using chiral catalysts to give lefetamine directly would in my opinion be harder to achieve than is the case with the asymmetric synthesis of PhCH2CH(NH2)Ph. Though I guess it might be possible somehow.

turd - 18-1-2010 at 05:50

http://www.orgsyn.org/orgsyn/prep.asp?prep=CV4P0605

The words asymmetric and symmetric are very unfortunate in that context and should be replaced by chiral and achiral. For example levo- and dextrotartaric acid are symmetric by twofold rotation but are definitely chiral. Chirality is the absence of improper rotations (i.e. operations with det(r)=-1) but says nothing on proper rotations. Same thing for crystals (e.g. quartz which has trigonal symmetry but is chiral). Also "chiral centre" is problematic, but you know all that of course...

DJF90 - 18-1-2010 at 05:50

Nicodem: I was not implying asymmetric induction, although Cram's rules covers that, generally by chelation, and this is a method of altering the stereoselectivity obtained in the reaction. I've attached an image I made quickly in ChemDraw to show what I mean...

Crams rules.JPG - 37kB

turd - 18-1-2010 at 05:58

??
Why is the first picture kinetically or thermodynamically favored over its mirror image?

Felkin-Anh, Cram & Burgi-Dunitz angle

Arrhenius - 18-1-2010 at 07:31

DJF90: Sorry but Felkin-Anh selectivity would apply in this case, not Cram, which is usually 'anti-Felkin' in the presence of a chelating moiety (usually beta, sometimes gamma to the carbonyl). That being said, Felkin-Anh will still give no facial selectivity here. The newman projection in the upper left is the Felkin model, which applies here. Rotate the phenyl (in the back) 180º and you'll get attack over the other benzylic hydrogen, giving the opposite enantiomer. Cram's rule does not apply here! Use the Felkin-Anh model and you'll find that there's no selectivity.

However, add an R group at the benzylic position (in back on your Newman) and you will direct attack of the nucleophile (hydride) over the hydrogen and give a pair of enantiomers with anti configuration.

Also! (this is very important!) Your nucleophile is drawn coming in at the wrong trajectory. It should approach at the Burgi-Dunitz angle of 107º from the "carbonyl".

I've incorporated all of these things in this drawing. Notice that there is a ~5Kcal/mol barrier of rotation about the C-C bond of the Newman projection, but there is no thermodynamic preference for one rotomer over the other. A barrier of <15Kcal/mole will equilibrate at room temperature, so it's fair to say we will have both in our reaction mixture.
Felkin-Anh.gif - 7kB

For being dismissed as a "kool" thread.. I'm glad we're discussing some very important concepts.

[Edited on 18-1-2010 by Arrhenius]

DJF90 - 18-1-2010 at 08:24

Arrhenius: Thanks for pointing this out. It appears that over the past year I've not looked at this stuff enough and have confused it. I recall now that Cram's rule is generally "the chelate effect", giving anti-selectivity to the Felkin-Ahn model - which appears to be what I was meaning all along. Burgi-Dunitz I agree is 107 degrees from the carbonyl; my drawing clearly shows what a long time its been since I've used this chemistry.

The point that I didnt think about before I was writing is that "at the back" we have tw hydrogens and a phenyl group, and hence we can get no selection. This will be the "asymmetric induction" that Nicodem was talking about in his previous post. My apologies for my misunderstanding/lack of memory.

[Edited on 18-1-2010 by DJF90]

sonogashira - 18-1-2010 at 15:02

http://www.orgsyn.org/orgsyn/prep.asp?prep=CV4P0605

DJF90 - 18-1-2010 at 15:24

Fairly high yielding overall, and I'm sure similar yields could be had using the dimethylimine. Alternatively, one could follow that procedure and then methylate the product. Eschweiler-Clarke conditions are appropriate here, as its not possible to over methylate to the quaternary ammonium salt.

Arrhenius - 18-1-2010 at 20:12

Haha.. cool. I proposed that route just up thread =P

turd - 18-1-2010 at 23:23

Quote: Originally posted by Paddywhacker

I only have two of the chemicals from list 1 in stock, but I have nine out of eleven from list two, and I have absolutely no interest in making illicit drugs. That says more about the lists, I think, than it says about me.

Words of sanity! Are "they" going to raid every kitchen? If we reached a point were everything you do means breaching some obscure law, then it's time to stop paying too much attention to the law.

Quote:

I've incorporated all of these things in this drawing. Notice that there is a ~5Kcal/mol barrier of rotation about the C-C bond of the Newman projection, but there is no thermodynamic preference for one rotomer over the other. A barrier of <15Kcal/mole will equilibrate at room temperature, so it's fair to say we will have both in our reaction mixture.

And even if the barrier was orders of magnitude higher the first part of the argument still holds: no thermodynamic and/or kinetic preference for any of the enantiomorphous rotamers so you would get them in the same ratio. (Unless you invent a novel prion like autocatalytic reaction and manage to somehow induce an enantiomeric excess to start with.)

Quote:

The first step is intriguing. I would have thought that the methylamine would be removed with the water phase. Does this work for phenylacetones...?

Nicodem - 19-1-2010 at 13:39

Quote: Originally posted by turd

The words asymmetric and symmetric were referring to the reaction and not to the structural symmetry as you misunderstood. I was trying to explain the stereochemical "dogma" that a reaction can give an asymmetric outcome (excess of one enantiomer over the other) only in an asymmetric starting environment. Structures can be chiral or achiral, but reactions proceed symmetrically or asymmetrically. But I do agree that "chiral centre" is a problematic phrase. As a student I too was forced to read Eliel's bible on stereochemistry and should know better, but old habits die hard.

Quote: Originally posted by turd

Quote:

http://www.orgsyn.org/orgsyn/prep.asp?prep=CV4P0605

The first step is intriguing. I would have thought that the methylamine would be removed with the water phase. Does this work for phenylacetones...?

Aldehydes (like benzaldehyde is) form way more stable imines than ketones do. In fact many aldehydes will form stable imines or their trimeric forms (hexahydro-s-triazines) even in water. Therefore I doubt you could do the same with a ketone using the same treatment. Ketones often require the use of SnCl4 to form enamines/imines and that is quite some harsh reagent.

Haha.. cool. I proposed that route just up thread =P

Still does not beat the simplicity of the Stevens rearrangement!

I can't imagine anything more simple using just two steps and three simple reagents, though it is true that it ends up with the racemic mixture.

DJF90 - 19-1-2010 at 13:49

As a student I too was forced to read Eliel's bible on stereochemistry and should know better, but old habits die hard.

Oh gosh I remember having to read that! What a nightmare! Perhaps I should revise it, I have finals this year :|

sonogashira - 19-1-2010 at 15:06

I can't imagine anything more simple using just two steps and three simple reagents, though it is true that it ends up with the racemic mixture.

Photoamination of stilbene? Could it be the great day I have surpassed the master?!!! Hehe, only joking

Edit - No it isn't! Only ammonia and primary amines from what I have seen... But here is the ammonia paper anyway.

Attachment: Photoamination of Stilbenes.pdf (546kB)
This file has been downloaded 986 times

[Edited on 19-1-2010 by sonogashira]

turd - 19-1-2010 at 23:37

Point taken, even though symmetric reaction is of course a fuzzy notion. A gas-phase chemist will think of a symmetric reaction when it consumes as many molecules as it generates. And to be fair, you also applied the term symmetric to the reactants and the reaction medium, when IMHO it would make more sense to call them chiral or with an enantiomeric excess. But since this is a forum and not a textbook we're not going to be holier than the pope.

Speaking of textbooks, I never heard of Eliel and probably never will look inside since this book probably has a rather high hair-loss factor. Indeed, it took me a long time to come up with the example of tartaric acid, while quartz was immediately evident.

Excuse me while I go into a corner and cry for a while...

On Rhodium's archive there is a procedure by LabTop who makes the phenylacetone n-methylimine with silica gel, but I'm not sure if it's not a little bit dubious. Of course I will not lose bad words on a procedure until I've tried it - a project for a future rainy day...

Back on topic: I think the original poster got all the needed pieces and I probably speak for everyone when I say: we want results! Maybe not to the final product, but N,N-dimethylbenzylamine and benzylbromide would be nice.

Klute - 20-1-2010 at 00:02

I used Labtop's method for phenylbutanones and methyl and dimethylamine, workep faily well, although I didn't use any silicagel, just anhydrous amine in MeOH, stirred for an hour at 10°C, then added NaBH4 in portions over a few hours. Steam distilled the amines, got 60-75% yields.

I also used the same technique with benzaldehdye although I realise now I could ahev used 40% aq. MeNH2 instead of going through the trouble of gassing MeOH...

kmno4 - 20-1-2010 at 02:19

Still does not beat the simplicity of the Stevens rearrangement!

It can be, but would you give some reference ?
Not about Stevens rearrangement at all but for this particular case. I could not find anything about it (use of KNH2 and 30% yield is not worth mentioning)

Nicodem - 20-1-2010 at 03:35

Only 30% with NaNH2? Too bad, but then who uses NaNH2 any more. However, the yield using tBuOK in refluxing toluene is quite good. The quat can be prepared by refluxing the mixture of BnNMe2 and BnCl in toluene before adding the base. Needles to say, BnNMe2 can be prepared from HNMe2 and BnCl or PhCHO by the known methods. The reaction works for some other Bn2R2NX where R is alkyl or part of an cycloaliphatic ring.

I will not post the exact reference because I don't want to play the spoonfeed game of the original poster, however it is in a certain RSC journal in one of the seminal papers from Stevens et al. where they study this rearrangement. The competing reaction is the Sommelet-Houser rearrangement. The ratio between the products of the two types of rearrangement is very dependent upon the base used. The best results were obtained by tBuOK>iPrOK>>MeOK if I remember well, MeOK giving almost exclusively the Sommelet-Houser rearrangement product.
Then there is also a paper by Wittig et al. in Ann. from 1951 where they form the ylide from Bn2Me2NBr by using PhLi and analyse the decomposition products (amine ylides decompose rapidly). The yield of lefetamine by this decomposition is 52% while the Sommelet-Houser rearrangement product (N,N-dimethyl-alpha-(o-tolyl)benzylamine) is 36%. The separation was done simply via differences in solubility of the hydrochlorides.

JohnWW - 20-1-2010 at 07:26

(cut)The words asymmetric and symmetric were referring to the reaction and not to the structural symmetry as you misunderstood. I was trying to explain the stereochemical "dogma" that a reaction can give an asymmetric outcome (excess of one enantiomer over the other) only in an asymmetric starting environment. Structures can be chiral or achiral, but reactions proceed symmetrically or asymmetrically. But I do agree that "chiral centre" is a problematic phrase. As a student I too was forced to read Eliel's bible on stereochemistry and should know better, but old habits die hard. (cut)

Does anyone know of a free download of Stereochemistry Of Organic Compounds, by E L Eliel (Wiley-1994)? I cannot find one.

However, using Google, I found another book edited by him, Topics In Stereochemistry:
http://rs358tl3.rapidshare.com/files/94358058/topics_in_ster... 14.6 Mb

As regards asymmetry in organic reactions, this thesis is relevant:
http://www.biorg.uu.se/Forskning/BLa/TorbenR/thesis_pub.pdf - Molecular Modeling Of Asymmetric Catalysis (2001) 907 Kb

[Edited on 21-1-10 by JohnWW]

solo - 20-1-2010 at 07:52

Topics in Stereochemistry, Volume 9
by: Norman L. Allinger, Ernest L. Eliel
en | Wiley
2008-11-22 08:45

Topics in Stereochemistry, Volume 4
by: Ernest L. Eliel, Norman L. Allinger
en | Wiley
2008-11-22 07:40

Topics in Stereochemistry, Volume 5
by: Ernest L. Eliel, Norman L. Allinger
en | Wiley
2008-11-22 08:00

Topics in Stereochemistry, Volume 8
by: Ernest L. Eliel, Norman L. Allinger
en | Wiley
2008-11-22 08:33

Topics in Stereochemistry, Volume 10
by: Ernest L. Eliel, Norman L. Allinger
en | Wiley
2008-11-22 08:52

Topics in Stereochemistry, Volume 1
by: Norman L. Allinger, Ernest L. Eliel
en | Wiley
2008-11-22 07:01

Topics in Stereochemistry, Volume 2
by: Norman L. Allinger, Ernest L. Eliel
en | Wiley
2008-11-22 07:23

Topics in Stereochemistry, Volume 3
by: Norman L. Allinger, Ernest L. Eliel
en | Wiley
2008-11-22 07:34

Topics in Stereochemistry, Volume 6
by: Norman L. Allinger, Ernest L. Eliel
en | Wiley
2008-11-22 08:09

Topics in Stereochemistry, Volume 7
by: Norman L. Allinger, Ernest L. Eliel
en | Wiley
2008-11-22 08:23

.............this may be of interest, found here.....

http://gigapedia.info/1/E.L.%20Eliel

kmno4 - 20-1-2010 at 09:46

...however it is in a certain RSC journal in one of the seminal papers from Stevens et al. .....

In have found it in part VII... but with no yield given. Procedure is not so simple as it looks.
Nevermind.
I gave 30% earlier for KNH2 in refluxing toluene , but it is my mistake and yield is 59%(+37% recovery of input compound)). In liquid NH3 there is 97% yield of another product (ortho substitution).
This paper is cited on given earlier webpage.
BTW I think that more a propos literature is "The chemistry of enamines" (from Patai series). Available on internet.

kafka - 20-1-2010 at 14:31

I apologize for doing such a terrible job creating my original post. i did several hours of research (yes not enough) before posting. i felt that i had looked into the different methods of synthesis and the amount of information i posted was much more than any other forum post or paper i could find. im sorry for not including sources. menawhile thank you everyone for the information and the great conversation. please understand im not asking to be spoon fed, i was asking for exactly what we have here, a wonderful discussion on the compound.

its been several years since O chem and i admit i love the lab work much more than the theory and for that reason i am very nervous about saying anything intelligent for fear that i will be wrong ;/

so back to the topic and again im sorry. This is a shot in the dark but its an idea based on the very beautiful Stevens arrangement posted earlier.

According to production of bronchodialator effects patent #3089862 from 1958 o-chlorophenethylamine reacted with 37% formic acid, 90% formaldehyde at reflux will produce 0-chloro-N,N-dimethylphenethylamine. so as of yet i have not found (i am looking) any direct evidence that this will work but what do you think of:

phenylethylamine + formic acid + formaldehyde ===> N,N-dimethylphenethylamine

=======>

==NaOH===>

This would then be reacted with Bromobenzene. then according to papers ive seen on the stevens arrangment NaOH is used to shift the carbon bond from the nitrogen onto the carbon chain. walla! is there any reason that bromobenzene would not work when replaced for benzyl bromide?

bromo benzene can be made rather easily if one has benzene and a brominating agent (br2 right?). PEA is very easy to get in pure form from the corner health food store even. formic acid and formaldehyde are rather common as well and the formic acid can be made. If you cant get a hold of NaOH, give up now

.references if requested

From there it would be a separation of enantomers. i have yet to find anything with tartaric acid but i will continue to look.

I understand that this was somewhat already mentioned but the specific precursors were not mentioned.

thanks for the input everyone. and again im sorry if im asking for to much. i feel that this post asks for some help but also gives some mildly new information as well.

kafka - 20-1-2010 at 17:25

sorry for the double post but i found another reference for phenethylamine to n,n-dimethylphenethylamine.

http://www3.interscience.wiley.com/journal/113342277/abstrac...

and
http://www.freepatentsonline.com/y2005/0033088.html

not exactly what i was hoping for but very close.

[Edited on 21-1-2010 by kafka]

DJF90 - 20-1-2010 at 17:45

is there any reason that bromobenzene would not work when replaced for benzyl bromide?

Yes, but I'm not going to spoonfeed you. Go and find out why.

[Edited on 21-1-2010 by DJF90]

kafka - 20-1-2010 at 18:23

so bromobenzene will not work with n,n-dimethylphenelethylamine for making lefetaimne correct? before i spend a good amount of time finding out why i want to make sure you dont think i ment bromobenzene for producing the product shown in the scheme that i copied and placed in my post for the stevensrearrangment.

we would want the carbon chain to be one carbon shorter than whats shown. the example given is one two long for lefetamine which i hoped to fix by using bromobenzene wich is one shorter than benzyl bromide. regardless ill go look into the mechanism some more.

im really trying to contribute here and discuss the chemistry not simply ask how to do it.

meanwhile how about :

Toluene + Cl2 ===> benzyl chloride

Toluene + Br2 (add MnO2?) = benzyl bromide
or ammonium bromide, toluene, h202, acetic acid

dimethylamine + benzyl chloride ===> n,n-dimethylbenzylamine
http://designer-drugs.com/pte/12.162.180.114/dcd/chemistry/b...

n,n-dimethylbenzylamine + benzyl bromide = product

again i dont see how this couldnt work but i am a noob as you all have so easily noticed. the oxygen on the reagent in the first part of the reaction in the scheme above really doesnt seem to come into play in the mechanism so im hoping leaving it out is a ok.

the great thing about these precursors is that they are all very easy to make. more citations upon request.

DJF90 - 20-1-2010 at 18:53

Before attempting (and likely failing) to undertake this sizable task, why dont you start with the basics? You need a good solid theory to be able to suggest any kind of reasonable synthesis, to know what will and won't work. There are many books recommended here for such purpose, and then you can actually understand the chemistry involved.

I am also disturbed by your continual reference to the easy obtention of supposed precursors. Whilst us chemists should always be resourceful, I would not appreciate you getting valuable sources of chemicals shut down/removed because you try making a scheduled substance with them and get busted by the feds.

psychokinetic - 20-1-2010 at 19:00

I'm interested in some pretty intense stuff, and thus, I'M LEARNING THE BASICS.

And it's fun.

kafka - 20-1-2010 at 20:41

i understand this is over my head but please instead of insulting me lets criticize my ideas or add to the thread.

really im trying to do my research before i post.

DJF90 - 20-1-2010 at 22:17

You misunderstand Kafka; There is no point criticising your ideas until you come up with plausible ones. And you won't be able to do that until you LEARN SOME CHEMISTRY. So get to it!

The fact you appreciate that this is over your head, yet you are still reluctant to learn the basics, makes me think that you don't CARE about the chemistry involved and you just want a "theoretical synthesis" to make an "adequequate amount" of Lefetamine, or something of "greater or equal value". You still did not explain what you meant by this...

You say you wanted a challenge, yet this is too much for you because you have little basic understanding. Set the bar a little lower and have another stab at it, then you can progress to something more complex like Lefetamine.

Sykes' "A guidebook to mechanistic chemistry" is a very good place to start, as it gives you a good foundation in mechanistic reasoning that you need as an organic chemist. Theres also a book by Suarez which is "200 exercises in mechanistic organic chemistry" - 2002, which you can then use to TEST your understanding. For stereochemistry I think the best book is Eliel's "Stereochemistry of organic compounds", and for general organic chemistry the textbook by Clayden et al. "Organic chemistry" is fantastic.

turd - 21-1-2010 at 02:01

so bromobenzene will not work with n,n-dimethylphenelethylamine for making lefetaimne correct?

Please, you're not ready to come up with your own reactions, so you will have to use reactions exactly as they're published (which means you'll have to learn to use a university library!). Don't try to be clever. Really, just don't try and follow published procedures, otherwise you will only end up frustrated. For the example at hand: have you not noticed that
1) in all examples on the rearrangement there was either a carbonyl or an aryl functionality next to the C.
2) the posters above are talking about strong bases.
? Even someone who is oblivious of organic chemistry (like me) would conclude that the C probably needs to be acidic.

N,N-dimethylbenzylamine is probably better made by reductive amination of benzaldehyde (bitter almond essential oil, you need it for cooking

). You will only learn by doing, so go ahead or let it be.

Quote:

I am also disturbed by your continual reference to the easy obtention of supposed precursors. Whilst us chemists should always be resourceful, I would not appreciate you getting valuable sources of chemicals shut down/removed because you try making a scheduled substance with them and get busted by the feds.

Come on, come back to reality. Chemicals getting removed from the market because a single amateur tries to make an obscure psychoactive? Absurd.

JohnWW - 21-1-2010 at 02:40

I have uploaded Sykes' book on my premium Rapidshare account, and there is a link for it in the Organic Books in the References section.

As for the book by G T Suarez, Google yields several free downloads, including:
http://rushim.ru/books/mechanizms/two-hundred-exercises-in-m... 1.25 Mb
and
http://rs41l33.rapidshare.com/files/268200770/Two_hundred_ex... 507 Kb

[Edited on 21-1-10 by JohnWW]

entropy51 - 21-1-2010 at 17:21

Quote:

Chemicals getting removed from the market because a single amateur tries to make an obscure psychoactive? Absurd.

Hardly. I worked for a chemical supplier a long time ago and we would get a call from some whacked out freak asking for something that we didn't know was a precursor. The company immediately stopped selling the stuff. I have to wonder where kewls get these strange ideas that the chemical industry is drug friendly.

turd - 22-1-2010 at 10:09

Even if your anecdotal evidence is true (you'll get the benefit of the doubt), this only proves that there are companies with silly business practices. The competition will rejoice.

My personal anecdotal evidence indicates the opposite of your conclusion: As a whacked out freak, kewl or whatever you wish to call me, I have never had problems buying potential precursors to various street drugs (and really, what isn't?). The various companies generally seem to have a "don't ask" policy, which is of course sane, since they want to keep their customers and customers value privacy. Only once I had to confirm with a signature that I will not use an oxidizer for making bombs. *shrug*

But aside from anecdotal evidence we could simply have a look at the facts:
para-formaldehyde and ammonium chloride, precursors to methylamine, in turn a key precursor to methamphetamine and MDMA: easily available.
benzaldehyde: well known precursor to amphetamine: easily available.
benzylbromide: well known precursor to (meth)amphetamine: easily available.
etc, etc, etc...
Or lets have a look at your beloved DEA list I chemicals (http://en.wikipedia.org/wiki/DEA_list_of_chemicals): Without exception, all listed chemicals are directly tied to the multi-kg production of major street drugs. Not a single one of them was scheduled because of some obscure route to an obscure psychoactive. Sorry to tell you, but reality completely contradicts your dream world.

PS: didn't you plan to refrain from posting off-topic stuff about your favourite subject?
Please discuss this kind of things in legal or whimsy.

Vogelzang - 23-1-2010 at 10:58

Vogelzang - 28-1-2010 at 16:00

This looks interesting.

Attachment: ja01215a018.pdf (233kB)
This file has been downloaded 1071 times

Arrhenius - 28-1-2010 at 21:12

I hope those yields convince you to take a different route.

Bronstein - 29-1-2010 at 11:06

Actually it would be pretty interesting to read the original paper on Lefetamine. The reference is J. Pharm. Soc. Japan 80, 283 (1960). That journal is available online, but it is missing some older issues, and that article is in one of them. Perhaps someone has it in a library nearby?

Vogelzang - 29-1-2010 at 14:08