sonogashira
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Dimethylaminoethanol chlorination
Does anyone know if it is possible to chlorinate dimethylaminoethanol (dmae) with HCl (conc. or gas) to get, ultimately, the chlorinated free base?
i.e:
HO-CH2-CH2-NMe2 ----HCl?----> Cl-CH2-CH2-NMe2
I have searched the literature for similar examples but the only ones I could find involved sulphur or phosphorous chlorides which I have no chance of
getting- ever.
If someone could even point me towards some literature method that would be incredibly helpful.
All the best 
[Edited on 15-4-2008 by sonogashira]
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solo
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High-temperature Chlorination of Amines and Acylamines
H. Holtschmidt
Angewandte Chemie International Edition in English
Volume 1, Issue 12 , Pages632 - 639
Abstract
High-temperature chlorination of acyl derivatives of primary and secondary amines and of tertiary aryl and alkyl amines usually yields compounds
containing either the imidochloride (monochloromethyleneamino) group I or the dichloroisocyanide (dichloromethyleneamino) group --N=C, . In many
cases, yields in the range of 80 to 9S % are obtained. Several ring-opening and ring-closing reactions occurring under the conditions of
hightemperature
chlorination are described.
Attachment: High-temperature Chlorination of Amines and Acylamines .pdf (705kB)
This file has been downloaded 994 times
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Sauron
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I'd chlorinate this with the TCT/DMF adduct in DCM at RT and expect nearly quantitative yields. See DeLuca's paper on alkyl chloride preparation.
TCT alone will do it but in lower yield and taking longer.
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MagicJigPipe
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As would I. However, since TCT is hard to come by (for some strange reason) and DMF is very expensive (for an average home chemist) I'd say try
Lucas' Reagent (HCl + ZnCl2). Your yields will suffer and I believe the reaction takes at least 24hrs to run on a primary alcohol but at least you
are using cheap materials. (1-dimethylamino-2-ethanol can be made easily by ethylene oxide + ammonia and then Eschweiler-Clarke methylation or by
reaction of ethylene oxide and dimethylamine). I never researched the specifics on those reactions (except for the ethylene oxide + ammonia) but I'm
sure it wouldn't be too hard to find info on.
I have tons of information and articles on the chlorination of primary and secondary (amino)alcohols without thionyl chloride if you are interested.
Although I haven't researched it in qite some time I'm sure I can locate the literature.
What are you trying to synthesize ultimately?
P.S. Lucas' Reagent will yield the HCl salt but should be easily turned into the freebase.
Good luck!
[Edited on 4-16-2008 by MagicJigPipe]
"There must be no barriers to freedom of inquiry ... There is no place for dogma in science. The scientist is free, and must be free to ask any
question, to doubt any assertion, to seek for any evidence, to correct any errors. ... We know that the only way to avoid error is to detect it and
that the only way to detect it is to be free to inquire. And we know that as long as men are free to ask what they must, free to say what they think,
free to think what they will, freedom can never be lost, and science can never regress." -J. Robert Oppenheimer
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Sauron
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You haven''/t been paying attention?
1. Make chlorine from TCCA and HCl 50/50 w/water.
2. Chlorinate MeSCN
You get TCT, plus a bunch of liquid, and if you continue chlorinating the liquid most of it becomes CCl4.
The DMF is optional, but, you can make DMF from dimethylamine and formic acid. You make dimethylamine from ammonium chloride and formalin soln.
HCl and anhydrous zinc chloride is a little horse and buggy. My proposal is much more contemporary and if you are willing to make the effort, entirely
OTC.
Oh, I forgot. MeSCN is from KSCN and MeI. MeI is from KI and Dimethyl sulfate. DMS, ask PainKilla or UTFSE.
Still OTC.
Or: DMS and barium thiocyanate. The latter from ammonium thiocyanate and barium hydroxide. Ammonium thiocyanate from ammonium dithiocarbonate and
heat. The dithiocarbonate from carbon disulfide and anhydrous ammonia gas in isopropyl acetate as diluent.
Are there no sellers of TCT (Cyanuric chloride)? in USA that sell to individuals?
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MagicJigPipe
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| Quote: |
Are there no sellers of TCT (Cyanuric chloride)? in USA that sell to individuals?
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\
Not that I have noticed. I said it was strange because it's really not very toxic or regulated. I know it is used a lot in the laboratory but when
it comes to industrial or commercial use (the reason it might be sold to individuals) it is relatively obscure.
And yes, I have been paying attention and I have much interest in that method of TCT production but I felt it couldn't hurt to tell him about the
easiest yet lowest yielding method. Some might not have the skills or equipment needed to make (or obtain) MeSCN. Hence my mentioning the virtually
OTC Lucas' Reagent.
| Quote: |
Oh, I forgot. MeSCN is from KSCN and MeI. MeI is from KI and Dimethyl sulfate. DMS, ask PainKilla or UTFSE.
Still OTC.
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Not OTC but close. Also, if one has a limited lab it would not be advisable to work with DMS or MeI.
By the way sonogashira, here is the link to the thread where Sauron describes a method of TCT synthesis (along with CCl4 and CHCl3):
https://sciencemadness.org/talk/viewthread.php?tid=10300&...
"There must be no barriers to freedom of inquiry ... There is no place for dogma in science. The scientist is free, and must be free to ask any
question, to doubt any assertion, to seek for any evidence, to correct any errors. ... We know that the only way to avoid error is to detect it and
that the only way to detect it is to be free to inquire. And we know that as long as men are free to ask what they must, free to say what they think,
free to think what they will, freedom can never be lost, and science can never regress." -J. Robert Oppenheimer
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Sauron
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BTW since when is anhydrous ZNCl2 OTC? I am unaware of it being available from chemical companies.
I mean, trinity might be accessible, but it is still a chemical vendor not a hardware store or DIY or auto supply etc.
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MagicJigPipe
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Virtually OTC. As in, you could purchase all of the chemicals needed to make it over the counter and is no harder to make than AlCl3. KI can only be
ordered.
Except in iodine tincture (which is now gone, at least in my area) but I don't consider that a viable source.
I'm not trying to start an argument as I agree that the TCT method is superior. But sometimes you just can't get exactly what you want so you have to
settle for second (4th or 5th really) best.
What is 1-dimethylamino-2-choroethane commonly used for? I've never heard of it being used for anything really.
"There must be no barriers to freedom of inquiry ... There is no place for dogma in science. The scientist is free, and must be free to ask any
question, to doubt any assertion, to seek for any evidence, to correct any errors. ... We know that the only way to avoid error is to detect it and
that the only way to detect it is to be free to inquire. And we know that as long as men are free to ask what they must, free to say what they think,
free to think what they will, freedom can never be lost, and science can never regress." -J. Robert Oppenheimer
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DJF90
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Tinner's fluid is a solution of ZnCl2, produced by dissolving Zn in HCl acid, and is available at the hardware store (at least in the UK). However I
think there may be an organic solvent involved because it smells like... well solventy I suppose (perhaps like paint stripper?). Maybe it can be
evaporated to leave zinc chloride behind, although it'd likely be acidic (?)(not all of the acid is neutralised by the zinc apparently).
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MagicJigPipe
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If there's any water in it, it is useless for Lucas' Reagent. If you dry to dehydrate it you will be left with ZnOHCl (according to Wikipedia which
is not always reliable but it sounds correct).
"There must be no barriers to freedom of inquiry ... There is no place for dogma in science. The scientist is free, and must be free to ask any
question, to doubt any assertion, to seek for any evidence, to correct any errors. ... We know that the only way to avoid error is to detect it and
that the only way to detect it is to be free to inquire. And we know that as long as men are free to ask what they must, free to say what they think,
free to think what they will, freedom can never be lost, and science can never regress." -J. Robert Oppenheimer
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Nicodem
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2-Chloroethyldimethylamine is a nitrogen mustard type of compound so don't go easy on it. Its hydrochloride is stable and can be handled safely, but
its free base is only stable in equilibrium with the N,N-dimethylaziridinium chloride and thus not something you want to play with,
especially if you value your health.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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Sauron
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In the general sense that anything with the Cl-CH2-CH2-N structure is in the nitrogen mustard ballpark, this is true, just as anything with a
2-chloroethylsulphide structure is a relative of sulfur mustard. However, it's the bis- and tris-(2-chloroethyl)amines and sulfides that are the real
mccoys, you can find methyl 2-chloroethyl sulfide in Org.Syn.
Not that I would recommend these as after shave lotions, you understand.
More alarmingly, IIRC there's a Russian variant of VS that is made from N,N-dimethyl-2-chloroethylamine. Or is my memory playing tricks on me again?
This does render MJP's question to sonogashira rather pregnant.
NB: the Russian VR component was N,N-diethyl-2-chloroethylamine but damn, that is close.
[Edited on 17-4-2008 by Sauron]
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Nicodem
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Well, yes, more than saying this compound is nitrogen mustard, I was more like warning that it has an identical effect on the organism. In
fact I would be more worried about this particular compound than the nitrogen mustards of the bis(2-chloroethyl) alkylamine type.
2-Chloroethyldimethylamine is more volatile, more reactive and what is most insidious, the molecule is small enough to cause irreparable damage to the
DNA. So I would expect it to be way more carcinogenic than the bis(2-chloroethyl)amine ones.
When using nitrogen mustards in organic synthesis, these are almost always prepared in situ from their respective hydrochlorides. The free
bases are too reactive to deal with unless unavoidable in which case they are prepared by basing the hydrochlorides and extracting in a suitable
solvent for use as their solutions. Even the less dangerous beta-halogeno primary or secondary alkylamine salts (like ClCH2CH2NH2*HCl or
(ClCH2CH2)2NH*HCl) are always dealt with care, though after free basing they form quite less reactive aziridines when compared to the aziridiniums
resulting from nitrogen mustards.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Sauron
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You gave good advice anyway. The fellow does not sound like he is set up for anything this nasty.
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Nicodem
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It is interesting that though the MSDS of this compound's hydrochloride does not mentions any carcinogenic risks. It is only classified as a T+, N
compound with the usual palette of scary risk and safety sentences. Though MSDS generally only mentions carcinogenicity after it is proved, thus
making them quite useless in this respect when dealing with the less commonly used compounds which were never tested for such activity.
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sonogashira
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| Quote: | Originally posted by Nicodem
In fact I would be more worried about this particular compound than the nitrogen mustards of the bis(2-chloroethyl) alkylamine type.
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In that case i'll keep well clear!!
To answer MagicJigPipe's question i was interested in adapting the indole alkylation method here to make 5-methyl-dmt (albeit in small yield) and putting it in my magicjigpipe! Since DMAE is readily (and cheaply) sold as a nutritional
supplement I thought that it may be worth a go.
Thanks for all the input anyway. Now that my memory has been refreshed I recall asking an almost identical question about ethyl chloride synthesis
which I'll have to have a look over again. The TCT route is new to me though so many thanks for pointing that out.
No need to worry about me nerve-gassing anyone Sauron. I doubt i'd get very far if i need help with chlorinating an alcohol anyway!!  My motivation was love not hate.
All the best to you all, and thanks.
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Sauron
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That should have occured to me since I authored the thread on melatonin synthesis not long ago. That's 5-methoxy-N-acetyltryptamine. I am no
authority on N,n-dialkyltryptamines but, I think you either build the side chain in when you make the indole, per Japp-Klingemann, or you start with
the indole and tack the side chain on using oxalyl chloride, then reduce it, and then aminate with dimethylamine.
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Sandmeyer
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| Quote: | Originally posted by Sauron
or you start with the indole and tack the side chain on using oxalyl chloride, then reduce it, and then aminate with dimethylamine.
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Do you meen to make tryprophol first and then substitute with dimethylamine? I see no point in doing that (esp since you still need LAH) the classical
route with oxalyl chloride, amidation, reduction (with LAH) is much more conveniant. The problem is that LAH is not directly OTC.
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Sauron
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I never said anything about OTC. And this would not be my personal favorite route, I'd go the Japp-Klingemann instead, But my target is not
5-hydroxy-DMT, it's melatonin. 5-methoxy-N-acetyltryptamine. I leave the dialkyltryptamines to others.
As to LAH, I have 500 g on hand. A 250 g can and five 50 g cans. No trouble ordering more anytime it's needed.
[Edited on 19-4-2008 by Sauron]
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Nicodem
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You can use chloroacetyl chloride instead to get indol-3-yl chloromethyl ketone, alkylate your amine of choice and reduce the amino ketone with NaBH4
which reduces the CO to CH2 in indolyl ketones. There is a page in Rhodium's archive for this as well, if I remember correctly.
But yes, essentially if you start with p-methylphenylhydrazine it would be optimal to use 4-dimethylaminobutanal or its dimethyl acetal as described
in literature. This would allow to get to the end compound in the same step as the indole ring formation (as Sauron proposed). However, though
p-methylphenylhydrazine is relatively easy to prepare (even from OTC chemicals), the synthesis of 4-dimethylaminobutanal or its dimethyl acetal is a
bit more involved.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Sauron
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I think we covered all this in the melatonin thread.4-chlorobutanol, oxidized most conveniently by PVPCC, the product converted to its acetal, the
4-chlorobutanal dimethyl acetal reacted with dimethylamine.
Using polyvinylpyridinium chlorochromate rather than PCC in my own idea. Avoids all that black mung.
However, that method is specific to dimethyltryptamines,
What I had in mind was p-anisidine, and the phthalimido-protected substituted acetoacetic ester, to give the protected tryptamine-2-carboxylate methyl
ester.
Saponify, decarboxylate and deprotect, home free. N-acetylate to melatonin. Pretty much all literature, some in Org.Syn., the rest mostly
Org.Reactions vol.10,
Annoying that the p-anisidine is a tad carcinogenic.
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Nicodem
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If such is the case (for melatonin synthesis) you should consider using 4-chlorobutanal for the Fischer cyclization since it should give you
5-methoxytryptamine directly. At least that is how you can prepare tryptamine from 4-chlorobutanal and phenylhydrazine. See:
Grandberg, Zuyanova, Afonia, Ivanova. Doklady Akad. Nauk SSSR 176 (1967) 583.
Grandberg et al. Khim. Geterotsikl. Soedin. (1968) 1038.
(references are from Sundberg's Indoles)
The drawback is in that p-methoxyphenylhydrazine is a bit hard to prepare and is only stable in salt form. As soon as you make the free base it starts
decomposing. At least it is commercially available, though quite expensive.
I think you can find these papers at the Hyperlab forum in the appropriate thread where this and related reactions were discussed (together with a
bunch of other papers about the Fischer cyclization, an OTC synthesis of 4-chlorobutanol and attempts at its oxidation).
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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