Methyl.Magic
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Tert-butyl alkylation with t-BuBr
Hey !!
I'd like to put a "t-butyl" group on a free amine by hoffman alkylation with t-butyl bromide (in DMF/K2CO3) .
I have a problem... The amine is probably too basic and the reaction prefer the elimination (isobutene) instead of nucleophile subsitution...
So I'm searching a methode to avoid the elimination or HBr. Perhaps working under high pressure and low temperature or transforming the primary amine
into N,N-dihalogenoamine, then adding the t-BuBr with AlCl3 as catalyst ???
Can you help me???
thank youu i!
PS : the substrate is tryptamine, Indole-3-(CH2-CH2-NH2)
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Sandmeyer
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I wouldn't use DMF in that rxn, but I don't have beilstein either, i doubt you'll get a high selectivity, but check this method:
http://www.orgsyn.org/orgsyn/prep.asp?prep=v77p0012
I've also seen method employing Hünig's base, but I don't have a specific example at hand right now, you could search yourself...
[Edited on 14-5-2007 by Sandmeyer]
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Eclectic
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Here a a bunch of routes to t-butylamine:
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv3...
You might need to start with t-butylamine and build the rest of the molecule off it...
[Edited on 5-14-2007 by Eclectic]
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Nicodem
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| Quote: | Originally posted by Methyl.Magic
I'd like to put a "t-butyl" group on a free amine by hoffman alkylation with t-butyl bromide (in DMF/K2CO3) .
I have a problem... The amine is probably too basic and the reaction prefer the elimination (isobutene) instead of nucleophile subsitution...
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As every organic chemistry book says about nucleophilic substitutions: the t-butyl halides can not undergo SN2 nucleophilic substitutions. They can,
in theory, undergo SN1 nucleophilic substitutions. However, SN1 substitutions only work well in neutral or preferably acidic environments but since
the amines are protonated in acidic media they are not nucleophilic anymore (so, no reaction). There are however exceptions using extreme conditions
where the tinny amount of deprotonated amine reacts with the tinny amount of the t-butyl carbocation in SN1 fashion. These conditions are however too
harsh to bee used on any but the most simple substrates (for example, see US4937383).
…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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Sandmeyer
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Eclectic,
He doesn't want to make t-butylamine, clearly, he has a starting material that he wants to use... But I agree that he shall use a different starting
material, I'd choose tryptophol, mezylate it and swap with t-butylamine...
[Edited on 16-5-2007 by Sandmeyer]
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Eclectic
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Yes, I got that. I just provided t-butylamine preps to illustrate methods of getting a t-butyl onto an amine nitrogen. It doesn't look too promising
with a sensitive indole nucleus already attached.
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Methyl.Magic
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| Quote: | Message original : Sandmeyer
Eclectic,
He doesn't want to make t-butylamine, clearly, he has a starting material that he wants to use... But I agree that he shall use a different starting
material, I'd choose tryptophol, mezylate it and swap with t-butylamine...
[Edited on 16-5-2007 by Sandmeyer] |
Yes, like you said and dont want to start it again ! I've succesfully synthetised tBuBr from tBuOH and HBr and decarboxylated tryptophan to tryptamine
by heating in acetophenone.
Nicodem you said that SN2 is possible in neutral conditions. Can I make the solution slightly acid, add tBuBr and gently go up the pH... ?
Or maybe making the carbocation with a sort of very weak lewis acid ?
I've seen a methode to t-alkylated amine: N,N-dichloro amine are prepared by treating the free amine with hypochlorite. Then, the t-alkyl halide is
added in the presence of AlCl3.
but I think hypoclorite can destroy the fragile tryptamine substrate.
Thank you for help !!!
[Edite le 16-5-2007 par Methyl.Magic]
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Nicodem
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| Quote: | Originally posted by Methyl.Magic
Nicodem you said that SN2 is possible in neutral conditions. Can I make the solution slightly acid, add tBuBr and gently go up the pH... ?
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No, I said the opposite, that it is well known that "the t-butyl halides can not undergo SN2 nucleophilic substitutions". There simply are no
known examples of SN2 substitutions on tertiary alkyl halides, there are only several SN1 examples (the typical school example is the solvolysis of
t-butyl chloride in acetone / water in neutral to give t-butanol in addition to isobutylene).
The example of alkylation with t-butyl halide you describe is an SN1 substitution where the amine is N,N-dihalogenated in order to prevent its
coordination with the acid used (AlCl3) but still being nucleophilic enough for the alkylation to proceed. Two equivalents of t-butyl halide gets
consumed by oxidation (to 1,2-dihalo-2-methylpropane or whatever else) in such a process to fit the oxidation numbers of the equation. But why do you
even bring up a method that is useless for tryptamine? Are you asking in general or for this exact substrate? If for N-(t-butyl)tryptamine, the only
sensible methods is either an alkylation in the reverse like the one Sandmeyer told you or to acylate t-butylamine with an appropriate acid chloride
followed by the reduction to the amine.
[Edited on by Nicodem]
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Methyl.Magic
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hola !
thank you nicodem, so I cant make an SN1 substitution : tryptamine is really basic and be immediatly protonated in acid environement ... Does a method
exist to t-alkylate the tryptophan before decarboxylate it ?
If it is definitly impossible I'll buy some indole acetic acid, transform it to ester or COCl, add t-butylamine and reduce the amide with LAH to get
N-t-butyltryptamine...
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Nicodem
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AFAIK, no method of tert-alkylation of any amine exists exept for the extreme ones mentioned in this thread (well, except maybe the addition of methyl
Grignard on acetone imine but that is already a two step and difficult method and probably inappropriate for tryptamine).
I'm not sure but I think the indol-3-ylacetyl chloride is relatively unstable so you might consider using a coupling reagent like DCC or CDI instead.
Another alternative is to acylate indole with chloroacetyl chloride, alkylate tert-butylamine with it and then reduce the resulting
(indol-3-yl)-CO-CH2-NH-(t-Bu) with NaBH4 to N-(t-Bu)-tryptamine (the ketone carbonyl reduces all the way to CH2 due to the 1,4-elimination of H2O from
the intermediate alcohol followed by the additional reduction of the resulting cyclic imine).
…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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Eclectic
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Google "Tihkal" for scads of substituted tryptamine chemistry.
Indole + oxalyl chloride, then amine, then reduce with LiAlH4.
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Methyl.Magic
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Yep
thank you very much !
I'll choose another way :
Does LAH reduce the amide to the amine with no chance of producing the aldehyde ?
(sorry for my english, I speak french)
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Nicodem
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The aminolysis of esters is a reaction highly subject to steric hindrance and with t-BuNH2 it might proceed exceedingly slowly. Unless you find a
literature example where the aminolisys of a methyl ester proceeds at a useful rate I would (again) suggest you to simply use CDI and skip that
esterification step.
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Nicodem
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| Quote: | Originally posted by Nicodem
I'm not sure but I think the indol-3-ylacetyl chloride is relatively unstable so you might consider using a coupling reagent like DCC or CDI instead.
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Apparently I was wrong. I don't know how stabile it is, but indol-3-ylacetyl chloride can be prepared and is described in:Journal of Medicinal Chemistry, 31 (1988) 831-836. (with SOCl2/CH2Cl2)
Journal of the American Chemical Society, 109 (1987) 442-446. (with PCl5/Et2O)
Acta Poloniae Pharmaceutica, 31 (1974) 151-155. (with PCl5)
EP0147085 (contains also examples of coupling of indol-3-ylacetic acid and amines with CDI)
For the reaction of indol-3-ylacetyl chloride with t-BuNH2 to give the amide you want check Organic Preparations and Procedures International,
15 (1983) 297-302.
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Methyl.Magic
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the problem is I dont have this catalyst (CDI)...
My reagents are limited...
I'll try to convert my IAA to Indole-3-ylacetoyl chloride and add the amine... Yes your purpose is very nice but I dont have CDI...
Thank you !
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Nicodem
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CDI (N,N'-carbonyldiimidazole) is not a catalyst. It is a coupling reagent just like the more known DCC, but is easier to use since the side products
(CO2 and imidazole) are easier to remove from the reaction mixture (as compared to N,N'-dicyclohexylurea from DCC). It is a bit strange that you can
obtain chemicals like indoleacetic acid and LiAlH4 while you can not obtain anything as ubiquitous as a coupling reagent.
Anyway, follow the instructions from that OPPI paper if you want to add the acid chloride step in your synthesis.
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