budullewraagh
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Indole from Ephedrine?
I just thought of something today:
Start with ephedrine, add chlorine to the phenyl group, and then isolate the ortho-addition products. Next, dehydrate, forming the alkene between the
1st and 2nd carbon atoms on the alkyl chain with respect to the phenyl group. Then, add LDA to deprotonate the amine and heat heavily to force a
substitution with the adjacent chlorinated phenyl carbon.
My only reservations are:
-directing the dehydration to result in the cis isomer- the trans wouldn't allow for substitution
-the possibility of the methyl group off the amine causing steric issues.
Disclaimer: This is all for theoretical fun.
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DDTea
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Very innovative!
First, so what we know what we're looking at: http://fr.wikipedia.org/wiki/Image:Ephedrine.png nice image for you.
But I'd go about it a bit differently from you. Ideally, one would start with Norephedrine instead of Ephedrine itself, but here's my method:
First do the ortho-chlorination on the benzene ring (Cl2 in FeCl3).
Next, oxizidize the benzylic -OH to a Ketone.
Then you must form an intermediate Benzyne between the 2 and 3 positions on the benzene ring using a very strong base, like Sodium Hydride. From
here, an electrophilic addition can be done to the benzene ring.
The first thing that triple bond sees is the adjacent proton on the amine, so it throws its electrons at him and bonds--HOPEFULLY putting it on the 3
position (though some 2-protonated contaminants may form). This leaves a positive charge on the 2 position on the benzene ring and a negative charge
on the Amine. Naturally, the two will go quite nicely together, forming your 5 membered ring!
Now why did I suggest forming the ketone? With it, you can do a grignard addition of an N,N-Dialkylaminoethyl Grignard agent, putting a substitution
product on the 3 position of the indole ring. From there, it will be easy to dehydrate the OH at position 3 on the indole ring and form your double
bond.
But there are two problems. If you use ephedrine, there will be a methyl group still attached to the indole nitrogen. This can be avoided by using
Norephedrine as the starting agent. The next problem is the methyl group on position 2 of the indole. I don't know how to overcome this latter
problem.
Wow, good thinking Bud...this is definitely worth experimenting with! For those of you with more experience in organic chemistry than I, please
point out and correct my errors. I hope you were able to follow what I was saying; try drawing pictures to help along.
EDIT: Hell! After you form the methcathinone, you could do a grignard reaction followed by an elimination right there!
[Edited on 5-24-06 by Samosa]
"In the end the proud scientist or philosopher who cannot be bothered to make his thought accessible has no choice but to retire to the heights in
which dwell the Great Misunderstood and the Great Ignored, there to rail in Olympic superiority at the folly of mankind." - Reginald Kapp.
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budullewraagh
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Good points about my idea- I'll think about it more today.
The reason I say that is that while your method looks pretty good, I'm a bit skittish about the electrophilic addition. Oxidizing the OH to the
ketone not only allows for grignards, but it also decreases the bendiness of the alkyl chain, making there be less likelihood that the ring formation
would occur. However, that could be fixed if we were to perform that oxidation post-ring formation.
The big question is whether we can get the electrophilic addition to occur and properly. I think the H+ would be more likely to add to the meta
carbon because of the extra stability provided to the ortho carbon by the adjacent alkyl group. Still, that triple bond is pretty far away from the
amine. This should be experimented with, however, and we can see from there what happens.
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DDTea
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| Quote: | Originally posted by budullewraagh
Good points about my idea- I'll think about it more today.
The reason I say that is that while your method looks pretty good, I'm a bit skittish about the electrophilic addition. Oxidizing the OH to the
ketone not only allows for grignards, but it also decreases the bendiness of the alkyl chain, making there be less likelihood that the ring formation
would occur. However, that could be fixed if we were to perform that oxidation post-ring formation.
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I didn't think about the bendiness of the chain; but I've found a quick solution to this by changing the steps around.
Do the addition of the N,N-dialkylethyl grignard to o-chloro-Methcathinone (or ideally, o-chloro-Cathinone), followed by an elimination between C1
and C2 on the chain. The double bond thus formed should allow extra sturdiness to the chain--locking the Amine into a position where it can react
more readily to form the ring.
Note the conjugation: one of the resonance structures of this has the amine as an iminium and C1 as a carbanion; this is good because it makes the
nitrogen more electrophilic and willing to bond to the benzyne intermediate which is now formed by reacting this compound with Sodium Hydride.
The triple bond is not happy at all, so it reaches out and deprotonates the amine, which cancels the charge on it and reforms the double bond between
C1 and C2. But there is still a carbocation on the ortho position of the Benzene ring; the Amine, with its regained lone electron pair, can now
bond with that, thus forming your tryptamine...well, an annoyingly methylated tryptamine, but still close.
EDIT: just noticed a problem with this method. The elimination can form two products--the desired one between C1 and C2, or a double bond from C1 to
the adjacent Carbon from the Grignard addition. Hmm, looks like steps will have to be rearranged again!
But on closer examination, I've noticed the ideal starting material is our friend Acetophenone. I'm sure that's watched by now...
[Edited on 5-24-06 by Samosa]
"In the end the proud scientist or philosopher who cannot be bothered to make his thought accessible has no choice but to retire to the heights in
which dwell the Great Misunderstood and the Great Ignored, there to rail in Olympic superiority at the folly of mankind." - Reginald Kapp.
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budullewraagh
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Or you could just not have the =O present in the first place and start with ephedrine.
I hope you meant aminium instead of iminium. You did, right? Otherwise, I don't understand.
The problem that we still have is that elimination will yield much more trans isomer, which wouldn't react with the ring. Any ideas?
[Edited on 24-5-2006 by budullewraagh]
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Organikum
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Interesting approach but why waste something like ephedrine for the stuff which makes shit smell like shit? Just a hint..
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budullewraagh
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It's fun and useful in the pharmaceutical industry
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Organikum
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And can be extracted in good yields from feces.
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DDTea
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| Quote: | Originally posted by budullewraagh
Or you could just not have the =O present in the first place and start with ephedrine.
I hope you meant aminium instead of iminium. You did, right? Otherwise, I don't understand.
The problem that we still have is that elimination will yield much more trans isomer, which wouldn't react with the ring. Any ideas?
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The reason I want the carbonyl present is because it will allow for grignard additions, which will result in 3-substituted indoles. But if you're
just interested in forming the Indole, it can be left as an alcohol.
I really do mean that an iminium will form--at least partially. You will have a conjugated system after the double bond formation--the ammonia can
throw its lone pair up (gaining a positive) charge, in turn moving electrons to C2 (forming a carbanion). In this resonance form, the Nitrogen
becomes very electrophilic, thus favoring ring formation.
This also deals with the "cis-trans" problem. In this resonance form, C1 is still able to rotate its bond such that the nitrogen is in a favorable
position to react.
Naturally, it won't be *entirely* bendable, but because of conjugation its properties won't be exactly as expected on first glance.
| Quote: | | And can be extracted in good yields from feces. |
That would be skatole that would be extracted, right?  And even if you did get
indole from feces...do you *really* want to be known as "the shit chemist?" 
[Edited on 5-25-06 by Samosa]
"In the end the proud scientist or philosopher who cannot be bothered to make his thought accessible has no choice but to retire to the heights in
which dwell the Great Misunderstood and the Great Ignored, there to rail in Olympic superiority at the folly of mankind." - Reginald Kapp.
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12AX7
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| Quote: | Originally posted by Samosa
...do you *really* want to be known as "the shit chemist?"
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Personally, I'd rather use it to make nitrates.
Tim
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budullewraagh
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Ah now I see. Good call with the conjugated pi system, Samosa. And then the grignard can happen. I may be able to research it where I'll be working
this summer. It's a shot in the dark, but possible. Do you think it's already been done?
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