Author Topic: PTC reissert synthesis, plus?  (Read 3302 times)

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ning

  • Guest
PTC reissert synthesis, plus?
« on: April 27, 2004, 09:26:00 PM »
Ning thinks anyone who can make Mandrax should be able to make tryptamines. Is the reissert synth popular amongst denizens of the hive?

It is attractive to ning for several reasons. First, OTC.
oxalic acid --> diethyl oxalate, easy.
toluene --> o-nitrotoluene, annoying but easy.

Now, how about the base?
Ning has refs where they use everything from NaNH2 to NaOMe to condense the ethyl/methyl oxalate with the nitrotoluene. What's up with that?

Helv. Chim. Acta 2001, pg 1456 suggests that the reason may bee that there is a tautomerism between the nitro and aci- forms of the nitrotoluene, and that while the nitro form has a pKa of 20.6, the aci form is only 3.6! I guess this means that once it is deprotonated, it would tautomerize to the aci-form and get stuck there, much like a nitroalkane.

(the paper also says nitromethane nitro=10.2, aci=3.25; nitroethane nitro=8.44, aci=4.41)

I have a lot of papers on this sort of thing, but to begin with, here's the pitch: Could the strong base bee replaced with PTC? NaOMe is not much stronger than hydroxide. Honestly, ning thinks the only reason hydroxide isn't used is because it would hydrolyze the oxalate ester. But, with carbonate or phosphate ion and solid-liquid PTC, this is not a problem. So why not PTC this?

It goes deeper than that, though. Ning has not seen ANY examples ANYWHERE of PTC claisen condensations. WTF not? It's just a carbanion reacting with an ester, right? Is ning missing anything? If not, then this should work.

The innovation (i.e. why are you making your own indole when you could buy it, dum dum) is that the intermediate form in the reissert synth is very convenient for another step that would greatly simplify the whole thing.













Molecule:

First, alkylate like this ("c1(N(=O)=O)ccccc1[C-]C(=O)C(=O)OCC.ClCCN(CC)CC>>c1(N(=O)=O)ccccc1C(C(=O)C(=O)OCC)CCN(CC)CC")














Molecule:

and then close the ring with Fe/HCl ("c1(n2)ccccc1c(c2C(=O)OCC)CCN(CC)CC")


Lastly, hydrolyze/decarboxylate.

See what ning's getting at? After the Claisen condensation, that benzylic methylene group becomes REALLY acidic, with all those electron-withdrawing groups nearby. To alkylate it would be so simple. And if you do that now, you don't have to worry about protecting the indole's amine group, because it isn't formed yet.

See JMC 1994, 1625 on page 1626 and 1628, where they alkylate such an indole precursor with methyl iodide.

Yield's not so hot, but there's many possible reasons for that.

Also, alkylation of ethyl phenylacetate and benzyl cyanide under PTC conditions with a number of various nucleophiles has been done. Particularly benzyl cyanide, I guess because it's an important industrial precursor.

pKa of benzyl cyanide (calculated) = 22.1
pKa of ethyl phenylacetate (calculated) = 19.4
pKa of ethyl benzylglyoxylate (calc'd) = 11

<

http://ibmlc2.chem.uga.edu/sparc/pka/singlepka.cfm

, a handy online pKa calculator>>

Keep in mind, kids, that's WITHOUT the o-nitro group to help things along. These bad boys are going to bee very easy to deprotonate.

In JOC(?) 1950, 918, they use a funny KOH/acetal solvent system to condense diethylaminoethyl chloride with indene, ethyl acetoacetate, and ethyl phenylacetate. In all cases, the yield was ~25%, but then, that's what they got for benzyl chloride as well. One is tempted to think it's their funky system. At least, it's a proof of concept.

Finally, JMC 1966, 191 offers the following instructions on making Br.Et.N.Et2, along with several others:

"Preparation of Basically Substituted Alkyl Bromide Hydrobromides--
The reaction of 48% HBr with the appropriate basically substituted alkanol according to the general procedure [org syn CV2, 91] gave the following new compounds in 80-87% yield:
2-bromoethyl methylethylamine HBr
N-2-bromoethyl N'-methyl piperazine HBr
N-3-bromopropyl N'-methyl piperazine HBr"

blah blah. Ning will try looking on the net for info about nitrogen mustards, because that's basically how they made them also--HCl + diethanol alkylamine or triethanolamine.
If some optimized procedure could bee found it would be nice, as PTCs like chloride ions better than bromides, and they're cheaper anyway. Ning is not sure what the easiest way to get an ethanol dialkylamine is, though. Except the hydrolysis of diphenhydramine (benadryl) would yield ethanoldimethylamine. Hmm...


So that's it. If ning's reasoning is correct, with:

2-hydroxy alkyl alkyl amine
NaBr
2-nitrotoluene
oxalic acid
PTC

you can probably make tryptamines. In bulk. With much research and experimentation.

What say ye, hive collective?


Nicodem

  • Guest
Ning, I would very much appreciate if you...
« Reply #1 on: April 28, 2004, 02:09:00 AM »
Ning, I would very much appreciate if you could scan a few of those papers dealing with nitronates, their tautomerism and pKa's (especialy for nitrotoluene. I'm very interested in that but these days I'm to lazy to go to the library. :P

The pKa prediction page is't that reliable. Benzylcianide has the measured pKa 20.8 (not 22.1).

You can't normaly alkylate phenylacetates in basic conditions since they self condense (Claisen rxn with itself). The same is probably true for ethyl benzylglyoxylate.

Maybe you could also provide us a esterification method for oxalic acid, preferably one that avoids oxalyl chloride or thionyl chloride?


ning

  • Guest
OK
« Reply #2 on: April 28, 2004, 08:23:00 AM »
I'll see what I can dig up about those papers. They're getting much too theoretical for poor ning's brain to handle.


You can't normaly alkylate phenylacetates in basic conditions since they self condense (Claisen rxn with itself). The same is probably true for ethyl benzylglyoxylate




If this was really true, why does the reissert synthesis work at all? All of those benzylglyoxalates would condense with each other. But they don't. I admit, it's strange...

And did you read my whole post? They DID alkylate a benzylglyoxalate. Admittedly in low yield, but it was done.


Maybe you could also provide us a esterification method for oxalic acid, preferably one that avoids oxalyl chloride or thionyl chloride?




heh heh. I did, some time before. Unfortunately, since TFSE is down, I can't refer you the post. It was on "OTC methylating agents" or something like that. Here's the Org Syn link, though:

http://www.orgsyn.org/orgsyn/prep.asp?prep=CV1P0261


http://www.orgsyn.org/orgsyn/prep.asp?prep=cv2p0414



The second one is better.
methyl oxalate is also a better alkylating agent than methyl carbonate, and more OTC, too.




Nicodem

  • Guest
The critique
« Reply #3 on: April 29, 2004, 11:04:00 AM »
Ning, sorry if the last time I didn't read and analyze your idea thoroughly. It takes some time, besides those java applets don’t work on my newer version of IE (even though the java is enabled!?). Anyway…here are my thoughts.

Ning has refs where they use everything from NaNH2 to NaOMe to condense the ethyl/methyl oxalate with the nitrotoluene. What's up with that?

Even though NaOMe/MeOH or NaOEt/EtOH is usually used for the condensation of dialkyloxaltes and nitrotoluenes, I’m quite convinced that NaOH/EtOH would work with minimal yield loss. The reason is that NaOH is basic enough to deprotonate nitrotolune even though this is a much, much slower process than a normal base+acid reaction (due to the pKa paradox you already well explained and the dearomatization energy barrier). But once the nitronate salt is formed it is a stable sodium salt ready to alkylate the oxalate ester much faster than any hydrolysis can occur (such a sodium salt is even less basic than sodium acetate and cannot bee expected to hydrolyze the oxalate with only minimal water present). Therefore the reason why NaOH/EtOH is not used might bee because of the organic chemists mentality (just ask a few org. chemists what they think why NaOEt should bee used and you will see what I mean). One of the important things I learned is that when you are set to improve, optimize, make cheaper, OTC and simple a published reaction procedure, you first have to understand how the brains of an organic chemist work. This helps a lot and their brains are actually simple to decode. :)

It goes deeper than that, though. Ning has not seen ANY examples ANYWHERE of PTC claisen condensations. WTF not? It's just a carbanion reacting with an ester, right?

It is not that simple. Besides the possibility that most esters have pKa’s too high for the PTC conditions there is always the old limitation inherent to the Claisen reaction. This reaction is great for the self condensation of esters (like for preparation of ethylacetoacetate) but when it come to the condensation of two different esters it has a terrible limitation: the more electrophylic of the esters must not have any alpha-hydrogens. This is because such ester is also the more acidic and thus the first to form the anion nucleophile as well as the most reactive towards it (self condensation is the consequence). There are ways to avoid this but they are beyond the possibilities of most bees here (like working at <-70°C or using NaH or LDA to first completely deprotonate the most reactive ester and then add the other…). This was actually already discussed in the P2P from PhCH2COOMe+AcOMe thread (sorry, no link - TFSE still does not work).

About the alkylation of the ‘reissert intermediate’ I think the best procedure would bee the same as proved the best for the alkylation of the ethyl nitroacetate (somewhere in the PEAs from nitroacetate thread- TFSE again). That is KHCO3,Bu4NCl/DMF otherwise the double alkylation product might predominate.

If this was really true, why does the reissert synthesis work at all? All of those benzylglyoxalates would condense with each other. But they don't.

Of all the compounds in the reaction mixture, the benzylglyoxalates are the most acidic and are therefore deprotonated at all time. Being deprotonated they lose their electrophilic character and can't alkylate other nucleophiles. On the other hand they are also the less nucleophilic - again because of their acidity. If however they nevertheless manage to alkylate an diethyl oxalate you have to consider the very high reversibility of such reactions yielding back the benzylglyoxalate and the oxalate.

PS: Thanks for the oxalates preparation links. Very nice.


ning

  • Guest
Wow, what a post
« Reply #4 on: April 29, 2004, 08:33:00 PM »
I'm honored you took the time to read and understand my megapost thing, and critique it carefully. It seems, then, that the method is possible?

I had another thought: It may bee possible to prevent overalkylation of the aci-nitrophenylglyoxylate, because after the Claisen condensation, the aci- compound only has one hydrogen left! This is a very tempting possibility...Is it correct thinking?












Molecule:

aci-alkylate! ("[O-]N(=O)=C1C=CC=CC1=[C-]C(=O)C(=O)OCC")



So, o-nitrotoluene would bee stirred with NaOH in ethanol for a day or two, and pH monitored to see what the deprotonation status was. When deprotonation was complete, a 2x excess of ethyl oxalate would be added and allowed to react. Following this, the dialkylaminoethylhalide of choice would be added in 2x excess with a pinch of NaI, the solution stirred, then acidified carefully with HCl and stirred until reversion to nitro form was complete. This would bee followed with basification, evaporation of solvent and extraction with ligroin, followed by precipitation with HCl gas (I guess).

Synthesis would continue with reduction by Fe/AcOH and hydrolysis/decarboxylation to the final tryptamine form. Yummy!
-------

Apparently, the equilibrium nitration % of o-nitrotoluene is about 60%. The other 38% or so of p-nitrotoluene is very handy for making DOM.
-----------
It would make ning so happy to see bees making multi-kilo loads of exotic tryptamines from toluene and deck bleach. Was the reissert synthesis overlooked mainly because people thought oxalate esters were impossible to make? Or was it the strong base required? I hope someone tries this. If it worked, it would make a real nice scientific paper, actually.


ning

  • Guest
To support KOH+EtOH idea
« Reply #5 on: April 30, 2004, 12:32:00 PM »
Found in my venerable "chemistry of organic compounds":

"In some polynitro compounds, however, one nitro group frequently undergoes a displacement reaction with basic reagents, nitrite being the other product."

o-nitrobenzene + KOH (aq) --> o-nitrophenol
o-nitrobenzene + KOH + EtOH --> o-nitroanisole
o-nitrobenzene + NH3 --> o-nitroaniline

They also mention ease of displacement of chloride from o-chloro and p-chloro nitrobenzene, but don't mention the conditions.

Beilstein~~~~~la la la


Nicodem

  • Guest
Double deprotonation or double trouble
« Reply #6 on: May 01, 2004, 05:00:00 AM »
Ning, as I see you just can’t avoid going wild with your theories. I like such an attitude, but I would prefer if you could filter your ideas with some reality checking before posting impulsively. I realize you do your best finding some literature references for your fantastic ideas and this should hopefully become a standard to many other bees, but waiting for the ideas to slowly settle down and ferment a little in some brain compartment can make then even more exquisite and of class. This is just a suggestion you don’t have to take too seriously. ;)

I had another thought: It may bee possible to prevent overalkylation of the aci-nitrophenylglyoxylate, because after the Claisen condensation, the aci- compound only has one hydrogen left!

Couldn't bee more wrong. First of all, you can’t double deprotonate a compound from the same carbon just like that. Even though the charges can redistribute, do you have any idea of the pKa a vinylic hydrogen have? Secondly, if you double deprotonate something you will also have a double nucleophile meaning that you will end up with a double alkylation product.

So, o-nitrotoluene would bee stirred with NaOH in ethanol for a day or two

When I said that the deprotonation of o-nitrotoluene is a much slower process than the usual acid-base reaction, I meant that it is not in the microseconds range of speed but maybe up to 8 magnitudes slower (in the 10 sec range – not days!). From my own experience I can tell you that p- and o-nitrotoluene deprotonate completely in few minutes when stirred in NaOH/EtOH. This can bee nicely followed by the slow change of color from the nitrotoluenes’ yellow to the dark brown-reddish color of the quinone-like structure of the anion counterpart (the nitronate form).

"In some polynitro compounds, however, one nitro group frequently undergoes a displacement reaction with basic reagents, nitrite being the other product."

Welcome to the fascinating and frustrating world of the aromatic nucleophylic reactions (BTW, you wrote o-nitrobenzene where it should bee o-dinitrobenzene). But how is this relevant to the topic?


ning

  • Guest
Obviously I haven't studied nitro compounds...
« Reply #7 on: May 01, 2004, 09:11:00 AM »
Obviously I haven't studied nitro compounds quite enough yet ::)

Nicodem, I'm glad you have some real experience with these compounds. I'm glad to hear it doesn't take that long. I heard that some nitro compounds

But, I really thought that the aci-nitro "quinone" deprotonated at the benzylic methyl group. Otherwise, how would it undergo the Claisen condensation? So then I figured, if it could do that with NaOH once, it would be able to do it again more easily when it had that nice alpa-hydrogenless electron withdrawing glyoxalate group attached. In any case, people have done it (the second alkylation, I mean), so it's possible. But I not at all clear on the actual exact mechanism.

If my understanding is correct, then (strange as it may seem), first the nitro group is deprotonated, the compound begins its dearomatization shift, and the vinylic hydrogen is removed. Then, that carbocation undergoes claissen condensation and becomes even more stable. Then we drop in a a halide of choice and blang! success. No more hydrogens left to substitute, until the "quinone" tautomerizes back to a benzene ring.

I would have researched this more, but this is very obscure chemistry, apparently. I'm having a real tough time finding information related to this type of tautomerization and its effects on pKa's, etc.

If it doesn't work like this, then how does it work?
Ning appreciates your patience 8)