Reductive methylation

IndoleAmine · Dreamreader Deluxe

Hehe, formaldehyde + formic + heat - sounds a bit like leuckart to me... Very Happy

- And while thinking about reactions involving indole and formaldehyde as a methylating agent, I just remember another synthesis using formaldehyde on indole compounds: the mannich reaction...

It is a very elegant method of direct aminoalkylation, also applicable to indoles, and is exemplified by the reaction of indole with formaldehyde and dimethylamine to give gramine:

Gramine via the Mannich-reaction

A mixture of 0.05 mol dimethylamine (in the form of its 40% aequous solution), 7 grams GAA and 0.05 mol formaldehyde (as the commercially available 30% solution) is cooled to 0°C and then added at once to 0.049 mol indole.
An exothermic reaction ensues, producing a clean solution, which is left to sit a couple of hours at room temperature and then basified with dilute NaOH solution. The excess base is filtered off, the filtercake washed with water and dried in the dessicator over KOH pellets. Yield 98% of theory, mp. 134°C uncorrected (recrystallized frome acetone or hexane).

H.Kuehn, O.Stein; Ber.Deut.Chem.Ges. 70 (1937), p. 567

I am just guessing now; but wouldn't replacing formaldehyde with acetaldehyde result in N,N,dimethyltryptamine? Embarassed

i_a

ApprenticeCook · DILLIGAF

Unfortunatly not...

The mannich reaction will connect the aldehyde to the amine and the indole across the double bond of the oxygen on the aldehyde...
So you end up with indole reacting with acetldehyde and N,N-dimethylamine to form 1-(1H-indol-3-yl)-N,N-dimethylethanamine...
or...

Please correct me if im wrong... Would be nice if i was and this method did work... hmmm
-AC

Lief · Thu Mar 17, 2005 4:58 am

IndoleAmine · Dreamreader Deluxe

Hi folks!

Lief: Interesting that the eschweiler is indeed a leuckart variation, I didn't know that before..

ApprenticeCook, you said "and the indole across the double bond of the oxygen on the aldehyde..." - I think you're wrong here (or hope so.. Wink

).

Let me try to explain:

As far as I can see, the aldehyde first acts as a reductive alkylating agent on the amine, giving an aminoalcohol which then finally under acidic conditions undergoes dehydration to something like a schiff base(?). Now either if formaldehyde or acetaldehyde are used, the amino group will always attach to the CHO carbon of the aldehyde molecule, and the rest of the aldehyde will dangle around freely around the amine/nitrogen.

..now with that in mind, lets look how this crazy intermediate schiff base CH2-N(CH3)2 sticks to the 3-carbon of indole - it works somewhat like and aldol condensation:

..as you can see, it attaches to the indole with its free carbon; not with the "ex-carbonyl and now-nitrogenous" side.

And this makes me hope it could work with acetaldehyde.

This and the fact that besides formadehyde, other active methyl/methylene group containing compounds like acetone can be used for aminoalkylations with the mannich rxn too; although in this case (acetone), excess of acetone/amine to mannich-base is necessary to avoid formation of bis-mannich bases (indole for example is a mannich base, as well as ketones, aldehydes, alipathic nitro compounds and other CH-acidic hydrocarbons).

And last but not least the fact that my books tell that mannich rxn would be a method of "aminoALKYLATION", not only aminomethylation. Sounds to me as if other aldehydes than HCHO should work too...

***

...the compound shown on the right side of your picture is probably the result of a mannich between acetone, dimethylamine and indole, I would guess? And if said case of bis-mannich base formation would occur with acetone, dimethylamine and indole (but with excess indole instead of excess acetone/amine), the result would probably look like that:

Could be, right?

Now someone who really has got a clue about indole chemistry (and not just a chemistry textbook and the wish to understand): please verify my rambling, and tell us whether the mannich works with acetaldehyde or not.
I'm afraid I'm not able to answer this question concisely by myself... Confused

i_a

ApprenticeCook · DILLIGAF

i_a whoops i think i am wrong!!! THIS MIGHT JUST WORK! lol sorry bout that....

Mannich Reaction:
This multi-component condensation of a nonenolizable aldehyde, a primary or secondary amine and an enolizable carbonyl compound affords aminomethylated products. The iminium derivative of the aldehyde is the acceptor in the reaction.
http://www.organic-chemistry.org/frames.htm?http://www.organic-chemistry.org/namedreactions/mannich-reaction.shtm

and for visula learners:
http://www.sumanasinc.com/webcontent/anisamples/chemistry/mannich.html

That it does! sorry all concerned.... didnt check my info before i spoke! The picture from link 1 uses what can be seen as what we want to do!!!

Someone crank up the hotplate and get this sauce cookin, i want to know if i need to get the indole cranking....
-AC

IndoleAmine · Dreamreader Deluxe

Cool - looking at these new rxn mechanism pictures you provided, I'm becoming more and more sure that the mannich could work with acetaldehyde...

To everyone with some excess indole lying around: please, please throw together 0.1mol acetaldehyde, 0.1mol dimethylamine in auequous solution and a healthy excess of GAA to donate enough protons to the soup, and pour the motherfucker straight onto 0.09mol indole (caution! This one stinks quite nasty!) which is happily stirring away sitting in ice/NaCl...

Then let stir couple hours, quench with lots of 5% NaOH, until pH = 12...

Extract with ether or cyclohexane (no halocarbons please!), wash with bicarb & brine, remove solvent...

......check the smell of the residue - IS IT SIMILAR TO BURNT PLASTIC? Does it solidify? (*pray*)....... Laughing

Its a simple reaction, simple workup - one just has to have the reagents at hand. Something that definitely has to be checked!!

i_a

Nicodem · Fri Mar 18, 2005 3:34 pm

Stop bringing misinformation!

The Mannich is an aminomethylation and hence it attaches a (dialkyl)aminomethyl group on nucleophyles like highly activated aromatics (indole, phenols...) or aldehydes/ketones trough their enolate form.

R-CO-CH3 + HCHO + HNR2 =[H+]=> R-CO-CH2-CH2-NR2

or

Ar-H + HCHO + HNR2 =[H+]=> Ar-CH2-CH2-NR2

Since acetaldehyde is an aldehyde it fits into the first reaction as well and hence it would selfcondense in the Mannich reaction conditions. But even if the Mannich on indole would be a much faster reaction than such side reactions, it would stil give the alpha-aminoalkyl product like ApprenticeCook already explained.

starl1ght · Fri Mar 18, 2005 8:55 pm

Eschweiler-Clark methylation of tryptamine will lead to pictet-spengler cyclisation and beta-carboline product (acidic conditions).

IndoleAmine · Dreamreader Deluxe

I got the idea from my org.chem textbook, it says the mannich rxn would be an "aminoalkylation".....

IndoleAmine · Dreamreader Deluxe

It would've been sooooo nice if it had turned out to work.... Crying or Very sad

Nicodem · Sat Mar 19, 2005 2:03 pm

Just to clarify...

Like I already said, if the ‘self-Mannich-condensation’ side reaction is considerably slower than the wanted reaction, then you get the product, but off course, you would maybe get 1-[indol-3-yl]-1-dimethylamino-ethane and certainly not DMT so all this discussion is inrelevant for the purposes of this thread.

In the given example of Robinson’s tropinone synthesis the case is just this. The diethyl acetonedicarboxylate is much more reactive as its nucleophylic enolate form is much, much more aboundant than that of succinaldehyde. The later has a pKa of about 19 while the former is about 10 million times more acidic (pKa ~11) and hence its higher reactivity toward the imminium electrophyle. This is why the true Mannich (that is: the not Robinson, Pictet-Spengler or whatever other aminoalkylation that bears its own name) is with formaldehyde which is the most electrophylic aldehyde without any alpha hydrogens (therefore no side reactions are possible and it can easily aminoalkylate ketones since they are less electrophylic and hence their immines don’t participate as electrophyles).

Lief · Sat Mar 19, 2005 7:02 pm

Guest · Sun Mar 20, 2005 4:52 am

[quote="IndoleAmine"]I got the idea from my org.chem textbook, it says the mannich rxn would be an "aminoalkylation".....

IndoleAmine · Dreamreader Deluxe

Nicodem: Yes, I noticed that it won't work as I looked at the tropinone synth... Sad

Anyway, thanks for clarifying that the carbonyl is the more electrophilic one in the case of acetaldehyde, that was exactly what I was unsure about. The self-condensation issue could surely be circumvented by cooling the rxn, should favor imine formation and minimize polymerization. But its obsolete anyway, since my textbook (it is the "Organikum" btw Mr. Green

) is dead wrong on that issue about mannich being an aminoalkylation, since it can at most produce secondary alkylamino chains Confused

- and who the f*** would want some atropine or gramine (I guess noone)..... Laughing

i_a