Sciencemadness Discussion Board

dialkylation of tryptamine with MeI and CsCO3

zephler1 - 2-9-2014 at 14:20

CsCO3 is known to alkylate amines in a mono or di substituted pattern in a very controlled fashion using alkyl halides. Could the dreaded Pictet Spengler and over alkylation of tryptamine be accomplished using CsCO3, MeI in dry DMF over 4A sieves?

A paper that might reference this is:

Synlett 2004(13): 2394-2396

however I do not have access to it - can someone help by posting it please?

Dan Vizine - 2-9-2014 at 15:44

I wouldn't expect your results to be any better than all the other dialkylation attempts. You'll get over-alkylation for sure.

The oxalyl chloride route is still the way to go.

zephler1 - 3-9-2014 at 07:41

Over alkylation is avoided using CsOH or CsCO3- it's called "The Cesium Effect"

[Edited on 3-9-2014 by zephler1]

Dan Vizine - 3-9-2014 at 08:55

You just may have something there. My experiences with Cs catalyzed alkylation were all with CsCO3, but CsOH seems to have different properties.

In an experiment to alkylate phenethylamine, BuBr + CsCO3 gave a 3:4 ratio of secondary to tertiary amines. Not so dramatic. But, using CsOH gave a 9:1 ratio at good yields. The authors said "this methodology was highly chemoselective to favor mono-N-alkylation over dialkylation". This doesn't say for sure that the cut off between your desired tertiary amine and the ring alkylated species will be so clear cut, but it is encouraging.

In an experiment to dialkylate tryptamine using CsOH, an alcohol (the alkylating agent) and Ph3P=NPh, it was found that tryptamine could be reacted with a diol, HO(CH2)4OH, to give the pyrrolidine derivative by dialkylating the primary N. The yield was 83% (isolated). This work is detailed here: G. Cami-Kobeci et al. / Bioorg. Med. Chem. Lett. 15 (2005) 535–537.

So, I'll revise my opinion to "cautiously optimistic".



[Edited on 3-9-2014 by Dan Vizine]

AvBaeyer - 3-9-2014 at 18:11

Dan Vizine:

The paper you cite does not speak to "an experiment to dialkylate tryptamine using CsOH, an alcohol (the alkylating agent) and Ph3P=NPh, [ in which] it was found that tryptamine could be reacted with a diol, HO(CH2)4OH, to give the pyrrolidine derivative by dialkylating the primary N. The yield was 83% (isolated). This work is detailed here: G. Cami-Kobeci et al. / Bioorg. Med. Chem. Lett. 15 (2005) 535–537."

The cited paper is for a method utilizing [Ir(COD)Cl]2 as a catalyst. Perhaps you know a more relevant reference to the use of CsOH/Ph3P=NPh?

AvB

Dan Vizine - 3-9-2014 at 19:22

If, by "more relevant", you actually mean to say "the correct one", then, yes, I can help you.

http://advertising8.com/n/n-alkylation-of-phenethylamine-and...



[Edited on 4-9-2014 by Dan Vizine]

zephler1 - 8-9-2014 at 04:12

can someone post a link to this paper?

Synlett 2004(13): 2394-2396

zed - 19-9-2014 at 15:44

Tryptamines best synthesized via the oxalyl chloride method?

Maybe. But, my friends have reported to me, that it is a nasty way to go.

Synthesis via the Indole Grignard+Dialkylaminoethyl Chloride method, works pretty well.
Yields are only about 25%, But an honest 25% is OK.

Some folks laud, synthesis via reduction of tryptamine imines with Sodium Cyano-Borohydride.

And, also, there is a school of thought that supposes synthesis via tryptophol is a good approach.

Direct synthesis via the Fischer Indole synthesis is not to be dismissed. Though preliminary synthesis of 4-Dialkylaminobutraldehyde might prove a challenge.



Dan Vizine - 20-9-2014 at 12:04

The first step to produce the bright yellow vinylogous amide is clean and has a good yield. Addition of Me2NH to the remaining acid chloride group goes in nearly quantitative yield and the resulting intermediate requires no purification before being suitable for reduction. Use of a modern reducing agent, like Red-Al for example, gives you a very simple work-up (if you add precisely the right amount of water during work-up, the inorganics separate as a paste) which goes in 60 - 70% yield. Fractional vacuum distillation will show little fore-run or pot residue. Yup, overall I'd say this is an excellent route.

For anybody doing synthesis work in a fume hood and with dry ice available this is just another set of reactions. Amide production from acid chlorides and amines is simple, direct, cheap. Reduction using Red-Al takes all the hazards out of hydride reductions. Standard stuff.

[Edited on 20-9-2014 by Dan Vizine]

Nicodem - 20-9-2014 at 13:28

I have to agree with Dan Vizine that the Speeter-Anthony synthesis is certainly the simplest, most straight forward and high yielding synthesis of tryptamines. Though not for the N,N-dimethyl compounds that are the obvious target of this topic, I have used it several times at work. The reaction of indoles with oxalyl chloride is one of the operationally so simple reactions that is like pure chemical meditation: a product rapidly precipitating pure directly out of the reaction mixture in near quantitative yield, with the additional aesthetic pleasure of the nice yellow colouration. What more can you desire? The amidation is trivial and the reduction with LiAlH4 or Red-Al just as well (yield is similar for both).

zed - 20-9-2014 at 14:04

Ah, this is news to me.

Are you suggesting that the Speeter- Anthony synthesis works well, but not with N,N,Dimethyl compounds?

Long ago, my old buddy Dr. Death reported to me that all seemed to be going well during his attempts, but he ended up with intractable crud that frustrated all of his attempts at isolating the desired final product.

Tell me more.

Nicodem - 20-9-2014 at 15:27

Quote: Originally posted by zed  
Are you suggesting that the Speeter- Anthony synthesis works well, but not with N,N,Dimethyl compounds?

No. It worked well for the N,N-dimethylated compounds for all those authors of the literature examples. What I said was that my experiences are on different tryptamines, probably of no interest to those who believe caesium carbonate is "CsCO3" and believe that the choice of base can prevent sterically unhindered primary amines from over-methylate with methyl iodide.

Dan Vizine - 20-9-2014 at 21:18

Quote: Originally posted by zed  
Ah, this is news to me.

Long ago, my old buddy Dr. Death reported to me that all seemed to be going well during his attempts, but he ended up with intractable crud that frustrated all of his attempts at isolating the desired final product.

Tell me more.


Sounds like he may have reversed the correct order of what is added to what in step 1. If you add oxalyl chloride to indole to you get what seems to be an intractable green plastic-like solid which is of low solubility in common solvents. If you do it correctly, indole being added to oxalyl chloride, it gives a beautiful yellow precipitate. This is because in the first case, as soon as the oxalyl chloride reacts at one end to give the indole glyoxyl chloride, this material immediately reacts at the remaining acid chloride end with all the excess indole floating around. You want the indole glyoxyl chloride to be floating around in excess oxalyl chloride, with which it won't react.

And, yes, I have to agree that the dimethyl cmpd. is produced in lower yield than the diethyl, but it's still a quite reasonable yield.


[Edited on 21-9-2014 by Dan Vizine]

Opylation - 16-5-2021 at 13:42

Is the issue with over-alkylation just with the beta nitrogen? Or is the issue also with the 1 nitrogen? If the issue is with a quaternary salt formed at the beta nitrogen I have seen procedures that are able to reduce the quaternary salt to a tertiary amine via the removal of a methyl group using sodium sulfide or potassium thioacetate. It’s actually not a bad process. I’ll attach the paper. I can’t remember if I’ve seen other papers about similar procedures with different reagents but I have a feeling that I have. Anyways..

Btw I’m a necromancer in my free time

[Edit] third times the charm?

[Edit 2] meh, I found another paper in my notes about tertiary N-methyl demethylations. I’ll post it below for anybody who’s curious

Attachment: anastasia2001.pdf (139kB)
This file has been downloaded 313 times

Attachment: rosenau2004.pdf (87kB)
This file has been downloaded 311 times

[Edited on 16-5-2021 by Opylation]