Sciencemadness Discussion Board

naphthoyl indole grignard question.

kineticz - 25-10-2016 at 03:25

Hi Guys, I want to preform a grignard reaction on a Indole molecule.

Now I am not that chem savy but I have taught myself basic level experimental organic chemistry. I preformed many basic-medium reactions with success and have learnt a lot from my failures.

Before SM member get irritated with me, I would like to add I'm not looking to be spoon feed. Just need some guidance.




Here is the reaction.

To magnesium chips (0.6g, 24.6mmol) wetted with ~2ml Et2O, was added a solution of EtBr ( 2.6g, 24.6mmol) in 25ml Et2O. The flask is cooled to -5 degrees C and added a solution of Indole (2.9g, 24.6mmol) in 25ml Et2O. After the addition of indole, the solution is allowed to reach RT and stirred for one hour. After this time, the flask is once again cooled to -5C, and is added a solution of 1-naphthoyl chloride (4.9g, 25.7mmol) in 25ml Et2O drop wise. After addition, let reach RT and stir for one hour. Then there is added 20-30ml of saturated ammonium chloride (aq.) and stirred for 15 minutes. The formed precipitate is crushed in the flask and best attempts are made to remove it from flask walls etc. The ppt is filtered and washed with copious amounts of dH2O and triturated in 100ml acetone/dH2O 1:1. Sucked dry, dried completely in air with radiant heat from a hotplate. Yield 3.5g (counting on indole 52%)



My Problem: I do not have access to anhy Ethanol, however I do have access to anhy Ether. I also have access to ethylmagnesium bromide 3M in ether solution. How I propose to do the reaction is below. Please correct me if I am wrong.

What I propose.
In a 250ml RBF with Drying tube, thermometer and addition funnel is added 5ml of EtMgBr (3m Ether solution), this solution is cooled down to -5c and to this is added Indole (2.9g, 24.6mmol) in 25ml anhy ether dropwise via Addition funnel (maintaining temp below 0C). After addition the flask is allowed to reach RT and stirred for one hour.

The flask is cooled again to -5c and this time 1-naphthoyl chloride (4.9g, 25.7mmol) in 25ml ether is added drop wise (keeping below 0c). After addition the flask is allowed to reach RT and stirred for one hour. Then add saturated ammonium chloride and stirred for 15mins.


Please correct me if any of my measurements are wrong above. If my proposed synth is completely wrong then please point me in the right direction.



Much appreciated and much loved. Kineticz

AvBaeyer - 25-10-2016 at 07:36

You are not as well accomplished as you presume. First, you should learn to understand organic nomenclature shorthand. Next, you are not running a Grignard reaction on indole. You are using a Grignard reagent as a strong base to carry out an acylation of indole. Finally, I believe that you are trying to make something for personal use and enjoyment.

This post should be routed to detritus where it will find its rightful archival home.

AvB

CuReUS - 25-10-2016 at 07:41

Quote: Originally posted by kineticz  
My Problem: I do not have access to anhy Ethanol

why do you need anhy ethanol ?
Quote:
If my proposed synth is completely wrong then please point me in the right direction.

whether the synth is right or wrong depends on what you want to make.What is your target compound ?



zed - 25-10-2016 at 12:23

Crap. I wouldn't do that, and I wouldn't use the product either.

Not enough known about it.

Since pot has now been legalized, in this part of the U.S., .....local interest in such products has waned.

Still, attach a picture, we will mull it over.

Keeping in mind, that Indoles are already extremely reactive at the 3-position, is this Grignard approach, really required? Recalling the Speeter-Anthony synthesis: Oxalyl Chloride attacks the 3-spot readily. Suppose it is possible, that an ordinary Acyl-chloride, doesn't pack as much punch. But, I would check carefully, before I went Grignard.

https://books.google.com/books?id=xgMzE330FDQC&pg=PA98&a...

PS. You aren't Chem savvy? Then you need a mentor. Plenty of ways to kill or cripple yourself, fooling around with Diethyl-Ether, Mg, Acid Chlorides, etc..



[Edited on 25-10-2016 by zed]

[Edited on 25-10-2016 by zed]

karlos³ - 28-10-2016 at 13:00

This reaction does work fine this way, I can confirm that from experience.
Also know who did the write-up, and thus know that is very viable.

Darkstar - 31-10-2016 at 15:52

Quote: Originally posted by zed  
Keeping in mind, that Indoles are already extremely reactive at the 3-position, is this Grignard approach, really required? Recalling the Speeter-Anthony synthesis: Oxalyl Chloride attacks the 3-spot readily. Suppose it is possible, that an ordinary Acyl-chloride, doesn't pack as much punch. But, I would check carefully, before I went Grignard.


Oxalyl chloride is significantly more reactive than most other acyl chlorides, allowing indole acylations with oxalyl chloride to proceed directly and without the need for a catalyst. In most cases, however, indole acylations generally require some sort of initial activation, either of the acyl chloride by a lewis acid catalyst, or of the indole ring via deprotonation of the nitrogen. This is especially true for acylations using acyl chlorides like 1-naphthoyl chloride, as the aromatic acyl chlorides are even less reactive than the normal acyl chlorides are.

I suppose simply throwing the indole and 1-naphthoyl chloride into some diethyl ether and then heating it at reflux would acylate the 3-position to some extent (albeit with garbage yields); however, wouldn't the unprotected nitrogen inevitably end up getting acylated as well, further lowering the already-poor yields and eating up even more of the 1-naphthoyl chloride? I know the nitrogen isn't as nucleophilic as the 3-carbon due to the partial delocalization of its lone pair into the aromatic ring system, but I imagine the nitrogen is still reactive enough to give varying degrees of 1-acylated, 3-acylated and 1,3-diacylated products. I guess you could always hydrolyze the diacylated products to the desired 3-acylindole, though. But if the OP's target molecule is ultimately some synthetic cannabinoid of the JWH family, he could probably get around this whole problem by just protecting the nitrogen by alkylating it first, and then attempting to acylate the indole ring without the use of a grignard reagent. The electron-donating alkyl chain should also make the 3-carbon more nucleophilic, too.

And as far as the OP's grignard approach, deprotonation by a grignard reagent is often employed when electrophilic substitution at the 3-position is desired. The indoyl anion that results after deprotonation coordinates with the magnesium halide ion to give an indoyl-magnesium complex that, in addition to being a better nucleophile, is also far more selective towards electrophilic attacks at the beta-carbon due to a combination of the increased electron density at the 1- and 3-position, and the relatively covalent nature of the N-MgX bond (effectively decreasing nitrogen's nucleophilicity). Similarly, when electrophilic substitution at the nitrogen is desired instead, deprotonation by a base that gives an indoyl anion with a more electropositive counterion like sodium or potassium is used, as the nitrogen-metal bond in this case is more ionic and disassociated than with magnesium, making the nitrogen a much better nucleophile.

Speaking of which, if the OP does decide to go the grignard acylation route, yields can supposedly be significantly improved by first converting the indole grignard reagent into a zinc salt via transmetalation with anhydrous ZnCl2, then reacting that with the acyl chloride instead. Just as magnesium's electronegativity causes it to favor 3-acylation due to the covalent nature of the N-Mg bond, the zinc complex favors 3-acylation even more so due to zinc being even more electronegative than magnesium.