Sciencemadness Discussion Board

Electronwithdrawing ester protecting group

vulture - 4-7-2008 at 09:22

Does anybody know of a protecting group for esters (or alcohols) which is electronwithdrawing and compatible with Grignard reagents? Most protecting groups for esters are electron donating and/or not compatible with Grignard reagents (nitrile functions for example). Working at temperatures lower than 0C is not desirable/possible.

[Edited on 4-7-2008 by vulture]

Ritter - 4-7-2008 at 09:47

Quote:
Originally posted by vulture
Does anybody know of a protecting group for esters (or alcohols) which is electronwithdrawing and compatible with Grignard reagents? Most protecting groups for esters are electron donating and/or not compatible with Grignard reagents (nitrile functions for example). Working at temperatures lower than 0C is not desirable/possible.

[Edited on 4-7-2008 by vulture]


Allyl? Without knowing more about your proposed scheme I suggest you consult Greene's Protective Groups in Organic Synthesis.

BTW, that dutch-belgian link doesn't work.



[Edited on 5-7-2008 by Ritter]

Nicodem - 5-7-2008 at 03:54

2-Alkyl-oxazoline protection is generally used to protect carboxylic groups (for example: R-COOH + HOCH2C(Me)2NH2 => 2-R-4,4-dimethyloxazoline). They are stable to Grignard reagents (even to LiAlH4!). But I'm not sure I understood what you mean by having to be electron withdrawing. How much electron withdrawing - more or less than the COOH group? The oxazoline is less electron withdrawing, I think.

Also, keep in mind that if you are trying to add a Grignard reagent on a highly reactive group, like aldehyde carbonyl for example, then you could actually get it done even without using protection groups (just make sure you use a double equivalent of RMgX since the COOH will quench it). The carboxylate salts are of very low reactivity toward the Grignard reaction, but they could also be of too low solubility so this highly depends on the specific reaction you are trying to perform. A similar approach would be to use the t-butyl ester as protection - it reacts slowly thus allowing for some chemoselectivity.

[Edited on 5/7/2008 by Nicodem]

vulture - 6-7-2008 at 01:38

It's an aromatic ester moiety which has to undergo a rather sensitive oxidative addition in a catalytic cycle and experiments show that electron donating groups slow or even kill the reaction.

As long as the protecting group is more electron withdrawing than H, it's fine.

The oxazoline suggestion is worth looking into, thanks.

[Edited on 6-7-2008 by vulture]

vulture - 8-10-2009 at 12:55

I'm currently trying to make an oxazoline from a benzoic acid using 2-amino-2-methyl-1-propanol. I found a standard JOC prep which boils down to dissolving the desired carboxylic acid and 2-amino-2-methyl-1-propanol, using toluene to remove water.

This, however, did not work, possibly because the acid didn't properly dissolve in toluene. Ethyl acetate (which also forms an azeotrope with water) got it into solution, but no reaction took place.

Now I was thinking of converting the carboxylic acid to the acid chloride first, then reacting it. I was also wondering if it would be possible to activate the carboxylic acid using DCC (N,N'-Dicyclohexylcarbodiimide) or would this stop at the amide stage? Other methods are also welcome.

Nicodem - 11-10-2009 at 01:44

I think that any amide coupling method you will use (either via acid chloride, N-acylisoure and so on) will stop at the amide stage unless some reaction modification. You would then need to dehydrate the amide into the oxazoline (SOCl2 or Ph3P/CCl4 are suggested by Greene et al).

I assume you used the J. Org. Chem., 26, 3821 (1961) that is mentioned in Protective Groups in Organic Synthesis (Greene&Wuts)?
Try with refluxing in xylene if toluene does not work. Maybe you can add a few mol% of boric acid to speed up the process. I don't think it matter much if the carboxylic acid is not soluble enough. At the addition of 2-amino-2-methyl-1-propanol you will have a two phase system anyway, since the amine benzoate should form a thick oily liquid at the bottom.

Unfortunately, I do not have any experience with this specific reaction. My experience with the formation oxazolines is limited to the reaction of benzonitriles with ethanolamine which proceeds easily by heating the reaction mixture in xylenes, in the presence of ~15mol% CaCl2. If you have the equivalent nitrile, maybe you can try this method instead?

vulture - 11-10-2009 at 02:03

Quote:

I assume you used the J. Org. Chem., 26, 3821 (1961) that is mentioned in Protective Groups in Organic Synthesis (Greene&Wuts)?


Not that one, but one with exactly the same procedure.

Quote:

Try with refluxing in xylene if toluene does not work. Maybe you can add a few mol% of boric acid to speed up the process. I don't think it matter much if the carboxylic acid is not soluble enough. At the addition of 2-amino-2-methyl-1-propanol you will have a two phase system anyway, since the amine benzoate should form a thick oily liquid at the bottom.


I will try using xylene. I also tried adding p-TsOH, which seemed to have little effect.
Quote:

Unfortunately, I do not have any experience with this specific reaction. My experience with the formation oxazolines is limited to the reaction of benzonitriles with ethanolamine which proceeds easily by heating the reaction mixture in xylenes, in the presence of ~15mol% CaCl2. If you have the equivalent nitrile, maybe you can try this method instead?


That's a good suggestion. Is the CaCl2 just added as a solid?

JohnWW - 11-10-2009 at 02:54

Quote: Originally posted by Nicodem  
(cut)
I assume you used the J. Org. Chem., 26, 3821 (1961) that is mentioned in Protective Groups in Organic Synthesis (Greene&Wuts)? (cut)

I have recently reuploaded two editions of this book. See the Organic Chemistry books section in References

Nicodem - 11-10-2009 at 04:38

Quote: Originally posted by vulture  

Quote:

Unfortunately, I do not have any experience with this specific reaction. My experience with the formation oxazolines is limited to the reaction of benzonitriles with ethanolamine which proceeds easily by heating the reaction mixture in xylenes, in the presence of ~15mol% CaCl2. If you have the equivalent nitrile, maybe you can try this method instead?


That's a good suggestion. Is the CaCl2 just added as a solid?


Yes. You can use the granulated CaCl2 that is commonly available as desiccant. It complexes with ethanolamine anyway. I used this method:
Quote:
General procedure for the preparation of starting materials:

A 2L round bottom flask was charged with 3-(trifluoromethane)benzonitrile (393 g, 2.297 mol) followed by ethanolamine (304 mL, 5.05 mol), CaCl2 (38.2 g, 345 mmol) and xylenes (200 mL). The reaction mixture was heated to 125 oC (internal temperature) over 45 min and stirred at this temperature for 17 hr. Then the reaction mixture was allowed to cool down to about 80 oC and toluene (200 mL) was added before to be cool down to room temperature. The crude reaction mixture was then transferred into a vessel containing 3.9 L of 0.1 M KH2PO4. The reaction flask was rinse with MTBE (800 mL) and water (400 mL). Heptane (2.8 L) was added to the extractor and the layers were cut. The aqueous layer was back extracted with MTBE (1 L) and heptane (1 L) and the combined organic layers were washed with water (2 x 2 L) before to be concentrated under vacuum. The crude residue was transferred into a 1 L RBF and was distilled under reduce pressure (110 oC @ 1 - 3 torr) to yield the oxazoline as a colorless oil (419 g, 85 %, 98 W%).

Cited from: Tetrahedron Letters, 49, 6707-6708. (from supplementary data) DOI:10.1016/j.tetlet.2008.09.061


You can find other literature examples where other cationic acids are used for catalysis (like zinc chloride or acetate) and chlorobenzene as solvent (for example: Synthetic Communications, 32, 363-368 where 2-methyl-2-aminopropanol is used).