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Author: Subject: Ketones from acyl chlorides and grignards via organozinc compounds
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[*] posted on 24-6-2012 at 21:34
Ketones from acyl chlorides and grignards via organozinc compounds


This is a reaction that I have seen mentioned here and there, but as of yet I haven't seen any practical example for it, like a synthesis procedure.

Grignard compounds react with acyl chlorides to form ketones:

R-Mg-Br + R'-COCl ---> R-CO-R' + MgBrCl

but the formed ketone immediately reacts with more grignard to form the tertiary alcohol R'-C(OH)R2. Adding the grignard to the acyl chloride and working at low temperature can slow down this secondary reaction somewhat, but the tertiary alcohol is still the main product due to the high reactivity of grignard reagents towards carbonyl groups.

Now I have read here and there that one might add anhydrous ZnCl2 to the grignard solution, forming an alkylzinc chloride (or dialkylzinc?) which is said to substitute only the halogen of the added acyl chloride, leaving the carbonyl group intact and thus allowing the preparation of a ketone in high yield.

This method is mentioned here, under the caption "Note on the possible usage of Zn-organics...":
http://www.erowid.org/archive/rhodium/chemistry/ketamine2.ht...
but no reference or procedure is given.

Does anyone have practical examples of ketone preparation from acyl chlorides and grignards via organozinc reagents, with detailed instructions and reaction conditions?
There are some cases where grignard + nitrile gives extremely low yields of ketone, or no product at all, and for such cases I want to learn about this alternative.






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[*] posted on 25-6-2012 at 01:28


GC - you may find it useful to note that ketones can be formed from the carboxylate salt and the alkyl-lithium reagent. The intermediate dianion is stable and upon workup the ketone is obtained. Obviously you'll want the carboxylate as an anhydrous solution, so generally you take the acid and treat with 2 eq. RLi, or an equivalent of LiH if the organolithium is of a valuable (e.g. previously synthesised) nature.
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[*] posted on 25-6-2012 at 03:05


The acylation of organozinc compounds is indeed an option to selectively obtain ketones, but the whole methodology become neglected due to the Weinreb ketone synthesis alternative. I would have to do a literature search to give you some general enough procedure for the ZnCl2-based methodology. The only article that I can think of from memory, because having it read time ago, is Tetrahedron 46, 6061-6066.

In my experience the transmetalation of grignards with ZnCl2 or ZnBr2 is troubled by the insolubility of the organozincates. A voluminous white precipitate of the insoluble organozincates forms in THF or other ethers. I had to use NMP as the solvent to get the subsequent Negishi coupling going at all on some arylzinc halides, and still the precipitate did not fully dissolve. Perhaps this is not a similar issue for their acylations, but I would not know for sure, since I have no experience with it. The above cited article indicates such polar solvents might not be needed, at least not for the particular case of 3-indolylzinc chloride acylations.

Also, keep in mind that the ketones can be obtained from grignards and acyl chlorides directly if certain conditions are met. Not always do the ketones react further. Additionally, certain reaction conditions (solvents and additives) highly increase the selectivity (for such an example, see DOI: 10.1039/SP533).




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[*] posted on 25-6-2012 at 08:57


@DJF90: That's very interesting. This would be the solution to my problem if it actually works.
Which cation has to be used as counterion with the carboxylate? Always lithium?
Does this really work with grignard reagents too?
Can I simply neutralize e.g. benzoic acid with LiOH, evaporate to dryness, dehydrate the salt over P2O5 in a desiccator and then suspend the lithium benzoate in ether and add a solution of e.g. cyclohexylmagnesium bromide to get phenyl cyclohexyl ketone after workup?
Do you have an example of such a preparation? I've never heard of this method before.

@Nicodem: I looked up the Weinreb synthesis since it was unknown to me. Looks simple and elegant, but the special reagent N,O-dimethylhydroxylamine hydrochloride has to be obtained, and it's remarkably expensive at Sigma.
Any idea how this reagent is synthesized?

Thanks for contributing your experience with organozincates.
If the intermediate is insoluble and voluminous then this method is perhaps not so advantageous.

In the OC textbooks the synthesis of ketones from grignards is generally done via the organocadmium compounds, but I don't have any cadmium salts and I'm not planning to make such toxic stuff in my home lab anyway.

I don't have access to the Tetrahedron article you posted. Can you give an excerpt of the relevant bits?

[Edited on 25-6-2012 by garage chemist]




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[*] posted on 27-6-2012 at 21:40


Here are two preparations of N,O-dimethylhydroxylamine hydrochloride. Dimethyl sulfate is a requisite chemical though.

Attachment: N,O-Dimethylhydroxylamine Hydrochloride.pdf (1.1MB)
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Attachment: Synthesis of N,O-dimethylhydroxylamine Hydrochloride.pdf (250kB)
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[*] posted on 27-6-2012 at 22:14


Hey GC,

The reaction must be done with a lithium reagent; a grignard is not a strong enough nucleophile in this case. As for the carboxylate, the few examples I've seen go from the acid with 2 eq. RLi, but I bet ifyou can make the lithium carboxylate another way and ensure it is anhydrous, it should work. I don't know if other counterions work, and if they do, how well. I'll try and find you some literature procedures later when I'm at the computer (no subscriber access on my phone). The dimethylhydroxylamine can be made by methylation of an oxime, followed by hydrolysis and subsequent methylation of the O-methylhydroxylamine.

EDIT:
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv5...

Also, for a WIDE overview, see M. J. Jorgenson, “Preparation of Ketones from the Reaction of Organolithium Reagents with Carboxylic Acids,” Org. React. 1970, 18, 1–98. The first 25 volumes of Organic Reactions have been uploaded by kmno4. Unfortunately I missed most of the download links before I could get them, although I've u2u'd him asking if he could make them available once more.

[Edited on 28-6-2012 by DJF90]
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[*] posted on 28-6-2012 at 13:13


Quote: Originally posted by garage chemist  
I don't have access to the Tetrahedron article you posted. Can you give an excerpt of the relevant bits?

See attachment. Consider also the alternative using NMP or DMF as an additive for increasing the selectivity toward the ketone (see the study in the OBC article referenced in the SyntheticPages example).

Consider also that some amides give moderate yields of the ketones upon the reaction with grignards. So instead of the reaction with the Weinreb amide, you can try the reaction with a morpholide or some other similarly simple tertiary amide. I don't know what kind of a ketone you want to make so I can't really do estimations on how appropriate this alternative is.

Quote: Originally posted by DJF90  
The reaction must be done with a lithium reagent; a grignard is not a strong enough nucleophile in this case.

Actually there are a few examples of this same reaction being performed with grignards. I currently don't have the time to find the references, but from memory, I can tell you the yields of the ketones were usually mediocre. I think only formic acid gives a relatively good yield (it gives the corresponding aldehyde, not ketone). I would dare to guess that yields would probably increase by the use of anhydrous LiCl as an acid catalyst, but as far as I know nobody bothered trying.

Attachment: 06061-06066.pdf (313kB)
This file has been downloaded 1580 times





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[*] posted on 11-7-2012 at 12:40


I have run Negishi couplings a few times, one example being WO2008/4698, Mitsubishi Tannabe, page 124-125. These were done in DME as the solvent, we used 2.5 eq of fine Zn dust (Rieke Metals brand zinc dust is better, but likely hard to obtain OTC), 2-10 mol% Pd (as the Pd(II)-Cl2(PPh3)2 complex in our case), and 1 eq each of the benzyl bromide and aryl chloride. Most worked at RT, but the reaction took anywhere from 2h to 4 days. Benzyl bromides work better (~10 fold faster) than chlorides. Some highly hindered (eg, 2, 6-dimethoxybenzyl halides) compounds gave little or no product.

This provides a benzyl phenyl ketone is this case. The yields varied from about 60-99 % in our cases. But these are all pretty decent yields.
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[*] posted on 17-7-2012 at 11:58


Here is a very obscure, but potentially very useful, alternative for the synthesis of ketones from acyl chlorides via in situ acylphosphonium salt formation followed by the addition of Grignards:

Reactions of in situ formed acyl tributylphosphonium ions with Grignard reagents as an effective route to ketones from acid chlorides
Hatsuo Maeda, Junko Okamoto, Hidenobu Ohmori
Tetrahedron Letters 1996, 37, 5381–5384.
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[*] posted on 8-8-2012 at 08:06


What about Haloketones instead of acyl chlorides?(like Phenylmagnesium bromide + 1-chloro butanone)

Ph-Mg-Br + R'(Cl)-CO-R" ---> Ph-R'-CO-R'' + MgBrCl
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