garage chemist
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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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DJF90
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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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Nicodem
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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).
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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garage chemist
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@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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benzylchloride1
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Here are two preparations of N,O-dimethylhydroxylamine hydrochloride. Dimethyl sulfate is a requisite chemical though.
Attachment: N,O-Dimethylhydroxylamine Hydrochloride.pdf (1.1MB)
This file has been downloaded 1226 times
Attachment: Synthesis of N,O-dimethylhydroxylamine Hydrochloride.pdf (250kB)
This file has been downloaded 1107 times
Amateur NMR spectroscopist
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DJF90
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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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Nicodem
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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 1824 times
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Nicodem
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Thread Moved
29-6-2012 at 09:05 |
Dr.Bob
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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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Nicodem
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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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Waffles SS
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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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