Methyllithium chemistry

[Cyrax]

This comes from March 4th ed. p 931:

RCOOLi + R'Li -->  RC(OLi)2R' --> RCOR'

Good yields of ketones can be obtained by treatement of the lithium salt of the carboxylic acid with an alkyllithium reagent, followed by hydrolysis.  R' may be aryl or primary, secondary, or tertiary alkyl.  MeLi and PhLi have been employed most often.  R may be alkyl or aryl, though lithium acetate gives low yield.  Tertiary alcohols are side products.

Now, this is my question: If lithium acetate gives low yields, will lithium phenylacetate also give low yields when one does the reaction with MeLi to get our precious ketone?

Do you think this reaction is interesting enough for some further research?

[Rhodium]

Yes, it is interesting enough for further research. In

https://www.thevespiary.org/rhodium/Rhodium/chemistry/p2p.azlactone.html

(the last step) the yield of P2P is ~50% with ~25% unreacted phenylacetic acid recovered, that is 70% yield based on reacted phenylacetic acid. That is much better than other PAA -> P2P conversions, and not smelly like the others.

Here are a few other references I haven't looked up, but they are all about making aryl-2-propanones from arylacetic acids and methyllithium. If you do get them, please post them, or email me scanned copies, and I'll OCR them.

JOC 29, 2813 (1964)
JOC 48, 1550 (1983)                    
JACS 55, 1258 (1933)
JACS 62, 2327 (1940)
JACS 92, 2590 (1970)
Synlett 459 (1995) - Mentioned in

Post 227076

(Lilienthal: "P2P from benzylchloride / LiAc / Li", Novel Discourse)

[Cyrax]

It must be possible to find a way to improve the yield of the MeLi + Phenylacetic acid --> P2P reaction. I'll do my best.

By the way, is MeLi a suspicious chemical?  I think you can buy solutions of THF / MeLi.  Therefore, one must not prepare the reagent.  Isn't this easy?

[Rhodium]

Also see

Post 227911

(foxy2: "Re: P2P from benzylchloride / LiAc / Li", Novel Discourse). I believe that it would be very expensive to buy ready-made MeLi, but if you want to buy it from a chem-company, it shouldn't be a particularly "hot" item.

[Cyrax]

I think that the reason why you got a moderate yield in p2p.azla is because the reaction time was only 1 hour.

In JOC (1975) vol 40 p 1770 they did a reaction between lithium n-butyrate with phenyllithium at varying reflux times:

                           Product % yield
Reflux Time(hours)    Ketone            Carbinol
0.5                     39                 30
1                       42                 28
2                       46                 30
3                       61                 21
4                       70                 10
5                       79                  5
10                      90                  0
24                      85                  0

Isn't this interesting !!!

I think that 1 hour reflux time is simply not enough.  The more because I found in JACS (1966) vol 88 p 3347 the following:  They did a reaction on cis-1-methyl-2-phenylcyclopropanecarboxylic acid with MeLi to yield the methylketone in a 90 % yield (!!!).  The reaction time was 15 hours.  Is everybody convinced?

Procedure:
400 ml of a 1.12 M solution of MeLi in ether was added over a period of 30 min to a magnetically stirred solution of 39.5 g (0.224 mole) of carboxylic acid in 100 ml of anhydrous ether.  After addition of the first 200 ml of white precipitate formed which on further addition became difficult to stirr.  The reaction mixture was stirred at room temperature for 15 hours and then 500 ml of a saturated solution of NH4Cl was added, very slow at first.  The two-phase system was stirred until the 2 layers became clear, they were seperated qnd the aqueous layer was extracted twice with ether.  The combomined extracts were washed with a saturated solution of NaCl and dried with anhydrous MgSO4.  The ether was removed and the residue was distilled through a small packed column at 0.14 mm to yield 35 g of ketone. 90 % yield.

This are only preliminary findings, but I think that reaction time is very important.

[Rhodium]

Great find Cyrax - do you think you could look up the refs I mentioned above to see if there is anything interesting to be found there?

[Cyrax]

Rhodium, I will certainly look up the refs. you gave me.  But it may take a while, because for the moment I have a lot of other things to do.

Mabey this is another interesting idea: Since the carbinol formation is a major competing process if the reaction was not carried out in such a way that all lithium compound had been consumed prior to hydrolysis, I think it can be a good idea to quench the reaction mixture with trimethylsilyl chloride and then to do the hydrolysis of the R-C(OLi)2-R' intermediate.  It is a fact that ny excess of lithium reagent that is present reacts extremely rapid with the ketone as it is formed by hydrolysis.

In JOC (1983) vol 48 p 1550 they did the reaction with cyclohexanecarboxylic acid
                       1) 4 eq. MeLi
 cyclohexane-COOH ---------------> cyclohexane-COCH3 (92%)
                       2) TMS-Cl
                       3) H20, H+

This is another thing I am going to look up.