Preparation of phenyl-2-butanone

[Kinetic]

SWIK and another bee (who shall remain nameless for now but should take most of the credit) require some phenyl-2-butanone for 'custom organic synthesis'. They have come up with some methods, and would like some help on the subject if possible;

Method used (works fine): Heating phenylacetic acid with excess propionic anhydride and anhydrous sodium acetate, then hydrolysis and treatment with dilute NaOH.
The problem with this method for SWIK is phenylacetic acid is impossible to buy, and illegal (although very easy) to manufacture without a license (this is not an option )

The proposed solutions are;

1) Add ethyllithium/ethylmagnesium bromide in anhydrous THF to phenylacetaldehyde to form the alcohol, then oxidise using any common method.
2) Add 1 equivalent of ethylmagnesium bromide in anhydrous THF to phenylacetyl chloride, the theory being that since the acid chloride is more reactive than the ketone, no alcohol will be formed.

Firstly, can anyone think of any other routes?
And second, for method 2), it should be best to use a less reactive Grignard, to inhibit formation of the alcohol. Would ethylmagnesium bromide work O.K? Or would something less reactive be more favourable/necessary, such as an organocopper reagent?

Thankyou kindly in advance...  

[Rhodium]

* Condense Benzaldehyde with 1-nitropropane to get the nitrostyrene, then hydrolyze it to the 2-butanone with the Nef Reaction.

* Condense benzaldehyde with 2-chlorobutyric acid under darzen condensation reaction, followed by hydrolysis.

[Dr_Heckyll]

To me that looks like a classical Friedel-Crafts: from butyric acid with thionyl chloride to butyryl chloride. Then the Friedel-Crafts: acylate benzene with the butyryl chloride using AlCl3 as catalyst. Can it be easier, can it be cheaper?


Dr. Heckyll & Mr. Jive by Men at Work
...tells my tale.

[Antoncho]

, then hydrolyze it to the 2-butanone with the Nef Reaction.

AFAIK, Nef rxn works only on nitroalkanes, not nitroalkenes, does it not?

I mean, if that was THAT simple - why bother w/iron in GAA or, as recently posted by outstanding Barium  - with SnCl2?



Just for the record - do nitrostyrenes form salts with alkali, and how stable those are?





Antoncho

[Rhodium]

Antoncho: You are of course correct, the nitroalkene must first be reduced with NaBH4 to the nitroalkane before you can use the Nef reaction.

The Fe/GAA or SnCl2 reduction to the ketone are also very good alternatives.

[terbium]

To me that looks like a classical Friedel-Crafts: from butyric acid with thionyl chloride to butyryl chloride. Then the Friedel-Crafts: acylate benzene with the butyryl chloride using AlCl3 as catalyst. Can it be easier, can it be cheaper?
Won't this give butyrophenone (1-phenyl-1-butanone) not the 1-phenyl-2-butanone that this fellow desires?

[PrimoPyro]

Terbium, it will indeed give the wrong structural isomer.

[Dr_Heckyll]

You're right, sorry, of course it will give the butyrophenone! I didn't read the original post carefully enough, and as I'm currently dealing a lot with substituted phenones as intermediates, it didn't occur to me that someone might actually want the 2-one instead of "my" 1-ones.        


Dr. Heckyll & Mr. Jive by Men at Work
...tells my tale.

[Kinetic]

Rhodium -

Condensing Benzaldehyde with 1-nitropropane was my first idea (see

Post 313641

(Kinetic: "Interesting!", Serious Chemistry)), but after a little research, prompted by Osmium's reply to that post, it seems that the yields for this reaction will be very low (see Pihkal #1 AEM for an examle).
I'm assuming this will be the case for all aldehydes + 1-nitropropanes, as the longer chain of the nitropropane will donate electrons to stabilise the other end of the molecule with the nitro group attached, and make it less susceptible to deprotonation (and therefore unable to react). Is this the case? Or will a suitably strong base increase the yield?
However, I have found a small note in a textbook made about the condensation of 1-nitrohexane and benzyl bromide, with THF as solvent, using  butyllithium as base, and HMPA (Hexamethylphosphoramide) as what seems to be a catalyst. This is done in two steps as alkyl halides are not compatible with BuLi. I'm afraid I don't have any references for this.
Has anyone heard of a high yielding synthesis using 1-nitropropane and benzaldehyde?

[Barium]

Kinetic: Do not dismiss the Knoevenagel condensation that quick. Just because ammonium acetate, cyclohexylamine, n-butylamine and a bunch of other well known condensation catalysts doesn´t work well here there are still ways to get that condensation going.

Basically it´s just about condensating the benzaldehyde with equimolar amounts of an amine to get an imine, then allow the formed imine to react with the nitroalkane.

I posted something about just this a few months ago. Do a search.

[Rhodium]

Here it is:

Post 317855

(Barium: "Knoevenhagel-Walter; another way", Methods Discourse)

[Kinetic]

Thankyou Barium, and Rhodium. Barium, I thought I had read all of your posts, but I must have missed that one   .
This is exactly what I need though, as I had a feeling there were ways to form P2B via the nitrostyrene, but didn't know where to look - TFSE didn't return much, as such a specific IUPAC name often doesn't, and I must admit I didn't know the name of the reaction...

When SWIK finally gets the time and his remaining chemicals, he will let you know the results .

You say n-butylamine and cyclohexylamine will not work here, but in Rhodium's method,

Post 103792

(Rhodium: "Re: Piperonal ---> MDA", Chemistry Discourse), it seems to work fine.
Will cyclohexylamine therefore substitute for the n-propylamine you use in your condensation, in

Post 317855

(Barium: "Knoevenhagel-Walter; another way", Methods Discourse)?

[hest]

all small prim. amines will work, and yes also cyclohexylamine.
I'll try this method next time i condense 3,4,5-trimethoxy-bnzaldehyde with nitromethane.

[Osmium]

Regarding economics and availbility of chemicals it might be best to start with butyrophenone. Reduce it to the alcohol, eliminate water and you end up with the alkene which can be used in every reaction that works for isosafrole.
I'm not fat just horizontally disproportionate.

[Aurelius]

why not just purchase the alkene instead on making it?  (unless it's more economical- haven't looked at prices)

[Kinetic]

OK, well obviously the original intention of this post was to make alpha-ethyl PEA and alpha-ethyl N-methyl PEA from P2B. But how about another method, partly adapted from Psycho Chemist's

https://www.thevespiary.org/rhodium/Rhodium/chemistry/ppa.html

, to make alpha-ethyl N-methyl PEA? I propose;

1.Acylate benzene with butyryl chloride/AlCl3
2.Add bromine as above link
3.Add alcoholic methylamine solution instead of alcoholic ammonia solution
4.Reduce using HI/red phosphorus, to give 1-phenyl-2-(N-methylamino)butane  

Can anyone think why this would/would not work? I expect the intermediate from step 3 (cathinone analogue) would be unstable to heat, since there is both an amine and ketone in the molecule, although in Psycho chemist's writeup there doesn't seem to be a problem. Would this intermediate ketone have to be reduced with sodium borohydride to the alcohol before attempting the red phosphorus/iodine reaction reduction of the final step?