Rhodium (Chief Bee)
03-16-02 02:00
No 283186
      Possible novel method for ketones  Bookmark   

This is a contribution from "CTH" which I got in an email today.

When reading Vogel in bed last night I noticed something funny. On p 620 there is a method for making hexan-2-one by refluxing ethyl acetoacetate, sodium ethoxide and propyl bromide, thus forming ethyl propylacetoacetate. This ester is hydrolysed to sodium propylacetoacetate with aq. NaOH and then treated with aq. H2SO4 to liberate the ketone.

For those who does not have access to Vogel here is what it says at p 619:

".....an electrophilic synthon from, for example, an alkyl halide could react at the anionic carbon site of the mesomeric species, generated from an alkyl methyl ketone with base. In practise such a procedure gives rise to many competing side reactions, e.g. self condensation of the alkyl methyl ketone, uncontrolled di- or tri-alkylation, alkylation at the alternative alpha-position, etc. Alpha-alkylation can be achieved by the use of of an activating group such as the carbethoxy group(-CO2Et). This group ensures regiospecific proton removal, usually with base under anhydrous conditions, and almost total conversion into the conjugate base. Following alkylation with an alkyl halide, the activating group is removed by the action of diluted alkali in the cold followed by acidification and boiling. An important extension is the further reaction of the alkylated beta-keto ester with base, followed by another alkylation step to give after appropriate hydrolysis the ketone. Ketones of great structual variety may therefore be prepared by careful selection of the starting beta-keto ester and the alkyl halides. The standard procedure is illustrated for the preparation of hexan-2-one from ethyl acetoacetate and propyl bromide, and it may be suitably adapted to the preparation of most alkyl(straight-chain and branched-chain) methyl ketones."

Here is what the reaction looks like. Please bear with me since I donīt have a chemical drawing program.

R1-C(=O)-C-CO2Et + (Na)OEt --> R1-C(=O)-(-C)-CO2Et + R2X --> R1-C(=O)-C(R2)-CO2Et + NaX

R1-C(=O)-C(R2)-CO2Et + cold dil. aq. NaOH, then dil. aq. H2SO4 and boiling --> R1-(=O)-C-R2 + EtOH + CO2

Prep of hexan-2-one:

Step 1. Generation of sodium ethoxide.

Fit a 2L three-necked flask with an efficient double surface condenser and a separatory funnel; close the central neck with a stopper. The apparatus must be perfectly dry. Place 34.5g(1.5 mol) clean sodium cut into small pieces in the flask and clamp the flask by the wide central neck. Measure out 1L super-dry ethanol and place about 500ml in the separatory funnel; insert calcium chloride guard tubes at the top of the condenser and the separatory funnel respectively. Place a larger bowl beneath the flask and have a large wet towel in readiness to control the vigour of the subsequent reaction.

Run in about 200ml of the absolute ethanol on to the sodium (1). A vigorous reaction takes place. If the ethanol refluxes violently in the condenser, cool the flask by wrapping it in the wet towel and also, if necessary, run a stream of cold water over it. As soon as the reaction moderates somewhat, introduce more alcohol to maintain rapid, but controllable refluxing. In this manner most of the sodium reacts rapidly and the time required to produce the solution of sodium ethoxide is considerably reduced. Finally add the remainder of the ethanol and reflux the mixture on a water bath until the sodium has reacted completely.

I wouldnīt bother with making the sodium ethoxide. Itīs a nasty procedure. Just buy it.

Step 2. Generation of ethyl propylacetoacetate.

Remove the stopper in the central neck and introduce a sealed mechanical stirrer. Add 195g(190ml, 1.5 mol) ethyl acetoacetate, stir the solution and heat to gentle boiling, then run in 205g(151ml, 1.66 mol) propyl bromide over a periode of 60 minutes. Continue the refluxing and stirring until the reaction mixture is neutral to moist litmus paper (6-10 hours); the reaction is then complete.

Cool the mixture and decant the solution from the sodium bromide; wash the salt with two 20ml portions of absolute ethanol and add the washings to the main solution. Distil off the ethanol, which contains a slight excess of propyl bromide, through a short fractionating column from a water bath. The residue of crude ethyl propylacetoacetate can be used direrctly in the preparation of hexan-2-one. If fairly pure ester is required, distil the crude product under diminished pressure and collect the fraction boiling at 109-113 deg C/27mm Hg (183g, 71%).

Step 3. Hydrolysis of the ester.

To prepare hexan-2-one add the crude ester or the redisilled ethyl propylacetoacetate to 1500ml 5%aq NaOH in a 4L flask equipped with a mechanical stirrer. Continue the stirring at room temperature for 4 hours; by this time the mono substituted acetoacetic ester is completely hydrolysed and passes into solution. Transfer the mixture to a large separatory funnel, allow to stand and remove the small quantity of unsaponified material which separates as an upper oily layer. Place the aqueous solution of sodium propylacetoacetate in a 3L two-necked flask fitted with a small separatory funnel and a wide bent delivery tube connected to a condenser set for downward distillation. Add 150ml 50% aq H2SO4(density 1.40) slowly through the separatory funnel with shaking; a vigorous evolution of carbon dioxide occurs.

When the latter has subsided, heat the reaction mixture slowly to the boiling point and distil slowly until the total volume is reduced by about 50%; by this time all the hexan-2-one sholuld have passed over. The distillate contains the ketone, ethanol and small quantities of acetic and valeric acids. Add small portions of solid sodium hydroxide to the distillate until it is alkaline and redistil the solution until 80-90% has been collected; discard the residue.

Separate the ketone layer from the water, and redistil the latter until about 30% of the material has passed over. Remove the ketone after salting out any dissolved ketone with potassium carbonate (2). Wash the combined ketone fractions four times with one-third the volume of 35-40% aq.CaCl in order to remove the alcohol. Dry over 15g anhydrous CaCl; it is best to shake in a separatory funnel with 1-2 g of CaCl, remove the saturated solution of CaCl as formed, and then allow to stand over 10g CaCl in a dry flask. Filter it and distil. Collect the hexan-2-one at 126-128 deg C. The yield is 71g (67%).

Notes

(1) The addition of the ethanol to the sodium, although attended by a very vigorous reaction which must be carefully controlled, is preferable to the reverse procedure of adding the sodium in small pieces to the ethanol. The latter method is longer and has the further disadvantage that it is necessitates frequent handling and exposure to the air of small pieces of sodium.

(2) A more complete recovery of the ketone from the aqueous solution may be obtained by repeted distillation of the aqueous layer until no appreciable amount of ketone is found in the distillate. The procedure outlined is, however, quite satisfactory.

Now, what if one could substitute the above propyl bromide for benzyl bromide or benzyl chloride. Wouldnīt that in step 2 give ethyl benzylacetoacetate which upon hydrolysis shold give the old phenylacetone? Perhaps in yield as low as 30-40%. But would that really matter considering the extreme low cost of raw materials. Is ethanol really necessary as reaction solvent? My guess is that any of the lower alcohols should work. Unless the tempreature is critical, which I doubt.

Ethyl acetoacetate- really cheap
Sodium ethoxide- really cheap
Benzyl chloride- dirt cheap
Benzyl bromide- cheap

Benzyl chloride or bromide is of course cheaper made from HCl or HBr and benzyl alcohol.

Comments please....

CTH
 
 
 
 
    halfapint
(Ubiquitous Precursor Medal Winner)
03-16-02 03:26
No 283228
      Re: Possible novel method for ketones  Bookmark   

"have a large wet towel in readiness to control the vigour of the subsequent reaction."
** ** **
"When you're hitchhiking, always carry a towel." hitchhiker's guide to the galaxy
** ** **
Mess comes in various guises. Folks who keep abreast of current events might choose to use one of the 2 or 3 ways Antoncho lately uncovered for preparing alkali metal alkoxides (Post 257912 (Antoncho: "Alkali metal alkoxides: finally, OTC!", Novel Discourse) et seq.) like sodium ethoxide, for those to whom buying it would bee almost as messy as making it with sodium.
** ** **
Acetoacetic ester is another one of those things, that it's easy to make if you have bases like metal alkoxides, and hard without.
** ** **
Seems like this might bee worth looking into. The anhydrous organic phases of this reaction, including making ethyl acetoacetate and then reacting it with benzyl halide, each in the presence of sodium ethoxide, are significantly difficult for the chemistry homeworker.  Having to really keep the wet air away from everything takes a bit of practice.

But that decarboxylation, in room-temperature dilute lye, followed by refluxing in acid, is so easy it would seem to make up for the exigencies undergone. Like a vacation.

a half a pints a half a pound a half a world a half a round
Sidearm n. Flask neck tube.
 
 
 
 
    Rhodium
(Chief Bee)
03-16-02 04:48
No 283266
      Re: Possible novel method for ketones  Bookmark   

It seems to be a variation on the theme found in the classic Organic Synthesis method ( ../rhodium/chemistry /phenylacetone.html#benzylcyanide ) but with the intermediate being the ethyl ester instead of the nitrile. It gets a thumbs up from me, as the starting material is benzyl chloride/benzyl alcohol, instead of benzyl cyanide, thereby saving the chemist one potentially dangerous step (substitution of benzyl chloride with sodium cyanide).
 
 
 
 
    Greensnake
(Newbee)
03-16-02 13:18
No 283436
      Re: Possible novel method for ketones  Bookmark   

>Wouldnīt that in step 2 give ethyl benzylacetoacetate which upon hydrolysis shold give the old phenylacetone?

No, you will get another ketone - 4-phenyl-2-butanone or benzylacetone by trivial name. One carbon too long.
 
 
 
 
    Rhodium
(Chief Bee)
03-16-02 19:53
No 283527
      Re: Possible novel method for ketones  Bookmark   

Ah... I never counted carbons. This reminds me of a method mentioned in Festers books, where he suggests the use of bromobenzene/acetoacetate for the production of P2P. This is not possible using the regular methods he described, as aryl halides does not undergo substitution reactions like that. However, there has been reports of the method working using superbasic reactions where the phenyl halide undergoes benzyne formation, which then adds to the acetoacetate anion. I have never seen a writeup on that though.
 
 
 
 
    cheeseboy
(I'm not Cheesie)
03-18-02 00:27
No 284018
      Re: Possible novel method for ketones  Bookmark   

Like Strike with his recipes that "Don't require distillation set ups" because they target the insolubilities of compounds in solvents. Then you run into a brick wall when halfway down the recipe it calls for a vacuum distillation with a strong kick ass vacuum, not a water aspirator!LOL

Cheeseboy-a whiteboy with Soul Like a black guy without soul
May The Source Bee With You Always.
 
 
 
 
    halfapint
(Ubiquitous Precursor Medal Winner)
05-06-02 13:11
No 305376
      Revision and Reconsideration
(Rated as: excellent)
 Bookmark   

Excerpted from US 2413493.

... controlled preparation of a suitable isomer-free intermediate derived from the acetoacetic ester.
... the initial formation of a methyl derivative by reacting the ester with a methyl halide, such as the chloride. The methyl residue is joined to the active carbon so that subsequent benzylation can result only in the introduction of the benzyl group in the proper place...

The novel procedures of the present invention will permit the securing of a desired product alpha-phenyl-beta-amino propane by reacting the sodium derivative of acetoacetic ester first with methyl halide such as methyl chloride and then reacting the sodium salt of the methyl derivative with benzyl chloride according to the following equations:



--



there has been disclosed a novel process for the preparation of alpha-phenyl-beta-amino-propane, substantially free from undesired side reaction products, which desirable result is essentially obtained by ensuring the initial methylation of the active carbon of aceto acetic ester used as a starting material, which may then be followed by benzylation of the methylated compound. As set out in the description of the isomer formation of alpha-amino-beta-phenyl propane, an initial benzylating step precludes the formation of the desired pure isomer-free-intermediate product benzyl methyl acetoacetic methyl ester which is especially suited for use in the preparation of pure alpha-phenyl-beta-armino propane free from its isomer alpha-amino-beta-phenyl propane.

........

 Briefly, the new process involves the methylation of acetoacetic acid methyl ester, and the substitution with benzyl compounds in the methyl acetoacetic acid methyl ester formed, to form benzyl methyl acetoacetic methyl ester. This benzyl ester is then contacted with aqueous ammonia for several days, with the results that a good yield of benzyl methyl acetamide is obtained.

This acetamide is then converted by means of the Hofmann reaction to form alpha-phenyl-beta-amino-propane. This amine can also be synthesized by forming benzyl methyl acetoacetic ethyl ester and then cleaving this product with sodium methylate solution to form methyl acetate and benzyl methyl acetic acid methyl ester. The methyl acetate is separated as a constant boiling mixture, after distilling off with the excess methanol. The benzyl methyl acetic acid methyl ester is hydrolyzed with sodium hydroxide solution to form a sodium salt of benzyl methyl acetic acid. The free acid is liberated, then dried and converted to its chloride by means of thionyl chloride. The chloride is converted to benzyl methyl acetamide by reaction with anhydrous ammonia in ether as a solvent. The amide is then converted to alpha-phenyl-beta-amino propane by means of the Hofmann reaction above described.

 In the preparation of the alpha-phenyl-beta-amino propane, the following detailed steps were taken and a detailed preparation of the several intermediates identified in the equations herein set out are given.

Methyl methyl aceto acetate

4440 grams of methyl acetate, containing 2% methyl alcohol, was weighed into a 12-liter flask provided with a reflux condenser. 230 grams of sodium metal, in the form of small pieces (approximately 1/2" x 1/2"), was added to the methyl acetate at once. Heat was applied to bring the reaction mixture to reftuxing temperature. After eleven hours all of the sodium dissolved. Excess methyl acetate was then distilled from the reaction mixture until all of the constant boiling mixture with methanol distilled off. 5000 cc. of benzol was then added and distillation continued until the last of the methyl acetate was recovered. 1200 grams of dimethyl sulphate was then added over a period of two hours at refluxing temperature. Refluxing was continued until reaction was neutral. The reaction mixture was then cooled to room temperature, and 1400 cc. of water added to dissolve the sodium methyl sulphate, The oil layer was separated, washed with two 1000 cc. portions of water and then fractionated. A yield of 882 grams of methyl methyl aceto acetate was obtained. B. P. 76.0-76.5° C. at 20 mm. 1700 grams of methyl acetate was recovered as constant boiling mixture, balance was recovered with the benzol. 

Methyl benzyl methyl aceto acetate

 750 grams of methyl methyl aceto acetate, as formed above, and 1690 cc. of methanol were placed in a 3-liter 3-neck flask provided with a reflux. 125 grams of sodium metal was added, a liquid temperature of 50° C. being maintained. The solution of the sodium compound was then added to 657 grams of benzyl chloride contained in a 5-liter flask. Two hours were required for the addition, and the temperature was held between 48-53° C. throughout. After several hours standing, allowing reaction to reach room temperature, a test portion indicated that the reaction was 99.59% complete. Excess alcohol was then distilled off until a liquid temperature of 83° C. was reached. The reaction product was then cooled to 20° C., and 1400 cc, of water was added to dissolve out salt. The oil was shaken with 10% caustic soda for 10 minutes and then washed with 500 cc. portions of water until neutral. The oil was then fractionated. 165 grams of benzyl chloride was recovered. A yield of 865 grams of methyl benzyl methyl aceto acetate was obtained.

Methyl benzyl acetic acid

855 grams of methyl benzyl methyl aceto acetate from the above run was reluxed with a sodium methylate solution (17 grams Na in 321 cc. methanol) far 3 to 4 hours, and then the constant boiling mixture of methyl acetate-methanol was slowly distilled off in the course of another 1 1/2 hours. The resulting benzyl methyl acetic acid methyl ester was then saponified by the addition of 120 grams of NaOH in the form of 30% aqueous solution. The sodium salt was given two extractions, using 200 cc. of xylol each time. The methyl benzyl acetic acid was liberated from the sodium salt by the addition of 50% H2SO4 solution. The oil was washed with water, the water washes were combined, extracted with xylene, and then added to the methyl benzyl acetic acid. The xylene was distilled from the acid under vacuum. A yield of 567 grams of methyl benzyl acetic acid was obtained. B. P. 150-155° C. at 8 mm.

Methyl benzyl acetyl chloride

502 grams of thionyl chloride was weighed into a 2-liter 3-neck flask provided with a thermometer, agitator, dropping funnel and reflux condenser. 472 grams of the above described methyl benzyl acetic acid was then added over a period of one hour. The temperature during addition varied between 30-40° C.  The excess thionyl chloride was then distilled off, and the acid chloride vacuum distilled. Yield: 420 grams of methyl benzyl acetyl chloride. B. P. 118-120° C. at 15 mm.

Methyl benzyl acetamide

420 grams of methyl benzyl acetyl chloride, formed as above, was converted to the amide by adding the chloride slowly to 4260 cc. of benzol, saturated with NH3 at 200° C., the NH3 always being in excess. After all of the chloride was in the reaction product was heated on a steam bath to 62° C., and the separated out ammonium chloride filtered off. The filtrate was then cooled to 10° C., and the crystals of the benzyl methyl acetamide filtered and dried. Yield: 336 grams methyl benzyl acetamide. Upon recrystallization from benzol there was obtained 286 grams of amide having a M. P. of 108.4° C.

Beta-amino propyl benzene

 230 grams of methyl benzyl acetamide, prepared as above, and melting between 107-108.4° C., was added to sodium hypochlorite solution, made by passing 109 grams of chlorine into a solution of 277 grams of sodium hydroxide in 453 cc. Of water. The reaction mixture was held at 0° C. for one hour. It was then slowly heated to 18° C., at which point considerable heat was given off and the solid went into solution. The flask, at this stage, had to be immersed in a freezing bath to prevent the temperature from getting too high. After the temperature was under control, the solution was heated to 58° C. whereupon the rearrangement occurred. The heating was continued until 70° C. was reached. The solution was cooled, the oil layer separated and the solution art treated with benzene, using 60 cc each time. The benzol solution was washed twice with 50 cc. portions of water and 148 grams of concentrated hydrochloric acid slowly added to it. The amine-hydrochloric acid solution was extracted twice with 30 cc. portion of benzol. The amine was then precipitated with sodium hydroxide solution (30%). The water from the precipitated amine was extracted three times with 60 cc. portions of benzol. The benzol solution was washed twice with 100 cc. washes and then vacuum distilled. Yield: 131 grams of purified amine, B. P. 105° C./30 mm., 69.0% of theory.

Results of the ethylation experiments using dimethyl sulfate and methyl iodide indicated that it was possible to get a much greater degree of ethylation using methyl iodide. It was found impossible to get the 108° C. amide by starting from mono benzyl ethyl aceto acetate; however, the 108° C. amide results from introducing the methyl group in ethyl aceto acetate first and then the benzyl group.

Methyl methyl aceto acetate was prepared from methyl acetate in good yields. A large run was made starting with methyl acetate and carrying the synthesis through to the amine. Time tests indicated that methyl benzyl methyl aceto acetate will go aver to methyl benzyl acetamide in aqueous ammonia to the extent of approximatelv 50% in two weeks, standing at room temperature.



--



a half a pints a half a pound a half a world a half a round
Demimonde n. Half a world.
 
 
 
 
    Greensnake
(Hive Bee)
05-06-02 18:49
No 305447
      Little correction  Bookmark   

Well, this is a nice illustration of the fact, that patents sometimes contain royal bullshit - that "logical extension" at the end, where meth is made, is crap - Hoffmann rearrangement DOES NOT work on substituted amides. Sure, one can make substituted methylamine from amide by trapping intermediate isocyanate with alcohol and reducing thus obtained carbamate with LAH, but no, not in one step directly from methylamide.
 
 
 
 
    Rhodium
(Chief Bee)
05-06-02 20:32
No 305474
      rxn mechanism?  Bookmark   

Sure, Figure #4 is bull... But how about the reaction in Figure #3? Why/how can the tertiary acetyl group leave like that to form an acetamide and an methyl benzyl acetamide?
 
 
 
 
    zed
(Hive Bee)
05-08-02 16:45
No 306247
      Working with sodium.  Bookmark   

They do mean super dry ethanol. Sodium can be positively devilish when it comes in contact with water. But, I remember it as being relatively easy to handle, if it is in wire or pellet form, and it is kept under kerosene or mineral oil, to protect it from air and moisture. Portion-wise addition might be OK, to control reaction tempo.. My concern would be with its low density; added portion-wise it might cling to the inside wall of a condensor, or the side of a reaction flask, instead of falling to the bottom of the flask, there to be safely covered by liquid.

Best to consider such things before-hand I suppose.

As for the Na under oil thing, LAlH4 in oil is much easier to work with than the dry sort. I have seen no mention of it in any posts. Should I assume that LAlH4 in oil has become "The Standard". And, thus is not mentioned?
 
 
 
 
    hest
(Hive Bee)
05-08-02 17:57
No 306282
      LAH is dry  Bookmark   

LAH is alwayes a dry powder or pellets.
 
 
 
 
    zed
(Hive Bee)
05-08-02 19:09
No 306307
      Anyone else have insight?  Bookmark   

Yow! Really? In days gone by, the preferred product was definitly treated with oil. It made it much easier to work with. The oil protected it from air and moisture, during transfers, thus improving the safety factor somewhat.

I know you prefer not to work with it. I don't like it either. But, I had friends that did reasonably OK with it. True, they eventually had earth-shaking problems, but the problems were related to scaling reactions up....much too big.... in diethylether, and going exothermic during hydrolysis. In runs that produced 4 to 8 oz. of product they were OK.. And they always used the oil treated product.
 
 
 
 
    halfapint
(Ubiquitous Precursor Medal Winner)
05-08-02 19:45
No 306316
      Meanwhile Zed's waiting at the bus stop  Bookmark   

Nobody around here wants to make sodium ethoxide with sodium in alcohol, Zed. Not cost effective. We'd rather use lye (NaOH) dissolved in alcohol then add unslaked lime (CaO), and filter off its precipitate to give our solution of sodium ethoxide in ethanol, as Antoncho ordered us to do in Post 257912 (Antoncho: "Alkali metal alkoxides: finally, OTC!", Novel Discourse). Or pull an equivalent trick with CaC, calcium carbide. That makes this amphetamine derivation lots easier, quicker and cheaper.


a half a pints a half a pound a half a world a half a round
Sidearm n. Flask neck tube.
 
 
 
 
    TrickEMethod
(Hive Bee)
05-16-02 17:44
No 309400
      Another one from Fester  Bookmark   

He gives an even easier(if it is accurate) synth using Toluene and Potassium Ethoxide to P2p in Adv. Tch....

I am late for an appointment, so i am simplifiing I will post bettter in an hour

C6H5CH3 + CH3C(O)OCH2CH3 + CH3CH2OK -> C6H5CHC(OK)CH3 ->
   + Acid -> C6H5CH2C(O)CH3

More details to follow, sorry gotta run

And on the eight day, God created Meth...
... and hasn't done much of anything usefull since!