Rhodium
(Chief Bee)
08-08-01 17:47
No 202649
      Meth via grignard rxn (Gazz Chim Italiana)
(Rated as: excellent)
    

After lugh provided me with a DjVu copy of this old article, I OCR'd it and tried to translating it to English from Italian, but as I can't read Italian, this text is a patchwork from altavista babelfish, and educated guesses from my side. If we have any italian speaking bees here, check the original Italian text linked below, and perhaps you can verify my translation.

It is a procedure for preparing the imine between methylamine and acetaldehyde, and then reacting this with benzyl chloride grignard to form methamphetamine in one step. It sounds fine and all except for the fact that there is no real hydrolysis step after the quenching of the grignard reagent. Is a simple acidification enough to hydrolyze the imine to the amine? Perhaps there is one, and I did not understand the wording?



Reactions of Grignard Reagents With Aliphatic Imines.
Vera Evdokimoff
Gazzetta Chimica Italiana, Vol 77, pp. 318-326 (1947) (../rhodium/djvu /evdokimoff.djvu)

The organomagnesium compound reacts with the imine to give a secondary amine as follows:



Busch et al has performed many experiments like this with aromatic imines (Schiff bases), but never with purely aliphatic imines. The reason for this ought to be the tendency of these to polymerize to compounds that does not conserve the imine functionality.

To overcome this difficulty, an etheral solution of equimolar amounts of the aldehyde and amine needed to form the desired imine, together with anhydrous sodium sulfate (to absorb the water formed in the condensation) is prepared immediately beforehand, and the solution added to a flask containing the pre-made grignard reagent.

The obtained products clearly show that the aldehyde and amine combines to give the desired imine, which in turn reacts with the grignard reagent to form a secondary amine. With acetaldehyde, methylamine and benzylmagnesiumchloride 1-phenyl-2-methylamino-propane is formed, also known as methamphetamine. As you can see yourself, this new method can afford this important symphatomimetic drug in a one-step reaction in 40% crude yield.

The preferred method of purification consists of decomposing the excess grignard reagent with water, acidifying the solution, washing the solution with ether to remove non-amine products, and then basifying and steam-distilling the solution. The distillate is acidified with hydrochloric acid and concentrated until dry. The residue is dissolved in a little absolute alcohol and precipitated with the addition of ether.

Beside the desired amine, the following products are found in the reaction mixture: Benzyl chloride (used in excess), toluene (from the quenching of benzylmagnesium chloride) and dibenzyl (from the coupling of benzylmagnesiumchloride with benzyl chloride).

Experimental:

Preparation of benzylmagnesium chloride:

In a flask equipped with an addition funnel and a cooling bath, benzylmagnesium chloride was prepared by dripping 24.4g (0.2 mol) of freshly distilled benzyl chloride (bp 179C) dissolved in ether in small portions onto 4.8 gram (0.2 mol) of cleaned magnesium turnings covered with ether. The initiation of the reaction can be facilitated by heating the magnesium turnings in a test-tube with an iodine crystal before use. After the addition of all the reagent, the solution was boiled until all the magnesium was dissolved.

Preparation of etheral methylamine:

In a fractional distilling apparatus there was introduced 15g of methylamine hydrochloride, and from an addition funnel, there was slowly added 30ml of a 40% sodium hydroxide solution. The evolved methylamine gas was lead into an ice-cooled flask filled with anhydrous ether and some anhydrous sodium sulfate. To prevent the escape of gas and enrance of moisture, the recieving flask was connected to a U-tube filled with mercury. A 5ml portion of the etheral solution of methylamine was poured into a little water and quickly titrated in the presence of methyl orange with a standardized acid solution to determine the concentration of methylamine.

Preparation of acetaldehyde:

The acetaldehyde was prepared immediately before use by the depolymerization of paraldehyde. In an apparatus similar to that for the production of methylamine, concentrated sulfuric acid was added to paraldehyde, which distilled at a temperature of 21C into a reciever cooled in ice.

Preparation of the imine and reaction with the grignard reagent:

A cold solution of etheral methylamine, containing 3.1g of the free base (0.1 mol) was mixed with a cooled etheral solution of 4.4g of acetaldehyde, whereupon the solution became turbid. Anhydrous sodium sulfate was added with swirling of the mixture to absorb the formed water, and the solution was decanted into the addition funnel of the flask containing the pre-made benzylmagnesium chloride, which in the meantime had been cooled in an ice-bath, and was added dropwise to the solution.

After it had all reacted the solution was acidified and washed with ether to remove by-products, basified with a sodium hydroxide solution and extracted repratedly with ether, the ether extracts dried over anhydrous sodium sulfate, filtered and concentrated to give an oil, which was neutralized by the addition of concentrated hydrochloric acid giving a wet, crystalline mass that was dried for several days in a desiccator containing both concentrated sulfuric acid and solid sodium hydroxide. The obtained crystals was recrystallized repeatedly from acetone to give colorless crystals of methamphetamine hydrochloride with a melting point of ca 140C, in ca 40% yield.
 
 
 
 
    Lilienthal
(Moderator)
08-08-01 19:14
No 202680
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

I have a crude translation checked by a real italian. I will look for it tomorrow.smile
 
 
 
 
    Scooby_Doo
(Newbee)
08-08-01 23:12
No 202731
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

CA 2586c-2587 1948 is the abstract to the above article and very much in english. The wording for the reaction and hydrolsis. The imine solution is added slowly to the ice cold benzylmagnesium chloride solution, then it was refluxed for 2 hours, the ether distilled off then the residue is heated on a steam bath for 2 hours, ether was added then ice and dil. sulfuric acid. The layers seperated and the aq. layer extracted with ether. They then go on to produce the picrate and HCl salts. Everything else is as Rhodium describes.
 
 
 
 
    tomjuan
(Newbee)
08-09-01 05:59
No 202771
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

I am a little confused - the author of this abstract apparently used 0.2 moles of benzylmagnesium chloride, but only 0.1 mole of the imine. Shouldn't the molar ratio be 1:1? Or I have failed to properly balance the equation for the final reaction?
 
 
 
 
    Osmium
(Stoni's sexual toy)
08-09-01 06:22
No 202776
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

They are probably using an excess of the cheaper or easier to prepare reagent to ensure a halfway decent yield.
 
 
 
 
    jim
(Hive Bee)
08-09-01 07:20
No 202789
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

I am a little confused here.  Adding the imine to the benzyl magnesium  chloride forms the amine, but the amine can still react with the grignard reagent!?  Maybe that's why the grignard and imine are added cold:  the imine is more reactive than the amine.  However, it seems to me that reverse addition of products wouls solve that problem,... doesn't it..?  Simply add the benzyl magnesium chloride to the imine thus avoiding the potential problem of amine reaction with grignard reagents.
 
 
 
 
    Rhodium
(Chief Bee)
08-09-01 07:51
No 202795
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

Adding BzMgCl to the imine does not produce the amine directly, but rather the MgCl salt of the amine, which is unreactive towards grignard reagents, with its negative charge on the nitrogen. The amine is released from its salt first in the acidic work-up.
 
 
 
 
    joyman
(Stranger)
10-31-01 08:13
No 230930
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

In the 80's this reaction was apparently performed incorrectly -  acetaldehyde was added by itself to the benzyl chloride without first making the imine. This led to a very toxic compound being formed that led to the dea going nuts trying to close down labs attempting to use the prep. was this the one where theyre chemists even published the ammended synthesis? - anyone know the source of this?

One thing has been nagging me and so i'll ask about it - i notice that the italian yield is low 40% - Even given a correct carrying out of the procedure as described, whats to stop some of this unidentified by product (from unreacted ch3cho + Menh2 maybe?) still forming and maybe even carrying though in the reaction/ clean up? how certain can we be about this?
 
 
 
 
    Rhodium
(Chief Bee)
10-31-01 08:23
No 230935
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

Distillation of the freebase and recrystallization of the formed methamphetamine salt will remove all such impurities.
 
 
 
 
    joyman
(Stranger)
10-31-01 08:48
No 230949
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

this probably should be emphasised for this reaction and for any bee intending to use the synth in practise.
 
 
 
 
    megamole
(Hive Bee)
11-01-01 06:37
No 231560
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

Maybe I'm mistaken, but I thought that when condensing acetaldehyde and methylamine, oligomerization was a big problem.Specifically, I thought that it tended to form 1,3,5-Trimethyl-[1,3,5]triazinane. Oh well; I could be wrong. Then again, maybe the trick is getting the right conditions so this doesn't happen. Does anybody have more information on this?
 
 
 
 
    Rhodium
(Chief Bee)
11-01-01 07:01
No 231566
      Re: Meth via grignard rxn (Gazz Chim Italiana)     

I believe that oligomerization is the big problem, that's why the reaction is done in the cold, and the yield isn't better than 40% even with an excess of benzylmagnesium chloride.
 
 
 
 
    Rhodium
(Chief Bee)
10-05-04 14:22
No 534582
      V. Evdokimoff: Chem. Abs. 42, 2586 (1948)
(Rated as: good read)
    

Here is the CA summary of the article dealt with in Post 202649 (Rhodium: "Meth via grignard rxn (Gazz Chim Italiana)", Novel Discourse)


Reactions of organomagnesium compounds with aliphatic azomethines and with hexamethylenetetramine. I.
Vera Evdokimoff
Chem. Abs. 42, 2586 (1948) [Gazz. chim. ital. 77, 31826(1947)]

Whereas the reaction RMgX + R'CH=NR" --> R'CHRN(MgX)R" -H2O-> RR'NHR" has been studied by Busch (Ber. 37, 2691(1904); 38, 1761(1905) ; C.A. 2, 2231) with arylaliphatic and aromatic azomethines, there is no literature on the same reaction with aliphatic azomethines, perhaps because the latter tend to polymerize to products without azomethinic function. This difficulty can be overcome by making equimol. wts. of the primary amine and aldehyde react in Et2O, fixing with anhyd. Na2SO4 the water formed in the condensation, and pouring the soln. immediately into excess organomagnesium reagent.

PhCH2Cl (24.4 g) in anhyd. Et2O, added slowly to 4.8 g. Mg (the reaction can best be started by inoculating with a little Mg previously heated with iodine), and heated on a steam bath, yields a soln. of PhCH2MgCl (I). MeNH2.HCl (15 g) and 30 cc. 40% aq. NaOH, distd. into ice-cold anhyd. Et2O contg. Na2SO4, give a soln. of MeNH2 (II), the concn. of which is detd. by titration. An ice-cold mixt. of 3.1 g. II in anhyd. Et2O, 4.4 g. freshly prepd. AcH, and excess anhyd. Na2SO4, agitated, allowed to stand cold several min., the Et2O soln. added slowly to the ice-cold soln. of I, refluxed 2 hrs., the Et2O distd., the residue heated 2 hrs. on a steam bath, Et2O added, ice and dil. H2SO4 added, the Et2O layer sepd., and the aq. layer (III) extd. with Et2O, gives a combined Et2O soln. (IV). The residual acidic aq. soln. (V) contains bases which give a ppt. with picric acid (VI).

A riptographic study of this reaction (cf. Toffoli, C.A. 33, 697; T. and Flamini, C.A. 40, 33604) indicated that VI ppts. a single compd. rather than a mixt., that under the exptl. conditions the soly. of the picrate is approx. 7 millimolar or 2.6%, that its soly. as an undissocd. compd. is very low, that the quantity of base formed is 0.04 M (160 mols. per 250 cc.), and that the reaction gives a theoretical yield of approx. 40%.

The main products of the reaction were sepd. by 2 methods. V, made alk. with NaOH, extd. with Et2O, the ext. dried by Na2SO4, filtered, evapd. to dryness, the oil residue salified by HCl, kept several days in a desiccator contg. H2SO4 and NaOH, and purified by acetone, yields PhCH2CHMe-NHMe.HCl (VII), mp 140C. A mixt. (VIII) of VII and d-rotatory VII (4:1) mp 140-5C; a mixt. of VII and VIII (1:1) mp 143-8C.

VI (0.2 that required for complete pptn.), added to V, filtered, excess VI added to the filtrate, and the ppt. dissolved in hot water, cooled very slowly, concd. below 45C in vacuo, and the part of the ppt. which mp 115-20C purified by water, yields the picrate, PhCH2CHMeNHMe.C6H2(NO2)2OH, mp 126C. IV, concd. and fractionally distd., yields liquids below 200, and bibenzil (IX), mp 52C, bp 284C.

By the same general procedure, I (0.2 mol.), HCHO, and II yield an acidic aq. liquor (X) and an Et2O soln. (XI). X, made alk. by NaOH, steam-distd., the distillate extd. with Et2O, the ext. dried by Na2SO4, evapd., 0.5 mL concd. HCl added, dried 2 days over H2SO4 and NaOH, dissolved in anhyd. EtOH, excess anhyd. Et2O added, and this last treatment repeated until cryst., yield PhCH2CH2NHMe.HCl, mp ~156C (cf. 156-7C of Decker and Becker, C.A. 7, 84, 1513). XI, evapd., and the residue fractionally distd., yields PhMe, PhCH2Cl, alc. substances (probably approx. 60% alcs. as judged by benzoylation), and IX.

From a mixt. of an Et2O soln. of 0.1 mol. I and 0.025 mol. anhyd. hexamethylenetetramine (XII) the Et2O was distd., 40 cc. xylene added, the mixt. heated 6 hrs. at 140C then to 180C (allowing the xylene to evap.), decompd. by ice, extd. with Et2O, NH4OH and NH4Cl added to the aq. liquor, extd. with Et2O, and the combined Et2O exts. evapd., yielding chiefly a basic resinous mixt. which could not be purified and was discarded. The aq. soln., neutralized by HCl, and 0.7 g. VI added, gives a resinous ppt., whereas the addn. of 2 g. of VI ppts. the picrate of II.

The reaction between I and XII, started as above but, after the xylene is distd., Et2O added, decompd. by ice and dil. HCl to obtain an acidic soln., the Et2O sepd., the aq. portion extd. with Et2O, the ext. evapd., and the residue fractionally distd., yields PhMe, PhCH2Cl, IX, and alcs., and a relatively large amt. of PhCH:CH2. The aq. soln., made alk., steam-distd., the distillate extd. with Et2O, the ext. dried by Na2SO4, evapd., the residue salified by concd. HCl, kept several days over H2SO4 and NaOH, dissolved in anhyd. EtOH, anhyd. Et2O added, allowed to stand several weeks, and the ppt. washed with anhyd. Et2O, yields PhCH2CH2NHMe.HCl.2H2O, mp 139-40C.




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