The Leukart Reaction

jimmydotcom · Mon May 02, 2005 2:03 am

Here is a tried-and-true version of the Leukart reaction, using P-2-P as the starting material:

In 2-L RB flask fitted with thermometer, Dean-Stark trap and condenser, place: 159 ml p-2-p (1.2 mol), 562 ml. N-Methyl formamide (9.6 mol) and 100 ml formic acid.

Heat slowly to reflux. When the reaction temperature reaches 172 degrees C, remove the Dean-Stark trap. It is critical to keep the reaction temp between 168 and 172 C (watch the reaction carefully during first 4 hours). Temp is controlled as follows:

When temp exceeds 172, add small amounts of formic acid to lower the temp.

When the temp dips below 168 C, re-insert the Dean-Stark trap and distill off H2O until the temp reaches 172.

Reflux for 8 hours. Cool to 0-10 degrees C in ice bath. Slowly add 500 ml concentrated HCl and reflux an additional 6 hours.

Cool to 0-10 C in ice bath. Dilute to 2 liters with distilled H2O. Divide into 2 portions, work up each as follows: extract 4 times with 250 ml NP solvent. Discard the solvent layers. Cool to 5 degrees C, then carefully add 6N NaOH until the mixture is strongly alkaline. Re-cool the mixture. Extract 3 - 5 times with NP solvent (ether, toluene, etc). Save the solvent layers. Extract solvent layers 3 times with cold distilled H2O. Dry solvent layer over anyhydrous MgSO4, then bubble with HCL gas to yield methedrine HCL.

Yields from 65-75 percent, based on P2P. THIS HAS BEEN PROVEN REPEATEDLY. Do NOT believe everything you read about the Leukart reaction!

Vitriodor · Tue May 03, 2005 2:44 am

IndoleAmine · Dreamreader Deluxe

n-methylformamide is hydrolyzed to methylamine under aequous acidic conditions (=HCl hydrolysis) - MeAm is a gas and removed effectively when solvent is removed with vacuum.... Wink

jimmydotcom · Tue May 10, 2005 8:32 pm

The work-up removes almost everything undesireable, with the exception of di-(phenylisopropyl) methylamine. Amounts of this side product are minimilized by the 7 molar excess of N-methyl formamide, and may be further minimalized by larger excesses. Vacuum distillation easily removes this side-product, which distills at a much higher boiling point than methedrine. One simply removes the collection flask once the vapor temperature starts to rise. Hands-on experience has indicated that this side-product composes less than 5% of the undistilled product.

Unreacted phenylacetone, formic acid and n-methylformamide are all removed during the previously posted work-up.

This reaction has been tried repeatedly with 3,4 methylenedioxy phenyl-2-propanone with 65-70% yields as well.

Vitriodor · Wed May 11, 2005 2:34 am

Maybe I didn´t make myself clear when I was discussing the second stage of the Leuckart reaction. I´m used to remove the excess of formic acid (which was used as a reductive agent and to maintain a slightly acidic environment) and (methyl)formamide after the reductive amination step, so PRIOR to the hydrolysis. Subsequently I proceed with the purified formyl derivative. What I understood from literature a diluted hydrochloric acid can be used for the hydrolysis in this case, whereas more concentrated hydrochloric acid is sometimes to be used when the entire reaction mixture is subjected to hydrolysis. From what Jimmydotcom wrote, I concluded that the entire reaction mixture was used for the hydrolysis. Some personal experimental work I did led to the conclusion that the amount of by-products increases when working with the crude reaction mixture, compared to hydrolysis of the purified formyl derivative.

It could be that part of the formamide is hydrolized to methylamine (and partially will be removed during the reflux), but there is still a number of side-reactions that will occur IMO.

The by-products can be effectively removed by (steam) or vacuum distillation, in combination with crystallization, I agree. Purification is not a problem, I was only concerned about the yield. But if your experience is a 60-70% yield then apparently your experimental work is better than mine Embarassed