Ritter Reaction on Safrole

[RussianBlue]

About 10 years ago I was looking through the Journal of Forensic Science primarily at articles on MDMA/MDA synthesis. I fuzzily recall what may have been an editorial item on how the Ritter reaction was a viable route from safrole to MDA. It struck me as interesting to the point where I needed to know if this was the case. Not wanting to break the Law of course I didn't attempt to synthesize MDA via this reaction and the amide intermediary. Accordingly, I understand that a chemist whose skill, quite strangely, was exactly equal to mine attempted to prove or disprove the viability of this pathway. To cut a long story short, he failed at every attempt. This did not surprise me as I felt the methylenedioxy ring was liable to interfere; whereas in the phenyl2propene to benezdrine pathway, not so. It also disproved the pompous assertions of someone who does chemistry to take away the freedom of those have had a love affair with the science as a creative endevour. I've always wondered if the practical method was in error or the theory of the proponent. Is anyone aware of this pathway yielding results.

[GC_MS]

The Ritter reaction doesn't work for MD(M)A because of the ring substituents, in this case the methylenedioxy structure. The resulting compound is a tetrahydroquinoline. Ring substituents in general make this reaction "fail" or work. The Ritter reaction has been propagated to synthesize MD(M)A in a popular underground chemistry book (was it Fester's?), but it didn't work, off course. There have been reports from the USA where the tetrahydroquinoline has been found in so-called MDMA preparations. The cooks obviously didn't taste their own dish... or didn't care about the consumers.

[Rhodium]

Is it really too much work to plug in "ritter reaction safrole" in the search engine to find

Post 280053

(Rhodium: "Why the Ritter Reaction Fails for Safrole", Chemistry Discourse)?

[UncleFester]

In SOMM 3, I put that ritter reaction with safrole because I read the same article as you by the chair of the chem dept of UCLA. It doesn't work. In later eds of SOMM, I cite the reason why...Chem abtracts Vol 22 page 86 "Cleavage of the Methylenedioxy Group".  Sulfuric acid rips apart the grouping.  Just because a guy holds a chair in chem doesn't mean you should listen to him.

[GC_MS]

In SOMM 3, I put that ritter reaction with safrole because I read the same article as you by the chair of the chem dept of UCLA. It doesn't work. In later eds of SOMM, I cite the reason why...Chem abtracts Vol 22 page 86 "Cleavage of the Methylenedioxy Group".  Sulfuric acid rips apart the grouping.  Just because a guy holds a chair in chem doesn't mean you should listen to him.

“The Ritter Reaction Using Safrole: An Encounter In Two Clandestine Labs”

Richard R. Laing and Brian Dawson, Health Protection Branch, Drug Analytical Service, Health Canada, 3155 Willingdon Green, Burnaby, B.C., V5G 4P2

In two recent MDA clandestine lab seizures, references were found relating to the Ritter reaction in which safrole, acetonitrile and concentrated sulphuric acid are reacted together at cold temperatures. In repeating the synthesis the desired intermediate N-acetyl MDA was not found at any stage of the reaction. The major reaction product, although seeming to relate to MDA was partially characterized using IR spectroscopy and mass spectrometry but require 1H and 13C NMR techniques for structure confirmation. The major product 3,4-dihydro 1,3-dimethyl-6,7-methylenedioxyisoquinoline does not appear to be the desired end product and has also recently been identified in two street samples from the Vancouver area.


“MDA From Safrole by the Ritter Reaction”

R. Kazlauskas and V. Murtaugh, Australian Government Analytical Laboratory, PO Box 385, Pymble, Sydney, NSW, Australia, 2071

The underground book by Uncle Fester, “Secrets of Methamphetamine Manufacture,” mentions use of the Ritter reaction to make MDA from safrole, by analogy to making amphetamine from allybenzene. But when the reaction is applied to safrole and acetonitrile, it gives only a low yield of the expected product, N-acetyl MDA. The major product appears to be an isoquinoline. It is suggested that clandestine lab chemists can use this compound as an indicator of the Ritter or related reactions.

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

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Now, where does it say that the methylenedioxy ring is ripped apart? It's not just for methylenedioxy ring substituents... Other substituents may result in similar reactions. Dihydroquinoline (and not tetrahydro, as I mentioned before... was confusing with THF), that is what you get, and in case of safrole, you'll have a methylenedioxy dihydroquinoline.

[RussianBlue]

Thanks to all for enlightening me. In future I will u.t.f.s.e.

[Antoncho]

While it is true that this rxn is no good for safrole, the reason for that has absolutely nothing to do with xcess sulfuric acid.

In fact, there's no need for high conc of H2SO4 in this rxn (have nice proc's, can post if interested) - its sole role is to create a carbanion from the alkene, in our case this is methylenedioxyphenyl-isopropyl (with "+" being situated on the middle atom of the chain). This carbanion then reacts w/acetonitrile which then rearranges to acetamide.

The substrates that can bee used in Ritter rxn need not bee specifically alkenes - any cpd that forms stable carbanions will do (anions must bee stable since nitrile group is a relatively poor 'trap' for them).


Now here's the real pitfall (from now on the ideas and drawings beelong to Fomalhaut of HyperLab, from

Post 404131 (missing)

(Fomalhaut: "Íåìíîãî òåîðèè...", Russian HyperLab)):




The positive charge on the nitrogen in nitrillium anion migrates to the adjacent carbon, which, being a perfect electrophil, plunges into the nearby ring, forming that methylenedioxy-dihydroisoquinoline.

Here's a very similar procedure  from Titze & Eicher: dihydroisoquinoline synth:




As you can see, they use a FC catalyst here.

But, the MAIN reason that Graaf-Ritter doesn't work on safrole is the fact that methylendioxyring is highly activated and thus is much much more prone to cyclization


But, OTOH, that offers us some other possibilities. You could Graaf-Ritter 'straight' allylbenzene and do next to anything to it (in terms of ring substitution, i mean), while it's still in acetamide-protected form.



Antoncho

[UncleFester]

When the Ritter reaction is run with safrole at normal operating temps rather than ice cold, the process produces a violent geyser out the top of the flask and some kind of polymeric product. This would correspond to the CA cite reaction conditions.

[SPISSHAK]

I must say that is a perfect mechanistic explanation.
Thanks I like to have a clear picture and you seem to know how to draw them.

[Antoncho]

Soooo......

Thanks I like to have a clear picture and you seem to know how to draw them.

Alas, i'm not that meticulous when it comes to explanation. As i noted above, it was Fomalhaut who both authored the idea and drew the rxns



Now, to summarize all of the above, after reading all those links and articles:


1. The 'classic' Ritter rxn is no good for safrol and all other methoxylated allylbenzenes.

2. This rxn DOES work to some extent at some milder conditions, as the clandestine market researches suggest.
It is not clear as to how good a yield one can obtain at best via this route.


Now, to give you guys smth to think of..... This reaction can bee run at lower temps and much reduced concentration of H2SO4, using AcOH as an adulterant:

To a stirred solution of 100g H2SO4 and 45g MeCN in 500mls GAA there's added 112g diisobutylene keeping the temp beelow 50 C. The mixtr is left overnight, diluted w/water, filtered......(etc)




Anyone cares to try on a small scale w/safrole or anethole?  Seems easy as well as sexy....

[Sunlight]

The first attempts I got a geiser, I guess it is just becuase the safrol polymerices violently in touch with sulfuric acid if not near 0 C. I tired it then with dilute acid in MeCN and I got about a 10 % of a yellow product with not special effects.

[Rhodium]

GC-MS and LC of Addition Products Formed from the Reaction of Allylbenzene and Related Arylpropenes with Acetonitrile and Sulfuric Acid
F. Taylor Noggle, C. Randall Clark and Jack DeRuiter

Journal of Chromatographic Science, Vol. 33, 256-262 (1995)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/forensic/ritter-rxn.allylbenzene.pdf)

Abstract
The synthesis of amphetamine and related compounds from several arylpropenes is investigated using gas chromatography-mass spectrometry and liquid chromatography. Treatment of allylbenzene with acetonitrile and sulfuric acid yields a mixture of 1-phenyl-2-acetamidopropane and 1-phenyl-1-acetamidopropane. Hydrolysis of this product mixture gives the corresponding propanamines, amphetamine and 1-phenyl-1-propanamine. When the isomeric compound trans-beta-methylstyrene is subjected to this reaction sequence, a single amine product, 1-phenyl-1-propanamine, is obtained. Treatment of the isomeric 3,4-methylenedioxyphenylpropenes (safrole and isosafrole) with acetonitrile and sulfuric acid followed by acid hydrolysis did not result in the formation of 3,4-methylenedioxyamphetamine (MDA). Safrole yields a dihydroisoquinoline derivative, whereas isosafrole gives simple dimers under these reaction conditions. The differences in the products obtained in these studies appear to be determined by differences in the electronic nature of the starting arylpropenes.