For those wishing to study the MDMA synthesis reaction, there is a significant roadblock:  the procurement of safrole.  Although it  is available naturally through sassafras root bark, and of course, in larger quantities through sassafras essential oil, because of the stiff regulations related to its distribution, it's perhaps safe to say that, outside of directly synthesizing it or steam-distilling it from the root bark, safrole is out-of-reach for most bees/wasps wishing to experiment.  

Back in the late 90s to early 2000s a number of us at the Hive (I had a different username back then) were working on a way to go from eugenol to allylpyrocatechol to safrole using a wide variety of reactions and reagents.  Various discussions on this topic have occurred over the years since then and  have proven valuable, but I think, for whatever reason, the proposed eugenol demethylation-methylenedioxylation scheme is somewhat dead in the water and not likely to be pursued vigorously by any newcomers to this craft.

That said, it's time for something radical which includes all or most of the desired features of an easy precursor synthesis:

1.  Use of (mostly) readily available and easy-to-procure OTC starting materials (precursors).
2.  Easy reaction that requires little skill and simple equipment.
3.  Catalysts that are completely OTC (such as common bases and acids).
4.  Non-suspicious purchasing of said starting materials.
5.  Reaction method that is relatively unknown to the establishment.

Isosafrole has proven to be a quite useful and reliable precursor for a number of MDMA synthesis reactions and a way produce it, while adhering as much as possible to the above limits, would certainly be desirable.

I believe I have rediscovered such a way (on paper).

The Baeyer Condensation is a very old.  It was developed in the late 1800s by Adolf Von Baeyer whose early experiments involved phenol and formaldehyde to form phenol-formaldehyde resins (which later led to the discovery of Bakelite) and the condensation between ketones and aldehydes (think Baeyer-Villiger) with aryl compounds, which would eventually be applied to the synthesis of DDT (DichloroDiphenylTrichloroethane; notorious banned pesticide) and Bisphenol A (4,4'-dihydroxy-2,2-diphenylpropane; used for epoxy glue).

The way the reaction works is that two aromatic molecules, substituted or no, in the presence of an acid or base catalyst, condense with an aldehyde or ketone to form a diarylalkane.  DDT is formed through the condensation of chlorobenzene and chloral; Bisphenol A, through the condesation of phenol and acetone.  And, if propionaldehyde were condensed with anisole, using a catalytic amount of acid or base (like simple H2SO4 or NaOH), 1,1-(dimethoxyphenyl)propane would result.

Supportive information on this reaction can be found in the following reference:

Synthesis of Substituted 1,1-Diarylethanes
D. S. Hoffenberg, E. M. Smolin, K. Matsuda
J. Chem. Eng. Data, 1964, 9 (1), pp 104–106

So what does all this mean?  Well diarylalkanes can easily be cleaved with either acids or bases (again, simple ones like H2SO4 or NaOH) into two molecules:  one that is an aromatic and one that is a 1-arylalkene.  For those that are confused, this means that propenylbenzenes can be formed in two steps.  Two substituted or unsubstituted benzene molecules react with one propionaldehyde molecule to form one intermediate, 1,1-diphenylpropane (and water).  This can then be cleaved (or “cracked”) to form one of the aforementioned benzene molcules and one molecule of the desired propenylbenzene.  To be clear, isosafrole is a propenylbenzene.  

Anisole is a very common aryl compound used in this type of reaction.  For those that have doubts that benzodioxole (methylenedioxybenzene) can substitute it, see US 2560173.

Following is a very good example of the above reaction taken from US 4026591:

EXAMPLE 1

a. Condensation

A mixture of 432 g (4 mols) of anisole and 4 g. of concentrated H3PO4 was heated to 150 C in a reaction vessel equipped with a stirrer, metering unit and descending condenser.  After the afore mentioned temperature has been reached, 58 g (1 mol) of propionaldehyde were added through the metering unti over a period of 1.5 hours and, at the same time, the water of reaction formed distilled off.  On completion of the addition, the upper phase of the reaction mixture was decanted from the phosphoric acid precipitated and the excess anisole removed from the reaction mixture by distillation, leaving 251.8 of condensation product consisting of pp'-, o,p'- and o,o'-1,1-dimethoxy diphenyl propane.  The yield amounted to 98.4%, based on the propionaldehyde used.

b.  Splitting

For splitting, 100 g of 1,1-dimethoxy diphenyl propane from the condensation stage (a) were heated to 200 C in a distillation apparatus fitted with a Claisen attachment, followed by the addition of 0.5 g of concentrated phosphoric acid.  The products formed during the splitting reaction distilled off over a period of 15 minutes at about 5 to 30 Torr.  According to analysis by gas chromotography, the distillate (95.5 g) contained 32.7 g of unsplit 1,1-dimethoxy diphenyl propane, 24.1 g of trans-p-anethole, 9.1 g of trans-o and cis-p-anethole and 1.2 g of p-propyl anisole, corresponding to a yield of 91.4% of anetholes, based on reacted condensate.

Pure trans-p-anethole was obtained from the product of splitting by fractional distillation:  b.p. 110 C/10 Torr.

Other very good examples of this reaction, with only slight experimental modifications (mostly related to the catalyst used), can be found in US 1798813, 2591651, 4071564, 4154769; GB 905994A; & CA 660173A .

So you think that's good?  Well, it gets even better!

For starters, lets consider the drawbacks to the above reaction.

1.  Uses propionaldehyde, which has a low boiling point, is volatile, and has a suffocating smell.  Could be synthesized but is not OTC.
2.  Forms water as a by-product, which must be removed somehow.

How to avoid all this?  Well, one need only review the contents of CA 708652A; GB 963294A; and as mentioned above, US 4026591.  

EXAMPLE 2

A mixture of 324 g (3 mols) of anisole and 4 g of concentrated H3PO4 was heated to 150 C in a 500 ml capacity reaction vessel equipped with a thermometer, stirrer and dropping funnel.  After the above-mentioned temperature had been reached, 64 g (0.432 mol) of o-anethole (2-methoxy-propen-1-yl benzene) were introduced into the thoroughly stirred anisole/phosphoric acid mixture over a period of 1 hour, followed by stirring for 1 hour at the same temperature.  The excess anisole was then distilled off at 50 C/5 Torr, leaving 110 g of a condensation product consisting predominantly of the o,p'-isomers of 1,1-dimethoxy diphenyl propane.  The yield was substantially quantitative.

For splitting, the condensate was heated to 200 C in the presence of the phosphoric acid left in the condensate.  The products of splitting formed, anisole, and the o-p-anetholes, distill off over a period of 10 minutes at 10 Torr.

Distillation of 55 g of 1,1-dimethoxy diphenyl propane gave 17.8 g of distillate which contained 14% of trans-p-anethole according to analysis by gas chromotography.  24.2 g of condensate were recovered.

The Example illustrates that o-anethole can be converted by the process according to the invention into trans-p-anethole.

A higher yield could likely have been obtained had a better acid or base catalyst been used, but more on this in a minute.  For now, what is important is that the desired p-anethole was obtained from undesired o-anethole by reacting it with anisole using the method already described.  So what I was thinking is that anethole, or, as some of the other patents listed above indicate, isoeugenol, could be used as a precursor to isosafrole by condensing it with benzodioxole (via NaOH or KOH catalyst, which will surely not effect the methylenedioxy bridge) and then be cleaved and distilled in the same pot by adding vacuum and increasing the temperature.

Another good example of the p-anethole condensation (this time with phenol) is taken from:

Arylalkylation of Phenols and Naphthols with Derivatives of styrene
Ng. Ph. Buu-Hoi, Henri Le. Bihan, Fernand Binon, Pierre Maleyran
J. Org. Chem., 1952, 17 [8], pp 1122–1127

EXPERIMENTAL

Condensation of anethole with phenol.  To a warm mixture of 94 g. of phenol and 10 g. of sulfuric acid, a solution of 74 g. of redistilled anethole in 100 ml. of toluene was added in small portions.  The mixture was refluxed for two hours, washed after cooling with an aqueous solution of sodium carbonate, then with water, and dried over sodium sulfate.  After evaporation of the solvent, the residue was vacuum-fractionated, giving 72 g. (60% yield) of crude (a-anisyl-n-propyl)phenol (II) boiling at 200-240/13 mm; after redistillation, the product formed a pale yellow, viscous oil, b.p. 212-217/13 mm.

In a nutshell, I call this process “transcoding” – as in, transcoding anethole to isosafrole.  Why transcoding?  Well, although that term is normally is applied to video editing, it pretty much sounds to me like converting propenylbenzenes between each other is the same thing.  One transcodes video formats such as, for example, .avi or .wmv to .mpeg or .vob – but they are all the same video, just with different containers.  In this way, I see anethole and isosafrole in much the same way.  They are both propenylbenzenes, just with different ring substituents.

For those who wish to dispute this, I'm just trying to make the reaction more easy to identify within our community and “transcoding” seems about as good a term as any other to use.  I think you all will agree that it's much better labeling it something like the “DDT” reaction.

Moving on.

I know what some of you are thinking:  How can anyone know that the cleavage reaction will prefer the formation of isosafrole over the original anethole starting material?  Well, although the above o-anethole reaction supports the desired outcome, I decided to research a bit further and I think I've found the answer to this question in US 3359317 (with support from US 3311660 & 4374272).

In it the authors are looking to synthesize an alkenyl-anilne which does not involve splitting bis-aminophenyl-alkanes.  Their solution?  In their own words:

It has now been found that alkenyl-anilines may be obtained readily and in good yields by heating hydroxy-phenyl-amino-phenyl-alkanes over alkaline catalysts and distilling off the alkenyl-anilines as and when they are formed, phenol being obtained as the other fission product.

The hydroxyphenyl-aminophenyl-alkanes are readily obtainable in good yields by the addition of aromatic amines on to alkenyl-phenols in the presence of acidic or basic catalysts according to the process of copending application Ser. No. 295,203 and now U.S. Patent No. 3,311,660.

Having regard to this process of production, the splitting of the hydroxyphenyl-aminophenyl-alkanes into alkenyl-anilines and phenols is surprising.  It was to have been expected that the splitting would lead to the reformation of the original starting materials.  In point of fact, the hydroxyphenyl-aminophenyl-alkanes can also be readily decomposed again into alkenyl-phenols and anilines by bringing them to decomposition temperatures over acidic catalysts.  On the other hand, by a purely thermal splitting, a mixture of alkenyl-phenols, alkenyl-anilines, phenols and anilines results.[/b]

So there you have it.  A means to transcode anethole or isoeugenol to isosafrole.  The only stopping block is the needed benzodioxole, which is reported to be easy as sin to make via catechol, DCM, NaOH and DMSO.

But for those of you stuck on forming allylpyrocatechol from eugenol, well, what about forming propenylpyrocatechol via this reaction?  My guess is that all that is needed is to replace benzodioxole with catechol, and continue from there.

If anyone has any questions, please feel free to ask.  But know this:  Neither I, nor anyone I know, has tried any part of this reaction (seriously), so I can't provide any experimental advice.  But anything dealing with the literature or theory, let me know.

Great work Sulfuro!

The patent you quoted US 4026591 is for contact lens cleaning, the correct patent is ;

Process for the production of anethole
United States Patent 4026951

edit; I had not noticed you had it in your references at the bottom.

Sentence should be as follows:  I think you all will agree that it's much better than labeling it something like the “DDT” reaction.

Sedit:

Thank you very much for helping to jump-start this thread!

Your question is a very good one.

To answer it, one need only look at the above patent reference (included as a PDF attachment with my write-up) US 4026951 (sorry, the one I listed, 4026591 is incorrect).  In it, anethole is synthesized via the Baeyer condensation using anisole and propionaldehyde.

But the other examples, like the synthesis for DDT, use chlorobenzene, and it isn't a phenol.  And in my write-up, to illustrate that propenylbenzenes can be transcoded, I included a patent that uses several anilines as substrates, and they aren't phenols either.  This reaction, BTW, works for simple benzene and toluene as well and I've attached a few patents as PDFs for those wishing to research a bit further.

But more to the point, as detailed in "Table II. 1,1-Diarylethanes from Phenols and Phenol Ethers with Paraldehyde" in the je60020a033.pdf "Synthesis of Substituted 1,1-Diarylethanes", "Anisole" and "Resorcinol di-Me-Ether" (1,3-dimethoxybenzene ?) are condensed with paraldehyde to form the expected ring substituted 1,1-diarylethanes, unfortunately in low yield -- 40% & 36%, respectively -- but the experimental reaction scheme kinda sucked as 65% aqueous H2SO4 was used as an acid catalyst (water appears to inhibit this reaction).

Interestingly, the anisole + phenol reaction in toluene using sulfuric acid as a catalyst actually makes me think the true catalyst is TsOH.  Anyone agree?

See https://www.hyperlab.info/inv/index.php?s=&act=ST&f=17&t=28557&hl=propionaldehyde

I must say that, while the production of isosafrole in two steps from benzodioxle and propionaldehyde may be useful, the synthesis of isosafrole from benzodioxole and eugenol is not inviting. If you can buy catechol then you can certainly buy propionaldehyde. The prep from eugenol is awkward because of the cost and the purification of the mixture of the alkenes.

Firstly, I need to make a correction.

". . . it would seem that neither of them was aware that propionaldehyde could be substituted with other propenylbenzenes (like anisole or eugenol) to effect the same reaction, which is really the point of my write-up."

I meant isoeugenol and not eugenol in the above sentence.

Enkidu:  While reaction of benzodioxole with isoeugenol is not ideal in terms of cost, it is in terms of the ready availability of eugenol and the downside to working with propionaldehyde.  I guess an additional drawback is the need to isomerize eugenol to isoeugenol, but that isn't very difficult.  That's why I really suggest the utility of anethole, because (apart from all of the aforestated reasons why propionaldehyde is not as desirable) it is readily available, it is a already a propenylbenzene (no need to isomerize), and it has an easy-to-identify smell (licorice). As for the awkwardness about having to deal with a mixture of isomers, well, we don't really know that will be the case.  Experimentation is key here, because we have a few literature references that hint strongly that switching catalysts (from acid to base) will make all the difference in the world in terms of the reaction's outcome, namely, one type of propenylbenzene and one isomer.

Sedit:  That's why I suggest using a base catalyst:  to avoid the potential cleavage problem and to ensure that the desired propenylbenzene is acquired (not the starting one).

As for the references provided by Russian Hyperlab members in the previously mentioned thread, not too many provide much more insight into this reaction, except two:

US 2504382A

(To give proper credit, most of this portion of the patent was already quoted by Neo Retro in the aforementioned Russian Hyperlab thread)

The 2,2-bis(para-alkoxyphenyl)propanes are prepared by condensing phenol with acetone in the presence of a dehydrating catalyst such as sulfuric acid or aluminum chloride.  2,2-bis(p-hydroxyphenyl)propane is thus obtained and this compound is etherfied by reaction with a suitable dialkyl sulfate to give a 2,2-bis(para-alkoxy-phenyl)propane of the type described.

Alternatively, in preparing a 2,2-bis(p-alkoxy-phenyl)propane, phenol  may first be etherfied to form a suitable n-alkylphenyl ether and the ether then reacted with acetone to give a toxic compound of the class employed in the compositions and methods of this invention.

While I am certainly not interested in the "toxic compound" mentioned above, I do appreciate the fact that in this reaction an "n-alkylphenyl ether" can be used in place of phenol, which supports the notion that phenol ethers can be used as starting materials in the Baeyer condensation.

US 4230893A

This patent describes a synthesis for synthesizing "1,1-di(4-hydroxy-3-methoxyphenyl)-2-alkoxypropane" for later conversion into 4-hydroxy-3-methoxy-phenylacetone or MVK (MethylVanillylKetone) via a reaction between two moles of guaiacol and one mole of 2-alkoxy propanol followed by basic elimination and acid hydrolysis.

I've had it in my library for almost a decade, harkening back to the eugenol demethylation era, but didn't pay too much attention to it back then.  Having seen it over at Russian Hyperlab yesterday made me re-review it.

Basically, it's a way to make phenylacetones instead of propenylbenzenes using the same reaction scheme as the aryl + propionaldehye route (but with 2-alkoxy propanol instead of propionaldehyde).

It's good, and deserves more than a second look, but it is also a fine example of how using aqueous acid catalyst systems in the Baeyer condensation is starting to seem kinda sucky, as indicated by the low yields.

Diphenyl methane biodegradable insecticides
United States Patent 4003950
http://www.freepatentsonline.com/4003950.html

Example I:
Dianisyl-2-chloropropane (i.e., 1,1-bis(p-methoxy phenyl)-2-chloropropane) is synthesized as follows: Two moles of anisole and one mole of 2-chloropropionaledehyde are added dropwise into about 5 volumes of a cold concentrated acid mixture consisting of a 1:1 mixture of glacial acetic acid and concentrated sulfuric acid, maintained at about 0° C by use of an ice bath. The reaction product is recovered after crystallization from ethanol, yielding white needleshaped particles having a melting point of about 78° C. The structure can be confirmed by nmr: The ?-carbon protons absorb as a doublet at ?1.35 and ?1.45, the methoxy protons as two singlets at ?3.617 and ?3.633, the ?-proton as a doublet at ?3.790 and ?3.950, and ?-proton as a multiplet at ?4.330-?4.818.

Aminated with methylamine, split and reduced with metal in acid to PMMA. Or aminated with ammonia split and reduced to PMA. PMDA (para-methoxydimethylamphetamine) is also seen in Japan as a drug of abuse! (in the paper below they state that only PMA is controlled not PMMA nor PMDA?).

Update on Clandestine Amphetamines and Their Analogues Recently Seen in Japan
Munehiro Katagi* and Hitoshi Tsuchihashi
Journal of Health Science, 48(1) (2002)
http://jhs.pharm.or.jp/data/48(1)/48_14.pdf