After enjoying reading the catechol -> piperonal route in TSII I hit a brickwall with the synth of this topic. An 'alcohol intermediate' is mentioned on page 246, nowhere is the actual chemical name mentioned and I've found it very hard to come up with anything through interwebz searching. No doubt my chemistry naivety is letting me down, as I can't deduce what the alcohol intermediate would mean in relation to piperonal.

Here's the writeup:

In the flask is stirring a solution of 14g Mg turnings and 50mL anhydrous ether and the bromine compound is dripped into the flask over a 20 minute period of time then the solution stirred for an extra 10 minutes. Next, a solution of 50g piperonal and 200mL anhydrous ether is placed in the separatory funnel and added drop wise to the Grignard reagent over 30 minutes time. The reaction mix is then refluxed for 8 hours, hydrolyzed by the addition of 75mL ice cold saturated ammonium chloride solution and vacuum filtered to remove the crud. The etherial filtrate is washed with ice cold 1.5N HCl solution, dried through Na2SO4 and the ether removed by distillation to afford residue of 62g of crude alcohol intermediate (almost 96% yield!).

The alcohol intermediate happens to be the exact kind of intermediate that was produced by the Grignard reagent reaction with propanal to produce isosafrole back-a-ways in the big chapter. So what the chemist does is apply 1g of KHSO4 to that crude alcohol intermediate and process it just as was done before to give isosafrole (yield = 91%!). This is a great little procedure.

Yes it certainly appears to be great, but an observation creep into mind..

With this route being so obviously feasible, in theory, why aren't more people attempting it? The steps from piperonal to isosafrole seem so few and with relatively easily procurable reagents, it seems silly not to go this route.

From piperonal to the alcohol intermediate, the only standout reagent seems to be ethyl bromide. Then from the alcohol intermediate to isosafrole you utilize KHSO4 to break off a OH group. Simple.

It all sounds very good on paper.
In theory, I wouldn't have much problem at all getting to piperonal - piperonal to isosafrole on the other hand usually involves more exotic reagents/solvents (such as nitroethane) via the more documented routes, which is quite impossible to pull off in my neighborhood. So if I knew the alcohol intermediate route was viable I'd have no problem getting, in theory, to isosafrole, with quite friendly yields.

Can anyone shed some light on this alcohol intermediate route? Attempts? Background information on the actual procedure thats being performed on piperonal?

Thanks

 Not sure why you'd think this route is easier than more common methods to isosafrole but you're wrong. The ethyl bromide used is extremely carcinogenic, grignards are very sensitive to water and need to be made, piperanol is harder to get than safrole. You could just buy sassafras oil, distill safrole, boil it for a bit under vacuum with some KOH, and have isosafrole. No toxic, hard to get, or sensitive reagents, sassafras oil is still readily available. Looking at it this way you can see why it's unpopular.

Grignard reactions suck. It's pretty hard to avoid that. More importantly, making an ethyl grignard from ethyl bromide really isn't any easier than simply making nitroethane from ethyl bromide! Nitroethane is a pretty cool guy, too; eh makes MDA adn doesnt afraid of anything.

Of course, if molly molly molly is what you're after, look up ethyl alpha-chloropropionate. Ethyl alpha-chloropropionate can be made by treating ethyl lactate (eco-friendly paint stripper) with HCl/ZnCl2 in an appropriate solvent (not water); the Darzen condensation with piperonal goes directly to MDP2P.

It's not something that gets talked about often because piperonal is hard to source and there are better and simpler things to do with catechol.

Catechol monoallyl ether — To stirred catechol (44 g.; 0.4 mole), dry acetone (125 ml.) and freshly fused potassium carbonate (24.5 g.; 0.35 mole), allyl bromide (26 ml.; 0.3 mole) was added dropwise. The reaction mixture was refluxed for 4 hr, acetone recovered and the product cooled and filtered. From the residue consisting of unreacted catechol, potassium carbonate and potassium bromide, catechol (9.9 g.) was recovered by extraction with ether. The filtrate was dissolved in ether, acidified and washed free of acid. It was dried, concentrated and distilled when catechol monoallyl ether (40 g.; yield 88.9%); bp 80-82°C/0.8-1.2 mm.; n30D 1.5354 (lit.5 bp 103-4.5°C/8 mm.; n21.3D 1.5408) was obtained. No other fraction distilled over.

3- and 4-allylcatechols — Catechol monoallyl ether (30 g.; 0.2 mole) was heated in nitrogen atmosphere to 200-5°C (oil bath). A vigorous reaction ensued and the product changed colour to red. The temperature was maintained for 5 min. and then the product chilled in ice bath. Fractional distillation gave first fraction (13.5 g.) consisting of 3-allylcatechol; bp 110-12°C/3 mm.; n30(D) 1.5600 (lit.5 bp 132.8°C/9 mm.; n30(D) 1.5595) (Found: C, 71.8; H, 6.5; C9H10O2 requires C, 71.98; H, 6.71%). A second fraction (bp 120-3°C/2 mm.; n30(D) 1.5606; yield 11.8 g.) was also obtained. This was redistilled and crystallized from benzene-petroleum ether as colourless needles of 4-allylcatechol; mp 48-48.5°C (lit.5 mp 48.5°C; bp 141-4°C/7 mm.; n29(D) 1.5600). Both the allyl catechols gave deep green colour with ferric chloride solution.

The interesting part of this is the separation of 3- and 4- allylcatechol. The way they do the Claisen is an absolute bastard; it involves a nitrogen atmosphere and lots of pressure. I wouldn't recommend attempting it. The photochemical reaction sounds much more reasonable. I imagine the yield is proportional to your patience. Claisen reactions are promoted by polar, hydrogen-bonding solvents.

This link may help alleviate some of the pain the Grignard presents (with all the ether being used) if one were to challenge that route: hxxp://www.degruyter.com/dg/viewarticle/j$002fmgmc.2002.25.12$002fmgmc.2002.25.12.745$002fmgmc.2002.25.12.745.xml

The nitroethane synthesis does look more promising now. Having a clean, safe sodium nitrite source definitely helps move things along.

Synthesis of safrole is of interest since it's possible all plant sources might be eradicated worldwide someday, but perhaps you should read:

http://www.erowid.org/archive/rhodium/chemistry/safrolefaq.html

and

http://www.erowid.org/archive/rhodium/chemistry/3base/safrole.plants/index.html

since as already mentioned it's still widely available  If you are determined to study various syntheses of safrole, you could start by studying the route from phenol to salicylaldehyde to catechol:

http://parazite.nn.fi/hiveboard/novel/000379220.html

or maybe other routes such as in:

http://parazite.nn.fi/hiveboard/novel/000332391.html

I'm well acquainted with safrole and its availability, in my country and in others. The steps from phenol to catechol are also well documented elsewhere. And while the links you posted are quite relevant I don't think they're quite specific enough to the actual thread topic. Much appreciated either way though.

and since you do have internet access maybe you should consider using Google Scholar to do your own research instead of hoping someone else will do it for you 

I do admit that not noticing the reference in TSII and looking it up was a major oversight on my part. In no way do I conceive of people doing my homework for me, nor do I advocate or encourage it. My intention behind this thread was to discover why this 'alcohol intermediate' route wasn't being utilized as numerously as other more popular methods and there have been some very helpful, enlightening responses. This thread may have some positive unintended consequences, even if it evolves only so far as collating information or having knowledgeable heads think about and revise their take on the route. Classic case in point: Hoffman going over a somewhat uninteresting ergot alkaloid derivative initially thought to be of only marginal use.

The difficulty of this route is not my main concern - the thorough documentation and conceivability of it is however. I put a call out there to see if anyone had attempted it and it appears not many have, or those that have think it not the most ideal route, and that says something. What that something means will depend on the person considering the route and their intentions.