Piperonal from 1,3-benzodioxole?

Ionium · Fri Mar 18, 2005 9:23 am

I was wondering why no one ever mentioned formylating 1,3-benzodioxole to give piperonal, using the methods described in these two documents:

http://12.162.180.114/dcd/chemistry/iap.html

http://rhodium.moppy.net/www.rhodium.ws/chemistry/indane.formylation.html

(I don't see the last one on The Watchers site, perhaps that's something you missed? Wink

)

Is there anything in these methods that for some reason wouldn't work if 1,3-benzodioxole was used instead of indane(I'm talking about the formylation, not the following steps)? I consider it very unlikely that no one has tried this, so please speak up!

Kinetic · Sat Mar 19, 2005 4:51 am

Perhaps someone has tried one or more of these formylations on 1,3-benzodioxole, but I have never heard of anyone doing so either. Although I am interested to see how benzodioxole would fare under the modified Duff conditions, the desired product of the reaction unfortunately illegal where I live Sad

so I won't try it.

Still, I have some comments you may find useful. As benzodioxole is a far less stable molecule than indane, you cannot simply apply a reaction which works on indane to benzodioxole.

The first formylation method you mention will not work when applied to benzodioxole, at least at room temperature. SnCl4 is a powerful Lewis acid and will preferentially cleave the dioxole ring. Using a lower temperature, perhaps -40C or so, should allow you to get away with formylation instead of trashing your precious substrate. This advice is based on my failure to acylate benzodioxole using propionyl chloride/SnCl4 at 0C. I have references which detail similar reactions being performed successfully at lower temperatures.

I don't know whether the fragile dioxole ring will survive the 12 hour reflux in trifluoroacetic acid. If you take a look at the article I adapted the Duff formylation of indane from, http://rhodium.moppy.net/www.rhodium.ws/chemistry/formylation.duff-hmta-tfa.html, you will see that a low yield of 6-formyl-1,4-benzodioxane (the paper calls this 4'-formylbenzo(1,4)dioxane) is recovered when the reaction is performed on 1,4-benzodioxane. Compounding the problem is the acetal-like structure of 1,3-benzodioxole. Acetals readily hydrolyse in acid (at least when water is present), so I would not be at all surprised to find that the hydrolysis dominates to such an extent that catechol is the only product observed. But please, try it and let us know. Perhaps it will work with anhydrous TFA.

The two step bromination/Bouveault aldehyde synthesis is the only method of the three I expect to go without a hitch. The bromation of benzodioxole works reasonably well using molecular bromine, but there are better methods. With molecular bromine and using DCM as solvent with cooling to 0C, dibromination is an unavoidable side-reaction and the yield of 5-bromobenzodioxole is about 70% (if my memory serves me correctly). If I did this again, I would try an oxidative bromination using a bromide salt, acid, and a suitable oxidant. Either the method posted by Nicodem at the Hive for the bromination of 1,4-dimethoxybenzene, the method using ammonium bromide and H2O2 (http://rhodium.moppy.net/www.rhodium.ws/chemistry/aromatic.bromination.nh4br-h2o2.html), or the route outlined in http://rhodium.moppy.net/www.rhodium.ws/chemistry/oxone.aromatic.bromination.html should work nicely.

The Grignard reaction to make 3,4-methylenedioxyphenylmagnesiumbromide is not particularly easy to initiate. If you take all the usual precautions, however, the reaction should initiate in refluxing THF. I used the Grignard I prepared in this way to make some 1-(1,3-benzodioxo-5-yl)-1-propanone (adding dropwise to propionyl chloride). For the aldehyde, you should add dry DMF to the freshly prepared Grignard reagent. This will almost certainly lead to a better yield than the 69% I reported; note the forerun of indane which is at least in part due to the wet DMF which was used straight from the bottle.

The indane formylation page, which was originally a post at the Hive, is only archived on the most recently updated Rhodium mirrors. It was oringinally uploaded to Rhodium's page late last summer.