Has psychokitty won the OTC safrole contest? I think so, my fellow bees.
It's been almost two years since this problem first reared it's ugly head. Many suggestions were made but none seemed to offer any hope of going directly from eugenol to safrole in at least two easy steps. Some of the more notable methods offered can be found on Rhodium's page (most of them from psychokitty and Rev. Drone).
At first, it seemed like eugenol or isoeugenol would offer the best starting point to get to safrole via MVK (MethylVanillylKetone) by way of the wacker on eugenol or the performic on isoeugenol. SWIMM managed to isomerize eugenol to isoeugenol in a novel efficient way utilizing KOH and a PTC (details also on Rhodiums page) but found that application of the modified performic on isoeugenol only served to waste alot of chemicals (SWIMM got back practically all of his starting isoeugenol from the mix). At first, SWIMM assumed the hydrogen peroxide to be at fault but when it was used in another performic reaction using isos_frole as the starting material, all went well. So regarding this problem, SWIMM is still swimming in the theoretical pool looking for answers. Any suggestions, fellow bees?
Anyway, although there are patented proceedures for carrying out the performic on isoeugenol, the yields and excessive mess factor really discourage SWIMM from pursuing them as possible ways to MVK. As for the wacker, a CA reference which kitty has indicates that low yields (30%) were obtained when eugenol was reacted with O2 and PdCl2-CuCl2 under various conditions. The nitrite wacker DOES work on eugenol to get MVK (80%) as indicated in the original US patent, but neither kitty nor SWIMM has never tried it and to his knowledge no one else has either. Either way, the problem of ether cleavage was still present whether one used eugenol, isoeugenol, or MVK as a starting point to get to the 3,4-dihydroxyphenyl compound.
Sooooooo, when the OTC safrole contest was in effect, LOTS of us (LOTS!!)contributed many interesting and potentially useful articles detailing many interesting and potentially useful ways to cleave that methoxyl group on the three position of eugenol. Pyridine hydrochloride, HCl, HBr, HI (alone or with a PTC), KOH, NaOH, alkaline earth metals in either alcohol or polar-aprotic solvents, AlCl3, AlBr3, AlI3, iodotrimethylsilane, chlorotrimethylsilane and NaI, boron tribromide, boron tricholide, and even boron tiflouride etherate were suggested as potential cleaving agents. Yet none of the articles ever used eugenol, isoeugenol, or MVK as the subject of their proceedures. Way back when, Drone used his Crossfire account to search for possible leads. Even so, to this cat's knowledge, no one has found a published proceedure detailing the synthesis of allylpyrocatechol from eugenol, or even propenylpyrocatechol from isoeugenol, or 3,4-dihydroxyphenylacetone from MVK . . . until now.
Before the OTC safrole synthesis contest, our beloved Rhodium had created a thread detailing the synthesis of protocatechualdehyde from vanillin using AlCl3, pyridine and DCM as solvent. He claimed that from what he had read of the article, he could see no reason why the same reaction couldn't be applied to eugenol. Well, browsing through kitty's stack of papers the other day, kitty came across a copy of Rhodium's thread. Only two bees had responded to it, and then, not suprisingly, the subject was quietly forgotten and the thread closed.
Wanting to know what Rhodium meant by "from what I have read of the article" kitty decided to hop over to the local library where they keep copies of JOC, and take a look at the article itself.
Here is the important stuff, basically what Rhodium reported about two years ago:
Protocatechualdehyde. -- Anhydrous aluminum chloride (9.7 g., 0.0724 mole) was suspended in a solution of 10 g. (0.0658 mole of vanillin in 100 ml of methylene chloride in an apparatus protected from atmospheric moisture. While stirring briskly and cooling to maintain the temperature at 30-35 deg C, 22.9 g (0.290 mole) of pyridine was added slowly. The reaction was vigorous; the resulting clear, light orange solution of the reaction complex was heated to reflux (45 deg C) and maintained at that temperature while stirring for 24 hrs. The solution, which had darkened only slightly during the reflux period, was cooled to 25 deg C and the product hydrolyzed, while stirring and maintaining the temperature at 25-30 deg C, by the addition of dilute (15-20%) hydrochloric acid until the mixture was definitely acidic to Congo Red indicator. Of the two phases present at this time, the lower methylene chloride layer contained most of the unchanged vanillin and essentially no protocatechualdehye; the latter was dissolved in the aqueous phase. Evaporation of the methylene dichloride solution yielded 0.8 g of vanillin. Extraction of the aqueous phase with ether followed by evaporation of the ehter left 7.9 g (87%) of pale yellow crystals of protocatechualdehyde melting at 153-154 deg C.
Not bad considering that the reaction is mild, the reagents are cheap, readily available, unwatched (except maybe pyridine), and recyclable. No harmful byproducts (such as MeBr) are formed and the proceedure is simple enough for even the most pathetic of bees. And, of course, it's always good that the yields are high.
Buuuut, the article didn't mention the use of any alkenyl precursors (i.e., eugenol) but did offer hope for MVK since 3-methoxy-4-hydroxy-acetophenone was used in the reaction yielding 3,4-dihydroxyacetophenone in 70% yield.
So, your favorite kitty went looking for other hopeful cleaving agents. Some of the more notable are the boron trihalide-dimethylsulfide complexes which are stable and can be safely handled at room temperature. This might give some hope to Drone's initial plan to apply boron tribromide as an efficient reagent for ether cleavage of eugenol. Anyway, here's the reference: Tetrahedron Letters 1980, 21, 3731.
Feeling a little discouraged, kitty decided to search the CA volumes. This had been done over two years ago (quite thoroughly) using numerous keywords too numerous to mention here. None, however, yielded any terribly useful proceedures. This time, following Rhodium's lead, kitty searched the index of each year after 1962 using the keyword "protocatechualdehyde" . . . and in volume 60 was found something interesting:
CA vol. 60 2847f
3-Alkylpyrocatechols. Monsanto Chemical Co (by Robert G. Lange). Fr. 1,330,382 (Cl. C 07c), June 21, 1963; U.S. Appl. June 21, 1961; 23 pp. o-Hydroxyphenyl alkyl ethers, which can contain a halogen, a C1-4 alkyl, ALKENYL, or alkoxy group, NO2, SO3H or SH on the ring are hydrolyzed with acids in the presence of a tertiary amine and AlCl3 in an inert org. solvent to give the title compds. Anhyd. AlCl3 (146.8 g) is added to a mixt. of 152 vanillin and 1500 ml of CH2Cl2 under anhydrous conditions, 348.0 g of pyridine added at 30-5 deg C, the mixt. heated 24 hrs. at 44 deg C, cooled to 20 deg C, and hydrolyzed with 15-20% HCl (acid to Congo red), the aq. phase sepd, the aq. mixt. extd. with ether, and the ext. evapd. the give protocatechualdehyde (I), m. 153-4 deg C, 87% yield.
Many other compounds were made, but to kitty, the most interesting one of them all is "3,4-(HO)2C6H3CH2CH:CH2"; namely, allylpyrocatechol from eugenol.
Hah!!! Kitty's won the contest!!! Yip-yip-yippie for the kitty!!!
Actually, Rhodium won, but didn't know it as he never proved his method. Kitty guesses they can both share the $1000 that Strike now owes them ($500 for Rhodium, and from kitty's half, $250 going to Drone as they agreed that through their collaboration, they would split the money; good luck to you Drone, wherever you are).
Honorable mention should go to Cherrie Baby, as she (he?) once offered an article which used AlI3 made in situ from Al and I2 to hydrolyze the methoxyl group of vanillin to protocatechualdehyde in high yield. More than likely, based on the information found in this post, that reaction will probably work on eugenol as well.
NOW, although this method looks ridiculously promising, there is still the issue about yields. Somebee will have to get ahold of the original french patent (or the corresponding U.S. Patent, if there is one) in order to find out just how much allylpyrocatechol one gets from using this oh-so-wonderful-looking reaction.
Comments?
--PK
