-------------------------------------------------------------------------- TMA-2 from Calamus oil: Oxidation of asarone via Wacker Oxidation -------------------------------------------------------------------------- This is a repeat of what I wrote under "TMA-2 from Calamus Oil", an idea that no one responded to. Asarone can probably be used in the Wacker oxidation just as isosafrole can. The expected yield of the P2P is about 66%, with the P1P derivitive being the only contaminant in abut 18% yield -- with their being no internal alkene anywhere! How do I know this? Well, in the article by Jiro Tsuji, et. al., entitled "A Palladium Catalyzed Conversion Of Halohydrins To Ketones" pulished in Tetrahedron Letters, vol. 23, no. 30, pp 3085-3088, 1982 is a new synthesis of various 1-ketones using palladium acetate and another exotic catalyst to effect what I guess is the rearrangement of a 1,2-halohydrin to form the ketone product. On the last page of the article is an interesting diagram with information which illustrates several reactions schemes. The first is the quantitative formation of the 1,2-halohydrin from isosafrole -- yes, they fucking used ISOSAFROLE as their example -- which is then rearranged to the 1-ketone in 75% yield. The second illustration is the one of particular interest, because it uses the standard Wacker oxidation to try and achieve the same goal falling short of expectation yielding 18% of MD-P1P and 66% of MD-P2P. (Awe! How absolutely fucking terrible for the researchers -- but not for us bees!) The third and last reaction is an oxidation of isosafrole using m-chloro perbenzoic acid to form the intermediate epoxide, which is then rearranged to the final MD-P2P via some boron triflouride reagent I'm not familiar with to yield MD-P2P in 69% yield. Well, it seems to me that if isosafrole can be oxidized to MD-P2P efficiently using the Wacker reaction, I see no reason why asarone cannot be made to do the same to produce its respective P2P. This may indeed be the boon for those wiching to synthesize TMA-2. After making the P2P, aminating it via sodium cyanoborohydride/ammonium acetate should be a snap! And remember, TMA-2 is about 3 times more potent than MDA, yielding in a sense, more product for less precursor! Furthermore, I don't believe that Calamus Oil has at this point the same scrutiny that Sassafras oil does. Those of you bees reading this, start to stock up and lets get some dreams posted! -------------------------------------------------------------------------- I happened to have two significant references to the above post: 1. "One-Pot Two-Steps Synthesis Of 1,2-Diol" - Syn. Comm., 19, 1939 (1989). The authors used propenyl benzene as one of their examples: To a stirred dispersion of propenylbenzene (3.0.10-3 mole) in distilled water (20 ml) the powdered m-chloroperbenzoic acid (3.3.10-3 mole) was added in small portions over a period of 5-10 min. At 0degC the mixture was stirred at 20degC for 1hr. If so desired, epoxide could be rearranged with the BF3 reagent as indicated in the first post, or, the reaction above could be continued by adding 10% H2SO4 (0.5 ml) and allowing the mixture to stand (stir?) for 4 hr. at 100degC. Solid NaOH is then added until the solution becomes limpid. The aqueous solution is saturated with NaCl and then extracted three times with ethylacetate. The extracts are dried and the solvent removed under reduced pressure. The crude diol is crystallized by ethylacetate or by 1:1 mixture of ethyl ether - n-pentane. The diol can then be dehydrated by any number of methods, the typical one being reflux for 2-3 hrs with 15-20% H2SO4. A few other references to effect the same transformation are more obscure but included here anyway: J Pharm Soc Jpn. 74, 975 (1954) J Assoc Off Anal Chem. 61, 951 (1978) An example of the reaction delineated in the two above references is provided in the experimental details of J.O.C 1984, 49, 1830-1832 "Electrochemical Proceedure for a Practical Preparation of Piperonal From Isosafrole" in which they prepare the 1,2-diol and the 1,2-halohydrin through an electro- chemical process. Anyway, here's there method of dehydrating the diol: A solution of the 1,2-diol (from isosafrole; 100mg, 0.5mmol) and p-TsOH (200mg) dissolved in a distilled benzene (20ml) was refluxed for 20 min. The usual workup gave MD-P2P (75mg, 84%). The same article presents two other references to effect the same reaction: The first is the Tetrahedron Letters article mentioned in the initial post. The second is Tetrahedron Letters, vol. 24, no. 28, pp 2857-2860, 1983. "Electrogenerated Acid As A Powerful Catalyst For The Transformation Of Epoxides To Ketones And Acetonides". Isosafrole-epoxide forms MD-P2P in 82% yield. The 1,2-halohydrins of isosafrole mentioned in the first post are formed quantitatively from N-bromosuccinimide, dimethylsulfoxide, water and isosafrole. The references are JACS, 90, 5948, (1968) and... Shit! I'm here staring at the Organic Syntheses article and there is no information on it that indicates where it can be found! I know that it isn't in the first three collective volumes. The article, however, is titled "Bromohydrins From Alkenes And N-Bromosuccinimide In Dimethylsulfoxide: erythro-2-Bromo-1,2-Diphenylethanol" and uses propenylbenzene as one of its examples. The final yield of bromohydrin was 92-95% Following is the experimental details: A 500ml, round-bottom flask equipped with a magnetic stirring bar and a thermometer is charged with 18g (100mmol) of (E)-stilbene (Note 1), 5ml (28mmol) of water, and 300ml (4.23 mole) of dimethylsulfoxide (DMSO) (Note 2). The resulting suspension is stirred for five minutes at room temperature (20-25degC)(Note 3). Stirring is continued as 35.6 g (200mmol) of N-Bromo- succinimide (NBS) (Note 4) is added in small portions over calculated 10 min. A yellow color appears when the first portion of NBS is added, and by the time the addition is complete, the solution is bright orange. During the addition the temperature of the mixture rises to 50-55°C, and all of (E)-stilbene dissolves. The contents of the flask are stirred for antoher fifteen minutes and poured into 1L of ice water; the product separates immediately as a white solid (Note 5). The aqueous slurry is transferred to a separatory funnel with the aid of 50ml portions of water and diethyl ether, and extracted with four 200ml portions of ether. The combined ethereal extracts are washed with 250ml of water and 250ml of sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated with a rotary evaporator at a water bath temperature of calculated 30°C. The pale yellow, crystalline residue is dissolved, to the extent possible, in 600ml of hot hexane, and the resulting suspension is filtered while hot, removing a small amount of insoluble impurity. Cooling the filtrate provides colorless fibers of analytically pure erythro-2-bromo-1,2-diphenylethanol, m.p. 83-84°C (Note 6); a second crop of crystals is obtained by concetrating the mother liquor to 200ml (Note 7). The combined yield is 22-24.9g (80-90% of theoretical) Keep in mind that to get the 1,2-bromohydrin of isosafrole, one has to use isosafrole in place of (E)-stilbene in the above experiment. NOTES: 1. Not applicable. Information is about where one can purchase (E)-stilbene. 2. Reagent Grade dimethylsulfoxide was used without purification. The amount of dimethylsulfoxide can be varied. A large excess is employed in this case to facilitate dissolution of the stilbene. This may or may not be applicable to isosafrole. Reagent grade DMSO may also not be required in this reaction. Technical grade can easily be obtained in pint amounts at feed stores that cater to those who raise horses and cattle. It is used medicinally as a topical agent for introducing drugs more easily through skin absorption. Cost is about $10.00 or less. It is there available on the shelf as DMSO. Note 3. The suspension may be warmed to dissolve the alkene more rapidly. If the suspension is warmed, it MUST be cooled below 30øC before proceeding further to prevent a vigorous reaction when the NBS is added. The submitters recommend that the warm suspension be cooled under an atmosphere of nitrogen. Note 4. Recommendations are given on purifying the NBS. Recrystallize from 10 times its weight in water. Probably not necessary though. Solutions of NBS in DMSO cannot be stored, since the solvent is oxidized by the brominating reagent. Note 5. The product does not appear to deteriorate if allowed to stand at this point. Note 6. The submitters recrystallized the product from 600ml of petroleum ether. Note 7. The submitters found that the residue (2.8g) obtained upon evaporation of the mother liquor was largely the end product contaminated with a small amount of succinimide. --------------------------------------------------------------------------