Isomerization of safrole

Isomerization of safrole and eugenol is reported to occur when these alkenes are irradiated in the presence of iron carbonyls. Co-ordinatively unsaturated iron carbonyls are first formed and subsequently give iron carbonyl-alkene complexes whose alkene ligands are then isomerized. A further reported photoinduced isomerization involves Fe(fnb-Ti -cot)(CO)3 (cot = cyclo-octatetraene), which on irradiation in a CH4 matrix at 12 K is converted into Fe(cfiair-Ti -cot)(CO)3 via Fe(T -cot)(CO)3 as intermediate. The results of these studies are related to the fluxional behaviour of Fe(i7 -cot)(CO)3 in solution. ... 

Isomerization Isomerization of safrole to isosafrole, of 2,3-dimethyl-1-butene and of 3,5-vinylbicyclo[2.2.1]heptene Isomerization of 1,2-propadiene to propyne Na/NaOH/AljO, K2O/AI2O3... 

Table 5. Comparative methods for base-catalyzed isomerization of safrole...

Isomerization of safrol to isosafrol proceeds at 300 K over Na/NaOH/Al203[6]. 

As described above, however, some rather small differences could appear, taking into account the superheating effect of the solvent under the action of microwaves in the absence of any stirring. This probably occurs in the isomerization of safrole and eugenol in ethanol under reflux (MW 1 h compared with A 5 h to obtain equivalent yields) [53]. 

Isomerization of safrole to isosafrole was realized in the same way by use of KOtBu/Aliquat under solvent-free conditions and exposure to MW (Eq. 63) [88],... 

My own experience with this reaction dates to the early 80s, when I decided to torment myself by trying it. Detailed cooking procedures using it can be found in Pikhal under MDMA. My experience with the KOH isomerization was that the conversion of safrole to isosaffole went cleanly at about 100% yield, as long as traces of moisture were excluded from the reaction. The conversion of isosafrole to methylenedioxy-phenylacetone is another matter. The yields are low, a lot of work is required because the formic acid and hydrogen peroxide must be removed from the reaction mixture under a vacuum before final treatment with sulfuric acid solution to yield the phenylacetone, and these vapors corrode the aspirator supplying the vacuum. This method stinks ... 

The phenolic primary alcohols derived in this way from phenylalanine (Phe, F) and in some systems from tyrosine (Tyr, Y) are incorporated into structural plant materials by linking carbohydrates (Chapter 11) together to form Ugnins. The same alcohols give rise to phenylpropenes, such as eugenol and safrole, which are commonly referred to as essential oils, while further oxidation and double-bond isomerization of p-coumaric acid leads to umbeUiferone (Figure 12.6). 

Figure 12.6. The phenylpropenes, eugenol and safrole ( essential oils ), and the lactone umbeUiferone, generated on oxidation (and double-bond isomerization) of p-coumaric acid.

What happens when isomerization is performed is that the double bond of the allylbenzene safrole migrates to the more energetically favorable position between the alpha and beta carbons of the propyl side chain. Thus isosafrole, a propenylbenzene, is born. 

To isomerize safrole to isosafrole one would like to have pure safrole to start with. This, usually, is not the case. Quasi-pure safrole from sassafras oil is ok. Straight-up sassafras oil is probably ok too, though not recommended. The safrole is then refluxed (boiled under a condenser) in a saturated KOHyethanoI solution for about a day and that s it. The temperature of reflux is about 120-140°C owing to the fact that the ethanol (usually boiling around 65-70°C) is saturated with the halide salt. 

The solvent is then washed 3 x 50mL dH20 and, if desired, can be washed once with lOOmL saturated NaCI solution. Finally, the solvent is dried through Na2S04, removed by vacuum distillation, and the first 5 to 10mL of oil that distills over is saved because it is isomerized safrole (iososafrole), which is suitable for reuse. The rest of the oil that comes over will be the ever lovely MD-P2P, which is perfectly suitable for amination by any method given in this book. 

An overview of the reactions over zeolites and related materials employed in the fields of refining, petrochemistry, and commodity chemicals reviewed the role of carbocations in these reactions.15 An overview appeared of the discovery of reactive intermediates, including carbocations, and associated concepts in physical organic chemistry.16 The mechanisms of action of two families of carcinogens of botanical origin were reviewed.17 The flavanoids are converted to DNA-reactive species via an o-quinone, with subsequent isomerization to a quinone methide. Alkenylbenzenes such as safrole are activated to a-sulfatoxy esters, whose SnI ionization produces benzylic cations that alkylate DNA. A number of substrates (trifluoroacetates, mesylates, and triflates) known to undergo the SnI reaction in typical solvolysis solvents were studied in ionic liquids several lines of evidence indicate that they also react here via ionization to give carbocationic intermediates.18... 

Safrol, eugenol methyl ether, apiol and isoapiol yield a mixture of two isomeric acetates, one of which is crystalline, the other syrupy. 

The different solvent-free techniques have been compared during safrole iso safrole isomerization (Table 5). Solvent-free PTC requires by far the least drastic conditions and only a stoichiometric equivalent amount of base. The use of a very strong base (KOtBu) means that the catalyst can be removed and an identical result can be achieved by increasing the time from 5 min to 3 h at 80°C... 

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