No direct synthesis of safrole has been recorded. The most recent attempt was made by Baker and Robinson (JCS, 1925, 127, 1424). They distilled the product of the action of silver oxide and water upon gamma-piperonylpropyltrimethylammonium iodide, but ended up obtaining isosafrole instead. In isosafrole, the double bond moves into the position of greater stability. Kawai (Sci. Papers Inst. Phys. Chem. Res., 1925, 3, 263) demonstrated that the monoallyl ether of pyrocatechol undergoes the Claisen rearrangement. This rearrangement results in an oil that he believed to be a mixture of 3- and 4-allyl-1,2-dihydroxybenzene.
The investigation has resulted in the isolation of both isomerides in a pure state. These isomerides are colorless, crystalline solids with melting points of 28°C and 48°C, respectively. The properties of the higher-melting isomeride align with those previously assigned to “4-allylbrenzcatechin,” which was obtained in small quantity from betel-leaf oil from Java. The second isomeride, 1,2-dihydroxy-3-allylbenzene, has not been described before. In order to convert these substances into safrole and o-safrole, methylenation was conducted by refluxing them gently with methylene iodide and anhydrous potassium carbonate in dry acetone solution. These mild conditions prevented any transformation into isomeric isosafroles during the reaction.
The synthetic product that is chemically similar to naturally occurring safrole was identified by creating a pentabromo-derivative (melting point 169°C) and an acetamido-derivative (melting point 162-163°C) and comparing them to the same derivatives obtained from natural safrole. The properties of a previously unknown isomeride called o-safrole (IV) were also documented. This isomeride has a similar odor and shares many other characteristics with safrole. The process of methylenation described earlier proceeds smoothly without the formation of undesirable tarry substances, making it potentially useful in other similar cases. Experimental details: Production of mono- and diallyl ethers of pyrocatechol.
In a flask, Pyrocatechol (132 g) and pure allyl bromide (144 g) were mixed with pure dry acetone (220ml). The mixture was finely powdered and freshly heated potassium carbonate (170 g) was gradually added with constant shaking. The entire solution was then refluxed for 6-8 hours on a water-bath. The condenser was fitted with a calcium chloride tube, following the method in Kawai’s study. After removing the acetone, water and dilute sulphuric acid were added, and the solution was extracted with ether. The extract was washed with dilute alkali solution to remove the monoallyl ether and unchanged pyrocatechol. The ethereal solution was dried with anhydrous sodium sulphate and then evaporated.
The yield of pure diallyl ether was 43 g (boiling point 124-125.5°C at 13mmHg). The alkali washings were immediately made acidic and the oil was dissolved in chloroform. After being washed multiple times with water to remove pyrocatechol, the chloroform was evaporated and the oil was distilled. This process resulted in 90g of pure monoallyl ether, with a boiling point of 107.5-109°C at 15mmHg. The yields of both ethers were significantly higher than those reported by Kawai under similar conditions. The occurrence of molecular rearrangement is noted.
The monoallyl ether (92 g) was heated in a flask, equipped with a ground-in condenser, in a paraffin bath at 170-180°C. Suddenly, the inner temperature increased to 265°C, causing momentary boiling. The color of the liquid changed to red. Once cooled, the product was fractionated under 15-16 mmHg. Two fractions were collected: one with a boiling point (bp) range of 142-152°C (66.2g) and the other with a bp range of 152-160°C (17.2g). A non-volatile residue (9g) that was resinous in nature remained. Upon standing, the second fraction turned solid and primarily consisted of 1,2-dihydroxy-4-allyl benzene. The melting point of this compound was 40-41°C after previous softening.
Kawai observed the formation of crystals in his higher fraction (bp 155-160°C/16 mmHg) and posited that they were caused by pyrocatechol, which was released during the rearrangement (compare Claisen, Annalen, 1913, 401, 21). However, no pyrocatechol was found in this particular instance, suggesting that the crystals were those of 1,2-dihydroxy-4-allylbenzene. Through repeated systematic refractionation of the aforementioned two fractions, both isomerides were isolated in a pure state. The ratio of 1,2-dihydroxy-3-allylbenzene to its isomeride in the rearranged product was approximately 5 to 4. 2-Dihydroxy-4-allylbenzene (II) is a colorless, waxy crystalline solid that can dissolve in water and most other solvents but has limited solubility in petroleum. It forms colorless needles with a melting point of 48°C when recrystallized from benzene-light petroleum and boils at 147-149°C/10mmHg and at 156-158°C/16mmHg.
The dibenzoyl derivative, which is known as the Schotten-Baumann, forms colorless prisms when separated from light petroleum. Its melting point is 71°C. These characteristics clearly indicate that the substance is the same as the “allylbrenzcatechin” found in Java betel-leaf oil. The 1,2-dihydroxy-3-allylbenzene (I) can be purified best through distillation under reduced pressure. It has a boiling point of 143-145°C/15 mmHg. When allowed to crystallize slowly, it forms large, colorless, flat prisms with a melting point of 28°C. However, it tends to remain in a liquid state below this temperature, making it difficult to recrystallize satisfactorily. It readily dissolves in most solvents except petroleum and is not as soluble in water as its isomeride. It shares a phenolic odor with its isomeride and in an aqueous solution, it produces an olive-green color when reacted with ferric chloride, which changes to wine-red upon the addition of sodium carbonate. Additionally, the dibenzoyl derivative separates from light petroleum in colorless prisms with a melting point of 60-61°C.
A mixture of Safrole (III) 1,2-Dihydroxy-4-allylbenzene (10 g) and methylene iodide (18 g) was dissolved in pure dry acetone (35ml). Finely powdered, freshly ignited potassium carbonate (20g) was gradually added with shaking to prevent caking. The mixture was gently refluxed on a water-bath for 12 hours. The acetone was then removed and the resulting product was made acidic with dilute sulphuric acid. It was then extracted with ether and the ethereal solution was washed multiple times with dilute aqueous sodium hydroxide, followed by water. The solution was dried over sodium sulphate and evaporated. When the residue was carefully distilled under reduced pressure, methylene iodide passed off first. After complete removal of methylene iodide, a fraction consisting of 2.5 g of a clear, colourless oil was collected. This oil was identified as safrole based on its characteristic odour. To further confirm its identity, its pentabromo-derivative was prepared by gradually adding excess bromine below 0°C and allowing the mixture to stand for several hours. The solid substance that separated out melted at 169°C after recrystallization from ethyl alcohol. A mixed melting point determination with the derivative prepared from ordinary safrole showed no depression.
The oil had an nD20 of 1.5381. As further evidence of its identity, 1.35 g of the synthetic substance were subjected to nitration using the conditions specified by Foulds and Robinson (JCS, 1914, 105, 1963). The resulting nitro-derivative was then reduced using tin and hydrochloric acid. The crude 6-aminosafrole was subsequently acetylated and the acetyl derivative was obtained as colorless needles by crystallization from methyl alcohol. It exhibited a melting point of 162-163°C, and a mixed melting-point determination with the corresponding derivative from naturally occurring safrole showed no depression. To synthesize o-Safrole (IV) ,2-Dihydroxy-3-allylbenzene (20 g), methylene iodide (36 g), potassium carbonate (40 g), and acetone (70ml) were gently refluxed for 14 hours. The resulting product was treated in a similar manner as described above in the synthesis of safrole. Methylene iodide was then removed under reduced pressure, and the portion boiling over 1.5°C was collected separately, yielding 7g.
The o-safrole was redistilled and collected at 102. 5-103°C/13mmHg. It has different boiling points at different pressures: 106-107°C/16mmHg and 226-227°C/762mmHg. o-Safrole is a clear, liquid oil that does not crystallize at -20°C and has a refractive index of 1.359. Its odor is pleasant, similar to safrole but not as strong (compare the odors of o-piperonal and piperonal; Perkin and Trikojus, JCS., 1926, 2927). When excess bromine is added to cooled o-safrole below 0°C, a vigorous reaction occurs. The resulting product solidifies overnight, is washed with ethyl alcohol, and crystallized from the same solvent, in which it is only slightly soluble. The resulting pentabromo-derivative forms colorless prisms with a melting point of 154°C, and the yield is almost complete.
