This
file is a part of the Rhodium site archive. This Aug 2004 static snapshot is
hosted by Erowid
as of May 2005 and is not being updated. > >
Back to Rhodium Archive Index > >

[www.rhodium.ws] ☯
[Chemistry
Archive]

A Synthesis of Safrole and o-Safrole

W.H. Perkin & V.M. Trikojus
J. Chem. Soc. 1663 (1927)

HTML by Rhodium

No direct synthesis of safrole has been recorded, the most recent attempt
being that of Baker and Robinson (JCS, 1925, 127, 1424), who distilled
the product of the action of silver oxide and water upon
gamma-piperonylpropyltrimethylammonium iodide, but obtained isosafrole, the
double bond moving into the position of greater stability. Kawai (Sci.
Papers Inst. Phys. Chem. Res., 1925, 3, 263) has shown that the monoallyl
ether of pyrocatechol undergoes the Claisen rearrangement to give an oil which
he considered to be a mixture of 3- and 4-allyl-1,2-dihydroxybenzene.

This matter has now been reinvestigated and, by repeated fractionation of the
product of the rearrangement, both of the above isomerides have been isolated in
a pure state as colourless, crystalline solids melting at 28°C and 48°C
respectively. As further confirmation of the course of the Claisen migration, it
has been found that the properties of the higher-melting isomeride
(II) are in accord with those assigned to the
"4-allylbrenzcatechin" which Schimmel and Co. (Centr., 1907, II, 1741)
isolated in small quantity from betel-leaf oil from Java. The second isomeride,
1,2-dihydroxy-3-allylbenzene (I), has not previously been
described.

In order to convert these substances into safrole (III) and
o-safrole (IV), respectively, methylenation was carried out,
with moderately good yields, by gently refluxing them with methylene iodide and
anhydrous potassium carbonate in dry acetone solution. By employing such mild
conditions, any change into the isomeric isosafroles during the course of the
reaction was inhibited. The identity of the synthetic product with naturally
occurring safrole has been established by preparing the pentabromo-derivative
(mp 169°C) and the acetamido-derivative (mp 162-163°C) and comparing these with
the same derivatives from natural safrole. The properties of the hitherto
unknown isomeride o-safrole (IV) (which resembles safrole in
odour and in many other ways) have been recorded. The process of methylenation
described above takes place very smoothly without formation of tarry products
and may prove to be valuable in other cases of this kind.

Experimental:

Mono- and Diallyl Ethers of Pyrocatechol

Pyrocatechol (132 g) and pure allyl bromide (144 g) were dissolved in pure
dry acetone (220ml), finely powdered, freshly heated potassium carbonate (170 g)
was added gradually with constant shaking, and the whole refluxed for 6-8 hours
on the water-bath, the condenser being fitted with a calcium chloride tube
(compare Kawai, loc. cit.). After removal of the acetone, addition of
water and dilute sulphuric acid, and extraction with ether, the monoallyl ether
and unchanged pyrocatechol were removed by washing the extract with dilute,
alkali solution, and the ethereal solution was then dried with anhydrous sodium
sulphate and evaporated. The yield of pure diallyl ether was 43 g (bp
124-125.5°C/13mmHg). The alkali washings were immediately acidified and the oil
was taken up in chloroform. After being repeatedly washed with water to remove
pyrocatechol, the chloroform was evaporated and the oil distilled, yielding 90g
of pure monoallyl ether, bp 107.5-109°C/15mmHg. The yields of both ethers were
considerably higher than those recorded by Kawai under almost analogous
conditions.

Molecular rearrangement

The monoallyl ether (92 g) was heated in a flask, fitted with a ground-in
condenser, in a paraffin bath at 170-180°C, the inner temperature suddenly rose
to 265°C with momentary boiling, the colour of the liquid changing to red. After
cooling, the product was fractionated under 15-16 mmHg and fractions, bp
142-152°C (66.2g) and 152-160°C (17.2 g), were collected, leaving a resinous,
non-volatile residue (9 g). The second fraction solidified on standing and
consisted chiefly of 1,2-dihydroxy-4-allyl benzene, melting at 40-41°C with
previous softening. Kawai noticed the formation of some crystals in his higher
fraction (bp 155-160°C/16 mmHg) and suggested that they were due to pyrocatechol
which had been set free during the rearrangement (compare Claisen, Annalen,
1913, 401, 21). In the present instance, however, no pyrocatechol was observed
and it is probable that his crystals were those of
1,2-dihydroxy-4-allylbenzene.

After repeated systematic refractionation of the above two fractions, both
isomerides were isolated in a pure condition, the proportion of
1,2-dihydroxy-3-allylbenzene to its isomeride in the rearranged product being
approximately 5 to 4. 1,2-Dihydroxy-4-allylbenzene (II) is a
colourless, waxy, crystalline solid soluble in water and most other solvents,
but sparingly soluble in petroleum. It forms colourless needles, mp 48°C, from
benzene-light petroleum and boils at 147-149°C/10mmHg and at
156-158°C/16mmHg.

The dibenzoyl derivative (Schotten-Baumann) separates from light petroleum in
colourless prisms, mp 71°C. These properties clearly indicate that the substance
is identical with the "allylbrenzcatechin" isolated from Java betel-leaf oil
(loc. cit.). 1,2-Dihydroxy-3-allylbenzene (I) is best
purified by distillation under reduced pressure and has bp 143.5--145°C/15 mmHg.
If allowed to crystallise slowly, it separates in large, colourless, flat
prisms, mp 28°C, but it has a tendency to remain liquid below this temperature.
Owing to this property, it was not found. possible to recrystallise it
satisfactorily. It dissolves readily in most solvents except petroleum, whilst
in water it is not as soluble as its isomeride.

It resembles its isomeride in having a phenolic odour and in aqueous solution
it gives with ferric chloride an olive-green colour, changing to wine-red on
addition of sodium carbonate. The dibenzoyl derivative separates from light
petroleum in colourless prisms, mp 60-61°C.

Safrole (III)

1,2-Dihydroxy-4-allylbenzene (10 g) and methylene iodide (18 g) were
dissolved in pure dry acetone (35ml) and finely powdered, freshly ignited
potassium. carbonate (20g) was gradually added with shaking to prevent caking.
After gently refluxing on the water-bath for 12 hours, the acetone was removed,
the product was made acid with dilute sulphuric acid and extracted with ether,
and the ethereal solution was repeatedly washed with dilute aqueous sodium
hydroxide and finally with water, dried over sodium sulphate, and evaporated. On
carefully distilling the residue under reduced pressure, methylene iodide first
passed over; when this had been completely removed, a fraction, bp
100-101.5°C/10-11mmHg, consisting of 2.5 g. of a clear, colourless oil, was
collected. This was identified as safrole by its characteristic odour and by
preparing its pentabromo- derivative by gradually adding excess of bromine below
0°C and allowing the mixture to stand for some hours; the solid substance which
had separated, after recrystallising from ethyl alcohol, melted at 169°C, and a
mixed melting point with the derivative prepared from ordinary safrole showed no
depression. The oil had nD20 1.5381. As an additional
proof of identity, 1.35 g of the synthetic substance were nitrated under the
conditions laid down by Foulds and Robinson (JCS, 1914, 105, 1963), the
nitro-derivative was reduced with tin and hydrochloric acid, and the crude
6-aminosafrole acetylated; the acetyl derivative crystallised from methyl
alcohol in colourless needles, mp 162-163°C, and a mixed melting-point
determination with the corresponding derivative from naturally occurring safrole
showed no depression.

o-Safrole (IV)

1,2-Dihydroxy-3-allylbenzene (20 g), methylene iodide (36 g), potassium
carbonate (40 g), and acetone (70ml) were gently refluxed for 14 hours, and the
product was treated in a manner similar to that described above in the synthesis
of safrole. Methylene iodide was removed under reduced pressure, and the
remainder (boiling over 1.5°C) collected separately. Yield 7g. It was
redistilled and collected at 102.5-103°C/13mmHg. It boils at 106-107°C/16mmHg
and at 226-227°C/762mmHg.

o-Safrole is a colourless, mobile oil which does not crystallise at -20°C and
has n20D 1.5359. It has an agreeable odour, similar to, but not so pronounced
as, that of safrole (compare the respective odours of o-piperonal and piperonal;
Perkin
and Trikojus, JCS., 1926, 2927). On the addition of excess of bromine to
o-safrole cooled below 0°C, a vigorous reaction occurs ; the product, which
solidifies on standing over-night, is washed with ethyl alcohol and crystallised
from the same solvent, in which it is only sparingly soluble. The resulting
pentabromo-derivative separates in colourless prisms, mp 154°C, and the yield is
almost quantitative.