Piperonal and Safrole from Vanillin and Eugenol

by Rhodium

Table of Contents
 Table of Contents
 Demethylation Reactions
o Vanillin Demethylation (Pyridine/AlCl3)
o Vanillin Demethylation (Nitrobenzene/AlBr3)
o Eugenol Demethylation with Lithium Diphenylphosphinate
o Eugenol Demethylation with Lithium Chloride in DMF
o Eugenol Demethylation (AlI3)
o Eugenol Demethylation (Pyridine HCl/Microwave)
 Methylenation Reactions
o Methylenation Of Catechols with Dichloromethane
o PTC Methylenation of Catechols
o PTC Methylenation of Protocatechualdehyde
o PTC Methylenation of Catechols
o KF Catalyzed Methylenation of Catechols
 References

Demethylation Reactions
Vanillin Demethylation with Pyridine and AlCl31

Anhydrous AlCl3 (9.7 g, 0.0724 mol) was suspended in a solution of 10g (0.0658 mol) 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°C, 22.9g (0.290 mol) of
pyridine was added slowly. The reaction was vigorous; the resulting clear light orange solution
of the reaction complex was heated to reflux (45°C) and maintained at that temperature with
stirring for 24 hours. The solution, which had darkened only slightly during the reflux period,
was cooled to 25°C and the product was hydrolyzed, while stirring and maintaining the
temperature at 25-30°C, by the addition of dilute (15-20%) HCl 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 small amount of the unchanged vanillin, and essentially no
protocatechuic acid, the latter was dissolved in the aqueous phase. Evaporation of the methylene
chloride yielded 0.8 g of vanillin. Extraction of the aqueous phase with ether followed by
evaporation of the ether left 7.9 g (87%) of pale yellow crystals of protocatechualdehyde melting
at 153-154°C.

Using the cheaper triethylamine in place of pyridine lowered the yield to 61.5%

Vanillin Demethylation with Nitrobenzene and AlBr32

A solution of 15.2 g (0.1 mole) of vanillin in 45 ml of nitrobenzene at 15°C is treated with a

solution of 53.4 g of anhydrous aluminium bromide in 60 ml of nitrobenzene. 125 ml of
nitrobenzene are added to the gel which forms with stirring (do not breath nitrobenzene vapors
or let it in contact with the skin. If contact occurs flush area with water for 15 min). Heat the
solution to 95°C and then let cool to room temperature. Allow to stand at room temperature for
30 minutes. The dark mixture is cooled and added to 1 L of water containing a little HCl. The
mixture is extracted with ether and the ether is then extracted with 5% NaOH. The hydroxide
solution is washed with ether and then acidified with dilute sulfuric acid. The acidic solution is
extracted with ether, dried, and then distilled off to leave ~12.8g (93%) of protocatechualdehyde.

Eugenol Demethylation with Lithium Diphenylphosphinate10

To a solution of 11.5 g (0.07 mol) of eugenol in 30 mL of dry THF was added stepwise 2.1 g
(0.07 mol) of a dispersion of NaH in oil (80%). After the evolution of gas had stopped a solution
of 13.4 g (0.07 mol) of LiPPh2 in 60 mL of THF was added. After stirring for 3 h, 2 mL of water
was added and the mixture was poured into 200 mL of degassed 0.2 N aqueous NaOH. The
yellow solution was washed with ether (4x). and the combined organic layers were extracted
with 100 mL of 0.2 N aqueous NaOH. The combined water layers were acidified with
concentrated HCl to pH 6. The resulting emulsion was extracted with ether, and the organic
layers were washed with water (5x), dried (MgSO4), and evaporated to dryness. Purification by
column chromatography (eluent: 2% MeOH in CHCl3) gave 5.97 g (57%) of a brownish oil
which could be further purified by sublimation. A yield of 3.9 g (37%) of 4-allylcatechol was
obtained as a bright white solid.

Eugenol Demethylation with Lithium Chloride in DMF11

A solution of 354 ml (2.30 mmol) of eugenol and 292 g (6.89 mol) of lithium chloride in 3.7 L of
N,N-dimethylformamide was refluxed for a total of 44 hours (h), and after 4 h, 18 h and then 7 h,
a further 292 g (6.89 mol) of lithium chloride were added each time. After cooling, 2 L of
toluene were added and the resultant precipitate was filtered off with suction and extracted with
toluene. The organic extracts were combined and concentrated on a rotary evaporator. After flash
chromatography (ether/pentane, 1:1, Rf = 0.37) on silica gel, 173 g (50%) of 4-allylcatechol were
obtained.

Eugenol Demethylation with AlI33

Summary: Reflux aluminium powder with iodine in benzene or cyclohexane for 90 min to
produce AlI3. Add equimolar amounts of vanillin, 0.25 eqv PTC (tetrabutylammonium iodide,
chloride may also work), reflux for 20 min, and isolate the protocatechualdehyde (88%)

Aluminum Triiiodide preparation

1 mol Al turnings (or foil or powder all work well, powder is the quickest closely followed by
foil then turnings a distant third) is combind with 1.5mol (note the excess of Al) of Iodine in
1000mL of cyclohexane (exchange solvent as needed but not diethyl ether!). This mix is stirred
under reflux until the red colour has turned to a grey (about 1.5hrs with powder, 2-3 with foil, 4+
with turnngs). At this point the heat is turned off and the AlI3in solvent allowed to cool to room
tempeature with stirring.

Reaction with Eugenol

In a dropping funnel, eugenol (1 mol), tetrabutylammonium iodide (1/360 mol) and a little
cyclohexane are combined. This is slowly dripped into the AlI3/cyclohexane mixture made in the
previous step with vigourous stirring and inert gas sheilding. After all the eugenol has been
added the solution is brought to reflux (it is a tan coloured slurry at this point, but upon refluxing
turns less viscous) for 1 hour. The solution is then cooled in an ice bath and hydrolysed with
~600mL of water, slowly.

The resultant mix is filtered under nitrogen and the solid collected immersed in ethyl acetate, this
is swirled for a couple of minutes, then filtered. The ethyl acetate is seperated from the water
(collected through the filtration) and removed and what you have left is a tan coloured solid with
a charactistic 'smoke' smell and a melting point 45-51°C, althought this range could be tightened
by recrystalisation or vac distillation with hot water in the condenser.

A few notes:

 If you are quick then maybe you can not bother with the inert atmoshpere in the workup,
however the filtering takes a long time (don't even consider using gravity) beacause the
Al is very finely divided and clogs up the filter paper. The use of a filtering aid like Celite
is recommended.
 It seems the reactant ratios are critical so get them right.
  The workup is a shit for large quantities, any suggested impovements would be
appreciated.

Eugenol Demethylation with Pyridine HCl4

Written by Startinout

Basically the microwave demethylation fucking rocks, as far as ease goes, but the downside is
because you need 5:1 pyridine HCl:eugenol.

I made my pyridine HCl by gassing pyridine with anhydrous HCl gas, this was pretty easy (just
gassed it for a while, some crystals formed but it was quite hot so i froze it, many more crystals
formed, filtered it, washed with ether, then put the crystals on the bench to dry, came back,
almost no crystals left and very sloppy, note-they are very deliquescent and they sublime so put
them in a closed container immediately post production.

Experimental

Microwave Demethylation

All I did was added eugenol in the weight ratio five parts pyridine HCl two parts eugenol (this is
molar 5:1), put this in a round bottom flask, stoppered it, microwaved in a normal microwave on
medium low (the paper uses 215 watt oven) for two minutes, the stuff melts and turns quite hot,
it was removed, cooled under the tap until it was room temp again (just felt it with my hand),
then microwaved again for two minutes etc etc, this process was repeated six times, the more you
do it the hotter it gets each time. After the sixth time i cooled it again, poured some cold water
from the fridge into into it and extracted it three times with ether, pooled the ether extracts,
removed the ether on the rotavap, the residue had no smell of clove oil whatsoever, just the
smokey smell of the demethylated product, so i assumed quantitative yeild cause I couldn't be
fucked vac distilling a room temp solid and/or GC'ing it, also the methylation requires an excess
of all other reagants anyway.

Methylenation

So I put in some DMF, some KF and stirred at room temp for 1hr, there is quite a noticable
colour change from light yellow brown to brightish orange red, then i added di-iodo-methane
because I had it but the paper uses dibromo so this should be fine (the paper also uses DCM if
anyone wants to try). The proportion of all these additives are by mole:

 1 mole di-hydroxy stuff

 5 moles KF
  1L DMF/mole di-hydroxy stuff
 1.1 mole Dihalomethane

Anyway after the dihalo (did you know diiodomethane has a density of 3.5g/mL!) stuff is added
the mix is heated to ~120°C for 1.5hr. If you have used DCM or DBrM it will reflux, DIM will
not at this temp). The mix is then cooled, water added then extract with ether, the ether cleaned
with water (to remove DMF), 5% NaOH (to remove any phenols), then the ether is vacuumed off
and the residue vaccum distilled, I added some high boiling paraffin to stop scorching from my
heating/stirring mantle.

My yeild of safrole (confirmed with a library FTIR match) was 30%, which sounds crap but
given

 I had never done it before

 I took heaps of shortcuts
 It all took little more than a morning
 There are heaps of areas where things can be tweaked and made more OTC
 It is reasonablely scaleable

Possible improvements to the above procedure (by Psychokitty)

1. After demethylating the eugenol using pyridine HCl, I would recrystallize the final
product using toluene or petroleum ether. That way you have a better idea just how good
or bad your yields are.
2. I would ditch the methylenation reaction that you've been using in favor of the biphasic
PTC reaction. It seems to be more simple and forgiving of mistakes.
3. I would try experimenting with the pyridine HCl reaction by reducing the pyridine HCl to
eugenol ratio. Maybe less could be used. Also, I would think very seriously about adding
a little PTC to the mix. It probably wouldn't hurt and actually might help a shitload. I
predict huge leaps and bound with that novel application.

Methylenation Reactions
Catechols (1,2-dihydroxybenzenes) reacts with dihalomethane to form a methylendioxybenzene
(1,3-benzodioxole) derivative under the influence of a base as a catalyst. Formaldehyde,
commonly used to form acetals of similar structure in aliphatic compounds, can not be used with
aromatic compounds.
The term catechols include pyrocatechol, protocatechualdehyde (3,4-dihydroxybenzaldehyde)
and 4-allylcatechol (3,4-dihydroxyallylbenzene). The dihalomethane used in the reaction can
either be methylene chloride (CH2Cl2, bp 40°C), methylene bromide (CH2Br2, bp 97°C) or
methylene iodide (CH2I2, bp 181°C). Mixed halomethanes can also be used, such as
bromochloromethane (CH2BrCl, bp 68°C). The reactivity (and also yields) are the highest with
the iodo derivatives and lowest with the chlorides. However, methylene chloride is several orders
of magnitude cheaper than methylene iodide per mole, and also easier to aquire, so there are pros
and cons of all the alternatives. The base, most commonly sodium hydroxide, is used to
deprotonate the phenols to diphenoxide dianions, making them much more reactive towards
dihalomethanes.

A side reaction in the methylenation of catechols is polymerization, resulting from two or more
phenols becoming linked together by the dihalomethane, forming undesired products like the one
depicted to the right. Suppression of the formation of such by-products can be effected by
keeping the concentration of catechol low in the reaction mixture compared to the
dihalomethane, for example by dripping a solution of the catechol into a solution of the
dihalomethane.

Many of the newer high-yielding methylenation procedures use a PTC (phase-transfer catalyst)
to catalyse the process. It helps carry water-soluble ions (phenoxide) into an organic layer (such
as dihalomethane), therefore accelerating the reaction.

Methylenation Of Catechols with Dichloromethane in DMSO7

This is one of the earliest successful high-yield methylenation of catechols reported using
dichloromethane. It is a bit outdated as it uses complicated equipment to perform the reaction,
but it is a good illustration of the reaction.

A mixture of 100ml dichloromethane and 500ml DMSO was stirred and heated to 125-130°C
under a wide-bore liebig condenser. The air was displaced by nitrogen, and then with 5-minute
intervals pelleted catechol (5.5g) and pelleted sodium hydroxide (4.15g) was added
simultaneously, until a total of 110g catechol and 83g of sodium hydroxide had been added
during 105 minutes. After a further 20 minutes, 20ml dichloromethane and 3g sodium hydroxide
was added and the stirring was continued for yet a further 70 minutes. The reflux condenser was
replaced by a Vigreux column and a constant-take-off distillation head. Water (50 ml) was added
and the benzodioxole-water azeotrope was distilled off at 98-100°, more water being added
slowly as distillation proceeded. Benzodioxole ceased to separate as a heavy oil from the
distillate after ca. 600 ml. of distillate had been collected. The aqueous distillate was extracted
with ether (3x60 ml) and the combined oil and extract was dried and distilled to yield benzo-1,3-
dioxole as a colourless oil; nD21 1.5377, bp 173-176°C (80°C/9 mmHg).
The same procedure applied to protocatechualdehyde (13.8g) gave 9.15g piperonal (61%) after
steam distillation.

The patented procedure below offers 1) higher yield, and 2) simplified addition of the reagents:

A solution of 110 g of catechol, 120 ml of 50% aqueous sodium hydroxide and 200 ml of DMSO
was heated to 98°C and stirred at that temperature for 30 minutes. This solution at 98°C. was
added over a 30 minute period to a refluxing solution of 120 ml of methylene dichloride in 300
ml of DMSO. Thereafter, the reaction mixture was stirred at reflux for 1.5 hours. Steam was then
passed into the mixture to achieve steam distillation of the product. The distillate (600 ml) was
extracted with 100 ml of methylene dichloride, which extract was washed once with 50 ml of
water. The methylene dichloride solution was then concentrated in vacuo at 40°C to yield 119.4g
of a colorless oil. Gas chromatographic analysis showed 97.5% methylenedioxybenzene. Yield
116.4g (95.4%).

PTC Methylenation of Catechol (Using Adogen 464)5

A mixture of water (20 mL), dibromomethane (150 mmol) and Adogen 464Note1 (1 mmol) was
vigorously stirred and heated to reflux. The air in the system was displaced by nitrogen. A
solution of the appropriate o-dihydroxy-benzene (100 mmol) and sodium hydroxide (250 mmol)
in water (50 mL) was added at such a rate that the addition was complete after 2 hours. After the
addition was complete, the reaction mixture was stirred and refluxed for a further hour. The
product was then isolatedNote2 and identified. Yields obtained were 76% to 86%.

It is important to ensure an adequate stirring rate [>400 rpm] and also to add slowly the solution
of catechoxide dianion to the reaction mixture, so as to avoid the possibility of intermolecular
reaction, producing dimers/polymers

Notes:

1. Adogen 464, is a methyltrialkylammonium chloride supplied by Aldrich Chemicals. The

Alkyl groups are a mixture of C8-C10 straight chains with an average of nine carbons. The
molecular weight, determined by titration, was found to be 457. Other PTC's, Such as
Aliquat 336 can be used. Dichloromethane may also be substituted for dibromomethane,
in that case increase the reaction time with one hour, and expect somewhat lower yields.
2. Isolation performed by steam-distilling the benzodioxole as in the reference above.

PTC Methylenation of Catechol (Using TBAB)6

100 ml of dichloromethane, 6.42 g of tetrabutylammonium bromideNote1 and 200 ml of water

were placed in an autoclave, and a total of 27.6 g (0.2 moles) of protocatecualdehyde and 24 g
(0.6 moles) of sodium hydroxide in 30 ml of water were added in stages at a temperature of
70°CNote2. The pressure increased to a maximum of 2.4 atm, and the reaction was continued for 4
hours. After this time the reaction mixture was cooled to ambient temperature, the organic phase
was separated and the excess methylene dichloride was recovered by distillation. 21g (70%) of
high purity piperonal were isolated.Note3
Notes:

1. Other tetraalkylammonium salts may not work - if any of the alkyl groups are lower than
4 carbons in length they are rapidly attacked by strong alkali [Hoffman elimination of the
quat] and the quarternary ammonium salt destroyed.
2. The patent reports temperatures between 30°C to 120°C. If dibromomethane is used
instead, the reaction may be carried out at reflux.
3. As the reaction products form they are extracted by the methylene dichloride, because of
which at the end of reaction it is sufficient to allow the organic layer to decant to obtain
simple and rapid separation of the reaction product from the starting compounds, which
remain in the aqueous layer. The methylene dichloride may first be distilled from the
organic phase and recycled, and then the methylenedioxy product may be distilled off at
high purity. The catalyst remains as a residue, and may be recovered and recycled. The
quantity of methylene dichloride may vary, but is preferably between 1 and 5 moles per
mole of the protocatecualdehyde. However it is always advantageous to operate with an
excess of methylene dichloride so as to work with a double phase and extract the product
in the organic phase. The catalysts are preferably used in quantities of from 1 to 10
mole% with respect to the protocatecualdehyde, and may be recycled. Sodium hydroxide
is preferably present in an amount between 30% and 150%, based on the mole equivalent
of the diphenol added. The concentration of the diphenol sodium salt in the aqueous
phase is advantageously maintained between 0.1% and 40% by weight. The reaction
occurs between 30°C and 120°C, but maximum reaction speed is obtained between 60°C
and 90°C.

PTC Methylenation of Catechol (Using CTAB)8

11.0 grams (0.1 mol) catechol is dissolved in 1000ml of 20% NaOH, and 3.2 grams (0.1 mol) of
cetyltrimethylammonium bromide (Cetrimonium Bromide, CTAB) is added. The mixture is
heated to 60°C for 30 minutes and then allowed to cool to room temperature, whereupon 21.2
grams (0.25 mol) of dichloromethane is added with stirring. The mixture is then heated to 80°C
with a good reflux condenser for 5 hours, the solution saturated with NaCl and filtered. The
solution is then extracted with 3x50 ml CH2Cl2, the pooled extracts washed with 50ml 20%
NaOH to remove any phenolic materials, and then with 50 ml brine. The solution is dried over
MgSO4, and the solvent removed under vacuum. Yield 90% of 1,3-benzodioxole.

KF Catalyzed Methylenation of Catechol9

A solution of 11.0 grams (0.1 mol) of catechol in 300 ml anhydrous DMF was shaken with 5.8g
(0.5 mol) of KF and the mixture warmed up somewhat. 9.35 g (0.11 mol) of CH2Cl2 was then
added to the cooled solution, and the mixture heated at 110-120°C with an efficient reflux
condenser for 2-3 hours. The cooled reaction mixture was extracted with ether, and the etheral
extracts washed with water to remove DMF and with cold 5% NaOH. The solution was dried
over MgSO4, and the solvent removed by evaporation. The residue was extracted with hot
hexane followed by cooling, and evaporation of the extracts to give a 90% yield of 1,3-
benzodioxole.
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3. Andersson, Synthesis 437 (1985)
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5. Bashall and Collins, Tet. Lett. (40), 5489 (1975)
6. British Patent 1,518,064
7. Bonthrone and Cornforth, J. Chem. Soc. (C) 1202 (1969)
8. Tetrahedron 44(21) 6677-6680 (1988)
9. J.H. Clark. H.L. Holland, J.M. Miller, Tetrahedron Lett. (38), 3361-3364 (1976)
10. J. Am. Chem. Soc. 117(48), 11906-11913 (1995)
11. European Patent 1,136,481