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Alkylation of phenolic aldehydes in a melt-phase reaction by trimethyl phosphate
                                   by Cesium
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Useful aldehydes can be prepared by alkylating corresponding phenolic aldehydes
by a variety of agents (alkyl halides, alkyl sulphites or sulphates). However,
the alkylating agents, e.g. dimethyl sulfate or methyl chloride, are themselves
acutely toxic and require special handling procedures. In US445300 a process for
the preparation of an alkylated phenolic ether comprising reacting a phenolic
compound at a temperature of at least the melting point of the phenol and in the
absence of a solvent with trimethyl phosphate as an alkylating agent (with low
toxicity and handling hazard) is described.

Examples of phenolic compounds that can be alkylated are such monohydric phenols
as phenol and o, m and p-cresol; phenolic aldehydes such as
protocatechualdehyde, vanillin, syringaldehyde, p-hydroxybenzaldehyde,
5-formylvanillin and salicylaldehyde; phenolic ketones such  as
p-hydroxyacetophenone, acetovanillone, acetosyringone, acetamidophenol and
guaiacol; and phenolic acids such as vanillic acid, syringic acid and
p-hydroxybenzoic acid. The alkylating agent may be essentially any compound
which is a source of a one to four carbon atom alkyl group. It may be either a
gas or a liquid. In general, the alkylating agents may be alkyl sulfonates such
as methyl and ethyl p-toluenesulfonate and methyl and ethyl benzenesulfonate;
trialkyl phosphates such as trimethyl and triethyl phosphate; and dialkyl
sulfites such as dimethyl and diethyl sulfite. (Other alkylating agents which
may be used are alkyl sulfates such as dimethyl sulfate, diisopropyl sulfate and
diethyl sulfate; alkyl halides such as methyl chloride, methyl bromide, methyl
iodide, ethyl chloride, ethyl bromide, ethyl iodide and similar propyl and butyl
halides).

EXAMPLE 1

In a three-neck flask (capacity 100 ml) equipped with a mechanical stirrer and
reflux condenser, 5.00 g (0.033 mol) of vanillin and 5.00 g (0.036 mol) of
anhydrous potassium carbonate were placed and the mixture was heated under a
nitrogen atmosphere to 85° C. The mixture was a clear to amber melt of vanillin
with carbonate in suspension. To this mixture was added 5.00 ml (0.043 mol) of
trimethyl phosphate over about 5 minutes while maintaining the reaction
temperature below 125° C. The mixture was maintained at about 80° C. for one
hour and then cooled to 40° C. The mixture was poured into 20 ml water and
extracted two times with 20 ml of methylene chloride. The combined extracts were
dried over anhydrous potassium carbonate, filtered, and concentrated to give 5.4
g (99%) of veratraldehyde as a pale oil.

EXAMPLE 4

In an apparatus similar to Example 1, 15.2 g (0.083 mol) of syringaldehyde and
15.0 g (0.11 mol) of potassium carbonate were heated to 105° C. under nitrogen
and 15 ml (0.12 mol) of trimethyl phosphate were added over 10 minutes. The
mixture was maintained at about 80° C. for 3 hours then cooled to 45° C. and
quenched with 50 ml of H2 O. The tan solid which precipitated was collected,
washed with 3×50 ml of water and dried to give 15 g (92%) of
3,4,5-trimethoxybenzaldehyde.

From US4065504 (melt-phase reaction with dimethyl sulfate):

EXAMPLE 1

A mixture of 100g of syringealdehyde (0.55 mol), 85.0g of sodium carbonate (0.80
mol) and 106.0g of dimethyl sulfate (0.84 mol) was placed in a round-bottomed
flask equipped with a reflux condenser, a stirrer and a dropping funnel. The
syringealdehyde was of about 99% purity and was obtained, by distillation, from
a crude mixture of vanillin and syringealdehyde produced by alkaline oxidation
of waste Kraft liquor. The dimethyl sulfate was of commercial quality (B.P.
75°-77°/15 mm) and the sodium carbonate was of reagent grade in some experiments
and of commercial grade in others. The flask was kept in a silicone oil bath on
a hot plate. The mixture as prepared at room temperature was a thick paste which
could be kneaded but could not be mixed by the stirrer driven by an electric
motor. When the temperature of the mixture reached 75° C the mixture became
fluid and was easily stirred by the blades of the stirrer. The temperature was
further raised to about 85° C and maintained at this temperature with stirring
for a total of about 2 hours. After the initial 35 minutes of this period the
reaction mixture began to thicken due to the consumption of dimethyl sulfate
and, in order to maintain it fluid, water in 5 gram portions was added from time
to time through the funnel while the stirring continued. In total about 60g of
water were added to the mixture during the reaction period. At the end of two
hours, the heating was discontinued and about 500 ml of hot water was added to
the mixture. The mixture was acidified with concentrated hydrochloric acid and
was then extracted three times with about 250 ml of benzene (toluene,...) and
the combined extract was washed with water. The benzene was removed by
distillation and the solid product was dried in a vacuum oven and weighed. The
yield was 106.9 g of 3,4,5-methoxybenzaldehyde, representing a yield of 99.3% of
the theoretical. Analysis by gas-liquid chromatography (g.l.c.) showed a purity
of 99.85% with syringealdehyde as the only detectable impurity.

EXAMPLE 2

50. of syringealdehyde (0.275 mol) 40g of sodium carbonate (0.38 mol) and 53.4g
of dimethyl sulfate (0.42 mol) were placed in a round-bottom flask and heated
substantially as in Example 1. When the temperature reached 75° C the reaction
mixture became fluid but after 30 minutes at a temperature between 80° and 87°
it began to thicken again. 30 ml. of water was then added dropwise while the
temperature was maintained for 1.2 hours. On completion of the reaction 250 ml
of hot water was added to the mixture. Then the mixture was cooled, the
solidified organic material separated by filtration, washed with water and
vacuum dried. The yield of 3,4,5-trimethoxybenzaldehyde was 99.6% with about
0.4% syringealdehyde remaining.

EXAMPLE 6

On mixing 50 g of vanillin (0.329 mol), 48.0 g of sodium carbonate (0.453 mol),
and 60.2 ml of diethyl sulfate (0.460 mol) a fluid mixture was obtained almost
immediately. The mixture was maintained at 80° for 3.5 hr. Water (25 ml) was
added in small portions over the last 2.0 hr. Work-up as in the previous
examples yielded 58.06 gm. (98.1%) of 4-ethoxy-3-methoxybenzaldehyde which
contained 2.4% vanillin.

EXAMPLE 7

20.g of p-hydroxybenzaldehyde (0.164 mol) was reacted with 29.0 g of dimethyl
sulfate (0.230 mol) and 22.0 g of sodium carbonate (0.20 mol) for 2 hr. at
75°-80° C. A total of 12 ml of water was added in small portions over the last
hour. Work-up by addition of water, acidification and benzene extraction yielded
22.27 g of p-methoxybenzaldehyde (99.9%) containing not more than 0.1%
p-hydroxybenzaldehyde.

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