--------------------------------------------------------------------------
            Discussions on the formylation of aromatic compounds
--------------------------------------------------------------------------

Drone 342:

Hydroquinone (or p-methoxyphenol), paraformaldehyde, SnCl4, and a dash of
an apropriate lewis base (Bu3N). Warm, and formylation is complete.
Conditions are fascile, and yields are high. Methylate, and you got
2,5-diemthoxybenzaldehyde. What's the ref for this "Wundersynth"? Why, its
none other than: J. Chem. Soc. Perkin Trans. 1, 1862-1865, (1980). BTW,
you're welcome.

--------------------------------------------------------------------------
Osmium:

This method only works for phenols. It is a selective ortho-formylation of
phenols, producing salicylic aldehydes.

FeCl3 and SnCl2 can most probably substitute for SnCl4 (with appropriate
base concentration change), making this procedure much cheaper. BTW, have a
look at the table in that ref, lenghtening reaction time (more than the
stated 8 hours) will produce higher yields with some phenols. Conversions
after 8hours are a little low, e.g. with p-MeO-phenol: about 60% conversion
of starting product after 8 hours, I guess 24 hours would be right.

In the general procedure in this ref. there is at least one typo: 0.4 mol
tributylamine is 74g not 54g. And 200ml toluene sounds wrong, too.

This procedure is also patented. US pat 4.151.201, if somebody wants to
check it.

--------------------------------------------------------------------------
Assholium:

Yet another procedure for formylation of phenols (predominantly para-subst).
Works great for indane  too (75%, 5-formylindane, bp 135-138 (23mm),
Beilstein Hauptwerk 7 p. 372, E III p. 1430)

JOC 37, 3972 (1972)

General procedure:

A mixture of 12,2 g of 2,6-xylenol (100 mmol), 14.0 g of HMTA (aka urotropine,
hexamine or hexamethylenetetramine) (100 mmol) and 150 ml of trifluoroacetic
acid was heated at reflux (83-90 C) for 12 hrs. The product were concentr.
and combined with 600 ml of ice water; the resulting mixture was stirred 15
min, made basic with Na2CO3 and extracted with ether. Evapn of the ether
soln left a yellow solid which was recryst. from CHCl3-pentane to afford
14.3 g of 3,5-dimethyl-4-hydroxy-benzaldehyde mp 113C

Yields from the formylation of a few selected compounds:

2,6-Dimethylanisole       74%
tert-Buthyl-bezole        75%
p-Xylene                  55%
Benzodioxane              37%
2,6-Di-tert-butyl-phenol  60%

--------------------------------------------------------------------------
Cesium:

Reimer-Tiemann formylation process for producing aldehydes (US4755613)

The invention relates to a process for preparing aromatic or hetero-aromatic
aldehydes by the Reimer-Tiemann formylation reaction. The process comprises
employing a solid alkaline hydroxide in order to carry out the reaction in a
solid/liquid medium. Such a process makes it possible to substantially increase
the yield of the Reimer-Tiemann reaction and to avoid tar formation entirely or
in large part.

EXAMPLE 1
100.cm3 of chloroform, 9.4 g of phenol, 20 g of anhydrous sodium hydroxide and
3.6 cm3 of water are placed in a 250 cm3 reactor provided with a coolant, a
mechanical stirrer and a thermometer, and the reaction medium temperature is
thermostatically maintained at 50° C. These conditions of the initial mixture
correspond to a hydration rate of 0.4 moles of water per mole of sodium
hydroxide (2 moles of water per mole of initial compound) and to 12.6 times as
much chloroform as initial compound (expressed in moles). Thereupon the
temperature of the reaction medium is raised to 58° C. for one hour. Next 12 g
of sodium hydroxide in powdered form are progressively added over a period of
two hours, the temperature being kept constant at 58° C. The reaction proceeds
for 1 hour. At the end of the reaction, the initial phenol has completely
disappeared. The residual chloroform is recovered and recycled. The mixture of
aldehydes is obtained in sodium form. It is neutralized until a neutral brine is
obtained. The salicylaldehyde can be recovered in conventional manner at a yield
close to 77% (9.4 g) with respect to the initial phenol by carrier vapor
distillation or by ether extraction. The p-hydroxybenzaldehyde is recovered at a
yield of 17% (2 g) by ether extraction from the acidified residual brine to pH
of 1.

EXAMPLE 7
10.cm3 of methanol and 90 cm3 of chloroform, also 6.2 g of guaiacol are placed
in a 250 cm3 reactor with a coolant, a mechanical stirrer and a thermometer.
Next 16 g of pulverulent sodium hydroxide and 6 g of water are added while
maintaining the mixture temperature at 0° C. These initial mixture conditions
correspond to a hydration rate of 0.825 moles of water per mole of sodium
hydroxide (6.6 moles of water per mole of initial compound [guaiacol]) and to
22.7 times as much chloroform as initial compound. Thereupon the mixture is
slowly returned to ambient temperature and is very gradually raised to 58° C.
Following the reaction, 16 g of pulverulent sodium hydroxide are progressively
added over a period of 2 hours. The temperature is kept constant for 1 hour.
Then the reaction mixture is cooled to 40° C. and the pH is returned to 2 by
gradually adding sulfuric acid. The chloroform phase is then separated from the
aqueous phase and is dried on sodium sulfate. The aqueous phase is extracted
again with ether. The organic phases next are evaporated. They contain the
aldehydes and the residual guaiacol. The yield is 32% in vanillin (2.4 g) and
38% in isovanillin (2.8 g).

EXAMPLE 8

10.cm3 of methanol, 190 cm3 of chloroform and 7.7 g of syringol are placed in a
250 cm3 reactor having a coolant, a mechanical stirrer and a thermometer. The
mixture is treated ultrasonically for 6 hours in a "BRANSONIC" cleaning tank (47
kHz, 180 w, 3 ceramics). After this pretreatment, 8 g of powder sodium hydroxide
and 0.9 g of water are added. These initial mixture conditions correspond to a
limit hydration rate of 0.25 moles of water per mole of sodium hydroxide (0.05
moles of water per mole of initial compound) and to 25.2 times as much
chloroform as initial compound expressed in moles. For a lesser hydration, the
yield drops considerably. The reaction proceeds in the tank under ultrasonics,
at 30° C. and for 2 hours 30 minutes. The syringaldehyde is obtained with a
yield of 12% (1.1 g).

Would be interesting to run this reaction with p-methoxyphenol (yields shouls be
approx. 60%) of hydroquinone.

--------------------------------------------------------------------------
Cesium:

Modification of Vilsmeier-Haack reaction

This variation eliminates the need of POCl3 for the formation of Vilsmeier
complex.

Vilsmeier-Haack reaction with Oxalyl Chloride: (for further detail see
US5599988)

2.4-Dihyroxybenzaldehyde:

A 1-L 3 neck flask equipped with a temperature thermocouple and an efficient
overhead stirrer is charged with DMF (46.37 g, 0.63 mole) and acetonitrile (350
mL). The reaction is treated dropwise with a solution of oxalyl chloride (66.12
g, 0.521 mole) in actionitrile dropwise over 20 min so that the temperature is
maintained at 20°-26° C. with a water bath. Gas evolution is noted and a thick
precipitate forms. The reaction is stirred at ambient temperature for 1 h to
insure complete conversion to the Viismeier reagent. The reaction is cooled in a
dry-ice bath to -14° to -17° C and a solution of resorcinol (26.87 g, 0.244
mole) in acetonitrile (75 mL) is added over 20 min. The Viismeier reagent
dissolves as the reaction with resorcinol occurs, and soon afterward the
precipitation of chloride salt 4--Scheme 4 begins. The reaction is stirred at
-15° C. for 35 min, then at 28°-32° C. for 2 h. The HPLC of the reaction
solution shows <6% of the starting material. After cooling to 3°-5° C. for 2 h,
the reaction is filtered and washed with cold acetonitrile (70 mL). The solid is
washed with hexane (30-40 mL) and the product dried. The Vilsmeier formamidinium
chloride is dried at 30°-35° C. at 0.05 mm of Hg for 24 h. The recovery is 42.3
g; the yield corrected for purity is 79%; it is a single component by HPLC, mp
170°-173° C.

Hydrolysis:

To water (250 mL) stirred at 40° C. is added the above salt (42.3 g, 0.209 mole)
in three portions. The reaction is heated to 50° C. for 0.5 h, and the reaction
is cooled. When the temperature had reached 35° C., sodium thiosulfate solution
(0.09M, 1-2 mL) is added to discharge the resulting pink color. The reaction is
cooled to 5° C., and stirred for 2 h. The mixture is filtered, the solid is
washed with cold water, and air dried at <35 ° C for 24 h giving
2,4-dimethoxybenzaldehyde (24.4 g, wt/wt assay by HPLC 97%; corrected yield: 69%
from resorcinol) an off-white solid, mp 134°-136° C. This product is identical
to that produced by the Vilsmeier-Haack reaction with phosphorus oxychloride .

Obviously, from hydroquinone one can prepare 2,5-dihydroxybenzaldehyde (and
further methylate it).


Vilsmeier-Haack reaction with thionyl chlorid (US4157333)

Piperonal

A process for preparing piperonal which comprises the steps of reacting
1,2-methylenedioxybenzene with an N-alkylformanilide and a condensing agent
comprising one or more compounds selected from the group consisting of phosgene,
phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, thionyl
bromide, sulfuryl chloride, sulfuryl bromide, phosphorus trichloride, and
phosphorus pentachloride, and then hydrolyzing the resulting reaction product.

To 108 g (0.80 mole) of N-methylformanilide cooled in an ice-water bath, 95.2 g
(0.80 mole) of thionyl chloride was added drop by drop with stirring. After
completion of the addition, the mixture was allowed to stand at room temperature
for 2 hours and then heated at 40°-50° C. for 1 hour under a reduced pressure of
60-80 mmHg. To the resulting yellow mixture, 97.6 g (0.80 mole) of
1,2-methylenedioxybenzene was added and kept at 15° C. After completion of the
addition, the reaction mixture was kept at 90° C. for 30 minutes, poured into
ice water, and allowed to stand for 1 hour. Then, the resulting mixture was
extracted with toluene. By vacuum distillation, the toluene was removed and the
distillate at 84°-85° C./30 mmHg was then collected to recover unreacted
1,2-methylenedioxybenzene. Subsequently, the distillate at 131°-134° C./10 mmHg
was collected to obtain piperonal. The yield (expressed in terms of mole
percentage based on the amount of N-methylformanilide used) and selectivity
(expressed in terms of mole percentage based on the amount of
1,2-methylenedioxybenzene having reacted) of piperonal were 55,6% and 95,1%,
respectively.

--------------------------------------------------------------------------


