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			Vilsmeier formylation of aromatic nuclei
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Indole-3-carboxaldehyde, posted by Drone #346

To make benzaldehydes using DMF and POCl3 (the way the professionals
do it) is just a Vilsmeyer reaction. The notes I have are for making
indole-3-carboxaldehyde, but it works equally well on benzenes.

This is actually a synth snagged from Org. Syn., Vol 4, pp 539-541.

In a 1-l. round-bottomed, three-necked flask fitted with an efficient
mechanical stirrer, a drying tube containing Drierite and a 125-ml.
dropping funnel is placed 288 ml. (274g, 3.74 moles) of freshly distilled
dimethylformamide. The flask and its contents are cooled in an ice-salt
bath for about 0.5 hour, and 86 ml. (144g., 0.94 moles) of freshly
distilled phosphorous oxychloride is subsequently added with stirring to
the dimethylformamide over a period of 0.5 hour. The pinkish color of the
formylation complex may be observed during this step. The 125-ml. dropping
funnel is replaced with a 200-ml. dropping funnel, and a solution of 100g.
(0.85 mole) of indole in 100 ml of dimethylformamide is added to the yellow
solution over a period of 1 houe during which time the temperature should
not rise above 10øC. Once the solution is well mixed, the dropping funnel
is replaced with a thermometer, and the temperature of the viscous solution
is brought to 35øC. The syrup is stirred efficiently atr this temperature
for 1 hour, or for 15 minutes longer than is necessary for the clear yellow
solution to become opaque, canary-yellow paste. At the end of the reaction
period, 300 g. of crushed ice is added to the paste with careful stirring,
producing a clear, cherry-red aqueous solution.

This solution is transferred with 100 ml. of water to a 3-l. three-necked
flask containing 200 g. of crushed ice and fitted with an efficient
mechanical stirrer and a separatory funnel containing a solution of 375 g.
(9.4 moles ) of sodium hydroxide in 1-l. of water The aqueous base is
added. The remaining two-thirds is added rapidly with efficient stirring
until about one-third of it has been added. The remaining two thirds is
added rapidly with efficient stirring, and the resulting suspension is
heated rapidly to the boiling point and allowed to cool to room
temperature, after which it is placed in a refrigerator overnight. The
precipitate is collected on a filter and resuspended in 1 l. of water. Most
of the inorganic material disolves, and the product is then collected on a
filter, washed with three 300-ml. portions of water and air-dried, yielding
about 120 g. (97%) of indole-3-aldehyde, mp 196-197øC. The indole-3-aldehyde
resulting from this prodcedure is sufficiently pure for most purposes, but
it may be recrystallized from ethanol if desired.

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Indole-3-aldehyde from indole

There was prepared a solution of 25.75 g indole in 100 mL DMF. A second solution
was also prepared by cooling 80 mL DMF in an external ice bath (internal
temperature about 12 °C), stirring well, and adding 20 mL POCl3 dropwise over
the course of 30 min. This was then warmed to 25 °C and the first solution of
indole in DMF was added dropwise (with continued stirring) over an additional 30
min. Stirring was continued for yet another 45 min, during which time the
temperature was raised to 40 °C. Yellow solids formed during this period. The
reaction mixture was poured onto chipped ice which produced a clear red
solution. This was made basic with the addition of 200 mL 5 N NaOH which allowed
the separation of a yellow solid. This was diluted by the addition of 200 mL hot
H2O and, after cooling again, the product was removed by filtration and washed
with cold H2O. This can be recrystallized from aqueous DMF to yield, after air
drying, 24.5 g (84%) of indole-3-carboxaldehyde as faint orange needles. 

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Improved Vilsmeer Haack procedure
Synthesis, 8, 543 (1975)

The Vilsmeer complex was prepd. by the dropwise addition of freshly 
distilled phosphorous oxychloride (55 ml) to dry DMFA (dimethylformamide, 
100 ml) during 15' with stirring and cooling in ice. The complex was 
allowed to warm to RT and was then added during 1.0-1.5 hr to a stirred 
soln of substrate (0.5 mol) in dry DMFA (100ml) at 100-110 C (bath temp). 
Heating and stirring was cont. 1-2 hr. The mixt. was poured into 
ice-water, made just basic bty addition Na2CO3 soln and exhaustively
extracted with ethylacetate; combined extracts were washed succesively 
with diloute HCL, H2O and saturated brine, and finally dried over Na2SO4; 
Yields, f.e. from 1,2,4-triMeo-benzene, 88% (needles from water, 
mp 112-112.5) from 2.5-dimethylanisol -> 76%, bp 85-86C (0.4 mm Hg),
from m-diMeO-benzene -> 99%, mp 68-69C (ethanol)
     

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JCS Perkins I, (1980) 1862-1865

"Treatment of phenols with 2 mol equiv. of paraformaldehyde in aprotic 
and poorly electron-donating solvents in the presence of selected metal 
halides coupled with suitable bases produces salicylaldehydes in high 
yields. The route is highly selective for ortho-formylation and also 
specific towards monoformylation..."

* Benzene or toluene is the solvent used
* Tin(IV)chloride is the catalyst
* Paraformaldehyde (mildewcide) is the reagent
* Hydroquinone (common photographic chemical) is the starting material
* Yields are around 90%, sometimes higher!

Experimental:

To a four-neck RB flask (2.5l) eq. with a reflux condenser, mech.
stirrer, termometer, and N2 source was added anhydrous toluene (200
ccm) an appr. phenol (1 mol) tributylamine (54 g, 0.4 mol) and SnCl4
(26 g, 0.1 mol). The mixture was stirred 20' at RT, then paraform was
added (66 g, 2.2 mol). The resulting yiellow soln was heated at 100
+- 0.5C at 8 hrs. After cooling the RM was poured into warter (5 l)
acidified to pH 2 with 2N HCl and extracted with ether. The ether
extract was washed with satur. brine, dried over Na2SO4 and conc. to
leave crude aldehyde. Product was purified by steam distillation and
if nesessary, by subseq. distillation and recryst. from pet. ether.
Yields, f.e. from p-methoxy-phenol, 85%, mp 51-52C.

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2,5-dimethoxybenzaldehyde

Pyrophosphoryl chloride (1.889g, 7.5 mmol) was added dropwise to a stirred 
mixture of cold (ice bath) N,N-dimethylformamide (0.731g, 10.0 mmol) and 
p-dimethoxybenzene (0.691g, 5.0 mmol). The resulting syrup was then heated at 
100°C for 48 hours. The cold product was basified with an aqueous solution of 
2M sodium hydroxide and extracted with dichloromethane and dried (MgSO4) and 
concentrated. Short-path distillation gave 2,5-dimethoxybenzaldehyde 
(0.332g 40%), mp 50-51°C. bp 80°C at 0.1 mmHg. 

Poor chemist's short-path distillation apparatus: Fit the collection flask 
directly to the distillation adapter without condenser. 

Ref: Tetrahedron 49(19) 4015-4034 (1993)

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2,5-dimethoxybenzaldehyde

The Vilsmeyer complex was prepared by 30 min addition of 92 ml phosphoryl chloride
(freshly opened ampoule) to 150 ml anhydrous DMF with stirring and cooling in ice.
Light orange solution was then added dropwise during 2 hrs to a stirred solution
of 116 g 1,4-dimethoxybenzene (prepared from hydroquinone and dimethyl sulphate
in water, not purified, well dried) in 150 ml dry DMF at 100 - 110 deg C (bath),
a calcium chloride guard tube was used. Heating was continued for 3 hrs. Resulting
black mixture was poured onto 1 liter of ice-water, neutralized with 20% NaOH
(pH = 7-8) and extracted with CH2Cl2 (3 x 150 ml). Combined extracts were washed
with 100 ml water, dried over Na2SO4 and distilled at atmospheric pressure (bath
temp. lower than 80 deg C). Crude black product was crystallized from a mixture 
of 120 ml ethanol and 80 ml water. Crystallization was finished in freezer. Yield 
106 g pure, light brown 2,5-dimethoxybenzaldehyde (76%, m.p. 52-53 deg C). 
Isolation of product by distillation under diminished pressure (bp 146C/10 mm.) 
should provide somewhat higher yield, of course.

J.C.S. Perkin 1, 1974, 1353-1354 

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