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Various Aromatic Formylations


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 10C. Once the solution is well mixed, the dropping funnel is replaced with a thermometer, and the temperature of the viscous solution is brought to 35C. 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 mole) 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 196-197C. The indole-3-aldehyde resulting from this prodcedure is sufficiently pure for most purposes, but it may be recrystallized from ethanol if desired.

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.

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 min 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 100-110C (bath temp). Heating and stirring was cont. 1-2 hr. The mixt. was poured into ice-water, made just basic by 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 112-112.5C) from 2,5-dimethylanisol -> 76%, bp 85-86C (0.4 mm Hg), from m-diMeO-benzene -> 99%, mp 68-69C (ethanol)


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 100C 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 50-51C. bp 80C 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)

Formylation of phenols with paraformaldehyde

Drone: 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.

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 8 hours 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.

"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!


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.

Ref: JCS Perkins I, (1980) 1862-1865


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%

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.


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.


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 58C. 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).


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).

2-hydroxy-5-methoxy-benzaldehyde by Reimer-Tiemann formylation of 4-methoxyphenol

200g of 4-methoxyphenol were dissolved in a solution of 190g of NaOH in 550mls water and the resulting soln was heated to 50C on a waterbath. To this soln maintained at 50-60C there were added dropwise 420g of chloroform and a solution of 560g of NaOH in 500mls water from two separate dropping funnels and the rxn was heated for 1 hr at the same temperature and atmospherical pressure. After cooling, the precipitated salt of 2-hydroxy-5-methoxybenzaldehyde was filtered and washed with 100ml alcohol. The sodium salt was dissolved in 800ml water and slightly acidified (1200ml 3N H2SO4 at RT) and extracted with 200ml toluene. The solvent was dried w/CaCl2 and evap'ed and the residue distilled at reduced pressure to give 132g (48-53%) of the title product, bp 110C/5mmHg.

Reference: British Patent 1,377,317

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 details see US Pat 5599988)2,4-Dihydroxybenzaldehyde:

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 170-173C.


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 chloride (US4157333)


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.

Reimer-Tiemann formylation of 4-Methoxyphenol (Org. React. Vol 28 p16)

Into a 2000ml three neck flask was placed 125g (1 mol) 4-Methoxyphenol and a still hot solution of 320g (8 mol) NaOH in 400ml H2O (Addition while hot helps the phenol to dissolve and avoid carbonate formation). The flask was set with a reflux condenser, dropping funnel and thermometer (using a Claisen adaptor) and mechanical stirrer then heated to ~70C on the oil bath. When this temperature had been reached, chloroform (160ml, 2 mol) was added dropwise (and portionwise) over the course of 4 hrs while maintaining the stirring and temperature, over this time the rxn became a very dark brown with a yellow green froth and a heavy brown precipitate (the sodium phenolate product). The reaction was allowed to stir for a further hour at the same temperature, allowed to cool and then transfered to a 5000ml flask with the aid of some hot water and subsequently acidified with H2SO4 (150-200ml 10 N). Acidification causes the product to rise to the top as a black oil. The black oil was transferred into a flask with some clean water and steam distilled (collect ~5000ml distillate). Quite a volume of black tar remains after this distillation. The yellow oil in the distillate was extracted with DCM and evaporated to yield 112g (74%) 2-hydroxy-5-methoxy-benzaldehyde, can be further purified by vacuum distillation under nitrogen (bp 133C/15mmHg).

This material was sufficiently pure for methylation to 2,5-Dimethoxybenzaldehyde and gave a 76% yield with Dimethylsulfate in aqueous NaOH.

Note: The alkali salts of this salicylaldehyde are quite prone to atmospheric oxidation.

Reimer-Tiemann formylation of 4-Methoxyphenol (Arch. Pharm. 308, p341 (1975))

160 g (4 Mol) NaOH and 62 g (0.5 Mol) 4-Methoxyphenol was dissolved in 600 ml of water, to which was added 120 ml of ethanol. The solution was warmed to 70 and over the course of 3 hours, 80 ml of CHCl3 (1 Mol) was added dropwise. After a half hour of stirring, the ethanol and CHCl3 were removed in vacuo, and the solution was acidified to a pH of 3 by addition of 10N H2SO4. The dark-colored organic phase was extracted with ether [and separated], the ether was removed, and the residue was further processed using steam. The 2-Hydroxy-5-methoxy-benzaldehyde came over using about 6-8 l of water and was separated off. The remaining aqueous distillate was saturated with NaCl and extracted with ether. The 2-Hydroxy-5-methoxy-benzaldehyde and the ethereal extract were combined, and dried over MgSO4. After removal of the solvent, there remained 48 g (63% yield) of the final product, with a mp of 2-4 (Lit. 4-5).

2,4-Dihydroxy-3-methyl-benzaldehyde (US Pat 3975309)

2,4-dihydroxy-3-methyl-benzaldehyde was prepared by Elfeed Thomas Jones and Alexander Robertson [Journal of the Chemical Society, London, page 1691 (1932)] by the condensation of 2,6-dihydroxytoluene with zinc cyanide and excess hydrogen chloride.

It may also be produced by placing 496 g of 2-methyl-resorcinol, 712 g of N-methyl-formanilide and 300 ml of benzene in a 3-necked five liter flask fitted with an agitator, reflux condenser, dropping funnel and thermometer. After a homogeneous solution is obtained by agitation at room temperature, 808 g of phosphorus oxychloride are added over a period of 2 hours, maintaining the reaction temperature at 25-30C. After the addition is completed, agitation is continued for about 4 hours at 25-30C with occasional cooling. During the reaction, 600ml of benzene are added to the reaction mixture.

The reaction mixture is cooled in an isopropanol-dry ice bath. 100 ml of ice water are added in one portion to the reaction mixture, followed by the addition with agitation of 2000 ml of a 50% aqueous sodium acetate solution over a period of 50 minutes (exothermic) allowing the reaction temperature to rise to a maximum of 65C. The reaction mixture is cooled to 20C and 1000 ml of a 50% aqueous acetate solution (precooled to 25C) are added under agitation in one portion. 800 ml of ethyl acetate (solvent) are added. The mixture is agitated for about 5 minutes and permitted to separate into an aqueous part and an organic layer, which is washed with 200 ml of water. The solvent (ethyl acetate) is removed by distillation under vacuum from a steam bath. The crude reaction product is cooled to 20C and the formed crystals are filtered on a Buchner funnel. The crystals are recrystallized from a solution of 1000 ml of water and 600 ml of methanol. This first crop weighed 310g, with a mp of 158-160C (GLC: 100%)

To the mother liquor are added 300 ml of benzene and 100 ml of ether. The reaction mixture separates into two layers. The organic layer is washed three times with 200 ml portions of water and neutralized with a 10% aqueous solution of sodium bicarbonate. The solvent is removed by distillation from a steam bath under an ejector vacuum. The formed crystals are collected on a Buchner funnel and recrystallized from a solution of 200 ml of benzene and 100 ml of hexane. This second crop weighed 150g, with a mp of 156-158C (GLC: 100%)

The combined two crops from above are placed in a 3 liter 3-necked flask with an agitator and 1500 ml of water are added. The product is steam distilled for approximately 1 hour. The steam distillation is necessary to remove traces of contaminants which give an off-odor to the product. From 426 g of the product, 420g of 2,4-dihydroxy-3-methyl-benzaldehyde having a melting point of 151.5-152.5C result after distillation.

Paraformaldehyde/Mg(OMe)2 Phenol Formylation

This formylation is high-yielding and requires no special chemicals to ortho-formylate phenols. A weak vacuum is used during the reaction to remove formed volatile by-products. It would be very well suitable for formylation of p-methoxyphenol. Another variation in the patent, which uses a dash of added pyridine pushes the yield upwards some more.

From US Pat 6,274,068:

A 2-liter round-bottomed flask was charged with magnesium (12 g, 0.49 mol), methanol (285 ml), toluene (120 ml) and magnesium methoxide (10 ml solution of 7.4% by weight magnesium methoxide in methanol). The reaction mixture was heated to reflux and the magnesium dissolved. Para-nonyl phenol (112.4 g) was added in one portion to the reaction mixture. The flask was then rigged for a fractional vacuum distillation and an azeotrope of methanol/toluene was distilled off an internal temperature of 70C at a pressure of 350 mmHg. Glacial acetic acid (28.5 ml, 0.5 mole) was added to the reaction mixture over a 1-hour period while maintaining the reaction temperature at 70C and the pressure at 350 mm Hg. When the addition of glacial acetic acid was complete, solid paraformaldehyde (46 g, a commercial sample containing 5-7% by weight water) was added over a 105-minute period. The reaction mixture was maintained at a temperature of 65C and a pressure of 350 mmHg, during the addition of paraformaldehyde, and the volatile reaction by-products were continually removed. When the paraformaldehyde addition was complete, the reaction temperature was increased to 75C. and maintained at that temperature for an additional 3 hours. Sulphuric acid (300 ml, 10% w/w) was added to the reaction mixture, which was then stirred for 1 hour. After phase separation, the organic phase was washed twice with 200 portion of water. The washed organic phase was then separated, dried and rendered free of the solvent to yield crude 5-nonyl salicylaldehyde. A 67% yield was obtained.

From Journal of the Chemical Society Perkins Transactions I, 1823-1831 (1994):

"2-Hydroxy-4-methylbenzaldehyde 2a. - Phenol (37.6 g, 0.4 mol) was added to magnesium methoxide (259 g of 8 wt% solution in methanol; 20.7 g, 0.24 mol) and the mixture was heated to reflux. Approximately half the methanol was distilled off and toluene (300 g) was added to the residue. The azeotropic mixture of toluene and methanol was removed by fractional distillation, until the temperature of the reaction mixture rose to 95 C. A slurry of paraformaldehyde powder (43.2 g, 1.44 mol) in toluene (75 g) was added in small portions over 1 h to the reaction mixture at 95 C with concurrent removal of volatile materials by distillation. Stirring was continued at 95 C for 1 h, after which [the] mixture was cooled to 25 C and added slowly to 10% sulfuric acid (450 g). The resulting mixture was stirred at 30-40 C for 2 h, after which the aqueous layer was separated and extracted with toluene (2x100 g). The combined organic layers and extracts were washed with 10% sulfuric acid (50 g) and water (50 g) and evaporated under pressure to give the aldehyde 2a as a pale yellow oil (48.35 g, 84% w/w by GC and 1H NMR comparison against a reference standard and against a commercial sample of known purity; 83% yield)...

"2-Hydroxy-4-methylbenzaldehyde 2c. and 2-Hydroxy-6-methylbenzaldehyde 2c. - In a similar way to that described above, 3-methoxyphenol (27.0 g, 0.25 mol), magnesium methoxide (0.15 mol) and paraformaldehyde powder (23.2 g 0.77 mol) gave the aldehyde 2j as a pale yellow oil which solidifies with time (31.5 g) and comprised 2-hydroxy-4-methylbenzaldehyde (64% by 1H NMR using 1,2-diphenylethane as the internal standard; 59% yield)...

2-Hydroxy-5-methoxybenzaldehyde 2j. - In a similar way to that for aldehyde 2c, 4-methoxyphenol (32.2 g, 0.25 mol), magnesium methoxide (0.15 mol) and paraformaldehyde powder (23.2 g 0.77 mol) gave the aldehyde 2j as a pale yellow oil (36.0 g; 97% w/w measured by GC and HPLC; 92% yield)"

Acta Chemica Scandinavica 53, p. 263-268 (1999) also describes a variation of this formylation

Magnesium Methoxide Preparation

Here are some references for articles describing the practical preparation of magnesium methoxide from Mg and MeOH. The trick to get it to start working is no surpise: a crystal or two of elemental iodine as the catalyst, and heat (60C)

  • Acta Chemica Scandinavica (1999) 53(12), 1117-1121.
  • Bulletin de la Societe Chimique du France, (1935) 5(2), Pp. 1202.
  • Journal of Medicinal Chemistry, (1993) 36(6), Pp. 758-764.
  • Journal of the Chemical Society Dalton Transactions, (1983) Pp. 2139-2142.
  • Tetrahedron Letters, (1996) 37(29), Pp. 5159-5160.
  • Zeitschrift fr anorganische und allgemeine Chemie, (1967) Pp. 207,215.