ORGLIST: Re: Phenolic formylation

Date view Thread view Subject view Author view Attachment view

From: Mr. (Dr.) Hardik M. Thakar (hardikthakar$##$
Date: Sun Oct 23 2005 - 23:43:06 EDT

  Dear Please see below refrence 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.=

 mechanical stirrer, a drying tube containing Drierite and a 125-ml. droppi=
ng funnel is placed 288 ml. (274g, 3.74 moles) of freshly distilled dimethy=
lformamide. The flask and its contents are cooled in an ice-salt bath for a=
bout 0.5 hour, and 86 ml. (144g., 0.94 moles) of freshly distilled phosphor=
ous oxychloride is subsequently added with stirring to the dimethylformamid=
e over a period of 0.5 hour. The pinkish color of the formylation complex m=
ay be observed during this step. The 125-ml. dropping funnel is replaced wi=
th 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 peri=
od 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 t=
hermometer, and the temperature of the viscous solution is brought to 35=
C. 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 becom=
e 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 m=
l. of water to a 3-l. three-necked flask containing 200 g. of crushed ice a=
nd fitted with an efficient mechanical stirrer and a separatory funnel cont=
aining 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 remainin=
g two thirds is added rapidly with efficient stirring, and the resulting su=
spension is heated rapidly to the boiling point and allowed to cool to room=
 temperature, after which it is placed in a refrigerator overnight. The pre=
cipitate 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 fi=
lter, washed with three 300-ml. portions of water and air-dried, yielding a=
bout 120 g. (97%) of indole-3-aldehyde, mp 196-197C. The indole-3-aldehy=
de resulting from this prodcedure is sufficiently pure for most purposes, b=
ut it may be recrystallized from ethanol if desired. --------------=
------------------------------------------------------------------ Ind=
ole-3-aldehyde from indole There was prepared a solution of 25.75 g indol=
e in 100 mL DMF. A second solution was also prepared by cooling 80 mL DMF i=
n 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 w=
armed to 25 C and the first solution of indole in DMF was added dropwise=
 (with continued stirring) over an additional 30 min. Stirring was continue=
d for yet another 45 min, during which time the temperature was raised to 4=
0 C. Yellow solids formed during this period. The reaction mixture was p=
oured onto chipped ice which produced a clear red solution. This was made b=
asic 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, afte=
r cooling again, the product was removed by filtration and washed with cold=
 H2O. This can be recrystallized from aqueous DMF to yield, after air dryin=
g, 24.5 g (84%) of indole-3-carboxaldehyde as faint orange needles. =

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

illed phosphorous oxychloride (55 ml) to dry DMFA (dimethylformamide, 100 m=
l) 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 sub=
strate (0.5 mol) in dry DMFA (100ml) at 100-110C (bath temp). Heating an=
d 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 satur=
ated brine, and finally dried over Na2SO4; Yields, f.e. from 1,2,4-triMeo-b=
enzene, 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) --------------------------------------------------------=
------------------------ 2,5-dimethoxybenzaldehyde Pyrophosphoryl ch=
loride (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 h=
ours. The cold product was basified with an aqueous solution of 2M sodium h=
ydroxide and extracted with dichloromethane and dried (MgSO4) and concentra=
ted. Short-path distillation gave 2,5-dimethoxybenzaldehyde (0.332g 40%), m=
p 50-51C. bp 80C at 0.1 mmHg. Poor chemist's short-path distilla=
tion apparatus: Fit the collection flask directly to the distillation adapt=
er without condenser. Ref: Tetrahedron 49(19) 4015-4034 (1993) =

-------- Formylation of phenols with paraformaldehyde Drone: Hydroqu=
inone (or p-methoxyphenol), paraformaldehyde, SnCl4, and a dash of an aprop=
riate lewis base (Bu3N). Warm, and formylation is complete. Conditions are =
fascile, and yields are high. Methylate, and you got 2,5-diemthoxybenzaldeh=
yde. Osmium: This method only works for phenols. It is a selective or=
tho-formylation of phenols, producing salicylic aldehydes. FeCl3 and S=
nCl2 can most probably substitute for SnCl4 (with appropriate base concentr=
ation 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 ar=
e a little low, e.g. with p-MeO-phenol: about 60% conversion of starting pr=
oduct after 8 hours, I guess 24 hours would be right. In the general p=
rocedure 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 pa=
tented. US pat 4.151.201, if somebody wants to check it. "Treatment of=
 phenols with 2 mol equiv. of paraformaldehyde in aprotic and poorly electr=
on-donating solvents in the presence of selected metal halides coupled with=
 suitable bases produces salicylaldehydes in high yields. The route is high=
ly selective for ortho-formylation and also specific towards monoformylatio=
n..." 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 (5=
4 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 he=
ated 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 extr=
act was washed with satur. brine, dried over Na2SO4 and conc. to leave crud=
e aldehyde. Product was purified by steam distillation and if nesessary, by=
 subseq. distillation and recryst. from pet. ether. Yields, f.e. from p-met=
hoxy-phenol, 85%, mp 51-52C. Ref: JCS Perkins I, (1980) 1862-1865 =

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

of 2,6-xylenol (100 mmol), 14.0 g of HMTA (aka urotropine, hexamine or hexa=
methylenetetramine) (100 mmol) and 150 ml of trifluoroacetic acid was heate=
d at reflux (83-90 C) for 12 hrs. The product were concentr. and combined w=
ith 600 ml of ice water; the resulting mixture was stirred 15 min, made bas=
ic with Na2CO3 and extracted with ether. Evapn of the ether soln left a yel=
low solid which was recryst. from CHCl3-pentane to afford 14.3 g of 3,5-dim=
ethyl-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 f=
ormylation process for producing aldehydes (US4755613) The invention rela=
tes to a process for preparing aromatic or hetero-aromatic aldehydes by the=
 Reimer-Tiemann formylation reaction. The process comprises employing a sol=
id alkaline hydroxide in order to carry out the reaction in a solid/liquid =
medium. Such a process makes it possible to substantially increase the yiel=
d 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 cm=
3 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 mo=
le of initial compound) and to 12.6 times as much chloroform as initial com=
pound (expressed in moles). Thereupon the temperature of the reaction mediu=
m is raised to 58 C. for one hour. Next 12 g of sodium hydroxide in powd=
ered form are progressively added over a period of two hours, the temperatu=
re 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 re=
sidual chloroform is recovered and recycled. The mixture of aldehydes is ob=
tained in sodium form. It is neutralized until a neutral brine is obtained.=
 The salicylaldehyde can be recovered in conventional manner at a yield clo=
se to 77% (9.4 g) with respect to the initial phenol by carrier vapor disti=
llation or by ether extraction. The p-hydroxybenzaldehyde is recovered at a=
 yield of 17% (2 g) by ether extraction from the acidified residual brine t=
o 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 m=
echanical stirrer and a thermometer. Next 16 g of pulverulent sodium hydrox=
ide 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 a=
s initial compound. Thereupon the mixture is slowly returned to ambient tem=
perature 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 mi=
xture 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 pha=
se and is dried on sodium sulfate. The aqueous phase is extracted again wit=
h 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 ch=
loroform and 7.7 g of syringol are placed in a 250 cm3 reactor having a coo=
lant, a mechanical stirrer and a thermometer. The mixture is treated ultras=
onically for 6 hours in a "BRANSONIC" cleaning tank (47 kHz, 180 w, 3 ceram=
ics). 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 hyd=
ration 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 chlorofor=
m as initial compound expressed in moles. For a lesser hydration, the yield=
 drops considerably. The reaction proceeds in the tank under ultrasonics, a=
t 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-Ti=
emann formylation of 4-methoxyphenol 200g of 4-methoxyphenol were diss=
olved 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 t=
here 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 f=
or 1 hr at the same temperature and atmospherical pressure. After cooling, =
the precipitated salt of 2-hydroxy-5-methoxybenzaldehyde was filtered and w=
ashed 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 re=
duced 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 f=
or the formation of Vilsmeier complex. Vilsmeier-Haack reaction with Oxalyl=
 Chloride: (for further details see US Pat 5599988)2,4-Dihydroxybenzaldehyd=
e: 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 ac=
etonitrile (350 mL). The reaction is treated dropwise with a solution of ox=
alyl 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. Ga=
s evolution is noted and a thick precipitate forms. The reaction is stirred=
 at ambient temperature for 1 h to insure complete conversion to the Viisme=
ier 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 wit=
h hexane (30-40 mL) and the product dried. The Vilsmeier formamidinium chlo=
ride 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. Hydrolysis: To water (250 mL) stirred at=
 40 C. is added the above salt (42.3 g, 0.209 mole) in three portions. T=
he reaction is heated to 50 C. for 0.5 h, and the reaction is cooled. Wh=
en 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 c=
ooled to 5 C., and stirred for 2 h. The mixture is filtered, the solid i=
s washed with cold water, and air dried at <35 C for 24 h giving 2,4-di=
methoxybenzaldehyde (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 id=
entical to that produced by the Vilsmeier-Haack reaction with phosphorus ox=
ychloride . Obviously, from hydroquinone one can prepare 2,5-dihydroxy=
benzaldehyde (and further methylate it). --------------------------=
------------------------------------------------------ Vilsmeier-Haack=
 reaction with thionyl chloride (US4157333) Piperonal A process for =
preparing piperonal which comprises the steps of reacting 1,2-methylenediox=
ybenzene with an N-alkylformanilide and a condensing agent comprising one o=
r more compounds selected from the group consisting of phosgene, phosphorus=
 oxychloride, phosphorus oxybromide, thionyl chloride, thionyl bromide, sul=
furyl chloride, sulfuryl bromide, phosphorus trichloride, and phosphorus pe=
ntachloride, and then hydrolyzing the resulting reaction product. To 1=
08 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. Afte=
r completion of the addition, the mixture was allowed to stand at room temp=
erature for 2 hours and then heated at 40-50 C. for 1 hour under a re=
duced 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 co=
mpletion 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 t=
oluene was removed and the distillate at 84-85 C./30 mmHg was then co=
llected to recover unreacted 1,2-methylenedioxybenzene. Subsequently, the d=
istillate at 131-134 C./10 mmHg was collected to obtain piperonal. Th=
e yield (expressed in terms of mole percentage based on the amount of N-met=
hylformanilide used) and selectivity (expressed in terms of mole percentage=
 based on the amount of 1,2-methylenedioxybenzene having reacted) of pipero=
nal were 55,6% and 95,1%, respectively. ---------------------------=
----------------------------------------------------- Reimer-Tiemann f=
ormylation of 4-Methoxyphenol (Org. React. Vol 28 p16) Into a 2000ml thre=
e neck flask was placed 125g (1 mol) 4-Methoxyphenol and a still hot soluti=
on of 320g (8 mol) NaOH in 400ml H2O (Addition while hot helps the phenol t=
o dissolve and avoid carbonate formation). The flask was set with a reflux =
condenser, dropping funnel and thermometer (using a Claisen adaptor) and me=
chanical stirrer then heated to ~70C on the oil bath. When this temperat=
ure had been reached, chloroform (160ml, 2 mol) was added dropwise (and por=
tionwise) over the course of 4 hrs while maintaining the stirring and tempe=
rature, 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 re=
action was allowed to stir for a further hour at the same temperature, allo=
wed 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 tr=
ansferred into a flask with some clean water and steam distilled (collect ~=
5000ml distillate). Quite a volume of black tar remains after this distilla=
tion. The yellow oil in the distillate was extracted with DCM and evaporate=
d to yield 112g (74%) 2-hydroxy-5-methoxy-benzaldehyde, can be further puri=
fied 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 oxidati=
on. ---------------------------------------------------------------=
----------------- Reimer-Tiemann formylation of 4-Methoxyphenol (Arch.=
 Pharm. 308, p341 (1975)) 160 g (4 Mol) NaOH and 62 g (0.5 Mol) 4-Methoxy=
phenol was dissolved in 600 ml of water, to which was added 120 ml of ethan=
ol. 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 eth=
anol and CHCl3 were removed in vacuo, and the solution was acidified to a p=
H of 3 by addition of 10N H2SO4. The dark-colored organic phase was extract=
ed with ether [and separated], the ether was removed, and the residue was f=
urther processed using steam. The 2-Hydroxy-5-methoxy-benzaldehyde came ove=
r using about 6-8 l of water and was separated off. The remaining aqueous d=
istillate was saturated with NaCl and extracted with ether. The 2-Hydroxy-5=
-methoxy-benzaldehyde and the ethereal extract were combined, and dried ove=
r MgSO4. After removal of the solvent, there remained 48 g (63% yield) of t=
he 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 [J=
ournal of the Chemical Society, London, page 1691 (1932)] by the condensati=
on of 2,6-dihydroxytoluene with zinc cyanide and excess hydrogen chloride.=

g of N-methyl-formanilide and 300 ml of benzene in a 3-necked five liter fl=
ask fitted with an agitator, reflux condenser, dropping funnel and thermome=
ter. After a homogeneous solution is obtained by agitation at room temperat=
ure, 808 g of phosphorus oxychloride are added over a period of 2 hours, ma=
intaining the reaction temperature at 25-30C. After the addition is comp=
leted, agitation is continued for about 4 hours at 25-30C with occasiona=
l 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, fol=
lowed by the addition with agitation of 2000 ml of a 50% aqueous sodium ace=
tate solution over a period of 50 minutes (exothermic) allowing the reactio=
n temperature to rise to a maximum of 65C. The reaction mixture is coole=
d to 20C and 1000 ml of a 50% aqueous acetate solution (precooled to 25=
C) are added under agitation in one portion. 800 ml of ethyl acetate (so=
lvent) 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 wit=
h 200 ml of water. The solvent (ethyl acetate) is removed by distillation u=
nder vacuum from a steam bath. The crude reaction product is cooled to 20=
C 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 metha=
nol. This first crop weighed 310g, with a mp of 158-160C (GLC: 100%) =

e reaction mixture separates into two layers. The organic layer is washed t=
hree times with 200 ml portions of water and neutralized with a 10% aqueous=
 solution of sodium bicarbonate. The solvent is removed by distillation fro=
m a steam bath under an ejector vacuum. The formed crystals are collected o=
n 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 156-158=
C (GLC: 100%) The combined two crops from above are placed in a 3 l=
iter 3-necked flask with an agitator and 1500 ml of water are added. The pr=
oduct is steam distilled for approximately 1 hour. The steam distillation i=
s 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-benzalde=
hyde having a melting point of 151.5-152.5C result after distillation=
. -----------------------------------------------------------------=
--------------- Paraformaldehyde/Mg(OMe)2 Phenol Formylation This fo=
rmylation is high-yielding and requires no special chemicals to ortho-formy=
late phenols. A weak vacuum is used during the reaction to remove formed vo=
latile by-products. It would be very well suitable for formylation of p-met=
hoxyphenol. Another variation in the patent, which uses a dash of added pyr=
idine 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 solutio=
n 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 rig=
ged for a fractional vacuum distillation and an azeotrope of methanol/tolue=
ne 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 mi=
xture over a 1-hour period while maintaining the reaction temperature at 70=
C and the pressure at 350 mm Hg. When the addition of glacial acetic aci=
d was complete, solid paraformaldehyde (46 g, a commercial sample containin=
g 5-7% by weight water) was added over a 105-minute period. The reaction mi=
xture was maintained at a temperature of 65C and a pressure of 350 mmHg,=
 during the addition of paraformaldehyde, and the volatile reaction by-prod=
ucts were continually removed. When the paraformaldehyde addition was compl=
ete, the reaction temperature was increased to 75C. and maintained at th=
at 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 w=
ater. The washed organic phase was then separated, dried and rendered free =
of the solvent to yield crude 5-nonyl salicylaldehyde. A 67% yield was obta=
ined. From Journal of the Chemical Society Perkins Transactions I, 182=
3-1831 (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 methan=
ol; 20.7 g, 0.24 mol) and the mixture was heated to reflux. Approximately h=
alf the methanol was distilled off and toluene (300 g) was added to the res=
idue. The azeotropic mixture of toluene and methanol was removed by fractio=
nal 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 wa=
s 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 w=
as stirred at 30-40 C for 2 h, after which the aqueous layer was separat=
ed and extracted with toluene (2x100 g). The combined organic layers and ex=
tracts were washed with 10% sulfuric acid (50 g) and water (50 g) and evapo=
rated 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 again=
st a commercial sample of known purity; 83% yield)... "2-Hydroxy-4-met=
hylbenzaldehyde 2c. and 2-Hydroxy-6-methylbenzaldehyde 2c. - In a similar w=
ay to that described above, 3-methoxyphenol (27.0 g, 0.25 mol), magnesium m=
ethoxide (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 co=
mprised 2-hydroxy-4-methylbenzaldehyde (64% by 1H NMR using 1,2-diphenyleth=
ane as the internal standard; 59% yield)... 2-Hydroxy-5-methoxybenzald=
ehyde 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 Magnesi=
um Methoxide Preparation Here are some references for articles describ=
ing 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 element=
al iodine as the catalyst, and heat (60C) Acta Chemica Scandinavica=
 (1999) 53(12), 1117-1121. Bulletin de la Societe Chimique du France, (1=
935) 5(2), Pp. 1202. Journal of Medicinal Chemistry, (1993) 36(6), Pp. 7=
58-764. Journal of the Chemical Society Dalton Transactions, (1983) Pp. =
2139-2142. Tetrahedron Letters, (1996) 37(29), Pp. 5159-5160. Zeitsch=
rift fr anorganische und allgemeine Chemie, (1967) Pp. 207,215.

ORGLIST - Organic Chemistry Mailing List
Website / Archive / FAQ:
To post a message (TO EVERYBODY) send to everybody$##$
To unsubscribe, send to everybody-request$##$ the message: unsubscribe your_orglist_password your_address

Date view Thread view Subject view Author view Attachment view

This archive was generated by hypermail 2.1.4 : Thu Feb 18 2010 - 16:58:10 EST