Antoncho
(Official Hive Translator)
06-08-02 01:17
No 318797
      Another interesting and easy formylation
(Rated as: excellent)
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This is another formylation procedure that should work on an electron-rich aromatic nuclei. The authors of the Patent US4394314 where it all comes from test this procedure primarily on various anilines, but they say the rxn can bee carried out w/non-amino electron-rich compounds.

Given the fact that the rxn conditions they use for formylating, say, dimethylaniline are pretty much the same that for Vilsmeier on the same compd (ambient temp), it seems quite natural to assume that this method can bee applied to a variety of substituted dimethoxybenzenes that require similar or slightly harsher conditions than dimethylaniline to bee formylated. The good thing is that the rxn can withstand higher temperatures (compare Ex.'s #1 and #14), although the yield drops by some 10%.
In any case, the procedure definitely can bee applied to indole - yield 86%wink
The formylating agent used is formamidine acetate, the preparation of which is also included beelow.





1. Formation of the aminal.

EXAMPLE 1

Dimethylaniline (12.1 g), 100 ml toluene, 25 g acetic anhydride and 11 g of formamidine acetate are stirred together under a nitrogen blanket at room temperature. The precipitate which formed is filtered and dried to yield 23.5 g (94.4% yield) of ##STR17## (m.p. 258.degree.-260.degree. C.).

EXAMPLE 13

Indole (11.7 g), 100 ml toluene, 12 g formamidine acetate and 25 g acetic anhydride are stirred together at room temperature overnight. The resulting precipitate is filtered, washed with toluene and dried in a vacuum oven at 50.degree. C. to yield 21.1 g (86% yield) of ##STR30## a white crystalline material melting at 221.degree. to 222.degree. C.


2. Hydrolysis of the aminal to the aldehyde:

(from Example 22)
 The aminal (19 g), prepared as described above, is added to a mixture of 500 ml of water and 25 ml concentrated hydrochloric acid with good agitation. The resulting mixture is heated to 50.degree. C. and held at that temperature for 2 hours. Then the reaction mixture is cooled to room temperature and 30 ml of 30% aqueous sodium hydroxide is added with stirring. After stirring for an additional hour, the mixture is filtered and the filter cake washed alkali-free with water. The product is dried in a 50.degree. C. vacuum oven to yield 10.6 g (93.23% yield) of p-diethylaminobenzaldehyde.




As you can see, everything is very simple. Now to the prep'n of formamidine acetate:




From OrgSyn: http://orgsyn.org/orgsyn/prep.asp?prep=cv5p0582

In a 500-ml. three-necked flask equipped with a reflux condenser, a gas-inlet tube (Note 1) reaching to the bottom of the flask, a thermometer, and a magnetic stirrer is placed a mixture of 90.0 g. of triethyl orthoformate (Note 2) and 49.2 g. of glacial acetic acid. The flask is immersed in an oil bath maintained at 125130 (Note 3). When the internal temperature of the mixture reaches 115, a moderate stream of ammonia is introduced. As the temperature decreases gradually, vigorous refluxing is observed (Note 4). Formamidine acetate starts to crystallize from the boiling mixture after 2030 minutes. The ammonia flow is continued until no further decrease in temperature is observed (Note 5). The mixture is cooled to room temperature, the precipitate collected by filtration and washed thoroughly with 50 ml. of absolute ethanol. The yield of colorless formamidine acetate is 53.055.8 g. (83.888.2%), m.p. 162164 (Note 6). Evaporation of the mother liquor under reduced pressure followed by chilling gives a small additional amount of product (1.02.2 g.) (Note 7).




Now, to make it all yet more OTC i thought i'd add to this a prep of triethylortoformate, also from OrgSyn:



http://orgsyn.org/orgsyn/prep.asp?prep=cv1p0258

In a 5-l. round-bottomed flask, fitted with an 80-cm. reflux condenser, are placed 3 l. of absolute alcohol (Note 1) and 490 g. (327 cc., 4.1 moles) of chloroform (Note 2). The flask is arranged for outside cooling by running water. To the solution, 207 g. (9 atoms) of clean sodium cut into pieces which will conveniently drop through the condenser is added during the course of about two hours. In order to add the sodium at this rate, the flask must be cooled during the addition. When the sodium has entirely reacted and the mixture has been cooled to room temperature, the sodium chloride which has separated is removed by suction filtration with the use of thoroughly dry apparatus (Note 3). The salt is washed on the filter with 200 cc. of absolute alcohol, and the washings are allowed to run into the main filtrate.
The solution is placed in a 3-l. flask fitted with an 80-cm. fractionating column (Note 4), and the excess chloroform and most of the alcohol are distilled off on a steam or water bath. The distillate is caught in a 2-l. suction flask protected from moisture by a drying tube. This distillation requires five or six hours. A mixture of chloroform and alcohol, weighing about 2000 g., is recovered and saved for the next run (Note 3). The liquid remaining in the flask is decanted from the small amount of salt which has separated, into a Claisen flask with a 30-cm. fractionating column (Note 5). The mixture is distilled at atmospheric pressure. The fraction boiling below 85 is mainly alcohol and is discarded. An intermediate fraction of about 100 g., boiling at 85140, contains about one-fourth of the total yield. This may be fractionated but is best added to a subsequent run. The orthoformic ester is collected at 140146 and weighs 120140 g. (2731 per cent of the theoretical amount). There is practically no higher-boiling material. Another distillation gives almost all the material boiling over a 2 range.
After the first run, 400 g. of chloroform and enough absolute alcohol (8001000 cc.) are added to the recovered chloroform-alcohol mixture to give a total volume of 3 l. The sodium is then added as before. After the excess of chloroform and alcohol has been distilled through the fractionating column, the intermediate fraction from the previous run is added before fractionating. The yield from such a run is about 200 g. (45 per cent of the theoretical amount) (Note 6) and (Note 7).




Now, this is all so great, but still not quite satisfactory beecause of the need for metallic sodium in this last preparation - knowing Antoncho's fondness of OTC routes (BTW, i think this is actually the ONLY known to the date formylation of non-phenolic rings that doesn't use POCl3 and other similarly disgusting and hard-to-get shit) - the bees could sorta expect that. But! The link section to that procedure contains an old German (?) ref that claims a process for making triethyl formate from chloroform and alcoholic sodium hydroxide, here it is:

Walter, J. prakt. Chem. (2) 48, 231 (1893)

Could anyone try to find that ref, please?


Best regards to everyone who's read this till the endwink,


Antoncho
 
 
 
 
    Rhodium
(Chief Bee)
09-07-02 09:23
No 353838
      OTC preparation of triethyl orthoformate
(Rated as: excellent)
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This is a free translation of J. prakt. Chem. (2) 48, 231 (1893), thanks to Hypo who retrieved the original german reference. It was written in an unusual old style, much like the first-person accounts you see here at the Hive, like "I mixed A and B, and then this and that happened, which I believe is due to so and so..."

The reaction: CHCl3 + 3 EtOH + 3 NaOH -> CH(OEt)3 + 3 NaCl + 3 H2O

I find his closing comment especially amusing; "The procedure is not fully optimized, but I feel there is no need for me to do that, as triethyl orthoformate is nowadays commercially available."

Triethyl orthoformate can be synthesized in two ways, either by the action of ethanol on formimidoethyl ether (Ber. 16, 356 and 1645) or by treating an etheral solution of chloroform and ethanol with sodium (Ber. 12, 115). The first reaction is claimed to give a quantitative yield, but the reaction requires the use of very toxic anhydrous hydrogen cyanide. The second requires the use of flammable and corrosive sodium metal, and gives a relatively poor yield, only 31g (21%) of triethyl orthoformate could be isolated from a reaction between 120g chloroform and 70g sodium metal. Therefore, a method using aqueous sodium hydroxide was sought. A few trials can be seen below:

200g NaOH was dissolved in 300ml water, and 150g chloroform and 200g 95% ethanol was added. The flask was shaken vigorously from time to time, and cooled in an ice-bath whenever the exothermic reaction made the chloroform phase boil. This was continued throughout the day, and then the solution was allowed to stand overnight. The solution was then heated in a water-bath for one hour to remove unreacted chloroform and after cooling and dilution with water, the solution was extracted twice with ether, and the extracts distilled. The fraction boiling between 140-150C consisted of triethyl orthoformate and weighed 30g.

140g NaOH in 200ml water was heated in a flask with a reflux condenser to 60C, and during 6h, a mixture of 120g CHCl3 and 150g ethanol was added dropwise, during which time the temperature rose to 70C. The reaction mixture was then stirred for another 30 min, diluted with water, cooled and extracted with ether. Distillation of the extracts gave 19.5g triethyl orthoformate boiling at 140-150C.

When a mixture of 60g CHCl3 and 76g ethanol was added dropwise to 300g 20% NaOH at 65-75C, only 2ml of product could be isolated by ether extraction.

When 130g NaOH was dissolved in only 50ml water with heating, and a mixture of 120g CHCl3 and 155g ethanol was added dropwise after the solution had cooled to 65C, the stirrer almost got stuck, and the addition had to be carefully controlled as to not overflow the condenser. After half of the solution had been added, stirring was much easier. After workup, the yield was 16.5g, and a lot of high-boiling residue was present in the distillation flask.

An identical run with 155g NaOH in 100ml water gave only 10g yield. If 120g CHCl3 was added very slowly to an ethanolic solution of NaOH, and the mixture left at room temp for 8 days, no ester could be isolated. Replacing the NaOH with CaO was also fruitless.
 
 
 
 
    phenyl
(Stranger)
09-07-02 09:33
No 353841
      how electron rich?  Bookmark   

How electron rich are we speaking?  Benzothiophene does have electrons but they are not available like in nitrogen.  any thoughts?
 
 
 
 
    Rhodium
(Chief Bee)
09-07-02 09:42
No 353846
      Click the patent link in Antoncho's post for ...  Bookmark   

Click the patent link in Antoncho's post for yourself and read what the authors say. If you had, you would have seen that thiophene is formylated in the 2-position using this method. Benzothiophene should react the same.
 
 
 
 
    Antoncho
(Official Hive Translator)
09-07-02 23:03
No 354151
      VERY good!  Bookmark   

Dearest Hypo and Rhodium!

Thank you very much!

This is just what we needed!

Now making, say, indolecarboxaldehyde in the kitchen seems to bee a practical thing - not to mention all possible implications in the PEA world!

A great article!


Antoncho