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%
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 125–130° (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 20–30 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 53.0–55.8 g. (83.8–88.2%), m.p. 162–164° (Note 6). Evaporation of the mother liquor under reduced pressure followed by chilling gives a small additional amount of product (1.0–2.2 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 85–140°, 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 140–146° and weighs 120–140 g. (27–31 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 (800–1000 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 end
,
Antoncho
