Organic Syntheses, CV 5, 582
Submitted by Edward C. Taylor, Wendell A. Ehrhart, and M. Kawanisi
1.
Checked by John J. Miller and William D. Emmons.
1. Procedure
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).
2. Notes
1. An open-end gas-inlet tube should be used rather than a fritted glass inlet because the latter becomes clogged.
2. Commercial
triethyl orthoformate, b.p. 50–52° (20 mm.) (Matheson, Coleman and Bell) is used without further purification. It has been reported that it is essential to this procedure that the
triethyl orthoformate be slightly wet. Commercial
triethyl orthoformate as available in the USA appears to fulfill this requirement, but the anhydrous reagent fails to react. If anhydrous
triethyl orthoformate is used, 3 drops of water should be added to ensure a slightly wet reagent (private communication from P. R. H. Speakman).
3. If the temperature is higher than 140°, the product is colored and the yield is lower.
4. This temperature decrease serves as a useful indication of the progress of the reaction.
5. The final temperature of the reaction mixture is usually 72–73°. Total working time is 60–70 minutes.
6. Recrystallization from
ethanol does not change the melting point.
7. This material is usually slightly colored and not so pure as the first crop.
3. Discussion
4. Merits of the Procedure
Because
formamidine hydrochloride is extremely deliquescent, considerable care must be exercised in its preparation if satisfactory results are to be achieved. Furthermore,
formamidine hydrochloride cannot be used directly in most condensation reactions; it must be treated first with a mole of base to liberate free
formamidine. The same restriction applies to the
methosulfate salt of formamidine; in addition, complications in synthesis may be anticipated in this latter case because
methyl hydrogen sulfate itself is an effective methylating agent.
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By contrast,
formamidine acetate is not hygroscopic and no particular care need be taken to protect it from atmospheric moisture. Furthermore,
formamidine acetate can be used directly without prior treatment with base in syntheses requiring free
formamidine.
2,7,8,9,10 Finally, this preparation of
formamidine is by far the simplest and most convenient yet reported; it obviates the necessity of using either toxic (
hydrogen cyanide) or cumbersome (
Raney nickel) reagents, and the method can be adapted to the preparation of N,N'-disubstituted formamidines by substitution of primary amines for
ammonia.
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