Organic Syntheses, Coll. Vol. 5, p.300 (1973); Vol. 41, p.13 (1961).
Caution! Isocyanides should be prepared in a hood since they have pungent odors and some are known to be toxic.
A solution consisting of 127 g. (1.00 mole) of N-cyclohexylformamide (Note 1)
, 500 ml. (490 g., 6.2 moles) of pyridine
, and 300 ml. of petroleum ether
) is charged into a 2-l., three-necked, round-bottomed flask
equipped with a Hershberg stirrer
,2 dropping funnel
, reflux condenser
, and thermometer
. The flask is immersed in an ice bath
, and 92 g. (0.60 mole) of phosphorous oxychloride
is added from the dropping funnel to the stirred mixture in the course of 30–40 minutes. The mixture is stirred under reflux for 10 minutes after all the phosphorus oxychloride
is added. The mixture is then cooled to 0–5°; this converts it to a heavy slurry. Ice water (800 ml.) is gradually added with stirring, and stirring of the cold mixture is continued until all solid material has dissolved. The organic phase is separated in a separatory funnel
. The aqueous phase is extracted with three 60-ml. portions of petroleum ether
, and the extracts are combined with the organic phase, which is then extracted with three 100-ml. portions of water, dried over 20 g. of magnesium sulfate
, and distilled through a 40-cm. vacuum-jacketed Vigreux column (Note 2)
. The petroleum ether
is rapidly removed under slightly reduced pressure from a bath at a temperature not exceeding 50–60°. Cyclohexyl isocyanide
, a colorless foul-smelling liquid (Note 3)
, is collected at 56–58° /11 mm.
; weight 73–79 g.
The checkers prepared N-cyclohexylformamide
by slowly adding 260 g. (3.52 moles) of ethyl formate
with stirring to 396 g. (4.00 moles) of cyclohexylamine
in a flask immersed in an ice bath. After the exothermic reaction ceased, the solution was refluxed for 2 hours and distilled through a 25-cm. Vigreux column
to give 403 g.
) of N-cyclohexylformamide
, b.p. 137–138° /10 mm.
The checkers used a 50-cm. spinning-band column
In order to minimize resinification of the cyclohexyl isocyanide
, distillation should be as rapid as possible and the temperature in the still pot should not exceed 90°.
Of the numerous dehydrating agent/base systems which have been used in the preparation of isonitriles, the phosgene/tertiary amine system seems to afford the best yields. Examples of the phosgene
procedure may be found in reference 5
. The disadvantage of phosgene
is its extreme toxicity and the difficulty with which it is handled by the novice. The present procedure is therefore the best combination of convenience and safety for the preparation of aliphatic isocyanides boiling above ethyl isocyanide
. (Methyl and ethyl isocyanides
may be prepared by using high-boiling amines like quinoline
.) It has been applied to the synthesis of the following isocyanides:5 isopropyl
), and benzyl
). In preparing isopropyl isocyanide
or t-butyl isocyanide
, the petroleum ether
should be of boiling point 30–35°
, as otherwise it is difficult to separate these low-boiling isocyanides in the indicated yield, and, even then, substantial amounts of isocyanide are found in the petroleum ether
This preparation is referenced from:
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