Checked by Curtis E. Adams and K. Barry Sharpless.
1. Procedure
Caution! Trimethylsilyl cyanide is very toxic. All reactions in this sequence should be carried out in a hood.
B.
trans-2-Isocyanocyclohexanol. A
250-mL, one-necked, round-bottomed flask is charged with
13.72 g (70 mmol) of [(trans-2-isocyanocyclohexyl)oxy]trimethylsilane,
12.12 g (210 mmol) of potassium fluoride (Note
7), and
100 mL of methanol. The reaction mixture is stirred magnetically for 5 hr at room temperature (23°C). The
methanol is removed under reduced pressure on a rotary evaporator to yield a white slurry. This slurry is added to the top of a
250-g, 60–200-mesh silica gel chromatography column and the column is eluted with
20% ethyl acetate–80% hexane solvent mixture (Note
8). The solvent is removed from those fractions containing the product under reduced pressure on a rotary evaporator to afford an oil that is redissolved in
methylene chloride, and the solution is filtered. The
methylene chloride is removed from the filtrate under reduced pressure on a rotary evaporator to yield
8.46 g (68 mmol,
97%) of white, crystalline
trans-2-isocyanocyclohexanol, mp
57.0–59.5°C (Note
9).
2. Notes
2.
Anhydrous zinc iodide was purchased from Alfa Products, Morton Thiokol, Inc., and used without further purification. In one run the checkers used
0.25 mmol of ZnI2 and obtained a better yield than when they used
0.19 mmol of ZnI2 (
84% yield instead of
73%).
4.
Cyclohexene oxide was purchased from Aldrich Chemical Company, Inc., and was used without purification.
5. The checkers also carried out this process in a fume hood. All glassware was rinsed afterward with
10% KOH solution or rinsed with
acetone and the rinses mixed with
10% KOH. The resulting
KOH solutions were treated with Chlorox overnight before being discarded.
6. This pure, colorless liquid showed the following physical properties: IR (neat) cm
−1: 2950, 2870, 2145, 1454, 1267, 1255, 1144, 1114, 1065, 1028, 931, 894, 884, 844, and 758;
1H NMR (60 MHz, CDCl
3/TMS) δ: 0.17 (s, 9 H), 0.95–2.30 (br m, 8 H), 3.00–3.73 (br m, 2 H);
1H NMR (250 MHz, CDCl
3) δ: 0.15 (s, 9 H), 1.25 (m, 3 H), 1.56 (m, 1 H), 1.67 (m, 2 H), 1.86 (m, 1 H), 2.13 (m, 1 H), 3.28 (m, 1 H), 3.56 (m, 1 H); density 0.882 g/mL.
8. Approximately 100-mL fractions are collected. The progress of the chromatography is followed by analysis of the eluting fractions with thin-layer chromatography developed with
iodine vapor. The checkers achieved equal success using
120 g of 70–230-mesh silica in a 30-mm × 250-mm column.
9. The product showed the following physical properties: IR (KBr) cm
−1: 3470, 3400, 2965, 2945, 2870, 2175, 1450, 1376, 1328, 1302, 1240, 1123, 1090, 1081, 1007, 919, 856, and 851;
1H NMR (60 MHz, CDCl
3/TMS) δ: 0.70–2.40 (br m, 8 H), 2.85 (d, 1 H,
J = 5), 3.00–3.90 (br m, 2 H);
1H NMR (250 MHz, CDCl
3) δ: 1.27 (m, 3 H), 1.56 (m, 1 H), 1.71 (m, 2 H), 2.02 (m, 1 H), 2.16 (m, 1 H), 2.35 (d, 1 H,
J = 4), 3.30 (m, 1 H), 3.60 (m, 1 H).
3. Discussion
This method of preparation of
trans-isocyanocyclohexanol is a version of our literature procedure.
2 It represents a general procedure that gives comparable yields with a wide variety of epoxides.
2 The method described is a new approach to the synthesis of isocyanides. Traditionally, isocyanides have been prepared by dehydration of formamides, the reaction of dihalocarbenes with primary amines, and the reaction of active halides and olefins with cyanides.
3,4,5
Isocyanides are useful intermediates because of their diverse reactivity.
4 The β-hydroxy isocyanides, which are prepared readily by our general procedure, are particularly useful because of their straightforward conversion to β-amino alcohols in acids and their catalyzed cyclization to oxazolines.
2
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