Organic Syntheses, CV 7, 433
Submitted by Asher Kalir and David Balderman
1.
Checked by Carl R. Johnson and Debra L. Monticciolo.
1. Procedure
Caution! The reaction should be carried out in a good hood.
A.
2-Azido-2-phenyladamantane. A
500-mL, three-necked, round-bottomed flask equipped with a
mechanical stirrer, a
pressure-equalizing dropping funnel, and a
thermometer is charged with
125 mL of chloroform and
13 g (0.2 mol) of sodium azide. The mixture is cooled with an
ice–salt bath to −5°C to 0°C, and
37.5 mL (0.5 mol) of trifluoroacetic acid is added, followed after 5–10 min with
22.8 g (0.1 mol) of 2-phenyl-2-adamantanol (Note
1). The resulting slurry is stirred for 4 hr at 0°C and then allowed to reach room temperature overnight. The mixture is cautiously neutralized with a slight excess of
12–15% aqueous ammonia solution and transferred to a
separatory funnel. The
chloroform layer is separated, and the aqueous solution is extracted with
50 mL of chloroform. The combined organic extracts are washed with 50 mL of water, separated, and dried over
magnesium sulfate. The solvent is removed in a
rotary evaporator. The oily residue solidifies on cooling. The yield is
23.6–24.8 g (
93–98%), mp
42–45°C. Recrystallization of a sample from
2-propanol raises the melting point to
47–48°C (Note
2).
B.
2-Phenyl-2-adamantanamine hydrochloride. A solution of
24 g (0.095 mol) of the crude 2-azido-2-phenyladamantane in
75 mL of 2-propanol is placed in a
1-L beaker fitted with a mechanical stirrer, and heated in a
water bath that can be removed quickly. Wet, active
Raney nickel (Note
3) and (Note
4) is added in portions at 60–70°C with stirring until the evolution of
nitrogen ceases (Note
5). The mixture is heated for an additional 10 min, filtered through a
Büchner funnel, and washed with
75 mL of 2-propanol in such a manner that the catalyst is always covered with liquid (Note
6). The filtrate is concentrated in a rotary evaporator under reduced pressure. The crude residue is dissolved in
75 mL of toluene and treated with
22 mL of concentrated hydrochloric acid while stirring. The
2-phenyl-2-adamantanamine hydrochloride is collected, triturated with
50 mL of warm acetone, filtered again, and air-dried. The yield is
22.5–24.0 g (
90–96%), and the product melts at
293–296°C (closed capillary) (Note
7) and (Note
8).
2. Notes
2. The product is characterized by IR (CCl
4) cm
−1: 2075;
1H NMR (CCl
4) δ: 1.72 and 2.40 (s, 14 H), 7.20 (s, 5 H).
3.
2-Adamantanone was obtained from Aldrich Chemical Company, Inc. Active
Raney nickel catalyst was obtained from W. R. Grace Company.
5. A large vessel is required because of excessive frothing. The frothing may be controlled by adding a little cold
2-propanol, by removing the heating, or by stopping the stirrer.
6.
Caution! Dry catalyst is pyrophoric.
7. The free
2-phenyl-2-adamantanamine may be liberated from the salt by adding a solution of
ammonia or
sodium hydroxide, extracting with
toluene, concentrating, and distilling under reduced pressure; bp
120–122°C (0.15 mm);
nD17 1.5850;
1H NMR (CCl
4) δ: 1.30 (s, 2H, NH
2), 1.68 and 2.26 (br s, 14 H, adamantane protons), 7.1 (m, 5H, Ph).
3. Discussion
The present procedure is an example of preparation of tertiary phenylcarbinylamines, and is in many cases superior to methods based on the Ritter reaction,
4 and Hofmann
5 or Curtius degradation.
6 The availability of starting materials, fair yields of products, and the simplicity of operations (there is no need to isolate any intermediates or to use a hydrogenation apparatus) are the main advantages of this procedure. The azide synthesis is adapted from procedures described for the preparation of
1,1-diphenyl-2-azidoethane7 and
1-phenyl-1-azidocyclohexane.
8 The azides are quite stable and could be distilled under reduced pressure. The amines and their substitution products are physiologically active agents.
4,9
A number of compounds have been prepared by this method (the isolation of hydrochloride can be omitted), as listed in Table I.
10
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