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Organic syntheses vol 58 - Sheppard W.A.

Sheppard W.A., Buchi G.H. Organic syntheses vol 58 - Wiley, 1978. - 123 p.
Download (direct link): organicsynthesesvol581978.pdf
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A dry 250-ml., one-necked, round-bottomed flask is equipped with a magnetic stirrer and a three-way stopcock. The flask is charged with 4g. (0.053 mole) of ethyl nitrite (Note 1), 4g. of dry tetrahydrofuran (Note 2), and 2.35 g. (0.033 mole) of pyrrolidine (Note 3). The stopcock is closed (Note 4), and the mixture is stirred at room temperature for 2 days. Excess ethyl nitrite, tetrahydrofuran, and the ethanol formed are removed from the N-nitrosopyrrolidine (Note 5) by stirring at 25° under reduced pressure (10 mm., water aspirator, Note 6) for 2 hours. The stopcock is fitted with a rubber septum, the air in the system is replaced by dry argon (Notes 4 and 7), and 50 ml. of tetrahydrofuran is injected by syringe. A solution of lithium diisopropyl amide is prepared in a separate dry 100-ml. flask by adding 21.1 ml. (0.034 mole) of a 1.61 M solution of butyllithium in hexane (Note 8) to a solution of 4.76 ml. (0.034 mole) of diisopropylamine (Note 9) in 25 ml. of tetrahydrofuran at —78° (dry ice-methanol bath) with
stirring under argon. The solution is warmed to 0° in 15 minutes and then added dropwise with a syringe within 4 minutes to the nitrosamine solution stirred at -78°. Stirring of the yellow to orange solution is continued at this temperature for 25 minutes. A solution of 5.46 g. (0.030 mole) of benzophenone in 12 ml. of tetrahydrofuran is then added dropwise by syringe (Note 10). The mixture is stirred for 12 hours at -78° and then warmed to 0° within 2 hours. After addition of 0.6 ml. (0.034 mole) of water, the flask is transferred from the argon line to a rotary evaporator (within the hood). Solvents and diisopropylamine are removed under reduced pressure in a 40° bath (Note 11). The remaining solid is dissolved with slight warming in 120 ml. of dry methanol (Note 12). Then 3.9 g. (66 equivalents) of Raney nickel (Note 13) is rinsed into the solution with 30 ml. of dry methanol. The reaction vessel is equipped again with the three-way stopcock, and the air in the flask is replaced by hydrogen (Note 7). The flask is filled five times with hydrogen from a balloon; during this operation vigorous stirring of the Raney nickel-methanol suspension is necessary. The flask is attached to a mercury bubbler to maintain 200 mm. of positive hydrogen pressure supplied from a cylinder, as shown in Figure 1. The reaction mixture is stirred for 3 hours at room temperature while a slow stream of hydrogen is passed through the system. The major part of the solution is decanted and filtered, and the remaining Raney-nickel suspension is extracted by
Figure 1
refluxing three times for 10 minutes each with 20 ml. of methanol (Note 14). The combined methanol solutions are concentrated under reduced pressure. The residue is dissolved in 150 ml. of ethyl ether and 100 ml. of water, the layers are separated (Note 15), and the aqueous layer is extracted three times with 50-ml. portions of ethyl ether. The combined extracts are dried over sodium carbonate and concentrated in a rotary evaporator to a total volume of 150 ml. Dry hydrogen chloride gas is bubbled into the solution with stirring until the mixture is acidic. The almost colorless precipitate of the hydrochloride is filtered, washed two times with 30-ml. portions of dry ethyl ether, and dried in a desiccator under reduced pressure for 3 hours. The product, m.p. 244-249° (dec.), weighs 5.99-6.11 g. (68-70% based on benzo-phenone). Analytically pure product is obtained by recrystallization from methanol-acetone, 5.06-5.20 g. (58-60%), m.p. 267-269° (dec.) (Note 16). The free base was obtained by treatment of the hydrochloride with 10% aqueous sodium hydroxide and extraction with ethyl ether to give colorless crystals, m.p. 82-83° (Note 17).
2. Notes
1. Ethyl nitrite is prepared as described in W. J. Semon and W. R. Damerell, Org. Syn., Coll. Vol. 2, 204 (1943), or purchased from Merck-Schuchardt and distilled before use, b.p. 17°. The volatile nitrite can be easily handled as a 50% tetrahydrofuran solution and stored in a refrigerator.
2. Technical-grade tetrahydrofuran, available from BASF-A G or Fisher Scientific Company, is dried by distillation, first from potassium hydroxide and then from lithium aluminum hydride. This tetrahydrofuran is used for all operations in this procedure. For a warning note regarding the purification of tetrahydrofuran, see Org. Syn., Coll. Vol. 5, 976 (1973).
3. Pyrrolidine, b.p. 87-88°, obtained from Aldrich Chemical Company, Inc. or BASF-A G is distilled from potassium hydroxide before use.
4. The three-way stopcock with standard-tapered joint must be securely fastened to the neck of the flask with wire, rubber band, or springs [see Figure 1 and D. Seebach and A. K. Beck, Org. Syn., 51, 39, 76 (1971)].
5. Nitrosamines are strong carcinogens2,3; N-nitrosopyrrolidine causes liver tumors in rats.2,4 Although the one-pot procedure described here prevents contact with the nitrosamine, utmost care must be used to avoid contact with the reaction mixture during all manipulations.
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