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Organic Synthess - McKusick B.C.

McKusick B.C., Boekelheide V., Emmons W.D. Organic Synthess - New York, 1963. - 134 p.
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The following examples may be cited to illustrate these generalizations. p-Toluic acid under conditions of the Birch reduction essentially as given in this procedure yields mainly 1,2,3,4-tetrahydro-/>-toluic acid (cis and tram) plus minor amounts of
1.4-dihydro-^-toluic acid (cis and tram)? o-Toluic acid gives
1.4-dihydro-0-toluic acid in 73% yield; 8 m-methoxybenzoic acid gives l,4,5,6-tetrahydro-3-methoxybenzoic acid in 32% yield;8
o-methoxybenzoic acid gives crude l,4-dihydro-2-methoxy-benzoic acid in 80% yield;10 3,4,5-trimethoxybenzoic acid gives
1.4-dihydro-3,5-dimethoxybenzoic acid in 87% yield;8 4-acet-aminobenzoic acid gives 1,4-dihydrobenzoic acid in 75% yield; * benzamide gives 1,4-dihydrobenzamide in 69% yield;8 m-meth-oxybenzamide gives l,4-dihydro-3-methoxybenzamide in 30% yield; • 3,4,5-trimethoxybenzamide gives l,4-dihydro-3,5-dimeth-oxybenzamide in 73% yield; * and 3,5-dimethoxybenzamide gives l,4-dihydro-3,5-dimethoxybenzamide in 59% yield.® Thus the present example of the Birch reduction illustrates a useful and general synthetic method for preparing dihydro aromatic derivatives.
1 Ciba Pharmaceutical Products Inc., Summit, New Jersey.
* H. Plieninger and G. Ege, Angew. Ckem., 70, SOS (1958).
* М. E. Kuehne and В. F. Lambert, J. Am. Chem. Soc., 81, 4278 (1959).
* G. W. Watt, Chem. Rev., 46, 317 (1950).
6 A. J. Birch, Quart. Rev. [London), 4, 69 (1950).
•A. J. Birch and H. F. Smith, Quart. Rev. (London), 12, 17 (1958).
7 C. D. Gutsche and H. H. Peter, Org. Syntheses, Coll. Vol. 4, 887 (1963).
8 A. J. Birch, J. Chem. Soc., 1950, 1551.
* A. J. Birch, P. Hextall, and S. Sternhell, Australian J. Chem., 7, 256 (1954).
10 М. E. McEntee and A. R. Pinder, J. Chem. Soc., 1957, 4419.
«-N,N-DIMETHYLAMINOPHENYLACETONITRILE (Glycinonitrile, N,N-dimethyl-2-phenyl-)
OH N(CH3)2
Submitted by Harold M. Taylor and Charles R. Hauser.1
Checked by W. Beuce Kover and John D. Roberts.
1. Procedure
A mixture of 1.5 1. of water and 624 g. (6.00 moles) of sodium bisulfite in a 5-1. beaker equipped with a mechanical stirrer is stirred until solution is complete. Benzaldehyde (Note 1) (636 g., 6.00 moles) is added and the mixture is stirred for 20 minutes, during which time a slurry of the benzaldehyde-bisulfite addition product is formed. A 25% aqueous solution of dimethylamine (1100 g.) containing 275 g. (6.13 moles) of the amine is run in, and stirring is continued as most of the addition compound dissolves. Hie beaker is immersed in an ice bath, and 294 g. (6.00 moles) of sodium cyanide (Caution! Toxic) is added over a period of 20-25 minutes.
The ice bath is removed after addition of the sodium cyanide, and the mixture is stirred for 4 hours. The organic layer is separated, and the aqueous layer is extracted with three 500-ml. portions of ether. The combined ethereal extracts and organic layer are washed with two 100-ml. portions of cold water and dried over anhydrous magnesium sulfate. The ethereal solution is filtered, and the ether is removed at atmospheric pressure. The feaidue is transferred to a vacuum distillation system and distilled under reduced pressure (Caution! See Note 2). The yield of «*dimethylaminophenylacetonitrile boiling at 88-90°/1.9-2.1 tan». i§ 842-844 g. (87-88%) (Notes 3 and 4).
2. Notes
1. Eastman Kodak benzaldehyde (white label grade) was used without further purification.
2. Occasionally the odor of hydrogen cyanide can be detected during the distillation, even when a trap filled with sodium hydroxide pellets precedes the usual trap cooled in dry ice and acetone to protect the pump. For safety, the vacuum pump should be placed in a hood, or provision should be made for the pump exhaust to be vented into a hood or out-of-doors during the distillation.
3. Anhydrous dimethylamine has been used by the submitters in a slightly different procedure to give yields up to 95% of the theory.
4. The checkers carried out the preparation with one-half of the specified quantities without any decrease in the yield.
3. Methods of Preparation
The procedure described above is a modification of that of Hauser, Taylor, and Ledford2 and of Luten3 which avoids use of anhydrous dimethylamine. It is related to the procedure of Goodson and Christopher4 that employs benzaldehyde, aqueous dimethylamine hydrochloride, and potassium cyanide.
The product can also be prepared from benzaldehyde, dimethylamine, and potassium cyanide in cold acetic acid and aqueous ethanol.5
4. Merits of the Preparation
The method can be used to prepare a number of a-aminonitriles from aliphatic or aromatic aldehydes and ketones and secondary aliphatic amines.®
The nitrile group of a-N,N-dimethylphenylacetonitrile can generally be replaced by an alkyl or aryl group of a Grignard reagent to form the corresponding tertiary amines.4-7 The a-hydrogen of the aminonitrile can be alkylated,2-7 and the resulting alkylation product can be converted to enamines2 or to ketones.7
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