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Org. Synth. 1972, 52, 124
DOI: 10.15227/orgsyn.052.0124
REDUCTIVE AMINATION WITH SODIUM CYANOBOROHYDRIDE: N,N-DIMETHYLCYCLOHEXYLAMINE
[Cyclohexanamine, 4,4-dimethyl-]
Submitted by Richard F. Borch1
Checked by K. Abe and S. Masamune.
1. Procedure
A solution of 21.4 g. (0.262 mole) of dimethylamine hydrochloride in 150 ml. of methanol is prepared in a 500-ml., round-bottomed flask. Potassium hydroxide (4 g.) is added in one portion to the magnetically stirred solution (Note 1). When the pellets are completely dissolved, 19.6 g. (0.200 mole) of cyclohexanone is added in one portion. The resulting suspension is stirred at room temperature for 15 minutes before a solution of 4.75 g. (0.0754 mole) of sodium cyanoborohydride (Note 2) and (Note 3) in 50 ml. of methanol is added dropwise over 30 minutes to the stirred suspension. After the addition is complete, the suspension is stirred for 30 minutes. Potassium hydroxide (15 g.) is then added, and stirring is continued until the pellets are completely dissolved. The reaction mixture is filtered with suction, and the volume of the filtrate is reduced to approximately 50 ml. with a rotary evaporator while the bath temperature is kept below 45° (Note 4) and (Note 5). To this concentrate is added 10 ml. of water and 25 ml. of saturated aqueous sodium chloride, and the layers are separated. The aqueous layer is extracted with two 50-ml. portions of diethyl ether. The organic layer previously separated and the ethereal extracts are combined and extracted with three 20-ml. portions of 6 M hydrochloric acid (Note 6). The combined acid layers are saturated with sodium chloride and extracted with four 30-ml. portions of ether (Note 7). The aqueous solution is cooled to 0° in an ice bath and brought to pH > 12 by addition of potassium hydroxide pellets to the stirred solution (Note 8) and (Note 9). The layers are separated, and the aqueous layer is extracted with two 40-ml. portions of ether. The combined organic layers are washed with 10 ml. of saturated aqueous sodium chloride, dried over anhydrous potassium carbonate, and freed of ether with a rotary evaporator (Note 4). This crude product is fractionated through a 15-cm. Vigreux column (Note 10). After 1–3 g. of a forerun, b.p. 144–155° (Note 11) is separated, the fraction boiling at 156–159° is collected, yielding 13.3–13.7 g. (52–54%) of N,N-dimethylcyclohexylamine, n25D 1.4521 (Note 12).
2. Notes
1. Precipitation of potassium chloride begins immediately; the presence of this solid does not interfere with the reaction, and removal by filtration will result in loss of dimethylamine.
2. Sodium cyanoborohydride is available as a pale brown solid from Alfa Inorganics, Inc.
3. The commercially available material can be used without further purification. Use of material purified by the published procedure2 gives a less colored crude product, but makes no improvement in yield or purity of the final product.
4. Since the product boils at 75° (15 mm.), care should be exercised to prevent loss of material in the evaporation process.
5. It is normal for additional potassium chloride to precipitate as the evaporation continues.
6. Caution! This addition of hydrochloric acid into a separatory funnel occurs with considerable heat evolution, causing the ether to boil. The initial addition must be carried out with gentle swirling and cooling.
7. GC analysis shows that the ethereal extract contains solely cyclohexanol (>98%).
8. The aqueous layer in this step is saturated with ether, and the addition of potassium hydroxide must be carried out gradually to prevent the contents of the flask from boiling over.
9. Copious amounts of potassium chloride precipitate during this addition. It is not necessary to remove the salt by filtration before the ether extraction.
10. A still pot with a volume of at least 100-ml. should be used for the distillation, since foaming occurs as the distillation proceeds.
11. On a 2-m. GC column packed with 10% Apiezon L and heated to 100°, the retention times for N,N-dimethylcyclohexylamine and cyclohexanol are 15 and 4 minutes, respectively. The composition of this forerun is 80–85% of the amine and 20–15% of the alcohol.
12. GC analysis of the product shows that the product is at least 99.2% pure and is contaminated only with trace amounts of cyclohexanol. The submitter reported a 62–69% yield (15.7–17.5 g.) using the indicated scale.
3. Discussion
N,N-Dimethylcyclohexylamine has been prepared by catalytic reductive alkylation3,4 and by the Leuckart reaction.5 The present method is experimentally simple, requires no special apparatus, and is generally applicable to the synthesis of a variety of primary, secondary, and tertiary amines, as illustrated in Table I.
TABLE I
REPRESENTATIVE REDUCTIVE AMINATIONS WITH NaBH3CN2

Compound

Amine

Product

Yield, %


Cyclohexanone

NH3

Cyclohexylamine

45

Cyclohexanone

CH3NH2

N-Methylcyclohexylamine

41

Cyclohexanone

CH3NHCH3

N,N-Dimethylcyclohexylamine

53

Acetophenone

NH3

α-Phenylethylamine

77

Acetophenone

CH3NH2

N-Methylphenethylamine

78

Isobutyraldehyde

PhNH2

N-Isobutylaniline

78

Glutaraldehyde

CH3NH2

N-Methylpiperidine

43


The submitter has found that use of sodium borohydride instead of sodium cyanoborohydride in the present procedure results in the almost exclusive formation of cyclohexanol with less than 3% of basic material.

References and Notes
  1. Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
  2. R. F. Borch, M. D. Bernstein, and H. D. Durst, J. Am. Chem. Soc., 93, 2897 (1971).
  3. J. D. Roberts and V. C. Chambers, J. Am. Chem. Soc., 73, 5030 (1951).
  4. W. S. Emerson, Org. React., 4, 174 (1948).
  5. R. D. Bach, J. Org. Chem., 33, 1647 (1968).

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

NH3

CH3NH2

PhNH2

potassium carbonate (584-08-7)

hydrochloric acid (7647-01-0)

methanol (67-56-1)

ether,
diethyl ether (60-29-7)

Cyclohexanol (108-93-0)

Cyclohexanone (108-94-1)

sodium chloride (7647-14-5)

Acetophenone (98-86-2)

potassium hydroxide (1310-58-3)

dimethylamine (124-40-3)

dimethylamine hydrochloride (506-59-2)

potassium chloride (7447-40-7)

cyclohexylamine (108-91-8)

isobutyraldehyde (78-84-2)

α-Phenylethylamine (3886-69-9)

N-Methylphenethylamine (589-08-2)

glutaraldehyde (111-30-8)

N-Methylpiperidine (626-67-5)

sodium borohydride (16940-66-2)

sodium cyanoborohydride (25895-60-7)

Cyclohexanamine, 4,4-dimethyl-

N,N-Dimethylcyclohexylamine (98-94-2)

N-Methylcyclohexylamine (100-60-7)

N-Isobutylaniline