Organic Syntheses, CV 6, 492
Submitted by Michael F. Lipton
1, Anwer Basha
1, and Steven M. Weinreb
1,2.
Checked by Charles W. Hutchins and Robert M. Coates.
1. Procedure
Caution!
Benzene has been identified as a carcinogen; OSHA has issued emergency standards on its use. All procedures involving
benzene should be carried out in a
well-ventilated hood, and glove protection is required.
A dry,
300-ml., two-necked, round-bottomed flask equipped with a
reflux condenser fitted with a
nitrogen inlet at its top, a
rubber septum, and a
magnetic stirring bar is charged with
100 ml. of benzene (Note
1) and flushed briefly with
nitrogen, after which
22 ml. (0.057 mole) of a 25% solution of trimethylaluminum in hexane (Note
2) is injected through the septum into the flask. The solution is stirred and cooled in an
ice–salt bath at −10° to −15°, and
2.47 g. (3.64 ml., 0.0549 mole) of dimethylamine (Note
3) is added slowly with a syringe. Twenty minutes after the addition is completed, the cooling bath is removed, and the contents of the flask are allowed to stir and warm slowly to room temperature over a 45-minute period. A solution of
7.10 g. (0.0500 mole) of methyl cyclohexanecarboxylate (Note
4) in
20 ml. of benzene (Note
1) is injected through the septum. The resulting solution is heated under reflux for 22 hours, cooled to room temperature, and hydrolyzed by slow, cautious addition of
82.5 ml. (0.055 mole) of 0.67 M hydrochloric acid (Note
5). The mixture is stirred for 30 minutes to ensure complete hydrolysis. The upper organic layer is separated, and the aqueous layer is extracted with three
25-ml. portions of ethyl acetate. The organic extracts are combined, washed with
sodium chloride solution, dried with anhydrous
magnesium sulfate, and evaporated under reduced pressure. Distillation of the residual liquid under reduced pressure through a
10-cm. Vigreux column affords a 0.1–0.6 g. forerun of unreacted ester and
6.40–7.25 g. (
83–93%) of
N,N-dimethylcyclohexanecarboxamide, b.p.
100° (5.5 mm.),
57–60° (0.08 mm.) (Note
6).
2. Notes
3.
Dimethylamine was obtained in a cylinder from the Linde Division, Union Carbide Chemical Corporation, and condensed in a dry, two-necked flask fitted with a rubber septum and cooled to −78° under
nitrogen.
4.
Cyclohexanecarboxylic acid is available from Aldrich Chemical Company, Inc., and conveniently esterified by the procedure of Harrison, Haynes, Arthur, and Eisenbraun.
3 A dry,
500-ml., round-bottomed flask is charged with
225 ml. of anhydrous methanol,
1.0 ml. of concentrated sulfuric acid, and
41.0 g. (0.320 mole) of cyclohexanecarboxylic acid. The flask is fitted with a
Soxhlet extractor containing 53 g. of Linde type 3A molecular sieves and a condenser bearing a
calcium chloride drying tube at its top. The solution is heated at reflux for 19 hours and cooled to room temperature. The
sulfuric acid is neutralized by adding
3.0 g. of sodium hydrogen carbonate, the salts are filtered, and the filtrate is evaporated under reduced pressure. The remaining liquid is distilled through a
15-cm. Vigreux column at reduced pressure, affording
35.7–36.8 g. (
79–81%) of
methyl cyclohexanecarboxylate, b.p.
73–76° (13 mm.).
5. To avoid excessive foaming at the beginning of the hydrolysis, the checkers recommend that the
hydrochloric acid solution be added 1 or 2 drops at a time. The rate of addition may be increased once the initially vigorous foaming subsides.
6. The spectral properties of the product are as follows: IR (neat) cm.
−1: 1640 (C=O);
1H NMR (CDCl
3), δ (multiplicity, number of protons, assignment): 1.05–1.95 (m, 10H, 5C
H2), 2.50 (m, 1H, C
H), 2.94 (s, 3H, NC
H3), 3.06 (s, 3H, NC
H3). A boiling point of
107–108° (7 mm.) has been reported for
N,N-dimethylcyclohexanecarboxamide.
4
3. Discussion
This procedure,
5 based on the work of Ishii and co-workers,
6 affords a mild and general method for converting a wide variety of esters to primary, secondary, and tertiary amides (Table I). While the preparation of the tertiary amide,
N,N-dimethylcyclohexanecarboxamide, described here is carried out in
benzene, aluminum amides derived from
ammonia and a variety of primary amines have been prepared by reaction with
trimethylaluminum in
dichloromethane and utilized for aminolysis in this solvent. Although 1 equivalent of dimethylaluminum amides, prepared from amines, was generally sufficient for high conversion within 5–48 hours, best results were obtained when 2 equivalents of the
aluminum reagent, prepared from
ammonia, was used. Diethylaluminum amides can also effect aminolysis, but with considerably slower rates.
TABLE I
PREPARATION OF AMIDES FROM ESTERS BY AMINOLYSIS WITH DIMETHYLALUMINUM AMIDES5
|
Ester |
Amine |
Reaction Time (hours)a |
Isolated Yield of Amide (%) |
|
|
NH3 |
2b |
70 |
|
NH3 |
16 |
69 |
|
NH3 |
12 |
86 |
|
|
48 |
76 |
|
|
45 |
74 |
|
|
40 |
77 |
CH3CO2(CH2)3CH3 |
C6H5NH2 |
40 |
78 |
C6H5CO2C2H5 |
C6H5CH2NH2 |
25 |
93 |
|
(CH3)3CNH2 |
45 |
79 |
|
|
|
Although the preparation of carboxamides by direct aminolysis is a well-known and widely studied reaction,
7 the synthetic utility of this process is limited. The reactions generally require long heating periods at relatively high temperatures, and the reagents and catalysts used are usually strong bases.
8 The present procedure has the advantages of lower temperatures and moderate reaction times. The aluminum amides are conveniently prepared
in situ and appear to be mild, nonbasic reagents, compatible with many functional groups.
5 The isolation is simple, since hydrolysis of the aluminum reagents and products affords only methane and acid-soluble aluminum salts. Another advantage is that amides of volatile amines may be prepared without the use of
sealed tubes.
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