Organic Syntheses, Coll. Vol. 6, p.474 (1988); Vol. 59, p.153 (1979).
Caution! Trifluoroacetic acid
is highly toxic; consequently Part B of this procedure must be conducted in a well-ventilated hood
A 500-ml., round-bottomed flask
equipped with a magnetic stirring bar
and a dropping funnel
is charged with 100 g. (1.0 mole) of aqueous 30% formaldehyde (Note 1)
. The solution is stirred and cooled in an ice bath
as 225 g. (2.0 moles) of a 40% solution of dimethylamine (Note 1)
in water is added dropwise. The resulting aqueous solution is allowed to stand overnight at room temperature, after which it is saturated with solid potassium hydroxide
. The two layers are separated, the upper layer is dried over potassium hydroxide
pellets, and the drying agent is removed. Distillation at atmospheric pressure through a Vigreux column
gives 85–88 g.
) of bis(dimethylamino)methane
, b.p. 81.5–83°
Formaldehyde and dimethylamine are available as aqueous 37% and 40% solutions, respectively, from Aldrich Chemical Company, Inc.
The submitters purchased trifluoroacetic acid from Prolabo, Paris, France, or E. Merck, Darmstadt, Germany
, and distilled it from phosphorus pentoxide
. This reagent is also available from Aldrich Chemical Company, Inc., and J. T. Baker Chemical Company.
The progress of the reaction can be monitored by taking 1
H NMR spectra at appropriate intervals. The following absorptions for dimethyl(methylene)ammonium trifluoroacetate
in trifluoroacetic acid
disappear as the reaction progresses: δ (multiplicity, number of protons, assignment): 3.89 (broad m, 6H, 2 NCH3
), 8.07 (broad m, 2H, N=CH2
Removing trifluoroacetic acid
by evaporation is tedious. The neutralization procedure given here produces insoluble salts that are readily separated by filtration.
The ratio of the isomeric amino ketones in the crude product can be determined from the relative intensities of the signals for the (CH3
C grouping in a 1
H NMR spectrum taken in trifluoroacetic acid
(see (Note 10)
). In CDCl3
these absorptions overlap.
To minimize losses of products during the distillation, the submitters used a circulating device to chill the condenser cooling water to 5–10°. In addition, the outlet to the vacuum line
was located as far as possible from the drip tip, and the receivers
were cooled in an ice bath.
H NMR spectrum of the product in trifluoroacetic acid
shows that the isomeric purity is greater than 90%. The 1
H NMR spectra for the isomeric amino ketones in both trifluoroacetic acid
, δ (multiplicity, coupling constant J
in Hz., number of protons, assignment): 1-(dimethylamino)-4-methyl-3-pentanone
), 1.16 (d, J
= 7, 6H, 2CCH3
), 2.98 (d, J
= 5, 6H, 2NCH3
), 3.31 (m, 4H, CH2
), 1.10 (d, J
= 7, 6H, 2CCH3
), 2.23 (s, 6H, 2NCH3
), 2.60 (s, 4H, CH2
), 1.53 (s, 6H, 2CCH3
), 2.45 (s, 3H, COCH3
), 3.15 (d, J
= 5, 6H, 2NCH3
), 3.40 (d, J
= 5, 2H, CH2
), 1.12 (s, 5H, 2CCH3
), 2.13 (s, 3H, COCH3
), 2.18 (s, 6H, 2NCH3
), 2.41 (s, 2H, CH2
The Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde
, and a primary or secondary amine.2 3
The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions, giving mixtures of isomeric β-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone,4
and the more highly branched β-amino ketone usually predominates.
In recent years a number of methods have been developed for the preparation of dialkyl(methylene)ammonium salts (Mannich reagents),5,6,7,8,9
and their use in Mannich-type condensation reactions under anhydrous conditions has improved the scope and efficiency of this important synthetic process.6,7,8,9,10,11,12,13
However, the orientation of the Mannich reaction may nevertheless be difficult to control. Apart from the work of the submitters, the preparation of isomerically pure Mannich bases has only been achieved by indirect methods in which specific enol derivatives are generated and allowed to react with dialkyl(methylene)ammonium salts.10,12,14
The Mannich reaction of β-keto esters affords isomerically pure β-dimethylamino β'-keto esters which may in turn be converted to specific α-methylene ketones.15
However, the β-amino ketones themselves are not as yet available by this method.
The submitters have found that the orientation of the reaction of Mannich reagents with unsymmetrical ketones in anhydrous solvents is highly dependent on the experimental conditions, the solvent, and the structures of the ketone and iminium ion reactants.11
Under conditions of kinetic control, the reaction of methyl ketones with dimethyl(methylene)ammonium trifluoroacetate
in trifluoroacetic acid
leads to amino ketones in which the more highly substituted isomer predominates (≥85% when the α'-position is tertiary and 80% when the α'-position is secondary). In contrast, reaction with diisopropyl(methylene)ammonium perchlorate
gives almost exclusively the less highly substituted isomer (100% when the α'-position is tertiary and 90% when it is secondary). Although the latter method directly affords the less highly substituted Mannich bases in yields greater than 80%, it cannot be utilized safely in large-scale preparative reactions owing to the hazardous nature of perchlorate salts.
The less highly substituted Mannich bases can also be prepared directly from ketones and dimethyl(methylene)ammonium trifluoroacetate
by the procedure reported here, which takes advantage of the isomerization of Mannich bases in trifluoroacetic acid
(In acetic acid
the Mannich bases undergo elimination of dimethylamine
to give α-methylene ketones.) This method is rapid and affords products, having an isomeric purity of at least 90%, without difficult separations. The 49–57%
yield of 1-(dimethylamino)-4-methyl-3-pentanone
obtained with this procedure compares favorably with the overall yields of amino ketones prepared by the indirect routes mentioned previously.
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