Organic Syntheses, CV 6, 474
Submitted by Michel Gaudry
1, Yves Jasor, and Trung Bui Khac.
Checked by Bernard L. Müller and George Büchi.
1. Procedure
Caution!
Trifluoroacetic acid is highly toxic; consequently Part B of this procedure must be conducted in a
well-ventilated hood.
A.
Bis(dimethylamino)methane. 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. (
83–86%) of
bis(dimethylamino)methane, b.p.
81.5–83°.
B.
1-(Dimethylamino)-4-methyl-3-pentanone. A
100-ml., two-necked, round-bottomed flask equipped with a magnetic stirring bar and a
pressure-equalizing dropping funnel bearing a
calcium chloride drying tube is charged with
50 ml. of anhydrous trifluoroacetic acid (Note
2). The
trifluoroacetic acid is stirred and cooled in an
ice–salt bath at −10° to −15° while
10.2 g. (0.100 mole) of bis(dimethylamino)methane is added over a 50-minute period (Note
3). The temperature of the resulting solution of
dimethyl(methylene)ammonium trifluoroacetate is kept below −10° as
8.6 g. (0.10 mole) of 3-methyl-2-butanone (Note
4) is gradually added. The cooling bath is removed and the solution is heated in an
oil bath at 65° for 1.5 hours (Note
5). The temperature of the oil bath is then raised to 145° (Note
6). After 1.5 hours the solution is cooled and the
trifluoroacetic acid is neutralized by adding the contents of the flask dropwise to an ice-cold solution of
100 g. of potassium carbonate in 100 ml. of water (Note
7). The crystals are collected by filtering through a
sintered-glass Büchner funnel and washed with two
50-ml. portions of dichloromethane. The aqueous filtrate is extracted with four
50-ml. portions of dichloromethane. The
dichloromethane extracts are combined, washed with 50 ml. of water, dried over anhydrous
sodium sulfate, and concentrated with a
rotary evaporator. The concentrate, which amounts to
12.7 g. (Note
8), is distilled under reduced pressure through an
18-cm. column packed with Raschig rings (Note
9), affording
7.0–8.2 g. (
49–57%) of
1-(dimethylamino)-4-methyl-3-pentanone, b.p.
49° (3 mm.) (Note
10).
2. Notes
1.
Formaldehyde and dimethylamine are available as aqueous 37% and 40% solutions, respectively, from Aldrich Chemical Company, Inc.
2. 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.
5. The progress of the reaction can be monitored by taking
1H 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 NC
H3), 8.07 (broad m, 2H, N=C
H2).
7. Removing
trifluoroacetic acid by evaporation is tedious. The neutralization procedure given here produces insoluble salts that are readily separated by filtration.
8. The ratio of the isomeric amino ketones in the crude product can be determined from the relative intensities of the signals for the (CH
3)
2C grouping in a
1H NMR spectrum taken in
trifluoroacetic acid (see (Note
10)). In CDCl
3 these absorptions overlap.
9. 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.
10. The
1H NMR spectrum of the product in
trifluoroacetic acid shows that the isomeric purity is greater than 90%. The
1H NMR spectra for the isomeric amino ketones in both
trifluoroacetic acid and CDCl
3, δ (multiplicity, coupling constant
J in Hz., number of protons, assignment):
1-(dimethylamino)-4-methyl-3-pentanone (
trifluoroacetic acid), 1.16 (d,
J = 7, 6H, 2CC
H3), 2.98 (d,
J = 5, 6H, 2NC
H3), 3.31 (m, 4H, C
H2C
H2); (CDCl
3), 1.10 (d,
J = 7, 6H, 2CC
H3), 2.23 (s, 6H, 2NC
H3), 2.60 (s, 4H, C
H2C
H2);
4-(dimethylamino)-3,3-dimethyl-2-butanone (
trifluoroacetic acid), 1.53 (s, 6H, 2CC
H3), 2.45 (s, 3H, COC
H3), 3.15 (d,
J = 5, 6H, 2NC
H3), 3.40 (d,
J = 5, 2H, C
H2N); (CDCl
3), 1.12 (s, 5H, 2CC
H3), 2.13 (s, 3H, COC
H3), 2.18 (s, 6H, 2NC
H3), 2.41 (s, 2H, C
H2N).
3. Discussion
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 in
acetonitrile 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.
11 (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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