Org. Synth. 1946, 26, 45
DOI: 10.15227/orgsyn.026.0045
LEPIDINE
Submitted by Fred W. Neumann, Nolan B. Sommer, C. E. Kaslow, and R. L. Shriner.
Checked by Cliff S. Hamilton and Robert F. Coles.
1. Procedure
In a
500-ml. Erlenmeyer flask are placed
20 g. (0.11 mole) of pure 2-chlorolepidine1 (Note 1),
9.3. g. (0.11 mole) of powdered anhydrous sodium acetate, and
200 ml. of glacial acetic acid. The mixture is heated to about 70° and shaken until solution is complete. The solution is transferred to a
pressure bottle of an apparatus for catalytic reduction,
2 equipped with a heating element and a variable resistance. The flask is rinsed with two
10-ml. portions of hot glacial acetic acid. Then
3 g. of palladium on carbon is added
(Note 2), the bottle is attached to the shaking machine, and the variable resistance is adjusted until the temperature of the liquid is between 55° and 70°
(Note 3). The bottle is swept out with
hydrogen, an initial pressure of about 1.8–2.2 atm. (26–33 lb.) is applied, and the shaking is started.
Hydrogen absorption is rapid during the first 15 minutes and then gradually slackens; the theoretical amount is absorbed in 1.5–2 hours. To ensure complete reduction, shaking is continued an additional 30 minutes. The warm acid solution is separated from the catalyst by filtration through a 1- to 2-mm. layer of Norit on a
Büchner funnel. The bottle and funnel are washed with three
30-ml. portions of glacial acetic acid. The
acetic acid is removed from the combined filtrates by heating to 70° under reduced pressure (
water pump, 25 mm.). The residue is dissolved in 50 ml. of water and transferred to a
500-ml. separatory funnel, an additional 25 ml. of water being used for washing. The water solution is made basic to litmus with
30% sodium hydroxide (about 40–100 ml.) and extracted with one
100-ml. portion of ether and then with two 50-ml. portions. The
ether extracts are combined and dried overnight with about
30 g. of solid potassium hydroxide. The
ether is removed by distillation from a
250-ml. flask, and the residue is transferred to a
modified 50-ml. distilling flask (Note 4), three
5-ml. portions of anhydrous ether being used to ensure complete transference. After the
ether is removed, the residue distils at
126–127°/14–15 mm. The product is colorless, water clear, and weighs
13–14 g. (
81–87%)
(Note 5) and
(Note 6).
2. Notes
1.
Pure
2-chlorolepidine, m.p.
58–59°, should be used.
2.
The catalyst is previously prepared in an apparatus for catalytic hydrogenation,
2 in which are placed
0.5 g. of palladous chloride,
3.0 g. of Norit, and 20 ml. of distilled water. The bottle is swept out with
hydrogen and then shaken with
hydrogen for 2–3 hours at 2–3 atm. (40 lb.) pressure. The
palladium on
carbon is collected on a Büchner funnel, washed with five 50-ml. portions of distilled water, then with five
50-ml. portions of 95% ethanol, and finally twice with
ether. Upon drying, about
3 g. of the catalyst is obtained. It is stored in a
vacuum desiccator over solid
sodium hydroxide. If the reduction of the
chlorolepidine does not proceed normally, the used catalyst should be removed by suction filtration and a fresh 3-g. portion of catalyst added. Failure of the reduction step is usually due to an inactive catalyst or to impurities in the
acetic acid or
chlorolepidine. The
palladium catalysts, prepared as described elsewhere in this volume, are also satisfactory for the reduction of
2-chlorolepidine.
3.
The reduction does not proceed smoothly at room temperature with the
palladium catalyst.
Raney nickel may be used as a catalyst with
ethanol containing
potassium hydroxide at room temperature, but about 15 hours is required for reduction.
4.
The submitters used a special flask having the shape and dimensions shown in
Fig. 17. The two necks were wrapped with asbestos cord. The checkers used an
ordinary Claisen flask (50 ml.).
Fig. 17.
5.
By distillation of the crude product from four runs, a yield of
92% was obtained.
6.
The submitters have followed the same procedure in preparing the compounds listed below from the corresponding 2-chloro derivatives. The
ether extractions and distillation steps were omitted when solid products were obtained.
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Product
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%
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%
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Compound
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Crude
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Purified
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B.P. or M.P.
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6-Methyllepidine
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100
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87
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B.p. 137°/12 mm.
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8-Methyllepidine
|
94
|
90
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M.p. 54–55°
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5,8-Dimethyllepidine
|
96
|
86
|
B.p. 154–56°/13 mm.
|
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6,8-Dimethyllepidine
|
100
|
91
|
M.p. 55–56°
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6-Methoxylepidine monohydrate
|
100
|
80
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M.p. 50–52°
|
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5,8-Dimethoxylepidine
|
98
|
90
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M.p. 94–95°
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2-Methyl-6-methoxyquinoline *
|
96
|
..
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M.p. 62–65°
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* From 2-methyl-4-chloro-6-methoxyquinoline.
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3. Discussion
The process described above is essentially that of Ainley and King,
3 who prepared
6-methoxylepidine.
Lepidine has also been prepared by the reduction of
2-chlorolepidine with
hydrogen and
Raney nickel,
4 with
tin5,6,7 8 or zinc7 and hydrochloric acid, and with concentrated
hydriodic acid and red phosphorus;
9 by the reduction of
2-iodolepidine with
iron and dilute sulfuric acid;
10 by the
zinc dust distillation of
2-hydroxy-4-methylquinoline under reduced pressure
11 or of
2-hydroxy-3-cyano-4-methylquinoline;
12 by the reduction of
2-hydroxy-4-methylquinoline with concentrated
hydriodic acid and
red phosphorus;
13 by the distillation of
1,2,3,4-tetrahydroquinoline-4-carboxylic acid with
zinc dust in a stream of
hydrogen;
14 by decarboxylation of
4-methylquinoline-2-carboxylic acid;
15 by leading vapors of
aniline and
crotonaldehyde over a contact catalyst at above 500°;
16 by heating
aniline and
vinyl methyl ketone with
sulfuric acid and nitrobenzene;
17 by heating
aniline and
β-hydroxyethyl methyl ketone in the presence of concentrated
sulfuric acid and
nitrobenzene18 or
aniline hydrochloride and ethanol;
19 by heating
aniline and
β-chloroethyl methyl ketone in the presence of concentrated
hydrochloric acid and
nitrobenzene or
arsenic acid20,21 or in the presence of
aniline hydrochloride,
ethanol, and
nitrobenzene;
22 by heating a mixture of
acetone, formaldehyde, and aniline hydrochloride;
23,24 by passing vapors of
acetylene and
aniline over
aluminum oxide at 360–420°;
25 and by passing vapors of
aniline and
acetaldehyde or
paraldehyde over
aluminum oxide in a
copper tube at 480°.
26 Campbell and Schaffner
27 have described the preparation of
lepidine in
70–73% yields by the reaction of
aniline hydrochloride with
methyl vinyl ketone,
1,3,3,-trimethoxybutane, or
1-methoxybutanone-3 in
ethanol in the presence of
ferric and zinc chloride.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
red phosphorus
ferric and zinc chloride
ethanol (64-17-5)
acetaldehyde (75-07-0)
sulfuric acid (7664-93-9)
acetylene (74-86-2)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ether (60-29-7)
sodium acetate (127-09-3)
aniline (62-53-3)
hydrogen (1333-74-0)
sodium hydroxide (1310-73-2)
formaldehyde (50-00-0)
iron (7439-89-6)
aniline hydrochloride (142-04-1)
tin (7440-31-5)
arsenic acid (1327-52-2)
Raney nickel (7440-02-0)
acetone (67-64-1)
carbon,
Norit (7782-42-5)
potassium hydroxide (1310-58-3)
zinc (7440-66-6)
palladium (7440-05-3)
Nitrobenzene (98-95-3)
hydriodic acid (10034-85-2)
palladous chloride (7647-10-1)
aluminum oxide (1344-28-1)
Lepidine (491-35-0)
2-Chlorolepidine,
chlorolepidine (634-47-9)
2-hydroxy-4-methylquinoline (607-66-9)
β-hydroxyethyl methyl ketone (590-90-9)
2-methyl-4-chloro-6-methoxyquinoline (50593-73-2)
6-Methyllepidine (826-77-7)
8-Methyllepidine (13362-80-6)
5,8-Dimethyllepidine
6,8-Dimethyllepidine
6-Methoxylepidine monohydrate
5,8-Dimethoxylepidine
2-Methyl-6-methoxyquinoline (1078-28-0)
6-methoxylepidine (41037-26-7)
2-iodolepidine
2-hydroxy-3-cyano-4-methylquinoline
1,2,3,4-tetrahydroquinoline-4-carboxylic acid
4-methylquinoline-2-carboxylic acid
crotonaldehyde (123-73-9)
vinyl methyl ketone,
methyl vinyl ketone (78-94-4)
β-chloroethyl methyl ketone (6322-49-2)
1,3,3,-trimethoxybutane (6607-66-5)
1-methoxybutanone-3 (6975-85-5)
paraldehyde (123-53-7)
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