Organic Syntheses, CV 6, 109
Submitted by P. Stütz and P. A. Stadler
1.
Checked by M. Cushman and G. Büchi.
1. Procedure
Caution! The following reactions should be conducted in a
well-ventilated hood, since in each step evil-smelling
sulfur compounds are either used as starting materials or generated during the reaction.
A.
2-Phenyl-1,3-dithiane. A
100 ml., two-necked, round-bottomed flask fitted with a
gas-inlet tube and a
drying tube containing glass wool is charged with
5.52 g. (5.28 ml., 0.0521 mole) of benzaldehyde,
5.6 g. (5.2 ml., 0.052 mole) of 1,3-propanedithiol, and
30 ml. of chloroform (Note
1). The flask is immersed in an
ice bath, and a slow stream of
hydrogen chloride gas is bubbled through the solution. When saturated (after
ca. 5 minutes), the reaction mixture is left at room temperature for 30 minutes, then evaporated at reduced pressure. The oily residue (Note
2) is taken up in
50 ml. of methanol and vigorously agitated to induce crystallization. The crystals are collected by filtration, washed with ligroin, and air dried. By condensing the mother liquors, two more crops may be obtained, giving a total of
9.5–9.7 g. (
93–95%) of
2-phenyl-1,3-dithiane, m.p.
69–70° (Note
3).
B.
2-Methylthio-2-phenyl-1,3-dithiane. A
2-l., three-necked, round-bottomed flask is fitted with a
mechanical stirrer, a gas inlet connected to a
nitrogen source, and a
pressure-equalizing dropping funnel. The apparatus is maintained under a positive pressure of
nitrogen and carefully protected from moisture throughout the ensuing reaction. The flask is charged with
37.2 g. (0.190 mole) of 2-phenyl-1,3-dithiane and
600 ml. of anhydrous tetrahydrofuran, and
0.228 mole of n-butyllithium in
hexane (Note
4) is placed in the funnel. With stirring, the flask is cooled with a −20° bath, and the
n-butyllithium solution is run into the flask over a 10-minute period. Stirring and cooling are continued for 2 hours, after which a solution of
32.2 g. (30.4 ml., 0.342 mole) of dimethyl disulfide (Note
5) in
50 ml. of anhydrous tetrahydrofuran is added over a 10-minute period. The cooling bath is then removed, and as the solution is stirred at room temperature a fine, white precipitate forms.
When the reaction mixture has been at room temperature for 90 minutes,
300 ml. of saturated aqueous sodium chloride is added slowly, followed by
500 ml. of chloroform. The resulting aqueous layer is separated and washed with three
100-ml. portions of chloroform, and the combined
chloroform solutions are dried with
sodium sulfate and decolorized with
activated carbon. Removal of
chloroform with a
rotary evaporator leaves an oily residue, which is readily crystallized from
100 ml. of methanol. The colorless crystals are collected by filtration and washed with
petroleum ether, giving
33.5–35.3 g. (
72–77%) of
2-methylthio-2-phenyl-1,3-dithiane, m.p.
76–78°. A second crop of crystalline product may be obtained from the mother liquors.
Stirring is continued for 2 hours at room temperature, and
methanol is added until a clear solution is obtained (
ca. 10 ml. of methanol is required, and some heat is generated). When the solution has cooled, it is washed successively with
200 ml. of aqueous 2 N potassium carbonate and 200 ml. of water. The aqueous phases are combined, washed with three
100-ml. portions of chloroform, and discarded. The organic phases are combined, dried over
sodium sulfate, and decolorized with activated
carbon. Concentration of the
chloroform solution obtained provides three crops of pale yellow crystals, which are washed with
30% hexane in chloroform and dried for 2 hours at 80°/0.1 mm, yielding
22.3–25.4 g. (
72–81%) of
3-(2-phenyl-1,3-dithian-2-yl)-1H-indole, m.p.
167–169° (Note
7). This material requires no further purification for use in Parts D or E.
D.
3-Benzoylindole. A
100-ml., three-necked flask fitted with a
magnetic stirring bar, a
condenser, and a pressure-equalizing dropping funnel is charged with
0.48 g. (0.0060 mole) of copper(II) oxide,
1.61 g. (0.0120 mole) of anhydrous copper(II) chloride (Note
8), and
40 ml. of acetone. The resulting suspension is brought to reflux with vigorous stirring, and a solution of
1.55 g. (0.00508 mole) of 3-(2-phenyl-1,3-dithian-2-yl)-1H-indole in
9 ml. of acetone and
1 ml. of N,N-dimethylformamide is added over 5 minutes. Reflux temperatures are maintained for 90 minutes, during which time the reaction mixture gradually turns yellow, then the mixture is cooled and filtered. The insoluble material is washed with three
20-ml. portions of hot 10% ethanol in dichloromethane, and the combined organic solutions are washed with
50 ml. of aqueous 2 N sodium carbonate (Note
9), dried over
sodium sulfate, and filtered. Concentration of the filtrate to a small volume under reduced pressure gives a residue which gradually deposits crystals. Filtration provides
0.94–0.97 g. (
85–88%) of pure
3-benzoylindole, m.p.
238–240°.
E.
3-Benzylindole. A suspension of
1.34 g. (0.0100 mole) of anhydrous copper(II) chloride (Note
8) and
2.72 g. (0.0200 mole) of anhydrous zinc chloride (Note
10) in
150 ml. of anhydrous tetrahydrofuran is prepared in a
500-ml., three-necked, round-bottomed flask fitted with a mechanical stirrer and a condenser connected to a
nitrogen source. This mixture is stirred at room temperature and maintained under a
nitrogen atmosphere while
3.04 g, (0.0800 mole) of lithium aluminum hydride is added cautiously in small portions (Note
11). The resulting exothermic reaction gives a black precipitate, which is stirred at room temperature for 45 minutes before
1.55 g. (0.00508 mole) of 3-(2-phenyl-1,3-dithian-2-yl)-1H-indole is added. Stirring is continued as the mixture is refluxed for 1 hour, cooled to room temperature, and quenched by careful dropwise addition of 10 ml. of water. The resulting slurry is diluted with
100 ml. of dichloromethane and filtered to remove inorganic salts, which are washed by digesting with three
50-ml. portions of refluxing dichloromethane. The combined filtrates are then washed with a solution of
4.0 g. (0.012 mole) of mercury(II) acetate in 100 ml. of water, dried over
sodium sulfate, filtered, and concentrated on a rotary evaporator, leaving about
1.1 g. of a yellow crystalline residue. Bulb-to-bulb distillation at 145–155° (0.1 mm.) yields
0.74–0.85 g. (
72–82%) of practically pure
3-benzylindole as pale yellow crystals, m.p.
102–105° (Note
12).
2. Notes
1.
benzaldehyde and 1,3-propanedithiol were purchased from the Aldrich Chemical Company, Inc., and used without further purification. Exclusion of moisture during the reaction is advantageous but not essential.
2. The checkers obtained a crystalline residue, which was triturated with
10 ml. of methanol and filtered.
5.
Dimethyl disulfide was obtained from the Aldrich Chemical Company, Inc., and used without further purification. The molar ratio used is the same as that in the original reference.
5
7.
1H NMR (CDCl
3), δ (multiplicity, coupling constant
J in Hz., number of protons): 1.5–2.2 (m, 2H), 2.7–3.0 (m, 4H), 7.0 (d,
J = 2.5, 1H), 7.1–7.5 (m, 6H), 7.7–8.2 (m, 4H). A sample recrystallized from
methanol–
chloroform melted at
183–185°. The submitters also obtained pure product, m.p.
181–183°, after chromatography on basic alumina with
20% petroleum ether in dichloromethane as eluent.
9. This extraction must be performed gently, since violent agitation will give an emulsion.
10.
Reagent grade anhydrous zinc chloride was obtained from Merck & Company, Inc.
11.
Lithium aluminum hydride was obtained from Fluka AG or from Ventron Corporation. One convenient technique for the addition is to weigh the reagent into an
Erlenmeyer flask, which is then connected to the reaction flask by a short piece of Gooch tubing. In this way the solid can be added in portions without exposing it to the atmosphere.
12. Various melting points are reported in the literature for
3-benzylindole:
96–98°,
7 103°, and 107°.
8
3. Discussion
There are other convenient methods for the preparation of
3-benzylindole7,8 and
3-benzoylindole.
9 The present procedure, however, has two useful elements of flexibility: it produces both 3-alkyl- and 3-acylindoles from a single precursor, and it tolerates the presence of a wide variety of substituents.
The pivotal step in this sequence is an electrophilic substitution on
indole. Although the use of 1,3-dithian-2-yl carbanions is well documented, it has been shown only recently that
1,3-dithian-2-yl carbenium ions can be used in a Friedel–Crafts type reaction. This was accomplished initially using
2-methoxy-1,3-dithiane or
2-methoxy-1,3-dithiolane and
titanium tetrachloride as the Lewis acid catalyst.
10 2-Substituted lysergic acid derivatives and 3-substituted indoles have been prepared under these conditions, but the method is limited in scope by the difficulties of preparing substituted
2-methoxy-1,3-dithianes.
1,3-Dithian-2-yl carbenium ions have also been prepared by protonation of ketene dithioacetals with
trifluroacetic acid,
11 but this reaction cannot be used to introduce
1,3-dithiane moieties into
indole.
The procedure described herein is fairly general for indoles, and since
2-methylthio-1,3-dithianes are readily available,
3,5 it should prove versatile. Two further examples are as follows:
In attempting to extend the method to other activated aromatics, it was found that pyrroles give mixtures of 2-and 3-substituted products, and that
naphthol ethers and
benzo[b]thiophene fail to react.
The hydrolytic step (Part D) uses conditions described by Narasaka, Sakashita, and Mukaiyama.
12 It was necessary to modify the original stoichiometry, since the recommended molar ratio of substrate:
copper(II) chloride:
copper(II) oxide (1:2:4) gave only a
57% yield of
3-benzoylindole. The more generally known
mercuric oxide-mercuric chloride hydrolysis
2 may also be used, and in the present case it gives a yield of about
90%. The reductive desulfurization of Part E, also based on the work of Mukaiyama,
13 is clearly superior to
Raney nickel desulfurization, which gives only
35–45% of
3-benzylindole.
Further, substantial progress leading to a generally applicable method is shown by the preparation of
2-chloro-1,3-dithiane and its application in electrophilic substitution reactions with reactive aromatic molecules like
phenol and
N,N-dimethylaniline.
17
So far, however, no reagent of the dithianylcarbocation type has been found which allows electrophilic substitution reactions with unactivated aromatic molecules such as
benzene.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
petroleum ether
2-methoxy-1,3-dithianes
2-methylthio-1,3-dithianes
mercuric oxide-mercuric chloride
ethanol (64-17-5)
potassium carbonate (584-08-7)
hydrogen chloride (7647-01-0)
Benzene (71-43-2)
methanol (67-56-1)
chloroform (67-66-3)
phenol (108-95-2)
sodium chloride (7647-14-5)
sodium carbonate (497-19-8)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
naphthol (90-15-3)
sulfur (7704-34-9)
mercury(II) acetate (1600-27-7)
benzaldehyde (100-52-7)
Raney nickel (7440-02-0)
acetone (67-64-1)
carbon,
activated carbon (7782-42-5)
zinc chloride (7646-85-7)
copper(II) chloride (7758-89-6)
xylene (106-42-3)
N,N-dimethylaniline (121-69-7)
copper(II) oxide (1317-38-0)
dichloromethane (75-09-2)
n-butyllithium (109-72-8)
Tetrahydrofuran (109-99-9)
lithium aluminum hydride (16853-85-3)
N,N-dimethylformamide (68-12-2)
Indole (120-72-9)
hexane (110-54-3)
titanium tetrachloride (7550-45-0)
boron trifluoride etherate,
boron trifluoride diethyl etherate (109-63-7)
calcium hydride (7789-78-8)
trifluroacetic acid (76-05-1)
dimethyl disulfide (624-92-0)
benzo[b]thiophene (95-15-8)
2-Butanol (78-92-2)
3-Benzoylindole,
Methanone, 1H-indole-3-ylphenyl- (15224-25-6)
1,3-propanedithiol (109-80-8)
2-Phenyl-1,3-dithiane (5425-44-5)
2-methylthio-2-phenyl-1,3-dithiane (34858-82-7)
3-Benzylindole,
1H-Indole, 3-(phenylmethyl) (16886-10-5)
1,10-phenanthroline (66-71-7)
1,3-dithian-2-yl carbenium
2-methoxy-1,3-dithiane
2-methoxy-1,3-dithiolane
1,3-Dithiane,
1,3-dithian (505-23-7)
1,3-dithian-2-yltrimethylammonium iodide
1,3-dithian-2-yl fluoroborate
trityl fluoroborate
2-chloro-1,3-dithiane
3-(2-phenyl-1,3-dithian-2-yl)-1H-indole (57621-00-8)
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