Org. Synth. 1995, 72, 125
DOI: 10.15227/orgsyn.072.0125
INDOLE-2-ACETIC ACID METHYL ESTERS: METHYL 5-METHOXYINDOLE-2-ACETATE
[1H-Indole-2-acetic acid, 5-methoxy-, methyl ester]
Submitted by Sandeep P. Modi
1, R. Christopher Oglesby
2, and Sydney Archer
1.
Checked by Katerina Matcheva and Ekkehard Winterfeldt.
1. Procedure
A.
5-Methoxy-2-nitrophenylacetic acid,
2.
3,4 A
1-L, three-necked, round-bottomed flask is equipped with a
magnetic stirring bar,
50-mL addition funnel, and a
reflux condenser fitted with an
inert gas (argon) inlet tube that is attached to a
mineral oil bubbler. The system is flushed with
argon, flame dried, cooled to room temperature, and maintained under a positive pressure of
argon. The reaction flask is charged with
18.8 g (0.34 mol) of anhydrous powdered sodium methoxide (Note 1) in
60 mL of anhydrous diethyl ether (Note 2). The flask is cooled in an
ice bath and
47.5 mL (0.35 mol) of diethyl oxalate (Note 1) is added over 5 min from the addition funnel. The ice bath is removed and the resulting mixture is stirred at room temperature for 15 min. At the end of this time a pale yellow, thick suspension results, to which
50 g (0.3 mol) of anhydrous powdered 3-methyl-4-nitroanisole,
1,
(Note 1) is added, followed by
75 mL of anhydrous ether (Note 2). The orange-red mixture is heated to reflux for 4 hr. After the flask is cooled to room temperature approximately 1 L of water is added to dissolve the resulting thick orange precipitate
(Note 3). The red solution is transferred to a
4-L beaker and kept cold using an ice-water mixture. Alternate portions of
30% hydrogen peroxide (Note 1) and
10 N sodium hydroxide (Note 4) are added to the cold red solution. Addition of
hydrogen peroxide bleaches the solution and addition of
sodium hydroxide restores the red color. This procedure is repeated 3 to 4 times until further addition of 10 N
sodium hydroxide solution does not result in a color change
(Note 5). The yellow brown solid is collected by filtration; it is impure starting material (wt 6–10 g)
(Note 6). The filtrate is poured into a 4-L beaker, cooled to 0°C, and acidified with concentrated
hydrochloric acid (Note 2) to precipitate
5-methoxy-2-nitrophenylacetic acid. The solid is collected on a
Büchner funnel, washed with cold water until the filtrate is neutral, and then dried to give
45.3–48.5 g (
70–75%) of an almost colorless product, mp
172–176°C (Note 7). Two recrystallizations in
methanol give colorless product, mp
175–176°C (Note 8).
B. Methyl (5-methoxy-2-nitrophenylacetyl)acetoacetate, 3 (
CAUTION, see (Note 13)). A 2-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, inert gas inlet, and two stoppers is flame dried and cooled to room temperature under an atmosphere of argon. The flask is charged with 42.5 g (0.20 mol) of 2 in 480 mL of anhydrous toluene (Note 2). To the resulting suspension is added 15.3 mL (0.21 mol) of thionyl chloride (Note 9) followed by 2 mL of anhydrous N,N-dimethylformamide (DMF) (Note 2). As soon as the DMF is added the color of the mixture turns light red. The mixture is stirred at room temperature overnight (Note 10). A 1-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, 250-mL pressure-equalizing funnel, and an inert gas inlet is flame dried and allowed to cool to room temperature under argon. The flask is charged with 10.1 g (0.49 mol) of 97% sodium hydride (Note 1) in 280 mL of dry tetrahydrofuran (THF) (Note 11) and then cooled to 0°C in an ice bath. A solution of 45.3 mL (0.42 mol) of methyl acetoacetate (Note 1) in 160 mL of dry THF (Note 11) is placed in the addition funnel and added dropwise to the reaction flask over a period of 45–50 min. After the addition is complete the light gray-colored solution is quickly transferred to a dried, 500-mL addition funnel (Note 12). The funnel is mounted on the flask containing the acid chloride solution. The solution of methyl acetoacetate anion is added to the crude acid chloride solution (Note 13) over 5 min and the resulting mixture is stirred overnight at room temperature. Water (350 mL) is added to the reaction mixture and the mixture is stirred for 15 min before being poured into a 2-L separatory funnel. The layers are separated and the aqueous layer is extracted with ether (2 × 150 mL). The combined organic layers are washed with brine and dried over sodium sulfate (Note 1). The filtered organic layer is concentrated under reduced pressure and the residue is dissolved in 100 mL of methanol. After cooling in the freezer overnight, the yellow crystals that separate are collected and dried to give 34.8–37.3 g (56–60%) of 3 (Note 14), (Note 15), suitable for use in the next step.
C. Methyl 4-(5-methoxy-2-nitrophenyl)-3-oxobutyrate, 4. A 1-L, three-necked flask equipped with a magnetic stirring bar, an inert gas inlet, and a stopper is charged with 25.2 g (0.08 mol) of 3 in 200 mL of reagent grade methanol (Note 2) followed by 20 mL of ammonium hydroxide (Note 2). The beige suspension turns red as soon as ammonium hydroxide is added. After about 15 min a white solid precipitates (Note 16). The mixture is stirred at room temperature for 30 min, filtered and the solid is washed with 10–15 mL of cold methanol. The filtrate is concentrated under reduced pressure and the residue is collected on a filter. This procedure is repeated once more (Note 17). After three filtrations the combined solid weighs 16.3–17.4 g (75–80%), which is suitable for use in the next step. Recrystallization from methanol gives a colorless product (Note 18).
D. Methyl 5-methoxyindole-2-acetate, 5. A flame dried, 1-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar and a condenser under argon is charged with 19.6 g (0.07 mol) of 4 followed by 450 mL of anhydrous methanol (Note 2). A slurry of 1.9 g of 10% palladium over activated carbon (Note 1) in 20 mL of anhydrous methanol is added to the flask (Note 19) followed by 53.5 g (0.8 mol) of ammonium formate (Note 1), (Note 20). The reaction mixture is stirred at room temperature for 1 hr (Note 21) and then filtered through a bed of Celite. The Celite is washed with 100 mL of anhydrous methanol and the solvents are removed under reduced pressure to give a beige solid. The residue is triturated with 350 mL of cold water and the insoluble material (Note 22) is filtered and then dried to give 13.5–14.3 g (84–89%) of 5 (Note 23).
2. Notes
1.
Sodium methoxide, 3-methyl-4-nitroanisole, diethyl oxalate, 30% hydrogen peroxide, 97% sodium hydride, methyl acetoacetate, sodium sulfate, 10% palladium on activated carbon, ammonium formate, and 5-methoxy-2-nitrophenylacetic acid were purchased from Aldrich Chemical Company, Inc., and were used without further purification.
2.
Anhydrous solvents such as
diethyl ether, N,N-dimethylformamide, toluene, and methanol were purchased from Mallinckrodt Inc. and were used without further drying. Concentrated
hydrochloric acid and ammonium hydroxide were also purchased from Mallinckrodt Inc.3.
Water was added in portions of 300–400 mL each to the reaction flask. The mixture was stirred for 5–10 min and the red solution was decanted into a separate flask. This procedure was repeated until all the solid went into solution.
4.
Sodium hydroxide was purchased from Fischer Scientific Company.5.
The total amounts of
30% hydrogen peroxide and 10 N
sodium hydroxide used were 60–70 mL and 20–25 mL, respectively.
6.
The melting point of the crude compound is
50–60°C; the NMR and IR correspond to starting material.
7.
The physical properties are as follows: m.p.
175–176°C (lit value:
3 174–176°C); IR (KBr) cm
−1: 3140–2740, 2660, 1715, 1620, 1580, 1510, 1410, 1340, 1320, 1290, 1260, 1200, 1175, 1090, 1040, 955, 850, 830, 760, 710, 630; NMR (DMSO-d
6) δ: 3.86 (s, 3 H, OCH
3), 3.97 (s, 2 H, CH
2), 7.04–7.10 (m, 2 H, H
4, H
6), 8.13 (d, 1 H, J = 8.8, H
3); MS m/e 212 (M+1).
8.
It is essential to have compound
2 as a colorless product; otherwise the yield in the next step is poor.
9.
Thionyl chloride was purchased from Aldrich Chemical Company, Inc., and distilled prior to use.
10.
If a clear solution did not result at the end of 16–18 hr, the mixture was warmed at 35–40°C for 1 hr or until a clear solution resulted; then it was cooled to room temperature.
11.
Reagent grade tetrahydrofuran was purchased from Mallinckrodt Inc. and freshly distilled from
sodium metal and
benzophenone.
12.
A
500-mL, pressure-equalizing funnel was
oven-dried and then cooled under
argon.
13.
5-Methoxy-2-nitrophenylacetyl chloride was never isolated from the reaction mixture. It is known
5,6 that
2-nitrophenylacetyl chloride is a potentially explosive material, but it is not documented that the 5-methoxy derivative is also hazardous.
5-Methoxy-2-nitrophenylacetyl chloride was also prepared as described by Rosenmund and his co-workers,
7 and was used in the crude form.
14.
Depending on the purity of the starting material, the yield of
3 has been as high as 80%.
15.
The analytical sample melted at
78–79°C after crystallization from
methanol. The spectra are as follows: IR (KBr) cm
−1: 2960, 2850, 1710, 1620–1390, 1350–1250, 1190, 1090, 1035, 950, 910, 890, 840, 760, 730, 630; NMR (CDCl
3) δ: 2.40 (s, 3 H, COCH
3), 3.84 (s, 3 H, COOCH
3), 3.99 (s, 3 H, OCH
3), 4.50 (s, 2 H, CH
2), 6.77 (d, 1 H, J = 2.6, H
6), 6.90 (dd, 1 H, J = 2.8, 9.0, H
4), 8.19 (d, 1 H, J = 9.0, H
3); MS m/e 310 (M+1).
16.
If there is no precipitate, a few crystals of starting material
3 are added to the reaction flask to initiate crystallization.
17.
After a total of three filtrations, the filtrate contained
5-methoxy-2-nitrophenyl-acetamide and
4-(5-methoxy-2-nitrophenyl)-4-oxobutyramide as the by-products in varying amounts.
18.
The physical properties are as follows: mp
85–87°C; IR (KBr) cm
−1: 3470, 3130, 2980, 2850, 1710, 1590, 1500, 1440, 1400, 1200, 1065, 1010, 865, 850, 760, 750, 700, 630, 620; NMR (CDCl
3) δ: 3.66 (s, 2 H, CH
2), 3.77 (s, 3 H, COOCH
3), 3.87 (s, 3 H, OCH
3), 4.20 (s, 2 H, ArCH
2), 6.73 (d, 1H, J=2.8, H
6), 6.89 (dd, 1 H, J = 2.8, 9.2, H
4), 8.19 (d, 1 H, J = 9.2, H
3); MS m/e 268 (M+1).
19.
Excess
ammonium formate was necessary for completion of the reaction.
20.
The slurry was prepared by adding ice-cold
methanol to
10% palladium on activated charcoal. The slurry was transferred to the reaction flask with a
pipet.
21.
The reaction was monitored by TLC, using silica gel plates and 2:1
ethyl acetate–
hexane.
22.
If an oil resulted, it was taken up in
ethyl acetate (150 mL) and the two layers were separated. The aqueous layer was extracted with
ethyl acetate (2 × 50 mL); the organic layers were combined, dried (Na
2SO
4) and concentrated under reduced pressure at 35–40°C to give
12.7–13.5 g (
80–85%) of product
5 as an oil that solidifies on cooling in the freezer.
23.
The physical properties are as follows: mp
96–98°C; IR (KBr) cm
−1: 3370, 3020, 2970, 2840, 1720, 1595, 1485, 1445, 1395, 1330, 1205, 1120, 1035, 1010, 980, 950, 845, 810, 770, 735, 695, 625
−1; NMR (CDCl
3) δ: 3.74 (s, 3 H, COOCH
3), 3.82 (s, 2 H, CH
2), 3.83 (s, 3 H, CH
3), 6.27 (d, 1 H, J = 1.0, H
3), 6.81 (dd, 1 H, J = 2.4, 8.8, H
6), 7.01 (d, 1 H, J = 2.4, H
4), 7.23 (d, 1 H, J = 8.8, H
7), 8.53 (s, 1 H, NH); MS m/e 220 (M+1). The product must be stored in the freezer; on the bench top it turns red.
24.
The physical properties for
methyl (2-nitrophenylacetyl)acetoacetate are as follows: mp
82–83°C; IR (KBr) cm
−1: 2960, 1705, 1515, 1400, 1335, 1080, 860, 790, 720 cm
−1; NMR (CDCl
3) δ: 2.41 (s, 3 H, COCH
3), 3.85 (s, 3 H, COOCH
3), 4.20 (s, 2 H, CH
2), 4.50 (s, 2 H, CH
2), 7.36–7.65 (m, 3 H), 8.16 (t, 1 H).
25.
The physical properties for
methyl 4-(2-nitrophenyl)-3-oxobutyrate are as follows: mp
50–51°C; IR (KBr) cm
−1: 2960, 1750, 1715, 1610, 1575, 1520, 1440, 1340, 1265, 1200, 1070, 1010, 795, 730, 705 cm
−1; NMR (CDCl
3) δ: 3.66 (2 H, COCH
2COOMe), 3.76 (s, 3 H, COOCH
3), 4.25 (s, 2 H, Ar-CH
2), 7.30 (d, 1 H, J = 7.2), 7.50 (t, 1 H), 7.6 (t, 1 H), 8.10 (d, 1 H, J = 6.8).
26.
The physical properties for
methyl indole-2-acetate are as follows: mp
71–74°C; IR (KBr) cm
−1: 3430, 3405, 3320, 3220, 1740, 1720, 1660, 1620, 1565, 1525, 1430, 1340, 1300, 1280, 1190, 1170, 1030, 860, 820, 790, 780, 730, 700 cm
−1; NMR (CDCl
3) δ: 3.61 (s, 3 H, COOCH
3), 3.71 (s, 2 H, CH
2), 7.42–7.58 (m, 4 H), 7.93 (m, 1 H), 7.97 (d, 1 H, J = 1.8).
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Compound
5 and its 5-H-analog can be prepared in one to two steps from the known intermediates
5-methoxyindole-2-acetonitrile and
indole-2-acetic acid, respectively.
5-Methoxyindole-2-acetonitrile is obtained in very poor overall yield when the patented procedure is followed.
8 Indole-2-acetic acid is prepared from
indole-2-carboxylic acid9,10 in five steps or from
indole11,12 in three steps. The first method involves six steps for the one carbon homologation and the overall yield is
23%. The second method involves protection and deprotection of the
indole nitrogen. In addition the reaction conditions for the lithiation step require a very low (−78°C) temperature and for the Wolff-Kishner step a very high (180°C) temperature. The procedure described here illustrates a general synthetic method for the preparation in three steps of substituted
indole-2-acetic acid methyl esters from
o-nitrophenylacetic acid and its derivatives. The overall yields are
30–40% and the reactions can be carried out on a large scale. The purity of the intermediates and the products is greater than 90% as determined by NMR. One of the intermediates,
o-nitrophenylacetyl chloride, is considered to be a potentially explosive material; therefore it is never isolated, but is used in its crude form. Although it is not known whether
5-methoxy-2-nitrophenylacetyl chloride is an explosive material, it is also prepared and used in its crude form.
Compound
5 and its 5-H-analog are useful intermediates in preparing a number of 5-substituted 6H-pyrido[4,3-b]carbazoles.
9,10,13 These pyridocarbazoles are potential antitumor agents.
The corresponding 5-H analogs of the title compound are prepared using the procedure described for compounds 3, 4, and 5 in 55–61%, 65–70%, and 80–86% yield, respectively.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
palladium over activated carbon
palladium on activated carbon, ammonium formate
hydrochloric acid (7647-01-0)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether,
diethyl ether (60-29-7)
sodium hydroxide (1310-73-2)
thionyl chloride (7719-09-7)
sodium sulfate (7757-82-6)
sodium methoxide (124-41-4)
toluene (108-88-3)
Benzophenone (119-61-9)
sodium (13966-32-0)
palladium on activated charcoal (7440-05-3)
hydrogen peroxide (7722-84-1)
ammonium hydroxide (1336-21-6)
ammonium formate (540-69-2)
Tetrahydrofuran (109-99-9)
N,N-dimethylformamide (68-12-2)
sodium hydride (7646-69-7)
Indole (120-72-9)
indole nitrogen
indole-2-carboxylic acid (1477-50-5)
hexane (110-54-3)
Methyl acetoacetate (105-45-3)
diethyl oxalate (95-92-1)
argon (7440-37-1)
INDOLE-2-ACETIC ACID METHYL ESTERS,
methyl indole-2-acetate,
indole-2-acetic acid methyl ester
Methyl 5-methoxyindole-2-acetate,
1H-Indole-2-acetic acid, 5-methoxy-, methyl ester (27798-66-9)
5-Methoxy-2-nitrophenylacetic acid (20876-29-3)
3-methyl-4-nitroanisole (5367-32-8)
Methyl (5-methoxy-2-nitrophenylacetyl)acetoacetate (130916-40-4)
methyl acetoacetate anion
Methyl 4-(5-methoxy-2-nitrophenyl)-3-oxobutyrate (130916-41-5)
5-Methoxy-2-nitrophenylacetyl chloride
2-nitrophenylacetyl chloride,
o-nitrophenylacetyl chloride (22751-23-1)
5-methoxy-2-nitrophenyl-acetamide
4-(5-methoxy-2-nitrophenyl)-4-oxobutyramide
methyl (2-nitrophenylacetyl)acetoacetate (160206-92-8)
methyl 4-(2-nitrophenyl)-3-oxobutyrate (119209-56-2)
5-methoxyindole-2-acetonitrile
indole-2-acetic acid
o-nitrophenylacetic acid (3740-52-1)
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