1. Introduction

Indole and its derivatives are a class of very effective drug intermediates. There have been many reviews reporting their synthesis methods.¹ We have briefly listed some commonly used synthesis methods for reference when synthesizing such compounds.

1 (a) G. W. Gribble, Contemp.Org. Synth., 1994, 145. (b) U. Pindur and R. Adam, J. Heterocycl.Chem., 1988, 25, 1. (c)C. J. Moody, Synlett, 1994, 681. (d) R. J. Sundberg, Indoles,Academic Press, San Diego, CA, 1996. (e) T. L. Gilchrist, J.Chem. Soc., Perkin Trans. 1, 1999, 2849. (f) G. W. Gribble, J.Chem. Soc., Perkin Trans. 1, 2000, 1045.

2. Fischer Indole Synthesis

The Fischer indole synthesis is a common method for synthesizing indoles. By heating phenylhydrazine under acid catalysis, one molecule of ammonia is eliminated to obtain 2-substituted or 3-substituted indole derivatives. In practical operation, aldehydes or ketones can often be used with equivalent amounts of phenylhydrazine heated under reflux in acid to obtain phenylhydrazone, which immediately undergoes rearrangement and ammonia elimination under acid catalysis to yield indole compounds. Common catalysts include zinc chloride, boron trifluoride, and polyphosphoric acid, while common acids include AcOH, HCl, trifluoroacetic acid, etc. The mechanism is roughly as follows:

4-Bromophenylhydrazine hydrochloride 1 (21 g) was suspended in 150 mL of acetic acid, and the mixture was heated to reflux. Then a solution of cyclohexanone 2 (9.3 mL) in 10 mL of acetic acid was added dropwise. After the addition, the mixture was stirred under reflux for another 2 h. Water (50 mL) was added dropwise slowly, cooled to room temperature, the solid was filtered, washed with water, dried, pale brown solid 3 (21.65g, 91 %) was obtained.

Ref: (a) B. Robinson, Chem. Rev., 1963, 373. (b) B. Robinson, Chem. Rev.,1969, 227. (c) H. Ishii, Accts. Chem. Res., 1981, 233. (d) B. Robinson, The Fischer Indole Synthesis, 1982, 923. (e) D. L. Hughes, Org. Prep. Proced.Int., 1993, 607. (f) S.M. Hutchins, K. T. Chapman, Tetrahedron Letters, 1996, 4869. (g) O. Miyata et al., ibid. 1999, 3601. (h) S. Wagaw et al., J. Am. Chem. Soc., 1999, 10251.

3. Synthesis of Indole from Nitrobenzene Derivatives

For indoles without substituents at positions 2 and 3, the industrial method mainly uses nitrobenzene derivatives as the starting material. Nitrobenzene derivatives with ortho-methyl, ortho-formyl, ortho-cyanoethyl, ortho-vinyl, and ortho-hydrogen can all be obtained by corresponding methods to yield indole.

3.1 Synthesis of Indole from Ortho-Methyl Nitrobenzene Derivatives

This method is currently the most commonly used. Ortho-methyl nitrobenzene derivatives react with DMF-DMA to obtain the corresponding enamine, and then the nitro group can be reduced by various methods to yield indole. The reduction method is generally through hydrogenation, but when sensitive functional groups exist in the molecule (for example: Br, I, or olefins), chemical reduction methods such as NH₂NH₂-Raney Ni, iron powder, TiCl₃, or zinc powder can be used to reduce to indole.

3.1.1 Example of Indole Synthesis from Ortho-Methyl Nitrobenzene Derivatives

To a solution of 4-methoxy-2-nitrotoluene 1 (17.9 g, 0.107 mol) in 200 mL of dry DMF was added DMF-DMA (42 mL, 0.316 mol) and pyrrolidine (10 mL, 0.12 mmol). The mixture was heated at 105 ⁰C for 19 h under nitrogen, then cooled, diluted with water and extracted with ether (8×50 mL). The ether layer was extracted with water (3×25 mL), dried with sodium sulfate, and concentrated to give a deep red oil 2 which was dissolved in ethyl acetate (150 mL), and to the solution was added 10% palladium on carbon (1.8 g). Hydrogenation at 50 p.s.i. with shaking for 3h and then filtration through celite gave a light brown filtrate. This filtrate is evaporated to purple oil, which was purified by chromatography on silica gel (eluent: DCM) to give 6-methoxyindole Yield: 76%

Ref: (a) Feldman, et al, Synthesis, 1986,735. (b) Kline.T.B. et al, J.Med. Chem., 1982, 908. (c) Schumacher, R.W. et al, Tetrahedron,1999, 935. (d) bromidge, S.M., et al, J. Med. Chem., 1998,1598. (e) Maehr, H. et al, J. Org. Chem. 1984, 1549. (f)Nicolaou, K.C. et al, J. Am. Chem. Soc., 2004, 10162.

3.2 Synthesis of Indole from Ortho-Formyl Nitrobenzene Derivatives

This ortho-formyl nitrobenzene derivative reacts with nitromethane to obtain the corresponding unsaturated nitro compound, which is then reduced to yield indole.

3.1.2 Example of Indole Synthesis from Ortho-Formyl Nitrobenzene Derivatives

To a solution of 2-nitro-benzaldehyde 1 (3.14 g, 0.02 mol) in nitromethane (40 mL) was added ammonia acetate (0.9 g,0.012 mol) under N₂ protection. Then it was heated to reflux for 1.25 h. After cooling to room temperature, it was poured into water and stirred for 30 min. Then it was extracted with DCM (50 mL×3), and the combined organic layer was washed with brine, dried over Na₂SO₄ and evaporated under vacuum. The residue was purified by flash column chromatography to yield 1.2 g pure 2-(2-nitro-vinyl)-nitrobenzene 2. Yield: 42%

To a solution of 2-(2-nitro-vinyl)-nitrobenzene 2(1.0 g, 0.005 mol) in ethanol (10 mL), glacial acetate acid (10 mL) and water (3 mL) was added iron powder (5.7 g, 0.1 mol) portionwise. After the addition, it was heated to 50 °C for 30 min. After cooling to room temperature, aq. NaHSO₃ was added to it and extracted with ether (50 mL×3). The combined organic layer was washed with saturated aq. NaHCO₃, dried over Na₂SO₄ and evaporated under vacuum. The residue was purified by flash column chromatography to yield 0.45 g 1H-indole 3. Yield: 75%

Ref: (a) Sinhababu, Achintya K.;Borchardt, Ronald T., J. Am. Chem. Soc., 1985, 7618, (b) He,Feng; Bo, Yunxin; Altom, Jason D.; Corey, E. J.; J. Am. Chem. Soc.,1999, 6771.

3.3 Example of Indole Synthesis from Ortho-Cyano Nitrobenzene Derivatives

To a solution of 2-nitro-1-naphthyl-acetonitrile (33g, 0.155 mol) in 630 mL of ethanol containing 10% water and 6.3 mL of pure acetic acid was added 19 g of 10% palladium-on-carbon. Then it was stirred at r.t. under 4 bars of hydrogen. After the reaction completed, the catalyst was filtered and the filtration was concentrated under reduced pressure. Then residue was dissolved in 250 mL of DCM, washed with 100 mL of 0.1 N KOH solution and then dried over Na₂SO₄, evaporated under reduced pressure to give the crude product, which was purified by column chromatography using cyclohexane/EA=4:1 as eluant to yield 13 g of 3H-benzo[e]indole. Yield: 50%

Ref: (a) Makosza, M. et al., Tetrahedron, 1995,7263. (b) Bromidge, S.M. et al., J. Med. Chem., 1998, 1598.

3.4 Example of Indole Synthesis from Ortho-Vinyl Nitrobenzene Derivatives

To a solution of 2-bromo-4-methylnitrobenzene 1 (1.00 g, 4.61 mmol) and vinyltri-n-butyltin (1.61 g, 5.07 mmol) in toluene (25 mL) was added, under a positive flow of argon, bis(dibenzylideneacetone) palladium (0) (265 mg, 0.46 mmol) together with triphenylphosphine (498 mg, 1.90 mmol). The solution was heated at reflux (19 h) whereupon a red solution containing a black precipitate was formed. The reaction mixture was cooled to ambient temperature, and the solvent was removed to give black oil. The oil was dissolved in dichloromethane (50 mL), washed with NH₄OH (10%, aq, 3 x 30 mL), and dried (MgSO₄). Removal of solvent gave yellow oil containing a smaller amount of black viscous oil. The crude product was purified by chromatography (hexanes-EtOAc, 19:1) to give 2-ethenyl-4-methylnitrobenzene (589 mg, 3.61mmol, 78%) as yellow oil 2.

To an oven-dried, threaded ACE glass pressure tube was added 2-ethenyl-4-methylnitrobenzene 2 (152 mg, 0.93 mmol), Pd(OAc)₂(13 mg, 0.06mmol), triphenylphosphine (62 mg, 0.24 mmol), and 4 mL of MeCN. The tube was fitted with a pressure head, the solution was saturated with CO (four cycles to 4 atm of CO), and the reaction mixture was heated to 70 °C (oil bath temperature) under CO (4 atm) until all starting material was consumed (15 h) as judged by TLC. The reaction mixture was diluted with HCl (aq, 10%, 10 mL) and extracted with Et₂O (3×10 mL). The combined organic phases were washed with HCl (aq, 10%, 10 mL) and dried (MgSO₄), and the solvent was removed to give the crude product. The crude product was purified by chromatography (hexanes-EtOAc, 9:1) to give 5-methylindole 3 (62 mg, 0.47 mmol, 51%) as faint yellow crystals.

Ref: Soederberg, B. et al, J.Org. Chem., 1997, 5838

4. Synthesis of Indole from Aniline Derivatives

Although not commonly used, some methods have been reported for synthesizing indole from aniline derivatives.

4.1 Aniline via Fok Alkylation and Reductive Cyclization to Synthesize Indole

To a stirred solution of boron trichloride (645 mg, 5.5mmol) in dry benzene (6 mL), a solution of 4-chloroaniline 1(638mg, 5 mmol) in dry benzene (6 mL) was added dropwise under ice-cooling. To the resulting mixture containing 4-chloroaniline boron trichloride complex, chloroacetonitrile (0.38 mL, 6 mmol) and aluminum trichloride (734 mg, 5.5 mmol) were added successively. The mixture was then refluxed for 6 h under nitrogen, becoming a solution of two layers. The evolved hydrogen chloride was absorbed through a drying tube containing silica gel or calcium chloride to a surface of aqueous sodium hydroxide. After cooling, ice 2N hydrochloric acid was added and a yellow precipitate was formed. To hydrolyze the ketimine of 2 the mixture was warmed at 80 °C under stirring until the precipitate had dissolved (ca. 30 min). The cooled mixture was extracted with chloromethane (three times) and the organic layer was washed with water, dried (MgSO₄), and concentrated. The neutral fraction obtained (744 mg) was recrystallized to obtain pure 2 (674 mg). Yield: 66%. The acidic layer was made alkaline with 2 N sodium hydroxide and extracted with dichloromethane. Washing, drying, and evaporation of the solvent gave the basic fraction (170 mg). Thin-layer chromatographic purification (silica gel, chloroform containing 10% methanol) gave recovered 1 (103 mg).

To a stirred solution of 5-chloro-2-amino-α-chloroacetophenone2(204 mg, l mmol) in dioxane (5mL) containing water(0.5 mL) was added sodium borohydride (1.1 mmol) and the solution was refluxed for 5.5 h. After removal of the solvent, water was added and the mixture was extracted with dichloromethane. The extract was dissolved in benzene and passed through a silica gel layer (ca. 2 g) to remove a polar fraction. The eluate with benzene was concentrated giving indole 3(one spot, on TLC, dichloromethane). Yield: 69%

Ref: (a) T. Sugsawa, M. Adachi, K. Sasakura, A.Kitagawa, J. Org.Chem., 1979, 578, (b) Gonzalez, J.C. et al, Synthesis, 2002, 475.

4.2 N-Hydroxyaniline DMAP Catalyzed Condensation with Propiolic Acid Esters to Synthesize 3-Carboxy Indole Derivatives

To a solution of N-benzyl-N-phenylhydroxylamine1 (86.2 mg, 0.426 mmol) in THF (15.0 mL) was added 4A molecular sieves. DMAP (6.0 mg, 0.049 mmol) and methyl propiolate 2 (54 mg, 0.562 mmol) were added to it at 0°C. The reaction mixture was stirred at 0 °C for 1 h, then at room temperature for 48 h. Ethyl acetate (5.0 mL) was added, and after filtration, the organic solution was washed with water (3 x 20 mL), brine, and then dried over magnesium sulfate. Following filtration, the organics are concentrated under reduced pressure and the resultant oil purified by flash column chromatography (hexanes: ethyl acetate= 7:3) to give 1-benzyl-1H-indole-3-carboxylic acid methyl ester 3 (95.6 mg; 82% yield) as a white solid (m.p. 67.0-67.5°C).

Ref: (a) R.Hwu, H.V. Patel, R.J. Lin, and M.O. Gray,J. Org. Chem., 1994, 1577

4.3 Nenitzescu Indole Synthesis

Nenitzescu is a relatively special method for synthesizing indole, where the final product generally has an aromatic ring on the nitrogen atom. For Nenitzescu reactions, different solvents in the final cyclization process will yield different cyclization products. The following compounds 4 and 5 are shown.

To a solution of (E)3-amino-but-2-enenitrile 1 (1.0 g, 12.2 mmol) in acetic acid (1.54 g, 25 mmol) and water (5 mL) was added aniline 2 (1.13 g,12.2 mol) at r.t.. After stirring for 30 min., the mixture was cooled in an ice bath and the product 3 was collected on a filter, dried in vacuum. (The mixture also can be extracted with acetic ether if there was no precipitate appearance.)

To the solution of 1,4-benzo quinone (0.96 g, 9.0 mmol) in acetic acid (4 mL) was added acetic anhydride (0.8 mL) at r.t.. After stirring for 30 min., a solution of (E)3-Phenylamino-but-2-enenitrile3(1.18 g,7.5 mmol) in acetic acid (4 mL) was added to it and the mixture was stirred overnight. Crude solid was collected after filtered, washed with a little acetic acid and water, dried in vacuum. The solid was purified by column chromatography on silica gel using EtOAc/petro ether (1:2) as eluent to yield 6-hydroxy-3-cynao-2-methyl-1-phenyl-indole 4. (30%)

Ref: (a) R. K. Brown, The Chemistry of Heterocyclic Compounds, (b) W. J. Houlihan, Ed., 1972, 413, (c) G. R. Allen, Jr.,Org. React. 1973, 337, (d) Synthetic applications: U.Kuecklander, W. Huehnermann, Arch. Pharm. 1979, 515, (e) J. L. Bernier, J. P., Henichart, J. Org. Chem. 1981, 4197, (f) M. Kinugawa et al.,J. Chem. Soc. Perkin Trans. I, 1995, 2677; (g) J. M. Pawlak et al., J.Org. Chem. 1996, 9055.

5. 2-Azido-3-Phenylacrylic Acid Ester Cyclization to Synthesize 2-Carboxy Indole Derivatives

By condensing azido acrylic acid esters with aromatic aldehydes, 2-azido-3-phenylacrylic acid esters can be obtained, which upon heating cyclize to generate indole 2-carboxylate derivatives. Generally, only electron-rich aromatic rings (electron-donating phenyl rings, furan, thiophene, pyrrole) can cyclize through this method. Due to the release of nitrogen gas during the reaction, the addition rate of 2-azido-3-phenylacrylic acid esters and the opening of the reaction vessel must be strictly controlled to avoid eruptions.

5.1 Example of Cyclization of 2-Azido-3-Phenylacrylic Acid Esters to Synthesize 2-Carboxy Indole Derivatives

To a solution of NaN₃ (60 g, 0.92 mol) in 240 mL of DMF was added dropwise chloro-acetic acid methyl ester 1 (75 mL, 0.86 mol) at 0 °C. After the addition, it was allowed to warm to r.t. and overnight. The reaction mixture was poured into 1.5 L of water and extracted with ether (500mL×3). The combined organic layer was washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure to yield 78.4 g yellow oil azido-acetic acid methyl ester 2. Yield: 90%

To 500 mL of methanol was added portionwise sodium (15.7 g, 0.68 mol). After the addition, it was heated to reflux for 30 min. Then a solution of 4-methoxy-benzaldehyde 3 (46.2 g, 0.34 mol) and azido-acetic acid methyl ester 2 (78 g, 0.68 g) in 100 mL of methanol was added dropwise to it. After the addition, it was stirred at 5 °C for 2 h and overnight at r.t.. Then the reaction mixture was poured into ice water and stirred for 10 min. Deposited and filtered. The solid was washed with water (50 mL×3), dried under vacuum to yield 54.3 g yellow solid 2-azido-3-(4-methoxy-phenyl)-acrylic acid methyl ester 4. Yield: 69%

To 600 mL of xylene was slowly added dropwise a solution of compound 4 (54 g, 0.23 mol) in 400 mL of xylene at reflux. After the addition, it was refluxed for 1 h and cooled to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residue was recrystallized with xylene to yield 28 g white solid 6-methoxy-1H-indole-2-carboxylic acid methyl ester 5. Yield: 59%

Reference: (a) Coowar, D. et al, J.Med. Chem., 2004, 6270, (b) Blair, J. B., et al, J. Med. Chem.,2000, 4701

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