2380-94-1

Basic information

• Product Name: 4-Hydroxyindole
• Synonyms: 1H-INDOL-4-OL;1H-INDOLE-4-OL;4-HYDROXY-1H-INDOLE;4-INDOLOL;4-HYDROXYINDOLE;INDOL-4-OL;4-Hydroxy Indole (4-Indolol);4-Hydroxxyindole
• CAS NO: 2380-94-1
• Molecular Formula: C₈H₇NO
• Molecular Weight: 133.15
• EINECS: 219-177-2
• Product Categories: blocks;IndolesOxindoles;Indoles and derivatives;pharmacetical;Heterocycles series;Pyrroles & Indoles;Indole;Indoles;Indole Derivatives;Simple Indoles;Chiral Compound;Pyrroles & Indoles;Heterocycles;Heterocycle-Indole series
• Mol File: 2380-94-1.mol
• Article Data: 31

Chemical Properties

• Melting Point: 97-99 °C(lit.)
• Boiling Point: 245.66°C (rough estimate)
• Flash Point: 161.4 °C
• Appearance: off-white cyrstalline solid
• Density: 1.1475 (rough estimate)
• Vapor Pressure: 0.000129mmHg at 25°C
• Refractive Index: 1.5260 (estimate)
• Storage Temp.: 0-6°C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 9.89±0.40(Predicted)
• Water Solubility: slightly soluble
• Sensitive: Air Sensitive
• BRN: 114905
• CAS DataBase Reference: 4-Hydroxyindole(CAS DataBase Reference)
• NIST Chemistry Reference: 4-Hydroxyindole(2380-94-1)
• EPA Substance Registry System: 4-Hydroxyindole(2380-94-1)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36-37/39
• WGK Germany: 3
• HazardClass: IRRITANT, KEEP COLD
• Hazardous Substances Data: 2380-94-1(Hazardous Substances Data)

Usage

Description

4-Hydroxyindole, a member of the hydroxyindoles class, is a 1H-indole substituted by a hydroxy group at position 4. It belongs to the phenols and hydroxyindoles categories and is characterized as an off-white crystalline solid. 4-Hydroxyindole has been reported to undergo glucouridination by human uridine 5′-diphospho-glucuronosyltransferase and is recognized as a Pindolol (P468000) impurity, which is a mixed adrenergic blocker and serotonin 5HT1A-receptor antagonist.

Uses

Used in Pharmaceutical Synthesis:
4-Hydroxyindole serves as an essential raw material or intermediate in the synthesis of pharmaceutical products. It is particularly useful in the development of medications targeting various health conditions.
Used in Industrial Polymers:
In the industrial sector, 4-Hydroxyindole is utilized as a key intermediate in the production of polymers, contributing to the development of new materials with specific properties and applications.
Used in Neuroprotection:
4-Hydroxyindole effectively inhibits Abeta peptide-induced amyloid fibril formation, which is associated with neurodegenerative diseases like Alzheimer's. It also helps prevent cell death induced by the peptide in culture, making it a potential candidate for neuroprotective applications.
Used in Anti-Inflammatory Agents:
4-Hydroxyindole is employed in the synthesis of anti-inflammatory angular pyrrolocoumarins, which are compounds with potential therapeutic benefits in reducing inflammation and related conditions.

Preparation

Synthesis of 4-hydroxyindole: Using resorcinol as raw material, 4-oxotetrahydrocoumarone carboxylic acid is prepared by isomerization, catalytic hydrogenation, and cyclization with ethyl bromopyruvate. It was added to methanol solution saturated with ammonia, and the reaction was heated in an autoclave to generate 4-oxotetrahydroindole. Finally, 4-hydroxyindole is obtained by dehydrogenation and isomerization.

InChI:InChI=1/C8H7NO/c10-8-3-1-2-7-6(8)4-5-9-7/h1-2,4-5,9H,3H2

Synthetic route

3-nitro-2-vinylphenol (195992-07-5) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With carbon monoxide; triphenylphosphine; palladium diacetate In acetonitrile under 3040 Torr; Heating;	96%
With carbon monoxide; palladium diacetate; triphenylphosphine In acetonitrile at 90℃; under 3051.25 Torr; for 50h;	96%

(4-Hydroxy-indol-1-yl)-phenyl-methanone (95969-15-6) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With potassium hydroxide at 0 - 20℃; for 2h;	96%

C10H9NO2 → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With sodium hydroxide at 0℃; for 1h;	95%

4-benzyloxy-1H-indole (20289-26-3) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With palladium on activated charcoal; hydrogen In methanol at 20℃; under 775.743 Torr; for 12h;	89.4%
With methanol; magnesium hydrosilicate; palladium Hydrogenation;

4-hydroxyindoline (85926-99-4) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With palladium on activated charcoal In o-xylene for 2.3h; Heating;	88%

(E)-6-benzyloxy-2-nitro-β-pyrrolidinostyrene → 1H-indol-4-ol (2380-94-1) + 4-benzyloxy-1H-indole (20289-26-3)

Conditions	Yield
With hydrogen; 5% rhodium-on-charcoal; nickel(II) nitrate In tetrahydrofuran; water at 20℃; for 32h;	A 6% B 88%
With hydrogen; 5% rhodium-on-charcoal; iron(II) acetate In tetrahydrofuran at 20℃; for 31h;	A 5% B 83%
With hydrogen; 5% rhodium-on-charcoal; tris(acetylacetonato)cobalt In tetrahydrofuran at 20℃; for 38h;	A 3% B 80%

4-acetoxy-N-tosylindole (112970-68-0) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With sodium hydroxide In methanol for 12h; Heating;	83%

2-(2-benzyloxy-6-nitrophenyl)acetonitrile (79966-73-7) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With hydrogen; acetic acid; 10% palladium on active carbon In ethanol under 2280 Torr; for 2h; Ambient temperature;	81%
With palladium 10% on activated carbon; hydrogen; acetic acid In ethanol	78%

1,5,6,7-tetrahydro-indol-4-one (13754-86-4) → 1H-indol-4-ol (2380-94-1) + 4-amino-1H-indole (5192-23-4)

Conditions	Yield
With ethene; 5%-palladium/activated carbon; ammonium acetate In acetonitrile at 90℃; under 760.051 Torr; for 15h; Reagent/catalyst; Schlenk technique;	A 11% B 80%

ethyl 4-hydroxy-1H-indole-1-carboxylate (75201-78-4) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
palladium on activated charcoal	75%

4-hydroxy-1-methoxycarbonylindole (81038-33-7) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With sodium hydroxide In methanol for 10h; Heating;	74.9%

1,5,6,7-tetrahydro-indol-4-one (13754-86-4) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
palladium on activated charcoal In various solvent(s) Heating;	69%
With diisobutyl ketone; palladium 10% on activated carbon at 190℃; for 48h; Inert atmosphere;	49%
With palladium on activated charcoal; hydrogen In 1,3,5-trimethyl-benzene at 160 - 161℃; for 48h;	67 % Chromat.

2-benzyloxy-6-nitrophenyl acetaldehyde (78283-30-4) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With hydrogen; platinum(IV) oxide; palladium on activated charcoal In methanol at 60℃; under 52956.6 Torr; for 15h;	67.7%

C16H16N4O4 → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With hydrogen; palladium on activated charcoal under 3102.9 Torr; for 6h;	55%

indole (120-72-9) → 6-hydroxy-1H-indole (2380-86-1) + indol-5-ol (1953-54-4) + 7-Indolol (2380-84-9) + 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With dihydrogen peroxide; edetate disodium; iron(II) sulfate; ascorbic acid phosphate buffer (pH=7.2);	A 10% B 30% C 10% D 50%

1-(p-toluenesulphonyl)-4-hydroxyindole (81038-34-8) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With sodium hydroxide In methanol for 10h; Heating;	42.1%

indole (120-72-9) → 6-hydroxy-1H-indole (2380-86-1) + indol-5-ol (1953-54-4) + 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With hydrogen fluoride; dihydrogen peroxide; antimony pentafluoride at -20℃; for 0.05h;	A 10% B 20% C 5%

acetic acid 1H-indol-4-yl ester (5585-96-6) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With methanol; ammonia

4-amino-1H-indole (5192-23-4) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
With hydrogenchloride; sodium nitrite 1.) water and methanol, 5 deg C, 5 min, 2.) water, 97 deg C, 50 min; Yield given. Multistep reaction;

1-(1H-indol-4-yloxy)-3-(isopropylamino)-2-propanol (13523-86-9) → 1H-indol-4-ol (2380-94-1) + 2-(1H-Indol-4-yloxy)-3-<(1-isopropyl)-amino>propan-1-ol

Conditions	Yield
With hydrogenchloride at 98℃; for 504h;

2-bromo-3-hydroxy-1-nitrobenzene (101935-40-4) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 30 percent / PPh3 / Pd(dba)2 / toluene / 17 h / Heating 2: 96 percent / PPh3, CO / Pd(OAc)2 / acetonitrile / 3040 Torr / Heating View Scheme
Multi-step reaction with 6 steps 1: 44 percent / triethylamine, 4-(dimethylamino)pyridine / CH2Cl2 / 10 h / Ambient temperature 2: 93 percent / iron / ethanol; acetic acid / 3.5 h / Heating 3: 60 percent / pyridine / 6 h / Ambient temperature 4: 36 percent / tetrakis(triphenylphosphine)palladium(0) / toluene / Heating 5: 58 percent / bis(acetonitrile)palladium chloride, p-benzoquinone, lithium chloride / dimethylformamide / 28 h / 100 - 110 °C 6: 83 percent / 20percent aq. NaOH / methanol / 12 h / Heating View Scheme

2,6-dinitrotoluene (606-20-2) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 94 percent / Et4NOTs / dimethylformamide / 0.83 h / Ambient temperature; 3.3 mAcm-2 2: 86 percent / H2 / Raney Ni (W-2) / methanol / 2 h / 55 - 65 °C / 3800 - 6840 Torr 3: 90 percent / aq. 70percent H3PO4 / 24 h / 220 °C 4: 88 percent / 10percent Pd/C / o-xylene / 2.3 h / Heating View Scheme
Multi-step reaction with 5 steps 1: 94 percent / Et4NOTs / dimethylformamide / 0.83 h / Ambient temperature; 3.3 mAcm-2 2: 86 percent / H2 / Raney Ni (W-2) / methanol / 2 h / 55 - 65 °C / 3800 - 6840 Torr 3: 92 percent / aq. 30percent H2SO4 / 24 h / 170 °C 4: 86 percent / aq. 30percent H3PO4 / 24 h / 220 °C 5: 88 percent / 10percent Pd/C / o-xylene / 2.3 h / Heating View Scheme

2-(2,6-dinitrophenyl)ethanol (77759-08-1) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 86 percent / H2 / Raney Ni (W-2) / methanol / 2 h / 55 - 65 °C / 3800 - 6840 Torr 2: 90 percent / aq. 70percent H3PO4 / 24 h / 220 °C 3: 88 percent / 10percent Pd/C / o-xylene / 2.3 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 86 percent / H2 / Raney Ni (W-2) / methanol / 2 h / 55 - 65 °C / 3800 - 6840 Torr 2: 92 percent / aq. 30percent H2SO4 / 24 h / 170 °C 3: 86 percent / aq. 30percent H3PO4 / 24 h / 220 °C 4: 88 percent / 10percent Pd/C / o-xylene / 2.3 h / Heating View Scheme

4-aminoindoline (52537-01-6) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / aq. 30percent H3PO4 / 24 h / 220 °C 2: 88 percent / 10percent Pd/C / o-xylene / 2.3 h / Heating View Scheme

2-(2,6-diaminophenyl)ethanol (118742-89-5) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / aq. 70percent H3PO4 / 24 h / 220 °C 2: 88 percent / 10percent Pd/C / o-xylene / 2.3 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 92 percent / aq. 30percent H2SO4 / 24 h / 170 °C 2: 86 percent / aq. 30percent H3PO4 / 24 h / 220 °C 3: 88 percent / 10percent Pd/C / o-xylene / 2.3 h / Heating View Scheme

meta-nitrophenol (554-84-7) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: anhydrous K2CO3 / dimethylformamide 2: 63 percent / tBuOK / dimethylformamide / 0.5 h / -20 - -10 °C 3: 81 percent / H2, acetic acid / Pd/C (10percent Pd) / ethanol / 2 h / 2280 Torr / Ambient temperature View Scheme

3-(benzyloxy)nitrobenzol (24318-00-1) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 63 percent / tBuOK / dimethylformamide / 0.5 h / -20 - -10 °C 2: 81 percent / H2, acetic acid / Pd/C (10percent Pd) / ethanol / 2 h / 2280 Torr / Ambient temperature View Scheme

4-nitro-1H-indoIe (4769-97-5) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydride / N,N-dimethyl-formamide / 4 h 3: sodium hydroxide / methanol / 10 h / Heating View Scheme
Multi-step reaction with 4 steps 1: sodium hydride / N,N-dimethyl-formamide / 4 h 2: titanium(III) chloride / methanol; water / 0.12 h / Ambient temperature 3: hydrogenchloride; sodium nitrite / 1.) water and methanol, 5 deg C, 5 min, 2.) water, 97 deg C, 50 min 4: sodium hydroxide / methanol / 10 h / Heating View Scheme
Multi-step reaction with 4 steps 1: sodium hydride / N,N-dimethyl-formamide; benzene / 17 h 2: titanium(III) chloride / methanol; water / 0.12 h / Ambient temperature 3: hydrogenchloride; sodium nitrite / 1.) water and methanol, 5 deg C, 5 min, 2.) water, 97 deg C, 20 min 4: sodium hydroxide / methanol / 10 h / Heating View Scheme

1-hydroxy-4-nitroindole (78283-23-5) → 1H-indol-4-ol (2380-94-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / methanol / 16 h / Ambient temperature 2: sodium hydride / N,N-dimethyl-formamide / 4 h 4: sodium hydroxide / methanol / 10 h / Heating View Scheme
Multi-step reaction with 4 steps 1: triethylamine / methanol / 43 h / Ambient temperature 2: sodium hydride / N,N-dimethyl-formamide / 4 h 4: sodium hydroxide / methanol / 10 h / Heating View Scheme
Multi-step reaction with 4 steps 1: ethyl bromoacetate; triethylamine / methanol / 92.5 h / Ambient temperature 2: sodium hydride / N,N-dimethyl-formamide / 4 h 4: sodium hydroxide / methanol / 10 h / Heating View Scheme

1H-indol-4-ol (2380-94-1) + benzyl bromide (100-39-0) → 4-benzyloxy-1H-indole (20289-26-3)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;	100%
With potassium carbonate In acetone for 20h; Ambient temperature;	95%
With potassium carbonate In acetone for 72h; Heating;	94%

1H-indol-4-ol (2380-94-1) + epichlorohydrin (106-89-8) → 4-(oxiranylmethoxy)-1H-indole (35308-87-3)

Conditions	Yield
With potassium hydroxide In dimethyl sulfoxide at 45℃; for 4h;	100%
Stage #1: 1H-indol-4-ol; epichlorohydrin With potassium hydroxide In dimethyl sulfoxide at 45℃; for 4h; Stage #2: With ammonium chloride In water	99%
With potassium hydroxide In dimethyl sulfoxide at 45℃; for 4h;	99%

1H-indol-4-ol (2380-94-1) + tert-butyldimethylsilyl chloride (18162-48-6) → 4-((tert-butyldimethylsilyl)oxy)-1H-indole (106792-40-9)

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;	100%
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 5h;	99%
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;	91%

1H-indol-4-ol (2380-94-1) → 4-hydroxyindoline (85926-99-4)

Conditions	Yield
Stage #1: 1H-indol-4-ol With sodium cyanoborohydride; acetic acid at 15 - 20℃; for 1.5h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	100%
With sodium cyanoborohydride In acetic acid at 15 - 20℃; for 1.5h;	100%
With sodium cyanoborohydride In acetic acid at 15 - 20℃;	99%

1H-imidazole (288-32-4) + 1H-indol-4-ol (2380-94-1) + ammonium chloride + tert-butyldimethylsilyl chloride (18162-48-6) → 4-t-butyldimethylsilyloxyindole

Conditions	Yield
In N-methyl-acetamide	100%

1H-indol-4-ol (2380-94-1) + 2-(3,4,5-trimethoxybenzylidene)malononitrile (5688-82-4) → 2-amino-4-(3,4,5-trimethoxyphenyl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carbonitrile

Conditions	Yield
With potassium fluoride In ethanol at 60℃; for 6h;	100%

1H-indol-4-ol (2380-94-1) + acetic anhydride (108-24-7) → acetic acid 1H-indol-4-yl ester (5585-96-6)

Conditions	Yield
With pyridine In dichloromethane at 0 - 25℃; Inert atmosphere; Large scale;	99.2%
With pyridine at 25 - 32℃;	98%
With pyridine In dichloromethane at 20℃; for 2h;	34 g

1H-indol-4-ol (2380-94-1) + methyl(2-hydroxyethyl)carbamic acid tert-butyl ester (57561-39-4) → N-methyl-N-[2-(1H-indol-4-yloxy)-ethyl]-carbamic acid tert-butyl ester (203921-48-6)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃; for 14h;	99%
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran for 16h; Ambient temperature;	77%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 16h;
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 72h;
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; Schlenk technique;	873.5 mg

1H-indol-4-ol (2380-94-1) + triisopropylsilyl chloride (13154-24-0) → 4-((triisopropylsilyl)oxy)-1H-indole (916574-98-6)

Conditions	Yield
With 1H-imidazole In dichloromethane at 20℃; for 7h;	99%
With 1H-imidazole In dichloromethane at 20℃;	80%
With 1H-imidazole In N,N-dimethyl-formamide at 20℃;

1H-indol-4-ol (2380-94-1) + 2-fluoroethyl bromide (762-49-2) → 4-(2-fluoroethoxy)indole (1240407-42-4)

Conditions	Yield
With potassium carbonate In acetone Reflux;	99%
With potassium carbonate In acetonitrile at 90℃; for 6h;	92%

1H-indol-4-ol (2380-94-1) + tert-butyl-(1-allyl-oxoindolin-3-ylidene)carbamate → C24H25N3O4

Conditions	Yield
With 3-(3,5-bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione In toluene at 25℃; for 12h; Friedel-Crafts Alkylation; enantioselective reaction;	99%

1H-indol-4-ol (2380-94-1) + tert-butyl (1-benzyl-5,7-dimethyl-2-oxoindolin-3-ylidene)carbamate (1673543-00-4) → C30H31N3O4

Conditions	Yield
With 3-(3,5-bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione In toluene at 25℃; for 12h; Friedel-Crafts Alkylation; enantioselective reaction;	99%

1H-indol-4-ol (2380-94-1) + 3-trifluoroethylidene oxindole → tert-butyl (2-((3R,4S)-2-oxo-4-(trifluoromethyl)-2,3,4,7-tetrahydropyrano[2,3-e]indol-3-yl)phenyl)carbamate

Conditions	Yield
With C32H28F6N4O3 In dichloromethane at -30℃; for 35h; Solvent; Temperature; Concentration; Friedel-Crafts Alkylation; enantioselective reaction;	99%

1H-indol-4-ol (2380-94-1) + C10H15N3O3 → tert-butyl (S)-(4-(4-hydroxy-1H-indol-5-yl)-1,3-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)carbamate

Conditions	Yield
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione In 1,2-dichloro-ethane at 0℃; Friedel-Crafts Alkylation; enantioselective reaction;	99%

1H-indol-4-ol (2380-94-1) + tert-butyl (3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)carbamate → tert-butyl (S)-(4-(4-hydroxy-1H-indol-5-yl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)carbamate

Conditions	Yield
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione In 1,2-dichloro-ethane at 0℃; for 18h; Reagent/catalyst; Solvent; Temperature; Friedel-Crafts Alkylation; enantioselective reaction;	99%

1H-indol-4-ol (2380-94-1) + C15H16ClN3O3 → tert-butyl (S)-(1-(2-chlorophenyl)-4-(4-hydroxy-1H-indol-5-yl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)carbamate

Conditions	Yield
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione In 1,2-dichloro-ethane at 0℃; Friedel-Crafts Alkylation; enantioselective reaction;	99%

1H-indol-4-ol (2380-94-1) + bromoacetic acid methyl ester (96-32-2) → methyl 2-((1H-indol-4-yl)oxy)acetate (157889-30-0)

Conditions	Yield
With potassium carbonate In acetone	98%
With caesium carbonate In acetonitrile at 20℃; for 0.583333h;	78%
With potassium carbonate In acetone at 20℃;

1H-indol-4-ol (2380-94-1) + (3-bromopropyl)({ [2-chloro-3-(trifluoromethyl)phenyl]methyl})(2,2-diphenylethyl)amine (612499-61-3) → (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(1H-indol-4-yloxy)-2-methyl-propyl]-amine (847990-40-3)

Conditions	Yield
With potassium carbonate In acetonitrile at 90℃;	98%
With potassium carbonate In acetonitrile at 90℃; Product distribution / selectivity;	98%

1H-indol-4-ol (2380-94-1) + 4-chlorobenzaldehyde (104-88-1) + malononitrile (109-77-3) → 2-amino-4-(4-chlorophenyl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carbonitrile

Conditions	Yield
With potassium fluoride In ethanol at 60℃; for 6h; Catalytic behavior; Reagent/catalyst; Solvent; Time; Green chemistry;	98%
Stage #1: 4-chlorobenzaldehyde; malononitrile With guanine-functionalized mesoporous silica In ethanol at 20℃; for 0.333333h; Knoevenagel Condensation; Green chemistry; Stage #2: 1H-indol-4-ol In ethanol at 80℃; for 3.5h; Michael Addition; Green chemistry;	76%

1H-indol-4-ol (2380-94-1) + tert-butyl (1-benzyl-6-chloro-2-oxoindolin-3-ylidene)carbamate (1426931-83-0) → C28H26ClN3O4

Conditions	Yield
With 3-(3,5-bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione In toluene at 25℃; for 12h; Friedel-Crafts Alkylation; enantioselective reaction;	98%

1H-indol-4-ol (2380-94-1) + (E) methyl 2-oxo-3-(2,2,2-trifluoroethylidene)indoline-1-carboxylate → methyl (2-((3R,4S)-2-oxo-4-(trifluoromethyl)-2,3,4,7-tetrahydropyrano[2,3-e]indol-3-yl)phenyl)carbamate

Conditions	Yield
With C32H28F6N4O3 In dichloromethane at -30℃; for 72h; Friedel-Crafts Alkylation; enantioselective reaction;	98%

1H-indol-4-ol (2380-94-1) + acetylacetone (123-54-6) + 2-oxopropanal (78-98-8) → 3-acetyl-4-(4-hydroxy-1H-indol-3-yl)hexane-2,5-dione

Conditions	Yield
In water at 80℃; for 5h;	98%

1H-indol-4-ol (2380-94-1) + tert-butyl (3-ethyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)carbamate → tert-butyl (S)-(3-ethyl-4-(4-hydroxy-1H-indol-5-yl)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)carbamate

Conditions	Yield
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione In 1,2-dichloro-ethane at 0℃; Friedel-Crafts Alkylation; enantioselective reaction;	98%

1H-indol-4-ol (2380-94-1) + tert-butyl (3-isopropyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)carbamate → tert-butyl (S)-(4-(4-hydroxy-1H-indol-5-yl)-3-isopropyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)carbamate

Conditions	Yield
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione In 1,2-dichloro-ethane at 0℃; Friedel-Crafts Alkylation; enantioselective reaction;	98%

1H-indol-4-ol (2380-94-1) + tert-butyl [5-oxo-1,3-diphenyl-1H-pyrazol-4(5H)-ylidene]carbamate → tert-butyl (S)-(4-(4-hydroxy-1H-indol-5-yl)-5-oxo-1,3-diphenyl-4,5-dihydro-1H-pyrazol-4-yl)carbamate

Conditions	Yield
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione In 1,2-dichloro-ethane at 0℃; Friedel-Crafts Alkylation; enantioselective reaction;	98%

1H-indol-4-ol (2380-94-1) + ethyl-3,3,3-trifluoropyruvate (13081-18-0) → ethyl 3,3,3-trifluoro-2-hydroxy-2-(4-hydroxy-1H-indol-3-yl)propanoate

Conditions	Yield
With aluminum (III) chloride In dichloromethane at 20℃; Friedel-Crafts Acylation;	97%

benzothiophene-3-carboxaldehyde (5381-20-4) + 1H-indol-4-ol (2380-94-1) + malononitrile (109-77-3) → 2-amino-4-(benzo[b]thiophen-3-yl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carbonitrile

Conditions	Yield
With potassium fluoride In ethanol at 60℃; for 6h; Green chemistry;	97%

1H-indol-4-ol (2380-94-1) + 1-benzyl-5-chloroisatin (26960-68-9) → (S)-1-benzyl-5-chloro-3-hydroxy-3-(4-hydroxy-1H-indol-5-yl)indolin-2-one + (+)-(R)-1-benzyl-5-chloro-3-hydroxy-3-(4-hydroxy-1H-indol-5-yl)indolin-2-one

Conditions	Yield
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione In diethyl ether at 20 - 25℃; enantioselective reaction;	A n/a B 97%

1H-indol-4-ol (2380-94-1) + C16H19N3O4 → tert-butyl (S)-(4-(4-hydroxy-1H-indol-5-yl)-1-(4-methoxyphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)carbamate

Conditions	Yield
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione In 1,2-dichloro-ethane at 0℃; Friedel-Crafts Alkylation; enantioselective reaction;	97%

Upstream product

• 5585-96-6 acetic acid 1H-indol-4-yl ester 
• 20289-26-3 4-benzyloxy-1H-indole 
• 120-72-9 indole 
• 5192-23-4 4-amino-1H-indole 
• 13754-86-4 1,5,6,7-tetrahydro-indol-4-one 
• 13523-86-9 1-(1H-indol-4-yloxy)-3-(isopropylamino)-2-propanol 
• 75201-78-4 ethyl 4-hydroxy-1H-indole-1-carboxylate 
• 112970-68-0 4-acetoxy-N-tosylindole 
• 81038-33-7 4-hydroxy-1-methoxycarbonylindole 
• 78283-30-4 2-benzyloxy-6-nitrophenyl acetaldehyde 
• 79966-73-7 2-(2-benzyloxy-6-nitrophenyl)acetonitrile 
• 81038-34-8 1-(p-toluenesulphonyl)-4-hydroxyindole 
• 85926-99-4 4-hydroxyindoline 
• 195992-07-5 3-nitro-2-vinylphenol 

Downstream Products

• 20289-26-3 4-benzyloxy-1H-indole 
• 124317-30-2 2-(1H-Indol-4-yloxy)-propionic acid ethyl ester 
• 4837-90-5 4-methoxy-1H-indole 
• 35308-87-3 4-(oxiranylmethoxy)-1H-indole 
• 61212-32-6 rac-3-(4-indolyloxy)propane-1,2-diol 
• 209728-00-7 (S)-1-(1H-indol-4-yloxy)-2,3-isopropylidenedioxypropane 
• 203921-46-4 N-Benzyl-N-[2-(1H-indol-4-yloxy)-ethyl]-carbamic acid tert-butyl ester 
• 26328-11-0 (S)-pindolol 
• 5585-96-6 acetic acid 1H-indol-4-yl ester 
• 7556-35-6 4-methoxy-1-methyl-1H-indole 
• 151720-06-8 1-chloro-3-(indol-4-yloxy)propane 
• 19499-82-2 5-(N,N-dimethylaminomethyl)indol-4-ol 
• 106792-40-9 4-((tert-butyldimethylsilyl)oxy)-1H-indole 
• 180160-98-9 4-(4-chlorobutoxy)-1H-indole 

Relevant articles and documents

A PHOTOCHEMICAL SYNTHESIS OF 4-HYDROXYINDOLE

1-Alkoxycarbonyl-4-hydroxyindoles were prepared in ca. 25percent yields from 5-(alkoxycarbonylamino)isoquinoline 2-oxides by irradiation in an aprotic solvent, followed by an acid treatment under solvolytic conditions. 1-benzyloxycarbonyl-4-hydroxyindole was then converted to the title compound by catalytic hydrogenation.

A facile synthesis of 4-hydroxy- and 4-aminoindoles through corresponding indolines

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Method for synthesizing 4 -hydroxyindole

The invention discloses a novel method for synthesizing 4 -hydroxyindole, and belongs to the field of medical intermediate synthesis. With 1, 3 - Cyclohexanedione reacts with 2 - aminoethanol to produce a corresponding enamine compound which is then converted to 4 - hydroxyindole in the presence of a supported or framework-type metal catalyst. The synthesis route is short in step, high-temperature reaction of the pressure vessel is avoided, 4 - hydroxyl indole synthesis efficiency and safety are improved. 2 - Aminoethanol is adopted as the synthetic raw material, the use of higher 2 - chloroacetaldehyde is avoided, the reaction by-product with 1 and 3 - cyclohexanedione is water, and the reaction by-product of the generated enamine under the action of the catalyst is H. 2 , 4 - Hydroxyl indole production cost is reduced.

4-hydroxyindole preparation method suitable for industrial production

The invention relates to the technical field of organic synthesis, in particular to a preparation method of a medical intermediate 4-hydroxyindole. The method includes: taking 1, 5, 6, 7-tetrahydro-4H-indole-4-one as the raw material, carrying out nucleophilic substitution reaction under the action of alkali to obtain an amino protection product (I), reacting the compound (I) with a halogenation reagent to obtain alpha-halogenated ketone (II), subjecting the compound (II) to elimination reaction under the action of alkali to remove HX so as to obtain a 4-hydroxyindole derivative (III), and finally conducting hydrolysis deprotection on the compound (III) to obtain 4-hydroxyindole (IV). The invention provides a simple industrial production route for 4-hydroxyindole, and the method has the advantages of simple reaction operation, avoidance of high temperature, high pressure and catalytic reaction, and low cost.