166599-84-4

Basic information

• Product Name: benzofuran-4-carboxylic acid
• Synonyms: benzofuran-4-carboxylic acid;4-BENZOFURANCARBOXYLICACID;1-Benzofuran-4-carboxylic acid;1-benzofurane-4-carboxylic acid
• CAS NO: 166599-84-4
• Molecular Formula: C₉H₆O₃
• Molecular Weight: 162.14214
• Mol File: 166599-84-4.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 326℃
• Flash Point: 151℃
• Appearance: /
• Density: 1.363
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.649
• Storage Temp.: Sealed in dry,Room Temperature
• PKA: 3.19±0.10(Predicted)
• CAS DataBase Reference: benzofuran-4-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: benzofuran-4-carboxylic acid(166599-84-4)
• EPA Substance Registry System: benzofuran-4-carboxylic acid(166599-84-4)

Safety Data

• Hazardous Substances Data: 166599-84-4(Hazardous Substances Data)

Usage

Uses

4-Benzofurancarboxylic Acid is a benzofuran derivative used in the preparation of dual orexin 1 and orexin 2 receptor antagonist which are useful for the treatment of sleep disorders.

InChI:InChI=1/C9H6O3/c10-9(11)7-2-1-3-8-6(7)4-5-12-8/h1-5H,(H,10,11)

Synthetic route

methyl benzofuran-4-carboxylate (41019-56-1) → benzofuran-4-carboxylic acid (166599-84-4)

Conditions	Yield
With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 16h;	99%
Stage #1: methyl benzofuran-4-carboxylate With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 16h; Stage #2: With hydrogenchloride In water	99%
With potassium hydroxide In methanol for 1h; Heating;	97%

methyl 2-hydroxy-2,3-dihydrobenzofuran-4-carboxylate (166599-85-5) → benzofuran-4-carboxylic acid (166599-84-4)

Conditions	Yield
Stage #1: methyl 2-hydroxy-2,3-dihydrobenzofuran-4-carboxylate; toluene-4-sulfonic acid In toluene for 5.46667h; Heating / reflux; Stage #2: With sodium hydroxide; water In toluene at 60℃; for 9h; Stage #3: With hydrogenchloride In water at 2 - 14℃; for 14.5h; Heating / reflux;	62%
Multi-step reaction with 2 steps 1: 67 percent / 85percent H3PO4 / a) RT, 10 min, b) 100 deg C, 15 min 2: 97 percent / 35percent KOH / methanol / 1 h / Heating View Scheme

methyl 3-(prop-2-enyloxy)benzoate (79250-46-7) → benzofuran-4-carboxylic acid (166599-84-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 41 percent / 1 h / 230 °C 2: 1.) O3, 2.) (CH3)2S / 1.) MeOH, -70 deg C, 30 min, 2.) MeOH, RT, overnight 3: 67 percent / 85percent H3PO4 / a) RT, 10 min, b) 100 deg C, 15 min 4: 97 percent / 35percent KOH / methanol / 1 h / Heating View Scheme

2-allyl-3-hydroxy-benzoic acid methyl ester (79950-39-3) → benzofuran-4-carboxylic acid (166599-84-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) O3, 2.) (CH3)2S / 1.) MeOH, -70 deg C, 30 min, 2.) MeOH, RT, overnight 2: 67 percent / 85percent H3PO4 / a) RT, 10 min, b) 100 deg C, 15 min 3: 97 percent / 35percent KOH / methanol / 1 h / Heating View Scheme

benzofuran-4-yl trifluoromethanesulfonate (177734-79-1) → benzofuran-4-carboxylic acid (166599-84-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine; palladium diacetate; 1,3-bis-(diphenylphosphino)propane / dimethyl sulfoxide / 18 h / 80 °C / 3102.97 Torr 2: lithium hydroxide; water / tetrahydrofuran; methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / dimethyl sulfoxide / 18 h / 80 °C / 3102.97 Torr 2: lithium hydroxide / tetrahydrofuran; water; methanol / 16 h / 20 °C View Scheme

4-hydroxybenzofuran (480-97-7) → benzofuran-4-carboxylic acid (166599-84-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine; dmap / dichloromethane / 2 h / 0 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / dimethyl sulfoxide / 18 h / 80 °C / 3102.97 Torr 3: lithium hydroxide / tetrahydrofuran; water; methanol / 16 h / 20 °C View Scheme

N,O-dimethylhydroxylamine*hydrochloride (6638-79-5) + benzofuran-4-carboxylic acid (166599-84-4) → N-methoxy-N-methylbenzofuran-4-carboxamide (209256-39-3)

Conditions	Yield
Stage #1: benzofuran-4-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With pyridine In dichloromethane at 0 - 20℃; for 18h;	93%
Stage #1: benzofuran-4-carboxylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With pyridine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 18h;	93%

benzofuran-4-carboxylic acid (166599-84-4) → 2,3-dihydrobenzofuran-4-carboxylic acid (209256-40-6)

Conditions	Yield
With hydrogen; palladium 10% on activated carbon In acetic acid under 3102.97 Torr; for 12h;	83%
With hydrogen; palladium 10% on activated carbon In ethanol at 20℃; under 3000.3 Torr; for 16h;
With hydrogen; palladium 10% on activated carbon In ethanol at 20℃; under 3000.3 Torr; for 16h;

tert-butyl (3R)3-aminopiperidine-1-carboxylate (188111-79-7) + benzofuran-4-carboxylic acid (166599-84-4) → (R)-3-[(benzofuran-4-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (1030389-11-7)

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 20h;	82%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 20h;	82%

(2RS)-(2-aminomethyl-azetidin-1-yl)-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone (1007873-82-6) + benzofuran-4-carboxylic acid (166599-84-4) → (2S)-Benzofuran-4-carboxylic acid{1-[5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl]-azetidin-2-ylmethyl}-amide (1007873-83-7)

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 20h;	78%

(S)-3-methylamino-4-phenyl-butyronitrile hydrochloride (1238071-95-8) + benzofuran-4-carboxylic acid (166599-84-4) → benzofuran-4-carboxylic acid ((S)-1-benzyl-2-cyanoethyl)(methyl)amide (1312557-94-0)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 20h;	78%

bis(2-fluorophenyl)iodonium trifluoromethanesulfonate (1034369-95-3) + benzofuran-4-carboxylic acid (166599-84-4) → C15H8O3

Conditions	Yield
With palladium diacetate; potassium carbonate In N,N-dimethyl-formamide at 110℃; for 24h;	50%

6a-naltrexamine hydrochloride (67025-97-2, 84774-95-8) + benzofuran-4-carboxylic acid (166599-84-4) → 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(benzofuran-4-carboxamido)morphinan

Conditions	Yield
Stage #1: benzofuran-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide for 1h; Molecular sieve; Cooling with ice; Inert atmosphere; Stage #2: 6a-naltrexamine hydrochloride In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Stage #3: With potassium carbonate In methanol at 20℃; Inert atmosphere;	45%

6β-naltrexamine (67025-97-2) + benzofuran-4-carboxylic acid (166599-84-4) → 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(benzofuran-4-carboxamido)morphinan

Conditions	Yield
Stage #1: benzofuran-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide for 1h; Molecular sieve; Cooling with ice; Inert atmosphere; Stage #2: 6β-naltrexamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Stage #3: With potassium carbonate In methanol at 20℃; Inert atmosphere;	42%

tert-butyl (2S)-2-(aminomethyl)azetidine-1-carboxylate (1007873-90-6) + benzofuran-4-carboxylic acid (166599-84-4) → (2S)-{[(benzofuran-4-carbonyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (1007873-91-7)

Conditions	Yield
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide Inert atmosphere;	30%

benzofuran-4-carboxylic acid (166599-84-4) → 2-iodo-benzofuran-4-carboxylic acid (1061591-03-4)

Conditions	Yield
Stage #1: benzofuran-4-carboxylic acid With tert.-butyl lithium In diethyl ether; pentane at -78℃; for 0.5h; Inert atmosphere; Stage #2: With iodine In diethyl ether; pentane at -78 - 20℃;	23%

(RS)-2-Cyclopropyl-2-[methyl-(2-methyl-5-phenyl-thiazole-4-carbonyl)-amino]-ethyl-ammonium chloride (1117693-67-0) + benzofuran-4-carboxylic acid (166599-84-4) → 2-methyl-5-phenyl-thiazole-4-carboxylic acid {(RS)-2-[(benzofuran-4-carbonyl)-amino]-1-cyclopropyl-ethyl}-methyl-amide (1117693-63-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide	22%

(RS)-2-cyclopropyl-2-[methyl-(2-methyl-5-phenyl-thiazole-4-carbonyl)amino]ethyl-ammonium chloride + benzofuran-4-carboxylic acid (166599-84-4) → 2-methyl-5-phenyl-thiazole-4-carboxylic acid {(RS)-2-[(benzofuran-4-carbonyl)-amino]-1-cyclopropyl-ethyl}-methyl-amide (1117693-63-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide	22%

benzofuran-4-carboxylic acid (166599-84-4) → benzofuran-4-carbonyl chloride (380899-56-9)

Conditions	Yield
With thionyl chloride; N,N-dimethyl-formamide Ambient temperature;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 19 - 20℃; for 2.5h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 5h;
With thionyl chloride for 2h; Heating / reflux;

benzofuran-4-carboxylic acid (166599-84-4) + tert-butyl alcohol (75-65-0) → tert-butyl (1-benzofuran-4-yl)carbamate (412336-05-1)

Conditions	Yield
With diphenyl phosphoryl azide; triethylamine for 18h; Heating;

(1R*,2S*,5S*)-2-aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester + benzofuran-4-carboxylic acid (166599-84-4) → (1R*,2S*,5S*)-2-{[(benzofuran-4-carbonyl)-amino]-methyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

Conditions	Yield
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.166667h;

benzofuran-4-carboxylic acid (166599-84-4) → 4-aminobenzofuran (412336-07-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: diphenoxyphosphoryl azide; Et3N / 18 h / Heating 2: 0.35 g / TFA / CH2Cl2 / 2.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: diphenylphosphoranyl azide; triethylamine / tert-butyl alcohol 2: trifluoroacetic acid / dichloromethane View Scheme

benzofuran-4-carboxylic acid (166599-84-4) → 4-(4-benzofuranylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline

Conditions	Yield
Multi-step reaction with 3 steps 1: diphenoxyphosphoryl azide; Et3N / 18 h / Heating 2: 0.35 g / TFA / CH2Cl2 / 2.5 h / 0 - 20 °C 3: 76 percent / HCl(g) / propan-2-ol / 90 °C View Scheme

benzofuran-4-carboxylic acid (166599-84-4) → Benzofuran-4-yl-[1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-methanone

Conditions	Yield
Multi-step reaction with 2 steps 1: SOCl2, DMF / Ambient temperature 2: EtAlCl2 / CH2Cl2; toluene / -78 - 20 °C View Scheme

2-allyl-3-hydroxy-benzoic acid methyl ester (79950-39-3) + benzofuran-4-carboxylic acid (166599-84-4) → tert-butyl (1-benzofuran-4-yl)carbamate (412336-05-1)

Conditions	Yield
With diphenylphosphoranyl azide; triethylamine In tert-butyl alcohol

(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (1038509-56-6) + benzofuran-4-carboxylic acid (166599-84-4) → (1S,3S,5S)-3-{[(benzofuran-4-carbonyl)-amino]-methyl}-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (1038509-59-9)

Conditions	Yield
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine for 2h;

tert-butyl (1S,2S,5R)-2-(aminomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1108172-95-7) + benzofuran-4-carboxylic acid (166599-84-4) → (1S,2S,5R)-2-{[(benzofuran-4-carbonyl)-amino]-methyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1108172-98-0)

Conditions	Yield
Stage #1: benzofuran-4-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.166667h; Stage #2: tert-butyl (1S,2S,5R)-2-(aminomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate In N,N-dimethyl-formamide

(1R,3S,4S)-3-aminomethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1181573-42-1) + benzofuran-4-carboxylic acid (166599-84-4) → (1R,3S,4S)-3-{[(benzofuran-4-carbonyl)-amino]-methyl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1181573-44-3)

Conditions	Yield
Stage #1: benzofuran-4-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide Stage #2: (1R,3S,4S)-3-aminomethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester In dichloromethane; N,N-dimethyl-formamide

(R)-tert-butyl 4-(aminomethyl)thiazolidine-3-carboxylate (391248-13-8) + benzofuran-4-carboxylic acid (166599-84-4) → (R)-4-{[(benzofuran-4-carbonyl)-amino]-methyl}-thiazolidine-3-carboxylic acid tert-butyl ester (1061591-40-9)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane

(2RS)-(2-aminomethyl-azetidin-1-yl)-biphenyl-2-yl-methanone (1007873-74-6) + benzofuran-4-carboxylic acid (166599-84-4) → (2S)-Benzofuran-4-carboxylic acid [1-(biphenyl-2-carbonyl)-azetidin-2-ylmethyl]-amide (1007873-72-4)

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 20h;

(2RS)-[1-(biphenyl-2-sulfonyl)azetidin-2-yl]methylamine (1007873-77-9) + benzofuran-4-carboxylic acid (166599-84-4) → (2S)-Benzofuran-4-carboxylic acid [1-(biphenyl-2-sulfonyl)-azetidin-2-ylmethyl]-amide (1007873-75-7)

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 20h;

C19H25N3O2S (1396788-43-4) + benzofuran-4-carboxylic acid (166599-84-4) → C28H29N3O4S

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl acetamide

Upstream product

• 41019-56-1 methyl benzofuran-4-carboxylate 
• 480-97-7 4-hydroxybenzofuran 
• 177734-79-1 benzofuran-4-yl trifluoromethanesulfonate 
• 166599-85-5 methyl 2-hydroxy-2,3-dihydrobenzofuran-4-carboxylate 
• 79950-39-3 2-allyl-3-hydroxy-benzoic acid methyl ester 
• 79250-46-7 methyl 3-(prop-2-enyloxy)benzoate 

Downstream Products

• 209256-41-7 (2,3-dihydro-benzofuran-4-yl)-methanol 
• 209256-42-8 2,3-dihydro-1-benzofuran-4-carbaldehyde 
• 209257-15-8 trans-[2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]methanamine 
• 173470-67-2 4-hydroxymethylbenzofurane 
• 1312557-94-0 benzofuran-4-carboxylic acid ((S)-1-benzyl-2-cyanoethyl)(methyl)amide 
• 1007873-75-7 (2S)-Benzofuran-4-carboxylic acid [1-(biphenyl-2-sulfonyl)-azetidin-2-ylmethyl]-amide 
• 1007873-83-7 (2S)-Benzofuran-4-carboxylic acid{1-[5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl]-azetidin-2-ylmethyl}-amide 
• 1007873-72-4 (2S)-Benzofuran-4-carboxylic acid [1-(biphenyl-2-carbonyl)-azetidin-2-ylmethyl]-amide 
• 1117693-63-6 2-methyl-5-phenyl-thiazole-4-carboxylic acid {(RS)-2-[(benzofuran-4-carbonyl)-amino]-1-cyclopropyl-ethyl}-methyl-amide 
• 412336-05-1 tert-butyl (1-benzofuran-4-yl)carbamate 
• 209256-40-6 2,3-dihydrobenzofuran-4-carboxylic acid 
• 412336-07-3 4-aminobenzofuran 

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