58861-48-6

Basic information

• Product Name: 2-(4-FLUOROPHENYL)THIOPHENE
• Synonyms: IFLAB-BB F2108-0130;2-(4-FLUOROPHENYL)THIOPHENE;AKOS BAR-1344;Thiophene, 2-(4-fluorophenyl)-;Canagliflozin Intermediate I;Canagliflozin INT2;2-(4-fluorophenyl)thiophen;Canagliflozin intermediate
• CAS NO: 58861-48-6
• Molecular Formula: C₁₀H₇FS
• Molecular Weight: 178.23
• EINECS: 1592732-453-0
• Mol File: 58861-48-6.mol
• Article Data: 53

Chemical Properties

• Melting Point: 51.0 to 55.0 °C
• Boiling Point: 252.316 °C at 760 mmHg
• Flash Point: 106.397 °C
• Appearance: /
• Density: 1.201 g/cm³
• Vapor Pressure: 0.031mmHg at 25°C
• Refractive Index: 1.578
• Storage Temp.: 2-8°C(protect from light)
• Solubility: soluble in Methanol
• CAS DataBase Reference: 2-(4-FLUOROPHENYL)THIOPHENE(CAS DataBase Reference)
• NIST Chemistry Reference: 2-(4-FLUOROPHENYL)THIOPHENE(58861-48-6)
• EPA Substance Registry System: 2-(4-FLUOROPHENYL)THIOPHENE(58861-48-6)

Safety Data

• Hazardous Substances Data: 58861-48-6(Hazardous Substances Data)

Usage

Chemical Properties

white solid

Uses

2-(4-Fluorophenyl)-thiophene can be used to prepare Canagliflozin (C175190) as sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor for treatment of type 2 diabetes mellitus.

InChI:InChI=1/C10H7FS/c11-9-5-3-8(4-6-9)10-2-1-7-12-10/h1-7H

Synthetic route

2-bromothiophene (1003-09-4) + 4-fluoroboronic acid (1765-93-1) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With Tedicyp; potassium carbonate; bis(η3-allyl-μ-chloropalladium(II)) In xylene at 130℃; for 20h; Suzuki cross-coupling reaction;	95%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In N,N-dimethyl-formamide at 120℃; for 15h; Inert atmosphere;	85%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 25 - 75℃; Inert atmosphere;	82.5%

2-bromothiophene (1003-09-4) + 4-flourophenylmagnesium bromide (352-13-6) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
Stage #1: 2-bromothiophene With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride In tetrahydrofuran at 2℃; for 0.666667h; Stage #2: 4-flourophenylmagnesium bromide In tetrahydrofuran at 10 - 23℃; for 1.66667h; Stage #3: With acetic acid In tetrahydrofuran; water at 7℃; for 0.75h;	95%
Stage #1: 2-bromothiophene; 1,3-bis-(diphenylphosphino)propane; palladium diacetate In tetrahydrofuran at 50℃; for 0.0833333h; Inert atmosphere; Stage #2: 4-flourophenylmagnesium bromide In tetrahydrofuran at 60℃; for 7h; Stage #3: With hydrogenchloride In tetrahydrofuran; water at 30℃; Cooling with ice;

2-Iodothiophene (3437-95-4) + 4-fluoroboronic acid (1765-93-1) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With potassium carbonate In water; N,N-dimethyl-formamide at 100℃; under 2585.81 Torr; for 0.333333h; Suzuki reaction; Microwave irradiation;	94%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In Dimethyl ether; water at 100℃; for 0.5h; Microwave irradiation;	86.1%
With potassium carbonate; Pd-N-heterocyclic carbene-organic silica In water; N,N-dimethyl-formamide at 100℃; for 0.16h; Suzuki reaction; microwave irradiation;	91 % Chromat.

thiophene boronic acid (6165-68-0) + 1-Bromo-4-fluorobenzene (460-00-4) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With potassium carbonate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine In ethanol; water at 90℃; Inert atmosphere;	92%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate In toluene at 90℃; for 0.5h; Schlenk technique; Inert atmosphere;	92%
With C33H48Cl2N4O9Pd; oxygen; potassium carbonate In water at 80℃; Suzuki-Miyaura Coupling;	85%
Stage #1: thiophene boronic acid; 1-Bromo-4-fluorobenzene With sodium carbonate In water; N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: With tetrakis(triphenylphosphine) palladium(0) In water; N,N-dimethyl-formamide at 85℃; for 3.03333h; Inert atmosphere;	82%

2-bromothiophene (1003-09-4) + 1-Bromo-4-fluorobenzene (460-00-4) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
Stage #1: 1-Bromo-4-fluorobenzene With iodine; magnesium In tetrahydrofuran at 36 - 40℃; for 4h; Inert atmosphere; Stage #2: 2-bromothiophene With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride In tetrahydrofuran at 20 - 25℃; for 5h; Temperature; Solvent; Inert atmosphere;	91.3%
Stage #1: 2-bromothiophene With magnesium In tetrahydrofuran at 30 - 45℃; Inert atmosphere; Stage #2: 1-Bromo-4-fluorobenzene With tetrakis(triphenylphosphine)nickel(0) In tetrahydrofuran at 60 - 80℃; for 6h; Inert atmosphere; Stage #3: With sulfuric acid In tetrahydrofuran; water at 40 - 60℃; pH=2.2; Reagent/catalyst;	87.6%
Stage #1: 2-bromothiophene With magnesium In tetrahydrofuran at 30 - 45℃; for 2h; Inert atmosphere; Sealed tube; Stage #2: 1-Bromo-4-fluorobenzene With tetrakis(triphenylphosphine)nickel(0) In tetrahydrofuran at 60 - 80℃; for 6h; Kumada Cross-Coupling; Inert atmosphere; Stage #3: With water at 40 - 60℃; Reagent/catalyst;	87.6%
Stage #1: 1-Bromo-4-fluorobenzene With magnesium In tetrahydrofuran; ethylene dibromide for 1.5h; Inert atmosphere; Stage #2: 2-bromothiophene With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II) In tetrahydrofuran at 10 - 75℃; for 0.5h;	75%
Stage #1: 1-Bromo-4-fluorobenzene With magnesium In 2-Me-THF Reflux; Inert atmosphere; Stage #2: 2-bromothiophene; 1,2-bis(diphenylphosphino)ethane nickel(II) chloride In 2-Me-THF at 2 - 22℃; Inert atmosphere; Stage #3: With acetic acid In 2-Me-THF; water for 0.25h; Inert atmosphere;

2-thienyl chloride (96-43-5) + 4-fluoroboronic acid (1765-93-1) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With potassium phosphate tribasic trihydrate; C31H41P; palladium diacetate In tetrahydrofuran at 110℃; for 3h; Suzuki-Miyaura Coupling; Inert atmosphere;	91%
With C27H39Br2N3Pd; potassium hydroxide In isopropyl alcohol at 82℃; for 0.166667h; Suzuki-Miyaura Coupling;	87%

1-ethoxythiocarbonylsulfanyl-4-(4-fluorophenyl)-4-oxobutyl 2,2-dimethylpropionate (517867-11-7) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With acetic acid; potassium iodide at 110℃; for 0.0833333h; Microwave irradiation;	88%
Multi-step reaction with 2 steps 1: titanium tetrachloride / dichloromethane / 0 - 20 °C / Inert atmosphere 2: silica gel / neat (no solvent) / 215 °C / Inert atmosphere View Scheme

4-fluoro-1-iodobenzene (352-34-1) + triethyl(thiophen-2-yl)germane → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With tris-(dibenzylideneacetone)dipalladium(0); silver tetrafluoroborate In N,N-dimethyl-formamide at 80℃; for 16h; chemoselective reaction;	88%

2-bromothiophene (1003-09-4) + 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (214360-58-4) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In Dimethyl ether; water at 70 - 75℃;	87%

thiophene boronic acid (6165-68-0) + 4-fluoro-1-iodobenzene (352-34-1) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; N,N-dimethyl-formamide at 85℃; Inert atmosphere;	86%
With tetrakis(triphenylphosphine) palladium(0) In water; N,N-dimethyl-formamide at 85℃; Inert atmosphere;	86%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; N,N-dimethyl-formamide at 85℃; for 3h;	86%

4-(4-fluorophenyl)-4-oxopropionic acid (366-77-8) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With tetraphosphorus decasulfide In toluene for 0.5h; Microwave irradiation;	85%

5-(4-fluorophenyl)thiophene-2-carboxaldehyde (249504-38-9) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With Pd-γ-Fe2O3 In cyclohexane at 130℃; for 24h; Inert atmosphere; Molecular sieve; Sealed tube;	83%

C10H8BrF → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With potassium sulfide; iodine In N,N-dimethyl-formamide at 110℃; for 11.8h; Inert atmosphere; chemoselective reaction;	76%

C26H37FOS → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
Stage #1: C26H37FOS With hydrazine hydrate In dimethyl sulfoxide at 80℃; Stage #2: With potassium hydroxide In dimethyl sulfoxide at 200℃; for 4h;	74.9%

thiophene boronic acid (6165-68-0) + C10H12FS(1+)*F6P(1-) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In ethanol at 40℃; for 3h;	74%

thiophene (188290-36-0) + 4-fluoroaniline (371-40-4) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With tert.-butylnitrite In acetonitrile at 25℃; for 0.75h; Flow reactor; Irradiation;	74%
Stage #1: 4-fluoroaniline With tetrafluoroboric acid; sodium nitrite In water at 0℃; for 1h; Green chemistry; Stage #2: thiophene With 3,4,5-trihydroxybenzoic acid In water; acetone at 20℃; for 12h; Inert atmosphere; Green chemistry;
Stage #1: 4-fluoroaniline With tetrafluoroboric acid; sodium nitrite In water at 0℃; for 0.666667h; Stage #2: thiophene In ethanol at 25℃; for 1h; Irradiation; Inert atmosphere;	80 %Chromat.
Stage #1: 4-fluoroaniline With tetrafluoroboric acid; sodium nitrite In water; acetone for 1h; Cooling; Stage #2: thiophene With 1,2,3,4-tetrahydrocarbazole In dimethyl sulfoxide Inert atmosphere; Darkness; regioselective reaction;

(Z)-1-(4-bromobut-3-en-1-yn-1-yl)-4-fluorobenzene → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With potassium ethyl xanthogenate; tetrabutyl phosphonium bromide In water at 130℃; for 20h; Schlenk technique; chemoselective reaction;	73%

2-bromothiophene (1003-09-4) + 4-flourophenylmagnesium bromide (352-13-6) → 2-(4-fluorophenyl)thiophene (58861-48-6) + 4,4'-difluorobiphenyl (398-23-2) + 2,2'-Bithiophene (492-97-7)

Conditions	Yield
Stage #1: 4-flourophenylmagnesium bromide With bismuth(III) chloride Stage #2: 2-bromothiophene With potassium phosphate; palladium diacetate; triphenylphosphine In N,N-dimethyl-formamide at 90℃; for 1h; Inert atmosphere;	A 72% B n/a C n/a

5-(4-fluorophenyl)thiophene-2-carboxylic acid (115933-30-7) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With copper In sulfolane at 200℃; for 2h;	72%

phenyl 5-(4-fluorophenyl)thiophene-2-carboxylate → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With nickel(II) acetate tetrahydrate; 1,2-bis-(dicyclohexylphosphino)ethane In toluene at 170℃; for 24h; Inert atmosphere; Glovebox; Sealed tube;	71%
With nickel(II) acetate tetrahydrate; 1,2-bis-(dicyclohexylphosphino)ethane In toluene at 170℃; for 24h;	71%

2-bromothiophene (1003-09-4) + 4-fluoro-1-iodobenzene (352-34-1) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
Stage #1: 2-bromothiophene With magnesium; ethylene dibromide In tetrahydrofuran at 20℃; for 0.75h; Kumada Cross-Coupling; Inert atmosphere; Stage #2: 4-fluoro-1-iodobenzene With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride In tetrahydrofuran at 20℃; Inert atmosphere; Reflux;	70%

4-[3-(4-fluorophenyl)-3-oxopropyl][1,3]dithietan-2-one (1509927-78-9) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With silica gel In neat (no solvent) at 215℃; Inert atmosphere;	70%

thiophene (188290-36-0) + 4-fluorobenzenediazonium tetrafluoroborate (459-45-0) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With cymantrene In dimethyl sulfoxide at 25℃; for 0.5h; Inert atmosphere; Irradiation; Flow reactor; regioselective reaction;	59%
With epi-Cercosporin In dimethyl sulfoxide at 20℃; for 8h; Schlenk technique; Inert atmosphere; Irradiation; Green chemistry; regioselective reaction;	57%
With graphitic carbon nitride/reduced graphene oxide nanocomposite In N,N-dimethyl-formamide at 20℃; for 1.5h; Inert atmosphere; UV-irradiation; Green chemistry;	60 %Chromat.

thiophene (188290-36-0) + 1-Bromo-4-fluorobenzene (460-00-4) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With palladium diacetate; potassium carbonate; catacxium A; Trimethylacetic acid In N,N-dimethyl-formamide at 110℃; for 12h; Schlenk technique; Inert atmosphere;	58%

potassim 4-fluorophenyltrifluoroborate + 2-(n-butyltellanyl)thiophene (403617-22-1) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; silver(l) oxide In methanol at 20℃; for 1.5h; Suzuki-Miyaura cross- coupling; Inert atmosphere;	56%

thiophen-2-yl magnesium bromide (5713-61-1) + 4-flourophenylmagnesium bromide (352-13-6) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
Stage #1: thiophen-2-yl magnesium bromide; 4-flourophenylmagnesium bromide With lithium chloride; manganese(ll) chloride In tetrahydrofuran at -10℃; Inert atmosphere; Stage #2: With oxygen In tetrahydrofuran at 10 - 20℃;	51%

thiophene (188290-36-0) + triethyl(4-fluorophenyl)germane → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
With (triphenylphosphine)gold(I) chloride; [bis(acetoxy)iodo]benzene; camphor-10-sulfonic acid In 1,4-dioxane at 70℃; for 16h;	48%

4-Fluorothiophenol (371-42-6) → 2-(4-fluorophenyl)thiophene (58861-48-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2.) NH4PF6 / 1.) MTBE, 23 deg C, 2.) acetone, 23 deg C 2: 74 percent / Pd(dppf)Cl2, K2CO3*H2O / aq. ethanol / 3 h / 40 °C View Scheme

2-(4-fluorophenyl)thiophene (58861-48-6) + C20H15NO → C30H20FNOS

Conditions	Yield
With 2-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-3-methylbutyric acid; C30H33O2Rh; silver fluoride In N,N-dimethyl-formamide at 60℃; for 48h; Inert atmosphere; Schlenk technique; enantioselective reaction;	99%

2-(4-fluorophenyl)thiophene (58861-48-6) + 1-(naphthalene-1-yl)benzo[h]isoquinoline → C33H20FNS

Conditions	Yield
With 2-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-3-methylbutyric acid; C30H33O2Rh; silver fluoride In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; Schlenk technique; enantioselective reaction;	98%

2-(4-fluorophenyl)thiophene (58861-48-6) + C23H14FN → C33H19F2NS

Conditions	Yield
With 2-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-3-methylbutyric acid; C30H33O2Rh; silver fluoride In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; Schlenk technique; enantioselective reaction;	97%

2-(4-fluorophenyl)thiophene (58861-48-6) → 2-bromo-5-(4-fluorophenyl)thiophene (1073313-97-9)

Conditions	Yield
With N-Bromosuccinimide In dichloromethane	95.3%

2-(4-fluorophenyl)thiophene (58861-48-6) + 5-bromo-2-methylbenzoic acid (79669-49-1) → (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophene-2-yl]methanone (1132832-75-7)

Conditions	Yield
Stage #1: 5-bromo-2-methylbenzoic acid With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20 - 25℃; Stage #2: 2-(4-fluorophenyl)thiophene With aluminum (III) chloride In dichloromethane at 0 - 25℃; for 12.5h; Solvent; Reagent/catalyst;	93.2%
Stage #1: 5-bromo-2-methylbenzoic acid With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 0 - 35℃; Stage #2: 2-(4-fluorophenyl)thiophene With aluminum (III) chloride In dichloromethane; N,N-dimethyl-formamide at 0 - 35℃;	89%
Stage #1: 5-bromo-2-methylbenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25 - 30℃; for 0.1h; Inert atmosphere; Stage #2: 2-(4-fluorophenyl)thiophene With aluminum (III) chloride In dichloromethane at 0 - 15℃; Inert atmosphere;	80.4%
Stage #1: 5-bromo-2-methylbenzoic acid With oxalyl dichloride In dichloromethane at 20℃; for 2h; Stage #2: 2-(4-fluorophenyl)thiophene With aluminum (III) chloride In dichloromethane at -15 - 35℃; for 4h;	80%

2-(4-fluorophenyl)thiophene (58861-48-6) + C8H7ClO2 → (2-methylphenyl)(5-(4-fluorophenyl)thiophen-2-yl)methanone

Conditions	Yield
With aluminum (III) chloride In dichloromethane at -20 - 20℃; for 3h; Inert atmosphere;	92%

2-(4-fluorophenyl)thiophene (58861-48-6) + C24H17N → C34H22FNS

Conditions	Yield
With 2-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-3-methylbutyric acid; C30H33O2Rh; silver fluoride In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; Schlenk technique; enantioselective reaction;	92%

2-(4-fluorophenyl)thiophene (58861-48-6) + 5-bromo-2-methylbenzoyl chloride (21900-41-4) → (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophene-2-yl]methanone (1132832-75-7)

Conditions	Yield
With aluminum (III) chloride In dichloromethane at -10 - 25℃; for 5.5h; Friedel-Crafts Acylation; Inert atmosphere;	90.1%
With aluminum (III) chloride In dichloromethane at 0 - 20℃; Friedel Crafts acylation;	85.7%
Stage #1: 2-(4-fluorophenyl)thiophene; 5-bromo-2-methylbenzoyl chloride With aluminum (III) chloride In dichloromethane at -10 - 20℃; for 2.5 - 3.5h; Stage #2: With hydrogenchloride; water In n-heptane; dichloromethane at -12℃;
Stage #1: 2-(4-fluorophenyl)thiophene; 5-bromo-2-methylbenzoyl chloride With aluminum (III) chloride In dichloromethane at 0 - 20℃; Stage #2: With water In tetrahydrofuran cooling with ice;

2-(4-fluorophenyl)thiophene (58861-48-6) + carbon dioxide (124-38-9) → 5-(4-fluorophenyl)thiophene-2-carboxylic acid (115933-30-7)

Conditions	Yield
With ethylaluminum dichloride In hexane; toluene at 100℃; under 22502.3 Torr; for 3h; Autoclave; Inert atmosphere; regioselective reaction;	90%

2-(4-fluorophenyl)thiophene (58861-48-6) + C8H6BrClO2 → C18H12BrFOS

Conditions	Yield
With aluminum (III) chloride In dichloromethane at -20 - 20℃; for 3h; Inert atmosphere;	90%

2-(4-fluorophenyl)thiophene (58861-48-6) + C24H17NO → C34H22FNOS

Conditions	Yield
With 2-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-3-methylbutyric acid; C30H33O2Rh; silver fluoride In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; Schlenk technique; enantioselective reaction;	90%

2-(4-fluorophenyl)thiophene (58861-48-6) + C25H17N → C35H22FNS

Conditions	Yield
With 2-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-3-methylbutyric acid; C30H33O2Rh; silver fluoride In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; Schlenk technique; enantioselective reaction;	90%

2-(4-fluorophenyl)thiophene (58861-48-6) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → 5-(4-fluorophenyl)thiophene-2-carboxaldehyde (249504-38-9)

Conditions	Yield
Stage #1: 2-(4-fluorophenyl)thiophene; N,N-dimethyl-formamide With tris(trimethylsilyl)amine; tetramethylammonium fluoride at 20℃; for 24h; Inert atmosphere; Sealed tube; Stage #2: With hydrogenchloride In water at 20℃; for 1.5h;	86%

2-(4-fluorophenyl)thiophene (58861-48-6) + 1-(pyren-1-yl)benzo[h]isoquinoline → C39H22FNS

Conditions	Yield
With 2-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-3-methylbutyric acid; C30H33O2Rh; silver fluoride In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; Schlenk technique; enantioselective reaction;	86%

2-(4-fluorophenyl)thiophene (58861-48-6) + 2,2,2-trifluoro-1-(1H-indol-3-yl)-1-(thiophen-2-yl)ethan-1-ol (1150561-00-4) → 3-(2,2,2-trifluoro-1-(5-(4-fluorophenyl)thiophen-2-yl)-1-(thiophen-2-yl)ethyl)-1H-indole

Conditions	Yield
With dodecylbenzenesulfonic acid In water at 80℃; for 24h; Green chemistry;	83%

2-(4-fluorophenyl)thiophene (58861-48-6) + 5-iodo-2-methylbenzoic acid (54811-38-0) → (5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone

Conditions	Yield
Stage #1: 5-iodo-2-methylbenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Stage #2: 2-(4-fluorophenyl)thiophene With aluminum (III) chloride In dichloromethane at -15 - 35℃; for 4h;	81%
Stage #1: 5-iodo-2-methylbenzoic acid With thionyl chloride In dichloromethane; N,N-dimethyl-formamide for 1h; Reflux; Stage #2: 2-(4-fluorophenyl)thiophene With aluminum (III) chloride In dichloromethane; N,N-dimethyl-formamide at 0 - 30℃; for 1h;	222 g

2-(4-fluorophenyl)thiophene (58861-48-6) + 5-iodo-2-methylbenzoyl chloride (108440-70-6) → (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1)

Conditions	Yield
With aluminum (III) chloride Solvent; Temperature; Friedel-Crafts Acylation;	80%
Stage #1: 5-iodo-2-methylbenzoyl chloride With aluminum (III) chloride In dichloromethane at 2℃; for 0.25h; Stage #2: 2-(4-fluorophenyl)thiophene In dichloromethane at 2 - 20℃; for 2.41667h; Product distribution / selectivity;

2-(4-fluorophenyl)thiophene (58861-48-6) + phenylboronic acid (98-80-6) → 2-(4-fluorophenyl)-4-phenylthiophene (1415605-87-6)

Conditions	Yield
With palladium(II) trifluoroacetate; cesium trifluoroacetate; p-benzoquinone; silver(l) oxide In acetic acid; trifluoroacetic acid at 20℃; for 15h; regioselective reaction;	80%

Upstream product

• 6165-68-0 thiophene boronic acid 
• 1003-09-4 2-bromothiophene 
• 1765-93-1 4-fluoroboronic acid 
• 403617-22-1 2-(n-butyltellanyl)thiophene 
• 352-13-6 4-flourophenylmagnesium bromide 
• 188290-36-0 thiophene 
• 371-40-4 4-fluoroaniline 
• 460-00-4 1-Bromo-4-fluorobenzene 
• 5713-61-1 thiophen-2-yl magnesium bromide 
• 214360-58-4 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 
• 3437-95-4 2-Iodothiophene 
• 371-42-6 4-Fluorothiophenol 
• 352-34-1 4-fluoro-1-iodobenzene 
• 95895-33-3 1-(bromoethynyl)-4-fluorobenzene 

Downstream Products

• 1132832-75-7 (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophene-2-yl]methanone 
• 898566-17-1 (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) 
• 1415605-87-6 2-(4-fluorophenyl)-4-phenylthiophene 
• 1030825-21-8 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methyl-phenyl)-D-glucopyranoside 
• 842133-18-0 canagliflozin 
• 866607-35-4 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 
• 1030825-20-7 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl bromide 
• 42545-43-7 2-(4-methoxyphenyl)thiophene 
• 1073313-97-9 2-bromo-5-(4-fluorophenyl)thiophene 

Relevant articles and documents

Synthesis of Substituted Thiophenes through Dehydration and Heterocyclization of Alkynols

A protocol was described for obtaining a variety of substituted thiophenes with functional potential via metal-free dehydration and sulfur cyclization of alkynols with elemental sulfur (S8) or EtOCS2K in moderate-to-good yields. The method provides the base-free generation of a trisulfur radical anion (S3?-) and its addition to alkynes as an initiator. This research broadens the applications of S3?-in the synthesis of sulfur-containing heterocycles.

Preparation method of canagliflozin intermediate 2-(4-fluorophenyl) thiophene

The invention relates to a preparation method of canagliflozin intermediate 2-(-4fluorophenyl) thiophene. The method comprises the following steps of: (1) enabling 2-bromothiophene to react with magnesium chips in a THF solvent to generate 2-thienyl magnesium bromide Grignard liquid; (2) carrying out catalytic Kumada coupling reaction on the 2-thienyl magnesium bromide Grignard liquid and p-fluorobromobenzene in the presence of a nickel or palladium complex as a catalyst, so as to obtain the 2-(-4fluorophenyl) thiophene. The method is good in product quality, high in yield, mild in reaction condition, simple to operate and easy to industrialize.

Preparation method of intermediate

The invention discloses a preparation method for a Canagliflozin intermediate. The preparation method comprises the steps that substituted bromobenzene as a starting material is reacted with bisdiboron to prepare a boride, and then the Canagliflozin intermediate is prepared through a Suzuki coupling reaction, a Friedel-Crafts acylation reaction and a reduction reaction. The preparation method hasthe advantages that the intermediate product CZ-2 is prepared through the Suzuki coupling reaction, the conditions are mild and easy to operate and control, and the product yield and the product purity are high; aryl methyl is introduced through the Friedel-Crafts acylation reaction, a main chain is built, by means of the route, the yield is high, technological conditions are easy to control, andthe preparation method is suitable for large-scale industrial production.