656-42-8

Basic information

• Product Name: 2,2-Difluorobenzodioxole-5-carboxaldehyde
• Synonyms: 2,2-Difluoro-5-formyl-1,3-benzodioxole, 3,4-(Difluoromethylenedioxy)benzaldehyde, 1,2-(Difluoromethylenedioxy)-4-formylbenzene;2,2-Difluorobenzo[d][1,3]dioxole-5-carbaldehyde;2,2-Difluoro-5-formylbenzodioxole 97%;2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde;2,2-DIFLUORO-1,3-BENZODIOXOLE-5-CARBOXALDEHYDE;2,2-DIFLUORO-1,3-BENZODIOXOLE-5-CARBOXYALDEHYDE;2,2-DIFLUORO-5-FORMYL-1,3-BENZODIOXOLE;2,2-DIFLUORO-5-FORMYLBENZODIOXOLE
• CAS NO: 656-42-8
• Molecular Formula: C₈H₄F₂O₃
• Molecular Weight: 186.11
• Product Categories: Heterocycles series;Aldehydes;Benzodiozoles, Benzodioxines & Benzodioxepines;Benzodiozoles, Benzodioxines & Benzodioxepines
• Mol File: 656-42-8.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 202-203 °C(lit.)
• Flash Point: 205 °F
• Appearance: /
• Density: 1.422 g/mL at 25 °C(lit.)
• Vapor Pressure: 0.191mmHg at 25°C
• Refractive Index: n20/D 1.5000(lit.)
• Storage Temp.: Keep in dark place,Sealed in dry,Room Temperature
• Water Solubility: Sparingly soluble in water (0.31 g/L at 25°C).
• Sensitive: Air Sensitive
• BRN: 1369253
• CAS DataBase Reference: 2,2-Difluorobenzodioxole-5-carboxaldehyde(CAS DataBase Reference)
• NIST Chemistry Reference: 2,2-Difluorobenzodioxole-5-carboxaldehyde(656-42-8)
• EPA Substance Registry System: 2,2-Difluorobenzodioxole-5-carboxaldehyde(656-42-8)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• WGK Germany: 3
• Hazardous Substances Data: 656-42-8(Hazardous Substances Data)

Usage

Uses

2,2-Difluoro-1,3-benzodioxole-5-carboxaldehyde is used as primary and secondary intermediate.

InChI:InChI=1/C8H4F2O3/c9-8(10)12-6-2-1-5(4-11)3-7(6)13-8/h1-4H

Synthetic route

2-thioxobenzo[d][1,3]dioxole-5-carbaldehyde (1269252-03-0) → 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8)

Conditions	Yield
With bromine trifluoride In CFCl3; chloroform at 0℃; for 0.0166667h;	95%

5-dichloromethyl-2,2-difluorobenzo-(1,3)-dioxole (149045-78-3) + hexamethylenetetramine (100-97-0) → 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8)

Conditions	Yield
With hydrogenchloride In water

5-bromo-2,2-difluoro-2H-1,3-benzodioxole (33070-32-5) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8)

Conditions	Yield
Stage #1: 5-bromo-2,2-difluoro-2H-1,3-benzodioxole With n-butyllithium In tetrahydrofuran for 0.166667h; Cooling with acetone-dry ice; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 2h; Cooling with acetone-dry ice; Stage #3: With water; ammonium chloride In tetrahydrofuran
Stage #1: 5-bromo-2,2-difluoro-2H-1,3-benzodioxole With isopropylmagnesium chloride In tetrahydrofuran at -10 - 0℃; for 5h; Inert atmosphere; Large scale; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -25℃; for 2h; Reagent/catalyst; Temperature; Inert atmosphere; Large scale;	28.6 g

3,4-dihydroxybenzaldehyde (139-85-5) → 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate / water / 2 h / 0 °C 2: bromine trifluoride / CFCl3; chloroform / 0.02 h / 0 °C View Scheme

2,2-difluoro-1,3-benzodioxole (1583-59-1) → 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: iron; bromine / 20 - 30 °C / Inert atmosphere; Large scale 2.1: isopropylmagnesium chloride / tetrahydrofuran / 5 h / -10 - 0 °C / Inert atmosphere; Large scale 2.2: 2 h / -25 °C / Inert atmosphere; Large scale View Scheme

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + 1-t-Butoxycarbonylpiperazine (57260-71-6) → tert-butyl 4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]piperazine-1-carboxylate

Conditions	Yield
With sodium tris(acetoxy)borohydride In tetrahydrofuran at 0 - 20℃;	99%
With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 16h;

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + (S)-2-methylpropane-2-sulfinamide (343338-28-3) → (S)-N-[(1E)-(2,2-difluoro-1,3-benzodioxol-5-yl)methylene]-2-methylpropane-2-sulfinamide

Conditions	Yield
With copper(II) sulfate In dichloromethane at 18 - 25℃; for 16h; Inert atmosphere;	95%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + toluene-4-sulfonic acid hydrazide (1576-35-8) → N'-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methylene)-4-methylbenzenesulfonohydrazide

Conditions	Yield
In ethanol Reflux;	88%
In methanol at 20℃; for 12h; Inert atmosphere; Sealed tube;

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + Methyltriphenylphosphonium bromide (1779-49-3) → 2,2-difluoro-5-vinylbenzo[d][1,3]dioxole

Conditions	Yield
Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran at 0℃; for 0.25h; Schlenk technique; Inert atmosphere; Stage #2: 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde In tetrahydrofuran at 0 - 25℃; for 48h; Schlenk technique; Inert atmosphere;	85%
Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;	80%
Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere;	76%
Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran at 0℃; for 0.25h; Schlenk technique; Inert atmosphere; Stage #2: 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde In tetrahydrofuran at 0 - 20℃; Schlenk technique; Inert atmosphere;	50%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + 2-heptylamine (123-82-0) → C15H21F2NO2

Conditions	Yield
With triethylsilane; palladium on carbon; TPGS-750-M In water at 45℃; for 4h;	85%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + methylmagnesium bromide (75-16-1) → 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol (1009032-10-3)

Conditions	Yield
Stage #1: 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde; methylmagnesium bromide In diethyl ether at 0 - 20℃; for 0.25 - 0.333333h; Stage #2: With water at 0℃;	83.5%

piperazine (110-85-0) + 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) → 1-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)piperazine (1093211-85-8)

Conditions	Yield
With hydrogen; 20% palladium hydroxide-activated charcoal In methanol; toluene at 20 - 70℃; under 760.051 Torr; for 36h;	83%
Stage #1: piperazine; 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde In methanol at 20℃; for 18h; Stage #2: With 20% palladium hydroxide on charcoal; hydrogen In methanol at 70℃; under 760.051 Torr;	83%
Stage #1: piperazine; 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde In methanol at 20℃; for 18h; Inert atmosphere; Stage #2: With 10 wt% Pd(OH)2 on carbon; hydrogen In methanol at 70℃; under 760.051 Torr;	83%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + cyclohexylamine (108-91-8) → N-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]cyclohexanamine (1443830-94-1)

Conditions	Yield
With sodium tris(acetoxy)borohydride In dichloromethane at 25℃; Molecular sieve;	82%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid hydrazide (662157-81-5) → 2',4'-difluoro-4-hydroxy-N'-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylidene] biphenyl-3-carbohydrazide

Conditions	Yield
In ethanol for 2h; Reflux;	82%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + (1S,3S,4R)-4-[(3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methylidene-octahydro-1H-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol → (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methylamino)methyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol

Conditions	Yield
Stage #1: 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde; (1S,3S,4R)-4-[(3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methylidene-octahydro-1H-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol In methanol for 0.5h; Reflux; Inert atmosphere; Stage #2: With methanol; sodium tetrahydroborate at 20℃; Inert atmosphere;	81%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + N-methyl-N-tosylpropiolamide → (±)-(4R,5R)-5-(2,2-difluorobenzo[d][1,3]dioxole-5-carbonyl)-2-methyl-4-(p-tolyl)isothiazolidin-3-one 1,1-dioxide

Conditions	Yield
With eosin Y disodium salt In acetonitrile at 80℃; for 48h; Smiles Aromatic Rearrangement; Schlenk technique; Inert atmosphere; Sealed tube; Irradiation; diastereoselective reaction;	80%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) → (2,2-difluoro-1,3-benzodioxol-5-yl)methanol (72768-97-9)

Conditions	Yield
With sodium tetrahydroborate In ethanol at 20 - 30℃; for 3.5h; Reagent/catalyst; Inert atmosphere; Large scale;	77.7%
With methanol; sodium tetrahydroborate

tetrahydrofuran-2,4-dione (4971-56-6) + 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + 1,10-phenanthroline-5-amine (54258-41-2) → (9aR,13S)-13-((3,4-difluoromethylenedioxy)phenyl)-9a-hydroxy-9a,10,12a,13-tetrahydrofuro[3,4-b]pyrido[3,2-f][1,10]phenanthrolin-12(9H)-one

Conditions	Yield
In ethanol Reflux;	77%

1-Phenylprop-1-yne (673-32-5) + 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) → 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-phenylbut-3-yn-1-ol

Conditions	Yield
With 2,2,6,6-tetramethyl-piperidine; (1,2,3,4,5-pentamethylcyclopentadienyl)(tetrahydrofuran)dicarbonyliron(II) tetrafluoroborate; boron trifluoride diethyl etherate In toluene at 100℃; for 24h;	76%

4-hydroxy-2(5H)-furanone (541-57-1) + 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) → 9-(2,2-difluoro-1,3-benzodioxol-5-yl)-6,9-dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (867069-17-8)

Conditions	Yield
Inert atmosphere; Reflux;	75%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + trimethylsilyl cyanide (7677-24-9) → 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-(trimethylsilyloxy)acetonitrile

Conditions	Yield
Stage #1: 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde With zinc(II) iodide In dichloromethane at 10 - 15℃; Stage #2: trimethylsilyl cyanide In dichloromethane at 20℃; for 1h;	75%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + 1,10-phenanthroline-5,6-dione (27318-90-7) → 2-(3',3'-difluoro-3,4-methylenedioxyphenyl)imidazo[4,5-f][1,10]phenanthroline (1187485-75-1)

Conditions	Yield
With ammonium acetate; acetic acid for 2h; Reflux;	74%
With ammonium acetate; acetic acid for 2h; Reflux;	74%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + [1-(6-ethyl-4,4-dimethyI-1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]-carbamic acid tert-butyl ester (1254928-30-7) → {1-[1-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethyl}-carbamic acid tert-butyl ester (1254928-67-0)

Conditions	Yield
With sodium cyanoborohydride In tetrahydrofuran at 65℃; for 20h; sealed tube;	74%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) → 3,4-(difluoromethylenedioxy)-6-nitrobenzaldehyde (294619-51-5)

Conditions	Yield
With nitric acid; trifluoroacetic acid In dichloromethane at -60 - 4℃; Nitration;	73%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) → (2,2-difluorobenzo-1,3-dioxol-5-yl)methyl 2,2-difluorobenzo-1,3-dioxole-5-carboxylate (1219810-39-5)

Conditions	Yield
With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; sodium formate; cyclohexyldiphenylphosphine In 1,4-dioxane at 80℃; for 20h; Tishchenko reaction; Inert atmosphere;	73%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) → 1-(2,2-difluorobenzo[1,3]dioxan-5-yl)ethanone oxime (146322-07-8)

Conditions	Yield
With hydroxylamine hydrochloride; sodium acetate In methanol at 20℃; for 6h;	72%

pyrrolidine (123-75-1) + 4-hydroxy[1]benzopyran-2-one (1076-38-6) + 2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) → C21H17F2NO5

Conditions	Yield
In dichloromethane at 20℃; for 2h;	71%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + 4-Phenyl-1-butene (768-56-9) → 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-methyl-4-phenylbutan-1-ol

Conditions	Yield
With chromium chloride; (±)N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II); phenylsilane; 1-fluoro-2,4,6-trimethylpyridin-1-ium tetrafluoroborate In tetrahydrofuran; acetonitrile at 22℃; for 24h; Inert atmosphere; chemoselective reaction;	71%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + malonic acid (141-82-2) → 3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acrylic acid (721-13-1)

Conditions	Yield
With piperidine; pyridine for 3h; Heating / reflux;	70%
With piperidine In pyridine for 3h; Heating / reflux;	70%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + malonic acid (141-82-2) → 3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acrylic acid (387350-55-2)

Conditions	Yield
With pyridine; piperidine for 3h; Knoevenagel Condensation; Heating / reflux;	70%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + 2-bromoprop-1-ene (557-93-7) → 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)butan-1-one

Conditions	Yield
With acetylacetonatodicarbonylrhodium(l); potassium formate; potassium carbonate; triphenylphosphine In 1,2-dimethoxyethane at 130℃; for 16h; Inert atmosphere; Sealed tube;	66%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + vinyl magnesium bromide (1826-67-1) → 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)prop-2-en-1-ol

Conditions	Yield
In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	64%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + 2-[(2-carboxyacetyl)amino]benzoic acid (53947-84-5) → (E)-2-[[3-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-oxo-2-propenyl]amino]benzoic acid

Conditions	Yield
With piperidine In toluene for 0.5h; Knoevenagel Condensation; Dean-Stark; Reflux;	62%

2,2-difluoro-2H-1,3-benzodioxole-5-carbaldehyde (656-42-8) + sodium chlorodifluoroacetate (1895-39-2) → 5-(2,2-difluorovinyl)-2,2-difluorobenzo[d][1,3]dioxole

Conditions	Yield
With triphenylphosphine In N,N-dimethyl-formamide at 100℃; Inert atmosphere;	62%

Upstream product

• 75-61-6 dibromodifluoromethane 
• 139-85-5 3,4-dihydroxybenzaldehyde 
• 1269252-03-0 2-thioxobenzo[d][1,3]dioxole-5-carbaldehyde 
• 33070-32-5 5-bromo-2,2-difluoro-2H-1,3-benzodioxole 
• 68-12-2 N,N-dimethyl-formamide 
• 1583-59-1 2,2-difluoro-1,3-benzodioxole 
• 149045-78-3 5-dichloromethyl-2,2-difluorobenzo-(1,3)-dioxole 
• 100-97-0 hexamethylenetetramine 

Downstream Products

• 1346528-50-4 JNJ-42165279 
• 1093211-85-8 1-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)piperazine 
• 1443831-02-4 4-chloro-N-cyclohexyl-N-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine 
• 1443830-73-6 4-{cyclohexyl[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]amino}-6-(4-morpholinyl)-1,3,5-triazine-2-carbonitrile 

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