63095-51-2

Basic information

• Product Name: (R)-4-Propyldihydrofuran-2(3H)-one
• Synonyms: brivaracetam intermediate 1;Brivaracetam Intermediate;(R)-4-propyl-dihydro-furan-2-one;(R)-Dihydro-4-propyl-2(3H)-furanone;(R)-4-propyldihydrofuran-2(3H)-one;(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one
• CAS NO: 63095-51-2
• Molecular Formula: C₇H₁₂O₂
• Molecular Weight: 128.17
• Mol File: 63095-51-2.mol
• Article Data: 47

Chemical Properties

• Boiling Point: 226.3±8.0 °C(Predicted)
• Appearance: /
• Density: 0.983±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Ethanol (Slightly), Methanol (Slightly)
• CAS DataBase Reference: (R)-4-Propyldihydrofuran-2(3H)-one(CAS DataBase Reference)
• NIST Chemistry Reference: (R)-4-Propyldihydrofuran-2(3H)-one(63095-51-2)
• EPA Substance Registry System: (R)-4-Propyldihydrofuran-2(3H)-one(63095-51-2)

Safety Data

• Hazardous Substances Data: 63095-51-2(Hazardous Substances Data)

Usage

Chemical Properties

(R)-4-Propyldihydrofuran-2(3H)-one is a yellow oily liquid, slightly soluble in chloroform, methanol and ethanol. It needs to be stored at 2-8°C.

Uses

(R)-Dihydro-4-propyl-2(3H)-furanone, is building block used in various chemical synthesis.

Synthesis

Add a solution of H5IO6 (24.429 g, 107.17 mmol) in water (43 mL) to a solution of (R)-2-benzylpentyl acetate (1.180 g) in CCl4 (27 mL) and CH3CN (27 mL) at 0 °C. Add RuCl3·nH2O (0.222 g, 1.07 mmol) slowly to the mixture at 0 °C. Stir the resultant mixture vigorously for 20 hours at room temperature. Quench the reaction with Et2O (50 mL) at 0 °C. Stir the mixture for 30 minutes. Extract the mixture with Et2O (3 × 50 mL). Wash the combined organic layers with brine (30 mL). Dry the combined organic layers over anhydrous Na2SO4. Filter the combined organic layers. Remove the solvent. Dissolve the oil in aqueous NaOH (1 mol L-1, 40 mL). Stir the resulting solution overnight at room temperature. Wash the solution with Et2O (30 mL). Acidify the solution with aqueous HCl (6 mol L-1, 15 mL) at 0 °C. Stir the mixture overnight at room temperature. Saturate the aqueous layer with NaCl. Extract the mixture with Et2O (5 × 40 mL). Wash the combined organic layers with water, saturated aqueous Na2S2O3 (30 mL) and brine (30 mL). Dry the combined organic layers over anhydrous Na2SO4. Filter the combined organic layers. Remove the solvent. Purify the residue by column chromatography on silica gel (hexane/acetone = 3/1) and distillation (162-209 °C/36 mmHg).

Synthetic route

(4R)-2-oxo-4-propyltetrahydrofuran-3-carboxylic acid → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
In toluene at 120℃; for 2h; Time;	99%

(R)-3-(hydroxymethyl)hexanenitrile → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With hydrogenchloride In water at 75℃; for 1h; Reagent/catalyst; Solvent;	95.6%

(R)-dihydro-4-(prop-1-enyl)furan-2(3H)-one → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol under 750.075 - 1500.15 Torr; Autoclave;	95%

(4R)-4-allyldihydrofuran-2(3H)-one (80758-91-4) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 35℃; for 6h; enantioselective reaction;	95%

(3R)-3-(hydroxymethyl)-N-[(1S)-1-phenylethyl]hexanamide → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With sulfuric acid In water at 100℃; for 6h;	95%

4-propyl-5H-furan-2-one (21963-27-9) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With bis(η5-cyclopentadienyl)ruthenium; (R,R)-(+)-2,2'-isopropylidene bis(4-isopropyl-2-oxazoline); hydrogen In methanol at 50℃; under 15001.5 Torr; Temperature; Pressure; Solvent; Reagent/catalyst; Autoclave;	93%
With water; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); copper(l) chloride; sodium t-butanolate In toluene; tert-butyl alcohol at 0 - 30℃; Inert atmosphere;	79.63%
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C / 9000.9 Torr 2: sodium hydroxide / water / 2 h / 30 °C View Scheme
Multi-step reaction with 4 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 9 h / 20 °C / 225.02 - 375.04 Torr / Large scale 2: sodium hydroxide / ethanol / 1 h / 20 °C / Large scale 3: 0.5 h / 20 °C / Large scale 4: hydrogenchloride / water / 3 h / 20 - 60 °C / Large scale View Scheme

cis-4-propyl-5-p-tolylthio-4,5-dihydrofuran-2(3H)-one (123975-96-2) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In toluene at 90 - 100℃; for 0.5h;	92%

(S)-3-p-toluenesulfonyl-γ-butyrolactone + n-propylmagnesium bromide (927-77-5) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With [2,2]bipyridinyl; copper(l) iodide; lithium methanolate In tetrahydrofuran at 0℃; for 24h; Reagent/catalyst; Solvent;	92%

C7H14O3*C14H15NO → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With hydrogenchloride In water at 20 - 60℃; for 3h; Large scale;	92%

(2R)-2-propyl-3-(1,3-dithian-2-ylidene)propanol (147725-41-5) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With toluene-4-sulfonic acid In dichloromethane for 1h; Ambient temperature;	90%

(R)-2-(2-methoxy-2-oxoethyl)pentanoic acid → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With dimethylsulfide borane complex In tetrahydrofuran at -20 - 0℃; for 3h; Reagent/catalyst;	90%

3-<(R)-<2-(1,1-dimethylethoxy)-2-oxoethyl>-1-oxopentyl>-4(S)-(phenylmethyl)-2-oxazolidinone (225377-55-9) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With sodium tetrahydroborate In methanol at -25 - 20℃; for 16h; Reagent/catalyst; Temperature;	89.25%
Multi-step reaction with 2 steps 1.1: dihydrogen peroxide; lithium hydroxide; water / tetrahydrofuran; water / 15 h / 5 - 25 °C / Cooling with ice 2.1: dimethyl sulfide borane / tetrahydrofuran / 16 h / 10 - 25 °C / Cooling with ice 2.2: 24 h / 0 - 25 °C View Scheme
Multi-step reaction with 3 steps 1: dihydrogen peroxide; lithium hydroxide / tetrahydrofuran / 2 h / 0 - 5 °C / Large scale 2: sodium tetrahydroborate; boron trifluoride-tetrahydrofuran complex / tetrahydrofuran / 5 h / 0 - 5 °C / Large scale 3: trifluoroacetic acid / 6 h / 60 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1: lithium hydroxide / tetrahydrofuran / 6 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran; water / 20 °C 3: trifluoroacetic acid / toluene / 20 - 30 °C View Scheme

C8H14O4 → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With sodium tetrahydroborate; water; calcium chloride In methanol; ethanol at 0 - 20℃;	86.9%

4-propyl-2-furanone → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With copper(II) choride dihydrate; 1,1′-binaphthalene-2,2′-diylbis[bis(4-methylphenyl)phosphine]; sodium t-butanolate In hexane; toluene at -25℃; for 5h; Reagent/catalyst; Inert atmosphere;	86.1%

(R)-3-(hydroxymethyl)hexanoic acid tert-butyl ester → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With trifluoroacetic acid In dichloromethane at 20℃; Cooling with ice;	85.6%
With trifluoroacetic acid at 60℃; for 6h; Large scale;	78%
In water at 25℃; for 1h;	n/a
With toluene-4-sulfonic acid In dichloromethane Reflux;
With hydrogenchloride; water at 30℃;

(R)-3-methoxycarbonylhexanoic acid → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With sodium tetrahydroborate; calcium chloride In methanol; ethanol; water at 0 - 30℃; for 12h;	85%
With sodium tetrahydroborate; calcium chloride In methanol; ethanol; water at 0 - 30℃;	85%
With sodium tetrahydroborate; calcium chloride In methanol; ethanol; water at 0℃; for 12h;	85%

(4R,5R)-5-amino-4-propyldihydrofuran-2(3H)-one → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With N,N,N,N,N,N-hexamethylphosphoric triamide; samarium diiodide In tetrahydrofuran at 0 - 20℃; for 0.5h;	85%

(±)-dihydro-4-propyl-2(3H)-furanone (72397-60-5) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
Stage #1: (±)-dihydro-4-propyl-2(3H)-furanone With titanium(IV) isopropylate In tetrahydrofuran at 75℃; Stage #2: With sulfuric acid In 1,4-dioxane; water at 80℃;	80%
With sodium hydroxide In water at 30℃; for 2h; Temperature;	36%
Multi-step reaction with 3 steps 1: sodium hydroxide / ethanol / 1 h / 20 °C / Large scale 2: 0.5 h / 20 °C / Large scale 3: hydrogenchloride / water / 3 h / 20 - 60 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1: triethylamine; water / 95 - 100 °C 2: sulfuric acid / water / 6 h / 100 °C View Scheme

(R)-2-((tert-butoxycarbonyl)methyl)pentanoic acid (112106-16-8) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
Stage #1: (R)-2-((tert-butoxycarbonyl)methyl)pentanoic acid With dimethyl sulfide borane In tetrahydrofuran at 10 - 25℃; for 16h; Cooling with ice; Stage #2: With hydrogenchloride In water at 0 - 25℃; for 24h; Temperature;	78%
Stage #1: (R)-2-((tert-butoxycarbonyl)methyl)pentanoic acid With dimethylsulfide borane complex In tetrahydrofuran at 20℃; Stage #2: With hydrogenchloride; trifluoroacetic acid In tetrahydrofuran at 50℃; for 12h;	52%
Multi-step reaction with 2 steps 1.1: triethylamine / toluene / 0.58 h / -6 - -5 °C / Inert atmosphere 1.2: 1.63 h / -6.6 - -3.4 °C 1.3: -18.7 °C / Inert atmosphere; Cooling 2.1: water / 1 h / 25 °C View Scheme

C7H14O3 → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With hydrogenchloride In water at 20℃; pH=3;	77%
With toluene-4-sulfonic acid In toluene for 20h; Reflux;	12 g
With toluene-4-sulfonic acid In toluene Reflux;	7.8 g

ethylmagnesium bromide (925-90-6) + (1S,5R)-ethyl 2-oxo-3-oxabicycio[3.1.0]hexane-1-carboxylate (145032-58-2) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
Stage #1: ethylmagnesium bromide With copper(l) iodide In 2-methyltetrahydrofuran at -30 - -20℃; for 0.5h; Stage #2: ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate In 2-methyltetrahydrofuran at -30℃; for 0.5h;	75%

n-propylmagnesium bromide (927-77-5) + C5H5F3O5S → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With zinc(II) chloride In tetrahydrofuran at -5 - 5℃; for 3h; Solvent; Inert atmosphere;	73%

diethyl (R)-2-(1-(tert-butyldimethylsilyloxy)pentan-2-yl)malonate → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With hydrogenchloride; acetic acid In water at 20℃; for 28h; Reflux;	70.9%

n-propylmagnesium bromide (927-77-5) + C4H5IO2 → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With zinc(II) chloride In tetrahydrofuran at -5 - 5℃; for 3h; Inert atmosphere;	63%

C9H18O3 → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 3h; Time; Reflux;	60%
With toluene-4-sulfonic acid In toluene for 3h; Time; Reflux;	59%
With toluene-4-sulfonic acid In toluene for 3h; Reflux;

(1S,5R)-3-oxabicyclo[3.1.0]hexan-2-one (75658-86-5) + ethylmagnesium bromide (925-90-6) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
Stage #1: ethylmagnesium bromide With copper(l) iodide In tetrahydrofuran at -40 - -30℃; for 1h; Stage #2: (1S,5R)-3-oxabicyclo[3.1.0]hexan-2-one With ammonium chloride In tetrahydrofuran; water at -20 - 0℃; Reagent/catalyst;	55%

C10H9NO7S + n-propylmagnesium bromide (927-77-5) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With zinc(II) chloride In tetrahydrofuran at -5 - 5℃; for 3h; Inert atmosphere;	49%

(2R,3S)-3,4-Dimethyl-2-phenyl-6-propyl-3,4,6,7-tetrahydro-2H-furo[3,2-f][1,4]oxazepin-5-one → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) + (-)-(S)-β-propyl-γ-butyrolactone (63095-60-3)

Conditions	Yield
In sulfuric acid; water; acetic acid Heating; Yield given. Yields of byproduct given. Title compound not separated from byproducts;

(4R,5S)-3-<1-oxo-3-(1,3-dithian-2-ylidene)-2-propylpropyl>-4-methyl-5-phenyl-2-oxazolidinone (147725-30-2) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 0 °C 2: 90 percent / TsOH / CH2Cl2 / 1 h / Ambient temperature View Scheme

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → (R)-γ-bromo-3-propylbutyric acid

Conditions	Yield
With hydrogen bromide; acetic acid In dichloromethane at 0 - 30℃; for 16h; Temperature;	100%
With hydrogen bromide In acetic acid at 40 - 50℃; for 4h; Large scale;	93%
With hydrogen bromide; acetic acid at 5 - 80℃; for 2.83h; Inert atmosphere;	91.95%
With hydrogen bromide In acetic acid at 5 - 80℃; for 3.16667h; Inert atmosphere; Large scale;	81%
With hydrogen bromide; acetic acid at 20 - 55℃;

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → C7H13IO2

Conditions	Yield
With trimethylsilyl iodide In dichloromethane at 0 - 30℃; for 2h; Inert atmosphere;	99.5%
With trimethylsilyl iodide In dichloromethane at 0 - 30℃; for 2h; Inert atmosphere;	99.5%
With trimethylsilyl iodide In dichloromethane at 0 - 30℃; for 2h; Inert atmosphere;	99.5%
With trimethylsilyl iodide In dichloromethane at 0 - 25℃; for 2h; Inert atmosphere;	97%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → 3-(hydroxymethyl)hexanoyloxy sodium

Conditions	Yield
With sodium hydroxide for 2h;	95%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → C6H11IO2

Conditions	Yield
With trimethylsilyl iodide In dichloromethane at 20℃; for 3h;	94%
With trimethylsilyl iodide In dichloromethane at 20℃; for 3h;	94%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) + ethanol (64-17-5) → ethyl (R)-γ-bromo-3-propylbutyrate

Conditions	Yield
With trimethylsilyl bromide In dichloromethane at 30℃; for 8h; Temperature; Solvent; Cooling with ice;	93%
With trimethylsilyl bromide In dichloromethane at 0 - 20℃;	87%
With trimethylsilyl bromide In dichloromethane at 20℃; for 6h; Inert atmosphere;

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) + L-2-aminobutyric acid (1492-24-6) → C11H21NO4

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 15h; Reagent/catalyst; Temperature;	90%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → C7H12Br2O

Conditions	Yield
With thionyl chloride; hydrogen bromide In toluene at 20℃; for 8h; Reagent/catalyst;	90%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → C6H11BrO2

Conditions	Yield
With trimethylsilyl bromide; zinc(II) chloride In dichloromethane at 20℃; for 28h;	89%
With trimethylsilyl bromide; zinc(II) chloride In dichloromethane at 20℃; for 28h;	89%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) + (S)-2-amino-butanamide (7324-11-0, 53726-14-0, 104652-77-9, 143164-46-9) → (R)-3-hydroxymethylhexanoic acid [(S)-1-carbamoylpropyl]amide

Conditions	Yield
With titanium(IV) isopropylate In tetrahydrofuran at 10 - 35℃; for 5h; Temperature; Solvent; Reagent/catalyst; Green chemistry;	84.15%
In ethanol for 24h; Solvent; Reflux;

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → (R)-3-(chloromethyl)hexanoyl chloride

Conditions	Yield
With thionyl chloride; zinc(II) chloride at 85℃; Concentration; Temperature;	79.7%
With thionyl chloride; zinc(II) chloride at 85℃;	66.5%

Upstream product

• 2082-59-9 pentanoic anhydride 
• 119346-66-6 (E)-ethyl 2-benzylidenepentanoate 
• 77124-15-3 (E)-3-phenyl-2-propyl-prop-2-enoic acid 
• 80758-91-4 (4R)-4-allyldihydrofuran-2(3H)-one 
• 6728-26-3 (E)-2-Hexenal 
• 1020270-31-8 (R)-3-(nitromethyl)hexanal 
• 4165-98-4 3-propylpentanedioic acid 
• 1314557-10-2 (R)-3-(aminomethyl)hexanoic acid 
• 75658-86-5 (1S,5R)-3-oxabicyclo[3.1.0]hexan-2-one 
• 925-90-6 ethylmagnesium bromide 

Downstream Products

• 357336-20-0 brivaracetam 
• 357336-99-3 ((2S)-2-[(4S)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide) 
• 910134-80-4 3-(3-methoxy-benzyl)-4-propyl-dihydro-furan-2-one 
• 357337-00-9 ((2R)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide) 

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