22515-18-0

Basic information

• Product Name: 4,4-DIFLUOROCYCLOHEXANONE
• Synonyms: 4,4-DIFLUOROCYCLOHEXANONE;4,4-Difluorocyclohexan-1-one;1,1,-Difluoro-4-oxocyclohexane;4,4-difluro-cyclohexanone;4,4-Difluorocyclohexanone;Cyclohexanone, 4,4-difluoro-;4,4-Difluorocyclohexanone(WX900093)
• CAS NO: 22515-18-0
• Molecular Formula: C₆H₈F₂O
• Molecular Weight: 134.12
• Product Categories: Alkyl Fluorinated Building Blocks;Building Blocks;C3 to C6;Carbonyl Compounds;Chemical Synthesis;Fluorinated Building Blocks;Ketones;Organic Building Blocks;Organic Fluorinated Building Blocks;Other Fluorinated Organic Building Blocks
• Mol File: 22515-18-0.mol
• Article Data: 11

Chemical Properties

• Melting Point: 35-36°C
• Boiling Point: 157.441 °C at 760 mmHg
• Flash Point: 65°C
• Appearance: /
• Density: 1.144 g/cm³
• Vapor Pressure: 2.754mmHg at 25°C
• Refractive Index: 1.396
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Water Solubility: Insoluble in water.
• CAS DataBase Reference: 4,4-DIFLUOROCYCLOHEXANONE(CAS DataBase Reference)
• NIST Chemistry Reference: 4,4-DIFLUOROCYCLOHEXANONE(22515-18-0)
• EPA Substance Registry System: 4,4-DIFLUOROCYCLOHEXANONE(22515-18-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-37
• WGK Germany: 3
• HazardClass: IRRITANT
• Hazardous Substances Data: 22515-18-0(Hazardous Substances Data)

Usage

Chemical Properties

White to brown solid

Uses

4,4-Difluorocyclohexanone is used as a pharmaceutical intermediate.

InChI:InChI=1/C6H8F2O/c7-6(8)3-1-5(9)2-4-6/h1-4H2

Synthetic route

8,8-difluoro-1,4-dioxaspiro[4,5]decane (176251-49-3) → 4,4-difluorocyclohexanone (22515-18-0)

Conditions	Yield
With hydrogenchloride; water at 100℃; for 12h;	93%
With hydrogenchloride In acetone for 1h; Inert atmosphere;	80%
With hydrogenchloride In water at 100℃; for 3h;	71%

4,4-difluoroheptanedioic acid diethyl ester (22515-16-8) → 4,4-difluorocyclohexanone (22515-18-0)

Conditions	Yield
(i) NaOEt, EtOH, (ii) aq. KOH; Multistep reaction;

4-oxopimelate (6317-49-3) → 4,4-difluorocyclohexanone (22515-18-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: SF4 / CH2Cl2; H2O 2: (i) NaOEt, EtOH, (ii) aq. KOH View Scheme

3-(fur-2-yl)crotonic acid (539-47-9) → 4,4-difluorocyclohexanone (22515-18-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: HCl / Heating 2: SF4 / CH2Cl2; H2O 3: (i) NaOEt, EtOH, (ii) aq. KOH View Scheme

cyclohexanedione monoethylene ketal (4746-97-8) → 4,4-difluorocyclohexanone (22515-18-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: difluoro-4-morpholinylsulfonium tetrafluoroborate; triethylamine tris(hydrogen fluoride) / dichloromethane / 24 h / 20 °C / Inert atmosphere 2: hydrogenchloride / acetone / 1 h / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: morpholinosulfur trifluoride / dichloromethane / 72 h / 0 - 20 °C / Inert atmosphere 1.2: 24 h 2.1: hydrogenchloride / water / 3 h / 100 °C View Scheme
Multi-step reaction with 2 steps 1: (bis-(2-methoxyethyl)amino)sulfur trufluoride; ethanol / dichloromethane / 2 h / 20 °C / Inert atmosphere 2: toluene-4-sulfonic acid / water; acetone / 24 h / Reflux View Scheme
Stage #1: cyclohexanedione monoethylene ketal With ethanol; (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: With toluene-4-sulfonic acid In water; acetone for 24h; Reflux;
Multi-step reaction with 2 steps 1.1: diethylamino-sulfur trifluoride / dichloromethane / 4 h / 0 - 35 °C 1.2: 20 °C 2.1: water; hydrogenchloride / 12 h / 100 °C View Scheme

trimethylsilyl cyanide (7677-24-9) + 4,4-difluorocyclohexanone (22515-18-0) → 4,4-difluoro-1-[(trimethylsilyl)oxy]cyclohexane carbonitrile (1394347-52-4)

Conditions	Yield
With copper(II) bis(trifluoromethanesulfonate) In dichloromethane at 20℃;	100%
With zinc(II) iodide In dichloromethane at 0 - 20℃; for 1h;
With zinc(II) iodide In dichloromethane at 0 - 20℃; for 1h;	1.5 g

4,4-difluorocyclohexanone (22515-18-0) + methyl (triphenylphosphoranylidene)acetate (21204-67-1) → methyl 2-(4,4-difluorocyclohexylidene)acetate (1189770-25-9)

Conditions	Yield
In tetrahydrofuran at 65℃; for 20h; Schlenk technique; Inert atmosphere;	100%

4,4-difluorocyclohexanone (22515-18-0) → 4,4-difluorocyclohexanol (22419-35-8)

Conditions	Yield
With methanol; sodium tetrahydroborate at 0 - 25℃; for 2h;	99%
With methanol; sodium tetrahydroborate at 20℃; for 1h;	94%
With methanol; sodium tetrahydroborate for 1h; Inert atmosphere; Cooling with ice;	91%

4,4-difluorocyclohexanone (22515-18-0) + ethyl (triphenylphosphoranylidene)acetate (1099-45-2) → ethyl 2-(4,4-difluorocyclohexylidene)-acetate (1283719-20-9)

Conditions	Yield
In toluene at 100℃; for 16h;	99%
In tetrahydrofuran at 65℃; Inert atmosphere;	97%

t-butoxycarbonylhydrazine (870-46-2) + 4,4-difluorocyclohexanone (22515-18-0) → N'-(4,4-difluorocyclohexyl)hydrazinecarboxylic acid tert-butyl ester (1214910-72-1)

Conditions	Yield
With hydrogen; acetic acid; platinum(IV) oxide In isopropyl alcohol at 20℃; under 2585.81 Torr; for 12h;	98%
With hydrogen; acetic anhydride; platinum(IV) oxide In isopropyl alcohol at 20℃; under 2585.81 Torr; for 12h;	98%
With hydrogen; platinum(IV) oxide; acetic acid In isopropyl alcohol at 20℃; under 2585.81 Torr; for 12h;	98%

1-phenylmethylpiperazine (2759-28-6) + trimethylsilyl cyanide (7677-24-9) + 4,4-difluorocyclohexanone (22515-18-0) → 1-(4-benzylpiperazin-1-yl)-4,4-difluorocyclohexanecarbonitrile

Conditions	Yield
Stage #1: 1-phenylmethylpiperazine; 4,4-difluorocyclohexanone With zinc(II) iodide In methanol; toluene at 25℃; for 1h; Inert atmosphere; Stage #2: trimethylsilyl cyanide In methanol; toluene for 16h; Inert atmosphere; Heating;	97%

trimethyl phosphonoacetate (5927-18-4) + 4,4-difluorocyclohexanone (22515-18-0) → methyl 2-(4,4-difluorocyclohexylidene)acetate (1189770-25-9)

Conditions	Yield
Stage #1: trimethyl phosphonoacetate With sodium hydride In tetrahydrofuran; mineral oil at 4℃; for 1h; Stage #2: 4,4-difluorocyclohexanone In tetrahydrofuran; mineral oil at 0 - 20℃;	95%
Stage #1: trimethyl phosphonoacetate With sodium hydride In tetrahydrofuran at 0 - 5℃; for 1h; Stage #2: 4,4-difluorocyclohexanone In tetrahydrofuran at 0 - 27℃; for 15h;	57%
Stage #1: trimethyl phosphonoacetate With sodium hydride In tetrahydrofuran at 5℃; for 1h; Stage #2: 4,4-difluorocyclohexanone In tetrahydrofuran at 5 - 20℃; Stage #3: With water In tetrahydrofuran

4,4-difluorocyclohexanone (22515-18-0) + phenylhydrazine hydrochloride (59-88-1) → 3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole (1423039-61-5)

Conditions	Yield
With acetic acid at 140℃; Inert atmosphere;	95%
With silica gel at 20℃; for 3h; Fischer Indole Synthesis; Milling;	46%

4,4-difluorocyclohexanone (22515-18-0) + vinyl magnesium bromide (1826-67-1) → 4,4-difluoro-1-vinylcyclohexan-1-ol

Conditions	Yield
In tetrahydrofuran at 0℃; for 1h; Grignard Reaction; Inert atmosphere;	94%

4,4-difluorocyclohexanone (22515-18-0) + N,N-dimethyl-formamide dimethyl acetal (4637-24-5) → (E)-2-((dimethylamino)methylene)-4,4-difluorocyclohexanone

Conditions	Yield
In N,N-dimethyl-formamide at 100℃; for 18h;	92%

4,4-difluorocyclohexanone (22515-18-0) + N-(benzyloxycarbonyl)phosphonoglycine trimethyl ester (100945-15-1) → methyl 2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexylidene)acetate

Conditions	Yield
Stage #1: N-(benzyloxycarbonyl)phosphonoglycine trimethyl ester With 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one at 15℃; for 0.5h; Wittig-Horner Reaction; Large scale; Stage #2: 4,4-difluorocyclohexanone In 1-methyl-pyrrolidin-2-one at 10 - 20℃; for 12h; Large scale;	90%
Stage #1: N-(benzyloxycarbonyl)phosphonoglycine trimethyl ester With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 10 - 35℃; for 0.5h; Stage #2: 4,4-difluorocyclohexanone In acetonitrile at 10 - 35℃;	84%

4,4-difluorocyclohexanone (22515-18-0) + ethyl 2-((tert-butyldimethylsilyl)oxy)-2-(diethoxyphosphoryl)acetate (1242990-43-7) → C16H28F2O3Si (1242990-75-5)

Conditions	Yield
Stage #1: ethyl 2-((tert-butyldimethylsilyl)oxy)-2-(diethoxyphosphoryl)acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: 4,4-difluorocyclohexanone In tetrahydrofuran at -78 - 20℃;	88%

sodium cyanide (773837-37-9) + 4,4-difluorocyclohexanone (22515-18-0) → 8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione (1393823-97-6)

Conditions	Yield
With ammonium carbonate In water at 0 - 60℃; for 26h;	88%

4,4-difluorocyclohexanone (22515-18-0) + N-benzyl-3-butenylamine (17150-62-8) → 1-benzyl-8,8-difluoro-4-methyl-1-azaspiro[4.5]decane

Conditions	Yield
With Ir(dMeppy)3; cyclohexa-1,4-diene; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; propionic acid In dichloromethane at 20℃; for 48h; Molecular sieve; Sealed tube; Inert atmosphere; Irradiation;	87%

4,4-difluorocyclohexanone (22515-18-0) + Ethyl 2-bromopropionate (535-11-5, 41978-69-2) → ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)propanoate

Conditions	Yield
With zinc In 1,4-dioxane at 100℃; for 24h;	85%

4,4-difluorocyclohexanone (22515-18-0) + tert-butyl (R)-3-(((4-(aminomethyl)benzyl)((S)-5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate → tert-butyl (R)-3-(((4-(((4,4-difluorocyclohexyl)amino)methyl)benzyl)((S)-5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Conditions	Yield
Stage #1: 4,4-difluorocyclohexanone; tert-butyl (R)-3-(((4-(aminomethyl)benzyl)((S)-5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate With acetic acid In dichloromethane at 20℃; for 2.5h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; Inert atmosphere;	84%

4,4-difluorocyclohexanone (22515-18-0) + cyanoacetic acid (372-09-8) → C8H9F2N

Conditions	Yield
With ammonium acetate In toluene at 160℃; for 3h;	84%

4,4-difluorocyclohexanone (22515-18-0) + tert-butyl diethylphosphonoacetate (27784-76-5) → tert-butyl 2-(4,4-difluorocyclohexylidene)acetate (1584139-35-4)

Conditions	Yield
Stage #1: tert-butyl diethylphosphonoacetate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: 4,4-difluorocyclohexanone In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	83%

4,4-difluorocyclohexanone (22515-18-0) + carbonic acid dimethyl ester (616-38-6) → methyl 5,5-difluoro-2-oxocyclohexane-1-carboxylate

Conditions	Yield
Stage #1: 4,4-difluorocyclohexanone With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: carbonic acid dimethyl ester In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 16h;	83%

4,4-difluorocyclohexanone (22515-18-0) + allylmagnesium bromide (2622-05-1) → 1-allyl-4,4-difluorocyclohexanol

Conditions	Yield
In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;	82%
In tetrahydrofuran at -74 - -60℃; for 2.66667h;	46%

4,4-difluorocyclohexanone (22515-18-0) + trimethylsulphonium iodide (2181-42-2) → 6,6-difluoro-1-oxaspiro[2.5]octane

Conditions	Yield
Stage #1: trimethylsulphonium iodide With potassium tert-butylate In tetrahydrofuran at 15℃; for 0.5h; Inert atmosphere; Stage #2: 4,4-difluorocyclohexanone In tetrahydrofuran at 15℃; for 16h;	82%

4,4-difluorocyclohexanone (22515-18-0) + trimethylsulfonium iodide (1030268-21-3) → 6,6-difluoro-1-oxaspiro[2.5]octane

Conditions	Yield
Stage #1: trimethylsulfonium iodide With potassium tert-butylate In tetrahydrofuran at 15℃; for 0.5h; Inert atmosphere; Stage #2: 4,4-difluorocyclohexanone In tetrahydrofuran at 15℃; for 16h; Inert atmosphere;	82%

tert-Butoxybis(dimethylamino)methane (5815-08-7) + 4,4-difluorocyclohexanone (22515-18-0) → (E)-2-((dimethylamino)methylene)-4,4-difluorocyclohexanone

Conditions	Yield
at 50℃; for 18h;	82%

4,4-difluorocyclohexanone (22515-18-0) + C28H38N4O2 → C34H46F2N4O2

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 12h;	81%

4,4-difluorocyclohexanone (22515-18-0) + 5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide → 6-bromo-8-chloro-4',4'-difluoro-spiro[2himidazo[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione

Conditions	Yield
With sulfuric acid In 1,4-dioxane at 100℃; for 8h;	80%

2-(pyrrolidin-3-yl)-1H-benzo[d]imidazole-4-carboxamide + 4,4-difluorocyclohexanone (22515-18-0) → 2-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-1H-benzo[d]imidazole-4-carboxamide

Conditions	Yield
With sodium cyanoborohydride In methanol at 20℃;	78.4%

4,4-difluorocyclohexanone (22515-18-0) + (piperidin-4-yl)carbamic acid tert-butyl ester (73874-95-0) → tert-butyl (1-(4,4-difluorocyclohexyl)piperidin-4-yl)carbamate (1262417-90-2)

Conditions	Yield
With acetic acid; tetramethylammonium triacetoxyborohydride In N,N-dimethyl-formamide	78%
Stage #1: 4,4-difluorocyclohexanone; (piperidin-4-yl)carbamic acid tert-butyl ester With acetic acid In tetrahydrofuran at 50℃; for 2h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 50℃; for 18h;

4,4-difluorocyclohexanone (22515-18-0) + 4-aminophenylacetic acid (1197-55-3) + 3-hydroxy-2-butanon (513-86-0, 52217-02-4) → 2-(4-(5,5-difluoro-2,3-dimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl)phenyl)acetic acid

Conditions	Yield
With acetic acid In ethanol at 100℃; for 4h; Inert atmosphere; Sealed tube; Microwave irradiation;	78%

indole (120-72-9) + 4,4-difluorocyclohexanone (22515-18-0) → 1-(4,4-difluorocyclohexyl)indole

Conditions	Yield
With formic acid; 10 mol% Pd(OH)2/C In water at 100℃; for 24h; Inert atmosphere;	78%
With formic acid; 10% palladium hydroxide on charcoal In water at 100℃; for 24h; Inert atmosphere;	78%

Upstream product

• 4746-97-8 cyclohexanedione monoethylene ketal 
• 176251-49-3 8,8-difluoro-1,4-dioxaspiro[4,5]decane 
• 539-47-9 3-(fur-2-yl)crotonic acid 
• 6317-49-3 4-oxopimelate 
• 22515-16-8 4,4-difluoroheptanedioic acid diethyl ester 

Downstream Products

• 1002729-01-2 methyl (2S,4S)-1-BOC-4-[(4,4-difluorocyclohexyl)amino]pyrrolidine-2-carboxylate 
• 1242990-75-5 C₁₆H₂₈F₂O₃Si 
• 1262417-90-2 tert-butyl (1-(4,4-difluorocyclohexyl)piperidin-4-yl)carbamate 
• 1262417-88-8 1-(4,4-difluorocyclohexyl)-piperidin-4-ylamine 
• 1262417-99-1 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-5-chloro-7-iodo-2,3-dihydro-1H-isoindol-1-one 
• 1262418-03-0 6-chloro-2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile 
• 1262418-07-4 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-5-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile 
• 1262416-98-7 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide 
• 1262396-19-9 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile 
• 1350894-82-4 C₁₈H₂₀F₂N₂S 
• 1350894-69-7 C₁₉H₁₉F₂NO₂S 
• 1344365-66-7 1-ethyl-4-trifluoromethylcyclohexanol 
• 1423039-48-8 4a-allyl-6-p-tolyl-2,3,4,4a-tetrahydro-1H-carbazole 
• 1557249-03-2 C₂₄H₃₁F₂N₅O₂Si 

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