1261817-10-0

Basic information

• Product Name: 2-Iodo-5-BroMobenzyl chloride
• Synonyms: 4-Bromo-2-(chloromethyl)-1-iodobenzene;2-Iodo-5-BroMobenzyl chloride;5-bromo-2-iodobenzyl chloride
• CAS NO: 1261817-10-0
• Molecular Formula: C7H5BrClI
• Molecular Weight: 331.37607
• EINECS: -0
• Mol File: 1261817-10-0.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 324.0±27.0 °C(Predicted)
• Appearance: /
• Density: 2.132±0.06 g/cm3(Predicted)
• CAS DataBase Reference: 2-Iodo-5-BroMobenzyl chloride(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Iodo-5-BroMobenzyl chloride(1261817-10-0)
• EPA Substance Registry System: 2-Iodo-5-BroMobenzyl chloride(1261817-10-0)

Safety Data

• Hazardous Substances Data: 1261817-10-0(Hazardous Substances Data)

Usage

General Description

2-Iodo-5-BromoBenzyl chloride is a chemical compound that is commonly used in organic synthesis and medicinal chemistry. It is a derivative of benzyl chloride, with the addition of iodine and bromine atoms. 2-Iodo-5-BroMobenzyl chloride is known for its reactivity as a substrate in various chemical reactions, including nucleophilic substitution and metal-catalyzed cross-coupling reactions. It is also used in the synthesis of pharmaceuticals, agrochemicals, and other fine chemicals due to its versatile properties. Additionally, 2-Iodo-5-BromoBenzyl chloride is a valuable building block for the production of various compounds with varied biological activities.

Synthetic route

(5-bromo-2-iodo-phenyl)-methanol (199786-58-8) → 4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0)

Conditions	Yield
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 1h;

tert-butyl 3-oxoazetidine-1-carboxylate (398489-26-4) + 4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-bromo-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate (1398609-80-7)

Conditions	Yield
Stage #1: 4-bromo-2-(chloromethyl)-1-iodobenzene With TurboGrignard In tetrahydrofuran at -40 - -33℃; for 1.5h; Inert atmosphere; Stage #2: tert-butyl 3-oxoazetidine-1-carboxylate In tetrahydrofuran at -40 - 20℃; for 18h;	85.2%
Stage #1: 4-bromo-2-(chloromethyl)-1-iodobenzene With TurboGrignard In tetrahydrofuran at -20 - -15℃; Stage #2: tert-butyl 3-oxoazetidine-1-carboxylate In tetrahydrofuran at -20 - 20℃;	290 g
Stage #1: 4-bromo-2-(chloromethyl)-1-iodobenzene With C4H9ClMg*LiCI In tetrahydrofuran at -20 - -15℃; Stage #2: tert-butyl 3-oxoazetidine-1-carboxylate In tetrahydrofuran at -20 - 20℃;	290 g
With TurboGrignard In tetrahydrofuran at -20 - 20℃;	290 g
Stage #1: 4-bromo-2-(chloromethyl)-1-iodobenzene With TurboGrignard In tetrahydrofuran at -15℃; for 0.583333h; Stage #2: tert-butyl 3-oxoazetidine-1-carboxylate In tetrahydrofuran at -30 - 20℃;	1.6 g

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) + phenyl 3-oxoazetidine-1-carboxylate → phenyl 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylate

Conditions	Yield
Stage #1: 4-bromo-2-(chloromethyl)-1-iodobenzene With TurboGrignard In tetrahydrofuran at -35 - -25℃; for 1.5h; Large scale; Stage #2: phenyl 3-oxoazetidine-1-carboxylate In tetrahydrofuran at -25 - 35℃; for 19h; Temperature; Large scale;	77%

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) + 2,2,-dimethyl-1,3-dioxan-5-one (74181-34-3) → 6'-bromo-2,2-dimethyl-spiro[1,3-dioxane-5,3'-1H-isobenzofuran]

Conditions	Yield
Stage #1: 4-bromo-2-(chloromethyl)-1-iodobenzene With TurboGrignard In tetrahydrofuran at -35℃; for 1.5h; Stage #2: 2,2,-dimethyl-1,3-dioxan-5-one In tetrahydrofuran at -35 - 20℃; Inert atmosphere;	72%

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) + 1-(3,3,3-trifluoropropanoyl)azetidin-3-one → 1-(6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl)-3,3,3-trifluoropropan-1-one

Conditions	Yield
Stage #1: 1-(3,3,3-trifluoropropanoyl)azetidin-3-one With lanthanium (III) chloride bis(lithium chloride) complex In tetrahydrofuran for 2.5h; Stage #2: 4-bromo-2-(chloromethyl)-1-iodobenzene With TurboGrignard In tetrahydrofuran at -20 - 20℃; for 21h; Reagent/catalyst; Temperature;	71%

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-acetyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate (1398609-81-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: TurboGrignard / tetrahydrofuran / -20 - -15 °C 1.2: -20 - 20 °C 2.1: triethylamine; palladium diacetate; 1,3-bis-(diphenylphosphino)propane / ethanol / 0.08 h / 90 °C / Inert atmosphere 2.2: 4 h / 90 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: C4H9ClMg*LiCI / tetrahydrofuran / -20 - -15 °C 1.2: -20 - 20 °C 2.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / ethanol / 4 h / 90 °C / Inert atmosphere 2.2: 2 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: TurboGrignard / tetrahydrofuran / 0.58 h / -15 °C 1.2: -30 - 20 °C 2.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / ethanol / 0.08 h / 90 °C / Inert atmosphere 2.2: 4 h / 90 °C / Inert atmosphere 2.3: 2 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: TurboGrignard / tetrahydrofuran / 1.5 h / -40 - -33 °C / Inert atmosphere 1.2: 18 h / -40 - 20 °C 2.1: 1,3-bis-(diphenylphosphino)propane; triethylamine / ethanol / 96 °C / Inert atmosphere; Sealed tube View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 6-[(E/Z)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylate (1398610-04-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: TurboGrignard / tetrahydrofuran / -20 - -15 °C 1.2: -20 - 20 °C 2.1: triethylamine; palladium diacetate; 1,3-bis-(diphenylphosphino)propane / ethanol / 0.08 h / 90 °C / Inert atmosphere 2.2: 4 h / 90 °C / Inert atmosphere 3.1: caesium carbonate / toluene / 2 h / 110 °C / Inert atmosphere; Dean-Stark View Scheme
Multi-step reaction with 3 steps 1.1: C4H9ClMg*LiCI / tetrahydrofuran / -20 - -15 °C 1.2: -20 - 20 °C 2.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / ethanol / 4 h / 90 °C / Inert atmosphere 2.2: 2 h / 20 °C 3.1: α,α,α-trifluorotoluene; caesium carbonate / toluene / 2 h / 110 °C / Dean-Stark; Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C View Scheme
Multi-step reaction with 3 steps 1.1: TurboGrignard / tetrahydrofuran / 0.58 h / -15 °C 1.2: -30 - 20 °C 2.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / ethanol / 0.08 h / 90 °C / Inert atmosphere 2.2: 4 h / 90 °C / Inert atmosphere 2.3: 2 h / 20 °C / Inert atmosphere 3.1: caesium carbonate / toluene / 6 h / 110 °C / Dean-Stark; Inert atmosphere View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-[3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-3'H-spiro[azetidine-3,1'-[2]benzofuran]-1-carboxylate (1575810-99-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / toluene / 6 h / Inert atmosphere; Reflux View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 5'-[3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-3'H-spiro[azetidine-3,1'-[2]benzofuran] (1575811-03-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / toluene / 6 h / Inert atmosphere; Reflux 3: hydrogenchloride / methanol / 0 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 5'-[3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-1-isobutyryl-3'H-spiro[azetidine-3,1'-[2]benzofuran] (1575794-94-3)

Conditions

Yield

Multi-step reaction with 4 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / toluene / 6 h / Inert atmosphere; Reflux 3: hydrogenchloride / methanol / 0 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 16 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-3'H-spiro[azetidine-3,1'-[2]benzofuran]-1-carboxylate (1575811-05-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / toluene / 6 h / Inert atmosphere; Reflux View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 5'-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-3'H-spiro[azetidine-3,1'-[2]benzofuran] (1575811-07-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / toluene / 6 h / Inert atmosphere; Reflux 3: hydrogenchloride / methanol / 0.25 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 5'-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine-1-yl]-1-[(methylsulfonyl)acetyl]-3'H-spiro[azetidine-3,1'-[2]benzofuran] (1575795-00-4)

Conditions

Yield

Multi-step reaction with 4 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / toluene / 6 h / Inert atmosphere; Reflux 3: hydrogenchloride / methanol / 0.25 h / 20 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 16 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 5'-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-1-isobutyryl-3'H-spiro[azetidine-3,1'-[2]benzofuran] (1575795-02-6)

Conditions

Yield

Multi-step reaction with 4 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / toluene / 6 h / Inert atmosphere; Reflux 3: hydrogenchloride / methanol / 0.25 h / 20 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 16 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate (1575810-06-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-3'H-spiro[azetidine-3,1'-[2]benzofuran]-1-carboxylate (1575811-10-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / toluene / 12 h / Inert atmosphere; Reflux View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 5'-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-3'H-spiro[azetidine-3,1'-[2]benzofuran] (1575811-13-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / toluene / 12 h / Inert atmosphere; Reflux 3: hydrogenchloride / methanol / 0.25 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 1-isobutyryl-5'-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-3'H-spiro[azetidine-3,1'-[2]benzofuran] (1575795-11-7)

Conditions

Yield

Multi-step reaction with 4 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; sodium t-butanolate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / toluene / 12 h / Inert atmosphere; Reflux 3: hydrogenchloride / methanol / 0.25 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran; ethyl acetate / 12 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-(4,4,4-trifluoro-3-(nitromethyl)-3-(3,4,5-trichlorophenyl)butanoyl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate (1575810-08-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 16 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate (1575810-11-5)

Conditions

Yield

Multi-step reaction with 5 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 16 h / 20 °C 5: hydrogen / ethanol; water / 16 h / 20 °C / Inert atmosphere View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 5'-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran] hydrochloride (1575810-14-8)

Conditions

Yield

Multi-step reaction with 6 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 16 h / 20 °C 5: hydrogen / ethanol; water / 16 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol / 0.5 h / 0 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 2-(methylsulfonyl)-1-(5'-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-yl)ethanone (1575794-22-7)

Conditions

Yield

Multi-step reaction with 7 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 16 h / 20 °C 5: hydrogen / ethanol; water / 16 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol / 0.5 h / 0 °C 7: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran; ethyl acetate / 16 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 2-methyl-1-(5'-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-yl)propan-1-one (1575794-26-1)

Conditions

Yield

Multi-step reaction with 7 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 16 h / 20 °C 5: hydrogen / ethanol; water / 16 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol / 0.5 h / 0 °C 7: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran; ethyl acetate / 16 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-3-(nitromethyl)butanoyl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate (1575810-19-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 16 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate (1575810-21-7)

Conditions

Yield

Multi-step reaction with 5 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 16 h / 20 °C 5: hydrogen / ethanol; water / 16 h / 20 °C / Inert atmosphere View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 5'-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran] hydrochloride (1575810-24-0)

Conditions

Yield

Multi-step reaction with 6 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 16 h / 20 °C 5: hydrogen / ethanol; water / 16 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol / 0.5 h / 0 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 1-(5'-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone (1575794-28-3)

Conditions

Yield

Multi-step reaction with 7 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 16 h / 20 °C 5: hydrogen / ethanol; water / 16 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol / 0.5 h / 0 °C 7: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine / tetrahydrofuran; ethyl acetate / 16 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 1-(5'-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-yl)-2-methylpropan-1-one (1575794-32-9)

Conditions

Yield

Multi-step reaction with 7 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 16 h / 20 °C 5: hydrogen / ethanol; water / 16 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol / 0.5 h / 0 °C 7: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran / 16 h / 20 °C View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → tert-butyl 5'-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl]-3'H-spiro[azetidine-3,1'-[2]benzofuran]-1-carboxylate (1575810-35-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: triethylamine / n-heptane / 16 h / 60 °C / Sealed tube View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-1-(3'H-spiro[azetidine-3,1'-isobenzofuran]-5'-yl)but-2-en-1-one hydrochloride (1575810-60-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3: caesium carbonate / toluene / 16 h / 110 °C 4: hydrogenchloride / methanol / 0.12 h / 120 °C / Microwave irradiation View Scheme

4-bromo-2-(chloromethyl)-1-iodobenzene (1261817-10-0) → 3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-1-(1-(2-(methylsulfonyl)acetyl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-5'-yl)but-2-en-1-one (1575810-62-6)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: TurboGrignard / tetrahydrofuran / -20 - 20 °C 2.1: 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine / ethanol / 16 h / 96 °C / Autoclave; Inert atmosphere 3.1: caesium carbonate / toluene / 16 h / 110 °C 4.1: hydrogenchloride / methanol / 0.12 h / 120 °C / Microwave irradiation 5.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h 5.2: 6 h / 20 °C View Scheme

Upstream product

• 199786-58-8 (5-bromo-2-iodo-phenyl)-methanol 

Downstream Products

• 1055901-15-9 2-(5-bromo-2-iodophenyl)acetonitrile 

Relevant articles and documents

Palladium(II)-Catalyzed Annulation of Alkynes with 2-(Cyanomethyl)phenylboronates Leading to 3,4-Disubstituted 2-Naphthalenamines

1,2-Bis(diphenylphosphino)ethane (dppe)-ligated palladium(II) complexes catalyze the annulation of internal alkynes with 2-(cyanomethyl)phenylboronates to provide 3,4-disubstituted-2-naphthalenamines in good yields. The annulation reaction proceeds under mild and neutral conditions and requires methanol as an essential solvent. In addition to symmetrical alkynes, unsymmetrical alkynes substituted by aryl, alkyl, and alkynyl groups participate in the annulation to afford the corresponding 2-naphthalenamines with electron-withdrawing sp2- and sp-carbons preferentially located at the C-3 position. Substituents including an alkyl or alkoxy group on the cyanomethyl moiety and a halogen atom on the benzene ring in the boronates are compatible with the reaction conditions. The annulation proceeds through the transmetalation of the palladium(II) complexes with the boronates and alkyne insertion followed by nucleophilic addition of the generated alkenylpalladium(II) species to the intramolecular cyano group. Stoichiometric reactions revealed that the methanol solvent was effective for both transmetalation and catalyst regeneration.