WO2010005280A2 - Process for the preparation of lipophilic 4-hydroxyalkyl bromobenzene derivatives - Google Patents

Process for the preparation of lipophilic 4-hydroxyalkyl bromobenzene derivatives Download PDF

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WO2010005280A2
WO2010005280A2 PCT/MY2009/000095 MY2009000095W WO2010005280A2 WO 2010005280 A2 WO2010005280 A2 WO 2010005280A2 MY 2009000095 W MY2009000095 W MY 2009000095W WO 2010005280 A2 WO2010005280 A2 WO 2010005280A2
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lipophilic
silylated
hydroxyalkyl
bromobenzene
bromide
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WO2010005280A3 (en
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Mohd Rais Ahmad
Nora'zah Abdul Rashid
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Mimos Berhad
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/333—Ion-selective electrodes or membranes
    • G01N27/3335—Ion-selective electrodes or membranes the membrane containing at least one organic component
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/403—Cells and electrode assemblies
    • G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS

Definitions

  • the present invention relates to the synthesis of 4-substituted bromobenzene compounds. More specifically, it relates to the preparation of bromobenzene compounds containing a long straight-chain hydrocarbon or long-chain fluorinated hydrophobic substituent with hydroxyl terminal group.
  • Grignard reagents derived from 4-substituted bromobenzene compounds are reactive towards carbonyl compounds such as ketones and aldehydes and Lewis acids such as boron trifluoride (BF 3 ), boron trichloride (BCI 3 ) and boranes (BR3).
  • boron trifluoride BF 3
  • BCI 3 boron trichloride
  • BR3 boranes
  • Reactions of phenylmagnesium bromides with appropriate mole- equivalent of boron halides and one equivalent of fluorinated triphenyl boranes produce, upon cation exchange, sodium and potassium salt of triphenyl borates.
  • Triphenyl borates are structurally bulky and therefore the negatively charged boron center is sterically shielded resulting in only weakly bound metal cations.
  • United States patent No. US 6,231,790 B1 discloses the reaction of a pentafluorophenyl magnesium halide with a boron trihalide in a solvent which is not an ether to produce a tetrakispentafluorophenyl magnesium halide.
  • the magnesium halide may be converted by reaction with a suitable cation, such as substituted ammonium, trityl or onium cation, to a compound comprising a weakly coordinating borate anion and an activating cation.
  • United States patent No. US 5,473,036 discloses a bromomagnesium tetrakis(fluorophenyl)borate reactible intermediate that can be formed by reacting at least four equivalents of fluorophenyl magnesium bromide with every one equivalent of boron trifluoride in ether solvent using a sufficient amount of heat to drive the reaction to completion.
  • This reactible intermediate can then be reacted with a salt containing a suitable cation, such as substituted ammonium, trityl or onium to form the desired combination of weakly coordinating boron anion and activating cation.
  • This invention describes synthesis of 4-substituted bromobenzene compounds having long-chain hydrocarbon or hydrophobic fluorinated carbon at the para position of brominated phenyl ring.
  • the long-chain hydrocarbon in the para position and the hydrophobic fluorinated carbon increases lipophilicity of the benzene compounds and, more importantly, the resulting borate salts.
  • this invention improves the efficiency of the lipophilic borate salts i.e. in creating loosely bound negative centers in polymeric membrane.
  • the lipophilic salt is immobilized through chemical bonding of the acrylate group to the polymer bacbone and hence, the lipophilic agents would have less tendency to leach and loss during contact with aqueous analyte.
  • the 4-substituted bromobenzene compounds in the present invention have wide synthetic applications, especially as when converted to its corresponding nucleophilic Grignard reagents.
  • the Grignard reagents are reactive towards boron compounds Lewis acids.
  • reaction of phenylmagnesium bromide with boron trihalides or boranes produce sterically hindered lipophilic borate salts which widely used to create anionic sites in chemical sensor membrane.
  • the 4-hydroxyalkyl bromobenzene derivatives in the present invention can be used to make suitable lipophilic agent that is economically viable for making hydrophobic membrane sensor for ion-selective electrode (ISE) and ion-sensitive field effect transistor (ISFET) chemical sensor devices.
  • ISE ion-selective electrode
  • ISFET ion-sensitive field effect transistor
  • the present invention discloses the synthesis of lipophilic 4-hydroxyalkyl bromobenzene derivatives namely silylated fluorinated 4-hydroxyalkyl bromobenzene 3, silylated 4-hydroxyalkyl bromobenzene 5 and silylated fluorinated 4-hydroxyalkyl bromobenzene 7.
  • silylated fluorinated 4-hydroxyalkyl bromobenzene 3. is synthesized from 4-bromophenylmagnesium bromide 1 and silylated lipophilic bromoalkyl alcohol 2 catalyzed by dilithium tetrachlorocuprate (Li 2 CuCI 4 ), and has the formula:
  • siiylated 4-hydroxyalkyI bromobenzene 5 is synthesized from 4- bromophenylmagnesium bromide 1 and siiylated hydroxyalkyl bromide 4 catalyzed by dilithium tetrachlorocuprate (LiaCuC-U), and has the formula:
  • siiylated fluorinated 4-hydroxyalkyl bromobenzene 7 from A- bromophenylmagnesium bromide 1 and siiylated hydroxyalkyl bromide 6 catalyzed by dilithium tetrachlorocuprate (UaCuCU), and has the formula:
  • siiylated lipophilic bromoalkyl alcohol 9 is synthesized from 2,2,3,3- tetrafluoro-1-propanol 8, n-butyilithium and dibromoalkane, and has the formula:
  • the siiylated lipophilic bromoalkyl alcohol 9 is siiylated lipophilic bromoalkyl alcohol 2 and has the formula:
  • the silylated lipophilic brornoalkyi alcohol 9 is silylated hydroxyalkyl bromide 6 and has the formula:
  • the lipophilic 4-hydroxyalkyI bromobenzene derivatives are used as immobilized lipophilic agent in hydrophobic chemical sensor membrane for ion sensitive field effect transistor (ISFET) and ion selective electrode (ISE) chemical sensor devices.
  • ISFET ion sensitive field effect transistor
  • ISE ion selective electrode
  • This present invention discloses the synthesis of lipophilic 4-hydroxyaIkyl bromobenzene derivatives having long-chain hydrocarbon or hydrophobic fluorinated carbon at the para position of brominated phenyl ring.
  • the long- chain hydrocarbon in the para position and the hydrophobic fluorinated carbon increases Iipophilicity of the benzene compounds and, more importantly, the resulting borate salts.
  • the present invention improves the efficiency of the lipophilic borate salts i.e. in creating loosely bound negative centers in polymeric membrane.
  • the lipophilic salt is immobilized through chemical bonding of the acrylate group to the polymer backbone and hence, the lipophilic agents would have fewer tendencies to leaching and loss during contact with aqueous analyte.
  • the 4-hydroxyalkyl bromobenzene derivatives in the present invention can be used to make suitable immobilized lipophilic agent that is economically viable for making hydrophobic membrane sensor for ion- selective electrode (ISE) and ion-sensitive field effect transistor (ISFET) chemical sensor devices for the defection of metal cations.
  • ISE ion- selective electrode
  • ISFET ion-sensitive field effect transistor
  • the present invention relates to the preparations of 4-substituted bror ⁇ obenzenes with long-chain alkyl and fluorinated hydrocarbon are carried out in multisteps synthesis in inert argon environment using commercially available starting materials and chemical reagents.
  • Silyl-protected 4-substituted bromobenzene compounds with, long-chain hydrocarbon or fluorinated carbon at the para position (carbon 4) are prepared by coupling reaction of 4-bromo-phenyImagnesium bromide 1 and appropriate alkyl bromides or fluorinated alkyl bromides.
  • Bromobenzene compounds 3, 5 and 7 with tert-butyl dimethyl silyl (TBS) protective group are prepared in one step by reacting equal mole ratio of 4- bromo-phenylmagnesium bromide 1 and a respective silylated brominated alcohols 2, 4 or 6.
  • the reaction is catalyzed by dilithium tetrachlorocuprate (U 2 CUCI 4 ) in anhydrous tetrahydrofuran solvent under inert argon environment.
  • Equations' 1-3 show the synthesis of bromobenzene compounds 3, 5 and 7.
  • An apparatus consisting of a round-bottomed a 100 ml three-necked flask equipped with addition funnel, thermometer, magnetic stir bar and a syringe inlet is set up and added with 50 ml of freshly distilled tetrahydrofuran (THF). Freshly prepared 4-bromophenyi magnesium bromide 1 (25 mmol) in 25 mL of tetrahydrofuran is added carefully using syringe. The system is flushed with a steady flow of argon.
  • reaction mixture is quenched with dilute hydrochloric acid and diluted with 300 ml_ of distilled water and extracted three times with 50 ml_ portions of diethyl ether.
  • the combined organic layers are washed with brine and dried successively with anhydrous sodium sulfate and magnesium sulfate and vacuum evaporated.
  • the residue is eluted through silica-gel column with hexane-ethyl acetate to give 75% yield.
  • Silylated 4-hydroxyalkyl bromobenzene 5 is prepared following the same procedure for preparation of 3, described earlier. Similarly, 25 mmol of freshly prepared 4-bromophenyl magnesium bromide 1 in 25 ml_ of tetrahydrofuran, 25 mmol of silylated hydroxyalkyl bromide 4 and catalytic amount (0.5 mmol) of dilithium tetrachlorocuprate (U 2 CUCI 4 ) used. The reaction afforded 72% yield of 5.
  • Li 2 CuCI 4 ⁇ - y Silylated fluorinated 4-hydroxyalkyl bromobenzene 7 is prepared following the same procedure for preparation of 3, described earlier. Likewise, 25 mmol of 4- bromophenyl magnesium bromide 1 in 25 mL of tetrahydrofuran, 25 mmol of silylated hydroxyalkyl bromide 6 and catalytic amount (0.5 mmol) of dilithium tetrachlorocuprate (Li 2 CuCU) used. The reaction afforded 78% yield of 7.
  • 2,2,3,3-tetrafluoro-i-propanol 8 (Aldrich Chemical Company) is freshly distilled over barium oxide before use. It is silylated with tert-butyl dimethyl chlorosilane using standard procedure.
  • a solution of 20 mmol of freshly distilled silylated 2,2,3,3-tetrafluoro-i-propanol 8 in 50 mL of anhydrous tetrahydrofuran is cooled with a dry ice-acetone bath and 23 mmol of n-butyllithium (2.5M in hexane) is added dropwi . se over 1 hour. After another hour of stirring in the cold bath, the cold bath is removed and replaced with ice-water bath.

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Abstract

Lipophilic bromobenzene compounds substituted at the para position with long-chain hydrocarbon or fluorinated. carbon and terminal hydroxy group can be prepared from 4-bromophenylmagnesium bromide and other reagents. When converted to its Grignard derivative, the 4-hydroxyalkyI bromobenzene are reactive towards boron trihalides or boranes to give borates having sterically shielded negative charge with loosely bound metal cation suitable for creating anionic sites in chemical sensor membrane.

Description

Process for the Preparation of Lipophilic 4-Hydroxyalkyl Bromobenzene
Derivatives
Field of the Invention
The present invention relates to the synthesis of 4-substituted bromobenzene compounds. More specifically, it relates to the preparation of bromobenzene compounds containing a long straight-chain hydrocarbon or long-chain fluorinated hydrophobic substituent with hydroxyl terminal group.
Background of the Invention
Long-chain hydrocarbon or fluorinated carbon at the para position of bromobenzene (4-substituted bromobenzene) can be converted to its corresponding phenylmagnesium bromide derivatives or generally known as Grignard reagent. Bromopentafluorobenzene can also be reacted with magnesium to generate a Grignard reagent such as pentafluorophenylmagnesium bromide. The phenylmagnesium bromide compound formally has a negative charge at the carbon center in position one and is therefore nucleophilic towards positively charge or electron-poor centers.
Grignard reagents derived from 4-substituted bromobenzene compounds are reactive towards carbonyl compounds such as ketones and aldehydes and Lewis acids such as boron trifluoride (BF3), boron trichloride (BCI3) and boranes (BR3). Reactions of phenylmagnesium bromides with appropriate mole- equivalent of boron halides and one equivalent of fluorinated triphenyl boranes produce, upon cation exchange, sodium and potassium salt of triphenyl borates. Triphenyl borates are structurally bulky and therefore the negatively charged boron center is sterically shielded resulting in only weakly bound metal cations. This type of loosely interacted lipophilic salts found wide application for creation of lipophilic anionic sites in chemical sensor membrane.and for solvent ion extraction. Grignard reagents such as pentafluorophenylmagnesium bromide reacted with boron trichloride, boron trifluoride, or the like similarly as a starting raw material for the source of boron to synthesize tris(pentafluorophenyl)borane,.and this is further reacted with pentafluorophenyllithium to produce tetrakis(pentafluorophenyl)borate derivatives.
United States patent No. US 6,231,790 B1 discloses the reaction of a pentafluorophenyl magnesium halide with a boron trihalide in a solvent which is not an ether to produce a tetrakispentafluorophenyl magnesium halide. The magnesium halide may be converted by reaction with a suitable cation, such as substituted ammonium, trityl or onium cation, to a compound comprising a weakly coordinating borate anion and an activating cation.
United States patent No. US 5,473,036 discloses a bromomagnesium tetrakis(fluorophenyl)borate reactible intermediate that can be formed by reacting at least four equivalents of fluorophenyl magnesium bromide with every one equivalent of boron trifluoride in ether solvent using a sufficient amount of heat to drive the reaction to completion. This reactible intermediate can then be reacted with a salt containing a suitable cation, such as substituted ammonium, trityl or onium to form the desired combination of weakly coordinating boron anion and activating cation.
This invention describes synthesis of 4-substituted bromobenzene compounds having long-chain hydrocarbon or hydrophobic fluorinated carbon at the para position of brominated phenyl ring. The long-chain hydrocarbon in the para position and the hydrophobic fluorinated carbon increases lipophilicity of the benzene compounds and, more importantly, the resulting borate salts. Unlike the borate salts used in the prior arts which can leach out from the membrane composition during long exposure to aqueous analyte solution, this invention improves the efficiency of the lipophilic borate salts i.e. in creating loosely bound negative centers in polymeric membrane. Moreover, the lipophilic salt is immobilized through chemical bonding of the acrylate group to the polymer bacbone and hence, the lipophilic agents would have less tendency to leach and loss during contact with aqueous analyte.
The 4-substituted bromobenzene compounds in the present invention have wide synthetic applications, especially as when converted to its corresponding nucleophilic Grignard reagents. In addition to nucleophilic reactions with a wide variety of carbonyl compounds, the Grignard reagents are reactive towards boron compounds Lewis acids. In appropriate mole equivalents, reaction of phenylmagnesium bromide with boron trihalides or boranes produce sterically hindered lipophilic borate salts which widely used to create anionic sites in chemical sensor membrane. The 4-hydroxyalkyl bromobenzene derivatives in the present invention can be used to make suitable lipophilic agent that is economically viable for making hydrophobic membrane sensor for ion-selective electrode (ISE) and ion-sensitive field effect transistor (ISFET) chemical sensor devices.
Summary of the Invention
The present invention discloses the synthesis of lipophilic 4-hydroxyalkyl bromobenzene derivatives namely silylated fluorinated 4-hydroxyalkyl bromobenzene 3, silylated 4-hydroxyalkyl bromobenzene 5 and silylated fluorinated 4-hydroxyalkyl bromobenzene 7.
The silylated fluorinated 4-hydroxyalkyl bromobenzene 3. is synthesized from 4-bromophenylmagnesium bromide 1 and silylated lipophilic bromoalkyl alcohol 2 catalyzed by dilithium tetrachlorocuprate (Li2CuCI4), and has the formula:
Bι-γ_/-(CH2) -,0(CFa)2CH2OTBS ' 3
The siiylated 4-hydroxyalkyI bromobenzene 5 is synthesized from 4- bromophenylmagnesium bromide 1 and siiylated hydroxyalkyl bromide 4 catalyzed by dilithium tetrachlorocuprate (LiaCuC-U), and has the formula:
Figure imgf000005_0001
The siiylated fluorinated 4-hydroxyalkyl bromobenzene 7 from A- bromophenylmagnesium bromide 1 and siiylated hydroxyalkyl bromide 6 catalyzed by dilithium tetrachlorocuprate (UaCuCU), and has the formula:
■ Br-4 /HChysCCFzfeCHsOTBS ?
The siiylated lipophilic bromoalkyl alcohol 9 is synthesized from 2,2,3,3- tetrafluoro-1-propanol 8, n-butyilithium and dibromoalkane, and has the formula:
Br(CH2) n(CF2)2eH2OTBS . 9 (n = 4 to 12)
The siiylated lipophilic bromoalkyl alcohol 9 is siiylated lipophilic bromoalkyl alcohol 2 and has the formula:
Br(CH2)10(CF2)2CH2OTBS (2) The silylated lipophilic brornoalkyi alcohol 9 is silylated hydroxyalkyl bromide 6 and has the formula:
Br(CH2)s(CF2)2CH20TBS (6)
The lipophilic 4-hydroxyalkyI bromobenzene derivatives are used as immobilized lipophilic agent in hydrophobic chemical sensor membrane for ion sensitive field effect transistor (ISFET) and ion selective electrode (ISE) chemical sensor devices.
Detailed Description of the Invention
This present invention discloses the synthesis of lipophilic 4-hydroxyaIkyl bromobenzene derivatives having long-chain hydrocarbon or hydrophobic fluorinated carbon at the para position of brominated phenyl ring. The long- chain hydrocarbon in the para position and the hydrophobic fluorinated carbon increases Iipophilicity of the benzene compounds and, more importantly, the resulting borate salts. The present invention improves the efficiency of the lipophilic borate salts i.e. in creating loosely bound negative centers in polymeric membrane. Moreover, the lipophilic salt is immobilized through chemical bonding of the acrylate group to the polymer backbone and hence, the lipophilic agents would have fewer tendencies to leaching and loss during contact with aqueous analyte. The 4-hydroxyalkyl bromobenzene derivatives in the present invention can be used to make suitable immobilized lipophilic agent that is economically viable for making hydrophobic membrane sensor for ion- selective electrode (ISE) and ion-sensitive field effect transistor (ISFET) chemical sensor devices for the defection of metal cations.
The present invention relates to the preparations of 4-substituted brorήobenzenes with long-chain alkyl and fluorinated hydrocarbon are carried out in multisteps synthesis in inert argon environment using commercially available starting materials and chemical reagents.
Most reagents are used as received without further purification. Solvents are freshly distilled before use. Purification of products are done as described as follows. Characterization are done using 500 MHz 1H Nuclear Magnetic Resonance (NMR), 13C NMR, Control Systems (COSY), Heteronuclear Chemical Shift Correlation (HETCOR) and elemental analysis.
Synthesis of Lipophilic 4-Hydroxyalkyl Bromobenzene Derivatives
Silyl-protected 4-substituted bromobenzene compounds with, long-chain hydrocarbon or fluorinated carbon at the para position (carbon 4) are prepared by coupling reaction of 4-bromo-phenyImagnesium bromide 1 and appropriate alkyl bromides or fluorinated alkyl bromides.
Bromobenzene compounds 3, 5 and 7 with tert-butyl dimethyl silyl (TBS) protective group are prepared in one step by reacting equal mole ratio of 4- bromo-phenylmagnesium bromide 1 and a respective silylated brominated alcohols 2, 4 or 6. The reaction is catalyzed by dilithium tetrachlorocuprate (U2CUCI4) in anhydrous tetrahydrofuran solvent under inert argon environment.
Equations' 1-3 show the synthesis of bromobenzene compounds 3, 5 and 7.
-== Br(CH2)io(.CF2)2CH2OTBS (2)
Br \ N\S } //~MQBT Br~\ /~(CH2)io(CF2)2CH2OTBS (Eqn. 1)
Li2CuCI4 *~ 1 3
Br(CH2)10CH2OTBS (4)
Br- ^HMgBr _^ *. Br-Z-V(CHz)10CH2OTBS (Eqn.2)
Li2CuCI4 v — 1J
Br(CH2)6(CF2)2CH2OTBS (6)
Br~\ /)~MQBτ Br NN /r"(CH2)6(CF2)2CH2OTBS (Eqn. 3)
Li2CuCI4
1 7
Synthesis of 4-Substituted Bromobenzene 3
The following procedure describes the preparation of silylated fluorinated 4- hydroxyalkyl bromobenzene 3 by coupling reaction of 4-bromo- phenylmagnesium bromide 1 and silylated lipophilic bromoalkyl alcohol 2 catalyzed by dilithium tetrachlorocuprate (U2CUCI4). S (2)
Br-<C /-(CH2)10(CF2)2CH2OTBS (Eqn. 1)
Figure imgf000008_0001
An apparatus consisting of a round-bottomed a 100 ml three-necked flask equipped with addition funnel, thermometer, magnetic stir bar and a syringe inlet is set up and added with 50 ml of freshly distilled tetrahydrofuran (THF). Freshly prepared 4-bromophenyi magnesium bromide 1 (25 mmol) in 25 mL of tetrahydrofuran is added carefully using syringe. The system is flushed with a steady flow of argon. Solution of silylated lipophilic bromoalkyl alcohol 2 (25 mmol) in 25 mL tetrahydrofuran is added into the round-bottom flask which already contained 0.5 mmol of dilithium tetrachlorocuprate (U2CUCI4) (catalytic amount), prepared earlier by mixing CuCI2 (0.142 g) and LiCI (0.071 g). The flask is chilled to about -3O0C and the Grignard reagent is added dropwise over 30 minutes with stirring. Stirring is continued at the same temperature for additional one hour, before the cold bath is removed. The reaction mixture is allowed to warm to room temperature and stirring is continued for an additional 8 hours. The reaction mixture is quenched with dilute hydrochloric acid and diluted with 300 ml_ of distilled water and extracted three times with 50 ml_ portions of diethyl ether. The combined organic layers are washed with brine and dried successively with anhydrous sodium sulfate and magnesium sulfate and vacuum evaporated. The residue is eluted through silica-gel column with hexane-ethyl acetate to give 75% yield.
Synthesis of 4-Substituted Bromobenzene 5 0CH2OTBS (Eqn.2)
Figure imgf000009_0001
Silylated 4-hydroxyalkyl bromobenzene 5 is prepared following the same procedure for preparation of 3, described earlier. Similarly, 25 mmol of freshly prepared 4-bromophenyl magnesium bromide 1 in 25 ml_ of tetrahydrofuran, 25 mmol of silylated hydroxyalkyl bromide 4 and catalytic amount (0.5 mmol) of dilithium tetrachlorocuprate (U2CUCI4) used. The reaction afforded 72% yield of 5.
Synthesis of 4- Substituted Bromobenzene 7
Br(CH2)6(CF2)2CH2OTBS (6)
Figure imgf000009_0002
*" Br-4 V-(CH2)6(CF2)2CH2OTBS (Eqn.3)
Li2CuCI4 ^-y Silylated fluorinated 4-hydroxyalkyl bromobenzene 7 is prepared following the same procedure for preparation of 3, described earlier. Likewise, 25 mmol of 4- bromophenyl magnesium bromide 1 in 25 mL of tetrahydrofuran, 25 mmol of silylated hydroxyalkyl bromide 6 and catalytic amount (0.5 mmol) of dilithium tetrachlorocuprate (Li2CuCU) used. The reaction afforded 78% yield of 7.
Synthesis of Siiylated Lipophilic Bromoalkyl Alcohols
. The following procedure describes the preparation of silylated derivative of lipophilic bromoalkyl alcohols by Iitbiation of silylated 2,2,3,3-tetrafluoro-1- propanol 8 and alkylation with appropriate medium- and long-chain silylated bromo alcohols (Eqn.4). 11-Bromo-1-undecanol 4 is commercially available (Aldrich Chemical Company) and is silylated with tert-butyl dimethylchloro silane using a standard procedure.
L n-BuLi, -78° C HCF2CF2CH2OTBS *► Br(CH2)n(CF2)2CH2OTBS (Eqn.4)
8 2. Br(CH2)nBr 9 (n = 4 to 12)
Commercially available, 2,2,3,3-tetrafluoro-i-propanol 8 (Aldrich Chemical Company) is freshly distilled over barium oxide before use. It is silylated with tert-butyl dimethyl chlorosilane using standard procedure.
HCF2CF2CH2OTBS 8
A solution of 20 mmol of freshly distilled silylated 2,2,3,3-tetrafluoro-i-propanol 8 in 50 mL of anhydrous tetrahydrofuran is cooled with a dry ice-acetone bath and 23 mmol of n-butyllithium (2.5M in hexane) is added dropwi.se over 1 hour. After another hour of stirring in the cold bath, the cold bath is removed and replaced with ice-water bath. The flask is re-chilled with dry ice-acetone bath and freshly distilled dibromoalkane (in this case 1 ,10-dibromodecane, 22 mmol) in 20 ml_ of tetrahydrofuran is added dropwise. The resulting colorless, reaction mixture is stirred for additional 1 hour. After warming the reaction mixture to room temperature it is quenched with saturated ammonium chloride and the organic layer is dried with magnesium sulfate and distilled under reduced pressure to give 81% yield of silyl ether 9 (n = 10).

Claims

UCLAIMS
1. A method of preparing lipophilic 4-hydroxyalkyl bromobenzene derivatives comprising the synthesis of silylated fluorinated 4-hydroxyalkyl bromobenzene 3 from 4-bromophenylmagnesium bromide 1 and silylated lipophilic bromoalkyl alcohol 2 catalyzed by dilithium tetrachlorocuprate (Li2CuCI4).
2. A method of preparing lipophilic 4-hydroxyalkyl bromobenzene derivatives comprising the synthesis of siiylated 4-hydroxyalkyl bromobenzene 5 from
4-bromophenylmagnesium bromide 1 and silylated hydroxyalkyl bromide 4 catalyzed by dilithium tetrachlorocuprate (U2CUCI4).
3. A method of preparing lipophilic 4-hydroxyalkyl bromobenzene derivatives comprising the synthesis of silylated fluorinated 4-hydroxyalkyl bromobenzene 7 from 4-bromophenylmagnesium bromide 1 and silylated hydroxyalkyl bromide 6 catalyzed by dilithium tetrachlorocuprate (Li2CuCI4).
4. The method of preparing lipophilic 4-hydroxyalkyl bromobenzene derivatives according to claim 1 wherein said silylated fluorinated 4- hydroxyalkyl bromobenzene 3 has the formula:
Figure imgf000012_0001
5. The method of preparing lipophilic 4-hydroxyalkyl bromobenzene derivatives according to claim 2 wherein said silylated 4-hydroxyalkyl bromobenzene 5 has the formula: Bt "Λ ,f~(CH2)ioCH2OTBS 5
6. The method of preparing lipophilic 4-hydroxyalkyl bromobenzene derivatives according to claim 3 wherein said silylated fluorinated 4- hydroxyalkyl bromobenzene 7 has the formula:
Br\ ,/-(CH2)B(CFa)2CH2OTBS
7. The method of preparing lipophilic 4-hydroxyalkyl bromobenzene derivatives according to claims 1 and 3 comprising the synthesis of silylated lipophilic bromoalkyl alcohol 9 from 2,2,3,3~tetrafluoro-1-propanol 8, n- butyllithium and dibromoalkane.
8. The method of preparing lipophilic 4-hydroxyalkyl bromobenzene derivatives according to claim 7 wherein said silylated lipophilic bromoalkyl alcohol 9 has the formula:
Br(CH2) n(CF2)2CH2OTBS 9 (n = 4 to 12)
9. The method of preparing lipophilic 4-hydroxyalkyl bromobenzene derivatives according to claim 7 wherein said silylated lipophilic bromoalkyl alcohol 9 is silylated lipophilic bromoalkyl alcohol 2.
10. The silylated lipophilic bromoalkyl alcohol 9 according to claim 9 wherein - said silylated lipophilic bromoalkyl alcohol 2 has the formula: Br(CH2) 10(CF2)2CH2OTBS (2)
11. The method of preparing lipophilic 4-hydroxyalkyl bromobenzene derivatives according to claim 7 wherein said silylated lipophilic bromoalkyl alcohol 9 is silylated hydroxyalkyl bromide 6.
12. The silylated lipophilic bromoalkyl alcohol 9 according to claim 11 wherein said silylated hydroxyalkyl bromide 6 has the formula:
Br(CH2)s(CF2)2CH20TBS (G)
13. The use of lipophilic 4-hydroxyalkyl bromobenzene derivatives according to claims 1-3 as immobilized lipophilic agent in hydrophobic chemical sensor membrane for chemical sensor.
14. The chemical sensor according to claim 13 is ion sensitive field effect transistor (ISFET) sensor device.
15. The chemical sensor according to claim 13 is ion selective electrode (ISE) sensor device.
PCT/MY2009/000095 2008-07-08 2009-07-06 Process for the preparation of lipophilic 4-hydroxyalkyl bromobenzene derivatives WO2010005280A2 (en)

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CN103058888A (en) * 2011-10-21 2013-04-24 上海朴颐化学科技有限公司 Preparation method of (R)-3-t-butyloxycarboryl-amino-4-(2, 4, 5-trifluorobenzene) butyric acid
JP2014534193A (en) * 2011-10-11 2014-12-18 ヘンケル ユーエス アイピー エルエルシー Preparation of novel fluoro compounds, process for preparation, and compositions produced therefrom

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US6790971B1 (en) * 1989-02-24 2004-09-14 Aventis Pharma S.A. 19-Nor-steroids

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014534193A (en) * 2011-10-11 2014-12-18 ヘンケル ユーエス アイピー エルエルシー Preparation of novel fluoro compounds, process for preparation, and compositions produced therefrom
CN103058888A (en) * 2011-10-21 2013-04-24 上海朴颐化学科技有限公司 Preparation method of (R)-3-t-butyloxycarboryl-amino-4-(2, 4, 5-trifluorobenzene) butyric acid

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