WO2016107578A1 - Sel de dibenzothiophénium s-(perfluoroalkyl) halogéné et ses procédés de production - Google Patents

Sel de dibenzothiophénium s-(perfluoroalkyl) halogéné et ses procédés de production Download PDF

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WO2016107578A1
WO2016107578A1 PCT/CN2015/099798 CN2015099798W WO2016107578A1 WO 2016107578 A1 WO2016107578 A1 WO 2016107578A1 CN 2015099798 W CN2015099798 W CN 2015099798W WO 2016107578 A1 WO2016107578 A1 WO 2016107578A1
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halogenated
perfluoroalkyl
dibenzothiophenium
salt
general formula
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PCT/CN2015/099798
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English (en)
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Teruo Umemoto
Bin Zhang
Tianhao ZHU
Xiaocong ZHOU
Yuanqiang Li
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Zhejiang Jiuzhou Pharmaceutical Co., Ltd.
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Priority claimed from CN201510112921.1A external-priority patent/CN106032369A/zh
Application filed by Zhejiang Jiuzhou Pharmaceutical Co., Ltd. filed Critical Zhejiang Jiuzhou Pharmaceutical Co., Ltd.
Priority to JP2017534695A priority Critical patent/JP6735278B2/ja
Priority to US15/539,145 priority patent/US10155739B2/en
Publication of WO2016107578A1 publication Critical patent/WO2016107578A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/76—Dibenzothiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/44—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by addition reactions, i.e. reactions involving at least one carbon-to-carbon double or triple bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present inventions relate to new S- (perfluoroalkyl) dibenzothiophenium salt which is useful electrophilic perfluoroalkylating agent, and its production methods.
  • a perfluoroalkyl group is a very useful functional group because it has unique properties such as high electronegativity, high stability, and high lipophilicity (for example, see, P. Kirsch, “Modern Fluoroorganic Chemistry, Synthesis, Reactivity, Applications” , Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim, 2004) .
  • a low perfluoroalkyl group of one to four carbons, in particular, a trifluoromethyl group is important for developing effective medicines, agrochemicals, and other useful materials.
  • there have been developed many useful medicines and agrochemicals having trifluoromethyl groups for example, see, K.L. Kirk, J.
  • electrophilic trifluoromethylating agents are particularly useful because they can directly trifluoromethylate nucleophilic organic molecules. Therefore, there have been reported many electrophilic trifluoromethylating agents to produce trifluoromethylated organic compounds (for example, see, S. Barata-Vallejo, B. Lantano, A. Postigo, Chem. Eur. J. 2014, 12, 16806-16829; Y. Macé, E. Magnier, Eur. J. Org. Chem. 2012, 2479-2494; N. Shibata et al., Beilstein J. Org. Chem., 2010, 6, No. 65) .
  • S- (trifluoromethyl) dibenzothiophenium salts (A) which are called as Umemoto reagent
  • Umemoto reagent are particularly useful reagents for preparing trifluoromethylated organic compounds [for example, see, C. Zhang, Organic &Biomolecular Chemistry, 2014, 12, 6580-6589; H. Li, Synlett, 2012, 23, 2289-2290; T. Umemoto et al. J. Am. Chem. Soc., 1993, 115, 2156-2164 (1993) ] .
  • step 1 reaction of 2-hydroxybiphenyl with dimethylthiocarbamoyl chloride;
  • step 2) isomerization by heating at high temperature;
  • step 3) hydrolysis with alkaline;
  • step 4) methylation with dimethyl sulfate;
  • step 5) chlorination with chlorine;
  • step 6) fluorination with triethylamine tris (hydrogen fluoride) ;
  • step 7) oxidation with hydrogen peroxide;
  • step 8) cyclization with fuming sulfuric acid;
  • step 9) exchange reaction of counter-anion with sodium trifluoromethanesulfonate or sodium tetrafluoroborate (see, T. Umemoto et al., J. Fluorine Chem. 1999, 98, 75-81)
  • the intermediate compound (H) was also prepared by the following processes as shown in Scheme 2 (see, S.S. Aiken, J.A.H. Lainton, and D.A. Widdowson, Electronic Conference on Trends in Organic Chemistry 1995, (ECTOC-1) , Eds H. S. Rzepa and J.M. Goodman (CD-ROM) , RSC Publications, http: //www. ch. ic. ac. uk/ectoc/papers/22/) .
  • this method required CF 2 Br 2 which is regulated as one of ozone-depleting substances and very expensive AgF.
  • This method also required multi-step processes for the production of Umemoto reagent.
  • this method required extremely toxic and explosive F 2 and used CFCl 3 solvent whose production was banned because of ozone-depleting substance.
  • Umemoto reagent and its analogs have another significant drawback that, when they are used as perfluoroalkylating agents, they produce dibenzothiophene (R) or its analog as a byproduct in a quantitative yield or in a high yield in addition to the perfluoroalkylated compounds as illustrated in Scheme 3.
  • the dibenzothiophene must be treated as a waste. This is a significant problem in current environmental issue.
  • Umemoto agent must satisfy all the following subjects: (1) short step and high cost-effective production, (2) powerful perfluoroalkylating capability, (3) recycle of the dibenzothiophene obtained after the perfluoroalkylation.
  • the current Umemoto reagent and Umemoto-type reagents have many serious shortcomings, because they do not satisfy the above subjects.
  • the present inventions are to provide a new halogenated S- (perfluoroalkyl) dibenzothiophenium salt which is useful as a powerful electrophilic perfluoroalkylating agent and to provide its cost-effective and green production methods.
  • the inventors have thoroughly studied an idea of making new and specified S- (perfluoroalkyl) dibenzothiophenium salt which can satisfy all the subjects stated above. As a consequence, they succeeded in making a new halogenated S- (perfluoroalkyl) dibenzothiophenium salt which can satisfy all the subjects.
  • the present invention relates to halogenated S- (perfluoroalkyl) dibenzothiophenium salt as presented by the following general formula (I) that is useful as a powerful electrophilic perfluoroalkylating agent.
  • Rf means a perfluoroalkyl group having 1 to 4 carbons;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each is a hydrogen atom or a halogen atom, provided that the total number of halogen atoms of R 1-8 is 1 to 5; and
  • X - is a conjugated base of Br ⁇ nsted acid
  • Rf are normal chain or branching perfluoroalkyl groups having 1 to 4 carbons, such as CF 3 , C 2 F 5 , n-C 3 F 7 , iso-C 3 F 7 , n-C 4 F 9 , sec-C 4 F 9 , iso-C 4 F 9 , and tert-C 4 F 9 .
  • CF 3 , C 2 F 5 , and iso-C 3 F 7 are preferable, and CF 3 is most preferable because it is the most significant functional group in the biochemical application such as medicines and agrochemicals.
  • a total number of halogen atoms of R 1-8 is one to five, and preferably two to four.
  • the halogen atom is a fluorine, chlorine, bromine, or iodine atom, and preferably a fluorine or chlorine atom because of less molecular weight and higher electronegativity.
  • a fluorine atom is the most preferable because of the smallest molecular weight and the highest electronegativity, and in addition, it can form the strongest carbon-fluorine (C-F) bond that is stable.
  • the smallest molecular weight of fluorine makes the product more effective perfluoroalkylating agent per weight.
  • the highest electronegativity makes the halogenated S- (perfluoroalkyl) dibenzothiophenium salt more powerful perfluoroalkylating agent. Therefore, the invented halogenated S- (perfluoroalkyl) dibenzothiophenium salts are more powerful than the Umemoto reagents (A) (see Examples 22-24 and Comparison Example 2 below) .
  • the strongest C-F bond makes it more effective to recover the fluorinated biphenyl from the dibenzothiophene obtained after the perfluoroalkylation by reduction reaction because of the high stability against the reduction reaction (see Examples 31 and 32 below) .
  • X - is a conjugated base of Br ⁇ nsted acid (HX) .
  • the ⁇ r ⁇ nsted acids include strong acids such as sulfuric acid, monomethyl sulfuric acid, chlorosulfonic acid, fluorosulfonic acid, methanesulfonic acid, trifluoromethanesulfonic aicd, difluoromethanesulfonic acid, trichloromethanesulfonic acid, trifluoroethanesulfonic acid, perfluoroethanesulfonic acid, perfluorobutanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, nitrobenzenesulfonic acid, dinitrobenzenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, hydrogen chloride (HCl) , hydrogen bromide (HBr) , HBF 4 , HBF 3 Cl, HBFCl 3
  • conjugated bases (X - ) HSO 4 - , CH 3 OSO 3 - , ClSO 3 - , FSO 3 - , CH 3 SO 3 - , CF 3 SO 3 - , CF 2 HSO 3 - , CCl 3 SO 3 - , CF 3 CH 2 SO 3 - , CF 2 HCF 2 SO 3 - , C 2 F 5 SO 3 - , C 3 F 7 SO 3 - , C 4 F 9 SO 3 - , C 6 H 5 SO 3 - , CH 3 C 6 H 4 SO 3 - , O 2 NC 6 H 4 SO 3 - , (O 2 N) 2 C 6 H 3 SO 3 - , CF 3 CO 2 - , CCl 3 CO 2 - , Cl - , Br - , BF 4 - , BF 3 Cl - , BFCl 3 - , BCl 4 -, SbF 6 - , SbCl
  • X - is CF 3 SO 3 - , Cl - , Br - , BF 4 - , PF 6 - , and HSO 4 - because of easy access and high stability
  • X - is CF 3 SO 3 - , Cl - , and BF 4 -
  • X - is Br - or HSO 4 -
  • it may be exist as alcohol adduct or hydrate such as Br - ⁇ (CH 3 OH) n or HSO 4 - ⁇ (H 2 O) n (n is positive number) (see Examples 10 and 14) .
  • Preferred embodiments of formula (I) can be compounds represented by formula (Ia) :
  • Rf and X - are the same as mentioned above, and R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 each is a hydrogen atom or a halogen atom, provided that the total number of halogen atoms of R 2-7 is 2 to 4)
  • a total number of halogen atoms of R 2-7 is two to four, and the halogen atom is a fluorine, chlorine, bromine, or iodine atom, and preferably a fluorine or chlorine atom because of less molecular weight and higher electronegativity.
  • a fluorine atom is the most preferable because of the smallest molecular weight and the highest electronegativity, and in addition, it can form the strongest carbon-fluorine (C-F) bond that is stable.
  • the smallest molecular weight of fluorine makes the product more effective perfluoroalkylating agent per weight.
  • the highest electronegativity makes the halogenated S- (perfluoroalkyl) dibenzothiophenium salt more powerful perfluoroalkylating agent. Therefore, the invented halogenated S- (perfluoroalkyl) dibenzothiophenium salts are more powerful than the Umemoto reagents (A) (see Examples 22-24 and Comparison Example 2 below) .
  • the strongest C-F bond makes it more effective to recover the fluorinated biphenyl from the dibenzothiophene obtained after the perfluoroalkylation by reduction reaction because of the high stability against the reduction reaction (see Examples 31 and 32 below) .
  • Rf and R 1-8 are the same as mentioned above, and M is a metal or an ammonium moiety, and R is an alkyl or haloalkyl group having 1 to 4 carbons
  • the method comprises reacting halogenated biphenyl represented by the general formula (II) with any combination of perfluoroalkanesulfinate salt represented by the general formula RfSO 2 M with trifluoromethanesulfonic anhydride [ (CF 3 SO 2 ) 2 O] , trifluoromethanesulfonic acid (CF 3 SO 3 H) , and/or carboxylic anhydride represented by the general formula (RCO) 2 O:
  • the present invention includes methods which comprise reacting halogenated biphenyl represented by the general formula (II) with perfluoroalkanesulfinate salt represented by formula RfSO 2 M and trifluoromethanesulfonic anhydride (see, Scheme 5, Method 1a) ; reacting halogenated biphenyl of formula (II) with perfluoroalkanesulfinate salt represented by formula RfSO 2 M, trifluoromethanesulfonic anhydride, and carboxylic anhydride represented by formula (RCO) 2 O (see, Scheme 5, Method 1b) ; reacting halogenated biphenyl represented by the general formula (II) with perfluoroalkanesulfinate salt represented by formula RfSO 2 M, trifluoromethanesulfonic acid, and carboxylic anhydride represented by formula (RCO) 2 O (see, Scheme 5, Method 1c) ; reacting halogenated biphenyl represented by the general formula (II) with
  • Method 1a can contain the process in which (first step) mixing perfluoroalkanesulfinate salt represented by the general formula RfSO 2 M with trifluoromethanesulfonic anhydride and (second step) mixing halogenated biphenyl represented by the general formula (II) with a mixture of the first step.
  • Method 1a can also contain the process in which (first step) mixing perfluoroalkanesulfinate salt represented by the general formula RfSO 2 M with trifluoromethanesulfonic anhydride and (second step) mixing a mixture of halogenated biphenyl represented by the general formula (II) and trifluoromethanesulfonic anhydride with a mixture of the first step.
  • the compound of the general formula (II) used in Method 1 is a known compound or the one that can be prepared easily by the known methods (for example, see, V. Penalva et al., Teterahedron Lett., 1998, 37, 2559-2560; Y. Ding et al, Tetrahedron Lett., 2012, 53, 6269-6272; B. Kaboudin et al., Synthesis, 2001, 91-96; J. Zhou et al., Journal of Chemical Research, 2012, 672-674; B. Kurscheid et al., Organometallics, 2012, 31, 1329-1334) .
  • the perfluoroalkanesulfinate salt of the general formula RfSO 2 M used in Method 1 is commercially available or the one that can be prepared easily by the reported methods (see, R.N. Hazeldine et al., J. Chem. Soc., 1955, 2901-2910; M. Tordeux et al., J. Org. Chem., 1989, 54, 2452-2453; R.P. Singh et al., Chem, Commun., 2002, 1818-1819; H.W. Roesky et al., J. Fluorine Chem., 1976, 7, 77-84; B.R. Langlois et al., J. Fluorine Chem., 2007, 128, 851-856) .
  • perfluroalkanesulfinate salts metal salts or ammonium salts of perfluoroalkanesulfinic acids having one to four carbons can be used.
  • suitable metal alkali metals, alkali earth metals, and transition metals are exemplified, and as suitable ammonium moiety, NH 4 , CH 3 NH 3 , C 2 H 5 NH 3 , (C 2 H 5 ) 3 NH, (CH 3 ) 4 N, (C 2 H 5 ) 4 N, (C 4 H 9 ) 4 N are exemplified.
  • alkali metal salts such as lithium trifluoromethanesulfinate, sodium trifluoromethanesulfinate, potassium trifluoromethanesulfinate, and cesium trifluoromethanesulfinate are more preferable because of its easy access.
  • Sodium trifluoromethanesulfinate and potassium trifluoromethanesulfinate are furthermore preferable because of its commercial availability.
  • the amount of the perfluoroalkanesulfinate salt of the formula RfSO 2 M can be suitably decided in a range of about 0.5 mol to about 10 mol, or preferably about 1 mol to about 5 mol for 1 mol of the compound of formula (II) .
  • Trifluoromethanesulfonic anhydride used in Method 1 is commercially available.
  • the amount can be suitably decided in a range of about 0.5 mol to about 10 mol, or preferably about 1 mol to about 5 mol for 1 mol of perfluoroalkanesulfinate salt of formula RfSO 2 M.
  • Trifluoromethanesulfonic acid used in Method 1 is commercially available.
  • the amount can be suitably decided in a range of about 0.5 mol to about 20 mol, or preferably about 1 mol to about 15 mol for 1 mol of perfluoroalkanesulfinate salt of formula RfSO 2 M.
  • R is an alkyl or haloalkyl group having 1 to 4 carbons
  • As an alkyl group methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl are exemplified.
  • a haloalkyl group chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, and pentafluoroethyl are preferably exemplified.
  • acetic anhydride As carboxylic anhydride, acetic anhydride, chloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, propionic anhydride, pentafluoropropionic anhydride, butyric anhydride, and isobutyric anhydride are preferably exemplified. Among them, acetic anhydride and trifluoroacetic anhydride are more preferable because of availability and trifluoroacetic anhydride is most preferable because of high reactivity.
  • the amount of the carboxylic anhydride can be suitably decided in a range of about 0.5 mol to about 20 mol, or preferably about 1 mol to about 15 mol for 1 mol of perfluoroalkanesulfinate salt of formula RfSO 2 M.
  • the reactions of Method 1 can be conducted with or without solvent.
  • solvent usable for the reaction
  • polar solvents such as nitromethane, nitroethane, 1-nitropropane, 2-nitropropane, nitrobenzene, sulfolane, 2-methylsulfolane, ethyl methyl sulfone, and so on
  • halocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, and so on
  • carboxylic acids such as acetic acid, propionic acid, trifluoroacetic acid, perfluoropropionic acid, and so on
  • mixtures of these solvents can be preferably exemplified.
  • the polar solvents such as nitromethane and sulfolane and the carboxylic acids such as trifluoroacetic acid are more preferable because of good yield of the product, and nitromethane is furthermore preferable because of its easy-to-handle neutral solvent and easy recovery due to its low boiling point.
  • the reaction temperature of Method 1 can be suitably selected from a range of about -50 °C to about +150 °C, more suitably, about -10 °C to about +100 °C.
  • the reaction time can be suitably selected so that the reaction is completed. It can be from about 0.5 hrs to several days, preferably with a few days.
  • Method 1a The reaction mechanism of Method 1a may be explained in the following way as shown in Scheme 6.
  • Perfluoroalkanesulfinate salt reacts with trifluoromethanesulfonic anhydride to produce perfluoroalkanesulfinyl trifluoromethanesulfonate (III) [RfS (O) OSO 2 CF 3 ] which can react with halogenated biphenyl of formula (II) to produce halogenated S- [ (perfluoroalkyl) sulfinyl) ] biphenyl represented by the general formula (IV) as an intermediate; and then, the intermediate reacts with other perfluoroalkanesulfinyl trifluoromethanesulfonate and/or trifluoromethanesulfonic anhydride, which exist in the reaction mixture, to produce the final S- (perfluoroalkyl) dibenzothiophenium trifluoromethanesulfonate of formula (I’
  • halogenated S- [ (perfluoroalkyl) sulfinyl) ] biphenyl represented by the general formula (IV) was detected as an intermediate in this invented reaction by 19 F NMR.
  • the 19 F NMR analysis of the intermediate reaction mixture in the reaction of 3, 3’ -difluorobiphenyl with sodium trifluoromethanesulfinate and trifluoromethanesulfonic anhydride showed a singlet signal of -73.24 ppm (-S (O) CF 3 ) which corresponded to 3, 3’ -difluoro-6- (trifluoromethylsulfinyl) biphenyl.
  • halogenated S- [ (perfluoroalkyl) sulfinyl] biphenyl represented by the general formula (IV) was synthesized by the reaction of halogenated biphenyl of formula (II) with sodium perfluoroalkanesulfinate and trifluoromethanesulfonic acid (see Example 15) .
  • the present invention includes halogenated S- [ (perfluoroalkyl) sulfinyl] biphenyl represented by the general formula (IV) as an intermediate for the preparation of halogenated S- (perfluoroalkyl) dibenzothiophenium salt of formula (I) .
  • the present invention also relates to the isolation method for S- (perfluoroalkyl) dibenzothiophenium trifluoromethanesulfonate of formula (I’ ) .
  • the method comprises washing the reaction mixture, which results from the reactions of halogenated biphenyl of formula (II) with the reactant (s) as mentioned above, with water and an organic solvent (s) which does not dissolve or scarcely dissolve the product, S-(perfluoroalkyl) dibenzothiophenium trifluoromethanesulfonate of formula (I’ ) .
  • the reaction mixture may preferably be the reaction residue obtained after the evaporation of the solvent after the reaction.
  • the reaction mixture may be the reaction mixture after the reaction.
  • the reaction solvents are exemplified above.
  • organic solvent for washing the reaction mixture does not dissolve or scarcely dissolve the product.
  • organic solvents for washing the reaction mixture ethers such as diethyl ether, dipropyl ether, di (isopropyl) ether, dibutyl ether, di (isobutyl) ether, di (sec-butyl) ether, tert-butyl methyl ether, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, dioxane, diglyme, and so on; esters such as ethyl acetate, propyl acetate, isopropyl acetate, ethyl propionate, and so on; halocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and so on; aromatics such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, fluorobenzene, benzo
  • the reaction mixture may be washed with a mixture of water and the organic solvent.
  • the reaction mixture may also be washed in a step-wise manner; it is washed with water and then with the organic solvent, or with the organic solvent and then with water. Washing with a mixture of water and the organic solvent is preferable because of shorter process number and production effectiveness.
  • water can remove byproducts which are trifluoromethanesulfonic acid and its salt, the carboxylic acid and its salt, and the starting material and reactants remained, which are trifluoromethanesulfinic acid and its salt, trifluoromethanesulfonic anhydride, trifluoromethanesulfonic acid, the carboxylic anhydride, and the carboxylic acid and its salt.
  • Water can remove other compounds which dissolve in water.
  • the organic solvents can remove the halogenated biphenyl remained and byproducts which are dissolved in the organic solvent (s) .
  • the organic solvents can remove other compounds which dissolve in the organic solvents.
  • the product, S- (perfluoroalkyl) dibenzothiophenium trifluoromethanesulfonate of formula (I’ ) can easily be isolated only by washing the reaction mixture with water and the organic solvent (s) mentioned above without the column chromatography separation process.
  • M’ is a hydrogen atom, a metal atom, or an ammonium moiety
  • (X’ ) - and X - each is a conjugated base of Br ⁇ nsted acid (HX’ or HX) , provided that (X’ ) - and X - are different)
  • X’ CF 3 SO 3 , Cl, Br, and HSO 4 are exemplified.
  • (M’ ) + X - are commercially available compounds or easily prepared by the conventional methods.
  • strong acids and their metal and ammonium salts are exemplified.
  • the preferable strong acids include sulfuric acid, fluorosulfonic acid, chlorosulfonic acid, trifluoromethanesulfonic acid, perfluorobutanesulfonic acid, trichloromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, HCl, HBr, HBF 4 , HPF 6 , HSbF 6 , HAsF 6 , HClO 4 , and so on.
  • the preferable metal and ammonium salts include CF 3 SO 3 Li, CF 3 SO 3 Na, CF 3 SO 3 K, CF 3 SO 3 Ag, CF 3 SO 3 NH 4 , C 4 F 9 SO 3 Na, (C 2 H 5 ) 3 NHCl, (CH 3 ) 4 NCl, (C 2 H 5 ) 4 NCl, (C 4 H 9 ) 4 NCl, (C 4 H 9 ) 4 NBr, LiHSO 4 , NaHSO 4 , KHSO 4 , AgHSO 4 , (CH 3 ) 4 NHSO 4 , (C 2 H 5 ) 4 NHSO 4 , (C 4 H 9 ) 4 NHSO 4 , LiBF 4 , NaBF 4 , KBF 4 , AgBF 4 , NH 4 BF 4 , (C 2 H 5 ) 3 NHBF 4 , (CH 3 ) 4 NBF 4 , (C 2 H 5 ) 4 NBF 4 , (C 4 H 9 ) 4 NBF 4 , LiPF
  • This process can be preferably done with a solvent for smooth reaction and high yield.
  • a suitable solvent a nitrile such as acetonitrile, propionitrile, and so on; a halocarbon such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane; an ether such as diethyl ether, tetrahydrofuran, dioxane, di (isopropyl) ether, tert-butyl methyl ether, dimethoxyethane, and so on; an aromatic compound such as benzene, toluene, chlorobenzene, benzotrifluoride, and so on; an alcohol such as methanol, ethanol, 2, 2, 2-trifluoroethanol, propanol, isopropanol, 1, 1, 1, 3, 3, 3-hexafluoro-2-propanol, butanol, iso-butanol, sec-butan
  • the reaction temperature can be selected from a range of about 0 °C to about 100 °C, preferably about room temperature to about 80 °C.
  • the reaction time can be selected so that the reaction is completed. It can be from about 10 min to a few days, preferably within a day.
  • This invention also relates to the reuse of halogenated dibenzothiophene represented by the following formula (V) which is obtained after the usage of the S- (perfluoroalkyl) dibenzothiophenium salt of formula (I) as a perfluoroalkylating agent.
  • halogenated dibenzothiophene of formula (V) can be reduced to produce halogenated biphenyl of formula (II) as shown in Scheme 9.
  • the reaction of Scheme 9 can be done by the reduction which are used for desulfurization of the sulfur compounds (see Examples 31 and 32 below) .
  • the halogenated biphenyl obtained by the desulfurization can be reused for the production of the halogenated S- (perfloroalkyl) dibenzothiophenium salt of this invention.
  • the present invention also relates to the production of halogenated S- (perfluoroalkyl) dibenzothiophenium salt of formula (I) using halogenated biphenyl of formula (II) , which is recovered by the reduction (desulfurization) of the halogenated dibenzothiophene of formula (V) obtained by the usage of the S- (perfluoroalkyl) dibenzothiophenium salt.
  • halogenated S- (perfluoroalkyl) dibenzothiophenium salt can be done by means of Method 1 using the recovered halogenated biphenyl of formula (II) . This can be done in the same way as described above except for the usage of the recovered halogenated biphenyl.
  • Trifluoromethanesulfonic anhydride can be prepared from the recovered trifluoromethanesulfonic acid or its salt by the conventional synthetic methods such as dehydration reaction with P 2 O 5 (see, T. Gramstad, R.N. Haszeldine, J. Chem. Soc., 1957, 4069-4079) : CF 3 SO 3 H + P 2 O 5 ⁇ (CF 3 SO 2 ) 2 O.
  • Halogenated S- (perfluoroalkyl) dibenzothiophenium salt represented by the above general formula (I) of the present invention is a useful electrophilic perfluoroalkylating agent of wide applications to prepare perfluoroalkylated organic compounds (see Examples 17-30 below) .
  • the invented halogenated S- (perfluoroalkyl) dibenzothiophenium salt can be prepared by a very short process such as a one-pot process (see Examples 1-7 below) and isolated by a simple filtration of the products precipitated by washing the reaction mixture with water and an organic solvent (see Examples 1-5, and 7 below) . These are highly useful for cost-effective production of the electrophilic perfluoroalkylating agent in industry.
  • the halogenated biphenyl is recovered from the reduction (desulfurization) of the halogenated dibenzothiophene obtained from the usage of the halogenated S- (perfluoroalkyl) dibenzothiophenium salt for the perfluoroalkylation of organic compounds (see Examples 31 and 32) .
  • Another reactant, trifluoromethanesulfonic anhydride may also be recovered from trifluoromethanesulfonic acid or salt obtained from the usage of the S- (perfluoroalkyl) dibenzothiophenium salt.
  • the recycle as shown in Scheme 10 can provide a highly cost-effective and environmentally friendly (green) production of the halogenated S- (perfluoroalkyl) dibenzothiophenium salt and a highly cost-effective and environmentally friendly (green) production of the perfluoroalkylated organic compounds. Therefore, the present invention of the new halogenated S- (perfluoroalkyl) dibenzothiophenium salt and its production methods can provide a highly effective and environmentally friendly perfluoroalkylating agent that is industrially very important.
  • 3' -Difluorobiphenyl (14.2 g, 74.7 mmol) was added to a stirred mixture of 14.0 g (90 mmol) of dried sodium trifluoromethanesulfinate and 100 mL of dry nitromethane under nitrogen atmosphere at room temperature (20°C) , and then the reactor was put on a water bath. After the mixture was stirred for 40 min, trifluoromethanesulfonic anhydride (50.6 g, 179.4 mmol) was added for 10 min and the reaction mixture was stirred at room temperature for 46 hrs.
  • the products of this invention were obtained and easily isolated by simple filtration from the reaction mixture in good yield.
  • the filtration procedure is particularly useful for the economical industrial large scale production.
  • 3' -Difluorobiphenyl 28.3 g 149 mmol was added to a stirred mixture of 32.9 g (211 mmol) of dried sodium trifluoromethanesulfinate and 100 mL of dry nitromethane under nitrogen atmosphere at room temperature, and then the reactor was put on an ice bath.
  • Trifluoromethanesulfonic anhydride (65.1 g, 231 mmol) was added for 40 min and then the reaction mixture was stirred for 2 hrs on an ice bath. After that, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hrs.
  • Trifluoroacetic anhydride (37.8 g, 180 mmol) was then added and the reaction mixture was stirred 17 hrs at room temperature. After the reaction solution was evaporated to dryness, 130 mL of toluene was added to the residue and the solvent was evaporated up. Into the residue, 130ml of water and 130ml of toluene were added and the mixture was stirred for 20 min.
  • 3' -Difluorobiphenyl (28.4 g, 149.5 mmol) was added to a stirred mixture of 25.3 g (162 mmol) of dried sodium trifluoromethanesulfinate and 100 mL of dry nitromethane under nitrogen atmosphere at room temperature, and then the reactor was put on a water bath. After the mixture was stirred for 35 min, trifluoromethanesulfonic anhydride (49.9 g, 177 mmol) was added for 10 min and then the reaction mixture was stirred for 30 min. Trifluoroacetic anhydride (37.2 g, 177 mmol) was added by one portion and the water bath was removed. The reaction mixture was stirred at room temperature for 22 hrs.
  • 3' -Difluorobiphenyl (14.2 g, 74.7 mmol) was added to a stirred mixture of 15.2 g (97.4 mmol) of dried sodium trifluoromethanesulfinate and 100 mL of dry nitromethane under nitrogen atmosphere at room temperature, and then the reactor was put on a water bath. After stirring for 20 min, trifluoromethanesulfonic anhydride (29.5 g, 105 mmol) was added for 6 min. After stirring for 50min, acetic anhydride (9.9 g, 97 mmol) was added by one portion. After stirring for 47 min, the water bath was removed and the reaction mixture was stirred at room temperature for 46 hrs.
  • Trifluoromethanesulfonic anhydride (60.8 g, 216 mmol) was added to a stirred mixture of 28.1 g (180 mmol) of dried sodium trifluoromethanesulfinate and 200 mL of dry nitromethane under nitrogen atmosphere at ice bath temperature. The mixture was stirred for 5 hr at room temperature. After that, 11.4 g (60 mmol) of 3, 3’ -difluorobiphenyl was added to the mixture, and the mixture was stirred for 41 hrs at room temperature.
  • Trifluoromethanesulfonic anhydride (6.08 g, 21.6 mmol) was added to a stirred mixture of 2.81 g (18 mmol) of dried sodium trifluoromethanesulfinate and 15 mL of dry sulfolane under nitrogen atmosphere at room temperature. The mixture was stirred for 24 hrs at room temperature. After that, a solution of 1.14 g (6.0 mmol) of 4, 4’ -difluorobiphenyl in 5 mL of dry sulfolane was added to the mixture, and the mixture was stirred for 23 hrs at room temperature.
  • Trifluoromethanesulfonic anhydride (30.4 g, 108 mmol) was added to a stirred mixture of 14.1 g (90.4 mmol) of dried sodium trifluoromethanesulfinate and 70 mL of dry nitromethane under nitrogen atmosphere at ice bath cooling. The mixture was stirred for 6 hrs at room temperature. After that, a solution of 6.8 g (30.1 mmol) of 3, 3’ , 4, 4’ -tetrafluorobiphenyl in 30 mL of dry nitromethane was added to the mixture, and the mixture was stirred for 43 hrs at room temperature.
  • the product of this invention was obtained and easily isolated by simple filtration from the reaction mixture in good yield.
  • the filtration procedure is particularly useful for the economical industrial large scale production.
  • Trifluoromethanesulfonic anhydride (6.08 g, 21.6 mmol) was added to a stirred mixture of dried sodium trifluoromethanesulfinate (2.81 g, 18 mmol) and dry nitromethane (15 mL) at room temperature under nitrogen atmosphere. After the mixture was stirred for 3 hrs, a solution of biphenyl (0.93 g, 6.0 mmol) in dry nitromethane (5 mL) was added, and the mixture was stirred for 60 hrs at room temperature.
  • Umemoto reagent S- (trifluoromethyl) dibenzothiophenium trifluoromethanesulfonate
  • biphenyl in place of 3, 3’ -difluorobiphenyl
  • the specified halogenated S- (perfluoroalkyl) dibenzothiophenium salts invented by the present invention are prepared in good yields. Accordingly, the invented compounds are particular useful, compared to the previous Umemoto reagent.
  • the starting material was dissolved in 12.5 mL of dry nitromethane and the mixture was cooled to 0-5 °C on an ice bath. Into the cooled solution was dropwise added 3.53 g (12.5 mmol) of trifluoromethanesulfonic anhydride.
  • 2, 8-Difluoro-S- (trifluoromethyl) dibenzothiophenium salt (0.75 mmol) was added to a stirred solution of methyl 1-oxo-2-indanecarboxylate (0.5 mmol) , K 2 CO 3 (1.5 mmol) , and tetrabutylammonium iodide (0.025 mmol) in 5 mL of N, N-dimethylformamide (DMF) at room temperature under nitrogen atmosphere. The mixture was stirred for 1 h. The reaction mixture was analyzed by 19 F NMR using 4-chlorobenzotrifluoride as a standard.
  • the 19 F NMR analysis showed that the trifluoromethylated product, methyl 1-oxo-2- (trifluoromethyl) indane-2-carboxylate, was produced in 85%, 91%, and 100%yield in Examples 18, 19, and 20, respectively (See Table 2) .
  • the CF 3 -product was isolated by the standard post-treatment and identified by spectral analysis: 19 F NMR (376.5 MHz, CDCl 3 ) ⁇ -69.3 (s, CF 3 ) .
  • the trifluoromethyl product was isolated by the standard post-treatment (extraction and column chromatography) and identified by spectral analysis; 19 F NMR with 1 H irradiation (376.5 MHz, CDCl 3 ) ⁇ -60.07 (s, CF 3 ) .

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Abstract

L'invention concerne un sel de dibenzothiophénium S-(perfluoroalkyl) halogéné représenté par la formule générale suivante (I). Ce composé est un réactif nouveau, réactif et utile au plan industriel pour les composés organiques de perfluoralkylation. Le réactif peut être préparé par un procédé monotope ou un procédé de réaction en deux étapes à partir d'un biphényle halogéné et est facile à isoler par un procédé de filtration. En outre, le biphényle halogéné peut être récupéré par désulfuration à partir d'un dibenzothiophène halogéné obtenu sous la forme d'un produit secondaire par l'utilisation du réactif.
PCT/CN2015/099798 2014-12-31 2015-12-30 Sel de dibenzothiophénium s-(perfluoroalkyl) halogéné et ses procédés de production WO2016107578A1 (fr)

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DE102018211606A1 (de) 2018-07-12 2020-01-16 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts Dibenzothiophensalz als Alkinylierungs- und Cyanierungsagens
WO2020127172A1 (fr) * 2018-12-19 2020-06-25 Merck Patent Gmbh Milieu cristallin liquide et afficheur à cristaux liquides comprenant celui-ci et composés
WO2022195221A1 (fr) 2021-03-17 2022-09-22 Bostik Sa Composition a base de monomeres (meth)acrylate
FR3120871A1 (fr) 2021-03-17 2022-09-23 Bostik Sa Composition à base de monomères (méth)acrylate
WO2023089252A1 (fr) 2021-11-22 2023-05-25 Bostik Sa Composition à base de monomères (méth)acrylate

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Publication number Priority date Publication date Assignee Title
DE102018211606A1 (de) 2018-07-12 2020-01-16 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts Dibenzothiophensalz als Alkinylierungs- und Cyanierungsagens
WO2020011935A1 (fr) 2018-07-12 2020-01-16 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts Sel de dibenzothiophène utilisé comme agent d'alcynylation et de cyanation
US11447462B2 (en) 2018-07-12 2022-09-20 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts Dibenzothiophene salt as alkynylating and cyanating agent
WO2020127172A1 (fr) * 2018-12-19 2020-06-25 Merck Patent Gmbh Milieu cristallin liquide et afficheur à cristaux liquides comprenant celui-ci et composés
WO2022195221A1 (fr) 2021-03-17 2022-09-22 Bostik Sa Composition a base de monomeres (meth)acrylate
FR3120871A1 (fr) 2021-03-17 2022-09-23 Bostik Sa Composition à base de monomères (méth)acrylate
FR3120872A1 (fr) 2021-03-17 2022-09-23 Bostik Sa Composition à base de monomères ( méth )acrylate
WO2023089252A1 (fr) 2021-11-22 2023-05-25 Bostik Sa Composition à base de monomères (méth)acrylate
FR3129402A1 (fr) 2021-11-22 2023-05-26 Bostik Sa Composition à base de monomères (méth)acrylate

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