WO2012148772A1 - Direct trifluoromethylations using trifluoromethane - Google Patents

Direct trifluoromethylations using trifluoromethane Download PDF

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WO2012148772A1
WO2012148772A1 PCT/US2012/034228 US2012034228W WO2012148772A1 WO 2012148772 A1 WO2012148772 A1 WO 2012148772A1 US 2012034228 W US2012034228 W US 2012034228W WO 2012148772 A1 WO2012148772 A1 WO 2012148772A1
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substrate
reaction mixture
trifluoromethyl
trifluoro
trifluoromethane
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G.K. Surya Prakash
Parag V. JOG
Patrice T.D. BATAMACK
George A. Olah
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University of Southern California USC
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Priority to US14/113,482 priority Critical patent/US9334253B2/en
Priority to JP2014508429A priority patent/JP6126079B2/en
Priority to ES12776629T priority patent/ES2701451T3/en
Priority to EP12776629.3A priority patent/EP2712367B1/en
Priority to CN201280032196.1A priority patent/CN103649263B/en
Publication of WO2012148772A1 publication Critical patent/WO2012148772A1/en
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
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    • C07C29/36—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 reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—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 reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/40—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 reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
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    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/16—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by oxidation of thiols, sulfides, hydropolysulfides, or polysulfides with formation of sulfo or halosulfonyl groups
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    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
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    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • 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
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
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    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes

Definitions

  • This invention relates to methods for direct trifluoromethylation of chlorosilanes, carbonyl compounds such as esters, aryl halides, aldehydes, ketones, chalcones, alkyl formates, alkyl halides, aryl halides, alkyl borates, carbon dioxide and sulfur using trifluoromethane (CF 3 H) as a non-ozone depleting, trifluoromethylating agent.
  • carbonyl compounds such as esters, aryl halides, aldehydes, ketones, chalcones, alkyl formates, alkyl halides, aryl halides, alkyl borates, carbon dioxide and sulfur using trifluoromethane (CF 3 H) as a non-ozone depleting, trifluoromethylating agent.
  • Trifluoromethyl group plays a pivotal role in many industrial sectors such as pharmaceuticals, agrochemicals, dyes, polymers and material chemistry. It is well-known that introduction of fluorine in pharmaceutical targets increases the possibility of such compounds to act as "lead compounds" by almost tenfold (Taj, S. A. S. Chemical Industry Digest, 2008, 21, 92-98). Trifluoromethyl group increases the lipophilicity of biologically active compounds so that they can be absorbed by the body easily and can reach specific binding sites more effectively (Mueller, K., Faeh, C. and Diederich, F. Science 2007, 317, 1881-1886; Cho, E. J., Senecal, T. D., Kinzel, T., Zhang, Y., Watson, D. A. and Buchwald, S. L. Science 2010, 328, 1679-1681).
  • TMS-CF 3 trifluoromethyltrimethylsilane
  • Ruppert- Prakash reagent Ruppert, I., Schlich, K. and Volbach, W. Tetrahedron Lett., 1984, 25, 2195- 2198; Ramaiah, P., Krishnamurti, R. and Prakash, G. K. S. Org. Synth., 1995, 72, 232-40).
  • Trifluoromethyltrimethylsilane, 1 acts as a "trifluoromethide” equivalent in nucleophilic trifluoromethylation reactions
  • Prakash, G. K. S., Krishnamurti, R. and Olah, G. A. J. Am. Chem. Soc, 1989, 111, 393-395 Variety of methods have already been developed using this reagent to carry out nucleophilic trifluoromethylation of aldehydes, ketones, esters, imines, and many other electrophiles (both achiral and prochiral).
  • Trifluoromethyl anion (CF 3 ⁇ ), due to its concentrated negative charge around the carbon atom, is known to decompose rapidly into fluoride ion (F ) and an electron deficient singlet carbene, difluorocarbene, (:CF 2 ) (Prakash, G. K. S. and Mandal, M. J. Fluorine Chem., 2001, 112, 123-131; Large, S., Roques, N.
  • Trifluoromethane a by-product of the Teflon industry, is produced in large amounts on an industrial scale. Its efficient production has already been reported via fluorination of methane with hydrogen fluoride and chlorine. (Webster, J. L. and Lerou, J. J. 1995, US 5,446,218 (A) 8 pp Cont-in-part of US Ser No 51,917, abandoned). It is a non toxic, non ozone-depleting gas, but has a powerful greenhouse effect, which rules out its use as a refrigerant.
  • the present invention relates to a method for preparing a trifluoromethylated substrate, which comprises reacting a fluoromethylatable substrate with a trifluoromethylating agent in the presence of a base under conditions sufficient to trifluoromethylate the substrate.
  • the fluoromethylatable substrate generally comprises a compound selected from the group consisting of chlorosilanes, carbonyl compounds such as esters, aryl halides, aldehydes, ketones, chalcones, alkyl formates, alkyl halides, aryl halides, alkyl borates, carbon dioxide and sulfur.
  • the preferred trifluoromethylating agent is trifluoromethane.
  • the substrate typically comprises chlorotrimethylsilane, chlorotriethylsilane, chlorotriisopropylsilane, chloro(t-butyldimethyl)silane, chloro(tris(trimethylsilyl)) silane, dichlorodiethylsilane, benzaldehyde, / anisaldehyde, 3-methylbenzaldehyde, 1- anthracenaldehyde, furan-2-carboxaldehyde, benzophenone, 4-methoxybenzophenone, 4- methylbenzophenone, 3-nitrobenzophenone, 4-fluorobenzophenone, chalcone, 4'- methoxychalcone, 4'-nitrochalcone, 4,4'-difluorochalcone, 4'-chlorochalcone, methyl benzoate, benzyl bromide, iodobenzene, 1-iodonaphthalene, 2-Iodoanisole, 3- nitro
  • the reaction is typically carried out in the presence of a solvent.
  • a solvent for trifluoromethylation of aryl halides the solvent is a polar aprotic solvent.
  • the solvent is tetrahydrofuran (THF), diethyl ether, polyethers, hydrocarbon solvents (toluene, benzene, etc.), dimethyl ether, dimethoxymethane (Glyme), dimethylformamide (DMF), N- methylpyrrolidone (NMP), hexamethyl phosphoric triamide (HMPA), dimethyl sulfoxide (DMSO), preferably dimethylformamide (DMF).
  • THF tetrahydrofuran
  • diethyl ether diethyl ether
  • polyethers polyethers
  • hydrocarbon solvents toluene, benzene, etc.
  • dimethyl ether dimethoxymethane
  • Dimethoxymethane dimethoxymethane
  • DMF dimethyl
  • the base comprises an alkoxide (polyalkoxide) or alkali metal salt of silazane (polysilazane) or a combination thereof.
  • the reaction conditions generally include a temperature of between about -90°C to about 130°C for a time between 30 minutes to 24 hours. A skilled artisan can determine the optimum conditions for any particular reactants by routine experimentation.
  • the method further comprises adding the base to a mixture that includes the substrate and the trifluoromethylating agent to form a reaction mixture, stirring the reaction mixture at about -80°C to -70°C and warming the reaction mixture to about room temperature to trifluoromethylate the substrate.
  • the reaction mixture is warmed to about room temperature for about 2 to 20 hours.
  • the reaction mixture is stirred vigorously either by magnetic stirring or mechanical stirring methods at all times.
  • the trifluoromethylating agent is trifluoromethane
  • the base comprises an alkoxide (polyalkoxide) or alkali metal salt of silazane (polysilazane) or a combination thereof
  • the method further comprises adding the trifluoromethylating agent to a mixture of a copper halide, a heterocyclic ligand containing 1-10 heteroatoms, the solvent and the aryl halide followed by addition of the base to form a reaction mixture, stirring the reaction mixture at about 80 to 120 °C and cooling the reaction mixture to about room temperature to trifluoromethylate the substrate.
  • the fluoromethylatable substrate comprises trialkylborates
  • these can be converted in situ to trifluoromethyltrifluoroborates.
  • the fiuoromethylatable substrate is elemental sulfur, it can be trifluoromethylated to a trifluoromethylated sulfur intermediate, which can then be oxidized in situ to form trifluoromethanesulfonic acid.
  • Preferred trifluoromethylated products include trifluoromethyl(trimethyl)silane, trifluoromethyl(triethyl)silane, trifluoromethyl(triisopropyl)silane, (trifluoromethyl)t- butyldimethylsilane, tris(trimethylsilyl)trifluoromethylsilane, diethyl bis(trifluoromethyl)silane, 2,2,2-trifluoro- 1 -phenylethanol, 2,2,2-trifluoro- 1 -(4- methoxyphenyl)ethanol, 2,2,2-trifluoro- 1 -m-tolylethanol, 2,2,2-trifluoro- 1 -(furan-2- yl)ethanol, 1 -(anthracen-9-yl)-2,2,2-trifluoroethanol, 2,2,2-trifluoro- 1 , 1 -diphenylethanol, 2,2,2-trifluoro- 1 -(4-methoxyphenyl)- 1
  • the invention also relates to the use of a trif uoromethylating agent for trifluoromethylating a fiuoromethylatable substrate in the presence of a base under conditions sufficient to trif uoromethylate the substrate.
  • the fiuoromethylatable substrate generally comprises a compound selected from the group consisting of carbonyl compounds, chlorosilanes, esters, aryl halides, aldehydes, ketones, chalcones, alkyl halides, alkyl formates, alkyl borates, carbon dioxide, and sulfur, and the preferred trifluoromethylating agent is trif uoromethane.
  • Figure 1 is a graph of the results of a low temperature 19 F NMR spectroscopic experiment.
  • the invention includes a convenient method of trifluoromethylation of a fluoromethylatable substrate or compound as noted as an example of a trifluoromethylating agent.
  • the invention now provides a direct trifluoromethylation method preferably using a trifluoromethane as a fluoromethylating species and trifluoromethylating agent.
  • a fluoromethylatable substrate or compound is the one that is capable of being trifluoromethylated in this fluoromethylation process.
  • a "trifluoromethylating species" as the term used herein is for an agent capable of generating a trifluoromethylating species that is capable of forming a bond with the fluoromethylatable substrate.
  • the present method is used for preparing a trifluoromethylated substrate by reacting a fluoromethylatable substrate with a trifluoromethylating agent in the presence of an alkoxide, polyalkoxide or metal salt of silazane (polysilazane) under conditions sufficient to trifluoromethylate the substrate; wherein the fluoromethylatable substrate preferably comprises a compound selected from the group consisting of carbonyl compounds, chlorosilanes, aldehydes, ketones, chalcones, esters, alkyl halides, alkyl formates, aryl halides, alkyl borates and sulfur.
  • the most preferred trifluoromethylating agent is trifluoromethane.
  • R3-S1-X where R could be substituted or unsubstituted alkyl or aryl groups and X could be any halogen except fluorine (F), preferably chlorine (CI).
  • R-CH 2 -X where R could be substituted or unsubstituted alkyl or aryl groups and X could be any halogen except fluorine (F).
  • Ar-X where Ar could be substituted or unsubstituted aryl ring and X could be any halogen except fluorine (F), preferably iodine (I). 5.
  • B(OR) 3 where R could be substituted or unsubstituted alkyl or aryl groups.
  • Any source of sulfur including all of the oxidation states of sulfur such as S(II), S(IV), etc., with the most preferred source being elemental sulfur.
  • Solvents used herein are not limited to etheral solvents (for carbonyl and R-CH 2 -X containing substrates), which contain at least one oxygen atom and in some cases hydrocarbons (containing only carbon and hydrogen) solvents with the absence of any heteroatoms.
  • Reactions can be performed in the temperature range of -78 °C to 130 °C, preferably at -78 °C in the first step of the reaction in case of halosilanes, -40 °C, for carbonyl and R-CH 2 -X containing substrates and 130 °C for aryl halides.
  • the preferred bases for this reaction comprises an alkoxide, polyalkoxide or alkali metal salt of silazane or a combination thereof and in particular are potassium salts of silazanes and polysilazanes, which contain nitrogen atoms (between 1-5, preferably 1) and silicon atoms (between 1-10, preferably 2) or alcohols with suitably branched alkyl group containing 1-20, preferably between 3-10 carbon atoms, with tertiary butyl being most preferred.
  • Base is dissolved in an appropriate solvent before the reaction and was present as slurry at the temperature at which the reaction is carried out.
  • the reaction time could be between 1-20 hours, preferably 1-5 hours for halosilanes and 1-16 hours for carbonyl substrates and aryl halides.
  • the alkoxide, polyalkoxide or silazane (polysilazane) salt base is added to a mixture containing the substrate and trifluoromethylating agent.
  • the reaction mixture is stirred at a first temperature, and is then warmed to a second temperature.
  • Preferably the mixture is warmed to room temperature, around 20 to 25 °C, for about 2 to 20 hours and preferably for about 5-6 hours.
  • Trifluoromethane gas is known to form hydrogen bonds (and hence dissolves readily) with many of the etheral solvents. Initial reactions were performed in dry tetrahydrofuran (THF). It is known that trifluoromethane forms a hydrogen bond with the oxygen of THF and hence has a good solubility in THF.
  • trifluoromethylsilanes such as trifluoromethyltriethylsilane (TES-CF 3 )
  • TES-CF 3 trifluoromethyltriethylsilane
  • the developed protocol was extended to synthesize other synthetically important trifluoromethylated silanes in good yields using ether as a solvent since the boiling points of most of the trifluoromethylated silanes were very close to the boiling point of toluene.
  • ketones chalcones, aromatic esters, benzyl halides and alkyl formates
  • Trifluoromethylation of non-enolizable ketones went uneventfully and the corresponding trifluorometylated products were obtained in good yields using KHMDS to deprotonate trifluoromethane in using diethyl ether as a solvent. More importantly, trifluoromethane used was in equimolar amounts compared with the ketone and KHMDS (Table 3). In case of enolizable ketones, aldol condensation prevailed in ether, in THF and toluene the trifluoromethylated products were absent.
  • formation of hemiaminal of DMF (as a reactive species, when reaction was carried out in DMF) can be ruled out as a "CF 3 " trapping species because HMPA (hexamethylphosphoric triamide), which cannot act as a trapping species also yielded 50% of the desired product under the identical reaction conditions (compare entries 3 vs 26, Table 2).
  • HMPA hexamethylphosphoric triamide
  • Nucleophilic trifluoromethylation using organoboron reagents, specifically potassium trialkyl trifluoroborates, is becoming increasingly popular.
  • the most common electrophiles include non-enolizable aldehydes, N-tosylimines (Levin, V. V., Dilman, A. D., Belyakov, P. A., Struchkova, M. I. and Tartakovsky, V. A. Tetrahedron Lett., 2011, 52, 281-284), aryl iodides (Knauber, T., Arikan, F., Roeschenthaler, G.-V. and Goossen, L. J. Chem.— Eur.
  • TMS-CF3 trifluoromethyltrimethylsilane
  • a direct trifluoromethylation of trialkyl borates using trifluoromethane (CF3H) is not reported.
  • trifluoromethane (CF 3 H) trifluoromethane
  • Trifluoromethylation of trialkyl borates (trimethyl borate and tri(n-butyl) borate) was achieved using trifluoromethane (1 equivalent) and KHMDS as a base in THF at -5 °C to RT.
  • the intermediate products (trifluoromethylated sulfur species, CF 3 Sn) obtained were subjected to complete oxidation using H 2 SO 4 / 30%> H 2 0 2 to obtain trifluoromethanesulfonic acid (CF3SO3H) in 18% conversion (NMR analysis, Scheme 4).
  • the reaction can be further optimized to achieve higher conversions.
  • CF 3 H was used from Synquest Laboratories and was used as received.
  • a gas mass flow controller from Aalborg (GFC-17) was used and was calibrated for CF 3 H.
  • Potassium hexamethyldisilazide (solid) was purchased from Aldrich and was stored under argon in a dry box.
  • Commercially available solutions of potassium hexamethyldisilazide, both in THF and toluene, were purchased from Gelest Inc. and were used as received. All the chlorosilanes were purchased from Gelest Inc. and were used as received except for chlorotrimethylsilane (TMSC1), which was freshly distilled over calcium hydride just prior to the reaction. All other electrophiles were purchased from commercial sources such as Aldrich or other chemical suppliers and were used as received. All the reactions were carried out
  • reaction mixture was cooled to room temperature and then hexafluorobenzene (CeF 6 ) (0.166 eq) was added to the reaction mixture and it was stirred at room temperature for 10 mins. An aliquot of reaction mixture was taken out and its NMR ( 19 F) was recorded. NMR yields were determined by NMR integrations and are reported in Table 3.
  • This bottle was cooled in ice and then 48% aqueous solution of hydrogen fluoride (6 mL) was added to it. The resulting solution was stirred at ambient temperature for 12-14 hours. After that, a solution of potassium hydroxide (3.15g in 30 mL of distilled water) was added slowly to the reaction mixture until reaction mixture remains slightly acidic. Potassium bicarbonate was added portion wise as a solid until C0 2 evolution ceased, and the reaction mixture had a pH greater than 7. Water was removed under vacuo to afford a white solid. A fine powder of this solid was made by grinding using mortar and pestle and the material was dried with a gentle heating of the flask with the heat gun.
  • the vial was cooled to 0 to -5 °C for 5 minutes. After ten minutes, CF 3 H was bubbled into this THF solution for 2 min (0.304 g, 4.34 mmol was added total at the rate of 52.5 ml/min). This reaction mixture was allowed to stir for ten minutes. After 10 minutes, trimethoxyborane (1 g, 4.34 mmol, 1.17 mL) was added to the reaction mixture neat. The resulting reaction mixture was stirred at 0 °C for 5 minutes.
  • This bottle was cooled in ice and then 48% aqueous solution of hydrogen fluoride (6 mL) was added to it. The resulting solution was stirred at ambient temperature for 12-14 hours. After that, a solution of potassium hydroxide (3.15g in 30 mL of distilled water) was added slowly to the reaction mixture until reaction mixture remains slightly acidic. Potassium bicarbonate was added portion wise as a solid until C0 2 evolution ceased, and the reaction mixture had a pH greater than 7. Water was removed under vacuo to afford white solid. A fine powder of this solid was made by grinding using mortar and pestle and the material was dried with a gentle heating of the flask with the heat gun.
  • the invention demonstrates the use of a trifluoromethylating agent for trifluoromethylating a fluoromethylatable substrate in the presence of an alkoxide (polyalkoxide) or metal salt of silazane (polysilazane) under conditions sufficient to trifluoromethylate the substrate; wherein the fluoromethylatable substrate preferably comprises a compound selected from the group consisting of aldehydes, ketones, chalcones, esters, alkyl halides, alkyl formates, aryl halides, alkyl borates and sulfur.

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Abstract

A direct trifluoromethylation method preferably using a trifluoromethane as a fluoromethylating species. In particular, the present method is used for preparing a trifluoromethylated substrate by reacting a fluoromethylatable substrate with a trifluoromethylating agent in the presence of an alkoxide or metal salt of silazane under conditions sufficient to trifluoromethylate the substrate; wherein the fluoromethylatable substrate includes chlorosilanes, carbonyl compounds such as esters, aryl halides, aldehydes, ketones, chalcones, alkyl formates, alkyl halides, aryl halides, alkyl borates, carbon dioxide or sulfur.

Description

DIRECT TRIFLUOROMETHYLATIONS USING TRIFLUOROMETHANE
TECHNICAL FIELD
This invention relates to methods for direct trifluoromethylation of chlorosilanes, carbonyl compounds such as esters, aryl halides, aldehydes, ketones, chalcones, alkyl formates, alkyl halides, aryl halides, alkyl borates, carbon dioxide and sulfur using trifluoromethane (CF3H) as a non-ozone depleting, trifluoromethylating agent.
BACKGROUND ART
Trifluoromethyl group plays a pivotal role in many industrial sectors such as pharmaceuticals, agrochemicals, dyes, polymers and material chemistry. It is well-known that introduction of fluorine in pharmaceutical targets increases the possibility of such compounds to act as "lead compounds" by almost tenfold (Taj, S. A. S. Chemical Industry Digest, 2008, 21, 92-98). Trifluoromethyl group increases the lipophilicity of biologically active compounds so that they can be absorbed by the body easily and can reach specific binding sites more effectively (Mueller, K., Faeh, C. and Diederich, F. Science 2007, 317, 1881-1886; Cho, E. J., Senecal, T. D., Kinzel, T., Zhang, Y., Watson, D. A. and Buchwald, S. L. Science 2010, 328, 1679-1681).
Consequently, the key challenge in the field is to develop safer, cheaper, environmentally friendly and more efficient trifluoromethylation methods. Nucleophilic trifluoromethylation is more attractive and well-studied to synthesize variety of trifluoromethylated building blocks. The most common reagent of choice for nucleophilic trifluoromethylation is trifluoromethyltrimethylsilane (TMS-CF3), 1, also known as Ruppert- Prakash reagent (Ruppert, I., Schlich, K. and Volbach, W. Tetrahedron Lett., 1984, 25, 2195- 2198; Ramaiah, P., Krishnamurti, R. and Prakash, G. K. S. Org. Synth., 1995, 72, 232-40). Trifluoromethyltrimethylsilane, 1, acts as a "trifluoromethide" equivalent in nucleophilic trifluoromethylation reactions (Prakash, G. K. S., Krishnamurti, R. and Olah, G. A. J. Am. Chem. Soc, 1989, 111, 393-395). Variety of methods have already been developed using this reagent to carry out nucleophilic trifluoromethylation of aldehydes, ketones, esters, imines, and many other electrophiles (both achiral and prochiral). (Prakash, G. K. S. and Yudin, A. K. Chem. Rev., 1997, 97, 757-786; Singh, R. P. and Shreeve, J. M. Tetrahedron, 2000, 56, 7613- 7632; Prakash, G. K. S. and Hu, J. ACS Symp. Ser., 2005, 911, 16-56; Mizuta, S., Shibata, N., Sato, T., Fujimoto, FL, Nakamura, S. and Toru, T. Synlett, 2006, 267-270; Kawai, FL, Kusuda, A., Mizuta, S., Nakamura, S., Funahashi, Y., Masuda, H. and Shibata, N. J. Fluorine Chem., 2009, 130, 762-765). TMS-CF3 (1) is commercially available and it is a very easy to handle liquid (bp = 54-55 °C), both on industrial and laboratory scale.
Synthesis of TMS-CF3 is also well studied and there are several methods, which are reported earlier (Ruppert, I., Schlich, K. and Volbach, W. Tetrahedron Lett., 1984, 25, 2195- 2198; Ramaiah, P., Krishnamurti, R. and Prakash, G. K. S. Org. Synth., 1995, 72, 232-40; Beckers, FL, Buerger, FL, Bursch, P. and Ruppert, I. J. Organomet. Chem., 1986, 316, 41-50; Pawelke, G. J. Fluorine Chem., 1989, 42, 429-33; Deffieux, D., Bordeau, M., Biran, C. and Dunogues, J. Organometallics, 1994, 13, 2415-2422; Grobe, J. and Hegge, J. Synlett, 1995, 641-2; Prakash, G. K. S., Yudin, A. K., Deffieux, D. and Olah, G. A. Synlett, 1996, 151-3; Martynov, B. I. and Stepanov, A. A. J. Fluorine Chem., 1997, 85, 127-128; Prakash, G. K. S., Hu, J. and Olah, G. A. J. Org. Chem., 2003, 68, 4457-4463; Prakash, G. K. S., Hu, J. and Olah, G. A. 2004, US 2004/0230079 (Al) , 33 pp; Prakash, G. K. S., Hu, J., Olah, G. A. and Wang, Y. 2005, US 2006/0052643 (Al), 28 pp). This reagent can be prepared by electrochemical procedures (Prakash, G. K. S., Deffieux, D., Yudin, A. K. and Olah, G. A. Synlett, 1994, 1057-8). In most of these methods the actual trifluoromethyl starting components include CF3I, (Pawelke, G. J. Fluorine Chem., 1989, 42, 429-33) CF3Br (Ruppert, I., Schlich, K. and Volbach, W. Tetrahedron Lett., 1984, 25, 2195-2198; Ramaiah, P., Krishnamurti, R. and Prakash, G. K. S. Org. Synth., 1995, 72, 232-40), etc. Both CF3Br and CF3I are known ozone depleting gases and moreover their use is being regulated (Montreal protocol), which has resulted in slowing down the development of the synthesis of TMS-CF3 on a large industrial scale. Intuitively, the simplest and rather atom economical source of the CF3 moiety would be trifluoromethane (CF3H). A multi-step synthesis of TMS-CF3 (1) using trifluoromethane (via trifluoromethyl sulfide, sulfoxides and sulfones) and chlorosilanes using Mg mediated trifluoromethylation method has already been reported. (Prakash, G. K. S., Hu, J. and Olah, G. A. J. Org. Chem., 2003, 68, 4457-4463; Prakash, G. K. S., Hu, J. and Olah, G. A. 2004, US 2004/0230079 (Al), 33 pp). However, a direct trifluoromethylation of chlorosilanes with trifluoromethane to synthesize 1 and other higher trifluoromethylated silanes is still elusive. This is mainly due to the inherent and very well documented instability of trifluoromethyl anion even at very low temperatures. Trifluoromethyl anion (CF3 ~), due to its concentrated negative charge around the carbon atom, is known to decompose rapidly into fluoride ion (F ) and an electron deficient singlet carbene, difluorocarbene, (:CF2) (Prakash, G. K. S. and Mandal, M. J. Fluorine Chem., 2001, 112, 123-131; Large, S., Roques, N. and Langlois, B. R. J. Org. Chem., 2000, 65, 8848-8856; Billard, T., Bruns, S. and Langlois, B. R. Org. Lett., 2000, 2, 2101-2103; Billard, T., Langlois, B. R. and Blond, G. Eur. J. Org. Chem., 2001, 1467-1471; Russell, J. and Roques, N. Tetrahedron, 1998, 54, 13771-13782; Langlois, B. R. and Billard, T. Synthesis, 2003, 185-194).
Trifluoromethane, a by-product of the Teflon industry, is produced in large amounts on an industrial scale. Its efficient production has already been reported via fluorination of methane with hydrogen fluoride and chlorine. (Webster, J. L. and Lerou, J. J. 1995, US 5,446,218 (A) 8 pp Cont-in-part of US Ser No 51,917, abandoned). It is a non toxic, non ozone-depleting gas, but has a powerful greenhouse effect, which rules out its use as a refrigerant. Use of trifluoromethane gas in synthetic organic chemistry is a great challenge for a variety of reasons such as its low boiling point (bp = -83 °C), relatively high pKa (25-28), and low reactivity (being a relatively weak acid). On the other hand, this also can be considered as an interesting opportunity to develop synthetically useful methods by which one could convert an unused and accumulating byproduct, which is of environmental concern (because of green-house warming potential) into practical interests.
In 1991, Shono and others showed that an electrochemically generated base using 2- pyrrolidone can be used to deprotonate trifluoromethane, which generates in situ trifluoromethyl anion equivalent which then trifluoromethylates aldehydes and ketones (Shono, T., Ishifune, M., Okada, T. and Kashimura, S. J. Org. Chem., 1991, 56, 2-4). Troupel and others also showed that a strong base generated by cathodic reduction of iodobenzene can deprotonate trifluoromethane and consequently can then add to aldehydes (Barhdadi, R., Troupel, M. and Perichon, J. Chem. Commun., 1998, 1251-1252). Later on, two research groups have carried out extensive work where trifluoromethane is used as a source of trifluoromethyl anion. Normant et al. published their work on trifluoromethylation of aldehydes by deprotonation of trifluoromethane using Dimsyl-K (base generated from DMSO) in DMF (Folleas, B., Marek, I., Normant, J.-F. and Jalmes, L. S. Tetrahedron Lett., 1998, 39, 2973-2976). It was postulated that an adduct of CF3 ~ and DMF (hemiaminolate) acts as a reservoir of CF3 " anion and it was the true trifluoromethyl transfer intermediate. Subsequently, Langlois, Roques and others reported trifluoromethylation of aldehydes, non- enolizable ketones and disulfides with an excess of CF3H and strong bases in DMF as a solvent, all of these are included herein as a reference (Large, S., Roques, N. and Langlois, B. R. J. Org. Chem., 2000, 65, 8848-8856; Roques, N., Russell, J., Langlois, B., Saint- Jalmes, L., Large, S. and et, a. 1998, WO 98/22435 (Al),105 pp; Roques, N. and Russell, J. 1997, US 6,355,849 (Bl), 32 p; Langlois, B., Billard, T. and Garlyauskayte, R. 2003, FR 2827285 (Al), 22 pp). However, this method is limited to the use of dimethylformamide (or any amide containing reagent) to trap the trifluoromethyl anion in a hemi-aminolate and in absence of which the reaction does not seem to work well. In addition, in all of the reported reactions excess of trifluoromethane was used to achieve the desired trifluoromethylation reactions.
Based on the above, it is quite clear that there is a need to develop newer more direct trifluoromethylation methods, which use trifluoromethane as a direct trifluoromethylating source. These methods should be synthetically useful and versatile; practical, unrestricted (without any prerequisite solvent trap such as DMF) in terms of solvents used for the reaction and without the use of excess of trifluoromethane gas. Most beneficial would be a single step reaction between trifluoromethyl anion (CF3 ~), generated in situ from trifluoromethane and a given electrophile under suitable reaction conditions. Such methods would not only solve the environmental problem, which we face in future due to excess accumulation of this gas but would also provide practical synthetic applications.
SUMMARY OF THE INVENTION
The present invention relates to a method for preparing a trifluoromethylated substrate, which comprises reacting a fluoromethylatable substrate with a trifluoromethylating agent in the presence of a base under conditions sufficient to trifluoromethylate the substrate. The fluoromethylatable substrate generally comprises a compound selected from the group consisting of chlorosilanes, carbonyl compounds such as esters, aryl halides, aldehydes, ketones, chalcones, alkyl formates, alkyl halides, aryl halides, alkyl borates, carbon dioxide and sulfur. Also, the preferred trifluoromethylating agent is trifluoromethane.
The substrate typically comprises chlorotrimethylsilane, chlorotriethylsilane, chlorotriisopropylsilane, chloro(t-butyldimethyl)silane, chloro(tris(trimethylsilyl)) silane, dichlorodiethylsilane, benzaldehyde, / anisaldehyde, 3-methylbenzaldehyde, 1- anthracenaldehyde, furan-2-carboxaldehyde, benzophenone, 4-methoxybenzophenone, 4- methylbenzophenone, 3-nitrobenzophenone, 4-fluorobenzophenone, chalcone, 4'- methoxychalcone, 4'-nitrochalcone, 4,4'-difluorochalcone, 4'-chlorochalcone, methyl benzoate, benzyl bromide, iodobenzene, 1-iodonaphthalene, 2-Iodoanisole, 3- nitroiodobenzene, 2-iodotoluene, 3-iodo-2-methoxynitrobenzene, 3-iodobenzotrifluoride, 2- iodopyridine, 3-iodopyridine, trimethoxyborate, tributylborate, elemental sulfur, methyl formate, or ethyl formate. When a ketone or carbonyl compound is used, it is preferably a non-enolizable compound.
The reaction is typically carried out in the presence of a solvent. For example, for trifluoromethylation of aryl halides the solvent is a polar aprotic solvent. Generally, however, the solvent is tetrahydrofuran (THF), diethyl ether, polyethers, hydrocarbon solvents (toluene, benzene, etc.), dimethyl ether, dimethoxymethane (Glyme), dimethylformamide (DMF), N- methylpyrrolidone (NMP), hexamethyl phosphoric triamide (HMPA), dimethyl sulfoxide (DMSO), preferably dimethylformamide (DMF).
The base comprises an alkoxide (polyalkoxide) or alkali metal salt of silazane (polysilazane) or a combination thereof. Also, the reaction conditions generally include a temperature of between about -90°C to about 130°C for a time between 30 minutes to 24 hours. A skilled artisan can determine the optimum conditions for any particular reactants by routine experimentation.
When the fluoromethylatable substrate comprises chlorosilanes, aldehydes, methyl benzoate, chalcones or non-enolizable ketones, the trifluoromethylating agent is trifluoromethane, and the base comprises an alkoxide (polyalkoxide) or alkali metal salt of silazane (polysilazane) or a combination thereof, the method further comprises adding the base to a mixture that includes the substrate and the trifluoromethylating agent to form a reaction mixture, stirring the reaction mixture at about -80°C to -70°C and warming the reaction mixture to about room temperature to trifluoromethylate the substrate. The reaction mixture is warmed to about room temperature for about 2 to 20 hours. Advantageoulsy, the reaction mixture is stirred vigorously either by magnetic stirring or mechanical stirring methods at all times.
When the fluoromethylatable substrate comprises aryl halides, the trifluoromethylating agent is trifluoromethane, and the base comprises an alkoxide (polyalkoxide) or alkali metal salt of silazane (polysilazane) or a combination thereof, the method further comprises adding the trifluoromethylating agent to a mixture of a copper halide, a heterocyclic ligand containing 1-10 heteroatoms, the solvent and the aryl halide followed by addition of the base to form a reaction mixture, stirring the reaction mixture at about 80 to 120 °C and cooling the reaction mixture to about room temperature to trifluoromethylate the substrate.
When the fluoromethylatable substrate comprises trialkylborates, these can be converted in situ to trifluoromethyltrifluoroborates. When the fiuoromethylatable substrate is elemental sulfur, it can be trifluoromethylated to a trifluoromethylated sulfur intermediate, which can then be oxidized in situ to form trifluoromethanesulfonic acid.
Preferred trifluoromethylated products include trifluoromethyl(trimethyl)silane, trifluoromethyl(triethyl)silane, trifluoromethyl(triisopropyl)silane, (trifluoromethyl)t- butyldimethylsilane, tris(trimethylsilyl)trifluoromethylsilane, diethyl bis(trifluoromethyl)silane, 2,2,2-trifluoro- 1 -phenylethanol, 2,2,2-trifluoro- 1 -(4- methoxyphenyl)ethanol, 2,2,2-trifluoro- 1 -m-tolylethanol, 2,2,2-trifluoro- 1 -(furan-2- yl)ethanol, 1 -(anthracen-9-yl)-2,2,2-trifluoroethanol, 2,2,2-trifluoro- 1 , 1 -diphenylethanol, 2,2,2-trifluoro- 1 -(4-methoxyphenyl)- 1 -phenylethanol, 2,2,2-trifluoro- 1 -phenyl- 1 -p- tolylethanol, 2,2,2-trifluoro- 1 -(3-nitrophenyl)- 1 -phenylethanol, 2,2,2-trifluoro- 1 -(4- fluorophenyl)- 1 -phenylethanol, (E)- 1,1,1 -trifluoro-2,4-diphenylbut-3-en-2-ol, (E)- 1,1,1- trifluoro-2-(4-methoxyphenyl)-4-phenylbut-3-en-2-ol, (E)- 1,1,1 -trifluoro-2-(4-nitrophenyl)-4- phenylbut-3-en-2-ol, (E)- 1,1,1 -trifluoro-2,4-bis(4-fluorophenyl)but-3-en-2-ol, (E)-2-(4- chlorophenyl)-l,l,l-trifluoro-4-phenylbut-3-en-2-ol, 2,2,2-trifluoro- 1-phenylethanone, 2,2,2- trifluoroethyl)benzene, (trif uoromethyl)benzene, 1-trif uoromethylnaphthalene, l-methoxy-2- (trifluoromethyl)benzene, 1 -nitro-3-(trifluoromethyl)benzene, 1 -methyl-2-
(trifluoromethyl)benzene, 2-methoxy- 1 -nitro-3-(trifluoromethyl)benzene, 1,3- bis(trifluoromethyl)benzene, 2-(trifluoromethyl)pyridine, 3 -(trifluoromethyl)pyridine, potassium (Trifluoromethyl)trifluoroborate, trifluoromethanesulfonic acid, l-methoxy-2,2,2- trifluoroethanol, or l-ethoxy-2,2,2-trifluoroethanol.
The invention also relates to the use of a trif uoromethylating agent for trifluoromethylating a fiuoromethylatable substrate in the presence of a base under conditions sufficient to trif uoromethylate the substrate. As noted herein, the fiuoromethylatable substrate generally comprises a compound selected from the group consisting of carbonyl compounds, chlorosilanes, esters, aryl halides, aldehydes, ketones, chalcones, alkyl halides, alkyl formates, alkyl borates, carbon dioxide, and sulfur, and the preferred trifluoromethylating agent is trif uoromethane. BRIEF DESCRIPTION OF THE DRAWING FIGURES
The benefits and advantages of the present invention will become better known and understood upon a review of the following detailed description in combination with the appended drawing figures, wherein: Figure 1 is a graph of the results of a low temperature 19F NMR spectroscopic experiment.
DETAILED DESCRIPTION OF THE INVENTION
The purpose and advantages of the present invention will be set forth in and will become apparent from the description that follows, as well as will be learned by the practice of the invention. Additional advantages of the invention will be realized and attained by the reactions particularly pointed out in the written description and claims hereof, as well as from the appended figures. To achieve these and other advantages and in accordance with the purpose of the invention, as embodied and described herein, the invention includes a convenient method of trifluoromethylation of a fluoromethylatable substrate or compound as noted as an example of a trifluoromethylating agent.
There has been a long standing interest, over the years, in improving synthetic methods for direct trifluoromethylation using trifluoromethane as a trifluoromethylating agent. New direct trifluoromethylation methods, using trifluoromethane (CF3H) as a "trifluoromethyl" source, to trifluoromethylate chlorosilanes, carbonyl compounds such as esters, aryl halides, aldehydes, ketones, chalcones, alkyl formates, alkyl halides, aryl halides, alkyl borates, carbon dioxide and sulfur are disclosed herein. The details of these methods are discussed below.
The invention now provides a direct trifluoromethylation method preferably using a trifluoromethane as a fluoromethylating species and trifluoromethylating agent. A fluoromethylatable substrate or compound is the one that is capable of being trifluoromethylated in this fluoromethylation process. A "trifluoromethylating species" as the term used herein is for an agent capable of generating a trifluoromethylating species that is capable of forming a bond with the fluoromethylatable substrate.
In particular, the present method is used for preparing a trifluoromethylated substrate by reacting a fluoromethylatable substrate with a trifluoromethylating agent in the presence of an alkoxide, polyalkoxide or metal salt of silazane (polysilazane) under conditions sufficient to trifluoromethylate the substrate; wherein the fluoromethylatable substrate preferably comprises a compound selected from the group consisting of carbonyl compounds, chlorosilanes, aldehydes, ketones, chalcones, esters, alkyl halides, alkyl formates, aryl halides, alkyl borates and sulfur. The most preferred trifluoromethylating agent is trifluoromethane. Thus, in the description that follows, reference will be made to this preferred embodiment. Specific electrophiles of the following nature are included in the invention:
1. R3-S1-X, where R could be substituted or unsubstituted alkyl or aryl groups and X could be any halogen except fluorine (F), preferably chlorine (CI).
2. Carbonyl compounds of the general formula R-CO-R' where R, R' = H, alkyl, aryl, O-alkyl and -CH=CH-Ar groups.
3. R-CH2-X, where R could be substituted or unsubstituted alkyl or aryl groups and X could be any halogen except fluorine (F).
4. Ar-X, where Ar could be substituted or unsubstituted aryl ring and X could be any halogen except fluorine (F), preferably iodine (I). 5. B(OR)3, where R could be substituted or unsubstituted alkyl or aryl groups.
6. Carbon dioxide.
7. Any source of sulfur including all of the oxidation states of sulfur such as S(II), S(IV), etc., with the most preferred source being elemental sulfur.
All the reactions are preferably performed under an inert atmosphere. Solvents used herein but are not limited to etheral solvents (for carbonyl and R-CH2-X containing substrates), which contain at least one oxygen atom and in some cases hydrocarbons (containing only carbon and hydrogen) solvents with the absence of any heteroatoms. Polar solvents containing an amide functionality (R-CO-NR', R, R'= H, substituted or unsubstituted alkyl or aryl group) were used for aryl halides (Ar-X). Reactions can be performed in the temperature range of -78 °C to 130 °C, preferably at -78 °C in the first step of the reaction in case of halosilanes, -40 °C, for carbonyl and R-CH2-X containing substrates and 130 °C for aryl halides. The preferred bases for this reaction comprises an alkoxide, polyalkoxide or alkali metal salt of silazane or a combination thereof and in particular are potassium salts of silazanes and polysilazanes, which contain nitrogen atoms (between 1-5, preferably 1) and silicon atoms (between 1-10, preferably 2) or alcohols with suitably branched alkyl group containing 1-20, preferably between 3-10 carbon atoms, with tertiary butyl being most preferred.
Base is dissolved in an appropriate solvent before the reaction and was present as slurry at the temperature at which the reaction is carried out. The reaction time could be between 1-20 hours, preferably 1-5 hours for halosilanes and 1-16 hours for carbonyl substrates and aryl halides.
In a preferred embodiment of the invention, the alkoxide, polyalkoxide or silazane (polysilazane) salt base is added to a mixture containing the substrate and trifluoromethylating agent. The reaction mixture is stirred at a first temperature, and is then warmed to a second temperature. Preferably the mixture is warmed to room temperature, around 20 to 25 °C, for about 2 to 20 hours and preferably for about 5-6 hours.
1. Fluoromethylation of Silicon containing substrates All the reaction conditions have been carefully optimized for each type of substrate.
The parameters which needed to be optimized include equivalent of trifluoromethane, base and substrate. Optimization in the amount of solvent was also helpful (see Table 1 for the details of optimization conditions). Trifluoromethane gas is known to form hydrogen bonds (and hence dissolves readily) with many of the etheral solvents. Initial reactions were performed in dry tetrahydrofuran (THF). It is known that trifluoromethane forms a hydrogen bond with the oxygen of THF and hence has a good solubility in THF. Initial attempt to deprotonate trifluoromethane with a commercial solution of potassium hexamethyldisilazide (1M in THF) in the presence of trimethylsilyl chloride (TMS-C1) at -40 °C, yielded, along with many other peaks, a new fluorine peak in 19F NMR at -67.3 ppm, which corresponded to the chemical shift of trifluoromethyl group in (trifluoromethyl)trimethylsilane (TMS-CF3). Optimization of all the reaction conditions was carried out to maximize the yield of trifluoromethylation of chlorosilane and minimize any side reactions to form other byproducts such as TMS-F (observed as a major side product in this reaction). The order of addition of all the reagents was optimized and the best optimized conditions in THF appeared to be the ones in which trifluoromethane was bubbled in dry THF at -78 °C followed by addition of neat TMS-C1. This mixture was stirred at -78 °C for few minutes before the addition of KHMDS (1M in THF solution) drop wise slowly with very efficient stirring. NMR (19F) of a reaction mixture aliquot removed after 15 minutes of stirring at -78 °C showed desired trifluoromethylated product in good conversion (-44%, by 1H NMR, internal standard, PhCF3).
Presence of potassium ions in reaction mixture is important which is also evident from the previous observations in the literature (Billard, T., Langlois, Bernard R. and Blond, G. Eur. J. Org. Chem., 2001, 1467-1471). In addition to this, isolation and purification of TMS- CF3 was extremely difficult when the reactions were performed in THF. Separation of TMS- CF3 from the tristrimethylsilylamine, which was formed in the reaction as a side product, was difficult. Therefore, other solvents were examined for this transformation. While most etheral solvents work very well for the transformation, toluene (an aromatic hydrocarbon solvent) as a solvent seemed to work well with minimum formation of TMS-F under the optimized conditions. Reaction conditions were then optimized in toluene (an aromatic hydrocarbon solvent), and with the optimized procedure the percent conversion to TMS-CF3 was greater than 90% and the pure product was isolated by distillation in overall 80% yield (See Table 1).
Optimization of Reaction Conditions for the direct trifluoromethylation of trimethylsilyl chloride (TMS-C1) using trifluoromethane (CF3H)
Figure imgf000012_0001
CH3 Temperature CH3
Figure imgf000012_0002
% Conversion
TMS- Temp.
Entry CF3H Base (eq) Solvent to 1 by 19F
Cl (eq) °C
NMR
0.1 M
16 KHMDS (1 eq)
0.2 (1 eq) 1 -78 THF 63
0.46 M
17 KHMDS (1 eq)
(1 eq) 1 -78 THF 63
0.5 M
18 KHMDS (1 eq)
(1 eq) i -78 THF 70
0.7 M
19 KHMDS (1 eq)
(1 eq) i -78 THF 66
1 M
20 KHMDS (1 eq)
(1 eq) i -78 THF 54
3.06 M
21 KHMDS (1 eq)
(1 eq) i -78 THF 55
0.5 M
22 KHMDS (1 eq)
(1 eq) i -78 Toluene 68
23 1 eq KHMDS (1 eq) 1.05 -78 Toluene 97 (80)*
24 1 eq KHMDS (1 eq) 1.05 -78 Diethyl ether 96
-isolated yield (see experimental section)
With the current interest in palladium catalyzed trifluoromethylation reactions, other trifluoromethylsilanes [such as trifluoromethyltriethylsilane (TES-CF3)] are becoming increasingly important source of the trifluoromethyl group because of their higher boiling points. The developed protocol was extended to synthesize other synthetically important trifluoromethylated silanes in good yields using ether as a solvent since the boiling points of most of the trifluoromethylated silanes were very close to the boiling point of toluene. Synthetic preparations of other trifluoromethylated silanes are very well established in the literature using trifluoromethyl halides, however, to the best of inventor's knowledge, the highest reported yield of (trifluoromethyl)triisopropylsilane is 9 % whereas with the present methodology, the same compound can be obtained in 78% isolated yield (Table 2). Table 2: Direct Trifluoromethylation of silyl chlorides using trifluoromethane (CF3H)
Figure imgf000014_0001
In addition to monotrifluoromethylation reactions, bistrifluoromethylation of dichlorodimethylsilane and dichlorodiethylsilane using this methodology to obtain bis (trifluoromethyl)dimethylsilane and bis(trifluoromethyl)diethylsilane, previously inaccessible compounds, respectively, in good yields. However, isolation of bis (trifluoromethyl) dimethyl silane was difficult owing to its low boiling point (bp 30 °C). The same methodology can also be applied to synthesize phenyltris(trifluoromethyl)silane (from trichlorophenylsilane), however, other products (based on 19F NMR) were observed in the reaction. Similarly, tetrakis(trifluoromethyl)silane (from silicon tetrachloride) was observed by 19F NMR along with other fluorinated products (possibly, mono, bis and tris trifluoromethylated silanes). Due to complexity of the 19F NMR, isolation and purification of these tris and tetrakis (trifluoromethylated) products was not pursued further.
2. Fluoromethylation of carbon electrophiles (aldehydes, non-enolizable
ketones, chalcones, aromatic esters, benzyl halides and alkyl formates)
Trifluoromethylation of aldehydes and non-enolizable ketones from fluoroform has already been reported. However, in all cases, excess of trifluoromethane was used and most of the reactions were carried out in presence of dimethylformamide (DMF), either as a solvent or in catalytic amounts. Encouraged by the results of trifluoromethylation of silanes in non polar solvents such as ether or toluene, trifluoromethylation of aldehydes and non-enolizable ketones was pursued under newly discovered reaction conditions. Trifluoromethylation of non-enolizable ketones went uneventfully and the corresponding trifluorometylated products were obtained in good yields using KHMDS to deprotonate trifluoromethane in using diethyl ether as a solvent. More importantly, trifluoromethane used was in equimolar amounts compared with the ketone and KHMDS (Table 3). In case of enolizable ketones, aldol condensation prevailed in ether, in THF and toluene the trifluoromethylated products were absent.
Table 3: Direct trifluoromethylation of aldehydes, non-enolizable ketones, chalcones, esters, alkyl halides and formates using trifluoromethane (CF3H)
Figure imgf000015_0001
Figure imgf000016_0001
- % Conversion based on F NMR analy
Not surprisingly, in case of aldehydes, when KHMDS was used as a base to deprotonate trifluoromethane in THF, none of the trifluoromethylated products were observed because of competitive Cannizaro reaction between two aldehydes molecules under the reaction conditions employed. However, when the reaction was carried out in dry THF (in complete absence of DMF) and with t-BuOK instead of KHMDS, trifluoromethylation of aromatic aldehydes was achieved, albeit in low yields, even with the use of one equivalent of trifluoromethane .
Mechanistically, the reaction to produce TMS-CF3 seem to proceed by deprotonation of trifluoromethane with potassium hexamethyldisilazide to generate trif uoromethyl anion, which immediately forms a pentacoordinated silicon species (A) with TMS-C1 which eventually looses chloride ion and generates trifluoromethyl trimethylsilane (Scheme 1). Scheme 1 :
Figure imgf000017_0001
In order to ascertain whether this mechanism is viable and if species A can be observed spectroscopically, a low temperature experiment was performed. At -78 °C, CF3H was bubbled into a solution of toluene-dg and its 19F NMR spectra were recorded. To this NMR tube, a solution of potassium hexamethyldisilazide and TMS-Cl (which was made previously by mixing the two reagents in toluene at -78 °C) was added. Immediately, 19F NMR spectrum of this reaction mixture was recorded and collection of 19F NMR was continued for 20 minutes (at the interval of 5 minutes) and then the temperature of the NMR probe was gradually increased from -78 °C to Room Temperature (RT) over a period of 45 mins. The first spectrum recorded soon after the addition of base and TMSCl mixture showed presence of the product peak (TMS-CF3) in addition to the unreacted CF3H doublet in 19F NMR (Figure 1). None of the substantial additional peaks in 19F NMR, besides a peak near 156 ppm which corresponds to TMS-F (a side product in this reaction) were observed. However, a small peak at -83 ppm was observed in all cases but unfortunately at this point its identity is not known. However, this experiment shows that the rate of formation of TMS-CF3 is very rapid, which could be explained by the well known affinity of CF3 anion for the electropositive silicon center to form the pentacoordinated species such as A.
In the case of aldehydes and non-enolizable ketones, the mechanism of the direct trifiuoromethylation using trifluoromethane would be different (Scheme 2). While it has been known earlier that the "free" trifluoromethyl anion (CF3 ~) is unstable even at very low temperatures, as mentioned above, trifiuoromethylation of aldehydes (including formaldehyde) and non-enolizable ketones was achieved, directly from trifluoromethane after deprotonation without subsequent trapping/stabilization of trifluoromethyl anion (generated in situ) with any other species. Scheme 2:
ydes:
Figure imgf000018_0001
OH CF3 H -enolizable ketones:
Figure imgf000018_0002
This methodology was extended to other electrophilic substrates such as chalcones, aromatic esters, benzyl halides, Cu salts, etc. Benzyl halides (chloride, bromide and iodide) showed only 10% conversion (by 19F NMR analysis) to the corresponding trifluoromethylated products and major product observed by NMR was the formation of benzyl fluoride. Aromatic esters also gave corresponding trifluromethylated ketones in 30% conversion (by 19F NMR analysis). Similarly, trifluoromethylation of both ethyl formate and methyl formate gave trifluoroacetaldehyde ethyl hemiacetal and trifluoroacetaldehyde methyl hemiacetal in about 20% conversion based on 19F NMR analysis. 3. Fluoromethylation of Aromatic Halides
Trifluoromethylation of aromatic halides using copper salts have already been reported (Kobayashi, Y. and Kumadaki, I. Tetrahedron Lett., 1969, 4095-6; McLoughlin, V. C. R. and Thrower, J. Tetrahedron, 1969, 25, 5921-40; Kobayashi, Y., Yamamoto, K. and Kumadaki, I. Tetrahedron Lett., 1979, 4071-2; Matsui, K., Tobita, E., Ando, M. and Kondo, K. Chem. Lett., 1981, 1719-20; Umemoto, T. and Ando, A. Bull. Chem. Soc. Jpn., 1986, 59, 447-52; Carr, G. E., Chambers, R. D., Holmes, T. F. and Parker, D. G. J. Chem. Soc, Perkin Trans. 1, 1988, 921-6; Clark, J. H., McClinton, M. A. and Blade, R. J. J. Chem. Soc, Chem. Commun., 1988, 638-9; Chen, Q. and Wu, S. J. Chem. Soc, Chem. Commun., 1989, 705-6; Willert-Porada, M. A., Burton, D. J. and Baenziger, N. C. J. Chem. Soc, Chem. Commun., 1989, 1633-4; Su, D., Duan, J. and Chen, Q. Tetrahedron Lett., 1991, 32, 7689-90; Paratian, J. M., Sibille, S. and Perichon, J. J. Chem. Soc, Chem. Commun., 1992, 53-4; Chen, Q. and Duan, J. J. Chem. Soc, Chem. Commun., 1993, 1389-91; Heaton, C. A., Miller, A. K. and Powell, R. L. J. Fluorine Chem., 2001, 107, 1-3; Cottet, F. and Schlosser, M. Eur. J. Org. Chem., 2002, 327- 330; Xiao, J.-C, Ye, C. and Shreeve, J. n. M. Org. Lett., 2005, 7, 1963-1965; Dubinina, G. G., Furutachi, H. and Vicic, D. A. J. Am. Chem. Soc, 2008, 130, 8600-8601; Dubinina, G. G., Ogikubo, J. and Vicic, D. A. Organometallics, 2008, 27, 6233-6235; Oishi, M., Kondo, H. and Amii, H. Chem. Commun., 2009, 1909-1911; Sato, K., Tarui, A., Omote, M., Ando, A. and Kumadaki, I. Synthesis, 2010, 1865-1882; Lundgren, R. J. and Stradiotto, M. Angew. Chem., Int. Ed., 2010, 49, 9322-9324; Morimoto, H., Tsubogo, T., Litvinas, N. D. and Hartwig, J. F. Angew. Chem. Int. Ed., 2011, 50, 3793-3798). However, the reagents used as a source of trifluoromethyl group have been silyl trifluoromethyl reagents or trifluoromethyl halides. Direct trifluoromethylation of unsubstituted aromatic halides using trifluoromethane (CF3H) has not been reported and hence it was pursued. Initially, reactions were carried out in DMF as a solvent. Optimization of the reaction conditions are reported in Table 3. For the convenience of handling the corresponding trifluoromethylated products, 1-iodonaphthalene was chosen as the starting aromatic halide instead of iodobenzene (naphthyl-CF3, bp = 215 °C vs Ph-CF3 bp = 103 °C).
As evident from Table 4, direct trifluoromethylation of aromatic iodide has been achieved using trifluoromethane as a trifluoromethyl source in moderate yields (~ 50%). Unfortunately, in the presence of 1,10-phenanthroline as a ligand, we did not observe any "CuCF3" species in the 19F NMR of the reaction mixture at room temperature or even at low (-10 °C) or high (100 °C) temperatures. However, in absence of 1,10-phenanthroline and in presence of an additive, a relatively stable CuCF3 species was observed in 19F NMR. Reactions can be carried out in the presence or in absence of the ligand, however reactions which do not use any ligand gave better yields of the corresponding trifluoromethylated arenes. Additives could be any acid component (such as HF) or even crown ethers, which can coordinate potassium ions in the reaction mixture and avoid decomposition of CuCF3 species via Cu=CF2 carbenoid intermediates. Mechanistically, formation of hemiaminal of DMF (as a reactive species, when reaction was carried out in DMF) can be ruled out as a "CF3" trapping species because HMPA (hexamethylphosphoric triamide), which cannot act as a trapping species also yielded 50% of the desired product under the identical reaction conditions (compare entries 3 vs 26, Table 2). Using the methodology described above, a variety of aryl halides have been trifluoromethylated directly using trifluoromethane trifluoromethylating reagent and the results obtained are summarized in Table 5.
Table 4: Optimization of Reaction Conditions for the direct trifluoromethylation of Aryl halides (Ar-X) using trifluoromethane (CF3H).
Base (E)
Temperatu
Ar-X + CF3H + CuX + 1 ,10-Phenanthroline Ar-CF3
OR Time
any additive Solvent F
x =
Figure imgf000020_0001
1.5
1 1 2 2 2 100 5 DMF nd 0
(NaH)
2 1 2 2 2 5 100 5 DMF nd 203 1 2 2 2 2 RT 24 DMF nd 204 1 3 2 2 2 RT 24 Toluene nd 05 1 3 3 3 3 100 5 DMF nd 606 1 2 2 2 2 100 5 HMPA nd 50
TREAT-HF
7 1.5 (Ph-I) 3 1 2 50 24 DMF 87 35
(0.4 eq)
nd- % yield not determined *-yield determined using CeFe as an internal reference
Table 5: Trifluoromethylation of aryl halides using trifluoromethane (CF3H).
Figure imgf000021_0001
:- % jze i determined using CeFe as an internal reference by F NMR 4. Fluoromethylation of trialkyl borates
Nucleophilic trifluoromethylation using organoboron reagents, specifically potassium trialkyl trifluoroborates, is becoming increasingly popular. The most common electrophiles include non-enolizable aldehydes, N-tosylimines (Levin, V. V., Dilman, A. D., Belyakov, P. A., Struchkova, M. I. and Tartakovsky, V. A. Tetrahedron Lett., 2011, 52, 281-284), aryl iodides (Knauber, T., Arikan, F., Roeschenthaler, G.-V. and Goossen, L. J. Chem.— Eur. J., 2011, 17, 2689-2697, S2689/1-S2689/83) and more recently aryl boronates (Khan, B. A., Buba, A. E. and Goossen, L. J. Chem.-Eur. J., 2012, 18, 1577-1581).
Syntheses of the above-mentioned organoboron reagents (potassium trialkyltrifluoromethyl borates) is reported in the literature (Molander, G. A. and Hoag, B. P. Organometallics, 2003, 22, 3313-3315; Kolomeitsev, A. A., Kadyrov, A. A., Szczepkowska- Sztolcman, J., Milewska, M., Koroniak, FL, Bissky, G., Barren, J. A. and Roeschenthaler, G.- V. Tetrahedron Lett., 2003, 44, 8273-8277). However, all of the reported methods use (trifluoromethyl)trimethylsilane (TMS-CF3) as a source of trifluoromethyl group. A direct trifluoromethylation of trialkyl borates using trifluoromethane (CF3H) is not reported. Based on our results with chlorosilanes, we pursued trifluoromethylation of trialkyl borates using trifluoromethane (CF3H) as a direct source of trifluoromethyl anion. Trifluoromethylation of trialkyl borates (trimethyl borate and tri(n-butyl) borate) was achieved using trifluoromethane (1 equivalent) and KHMDS as a base in THF at -5 °C to RT. While potassium trif uoromethyltrimethyl borate (CF3-B(OMe)3K) was observed by 19F NMR in good yield (compared to internal standard C6F6), isolation of the salt in its pure form from the reaction mixture was difficult. This could possibly be due to the unreacted KHMDS being present in the reaction mixture which decomposed the desired product by further reacting with it. Hence we decided to f uorinate the potassium trifluoromethyltrimethyl borate using 48% HF (aq) in situ and isolate the corresponding potassium trifluoromethyltrifluoroborate salt. This transformation occurred smoothly and we were able to isolate both potassium trifluoromethyltrifluoroborate salts from both potassium trifluoromethyltrimethyl borate and potassium trifluoromethyltri-n-butyl borate (Scheme 3). This shows that trifluoromethylation of trialkyl borates can be achieved directly from trifluoromethane under basic conditions in THF, again in complete absence of DMF. This also proves that the "naked" trifluoromethyl anion formed after deprotonation of trifluoromethane can be used directly as a trifluoromethyl source (CF3 source) without any stabilization of the anion as opposed to previous claims in the literature (Large, S., Roques, N. and Langlois, B. R. J. Org. Chem., 2000, 65, 8848-8856; Billard, T., Bruns, S. and Langlois, B. R. Org. Lett., 2000, 2, 2101-2103; Billard, T., Langlois, B. R. and Blond, G. Eur. J. Org. Chem., 2001, 1467-1471; Russell, J. and Roques, N. Tetrahedron, 1998, 54, 13771-13782; Langlois, B. R. and Billard, T. Synthesis, 2003, 185- 194).
Scheme 3: Direct trifluoromethylation of trialkyl borates using trifluoromethane (CF3H).
Figure imgf000023_0001
Figure imgf000023_0002
5. Fluoromethylation of Elemental Sulfur
Direct trifluoromethylation of elemental sulfur using trifluoromethane and subsequent oxidation of the products obtained would be the most logical and direct synthesis of trifluoromethanesulfonic acid (CF3SO3H, trifluoromethanesulfonic acid). Incidentally, this approach has been attempted in the literature (Mukhopadhyay, S., Bell, A. T., Srinivas, R. V. and Smith, G. S. Org. Process Res. Dev., 2004, 8, 660-662) albeit with only limited success (1.5% yield based on CF3H). This method uses CF3H in excess, and is carried out in DMF as a solvent, which is known to trap trifluoromethyl anion (CF3 ).
Based on the success with direct trifluoromethylation using CF3H, direct trifluoromethylation of elemental sulfur (one of the cheapest source of sulfur available) was achieved. After carefully screening a variety of reaction conditions such as form of sulfur (activated, sublimed, etc.), solvents (THF, Toluene, etc), temperatures (-80 to room temperature), reaction times (l-24h), etc., a method was developed to directly trifluoromethylate elemental sulfur. The method does not use excess of CF3H and is not carried out in DMF. The intermediate products (trifluoromethylated sulfur species, CF3Sn) obtained were subjected to complete oxidation using H2SO4/ 30%> H202 to obtain trifluoromethanesulfonic acid (CF3SO3H) in 18% conversion (NMR analysis, Scheme 4). The reaction can be further optimized to achieve higher conversions.
Scheme 4: Direct trifluoromethylation of elemental sulfur using trifluoromethane (CF3H).
2 eq KH DS 30% H202
CF3H -f" Sg CF3Sn CF3SO3H 1 eq 2 eq THF, -78 °C H,SO,
18% by 100% by
3h to rt
19F NMR 9F NMR
from
CF3Sn
EXAMPLES
General: CF3H was used from Synquest Laboratories and was used as received. A gas mass flow controller from Aalborg (GFC-17) was used and was calibrated for CF3H. Potassium hexamethyldisilazide (solid) was purchased from Aldrich and was stored under argon in a dry box. Commercially available solutions of potassium hexamethyldisilazide, both in THF and toluene, were purchased from Gelest Inc. and were used as received. All the chlorosilanes were purchased from Gelest Inc. and were used as received except for chlorotrimethylsilane (TMSC1), which was freshly distilled over calcium hydride just prior to the reaction. All other electrophiles were purchased from commercial sources such as Aldrich or other chemical suppliers and were used as received. All the reactions were carried out
1 13 29 11 under argon atmosphere using dry solvents unless mentioned otherwise. H, C, Si, B and 19F NMR were recorded on 400 MHz NMR instrument with CDC13 (containing CFC13 for 19F, boric acid for UB, TMS for 29Si as standards for respective chemical shift values).
EXAMPLE 1
Preparation of Trifluoromethyl(trimethyl)silane:
To a 1000 ml three necked round bottom flask with a magnetic stirrer was added 376 ml of commercially available solution of potassium hexamethyldisilazide (0.6 M in toluene). This solution was then cooled to -85 °C using acetone/liquid nitrogen cooling bath for 20 minutes. A freshly distilled chlorotrimethylsilane (30 ml) was then added drop wise to the solution of hexamethyldisilazide in toluene. Resulting reaction mixture was stirred at -85 °C for 20 minutes. After 20 minutes, CF3H was bubbled in to the reaction mixture for 1 hour 38 minutes (15.8 g, bubbling rate 52.5 ml/min). After the bubbling of CF3H was over the resulting reaction mixture was stirred vigorously at -85 °C for 5 hours. After 5 hours, the resulting reaction mixture was slowly warmed to room temperature and then was stirred at room temperature for 2 hours. After 2 hours, air condenser along with head distillation apparatus with the thermometer was attached and reaction mixture was distilled. Fractions in the temperature range of 25-45 °C were collected as minor fractions and a major fraction was collected between 52-58 °C. Major fraction contained mainly TMSCF3 and (some) TMS-F mixture. This fraction was distilled again to obtain pure Trifluoromethyl(trimethyl)silane (TMSCF3) 25.8 g, 80% yield. 1H NMR (400 MHz): δ 0.27 (s); 13C NMR (100.5 MHz): δ - 5.18 (s, CH3), 132.23 (q, .¥ = 322 Hz, CF3). 19F NMR (376.3 MHz): δ -67.3 (s); 29Si NMR (79.5 MHz): δ 4.1 (q, 2JSi-F = 37.9 Hz, 1 Si).
EXAMPLE 2
Preparation of Trifluoromethyl(triethyl)silane:
To a 250 ml round bottom flask with magnetic stirrer, under argon was added 140 ml of diethyl ether. This reaction flask was cooled to -78 °C using dry ice/acetone bath and was stirred at that temperature for ten minutes. After ten minutes, CF3H was bubbled into this ether solution for 16 min 17 sec (2.5g was added total at the rate of 52.5 ml/min to obtain 0.25 M solution in ether). After 10 minutes, chlorotriethylsilane (5.32 g) was added to the reaction mixture dropwise and the resulting reaction mixture was stirred at -78 °C for ten minutes. After ten minutes, a solution of potassium hexamethyldisilazide in ether (7.4 g in 52 ml, 0.625 M solution in ether) was added dropwise to the reaction mixture and the resulting yellowish reaction mixture was stirred at -78 °C for 2 hours and then was gradually warmed to room temperature and stirred at room temperature for 1 hour. Ether was removed under vacuo and the residue obtained was dissolved in pentane (150 ml). Organic layer (pentane) layer was washed with water once (1 x 30 ml) and was further washed with cold concentrated sulfuric acid (98%) (4 x 15 ml) to remove most of the siloxane and silanols formed in the reaction. Organic layer was then washed with water (5 x 50 ml) until pH of the water showed neutral and dried over sodium sulfate. Solvent (pentane) was removed under vacuo to obtain crude product which was distilled under vacuo to obtain pure (trifluoromethyl)triethylsilane 4.6 g, 71 % yield. 1H NMR (400 MHz): δ 0.79 (q, 3JH_H = 7.9 Hz, 6 H), 1.04 (t, 3JH_H = 7.9 Hz, 9 H), 13C NMR (100.5 MHz): δ 0.86 (s, CH2), 6.53 (s, CH3), 132.24 (q, C-F = 324 Hz, CF3), 19F NMR (376.3 MHz): δ -61.3 (s), 29Si NMR (79.5 MHz): δ 7.7 (q, 2JSI-F = 32 Hz, 1 Si).
EXAMPLE 3
Preparation ofTrifluoromethyl(triisopropyl)silane
A similar procedure to the one reported in EXAMPLE 2 was followed except chlorotriisopropylsilane (5.02g, 26 mmol, 1 eq) was used as the substrate to obtain (trifluoromethyl)triisopropylsilane 4.6 g, 78 % yield, bp 48 °C/10 mm Hg. 1H NMR (400 MHz): δ 1.15 (d, 3JH_H = 7.4 Hz, 18 H), 1.31 (m, 3 H); 13C NMR (100.5 MHz): δ 9.47 (s, CH), 17.9 (s, CH3), 132.5 (q, VC-F = 325 Hz, CF3); 19F NMR (376.3 MHz): δ -55.4 (s); 29Si NMR (79.5 MHz): δ 5.99 (q, 2JSi-F = 27 Hz, 1 Si).
EXAMPLE 4
Preparation of (Trifluoromethyl)t-butyldimethylsilane:
A similar procedure to the one reported in EXAMPLE 2 was followed except chloro(t- butyldimethyl)silane (5.02g, 33.3 mmol, 1 eq) was used as the substrate to obtain pure (trifluoromethyl)t-butyldimethylsilane 2.6g, 42.3 % yield. 1H NMR (400 MHz): δ 0.22 (s, 6 H), 1.01 (s, 9 H); 13C NMR (100.5 MHz): δ -8.73 (s, CH3), 26.0 (s, C-CH3), 132.0 (q, CF = 324 Hz, CF3); 19F NMR (376.3 MHz): δ -61.8 (s); 29Si NMR (79.5 MHz): δ 8.33 (s, 2JSi-F = 33.1 Hz, 1 Si).
EXAMPLE 5
Preparation of Tris(trimethylsilyl)trifluoromethylsilane:
A similar procedure to the one reported in EXAMPLE 2 was followed except chloro(tris(trimethylsilyl))silane (5.25g, 18.5 mmol, 1 eq) was used as the substrate to obtain pure tris(trimethylsilyl)trifiuoromethylsilane 4.04 g, 68 % yield. 1H NMR (400 MHz): δ 0.26 (s); 13C NMR (100.5 MHz): δ 0.49 (s, CH3), 136.8 (q, .¥ = 328 Hz, CF3); 19F NMR (376.3 MHz): δ -41.4 (s); 29Si NMR (79.5 MHz): δ -66.9 (q, 2JSi-F = 27 Hz, 1 Si), -12.5 (q, 2JSi-F = 4.4 Hz, 3 Si). EXAMPLE 6
Preparation of Diethyl bis(trifluoromethyl)silane:
A similar procedure to the one reported in EXAMPLE 2 was followed except dichlorodiethylsilane (5.12g, 32.5 mmol, 1 eq) was used as the substrate along with 2eq each of CF3H and KHMDS to obtain pure diethyl bis(trifluoromethyl)silane 3.2 g, 44 % yield. 1H NMR (400 MHz): δ 1.08 (m, CH2), 1.16 (m, CH3); 13C NMR (100.5 MHz): δ -1.10 (s, CH2), 5.55 (s, CH3), 128.6 (qq, .¥ = 319 Hz, 3.35 Hz, CF3); 19F NMR (376.3 MHz): δ -60.2 (s); 29Si NMR (79.5 MHz): δ -2.43 (sept, 2JSI-F = 39.4 Hz, 1 Si). EXAMPLE 7
Preparation of 2 ',2 ,2-trifluoro-l -phenylethanol:
To a 50 ml round bottom flask with stirrer under argon was added 15 ml of dry THF. This reaction flask was flushed with argon for 5 minutes before it was cooled to -40 °C using dry ice/acetone and was stirred at that temperature for ten minutes. After ten minutes, CF3H was bubbled into this THF solution for 2 min 10 sec (0.3 g, 4.8 mmol was added total at the rate of 52.5 ml/min). This reaction mixture was allowed to stir for ten minutes. After 10 minutes, benzaldehyde (0.5 g, 4.7 mmol) was added to the reaction mixture dropwise and the resulting reaction mixture was stirred at -40 °C for ten minutes. After ten minutes, a solution of potassium tert-butoxide (4.7 ml, 4.7 mmol, 1 M solution in THF) was added dropwise to the reaction mixture and the resulting yellowish reaction mixture was stirred at -40 °C for 1 hour and then was gradually warmed to room temperature and stirred at room temperature for 10 hours. THF was removed under vacuo and the residue obtained was dissolved in ether and washed with water (25 ml x 2) followed by brine (25 ml x 2). Organic layer was dried over sodium sulfate and ether was removed under vacuo to obtain crude product. Column purification with ethyl acetate :hexane (1 :9) gave pure product as colorless oil 0.41g (49.4%). 1H NMR (400 MHz): δ 2.54 (d, 4.53 Hz, 1H, OH), 5.03 (m, 1H, C-H), 7.42 (m, 3H, Ar-H), 7.48(m, 2H, Ar-H); 13C NMR (100.5 MHz): δ 67.2 (q, 2JC-CF3 = 34.1 Hz, C-CF3), 110.1, 110.7, 123.4 (q, CF = 282.4 Hz, CF3), 143.6, 147.1; 19F NMR (376.3 MHz): δ -77.4 (d, 3JF_H = 6.42Hz); MS (EI) : m/z 176, 107 (M+-CF3), 79. EXAMPLE 8
Preparation of 2,2,2-trifluoro-l-(4-methoxyphenyl)ethanol:
A similar procedure to the one reported in EXAMPLE 7 was followed except p- anisaldehyde (0.5g, 3.67 mmol, 1 eq) was used as the substrate. Column purification with ethyl acetate:hexane (3:7) gave pure product as colorless oil 0.32g (42.2%). 1H NMR (400 MHz): δ 2.61 (broad, 1H, OH), 3.82 (s, OCH3), 4.96 (m, 1H, C-H), 6.93 (d, 8.7 Hz, 2H, Ar- H), 7.39 (m, 8.4 Hz, 2H, Ar-H); 13C NMR (100.5 MHz): δ 55.3 (s, OCH3), 77.3 (q, 2JC_CF3 = 32.1 Hz, C-CF3), 114.0, 124.5 (q, C-F = 282 Hz, CF3), 125.7, 128.8, 160.4; 19F NMR (376.3 MHz): δ -75.6 (d, 3JF_H = 6.4 Hz); MS (EI): 206 (m/z), 137 (M+-CF3), 109, 77.
EXAMPLE 9
Preparation of 2 ,2 ,2-trifluoro-l-m-tolylethanol:
A similar procedure to the one reported in EXAMPLE 7 was followed except 3- methylbenzaldehyde (0.5g, 4.16 mmol, 1 eq) was used as the substrate. Column purification with ethyl acetate :hexane (2:8) gave pure product as colorless oil 0.27g (34.1%). 1H NMR (400 MHz): δ 2.31 (s, Ar-CH3), 2.45 (d, 4.6 Hz, 1H, OH), 4.91 (m, 1H, C-H), 7.20 (m, 4H, Ar-H), 13C NMR (100.5 MHz): δ 21.3 (s, Ar-CH3), 72.7 (q, 2JC_CF3 = 32 Hz, C-CF3), 124.0 (q, CF = 282 Hz, CF3), 124.5, 128.0, 128.5, 130.3, 133.9, 138.4; 19F NMR (376.3 MHz): δ - 78.8 (d, 3JF_H = 6.7 Hz); MS (EI): 190 (m/z), 121 (M+-CF3), 91, 77.
EXAMPLE 10
Preparation of 2 ,2 ,2-trifluoro-l-(furan-2-yl)ethanol:
A similar procedure to the one reported in EXAMPLE 7 was followed except furan-2- carbaldehyde (0.5g, 5.2 mmol, 1 eq) was used as the substrate. Column purification with ethyl acetate:hexane (2:8) gave pure product as colorless oil 0.37g (42.8%). 1H NMR (400 MHz): δ 2.60 (d, 7.3 Hz, 1H, OH), 5.06 (m, 1H, C-H), 6.43 (dd, 3.39, 1.87 Hz, 1H, Ar-H), 6.53 (d, 3.32 Hz, 1H, Ar-H), 7.48 (m, 1H, Ar-H); 13C NMR (100.5 MHz): δ 67.3 (q, 2JC_CF3 = 34 Hz, C- CF3), 110.11, 110.76, 123.3 (q, CF = 282 Hz, CF3), 143.6; 19F NMR (376.3 MHz): δ -78.5 (d, JF-H = 6.5 Hz); MS (EI): decomposed. EXAMPLE 11
Preparation of l-(anthracen-9-yl)-2 ,2 ,2-trifluoroethanol:
A similar procedure to the one reported in EXAMPLE 7 was followed except 1- anthracenaldehyde (0.5g, 2.42 mmol, 1 eq) was used as the substrate. Column purification with ethyl acetate :hexane (1.5:8.5) gave pure product as colorless oil 0.34g (50.7%). 1H NMR (400 MHz): δ 3.0 (br, 1H, OH), 6.68 (q, 3JF_H = 8.0 Hz, 1H, C-H), 7.51 (m, 2H, Ar-H) 7.59 (m, 2H, Ar-H), 8.05 (d, 8.4 Hz, 2H, Ar-H), 8.16 (br, 1H, Ar-H), 8.56 (m, 1H, Ar-H), 8.99 (br, 1H, Ar-H); 13C NMR (100.5 MHz): δ 70.1 (q, 2JC_CF3 = 33 Hz, C-CF3), 120.0 (q, = 227 Hz, CF3), 122.5, 123.8, 124.0, 125.0, 126.2, 127.0, 127.2, 129.2, 129.5, 130.8, 134.1; 19F NMR (376.3 MHz): δ -74.5 (d, 3JF_H = 8 Hz); MS (EI): 276 (m/z), 207 (M+-CF3), 178.
EXAMPLE 12
Preparation of 2,2,2-trifluoro-l, I -diphenylethanol:
To a 50 ml round bottom flask with stirrer under argon was added 10 ml of dry ether. This reaction flask was flushed with argon for 5 minutes before it was cooled to -50 °C using dry ice/acetone and was stirred at that temperature for ten minutes. After ten minutes, CF3H was bubbled into this ether solution for 1 min 15 sec (0.19 g, 2.7 mmol was added total at the rate of 52.5 ml/min). This reaction mixture was allowed to stir for ten minutes. After 10 minutes, a solution of benzophenone (0.5 g, 2.7 mmol) in dry ether (5 ml) was added to the reaction mixture dropwise and the resulting reaction mixture was stirred at -40 °C for ten minutes. After ten minutes, a solution of potassium hexamethyldisilazide in ether (0.54 g in 5 ml, 2.7 mmol) was added dropwise to the reaction mixture and the resulting yellowish reaction mixture was stirred at -40 °C for 1 hour and then was gradually warmed to room temperature and stirred at room temperature for 10 hours. Reaction mixture was transferred to the separatory funnel and was washed with 5 ml of 1 N HC1, followed by saturated NaHC03 solution. Organic layer was washed with water (25 ml x 2) followed by brine (25 ml x 2) and then it was dried over sodium sulfate. Ether was removed under vacuo to obtain crude product. Column purification with pentane: acetone (9.5:0.5) gave pure product as colorless oil 0.49 g (71%). 1H NMR (400 MHz): δ 2.90 (s, 1H, OH), 7.37 (m, 6H, Ar-H), 7.5(m, 4H, Ar- H); 13C NMR (100.5 MHz): δ 79.4 (q, 2JC-CF3 = 28 Hz, C-CF3), 125.3 (q, VC-F = 286 Hz, CF3), 127.4, 128.2, 128.6, 139.3; 19F NMR (376.3 MHz): δ -74.8 (s, CF3); MS (EI): 252 (m/z), 183 (M+-CF3), 105, 77. EXAMPLE 13
Preparation of 2,2,2-trifluoro-l -(4-methoxyphenyl)-l -phenylethanol: A similar procedure to the one reported in EXAMPLE 12 was followed except 4- methoxybenzophenone (0.5 g, 2.4 mmol, 1 eq) was used as the substrate. Column purification with pentane: acetone (9: 1) gave pure product as colorless oil 0.36 g (54%). 1H NMR (400 MHz): δ 2.87 (s, 1H, OH), 3.81 (s, 3H, Ar-CH3), 6.88 (m, 2H, Ar-H), 7.37 (m, 5H, Ar-H),
7.50 (m, 2H, Ar-H); 13C NMR (100.5 MHz): δ 55.2, 79.1 (q, 2JC_CF3 = 28 Hz, C-CF3), 113.5, 125.5 (q, C-F = 286 Hz, CF3), 127.3, 128.1, 128.5, 128.7, 131.5, 139.5, 159.5; 19F NMR (376.3 MHz): δ -75.0 (s, CF3); MS (EI): 282 (m/z), 213 (M+-CF3), 135, 105, 77.
EXAMPLE 14
Preparation of 2,2,2-trifluoro-l -phenyl- 1-p-tolylethanol:
A similar procedure to the one reported in EXAMPLE 12 was followed except 4- methylbenzophenone (0.5 g, 2.6 mmol, 1 eq) was used as the substrate. Column purification with pentane: acetone (9.5:0.5) gave pure product as colorless oil 0.36 g (53%). 1H NMR (400 MHz): δ 2.37 (s, 3H, Ar-CH3), 2.87 (s, 1H, OH), 7.18 (m, 2H, Ar-H), 7.38 (m, 5H, Ar-H),
7.51 (m, 2H, Ar-H) 13C NMR (100.5 MHz): δ 21.0, 79.3 (q, 2Jc_cF3 = 28 Hz, C-CF3), 125.4 (q, CF = 286 Hz, CF3), 127.2, 127.3, 128.1, 128.5, 128.9, 136.4, 138.5, 139.3; 19F NMR (376.3 MHz): δ -74.9 (s, CF3); MS (EI): 266 (m/z), 197 (M+-CF3), 119, 105, 91.
EXAMPLE 15
Preparation of 2,2,2-trifluoro-l -(3-nitrophenyl)-l -phenylethanol: A similar procedure to the one reported in EXAMPLE 12 was followed except 3- nitrobenzophenone (0.5 g, 2.2 mmol, 1 eq) was used as the substrate. Column purification with pentane: acetone (8.5: 1.5) gave pure product as colorless oil 0.51 g (78%). 1H NMR (400 MHz): δ 3.16 (s, OH), 7.41 (m, 3H, Ar-H), 7.49 (m, 2H, Ar-H), 7.54 (m, 1H, Ar-H), 7.8 (m, 1H, Ar-H), 8.22 (m, 1H, Ar-H), 8.43 (m, 1H, Ar-H), 13C NMR (100.5 MHz): δ 79.0 (q, 2JC_CF3 = 29 Hz, C-CF3), 122.6, 123.6, 124.9 (q, lJC- = 282 Hz, CF3), 127.0, 128.8, 129.1, 129.3, 133.6, 138.4, 141.0, 148.0; 19F NMR (376.3 MHz): δ -74.9 (s, CF3); MS (EI): 297 (m z), 228 (M+-CF3), 150, 105, 77. EXAMPLE 16
Preparation of 2,2,2-trifluoro-l -(4-fluorophenyl)-l -phenylethanol: A similar procedure to the one reported in EXAMPLE 12 was followed except 4- fluorobenzophenone (0.5 g, 2.5 mmol, 1 eq) was used as the substrate. Column purification with pentane: acetone (9.5:0.5) gave pure product as colorless oil 0.55 g (81%). 1H NMR (400 MHz): δ 2.91 (s, 1H, OH), 7.05 (m, 2H, Ar-H), 7.38 (m, 3H, Ar-H), 7.48 (m, 4H, Ar-H); 13C NMR (100.5 MHz): δ 79.1 (q, 2JC_CF3 = 29 Hz, C-CF3), 115.0, 115.2, 125.2 (q, c* = 286 Hz, CF3), 127.2, 128.4, 128.8, 129.4, 129.5, 135.0, 139.2, 161.4, 163.9; 19F NMR (376.3 MHz): δ -75.0 (s, CF3), -113.64 (m, Ar-F); MS (EI): 270 (m/z), 201 (M+-CF3), 123, 95, 77.
EXAMPLE 17
Preparation of (E)-l,l,l-trifluoro-2,4-diphenylbut-3-en-2-ol:
A similar procedure to the one reported in EXAMPLE 12 was followed except chalcone (0.2 g, 0.96 mmol, 1 eq) was used as the substrate. Column purification with pentane:ether (8:2) gave pure product as an oil 0.18 g (67%). 1H NMR (400 MHz): δ 7.67 (m, 2H), 7.38 (m, 8H), 6.92 (d, J = 16.1 Hz, 1H), 6.76 (d, J = 16.1 Hz, 1H), 2.75 (br, 1H); 13C NMR (100.5 MHz): δ 137.33, 135.45, 133.50, 128.79, 128.71, 128.62, 128.35, 126.89, 126.79, 126.42, 125.19 (J = 286 Hz), 123.56, 120.72, 77.20 (J = 29.1 Hz); 19F NMR (376.3 MHz): δ -79.03 (s, 3F).
EXAMPLE 18
Preparation of (E)-l, 1, l-trifluoro-2-(4-methoxyphenyl)-4-phenylbut-3-en-2-ol A similar procedure to the one reported in EXAMPLE 12 was followed except 4'- methoxychalcone (0.2 g, 0.84 mmol, 1 eq) was used as the substrate. Column purification with pentane:ether (6:4) gave pure product as an oil 0.16 g (63%). 1H NMR (400 MHz): δ 7.67 (m, 2H), 7.39 (m, 5H), 6.90 (m, 2H), 6.81 (d, J = 16.0 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 3.82 (s, 3H), 2.84 (br, 1H); 13C NMR (100.5 MHz): δ 159.87, 137.52, 133.08, 128.68, 128.27, 128.17, 126.85, 125.5 (J = 286 Hz), 124.15, 114.09, 77.20 (J = 28.7 Hz), 77.00, 55.28; 19F NMR (376.3 MHz): δ -79.05 (s, 3F). EXAMPLE 19
Preparation of (E)-l, 1, l-trifluoro-2, 4-bis(4-fluorophenyl)but-3-en-2-ol A similar procedure to the one reported in EXAMPLE 12 was followed except 4,4'- difluorochalcone (0.2 g, 0.81 mmol, 1 eq) was used as the substrate. Column purification with pentane:ether (8:2) gave pure product as an oil 0.10 g (38%). 1H NMR (400 MHz): δ 7.59 - 7.66 (m, 2H), 7.40 (dd, J = 8.7, 5.3 Hz, 2H), 6.98 - 7.15 (m, 4H), 6.83 (d, J = 16.1 Hz, 1H), 6.61 (d, J = 16.1 Hz, 1H), 2.66 (br, 1H); 13C NMR (100.5 MHz): δ 164.18, 161.66, 133.01, 132.74, 131.43, 128.81, 128.62, 125.94, 115.88, 115.42, 77.00; 19F NMR (376.3 MHz): δ - 79.35 (s, 3F), -112.91, -113.46.
EXAMPLE 20
Preparation of ((E)-2-(4-chlorophenyl)-l,l,l-trifluoro-4-phenylbut-3-en-2-ol
A similar procedure to the one reported in EXAMPLE 12 was followed except 4'- chlorochalcone (0.2 g, 0.83 mmol, 1 eq) was used as the substrate. Column purification with pentane:ether (8:2) gave pure product as an oil 0.155 g (60%). 1H NMR (400 MHz): δ 7.58 (d, J = 8.9 Hz, 2H), 7.38 (m, 8H), 6.86 (d, J = 16.1 Hz, 1H), 6.69 (d, J = 16.1 Hz, 1H), 2.66 (br, 1H); 13C NMR (100.5 MHz): δ 135.7, 135.2, 134.9, 134.1, 128.8, 128.7, 128.5, 128.4, 126.9, 126.0, 124.8 (J = 286 Hz), 77.0 (J = 29.1 Hz); 19F NMR (376.3 MHz): δ -79.3 (s, 3F).
EXAMPLE 21
General procedure for the trifluoromethylation of unsubstituted aromatic halides In a 10-15 mL vial with a magnetic stirrer, copper (I) chloride (0.3 g, 3.0 mmol, leq) was added and the vial was sealed in the glove box under argon. To this vial, under argon 3 mL of dry DMF was added and the resulting reaction mixture was stirred at room temperature for 5 minutes. To this reaction mixture a solution of t-BuOK in DMF (0.68 g, 6.06 mmol, 2 eq) was added drop wise and the resulting reaction mixture was stirred at room temperature for 5 minutes. After 5 minutes, CF3H was bubbled into this THF solution for 4 min 11 sec (0.636 g, 9.09 mmol was added total at the rate of 52.5 ml/min, 3 eq) and the resulting reaction mixture was stirred at room temperature for 10 minutes. After 10 minutes, a solution of triethylamine trihydrofluoride (TREAT HF) (0.195g, 1.21 mmol, 198 μί) was added to the reaction mixture neat. To the same reaction mixture iodobenzene (0.927g, 4.54 mmol, 1.5 eq) was added neat and the resulting reaction mixture was heated at 50 °C for 24 hours. The reaction mixture was cooled to room temperature and then hexafluorobenzene (CeF6) (0.166 eq) was added to the reaction mixture and it was stirred at room temperature for 10 mins. An aliquot of reaction mixture was taken out and its NMR (19F) was recorded. NMR yields were determined by NMR integrations and are reported in Table 3.
General procedures for the trifluoromethylation of trialkyl borates
EXAMPLE 22
Potassium (trifluoromethyl)trifluoroborate (K[CF }-BF }]) from
Trimethoxyborate [B( OCHs)s]:
In a 10-15 mL vial with magnetic stirrer under argon was added 10 ml of dry THF. The vial was cooled to 0 to -5 °C for 5 minutes. After ten minutes, CF3H was bubbled into this THF solution for 4 min 26 sec (0.674 g, 9.62 mmol was added total at the rate of 52.5 ml/min). This reaction mixture was allowed to stir for ten minutes. After 10 minutes, trimethoxyborane (1 g, 9.62 mmol, 1.07 mL) was added to the reaction mixture neat. The resulting reaction mixture was stirred at 0 °C for 5 minutes. After 5 minutes, a solution of potassium hexamethyldisilazide (KHMDS) in THF (1.92g, 9.62 mmol, 1 eq) was added to the reaction mixture drop wise and the resulting yellowish reaction mixture was stirred at 0 °C for 1-2 hrs and then the reaction mixture was allowed to warm to room temperature slowly overnight for 16 h. After 16 hours, 30 ml of water was added to the reaction mixture and the reaction mixture was stirred for 15 minutes. Reaction mixture was concentrated under vacuo to remove volatiles. Reaction mixture was further concentrated to half of its original volume under vacuo to remove water. Crude product obtained was transferred to a polyethylene (NALGENE®) bottle. This bottle was cooled in ice and then 48% aqueous solution of hydrogen fluoride (6 mL) was added to it. The resulting solution was stirred at ambient temperature for 12-14 hours. After that, a solution of potassium hydroxide (3.15g in 30 mL of distilled water) was added slowly to the reaction mixture until reaction mixture remains slightly acidic. Potassium bicarbonate was added portion wise as a solid until C02 evolution ceased, and the reaction mixture had a pH greater than 7. Water was removed under vacuo to afford a white solid. A fine powder of this solid was made by grinding using mortar and pestle and the material was dried with a gentle heating of the flask with the heat gun. The powder was transferred in to a 300 mL of boiling acetonitrile and filtered while hot. The filtrate was removed under vacuo to afford pure product as a white powder (0.91 g, 53% yield). Analytically pure sample was obtained by recrystallization from 2: 1 mixture of ethanol/2- propanol. 19F NMR (376.3 MHz, D20): δ -76.7 (q, J = 33.6 Hz, CF3), -155.0 (q, J = 40.7 Hz, 3F); UB NMR (128.3 MHz, D20): δ 0.8 (qq, J= 40.7, 33.6, IB) EXAMPLE 23
Potassium (trifluoromethyl)trifluoroborate (K[CFs-BFs]) from
Tri(n-butyl)borate [B(OCH2CH2CH2CH3)3] :
In a 10-15 mL vial with magnetic stirrer under argon was added 10 ml of dry THF.
The vial was cooled to 0 to -5 °C for 5 minutes. After ten minutes, CF3H was bubbled into this THF solution for 2 min (0.304 g, 4.34 mmol was added total at the rate of 52.5 ml/min). This reaction mixture was allowed to stir for ten minutes. After 10 minutes, trimethoxyborane (1 g, 4.34 mmol, 1.17 mL) was added to the reaction mixture neat. The resulting reaction mixture was stirred at 0 °C for 5 minutes. After 5 minutes, a solution of potassium hexamethyldisilazide (KHMDS) in THF (0.866g, 4.34 mmol, 1 eq) was added to the reaction mixture drop wise and the resulting yellowish reaction mixture was stirred at 0 °C for 1-2 hrs and then the reaction mixture was allowed to warm to room temperature slowly overnight for 16 h. After 16 hours, 30 ml of water was added to the reaction mixture and the reaction mixture was stirred for 15 minutes. Reaction mixture was concentrated under vacuo to remove volatiles. Reaction mixture was further concentrated to half of its original volume under vacuo to remove water. Crude product obtained was transferred to a polyethylene (NALGENE®) bottle. This bottle was cooled in ice and then 48% aqueous solution of hydrogen fluoride (6 mL) was added to it. The resulting solution was stirred at ambient temperature for 12-14 hours. After that, a solution of potassium hydroxide (3.15g in 30 mL of distilled water) was added slowly to the reaction mixture until reaction mixture remains slightly acidic. Potassium bicarbonate was added portion wise as a solid until C02 evolution ceased, and the reaction mixture had a pH greater than 7. Water was removed under vacuo to afford white solid. A fine powder of this solid was made by grinding using mortar and pestle and the material was dried with a gentle heating of the flask with the heat gun. The powder was transferred in to a 300 mL of boiling acetonitrile and filtered while hot. The filtrate was removed under vacuo to afford pure product as a white powder (0.51 g, 66% yield). Analytically pure sample was obtained by recrystallization from 2: 1 mixture of ethanol/2-propanol. 19F NMR (376.3 MHz, D20): δ -76.7 (q, J= 33.6 Hz, CF3), -155.0 (q, J= 40.7 Hz, 3F); UB NMR (128.3 MHz, D20): δ 0.8 (qq, J= 40.7, 33.6, IB). General procedure for the trifluoromethylation of elemental sulfur
EXAMPLE 24
To a 50 ml round bottom flask with stirrer under argon was added elemental sulfur (0.45 g, 14.2 mmol, 2 eq) followed by 10 ml of dry THF. This reaction flask was flushed with argon and it was cooled to -78 °C using dry ice/acetone and was stirred at that temperature. CF3H was bubbled into this THF solution for 3 min 30 sec (0.5 g, 7.14 mmol was added total at the rate of 52.5 ml/min). This reaction mixture was allowed to stir for few minutes. A solution of potassium hexamethyldisilazide in THF (2.84 g in 5 ml, 14.2 mmol) was added drop wise to the reaction mixture and the resulting yellowish reaction mixture was stirred at -78 °C for 1 hour and then was gradually warmed to room temperature and stirred at room temperature for 10 hours. Reaction mixture was reduced to half of its original volume under vacuo and then transferred to the separatory funnel and was extracted with pentane. Organic layer was washed with water (25 ml x 2) followed by brine (25 ml x 2) and then it was dried over sodium sulfate. Pentane was removed under vacuum to obtain crude product. This crude product was put in the 50 ml round bottom flask and it was oxidized with 6 eq of 30% aq H202 and 1 eq of H2SO4 and allowed to stir at room temperature for 1 h. After 1 h, 19F NMR was recorded which showed complete conversion of the crude product to trifluoromethanesulfonic acid (19F NMR at -78 ppm as the only peak in the spectrum).
Accordingly, the invention demonstrates the use of a trifluoromethylating agent for trifluoromethylating a fluoromethylatable substrate in the presence of an alkoxide (polyalkoxide) or metal salt of silazane (polysilazane) under conditions sufficient to trifluoromethylate the substrate; wherein the fluoromethylatable substrate preferably comprises a compound selected from the group consisting of aldehydes, ketones, chalcones, esters, alkyl halides, alkyl formates, aryl halides, alkyl borates and sulfur.

Claims

THE CLAIMS
What is claimed is: 1. A method for preparing a trifluoromethylated product, which comprises reacting a fluoromethylatable substrate with a trifluoromethylating agent in the presence of a base under conditions sufficient to trifluoromethylate the substrate; wherein the
fluoromethylatable substrate comprises a compound selected from the group consisting of chlorosilanes, carbonyl compounds such as esters, aryl halides, aldehydes, ketones, chalcones, alkyl formates, alkyl halides, aryl halides, alkyl borates, carbon dioxide and sulfur.
2. The method of claim 1, wherein the trifluoromethylating agent is
trifluoromethane . 3. The method of claim 1, wherein the substrate comprises chlorotrimethylsilane, chlorotriethylsilane, chlorotriisopropylsilane, chloro(t-butyldimethyl)silane,
chloro(tris(trimethylsilyl)) silane, dichlorodiethylsilane, benzaldehyde, /?-anisaldehyde, 3- methylbenzaldehyde, l-anthracenaldehyde,furan-2-carboxaldehyde, benzophenone, 4- methoxybenzophenone, 4-methylbenzophenone, 3-nitrobenzophenone, 4- fluorobenzophenone, chalcone, 4 '-methoxy chalcone, 4'-nitrochalcone, 4,4'-difluorochalcone, 4'-chlorochalcone, methyl benzoate, benzyl bromide, iodobenzene, 1-iodonaphthalene, 2- Iodoanisole, 3-nitroiodobenzene, 2-iodotoluene, 3-iodo-2-methoxynitrobenzene, 3- iodobenzotrifluoride, 2-iodopyridine,
3-iodopyridine, trimethoxyborate, tributylborate, elemental sulfur, methyl formate, or ethyl formate.
4. The method of claim 1, wherein the ketone or carbonyl compound is a non- enolizable compound.
5. The method of claim 1, wherein the reaction is carried out in the presence of a solvent.
6. The method of claim 5, wherein trifluoromethylation of aryl halides is carried out in the presence of a polar aprotic solvent.
7. The method of claim 5, wherein the solvent is tetrahydrofuran (THF), diethyl ether, polyethers, hydrocarbons (toluene, benzene, etc), dimethyl ether, dimethoxymethane (Glyme) or dimethylformamide (DMF), N-methylpyrrolidone (NMP), hexamethyl phosphoric triamide (HMPA), dimethyl sulfoxide (DMSO), preferably dimethylformamide (DMF).
8. The method of claim 1, wherein the base comprises an alkoxide, polyalkoxide or alkali metal salt of silazane, polysilazanes or a combination thereof.
9. The method of claim 1, wherein the reaction conditions include a temperature of between about -90°C to about 130°C for a time between 30 minutes to 24 hours.
10. The method of claim 1, wherein the fluoromethylatable substrate comprises chlorosilanes, aldehydes, methyl benzoate, chalcones or non-enolizable ketones, the trifluoromethylating agent is trifluoromethane, the base comprises an alkoxide (polyalkoxide) or alkali metal salt of silazane, polysilazanes or a combination thereof, and the method further comprises adding the base to a mixture that includes the substrate and the trifluoromethylating agent to form a reaction mixture, stirring the reaction mixture at about -80°C to -70°C and warming the reaction mixture to about room temperature to trifluoromethylate the substrate.
11. The method of claim 10, wherein the reaction mixture is warmed to about room temperature for about 2 to 20 hours.
12. The method of claim 1, wherein the fluoromethylatable substrate comprises halosilane, the trifluoromethylating agent is trifluoromethane, the base comprises an alkoxide, polyalkoxide or alkali metal salt of silazane, polysilazanes or a combination thereof, and the method further comprises adding either trifluoromethylating agent to a mixture of halosilane and base or adding base to a mixture of trifluoromethylating agent and silyl halide or a combination thereof to form a reaction mixture, stirring the reaction mixture at -85 °C to room temperature to trifluoromethylate the substrate.
13. The method of claim 1, wherein the fluoromethylatable substrate comprises substrate containing carbonyl group, the trifluoromethylating agent is trifluoromethane, the base comprises an alkoxide, polyalkoxide or alkali metal salt of silazane, polysilazanes or a combination thereof, and the method further comprises adding either trifluoromethylating agent to a mixture of substrate containing carbonyl group and base or adding base to a mixture of trifluoromethylating agent and substrate containing carbonyl group or a combination thereof to form a reaction mixture, stirring the reaction mixture at -50 °C to room temperature to trifluoromethylate the substrate.
14. The method of claim 1, wherein the fluoromethylatable substrate comprises aryl halides, the trifluoromethylating agent is trifluoromethane, the base comprises an alkoxide (polyalkoxide) or alkali metal salt of silazane, polysilazanes or a combination thereof, and one of the method further comprises adding the trifluoromethylating agent to a mixture of a copper halide, a heterocyclic ligand containing 1-10 heteroatoms, the solvent and the aryl halide followed by addition of the base to form a reaction mixture, stirring the reaction mixture at about 80 to 120 °C and cooling the reaction mixture to about room temperature to trifluoromethylate the substrate and the other method further comprises adding the trifluoromethylating agent to a mixture of a copper halide and base followed by an additive and aryl halide to form a reaction mixture, stirring the reaction mixture at about 50 °C and cooling the reaction mixture to about room temperature to trifluoromethylate the substrate.
15. The method of claim 1, wherein the fluoromethylatable substrate comprises trialkylborates which are in situ converted to trifluoromethyltrifluoroborates.
16. The method of claim 1, wherein the fluoromethylatable substrate comprises substrate containing trialkyl borate group, the trifluoromethylating agent is trifluoromethane, the base comprises an alkoxide, polyalkoxide or alkali metal salt of silazane, polysilazanes or a combination thereof, and the method further comprises adding base to a mixture of trifluoromethylating agent and substrate containing trialkyl borate group or a combination thereof to form a reaction mixture, stirring the reaction mixture at -5 °C to room temperature to trifluoromethylate the substrate followed by addition of fluorinating agent and stirring the reaction mixture at room temperature for 12-24 hours.
17. The method of claim 1, wherein the fluoromethylatable substrate is elemental sulfur which is trifluoromethylated to a trifluoromethylated sulfur intermediate, which is then oxidized in situ to trifluoromethanesulfonic acid.
18. The method of claim 1, wherein the fluoromethylatable substrate comprises substrate containing sulfur atom, preferably elemental sulfur and the trifluoromethylating agent is trifluoromethane, the base comprises an alkoxide, polyalkoxide or alkali metal salt of silazane, polysilazanes or a combination thereof, and the method further comprises adding base to a mixture of trifluoromethylating agent and substrate containing sulfur atom, preferably elemental sulfur or a combination thereof to form a reaction mixture, stirring the reaction mixture at -78 °C to room temperature to trifluoromethylate the substrate followed by addition of oxidizing agent, acid and stirring the reaction mixture at room temperature for 12- 24 hours.
19. The method of claim 1, wherein the reaction mixture is stirred vigorously either by magnetic stirring or mechanical stirring methods at all times.
20. The method of claim 1, wherein the trifluoromethylated substrate is
trifluoromethyl(trimethyl)silane, trifluoromethyl(triethyl)silane,
trifluoromethyl(triisopropyl)silane, (trifluoromethyl)t-butyldimethylsilane,
tris(trimethylsilyl)trifluoromethylsilane, diethyl bis(trifluoromethyl)silane, 2,2,2-trifluoro- 1- phenylethanol, 2,2,2-trifluoro- 1 -(4-methoxyphenyl)ethanol, 2,2,2-trifluoro- 1 -m-tolylethanol, 2,2,2-trifluoro- 1 -(furan-2-yl)ethanol, 1 -(anthracen-9-yl)-2,2,2-trifluoroethanol, 2,2,2-trifluoro- 1 , 1 -diphenylethanol, 2,2,2-trifluoro- 1 -(4-methoxyphenyl)- 1 -phenylethanol, 2,2,2-trifluoro- 1 - phenyl- 1 -p-tolylethanol, 2,2,2-trifluoro- 1 -(3-nitrophenyl)- 1 -phenylethanol, 2,2,2-trifluoro- 1 - (4-fluorophenyl)- 1 -phenylethanol, (E)- 1 , 1 , 1 -trifluoro-2,4-diphenylbut-3 -en-2-ol, (E)- 1 , 1 , 1 - trifluoro-2-(4-methoxyphenyl)-4-phenylbut-3-en-2-ol, (E)- 1,1,1 -trifluoro-2-(4-nitrophenyl)-4- phenylbut-3-en-2-ol, (E)- 1,1,1 -trifluoro-2,4-bis(4-fluorophenyl)but-3-en-2-ol, (E)-2-(4- chlorophenyl)- 1,1,1 -trifluoro-4-phenylbut-3-en-2-ol, 2,2,2-trifluoro- 1 -phenylethanone, 2,2,2- trifluoroethyl)benzene, (trifluoromethyl)benzene, 1-trif uoromethylnaphthalene, l-methoxy-2- (trifluoromethyl)benzene, 1 -nitro-3-(trifluoromethyl)benzene, 1 -methyl-2- (trifluoromethyl)benzene, 2-methoxy- 1 -nitro-3-(trifluoromethyl)benzene, 1 ,3- bis(trifluoromethyl)benzene, 2-(trifluoromethyl)pyridine, 3 -(trifluoromethyl)pyridine, potassium (Trifluoromethyl)trifluoroborate, trifluoromethanesulfomc acid, l-methoxy-2,2,2- trifluoroethanol, or l-ethoxy-2,2,2-trifluoroethanol.
21. Use of a trifluoromethylating agent for trifluoromethylating a
fluoromethylatable substrate in the presence of a base under conditions sufficient to trifluoromethylate the substrate; wherein the fluoromethylatable substrate comprises a compound selected from the group consisting of carbonyl compounds, chlorosilanes, esters, aryl halides, aldehydes, ketones, chalcones, alkyl halides, alkyl formates, alkyl borates, carbon dioxide, and sulfur.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5446218A (en) 1993-04-26 1995-08-29 E. I. Du Pont De Nemours And Company Preparation of fluorinated methanes
WO1998022435A1 (en) 1996-11-15 1998-05-28 Rhodia Chimie Compounds useful for perhalogenoalkylation, reagent for implementing these compounds and synthesis method for obtaining these compounds
US6355849B1 (en) 1995-11-23 2002-03-12 Rhodia Chimie Process of use in perfluoroalkyation and reactant for making use of this process
FR2827285A1 (en) 2001-07-10 2003-01-17 Rhodia Chimie Sa Composition for use in perfluoro-alkoylation reactions comprises a special fluoroacyl or fluorinated organosulfinyl compound and a basic system containing or forming an alcoholate
US20030153778A1 (en) * 2001-11-29 2003-08-14 G.K. Surya Prakash Magnesium mediated preparation of fluorinated alkyl silanes
US20040230079A1 (en) 2003-01-13 2004-11-18 G.K.Surya Prakash Methods for nucleophilic fluoromethylation
US20060052643A1 (en) 2004-03-26 2006-03-09 Prakash G K S Nucleophilic substitution reactions of difluorormethyl phenyl sulfone with alkyl halides leading to the facile synthesis of terminal 1,1-difluoro-1-alkenes and difluoromethylalkanes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5446218A (en) 1993-04-26 1995-08-29 E. I. Du Pont De Nemours And Company Preparation of fluorinated methanes
US6355849B1 (en) 1995-11-23 2002-03-12 Rhodia Chimie Process of use in perfluoroalkyation and reactant for making use of this process
WO1998022435A1 (en) 1996-11-15 1998-05-28 Rhodia Chimie Compounds useful for perhalogenoalkylation, reagent for implementing these compounds and synthesis method for obtaining these compounds
FR2827285A1 (en) 2001-07-10 2003-01-17 Rhodia Chimie Sa Composition for use in perfluoro-alkoylation reactions comprises a special fluoroacyl or fluorinated organosulfinyl compound and a basic system containing or forming an alcoholate
US20030153778A1 (en) * 2001-11-29 2003-08-14 G.K. Surya Prakash Magnesium mediated preparation of fluorinated alkyl silanes
US20040230079A1 (en) 2003-01-13 2004-11-18 G.K.Surya Prakash Methods for nucleophilic fluoromethylation
US20060052643A1 (en) 2004-03-26 2006-03-09 Prakash G K S Nucleophilic substitution reactions of difluorormethyl phenyl sulfone with alkyl halides leading to the facile synthesis of terminal 1,1-difluoro-1-alkenes and difluoromethylalkanes

Non-Patent Citations (63)

* Cited by examiner, † Cited by third party
Title
BARHDADI ET AL.: "Coupling of fluoroform with aldehydes using an electrogenerated base.", J. CHEM. COMMUN., 1998, pages 1251 - 1252, XP055135183 *
BARHDADI, R.; TROUPEL, M.; PERICHON, J., CHEM. COMMUN., 1998, pages 1251 - 1252
BECKERS, H.; BUERGER, H.; BURSCH, P.; RUPPERT, I., J. ORGANOMET. CHEM., vol. 316, 1986, pages 41 - 50
BILLARD ET AL.: "New Stable Reagents for the Nucleophilic Trifluoromethylation.", 1. TRIFLUOROMETHYLATION OF CARBONYL COMPOUNDS WITH N-FORMYLMORPHOLINE DERIVATIVES ORG. LETT., vol. 2, no. 14, 2000, pages 2101 - 2103, XP055135184 *
BILLARD ET AL.: "Trifluoromethylation of Nonenolizable Carbonyl Compounds with a Stable Piperazino Hemiaminal of Trifluoroacetaldehyde", EUR. J. ORG. CHEM., vol. 2001, no. 8, 2001, pages 1467 - 1471, XP055135185 *
BILLARD, T.; BRUNS, S.; LANGLOIS, B. R., ORG. LETT., vol. 2, 2000, pages 2101 - 2103
BILLARD, T.; LANGLOIS, B. R.; BLOND, G., EUR. J. ORG. CHEM., 2001, pages 1467 - 1471
BILLARD, T.; LANGLOIS, BERNARD R.; BLOND, G., EUR. J. ORG. CHEM., 2001, pages 1467 - 1471
CARR, G. E.; CHAMBERS, R. D.; HOLMES, T. F.; PARKER, D. G., J. CHEM. SOC., PERKIN TRANS., vol. 1, 1988, pages 921 - 6
CHEN, Q.; DUAN, J., J. CHEM. SOC., CHEM. COMMUN., 1993, pages 1389 - 91
CHEN, Q.; WU, S., J. CHEM. SOC., CHEM. COMMUN., 1989, pages 705 - 6
CHO ET AL.: "The Palladium-Catalyzed Trifluoromethylation of Aryl Chlorides.", SCIENCE, vol. 328, no. 5986, 2010, pages 1679 - 1681, XP055135179 *
CHO, E. J.; SENECAL, T. D.; KINZEL, T.; ZHANG, Y.; WATSON, D. A.; BUCHWALD, S. L., SCIENCE, vol. 328, 2010, pages 1679 - 1681
CLARK, J. H.; MCCLINTON, M. A.; BLADE, R. J., J. CHEM. SOC., CHEM. COMMUN., 1988, pages 638 - 9
COTTET, F.; SCHLOSSER, M., EUR. J. ORG. CHEM., 2002, pages 327 - 330
DEFFIEUX, D.; BORDEAU, M.; BIRAN, C.; DUNOGUES, J., ORGANOMETALLICS, vol. 13, 1994, pages 2415 - 2422
DUBININA, G. G.; FURUTACHI, H.; VICIC, D. A., J. AM. CHEM. SOC., vol. 130, 2008, pages 8600 - 8601
DUBININA, G. G.; OGIKUBO, J.; VICIC, D. A., ORGANOMETALLICS, vol. 27, 2008, pages 6233 - 6235
FOLLEAS, B.; MAREK, I.; NORMANT, J.-F.; JALMES, L. S., TETRAHEDRON LETT., vol. 39, 1998, pages 2973 - 2976
GROBE, J.; HEGGE, J., SYNLETT, 1995, pages 641 - 2
HASZELDINE ET AL.: "Perfluoroalkyl derivatives of sulphur. Part I. Trifluoromethanesulphonic acid", JOUMAL OF THE CHEMICAL SOCIETY, 1954, pages 4228 - 4232, XP055135182 *
HEATON, C. A.; MILLER, A. K.; POWELL, R. L., J. FLUORINE CHEM., vol. 107, 2001, pages 1 - 3
KAWAI, H.; KUSUDA, A.; MIZUTA, S.; NAKAMURA, S.; FUNAHASHI, Y.; MASUDA, H.; SHIBATA, N. J., FLUORINE CHEM., vol. 130, 2009, pages 762 - 765
KHAN, B. A.; BUBA, A. E.; GOOSSEN, L., J. CHEM.-EUR. J., vol. 18, 2012, pages 1577 - 1581
KNAUBER, T.; ARIKAN, F.; ROESCHENTHALER, G.-V.; GOOSSEN, L., J. CHEM.--EUR. J., vol. 17, no. 2689-2697, 2011, pages S2689,1 - S2689,83
KOBAYASHI, Y.; KUMADAKI, I., TETRAHEDRON LETT., 1969, pages 4095 - 6
KOBAYASHI, Y.; YAMAMOTO, K.; KUMADAKI, I., TETRAHEDRON LETT., 1979, pages 4071 - 2
KOLOMEITSEV, A. A.; KADYROV, A. A.; SZCZEPKOWSKA-SZTOLCMAN, J.; MILEWSKA, M.; KORONIAK, H.; BISSKY, G.; BARTEN, J. A.; ROESCHENTHA, TETRAHEDRON LETT., vol. 44, 2003, pages 8273 - 8277
LANGLOIS, B. R.; BILLARD, T., SYNTHESIS, 2003, pages 185 - 194
LARGE, S.; ROQUES, N.; LANGLOIS, B. R., J. ORG. CHEM., vol. 65, 2000, pages 8848 - 8856
LEVIN, V. V.; DILMAN, A. D.; BELYAKOV, P. A.; STRUCHKOVA, M. I.; TARTAKOVSKY, V. A., TETRAHEDRON LETT., vol. 52, 2011, pages 281 - 284
LUNDGREN, R. J.; STRADIOTTO, M., ANGEW. CHEM., INT. ED., vol. 49, 2010, pages 9322 - 9324
MARTYNOV, B. I.; STEPANOV, A. A., J. FLUORINE CHEM., vol. 85, 1997, pages 127 - 128
MATSUI, K.; TOBITA, E.; ANDO, M.; KONDO, K., CHEM. LETT., 1981, pages 1719 - 20
MCLOUGHLIN, V. C. R.; THROWER, J., TETRAHEDRON, vol. 25, 1969, pages 5921 - 40
MIZUTA, S.; SHIBATA, N.; SATO, T.; FUJIMOTO, H.; NAKAMURA, S.; TORU, T., SYNLETT, 2006, pages 267 - 270
MOLANDER, G. A.; HOAG, B. P., ORGANOMETALLICS, vol. 22, 2003, pages 3313 - 3315
MOLANDER.: "Improved Synthesis of Potassium (Trifluoromethyl) trifluoroborate [K(CF3BF3)].", ORGANOMETALLICS, vol. 22, no. 16, 2003, pages 3313 - 3315, XP055135180 *
MORIMOTO, H.; TSUBOGO, T.; LITVINAS, N. D.; HARTWIG, J. F., ANGEW. CHEM. INT. ED., vol. 50, 2011, pages 3793 - 3798
MUELLER, K.; FAEH, C.; DIEDERICH, F., SCIENCE, vol. 317, 2007, pages 1881 - 1886
MUKHOPADHYAY, S.; BELL, A. T.; SRINIVAS, R. V.; SMITH, G. S., ORG. PROCESS RES. DEV., vol. 8, 2004, pages 660 - 662
OISHI, M.; KONDO, H.; AMII, H., CHEM. COMMUN., 2009, pages 1909 - 1911
PARATIAN, J. M.; SIBILLE, S.; PERICHON, J., J. CHEM. SOC., CHEM. COMMUN., 1992, pages 53 - 4
PAWELKE, G., J. FLUORINE CHEM., vol. 42, 1989, pages 429 - 33
PRAKASH, G. K. S.; DEFFIEUX, D.; YUDIN, A. K.; OLAH, G. A., SYNLETT, 1994, pages 1057 - 8
PRAKASH, G. K. S.; HU, J., ACS SYMP. SER., vol. 911, 2005, pages 16 - 56
PRAKASH, G. K. S.; HU, J.; OLAH, G. A., J. ORG. CHEM., vol. 68, 2003, pages 4457 - 4463
PRAKASH, G. K. S.; KRISHNAMURTI, R.; OLAH, G. A., J. AM. CHEM. SOC., vol. 111, 1989, pages 393 - 395
PRAKASH, G. K. S.; MANDAL, M., J. FLUORINE CHEM., vol. 112, 2001, pages 123 - 131
PRAKASH, G. K. S.; YUDIN, A. K., CHEM. REV., vol. 97, 1997, pages 757 - 786
PRAKASH, G. K. S.; YUDIN, A. K.; DEFFIEUX, D.; OLAH, G. A., SYNLETT, 1996, pages 151 - 3
RAMAIAH, P.; KRISHNAMURTI, R.; PRAKASH, G. K. S., ORG. SYNTH., vol. 72, 1995, pages 232 - 40
RUPPERT, I.; SCHLICH, K.; VOLBACH, W., TETRAHEDRON LETT., vol. 25, 1984, pages 2195 - 2198
RUSSELL, J.; ROQUES, N., TETRAHEDRON, vol. 54, 1998, pages 13771 - 13782
SATO, K.; TARUI, A.; OMOTE, M.; ANDO, A.; KUMADAKI, I., SYNTHESIS, 2010, pages 1865 - 1882
See also references of EP2712367A4
SHONO, T.; ISHIFUNE, M.; OKADA, T.; KASHIMURA, S., J. ORG. CHEM., vol. 56, 1991, pages 2 - 4
SINGH, R. P.; SHREEVE, J. M., TETRAHEDRON, vol. 56, 2000, pages 7613 - 7632
SU, D.; DUAN, J.; CHEN, Q., TETRAHEDRON LETT., vol. 32, 1991, pages 7689 - 90
TAJ, S. A. S., CHEMICAL INDUSTRY DIGEST, vol. 21, 2008, pages 92 - 98
UMEMOTO, T.; ANDO, A., BULL. CHEM. SOC. JPN., vol. 59, 1986, pages 447 - 52
WILLERT-PORADA, M. A.; BURTON, D. J.; BAENZIGER, N. C., J. CHEM. SOC., CHEM. COMMUN., 1989, pages 1633 - 4
XIAO, J.-C.; YE, C.; SHREEVE, J. N., M. ORG. LETT., vol. 7, 2005, pages 1963 - 1965

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