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WO2016183101A1 - Arylation catalysée par le palladium de fluoroalkylamines - Google Patents

Arylation catalysée par le palladium de fluoroalkylamines Download PDF

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WO2016183101A1
WO2016183101A1 PCT/US2016/031675 US2016031675W WO2016183101A1 WO 2016183101 A1 WO2016183101 A1 WO 2016183101A1 US 2016031675 W US2016031675 W US 2016031675W WO 2016183101 A1 WO2016183101 A1 WO 2016183101A1
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aryl
group
organic groups
catalyst
containing organic
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Andrew T. BRUSOE
John F. Hartwig
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University of California Berkeley
University of California San Diego UCSD
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University of California San Diego UCSD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C07C209/10—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • One aspect involves a method of forming a fiuoroalkylaniline, the method including reacting a fluoroalkylamine with an aryl or heteroaryl halide using a palladium-containing catalyst in the presence of an oxygen-containing base having a conjugate acid pKa in dimethyl sulfoxide of less than about 32.
  • the fiuoroalkylaniline is enantioenriched.
  • the fiuoroalkylaniline formed includes the structure selected from the group consisting of:
  • Ri is an aryl or heteroaryl group including any one or more of the following substituents: carbon-containing organic groups, halogen-containing organic groups, sulfur- containing organic groups, phosphorous-containing organic groups, and organic groups including a hydrogen atom; and R 2 is any of the following organic groups: carbon-containing organic groups, halogen-containing organic groups, sulfur-containing organic phosphorous-containing organic groups, and organic groups including a hydrogen atom.
  • the fluoroalkylaniline formed is any of the following structures:
  • the fluoroalkylamine is any one of trifluoroethylamine, difluoroethylamine, pentafluoropropylamine, difluorophenethylamine, trifluoroisopropylamine, and 2-(trifluoromethylpyrrolidine).
  • the aryl or heteroaryl halide includes the chemical structure R— X, wherein X is selected from any one or more of the following: chlorine, bromine, and iodine; and R is an aryl or heteroaryl group including a functional group sensitive to strong base and nucleophiles.
  • the functional group may be any of unprotected acetophenones, free alcohols, amides, unconjugated esters, cinnamate esters, nitriles, methyl aryl sulfoxide, and non-enolizable aldehydes.
  • the aryl or heteroaryl halide includes an aryl chloride or bromide without an acidic N-H bond.
  • the aryl or heteroaryl halide is any one or more of the following: heteroaryl halides of 2-, 3-, and 4-halopyridines, pyrimidines, quinoxalines, thiophenes, indoles, and thiobenzoxazoles.
  • the aryl or heteroaryl halide is any one or more of the following: aryl bromides, aryl chlorides, heteroaryl bromides, and heteroaryl chlorides.
  • the base is derived from a phenoxide. In some embodiments, the base is nitrogen-free. In some embodiments, the base is KOPh. [0012]
  • the palladium-containing catalyst may be ligated with any one or more of the following compounds: phosphines, phophites, phosphoramidites, phosphoramides, N-heterocyclic carbenes, monophosphines, and
  • the reaction may form a palladium complex including a monophosphine.
  • the ratio of palladium to ligand to form the palladium complex is about 1 :2.
  • Another aspect involves a method of forming a fluoroalkylaniline, the method including reacting a fluoroalkylamine with an aryl or heteroaryl sulfonate or phosphate using a palladium- containing catalyst in the presence of an oxygen-containing base having a conjugate acid pKa in dimethyl sulfoxide of less than about 32.
  • the aryl or heteroaryl sulfonate or phosphate may include the chemical structure R— X, wherein X is any sulfonate or phosphate, and R is an aryl or heteroaryl group including a functional group sensitive to strong base and nucleophiles.
  • the functional group may be any of unprotected acetophenones, free alcohols, amides, unconjugated esters, cinnamate esters, nitriles, methyl aryl sulfoxide, and non-enolizable aldehydes.
  • the fluoroalkylamine is any one of trifluoroethylamine, difluoroethylamine, pentafluoropropylamine, difluorophenethylamine, trifluoroisopropylamine, and 2-(trifluoromethylpyrrolidine).
  • the fluoroalkylaniline formed includes any of the following structures:
  • Ri is an aryl or heteroaryl group including any one or more of the following substituents: carbon-containing organic groups, halogen-containing organic groups, sulfur- containing organic groups, phosphorous-containing organic groups, and organic groups including a hydrogen atom; and R 2 is any of the following organic groups: carbon-containing organic groups, halogen-containing organic groups, sulfur-containing organic groups, phosphorous-containing organic groups, and organic groups including a hydrogen atom.
  • the aryl or heteroaryl halide is any one or more of the following: aryl bromides, aryl chlorides, heteroaryl bromides, and heteroaryl chlorides.
  • the base is derived from a phenoxide. In some embodiments, the base is nitrogen-free. In some embodiments, the base is KOPh.
  • the palladium-containing catalyst may be ligated with any one or more of the following compounds: phosphines, phophites, phosphoramidites, phosphoramides, N-heterocyclic carbenes, monophosphines, and
  • Another aspect involves a method of forming a fluoroalkylaniline, the method including reacting a fluoroalkylamine with a halogen-containing reactant using a palladium-containing catalyst in the presence of a base, whereby the reactant is any of chloroarenes, chloroheteroarenes, bromoarenes, and bromoheteroarenes; and whereby the reactant is not bromoindazole.
  • the fluoroalkylamine is any of trifluoroethylamine, difluoroethylamine, pentafluoropropylamine, difluorophenethylamine, trifluoroisopropylamine, and 2-(trifluoromethylpyrrolidine).
  • the fluoroalkylaniline formed includes the structure selected from the group consisting of:
  • Ri is an aryl or heteroaryl group including any one or more of the following substituents: carbon-containing organic groups, halogen-containing organic groups, sulfur- containing organic groups, phosphorous-containing organic groups, and organic groups including a hydrogen atom; and R 2 is any of the following organic groups: carbon-containing organic groups, halogen-containing organic groups, sulfur-containing organic groups, phosphorous-containing organic groups, and organic groups including a hydrogen atom.
  • Another aspect is a fluoroalkylaniline prepared by any of the above-described methods.
  • Another aspect is an enantioenriched fluoroalkylaniline product.
  • Figure 1 shows chemical structures of various aniline derivatives and fluorinated amine derivatives.
  • Figure 2A shows the chemical reaction associated with methods of certain disclosed embodiments.
  • Figure 2B is a chemical structure of CyPFtBu.
  • Figure 2C shows a reactant and catalyst for experiments conducted in accordance with certain disclosed embodiments.
  • Figure 3A depicts chemical structures for variations of BippyPhos, BuBrettPhos, JackiePhos, and tBuXPhos.
  • Figure 3B depicts a reaction for coupling of trifluoroethylamine with 4- «-butylbromobenzene used in an experiment.
  • Figure 4A shows a chemical reaction of fluoroalkylamination of aryl halides used for performing certain experiments in accordance with certain disclosed embodiments, as well as chemical structures for compounds derived from the experiment.
  • Figure 4B depicts chemical structures for compounds derived an experiment for fluoroalkylamination of aryl halides.
  • Figure 5 shows chemical structures of compounds having functional groups sensitive to base or nucleophiles such as the oxygen-containing functional group which are used in experiments described herein.
  • Figure 6 shows chemical structures of the compounds derived from conducting an experiment in accordance with certain disclosed embodiments.
  • Figure 7 shows a chemical reaction used for an experiment on derivatization of coupled produced in accordance with certain disclosed embodiments.
  • Figure 8 shows a chemical reaction used as a model reaction for mechanistic studies.
  • Figure 9 is a depiction of the resting state structure of the catalyst [(tBuBippyPhos)Pd(Ar)-(OPh)] shown with 50% thermal ellipsoid without hydrogen atoms.
  • Figures 10A and 10B show example mechanisms consistent with observed resting state and reaction kinetics derived from experiments performed in accordance with certain disclosed embodiments.
  • Figure 11A shows the chemical reaction for reacting [(tBuBippyPhos)Pd(Ar)-(OPh)] to form 4-fluoro-N-trifluoroethylaniline.
  • Figure 11B is a plot of 1/Initial Rate versus the concentration of phenol used to determine the reaction order in phenol as used in an experiment.
  • Figures 12A and 12B show reactions performed in an experiment to form fluoroalkylanilines with retention of the high enantioerichment of the starting chiral fluoroalkylamine.
  • acetamide is found in the highest grossing prescription drug off all time (Lipitor) and the most commonly administered over-the- counter pain drug (Tylenol).
  • Teylenol the most commonly administered over-the- counter pain drug
  • many of the most widely applied herbicides e.g. Metolachlor
  • common pigment chromophores e.g. Mauveine A
  • Aniline derivatives containing electron-withdrawing substituents are more valuable than the parent anilines in medicinal chemistry because anilines are prone to oxidation.
  • N-alkyl anilines are susceptible to aerobic or metabolic degradation to the corresponding aniline via oxidation by cytochrome P450, and the parent anilines are usually oxidized further to N-aryl hydroxylamines that generate carcinogenic arenium ions.
  • anilines derivatives such as sulfonamides, amides, ureas, or carbamates, possessing electron-withdrawing groups are the derivatives most commonly contained in pharmacophores and agrophores.
  • fluoroalkylanilines have been shown to be more stable toward P450-mediated oxidation than alkyl anilines lacking fluorine atoms. While sharing the electronic properties of the sulfonyl and carbonyl derivatives, the solubility properties, intermolecular interactions, and steric properties of fluoroalkyl anilines are distinct from those of sulfonyl and carbonyl derivatives.
  • Figure 1 shows some aniline derivatives and fluorinated amine derivative examples.
  • Compound 101 is acetaminophen
  • compound 103 is Metolachlor
  • compound 105 is Mauveine A
  • compound 107 is Quazepam (Doral) from Schering Corporation
  • compound 109 is Flupyradifurone from Bayer CropScience
  • compound 111 is a generic structure of fluorinated benzene diamines from L'Oreal, where R is F or CF 3 .
  • Metal-catalyzed C-N coupling reactions provides a general method for preparing fluorinated anilines and allows evaluation of these substructures as part of studies on structure- activity relationships by conducting reactions on the same aryl halide intermediate as would be used to introduce other substituents from nitrogen, oxygen or carbon nucleophiles.
  • general conditions for cross couplings of aryl halides with fluorinated amines have not been reported. Buchwald et al.
  • aryl compounds may include heteroaryl compounds.
  • the products of these reactions are valuable because anilines typically use the presence of an electron withdrawing substituent on nitrogen to suppress aerobic or metabolic oxidation, and the fluoroalkyl groups have distinct steric properties and polarity from more common electron-withdrawing amide and sulfonamide units.
  • the fluoroalkylaniline products are unstable under typical conditions for C-N coupling reactions (heat and strong base).
  • the reactions conducted with the weaker base KOPh which has rarely been used in cross-coupling to form C-N bonds, occurs in high yield in the presence of a catalyst derived from commercially available AdBippyPhos (adamantyl-BippyPhos) and [Pd(allyl)Cl] 2 .
  • Weaker bases suitable for use in various disclosed embodiments may have a conjugate acid pKa in DMSO (dimethyl sulfoxide) of less than about 32, less than about 25, or less than about 20.
  • any oxygen-containing base may be used. Under these conditions, the reactions occur with low catalyst loadings (less than about 0.50 mol% for most substrates) and tolerate the presence of various functional groups that react with the strong bases that are typically used in Pd-catalyzed C-N cross coupling reactions of aryl halides.
  • the resting state of the catalyst is the phenoxide complex, (BippyPhosPd(Ar)OPh); due to the electron-withdrawing property of the fluoroalkyl substituent, the turn-over limiting step of the reaction is reductive elimination to form the C-N bond.
  • the synthesis of trifluoroethyl, difluoroethyl, pentafluoropropyl, and difluorophenethyl anilines by palladium-catalyzed coupling of fluoroalkylamines with chloroarenes, chloroheteroarenes, bromoarenes, and bromoheteroarenes except for bromoindazole may be performed in the presence of any suitable base, including bases that do not include oxygen.
  • aryl bromides and chlorides with primary amines containing fluorine ⁇ -to nitrogen.
  • the reaction occurs with a wide substrate scope, under mild conditions, and with inexpensive reagents, precatalysts, and ligand.
  • One key to developing this process was revealing that strong base leads to decomposition of the product and, therefore, identifying a base that is sufficiently weak to avoid decomposition of the coupled product but sufficiently strong to induce formation of the arylpalladium amido intermediate.
  • a second feature of the reaction is the resting state for operations in which AdBippyPhos is used as a ligand; the major palladium complex in the reaction is an adduct with the phenoxide base.
  • a third unusual feature is the rate-limiting step. The electron-withdrawing property of the fluoroalkyl group retards reductive elimination to form the C-N bond, and kinetic studies indicate that this step has the highest energy transition state, even though the reaction is conducted with a palladium catalyst containing a class of ligand that typically leads to fast reductive elimination.
  • Disclosed embodiments are also suitable for forming enantioenriched anilines.
  • enantioenriched amines may be used to form enantioenriched anilines as disclosed embodiments do not cause enantioenriched amines to become racemic during the reaction.
  • a certain quantity of an enantioenriched aniline may be produced using disclosed embodiments. For example, at least about 0.5 mmol, or at least about 1.0 mmol, or at least about 5.0 mmol, or at least about 10.0 mmol of an enantioenriched aniline may be generated.
  • An enantioenriched compound is defined as having an enantiopurity greater than 0% enantiomeric excess.
  • an enantioenriched compound may be in enantiomeric excess of at least 99% (w/w) over the opposite enantiomer.
  • an enantioenriched compound may be in enantiomeric excess of at least 95% (w/w) over the opposite enantiomer.
  • an enantioenriched compound may be in enantiomeric excess of at least 90% (w/w) over the opposite enantiomer.
  • an enantioenriched compound may be in enantiomeric excess of at least 70% (w/w) over the opposite enantiomer.
  • a highly enantioenriched compound includes only one enantiomer detectable by supercritical fluid chromatography.
  • an enantiopure sample of a fluoroalkylaniline product has only one chiral form.
  • Any suitable primary or secondary amine including such amines that include fluorine may form an aniline under certain process conditions.
  • other suitable catalysts may be selected to react with a highly fluorinated amine to yield a highly fluorinated aniline in accordance with disclosed embodiments.
  • alkali metal phenoxides are stable enough to be handled in air, the phenoxides used in these reactions should have contact with air minimized because metal phenoxides can undergo aerobic oxidation to produce dark colored impurities.
  • the products of phenoxide oxidation may be capable of oxidizing either palladium or the BippyPhos ligand. Therefore, the phenoxides may be prepared as described herein and stored under an inert atmosphere of argon or nitrogen.
  • the phenoxides can be prepared and used in situ by premixing a slight excess of phenol (1.10 equiv) with KOtBu (1.05 equiv) or NaOtBu (1.05 equiv) in the dioxane used to conduct the reaction. While the reaction to produce compound 401 as shown in Figure 4A can be conducted with sodium phenoxide as the base, the scope and mechanism of the reaction with potassium phenoxides is provided herein.
  • Dioxane (2 mL minus the volume of catalyst solution to be added), benzotrifluoride (0.500 mmol, 1.00 equiv, 61.4 uL), liquid aryl halides (0.500 mmol, 1.00 equiv), a dioxane solution of the catalyst (5.00 mM, 10.0 mM BippyPhos, 2.50 mM [Pd(allyl)Cl] 2 ) and trifluoroethylamine (1.00 mmol, 2.00 equiv, 78.5 uL) were added to the vial containing potassium phenoxide. The vial was sealed with a Teflon-lined cap and removed from the glove box.
  • the reaction was heated at 100 °C until 19 F NMR spectra of aliquots showed that the reaction had occurred to greater than 95% conversion or that no additional product was being formed.
  • the reaction was cooled to room temperature, diluted with hexanes, and filtered through a short plug of silica.
  • the silica plug was then rinsed with ethyl acetate and concentrated to give an oil or solid, which were purified by column chromatography by eluting with EtOAc/Hexanes or MeOH/CH 2 Cl 2 . Some products co-elute with the phenol that is generated in the reaction. Phenol was removed from these products by passing the purified product through a plug of basic alumina, eluting with dichloromethane, or by washing an ethereal solution of the aniline with 0.1 M aqueous KOH.
  • Compound 302 of Figure 3B shows the chemical structure for BrettPhos, where R is iBu for iBuBrettPhos, or R is 3,5-bis-CF 3 -Ph for JackiePhos.
  • Compound 303 shows the chemical structure for iBuXPhos where R is iBu.
  • BippyPhos derivatives all of which are commercially available and readily synthesized, form complexes that catalyze this transformation.
  • the reaction of trifluoroethylamine with 4-n-butyl bromobenzene catalyzed by the complex generated from [Pd(allyl)Cl] 2 and iBuBippyPhos formed the product in same yield as the system derived from AdBippyPhos.
  • the yields and conversions for reactions of aryl halides other than 4-ft-butyl bromobenzene were typically higher for reactions conducted with AdBippyPhos than for those conducted with iBuBippyPhos.
  • reaction of trifluoroethylamine with 3-chloropyridine to produce compound 414 of Figure 4B occurred to full conversion with a catalyst loading of 0.400 mol % when generated from a 1 : 1 ratio of Pd to ligand, whereas the same reaction required 0.250 mol % of catalyst to occur to completion with a 1 :2 ratio of Pd to ligand.
  • Figures 4 ⁇ and 4B summarize the scope of the reaction of trifluoroethylamine 202 with a variety of aryl and heteroaryl bromides and chlorides (compound 211, where X is CI or Br and trifluoroethylamine is provided in 2.0 equivalents) under the conditions shown in Table 1 to generate a variety of products 480.
  • the yields refer to isolated material from reactions with 0.5 mmol of aryl or heteroaryl halide.
  • the yield for those labeled "a” were measured by X H MR spectroscopy.
  • the pyridinium hydrochloride salt in those labeled "b” was used with 2.05 equivalents of KOPh.
  • Compound 402 was obtained as a colorless oil using the stated general procedure with the catalyst loadings specified below. It was purified by column chromatography, eluting with 2.5% ethyl acetate in hexanes.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 0.200 mol%> catalyst, 100%> yield.
  • the catalyst loading and isolated yield for aryl bromide was as follows: 0.400 mol% catalyst, 98% yield.
  • Compound 403 was obtained as a colorless oil using the stated general procedure with the catalyst loadings specified below. It was purified by column chromatography, eluting with 5.0% ethyl acetate in hexanes.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 0.400 mol%> catalyst, 93% yield.
  • the catalyst loading and isolated yield for aryl bromide was as follows: 0.200 mol% catalyst, 96% yield.
  • Compound 404 was obtained as a colorless oil using the stated general procedure with the catalyst loading specified below. It was purified by column chromatography, eluting with 10% to 20%) ethyl acetate in hexanes. This oil discolors rapidly at room temperature. The catalyst loading and isolated yield for aryl bromide was as follows: 0.200 mol% catalyst, 96% yield.
  • Compound 405 was obtained as a white solid using the stated general procedure with the catalyst loadings specified below. It was purified by column chromatography, eluting with 5.0%> to 10%) to 20%) ethyl acetate in hexanes.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 0.250 mol% catalyst, 87% yield.
  • the catalyst loading and isolated yield for aryl bromide was as follows: 0.350 mol% catalyst, 86% yield.
  • Compound 406 was obtained as a colorless oil using the stated general procedure with the catalyst loadings specified below. It was purified by column chromatography, eluting with 5.0%> ether in pentane. This compound is volatile.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 0.150 mol% catalyst, 86% yield.
  • the catalyst loading and isolated yield for aryl bromide was as follows: 0.100 mol% catalyst, 99% yield.
  • Compound 407 was obtained as a colorless oil using the stated general procedure with the catalyst loading specified below. It was purified by column chromatography, eluting with 5.0%> ethyl acetate in hexanes. The catalyst loading and isolated yield for aryl bromide was as follows: 0.100 mol% catalyst, 100% yield.
  • Compound 410 was obtained as a light yellow solid using the stated general procedure with the catalyst loading specified below. It was purified by column chromatography, eluting with 1.0% methanol, 25% dichloromethane in hexanes. The catalyst loading and isolated yield for aryl chloride was as follows: 0.800 mol% catalyst, 88% yield.
  • Compound 412 was obtained as a colorless oil using the stated general procedure with the catalyst loadings specified below. It was purified by column chromatography, eluting with 1.3% ethyl acetate in hexanes.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 0.300 mol% catalyst, 95% yield.
  • the catalyst loading and isolated yield for aryl bromide was as follows: 0.500 mol% catalyst, 90% yield.
  • the catalyst loading and NMR yield for aryl chloride was as follows: 0.650 mol% catalyst, 90% yield (determined by 1H MR).
  • the catalyst loading and NMR yield for aryl bromide was as follows: 0.650 mol% catalyst, 89% yield (determined by 1H NMR).
  • Compound 416 was produced using the general procedure except that the hydrochloride salt of the heteroaryl bromide was used. Therefore, 2.05 equiv of potassium phenoxide were added to these reactions. Compound 416 is known and was not isolated. The yield was determined by X H NMR spectroscopy by adding 1,3,5-trimethoxybenzene (0.167 mmol) at the end of the reaction. The catalyst loading and NMR yield for aryl bromide was as follows: 0.650 mol% catalyst, 80% yield (determined by 1H NMR)
  • Compound 420 was obtained as a colorless oil using the stated general procedure with the catalyst loadings specified below. It was purified by column chromatography, eluting with 10% ether in pentane. This oil discolors rapidly at room temperature and is volatile.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 1.50 mol% catalyst, 85% yield.
  • the catalyst loading and isolated yield for aryl bromide was as follows: 1.50 mol% catalyst, 94% yield.
  • Compound 421 was obtained as a yellow solid using the stated general procedure with the catalyst loading specified below. It was purified by column chromatography, eluting with 2.5% ethyl acetate in hexanes.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 0.100 mol% catalyst, 85% yield.
  • EXPERIMENT 5 FLUOROALKYLANILINES DERIVED FROM DIFLUOROETHYL-, PENTAFLUOROPROPYL-, AND ⁇ , ⁇ -D IFLUOROPHENETHYL AMINE
  • Compound 535 was obtained as a colorless oil using the stated general procedure with the catalyst loadings specified below. It was purified by column chromatography, eluting with 10% to 20%) ethyl acetate in hexanes.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 0.400 mol% catalyst, 99% yield.
  • the catalyst loading and isolated yield for aryl bromide was as follows: 0.300 mol% catalyst, 92% yield.
  • Compound 536 was obtained as a colorless oil using the stated general procedure with the catalyst loadings specified below using 1.10 equiv of difluorophenethylamine on a 0.350 mmol scale. It was purified by column chromatography, eluting with 10% ethyl acetate in hexanes.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 0.600 mol% catalyst, 93%) yield.
  • the catalyst loading and isolated yield for aryl bromide was as follows: 0.300 mol% catalyst, 82% yield.
  • Compound 537 was obtained as a colorless oil using the stated general procedure with the catalyst loadings specified below.
  • Compound 540 was obtained as a colorless solid using the stated general procedure with the catalyst loadings specified below. It was purified by column chromatography, eluting with 1%) triethylamine and 20% to 50% ethyl acetate in hexanes.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 0.250 mol% catalyst, 94% yield.
  • the catalyst loading and isolated yield for aryl bromide was as follows: 0.400 mol% catalyst, 92% yield.
  • Compound 541 was obtained as a colorless solid using the stated general procedure with the catalyst loadings specified below. It was purified by column chromatography, eluting with 1%) triethylamine and 20% to 50% ethyl acetate in hexanes.
  • the catalyst loading and isolated yield for aryl chloride was as follows: 0.250 mol% catalyst, 90% yield.
  • the catalyst loading and isolated yield for aryl bromide was as follows: 0.200 mol% catalyst, 96% yield.
  • EXPERIMENT 7 MECHANISTIC STUDIES OF THE COUPLING OF ARYL HALIDES WITH
  • Typical conditions for the Pd-catalyzed coupling reactions to form C-N bonds include strong alkoxide or amide bases, rather than the phenoxide base in the reactions reported here.
  • the fluorinated amines that undergo coupling under these conditions are less basic than the non- fluorinated aliphatic amines that are typically coupled with aryl halides. Therefore, the mechanism of the amination of fluoroalkylamines under the catalytic reaction conditions developed was studied ( Figure 8) to determine the effect of the low basicity and solubility of potassium phenoxide and low nucleophilicity of the amine on the reaction.
  • the reaction was conducted with 0.667 mol % of an equimolar amount of the phenoxide complex 946 and tBuBippyPhos as catalyst, aryl halide 844 as limiting reagent, 1.05 equiv 4- «-Bu-PhOK, and 2.00 equiv trifluoroethylamine in dioxane.
  • the amination reaction was found to be 0 th order in l-chloro-4-fluorobenzene and tBuBippyPhos; it was found to be 1 st order in trifluoroethylamine and in palladium phenoxide complex 946.
  • Figures 10A and 10B are example mechanisms that fit the kinetic data. Both mechanisms include oxidative addition to form an arylpalladium halide complex, conversion of the arylpalladium halide complex to an arylpalladium fluoroalkylamido species, and reductive elimination to form Pd(0) and the C-N bond in the fluoroalkylamido product.
  • the first mechanism involves turnover-limiting reductive elimination
  • the second mechanism involves turnover-limiting formation of a palladium amido complex ( Figure 10B).
  • Oxidative addition of the aryl halide occurs to the palladium(O) species ligated by tBuBippyPhos to generate a tBuBippyPhos(Ar)X complex.
  • This complex reacts with phenoxide to generate the catalyst resting state, phenoxide complex 946.
  • Complex 946 reacts reversibly with trifluoroethylamine to form an amido complex. The transition state with the highest energy is that for reductive elimination.
  • the resting state of the catalyst in the current study is also unique for a coupling to form an arylamine and allows an unusually direct view of the formation of the amido complex.
  • the amido complex has been proposed to form in cross-coupling reactions by coordination of the amine, followed by deprotonation of the bound amine by the base, or by formation of an alkoxide complex, followed by proton transfer to convert the alkoxide complex to an amido complex.
  • the most commonly proposed mechanism is that involving coordination of the amine and deprotonation because an open coordination site is available for binding of the amine.
  • the catalyst resting state for various disclosed embodiments is the phenoxide complex [(iBuBippyPhos)Pd(Ar)(OPh)] (946).
  • the observation of this complex is the first evidence that a monophosphine ligated arylpalladium phenoxide or alkoxide complex can be an intermediate in the coupling process.
  • the turnover- limiting step for the reaction is reductive elimination.
  • the kinetic data provide rare evidence that reductive elimination to form a C-N bond can be rate-limiting during cross-coupling reactions to form amines catalyzed by complexes of the commonly used bulky monophosphines.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne des procédés de synthèse de trifluoroéthylanilines, de difluoroéthylanilines, de pentafluoropropylanilines et de difluorophénéthylanilines par couplage catalysé par le palladium de fluoroalkylamines avec des bromures d'aryle et des chlorures d'aryle. Les réactions sont effectuées avec une base plus faible, telle que KOPh, en présence d'un catalyseur dérivé d'AdBippyPhos et de [Pd(allyle)Cl]2. Les réactions se produisent avec des charges de catalyseur inférieures à environ 0,50 % en moles et tolèrent la présence de divers groupes fonctionnels qui réagissent avec les bases fortes qui sont utilisées de manière caractéristique dans des réactions de couplage croisé C-N catalysées par Pd d'halogénures d'aryle. L'état résiduel du catalyseur est le complexe phénoxyde (BippyPhosPd(Ar)OPh) ; en raison de la propriété d'attraction d'électrons du substituant fluoroalkyle, l'étape limitant l'évolution de la réaction est l'élimination réductrice pour former la liaison C-N.
PCT/US2016/031675 2015-05-11 2016-05-10 Arylation catalysée par le palladium de fluoroalkylamines Ceased WO2016183101A1 (fr)

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CN108997144A (zh) * 2018-07-13 2018-12-14 沅江华龙催化科技有限公司 一种铁卟啉催化芳香伯胺三氟乙基化的方法
CN108997145A (zh) * 2018-07-13 2018-12-14 沅江华龙催化科技有限公司 一种铁卟啉催化芳香仲胺三氟乙基化的方法
CN111116653A (zh) * 2020-01-02 2020-05-08 河北工业大学 一种吡唑联三氮唑膦化合物的制备方法
CN117105792A (zh) * 2023-08-30 2023-11-24 济南正光化工科技开发有限公司 一种2，2-二氟乙胺的合成方法

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108997144A (zh) * 2018-07-13 2018-12-14 沅江华龙催化科技有限公司 一种铁卟啉催化芳香伯胺三氟乙基化的方法
CN108997145A (zh) * 2018-07-13 2018-12-14 沅江华龙催化科技有限公司 一种铁卟啉催化芳香仲胺三氟乙基化的方法
CN108997145B (zh) * 2018-07-13 2021-01-15 沅江华龙催化科技有限公司 一种铁卟啉催化芳香仲胺三氟乙基化的方法
CN108997144B (zh) * 2018-07-13 2021-01-15 沅江华龙催化科技有限公司 一种铁卟啉催化芳香伯胺三氟乙基化的方法
CN111116653A (zh) * 2020-01-02 2020-05-08 河北工业大学 一种吡唑联三氮唑膦化合物的制备方法
CN111116653B (zh) * 2020-01-02 2022-08-12 河北工业大学 一种吡唑联三氮唑膦化合物的制备方法
CN117105792A (zh) * 2023-08-30 2023-11-24 济南正光化工科技开发有限公司 一种2，2-二氟乙胺的合成方法

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