WO2011008618A1 - Formation de liaison carbone-fluor catalysée par un métal - Google Patents

Formation de liaison carbone-fluor catalysée par un métal Download PDF

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WO2011008618A1
WO2011008618A1 PCT/US2010/041308 US2010041308W WO2011008618A1 WO 2011008618 A1 WO2011008618 A1 WO 2011008618A1 US 2010041308 W US2010041308 W US 2010041308W WO 2011008618 A1 WO2011008618 A1 WO 2011008618A1
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hydrogen
propyl
ligand
certain embodiments
group
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Mark Saeys
Stephen Leffler Buchwald
Donald Allen Watson
Mingjuan Su
Georgiy Teverovskiy
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National University Of Singapore
Massachusetts Institute Of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2282—Unsaturated compounds used as ligands
    • B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/04—Substitution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/20—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms
    • C07C17/202—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction
    • C07C17/208—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction the other compound being MX
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/824—Palladium

Definitions

  • Radioactive 18 F-labelled organic compounds are also widely used as contrast agents for positron emission tomography (PET).
  • PET positron emission tomography
  • Halex reaction can be performed at room temperature when using anhydrous tetrabutylammonium fluoride, but the scope is limited and the fluoride source is not readily amenable to the preparation of 18 F-labelled compounds (H. Sun, S. G. DiMagno, Angew. Chem. Int. Ed. 45, 2720 (2006)).
  • One aspect of the invention relates to a metal-catalyzed direct conversion of aryl halides and sulfonates into their corresponding aryl fluorides. Another aspect of the invention relates to a metal-catalyzed direct conversion of heteroaryl halides and sulfonates into their corresponding heteroaryl fluorides. Another aspect of the invention relates to a metal-catalyzed direct conversion of vinyl halides and sulfonates into their corresponding vinyl fluorides.
  • simple fluoride sources such as AgF and CsF, are used.
  • the transformation tolerates a number of functional groups, allowing for introduction of fluorine atoms into highly functionalized organic molecules.
  • Figure 1 depicts a scheme showing a metal-catalyzed fluorination; the proposed catalytic cycle for the same; and examples of two ligands which may be used for the metal- catalyzed fluorination.
  • Figure 2 depicts a scheme showing the preparation of and reductive elimination from [2 # PdAr(F)] complexes; and an x-ray structure of complex 4.
  • Figure 3 depicts the catalytic conversion of aryl bromide 8 to aryl fluoride 7.
  • Figure 4 depicts a table showing the optimization of fluorination of aryl triflates.
  • Figure 5 depicts examples of the fluorination of aryl triflates.
  • Figure 6 depicts a table showing regioisomers for the tolyl and anisole series, and a comparison with the ratios obtained from a reported fluorination of bromoaryls that proceeds via a benzyne intermediate.
  • Figure 7 depicts a table showing the results of a particular fluorination in a number of solvents, and the results of fluorinations of other triflates which gave mixtures of regioisomeric products.
  • Figure 8 depicts a representative procedure for the fluorination reaction of aryl triflates (i.e., X is -OTf).
  • Figure 9 depicts (Brettphos)Pd(2-Me,4-CF 3 C 6 H 3 )(Br) and its 1 FI NMR spectrum.
  • Figure 10 depicts (Brettphos)Pd(2-Me,4-CF 3 C 6 H 3 )(F) (4) and its 1 FI NMR spectrum.
  • Figure 11 depicts (Brettphos)Pd(2-Me,4-CNC 6 H 3 )(Br) and its 1 H NMR spectrum.
  • Figure 12 depicts (Brettphos)Pd(2-Me,4-CNC 6 H 3 )(F) (5) and its 1 FI NMR spectrum.
  • Figure 13 depicts the reductive elimination of (Brettphos)Pd(2-Me,4-CF 3 C 6 H 3 )(F)
  • Figure 14 depicts (Brettphos)Pd(2-Me,4-CNC 6 H 3 )(F) (5), and a graph depicting the effect of an additive on the reaction.
  • Figure 15 depicts the results of a particular fluorination reaction using a range of ligands.
  • Figure 16 depicts the results of a particular fluorination reaction using a range of palladium sources.
  • Figure 17 depicts the results of two fluorination reactions using a range of solvents.
  • Figure 18 depicts the results of a particular fluorination reaction using a range of additives.
  • Figure 19 depicts the conversion of 1-naphthyl trifluoromethanesulfonate to 1- fluoronaphthalene using ligand L21 at two temperatures.
  • Figure 20 depicts the results of a particular fluorination reaction using chloro and iodo substrates.
  • Figure 21 depicts the activation energies for carbon- fluorine bond- forming reductive elimination.
  • Figure 22 depicts the biarylphosphine ligands (L1-L20) and palladium-bound aryl groups (21a-28a).
  • Figure 23 depicts the activation energies for carbon-fluorine bond-forming reductive elimination.
  • Figure 24 depicts contour diagrams of p(r) for 43 at its transition state.
  • the solid circles represent the atom center, the solid triangle is the (3, -1) critical point located between the two atoms, and the line between them is the bond path connecting F and H (see illustration on the right).
  • Figure 25 depicts the standard Hammett plots for reductive elimination of aryl fluorides from [Ll-PdAr(F)] .
  • thermolysis of 4 and 5 was examined at 100 0 C in toluene and it was found that reductive elimination to form 6 and 7 occurs in yields of 15% and 25%, respectively ( Figure 2). It was determined that these reductive eliminations take place with first order kinetics with half-lives of 14 and 16 min. The yields could be increased to 45% of 6 and 55% of 7 if the reductive eliminations were conducted in the presence of an excess of the corresponding aryl bromide. The lower yield in the absence of added aryl bromide suggests that the 2 -Pd 0 complex that results from reductive elimination further reacts with remaining [2-PdAr(F)] complex.
  • aryl triflates have significant scope. Simple aromatic substrates, like biphenyl triflate, react rapidly to provide aryl fluoride 12 in high yield. Hindered substrates such as 4 acetyl-2,6-dimethylphenyl triflate are also efficiently converted to product (13). Electron-deficient ones can be transformed using only 2 mol% of catalyst (14, 18, 19). Importantly, a variety of heterocyclic substrates can also be successfully employed using these fluorination conditions. Flavones (17), indoles (21), and quinolines (22-24) all gave product in good yield. More complex aryl triflates derived from fluorescein (20) and quinine (25) could also be effectively converted to their fluorinated analogues, demonstrating that this method can be used in the preparation of
  • one aspect of the present invention relates to a transition metal-catalyzed fluorination reaction that comprises combining an fluoride source with a substrate aryl, heteroaryl or vinyl group bearing an activated group X.
  • the reaction includes at least a catalytic amount of a transition metal catalyst, comprising a ligand, and the combination is maintained under conditions appropriate for the metal catalyst to catalyze the reaction.
  • Suitable substrates include compounds derived from simple aromatic rings (single or polycyclic) such as benzene, naphthalene, anthracene and phenanthrene; or heteroaromatic rings (single or polycyclic), such as pyrrole, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, thiazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, carboline
  • the aryl substrate may be selected from the group consisting of phenyl and phenyl derivatives, heteroaromatic compounds, polycyclic aromatic and heteroaromatic compounds, and functionalized derivatives thereof.
  • Suitable aromatic compounds derived from simple aromatic rings and heteroaromatic rings include but are not limited to, pyridine, imidizole, quinoline, furan, pyrrole, thiophene, and the like.
  • Suitable aromatic compounds derived from fused ring systems include but are not limited to naphthalene, anthracene, tetralin, indole and the like.
  • Suitable aromatic compounds may have the formula ZpArX, where X is an activated substituent.
  • An activated substituent, X is characterized as being a good leaving group.
  • the leaving group is a group such as a halide or sulfonate.
  • Suitable activated substituents include, by way of example only, halides such as chloride, bromide and iodide, and sulfonate esters such as triflate, mesylate, nonaflate and tosylate.
  • the leaving group is a halide selected from iodine, bromine, and chlorine.
  • the leaving group is a phosphonate, ammonium salt, ester or alkyloxy leaving group.
  • Z represents one or more optional substituents on the aromatic ring, though each occurrence of Z (p>l) is independently selected.
  • each incidence of substitution independently can be, as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (e.g., an ester, a carboxylate, or a formate), a thiocarbonyl (e.g., a thiolester, a thiolcarboxylate, or a thiolformate), a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a halogen, a lower al
  • n and m are independently for each occurrence zero or an integer in the range of 1 to 6.
  • P is preferably in the range of 0 to 5.
  • p may be adjusted appropriately.
  • the substitution is limited to the para- and/or meta- position, relative to the X substituent.
  • chelating substituents are excluded from the ortho-position, again relative to the X substituent.
  • suitable substituents Z include alkyl, aryl, acyl, heteroaryl, amino, carboxylic ester, carboxylic acid, hydrogen, ether, thioether, amide, carboxamide, nitro, phosphonic acid, hydroxyl, sulfonic acid, halide, pseudohalide groups, and substituted derivatives thereof, and p is in the range of 0 to 5.
  • the reaction is anticipated to be compatible with acetals, amides and silyl ethers. For fused rings, where the number of substitution sites on the aromatic ring increases, p may be adjusted
  • substrate aryl, heteroaryl and vinyl groups are useful in the methods of the present invention.
  • the choice of substrate will depend on the desired product, and an appropriate substrate will be made apparent to the skilled artisan by these teachings. It will be understood that the substrate preferably will not contain any interfering
  • the "transition metal catalyst" of the present invention shall include any catalytic transition metal and/or catalyst precursor as it is introduced into the reaction vessel and which is, if necessary, converted in situ into the active form, as well as the active form of the catalyst which participates in the reaction.
  • the transition metal catalyst complex is provided in the reaction mixture is a catalytic amount. In certain embodiments, that amount is in the range of 0.0001 to 20 mol% or 0.05 to 15 mol%, or is about 10 mol%, with respect to the substrate. In the instance where the molecular formula of the catalyst complex includes more than one metal, the amount of the catalyst complex used in the reaction may be adjusted accordingly.
  • Pd 2 (dba) 3 has two metal centers; and thus the molar amount of Pd 2 (dba) 3 used in the reaction may be halved without sacrificing catalytic activity.
  • catalysts containing palladium and nickel are preferred. It is expected that these catalysts will perform similarly because they are known to undergo similar reactions, namely oxidative-addition reactions and reductive-elimination reactions, which are thought to be involved in the formation of the products of the present invention.
  • any transition metal e.g., having d electrons
  • the metal will be selected from the group of late transition metals, e.g., preferably from Groups 5-12 and even more preferably Groups 7-11.
  • suitable metals include platinum, palladium, iron, nickel, ruthenium and rhodium.
  • the particular form of the metal to be used in the reaction is selected to provide, under the reaction conditions, metal centers which are coordinately unsaturated and not in their highest oxidation state.
  • the metal core of the catalyst should be a low valent transition metal, such as Pd or Ni with the ability to undergo oxidative addition to A-X bond.
  • the transition metal is Rh or Fe, which are isoelectonic with Pd(O).
  • suitable transition metal catalysts include soluble or insoluble complexes of platinum, palladium and nickel. Nickel and palladium are particularly preferred and palladium is most preferred.
  • a low- valent metal center is presumed to participate in the catalytic carbon-heteroatom or carbon-carbon bond forming sequence. Thus, the metal center is desirably in the low- valent state or is capable of being reduced to metal(O).
  • Suitable soluble palladium complexes include, but are not limited to, (COD)Pd(CH 2 TMS) 2 ,
  • the active species for the oxidative-addition step may be in the metal (+1) oxidation state.
  • the coupling can be catalyzed by a palladium catalyst which palladium may be provided in the form of, for illustrative purposes only, Pd/C, PdCl 2 , Pd(OAc) 2 ,
  • the reaction can be catalyzed by a nickel catalyst which nickel may be provided in the form of, for illustrative purposes only, Ni(acac) 2 , NiCl 2 [P(C 6 Hs)J 2 , Ni(l,5-cyclooctadiene) 2 , Ni(1, 10- phenanthroline) 2 , Ni(dppf) 2 , NiCl 2 (dppf), NiCl 2 (1, 10-phenanthroline), Raney nickel and the like, wherein "acac " represents acetylacetonate.
  • the catalyst will preferably be provided in the reaction mixture as metal-ligand complex comprising a bound supporting ligand, that is, a metal-supporting ligand complex.
  • the ligand effects can be key to favoring, inter alia, the reductive elimination pathway or the like which produces the products, rather than side reactions such as ⁇ -hydride elimination.
  • the ligand if chiral, can be provided as a racemic mixture or a purified stereoisomer.
  • the catalyst complex may include additional supporting ligands as required to obtain a stable complex.
  • the ligand can be added to the reaction mixture in the form of a metal complex, or added as a separate reagent relative to the addition of the metal.
  • the supporting ligand may be added to the reaction solution as a separate compound or it may be complexed to the metal center to form a metal-supporting ligand complex prior to its introduction into the reaction solution.
  • Supporting ligands are compounds added to the reaction solution which are capable of binding to the catalytic metal center.
  • the supporting ligand is a chelating ligand.
  • the supporting ligands suppress unwanted side reactions as well as enhance the rate and efficiency of the desired processes. Additionally, they typically prevent precipitation of the catalytic transition metal.
  • the present invention does not require the formation of a metal-supporting ligand complex, such complexes have been shown to be consistent with the postulate that they are intermediates in these reactions and it has been observed the selection of the supporting ligand has an affect on the course of the reaction.
  • the supporting ligand is present in the range of 0.0001 to 40 mol% relative to the limiting reagent.
  • the ratio of the supporting ligand to catalyst complex is typically in the range of about 1 to 20. These ratios are based upon a single metal complex and a single binding site ligand. In instances where the ligand contains additional binding sites (i.e., a chelating ligand) or the catalyst contains more than one metal, the ratio is adjusted accordingly.
  • the supporting ligand BINAP contains two coordinating phosphorus atoms and thus the ratio of BINAP to catalyst is adjusted downward to about 1 to 10.
  • Pd 2 (dba)3 contains two palladium metal centers and the ratio of a non-chelating ligand to Pd 2 (dba) 3 is adjusted upward to 1 to 40.
  • the transition metal catalyst includes one or more phosphine or aminophosphine ligands, e.g., as a Lewis basic ligand that controls the stability and electron transfer properties of the transition metal catalyst, and/or stabilizes the metal intermediates.
  • Phosphine ligands are commercially available or can be prepared by methods similar to known processes.
  • the phosphines can be monodentate phosphine ligands, such as di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxybiphenyl-2- yl)phosphine (BrettPhos), dicyclohexyl(2',4',6'-triisopropyl-3 ,6-dimethoxybiphenyl-2- yl)phosphine (tBuBrettPhos), trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, tricyclohexylphosphine, trimethyl phosphite, triethyl phosphite, tripropyl phosphite, triisopropyl phosphite, tributyl phosphite, triis
  • phosphine ligand such as 2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (BINAP), l,2-bis(dimethylphosphino)ethane, 1,2- bis(diethylphosphino)ethane, 1 ,2-bis(dipropylphosphino)-ethane, 1 ,2- bis(diisopropylphosphino)ethane, 1 ,2-bis(dibutylphosphino)ethane, 1 ,2- bis(dicyclohexylphosphino)ethane, 1 ,3-bis(dicyclohexylphosphino)propane, 1 ,3-bis(diiso- propylphosphino)propane, l,4-bis(diisopropylphosphine ligand
  • BINAP 2,2'- bis(diphenylphosphino)-l,
  • the aminophosphines may be monodentate, e.g., each molecule of aminophosphine donates to the catalytic metal atom only a Lewis basic nitrogen atom or a Lewis basic phosphorus atom.
  • the aminophosphine may be a chelating ligand, e.g., capable of donating to the catalytic metal atom both a Lewis basic nitrogen atom and a Lewis basic phosphorus atom.
  • Phase-transfer catalysis is a technique for enhancing the reactivity of anions which are soluble in one phase, with an organic reactant which is soluble in another phase, in a system in which the two phases are immiscible.
  • phase-transfer catalysts include ammonium or phosphonium salts, polyethylene glycols, polyethylene glycol ethers, polyethylene glycol esters and crown ethers.
  • the phase-transfer catalyst is a poly(ethylene) glycol (PEG), which may have one or both ends "capped” as an ether (e.g., a methyl ether) or an ester (e.g. a methyl ester).
  • PEGs are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 300 g/mol to
  • n 10,000,000 g/mol.
  • a general depiction of PEG is shown below, wherein n is an integer.
  • the phase-transfer catalyst is PEG 2000, Me 2 PEG 2000, PEG 3400 or Me 2 PEG 3400.
  • the phase-transfer catalyst is a crown ether. Crown ethers consist of a ring containing several ether groups.
  • crown ethers are oligomers of ethylene oxide (i.e., with -CH 2 CH 2 O- as the repeating unit).
  • the phase transfer catalyst is a crown ether is selected from the group consisting of 18-crown-6, 15-crown-5 and 12-crown-4, and mixtures thereof.
  • the subject reactions are carried out in a liquid reaction medium.
  • the reactions may be run without addition of solvent.
  • the reactions may be run in an inert solvent, preferably one in which the reaction ingredients, including the catalyst, are substantially soluble.
  • Suitable solvents include ethers such as diethyl ether, 1,2- dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, water and the like;
  • halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, xylene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2- butanone; polar aprotic solvents such as acetonitrile, dimethylformamide and the like; or combinations of two or more solvents.
  • the invention also contemplates reaction in a biphasic mixture of solvents, in an emulsion or suspension, or reaction in a lipid vesicle or bilayer. In certain embodiments, it may be preferred to perform the catalyzed reactions in the solid phase with one of the reactants or a ligand anchored to a solid support.
  • the fluoride source is an alkali metal fluoride, an alkali earth metal fluoride or a transition metal fluoride.
  • the fluoride source is NaF, KF, CsF, tetraalkylammonium fluoride, tetrafluoroborate (AgBF 4 ) or tetraalkylphosphonium fluoride.
  • the fluoride source used in a method of the invention is [ 18 F]fluoride source.
  • the [ 18 F]fluoride source is Na 18 F,
  • the methods of the invention enable the formation of carbon- fluoride bonds via a transition metal catalyzed reaction under conditions that would not yield appreciable amounts of the observed product(s) using methods known in the art.
  • the present invention relates to a method represented by Scheme 1: fluoride source
  • A is selected from the group consisting of optionally substituted aryl, optionally
  • Y is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • X is selected from the group consisting of -Cl, -Br, -I, -OS(O) 2 alkyl,
  • the fluoride source is an alkali metal fluoride, an alkali earth metal fluoride or a transition metal fluoride
  • the transition metal source comprises Ni, Pd or Pt;
  • the ligand is a phosphine-containing ligand, and is achiral or, when chiral, is a single stereoisomer or a mixture of stereoisomers.
  • the present invention relates to any one of the aforementioned methods, wherein A is optionally substituted aryl.
  • the present invention relates to any one of the aforementioned methods, wherein A is an optionally substituted phenyl or optionally substituted naphthyl.
  • the present invention relates to any one of the aforementioned methods, wherein A is optionally substituted heteroaryl.
  • the present invention relates to any one of the
  • the present invention relates to any one of the aforementioned methods, wherein X is selected from the group consisting of -Cl, -Br, and -I. [0082] In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein X is -Br.
  • the present invention relates to any one of the aforementioned methods, wherein X is selected from the group consisting of -OS(O) 2 alkyl,
  • the present invention relates to any one of the aforementioned methods, wherein X is -OTf.
  • the present invention relates to any one of the aforementioned methods, wherein the fluoride source is AgF, CsF or KF.
  • the present invention relates to any one of the aforementioned methods, wherein the fluoride source is CsF.
  • the present invention relates to any one of the aforementioned methods, wherein the fluoride source comprises 18 F " .
  • the present invention relates to any one of the aforementioned methods, wherein the fluoride source is Cs 18 F.
  • the present invention relates to any one of the aforementioned methods, wherein about 1 molar equivalent of the fluoride source is used relative to the substrate.
  • the present invention relates to any one of the aforementioned methods, wherein about 1.5 molar equivalents of the fluoride source are used relative to the substrate.
  • the present invention relates to any one of the aforementioned methods, wherein about 3 molar equivalents of the fluoride source are used relative to the substrate.
  • the present invention relates to any one of the aforementioned methods, wherein about 4.5 molar equivalents of the fluoride source are used relative to the substrate.
  • the present invention relates to any one of the aforementioned methods, wherein about 6 molar equivalents of the fluoride source are used relative to the substrate.
  • the present invention relates to any one of the aforementioned methods, wherein the transition metal source comprises Pd. [0095] In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the transition metal source comprises only one transition metal, which transition metal is Pd.
  • the present invention relates to any one of the
  • transition metal source is selected from the group consisting Of (COD)Pd(CH 2 TMS) 2 , Pd 2 dba 3 , [allylPdCl] 2 , [cinnamylPdCl] 2 and tmedaPdMe 2 .
  • the present invention relates to any one of the
  • the ligand is a monophosphine ligand.
  • the present invention relates to any one of the
  • the ligand is a biphenyl-based monophosphine ligand.
  • the present invention relates to any one of the
  • the ligand is a ligand described in International
  • the present invention relates to any one of the
  • the ligand is a biphenyl ligand as described in International Application No. PCT/US2008/086651 (see, for example, pages 19-38, which are hereby incorporated by reference).
  • the present invention relates to any one of the
  • monophosphine ligand an optionally substituted phenyl-heteroaryl monophosphine ligand, or an optionally substituted heteroaryl-heteroaryl monophoshine ligand.
  • the present invention relates to any one of the
  • R is alkyl, adamantyl, fluoroalkyl, cycloalkyl, aryl, heteroaryl, heterocycyl, aryloxy, or heteroaryloxy;
  • R 1 is hydrogen, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, alkyl amino, dialkyamino, acylamino, N-lactamyl or imidyl;
  • R 2 is hydrogen or alkyl;
  • R 3 is hydrogen or alkyl;
  • R 4 is hydrogen, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, or dialkyl amino;
  • R 7 is hydrogen, alkyl, fluoroalkyl, aryl, or -C(aryl)
  • the present invention relates to any one of the aforementioned methods, wherein R is selected from the group consisting of cyclohexyl, t-
  • the present invention relates to any one of the aforementioned methods, wherein R is cyclohexyl.
  • the present invention relates to any one of the aforementioned methods, wherein R is t-butyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is methyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is methoxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is i-propyloxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is trifluoromethyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is trifluoromethoxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is dimethyl amino.
  • the present invention relates to any one of the aforementioned methods, wherein R 2 is hydrogen.
  • the present invention relates to any one of the aforementioned methods, wherein R 2 is methyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 3 is hydrogen. [0115] In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein R 3 is methyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 4 is hydrogen.
  • the present invention relates to any one of the aforementioned methods, wherein R 4 is methyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 4 is methoxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is hydrogen; R 2 is hydrogen; R 3 is hydrogen; and R 4 is hydrogen.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is methyl; R2 is methyl; R3 is methyl; and R4 is methyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is methoxy; and R 4 is methoxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is i-propyloxy; and R 4 is methoxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is methoxy; and R 4 is methyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is methoxy; R 2 is hydrogen; R 3 is hydrogen; and R 4 is methoxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is i-propyloxy; R 2 is hydrogen; R 3 is hydrogen; and R 4 is methoxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is methoxy; R 2 is hydrogen; R 3 is hydrogen; and R 4 is methyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 1 is dimethyl amino; R 2 is hydrogen; R 3 is hydrogen; and
  • R 4 is hydrogen
  • the present invention relates to any one of the aforementioned methods, wherein R 5 is hydrogen. [0129] In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein R 5 is i-propyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 5 is methoxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 6 is hydrogen.
  • the present invention relates to any one of the aforementioned methods, wherein R 6 is trifluoromethyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 6 is methoxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 7 is hydrogen.
  • the present invention relates to any one of the aforementioned methods, wherein R 7 is alkyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 7 is i-propyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 7 is t-butyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 7 is -C(Ph) 3 .
  • the present invention relates to any one of the aforementioned methods, wherein R 7 is trifluoromethyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 7 is aryl.
  • the present invention relates to any one of the aforementioned methods, wherein R 8 is hydrogen.
  • the present invention relates to any one of the aforementioned methods, wherein R 8 is trifluoromethyl.
  • the present invention relates to any one of the aforementioned methods, wherein R 8 is methoxy.
  • the present invention relates to any one of the aforementioned methods, wherein R 9 is hydrogen. [0146] In certain embodiments, the present invention relates to any one of the
  • the present invention relates to any one of the
  • R 9 is i-propyl
  • the present invention relates to any one of the
  • R 5 is i-propyl
  • R 9 is i-propyl
  • the present invention relates to any one of the
  • R 5 is i-propyl
  • R 7 is t-butyl
  • R 9 is i-propyl
  • the present invention relates to any one of the
  • R 5 is i-propyl
  • R 7 is trifluoromethyl
  • R 9 is i-propyl
  • the present invention relates to any one of the
  • R 5 is i-propyl
  • R 7 is i-propyl
  • R 9 is i-propyl
  • the present invention relates to any one of the
  • R 5 is i-propyl
  • R 6 is hydrogen
  • R 7 is trifluoromethyl
  • R 8 is hydrogen
  • R 9 is i-propyl
  • the present invention relates to any one of the
  • R 5 is i-propyl
  • R 6 is hydrogen
  • R 7 is t-butyl
  • R 8 is hydrogen
  • R 9 is i-propyl
  • the present invention relates to any one of the
  • R 5 is i-propyl
  • R 6 is hydrogen
  • R 7 is i-propyl
  • R 8 is hydrogen
  • R 9 is i-propyl
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • R 5 is hydrogen; R 6 is trifluoromethyl; R 7 is hydrogen; R 8 is trifluoromethyl; and R 9 is hydrogen.
  • the present invention relates to any one of the
  • ligand is selected from the group consisting of (tBuBrettPhos),
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • Ni, Pd or Pt is present in between about 2 mol% and about 10 mol% relative to the substrate.
  • the present invention relates to any one of the
  • the temperature is between about 25°C and about 200 0 C.
  • the present invention relates to any one of the
  • the temperature is between about 70 0 C and about 0 C.
  • the present invention relates to any one of the
  • the temperature is about 100 0 C.
  • the present invention relates to any one of the
  • the temperature is about 130 0 C.
  • the present invention relates to any one of the
  • the solvent is toluene, benzene, dibutyl ether, THF, cyclohexane, n-heptane, 1,4-dioxane, DME, ⁇ , ⁇ , ⁇ -trifluorotoluene, DMF, or a mixture thereof.
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the
  • the present invention relates to any one of the aforementioned methods, further comprising a solubilizing additive.
  • the present invention relates to any one of the aforementioned methods, wherein the solubilizing additive is PEG wherein one or both ends of the PEG may be capped as alkyl ethers.
  • the present invention relates to any one of the aforementioned methods, wherein the solubilizing additive is PEG 2000, Me 2 PEG 2000, PEG
  • the present invention relates to any one of the aforementioned methods, wherein the reaction is done under anhydrous conditions.
  • the reactions typically proceed at mild temperatures and pressures to give high yields of the product aryl fluoride, heteroaryl fluoride, or vinyl fluoride.
  • yields of desired products greater than 45%, greater than 75%, and greater than 80% may be obtained from reactions at mild temperatures according to the invention.
  • microwave refers to that portion of the electromagnetic spectrum between about 300 and 300,000 megahertz (MHz) with wavelengths of between about one millimeter (1 mm) and one meter (I m). These are, of course, arbitrary boundaries, but help quantify microwaves as falling below the frequencies of infrared radiation but above those referred to as radio frequencies. Similarly, given the well-established inverse relationship between frequency and wavelength, microwaves have longer wavelengths than infrared radiation, but shorter than radio frequency wavelengths. Microwave-assisted chemistry techniques are generally well established in the academic and commercial arenas.
  • Microwaves have some significant advantages in heating certain substances.
  • the microwaves when microwaves interact with substances with which they can couple, most typically polar molecules or ionic species, the microwaves can immediately create a large amount of kinetic energy in such species which provides sufficient energy to initiate or accelerate various chemical reactions.
  • Microwaves also have an advantage over conduction heating in that the surroundings do not need to be heated because the microwaves can react instantaneously with the desired species.
  • reaction processes of the present invention can be conducted in continuous, semi-continuous or batch fashion and may involve a liquid recycle operation as desired.
  • the processes of this invention are preferably conducted in batch fashion.
  • the manner or order of addition of the reaction ingredients, catalyst and solvent are also not generally critical to the success of the reaction, and may be accomplished in any conventional fashion.
  • the reaction can be conducted in a single reaction zone or in a plurality of reaction zones, in series or in parallel or it may be conducted batchwise or continuously in an elongated tubular zone or series of such zones.
  • the materials of construction employed should be inert to the starting materials during the reaction and the fabrication of the equipment should be able to withstand the reaction temperatures and pressures.
  • Means to introduce and/or adjust the quantity of starting materials or ingredients introduced batchwise or continuously into the reaction zone during the course of the reaction can be conveniently utilized in the processes especially to maintain the desired molar ratio of the starting materials.
  • the reaction steps may be effected by the incremental addition of one of the starting materials to the other. Also, the reaction steps can be combined by the joint addition of the starting materials to the metal catalyst. When complete conversion is not desired or not obtainable, the starting materials can be separated from the product and then recycled back into the reaction zone.
  • the processes may be conducted in either glass lined, stainless steel,
  • reaction zone may be fitted with one or more internal and/or external heat exchanger(s) in order to control undue temperature fluctuations, or to prevent any possible "runaway" reaction temperatures.
  • one or more of the reactants can be immobilized on or incorporated into a polymer or other insoluble matrix by, for example, derivativation with one or more of the substituents of the aryl group.
  • the subject fluorination can be used as part of combinatorial synthesis schemes to yield libraries of aryl fluorides, heteroaryl fluorides and/or vinyl fluorides.
  • another aspect of the present invention relates to use of the subject method to generate variegated libraries of aryl fluorides, heteroaryl fluorides and/or vinyl fluorides, and to the libraries themselves.
  • the libraries can be soluble or linked to insoluble supports, e.g., through a substituent of a reactant (prior to carrying out a reaction of the present invention), e.g., the aryl group, heteroaryl group or vinyl group.
  • the methods of the invention can be used to produce synthetic intermediates that, after being subjected to additional methods known in the art, are transformed to desired end products, e.g., lead compounds in medicinal chemistry programs, pharmaceuticals, insecticides, antivirals and antifungals.
  • substrate aryl group refers to such groups containing an electrophilic atom which is susceptible to the subject fluorination reaction, e.g., the electrophilic atom bears a leaving group.
  • electrophilic atom which is susceptible to the subject fluorination reaction, e.g., the electrophilic atom bears a leaving group.
  • the substrate is represented by A-X, and X is the leaving group.
  • the aryl, heteroaryl or vinyl group, A is said to be substituted if, in addition to X, it is substituted at yet other positions.
  • the substrate aryl, heteroaryl or vinyl groups are a component of a larger molecule.
  • nucleophile is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons.
  • Electrophilic moieties useful in the method of the present invention include halides and sulfonates.
  • electrophilic atom refers to the atom of the substrate aryl moiety which is attacked by, and forms a new bond to the nucleophilic heteroatom of the hydrazine and the like. In most (but not all) cases, this will also be the aryl ring atom from which the leaving group departs.
  • electron- withdrawing group is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms.
  • a quantification of the level of electron- withdrawing capability is given by the Hammett sigma (s) constant. This well known constant is described in many references, for instance, J. March, Advanced Organic Chemistry, McGraw Hill Book Company, New York, (1977 edition) pp. 251-259.
  • Exemplary electron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, cyano, chloride, and the like.
  • Exemplary electron- donating groups include amino, methoxy, and the like.
  • reaction product means a compound which results from the reaction of the fluoride source and the substrate.
  • reaction product will be used herein to refer to a fluorinated aryl, heteroaryl or vinyl group.
  • catalytic amount is recognized in the art and means a
  • a catalytic amount means from 0.0001 to 90 mole percent reagent relative to a reactant, more preferably from 0.001 to 50 mole percent, still more preferably from 0.01 to 10 mole percent, and even more preferably from 0.1 to 5 mole percent reagent to reactant.
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • alkenyl as used herein, means a straight or branched chain
  • alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, A- pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tertbutoxy, pentyloxy, and hexyloxy.
  • alkoxysulfonyl as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxy sulfonyl and propoxy sulfonyl.
  • arylalkoxy and "heteroalkoxy” as used herein, means an aryl group or heteroaryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of arylalkoxy include, but are not limited to, 2-chlorophenylmethoxy, 3-trifluoromethylethoxy, and 2,3-methylmethoxy.
  • arylalkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • alkyl means a straight or branched chain hydrocarbon containing from
  • alkyl 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
  • alkylcarbonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,
  • alkylcarbonyloxy and "arylcarbonyloxy” as used herein, means an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
  • Representative examples of arylcarbonyloxy include, but are not limited to phenylcarbonyloxy .
  • alkylsulfonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • alkylthio means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.
  • alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • arylthio alkenylthio
  • arylakylthio for example, are likewise defined.
  • alkynyl as used herein, means a straight or branched chain
  • alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • amino refers to radicals of both unsubstituted and substituted amines appended to the parent molecular moiety through a nitrogen atom.
  • the two groups are each independently hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,
  • arylcarbonyl or formyl.
  • Representative examples include, but are not limited to
  • aromatic refers to a planar or polycyclic structure characterized by a cyclically conjugated molecular moiety containing 4n+2 electrons, wherein n is the absolute value of an integer.
  • Aromatic molecules containing fused, or joined, rings also are referred to as bicylic aromatic rings.
  • bicyclic aromatic rings containing heteroatoms in a hydrocarbon ring structure are referred to as bicyclic heteroaryl rings.
  • aryl as used herein, means a phenyl group or a naphthyl group.
  • the aryl groups of the present invention can be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkenyl, alkoxy,
  • arylene is art-recognized, and as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms of an aryl ring, as defined above.
  • arylalkyl or “aralkyl” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl, and 2-naphth-2-ylethyl.
  • arylalkoxy or “arylalkyloxy” as used herein, means an arylalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen.
  • heteroarylalkoxy as used herein, means an heteroarylalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen.
  • arylalkylthio as used herein, means an arylalkyl group, as defined herein, appended to the parent molecular moiety through an sulfur.
  • heteroarylalkylthio as used herein, means an heteroarylalkyl group, as defined herein, appended to the parent molecular moiety through an sulfur.
  • arylalkenyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkenyl group.
  • a representative example is phenylethylenyl.
  • arylalkynyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkynyl group.
  • a representative example is phenylethynyl.
  • arylcarbonyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.
  • arylcarbonylalkyl as used herein, means an arylcarbonyl group, as defined herein, bound to the parent molecule through an alkyl group, as defined herein.
  • arylcarbonylalkoxy as used herein, means an arylcarbonylalkyl group, as defined herein, bound to the parent molecule through an oxygen.
  • aryloxy means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen.
  • heteroaryloxy means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen.
  • biphenyl and "binaphthylene” refer to the ring systems below.
  • the numbers around the peripheries of the ring systems are the positional numbering systems used herein.
  • the capital letters contained within the individual rings of the ring systems are the ring descriptors used herein.
  • phenyl-heteroaryl and “heteroaryl-heteroaryl” refer to ring systems similar to those shown above for biphenyl, wherein one of the phenyl rings is replaced with an heteroaryl ring, as defined below.
  • Any position on the phenyl-heteroaryl or heteroaryl- heteroaryl may be substituted with a substituent independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, amido, amino, carboxy, cyano, formyl, halo, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkyl, mercapto, nitro, phosphinyl, silyl and silyloxy.
  • a substituent independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl
  • cycloalkyl as used herein, means monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbons containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds but does not amount to an aromatic group.
  • a cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • cycloalkoxy as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen.
  • cyano as used herein, means a -CN group.
  • halo or halogen means -Cl, -Br, -I or -F.
  • haloalkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkyl means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • heterocyclyl include non-aromatic, ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system) and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • heterocyclic rings azepines, azetidinyl,
  • morpholinyl oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl.
  • heterocyclyl groups of the invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, amido, amino, carboxy, cyano, formyl, halo, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkyl, mercapto, nitro, phosphinyl, silyl and silyloxy.
  • heteroaryl as used herein, include aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • heteroatom such as nitrogen, oxygen, or sulfur.
  • heteroaryl groups of the invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, amido, amino, carboxy, cyano, formyl, halo, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkyl, mercapto, nitro, phosphinyl, silyl and silyloxy.
  • heteroarylene is art-recognized, and as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms of a heteroaryl ring, as defined above.
  • heteroarylalkyl or “heteroaralkyl” as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heteroarylalkyl include, but are not limited to, pyridin-3-ylmethyl and 2-(thien-2-yl)ethyl.
  • hydroxy as used herein, means an -OH group.
  • hydroxyalkyl as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to,
  • mercapto as used herein, means a -SH group.
  • nitro as used herein, means a -NO 2 group.
  • phosphinyl as used herein includes derivatives of the H3P- group, wherein the hydrogens are independently replaced with alkyl, adamantyl, fluoroalkyl, cycloalkyl, aryl, heteroaryl, heterocycyl, aryloxy, or heteroaryloxy groups.
  • sil as used herein includes hydrocarbyl derivatives of the silyl (H 3 Si-
  • hydrocarbyFbSi- hydrocarbyFbSi-
  • a hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl.
  • the hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert- butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS), and [2-
  • silyloxy as used herein means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom.
  • each expression e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, /?-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, /?-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, /?-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl,
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.
  • a "polar solvent” means a solvent which has a dielectric constant ( ⁇ ) of 2.9 or greater, such as DMF, THF, ethylene glycol dimethyl ether (DME), DMSO, acetone, acetonitrile, methanol, ethanol, isopropanol, n-propanol, t-butanol or 2-methoxyethyl ether.
  • Preferred polar solvents are DMF, DME, NMP, and acetonitrile.
  • An "aprotic solvent” means a non-nucleophilic solvent having a boiling point range above ambient temperature, preferably from about 25 0 C to about 19O 0 C, more preferably from about 8O 0 C to about 16O 0 C, most preferably from about 8O 0 C to 15O 0 C, at atmospheric pressure.
  • solvents are acetonitrile, toluene, DMF, diglyme, THF or DMSO.
  • a "polar, aprotic solvent” means a polar solvent as defined above which has no available hydrogens to exchange with the compounds of this invention during reaction, for example DMF, acetonitrile, diglyme, DMSO, or THF.
  • a "hydroxylic solvent” means a solvent that comprises a hydroxyl moiety; for example, water, methanol, ethanol, tert-butanol, and ethylene glycol are hydroxylic solvents.
  • Methyl 4-fluoro-3-methylbenzoate Methyl 4-bromo-3-methylbenzoate (27.5 mg, 0.12 mmol), BrettPhos (6.4 mg, 0.012 mmol, 10 mol%), (COD)Pd(CH 2 TMS) 2 (2.3 mg, 0.006 mmol, 5 mol%), AgF (22.8 mg, 0.18 mmol, 1.5 equivalents) and toluene (2 mL) were added to an oven dried resealable screw top test tube equipped with a stir bar. The tube was then sealed with a cap and taken out of the glove box, wrapped in aluminum foil and placed into a preheated 130 0 C oil bath with adequate stirring.
  • the yield is determined by comparing integration of the 19 F NMR resonance of/?-Fluorotoluene (-118 ppm) and that of methyl 4- fluoro-3-methylbenzoate (-106 ppm, 0.100 mmol, 83% yield). GC/MS analysis of the sample confirmed that the only compound in solution is methyl 4-fluoro-3-methylbenzoate.
  • Toluene (2 mL) was promptly added via syringe in such a manner that any reagent on the side of the test tube was washed down to the bottom of the tube.
  • the test tube was then placed in a pre-heated oil bath at the indicated temperature and it was stirred for 18 h. After cooling to room temperature, dodecane (28.9 ⁇ L) was added, the reaction was diluted with EtOAc ( ⁇ 1 mL) and the resulting mixture was filtered through a plug of Celite® and it was analyzed by GC.
  • 2-Fluorobiphenyl The preparation of 2-fluorobiphenyl is depicted in Figure 8 (bottom). To an oven-dried screw-cap test tube equipped with a magnetic stir bar was added 2-biphenyl trifluoromethanesulfonate (302 mg, 1 mmol, 1.0 eq), cesium fluoride (304 mg, 2 mmol, 2.0 eq), [Pd(cinnamyl)Cl] 2 (10.4 mg, 0.02 mmol) and fBuBrettPhos (29.4 mg, 0.06 mmol) inside a glovebox. The test tube was then sealed off with a screw-cap and taken out of the glovebox.
  • Toluene (5 mL) was promptly added via syringe in such a manner that any reagent on the side of the test tube was washed down to the bottom of the tube.
  • the test tube was then placed in a pre-heated oil bath at 110 0 C and stirred for 12 h. After cooling to room temperature, the reaction was diluted with EtOAc (about 5 mL) and the resulting mixture was filtered through a plug of Celite®. An aliquot of the filtrate was taken out for GC analysis. The rest of the filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel using hexane to give the title compound as a white solid; m.p.
  • Dialkylbiarylphosphine ligands such as BrettPhos (B. P. Fors, D. A. Watson, M. R. Biscoe, S. L. Buchwald, J. Am. Chem. Soc. 130, 13552-13554 (2008)) were also considered.
  • the BrettPhos family of phosphines had not been examined in the area of fluorination prior to the presently described studies.
  • the activation energy for carbon- fluorine bond- forming reductive elimination was evaluated to be lowest among the three types of phosphine ligands (42). This result suggests that dialkylbiarylphosphine could be used as supporting ligands in fluorination.
  • Dialkylbiarylphosphines were investigated as supporting ligands in fluorination studies.
  • Ligand Preparation Ligands L1-L20 and palladium-bound aryl groups 21a-28a are identified in Figure 22.
  • BrettPhos (Ll) was synthesized as described by Fors et al. (B. P. Fors, D. A. Watson, M. R. Biscoe, S. L. Buchwald, J. Am. Chem. Soc. 130, 13552-13554 (2008)) and as follows:
  • the Grignard solution was first prepared using magnesium shavings and 2,4,6- triisopropylbromobenzene. Iodine chips, in a solution of THF, were next added to obtain BrettPhos-I with an experimental yield of 65%. Chlorodicyclohexylphosphine was added to BrettPhos-I, and with recrystallization, afforded BrettPhos with an experimental yield of 76% (derived from an average of two runs).
  • Crystals were grown from THF, separated, and isolated with yields ranging from 80 to 90%.
  • Transmetalation Transmetalated complexes were then synthesized. Silver(I) fluoride was added to the biarylphosphine arylpalladium bromide complexes in a solution of dichloromethane to yield the transmetalated biarylphosphine arylpalladium fluoride complexes as follows:
  • Tetrahydropyran (L5) was also considered due to its structural similarity to cyclohexane. Notably, L5 has electron- withdrawing character, which was postulated to contribute to its lower activation energy compared with Ll. By contrast, aryl and heteroaryl substituents (e.g., L4 and L9-L12), which are less electron donating, were found to be less favored for reductive elimination. These results suggest that the dialkyl substituents have an important impact on the electronic properties at the metal center, which is believed to be one of the essential factors affecting the fluorination reaction.
  • aryl and heteroaryl substituents e.g., L4 and L9-L12
  • Figure 24 illustrates the interaction between the /? ⁇ r ⁇ -isopropyl substituent and a fluorine atom. The same effect was observed with tert- butyl substituent. These results suggest that there is an attractive force between the/? ⁇ ra-substituent and fluorine. Reductive elimination thus requires inputs of energy for both breaking the Pd-F bond and disruption of the attraction between the fluorine and hydrogen atoms. Hence, higher activation barriers are observed for Ll and L13, which exhibit this attractive force between the /? ⁇ ra-substituent and fluorine.
  • LlPd(Ar)(F) is presented in Figure 25.
  • a near linear free-energy relationship is obtained.
  • the positive p values evaluated suggest that there is a proportional relationship between the presence of less electron-donating aryl groups and the rate of carbon-fluorine bond- forming reductive elimination.

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Abstract

Selon un aspect, l’invention concerne une conversion catalysée par un métal d’halogénures et de sulfonates d’aryle en fluorures d’aryle correspondants. Selon un autre aspect, l’invention concerne la conversion catalysée par un métal d’halogénures et de sulfonates d’hétéroaryle en fluorures d’hétéroaryle correspondants. Selon un autre aspect, l’invention concerne la conversion catalysée par un métal d’halogénures et sulfonates de vinyle en fluorures de vinyle correspondants. Dans certains modes de réalisation, on utilise des sources de fluorure simples, telles que AgF et CsF. Dans d’autres modes de réalisation, les transformations tolèrent une grande gamme de groupes fonctionnels, ce qui permet l’introduction d’atomes de fluor dans des molécules organiques hautement fonctionnalisées.
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US8895737B2 (en) 2010-07-16 2014-11-25 Shashank Shekhar Process for preparing antiviral compounds
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US9255074B2 (en) 2010-07-16 2016-02-09 Abbvie Inc. Process for preparing antiviral compounds
CN116444390A (zh) * 2023-04-25 2023-07-18 南京大学 碳-氟/碳-氯偶联直接得到（多）氟芳基联苯的方法

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Cited By (12)

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Publication number Priority date Publication date Assignee Title
US8841487B2 (en) 2010-07-16 2014-09-23 Abbvie Inc. Phosphine ligands for catalytic reactions
US8895737B2 (en) 2010-07-16 2014-11-25 Shashank Shekhar Process for preparing antiviral compounds
US8975443B2 (en) 2010-07-16 2015-03-10 Abbvie Inc. Phosphine ligands for catalytic reactions
US9200021B2 (en) 2010-07-16 2015-12-01 Abbvie Inc. Phosphine ligands for catalytic reactions
US9255074B2 (en) 2010-07-16 2016-02-09 Abbvie Inc. Process for preparing antiviral compounds
US9266913B2 (en) 2010-07-16 2016-02-23 Abbvie Inc. Phosphine ligands for catalytic reactions
US9381508B2 (en) 2010-07-16 2016-07-05 Abbvie Inc. Phosphine ligands for catalytic reactions
US9434698B2 (en) 2010-07-16 2016-09-06 Abbvie Inc. Process for preparing antiviral compounds
US9669399B2 (en) 2010-07-16 2017-06-06 Abbvie Inc. Phosphine ligands for catalytic reactions
US9732045B2 (en) 2010-07-16 2017-08-15 Abbvie Inc. Process for preparing antiviral compounds
CN105273006A (zh) * 2015-11-02 2016-01-27 盘锦格林凯默科技有限公司 2-二环己基膦-2,4,6-三异丙基联苯的制备方法
CN116444390A (zh) * 2023-04-25 2023-07-18 南京大学 碳-氟/碳-氯偶联直接得到（多）氟芳基联苯的方法

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