WO2009149347A1

WO2009149347A1 - High-valent palladium fluoride complexes and uses thereof

Info

Publication number: WO2009149347A1
Application number: PCT/US2009/046401
Authority: WO
Inventors: Tobias Ritter; Takeru Furuya; David Powers
Original assignee: President And Fellows Of Harvard College
Priority date: 2008-06-05
Filing date: 2009-06-05
Publication date: 2009-12-10
Also published as: US20110212936A1; EP2303897A1; US8686158B2; EP2303897A4

Abstract

The present invention provides novel high-valent palladium fluoride complexes. The complexes typically include multi-dentate ligands that stabilize the octahedral coordination sphere of the palladium(IV) atom. These complexes are useful in fluorinating organic compounds, in particular aryl-containing compounds. The invention is particularly useful for fluorinating compounds with ¹⁹F for PET imaging.

Description

High-Valent Palladium Fluoride Complexes and Uses Thereof

Related Applications

This application claims priority under 35 U.S. C. §119 from U.S. provisional application serial number 61/059,142 filed June 5, 2008, the entire contents of which is incorporated by reference.

Background of the Invention

The regioselective fluorination of organic compounds is an important challenge in the synthesis of pharmaceuticals and agrochemicals (see, for example, Muller et al., Science

2007, 317, 1881-1886; Park et al, Annual Review of Pharmacology and Toxicology 2001, 41, 443-410; Bohm et al, ChemBioChem 2004, 5, 637-643; and Jeschke, ChemBioChem. 2004, 5, 570-589).

Syntheses of simple fluoroarenes currently rely on the pyrolysis of diazonium tetrafluoroborates (BaIz, G.; Schiemann, G. Ber. DeM. Chem. Ges. 1927, 60, 1186-1190), direct fluorination using highly reactive, elemental fluorine (Sandford, J. Fluorine Chem. 2007, 128, 90-104), or nucleophilic aromatic substitution reactions of electron-poor aromatic systems by displacement of other halogens or nitro groups (Sun et al., Angew. Chem., Int. Ed. 2006, 45, 2720-2725; Adams et al., Chem. Soc. Rev. 1999, 28, 225-231). The reductive elimination of arylfluorides from palladium(II) fluoride complexes is an attractive potential alternative that has been investigated by Grushin (Grushin, Chem. — Eur. J. 2002, 8, 1006- 1014) over the past decade and more recently by Yandulov. A single substrate — p- fluoronitrobenzene — has been prepared successfully in 10% yield in the Yandulov study from a stoichiometric palladium fluoride complex (Yandulov et al., J. Am. Chem. Soc. 2007, 129, 1342-1358). Directed electrophilic fluorination of phenylpyridine derivatives and related structures using catalytic palladium(II) acetate and N-fluoropyridinium salts has been reported by Sanford in 2006 (Hull et al, J. Am. Chem. Soc. 2006, 128, 7134-7135). Taking advantage of the directing effect of a pyridine substituent, proximal carbon-hydrogen bonds can be fluorinated using microwave irradiation at high temperatures (100-150 ⁰C, 1-4 h, 33- 75% yield). However, the fact that there is an absence in the literature of any general, functional-group-tolerant fluorination reaction methodology reflects the difficulty of forming carbon-fluorine bonds. The use of ¹⁸F-labelled organic compounds for positron-emission tomography (PET) requires the controlled, efficient introduction of fluorine into functionalized molecules (see, for example, Couturier et al., Eur. J. Nucl. Med. MoI. Imaging 2004, 31, 1182-1206; Lasne et al., "Chemistry of beta(+)-emitting compounds based on fluorine-18" In Contrast Agents II, 2002; Vol. 222, pp 201-258; and Phelps, Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 9226- 9233). PET has been used to measure presynaptic accumulatiotfof ¹⁸F-fiuorodopa tracer in the dopaminergic regions of the brain (see, for example, Ernst et al., "Presynaptic Dopaminergic Deficits in Lesch-Nyhan Disease" New England Journal of Medicine (1996) 334:1568-1572), but fluorination of other organic compounds has been difficult due to lack of an appropriate fluorination method.

Despite the utility of fluorinated organic compounds in multiple pharmaceutical, diagnostic, and agrochemical applications, C-F bond formation remains a challenging organic transformation with no broadly applicable solutions.

Summary of the Invention

While high-valent palladium complexes may be intermediates in the transformations described above, none have been reported to date. Although discrete high-valent palladium fluorides are potential intermediates, electrophilic palladium-carbon bond cleavage is a mechanistic alternative which has not been ruled out. While hundreds of early transition metal fluorides have been structurally characterized (Murphy et al., Chem. Rev. 97:3425-

3468, 1997; which is incorporated herein by reference), only eight palladium complexes with terminal fluoride ligands can be found in the Cambridge Structural Database, none of which contain a palladium center in an oxidation state other than +2 (Fraser et al, J. Am. Chem. Soc. 119:4769-4770, 1997; Marshall et al, Organometallics, 17:5427-5430, 1998; Roe et al, Organometallics, 19: 4575-4582, 2000; Grushin et al., Angew. Chem. Int. Ed., 41 :4476-4479, 2002; Yahav et al, J. Am. Chem. Soc. 125:13634-13635, 2003; Jasim et al, Organometallics, 23:6140-6149, 2004; each of which is incorporated herein by reference).

The present invention provides novel high-valent palladium fluoride complexes and method of using these complexes in the fluorination of organic compounds. The inventive system is particularly useful in preparing ¹⁸F-labeled compounds for PET imaging. The complexes are typically palladium(IV) fluoride complexes as described herein. The complexes include two fixed ligands that stabilize the high-valent palladium complex. In certain embodiments, one of the ligands is a bidentate ligand, and the other ligand is a tridentate ligand. The inventive system was envisioned due to the limited nature of nucleophilic F^" chemistry. The inventive system relies on the transfer of electrophilic F⁺, which is analogous to the commercially available fluorinating reagent, Selectfluor^® (N- chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate)).

In one aspect, the invention features a palladium complex of formula (I):

(I) wherein: the dashed line represents the presence or absence of a bond; Pd has a valency of +4; n is an integer between 0 and 4, inclusive; m is an integer between 0 and 3, inclusive; each occurrence of R_A is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR'; -C(=O)R'; -CO₂R'; - CN; -SCN; -SR'; -SOR'; -SO₂R'; -NO₂; -N(R')₂; -NHC(O)R'; or -C(R')₃; wherein each occurrence of R' is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; wherein two RA may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; each occurrence of R_B is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR"; -C(=O)R"; -CO₂R"; - CN; -SCN; -SR"; -SOR"; -SO₂R"; -NO₂; -N(R")₂; -NHC(O)R"; or -C(R")₃; wherein each occurrence of R" is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; each occurrence of Rc is independently hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; wherein Rc and R_B may be taken together to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and wherein Rc and R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring;

R-Di, R_D2, R_D3_> and R_D4 are each independently cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; Z^' is an anion such as halide, acetate, tosylate, azide, tetrafluoroborate, tetraphenylborate, tetrakis(pentafluorophenyl)borate,

hexafluorophosphate, phosphate, sulfate, perchlorate, trifluoromethanesulfonate or hexafiuoroantimonate; and

T F- compo ^•ses 18T F^H or 19 Fτ-. In some embodiments, Rc is hydrogen. In some embodiments, Rc is methyl.

In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

In some embodiments, two R_A are taken together to form an aryl ring (e.g., a phenyl ring). In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, at least one R_B is hydrogen. In some embodiments, both R_B are hydrogen. In some embodiments, at least one R_B is Ci-C₆ alkyl. In some embodiments, both R_B are methyl.

In some embodiments, R_B and Rc are taken together form a heterocyclic ring. In some embodiments, R_B and R_c taken together form a heteroaryl ring (e.g., a pyridyl ring).

In some embodiments, R_A and R_c are taken together form an aryl ring (e.g., a phenyl ring).

In some embodiments, the dashed line represents the absence of a bond. In some embodiments, the dashed line represents the presence of a bond. In some embodiments, R_Di, R_D2, R_D3 and Rm are each a 5-membered heteroaryl ring. In some embodiments, R_Di, R_D2, R_D3 and R_D4 are each a pyrazolyl ring (e.g., an unsubstituted pyrazolyl ring).

In some embodiments, R_DI, R_D2 and R_D3 are each a 5-membered heteroaryl ring, and R_D4 is an alkyl group. In some embodiments, R_DI, R_D2 and R_D3 are each a pyrazolyl ring, and R_D4 is a tert-butyl group. In some embodiments, R_DI, R_D2 and R_D3 are each a pyrazolyl ring, and R_D4 is an n-butyl group.

In some embodiments, R_DI, R_D2 and R_D3 are each a 5-membered heteroaryl ring, and R_D4 is an aryl group. In some embodiments, R_DI, R_D2 and R_D3 are each a pyrazolyl ring, and R_D4 is a phenyl ring.

In some embodiments, R_Di and R_D2 are each a 5-membered heteroaryl ring, R_D3 is an alkoxy group and R_D4 is an alkyl group. In some embodiments, R_DI and R_D2 are each a pyrazolyl ring, R_D3 is an isopropoxy group and R_D4 is a tert-butyl group. In some embodiments, R_DI and R_D2 are each a pyrazolyl ring, R_D3 is an isopropoxy group and R_D4 is an n-butyl group.

In some embodiments, R_Di and R_D2 are each a 5-membered heteroaryl ring, R_D3 is an alkoxy group and R_D4 is an aryl group. In some embodiments, R_Dj and Rø₂ are each a pyrazolyl ring, R_D3 is an isopropoxy group and R_D4 is a phenyl ring.

In some embodiments, the anion is trifluoromethanesulfonate. In some embodiments, the anion is hexafluorophosphate. In some embodiments, the anion is a halide.

In some embodiments, the complex has the following formula:

In some embodiments, the complex has the following formula:

In one aspect, the invention features a method of fluorinating an organic compound, the method comprising mixing a palladium complex of formula (I) with a substrate under conditions sufficient to fluorinate the substrate, thereby providing a fluorinated organic compound. In some embodiments, the fluorinated organic compound comprises ¹⁸F or ¹⁹F.

In some embodiments, the substrate is an organic compound comprising an enol silyl ether, and the fluorinated organic compound is an α-fluorinated ketone. In some embodiments, the substrate is a palladium(II) aryl complex, and the fluorinated organic compound is a fluorinated aryl compound. In some embodiments, the substrate is an arylsilver complex, and the fluorinated organic compound is a fluorinated aryl compound.

In some embodiments, the method further comprises a solvent. In some embodiments, the solvent is a polar aprotic solvent (e.g., methylene chloride, dichloroethane or tetrahydrofuran). In some embodiments, the solvent is a nonpolar solvent (e.g., benzene).

In some embodiments, the method further comprises an inert atmosphere. In some embodiments, the reaction is performed under anhydrous conditions. In some embodiments, the reaction comprises a source of energy. In some embodiments, the reaction comprises heat.

In some embodiments, the fluorinated organic compound comprises an aryl group. In some embodiments, the fluorinated organic compound is an imaging agent (e.g., a PET imaging agent). In some embodiments, the fluorinated organic compound is a pharmaceutically acceptable compound or a prodrug thereof.

In one aspect, the invention features a method of storing a palladium complex of formula (I), the method comprising maintaining the palladium complex in a sealed container for at least 12 hours.

In some embodiments, the sealed container is a vial. In some embodiments, the sealed container is an ampule. In some embodiments, the sealed container is substantially free of dioxygen. In some embodiments, the sealed container contains an inert gas.

In one aspect, the invention features a composition comprising a palladium complex of formula (I) and an additional component.

In some embodiments, the component is a substrate. In some embodiments, the substrate is an organic compound comprising an enol silyl ether. In some embodiments, the substrate is a palladium(II) aryl complex. In some embodiments, the substrate is an arylsilver complex. In some embodiments, the cqmponent is a reagent. In some embodiments, the composition comprises a plurality of reagents.

In some embodiments, the component is a solvent. In some embodiments, the solvent is a polar aprotic solvent (e.g., methylene chloride, dichloroethane or tetrahydrofuran). In some embodiments, the solvent is a nonpolar solvent (e.g., benzene).

In one aspect, the invention features a kit comprising a palladium complex of formula (I) and a container.

In some embodiments, the container is a vial. In some embodiments, the container is a sealed ampule. In some embodiments, the container is substantially free of dioxygen. In some embodiments, the container contains an inert gas.

In some embodiments, the kit further comprises instructions for use of the palladium complex. In some embodiments, the kit further comprises a reagent.

In some embodiments, the kit further comprises a substrate. In some embodiments, the substrate is an organic compound comprising an enol silyl ether. In some embodiments, the substrate is a palladium(II) aryl complex. In some embodiments, the substrate is an arylsilver complex.

In one aspect, the invention features a palladium complex of formula (II):

(H) wherein the dashed line represents the presence or absence of a bond; Pd has a valency of +2; n is an integer between 0 and 4, inclusive; m is an integer between 0 and 3, inclusive; each occurrence of R_A is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR'; -C(=O)R'; -CO₂R'; - CN; -SCN; -SR'; -SOR'; -SO₂R'; -NO₂; -N(R')₂; -NHC(O)R'; or -C(R')₃; wherein each occurrence of R' is independently a hydrogen, a protecting group, an* aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; wherein two R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; each occurrence of R_B is independently hydrogen; halogen; cyclic δr acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR"; -C(=O)R"; -CO₂R"; - CN; -SCN; -SR"; -SOR"; -SO₂R"; -NO₂; -N(IT)₂; -NHC(O)R"; or -C(R")₃; wherein each occurrence of R" is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; each occurrence of Rc is independently hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; wherein Rc and R_B may be taken together to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and wherein Rc and R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; and

R_DI, R_D2, R_D3, and Rp₄ are each independently cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl;

In some embodiments, Rc is hydrogen. In some embodiments, Rc is methyl.

In some embodiments, n is O. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, two R_A are taken together to form an aryl ring (e.g., a phenyl ring).

In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, at least one R_B is hydrogen. In some embodiments, both R_B are hydrogen. In some embodiments, at least one R_B is Ci-C₆ alkyl (e.g., methyl). In some embodiments, R_B and Rc are taken together form a heterocyclic ring. In some embodiments, R_B and Rc taken together form a heteroaryl ring (e.g., a pyridyl ring).

In some embodiments, R_A and Rc are taken together form an aryl ring (e.g., a phenyl ring). In some embodiments, the dashed line represents the absence of a bond. In some embodiments, the dashed line represents the presence of a bond.

In some embodiments, R_Di, R_D2, Rp₃ and R_D4 are each a 5-membered heteroaryl ring. In some embodiments, R_DI, R_D2, R_D3 and R_D4 are each a pyrazolyl ring (e.g., an unsubstituted pyrazolyl ring). In some embodiments, R_Di, RQ₂ and R_D3 are each a 5-membered heteroaryl ring, and

R_D4 is an alkyl group. In some embodiments, R_DI, R_D2 and R_D3 are each a pyrazolyl ring, and R_D4 is a tert-butyl group. In some embodiments, R_DI, R_D2 and R_D3 are each a pyrazolyl ring, and R_D4 is an n-butyl group.

In some embodiments, R_Di and R_D2 are each a 5-membered heteroaryl ring, Rp₃ is an alkoxy group and R_D4 is an alkyl group. In some embodiments, R_DI and R_D2 are each a pyrazolyl ring, R_D3 is an isopropoxy group and R₀₄ is a tert-butyl group. In some embodiments, R_DI and R_D2 are each a pyrazolyl ring, R_D3 is an isopropoxy group and R_D4 is an n-butyl group.

In some embodiments, R_Di and R_D2 are each a 5-membered heteroaryl ring, R_D3 is an alkoxy group and R_D4 is an aryl group. In some embodiments, R_DI and R_D2 are each a pyrazolyl ring, RQ₃ is an isopropoxy group and R_D4 is a phenyl ring. In some embodiments, the palladium complex has the following formula:

In one aspect, the invention features a method of fluorinating an organic compound, the method comprising reacting a palladium complex of formula (II) with a fluorinating agent and a substrate, under conditions sufficient to fluorinate the substrate, thereby providing a fluorinated organic compound. In some embodiments, the substrate is an organic compound comprising an enol silyl ether, and the fluorinated organic compound is an α-fluorinated ketone. In some embodiments, the substrate is a palladium(II) aryl complex, and the fluorinated organic compound is a fluorinated aryl compound. In some embodiments, the substrate is an arylsilver complex, and the fluorinated organic compound is a fluorinated aryl compound.

In some embodiments, the fluorinating agent comprises ¹⁸F or ¹⁹F. In some embodiments, the fluorinating agent is N-chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor^®). In some embodiments, the fluorinating agent is XeF₂. In some embodiments, the fluorinating agent is iV-fluoropyridinium trifluoromethanesulfonate. In some embodiments, the fluorinating agent is 7V-fluoro-2,4,6- trimethylpyridinium hexafluorophosphate.

In some embodiments, the method further comprises a solvent. In some embodiments, the solvent is a polar aprotic solvent (e.g., methylene chloride, dichloroethane or tetrahydrofuran). In some embodiments, the solvent is a nonpolar solvent (e.g., benzene). In some embodiments, the method further comprises an inert atmosphere. In some embodiments, the reaction is performed under anhydrous conditions. In some embodiments, the reaction comprises a source of energy. In some embodiments, the reaction comprises heat.

In some embodiments, the palladium complex of formula (II) is combined with the fluorinating agent prior to the addition of the substrate. In some embodiments, the method proceeds via an intermediate palladium complex of formula (I). In some embodiments, the intermediate palladium complex is isolated.

In some embodiments, the fluorinated organic compound is an imaging agent (e.g., a PET imaging agent). In some embodiments, the fluorinated organic compound is a pharmaceutically acceptable compound or a prodrug thereof. In one aspect, the invention features a method of making a fluorinated Pd(IV) complex, the method comprising reacting a palladium complex of formula (II) with a fluorinating agent, to provide the fluorinated Pd(IV) complex.

In some embodiments, the fluorinating agent comprises ⁸F or ¹⁹F. In some embodiments, the fluorinating agent is N-chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor^®). In some embodiments, the fluorinating agent is XeF₂. In some embodiments, the fluorinating agent is N-fluoropyridinium trifluoromethanesulfonate. In some embodiments, the fluorinating agent is iV-fluoro-2,4,6- trimethylpyridinium hexafluorophosphate. In some embodiments, the method further comprises a solvent. In some embodiments, the solvent is a polar aprotic solvent (e.g., methylene chloride, dichloroethane or tetrahydrofuran). In some embodiments, the solvent is a nonpolar solvent (e.g., benzene).

In one aspect, the invention features a method of storing a palladium complex of formula (II), the method comprising maintaining the palladium complex in a sealed container for at least 12 hours. In some embodiments, the sealed container is a vial. In some embodiments, the sealed container is an ampule. In some embodiments, the sealed container is substantially free of di oxygen. In some embodiments, the sealed container contains an inert gas.

In one aspect, the invention features a composition comprising a palladium complex of formula (II) and an additional component. In some embodiments, the component is a fluorinating agent. In some embodiments, the fluorinating agent comprises ¹⁸F or ¹⁹F. In some embodiments, the fluorinating agent is N-chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor ). In some embodiments, the fluorinating agent is XeF₂. In some embodiments, the fluorinating agent is iV-fluoropyridinium trifluoromethanesulfonate. In some embodiments, the fluorinating agent is 7V-fluoro-2,4,6-trimethylpyridinium hexafluorophosphate.

In some embodiments, the component is a substrate. In some embodiments, the substrate is an organic compound comprising an enol silyl ether. In some embodiments, the substrate is a palladium(II) aryl complex. In some embodiments, the substrate is an arylsilver complex. In some embodiments, the component is a reagent. In some embodiments, the composition comprises a plurality of reagents.

In some embodiments, the component is a solvent. In some embodiments, the solvent is a polar aprotic solvent (e.g., methylene chloride, dichloroethane or tetrahydrofuran). In some embodiments, the solvent is a nonpolar solvent (e.g., benzene). In one aspect, the invention features a kit comprising a palladium complex of formula

(II) and a container.

In some embodiments, the container is a vial. In some embodiments, the container is a sealed ampule. In some embodiments, the container is substantially free of dioxygen. In some embodiments, the container contains an inert gas. In spme embodiments, the kit further comprises instructions for use of the palladium complex.

In some embodiments, the kit further comprises a reagent. In some embodiments, the reagent is a fluorinating agent. In some embodiments, the fluorinating agent comprises ¹⁸F or ¹⁹F. In some embodiments, the fluorinating agent is N-chloromethyl-N'- fluorotriethyldhediammonium bis(tetrafluoroborate) (Selectfluor^®). In some embodiments, the fluorinating agent is XeF₂. In some embodiments, the fluorinating agent is TV- fluoropyridinium trifluoromethanesulfonate. In some embodiments, the fluorinating agent is 7V-fluoro-2,4,6-trimethylpyridinium hexafluorophosphate.

In some embodiments, the kit further comprises a substrate. In some embodiments, the substrate is an organic compound comprising an enol silyl ether. In some embodiments, the substrate is a palladium(II) aryl complex. In some embodiments, the substrate is a arylsilver complex.

In one aspect, the invention features a method of preparing a palladium fluoride complex of formula:

the method comprising steps of: reacting a palladium chloride complex of formula:

with nucleophilic F^" under suitable conditions to yield a complex of formula:

In some embodiments, the nucleophilic F^" is provided by AgF. In some embodiments, the nucleophilic F^" is ¹⁸F^" .

This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference.

Brief Description of the Drawings

Figure 1 is an exemplary synthesis of a palladium(IV) fluoride complex.

Figure 2 is an ORTEP drawing of a palladium(IV) fluoride complex with ellipsoids drawn at 50% probability. Hydrogen atoms, the PF₆ ^" counterion, and solvent molecules are omitted for clarity. Representative bond lengths L Aj : Pd(I)-F(I), 1.923(4); Pd(l)-N(2), 2.005(6); Pd(l)-C(2), 2.024(8); Pd(I)-N(O), 2.031(7); Pd(I)-N(I), 2.089(7); Pd(l)-N(4), 2.154(7). Representative angles [°]: F(l)-Pd(l)-N(2), 175.4(2); F(l)-Pd(l)-C2, 88.4(3); F(l)-Pd(l)-N(6), 87.5(3); F(I)-Pd(I)-N(I), 91.1(2); F(l)-Pd(l)-N(4), 89.8(2); N(2)-Pd(l)- C(2), 90.4(3); C(2)-Pd(l)-N(6), 98.2(3); N(2)-Pd(l)-N(l), 93.1(3); N(6)-Pd( I)-N(I), 178.0(3); C(2)-Pd(l)-N(4), 177.6(3).

Figure 3 is a ¹H NMR spectrum of the palladium(II) chloride dimer:

Figure 4 is a 13 C NMR spectrum of the palladium(II) chloride dimer:

Figure 5 i •s i H NMR spectrum of the palladium(II) borate:

Figure 6 is 11 B NMR spectrum of the palladium(II) borate:

Figure 7 is 11 B NMR spectrum of the palladium(IV) fluoride complex:

Figure 8 is 19 F NMR spectrum of the palladium(IV) fluoride complex:

Figure 9 is 31 P NMR spectrum of the palladium(IV) fluoride complex:

Definitions

Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March 's Advanced Organic Chemistry, 5^{l 1} Edition, John Wiley & Sons, Inc., New York, 2001 ; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^ld Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

Certain compounds of the present invention can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain embodiments, mixtures of stereoisomers or diastereomers are provided.

Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. In addition to the above-mentioned compounds per se, this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds.

Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched." "Optically-enriched," as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al, Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

As used herein, a "bond" refers to a single bond.

The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). The term "aliphatic" or "aliphatic group", as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-10 carbon atoms. In certain embodiments, aliphatic groups contain 1-8 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbon atoms, 1- 3 carbon atoms, or 1-2 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The term "unsaturated", as used herein, means that a moiety has one or more double or triple bonds.

The terms "carbocyclyl" and "carbocyclic" refer to saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring systems, as described herein, having from 3 to 10 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In certain embodiments, the cycloalkyl has 3-6 carbons. The terms "cycloaliphatic", "carbocycle" or "carbocyclic" also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.

The term "alkyl," as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals derived from an aliphatic moiety containing between one and six carbon atoms by removal of a single hydrogen atom. In certain embodiments, the alkyl group employed in the invention contains 1-10 carbon atoms. In certain embodiments, the alkyl group employed contains 1-8 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbon atoms, 1-3 carbon atoms, or 1-2 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n- heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like. The term "alkenyl," as used herein, denotes a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. In certain embodiments, the alkenyl group employed in the invention contains 2-10 carbon atoms. In certain embodiments, the alkenyl group employed in the invention contains 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2-3 carbon atoms or 2 carbon atoms. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.

The term "alkynyl," as used herein, refers to a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. In certain embodiments, the alkynyl group employed in the invention contains 2-10 carbon atoms. In certain embodiments, the alkynyl group employed in the invention contains 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2-3 carbon atoms or 2 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

The term "aryl" refers to monocyclic, bicyclic or tricyclic aromatic ring system having a total of five to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to a monocyclic or polycyclic aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl, phenanthrenyl, phenalenyl, and the like, which may bear one or more substituents. Also included within the scope of the term aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like.

The term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5 to 14 ring atoms, wherein the ring atoms include carbon atoms and from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/J-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahy,droquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l ,4-oxazin- 3(4H)-one. A heteroaryl group may be mono- or bi cyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring" any of which terms include rings that are optionally substituted. As used herein, the terms "heterocyclyl" and "heterocyclic ring" are used interchangeably and refdr to a monocyclic, bicyclic or tricyclic nonaromatic ring sytem that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one to five heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as in TV-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", and "heterocyclyl ring", are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic.

As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable^" carbon atom of an "optionally substituted" group are independently halogen; -(CH₂)(MR';

-0-(CH₂)_O_ ₄C(O)OR'; -(CH₂)o^CH(OR')₂; -(CH₂)₀^SR'; -(CH₂)_O^Ph, which may be substituted with R';

which may be substituted with R'; -CH=CHPh, which may be substituted with R' ; -NO₂; -CN; -N₃; -(CH₂)₀^N(R')₂; -(CH₂)<_MN(R')C(0)R' ; -

N(R')C(S)R'; -(CH₂)o-4N(R')C(0)NR'₂; -N(R')C(S)NR'₂;

- N(R')N(R')C(O)R'; -N(R')N(R')C(O)NR'₂; -N(R')N(R')C(O)OR'; -(CH₂)₀^C(O)R°; - C(S)R⁰; -(CH₂)(_MC(O)OR'; -(CH₂)₀^C(O)SR'; -(CH₂)₀^C(O)OSiR'₃; -(CH₂)_O^OC(O)R'; -OC(O)(CH₂)_O^SR-, SC(S)SR'; -(CH₂)₀^SC(O)R'; -(CH₂)(_MC(O)NR'₂; -C(S)NR'₂; - C(S)SR'; -SC(S)SR', -(CH₂)₀_₄OC(O)NR'₂; -C(O)N(OR' )R'; -C(O)C(O)R'; -

C(O)CH₂C(O)R'; -C(NOR')R'; -(CH₂)₀^SSR'; -(CH₂)o-₄S(0)₂R'; -(CH₂)₀-₄S(O)₂OR'; - (CH₂)_O^OS(O)₂R'; -S(O)₂NR'₂; -(CH₂>_MS(0)R'; -N(R')S(O)₂NR'₂; -N(R')S(O)₂R'; - N(0R')R'; -C(NH)NR'₂; -P(O)₂R'; -P(O)R'₂; -OP(O)R'₂; -OP(O)(OR')₂; SiR'₃; -(Ci_-4 straight or branched alkylene)O-N(R')₂; or -(C₁^ straight or branched alkylene)C(O)O- N(R')₂, wherein each R' may be substituted as defined below and is independently hydrogen, Ci_₆ aliphatic, -CH₂Ph, -0(CH₂)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R', taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R' (or the ring formed by taking two independent occurrences of R' together with their intervening atoms), are independently halogen, - (CH₂)o-₂R ^', -(haloR"), -(CH₂)₀_₂OH, -(CH₂)₀_₂OR", -(CH₂)₀-₂CH(OR")₂; -0(haloR"), -CN, -N₃, -(CH₂)_O-2C(O)R", -(CH₂)o_₂C(0)OH, -(CH₂)₀-₂C(O)OR", -(CH₂)₀_₂SR", -(CH₂)₀-₂SH, -(CH₂)o_₂NH₂, -(CH₂)o-₂NHR", -(CH₂)₀_₂NR"₂, -NO₂, -SiR",, -OSiR"₃, -C(O)SR", -(C_1-4 straight or branched alkylene)C(O)OR", or -SSR" wherein each R" is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from C₁-^ aliphatic, -CH₂Ph, -0(CH₂)o~iPh, or a 5-6— membered saturated, partiajly unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R' include =0 and =S. Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR^* ₂, =NNHC(0)R^*, =NNHC(O)OR^*, ^* =NNHS(O)₂R^*, =NR^*, =NOR^", -O(C(R^* ₂»₂-₃θ-, or -S(C(R^* ₂))₂_₃S- wherein each independent occurrence of R is selected from hydrogen, Ci_₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted" group include: -O(CR ₂)₂-₃O-, wherein each independent occurrence of R^* is selected from hydrogen, Q_₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R include halogen, -R", -(haloR"), - OH, -OR", -O(haloR"), -CN, -C(O)OH, -C(O)OR", -NH₂, -NHR", -NR"₂, or -NO₂, wherein each R" is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Cj-₄ aliphatic, -CH₂Ph, -0(CH₂)_O-_IPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R⁺, -NR¹ ₂, -C(O)R⁺, -C(O)OR ^;, -C(O)C(O)R⁺, -C(O)CH₂C(O)R¹, -S(O)₂R⁺, - S(O)₂NR^!2, -C(S)NR¹Z, -C(NH)NR¹ ₂, or -N(R^S(O)₂R¹ ; wherein each R¹ is independently hydrogen, C^₆ aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R¹, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R' are independently halogen, -R", - (haloR"), -OH, -OR", -O(haloR"), -CN, -C(O)OH, -C(O)OR", -NH₂, -NHR", -NR"₂, or - NO₂, wherein each R" is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C₁-^ aliphatic, -CH₂Ph, -0(CH₂)(MPh, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. An "suitable amino-protecting group," as used herein, is well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Suitable amino-protecting groups include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylm ethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-( 10,10-dioxo-l 0,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate

(TCBOC), l-methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l- methylethyl carbamate (ϊ-Bumeoc), 2-(2'— and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N₁N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, JV-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), />-methoxybenzyl carbamate (Moz), /?-nitobenzyl carbamate, j9-bromobenzyl carbamate, p— chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diplienylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2— (1,3— dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, m— chloro-/τ-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, phenothiazinyl-(10)-carbonyl derivative, iV -p-toluenesulfonylaminocarbonyl derivative, N'-phenylaminothiocarbonyl derivative, t-amyl carbamate, iS-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2- dimethoxycarbonylvinyl carbamate, o-(NN-dimethylcarboxamido)benzyl carbamate, 1,1- dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p '— methoxyphenylazo)benzyl carbamate, 1 -methyl cyclobutyl carbamate, 1 -methyl cyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1 -(3,5- dimethoxyphenyl) ethyl carbamate, l-methyl-l-(p-phenylazophenyl)ethyl carbamate, 1- methyl- 1-phenylethyl carbamate, l-methyl-l-(4-pyridyl)ethyl carbamate, phenyl carbamate, />-(phenylazo)benzyl carbamate, 2,4,6-tri-^-butylphenyl carbamate, 4- (trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3- phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, />-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (TV'-dithiobenzyloxycarbonylamino)acetamide, 3~(p-~ hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4— chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, 7V-acetylmethionine derivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin- 2-one, 7V-phthalimide, iV-dithiasuccinimide (Dts), iV-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, 7V-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l^-dimethyl-l^jS-triazacyclohexan^-one, 5-substituted l,3-dibenzyl-l,3,5- triazacyclohexan-2-one, 1 -substituted 3,5-dinitro-4-pyridone, iV-methylamine, N- allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N- (l-isopropyl-4-nitro-2^oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N- benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N- triphenylmethylamine (Tr), N^[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9- phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N- ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1 ,1- dimethylthiomethyleneamine, 7V-benzylideneamine, N-zT-methoxybenzylideneamine, N- diphenylmethyleneamine, N— [(2-pyridyl)mesityl]methyleneamine, N-(N',N - dimethylaminomethylene)amine, NN'-isopropylidenediamine, N-p-nitrobenzylideneamine, N— salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, TV-cyclohexylideneamine, TV-(5,5-dimethyl-3-oxo- l-cyclohexenyl)amine, TV-borane derivative, TV-diphenylborinic acid derivative, TV- [phenyl(pentacarbonyl chromium- or tungsten)carbonyl] amine, TV-copper chelate, TV-zinc chelate, TV-nitroamine, /V-nitrosoamine, amine TV-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl ° phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys), /M:oluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6~dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3 ,5,6-tetramemyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9— anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

A "suitable hydroxyl protecting group" as used herein, is well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, A— methoxytetrahydropyranyl (MTHP), 4—methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, l-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), 1 ,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-"2-yl, 1-ethoxyethyl, l-(2-chloroethoxy)ethyl, 1-methyl-l-methoxyethyl, 1-methyl-l-benzyloxyethyl, 1- methyH -benzyl oxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl)ethyl, t-butyl, ^HyI, £>-chlorophenyl, ^-methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4— dimethoxybenzyl, ø-nitrobenzyl, p— nitrobenzyl, /?-halobenzyl, 2,6-dichlorobenzyl, jt?-cyanobenzyl, j^-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl--2- picolyl N-oxido, diphenylmethyl, p,p '-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, />-methoxyphenyldiphenylmethyl,

methoxyphenyl)phenylmethyl, tr!(p-methoxyphenyl)methyl, 4—(4'- bromophenacyloxyphenyl)diphenylmethyl, 4,4',4' '-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4' '-tris(levulinoyloxyphenyl)methyl, 4,4',4"- tris(benzoyloxyphenyl)methyl, 3-(imidazol-l-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-l '-pyrenylmethyl, 9-anthxyl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl- 10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, r-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri— p— xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), ^-butylmethoxyphenylsilyl (TBMPS), formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, /7-chlorophenoxyacetate, 3-phenylpropionate, A- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, j9-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fiuorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl j9-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl />-nitrobenzyl carbonate, alkyl ^-benzyl thiocarbonate, 4-ethoxy^l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o— (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, A- (methylthiomethoxy)butyrate, 2-(methylthiomethoxyrnethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(l,l,3,3-tetramethylbutyl)phenoxyacetate, 2,4— bis(l,l-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (£)-2-methyl-2-butenoate, o-(methoxycarbonyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N -tetrame&ylphosphorodiamidate, alkyl 7V-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). For protecting"!^- or 1,3-diols, the protecting groups include methylene acetal, ethylidene acetal, l-£-butylethylidene ketal, 1— phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, jp-mefhoxybenzylidene acetal, 2,4— dimethoxybenzylidene ketal, 3,4— dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1-mefhoxyethylidene ortho ester, 1-ethoxyefhylidine ortho ester, 1 ,2-dimethoxyethylidene ortho ester, α-methoxybenzylidene ortho ester, l-(AζiV-dimethylamino)efhylidene derivative, a-(N,N'- dimethylamino)benzylidene derivative, 2-oxacyclopentylidene ortho ester, di-£-butylsilylene group (DTBS), l,3-(l,l,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra-t- butoxydisiloxane-l,3-diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

A "pharmaceutically acceptable form thereof includes any pharmaceutically acceptable salts, isomers, and/or polymorphs of a palladium complex, or any pharmaceutically acceptable salts, prodrugs and/or isomers of an organic compound, as described below and herein.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-efhanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(Ci_₄alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

As used herein, the term "prodrug" refers to a derivative of a parent compound that requires transformation within the body in order to release the parent compound. In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs are typically designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent compound. The advantage of a prodrug can lie in its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it enhances absorption from the digestive tract, or it may enhance drug stability for long-term storage. The compounds of the invention readily undergo dehydration to form oligomeric anhydrides by dehydration of the boronic acid moiety to form dimers, trimers, and tetramers, and mixtures thereof. These oligomeric species hydrolyze under physiological conditions to reform the boronic acid. As such, the oligomeric anhydrides are contemplated as a "prodrug" of the compounds of the present invention, and may be used in the treatment of disorder and/or conditions a wherein the inhibition of FAAH provides a therapeutic effect. As used herein, the term "isomers" includes any and all geometric isomers and stereoisomers. For example, "isomers" include cis— and trans-isomevs, E- and Z- isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. For instance, an isomer/enantiomer may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched." "Optically- enriched," as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

As used herein, "polymorph" refers to a crystalline complex or compound existing in more than one crystalline form/structure. When polymorphism exists as a result of difference in crystal packing it is called packing polymorphism. Polymorphism can also result from the existence of different conformers of the same molecule in conformational polymorphism. In pseudopolymorphism the different crystal types are the result of hydration or solvation. As used herein "coordinated" means the organic compound is associated with the palladium atom.

Detailed Description of Certain Embodiments of the Invention

The present invention provides novel high-valent palladium fluoride complexes. The complexes have terminal fluoride ligands, and the palladium center has an oxidation state greater than +2. In certain embodiments, the palladium center has an oxidation state of +4. The ligands surrounding the complex stabilize the octahedral coordination sphere, thus disfavoring reductive elimination and other reductive pathways. These complexes are useful in transferring a eletrophilic F⁺ to an organic compound. In particular, the inventive complexes are useful in labelling a compound with ¹⁸F for positron emission tomography (PET). Also described herein are compositions, reaction mixtures and kits comprising the palladium complexes. Also described herein are methods for fluorinating organic compounds using a palladium complex, e.g., a palladium complex described herein.

High-Valent Palladium Complexes The present invention provides novel high-valent palladium fluoride complexes. In certain embodiments, the complex is a Pd (IV) complex. Typically, the complex comprises one or more bidentate or tridentate ligands. Such ligands, particularly "scorpionate ligands," are thought to stabilize the octahedral coordination sphere of the palladium(IV) center and thus prevent reductive elimination or other reductive pathways from an octahedral d palladium(IV) to a square planar d⁸ palladium(II).

In certain embodiments, the inventive high-valent palladium fluoride complex is of the formula:

wherein: the dashed line represents the presence or absence of a bond;

Pd has a valency of +4; n is an integer between 0 and 4, inclusive; m is an integer between 0 and 3, inclusive; each occurrence of R_A is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR'; -C(=O)R'; -CO₂R'; - CN; -SCN; -SR'; -SOR'; -SO₂R'; -NO₂; -N(R')₂; -NHC(O)R'; or -C(R')₃; wherein each occurrence of R' is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; wherein two R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; each occurrence of R_B is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR"; -C(=O)R"; -CO₂R"; - CN; -SCN; -SR"; -SOR"; -SO₂R"; -NO₂; -N(R")₂; -NHC(O)R"; or -C(R")₃; wherein each occurrence of R" is independently a hydrogen, a protecting group, an aliphatic moiety, a heteφaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; each occurrence of Rc is independently hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbrdnched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; wherein Rc and R_B may be taken together to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and wherein R_c and R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring;

Z^" is an anion such as halide, acetate, tosylate, azide, tetrafluoroborate, tetraphenylborate, tetrakis(pentafluorophenyl)borate, [B[3,5-(CF₃)₂C₆H₃]₄]^", hexafluorophosphate, phosphate, sulfate, perchlorate, trifluoromethanesulfonate or hexafluoroantimonate; and

F comprises ¹⁸F or ¹⁹F.

wherein the dashed line represents the presence or absence of a bond;

Pd has a valency of +4; n is an integer between 0 and 4, inclusive; m is an integer between 0 and 3, inclusive; each occurrence of R_A is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR'; -C(=O)R'; -CO₂R'; - CN; -SCN; -SR'; -SOR'; -SO₂R'; -NO₂; -N(R')₂; -NHC(O)R'; or -C(R')₃; wherein each occurrence of R' is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; wherein two R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; each occurrence of R_B is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR"; -C(=O)R"; -CO₂R"; - CN; -SCN; -SR"; -SOR"; -SO₂R"; -NO₂; -N(R")₂; -NHC(O)R"; or -C(R")₃; wherein each occurrence of R" is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;

R_DI, R_D2, R_D3, and R₀₄ are each independently cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; Z^" is an anion such as halide, acetate, tosylate, azide, tetrafiuoroborate, tetraphenylborate, tetrakis(pentafluorophenyl)borate, [8[3,5-(CFs)₂CeH₃J₄]^", hexafluorophosphate, phosphate, sulfate, perchlorate, trifluoromethanesulfonate or hexafluoroantimonate; and

F comprises ¹⁸F or ¹⁹F.

The counteranion Z^" may be any suitable anion. In certain embodiments, the counteranion has a charge of -1. In certain embodiments, the counteranion has a charge of -2. In certain embodiments, the counteranion has a charge of -3. The counteranion may be an organic or inorganic anion. In certain embodiments, the counteranion is an inorganic anion such as phosphate, hexafluorophosphate, hexafluoroantimonate, sulfate,"perchlorate, azide, a halide such as fluoride, chloride, bromide or iodide, etc. In other embodiments, the counteranion is an organic anion such as a carboxylate (e.g., acetate), sulfonate, phosphonate, borate, etc. In certain embodiments, the counteranion is trifluoromethanesulfonate (triflate). In certain embodiments, the counteranion is tosylate. In certain embodiments, the counteranion is mesylate. In certain embodiments, the counteranion is hexafluorophosphate. In certain embodiments, the counteranion is tetraphenylborate. In certain embodiments, the counteranion is tetrafluoroborate. In certain embodiments, the counteranion tetrakis(pentafluorophenyl)borate. In certain embodiments, the counteranion is hexafluoroanimonate. In certain embodiments, the counterion is [B[3,5-(CF₃)₂C6H₃]₄]^~, commonly abbreviated as [BAr^F ₄]^~.

In certain embodiments, n is 0, in which case the phenyl ring is unsubstituted. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. For the case where n is 1 or more, the substituents on the phenyl ring may have any substitution pattern.

In certain embodiments, m is 0. hi certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3.

In certain embodiments, the dashed line represents a bond, thus forming an imine moiety. In other embodiments, the dashed line represents the absence of a bond resulting in only a single bond between the carbon atom and nitrogen atom.

In certain embodiments, at least one R_A is halogen. In certain embodiments, at least one occurrence of R_A is aliphatic. In certain embodiments, at least one occurrence of R_A is Ci-C₆ alkyl. In certain embodiments, at least one occurrence of R_A is methyl. In certain embodiments, at least one occurrence of R_A is ethyl. In certain embodiments, at least one occurrence of R_A is propyl. In certain embodiments, at least one occurrence of R_A is butyl. In certain embodiments, at least one occurrence of R_A is heteroaliphatic. In certain embodiments, at least one occurrence of R_A is acyl. In certain embodiments, at least one occurrence of R_A is aryl. In certain embodiments, at least one occurrence of R_A is heteroaryl. In certain embodiments, at least one occurrence of R_A is -OR'. In certain embodiments, at least one occurrence of R_A is -N(R')₂. In certain embodiments, at least one occurrence of R_A is -SR'. In certain embodiments, at least one occurrence of R_A is -NO₂. In certain embodiments, at least one occurrence of R_A is -CN. In certain embodiments, at least one occurrence of R_A is -SCN. In certain embodiments, two occurrences of R_A taken together form a cyclic moiety. Such a cyclic moeity may be carbocyclic or heterocyclic. In certain embodiments, the cyclic moiety is a substituted or unsubstituted phenyl moiety. In certain embodiments, the cyclic moiety is an unsubstituted phenyl moiety. In certain embodiments, the cyclic moiety is a substituted or unsubstituted heteroaryl moiety.

In certain embodiments, at least one occurrence of R_B is hydrogen. In certain embodiments, both R_B are hydrogen. In certain embodiments, at least one occurrence of R_B is aliphatic. In certain embodiments, both occurrences of R_B are aliphatic. In certain embodiments, both occurrences of R_B are Ci-C₆ alkyl. In certain embodiments, both occurrences of R_B are methyl. In certain embodiments, both occurrences of R_B are ethyl. In certain embodiments, both occurrences of R_B are propyl. In certain embodiments, both occurrences of R_B are butyl. In certain embodiments, at least one occurrence of R_B is heteroaliphatic. In certain embodiments, both occurrences of R_B are heteroaliphatic. In certain embodiments, at least one occurrence of R_B is acyl. In certain embodiments, at least one occurrence of R_B is aryl. In certain embodiments, at least one occurrence of R_B is heteroaryl.

In certain embodiments, both R_B are the same. In certain embodiments, the two R_B are different.

In certain embodiments, both R_B are taken together to form a heterocyclic moiety. In certain embodiments, both R_B are taken together to form a 5-membered heterocyclic moiety. In certain embodiments, both R_B are taken together to form a 6-membered heterocyclic moiety. In certain embodiments, both R_B are taken together to form an optionally substituted heteroaryl moiety.

In certain embodiments, one R_B moiety is covalently attached to a methylene group connecting the phenyl ring to the N atom, thus forming a heterocyclic moiety. Such a heterocyclic moiety may be a heteroaryl moiety. For example, in certain embodiments, the heterocyclic moiety is a pyridinyl moiety.

In certain embodiments, Rc is hydrogen. In certain embodiments, R_c is aliphatic. In certain embodiments, Rc is Ci-C₆ alkyl. In certain embodiments, Rc is methyl. In certain embodiments, Rc is ethyl. In certain embodiments, Rc is propyl. In certain embodiments, Rc is butyl. In certain embodiments, Rc is heteroaliphatic. In certain embodiments, Rc is heteroaliphatic. In certain embodiments, Rc is acyl. In certain embodiments, Rc is aryl. In certain embodiments, R_c is heteroaryl. In certain embodiments, one R_B and R_c are taken together to form a heterocyclic moiety. In certain embodiments, one R_B and Rc are taken together to form a 5-membered heterocyclic moiety. In certain embodiments, one R_B and Rc are taken together to form a 6-membered heterocyclic moiety. In certain embodiments, one R_B and R_c are taken together to form an optionally substituted heteroaryl moiety.

In certain embodiments, R_DI, R_D2, R_D3 and R_D4 all represent optionally substituted heteroaryl moieties. In certain embodiments, at least one of R_DI, R_D2, R_D3 and R_D4 is an unsubstituted heteroaryl moiety. In certain embodiments, RD_I, R_D2, R_D3 and R_D4 are all unsubstituted heteroaryl moieties. In certain embodiments, R_DI, RD₂, RD₃ and R_D4 are all optionally substituted 5-membered heteroaryl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all nitrogen-containing 5-membered heteroaryl moieties, which are optionally substituted. In certain embodiments, R_Di, R_D2, R_D3 and RD₄ are all optionally substituted pyrazolyl moieties. In certain embodiments, R_DI, R_D2> R_D3 and R_D4 are all optionally substituted imidazolyl moieties. In certain embodiments, R_Di, R_D2, R_D3 and R_D4 are all optionally substituted pyrrolyl moieties. In certain embodiments, RD_I, R_D2, R_D3 and R_D4 are all are optionally substituted thiazolyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted oxazolyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted 6-membered heteroaryl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all nitrogen-containing 6-membered heteroaryl moieties, which are optionally substituted. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted pyridinyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted pyrazinyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted pyrimidinyl moieties. In certain embodiments, R_DI, R_D2> R_D3 and R_D4 are all optionally substituted pyridazinyl moieties. In certain embodiments, all of R_DI, R_D2, RD₃ and R_D4 of the borate ligand are the same. In other embodiments, all of R_DI, R_D2, R_D3 and R_D4 of the borate ligand are not the same. For example, a combination of heterocycle may constitute the borate ligand. In certain embodiments, a combination of heteroaryl moieties may constitute the borate ligand.

In certain embodiments, the palladium complex comprises a bidentate ligand of one of the formulae:

These ligands make a five-membered ring with the palladium atom with the nitrogen and a carbon coordinated to the central palladium.

In certain embodiments, the palladium complex is of the formula:

In certain embodiments, the palladium complex is of the formula:

In certain embodiments, the palladium complex is of the formula:

In certain embodiments, the palladium complex is of the formula:

In certain embodiments, the palladium complex is of the formula:

In certain embodiments, the palladium complex is of the formula:

In certain embodiments, the palladium complex is of the formula:

In certain embodiments, the palladium complex is of the formula:

Preparation of High-Valent Palladium Fluoride Complexes

The inventive palladium complexes are typically prepared starting from disodium tetrachloropalladate. As would be appreciated by one of skill in the art, other palladium salts may also be used to prepare the inventive complexes. The starting material is subjected to cyclometallation to yield a palladium(II) chloride dimer. The chloride ligands are then substituted using the desired borate ligand to yield a palladium(II) borate, which is then oxidized with a fluorine-containing oxidizing reagent (e.g., 1 -fluoro-pyridinium triflate, 2,4,6-trimethylpyridiniurn hexafluorophosphate, etc.) to yield the inventive palladium(IV) complex. An exemplary synthesis of a palladium(IV) fluoride complex is shown in Figure 1. In certain embodiments, the method of preparing an inventive palladium(IV) fluoride complex comprises (1) cyclometallating a ρalladium(II) salt with a bidentate ligand comprising a carbon-based with a carbon donor and a nitrogen donor to yield a palladium(II) chloride dimer; (2) reacting the palladium(H) dimer with a tridentate borate ligand under suitable conditions to yield a palladium(II) borate; and oxidizing the palladium(II) borate with a fluorinating reagent under suitable conditions to yield a palladium(IV) fluoride complex.

In certain embodiments, the bidentate ligand is of the formula:

wherein the dashed line represents the presence or absence of a bond; n is an integer between 0 and 4, inclusive; m is an integer between 0 and 3, inclusive; each occurrence of R_A is independently hydrogen; halogen; cyclic or acyclic,, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR'; -C(=O)R'; -CO₂R'; - CN; -SCN; -SR'; -SOR'; -SO₂R'; -NO₂; -N(R')₂; -NHC(O)R'; or -C(R')₃; wherein each ^* occurrence of R' is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; wherein two RA may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; and each occurrence of R₅ is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR"; -C(=0)R"; -CO₂R"; - CN; -SCN; -SR"; -SOR"; -SO₂R"; -NO₂; -N(R")₂; -NHC(O)R"; or -C(JT)₃; wherein each occurrence of R" is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and each occurrence of Rc is independently hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; wherein Rc and R_B may be taken together to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and wherein Rc and R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring. In certain embodiments, the borate ligand is tetrapyrazolylborate. In certain embodiments, the borate ligand is phenyltris(methimazolyl)borate.

In certain embodiments, an intermediate in the synthesis of a palladium(IV) fluoride complex is of the formula:

wherein the dashed line represents the presence or absence of a bond; Pd has a valency of +2; n is an integer between 0 and 4, inclusive; m is an integer between 0 and 3, inclusive; each occurrence of R_A is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR'; -C(=O)R'; -CO₂R'; - CN; -SCN; -SR'; -SOR'; -SO₂R'; -NO₂; -N(R')₂; -NHC(O)R'; or -C(R')₃; wherein each occurrence of R' is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; wherein two R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; each occurrence of R_B is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR"; -C(=O)R"; -CO₂R"; - CN; -SCN; -SR"; -SOR"; -SO₂R"; -NO₂; -N(R")₂; -NHC(O)R"; or -C(JT)₃; wherein each occurrence of R" is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; each occurrence of Rc is independently hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; wherein Rc and R_B may be taken together to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and wherein Rc and R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; and R_Di, R_D2, R_D3, and R_D4 are each independently cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl.

In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3.

In certain embodiments, at least one R_A is halogen. In certain embodiments, at least one occurrence of R_A is aliphatic. In certain embodiments, at least one occurrence of R_A is Ci-C₆ alkyl. In certain embodiments, at least one occurrence of R_A is methyl. In certain embodiments, at least one occurrence of R_A is ethyl. In certain embodiments, at least one occurrence of R_A is propyl. In certain embodiments, at least one occurrence of R_A is butyl. In certain embodiments, at least one occurrence of R_A is heteroaliphatic. In certain embodiments, at least one occurrence of R_A is acyl. In certain embodiments, at least one occurrence of R_A is aryl. In certain embodiments, at least one occurrence of R_A is heteroaryl. In certain embodiments, at least one occurrence of R_A is -OR'. In certain embodiments, at least one occurrence of R_A is -N(R')₂. In certain embodiments, at least one occurrence of R_A is -SR'. In certain embodiments, at least one occurrence of R_A is -NO₂. In certain embodiments, at least one occurrence of R_A is -CN. In certain embodiments, at least one occurrence of RA is -SCN.

In certain embodiments, two occurrences of R_A taken together form a cyclic moiety. Such a cyclic moeity may be carbocyclic or heterocyclic. In certain embodiments, the cyclic moiety is a substituted or unsubstituted phenyl moiety. In certain embodiments, the cyclic moiety is an unsubstituted phenyl moiety. In certain embodiments, the cyclic moiety is a substituted or unsubstituted heteroaryl moiety.

In certain embodiments, at least one occurrence of R_B is hydrogen. In certain embodiments, both R_B are hydrogen. In certain embodiments, at least one occurrence of R_B is aliphatic. In certain embodiments, both occurrences of R_B are aliphatic. In certain embodiments, both occurrences of R_B are C₁-C₆ alkyl. In certain embodiments, both occurrences of R_B are methyl. In certain embodiments, both occurrences of R_B are ethyl. In certain embodiments, both occurrences of R_B are propyl. In certain embodiments, both occurrences of R_B are butyl. In certain embodiments, at least one occurrence of R_B is heteroaliphatic. In certain embodiments, both occurrences of R_B are heteroaliphatic. In certain embodiments, at least one occurrence of R_B is acyl. In certain embodiments, at least one occurrence of R_B is aryl. In certain embodiments, at least one occurrence of R_B is heteroaryl.

In certain embodiments, one R_B moity is covalently attached to a methylene group connecting the phenyl ring to the N atom, thus forming a heterocyclic moiety. Such a heterocyclic moiety may be a heteroaryl moiety. For example, in certain embodiments, the heterocyclic moiety is a pyridinyl moiety. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 all represent optionally substituted heteroaryl moieties. In certain embodiments, at least one of R_DI, RD₂, R_D3 and RQ₄ is an unsubstituted heteroaryl moiety. In certain embodiments, RD_I, RD2, R_D3 and RD₄ are all unsubstituted heteroaryl moieties. In certain embodiments, R_Di, R_D2, R_D3 and R_D4 are all optionally substituted 5-membered heteroaryl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all nitrogen-containing 5-membered heteroaryl moieties, which are optionally substituted. In certain embodiments, R_DI, R_D2, RD₃ and R_D4 are all optionally substituted pyrazolyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted imidazolyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted pyrrolyl moieties. In certain embodiments, R_DI , R_D2, R_D3 and R_D4 are all are optionally, substituted thiazolyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and RQ₄ are all optionally substituted oxazolyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted 6-membered heteroaryl moieties. In certain embodiments, R_Di, R_D2, R_D3 and R_D4 are all nitrogen-containing 6-membered heteroaryl moieties, which are optionally substituted. In certain embodiments, RD_I, RD2, R_D3 and RD₄ are all optionally substituted pyridinyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted pyrazinyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted pyrimidinyl moieties. In certain embodiments, R_DI, R_D2, R_D3 and R_D4 are all optionally substituted pyridazinyl moieties. In certain embodiments, all of R_DI, R_D2, R_D3 and R_D4 of the borate ligand are the same. In other embodiments, all of R_DI, R_D2, R_D3 and R_D4 of the borate ligand are not the same. For example, a combination of heterocycle may constitute the borate ligand. In certain embodiments, a combination of heteroaryl moieties may constitute the borate ligand.

In certain embodiments, the intermediate comprises a bidentate ligand of one of the formulae:

These ligands make a five-membered ring with the palladium atom with the nitrogen and a carbon coordinated to the central palladium. In certain embodiments, the intermediate is of the formula:

In certain embodiments, the intermediate is of the formula:

In certain embodiments, the intermediate is of the formula:

In certain embodiments, the intermediate is of the formula:

Fluorinating Agents

As generally described above, the process for preparing the high-valent palladium(IV) fluoride complexes utilizes a fluorinating agent. In certain embodiments, the fluorinating agent is an electrophilic fluorinating agent. In certain embodiments, the fluorinating agent is commercially available. In certain embodiments, the electrophilic fluorinating agent is an inorganic fluorinating agent. Exemplary electrophilic fluorinating agents include, but are not limited to, N-fluoropyridimum triflate, N-fluoro-2,4,6-trimethylpyridinium triflate, N- fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, N-fluoro~2,6-dichloropyridinium tetrafluoroborate, N-fluoro- 2,6-dichloropyridinium triflate, N-fluoropyridinium pyridine heptafluorodiborate, N-fluoropyridinium tetrafluoroborate, N-fluoropyridinium triflate, N-- fluoroarylsulfonimide (e.g., N-fluorobenzenesulfonimide), N-chloromethyl-N'- fluorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor^®), and XeF₂. In certain embodiments, the fluorinating agent is Selectfluor^®. In certain embodiments, the fluorinating agent is N-fluoropyridinium triflate. In certain embodiments, the fluorinating agent is N- fluoro-2,4,6-trimethylpyridinium triflate. In certain embodiments, the fluorinating agent is N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate. In certain embodiments, the fluorinating agent is N-fluoro-benzenesulfonimide. In certain embodiments, the fluorinating agent is xenon difluoride. In certain embodiments, the fluorinating agent is N-chloromethyl- N'-fluorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor^®).

The fluorinating agent may be enriched with a particular isoptope of fluorine. In certain embodiments, the fluorinating agent is labeled with ¹⁹F (i.e., transfers an ¹⁹F fluorine substituent to the organic compound). In certain embodiments, reaction of the ¹⁹F fluorinating agent in the inventive process provides a fluorinated ¹⁹F-labeled organic compound.

I R I R

In certain embodiments, the fluorinating agent is labeled with F (i.e., transfers an F fluorine substituent to the organic compound). In certain embodiments, reaction of the ¹⁸F fluorinating agent in the inventive process provides a fluorinated ¹⁸F-labeled organic compound. However, in certain embodiments, the fluorinating agent is labeled with a mixture of

¹⁸F and ¹⁹F. In certain embodiments, reaction of the fluorinating agent with a mixture of ¹⁹F and ¹⁸F in the inventive process provides a mixture of fluorinated ¹⁹F-labeled organic compound and fluorinated F-labeled organic compound. In certain embodiments, the portion of each of ¹⁹F and ¹⁸F in the mixture is known. Any of the above fluorinated agents may be labeled with ¹⁹F or ¹⁸F.

For example, in certain embodiments, the fluorinating agent is ^!9F-labeled N- chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor^®) or ¹⁹F- labeled XeF₂. In certain embodiments, the fluorinating agent is ¹⁹F-labeled N-chloromethyl- N'-fluorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor^®). In certain embodiments, the fluorinating agent is ¹⁹F-labeled XeF₂.

In certain embodiments, the fluorinating agent is ¹⁸F-labeled XeF₂.

The inventive high-valent palladium(IV) fluoride complexes may also be prepared using nucleophilic fluoride rather than electrophilic fluorinating reagent. In general, this may be accomplished by first preparing the analogous high-valent palladium(IV) chloride (or other halogen) complex and subjecting the complex to halogen metathesis using AgF as shown in the scheme below.

Oxidation of the palladium(II) intermediate with PhICl₂ affords the Pd (IV) chloride complex. Reaction of the Pd (IV) chloride complex with AgF under suitable conditions then yields the Pd (IV) fluoride complex.

Uses

The inventive high-valent palladium(IV) fluoride complexes possess an electrophilic fluoride and thus are reactive toward nucleophiles such as palladium(II) complexes {e.g., palladium(II) aryl complexes), PPh₃, enamines, and enol silyl ethers. Although electrophilic fluorinating reagents including acetyl hypofluorites, xenon difluoride, and nitrogen fluorides are commercially available, they are expensive and tend to be poorly regioselective. The inventive complexes may also be useful in fluorination reactions by providing electrophilic F⁺. In particular, the high valent palladium complexes may be useful in conjunction with other transition metal reagents or catalysts for transfering the electrophilic F to an organic compound.

In certain embodiments, the inventive high-valent palladium fluoride complexes described herein are used in conjunction with the palladium(II)-mediated fluorination reactions described in U.S. provisional patent application, USSN 61/063,096, filed January

31, 2008, and USSN 61/050,446, filed May 5, 2008. Such reactions are particularly useful in preparing aryl fluorides.

In certain embodiments, the inventive high-valent palladium fluoride complexes are reacted with enol silyl ethers under suitable conditions to yield alpha-fluorinated carbonyl compounds. In certain embodiments, the starting material is cyclohexanone enol trimethylsilyl ether. In certain embodiments, the inventive high-valent palladium fluoride complexes are reacted with enamines under suitable conditions to yield fluorinated compounds.

Organic compounds As generally described above, the invention provides a process for fhiorinating an organic or organometallic compound using a high-valent palladium(IV) fluoride complex. In certain embodiments, the organic or organometallic compound has a particular substituent that is replaced with the fluoride from the complex. The organic compound utilized in the inventive process includes, but is not limited to, small organic molecules and/or large organic molecules. A small organic molecule include any molecule having a molecular weight of less than 1000 g/mol, of less than 900 g/mol, of less than 800 g/mol, of less than 700 g/mol, of less than 600 g/mol, of less than 500 g/mol, of less than 400 g/mol, of less than 300 g/mol, of less than 200 g/mol or of less than 100 g/mol. A large organic molecule include any molecule of between 1000 g/mol to 5000 g/mol, of between 1000 g/mol to 4000 g/mol, of between 1000 g/mol to 3000 g/mol, of between 1000 g/mol to 2000 g/mol, or of between 1000 g/mol to 1500 g/mol. Organic compounds include, but are not limited to, aryl compounds, heteroaryl compounds, carbocyclic compounds, heterocyclic compounds, aliphatic compounds, heteroaliphatic compounds, as well as polymers, peptides, glycopeptides, and the like.

In certain embodiments, the organic compound is an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl compound. In certain embodiments, the organic compound is an aryl-containing compound. In certain embodiments, an organic compound is a polymer.

In certain embodiments, an organic compound is a peptide. In certain embodiments, an organic compound is biologically active. For example, in certain embodiments, the organic compound is an agrochemical. In certain embodiments, the organic compound is an insecticide or a pheromone of insect origin. In certain embodiments, the organic compound is pharmaceutical agent. For example, in certain embodiments, the pharmaceutical agent is an anti-emetic, anti-coagulant, antiplatelet, anti-arrhythmic, anti-herpertensive, anti-anginal, a lipid-modifying drug, sex hormone, anti-diabetic, antibiotic, anti-viral, anti-fungal, anti-cancer, immuno stimulant, immunosuppressant, anti-inflammatory, anti-rheumatic, anesthetic, analgesic, anticonvulsant, hypnotic, anxiolytic, anti-psychotic, barbituate, antidepressant, sedative, anti-obesity, antihistimc, anti-eleptic, anti-manic, opioid, anti-Parkinson, anti-Alzheimers, anti-dementia, an anti-substance dependance drug, cannabinoid, 5HT-3 antagonist, monoamine oxidase inhibitor (MAOI), selective serotonin reuptake inhibitor (SSRI), or stimulant. In certain embodiments, the pharmaceutical agent is a psychotropic agent. In certain embodiments, the pharmaceutical agent is any pharmaceutical agent approved by the United States Food and Drug Administration (FDA) for administration to a human (see, e.g., www.accessdata. fda. gov/scripts/cder/drugsatfda) .

In certain embodiments, the pharmaceutical agent is an antibiotic. In certain embodiments, the pharmaceutical agent is a lipid modifying drug. In certain embodiments, the^* pharmaceutical agent is a CNS drug (i.e., drug acting on the Central Nervous System). CNS drugs include, but are not limited to, hypnotics, anxiolytics, antipsychotics, barbituates, antidepressants, antiobesity, antihistimes, antieleptics, antimanics, opioids, analgesics, anti- Parkinson, anti-Alzheimers, anti-dementia, anti-substance dependance drugs, cannabinoids, 5HT-3 antagonists, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs) and stimulants. Exemplary antibiotics, lipid modifying drugs and CNS drugs are provided below in Table 1.

In certain embodiments, the organic compound, after fluorination, is biologically active. In certain embodiments, the organic compound, pπor to fluorinated, is also biologically active.

In certain embodiments, the process provides after fluorination of the organic compound a known biologically active fluorinated compound, such as a fluorinated agrochemical or fluorinated pharmaceutical agent.

For example, in certain embodiments, the process provides after fluorination of the organic compound the known fluorinated pharmaceutical agent LIPITOR:

In certain embodiments, the process provides after fluorination of the organic compound the known fluorinated pharmaceutical agent PAXIL:

In certain embodiments, the process provides after fluorination of the organic compound the known fluorinated pharmaceutical agent LEXAPRO:

However, in certain embodiments, the process provides after fluorination of the organic compound a new biologically active fluorinated compound, such as a fluorinated derivative of a known agrochemical or pharmaceutical agent. In this context, a "fluorinated derivative of a known compound" is a known compound which is labeled with fluorine (i.e., one or more substituents of a known compound are replaced with fluorine).

For example, in certain embodiments, the process provides after fluorination of the organic compound a fluorinated derivative of the pharmaceutical agent vancomycin:

In certain embodiments, the process provides after fhiorination of the organic compound a fluorinated derivative of the pharmaceutical agent MORPHINE:

In certain embodiments, the process provides after fluorination of the organic compound the known fluorinated pharmaceutical agent ZYPREXA:

In certain embodiments, the process provided after fluorination of the organic compound a fluorinated derivative of the pharmaceutical agent tetracycline:

Exemplary Reaction Conditions

Described herein are compositions comprising a palladium complex described herein, including a reaction mixture, e.g., a reaction mixture that is present during a method or process described herein. As defined generally herein, in certain embodiments, the process comprises mixing a substrate and a palladium(IV) complex described herein, under conditions sufficient to fluorinate the organic compound, to thereby provide a fluorinated organic compound. In other embodiments, the process requires mixing a palladium(II) complex described herein with a fluorinating agent and a substrate, under conditions sufficient to fluorinate the substrate, thereby providing a fluorinated organic compound. In certain embodiments, the palladium(II) complex is combined with the fluorinating agent prior to addition of the substrate. In certain embodiments, this step results in formation of an intermediate palladium(IV) complex, which may or may not be isolated.

In certain embodiments, the palladium complex is bound to a solid support.

The substrate may be an organic compound comprising an enol silyl ether, or an organometallic compound such as a palladium(II) aryl complex or an arylsilver complex.

In certain embodiments, the method further comprises a solvent. In certain embodiments, the solvent is an organic solvent. In certain embodiments, the solvent is an aprotic solvent. Exemplary organic solvents include, but are not limited to, benzene, toluene, xylenes, methanol, ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, ethyl ether, tetrahydrofuran, methylene chloride, dichloroethane and chloroform, or a mixture thereof. In certain embodiments, the solvent is acetonitrile. In certain embodiments, the solvent is methylene chloride. In certain embodiments, the solvent is tetrahydrofuran. In certain embodiments, the solvent is dichloroethane. In certain embodiments, the solvent is benzene.

In certain embodiments, the reaction further comprises heating. In certain embodiments, the reaction takes place under an inert atmosphere (e.g, an atmosphere of an inert gas such as nitrogen or argon). In certain embodiments/the, reaction takes place under anhydrous conditions (e.g., conditions that are substantially free of water).

Applications The present invention provides a process for fluorination of organic compounds, and, as such, has many useful applications. In certain embodiments, the fluorination reaction is regiospecific.

Introduction of fluorine into a certain position of bioactive compound such as a pharmaceutical agent and an agricultural chemical may remarkably reduce the toxicity of the compound. This is due to the mimic and blocking effect characterized by fluorine. Many compounds, such as 5-fluorouracil, have been reported as successful examples.

Attempts to efficiently synthesize fluorine-containing compounds are performed in many fields. Methods to introduce fluorine into a certain position through the use of fluorinating agents or the use of fluorine-containing building blocks have been reported (see, for example, Liu et al., J. Am. Chem. Soc. (1981) 103:7195; Lovey et al, J. Med. Chem. (1982) 25:71 ; and Kikuchi et al, Juki Gosei Kagaku Kyokaishi (1997) 55:88).

Organofluorine compounds are emerging as chemical specialties of significant and increasing commercial interest. A major driver has been the development of fluorine- containing bio-active molecules for use as medicinal and plant— protection agents. Other new applications involving organofluorine chemistry are in the synthesis of liquid crystals, surface active agents, specialty coatings, reactive dyes, and even olefin polymerization catalysts.

F-fluorinated organic compounds may be useful for magnetic resonance imaging (MRI) technology. MRI is a is primarily a medical imaging technique most commonly used in radiology to visualize the structure and function of the body. It provides detailed images of the body in any plane. MRI contrast agents are a group of contrast media used to improve the visibility of internal body structures in MRI. Contrast agents alter the relaxation times of tissues and body cavities where they are present, which depending on the image weighting can give a higher or lower signal. Fluorine-containing constrast agents may be especially useful due to the lack of fluorine chemistry in the human body. This could, for example provide a detailed view of acidic regions, such as those containing cancer cells. ¹⁹F-labeled MRI contrast agents may add chemical sensitivity to MRI and could be used to track disease progression without the need to take tissue or fluid samples.

¹⁹F-fluorinated organic compounds may also be useful as probes for nuclear magnetic resonance (NMR) spectroscopy. Fluorine has many advantages as a probe for NMR spectroscopy of biopolymers. ¹⁹F has a spin of one-half, and its high gyromagnetic ratio contributes to its high sensitivity (approximately 83% of the sensitivity of ¹H). It also facilitates long-range distance measurements through dipolar-dipolar coupling. Moreover, the near-nonexistence of fluorine atoms in biological systems enables ¹⁹F NMR studies without background signal interference. Furthermore, the chemical shift of ¹⁹F has been shown to be very sensitive to its environment.

¹⁸F-fluorinated organic compounds are particularly useful for positron-emission tomography (PET) imaging technology. PET is a noninvasive imaging technology that is currently used in the clinic to image cancers and neurological disorders at an early stage of illness. PET tracers are molecules which incorporate a PET-active nucleus and can therefore be visualized by their positron emission in the body. The fluorine isotope ¹⁸F is the most common nucleus for PET imaging because of its superior properties to other nuclei.

A commonly used PET tracer is 2-deoxy-2-fluoroglucose (FDG), which behaves like glucose in the body and is transported to sites of high metabolism such as cancer cells. FDG is not itself metabolized and therefore accumulates in cancer tissues, which in turn can be visualized. The non-invasive nature and the high sensitivity render PET a powerful method for early cancer identification using FDG.

The ¹⁸F radioisotope has a half-life of 109 minutes. The short half-life dictates restrictions on chemical synthesis of PET tracers, because introduction of the fluorine atom

1 R has to take place at a very late stage of the synthesis to avoid the unproductive decay of F

1 R before it is injected into the body. Fluoride ion is the most common reagent to introduce F but the specific chemical properties of the fluoride ion currently limit the available pool of PET tracers. Due to the narrow functional group compatibility of the strongly basic fluoride ion, only a limited set of chemical reactions can be employed for fluorination, and hence the synthesis of PET tracers is limited to fairly simple molecules such as FDG. The field of PET imaging would benefit from the availability of a new method that is capable of introducing radiolabeled fluoride into structurally more complex organic molecules. An easy access to drug-based PET tracers would simplify determining the fate of such drugs in the body and thereby help to identify and understand their mode of action, bioavailability and time- dependent biodistribution.

Methods of treatment

A fluorinated compound described herein, such as a fluorinated pharmaceutical agent, can be administered to cells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and/or diagnose a variety of disorders, including those described herein below. In some embodiments, the fluorinated compound is made by a method described herein.

As used herein, the term "treat" or "treatment" is defined as the application or administration of a compound, alone or in combination with, a second compound to a subject, e.g., a patient, or application or administration of the compound to an isolated tissue or cell, e.g., cell line, from a subject, e.g., a patient, who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e.g., to prevent at least one symptom of the disorder or to delay onset of at least one symptom of the disorder).

As used herein, an amount of a compound effective to treat a disorder, or a "therapeutically effective amount" refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.

As used herein, an amount of a compound effective to prevent a disorder, or a "a prophylactically effective amount" of the compound refers to an amount effective, upon single- or multiple-dose administration to the subject, in preventing or delaying the occurrence of the onset or recurrence of a disorder or a symptom of the disorder. As used herein, the term "subject" is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject. The term "non-human animals" of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.

Described herein are compounds and compositions useful in the treatment of a disorder. In general, the compounds described herein are fluorinated derivatives of a pharmaceutical agent (e.g., a fluorinated estrone). Also envisioned herein are other compounds, wherein one or more fluorine moieties have been added to the pharmaceutical agent, e.g., replacing a hydrogen or functional group such as an -OH with a fluorine.

Compositions and routes of administration

The compositions delineated herein include the fluorinated compounds delineated herein, such as fluorinated pharmaceutical agents, as well as additional therapeutic agents if present, in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein. In some embodiments, the fluorinated compound is made by a method described herein.

The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable earners, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic paYenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleurή, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention. The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention.

Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this, invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.

Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

Kits

A compound described herein (e.g., a palladium complex described herein, an organic compound, a fluorinating agent, or a fluorinated compound, such as a fluorinated pharmaceutical agent) may be provided in a kit. The kit includes (a) a compound used in a method described herein, and, optionally (b) informational material. The informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the compounds for the methods described herein. In some embodiments, the palladium complex is bound to a solid support.

The informational material of the kits is not limited in its form. In one embodiment, the informational material can include information about production of the compound, molecular weight of the compound, concentration, date of expiration, batch or production site information, and so forth. In one embodiment, the informational material relates to methods for administering the compound. In one embodiment, the informational material can include instructions to administer a compound described herein in a suitable manner to perform the methods described herein, e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein). In another embodiment, the informational material can include instructions to administer a compound described herein to a suitable subject, e.g., a human, e.g., a human having or at risk for a disorder described herein.

The informational material of the kits is not limited in its form. In many cases, the informational material, e.g., instructions, is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet. However, the informational material can also be provided in other formats, such as Braille, computer readable material, video recording, or audio recording. In another embodiment, the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about a compound described herein and/or its use in the methods described herein. Of course, the informational material can also be provided in any combination of formats.

In addition to a compound described herein, the composition of the kit can include other ingredients, such as a solvent or buffer, a stabilizer, a preservative, a flavoring agent (e.g., a bitter antagonist or a sweetener), a fragrance, a dye or coloring agent, for example, to tint or color one or more components in the kit, or other cosmetic ingredient, and/or a second agent for treating a condition or disorder described herein. Alternatively, the other ingredients can be included in the kit, but in different compositions or containers than a compound described herein. In such embodiments, the kit can include instructions for admixing a compound described herein and the other ingredients, or for using a compound described herein together with the other ingredients. In some embodiments, the components of the kit are stored under inert conditions

(e.g., under Nitrogen or another inert gas such as Argon). In some embodiments, the components of the kit are stored under anhydrous conditions (e.g., with a desiccant). In some embodiments, the components are stored in a light blocking container such as an amber vial. A compound described herein can be provided in any form, e.g., liquid, dried or lyophilized form. It is preferred that a compound described herein be substantially pure and/or sterile. When a compound described herein is provided in a liquid solution, the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being preferred. When a compound described herein is provided as a dried form, reconstitution generally is by the addition of a suitable solvent. The solvent, e.g., sterile water or buffer, can optionally be provided in the kit.

The kit can include one or more containers for the composition containing a compound described herein. In some embodiments, the kit contains separate containers, dividers or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet. In other embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label. In some embodiments, the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of a compound described herein. For example, the kit includes a plurality of syringes, ampules, foil packets, or blister packs, each containing a single unit dose of a compound described herein. The containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.

The kit optionally includes a device suitable for administration of the composition, e.g., a syringe, inhalant, pipette, forceps, measured spoon, dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any such delivery device. In a preferred embodiment, the device is a medical implant device, e.g., packaged for surgical insertion.

Examples

The examples below are included merely for purposes of illustration of certain aspects and embodiments of the present invention and is not intended to limit the invention.

Example 1 - Synthesis and Characterization of a Palladium(IV) Fluoride

High-valent palladium fluorides are potential intermediates and reagents for the synthesis of aryl fluorides, which are important as pharmaceuticals and as tracers for positron-emission tomography (Mϋller, K.; Faeh, C; Diederich, F. Science 2007, 317, 1881 — 1886; Lasne, M. C; Perrio, C; Rouden, J.; Barre, L.; Roeda, D.; Dolle, F.; Crouzel, C,

Chemistry of beta(+)-emitting compounds based on fluorine-18. In Contrast Agents II, 2002; Vol. 222, pp 201-258; each of which is incorporated herein by reference). We have recently reported the palladium-mediated fluorination of arylboronic acids to form functionalized fluoroarenes and speculated on the intermediacy of discrete high-valent palladium fluorides. High-valent palladium fluoride complexes have also been suggested in other carbon-fluorine bond formations. In 2006, Sanford published the palladium-catalyzed fluorination of phenylpyridine derivatives and related substrates using electrophilic fluorination sources as oxidants under microwave irradiation at 100-150 °C (Hull, K. L.; Anani, W. Q.; Sanford, M. S. J Am. Chem. Soc. 2006, 128, 7134-7135; incorporated herein by reference). While high- valent palladium complexes maybe intermediates in this transformation, none have been reported to date. In 2008, Vigalok and Vedernikov communicated the formation of fluorobenzene and iodobenzene in 10% and 90% yield, respectively, upon treatment of a diphosphine arylpalladium iodide with l-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (Yahav-Levi, A.; Goldberg, I.; Vigalok, A.; Vedernikov, A. N. J. Am. Chem. Soc. 2008, 130, 724-731 ; incorporated herein by reference). The transient formation of a palladium(IV) fluoride followed by either carbon-iodine or carbon-fluorine bond formation via reductive elimination is a potential mechanistic pathway that would explain the observed products. Although discrete high-valent palladium fluorides are potential intermediates in all three examples - Sanford' s, Vigalok' s, and our own - electrophilic palladium-carbon bond cleavage is a mechanistic alternative which has not been ruled out in any of these examples; in no instance has a high-valent palladium fluoride been observed. In 1992, Canty reported the reaction of a palladium(IV) bromide with silver (I) fluoride to presumably generate a benzyldimethylpalladium(IV) fluoride that was observed by ¹H NMR (Canty, A. J.; Traill, P. R.; Skelton, B. W.; White, A. H. J. Organomet. Chem. 1992, 433, 213-222; incorporated herein by reference). While hundreds of early transition metal fluorides have been structurally characterized (Murphy, E. F.; Murugavel, R.; Roesky, H. W. Chem. Rev. 1997, 97, 3425-3468; incorporated herein by reference), only eight palladium complexes with terminal fluoride ligands can be found in the Cambridge Structural Database, none of which contain a palladium center in an oxidation state other than +11 (Fraser, S. L.; Antipin, M. Y.; Khroustalyov, V. N.; Grushin, V. V. J. Am. Chem. Soc. 1997, 119, 4769-4770; Marshall, W. J.; Thorn, D. L.; Grushin, V. V. Organometallics 1998, 17, 5427-5430; Roe, D. C; Marshall, W. J.; Davidson, F.; Soper, P. D.; Grushin, V. V. Organometallics 2000, 19, 4575-4582; Grushin, V. V.; Marshall, W. J. Angew. Chem., Int. Ed. 2002, 41, 4476-4479; Yahav, A.; Goldberg, L; Vigalok, A. J. Am. Chem. Soc. 2003, 125, 13634-13635; Jasim, N. A.; Perutz, R. N.; Whitwood, A. C; Braun, T.; Izundu, J.; Neumann, B.; Rothfeld, S.; Stammler, H.-G. Organometallics 2004, 23, 6140-6149; Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 12644-12645; Kaspi, A. W.; Yahav-Levi, A.; Goldberg, L; Vigalok, A. Inorg. Chem. 2008, 47, 5-7; each of which is incorporated herein by reference). In this Example, the synthesis of a well-defined organometallic palladium(IV) fluoride and its characterization are described. To our knowledge, no high-valent palladium fluoride has previously been characterized by either ¹⁹F NMR or X-ray crystallography. Three structural design elements were considered to synthesize a stable palladium(IV) fluoride. Firstly, we targeted complexes containing a single carbon-based ligand. Carbon- based ligands are strong σ-donors and can thus stabilize high-valent palladium centers, but the presence of multiple carbon-based ligands can result in carbon-carbon reductive elimination with concurrent reduction of the metal center (Canty, A. J.; Traill, P. R.; Skelton, B. W.; White, A. H. J. Organomet. Chem. 1992, 433, 213-222; incorporated herein by reference). Similarly, other X-type ligands, such as amido and alkoxide ligands, can support high-valent metal centers by both σ- and π-donation, but also participate in reductive elimination from palladium(IV) to form carbon-X bonds (Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790-12791 ; Pawlikowski, A. V.; Getty, A. D.; Goldberg, K. I. J. Am. Chem. Soc. 2007, 129, 10382-10393; each of which is incorporated herein by reference). Secondly, neutral nitrogenous donors were selected because they are known to stabilize high-valent metal centers and typically do not participate in reductive elimination (Berry, J. F.; Bill, E.; Bothe, E.; George, S. D.; Mienert, B.; Neese, F.; Wieghardt, K. Science 2006, 312, 1937-1941; incorporated herein by reference). Finally, we envisioned rigid ligand scaffolds would stabilize the anticipated octahedral coordination sphere of palladium(IV) and thus disfavor reductive elimination and other reductive pathways from an octahedral d⁶ palladium(IV) to a square planar d⁸ palladium(II) (Campora, J.; Palma, P.; del Rio, D.; Lopez, J. A.; Alvarez, E.; Connelly, N. G. Organometallics 2005, 24, 3624-3628; incorporated herein by reference). Tetrapyrazolylborate (Tp) ligands position three neutral nitrogen donor atoms in a facial geometry for chelation to a transition metal (Trofimenko, S. J. Am. Chem. Soc. 1967, 89, 3170-3177; Trofimenko, S. Ace. Chem. Res. 1971, 4, 17-22; Trofimenko, S. Chem. Rev. 1993, 93, 943-980; each of which is incorporated herein by reference). The Tp ligand has been used in organometallic chemistry to stabilize octahedral complexes due to the three N-Metal-N bond angles near 90°. The N₁N- dimethylaminonaphthyl ligand was selected because it can be installed on palladium by cyclometallation to form a rigid, electron-rich five-membered chelate.

Cyclometallation of TV.TV-dimethyl-l-naphthylmethanamine (1) with disodium tetrachloropalladate afforded the palladium(II) chloride dimer (2) in 58% yield {Figure 1). The chloride ligands were subsequently substituted using one equivalent of potassium tetrapyrazolylborate per palladium to afford the ρalladium(II) borate 3 in 74% yield. Line broadening in the ¹H and ¹³C NMR spectra of 3 at room temperature is consistent with previously observed dynamic coordination/dissociation of the pyrazolyl ligands of the Tp ligand to palladium (Onishi, M.; Ohama, Y.; Sugimura, K.; Hiraki, K. Chem. Lett. 1976, 955-958; incorporated herein by reference); sharper resonances could be observed at -50 ⁰C. Oxidation of 3 with commercially available 1-fluoro-pyridinium triflate (4) afforded a discrete new compound by ¹H and ¹⁹F NMR. A ¹⁹F NMR fluorine resonance was observed at -287.4 ppm; no other values for ¹⁹F NMR resonances of high-valent palladium fluorides are available, but ¹⁹F NMR shifts of palladium(II) fluorides have been reported in a range from - 268 to -301 ppm (Fraser, S. L.; Antipin, M. Y.; Khroustalyov, V. N.; Grushin, V. V. J. Am. Chem. Soc. 1997, 119, 4769-4770; Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 12644-12645; each of which is incorporated herein by reference). Additionally, the line broadening in the NMR spectra observed for 3 was not observed for the new compound 5. The palladium fluoride 5 was unstable toward water and when heated in an acetone solution to 50 ⁰C; purification, isolation or structural characterization of 5 was not pursued.

The more stable palladium(IV) fluoride 7 could be prepared when using 1-fluoro- 2,4,6-trimethylpyridinium hexafluorophosphate (6), an electrophilic fluorination reagent specifically prepared for this purpose (eq 1). The palladium(IV) fluoride complex 7 with a hexafluorophosphate counteranion is more stable than the palladium triflate 5. High-valent palladium fluoride 7 is a moisture- and air-stable orange solid that can be stored in ambient atmosphere without decomposition for at least one week. The solution structure of 7 was characterized by five NMR-active nuclei. Similar to the ¹⁹F NMR resonance observed for 5, a ¹⁹F NMR resonance for 7 is observed is at -294.0 ppm in addition to the hexafluorophosphate resonance at -72.7 ppm. The NMR data is consistent with a cationic octahedral palladium(lV) fluoride complex in which three of the four pyrazolyl substituents of the Tp ligand are complexed to palladium. A V_F-_H coupling of 3.4 Hz from one benzyl hydrogen to the terminal fluoride in the ¹H NMR of 7 was observed. In addition, a coupling constant of 6.5 Hz was observed in the ¹³C NMR spectrum for one of the carbon atoms of the two amine methyl groups that we attribute to a ³Jp-_C coupling. An H-F HSQC NMR experiment was performed which both confirmed the V_F-_H coupling and demonstrated the simultaneous coordination of the dimethylamino ligand and the fluoride ligand to palladium in solution.

To unambiguously establish the connectivity of 7, crystals suitable for X-ray crystallographic analysis were obtained by cooling a solution of 7 that was heated at reflux in methylene chloride/hexane/benzene. The compound crystallized"as prange-yellow plates in the triclinic space group P 1. Disorder was observed only for the hexafluorophosphate counteranion, which was treated with a two-site disorder model [P(I), F(2), F(3), F(4), F(5), F(6), F(7)] and [P(I'), F(2'), F(3'), F(4'), F(5'), F(6'), F(V)] with refined site occupancy factors of 0.80 (2) and 0.20 (2), respectively. The disorder model was included in the least-squares refinement with mild rigid-bond, similar U₁,, 1,2- and 1,3-distance restraints. The cationic palladium fragment of the complex was fully ordered. The solid state structure of 7 confirmed the solution structure as a palladium(IV) complex with a terminal fluoride ligand {Figure 2). The palladium-fluorine bond distance is 1.923(4) A, which is the shortest palladium-fluorine bond observed to date. The other bond lengths and angles are within the expected values of a d⁶ octahedral palladium(IV) complex supported by a Tp ligand.

In conclusion, we report the synthesis and characterization of an organometallic palladium(IV) fluoride complex. The complex is stable to air and moisture and thermally stable to at least 60 ⁰C.

Materials and Methods

All reactions were carried out under an ambient atmosphere. Reactions were magnetically stirred and monitored by thin layer chromatography (TLC) using EMD TLC plates pre-coated with 250 μm thickness silica gel 60 F254 plates and visualized by fluorescence quenching under UV light. In addition, TLC plates were stained using eerie ammonium molybdate or potassium permanganate stain. Flash chromatography was performed on Dynamic Adsorbents Silica Gel 40-63 μm particle size using a forced flow of eluant at 0.3-0.5 bar pressure (Still, W. C; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2925-2927; incorporated herein by reference). Concentration under reduced pressure was performed by rotary evaporation at 25-30 ⁰C at appropriate pressure. Purified compounds were further dried under high vacuum (0.01-0.05 Ton"). Yields refer to purified and spectroscopically pure compounds. Melting points were measured on a Buchi 510 apparatus. All melting points were measured in open capillaries and are uncorrected. NMR spectra were recorded on either a Varian Unity/Inova 600 spectrometer operating at 600 MHz for ¹H acquisitions, a Varian Unity/Inova 500 spectrometer operating at 500 MHz and 125 MHz for ¹H and ¹³C acquisitions, respectively, a Varian Mercury 400 spectrometer operating at 375 MHz and 160 MHz for ¹⁹F and ³¹P acquisitions, respectively, or a Varian Mercury 300 spectrometer operating at 100 MHz for ¹¹B acquisitions. Chemical shifts are reported in ppm with the solvent resonace as the internal standard. Data is reported as follows: s = singlet, br = broad, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet; coupling constants in Hz; integration. High-resolution mass spectra were obtained on Jeol AX-505 or SX- 102 spectrometers at the Harvard University Mass Spectrometry Facilities. Na₂PdCl₄-SH₂O and KBH₄ were purchased from Strem. 1 -Naphthaldehyde, Me₂NH-HCl, and NH₄PF₆ were purchased from Alfa Aesar. Pyrazole was obtained from Aldrich and l-fiuoro-2,4,6- trimethylpyridinium triflate was purchased from TCI America and used as received.

Experimental Data

Experimental Procedures and Compound Characterization Potassium tetra( 1 //-pyrazol- 1 -yl)borate

As solids, KBH₄ (1.0Og, 18.6 mmol, 1.00 equiv) and pyrazole (7.61 g, 112 mmol, 6.00 equiv) are combined. This mixture is heated to 250 ⁰C for 16 hours, after which time the melt is cooled to room temperature. The residue is triturated with Et₂O (100 mL) and isolated by filtration. Washing with additional Et₂O (2 x 50 mL) affords 3.60 g of the title compound as a colorless solid (61% yield).

Melting Point: 248-249 ⁰C. NMR Spectroscopy: ¹H NMR (600 MHz, D₂O, 23 ⁰C, δ): 7.49 (s, 4H), 7.19 (d, J= 2.0 Hz, 4H), 6.14 (s, 4H). ¹³C NMR (125 MHz, D₂O, 23 ⁰C, δ): 138.85, 132.84, 102.42. ¹¹B NMR (100 MHz, D₂O, 23 ⁰C, δ): -1.30. Mass Spectrometry: LRMS-FIA (m/z): 279.1. These spectroscopic data correspond to reported data (Niedenzu, K.; Niedenzu, P.M. Inorg. Chem. 1984, 23, 3713-3716; incorporated herein by reference).

l-Fluoro-2,4,6-trimethylpyridinium hexafluorophosphate (6)

To l-fluoro-2,4,6-trimethylpyridinium triflate (1.00 g, 3.46 mmol, 1.00 equiv) in 30 mL H₂O is added NH₄PF₆ (1.13 g, 6.91 mmol, 2.00 equiv) in one portion at 23 ⁰C. The suspension is stirred for 1.5 hours before the solid is isolated by filtration. Recrystallization from hexanes/acetone (30 mL, 1:1 (v/v)) affords 722 mg of the title compound as a colorless solid (73% yield)

Melting Point: 182-184 ⁰C. NMR Spectroscopy: ¹H NMR (500 MHz, acetonitrile-J3, 23 ⁰C, δ): 7.64 (d, J = 6.6 Hz, 2H), 2.74 (d, J= 4.1 Hz, 6H), 2.54 (s, 3H). ¹³C NMR (125 MHz, acetonitrile-t/3, 23 ⁰C, δ): 160.15 (d, J= 2.7 Hz), 148.06 (d, J= 2.7 Hz), 129.30 (d, J = 3.7 Hz), 21.76 (s), 16.32 (d, J= 6.4 Hz). ¹⁹F NMR (375 MHz, acetonitrile-J3, 23 ⁰C, δ): 15.53 (br s), -73.36 (d, J= 705.6 Hz). ³¹P (160 MHz, acetonitrπWJ, 23 ⁰C, δ): -143.55

(quin, J= 705.9 Hz). Mass Spectrometry: HRMS-FIA (m/z): calcd for [M - PF₆], 140.0870. Found, 140.0867.

JV,iV-dimethyl (naphthalene- 1 -yl)methanamine ( 1 )

92% 1

To 1-naphthaldehyde (1.50 g, 9.62 mmol, 1.00 equiv) in 40 mL THF is added NaOAc (0.79 g, 9.62 mmol, 1.00 equiv), Me₂NH-HCl (863 mg, 10.6 mmol, 1.10 equiv), and AcOH (0.11 mL, 1.9 mmol, 0.20 equiv) at 23 ⁰C. NaBH(OAc)₃ (4.08 g, 19.3 mmol, 2.00 equiv) is added in three portions over five minutes. The suspension is stirred for 12 hours before solvent is removed in vacuo. To the residue is added 10 mL sat. NaHCO_3(aq) and 10 mL CH₂Cl₂. The phases are separated and the aqueous phase is extracted with CH₂Cl₂ (3 x 10 mL). The combined organic phase is concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with hexanes/EtOAc 3:2 (v/v) to afford 1.64 g of the title compound as a colorless liquid (92% yield). R/= 0.38 (hexane/EtOAc 2:3 (v/v)). NMR Spectroscopy: ¹H NMR (600 MHz, CDCl₃,

23 ⁰C, δ): 8.27 (d, J = 8.5 Hz, IH), 7.85 (d, J= 8.2 Hz, IH), 7.79 (dd, J= 6.7 Hz, 2.9 Hz, IH), 7.53 (ddd, J = 8.0 Hz, 6.5 Hz, 1.0 Hz, IH), 7.48 (ddd, J= 6.5 Hz, 5.5 Hz, 1.0 Hz, IH), 7.43- 7.40 (m, 2H), 3.82 (s, 2H), 2.31 (s, 6H). ¹³C NMR (125 MHz, CDCl₃, 23 ⁰C, δ): 134.85, 133.84, 132.52, 128.40, 127.95, 127.38, 125.98, 125.56, 125.06, 124.49, 62.60, 45.69. Mass Spectrometry: HRMS-FIA (m/z): calcd for [Ci₃Hi₅N + H], 186.1277. Found, 186.1286. These spectroscopic data correspond to reported data (Gay, R.L.; Hauser, CR. J. Am. Chem. Soc. 1967, 89, 2297-2303; incorporated herein by reference).

Di-μ-chloro-bis(7V, jV-dimethyl- 1 -naphthylamine-8-C,N)dipalladium(II) (2)

58%

To ΛζTV-dimethy^naphthalene-l-y^methanamine (1) (284 mg, 1.53 mmol, 1.00 equiv) in 15 mL MeOH is added Na₂PdCl₄-3H₂O (554 mg, 1.53 mmol, 1.00 equiv) in one portion at 23 ⁰C. A red precipitate is immediately observed. After stirring for three hours, the solid is isolated by filtration and is subsequently washed with MeOH. The solid is suspended in 30 mL benzene and heated to reflux. The suspension is filtered through celite and the filtrate is cooled to room temperature. Upon addition of 30 mL hexanes, precipitation of the title compound is observed. Filtration affords 579 mg of the title compound as an orange solid (58% yield). Melting Point: 220-221 ⁰C (decomp.). NMR Spectroscopy: ¹H NMR (500 MHz,

CD₂Cl₂, 23 ⁰C, δ): 7.79 (d, J= 7.1 Hz, IH), 7.58-7.56 (m, IH), 7.42-7.36 (m, 4H), 4.47 (d, J = 5.5 Hz, 2H), 3.00 (d, J= 9.5 Hz, 6H). ¹³C NMR (125 MHz, CD₂Cl₂, 23 ⁰C, δ): 143.25, 143.19, 141.75, 132.03, 131.83, 131.39, 129.27, 128.90, 128.65, 126.04, 125.00, 124.85, 124.63, 123.84, 71.88, 71.63, 53.80, 53.58. Mass Spectrometry: LRMS-FIA (m/z): 650.0. These spectroscopic data correspond to reported data (Julia, M.; Duteil, M.; Lallemand, J.Y. J. Organomet. Chem. 1975, 102, 239-243; Cope, A.C.; Friedrich, E.C. J. Am. Chem. Soc. 1968, 90, 909-913; each of which is incorporated herein by reference).

(7V,7V-dimethyl[naphthalen- 1 -yl]methanamino)(tetrapyrazolylborate)palladium(II) (3)

74% " Jo di-μ-chloro-bis(7V,7V-dimethyl-l-naphthylamine-8-C,N)dipalladium(II) (2) (252 mg, 0.387 mmol, 1.00 equiv) in 7 niL THF is added potassium tetra(lH-pyrazol-l-yl)borate (KBpz₄) (246 mg, 0.774 mmol, 2.00 equiv) in one portion at 23 ⁰C. The orange suspension is heated at 50 ⁰C for 8 hours at which time a white suspension is observed. Solvent is removed in vacuo and the residue is dissolved in 15 mL CH2CI2. The suspension is filtered through celite and sblvent is removed in vacuo. Trituration with Et₂O (100 mL) and filtration affords 326 mg of the title compound as a colorless solid (74%).

R/= 0.40 (EtOAc). Melting Point: 194-195 ⁰C (decomp.). NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃, -50 ⁰C, δ): 7.86 (s, IH), 7.82 (d, J= 7.6 Hz, IH), 7.71 (br s, IH), 7.66 (br s, IH), 7.59 (d, J= 8.0 Hz), 7.55-7.40 (m, 8H), 6.81 (d, J= 8.5 Hz, IH), 6.76 (br s, IH), 6.36 (br s, IH), 6.32 (s, IH), 6.29 (s, IH), 6.13 (s, IH), 4.72 (d, J= 14 Hz, IH), 4.09 (d, J= 14 Hz, IH), 2.90 (s, 3H), 2.17 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, -50 ⁰C, δ): 147.94, 144.03, 142.13, 141.20, 140.83, 136.65 (br), 136.40 (br), 136.25 (br), 135.40, 134.23, 132.53, 130.82, 128.40, 128.24, 128.06, 125.58, 124.73, 124.14, 123.22, 106.43, 105.47, 104.96, 71.13, 52.86, 50.99. ¹¹B NMR (100 MHz, CDCl₃, 23 ⁰C, δ): 1.14. Mass Spectrometry: HRMS-FIA (m/z): calcd for [C₂₅H₂₆BN₉Pd + H], 570.1512. Found, 570.1492.

(iV,iV-dimethyl)naphthalene- 1 -yl]methanamino)(tetrapyrazolylborate) palladium(IV) fluoride hexafluorophosphate (7)

To (ΛζJV-dimethyl [naphthalen- 1 -yl]methanamino)(tetrapyrazolylborate)palladium(II) (3) (148 mg, 0.260 mmol, 1.00 equiv) suspended in 4.0 mL CH₂Cl₂ is added l-fluoro-2,4,6- trimethylpyridinium hexafluorophosphate (6) (74.2 mg, 0.260 mmol, 1.00 equiv) in one portion at 23 ⁰C. After two hours, solvent is removed in vacuo. Trituration with Et₂O (5 mL) followed by recrystallization from CH₂Cl₂/ benzene affords 128 mg of the title compound as an orange solid (67%).

Melting Point: 142-144 ⁰C. NMR Spectroscopy: ¹H NMR (500 MHz, CDCl₃, 23 ⁰C, δ): 8.80 (d, J= 2.6 Hz, IH), 8.25 (d, J= 2.2 Hz, IH), 8.18 (d, J= 2.1 Hz, IH), 8.13 (d, J = 2.5 Hz, IH), 8.03 (d, J= 1.5 Hz, IH), 8.01 (d, J= 8.5Hz, IH), 7.94 (d, J= 8.1 Hz, IH), 7.76 (br s, IH), 7.72 (dd, J= 7.3 Hz, 7.0 Hz, IH), 7.69-7.64 (m, 2H), 7.15 (d, J= 2.2 Hz, IH), 6.77 (dd, J= 2.1 Hz, 2.1 Hz, IH), 6.66 (d, J= 9.5 Hz, IH), 6.61 (dd, J= 2.3 Hz, 2.2 Hz, IH), 6.54-6.53 (m, 2H), 6.33 (dd, J= 2.3 Hz, 2.2 Hz , IH), 5.46 (d, J= 15.0 Hz, IH), 4.87 (d, J_H,H = 15.0 Hz, J_H,_F = 3.4 Hz, IH), 3.54 (d, J_H,F = 2.1 Hz, 3H), 3.06 (s, 3H). ¹⁹F NMR (375 MHz, CDCl₃, 23 ⁰C, δ): -72.65 (d, J= 712.6 Hz), -293.96 (s). ³¹P NMR (160 MHz, CDCl₃, 23 ⁰C, 5): -143.22 (quin, J= 713.3 Hz). ¹¹B NMR (100 MHz, CDCl₃, 23 °C, δ): 1.64. Mass Spectrometry: HRMS-FIA (m/z): calcd for [M - PF₆I, 588.1418. Found, 588.1419. Crystal structure is shown in the X-ray Crystallographic Analysis section.

(AfiV-dimethyl)naphthalene-l -yl]methanammo)(tetrapyrazolylborate) palladium(IV) fluoride triflate (5)

To (7V,7V-dimethyl[naphthalen- 1 -yl]methanamino)(tetrapyrazolylborate)palladium(II) (3) (5.7 mg, 0.010 mmol, 1.0 equiv) suspended in 0.5 mL acetone-J<5 is added 1-fluoro- pyridinium triflate (2.5 mg, 0.010 mmol, 1.0 equiv) in one portion at 0 ⁰C. After stirring 20 minutes at 0 ⁰C, the reaction mixture is wanned to 23 ⁰C and further stirred for 30 minutes. NMR Spectroscopy: ¹H NMR (500 MHz, acetone-^, 23 ⁰C, δ): 8.79 (d, J= 2.0 Hz, IH), 8.64-8.58 (m, 2H), 8.50 (d, J= 1.5 Hz, IH), 8.47 (d, J= 1.5 Hz, IH), 8.45 (d, J= 2.0 Hz, IH), 8.12-8.07 (m, 3H), 8.00 (br s, IH), 7.86-7.80 (m, 2H), 7.79 (d, J= 2.0 Hz, IH), 7.68

(ddd, J= 7.5 Hz, 7.0 Hz, 2.0 Hz, IH), 7.59 (dd, J= 7.5 Hz, 7.0 Hz, IH), 7.41 (dd, J= 6.0 Hz, 4.5 Hz, IH), 6.82 (dd, J= 1.5 Hz, 1.5 Hz, IH), 6.72 (dd, J= 2.0 Hz, 2.0 Hz, IH), 6.70 (dd, J = 2.0 Hz, 2.0 Hz, IH), 6.63 (d, J= 2.0 Hz, IH), 6.49 (dd, J= 2.0 Hz, 2.0 Hz, IH), 5.50 (d, J = 12.5 Hz, IH), 4.87 (d, J_H,H = 12.5 Hz, J_H,F = 4.5 Hz, IH), 3.62 (s, 3H), 3.24 (s, 3H). ¹⁹F NMR (375 MHz, acetone-^, 23 ⁰C, δ): -79.5 (s, 3F), -287.4 (s, IF).

X-ray Crystallographic Analysis Experimental The compound was crystallized from a dichloromethane/benzene/hexaμe solution as orange-yellow plates. A crystal 0.050 mm x 0.075 mm x 0.100 mm in size was selected, mounted on a nylon loop with Paratone-N oil, and transferred to a Bruker SMART APEX II diffractometer equipped with an Oxford Cryosystems 700 Series Cryostream Cooler and Mo Ka radiation (λ = 0.71073 A). A total of 1855 frames were collected at 193 (2) K with an oscillation range of 0.5°/frame, and an exposure time of 30 s/frame using the APEX2 suite of software. (Bruker AXS, 2006a) Data were collected to θ_max = 22.50° rather than the routine value of θ_max = 27.50° because the crystal examined did not exhibit usable diffraction beyond 22.50°. Unit cell refinement on all observed reflections, and data reduction with corrections for Lp and decay were performed using SAINT. (Bruker AXS, 2006b) Scaling and a numerical absorption correction were done using SADABS. (Bruker AXS, 2004) The minimum and maximum transmission factors were 0.9237 and 0.9608, respectively. A total of 18585 reflections were collected, 4559 were unique (R_1n, = 0.0763),and 3098 had /> 2σ(7). The lack of systematic absences was consistent with the compound having crystallized in the tri clinic space group Pl or P l. The centrosymmetric space group P l (No. 2) was selected. The observed mean \E²-\ \ value was 0.867 (versus the expectation values of 0.968 and 0.736 for centric and noncentric data, respectively).

The structure was solved by direct methods and refined by full-matrix least-squares on F² using SHELXTL. (Bruker AXS, 2001) The asymmetric unit was found to contain one (fluoro)[l-{(dimethyl-amino)-methyl}naphthalenyl](tetrapyrazoylborate)palladium(IV) cation, one hexafluorophosphate anion, a half-molecule of benzene, and one dichloro- methane. All of the nonhydrogen atoms were refined with anisotropic displacement coefficients. The hydrogen atoms were assigned isotropic displacement coefficients U(H) = 1.2U(C) or 1.5[/(C_methyi), and their coordinates were allowed to ride on their respective carbons. The hexafluorophosphate anion was treated with a two-site disorder model [P(I), F(2), F(3), F(4), F(5), F(6), F(7)] and [P(F), F(2'), F(3'), F(4'), F(5'), F(O¹), F(7')] with refined site occupany factors of 0.80 (2) and 0.20 (2), respectively, and included in the least-squares refinement with mild rigid-bond, similar U_1J , 1,2- and 1,3-distance restraints. The refinement converged to R(F) = 0.0603, wR(F²) = 0.1534, and S = 1.079 for 3098 reflections with /> 2σ(/), and R(F) = 0.1011 , WR(F²) = 0.1783, and S = 1.079 for 4559 unique reflections, 517 parameters, and 252 restraints. The maximum |Δ/σ| in the final cycle of least-squares was less than 0.001, and the residual peaks on the final difference-Fourier map ranged from - 0.864 to 1.312 eA^~3. Scattering factors were taken from the International Tables for Crystallography, Volume C. (Maslen et al, 1992, and Creagh & McAuley, 1992)

References

Bruker AXS (2001). SHELXTL v6.12. Bruker Analytical X-ray Systems Inc., Madison,

Wisconsin, USA.

Bruker AXS (2004). SADABS. Bruker Analytical X-ray Systems Inc., Madison, Wisconsin,

USA. Bruker AXS (2006a). APEX2 v2.1-0. Bruker Analytical X-ray Systems Inc., Madison,

Wisconsin, USA.

Bruker AXS (2006b). SAINT V7.34A. Bruker Analytical X-ray Systems Inc., Madison,

Wisconsin, USA.

Creagh, D. C. & McAuley, W. J. (1992). International Tables for Crystallography: Mathematical, Physical and Chemical Tables, VoI C, edited by A. J. C. Wilson, pp. 206-222.

Dordrecht, The Netherlands: Kluwer.

Maslen, E. N., Fox, A. G. & O'Keefe, M. A. (1992). International Tables for

Crystallography: Mathematical, Physical and Chemical Tables, VoI C, edited by A. J. C.

Wilson, pp. 476-516. Dordrecht, The Netherlands: Kluwer.

R(F) = Rl = Σ ||F₀|-|Fc|| / ∑|F₀|, wR(F²) = wR2 = [ Σ w (F_O ²-F_C ²)² / Σ w (F₀ ²)² ]^1/2, and S = o ^y o o 1 /o

Goodness-of-fit on F = [ Σ w (F₀ -F₀ ) / (n-p) ] , where n is the number of reflections and p is the number of parameters refined.

Table 2. Crystal data and structure refinement for 7

Identification code 7 = [PdF(C12H12BN8)(C13H14N)] (PF6) . 0.5(C6H6) . CH2C12

Empirical formula C29 H31 B C12 F7 N9 P Pd Formula weight 857.71 Temperature 193(2) K Wavelength 0.71073 A Crystal system Triclinic Space group P -I Unit cell dimensions a = 11.7615(6) A α= 66.456(3)° b = 11.9764(6) A β= 86.013(4)° c = 13.5288(7) A γ = 89.291(4)° Volume 1742.56(15) A³ Z 2

Density (calculated) 1.635 Mg/m³ Absorption coefficient 0.806 mm^"1 F(OOO) 862 Crystal size 0.100 x 0.075 x 0.050 mm³

Theta range for data collection 1.65 to 22.50°. Index ranges -12<=h<=l l, -12<=k<=12, -14<=1<=14 Reflections collected 18585 Independent reflections 4559 [R(int) = 0.0763] Completeness to theta = 22.50° 100.0 % Absorption correction Numerical Max. and min. transmission 0.9608 and 0.9237 Refinement method Full-matrix least-squares on F^ Data / restraints / parameters 4559 / 252 / 517 Goodness-of-fit on F^ 1.079

Final R indices [I>2sigma(I)] Rl - 0.0603, wR2 = 0.1534 R indices (all data) Rl = 0.101 l, wR2 = 0.1783 Largest diff. peak and hole 0.525 and -0.543 e.A^"3 Other Embodiments

The foregoing has been a description of certain embodiments of the invention. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

A palladium complex of formula (I):

(I) wherein: the dashed line represents the presence or absence of a bond;

Pd has a valency of +4; n is an integer between 0 and 4, inclusive; m is an integer between 0 and 3, inclusive; each occurrence of R_A is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR'; -C(=O)R'; -CO₂R'; - CN; -SCN; -SR'; -SOR'; -SO₂R'; -NO₂; -N(R')₂; -NHC(O)R'; or -C(R')₃; wherein each occurrence of R' is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; wherein two RA may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; each occurrence of R_B is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR"; -C(=O)R"; -CO₂R"; - CN; -SCN; -SR"; -SOR"; -SO₂R"; -NO₂; -N(R")₂; -NHC(O)R"; or -C(R")₃; wherein each occurrence of R" is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; each occurrence of Rc is independently hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; wherein Rc and R_B may be taken together to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and wherein R_c and R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring;

R-Di, R-D2, R_D3, and Rm are each independently cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; Z^" is an anion such as halide, acetate, tosylate, azide, tetrafluoroborate, tetraphenylborate, tetrakis(pentafluorophenyl)borate, [8[3,5-(CFa)₂CeHs]₄]^", hexafluorophosphate, phosphate, sulfate, perchlorate, trifluoromethanesulfonate or hexafluoroantimonate; and

F comprises ¹⁸F or ¹⁹F.

2. The palladium complex of claim 1, wherein Rc is hydrogen.

3. The palladium complex of claim 1, wherein Rc is methyl.

4. The palladium complex of claim 1 , wherein n is 0.

5. The palladium complex of claim 1 , wherein n is 1.

6. The palladium complex of claim 1 , wherein n is 2.

7. The palladium complex of claim 1, wherein two R_A are taken together to form an aryl ring.

8. The palladium complex of claim 7, wherein two R_A are taken together to form a phenyl ring.

9. The palladium complex of claim 1 , wherein m is 1.

^* 10. The palladium complex of claim 1, wherein m is 2.

11. The palladium complex of claim 1 , wherein at least one R_B is hydrogen.

12. The palladium complex of claim 1, wherein both R_B are hydrogen.

13. The palladium complex of claim 1, wherein at least one R_B is CpC₆ alkyl.

14. The palladium complex of claim 1, wherein both R_B are methyl.

15. The palladium complex of claim 1, wherein R_B and Rc are taken together form a heterocyclic ring.

16. The palladium complex of claim 1 , wherein R_B and Rc taken together form a heteroaryl ring.

17. The palladium complex of claim 16, wherein R_B and Rc taken together form a pyridyl ring.

18. The palladium complex of claim 1 , wherein R_A and Rc are taken together form an aryl ring.

19. The palladium complex of claim 18, wherein R_A and Rc are taken together form a phenyl ring.

20. The palladium complex of claim 1, wherein the dashed line represents the absence of a bond.

21. The palladium complex of claim 1 , wherein the dashed line represents the presence of a bond.

22. The palladium complex of claim 1 , wherein R_D1, R_D2, R_D3 and R_D4 are each a 5- membered heteroaryl ring.

23. The palladium complex of claim 22, wherein R_Di, Rp₂, R_D3 and Rp₄ are each a pyrazolyl ring.

24. The palladium complex of claim 23, wherein R_Di, R_D2, R_D3 and R_D4 are each an unsubstituted pyrazolyl ring.

25. The palladium complex of claim 1 , wherein R_DI, R_D2 and R_D3 are each a 5-membered heteroaryl ring, and Rp₄ is an alkyl group.

26. The palladium complex of claim 25, wherein R_Di, R_D2 and R_D3 are each a pyrazolyl ring, and Rø₄ is a tert-butyl group.

27. The palladium complex of claim 25, wherein R_DI, R_D2 and R_D3 are each a pyrazolyl ring, and R_D4 is an n-butyl group.

28. The palladium complex of claim 1, wherein R_DI, R_D2 and R_D3 are each a 5-membered heteroaryl ring, and R_D4 is an aryl group.

29. The palladium complex of claim 25, wherein R_Di, R_D2 and R_D3 are each a pyrazolyl ring, and R_D4 is a phenyl ring.

30. The palladium complex of claim 1, wherein R_DI and R_D2 are each a 5-membered heteroaryl ring, R_D3 is an alkoxy group and R_D4 is an alkyl group.

31. The palladium complex of claim 30, wherein R_D] and R_D2 are each a pyrazolyl ring, R_D3 is an isopropoxy group and R_D4 is a tert-butyl group.

32. The palladium complex of claim 30, wherein R_Di and R_D2 are each a pyrazolyl ring, Rø3 is an isopropoxy group and R_D4 is an n-butyl group.

33. The palladium complex of claim 1, wherein R_DI and Rø₂ are each a 5-membered heteroaryl ring, R_D3 is an alkoxy group and R_D4 is an aryl group.

34. The palladium complex of claim 33, wherein R_Di and R_D2 are each a pyrazolyl ring, R_D3 is an isopropoxy group and R_D4 is a phenyl ring.

35. The palladium complex of claim 1, wherein the anion is trifluoromethanesulfonate.

36. The palladium complex of claim 1, wherein the anion is hexafluorophosphate.

37. The palladium complex of claim 1 , wherein the anion is a halide.

38. The palladium complex of claim 1, wherein the complex has the following formula:

39. The palladium complex of claim 1, wherein the complex has the following formula:

40. A method of fluorinating an organic compound, the method comprising mixing a palladium complex of formula (I) with a substrate under conditions sufficient to fluorinate the substrate, thereby providing a fluorinated organic compound.

41. The method of claim 40, wherein the fluorinated organic compound comprises ¹⁸F or

¹⁹F.

42. The method of claim 40, wherein the substrate is an organic compound comprising an enol silyl ether, and the fluorinated organic compound is an α-fluorinated ketone.

43. The method of claim 40, wherein the substrate is a palladium(II) aryl complex, and the fluorinated organic compound is a fluorinated aryl compound.

44. The method of claim 40, wherein the substrate is an arylsilver complex, and the fluorinated organic compound is a fluorinated aryl compound.

45. The method of claim 40, further comprising a solvent.

46. The method of claim 45, wherein the solvent is a polar aprotic solvent.

47. The method of claim 46, wherein the solvent is methylene chloride.

48. The method of claim 46, wherein the solvent is dichloroethane.

49. The method of claim 46, wherein the solvent is tetrahydrofuran.

50. The method of claim 45, wherein the solvent is a nonpolar solvent.

51. The method of claim 50, wherein the solvent is benzene.

52. The method of claim 40, further comprising an inert atmosphere.

53. The method of claim 40, wherein the reaction is performed under anhydrous conditions.

54. The method of claim 40, wherein the reaction comprises a source of energy.

55. The method of claim 54, wherein the reaction comprises heat.

56. The method of claim 40, wherein the fluorinated organic compound comprises an aryl group.

57. The method of claim 40, wherein the fluorinated organic compound is an imaging agent.

58. The method of claim 57, wherein the fluorinated organic compound is a PET imaging agent.

59. The method of claim 40, wherein the fluorinated organic compound is a pharmaceutically acceptable compound or a prodrug thereof.

60. A method of storing a palladium complex of formula (I), the method comprising maintaining the palladium complex in a sealed container for at least 12 hours.

61. The method of claim 60, wherein the sealed container is a vial.

62. The method of claim 60, wherein the sealed container is an ampule.

63. The method of claim 60, wherein the sealed container is substantially free of dioxygen.

64. The method of claim 60, wherein the sealed container contains an inert gas.

65. A composition comprising a palladium complex of formula (I) and an additional component.

66. The composition of claim 65, wherein the component is a substrate.

67. The composition of claim 66, wherein the substrate is an organic compound comprising an enol silyl ether.

68. The composition of claim 66, wherein the substrate is a palladium(II) aryl complex.

69. The composition of claim 66, wherein the substrate is an arylsilver complex.

70. The composition of claim 65, wherein the component is a reagent.

71. The composition of claim 65, wherein the composition comprises a plurality of reagents.

72. The composition of claim 65, wherein the component is a solvent.

73. The composition of claim 72, wherein the solvent is a polar aprotic solvent.

74. The composition of claim 73, wherein the solvent is methylene chloride.

75. The composition of claim 73, wherein the solvent is dichloroethane.

76. The composition of claim 73, wherein the solvent is tetrahydrofuran.

77. The composition of claim 72, wherein the solvent is a nonpolar solvent.

78. The composition of claim 77, wherein the solvent is benzene.

79. A kit comprising a palladium complex of formula (I) and a container.

80. The kit of claim 79, wherein the container is a vial.

81. The kit of claim 79, wherein the container is a sealed ampule.

82. The kit of claim 79, wherein the container is substantially free of dioxygen.

83. The kit of claim 79, wherein the container contains an inert gas.

84. The kit of claim 79, further comprising instructions for use of the palladium complex.

85. The kit of claim 79, further comprising a reagent.

86. The kit of claim 79, further comprising a substrate.

87. The kit of claim 86, wherein the substrate is an organic compound comprising an enol silyl ether.

88. The kit of claim 86, wherein the substrate is a palladium(II) aryl complex.

89. The kit of claim 86, wherein the substrate is an arylsilver complex.

90. A palladium complex of formula (II):

(H) wherein the dashed line represents the presence or absence of a bond; Pd has a valency of +2; n is an integer between 0 and 4, inclusive; m is an integer between 0 and 3, inclusive; each occurrence of R_A is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR'; -C(=O)R'; -CO₂R'; - CN; -SCN; -SR'; -SOR'; -SO₂R'; -NO₂; -N(R')₂; -NHC(O)R'; or -C(R')₃; wherein each occurrence of R' is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; wherein two R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; each occurrence of R_B is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR"; -C(=O)R"; -CO₂R"; - CN; -SCN; -SR"; -SOR"; -SO₂R"; -NO₂; -N(R")₂; -NHC(O)R"; or -C(R")₃; wherein each occurrence of R" is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; each occurrence of Rc is independently hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; wherein Rc and R_B may be taken together to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and wherein Rc and R_A may be taken together to form a substituted or unsubstituted carbocyclic, heterocyclic, aryl or heteroaryl ring; and

R_DI, RD₂, R_D3, and RD4 are each independently cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl;

91. The palladium complex of claim 90, wherein Rc is hydrogen.

92. The palladium complex of claim 90, wherein Rc is methyl.

93. The palladium complex of claim 90, wherein n is 0.

94. The palladium complex of claim 90, wherein n is 1.

95. The palladium complex of claim 90, wherein n is 2.

96. The palladium complex of claim 90, wherein two R_A are taken together to form an aryl ring.

97. The palladium complex of claim 96, wherein two R_A are taken together to form a phenyl ring.

98. The palladium complex of claim 90, wherein m is 1.

99. The palladium complex of claim 90, wherein m is 2.

100. The palladium complex of claim 90, wherein at least one R_B is hydrogen.

101. The palladium complex of claim 90, wherein both R_B are hydrogen.

102. The palladium complex of claim 90, wherein at least one R_B is Ci-Cζalkyl.

103. The palladium complex of claim 90, wherein both R_B are methyl.

104. The palladium complex of claim 90, wherein R_B and Rc are taken together form a heterocyclic ring.

105. The palladium complex of claim 90, wherein R_B and Rc taken together form a heteroaryl ring.

106. The palladium complex of claim 105, wherein R_B and Rc taken together form a pyridyl ring.

107. The palladium complex of claim 90, wherein R_A and Rc are taken together form an aryl ring.

1Q8. The palladium complex of claim 107, wherein R_A and Rc are taken together form a phenyl ring.

109. The palladium complex of claim 90, wherein the dashed line represents the absence of a bond.

110. The palladium complex of claim 90, wherein the dashed line represents the presence of a bond.

111. The palladium complex of claim 90, wherein R_DI , R_D2, R_D3 and R_D4 are each a 5- membered heteroaryl ring.

112. The palladium complex of claim 111, wherein R_Di, R_D2, R_D3 and R_D4 are each a pyrazolyl ring.

113. The palladium complex of claim 112, wherein R_Di, R_D2, R_D3 and R₀₄ are each an unsubstituted pyrazolyl ring.

114. The palladium complex of claim 90, wherein R_Dj, R_D2 and R_D3 are each a 5- membered heteroaryl ring, and Rp₄ is an alkyl group.

115. The palladium complex of claim 114, wherein R_Dj, R_D2 and R_D3 are each a pyrazolyl ring, and R_D4 is a tert-butyl group.

1 16. The palladium complex of claim 114, wherein R_Di, R_D2 and R_D3 are each a pyrazolyl ring, and R₀₄ is an n-butyl group.

117. The palladium complex of claim 90, wherein R_DI, R_D2 and Rp3 are each a 5- membered heteroaryl ring, and R_D4 is an aryl group.

118. The palladium complex of claim 117, wherein R_DI, R_D2 and R_D3 are each a pyrazolyl ring, and R₀₄ is a phenyl ring.

119. The palladium complex ofclajm 90, wherein R_Di and R_D2 are each a 5-membered heteroaryl ring, R_D3 is an alkoxy group and R_D4 is an alkyl group.

120. The palladium complex of claim 119, wherein R_DI and R_D2 are each a pyrazolyl ring, R_D3 is an isopropoxy group and R_D4 is a tert-butyl group.

121. The palladium complex of claim 119, wherein R_DI and R_D2 are each a pyrazolyl ring, R_D3 is an isopropoxy group and R_D4 is an n-butyl group.

122. The palladium complex of claim 90, wherein R_DI and R_D2 are each a 5-membered heteroaryl ring, R_D3 is an alkoxy group and R_D4 is an aryl group.

123. The palladium complex of claim 122, wherein R_DI and R_D2 are each a pyrazolyl ring, R_D3 is an isopropoxy group and R_D4 is a phenyl ring.

124. The palladium complex of claim 90, wherein the palladium complex has the following formula:

125. A method of fluorinating an organic compound, the method comprising reacting a palladium complex of formula (II) with a fluorinating agent and a substrate, under conditions sufficient to fluorinate the substrate, thereby providing a fluorinated organic compound.

126. The method of claim 125, wherein the substrate is an organic compound comprising an enol silyl ether, and the fluorinated organic compound is an α-fluorinated ketone.

127. The method of claim 125, wherein the substrate is a palladium(II) aryl complex, and the fluorinated organic compound is a fluorinated aryl compound.

128. The method of claim 125, wherein the substrate is an arylsilver cpmplex, and the fluorinated organic compound is a fluorinated aryl compound.

129. The method of claim 125, wherein the fluorinating agent comprises ¹⁸F or ¹⁹F.

130. The method of claim 125, wherein the fluorinating agent is N-chlordmethyl-N'- fluorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor^®).

131. The method of claim 125, wherein the fluorinating agent is XeF₂.

132. The method of claim 125, wherein the fluorinating agent is 7V-fluoropyridinium trifluoromethanesulfonate.

133. The method of claim 125, wherein the fluorinating agent is iV-fluoro-2,4,6- trimethylpyridinium hexafluorophosphate.

134. The method of claim 125, further comprising a solvent.

135. The method of claim 134, wherein the solvent is a polar aprotic solvent.

136. The method of claim 135, wherein the solvent is methylene chloride.

137. The method of claim 135, wherein the solvent is dichloroethane.

138. The method of claim 135, wherein the solvent is tetrahydrofuran.

139. The method of claim 134, wherein the solvent is a nonpolar solvent.

140. The method of claim 139, wherein the solvent is benzene.

141. The method of claim 125, further comprising an inert atmosphere.

142. The method of claim 125, wherein the reaction is performed under anhydrous conditions.

143. The method of claim 125, wherein the reaction comprises a source of energy.

144. The method of claim 143 , wherein the reaction comprises heat.

145. The method of claim 125, wherein the palladium complex of formula (II) is combined with the fluorinating agent prior to the addition of the substrate.

146. The method of claim 125, wherein the method proceeds via an intermediate palladium complex of formula (I) (claim 1).

147. The method of claim 146, wherein the intermediate palladium complex is isolated.

148. The method of claim 125, wherein the fluorinated organic compound is an imaging agent.

149. The method of claim 148, wherein the fluorinated organic compound is a PET imaging agent.

150. The method of claim 125, wherein the fluorinated organic compound is a pharmaceutically acceptable compound or a prodrug thereof.

151. A method of making a fluorinated Pd(IV) complex, the method comprising reacting a palladium complex of formula (II) with a fluorinating agent, to provide the fluorinated Pd(IV) complex.

152. The method of claim 151, wherein the fluorinating agent comprises ¹⁸F or ¹⁹F.

153. The method of claim 151, wherein the fluorinating agent is N-chloromethyl-N'- fluorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor^®).

154. The method of claim 151 , wherein the fluorinating agent is XeF₂.

155. The method of claim 151, wherein the fluorinating agent is N-fluoropyridinium trifluoromethanesulfonate.

156. The method of claim 151, wherein the fluorinating agent is iV-fluoro-2,4,6- trimethylpyridinium hexafluorophosphate.

157. The method of claim 151, further comprising a solvent.

158. The method of claim 157, wherein the solvent is a polar aprotic solvent.

159. The method of claim 158, wherein the solvent is methylene chloride.

160. The method of claim 158, wherein the solvent is dichloroethane.

161. The method of claim 158, wherein the solvent is tetrahydrofuran.

162. The method of claim 157, wherein the solvent is a nonpolar solvent.

163. The method of claim 162, wherein the solvent is benzene.

164. The method of claim 151, further comprising an inert atmosphere.

165. The method of claim 151, wherein the reaction is performed under anhydrous conditions.

166. The method of claim 151, wherein the reaction comprises a source of energy.

167. The method of claim 151 , wherein the reaction comprises heat.

168. A method of storing a palladium complex of formula (II), the method comprising maintaining the palladium complex in a sealed container for at least 12 hours.

169. The method of claim 168, wherein the sealed container is a vial.

170. The method of claim 168, wherein the sealed container is an ampule.

171. The method of claim 168, wherein the sealed container is substantially free of dioxygen.

172. The method of claim 168, wherein the sealed container contains an inert gas.

173. A composition comprising a palladium complex of formula (II) and an additional component.

174. The composition of claim 173, wherein the component is a fluorinating agent.

175. The composition of claim 174, wherein the fluorinating agent comprises ¹⁸F or ¹⁹F.

176. The composition of claim 174, wherein the fluorinating agent is N-chloromethyl-N'- fiuorotriethylenediammonium bis(tetrafluoroborate) (Selectfluor^®).

177. The composition of claim 174, wherein the fluorinating agent is XeF₂.

178. The composition of claim 174, wherein the fluorinating agent is 7V-fluoropyridinium trifluoromethanesulfonate.

179. The composition of claim 174, wherein the fluorinating agent is 7V-fluoro-2,4,6- trimethylpyridinium hexafluorophosphate.

180. The composition of claim 173, wherein the component is a substrate.

181. The composition of claim 180, wherein the substrate is an organic compound comprising an enol silyl ether.

182. The composition of claim 180, wherein the substrate is a palladium(II) aryl complex.

183. The composition of claim 180, wherein the substrate is an arylsilver complex.

184. The composition of claim 173, wherein the component is a reagent.

185. The composition of claim 173, wherein the composition comprises a plurality of reagents.

186. The composition of claim 173, wherein the component is a solvent.

187. The composition of claim 186, wherein the solvent is a polar aprotic solvent.

188. The composition of claim 187, wherein the solvent is methylene chloride.

189. The composition of claim 187, wherein the solvent is dichloroethane.

190. The composition of claim 187, wherein the solvent is tetrahydrofuran.

191. The composition of claim 186, wherein the solvent is a nonpolar solvent.

192. The composition of claim 191, wherein the solvent is benzene.

193. A kit comprising a palladium complex of formula (II) and a container.

194. The kit of claim 193, wherein the container is a vial.

195. The kit of claim 193, wherein the container is a sealed ampule.

196. The kit of claim 193, wherein the container is substantially free of dioxygen.

197. The kit of claim 193, wherein the container contains an inert gas.

198. The kit of claim 193, further comprising instructions for use of the palladium complex.

199. The kit of claim 193, further comprising a reagent.

200. The kit of claim 193, wherein the reagent is a fluorinating agent.

201. The kit of claim 200, wherein the fluorinating agent comprises ¹⁸F or ¹⁹F.

202. The kit of claim 200, wherein the fluorinating agent is N-chloromefhyl-N'- fluorotriethylenectiammonium bis(tetrafluoroborate) (Selectfluor^®).

203. The kit of claim 200, wherein the fluorinating agent is XeF₂.

204. The kit of claim 200, wherein the fluorinating agent is 7V-fluoropyridinium trifluoromethanesulfonate.

205. The kit of claim 200, wherein the fluorinating agent is N-fluoro-2,4,6- trimethylpyridinium hexafluorophosphate.

206. The kit of claim 193, further comprising a substrate.

207. The kit of claim 206, wherein the substrate is an organic compound comprising an enol silyl ether.

208. The kit of claim 206, wherein the substrate is a palladium(II) aryl complex.

209. The kit of claim 206, wherein the substrate is a arylsilver complex.

210. A method of preparing a palladium fluoride complex of formula:

with nucleophilic F^" under suitable conditions to yield a complex of formula:

211. The method of claim 210, wherein the nucleophilic F^" is provided by AgF.

212. The method of claim 210, wherein the nucleophilic F^" is 18τ F^"