WO2018217637A1 - Au(iii) complexes for [18f] trifluoromethylation and methods for producing the same - Google Patents

Abstract

Au(III) complexes for [18F] trifluoromethylation and methods for producing the same are disclosed. A gold complex comprises Au(CF3)2LR, wherein L comprises a solubility supporting ligand and R comprises an organic substituent. The Au(III) complex can be used to prepare a positron emitting isotope that can be used as tracers for positron emitting tomography (PET) scans.

Description

AU(III) COMPLEXES FOR [18F] TRIFLUOROMETHYLATION AND METHODS FOR PRODUCING THE SAME

REFERENCE TO GOVERNMENT FUNDING

[0001] This invention was made with Government support under GM 1 18190, awarded by the National Institutes of Health. The Government has certain rights in the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. § 1 19(e) to U.S.

provisional patent application serial no. 62/509,230, filed on May 22, 2017, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0003] The present disclosure relates generally to Au(lll) complexes for [18F] Trifluoromethylation and methods for producing the same.

BACKGROUND

[0004] Certain compounds called "tracers" are used for positron emission tomography (PET) or PET scans. Generating the compounds that can be used as tracers in the PET scans can be challenging. For example, the compounds may be based off of certain chemical positron emitting isotopes with short half- lives, such as fluorine 18 (¹⁸F) or carbon 1 1 (¹¹C), for example. For example, these positron emitting isotopes can have half-lives as short as 1 10 minutes.

[0005] As a result, there are challenges to current techniques to prepare the tracers used for PET scans. For example, the positron emitting isotopes need to be installed and given to the patient before the half-life of the isotope expires (e.g., within 1 10 minutes).

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] The teaching of the present disclosure can be readily understood by considering the following detailed description in conjunction with the

accompanying drawings, in which:

[0007] FIG. 1 illustrates an example retrosynthetic paradigm for CF3 radiosynthesis using copper;

[0008] FIG. 2 illustrates an example discovery of formal C(sp³)-CF3 reductive elimination from Au(lll) of the present disclosure;

[0009] FIG. 3 illustrates examples of synthetic versatility of

bis(trifluoromethyl) gold complexes;

[0010] FIG. 4 illustrates an example of radiosynthesis via C-0F reductive elimination from Au(ll l) of the present disclosure;

[0011] FIG. 5 illustrates an example three dimensional molecule model of frans-methylbis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3-dihydro-2H- imidazol-2-ylidene-gold(lll);

[0012] FIG. 6 illustrates an example three dimensional molecule model of fra 7s-methylbis(trifluoromethyl)-tricyclohexylphosphine-gold(lll);

[0013] FIG. 7 illustrates an example three dimensional molecule model of

Bromo-(1 , 1 -difluoroethyl)trifluoromethyl-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3- dihydro-2H-imidazol-2-ylidene-gold(lll);

[0014] FIG. 8 illustrates an example three dimensional molecule model of fra 7S-chlorobis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3-dihydro-2H- imidazol-2-ylidene-gold(lll);

[0015] FIG. 9 illustrates an example three dimensional molecule model of frans-allylbis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3-dihydro-2H- imidazol-2-ylidene-gold(lll);

[0016] FIG. 10 illustrates an example three dimensional molecule model of fra 7S-(3-(4-acetylphenyl)propyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6- diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll);

[0017] FIG. 1 1 illustrates an example three dimensional molecule model of trans Bromo-((4-(4-acetylphenyl)-1 , 1 -difluorobutyl))-trifluoromethyl-1 ,3-Bis(2,6- diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll);

[0018] FIG. 12 illustrates an example three dimensional molecule model of cis Bromo-((4-(4-acetylphenyl)-1 , 1 -difluorobutyl))-trifluoromethyl-1 ,3-Bis(2,6- diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll);

[0019] FIG. 13 illustrates an example three dimensional molecule model of frans-(cyclopropylmethyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3- dihydro-2H-imidazol-2-ylidene-gold(lll); [0020] FIG. 14 illustrates graphical data for concentrations of intermediate compounds observed using a first drying method;

[0021] FIG. 15 illustrates graphical data for concentrations of intermediate compounds observed using a second drying method;

[0022] FIG. 16 illustrates an example first order decay based on the graphical data illustrated in FIG. 15;

[0023] FIG.17 illustrates graphical data for concentrations of intermediate compounds observed using a first drying method;

[0024] FIG. 18 illustrates graphical data for concentrations of intermediate compounds observed over time including isomer formation;

[0025] FIG. 19 illustrates a graphical representation of total counts of a first run for radiochemical conversion of [¹⁸F]-1 -(4-(4,4,4-trifluorobutyl)phenyl)ethan-

1 -one;

[0026] FIG. 20 illustrates a graphical representation of total counts of a second run for radiochemical conversion of [¹⁸F]-1 -(4-(4,4,4- trifluorobutyl)phenyl)ethan-1 -one;

[0027] FIG. 21 illustrates a graphical representation of total counts of a third run for radiochemical conversion of [¹⁸F]-1 -(4-(4,4,4-trifluorobutyl)phenyl)ethan- 1 -one;

[0028] FIG. 22 illustrates a graphical representation of total counts of a fourth run for radiochemical conversion of [¹⁸F]-1 -(4-(4,4,4- trifluorobutyl)phenyl)ethan-1 -one;

[0029] FIG. 23 illustrates a graphical representation of total counts of a fifth run for radiochemical conversion of [¹⁸F]-1 -(4-(4,4,4-trifluorobutyl)phenyl)ethan- 1 -one;

[0030] FIG. 24 illustrates a graphical representation of total counts of a first run for radiochemical conversion of [¹⁸F]- 5,5,5-trifluoropentyl 2-naphthoate;

[0031] FIG. 25 illustrates a graphical representation of total counts of a second run for radiochemical conversion of [¹⁸F]- 5,5,5-trifluoropentyl 2- naphthoate;

[0032] FIG. 26 illustrates a graphical representation of total counts of a third run for radiochemical conversion of [¹⁸F]- 5,5,5-trifluoropentyl 2-naphthoate;

[0033] FIG. 27 illustrates a graphical representation of total counts of a first run for radiochemical conversion of [¹⁸F]-3-(2-cyano-3-

(trifluoromethyl)phenoxy)phenyl-4, 4, 4-trifluorobutane-1 -sulfonate;

[0034] FIG. 28 illustrates a graphical representation of total counts of a second run for radiochemical conversion of [¹⁸F]-3-(2-cyano-3-

(trifluoromethyl)phenoxy)phenyl-4, 4, 4-trifluorobutane-1 -sulfonate;

[0035] FIG. 29 illustrates a graphical representation of total counts of a third run for radiochemical conversion of [¹⁸F]-3-(2-cyano-3-

(trifluoromethyl)phenoxy)phenyl-4, 4, 4-trifluorobutane-1 -sulfonate; and

[0036] FIG. 30 illustrates a report of HPLC Analysis of isolated [¹⁸F] BAY 59-

3074.

[0037] To facilitate understanding, identical reference numerals have been used, where possible, to designate identical elements that are common to the figures.

DETAI LED DESCRIPTION

[0038] The present disclosure provides a new gold complex, precursor and processes for producing the same. The gold complex and precursors of the present disclosure can be activated to generate [18F] Trifluorom ethyl compounds that can be used for various different applications, such as, tracers used in positron emission tomography (PET) scans.

[0039] The dual nature of the trifluoromethyl substituent as both crucial pharmaceutical functional group and synthetic frustration stems from a common cause: strong, non-interacting C-F bonds lend metabolic stability while simultaneously limiting the ability for chemical transformations to forge the relevant bonds and install the CF₃ unit. Generally speaking, nucleophilic (i.e. the Ruppert-Prakash reagent) or metal mediated (e.g. CUCF3) chemistry is employed to deliver a preformed CF3 unit to an organic substrate, though the latter class of chemistries is often plagued by the slow direct reductive elimination of fluoroalkyl ligands. Nonetheless, these modern protocols have aided the continuing proliferation of trifluoromethyl containing compounds in medicinal chemistry, including several high-profile blockbuster drugs.

[0040] When these same synthetic considerations are extended towards synthesis of radiolabeled PET tracers containing ¹⁸F isotopes, the situation becomes more complex. As noted above, the biomedical applications of positron emission tomography (PET) rely upon the availability of radiolabeled tracers in which a radioactive positron emitting isotope, most commonly [¹⁸F] (half-life (ti/2) - 1 10 min), is incorporated into a molecule of biological importance. These compounds can be used for high-resolution real-time imaging of tissue-level phenomena, enabling direct interrogation of disease states and mechanisms of bioactivity. However, nucleophilic substitution (i.e. SN2 or

chemistry, employed for the majority of organic fluoride radiosynthesis, is generally incompatible with the stereoelectronic demands of the CF3 unit. Rather, in the most successful copper-mediated technology, a "CF2" precursor is reacted with radiofluoride to generate the relevant CF3 unit prior to incorporation into the tracer via organometallic intermediates. Reaction A of FIG. 1 illustrates an example of this reaction.

[0041] An isolable yet reactive difluoroalkyl metal substituent which affords the corresponding CF3 unit upon treatment with radiofluoride would represent an alternative retrosynthetic paradigm by which to access these important tracer compounds. The present disclosure provides a class of Au(lll) complexes which match exactly this profile of reactivity, simultaneously providing synthetic access to the requisite precursors and enabling their implementation for radiofluorination, as shown in reaction B of FIG. 1 . The development of this advance has depended on detailed mechanistic

investigation of an unexpected trifluoromethylated compound observed upon treatment of a complex 1 a with B(CeFs)3 (2) that is illustrated in reaction A of FIG. 2, namely the formal product of C(sp³)-CF3 reductive elimination from the gold center. It should be noted that some compounds are abbreviated with numbers as labeled in the figures or after the compound name illustrated and described in the examples below.

[0042] In one example, ¹⁹F-NMR monitoring was performed on the formal reductive elimination of Me-CF3 from the complex 1 a in the presence of stoichiometric 2 at -15 degrees Celsius (°C) to investigate the mechanism noted above. The reaction showed clean first-order kinetics (as shown in FIG. 26), consistent with catalytic action of 2. At catalytic loadings of 2, IPr-Au-CF3 (3a) was the major Au-containing product, with complete conversion observed in less than 5 minutes at room temperature. The same reactivity was observed with the related phosphine complex 1 b illustrated in reaction A of FIG. 2.

Addition of 10 equivalents Me₃SiBr to the 2-catalyzed reductive elimination formed an isolable Au(lll) complex (4), bearing bromide and α,α-difluoroethyl substituents, as a mixture of two coordination isomers, as shown in reaction B of FIG. 2. Treatment of 4 with AgF leads to the gradual formation of MeCF3 and 3, as shown in reaction C of FIG. 2. Taken together, these results implicate an overall mechanism, as shown in reaction D of FIG. 2, in which fluoride abstraction (/^') from a CF₃ moiety of 1 by the borane 2 results in an intermediate difluorocarbenoid (or alternatively the carbenium resonance form, shown) which undergoes migratory insertion (ii) of the alkyl fragment followed by formal C-F reductive elimination (//^'/^') to afford trifluoroethane. Additional experiments in support of this proposal include the formation of MeCF20Tf when stoichiometric TMS-OTf is used in place of 2, as shown in FIG.26, and the observation of an intermediate aquo complex of the migratory insertion product during low temperature kinetics in wet CD2CI2, as shown in FIGs. 24, 25, 27, and 28.

[0043] To various extents, these elementary steps have been observed previously at gold; in particular, earlier work on C-F reductive elimination suggests that an outer-sphere mechanism with considerable carbocationic character is operative. Although migratory insertion at Au(lll) is comparatively rarer, Density Functional Theory (DFT) calculations suggest that a-insertion to the difluorocarbene occurs readily (ΔΗ* < 4 kcal/mol). Such a low barrier likely explains why competitive hydrolysis of the difluorocarbene, common in metal halocarbene complexes, is not observed here even in wet solvent. Regardless, this mechanism is unusual because it represents a formal C(sp³)-CF3 reductive elimination, itself rarely if ever observed, by a catalytic process involving iterative disassembly and reassembly of the CF3 moiety.

[0044] It was noted that interception of the rebounding fluoride and introduction of a radiolabeled surrogate held promise for the synthesis of PET traces, provided that more complex organic substituents could be employed than the parent methyl in 1 of reaction A in FIG. 3. Diversification of the organic fragment beyond the simple methyl analogue was accomplished by means of a variety of synthetic manipulations (including hydroboration, cross-metathesis, hydrogenation, and aluminum hydride reduction) of n_, ¹-allyl 6 of reaction A in FIG. 3, allowing the preparation of complex derivatives. Reductive elimination from the elaborated derivatives could likewise be triggered with 2 of reaction A of FIG. 3, ultimately affording reductive elimination products such as 8 and 1 1 of reaction A of FIG. 3. Similar diversity was seen in the chemistry of arylgold complex 12 of reaction B in FIG. 3 (including aromatic nitration without rupture of the gold-carbon bond), enabling the synthesis of Leflunomide via C-CF3 reductive elimination from an advanced intermediate, as shown in FIG. 3B.

[0045] in order to further demonstrate the utility and functional group tolerance of this method, the Bayer lead compound BAY 59-3074 was prepared via straightforward elaboration of 6 of reaction C in FIG. 3. In addition to the depicted transformations, the complexes were also found to be tolerant of Simmons-Smith cyclopropanation, osmium-catalyzed dihydroxylation, periodate-mediated diol cleavage, and palladium-catalyzed cross coupling. Cleavage of the Au-C bond was only observed in the presence of exceptionally strong acids (CF3SO3H) and elemental halogens (e.g. Br2). In addition, initial Au-C bond construction can also be achieved with dialkyl zinc or copper acetylide reagents, expanding the diversity of accessible structures

(compounds S10 and S1 1 , shown below). All of the intermediate gold complexes exhibited complete air and water tolerance, and were universally amenable to purification by silica gel column chromatography. As such, the Au moiety is regarded as a triggerable, but otherwise inert functional group, enabling routine chemical synthesis akin to typical organic substrates. Though synthetically tolerant metal complexes have been previously reported, such broad compatibility is rare, especially for Au(lll), which tends to be highly sensitive toward reductive decomposition.

[0046] For the radiochemical protocol, introduction of fluoride to complexes analogous to 4 in reactions A-C of FIG. 2 were initially envisioned. However, the silver mediated reductive elimination, as shown in reaction C of FIG. 2, was deemed too sluggish for these purposes, requiring the development of a modified strategy. Although complexes with several other counterions (such as triflate and tosylate) rapidly eliminated alkyl-CF₂X, the corresponding acetate complex exhibited an appropriate blend of stability and reactivity to enable nucleophilic reductive elimination when treated with 2, shown in reactions A and B of FIG. 2, and a suitable fluoride source. An example of the activation of the gold complex and the ligand exchange described above, is illustrated in reaction A of FIG. 4. Borane 2, shown in reaction A of FIG. 4, was required for rapid reductive elimination to occur; in its absence, the intermediate [Au(lll)]-F persisted for long enough to be observed by ¹⁹F-NMR spectroscopy, and side- reactions arising from base-mediated decomposition or glass-etching occurred alongside slow reductive elimination, consistent with an outer-sphere mechanism for C-F bond formation assisted by 2. The combined protocol was directly translated to a radiological analogue, affording the corresponding radiolabeled reductive elimination products starting from KF and

Kryptofix[2.2.2], as shown in reaction B of FIG. 4.

[0047] Several features of this protocol merit additional comment. First, aromatic complexes remain inaccessible for radiochemical functionalization by this method due to the rapid reductive elimination of the benzylic difluoroalkyl moiety; treatment of phenyl complex 10 with MesSiBr and 2 results in PhCF2Br rather than an isolable Au(lll) complex. As such, the scope of this protocol remains fully complementary to the corresponding Cu-mediated analogue via CuCFs. Second, isolation of [¹⁸F]-BAY 59-3074 by preparative HPLC afforded an isolated radiochemical yield of 6% and a specific activity of 8 millicurie per micro mol (mCi/μιτιοΙ) starting from 71 mCi of [¹⁸F]-fluoride. Such a specific activity is on par with that of many CuCF3-based protocols, though values ranging from 2.7 to 860 mCi/ μιηοΙ have been obtained depending on the preparative method; it should be noted that these are all much lower than classical nucleophilic substitution methodologies for alkyl fluoride synthesis (typically in excess of 1000 mCi/ μιηοΙ), highlighting an important direction for future development of radiotrifluoromethylation. Finally, the cost associated with the use of stoichiometric organogold reagents, though substantial by the metrics of process-scale pharmaceutical preparation, are relatively small in this context given the low concentrations required, the cost of ¹⁸F production, and the costs of the associated medical imaging technology.

[0048] In any case, the protocol established here represents an important proof-of-concept, in the radiosynthesis of organic trifluoromethyl groups by a retrosynthetic paradigm involving C-F reductive elimination. The broader mechanistic framework consisting of fluoride-rebound reductive elimination upon which this radiochemical reaction is built should also have implications for the understanding of transition metal catalysis, as it seems probable that such a mechanism is in fact operative in the related copper-mediated protocols currently in use (both in the radiochemical and non-radiochemical contexts). Furthermore, the present disclosure suggests a promising direction for the development of organometallic reagents writ large via catalytically-triggered reductive elimination of functionally tolerant complexes.

EXAMPLES

[0049] Materials and Methods

[0050] Unless stated otherwise, all reactions were performed in oven-dried or flame-dried glassware. All glassware was cleaned using aqua regia to remove metal impurities. NMR Tubes used for reductive elimination studies with B(C6F5)3 were additionally silylated with hexamethdisilazane at 100 °C prior to use. Reactions were sealed with rubber septa under a nitrogen atmosphere and were stirred with Teflon-coated magnetic stir bars. Dry tetrahydrofuran (THF), toluene (Tol), dimethylfomamide (DMF), acetonitrile (MeCN),

triethylamine (TEA), diethyl ether (Et20), benzene (PhH), and dichloromethane (DCM) were obtained by passing these previously degassed solvents through activated alumina columns.

[0051] All other reagents were used as received, with the following exceptions: Tris(pentafluorophenyl) borane was purchased from Strem

Chemical and purified by hot filtration and recrystallization from hexanes followed by vacuum sublimation at 100 °C. Trimethylbromosilane was purified by distillation, lodomethane was purified by passing neat over a pad of basic alumina. For all reactions conducted in a glovebox, reagents were thoroughly dried and degassed by standard methods prior to use.

[0052] Reactions were monitored by thin layer chromatography (TLC) on Silicycle Siliaplate™ glass backed TLC plates (250 μιη thickness, 60 A porosity, F-254 indicator) and visualized by UV irradiation or by staining as indicated. Volatile solvents were removed under reduced pressure with a rotary evaporator and dried on high vacuum on a Schlenk line. H NMR, C NMR, F NMR, and P NMR spectra were taken with Bruker spectrometers operating at 300, 400, 500, or 600 MHz for H. Chemical shifts are reported relative to the residual solvent signal (H NMR: δ = 5.32; C NMR: δ = 53.84 for DCM-d₂). NMR data are reported as follows: chemical shift (multiplicity, coupling constants where applicable, number of hydrogens). Splitting is reported with the following symbols: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, hept = heptet, m = multiplet. High-resolution mass spectra (HRMS) were performed on a Thermo LTQ-FT-ICR (7T, ESI) by the QB3 mass spectral facility at the University of California, Berkeley. Elemental Analyses were performed by the Microanalytical Facility at the University of California, Berkeley.

[0053] Chloro(dimethylsulfide)gold(l) was prepared by reduction of AuCb (purchased from Strem) according previously reported procedures.

Tetraphenylphosphonium bis(trifluoromethyl)aurate was prepared from chloro(dimethylsulfide)gold(l) and TMSCF3 as previously reported and purified by repeated precipitation from DCM with diethyl ether.

[0054] Most of the gold complexes reported herein are moderately light sensitive, so reactions, work up procedures, and purifications were conducted with exclusion of light, and all complexes were stored wrapped in aluminum foil.

[0055] Synthetic Procedures

Tetraphenylphosphonium frans-bis(trifluoromethyl)dichloroaurate, S1

[0056] This compound was prepared using a modification of existing literature precedent. Treatment of a solution of tetraphenylphosphonium bis(trifluoromethyl)aurate (5.29 grams (g), 7.84 millimoles (mmol)) in

dichloromethane (78 milliliter (ml_), 0.1 molar (M)) with freshly prepared iodobenzene dichloride (4.31 g, 15.68 mmol, 2 equiv, added as a solid) resulted in immediate color change from colorless to yellow. The mixture was stirred for 30 minutes and concentrated. The crude solid was washed with copious diethyl ether, extracted with THF, and filtered. Concentration of the THF extract afforded the desired product as a colorless solid (5.8 g, 99% yield). Spectra were consistent with those previously reported.

Tetraphenylphosphonium frans-bis(trifluoromethyl)methyliodoaurate, S2

PPh₄ p_ph4

[0057] Tetraphenylphosphonium bis(trifluoromethyl)aurate (1 .1 Og, 1 .6 mmol) was dissolved in iodomethane (30.1 mL, 410 mmol, 250 equiv), and the mixture was heated with stirring at 30 °C for 18 hours (hrs). The mixture was

concentrated, extracted with dichloromethane, and filtered through a glass fiber filter. The filtrate was layered with diethyl ether, and placed in a freezer at -20 °C, resulting in the formation of colorless crystals which were collected by filtration (1 .18g, 89% yield). X-ray quality crystals were grown by vapor diffusion of diethyl ether into a dilute dichloromethane solution.

frans-methylbis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3- dihydro-2H-imidazol-2-ylidene-gold(lll), 1 a

[0058] In a nitrogen-filled glovebox, S2 (245 milligrams (mg), 0.30 mmol, 1 .05 equiv) was slurried in Toluene (5 mL) and a solution of IPr free carbene (1 13 mg, 0.29 mmol, 1 .0 equiv) in Toluene (15 mL) was added. The mixture was sealed and brought out of the glovebox, sonicated for 8 minutes, and then stirred for an additional 20 minutes. The mixture was concentrated onto Silica, and purified by chromatography eluting with 5% diethyl ether in hexanes, affording the desired product as a colorless solid (179 mg, 81 % yield). X-ray quality crystals were obtained by layering hexanes onto a solution of 1 a in diethyl ether. A three dimensional molecule model is illustrated in FIG. 5. fraA7S-methylbis(trifluoromethyl)-tricyclohexylphosphine-gold(lll), 1 b

[0059] In a nitrogen-filled glovebox, S2 (73 mg, 0.09 mmol, 1 .05 equiv) was slurried in Toluene (5 mL) and a solution of tricyclohexylphosphine (24 mg, 0.085 mmol, 1 .0 equiv) in Toluene (10 mL) was added. The mixture was sealed and brought out of the glovebox, sonicated for 8 minutes, and then stirred for an additional 20 minutes. The mixture was concentrated onto Silica, and purified by chromatography eluting with 5% diethyl ether in hexanes, affording the desired product as a colorless solid (52 mg, 99% yield). X-ray quality crystals were obtained by vapor diffusion of hexanes into a solution of 1 b in THF. A three dimensional molecule model is illustrated in FIG. 6.

Bromo-(1 ,1 -difluoroethyl)trifluoromethyl-1 ,3-Bis(2,6-diisopropylphenyl)- 1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll), 4

Major Isomer Minor Isomer

[0060] To a solution of 1 a (370 mg, 0.5 mmol) in dichloromethane (20 mL) was added bromotrimethylsilane (0.66 mL, 5 mmol, 10 equiv) followed by a solution of tris(pentafluorophenyl)borane (25.6 mg, 0.05 mmol, 0.1 equiv, prepared in a nitrogen filled glovebox) in 5 mL of DCM. The mixture was monitored by TLC for consumption of starting material [Note: the rate varies depending on the purity of the silane and borane reagents]. [0061] After 45 minutes of stirring at room temperature, the mixture was quenched by the addition of saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted twice with additional dichloromethane. The combined organic fractions were dried over Na2S0₄, filtered, and concentrated. The resulting mixture of isomers was purified by chromatography on silica gel eluting with a mixture of Hexanes/DCM/Et20 (85/7.5/7.5) to afford the title compound as a colorless solid containing a mixture of isomers in a -2: 1 ratio (282 mg, 70%). A three dimensional molecule model is illustrated in FIG. 7.

[0062] For the purposes of characterization, the isomers can be carefully separated by repeated chromatography eluting with (90:5:5

Hexanes/DCM/Et20) to afford fractions of each isomer. Over the course of repeated chromatography additional decomposition byproducts are formed which have not been identified but which can be partially removed by subsequent recrystallization from PhH/Hexanes. The major isomer was assigned structurally by X-ray diffraction and by the CNMR shift for the carbene carbon which was consistent with a trans halide substituent (cf. 5 below). The minor isomer was assigned by its CNMR, which showed a quartet of triplets for the carbene carbon with ca. twice the coupling constant for C-CF3 as for C- CF2Me, as well as its 1 D-NOE spectrum which showed an interaction between the isopropyl methine and the CF2Me protons. frans-chlorobis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3- dihydro-2H-imidazol-2-ylidene-gold(lll), 5

[0063] In a nitrogen-filled glovebox, S1 (3.8 g, 5.04 mmol, 1 equiv) was slurried in Toluene (30 ml_) and a solution of IPr free carbene (1 .96 g, 5.04 mmol, 1 equiv) in Toluene (70 ml_) was added. The mixture was sealed and brought out of the glovebox, sonicated for 8 minutes, and then stirred for an additional 1 hour. The mixture was concentrated onto Silica, and purified by chromatography eluting with 50% dichloromethane in hexanes, affording a pale yellow solid which was washed with hexanes to remove the co-eluting color impurity. This afforded the desired product as a colorless solid (3.2 g, 84% yield). X-ray quality crystals were obtained by vapor diffusion of hexanes into a saturated THF solution. A three dimensional molecule model is illustrated in FIG. 8. fraA7S-allylbis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3-dihydro- -imidazol-2-ylidene-gold(lll), 6

[0064] To a solution of 5 (1 .0 g, 1 .32 mmol) in THF (65 ml_, 0.02 M) in a schlenk bomb was added allyl magnesium chloride (6.6 ml_ of a 2M THF solution, 13.2 mmol, 10 equiv). The flask was sealed with a teflon valve and heated at 40 °C for 12 hours. Upon cooling, the mixture was quenched with H2O and extracted three times with diethyl ether. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography eluting with 70:30 Hexanes/DCM yielding the title compound as a colorless solid (930 mg, 92%). A three dimensional molecule model is illustrated in FIG. 9. fraA7S-(E)-(3-(4-acetylphenyl)allyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6- diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene-gold(lll), S3

[0065] 6 (529 mg, 0.693 mmol), 4-vinylacetophenone (405 mg, 2.77 mmol, 4 equiv), and Grubbs 2^nd Generation Catalyst (25 mg, 0.035 mmol, 5 mol%) were weighed into a Schlenk bomb. Dichloromethane (18 ml_) was added, the flask was sealed and the mixture was heated at 40 °C for 12 hours. The mixture was concentrated onto silica gel and purified by chromatography eluting on a gradient from 90:5:5 H ex/DC M/Et₂0 to 80: 10: 10 Hex/DCM/Et₂0 affording 468 mg of the title compound as a colorless solid alongside 88 mg of starting material (76% yield, 91 % brsm). Recrystallization from Et₂0/Hexanes at -20 °C affords the diethyl ether solvate.

frans-(3-(4-acetylphenyl)propyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6- diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene-gold(lll), 7

[0066] S3 (468 mg, 0.53 mmol) was dissolved in ethyl acetate (50 ml_, 0.01 M) and rhodium on carbon (109 mg of 5 wt%, 10 mol% Rh) was added. The mixture was sparged with N₂ with stirring for 10 minutes, then with H₂ (via balloon) for 10 minutes. The mixture was left under a static atmosphere of H₂ and monitored by TLC, staining with p-Anisaldehyde (the two compounds are co-polar, but the starting complex stains pink and the product stains orange upon heating). After 6.5 hours, consumption of starting material was observed, and H2 was removed by sparging with N2. The mixture was filtered through a pad of celite eluting with ethyl acetate and concentrated onto silica gel.

Chromatography eluting with 85:7.5:7.5 Hexanes/DCM/Et20 afforded the title compound as a colorless solid (274 mg, 60% yield). A three dimensional molecule model is illustrated in FIG. 10.

[0067] Alternate procedure:

[0068] In a nitrogen filled glovebox, to 6 (0.1 1 mmol, 84 mg) was added 9- BBN-H (0.95 equiv, 12.7 mg) and THF (3 ml_). The mixture was stirred overnight, and then Pd(dppf)Cl2 (2.5 mg, 3 mol%), NaOMe (18 mg, 3 equiv), and 4-acetyl-bromobenzene (25 mg, 1 .1 equiv) were added. The mixture was heated at 65 °C for 1 .5 hours and then concentrated. The crude product was purified by column chromatography eluting with 85:7.5:7.5 Hexanes/DCM/Et20 afforded the title compound as a colorless solid (42 mg, 44% yield). It should be noted that though more rapid than the 2 step metathesis/hydrogenation procedure, this procedure was found to be less reliable for large scale synthesis of the desired compound.

Bromo-((4-(4-acetylphenyl)-1 ,1 -difluorobutyl))-trifluoromethyl-1 ,3-Bis(2,6- diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll) (mixture of coordination isomers), 18 + isomer

[0069] To a solution of 7 (160 mg, 0.18 mmol) in dichloromethane (5 ml_) in a schlenk bomb was added bromotrimethylsilane (0.24 ml_, 1 .81 mmol, 10 equiv) followed by tris(pentafluorophenyl) borane (46 mg, 0.09 mmol, 50 mol%) in dichloromethane (4 ml_). The mixture was sealed with a teflon valve and heated at 40 °C for 24 hours. Saturated aqueous sodium bicarbonate was added, and the layers were separated. The aqueous layer was extracted 3x with DCM, and the combined organic layers were dried over Na2S0₄, filtered, and concentrated. The crude residue was purified by column chromatography on Si0₂, eluting on a gradient from 85:7.5:7.5 to 80: 10: 10 Hexanes/DCM/Et₂0 affording 105 mg of the title compound as a 55:45 mixture of two isomers as well as 36 mg of recovered starting material (61 % yield, 78% brsm).

[0070] The trans isomer crystallizes preferentially from Toluene/Hexanes, but does not afford material of sufficient isomeric purity for characterization purposes. A three dimensional molecule model is illustrated in FIG. 1 1 . A hexanes extract of a mixture enriched in the cis isomer gave a co-crystal of isomers suitable for X-ray diffraction upon slow evaporation. A three dimensional molecule model is illustrated in FIG. 12. These data were modeled to extract structures for each isomer by accounting for substitutional disorder and refined to an occupancy of approximately 60/40 favoring the trans isomer.

Acetato-((4-(4-acetylphenyl)-1 ,1 -difluorobutyl))-trifluoromethyl-1 ,3-Bis(2,6- diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll) (mixture of coordination isomers), 21 + isomer

+ isomer

[0071] 18 (130 mg, 0.137 mmol) was dissolved in dichloromethane (1 .8 mL) and methanol (18 mL) and silver acetate (227 mg, 1 .37 mmol, 10 equiv) was added. The mixture was sonicated briefly and stirred for 12 hours at room temperature in the dark. The mixture was filtered, and the filter cake was washed with dichloromethane. The combined filtrates were concentrated, and the residue was again extracted with dichloromethane, filtered and

concentrated affording the product as a colorless solid (126 mg). The resulting product was used as soon as possible without further purification. Storage, even at -20 °C results in the gradual reductive elimination of R-CF2OAC. irans-(E)-(4-methoxy-4-oxobut-2-en-1-yl)-bis(trifluoromethyl)-1,3-Bis(2,6- diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene-gold(lll), 9

[0072] 6 (76 mg, 0.1 mmol), and Grubbs 2^nd Generation Catalyst (3 mg, 3 mol%) were weighed into a Schlenk bomb. Dimethyl maleate (0.06 mL, 0.5 mmol) in dichloromethane (6 mL) was added, the flask was sealed and the mixture was heated at 40°C for 1 .5 hours. The mixture was concentrated onto silica gel and purified by chromatography eluting on a gradient from 30% to 50% DCM in Hexanes. The residue was dried in vacuo over night to remove residual dimethyl maleate affording 72 mg of the title compound (87% yield). frans-(4-methoxy-4-oxobutyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6- diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene-gold(lll), S4

[0073] 9 (288 mg, 0.35 mmol) was dissolved in a 1 : 1 mixture of ethyl acetate and methanol (35 ml_). Pd/C (5 wt% palladium, 180 mg, 25 mol% loading) was added, and the mixture was degassed by sparging with N2 for 5 minutes. A hydrogen balloon was then affixed to the flask and the solution was sparged for 5 minutes and then left under a static atmosphere of H2. TLC analysis after 1 .5 hours showed complete consumption of the starting material, and the H2 was removed by sparging with N2. The mixture was filtered through a pad of celite, and concentrated. The crude residue was purified by chromatography on silica gel eluting with 85:7.5:7.5 Hexanes/DCM/Et20, affording the title compound as a colorless solid (272 mg, 94% yield). frans-(4-hydroxybutyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)- -dihydro-2H-imidazol-2-ylidene-gold(lll), S5

[0074] A solution of S4 (220 mg, 0.267 mmol) in DCM (16 mL) was cooled to -78 °C in a dry ice/acetone bath. A solution of DI BAL-H (1 M in heptane, 1 .35 mL, 5 equiv) was added dropwise, and the solution was stirred for 1 hour at -78 °C. Saturated aqueous ammonium chloride (1 mL) was added in one portion and the mixture was warmed to room temperature, diluted with saturated aqueous Rochelle's salt, and stirred for 1 hour. The layers were separated, and the aqueous layer was extracted 2x with DCM. The combined organic layers were dried over Na2S0₄, filtered and concentrated. It should be noted that in cases where residual aldehyde remained, the crude mixture was treated with sodium borohydride in methanol to achieve complete conversion. The crude mixture was purified by column chromatography on S1O2 eluting with on a gradient from 8: 1 : 1 to 6:2:2 Hexanes/DCM/Et20 affording the title compound as a colorless solid (191 mg, 90% yield).

frans-(4-((2-naphthoyl)oxy)butyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6- diiso ropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll), 10

[0075] S5 (70 mg, 0.088 mmol), 2-naphthoic acid (15 mg, 1 equiv), and triphenylphosphine (35 mg, 1 .5 equiv) were dissolved in dry THF (9 mL), and the mixture was cooled to 0 °C. A solution of DIAD (27 mg, 1 .5 equiv) in 1 mL of THF was added dropwise. The mixture was allowed to reach room temperature and stirred for 19 hours at which point a solution of brine was added. The layers were separated and the aqueous layer was extracted 3x with DCM. The combined organic layers were dried over MgS0₄, filtered, and concentrated. Column chromatography on S1O2 eluting with 8: 1 :1

Hexanes/DCM/Et20 afforded the desired product as a colorless solid (80 mg, 95% yield).

Bromo-(5-((2-naphthoyl)oxy)-1 ,1 -difluoropentyl)-trifluoromethyl-1 ,3- -ylidene-gold(lll)

+ isomer

[0076] In a schlenk bomb, 10 (135 mg, 0.14 mmol) was dissolved in 6 mL of dichloromethane, and 0.19 mL (10 equiv) of TMSBr was added. A solution of B(C6F5)3 (72 mg, 1 equiv) in dichloromethane (3 mL) was added and the mixture was monitored for consumption of the starting material using TLC. After 30 minutes the mixture was quenched with saturated aqueous bicarbonate solution, and the layers were separated. The aqueous layer was washed with DCM 2x, and the combined organics were dried over Na2S0₄, filtered, and concentrated. Chromatography on S1O2 eluting with 8: 1 : 1 Hex/DCM/Et20 afforded the title compound as a colorless solid (103 mg, 72% yield).

Acetato-(5-((2-naphthoyl)oxy)-1 ,1 -difluoropentyl)-trifluoromethyl-1 ,3- Bis(2,6-diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll) (mixture of coordination isomers), 22 + isomer

+ isomer

[0077] 19 (57 mg, 0.056 mmol) was dissolved in dichloromethane (0.6 mL) and methanol (6 mL) and silver acetate (93 mg, 0.56 mmol, 10 equiv) was added. The mixture was sonicated briefly and stirred for 12 hours at room temperature in the dark. The mixture was filtered, and the filter cake was washed with dichloromethane. The combined filtrates were concentrated, and the residue was again extracted with dichloromethane, filtered and

concentrated, affording the product as a colorless solid (50 mg). The resulting product was used as soon as possible without further purification. Storage, even at -20 °C, results in the gradual reductive elimination of R-CF2OAC.

frans-phenylbis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3- dihydro-2H-imidazol-2-ylidene-gold(lll), 12

[0078] In a nitrogen filled glovebox, 5 (1 .52 g, 2 mmol) and diphenyl zinc (1 .1 g, 5 mmol, 2.5 equiv) were combined in a schlenk bomb and dissolved in toluene (125 mL). The flask was sealed with a teflon valve, removed from the glovebox and heated at 40 °C for 1 .5 hours. Upon cooling, the mixture was quenched with H2O and extracted three times with diethyl ether. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography eluting with 7:3 Hexanes/DCM yielding the title compound as a colorless solid (1 .56 g, 97%). frans-(4-aminophenyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)- 1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll), 13

para/ortho

[0079] Stage 7: 12 (802 mg, 1 mmol) and tetramethylammonium nitrate (408 mg, 3 mmol, 3 equiv) were slurried in DCM (100 ml_) and the mixture was cooled to 0 °C in an ice bath. Trifluoroacetic anhydride (0.70 ml_, 5 mmol, 5 equiv) was added dropwise and the mixture was removed from the ice bath and allowed to warm to room temperature. The reaction was monitored by TLC for consumption of starting material. After 3 hours the mixture was quenched with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried with MgS0₄, filtered and concentrated. The crude mixture was filtered through a short pad of silica with DCM, and the resulting mixture (1 .7: 1 para/ortho nitroaryl gold complex, 840 mg) was used without further purification.

[0080] Stage 2: The above crude product, ammonium formate (624 mg, 10 equiv) and 5% Pd/C (525 mg, 25% loading by Pd) were combined in a flask under N2. Ethyl Acetate and Methanol (1 :2, 45 ml_ total) were degassed by sparging and added to the solids with stirring. The mixture was monitored by TLC for the consumption of the para isomer of the nitroaryl gold complex. After 2 hours, the mixture was filtered through a pad of celite with ethyl acetate and concentrated. The crude mixture was extracted with dichloromethane, the insoluble solids were filtered off, and DCM extract was concentrated onto silica gel. This was dry-loaded onto a column and purified by chromatography eluting on a gradient from 8: 1 : 1 to 10:5:5 (Hexanes/DCM/Et₂0) to afford the title compound as a colorless solid (390 mg, 48% yield over 2 steps), as well as 170 mg of unreacted ortho-nitro complex (20%). fraA7S-(4-(5-methylisoxazole-4-carboxamido)phenyl)-bis(trifluoromethyl)-

1,3-Bis(2,6-diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll),

14

[0081] 13 (160 mg, 0.2 mmol) and triethylamine (80 μΙ_, 3 equiv) were dissolved in DCM (2 ml_) and the mixture was cooled to 0 °C in an ice bath. 5- methylisoxazole-4-carbonyl chloride (prepared from the commercially available acid by treatment with oxalyl chloride and catalytic DMF) in dichloromethane (2 ml_) was added dropwise, resulting in a gradual color change from pale yellow to dark purple. The reaction was monitored by TLC for consumption of starting material while maintaining the temperature at 0 °C. After 1 hour the mixture was quenched with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried with Na2S0₄, filtered and concentrated. The crude mixture was purified by silica gel chromatography eluting on a gradient from 30:5:5 to 6:2:2 (Hex/DCM/Et₂0) affording the desired product as a pale yellow solid (142 mg, 76% yield). frans-(3-hydroxypropyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6- diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene-gold(lll), S6

[0082] In a nitrogen filled glovebox, 6 (382 mg, 0.5 mmol) and solid 9- borabicyclo[3.3.1 ]nonane (64 mg, 0.525 mmol, 1 .05 equiv) were dissolved in THF (25 mL total) and combined in a round bottom flask. The flask was sealed with a rubber septum, brought out of the box and stirred for 12 hours under an N2 atmosphere on a Schlenk line. 5 mL of 1 M aqueous NaOH followed by 5 mL of 35% aqueous hydrogen peroxide were injected and the mixture was stirred for an additional hour. The mixture was diluted with water and extracted 3x with dichloromethane. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography eluting with 3: 1 : 1 Hexanes/DCM/Et20 affording the desired product as a colorless solid (290 mg, 74% yield). frans-(3-iodopropyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)- 1 3-dihydro-2H-imidazol-2-ylidene-gold(lll), 15

[0083] Triphenylphosphine (291 mg, 1 .1 1 mmol, 3 equiv) and imidazole (76 mg, 1 .1 1 mmol, 3 equiv) were dissolved in DCM (12 mL) and cooled to 0 °C in an ice bath. Solid iodine (282 mg, 1 .1 1 mmol, 3 equiv) was added and stirred 15 minutes resulting in a yellow-orange solution. S6 (290 mg, 0.37 mmol) in DCM (6 mL) was added slowly and the mixture was removed from the ice bath and allowed to warm to room temperature. After 20 minutes TLC showed complete consumption of the starting material. The mixture was filtered, washing the insoluble material with additional DCM and concentrated directly onto silica which was dry loaded onto a column and purified by chromatography eluting with 5: 1 : 1 H ex/DC M/Et₂0. The resulting product was washed with cold hexanes to remove residual co-eluting PP i3, to afford the title compound as a colorless solid (280 mg, 85% yield). 3-dihydro-2H-

[0084] 15 (280 mg, 0.313 mmol) and potassium thioacetate (40 mg, 1 .1 equiv) were combined in a Schlenk bomb and dissolved in THF (7 ml_). The mixture was degassed by sparging with N2, sealed with a teflon valve and heated at 70 °C for 12 hours. Upon cooling, the mixture was filtered, washing the filter cake with diethyl ether, and concentrated directly onto silica which was dry loaded onto a column and purified by chromatography eluting on a gradient (18: 1 : 1 to 8: 1 : 1 H ex/DC M/Et₂0) to afford the title compound as a yellow solid (217 mg, 82% yield). trans-(3-(chlorosulfonyl)propyl)-bis(trifluoromethyl)-1,3-Bis(2,6- diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll), 16

[0085] S7 (226 mg, 0.27 mmol) was dissolved in 13.5 mL of acetonitrile, and 2.7 mL of 2M aqueous HCI was added, followed by N-Chlorosuccinimide (144 mg, 4 equiv). The mixture was stirred under air for 1 hour at which time TLC showed consumption of the starting material. The reaction mixture was diluted with diethyl ether and water, and the layers were separated. The aqueous layer was extracted 2x with diethyl ether, and the combined organic fractions were again washed with water before drying with sodium sulfate, filtration, and concentration. Column Chromatography on silica gel eluting with 85:7.5:7.5 H ex/DC M/Et₂0 afforded the title compound as a colorless solid (203 mg, 87% yield).

frans-(1 ,3-bis(2,6-diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene)(3- ((3-(2-cyano-3-

(trifluoromethyl)phenoxy)phenoxy)sulfonyl)propyl)bis(trifluoromethyl)gol

[0086] 16 (170 mg, 0.196 mmol), in dichloromethane (10 mL) was added to a solution of 2-(3-hydroxyphenoxy)-6-(trifluoromethyl)benzonitrile (57 mg, 1 .05 equiv) and trimethylamine (40 μί, 1 .5 equiv) in dichloromethane (10 mL). The solution was stirred for 25 minutes at which point the TLC showed complete consumption of the starting material. Chromatography on silica gel eluting on a gradient from 8: 1 : 1 to 7: 1 .5: 1 .5 Hexanes/DCM/Et20 afforded the title compound as a colorless solid (184 mg, 85% yield). Bromo-(4-((3-(2-cyano-3-(trifluoromethyl)phenoxy)phenoxy)sulfonyl)-1 ,1 - difluorobutyl)-trifluoromethyl-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3-dihydro- 2H-imidazol-2- lidene-gold(lll) (mixture of coordination isomers), 20

+ isomer

[0087] In a schlenk bomb, 17 (1 16 mg, 0.104 mmol) was dissolved in 3 ml_ of DCE, and TMSBr (0.14 ml_, 10 equiv) followed by a solution of 2 (53 mg, 1 equiv) in 3 ml_ of DCE. The flask was sealed with a Teflon valve and the solution was heated to 80 °C and monitored by TLC for consumption of the starting material. After 1 hour, the solution was cooled to room temperature and quenched with aqueous sodium bicarbonate. The layers were separated, the aqueous layer was extracted with DCM, and the combined organic layers were dried over Na2S0₄, filtered, and concentrated.

[0088] Purification by column chromatography on silica (7: 1 .5: 1 .5

H ex/DC M/Et20 eluent) afforded the product as a colorless solid, which was further purified by precipitation from diethyl ether with hexanes (60 mg, 55% yield).

Acetato-(4-((3-(2-cyano-3-(trifluoromethyl)phenoxy)phenoxy)sulfonyl)-1 ,1 - difluorobutyl)-trifluoromethyl-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3-dihydro- 2H-imidazol-2-ylidene-gold(lll) (mixture of coordination isomers), 23 + isomer

[0089] 20 (60 mg, 0.051 mmol) was dissolved in a mixture of 0.6 mL of dichloromethane and 6 mL of methanol, and 85 mg (10 equiv) of silver acetate was added. The mixture was stirred vigorously overnight at room temperature in the dark. The resulting mixture was filtered, concentrated, extracted with DCM, filtered again, and concentrated (56 mg, colorless solid). The resulting product was used as soon as possible without further purification. Storage, even at -20 °C, results in the gradual reductive elimination of R-CF2OAC.

frans-(cyclopropylmethyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6- diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll), S8

[0090] In a nitrogen filled glovebox, 6 (76 mg, 0.1 mmol) and diethyl zinc (0.2 mL of 1 M hexanes solution, 2 equiv) were dissolved in DCE (3 mL) in a round bottom flask. Chloroiodomethane (71 mg, 4 equiv) in 3 mL of DCE was added and the mixture was sealed with a rubber septum, brought out of the box and stirred for 1 hour under an N2 atmosphere on a Schlenk line. 5 mL of H2O were injected and the mixture was extracted 3x with diethyl ether. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography eluting with 1 : 1

Hexanes/DCM affording the desired product as a colorless solid (69 mg, 88 % yield). A three dimensional molecule model is illustrated in FIG. 13. frans-(2,3-dihydroxypropyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6- diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene-gold(lll), S9

[0091] 6 (1 10 mg, 0.144 mmol) and potassium osmate dihydrate (1 mg, 0.02 equiv) were dissolved in 1 : 1 THF/H2O (6 ml_) in a round bottom flask. N- methylmorpholine-N-oxide (34 mg, 2 equiv) was added, and additional THF ~ 1 ml_ was added to solubilize the gold complex. The mixture was stirred for 12 hours under air, then 5 ml_ of 1 M aqueous sodium bisulfate was added, and the mixture was extracted 3x with diethyl ether. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography eluting with 3: 1 : 1 Hexanes/DCM/Et20 affording the desired product as a colorless solid (80 mg, 70% yield). frans-(2-oxoethyl)-bis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3- dihydro-2H-imidazol-2-ylidene-gold(lll), S9

[0092] 6 (75 mg, 0.095 mmol) and sodium periodate (100 mg, 5 equiv) were dissolved in 4: 1 DCM/H2O (2.5 ml_). The mixture was vigorously stirred for 18 hours under air, diluted with DCM and washed 3x with brine. The organic layer was dried with sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography eluting with 85:7.5:7.5

Hexanes/DCM/Et20 affording the desired product as a colorless solid (36 mg, 50% yield). frans-ethyl-bis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)-1 ,3-dihydro- -imidazol-2-ylidene-gold(lll), S10

[0093] In a schlenk bomb, 5 (76 mg, 0.1 mmol) was dissolved in THF (10 ml_) and a solution of 1 .1 M Et2Zn in hexanes was added (1 .8 ml_, 20 equiv). The flask was sealed with a Teflon needle valve and the mixture was heated at 60 °C for 12 hours. Upon cooling, the mixture was quenched carefully with water and extracted 3x with diethyl ether. The organic layer was dried with sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography eluting with 6:4 Hexanes/DCM affording the desired product as a colorless solid (47 mg, 62% yield). frans-phenylethynyl-bis(trifluoromethyl)-1 ,3-Bis(2,6-diisopropylphenyl)- 1 ,3-dihydro-2H-imidazol-2-ylidene-gold(lll), S11

[0094] In a flame-dried round-bottom flask under N2, 5 (76 mg, 0.1 mmol) was dissolved in 9 ml_ of DCM. In a separate flame-dried round-bottom flask under N2, Cul (8 mg, 0.04 mmol, ,4 equiv) was slurried in DCM (1 ml_) and phenylacetylene (.07 ml_, 6 equiv) and trimethylamine (1 ml_, 70 equiv) was added and stirred until the mixture turned yellow. This latter solution was transferred via syringe to the [Au] solution and the mixture was stirred at room temperature for 15 hours at which point TLC indicated complete conversion. The mixture was directly concentrated onto silica gel and purified by column chromatography eluting on a gradient from 6: 1 to 2: 1 Hexanes/DCM to afford the product as a colorless solid (78 mg, 93%).

Reductive Elimination of Trifluoroethane (Catalytic Borane)

[0095] In a nitrogen-filled glovebox, to a solution of 1 a (7.4 mg, 0.01 mmol) in DCM-d2 (0.3 ml_) in a silylated NMR tube was added a solution of tris(pentafluorophenylborane) in DCM-ck (1 mg, 0.002 mmol, in 0.3 ml_, prepared a stock solution). The mixture was capped with an NMR-tube septum and sealed with electrical tape. Analysis by FNMR after 5 minutes showed the complete consumption of 1 , formation of Me-CF3 as the major product, along with C6F5H, and IPr-Au-CF3 as the major Au-containing product.

Reductive Elimination of Trifluoroethane (Stoichiometric Borane)

[0096] In a nitrogen-filled glovebox, to a solution of 1 a (7.4 mg, 0.01 mmol) in DCM-d2 (0.3 mL) in a silylated NMR tube was added a solution of

tris(pentafluorophenylborane) in DCM-ck (10.2 mg, 0.02 mmol, in 0.3 mL). The mixture was capped with an NMR-tube septum and sealed with electrical tape. Analysis by FNMR after 5 minutes showed the complete consumption of 1 , formation of Me-CF₃ as the major product, along with C6F5H, and IPr-Au-GsFs as the exclusive Au-containing product.

Reductive Elimination of Trifluoroethane (Stoichiometric Borane with Alkene Trap)

[0097] In a nitrogen-filled glovebox, to a solution of 1 a (7.4 mg, 0.01 mmol) and tetramethylethylene (1 .6 mg, 0.02 mmol, prepared as a stock solution) in DCM-c(2 (0.3 mL) in a silylated NMR tube was added a solution of

tris(pentafluorophenylborane) in DCM-ck (10.2 mg, 0.02 mmol, in 0.3 mL). The mixture was capped with an NMR-tube septum and sealed with electrical tape. Analysis by FNMR after 5 minutes showed the complete consumption of 1 , formation of Me-CF3 as the major product, along with C6F5H, 1 , 1 ,2,2-dimethyl- 3,3-difluorocyclopropane, and IPr-Au-GsFs as the exclusive Au-containing product. GC-MS analysis of the mixture also indicated the presence of the difluorocyclopropane product (m/z = 41 , 1 19, and 134, consistent with literature spectrum). eductive Elimination of Difluoroethyltriflate (Stoichiometric TMSOTf)

[0098] In a nitrogen filled glovebox, 1 a (7.4 mg, 0.01 mmol) was dissolved in DCM-ci2 (0.3 mL) in a silylated NMR tube and a solution of TMSOTf (4.4 mg, 2 equiv) in DCM-d2 (0.3 mL) was added. The solution was capped with a rubber septum and heated at 40 °C. Conversion was monitored by FNMR, indicating the formation of MeCF₂OTf {F NMR (376 MHz, Methylene Chloride-cfe) δ -57.59 (qq, J = 14.7, 5.6 Hz, 2F), -74.1 1 (d, J = 5.6 Hz, 3F)}³¹ , along with IPrAuOTf and TMSF. An intermediate was also detected and assigned as the difluoroethyl Au(l ll) triflate shown above by analogy to 4 {¹⁹F NMR (376 MHz, Methylene Chloride-^) δ -34.51 (t, J = 1 1 .9 Hz, 3F), -61 .14 - -61 .50 (m, 2F), -71 .04 (s, 3F)}. (48)

Reductive Elimination of Trifluoroethane (Silver Mediated from 4)

[0099] 4 (39 mg, 0.05 mmol) was dissolved in DCM-d2 (1 mL), and silver fluoride was added (64 mg, 10 equiv). The mixture was sonicated briefly and stirred vigorously for 12 hours in the dark. The mixture was filtered directly into an NMR tube, and an additional 64 mg (10 equiv) of AgF was added. The tube was sealed with a rubber septum and sonicated for an additional 20 minutes. The mixture was allowed to stand with occasional agitation for an additional 24 hours, with NMR spectra recorded periodically. These indicated the formation of two isomers of an intermediate Au(lll)-fluoride which is observable, as well as another unidentified Au(ll l) product. The majority of the material is observed to convert to I PrAuCFs and MeCF3, with a small amount of 1 , 1 -difluoroethylene formed as a byproduct. After 36 hours, the starting complex was consumed, with 32% conversion to IPrAuCFs observed, the remainder of the mass balance taken up by the Au(lll)-F and unidentified Au(l ll) species. For ease of interpretation, the X-axis has been segmented to show relevant peaks.

Reductive Elimination of Trifluoroethane (PCy-3; Catalytic Borane)

20 mol%

[00100] In a nitrogen-filled glovebox, to a solution of 1 b (6.1 mg, 0.01 mmol) in DCM-d2 (0.3 ml_) in a silylated NMR tube was added a solution of

tris(pentafluorophenylborane) in DCM-ck (1 mg, 0.002 mmol, in 0.3 ml_, prepared a stock solution). The mixture was capped with an NMR-tube septum and sealed with electrical tape. Analysis by FNMR after 5 minutes showed the complete consumption of 1 , formation of Me-CF3 as the major product, along with Cy3P-Au-CF3 as the major Au-containing product.

Reductive Elimination of Trifluoroethane (Stoichiometric Borane)

[00101] In a nitrogen-filled glovebox, to a solution of 1 b (6.1 mg, 0.01 mmol) in DCM-d2 (0.3 ml_) in a silylated NMR tube was added a solution of tris(pentafluorophenylborane) in DCM-ck (10.2 mg, 0.02 mmol, in 0.3 mL). The mixture was capped with an NMR-tube septum and sealed with electrical tape. Analysis by FNMR after 5 minutes showed the complete consumption of 1 , formation of Me-CF3 as the major product, along with C6F5H, and IPr-Au-GsFs as the exclusive Au-containing product.

Reductive Elimination of Trifluorotoluene (Stoichiometric Borane)

[00102] In a nitrogen-filled glovebox, to a solution of 12 (8 mg, 0.01 mmol) in DCM-c(2 (0.3 mL) in a silylated NMR tube was added a solution of

tris(pentafluorophenylborane) in DCM-ck (10.2 mg, 0.02 mmol, in 0.3 mL). The mixture was capped with an NMR-tube septum and sealed with electrical tape. Analysis by FNMR after 5 minutes showed the almost complete consumption of 12, formation of PI-1-CF3 as the major product, along with C6F5H, and IPr-Au- C6F5 as the major Au-containing product.

Reductive Elimination of Bromodifluorotoluene (Catalytic Borane)

[00103] In a nitrogen-filled glovebox, to a solution of 12 (7.4 mg, 0.01 mmol) in DCM (0.3 mL) in a silylated NMR tube was added TMS-Br (0.01 mL, 10 equiv) followed by a solution of tris(pentafluorophenylborane) in DCM (0.5 mg, 0.001 mmol, in 0.3 mL). The mixture was capped with an NMR-tube septum and sealed with electrical tape. Analysis by FNMR after 1 hour showed -15% conversion to afford a mixture of PhCF2-3r and TMS-F. Peaks for 2 are too small to be seen at this scale.

Reductive Elimination of 1 -(4-(4,4,4-trifluorobutyl)phenyl)ethan-1 -one (Stoichiometric Borane)

[00104] In a nitrogen filled glovebox, to a solution of 7 (66 mg, 0.075 mmol) in 2 ml_ of DCM was added a solution of B(C6Fs)3 (77 mg, 0.15 mmol) in 2 ml_ of DCM. An immediate color change to pale yellow occurred, and the mixture was capped with a septum cap, and brought out of the glovebox.

[00105] After 10 minutes, TLC analysis indicated complete consumption of the starting material, and a solution of saturated aqueous sodium bicarbonate was injected through the septum, and the mixture was vigorously stirred for 10 minutes. The solution was diluted with water and dichloromethane. The organic layer was separated and the aqueous layer was washed 2x with DCM. The combined organic layers were dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by column chromatography eluting with (18:1 : 1 Hexanes/DCM/Et₂0) to afford the title compound (12 mg, 70% yield).

[00106] When conducted in an NMR tube on 0.005 mmol scale, 97% yield by FNMR was observed.

Reductive Elimination of 5,5,5-trifluoropentyl 2-naphthoate (Stoichiometric Borane)

[00107] In a nitrogen filled glovebox, to a solution of 10 (54 mg, 0.058 mmol) in 2 mL of DCM was added a solution of B(C6Fs)3 (59 mg, 0.1 16 mmol) in 2 mL of DCM. An immediate color change to orange occurred, and the mixture was capped with a septum cap and brought out of the glovebox. TLC analysis after 45 minutes indicated complete consumption of the starting material.

[00108] A solution of saturated aqueous sodium bicarbonate was injected through the septum, and the mixture was vigorously shaken. The septum was removed and the solution was diluted with water and dichloromethane. The organic layer was separated and the aqueous layer was washed 2x with DCM. The combined organic layers were dried over MgS0₄, filtered, and

concentrated. The crude residue was purified by silica gel chromatography (97:3 Hexanes/Et20). The resulting residue was extracted with cold hexanes to remove the desired product from co-eluting I PrAuCeFs (12 mg, 60%).

[00109] When conducted in an NMR tube on 0.005 mmol scale, 80% yield by FNMR was observed.

Reductive Elimination of Leflunomide (Stoichiometric Borane)

[00110] In a nitrogen filled glovebox, to a solution of 14 (5.2 mg, 0.0056 mmol) in 0.3 mL of DCM-ck in a silylated NMR tube was added a solution of B(C₆F₅)3 (5.6 mg, 0.01 1 mmol) in 0.3 mL of DCM-d₂. An immediate color change to pale yellow occurred, and the mixture was capped with an NMR tube septum and sealed with electrical tape. The mixture was heated at 40 °C in an oil bath for 15 hours, at which point HNMR and FNMR spectra were recorded, indicating complete conversion to the desired product relative to [Au].

[00111] A solution of saturated aqueous sodium bicarbonate was injected through the septum, and the mixture was vigorously shaken. The septum was removed and the solution was diluted with water and dichloromethane. The organic layer was separated and the aqueous layer was washed 2x with DCM. The combined organic layers were dried over MgS0₄, filtered, and

concentrated. The crude residue was purified by prep TLC (70: 15: 15

Hexanes/DCM/Et₂0) to afford the title compound (1 .5 mg, 98% yield).

Reductive Elimination of BAY 59-3074 (Stoichiometric Borane)

[00112] In a nitrogen filled glovebox, to a solution of 17 (22 mg, 0.02 mmol) in 0.5 mL of DCM-d₂ in a silylated NMR tube was added a solution of B(CeF₅)3 (20 mg, 0.04 mmol) in 0.5 mL of DCM-cfc. An immediate color change to pale yellow occurred, and the mixture was capped with an NMR tube septum and sealed with electrical tape. After 2 hours, HNMR and ¹⁹FNMR spectra were recorded, indicating complete conversion to the desired product relative to [Au].

[00113] A solution of saturated aqueous sodium bicarbonate was injected through the septum, and the mixture was vigorously shaken. The septum was removed and the solution was diluted with water and dichloromethane. The organic layer was separated and the aqueous layer was washed 2x with DCM. The combined organic layers were dried over MgS0₄, filtered, and concentrated. The crude residue was purified by prep TLC (6:2:2

Hexanes/DCM/Et₂0) to afford the title compound (6 mg, 67% yield).

[00114] Low Temperature NMR Reaction Monitoring

[00115] General procedure for kinetics

[00116] In a nitrogen filled glovebox, a solution of 1 (7.40 mg, 0.01 mmol in 400 μΙ_ DCM-d2, prepared as a stock solution) was combined with 1 - trifluoromethyl napthalene (internal standard, 1 .96 mg, 0.01 mmol in 100 μΙ_ DCM-d2, prepared as a stock solution) in a silylated NMR tube and fitted with a septum cap and sealed with electrical tape. In a separate septum-capped 2 dram vial was prepared a solution of B(C6Fs)3 in DCM-d2 (102 mg in 1000 μΙ_).

[00117] The two solutions were brought out of the glovebox and connected to N2 atmosphere on a Schlenk line. The NMR tube solution was cooled to -78 °C, and a portion of the B(C6Fs)3 solution (100 μΙ_, 0.02 mmol) was added dropwise via syringe.

[00118] The mixture was agitated briefly, and then injected into a pre-cooled, tuned, and shimmed NMR probe at -15 °C. FNMR scans were collected at 60 second intervals, utilizing one scan per time point.

[00119] Kinetic Traces

[00120] The data presented in FIGs. 24-27 represent three trials conducted using distinct drying methods for the DCM solvent, and the varying

concentrations of observed intermediate (displaying 3:2 integrating,

triplet/multiplet signals akin to 4) are taken as evidence for the formation of an intermediate aquo species. The data is represented as concentration (e.g., in mmol) of the species over time (e.g., in seconds). A small amount of a second isomer of this putative aquo is observed, in a direct parallel to 4, but its contribution to the overall mass balance is small at early reaction times. FIG. 28 illustrates an example of the concentration of species over time including isomer formation.

[00121] Under these conditions, IPrAuGsFs does not form in substantial quantities until the mixture is warmed to room temperature. IPrAuCF3 is not observed, potentially due to exchange broadening via reversible C-F abstraction.

Radiochemistry Cold Run

[00122] To a solution of 0.05M aqueous hydrofluoric acid (0.1 mL, 0.005 mmol) was added potassium carbonate (1 .4 mg, 2 equiv) and Kryptofix [2.2.2] (3.8 mg, 2 equiv), and acetonitrile (0.4 mL). The mixture was concentrated at 30 °C, and the process was repeated 2x with 0.4 mL of additional acetonitrile.

[00123] The resulting residue was extracted 2x with 0.1 mL of

dichloromethane, and placed into a septum capped vial. After purging the headspace with nitrogen, a solution of 2 (12.7 mg, 5 equiv) in 0.3 mL of dichloromethane was added, followed by the corresponding [Au]-OAc complex (0.006 mmol) in 0.3 mL of DCM. The entire mixture was then transferred into a septum capped NMR tube.

[00124] Note that the spectra are not locked to deuterated solvent. Due to the longer reaction time for 23, I PrAuGsFs is formed from IPrAuCF3. Additionally, difluoroalkene resulting from elimination is seen in the reaction from 23.

[00125] Radiochemistry

[00126] No-carrier-added ¹⁸F-fluoride was produced by -10 MeV proton irradiation of 97+% enriched [^{1 8}0]H20 at low pressure in a Niobium target by the ¹⁸0(p,n)¹⁸F nuclear reaction on the Biomedical Isotope Facility CTI RDS 1 1 1 -DV001 cyclotron. The [¹⁸0]H₂0/¹⁸F^" (25 μΙ) was transferred into a conical glass vial containing Kryptofix® 222 (3.5 mg, 9.3 μιηοΙ), and K2CO3 (0.375 mg, 2.7 μιηοΙ) in 400 μί of CH3CN/H2O. The water was removed by azeotropic distillation with anhydrous CH3CN (0.4 mL) at 100 °C in vacuo, under a stream of nitrogen. The azeotropic drying process was repeated two additional times. Residual acetonitrile was found to substantially slow the reaction, so care was taken to thoroughly dry the remaining fluoride.

[00127] The residue was extracted with dichloromethane (2x 0.1 mL) to a glass vial and capped with a septum cap. This transferred on average 88 ± 1 % of the radioactivity (n =1 1 ). Initial activities listed below are for the reaction vial post transfer, and total times include azeotropic drying. The headspace was purged with N2 for 2 minutes, and a solution of tris(pentafluorophenyl)borane in dichloromethane (0.25 ml_ of 0.1 M solution, 25 μιηοΙ) was injected through the septum followed by a solution of the relevant Au(l ll) acetate complex (5 μιηοΙ) in dichrolomethane (0.25 ml_). After the indicated reaction time, the solution was spotted onto a TLC plate, eluted with the indicated solvent mixture, and the radiochemical conversion was measured using a radio-TLC scanner (AR-2000 Imaging Scanner, Bioscan) as counts with identical retention as an authentic sample of the product as a fraction of total counts. The total counts for run 1 of the radiochemical conversion of [¹⁸F]-1 -(4-(4,4,4-trifluorobutyl)phenyl)ethan-1 - one are illustrated in FIG. 19 with the corresponding table of data. The total counts for run 2 of the radiochemical conversion of [¹⁸F]-1 -(4-(4,4,4- trifluorobutyl)phenyl)ethan-1 -one are illustrated in FIG. 20 with the

corresponding table of data. The total counts for run 3 of the radiochemical conversion of [¹⁸F]-1 -(4-(4,4,4-trifluorobutyl)phenyl)ethan-1 -one are illustrated in FIG. 21 with the corresponding table of data. The total counts for run 4 of the radiochemical conversion of [¹⁸F]-1 -(4-(4,4,4-trifluorobutyl)phenyl)ethan-1 -one are illustrated in FIG. 22 with the corresponding table of data. The total counts for run 5 of the radiochemical conversion of [¹⁸F]-1 -(4-(4,4,4- trifluorobutyl)phenyl)ethan-1 -one are illustrated in FIG. 23 with the

corresponding table of data. The total counts for run 1 of the radiochemical conversion of [¹⁸F]- 5,5,5-trifluoropentyl 2-naphthoate are illustrated in FIG. 24 with the corresponding table of data. The total counts for run 2 of the radiochemical conversion of [¹⁸F]- 5,5,5-trifluoropentyl 2-naphthoate are illustrated in FIG. 25 with the corresponding table of data. The total counts for run 3 of the radiochemical conversion of [¹⁸F]- 5,5,5-trifluoropentyl 2-naphthoate are illustrated in FIG. 26 with the corresponding table of data. The total counts for run 1 (* Eluted twice with 30:70 Et20/Hex instead of once with 10:90) of the radio chemical conversion of [¹⁸F]-3-(2-cyano-3-

(trifluoromethyl)phenoxy)phenyl-4,4,4-trifluorobutane-1 -sulfonate are illustrated in FIG. 27 with the corresponding table of data. The total counts for run 2 of the radio chemical conversion of [¹⁸F]-3-(2-cyano-3-

(trifluoromethyl)phenoxy)phenyl-4,4,4-trifluorobutane-1 -sulfonate are illustrated in FIG. 28 with the corresponding table of data. The total counts for run 3 of the radio chemical conversion of [¹⁸F]-3-(2-cyano-3-

(trifluoromethyl)phenoxy)phenyl-4,4,4-trifluorobutane-1 -sulfonate are illustrated in FIG.29 with the corresponding table of data.

[¹⁸F]-1 -(4-(4,4,4-trifluorobutyl)phenyl)ethan-1 -one

Reaction Time: 8 minutes

TLC solvent: 7:3 Hexanes/Diethyl Ether The radiochemical conversions obtained were as follows for 5 trials: o Run I Initia Il A Ac *t^■iv^■i*ty T To *ta Il T T-ime ^ Radiochemical

³ Conversion (TLC)

1 6.55 mCi 24 min 38.4%

2 1.30 mCi 23 min 52.0%

3 0.73 mCi 22 min 24.3% L 31.2 + 13.8%

4 0.72 mCi 28 min 18.4%

5 0.57 mCi 32 min 22.7%

Table 1

[¹⁸F]- 5,5,5-trifluoropentyl 2-naphthoate

Reaction Time: 10 minutes

TLC solvent: 7:3 Hexanes/Diethyl Ether The radiochemical conversions obtained were as follows for 3 trials: Radiochemical

Run Initial Activity Total Time ^ _/T1

' Conversion (TLC)

1 3.92 mCi 40 min 23.8%

2 1.79 mCi 36 min 23.3% 26.8 + 5.6% 3 0.95 mCi 44 min 33.3%

Table 2

[¹⁸F]-3-(2-cyano-3-(trifluoromethyl)phenoxy)phenyl-4,4,4-trifluorobutane-1

Reaction Time: 25 minutes

TLC solvent: 1 :9 Hexanes/Diethyl Ether (Note: F-B(C6Fs)3 is mobile at this solvent polarity)

The radiochemical conversions obtained were as follows for 3 trials: Run Initial Activity Tota Il - Tr-ime ^ Radiochem .i_c.al

¹ Conversion (TLC)

1 5.06 mCi 52 min 6.3%

2 1.60 mCi 56 min 12.0% 11.7 ± 5.3% 3 1.11 mCi 63 min 16.9%

Table 3

[00128] Isolation and Specific Activity ofp⁸F] BA Y 59-3074

[00129] No-carrier-added ¹⁸F-fluoride was produced by -10 MeV proton irradiation of 97+% enriched [^{1 8}0]H20 at low pressure in a Niobium target by the ¹⁸0(p,n)¹⁸F nuclear reaction on the Biomedical Isotope Facility CTI RDS 1 1 1 -DV001 cyclotron. The [¹⁸0]H₂0/¹⁸F- (125 μΙ, 71 .3 mCi) was transferred into a conical glass vial containing Kryptofix® 222 (3.5 mg, 9.3 μιηοΙ), and K2CO3 (0.375 mg, 2.7 μιηοΙ) in 400 μΙ_ of CH3CN/H2O. The water was removed by azeotropic distillation with anhydrous CH3CN (0.4 mL) at 100 °C in vacuo, under a stream of nitrogen. The azeotropic drying process was repeated four additional times. Residual acetonitrile was found to substantially slow the reaction, so care was taken to thoroughly dry the remaining fluoride.

[00130] The residue was extracted with dichloromethane (2x 0.1 mL) to a glass vial and capped with a septum cap. (This transferred 86% of the radioactivity.) The headspace was purged with N2 for 2 minutes, and a solution of tris(pentafluorophenyl)borane in dichloromethane (0.25 mL of 0.1 M solution, 25 μιηοΙ) was injected through the septum followed by a solution of 23 (5.8 mg, 5 μιηοΙ) in dichrolomethane (0.25 mL). After 25 minutes, the reaction was concentrated to dryness, without heating, in vacuo. 1 mL of acetonitrile was added, and the mixture was diluted with 1 mL of H2O and filtered through an alumina Sep-Pak (Water, Alumina N Plus Light Cartridge, 280 mg, 50-300 μιη mesh). The vial was rinsed with an additional 1 mL of 1 : 1 MeCN/hbO which was also filtered through the same alumina setpak. The filtrate was injected onto a prep HPLC column (Phenomenex Luna 10 μιη, 100A C-18(2), 10 x 250 mm) and eluted at 5 mL/min with 70:30 MeCN/hbO. The product was collected between 8.6 and 10 minutes, affording a 7 mL fraction totaling 3.94 mCi (decay corrected to the end of reaction, 6% RCY). This was analyzed by HPLC

(Phenomenex Luna C18(2), 10 μιη, 100A, 150 x 4.6 mm column, eluting 1 mL/min with 70:30 MeCN/hbO), affording a specific activity measurement of 8 mCi/μιτιοΙ based on a calibration curve determined using authentic BAY 59- 3074. The report is reproduced in FIG. 30.

[00131] Table 4 below represents X-Ray crystallography data and structure refinement for compound 1 a described above. Table 5 below represents X-Ray crystallography data and structure refinement for compound 1 b described above. Table 6 below represents X-Ray crystallography data and structure refinement for compound 4 described above. Table 7 below represents X-Ray crystallography data and structure refinement for compound 5 described above. Table 8 below represents X-Ray crystallography data and structure refinement for compound 6 described above. Table 9 below represents X-Ray

crystallography data and structure refinement for compound 7 described above. Table 10 below represents X-Ray crystallography data and structure refinement for compound 18 described above. Table 1 1 below represents X-Ray crystallography data and structure refinement for compound S2 described above. Table 12 below represents X-Ray crystallography data and structure refinement for compound S8 described above.

X-Ray Crystallography Data

Table 4

Crystal data and structure refinement for 1 a.

Identification code shelx

Empirical formula C30 H39 Au1 F6 N2

Formula weight 738.60

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Orthorhombic

Space group P b c a

Unit cell dimensions a = 19.3702(6) A alpha= 90°.

b = 16.5858(5) A beta= 90°. c = 37.4869(12) A gamma = 90°.

Volume 12043.4(6) A3

Z 17

Density (calculated) 1 .629 Mg/m3

Absorption coefficient 4.944 mm-1

F(000) 5856

Crystal size 0.200 x 0.200 x 0.040 mm³

Theta range for data collection 1 .512 to 25.365°.

Index ranges -21 <=h<=23, -19<=k<=18, -45<=l<=45 Reflections collected 1 1 1842

Independent reflections 1 1032 [R(int) = 0.0468]

Completeness to theta = 25.000 100.0 %

Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.646 and 0.457

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1 1032 / 0 / 721

Goodness-of-fit on F2 1 .1 12

Final R indices [l>2sigma(l)] R1 = 0.0325, wR2 = 0.0746

R indices (all data) R1 = 0.0401 , wR2 = 0.0779

Extinction coefficient n/a

Largest diff. peak and hole 3.291 and -0.739 e.A"³

Table 5

Crystal data and structure refinement

Identification code shelx

Empirical formula C21 H36 Au F6 P

Formula weight 630.43

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Orthorhombic

Space group P n m a

Unit cell dimensions a = 14.6624(5) A a= 90°.

b = 16.5973(5) A b= 90°.

c = 9.1732(3) A g = ^: 90°

Volume 2232.36(13) A³

Z 4

Density (calculated) 1 .876 Mg/m³

Absorption coefficient 6.716 mm^"1

F(000) 1240

Crystal size 0.300 x 0.240 x 0.200 mm³

Theta range for data collection 2.454 to 25.347°.

Index ranges -17<=h<=17, -19<=k<=19, -1 1 <=K=1 1 Reflections collected 40240

Independent reflections 21 18 [R(int) = 0.0392]

Completeness to theta = 25.000 100.0 %

Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.646 and 0.557 Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 21 18 / 0 / 139

Goodness-of-fit on F2 1 .143

Final R indices [l>2sigma(l)] R1 = 0.0248, wR2 = 0.0586

R indices (all data) R1 = 0.0280, wR2 = 0.0602

Extinction coefficient n/a

Largest diff. peak and hole 2.447 and -0.662 e.A-3

Table 6

Crystal data and structure refinement for 4.

Identification code shelx

Empirical formula C30 H39 Au Br F5 N2

Formula weight 799.51

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Monoclinic

Space group P 21 /n

a = 20.6333(15) A, alpha = 90 deg.

Unit cell dimensions b = 9.9414(7) A, beta = 107.3480(10) deg.

c = 16.0121 (12) A, gamma = 90 deg.

Volume 3135.1 (4) A³

Z 4

Density (calculated) 1 .694 Mg/m^A3

Absorption coefficient 6.018 mm^A-1

F(000) 1568

Crystal size 0.300 x 0.300 x 0.200 mm

Theta range for data collection 2.068 to 25.359°

Index ranges -24<=h<=24, -1 1 <=k<=1 1 , -19<=l<=1 Reflections collected 97533

Independent reflections 5736 [R(int) = 0.0269]

Completeness to theta = 25.000° 100.0 %

Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.745 and 0.588

Refinement method Full-matrix least-squares on F^A2

Data / restraints / parameters 5736 / 0 / 348

Goodness-of-fit on F2 1 .058

Final R indices [l>2sigma(l)] R1 = 0.0300, wR2 = 0.0785

R indices (all data) R1 = 0.0313, wR2 = 0.0795

Extinction coefficient n/a

Largest diff. peak and hole 2.261 and -1 .658 e.A-³

Table 7

Crystal data and structure refinement r 5.

Identification code shelx

Empirical formula C29 H36 Au CI F6 N2

Formula weight 759.01

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Monoclinic

Space group P 21/n

Unit cell dimensions a = 1 1 .6081 (6) A, alpha= 90°.

b = 17.2245(9) A, beta= 105.8830(10)°. c = 15.6653(8) A, gamma = 90°.

Volume 3012.6(3) A3

Z 4

Density (calculated) 1 .673 Mg/m3

Absorption coefficient 5.030 mm^"1

F(000) 1496

Crystal size 0.100 x 0.080 x 0.040 mm³

Theta range for data collection 1 .796 to 25.409∞.

Index ranges -13<=h<=14, -20<=k<=20, -18<=l<=18 Reflections collected 82795

Independent reflections 5531 [R(int) = 0.0823]

Completeness to theta = 25.000°° 100.0 % Absorption correction Semi-empirical from equivalents

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 5531 / 0 / 369

Goodness-of-fit on F2 1 .056

Final R indices [l>2sigma(l)] R1 = 0.0428, wR2 = 0.0956

R indices (all data) R1 = 0.0564, wR2 = 0.1031

Extinction coefficient n/a

Largest diff. peak and hole 3.188 and -1 .027 e ~-3

Table 8

Crystal data and structure refinement 6.

Identification code shelx

Empirical formula C32 H41 Au F6 N2

Formula weight 764.63

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Orthorhombic, P b c a

a = 16.3403(1 1 ) A, alpha = 90 deg.

Unit cell dimensions b = 17.0007(1 1 ) A, beta = 90 deg.

c = 23.2921 (15) A, gamma = 90 deg.

Volume 6470.5(7) Α^Λ3

Z 8

Density (calculated) 1 .570 Mg/m^A3

Absorption coefficient 4.605 mm^A-1

F(000) 3040

Crystal size 0.200 x 0.100 x 0.100 mm

Theta range for data collection 1 .749 to 25.390°

Index ranges -19<=h<=19, -20<=k<=20, -28<=l<=28 Reflections collected 144595

Independent reflections 5953 [R(int) = 0.0352]

Completeness to theta = 25.000° 100.0 %

Refinement method Full-matrix least-squares on F^A2 Data / restraints / parameters 5953 / 0 / 370

Goodness-of-fit on F2 1 .155

Final R indices [l>2sigma(l)] R1 = 0.0309, wR2 = 0.0753

R indices (all data) R1 = 0.0341 , wR2 = 0.0774

Extinction coefficient n/a

Largest diff. peak and hole 3.800 and -1 .210 e.A-3

Table 9

Crystal data and structure refinement for 7.

Identification code shelx

Empirical formula C40 H49 Au F6 N2 O

Formula weight 884.78

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Monoclinic, P 21/n

a = 12.1671 (6) A, alpha = 90 deg. b = 22.4672(1 1 ) A .beta = 105.4170(10)

Unit cell dimensions

deg.

c = 14.5163(7) A, gamma = 90 deg.

Volume 3825.4(3) Α^Λ3

Z 4

Density (calculated) 1 .536 Mg/m^A3

Absorption coefficient 3.908 mm^A-1

F(000) 1776

Crystal size 0.200 x 0.120 x 0.100 mm

Theta range for data collection 1 .714 to 25.373°

Index ranges -14<=h<=14, -26<=k<=27, -17<=l<=17

Reflections collected 1 14481

Independent reflections 7027 [R(int) = 0.0374]

Completeness to theta = 25.000° 100.0 %

Refinement method Full-matrix least-squares on F^A2

Data / restraints / parameters 7027 / 0 / 451 Goodness-of-fit on F2 1 .138

Final R indices [l>2sigma(l)] R1 = 0.0341 , wR2 = 0.0788

R indices (all data) R1 = 0.0386, wR2 = 0.0823

Extinction coefficient n/a

Largest diff. peak and hole 3.633 and -1 .245 e.A"³

Table 10

Crystal data and structure refinement for 18.

Identification code shelx

Empirical formula C40 H49 Au Br F5 N2 O

Formula weight 945.69

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Monoclinic, P 21 /c

a = 9.2424(3) A, alpha = 90 deg.

Unit cell dimensions b = 20.6341 (6) A, beta = 101 .456(2) deg.

c = 23.2072(6) A, gamma = 90 deg.

4337.6(2) Α^Λ3 4337.6(2) Α^Λ3

Z 4

Density (calculated) 1 .448 Mg/m^A3

Absorption coefficient 4.364 mm^A-1

F(000) 1880

Crystal size 0.300 x 0.100 x 0.100 mm

Theta range for data collection 1 .332 to 25.386°

Index ranges -1 1 <=h<=1 1 , -24<=k<=24, -27<=l<=27 Reflections collected 99742

Independent reflections 7958 [R(int) = 0.0791 ]

Completeness to theta = 25.000° 100.0 %

Absorption correction None

Refinement method Full-matrix least-squares on F^A2

Data / restraints / parameters 7958 / 48 / 497

Goodness-of-fit on F2 1 .148 Final R indices [l>2sigma(l)] R1 = 0.0585, wR2 = 0.1599

R indices (all data) R1 = 0.0768, wR2 = 0.1675

Extinction coefficient n/a

Largest diff. peak and hole 1 .928 and -0.625 e.A"³

Table 1 1

Crystal data and structure refinement S2.

Identification code shelx

Empirical formula C27 H23 Au F6 I P

Formula weight 816.29

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Monoclinic

Space group P 21 /n

a = 7.5619(3) A, a = 90°.

Unit cell dimensions b = 14.3616(5) A, b = 95.4860(10)°.

c = 24.1 182(9) A, g = 90°

Volume 2607.26(17) A³

Z 4

Density (calculated) 2.080 Mg/m³

Absorption coefficient 6.946 mm^"1

F(000) 1544

Crystal size 0.500 x 0.500 x 0.500 mm³

Theta range for data collection 1 .652 to 25.361 °

Index ranges -9<=h<=9, -17<=k<=17, -29<=l<=29 Reflections collected 73049

Independent reflections 4778 [R(int) = 0.0341 ]

Completeness to theta = 25.000° 100.0 %

Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.745 and 0.588

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4778 / 0 / 325

Goodness-of-fit on F2 1 .130

Final R indices [l>2sigma(l)] R1 = 0.0204, wR2 = 0.0481

R indices (all data) R1 = 0.021 1 , wR2 = 0.0484

Extinction coefficient n/a

Largest diff. peak and hole 1 .471 and -0.799 e.A^"3

Table 12

Crystal data and structure refinement for S8.

Identification code shelx

Empirical formula C33 H43 Au F6 N2

Formula weight 778.66

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system, space group Orthorhombic, P b c a

Unit cell dimensions a = 15.9214(14) A alpha = 90 deg.

b = 17.6740(15) A beta = 90 deg. c = 23.278(2) A gamma = 90 deg.

Volume 6550.2(10) Α^Λ3

Z, Calculated density 8, 1 .579 Mg/m^A3

Absorption coefficient 4.550 mm^A-1

F(000) 3104

Crystal size 0.140 x 0.060 x 0.060 mm

Theta range for data collection 1 .750 to 25.384 deg.

Limiting indices -19<=h<=19, -21 <=k<=21 , -28<=l<=28

Reflections collected / unique 214909 / 6017 [R(int) = 0.0352]

Completeness to theta = 25.000 100.0 %

Absorption correction None

Refinement method Full-matrix least-squares on F^A2

Data / restraints / parameters 6017 / 6 / 379

Goodness-of-fit on F^A2 1 .157 Final R indices [l>2sigma(l)] R1 0.0345, wR2

R indices (all data) R1 0.0393, wR2

Extinction coefficient n/a

Largest diff. peak and hole 3.893 and -1 .409 e.A^A-3

[00132] While various embodiments have been described above, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of a preferred embodiment should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

IN THE CLAIMS What is claimed is:

1 . A gold type 3 (Au(lll)) complex, comprising:

Au(CF3)2LR, wherein C comprises carbon, F comprises fluoride, L comprises a solubility supporting ligand and R comprises an organic substituent.

2. The Au(lll) complex of claim 1 , wherein L comprises isopropyl (IPr) or tricyclohexylphosphine (P(Cy)3).

3. The Au(lll) complex of claim 1 , wherein the Au(lll) complex is used to prepare a positron emitting isotope.

4. The Au(lll) complex of claim 3, wherein the positron emitting isotope comprises fluoride 18 (¹⁸F).

5. A precursor formed from a gold type 3 (Au(lll)) complex, comprising:

Au(CF3)(CF2R)LX, wherein C comprises carbon, F comprises fluoride, L comprises a solubility supporting ligand, R comprises an organic substituent, and X comprises an X-type ligand.

6. The precursor of claim 5, wherein the X-type ligand comprises bromine (Br).

7. The precursor of claim 5, wherein the X-type ligand comprises Acetate (OAc).

8. The precursor of claim 5, wherein a radiochemistry procedure is applied to the precursor to generate a positron emitting isotope.

9. The precursor of claim 8, wherein the positron emitting isotope comprises fluoride 18 (¹⁸F).

10. A method, comprising:

activating a gold type 3 (Au(lll)) complex comprising Au(CF₃)₂LR, wherein C comprises carbon, F comprises fluoride, L comprises a solubility supporting ligand and R comprises an organic substituent to form a precursor comprising Au(CF3)(CF2R)LX, wherein X comprises an X-type ligand; and performing a ligand exchange on the precursor.

1 1 . The method of claim 10, further comprising:

applying a radiochemistry procedure on the precursor to produce a trifluoromethyl containing positron emission tomography (PET) tracer.

12. The method of claim 1 1 , wherein the PET tracer comprises RF3p⁸F].

13. The method of claim 10, wherein the activating is performed with MesSiBr and dicholormethane or dicholoroethane at 80 degrees Celsius.

14. The method of claim 10, wherein the performing the ligand exchange when X is bromine comprises:

replacing bromine with acetate.

15. The method of claim 14, wherein the ligand exchange is performed with AgOAc, dichloromethane, and methylhydroxide.