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Iodonium compounds play a pivotal role in 18F-fluorination of radiopharmaceuticals containing non-activated arenes. However, preparation of these species is limited to oxidation conditions or exchange with organometallics that are prepared from aryl halides. Herein we describe a novel ‘one-pot’ process to assemble aryl(isoquinoline)iodonium salts in 40-94% yields from mesoionic carbene silver complex and Aryl-I-Py2(OTf)2. The method is general, practical, and compatible with well-functionalized molecules as well as useful for the preparation of a wide range of 18F-labeled isoquinolines resulting in up to 92% radiochemical conversion. As proof of concept, a fluorinated isoquinoline alkaloid, 18F-aspergillitine is prepared in 10% isolated radiochemical yield from the corresponding phenyl(aspergillitine)iodonium salt.
Fluorine-18 (18F, t½ = 109.7 min) is the most widely used nuclide for positron emission tomography (PET). New methodologies to incorporate [18F]fluoride into a variety of unprecedented targeted molecular probes has become a major focus of academic and industrial PET research programs. Attributed to the increasing prevalence of fluorine-containing pharmaceuticals and obstacles to the access of low specific activity electrophilic [18F]F2, focused efforts have been made to design novel methods to radiolabel non-activated arenes using nucleophilic [18F]fluoride ion. Among these advances include transition metal-mediated reactions, and metal-free sulfonium & iodonium-based approaches. In particular, radiofluorination based on iodoniumylide precursors has demonstrated a wide range of compatibility in the labeling of well-functionalized molecules and radiopharmaceuticals, for instance, [18F]FPPMP,[5h] [18F]FPPMP,[5h] [18F]-5-fluorouracil,[5i] [18F]-safinamide,[5m] [18F]-meta-fluorobenzylguanidine ([18F]mFBG),[5m] [18F]fluoro-meta-tyrosine ([18F]FMT)[5m] and [18F]3-fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB),[5j] as well as application of 18F-azido arenes in bioconjugation reactions.[5k,5l] Diaryliodonium salts have also shown to be useful in the production of PET radiotracers, including [18F]TFB,[5d] [18F]flumazenil, [18F]mFBG, [18F]6-fluorodopamine,[5g,8] [18F]FPhe,[5g] [18F]DAA1106,[5g] and [18F]6-F-DOPA.[5e,9] Despite the significant role of radiofluorination using iodonium methods in the PET tracer development, the preparation of these hypervalent iodine precursors necessitates oxidation of iodoarene in acid media or exchange with organometallic species, for example stannylated/boronated compounds, which are prepared from “Miyaura borylation” type cross-coupling reactions with the corresponding aryl halides (Scheme 1a). These common procedures have potential risks of contamination, if heavy metal reagents, for example tin, is utilized or show incompatibility with oxidation conditions in the presence of sensitive functionalities, including alkene and nitrogenous compounds. Therefore there is an unmet need for a robust and efficient method to prepare iodonium precursors for radiofluorination to fully realize the translational potential of these methods in the preparation of radiopharmaceuticals for molecular imaging and personalized medicine.
Isoquinoline is often found in biological natural products and utilized as a pharmacophore in drug discovery. For instance, the natural product berberine shows therapeutic potential in treatment of cancer and diabetes, and aspergillitine, isolated from Aspergillus versicolor in marine sponge, exhibited antibacterial activity against Bacillus subtilis. Fluorine incorporation into isoquinoline has been proven to reduce in vivo metabolism, particularly as a bioisostere of hydrogen to block oxidation at C-4 (the major metabolism), and thus serves as a valuable fluorine-containing component in pharmaceutical design, for example Glanatec®.[17d] For the purpose of molecular imaging by PET, 18F-isotopologues of fluoroisoquinoline would provide a unique and non-invasive way to track in vivo behavior of labeled drug candidates and their interactions with biological targets. However, there are only limited methods for the synthesis of fluoroisoquinolines with common theme focused on the electrophilic fluorinating agents, including Selectfluor and N-fluorobenzenesulfonylimide (NFSI). Applying these approaches for radiofluorination would require an electrophilic fluorinating agent, nearly all of which are generated from gaseous [18F]F2 and only available in a few PET centers worldwide with specialized apparatus, and also associated with serious shortcomings, i.e., unselective fluorination and low specific activities. In order to obviate the need for electrophilic fluorinating reagents during 18F-fluoroisoquinoline preparation, we report a new and efficient process for synthesis of aryl(isoquinoline)iodonium salts by sequential silver-catalyzed amination of alkynes and exchange with hypervalent iodine reagents (Scheme 1b). This approach represents the first example of diaryliodonium salts prepared from mesoionic carbene-metal [(mic)M] complex (2 or 3), which eradicates the use of aryl halides in oxidation or metal halide exchange conditions. Using concomitant isoprene emission as the driving force, the ‘one-pot’ cyclization provides high yields for a wide range of aryl(isoquinoline)iodonium salts and demonstrates their usefulness in the (radio)fluorination of isoquinolines and synthesis of fluorinated natural product 18F-fluoroaspergillitine.
Our mechanistic investigations[19d] (Section 11 for plausible mechanism in supplementary information, SI) on the Ag-catalyzed amination of alkynes delineated an unusual mesoionic carbene silver [(mic)Ag] complex 3, which makes the isoquinoline C-4 position accessible after the alkyne cyclization. We found that when silver complex 3 was treated with hypervalent iodine reagent PhIPy'2(OTf)2 (Py’ = p-methoxypyridine), an unprecedented I(III) adduct appeared in near quantitative yield, which was subsequently characterized as 4a by X-ray crystallography (Scheme 2 and Section 14, SI). This serendipitous discovery inspired us to speculate that an apparent ‘umpolung’ would occur at C-4 if nucleophiles, for example fluoride ion, can be introduced to the newly formed aryl(isoquinoline)iodonium(III) species to furnish the synthesis of fluorinated isoquinoline instead of “18F” electrophiles. Therefore, we adopted this one-pot tandem protocol involving Ag-catalyzed amination of alkynes and exchange with I(III) reagent to create a new and efficient approach to prepare diaryliodonium precursors for the synthesis of [18F]fluoroisoquinolines.
Initial efforts were focused on the exploration of a concise and general protocol to assemble diaryliodonium products (Table 1). The imine 1a was readily synthesized in 90% yield via condensation reactions between the corresponding aldehyde and tert-butyl amine. Treatment of substrate 1a by catalytic amount of AgNO3 (20 mol%) at 0 °C for 20 minutes, followed by addition of PhIPy'2(OTf)2, provided product 4a in 80% yield. (entry 1). Efforts towards optimization of this one-pot method indicated that addition of Pyox ligand or base did not effectively increase the reaction yields (entries 2-3). Silver salts screening showed that AgNO3 is most effective (entries 4-6). Increase of AgNO3 loading (to 1 equiv.) improved the yield to 95% (entries 7-8). When other hypervalent iodine reagents, such as PhI(OAc)2 and PhI(OCOCF3)2, were employed, the desired product 4a was also provided, yet in 30% yield using PhI(OAc)2, and 78% yield using PhI(OCOCF3)2 (enties 9-10). When we switched PhIPy'2(OTf)2 to PhIPy2(OTf)2, the reaction could avoid contamination with an unknown impurity from AgPy' complex, and improve the yield to 98% by 19F-NMR spectroscopy. As a result, the final product 4a was obtained in 88% isolated yield (entry 11). Finally, other transition metal catalysts, such as Cu(CH3CN)4OTf, Pd(O2CCF3)2, PtCl2 and AuCl3 which are used in the cyclization of alkyl-imine 1a in the literatures,20 were also investigated. However, none of desired products 4a was detected. These observations reveal the unique reactivity of (MIC)Ag complex to hypervalent iodine reagent.
The scope and practicality of this tandem alkynyl-imine cyclization and hypervalent iodine exchange was investigated and the results are summarized in Table 2. Alkynyl-imines with a series of substituents (R) on the (hetero)aromatic ring, including electron-withdrawing fluorine, electron-donating methoxy and methyl groups, were compatible with current transformation to afford products 4a-f in good to excellent yields of 51-90%. For the substituents (R’) in the terminal alkynes, various functional groups like ester, cyclopropyl and alkenyl, were tolerated to give desired products 4g-j in 40-94% yields. Furthermore, substrates with various aryl groups in terminal alkyne showed excellent compatibility in the reaction and provided 4k-q with 60-89% yields, along with one thienopyridine salt 4r of 42% yield. It is worth noting that the reaction of 1a can be readily scaled up to gram-scale to obtain the desired phenyl(isoquinoline)iodonium salt 4a in 90% yield.
We next studied the regioselectivity of fluorination reactions on phenyl(isoquinoline) iodonium salts 4 under nonradioactive conditions. The fluorination was carried out with KF (1.1 equiv.) and 18-crown-6 (0.4 equiv.) in DMF at 100 °C for 40 min with or without Cu(OTf)2 catalyst. In the presence of copper(II) catalyst, fluorination of iodonium salt 4a predominately occurred in the phenyl group to provide fluorobenzene in 73% yield determined by 19F-NMR spectroscopy. The desired positional selectivity, i.e., fluorination at the C-4 of isoquinoline was achieved in the absence of metal catalyst and delivered the favorable fluorinated product 5a in 70% NMR yield (equation 1). These observations were consistent with prior reports,[5d, 21] and indicated the translation to radiofluorination and control of 18F-regioselectivity could be achieved from nucleophilic [18F]fluoride ion under transition metal free conditions. In addition, this method can be used to prepare non-radioactive standard compound in line with radiolabeling, and requires no ad hoc route for 19F-standard preparation.
A variety of phenyl(isoquinoline)iodonium salts were fluorinated with nucleophilic 19F or [18F]fluoride ion under transition metal free protocols (See conditions B in Table 3 and Section 7.3 in SI for optimal radiolabeling conditions). Fluorinated and radiofluorinated isoquinolines were obtained in 54-88% isolated chemical yields and 11-92% radiochemical conversions, respectively, which demonstrated the compatibility with diverse functionalities with alkyl, aryl, alkenyl, halide, cyclopropyl, and ester groups. The scope of this method was further extended to other fused pyridines. The results of fluorination (82%) and radiofluorination (77%) showed that this protocol was equally applicable to the synthesis of thienopyridine (Table 3, 5r and 6r). In particular, to verify the efficiency and practical use of this method, two radiochemical purification methods, i.e., solid phase extraction and semi-preparative HPLC, were utilized to isolate and purify [18F]fluoroisoquinolines. Compounds 6j, 6m, 6p, 6r and 6a, 6l were isolated in 51-65% yields by SPE and 40-48% yields by HPLC, respectively. The specific activity of 3-n-butyl-4-[18F]fluoro-7-fluoroisoquinoline (6a) was determined to be 1.53 Ci/μmol and is suitable for the majority of in vivo PET imaging studies, including most low density biological targets. We then studied the regioselectivity of (radio)fluorination by measuring the ratio of desired fluoroisoquinoline 5a/6a and byproduct 4-fluorobiphenyl (8a/9a) under both non-radioactive and 18F-labeling conditions. As shown in Equation 2, labeling precursor 7 was prepared from a new hypervalent reagent Ph-PhIPy2(OTf)2 in 77% yield. Both fluorination and radiofluorination demonstrated excellent and desired regioselectivity (>20:1) based on the results on iodonium salt 7.  In addtion to fluoride, other nucleophiles, such as acetate and azide, are also compatible to the nucleophilic substition of phenyl(isoquinoline)iodonium salts. The related isoquinoline derivates 10-16 were obtained in good to excellent yields (58-84%, See Section 5 in SI).
To demonstrate the utility of this method, we synthesized both fluorinated and radiofluorinated marine natural product aspergillitine by the corresponding phenyl(isoquinoline)iodonium salt derived from the tandem cyclization and iodine(III) exchange. The synthesis commenced with triflate 17,[15b] followed by Sonogashira coupling with propyne and condensation with t-butyl amine to generate alkyne 19 in two steps around 50% yield (Scheme 3). An efficient silver-mediated amination of alkyne 19 followed by rapid exchange with PhIPy2(OTf)2 furnished phenyl(aspergillitine) iodonium salt 20 in 80% yield. Fluorination using KF and 18-crown-6 gave fluoroaspergillitine (21) in 32% yield and the radiosynthes is of [18F]fluoroaspergillitine (22) was achieved in 26 ± 2% radiochemical conversions with 10 ± 1% isolated radiochemical yields (n = 3) by HPLC.
In summary, a novel method for the convenient access to [18F]isoquinolines has been developed, which is enabled by a sequential process involving a silver-mediated amination of alkynes and fluorination of phenyl(isoquinoline)-iodonium salts. The methodology has proven to apply to a broad scope of substrates and afford the desired isoquinolines and [18F]isoquinolines in satisfactory to excellent yields. As proof of concept, fluorinated natural product 18F-fluoroaspergillitine was prepared in 10% isolated radiochemical yield. The conceptual advantages of diaryliodonium salts preparation from mesoionic carbene silver intermediate, followed by iodonium exchange showcased in the simple setup and easy handling procedure, and excellent compatibility with a variety of functional groups, all of which warrant this method useful for further applications in [18F]fluoroisoquinoline and other related fluorinated heterocyclic aromatic syntheses.
We are grateful for financial support from the National Basic Research Program of China (No. 973-2015CB856600), and the National Natural Science Foundation of China (No. 21225210, 21472219 and 21532009). R.C. is supported by China Scholarship Council (201506250036). S.H.L is a recipient of NIH career development award (DA038000).
Supporting information for this article is given via a link at the end of the document.