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. Author manuscript; available in PMC: 2022 May 12.
Published in final edited form as: J Am Chem Soc. 2021 Apr 29;143(18):6915–6921. doi: 10.1021/jacs.1c00523

Sequential Ir/Cu-Mediated Method for the meta-Selective C─H Radiofluorination of (Hetero)Arenes

Jay S Wright [a],†, Liam S Sharninghausen [b],†, Sean Preshlock [a],†, Allen F Brooks [a], Melanie S Sanford [b],*, Peter J H Scott [a],*
PMCID: PMC8832069  NIHMSID: NIHMS1775312  PMID: 33914521

Abstract

This Article describes a sequential Ir/Cu-mediated process for the meta-selective C─H radiofluorination of (hetero)arene substrates. In the first step, Ir-catalyzed C(sp2)─H borylation affords (hetero)aryl pinacolboronate (BPin) esters. The intermediate organoboronates are then directly subjected to copper-mediated radiofluorination with [18F]tetrabutylammonium fluoride to afford fluorine-18 labeled (hetero)arenes in high radiochemical yield and radiochemical purity. This entire process is performed on a bench-top without Schlenk or glovebox techniques and circumvents the need to isolate (hetero)aryl boronate esters. The reaction was automated on a TracerLab FXFN module with 1,3-dimethoxybenzene and a meta-tyrosine derivative. The products, [18F]1-fluoro-3,5-dimethoxybenzene and an 18F-labeled meta-tyrosine derivative, were obtained in 37 ± 5% isolated radiochemical yield and >99% radiochemical purity and 25% isolated radiochemical yield and 99% radiochemical purity, and 0.52 Ci/μmol (19.24 GBq/μmol) molar activity (Am), respectively.

Graphical Abstract

Authors are required to submit a graphic entry for the Table of Contents (TOC) that, in conjunction with the manuscript title, should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept, or theorem, etc., that is discussed in the manuscript. Consult the journal’s Instructions for Authors for TOC graphic specifications.

graphic file with name nihms-1775312-f0001.jpg

Introduction

Positron emission tomography (PET) with 18F-labeled radiotracers is widely used for the detection, staging, and study of disease.1,2 While numerous 18F-containing molecules have been deployed in PET, those containing aromatic C─18F bonds are particularly desirable due to their resistance to metabolic defluorination. As such, there is a pressing need for synthetic methods for the late-stage radiofluorination of (hetero)arenes, particularly those that are fast (due to the short ~110 min half-life of 18F), use nucleophilic [18F]fluoride (which has high molar activity and is readily available from small medical cyclotrons), and are translatable to automated clinical production laboratories.

Most existing protocols for the nucleophilic radiofluorination of (hetero)arenes are limited in scope and/or utilize precursors that require multi-step syntheses (Scheme 1A). For instance, classical SNAr radiofluorination reactions require highly electron deficient (hetero)aryl halide/pseudohalide substrates.3 This electronic limitation has been overcome by moving to alternative mechanistic pathways and/or precursors, including those involving diazonium salts,4 triazenes,5 organo-nickel6 or -palladium complexes,7 phenols,8-10 hypervalent iodine derivatives,11-13 organoboron or stannane reagents,14-17 or sulfur-substituted aromatics.18-19 However, challenges with the synthesis, handling, isolation, scalability, and/or long-term storage of these precursors continue to limit widespread application of many of these methods in clinical settings.20-23 The Cu-mediated radiofluorination (CMRF) of organoboron precursors is a general (in terms of substrate scope) and practical (in terms of precursor availability and translation to automated syntheses) radiofluorination strategy that has been widely adopted for clinical use.24 Although many simple aryl boron reagents exhibit high bench-top stability, the purification, storage, and/or handling of highly functionalized (hetero)arylboron compounds (for example those derived from the late-stage borylation of bioactive scaffolds) as well as of 2-azaaryl and polyfluorinated aryl boron derivatives can be quite challenging.25

Scheme 1.

Scheme 1.

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(A) Radiofluorination of prefunctionalized precursors. (B) Existing C─H radiofluorination approaches. (C) C─H radiofluorination using sequential Ir/Cu mediated processes (this work).

An attractive alternative would be to directly use C(sp2)─H substrates as precursors for nucleophilic radiofluorination. The (hetero)arene substrates of these transformations are exceptionally stable and readily available. However, there are major challenges to realizing this approach, including (1) developing strategies for the rapid activation/radiofluorination of traditionally inert C(sp2)─H bonds and (2) controlling the selectivity of 18F incorporation when there are multiple C(sp2)─H sites. Several recent reports have shown the feasibility of C(sp2)─H radiofluorination in limited contexts (Scheme 1B). For instance, aminoquinoline directing groups were used to control reactivity and selectivity in ortho-selective C(sp2)─H CMRF of (hetero)arenes.26 Additionally, para-selective electrophilic aromatic substitution (EAS) on electron rich (hetero)arenes was employed for the in situ generation of hypervalent iodine precursors for CMRF.27 A related para-selective EAS reaction was leveraged to access aryl sulfonium salts, which then undergo uncatalyzed nucleophilic radiofluorination.28 Finally, an organic photoredox approach was utilized to achieve para-selective nucleophilic radiofluorination of electron rich (hetero)arenes.29 In this report, we demonstrate a sequential Ir/Cu-mediated C(sp2)─H radiofluorination with a wide substrate scope, complementary site selectivity, and high operational simplicity compared to existing methods (Scheme 1C). This transformation merges the Ir-catalyzed C(sp2)─H borylation of (hetero)arenes30,31 with Cu-mediated radiofluorination to achieve meta-selective 18F-labeling of electronically diverse (hetero)arene substrates.

Results and Discussion

Although other tandem Ir C─H borylation sequences have been reported,32 we anticipated three major challenges for combining Ir-catalyzed C(sp2)─H borylation and Cu-mediated radiofluorination of the resulting (hetero)aryl boronate esters. First, CMRF reactions are well-known to be highly sensitive to conditions (e.g., solvent, ligands, additives),33,34 thus creating potential compatibility issues with the Ir catalysis. Second, due to the sensitivity of the active Ir catalyst, the Ir-catalyzed reaction is most commonly conducted with rigorous exclusion of air and moisture, which is not feasible in standard radiochemistry labs. Third, Ir-catalyzed C(sp2)─H borylation proceeds with modest site selectivity for certain classes of substrates, which could ultimately result in mixtures of radiofluorinated products.

We first probed the anticipated compatibility issues by conducting the CMRF of 1-BPin in the presence of different components of the Ir-catalyzed C─H borylation reaction (Table 1). Under standard radiofluorination conditions (20 μmol 1-BPin, 0.25 equiv of Cu(py)4(OTf)2, [18F]tetrabutylammonium fluoride ([18F]TBAF) in DMA at 120 ºC for 20 min), 1-18F is formed in 80% radiochemical yield (RCY; entry 1), which was measured by multiplying radiochemical conversion (RCC) values obtained via radio-thin-layer chromatography (rTLC) analysis by radiochemical purity (RCP) values obtained via radio-high-performance liquid chromatography (rHPLC) analysis. However, as predicted, the addition of various C─H borylation reaction components significantly lowers the yield of 1-18F. Iridium sources containing chloride ligands (e.g., [Ir(COD)Cl]2, entry 2), are particularly problematic, likely due to competing reactions of the Cl− ion. Consistent with this proposal, the addition of 5 μmol of tetrabutylammonium chloride (TBACl, entry 6) completely shuts down the CMRF reaction. Moving to the halide-free Ir precursor [Ir(COD)OMe]2 restores the yield to ~80% (entry 3).

Table 1.

Impact of catalysts/ligands/reagents on Ir-catalyzed C─H borylation on CMRF of 1-BPin. Unless otherwise stated, RCYs are non-isolated and are calculated by multiplying RCC (measured via radio-TLC) by the RCP (measured via radio-HPLC).

graphic file with name nihms-1775312-t0007.jpg
entry [Cu]
(μmol)		 additive
(μmol)		 RCY (%)
1 5 none 80 ± 10
2 5 [Ir(COD)Cl]2 (3) 42 ± 10
3 5 [Ir(COD)OMe]2 (3) 80 ± 6
4 5 tmphen (6) 49 ± 13
5 5 dtbpy (6) 58 ± 3
6 5 TBACl (6) 0
7 20 none 92 ± 1
8 20 tmphen (6) 88 ± 3
9 20 dtbpy (6) 91 ± 3
10 20 B2Pin2 (10) 36 ± 6
11 20 HBPin (20) 43 ± 9
12 20 n-BuOH (550) 96 ± 3
13 20 B2Pin2 (10) &
n-BuOH (550)		 83 ± 5
14 20 HBPin (10) &
n-BuOH (550)		 86 ± 2
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Common ligands for Ir-catalyzed C─H borylation, 4,4’-di-tert-butylbipyridine (dtbpy) and 3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen), also impede radiofluorination (entries 4, 5). We hypothesize that these ligate the Cu and render it less reactive. To mitigate this issue, the Cu loading was increased from 5 μmol (equimolar with the added ligands) to 20 μmol (>3-fold excess relative to the dtbpy/tmphen). This change in stoichiometry restores the radiofluorination yield to >80% (entries 7-9). Finally, B2Pin2 and HBPin inhibit the radiofluorination step (entries 10, 11). We hypothesized that this could be addressed by using an alcohol additive to quench reactive boron species.35,36 Indeed, the addition of 30 equiv of n-BuOH37,38 renders the radiofluorination reaction insensitive to boron additives (entries 13, 14).39

The C─H borylation step was next evaluated using the most compatible precatalyst and ligand, [Ir(COD)OMe]2/tmphen. Initial studies focused on identifying an operationally simple bench-top procedure, since most radiochemistry laboratories lack specialized equipment for air-free reactions. These studies revealed that the ligand, catalyst, and solvent for C─H borylation can be dispensed into a vial under ambient conditions followed by a 2 min argon sparge of the resulting solution. Subsequent addition of HBPin and 1-H followed by heating at 80 °C for 16 h results in the formation of 1-BPin in 82% NMR yield and 16 : 1 meta : ortho selectivity. This is comparable to the 92% NMR yield and identical regioselectivity obtained under rigorously dry/air-free conditions.

The two steps of the sequence were next combined by adding n-BuOH to the crude C─H borylation mixture and then directly subjecting this solution to radiofluorination with Cu(py)4(OTf)2 and [18F]TBAF in DMA at 120 ºC for 20 min. As shown in Scheme 2, this sequence affords 1-18F in 88 ± 6% non-isolated RCY and 16 : 1 meta : ortho selectivity, as confirmed by rHPLC. Importantly, the RCY is based on 18F as the limiting reagent.40 This sequence was directly translated to automated radiosynthesis by loading the crude C─H borylation mixture into a TracerLab FXFN synthesis module. Under automated conditions, 1-18F is produced in 37 ± 5% isolated RCY and >99% radiochemical purity (RCP, n=3), illustrating the potential for clinical translation (Scheme 2, see SI for full details).

Scheme 2.

Scheme 2.

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Sequence for C─H radiofluorination of 1-H. See SI for complete experimental details. Non-isolated RCY is calculated by multiplying RCC (measured via radio-TLC) by the RCP (measured via radio-HPLC). Isolated RCY refers to the isolated recovery of the labeled product following semi-preparative HPLC purification.

This optimized sequence is effective for the 18F-labeling of electronically diverse 1,3-disubstituted arenes, affording 1-18F to 11-18F in RCYs ranging from 8 to 88% (Scheme 3).41,42 In these examples, the 18F-labeled product is formed with high meta-selectivity, and regioisomers could be separated and quantified using analytical or semi-preparative HPLC (see SI). The C─H borylation site-selectivity is lowest for substrates bearing relatively small cyano and fluoro substituents (9-11), as expected for the sterically-controlled C─H functionalization step.43,44 However, the isomer ratio in the 18F-labeled products is typically higher than that observed in the C─H borylation step. For instance, the Ir-catalyzed C─H borylation of 9-H proceeds ortho- and meta- to the nitrile substituent with 5 : 1 selectivity favoring the less sterically congested metaboronate. However, the radiolabeling reaction affords 9-18F in 10 : 1 selectivity favoring the same position.45 Even more strikingly, C─H borylation of methyl 3-fluorobenzoate 11 affords a 2.5 : 1 mixture of isomers ArBPin a and b (Scheme 4A); however, after radiofluorination, 11-18F is formed as a 41 : 1 mixture favoring the meta-isomer b.

Scheme 3.

Scheme 3.

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Substrate scope. See SI for complete experimental details and minor changes to the Cu mediator structure and temperature for different substrates. Unless otherwise stated, RCYs are non-isolated and are calculated by multiplying RCC (measured via radio-TLC) by the RCP (measured via radio-HPLC).

Scheme 4.

Scheme 4.

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A. Highly meta-selective CMRF preceded by non-selective C─H borylation of fluorinated 12-H. B. Highly C-6 selective CMRF of indole 16-H via BPin adduct c. Yields are non-isolated RCYs and are calculated by multiplying RCC (measured via radio-thin-layer chromatography) by the RCP (measured via radio-HPLC).

NMR studies show that the selectivity enhancement in both 9 and 11 is due to facile decomposition of the ortho-borylated intermediates under CMRF conditions. This decomposition occurs via a combination of protodeboronation and oxidation pathways (see SI for complete details).46,47 Notably, it is well documented that ortho-fluorine substituents accelerate protodeboronation in various media, supporting these conclusions.48,25a

Arenes with other substitution patterns are similarly effective substrates for this sequence. For instance, veratrole 13-H undergoes selective C─H borylation/radiofluorination to afford 13-18F in 83% RCY. The C─H borylation of 1-(2-methoxyphenyl)ethan-1-one 14-H is slow at room temperature but proceeds efficiently at 80 ºC to afford 2: 1 selectivity for the site para- to the acetyl substituent. The isomer ratio is enhanced in the CMRF step, resulting in 14-18F as a 3.4 : 1 mixture of isomers.49 Anisole 15-H undergoes C─H borylation to generate a 3.3 : 1 : trace mixture of the meta : para : ortho boronate esters. Here again, the meta-selectivity is modestly enhanced in the CMRF step (15-18F is generated in a 12 : 3 : 1 mixture). Notably, this meta-selectivity with 15-H is complementary to that obtained in C─H radiofluorination reactions involving EAS or radical cation pathways (where the para-isomer is strongly favored, Scheme 1B).27,28a,50 This protocol is also compatible with modified C─H borylation systems that override intrinsic substrate regiochemistry.51 For example, indole 16-H undergoes selective C─H borylation at C-6 through the in situ installation of a traceless BPin directing group at the N-H bond prior to the C─H borylation to form adduct c (Scheme 4B, see SI for protocol).

A final noteworthy feature of this sequence is that it does not require either (1) high conversion in the C─H borylation step or (2) the generation of isolable boronate esters. This is exemplified by the formation of product 8-18F. The Ir-catalyzed C─H borylation of 2-bromo-4-methylpyridine proceeds in low (<10%) yield as determined by 1H NMR spectroscopy. Furthermore, the intermediate 2-pyridyl-substituted boronate ester is notoriously unstable.25b,c,52 Nonetheless, this substrate was successfully functionalized in 8% RCY, thereby circumventing the need to synthesize, isolate, and store the boronate ester precursor.53

The ability to directly and selectively convert bioactive molecules into radiofluorinated analogues offers opportunities to streamline 18F-radiotracer synthesis and development. As such, it is critical to evaluate this method in the context of such scaffolds (Scheme 5). Under the standard C─H borylation/CMRF conditions, the anesthetic lidocaine reacts to furnish 17-18F in 15 ± 8% RCY. Notably, this radiolabeling approach is complementary to Hooker’s synthesis of the 18F-fluoroethyl analogue [18F]radiocaine.54

Scheme 5.

Scheme 5.

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Tandem C─H radiofluorination of pharmaceutically relevant scaffolds. See SI for complete experimental details and minor changes to the Cu mediator and temperature for different substrates. Unless otherwise stated, RCYs are non-isolated and are calculated by multiplying RCC (measured via radio-thin-layer chromatography) by the RCP (measured via radio-HPLC). Isolated RCY refers to the isolated recovery of the labeled product following semi-preparative HPLC purification.

Protected aromatic amino acid derivatives undergo high yielding radiofluorination to afford products such as 18-18F and 19-18F. These have potential applications for imaging dopaminergic metabolism and tumor proliferation.55 Automated labeling was followed by semi-preparative HPLC purification to afford 18-18F in 25% isolated RCY, 99% RCP, and 0.52 Ci/μmol (19.24 GBq/μmol) Am (n=2). ICP-MS analysis of 18-18F obtained from this procedure indicated an Ir content of 13.46 ng, which is below the exposure limits (e.g. parenteral = 10 μg/day) stipulated for human use.56 This analysis further emphasizes the suitability of this radiolabeling method for use in conjunction with human PET imaging studies. Furthermore, manual labeling of 19-H to afford phenylalanine derivatives was achieved following acidic deprotection in HCl, and the meta- and para-regiosomers were separated using analytical rHPLC.57 Over the C─H radiofluorination protocol and the subsequent deprotection 19-18F was obtained in >99% ee as determined via chiral HPLC analysis.

This method is also effective for the meta-selective radiofluorination of a protected guanidine. Deprotection of the crude product with trifluoroacetic acid delivered 20-18F. Notably, previous access to related imaging agents required the multi-step synthesis of iodonium precursors.58 Finally, the densely functionalized cannabinoid receptor 2 partial agonist GW405833 undergoes C─H radiofluorination to afford 21-18F in 60 ± 3% RCY. Multiple attempts to chromatographically isolate the boronate ester intermediate of this transformation led to the recovery of protodeboronated GW405833 substrate. Our approach enables high-yielding radiofluorination by circumventing the requirement to isolate/store this boronate. Once again, the incorporation of 18F onto the aromatic ring complements existing radiolabeling strategies for this molecule, which involve the multi-step installation of a [18F]fluoroethyl group.59 Overall, these examples highlight the broad functional group compatibility of the method, including tolerance of esters, amines, indoles, amides, and protected guanidines.

Conclusions

In summary, this report describes the development of a method for the meta-selective borylation/CMRF of aromatic C─H bonds. This approach enables the rapid and selective 18F-labeling of lead compounds for the development of imaging agents. Execution of the tandem procedure is operationally simple and readily translated to automated synthesis on a TracerLab FXFN module. As such, we anticipate that it can be adopted for both exploratory and clinical radiosyntheses of 18F PET imaging agents.

Supplementary Material

Supplementary Information

ACKNOWLEDGMENT

This work was supported by the NIH [Award Number R01EB021155 (J.S.W., M.S.S. and P.J.H.S.) and Award Number F32GM136022 (L.S.S.)]. Our gratitude is extended to Angela Dial (University of Michigan Earth and Environmental Science Department) for performing ICP-MS analysis.

Footnotes

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.
  • Materials and methods; preparation of precursors and reference standards; radiofluorination details; screening information; NMR spectra; HPLC traces.

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