C–H ¹⁸F-Fluorination of 8-Methylquinolines with Ag[¹⁸F]F

Abstract

This report describes a Pd-mediated C-H radiofluorination of 8-methylquinoline derivatives with no-carrier-added Ag[¹⁸F]F. To achieve this transformation, a new method was developed for the generation of Ag[¹⁸F]F using a sep-pak cartridge. The C–H radiofluorination was then optimized and applied to a series of substituted 8-methylquinoline derivatives. Finally, this method was fully automated using a radiochemistry synthesis module.

Positron emission tomography (PET) is a functional imaging technique that is used for clinical diagnostic imaging as well as for research applications in both healthcare and the pharmaceutical industry.^1,2 Fluorine-18 (¹⁸F) is one of the most commonly used PET radionuclides, mainly due to its useful half-life (110 min) and exceptional imaging properties. As such, new synthetic methods that enable the late-stage formation of a C–¹⁸F bond are of great interest to the field of radiochemistry.³

Incorporation of ¹⁸F at an sp³ carbon is one of the most widely used labelling strategies. This is typically achieved via nucleophilic displacement of an appropriate leaving group with [¹⁸F]fluoride (Figure 1a).⁴ Indeed, the production of 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) by the reaction of mannose triflate with K[¹⁸F]F is one of the most widely used labelling reactions in PET radiochemistry.⁵ However, this approach often necessitates complex multi-step syntheses of labelling precursors before any radiochemistry development can be undertaken. This is time consuming and not ideal for synthesizing libraries of radiotracers for screening purposes.

Fig 1.

Approaches to benzylic radiofluorination

The direct conversion of carbon–hydrogen bonds to carbon–¹⁸F bonds would provide more straightforward and atom economical access to radiotracers containing C(sp³)–¹⁸F bonds.⁶ To date, methods for the direct conversion of C(sp³)–H bonds to C–¹⁸F bonds using high molar activity nucleophilic ¹⁸F^- remain extremely limited. Recent seminal work by Hooker and Groves demonstrated proof-of-concept through Mn-mediated benzylic C-H fluorination using [¹⁸F]fluoride (Figure 1b).⁷ However, new, complementary methods are needed in order to realize the full potential of this approach.

In 2012, the Sanford group reported the C(sp³)–H fluorination of 8-methylquinoline derivatives using Pd-based catalysts and AgF as a fluoride source (Figure 1c).⁸ In this Communication we report the adaptation of this transformation for use with [¹⁸F]fluoride. As detailed below, the translation to radiofluorination required the development of a new method for the preparation of Ag[¹⁸F]F as well as significant reaction optimization. Ultimately, these studies delivered a robust and automatable process for the radiofluorination of 8-methylquinoline substrates.⁹

Our initial studies examined the radiofluorination of 8-methylquinoline (1H) using K[¹⁸F]F•kryptofix®2.2.2 (K[¹⁸F]F •K_2.2.2), the most readily available source of ¹⁸F. These reactions were conducted using conditions otherwise analogous to those for the ¹⁹F-fluorination (10 mol % of Pd(OAc)₂, 2 equiv of PhI(OPiv)₂ in dichloromethane). As shown in eq. 1, none of the ¹⁸F-labeled product 1¹⁸F was detected by radio-TLC or radio-HPLC under these conditions. One possible explanation for this result is the change in stoichiometry of fluoride (from 5 equiv relative to 1H in the ¹⁹F-fluorination to ≤0.0002 equiv relative to 1H in the ¹⁸F-fluorination). To test for this possibility, we next conducted the radiofluorination in the presence of 5 equiv of carrier KF. However, product 1¹⁸F was still not detected under these conditions (eq. 1).

(1)

On the basis of these preliminary results, we concluded that the counterion associated with fluoride (Ag⁺ in the case of the successful ¹⁹F-fluorination reactions) was likely critical for this transformation. As such, we next sought a straightforward, automatable method for accessing Ag[¹⁸F]F. Notably, Ag[¹⁸F]F has been reported in the [¹⁸F]fluorine literature,¹⁰ but its preparation typically required specialized equipment (e.g. custom cyclotron targets,^10a platinum reaction vessels^10e) or insoluble silver sources (Ag₂O,^10b,d,f silver wool^10c) that are not readily adaptable to modern automated radiosynthesis modules.

We reasoned that Ag[¹⁸F]F could be prepared by the elution of [¹⁸F]fluoride from a quarternary methyl ammonium (QMA) ion exchange cartridge using an aqueous solution of a Ag⁺ salt (Table 1 and Supporting Information). Notably, an analogous procedure (involving elution with aqueous K₂CO₃) is routinely used to produce K[¹⁸F]F (Table 1, entry 1). Furthermore, we have recently reported that solutions of other eluents (e.g., copper salts, bases) are effective for eluting [¹⁸F]fluoride from QMA cartridges.¹¹ Initial attempts to use Ag₂CO₃ as an eluent afforded no [¹⁸F]fluoride recovery (Table 1, entry 2), likely due to the poor water solubility of Ag₂CO₃. Consistent with this explanation, the use of more water-soluble AgOTf led to near quantitative recovery of Ag[¹⁸F]F (Table 1, entry 3). The use of aqueous solutions of silver salts does require an azeotropic drying step; however, attempts to elute with silver salts formulated in MeCN were unsuccessful (Table 1, entry 4). Even when using water soluble silver salts, heterogeneous mixtures were obtained following elution. This heterogeneity is likely due to the formation and co-elution of insoluble AgHCO₃ due to standard QMA preconditioning with NaHCO₃.^‡ This issue was addressed by changing the pre-conditioning reagent. For operational simplicity, we pre-conditioned with KOTf and then used AgOTf for elution (Table 1, entry 5). ^§,∥

Table 1.

Elution Strategies for Generation of Ag[¹⁸F]F

Entry	Precond. Salta	QMA Eluentb (MX)	Recovery of M[18F]F (%)
1	NaHCO3	K2CO3	97
2	NaHCO3	Ag2CO3	0
3	NaHCO3	AgOTf	98
4	NaHCO3	AgOTf	0c
5	KOTf	AgOTf	94

^aQMA was flushed with 10 mL of 0.5 M aq. solution;

^bQMA was eluted with 0.5 mL of 0.05 M aq. solution;

^cQMA eluent was dissolved in MeCN.

With a reliable and straightforward route to Ag[¹⁸F]F in hand, we next revisited the C–H radiofluorination of 1H. As shown in Table 2, the use of Ag[¹⁸F]F in combination with K_2.2.2 afforded 1¹⁸F in 3 ± 1% RCC (entry 1, n = 2). Pre-stirring PhI(OPiv)₂ and Ag[¹⁸F]F in CH₂Cl₂ prior to the addition of Pd/substrate resulted in an enhanced RCC of 8 ± 2% (entry 2, n = 2). As such, this pre-stirring step was included in all subsequent experiments. A series of I^III oxidants was next evaluated, and PhI(OAc)₂ was found to afford slightly higher RCC than PhI(OPiv)₂ (11% versus 8%, entries 2 and 3). The need for a high reaction temperature (145 ^oC) in conjunction with CH₂Cl₂ (bp = 40 ^oC) as the reaction solvent was unexpected. However, the use of higher boiling solvents (e.g., C₂H₄Br₂ or CH₂Br₂/CH₂Cl₂ mixtures) led to no improvement in RCC (entry 4 and Supporting Information). Changing the catalyst from Pd(OAc)₂ to Pd₂(dba)₃ resulted in an improvement to 18 ± 2% RCC (entry 4, n = 2). Tripling the amount of precursor (to 0.042 mmol) while retaining the stoichiometry of the other reactants and reagents resulted in a further increase to 21 ± 5% (n = 7) RCC of 1¹⁸F (entry 6). Notably, an even higher RCC (51 ± 10%, n = 2) was obtained upon the addition of 5 equiv of carrier AgF under otherwise analogous conditions (entry 7).^¶

Table 2.

Radiofluorination Optimization Studies^a

Entry	[Pd]	Oxidant	RCY (%)#
1	Pd(OAc)2	PhI(OPiv)2	3±1 (n=2)
2	Pd(OAc)2	PhI(OPiv)2	8±2b (n=2)
3	Pd(OAc)2	PhI(OAc)2	11±2b (n=2)
4	Pd(OAc)2	PhI(OAc)2	13±1b,c (n=2)
5	Pd2(dba)3	PhI(OAc)2	18±2b(n=2)
6	Pd2(dba)3	PhI(OAc)2	21±5b,d (n=7)
7	Pd2(dba)3	PhI(OAc)2	51±10 (n = 2)b,e

^aGeneral conditions: aliquots of a prestirred stock solution containing Ag[¹⁸F]F (92.5–129.5 MBq) and oxidant (2 equiv) in CH₂Cl₂ (200 μL) were added to vials containing substrate (0.014 mmol) and [Pd] (10 mol %) in CH₂Cl₂ (550 μL);

^breaction included pre-stirring step;

^cC₂H₄Br₂:CH₂Cl₂ [2:1] used as reaction solvent;

^d3-fold scale up of substrate (0.042 mmol) while retaining stoichiometry of other reactants/reagents;

^e5 equiv. AgF added to reaction.

The no-carrier-added radiofluorination conditions were next applied to a series of 8-methylquinoline derivatives (2H-10H, Table 3). The method is compatible with a range of functional groups that is comparable to those used in the ¹⁹F reaction. For instance, C–H radiofluorination proceeds with 8-methylquinoline derivatives bearing electron-withdrawing (2-4) and electron-neutral (5-9) substituents. Ketone (2) and halogen (4–6) substituents on the quinoline core proved compatible, offering the potential for downstream chemistry to be conducted after radiolabeling.¹² In contrast, no product was observed for a substrate bearing the electron donating methoxy substituent (10), consistent with the constraints reported for the original ¹⁹F-fluorination reaction.

Table 3.

Substrate Scope

Entry	R (#)	RCY (%)#
1	H (118F)	21 ± 5 (n=7)
2	Ac (218F)	13 ± 3 (n=5)
3	CN (318F)	20 ± 5 (n=4)
4	F (418F)	16 ± 2 (n=7)
5	I (518F)	14 ± 1 (n=4)
6	Br (618F)	12 ± 3 (n=5)
7	Cl (718F)	11 ± 2 (n=4)
8	Me (818F)	15 ± 2 (n=5)
9	Ph (918F)	14 ± 2 (n=5)
10	MeO (1018F)	0 (n=7)

^aGeneral conditions: aliquots of a prestirred stock solution containing Ag[¹⁸F]F (92.5–129.5 MBq) and PhI(OAc)₂ (2 equiv) in CH₂Cl₂ (200 μL) were added to vials containing substrate (0.042 mmol) and Pd₂(dba)₃ (10 mol %) in CH₂Cl₂ (550 μL). Reactions were heated at 145 ^oC for 30 min, RCC was determined by radio-TLC.

Finally, we automated the synthesis of 1¹⁸F using ~55.5 GBq of [¹⁸F]fluoride in a GE TRACERlab FX_FN synthesis module (Scheme 2). The prestirring/heating of the mixture of Ag[¹⁸F]F•K_2.2.2 and PhI(OAc)₂ in the reactor was followed by the addition of Pd catalyst and substrate (1H). Under these automated conditions, 1¹⁸F was formed in 4 ± 1% RCY,^# 39 ± 15 GBq/mmol molar activity and an estimated activity yield (AY) of 1.1 ± 0.5 GBq (n = 2). We note that the automated radiochemical yield provides enough product for preclinical studies, but will require further optimization before this method can be applied in routine radiosyntheses. However, overall this operationally simple procedure demonstrates proof-of-concept that this Pd-mediated C-H radiofluorination is feasible, and that the method could ultimately be applicable to the late-stage radiofluorination of bioactive molecules.

Scheme 2.

Automated Synthesis of 1¹⁸F^#

In conclusion, this paper reports a new method for generating no-carrier-added Ag[¹⁸F]F by using soluble silver salts to elute [¹⁸F]fluoride from a QMA cartridge. This Ag[¹⁸F]F was then applied to the Pd-catalyzed C–H radiofluorination of 8-methylquinoline derivatives. The chemistry was optimized for and applied to the radiolabeling of a series of 8-methylquinoline derivatives, providing moderate RCCs and high molar activity. Ongoing work is focused on leveraging now readily accessible Ag[¹⁸F]F to achieve a variety of other radiofluorination reactions.¹³