Transition-metal-free reductive coupling of an 18F-labeled nitro-arene with boronic acids as a potential access to 18F-labeled fenamates

Objectives

A recently developed synthetic route for the transition metal-free reductive coupling of aryl boronic acids with nitro1 or nitroso2 substituted arenes gives access to a variety of diaryl amines like fenamates.3 Radiotracers targeting COX-2 have been developed and tested as PET tracer but no clinically approved radiotracer emerged up to now. Aim of this project is to evaluate this novel synthetic route as a general access to 18F-labeled N,N-diaryl amines which are principally not activated for 18F-labeling by nucleophilic aromatic substitution, and by that access to fenamates like flufenamic acid as COX-targeting radiotracers in a wider sense. In this report, we present first results with focus on radiolabeling and reactivity of an asymmetric 18F-labeled nitro-arene.

Methods

The asymmetric sydnone-substituted nitroarene was radiolabeled under optimized conditions with fluorine-18 using K222/K2CO3 in DMF at 90°C and was purified by a C18-based solid phase extraction (SPE). Elution from the dried C18 SPE-cartridge with ortho-dichlorobenzene over a SEP-Pak Dry cartridge provided the intermediate [18F]A for further testing and optimization of the reductive coupling step. Subsequent radiochemical conversion of [18F]A with different boronic acids was monitored via radio-UHPLC. 3-Cyanophenyl boronic acid was used to optimize the coupling reaction with [18F]A with respect to the parameters base/reducing agent, temperature, reaction time. Furthermore, [18F]A was subjected to the reaction with other ortho-, meta-, and para-substituted boronic acids to get a first impression about the scope of this reaction.

Results

[18F]A was isolated after radiolabeling and purification by SPE in 16-54% isolated RCY (n=4). Optimizations using aliquots of 50 µL allowed for optimization of several reaction conditions with one batch of [18F]A. Triphenylphosphine but not triethylphosphite was found to mediate the reductive coupling of 3-cyanophenylboronic acid at reaction temperatures of 140°C and 170°C. Compared to 170°C, radiochemical conversion of [18F]A was found to be slightly higher at 180°C. A clear rationale for the amount of boronic acid and PPh3 was not found since both ratios of 5.4 to 2.5 as well as 2.4 to 4.2 gave highest RCC at 180°C. [18F]A was found to react with a variety of different boronic acids, although proof of identity for the reaction products to the respective diarylamines has still to be performed. In general, however, reaction kinetics were found to be slow leading to radiochemical conversions above 80% only after a reaction time of 80 min which represents a main limitation for radiochemical reactions using fluorine-18.

Conclusion

18F-labeling of N,N-diarylamines represents a challenge for classical nucleophilic aromatic substitution approaches. The use of an 18F-labeled nitroarene and a transition-metal free reductive coupling methodology gave access to this type of compounds but slow reaction kinetics likely hinders the general use in 18F-chemistry. Hence, the evaluation of a respective nitrosoarene is currently under the way representing a highly attractive alternative in this regard due to the much faster reaction kinetics.

References

1. a) Nykaza, J.Am.Chem.Soc. 2020, 142, 6786. b) Roscales, Adv.Synth.Catal. 2020, 362, 111.

2. Roscales, Org.Lett. 2018, 20, 1667; 3. Roscales, J.Chem.Educ. 2019, 96, 1738.

Figure 1. Radiosynthesis of flufenamic acid derivates by transition metal-free reductive coupling with [18F]A