Effect of Added Cu ( OTf ) 2 on the Cu ( OTf ) 2 ( Py ) 4-Mediated Radiofluorination of Benzoyl and Phthaloylglycinates

Cu(OTf)2(Py)4 mediated radiofluorination of the boronate esters of ethyl benzoyl and phthaloylglycinates (11 and 16) using 10 mol% of the copper complex following the literature procedure did not provide the fluorinated products. However, the addition of Cu(OTf)2 resulted in the radio-fluorination of the boronate esters 11 and 16 to obtain ethyl 4-[F]fluorobenzoyl glycinate, 17, (48%) and ethyl 3-[F]phthaloylglycinate (41%) respectively.


INTRODUCTION
Positron Emission Tomography (PET) and its related hybrid technologies such as PET/CT and PET/MR are non-invasive imaging modalities that provide in vivo physicochemical, pharmaco-kinetic information, measurement and quantification of biochemical processes [1][2][3][4].The unique sensitivities of these techniques allow the detection of cellular changes during disease progression.PET imaging provides quantitative bio-distribution data of molecular probes.Positron annihilation by electron releases two antiparallel γ-photons that are detected simultaneously by γ-cameras and used to construct the PET images.Currently PET is used clinically to detect cancers [5,6], cardiovascular diseases, and neurological disorders [7].Also PET has become an important tool in drug discovery and development [8].Of several short lived β + -emitting (positron) nuclides available, the most attractive is fluorine-18 because of its low energy, moderate half-life (109.6 min), and its easy availability in "no-carrier-added" form.During the past decade, various transition-metal-mediated [9][10][11][12] (Ag, Pd, Ni, Cu) fluorination methods have been transferred to radiochemistry.Among these, Cu-promoted [13][14][15][16] fluorination methods are the most versatile (Cu is less toxic compared to Pd and Ni) for preparing 18 F-fluorinated aromatics and hetero aromatics (Figure 1).

MATERIALS AND METHODS
All reagents and solvents were purchased from Acros or Aldrich and were used as received.
Similarly boronate ester 1 can form the glycinate complex 7 by replacing two pyridines of the pyridine copper complex Cu(OTf) 2 (Py) 4 .As the pyridine copper complex is consumed to form glycinate complex 7, there is no copper available to mediate the fluorodeboronation resulting in no product formation.Scheme 1. Attempted radio-fluorination of piracetam analogue.Natural Science Table 1.Radiofluorination of 11 and 16 (0.06 mmol) with 10 mol% of Cu(OTf) 2 (Py) 4 and the effect of variable amounts of Cu(OTf) 2 on radiochemical yields.a : reaction conditions using the procedure reported in the literature [15].The yields were obtained by radio-TLC using Bioscan.The identity of products was determined by comparing with the R f values of the standards.

No
Cu(OTf) 2 mol% Solvent Compound 17% RCY Compound 18% RCY In order to further test this observation, we attempted to fluorinate easily accessible benzoylglycinate and phthaloylglycinate boronate esters 11 and 16 using 10 mol% ofCu(OTf) 2 (Py) 4 As expected, both the reactions failed.However by adding Cu(OTf) 2 to the reaction mixture, we observed product formation.This prompted us to systematically study the effect of added Cu(OTf) 2 ; the results are presented in Table 1   The radiofluorination of the boronate esters 11 and 16 was performed with 10 mol% of complex Cu(OTf) 2 (Py) 4 (Scheme 3) and the effect of different mol equivalents of Cu(OTf) 2 was studied.The radiolabeling of the boronate esters was carried out in the Advion NanoTek Microfludic Synthesizer.Using the drying macros of NanoTek LF 1.4 software, a complex of kryptofix 222/K 2 CO 3 /[ 18 F]fluoride was thoroughly dried and allowed to react with the boronate esters 11 and 16 in the presence of Cu(OTf) 2 (Py) 4 and Cu(OTf) 2 in DMF at 110˚C for 20 min to obtain fluorinated compounds 17 and 18 respectively.The yields for the compounds 17 and 18 were maximized using one mole equivalent of Cu(OTf) 2 in 1 mL of DMF as shown in Table 1 and Figure 3.
Following the reaction conditions from the literature [15] using 10 mol% of Cu(OTf) 2 (Py) 4 and 0.4 ml of dimethyl formamide, no fluorination products were obtained.Fluorinated products 17 and 18 were prepared using diluted reaction mixture in 1 mL (2.5 times more diluted than literature method)) of dimethyl formamide and varying amounts of copper triflate.The highest radiochemical yields for 17 (48%) and 18 (41%) were obtained with 100 mol% of copper triflate.Radiofluorination of the boronate ester 1 resulted in relatively lower yields (20% ± 5%) of [ 18 F]fluorophenyl piracetam 2. Further studies to improve reaction yields are underway.

Figure 2 .
Figure 2. Copper complexes of compounds with glycinate motif.