Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

Abstract

Carbazole/cyanobenzene photocatalysts promote the direct isotopic carboxylate exchange of C(sp 3 )-acids with labelled CO2. Substrates that are not compatible with transition metal catalyzed degradation-reconstruction approaches or prone to thermally induced reversible decarboxylation undergo isotopic incorporation at room temperature in short reaction times. The radiolabelling of drug molecules and precursors with [ 11 C]CO2 is demonstrated.The synthesis of isotopically labelled molecules is essential to drug development and nuclear medicine. As drug candidates move towards clinical research and human trials, absorption, distribution, metabolism, and excretion (ADME) studies require compounds enriched with long-lived radioisotopes like 3 H and 14 C. 1 Positron emission tomography (PET) techniques that probe the advance of disease states and can determine the efficacy of drug treatment require molecular targets radiolabelled with short-lived positron-emitting isotopes such as 11 C or 18 F. 2 The limited availability and high cost of isotopically enriched precursors make the preparation of complex targets challenging. For PET studies, compounds must be synthesized and purified within a few half-lives of the radiolabel ( 11 C t1/2 = 20.3 minutes). Approaches that selectively introduce isotopic labels from feedstock sources with compatibility towards common structural motifs found in clinical candidates will have a positive impact on both drug discovery efforts and medical imaging.Metal-catalyzed 1 H/ 3 H exchange is widely used in drug development to introduce long-lived radiolabels into target molecules. [3][4][5][6][7][8][9] The loss of 3 H labels through (bio)chemical reactions and metabolic shifting due to primary kinetic isotope effects are liabilities of 3 H-labelling approachs. 10-11 ADME tracer compounds with greater stability can be obtained by using 14 C radiolabels. 12 Similarly, 11 C-isotopologues of native bioactive molecules enable PET probe generation without changes to their biological or pharmacological properties. 13 The incorporation of 14 C, 13 C or 11 C (*C) units into drug molecules or precursors by the formation of a *C-C bond is challenging and often requires revised synthetic pathways to introduce the label from *CO, 14-18 *CH3I, [19][20] or other small molecules derived by reduction of *CO2. [21][22][23][24][25] The direct exchange of carboxylate groups with CO2 offers the potential for simple and cost-effective syntheses of C-labelled small molecules, particularly as CO2 (or BaCO3) is the feedstock for all radiolabelled carbon-based precursors. 26 The easy conversion of carboxylic acids into other common functionalities (esters, amides, ketones, alcohols) makes this an attractive tactic for isotope incorporation.The use of redox active hydroxyphthalimide ester substrates in combination with Ni-based mediators and stoichiometric metal reductants enables carboxylate groups to undergo net exchange with CO2 (Fig 1A ). [27][28] These reactions are limited to primary alkyl or cyclic secondary a...

Electrochemical Activation of Diverse Conventional Photoredox Catalysts Induces Potent Photoreductant Activity**

“…These data are consistent with turnover limiting photoreduction of 30 and minimal catalyst decomposition or product inhibition (see SI for details). As with NpMI , addition of 31 excluded product inhibition and suggests 4‐DPAIPN decomposition occurs [99–102] but is attenuated relative to NpMI . These data indicate that the improved performance of 4‐DPAIPN can be attributed to it forming a more robust electron‐primed photoredox catalyst.…”

Acridinium Salts and Cyanoarenes as Powerful Photocatalysts: Opportunities in Organic Synthesis

“…[44] Very recently,t he group of Rotstein and Lundgren reported an ew method for direct isotopic carboxylate exchange by using cyanoarene catalyst PC10. [45] It turns out that an alkylative decyanation of PC10 by phenylacetic acid takes place in situ to yield the more-active catalyst PC18.The authors demonstrated that the exchange process takes place under an atmospheric pressure of 13 CO 2 .T he labeling of primary,s econdary,a sw ell as tertiary carboxylic acid derivatives occur under mild reaction conditions.I nterestingly,t he substrate contains aw ide variety of complex functional groups of high interest. More interestingly,t he concept was extended to 11 C-labeling with 11 CO 2 under catalytic conditions of PC18,w hich actually constitutes abreakthrough in radiolabeling applications (Scheme 31).…”

Electrochemical Activation of Diverse Conventional Photoredox Catalysts Induces Potent Photoreductant Activity**

“…Forschungsartikel rapid deactivation of NpMI under these conditions.I ns tark contrast, an analogous "same excess" experiment with 4-DPAIPN resulted in clean first order reaction profiles that nearly overlay.T hese data are consistent with turnover limiting photoreduction of 30 and minimal catalyst decomposition or product inhibition (see SI for details). As with NpMI,a ddition of 31 excluded product inhibition and suggests 4-DPAIPN decomposition occurs [99][100][101][102] but is attenuated relative to NpMI.T hese data indicate that the improved performance of 4-DPAIPN can be attributed to it forming am ore robust electron-primed photoredox catalyst. Indeed, the initial rate of dehalogenation promoted by NpMI is faster than 4-DPAIPN but rapid decomposition of this catalyst renders it ineffective for more challenging substrates that are slower to fragment following reduction.…”