Recent Progress in Metal Catalyzed Direct Carboxylation of Aryl Halides and Pseudo Halides Employing CO₂: Opportunities for ¹¹C Radiochemistry

Abstract

Carbon dioxide (CO2) as a synthon in organic transformations is very useful, especially when combined with transition metal catalysts. CO2 insertion on carbon(Aryl)‐metal is are an elegant route to construct carbon–carbon bonds. A limited number of reports have been published to date on the direct conversion of aryl halides (or pseudo halides) to aryl carboxylic acids using transition metal catalysts. These reactions place great demand on the choice of catalyst, starting material, and reducing agent. However, these approaches could be of interest for the synthesis of a wide range of biologically active small molecules. Such transformations have already been applied for the synthesis of radiolabeled compounds for imaging with positron emission tomography (PET) using cyclotron produced [11C]CO2 and may be applicable to the production of a diverse range of PET tracers.

Copper(I)-Mediated 11C-Carboxylation of (Hetero)arylstannanes

“…Novel transition-metal-catalyzed carboxylation reactions with CO 2 in organic synthesis have been extensively applied for large-scale industrial applications 1,2 as well as for accessing isotopically labeled carboxylic acids from [ 13 C]CO 2 or [ 14 C]CO 2 . 3,4 [ 11 C]CO 2 is a cyclotron-generated building block produced by the proton bombardment of nitrogen gas ( 14 N(p,α) 11 C; t 1/2 = 20.3 min) in the presence of trace oxygen.…”

Ni-Catalyzed Direct Carboxylation of an Unactivated C–H Bond with CO2

“…Despite its significant kinetic inertness and thermodynamic stability, CO 2 is an abundant, nontoxic, inexpensive, and renewable C1 feedstock in synthetic chemistry . The conversion of CO 2 into fine chemicals has attracted considerable attention, especially the formation of carboxylic acids, , which are building blocks in many valuable synthetic compounds …”

“…As an abundant and cheap first-row transition metal, nickel has been extensively studied in homogeneous catalysis because of its distinguishing characteristics . Ni-catalyzed reductive carboxylation of organic (pseudo)­halides with CO 2 is one of the most well-established strategies. , The Ni(0)–Ni­(II)–Ni­(I) catalytic cycle was suggested for these reactions, and CO 2 was inserted into the more nucleophilic C–Ni­(I) bond. Very recently, Murakami reported the carboxylation of benzylic and aliphatic C–H bonds with CO 2 induced by light, ketone, and nickel (Scheme b).…”

[Carboxyl‐11C]Labelling of Four High‐Affinity cPLA2α Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography

“…Because of extensivei onizationa tp hysiological pH, [ 11 C]carboxylic acids (pK a % 4) do not generally crosst he blood-brain barrier (BBB), but some, such as [ 11 C]arachidonic acid (clogD,4 .89) do enter brain, even if only to al imited extent. [17,23,24] In this study,t he carboxyl group also provided ag eneric site for labellingw ith carbon-11( t 1/2 = 20.4 min). Here, we describe the labellingo f 1-4 in their carboxyl groups, for preliminarye valuation as PET radioligands for cPLA2a in mice.…”

“…Thus, “first‐generation” radioligands for cPLA2α are likely to contain a carboxyl group. Because of extensive ionization at physiological pH, [ 11 C]carboxylic acids (p K a ≈4) do not generally cross the blood–brain barrier (BBB), but some, such as [ 11 C]arachidonic acid (clog D , 4.89) do enter brain, even if only to a limited extent . In this study, the carboxyl group also provided a generic site for labelling with carbon‐11 ( t 1/2 =20.4 min).…”