13 research outputs found
Transition Metal-Catalyzed Fluorination/ [18]fluorination and Decarbonylative Carbon Heteroatom Bond Formation
The development of novel methods to incorporate fluorine and fluoroalkyl groups into
organic molecules is highly desirable, as these substituents can impart unique stability,
reactivity and biological properties. Over the past decade, tremendous efforts have
been expended to develop transition metal-catalyzed aromatic fluorination
methodologies. Nevertheless, carbonâfluorine bond formation remains challenging,
especially in the context of general, functional group-tolerant late-stage fluorinations of
arenes. Ultimately, gaining direct accessibility to highly functionalized and complex
fluorinated pharmaceutical and radiopharmaceutical precursors is a central objective of
this field.
Chapter 1 describes the key challenges in the field CâF bond formation key
considerations in industry, as well as the relevant history and precedent for the work
detailed herein.
Chapter 2 begins with our initial development of the copper-catalyzed fluorination
of unsymmetrical diaryliodonium salts with KF. This transformation proceeds with high
chemoselectivity and yields. Detailed computational and experimental mechanistic
analyses established the key role of the solvent in catalysis and rationalized the
chemoselectivity in Cu-catalyzed reactions of unsymmetrical iodonium salts.
Chapter 3 describes detailed efforts into the translation of the Cu-catalyzed
fluorination of diaryliodonium salts to radiofluorination. The fluorine-18 radionuclide is
the most widely utilized for in vivo imaging by positron emission tomography. However,
the lack of rapid, practical radiofluorination methods hinders newly developed
radiotracers entering into clinic. We have identified conditions that rapidly incorporate
fluorine-18 into electron-rich arenes in 20 minutes under mild conditions. Importantly
this chemistry can be further applied to synthesize clinically important radiotracers.
Chapter 4 details the exploration of the Cu-mediated radiofluorination of aryl
boronates and aryl halides. Extensive studies on developing a new elution method
allowed operationally simple, highly reproducible means to make anhydrous fluoride-18
effective for Cu catalysis.
Chapter 5 investigates a novel Pa-catalyzed decarbonylative fluorintion method
to incorporate a carbon-fluorine bond. The protocol aims to utilize aroyl fluorides as both
the fluorine and arene source that oxidatively adds to metals in a single step, thereby
minimizing the complexity and waste in this step of the synthesis. This work was further
extended to form various carbon-heteroatom bonds, starting from acid chlorides in one
pot.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/133480/1/naokoi_1.pd
Automated synthesis of PET radiotracers by copperĂą mediated 18FĂą fluorination of organoborons: Importance of the order of addition and competing protodeborylation
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142980/1/jlcr3583_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142980/2/jlcr3583.pd
Pd-Catalyzed Decarbonylative Cross-Couplings of Aroyl Chlorides
This report describes a method for
Pd-catalyzed decarbonylative
cross-coupling that enables the conversion of carboxylic acid derivatives
to biaryls, aryl amines, aryl ethers, aryl sulfides, aryl boronate
esters, and trifluoromethylated arenes. The success of this transformation
leverages the Pd<sup>0</sup>/Brettphos-catalyzed decarbonylative chlorination
of aroyl chlorides, which can then participate in diverse cross-coupling
reactions <i>in situ</i> using the same Pd catalyst
Palladium- and Nickel-Catalyzed Decarbonylative CâS Coupling to Convert Thioesters to Thioethers
This
Letter describes the development of a catalytic decarbonylative
CâS coupling reaction that transforms thioesters into thioethers.
Both Pd- and Ni-based catalysts are developed and applied to the construction
of diaryl, aryl alkyl, and heterocycle-containing thioethers
Mechanistic Investigations of Cu-Catalyzed Fluorination of Diaryliodonium Salts: Elaborating the Cu<sup>I</sup>/Cu<sup>III</sup> Manifold in Copper Catalysis
A combination
of experimental and density functional theory (DFT) investigations
suggests that the Cu-catalyzed fluorination of unsymmetrical diaryliodonium
salts with general structure [MesÂ(Ar)ÂI]<sup>+</sup> in <i>N</i>,<i>N</i>âČ-dimethylformamide proceeds through a
Cu<sup>I</sup>/Cu<sup>III</sup> catalytic cycle. A low concentration
of fluoride relative to combined iodonium reagent plus copper ensures
that [MesÂ(Ar)ÂI]<sup>+</sup> is available as the reactive species for
oxidative âAr<sup>+</sup>â transfer to a Cu<sup>I</sup> center containing one or two fluoride ligands. A series of different
possible Cu<sup>I</sup> active catalysts (containing fluoride, triflate,
and DMF ligands) have been evaluated computationally, and all show
low-energy pathways to fluorinated products. The oxidation of these
Cu<sup>I</sup> species by [MesÂ(Ar)ÂI]<sup>+</sup> to form <i>cis</i>-ArÂ(F)ÂCu<sup>III</sup> intermediates is proposed to be rate-limiting
in all cases. ArâF bond-forming reductive elimination from
Cu<sup>III</sup> is computed to be very facile in all of the systems
examined. The conclusions of the DFT experiments are supported by
several experimental studies, including tests showing that Cu<sup>I</sup> is formed rapidly under the reaction conditions and that
the fluoride concentration strongly impacts the reaction yields/selectivities
Cu-Catalyzed Fluorination of Diaryliodonium Salts with KF
A mild Cu-catalyzed nucleophilic fluorination of unsymmetrical diaryliodonium salts with KF is described. This protocol preferentially fluorinates the smaller aromatic ligand on iodine(III). The reaction exhibits a broad substrate scope and proceeds with high chemoselectivity and functional group tolerance. DFT calculations implicate a Cu<sup>I</sup>/Cu<sup>III</sup> catalytic cycle
Copper-Catalyzed [<sup>18</sup>F]Fluorination of (Mesityl)(aryl)iodonium Salts
A practical, rapid, and highly regioselective
Cu-catalyzed radiofluorination
of (mesityl)Â(aryl)Âiodonium salts is described. This protocol utilizes
[<sup>18</sup>F]ÂKF to access <sup>18</sup>F-labeled electron-rich,
-neutral, and -deficient aryl fluorides under a single set of mild
conditions. This methodology is applied to the synthesis of protected
versions of two important radiotracers: 4-[<sup>18</sup>F]Âfluorophenylalanine
and 6-[<sup>18</sup>F]ÂfluoroDOPA
Synthesis of [<sup>18</sup>F]Arenes via the Copper-Mediated [<sup>18</sup>F]Fluorination of Boronic Acids
A copper-mediated
radiofluorination of aryl- and vinylboronic acids
with K<sup>18</sup>F is described. This method exhibits high functional
group tolerance and is effective for the radiofluorination of a range
of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and
vinylboronic acids. This method has been applied to the synthesis
of [<sup>18</sup>F]ÂFPEB, a PET radiotracer for quantifying metabotropic
glutamate 5 receptors