Herein is reported a substantially improved synthesis of 2-substituted benzimidazoles by condensa... more Herein is reported a substantially improved synthesis of 2-substituted benzimidazoles by condensation of 1,2-diaminoarenes and aldehydes using methanol as the reaction medium. The developed method afforded moderate to excellent yields (33–96%) at ambient temperature, displays high functional group tolerance, is conducted open to air, and requires only one minute reaction time under catalyst- and additive-free conditions. Moreover, the efficient protocol permits scale-up to multi-gram scale synthesis of benzimidazoles and will become a method of choice when constructing such heterocyclic systems.
Visible-light photocatalyzed (VLPC) late-stage C-H functionalization is a powerful addition to th... more Visible-light photocatalyzed (VLPC) late-stage C-H functionalization is a powerful addition to the chemical synthesis toolkit. VLPC has a demonstrated potential for discovery of elusive and valuable transformations, particularly in functionalization of bioactive heterocycles. In order to fully harvest the potential of VLPC in the context of complex molecule synthesis, a thorough understanding of the elementary processes involved is crucial. This would enable more rational design of suitable reagents and catalysts, as well as prediction of activated C-H sites for functionalization. Such knowledge is essential when VLPC is to be employed in retrosynthetic analysis of complex molecules. Herein, we present a density functional theory (DFT) study of mechanistic details in the C-H functionalization of bioactive heterocycles exemplified by the methylation of the antifungal agent voriconazole. Moreover, we show that readily computed atomic charges can predict major site-selectivity in good agreement with experimental studies and thus be informative tools for the identification of active C-H functionalization sites in synthetic planning.
We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin‐relea... more We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin‐releasing hormone receptor (GnRH−R) antagonists with nanomolar binding affinity. A small library of GnRH−R antagonists was synthesised in 20–67 % overall yield with the aim of identifying a high‐affinity antagonist capable of crossing the blood–brain barrier. Binding affinity to rat GnRH−R was determined by autoradiography in competitive‐binding studies against [125I]buserelin, and inhibition constants were calculated by using the Cheng–Prusoff equation. The radioligands were obtained in 46–79 % radiochemical yield and >95 % purity and with a molar activity of 19–38 MBq/nmol by direct nucleophilic radiofluorination. Positron emission tomography imaging in rat under baseline conditions in comparison to pretreatment with a receptor‐saturating dose of GnRH antagonist revealed saturable uptake (0.1 %ID/mL) into the brain.
We report a methane sensor based on an integrated Mach-Zehnder interferometer, which is cladded b... more We report a methane sensor based on an integrated Mach-Zehnder interferometer, which is cladded by a styrene-acrylonitrile film incorporating cryptophane-A. Cryptophane-A is a supramolecular compound able to selectively trap methane, and its presence in the cladding leads to a 17-fold sensitivity enhancement. Our approach, based on 3 cm-long low-loss Si<sub>3</sub>N<sub>4</sub> rib waveguides, results in a detection limit as low as 17 ppm. This is 1-2 orders of magnitude lower than typically achieved with chip-scale low-cost sensors.
In this communication, we report the synthesis and characterization of a library of small molecul... more In this communication, we report the synthesis and characterization of a library of small molecule antagonists of the human gonadotropin releasing hormone receptor based upon the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole scaffold via Cu-catalysed azide alkyne cycloaddition.
The synthesis of novel 5,7-diaryl and diheteroaryl indoles has been explored via efficient double... more The synthesis of novel 5,7-diaryl and diheteroaryl indoles has been explored via efficient double Suzuki-Miyaura coupling. The method notably employs a low catalyst loading of Pd(PPh3)4 (1.5 mol%/coupling) and water...
The design and use of chiral dirhodium(II) paddlewheel complexes as catalysts for asymmetric meta... more The design and use of chiral dirhodium(II) paddlewheel complexes as catalysts for asymmetric metal carbenoid and metal nitrenoid reactions, and as Lewis acids have become areas of considerable interest during the past two decades. The metal carbenoid chemistry is especially versatile, encompassing transformations such as C-H insertions, cyclopropanations and ylide formation. A number of different classes of dirhodium(II) catalysts have been found to be broadly effective in this chemistry. This review will highlight that many of these catalysts have higher symmetry than the individual chiral ligands themselves. An introduction of theoretical aspects concerning the structure and symmetry of chiral dirhodium(II) complexes will be given followed by an overview of the major classes of catalysts developed to date. Some representative examples of the synthetic potential of these catalysts will also be discussed.
Visible-light photoredox catalysis has come forth as a powerful activation mode in chemical synth... more Visible-light photoredox catalysis has come forth as a powerful activation mode in chemical synthesis, affording the development of a multitude of new strategies for molecular construction. However, detailed mechanistic knowledge of the various subprocesses involved is lacking, and new tools for addressing this are needed to drive innovation forward in the area. Herein, we describe predictions of ground- and excited-state redox potentials of ruthenium and iridium photocatalysts using nonrelativistic and scalar relativistic zero-order regular approximation density functional theory (DFT) methods. The computed redox potentials were correlated with experimental values and found to reproduce them well. Relativistic corrections were found to be important to reproduce experimental data. Moreover, the computational protocol allows us to estimate redox potentials that are not currently available in the literature or are difficult to determine experimentally. The mechanistic details of the photocatalyzed C–H funct...
Herein is reported a substantially improved synthesis of 2-substituted benzimidazoles by condensa... more Herein is reported a substantially improved synthesis of 2-substituted benzimidazoles by condensation of 1,2-diaminoarenes and aldehydes using methanol as the reaction medium. The developed method afforded moderate to excellent yields (33–96%) at ambient temperature, displays high functional group tolerance, is conducted open to air, and requires only one minute reaction time under catalyst- and additive-free conditions. Moreover, the efficient protocol permits scale-up to multi-gram scale synthesis of benzimidazoles and will become a method of choice when constructing such heterocyclic systems.
Visible-light photocatalyzed (VLPC) late-stage C-H functionalization is a powerful addition to th... more Visible-light photocatalyzed (VLPC) late-stage C-H functionalization is a powerful addition to the chemical synthesis toolkit. VLPC has a demonstrated potential for discovery of elusive and valuable transformations, particularly in functionalization of bioactive heterocycles. In order to fully harvest the potential of VLPC in the context of complex molecule synthesis, a thorough understanding of the elementary processes involved is crucial. This would enable more rational design of suitable reagents and catalysts, as well as prediction of activated C-H sites for functionalization. Such knowledge is essential when VLPC is to be employed in retrosynthetic analysis of complex molecules. Herein, we present a density functional theory (DFT) study of mechanistic details in the C-H functionalization of bioactive heterocycles exemplified by the methylation of the antifungal agent voriconazole. Moreover, we show that readily computed atomic charges can predict major site-selectivity in good agreement with experimental studies and thus be informative tools for the identification of active C-H functionalization sites in synthetic planning.
We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin‐relea... more We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin‐releasing hormone receptor (GnRH−R) antagonists with nanomolar binding affinity. A small library of GnRH−R antagonists was synthesised in 20–67 % overall yield with the aim of identifying a high‐affinity antagonist capable of crossing the blood–brain barrier. Binding affinity to rat GnRH−R was determined by autoradiography in competitive‐binding studies against [125I]buserelin, and inhibition constants were calculated by using the Cheng–Prusoff equation. The radioligands were obtained in 46–79 % radiochemical yield and >95 % purity and with a molar activity of 19–38 MBq/nmol by direct nucleophilic radiofluorination. Positron emission tomography imaging in rat under baseline conditions in comparison to pretreatment with a receptor‐saturating dose of GnRH antagonist revealed saturable uptake (0.1 %ID/mL) into the brain.
We report a methane sensor based on an integrated Mach-Zehnder interferometer, which is cladded b... more We report a methane sensor based on an integrated Mach-Zehnder interferometer, which is cladded by a styrene-acrylonitrile film incorporating cryptophane-A. Cryptophane-A is a supramolecular compound able to selectively trap methane, and its presence in the cladding leads to a 17-fold sensitivity enhancement. Our approach, based on 3 cm-long low-loss Si<sub>3</sub>N<sub>4</sub> rib waveguides, results in a detection limit as low as 17 ppm. This is 1-2 orders of magnitude lower than typically achieved with chip-scale low-cost sensors.
In this communication, we report the synthesis and characterization of a library of small molecul... more In this communication, we report the synthesis and characterization of a library of small molecule antagonists of the human gonadotropin releasing hormone receptor based upon the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole scaffold via Cu-catalysed azide alkyne cycloaddition.
The synthesis of novel 5,7-diaryl and diheteroaryl indoles has been explored via efficient double... more The synthesis of novel 5,7-diaryl and diheteroaryl indoles has been explored via efficient double Suzuki-Miyaura coupling. The method notably employs a low catalyst loading of Pd(PPh3)4 (1.5 mol%/coupling) and water...
The design and use of chiral dirhodium(II) paddlewheel complexes as catalysts for asymmetric meta... more The design and use of chiral dirhodium(II) paddlewheel complexes as catalysts for asymmetric metal carbenoid and metal nitrenoid reactions, and as Lewis acids have become areas of considerable interest during the past two decades. The metal carbenoid chemistry is especially versatile, encompassing transformations such as C-H insertions, cyclopropanations and ylide formation. A number of different classes of dirhodium(II) catalysts have been found to be broadly effective in this chemistry. This review will highlight that many of these catalysts have higher symmetry than the individual chiral ligands themselves. An introduction of theoretical aspects concerning the structure and symmetry of chiral dirhodium(II) complexes will be given followed by an overview of the major classes of catalysts developed to date. Some representative examples of the synthetic potential of these catalysts will also be discussed.
Visible-light photoredox catalysis has come forth as a powerful activation mode in chemical synth... more Visible-light photoredox catalysis has come forth as a powerful activation mode in chemical synthesis, affording the development of a multitude of new strategies for molecular construction. However, detailed mechanistic knowledge of the various subprocesses involved is lacking, and new tools for addressing this are needed to drive innovation forward in the area. Herein, we describe predictions of ground- and excited-state redox potentials of ruthenium and iridium photocatalysts using nonrelativistic and scalar relativistic zero-order regular approximation density functional theory (DFT) methods. The computed redox potentials were correlated with experimental values and found to reproduce them well. Relativistic corrections were found to be important to reproduce experimental data. Moreover, the computational protocol allows us to estimate redox potentials that are not currently available in the literature or are difficult to determine experimentally. The mechanistic details of the photocatalyzed C–H funct...
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