Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C–CN Bond Activation

2021 ◽  
Vol 143 (12) ◽  
pp. 4817-4823
Author(s):  
Sean W. Reilly ◽  
Yu-hong Lam ◽  
Sumei Ren ◽  
Neil A. Strotman
Keyword(s):  
Carbon Isotope ◽  
Late Stage ◽  
Isotope Exchange ◽  
Bond Activation ◽  
Aryl Nitriles

Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C–CN Bond Activation

2021 ◽  
Author(s):  
Sean Reilly ◽  
Yu-hong Lam ◽  
Sumei Ren ◽  
Neil Strotman
Keyword(s):  
Carbon Isotope ◽  
Late Stage ◽  
Isotope Exchange ◽  
Functional Group ◽  
Bond Activation ◽  
De Novo ◽  
Parent Compound ◽  
One Pot ◽  
Aryl Nitriles ◽  
Labeling Approach

<div> <p>A facile one-pot strategy for <sup>13</sup>CN and <sup>14</sup>CN exchange with aryl, heteroaryl, and vinyl nitriles using a Ni phosphine catalyst and BPh<sub>3</sub> is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN)<sub>2</sub> to facilitate enrichment using the non-labeled parent compound as the starting material, eliminating <i>de novo</i> synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is disclosed, including the preparation of [<sup>14</sup>C]<a>belzutifan</a> to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh<sub>3</sub> is not critical for the oxidative addition step and instead plays a role in facilitating CN exchange on Ni. This CIE method dramatically reduces the synthetic steps and radioactive waste involved in preparation of <sup>14</sup>C labeled tracers for clinical development.</p> </div>

scholarly journals Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C–CN Bond Activation

2021 ◽  
Author(s):  
Sean Reilly ◽  
Yu-hong Lam ◽  
Sumei Ren ◽  
Neil Strotman
Keyword(s):  
Carbon Isotope ◽  
Late Stage ◽  
Isotope Exchange ◽  
Functional Group ◽  
Bond Activation ◽  
De Novo ◽  
Parent Compound ◽  
One Pot ◽  
Aryl Nitriles ◽  
Labeling Approach

<div> <p>A facile one-pot strategy for <sup>13</sup>CN and <sup>14</sup>CN exchange with aryl, heteroaryl, and vinyl nitriles using a Ni phosphine catalyst and BPh<sub>3</sub> is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN)<sub>2</sub> to facilitate enrichment using the non-labeled parent compound as the starting material, eliminating <i>de novo</i> synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is disclosed, including the preparation of [<sup>14</sup>C]<a>belzutifan</a> to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh<sub>3</sub> is not critical for the oxidative addition step and instead plays a role in facilitating CN exchange on Ni. This CIE method dramatically reduces the synthetic steps and radioactive waste involved in preparation of <sup>14</sup>C labeled tracers for clinical development.</p> </div>

scholarly journals Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C–CN Bond Activation

2021 ◽  
Author(s):  
Sean Reilly ◽  
Yu-hong Lam ◽  
Sumei Ren ◽  
Neil Strotman
Keyword(s):  
Carbon Isotope ◽  
Late Stage ◽  
Isotope Exchange ◽  
Functional Group ◽  
Bond Activation ◽  
De Novo ◽  
Parent Compound ◽  
One Pot ◽  
Aryl Nitriles ◽  
Labeling Approach

<div> <p>A facile one-pot strategy for <sup>13</sup>CN and <sup>14</sup>CN exchange with aryl, heteroaryl, and vinyl nitriles using a Ni phosphine catalyst and BPh<sub>3</sub> is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN)<sub>2</sub> to facilitate enrichment using the non-labeled parent compound as the starting material, eliminating <i>de novo</i> synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is disclosed, including the preparation of [<sup>14</sup>C]<a>belzutifan</a> to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh<sub>3</sub> is not critical for the oxidative addition step and instead plays a role in facilitating CN exchange on Ni. This CIE method dramatically reduces the synthetic steps and radioactive waste involved in preparation of <sup>14</sup>C labeled tracers for clinical development.</p> </div>

scholarly journals Nickel-Catalyzed Thiolation of Aryl Nitriles

2021 ◽  
Author(s):  
Tristan Delcaillau ◽  
Bill Morandi
Keyword(s):  
Late Stage ◽  
Functional Group ◽  
Bond Activation ◽  
Bond Formation ◽  
Aryl Nitriles

<div>A nickel-catalyzed thiolation of aryl nitriles has been developed to access functionalized aryl thioethers. The ligand dcype (1,2 Bis(dicyclohexylphosphino)ethane) as well as the base KOtBu (potassium tert-butoxide) are essential to achieve this transformation. This scalable and practical process involves both a C–C bond activation and a C–S bond formation. Furthermore, this reaction shows a high functional-group tolerance and enables the late-stage functionalization of important molecules.</div>

scholarly journals Nickel-Catalyzed Thiolation of Aryl Nitriles

2021 ◽  
Author(s):  
Tristan Delcaillau ◽  
Bill Morandi
Keyword(s):  
Late Stage ◽  
Functional Group ◽  
Bond Activation ◽  
Bond Formation ◽  
Aryl Nitriles

<div>A nickel-catalyzed thiolation of aryl nitriles has been developed to access functionalized aryl thioethers. The ligand dcype (1,2 Bis(dicyclohexylphosphino)ethane) as well as the base KOtBu (potassium tert-butoxide) are essential to achieve this transformation. This scalable and practical process involves both a C–C bond activation and a C–S bond formation. Furthermore, this reaction shows a high functional-group tolerance and enables the late-stage functionalization of important molecules.</div>

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

2021 ◽  
Vol 143 (5) ◽  
pp. 2200-2206
Author(s):  
Duanyang Kong ◽  
Maxime Munch ◽  
Qiqige Qiqige ◽  
Christopher J. C. Cooze ◽  
Benjamin H. Rotstein ◽  
...  
Keyword(s):  
Carbon Isotope ◽  
Carboxylic Acids ◽  
Isotope Exchange ◽  
Photoredox Catalysis

scholarly journals A Photochemical Strategy for Carbon Isotope Exchange with CO2

2020 ◽  
Author(s):  
Victor Babin ◽  
Alex Talbot ◽  
Alexandre Labiche ◽  
Gianluca Destro ◽  
Antonio Del Vecchio ◽  
...  
Keyword(s):  
Carbon Isotope ◽  
Isotope Exchange ◽  
Thermal Conditions ◽  
Single Step ◽  
Structural Modifications ◽  
Mild Conditions ◽  
Stark Contrast ◽  
Acetic Acids

A novel photocatalytic approach for carbon isotope exchange is reported. Utilizing [<sup>13</sup>C]CO<sub>2</sub> as primary C1 sources, this protocol allows the insertion of the desired carbon isotope into phenyl acetic acids without the need of structural modifications or pre-functionalization, in one single step. The exceptionally mild conditions required for this traceless transformation are in stark contrast with previous methods requiring the use of harsh thermal conditions.

scholarly journals Synthesis of (−)-Picrotoxinin by Late-Stage Strong Bond Activation

2020 ◽  
Vol 142 (26) ◽  
pp. 11376-11381 ◽  
Author(s):  
Steven W. M. Crossley ◽  
Guanghu Tong ◽  
Michael J. Lambrecht ◽  
Hannah E. Burdge ◽  
Ryan A. Shenvi
Keyword(s):  
Late Stage ◽  
Bond Activation ◽  
Strong Bond ◽  
Strong Bond Activation
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