K2CO3/18-Crown-6-Catalyzed Selective H/D Exchange of Heteroarenes with Bromide as a Removable Directing Group

Gu, Jian-Guo; Wang, Cai-Xia; Hu, Guang-Qi; Shen, Kang; Zhang, Hong-Hai

doi:10.1021/acs.orglett.3c00883

Title: K₂CO₃/18-Crown-6-Catalyzed Selective H/D Exchange of Heteroarenes with Bromide as a Removable Directing Group

Journal Article · 26 April 2023 · Organic Letters

DOI: https://doi.org/10.1021/acs.orglett.3c00883 · OSTI ID:1976038

Gu, Jian-Guo ^[1]; Wang, Cai-Xia ^[1]; Hu, Guang-Qi ^[1]; Shen, Kang ^[1];

^[2]

Nanjing Tech Univ. (China)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Center for Nanophase Materials Sciences (CNMS)

Here, the K₂CO₃/18-crown-6-catalyzed H/D exchange of heretoarenes in high atom % deuterium incorporation is disclosed. The use of a weak base as a catalyst leads to excellent site selectivity and broad functional group tolerance. Control experiments indicated that the use of bromide, which enhances the adjacent C–H bond reactivity, as a removable directing group is essential. Moreover, conversion of bromide to other functional groups is also performed to construct other useful deuterated compounds.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Natural Science Foundation of China (NSFC)

Grant/Contract Number:: AC05-00OR22725; 22075135

OSTI ID:: 1976038

Journal Information:: Organic Letters, Vol. 25, Issue 17; ISSN 1523-7060

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

References (50)

Palladium(II)‐Initiated Catellani‐Type Reactions Cheng, Hong‐Gang; Chen, Shuqing; Chen, Ruiming Angewandte Chemie International Edition, Vol. 58, Issue 18 https://doi.org/10.1002/anie.201813491	journal	April 2019
Mild Reaction Conditions for the Terminal Deuteration of Alkynes Bew, Sean P.; Hiatt-Gipson, Glyn D.; Lovell, Jenny. A. Organic Letters, Vol. 14, Issue 2 https://doi.org/10.1021/ol2029178	journal	January 2012
A Facile Debromination Reaction: Can Bromide Now Be Used as a Protective Group in Aromatic Systems? Choi, Han Young; Chi, Dae Yoon Journal of the American Chemical Society, Vol. 123, Issue 37 https://doi.org/10.1021/ja0164374	journal	August 2001
Cryptocatalytic 1,2-Alkene Migration in a σ-Alkyl Palladium Diene Complex Evans, Louise A.; Fey, Natalie; Lloyd-Jones, Guy C. Angewandte Chemie International Edition, Vol. 48, Issue 34 https://doi.org/10.1002/anie.200901468	journal	July 2009
Catalytic Asymmetric Direct-Type 1,4-Addition Reactions of Simple Amides Suzuki, Hirotsugu; Sato, Io; Yamashita, Yasuhiro Journal of the American Chemical Society, Vol. 137, Issue 13 https://doi.org/10.1021/jacs.5b01943	journal	March 2015
Metal-Mediated Halogen Exchange in Aryl and Vinyl Halides: A Review Evano, Gwilherm; Nitelet, Antoine; Thilmany, Pierre Frontiers in Chemistry, Vol. 6 https://doi.org/10.3389/fchem.2018.00114	journal	April 2018
Preparation of α-labeled aldehydes by base-catalyzed exchange reactions Ariza, Xavier; Asins, Guillermina; Garcia, Jordi Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 53, Issue 8 https://doi.org/10.1002/jlcr.1759	journal	April 2010
A convenient synthesis of deuterium labeled amines and nitrogen heterocycles with KOt-Bu/DMSO-d6 Hu, Yu; Liang, Liang; Wei, Wen-tao Tetrahedron, Vol. 71, Issue 9 https://doi.org/10.1016/j.tet.2015.01.015	journal	March 2015
Base‐Mediated Remote Deuteration of N ‐Heteroarenes – Broad Scope and Mechanism Kopf, Sara; Liu, Jiali; Franke, Robert European Journal of Organic Chemistry, Vol. 2022, Issue 19 https://doi.org/10.1002/ejoc.202200204	journal	April 2022
The Buchwald–Hartwig Amination After 25 Years Dorel, Ruth; Grugel, Christian P.; Haydl, Alexander M. Angewandte Chemie International Edition, Vol. 58, Issue 48 https://doi.org/10.1002/anie.201904795	journal	November 2019
Using Deuterium in Drug Discovery: Leaving the Label in the Drug Gant, Thomas G. Journal of Medicinal Chemistry, Vol. 57, Issue 9 https://doi.org/10.1021/jm4007998	journal	December 2013
Deuteration of Extremely Weak Organic Acids by Enhanced Acid-Base Reactivity in Supercritical Deuteroxide Solution Yao, Jiong; Evilia, Ronald F. Journal of the American Chemical Society, Vol. 116, Issue 25 https://doi.org/10.1021/ja00104a003	journal	December 1994
Kinetic Control in Direct -Silyloxy Ketone Synthesis: A New Regiospecific Catalyzed Cross Silyl Benzoin Reaction Linghu, Xin; Johnson, Jeffrey S. Angewandte Chemie International Edition, Vol. 42, Issue 22 https://doi.org/10.1002/anie.200250554	journal	June 2003
Ag ₂ CO ₃ -Catalyzed H/D Exchange of Five-Membered Heteroarenes at Ambient Temperature Li, En-Ci; Hu, Guang-Qi; Zhu, Yu-Xing Organic Letters, Vol. 21, Issue 17 https://doi.org/10.1021/acs.orglett.9b02369	journal	August 2019
Potassium tert-butoxide promoted regioselective deuteration of pyridines Li, Yan; Zheng, Chenxu; Jiang, Zhi-Jiang Chemical Communications, Vol. 58, Issue 21 https://doi.org/10.1039/D1CC07128A	journal	January 2022
Controlled Tetradeuteration of Straight‐Chain Fatty Acids: Synthesis, Application, and Insight into the Metabolism of Oxidized Linoleic Acid Watanabe, Ayako; Hama, Kotaro; Watanabe, Kohei Angewandte Chemie International Edition, Vol. 61, Issue 25 https://doi.org/10.1002/anie.202202779	journal	April 2022
Facile and Economical Electrochemical Dehalogenative Deuteration of (Hetero)Aryl Halides Lu, Lijun; Li, Hao; Zheng, Yifan CCS Chemistry, Vol. 3, Issue 11 https://doi.org/10.31635/ccschem.020.202000512	journal	November 2021
What are the pKa values of C–H bonds in aromatic heterocyclic compounds in DMSO? Shen, Kuang; Fu, Yao; Li, Jia-Ning Tetrahedron, Vol. 63, Issue 7 https://doi.org/10.1016/j.tet.2006.12.032	journal	February 2007
General and Practical Potassium Methoxide/Disilane-Mediated Dehalogenative Deuteration of (Hetero)Arylhalides Wang, Xin; Zhu, Ming-Hui; Schuman, David P. Journal of the American Chemical Society, Vol. 140, Issue 35 https://doi.org/10.1021/jacs.8b07597	journal	August 2018
Base-Catalyzed H/D Exchange Reaction of Difluoromethylarenes Huang, Linwei; Liu, Wei; Zhao, Liang-Liang The Journal of Organic Chemistry, Vol. 86, Issue 5 https://doi.org/10.1021/acs.joc.0c02827	journal	February 2021
Highly Diastereoselective Crown Ether Catalyzed Arylogous Michael Reaction of 3-Aryl Phthalides Sicignano, Marina; Dentoni Litta, Antonella; Schettini, Rosaria Organic Letters, Vol. 19, Issue 16 https://doi.org/10.1021/acs.orglett.7b02113	journal	August 2017
Synthesis of Deuterated Benzopyran Derivatives as Selective COX-2 Inhibitors with Improved Pharmacokinetic Properties Zhang, Yanmei; Tortorella, Micky D.; Wang, Yican ACS Medicinal Chemistry Letters, Vol. 5, Issue 10 https://doi.org/10.1021/ml500299q	journal	August 2014
Effect of Buffer General Acid−Base Catalysis on the Stereoselectivity of Ester and Thioester H/D Exchange in D₂O Mohrig, Jerry R.; Reiter, Nicholas J.; Kirk, Randy Journal of the American Chemical Society, Vol. 133, Issue 13 https://doi.org/10.1021/ja200014c	journal	March 2011
A readily observed base-catalyzed isotopic exchange in a 2,4-dinitroalkyl benzene Backstrom, Nick; Watt, C. Ian F. Tetrahedron Letters, Vol. 50, Issue 26 https://doi.org/10.1016/j.tetlet.2009.02.002	journal	July 2009
Base-catalyzed H/D exchange of polychlorinated biphenyls Xiang, Zhihao; Huang, Shiqing; Zhao, Liang-Liang Tetrahedron Letters, Vol. 110 https://doi.org/10.1016/j.tetlet.2022.154200	journal	November 2022
Deuterium Exchange between Arenes and Deuterated Solvents in the Absence of a Transition Metal: Synthesis of D-Labeled Fluoroarenes: Deuterium Exchange between Arenes and Deuterated Solvents in the Absence of a Transition Metal: Synthesis of D-Labeled Fluoroarenes Salamanca, Vanesa; Albéniz, Ana C. European Journal of Organic Chemistry, Vol. 2020, Issue 22 https://doi.org/10.1002/ejoc.202000284	journal	March 2020
Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design Meanwell, Nicholas A. Journal of Medicinal Chemistry, Vol. 54, Issue 8 https://doi.org/10.1021/jm1013693	journal	April 2011
Radical deuteration Li, Nian; Li, Yantao; Wu, Xiaopeng Chemical Society Reviews, Vol. 51, Issue 15 https://doi.org/10.1039/D1CS00907A	journal	January 2022
Base-catalyzed aryl halide isomerization enables the 4-selective substitution of 3-bromopyridines Puleo, Thomas R.; Bandar, Jeffrey S. Chemical Science, Vol. 11, Issue 38 https://doi.org/10.1039/D0SC02689A	journal	January 2020
Synthesis of Multideuterated (Hetero)aryl Bromides by Ag(I)-Catalyzed H/D Exchange Hu, Guang-Qi; Bai, Jing-Wen; Li, En-Ci Organic Letters, Vol. 23, Issue 5 https://doi.org/10.1021/acs.orglett.0c04139	journal	February 2021
Kinetic Isotope Effects in Asymmetric Reactions Giagou, Thomas; Meyer, Matthew P. Chemistry - A European Journal, Vol. 16, Issue 35 https://doi.org/10.1002/chem.201001018	journal	July 2010
Pd Metal Catalysts for Cross-Couplings and Related Reactions in the 21st Century: A Critical Review Biffis, Andrea; Centomo, Paolo; Del Zotto, Alessandro Chemical Reviews, Vol. 118, Issue 4 https://doi.org/10.1021/acs.chemrev.7b00443	journal	February 2018
Hydrogen/Deuterium (H/D) Exchange Catalysis in Alkanes Sattler, Aaron ACS Catalysis, Vol. 8, Issue 3 https://doi.org/10.1021/acscatal.7b04201	journal	January 2018
Silver salt enabled H/D exchange at the β-position of thiophene rings: synthesis of fully deuterated thiophene derivatives Sheng, Fei-Fei; Li, En-Ci; Bai, Jing-Wen Organic & Biomolecular Chemistry, Vol. 20, Issue 6 https://doi.org/10.1039/D1OB02285G	journal	January 2022
Pd- and Pt-catalyzed H/D exchange methods and their application for internal MS standard preparation from a Sanofi-Aventis perspective Atzrodt, Jens; Derdau, Volker Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 53, Issue 11-12 https://doi.org/10.1002/jlcr.1818	journal	September 2010
Development of a QuEChERS-Based Stable-Isotope Dilution LC-MS/MS Method To Quantitate Ferulic Acid and Its Main Microbial and Hepatic Metabolites in Milk Waterstraat, Martin; Hildebrand, Andreas; Rosler, Margit Journal of Agricultural and Food Chemistry, Vol. 64, Issue 45 https://doi.org/10.1021/acs.jafc.6b03318	journal	November 2016
Reductive Dehalogenation of Aryl Bromides and Chlorides and Their Use as Aryl Blocking Groups Jimenez, Leslie; Ramanathan, Ahalya Synthesis, Vol. 2010, Issue 02 https://doi.org/10.1055/s-0029-1217112	journal	November 2009
Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules Kopf, Sara; Bourriquen, Florian; Li, Wu Chemical Reviews, Vol. 122, Issue 6 https://doi.org/10.1021/acs.chemrev.1c00795	journal	February 2022
Catalytic Stereoinversion ofL-Alanine to DeuteratedD-Alanine Moozeh, Kimia; So, Soon Mog; Chin, Jik Angewandte Chemie International Edition, Vol. 54, Issue 32 https://doi.org/10.1002/anie.201503616	journal	June 2015
Big interest in heavy drugs Sanderson, Katharine Nature https://doi.org/10.1038/458269a	journal	March 2009
A practical and efficient method for late-stage deuteration of terminal alkynes with silver salt as catalyst Wu, Ding-Chuan; Bai, Jing-Wen; Guo, Lei Tetrahedron Letters, Vol. 66 https://doi.org/10.1016/j.tetlet.2020.152807	journal	March 2021
A Simple and Cost-Effective Method for the Regioselective Deuteration of Phenols Zhan, Miao; Xu, Ruixue; Tian, Ye European Journal of Organic Chemistry, Vol. 2015, Issue 15 https://doi.org/10.1002/ejoc.201500192	journal	April 2015
Suzuki Polycondensation: Polyarylenes à la Carte Sakamoto, Junji; Rehahn, Matthias; Wegner, Gerhard Macromolecular Rapid Communications, Vol. 30, Issue 9-10 https://doi.org/10.1002/marc.200900063	journal	May 2009
C−H Functionalisation for Hydrogen Isotope Exchange Atzrodt, Jens; Derdau, Volker; Kerr, William J. Angewandte Chemie International Edition, Vol. 57, Issue 12 https://doi.org/10.1002/anie.201708903	journal	February 2018
On the Interpretation of Deuterium Kinetic Isotope Effects in CH Bond Functionalizations by Transition-Metal Complexes Simmons, Eric M.; Hartwig, John F. Angewandte Chemie International Edition, Vol. 51, Issue 13 https://doi.org/10.1002/anie.201107334	journal	March 2012
Lipidomics Reveals Dramatic Physiological Kinetic Isotope Effects during the Enzymatic Oxygenation of Polyunsaturated Fatty Acids Ex Vivo Navratil, Aaron R.; Shchepinov, Mikhail S.; Dennis, Edward A. Journal of the American Chemical Society, Vol. 140, Issue 1 https://doi.org/10.1021/jacs.7b09493	journal	December 2017
Palladium-catalyzed Br/D exchange of arenes: selective deuterium incorporation with versatile functional group tolerance and high efficiency Zhang, Hong-Hai; Bonnesen, Peter V.; Hong, Kunlun Organic Chemistry Frontiers, Vol. 2, Issue 9 https://doi.org/10.1039/C5QO00181A	journal	January 2015
Base‐Catalyzed Selective Deuteration of Alkynes Kumar, Shiv; Patel, Monika; Verma, Akhilesh K. Asian Journal of Organic Chemistry, Vol. 10, Issue 9 https://doi.org/10.1002/ajoc.202100405	journal	August 2021
Highly selective single and multiple deuteration of unactivated C(sp3)-H bonds Li, Nian; Li, Jinhang; Qin, Mingzhe Nature Communications, Vol. 13, Issue 1 https://doi.org/10.1038/s41467-022-31956-3	journal	July 2022
Heavy drugs draw heavy interest from pharma backers Katsnelson, Alla Nature Medicine, Vol. 19, Issue 6 https://doi.org/10.1038/nm0613-656	journal	June 2013