Cobalt-catalyzed dehalogenative deuterations with D2O

doi:10.1016/S1872-2067(23)64624-8

Abstract

Abstract:

The regioselective incorporation of deuterium to organic skeletons has gained ever-growing attention among scientific community. Herein, we present a robust and general protocol for site-specific deuteration through the cobalt catalyzed dehalogenative process. Using D₂O as the economical deuterium reagent, we achieved excellent substrate compatibility across a wide collection of organohalides or pseudo-halides, such as aryl, alkenyl, benzyl, allyl, or alkyl halides and propargyl acetates. Preliminary experimental evidences and related DFT calculation are also presented to support a mechanistic scenario involving a Co(I)-C(III)-Co(I) cycle. The generality and potential utilization of this moisture-insensitive catalysis have also been demonstrated by the selective deuterodehalogenation of drug-like candidates, concise synthesis of D-labeled pharmaceutical molecule, as well as the stepwise hydrogen isotope exchange of bioactive compounds.

Key words: Cobalt catalysis, Deuterodehalogenation, Site-specific deuteration, Organohalides, D-labeled pharmaceutical

Bing-Zhi Chen, Ding-Wei Ji, Bo-Chao Zhou, Xiao-Yu Wang, Heng Liu, Boshun Wan, Xiang-Ping Hu, Qing-An Chen. Cobalt-catalyzed dehalogenative deuterations with D₂O[J]. Chinese Journal of Catalysis, 2024, 59: 250-259.

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URL: https://www.cjcatal.com/EN/10.1016/S1872-2067(23)64624-8

https://www.cjcatal.com/EN/Y2024/V59/I4/250

Figures/Tables 7

Fig. 1. Transition-metal-catalyzed deuterodehalogenation reactions. (A) Hydrogen's isotope deuterium and its applications. (B) Metal-promoted or -catalyzed dehalogenative deuterations. (C) This work: Co-catalyzed dehalogenative deuterations with D2O.

Fig. 2. Optimization of reaction conditions. Reaction conditions: substrate (0.10 mmol), MLn (dimer 2.5 mol% or monomer 5 mol%), PPh3 (10 mol%) or ligand (5 mol%), Mn (0.15 mmol), ZnI2 (0.15 mmol), CH3CN (1.0 mL), 80 °C, 30 min. Yield and deuterium incorporation were determined by 1H NMR spectroscopy analysis with 1,3,5-trimethoxybenzene as the internal standard. aCH3CN (0.5 mL).

Fig. 3. Co-catalyzed deuterodehalogenation reactions with D2O. Reaction conditions: Substrate (0.20 mmol), CoBr2 (5 mol%), Ligand (5 mol%), Mn (0.30 mmol), ZnI2 (0.30 mmol), D2O (2.0 mmol), CH3CN (2.0 mL), 80 °C, 30 min. Dppf was used as a ligand for aryl halides 1, bipyridine was used as a ligand for substrates 3, 5 and 7. Deuterium incorporation was determined by 1H NMR spectroscopy analysis and isolated yields were reported for all cases. a DMF (1.0 mL) and bipyridine were used instead of CH3CN and dppf. b CH3CN (1.0 mL) was used as solvent for the synthesis of 6. c Extend the reaction time to 12 h.

Fig. 4. Substrate scope of propargyl acetates. Reaction conditions: Substrate (0.20 mmol), CoBr2 (5 mol%), dppf (5 mol%), Mn (0.30 mmol), ZnI2 (0.30 mmol), D2O (2.0 mmol), CH3CN (2.0 mL), 80 °C, 30 min. Deuterium incorporation was determined by 1H NMR spectroscopy analysis and isolated yields were reported for all cases. See the Supporting Information for full experimental details. a BINAP was used instead of dppf. b10 mmol scale, 2 h.

Fig. 5. Selective deuteration of drug-like molecules. Deuterium incorporation was determined by 1H NMR spectroscopy analysis and isolated yields were reported for all cases. See the Supporting Information for full experimental details.

Fig. 6. Stepwise hydrogen isotope exchange for drug molecules. Deuterium incorporation was determined by 1H NMR spectroscopy analysis and isolated yields are reported for all cases. See the Supporting Information for full experimental details.

Fig. 7. Mechanistic studies and proposed mechanism. a DFT calculations were performed at the M06-L/6-311++G(2df,2p)-SDD(Co)/SMD(Acetonitrile)//M06-L/6-31G(d)-SDD(Co) level of theory.

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Cobalt-catalyzed dehalogenative deuterations with D₂O

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