Visible Light Promoted Direct Deuteration of Alkenes via Co(III)–H Mediated H/D Exchange

Abstract

Open AccessCCS ChemistryCOMMUNICATIONS22 Dec 2022Visible Light Promoted Direct Deuteration of Alkenes via Co(III)–H Mediated H/D Exchange Zongbin Jia and Sanzhong Luo Zongbin Jia Department of Chemistry, Center of Basic Molecular Science (CBMS), Tsinghua University, Beijing 100084 and Sanzhong Luo *Corresponding author: E-mail Address: [email protected] Department of Chemistry, Center of Basic Molecular Science (CBMS), Tsinghua University, Beijing 100084 https://doi.org/10.31635/ccschem.022.202202476 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We report herein a visible light-mediated direct deuteration of alkenes with D2O or deuterated methanol (MeOD) using a cobaloxime as a hydrogen/deuterium (H/D) exchange catalyst. The synergistic photoredox/Co catalysis enabled facile deuterium (D)-incorporation of a variety of terminal and internal alkenes at either terminal or benzylic positions. We proposed that this process proceeded through a sequence of reversible addition-elimination reactions and fast proton exchange involving Co(III)–H, which was generated in situ by photoreduction. Download figure Download PowerPoint Introduction Direct hydrogen/deuterium (H/D) exchange of C–H bonds with readily available deuterium sources such as D2O is arguably the most straightforward and economic strategy1–3 in D-labeling, which is of great importance in molecular tracing and drug discovery.4–6 Due to the thermostability of C–H bonds, catalytic systems capable of reversible and facile C–H bond activations are generally required to facilitate direct H/D exchange. Hence, the development of a new catalytic strategy is in high demand to enable selective D-labeling of a distinctive chemical entity.7 Four-coordinated planar cobalt hydrides (Co(III)–H) are versatile catalytic intermediates in chemical and energy-transforming processes such as hydrogen-gas evolution8–12 (Scheme 1a, Path A) and hydrofunctionalization of alkenes (Scheme 1a, Path B).13–25 Recently, planar Co(III)–H catalysis has been further advanced toward isomerization of alkenes and dehydrogenative allylic alkylation under either photoredox or electrochemical conditions.26–39 In these processes, we and others have observed that in-situ generated Co(III)–H species would tend to undergo a fast and reversible addition-elimination process with alkenes,29,33–35,39 a salient feature that remains unexploited. On the other hand, Co(III)–H is also acidic enough to undergo a facile proton exchange, with pKa(Co–H) = 10–14 as a result of filled d8-electron configuration of Co(I) (Scheme 1a, Path C).40,41 On these bases, we envisioned that Co(III)–H might mediate selective H/D exchange of alkene C–H bonds with deuterium sources such as D2O by combining its reversible alkene addition and acidity (Scheme 1b). Previously, transition metal catalysts such as Ir, Ru, and Pd have been reported for direct deuterium (D)-incorporation of terminal styrenes and acrylic acid derivatives.42–52 Metal-free catalysis has also been explored in this regard but is limited to electron-deficient alkenes or styrenes.53–55 Herein, we report a visible light photochemical protocol involving planer Co(III)–H that enables selective H/D exchange of a wide range of alkenes including both terminal and internal alkenes with readily available deuterium resources (Scheme 1b).56,57 Scheme 1 | Direct deuteration by catalytic H/D exchange strategy. Download figure Download PowerPoint Results and Discussion In our initial studies, the deuteration of 2-aryl-1-propene 1a was used as the model reaction using D2O as the deuterium source. Co(chgH)2DMAPCl (chgH = cyclohexylglyoxime, DMAP = 4-dimethylaminopyridine, Cl = chloride) 3a and Ir(ppy)2dtbbpyPF6 ([Ir], ppy = 2-phenyl-4-pyridine, dtbbpy = 4,4′-ditert-butyl-2,2′-bipyridine) were introduced as H/D exchange catalyst and photoredox reduction catalyst, respectively. After extensive experiments, a combination of cobaloxime 3a (8 mol %), [Ir] (0.5 mol %), N,N-diisopropylethylamine (DIPEA, 20 mol %), and D2O (166 equiv, D/H = 66∶1) was identified as the optimized conditions to afford the deuterated product 2a with 99% isolated yield and 97% D-incorporation (Table 1, entry 1). Both the allylic and vinylic positions were deuterated with a high ratio. DIPEA was preferred to other Lewis bases such as Triethylamine (Et3N), 1,4-Diazabicyclo[2.2.2]octane (DABCO), and 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), with no observable D-incorporation in the latter two organic bases (Table 1, entries 2 and 3). Presumably, DIPEA might have played a dual role first as a reductant for photoredox generation of the catalytically active Co(III)–H and second, as an organic base to promote subsequent proton exchange. Different cobaloximes showed similar reactivity, whereas no deuterium incorporation was observed for Co(salen) 3d (Table 1, entries 4–6). The use of deuterated methanol (MeOD) as the deuterium source showed a comparable result (Table 1, entry 7). Control experiments revealed that any of the catalytic systems was essential in the reaction, as no deuteration was observed in their absence (Table 1, entry 8). The reaction also did not proceed in the dark without light irradiation (Table 1, entry 9). Table 1 | Screening and Optimizationa Entry Variation from Above Conditions Yield of 2a or Recovered 1a (%) D (%) 1 None 99 97 2 Et3N instead of DIPEA 87 97 3 DBU or DABCO 93/95 0 4 3b instead of 3a 74 97 5 3c instead of 3a 81 97 6 3d instead of 3a 99 0 7 MeOD as solvent 75 95 8 w/o 3a or DIPEA or [Ir] 95/99/99 0 9 In the dark 95 0 aReaction conditions: 1a (0.1 mmol), 3a (8 mol %), [Ir] (0.5 mol %), DIPEA (20 mol %), 0.3 mL of D2O and 0.6 mL MeCN, deaerated and irradiated for 36 h by 30 W blue LED under room temperature. Yield of the isolated product. Deuterium incorporation percentages were detected by 1H NMR analysis. DIPEA, N,N-diisopropylethylamine; MeCN, methyl cyanide; MEOD, deuterated methanol; DBU, 1,8-Diazabicyclo[5.4.0]undec-7-ene; DABCO, 1,4-Diazabicyclo[2.2.2]octane; LED, light-emitting diode; 1H NMR, proton nuclear magnetic resonance. Under the optimized reaction conditions, the substrate scope was then examined. As shown in Scheme 2, 2-aryl-1-propenes bearing para-substituents on the aryl ring such as alkyl ( 2c– 2f), alkoxyl ( 2g), thioxyl ( 2h), phenyl ( 2i), phenoxyl ( 2j), and halogen ( 2k) were well-tolerated in the reactions to afford the desired products with high yields (85–99%) and D-incorporation (>94%) (Scheme 2, entries 2–11). Substrates with strong electron-withdrawing substituents (–CF3 and –CO2Me) on the phenyl ring also worked well, providing the corresponding deuterated products with excellent results (Scheme 2, entries 12 and 13). Meanwhile, meta- and di-substituted aryl propenes reacted smoothly with satisfying results (Scheme 2, entries 14–16). Slightly decreased D-incorporation was observed for 1-naphthyl propene 2r and 2q bearing ortho-substituents (Scheme 2, entries 17 and 18), likely due to steric effect. This strategy was not limited to aryl propenes; heteroaromatic groups such as thienyl and pyridyl-substituted alkenes all worked well in the reaction (Scheme 2, entries 19–21). Further, the reaction worked with N-pyrrolidinone-enamine to give the deuterated 2v, albeit with rather lower D-incorporation. Scheme 2 | Substrate scope. Reaction conditions: 1 (0.2 mmol), 3a (8 mol %), [Ir] (0.5 mol %), DIPEA (20–50 mol %), 0.6 mL of D2O and 1.2 mL MeCN (for condition A); 0.6 mL of MeOD and 2.0 mL DMF (for condition B); 3d (1 mol %) instead of 3a and 0.5 mL MeOD (for condition C) as the solvent, deaerated and irradiated for 5–36 h by 30 W blue LED under room temperature. Yield of the isolated product. Deuterium incorporation percentages were detected by 1H NMR analysis. a 1.0 equiv of DIPEA added. b Reaction under condition C. MeOD, deuterated methanol; MeCN, methyl cyanide; DIPEA, N,N-diisopropylethylamine; LED, light-emitting diode; 1H NMR, proton nuclear magnetic resonance. Download figure Download PowerPoint Delightfully, alkyl propene could be applied to the H/D exchange reaction, and the target deuterated 2-adamantyl propene 2w could be obtained with 99% yield and 91% D-incorporation using Co(salen) 3d in MeOD solutions (condition C, Scheme 2, entry 23). 1,1-Diaryl ethylene with para-substituents on the aryl ring as methyl, alkoxyl, or halogen unit could all be efficiently D-labeled on terminal alkenes (Scheme 2, entries 27–30). Moreover, α-CF3 substituted styrenes could be incorporated to produce terminal bis-deuterated adducts in high yields, with moderate to good D-incorporation (up to 89%) (Scheme 2, entries 31–35). The current catalytic protocol could be extended to simple styrenes by using MeOD in dimethylformamide (DMF) as the deuterium source (condition B, for the optimization details, see the Supporting Information). The reaction afforded selectively terminal deuterated styrene 2al with 86% yield and 91% D-incorporation (condition B, Scheme 2, entry 38). As shown, MeOD/DMF represented a general deuterium reservoir for the preparation of deuterated styrene derivatives bearing either electron-withdrawing ( 2an) or electron-donating groups ( 2ao– 2av) with good yields (63–96%) and high D-incorporation (up to 93%, Scheme 2, entries 39–48). Deuterium incorporation at the C1, C2, and C3 positions was observed with indene 2aw (Scheme 2, entry 49). Internal alkenes such as 1-phenylpropenes (Scheme 2, entries 50 and 51) and cinnamyl alcohol derivatives (Scheme 2, entries 52–56) worked regioselectively to afford monodeuterated adducts in high yields and good D-incorporation ratio. Notably, a free alcohol group was tolerated in the reactions (entries 52–54). While 1-phenyl-1,3-butadiene gave the corresponding deuterated product 2be at only the terminal position (Scheme 2, entry 57). When 1-methylene-tetrahydronaphthalene 4a was applied, an isomerized product 5a was obtained with D-incorporation at both olefinic and allylic positions (Scheme 3, entry 1). Similar results were also observed for other α-substituted styrenes (Scheme 3, entries 2–4). 4-Substituted methylenecyclohexane gave monodeuterated and isomerized products when 3d was used as a catalyst (condition C, Scheme 3, entries 5 and 6, see Supporting Information for the optimization details). Further, the estrone derivative 4g bearing methylenecyclopentane ring exclusively gave an isomerized product 5g (Scheme 3, entry 7) with high D-incorporation at both allylic and olefinic positions. Scheme 3 | Scope of isomerization and deuteration. Reaction conditions: 4 (0.2 mmol), 3a (8 mol %), [Ir] (0.5 mol %), DIPEA (20∼50 mol %), 0.6 mL of D2O and 1.2 mL MeCN (for condition A); or 3d (1 mol %) instead of 3a and 1.0 mL MeOD (for condition C) as the solvent, deaerated and irradiated for 5–36 h by 30 W blue LED under room temperature. Yield of the isolated product. Deuterium incorporation percentages were detected by 1H NMR analysis. DIPEA, N,N-diisopropylethylamine; MeCN, methyl cyanide; MeOD, deuterated methanol; LED, light-emitting diode; 1H NMR, proton nuclear magnetic resonance. Download figure Download PowerPoint Next, we challenged the current strategy in the late-stage deuteration of structurally complex substrates originating from natural products and pharmaceuticals. First, diacetone-D-glucose derivative and menthol-containing 2-aryl propenes transformed into the corresponding products with high levels of D-incorporation (Scheme 2, entries 24 and 25). Furthermore, an excellent yield was obtained for β-estradiol derivative 2z, with moderate deuteration seemed to be caused by low solubility (Scheme 2, entry 26). Of further significance was the observation that our protocol enabled late-stage deuteration of pharmaceutically active fenofibrate and ketoprofen derivatives in high yields and good levels of D-incorporation (Scheme 2, entries 36 and 37). Finally, steroid derivatives bearing methylenecyclopentane groups such as stanolone 5h and androsterone 5i could be applied to give deuterated products with satisfactory results (Scheme 3, entries 8 and 9). A gram-scale deuteration of 1,1-diphenyl ethylene 1aa was performed to probe the practicability, and comparable results were obtained in the presence of a reduced loading of catalysts and D2O (Scheme 4, entry 1, D/H = 41∶1). Moreover, D2O could be recovered from the reaction mixture and engaged in a second cycle showing comparable results (Scheme 4, entry 2). Excellent results on gram-scale deuteration were also observed with other alkenes such as 2-aryl-propene 2a, fenofibrate derivative 2aj, as well as alkyl substituted propene 2w (Scheme 4, entries 3–5), thereby further highlighting the practicability of current H/D exchange reactions. Scheme 4 | Gram-scale reactions. Reactions were performed on a 10–20 mmol scale under corresponding conditions (see Supporting Information for details). Yield of the isolated product. Deuterium incorporation percentages were detected by 1H NMR analysis. a 3d as catalyst and MeOD as solvent. MeOD, deuterated methanol. Download figure Download PowerPoint Control experiments were conducted to elucidate this deuterium incorporation process. First, treating (1-(2-phenylcyclopropyl)vinyl)benzene 1bf under the condition C, the corresponding ring-open product 2bf was obtained with 65% yield and 36% D-incorporation on the methyl position, providing direct support to a radical-like mechanism (Scheme 5a). Under the catalytic conditions, only a trace amount of hydrogen gas was observed, indicating that the normally observed hydrogen evolution via Co(III)–H was largely suppressed under the present basic conditions (Scheme 5b, entry 1). The use of alkyl cobalt 3e, a known compound that is capable of in-situ generating Co(III)–H,58 was also found to promote the H/D exchange albeit not as effective as the photoreduction system. In this case, improved results were obtained by increasing the amount of DIPEA or using DABCO as a base (Scheme 5b, entries 2–4), suggesting the photoredox system of [Ir]/DIPEA was responsible both for the generation of Co(III)–H and the subsequent proton exchange.59,60 Light on–off experiments showed that the deuteration process was completely suppressed without light, indicating a photocatalytic effect on the subsequent reversible addition-elimination process (Scheme 5c).58 Scheme 5 | Mechanistic insights. Reactions were performed on a 0.1 mmol scale under corresponding conditions. Yield of the isolated product. Deuterium incorporation percentages were detected by 1H NMR analysis. 1H NMR, proton nuclear magnetic resonance. Download figure Download PowerPoint Based on the previous reports and our mechanism studies,26–32,39,61–63 a catalytic cycle was proposed as illustrated in Scheme 6. [Ir] combined with DIPEA provides an efficient photoreduction system to generate the key Co(III)–H specie via a sequence electron and proton transfer process. The Stern–Volmer fluorescence quenching experiments indicated that [Ir(III)]* mainly followed the oxidative quenching process with cobaloxime 3a ( Supporting Information Figure S9).a Subsequently, Co(III)–H underwent H/D exchange with a deuterium reservoir; the following addition to alkene 1 then delivered a singly deuterated alkyl cobalt A. The intermediate A readily underwent a photomediated homolysis and hydrogen radical abstraction to furnish the deuterated product 2-D1, regenerating Co(III)–H species. Subsequently, repeated addition/elimination process produced the desired deuterated alkene 2. The observed regioselectivity could be explained by considering the inherent radical feature of alkyl–Co(III) intermediate A of which the formation of the stable benzylic or tertiary radical center was generally preferred as a result of the fragile nature of the C–Co bond. Scheme 6 | Proposed catalytic cycle. Download figure Download PowerPoint Conclusion We have developed a visible light-promoted direct deuteration of alkenes based on Co(III)–H medicated reversible H/D exchange strategy. This operationally simple and cost-effective protocol serves as a general and practical approach to various alkenes, including 2-aryl-propenes styrenes and alkyl alkenes, and could enable late-stage D-incorporation with structurally complex molecules. Furthermore, the current strategy is convenient and amenable for scale-up and will accelerate the construction of new deuterated compounds for drug discovery. Footnote a A reductive quenching pathway between [IrIII]* and DIPEA could not be excluded, for details see Supporting Information. Supporting Information Supporting Information is available and includes general information, substrates synthesis, optimization details, general experimental procedures, compound characterization, mechanistic studies, and details of NMR spectra. Conflict of Interest There is no conflict of interest to report. 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