Photocatalytic direct oxygen-isotopic labelings of carbonyls in ketones and aldehydes with oxygen-isotopic waters

Xianjin Zhu,Yong Liu,Lunyu Ou,Haijun Yang,Hua Fu

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education),Department of Chemistry,Tsinghua University,Beijing 100084,China

Keywords:Oxygen-isotopic labeling Photocatalysis Oxygen-isotopic waters Compounds containing carbonyls Alkanesulfinates

ABSTRACT Oxygen-isotopic labelings play important roles in identifying and understanding chemical and biological processes.Direct C=O to C=18O or C=17O conversion in a single step leading to labeled compounds can alleviate synthetic burdens without the need for resynthesis.Here we describe a photocatalytic oxygenisotopic labeling protocol that can efficiently and selectively install 18O and 17O on carbonyls of ketones and aldehydes via oxygen isotope exchange with oxygen-isotopic waters (H218O or H217O) as the sources of oxygen isotopes,in which light and oxygen-enabled sodium alkanesulfinates catalyzed this process.This strategy was extended to the in-situ formed ketones from the photocatalytic aerobic oxidation of alkyl arenes and secondary alcohols.Furthermore,reduction of the oxygen-isotopically labeled aldehydes with NaBH4 provided the corresponding oxygen-isotopically labeled primary alcohols.We believe that the oxygen-isotopically labeling method will be widely used in chemistry,biology and medicine fields.

The isotopes of elements have become important tools in chemistry,biology and medicine fields,and they are widely used in spectroscopy,mass spectrometry and mechanistic and pharmacokinetic investigations [1].Beyond the widespread applications,there has been much attention in incorporating isotopes into drug molecules [1].For example,a deuterated drug,deutetrabenazine approved by the United States’Food and Drug Administration,is used in the treatment of Huntington’s disease [2].The replacement of hydrogen with its isotopes has received much attention as a way to change the absorption,distribution,metabolism and excretion (ADME) properties of drug candidates [1,3–5].However,there has been less attention in the oxygen-isotopic labeling relative to the hydrogen-isotopic labeling [6–8].In fact,18O and17Olabeled molecules for high resolution mass spectrometry (HRMS)and17O-labeled molecules for nuclear magnetic resonance (NMR)spectroscopy are advantageous in rapid identifying drug metabolites in very complex samples [9].18O2and17O2are the simplest oxygen sources,and they have been used in the transition metalcatalyzed aerobic oxidation [10,11].However,the aerobic oxidation with the gaseous reagents that are not easily stored and taken is incompatible with many common functional groups and suffers from some environmental problems for use of harmful transition metals.Water is a green and cheap medium or reactant for chemical transformation [12–14],the bench-stable waters,H218O and H217O,are idea oxygen isotope sources,and they have been used in labeling of organic molecules [15–20].The direct conversion of widespread C=O bonds into C=18O and C=17O bonds with H218O and H217O as the oxygen-isotopically labeled sources is simple,convenient and environmentally friendly.Furthermore,direct C=O to C=18O or C=17O conversion in a single step leading to labeled compounds should alleviate synthetic burdens without the need for resynthesis.Although the oxygen-isotopical labeling of carbonyls in aldehydes and ketones in the presence of acid was reported before,the labeling rates for ketones were lower,and the scope of substrates was limited [21].

Visible light photocatalysis has become a thriving area of chemical research for its simplicity,economy and reaction novelty [22–30],and the efficiency of reactions highly depends on the suitable photocatalysts [31–34].The existing photocatalysts mainly are precious transition-metal complexes [35–37] and elaborate organic dyes [38].Very recently,we have developed the efficient and environmentally friendly light and oxygen-enabled sodium trifluoromethanesulfinate-mediated selective aerobic oxidations of alkyl arenes and alcohols for the first time [39,40].Later,several research groups used our photocatalytic systems to develop some useful reactions [41–45].Here,we want to explore a new strategy for direct oxygen-isotopic labeling of carbonyls in ketones and aldehydes (1) with oxygen-isotopic waters (H218O or H217O) by using our photocatalytic systems (Scheme 1A).In our previous investigations [39,40],we found that theinsituformed pentacoordinate sulfide (4) derived from sodium trifluoromethanesulfinate (3)and oxygen could act as the photocatalyst.A detailed description of our proposed mechanistic cycle is outlined in Scheme 1B.Initial photoexcitation of4would generate4?,and single-electron transfer (SET) of4?to oxygen would lead to superoxide anion radical5and radical6leaving Na+(At this time,two electron-deficient groups,radical6and Na+,should be separated each other).A proton transfer from oxygen-isotopic water to5would form radical7and oxygen-isotopic hydroxyl anion (8) [38],complexation of carbonyl compound (1) with Na+would give9,and nucleophilic attack of8to9would lead to10.SET of10to6would provide11freeing radical12and Na+,and combination of11with Na+would regenerate4.Meanwhile,transfer of hydrogen radical in7to12would afford hydrate13releasing oxygen,and dehydration of13would give the oxygen-isotopically labeled carbonyl compound (2)or unlabeled1.Addition of excess amount of oxygen-isotopic water (10 equiv.) in the reaction system would greatly improve yield of2.

Scheme 1.Our design on photocatalytic direct oxygen-isotopic labeling of carbonyls in ketones and aldehydes with oxygen-isotopic waters.(A) Reaction route.(B) Proposed catalytic cycle for the photoredox-catalyzed protocol.

With this mechanistic design in hand,we first screened various conditions for18O-labeling of acetophenone (14) (see Tables S1-S7 in Supporting information for details).Here,we summary some key reaction parameters (Table 1).The results showed that the conditions,using 2 mol% sodium trifluoromethanesulfinate (3)relative to14as the precursor of photosensitizer,acetonitrile as the solvent with irradiation of a 3 W light emitting diode (LED)bulb (400–405 nm) under oxygen atmosphere (1 atm),gave18Olabeled acetophenone (15) in 85%18O-labeling rate (LR) with 15%of unlabeled acetophenone (14) remaining without occurrence of any by-product (entry 1).When 5 mol% sodium benzenesulfinate(16) or 10 mol% sodium ethanesulfinate (17) replaced 2 mol%3as the precursor of photosensitizer,and 86% and 85% LRs were provided,respectively (entries 2 and 3).This transformation did not work in the presence of 10 mol% sodium trifluoromethanesulfonate (CF3SO3Na) (18) instead of3(entry 4).No18O-labeled product was observed in the absence of sulfinate (entry 5).Irradiationwith 530–535 nm LED could not induce this transformation (entry 6).When 450–455 nm,420–425 nm,380–425 nm LED or compact fluorescent light (34 W) bulbs were used as the light sources,82%,82%,79% and 75% LRs were afforded,respectively (entries 7–10).This transformation was not performed without irradiation of light (entry 11).82% LB was provided with air instead of oxygen atmosphere (entry 12).This transformation did not occur in the absence of oxygen (entry 13).The results above showed that none was dispensable for oxygen,light and sulfinate in this transformation.Other solvents,dichloromethane (CH2Cl2),1,2-dichloroethane(ClCH2CH2Cl),tetrahydrofuran (THF),ethyl acetate (CH3COOEt) and dimethyl sulfoxide (DMSO),were attempted (entries 14–18),and they were inferior to acetonitrile.More investigations on the reaction parameters were performed in Tables S1-S7.Therefore,the optimal conditions for the oxygen-isotopic labeling of ketones are as follows: 3 W LED bulb (400–405 nm) as the light source,catalytic amount of sulfinate (2 mol% sodium trifluoromethanesulfinate (3),5 mol% sodium benzenesulfinate (16) or 10 mol% sodium ethanesulfinate (17)) as the precursor of photosensitizer in acetonitrile under atmosphere of oxygen at room temperature.

Table 1Investigations of key reaction parameters.a

Having established the optimal conditions for this18O-labeling of ketones,we investigated scope of substrates.As shown in Scheme 2,various ketones are amenable to this light and oxygenenabled sulfinate-mediated selective18O-labeling strategy,they were performed well,and almost no side-products were observed.First,twenty aryl methyl ketones underwent this18O-labeling under the optimal conditions in Table 1 (15,19–37),and three sulfinates (3,16and17) as the precursors of photocatalysts were effective.Substituents on aromatic rings of the aryl methyl ketones did not obviously affect18O-labeling rates of ketones including neutral (15,35–37,75%-86% LRs),electron-rich (19–25,74%-87% LRs),weak electron-deficient (26–30,72%-87% LRs),and strong electron-deficient (31–34,62%-91% LRs) groups.Interestingly,18O-labeling of25containing amide group selectively occurred on the ketone rather than on the amide because hydrate formation of the amide was much more difficult than formation of the ketone hydrate (13in Scheme 1).Other carbonyl compounds including carboxylic acids,esters,amides,thioamide,ureas and anhydrides were attempted to perform this18O-labeling,and they did not work,which indicated that the present method exhibited high selectivity (Scheme S1 in Supporting information).Subsequently,aryl alkyl ketones containing different alkyls were tested under the standard conditions,and we found that different alkyls including trifluoromethyl (38,82%-89% LRs),ethyl (39,77%-87% LRs),cyclopentyl (40,74%-80% LRs) and cyclohexyl (41,54%-70% LRs)showed some different18O-labeling efficiency.Next,two cyclic ketones were used as the substrates,and they provided the satisfactory18O-labeling rates (42and43,77%-83% LRs).Ketones containing ether (44) and bromo (45) groups were tested,and 69%-90%LRs were achieved.Thirteen aliphatic ketones including chain (46–49,58) and cyclic (50–57) ketones were applied,and this18Olabelings were performed well (76%-91% LRs).Three aliphatic ketones containing ester groups were selectively labeled on the carbonyls of the ketones rather than on those of the ester groups(59–61,79%-90% LRs).We attempted threeα,β-unsaturated ketones (62–64),and 53%-90% LRs were obtained.Finally,various diaryl ketones were investigated,and we found that more amounts of sulfinates (25 mol% CF3SO2Na (3),25 mol% PhSO2Na (16),50 mol% EtSO2Na (17)) were needed and18O-labeling rates of the diaryl ketones (65–73,50%-77% LRs) were lower than those of the aryl alkyl ketones and aliphatic ketones above.The results can be attributed to conjugative effect and steric hindrance of two aryls in the diaryl ketones,which is unfavorable for formation of the corresponding hydrates.It is worthwhile to note that the18O-labeling of fenofibrate (73) (an effective marketed hypolipidemic drug [46])containing an ester group also was selectively performed on the ketone rather than on the ester.

Scheme 2.Investigations of substrate scope on the 18O-labeling of ketones.Reaction conditions: ketone (1) (0.1 mmol),99% 18O-labeled H218O (1.0 mmol,10 equiv.),MeCN(1.0 mL) under O2 atmosphere and light irradiation at room temperature for 12 h.(i) In the presence of 2 mol% CF3SO2Na (3).(ii) In the presence of 5 mol% PhSO2Na (16).(iii) In the presence of 10 mol% EtSO2Na (17).(iv) In the presence of 25 mol% CF3SO2Na (3).(v) In the presence of 25 mol% PhSO2Na (16).(vi) In the presence of 50 mol%EtSO2Na (17).The 18O-labeling rates (LRs) were determined by GC–MS (see Supporting information for calculation of 18O-labeling rate (LR)).

Scheme 3.18O-Labeling of aldehydes.Reaction conditions: aldehyde (0.2 mmol),99% 18O-labeled H218O (2.0 mmol,10 equiv.),MeCN (1.0 mL) under O2 atmosphere and irradiation with 3 W white LED at room temperature for 8 h.(i) In the presence of 2.0 mol% CF3SO2Na (3).(ii) In the presence of 10 mol% EtSO2Na (17).Isolated yields.The 18O-labeling rates (LRs) were determined by GC–MS (see Supporting information for calculation of 18O-labeling rates (LRs)).

Inspired by the excellent results in Scheme 2,we attempted to extend the substrate scope.First,18O-labeling of aldehydes was investigated.As shown in Scheme 3,we found that18O-labeled aldehydes in the presence of 2 mol% CF3SO2Na (3) or 10 mol%EtSO2Na (17) were major products with small amount of unlabeled aldehydes remaining and newly-formed carboxylic acids appearing.Meanwhile,we also performed one-pot two-step process including18O-labeling of aldehydes and reduction of the18O-labeled aldehydes with NaBH4to the corresponding18O-labeled alcohols.Eleven aromatic formaldehydes provided satisfactory yields and18Olabeling rates including neutral (74,75,92–95,69%-76% yields,70%-83% LRs),electron-rich (76–85,69%-81% yields,69%-85%LRs),weak electron-deficient (86–89,70%-79% yields,73%-85%LRs),and strong electron-deficient (90and9171%-76% yields,75%-80% LRs) groups.Two heteroaryl formaldehydes containing furan or thiophenol rings also were suitable substrates (96–99,61%-76% yields,74%-82% LRs).Twoα,β-unsaturated aldehydes(100–103) were attempted,and 67%-73% yields and 53%-84% LRs were provided.An aliphatic aldehyde,3-phenylpropanal,was used as the substrate,and it gave18O-labeled products104and105in 73%-75% yields with 67%-81% LRs.

In our previous research,we developed the light and oxygenenabled sodium trifluoromethanesulfinate-mediated selective aerobic oxidation of alkyl arenes and secondary alcohols to ketones[39,40].Here,we attempted sequential aerobic oxidation of alkyl arenes and secondary alcohols to ketones and18O-labeling of the ketones.As shown in Scheme 4,nine examples were performed with 25 mol% sodium trifluoromethanesulfinate (3) as the precursor of photocatalyst,and they afforded the satisfactory results (15,27,32,35,37,39,65,106and107,82%-91% yields,57%-74%LRs).As shown in Scheme 5,fourteen secondary alcohols were performed this domino strategy,and excellent yields and satisfactory18O-labeling rates were obtained (15,20,21,26,31,36,39,41,54,65,66,68,71and72,75%-92% yields,68%-80% LRs).Finally,we explored17O-labeling of ketones and an aldehyde.Here,we used lower concentration of H217O (40%17O-labeled H217O)because of its high sensitivity in17O NMR spectroscopy and cost concern.As shown in Scheme 6A,five ketones were effectively labeled with 40%17O-labeled H217O (108–112,25%-36% LRs).Testosterone (112) exhibits some biological activity including adjusting the metabolism of carbohydrates,lipids and proteins and influencing muscle growth and adipogenesis [47].Subsequently,aldehyde113was performed one-pot two-step process including17Olabeling and reduction with NaBH4,and primary alcohol115was obtained in 71% yield with 32% LB.Therefore,the results above showed that our environmentally friendly oxygen-isotopically labeling method was effective.We also attempted18O-labeling of dicarbonyl compound,1,3-cyclohexanedion (116) with 10 equiv.of 99%18O-labeled H218O in the presence of 2 mol% CF3SO2Na (3) or 10 mol% EtSO2Na (17),and the single18O-labeled (117) and double18O-labeled (118) products were obtained in 37.6% or 37.1% and 60.6% or 58.1% LBs,respectively (Scheme 6B).

Scheme 4.Aerobic oxidative 18O-labeling of alkyl arenes leading to 18O-labeled ketones.Reaction conditions: alkyl arene (0.1 mmol),99% 18O-labeled H218O (1.0 mmol,10 equiv.),CF3SO2Na (3) (0.025 mmol,25 mol%),MeCN (1.0 mL) under O2 atmosphere and irradiation with 3 W 400–405 nm LED at room temperature for 12 h.Isolated yields.The 18O-labeling rates (LRs) were determined by GC–MS (See Supporting information for calculation of 18O-labeling rates (LRs)).

Scheme 5.Aerobic oxidative 18O-labeling of alcohols leading to 18O-labeled ketones.Reaction conditions: alcohol (0.1 mmol),99% 18O-labeled H218O (1.0 mmol,10 equiv.),CF3SO2Na (3) (0.025 mmol,25 mol%),MeCN (1.0 mL) under O2 atmosphere and irradiation with 3 W 400–405 nm LED at room temperature for 12 h.Isolated yields.The 18O-labeling rates (LRs) were determined by GC–MS (See Supporting information for calculation of 18O-labeling rates (LRs)).

Scheme 6.(A) 17O-Labeling of ketones and an aldehyde.Reaction conditions: ketone (0.1 mmol),40% 17O-labeled H217O (1.0 mmol,10 equiv.),MeCN (1.0 mL) under O2 atmosphere and irradiation with 3 W white LED at room temperature for 8 h.(i) In the presence of 2.0 mol% CF3SO2Na (3).(ii) In the presence of 10 mol% EtSO2Na (17).The 17O-labeling rates (LRs) were determined by GC–MS or ESI-MS (See Supporting information for calculation of 17O-labeling rates (LRs)).(B) 18O-Labeling of 1,3-cyclohexanedion.(i) In the presence of 2 mol% CF3SO2Na (3).(ii) In the presence of 10 mol% EtSO2Na (17).The 18O-labeling rates (LRs) were determined by GC–MS (See Supporting information for calculation of 18O-labeling rates).

We explored mechanism on the photocatalytic direct oxygenisotopic labeling.In previous study,we conducted density functional theory (DFT) calculations and analysis,and found that pentacoordinate sulfide (4) derived from sodium trifluoromethanesulfinate (3) and oxygen could act as the photocatalyst [39].Here,we investigated treatment of PhSO2Na (16) or EtSO2Na (17) with oxygen,and found that formation of the corresponding pentacoordinate sulfides16′and17′were feasible (Tables S8-S15,Schemes S2 and S3 in Supporting information).When 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) was added to the reaction system,no oxygen-isotopic product was observed (Supporting information),which indicated that the present oxygen-labeling underwent a radical process.More controlled experiments were performed (see Supporting information for details).All the results show that the proposed mechanism in Scheme 1 is reasonable.

In conclusion,we have developed a photocatalytic direct oxygen-isotopic labeling protocol,in which18O and17O-labelings of carbonyls in ketones and aldehydes were efficient and selective in a single step using oxygen-isotopic waters (H218O or H217O) as the sources of oxygen isotopes.This strategy was extended to thein-situformed ketones from the aerobic oxidation of alkyl arenes and secondary alcohols.Furthermore,the reduction of the oxygenisotopically labeled aldehydes with NaBH4provided the corresponding oxygen-isotopically labeled primary alcohols.The present oxygen-isotopically labeling method shows some advantages including inexpensive and readily available alkanesulfinates as the precursors of photocatalysts,simple and easy operational reaction conditions,use of environmentally friendly chemicals and high selectivity of the reactions.We believe that the oxygen-isotopically labeling method will be widely used in chemistry,biology and medicine fields.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by Natural Science Foundation of Beijing Municipality (No.2222011),National Natural Science Foundation of China (No.22077074) and China Postdoctoral Science Foundation (No.2021M701869).

Supplementary materials

Supplementary material associated with this article can be found,in the online version,at doi:10.1016/j.cclet.2023.108454.