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. Author manuscript; available in PMC: 2023 May 29.
Published in final edited form as: J Labelled Comp Radiopharm. 2023 Feb 26;66(3):86–94. doi: 10.1002/jlcr.4015

Highly selective catalytic transfer hydrodeuteration of cyclic alkenes

Samuel J Hintzsche 1, Zoua Pa Vang 1, Emanuel Rivera Torres 1, Mykaela Podoski 1, Joseph R Clark 1
PMCID: PMC10226366  NIHMSID: NIHMS1899155  PMID: 36772856

Abstract

Selective deuterium installation into small molecules is becoming increasingly desirable not only for the elucidation of mechanistic pathways and studying biological processes but also because of deuterium’s ability to favorably adjust the pharmacokinetic parameters of bioactive molecules. Fused bicyclic moieties, especially those containing heteroatoms, are prevalent in drug discovery and pharmaceuticals. Herein, we report a copper-catalyzed transfer hydrodeuteration of cyclic and heterocyclic alkenes, which enables the synthesis of chromans, quinolinones, and tetrahydronaphthalenes that are precisely deuterated at the benzylic position. We also demonstrate the ability to place one deuterium atom at the homobenzylic site of these scaffolds with high regioselectivity by swapping transfer reagents for their isotopic analogs. Furthermore, examples of chemoselective transfer hydrogenation and transfer deuteration are disclosed, allowing for the simultaneous incorporation of two vicinal hydrogen or deuterium atoms into a double bond.

Keywords: copper, deuteration, hydrodeuteration, hydrogenation, transition metal catalysis

1 |. INTRODUCTION

In the years since 1932, when the discovery of deuterium was first reported,1 this heavy isotope has found increased application within the fields of chemistry and biochemistry. For example, deuterium-labeled compounds are frequently used for kinetic isotope effect measurements and elucidation of reaction mechanisms.2–6 Deuterated small molecule probes also serve to determine the stereochemical course of enzymatic or microbiological reactions and to study biosynthetic pathways.7–16 Furthermore, deuterated compounds can serve as valuable tools for spectroscopy or standards for high-resolution mass spectrometry (HRMS) in both analytical and physical chemistry.14,17–19 Beyond use as tools for investigating chemical processes, strategic incorporation of deuterium into small molecule drugs may enhance drug stability to oxidative processes such that pharmacokinetic parameters and safety profiles relative to hydrogen-containing drug analogs are improved.14,18,20–22 The FDA approval of the first deuterated drug, deutetrabenazine,23 and recent approval of Bristol Myers Squibb’s TYK2,24 underscores the significance of selective deuterium labeling for modulating absorption, distribution, metabolism, and excretion (ADME). Given the widespread applications of deuterium, an increasing interest exists for developing selective reactions for installing deuterium into small molecules. The focus of the present study is the selective incorporation of deuterium into cyclic and heterocyclic alkene structures.

Despite the broad applications of deuterium-labeled molecules in chemistry, existing reactions to incorporate deuterium into small molecules pose selectivity challenges for precisely incorporating an exact quantity of deuterium at a target position. While hydrogen isotope exchange (HIE) reactions are powerful for late-stage deuteration of complex molecules,19,25–29 it remains challenging to control the placement and quantity of deuterium at a specific site within the target molecule, especially in the synthesis of deuterated ring structures (Scheme 1a).30 Consequently, large mixtures of isotopomer and isotopologue products are formed in many reactions, leading to inseparable isotopic impurities, which are not able to be appropriately quantified and characterized using traditional analysis techniques such as NMR or mass spectrometry. This could pose future challenges in deuterated drug synthesis, where recommendations for synthetic methods, analytical methods, and specifications are under active consideration.31 Reductive deuteration protocols offer opportunities for achieving higher selectivity in both the quantity and placement of deuterium25; however, reaction scope is generally limited to substrates containing more highly polarized functionality.32–34

SCHEME 1.

SCHEME 1

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Recent methodologies for the installation of deuterium.

Alternatively, transfer hydrodeuteration reactions offer opportunities for highly selective deuteration reactions to occur across various alkene types.35–38 For example, transition metal catalyzed methods may operate in a manner such that the introduction of separate hydrogen and deuterium donors enables the incorporation of each atom at distinct points within the catalytic cycle, even in unactivated alkene-containing substrates. A seminal report by the Webster group in 2019 demonstrated that an iron-catalyzed transfer hydrodeuteration could promote a Markovnikov selective transfer hydrodeuteration of both terminal aliphatic olefins and styrene derivatives (Scheme 1b).39,40 More recently, our group reported several Cu-catalyzed alkene transfer hydrodeuteration reactions that precisely incorporate one deuterium atom and one hydrogen atom across a double bond with high fidelity.41–43 The transfer hydrodeuteration was extended to acyclic aryl alkene substrate types to achieve the synthesis of small molecules containing exactly one deuterium atom at the benzylic position (Scheme 1c).41 Despite the broad alkenyl arene substrate scope, cyclic alkene types were not explored. Considering the prevalence of cyclic ring structures in pharmaceuticals,44 especially heterocycles,45 we were interested in extending our reaction to aryl alkenes in which the alkene is contained in a ring. This type of precision deuteration would expand access to selectively deuterated cyclic hydrocarbon frameworks along with selectively deuterated heterocycles such as chromans and quinolinones (Scheme 1d).

2 |. RESULTS AND DISCUSSION

A key challenge in our initial investigation of cyclic alkene types for Cu-catalyzed transfer hydrodeuteration was reaching complete conversion to the desired selectively deuterated product. If full conversion is not achieved, the recovered starting material remains difficult to separate from the desired deuterated product. We investigated the optimal reaction conditions using commercially available 1,2-dihydronaphthalene 1 as a substrate and were pleased to see that the reaction proceeded smoothly, resulting in a 77% yield and 98% deuterium incorporation of product 2 using Cu (OAc)2 (2 mol%), the DTB-DPPBz ligand (2.2 mol%), ethanol-OD (2.6 equiv) as the deuterium source, dimethoxymethylsilane (DMMS; 4 equiv) and THF as the solvent, while performing the reaction at 40°C for 24 h (entry 1, Table 1). We investigated lowering catalyst/ligand loading (1 mol%/1.1 mol%) and silane loading (3 equiv) and found the reaction to proceed similarly well (entry 2). Investigation of other alcohol-OD sources revealed that using ethanol-OD or isopropanol-d8 results in full conversion to desired product 2 (entries 1–4). Using D2O as the deuterium source is detrimental to reactivity, providing only 17% of the desired product 2 (entry 5), while methanol-OD and tBu-OD gave diminished yields relative to ethanol-OD and isopropanol-d8 (entries 6–7). Changing the silane source to polymethylhydrosiloxane (PMHS) resulted in a similarly efficient reaction when compared with entry 3 (entry 8). Similar success was also observed when the reaction was performed at room temperature (entry 9). While entries 1, 2, 3, 4, 8, and 9 resulted in high yields of the desired product 2, reaction conditions in entry 1 were generally used for evaluation of the substrate scope. This was because more challenging substrate types (e.g., those containing a heterocycle or heteroatom functionality) did not always reach completion under milder conditions, often leading to inseparable mixtures of product and trace starting material. Attempts to modify our protocol for reaction setup outside a glovebox did not result in productive reactions, and we determined that a glovebox is necessary for consistent conversion to the desired product. We believe that the presence of O2 inhibits the catalytic activity, and the presence of H2O creates a scenario where competitive protodecupration can occur instead of deuterodecupration with the deuterated alcohol, resulting in decreased deuterium incorporation.

TABLE 1.

Transfer hydrodeuteration optimization studies.

graphic file with name nihms-1899155-t0006.jpg
Entry D-source Silane Yielda RSM
1 EtOD DMMS (4) 77%b —
2 EtOD DMMS (3) 80%c —
3 EtOD DMMS (3) 91% —
4 IPA-d8 DMMS (3) 77% —
5 D2O DMMS (3) 17% 83%
6 MeOD DMMS (3) 47% 33%
7 tBuOD DMMS (4) 65% 10%
8 EtOD PMHS (3) 90% —
9 EtOD DMMS (3) 85%d —
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Note: All deuterium incorporations greater than 95%. With optimal conditions (entry 1), deuterium incorporation is 98%.

Abbreviations: D2O, deuterium oxide; DMMS, dimethoxymethylsilane; EtOD, ethanol-OD; IPA-d8, isopropanol-d8; MeOD, methanol-OD; PMHS, polymethylhydrosiloxane; RSM, recovered starting material; tBuOD, tert-butyl-OD.

a

1H NMR yield using 1,3,5-trimethylbenzene as an internal standard.

b

Isolated yield.

c

1 mol% catalyst loading.

d

Reaction performed at room temperature.

In addition to 1,2-dihydronaphthalene, an unsaturated bicyclo[4.3.0] moiety was also successfully employed under the reaction conditions. This was demonstrated using 1H-indene, which rendered the desired product 3 in an 81% 1H NMR yield with 96% deuterium incorporation at the benzylic site (Scheme 2). In this example, the reaction did not reach completion using EtOD, and we found that complete conversion was observed with 2-propanol-d8 at 60°C using 5 mol% Cu(OAc)2 and 5.5 mol% DTB-DPPBz. Attempts to expand our optimized conditions to more complex substrates continued with the hydrodeuteration of dihydronaphthyl derivatives. The bicyclic reaction product is a common structural feature of several important natural product classes, such as steroids and diterpenes. Electron-withdrawing protecting groups such as pivalate, triflate, and toluenesulfonyl functionalities were tolerated under the reaction conditions (4–6). Furthermore, an electron-rich dihydronaphthyl derivative afforded product 7 in good yield with excellent deuterium incorporation, indicating the electronics of the arene would not have a detrimental impact on the hydrodeuteration reaction of these cyclic alkene types.

SCHEME 2.

SCHEME 2

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Transfer hydrodeuteration of cyclic alkenes.

We were also interested in evaluating our transfer hydrodeuteration protocol on other common cyclic alkene motifs, particularly those containing heteroatoms (Scheme 3). 2H-Chromenes, which are an important class of heterocyclic compounds that exhibit a variety of biological activities, provided intriguing targets. Transfer hydrodeuteration of these scaffolds would offer access to precisely deuterated chromane-d1 derivatives, which have potential as structural features of small molecule drugs and vitamins, including E vitamins and nebivolol. The olefin of 2H-chromene underwent transfer hydrodeuteration to produce 8 in a 70% yield with 93% deuterium incorporation. Selectively deuterated products 9 and 10 were also accessed from the corresponding 2H-chromene substrates (see Supporting Information for substrate structures), and a 99% deuterium incorporation was realized in both cases. Additionally, 11, a structural analog of tocopherol (vitamin E), was isolated in a 97% yield with 97% deuterium incorporation at the benzylic site. Selectively deuterated chromanes 12 and 13, containing highly electron-rich arenes, were also accessible in moderate to good yields. Introducing electron withdrawing functionality to 2H-chromene did not appear to have a detrimental impact on reactivity, and 6-fluoro-2H-chromene was deuterated to give product 14 in a 63% yield with a 99% deuterium incorporation. Additionally, fused tricyclic chromane-d1 15 was accessed in 93% yield and with excellent deuterium incorporation, albeit with a requirement for elevated catalyst loading. Introducing a sterically constrained environment proximal to the double bond of 16 did not appear to affect performance or deuterium incorporation; however, it should be noted that the product was isolated with a diastereomeric ratio of 70:30 (see Supporting Information for details).

SCHEME 3.

SCHEME 3

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Transfer hydrodeuteration of heterocyclic alkenes.

Quinolinones were another attractive target for our transfer hydrodeuteration protocol because they are prevalent in pharmaceuticals and natural products with anticancer, antiviral, and antihypertensive properties.46,47 Encouragingly, such an aryl unsubstituted α,β-unsaturated amide underwent efficient and chemoselective hydrodeuteration at the benzylic position of the alkene without reduction of the carbonyl to give product 17 in 90% yield (Scheme 3). Introducing electron density to the bicyclic structure via installation of a methoxy group resulted in isolation of 18 in an 80% yield and excellent deuterium incorporation. Changing the electronics of the arene with the addition of a bromine atom to the structure did not appear to have a negative effect on the desired reactivity, with product 19 showing full conversion and excellent deuterium incorporation at only the benzylic position. Importantly, no reductive dehalogenation side reactions were observed at the aryl bromide site. We also attempted the transfer hydrodeuteration of a dihydro-quinoline substrate; however, the desired mono-deuterated tetrahydroquinoline product 20 was not observed in a synthetically useful yield and had diminished deuterium incorporation.

We have previously postulated that because hydrogen and deuterium atoms are introduced at distinct points within the catalytic cycle of our Cu-catalyzed alkene transfer hydrodeuteration reaction, it is possible to “switch” the regioselective outcome of the reaction by simply modifying the hydrogen and deuterium transfer reagents.41,48 This important selectivity principle of our reaction design permits full control over the quantity and placement of deuterium across a π-bond functionality, and we sought to exploit this unique reaction feature in cyclic alkene substrate types. We first investigated the regioselective incorporation of deuterium at the homobenzylic site by using a deuterated silane and 2-propanol (Scheme 4a). This reaction was performed across three distinct cyclic alkene substrate types, leading to the synthesis of selectively deuterated quinolinone-d1 21, tetrahydronaphthalene-d1 22 and chromane-d1 23 in high yield and excellent levels of deuterium incorporation (80%–90% yield and 92%–98% D inc.). The corresponding transfer deuteration reaction was investigated by using DSiMe(OMe)2 and isopropanol-d8 as the deuterium transfer reagents. This led to a high yield and excellent deuterium incorporation across the resulting cyclic products 24–26 (65%–90% yield and ≥92% D inc. at both C1 and C2, Scheme 4b). Lastly, the analogous transfer hydrogenation reaction was performed by changing to the normal isotopic species for both transfer reagents. This resulted in 27–29 being isolated in moderate to good yield (55%–80% yield, Scheme 4c).

SCHEME 4.

SCHEME 4

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Switchable selectivity substrate scope.

In our previous reports of switchable selectivity for both alkyne and alkene transfer hydrodeuteration reactions, we were only able to reach modest levels of deuterium incorporation at the target site.41,42,48 We postulated this was due to the synthesis of the DSiMe(OMe)2 where hexane is used as a solvent, and purification involved a distillation after the reaction reached completion. Consequently, the deuterium transfer reagent was isolated as a solution in hexane. While precautions were taken to avoid exposure of the DSiMe(OMe)2 to air and water, any trace hydrogen impurities will likely have a significant impact on deuterium incorporation levels in the transfer hydrodeuteration/deuteration reactions. In the present work, we modified the procedure such that decane was used as the solvent for the DSiMe(OMe)2 gram-scale synthesis (Equation 1). This permitted that DSiMe(OMe)2 could be distilled and isolated neat (see Section 3.2). Ultimately, higher levels of deuterium incorporation at the homobenzylic site (>90% in all cases) could be achieved with this protocol.

2 |. (1)

3 |. EXPERIMENTAL

3.1 |. General

The following chemicals were purchased from commercial vendors and were used as received: Cu(OAc)2 (99.999% from Alfa Aesar); dimethoxy(methyl) silane (TCI); ethanol-OD (Millipore Sigma); 2-propanol-d8 (Fischer Scientific), 2-propanol (Alfa Aesar); triphenylphosphinegold(I) bis(trifluoromethanesulfonyl) imidate (Strem Chemicals) (note that this catalyst was synthesized based on a modification of a previously reported procedure)49; 1,2-dihydronaphthalene (Ambeed), 1,2-dihydroquinolin-2-one (Oakwood Chemicals); trifluoromethanesulfonic anhydride (Oakwood Chemicals); 7-methoxy-1-tetralone (Ambeed); 6-hydroxyquinolin-2(1H)one (Ambeed); chloro(triphenylphosphine)gold(I) (Ambeed); silver bis(trifluoromethanesulfonyl)imide (Ambeed); potassium carbonate (Ambeed); 7-hydroxy-3,4-dihydronaphthalene (Ambeed); 6-bromoquinolin-2(1H)-one (Ambeed); dimethylformamide (Oakwood Chemicals); methylene chloride (CH2Cl2) (Fischer Scientific); diethyl ether (Fisher Scientific); hexanes (Fisher Scientific); ethyl acetate (Fisher Scientific); sodium hydride 60% in oil dispersion (Oakwood Chemicals); propargyl bromide (80% wt. in toluene) (Oakwood Chemicals); and triethylamine (Oakwood Chemicals). Anhydrous tetrahydrofuran (THF) was purified by an MBRAUN solvent purification system (MB-SPS). Chloroform-d (CDCl3) was stored over 3 Å molecular sieves. Dry triethylamine was obtained by distillation over KOH followed by storage over 3 Å molecular sieves and KOH. 1,2-Bis[bis[3,5-di(t-butyl)phenyl]phosphino]benzene (DTB-DPPBz) was synthesized according to a previously reported procedure.50 Decane was distilled over 3 Å molecular sieves and degassed with N2 prior to use. Hexanes were distilled prior to use in column chromatography. Thin-layer chromatography (TLC) was conducted with Silicycle silica gel 60Å F254 pre-coated plates (0.25 mm) and visualized with UV and KMnO4 stains. Flash chromatography was performed using Silia Flash® P60, 40–60 mm (230–400 mesh), purchased from Silicycle. For reactions that required heating (optimization, transfer hydrodeuteration, transfer hydrogenation, and deuteration reactions), a PolyBlock for 2-dram vials was used on top of a Heidolph heating/stir plate. 1H NMR spectra were recorded on a Varian 300, 400, or 600 MHz spectrometer and are reported in ppm using solvent as an internal standard (CHCl3 at 7.26 ppm). Data reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad; coupling constant(s) in Hz; integration. 13C NMR spectra were recorded on a Varian 76 or 101 MHz spectrometer and are reported in ppm using solvent as an internal standard (CDCl3 at 77.16 ppm). 19F NMR spectra were recorded on a Varian 376 MHz spectrometer. 2H NMR spectra were recorded on a Varian 61 MHz spectrometer using CHCl3. Labeled solvent impurities were calculated out when reporting isolated yields. Deuterium incorporation was calculated by integration of the benzylic proton(s) of the desired product in the 1H NMR, and regioselectivity was confirmed using 2H NMR. High-resolution mass spectra were obtained for all new compounds not previously reported using the resources of the Chemistry Instrument Center (CIC), University at Buffalo, SUNY, Buffalo, NY, and the Shimadzu Analytical Instrumentation Laboratory and Research Center at the University of Wisconsin-Milwaukee. Specifically, high resolution accurate mass analysis was conducted using the following instruments: a Thermo Q-Exactive GC-Orbitrap Mass Spectrometer, provided through funding from the National Science Foundation, MRI-1919594; a Shimadzu QTOF LCMS-9030; and a Shimadzu Nexera X2 HPLC.

3.2 |. Synthesis of DSiMe(OMe)2

To an oven-dried 500 mL Schlenk flask equipped with a Teflon stir bar in a N2 filled glovebox was added Pt (PPh3)4 (585.8 mg, 0.471 mmol, 0.01 equiv), dimethoxy(methyl)silane (5.81 mL, 47.1 mmol, 1 equiv), and distilled and degassed decane (2.4 mL, 0.05M). The Schlenk flask was sealed with a rubber septum, removed from the glovebox, connected to a manifold, and cooled to −78°C using liquid N2. A single freeze-pump-thaw cycle was performed, then the Schlenk flask was backfilled with D2 gas from a D2-purged balloon at room temperature. The flask was sealed with parafilm and heated to 60°C. After 2 h, the reaction was cooled to room temperature and a single freeze-pump-thaw was performed again, backfilling with D2 gas. The process of freeze-pump-thawing, backfilling with D2 gas, then heating was repeated at least six times or until the 1H NMR showed ≥98% deuterium incorporation. It is important to maintain a N2 (g) inert atmosphere while obtaining a minimal quantity of sample for 1H NMR analysis.

The solution was then transferred to a 50 mL two-neck oven-dried round-bottom flask with a short-path distillation apparatus attached. The short-path distillation apparatus was vacuum purged with nitrogen three times before performing the DSiMe(OMe)2 mixture transfer. This was achieved through a cannula connecting the Schlenk flask with the two-neck round-bottom flask, using positive pressure with nitrogen gas to maintain the inert atmosphere. After the transfer of DSiMe(OMe)2, the mixture was heated with an oil bath up to 150°C. Once the silane was distilled into the pre-weighed receiving flask, it was taken off heat, and the receiving flask was disconnected with positive nitrogen pressure to keep air and moisture out of the flask. A 58% yield of the pure, clear, and colorless liquid was obtained (2.928 g of product, ≥98% D inc.). The receiving flask was tightly capped, sealed with Parafilm, and stored in a freezer at −20°C.

3.3 |. General procedure for the transfer hydrodeuteration of cyclic aryl alkenes

In a N2-filled glovebox, DTB-DPPBz (6 mg, 0.0066 mmol, 0.022 equiv), Cu(OAc)2 (30 μL of a 0.2 M solution in THF, 0.006 mmol, 0.02 equiv), and THF (120 μL) were added to an oven-dried 2-dram vial followed by dropwise addition of dimethoxy(methyl)silane (148 μL, 1.20 mmol, 4 equiv). A color change from green/blue to yellow/orange was observed while stirring for 15 min while the next step was carried out. In a separate oven-dried 1-dram vial was added the alkene substrate (0.30 mmol, 1 equiv), THF (0.150 mL), and ethanol-OD/2-propanol-d8 (2.6 equiv based on substrate). The solution in the 1-dram vial was added dropwise over 20 s to the 2-dram vial. The total volume of THF was calculated based on having a final reaction concentration of 1 M based on the alkene substrate. The 2-dram vial was capped with a red pressure relief cap, taken out of the glovebox, and stirred for 20–24 h at the appropriate temperature. Upon completion, diethyl ether (10 mL × 2) was added to the reaction vial, at which point the reaction was filtered through a 1″ silica plug with 20 mL of diethyl ether followed by 80 mL of diethyl ether to elute the remaining product into a 200 mL round-bottom flask. After removing the diethyl ether from the mixture, the crude product was purified by flash column chromatography (SiO2, ethyl acetate/distilled hexanes, or dichloromethane/distilled hexanes).

4 |. CONCLUSIONS

In summary, we have expanded upon our previously published work by demonstrating a highly regioselective alkene transfer hydrodeuteration of cyclic olefins, including those which are a part of motifs commonly found in biologically active molecules. Dihydronaphthalene, chromene, and quinolinone scaffolds were shown to undergo catalytic transfer hydrodeuteration for the installation of precisely one deuterium atom at the benzylic site. By simply switching the deuterium and hydrogen transfer reagents, one deuterium atom can also be introduced regioselectively at the homobenzylic site. Additionally, chemoselective hydrogenation and deuteration of the alkene can be performed. We anticipate this reaction methodology will facilitate future studies that employ selectively deuterated small molecules.

Supplementary Material

SI

ACKNOWLEDGEMENTS

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35 GM147441–01. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. J.R.C. acknowledges the donors of the American Chemical Society Petroleum Research Fund (65384-DNI1) for partial support of this research and Marquette University for financial support in the form of start-up funds. Z.P.V. thanks Marquette University Department of Chemistry for an Eisch Fellowship, MGS Summer Fellowship, and Schmidt Fellowship. We acknowledge the University at Buffalo Chemistry Instrument Center and University of Wisconsin-Milwaukee Shimadzu Analytical Instrumentation Laboratory and Research Center for performing HRMS analyses. We thank Mitchell Mills for carrying out initial reaction studies.

Footnotes

CONFLICT OF INTEREST STATEMENT

The authors declare no competing financial interest.

SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available in the supporting information of this article.

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Associated Data

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Supplementary Materials

SI
NIHMS1899155-supplement-SI.pdf (3.1MB, pdf)

Data Availability Statement

The data that support the findings of this study are available in the supporting information of this article.

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