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DOI: 10.1055/a-2538-1198
synpacts

Nickel-Catalyzed Deuteroalkylation Using Thianthrenium Salts

Jie Zhang
,
Zhuangzhi Shi∗

We would like to thank the National Key R&D Program of China (2022YFA1503200), the National Natural Science Foundation of China (Grants 22025104, 22171134, and 21972064), and the Fundamental Research Funds for the Central Universities (Grant 020514380254) for their financial support.
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Abstract

Isotopically labeled compounds are essential in both organic and pharmaceutical chemistry. The standard methods for synthesizing such molecules often involve the use of deuterated building blocks, allowing the incorporation of functional groups and deuterium into the target molecule in one step. In this Synpacts article, we highlight our approach to accessing various a-deuterated alkyl thianthrenium (TT) salts through a pH-dependent hydrogen-isotope-exchange process using D2O as a cheap source of deuterium. Through the in situ formation of isotopically labeled alkyl halides, these TT salts exhibit exceptional compatibility with a range of nickel-catalyzed hydrodeuteroalkylations of nonactivated olefins and with nickel-catalyzed cross-electrophile coupling reactions with alkyl, alkenyl, and (het)aryl bromides. This technique has proven to be invaluable for accessing a range of deuterium-labeled compounds, particularly those of pharmaceutical significance.


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Key words

deuteriation - thianthrenium salts - hydrodeuteroalkylation - nickel catalysis - metallaphotoredox reaction - pharmaceutical chemistry
1

Introduction

Deuterium, a stable and naturally occurring isotope of hydrogen characterized by the presence of an extra neutron, exhibits an enhanced stability in C–D bonds compared with C–H bonds. Moreover, compounds labeled with deuterium serve crucial roles in elucidating kinetic isotope effects in mechanistic studies and can function as essential internal standards in quantitative mass spectrometry. This makes the exploration of deuterium-labeled molecules a promising avenue for fostering innovation and discovery in functional molecules across multiple scientific disciplines.[1] Recently, deuterated aliphatic groups, which are widespread in many drug molecules, have become particularly valuable.[2] This was firstly emphasized by the US Food and Drug Administration’s groundbreaking approval in 2017 of deutetrabenazine (Austedo) for treating Huntington’s disease, highlighting the importance of this advancement.[3] Additionally, clinical trials involving deuterated alkyl-containing drugs, such as CTP-543,[4] CTP-499,[5] PHA-022121, and RT001,[6] have shown promising results (Figure [1a]). Because many of the top-selling commercial drugs contain at least one alkyl group, a flexible synthetic strategy to produce isotopically labeled functionalized alkanes would offer significant advantages.[7]

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Figure 1 Background
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Scheme 1 Feasibility exploration, synthesis, and transformation of deuterated alkyl TT salts

Incorporating deuterated building partners in synthetic chemistry facilitates the efficient production of deuterium-labeled compounds. This approach permits the simultaneous introduction of both functional groups and deuterium atoms in a single synthetic step, facilitating the construction of a target molecule with a high degree of deuterium incorporation and precisely controlled deuterated sites. Although this method has proven effective in synthesizing deuterium-containing drugs, its progress has been impeded by the limited availability of easily accessible deuterated reagents. Alkyl halides (such as Cl, Br, and I) and pseudohalides (such as OTf and OTs) are readily available and widely employed as electrophilic alkylation reagents in the organic area. However, hydrogen-isotope exchange of alkyl (pseudo)halides to produce isotopically labeled alkyl electrophiles can pose significant synthetic challenges because of the low pK a of α-C–H bonds and the reactivity of carbon–functional group bonds (Figure [1b]; top). The α-deuteration of carboxylic acids should be possible, but these compounds exhibit a low electrophilicity, necessitating the generation of redox-activated esters to promote decarboxylative substitution (Fig. [1b]; bottom).[8] This approach offers additional avenues for deuterium-labeled alkyl thianthrenium (TT) salts to serve as versatile organic electrophilic reagents in chemical reactions.


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Synthesis of d 2-Labeled Alkyl Thianthrenium Salts

Sulfonium salts, characterized by positively charged sulfur ions with three substituted organic groups, are highly versatile compounds that serve as invaluable aryl and alkyl electrophiles in numerous chemical transformations.[9] Among these compounds, aryl TT salts are notable for their exceptional versatility, acting as reaction intermediates with high reactivities in a wide range of chemical transformations.[10] Recently, Ritter and his team have achieved remarkable success in using aryl TT salts for halogenation (I, Br, Cl, and F[11])[12] and hydrogen-isotope labeling[13] by carbon–sulfur bond cleavage, a process facilitated by transition-metal catalysis. Our group,[14] alongside other researchers,[15] has conducted thorough investigations into alkyl TT salts, significantly broadening the chemical horizon for alkyl (pseudo)halides. We have carried on further computational studies to investigate the characteristics of the alkyl TT salt 1 (Scheme [1a]). These studies showed that 1 exhibits a comparatively lower pK a value for its α-hydrogen and a lower bond-dissociation energy (BDE) than conventional alkyl (pseudo)halides, such as OTf (V), OTs (IV), I (III), Br (II), and Cl (I), indicating that the alkyl TT salt 1 has a better leaving ability.

Based on these results, a diverse array of d 2-labeled alkyl TT salts were prepared by a modular approach through a simple pH-dependent hydrogen-isotope-exchange process, taking 2.0 equivalents of K2CO3 as a base and MeCN as a solvent, and using D2O as a convenient and cheap source of deuterium, at room temperature for six hours (Scheme [1b]). Thanks to the excellent leaving ability of TT salts, we developed a highly versatile platform that employs TT salts for the efficient generation of deuterium-labeled alkyl electrophiles in combination with inorganic salts. Taking the complex molecule 2, derived from a natural product, as an example, the compound readily undergoes iodination (3a), bromination (3b), chlorination (3c), fluorination (3d), trifluoromethylthiolation (3e), cyanation (3f), or azidation (3g) with the corresponding inorganic salts, resulting in good yields and high deuterium incorporation (Scheme [1c]).


# 3

Hydrodeuteroalkylation of Nonactivated Olefins with d 2-Labeled Alkyl Thianthrenium Salts

During the past decade, the need to form C–C bonds by functionalizing olefin feedstocks has soared.[16] A remarkable approach in this endeavor involves the catalytic addition of a metal hydride species to nonactivated olefins, resulting in modification of a latent carbogenic nucleophile.[17] A seminal study conducted by the groups of Fu and Liu in 2016 produced a significant breakthrough in organic chemistry, specifically in the realm of alkene transformations. This research showcased a Ni-catalyzed anti-Markovnikov hydroalkylation reaction of nonactivated alkenes using alkyl iodides as radical precursors.[18] A variety of electrophilic coupling partners, including halides,[19] sulfonates,[20] and pyridinium salts,[21] have been employed in hydroalkylation reactions. However, the corresponding hydrodeuteroalkylation process faces challenges due to the scarcity of suitable deuterated alkyl sources. We successfully realized a hydrodeuteroalkylation of nonactivated olefins by using d 2-labeled alkyl TT salts as reaction partners and nickel hydride as the catalyst; notably, alkyl iodides generated in situ were the key intermediates.[22]

We investigated the scope of both d 2-labeled alkyl TT salts and nonactivated olefins, which exhibit high efficacy in this transformation process, and some selected examples are presented in Scheme [2]. Firstly, we evaluated a range of α-deuterated alkyl TT salts. TT salts with a simple alkyl group, a sensitive fluorine or chlorine atom, or a terminal olefin group gave the desired products 4–7 with acceptable yields and good deuterium incorporation. Deuterated alkyl TT salts containing a heteroarene group, such as thiophene, or substituted arenes with functional groups such as CF3 or CN performed smoothly, producing the corresponding products 8–10 in good yields. TT salts derived from lithocholic acid and cholesterol were compatible with this reaction system (11 and 12). We then examined various olefins. Notably, monosubstituted and 1,1-disubstituted olefins were both successful substrates (13–15). An olefin featuring a sensitive chloroalkyl motif showed exceptional chemoselectivity, yielding the desired product 16 exclusively.

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Scheme 2 Scope and synthetic application of the hydrodeuteroalkylation of nonactivated olefins

Olefins bearing a heteroarene or those derived from drug molecules were also compatible with the system (17–20). In particular, this approach permitted access to various drug molecules, including deuterated (perfluorohexyl)octane (Miebo; 21) for dry-eye disease[23] and three different deuterated derivatives of pentifylline (22–24) with deuterium at different carbon locations; the latter drug is used to improve blood flow in patients with circulation problems.[24]


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Metallaphotoredox Deuteroalkylation of Alkyl Bromides, Enol Triflates, and (Het)Aryl Bromides with d 2-Labeled Alkyl Thianthrenium Salts

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Scheme 3 Scope and synthetic application of deuteroalkylation of (het)aryl bromides, enol triflates, and alkyl bromides

The unique capability of our d 2-labeled alkyl TT salts permits a remarkable type of cross-electrophile coupling reaction in the presence of a photocatalyst and nickel catalyst to forge C–C bonds with a wide variety of alkyl, vinyl, aryl, or hetaryl halides.[25] As a result, the incorporation of the d 2-methylene motif at specific locations within an organic compound, for example at allylic or benzylic positions or within alkyl chains adjacent to heteroatoms, could be controlled precisely. This technological advance has significantly transformed the preparation of deuterium-labeled compounds, providing a powerful tool for research and development in various scientific fields. This innovative method involves the in situ generation of d 2-labeled alkyl bromide intermediates directly in the reaction process. Further investigations have been made to explore the scope of both reaction partners, and some selected examples are shown in Scheme [3a]. To our delight, the reaction conditions demonstrated exceptional tolerance to a diverse array of functional groups. Initially, we explored the scope of the d 2-labeled alkyl TT salt. A wide range of groups including phenyl, thienyl, benzofuryl, chloro, trifluoromethyl, triple bonds, carbazole, and phthalimide were easily accommodated (25–33). TT salts derived from lithocholic acid, cholesterol, or estrone were compatible with this reaction system (34–36). Next, efforts were made to determine the scope of enol triflates and(het)aryl bromides. A variety of hetaryl bromides, including pyridinyl, quinolinyl, isoquinolinyl, indazolyl, and pyrimidinyl bromides, were found to be compatibility with this reaction, delivering the desired products 37–41 in satisfactory yields. A d-phenylalanine-derived substrate containing an amide and an ester group also proved to be compatible with this reaction, giving the corresponding product 42 in a good yield. Besides, this approach was found to be exceptionally effective in reactions with secondary or primary alkyl bromides, enabling the preparation of the desired alkanes 46–51 with more than 96% deuterium incorporation at designated positions. Satisfyingly, deuterated versions of three important drug molecules were successfully synthesized by this approach (Scheme [3b]): deuterated prothionamide 52,[26] an orally administered antitubercular drug; deuterated metoprolol 53,[27] used for lung-cancer treatment; and deuterated bezafibrate 54,[28] employed to control lipid levels in the blood.


# 5

Conclusion

In summary, by employing a hydrogen-isotope-exchange process using D2O, we have created a diverse collection of deuteroalkylation reagents from alkyl-substituted TT salts. These readily available d 2-TT salts have demonstrated a remarkable reactivity in halogenation reactions, resulting in the creation of isotopically labeled alkyl halides, which can serve as excellent electrophilic coupling reagents. These readily available d 2-TT salts can participate in nickel-catalyzed hydrodeuteroalkylations of nonactivated olefins and metallaphotoredox-catalyzed cross-electrophile coupling reactions with alkyl bromides, enol triflates, and (het)aryl bromides through in situ generation of deuterated alkyl halides. Our technique boasts several remarkable advantages: it utilizes commercially available catalysts, facilitating broad applicability; it offers precise deuteration control, ensuring regioselectivity and cross-selectivity; it eliminates the need for metal reductants, simplifying the workflow and reducing process complexity; and it achieves high deuterium-incorporation rates, permitting precise deuteration in the prepared compounds. We surmise that our TT salts might serve as reaction partners in other types of free-radical reactions or metal-catalyzed coupling reactions


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We are grateful to the High-Performance Computing Center of Nanjing University for performing the numerical calculations reported in this paper on its blade cluster system.


Corresponding Author

Zhuangzhi Shi
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University
Nanjing 210093
P. R. of China   

Publication History

Received: 11 December 2024

Accepted after revision: 12 February 2025

Accepted Manuscript online:
12 February 2025

Article published online:
20 June 2025

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Zoom Image
Figure 1 Background
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Scheme 1 Feasibility exploration, synthesis, and transformation of deuterated alkyl TT salts
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Scheme 2 Scope and synthetic application of the hydrodeuteroalkylation of nonactivated olefins
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Scheme 3 Scope and synthetic application of deuteroalkylation of (het)aryl bromides, enol triflates, and alkyl bromides