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. 2026 Sep 22. Online ahead of print. doi: 10.1039/d6sc03423c

Rhodium-catalyzed ortho-deuteration of anilines

Annick Vander Eyken a, Gwilherm Evano a,b,✉
PMCID: PMC13617612  PMID: 42807366

Abstract

A practical and highly regioselective rhodium-catalyzed protocol for the site-selective ortho-deuteration of anilines via a traceless aminophosphine directing group is reported. The method relies on readily available [Rh(COD)Cl]2 as catalyst and heavy water as an inexpensive and operationally simple deuterium source, and proceeds under mild conditions. Complete regioselectivity for the ortho and ortho′ positions is consistently achieved, with high levels of deuterium incorporation as well as broad functional group tolerance. The deuteration moreover extends beyond simple anilines to more complex scaffolds, including tetrahydroisoquinolines, carbazoles, diarylamines or naphthylamines.

A practical and highly regioselective rhodium-catalyzed protocol for the site-selective ortho-deuteration of anilines via a traceless aminophosphine directing group is reported.graphic file with name d6sc03423c-ga.webp

1. Introduction

Deuterated molecules have emerged as strategically important compounds across modern chemical research, owing to the unique physicochemical consequences of isotopic substitution. Replacement of protium by deuterium subtly alters bond vibrational frequencies, zero-point energies, and reaction kinetics without perturbing electronic structure.1 These effects underpin the widespread use of deuterium in mechanistic studies, isotope labeling, and analytical chemistry, while simultaneously enabling functional modulation of molecular behavior. As such, deuterium incorporation has evolved from a purely diagnostic strategy into a deliberate design element.

In medicinal chemistry for instance, deuteration has attracted a great deal of attention as a mean to fine-tune metabolic stability and pharmacokinetic profiles.2 The kinetic isotope effect associated with C–D bonds can reduce the rate of oxidative metabolism at labile positions, offering a rational approach to modulate clearance, extend half-life, and improve exposure without altering target affinity or selectivity. Deuteration has been also used to inhibit drug–drug interactions or to reduce epimerization. Early efforts to harness this subtle yet important structural modification largely focused on creating deuterated versions of existing marketed drugs through a so-called “deuterium switch” strategy, exemplified by deutetrabenazine 1d6 (Fig. 1A), the first deuterated drug approved by the FDA in 2017 3 which was quickly followed by other deuterated drugs such as donafenib 2d3 4 or deuruxolitinib 3d8.5 More recently, attention has shifted toward the use of deuteration in the discovery of novel chemical entities, culminating in the FDA approval of the first de novo deuterated drug, deucravacitinib 4d3, in 2022.6

Fig. 1. Representative examples of deuterated (A) and aniline (B) drugs.

Fig. 1

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Outside the pharmaceutical arena, deuterated molecules play essential roles in many scientific areas such as, for instance, biochemistry/life sciences7 and materials science,8 or to prove reaction mechanisms.9 Collectively, these diverse applications combined with the constant growth in the use of deuterium-labelled compounds continue to drive demand for efficient, selective, and synthetically accessible routes to deuterated compounds. Accordingly, the development of new methods for deuterium incorporation – particularly those that are mild, regioselective, and broadly applicable – remains a timely and significant objective in contemporary organic synthesis.

In this context, processes enabling the site-selective deuteration of anilines are important and hold a great potential, anilines being at the core structure of a number of drugs and biologically active compounds, with representative examples shown in Fig. 1B,10 in addition to being key building blocks for a range of applications. Among all strategies, the most effective is undoubtedly based on Hydrogen Isotope Exchange (HIE), its efficiency being directly correlated both to the regioselectivity and the level of deuterium incorporation, two points that are notably crucial in drug development.11 Historically, deuterium incorporation into anilines has been accomplished using strong Brønsted or Lewis acids or bases at elevated temperatures, typically resulting in poor regioselectivity and limited functional group tolerance (Fig. 2A).12 Milder conditions have been reported in certain cases, notably employing perchloric acid13 or tetrabutylammonium hexafluorophosphate in HFIP;14 however, these methods often raise concerns regarding safety and/or practicality. Alternative approaches based on homogeneous15 or heterogeneous16 metal catalysts, as well as organic dyes,17 have also been described. Nevertheless, significant limitations remain, including catalyst availability, reaction conditions, the nature of the deuterium source, and, most importantly, control over regioselectivity and the extent of deuterium incorporation.

Fig. 2. Selected representative approaches for the deuteration of anilines (A) and our approach (B).

Fig. 2

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Building on our interest in C–H functionalization reactions,18 the current limitations in the synthesis of selectively deuterated anilines, and our recently reported rhodium-catalyzed ortho-arylation of anilines,19 we envisioned extending this strategy to their selective deuteration. We anticipated that the readily installable aminophosphine directing group in 9 should indeed control its selective deuteration at the ortho positions using heavy water as an ideal and practical deuterium source (Fig. 2B). In addition to promoting site selectivity,19,20 this traceless directing group21 is moreover expected to prevent catalyst deactivation by the free aniline and to be readily cleaved under acidic conditions, thereby affording the desired selectively deuterated aniline 8d2.

2. Results and discussion

2.1. Reaction optimization

With this objective in mind, we initiated our investigation by evaluating the validity of our working hypothesis. The conditions previously developed for the ortho-arylation of anilines (Fig. 3, conditions A) were therefore adapted to the present deuteration study, using 9a as a model substrate and three equivalents of D2O as the deuterium source. As shown in Fig. 3, we were pleased to observe a complete regioselectivity for deuteration at the ortho positions. However, the level of deuterium incorporation remained modest, 8ad2 being obtained with only 24% deuterium incorporation.

Fig. 3. Optimization of the rhodium-catalyzed ortho-deuteration of anilines. Deuteration levels determined by 1H NMR analysis.

Fig. 3

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Subsequent optimization aimed at identifying the best compromise between regioselectivity, yield, and deuterium incorporation. First, a comparison of D2O and CD3OD – both readily available, practical, and inexpensive deuterium sources – revealed the clear superiority of D2O. Next, a brief catalyst screening further established that [Rh(COD)Cl]2 provided the highest level of deuterium incorporation. Given the likely reversibility of the C–H activation/deuteration process, the influence of D2O stoichiometry was next examined. Increasing the amount of heavy water to ten equivalents proved optimal, whereas larger quantities were detrimental, presumably due to solubility issues. The nature of the base was shown to have a pronounced impact on the reaction efficiency, prompting replacement of potassium carbonate with lithium acetate. Although sodium acetate afforded comparable deuterium incorporation, it was not retained because of its lower solubility and higher hygroscopicity.

Next, toluene was found to be advantageously replaced by either 1,4-dioxane or THF and the catalyst loading could be reduced to down to 1 mol%. To ensure a better reproducibility however, we decided to keep 2.5 mol% of the rhodium catalyst in 1,4-dioxane. Evaluating the effects of the temperature and reaction time showed that the reaction was best performed at 60 °C and that 5 hours were optimal, lower levels of deuteration being noted with shorter reaction times.

At this stage, an efficient protocol was thus established, enabling quantitative recovery of the aniline with 88% deuterium incorporation and complete regioselectivity at the two ortho positions (Fig. 3, conditions B). Concerns regarding the use of more volatile anilines – more conveniently isolated as their hydrochloride salts – however prompted further refinement of some reaction parameters and a final fine-tuning led to a more practical procedure using a higher amount of D2O in refluxing THF (Fig. 3, conditions C, see Supplementary Information for details). While the use of THF enabled a more efficient and cleaner deuteration, the use of a higher amount of D2O was selected since a preliminary study with other substrates revealed higher deuteration levels using 20 equivalents of D2O rather than 10. Importantly, we confirmed that the acidic workup employed to cleave the aminophosphine directing group did not diminish the degree of deuterium incorporation by reacting deuterated aniline 8ad2 under harsher conditions compared to the ones utilized for the acidic workup (i.e. longer time: aq. HCl (4 N) for 1 hour while 5 minutes only are used for the acidic workup): an identical level of deuteration was measured after this protracted acidic treatment. Protonation of the amine under the reaction conditions likely prevents competing protonation of the aromatic ring, thereby preserving the deuterium content.

We then briefly investigated the influence of the directing group (Fig. 3, right) and while other aminophosphines 9′ were found to efficiently promote the ortho-deuteration, a competing C(sp3)–H deuteration of the methyl group was noted when these were substituted by alkyl groups. All other cleavable directing groups, including amides, carbamates and ureas failed to promote the deuteration, thus highlighting the superiority and uniqueness of the aminodiphenylphosphine. As an important note, although a one pot procedure involving telescoped directing group installation from the starting aniline with chlorodiphenylphosphine and further in situ deuteration failed, the directing group is not lost in the process and a direct precursor can be recovered since diphenylphosphine oxide is formed quantitatively during the hydrolysis step, as evidenced by quantitative 31P NMR of the crude reaction mixture.

2.2. Reaction scope

With the optimized conditions in hand, we next investigated the scope and limitations of the ortho-deuteration protocol using a series of aminophosphines 9 with representative steric and electronic properties: results from these studies are shown in Fig. 4. The influence of the substituent on the nitrogen atom was first examined. Methyl, butyl, and benzyl substituents afforded comparable results, with the corresponding deuterated anilines 8bd2, 8cd2 and 8dd2 isolated in 74–89% yield and exhibiting deuterium incorporation at the ortho and ortho′ positions ranging from 85% to 91%. These levels compare favorably with those reported in previously described methods. In all cases, no deuterium incorporation at other positions was detected. The reaction also proceeded in the absence of an N-substituent, providing ortho,ortho′-bisdeuterated aniline 8ed2 in moderate yield, albeit with somewhat lower deuterium incorporation.

Fig. 4. Scope of the rhodium-catalyzed ortho-deuteration of anilines. Deuteration levels determined by 1H NMR analysis. # Hydrochloride salt formed by addition of 4 N HCl in 1,4-dioxane; ≠ deuteration level at ortho- and ortho′- positions determined on the free base to avoid overlapping peaks in the 1H NMR spectra of the hydrochloride.

Fig. 4

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To gain insight into the influence of the electronic properties of the starting aminophosphine 9 on the efficiency of the deuteration process, we next examined the effect of para-substituents. This position was selected because it is sufficiently remote from the reactive centers to exert minimal steric influence. Gratifyingly, efficient deuteration was observed in all cases, irrespective of the electronic nature of the substituent. Electron-donating groups such as methyl (8fd2 and 8gd2), phenyl (8ad2 and 8hd2), and a strongly donating methoxy (8id2 and 8jd2), as well as electron-withdrawing substituents including a fluorine (8kd2 and 8ld2) or a nitro (8md2), were well tolerated and afforded comparable results. Overall, the deuteration proved largely insensitive to the electronic density of the starting aniline. In this series, comparable outcomes were obtained with either a methyl or a benzyl substituent on the nitrogen atom. The only exception was 8gd2, which provided both a lower isolated yield and a reduced level of deuterium incorporation for reasons that remain unclear.

The presence of an ortho-substituent was equally well tolerated, as highlighted with the deuteration to 8nd1, 8od1 and 8pd1, all of which were isolated with good to excellent levels of deuterium incorporation. In the case of 8pd1, the noticeably lower isolated yield can be attributed to its high volatility, resulting in partial material loss prior to isolation as the corresponding hydrochloride.

We next examined substitution at the more challenging meta position, where the two ortho and ortho′ positions are inequivalent. meta-Substitution revealed a subtle yet informative interplay of steric and electronic effects, highlighting the combined influence of these factors on the outcome of the reaction. In the presence of a phenyl group at the meta position for instance (8qd2 and 8rd2), deuteration occurred predominantly at the less hindered ortho site (90–93%D), whereas only limited incorporation (14–44%D) was observed at the ortho′ position shielded by the phenyl ring. Replacing the aromatic substituent with a methoxy group led to a markedly different outcome: deuteration took place at both ortho and ortho′ positions (8sd2 and 8td2), with a clear preference for the more hindered site, most likely due to coordination of the ether oxygen to the metal center. In contrast, introduction of a smaller fluorine substituent resulted in nearly identical deuterium incorporation at the ortho and ortho′ positions (8ud2 and 8vd3). In the latter case, partial and unexpected deuteration at the benzylic position was also observed. The presence of two substituents at the para and meta positions was moreover well tolerated, as highlighted with the deuteration to 8wd2 and 8xd2, further highlighting the generality and broad scope of the method. Notably, the rhodium-catalyzed deuteration could also be applied to an estrone-derived aniline, affording 8yd2 in 97% yield with preferential deuteration at the least hindered position and no detectable deuterium incorporation elsewhere. The directed deuteration was also utilized for the synthesis of regioselectively deuterated benzocaine 8zd2 from the corresponding aminophosphine: while no competing deuteration ortho to the ester was observed, indicating the strong directing ability of the aminophosphine, the presence of an additional coordinating moiety was found to be detrimental since a low level of deuteration (17%D) was obtained in this case.

Finally, it ought to be mentioned that the directed deuteration is not limited to simple anilines since regioselectively deuterated tetrahydroisoquinoline 8aad1, carbazole 8abd2 and diarylamine 8acd4 could be obtained in good to excellent yields and with high levels of deuterium incorporation, up to four deuterium atoms being introduced in the last case.

2.3. Iterative (multi-round) deuteration

While the use of an aminophosphine directing group allows to reach full control of the regioselectivity of the deuteration with good levels of deuterium incorporation, higher degrees of deuteration and/or the use of less equivalents of heavy water could be desirable, notably for some targeted applications. In this perspective, we briefly evaluated the possibility of iterative (multi-round) deuteration to potentially tackle both these limitations, using aminophosphine 9g for which limited yields and deuterium incorporation were obtained during the scope and limitation studies.

With this aminophosphine 9g, iterative deuterations were evaluated using our optimized conditions applied once, twice or thrice, the directing group being cleaved by acidic treatment only after the multi-round deuterations were performed. As shown in Fig. 5, iterative deuteration using 20 equivalents of D2O enabled reaching a higher level of deuteration since 83%D could be obtained after three cycles while 73%D was attained after a single one, with an identical yield being obtained regardless of the number of cycles. This iterative process was actually found to be more efficient, practical and coherent using less D2O, as notably highlighted with the 57% deuteration obtained after three cycles using only 2 equivalents of D2O while only 14%D was reached after a single cycle.

Fig. 5. Iterative (multi-round) deuteration and influence of the amount of heavy water. Deuteration levels determined by 1H NMR analysis.

Fig. 5

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2.4. Extension to naphthylamines

In a final effort to demonstrate the generality and usefulness of the rhodium-catalyzed directed deuteration of aminophosphines, its extension to naphthylamines was next briefly examined. As highlighted by results summarized in Fig. 6, their regioselective deuteration proceeded smoothly. The use of an aminophosphine derived from 1-naphthylamine, 10, resulted in exclusive deuteration at C2 (11d1) while exclusive deuteration at C3 was noted starting from 2-naphthylamine derivatives, the lack of deuteration at C1 being attributed to the involvement of a more constrained rhodacycle.

Fig. 6. Extension to the regioselective deuteration of naphthylamines. Deuteration levels determined by 1H NMR analysis.

Fig. 6

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2-Naphthylamine 13d1 regioselectively deuterated at C3 could indeed be obtained in 69% yield and 91% of deuterium incorporation while aminophosphine 14, incorporating both an aniline and a 2-naphthylamine moiety, was triply deuterated at the ortho, ortho′ and C3, providing product 15d3 in good yield and with satisfactory levels of deuterium incorporation.

2.5. Mechanistic considerations

Based on our previously reported comprehensive experimental and theoretical studies on the rhodium-catalyzed directed ortho-arylation of anilines,19 the catalytic cycle depicted in Fig. 7 can be proposed for their deuteration. The cycle starts from monomeric rhodium(i) complex [Rh]B coordinated with two aminophosphines 9, this complex resulting from the dissociation of [Rh(COD)Cl]2 in the presence of 9 and subsequent displacement of the labile COD ligand in [Rh]A by 9. Starting from this low valence rhodium(i) complex [Rh]B, a coordination of the acetate to the metallic center ([Rh]C) would initiate a concerted-metallation-deprotonation (CMD) yielding to cyclometallated complex [Rh]D, the aminophosphine acting as a directing group to coordinate with rhodium. This step was shown to be endergonic and reversible,19 therefore enabling the incorporation of deuterium by deutero-demetallation from intermediate [Rh]Dd1, itself formed by HIE from [Rh]D and D2O. Ligand exchange would close the catalytic cycle and yield the monodeuterated aminophosphine 9d1 which could then undergo a second deuteration at the ortho′ position (not shown).

Fig. 7. Representative examples of deuterated and aniline drugs.

Fig. 7

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3. Conclusions

In summary, we have developed a practical and highly regioselective rhodium-catalyzed protocol for the ortho-deuteration of anilines via a traceless aminophosphine directing group. The method relies on readily available [Rh(COD)Cl]2 as catalyst and heavy water as an inexpensive and operationally simple deuterium source, and proceeds under mild conditions. Complete regioselectivity for the ortho and ortho′ positions is consistently achieved, with high levels of deuterium incorporation and broad functional group tolerance. The protocol accommodates a wide range of N-substituents and tolerates diverse para-, meta-, and ortho-substituents, demonstrating only limited sensitivity to electronic effects. Importantly, the strategy extends beyond simple anilines to more complex scaffolds, including tetrahydroisoquinolines, carbazoles, diarylamines, naphthylamines, and even an estrone-derived substrate, highlighting its generality and synthetic utility.

Overall, this work provides a robust and simple solution for the site-selective deuteration of anilines. By combining a removable directing group with practical reaction conditions and an inexpensive deuterium source, the present method offers a valuable addition to the toolbox of hydrogen isotope exchange chemistry. Given the central role of aniline motifs in pharmaceuticals, agrochemicals, and functional materials, we anticipate that this approach will find application in medicinal chemistry, mechanistic investigations, and isotopic labeling studies.

Author contributions

G. E. designed and conducted the project. A. V. E. carried out the reaction optimization, substrate synthesis, scope and limitation studies and all characterization. G. E. wrote the manuscript and A. V. E. the experimental section. All authors have reviewed and approved the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Supplementary Material

SC-OLF-D6SC03423C-s001

Acknowledgments

Our work was supported by the Université libre de Bruxelles (ULB), the Fonds de la Recherche Scientifique (FNRS) under grant no. CDR J.0077.24, and the Walloon region (Biogreen platform). A.V.E. thanks the Fonds pour la formation à la Re-cherche dans l’Industrie et dans l’Agriculture (F.R.I.A.) for a graduate fellowship. We gratefully acknowledge Dr Gaël De Leener and Mr Jean Allart (ULB) for their help with HRMS.

Data availability

The data underlying this study are available in the published article and its supplementary information (SI). Supplementary information: experimental procedures, characterization, copies of 1H, 13C, 19F and 31P NMR spectra for all new compounds (PDF). See DOI: https://doi.org/10.1039/d6sc03423c.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SC-OLF-D6SC03423C-s001
SC-OLF-D6SC03423C-s001.pdf (10.8MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its supplementary information (SI). Supplementary information: experimental procedures, characterization, copies of 1H, 13C, 19F and 31P NMR spectra for all new compounds (PDF). See DOI: https://doi.org/10.1039/d6sc03423c.

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