Enhancing Reactivity and Selectivity of H₂-driven Copper Hydride Chemistry with Bifunctional N-heterocyclic Carbene Ligands Bearing Basic Subunits

Abstract

This synpacts article highlights two recent developments in H₂-driven copper hydride chemistry with bifunctional N-heterocyclic carbene (NHC) ligands. Two distinct bifunctional copper(I) complexes emerge, each with different, basic nitrogen-based, catalytically active functional groups. A guanidine-appended NHC enables a site-selective catalytic hydrogenation of the so-called “privileged” amides in the presence of other, structurally closely related amides. Furthermore, a second bifunctional NHC ligand bearing a basic 2-iminopyridine subunit allows for catalytic hydrogenation of alkynes and conjugated amides under low H₂ pressure. Both catalysts are placed into a common context by discussing the fundamental mechanism of heterolytic H₂ activation and the fate of the resulting proton.

Keywords

N-heterocyclic carbenes - Copper - Hydrogen - Catalysis - Organocatalysis - Hydrogenation - Coordination chemistry

1

Introduction

Copper hydride complexes are important and selective reducing agents in organic synthesis.[1] While originally reported as stoichiometric reducing agents,[2] the large majority of modern copper hydride chemistry is based on hydrosilanes as terminal reducing agents.[3] As an attractive and atom-economic alternative, dihydrogen (H₂) has emerged as a potential stoichiometric hydride source for copper hydride chemistry.[4] [5] This approach fundamentally relies on a heterolytic H–H bond cleavage mechanism that is realized along a Cu–O bond (that is either present in the catalyst or is forged in situ by alkoxide additives), realizing a long-standing literature hypothesis.[6] In this manner, a “hydride equivalent” (the copper hydride complex) and a “proton equivalent” in the form of an alcohol are formed ([Scheme 1a]).

N-heterocyclic carbene (NHC) ligands have shown to give rise to efficient copper(I) complexes for catalytic hydrogenations or H₂-driven reductive transformations.[4] [7] In the former, both the “hydride equivalent” as well as the “proton equivalent” are transferred to a substrate. On the contrary, in the latter case, only the “hydride equivalent” is employed to effect a new catalytic bond-forming reaction.[8]

Further extending general reactivity of H₂-activation and hydride transfer, our group has investigated bifunctional NHC ligands, which also bear a second, catalytically active unit.[9] [10] [11] In this approach, guanidine or 2-iminopyridine groups have been investigated as ancillary basic moieties ([Scheme 1b]).

Both subunits, the guanidine as well as the 2-iminopyridine, are strongly basic and thus can take up the “proton equivalent” during the catalytic process. This enables a variety of follow-up reactions that significantly alter the course of typical copper hydride reactivity: on the one hand, for the NHC ligand bearing the guanidine subunit, protonation leads to the formation of a guanidinium ion,[9] a potential hydrogen-bond donor ([Scheme 1c], left). This is exploited for molecular recognition and site-selective hydrogenations of amides. On the other hand, the basic 2-iminopyridine unit ([Scheme 1c], right) allows for coordination of the alcohol (and thus the “proton equivalent” after heterolytic H–H bond cleavage). As a result, the overall catalytic hydrogenation is sped up by facilitating the protodecupration step.[11] The 2-iminopyridine-appended ligands give rise to highly reactive catalysts, allowing for the catalytic hydrogenation of so far unreactive substrates such as conjugated amides.

Scheme 1 Mechanistic hypothesis of heterolytic H₂ activation with copper(I) complexes and design of bifunctional NHC ligands for copper hydride chemistry.

2

Site-Selective Hydrogenation of Amides

Generally, copper(I) hydride complexes are known to be “soft” reducing agents and are unable to reduce “hard” electrophiles such as carboxylic acid derivatives.[1] The integration of a guanidine moiety within the copper(I)/NHC complex allowed for the first time for a catalytic reduction of esters with homogeneous copper complexes using H₂ as terminal reducing agent.[9] This process is proposed to occur via hydrogen bonding by an in situ generated guanidinium ion coordinating the ester substrate, which effects (i) the activation of the ester by hydrogen bonding interactions and (ii) the facilitations of a hydride delivery through proximity-driven interactions.

Extending this concept to the even lesser reactive amides, we observed pronounced differences in reactivity among structurally similar benzamides:[10] while amides derived from unfunctionalized linear or cyclic amines showed low reactivity, significantly increased conversions were observed for amides constructed from N-heterocyclic amines, indicating a distinct preference of the catalyst for “privileged” amide motifs (highlighted in purple in [Scheme 2]).

In this vein, a range of morpholine-derived amides 1a–1d could efficiently be reduced to the corresponding alcohols in generally good yields (31–77%, [Scheme 2a]). The reaction also proved amenable to scale-up, as illustrated by the gram-scale catalytic hydrogenation of 1a, affording the alcohol in good yield (72%). The successful catalytic reduction of thiophene-derived amide 1b underscores that heteroaromatics are also tolerated by the catalyst. Aliphatic amides such as 1c and 1d show a generally lower reactivity due to concomitate enolate formation under basic conditions. Nevertheless, they could be converted to the desired products in moderate to good yields of 77% and 31%, respectively. Particularly noteworthy is the reduction of amide 1d bearing a terminal alkene: As a hallmark for catalytic hydrogenations with copper(I)/NHC complexes, unactivated alkenes remain intact during catalytic amide reduction, showcasing the remarkable chemoselectivity of the bifunctional copper(I)/NHC complexes. Moreover, several heterocycle-derived amides 1e–1h underwent smooth reduction, underscoring the applicability of the method across a range of “privileged” amides. We could also show that the reduction of amides to the corresponding alcohols is not effectively realizable with standard aluminum hydride reducing agents.

Building upon the observed reactivity of “privileged” amides bearing heterocyclic amines, we showed that a site-selective catalytic hydrogenation of diamides is feasible ([Scheme 2b]): in this vein, we examined intramolecular competition scenarios using terephthalic acid-derived diamides bearing two distinct amide moieties. Selective reduction of morpholine-derived “privileged” amides in 5a–5c to the corresponding alcohols was achieved in the presence of structurally similar, but less reactive amides (derived from diethylamine, 2-aminoethanol, and piperidine) within the same molecule. High levels of site-selectivity were maintained in all cases, with only the piperidine-containing diamide 5c showing minor formation (6%) of the nonprivileged reduction product 7c. These results highlight the unique capacity of the bifunctional copper(I)/NHC catalyst to differentiate between electronically and sterically similar amide groups within a single molecule – an ability that has not been achieved with typical stoichiometric hydride reagents or any other catalyst.

Scheme 2 Catalytic hydrogenation of “privileged” amides with a bifunctional copper(I)/NHC catalyst, substrate scope, and site-selectivity. (In all cases, the starting materials are displayed to highlight the presence of the heterocyclic amide structure that is key for reactivity. All substrates react to the corresponding primary alcohols.)

3

Proximity Effect-driven Catalytic Alkyne Semihydrogenations and 1,4-Hydrogenations of Conjugated Amides

Bringing two reactive molecules in close contact through noncovalent interactions can be exploited to enhance reaction rates and selectivities. This approach is coined “proximity effect.”[12] Generally, in H₂-driven copper hydride chemistry, the need for high H₂ pressure (and thus specialized equipment) as well as the need for stoichiometric alkoxide additives are two limitations of the overall methods.[4] [8b] [8c] [13] We therefore hypothesized that one reason for an overall sluggish performance of the catalysts could be a slow final protodecupration as rate-determining step. This could be caused by a low reactive concentration of the “proton equivalent,” i.e., the alcohol, in the reaction media. To overcome the challenge, we developed an NHC-based bifunctional catalyst featuring a 2-iminopyridine subunit, which could serve two purposes: (i) it could serve as proton shuttle via aromatization to a pyridinium ion and (ii) as an alcohol-binding unit, enhancing the local concentration of “proton equivalent” via a proximity effect. Overall, this should enhance the rate of the protodecupration step in the catalytic cycle. We found that the resulting catalyst 10 ([Scheme 3]) outperforms the reported copper(I) catalysts in H₂-driven reactions, as showcased by the fact that the now H₂ pressure as low as 1 bar suffices to effect the corresponding catalytic reactions. This enables for the first time the realization of H₂-driven copper hydride chemistry in standard laboratory glassware. Furthermore, the newly designed catalyst offers excellent functional group tolerance in chemo- and stereoselective alkyne semihydrogenations ([Scheme 3a]) and enables the challenging and unprecedented hydrogenation of α,β-unsaturated amides (conjugated amides, [Scheme 3b]).

With regards to catalytic alkyne semihydrogenations, a high (Z)-selectivity and high chemoselectivity (no overreduction to the corresponding alkanes) were maintained even with low H₂ pressure employed ([Scheme 3a]): in this vein, the catalytic semihydrogenations of alkynes 8a–8d proceeded efficiently independent of the electronic nature and notably tolerate nitrile 8b and halogen-containing substrates such as 8c–8d. The low pressure reactions with catalyst 10 yields the corresponding (Z)-stilbenes 9c–9d while minimizing previously observed[7a] detrimental proto-dehalogenation. A variety of heterocycles as exemplified by pyridine 8e were also tolerated as well as terminal alkynes such as 8f. Both examples underscore the significantly larger tolerance of catalyst 10 toward functional groups as compared to other copper(I) hydrogenation catalysts.[4]

Scheme 3 Catalytic hydrogenation of alkynes and conjugated amides under low H₂ pressure with bifunctional catalyst 10. (For a), the starting materials are given; for (b) the products are given.

To demonstrate the superior reactivity of the copper hydride complexes resulting from complex 10, we chose to benchmark the newly developed catalytic protocol against α,β-unsaturated amides, which have so far never been reported to be amenable to reduction by copper(I) hydride complexes ([Scheme 3b]). In fact, the catalytic hydrogenation of this substrate class has rarely been reported and typically requires precious metals and elevated H₂ pressure.[14] Their low reactivity led to the use of conjugated amides as typical building blocks for a wide variety of biologically active compounds. The bifunctional copper(I)/NHC complex 10 enables an efficient 1,4-reduction of a large variety conjugated amides 11 under low H₂ pressure. Using this protocol, a range of cinnamides were efficiently reduced to corresponding saturated amides 12a–12d in good yields. Notably, both a ketone and an oxime as in 12b and 12c, respectively, remained intact under the reaction conditions. This highlights the protocol’s excellent chemoselectivity. Amino acid derivatives as exemplified by 11d were reduced without concomitant racemization of the stereocenter, outperforming related bifunctional catalysts disclosed earlier.[9a] Remarkably, the catalytic protocol based on bifunctional copper(I) catalyst 10 enabled the efficient reduction of conjugated amide subunits in various drug molecules affording saturated amides 12e–12h in good yields. In this vein, saturated amides of a cytisine (12e), piperlogumine derivative (12f), dopamine (12g), and piperlotine A (12h) derivatives were efficiently afforded by the catalytic hydrogenation of the corresponding conjugated amides. Importantly, the catalytic protocol enables the isotope labeling of conjugated amide subunits with very high isotope incorporation when one changes to D₂ as deuteride source. As an example, the deuteration of ilepcimide 11i gives the corresponding deuterated product 12i with 96% deuterium incorporation in the β-position of the amide, i.e., at the locus where the hydride/deuteride is delivered by the catalyst. This example shows the potential of the method for isotope labeling of biologically active molecules with D₂.

4

Conclusions and Outlook

The two highlighted examples display the potential of multifunctional catalysts and ligand design, with H₂-driven copper(I) hydride catalysis serving as case-in-point. By appending known and established NHC ligands with additional functional groups or reactive subunits, the typical reactivity of the respective metal/NHC complexes can be significantly broadened and enlarged. This is shown by the catalytic reduction of amides (i.e., functional groups with a generally low reactivity) with seemingly “soft” nucleophilic copper(I) hydride intermediates. Furthermore, the highlighted example of an iminopyridine-appended NHC ligand in combination with a copper(I)-catalyzed hydrogenation method underscores that through design of ligands, specific steps of the catalytic cycle can be addressed and altered. As a result, the overall resulting catalyst is among the copper(I) complexes with the highest reactivity toward H₂ so far and furthermore displays an unprecedented substrate scope. In this manner, the reactivity can be expanded to conjugated amides, which had previously been reported to be unreactive toward copper(I) hydrides. Both reactivities highlighted here significantly expand the general reactivity of copper(I) hydride complexes and could serve as stepping stone for the development of more H₂-driven methods in the future. Furthermore, it is the hope of the authors that this highlight serves in a more general sense to put catalysis with 3d metals especially in the field of catalytic hydrogenations, a field dominated by noble metals, into the spotlight.

Giriraj Pal

Giriraj Pal holds an MSc from IIT Delhi, India and worked on photoinduced radical cascade reactions under the supervision of Prof. Sudipta Raha Roy. He is a PhD student in the Teichert group since 2023 and his research focuses on method development of H₂-driven reactions.

Maximilian Voigtländer

Maximilian Voigtländer studied chemistry at TU Chemnitz and has carried out his MSc thesis in the Teichert group. He is currently a PhD student in the same group and his research deals with method development and especially bifunctional catalysts.

Dimitrios-Ioannis Tzaras

Dimitrios-Ioannis Tzaras has studied chemistry in the National and Kapodistrian University of Athens and received his MSc degree from the same university, under the supervision of Professor Christoforos Kokotos. He has recently completed his PhD studies under the supervision of Professor Johannes F. Teichert in the Technische Universität Chemnitz, working in the field of transition metal catalysis.

Mahadeb Gorai

Mahadeb Gorai, a chemistry graduate from IIT Kharagpur, India, with a Master's thesis carried out in the group of Prof. Modhu Sudan Maji. He has recently finished his PhD in the Teichert group. His research was focused on bifunctional catalysts in copper hydride chemistry.

Johannes Teichert

Johannes Teichert studied chemistry at Philipps-Universität Marburg and Université Paul Sabatier Toulouse and has obtained his PhD in the group of Ben L. Feringa at Rijksuniversiteit Groningen. After a postdoctoral fellowship in the group of Jeffrey Bode (ETH Zürich), he has started his independent research at TU Berlin. Since 2021, he is professor for organic chemistry at TU Chemnitz. The research of the Teichert group includes transition metal catalysis, novel π systems, and photochemistry.

Note: Picture has been generated with the use of AI.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 30 June 2025

Accepted after revision: 29 August 2025

Article published online:
18 September 2025