RECENT ADVANCES IN BASE METAL-CATALYZED COOPERATIVE TRANSFER HYDROGENATION AND HYDRODEUTERATION OF ALKENES

Abstract

Catalytic alkene hydrogenation is a powerful method that has been widely used in the syntheses of valuable products ranging from commodity chemicals to pharmaceuticals. Hydrogenation has also been a key strategy for selectively introducing heavy hydrogen isotopes to small molecules, a key strategy for metabolism studies and even the synthesis of “heavy drugs,” where the hydrogen isotope is a key element of the active pharmaceutical ingredient. Traditional hydrogenations with pressurized H₂ gas are atom economic but often require complex reaction setups or expensive metal catalysts. Further, use of diatomic hydrogen necessarily limits the ability to incorporate different hydrogen isotopes at each alkene position, with H₂, D₂, and T₂ each resulting in compete labeling of the alkene. In response to these challenges, a recent and growing movement has sought to develop transfer hydrogenation methods using non-H₂ hydrogen sources and earth abundant element catalysts to simplify reaction operation. Excitingly, recent developments have delivered transfer hydrogenations that proceed using cooperative hydrogen donor reagents, permitting the controllable incorporation of different hydrogen isotopes at each position of the alkene via reagent control. In this Digest, we disclose recent advances in Earth-abundant metal-catalyzed cooperative transfer hydrogenation of alkenes with various combinations of two distinct transfer hydrogen reagents as non-H₂ hydrogen sources.

1. Introduction

Alkenes are important feedstock for the chemical industry and a major platform for the development of basic organic synthetic methods. Of the diverse reactions of alkenes, catalytic hydrogenation continues to attract academic and industrial interest, with applications varying from commodity chemicals to pharmaceuticals [1,2]. Traditionally, direct hydrogenation with highly pressurized H₂ gas is widely employed (Scheme 1a). Although this strategy represents a great example of atom economy and can be scaled inexpensively to industrial levels, the use of pressurized H₂ gas can be associated with serious hazard (i.e., fire and explosion) leading to the requirement for special gas handling engineering controls [3]. In addition, many hydrogenation processes are developed using either low-cost Raney-Ni, a pyrophoric substance that is difficult to handle, or expensive noble metal catalysts such as Pd and Pt. Selective alkene hydrogenation can also be challenging to achieve in the presence of other reducible functional groups such as ketones or aldehydes [1,2]. Finally, while hydrogenation using diatomic hydrogen has been used to introduce heavy hydrogen isotopes, the high cost of heteroisotopic form (HD) and difficulty in controlling regioselectivity of isotope composition can hinder its practicality in monodeuteration of alkenes. These applications are particularly useful for metabolic studies or even the synthesis of “heavy drugs”, where the incorporation of deuterium is part of the active pharmaceutical ingredient [4–6]. Thus, while many powerful hydrogenation approaches have been developed using H₂ gas, there is a need for new hydrogenation methods able to function with non-gaseous reagents, non-pyrophoric earth abundant element catalysts, able to introduce different hydrogen isotopes at each alkene position and exhibiting high chemoselectivity for alkene hydrogenation.

Scheme 1.

Methods for hydrogenation of alkenes

Transfer hydrogenation (TH), the addition of two hydrogen atoms from non-H₂ hydrogen source(s) to an alkene, is an attractive alternative to traditional direct hydrogenation reactions using H₂ [7–21]. Inspired by the Meerwein–Ponndorf–Verley reduction [7], the TH commonly occurs with two hydrogen atoms arriving from the same hydrogen donor (Scheme 1b) [8,9]. The TH approach is advantageous as it does not require hazardous pressurized H₂ gas nor complicated experimental setups. Additionally, many robust, readily accessible metal catalysts and/or precatalysts as well as organocatalysts can be used in TH reactions, simplifying reaction schemes. Asymmetric [8,10,11] and catalyst-free TH [12] reactions have been developed, further demonstrating the versatility of this approach.

A further advantage of this approach is the ability to perform cooperative TH, a subclass of TH wherein hydrogen atoms are derived from two different hydrogen donors, which has recently emerged as an attractive method (Scheme 1c) [13–21]. The combination of two hydrogen atom donors allows the cooperative TH to occur with distinct mechanisms to both TH using a single reagent and hydrogenation using H₂, allowing for new elements of selectivity to be achieved. In particular, using reagents with cooperative protic and hydridic hydrogen donor character allows for selective transfer hydrodeuteration (THD) reactions, allowing for monoisotopically labeled products to be regioselectively synthesized from alkene starting materials.

Cooperative TH reactions can be broadly classified into two groups: non-radical organometallic and radical. Here we will overview recent advances in each of these categories and their applications in THD.

2. Non-radical organometallic cooperative transfer hydrogenation and hydrodeuteration

Non-radical cooperative TH occurs via an organometallic redox-neutral mechanism (Scheme 2) [13–15]. Hydride transfer from the hydridic, reducing hydrogen atom donor (NaBH₄, HBpin, or silanes) to the metal catalyst generates a metal hydride intermediate which subsequently undergoes migratory insertion to the alkene substrate furnishing an alkylmetal intermediate. Finally, protonation of the alkylmetal intermediate by the protic hydrogen atom donor produces the final hydrogenated product and regenerates the active metal catalyst. While presenting a concise mechanism for TH, this approach also has several competing off-cycle reactions, including protonation of the metal hydride to release H₂ gas, consuming both hydrogen donors unproductively, and isomerization of the alkylmetal intermediate, scrambling the position of the second hydrogen atom. Recent advances in organometallic cooperative TH of alkenes have focused tuning the hydrogen transfer agents to minimize these competing off-cycle reactions.

Scheme 2.

Plausible mechanism of Cooperative TH by organometallic methods.

In 2014, Thomas and coworkers reported an iron catalyzed-cooperative TH using NaBH₄ as a hydridic hydrogen donor and EtOH as a protic hydrogen donor (Scheme 3a) [13]. Using simple iron triflate, a variety of monosubstituted alkenes and styrenes were reduced to corresponding alkanes in up to 83% isolated yield. The reactions tolerated different functional groups including halides (F, Cl, and Br), ethers, esters, amides (excluding primary amides); however, substrates bearing a carboxyl, ketone or free alcohol group furnished the corresponding product in poor yields (up to 25%). Interestingly, acrylate and acrylamide derivatives were chemoselectively reduced at the alkene while internal and 1,1-disubstituted alkenes were unreactive under the optimal conditions. While presenting a concise and simple approach to cooperative TH, this system was unable to be used for selective THD as deuterium-labelling experiments using NaBD₄ and EtOH gave a mixture of deuterated and non-deuterated alkanes with deuterium being incorporated to both carbons of the double bond.

Scheme 3.

Organometallic methods for cooperative TH.

In 2019, Webster and coworkers reported the cooperative TH of alkenes catalyzed by a well-defined iron(II) β-diketiminate complex, with HBpin as a the hydridic hydrogen donor and nBuNH₂ or aniline as the protic hydrogen donor (Scheme 3b, top) [14]. The reactions tolerated terminal (both mono and 1,1-disubstituted) and internal alkenes, generating the desired alkanes in up to nearly quantitative yield. This enhanced reactivity compared to the iron-triflate-catalyzed reaction (Scheme 3a) represents an advantage of using this approach. Further, deuterium-labeling studies showed regioselective deuterium incorporations with DBpin and PhND₂, in which the deuterium derived from DBpin incorporated to the internal carbon of the double bond while the deuterium derived from PhND₂ incorporated to the terminal carbon, enabling selective and predictable THD.

In 2021, Webster and coworkers extended their system of cooperative TH of alkenes using sustainable PMHS as the hydridic hydrogen donor, nBuOH as the protic hydrogen donor, and neat substrate as the reaction medium (Scheme 3b, bottom) [15]. This solvent-free TH reduced terminal (both mono and disubstituted) and internal alkenes to corresponding alkanes in up to 85% spectroscopic yields. Deuteration proceeded with moderate positional selectivity using nBuOD as the protic hydrogen atom donor due to iron-alkyl isomerization. By contrast, the use of PhND₂ as the D⁺ source gives high selectivity for deuteration at the terminal position of unactivated alkenes. However, this system was unable to achieve selective THD when reducing styrene derivatives.

Toward overcoming this challenge, the Clark group reported a copper-catalyzed THD of vinylarenes using DMMS as a hydridic hydrogen source and EtOD as protic deuterium source in 2019 (Scheme 4a) [16]. The reaction generated various benzylic-deuterated arylalkanes in up to 99% yield with up to 99:1 rr. Switchable deuterium selectivity can be achieved by using deuterated silane and EtOH, furnishing homobenzylic-deuterated arylalkanes. Building on this reactivity, they developed the first enantioselective THD of vinylarenes catalyzed by a chiral copper complex prepared in situ from Cu(OAc)₂ and (R)-DTBM-SEGPHOS (Scheme 4a) [17]. Three chiral benzylic-deuterated arylalkanes were produced in high regio- and enantio-selectivities (up to >99:1 rr and 98.1% ee, selectively). In 2022, the group further extended copper-catalyzed THD to encompass unactivated alkenes, using DMMS as a hydride and d₈-IPA as a deuterium source (Scheme 4b) [18]. In contrast to the THD of vinylarenes, in which deuterium from the alcohol is Markovnikov-selectively incorporated to the product, the reaction of unactivated alkenes favored anti-Markovnikov selectivity furnishing the terminally deuterated alkane products.

Scheme 4.

Organometallic methods for cooperative THD.

3. Radical cooperative transfer hydrogenation

An alternative approach to TH has built on advances in hydrogen atom transfer (HAT) chemistry [22–25] which have allowed radical hydrogenation of alkenes to be achieved under mild conditions. Building upon radical hydration reactions [26], several recent radical hydrogenation methods are proposed to occur via metal-catalyzed hydrogen atom transfer (MHAT) from a metal hydride to the alkenyl substrate, generating a carbon-centered radical [27]. Subsequent interception of this carbon-centered radical with a second HAT furnishes the alkane product (Scheme 5a) [18], permitting hydrogenation via two separate HAT steps. Notably, the inclusion of the oxidant tert-butyl hydroperoxide (TBHP) is critical for catalytic turnover of systems using a single HAT catalyst such as cobalt or manganese [19,28,29]. The manganese MHAT TH reactions developed by Shenvi have been shown to derive the majority of both hydrogen atoms from the silane reductant, potentially both via MHAT from the catalyst [28,29], showing that these reactions are not cooperative TH and precluding selective THD. By contrast, an cooperative TH approach was reported in 2014 by the Herzon group using a cobalt MHAT catalyst, Et₃SiH as a hydridic hydrogen source and 1,4-cyclohexadiene (1,4-CHD) as a radical hydrogen atom source. This system achieves cooperative hydrogen delivery through MHAT to the alkene from the cobalt hydride followed by 1,4-CAD to intercept the carbon-centered radical in the second HAT step (Scheme 5a) [19]. Fluoro, chloro, bromo, iodo, and 1,1-dihaloalkenes were tolerated under the optimal reaction conditions, representing excellent vinyl halide chemocompatibility compared to organometallic TH methods. While a stoichiometric amount of Co(acac)₃ (1 equiv) was employed in some examples, the addition of PCy₃ (25 mol%) allowed the loading of Co(acac)₃ to be lowered to 25 mol% in many cases. In 2015, the Herzon group expanded this cooperative TH to encompass a variety of alkene substrates [20]. Using stoichiometric amount of Co(acac)₃ (1 equiv), 1,1-disubstituted and trisubstituted alkenes were reduced to the corresponding alkanes in good-to-high yield whereas low yields were achieved in the reactions of monosubstituted and 1,2-disubstituted alkenes.

Scheme 5.

Radical-based methods for cooperative TH.

While powerful, these MHAT methods require stoichiometric TBHP oxidant in addition to the stoichiometric silyl hydride source, making them inefficient from a redox standpoint. Furthermore, TBHP is a strong oxidant with the capacity for uncontrolled thermal decomposition at elevated temperatures, presenting another consideration to use of these methods. To avoid the addition of stochiometric strong oxidant and open the possibility for selective THD, our group recently reported alkene hydrogenation via cooperative hydrogen atom transfer (cHAT), a dual-catalytic strategy wherein each HAT step is performed by a catalyst with distinct donor character, in this case an iron MHAT catalyst and a thiol HAT cocatalyst, and cooperative hydrogen donors, with phenylsilane serving as a hydridic donor and ethanol as a protic donor (Scheme 5b) [21,30]. We proposed the carbon-centered radical generated from the iron MHAT cycle can be intercepted by a separate radical trapping HAT catalyst to furnish the alkane product. The presence of a thiol catalyst was critical not only to deliver the hydrogen atom from the protic solvent (EtOH) to the carbon-centered radical but also to reoxidize the iron catalyst (from the Fe^II state formed after MHAT to the Fe^III state able to accept hydride from the silane) for the catalyst turnover. A variety of terminal and internal alkenes can be reduced in good-to-high yields with many functional groups (ester, amide, vinyl halides, etc.) tolerated. Although performing the reaction under air led to reduced efficiency and significant hydration side products, rigorous exclusion of oxygen was not required. Importantly, deuterium-labeling experiments clearly showed the provenance of each hydrogen atom, with selective monodeuteration possible by either replacing phenylsilane with phenylsilane-d₃ or using deuterated solvent (CD₃OD), allowing for THD to be achieved via a radical mechanism and opening the door to further development of this disconnection strategy.

4. Conclusion and outlook

Significant breakthroughs of cooperative transfer hydrogenation (TH) have been achieved in the past few years using both non-radical organometallic and radical mechanisms. This interest in cooperative TH has been driven by many factors, including its operational simplicity when compared to the traditional direct hydrogenation with a pressurized H₂ gas, its compatibility with earth-abundant catalysts and its wide functional group tolerance. Additionally, since the hydrogen atoms are delivered from two different hydrogen transfer reagents, transfer hydrodeuteration (THD) is possible for high selectivity of deuterium incorporated to the alkane products.

Possible future directions for cooperative TH are numerous. For broadening applications of the organometallic approach generally, exploration of Earth-abundant metal catalysts other than iron and copper and new ligand frameworks may prove fruitful, as the Webster Group’s work with iron complexes demonstrated the extreme effect of ancillary ligands (Scheme 3b). For radical-based methods generally, reaction conditions could be redesigned to allow the use of lower catalyst loadings, more sustainable hydridic hydrogen sources, and reduction of the reaction time and improved substrate scope. Further, enantioselective cooperative TH via a radical mechanism has not yet been demonstrated, representing a major new frontier in this mechanistic approach.

With regard to THD, enantioselective THD remains underdeveloped. The Clark group’s pioneering efforts using organometallic copper catalysis on styrenyl substrates (Scheme 4a) represents the state-of-the-art for this disconnection strategy. For organometallic methods, engagement of non-styrenyl substrates remains a significant challenge. Building on the lack of enantioselective cooperative TH reactions proceeding via radical mechanisms, enantioselective THD is similarly unknown for this open-shell approach. Further development of these reactions could be of great value to the synthesis of optically active, isotopically labeled bioactive molecules for metabolic studies and even “heavy drug” synthesis.