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Catalytic, Enantioselective Hydrogenation of Heteroaromatic Compounds

Lei Shi and Yong-Gui Zhou

Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, P. R. China

Introduction

Direct, enantioselective, catalytic hydrogenation of heteroarenes, as depicted in Scheme 1, provides straightforward, atom-economical access to the corresponding chiral heterocycles, which are found as common structural motifs in many important biologically active reagents and alkaloids. Compared with other well-studied prochiral substrates (e.g., ketones, imines, and olefins), the enantioselective hydrogenation of heteroarenes is a more recent development. The major challenges in accomplishing this transformation include the high stability of these aromatic compounds and the poisoning effects of nitrogen or sulfur atoms on the chiral catalysts.

Scheme 1

Heteroarenes comprise a very large compound family with diverse structural features, which display drastically different reactivities for each type of heteroarene substrate under hydrogenation conditions. The hydrogenation of six-membered, monocyclic heteroaromatic compounds, such as pyridines, pyrimidines, and pyrazines, are much more difficult because of their high aromaticity.1, 2 Active five-membered heteroaromatic compounds containing nitrogen, oxygen, or sulfur atoms are also challenging substrates, given their ability to deactivate metal catalysts and to participate in side reactions. For bicyclic aromatic compounds, the ring containing the heteroatom is usually hydrogenated prior to the carbocycle, with the ring having the higher stability often remaining intact during the hydrogenation process. To date, most successful examples in this field are largely limited to bicyclic aromatic and monocyclic heteroaromatic compounds containing nitrogen and/or oxygen atoms.

By using chiral, metallic complexes or organocatalysts, various heteroarenes such as quinolines, isoquinolines, quinoxalines, pyridines, indoles, pyrroles, imidazoles, oxazoles, and furans can be smoothly hydrogenated with good to excellent enantioselectivities. In the transformations catalyzed by metallic complexes, additives (e.g., halogenating reagents, chloroformates, Brønsted acids, etc.) often play key roles. Mechanistically, the additives can activate the metal catalyst (e.g., I2) or activate the substrate (e.g., Brønsted acids). Organocatalysts, especially chiral phosphoric acids (CPAs), catalyze enantioselective transfer hydrogenations employing the Hantzsch ester (HEH) or silanes as the hydride source; this is a unique and efficient method to reduce certain N-heteroaromatic compounds, although the substrate scope is limited. A novel metal/organic relay enantioselective catalysis strategy has also been introduced. This kind of cascade reduction process mimics the cofactor nicotinamide adenine dinucleotide (NADH) cycle using an NADH mimic and dihydrogen, both of which are easy to regenerate.

A number of total syntheses that feature enantioselective hydrogenation of heteroaromatic compounds as key steps are described in the section "Applications to Synthesis". These examples highlight the generality of this method. Some related synthetic approaches to chiral heterocyclic compounds are described in the section "Comparison with Other Methods".

Several specific reviews and personal accounts have been published previously.3-15 This chapter covers the literature up to 2015.

Mechanism and Stereochemistry

The diverse structural features of heteroarenes, combined with the presence of both carbon-carbon double bonds and carbon-heteroatom double bonds, increase the mechanistic complexity of the hydrogenation reactions. As a result, it is unlikely that a single mechanism encompasses all types of substrates under the different catalysis conditions. Detailed mechanistic studies are still lacking to date. In this section, those mechanistic concepts that have been generally accepted and well clarified with experimental and computational data will be discussed.

Transition-Metal-Catalyzed Hydrogenation

Hydrogenation of Quinolines

Quinolines are the most intensively investigated substrate class for transition-metal-catalyzed hydrogenation. Under most reaction conditions, a 1,2,3,4-tetrahydroquinoline is obtained as the reduced product. When a chloroformate is used as an activator, only 1,2-C=N reduction occurs to produce an N-protected 1,2-dihydroquinoline. Two stepwise reaction pathways can be considered, as depicted in Scheme 2. The first pathway involves 1,2-hydride addition followed by 3,4-hydride addition. Alternatively, the second pathway involves 1,4-hydride addition, affording the partially hydrogenated enamine intermediate. A rapid acid-catalyzed enamine-imine isomerization to afford the imine ensues, followed by 1,2-hydride addition to the imine to provide the hydrogenated product. The second path has been generally accepted by most authors.16-18 This mechanistic hypothesis is supported by some direct evidence, including deuteration studies and reaction intermediate detection.18 For example, when the reaction is performed with Ru(OTf)[(1R,2R)-Ts-DPEN](4-cymene) (Ru/L1) (DPEN?=?1,2-diphenylethylenediamine) under 50 atm of D2, 100% deuterium incorporation at both the C2 and C4 positions is observed (Scheme 3).18 When hydrogenation is carried out in CD3OD under H2, the deuterium atoms are found only at N and C3 (Scheme 3).18 Moreover, the key intermediate 1 has been spectroscopically characterized by 1H NMR and ESI-HRMS in a Ru-catalyzed hydrogenation process.18 The combination of these observations suggests that path 2 is favored. Furthermore, a computational analysis also shows that path 2 has a lower energy barrier than that of path 1 under catalysis by a homogeneous iridium complex.17

Scheme 2

Scheme 3

Hydrogenation of Indoles

Unprotected indoles are highly nucleophilic and react with strong Brønsted acids, such as D/L-camphorsulfonic acid (D/L-CSA) or 4-toluenesulfonic acid (TsOH), to generate iminium salts (by protonation of the C2-C3 double bond), which are efficiently hydrogenated (Scheme 4).19 This type of acid activation strategy is mainly employed in hydrogenations catalyzed by chiral palladium complexes and certain organocatalytic transfer hydrogenations because other catalysts do not tolerate the harshly acidic reaction conditions.

Scheme 4

The mechanism of acid-mediated hydrogenation of indoles has been investigated using isotopic labeling experiments. When the hydrogenation of 2-methylindole is carried out in deuterated trifluoroethanol (TFE), 1H NMR spectroscopic analysis of the hydrogenated product shows that two deuterium atoms are incorporated into the C3 position, which suggests that a reversible process of protonation and deprotonation takes place (Scheme 5), and that the tautomerization is faster than hydrogenation.19 When 2-methylindole is subjected to D2, 2-deuterio-2-methylindoline is formed with 92% deuterium incorporation, and no deuterium is incorporated at C3 (Scheme 5).19 Combined with other mechanistic studies, a stepwise, ionic, outer-sphere hydrogenation mechanism is proposed,20 which features protonation of the indole and hydride transfer from Pd-H to a protonated indole intermediate.

Scheme 5

Acid-promoted dehydration of 3-(a-hydroxyalkyl)indoles or detosylation of 3-(a-toluenesulfonamidoalkyl)indoles produces vinylogous iminium ion intermediates that readily undergo hydrogenation.21, 22 Because the substituted indoles can be prepared by Friedel-Crafts alkylation, the combination of reductive alkylation of 2-substituted indoles and enantioselective hydrogenation of 2,3-disubstituted indoles leads to a rapid and divergent approach to chiral 2,3-disubstituted indolines. Results of a deuteration study suggest a sequence comprised of Friedel-Crafts alkylation/dehydration/reduction reactions promoted by acid (Scheme 6).23

Scheme 6

Chiral Phosphoric Acid Catalyzed Hydrogenation

Hydrogenation of Quinolines

Chiral phosphoric acid catalyzed transfer hydrogenation of quinolines using the Hantzsch ester (HEH) represents an effective, metal-free method to reduce N-heteroarenes. Mechanistically, this transformation is inspired by the redox behavior of NADH in nature, mimicking the reaction of glutamate dehydrogenase.10 In the presence of a chiral phosphoric acid, protonation of the nitrogen atom of the substrate results in the formation of an active iminium ion and a chiral ion pair.24 Meanwhile, HEH also interacts with the chiral phosphoric acid through hydrogen-bonding between the N-H and P=O. The hydrogen-bond network guides the subsequent enantioselective hydride transfer. As shown in Scheme 7, the biomimetic transfer hydrogenation of...