Ruthenacycles and Iridacycles As Transfer Hydrogenation Catalysts

Home , Asymmetric hydrogenation, Transfer hydrogenation

Review Ruthenacycles and Iridacycles as Transfer Hydrogenation Catalysts

Vincent Ritleng 1,* and Johannes G. de Vries 2,*

1 Ecole européenne de Chimie, Polymères et Matériaux, Université de Strasbourg, CNRS, LIMA, UMR 7042, 25 rue Becquerel, 67087 Strasbourg, France 2 Leibniz Institut für Katalyse, e. V. Albert-Einstein Strasse 29a, 18059 Rostock, Germany * Correspondence: [email protected] (V.R.); johannes.devries@catalysis.de (J.G.d.V.)

Abstract: In this review, we describe the synthesis and use in hydrogen transfer reactions of ruthenacycles and iridacycles. The review limits itself to metallacycles where a ligand is bound in bidentate fashion to either ruthenium or iridium Via a carbon–metal sigma bond, as well as a dative bond from a heteroatom or an N-heterocyclic carbene. Pincer complexes fall outside the scope. Described are applications in (asymmetric) transfer hydrogenation of aldehydes, ketones, and imines, as well as reductive aminations. Oxidation reactions, i.e., classical Oppenauer oxidation, which is the reverse of transfer hydrogenation, as well as dehydrogenations and oxidations with oxygen, are described. Racemizations of alcohols and secondary amines are also catalyzed by ruthenacycles and iridacycles.

Keywords: metallacycle; ruthenium; iridium; transfer hydrogenation; oxidation; ketone

1. Introduction In this review, the use of cyclometalated complexes based on ruthenium and iridium Citation: Ritleng, V.; de Vries, J.G. in hydrogen transfer reactions is described. In the definition we use here, a cyclometalated Ruthenacycles and Iridacycles as complex has one anionic carbon–metal σ-bond and is additionally stabilized by a single Transfer hydrogenation Catalysts. intramolecular dative bond from the same ligand [1]. Thus, metal pincer complexes are Molecules 2021, 26, 4076. https:// outside the scope of this review. doi.org/10.3390/molecules26134076 2. Ruthenacycles as Transfer Hydrogenation Catalysts Academic Editor: Michal Szostak The transfer hydrogenation (TH) of ketones is by far the most studied reaction with ruthenacycles, in particular with CN-ruthenacycles, as will become apparent in the fol- Received: 4 June 2021 lowing pages. Most of the published work deals with racemic reductions. Noteworthy, Accepted: 29 June 2021 Published: 3 July 2021 the most important contribution in asymmetric transfer hydrogenation comes from the work of Pfeffer and his collaborators. This review is dedicated to Michel Pfeffer for his pioneering work in this field. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 2.1. Transfer Hydrogenation of Ketones published maps and institutional affil- iations. The first examples of catalytic application of cyclometalated ruthenium complexes in ketone transfer hydrogenation appeared in 2004 in two successive contributions from the group of Baratta [2,3]. These reports followed a publication from Van Koten in 2000 [4] that for the first time described interesting catalytic properties of a ruthenium NCN– pincer complex for TH. In these reports, Baratta et al. described the synthesis of a novel Copyright: © 2021 by the authors. κ2 C,P − Licensee MDPI, Basel, Switzerland. class of cycloruthenated complexes bearing the anionic ( - )-[2-CH2-6-MeC6H3PPh2] δ This article is an open access article ligand. These species resulted from the reaction of the 14-electron -agostic [RuCl2{(2,6- distributed under the terms and Me2C6H3PPh2)2] complex with formaldehyde in the presence of triethylamine Via cy- conditions of the Creative Commons clometalation of an ortho-methyl group and aldehyde decarbonylation. Among the new Attribution (CC BY) license (https:// cyclometalated complexes, the derivatives 1 and 2 bearing 2-(aminomethyl)pyridine (ampy) creativecommons.org/licenses/by/ and ethylenediamine (en), respectively, were both found active for the TH of acetophenone 4.0/). (0.1 M) in isopropanol at reflux in the presence of NaOH (2 mol.%) as base and activator.

Molecules 2021, 26, 4076. https://doi.org/10.3390/molecules26134076 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 50

Molecules 2021, 26, 4076 2 of 45 cyclometalated complexes, the derivatives 1 and 2 bearing 2-(aminomethyl)pyridine (ampy) and ethylenediamine (en), respectively, were both found active for the TH of acetophenone (0.1 M) in isopropanol at reflux in the presence of NaOH (2 mol.%) as base and Whenactivator.2 (0.1 When mol.%) 2 (0.1 was mol.%) used, quantitativewas used, quantitative conversion conversion to 1-phenylethanol to 1-phenylethanol was achieved was afterachieved 30 min after reaction, 30 min whereas, reaction, when whereas,1 (0.05 when mol.%) 1 (0.05 was used,mol.%) 98% was conversion used, 98% was conversion reached inwas only reached 5 min (Schemein only 15). min Thus, (Scheme complex 1). 1Thus,(0.05 complex mol.%) was 1 (0.05 found mol.%) to be highlywas found active to for be thehighly reduction active offor a the number reduction of aryl of alkyl, a number diaryl, of and aryl dialkyl alkyl, ketonesdiaryl, and achieving dialkyl turnover ketones −1 frequenciesachieving turnover at 50% conversion frequencies (TOF at 50%50) of conversion up to 63,000 (TOF h 50and) of up turnover to 63,000 numbers h−1 and as turnover high as 9000numbers in 2 h as when high aas loading 9000 in of 2 0.01h when mol.% a loading was used of 0.01 (Scheme mol.%1). was These used Values (Scheme were 1). among These thevalues highest were reported among the in the highest literature reported at the in time the literature [4–8]. at the time [4–8].

1 (0.05 mol%) or 2 (0.1 mol%) PPh2 PPh2 OH O NaOH (2 mol%) CO CO Ru Ru 1 2 i- 1 2 R R PrOH / 82 °C R R H2N Cl H2N Cl 0.1 M N NH2 1 2

O O O O

Cl Cl Cl 1: 98% in 5 min 1: 99% in 10 min 1: 95% in 5 min 1: 98% in 10 min −1 TOF = 28,800 h−1 −1 −1 TOF50 = 60,000 h 50 TOF50 = 36,000 h TOF = 17,700 h TON = 1960 TON = 1980 TON = 1900 TON = 1960 2: > 99% in 30 min (TON up to 9000 in 2 h −1 TOF50 = 2800 h with 0.01 mol%) TON = 1000 O O O O

1: 99% in 10 min 1: 95% in 10 min 1: 99% in 15 min 1: 99% in 15 min −1 −1 −1 −1 TOF50 = 63,000 h TOF50 = 30,000 h TOF50 = 19,000 h TOF50 = 33,600 h TON = 1980 TON = 1900 TON = 1980 TON = 1980 SchemeScheme 1.1.TH TH ofof ketonesketones catalyzedcatalyzed byby thetheCP CP--cycloruthenatedcycloruthenated complexes complexes1 1and and2 2. .

RegardingRegarding thethe mechanism,mechanism, itit waswas postulatedpostulated byby thethe authorsauthors thatthat1 1could couldreact react with with thethe basebase toto affordafford the the corresponding corresponding amide amide complex complex thatthat could could subsequently subsequently reactreact withwith isopropanolisopropanol toto yield yield the the key key ruthenium ruthenium hydride hydride amine amine species species [9]. [Alternatively,9]. Alternatively, the latter the lattercould couldbe generated be generated through through the alkoxide the alkoxide route [10]. route Whatever [10]. Whatever the exact the route, exact the route, high thecatalytic high catalytic performance performance of 1 was of tentatively1 was tentatively ascribed ascribed to the combined to the combined presence presence of a bifunc- of a bifunctionaltional Ru–H/N–H Ru–H/N–H motif [11,12] motif [and11,12 of] anda stable of a Ru–C stable σ Ru–C-bondσ that-bond would that prevent would prevent catalyst catalystdeactivation deactivation [2]. [2]. BarattaBaratta etet al.al. recentlyrecently extendedextended thethe librarylibrary ofof ruthenacyclicruthenacyclic complexescomplexes bearingbearing thethe 2 − anionicanionic (κ(κ-2-CC,P,P)-[2-CH)-[2-CH22-6-MeC-6-MeC66HH33PPh2]]− ligandligand by by synthesizing synthesizing the seriesseries ofof dicarbonyldicarbonyl derivativesderivatives3 3––55depicted depicted in in Scheme Scheme2 [2 13[13].].The Theamine aminefree free complex complex3 3(0.1 (0.1 mol.%)mol.%) displayed displayed poorpoor activityactivity in the TH TH of of acetophenone acetophenone (0.1 (0.1 M) M) in inthe the presence presence of NaO of NaOiPr i(2Pr mol%) (2 mol%) as a asbase a base in 2-propanol in 2-propanol at reflux, at reﬂux, affording affording only 48% only conversion 48% conversion into 1-phenylethanol into 1-phenylethanol after 8 h afterreaction. 8 h reaction.In situ addition In situ of addition the bidentate of the ligands, bidentate en ligands,or ampy (2en equiv.),or ampy to(2 3 equiv.),dramatically to 3 dramatically increased the catalytic activity of the latter, resulting in a TOF between 1200 increased the catalytic activity of the latter, resulting in a TOF50 between50 1200 and 30,000 −1 andh−1, 30,000thus suggesting h , thus an suggesting accelerating an accelerating N–H effect upon N–H effectcoordination upon coordination to the metal to center. the metal This center.was confirmed This was by conﬁrmed the activity by observed the activity with observed the isolated with cationic the isolated dicarbonyl cationic species dicarbonyl 4 and species5, which4 andwere5 about, which the were same about as those the sameobserved as those with observedthe in situ with generated the in 3 situ/en and generated 3/ampy 3systems,/en and 3respectively/ampy systems, (Scheme respectively 2). Similarly (Scheme to2 what). Similarly was observed to what waswith observed the neutral with mono the neutral mono carbonyl derivatives 1 and 2 [2,3], the ampy derivative 5 displayed the highest −1 −1 activity with TOF50 Values ranging between 17,000 h and 30,000 h depending on the nature of the alkali base (NaOiPr, KOH, or KOtBu).

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Molecules 2021, 26, 4076 carbonyl derivatives 1 and 2 [2,3], the ampy derivative 5 displayed the highest activity3 with of 45 TOF50 values ranging between 17,000 h−1 and 30,000 h−1 depending on the nature of the alkali base (NaOiPr, KOH, or KOtBu).

3 (480 min): 48% −1 O 3, 4 or 5 (0.1 mol%) OH 3/en (60 min): 65%; TOF50 = 1200 h i −1 NaO Pr (2 mol%) 4 (60 min): 92%; TOF50 = 1500 h −1 i-PrOH / 82 °C 3/am py (40 min): 99%; TOF50 = 30,000 h −1 5 (5 min): 91%; TOF50 = 18,000 h 0.1 M −1 5 (KOH) (5 min): 91%; TOF50 = 17,000 h −1 5 (KOtBu) (5 min): 92%; TOF50 = 30,000 h

Cl− Cl−

PPh2 PPh2 PPh2 CO + CO + CO Ru Ru Ru Cl CO H2N CO H2N CO PPh2 NH2 N

3 4 5

SchemeScheme 2.2. THTH ofof acetophenoneacetophenone catalyzedcatalyzed byby thethe dicarbonyldicarbonyl CPCP-cycloruthenated-cycloruthenated complexescomplexes 33––55..

◦ AsAs forfor thethe mechanism, mechanism, control control experiments experiments run run with with4 at 4 85at 85C °C under under reduced reduced pressure pres- −2 (10sure (10mmHg)−2 mmHg) cleanly cleanly led to led the to formation the format ofion the of mono-carbonyl the mono-carbonyl complex complex2. This 2 result,. This to-re- gethersult, together with the with fact thatthe fact both that1 and both2 are 1 and twice 2 asare active twice as as5 andactive4, respectively,as 5 and 4, respectively, suggested a possiblesuggested thermal a possible dissociation thermal of dissociation one CO ligand of one asthe CO initial ligand step as ofthe the initial reaction step mechanism.of the reac- Thistion thermalmechanism. CO displacementThis thermal inCO the displacement presence of2-propanol in the presence and an of alkali2-propanol base would and an lead al- tokali the base catalytically would lead active to the Ru catalytically monohydride active species Ru thatmonohydride would then species reduce that acetophenone would then with the help of “a hydrogen bonding network promoted by the NH function”[13]. reduce acetophenone with the help of “a hydrogen bonding network2 promoted by the NH2 κ2 − functionFollowing” [13]. their work with the anionic ( -C,P)-[2-CH2-6-MeC6H3PPh2] ligand and the observation of the dramatic N–H accelerating effect upon coordination of ampy to Following their work with the anionic (κ2-C,P)-[2-CH2-6-MeC6H3PPh2]− ligand and the ruthenium center [2,3], Baratta and his collaborators reported the synthesis of com- the observation of the dramatic N–H accelerating effect upon coordination of ampy to the plex 6 bearing an orthometalated phenyl-substituted N-heterocyclic carbene (NHC) ligand ruthenium center [2,3], Baratta and his collaborators reported the synthesis of complex 6 in combination with ampy [14]. In the presence of NaOH (2 mol.%) as a cocatalyst, 6 bearing an orthometalated phenyl-substituted N-heterocyclic carbene (NHC) ligand in (0.05 mol.%) proved highly active for the TH of a small Variety of aryl, alkyl, and di- combination with ampy [14]. In the presence of NaOH (2 mol.%) as a cocatalyst, 6 (0.05 alkyl ketones from isopropanol at reﬂux, with TOF Values ranging from 50,000 h−1 in mol.%) proved highly active for the TH of a small 50variety of aryl, alkyl, and dialkyl ke- the cases 20-chloroacetophenone and 5-hexen-2-one to 120,000 h−1 in the case of 30,40- tones from isopropanol at reflux, with TOF50 values ranging from 50,000 h−1 in the cases dimethoxyacetophenone (Scheme3). The latter proved, thus, to be even more active than 2′-chloroacetophenone and 5-hexen-2-one to 120,000 h−1 in the case of 3′,4′-dimethoxyace- the CP-cyclometalated mono-carbonyl complex 1, suggesting that the CC-orthometalated tophenone (Scheme 3). The latter proved, thus, to be even more active than the CP-cy- carbene with ampy is a particularly favorable combination for obtaining a highly active clometalated mono-carbonyl complex 1, suggesting that the CC-orthometalated carbene catalyst. It is noteworthy, however, that 6 showed almost no activity at room temperature. Furthermore,with ampy is a noparticularly activity was favorable observed combination in the absence for obtaining of a base, a highly which active suggested catalyst. the It intermediacyis noteworthy, of however, a monohydride that 6 showed species thatalmost could no activity be generated at room through temperature. the alkoxide/ Further-β- eliminationmore, no activity route. was The observed high catalytic in the performance absence of a of base,6 would which then, suggested similarly the to intermediacy1, be due to theof a combined monohydride presence species of an that Ru–H/N–H could be motifgenerated and of through a stable orthometalatedthe alkoxide/β-elimination ligand that wouldroute. The prevent high catalyst catalytic deactivation. performance Regrettably, of 6 would no then, mechanistic similarly investigation to 1, be due wasto the carried com- outbined to sustainpresence these of an assumptions. Ru–H/N–H motif and of a stable orthometalated ligand that would preventSurprisingly, catalyst deactivation. other examples Regrettably, of CC-ruthenacycles no mechanistic comprising investigation similar was orthometalated carried out aryl-substitutedto sustain these assumptions. NHC ligands only appeared about a decade later. In a study aiming, among others, at establishing the inﬂuence of disparate electronic properties exerted by different cyclometalated groups on the catalytic activity of the resulting complexes, Choudhury et al. reported the synthesis, electronic characterization, and catalytic behavior of the bimetallic NHC-pyridyl and NHC-phenyl ruthenacycles 7 and 8, depicted in Figure1[ 15]. The RuII/RuIII oxidation potential Values measured for the cyclometalated ruthenium centers of 7 and 8 clearly established that the NHC-phenyl chelate is more electron-donating than the NHC-pyridyl chelate (0.812 V for 7 Vs. 0.596 V for 8). Both complexes (1 mol.%) proved to be moderately active for the TH of acetophenone (0.2 M) from isopropanol at 100 ◦C in the presence of a large amount of KOH (20 mol.%). Nevertheless, the electron-rich NHC-phenyl complex 8 was found to be a little more active Molecules 2021, 26, x FOR PEER REVIEW 4 of 50

6 (0.05 mol%) N N O NaOH (2 mol%) OH Ph N N R1 R2 i-PrOH / 82 °C R1 R2 Ru Ph Ph P Cl 0.1 M 3 NH2 6

O O O O MeO MeO Molecules 2021, 26, 4076 4 of 45 Cl MeO 99% in 5 min 90% in 10 min 98% in 10 min 98% in 2 min −1 −1 −1 −1 TOF50 = 110,000 h TOF50 = 50,000 h TOF50 = 70,000 h TOF = 120,000 h thanTON the = relatively 1980 electron-poorTON = 1800 NHC-pyridylTON complex = 1960 7 with 92%TON conversion = 1960 after 3.5 h −1 reaction(3% in 1 h (TON at 25 °C) = 92; TOF = 26.3 h ) for the former and onlyO 63% conversion after the same time for the latterO (TON = 63; TOF =O 18 h−1). A similar trend was observed with 5 the corresponding IrCp* (Cp* = η -C5Me5) complexes, which proved twice more active. Noteworthy, although complexes 7 and 8 possess two ruthenium centers in different en- 96% in 10 min 96% in 15 min 99% in 5 min Molecules 2021, 26, x FOR PEER REVIEWvironments, control experiments supported that the activity of the pyridine-coordinated4 of 50 TOF = 70,000 h−1 TOF = 50,000 h−1 TOF = 100,000 h−1 metal center was50 signiﬁcantly lower50 than that of the cyclometalated50 center. TON = 1920 TON = 1920 TON = 1980 Scheme 3. Highly efficient TH of ketones catalyzed by the CC-orthoruthenated complex 6.

6 (0.05 mol%) N Surprisingly, other examples of CC-ruthenacycles comprisingN similar orthometalated O OH Ph aryl-substituted NHCNaOH ligands (2 mol%) only appeared about a decade later. N N In aR study1 R2 aiming,i-PrOH among / 82 °C others,R1 R at2 establishing the influenceRu of disparate electronic Ph Ph P Cl properties0.1 exerted M by different cyclometalated groups 3on the catalytic activity of the re- NH2 6 sulting complexes, Choudhury et al. reported the synthesis, electronic characterization, and catalyticO behavior of the bimetallicO NHC-pyridylO and NHC-phenyl ruthenacyclesO 7 MeO and 8, depicted in Figure 1 [15]. The RuII/RuMeOIII oxidation potential values measured for the cyclometalated ruthenium centers of 7 and 8 clearly established that the NHC-phenyl che- Cl MeO late is more electron-donating than the NHC-pyridyl chelate (0.812 V for 7 vs. 0.596 V for 99% in 5 min 90% in 10 min 98% in 10 min 98% in 2 min 8). Both complexes−1 (1 mol.%) proved−1 to be moderately active−1 for the TH of acetophenone−1 TOF50 = 110,000 h TOF50 = 50,000 h TOF50 = 70,000 h TOF = 120,000 h (0.2 TONM) from = 1980 isopropanolTON at 100 = 1800 °C in the presenceTON = 1960of a large amountTON of = KOH1960 (20 mol.%). Nevertheless,(3% in 1 h at 25 the°C) electron-rich NHC-phenyl complex 8 was foundO to be a little more active than the relatively electron-poorO NHC-pyridylO complex 7 with 92% conversion after 3.5 h reaction (TON = 92; TOF = 26.3 h−1) for the former and only 63% conversion after the same time for the latter (TON = 63; TOF = 18 h−1). A similar trend was observed with the corre- 96% in 10 min 96% in 15 min 99% in 5 min 5 sponding IrCp* (Cp* = η -C−1 5Me5) complexes, which−1 proved twice more−1 active. Notewor- TOF50 = 70,000 h TOF50 = 50,000 h TOF50 = 100,000 h thy, although complexes 7 and 8 possess two ruthenium centers in different environ- TON = 1920 TON = 1920 TON = 1980 ments, control experiments supported that the activity of the pyridine-coordinated metal Scheme 3. Highly efficient TH of ketones catalyzed by the CC-orthoruthenated complex 6. Schemecenter was 3. Highly significantly efficient THlower of ketonesthan that catalyzed of the bycyclometalated the CC-orthoruthenated center. complex 6. Surprisingly, other examples of CC-ruthenacycles comprising similar orthometalated aryl-substituted NHC ligands only appeared about a decade later. In a study aiming,Ru Cl among others, Ruat establishingCl the influence of disparate electronic propertiesCl exerted by different cyclometalated groups on the catalytic activity of the re- N N sultingCl complexes,N N Choudhury et al. reportedN the synthesis,Cl electronic characterization, Ru N Cl and catalytic behavior 7of the bimetallic8 NHC-pyridylRu and NHC-phenyl ruthenacycles 7 and 8, depicted in Figure 1 [15]. The RuII/RuIII oxidation potential values measured for the cyclometalated ruthenium centers of 7 and 8 clearly established that the NHC-phenyl che- Figurelate is more1. 1. Bimetallic Bimetallicelectron-donating complexes complexes 7 and than 78 bearingtheand NHC-pyridyl8 abearing CC-cyclometalated a chelateCC-cyclometalated (0.812 NHC-pyridyl V for NHC-pyridyl7 orvs. NHC-phenyl 0.596 V for or NHC-phenylligand.8). Both complexes ligand. (1 mol.%) proved to be moderately active for the TH of acetophenone (0.2 M) from isopropanol at 100 °C in the presence of a large amount of KOH (20 mol.%). Nevertheless,Monometallic the electron-rich complexes bearingNHC-phenylbearing closelyclosely complex relatedrelated 8 CC wasCC-cycloruthenated-cycloruthenated found to be a little NHC-phenylNHC-phenyl more active ligandsligandsthan the werewere relatively thenthen successivelysuccessivelyelectron-poor describeddescribed NHC-pyridyl byby thethe complex groupsgroups 7 ofof with RameshRamesh 92% [conversion[16]16] andand RitRit after [[17],17], 3.5 andand h studiedreaction for (TON the TH= 92; of TOF acetophenone = 26.3 h−1) fromfor the isopropanol former and at only reflux. 63% While conversion Ramesh after et al. the studied same thetime influence for the latter of the (TON nature = of 63; the TOF wingtip = 18 h substituents−1). A similar in trend their series was observed of three complexes with the corre-9a–c, Rit et al. studied the influence of the nature of a substituent in meta-position to the sponding IrCp* (Cp* = η5-C5Me5) complexes, which proved twice more active. Notewor- C–Ru bond on the cyclometalated phenyl ring of complexes 10a–c (Scheme4 ). As the thy, although complexes 7 and 8 possess two ruthenium centers in different environ- reaction conditions changed from one study to the other, notably regarding the amount of ments, control experiments supported that the activity of the pyridine-coordinated metal base (KOH) that Varied from 6.25 mol.% with 9a–c to 20 mol.% with 10a–c, it is difficult center was significantly lower than that of the cyclometalated center. compare the two series of complexes. Nevertheless, conclusions can be drawn within each series. Thus, among complexes 9, the 9a derivative, bearing an n-butyl substituent, proved to be more active than 9b and 9c, bearing bulkier isopropyl and benzyl wingtips, respectively [16].Ru Interestingly,Cl the catalystRu Cl loading of 9a could even be decreased to 0.2Cl mol.%, allowing a TON of 460, which is from far the highest Value observed for the N N CCCl-cyclometalatedN N complexes 7–10, alongN with a much lowerCl amount of KOH than in the Ru N Cl 7 8 Ru

Figure 1. Bimetallic complexes 7 and 8 bearing a CC-cyclometalated NHC-pyridyl or NHC-phenyl ligand.

Monometallic complexes bearing closely related CC-cycloruthenated NHC-phenyl ligands were then successively described by the groups of Ramesh [16] and Rit [17], and

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studied for the TH of acetophenone from isopropanol at reflux. While Ramesh et al. studied the influence of the nature of the wingtip substituents in their series of three complexes 9a–c, Rit et al. studied the influence of the nature of a substituent in meta-position to the C–Ru bond on the cyclometalated phenyl ring of complexes 10a–c (Scheme 4). As the reaction conditions changed from one study to the other, notably regarding the amount of base (KOH) that varied from 6.25 mol.% with 9a–c to 20 mol.% with 10a–c, it is difficult compare the two series of complexes. Nevertheless, conclusions can be drawn within each series. Thus, among complexes 9, the 9a derivative, bearing an n-butyl substituent, proved to be more active than 9b and 9c, bearing bulkier isopropyl and benzyl wingtips, respec- Molecules 2021, 26, 4076 5 of 45 tively [16]. Interestingly, the catalyst loading of 9a could even be decreased to 0.2 mol.%, allowing a TON of 460, which is from far the highest value observed for the CC-cyclometalated complexes 7–10, along with a much lower amount of KOH than in the cases of casescomplexes of complexes 7, 8, and7 10a, 8,– andc [15–17].10a–c [ 15Among–17]. Amongcomplexes complexes 10, the m10-OMe, the mderivative-OMe derivative 10c (0.5 10cmol.%)(0.5 displayed mol.%) displayed the best theactivity, best activity,with 95% with conversion 95% conversion to 1-phenylathanol to 1-phenylathanol after 1 h reac- after −1 1tion hreaction (TOF = 190 (TOF h− =1), 190and h the), m and-CF the3 derivativem-CF3 derivative 10b displayed10b displayed the lowest, the with lowest, only with53% − onlyconversion 53% conversion after 1 h (TOF after 1= h106 (TOF h−1 =). 106This h almost1). This twofold almost difference twofold difference in catalytic in catalytic activity activitybetween between 10c and 10c10band could10b becould attributed be attributed to the presence to the presence of an electron-richer of an electron-richer Ru(II) center Ru(II) 13 centerin 10c, inas10c evidenced, as evidenced by the by higher the higher chemical chemical shift of shift the ofcarbene the carbene carbon carbon in its in13C-NMR its C- NMRspectrum spectrum (δ(CNHC (δ(C) =NHC 185.4) = 185.4(10c), ( 10c187.0), 187.0 (10a (),10a and), and 188.0 188.0 (10b (10b) ppm),) ppm), and and by by its its lower II III RuII/Ru/RuIII redoxredox potential potential (E (E1/21/2 = 72= 72mV mV (10c (10c), 101), 101 mV mV (10a (10a), 224.5), 224.5 mV mV (10b (10b) vs.) Vs. Fc) Fc)[17]. [17 ].

O 9a–c (0.2-0.5 mol%) / KOH (6.25 mol%) / 7 h OH or 1 0 a –c (0.5 mol%) / KOH (20 mol%) / 1 h i-PrOH / 82 °C 0.32 M (9a–c) 0.2 M (10a–c) 9a (0.5 mol%): 96%; TOF = 27.4 h−1; TON = 192 9a (0.2 mol%): 92%; TOF = 65.7 h−1; TO N = 460 9b (0.5 mol%): 87%; TOF = 24.9 h−1; TON = 174 9c (0.5 mol%): 80%; TOF = 22.9 h−1; TON = 160 10a: 68%; TOF = 136 h−1; TON = 136 10b: 53%; TOF = 106 h−1; TON = 106 10c: 95%; T O F = 1 9 0 h −1; TON = 190

9a: R = nBu 10a: R = H Ru Cl Ru Br 9b: R = iPr R 10b: R = CF3 R 9c: R = CH2Ph 10c: R = OMe N N N N

Scheme 4. TH of acetophenone catalyzed by CC-cycloruthenated complexescomplexes 9a–c and 10a10a–cc..

The reaction scopes of both 9a (0.2 mol.%, KOH (6.25 mol.%)) and 10c (0.5 mol.%, KOH (20 mol.%)) were studied under their re respectivespective optimized conditions. Noteworthy, Noteworthy, both complexes were shown to reduce a large panelpanel of ketones (16 substr substratesates in each case), including aryl alkyl, diaryl, heteroaryl alkyl, and cycliccyclic andand acyclicacyclic dialkyldialkyl ketones,ketones, withwith good to excellent efficiencyefficiency [[16,17].16,17]. Mechanistic investigations in the case of 10a resulted in evidence for the formation of a Mechanistic investigations in the case of 10a resulted in evidence for the formation ruthenium hydride species upon reaction of 10a with KOH in refluxing isopropanol, which of a ruthenium hydride species upon reaction of 10a with KOH in refluxing isopropanol, suggested the possible intermediacy of such species in the catalytic cycle [17]. This as- which suggested the possible intermediacy of such species in the catalytic cycle [17]. This sumption was further substantiated by the quantitative reduction of 4-chlorobenzaldehyde assumption was further substantiated by the quantitative reduction of 4-chlorobenzalde- (see Section 2.4) to the corresponding alcohol when the latter was treated with the in hyde (see Section 2.4) to the corresponding alcohol when the latter was treated with the situ generated ruthenium hydride. On this basis, the authors of this study proposed a in situ generated ruthenium hydride. On this basis, the authors of this study proposed a classical monohydride mechanism, with formation of the ruthenium hydride intermediate classical monohydride mechanism, with formation of the ruthenium hydride intermedi- by β-H-elimination from the corresponding ruthenium isopropoxide species. ate by β-H-elimination from the corresponding ruthenium isopropoxide species. In the same study, Rit et al. also reported the catalytic activity in Various TH reactions of a related CC-ruthenacycle 11a bearing an orthometalated mesoionic triazolylidene ligand (Figure2). The latter (0.5 mol.%) displayed poor activity in ketone TH compared to complexes 9–10 with only 25% conversion of acetophenone (0.2 M) to 1-phenylethanol after 1 h reaction in the presence of KOH (20 mol.%) in refluxing isopropanol [17]. This poor activity, nevertheless, contrasted with the total absence of activity of its chlorinated analog 11b, as reported by Albrecht et al. for the tentative TH of benzophenone (0.2 M) from isopropanol in the presence of 10 mol.% KOH under otherwise similar conditions [18]. Molecules 2021, 26, x FOR PEER REVIEW 6 of 50

Molecules 2021, 26, x FOR PEER REVIEW 6 of 50

In the same study, Rit et al. also reported the catalytic activity in various TH reactions of a relatedIn the same CC-ruthenacycle study, Rit et al.11a also bearing reported an orthometalated the catalytic activity mesoionic in various triazolylidene TH reactions lig- ofand a related(Figure CC 2).-ruthenacycle The latter (0.5 11a mol.%) bearing displayed an orthometalated poor activity mesoionic in ketone triazolylidene TH compared lig- to andcomplexes (Figure 9 2).–10 The with latter only (0.5 25% mol.%) conversion displayed of acetop poor henoneactivity (0.2in ketone M) to TH1-phenylethanol compared to complexesafter 1 h reaction 9–10 with in the only presence 25% conversion of KOH (20 of mol.%)acetophenone in refluxing (0.2 M) isopropanol to 1-phenylethanol [17]. This afterpoor 1activity, h reaction nevertheless, in the presence contrasted of KOH with (20 the mol.%) total absence in refluxing of activity isopropanol of its chlorinated [17]. This pooranalog activity, 11b, as nevertheless, reported by contrastedAlbrecht et with al. for the th totale tentative absence TH of ofactivity benzophenone of its chlorinated (0.2 M) analogfrom isopropanol 11b, as reported in the bypresence Albrecht of et10 al. mol.% for th KOHe tentative under THotherwise of benzophenone similar conditions (0.2 M) Molecules 2021, 26, 4076 6 of 45 from[18]. isopropanol in the presence of 10 mol.% KOH under otherwise similar conditions [18].

Figure 2. Poorly active and inactive CC-orthometalated triazolylidene Ru(II) complexes 11a and 11b. Figure 2. PoorlyPoorly active and inactive CCCC-orthometalated-orthometalated triazolylidene triazolylidene Ru(II) Ru(II) complexes complexes11a 11aand and11b . 11b. In 2017, Zhu et al. reported the synthesis of a series of half-sandwich five-memberedfive-membered 2 3 CP-ruthenacyclicIn 2017, Zhu etcomplexes complexes al. reported 12a12a the––cc, , 13,synthesis13, andand 1414 ofbyby a intramolecular series intramolecular of half-sandwich C( C(spsp)–H2)–H five-memberedor orC(sp C()–Hsp3)–H ac- 6 6 CPactivationtivation-ruthenacyclic of ofthe the corresponding correspondingcomplexes 12a phos– phosphinesc, phines13, and or14 or phosphinitesby phosphinites intramolecular with with [Ru(C( [Ru(sp2η)–Hη-p--cymene)Cl por-cymene)Cl C(sp3)–H2] 2ac-2 in]2 tivationinthe the presence presence of the of corresponding sodium of sodium acetate acetate phos [19]. [19phines All]. All comp or complexes phosphiniteslexes were were fully with fully characterized, [Ru( characterized,η6-p-cymene)Cl and and their2 their]2 re-in thereactivityactivity presence was was ofbriefly brieflysodium studied. studied. acetate In [19]. Inparticular, particular, All comp the thelexes authors authors were evaluated fully evaluated characterized, the the catalytic catalytic and activity their activity re- of activityofcomplexes complexes was 12 briefly–1214– for14 studied. forthe theTH THofIn benzophenoneparticular, of benzophenone the (0.267authors (0.267 M) evaluated from M) fromisopropanol the isopropanol catalytic at reflux activity at refluxin the of complexesinpresence the presence of 12 KOH–14 of for (10 KOH the mol.%) TH (10 of mol.%) asbenzophenone a base. as a With base. (0.267 the With exception M) the from exception isopropanolof the ofdiisopropyl(1-naph- the at diisopropyl(1- reflux in the presencenaphtyl)phosphinetyl)phosphine of KOH complex (10 complex mol.%) 12b and12b as andofa base.the of the1-naphtyl-diisop With 1-naphtyl-diisopropylphosphinite the exceptionropylphosphinite of the diisopropyl(1-naph- derivative derivative 14, tyl)phosphine14which, which proved proved complexless less active, active, 12b all and allcomplexes complexesof the 1-naphtyl-diisop reduced reduced benzophenone benzophenoneropylphosphinite in 90% in 90% yield derivative yield or ormore more 14 in, whichin48 48h with h proved with a catalyst a less catalyst active, loading loading all of complexes 0.5 of mol.%, 0.5 mol.%, reduced thus thus achieving benzophenone achieving TON TON of in180 of90% or 180 more,yield or more, oralbeit more albeit with in 48withvery h with Verylow TOFa low catalyst values TOF Valuesloading (Scheme (Scheme of 5).0.5 Nomol.%,5). mechanistic No thus mechanistic achieving investigation investigation TON of was 180 carried was or more, carried out. albeit out. with very low TOF values (Scheme 5). No mechanistic investigation was carried out. −1 O 12a–c, 13 or 1 4 (0.5 mol%) OH 12a: 90%; TOF = 3.75 h ; TON = 180 −1 KOH (10 mol%) 12b: 70%; TOF = 2.92 h−1 ; TON = 140 O 12a–c, 13 or 1 4 (0.5 mol%) OH 12a: 90%; TOF = 3.75 h ; TON = 180 12c: 98%; TOF = 4.08 h−1; TON = 196 i-PrOHKOH /(10 82 mol%)°C / 48 h 12b: 70%; TOF = 2.92 h−1; TON = 140 13: 96%; TOF = 4.00 h−1; TON = 192 12c: 98%; TOF = 4.08 h−1; TON = 196 0.267 M i-PrOH / 82 °C / 48 h 14: 58%; TOF = 2.42 h−1; TON = 116 13: 96%; TOF = 4.00 h−1; TON = 192 0.267 M 14: 58%; TOF = 2.42 h−1; TON = 116

Ru Ru Cl Ru Cl Cl Ru RuPiPr Ru i PR2Cl Cl2 P PrCl2 12a: R = Ph, R' = H O i PR2 12b: R = iPr, R' = H P Pr2 PiPr2 R' 12a12c:: RR == Ph,iPr, R' = HMe 13 O 14 12b: R = iPr, R' = H R' 12c: R = iPr, R' = Me 13 14 Scheme 5. TH of benzophenone catalyzed by the CP-cyclometalated-cyclometalated phosphine– or phosphinite– Ru(II) complexes 12a–c, 13, and 14.. Scheme 5. TH of benzophenone catalyzed by the CP-cyclometalated phosphine– or phosphinite– Ru(II) complexes 12a–c, 13, and 14. A series of eight half-sandwich CN-cycloruthenated complexes 15a–h were similarly prepared by intramolecular C–H activation of the ligands displayed in SchemeScheme6 6 with with A6 series of eight half-sandwich CN-cycloruthenated complexes 15a–h were similarly [Ru(η6 -p-cymene)Cl ] in the presence of potassium acetate, and investigated for their prepared[Ru(η -p-cymene)Cl by intramolecular22]2 2in the presenceC–H activation of potassium of the acetligandsate, anddisplayed investigated in Scheme for their 6 with ac- activity in the TH of aromatic ketones from isopropanol at reﬂux in the presence of KOH [Ru(tivityη 6in-p -cymene)Clthe TH of aromatic2]2 in the ketones presence from of potassium isopropanol acet atate, reflux and in investigated the presence for of theirKOH ac- as as a base [20]. Optimization studies established the necessity of using an amount of base tivitya base in [20]. the OptimizationTH of aromatic studies ketones established from isop thropanole necessity at reflux of using in the an presence amount of of KOH base as ashigh high as 25 as mol.% 25 mol.% to observe to observe an appreciable an appreciable reaction reaction rate ratein the in presence the presence of 1 mol.% of 1 mol.% of 15a of– a base [20]. Optimization studies established the necessity of6 using an amount of base as 15a–h. Under these conditions, complexes 15a–f and [Ru(6 η -p-cymene)Cl ] all achieved highh. Under as 25 thesemol.% conditions, to observe ancomplexes appreciable 15a –reactionf and [Ru( rateη in-p the-cymene)Cl presence2] of2 all 12 mol.% 2achieved of 15a full– full conversion of acetophenone (0.0423 M) to 1-phenylethanol in 8 h. The slightly reduced hconversion. Under these of acetophenone conditions, complexes (0.0423 M) 15a to– f1- andphenylethanol [Ru(η6-p-cymene)Cl in 8 h. The2]2 allslightly achieved reduced full activity observed with 15g and 15h was tentatively attributed to the low solubility of 15g conversionin isopropanol of acetophenone and to the substitution (0.0423 M) of theto 1- chloridephenylethanol ligand by in triphenylphosphine8 h. The slightly reduced in 15h. activityEvaluation observed of the reactionwith 15g scope and 15h of 15a was, 15e, tentativelyand 15f revealedattributed similar to the conversions low solubility for of the 15g 14 aromatic and heteroaromatic ketones investigated with the three complexes. Due to this similarity in activity and to the apparent absence of inﬂuence of the cyclometalated ligand, the authors suspected that the cycloruthenated complexes 15a–h might be precatalysts undergoing a transformation to a common species acting as the catalyst. An array of control experiments, including stoichiometric NMR studies, kinetic monitoring, transmission electron microscopy (TEM), dynamic light scattering (DLS), and X-ray photoelectron spectroscopy (XPS), indeed allowed establishing the demetalation of the cyclometalated ligands under these basic conditions, as well as the formation of catalytically active Ru(0) nanoparticles [20]. Molecules 2021, 26, x FOR PEER REVIEW 7 of 50

Molecules 2021, 26, x FOR PEER REVIEW 7 of 50

in isopropanol and to the substitution of the chloride ligand by triphenylphosphine in in15h isopropanol. Evaluation and of the to reactionthe substitution scope of of15a the, 15e, chloride and 15f ligand revealed by triphenylphosphinesimilar conversions forin 15hthe .14 Evaluation aromatic ofand the heteroaromatic reaction scope ketonesof 15a, 15e, investigated and 15f revealed with the similar three complexes.conversions Due for theto this 14 aromaticsimilarity and in activity heteroaromatic and to the ketones apparent investigated absence of withinfluence the three of the complexes. cyclometalated Due toligand, this similarity the authors in activitysuspected and that to the the apparent cycloruthenated absence complexesof influence 15a of –theh might cyclometalated be precat- ligand,alysts undergoing the authors asuspected transformation that the to cycloruthenated a common species complexes acting as 15a the–h catalyst. might be An precat- array alystsof control undergoing experiments, a transformation including stoichiometric to a common NMR species studies, acting kinetic as the monitoring,catalyst. An trans-array ofmission control electron experiments, microscopy including (TEM), stoichiometric dynamic light NMR scattering studies, (DLS), kinetic and monitoring, X-ray photoelec- trans- missiontron spectroscopy electron microscopy (XPS), indeed (TEM), allowed dynamic esta lightblishing scattering the demetalation (DLS), and X-rayof the photoelec- cyclomet- Molecules 2021, 26, 4076 tronalated spectroscopy ligands under (XPS), these indeed basic conditions, allowed esta asblishing well as thethe formation demetalation of catalytically of the cyclomet- active7 of 45 alatedRu(0) nanoparticlesligands under [20]. these basic conditions, as well as the formation of catalytically active Ru(0) nanoparticles [20]. 15a–h (1 mol%) η6 O or [Ru(15a–-hp -cymene)Cl(1 mol%) 2]2 OH KOHη6 (25 mol%) O or [Ru( -p-cymene)Cl2]2 OH 15a–f: X = Cl Ru X i-PrOHKOH (25 / 82 mol%) °C / 8 h 15g: X = I Ru 15a–f: X = Cl − N X 15h: X = PPh3, PF6 0.0423 M i-PrOH / 82 °C / 8 h E 15g: X = I −1 − 15a–f: 100%; TOF = 12.5 h ; TON = 100 N 15h: X = PPh3, PF6 0.0423 M −1 E 15a–1 5 g : f : 100%; 85%; TOFTOF == 12.510.6 hh−1;; TONTON == 10085 −1 11 5 5 g h :: 85%;89%; TOFTOF == 10.611.1 hh−1;; TONTON == 8589 η6 −1 [Ru( - p -cymene)Cl 1 5 h :2 ] 2 : 89%;98%; TOFTOF == 11.112.3 hh−1;; TONTON == 8998 η6 −1 [Ru( -p-cymene)Cl2]2: 98%; TOF = 12.3 h ; TON = 98 H H H H H H H H H N + I− H H H H N N H N N N N N N + − N S N N N I N N O N N N N S N a,h b c Od e f g a,h b c d e f g Scheme 6. TH of acetophenone catalyzed by the CN-cycloruthenated complexes 15a–h. Scheme 6. TH of acetophenone catalyzed by the CN-cycloruthenated complexescomplexes 15a15a––h.. More recently, Albrecht et al. reported the synthesis and catalytic activity in ketone More recently, Albrecht et al. reported the synthesis and catalytic activity in ketone TH TH ofMore the half-sandwichrecently, Albrecht CN -ruthenacycleet al. reported 16 the bearing synthesis a hybrid and catalytic chelating activity ligand in compris- ketone of the half-sandwich CN-ruthenacycle 16 bearing a hybrid chelating ligand comprising a THing ofa pyridylideneamide the half-sandwich CNnitrogen-ruthenacycle atom as one16 bearing strong σa -donorhybrid sitechelating and an ligand orthometalated compris- pyridylideneamide nitrogen atom as one strong σ-donor site and an orthometalated phenyl ingphenyl a pyridylideneamide ring as the second nitrogen donor site atom [21]. as oneThe stronglatter was σ-donor compared site and to ansimilar orthometalated complexes ring as the second donor site [21]. The latter was compared to similar complexes bearing phenylbearing ring a pyridine, as the second a pyridylidene, donor site another [21]. The pyridylideneamide, latter was compared or a to triazolylidene similar complexes as the a pyridine, a pyridylidene, another pyridylideneamide, or a triazolylidene as the second bearingsecond donora pyridine, site. Aa pyridylidene,combination of another NMR andpyridylideneamide, cyclovoltammetric or studiesa triazolylidene allowed asestab- the donor site. A combination of NMR and cyclovoltammetric studies allowed establishing lishing considerable electronic variation in this series of complexes with decreasing donor considerablesecond donor electronic site. A combination Variation in of this NMR series and of cyclovoltammetric complexes with decreasing studies allowed donor abilityestab- ability in the order phenyl > pyridylideneamide ~ triazolylidene ~ pyridylidene > pyridine. inlishing the orderconsiderable phenyl electronic > pyridylideneamide variation in this ~ triazolylidene series of complexes ~ pyridylidene with decreasing > pyridine. donor Interestingly, the cyclometalated phenyl complex 16 (1 mol.%) proved to be by far the Interestingly,ability in the order the cyclometalated phenyl > pyridylideneamide phenyl complex ~16 triazolylidene(1 mol.%) proved ~ pyridylidene to be by far > pyridine. the most activeInterestingly,most active precatalyst, precatalyst, the cyclometalated achieving achieving full reduction phenyl full reduct complex of benzophenoneion of 16 benzophenone (1 mol.%) (0.2 M)proved in(0.2 4h M)to in be thein by4 presence h far in thethe ofmostpresence 10 mol.%active of KOHprecatalyst,10 mol.% in reﬂuxing KOH achieving in isopropanolrefluxing full reduct isop (Schemeropanolion of 7benzophenone), (Scheme whereas 7), the whereas others(0.2 M) required thein 4others h in 24 there- h topresencequired reach 24 conversions of h 10to mol.%reach ranging converKOH insions from refluxing ranging 45% toisop 96%fromropanol under 45% to(Scheme the 96% same under 7), conditions. whereas the same the Noteworthy, conditions. others re- kineticquiredNoteworthy, studies24 h to kinetic stronglyreach studiesconver suggested sionsstrongly thatranging suggested all these from complexes that45% allto these96% operate under complexes through the same operate a mononuclear conditions. through reactionNoteworthy,a mononuclear mechanism. kinetic reaction studies mechanism. strongly suggested that all these complexes operate through a mononuclear reaction mechanism.

O 16 (1 mol%) OH KOH (10 mol%) O 16 (1 mol%) OH Ru Cl i-PrOHKOH (10/ 82 mol%) °C / 4 h Ru NCl 0.2 M i-PrOH / 82 °C / 4 h N 100% N TOF = 25 h−1; TON = 100 O N 16 0.2 M 100% TOF = 25 h−1; TON = 100 O 16 SchemeScheme 7.7. THTH ofof benzophenonebenzophenone catalyzedcatalyzed bybythe theCN CN-cyclometalated-cyclometalated phenyl-pyridylideneamide phenyl-pyridylideneamide complexSchemecomplex 7.1616 .TH. of benzophenone catalyzed by the CN-cyclometalated phenyl-pyridylideneamide 2.2.complex Base-Free 16. Transfer Hydrogenation of Ketones Triggered by Cyclometalation 2.2. Base-Free Transfer Hydrogenation of Ketones Triggered by Cyclometalation 2.2. Base-FreeIn addition Transfer to the aboveHydrogenation described ofclassical Ketones examplesTriggered ofby ketoneCyclometalation TH with ruthenacycles in the presence of an alkali base, a couple of examples of base-free reactions, where the catalytic transformation was triggered by the cylometalation of a ligand, have also been reported.

The ﬁrst such example appeared as early as 2002 in a report from Fogg et al. [22].

In this report, mainly dedicated to h2 hydrogenation, the anionic trihydride complex K[Ru(Cy2P(CH2)4PCy2)(CO)H3]·KBHsBu3 (17) (0.033 mol.%) was shown to achieve the TH of benzophenone to 1,2-diphenylethanol with 55% conversion after 24 h reaction in isopropanol at 60 ◦C in the absence of a base (Scheme8A). Control experiments following hydrogenation reactions revealed the presence of a single species, identiﬁed by NMR, XRD, and elemental analyses as the ruthenacyclic monohydride complex 18 bearing an orthometalated benzophenone ligand. The same complex was also formed by reaction of 17 with a threefold excess of benzophenone (Scheme8B). Both these results suggested that 18 was the actual TH catalyst. Molecules 2021, 26, x FOR PEER REVIEW 8 of 50

In addition to the above described classical examples of ketone TH with ruthenacycles in the presence of an alkali base, a couple of examples of base-free reactions, where the catalytic transformation was triggered by the cylometalation of a ligand, have also been reported. The first such example appeared as early as 2002 in a report from Fogg et al. [22]. In this report, mainly dedicated to H2 hydrogenation, the anionic trihydride complex K[Ru(Cy2P(CH2)4PCy2)(CO)H3]·KBHsBu3 (17) (0.033 mol.%) was shown to achieve the TH of benzophenone to 1,2-diphenylethanol with 55% conversion after 24 h reaction in isopropanol at 60 °C in the absence of a base (Scheme 8A). Control experiments following hydrogenation reactions revealed the presence of a single species, identified by NMR, XRD, and elemental analyses as the ruthenacyclic monohydride complex 18 bearing an orthometalated benzophenone ligand. The same complex was also formed by reaction of Molecules 2021, 26, 4076 8 of 45 17 with a threefold excess of benzophenone (Scheme 8B). Both these results suggested that 18 was the actual TH catalyst.

− CO A. O 17 (0.0333 mol%) OH Cy2 no base P H + K Ru •KBHsBu3 i-PrOH / 60 °C / 24 h P H Cy2 H 17 1 M 55% TOF = 68.75 h−1; TON = 1650

B. CO − Cy2 PCy2 P H O Ph + 3 Ph2CO Cy2P K Ru •KBHsBu3 Ru P H - 2 KOCHPh2 OC Cy2 H - BsBu3 H 17 - H2 18 Scheme 8. SchemeBase-free 8. THBase-free of benzophenone TH of benzophenone triggered triggered by its orthometalation by its orthometalation upon reactionupon reaction with complexwith com-17 (A) and orthometalationplex 17 of benzophenone(A) and orthometalation (B). of benzophenone (B).

Another exampleAnother of this exampletype came of from this th typee group came of from Williams the group in 2005 of with Williams the base- in 2005 with the free TH of severalbase-free ketones TH catalyzed of several by ketones the complex catalyzed 19, [Ru(IMes)(PPh by the complex3)2(CO)H19, [Ru(IMes)(PPh2] (IMes = 3)2(CO)H2] ◦ 1,3-dimesitylimidazol-2-ylidene),(IMes = 1,3-dimesitylimidazol-2-ylidene), in benzene-d6 at 50 °C inin benzene-the presenced6 at of 50 5 equiv.C in the of presence iso- of 5 equiv. propanol as theof hydrogen isopropanol donor as the (Scheme hydrogen 9A) donor [23]. (Scheme The latter9A) was [ 23 ].moderately The latter was efficient, moderately efﬁcient, achieving TONachieving ranging only TON from ranging 24 to only 38 with from aryl 24 alkyl to 38 and with diaryl aryl alkyl ketones, and as diaryl well ketones,as a as well as TON of 49 witha TONcyclohexanone of 49 with cyclohexanonein 12 h. Interestingly, in 12 h. however, Interestingly, a reversible however, C–H a reversible bond C–H bond activation processactivation was found process to be was at foundthe origin to be of at the the catalytic origin of transformation. the catalytic transformation. Indeed, Indeed, complex 19 wascomplex shown 19to undergowas shown a facile to undergo dehydrogenation a facile dehydrogenation reaction in the reactionpresence in of the a presence of a ketone such asketone acetone such or cyclohexanone as acetone or cyclohexanone at 50 °C to yield at the 50 ◦ cyclometalatedC to yield the cyclometalated complex 20 complex 20 in which one Cinsp which3–H bond one Cofsp one3–H mesityl bond of group one mesityl of the groupIMes ligand of the IMeswas ligandactivated. was Fur- activated. Further- Molecules 2021, 26, x FOR PEER REVIEW 9 of 50 thermore, the startingmore, the complex starting 19 complex could be19 easilycould regenerated be easily regenerated by the addition by the of addition 2-propa- of 2-propanol to ◦ nol to 20 at 50 °C20 at(Scheme 50 C(Scheme 9B). 9B).

A. 19 (2 mol%) O OH N N no base 1 2 R1 R2 i-PrOH (5 equiv.) R R Ph3P H Ru C D / 50 °C / 12 h 6 6 OC H 0.6–0.8 M 6 examples PPh 19 47–99% 3 TOF = 2.00–4.08 h−1; TON = 24–49

B. N N N N

(CH3)2CO / 50 °C Ph3P H Ph3P CH2 Ru Ru OC H i-PrOH / 50 °C OC H PPh3 PPh3 20 Scheme 9. 9. Base-freeBase-free TH THof ketones of ketones triggered triggered by the byorthometalation the orthometalation of the IMes of theligand IMes of complex ligand of19 complex(A) and reversible19 (A) and orthometalation reversible orthometalation of the IMes ligand of the of IMes complex ligand 19 of (B complex). 19 (B).

A lastlast exampleexample came from aa seriesseries ofof twotwo articlesarticles fromfrom ThielThiel etet al.al. [[24,25],24,25], inin whichwhich ((ηη66-arene)Ru(II) complexescomplexes 21a–cc,, bearingbearing aa 2-(pyrimidin-4-yl)pyridine ligandligand substitutedsubstituted at thethe 2-position2-position ofof thethe pyrimidinylpyrimidinyl ringring byby aa tertiarytertiary amine,amine, werewere shownshown toto catalyzecatalyze thethe base-free THTH ofof Various various ketones. ketones. As As demonstrated demonstrated by by a combination a combination of NMR of NMR spectroscopy, spectros- kineticcopy, kinetic studies, studies, collision-induced collision-induced dissociation dissociation (CID) (CID) ESI-MS ESI-MS measurements, measurements, and DFTand calculation,DFT calculation, these these base-free base-free THs THs were were triggered triggered by the by roll-overthe roll-over cyclometalation cyclometalation of the of 0 Nthe,N N-chelating,N′-chelating ligand ligand leading leading to to a 16-electrona 16-electron cyclometalated cyclometalated active active species species that that wouldwould thenthen follow a a classical classical monohydride monohydride mechanism mechanism (Scheme (Scheme 10). 10 According). According to these to these data, data, the thetriggering triggering roll-over roll-over cyclometalation cyclometalation was was found found especially especially favorable favorable for for 2-(pyrimidin-4- 2-(pyrimidin-4- yl)pyridineyl)pyridine ligandsligands bearing bearing a a tertiary tertiary amine amine at theat the 2-position 2-position of the of pyrimidinethe pyrimidine ring becausering be- 0 thecause latter the weakenslatter weakens the Ru–N the Ru–Nbond′ bybond both by steric both andsteric electric and electric factors. factors.

Molecules 2021, 26, 4076 9 of 45 Molecules 2021, 26, x FOR PEER REVIEW 10 of 50

O 21a–c (0.5 mol%) OH no base R R’ − X 21a: R = Me, R’ = iPr; NR2 = NMe2, + i-PrOH / 82 °C / 24 h Ru X = BPh N Cl 4 21b: R = R’ = H, NR = NMe ; 0.27 M 2 2 N NR2 21a: 100%; TOF = 8.3 h−1; TON = 200 X = BF4 21b: 53%; TOF = 4.4 h−1; TON = 106 N 21c: R = Me, R’ = iPr, NR2 = N(CH2)4, 21c: > 80%; TOF > 6.7 h−1; TON > 160 X = BPh4

R R’ + Ru N Cl

N NR2

- HCl OH R R’ OH Ph + Ru N

N N R R’ R R’ NR2 + + Ru Ru N O Ph N O

N NR2 N NR2

N N R R’ + Ru H O N O N NR2 Ph N SchemeScheme 10. 10. Base-freeBase-free TH THof acetophenone of acetophenone triggered triggered by roll-over by roll-over cyclometalation cyclometalation of the 2-(2-dialkyl- of the 2-(2- dialkylaminopyrimidin-4-yl)pyridineaminopyrimidin-4-yl)pyridine ligand of ligand complexes of complexes 21a–c and21a proposed–c and proposedmechanism. mechanism.

The most most active active 2-(pyrimidin-4-yl)pyridine 2-(pyrimidin-4-yl)pyridine complex complex 21a was21a shownwas shown to efficiently to efﬁciently cat- catalyzealyze the the base-free base-free reduction reduction of 11 of aromatic 11 aromatic and and aliphatic aliphatic ketones ketones (0.27 (0.27 M) in M) isopropanol in isopropanol Molecules 2021, 26, x FOR PEER REVIEWat reflux with a catalyst loading of 0.5 mol.% (Scheme 11). With the exception of11 methylof 50 at reﬂux with a catalyst loading of 0.5 mol.% (Scheme 11). With the exception of methyl ββ-naphtyl ketone, ketone, all all substrates substrates were were converted converted with with yields yields over over 80% 80% in 24 in h 24 [25]. h [25 ].

SchemeScheme 11. 11. Base-freeBase-free TH TH of ketones of ketones catalyzed catalyzed by 21a by. 21a.

2.3. Asymmetric Transfer Hydrogenation of Ketones The first example of application of ruthenacycles in asymmetric transfer hydrogenation (ATH) of ketones appeared in 2005 as a joint contribution of the groups of Michel Pfeffer in Strasbourg and Johannes G. de Vries at DSM [26]. This report, whose genesis started with a 2 month stay of Vincent Ritleng—then a PhD student of Michel Pfeffer—in DSM in 2000 [27], followed closely those from Baratta’s group [2,3], which described for the first time the use of ruthenacycles as efficient precatalysts for the same reaction in its racemic version (see Section 2.1). In this initial report, azaruthenacycles 22a–c obtained by cyclometalation of enantiopure aromatic primary and secondary amines with [Ru(η6- C6H6)Cl2]2 were shown to be efficient catalysts for the asymmetric transfer hydrogenation of acetophenone (0.01–0.1 M) in isopropanol with TOF at the end of the reaction up to 190 h−1 at room temperature (22c, 0.1 mol.%) and enantiomeric excesses (ee) ranging from 38% (22a) to 85% (22b, 0 °C) (Scheme 12) [26].

O 22a,b (1 mol%) / KOtBu (5 mol%) OH or 22c (0.01 mol%) / KOtBu (0.5 mol%)

i-PrOH / RT (22a,c) or 0°C (22b) 0.1 M (22a,b) 0.01 M (22c) 22a (1 h): 97%; 38% ee; TON = 97; TOF = 97 h−1 22b (2 h): 95%; 85% ee; TON = 95; TOF = 47.5 h−1 22c (4 h): 76%; 61% ee; TON = 760; TOF = 190 h−1

− − − PF6 PF6 PF6 + + + Ru Ru NCMe NCMe Ru NCMe

NH2 NH Ph NH2

22a 22b 22c

Scheme 12. ATH of acetophenone with Pfeffer’s azaruthenacycles 22.

Molecules 2021, 26, x FOR PEER REVIEW 11 of 50

Molecules 2021, 26, 4076 10 of 45 Scheme 11. Base-free TH of ketones catalyzed by 21a.

2.3.2.3. Asymmetric Asymmetric Transfer Transfer Hydrogenation Hydrogenation of of Ketones Ketones TheThe first first example example of application ofof ruthenacyclesruthenacycles in in asymmetric asymmetric transfer transfer hydrogenation hydrogenation(ATH) (ATH) of ketones of ketones appeared appeared in 2005 in 2005 as a jointas a contributionjoint contribution of the of groups the groups of Michel of Michel Pfeffer Pfefferin Strasbourg in Strasbourg and Johannes and Johannes G. de VriesG. de at Vries DSM at [ 26DSM]. This [26]. report, This report, whose whose genesis genesis started startedwith a with 2 month a 2 month stay of stay Vincent of Vincent Ritleng—then Ritleng—then a PhD a studentPhD student of Michel of Michel Pfeffer—in Pfeffer—in DSM DSMin 2000 in 2000 [27], [27], followed followed closely closely those those from from Baratta’s Baratta’s group group [2,3 ],[2,3], which which described described for for the thefirst first time time the the use use of of ruthenacycles ruthenacycles as as efficient efficient precatalysts precatalysts forfor thethe same reaction in in its its racemicracemic version Version (see (see Section Section 2.1). 2.1 In). Inthis this initial initial report, report, azaruthenacycles azaruthenacycles 22a–22ac obtained–c obtained by cyclometalationby cyclometalation of enantiopure of enantiopure aromatic aromatic primary primary and and secondary secondary amines amines with with [Ru( [Ru(ηη6-6- CC6H6H6)Cl6)Cl2]2 ]were2 were shown shown to to be be efficient efficient catalysts catalysts for for the the asymmetric asymmetric transfer transfer hydrogenation hydrogenation ofof acetophenone acetophenone (0.01–0.1 (0.01–0.1 M) M) in inisopropanol isopropanol with with TOF TOF at the at theend end of the of reaction the reaction up to up 190 to h190−1 at h room−1 at roomtemperature temperature (22c, 0.1 (22c mol.%), 0.1 mol.%) and enantiomeric and enantiomeric excesses excesses (ee) ranging (ee) ranging from 38% from (22a38%) to (22a 85%) to (22b 85%, 0 (22b °C), (Scheme 0 ◦C) (Scheme 12) [26]. 12)[ 26].

O 22a,b (1 mol%) / KOtBu (5 mol%) OH or 22c (0.01 mol%) / KOtBu (0.5 mol%)

− − − PF6 PF6 PF6 + + + Ru Ru NCMe NCMe Ru NCMe

NH2 NH Ph NH2

22a 22b 22c

SchemeScheme 12. 12. ATHATH of of acetophenone acetophenone with with Pfeffer’s Pfeffer’s azaruthenacycles azaruthenacycles 2222. .

Interestingly, the synthesis of these ruthenacycles could be performed in situ, thus allowing the easy screening of a library of chiral primary and secondary amines through a high-throughput experiment (HTE) (Scheme 13)[26,28]. From this screening, it appeared that the majority of the ligands led to catalysts with interesting activity. In particular, the catalyst based on 1-naphtylethylamine 22c turned out to be Very fast, with TON and TOF Values that could reach 10,000 and 30,000 h−1, respectively, at 80 ◦C with a loading of 0.01 mol.% [29]. Furthermore, the catalyst based on 2,5-diphenylpyrrolidine h induced the highest enantioselectivity (89%). The lack of reactivity observed with the aliphatic amine f suggested the necessity to form a ruthenacycle to elicit transfer hydrogenation activity, the cyclometalation of f being obviously hampered by the lack of aromatic protons. Furthermore, the much reduced activity observed with the tertiary aromatic amine, N,N-dimethylbenzylamine [26], suggested a ligand cooperative mechanism involving the NH proton as in the Noyori transfer hydrogenation mechanism [11,12]. This assumption was later confirmed by a detailed mechanistic study [30] that allowed the identification of diastereomeric ruthenium-hydride intermediates and demonstrated the formation of a substrate–catalyst complex Via hydrogen bonding between the O-atom of the substrate and the N–H unit of the catalyst and the subsequent hydride transfer to the substrate through a 6-membered transition state by an elegant combination of NMR studies and kinetic measurements. A brief study of the reaction scope (nine ketones) with complexes 22b and 22h established that electron-deficient aromatic ketones such as 3,5-di-trifluoromethyl-acetophenone are hydrogenated Very fast (TOF > 500 h−1) but with low enantioselectivity (29%) [31]. Branching in the α-position on the aliphatic side of the ketone led to much improved enantioselectivity, in particular with 22b (89% to 98% ee). Tetralone also was reduced with excellent enantioselectivity (94%), but with catalyst 22h. Lastly, both catalysts were able Molecules 2021, 26, x FOR PEER REVIEW 12 of 50

η6 [Ru( -C6H6)Cl2]2 + chiral amine + KPF6 + NaOH

1) CH3CN, 40 °C, 24 h 2) removal of CH3CN O OH ruthenacycle 22a–i (1.8 mol%) + tBuOK * i-PrOH / 0 °C or RT 2.7 mol% 0.093 M

H2N NH2

N H

a 38% b 80 (85)% c 54%

NH2 NH2 NH2

d 10% e 30% f –

HN Ph N H N H

g 76% h 89% i 69 (86)%

SchemeScheme 13. 13. HTEHTE screening screening of of chiral chiral amines amines in in Pfeffer’s Pfeffer’s ATH ATH of of acetophenone acetophenone (ee (ee givengiven below below ligand ligand structure;structure; values Values between between brackets brackets obtained obtained at at 0 0°C).◦C).

TheSince lack this of seriesreactivity of papers observed from with the the Pfeffer aliphatic and deamine Vries f suggested groups [26 the,27 ,necessity29–32] were to formpublished, a ruthenacycle to our knowledge, to elicit transfer only two hydrogenation more examples activity, have the appeared cyclometalation Very recently of f being which obviouslyreported lowerhamperedees: in by 2018 the fromlack of the aromatic group of protons. Baratta, Furthermore, and in 2019 from the much that of reduced Grabulosa. activity Asobserved part of theirwith workthe tertiary on CP-cyclometalated aromatic amine, dicarbonyl N,N-dimethylbenzylamine complexes as racemic [26], ketone sug- gestedTH catalysts a ligand (see cooperative Section 2.1 mechanism, Scheme 2involving)[ 13], Baratta the NH et proton al. also as reportedin the Noyori the synthesis transfer of the chiral complex 23, as a mixture of two diastereomers in a 1:1 ratio, by reaction hydrogenation mechanism [11,12]. This assumption was later confirmed by a detailed of 3 in methanol at reﬂux with (R,R)-1,2-diphenylethylenediamine. In the presence of mechanistic study [30] that allowed the identification of diastereomeric ruthenium-hy- NaOiPr (2 mol.%) in isopropanol at reﬂux, 23 (0.2 mol.%, as a diastereomeric mixture) dride intermediates and demonstrated the formation of a substrate–catalyst complex via quantitatively reduced acetophenone to (S)-1-phenylethanol in 40 min with a moderate ee of hydrogen bonding between the O-atom of the substrate and the N–H unit of the catalyst 68% (Scheme 14). When the reaction was carried out at lower temperature (60 ◦C), only 15% and the subsequent hydride transfer to the substrate through a 6-membered transition conversion was observed after 8 h, with no substantial increase in ee. By comparison with state by an elegant combination of NMR studies and kinetic measurements. other ruthenium systems with (R,R)- or (S,S)-1,2-diphenylethylenediamine, which gave A brief study of the reaction scope (nine ketones) with complexes 22b and 22h estab- similar ees in related hydrogenation reactions [33,34], the authors reasonably postulated lished that electron-deficient aromatic ketones such as 3,5-di-trifluoromethyl-acetophe- that the enantioselectivity of this reduction is mainly controlled by the chiral ligand [13]. −1 none are hydrogenated very fast (TOF > 500 h ) but with low enantioselectivity6 (29%) In 2019, Grabulosa and coworkers reported that the reactions of [Ru(η -p-cymene)Cl2]2 [31]. Branching in the α-position on the aliphatic side of the ketone led to much improved with P-stereogenic 1-naphtyl-, 9-phenantryl-, or 1-pyrenyl-substituted phosphines in enantioselectivity,methanol in the presence in particular of sodium with acetate22b (89% afforded to 98% the ee). corresponding Tetralone also neutral was reduced cycloruthen- with excellentated complexes enantioselectivity24–26 in low (94%), yields, but andwith that catalyst the latter 22h. speciesLastly, both could catalysts act as catalysts were able for the transfer hydrogenation of acetophenone after 15 min activation in isopropanol at 82 ◦C in the presence of KOtBu [35]. The precatalyst 3c bearing cyclometalated 1-naphtyl- substituted phosphinite showed the highest activity with full conversion already after 2 h reaction, but was completely unselective, similarly to the other 1-naphtyl-substituted monophosphine complexes 24a and 24b (Scheme 15). The bulkier 9-phenantryl- and 1-pyrenyl-substituted cycloruthenated phosphine complexes 25 and 26 showed lower ac- Molecules 2021, 26, x FOR PEER REVIEW 13 of 50

to reduce selectively, i.e., without reducing the C–C double bonds, 4-acetyl-styrene and 2- acetylfuran with very good enantioselectivity (86% to 87% ee) [32]. Since this series of papers from the Pfeffer and de Vries groups [26,27,29,30–32] were published, to our knowledge, only two more examples have appeared very recently which reported lower ees: in 2018 from the group of Baratta, and in 2019 from that of Grabulosa. As part of their work on CP-cyclometalated dicarbonyl complexes as racemic ketone TH catalysts (see Section 2.1, Scheme 2) [13], Baratta et al. also reported the synthesis of the chiral complex 23, as a mixture of two diastereomers in a 1:1 ratio, by reaction of 3 in methanol at reflux with (R,R)-1,2-diphenylethylenediamine. In the presence of NaOiPr (2 Molecules 2021, 26, 4076 12 of 45 mol.%) in isopropanol at reflux, 23 (0.2 mol.%, as a diastereomeric mixture) quantitatively reduced acetophenone to (S)-1-phenylethanol in 40 min with a moderate ee of 68% (Scheme 14). When the reaction was carried out at lower temperature (60 °C), only 15% tivityconversion with a was Very observed slightly enhancedafter 8 h, with enantioselectivity no substantial (5% increase to 8% inee ).ee This. By comparison quasi absence with of enantioselectivityother ruthenium systems may be attributedwith (R,R to)- or the (S,S existence)-1,2-diphenylethylene of complexes 24–diamine,26 as diastereomeric which gave mixtures.similar ees Thus,in related for instance,hydrogenation the non-cyclometalated reactions [33],[34], dichloro-analoguethe authors reasonably of 24b postulated, gave a slightlythat the higherenantioselectivityee of 13% for of a this conversion reduction of 75%is mainly after 5controlled h under similar by the reaction chiral ligand conditions. [13].

Cl− Cl−

O 23 (0.2 mol%) OH PPh2 Ph2P NaOiPr (2 mol%) + CO OC + Ru Ru i-PrOH / 82 °C / 40 min H2N CO OC NH2 NH2 H2N 0.1 M 99%; 68% ee Ph Ph −1 Ph TON = 495; TOF50 = 1500 h Ph 23 (1:1 diastereomeric mixture)

Molecules 2021, 26, x FOR PEER REVIEW 14 of 50 Scheme 14. 14. ATHATH of acetophenone of acetophenone catalyzed catalyzed by the by 1:1 the diastereomeric 1:1 diastereomeric mixture mixtureof the CP of-cyclomet- the CP- cyclometalatedalated dicarbonyl dicarbonyl complex complex23. 23.

In 2019, Grabulosa and 24acoworkers: 70%; < 5%re portedee; TOF =that 14.0 theh−1; TONreactions = 70 of [Ru(η6-p-cy- O 24–26 (1 mol%) OH −1 KOmene)CltBu (5 mol%)2]2 with P-stereogenic* 24b1-naphtyl-,: 96%; < 5%9-phenantryl ee; TOF = 19.2-, or h 1-pyrenyl-substituted; TON = 96 phos- 24c: >99%; < 5% ee; TOF = 20.0 h−1; TON = 100 i- phines in methanol in the presence of sodium acetate afforded the corresponding neutral PrOH / 82 °C / 5 h −1 cycloruthenated complexes 2425–26: in 63%; low yields,8% ee; TOFand = that 12.6 theh ; latterTON = 63species could act as 0.16 M −1 catalysts for the transfer hydrogenation26: 40%; of acet5% eeophenone; TOF = 8.0 after h ; 15 TON min = 40activation in isopropanol at 82 °C in the presence of KOtBu [35]. The precatalyst 3c bearing cyclometalated 1- naphtyl-substituted phosphinite showed the highest activity with full conversion already Cl Ru Cl Ru Cl Ru after 2 h reaction,R but was completelyMe unselective, similarlyMe to the other 1-naphtyl-substi- P P P tuted monophosphinePh complexes 24aPh and 24b (Scheme 15).Ph The bulkier 9-phenantryl- and 1-pyrenyl-substituted cycloruthenated phosphine complexes 25 and 26 showed lower activity with a very slightly enhanced enantioselectivity (5% to 8% ee). This quasi absence of 24a (R = Me), 24b (R = i-Pr) 25 26 enantioselectivity24c (R = OMe) may be attributed to the existence of complexes 24–26 as diastereomeric mixtures. Thus, for instance, the non-cyclometalated dichloro-analogue of 24b, gave a Scheme 15. ATHScheme of acetophenone 15. ATHslightly of acetopheno catalyzed higher byneee CPofcatalyzed -cycloruthenated13% for by a CP conversion-cycloruthenated complexes of 75%24– complexes26 afterwith 5P -stereogenich 24 under–26 with similar monophosphinesP-stere- reaction condi- bearing a polycyclicogenic monophosphines aromatictions. substituent. bearing a polycyclic aromatic substituent.

2.4. Transfer Hydrogenation2.4. Transfer Hydrogenation of Aldehydes of Aldehydes The transfer hydrogenationThe transfer hydrogenation of aldehydes is of rarely aldehydes studied, is rarely and the studied, catalytic and efficiency the catalytic efficiency is generally foundis generally to be very found low to with be Very limited low withsubstrate limited scope substrate along with scope the along formation with the formation of aldol condensationof aldol condensationor carboxylic acid or carboxylic byproducts acid [36]. byproducts We are, thus, [36 ].aware We are,of only thus, one aware of only example of theone use example of a ruthenacycle of the use as of effici a ruthenacycleent catalyst for as efficientthis transformation. catalyst for In this their transformation. extensive studyIn their of CC extensive-cyclometalated study of CCNHC-phenyl--cyclometalated and NHC-phenyl-triazolylidene-phenyl-Ru(II) and triazolylidene-phenyl- complexes (seeRu(II) Sections complexes 2.1 and (see 2.5) Sections[17], Rit 2.1et al. and also 2.5 evaluated)[17], Rit the et al.activity also evaluatedof ruthena- the activity of cycles 10a–c andruthenacycles 11a for the10a TH– cofand benzaldehyde.11a for the TH Whereas of benzaldehyde. the NHC-phenyl Whereas species the NHC-phenyl 10a– species c (0.1 mol.%, 10aKOH–c (0.1(10 mol.%) mol.%, KOHin isopropanol (10 mol.%) at in reflux) isopropanol produced at reflux) significant produced amounts significant of amounts benzoic acid/benzoateof benzoic as acid/benzoate byproduct to as benzyl byproduct alcohol, to benzyl possibly alcohol, through possibly base-assisted through base-assisted Cannizaro reaction,Cannizaro the reaction,triazolylidene-phenyl the triazolylidene-phenyl complex 11a complex produced11a producedbenzyl alcohol benzyl in alcohol in 95% 95% yield underyield the under same the reaction same reaction conditions conditions with no with detectable no detectable side-product side-product (Scheme (Scheme 16). The −1 16). The reactionreaction could could be achieved be achieved within within 20 min, 20 min,giving giving a TOF a TOFof 2850 of 2850h−1. h . The 3- and 4-substituted benzaldehydes containing both electron-withdrawing and electron-donating substituents were all effectively reduced to the corresponding alcohol (nine examples). Only 4-methoxybenzaldehyde required a longer reaction time (TOF = 395 h−1), probably due to the reduced electrophilicity of its aldehyde moiety. In addition, the heteroaromatic substrate, 5-bromo-2-thiophene, was also reduced efficiently, and the bulky 1-naphtylaldehyde was converted to the corresponding alcohol in 65% yield.

Scheme 16. TH of aldehydes catalyzed by the cyclometalated triazolylidene-phenyl complex 11a.

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24a: 70%; < 5% ee; TOF = 14.0 h−1; TON = 70 O 24–26 (1 mol%) OH −1 KOtBu (5 mol%) * 24b: 96%; < 5% ee; TOF = 19.2 h ; TON = 96 24c: >99%; < 5% ee; TOF = 20.0 h−1; TON = 100 i-PrOH / 82 °C / 5 h 25: 63%; 8% ee; TOF = 12.6 h−1; TON = 63 0.16 M 26: 40%; 5% ee; TOF = 8.0 h−1; TON = 40

Cl Ru Cl Ru Cl Ru R Me Me P P P Ph Ph Ph

24a (R = Me), 24b (R = i-Pr) 25 26 24c (R = OMe)

Scheme 15. ATH of acetophenone catalyzed by CP-cycloruthenated complexes 24–26 with P-stereogenic monophosphines bearing a polycyclic aromatic substituent.

2.4. Transfer Hydrogenation of Aldehydes The transfer hydrogenation of aldehydes is rarely studied, and the catalytic efficiency is generally found to be very low with limited substrate scope along with the formation of aldol condensation or carboxylic acid byproducts [36]. We are, thus, aware of only one example of the use of a ruthenacycle as efficient catalyst for this transformation. In their extensive study of CC-cyclometalated NHC-phenyl- and triazolylidene-phenyl-Ru(II) complexes (see Sections 2.1 and 2.5) [17], Rit et al. also evaluated the activity of ruthenacycles 10a–c and 11a for the TH of benzaldehyde. Whereas the NHC-phenyl species 10a– c (0.1 mol.%, KOH (10 mol.%) in isopropanol at reflux) produced significant amounts of benzoic acid/benzoate as byproduct to benzyl alcohol, possibly through base-assisted Molecules 2021, 26, 4076 Cannizaro reaction, the triazolylidene-phenyl complex 11a produced benzyl alcohol13 of 45in 95% yield under the same reaction conditions with no detectable side-product (Scheme 16). The reaction could be achieved within 20 min, giving a TOF of 2850 h−1.

SchemeScheme 16.16. TH of aldehydes catalyzedcatalyzed byby thethe cyclometalatedcyclometalated triazolylidene-phenyltriazolylidene-phenyl complexcomplex 11a11a..

2.5. Transfer Hydrogenation of Aldimines Despite the importance of amines for the synthesis of bioactive compounds, agro-

chemicals, fragrance, and industrially relevant polymers, ruthenium-catalyzed TH of aldimines has, comparatively to ketones, only been scarcely reported [23], and we are, in this case also, aware of only one example using ruthenacycles that comes from the work of Rit et al. [17]. Similarly to what was observed with ketones (see Section 2.1, Scheme4 ), the electron-rich p-methoxy-substituted NHC-phenyl-Ru(II) complex 10c (2 mol.%, KOH (20 mol.%)) performed better than the electron-poor p-triﬂuoromethyl-substituted derivative 10b and the electron-neutral derivative 10a, achieving full reduction of N-benzylideneaniline to N-benzylaniline (98%) in 10 h in isopropanol at reﬂux (vs. 99% in 24 h with 10a and 73% in 24 h with 10b). In accordance with its low activity in ketone reduction, the triazolylidene-phenyl derivative 11a proved also ineffective in this transformation (17% conversion in 24 h). Substantial decomposition of the imine products to the corresponding anilines and aldehydes/alcohols was, however, observed in some cases with 10c, and the substrate scope was studied with 10a (Scheme 17). Electron-withdrawing substituents at the 3- or 4-position of the C-phenyl ring of aldimines substantially enhanced the reaction rate with TOF’s ranging from 6.1 to 24.8 h−1 whereas electron-donating substituents at the 4-position of C-phenyl ring slowed down the reaction with TOF Val- ues around 1.8 h−1 Vs. 2.08 h−1 for N-benzylideneaniline. Variations of the substituents on the N-phenyl ring had less effects on the reaction rate. 1-Naphtyl-based aldimine (TOF = 8.38 h−1) was reduced faster than 2-naphtyl-based aldimine (TOF = 1.88 h−1). Lastly, in contrast to the N-aromatic aldimines that were screened, the N-alkyl aldimine, N-benzylidene butylamine, proved a relatively poor substrate for this catalytic system with only 60% conversion to the corresponding amine after 24 h reaction. MoleculesMolecules2021 2021, ,26 26,, 4076 x FOR PEER REVIEW 1416 of of 45 50

SchemeScheme 17.17. THTH ofof aldehydesaldehydes catalyzedcatalyzed byby thethe cyclometalatedcyclometalated triazolylidene-phenyltriazolylidene-phenyl complexcomplex10a 10a..

2.6.2.6. AsymmetricAsymmetric TransferTransfer HydrogenationHydrogenation of of Imines Imines AmongAmong thethe methodsmethods availableavailable toto generategenerate opticallyoptically activeactive amines,amines, asymmetricasymmetric hy-hy- drogendrogen transfertransfer onon prochiralprochiral iminesimines isis ofof highhigh economiceconomic andand fundamentalfundamental importance.importance. Nevertheless,Nevertheless, thethe onlyonly knownknown exampleexample toto datedate withwith half-sandwichhalf-sandwich ruthenacyclesruthenacycles comescomes fromfrom the the groups groups of of de de Vries Vries and and Pfeffer Pfeffer with with the CNthe-metalacyclic CN-metalacyclic complex complex22h. In22h their. In brieftheir study,brief study, they showed they showed that 22h thatwas 22h able was to reduce able to the reduce three ketiminesthe three displayedketiminesin displayedScheme 18 in ◦ withScheme low 18 to moderatewith low yieldsto moderate and reasonable yields and enantioselectivity reasonable enantioselectivity in dichloromethane in dichloro- at 20 C inmethane the presence at 20 °C of in a the dry presence 1:1 mixture of a ofdry formic 1:1 mixture acid and of formic triethylamine acid and as triethylamine the hydrogen as sourcethe hydrogen [32]. Of source note, [32]. among Of thenote, tested among complexes the tested22 complexes, 22h was the22, 22h only was one the to only give oneees superiorto give ee tos 40%.superior In particular, to 40%. In the particular, catalysts derivedthe catalysts from derived the primary from amines the primary led to aminesamines withled toee samines below with 20%. ee Theses below results 20%. were These in lineresults with were the mechanisticin line with studiesthe mechanistic performed studies with acetophenoneperformed with that acetophenone showed that ruthenacyclesthat showed basedthat ruthenacycles on chiral primary based amines on chiral were primary unable toamines induce were high unableees because to induce of the high formation ees because of diastereomeric of the formation Ru of hydride diastereomeric intermediates Ru hy- thatdride display intermediates competitive that ratesdisplay but competitive opposite enantioselectivities rates but opposite [30 enantioselectivities]. [30]. 2.7. Transfer Hydrogenation of Alkynes and Alkenes Examples of ruthenium-catalyzed TH of alkynes and/or alkenes are exceedingly rare, and we are aware of only two examples with ruthenacycles, one that deals with the partial hydrogenation of alkynes to alkenes [37] and another one that deals with the TH of alkenes to alkanes [38]. In a Very complete and elegant study, Djukic and Pfeffer reported that the µ-chlorido, µ-hydroxy-bridged dicarbonyl ruthenacycles 27 and 28 (2.5 mol.%) behaved as efﬁcient precatalysts for the TH of diphenylacetylene to stilbene from 1-indanol in toluene at 90 ◦C in the absence of a base (Scheme 19)[37]. complexes 27 and 28 were obtained by the highly stereoselective reaction of their µ-dichlorido bridged congeners with water in the presence of Na2CO3. Noteworthy, the µ-dichlorido-bridged precursors could also achieve the partial TH of diphenylacetylene and a couple of other diarylalkynes in the presence of water

Molecules 2021, 26, x FOR PEER REVIEW 17 of 50

HN N *

22h (1 mol%) R −1 R R = H or Cl HCO2H/Et3N (1:1) R = H: 52%; 60% ee; TOF = 2.74 h ; TON = 52 R = Cl: 11%; 71% ee; TOF = 0.58 h−1; TON = 11 MeO CH2Cl2 / 20 °C / 19 h MeO or N or MeO NH MeO * −1 − 21%; 60% ee; TOF = 1.11 h ; TON = 21 PF6 + Ru NCMe NH 22h

Molecules 2021, 26, 4076 15 of 45 Scheme 18. ATH of imines with Pfeffer’s azaruthenacycle 22h.

2.7. Transfer Hydrogenation of Alkynes and Alkenes Molecules 2021, 26, x FOR PEER REVIEWand of a soft inorganic base, ingredients necessary for the production of the µ-chlorido,17 of 50 Examples of ruthenium-catalyzed TH of alkynes and/or alkenes are exceedingly rare, µand-hydroxy-bridged we are aware of complexes only two examples27 and 28 with. ruthenacycles, one that deals with the partial hydrogenation of alkynes to alkenes [37] and another one that deals with the TH of alkenes to alkanes [38]. HN In a veryN complete and elegant study, Djukic and Pfeffer* reported that the μ-chlorido, μ-hydroxy-bridged dicarbonyl22h ruthenacycles 27 and 28 (2.5 mol.%) behaved as efficient (1 mol%) R −1 precatalystsR R = for H or the Cl TH of diphenylacetyleneHCO2H/Et3N (1:1) to stilbeneR = H: 52%; from 60% 1-indanol ee; TOF = 2.74 in tolueneh ; TON =at 52 90 °C in the absence of a base (Scheme 19) [37]. ComplexesR = Cl: 27 11%; and 71% 28 wereee; TOF obtained = 0.58 h−1 by; TON the = 11highly MeO CH2Cl2 / 20 °C / 19 h stereoselective reaction of their μ-dichlorido bridged congenersMeO with water in the presence or of Na2CO3. Noteworthy, Nthe μ-dichlorido-bridged precursorsor could also achieve the par- MeO NH tial TH of diphenylacetylene and a couple of other diarylalkynesMeO in the* presence of water −1 and of a soft inorganic base, ingredients necessary− for the21%; production 60% ee; TOF of = 1.11the hμ-chlorido,; TON = 21 μ- PF6 hydroxy-bridged complexes 27 and+ 28. Ru Owing to its higher solubility inNCMe toluene, complex 27 showed a higher activity than 28, achieving full partial hydrogenationNH to Z-stilbene and subsequent isomerization to E- stilbene in 6 h. The Z–E isomerization22h of alkenes was favored by the use of an excess

amount of 1-indanol as shown by the formation of 86:14 and 1:99 Z/E mixtures after 24 h SchemereactionScheme 18.18. with ATH 28 of in imines the presence with Pfeffer’s Pfeffer’s of 1 azaruthenacycleand azaruthenacycle 2 equiv. of 22h 1-indanol,22h. . respectively (Scheme 19).

2.7. Transfer Hydrogenatio27–n28 of (2.5 Alkynes mol%) and Alkenes 1-indanol (1 or 2 equiv.) Ph ExamplesPh Ph of ruthenium-catalyzed TH of alkynes +and/or alkenes are exceedingly rare, Ph Ph and we are aware of onlytoluene two examples/ 90 °C with ruthenacycles,Ph one that deals with the partial hydrogenation0.11 M of alkynes to alkenes [37] and anotherZE one that deals with the TH of alkenes to27 alkanes (1 equiv. of[38]. 1-indanol, 4 h): 77%, Z/E = 97 : 3 (TOF = 7.7 h−1; TON = 31) −1 27 (1 Inequiv. a very of 1-indanol, complete 6 and h): 100%, elegant Z/ Estudy, = 0 : Djukic100 (TOF and = 6.67 Pfeffer h ; TONreported = 40) that the μ-chlorido, −1 μ28-hydroxy-bridged (1 equiv. of 1-indanol, dicarbonyl 4 h): 34%, ruthenacycles Z/E = 99 : 1 (TOF27 and = 3.4 28 h(2.5; TON mol.%) = 14) behaved as efficient 28 (1 equiv. of 1-indanol, 24 h): 100%, Z/E = 86 : 14 (TOF = 1.67 h−1; TON = 40) precatalysts for the TH of diphenylacetylene to stilbene from 1-indanol in toluene at 90 °C 28 (2 equiv. of 1-indanol, 24 h): 100%, Z/E = 1 : 99 (TOF = 1.67 h−1; TON = 40) in the absence of a base (Scheme 19) [37]. Complexes 27 and 28 were obtained by the highly stereoselective reaction of their μ-dichlorido bridged congeners with water in the presence of Na2CO3. Noteworthy, the μ-dichlorido-bridged precursors could also achieve the partial TH of diphenylacetyleneCO andtBu a couple of other diarylalkynesCO in the presence of water OC Ru N OC Ru N andtBu of a soft inorganic base, ingredients necessary for the production of the μ-chlorido, μ- O O hydroxy-bridgedH complexes 27 and 28. H N Cl N Cl Owing toRu its higher solubility in toluene, complexRu 27 showed a higher activity than 28, achieving full partialCO hydrogenation to Z-stilbene COand subsequent isomerization to E- CO CO stilbene in 6 h. The Z–E isomerization of alkenes was favored by the use of an excess amount of 1-indanol as27 shown by the formation of 86:14 28and 1:99 Z/E mixtures after 24 h

reaction with 28 in the presence of 1 and 2 equiv. of 1-indanol, respectively (Scheme 19). Scheme 19. Base-free TH of diphenylacetylene to Z- and/or E-stilbene catalyzed by µ-chlorido,µ- hydroxy-bridged dicarbonyl27–28 ruthenacycles (2.5 mol%) 27 and 28. 1-indanol (1 or 2 equiv.) Ph Ph Ph + Ph Ph Owing to its highertoluene solubility / 90 °C in toluene, complexPh 27 showed a higher activity than 28, achieving0.11 M full partial hydrogenation to ZEZ-stilbene and subsequent isomerization to E27-stilbene (1 equiv. inof 1-indanol, 6 h. The 4Z h):–E 77%,isomerization Z/E = 97 : 3 of (TOF alkenes = 7.7 was h−1; favoredTON = 31) by the use of an excess amount27 (1 equiv. of of 1-indanol 1-indanol, as 6 h): shown 100%, by Z/E the = formation0 : 100 (TOF of= 6.67 86:14 h−1; and TON 1:99 = 40)Z/E mixtures after 24 h −1 reaction28 (1 equiv. with of 1-indanol,28 in the 4 presenceh): 34%, ofZ/E 1 = and 99 : 1 2 equiv. (TOF = of 3.4 1-indanol, h ; TON = respectively 14) (Scheme 19). 28 Z E −1 (1Regarding equiv. of 1-indanol, the mechanism, 24 h): 100%, complexes/ = 86 : 14 (TOF27 and = 1.6728 h were; TONshown, = 40) upon reaction with 28 (2 equiv. of 1-indanol, 24 h): 100%, Z/E = 1 : 99 (TOF = 1.67 h−1; TON = 40) secondary alcohols, to produce ruthenium hydride species that are believed to be the active species. In addition, the determination of a kH/kD isotopic effect of 7.0 ± 0.2 with 1-d-1-indanol allowed the authors to establish that the partial hydrogenation of diphenylacetylene reliesCO on thetBu hydrogen transfer fromCO 1-indanol Via C–H bond cleavage OC Ru N OC Ru N oftBu a putative alkoxy ligand coordinated to the Ru(II) center in a rate-determining step. O H O H Furthermore,N a controlCl experiment performedN with 1-indanoneCl and D2O in the presence of 28, which resultedRu in 40% deuterium incorporationRu at the methylene C in the α-position to CO CO the carbonyl, suggestedCO that 1-indanone is notCO innocent and that it may contribute to the

27 28

Molecules 2021, 26, x FOR PEER REVIEW 18 of 50

Scheme 19. Base-free TH of diphenylacetylene to Z- and/or E-stilbene catalyzed by μ-chlorido,μ- hydroxy-bridged dicarbonyl ruthenacycles 27 and 28.

Regarding the mechanism, complexes 27 and 28 were shown, upon reaction with secondary alcohols, to produce ruthenium hydride species that are believed to be the active species. In addition, the determination of a kH/kD isotopic effect of 7.0 ± 0.2 with 1-d- 1-indanol allowed the authors to establish that the partial hydrogenation of diphenylacetylene relies on the hydrogen transfer from 1-indanol via C–H bond cleavage of a putative alkoxy ligand coordinated to the Ru(II) center in a rate-determining step. Further- Molecules 2021, 26, 4076 16 of 45 more, a control experiment performed with 1-indanone and D2O in the presence of 28, which resulted in 40% deuterium incorporation at the methylene C in the α-position to the carbonyl, suggested that 1-indanone is not innocent and that it may contribute to the overalloverall catalyticcatalytic processprocess byby facilitatingfacilitating thethe formationformation ofof thethe rutheniumruthenium hydridehydride fromfrom thethe µμ-chlorido,-chlorido,µμ-hydroxy-bridged-hydroxy-bridged precatalystprecatalyst throughthrough thethe formationformation ofof rutheniumruthenium enolates.enolates. OnOn thethe basisbasis of of these these results, results, the the authors authors proposed proposed the the mechanisms mechanisms depicted depicted in Schemein Scheme 20 for20 thefor the generation generation of the of catalyticallythe catalytically active active ruthenium ruthenium hydride hydride species species (Scheme (Scheme 20A) 20A) and theand partial the partial TH of TH alkynes of alkynes (Scheme (Scheme 20B). 20B).

SchemeScheme 20.20. GenerationGeneration ofof thethe catalyticallycatalytically activeactive rutheniumruthenium hydridehydride speciesspecies fromfrom thethe µμ-chlorido,-chlorido,µμ-- hydroxy-bridgedhydroxy-bridged ruthenacyclesruthenacycles27 27and and28 28( A(A)) and and partial partial TH TH of of alkynes alkynes ( B(B).).

TheThe onlyonly exampleexample ofof THTH ofof alkenesalkenes thatthat wewe areare awareaware ofof comescomes fromfrom thethe groupgroup ofof Williams,Williams, who who reported reported in in 2007 2007 that that the the C–H C–Hactivated activatedcarbene carbenecomplex complex29 29could could achieve achieve thethe base-freebase-free THTH ofof trimethylvinylsilane trimethylvinylsilane usingusing isopropanol isopropanol as as reductant reductant in in benzene- benzene-dd66at at ◦ 5050 °CC withwith moderatemoderate efﬁciencyefficiency (Scheme(Scheme 2121A)A) [[38].38]. SimilarlySimilarly toto whatwhat waswas observedobserved withwith complexescomplexes 1919//2020 [23],[23], the the key key to to the the hydrogen hydrogen transfer transfer chemistry chemistry of of29 29appearedappeared to be to the be thereversible reversible C–H C–H bond bond activation activation of the of coordinated the coordinated carbene carbene ligand. ligand. Indeed, Indeed, reactions reactions of the ofcyclometalated the cyclometalated complex complex 29 with29 isopropanolwith isopropanol produced produced the dihydride the dihydride complex complex 30 bearing30 bearingthe non-metalated the non-metalated carbene, carbene,and, when and, a sample when aof sample 30 was of reacted30 was with reacted excess with trimethyl- excess trimethylvinylsilane at 50 ◦C, 29 was regenerated along with an isomer 31 bearing the triphenylphosphine ligands in trans. The latter could similarly be converted back to 30 by reaction with isopropanol (Scheme 21B). This, together with control experiments of phosphine ligand exchange, suggested that these species are able to react by facile phosphine dissociation, which, in addition to the reversible C–H activation process, is likely to be relevant to the observed catalytic activity. Molecules 2021, 26, x FOR PEER REVIEW 19 of 50 Molecules 2021, 26, x FOR PEER REVIEW 19 of 50

vinylsilanevinylsilane atat 5050 °C,°C, 2929 waswas regeneratedregenerated alongalong withwith anan isomerisomer 3131 bearingbearing thethe tri-tri- phenylphosphinephenylphosphine ligandsligands inin transtrans.. TheThe latterlatter couldcould similarlysimilarly bebe convertedconverted backback toto 3030 byby reactionreaction withwith isopropanolisopropanol (Scheme(Scheme 21B).21B). This,This, togethertogether withwith controlcontrol experimentsexperiments ofof phos-phosphine ligand exchange, suggested that these species are able to react by facile phosphine Molecules 2021, 26, 4076 phine ligand exchange, suggested that these species are able to react by facile phosphine17 of 45 dissociation,dissociation, which,which, inin additionaddition toto thethe reversiblereversible C–HC–H activationactivation process,process, isis likelylikely toto bebe relevantrelevant toto thethe observedobserved catalyticcatalytic activity.activity.

Scheme 21. Base-free TH of trimethylvinylsilane catalyzed by the hydrido-ruthenacycle 29 (A) and SchemeScheme 21.21. Base-freeBase-free THTH ofof trimethylvinylsilanetrimethylvinylsilane catalyzedcatalyzed byby thethe hydrido-ruthenacyclehydrido-ruthenacycle 2929 ((AA)) andand reversible C–H bond activation of the carbene ligand (B). reversiblereversible C–HC–H bondbond activationactivation ofof thethe carbenecarbene ligandligand ((BB).).

2.8.2.8. Oppenauer Oppenauer Alcohol Alcohol OxidationOxidation TheThe reversereverse reactionreactionreaction of ofof ketone ketoneketone TH, TH,TH, i.e., i.e.,i.e., alcohol alalcoholcoholoxidation oxidationoxidation to toto the thethe ketone ketoneketone using usingusing a aa sacrifi- sacri-sacri- cialficialficial ketone ketoneketone (usually (usually(usually acetone) acetone)acetone) as asas a hydrogen aa hydrogenhydrogen acceptor, acceptor,acceptor, has hashas been beenbeen much muchmuch less lessless studied, studied,studied, probably prob-prob- becauseablyably becausebecause the extent thethe extentextent of alcohol ofof alcoholalcohol oxidation oxidationoxidation is limited isis limitedlimited by byby the thethe attainment attainmentattainment of ofof an anan equilibrium equilibriumequilibrium pointpoint basedbased onon thethe relativerelative oxidationoxidation potentialspotentials ofof thethe ketoneketone productproduct andand ofof thethe sacrificialsacrificialsacrificial ketoneketone [[39].[39].39]. Thus,Thus, onlyonly aa couplecouple ofof examplesexamples havehave beenbeen reportedreported withwithwith ruthenacycles.ruthenacycles.ruthenacycles. AA first firstfirst example example appearedappeared inin in 20052005 2005 withwith with thethe the carbenecarbene carbene complexcomplex complex 191919,, which,which,, which, inin in additionaddition addition toto tothethe the base-freebase-free base-free THTH TH ofof ketones ofketones ketones (see(see (see SectionSection Section 2.2,2.2, 2.2 SchemeScheme, Scheme 9A),9A),9A), waswas was shownshown shown toto catalyzecatalyze to catalyze thethe theoxi-oxi- oxidationdationdation ofof ofaa smallsmall a small setset set ofof of secondarysecondary secondary alcoholsalcohols alcohols intointo into ketonesketones ketones usingusing using acetoneacetone as as thethe hydrogenhydrogenhydrogen acceptoracceptor (Scheme(Scheme(Scheme 22 22)22))[ 23[23].[23].]. Owing OwingOwing to toto the thethe reversible reversiblereversible C–H C–HC–H bond bondbond activation activationactivation process processprocess leading leadingleading to 20 19 complextoto complexcomplex in2020 the inin presencethethe presencepresence of a ketoneofof aa ketoneketone and leading andand leadingleading back to backbackin toto the 1919 presenceinin thethe presencepresence of an alcohol ofof anan (Scheme9B), the reaction occurred in the absence of a base. alcoholalcohol (Scheme(Scheme 9B),9B), thethe reactionreaction occurredoccurred inin thethe absenceabsence ofof aa base.base.

SchemeScheme 22.22. AlcoholAlcohol oxidationoxidation byby base-freebase-free THTH withwith acetoneacetone catalyzedcatalyzed bybyby 19 1919... Another base-free alcohol oxidation by TH was reported 2 years later by the same AnotherAnother base-freebase-free alcoholalcohol oxidationoxidation byby THTH waswas reportedreported 22 yearsyears laterlater byby thethe samesame group with the hydrido-ruthenacycle 2929 (2(2 mol.%)mol.%) thatthat waswas shownshown toto yieldyield 80%80% oxidationoxidation group with the hydrido-ruthenacycle 29 (2 mol.%) that was shown to yield 80% oxidation◦ of 4-fluoro- 4-ﬂuoro-α-methylbenzyl-methylbenzyl alcohol alcohol to to the the corresponding corresponding ketone ketone in in only only 1 1h hat at50 50°C inC Molecules 2021, 26, x FOR PEER REVIEWof 4-fluoro- α-methylbenzyl alcohol to the corresponding ketone in only 1 h at 5020 °C of− 50in1 inbenzene- benzene-d6 ind 6thein presence the presence of 5 equiv. of 5 equiv.of acetone, of acetone, thus achieving thus achieving a TOF of 40 a TOFh−1 (Scheme of 40 h 23) benzene-d6 in the presence of 5 equiv. of acetone, thus achieving a TOF of 40 h−1 (Scheme 23) (Scheme 23)[38]. [38].[38].

Scheme 23.23. OxidationOxidation ofof 4-ﬂuoro-4-fluoro-αα-methylbenzyl-methylbenzyl alcohol alcohol by by base-free base-free TH TH with with acetone acetone catalyzed catalyzed by theby the hydrido-ruthenacycle hydrido-ruthenacycle29. 29.

The μ-chlorido,μ-hydroxy-bridged homolog 32 of the alkyne TH catalysts 27 and 28 was shown in an earlier communication by Djukic and Pfeffer to catalyze the related Op- penauer oxidation of indanol in acetone at 80 °C with a catalyst loading of 5 mol.% in the absence of a base (Scheme 24) [40]. In agreement with their work with the ruthenacycles 27 and 28 (see Schemes 19 and 20) [37], the authors suggested that the process could rely on the formation of a ruthenium-hydride species.

(OC)3Cr OH O 32 (5 mol%) CO OC Ru N acetone / 80 °C / 15 h O H N Cl 95% Ru TOF = 1.27 h−1 CO TON = 19 CO

(OC)3Cr 32

Scheme 24. Oxidation of indanol by base-free TH with acetone catalyzed by the μ-chlorido,μ-hydroxy-bridged ruthenacycle 32.

2.9. Alcohol Racemization and Dynamic Kinetic Resolution Dynamic kinetic resolution (DKR), in which rapid metal-catalyzed racemization of the undesired enantiomer is coupled with an enzymatic kinetic resolution, is an attractive methodology to obtain valuable enantiomerically pure amines and alcohols in 100% yield [41–43]. To this end, a small number of the ruthenacycles initially developed for ketone TH (or closely related analogues) have been studied in alcohol racemization. The exceptionally active ketone TH catalyst 6 (2 mol.%), initially reported by Baratta et al. (see Scheme 3) [14], was shown by Arends and collaborators to achieve the full racemization of (S)-1-phenylethanol in 30 min in toluene at 70 °C in the presence of KOtBu (4 mol.%) as activator (Scheme 25) [44]. However, under DKR conditions, i.e., when the lipase CAL B or the acyl donor i-PrOAc was present, the active species resulting from 6 was greatly deactivated, and enantiomeric excesses of 31% and 47% were attained after 30 min reaction (Scheme 25).

A. 6 (2 mol%) / KOtBu (4 mol%) OH or OH B. 6 (1 mol%) / KOtBu (1 equiv.) / additives toluene / 70 °C / 0.5 h

Conditions A: 1.0 M, eeinitial = 100% Conditions B: 0.2 M, eeinitial = 50% No additive: 0% ee; TOF = 50 h−1 i-PrOAc (8 equiv.): 47% ee; TOF = 3 h−1 −1 CAL B (20 mg) / K2CO3 (1 equiv.): 31% ee; TOF = 19 h

Scheme 25. Racemization of (S)-1-phenylethanol catalyzed by the CC-ruthenacycle 6 under various conditions.

Molecules 2021, 26, x FOR PEER REVIEW 20 of 50 Molecules 2021, 26, x FOR PEER REVIEW 20 of 50

Molecules 2021, 26, 4076 Scheme 23. Oxidation of 4-fluoro-α-methylbenzyl alcohol by base-free TH with acetone catalyzed18 of 45 Scheme 23. Oxidation of 4-fluoro-α-methylbenzyl alcohol by base-free TH with acetone catalyzed by the hydrido-ruthenacycle 29. by the hydrido-ruthenacycle 29. The μ-chlorido,μ-hydroxy-bridged homolog 32 of the alkyne TH catalysts 27 and 28 TheThe µμ-chlorido,μµ-hydroxy-bridged homolog homolog 3232 ofof the the alkyne alkyne TH TH catalysts catalysts 2727 andand 28 was shown in an earlier communication by Djukic and Pfeffer to catalyze the related Op- 28waswas shown shown in an in anearlier earlier communication communication by Djuk by Djukicic and and Pfeffer Pfeffer to catalyze to catalyze the related the related Op- penauer oxidation of indanol in acetone at 80 °C with a catalyst loading of 5 mol.% in the Oppenauerpenauer oxidation oxidation of indanol of indanol in acetone in acetone at 80 at °C 80 ◦withC with a catalyst a catalyst loading loading of 5 of mol.% 5 mol.% in the in absence of a base (Scheme 24) [40]. In agreement with their work with the ruthenacycles theabsence absence of a of base a base (Scheme (Scheme 24) 24 [40].)[40 ].In In agreem agreementent with with their their work work with with the ruthenacycles 27 and 28 (see Schemes 19 and 20) [37], the authors suggested that the process could rely 2727 andand 2828 (see(see SchemesSchemes 1919 andand 2020))[ [37],37], thethe authorsauthors suggestedsuggested thatthat thethe processprocess couldcould relyrely on the formation of a ruthenium-hydride species. onon thethe formationformation ofof aa ruthenium-hydrideruthenium-hydride species.species.

(OC)3Cr (OC)3Cr OH O CO OH 32 (5 mol%) O 32 (5 mol%) OC Ru CON OC Ru N acetone / 80 °C / 15 h O acetone / 80 °C / 15 h O H N H Cl 95% N Cl 95% Ru TOF = 1.27 h−1 Ru CO TOF = 1.27 h−1 TON = 19 CO CO TON = 19 CO (OC)3Cr 32 (OC)3Cr 32

Scheme 24. Oxidation of indanol by base-free TH with acetone catalyzed by the μ-chlorido,μ-hy- SchemeScheme 24.24. OxidationOxidation of of indanol indanol by by base-free base-free TH TH with with acetone acetone catalyzed catalyzed by bythe theμ-chlorido,µ-chlorido,μ-hy-µ- droxy-bridged ruthenacycle 32. hydroxy-bridgeddroxy-bridged ruthenacycle ruthenacycle 3232. . 2.9. Alcohol Racemization and Dynamic Kinetic Resolution 2.9.2.9. Alcohol Racemization andand DynamicDynamic KineticKinetic ResolutionResolution Dynamic kinetic resolution (DKR), in which rapid metal-catalyzed racemization of DynamicDynamic kinetickinetic resolutionresolution (DKR),(DKR), inin whichwhich rapidrapid metal-catalyzedmetal-catalyzed racemizationracemization ofof the undesired enantiomer is coupled with an enzymatic kinetic resolution, is an attractive thethe undesired enantiomer enantiomer is is coupled coupled with with an an en enzymaticzymatic kinetic kinetic resolution, resolution, is an is anattractive attrac- methodologytive methodology to obtain to obtain valuable Valuable enantiomerically enantiomerically pure amines pure amines and alcohols and alcohols in 100% in 100%yield methodology to obtain valuable enantiomerically pure amines and alcohols in 100% yield [41–43].yield [41 To–43 this]. To end, this a end,small a number small number of the ruthenacycles of the ruthenacycles initially initially developed developed for ketone for [41–43]. To this end, a small number of the ruthenacycles initially developed for ketone THketone (or closely TH (or related closely relatedanalogues) analogues) have been have studied been studied in alcohol in alcoholracemization. racemization. TH (or closely related analogues) have been studied in alcohol racemization. TheThe exceptionally exceptionally active active ketone ketone TH THcatalyst catalyst 6 (2 mol.%),6 (2 mol.%), initially initially reported reported by Baratta by The exceptionally active ketone TH catalyst 6 (2 mol.%), initially reported by Baratta etBaratta al. (see et Scheme al. (see 3) Scheme [14], was3)[ shown14], was by shownArends byand Arends collaborators and collaborators to achieve the to full achieve rac- et al. (see Scheme 3) [14], was shown by Arends and collaborators to achieve the full rac- emizationthe full racemization of (S)-1-phenylethanol of (S)-1-phenylethanol in 30 min inin 30toluen mine in at toluene 70 °C in at 70the◦ Cpresence in the presence of KOtBu of emization of (S)-1-phenylethanol in 30 min in toluene at 70 °C in the presence of KOtBu (4KO mol.%)tBu (4 mol.%)as activator as activator (Scheme (Scheme 25) [44]. 25 )[Ho44wever,]. however, under under DKR DKRconditions, conditions, i.e., when i.e., when the (4 mol.%) as activator (Scheme 25) [44]. However, under DKR conditions, i.e., when the lipasethe lipase CAL CAL B or B the or theacyl acyl donor donor i-PrOAci-PrOAc was was present, present, the the active active species species resulting resulting from from 6 lipase CAL B or the acyl donor i-PrOAc was present, the active species resulting from 6 was greatly deactivated, and enantiomeric excesses excesses of of 31% and 47% were attained after was greatly deactivated, and enantiomeric excesses of 31% and 47% were attained after 3030 min min reaction (Scheme 25).25). 30 min reaction (Scheme 25). A. 6 (2 mol%) / KOtBu (4 mol%) OH A. 6 (2 mol%) or/ KOtBu (4 mol%) OH OH OH B. 6 (1 mol%) / KOtBuor (1 equiv.) / additives B. 6 (1 mol%) / KOtBu (1 equiv.) / additives toluene / 70 °C / 0.5 h toluene / 70 °C / 0.5 h Conditions A: 1.0 M, eeinitial = 100% Conditions A: 1.0 M, eeinitial = 100% Conditions B: 0.2 M, eeinitial = 50% Conditions B: 0.2 M, eeinitial = 50% No additive: 0% ee; TOF = 50 h−1 No additive: 0% ee; TOF = 50 h−1 i-PrOAc (8 equiv.): 47% ee; TOF = 3 h−1 i-PrOAc (8 equiv.): 47% ee; TOF = 3 h−1 CAL B (20 mg) / K CO (1 equiv.): 31% ee; TOF = 19 h−1 2 3 −1 CAL B (20 mg) / K2CO3 (1 equiv.): 31% ee; TOF = 19 h

SchemeScheme 25. 25. RacemizationRacemization of ( ofS)-1-phenylethanol (S)-1-phenylethanol catalyzed catalyzed by the by CC the-ruthenacycleCC-ruthenacycle 6 under6 vari-under Scheme 25. Racemization of (S)-1-phenylethanol catalyzed by the CC-ruthenacycle 6 under vari- ousVarious conditions. conditions. ous conditions. In the same report, Arends et al. described the synthesis of the achiral analogue 33 of the azaruthenacycle 22a (see Scheme 12)[26] and its use for the racemization of (S)-1- phenylethanol [44]. The cycloruthenated benzylamine complex 33 (5 mol.%) displayed a

reasonable activity compared to 6, achieving full racemization of (S)-1-phenylethanol in 18 h at 70 ◦C in the presence of 5 mol.% KOtBu (Scheme 26A). Furthermore, 33 proved stable under DKR conditions, and rac-1-phenylethanol was converted at 96% in 86% enantiopure (R)-1-phenylethyl acetate after 48 h reaction by using a catalytic combo of 33 and CAL B, with the only byproduct being acetophenone (Scheme 26B). Molecules 2021,, 26,, xx FORFOR PEERPEER REVIEWREVIEW 21 of 50

InIn thethe samesame report,report, ArendsArends etet al.al. descridescribed the synthesis of the achiral analogue 33 ofof thethe azaruthenacycleazaruthenacycle 22a (see(see SchemeScheme 12)12) [26][26] andand itsits useuse forfor thethe racemizationracemization ofof ((S)-1-phe-)-1-phenylethanol [44]. The cycloruthenated benzylamine complex 33 (5(5 mol.%)mol.%) displayeddisplayed aa rea-reasonable activity compared to 6,, achievingachieving fullfull racemizationracemization ofof ((S)-1-phenylethanol)-1-phenylethanol inin 1818 hh at 70 °C in the presence of 5 mol.% KOttBu (Scheme 26A). Furthermore, 33 provedproved stablestable

Molecules 2021, 26, 4076 under DKR conditions, and rac-1-phenylethanol-1-phenylethanol waswas convertedconverted atat 96%96% inin 86%86% enantiopureenantiopure19 of 45 ((R)-1-phenylethyl)-1-phenylethyl acetateacetate afterafter 4848 hh reactionreaction byby usingusing aa catalyticcatalytic combocombo ofof 33 andand CALCAL B,B, with the only byproduct being acetophenone (Scheme 26B).

A. − OH 33 (5(5 mol%)mol%) OH PF66 KOtBu (5 mol%) + Ru NCMe toluenetoluene // 7070 °C°C // 1818 hh NH22 1 M 0% ee 33 TON = 10 TOF = 0.56 h−1

B. OH 33 (5(5 mol%)mol%) // KOKOtBu (5 mol%) OAc OAc CAL B (20 mg) / K CO (1(1 equiv.)equiv.) OH + 22 33 + toluenetoluene // 7070 °C°C // 4848 hh P == 280280 mbarmbar (2(2 equiv.)equiv.) 86% > 99% ee SchemeScheme 26.26. Racemization ofof (S)-1-phenylethanol)-1-phenylethanol catalyzedcatalyzedcatalyzed bybyby thethethe CNCN-ruthenacycle-ruthenacycle-ruthenacycle 33 33 ( ((AA))) andandand DKRDKRDKR ofof 1-phenylethanol1-phenylethanol catalyzedcatalyzed byby 3333 andandand CALCALCAL BBB (((BB).).).

TheThe closely related related derivative derivative 3434 (4(4(4 mol.%)mol.%) mol.%) waswas was similarlysimilarly similarly shownshown shown bybyby PfefferPfeffer Pfeffer andand and dede deVries Vries to catalyze to catalyze the theracemization racemization of ( ofS)-1-phenylethanol)-1-phenylethanol (S)-1-phenylethanol inin thethe in thepresencepresence presence ofof KOKO oftt KOBu t(5.2Bu (5.2mol.%) mol.%) [31,45]. [31, 45Interestingly,]. Interestingly, the thereaction reaction could could be carried be carried out outin various in Various solvents solvents at RT at RTincludingincluding including waterwater water (Scheme(Scheme (Scheme 27).27). TheThe27). CN The-ruthenacycle-ruthenacycleCN-ruthenacycle 34 proved,proved,34 proved, however,however, however, inefficientinefficient inefﬁcient forfor thethe forracemization the racemization of (R)-2-chloro-1-phenylethanol,)-2-chloro-1-phenylethanol, of (R)-2-chloro-1-phenylethanol, whichwhich prprevented which prevented its use for itsthe use chemo-en- for the chemo-enzymaticzymatic DKR of β-haloalcohols DKR-haloalcohols of β-haloalcohols toto affordafford enantiopureenantiopure to afford enantiopure epepoxides epoxideswith the help with of the a helphaloal- of acohol haloalcohol dehalogenase dehalogenase [46]. [46].

− OH 34 (4(4 mol%)mol%) OH PF66 X KOtBu (5.2 mol%) X + Ru NCMe solvent / T NHMe 34

X = H; 0.1 M; toluene / 7 h: 8% ee;; TONTON == 11.5;11.5; TOFTOF == 1.641.64 hh−1 1.01.0 M;M; i-PrOH-PrOH // 11 h:h: 2%2% ee;; TONTON == 12.3;12.3; TOFTOF == 12.312.3 hh−1 −1 0.50.5 M;M; HH22O / 46 h: 8% ee;; TONTON == 11.5;11.5; TOFTOF == 0.250.25 hh −1 X = Cl; 1.0 M; i-PrOH-PrOH // 55 h:h: 84%84% ee;; TONTON == 2.0;2.0; TOFTOF == 0.40.4 hh SchemeScheme 27. RacemizationRacemization of of (S)-1-phenylethanol)-1-phenylethanol (S)-1-phenylethanol catalyzedcatalyzed catalyzed byby the bythe theCN-ruthenacycle-ruthenacycleCN-ruthenacycle 34 underunder34 under vari-vari- Variousous conditions. conditions.

AA control control experiment experiment demonstrated demonstrated that that the the deactivation deactivation of 34 of inin34 thethein racemizationracemization the racemiza- ofof tion((R)-2-chloro-1-phenylethanol)-2-chloro-1-phenylethanol of (R)-2-chloro-1-phenylethanol waswas duedue was toto thethe due formationformation to the formation ofof smallsmall amountsamounts of small ofof amounts 2-chloroace-2-chloroace- of 2- chloroacetophenone,tophenone,tophenone, whichwhich reactreact which almostalmost react instantaneouslyinstantaneously almost instantaneously withwith thethe rutheniumruthenium with the hydridehydride ruthenium activeactive hydride speciesspecies Molecules 2021, 26, x FOR PEER REVIEW 22 of 50 active35—generated species 35by—generated action of KO byttBu action on 34 of (Scheme(Scheme KOtBu 28)—to28)—to on 34 (Scheme yieldyield aa novelnovel28)—to cycloruthenatedcycloruthenated yield a novel cycloruthenatedspecies, whose exact species, nature whose could exact not nature be determined could not [45]. be determined [45].

Scheme 28. Formation of the racemization active species 3535..

3. Iridacycles as Transfer HydrogenationHydrogenation CatalystsCatalysts A mini-review about the use of iridacycle Cp*-complexes as catalysts for the produc- tiontion of ﬁnefine chemicalschemicals waswas publishedpublished inin 20182018 [[47].47]. Wang andand XiaoXiao publishedpublished anan accountaccount ofof theirtheir ownown workwork on on the the use use of of iridacycles iridacycles for fo (transfer)r (transfer) hydrogenation hydrogenation and and dehydrogenation dehydrogena- reactionstion reactions [48]. [48].

3.1. Transfer Hydrogenation of Ketones Ikariya and coworkers synthesized iridacycles 36, 39, and 40 via reaction between [Cp*IrCl2]2 and the appropriate benzylamines in CH2Cl2 at room temperature in the presence of NaOAc. Treatment of these complexes with KOtBu led to formation of the 16 electron amide complexes, such as 37. Reaction of these with isopropanol resulted in the hydride complexes such as 38. These complexes were tested in the TH of acetophenone (Scheme 29, percentages indicate yield of 1-phenylethanol) [49]. Reactions using the chloride complexes were performed in the presence of 1.5 equiv. of KOtBu. For comparison, the same reaction was performed using the classical Noyori–Ikariya iridium TH catalyst 41 in the presence of KOtBu. It turned out that the reactions using the iridacycles were much faster than the one catalyzed by 41, although the enantioselectivity of the product 1-phenylethanol was substantially lower upon use of the chiral analogues 39 and 40.

Scheme 29. Performance of iridacycles 36–41 as catalysts in the TH of acetophenone.

In a similar vein, Kuwata, Ikariya, and coworkers prepared iridacycles 42 by reacting acetophenone oximes with [Cp*IrCl2]2 and NaOAc in CH2Cl2 at room temperature. Treat- ment with base in CH2Cl2 led to the dimeric complexes 43 (Scheme 30). Upon treatment with base in isopropanol, these dimers formed the monohydride complexes 44 that were moderately active as TH catalyst [50]. The authors assumed that the dimer 44a can disso- ciate in a monohydride 45 and complex 46. Complex 46 can be reduced by isopropanol into 45. These catalysts were used for the TH of a small set of substituted acetophenones.

Molecules 2021, 26, x FOR PEER REVIEW 22 of 50

Scheme 28. Formation of the racemization active species 35.

3. Iridacycles as Transfer Hydrogenation Catalysts A mini-review about the use of iridacycle Cp*-complexes as catalysts for the production of fine chemicals was published in 2018 [47]. Wang and Xiao published an account of Molecules 2021, 26, 4076 20 of 45 their own work on the use of iridacycles for (transfer) hydrogenation and dehydrogenation reactions [48].

3.1.3.1. TransferTransfer HydrogenationHydrogenation ofof KetonesKetones IkariyaIkariya andand coworkerscoworkers synthesizedsynthesized iridacyclesiridacycles 3636,, 39,39, andand 4040Via via reactionreaction betweenbetween [Cp*IrCl[Cp*IrCl22]2 andand the the appropriate appropriate benzylamines benzylamines in inCH CH2Cl22Cl at 2roomat room temperature temperature in the in pres- the presenceence of NaOAc. of NaOAc. Treatment Treatment of these of thesecomplexes complexes with KO withtBu KO ledtBu to formation led to formation of the 16 of elec- the 16tron electron amide amidecomplexes, complexes, such as such 37. Reaction as 37. Reaction of these of with these isopropanol with isopropanol resulted resulted in the hy- in thedride hydride complexes complexes such suchas 38 as. These38. These complexes complexes were were tested tested in in the the TH TH of of acetophenoneacetophenone (Scheme(Scheme 29,29, percentages percentages indicate indicate yield yield of of1-ph 1-phenylethanol)enylethanol) [49]. [49 Reac]. Reactionstions using using the chlo- the chlorideride complexes complexes were were performed performed in inthe the presence presence of of 1.5 1.5 equiv. equiv. of of KO KOttBu.Bu. For comparison, thethe samesame reactionreaction waswas performedperformed usingusing thethe classicalclassical Noyori–IkariyaNoyori–Ikariya iridiumiridium THTH catalystcatalyst 4141 inin thethe presencepresence ofof KOKOttBu.Bu. ItIt turnedturned outout thatthat thethe reactionsreactions usingusing thethe iridacyclesiridacycles werewere muchmuch fasterfaster thanthan thethe oneone catalyzedcatalyzed byby 4141,, althoughalthough thethe enantioselectivityenantioselectivity ofof thethe productproduct 1-phenylethanol1-phenylethanol waswas substantiallysubstantially lowerlower uponupon useuse ofof thethe chiralchiral analoguesanalogues39 39and and40 40..

SchemeScheme 29.29. PerformancePerformance ofof iridacyclesiridacycles 3636––4141 asas catalystscatalysts inin thethe THTH ofof acetophenone.acetophenone.

InIn aa similarsimilar Vein,vein, Kuwata,Kuwata, Ikariya,Ikariya, andand coworkerscoworkers preparedprepared iridacyclesiridacycles42 42by by reactingreacting acetophenoneacetophenone oximesoximes withwith [Cp*IrCl[Cp*IrCl22]]22 and NaOAc inin CHCH22Cl2 atat room room temperature. Treat- ment with base in CH Cl led to the dimeric complexes 43 (Scheme 30). Upon treatment ment with base in CH22Cl22 led to the dimeric complexes 43 (Scheme 30). Upon treatment withwith basebase inin isopropanol,isopropanol, thesethese dimersdimers formedformed thethe monohydridemonohydride complexescomplexes 4444 thatthat werewere moderatelymoderately activeactive asas THTH catalyst catalyst [ 50[50].]. The The authors authors assumed assumed that that the the dimer dimer44a 44acan can dissoci- disso- ateciate in in a monohydridea monohydride45 45and and complex complex46. 46 complex. Complex46 can 46 becan reduced be reduced by isopropanol by isopropanol into 45into. These 45. These catalysts catalysts were were used used for the for TH the of TH a small of a small set of set substituted of substituted acetophenones. acetophenones. however, for decent conversions, 5 mol.% of catalyst was needed at a temperature of 50 ◦C and a duration of 15 h. These results are in stark contrast to the results obtained with the amine-based iridacycles of Scheme 29, which were orders of magnitude faster. Xue, Xiao, and coworkers examined the use of iridacycles 47a–e ligated by acetophenone- N-aryl-imines as TH catalyst for aldehydes and ketones in water, using formate salts as reductant [51]. The authors found a strong dependence of the rate of the reaction on the pH of the aqueous solution (Scheme 31). The optimum pH was in the acidic region. This was explained by the authors to be necessary for the activation of the ketone as this type of catalyst does not have an NH available that can form a hydrogen bond with the ketone oxygen atom. Molecules 2021, 26, x FOR PEER REVIEW 23 of 50

However, for decent conversions, 5 mol.% of catalyst was needed at a temperature of 50 °C and a duration of 15 h. These results are in stark contrast to the results obtained with the amine-based iridacycles of Scheme 29, which were orders of magnitude faster.

KOtBu KOtBu (1.2 eq.) R Ir (1.1 eq.) O Molecules 2021, 26, x FOR PEER REVIEWR Ir CH2Cl2, rt Ir O Ir H N 23 of 50 Cl N H iPrOH, rt N Ph NH.HCl (2 eq.) R N R O Ir N 2 O R OH CH2Cl2, −78 °C to rt However,42a R = H for decent conversions, 5 mol.%43 of catalyst was needed at 44a temperature of 50 Molecules 2021, 26, 4076 42b R = Me 21 of 45 °C and a duration of 15 h. TheseO resultsOH are in stark contrast to the results obtained with the amine-based iridacycles of Scheme 29, which were orders of magnitude faster. Ar Ar

KOtBu KOtBu (1.2 eq.) R Ir (1.1 eq.) O R Ir CH2Cl2, rt Ir O Ir H N Cl N H Ir Ir iPrOH, rt N Ph NH.HCl (2 eq.)H +R N R O Ir 44a N 2 O R OH CH Cl −78 °C to rt 2 2, N N OH O− 42a R = H 4543 46 44 42b R = Me O OH

Ar O Ar OH

Scheme 30. Oxime-based iridacycles as catalysts for the TH of acetophenones.

Ir Ir H 44aXue, Xiao, and coworkers examined+ the use of iridacycles 47a–e ligated by acetophe- N N none-N-aryl-imines as TH catalystOH for aldehydes andO− ketones in water, using formate salts as reductant [51]. The authors45 found a strong de 46pendence of the rate of the reaction on the pH of the aqueous solution (Scheme 31). The optimum pH was in the acidic region. This

was explained by the authors to beO necessaryOH for the activation of the ketone as this type of catalyst does not have an NH available that can form a hydrogen bond with the ketone

oxygen atom. SchemeScheme 30.30. Oxime-based iridacycles as catalysts catalysts for for the the TH TH of of acetophenones. acetophenones.

Xue, Xiao, and coworkers examined the use of iridacycles 47a–e ligated by acetophenone-N-aryl-imines as TH catalyst for aldehydes and ketones in water, using formate salts as reductant [51]. The authors found a strong dependence of the rate of the reaction on the pH of the aqueous solution (Scheme 31). The optimum pH was in the acidic region. This was explained by the authors to be necessary for the activation of the ketone as this type of catalyst does not have an NH available that can form a hydrogen bond with the ketone Molecules 2021, 26, x FOR PEER REVIEW 24 of 50 oxygen atom.

Scheme 31. pH dependency of TH with imine-based iridacycles 47a and 47b (graphs reproduced Scheme 31. pH dependency of TH with imine-based iridacycles 47a and 47b (graphs reproduced fromfrom [51] [51 with] with permission permission from from the the Royal Royal Society Society of ofChemistry). Chemistry). All catalysts were screened in the TH of acetophenone. highest yields of 1-phenylethanol All catalysts were screened in the TH of acetophenone. Highest yields of 1-phenyleth- were obtained with the cyanide containing catalysts. Thus, catalyst 47c was used for the anol were obtained with the cyanide containing catalysts. Thus, catalyst 47c was used for reduction of a range of substituted acetophenones and aliphatic ketones, such as cyclohex- the reduction of a range of substituted acetophenones and aliphatic ketones, such as cy- anone and 2-octanone, as well as a range of substituted benzaldehydes, to alcohols with yields clohexanone and 2-octanone, as well as a range of substituted benzaldehydes, to alcohols ranging from 91–100%. These reactions were performed at an S/C ratio of 2000 at pH 2.5 and with yields ranging from 91–100%. These reactions were performed at an S/C ratio of 2000 80 ◦C and took either 4 or 12 h. at pH 2.5 and 80 °C and took either 4 or 12 h. The Xiao group synthesized another six iridacycles 48–53 and applied these in the The Xiao group synthesized another six iridacycles 48–53 and applied these in the TH of α-substituted ketones using formate salts as reductant in water [52]. Initially, the TH of α-substituted ketones using formate salts as reductant in water [52]. Initially, the six catalysts were compared in the TH of 1-phenoxyacetone, by measuring the yield of the sixproduct catalysts alcohol were compared after 0.5 h in at the 0.1 TH mol.% of 1-ph of catalystenoxyacetone, and 80 ◦ byC (Schememeasuring 32). the Catalyst yield of53 thewas productso active alcohol that itafter was 0.5 also h at tested 0.1 mol.% at lower of catalyst catalyst/substrate and 80 °C (Scheme ratios; at 32). S/C Catalyst = 10,000, 53 was it was so active that it was also tested at lower catalyst/substrate ratios; at S/C = 10,000, it was still possible to reach 99% conversion after 2 h. This catalyst (53) was then used for the TH of a range of aryloxyacetophenones, perfluoroalkoxy-acetophenones, aryloxyacetones, and aliphatic 2-alkoxy-ketones using the conditions of Scheme 32, but at 0.01 mol.% of catalyst for 14 h. Excellent isolated yields were reported for all product alcohols (86–97%). Catalyst 51 (0.1 mol.%) was next used for the reduction of a range of acetophenones, α- substituted with hydroxy, chloro, dichloro, fluoro, trifluoro, nitrile, ester, N-morpholino, and dimethoxy, at 80 °C over 18 h. The product alcohols were obtained in yields ranging from 86–96%. The same catalyst (0.1 mol.%) was also used for the reduction of α- and β- ketoesters (80 °C, 14 h) to the hydroxyesters in yields from 91–96%. Catalyst 51 (0.1 mol.%) was not selective for the reduction of α,β−unsaturated ketones; however, it was capable of reducing the carbonyl group selectively in the reduction of α,β-unsaturated aldehydes (80 °C, 6 h). A number of cinnamaldehyde and aliphatic α,β-unsaturated aldehydes were reduced selectively to the allylic alcohols with yields from 78–92%.

Molecules 2021, 26, 4076 22 of 45

still possible to reach 99% conversion after 2 h. This catalyst (53) was then used for the TH of a range of aryloxyacetophenones, perfluoroalkoxy-acetophenones, aryloxyacetones, and aliphatic 2-alkoxy-ketones using the conditions of Scheme 32, but at 0.01 mol.% of catalyst for 14 h. Excellent isolated yields were reported for all product alcohols (86–97%). Catalyst 51 (0.1 mol.%) was next used for the reduction of a range of acetophenones, α- substituted with hydroxy, chloro, dichloro, fluoro, trifluoro, nitrile, ester, N-morpholino, and dimethoxy, at 80 ◦C over 18 h. The product alcohols were obtained in yields ranging from 86–96%. The same catalyst (0.1 mol.%) was also used for the reduction of α- and β- ketoesters (80 ◦C, 14 h) to the hydroxyesters in yields from 91–96%. Catalyst 51 (0.1 mol.%) was not selective for the reduction of α,β-unsaturated ketones; however, it was capable of reducing the carbonyl group selectively in the reduction of α,β-unsaturated aldehydes Molecules 2021, 26, x FOR PEER REVIEW ◦ 25 of 50 (80 C, 6 h). A number of cinnamaldehyde and aliphatic α,β-unsaturated aldehydes were reduced selectively to the allylic alcohols with yields from 78–92%.

OH O O O 48-54 (0.1 mol%)

HCO2H/HCO2Na H2O, pH 4.5, 80 °C, 0.5h

O O N O 2 Ir Cl Ir Cl Ir Cl N OMe N OMe N OMe

48 (88%) 49 (96%) 50 (59%)

Ir Cl Ir Cl Ir Cl N OMe N OMe N OMe

51 (98%) 52 (75%) 53 (>99%) Scheme 32.32. Comparison of iridacycle catalysts 48–53 inin thethe transfertransfer hydrogenationhydrogenation ofof 1-phenoxyacetone1-phenoxyacetone (yields(yields ofof thethe alcohol inin brackets).brackets).

Albrecht and coworkers coworkers tried tried to to increase increase the the electron electron donicity donicity of of the the amine amine ligand ligand in thein the iridacycles iridacycles by byintroducing introducing an anN-methyl-1,4-dihydropyridyleneN-methyl-1,4-dihydropyridylene substituent substituent on onthe theni- trogennitrogen atom atom (Scheme (Scheme 33) 33 [53].)[53 However,]. however, in doin in doingg so, so,the theproton proton on the on nitrogen the nitrogen atom atom that playsthat plays an important an important role role in the in the outer outer sphere sphere mechanism mechanism is is sacrificed. sacriﬁced. As As a a result, these catalysts are are much much slower slower than than for for instance instance iridacycles iridacycles 36–3640– 40thatthat are arehighly highly active active at am- at bientambient temperature. temperature. The Thecatalysts catalysts were were tested tested at 1 mol.% at 1 mol.% in the in TH the of TH benzophenone of benzophenone using ◦ isopropanolusing isopropanol as reductant as reductant and solvent and solvent at 82 °C, at and 82 C,the and conversion the conversion was measured was measured after 2, 4,after and 2, 24 4, h and (Table 24 h 1). (Table Since1). catalyst Since catalyst54d was54d clearlywas the clearly fastest, the this fastest, catalyst this was catalyst used was for theused reduction for the reduction of a small of set a small of ketones set of ketonescomprising comprising cyclohexanone, cyclohexanone, aryl-substituted aryl-substituted acetophenones,acetophenones, and 2-, and 3-, 2-,and 3-, 4-acetylpryridine. and 4-acetylpryridine. All substrates All substrates could be could fully be reduced fully reduced within within1–4 h at 1–4 1 mol.% h at 1 of mol.% catalyst of catalyst and reflux and of reﬂux isopropanol. of isopropanol.

Scheme 33. Synthesis of N-methyl-1,4-dihydropyridylene substituted iridacycles 54a–e and 55a,b.

Molecules 2021, 26, x FOR PEER REVIEW 25 of 50

OH O O O 48-54 (0.1 mol%)

HCO2H/HCO2Na H2O, pH 4.5, 80 °C, 0.5h

O O N O 2 Ir Cl Ir Cl Ir Cl N OMe N OMe N OMe

48 (88%) 49 (96%) 50 (59%)

Ir Cl Ir Cl Ir Cl N OMe N OMe N OMe

51 (98%) 52 (75%) 53 (>99%) Scheme 32. Comparison of iridacycle catalysts 48–53 in the transfer hydrogenation of 1-phenoxyacetone (yields of the alcohol in brackets).

Albrecht and coworkers tried to increase the electron donicity of the amine ligand in the iridacycles by introducing an N-methyl-1,4-dihydropyridylene substituent on the nitrogen atom (Scheme 33) [53]. However, in doing so, the proton on the nitrogen atom that plays an important role in the outer sphere mechanism is sacrificed. As a result, these catalysts are much slower than for instance iridacycles 36–40 that are highly active at ambient temperature. The catalysts were tested at 1 mol.% in the TH of benzophenone using isopropanol as reductant and solvent at 82 °C, and the conversion was measured after 2, 4, and 24 h (Table 1). Since catalyst 54d was clearly the fastest, this catalyst was used for

Molecules 2021, 26, 4076 the reduction of a small set of ketones comprising cyclohexanone, aryl-substituted23 aceto- of 45 phenones, and 2-, 3-, and 4-acetylpryridine. All substrates could be fully reduced within 1–4 h at 1 mol.% of catalyst and reflux of isopropanol.

Molecules 2021, 26, x FOR PEER REVIEW 26 of 50

SchemeScheme 33.33. Synthesis ofof NN-methyl-1,4-dihydropyridylene-methyl-1,4-dihydropyridylene substitutedsubstituted iridacyclesiridacycles 54a54a––ee andand 55a55a,,bb..

Table 1.1. Rate comparison ofof iridacyclesiridacycles 54a54a––ee andand 55a,b55a,b inin thethe THTH ofof benzophenone.benzophenone.

EntryEntry Catalyst Catalyst Yield Yield 2 h 2 h Yield Yield 4 h 4 h Yield Yield 24 24 h h 1 1 54a 54a 7 727 2799 99 2 2 55a 55a 4 428 2899 99 3 3 55b 55b 2 213 1399 99 4 54b 77 99 n.d. 4 5 54b 54c 77 3099 96n.d. 99 5 6 54c 54d 30 9396 9999 n.d. 6 7 54d 54e 93 299 4n.d. 30 7 54e 2 4 30 Choudhoury and coworkers synthesized a series of iridacycles based on 1-aryl- or 1-benzyl-substitutedChoudhoury andN -heterocycliccoworkers synthesized carbenes (NHCs) a series (Schemeof iridacycles 34)[54 based]. Next, on they1-aryl- investi- or 1- benzyl-substitutedgated the yield of the N TH-heterocyclic of acetophenone carbenes as a(NHCs) function (Sch of theeme steric 34) [54]. properties Next, they of the investi- ligand gatedexpressed the yield in bite-angles, of the TH as of well acetophenone as yaw-angles as a (the function deviation of the from steric the properties ideal 180◦ ofangle the ligandbetween expressed the Ir-C bond in bite-angles, to the NHC as and well the as angle yaw-angles of the NHC (the itselfdeviation [55]). from The reactionsthe ideal were180° performedangle between in isopropanol the Ir-C bond containing to the NHC 20 mol.%and th ofe angle KOH of at the 100 NHC◦C for itself 90 min.[55]). Although, The reac- tionsin general, were performed it is much betterin isopropanol to investigate containing these correlations20 mol.% of basedKOH at on 100 rates, °C ratherfor 90 thanmin. yields,Although, it does in general, give a ﬁrstit is impressionmuch better about to investigate a possible these relationship. correlations It turnedbased on out rates, that ratherreductions than withyields, catalysts it does 56agive– ea werefirst impression rather slow, about leading a possible to yields relationship. of 1-phenylethanol It turned outof 30–50%, that reductions whereas with using catalysts catalysts 56a–57ae were–b and rather catalysts slow, leading57d–e ledto yields to yields of 1-phenyleth- of 80–99%. anolResults of 30–50%, with catalyst whereas57c usingwere alsocatalysts poor 57a (45%),–b and due catalysts to the strongly 57d–e led electron-withdrawing to yields of 80–99%. Resultsnature ofwith the catalyst nitro group. 57c were They also also poor constructed (45%), due a hammettto the strongly plot by electron-withdrawing reducing a series of natureacetophenones of the nitro with group. different Theypara alsosubstituents. constructed This a Hammett resulted in plot a ρ Valueby reducing of 1.25, a signifying series of acetophenonesthe development with of different a negative para charge substituents. on the acetophenone This resulted in a the ρ value transition of 1.25, state. signify- The ingauthors the development assumed that, of in a thenegative TS, the charge hydride on the is transferred acetophenone in an in inner the transition sphere mechanism state. The authorsto the ketone, assumed leading that, in to the a partial TS, the negative hydride charge is transferred on oxygen. in an Ligandsinner sphere57 have mechanism a larger tobite-angle the ketone, and leading a smaller to yaw-anglea partial negative than ligands charge56 on. Thus,oxygen. the Ligands authors 57 concluded have a larger that bite-anglethe hydricity and of a the smaller iridium yaw-angle hydride increasesthan ligands with 56 increasing. Thus, the bite-angle authors concluded and/or decreasing that the yawhydricity angle. of the iridium hydride increases with increasing bite-angle and/or decreasing yaw angle.

R1 N I−/Br−

0.5 eq. [Ir(Cp*)Cl2]2 I 1 N 2 R 3 eq. Cs2CO3 R Ir N n 10 eq. NaOAc, 3 eq. KI N CH3CN, reflux, 10h n R2 56a n = 0, R1 = Me, R2 = H 57a n = 1, R1 = Me, R2 = H 1 2 1 2 56b n = 0, R = CH2Ph, R = H 57b n = 1, R = CH2Ph, R = H 1 2 1 2 56c n = 0, R = Me, R = NO2 57c n = 1, R = Me, R = NO2 56d n = 0, R1 = Me, R2 = OMe 57d n = 1, R1 = Me, R2 = OMe 1 2 1 2 56e n = 0, R = Me, R = Me 57e n = 1, R = Me, R = Me Scheme 34. N-aryl and N-benzyl N-heterocyclic carbene-based iridacycles 56a–e and 57a–e.

Kuwata and coworkers synthesized two new iridacycles 58 based on 5-alkyl-3-benzyl-pyrazoles (Scheme 35) [56]. Treatment of 58a with KOtBu in toluene resulted in the formation of a hydroxy-bridged dimer 59, whereas treatment with KOtBu in isopropanol led to formation of the hydride-bridged dimer 60 (Scheme 36). Interestingly, treatment of 58b with KOtBu in isopropanol led to a mixture of monomeric hydrides. This is reflected in the performance of 58a and 58b at 5 mol.% in the TH of acetophenone with isopropanol

Molecules 2021, 26, x FOR PEER REVIEW 26 of 50

Table 1. Rate comparison of iridacycles 54a–e and 55a,b in the TH of benzophenone.

Entry Catalyst Yield 2 h Yield 4 h Yield 24 h 1 54a 7 27 99 2 55a 4 28 99 3 55b 2 13 99 4 54b 77 99 n.d. 5 54c 30 96 99 6 54d 93 99 n.d. 7 54e 2 4 30

Choudhoury and coworkers synthesized a series of iridacycles based on 1-aryl- or 1- benzyl-substituted N-heterocyclic carbenes (NHCs) (Scheme 34) [54]. Next, they investigated the yield of the TH of acetophenone as a function of the steric properties of the ligand expressed in bite-angles, as well as yaw-angles (the deviation from the ideal 180° angle between the Ir-C bond to the NHC and the angle of the NHC itself [55]). The reactions were performed in isopropanol containing 20 mol.% of KOH at 100 °C for 90 min. Although, in general, it is much better to investigate these correlations based on rates, rather than yields, it does give a first impression about a possible relationship. It turned out that reductions with catalysts 56a–e were rather slow, leading to yields of 1-phenylethanol of 30–50%, whereas using catalysts 57a–b and catalysts 57d–e led to yields of 80–99%. Results with catalyst 57c were also poor (45%), due to the strongly electron-withdrawing nature of the nitro group. They also constructed a Hammett plot by reducing a series of acetophenones with different para substituents. This resulted in a ρ value of 1.25, signifying the development of a negative charge on the acetophenone in the transition state. The authors assumed that, in the TS, the hydride is transferred in an inner sphere mechanism to the ketone, leading to a partial negative charge on oxygen. Ligands 57 have a larger bite-angle and a smaller yaw-angle than ligands 56. Thus, the authors concluded that the Molecules 2021, 26, 4076 24 of 45 hydricity of the iridium hydride increases with increasing bite-angle and/or decreasing yaw angle.

R1 N I−/Br−

0.5 eq. [Ir(Cp*)Cl2]2 I 1 N 2 R 3 eq. Cs2CO3 R Ir N n 10 eq. NaOAc, 3 eq. KI N CH3CN, reflux, 10h n R2 56a n = 0, R1 = Me, R2 = H 57a n = 1, R1 = Me, R2 = H 1 2 1 2 56b n = 0, R = CH2Ph, R = H 57b n = 1, R = CH2Ph, R = H 1 2 1 2 56c n = 0, R = Me, R = NO2 57c n = 1, R = Me, R = NO2 56d n = 0, R1 = Me, R2 = OMe 57d n = 1, R1 = Me, R2 = OMe 1 2 1 2 56e n = 0, R = Me, R = Me 57e n = 1, R = Me, R = Me SchemeScheme 34.34. NN-aryl-aryl andand NN-benzyl-benzyl NN-heterocyclic-heterocyclic carbene-basedcarbene-based iridacyclesiridacycles 56a56a––ee andand 57a57a––ee..

KuwataKuwata andand coworkers coworkers synthesized synthesized two two new new iridacycles iridacycles58 58based based on on 5-alkyl-3-benzyl- 5-alkyl-3-ben- pyrazoleszyl-pyrazoles (Scheme (Scheme 35)[ 35)56 ].[56]. Treatment Treatment of of58a 58awith with KO KOtButBu in in toluene toluene resulted resulted inin thethe formationformation ofof aa hydroxy-bridgedhydroxy-bridged dimerdimer 5959,, whereaswhereas treatmenttreatment withwith KOKOttBuBu inin isopropanolisopropanol Molecules 2021, 26, x FOR PEER REVIEW 27 of 50 Molecules 2021, 26, x FOR PEER REVIEWledled toto formationformation of the the hydride-bridged hydride-bridged dimer dimer 6060 (Scheme(Scheme 36). 36). Interestingly, Interestingly, treatment treatment27 of 50of of58b58b withwith KO KOtButBu in isopropanol in isopropanol led ledto a tomixture a mixture of monomeric of monomeric hydrides. hydrides. This is This reflected is re- ﬂectedin the performance in the performance of 58a and of 58b58a atand 5 mol.%58b at in 5 the mol.% TH of in acetophenone the TH of acetophenone with isopropanol with ◦ isopropanol(1 equiv. KO(1tBu, equiv. 50 °C, KO t15Bu, h) 50 in C,which 15 h) 58bin which is clearly58b isthe clearly faster the catalyst. faster catalyst.The authors The au-at- (1 equiv. KOtBu, 50 °C, 15 h) in which 58b is clearly the faster catalyst. The authors at- thorstributed attributed this to the this hydride to the hydride bridged bridged dimer 60 dimer being60 notbeing or less not oractive, less active,which whichwouldwould neces- tributed this to the hydride bridged dimer 60 being not or less active, which would neces- necessitatesitate the dissociation the dissociation of the of dimer the dimer to obtain to obtain the active the active monomeric monomeric iridium iridium hydride. hydride. sitate the dissociation of the dimer to obtain the active monomeric iridium hydride.

[Ir(Cp*)(OAc)2]2 [Ir(Cp*)(OAc) ] 1. toluene 2 2 1. toluene + H 80-100 °C Cl H + H 80-10014–15h °C Ir Cl H N N N N N 14–15h Ir N N R 2. KCl N R R 2. KCl R CH2Cl2/H2O CH2Cl2/H2O 58a R = Me (29%) 58a R = Me (29%) 58b R = tBu (>99%) 58b R = tBu (>99%) SchemeScheme 35.35. 5-Alkyl-3-benzylpyrazole-based iridacycles iridacycles 58a58a,b,b andand their their performance performance in in the the transfer trans- Scheme 35. 5-Alkyl-3-benzylpyrazole-based iridacycles 58a,b and their performance in the transfer ferhydrogenation hydrogenation of acetopheno of acetophenonene at 5 atmol.% 5 mol.% (yield (yield of 1-phenylethanol of 1-phenylethanol after 15 after h at 15 50 h °C at in 50 isopro-◦C in hydrogenationpanol in brackets). of acetopheno ne at 5 mol.% (yield of 1-phenylethanol after 15 h at 50 °C in isopro- isopropanolpanol in brackets). in brackets).

Scheme 36. Formation of dimers 59 and 60 upon treatment of 58a with base. Scheme 36. Formation of dimers 59 and 60 upon treatment ofof 58a58a withwith base.base. Zhang, Li, and coworkers prepared “abnormal” N-heterocyclic carbene phosphine Zhang, Li,Li, andand coworkerscoworkers preparedprepared “abnormal”“abnormal” NN-heterocyclic-heterocyclic carbenecarbene phosphinephosphine bidentate iridium complexes 61a and b, in which the iridium is bound to C5 rather than bidentate iridium complexes 61a and b,, inin whichwhich thethe iridiumiridium isis boundbound toto C5C5 ratherrather thanthan C2 of the imidazolium compound (Scheme 37) [57]. These iridacyclic complexes were C2 ofof thethe imidazoliumimidazolium compoundcompound (Scheme(Scheme 3737))[ [57].57]. TheseThese iridacycliciridacyclic complexescomplexes werewere found to be highly active at 0.1 mol.% in the TH of acetophenone (5 mol.% KOH, refluxing foundfound toto bebe highly active atat 0.1 mol.% in thethe TH of acetophenone (5 mol.% KOH, reﬂuxingrefluxing isopropanol, 5 h). In addition, catalyst 61b was used for TH of a range of aromatic and isopropanol,isopropanol, 5 h).h). In addition, catalyst 61b was used for TH of aa rangerange ofof aromaticaromatic andand aliphatic ketones, leading to the formation of the alcohols in good yields. The catalyst was aliphatic ketones,ketones, leadingleading toto thethe formationformation ofof thethe alcoholsalcohols inin goodgood yields.yields. TheThe catalystcatalyst waswas also used for the reduction of α,β-unsaturated aldehydes and ketones (0.5 mol.% catalyst, also used for the reduction of α,,β-unsaturated aldehydes and ketones (0.5 mol.% catalyst, 5 mol.% KOH, refluxing isopropanol) to yield the fully saturated alcohols in good yields. 5 mol.% KOH, reﬂuxingrefluxing isopropanol)isopropanol) toto yieldyield thethe fullyfully saturatedsaturated alcoholsalcohols inin goodgood yields.yields. R Ph2 Ph Ph NR PF − 2 2 6 PhP 2 HPhP Cs CO PhP N PF − 0.5 eq [Ir(COD)Cl]2 Ir 2 2 3 2 6 Ir ClP H P Cs CO P 0.5 eq [Ir(COD)Cl]2 N Ir N MeCN2 3 Ir N N Cl Ir Ir N CH2Cl2, rt N Cl N MeCN N CH Cl rt N − N − N − 2 2, PF6 Cl PF6 PF6 RN PF − RN PF − RN PF − R 6 R 6 R 6 PPh2 61a R = Me PPh 2 61a61b RR == iMePr 61b R = iPr Scheme 37. “Abnormal” N-heterocyclic carbene phosphine bidentate iridium complexes 61a,b. Scheme 37. “Abnormal” N-heterocyclic carbene phosphine bidentate iridium complexes 61a,b. 3.2. Asymmetric Transfer Hydrogenation of Ketones 3.2. Asymmetric Transfer Hydrogenation of Ketones Ikariya and coworkers reported the first ATH of acetophenone using iridacycle cata- Ikariya and coworkers reported the first ATH of acetophenone using iridacycle catalysts 39 and 40 (Scheme 29), resulting in the production of 1-phenylethanol in 38% and lysts 39 and 40 (Scheme 29), resulting in the production of 1-phenylethanol in 38% and 66% ee, respectively [49] . 66% ee, respectively [49] . Pfeffer, de Vries, and coworkers expanded upon their earlier finding that chiral Pfeffer, de Vries, and coworkers expanded upon their earlier finding that chiral ruthenacycles are excellent ATH catalysts [26], and they also synthesized iridacycles and ruthenacycles are excellent ATH catalysts [26], and they also synthesized iridacycles and rhodacycles to be tested in the ATH of ketones. Cyclometalation of (R,R)-2,5-diphenyl- rhodacycles to be tested in the ATH of ketones. Cyclometalation of (R,R)-2,5-diphenylpyrrolidine resulted in a mixture of the desired iridacycle 62 and the dehydrogenated pyrrolidine resulted in a mixture of the desired iridacycle 62 and the dehydrogenated analogous imine iridacycle 63, which was inseparable [58]. It was possible to synthesize analogous imine iridacycle 63, which was inseparable [58]. It was possible to synthesize iridacycle 63 in pure form, and this compound turned out to be inactive as a TH catalyst. iridacycle 63 in pure form, and this compound turned out to be inactive as a TH catalyst. Consequently, the mixture of 62 and 63 was used for the ATH of a range of aromatic ke- Consequently, the mixture of 62 and 63 was used for the ATH of a range of aromatic ketones (Scheme 38) [32]. Very good enantioselectivities were obtained from 74–96%. tones (Scheme 38) [32]. Very good enantioselectivities were obtained from 74–96%.

Molecules 2021, 26, x FOR PEER REVIEW 27 of 50

(1 equiv. KOtBu, 50 °C, 15 h) in which 58b is clearly the faster catalyst. The authors attributed this to the hydride bridged dimer 60 being not or less active, which would neces- sitate the dissociation of the dimer to obtain the active monomeric iridium hydride.

[Ir(Cp*)(OAc) ] 2 2 1. toluene + H 80-100 °C Cl H 14–15h Ir N N N N R 2. KCl R CH2Cl2/H2O 58a R = Me (29%) 58b R = tBu (>99%) Scheme 35. 5-Alkyl-3-benzylpyrazole-based iridacycles 58a,b and their performance in the transfer hydrogenation of acetophenone at 5 mol.% (yield of 1-phenylethanol after 15 h at 50 °C in isopropanol in brackets).

Scheme 36. Formation of dimers 59 and 60 upon treatment of 58a with base.

Zhang, Li, and coworkers prepared “abnormal” N-heterocyclic carbene phosphine bidentate iridium complexes 61a and b, in which the iridium is bound to C5 rather than C2 of the imidazolium compound (Scheme 37) [57]. These iridacyclic complexes were found to be highly active at 0.1 mol.% in the TH of acetophenone (5 mol.% KOH, refluxing isopropanol, 5 h). In addition, catalyst 61b was used for TH of a range of aromatic and Molecules 2021, 26, 4076 aliphatic ketones, leading to the formation of the alcohols in good yields. The catalyst25 was of 45 also used for the reduction of α,β-unsaturated aldehydes and ketones (0.5 mol.% catalyst, 5 mol.% KOH, refluxing isopropanol) to yield the fully saturated alcohols in good yields. R Ph − 2 Ph2 Ph2 N PF6 P H Cs CO 0.5 eq [Ir(COD)Cl]2 Ir P 2 3 P Cl Ir Ir N N N MeCN N CH2Cl2, rt Cl N PF − N PF − N PF − R 6 R 6 R 6

PPh2 61a R = Me 61b R = iPr Scheme 37. “Abnormal” N-heterocyclic carbene phosphine bidentate iridium complexes 61a,b. Scheme 37. “Abnormal” N-heterocyclic carbene phosphine bidentate iridium complexes 61a,b. 3.2. Asymmetric Transfer Hydrogenation of Ketones 3.2. AsymmetricIkariya and Transfer coworkers Hydrogenation reported the of Ketones ﬁrst ATH of acetophenone using iridacycle catalysts Ikariya39 and 40and(Scheme coworkers 29), reported resulting the in thefirst production ATH of acetophenone of 1-phenylethanol using iridacycle in 38% and cata- 66% eelysts, respectively 39 and 40 [(Scheme49]. 29), resulting in the production of 1-phenylethanol in 38% and 66% eePfeffer,, respectively de Vries, [49] and . coworkers expanded upon their earlier ﬁnding that chiral ruthenacyclesPfeffer, de are Vries, excellent and ATHcoworkers catalysts expanded [26], and upon they their also synthesizedearlier finding iridacycles that chiral and rhodacyclesruthenacycles to are be excellent tested in ATH the ATH catalysts of ketones. [26], and Cyclometalation they also synthesized of (R, Riridacycles)-2,5-diphenyl- and pyrrolidinerhodacycles resultedto be tested in a in mixture the ATH of of the ketones. desired Cyclometalation iridacycle 62 and of the(R,R dehydrogenated)-2,5-diphenyl- analogouspyrrolidine imine resulted iridacycle in a mixture63, which of the was desired inseparable iridacycle [58]. 62 It wasand possiblethe dehydrogenated to synthesize iridacycleanalogous 63iminein pure iridacycle form, and63, which this compound was inseparable turned [58]. out toIt was be inactive possible as to a THsynthesize catalyst. Molecules 2021, 26, x FOR PEER REVIEWiridacycle 63 in pure form, and this compound turned out to be inactive as a TH catalyst.28 of 50 Consequently, the mixture of 62 and 63 was used for the ATH of a range of aromatic ketones (SchemeConsequently, 38)[32 the]. Very mixture good of enantioselectivities 62 and 63 was used were for the obtained ATH of from a range 74–96%. of aromatic ketones (Scheme 38) [32]. Very good enantioselectivities were obtained from 74–96%.

SchemeScheme 38. 38. 2,5-Diphenylpyrrolidine2,5-Diphenylpyrrolidine based iridacycles based iridacycles for the ATH for of the aromatic ATH ketones of aromatic (time, yield, ketones ee). (time, yield, ee). Later, Barloy, Pfeffer, and coworkers used the cyclometalation method developed by DaviesLater, [59] Barloy, on 2,5-diphenylpyrrolidine Pfeffer, and coworkers and used were the able cyclometalation to prepare 62 method in pure developed from in good by Daviesyield [60]. [59 ]This on 2,5-diphenylpyrrolidinemethodology was also used and for were the able preparation to prepare of62 a setin pureof three from iridacycles in good yield64a–c [ 60which]. This they methodology obtained via was cyclometalation also used for the of preparation4,5-disubstituted of a set imidazolines. of three iridacycles The iri- 64adacycles–c which were they tested obtained in the ATH Via cyclometalation of acetophenone of (1 4,5-disubstitutedmol.% of catalyst, imidazolines.5 mol.% of KO ThetBu, iridacyclesrefluxing isopropanol). were tested Enantioselectivities in the ATH of acetophenone obtained were (1 mol.%very low of (Scheme catalyst, 39). 5 mol.% Conver- of KOsiontBu, and reﬂuxing enantioselectivity isopropanol). was Enantioselectivitiesmeasured after 4 and obtained 20 h. The were authors Verylow noted (Scheme some ero-39). Conversionsion of ee over and time. enantioselectivity was measured after 4 and 20 h. The authors noted some erosion of ee over time.

R N [Ir(Cp*)Cl2]2 Ir Cl N R NaOAc N R H CH Cl rt 2 2, N R H

64a R = H (100%, –) 64b R = –(CH2)4– (67%, 1% ee) 64c R = Ph (65%, 8% ee) Scheme 39. Iridacycles based on 4,5 disubstituted imidazolines and performance in the ATH of acetophenone (yield of 1-phenylethanol and ee after 20 h shown).

Kayaki, Ikariya, and coworkers synthesized three chiral iridacycles by cyclometalation of the primary amines [61]. Treatment of 40 with KOtBu in CH2Cl2 resulted in the formation of a dimeric complex 67 in which the two 16e complexes are fused by a four- membered ring formed by the bonds between iridium and the nitrogen atom of the second complex. However, treatment of 65 or 66 with base in the same way allowed isolation of the monomeric 16e complexes 68 and 69 (Scheme 40). The complexes 67–69 were tested in the ATH of acetophenone (0.1 mol.%, no base, isopropanol, 30 °C). Catalysts 68 and 69 were clearly faster than the dimeric catalyst 67. With all three catalysts, decent enantioselectivities were achieved. The authors noted erosion of ee over time. In an experiment at S/C = 200, reactions were complete within 1 h; if the reactions were left for longer periods, the ee gradually diminished to reach close to zero after 20 h. Indeed, Feringa, de Vries and coworkers earlier established that iridacycles are excellent alcohol racemization catalysts [45].

Molecules 2021, 26, x FOR PEER REVIEW 28 of 50

Scheme 38. 2,5-Diphenylpyrrolidine based iridacycles for the ATH of aromatic ketones (time, yield, ee).

Later, Barloy, Pfeffer, and coworkers used the cyclometalation method developed by Davies [59] on 2,5-diphenylpyrrolidine and were able to prepare 62 in pure from in good yield [60]. This methodology was also used for the preparation of a set of three iridacycles 64a–c which they obtained via cyclometalation of 4,5-disubstituted imidazolines. The iridacycles were tested in the ATH of acetophenone (1 mol.% of catalyst, 5 mol.% of KOtBu,

Molecules 2021, 26, 4076 refluxing isopropanol). Enantioselectivities obtained were very low (Scheme 39). Conver-26 of 45 sion and enantioselectivity was measured after 4 and 20 h. The authors noted some erosion of ee over time.

R N [Ir(Cp*)Cl2]2 Ir Cl N R NaOAc N R H CH Cl rt 2 2, N R H

64a R = H (100%, –) 64b R = –(CH2)4– (67%, 1% ee) 64c R = Ph (65%, 8% ee) Scheme 39. IridacyclesIridacycles based based on on 4,5 4,5 disubstituted disubstituted imid imidazolinesazolines and and performance performance in the in theATH ATH of ace- of acetophenonetophenone (yield (yield of 1-phenylethanol of 1-phenylethanol and and ee afteree after 20 20h shown). h shown).

Kayaki, Ikariya,Ikariya, andand coworkerscoworkers synthesizedsynthesized threethree chiralchiral iridacyclesiridacycles byby cyclometa- cyclomet- lationalation of of the the primaryprimary aminesamines [[61].61]. Treatment Treatment of of 4040 withwith KO KOtButBu in inCH CH2Cl22Cl resulted2 resulted in the in theformation formation of a ofdimeric a dimeric complex complex 67 in67 whichin which the two the 16e two complexes 16e complexes are fused are fused by a four- by a four-memberedmembered ring formed ring formed by the bybonds the between bonds between iridium and iridium the nitrogen and the atom nitrogen of the atom second of thecomplex. second However, complex. treatment however, of treatment 65 or 66 ofwith65 baseor 66 inwith the basesame in way the allowed same way isolation allowed of isolationthe monomeric of the 16e monomeric complexes 16e 68 complexes and 69 (Scheme68 and 40).69 (SchemeThe complexes 40). The 67– complexes69 were tested67–69 in ◦ werethe ATH tested of inacetophenone the ATH of acetophenone(0.1 mol.%, no(0.1 base, mol.%, isopropanol, no base, 30 isopropanol, °C). Catalysts 30 68C). and Cata- 69 lystswere 68clearlyand 69fasterwere than clearly the dimeric faster than catalyst the 67 dimeric. With catalystall three67 catalysts,. With all decent three enantiose- catalysts, decentlectivities enantioselectivities were achieved. The were authors achieved. noted The erosion authors of ee noted over erosion time. In of anee experimentover time. Inat anS/C experiment = 200, reactions at S/C were = 200, complete reactions within were 1 completeh; if the reactions within 1 were h; if theleft reactionsfor longer were periods, left for longer periods, the ee gradually diminished to reach close to zero after 20 h. Indeed, Molecules 2021, 26, x FOR PEER REVIEWthe ee gradually diminished to reach close to zero after 20 h. Indeed, Feringa, de Vries29 andof 50 Feringa,coworkers de earlier Vries andestablished coworkers that earlier iridacycles established are excellent that iridacycles alcohol racemization are excellent catalysts alcohol racemization[45]. catalysts [45].

– PF6

Ir Ir Ir Cl Cl NCCH3 TBDMSO NH2 NH2 NH2

40 65 66 KOtBu KOtBu CH2Cl2 KOtBu CH2Cl2 CH2Cl2

Ir H N OTBDMS Ir Ir TBDMSO N NH NH H Ir

67 (28h, 79%, 61% ee) 68 (1h, 88%, 63% ee) 69 (1h, 83%, 69% ee at –30 °C: 4h, 78%, 81% ee) SchemeScheme 40.40. ChiralChiral iridacycleiridacycle complexescomplexes and their performance in the ATH ofof acetophenoneacetophenone (time,(time, yield,yield, eeee).).

LeungLeung andand coworkerscoworkers examined examined the the cyclometalation cyclometalation of of (S )-(SN)--methyl-N-methyl-N-naphthy-1-yl-N-naphthy-1- ethylamineyl-ethylamine using using [Ir(Cp*)Cl [Ir(Cp*)Cl2]22]and2 and NaOAc NaOAc in in CH CH2Cl2Cl2 2at at RT.RT.Surprisingly, Surprisingly,they they foundfound aa mixturemixture ofof thethe expectedexpected iridacycleiridacycle 7070 andand aa smallsmall amountamount ofof thethe analogousanalogous demethylateddemethylated iridacycleiridacycle 71 (Scheme(Scheme 4141))[ [62].62]. They managed to isolateisolate both compounds in pure form. IridacycleIridacycle 7070 waswas investigatedinvestigated extensively.extensively. TheThe complexcomplex isis aa purepure diastereomerdiastereomer and,and, eveneven afterafter treatmenttreatment with base followed by treatmenttreatment with hCl,HCl, thethe samesame singlesingle diastereomerdiastereomer waswas obtained.obtained. BothBoth 7070 and 71 were examined asas catalysts inin the ATH ofof acetophenoneacetophenone andand ◦ foundfound toto showshow Veryvery similarsimilar behaviorbehavior inin termsterms ofof rate rate and and enantioselectivity. enantioselectivity. At At− −1515 °CC with both catalysts (2 mol.%), activated by KOtBu, over 90% conversion was reached after 30 min and the ee of the product alcohol was 60% in both cases. Catalyst 70 was also tested at −30 °C and, in this case, 97% conversion was reached after 1.5 h, and the product had an ee of 69%. At room temperature, the reaction catalyzed by 70 was finished within 15 min and the product was obtained with 52% ee. The same catalyst was capable of reducing acetophenone without activation by base at RT, but the reaction was rather slow and needed 97 h to reach 75% conversion and an ee of 58%.

Scheme 41. Iridacycles obtained by cyclometalation of (S)-N-methyl-N-naphthy-1-yl-ethylamine.

Chen, Xiao, and coworkers examined the cyclometalation of methyl (S)-2-phenyl-oxazoline-4-carboxylate [63]. Depending on the amount of water in the solvent CH2Cl2, they found varying amounts of complexes 72 and 73 (Scheme 42). By performing the reaction in ultra-dry solvent in the presence of MS 4 Å, it was possible to obtain 72 in 99% purity. On the other hand, addition of 2 vol.% of water to the solvent resulted in almost exclusive formation of complex 73. Both complexes were tested in the ATH of p-nitro-acetophenone using the HCO2H/Et3N azeotropic mixture (5:2) as reductant in various solvents. Reac- tions catalyzed by iridacycle 72 were slow in all solvents and afforded the product with

Molecules 2021, 26, x FOR PEER REVIEW 29 of 50

– PF6

Ir Ir Ir Cl Cl NCCH3 TBDMSO NH2 NH2 NH2

40 65 66 KOtBu KOtBu CH2Cl2 KOtBu CH2Cl2 CH2Cl2

Ir H N OTBDMS Ir Ir TBDMSO N NH NH H Ir

67 (28h, 79%, 61% ee) 68 (1h, 88%, 63% ee) 69 (1h, 83%, 69% ee at –30 °C: 4h, 78%, 81% ee) Scheme 40. Chiral iridacycle complexes and their performance in the ATH of acetophenone (time, yield, ee).

Leung and coworkers examined the cyclometalation of (S)-N-methyl-N-naphthy-1- yl-ethylamine using [Ir(Cp*)Cl2]2 and NaOAc in CH2Cl2 at RT. Surprisingly, they found a mixture of the expected iridacycle 70 and a small amount of the analogous demethylated iridacycle 71 (Scheme 41) [62]. They managed to isolate both compounds in pure form. Iridacycle 70 was investigated extensively. The complex is a pure diastereomer and, even Molecules 2021, 26, 4076 after treatment with base followed by treatment with HCl, the same single diastereomer27 of 45 was obtained. Both 70 and 71 were examined as catalysts in the ATH of acetophenone and found to show very similar behavior in terms of rate and enantioselectivity. At −15 °C withwith both catalysts (2 (2 mol.%), mol.%), activated activated by by KO KOtBu,tBu, over over 90% 90% conversion conversion was wasreached reached after after30 min 30 and min the and ee theof theee productof the product alcohol alcoholwas 60% was in both 60% cases. in both Catalyst cases. 70 Catalyst was also70 testedwas alsoat −30 tested °C and, at − in30 this◦C and,case, in97% this conversion case, 97% was conversion reached was after reached 1.5 h, and after the 1.5 product h, and thehad productan ee of had69%. an Atee roomof 69%. temperatur At room temperature,e, the reaction the catalyzed reaction by catalyzed 70 was byfinished70 was within ﬁnished 15 withinmin and 15 the min product and the was product obtained was obtainedwith 52% with ee. The 52% sameee. The catalyst same was catalyst capable was of capable reducing of reducingacetophenone acetophenone without withoutactivation activation by base byat baseRT, atbut RT, the but reaction the reaction was rather was rather slow slow and andneeded needed 97 h 97 to hreach to reach 75% 75% conversion conversion and andan ee an ofee 58%.of 58%.

SchemeScheme 41.41. IridacyclesIridacycles obtainedobtained byby cyclometalationcyclometalation ofof ((SS)-)-NN-methyl--methyl-NN-naphthy-1-yl-ethylamine.-naphthy-1-yl-ethylamine.

Chen,Chen, Xiao, and and coworkers coworkers examined examined the the cyclometalation cyclometalation of ofmethyl methyl (S)-2-phenyl-ox- (S)-2-phenyl- oxazoline-4-carboxylateazoline-4-carboxylate [63]. [63 Depending]. Depending on onthe theamount amount of water of water in the in thesolvent solvent CH2 CHCl2,2 theyCl2, theyfound found varying Varying amounts amounts of complexes of complexes 72 and72 73and (Scheme73 (Scheme 42). By 42 performing). By performing the reaction the reactionin ultra-dry in ultra-dry solvent in solvent the presence in the presence of MS 4 ofÅ, MS it was 4 Å, possible it was possible to obtain to 72 obtain in 99%72 inpurity. 99% purity. On the other hand, addition of 2 Vol.% of water to the solvent resulted in almost Molecules 2021, 26, x FOR PEER REVIEWOn the other hand, addition of 2 vol.% of water to the solvent resulted in almost exclusive30 of 50 exclusiveformation formation of complex of 73 complex. Both complexes73. Both were complexes tested in were the testedATH of in p-nitro-acetophenone the ATH of p-nitro- acetophenone using the hCO H/Et N azeotropic mixture (5:2) as reductant in Various using the HCO2H/Et3N azeotropic2 mixture3 (5:2) as reductant in various solvents. Reac- solvents.tions catalyzed Reactions by iridacycle catalyzed 72 by were iridacycle slow 72in allwere solvents slow in and all solventsafforded andthe product afforded with the productvery low with enantioselectivity. Very low enantioselectivity. In contrast, use Inof contrast,complex 73 use resulted of complex in a fast73 reaction,resulted inand, a fastin CH reaction,2Cl2, the and, product in CH was2Cl 2obtained, the product with was73% obtainedee. Next, the with authors 73% ee .examined Next, the the authors influ- examinedence of the the structure inﬂuence of the of thebase structure and the form of theic baseacid/base and the ratio. formic Best acid/baseresults were ratio. obtained Best resultsusing i were-PrNH obtained2 as base using andi -PrNHa formic2 as acid/base base and aratio formic of acid/base2.0 (Figure ratio 1a). ofThe 2.0 authors (Figure3 a).ex- Theplained authors this explainedby assuming this bya transition assuming state a transition for the statehydride forthe transfer hydride in transferwhich the in whichproto- thenated protonated base plays base the playsrole of the proton role ofshuttle proton (Figure shuttle 1b). (Figure The authors3b). The used authors these used optimized these optimizedconditions conditions for the reduction for the reductionof a range of a20 range different of 20 substituted different substituted acetophenones acetophenones and other andaryl otherketones aryl with ketones ees ranging with ee sfrom ranging 92–99%. from 92–99%.

SchemeScheme 42.42. ProductsProducts ofof thethe cyclometalationcyclometalation ofof methylmethyl ((SS)-2-phenyl-oxazoline-4-carboxylate.)-2-phenyl-oxazoline-4-carboxylate.

Baya, Mata, and coworkers prepared two NHC-ligated iridacycles 74a and 74b Via reaction of Ir(Cp*)(NHC)Cl2 with (R)-1-naphth-1-yl-ethylamine under the inﬂuence of AgOAc and KPF6 [64]. After treatment with base, which presumably deprotonates the amine group to from the amide complex. These complexes were active as ATH catalysts. A small set of four aromatic and one aliphatic ketone was reduced to the alcohols with ees between 2% and 58% (Scheme 43). This activity is somewhat surprising as no ligand position is available for the formation of a hydride. On the basis of DFT calculations, the authors proposed a Meerwein–Ponndorf–Verley type mechanism in which the amide group deprotonates isopropanol, which transfers its hydride to the ketone, which is protonated by the remaining proton of the amide ligand. The proposed transition state is depicted in Figure4.

Figure 1. (a) Effect of the structure of base and the formic acid/base ratio on the enantioselectivity of the ATH of p-nitro-acetophenone catalyzed by 73. (b) Proposal for the transition state of the hydride transfer (a), reprinted with permission from [63]; copyright 2018 American Chemical Society.

Baya, Mata, and coworkers prepared two NHC-ligated iridacycles 74a and 74b via reaction of Ir(Cp*)(NHC)Cl2 with (R)-1-naphth-1-yl-ethylamine under the influence of AgOAc and KPF6 [64]. After treatment with base, which presumably deprotonates the amine group to from the amide complex. These complexes were active as ATH catalysts. A small set of four aromatic and one aliphatic ketone was reduced to the alcohols with ees between 2% and 58% (Scheme 43). This activity is somewhat surprising as no ligand position is available for the formation of a hydride. On the basis of DFT calculations, the authors proposed a Meerwein–Ponndorf–Verley type mechanism in which the amide group deprotonates isopropanol, which transfers its hydride to the ketone, which is protonated by the remaining proton of the amide ligand. The proposed transition state is depicted in Figure 2.

Molecules 2021, 26, x FOR PEER REVIEW 30 of 50

very low enantioselectivity. In contrast, use of complex 73 resulted in a fast reaction, and, in CH2Cl2, the product was obtained with 73% ee. Next, the authors examined the influence of the structure of the base and the formic acid/base ratio. Best results were obtained using i-PrNH2 as base and a formic acid/base ratio of 2.0 (Figure 1a). The authors explained this by assuming a transition state for the hydride transfer in which the protonated base plays the role of proton shuttle (Figure 1b). The authors used these optimized conditions for the reduction of a range of 20 different substituted acetophenones and other aryl ketones with ees ranging from 92–99%.

Molecules 2021, 26, 4076 28 of 45 Scheme 42. Products of the cyclometalation of methyl (S)-2-phenyl-oxazoline-4-carboxylate.

FigureFigure 1. 3. ((a)) Effect of thethe structurestructure ofof base base and and the the formic formic acid/base acid/base ratio ratio on on the the enantioselectivity enantioselectivity of Molecules 2021,, 26,, xx FORFOR PEERPEER REVIEWREVIEWofthe the ATH ATH of pof-nitro-acetophenone p-nitro-acetophenone catalyzed catalyzed by 73by.( 73b). ( Proposalb) Proposal for thefor transitionthe transition state state of the of hydridethe31 ofhy- 50

Baya, Mata, and coworkers prepared two NHC-ligated iridacycles 74a and 74––b via PF66 reaction of Ir(Cp*)(NHC)Cl2 with (MeR)-1-naphth-1-yl-ethylamineNH under theR influence of Me NH22 N AgOAc N AgOAc and KPF6 [64]. After +treatment with base, which presumably deprotonates the KPF 6 IrIr amine group toCl fromIrIr theR amide complex. These complexes6 were active as NATH catalysts. N NH 2R N MeCN 2R Cl A small set of four aromaticRN and one aliphatic ketone4h, rt was reduced to the alcohols with ees between 2% and 58% (Scheme 43). This activity is somewhat surprisingMe as no ligand po- 74a R - Me sition is available for the formation of a hydride. On the basis74a R -of Me DFT calculations, the 74b RR == nBu authors proposed a Meerwein–Ponndorf–Verley type mechanism in which the amide group deprotonates isopropanol, which transfers its hydride to the ketone, which is pro- O OH 1 mol% Cat. OH O tonated by the remaining+ proton of the amide ligand. The proposed+ transition state is de- 1 2 NaOtBu 1 2 R1 R2 NaOtBu R1 R2 picted in Figure 2. 30 °C, 8h

O O O O O

74a 100%, 20% ee 95%, 12% ee 58%, 16% ee 63%,63%, 2%2% eeee 92%,92%, 19%19% eeee 74b 99%, 55% ee 56%, 24% ee 23%, 58% ee 50%, 15% ee 36%, 22%ee 74b 99%, 55% ee 56%, 24% ee 23%, 58% ee 50%, 15% ee 36%, 22%ee SchemeScheme 43.43. CationicCationic NHC-ligatedNHC-ligated iridacyclesiridacycles asas catalystscatalysts forfor thethe ATHATH ofof aromaticaromatic ketones. ketones.

FigureFigure 4.2. TransitionTransition statestate forfor MPVMPV mechanismmechanism inin ATHATH catalyzed catalyzed by by74a 74aand and74b 74b...

3.3.3.3. OxidationOxidation andand DehydrogenationDehydrogenation ofof Alcohols to Aldehydes, Ketones, Ketones, Carboxylic Carboxylic Acids, Acids, or or Esters Esters IkariyaIkariyaIkariya andandand coworkerscoworkerscoworkers investigated investigatedinvestigated the thethe iridacycles iridacyclesiridacycles 36 36––3838 and andand iridacycle iridacycleiridacycle 75 75 asas catalystcatalyst forforfor thethethe oxidation oxidationoxidation of ofof 1-phenylethanol 1-phenylethanol1-phenylethanol with withwith air aiai inr THFin THF at room at room temperature temperature (Scheme (Scheme 44)[ 6544)]. [65].[65]. AllAll catalystscatalysts withwith thethe exceptionexception ofof 75 werewere quitequite effective,effective, althoughalthough 1010 mol.%mol.% ofof cat-catalyst was needed. The lack of activity with 75 cancan bebe explainedexplained byby assuming an iridium hydride amine/iridium amide redox couple is operative in this reaction. Next, the catalyst 37a was used for the oxidation of a series of substituted 1-phenyl-ethanols, benzhydrol, and 4-phenyl-butan-2-ol in good yield. Cyclohexenol was oxidized to cyclohexanone in 47% yield. Oxidation of hydroxyketones was slow, and benzil was formed in only 10% yield from benzoin. Similarly, methyl mandelate could nott bebe oxidized.oxidized. OxidationOxidation ofof diolsdiols toto thethe hydroxyketoneshydroxyketones waswas possiblepossible inin yieldsyields fromfrom 31–34%.31–34%. BenzylBenzyl alcoholsalcohols werewere oxidizedoxidized toto thethe benzylbenzyl benzoatesbenzoates inin yieldsyields fromfrom 62–72%62–72% usingusing catalystcatalyst 36a.. OxidativeOxidative esterificationesterification of aliphatic alcohols was more problematic and gave the products in 45–46% yields. The authors assumed a mechanism in which the dehydrogenation of the alcohol takes place concertedly on the 16 electron iridacycle 37a toto givegive thethe protonatedprotonated hydridehydride complexcomplex 38a.. The hydride complex next reacts with oxygen to reform the complex 37a..

Molecules 2021, 26, 4076 29 of 45

All catalysts with the exception of 75 were quite effective, although 10 mol.% of catalyst was needed. The lack of activity with 75 can be explained by assuming an iridium hydride amine/iridium amide redox couple is operative in this reaction. Next, the catalyst 37a was used for the oxidation of a series of substituted 1-phenyl-ethanols, benzhydrol, and 4-phenyl-butan-2-ol in good yield. Cyclohexenol was oxidized to cyclohexanone in 47% yield. Oxidation of hydroxyketones was slow, and benzil was formed in only 10% yield from benzoin. Similarly, methyl mandelate could not be oxidized. Oxidation of diols to the hydroxyketones was possible in yields from 31–34%. Benzyl alcohols were oxidized to the benzyl benzoates in yields from 62–72% using catalyst 36a. Oxidative esteriﬁcation of aliphatic alcohols was more problematic and gave the products in 45–46% yields. The authors assumed a mechanism in which the dehydrogenation of the alcohol takes place Molecules 2021, 26, x FOR PEER REVIEW 32 of 50 concertedly on the 16 electron iridacycle 37a to give the protonated hydride complex 38a. The hydride complex next reacts with oxygen to reform the complex 37a.

SchemeScheme 44.44. PerformancePerformance ofof iridacycles iridacycles in in the the aerobic aerobic oxidation oxidation of 1-phenylethanolof 1-phenylethanol (yield (yield of acetophe- of aceto- nonephenone in brackets; in brackets; * no * base no base was was used). used).

TheThe chiral iridacycle 76,76, asas well well as as a anumber number of of iridium iridium complexes complexes based based on on chiral chiral N- Nsulfonated-sulfonated diamines diamines such such as 77, as was77, was tested tested in the in kinetic the kinetic resolution resolution of secondary of secondary alcohols al- coholsvia oxidation Via oxidation [66]. Iridacycle [66]. Iridacycle 76 (10 mol.%,76 (10 1M mol.%, substrate 1 M substrateconcentration concentration in THF)) was in THF) used wasfor the used oxidation for the of oxidation 1-phenylethanol of 1-phenylethanol at room temperature, at room temperature, and the reaction and was the reactionstopped wasafter stopped4 h when after 48% 4 of h alcohol when 48% was ofunconverted alcohol was (Table unconverted 2). Lowering (Table the2). concentration Lowering the of concentrationthe substrate to of 0.1 the M substrate improved to 0.1the Mee to improved 48%, but the nowee to75 48%,h was but needed now 75to hreach was the needed 52% toconversion. reach the 52%In the conversion. end, the catalysts In the end,based the on catalysts the sulfonated based ondiamines the sulfonated performed diamines better. performedWith catalyst better. 77, it With was catalyst possible77 to, it reach was possible98% ee after to reach 52% 98% conversionee after 52%at 0.2 conversion M substrate at 0.2concentration, M substrate whereas, concentration, at 1.0 M, whereas, it was possible at 1.0 M, to it reach was possible 84% ee after to reach 56% 84% conversion.ee after56% The conversion.authors gave The no authorsexplanation gave for no the explanation concentration for the effect. concentration effect. Interestingly, oxygen is not even necessary to oxidize alcohols. It is also possible

to use an iridacycle as a dehydrogenation catalyst. Fujita, Yamaguchi, and coworkers examined the use of benzopyridone-based iridacycle 78 in the dehydrogenation of benzyl Table 2. Aerobic oxidative kinetic resolution of secondary alcohols. alcohols (Scheme 45)[67]. The products were obtained in excellent yields, i.e., around 90% yield when no substituents or electron-donating substituents were present. For benzyl alcohols carrying electron-withdrawing substituents, it was necessary to raise the temperature by carrying out the reaction in refluxing xylene and using Na2CO3 as base. Even aliphatic alcohols such as cyclohexylmethanol and 1-octanol could be dehydrogenated to the aldehydes by using 5 mol.% of catalyst with refluxing xylene as solvent in 62% and 46% yield, respectively. The dehydrogenation of secondary alcohols was even more facile and could be performed using between 0.1 and 0.5 mol.% of catalyst in refluxing xylene without any base yielding the ketones in yields Varying from 90–100%. The authors assumed that an inner-sphere mechanism is operative. Concentration of Recovered ee of Alcohol Catalyst t (h) 1-phenylethanol Alcohol (%) (%) 76 1.0 M 4 48 14 76 0.1 M 75 48 42 77 1.0 M 22 44 84 77 0.2 M 38 48 98

Interestingly, oxygen is not even necessary to oxidize alcohols. It is also possible to use an iridacycle as a dehydrogenation catalyst. Fujita, Yamaguchi, and coworkers examined the use of benzopyridone-based iridacycle 78 in the dehydrogenation of benzyl alcohols (Scheme 45) [67]. The products were obtained in excellent yields, i.e., around 90% yield when no substituents or electron-donating substituents were present. For benzyl alcohols carrying electron-withdrawing substituents, it was necessary to raise the temperature by carrying out the reaction in refluxing xylene and using Na2CO3 as base. Even aliphatic alcohols such as cyclohexylmethanol and 1-octanol could be dehydrogenated to the aldehydes by using 5 mol.% of catalyst with refluxing xylene as solvent in 62% and 46%

Molecules 2021, 26, x FOR PEER REVIEW 32 of 50

Scheme 44. Performance of iridacycles in the aerobic oxidation of 1-phenylethanol (yield of acetophenone in brackets; * no base was used).

The chiral iridacycle 76, as well as a number of iridium complexes based on chiral N- sulfonated diamines such as 77, was tested in the kinetic resolution of secondary alcohols via oxidation [66]. Iridacycle 76 (10 mol.%, 1M substrate concentration in THF)) was used for the oxidation of 1-phenylethanol at room temperature, and the reaction was stopped after 4 h when 48% of alcohol was unconverted (Table 2). Lowering the concentration of the substrate to 0.1 M improved the ee to 48%, but now 75 h was needed to reach the 52% conversion. In the end, the catalysts based on the sulfonated diamines performed better. With catalyst 77, it was possible to reach 98% ee after 52% conversion at 0.2 M substrate concentration, whereas, at 1.0 M, it was possible to reach 84% ee after 56% conversion. The Molecules 2021, 26, 4076 30 of 45 authors gave no explanation for the concentration effect.

Table 2.2. Aerobic oxidative kinetickinetic resolutionresolution ofof secondarysecondary alcohols.alcohols.

Molecules 2021, 26, x FOR PEER REVIEW 33 of 50 ConcentrationConcentration of of Recovered ee of Alcohol CatalystCatalyst t (h)t (h) Recovered Alcohol (%) ee of Alcohol (%) 1-phenylethanol1-phenylethanol Alcohol (%) (%) 7676 1.0 M 4 48 14 yield, respectively. The1.0 dehydrogenation M 4 of secondary 48alcohols was even more 14 facile and 7676 0.1 M0.1 M 75 75 48 48 42 could be performed using between 0.1 and 0.5 mol.% of catalyst in refluxing xylene with- 7777 1.0 M1.0 M 22 22 44 44 84 out any77 base yielding0.2 the M ketones in yields 38 varying from 48 90–100%. The authors 98 assumed 77 0.2 M 38 48 98 that an inner-sphere mechanism is operative.

yield when no substituentsCH2Cl2 or electron-donating substituents were present. For benzyl al- rt, 24h cohols carrying electron-withdrawing substitu78 ents, it was necessary to raise the temperature by carrying out the reaction in refluxing xylene and using Na2CO3 as base. Even aliphatic alcohols such2 mol%as cyclohexylmethanol 78 and 1-octanol could be dehydrogenated to the 5 mol% NaOMe aldehydesR OH by using 5 mol.% of catalystRCHO with+ H2 refluxing xylene as solvent in 62% and 46% Toluene Reflux, 20h

OH O 0.1–0.5 mol% 78 + H2 R1 R2 Xylene R1 R2 Reflux, 20h Scheme 45.45. Iridacycle-catalyzed dehydrogenationdehydrogenation ofof primaryprimary andand secondarysecondary alcohols.alcohols.

Das and coworkers investigated the use of iridacycles 79a and b in the dehydrogena- dehydrogena- tiontion of alcohols alcohols to to the the carboxylic carboxylic acids acids in inrefluxing refluxing toluene toluene [68]. [68 The]. The reaction reaction needs needs a stoi- a stoichiometricchiometric base, base, and andKOH KOH was wasfound found to perform to perform best. best.Use of Use weaker of weaker bases such bases as such K2CO as3 Kand2CO Cs3 2andCO3 Cs led2CO to 3noled reaction. to no reaction. Catalyst Catalyst 79a was79a foundwasfound to perform to perform better better than than79b, 79bpre-, presumablysumably because because of ofthe the electr electron-donatingon-donating substituent substituent of of 79a79a. .Instability Instability of of the aldehydealdehyde group of 79b79b turnedturned outout notnot toto bebe thethe reasonreason forfor thethe lowerlower reactivity.reactivity. AA rangerange ofof benzylbenzyl alcohols was synthesized in this manner in yields between 80% 80% and and 90% 90% (Scheme(Scheme 4646).). Electron-withdrawing substituents and ortho-substituents reduced the yields of the acids. TheThe acids were isolated isolated by by acidification acidification at at the the end end of of the the reaction. reaction. Some Some mechanistic mechanistic re- researchsearch was was performed. performed. The The authors authors were were able able to tomeasure measure the the production production of 2 of equiv. 2 equiv. of ofhydrogen hydrogen at atthe the end end of of the the reaction. reaction. The The first first step step is is the the production production of the aldehyde. ThisThis intermediateintermediate cancan bebe convertedconverted intointo thethe acidacid Viavia two different pathways:pathways: either Viavia Canniz- zaro reaction or Via the catalyzed dehydrogenation of the hydrate of the aldehyde. The zaro reaction or via the catalyzed dehydrogenation of the hydrate of the aldehyde. The authors were able to prove that both mechanisms were operative. The catalyst was highly authors were able to prove that both mechanisms were operative. The catalyst was highly active and could be used at 0.1 mol%. It was also reused three times with any discernable active and could be used at 0.1 mol%. It was also reused three times with any discernable loss in yield. A maximum of 5000 turnovers was reached in the oxidation of benzyl alcohol. loss in yield. A maximum of 5000 turnovers was reached in the oxidation of benzyl alcohol.

F [Ir(Cp*)Cl ] Br– 2 2 Br F Cs2CO3, NaOAc R Ir N R N N Excess KBr N CH3CN, reflux, 10h 79a R = OMe 79b R = CHO

1. 79a (0.1 mol%), KOH (1.1 eq.) O Toluene, reflux 1 R OH R OH + 2H2 + KCl 2. HCl/H2O

R1 = aryl, 30–94% yield R1 = fur-2-yl, 80% R1 = pyrid-2-yl*, 71% 1 R = n-C4H9*, 82% 1 R = n-C8H17*, 75% 1 R = CH3CH2CH(CH3)CH2*, 0%

Molecules 2021, 26, x FOR PEER REVIEW 33 of 50

yield, respectively. The dehydrogenation of secondary alcohols was even more facile and could be performed using between 0.1 and 0.5 mol.% of catalyst in refluxing xylene without any base yielding the ketones in yields varying from 90–100%. The authors assumed that an inner-sphere mechanism is operative.

Cl O Ir O [Ir(Cp*)Cl2]2 HN NaOAc N

CH2Cl2 rt, 24h 78

2 mol% 78 5 mol% NaOMe R OH RCHO + H2 Toluene Reflux, 20h

OH 0.1–0.5 mol% 78 O + H2 R1 R2 Xylene R1 R2 Reflux, 20h Scheme 45. Iridacycle-catalyzed dehydrogenation of primary and secondary alcohols.

Das and coworkers investigated the use of iridacycles 79a and b in the dehydrogenation of alcohols to the carboxylic acids in refluxing toluene [68]. The reaction needs a stoichiometric base, and KOH was found to perform best. Use of weaker bases such as K2CO3 and Cs2CO3 led to no reaction. Catalyst 79a was found to perform better than 79b, presumably because of the electron-donating substituent of 79a. Instability of the aldehyde group of 79b turned out not to be the reason for the lower reactivity. A range of benzyl alcohols was synthesized in this manner in yields between 80% and 90% (Scheme 46). Electron-withdrawing substituents and ortho-substituents reduced the yields of the acids. The acids were isolated by acidification at the end of the reaction. Some mechanistic research was performed. The authors were able to measure the production of 2 equiv. of hydrogen at the end of the reaction. The first step is the production of the aldehyde. This intermediate can be converted into the acid via two different pathways: either via Canniz- zaro reaction or via the catalyzed dehydrogenation of the hydrate of the aldehyde. The authors were able to prove that both mechanisms were operative. The catalyst was highly

Molecules 2021, 26, 4076 active and could be used at 0.1 mol%. It was also reused three times with any discernable31 of 45 loss in yield. A maximum of 5000 turnovers was reached in the oxidation of benzyl alcohol.

F [Ir(Cp*)Cl ] Br– 2 2 Br F Cs2CO3, NaOAc R Ir N R N N Excess KBr N CH3CN, reflux, 10h 79a R = OMe 79b R = CHO

1. 79a (0.1 mol%), KOH (1.1 eq.) O Toluene, reflux 1 R OH R OH + 2H2 + KCl 2. HCl/H2O

R1 = aryl, 30–94% yield R1 = fur-2-yl, 80% R1 = pyrid-2-yl*, 71% 1 R = n-C4H9*, 82% 1 R = n-C8H17*, 75% 1 R = CH3CH2CH(CH3)CH2*, 0% Scheme 46. Iridacycle-catalyzed dehydrogenation of alcohols to acids (* isolated as potassium salt).

Surprisingly, no Oppenauer-type oxidations were reported with iridacycles, although there is one report on the use of an iridium-pincer complex (outside the scope of the review) [69].

3.4. Transfer Hydrogenation of Imines and Reductive Amination Xiao and coworkers discovered the activity of the acetophenone imine-based iridacycles by accident in the course of investigating the reactivity of iridium complexes based on tosylated diamines when they tested the activity of the catalyst precursor in the hydrogenation of 2-heptanone anisidylimine [70]. They were able to isolate the corresponding iridacycle from the reaction mixture. Next, they compared the activity of premade irida- ◦ cycles 47a,b and 80 in the TH of the same substrate at 80 C using hCO2H/Et3N (5:2) in triﬂuoroethanol as reductant. The three premade iridacycles were much faster than the in situ formed iridacycle from [Ir(Cp*)Cl2]2 with 47b > 47a >> 80. The poor reactivity of the iridacycle based on the amine 80 is surprising since Pfeffer and de Vries found quite the reverse in the TH of ketones with isopropanol where the imine-based catalyst was inactive [32]. The authors did not offer any explanation. The TH using catalyst 47b is extremely fast with an initial TOF of 1.9 × 104. The authors assumed that a direct hydride transfer from the iridium hydride to the protonated imine takes place. A range of imine substrates was reduced in excellent yield using only 0.1 mol.% of catalyst 47b (Scheme 47a). Catalyst 47a was used for the direct reductive amination Via TH (Scheme 47b). here, the use of triﬂuoroethanol was not necessary and methanol could be used. Depending on the type of substrate, 0.1 or 0.5 mol.% of catalyst was used. It was even possible to use complex 47a as catalyst for a direct reductive amination using ammonium formate as the amine donor (Scheme 47c). In a later publication, the direct reductive amination was examined further, and seven iridacycles were screened [71]. complex 51 (see Scheme 48 for structure) gave the best results, and a large number of aromatic ketones were converted into the primary amines with excellent yields using only 0.1 mol.% of catalyst. The mechanism of the imine TH was investigated using kinetics, NMR studies, and DFT calculations [72]. It turned out that hydride formation from the iridacycle formate complex is the rate-determining step. The hydride transfer occurs directly on the protonated imine without the imine binding to the metal. Molecules 2021, 26, 4076 32 of 45 Molecules 2021, 26, x FOR PEER REVIEW 35 of 50

R1 MeO Ir Cl Ir Cl N R2 N OMe

47a R1 = R2 = OMe 80 47b R1 = CN, R2 = OMe

R3 R3 N 0.1 mol% 47b HN (a) HCO2H/Et3N (5:2) 1 2 1 2 R R CF3CH2OH, 80 °C R R 0.5-5h R1 = alkyl, phenyl, naphthyl 91–97% R2 = H, Me, Et R3 = 4-anisyl, benzyl, cyclohexyl

R3 O 0.1 mol% 47a HN 3 (b) R NH2 + HCO2H/Et3N (5:2) 1 2 1 2 R R CH3OH, 80 °C, 12h R R R1 = alkyl, aryl 65–99% R2 = H, alkyl 3 R NH2 = alkyl amines, p-anisidine, aminoalcohols, amino acids

O 0.5 mol% 47a NH2 (c) HCO NH + 2 4 HCO H/Et N (5:2) R1 R2 2 3 R1 R2 CH3OH, 80 °C R1 = aryl 5–24h 83–95% 2 R = alkyl, CO2Me, CH2CO2Me Molecules 2021, 26, x FOR PEER REVIEWScheme 47. Iridacycle-catalyzed imine hydrogenation (a) and reductive amination of ketones36 ofto 50 Scheme 47. Iridacycle-catalyzed imine hydrogenation (a) and reductive amination of ketones to secondarysecondary aminesamines ((bb)) andand toto primaryprimary aminesamines ((cc).).

The mechanism of the imine TH was investigated using kinetics, NMR studies, and DFT calculations [72]. It turned out that hydride formation from the iridacycle formate R3 O 0.1 mol% 51 HN Ir complex3 is the rate-determining step. The hydride transfer occursCl directly on the proto- R NH2 + N OMe nated imine withoutHCO the2H/NaO imine2CH binding (pH4.8) to the metal. R1 R2 H O, 80 °C, 2h R1 R2 The same group found2 that the iridacycle-catalyzed reductive amination of alde- hydes1 and ketones2 with amines3 via TH can also be performed51 using formate salts in water R = aryl; R = alkyl, CH2CO2Me; R = aryl, alkyl in an “on-water” procedure as the catalysts are not soluble in water [73]. This reaction is SchemeSchemeagain crucially 48. 48. On-waterOn-water dependent iridacycle-catalyzed iridacycle-catalyzed on the pH reductiveof reductive the wa TH.ter TH. with the lower pH preferred since this not only catalyzes the imine formation, but the acid also protonates the imine, which al- XiaoThe sameand coworkers group found also that used the the iridacycle-catalyzed reductive amination reductive technology amination they of developed aldehydes lows the transfer of hydride from the iridacycle. At the optimum pH, the reduction of the forand the ketones formation with of amines N-aryl Viaand TH N-alkyl can also 5-methyl-pyrrolidinones be performed using formate from levulinic salts in acid water and in ketone to the alcohol is a major side-reaction, which could be mitigated by working at a foran the “on-water” formation procedure of N-arylas and the N catalysts-alkyl 6-methyl-piperidones are not soluble in water from [5-oxo-hexanoic73]. This reaction acid is somewhat higher pH. In the end, pH 4.8 was chosen as compromise as formation of alco- (Schemeagain crucially 49) [74]. dependent The reaction on was the pHperformed of the water using with anilines the lowerof alkylamines pH preferred in an sinceaqueous this hol is largely suppressed at this pH. Seven iridacycles based on para-substituted acetophe- formicnot only acid/sodium catalyzes formate the imine buffer formation, at pH 3.5 but and the 80 acid °C. With also protonatesmost substrates, the imine, an S/C which ratio none-N-phenylimine were screened, and best results were obtained with catalyst 51. In- ofallows 2000 could the transfer be used, of and hydride the reaction from the was iridacycle. finished At within the optimum 1 h. More pH, sluggish the reduction substrates of terestingly, performance of the TH in methanol or DMF led to homogeneous systems, but neededthe ketone a S/C to of the 200–500. alcohol Yields is a major of the side-reaction, products were which excellent. could be mitigated by working atthe a rate somewhat of the higherreactions pH. in Inthese the solvents end, pH was 4.8was substantially chosen as lower, compromise supporting as formation the “on- ofwater” alcohol effect. is largely A range suppressed of aromatic at ketones this pH. was Seven subjected iridacycles to reductive based onaminationpara-substituted with ani- acetophenone-lines of alkylaminesN-phenylimine at 0.1 mol.% were of screened, catalyst with and besta sodium results formate/formic were obtained acid-buffered with catalyst 51aqueous. Interestingly, solution performance at 80 °C (Scheme of the 48). TH Yiel in methanolds were generally or DMF led abov to homogeneouse 90% with substituted systems, butanilines the rateand ofsomewhat the reactions lower inwith these alkylamines. solvents was substantially lower, supporting the “on-water” effect. A range of aromatic ketones was subjected to reductive amination with anilines of alkylamines at 0.1 mol.% of catalyst with a sodium formate/formic acid-buffered

Scheme 49. Iridacycle-catalyzed reductive amination of keto acids to form pyrrolidinones and piperidones.

Albrecht and coworkers tested the iridacycles of Scheme 33 in the transfer hydrogenation of benzaldehyde N-phenylimine in the presence of catalytic KOH in refluxing isopropanol. Although the five complexes performed quite differently in the TH of acetophenone, in the TH of this substrate, all five catalysts were equally fast. In the end, catalyst 54b was selected for the TH of a small set of N-aryl and N-alkyl benzaldehyde imines in good yields. Reduction of an acetophenone based imine was very slow [53].

3.5. Asymmetric Hydrogenation of Imines Pfeffer, de Vries, and coworkers used iridacycle 62 for the ATH of three imines using a 1:1 mixture of formic acid and triethylamine in dichloromethane at room temperature (Scheme 50) [32]. Yields were good and enantioselectivities between 57% and 77% were obtained. The authors noted the importance of working under strict exclusion of water to prevent hydrolysis of the imine. This was achieved by adding dry Et3N to the azeotropic mixture of formic acid and triethyl amine (5:2) to achieve a 1:1 ratio.

Molecules 2021, 26, x FOR PEER REVIEW 36 of 50

R3 O 0.1 mol% 51 HN Ir 3 Cl R NH2 + HCO2H/NaO2CH (pH4.8) N OMe Molecules 2021, 26, 4076 1 2 1 2 33 of 45 R R H2O, 80 °C, 2h R R

1 2 3 51 R = aryl; R = alkyl, CH2CO2Me; R = aryl, alkyl aqueousScheme 48. solution On-water at 80iridacycle-catalyzed◦C (Scheme 48). reductive Yields were TH. generally above 90% with substituted anilines and somewhat lower with alkylamines. XiaoXiao andand coworkerscoworkers alsoalso usedused thethe reductivereductive amination amination technologytechnology theythey developed developed forfor thethe formationformation ofofN N-aryl-aryl andandN N-alkyl-alkyl 5-methyl-pyrrolidinones5-methyl-pyrrolidinones fromfrom levulinic levulinic acid acid and and forfor thethe formationformation ofofN N-aryl-aryl and andN N-alkyl-alkyl 6-methyl-piperidones 6-methyl-piperidones fromfrom 5-oxo-hexanoic 5-oxo-hexanoic acid acid (Scheme(Scheme 49 49))[ [74].74]. TheThe reactionreaction waswas performedperformed using using anilinesanilines of of alkylaminesalkylamines in in an an aqueous aqueous formicformic acid/sodium acid/sodium formateformate bufferbuffer at at pH pH 3.5 3.5 and and 80 80◦ °C.C. With With most most substrates, substrates, an an S/C S/Cratio ratio ofof 20002000 couldcould bebe used,used, andand thethe reactionreaction waswas ﬁnishedfinished within within 1 1 h. h. MoreMore sluggishsluggish substrates substrates neededneeded aa S/CS/C of 200–500. Yields of the products were excellent.excellent.

SchemeScheme 49. Iridacycle-catalyzedIridacycle-catalyzed reductive reductive amination amination of keto of ketoacids acidsto form to pyrrolidinones form pyrrolidinones and pi- andperidones. piperidones.

AlbrechtAlbrecht andand coworkerscoworkers testedtested thethe iridacyclesiridacycles ofof SchemeScheme 3333 inin thethe transfertransfer hydro-hydro- genationgenation ofof benzaldehydebenzaldehyde NN-phenylimine-phenylimine inin thethe presencepresence ofof catalyticcatalytic KOHKOH inin refluxing refluxing isopropanol.isopropanol. AlthoughAlthough the five five complexes complexes perf performedormed quite quite differently differently in in the the TH TH of of aceto- ace- tophenone,phenone, in inthe the TH TH of this of this substrate, substrate, all five all catalysts five catalysts were wereequally equally fast. In fast. the end, In the catalyst end, catalyst54b was54b selectedwasselected for the TH for of the a THsmall of set a small of N-aryl set of andN-aryl N-alkyl and benzaldehydeN-alkyl benzaldehyde imines in iminesgood yields. in good Reduction yields. Reduction of an acetophe of annone acetophenone based imine based was imine very wasslow Very [53]. slow [53]. 3.5. Asymmetric Hydrogenation of Imines 3.5. Asymmetric Hydrogenation of Imines Pfeffer, de Vries, and coworkers used iridacycle 62 for the ATH of three imines using Pfeffer, de Vries, and coworkers used iridacycle 62 for the ATH of three imines using a 1:1 mixture of formic acid and triethylamine in dichloromethane at room temperature a 1:1 mixture of formic acid and triethylamine in dichloromethane at room temperature (Scheme 50)[32]. Yields were good and enantioselectivities between 57% and 77% were (Scheme 50) [32]. Yields were good and enantioselectivities between 57% and 77% were obtained. The authors noted the importance of working under strict exclusion of water to Molecules 2021, 26, x FOR PEER REVIEWobtained. The authors noted the importance of working under strict exclusion of water37 of 50to prevent hydrolysis of the imine. This was achieved by adding dry Et3N to the azeotropic prevent hydrolysis of the imine. This was achieved by adding dry Et3N to the azeotropic mixture of formic acid and triethyl amine (5:2) to achieve a 1:1 ratio. mixture of formic acid and triethyl amine (5:2) to achieve a 1:1 ratio.

SchemeScheme 50.50. ATHATH ofof iminesimines usingusing iridacycleiridacycle62 62as as catalyst.catalyst.

Gong,Gong, Meggers,Meggers, andand coworkerscoworkers earlierearlier developeddeveloped aa chiral-at-metalchiral-at-metal iridacycle,iridacycle, whichwhich theythey appliedapplied forfor thethe ATHATH ofof cycliccyclic sulfonyliminessulfonylimines usingusing ammoniumammonium formateformate asas aa reducingreducing agent (Scheme 51) [75]. The catalyst was highly active and could be used at 0.05–0.2 mol.% at 60 °C. Yields of the products were excellent and enantioselectivities were between 94% and 98%. The authors performed some mechanistic investigations and found that the first event is the formation of a complex between 81 and NH3. This complex is next converted to the hydride complex Ir(C-N)2(NH3)H. It was proposed that the ammonium group plays a major role in the positioning of the substrate resulting in very high enantioselectivities.

– PF6

tBu N N O O O O Me S 81 (0.05–0.2 mol%) S MeCN 1 1 Ir Me R N R NH MeCN HCO2NH4 (9 eq) N R2 DMF/H2O (2:1), 60 °C R2 N tBu 94–98% ee

81 Scheme 51. Chiral-only-at-metal iridacycle catalyzed enantioselective TH of sulfonylimines.

Xiao and coworkers screened 15 different chiral iridacycles based on 4,5-diaryl-substituted 2-phenyl-oxazolines and imidazolines in the enantioselective reductive amination of acetophenone with p-anisidine using the formic acid triethylamine azeotrope in isopropanol as reductant at ambient temperature [76]. From this screening, iridacycle 82 came out as the best one, inducing the highest enantioselectivity. This catalyst was then used in enantioselective direct reductive amination of aromatic ketones and anilines or benzyl amines (Scheme 52). As reductant, the azeotropic formic acid/triethylamine mixture in isopropanol was used. In cases where the yield was low, it was possible to improve this by using a sodium formate/formic acid buffer in water with 10 vol.% of 2-MeTHF as cosolvent, to increase solubility. However, this did not affect the enantioselectivity.

Molecules 2021, 26, x FOR PEER REVIEW 37 of 50

Scheme 50. ATH of imines using iridacycle 62 as catalyst. Molecules 2021, 26, 4076 34 of 45 Gong, Meggers, and coworkers earlier developed a chiral-at-metal iridacycle, which they applied for the ATH of cyclic sulfonylimines using ammonium formate as a reducing agent (Scheme 5151))[ [75].75]. The catalyst was highly active and could be used at 0.05–0.2 mol.% at 60 ◦°C.C. Yields of the products were excellentexcellent and enantioselectivities were between 94% and 98%. The authors performed some mechanistic investigations andand foundfound thatthat thethe ﬁrstfirst event is the formation ofof aa complexcomplex betweenbetween 8181 andand NHNH33.. ThisThis complexcomplex isis nextnext convertedconverted to the hydride complex Ir(C-N)Ir(C-N)22(NH33)H. It was was proposed proposed that the ammonium group playsplays a major role in the positioning ofof thethe substratesubstrate resultingresulting inin Veryvery highhigh enantioselectivities.enantioselectivities.

– PF6

tBu N N O O O O Me S 81 (0.05–0.2 mol%) S MeCN 1 1 Ir Me R N R NH MeCN HCO2NH4 (9 eq) N R2 DMF/H2O (2:1), 60 °C R2 N tBu 94–98% ee

81 Scheme 51. Chiral-only-at-metal iridacycle catalyzed enantioselective THTH ofof sulfonylimines.sulfonylimines.

Xiao and and coworkers coworkers screened screened 15 15 different different chiral chiral iridacycles iridacycles based based on 4,5-diaryl-sub- on 4,5-diaryl- substitutedstituted 2-phenyl-oxazolines 2-phenyl-oxazolines and andimidazolines imidazolines in the in enantioselective the enantioselective reductive reductive amination ami- nationof acetophenone of acetophenone with p-anisidine with p-anisidine using the using formic the acid formic triethylamine acid triethylamine azeotrope azeotrope in isopro- in isopropanolpanol as reductant as reductant at ambient at ambient temperature temperature [76]. From [76]. Fromthis screening, this screening, iridacycle iridacycle 82 came82 cameout as outthe asbest the one, best inducing one, inducing the highest the highest enantioselectivity. enantioselectivity. This catalyst This catalyst was then was used then in usedenantioselective in enantioselective direct reductive direct reductive amination amination of aromatic of aromatic ketones ketonesand anilines and anilines or benzyl or benzylamines amines (Scheme (Scheme 52). As 52 reductant,). As reductant, the azeotr the azeotropicopic formic formic acid/triethylamine acid/triethylamine mixture mixture in inisopropanol isopropanol was was used. used. In cases In cases where where the theyiel yieldd was was low, low, it was it was possible possible to improve to improve this Molecules 2021, 26, x FOR PEER REVIEW 38 of 50 thisby using by using a sodium a sodium formate/formic formate/formic acid buffer acid buffer in water in water with 10 with vol.% 10 Vol.%of 2-MeTHF of 2-MeTHF as cosol- as cosolvent,vent, to increase to increase solubility. solubility. However, however, this thisdid didnot notaffect affect the theenantioselectivity. enantioselectivity.

Scheme 52.52. Enantioselective reductive aminationamination catalyzedcatalyzed byby iridacycleiridacycle 8282..

3.6. Transfer HydrogenationHydrogenation ofof HeterocyclesHeterocycles Xiao andand coworkerscoworkers examinedexamined thethe transfertransfer hydrogenationhydrogenation ofof nitrogennitrogen heterocyclesheterocycles using three different catalysts: [Ir(COD)(NHC)(PPh )]BF , [Rh(Cp*)(Ts-DPEA)]OTf, and using three different catalysts: [Ir(COD)(NHC)(PPh33)]BF44, [Rh(Cp*)(Ts-DPEA)]OTf, and iridacycleiridacycle 51.. Whereas Whereas hardly hardly any any reactivity reactivity was was observed observed with with the the first ﬁrst two two catalysts, catalysts, the the iridacycle performed Very well, and quinolines (26 examples) could be reduced to the iridacycle performed very well, and quinolines (26 examples) could be reduced to the 1,2,3,4-tetrahydroquinolines in excellent yields using only 0.1 mol.% of 51 in an aqueous 1,2,3,4-tetrahydroquinolines in excellent yields using only 0.1 mol.% of 51 in an aqueous sodium formate/formic acid buffer at pH4.5 at 30 ◦C (Scheme 53). This method did not sodium formate/formic acid buffer at pH4.5 at 30 °C (Scheme 53). This method did not work on isoquinoline or on 2-phenylpyridine. Nevertheless, it was possible to reduce these work on isoquinoline or on 2-phenylpyridine. Nevertheless, it was possible to reduce classes of compounds after quaternization, although it was necessary, in this case, to per- these classes of compounds after quaternization, although it was necessary, in this case, form the reaction at reﬂux. In this way, six isoquinolinium compounds and 10 pyridinium to perform the reaction at reflux. In this way, six isoquinolinium compounds and 10 pyr- compounds were reduced. Interestingly, pyridinium salts carrying electron donating sub- idinium compounds were reduced. Interestingly, pyridinium salts carrying electron do- stituents in the 3- or 4-position were reduced to the 1,2,3,5-tetrahydropyridines, whereas nating substituents in the 3- or 4-position were reduced to the 1,2,3,5-tetrahydropyridines, those with electron withdrawing substituents were fully reduced to the piperidines. whereas those with electron withdrawing substituents were fully reduced to the piperidines.

MoleculesMolecules 20212021,, 2626,, 4076x FOR PEER REVIEW 3539 ofof 4550

0.1 mol% 51 Ir 1 2 Cl R1 R2 R R N OMe HCO2H/NaO2CH (pH 4.5) N N H2O, 30 °C, 14h H 82–96% 51 2 R2 R 1 R1 R N N R – R 0.1 mol% 51 X 90–99% HCO2H/NaO2CH (pH 4.5) H2O, reflux, 24-36h R1 R1 N X– N R R 80–94% 2 2 R 0.1 mol% 51 R R1 R1 N HCO2H/NaO2CH (pH 4.5) N H H2O, 30 °C, 16h H 33–96% H N N

N N 90% H

N 0.1 mol% 51 N H 82% HCO2H/NaO2CH (pH 4.5) H2O, 30 °C, 16h

N N N HN 96%

N N H 99% Scheme 53.53. Iridacycle-catalyzed THTH ofof nitrogennitrogen heterocycles.heterocycles.

This can can be be explained explained by by assuming assuming that, that, in the in thelatter latter case, case, the first the step ﬁrst is step a 1,4-reduc- is a 1,4- reduction,tion, whereas, whereas, in the in former the former case,case, it is ita 1,2-reduction. is a 1,2-reduction. Whereas Whereas unprotected unprotected indoles indoles are areproblematic problematic substrates substrates for forhomogeneous homogeneous hydr hydrogenation,ogenation, transfer transfer hydrogenation hydrogenation of inof ◦ indolesdoles proceeded proceeded effortlessly effortlessly using using 0.1 0.1mol.% mol.% of 51 of at51 30at ° 30C. TheC. Theauthors authors tested tested seven seven sub- substrates,strates, of which of which only only 2-phenyl-indole 2-phenyl-indole coul couldd not not be be reduced. reduced. Quinoxaline Quinoxaline was converted toto 1-formyl-1,2,3,4-tetrahydroquinoxaline.1-formyl-1,2,3,4-tetrahydroquinoxaline. Acridine Acridine was was reduced reduced to dibenzopiperidine.to dibenzopiperidine. 2,9- Dimethyl-1,10-phenanthroline2,9-Dimethyl-1,10-phenanthroline was was reduced reduced to the to 1,2,3,4-tetrahydro-product the 1,2,3,4-tetrahydro-product exclusively. exclu- 1sively.H-Cyclopenta[b]pyridine 1H-Cyclopenta[b]pyridine was selectively was selectively reduced reduced on the on cyclopentadiene the cyclopentadiene part to part yield to cyclopentanopyridine.yield cyclopentanopyridine. Hou and coworkers coworkers immobilized immobilized the the iridacycle iridacycle which which they they prepared prepared from from 4- 4-(benzo[d]oxazol-2-yl)phenol(benzo[d]oxazol-2-yl)phenol 83b83b onon mesoporous mesoporous silica silica (SBA-15 (SBA-15 and and on on silylated SBA-15) (Scheme(Scheme 54)54)[ [77].77]. The The resulting resulting catalyst catalyst 84a84a waswas used used for the for TH the of TH quinolines. of quinolines. If the formic If the formic acid/sodium formate buffer system that was developed by Xiao and coworkers acid/sodium formate◦ buffer system that was developed by Xiao and coworkers was used wasat 80 used °C, atisoquinoline 80 C, isoquinoline was reduced was reduced to the to1,2,3,4-tetrahydroquinoline, the 1,2,3,4-tetrahydroquinoline, which which was wasformylated formylated in excellent in excellent yield. yield. If formic If formic acid acid was wasused used in water in water or in or the in thepresence presence of a of so- a sodiumdium acetate/acetic acetate/acetic acid acid mixture, mixture, no no form formylationylation occurred. occurred. There There was was no difference inin performance between 84a and 84b. The authors compared the rate of the immobilized cata- performance between 84a and 84b. The authors compared the rate of the immobilized

MoleculesMolecules 20212021,, 2626,, 4076x FOR PEER REVIEW 3640 ofof 4550 Molecules 2021, 26, x FOR PEER REVIEW 40 of 50

lystcatalystcatalyst84a with 84a84a withwith that thatthat of 83a of, 83a which, which is an isis unfair anan unfairunfair comparison comparisoncomparison as Xiao as as Xiao Xiao and and coworkersand coworkers coworkers showed showed showed that thethatthat methoxy thethe methoxymethoxy substituent substituentsubstituent leads leads to faster toto fasterfaster reaction. reaction.reaction. The The The immobilized immobilized immobilized catalyst catalyst catalyst had had had a faster a afaster faster onset;onset;onset; however, however,however, in the in the end, end, both both catalysts catalysts needed neededneeded the same thethe samesame time time fortime complete for for complete complete conversion conversion conversion of the substrate.ofof thethe substrate.substrate. The immobilized The immobilized catalyst could catalystcatalyst be reused couldcould 12 bebe times reusedreused inthe 1212 reduction/formylation timestimes inin thethe reduc-reduc- reactiontion/formylationtion/formylation with only reactionreaction 20% loss with in yield onlyonly after20%20% lossloss the 12thinin yieldyield time. after after Nevertheless, the the 12th 12th time. time. the Nevertheless, Nevertheless, usefulness of the thethe immobilizationusefulnessusefulness ofof the remains immobilization questionable remains in View questionablequestionable of the increased inin view view cost of of the andthe increased increased the loss ofcost cost activity and and overthethe lossloss time ofof [ activity78activity]. over time [78].

SchemeScheme 54.54. ImmobilizationImmobilization of iridacycle catalysts catalysts 83a83a,,,bb.. .

XiaoXiao and andand coworkers coworkers tested tested 15 15 different different chiral chiralchiral iridacycles iridacyclesiridacycles based based based on on 4,5-diaryl-substitutedon 4,5-diaryl-substi- 4,5-diaryl-substi- 2-phenyl-oxazolinestutedtuted 2-phenyl-oxazolines2-phenyl-oxazolines and imidazolines and imidazolines in the in enantioselectivein thethe enantioselectiveenantioselective hydrogenation hydrogenation hydrogenation of N-benzyl of of N N- - 2-phenylpyridiniumbenzylbenzyl 2-phenylpyridinium2-phenylpyridinium bromide bromide using the usingusing azeotropic thethe azeotropicazeotropic mixture ofmixture mixture formic of acidof formic formic and triethylamineacid acid and and tri- tri- inethylamineethylamine isopropanol inin isopropanol as solvent at as room solvent temperature atat roomroom temperaturetemperature [76]. Best results[76].[76]. Best Best (55% results resultsee) were(55% (55% obtainedee ee) )were were ◦ withobtainedobtained iridacycle withwith iridacycle85. This could85. This be couldcould further bebe improved furtherfurther improvedimproved to 77% atto to −77% 77%10 at C.at − − Reduction1010 °C. °C. Reduction Reduction of two moreofof twotwo 2-substituted moremore 2-substituted2-substituted pyridines pyridines was reported waswas reportedreported (Scheme (Scheme(Scheme 55). 55). 55).

1 mol% 85 1 mol% 85 OO O 2 HCO2H/Et3N (5:2) 1 O NN RR2 HCO2H/Et3N (5:2) N * RR1 IrIr Cl Br–– iPrOH, –10 °C, 16h * Cl Ph Br iPrOH, –10 °C, 16h NN Ph PhPh Ph 85 N Ph 1 85 HN Ph R1 = Ph,Ph, 99%,99%, 77%ee77%ee H 1 R1 = PMP, 68%, 75%ee R1 = PMP, 68%, 75%ee R1 = CH2Ph, 75%, 10%ee R = CH2Ph, 75%, 10%ee SchemeScheme 55.55. AsymmetricAsymmetric transfer hydrogenation of of pyridinium pyridinium salts. salts. 3.7. Dehydrogenation of Heterocycles

Xiao and coworkers examined the acceptorless dehydrogenation of 1,2,3,4-tetrahydroquinolines using iridacycles 86a–f as catalyst (Scheme 56). From the first screen, complex 86d achieved the highest conversion. A solvent screen uncovered a strong solvent dependence. Of all the tested solvents, i.e., polar, nonpolar, and protic solvents, trifluoroethanol (TFE) emerged as the only solvent that resulted in Very good yields of the dehydrogenated products [79]. The authors were able to dehydrogenate a range of substituted 1,2,4-tetrahydroquinolines. The dehydrogenation is surprisingly selective for nitrogen compounds; a hydroxymethyl substituent survived the reaction unchanged. Tetrahydroisoquinolines could also be dehydrogenated in excellent yields, with the exception of the unsubstituted compound, which was converted to isoquinoline in only 30% yield. Indolines and 1,2,3,4-tetrahydroquinoxalines were also dehydrogenated to the indoles and quinoxalines, respectively, in good yields. Chen, Lu, and coworkers decided to immobilize the iridacycle catalyst. Thus, they synthesized pyrene-tagged iridacycle 86g (Scheme 56) by reacting the phenol group of the iridacycle with 1-pyrenylsulfonylchloride. This compound was immobilized on carbon nanotubes, and the immobilized catalyst was used for the dehydrogenation of indolines [80]. They had to use a mixture trifluoroethanol and water to assure the strong attachment between the pyrene and the carbon nanotubes. It was necessary to perform the reaction at 1 mol.% of catalyst, which is 10-fold more than the homogeneous catalysts from Xiao, which again shows the futility of an immobilization approach. In addition, the reaction

Molecules 2021, 26, x FOR PEER REVIEW 41 of 50

3.7. Dehydrogenation of Heterocycles Xiao and coworkers examined the acceptorless dehydrogenation of 1,2,3,4-tetrahydroquinolines using iridacycles 86a–f as catalyst (Scheme 56). From the first screen, complex 86d achieved the highest conversion. A solvent screen uncovered a strong solvent dependence. Of all the tested solvents, i.e., polar, nonpolar, and protic solvents, trifluoro-

Molecules 2021, 26, 4076 ethanol (TFE) emerged as the only solvent that resulted in very good yields of the37 dehy- of 45 drogenated products [79]. The authors were able to dehydrogenate a range of substituted 1,2,4-tetrahydroquinolines. The dehydrogenation is surprisingly selective for nitrogen compounds; a hydroxymethyl substituent survived the reaction unchanged. Tetrahydroi- temperaturesoquinolines hadcould to also be raised be dehydrogenated to 100 ◦C. The in catalyst excellent could yields, be reused with the a number exception of timesof the withunsubstituted some loss ofcompound, activity after which each was run. converted The catalyst to was isoquinoline compared within only the 30% homogeneous yield. In- analogue,dolines and albeit 1,2,3,4-tetrahydroquinoxalines at high temperature and high were catalyst also loading; dehydrogenated hence, not to surprisingly, the indoles both and catalystsquinoxalines, led to respectively, good yields. in This good comparison yields. needs to be done on rate rather than yield.

R2 Ir Cl N R1 R3

86a R1 = R2 = R3 = H 86b R1 = R2 = OMe, R3 = H 1 2 3 86c R = OMe, R = NO2, R = H 86d R1 = OMe, R2 = H, R3 = OMe 1 2 3 86e R = OMe, R = H, R = NO2 86f R1 = R2 = R3 = OMe 86g R1 = OMe, R2 = 1-Pyrenesulfonyloxy

R2 86d (0.1 mol%) R2 + H R1 R1 2 TFE, reflux N N H 20h, under N2 1 81–97% R = 2-,3- or 4-Me, 2-Ph or 2-CH2OH R2 = H, Me, OMe, F, Cl

R2 86d (0.1 mol%) R2 + H R1 R1 2 NH TFE, reflux N 2 R2 R 20h, under N2 R1 = 1 or 3-alkyl, R2 = H, OMe 82–96%, 30% for R1, R2 = H

R2 86d (0.1 mol%) 2 R1 R R1 + H TFE, reflux 2 N 20h, under N N H 2 H R1 = H, Me, di-methyl, Ph 90–98% R2 = H, OMe, Cl H N N 2 1 86d (0.1 mol%) + H R R R2 R1 2 N N H TFE, reflux 20h, under N 2 62-–93% R1 = H, Me, Phe R2 = Me SchemeScheme 56.56. Iridacycle-catalyzedIridacycle-catalyzed acceptorlessacceptorless dehydrogenationdehydrogenation ofof nitrogennitrogen heterocycles.heterocycles.

3.8. BorrowingChen, Lu, Hydrogen and coworkers Reactions decided to immobilize the iridacycle catalyst. Thus, they synthesizedSingh and pyrene-t coworkersagged reacted iridacycle a bidentate 86g (Scheme imino thio 56) (orby reacting seleno) ligand the phenol with [Ir(Cp*)Cl group of 2the]2 iniridacycle methanol with at room1-pyrenylsulfonylchloride. temperature and isolated This thecompound complexes wasIa immobilizedand Ib in good on carbon yields (Schemenanotubes, 57) and [81]. the If theimmobilized same reaction catalyst was was performed used for at the 50 dehydrogenation◦C in the presence of of indolines sodium acetate, the iridacycles 87a and 87b were obtained. All four complexes performed well in the TH of acetophenones and benzaldehydes. Next, the authors examined their application in the borrowing hydrogen alkylation of anilines with benzyl alcohol. In these reactions, the alcohol is first dehydrogenated to the aldehyde, which reacts with the aniline to form the imine, which is reduced with the hydrogen equivalents produced in the first dehydrogenation. The products were obtained in excellent yields. The iridacycles gave slightly lower yields than the complexes Ia and Ib. In addition, the sulfur-containing complexes performed slightly better than the selenium-containing complexes. Molecules 2021, 26, x FOR PEER REVIEW 42 of 50

[80]. They had to use a mixture trifluoroethanol and water to assure the strong attachment between the pyrene and the carbon nanotubes. It was necessary to perform the reaction at 1 mol.% of catalyst, which is 10-fold more than the homogeneous catalysts from Xiao, which again shows the futility of an immobilization approach. In addition, the reaction temperature had to be raised to 100 °C. The catalyst could be reused a number of times with some loss of activity after each run. The catalyst was compared with the homogeneous analogue, albeit at high temperature and high catalyst loading; hence, not surprisingly, both catalysts led to good yields. This comparison needs to be done on rate rather than yield.

3.8. Borrowing Hydrogen Reactions Singh and coworkers reacted a bidentate imino thio (or seleno) ligand with [Ir(Cp*)Cl2]2 in methanol at room temperature and isolated the complexes Ia and Ib in good yields (Scheme 57) [81]. If the same reaction was performed at 50 °C in the presence of sodium acetate, the iridacycles 87a and 87b were obtained. All four complexes performed well in the TH of acetophenones and benzaldehydes. Next, the authors examined their application in the borrowing hydrogen alkylation of anilines with benzyl alcohol. In these reactions, the alcohol is first dehydrogenated to the aldehyde, which reacts with the aniline to form the imine, which is reduced with the hydrogen equivalents produced in the first dehydrogenation. The products were obtained in excellent yields. The iridacycles Molecules 2021, 26, 4076 38 of 45 gave slightly lower yields than the complexes Ia and Ib. In addition, the sulfur-containing complexes performed slightly better than the selenium-containing complexes.

– PF6

Cl N Ir Ia E = S E MeOH Ib E = Se rt, 8h

NaOAc + [Ir(Cp*)Cl2]2 + NH PF MeOH, 50 °C 4 6 – N 8h PF6 E

E = S, Se Ir N E 87a R = S 87b R = Se

NH NH 0.3 mol% 87a or 87b OH 2 Toluene, 100 °C, 4h R1 + R2 R1 R2 77–93% R1 = H, Me, OMe, Br, Cl 2 R = H, Me, OMe, Br, Cl, F SchemeScheme 57.57.Iridacycle-catalyzed Iridacycle-catalyzed borrowingborrowing hydrogen hydrogen alkylation alkylation of of anilines anilines with with benzyl benzyl alcohols. alcohols.

ZhaoZhao andand coworkerscoworkers examinedexamined thethe enantioselective enantioselective synthesissynthesis ofof 2-aryl-substituted 2-aryl-substituted 1,2,3,4-tetrahydroquinolines1,2,3,4-tetrahydroquinolines via Via a a borrowing borrowing hydrogen hydrogen reaction reaction from from racemic racemic 1-aryl-sub- 1-aryl- substitutedstituted 4-(2-aminophenyl)propanols 4-(2-aminophenyl)propanols [82]. [82 In]. this In this reaction, reaction, the thealcohol alcohol is first is ﬁrst dehydrogen- dehydro- Molecules 2021, 26, x FOR PEER REVIEW 43 of 50 genatedated to the to theketone, ketone, which which reacts reacts with withthe anil theine aniline to form to formthe 3,4-didhydroquinoline, the 3,4-didhydroquinoline, which whichis enantioselectively is enantioselectively reduced reduced to the totetrahyd the tetrahydroquinolineroquinoline (Scheme (Scheme 58). They 58). Theytested tested a range a range of nine chiral and nonchiral iridium catalysts in combination with a chiral BINOL- orof nine SPINOL-based chiral and nonchiral phosphoric iridium acid. catalysts highest in combination enantioselectivities with a chiral were BINOL- obtained or SPI- with a com- binationNOL-based of phosphoric iridacycle acid.37a Highestand phosphoric enantioselectivities acid A1 were. A range obtained of with aryl-substituted a combina- starting materialstion of iridacycle were converted37a and phosphoric in Very goodacid A1 yield. A range andexcellent of aryl-substitutedees. Only starting the 2-furyl mate- compound rials were converted in very good yield and excellent ees. Only the 2-furyl compound was was isolated in somewhat lower yield (73%) and had lower ee (56%). The cyclohexyl isolated in somewhat lower yield (73%) and had lower ee (56%). The cyclohexyl com- ee compoundpound was also was obtained also obtained in 95% yield in 95% and yield 80% ee and. 80% .

OH O DMC, Sieves 4Å, 80 °C, 18h Ar Ar

NH2 NH2

Ir Ir H NH NH2 Ph 37aPh 5 mol% Ph Ph 38a

N Ar R1 N Ar H O O 73–98% 1 mol% 56–94%ee P O OH

R1 A1 1 R = 2,4,6-Cy3C6H2 Scheme 58. 58. EnantioselectiveEnantioselective synthesis synthesis of 2-aryl-susbtit of 2-aryl-susbtituteduted tetrahydroquinolines tetrahydroquinolines via a borrowing Via a borrowing hy- hydrogen reaction. drogen reaction. Zhang, Xia, and coworkers also used the borrowing hydrogen technology in combination with Ikariya iridacycle 36 for the diastereoselective conversion of racemic alcohols to amines [83]. Reaction of the racemic alcohol with t-butanesulfinamide, catalyzed by iridacycle 36 activated by 20 mol.% KOH resulted in the formation of the t-butylsulfinyl- amines with diastereoselectivites that were mostly better than 17:1 and, in many cases, better than 19:1 (Scheme 59). The sulfinyl protecting group was easily removed by acidic hydrolysis in 90% yield.

Molecules 2021, 26, x FOR PEER REVIEW 43 of 50

of nine chiral and nonchiral iridium catalysts in combination with a chiral BINOL- or SPI- NOL-based phosphoric acid. Highest enantioselectivities were obtained with a combination of iridacycle 37a and phosphoric acid A1. A range of aryl-substituted starting mate- rials were converted in very good yield and excellent ees. Only the 2-furyl compound was isolated in somewhat lower yield (73%) and had lower ee (56%). The cyclohexyl compound was also obtained in 95% yield and 80% ee.

OH O DMC, Sieves 4Å, 80 °C, 18h Ar Ar

NH2 NH2

Ir Ir H NH NH2 Ph 37aPh 5 mol% Ph Ph 38a

N Ar R1 N Ar H O O 73–98% 1 mol% 56–94%ee P O OH

R1 A1 R1 = 2,4,6-Cy C H Molecules 2021, 26, 4076 3 6 2 39 of 45 Scheme 58. Enantioselective synthesis of 2-aryl-susbtituted tetrahydroquinolines via a borrowing hydrogen reaction.

Zhang, Xia, and coworkers alsoalso usedused thethe borrowingborrowing hydrogenhydrogen technologytechnology inin combina-combi- tionnation with with Ikariya Ikariya iridacycle iridacycle36 36for for the the diastereoselective diastereoselective conversion conversion of of racemic racemic alcohols alcohols to aminesto amines [83 ].[83]. Reaction Reaction of theof the racemic racemic alcohol alcohol with witht-butanesulfinamide, t-butanesulfinamide, catalyzed catalyzed by irida- by cycleiridacycle36 activated 36 activated by 20 by mol.% 20 mol.% KOH KOH resulted resulted in the in formation the formation of the oft -butylsulfinylaminesthe t-butylsulfinyl- withamines diastereoselectivites with diastereoselectivite that weres that mostly were better mostly than better 17:1 than and, 17:1 in many and, cases,in many better cases, than 19:1better (Scheme than 19:1 59 ).(Scheme The sulfinyl 59). The protecting sulfinyl group protecting was easilygroup removed was easily by removed acidic hydrolysis by acidic in 90%hydrolysis yield. in 90% yield.

Ir Cl NH2 (5 mol%) O S OH O Ph HN tBu NH + 36 Ph HCl in dioxane 2 S R R2 H2N tBu KOH (20 mol%) R1 R2 MeOH, rt, 0.5h R1 R2 1 toluene, reflux, 24h R1 = aryl, pyridin-3-yl, 50–94% 4-phenyl-butan-2yl dr> 17:3 in most cases 2 R = Me, Et Molecules 2021, 26, x FOR PEER REVIEWScheme 59. Diastereoselective synthesis of primary amines using iridacycle-catalyzed borrowing44 of 50 Scheme 59. Diastereoselective synthesis of primary amines using iridacycle-catalyzed borrowing hydrogenhydrogen chemistry. chemistry.

3.9. Racemization of Alcohols and Amines 3.9. Racemization of Alcohols and Amines Feringa, de Vries, and coworkers synthesized three benzylamine-based iridacycles Feringa, de Vries, and coworkers synthesized three benzylamine-based iridacycles 88a–c, which differed in the substitution on the amino group [31,45]. They were tested 88a–c, which differed in the substitution on the amino group [31,45]. They were tested in in the racemization of enantiopure 1-phenylethanol, as well as enantiopure 1-phenyl-2- the racemization of enantiopure 1-phenylethanol, as well as enantiopure 1-phenyl-2-chlo- chloroethanol, at room temperature (Scheme 60). With both substrates, the catalyst based on theroethanol, secondary at room amine temperature88b performed (Scheme much 60). better With than both the substrates, other two catalyststhe catalyst (Scheme based 60 on). Untilthe secondary today, this amine is one 88b of performed the fastest racemizationmuch better than catalysts the other known. two catalysts (Scheme 60). Until today, this is one of the fastest racemization catalysts known.

Scheme 60. Use of iridacycles 88a–c as alcohol racemization catalysts for 1-phenylethanol (a) and Scheme 60. Use of iridacycles 88a–c as alcohol racemization catalysts for 1-phenylethanol (a) and 1,phenyl-2-chloro-ethanol ((bb)) atat roomroom temperaturetemperature (graphs(graphs copiedcopied fromfrom [[31].31]. Iridacycle 88b is also active in the presence of water, which allowed its use as racem- Iridacycle 88b is also active in the presence of water, which allowed its use as race- ization catalyst in the dynamic kinetic resolution (DKR) of racemic halohydrins [46]. The mization catalyst in the dynamic kinetic resolution (DKR) of racemic halohydrins [46]. The enzyme haloalcohol dehalogenase catalyzes the interconversion of halohydrins and epox- enzyme haloalcohol dehalogenase catalyzes the interconversion of halohydrins and epoxides. The enzyme selectively converts the R-enantiomer to the analogous epoxide. In ides. The enzyme selectively converts the R-enantiomer to the analogous epoxide. In the the presence of an alcohol racemization catalyst, it should be possible to racemize the remainingpresence ofS an-enantiomer, alcohol racemization allowing full catalyst, conversion it should of the be racemate possible toto theracemize enantiopure the remain- epox- ing S-enantiomer, allowing full conversion of the racemate to the enantiopure epoxide. Unfortunately, the enzyme and catalyst 88b were mutually incompatible. Both were deactivated in each other’s presence, even in a two-phase aqueous/organic system. This problem could be solved by adding serum albumin, a protein that preferentially resides at the aqueous organic interphase and, in this way, creates a barrier between the two catalysts. In addition, the solution of 88b was slowly added over time to mitigate its decomposition. In this way, it was possible to convert 1-phenyl-2-chloroethanol to (R)- styrene oxide in 90% yield and 98% ee (Scheme 61) [46].

Molecules 2021, 26, 4076 40 of 45

ide. Unfortunately, the enzyme and catalyst 88b were mutually incompatible. Both were deactivated in each other’s presence, even in a two-phase aqueous/organic system. This problem could be solved by adding serum albumin, a protein that preferentially resides at the aqueous organic interphase and, in this way, creates a barrier between the two catalysts. In addition, the solution of 88b was slowly added over time to mitigate Molecules 2021, 26, x FOR PEER REVIEW 45 of 50 its decomposition. In this way, it was possible to convert 1-phenyl-2-chloroethanol to (R)-styrene oxide in 90% yield and 98% ee (Scheme 61)[46].

SchemeScheme 61. 61. DynamicDynamic kinetic kinetic resolution resolution of of halohydrins halohydrins using using iridacycle iridacycle 88b88b asas racemization racemization catalyst. catalyst.

CatalystCatalyst 88b88b waswas further further tested tested on on a a range range of of other other aromatic aromatic and and aliphatic aliphatic alcohols. alcohols. With allall methylmethyl alcohols, alcohols, small small amounts amounts of theof the ketones ketones were were formed formed as side-product, as side-product, which whichis an indication is an indication of the of fact the that fact the that ketone the ke reductiontone reduction is the rate-determiningis the rate-determining step in step these in theseracemizations. racemizations. TheyThey also also investigated investigated the the use use of of these these ir iridacyclesidacycles for the racemization of secondary amineamine [45]. [45]. Catalysts Catalysts 88a88a–c– cwerewere efficient efﬁcient in in the the racemization racemization of of ( S)-)-α-methyl--methyl-NN-- methylbenzylamine, since complete racemization was observed within 8 h in chloroben- methylbenzylamine, since complete racemization◦ was observed within 8 h in chloroben- zenezene and withinwithin 1616 hh in in toluene toluene at at 100 100C °C when when using using 2 mol.% 2 mol.% of catalyst. of catalyst. however, However, the most the mostactive active catalyst catalyst88b possessing 88b possessing a secondary a secondary amine amine as the as ligand the ligand seemed seemed to be deactivatedto be deac- tivatedunder theunder reaction the reaction conditions. conditions. It was foundIt was thatfound this that was this due was to due dehydrogenation to dehydrogenation of the ligand to the imine. Consequently, the authors designed three new iridacycles 89–91 for of the ligand to the imine. Consequently, the authors designed three new iridacycles 89– use as amine racemization catalyst. Catalyst 89 could possibly still be oxidized and, hence, 91 for use as amine racemization catalyst. Catalyst 89 could possibly still be oxidized and, catalyst 90 was also synthesized to establish if this catalyst is still active. Catalyst 91 was hence, catalyst 90 was also synthesized to establish if this catalyst is still active. Catalyst synthesized to establish the importance of the presence of the NH group. Catalyst 89 was 91 was synthesized to establish the importance of the presence of the NH group. Catalyst capable of racemizing the secondary amine completely in 40 min; within 5 min, the ee 89 was capable of racemizing the secondary amine completely in 40 min; within 5 min, was already reduced to 50%. For catalyst 90, these Values were 3 h and 20 min. Catalyst the ee was already reduced to 50%. For catalyst 90, these values were 3 h and 20 min. 91 was still capable of racemizing the secondary amine, but needed 16 h to reach 26% ee, Catalyst 91 was still capable of racemizing the secondary amine, but needed 16 h to reach establishing the importance of the NH functionality (Scheme 62). Use of chlorobenzene 26% ee, establishing the importance of the NH functionality (Scheme 62). Use of chloro- as solvent increased the rate of the racemization, and catalyst 89 was capable of racemiz- benzene as solvent increased the rate of the racemization, and catalyst 89 was capable of ing the secondary amine at 60 ◦C, reaching 50% ee in 1.5 h and full racemization in 16 h. racemizing the secondary amine at 60 °C, reaching 50% ee in 1.5 h and full racemization This would allow the application in enzymatic DKR reactions. Catalyst 89 was used for inthe 16 racemization h. This would of aallow series the of application chiral amines; in enzymatic however, in DKR the attemptedreactions. Catalyst racemization 89 was of usedprimary for the amines, racemization dimers were of a formed.series of chiral amines; however, in the attempted racemization of primary amines, dimers were formed.

Molecules 2021, 26, 4076 41 of 45 Molecules 2021, 26, x FOR PEER REVIEW 46 of 50

Molecules 2021, 26, x FOR PEER REVIEW 46 of 50

NHMe NHMe Catalyst NHMe NHMe Catalyst Toluene 100 °C Toluene 100( S°C) rac (S) rac – – PF – PF6 PF6 6 – – PF – PF6 PF6 6 Ir NCH2Me Ir NCMe Ir NCMe N N N Ir NCH2Me Ir NCMe Ir NCMe N N N N N O H H 89 90 91 N N O H H 890%ee after 40 90 min 0%ee after 91 3h 26%ee after 16h 0%ee after 40 minScheme 0%ee 62. Iridacycle after 3h catalysts forfor26%ee thethe racemizationracemization after 16h ofof secondarysecondary amines.amines. Scheme 62. Iridacycle catalysts for the racemization of secondary amines. Kroutil developed a a novel novel concept concept for for a dyna a dynamicmic kinetic kinetic resolution resolution [84]. [84 The]. Thegoal goal was Kroutil developedwasto deracemize to a deracemize novel concept racemic racemic for chlorohydrins a dyna chlorohydrinsmic kinetic by oxidizing by resolution oxidizing them [84]. them in Thean in Oppenauer goal an Oppenauer was oxidation oxidation cata- to deracemize racemiccatalysedlysed chlorohydrinsby iridacycle by iridacycle 88b by oxidizingto88b theto chloroketones the them chloroketones in an Oppenauerand, and,at the at sameoxidation the sametime, cata- time,use an use alcohol an alcohol dehy- lysed by iridacycledehydrogenasedrogenase 88b to the enzyme chloroketones enzyme (ADH (ADH from and, fromRodococcus at theRodococcus same Ruber time, Ruber) for use the) foran enantioselective alcohol the enantioselective dehy- reduction reduction of the drogenase enzymeofchloroketone (ADH the chloroketone from toRodococcus obtain to obtain the Ruber enantiopure the) for enantiopure the enantioselective chlorohydrin. chlorohydrin. Thereduction Thecombination combination of the of an of oxidation an oxida- chloroketone to obtaintionand a and reductionthe a enantiopure reduction in a single in chlo a single reactionrohydrin. reaction is, Theof is,course, combination of course, highly highly ambitiousof an ambitiousoxidation and, in and, practice, in practice, many and a reduction inmanyhurdles a single hurdles had reaction to hadbe overcome. is, to beof course, overcome. It was highly necessary It was ambitious necessary for thermodynamicand, for in thermodynamic practice, reasonsmany reasons to use a to chloro- use a hurdles had to bechloroketoneketone overcome. as oxidant It aswas oxidant as,necessary with as, simple with for thermodynamic simple aliphatic aliphatic ketones, reasons ketones, the equilibriu to the use equilibrium a chloro-m was too was much too on much the ketone as oxidantonside as, the withof side the simple ofchlorohydrin. the aliphatic chlorohydrin. Theketones, initially The the initially chosenequilibriu chosen chloroacetonem chloroacetonewas too much was was anon excellentthe an excellent oxidant oxidant for for the iridacycle-catalyzed oxidation; however, unfortunately, it was also rapidly reduced side of the chlorohydrin.the iridacycle-catalyzed The initially chosen oxidation; chloroacetone however, was unfortunately, an excellent oxidantit was also for rapidly reduced by the enzyme. In the end, the sterically hindered 2-chloro-6,6-dimethylcyclohexanone, the iridacycle-catalyzedby the enzyme.oxidation; In however, the end, theunfortunately, sterically hindered it was also 2-chloro-6,6-dimethylcyclohexanone, rapidly reduced which is not a substrate for the enzyme, had to be used as oxidant. Next, the reductant by the enzyme. Inwhich the end, is not the a substratesterically for hindered the enzyme, 2-chloro-6,6-dimethylcyclohexanone, had to be used as oxidant. Next, the reductant for for the enzyme had to be chosen such that it could not reduce the iridacycle catalyst. which is not a substratethe enzyme for the had enzyme, to be chosen had to suchbe used that as it oxidant.could not Next, reduce the the reductant iridacycle for catalyst. Luckily, Luckily, this iridacycle could not be reduced by formic acid and, thus, the ADH was the enzyme had tothis be iridacyclechosen such could that not it co beuld reduced not reduce by formic the iridacycle acid and, catalyst. thus, the Luckily, ADH was coupled with coupled with a formate dehydrogenase (FDH). Although the enzyme on its own was this iridacycle coulda formate not be dehydrogenasereduced by formic (FDH). acid Althoughand, thus, ththee enzymeADH was on coupled its own waswith capable of reduc- capable of reducing the substrates with 99% ee, this was unfortunately not achieved in a formate dehydrogenaseing the substrates (FDH). Although with 99% th eee, enzymethis was on unfortunately its own was not capable achieved of reduc- in the coupled system the coupled system (Scheme 63). Three different substrates were subjected to the coupled ing the substrates(Scheme with 99% 63). ee, Three this was different unfortunately substrates not were achieved subjected in the to coupled the coupled system reactions: 1-phenyl- reactions:2-chloro-ethanol 1-phenyl-2-chloro-ethanol (40% ee), 3-benzyloxy-1-chloracetone (40% ee), 3-benzyloxy-1-chloracetone (6% ee), and 1-cyclohexyl-2-chloro- (6% ee), and (Scheme 63). Three different substrates were subjectedee to the coupledee reactions: 1-phenyl- 1-cyclohexyl-2-chloro-ethanolethanol (29% ee). The lower ee (29%was ascribed). The lowerto the racemizingwas ascribed action to the of the racemizing iridacycle. action 2-chloro-ethanol of(40% the ee iridacycle.), 3-benzyloxy-1-chloracetone (6% ee), and 1-cyclohexyl-2-chloro- ethanol (29% ee). The lower ee 88bwas (2 ascribed or 5 mol%) to the racemizing action of the iridacycle. buffer pH7/toluene (7:3) ADH-A PF – 88b (2 orOH 5 mol%) 30 °C O OH 6 buffer pH7/toluene (7:3) Cl ADH-A Cl Cl PF – OH R30 °C O R OH R 6 Ir NCMe Cl Cl Cl R O R OH R NADH NAD+ NHMe Cl Cl Ir NCMe O OH NADH NAD+ NHMe CO – 88b Cl Cl 2 HCO2 FDH CO – 88b 2 HCO2 FDH Scheme 63. Deracemization of racemic chlorohydrines using combined iridacycle-catalyzed oxida- Scheme 63. Deracemization of racemic chlorohydrines using combined iridacycle-catalyzed oxidation and enzyme- Scheme 63. Deracemizationtion and enzyme-catalyzedof racemic chlorohydrines reduction. using combined iridacycle-catalyzed oxida- catalyzedtion reduction. and enzyme-catalyzed reduction. 4. Conclusions 4. Conclusions 4. ConclusionsRuthenacycles and iridacycles have been used for a large range of TH reactions. They Ruthenacyclesform andRuthenacycles an iridacycles interesting have andclass been iridacycles that used is characterized for have a large been range usedby the of for extremelyTH a large reactions. range easy Theyof synthesis TH reactions. of the Theycata- form an interestingformlyst class and an that interesting a surprisingly is characterized class thathigh isby stability. characterized the extremely This allows by easy the extremelysynthesisfor very highof easy the synthesisturnover cata- ofnumbers the catalyst and lyst and a surprisinglyandturnover a surprisingly high frequencies. stability. high ThisThe stability. catalystsallows This for areallows very made high for via Very turnovercyclometalation high turnovernumbers of numbers andcommercially and turnover availa- turnover frequencies.frequencies.ble catalyst The catalysts precursors The catalysts are made in a are single, via made cyclometalation usually Via cyclometalation high-yielding of commercially of step. commercially They availa- have available been applied catalyst for ble catalyst precursorsprecursorsTH of in ketones, a single, in a imines, single, usually and usually high-yielding nitrogen high-yielding heterocycles, step. They step. haveas Theywell been as have forapplied enantioselective been for applied for variants TH of TH of ketones, imines,ketones,thereof. and They imines, nitrogen have and alsoheterocycles, nitrogen been heterocycles,used as for well the as oxidation asfor well enantioselective as of for alcohols, enantioselective variants as Oppenauer Variants oxidation thereof. thereof. They haveThey also have been also used been for used the oxidation for the oxidation of alcohols, of alcohols, as Oppenauer as Oppenauer oxidation oxidation catalyst, in

Molecules 2021, 26, 4076 42 of 45

combination with oxygen, and simply as dehydrogenation catalyst. In particular, this latter reaction has been used for the dehydrogenation of tetrahydro-quinolines and -isoquinolines, as well as indoles. Not surprisingly, they have also been used as racemization catalysts for alcohols and secondary and tertiary amines. This also allowed their use in dynamic kinetic resolutions in combination with lipases or haloalcohol dehalogenase enzymes. It is clear that many more applications of these catalysts can be expected in the near future, in particular of the chiral Variants.

Author Contributions: Writing—original draft preparation, review, and editing, V.R. and J.G.d.V. Both authors read and agreed to the published Version of the manuscript. Funding: This research received no external funding. Acknowledgments: Both authors thank Michel Pfeffer for many years of Very pleasant collaboration, as well as support. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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