Asymmetric Hydrogenation of Heteroarenes with Multiple … · 2020. 8. 28. · 2).11 The enantioselective hydrogenation of fluorinated aromatic pyrazol-5-ols 7 was carried out using

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Z.-P. Chen, Y.-G. Zhou Short ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 X© Georg Thieme Verlag Stuttgart · New York2016, 48, 1769–1781short review

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Asymmetric Hydrogenation of Heteroarenes with Multiple HeteroatomsZhang-Pei Chen Yong-Gui Zhou*

State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. of [email protected]

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Received: 30.01.2016Accepted after revision: 18.03.2016Published online: 20.04.2016DOI: 10.1055/s-0035-1561622; Art ID: ss-2016-h0076-sr

Abstract Enantiopure heterocyclic architectures containing two ormore heteroatoms in the ring system have attracted considerable at-traction due to this motif playing a role of great importance in asym-metric synthesis and the pharmaceutical chemistry. This review focusedon recent advances in the homogeneous asymmetric hydrogenation ofheteroarenes with multiple heteroatoms, which provide an efficientand practical method to structural diverse chiral heterocyclic com-pounds.1 Introduction2 Asymmetric Hydrogenation of Five-Membered-Ring Hetero-

arenes2.1 Imidazoles and Oxazoles2.2 Pyrazole Derivatives2.3 Benzisoxazoles3 Asymmetric Hydrogenation of Six-Membered-Ring Heteroarenes3.1 Quinoxalines3.2 Quinazolines3.3 Pyrimidines3.4 Pyrazines4 Asymmetric Hydrogenation of Fused Nitrogen Heteroarenes4.1 Heteroarenes Containing a Ring-Junction Nitrogen4.2 Heteroarenes Containing a Fused Pyridine Ring5 Conclusions and Outlook

Key words hydrogenation, enantioselectivity, heteroarenes, hetero-cycles, asymmetric catalysis

1 Introduction

Heterocyclic architectures containing N, O, or other het-eroatoms in the cyclic rings are omnipresent in many bioac-tive natural products, synthetic drugs, and materials sci-ence.1 Particularly, enantiopure heterocyclic compoundshave a wide range of applications and resonate across nu-

merous disciplines.2 Accordingly, the preponderance of chi-ral heterocyclic compounds has expedited the explorationof efficient and environmentally benign synthetic methodsfor their preparation. Among the methods for their prepara-tion, asymmetric hydrogenation reactions are the most at-tractive methodologies and the need for the developmentof practical, highly efficient, and enantioselective hydroge-nation protocols for heteroaromatic substrates is evident.3

Zhang-Pei Chen (left) was born in Hubei Province, China, in 1988. Af-ter receiving his B.S. degree from Northeast Forestry University in 2011, he joined the Zhou research group at Dalian Institute of Chemical Phys-ics, Chinese Academy of Sciences. He is currently working on his Ph.D. dissertation and his research interests are mainly focused on the asym-metric hydrogenation of heteroaromatic compounds and the develop-ment of new catalytic asymmetric reactions.Yong-Gui Zhou (right) was born in Hubei Province, China, in 1970. Af-ter completing his Ph.D. degree at the Shanghai Institute of Organic Chemistry in 1999, under the supervision of Profs. Li-Xin Dai and Xue-Long Hou, he joined Xumu Zhang’s group at Pennsylvania State Univer-sity as a postdoctoral fellow that same year. In 2002 he began his inde-pendent research career at the Dalian Institute of Chemical Physics, Chinese Academy of Sciences, where currently he is a professor of or-ganic chemistry. His research interests include the development of cat-alytic asymmetric reactions, mechanistic elucidation, and asymmetric synthesis.

© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1769–1781

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Compared with the elaborate exploitation of the catalyt-ic asymmetric hydrogenation of olefins, ketones, andimines, the asymmetric hydrogenation of heteroarenes re-mains much less explored.4 Several difficulties in this areaare as follows: (i) the inherent stability resulting from aro-maticity and the corresponding harsh conditions needed todestroy this stability which adversely affects the enantiose-lectivity and chemoselectivity; (ii) strong coordination ef-fects of the heteroatoms can poison or deactivate the chiralcatalysts; (iii) both lack of a secondary coordinating groupand the strong coordination effects of the heteroatoms canresult in lack of stereoselective control; (iv) in addition, thefacile cleavage of bonds between heteroatoms makes che-moselectivity difficult to control. In general, the low activi-ty and poor stereoselectivity and chemoselectivity consti-tute the major stumbling blocks for the asymmetric hydro-genation of heteroarenes.

Despite these difficulties, synthetic chemists continueto make progress in this field5 and various strategies forovercoming these problems have been developed, includingcatalyst activation, substrate activation, and relay catalysis(Figure 1).

Figure 1 Strategies for asymmetric hydrogenation of heteroarenes

Catalyst activation includes the tuning of electronic andsteric effects of ligands, the exploration of efficient transi-tion-metal precursors, and the examination of additive ef-fects. Since there is no ‘universal’ ligand that can be appliedin every reaction, the development of efficient ligands is ofgreat significance and highly desirable.6 To date, manystructurally diverse and electronically variant phosphine-containing and phosphine-free ligands have been designedand applied to the chemistry of this field. In addition, dif-ferent types of transition-metal precursors have been ex-plored, such as transition-metal complexes of Ru, Rh, Ir, orPd. Furthermore, after the initial finding that iodine can fa-cilitate the iridium-catalyzed asymmetric hydrogenation ofquinolines,7 the addition of halogen additives has gained inpopularity and it has become a widely used activation strat-egy for the hydrogenation of heteroarenes. All in all, the

core target of the catalyst activation strategy is to search forefficient catalytic systems for different types of heteroaro-matics.

Substrate activation generally utilizes the partial de-struction of the aromaticity of heteroarenes with the assis-tance of various activators that interacted with certain sub-strates. In summary, the following three methods are fre-quently utilized to effectuate the activation of differentkinds of heteroarenes.8 The first method is performed bydecreasing aromaticity through the formation of a positive-ly charged derivative of the aromatic heterocycle, such asthe formation of salts with Brønsted acids. The second ap-proach is to introduce a tethering auxiliary group to assistits coordination to the metal center and facilitate hydroge-nation, such as the attachment of acyl motifs to the corre-sponding aromatic compounds. The last technique isachieved by partially breaking the aromaticity of heteroaro-matic compounds with the aid of additives, and this is fol-lowed by asymmetric hydrogenation.

Currently, the hydrogenation or reduction of het-eroarenes inevitability results in the sequential reductionof carbon–heteroatom or carbon–carbon double bonds, andthus an elegant strategy was established that has changedthis field. This strategy is known as relay catalysis, which iscomposed of two hydrogenation catalysis procedures: cata-lyst I hydrogenates the aromatic substrates to afford partialhydrogenation intermediates, and chiral catalyst II enantio-selectively reduces the corresponding intermediates to fur-nish chiral products.

Thanks to the indefatigable efforts of chemists, someimportant advances in the homogeneous asymmetric hy-drogenation of heteroaromatic compounds have beenachieved by employing both chiral organometallic catalystsand organocatalysts, and a few of excellent reviews on thistopic have already been published. However, to the best ofour knowledge, none of these reviews provided a compre-hensive and timely overview of the asymmetric hydrogena-tion of more complicated heteroarenes with multiple het-eroatoms. Considering the extensive utility of such scaf-folds for the construction of building blocks in medicinaland synthetic chemistry, and combining this with high-lighting the efforts that promote the development of asym-metric hydrogenation reactions, this short review summa-rizes progress in this field. Other related works on theasymmetric hydrogenation of heteroaromatics are not in-cluded.

2 Asymmetric Hydrogenation of Five-Mem-bered-Ring Heteroarenes

The asymmetric hydrogenation of 1,3- and 1,2-azoleshas attracted a lot of attention in recent years. These com-pounds each contain one heteroatom in an environmentanalogous to that of the nitrogen in pyridine, an imine ni-


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trogen, and another heteroatom like the nitrogen in pyrrole,a secondary amine nitrogen, or like the oxygen in furan.Consequently, asymmetric hydrogenation of these com-pounds is inescapably confronted with strong coordinationeffects and the facile cleavage of the heteroatom–heteroat-om bond or carbon–heteroatom bond.

2.1 Imidazoles and Oxazoles

In line with the catalyst activation strategy, Kuwano andco-workers disclosed the first successful catalytic asymmet-ric hydrogenation of imidazole with a trans-chelating bis-phosphine Ru–PhTRAP complex as the catalyst (Scheme 1).9In the presence of a catalytic amount of basic additive tri-ethylamine to improve the reactivity, a series of 2-phenyl-4-alkyl-substituted N-Boc-imidazoles 1 were hydrogenatedto the corresponding imidazolines with excellent enanti-oselectivities and yields. However, replacing the phenylsubstituent at C2-position with ethyl or utilizing 2,4-dia-rylimidazoles as substrates resulted in a dramatic fall in thereaction activity and enantioselectivity.

Scheme 1 Asymmetric hydrogenation of imidazoles and oxazoles

Oxazoles represent another type of 1,3-azole, and theywere also hydrogenated by the effective Ru-PhTRAP com-plex catalytic system, affording oxazolines with high to ex-cellent ee. Both 2,4- and 2,5-disubstituted oxazoles werehydrogenated smoothly. For 4-substituted 2-phenyloxaz-oles 3, the basic additive was changed to N,N,N′,N′-te-tramethylguanidine (TMG) to accelerate the selective hy-drogenation. In contrast, such additive was unnecessary for5-substituted 2-phenyloxazoles 5 and toluene was found tobe the best solvent in terms of enantioselectivity. In addi-tion, the hydrogenolysis or acid-facilitated hydrolysis of theobtained chiral imidazolines and oxazolines could providevaluable acyclic chiral 1,2-diamine and β-amino alcohols,respectively, without loss of enantiopurity.

2.2 Pyrazole Derivatives

The asymmetric hydrogenation of pyrazole derivativesis undoubtedly a straightforward method for the synthesisof chiral five-membered heterocyclics with two contiguousnitrogen atoms that play a role of great importance inasymmetric synthesis and the pharmaceutical chemistry.10

Unfortunately, this area of research, the direct asymmetrichydrogenation of pyrazole derivatives, has, for a long time,been in a developmental phase due to the electronically en-riched nature and multitudinous reaction possibilities forthese compounds. In 2015, Zhou and co-workers reportedthe first asymmetric hydrogenation of fluorinated pyrazol-5-ols by capturing one of the active tautomers with anequivalent amount of Brønsted acid as an activator (Scheme2).11 The enantioselective hydrogenation of fluorinatedaromatic pyrazol-5-ols 7 was carried out usingPd(OCOCF3)2/L2/TFA in dichloromethane to provide a widevariety of 2,5-disubstituted pyrazolidinones 8 in high yieldsand enantioselectivities. The electronic properties of thesubstituents on phenyl ring had little effect on the activityand enantioselectivity, but the hydrogenation of a stericallyhindered 2-o-tolyl-substituted pyrazol-5-ol had only mod-erate 82% enantioselectivity and low reactivity even with ahigher catalyst loading.

Scheme 2 Asymmetric hydrogenation of fluorinated pyrazol-5-ols

When the TangPhos L3 was employed as the ligand andsimultaneously elevating the temperature, a range of pyra-zol-5-ol substrates bearing a 4-alkyl substituent could behydrogenated smoothly with excellent enantioselectivitiesand diastereoselectivities. Moreover, pentafluoroethyl-sub-stituted pyrazol-5-ols are also suitable substrates providingthe corresponding pyrazolidinones with up to 95% ee.

In principle, pyrazol-5-ol compounds exist in three tau-tomeric forms, i.e. the OH-, NH- and CH-forms (Scheme 3).To verify the hypothesis that this hydrogenation was car-ried out by capture of the active tautomer, the hydrogena-tion of three substrates, form A type 11, form B type 12, andform C type 13, was carried out under the optimized reac-tion conditions. No reaction was observed for substrate 11;

N

N

Boc

R

Ph

N

N

Boc

R

Ph

N

O

R

Ph

N

O

R

Ph

N

O Ph

N

O PhR R

Fe Fe

L1 Ph-Trap

ee: 86–99%

ee: 72–98%

ee: 50–97%

MePPh2

H

HPh2P Me

Ru(cod)(η3-methylallyl)2/L1

Et3N, H2 (50 atm), 80 °CS/C = 40


TMG, H2 (50 atm), 80 °CS/C = 40


toluene, H2 (50 atm), 80 °CS/C = 40

1 2

3 4

5 6

NN

OH

F3C

ArNH

N

O

F3C

Ar

Pd(OCOCF3)2/L2TFA

H2 (82 atm), 60 °C, CH2Cl2

S/C = 507 8

MeO PPh2

PPh2MeO

L2 (S)-MeO-Biphep

NN

OH

RF

ArNH

N

O

RF

Ar

Pd(OCOCF3)2/L3 L-CSA

H2 (82 atm), 100 °C, TFE

S/C = 25

R R

9 10

L3 (S,S',R,R')-

TangPhos

PP

H

HtButBu

ee: 82–96%

dr > 20:1

ee: 88–95%

R = H, Me, Et, nPr, BnRF = CF3, C2F5


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and for substrate 12, low 10% ee and 14% yield were ob-tained; in a sharp contrast, the CH-form substrate 13 gaveexcellent 91% ee with 89% yield. Based on these experimen-tal results, it was proposed that the reaction experienced aBrønsted acid promoted tautomerization process of aro-matic compound A to form CH-form tautomer C, followedby Pd-catalyzed asymmetric hydrogenation of the relativelyactive tautomer C to give enantioenriched pyrazolidinones.In addition, these results demonstrated the practicability ofthe substrate activation strategy in the asymmetric hydro-genation of intractable isomerizable heteroarenes.

Scheme 3 Mechanism investigation

2.3 Benzisoxazoles

The hydrogenation of heteroarenes containing an N–Obond, such as isoxazoles and benzisoxazoles, is a challeng-ing task. The major difficulty is that the N–O bond is facileto break down and the free amino group generated in situwould poison the catalyst under the hydrogenation condi-tions. The Kuwano group first reported the asymmetric hy-drogenation of benzisoxazoles with [RuCl(p-cymene)L1]Clas the catalyst.12 In this transformation, the N–O bond ofthe benzisoxazole substrate was reductively cleaved by theruthenium complex and the C–N double bond of the result-ing imine was hydrogenated stereoselectively. As depictedin Scheme 4, a number of 3-substituted benzisoxazoles 14were reduced with high yields in the presence of an acylat-ing reagent, and afforded the corresponding α-substitutedo-hydroxybenzylamines 15 with up to 57% ee.

To investigate the mechanism, a series of reactions us-ing imine 16a as the substrate were conducted (Scheme 5).First, no formation of N-Cbz-imine was observed when 16awas treated with Cbz-OSu in the absence of Ru catalyst.Next, the hydrogenation of 16a with Ru catalyst in the ab-sence of Cbz-OSu produced only a small amount of the ex-pected primary amine 17a. At last, in the presence of Rucatalyst and Cbz-OSu, the reduction of imine 16a conductedfavorably to give 15a in high yield with 56% ee. In light ofthese observations, they proposed that the hydrogenationof benzisoxazoles occurs through the pathway presented inScheme 5. The ruthenium catalyst initially cleaved the N–Obond in benzisoxazole 14 to give imine 16, and subsequent-

ly hydrogenation of the C–N double bond in 16 occurredprior to Cbz protection of the nitrogen atom. Although theresulting primary amine 17 strongly inhibits the catalysisof the PhTRAP–ruthenium complex, the generated aminogroup was rapidly captured by the coexistent Cbz-OSu un-der the hydrogenation conditions. Thus, the rapid acylationeffectively avoids the inhibition of the ruthenium catalystby the free amino group of 17.

Scheme 5 Possible pathway for the asymmetric hydrogenation of ben-zisoxazoles

3 Asymmetric Hydrogenation of Six-Mem-bered-Ring Heteroarenes

3.1 Quinoxalines

The asymmetric hydrogenation of quinoxalines, whichdirectly provides chiral tetrahydroquinoxalines, has alreadyattracted much attention over the last decade.13 Varioustransition-metal-catalyzed enantioselective hydrogenationand organocatalyzed asymmetric transfer hydrogenationreactions of quinoxalines have been developed. Very re-cently, an emerging reaction, the metal-free chiral frustrat-

NN R2

O

R1NH

N R2

O

R1N

N R2

OH

R1

OH-form (A) NH-form (B) CH-form (C)

aromatic substrate

NN

OMe

PhN

N

O

Ph

11N

N

O

Ph

12 13MeF3C F3CF3C

active tautomer

Scheme 4 Catalytic asymmetric hydrogenation of benzisoxazoles

[RuCl(p-cymene)L1]Cl

Cbz-OSu, H2 (50 atm), THF

S/C = 40

NO

R

OH

R

NHCbz

OH

Et

NHCbz

15a 89%, 52% ee

OH

CH2CH2Ph

NHCbz

15b 87%, 35% ee

OH

iPr

NHCbz

15c 99%, 40% ee

OH

Me

NHCbz

15d 78%, 48% ee

OH

Ph

NHCbz

15e 74%, 55% ee

OH

Me

NHCbz

15f 87%, 57% ee

Me

OH

Me

NHCbz

15g 76%, 25% ee

OH

Me

NHCbz

15h 69%, 40% ee

MeO OH

Me

NHCbz

15i 76%, 38% ee

14 15

OMe

F

MeO

OH

R

NHH2

[Ru] [Ru]

H2

OH

R

NH2

Cbz-OSu

16 17

OH

Et

NH

16a

OH

Et

NH2

17a

NO

R14

OH

R

NHCbz

15


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ed Lewis pair (FLP) catalyzed asymmetric hydrogenationusing molecular hydrogen gas as the hydrogen source, hasalso been introduced into this chemistry.

3.1.1 Transition-Metal-Catalyzed Asymmetric Hydro-genation

Since the first example of the asymmetric hydrogena-tion of quinoxalines catalyzed by chiral rhodium catalyst in1987,14 miscellaneous transition-metal catalysts includingrhodium,15 iridium,16 and ruthenium complexes,17 havebeen applied to this transformation. Early reported catalyt-ic systems suffered from low enantioselectivities or limitedsubstrate scope. On the basis of activation strategies dis-cussed vide supra, significant progress has now beenachieved by several research groups. In order to avoid theoverlap with the contents of previous review articles,5 wewill provide a overview in this short review (Table 1).

3.1.2 Enantioselective Catalytic Reduction of Quinox-alines with Chiral Phosphoric Acid

In 2010, Rueping and co-workers first disclosed theasymmetric transfer hydrogenation of aryl-substituted qui-noxalines activated by a catalytic amount of chiral BINOL-derived phosphoric acid (R)-L17 or (R)-L18 with a Hantzschester as the hydrogen source (Scheme 6).18 The mechanisminvolved transfer hydrogenation of the sterically less hin-dered C=N bond with Brønsted acid promoted protonationof the quinoxaline to generate the partial hydrogenated di-hydroquinoxaline, and this was followed by asymmetrictransfer hydrogenation of the sterically hindered C=N bondto give the desired chiral tetrahydroquinoxaline. Subse-quently, Zhou and co-workers reported a relay catalysis toprepare chiral tetrahydroquinoxalines using a combinationof achiral ruthenium complex [Ru(p-cymene)I2]2 and phos-phoric acid (S)-L18.19 With this metal/Brønsted acid relaycatalyst system, a variety of quinoxalines were hydrogenat-ed to provide 1,2,3,4-tetrahydroquinoxalines in high yields

Table 1 Metal-Catalyzed Asymmetric Hydrogenation of Quinoxalines

Catalytic System S/C Hydrogen source ee (%) Ref.

Rh Rh(I)-L4 50–100 H2 (7 atm) 2–3 14

Rh(I)-L5 50–100 H2 (20 atm) 11–23 15

Ir Ir(III)-L6 100 H2 (5 atm) 90 16a

[IrCl(cod)]2/I2/L7 100 H2 (48 atm) 81–98 16b

[IrCl(cod)]2/L8 50 H2 (25 atm) 75–96 16c,d

[IrCl(cod)]2/I2/L9 100 H2 (48 atm) 72 16e

[IrCl(cod)]2/L10 200 H2 (80 atm) 70 16f

{[IrH-L11]2}(μ-Cl)3+Cl– 100 H2 (30 atm) 86–95 16g–i

[IrCl(cod)]2/I2/L12 50 Et3SiH/H2O 58–78 16j

Ru Ru-L13 100–9400 H2 (20 atm) 96–99 17a

Ru-L14 100 H2 (80 atm) 95–99 17b

RuCl2[L15][L16] 1000 H2 (29 atm) 73 17c,d

Bn

PPh2PPh2

L5 BDPBzP

Me MeO

O

Me

PPh2

PPh2

L4 DIOP

Me

H

HIr

H

PN

P H

Ir(III)-L6 P = PPh2

Me

OPPh2

OPPh2

L7 H8-BINAPO

(S)-DifluorPhosPP =

-O

O

O

O

PPh2

PPh2

L12 (S)-SegPhos

RuFArB

H2NNSO2R

Ph

Ph

R = 4-CF3C6H4

L10

PPh2

Ph

OMe

OP

O

O

R = 4-MeOC6H4Ru-L14 Ar = 3,5-(CH3)2C6H3

O

O

O

O

Ar2P

PAr2

Ru

Cl H2N

R

iPr

H

H2N

O

O

PPh2

PPh2

L9 (R,R,Sax)-C3*-TunePhos

Me

Me

P

P

Ir

Cl

Ir

Cl

ClP

P

H H +

[Cl]

{[IrH-L11]2}(μ-Cl)3+Cl-

PAr2

PAr2

L16 Ar = XylL15 (S,S)-DACH

H2N

H2N

MeORu-L13

L8 PipPhos

O

OP-NR2


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with good to excellent enantioselectivities (up to 96% ee). Incontrast to the catalysis reported by Rueping, this reactionwent by another mechanistic route. After partial hydroge-nation of the 2-arylquinoxaline, the intermediate was enan-tioselectively reduced through convergent asymmetric dis-proportionation, in which a self-transfer hydrogenationprocess was involved.

Scheme 6 Asymmetric transfer hydrogenation of quinoxalines

The same chiral phosphoric acid (S)-L18 can provideproducts with the opposite absolute configuration underthese two catalytic systems. The origin of enantioreversalcan be explained by the stereochemical model as illustratedin Scheme 7. For the combination of metal complexes andorganic molecules in the cooperative strategy developed byZhou, the hydrogenation of 18a firstly delivers intermediate3,4-dihydroquinoxaline 20a by using an achiral rutheni-um(II) as the catalyst. Then 20a interacts with chiral phos-phoric acid (S)-L18 through two hydrogen bonds. These hy-drogen bonds with the phosphate and the effect of sterichindrance construct the ‘three-point contact model’ thatdetermines the stereoselectivity in the disproportionationof 3,4-dihydroquinoxaline 20a. Comparatively, in the pureorganocatalytic process developed by Rueping’s group,20a/(S)-L18/HEH 1 form another ‘three-point contact mod-el’ leading to Re-face reduction. The reversal of enantiose-lectivity perhaps lies in the different steric demand be-tween 1,2-hydride transfer pathway in the self-transfer hy-drogenation of 20a and 1,4-hydride transfer pathway usingHEH 1.

Scheme 7 Origin of enantioreversal in asymmetric transfer hydroge-nation

In 2012, Zhou employed dihydrophenanthridine (DH-PD) as a regenerable organic hydrogen source for the enan-tioselective transfer hydrogenation of 2-aryl-substitutedquinoxalines affording the products in 96–99% yields andwith 85–95% ee (Scheme 8).20 Using a catalytic amount ofhydride precursor phenanthridine, the demand for [Ru(p-cymene)I2]2 could be reduced to 0.5 mol% and hydrogenpressure could be decreased to 7 atm. Notably, the dihy-drophenanthridine acts as an efficient hydride shuttle tobridge hydride transfer from the transition-metal center tothe unsaturated substrates in this reaction.

Beller and co-workers demonstrated another catalyticstrategy by the combination of an iron-based complex withchiral Brønsted acids (S)-L18 to accelerate the enantioselec-tive hydrogenation of quinoxalines without the use of aprecious metal catalyst and chiral ligand (Scheme 9).21 Em-ploying achiral Fe complex 21 as a co-catalyst makes thistransformation a benign and efficient process. Apart from2-aryl-substituted quinoxalines, 2-alkyl-substituted sub-strates were also appropriate substrates providing the cor-responding hydrogenated products in good yields and withmoderate to excellent ee.

N

N

Ar18

NH

HN

Ar19

O

O

Ar'

Ar'

PO

OH

80–98% ee

(R)-L17 Ar' = 2,4,6-(i-Pr)3C6H2(R)-L18 Ar' = 9-anthryl

83–96% ee

(R)-L17 or (R)-L18

HEH 1

NH

CO2EtEtO2CHH

HEH 1

N

N

Ar18

NH

HN

Ar19

[Ru(p-cymene)I2]2, (S)-L18

H2 (41 atm)

NH

HN

Ph

(R)-19a: 90% ee

relay catalysis by Zhou (1,2-H transfer)

si-face

N

NPh

H O

P

O O

O

N

NPh

H

H

HH

20a

20a(S)-L18

pure organocatalytic process by Rueping (1,4-H transfer)

N

NPh

H

H

O

NH

HN

Ph

HEH 1

(S)-19a: 90% ee

NH

HH

R

RP

O O

O

re-face

20a

(S)-L18

*

*

partialhydro-

genation18a

HEH 1

Scheme 8 Asymmetric reduction of quinoxalines with DHPD

NH

H

N

H

[Ru(p-cymene)I2]2 H2 (7 atm)

chiral phosphoric acid

enantioselectivetransfer

hydrogenation

N

N

Ar18

NH

HN

Ar

19

DHPD

phenanthridineee: 85–95%


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Scheme 9 Asymmetric reduction of quinoxalines with iron complex 21

3.1.3 Chiral Frustrated Lewis Pair Catalyzed Asym-metric Hydrogenation

The recently emerging FLP chemistry provides a break-through approach for metal-free hydrogenation with mo-lecular hydrogen since catalytic hydrogenation has longbeen dominated by transition-metal catalysis.22 A widerange of unsaturated compounds proved to be effectivesubstrates for FLP-catalyzed hydrogenation. In 2015, Du andco-workers developed a cis-selective hydrogenation of 2,3-disubstituted quinoxalines using chiral borane catalystsgenerated by the in situ hydroboration of the chiral dieneL19 with HB(C6F5)2 under mild reaction conditions (Scheme10).23 A broad scope of 2-alkyl-3-aryl-substituted quinoxal-ines were successfully hydrogenated to furnish 1,2,3,4-tet-rahydroquinoxalines with moderate to excellent ee and ex-cellent diastereoselectivities. However, 2,3-dialkyl- and 2,3-diaryl-substituted quinoxalines were not suitable sub-strates. This asymmetric hydrogenation can be carried outon a relatively large scale.

3.2 Quinazolines

Over past decades, the synthesis of chiral dihydro-quinazolines and tetrahydroquinazolines has drawn moreand more attention due to the fact that they are present as

potent T-type Ca2+ channel blockers and potential α-adren-ergic blockers, respectively.24 Under the guideline of de-creasing aromaticity through the formation of a positivelycharged derivatives, the Mashima group reported the asym-metric hydrogenation of quinazolinium salts by utilizinghalide-bridged dinuclear iridium complexes {[IrH-L12]2}(μ-Cl)3

+Cl– as the catalyst to afford the corresponding 1,2,3,4-tetrahydroquinazolines with high enantiomeric excessalong with moderate to good yields (Table 2).25

Although it has excellent enantioselectivity, this methodsuffered from low chemoselectivity with the partially hy-drogenated 3,4-dihydroquinazolines 24 and 1,2-dihydro-quinazolines 25 as side products. According to time-coursestudies, the authors propose that this reaction proceedspreferentially through initial 1,2-reduction, followed byasymmetric hydrogenation of the imines to produce thechiral tetrahydroquinazolines. The partially hydrogenatedproducts 24 and 25 remain intact as side products primari-ly due to the stability of this type of imine under these hy-drogenation conditions.

FeOC H

CO

TMS

OH

TMSN

N

R

18

NH

HN

R

19

(S)-L18, H2 (5 atm)

ee: 60–94%R = aryl, alkyl

21 (3–5 mol%)

21

Scheme 10 Chiral frustrated Lewis pair catalyzed asymmetric hydroge-nation

N

N

R1 NH

HN

R1

18 19

R2 R2HB(C6F5)2,chiral diene L19

H2 (20 atm), tolueneS/C = 20

NH

HN

Ph

Me

19b 82%, 89% ee

NH

HN

Ph

Me

19d 72%, 67% ee

Me

NH

HN

Ph

Me

19f 87%, 92% ee

NH

HN

Ph

Me

19c 85%, 90% ee

NH

HN

Ph

Me

19e 93%, 77% ee

MeO

Br

MeNH

HN

Ph

Me

19g 75%, 96% ee

Cl

Ar

Ar L19

Table 2 Asymmetric Hydrogenation of Quinazolines

Substrate R1/R2/R3 Yield (%) of 23

ee (%) of 23

Yield (%) of 24

Yield (%) of 25

22a·HCl Ph/H/H 89 99 11 –a

22b·HCl p-F3CC6H4/H/H 82 99 6 10

22c·HCl p-ClC6H4/H/H 87 >99 7 5

22d·HCl p-MeC6H4/H/H 81 97 8 2

22e·HCl p-MeOC6H4/H/H 66 98 14 20

22f·HCl m-MeC6H4/H/H trace – 2 89

22g·HCl m-F3CC6H4/H/H 35 97 63 –a

22h·HCl o-MeC6H4/H/H trace – 2 94

22i·HCl Ph/Br/H 89 96 6 –a

22j·HCl Ph/Cl/H 78 97 2 1

22k·HCl Ph/OMe/OMe –a – –a 36a Not determined.

N

N

HCl

R1

{[IrH-L12]2}(μ-Cl)3+Cl–

H2 (30 atm), CH2Cl2S/C = 100

NH

NH

∗∗R1

N

NH

∗∗R1

NH

N

R1+

R2

R3

22·HCl 23 24

25

R2

R3

R2

R3

R2

R3

{[IrH-L12]2}(μ-Cl)3+Cl–

P

P

Ir

Cl

Ir

Cl

ClP

P

H H +

(S)-SegPhos (L12)PP =

[Cl]–

+


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3.3 Pyrimidines

Despite the prevalence of the six-membered cyclic ami-dines products in natural products and potent pharmaceu-tical compounds,26 the asymmetric hydrogenation of py-rimidines has remained unexplored in organic synthesis.This might be ascribed to both pyrimidines and amidineproducts binding strongly to the metal center in the catalystand leading to the deterioration of the catalytic reactivity.

In 2015, Kuwano and co-workers developed a substrateactivation strategy for the hydrogenation of pyrimidineswith ligand L20, [IrCl(cod)]2, iodine, and excess of Lewisacid (Scheme 11).27 By employing Yb(OTf)3 as an activator, avariety of 2,4-disubstituted pyrimidines 26 were convertedinto cyclic amidines 27 efficiently with high enantiomericexcesses and yields. However, the pyrimidines with an elec-tron-withdrawing group at the C4 position produced ami-dines 27h and 27l with low enantiomeric excesses albeitwith high yields. Notably, a pyrimidine bearing no substitu-ent at C2 was also hydrogenated to 27n with a high ee.When introducing the bulky tert-butyl substituent at C4,the substrate underwent hydrogenation at its N1–C6 bond,but the C4–C5 double bond remained intact to give partiallyhydrogenated product 28a as the sole product.

According to control and labeled experiments, the au-thors suggest that the hydrogenation proceeds through thefollowing pathway (Scheme 12). First, partially hydrogena-

tion of pyrimidine 26 gives dihydropyrimidine 28, com-pound 28 could be activated by coordination to Yb(OTf)3and [Ir]–H is inserted into the C–C double bond of 28 toform intermediate I. The transformation of I into 27 pro-ceeds through the migration of the iridium atom. Further-more, the addition of Yb(OTf)3 is crucial for the stereoselec-tivity and reactivity because its facilitates the hydrogena-tion of intermediate 28 as well as promoting the initialreduction of the N1–C6 double bond in pyrimidine 26.

Scheme 12 Proposed pathway for the hydrogenation of pyrimidines

3.4 Pyrazines

Optically active chiral piperazines are ubiquitous sub-structures in natural alkaloids and many biologically rele-vant molecules.28 Among the many synthetic approaches,the asymmetric hydrogenation of readily available pyra-zines is undoubtedly the most direct and effective approachto these optically active compounds. However, until now,there are only limited reports of the transition-metal-cata-lyzed asymmetric hydrogenation of pyrazines or partiallyreduced pyrazines. From the reported methods, two mainhydrogenation approaches are used to afford the chiral pip-erazines: (i) the indirect enantioselective hydrogenation ofa partial hydrogenated intermediate that is generated bythe Pd/C-catalyzed hydrogenation of pyrazines; (ii) the di-rect enantioselective hydrogenation of pyrazinecarboxylicacid derivatives with a chiral catalyst.

Rossen and co-workers found that the tetrahydropyra-zine 30, which was readily obtained by partial hydrogena-tion of the corresponding pyrazines 29 with Pd/C and pro-tected with commonly used protecting groups, could be en-antioselectively hydrogenated to give the chiral piperazines31 with moderate 69% ee (Scheme 13).29 Further investiga-tion demonstrated that the Rh–BINAP complex was an effi-cient catalyst for the hydrogenation of 30g to furnish piper-azine 31g with 99% ee. There are also a few reports of theasymmetric hydrogenation of other types of tetrahydropyr-azines and dihydropyrazines, but they are not discussedhere.30

Scheme 11 Asymmetric hydrogenation of pyrimidines

N

N [IrCl(cod)]2/L20, I2

Yb(OTf)3, EtOAcS/C = 100

R2 R1

NH

NR2 R1

+ H2

(50 atm)

NH

NMe 2-FC6H4

NH

NcHex 2-MeC6H4

NH

NEt 2-MeC6H4

27d 92%, 92% ee 27e 68%, 97% ee 27f >99%, 96% ee

NH

NEtO2C 2-MeC6H4

NH

NF3C 2-MeC6H4

NH

NPh 2-MeC6H4

27l 80%, 22% ee

27h 94%, 9% ee 27i 94%, 99% ee

NH

NAcOH2C Ph

NH

NPh Me

NH

NPh NMe2

27k 80%, 88% ee27j 92%, 92% ee

27g 87%, 91% ee

NH

NMe Ph

NH

NMe 4-F3CC6H4

NH

NMe 4-MeOC6H4

27a 94%, 88% ee 27b 87%, 86% ee 27c 93%, 86% ee

26 27

FePtBu2

CH3

PPh2

L20

NH

NMe

NH

NPh

NH

NtBu

27m 99%, 87% ee 27n 83%, 90% ee 28a 99% yield

2-MeOC6H4 2-MeC6H4

24

N

NR2 R1

26

NH

NR2 R1

28

NH

NH

R1R2

[Ir]

H

Yb(OTf)3

NH

NH

R1R2

[Ir]

Yb(OTf)3

H

NH

NH

R1R2

H

[Ir]

Yb(OTf)3

partialhydrogenation [Ir]–H

Yb(OTf)3

27I II III

Ir–H

NH

NR2 R1


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Scheme 13 Indirectly asymmetric hydrogenation of pyrazines

In 1997, Fuchs reported the first asymmetric hydroge-nation of pyrazinecarboxylic acid derivatives by using ho-mogeneous [Rh(nbd)Cl]2/diphosphine with up to 78% ee(Scheme 14).31 However, only limited substrates scope waspublished and other kinds of pyrazines still remain untest-ed.

4 Asymmetric Hydrogenation of Fused Nitrogen Heteroarenes

4.1 Heteroarenes Containing a Ring-Junction Nitrogen

4.1.1 Pyrrolo[1,2-a]pyrazine Derivatives

The asymmetric hydrogenation of pyrrolo[1,2-a]pyra-zines has emerged as one of the most attractive syntheticprotocols for the construction of chiral 1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazines which are a very important class ofheterocycles for their potential biological activities.32 Re-cently, Zhou and co-workers reported a substrate activationstrategy to facilitate the iridium-catalyzed enantioselectivehydrogenation of N-benzylated pyrrolo[1,2-a]pyraziniumsalts (Scheme 15).33 This transformation employed[IrCl(cod)]2 as the iridium precursor and L24 as ligand withan equivalent amount of cesium carbonate. Substrates witharyl substituents in the pyrazinium ring (R1 = aryl groups)provided the hydrogenated products with 80 to 95% ee.

However, replacement of the aryl groups by alkyl substitu-ents at the same position or utilizing the diaryl-substituted32l as the substrate led to a slight drop in the enantioselec-tivity.

Scheme 15 Asymmetric hydrogenation of pyrrolo[1,2-a]pyraziniums

A possible reaction pathway is shown in Scheme 16, thearomatic substrate first undergoes a 1,2-hydride addition togive 1,2-dihydropyrrolo[1,2-a]pyrazine intermediate A,which isomerizes to an iminium salt B in the presence of insitu generated HBr. Subsequent hydrogenation of the imini-um salt provides the product. The in situ generated HBr isimportant for this reaction to proceed, but it also causespartial racemization of 33 through enamine/iminium isom-erization involving the pyrrole ring. The addition of cesium

N

N

COX

1. Pd/C, H2

N

N

COX2. protection

COR

COR

N

N

COX

COR

COR

[Rh(L21)(cod)]OTf

H2 (70 atm), TFES/C = 33

N

∗∗

HN

CO2Me

O Me

31a 95%, 32% ee

N

∗∗

N

CO2Me

O OBn

31b 57%, 56% ee

Boc

N

∗∗

N

CO2Me

O OtBu

31c 94%, 49% ee

Boc

N

∗∗

HN

CONHtBu

O Me

31d 97%, 39% ee

N

∗∗

N

CONHtBu

O Me

31e 98%, 69% ee

Ac

N

∗∗

N

CONHtBu

O OBn

31f 83%, 65% ee

Boc

N

N

CO2Me

O OBn

[Rh(L22)(cod)]OTf

H2 (70 atm), MeOHS/C = 50

N

∗∗

N

CO2Me

O OBn

Boc

31g 96%, 99% ee L22 (R)-BINAP30g

Boc

PPh2

PPh2

29 30 31

P

P

Et

Et

Et

Et

L21 Et-DuPhos

Scheme 14 Asymmetric hydrogenation of pyrazines

N

N

EWG NH

HN

EWG

[Rh(nbd)Cl]2/L23

H2 (50 atm), 70 °CS/C = 22–100

3129

FePCy2

CH3

PPh2

NH

HN

CONHtBu NH

HN

CO2tBu

30h 80%, 78% ee 30i 67%, 78% ee

NH

HN

CO2Me

30j 85%, 4% ee

L23

N

N

R1

Bn

Br

R2

[IrCl(cod)]2/L24

Cs2CO3, THF, H2 (27 atm)S/C = 33

N

N

R1

Bn

R2O

O

PPh2

PPh2

L24 (S,S,Rax)-C3*-TunePhos32

33

N

NBn

33a 97%, 92% ee

N

NBn

33b 91%, 89% ee

N

NBn

33c 90%, 93% ee

Me OMe

N

NBn

33d 93%, 80% ee

N

NBn

33e 96%, 94% ee

N

NBn

33f 97%, 95% ee

Cl

Me CF3

N

NBn

33g 95%, 88% ee

N

NBn

33h 93%, 87% ee

N

NBn

33i 94%, 94% ee

CN

N

N

Me

Bn

33j 97%, 60% ee

N

NBn

33k 93%, 73% ee

N

NBn

33l 85%, 75% ee

PhMe

Ph F


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carbonate increases the conversion and prohibits the race-mization of the products dramatically by gradually trappingthe excess generated Brønsted acid.

Scheme 16 A proposed hydrogenation mechanism

4.1.2 [1,2,3]Triazolo[1,5-a]pyridines

The enantioselective reduction of [1,2,3]triazolo[1,5-a]pyridines is a straightforward way to access novel andstructural diverse chiral heterocyclic derivatives, and there-fore is highly interesting for medicinal chemistry re-search.34 Glorius and co-workers have successfully applied achiral ruthenium–NHC complex as the catalyst for the high-yielding and completely regioselective asymmetric hydro-genation of substituted [1,2,3]triazolo[1,5-a]pyridines(Scheme 17).35 The hydrogenation of different kinds of al-kyl-substituted substrates proceeded with perfect conver-sion and moderate enantioselectivities. It is noteworthythat the enantiomeric ratio decreased slightly when thelength of the alkyl chains was increased, while perfect con-versions to the desired products were maintained. The re-action of 7-phenethyl-[1,2,3]triazolo[1,5-a]pyridine (34e)also gave the product 35e with 66% ee.

4.2 Asymmetric Hydrogenation of Heteroarenes Containing Fused Pyridine Rings

4.2.1 1,5-Naphthyridines

Chiral tetrahydronaphthyridine and diazadecalin ringsystems are important structural units that have showngreat potential for pharmaceutical development.36 Fan andco-workers recently reported the first asymmetric hydroge-nation of 2,6-disubstituted and 2,3,6-trisubstituted 1,5-naphthyridines to produce optically pure tetrahydronaph-thyridines with chiral cationic ruthenium diamine com-plexes as the catalyst (Scheme 18).37

A wide scope of 1,5-naphthyridine derivatives were suc-cessfully hydrogenated to give 1,2,3,4-tetrahydro-1,5-naph-thyridines with up to 99% ee. Substrates bearing symmetri-cal 2,6-dialkyl substituents gave excellent enantioselectivi-ties and yields. However, the hydrogenation ofunsymmetrical 2,6-dialkyl-substituted substrates gave lowregioselectivities albeit with high ee. Interestingly, only the

pyridyl ring bearing an alkyl group was hydrogenated when2-aryl-6-alkyl substrates were subjected to this conversion.In addition, in the unsymmetrical 2,6-diaryl-substitutedsubstrates, the pyridyl rings bearing the more electron-richsubstituents were more easily hydrogenated under theseconditions. Significantly, by using a heterogeneous PtO2 cat-alyst, the remaining pyridine ring could also be hydrogenat-ed to give the chiral 2,6-disubstituted 1,5-diaza-cis-decalinswith identical enantioselectivity.

To further understand the mechanism and the origins ofenantioselectivity, theoretical calculations were carriedout. The computational results indicated that the final 1,2-hydride addition should proceed through an ionic pathwayinvolving the transition states depicted in Scheme 19. In thecase of substrates bearing at least one alkyl group at the C2-position, the enantioselectivity originates from the CH/π at-traction between the η6-arene ligand in the Ru complex andthe fused pyridine ring of the dinaphthyridine via a 10-membered-ring transition state with the participation ofthe TfO– anion. In contrast, for 2,6-diaryl-substituted 1,5-

N

N

R

Bn

Br "Ir–H"N

N

R

BnHBr +

HBr

isomerization

N

N

R

Bn

Br "Ir–H"N

N

R

Bn

32 A

B 33

Scheme 17 Scope of the [1,2,3]triazolo[1,5-a]pyridines

N NN

R

**N N

N

R

NHC•HBF4 L25[Ru(cod)(2-methylallyl)2]

KOtBu, H2 (100 atm)S/C = 20

** N NN

Me

35a 99%, 66% ee

** N NN

Et

35b 99%, 66% ee

** N NN

n-C5H11

35c 99%, 56% ee

**N N

N

n-C13H27

35d 99%, 55% ee

**N N

N

35e 99%, 66% ee

Bn

L25 Ar = 2-naphthyl34 35

N N

BF4

Ar Ar

Scheme 18 Asymmetric hydrogenation of 1,5-naphthyridines

Ru-L26H2 (50 atm)

EtOH or MeOHS/C = 50–500N

N

R3

R1

R2 N

∗∗

∗∗HN

R3

R1

R2

RuTfO

H2NNSO2R'

PhPh

R''

N

HN

Me

Me

37a 95%, 99% ee

N

HN

nBu

nBu

37b 90%, 95% ee

N

HN

Me

nBu

37d1 48%, 99% ee

N

HN

nBu

Me

37d2 45%, 99% ee

N

HN

Ph

Me

37f 95%, 98% ee

N

HN

4-F3CC6H4

Ph

37e 78%, 80% ee

N

HN

4-F3CC6H4

Me

37c 95%, 99% ee

N

HN

Ph

37h 91%, 12% ee

NH

N

Ph

nPr

37g 90%, 64% ee

Et

36 37Ru-L26


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naphthyridines, the enantioselectivity originates from theCH/π attraction between the η6-arene ligand in the rutheni-um complex and the substituted phenyl ring, instead of thefused pyridine ring. Finally, the metal–hydride intermedi-ate attacks the Si face of the imine moiety to give the R-con-figured product.

Scheme 19 Proposed transition states

4.2.2 1,10-Phenanthrolines

Due to its high stability and strong coordination ability,1,10-phenanthroline and its derivatives containing twosegregated pyridyl rings are good bidentate ligands for cata-lytic reactions, and, therefore, the direct asymmetric hydro-genation of these compounds is difficult. After continuoustrial and error by organic chemists, the enantioselective hy-drogenation of 1,10-phenanthrolines has been completedthrough two different pathways by employing, respectively,organocatalysis and transition-metal catalysis.

In 2008, the Metallinos group documented the enantio-selective transfer hydrogenation of 2-substituted and 2,9-disubstituted 1,10-phenanthrolines by utilizing Brønstedacid L27 as catalyst and HEH 1 as the hydrogen source(Scheme 20).38 For the monosubstituted compounds, poorto moderate yields and moderate to high enantioselectivi-ties were obtained for the desired products (11–54% yield,40–95% ee). Significant improvement in yields was ob-tained with symmetrical 2,9-dialkyl-1,10-phenanthrolines(72–88% yield), although the diastereoselectivities still re-mained at a low level (3:2 ent/meso).

The enantioselective and diastereoselective hydrogena-tion of substituted 1,10-phenanthrolines using phosphine-free chiral cationic ruthenium diamine catalyst Ru–L28(Scheme 21) was developed by the Fan group.39 With differ-ent catalytic protocols, selective or full reduction of the twopyridyl rings were achieved providing an efficient and prac-tical approach for the synthesis of chiral 1,2,3,4-tetrahydro-1,10-phenanthroline and octahydro-1,10-phenanthrolinederivatives with excellent enantioselectivities and diastereo-selectivities. In combination with dehydrogenation underan air atmosphere, a variety of 2- and 2,9-substituted 1,10-phenanthroline derivatives were smoothly reduced to chi-

ral 1,2,3,4-tetrahydro-1,10-phenanthrolines with excellentee (87 to 99% ee). However, for the unsymmetrical 2-alkyl-and 2,9-dialkyl-substituted 1,10-phenanthroline substratesonly moderate regioselectivities were obtained and the tet-rahydrophenanthrolines 40 were obtained with high enan-tioselectivities.

By elevating the catalyst loading and after completion ofthe hydrogenation directly decomposing the rutheniumcatalyst to avoid the dehydrogenation of the products, awide range of 2-alkyl-substituted and 2,9-dialkyl-substitut-ed octahydro-1,10-phenanthrolines were isolated in goodyields with up to 99% ee and greater than 20:1 d.r. (Scheme

N

NRu

TsN

NPh

Ph

Hax

Heq

H

H

H

HH

OS

O

F3CO

Si face attack, (R)-product2-alkyl-substituted 1,5-naphthyridine

RuTsN

NPh

Ph

Hax

Heq

H

Si face attack, (R)-product2,6-diaryl-substituted 1,5-naphthyridine

OS

O

F3CO

N

N

F3C

CF3

H

H

Scheme 20 Organocatalyzed asymmetric transfer hydrogenation

(R)-L27, HEH 1

N N

R R'NH HN

R R'

benzene, 60 °CS/C = 10–20

O

O

Ar

Ar

PO

OH

Ar = 9-phenanthryl(R)-L27

38 39

R = R' = Me, nBu:72–88%, 99% ee(3:2 ent/meso)

R = H, R' = Me, nBu,

iPr, Ph, CH2NHAc:

11–54%, 40–95% ee

Scheme 21 Asymmetric hydrogenation of 1,10-phenanthrolines to af-ford 1,2,3,4-tetrahydro-1,10-phenanthrolines

1) Ru-L28H2 (50 atm)S/C = 100

N N

R1 R2N HN

R1 R2

2) stirred for 12 hunder air

N HN

Me Me

40a 100%, 99% ee

N HNnPr nPr

40b 100%, >99% ee

N HNiPr iPr

40c 100%, 98% ee

N HNsBu sBu

40d 100%, 99% ee

N HNiBu iBu

40e 100%, >99% ee

N HNnC6H13

nC6H13

40f 100%, >99% ee

N HNnBu Me

40g1 60%, >99% ee

N HN

Me nBu

40g2 40%, >99% ee

N HNnBu

40i1 41%, 92% ee

N HN

40i2 59%

N HN

Ph nBu40j >95%, >99% ee

N HN

Ph Ph

40h 100%, 87% ee

38 40

RuTfO

H2NN

PhPh

Ts

Ru-L28

nBu


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22). Unfortunately, 2,9-diaryl-substituted 1,10-phenanth-rolines did not give the corresponding 2,9-diaryl-substitut-ed octahydro-1,10-phenanthrolines under these condi-tions.

Scheme 22 Asymmetric hydrogenation of 1,10-phenanthrolines to af-ford octahydro-1,10-phenanthrolines

5 Conclusions and Outlook

This review has documented recent advances in the ho-mogeneous asymmetric hydrogenation of heteroareneswith multiple heteroatoms. Three different strategies forthe hydrogenation of heteroarenes including catalyst acti-vation, substrate activation, and relay catalysis have beensystematically summarized. Despite much progress, thereremains great opportunities for progress and developmentsin this field of research. As there is a great diversity of het-eroarenes, a vast number of heteroarenes with multiple he-teroatoms are still unexplored and the asymmetric hydro-genation of such compounds is full of challenge. Future ef-forts may focus on the substrates as follows, heteroarenescontaining free hydroxyl, amido, or other electron-enrichedfunctional groups, such as amino-pyrimidine, oxy- andamino-1,2-azoles; five-membered-ring heteroarenes, suchas isothiazoles, thiazoles, benzannulated azoles, thieno[2,3-d]imidazoles, oxadiazoles, and thiadiazoles; bicyclic het-eroaromatic compounds containing a fused pyridine, py-rimidine, triazine, or pyrazine motif, such as aza-indoles,purines, aza-indolizines; other tricyclic fused molecules,such as cyclazines. In view the development of catalysts andnovel strategies, together with the exciting reports on theapplication of substrate activation to improve the efficiencyof asymmetric hydrogenation, we believe that there will bemore breakthroughs in the research in this field.

Acknowledgment

Financial support from the National Natural Science Foundation ofChina (21532006) is acknowledged

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Ru-L28 (2.0 mol%)+ H2

(50 atm)N N

R1 R2NH HN

R1 R238 39

MeOHS/C = 50

NH HN

Me Me

39a 90%, >99% ee

NH HNnPr nPr

39b 87%, >99% ee

NH HNiPr iPr

39c 87%, >99% ee

NH HNnBu nBu

39d 91%, >99% ee

NH HNsBu sBu

39e 91%, 99% ee

NH HNiBu iBu

39f 87%, >99% ee

NH HNnC6H13

nC6H13

39g 89%, >99% ee

NH HNnBu Me

39h 87%, >99% ee

NH HNnBu

39i 89%, 98% ee


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