Caffeine-derived-iron catalyzed carbonyl-ene and Diels-Alder reactions and development of an NHC-diol ligand family

(1)

Caffeine-derived-iron catalyzed carbonyl-ene

and Diels-Alder reactions and development

of an NHC-diol ligand family

Thè se

Di Meng

Doctorat en chimie

Philosophiæ doctor (Ph. D.)

Qué bec, Canada

© Di Meng, 2018

(2)

Caffeine-derived-iron catalyzed carbonyl-ene

and Diels-Alder reactions and development

of an NHC-diol ligand family

Thè se

Di Meng

Sous la direction de :

(3)

iii

RÉ SUMÉ

Cette thè se de doctorat met en é vidence l'utilisation de catalyseurs de fer qui pré sentent de nombreux avantages par rapport aux autres mé taux de transition. En effet, le fer est moins coû teux, respectueux de l’environnement et présente des activités catalytiques inté ressantes. Du fait de ces caracté ristiques, la catalyse au fer a connu un ré el essor ces 15 derniè res anné es. Cette thè se pré sente la ré action de type carbonyl-è ne intermolé culaire catalysé e par des sels de fer(II) et de fer(III), utiles pour leur rôle d’acides de Lewis, en employant plusieurs alcè nes avec le 3,3,3-trifluoropyruvate d'é thyle. Les sels de FeII_{, notamment FeCl}₂_{, Fe(OAc)}₂_{, Fe(NTf)}₂_{, Fe(ClO}₄₎₂_·6H₂_O,

Fe(BF4)2·6H2O et Fe(OTf)2, ont é té utilisé s pour catalyser cette transformation. Un systè me efficace

utilisant le Fe(BF4)2 anhydre a é té dé veloppé pour catalyser la ré action carbonyl-è ne

intermolé culaire de multiples alcè nes avec le 3,3,3-trifluoropyruvate d’éthyle, et aussi la ré action carbonyl-è ne intramolé culaire du (S)-citronellal. Des rendements entre 36-87% en produits-è ne, soit des alcools homoallyliques et de produits de cyclisation du citronellal ont été obtenus par l’utilisation de diffé rents alcè nes disubstitué s. Les carbè nes N-hé té rocycliques (NHC) sont reconnus comme des ligands prometteurs en catalyse avec des mé taux de transition. Trois sels de xanthinium dé rivé s de la café ine ont é té utilisé s comme pré curseurs NHC pour dé velopper des complexes fer-ligand NHC pour les ré actions carbonyl-è ne intra- et intermolé culaires. Les conditions optimales ont é té é tudié es, notamment le choix du sel de fer, du solvant, de la charge catalytique et du contreanion. Fe(OTf)2 est apparu comme le meilleur catalyseur lorsque complexé au ligand NHC dé rivé du sel

de xanthinium café ine mé thylé . Avec [NHC-Fe]2+_(SbF₆₎₂₂₋_{comme catalyseur, des rendements de}

22% à 99% en alcools homoallyliques ont é té obtenus pour la ré action carbonyl-è ne en employant divers énophiles et le trifluoropyruvate d’éthyle. De plus, NHC-FeIII_Cl₂_[SbF₆_{] s’est avéré être un}

catalyseur efficace et sélectif pour la transformation du citronellal en produit désiré, l’isopulé gol. L’aspect recyclable du sel de xanthinium dé rivé de la café ine lié au Fe(OTf)2 a é té é valué dans la

ré action de Diels-Alder en employant des solvants verts, comme le dimé thyl carbonate. Le catalyseur a pu ê tre recyclé cinq fois et des rendements identiques ont é té obtenus. Diffé rents substrats ont é té testé s dont des composé s dicarbonylé s bidendates, cé tones, aldé hydes et esters. Les ligands NHC alkoxylé s ont é té dé veloppé s comme famille é mergente de ligands dans les réactions d’addition conjuguées énantiosélectives. Enfin, de nouveaux ligands NHC-diol ont é té synthé tisé s et testé s dans la ré action carbonyl-è ne. Ces derniers sont prometteurs en catalyse asymé trique et notamment en catalyse utilisant des mé taux de transition.

(4)

iv

ABSTRACT

Iron has many advantages compared to other transition metals in homogeneous catalysis, such as relatively cheap price, eco-friendly, good catalytic activities. Hence, these features boosted the development of iron catalysis since 15 years ago. In this thesis, various iron salts including FeII_and

FeIII_{were examined as Lewis acid catalysts in the intermolecular carbonyl-ene reaction of various}

alkenes and ethyl 3,3,3-trifluoropyruvate. FeII _{salts, such as FeCl}₂_{, Fe(OAc)}₂_{, Fe(NTf)}₂_,

Fe(ClO4)·6H2O, Fe(BF4)2·6H2O, Fe(OTf)2, were found to be effective in catalyzing the reaction. An

anhydrous Fe(BF4)2 catalytic system was developed for both of an intermolecular carbonyl-ene

reaction of various alkenes and ethyl 3,3,3-trifluoropyruvate and an intramolecular carbonyl-ene reaction of (S)-citronellal. The ene-products, i.e. homoallylic alcohols, were afforded in 36-87% yields giving a scope of various with 1,1-disubstituted alkenes and the cyclization of citronellal. N-heterocyclic carbenes (NHC) are recognized as promising ligands in transition metals catalysis. Three caffeine-derived xanthinium salts were used as NHC precursors to transition metals iron for developing an NHC-iron catalyst in the intermolecular carbonyl-ene reaction and the intramolecular carbonyl-ene reaction of citronellal. Optimized conditions were developed from the screening of iron salts, solvents, catalyst loading and counter anions. Fe(OTf)2 was found to efficiently catalyze the

reaction while complexed with NHC ligand derived from methylated caffeine xanthinium salt. Caffeine-derived-[NHC-Fe]2+_(SbF₆₎₂₂₋_{catalyzed carbonyl-ene reaction of various enophiles with}

ethyl trifluoropyruvate afforded 22-99% yields in homoallylic alcohols. NHC-FeCl2[SbF6] was

efficiently and selectively used as a catalyst to convert citronellal into the desired isopulegol. Caffeine-derived xanthinium salt was designed with Fe(OTf)2 as a recyclable catalyst for Diels-Alder

reaction in dimethyl carbonate used as a green solvent. Several other green solvents were examined to further study the application of green solvents in organic synthesis. The catalyst, derived from a caffeine-derived xanthinium salt and Fe(OTf)2, was recycled up to five times, while maintaining the

same level of yields for the Diels-Alder reaction and recyclability. A relative large scope of substrates including bidentate dicarbonyl compounds, ketones, aldehydes, and esters were tested. Alkoxyl-NHC ligands were developed as a rising family of ligands in enantioselective conjugate addition. A series of new NHC-diol ligands were designed and tested in the carbonyl-ene reaction. These newly developed ligands are promising systems in asymmetric catalysis and transition metal catalysis.

(5)

v

List of Schemes

Scheme 1−1 The discovery of Fenton's reagent ... 3

Scheme 1−2 The mechanism of Fenton’s reagent ... 3

Scheme 1−3 The Haber-Bosch process ... 5

Scheme 1−4 The Fischer-Tropsch process ... 5

Scheme 1−5 Reppe's alcohol synthetic route ... 6

Scheme 1−6 FeCl3 catalyzed allylation of aldehydes and allyltrimethyl silane ... 7

Scheme 1−7 FeCl3·6H2O catalyzed Michael addition ... 7

Scheme 1−8 Iron catalyzed enantioselective Michael addition by the assistance of a chiral auxiliary ... 8

Scheme 1−9 Iron catalyzed cycloaddition of diallenes with carbon monoxide... 8

Scheme 1−10 Iron catalyzed isomerization of allylic alcohols ... 8

Scheme 1−11 A bis-imino-pyridyl iron complex catalyzed polymerization ... 9

Scheme 1−12 Trifluoromethylation of terminal olefins by using FeCl2 ... 9

Scheme 1−13 Aerobic oxidative coupling of naphthols by using a salen-iron complex ...10

Scheme 1−14 Asymmetric O−H insertion by using a chiral spiro-bisoxazoline-iron complex ...10

Scheme 1−15 Oxidative esterification of aromatic aldehyde by an iron-NHC catalyst ...11

Scheme 1−16 The hydrogenation of alkynes to alkenes by using a phosphine-iron complex ...11

Scheme 1−17 Second generation of Grubbs’s catalyst with a NHC as a ligand for alkene metathesis reaction ...13

Scheme 1−18 A cyclopropanation study of diazoacetate and toluene by Eduard Buchner ...14

Scheme 1−19 The first NHC-Iron complex by Ö fele ...16

Scheme 1−20 NHC-Fe in Kumada-type cross-coupling reaction ...17

Scheme 1−21 Regioselective allylic alkylation by using NHC-Fe ...18

Scheme 1−22 Selective NHC-iron catalyzed borylation ...18

(10)

x

Scheme 1−24 Hydrogenation by Py-bisNHC-Fe complex ...19

Scheme 1−25 Atom transfer radical polymerization catalyzed by bisNHC-FeBr2 ...19

Scheme 1−26 Oxidation of aromatic hydrocarbons catalyzed by Py-NHC-Fe complex ...20

Scheme 1−27 Carbometalation with methyl Grignard reagents catalyzed by NHC-iron ...20

Scheme 1−28 Hydrosilylation by NHC-Fe catalysis ...21

Scheme 1−29 Bis-oxazoline-Cu catalyzed glyoxylate-ene reaction of an aldehyde and a ketone .22 Scheme 1−30 Carbonyl-ene reaction of ethyl trifluoropyruvate with -methylstyrene ...23

Scheme 1−31 Alkylation of caffeine ...25

Scheme 1−32 The application of bis-NHC-PdI2 in Suzuki cross-coupling reaction ...26

Scheme 2−1 Metal triflate catalyzed carbonyl-ene reaction of ethyl trifluoropyruvate ...38

Scheme 2−2 Iron salts catalyzed carbonyl-ene reaction ...38

Scheme 2−3 Optimization of solvents ...40

Scheme 2−4 Carbonyl-ene reaction of various alkenes and ethyl trifluoromethyl pyruvate ...41

Scheme 2−5 Intramolecular carbonyl-ene reaction of (S)-(+)-citronellal...43

Scheme 2−6 Caffeine as reactant and a stabilizing ligand ...45

Scheme 2−7 Caffeine act as a ligand to iron salts in carbonyl-ene reaction ...46

Scheme 2−8 Iron-Bolm’s ligand catalyzed Mukaiyama Aldol reaction ...47

Scheme 2−9 Bipyridine as a ligand to ironII triflate in catalyzing carbonyl-ene reaction ...47

Scheme 2−10 Formation of caffeinium salts by alkylation of caffeine ...49

Scheme 2−11 Ligand 1-derived NHC-Fe(OTf)2 catalyzed carbonyl-ene reaction ...50

Scheme 2−12 Examination of different solvents in ligand 1-derived-NHC-iron catalyzed carbonyl-ene reaction...52

Scheme 2−13 Ligand 2-derived-NHC with different iron salts in catalyzing carbonyl-ene reaction 53 Scheme 2−14 Study of solvent effect using ligand 2-derived-NHC iron catalyzed carbonyl-ene reaction ...54

(11)

xi

Scheme 2−16 Development of ligand 2-derived-NHC-FeIII_{in carbonyl-ene reaction ...57}

Scheme 2−17 Testing different alkenes with the catalyst of ligand 2 derived-NHC-Fe(SbF6)2 in carbonyl-ene reaction of trifluoropyruvate ...58

Scheme 2−18 Further optimization of using substrate mehylenecyclohexane by ligand 1 and Fe(OTf)2 ...60

Scheme 2−19 Further optimization of using substrate methylenecyclohexane with ligand 2 and Fe(SbF6)2 ...61

Scheme 2−20 Development of NHC-iron catalyst in the intramolecular carbonyl-ene reaction of the cyclization of citronellal ...62

Scheme 2−21 Comparison of ligand 1 with ligand 4 and ligand 2 with ligand 5 in NHC-iron catalyzed carbonyl-ene reaction ...65

Scheme 2−22 Synthesis protocol of a free carbene, 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene, IMes ...67

Scheme 2−23 Structures of caffeine and ligand 1 ...68

Scheme 2−24 Determination of caffeine derived NHC by method 1 ...70

Scheme 2−25 Determination of caffeine derived NHC using method 2 ...70

Scheme 2−26 Determination of caffeine derived NHC using method 3 ...71

Scheme 2−27 Synthesis of caffeine-derived NHC-iron complexes ...73

Scheme 3−1 An example of asymmetric Diels-Alder reaction ...80

Scheme 3−2 Prochiral center as stereochemical control element in N-acyloxazolinone in D-A ...80

Scheme 3−3 FeIII_{as Lewis acid catalyzed Diels-Alder reaction ...83}

Scheme 3−4 Preparation of caffeine derived-imidazolium salts and the iron-caffeinium catalysts 1−4 ...84

Scheme 3−5 Optimization of Diels-Alder reaction ...86

Scheme 3−6 Recyclability test using catalyst C1 ...88

Scheme 3−7 Caffenium iron catalyst catalyzed carbonyl-ene reaction ...93

Scheme 3−8 FeCl3 promoted acetylation of benzyl alcohol acetic anhydride...94

Scheme 3−9 Application of caffeine derived imidazolium-Fe(OTf)2 catalyst in acetylation of benzyl alcohol and acetic anhydride ...94

(12)

xii

Scheme 4−1 Arnold’s NHC-Cu-alkoxide complex ...99

Scheme 4−2 Formation of mono-NHC-Cu by transmetallation of NHC-Li alkoxide with CuCl2 ...99

Scheme 4−3 Enantioselective conjugate addition of diethyl zinc to cyclohexanone ...99

Scheme 4−4 Synthesis of a bidentate alkoxyl-NHC-Ru complex in Hoveyda’s group ...100

Scheme 4−5 Alkoxyl-NHC-Ru complex catalyzed metathesis...100

Scheme 4−6 Alkoxyl-Cu-NHC generated through transmetalation with relative alkoxyl-Ag-NHC complex in catalyzing allylic alkylation ...101

Scheme 4−7 Alkoxyl-Rh/Ir-NHC complexes in catalyzing hydrosilylation reaction ...101

Scheme 4−8 Ionic liquid incorporating hydroxyl group by using chiral L-valine ...102

Scheme 4−9 L-Leucinol derived NHC-alkoxyl bidentate ligands with Cu(OTf)2 in enantioselective conjugate addition ...102

Scheme 4−10 Synthesis of NHC-diol ligands by Wilhelm ...103

Scheme 4−11 Synthesis of NHC-diol ligands by epoxide-opening reaction ...104

Scheme 4−12 NHC-diol-copper and -iron catalyzed asymmetric addition of an enantioselective conjugate addition ...104

Scheme 4−13 NHC-diol ligand modified Fe3O4/Pd nanoparticle in catalyzing α-arylation of ketones ...105

Scheme 4−14 Fe-Bolm’s ligand catalyzed Mukaiyama aldol reaction ...105

Scheme 4−15 Pyridine-bisNHCs-iron complexes catalyzed Kumada-type cross-coupling...106

Scheme 4−16 Preparation of (R)-tert-butyloxirane by oxidation and resolution...107

Scheme 4−17 Synthesis of NHC-diol ligand from (S,S)-1,2-diphenyl-ethylene trans-diamine...108

Scheme 4−18 Synthesis of NHC-diol ligand from enantiomeric enriched (R,R)-1,2-diaminocyclohexane ...109

Scheme 4−19 Epoxide opening reaction of (R)-tert-butyloxirane by imidazole ...109

Scheme 4−20 Synthesis of ligands 4-7 ...110

Scheme 4−21 Complexation of ligand 6 with Ag2O and its proposed structure ...111

(13)

xiii

Scheme 4−23 Iron-C2 symmetric ligands catalyzed carbonyl-ene reaction ...114

Scheme 4−24 Synthesis of “a porphyrin-inspired ligand” and a desired/expected NHC precursor base on the ligand ...117 Scheme 4−25 Catalytic tests in carbonyl-ene reaction and epoxide-opening reaction ...118

(14)

xiv

List of Figures

Figure 1−1 Significant NHC-metal complexes in the development of NHC history ...15

Figure 1−2 BisNHC-Fe complexes in cross-coupling reactions ...17

Figure 1−3 Other NHC-Fe complexes in the reduction of double bonds ...21

Figure 1−4 The development of catalysts for the trifluoropyruvate-ene reaction ...23

Figure 1−5 The first caffeine derived-NHC-Hg complex ...25

Figure 1−6 Development of various caffeine derived-NHC-metal complexes...26

Figure 2−1 Reaction scope of different of alkenes ...42

Figure 2−2 Postulated mechanism ...43

Figure 2−3 Reaction scope of ligand 2 derived-NHC-Fe(SbF6)2 catalysis in carbonyl-ene reaction ...59

Figure 2−4 Postulated mechanism of the NHC-Fe catalyzed carbonyl-ene reaction of ethyl trifluoropyruvate and -methylstyrene ...64

Figure 2−5 Electronic property of caffeine derived-NHC-Fe bonding orbital ...66

Figure 2−6 1_{H NMR of caffeine and ligand 1 ...69}

Figure 2−7 Determination of caffeine derived NHC using method 1 ...70

Figure 2−8 Determination of caffeine derived NHC using method 2 ...71

Figure 2−9 Determination of caffeine derived NHC by method 3 ...72

Figure 2−10 Caffeine derived-NHC generated without Fe(OTf)2 in CH2Cl2 ...74

Figure 2−11 Caffeine derived-NHC generated with Fe(OTf)2 in CH2Cl2 ...75

Figure 3−1 FeII_/FeIII_{-catalyzed enantioselective Diel-Alder reaction ...82}

Figure 3−2 Iron complexes catalyzed Diels-Alder reaction ...83

Figure 4−1 Modified alkoxyl-NHC by 2,6-di-isopropyl group or adamantyl group ...101

Figure 4−2 Synthesis of NHC-diol ligands developed by Wilhelm ...103

Figure 4−3 Pyridine bisNHC-diol type of ligands developed in literature ...106

(15)

xv

Figure 4−5 NHC-diol ligands 6b-11b ...111 Figure 4−6 Postulated coordination of Box-FeII_{and Py-Box-Fe}II_...116

(16)

xvi

List of Tables

Table 1−1 The development of catalysts for the trifluoropyruvate-ene reaction ...24

Table 2−1 Screening of a few metal triflate Lewis acids ...38

Table 2−2 Screening of iron salts in carbonyl-ene reaction ...39

Table 2−3 Screening of solvents in carbonyl-ene reaction ...41

Table 2−4 Caffeine as a ligand in iron-catalyzed carbonyl-ene reaction ...46

Table 2−5 Optimization of Bipyridine-Fe(OTf)2 catalyzed carbonyl-ene reaction ...48

Table 2−6 Optimization of Ligand 1-derived NHC-Fe(OTf)2 catalyzed carbonyl-ene reaction ...51

Table 2−7 Screening of different solvents in ligand 1-derived-NHC-iron catalyzed carbonyl-ene reaction ...52

Table 2−8 Screening of different iron salts with Ligand 2-derived-NHC in catalyzing carbonyl-ene reaction of ethyl trifluoromethyl pyruvate ...53

Table 2−9 Screening of various solvents using ligand 1-derived-NHC iron catalyzed carbonyl-ene reaction ...54

Table 2−10 Development of anhydrous Fe(BF4)2 and Fe(SbF6)2 with ligand 1-3 ...56

Table 2−11 Variation of the composition of the desirable catalytic species in the reaction by using FeCl3 and AgSbF6 with ligand 2 ...57

Table 2−12 Further optimization for the reaction of mehylenecyclohexane using ligand 1 and Fe(OTf)2 ...60

Table 2−13 Further optimization of using substrate mehylenecyclohexane with ligand 2 and Fe(SbF6)2 ...61

Table 2−14 Optimization of NHC-iron catalyst in the intramolecular carbonyl-ene reaction of the cyclization of citronellal ...63

Table 2−15 Synthesis of caffeine-derived NHC-iron complexes...73

Table 3−1 Optimization of the Diels-Alder reaction ...86

Table 3−2 Screening of selected “green” solvents ...88

Table 3−3 Recyclability in 5 runs and yield of each run ...89

(17)

xvii

Table 3−5 Less reactive substrates in the reaction scope ...92

Table 3−6 Caffenium iron catalyst catalyzed carbonyl-ene reaction ...93

Table 4−1 Application of NHC-diol ligand with iron in testing carbonyl-ene reaction ...112

(18)

xviii

List of Abbreviations

Å angströ m

ATRP atom transfer radical polymerization

Bipy 2,2’-bipyridine Boc tert-butyloxycarbonyl Box bis-oxazoline CO carbonyl COD 1,5-cyclooctadiene Cp- cyclopentyl

CPME cyclopentyl methyl ether

D-A Diels-Alder

DCE 1,2-dichloroethane

DCM dichloromethane

DIPP 2,6-diisopropylphenyl

DMC dimethyl carbonate

DME dimethyl ether

DMF dimethylformamide

DMSO dimethyl sulfoxide

EtOAc ethyl acetate

ee enantiomeric excess

F−T Fischer−Tropsch process

HPLC high-performance liquid chromatography

IL ionic liquid

IMes 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene

KHMDS potassium bis(trimethylsilyl)amide

LUMO lowest unoccupied molecular orbital

(19)

xix

NHC N-heterocyclic carbene

NMP N-methyl-2-pyrrolidone

NMR nuclear magnetic resonance

NP nanoparticle

Ph phenyl

Pybox pyridine-2,6-bis-oxazoline

TBME tert-butyl methyl ether

tBu tert-butyl

THF tetrahydrofuran

Tr triphenylmethane

(20)

xx

ACKNOWLEDGEMENTS

Life is a story for everyone, and one needs to write it with the help of others. I am immensely grateful to all the people who gave me so much help, patience, courage, enlightenment, and love. All the streams flow together, and it becomes a river. All the support together from those who played significant roles during my doctoral studies bolstered my Ph. D. and the completion of this thesis.

At first, I want to give my deep thanks to my supervisor Professor Thierry Ollevier for so much effort he put into each step in the past four years. For starting from learning the basics of organic chemistry to pursuing a challenging project, it was an impossible mission without the guidance of my professor. I am very grateful for helping me face the challenges in my Ph. D. His rich knowledge and experience, optimism, and creative thinking propelled my study and work.

I deeply thank China Scholarship Council for providing me a four year doctoral scholarship.

I wish to acknowledge all the group members for their help, time and enthusiasm. I feel thankful for Mathieu Lafantaisie for his help during my first year in Qué bec. I will always remember that Dr. Martin Pichette Drapeau spent much time in helping me be familiar with the laboratory techniques. A huge thank-you also to my colleagues Dr. Angela Jalba and Dr. Hoda Keipour, who are such diligent people and shared many responsibilities in the laboratory. A warm hug will be given to Dr. Jamil Kraïem for his trust and the short, but humorous, and relaxed time working together. An enormous thank-you to each of the following awesome people: Mao Li, Dazhi Li, Dandan Miao and Wan Xu for the wonderful time together in our lives and so much communication and sharing and help, Samuel Lauzon, Samuel Cashman-Kadri, Virginie Carreras, Nour Tanbouza, Claire Besnard for passing precious time in lab.

I want to give Mr. Pierre Audet a deep thank for many useful discussions and help on NMR and MS. A sincere thank must be given to the departmental staff: Denyse Michaud, Mé lanie Tremblay, Christian Cô té , Magali Goulet, Marie Tremblay and Jean Laferriè re. I would like to thank Professor John Boukouvalas for his courses. Also, I appreciate Ramesh Muddala for his help in laboratory.

Moreover, I would like to thank Xiaomian, Zhijun, Min, Shuang, Sarah, Ghislain, Asende, Diego, Mauricio, Paolo, Cynthia, et al. Last, my family is always the place full of love and courage where I can restart my journey.

(21)

1

Chapter one

Introduction

1.1 Iron catalysis and the objectives of the research

Iron is situated in the middle of the d-block in periodic table. As the second most abundant metal on earth, it is ubiquitous in the crust of our planet. The principal iron ores are hematite (Fe2O3), magnetite

(Fe3O4), and siderite (FeCO3). There are also other ores such as pyrite (Fe2S2), magnetite (FeTiO3),

and ferropericlase (Mg, Fe)O. Pure iron that smelted from iron ores has been found as early as 2,000 B.C. Iron chemistry was advanced in a slow pace for thousands of years until the last century. Important applications of iron in heterogeneous catalysis in modern times include its use in the Haber process for ammonia synthesis and the Fishcher−Tropsch process for producing gasoline.1

Since the past 40 years, beyond doubt, iron has emerged as a rising star in emulating other transition metals especially noble metals in homogeneous catalysis. Comprehensive reviews and in-depth analyses of iron catalysis provided insights of its development and future. A significant article entitled as “Iron Catalyzed Reactions in Organic Synthesis” was published in 2004 by Bolm et al.2_{After that,}

tremendous work took place and a vast number of reviews, highlighted articles, and books have been published. Iron was demonstrated to catalyze a large scope of transformations in the reviews “Iron Catalysis in Organic Synthesis”,3_{and “Iron Catalysis in Organic Synthesis: A Critical}

Assessment of What It Takes To Make This Base Metal a Multitasking Champion” provided a profound analysis of the emerging uses of iron.4_{Various aspects of iron have been reviewed such}

as the application of iron(III) chloride,5_{iron-catalyzed cycloaddition reactions,}6_{cross-coupling}

reactions,7_{enantioselective transformations,}8_{NHC metal catalysis,}9_{iron phosphine catalysts,}10

application of ferrocenes11_{etc. The reasons for the development in iron chemistry were addressed}

in the reviews above.

The abundance of iron makes it much cheaper than other metals applied in catalysis. Due to the increasing price of the transition metals or other rare metals for the past ten years, the demand for cheap alternative was claiming.12_{Moreover, many iron salts are readily available as commercial}

(22)

2

products13_{and methods of incorporating different moieties for tuning electronic or steric properties}

were discovered and readily converted into relevant applications.3

The electronic configuration of iron is 1s2_2s2_2p6_3s2_3p6_4s2_3d6_{, and the oxidation state of iron varies}

from −2 to +6. The broad span makes it useful in reduction and oxidation reaction. Another characteristic was the ability to transfer electrons, which facilitates the coupling reaction or polymerization. Lewis acidity varies from moderate to high, which actually is correlated with the oxidation state. Hence, the modification of the electronic property of iron provides a way for new discoveries.3

Iron is categorized as relatively non-toxic and environmental benign. It was disclosed that none of the biocatalyst evolved from nature derived from noble metals, but iron is extensively used by all forms of life.14_{Furthermore, iron is considered as causing “minimum safety concern” in drug}

developing process and is bearing a much higher tolerable limitation than other metals. Research in iron catalysis was described as “the most rewarding”. Considering that iron covers almost the full scope of organic transformations, the large scale industrial application will be the most economically beneficial. There are enormous opportunities for discovering new methodologies of iron catalysis.

Many remarkable applications of iron chemistry were selected from the literature and reviewed herein to highlight to a clear perspective of its development. Fenton oxidation process is deemed as the first application in the history of iron catalysis. In 1876, H. J. H. Fenton described a colored product from the mixture of tartaric acid, hydrogen peroxide, and a low concentration of ferrous salt. In 1894, Fenton reported the phenomenon that adding alkali metal to an aqueous solution of tartaric acid with certain oxidizing agents in the presence of a FeII+_{salt makes the solution turn to a violet colour}

(Scheme 1−1).15_{Further experiments by using standard solutions of tartaric acid, ferrous sulphate,}

and hydrogen peroxide brought more insight into the phenomenon. A small quantity, but essential as a catalyst, of iron salt was enough to promote the oxidation of tartaric acid with hydrogen peroxide. The formula of the product was given in the article and the mechanism was proposed. Tartaric acid was oxidized by hydrogen peroxide to form dihydroxymaleic acid, which formed a violet colored complex with FeIII_{. Ferrous salt was the catalyst in the process and was regenerated through}

oxidation-reduction. Oxygen was involved in forming a peroxide radical with tartaric acid carbon-centered radical (Scheme 1−1).16

(23)

3

Scheme 1−1 The discovery of Fenton's reagent

Subsequently, the solution of ferrous salt and hydrogen peroxide was named as “Fenton’s reagent”. In the solution, a disproportionation of hydrogen peroxide took place. The generally accepted mechanism of the Fenton’s reagent was demonstrated (Scheme 1−2). Hydroxyl radical was formed in the oxidation process of Fe2+_{to Fe}3+_{by hydrogen peroxide, and Fe}2+_{was regenerated by the}

reduction of another molecule of hydrogen peroxide while producing a hydroperoxyl radical. Two free radicals generated in the process promoted secondary reactions. The HO· has high oxidative power and non-selectively oxidizes organic compounds to carbon dioxide and water. (Scheme 1−2)

Scheme 1−2 The mechanism of Fenton’s reagent

The process was largely indluenced by pH, temperature, concentrations of iron and hydrogen peroxide. The hydroxyl radical reacts with most organic molecules and many inorganic substances at a higher rate than other conventional oxidants such as chlorine, O2, O3, or KMnO4. Hence, due to

the strong oxidative power, the application of Fenton’s reagent has been extended to industrial wastewaters with a wide range of contaminants. For example, amino acids were oxidized to the corresponding -ketonacid and aldehydes and carboxylic acids containing one less carbon in the deamination-decarboxylation proceses.17_{Fenton’s oxidation has been used to process a wide range}

(24)

4

of industrial wastewaters such as chemical, pharmaceutical, textile, paperpulp, cosmetic, cork processing wastewaters etc. with remarkable progress in decreasing the toxicity to the environment. Fenton’s reaction was promoted to Fenton’s chemistry involving Fenton-like processes generating hydroxyl radicals catalyzed by different Fe-hydroxides or Fe-oxides, which was known as advanced oxidation processes (AOPs). Various ways of AOPs were applicable such as homogeneous Fenton, heterogeneous Fenton, photo-Fenton, photocatalysis, and ozonation etc.18,19

Haber-Bosch process is a milstone in the history of iron catalysis since it was patented in 1910 and started to produce ammonia in 1913.20_{Iron was applied as an heterougeneous catalyst in the}

synthesis of ammonia from elemental nitrogen and hydrogen.7_{This artificial nitrogen fixation process}

has been called the most important invention in the 20th_{century. The significance of the invention}

was discussed from the aspects of population growth, environment changes, biodiversity, economy, industrial production etc.21_{The reaction itself is intriguing as it demonstrates the role that iron plays.}

High pressure and high temperature were applied for the industrial process, and the iron used was generally magnetite (Fe3O4), doped with irreducible oxides K2O on a supportive alumina or silica

(Scheme 1−3). Potassium was a promoter as to donate electrons to the neighboring iron. Gaseous nitrogen and hydrogen are adsorbed on iron particles. Kinetic studies show that nitrogen-chemisorption on the surface of iron is the rate-limiting step. As a result, iron catalyst requires high energy input, as well as the high temperature and high pressure, to increase the reaction rate and keep the adsorption-desorption equilibrium to shift toward the product. In the process, ammonia formed from molecular nitrogen and hydrogen on iron surface.22

The mechanism of understanding how nitrogen N2 reacted, whether N2 dissociated or not is a

long-lasting question. It was not able to discriminate the real reaction mechanism in the industrial process based on the kinetic study alone. One mechanism is welcomed. According to it, during the process N2 triple bonds and single bond of H2 were cleaved and elemental N and H form bonds from N-H,

NH2, to NH3.23 However, the nature of reactive species in the mechanisms proposed is still

controversial. Studies of new iron catalysts for nitrogen activation are still ongoing.24_{Although the}

development of Ru and Co catalyst for improving the thermodynamic efficiency and transition metals catalysis under homogeneous and ambient conditions, the catalyst used presently in industry is not

(25)

5

different from the one developed a century ago. Iron catalysis is still unshakable in the nitrogen-fixation field nowadays.25

Scheme 1−3 The Haber-Bosch process

While Haber-Bosch process propelled the growth of population in providing fertilizers, the Fischer-Tropsch process (F-T) dealt with the energy demand for fuel. It discovers a route of converting natural resources of carbon monoxide and hydrogen into liquid hydrocarbons in a metal catalyzed heterogeneous catalysis process. Only the metals Fe, Ni, Co, and Ru exhibited suitable catalytic efficiency for the F-T process. But Ni is too selective towards CH4 while Ru suffers from extreme high

price. Fe and Co are the choices for industrial scale application. Iron pre-catalyst used in the process are currently prepared by precipitation technology from using iron oxides and doped with Cu, K2O

and bound with Si. The pre-catalyst needs to be activitated by reducing under H2 or CO atmosphere.

Similar as the Haber-Bosch process, the exact structural composition of the active site in iron-based catalyst system is still ambiguous to determine. The mechanism of the production of hydrocarbons on iron surface in the F-T process is described in Scheme 1−4. Iron oxides were activated by hydrogen H2 and carbon monoxide CO, then on the surface the reaction took place in the order of

reactant adsorption, chain initiation, chain growth, chain termination. Finally, the alkanes, alkenes, and oxygenates products were generated.

(26)

6

Haber-Bosch and Fischer-Tropsch processes are famous application of iron-based catalysts in heterogeneous chemistry. The Reppe synthesis of iron catalyzed alcohols from CO and water in 1953 is usually viewed as the prelude to the development of homogeneous iron catalysis (Scheme 1−5).27_{Significant advancement of transition metal based homogeneous catalysis started in the}

second half of the twentieth century.

Scheme 1−5 Reppe's alcohol synthetic route

Chronologically, iron was pioneered in the 1970s in the research of cross-coupling reaction. But the real breakthrough in homogeneous iron catalysis was the iron-porphyrin complex for oxidation reactions after the investigation of the complex.14_{In the 1970s, cytochromes P-450, as a unique}

class of hemoproteins, was known for oxygen transfer and was used to catalyze the hydroxylation.28,29_{Single oxygen donor, such as hydroperoxides, peroxy acids, and iodosylbenzene,}

was believed to behave similarly with iron-porphyrin species as hemoprotein enzyme in the biological process.29_{In 1979, two years later after the major advance in asymmetric catalytic epoxidation by}

Sharpless and Yamada,30_{Groves reported the hydroxylation and epoxidation of hydrocarbons}

catalyzed by a porphyrin-iron complex with iodosylbenzene as an oxygen source.28_{During this period,}

oxygen transfer in blood cell was a research interest.31_{A few years later, he disclosed an}

enantioselective version of epoxidation by using a chiral iron porphyrin catalyst.32_{Since then, in the}

1980s and 1990s, a slow increase of iron-catalyzed reactions in organic synthesis was observed in various branches. Untill the summary of iron was in a general review by Bolm in 2004, the research of iron was still underrepresented compared to other transition metals.2

For 1980 to 2004, major advancements, such as addition reactions, substitution reactions, oxidation reactions, polimerizations etc. have took place. Iron salts performed mainly as catalysts in the non-asymmetric catalysis, while significant breakthrough was achieved in enantioselective transformations such as in Diel-Alder reactions, 1,3-dipolar cycloadditions and sulfoxidations. The compiled results were highly attractive and surprisingly encouraging for the organic chemistry field.2

FeCl3 and its hexahydrated salt FeCl3·6H2O were used extensively in transformation processes.5

(27)

7

developed by using anhydrous FeCl3, and the reaction led to homoallylic alcohols in high yields within

short reaction times for a large scope (Scheme 1−6). Only when using electron-rich aromatic aldehyde substrates, such as p-tolualdehyde and p-anisaldehyde, almost no yield was obtained. An improvised way was used by converting the aldehydes to acetals and the reaction promoted smoothly in high yields.33

Scheme 1−6 FeCl3 catalyzed allylation of aldehydes and allyltrimethyl silane

FeCl3·6H2O was considered as the best catalyst for Michael addition. Excellent results had been

obtained for the substrates of cyclic and acyclic β-dicarbonyls to various acceptors at low catalyst loadings. But for specific substrates such as 1,2-disubstituted Z-enones as acceptors, there was no efficiency; while for E-substituted substrates, the reactions afforded mixtures of kinetic diastereomers (Scheme 1−7).34

Scheme 1−7 FeCl3·6H2O catalyzed Michael addition

Chiral auxiliaries were used to develop an iron catalyzed enantioselective Michael addition. An -amino acid amide was used with an -ketone ester to form a chiral enamine which was the nucleophile to methylvinyl ketone under the catalyzing of FeCl3·6H2O. In the early stage of

(28)

8

Scheme 1−8 Iron catalyzed enantioselective Michael addition by the assistance of a chiral auxiliary

Iron salts such as FeBr2, FeCl2, Fe(acac)3, Fe(DBM)2, FeSO4, Fe(ClO4)2, FeCl2[P(OEt)3]3 etc. were

developed in various reations.2_{Among which the iron carbonyl compoumds were employed in}

cycloadditions and isomerization. A five-membered carboxylic ring was formed in a [4+1] reaction of carbon monoxide and diallenes catalyzed by Fe(CO)5. The mechanism revealed a “π-facial

coordination” between the diallene substrate and iron, and a metallocyclopentene intermediate was formed from the coordinated substrate. The dialkyly denecyclopentenones were produced in a high yield (Scheme 1−9).36

Scheme 1−9 Iron catalyzed cycloaddition of diallenes with carbon monoxide

Iron carbonyl derivatives are effective in the photocatalytic isomerization of alkenes. The initiation of the process requires thermal or photo assistance. Although high yields could be afforded, selectivity of the reaction towards the desired product is difficult to control. But still the isomerization of allylic alcohols was developed (Scheme 1−10).37

Scheme 1−10 Iron catalyzed isomerization of allylic alcohols

The imine group as a functional ligand to iron such as bis-imino-pyridyl iron complexes were developed in polymerization (Scheme 1−11). Polyethylene is one the most produced polymers

(29)

9

products in the world. Iron complexes formed with 2,6-bis-iminopyridyl ligands were proved to be very efficient in the polymerization of ethylene to polyethylene. The efficiencies of such iron catalyst were described as remarkably high since the TOFs were achieved more than 107_{/h and compared}

with Ziegler-Natta systems.38_{The results obtained with iron have been proven to be superior to those}

with colbalt species.

Scheme 1−11 A bis-imino-pyridyl iron complex catalyzed polymerization

For the past fifteen years, there was a rapid increase in developing new iron catalyst species and breakthrough in homogeneous catalysis.2-11_{New transformations of using iron salts have been}

achieved. For example, the trifluoromethylation of terminal olefins was catalyzed by FeCl2 between

2-arylvinyltrifluoroborates and Togni’s reagent II (Scheme 1−12).39_{The yields afforded were from}

good to high. The configuration of the products was influenced by the original olefins, and high stereoselectivity and mixtures were both afforded.

Scheme 1−12 Trifluoromethylation of terminal olefins by using FeCl2

An efficient approach to enantiometic enriched binaphthalene-diols using atmospheric oxygen as oxidant was developed while benefited from a salan-iron complexes as catalyst (Scheme 1−13). The high yields and high ee rank the aerobic oxidative coupling of naphthols highly valuable to accessing to chiral ligands and organocatalysts. More interestingly, two different substituted 2-naphthols were applicable to the method.40

(30)

10

Scheme 1−13 Aerobic oxidative coupling of naphthols by using a salen-iron complex

A limited number of chiral iron catalyst was reported and proven to be more efficient than other transition metals. However, a family of chiral spiro-bisoxazoline-iron complex was designed and verified as higly efficient catalyst for asymmetric O─H bond insertion reactions by Zhou (Scheme 1−14). It is worth to mention that a common iron salt FeCl2·4H2O was chosen. Mild conditions were

developed for a wide range of alcohols and even water with diazo ester compounds.41

Scheme 1−14 Asymmetric O−H insertion by using a chiral spiro-bisoxazoline-iron complex

N-heterocyclic carbene was emerging as a ligand to transition metals.9_{Esters are important}

functional groups in natural and synthetic molecules.42_{The direct oxidative esterification of}

aldehydes provides an alternative to conventional routes.42_{Upon analysis of the limitation of the}

(31)

11

yields in the literature, an aerobic oxidative esterification of aromatic aldehyde with boronic acids was disclosed by using Fe(OTf)2 with NHC as a catalyst. Up to 97% yields with avarious of aromatic

aldehydes and boronic acids (Scheme 1-15).43

Scheme 1−15 Oxidative esterification of aromatic aldehyde by an iron-NHC catalyst

Catalytic hydrogenation of olefins in the presence of iron compound as a catalyst dated back to the 1960s.44_{(Pyridyl)diimine type of ligand was often used with iron in the reduction transformations.}45

The transformation of alkynes to alkene by transition-metal catalysts is employed in many processes.46_{Another type was incorporating phosphine as a coordinating ligand to iron in this}

transformation. An acridine-based PNP iron complex was proven to catalyze a semi-hydrogenation of alkynes to E-alkenes using H2.47

(32)

12

1.2 General objectives of the thesis

Transition metal catalysis is one of research interest in our group. Methodologies for asymmetric Mukaiyama reaction, epoxide openning reaction, hydrosilylation, oxidation, Michal addition, etc. were reported using iron bipyridine type catalysts.48_{The objectives of this research are to continue to focus}

on iron catalysis and to discover new iron catalysts on expending the less “iron-involved” transformations. In one of the projects of this research, carbonyl-ene reaction was chosen due to the less developed situation of iron in this type of carbon bond forming process. Another one was Diels-Alder reaction on the purpose of recycling the catalyst and developing alternative solvent to tranditional methods.

1.3 N-Heterocyclic carbene (NHC) chemistry

This part focuses on the development of an NHC-iron catalyst as a Lewis acid for the carbonyl-ene reaction. The opening includes a short summary of the history of caffeine-derived N-heterocyclic carbene chemistry, iron-NHC chemistry and the development of carbonyl-ene reaction.

Carbene is defined as a neutral divalent carbon containing six valence electrons.49_{N-heterocyclic}

carbenes originally derived from imidazolium salts, was later on diversified in their structure and functionalization.50_{N-heterocyclic carbenes have been applied as ligands with late transition metals}

from group 7 to group 11.51_{The most famous application of N-heterocyclic carbene is the second}

generation of Grubbs’s catalysts for alkene metathesis, arisen from the substitution of phosphine ligands by IMes (NHC) (Scheme 1−1).52_{The second generation of Grubbs’s catalyst was the main}

breakthrough for the development of metathesis, which was demonstrated initially by Y. Chauvin, R. H. Grubbs, and R. R. Schrock, respectively, who shared the Nobel Prize in chemistry in 2005.52_Many

crucial historical moments became essential for the development of N-heterocyclic carbenes in history.

N-heterocyclic carbene (NHC) has been a hot topic in organic chemistry for the past two decades since the first successful isolation and characterization of a free crystalline carbene by Arduengo in 1991.53_{IThis discovery triggered the enthusiasm of researchers for the role that N-heterocyclic}

carbenes as ligands could play in. Then, for the past 27 years, intensive research activity was invested in this area.54

(33)

13

Scheme 1−17 Second generation of Grubbs’s catalyst with a NHC as a ligand for alkene metathesis reaction

This milestone of Arduengo’s carbene was built on the contribution of many pioneers’ work. In the 1800s, the development of coordination chemistry progressively built up since that period.55

Coordination complexes such as copper vitriol, Prussian blue, etc. were known in 1800s, but the structures of these compounds were unclear. The formula of Prussian is Fe7(CN)18 or

Fe4[Fe(CN)6]3·xH2O. Now we know that the Fe(II) centers are surrounded by six carbon ligands of

cyanides in an octahedral configuration while the Fe(III) centers are octahedrally surrounded on average by 4.5 nitrogen atoms and 1.5 oxygen atoms.56-57_{The copper vitrol (CuSO}₄_·xH₂_{O) usually}

has a pentahydrate structure while the copper centers are interconnected with a sulfate anion.25_But

in those days, because of the absence of X-ray crystallography technology, the coordination of ligands was hardly understood. The breakthrough in coordination chemistry was made by a Swiss chemist, Alfred Werner, in1893. He correctly proposed the structure of CoCl3(NH3)6 and the

geometric isomers of the complex [CoCl2(NH3)6]Cl, in which the six NH3 and two Cl¯ occupy the

octahedral vertices of Co3+_{and one Cl¯ is dissociated. The geometric configuration and the valence}

theory laid the foundation of modern coordination chemistry.58-60_{Because of this significant work,}

Alfred Werner won the Nobel Prize in chemistry in 1913.

Another event in coordination chemistry was the introduction of the concept of “Ligand”. In the complexes, the coordinated part of transition metals was commonly recognized as a coordinated ion or molecule rather than a ligand. A contemporary German chemistry named Alfred Stock firstly used the concept of “Ligand”, which was derived from a Latin word “ligare” meaning to bind, referring to the counterpart in the complexes in boron and silicon chemistry in 1916.61_{But until 1948, H. Irving}

(34)

14

in the academic word.62_{The development of coordination chemistry including the concept of “Ligand”}

was crucial for N-heterocyclic carbene chemistry. Contemporarily, the carbene chemistry was advancing slowly since 1903 at the background of the development of coordination chemistry. Approximately 50 years after the two great chemists’ contribution, the field of metal-carbene and NHC started to be explored.

In 1907, German researcher Eduard Buchner won the Nobel Prize for cell-free fermentation. In 1903, Eduard Buchner and Leon Feldmann published an article about a cyclopropanation study of diazoacetate and toluene (Scheme 1−2). In this experiment 400 grams of distilled toluene and 50 grams of diazoacetate were heated together to give 1 gram of cyclopropanation product. Although the yield was low, inspired by the enlightenment and analysis of the result, Buchner firstly postulated the concept of carbene.63

Scheme 1−18 A cyclopropanation study of diazoacetate and toluene by Eduard Buchner

It was worth mentioning that Chugajev’s NHC-Pt complex, which was synthesized in 1915,64_was

believed to be the first N-heterocyclic carbene, but the structure was identified several decades later after much progress in carbene chemistry was achieved by Fischer’s pioneered work.65_{After several}

decades, the methodology was proved to be applicable to the synthesis of NHC complexes.66_The

term carbene was introduced in organic chemistry in1954 by Doering and Hoffmann67_{and into}

organometallic chemistry in 1964 by Fischer and Maasboel.68_{Doering and Hoffmann disclosed the}

formation of dichlorocarbene [: CCl2] from chloroform in the presence of KOtBu, followed by its

addition to olefins.68_{Metal-carbene chemistry started from Fischer’s seminal work with tungsten}

hexacarbonyl (W(CO)6), which represented constituted the first Fischer-type carbene.69 The

fischer-type carbene is an electrophilic heteroatom-stabilized carbene coordinated to low-oxidation state metals, such as Cr, Mo, and W.69_{After a decade, another type of carbene complex was introduced}

by Schrock, in which the metals have high oxidation states.70_{Schrock-type carbenes are nucleophilic}

complexes that show Wittig’s ylide-style reactivity and that have been debated as ylides.71_But

(35)

15

carbene could change from exhibiting an electrophilic to a nucleophilic character by the influence of its neighbouring substituents, Wanzlick discussed the tendency of dissociation of bis-[1,3-diphenyl-2-imidazolidine] and pointed out that this was a source of nucleophilic carbene as well as thiamine. However, he questioned the existence of such particularly stable carbene since carbene was very reactive and sensitive to chemicals or moisture, and dimerization.72

However, four years later in 1968, Ö fele synthesized an NHC-Cr(CO)5 complex obtained from

heating 1,3-dimethyl imidazolium pentacarbonyl hydrido chromate [HCr(CO)5]¯ (Figure 1−1).73 In the

same year, Wanzlick synthesized the bis-NHC-Hg complex by using 1,3-diphenyl imidazolium perchlorate salt with mercury acetate Hg(OAc)2 in DMSO in thermal condition (Figure 1).74 The two

complexes of Wanzlick and Ö fele were both identified as the first description of organometallic complexes with NHCs as ligands. Although N-heterocyclic carbenes were used as ligands for Hg and Cr respectively in Öfele and Wanzlick’s cases, the significance of these compounds was questioned, and the question of the existence of such carbene potentially as a ligand still lasted till the isolation of Arduengo’s carbene.

Figure 1−1 Significant NHC-metal complexes in the development of NHC history

All these efforts promoted the development of the early stage of carbene chemistry. After that, a realization of NHCs as potential ligands in homogeneous catalysis75_{brought a massive input of}

research notably by Herrmann76_{, Enders}77_{, Dixneuf, and Ç etinkaya.}78_{For the past twenty years, a}

dramatic increase in research and published articles on N-heterocyclic carbene was noticed.79_The

properties of NHCs explained the success.79_{NHCs are stronger donor ligands than phosphines and}

the variation of the nitrogen cyclic ring together with the variation of N-substituents could promote a fine-tuning of the electronic properties of the carbene. The N-substituents could provide a chiral induction when used with transition metals. The N-heterocyclic carbenes could even take part in organic transformations as organocatalysts. NHCs were applied in the medicinal and materials fields,

(36)

16

as well as in organic chemistry. Numerous N-heterocyclic carbenes were designed, and research related to the synthesis of NHC-metal complexes, electronic properties, efficiency in many different reactions etc. was performed in a flourishing period.80_{The primary applications of NHCs were still}

their use as supporting ligands with late transition metals from d-block in homogeneous catalysis, especially the cases in NHC-Ru catalyzed metathesis and NHC-Pd catalyzed cross-coupling reactions. There was a quite much effort dedicated to other metals, such as Co, Rh, Ir, Ni, Cu, Ag and Au.81_{However, the applications of NHCs with Fe was much less studied but still promising due}

to the work already published.82-84

1.4 The development of Iron-NHC chemistry

Although the first example of an iron-containing NHC compound was published one year after the examples of NHC-metals synthesized by Wanzlick and Ö fele in 1968 respectively, it was rather slow for the development of iron-NHC complex and catalytic applications in organic chemistry. It was worth highlighting the first NHC-Iron complex in history, which was synthesized by Ö fele by the same procedure as the first NHC-transition metal complex in 1969;85_{1,3-dimethyl imidazolium}

tetracarbonylhydrid-iron [HFe(CO)4]¯ in thermal conditions generated the corresponding

NHC-Fe(CO)4 (Scheme 1−3). Later, iron-NHCs were mainly used for the research of hydrogenase

modeling studies and organometallic synthesis.86

Scheme 1−19 The first NHC-Iron complex by Ö fele

Iron has been known for centuries and used in coordination and organometallic chemistry for decades.87,88_{The trend was evolving from inorganic iron salts to ligands coordinated to iron as}

molecular complexes. Comprehensive reviews of iron-catalyzed reactions were reported by Bolm in 20042_{, Liu in 2010}89_{and Gopalaiah in 2013}8_{, and the application iron-NHCs by Darcel in 2013}90_and

Kü hn in 201457_{. Iron, which has many advantages, such as its abundance on earth, low cost, and}

environmentally benign character, has emerged as a promising substitute for other late transition metals such as Pd, Rh, and Ru. But there are still limited applications of iron-NHCs in a relatively

(37)

17

small reaction scope, in which the most relevant developments were C─C bond formation, reduction reactions and carbon-heteroatom bond formation reactions.88-100

After the first iron-NHC complex synthesis, it took three decades for the first application of iron-NHC in homogeneous catalysis to appear. In 2000, Grubbs used an active Bis-NHC-FeCl2/FeBr2 complex

for atom transfer radical polymerization (ATRP).91_{Since then, more iron-NHCs were developed for}

catalytic tests. Usually, iron-NHCs catalyzed reactions were described according to reaction names, but those applications could be categorized by the bond nature involved in the transformation.

1.4.1 Carbon−halide bond

In carbon-carbon bond forming reactions, several types of Iron-NHCs were developed, but only in Kumada-type cross-coupling as shown below (Scheme 1−4).92_{These complexes take advantage of}

a coordination of bis-NHC to one equivalent of iron salt (Figure 1−2).93_{Both primary and secondary}

alkyl halides including fluoride to iodide could be used.92_{A simplified mechanism was proposed by}

Bedford involving single-electron transfer to generate an alkyl radical in the process.94_{But in}

combining with other examples, bis-NHC-iron complexes (Figure 1−2) below showed much affinity toward the carbon−halide bond of sp3_{carbon or sp}2_carbon.95

Scheme 1−20 NHC-Fe in Kumada-type cross-coupling reaction

(38)

18

1.4.2 Carbon−carbon double and triple bond

Allylic alkylation is a versatile tool for C─C bond formation.96_{Iron-NHCs showed somewhat efficient}

catalytic effectiveness in this transformation. Plietker performed a regioselective allylic alkylation between an isobutyl allyl carbonate and various Michael donors. High regioselectivities were observed (Scheme 1−5).97_{The author proposed a mechanism involving the coordination of NHC-Fe}

with the Carbon-carbon double bond to provide steric demand. Different π-allyl-iron complexes were employed to enhance the catalytic activity and to explain the regioselectivity through a π-allyl mechanism. Later, the author succeeded in using thiols and sulfones as sulfur nucleophiles in the reaction with isobutyl carbonates.98

Scheme 1−21 Regioselective allylic alkylation by using NHC-Fe

In 2010, a selective iron-NHC catalyzed borylation of furans and thiophenes was reported. A methylated piano stool complex activated the 2-position of furan and the addition of an intermediary iron hydride to tert-butyl ethylene allowed the regeneration of the activated iron-furan (Scheme 1−6).99_{In 2013, an iron bis-imino-pyridine-bis-NHC catalyzed hydroboration of alkenes was reported,}

which revealed the activation of carbon-carbon double bond by iron-NHC (Scheme 1−7).100

(39)

19

Scheme 1−23 Hydroboration of alkenes catalyzed by a Py-bisNHC-Fe complex

The same type of bis-imino-pyridine-bis-NHC-iron compound was used for the hydrogenation of alkenes in 2012 by Chirik (Scheme 1−8).101_{The efficiency of the reaction was attributed to the}

electron-rich property of low-valent Fe(0) which makes it able to activate the alkene. An isotopic labeling experiment using D2 revealed that isomerization was happening during the process.

Scheme 1−24 Hydrogenation by Py-bisNHC-Fe complex

Atom transfer radical polymerization (ATRP) is an important polymerization method.102_{It was the}

first catalytic application of iron-NHC. Grubbs conducted the first catalytic application of iron-NHC in a structural transformation in 2000. The polymerization of styrene and methyl methacrylate were conducted by Grubbs in 2000 (Scheme 1−9).91_{The double bonds were activated by bis-NHC-FeBr}₂

complex. The rate of polymerization detected was in the highest list for ATRP in organic solvents.

Scheme 1−25 Atom transfer radical polymerization catalyzed by bisNHC-FeBr2

In 2017, a molecular iron-NHC complex was used catalytically for the oxidation of aromatic hydrocarbons (Scheme 1−10).103_{A bis-(pyridine-NHC)-iron was used to activate the aromatic}

(40)

p-20

xylene by hydrogen peroxide (H2O2) in acetonitrile. Mechanistic studies revealed a process that

includs either an iron-arene activation or an iron-arene oxide path.

Scheme 1−26 Oxidation of aromatic hydrocarbons catalyzed by Py-NHC-Fe complex

The first NHC-iron catalyzed cyclization of triynes was performed by Okamoto in 2005.104_The

NHC-iron generated in situ using a catalytic amount of zinc was very efficient in the process. A reduced Fe (Fe3+_{to Fe}2+_{) with triynes formed an iron metallacyclopentadiene complex for the further}

cyclization. Although the mechanism was not proved from direct evidence, the affinity of iron-NHC to carbon-carbon triple bonds was indicated. Hilt reported a ring expansion of epoxides by using a similar procedure.105_{In 2016, methyl phenylacetylene was used as a substrate for the}

carbometalation with methyl Grignard reagent catalyzed by NHC-iron, as shown below (Scheme 1−11).106

Scheme 1−27 Carbometalation with methyl Grignard reagents catalyzed by NHC-iron 1.4.3 Carbon−heteroatom double bond

Compared with other applications of NHC-Fe complexes, much more progress was obtained in the selective reduction of double bonds of aldehydes, ketones, esters, amides, imines and even sulfoxides by hydrosilylation.107_{The most frequently used iron-NHCs had same ligands involving}

(41)

21

1−12). Other examples of iron-NHCs that were used in double bond reductions are shown in Figure 1−3.107

Scheme 1−28 Hydrosilylation by NHC-Fe catalysis

Figure 1−3 Other NHC-Fe complexes in the reduction of double bonds

Although more and more NHC complexes were designed, the catalytic applications of iron-NHCs were insufficient in homogeneous catalysis within the scope of iron-catalyzed synthetic chemistry. To explore iron-NHC combination, we were very interested in seeking routes in carbonyl-ene reaction due to the excellent reactivity of iron in complexing/coordinating with carbonyl groups such as in the aldol reaction, Michael addition, Nazarov cyclization, and allylation of carbonyl compounds, as highlighted above.

1.5 The development of carbonyl-ene reaction

1.5.1 Definition and advantages of carbonyl-ene reaction

The carbonyl-ene reaction is defined as a pericyclic process between an alkene bearing an allylic hydrogen and a double bond, in which the migration of the double bond and 1,5-hydrogen shift takes place at the same time. The intermolecular ene reaction and the intramolecular ene reaction are both possible. Carbon-carbon bond forming processes with a carbonyl group often involves a metal reagent as a nucleophile. But the carbonyl-ene reaction is potentially 100% atom-efficient and does not generate waste.108

(42)

22

1.5.2 Development of catalysts

The carbonyl-ene reaction can proceed without any catalyst or promoter, but to overcome the high activation barriers, it needs moderate to high temperatures.109_{However, the development of}

promoters or Lewis acid catalysts for this reaction has been carried out. Comprehensive reviews on the development of catalytic carbonyl-ene reactions were published by Mikami in 1992109_and

2010,110_{and Clarke in 2008,}107_{respectively. The most commonly used promoters were aluminum}

salts, such as AlMe2Cl, which promotes the reaction at temperatures as low as −78 °C.111 Lewis acid

catalysts, such as SnCl4,112 BF3∙Et2O,113 and others,114 were used for accelerating the reaction

without being consumed. The more detailed research was conducted on commercially important citronellal cyclisation and glyoxylate-ene reaction. Moreover, the demand for high enantiomerically pure products boosted the development of chiral catalysts. Classical catalysts such as BINOL-Ti,115

and Bis-oxazoline-Cu116_{were developed for the glyoxylate-ene reaction in the 1980s as well as the}

subsequent Schiff base-Cr117_{. Other metals were also on the list, such as Co, Ni, Sc, Pd, and Pt.}118

Scheme 1−29 Bis-oxazoline-Cu catalyzed glyoxylate-ene reaction of an aldehyde and a ketone

The development of catalysts for the glyoxylate-ene reaction was applied to intermolecular-ene reaction of aldehydes, but the process with ketones is more difficult since ketones are less electrophilic than aldehydes. An example is given in Scheme 1−13, in which the bis-oxazoline catalyzed glyoxylate-ene reaction is performed in a much more effortless way than the ene reaction with a ketone.119_{If the ketone is activated, for example with using ethyl trifluoropyruvate as the}

(43)

23

1.5.3 Development of catalysts for the ethyl trifluoropyruvate-ene reaction

Ethyl trifluoropyruvates, used as activated ketones, allow the formation of tetra-substituted stereogenic centers containing a trifluoromethyl group, which is present in numerous building blocks

Scheme 1−30 Carbonyl-ene reaction of ethyl trifluoropyruvate with -methylstyrene

Figure 1−4 The development of catalysts for the trifluoropyruvate-ene reaction

for pharmaceuticals and agrochemicals.120_{Methyl styrene and ethyl trifluoropyruvate were often}

used in model reactions for catalytic tests. Since 2004 several catalysts were used for the ethyl trifluoropyruvate-ene reaction including organocatalysts, Brø nsted acids, carbocations, and Lewis acid catalysts derived from transition metals, as shown below (Scheme 1−14, Figure 1−4 and Table

(44)

24

1−1). In Table 1−1 we can see that every two years on average a new catalyst was developed. Transition metals, such as palladium ruthenium and indium, belong to the list of chiral catalysts. 120-128_{However, to the best of our knowledge, there are only two precedents of stoichiometric use of}

FeCl3 in intramolecular carbonyl-ene cyclization reactions.129 Consequently, the development of a

new iron-catalyzed ene reaction is in high need due to its high potential in synthetic organic chemistry.

Year Catalyst Yield (%) ee (%)

2004 120 _BINAP-Pd ₉₉ ₉₃ 2007 121 _thiourea ₉₇ ₃₀ 2008 122 Phosphoric-amide acid 76 96 2010 123 _{di-phosphine-Pd} ₆₄ ₉₁ 2010 124 _Py-box-In ₉₉ ₉₅ 2012 125 _{Phosphoric-Ca} ₆₈ ₉₄ 2013 126 _Ru2+ ₈₉ ₉₃ 2015 127 _carbocation ₆₁ ₈₄

Table 1−1 The development of catalysts for the trifluoropyruvate-ene reaction 1.6 Synthetic organic chemistry of caffeine

Caffeine is a central nervous system stimulant and is a member of the methyl-xanthine class.130_Its

unique structure makes it ready for the synthesis of N-heterocyclic carbenes (Scheme 1−15). Caffeine, named as 1,3,7-trimethylxanthine, can be alkylated at the N9_{position. One of the easiest}

ways of the alkylation is to install a methyl group at the N9_{position to form}

1,3,7,9-tetramethylxanthine. Suitable methods using dimethyl sulfate,131a_{methyl tosylate,}131b_{and methyl}

iodide132_{as alkylating reagents were reported as early as in 1962, but it took 14 years for caffeine}

Caffeine-derived-iron catalyzed carbonyl-ene and Diels-Alder reactions and development of an NHC-diol ligand family

Caffeine-derived-iron catalyzed carbonyl-ene

and Diels-Alder reactions and development

of an NHC-diol ligand family

Thè se

Di Meng

Doctorat en chimie

Philosophiæ doctor (Ph. D.)

Qué bec, Canada

© Di Meng, 2018

Caffeine-derived-iron catalyzed carbonyl-ene

and Diels-Alder reactions and development

of an NHC-diol ligand family

Thè se

Di Meng

Sous la direction de :

RÉ SUMÉ

ABSTRACT

Table of Contents

List of Schemes

List of Figures

List of Tables

List of Abbreviations

ACKNOWLEDGEMENTS

Chapter one

Introduction