Non-Enantioselective and Enantioselective Synthetic
Transformations using Copper and Iron Salts for Diazo
Insertion Reactions into Si–H and S–H Bonds and
Hydrosilylation Reactions of Ketones
Thèse
Hoda Keipour
Doctorat en chimie
Philosophiæ doctor (Ph. D.)
Non-Enantioselective and Enantioselective Synthetic
Transformations using Copper and Iron Salts for Diazo
Insertion Reactions into Si–H and S–H Bonds and
Hydrosilylation Reactions of Ketones
Thèse
Hoda Keipour
Sous la direction de:
Résumé
Cette thèse décrit la découverte de transformations synthétiques énantiosélectives et non énantiosélectives dans lesquelles des catalyseurs chiraux et environnementalement bénins à base de cuivre, de fer et de zinc sont utilisés pour des réactions d’insertion de diazos dans les liaisons Si–H et S–H et pour des réactions d’hydrosilylation de cétones. Des réactions énantiosélectives et non énantiosélectives d’insertion de métal-carbènes d’α-diazoesters catalysées par le cuivre et le fer dans les liaisons Si–H et S–H sont décrites. Nous avons réussi à développer un protocole efficace pour la réaction d’insertion de métal-carbènes d’α-diazoesters catalysée par le cuivre et le fer dans les liaisons Si–H et S–H. Avec l’utilisation de [(MeCN)4Cu]PF6 et de Fe(OTf)2, une grande variété d’α-silylesters ont été
synthétisés avec des bons et des excellents rendements (jusqu’à 98%). Ces catalyseurs peuvent aussi être utilisés efficacement pour l’insertion de métal-carbène dans la liaison S– H avec des bons rendements (jusqu’à 90%). Des résultats prometteurs ont été obtenus pour les réactions d’insertion de métal-carbènes d’α-diazoesters catalysées par le fer dans la liaison Si–H avec l’utilisation du DMC comme solvant vert en remplacement de CH2Cl2.
Plusieurs ligands diamines chiraux ont été testés pour développer une réaction d’insertion de métal-carbène hautement énantiosélective dans la liaison Si–H avec l’utilisation du sel de cuivre peu coûteux [(MeCN)4Cu]PF6 comme catalyseur. Un excellent rendement ainsi
qu’une excellente énantiosélectivité (rendement de 85%, 99:1 er) ont été obtenus lorsque les ligands contenant un cœur (R,R)-diaminocyclohexane et des groupements mésityles ont été utilisés. Il s’agit d’un très bon exemple de réaction hautement énantiosélective d’insertion dans la liaison Si–H avec l’utilisation d’aryldiazoacétates, de sources de silane peu coûteuses en comparaison avec d’autres et de ligands diamines chiraux facilement synthétisables ayant été utilisés pour la première fois dans la réaction d’insertion énantiosélective de métal-carbène dans la liaison Si–H. Nous avons découvert que les diamines chirales, facilement disponibles, sont aussi des ligands efficaces pour la réduction d’aryle-cétones avec le catalyseur Zn(OAc)2. Les alcools recherchés ont été obtenus avec
des hauts rendements et de très bons rapports énantiomériques (rendements jusqu’à 99%,
er jusqu’à 99:1). Nous avons aussi obtenu de bons résultats pour l’hydrosilylation de la
(rendement de 85%, 80:20 er). Sur la base des informations retrouvées dans la littérature, il n’y a que quelques exemples d’hydrosilylations asymétriques de la p-phényltrifluoroacetophénone avec l’utilisation de ZnEt2 comme catalyseur et de très faibles
Abstract
This thesis describes the development of non-enantioselective and enantioselective synthetic transformations using copper, iron, and zinc salts as environmentally benign catalysts for diazo insertion reactions into the Si–H and S–H bonds and hydrosilylation reactions of ketones. Non-enantioselective and enantioselective copper and iron-catalyzed metal carbene insertion reactions of α-diazoesters into Si–H and S–H bonds are described. We successfully developed an efficient copper and iron-catalyzed protocol for the metal carbene insertion reaction of α-diazoesters into Si–H and S–H bonds. By using [(MeCN)4Cu]PF6 and Fe(OTf)2, a wide range of α-silylesters were synthesized in good to
excellent yields (up to 98%). These catalysts have been shown to be efficient for metal carbene insertion into S–H bond in high yields (up to 90%) as well. Excellet results have been obtained for iron-catalyzed carbene insertion reactions of α-diazoesters into Si–H bond using DMC as a green solvent instead of CH2Cl2. Several chiral diamine ligands were
tested to develop a highly enantioselective metal carbene insertion reaction into the Si–H bond using the inexpensive copper salt [(MeCN)4Cu]PF6 as catalyst. Excellent yield and enantioselectivity (85% yield, 99:1 er) were obtained when the ligands containing a (R,R)-diaminocyclohexane core and mesityl groups were used. This is the very good example of highly enantioselective Si–H bond insertion reactions using aryldiazoacetates and inexpensive silane sources compare to others and easy-to-synthesize chiral diamine ligands that have been used for the first time for enantioselective Si–H bond insertion reaction. We have found that the readily available chiral diamines are also efficient ligands for the reduction of aryl ketones using Zn(OAc)2 as catalyst. The desired alcohols were obtained
in high yields and very good enantiomeric ratios (up to 99% yields, up to 99:1 er). We also obtained good results for the hydrosilylation of p-phenyltrifluoroacetophenone using a
bipybox-iPr/Fe(OAc)2 system (85% yield, 80:20 er). Based on the information in the
literature, there are just a few examples on asymmetric hydrosilylation of p-phenyltrifluoroacetophenone using ZnEt2 with very low enantioselectivities.
Table of Contents
Résumé ... III Abstract ... V List of Figures ... X List of Schemes ... XI List of Tables ... XIV List of Abbreviation ... XV Acknowledgments ... XIX
Chapter 1 General Introduction ... 2
1.1 Transition metal catalysis ... 2
1.2 Carbenes and metal carbenes ... 3
1.2.1 Carbenes ... 3
1.2.2 Metal carbenes ... 5
1.2.2.1 Copper catalysts for metal carbene generation ... 6
1.2.2.2 Iron catalysts for metal carbene generation ... 7
1.3 Chemistry of diazo compounds ... 8
1.3.1 Diazo compounds: properties ... 8
1.3.2 Diazo compounds: preparations ... 10
1.3.2.1 Diazotization of primary amines ... 11
1.3.2.2 Diazo transfer into an activated methylene group (Regitz diazo transfer reaction) . 12 1.3.2.3 Base treatment of sulfonylhydrazones (Bamford-Stevens reaction) ... 12
1.3.2.4 Base mediated cleavage of N-alkyl-N-nitroso sulfonamides ... 13
1.3.2.5 Oxidation of hydrazones ... 13
1.3.2.6 Miscellaneous preparations ... 14
1.4 Reactivities and decomposition methods of diazo compounds ... 15
1.4.1 Non-metal carbene pathway ... 15
1.4.1.1 Huisgen reaction ... 15
1.4.1.2 aza-Darzens reaction ... 16
1.4.1.3 Roskamp and Tiffeneau-Demjanow-type reactions ... 16
1.4.1.4 Arndt-Eistert via a Wolff rearrangement ... 17
1.4.2 Transition metal carbene pathway ... 17
1.4.2.1 Insertion reactions ... 18
1.4.2.2 Cyclopropanation ... 19
1.4.2.3 Ylide generation ... 19
Chapter 2 Metal Carbene Insertion Reactions into Si–H and S–H Bonds ... 22
2.1 Catalytic carbene insertion reactions into the Si–H bond ... 22
2.1.1 Introduction ... 22
2.1.2Catalysis ... 23
2.1.2.1 Rhodium catalysis ... 23
2.1.2.2 Reaction mechanism for rhodium(II) catalysis ... 40
2.1.2.3 Copper catalysis ... 41
2.1.2.4 Iridium catalysis ... 50
2.1.2.5 Silver catalysis ... 52
2.1.2.6 Ruthenium catalysis ... 53
2.2 Catalytic carbene insertion reactions into the S–H bond ... 55
2.3 Copper-catalyzed carbene insertion reactions of α-diazoesters into Si–H and S–H bonds ... 57
2.3.1 Introduction ... 57
2.3.2 Results and discussions ... 58
2.3.2.1 Synthesis of diazo compounds ... 58
2.3.2.2 Catalyst effect ... 59
2.3.2.3 Solvent effect ... 61
2.3.2.4 Screening of copper-catalyzed Si–H bond insertion reaction of α-aryl-α-diazoacetates ... 62
2.3.2.5 Screening of copper-catalyzed S–H bond insertion reaction of α-aryl-α-diazoacetate ... 63
2.3.2.6Competition experiments ... 64
2.3.2.7 Derivatization of α-silylesters ... 66
2.3.3 Summary ... 69
2.4 Iron-catalyzed carbene insertion reactions of α-diazoesters into Si–H and S–H bonds 70 2.4.1 Introduction ... 70
2.4.2 Results and discussion ... 71
2.4.2.1 Catalyst effect ... 71
2.4.2.2 Catalyst loading effect ... 72
2.4.2.3 Solvent effect ... 73
2.4.2.4 Screening of iron-catalyzed Si–H bond insertion reaction of α-aryl-α-diazoacetates using Et3SiH ... 74
2.4.2.5 Screening of iron-catalyzed Si–H bond insertion reaction of α-aryl-α-diazoacetates using different silane sources ... 75
2.4.2.6 Screening of iron-catalyzed Si–H bond insertion reaction of α-alkyl-α-diazoacetates and trifluorodiazoalkane using different silane sources ... 77
2.4.2.7 Screening of iron-catalyzed S–H bond insertion reaction of α-aryl-α-diazoacetates ... 78
2.4.2.8Competition experiments ... 79
2.4.2.9Kinetic isotope effect ... 80
2.4.2.10Proposed mechanism for α-diazo insertion reaction into the Si–H bond ... 81
2.4.3 Summary ... 81
2.5 Enantioselective copper-catalyzed carbene insertion reaction of α-diazoesters into the Si–H bond ... 83
2.5.1 Results and discussions using chiral diamine ligand ... 83
2.5.1.1 Temperature effect ... 86
2.5.1.2 Solvent effect ... 88
2.5.1.3 Effect of different silane source ... 88
2.5.1.4 Proposed mechanism for diazo insertion reaction into the Si–H bond ... 89
2.5.2 Results and discussions using bipyridine-diol ligand ... 90
2.5.3 Summary ... 94
2.6 Promising results and future work for diazo insertion reaction ... 95
Chapter 3 Asymmetric Hydrosilylation of Ketones ... 99
3.1 Metal catalyzed asymmetric hydrosilylation of ketone ... 99
3.1.1 Introduction ... 99
3.1.2 Iron catalysis in asymmetric hydrosilylation of ketone ... 101
3.1.3 Zinc catalysis in asymmetric hydrosilylation of ketone ... 105 3.2 Iron-catalyzed asymmetric hydrosilylation of ketones using chiral
3.2.1 Results and discussion ... 107
3.2.1.1 Chiral bipybox ligands effect ... 107
3.2.1.2 Catalyst, solvent, and additive effect ... 107
3.3 Bipybox-iPr/Fe(OAc)2 system effect on the asymmetric hydrosilylation of p-phenyltrifluoroacetophenone ... 110
3.3.1 Introduction ... 110
3.3.2 Results and discussions ... 111
3.3.2.1 Synthesis of substrate ... 111
3.3.2.2 Catalyst and silane effect ... 111
3.3.2.3 Solvent effect ... 112
3.4 Zinc-catalyzed asymmetric hydrosilylation of ketones using chiral diamine and bipyridine-diol ligands ... 116
3.4.1 Results and discussion ... 116
3.5 Summary ... 121
3.6 Promising results and future work ... 122
Chapter 4 General Conclusion ... 124
4.1 Copper-catalyzed carbene insertion reactions of α-diazoesters into Si–H and S–H bonds ... 124
4.2 Iron-catalyzed carbene insertion reactions of α-diazoesters into Si–H and S–H bonds ... 126
4.3 Enantioselective copper-catalyzed carbene insertion reaction of α-diazoesters into the Si–H bond ... 127
4.4 Iron and Zinc-catalyzed asymmetric hydrosilylation of ketone using chiral diamine and bipyridine-diol ligands ... 127
4.5 Future work ... 128
Experimental section ... 131
General experimental procedure ... 131
Experimental procedures and characterization data ... 133
References ... 187
Copies of 1 H NMR and 13 C NMR ... 194
List of Figures
Figure 1.1 Singlet and triplet carbenes ... 3
Figure 1.2 Fischer carbenes and schrock carbenes ... 5
Figure 1.3 Classification of metal carbene species ... 6
Figure 1.4 Cyclic diazirine structure and linear diazo structure ... 9
Figure 1.5 Mesomeric structures of diazo carbonyl compounds ... 10
Figure 1.6 Relative basicity of selected diazo compounds ... 10
Figure 1.7 Selected common methods for the synthesis of diazo compounds via buildup or introduction of diazo group ... 11
Figure 1.8 Selected common examples for metal-catalyzed carbene transfer reactions of diazo compounds ... 17
Figure 1.9 Mechanism for catalytic decomposition of diazo compounds ... 18
Figure 1.10 Ylide formation ... 20
Figure 2.1 General scheme for diazo insertion reaction into the Si–H bond ... 23
Figure 2.2 Concerted addition of the Si–H bond into an electrophilic Rh-carbene center ... 30
Figure 2.3 Proposed mechanism for carbene formation ... 40
Figure 2.4 Cu-catalyzed carbene insertion reactions of α-diazoesters into Si–H and S–H bonds ... 57
Figure 2.5 Fe-catalyzed α-diazo insertion reactions into Si–H and S–H bonds ... 71
Figure 2.6 Proposed mechanism for the α-diazoesters and Et3SiH to α-triethylsilylesters in the presence of catalytic amount of Fe(OTf)2 ... 81
Figure 2.7 Proposed mechanism for the α-diazoesters and Et3SiH to α-triethylsilylesters in the presence of chiral diamine L1b/[(MeCN)4Cu]PF6 ... 90
Figure 3.1 Selected valuable bioactive targets derived from chiral alcohols ... 100
Figure 3.2 Asymmetric hydrosilylation of ketones ... 100
List of Schemes
Scheme 1.1 Carbene formation by α-elimination ... 4
Scheme 1.2 Carbene formation by decomposition of α-diazocarbonyl compounds ... 4
Scheme 1.3 Carbene formation from a tosylhydrazone ... 4
Scheme 1.4 Synthesis of ethyl α-diazoacetate ... 9
Scheme 1.5 Experimental evidence for linear structure of ethyl α-diazoacetate ... 9
Scheme 1.6 Diazotization of aromatic amines ... 11
Scheme 1.7 Regitz diazo transfer reaction via direct diazo transfer or de-acylating diazo transfer . 12 Scheme 1.8 Bamford-Stevens reaction ... 13
Scheme 1.9 Cleavage of N-nitrosamide ... 13
Scheme 1.10 The synthesis of α-phenyl-α-diazomethane ... 14
Scheme 1.11 Preparation of diazoester starting from bromoacetyl bromide ... 14
Scheme 1.12 Phosphine-mediated preparation of diazo compounds using azide ... 15
Scheme 1.13 Forster's reaction ... 15
Scheme 1.14 Huisgen reaction ... 16
Scheme 1.15 Preparation of aziridine from nucleophilic addition of diazo compound ... 16
Scheme 1.16 Homologation of acyclic carbonyl and ring expansion of cyclic ketone ... 16
Scheme 1.17 Arndt-Eistert via a Wolff rearrangement ... 17
Scheme 1.18 The first intramolecular cyclopropanation reaction ... 19
Scheme 2.1Synthesis of α-silylesters and α-silylketones using RhII-catalyzed decomposition of diazo compounds in the presence of organosilanes ... 24
Scheme 2.2 a) One-pot synthesis of α-(alkoxysilyl)acetic esters b) diethyl fumarate and maleate as by-products of RhII-catalyzed insertion reaction ... 25
Scheme 2.3 Metal carbene insertion reaction into the Si–H bond using Rh2(OAc)2 as catalyst ... 26
Scheme 2.4 Metal carbene insertion reaction of (–)-menthyl α-diazoesters into the Si–H bond using Rh2(OAc)4 as catalyst ... 26
Scheme 2.5 Asymmetric insertion reaction of RhII-carbene into Si–H or O–H bonds ... 26
Scheme 2.6 Synthesis of α-allylsilanes using RhII-vinyl carbene insertion reaction into the Si–H bond ... 27
Scheme 2.7 Synthesis of 3,3-disubstituted 3-silaglutarates ... 28
Scheme 2.8 The dirhodium(II)-catalyzed asymmetric Si–H bond insertion reaction of methyl α-phenyl-α-diazoacetate ... 28
Scheme 2.9 Competition experiment and kinetic isotope effect ... 29
Scheme 2.10 RhII-prolinate catalyzed decomposition of methyl α-phenyl-α-diazoacetate and methyl α-vinyl-α-diazomethanes in the presence of PhMe2SiH ... 30
Scheme 2.11 Synthesis of α-allylsilanes using RhII-vinyl carbene insertion reaction into the Si–H bond ... 31
Scheme 2.12 Enantioselective Si–H bond insertion reaction of methyl α-phenyl-α-diazoester with different silanes ... 33
Scheme 2.13 Enantioselective synthesis of 6-(S)-triethylsilyl-α-methyl-α-cyclohexenone by catalytic insertion reaction of α-diazoketone into the Si–H bond ... 33
Scheme 2.14 Asymmetric insertion of methyl α-aryl-α-diazoesters into the Si–H bond ... 35
Scheme 2.15 A stereoselective synthesis of the antibiotic (−)-virginiamycin M2 ... 36
Scheme 2.16 Si–H bond insertion reactions with ethyl α-bromo-α-diazoacetate ... 37
Scheme 2.17 RhII-catalyzed Si−H bond insertion reaction of methyl α-aryl-α-diazoacetates ... 37
Scheme 2.18 Asymmetric Si−H bond insertion reaction of α-diazoesters using chiral rhodium catalysis ... 38
Scheme 2.20 Asymmetric Si−H insertion reaction of α-diazophosphonates using chiral rhodium
catalysis ... 39
Scheme 2.21 Reaction of PhMe2SiH with methyl α-diazoacetate in the presence of copper ... 41
Scheme 2.22 CuII-catalyzed carbene insertion reaction of menthyl α-methyl-α-diazoesters into the Si–H bond ... 42
Scheme 2.23 Synthesis of α-silylaceticesters catalyzed by a copper schiff-base complex ... 43
Scheme 2.24 Asymmetric copper-catalyzed diazo insertion reaction into the Si–H bond ... 45
Scheme 2.25 Copper-catalyzed asymmetric Si–H bond insertion reaction of methyl α-allyl-α-diazoacetate with PhMe2SiH ... 46
Scheme 2.26 Copper-catalyzed asymmetric Si–H bond insertion reaction of methyl α-phenyl-α-diazoacetate with PhMe2SiH ... 47
Scheme 2.27 Copper-catalyzed asymmetric Si–H bond insertion reaction of α-aryl-α-diazoacetate ... 47
Scheme 2.28 Copper-catalyzed Si–H bond insertion reaction ... 48
Scheme 2.29 Copper-catalyzed 2,2,2-trifluoro-1-diazoethane insertion reaction into the Si–H bond ... 48
Scheme 2.30 Copper-catalyzed enantioselective Si–H bond insertion reaction ... 49
Scheme 2.31 Copper-catalyzed Si–H bond insertion reaction ... 50
Scheme 2.32 Asymmetric Si–H bond insertion reaction with methyl α-aryl-α-diazoacetates ... 51
Scheme 2.33 Asymmetric iridium-catalyzed Si–H bond insertion reaction ... 51
Scheme 2.34 Si–H bond insertion reaction with methyl α-aryl-α-diazoacetate catalyzed by chiral iridium porphyrin ... 52
Scheme 2.35 AgI-Catalyzed carbene insertion reaction into the Si–H bond ... 53
Scheme 2.36 RuII-Pheox catalyzed enantioselective Si–H bond insertion reaction ... 54
Scheme 2.37 RuII-Pheox catalyzed enantioselective Si–H bond insertion reaction ... 54
Scheme 2.38 Enantioselective Si–H bond insertion reaction using biocatalyst ... 55
Scheme 2.39 Preparation of α-diazoesters via diazo transfer reaction ... 58
Scheme 2.40 Copper-catalyzed Si–H bond insertion reaction of α-aryl-α-diazoacetate ... 63
Scheme 2.41 Copper-catalyzed S–H bond insertion reaction of α-diazoesters with various thiols . 64 Scheme 2.42 Competition experiments: copper-catalyzed Si–H bond insertion versus S–H bond insertion with 2.1a and copper-catalyzed Si–H bond insertion versus cyclopropanation with 2.1a ... 65
Scheme 2.43 Competition experiments: copper-catalyzed Si–H bond insertion versus cyclopropanation with 2.1n ... 66
Scheme 2.44 Derivatization of α-silylester 2.3a: Tamao-Fleming oxidation ... 66
Scheme 2.45 Derivatization of α-silylester 2.2a: Peterson elimination ... 67
Scheme 2.46 Derivatization of 2.2a: synthesis of α-allylsilane and proposed mechanism ... 68
Scheme 2.47 Nuclear overhauser effect (NOE) experiment ... 69
Scheme 2.48 Iron-catalyzed Si–H bond insertion reaction of α-aryl-α-diazoacetates ... 75
Scheme 2.49 Iron-catalyzed Si–H bond insertion reaction of α-aryl-α-diazoacetatewith various silanes ... 76
Scheme 2.50 Preparation of α-alkyl-α-diazoacetates and trifluorodiazoalkane ... 77
Scheme 2.51 Iron-catalyzed Si–H bond insertion reaction of various diazo compounds ... 78
Scheme 2.52 Iron-catalyzed Si–H bond insertion reaction of α-diazoesters with various thiols ... 79
Scheme 2.53 Competition experiment: iron-catalyzed Si–H bond insertion versus cyclopropanation with 2.1n ... 80
Scheme 2.54 Kinetic isotope effect ... 80
Scheme 2.55 Enantioselective α-hydroxylation methods ... 84
Scheme 2.56 Synthesis of chiral diamine ligands ... 85
Scheme 2.58 Copper-catalyzed asymmetric Si–H bond insertion reaction of methyl α-diazophenylacetate 2.1a with Et3SiH: optimization of conditions using different
solvents ... 88
Scheme 2.59 Copper-catalyzed asymmetric Si–H bond insertion reaction of methyl α-diazophenylacetate 2.1a with PhMe2SiH: optimization of conditions using different copper salts. ... 89
Scheme 2.60 Synthesis of bolm's ligand ... 91
Scheme 2.61 Ligand screening for copper-catalyzed asymmetric Si–H insertion of methyl α-phenyl-α-diazoacetate 2.1a ... 93
Scheme 2.62 Ligand and conditions optimization for copper and iron-catalyzed asymmetric Si–H insertion of methyl α-phenyl-α-diazoacetate 2.1a ... 94
Scheme 2.63 Diazo insertion reaction into the Si–H bond using green solvent ... 95
Scheme 2.64 Asymmetric C–H functionalization of indoles using a copper salt and a diimine ligand ... 96
Scheme 2.65 Enantioselective Si–H insertion reactions of 2,2,2-trifluoro-diazoethane ... 97
Scheme 3.1 Asymmetric hydrosilylation of aryl ketones catalysed by Fe-pybox and Fe-bopa complexes ... 102
Scheme 3.2 Chiral FeIII-bis(oxazolinyl) catalysts for asymmetric hydrosilylation ... 102
Scheme 3.3 Chiral FeII-bis(oxazolinyl) catalysts and their use in asymmetric hydrosilylation ... 103
Scheme 3.4 Preparation of FeII phebox and pybox ligands for asymmetic hydrosilylation ... 103
Scheme 3.5 Chiral FeII-complexes used for hydrosilylation ... 104
Scheme 3.6 Chiral diamine ligands disclosed by Togni ... 105
Scheme 3.7 Iron-catalyzed asymmetric hydrosilylation of ketones ... 105
Scheme 3.8 Zinc-catalyzed asymmetric hydrosilylation of ketones ... 106
Scheme 3.9 Proposed catalytic cycle for hydrosilylation of ketones ... 109
Scheme 3.10 Hydrosilylation mechanism with acetophenone Fe(OAc)2-bipybox-ipr ligand ... 109
Scheme 3.11 The ligand used for asymmetric hydrosilylation of p-phenyltrifluoroacetophenone 2.17 ... 110
Scheme 3.12 Synthesis of p-phenyltrifluoroacetophenone 2.17 ... 111
Scheme 3.13 Total synthesis of chiral bis(oxazolinyl)bipyridine L3f ... 114
Scheme 3.14 Decarboxylation mechanism ... 115
Scheme 3.15 Asymmetric hydrosilylation of acetophenone 3.1a using different diamine ligands 117 Scheme 3.16 Asymmetric hydrosilylation of ketones catalyzed by Zn(OAc)2/diamine L1b ... 118
Scheme 3.17 Asymmetric hydrosilylation of different ketones catalyzed by Zn(OAc)2 ... 119
Scheme 3.18 Asymmetric hydrosilylation of acetophenone using diamine ligand L1b and Co(OAc)2 ... 120
Scheme 3.19 Ligand screening for the asymmetric hydrosilylation of acetophenone ... 121
Scheme 3.20 Synthesis of the bis(pyrrolidine)bipyridine chiral ligand ... 122
Scheme 3.21 Asymmetric hydrosilylation of acetophenone using L4/Co(OAc)2 ... 122
Scheme 4.1 Copper-‐catalyzed Si–H and S–H bonds insertion reaction of α-diazoacetates ... 124
Scheme 4.2 Derivatization of α-silylester ... 125
Scheme 4.3 Competition experiments ... 125
Scheme 4.4 Competition experiments ... 125
Scheme 4.5 Copper-catalyzed asymmetric insertion reaction of methyl α-diazophenylacetate into Si–H bond ... 127
Scheme 4.6 Asymmetric hydrosilylation of ketones catalyzed by Zn(OAc)2/diamine ligand ... 128
List of Tables
Table 2.1 Enantioselective intermolecular Si–H bond insertion reaction of methyl
α-phenyl-α-diazoesters catalyzed by chiral RhII complexes ... 32
Table 2.2 Preparation of chiral α-allylsilane bearing a silyl group ... 34
Table 2.3 Optimization of RhII-catalyzed carbene insertion reaction into the Si−H bond ... 36
Table 2.4 Asymmetric copper-catalyzed diazo insertion reaction into the Si–H bond ... 44
Table 2.5 Screening of copper sources for Si–H bond insertion of methyl α-phenyl-α-diazoacetate 2.1a ... 60
Table 2.6 Screening of solvents for Si–H bond insertion reaction of methyl α-phenyl-α-diazoacetate 2.1a ... 62
Table 2.7 Screening of FeII/FeIII sources for Si–H bond insertion of methyl α-phenyl-α-diazoacetate 2.1a ... 72
Table 2.8 Screening of catalyst loading for Si–H bond insertion reaction of methyl α-phenyl-α-diazoacetate 2.1a ... 73
Table 2.9 Screening of solvents for Si–H bond insertion reaction of methyl α-phenyl-α-diazoacetate 2.1a ... 74
Table 2.10 Copper-catalyzed carbene insertion reaction of methyl α-phenyl-α-diazoacetate 2.1a into Si–H bond ... 87
Table 2.11 Ligand and conditions optimization for copper-catalyzed asymmetric Si−H insertion of methyl α-phenyl-α-diazoacetate 2.1a ... 92
Table 2.12 Asymmetric C–H functionalization of indoles using bolm's ligand ... 96
Table 3.1 Ligand screening for the asymmetric hydrosilylation of acetophenone using Fe(OAc)2 -bipybox ligands ... 108
Table 3.2 Asymmetric hydrosilylation of p-phenyltrifluoroacetophenone 2.17 using bipybox-ipr L3a ... 112
Table 3.3 Asymmetric hydrosilylation of p-phenyltrifluoroacetophenone 2.17 using bipybox-ipr 4.3a ... 113
List of Abbreviations
[α]D optical rotation
Å Angström
ABSA p-acetamidobenzenesulfonyl azide
Ac acetyl acac acetoacetate Alk alkyl aq aqueous Ar aryl bipy bipyridine
bipybox bipyridine bis(oxazoline)
Bn benzyl box bis(oxazoline) br broad Bu butyl tBu tert-butyl Bz benzoyl c concentration ºC centigrade 13 C carbon (NMR) cat. catalytic/catalyst Cy cyclohexyl d doublet DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
DCE 1,2-dichloroethane
de diastereomeric excess
DIBAL-H diisobutylaluminium hydride
DMC dimethyl carbonate
DME 1,2-dimethoxyethane
DMF dimethyl formamide
DMSO dimethyl sulfoxide
dr diastereomeric ratio
EDG electron donating group
ee enantiomeric excess
equiv molar equivalent(s)
er enantiomeric ratio
Et ethyl
EWG electron withdrawing group
g gram
h hour(s)
1
H proton (NMR)
Hex hexanes
HPLC high performance liquid chromatography
HRMS high resolution mass spectrometry
hν light irradiation
Hz hertz
L ligand
m multiplet
m- meta-
M mol/metal
mCPBA meta-chloroperoxybenzoic acid
Me methyl Mes mesityl mg milligram min minute(s) mL milliliters mmol millimoles mp melting point Ms mesyl/methanesulfonyl MS molecular sieves n normal N normal
NMR nuclear magnetic resonance
NOE nuclear overhauser effect
o- ortho-
Ph phenyl
ppm part per milion
Pr propyl
iBu iso-butyl iPr iso-propyl
pybox pyridine bis(oxazoline|)
q quartet
quant. quantitative yield
R undefined substituent
Rf retardation factor
rt room temperature (22 ºC)
tBu tert-butyl
THF tetrahydrofuran
TLC thin layer chromatography
Ts tosyl
UV ultraviolet
Acknowledgments
Reflecting back of the last four years of my PhD, I now fully appreciate the importance of my mentors and colleagues along the way. I wish I was not restricted to mere words to express my gratitude to those who helped make this journey a successful and memorable experience.
First and foremost I would like to thank my supervisor, Professor Thierry Ollevier, for his positive support during the course of my thesis. The mentoring he provided me extends far beyond scientific knowledge. Above all, I am grateful for the scientific freedom he grants his students. From our perspective, this can sometimes be daunting, but it is an immensely rewarding experience. I also want to acknowledge his generosity in allowing me to present my research efforts at several conferences and meetings.
For inspiration and advice, I am indebt to great past mentor: Professor Mohammad A. Khalilzadeh who showed me the beauty residing in chemistry and believed I could make it as an organic chemist.
Special thanks to the members of my Ph.D. jury, Professors André Charette, Denis Giguère, and Paul A. Johnson, for taking the time and effort to read through this thesis and for the constructive comments and suggestions.
I want to thank all past and present members of the group for the stimulating working atmosphere and the lifelong friendships. I want to especially acknowledge Angela Jalba, Mao Li, Di Meng, Dazhi Li, Virgine Carreras, Samuel Lauzon, Nour Tanbouza, Xu Wan, Mathieu Lafantaisie, and Martin Pichette Drapeau. A special thanks to Angela Jalba for her friendship, support, and admirable patience in sharing what was often a crowded cubicle. I like to think that supporting each other allowed us to accomplish more than what we could have taken on separately.
Mentoring students is probably one of the greatest pleasures of my academic research. I was fortunate to supervise very talented students. I thank Samuel Lauzon, Léo Delage-Laurin and Pierre-Louis Lagueux-Tremblay for reminding me to keep an insatiable appetite for learning, Nour Tanbouza and Samuel Cashman-Kadri for proofreading my
thesis and manuscripts, Anaëlle Edon, Shan Shi, Alexandre Agostinis, and Carolina Plaice for their eager enthusiasm and contagious optimism.
I would like to thank my colleagues in the Department of Chemistry, the groups of Professors Boukouvalas, Paquin, Morin, and Giguère for their availability, whether for chemical loans or equipment loans. I would also like to thank all the staff of the Department of Chemistry, Mélanie Tremblay, Denyse Michaud, Marie Tremblay, Magali Goulet, Jean Laferrière, Christian Côté, and Pierre Audet for their great professionalism and availability. I would like to thank Professor Anna Ritcey, head of chemistry department during my Ph.D. study.
My special thanks to my best friends Bahigeh Mahdavi, Hojjat Mahi, and Mr Girard's family. They have always been there when I needed someone through troubles and success and their great company made my life more relaxing and easier in Québec.
I sincerely thank my family, for their love, support and understanding thoughout what were sometimes difficult times. They have been the most supportive and helpful people in everything I have decided to accomplish during my life. They have given me the best love and support than anyone could ask for. For my great father and amazing mother, for everything they have done for me I will be all my life grateful. Thank you.
Hoda Keipour
Chapter 1
Chapter 1
General Introduction
1.1 Transition metal catalysis
Transition metal catalysis plays an important role in both industry and in academia where selectivity, activity, and stability are crucial parameters to control. Transition metal catalysis is a key technology for the advancement of green chemistry, specifically for waste prevention, reduction of energy consumption, achieving high atom efficiency, and becoming more economical.1
There is a growing demand for chiral intermediates in the pharmaceutical and agrochemical industries. These compounds have to be obtained in high yields with high optical purities and in low costs. Research in catalytic asymmetric reactions is one of the most important fields in modern organic chemistry, and many excellent catalysts have been developed. A broad range of technologies is encompassed by asymmetric catalysis. All these processes are mediated by a complex bearing rhodium, ruthenium, or iridium as metal of interest. However, the limited availability of precious metals, their high price, and their toxicity diminish their attractiveness in the long term, and more economical and environmentally friendly alternatives have to be found.2
Iron and copper salts are usually non-toxic and very abundant on earth, and consequently they are among the most inexpensive, easy to handle, and environmentally-friendly metal derivatives.3 In this new economic and environmental race, the use of iron in catalysis has
witnessed tremendous activity in recent years.4
Over the years, our laboratory has assumed a strong leadership in green Lewis acid catalysts.5
Recently, we developed efficient non-enantioselective and non-enantioselective processes using new green catalysts.6
We set up general applications and a broad scope for new classes of iron and copper catalysts. Based on the excellent results obtained in transition metal using green metal catalysis,5-6
we decided to find green catalytic systems for non-asymmetric and asymmetric diazo insertion reactions into Si–H and S–H bonds,7
1.2 Carbenes and metal carbenes
1.2.1 CarbenesCarbenes, considered only as transient species for a long time, have become ubiquitous in organometallic chemistry. Their interaction with a metal center, which allows for their classification as a function of the nature of the carbene–metal bond, has inspired the investigations of many research groups in every area of chemistry, from physical chemistry to organic synthesis.9 Carbenes are neutral species containing a divalent carbon atom with
only six electrons. Carbenes, either in the singlet or triplet state, are highly electrophilic species (Figure 1.1).
Figure 1.1 Singlet and triplet carbenes
Carbenes are usually formed by the loss of a stable, small substituent. There are three main reactions for the formation of carbenes: α-elimination, formation from tosylhydrazones, and generation from diazo compounds.9 Carbenes can be formed by α-elimination from
trihalomethane, by treatment with a base (hydroxide/alkoxide) followed by loss of a halogen ion (Scheme 1.1). They can be formed from dihalomethane by deprotonation with stronger base such as lithium diisopropylamide (LDA) and even from primary alkyl chloride using powerful bases such as phenylsodium or tBuLi/tBuOK.10
R R'
R R'
Singlet
Has both electrons in one orbital Highly reactive and short-lived species
R R' sp hybridized (linear) sp 2 hybridized (bent) p p p sp2 Triplet
Has both electrons in two orbitals Only one orbital is stabilized by bending
R R' sp hybridized (linear) p p p sp2 sp2 hybridized (bent)
Scheme 1.1 Carbene formation by α-elimination
Another way to form carbenes is by decomposition of α-diazocarbonyl compounds using heat or light (Scheme 1.2).11
The formation of carbenes by diazoalkane decomposition can be performed more safely if the diazoalkane is just an intermediate of the reaction. Useful starting materials for this kind of reaction are tosylhydrazones (Scheme 1.3).12
In this case the diazoalkane formed is not isolated but is decomposed thermally or photochemicaly to give the carbene.
Scheme 1.2 Carbene formation by decomposition of α-diazocarbonyl compounds
Scheme 1.3 Carbene formation from a tosylhydrazone H Br Br Br base Br Br Br – Br– Br Br Ph Ph H H CHBr 3, tBuOK pentane, 0–25 ºC Ph Ph Br Br 78% R O N2 R O N2 Δ or hν R O Ph CO2Me N2 Ph PhCF3, 102 ºC, 12 h Ph Ph CO2Me 90%, 79:21 dr H R1 R2 O R1 R2 N N H Ts Base R1 R2 N N R1 R2 N N Δ or hν R1 R2 N H N Ts 1. LiHMDS, THF –78 ºC to rt 2. BnEt3NCl toluene, 40 ºC NHBOC CO2PNB CO2PNB NHBOC 36%, 72:28 (E:Z) CO2H NH2 Coronamic acid Ts
These reactions are very substrate limited due to the high reactivity of carbenes, which means that few functionalities are compatible. In order to extend the scope of the reaction, milder conditions have been developed for the formation of carbenes. The use of transition metals such as copper or rhodium to promote carbene formation via diazocarbonyl decomposition is common in modern synthetic chemistry. The carbenes formed this way remain complexed to the transition metal and are called metal carbenes.
1.2.2 Metal carbenes
Metal-catalyzed carbene transfer reactions of diazo compounds have proved to be useful methodologies in organic synthesis.13
Diazo compounds, which are commonly used as carbene precursors, have been extensively employed as versatile cross-coupling partners in various transition metal catalyzed reactions.14
Diazo compounds can be converted into highly reactive free carbene intermediates under thermolytic or photolytic conditions. Because of the limited synthetic applications and their lack of selectivity in many chemical transformations, there has been a significant interest in the development of transition metal-catalyzed decomposition of diazo compounds.15
Fischer carbenes16
and Schrock carbenes17
are different types of transition metal carbene complexes. Fischer carbenes have more electrophilic character because of the direct C→M donation which results in a positively charged carbon atom. They are usually found with low oxidation state metals, such as Mo, Cr, and W. On the other hand, Schrock carbenes are more nucleophilic because they form two polarized covalent bonds, giving a negative charge on the carbon atom, and usually found with high oxidation state metals, such as Ti and Ta (Figure 1.2).18
Figure 1.2 Fischer carbenes and Schrock carbenes MLn R1 R2 δ+ δ– MLn R1 R2 MLn R1 R2 δ+ δ– Fischer carbenes electrophilic in nature π accepter metal ligands low oxidation state
Metal Carbene Schrock carbenes
nucleophilic in nature non π acceptor metal ligands high oxidation state R1
R2 M
R1
The reactivity profile of transition metal carbenes is highly influenced by the nature of the substituents on the metal carbenes and the type of metal. Consequently, reviews on metal carbenes often classify them into three distinct categories: acceptor metal carbenes, acceptor/acceptor metal carbenes, and donor/acceptor metal carbenes.19
Generally, an acceptor substituent makes the metal carbenes species more electrophilic as well as more reactive, whereas a donor group makes the metal carbenes more stable and, thus, more selective in reactions (Figure 1.3).20
Figure 1.3 Classification of metal carbene species
There is a general agreement that transition metal catalysts react with the diazo compound to generate an electrophilic metal carbene, as originally suggested by Yates.21
A wide range of transition metal complexes have been used for the decomposition of α-diazo carbonyl compounds. Copper and rhodium complexes are particularly effective catalysts for reactions with diazo compounds and an increasing number of chemical syntheses are based on these catalytic complexes.7b
1.2.2.1 Copper catalysts for metal carbene generation
Copper is a group IB (Group 11) element in the first transition series with atomic number 29, a relative atomic mass of 63.546, and an electron configuration of 1s2 2s2 2p6 3s2 3p6 3d10
4s1
for elemental Cu0
. The more common oxidation states of copper include 0, I, II, III, and IV. CuI
is a d10
transition metal that shares formal stoichiometry with the alkali metals, but retains its transition metal character.22
Two-coordinate copper forms linear complexes,
Acceptor metal carbene
Acceptor/Acceptor metal carbene Acceptor/Donor metal carbene
MLn H EWG MLn EWG EWG MLn EWG EDG
EWG = CO2R, COR, CONR2, CN, PO(OR)2, CF3
EDG = vinyl, aryl, heteroaryl M = Pd, Rh, Ru, Cu, Ag, Fe, etc
More stable and selective
are most often tetrahedral, but can also be square-planar. Six-coordinate copper complexes are octahedrally arranged.22
CuII
is a d9
transition metal with a trigonal-planar geometry in three-coordinate complexes, while four-coordinate species have been found in both distorted tetrahedral and square-planar geometries.22
Five-coordinate systems are trigonal-bipyramidal, and six coordinate complexes are commonly octahedral. In addition to copper metal, both CuI
and CuII
complexes can decompose α-diazo compounds.15
Copper catalysts for α-diazo compounds decomposition are traditionally classified as either heterogeneous or homogeneous. Some examples of hetereogeneous copper catalysts are Cu powder, Cu2O, CuSO4.
15
Homogeneous copper catalysts such as Cu(OTf) was developed later and have since played major roles. Because CuII
is reduced to CuI
by the diazo functionality, CuI
is probably the active catalytic species.23
Since Cu(OTf)2 is much easier to handle, it is
often employed in the place of Cu(OTf). Other homogeneous catalysts such as Cu(acac)2
and [(MeCN)4Cu]PF6 have been used for cyclopropanation, diazo insertion reactions into
X–H (X = C, N, O) bonds, and ylide formation.15
These copper salts have the unique ability to be altered electronically without change of the overall geometry of the complex. 1.2.2.2 Iron catalysts for metal carbene generation
The use of iron compounds as catalysts in organic synthesis is attractive for a number of reasons. It is the most abundant metal in the earth's crust after aluminum and therefore is much cheaper than the precious metals that are often applied.3 The considerable increase of
prices for many transition and rare earth metals over the past decade demands cheap alternatives.2a
On the other hand, various iron compounds are incorporated in biological systems. As a result, a relatively low toxicity of many iron species is observed, which is of importance for many applications especially in the pharmaceutical industry, the food industry, and cosmetics. Regarding the catalytic efficiency and broad applicability, at present iron is still behind palladium as the most versatile catalytic metal in organic synthesis.2a
However, the tremendously increasing number of publications demonstrates that iron is catching up. Unlike palladium, iron can adopt oxidation states from +II to +V (rarely +VI).4
Thus, in low oxidation states it may be operative as an iron-centered nucleophile and catalyze reactions such as nucleophilic substitutions. In contrast to this rather new area, iron Lewis acid catalyzed reactions have been known for a long time, for
example electrophilic aromatic substitutions. This applies to iron catalysts in the common oxidation states +II and +III.4
An extensively investigated research area deals with iron-catalyzed oxidation reactions preferably of nonactivated C–H bonds. This rapidly developing field relies on iron in high oxidation states (+III, +IV, or even +V).4
Iron features not only a broad spectrum of oxidation states but also the ability to transfer one or two electrons to a substrate. This opens up the possibility for radical reactions and also for two-electron transfer processes which commonly proceed in metal-catalyzed coupling reactions, such as oxidative addition and reductive elimination. For cross coupling processes, the redox couple FeI
/FeIII
has emerged as a potent system.24
Moreover, the diverse possibilities provided by the large number of accessible oxidation and spin states can be even extended by applying designed ligands which interfere actively in the catalytic process. Iron can undergo facile changes in its oxidation state and possesses distinct Lewis acid character, and these properties have afforded iron a privileged position as catalyst in the transformations of diazo compounds. Iron has rarely been used in asymmetric metal carbene insertion reactions.25
Weak coordination between iron and the corresponding chiral ligands may account for the unsuccessful chiral induction of iron catalysts in asymmetric insertion reactions.25
It has been reported that increasing the rigidity of the ligands might increase the stability of the iron complexes and thus improve chiral induction.25
Having this notion in mind, one can predict that in the coming years we will see a large number of fascinating new iron catalyzed reactions and their application in organic synthesis.
1.3 Chemistry of diazo compounds
1.3.1 Diazo compounds: propertiesThe first diazo compound, ethyl α-diazoacetate (EDA), was synthesized by Curtius in 1883,26 by the reaction of glycine ethyl ester with sodium nitrite in acidic conditions. After
that, diazo compounds have shown to be very useful and important intermediates in organic synthesis (Scheme 1.4).27
Scheme 1.4 Synthesis of ethyl α-diazoacetate
The geometry of the diazo group was unclear for a long time and was assumed to be a cyclic structure of type A (Figure 1.4). In 1911, Thiele proposed a linear structure B for the diazo group in contrast to the cyclic diazirine structure A (Figure 1.4).28
Figure 1.4 Cyclic diazirine structure and linear diazo structure
Experimental proof for the linearity of the diazo group was then reported by Clusius in 1957.29
In this experiment, ethyl glycinate was diazotized using 15
N-labeled sodium nitrite,
and the corresponding labeled ethyl α-diazoacetate was reductively cleaved to glycine and ammonia. This resulted in a clean formation of 15N-ammonia and unlabeled glycine. The
cyclic structure could thus be excluded, since no scrambling of the label was observed (Scheme 1.5). The bond state for α-diazocarbonyl compounds may be described essentially by the resonance structures in Figure 1.5. It is important that the negative charge of the diazo carbon (A, Figure 1.5) can be shifted to the carbonyl group, whereby a diazoniumenolate structure C is formed. For such structures, lengthening the C–N bond and shortening of the N–N bond is expected.
Scheme 1.5 Experimental evidence for linear structure of ethyl α-diazoacetate
EtO NH2.HCl O NaNO2.NaOAc EtO O N2 H2O, toluene pH = 3.5 99% R1 N R2 N R1 R2 N N B A EtO NH2.HCl O Na15NO 2 H+ EtO O 15N 2 Zn CH3COOH EtO O NH2 + 15NH 3
Figure 1.5 Mesomeric structures of diazo carbonyl compounds
Diazo compounds are inherently reactive molecules due to their high nitrogen content and their readiness to release the thermodynamically stable dinitrogen. Firstly, they are themally and photochemically unstable and generate free carbenes upon heating or hν activation.30
Stability towards heating is increased by mesomeric stabilizing substituents (such as esters) and decrease upon substitution with electron-donating (such as alkyl) substituents. Second, diazo compounds are acid-labile compounds due to significant contribution of the resonance structure B (Figure 1.5) bearing a carbanion. Diazomethane is the most labile compound, and unstabilized diazoalkanes are generally much more acid-labile than electron-withdrawing substituted ones (Figure 1.6).30
Figure 1.6 Relative basicity of selected diazo compounds 1.3.2 Diazo compounds: preparations
Diazo compounds can be made via different routes and depend on the exact structure of the diazo reagent and the desired subsequent use to assign which protocol should be employed. The most important synthetic pathways to diazo compouds have been summarized in Figure 1.7 and less regularly employed techniques will be discussed miscellaneously. a) Diazotization of primary amines
b) Diazo transfer into an activated methylene group c) Base treatment of sulfonylhydrazones
d) Base mediated cleavage of N-alkyl-N-nitroso sulfonamides
R1 N N R1 N N A B R1 N N C R2 O O R2 O R2 H N2 H = H N2 > H N2 Ph > Ph N2 Ph > Ph N2 CO2Et > EtO2C N2 CO2Et Basicity
Figure 1.7 Selected common methods for the synthesis of diazo compounds via buildup or introduction of diazo group
1.3.2.1 Diazotization of primary amines (a)
Diazotization of primary aliphatic amines with an α-activating group is one of the common ways to prepare α-acceptor diazo compounds and was used in the synthesis of the first reported diazo compound, ethyl α-diazoacetate. The diazotization of certain amines with nitrous acid under acidic conditions furnishes the corresponding α-diazo compound (Scheme 1.6).31
Scheme 1.6 Diazotization of aromatic amines
R1 N2 R2 R1 NH2 R2 NaNO2 HX R1 R2 RSO2N3 R1 N R2 base R1 N R2 base R1 N R2 oxidant b c d e a NH2 NHTs N R3 NO NH2 R1 O OR2 N2 R1 O OR2 HNO2/H2SO4
1.3.2.2 Diazo transfer into an activated methylene group (Regitz diazo transfer reaction) (b)
The diazo transfer reaction was discovered by Regitz in 1967.32
The reaction transfers a diazo group from an organoazide bearing an electron-withdrawing group (usually a sulfonyl azide) onto an activated methylene or methane group (Scheme 1.7). The reaction is used to prepare compounds bearing an electron-withdrawing group such as α-diazoacetate and α-diazoketones.
Scheme 1.7 Regitz diazo transfer reaction via direct diazo transfer or de-acylating diazo transfer
1.3.2.3 Base treatment of sulfonylhydrazones (Bamford-Stevens reaction) (c)
Bamford-Stevens reaction is a general method for the preparation a wide range of diazo compounds from the corresponding ketones or aldehydes.33
The standard procedure involves condensation of the required ketone or aldehyde with tosylhydrazine. The reaction is usually achieved by heating the substrate in a presence of a base and harsh conditions often lead to low yields of the sensitive diazo compounds. The method is particularly indicated for the preparation of semi-stabilized diazo compounds like aryl-substitued diazo compounds, since they offer increased thermal stability (formation of free carbene) as a contrast to the aliphatic diazo compounds which renders their preparation difficult when using this methodology, and the oxidation of hydrazones is preferred. As an example, tosyl hydrazoacetyl ester afforded α-diazoacetate upon treatment with triethylamine in dichloromethane (Scheme 1.8).
R2 R1 O O RSO2N3 base R2 R1 O O N2 + RSO2NH2 R2 R1 O H OEt O base R 2 R1 O H O RSO2N3 base R2 R1 O N2 + RSO2NH CHO
Scheme 1.8 Bamford-Stevens reaction
1.3.2.4 Base mediated cleavage of N-alkyl-N-nitroso sulfonamides (d)
Another base-mediated preparation of diazo compounds is the decomposition of nitrosamides which first found application in the preparation of diazomethane by Pechmann in 1891.34
Various N-substituents have been employed, such as carbamates, ureas, and sulfonamides.35
Carbamates were used in the early days of diazo chemistry, and were later replaced by urea-derived reagents. Using pyridine as a base for the cleavge reaction, the sensitive α-diazo penicillin has been prepared from the N-nitrosoamide which was prepared from penicillin derivatives following the method of Hauser and Sigg (Scheme 1.9).36
Scheme 1.9 Cleavage of N-nitrosamide 1.3.2.5 Oxidation of hydrazones (e)
The method is related to the previously described Bamford-Stevens reaction, however this time an external oxidant is used to prepare the diazo compound. This method usually employs a hydrazine of the corresponding ketone that is treated with a stoichiometric oxidant in a polar organic solvent. The first oxidant used was mercury oxide which was reported by Curtius in 1889.37
The use of two other oxidants, Pb(OAc)4 and MnO2, was
later developed.38
Recently, Javed and Brewer developed a method using Swern oxidation under mild and metal-free conditions (Scheme 1.10),39
Furrow and Meyers used a difluoroiodobenzene reagent as oxidant.40
O N O NTs H Et3N CH2Cl2 O N2 O 87% N S O O O CH2CCl3 H H N N O PhO O N S O O O CH2CCl3 H Pyridine CH2Cl2 N2 72%
Scheme 1.10 The synthesis of α-phenyl-α-diazomethane 1.3.2.6 Miscellaneous preparations
Some other methods for the preparation of diazo compounds are worth mentioning here. The first one was published by Fukuyama and described the preparation of a wide range of diazoacetates starting from bromoacetyl bromide (Scheme 1.11).41
Scheme 1.11 Preparation of diazoester starting from bromoacetyl bromide
In 2009, Raines showed that a newly designed phosphine reagent bearing an acylating reagent could be used in the direct transformation of azides into diazo compounds.42
The reaction is believed to occur via the formation of a transient phosphazide, which is subsequently trapped intramolecularly by the neighboring acylating group (Scheme 1.12). This intermediate then reacts with water to form the phosphine oxide and the corresponding acyltriazene that collapses into the diazo compound.
N NH2 Me2SCl2 N2 Et3N, THF 87% O O Br HN NH Ts Ts DBU, THF Ph O O N2 Ph 88%
Scheme 1.12 Phosphine-mediated preparation of diazo compounds using azide
Forster's reaction is scarcely used for the preparation of diazoalkanes. This reaction involves the reaction of an oxime with chloramine (generated from sodium hypochlorite and ammonia) to form the diazoketone (Scheme 1.13) and was first reported by Forster in 1915.43
The strong oxidizing nature of chloramine has been a limitation to the larger development of this method. However, a modification using hydroxylamine o-sulfonic acid has been published later, in which the solid reagent is used as a convenient alternative to chloramine.44
Although its use is not widespread, the Forster's reaction proved useful in certain cases.
Scheme 1.13 Forster's reaction
1.4 Reactivities and decomposition methods of diazo compounds 1.4.1 Non- metal carbene pathway
Selected examples of reactions with diazo compounds without carbene or metal carbene intermediates are summarized here.
1.4.1.1 Huisgen reaction: The 1,3-dipolar cycloaddition of diazo compounds with dipolarophiles is a common reaction with diazo compounds to prepare heterocycles such as pyrazoles or pyrazolines and demonstrates the ambiphilic character of diazo compounds (Scheme 1.14).45 N3 Ph NHBn O + O P O N O O Ph Ph THF/H2O N2 Ph NHBn O 81% NaHCO3 R1 N O R2 HO NH2Cl R1 N2 O R2
Scheme 1.14 Huisgen reaction
1.4.1.2 aza-Darzens reaction: This reaction is a method to prepare aziridines from nucleophilic addition of diazo compounds to imines under Lewis or Brønsted acid activation (Brookhart-Templeton aziridination, Scheme 1.15).46
Scheme 1.15 Preparation of aziridine from nucleophilic addition of diazo compound 1.4.1.3 Roskamp and Tiffeneau-Demjanow-type reactions: The homologation of acyclic carbonyls47
or ring expansion of cyclic ketones48
are common examples for rearrangements caused by nucleophilic addition of diazo compounds to carbonyls (Scheme 1.16).
Scheme 1.16 Homologation of acyclic carbonyl and ring expansion of cyclic ketone
Selected examples of reactions with diazo compounds with a carbene intermediate is described here. MeO N2 + O OMe O MeO O NH N MeO O 52% H OEt N2 O + Ph Ph N BF 3 hexane N Ph Ph OEt O 93% N2 + O Sc(OTf)3 toluene O H O + OEt O SnCl2 O OEt O N2 88% 80%
1.4.1.4 Arndt-Eistert via a Wolff rearrangement: Scheme 1.17 demonstrates an example of a reaction involving free carbenes known as the Arndt-Eistert via a Wolff rearrangement.49
Scheme 1.17 Arndt-Eistert via a Wolff rearrangement 1.4.2 Transition metal carbene pathway
A wide variety of transformations can occur with these transition metal carbenes, such as X–H (X = C, N, O, Si, S, etc.) bond insertion reactions, cyclopropanation, ylide generation, and rearrangements. Their chemoselectivity was found to be dependent on the metal species, ligands, and substrates.30
Selected common examples for metal-catalyzed carbene transfer reactions of diazo compounds are shown in Figure 1.8.
Figure 1.8 Selected common examples for metal-catalyzed carbene transfer reactions of diazo compounds N O OH O O2N O 1. EtOCOCl, Et3N 2. TMSCHN2 N O O O2N O Ag MeOH N2 N O O2N O O OMe 77% overall yield R2N–H R1 R2 R2N H R1 R2 RO H R1 R2 RS H R1 R2 R3Si H R1 R2 MLn R H R1 R2 R OH R R1 R2 HO R R1 R2 R3C H RS–H R3Si–H RO–H R3C–H
The generally accepted mechanism for catalytic decomposition of diazo compounds starts with nucleophilic addition of the diazo compound to the metal complex to form the diazonium ion adduct followed by loss of nitrogen gas to produce a corresponding metal carbene.14b
An electron rich substrate (S:) can then react with the electrophilic metal carbene, resulting in the regeneration of the transition metal complex (Figure 1.9).
Figure 1.9 Mechanism for catalytic decomposition of diazo compounds 1.4.2.1 Insertion reactions
X–H insertion reactions of metal carbene are well known for X = O, S, N, Si or C. The low bond polarity of C–H bonds in comparison with O–H, S–H, or N–H bonds, combined with the formation of a carbon-carbon bond, make this a reaction of great interest. Insertion reactions of carbenes into C–H bonds was reported for the first time by Werner in 1942.50
Although insertion reactions can proceed both intermolecularly and intramolecularly, intermolecular C–H bond insertion reactions tend to be unselective and intramolecular reactions often compete. Multiple products are generally obtained from intermolecular C– H bond insertion reactions and a highly electrophilic catalyst is usually required to minimise competitive reactions. In comparison, intramolecular metal carbene insertion reactions tend to be selective, even when moderately electrophilic complexes are used to generate the metal carbene, and generally proceed relatively efficiently.20
MLn R1 R2 N2 R1 R2 R1 R2 LnM N2 R1 R2 MLn S S N2
1.4.2.2 Cyclopropanation
A very common reaction involving metal carbenes is cyclopropanation. During the cyclopropanation reaction, an olefin reacts with a metal carbene to form a cyclopropyl ring. Three-membered rings are very important building blocks, as they are structural subunits in many biologically active natural products and are present in many synthetic intermediates. Therefore, the cyclopropanation reaction of diazoketones has received substantial attention during the last few decades. While transition metal catalysed cyclopropanation was first reported in 1906,51 it was not until the late 1960's that the
catalyst development became an interest and the reaction gained importance. Initially, catalytic cyclopropanation using diazocarbonyl compounds was focused on intermolecular reactions. As catalysts were limited to a few, often insoluble complexes, it was difficult to obtain selectivity during these intermolecular reactions.52
Following the report of the first intramolecular cyclopropanation reaction by Stork and Ficini in 1961, interest in this procedure significantly increased. In this case, the diazoketone underwent intramolecular cyclopropanation in moderate yields when treated with copper bronze (Scheme 1.18).
Scheme 1.18 The first intramolecular cyclopropanation reaction 1.4.2.3 Ylide generation
The realization in the 1950s that carbenes and metal carbenes could engage in ylide formation has had a profound effect on the development of diazocarbonyl compounds as synthetic intermediates. Carbenes derived from diazocarbonyl compounds exhibit highly electrophilic properties which dictate one of their most characteristic reactions: ylide formation with heteroatomic species. Metal carbenes can thus readily form adducts by reacting with Lewis bases (B:). The most common Lewis bases utilized to generate ylides include ethers, sulfides, amines, and carbonyl compounds, forming oxonium, sulfur, nitrogen, and carbonyl ylides, respectively. The adduct generated may either dissociate
N2
O
Copper bronze O
from the catalytic species to form a “free ylide” or react as a metal-ligated ylide complex (Figure 1.10).30
Figure 1.10 Ylide formation
R1 R2 MLn B: R1 R2 MLn R1 R2 MLn R1 R2 B + MLn B: = x x = O, S O N B
Chapter 2
Metal carbene insertion reactions
into Si–H and S–H bonds
Chapter 2
Metal carbene insertion reactions into Si–H and S–H bonds
2.1 Catalytic carbene insertion reactions into the Si–H bond
7b2.1.1 Introduction
The catalytic insertion reaction of diazo compounds into X–H (X = heteroatom) bonds is a very powerful transformation due to the highly synthetic potential of the generated building blocks.53
In the past decades, chiral silanes have been particularly popular for stereoselective transformations in organic synthesis.54
Various methods using different kinds of catalysts have been discovered sharing the common aim to enhance the selectivity of these insertion reactions. Remarkable methodological advances have been made in the catalytic asymmetric and non-asymmetric diazo insertion reactions into the C–H bond. Crucial breakthroughs have been obtained for diazo insertion reactions into the C–H bond and some reviews have summed up the progresses in this topic,55
but almost no review has specifically focused on the advancement in catalytic carbene insertion reactions into the Si–H bond. Silicon constitutes almost 30% of the mass of Earth's crust. Whereas natural supplies of silicon are abundant, versatile methods for synthesizing organosilicon derivatives are not numerous. Metal-catalyzed carbene transfer reactions of diazo compounds have proved to be a useful methodology in organic synthesis.13
C–Si bond-forming methods, introducing silicon motifs into organic molecules, rely on multistep synthetic routes to prepare and optimize the synthesis of reagents or catalysts. Insertion reactions of diazo compounds into the Si–H bond have already been well-established since 1988.56 However, they have not received much attention compared to
their N−H and O−H counterparts. Recently, there have been a few notable developments, particularly in the field of asymmetric reactions of diazo compounds into the Si–H bond,
R1 R2 N2 + R3Si–H R1 R2 H R3Si and/or R1 R2 H R3Si Rh, Cu, Ir, Ag, Ru, Fe
where chiral copper, rhodium, iridium, and ruthenium catalysts have shown to be very promising.7b
Various methods using diverse types of catalysts have been developed, with the objective of enhancing the selectivity of Si–H bond insertion reactions (Figure 2.1).
Figure 2.1 General scheme for diazo insertion reaction into the Si–H bond
The insertion reaction of carbene species into the Si–H bond was first reported by Kramer and Wright who studied the reaction of diazoalkanes with organosilanes.57
They mentioned that diazomethane reacts with organosilicon hydrides exclusively in the presence of ultraviolet light or copper powder. In this study, they suggested that the reaction involves the insertion of a carbene. The yields of methyl derivatives were shown to be dependent on the steric hindrance of the substituents on the silane. They also showed that diazoethane presents a similar reactivity with phenylsilane giving ethylphenylsilane, in a low yield of 5%though.
2.1.2Catalysis
2.1.2.1 Rhodium Catalysis The RhII
-catalyzed insertion reactions of α-diazoesters and α-diazoketones into the Si–H bond, resulting in the formation of α-silylesters and α-silylketones, was first reported by Doyle in 1988.56
In this study, the reactions were performed using 1 mol% of Rh2(OAc)4 at
room temperature. The diazo compounds were slowly added to the mixture of silane sources and Rh2(OAc)4, by means of a syringe pump to minimize dimerization into the
tri/tetra-substituted olefin. The desired insertion reaction products were obtained in high yields (up to 95%) (Scheme 2.1).
N2 LnM R1 R2 N2 R1 R2 R1 R2 H R3Si R1 R2 N2 + R3Si–H LnM and/or R1 R2 H R3Si MLn R1 R2 H R3Si and/or R1 R2 H R3Si R3Si–H
