Transition Metal-catalyzed Carbon-carbon And Carbon-nitrogen Bond .
TRANSITION METAL-CATALYZED CARBON-CARBONAND CARBON-NITROGEN BOND FORMATION ANDASYMMETRIC CATALYSIS WITH BISOXAZOLIDINELIGANDSA Dissertationsubmitted to the Faculty of theGraduate School of Arts and Sciencesof Georgetown Universityin partial fulfillment of the requirements for thedegree ofDoctor of Philosophyin ChemistryByHanhui XuGeorge Washington University, M.S.Washington, DCDecember 19, 2011
TRANSITION METAL-CATALYZED CARBON-CARBON ANDCARBON-NITROGEN BOND FORMATION ANDASYMMETRIC CATALYSIS WITH BISOXAZOLIDINELIGANDSHanhui XuThesis Advisor: Christian Wolf, Ph. D.ABSTRACTPalladium-phosphinous acids and chlorophosphine analogues have attractedincreasing interest due to their high catalytic activity in various organic transformations,long shelf-life and facile handling. In this thesis, it is reported that these catalysts are veryuseful in Negishi cross-couplings of aryl or acyl halides with aliphatic and aromaticorganozinc reagents. Similarly, palladium-phosphinous acids were employed in theformation of sterically hindered biaryls exhibiting at least two ortho substituents fromaryl halides and aryl Grignard reagents.Due to an ever-increasing demand of inexpensive and environmentally friendlycarbon–nitrogen bond formation protocols for large-scale industrial applications, coppercatalyzed amination has emerged as an important synthetic strategy. A highly efficientCu2O-catalyzed C-N bond formation protocol suitable to amination of aryl halides withammonia, amines and amides was developed. This reaction tolerates a wide range offunctional groups and provides a wide range of C-N coupling products in up to 99% yield.The chemoselectivity, experimental simplicity, and the low cost of the catalytic systemare quite remarkable.In addition to the widely explored oxazolines ligands, oxazolidines bearing aii
nonplanar, sterically more demanding saturated scaffold have been applied to variousasymmetric reactions in recent years. A highly enantioselective copper-bisoxazolidinecatalyzed nitroaldol reaction with aliphatic and aromatic trifluoromethyl ketones and αketo esters was developed to provide a wide range of functionalized chiral tertiaryalcohols. Finally, a practical enantioselective synthesis of N-substituted 1,3diaminopropanols via copper-bisoxazolidine catalyzed nitroaldol reaction of α-ketoamides and subsequent reduction of the nitro and amide groups was introduced. Thisroute involves the first catalytic asymmetric intermolecular carbon-carbon bondformation with α-keto amides.iii
AcknowledgementsI would like to thank my mentor Dr. Christian Wolf for his never ending supportand guidance throughout my Ph. D. studies. I have always admired Christian’s passionfor his group, his students and the chemistry. From my first day in the “Wolf pack”,Christian truly guided me by example and taught me to work diligently, effectively, andto always think critically about my experiments and observations. Without a doubt, Imade the right choice to attend Georgetown and to join the Wolf group. In my future,Christian will be a great example for me to follow. Christian, thank you so much for yourhelp as an advisor and as a friend over the past few years.I would also like to sincerely thank my committee members with whom I havebeen discussing chemistry throughout the years: Dr. Steven Metallo, Dr. Bahram Moasser,Dr. Timothy Warren and Dr. Richard Weiss. All of my committee members have helpedme become a well-rounded scientific researcher. Thank you all very much for your time,support, and guidance.I would also like to thank current and former group members of the “Wolf pack:”Dr. Xuefeng Mei, Dr. Rachel Lerebours, Dr. Shuanglong Liu, Dr. Kekeli Ekoue-Kovi, Dr.Kimberly Yearick Spangler, Dr. Jayakumar Natarajan, Dr. Daniel Iwaniuk, Dr. MarwanGhosn, Mikki Boswell, Max Moscowitz, Peng Zheng, Andrea Cook and Keith Bentley. Ithank you all for working with me during my Ph.D. studies, for helping me to grow as aresearcher, and for being part of the “Wolf pack” with me. I also thank my hard-workingundergraduate student, Olivia Chitayat, for helping with the Malaria project.iv
I would like to thank the Department of Chemistry, the Graduate School of Artsand Sciences, and Georgetown University for the opportunity to complete my graduatestudies. I also thank Ms. Kay Bayne, Ms. Inez Traylor, Dr. Mo Itani, Dr. Steve Hannum,Mr. Travis Hall, Mr. Bill Craig, Dr. Li Ercheng and Ms. Yen Miller for all of theadministrative support during my graduate studies at Georgetown University. I alsogratefully thank the funding from National Science Foundation.I would especially like to thank my wife, Lu Sun, and my son Kevin for alwaysbeing there for me, for their constant support and for their belief in me. I would also liketo thank my parents, Kangsheng and Faxiang for their support from when I was a childuntil now. Without them, I would not have been able to achieve what I have alreadyaccomplished.I will always remember the time I have spent at Georgetown and the memoriesinvolving many more people than those mentioned here. Thanks everyone who hasinfluenced me and played a role in my life.v
Table of ContentsAbstract . iiAcknowledgements ivList of Figures . ixList of Schemes .xiiiList of Tables .xxList of Abbreviations .xxiiChapter I: Introduction .11.1 Palladium-Catalyzed Carbon-Carbon Bond Formation .61.2 Copper-Catalyzed Carbon-Nitrogen Bond Formation 171.3 Asymmetric Catalysis With Oxazolidine Ligands .341.4 References .45Chapter II: Objectives 61Chapter III: Synthesis and Applications of Palladium-Phosphinous Acids inCross-Coupling Reactions 633.1 Introduction 633.2 Palladium-Phosphinous Acid-Catalyzed Kumada-Corriu CrossCoupling .703.3 Palladium-phosphinous Acid-catalyzed Negishi Cross-Coupling .76vi
3.4 Analysis of the Stereodynamics of 2,2’-Disubstituted Biphenyls byDynamic Chromatography .903.5 Conclusion .963.6 Experimental Section . 983.7 References . 121Chapter IV: Copper-Catalyzed Amination and Amidation .1344.1 Introduction 1344.2 Copper Catalyzed Coupling of Aryl Chlorides, Bromides and Iodideswith Amines and Amides .1354.3 Copper-catalyzed Coupling of Aryl Chlorides, Bromides and Iodideswith Aqueous Ammonia 1414.4 Conclusion .1484.5 Experimental Section . 1494.6 References . 161Chapter V: Asymmetric Catalysis with Bisoxazolidine Ligands .1695.1 Introduction 1695.2 Asymmetric Nitroaldol Reaction of Trifluoromethyl Ketones with aCu(II)-Bisoxazolidine Catalyst . 1735.3 Asymmetric Nitroaldol Reaction of α-Ketoesters with a Cu(II)Bisoxazolidine Catalyst .vii180
5.4 Asymmetric Synthesis of Chiral 1,3-Diaminopropanols viaBisoxazolidine-Catalyzed C-C Bond Formation with α-Keto Amides. 1835.5 Conclusion .1945.6 Experimental Section . 1955.7 References . 253viii
List of FiguresChapter IFigure 1.Examples of pharmaceutical drugs synthesized via theHeck reaction 2Figure 2.Synthesis of Dragamacidin F via Suzuki coupling and 5HT1A agonist via Negishi coupling . .2Figure 3.Structures of Lipitor, Nexium and Plavix . .3Figure 4.Structures of C2-symmetric ligands . 5Figure 5.Some effective ligands for Pd-catalyzed cross-couplingreactions . . . Figure 6.10General structures of oxazolidines (left) and oxazolines(right). MM2 calculations of the corresponding (2R,3S)-2amino-3-butanol derived ligands (bottom) .Figure 7.35Structures of selected chiral oxazolidine ligands that havebeen used in asymmetric catalysis 36Chapter IIIFigure 1.Structures of palladium-phosphinous acids and palladiumchlorophosphines . 65Figure 2.Structures of new phosphine oxides L1-L9 (top) andformation of (RR’POH)2ML2 (bottom) . .Figure 3.Simulated chromatographic elution profiles showingix77
baseline enantioseparation (top left) and increasingcontribution of on-column racemization until peakcoalescence is reached (bottom right) . .Figure alcel OD using hexanes as mobile phase . .Figure -cyclohexyl-2’-phenylbiphenyl .Figure 8.93onChiralcel OD using hexanes as mobile phase . .Figure 7.932-phenyl-2’-isopropylbiphenyl .Figure 6.9294Rotational energy barriers, G , of 2,2’-disubstitutedbiaryls . .95Chapter VFigure 1.Catalytic cycle of the Henry reaction using Cu(OAc) andbisoxazolidine L1 . Figure diaminopropanols leading to α-keto amides. .184Figure 3.Structures of bisoxazolidines L1-L7 185Figure 4.X-ray crystallographic structure of 38. Ellipsoids drawn atthe 50% probability level .x207
Figure 5.Top: Structures of the (R)-CSA and (S)-85. Bottom:Simultaneous hydrogen bonding, π-π-interaction (face-toface interaction)interaction)and CH/π-interaction 5-dinitrobenzamide (left) and (S)-85. The structures of the(R)-CSA and (S)-85 were obtained by crystallography andmolecular modeling, respectively .Figure 6.234Selected regions of the 1H NMR spectra obtained with the(R)-CSA and amide 85. (A) Signals of the diastereotopicmethylene protons (d, J 16.0 Hz) and the broad singlet ofthe alcohol proton in 85, (B) Equimolar amounts of (R)CSA and racemic 85, (C) (R)-CSA and enantioenriched 85(90% ee) at 25 oC, (D) (R)-CSA and enantioenriched 85(90% ee) at 0 oC, (E) (R)-CSA and enantioenriched 85(90% ee) at -20 oC. All spectra were recorded in CDCl3using equimolar amounts of (R)-CSA and 85. .Figure 7.236Selected regions of the 1H NMR spectra obtained with (R)CSA and 117. (A) Signals of the diastereotopic methyleneprotons and the broad singlet of the alcohol proton in 117,(B) (R)-CSA and enantioenriched 117 (87% ee). Allspectra were recorded in CDCl3 at room temperature usingequimolar amounts of (R)-CSA and 117 . 237xi
Figure 8.Selected regions of the 1H NMR spectra obtained with (R)CSA and amide 118. (A) Signals of the diastereotopicmethylene protons and the broad singlet of the alcoholproton, (B) (R)-CSA and enantioenriched nitroaldolproduct (26% ee). All spectra were recorded in CDCl3 atroom temperature using equimolar amounts of (R)-CSAand the substrate Figure 9.238Selected regions of the 1H NMR spectra obtained with (R)CSA and the TMS derivative of 85. (A) Signals of thediastereotopic methylene protons in TMS-85, (B) (R)-CSAand racemic TMS-85, (C) (R)-CSA and enantioenrichedTMS-85 (90% ee). All spectra were recorded in CDCl3 atroom temperature, using equimolar amounts of (R)-CSAand TMS-85 . 239xii
List of SchemesChapter IScheme 1.Racemization of the two enantiomers of Thalidomide Scheme 2.Bisoxazoline-catalyzed asymmetric Diels-Alder reactionwith enantiofacial control .Scheme 3.7Formation of trans-[Pd(C6Cl2F3)I(PPh3)2] via obenzenetopalladium(0) . .Scheme 5.6Catalytic cycle of the Pd-catalyzed Suzuki and Negishicross-coupling . .Scheme 4.38Suzuki coupling of aryl chlorides and organoboronicacids. . . . 9Scheme 6.Isolation of a transmetallation intermediate in a Stillecoupling . . .Scheme l)phosphines . . .Scheme Buchwald ligands . . .Scheme 9.912Suzuki, Heck and Stille coupling using a tri-tertbutylphosphine-derived palladium catalyst .13Scheme 10.Palladium-catalyzed Suzuki coupling of 2-chloropyridines.14Scheme 11.Sonogashira coupling of aryl bromides and iodides using axiii
palladacycle . . . .14Scheme 12.Phosphinito palladium pincer catalyzed Heck reaction .15Scheme aldehyde with butyl acrylate . Scheme 14.Negishi coupling of alkyl bromides using an NHC-derivedpalladium catalyst . . . .Scheme 15.20Copper-catalyzed N-arylation of aniline using 2,2’bipyridine and phosphines . . .Scheme 20.19Copper-catalyzed N-arylation of aryl halides usingphenanthroline ligands . . . Scheme 19.18Copper-catalyzed N-arylation of (S)-valine with arylbromide . . . .Scheme 18.17Proposed catalytic cycles of the copper-mediated couplingof aryl halides . . . .Scheme 17.16Copper-mediated Ullmann-Goldberg coupling of arylhalides . . . .Scheme 16.1521Copper-catalyzed N-arylation of aniline using pyrrole-2carboxylic acid . . . .22Scheme 21.Copper-catalyzed amination reaction of anthranilic acids 23Scheme 22.Copper-catalyzedScheme 23.aminationofbromo-andchloropyridine . . . .23Copper-catalyzed N-arylation reaction of aliphatic amines.24xiv
Scheme 24.Copper-catalyzed amination of aryl bromides using N,Ndiethyl salicylamide . . . 25Scheme 25.Buchwald’s chemoselective cross-coupling of β-aminoalcohols . . . . . 26Scheme 26.Copper-catalyzed amination of aryl iodides with alkylamines . . . . . 26Scheme 27.Copper-catalyzed amination of aryl bromides using βdiketones . . . . . 27Scheme 28.Copper-catalyzed amidation of aryl halides using diamineligands . . . . .Scheme 29.Copper-catalyzed amidation of aryl iodides using aminoacids as ligands . . . Scheme 30.2829Copper-catalyzed amidation of aryl bromides usingmicrowave irradiation . . . 30Scheme 31.Copper-catalyzed synthesis of aniline using proline asligand . . . . .Scheme 32.Copper-catalyzedsynthesisofanilineusing 2,2,2-trifluoroacetamide . . .Scheme 33.32Copper-catalyzed synthesis of aniline using NH4Cl oraqueous NH3 . . . . .Scheme 34.3133Copper-catalyzed synthesis of aniline derivative usingaqueous NH3 . . . . .xv33
Scheme ehydes. . . . . .37Scheme 36.Alkynylation of aldehydes with bisoxazolidine L37 .37Scheme 37.Asymmetric alkynylation of ketones . . 38Scheme 38.Pd-catalyzed asymmetric allylic alkylation . 39Scheme 39.Pd-catalyzed asymmetric allylic alkylation of dimethylmalonate using ligands 29, 43 and 44. Asymmetricinduction observed with ligand 29 is shown . .Scheme 40.40Pd-catalyzed asymmetric allylic alkylation of dimethylmalonate using ligands L34 and L45-49. Results obtainedby microwave irradiation are shown in parentheses. .Scheme 41.40Pd-catalyzed asymmetric allylic alkylation of dimethylmalonate using phosphinooxazolidine ligands L31 andL50-52. . . . . .Scheme 42.41Formation of palladium complex L53 and asymmetricDiels-Alder reaction between three 1,3-oxazolidin-2-onedienophiles and cyclopentadiene. . . .42Scheme 43.Nagano’s organocatalytic Diels-Alder reaction. . 43Scheme 44.Selected examples of the bisoxazolidine L35-catalyzedScheme 45.Henry reaction in the presence of dimethylzinc. . 44Nitroaldol reaction using nitroethane as prenucleophile .44xvi
Chapter IIIScheme 1.Tautomeric equilibrium of secondary phosphine oxides andformation of a transition metal complex. . .Scheme 2.Platinum-phosphinous acid catalyzed hydroformylation of1-heptene . . . . .Scheme responding Pd-phosphinous acid complexes. . . 65Scheme 4.Heck coupling of 4-chloroacetophenone using POPd orPOPd1 . . . . .Scheme 5.66Heck and Stille coupling of 4-chloroquinaldine usingPOPd . . . . . 67Scheme 6.Suzuki coupling of aryl and vinyl chlorides using POPd 67Scheme 7.Amination and thiation of aryl chlorides using POPd,POPd1 and POPd2 . . . . . 68Scheme 8.Negishi and Kumada coupling of aryl halides. . .69Scheme 9.Hiyama coupling of aryl chloride using POPd1. .69Scheme 10.Sonogashira coupling of aryl chloride catalyzed POPd.70Scheme ides . . . . . 76Scheme 12.Synthesis of phosphine oxides using t-BuPCl2. . .78Scheme 13.Synthesis of phosphine oxides using P(OEt)3. . .79Scheme 14.FCA routes towards 3-chloro-2’-methylbenzophenone, 145,xvii
and some regioisomers . . . . .90Conformational energies of cyclohexanes 170 and 171 . 96Scheme 1.Copper catalyzed arylation of (S)-Ala and (S)-Leu-OMe .139Scheme 2.Cu-catalyzed amination of aryl chlorides with LiNH2 .147Scheme 15.Chapter IVChapter VScheme xazolidinesaminoalcoholsbywithketones . . . . . . 170Scheme 2.Synthesis of bisoxazolidine catalyst ( )-L1 . 170Scheme 3.Enantioselective alkynylation and alkylation of aldehydeswith bisoxazolidine ( )-L1. . . . . 171Scheme 4.Henry reaction of aldehydes with bisoxazolidine ( )-L1 .Scheme luoroacetophenone and nitromethane in the presence of10 mol% of L1 and Cu(OTf)2 at room temperature. .Scheme 6.Nitroaldol reaction with nitroethane and X-ray structure of38 . . . . . . .Scheme oacetate . . . . . .xviii179180
Scheme 8.Synthesis of Ligands L2 and L3 . . . .xix186
List of TablesChapter IIITable 1.Kumada-Corriu coupling of aryl bromides with palladiumand nickel-derived phosphinous acids . 72Table 2.Cross-coupling of aryl chlorides with Grignard reagents .Table 3.Negishi coupling of 4-chloroanisole, 29, and 2-tolylzinc74chloride, 30, in the presence of palladium-phosphinousacids . .Table orides . .Table -catalyzed coupling of aryl halides with vinylzincand alkylzinc reagents . .Table 7.82arylbromides and iodides . .Table 6.8186POPd-catalyzed coupling of acyl chlorides and organozincreagents . 88Chapter IVTable 1.Copper(I)-catalyzed amination of aryl bromides andiodides .136Table 2.Copper(I)-catalyzed amination of aryl chlorides . 138Table 3.Copper(I)-catalyzed amidation of aryl halides .xx140
Table 4.Copper-catalyzed amination of aryl halides .144Table 5.Copper-catalyzed amination of aryl chlorides . 147Chapter VTable 1.Effect of catalytic amine additives on the asymmetricnitroaldol reaction with 1,1,1-trifluoroacetophenone 175Table 2.Scope of the asymmetric nitroaldol reaction 177Table 3.Enantioselective niroaldol reaction with α-ketoesters . .181Table 4.Bisoxazolidine-catalyzed asymmetric nitroaldol reaction ofN-phenyl 2-oxo-2-phenylacetamide .188Table 5.Effect of base additives in THF and ACN 189Table 6.Enantioselective niroaldol reaction with α-keto amides .190Table 7.Synthesis of chiral 1,3-diaminopropanols .193xxi
List of AbbreviationsAAAasymmetric allylic haleneBnbenzylt-Boctert-butyl acetamideBun-butylt-Butert-butylt-BuOHtert-butyl alcoholt-BuOKpotassium tert-butoxideCDAchiral derivatizing agentsCEcapillary electrophoresiscod1,5-cyclooctadieneCSAchiral solvating agentsCycyclohexylxxii
ibenzylidineacetoneDHPLCdynamic high-performance liquid tamideDMAP4-dimethylaminopyridineDMFdimethyl formamideDMSOdimethyl sulfoxideEDC1-ethyl-3-(3-dimethylaminopropyl) carbodiimideeeenantiomeric excessFCAFriedel-Crafts acylationGCgas chromotgraphyHPLChigh-performance liquid chromatographyIPA2-propanolLeuleucineMEKCmicellar electrokinetic chromatographyMPAmethoxyphenylacetic acidMTPAmethoxytrifluoromethyl-phenylacetic terocyclic carbeneNMMN-methyl morpholineNMPN-methylpyrolidinonexxiii
NMRnuclear magnetic resonancePh1-phoxidedihydrogen adate(2-)POPddihydrogen dihydrogen palladate(2-)POPd-Brdihydrogen o-tolylphosphinePTSAp-toluenesulfonic sphine) palladate(II) dimerPXPd6dichloro(chlorodicyclohexylphosphine) palladate(II) dimerPXPd7dichlorobis(chlorodicyclohexylphosphine) palladate(II)SFCsuper critical fluid chromatographyxxiv
oxolane-4,5-dimethanolTBAFtetrabutylammonium fluorideTBAOActetrabutylammonium acetateTBMEmethyl tert-butyl etherTFAtrifluoroacetic ylethylenediamineTMStetramethylsilanexxv
Chapter I: IntroductionThe first synthesis of acetic acid by Kolbe in 1848 initiated a vigorous searchfor methods that allow the construction of complex organic compounds.1 Throughthese efforts, a variety of powerful reactions for carbon–carbon bond formationincluding aldol reactions, 2 the Diels–Alder reaction, 3 the Grignard reaction, 4cross-coupling reactions, 5 the Michael reaction, 6 the Wittig reaction 7 and olefinmetathesis 8 have been introduced. These discoveries have had huge impacts onacademic research and industrial processes, and the development of the Grignardreaction (1912), the Diels-Alder reaction (1950), the Wittig reaction (1979), olefinmetathesis (2005) and cross-coupling reactions (2010)9 have been awarded with theNobel Prize in Chemistry.During the past half century, transition metals have played a more and moreimportant role in synthetic chemistry and a large number of transition metal-catalyzedreactions including the Heck reaction,10 the Negishi reaction,11 the Suzuki reaction,12the Stille reaction, 13 the Kumada-Corriu reaction, 14 and the Hartwig-Buchwaldcoupling15 have been developed to produce an enormous range of organic compounds.These and other catalytic reactions have become powerful synthetic methods withmany industrial applications. For example, one of the key synthetic steps towardsPaclitaxel, which is a successful drug for the treatment of various cancers, employsthe Heck reaction to create the eight-membered ring as shown in Figure 1.16 Anotherexample is the synthesis of Morphine via an intramolecular Heck coupling (Figure1).171
Figure 1. Examples of pharmaceutical drugs synthesized via the Heck reaction.17The syntheses of many natural products as well as industrial chemicals includeSuzuki and Negishi couplings to form new carbon-carbon bonds: Two Suzukicouplings are used for the synthesis of the antiviral marine alkaloid dragmacidin F,18and Negishi coupling provides access to 5-HT1A agonist, a partial ergot alkaloid,(Figure 2).19Figure 2. Synthesis of Dragamacidin F via Suzuki coupling and 5-HT1A agonist viaNegishi coupling.18,19A variety of biologically active compounds including flavors, fragrances,nutrients, and pharmaceuticals are chiral. More than half of current top-selling drugsincluding Lipitor, Plavix and Nexium are marketed as single enantiomers (Figure 3).20With such a compelling economic impact, the high and increasing demand forenantiopure chemicals requires continuing progress in the development of newsynthetic methodologies, analytical techniques and chiral catalysts.21,252
H3COOHNNHNNS OCH3OHOHFNClOHOCH3OOCH3NSCH3OHLipitor2008 global earnings: 12.4 billionNexium2007 global earnings: 5.2 billionPlavix2009 global earnings: 6.6 billionFigure 3. Structures of Lipitor, Nexium and Plavix.20The enantiomers of biologically active compounds may exhibit totally differentbiochemical and pharmacological activities. 22 The chiral drug thalidomide wasprescribed to pregnant women to relieve morning sickness in racemic form in Europein the late 1950s.23 In 1961, it was removed from the market due to its strongteratogenic effect. The (S)-enantiomer of thalidomide was found to cause severe birthdefects.24 Furthermore, the use of the pure (R)-enantiomer of thalidomide is not safedue to its fast racemization under physiological conditions generating the teratogenic(S)-enantiomer (Scheme 1).25Since this tragedy, the significance of thestereochemical purity of biologically active molecules has received intensive attentionand the stereochemical properties of chiral compounds are carefully investigatedduring modern drug development.Scheme 1. Racemization of the two enantiomers of Thalidomide.253
Enantiopure chemicals are often prepared via racemic synthesis followed rcrystallizationofdiastereomeric derivatives. A major drawback of these approaches is that additionalseparation steps are required, and moreover, the maximum yield of the product is 50%unless the unwanted enantiomer can be reused in an enantioconvergent process toproduce the desired product. By contrast, asymmetric synthesis can afford enantiopureproducts in up to 100% yield with superior atom economy. Various syntheticapproaches using chiral reagents, chiral auxiliaries and catalysts have been reported todate.25 According to Eliel, one can use the following criteria for evaluating thesuccess and usefulness of an asymmetric synthesis procedure:261. Highstereoselectivity and yield, preferentially both above 90%; 2. Easy recovery of chiralcatalysts or auxiliaries; 3. Chiral auxiliaries, reagents, or catalysts should be availableat low cost in both enantiomeric forms; 4. Broad application scope.The remarkable advance of asymmetric catalysis and ligand design caninarguably be attributed to the introduction of the C2-symmetric ligand DIOP byKagan in 1971.27 This seminal work set the stage for the development of otherprivileged ligands, such as BINOL and BINAP,28Semicorrins,29Salen,30DUPHOS,31 and TADDOL,32 which have proved to be exceptionally versatile andeffective in a wide variety of catalytic asymmetric reactions (Figure 4).33 Similarly,bisoxazolines have found widespread use due to their ease of preparation andimpressive application scope,34including Diels-Alder and ene reactions,Mukaiyama aldol reactions,36 cyclopropanations,37 and aziridinations.38435
Figure 4. Structures of C2-symmetric ligands.While the molecular design of these ligands is quite different, they all have arigid, bidentate and C2-symmetric structure which can effectively reduce the numberof possible transition states. For example, in a bisoxazoline-catalyzed asymmetricDiels-Alder reaction, coordination of the prochiral dienophile to the chiral Lewis acidcatalyst can occur with two different substrate orientations (Scheme 2). Due to theC2-symmetry of the chiral bisoxazoline ligand, only the Re-face of the dienophile isaccessible in either pathway which provides the identical transition state favoringformation of the (S)-cycloadduct. Accordingly, C2-symmetric catalysts often providesuperior stereoselectivities and yields compared to other catalyst designs.5
OSi-face approachis disfavored)(OONRONNCuO2 NCu2 O ONROONRRH(S)OOONORe-face approachis favoredOONNRORONO)(Cu2 O OSi-face approachis disfavoredHO(S)NRe-face approachis ls-Alderreactionwithenantiofacial control.1-1 Palladium-Catalyzed Carbon-Carbon Bond FormationDuring the past decades, various transition metal complexes with excellentcatalytic activity have been introduced to carbon-carbon bond formation dingboronicacids,39organostannanes, 40 organosiloxanes, 41 organozinc, 42 and Grignard reagents. 43Especially, a variety of palladium and nickel complexes bearing ligands such as bulky,electron-rich phosphines,43a-d N-heterocyclic carbenes43e and phosphinous acids43fhave shown high efficiency in various cross-couplings. T
TRANSITION METAL-CATALYZED CARBON-CARBON AND CARBON-NITROGEN BOND FORMATION AND ASYMMETRIC CATALYSIS WITH BISOXAZOLIDINE LIGANDS A Dissertation submitted to the Faculty of the Graduate School of Arts and Sciences of Georgetown University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry By
transition metal-catalyzed processes [14, 15, 16] which have the biggest role in the synthesis of these heterocycles and the metal free-catalyzed processes. Herein, this review will focus on recently methodology using transition metal-catalyzed (Pd, Ni, Cu, Au, Fe and Rh) as well as transition metal free-catalyzed methods. 2. 1.
Abstract The plethora of transformations attainable by the transition-metal-catalyzed reactions of arynes has found immense contemporary interest in the scientific community. This review highlights the scope and importance of transition-metal-catalyzed aryne reactions in the field of synthetic organic chemistry reported to date. It covers transfor-
product for the metal-free electroreductive carboxylation. 11 The transition-metal-catalyzed electroreductive carbox-ylation of aryl halides with CO 2 is a promising tool for the preparation of arenecarboxylic acids.12 However the reac-tion scope is quite restricted. In 2009, Correa and Martín re-ported a Pd-catalyzed carboxylation reaction of .
2010 Heck, Suzuki and Negishi for "palladium-catalyzed cross couplings in organic synthesis". . transition metal-catalyzed industrial processes, permitting the efficient generation of acetaldehyde . The resulting -alkyl (or -vinyl complex) I, could undergo a demetallation process involving a hydrogen atom on the carbon in position (β-H .
In recent years, GVL has been used in several transition metal catalyzed processes such as, among others, the palladium-catalyzed Hiyama,[23] Mizoroki-Heck[24] and Sonogashira[25] cross-coupling reactions, platinum-[26] and rhodium-catalyzed[27] hydroformylations and palladium-catalyzed aminocarbonylation reactions.[28]
mediated and transition-metal-catalyzed approaches. This review sum-marizes the advances in alkyl Heck-type reactions from its discovery early in the 1970s up until the end of 2018. 1 Introduction 2 Pd-Catalyzed Heck-Type Reactions 2.1 Benzylic Electrophiles 2.2 α-Carbonyl Alkyl Halides 2.3 Fluoroalkyl Halides 2.4 α-Functionalized Alkyl Halides
in Chemistry. 15 The transition-metal-catalyzed activation of amide N-C bonds holds an enormous potential for wide-spread practical applications in organic synthesis due to: (1) the inherent benefits of amides as acyl or aryl electro-philic precursors in general metal-catalyzed reaction mani-folds;11,12 (2) myriad potential metal-catalyzed .
and STM32F103xx advanced ARM-based 32-bit MCUs Introduction This reference manual targets application developers. It provides complete information on how to use the low-, medium- and high-density STM32F101xx, STM32F102xx and STM32F103xx microcontroller memory and peripherals. The low-, medium- and high-density STM32F101xx, STM32F102xx and STM32F103xx will be referred to as STM32F10xxx .
