molecules Communication PlanarCommunication Chiral [2.2]Paracyclophane-Based Bisoxazoline LigandsPlanar Chiral and Their [2.2]Paracyclophane-Based Applications in Cu-Mediated Bisoxazoline N–H InsertionLigands and Reaction Their Applications in Cu-Mediated N–H Insertion1, Reaction1, 1 2 1,3, Daniel M. Knoll y , Yuling Hu y, Zahid Hassan , Martin Nieger and Stefan Bräse * 1 DanielInstitute M. ofKnoll Organic 1,†, Yuling Chemistry Hu (IOC),1,†, Zahid Karlsruhe Hassan Institute 1, Martin of Nieger Technology 2 and (KIT), Stefan Fritz-Haber-Weg Bräse 1,3,* 6, 76131 Karlsruhe, Germany; [email protected] (D.M.K.); [email protected] (Y.H.); 1 [email protected] Institute of Organic Chemistry (Z.H.) (IOC), Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 2 DepartmentKarlsruhe, Germany; of Chemistry, [email protected] University of Helsinki, (D.M.K.); P.O. [email protected] Box 55 A.I. Virtasen aukio (Y.H.); 1, 00014 Helsinki, Finland; martin.nieger@helsinki.fi[email protected] (Z.H.) 2 3 Institute Department of Toxicology of Chemistry, and University Genetics (ITG), of Helsinki, Karlsruhe P.O. InstituteBox 55 A.I. of Virtasen Technology aukio (KIT), 1, 00014 Helsinki, Hermann-von-Helmholtz-PlatzFinland; [email protected] 1, D-76344 Eggenstein-Leopoldshafen, Germany 3 * Correspondence: Institute of Toxicology [email protected]; and Genetics Tel.: (ITG),+49-7216-084-2902 Karlsruhe Institute of Technology (KIT), Hermann-von- TheseHelmholtz-Platz authors contributed 1, D-76344 equally Eggenstein-Leopoldshafen, to this work. Germany. y * Correspondence: [email protected]; Tel.: +49-7216-084-2902 † These authors contributed equally to this work. Received: 15 October 2019; Accepted: 7 November 2019; Published: 14 November 2019 Received: 15 October 2019; Accepted: 7 November 2019; Published: date Abstract: New catalysts for important C–N bond formation are highly sought after. In this work, we demonstrateAbstract: New the synthesiscatalysts for and important viability C–N of a bond new classformation of planar are highly chiral sought [2.2]paracyclophane-based after. In this work, bisoxazolinewe demonstrate (BOX) the ligands synthesis for theand copper-catalyzedviability of a new class N–H of insertion planar chiral of α -diazocarbonyls[2.2]paracyclophane-based into anilines. Thebisoxazoline reaction features (BOX) aligands wide substratefor the copper-catalyzed scope and moderate N–H toinsertion excellent of yields,α-diazocarbonyls and delivers into the valuableanilines. products The reaction at ambient features conditions. a wide substrate scope and moderate to excellent yields, and delivers the valuable products at ambient conditions. Keywords: [2.2]paracyclophane ligands; N–H insertion; α-diazocarbonyls; planar chirality; copperKeywords: catalysis [2.2]paracyclophane ligands; N–H insertion; α-diazocarbonyls; planar chirality; copper catalysis 1. Introduction 1. Introduction The copper-catalyzed N–H insertion of carbenoids such as easily prepared α-diazocarbonyls is The copper-catalyzed N–H insertion of carbenoids such as easily prepared α-diazocarbonyls is a powerfula powerful method method for for the the preparation preparation ofof highlyhighly valuablevaluable bioactive bioactive molecules molecules and and pharmaceutical pharmaceutical productsproducts[1]. [1]. In In the the past past decade, decade, variousvarious enantioselective chelating chelating ligands ligands based based on on the the bis(oxazoline) bis(oxazoline) motifsmotifs have have been been established established for for this this transformation transformation ( (FigureError! Reference1)[2–8]. source not found.) [2–8]. BOX N,N-ligands O R O O O R N N N R N R X N N N R N R R O R O O O I II III IV X = CH2, (CH2)2, CMe2 FigureFigure 1. Representative1. Representative classes classes of bisoxazoline-containing of bisoxazoline-containingN,N -ligandN,N-ligand systems systems used inused asymmetric in asymmetric catalysis. catalysis. While SpiroBOX IV (Figure1) combines axial chirality from the spiro backbone with the central chiralityWhile of the SpiroBOX 2-substituted IV (Error! BOX Reference moiety, [2.2]paracyclophane source not found.) combines (PCP) exhibits axial chirality planar from chirality, the spiro which hasbackbone previously with demonstrated the central chirality remarkable of the performance 2-substituted as BOX planar moiety, chiral [2.2]paracyclophane ligand or chiral catalyst (PCP) in asymmetricMolecules 2019 catalysis, 24, x; doi:[ FOR9]. NotablePEER REVIEW examples include the addition of alkyl,www.mdpi.com/journal/molecules aryl, alkynyl, and alkenyl Molecules 2019, 24, 4122; doi:10.3390/molecules24224122 www.mdpi.com/journal/molecules MoleculesMolecules 2019 2019, 24, 24, x, xFOR FOR PEER PEER REVIEW REVIEW 2 of 215 of 15 Moleculeshasexhibits previously2019 planar, 24, 4122 demonstrated chirality, which remarkable has previously performance demonstrated as planar remarkable chiral ligand performance or chiral as catalystplanar2 of in 14 asymmetricchiral ligand catalysis or chiral [9]. catalyst Notable in asymmetric examples include catalysis the [9]. addition Notable examplesof alkyl, aryl,include alkynyl, the addition and alkenyl of zincalkyl, reagentsreagents aryl, alkynyl, to to aromatic aromatic and and alkenyland aliphatic aliphatic zinc reagents aldehydes aldehydes to andaromatic and imines imines and that thataliphatic are are catalyzed catalyzedaldehydes by by PCPand PCP ligands[imines ligands[10– that10– 14]. are catalyzed by PCP ligands[10–14]. The PCP core allows different substituents to be positioned The14]. PCPThe corePCP allowscore allows different different substituents substituents to be positioned to be positioned regioselectively regioselectively using carefully using carefully chosen regioselectively using carefully chosen reaction parameters [15]. PCP displays planar chirality if only reactionchosen reaction parameters parameters [15]. PCP [15]. displays PCP displays planar chiralityplanar chirality if only oneif only substituent one substituent is introduced is introduced to one one substituent is introduced to one of the two aromatic benzene rings (decks). If the other deck is ofto theone twoof the aromatic two aromatic benzene benzene rings (decks). rings (decks). If the otherIf the deckother isdeck substituted is substituted as well, as especiallywell, especially with withsubstituted both substituents as well, especially being identical, with both only substituents the pseudo being‐ortho identical,and pseudo only‐meta the PCPpseudo- exhibitortho chirality, and bothpseudo- substituentsmeta PCP being exhibit identical, chirality, only as the the other pseudo- twoortho PCP andisomers pseudo- showmeta higherPCP symmetry exhibit chirality, (Error! as as the other two PCP isomers show higher symmetry (Figure 2) [15]. Thus, the pseudo‐ortho PCP theReference other two source PCP not isomers found. show2) [15]. higher Thus, symmetrythe pseudo- (Figureortho PCP2)[ isomer15]. Thus, is the themost pseudo- suitableortho for aPCP isomer is the most suitable for a chelating BOX ligand with PCP as the backbone – referred to here as isomerchelating is the BOX most ligand suitable with for PCP a chelating as the backbone BOX ligand – referred with PCP to here as the as backbone[2.2]paracyclophane-based – referred to here as [2.2]paracyclophane‐based bisoxazoline (PCPBOX). [2.2]paracyclophane-basedbisoxazoline (PCPBOX). bisoxazoline (PCPBOX). FigureFigure 2.2. 2. AchiralAchiral Achiral and and and chiral chiralchiral isomers isomersisomers of of homodisubstituted homodisubstitutedhomodisubstituted PCP PCP PCP with with with the the substituents the substituents substituents on on di ffdifferentonerent different decks. Thedecks.decks. pseudo- The The pseudo orthopseudo-isomer‐orthoortho isomer isisomer the most isis the suitable most suitablesuitable candidate candidate candidate for PCPBOX for for PCPBOX PCPBOX ligands. ligands. ligands. MukaiMukai et et al. al. recently recently reportedreported on PCPphBOX that that employed employed phenyl phenyl spacers spacers bearing bearing a sterically a sterically demanding substituent between PCP and BOX (Scheme 1). These PCPphBOX served as promising demanding substituent between PCP and BOXBOX (Scheme(Scheme1 1).). These These PCPphBOX PCPphBOX served served as as promising promising chiral ligands for the asymmetric copper-catalyzed inter- and intra-molecular aromatic O–H insertion chiral ligands for the asymmetric copper copper-catalyzed‐catalyzed inter-inter‐ and intra-molecularintra‐molecular aromatic O–H insertion reaction with up to 80%ee [16,17]. Mukai et al. additionally investigated PCPBOX ligands, with reaction withwith up up to to 80% 80%ee [ee16 ,[16,17].17]. Mukai Mukai et al. et additionally al. additionally investigated investigated PCPBOX PCPBOX ligands, ligands, with phenyl, with biphenyl,phenyl, andbiphenyl, without and the without phenyl the as phenyl spacer as groups spacer for groups comparative for comparative studies. studies. We thus We set thus out set to exploreout phenyl,to explore biphenyl, the PCPBOX and without ligands the in copper-catalyzedphenyl as spacer N–H groups insertion for comparative to expand on studies. their versatility We thus. set out theto explore PCPBOX the ligands PCPBOX in copper-catalyzedligands in copper N–H‐catalyzed insertion N–H to insertion expand onto expand their versatility. on their versatility. Scheme 1. The earlier work of Mukai et al. on copper-catalyzed O–H insertion reaction and this