Very high asymmetric inductions result in the Pd-catalyzed intramolecular arylation of amides to give 3,3-disubstituted oxindoles when new in situ-generated chiral N-heterocyclic carbene (NHC*) ligands are employed. Structural studies show that conformational locking to minimize allylic strain is the key to understanding the function of these ligands. New applications of these ligands in the frontier area of asymmetric coupling reactions involving C(sp3)-H bonds are detailed. Highly enantioenriched fused indolines are accessible using either preformed- or in situ-generated Pd-NHC* catalysts. Remarkably, this occurs at high temperature (140-160 °C) via excellent asymmetric recognition of an enantiotopic C-H bond in an unactivated methylene uni

Jia, Yixia

Katayev, Dmitry

Kündig, E. Peter

Nakanishi, Masafumi

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1741Pure Appl. Chem., Vol. 84, No. 8, pp. 1741–1748, 2012.http://dx.doi.org/10.1351/PAC-CON-12-02-10© 2012 IUPAC, Publication date (Web): 1 July 2012Asymmetric Pd-NHC*-catalyzed couplingreactions*E. Peter Kündig‡, Yixia Jia, Dmitry Katayev, and Masafumi NakanishiDepartment of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet,1211 Geneva 4, SwitzerlandAbstract: Very high asymmetric inductions result in the Pd-catalyzed intramolecular aryla-tion of amides to give 3,3-disubstituted oxindoles when new in situ-generated chiralN-hetero cyclic carbene (NHC*) ligands are employed. Structural studies show that confor-mational locking to minimize allylic strain is the key to understanding the function of theseligands.New applications of these ligands in the frontier area of asymmetric coupling reactionsinvolving C(sp3)–H bonds are detailed. Highly enantioenriched fused indolines are accessi-ble using either preformed- or in situ-generated Pd-NHC* catalysts. Remarkably, this occursat high temperature (140–160 °C) via excellent asymmetric recognition of an enantiotopicC–H bond in an unactivated methylene unit.Keywords: asymmetry; C–H bond reactivity; coupling reactions; N-heterocyclic carbenes;palladium. INTRODUCTIONChiral bidentate phosphorous ligands are ubiquitous in asymmetric transition-metal catalysis. In mostcases, the chiral ligand backbone orients the stereocontrol elements—often aryl substituents—on phos-phorus, such as to generate the appropriate chiral environment for the catalytic reaction [1]. We haveused this ourselves extensively in the design of chiral Fe- and Ru-Lewis acids for [4 + 2] and [3 + 2]cycloaddition reactions as shown in Scheme 1 [2]. Interestingly, in these reactions the ground-state coordination of the carbonyl substrate shows ananti-s-trans arrangement for both enals and enones. With enals, this is also the reactive conformation,whereas α,β-unsaturated ketones react via a syn-s-trans transition state [2g,l].*Pure Appl. Chem. 84, 1673–1784 (2012). A collection of invited papers based on presentations at the 16th InternationalSymposium on Organometallic Chemistry Directed Towards Organic Synthesis (OMCOS-16), Shanghai, China, 24–28 July2011.‡Corresponding authorRecent developments in catalysis include the use of monodentate rather than bidentate ligands.Bulky monodentate ligands are very promising because the availability of an additional coordinationsite enables new transformations. An impressive example is the family of monodentate ligands reportedby the Buchwald group [3]. Asymmetric induction with chiral monodentate ligands is difficult, how-ever, because they lack the stereodirecting chiral backbone that has proven so successful in generatinga well-defined chiral environment. The design and use of chiral monodentate ligands is still in its earlystage, and when compared to the vast arsenal of chiral bidentate ligands, chiral monodentate phosphinesthat have found successful applications are scarce, even if one includes ligands that can temporarily actas bidentates by weak coordination, such as phosphoramidates [4]. Lacking the chiral backbones andthe rigidity of bidentate ligands, different stereodirecting elements must be built in for the applicationof chiral monodentate ligands in asymmetric catalysis [5].We focused on N-heterocyclic carbene (NHC) ligands [6], and in this presentation we will showthat the concept of minimization of the A1,3-strain [7] offers a powerful method to achieve the goal ofhigh asymmetric induction with chiral monodentate NHCs.RESULTS AND DISCUSSIONNew chiral monodentate N-heterocyclic carbene IigandsC2-symmetric NHC-ligands L1 and L2 derived from (S)-2,2-dimethyl-1-(o-tolyl)propan-1-amine andanalogs are readily prepared in enantiopure form [8] (Scheme 2). An X-ray structure of the complex [Pd(allyl)L1I] revealed that large groups at the stereogenic cen-ters C* enforce coplanarity of the C(ligand)–Pd and C*–H bonds [8a,9]. Rotation around the N–C*bond would lead to a sharp increase in allylic strain. This fixes the aryl groups in space. Their orienta-tion is determined by the aryl o-substituent. Again, minimization of A1,3-strain is at play and as can beseen in Fig 1: the C(Ar)–CH3 bond is coplanar with the C*–H bond. The place and orientation of theligand aryl groups are thus determined by the minimization of A1,3 strain. E. P. KÜNDIG et al.© 2012, IUPAC Pure Appl. Chem., Vol. 84, No. 8, pp. 1741–1748, 20121742Scheme 1 One-point binding transition-metal Lewis acid catalysts for cycloaddition reactions.Pd-catalyzed asymmetric intramolecular arylation of anilidesOur first application of these ligands was in the asymmetric intramolecular arylation of amides to give3-aryl, 3-alkyl oxindoles and 3-aryl, 3-alkoxy (or amino) oxindoles. Pioneered by Hartwig and hisgroup some years earlier [10], we reported the first efficient asymmetric version of this elegant route to3,3-disubstituted oxindoles [8,11]. A selection of results is shown in Scheme 3.© 2012, IUPAC Pure Appl. Chem., Vol. 84, No. 8, pp. 1741–1748, 2012Asymmetric Pd-catalyzed coupling reactions 1743Scheme 2 Synthesis of ligand precursor immidazolium and dihydroimidazolium salts.Fig. 1 X-ray structure of fragment [PdL1] in the complex [Pd(allyl)L1I]. For clarity, the allyl and iodide ligandswere removed.Indolines via Pd-catalyzed asymmetric C–C coupling involving an unactivatedmethylene groupThe direct functionalization of unactivated C(sp3)–H bonds remains a major challenge in organic syn-thesis [12]. Mechanistic and theoretical studies indicate metalation of C–H bonds to occur via an innersphere carboxylate-assisted concerted deprotonation pathway [13]. In Pd-catalyzed intramolecular reac-tions, the coordination of an internal base, the substrate, and the agostic C–H–Pd interaction leave onlyone coordination site open. Monodentate ligands are thus required for this transformation. Indeed, lit-erature examples show electron-rich phosphines such as P(cyclohexyl)3 to be best [12,14]. An efficientasymmetric C–H activation in which the catalyst selects one of the two enantiotopic hydrogens of amethylene group remained to be uncovered [5,15]. This was a crucial test for the chiral carbene Pd cat-alyst because it not only required a high stereocontrol, but in addition the catalyst needed to be stableat the high temperatures required for this transformation. We therefore started with preformed Pd car-bene complexes. Optimization of initial results showed that the reaction could be realized in high yieldE. P. KÜNDIG et al.© 2012, IUPAC Pure Appl. Chem., Vol. 84, No. 8, pp. 1741–1748, 20121744Scheme 3 Enantioenriched 3,3-disubstituted oxindoles via asymmetric arylation of anilides.and high asymmetric induction (Scheme 4) [15c]. Complexes incorporating the dihydroimidazolium-derived ligands, such as L2, afforded the product in low yield due to lack of stability of the Pd-NHCunit above 120 °C. This was manifested by the precipitation of Pd black. The increased yield with L4is ascribed to the higher thermal stability of its Pd complex compared to that containing L1.The next step consisted in finding conditions whereby the Pd-carbene catalyst was generated insitu. A reduction of catalyst loading and of reaction time was also achieved by raising the temperatureto 160 °C. A selection of results is shown in Scheme 5.We propose the reaction mechanism as shown in Scheme 6. The [Pd(π-cinnamyl)Cl]2 dimer iscleaved with the NHC ligand. The latter is generated in situ from L4-HI and cesium pivalate. Nucleophilic addition of pivalate to the cinnamyl ligand followed by alkene dissociation gener-ates the Pd(0)-L4 catalyst [16]. Oxidative addition of carbamate 1 and bromide/pivalate exchange is fol-© 2012, IUPAC Pure Appl. Chem., Vol. 84, No. 8, pp. 1741–1748, 2012Asymmetric Pd-catalyzed coupling reactions 1745Scheme 4 Indoline synthesis via asymmetric intramolecular C(Ar)–C(sp3)–H coupling.Scheme 5 Indoline synthesis via asymmetric intramolecular C(Ar)–C(sp3)–H coupling: In situ generation of thechiral catalyst.lowed by C–H bond activation and reductive elimination to produce the fused indoline 2 and regenera-tion of the catalyst. Excellent mechanistic analyses of the C–H bond activation step in the base assistedconcerted metalation deprotonation mechanism of C(sp3)–H activation of Me groups has been reported,and an adaption to the reaction leading to the fused enantioenriched indolines is shown in Scheme 6[13].CONCLUSIONChiral readily synthesized NHC ligands derived from chiral 2,2-dimethyl-1-arylpropane-1-amines weresuccessfully applied to the intramolecular α-arylation of anilides to give 3,3-disubstituted oxindoleswith high asymmetric induction. More spectacular, the same ligands find application in the synthesis ofhighly enantioenriched indolines via Pd-catalyzed C–H activation. This reaction requires temperaturesof 140–160 °C. It is extraordinary that, despite the high temperature, this transformation occurs via highasymmetric recognition of an enantiotopic C–H bond in an unactivated methylene unit. The concept ofplacing stereocontrol elements at the appropriate place by using minimization of allylic strain is shownto be viable and promising for future applications.REFERENCES AND NOTES1. A. Börner (Ed.). Phosphorous Ligands in Asymmetric Catalysis, Wiley-VCH, Weinheim (2008).2. (a) E. P. Kündig, C. M. Saudan, G. Bernardinelli. Angew. Chem., Int. Ed. 38, 1220 (1999); (b)E. P. Kündig, C. M. Saudan, V. Alezra, F. Viton, G. Bernardinelli. Angew. Chem., Int. Ed. 40, 4481(2001); (c) E. P. Kündig, C. M. Saudan, F. Viton. Adv. Synth. Catal. 343, 51 (2001); (d) F. Viton,G. Bernardinelli, E. P. Kündig. J. Am. Chem. 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Asymmetric Pd-NHC*-catalyzed coupling reactions

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