Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.New bimetallic Zn/Zr salen-type systems were employed as catalysts in the asymmetric intramolecular hydroamination reaction. High enantioselectivity for the formation of piperidines of up to 98% ee were observed.DFG, TRR 88, Kooperative Effekte in homo- und heterometallischen Komplexen (3MET

Biyikal, Mustafa

Blechert, Siegfried

Hussein, Lenard

Purkait, Nibadita

Roesky, Peter W.

Tausch, Eugenia

Chemical Communications

DepositOnce (Techn. Univ. Berlin)

3862 | Chem. Commun., 2014, 50, 3862--3864 This journal is©The Royal Society of Chemistry 2014Cite this:Chem. Commun., 2014,50, 3862Highly enantioselective hydroamination tosix-membered rings by heterobimetallic catalysts†Lenard Hussein,*a Nibadita Purkait,a Mustafa Biyikal,a Eugenia Tausch,bPeter W. Roeskyb and Siegfried Blechert*aNew bimetallic Zn/Zr salen-type systems were employed as catalysts inthe asymmetric intramolecular hydroamination reaction. High enantio-selectivity for the formation of piperidines of up to 98%eewere observed.The catalytic addition of an amine N–H bond to unsaturatedcarbon–carbon bonds (hydroamination), to give nitrogen containingmolecules in a facile and highly atom-economical way is of greatinterest for academic and industrial research.1 Hydroamination hasa high activation barrier. To lower the activation barrier catalyticsystems were employed, which either activate the C–Cmultiple bondor the N–H function. Catalytic hydroamination has been intenselystudied in the last decades.1,2 Early results of the intramolecularasymmetric hydroamination reactions were reported by Marks et al.using chiral ansa-lanthanocene.3 Significant research activities in thearea of asymmetric inter- and intramolecular hydroamination reac-tions have been observed for about ten years now.4 Although highyields with excellent ee values were reported for the intramolecularhydroamination, the asymmetric hydroamination of alkenes hasremained a challenging task because the excellent results are mainlylimited to the formation of pyrrolidines, whereas the ee valuesobtained for the formation of piperidines are less impressive.2,5 Tothe best of our knowledge the highest ee for this reaction was 82%.5eIn the last few years we and others introduced zinc compounds ascatalysts for the hydroamination of alkenes and alkynes.6 Withinthese research eﬀorts we reported on the dimeric tetranuclear zinccomplexes derived from a novel type of ortho-aminated salicyl-aldimine, which showed high reactivity for the intramolecular hydro-amination reaction of non-activated alkenes at room temperature.7With an aim to generate an enantioselective catalyst for the hydro-amination, we now introduced chirality into the ligand by synthesiz-ing a salen-type ligand with several stereocenters (Scheme 1).Starting from tropolone 1, 2 could be obtained after bromination withBr2 in MeOH followed by a Mitsunobu-reaction with PPh3, DIAD andMeOH to give 3. A reaction with optically active 1-phenylethylamineand subsequent rearrangement reaction with isopropylaminefollowed by treatment with HCl led to the ortho-aminated salicyl-aldehyde 4. A subsequent condensation with chiral 1,2-diaminocyclo-hexane gave the chiral brominated salen ligand L-1. Reacting L-1 withM(OAc)2 (M = Cu and Zn) resulted in the corresponding copper andzinc complexes Cu-1a and Zn-1. The solid state structure of Zn-1 wasestablished by single crystal X-ray diﬀraction. Zn-1 crystallizes fromd6-DMSO (Fig. 1). The Zn atom is penta-fold coordinated, forming adistorted square pyramid. The deprotonated salen ligand coordinatesin the plane while the DMSO molecule is localized in the apex of thesquare pyramid. The Zn–O and Zn–N bond distances to thesalen ligand are in the expected range of Zn1–N1 2.077(5) Å,Zn1–N2 2.088(5) Å, Zn1–O3 1.978(5) Å, and Zn1–O4 1.969(4) Å.We used the transformation of 2,2-diphenylhex-5-en-1-amine (I)to 2-methyl-5,5-diphenylpiperidine (II) as a test-reaction (Table 1and Table S1, ESI†). Since an initial test with in situ generated Zn-1Scheme 1 Synthesis of the ligand L-1, Cu-1a and Zn-1.a Institut fu¨r Chemie, Technische Universita¨t Berlin, Straße des 17. Juni 135,10623 Berlin, Germany. E-mail: blechert@chem.tu-berlin.deb Institut fu¨r Anorganische Chemie, Karlsruher Institut fu¨r Technologie (KIT),Engesserstr. 15, Geb. 30.45, 76131 Karlsruhe, Germany† Electronic supplementary information (ESI) available. CCDC 965327–965329.For ESI and crystallographic data in CIF or other electronic format see DOI:10.1039/c3cc48874hReceived 20th November 2013,Accepted 19th February 2014DOI: 10.1039/c3cc48874hwww.rsc.org/chemcommChemCommCOMMUNICATIONPublished on 04 March 2014. Downloaded by TU Berlin - Universitaetsbibl on 25/02/2016 12:05:12. View Article OnlineView Journal  | View IssueThis journal is©The Royal Society of Chemistry 2014 Chem. Commun., 2014, 50, 3862--3864 | 3863from L1 and an excess of ZnMe2 did not show any conversion(Table S1, ESI,† entry 1), we investigated the application ofdiﬀerent bimetallic catalytic systems for the test reactions. Thecombination of L1, ZnMe2 and Zr(NMe2)4 and the combinationof Zn-1 and Zr(NMe2)4 resulted in high conversion and 96% ee(Table S1, ESI,† entries 2 and 5). Zr(NMe2)4 and its derivatives areknown as catalysts for the hydroamination reaction.5b,c,8 The isolatedmetalloligand Zn-1 in combination with Zr(NMe2)4 showed the sameee as the in situ generated systembut a slightly lower conversion.Whilekeeping the Zr-source, ZnMe2 was exchanged by Cu(OAc)2, whichresulted in 96% conversion and 77% ee (Table S1, ESI,† entry 6). Incontrast, by using the metalloligand Cu-1a and Zr(NMe2)4 full conver-sion and 96% eewere obtained (Table S1, ESI,† entries 7 and 8). Theseresults could be obtained with a catalyst concentration as low as5 mol% Cu-1a and 5 mol% Zr(NMe2)4. In comparison, by using onlyZr(NMe2)4 with L-1 as a catalyst full conversion but only 77% ee wasobserved (Table S1, ESI,† entry 9). This clearly shows the influence ofthe bimetallic system. Besides the metals the ligand system alsostrongly influences the reactions. By using the Jacobsen-ligand(Scheme S1, ESI†) instead of L1 no conversion was observed in thetest reaction. Since Zn-1 alone is catalytically inactive we suggest thatthe 3dmetal just stabilizes the salen ligand by forming a rigid scaﬀold(metalloligand), which binds to Zr forming a chiral Zr amido catalyst.Next we were interested in the influence of the stereocenters onthe selectivity. Cu-1a has four stereocenters (two at the cyclohexylring and two at the phenylethyl moiety), which were systematicallyvaried leading to the complexes Cu-1b, Cu-1c, and Cu-1d(Scheme 2). All new complexes were synthesized similar to Cu-1a.Cu-1a and Cu-1b are both composed of (1S,2S)-1,2-diaminocyclohexane, but diﬀer in the configuration of the1-phenylethylamine-group, while Cu-1c and Cu-1d are basedon (1R,2R)-1,2-diaminocyclohexane carrying diﬀerent stereo-information at the 1-phenylethylamine-group. These metallo-ligands in combination with Zr(NMe2)4 were applied in the testreaction (Table S2, ESI†). The results clearly show that the 1,2-diamino-cyclohexane-group is responsible for the configuration of the product.The ligands Cu-1a and Cu-1b bearing a (1S,2S)-1,2-diaminocyclo-hexane group in the ligand scaﬀold (Table S2, ESI,† entries 1 and 2)gave the opposite enantiomer compared toCu-1c andCu-1dwhich arebased on (1R,2R)-1,2-diaminocyclohexane (Table S2, ESI,† entries 3and 4). Changing the configuration at the 1-phenylethylamine moietyresulted in only a minor impact on the ee’s. On the other hand wecould show for the related ligand L2 (see below) that a replacement ofthe 1-phenylethylamine moiety by other groups is not beneficial.To investigate the role of the bromine atoms in the ligand abromine-free salen ligand (L-2) was synthesized (Scheme 3).Fig. 1 Solid state structure of Zn-1 (left, only one of two independentmolecules is shown) and Cu-2 (right), omitting the hydrogen atoms.Table 1 Asymmetrical intramolecular hydroamination reactionsEntry Substrate ProductTime(h)Conversion(%)ee(de)(%)1aa 84 81 981b 18 99 972 48 55 683 24 99 224 24 99 745 24 99 296 41 99 777 24 99 51(34)8 26 99 8(27)0.25 mmol substrate, 10 mol% of L-2, 15 mol% of ZnMe2, 15 mol% ofZr(NMe2)4, 0.5 ml toluene-d8, 80 1C, sealed NMR-tube, conversions weredetermined by 1H-NMR, ee were determined by HPLC. a 10 mol% ofL-2, 10 mol% of ZnMe2, 9.5 mol% of Zr(NMe2)4 were used.Scheme 2 Synthesized metalloligands with diﬀerent configurations atthe stereocenters.Communication ChemCommPublished on 04 March 2014. Downloaded by TU Berlin - Universitaetsbibl on 25/02/2016 12:05:12. View Article Online3864 | Chem. Commun., 2014, 50, 3862--3864 This journal is©The Royal Society of Chemistry 2014Commercially available 2,6-dibromophenol 5 was protected withMOMCl to obtain 6. A Buchwald–Hartwig reaction with opticallyactive (R)-1-phenylethylamine led to 7 and formylation resultedin 8. After deprotection with 6 M HCl compound 9 was obtained. Asubsequent condensation of 9 with (1S,2S)-1,2-diaminocyclohexaneprovided L-2. Reaction of L-2 with M(OAc)2 (M = Cu and Zn)resulted in the formation of the corresponding copper and zinccomplexes Cu-2 and Zn-2. The solid state structures of Cu-2 andZn-2 were established using single crystal X-ray diffraction (Fig. 1and Fig. S17, ESI†). The Cu atom is four-fold coordinated forming asquare planar arrangement. The Cu–O and Cu–N bond distances tothe salen ligand are in the expected range of Cu–O1 1.905(3) Å, Cu–O2 1.919(3) Å, Cu–N1 1.960(4) Å, and Cu–N2 1.944(4) Å. The solidstate structure of Zn-2 is comparable to that of Zn-1.To compare the bromine free ligand L-2 with the brominecontaining system L-1, Cu-2 and Zn-2 and in situ prepared Zn-2 (fromL-2 and ZnMe2) were applied in the test reaction. In all casesZr(NMe2)4 was used to mediate the reaction (Table S3, ESI†). Thecombination L-2 with ZnMe2 and Zr(NMe2)4 (97% ee; Table S3, ESI,†entry 3) is the most eﬃcient system by a small margin for the testreaction. It is also slightly better than the combination of L-1 withZnMe2 and Zr(NMe2)4 (Table S1, ESI,† entry 2).With the newbrominefree system in hand we then optimized the ligand to metal ratio.In the test reaction the highest ee’s (98%) were obtained by using10 mol% of L-2, 10 mol% of ZnMe2 and a slight deficiency of9.5 mol% of Zr(NMe2)4 (Table 1, entry 1a). Since after 84 h only aconversion of 81% was obtained, a ratio of 10 mol% of L-2, 15 mol%of ZnMe2 and 15 mol% of Zr(NMe2)4 was tested (Table 1, entry 1b,and Table S4, ESI†, entry 4). The slightly worse enantioselectivity(97%) in combination with a moderate catalyst loading, higherconversion (99%) and shorter reaction times (18 h) convinced us touse this ratio for an extended substrate screening (Table 1). For thetest reaction we observed the highest ee’s which were, to the best ofour knowledge, ever observed for the hydroamination/cyclization of asix-membered ring. Although the other substrates were not convertedwith such an impressive enantioselectivity some of the observed ee’sare still higher than any reported in the literature.1 Compared to Isubstrate III in which both phenyl groups are in 3-position gave only68% ee (entry 2). Using substrateVwhich has a similar scaﬀold than Ifor the formation of a five membered ring resulted in the formationof 2-methyl-4,4-diphenylpyrrolidine (VI) in 99% conversion and 22%ee (entry 3). Substituents on the phenyl rings of the substrates havealso a strong influence on the enantioselectivity. Substrates withp-CH3 (VII) or m-MeO substituents (IX) at the phenyl groups werecyclized in a selectivity of 74% ee (VIII, entry 4) and 29% ee(X, entry 5). We suggest that the MeO group may interact as aLewis-base with the Lewis-acidicmetals and thus cause a significantlydiﬀerent transition state in the catalytic reaction. In contrast a cyclo-hexyl-group on the substrate (XI) does not interact with the metals ofthe catalysts. 77% ee was observed in the conversion of XI to XII(entry 6). Besides the enantioselectivity the diastereoselectivity wasalso investigated by using substrates XIII andXV. Formation of the sixmembered ring XIV by using XIII resulted in 51% ee and 34% de(entry 7) while the five membered ring XVI was formed with only8% ee and 27% de (entry 8). In both cases full conversion wasobserved.We prepared two new salen-type ligands with four stereocenters.Reactions of these ligands with appropriate Zn(II) or Cu(II) sourcesresulted in Zn and Cu salen complexes. These complexes are notactive as catalysts. The metal only acts as a template by formingrigid metalloligands. Reacting these metalloligands with Zr(NMe2)4resulted in very active and selective catalysts. Using our catalyticsystem piperidines could be formed by asymmetric hydroaminationin ee’s of up to 98%. These are the highest ee’s reported so far.Currently, we do not know the structure of the catalysts, but weanticipate that Zr(NMe2)4 reacts with the NH function of thephenylethyl moiety of the metalloligand. By extrusion of Me2NH aZr-amido species may be formed in which the zirconium atom isbound to themetalloligand. Currently, investigations are in progressto get a deeper insight into the reported bimetallic9 catalytic system.This work was supported by the Deutsche Forschungsge-meinschaft, the transregional collaborative research centerSFB/TRR 88 ‘‘Cooperative eﬀects in homo- and hetero-metalliccomplexes (3MET)’’, and the Fonds der Chemischen Industrie.Notes and references1 T. E. Mu¨ller, K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada, Chem.Rev., 2008, 108, 3795–3892.2 A. L. Reznichenko and K. C. Hultzsch, Organometallics, 2013, 32,1394–1408.3 M. A. Giardello, V. P. Conticello, L. Brard, M. R. Gagne and T. J. Marks,J. Am. Chem. Soc., 1994, 116, 10241–10254.4 (a) N. Nishina and Y. Yamamoto, in Topics in Organometallic Chemistry,ed. V. P. Ananikov and M. Tanaka, Springer, Berlin, Heidelberg, 2013,vol. 43, pp. 115–143; (b) A. Reznichenko and K. Hultzsch, in Topics inOrganometallic Chemistry, ed. V. P. Ananikov and M. Tanaka, Springer,Berlin, Heidelberg, 2013, vol. 43, pp. 51–114.5 (a) Y. Zhang, W. Yao, H. Li and Y. Mu, Organometallics, 2012, 31,4670–4679; (b) K. Manna, S. Xu and A. D. Sadow, Angew. Chem., Int. Ed.,2011, 50, 1865–1868; (c) K. Manna,W. C. Everett, G. Schoendorﬀ, A. Ellern,T. L. Windus and A. D. Sadow, J. Am. Chem. Soc., 2013, 135, 7235–7250;(d) D. V. Gribkov, K. C. Hultzsch and F. Hampel, J. Am. Chem. Soc., 2006,128, 3748–3759; (e) P. D. Knight, I. Munslow, P. N. O’Shaughnessy andP. Scott, Chem. Commun., 2004, 894–895.6 J. Jenter, A. Lu¨hl, P. W. Roesky and S. Blechert, J. Organomet. Chem.,2011, 696, 406–418.7 M. Biyikal, K. Lo¨hnwitz, P.W.Roesky and S. Blechert, Synlett, 2008, 3106–3110.8 (a) D. C. Leitch, R. H. Platel and L. L. Schafer, J. Am. Chem. Soc., 2011, 133,15453–15463; (b) K. Born and S. Doye, Eur. J. Org. Chem., 2012, 764–771.9 S. Matsunaga and M. Shibasaki, Chem. Commun., 2014, 50, 1044–1057.Scheme 3 Synthesis of the ligand L-2, Cu-2 and Zn-2.ChemComm CommunicationPublished on 04 March 2014. Downloaded by TU Berlin - Universitaetsbibl on 25/02/2016 12:05:12. View Article Online

Highly enantioselective hydroamination to six-membered rings by heterobimetallic catalysts

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Highly enantioselective hydroamination to six-membered rings by heterobimetallic catalysts

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