[Ir(COD)Cl]2 as a Catalyst Precursor for the Intramolecular

Published on Web 12/09/2009

[Ir(COD)Cl]2 as a Catalyst Precursor for the Intramolecular Hydroamination of Unactivated Alkenes with Primary Amines and Secondary Alkyl- or Arylamines: A Combined Catalytic, Mechanistic, and Computational Investigation Kevin D. Hesp,† Sven Tobisch,*,‡ and Mark Stradiotto*,† Department of Chemistry, Dalhousie UniVersity, Halifax, NoVa Scotia B3H 4J3, Canada, and School of Chemistry, UniVersity of St Andrews, St Andrews, KY16 9ST, United Kingdom Received September 30, 2009; E-mail: [email protected]; [email protected]

Abstract: The successful application of [Ir(COD)Cl]2 as a precatalyst for the intramolecular addition of primary as well as secondary alkyl- or arylamines to unactivated olefins at relatively low catalyst loading is reported (25 examples), along with a comprehensive experimental and computational investigation of the reaction mechanism. Catalyst optimization studies examining the cyclization of N-benzyl-2,2-diphenylpent4-en-1-amine (1a) to the corresponding pyrrolidine (2a) revealed that for reactions conducted at 110 °C neither the addition of salts (NnBu4Cl, LiOTf, AgBF4, or LiB(C6F5)4 · 2.5OEt2) nor phosphine coligands served to enhance the catalytic performance of [Ir(COD)Cl]2. In this regard, the rate of intramolecular hydroamination of 1a employing [Ir(COD)Cl]2/L2 (L2 ) 2-(di-t-butylphosphino)biphenyl) catalyst mixtures exhibited an inverse-order dependence on L2 at 65 °C, and a zero-order rate dependence on L2 at 110 °C. However, the use of 5 mol % HNEt3Cl as a cocatalyst was required to promote the cyclization of primary aminoalkene substrates. Kinetic analysis of the hydroamination of 1a revealed that the reaction rate displays first order dependence on the concentration of Ir and inverse order dependence with respect to both substrate (1a) and product (2a) concentrations; a primary kinetic isotope effect (kH/kD ) 3.4(3)) was also observed. Eyring and Arrhenius analyses for the cyclization of 1a to 2a afforded ∆Hq ) 20.9(3) kcal mol-1, ∆Sq ) -23.1(8) cal/K · mol, and Ea ) 21.6(3) kcal mol-1, while a Hammett study of related arylaminoalkene substrates revealed that increased electron density at nitrogen encourages hydroamination (F ) -2.4). Plausible mechanisms involving either activation of the olefin or the amine functionality have been scrutinized computationally. An energetically demanding oxidative addition of the amine N-H bond to the IrI center precludes the latter mechanism and instead activation of the olefin CdC bond prevails, with [Ir(COD)Cl(substrate)] M1 representing the catalytically competent compound. Notably, such an olefin activation mechanism had not previously been documented for Ir-catalyzed alkene hydroamination. The operative mechanistic scenario involves: (1) smooth and reversible nucleophilic attack of the amine unit on the metalcoordinated CdC double bond to afford a zwitterionic intermediate; (2) Ir-C bond protonolysis via stepwise proton transfer from the ammonium unit to the metal and ensuing reductive elimination; and (3) final irreversible regeneration of M1 through associative cycloamine expulsion by new substrate. DFT unveils that reductive elimination involving a highly reactive and thus difficult to observe IrIII-hydrido intermediate, and passing through a highly organized transition state structure, is turnover limiting. The assessed effective barrier for cyclohydroamination of a prototypical secondary alkylamine agrees well with empirically determined Eyring parameters.

Introduction

The hydroamination of alkenes, alkynes, and related unsaturated substrates represents an attractive strategy for the construction of nitrogen-containing compounds that circumvents the formation of byproduct in the creation of a C-N linkage.1 In particular, intramolecular variants of these reactions are appealing as atom-economical routes to nitrogen-containing heterocycles that are prevalent in naturally occurring and/or biologically active molecules.2 Although the synthetic potential of cyclohydroamination is significant, general methods for promot† ‡

Dalhousie University. University of St Andrews.

10.1021/ja908316n  2010 American Chemical Society

ing the intramolecular hydroamination of unactivated aminoalkenes under mild conditions and with broad substrate scope are still lacking. A diverse number of catalyst systems are known to effect such cyclizations,1a including (but not restricted to) those based on rare earth elements and actinides,3 alkali and alkaline earth metals,4 Group 4 metals,5 and Brønsted acids;6 nonetheless, the pursuit of increased substrate scope and functional group tolerance has prompted the development of alternative catalysts based on metals from Groups 8-11. While progress has been made in the use of Fe,7 Pd,8 and Au9,10 catalysts for the intramolecular addition of secondary amides, carbamates, or ureas to unactivated olefins, the identification of late metal catalysts for analogous transformations involving J. AM. CHEM. SOC. 2010, 132, 413–426

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secondary alkyl- or arylamines, as well as primary amines, has proven more elusive. The first catalyst system of this type was described in 2005 by Widenhoefer and co-workers,11 who reported the use of [PtCl2(H2CdCH2)]2/PPh311a and later PtCl2/ (1) (a) Mu¨ller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. ReV. 2008, 108, 3795. (b) Hartwig, J. F. Nature 2008, 455, 314. (c) Widenhoefer, R. A. Chem.sEur. J. 2008, 14, 5382. (d) Chianese, A. R.; Lee, S. J.; Gagne´, M. R. Angew. Chem., Int. Ed. 2007, 46, 4042. (e) Severin, R.; Doye, S. Chem. Soc. ReV. 2007, 36, 1407. (f) Brunet, J.-J.; Chu, N.-C.; Rodriguez-Zubiri, M. Eur. J. Inorg. Chem. 2007, 4711. (g) Aillaud, I.; Collin, J.; Hannedouche, J.; Schulz, E. Dalton Trans. 2007, 5105. (h) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555. (i) Hultzsch, K. C. AdV. Synth. Catal. 2005, 347, 367. (j) Hultzsch, K. C. Org. Biomol. Chem. 2005, 3, 1819. (k) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079. 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biarylphosphine11b for the cyclization of secondary alkylaminoalkenes, including one example involving a 1,1-disubstituted olefin. In 2008, Liu and Hartwig12 disclosed the use of [Rh(COD)2]BF4/Cy-DavePhos (COD ) η4-cyclooctadiene; CyDavePhos ) 2-dicyclohexylphosphino-2′-N,N-dimethylaminobiphenyl) for the hydroamination of aminoalkenes that feature primary or secondary alkylamines and terminal or internal alkenes. In the same year, the use of Rh and Ir complexes supported by pincer-type N-heterocyclic carbene ligands for the cyclization of terminal alkenes by pendant secondary alkyl- and phenylamines was described by Hollis and co-workers.13 Following the appearance of our preliminary report in this area,14 Sawamura and co-workers15 disclosed the use of Cu(OtBu)/ Xantphos (Xantphos ) 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) for the hydroamination of alkenes by tethered primary or secondary alkylamines, including an example of a 1,1-disubstituted secondary aminoalkene substrate. Notwithstanding this recent progress, the identification of late metal catalysts for use in promoting the intramolecular addition of primary as well as secondary alkyl- and arylamines to both terminal and internal olefins remains an important and significant challenge. Furthermore, with the exception of the NMR spectroscopic characterization of catalytic intermediates in the breakthrough Pt catalyst system disclosed by Bender and Widenhoefer,11a no kinetic or mechanistic data pertaining to the cyclohydroamination of alkylamino-alkenes are provided in the ensuing reports.12-15 Encouraged by advances in the Ir-mediated intermolecular hydroamination of activated alkenes,16-18 as well as recent progress in the Ir-catalyzed cyclohydroamination of alkynes,16,19 we sought to expand further the synthetic repertoire of late metal-mediated hydroamination through the identification of simple Ir precatalysts that exhibit useful substrate scope in the (8) (a) Cochran, B. M.; Michael, F. E. J. Am. Chem. Soc. 2008, 130, 2786. (b) Cochran, B. M.; Michael, F. E. Org. Lett. 2008, 10, 329. (c) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246. (9) (a) Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2006, 4143. (b) Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2006, 8, 5303. (c) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798. (d) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707. (e) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747. (10) The Au-catalyzed intermolecular hydroamination of simple R-olefins with cyclic ureas has been reported recently: Zhang, Z.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 5372. (11) (a) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070. (b) Bender, C. F.; Hudson, W. B.; Widenhoefer, R. A. Organometallics 2008, 27, 2356. (12) Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570. (13) Bauer, E. B.; Andavan, G. T. S.; Hollis, T. K.; Rubio, R. J.; Cho, J.; Kuchenbeiser, G. R.; Helgert, T. R.; Letko, C. S.; Tham, F. S. Org. Lett. 2008, 10, 1175. (14) For our preliminary report of the use of [Ir(COD)Cl]2 as a pre-catalyst for the intramolecular hydroamination of secondary alkyl- or arylamines (but not primary amines) and unactivated olefins, see: Hesp, K. D.; Stradiotto, M. Org. Lett. 2009, 11, 1449. (15) Ohmiya, H.; Moriya, T.; Sawamura, M. Org. Lett. 2009, 11, 2145. (16) Dorta, R. In Iridium Complexes in Organic Synthesis; Oro, L. A., Claver, C., Eds.; Wiley-VCH: Weinheim, 2009; p 145. (17) (a) Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem. Soc. 1988, 110, 6738. (b) Dorta, R.; Egli, P.; Zu¨rcher, F.; Togni, A. J. Am. Chem. Soc. 1997, 119, 10857. (18) Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 12220. (19) For some recent reports, see: (a) Field, L. D.; Messerle, B. A.; Vuong, K. Q.; Turner, P. Dalton Trans. 2009, 3599. (b) Ebrahimi, D.; Kennedy, D. F.; Messerle, B. A.; Hibbert, D. B. Analyst 2008, 817. (c) Burling, S.; Field, L. D.; Messerle, B. A.; Rumble, S. L. Organometallics 2007, 26, 4335. (d) Lai, R.-Y.; Surekha, K.; Hayashi, A.; Ozawa, F.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Organometallics 2007, 26, 1062. (e) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 5437.

[Ir(COD)Cl]2 as a Catalyst Precursor

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Table 1. Screening of Group 9 Catalyst Precursors for the Intramolecular Hydroamination of 1a to Give 2aa entry

catalyst precursor

conversion to 2ab

1-1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9

[Ir(COD)Cl]2 [Ir(COE)2Cl]2 [Ir(COD)OMe]2 [(η5-C5Me5)IrCl2]2 [Rh(COD)Cl]2 [Ir(COD)2]BF4 [Ir(MeCN)2(COD)]BF4 [Ir(COD)PCy3(py)]PF6 none

>95 10 7