Preparation and Characterization of Two New N-Heterocyclic Carbene

Jul 13, 2010 - Carbene Gold(I) Complexes and Comparison of Their Catalytic ... Two new gold complexes (9, 11) are prepared and their structures are ...
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Organometallics 2010, 29, 3450–3456 DOI: 10.1021/om100504z

Preparation and Characterization of Two New N-Heterocyclic Carbene Gold(I) Complexes and Comparison of Their Catalytic Activity to Au(IPr)Cl Benjamin W. Gung,*,† Lauren N. Bailey,† Derek T. Craft,† Charles L. Barnes,‡ and Kristin Kirschbaum§ †

Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, ‡Elmer O. Schlemper X-ray Diffraction Center, University of Missouri;Columbia, Columbia, Missouri 65211, and §Department of Chemistry, University of Toledo, Toledo, Ohio 43606 Received May 23, 2010

Gold catalysts with N-heterocyclic carbene ligands have become an attractive tool for organic synthesis. Two new gold complexes (9, 11) are prepared and their structures are determined by X-ray structural analysis. Their catalytic activities have been studied with a new intramolecular cyclopropanation reaction starting from the propargyl esters tethered to a terminal alkene. Although no or low enantioselectivity was observed with 9 or 11, the insight gained from this study is the importance of the steric effects of the NHC ligand.

Introduction N-Heterocyclic carbenes (NHCs) have emerged as a class of ligands with exceptional properties,1 mainly due to their outstanding performance in metal-catalyzed reactions.2,3 *To whom correspondence should be addressed. E-mail: gungbw@ muohio.edu. (1) Hahn, F. E.; Jahnke, M. C. Heterocyclic Carbenes: Synthesis and Coordination Chemistry. Angew. Chem., Int. Ed. 2008, 47 (17), 3122– 3172. (2) Baskakov, D.; Herrmann, W. A.; Herdtweck, E.; Hoffmann, S. D. N-Heterocyclic Carbenes. 49. Chiral N-Heterocyclic Carbenes with Restricted Flexibility in Asymmetric Catalysis. Organometallics 2007, 26 (3), 626–632. (3) Cesar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chiral N-Heterocyclic Carbenes As Stereodirecting Ligands in Asymmetric Catalysis. Chem. Soc. Rev. 2004, 33 (9), 619–636. (4) de Fremont, P.; Scott, N. M.; Stevens, E. D.; Nolan, S. P. Synthesis and Structural Characterization of N-Heterocyclic Carbene Gold(I) Complexes. Organometallics 2005, 24 (10), 2411–2418. (5) de Fremont, P.; Marion, N.; Nolan, S. P. Cationic NHC-Gold(I) Complexes: Synthesis, Isolation, and Catalytic Activity. J. Organomet. Chem. 2009, 694 (4), 551–560. (6) Marion, N.; Carlqvist, P.; Gealageas, R.; de Fremont, P.; Maseras, F.; Nolan, S. P. [(NHC)Au-I]-Catalyzed Formation of Conjugated Enones and Enals: An Experimental and Computational Study. Chem.;Eur. J. 2007, 13 (22), 6437–6451. (7) Marion, N.; Gealageas, R.; Nolan, S. P. [(NHC)Au-I]-Catalyzed Rearrangement of Allylic Acetates. Org. Lett. 2007, 9 (14), 2653–2656. (8) Alonso, I.; Trillo, B.; Lopez, F.; Montserrat, S.; Ujaque, G.; Castedo, L.; Lledos, A.; Mascarenas, J. L. Gold-Catalyzed [4Cþ2C] Cycloadditions of Allenedienes, including an Enantioselective Version with New Phosphoramidite-Based Catalysts: Mechanistic Aspects of the Divergence between [4Cþ3C] and [4Cþ2C] Pathways. J. Am. Chem. Soc. 2009, 131, 13020. (9) Trillo, B.; Lopez, F.; Montserrat, S.; Ujaque, G.; Castedo, L.; Lledos, A.; Mascarenas, J. L. Gold-Catalyzed [4Cþ3C] Intramolecular Cycloaddition of Allenedienes: Synthetic Potential and Mechanistic Implications. Chem.;Eur. J. 2009, 15 (14), 3336–3339. (10) Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. Intramolecular [4þ2] Cycloadditions of 1,3-Enynes or Arylalkynes with Alkenes with Highly Reactive Cationic Phosphine Au(I) Complexes. J. Am. Chem. Soc. 2005, 127 (17), 6178–6179. pubs.acs.org/Organometallics

Published on Web 07/13/2010

Structurally well-defined Au(NHC)Cl complexes have been prepared and found to be effective precatalysts comparable to or better than Au(I)PR3Cl complexes.4-10 We recently reported a tandem [3,3]-rearrangement/[4Cþ3C]11,12 cycloaddition reaction catalyzed by the previously reported Au(NHC)Cl/AgSbF6 complex, where NHC = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene (IPr), I, Chart 1, developed by Nolan and co-workers.4 In an effort to conduct the [4Cþ3C] cycloaddition reaction in an enantioselective manner, we needed chiral Au(NHC)Cl complexes. However, currently only a few chiral Au(NHC)Cl complexes with catalytic activity have been reported, in contrast to their Au(I)PR3Cl counterparts,13,14 which have been successfully used in enantioselective reactions.15-27 Unfortunately, the Au(I) salt with a phosphine ligand did not work as well as (11) Gung, B. W.; Craft, D. T.; Bailey, L. N.; Kirschbaum, K. GoldCatalyzed Transannular [4þ3] Cycloaddition Reactions. Chem.;Eur. J. 2010, 16, 639. (12) Gung, B. W.; Bailey, L. N.; Wonser, J. Gold-Catalyzed Intermolecular [4C þ 3C] Cycloaddition Reactions. Tetrahedron Lett. 2010, 51, 2251. (13) Matsumoto, Y.; Selim, K. B.; Nakanishi, H.; Yamada, K.; Yamamoto, Y.; Tomioka, K. Chiral Carbene Approach to GoldCatalyzed Asymmetric Cyclization of 1,6-Enynes. Tetrahedron Lett. 2010, 51 (2), 404–406. (14) Matsumoto, Y.; Yamada, K. I.; Tomioka, K. C-2 Symmetric Chiral NHC Ligand for Asymmetric Quaternary Carbon Constructing Copper-Catalyzed Conjugate Addition of Grignard Reagents to 3-Substituted Cyclohexenones. J. Org. Chem. 2008, 73 (12), 4578– 4581. (15) Munoz, M. P.; Adrio, J.; Carretero, J. C.; Echavarren, A. M. Ligand Effects in Gold- and Platinum-Catalyzed Cyclization of Enynes: Chiral Gold Complexes for Enantioselective Alkoxycyclization. Organometallics 2005, 24 (6), 1293–1300. (16) Gonzalez-Arellano, C.; Corma, A.; Iglesias, M.; Sanchez, F. Enantioselective Hydrogenation of Alkenes and Imines by a Gold Catalyst. Chem. Commun. 2005, 27, 3451–3453. (17) Kadzimirsz, D.; Hildebrandt, D.; Merz, K.; Dyker, G. Isoindoles and Dihydroisoquinolines by Gold-Catalyzed Intramolecular Hydroamination of Alkynes. Chem. Commun. 2006, 6, 661–662. r 2010 American Chemical Society

Article Chart 1. Initial Screen of Gold Complexes for Intramolecular [4Cþ3C] Cycloaddition Reactions

Au(I) with a NHC ligand for the tandem 3,3-rearrangement/ [4þ3] cycloaddition reaction.12 Among the Au(I)PR 3 Cl complexes used in our study of the transannular [4Cþ3C] cycloaddition reaction, only the Au(I) catalyst (II, Chart 1) with a Buchwald ligand worked well.11,10 However even this catalyst was ineffective for the corresponding interor intramolecular versions of tandem 3,3-rearrangement/ [4Cþ3C] cycloaddition reactions.12 On the other hand, Au(IPr)Cl complex I proved to be effective as a precatalyst in the intermolecular [4Cþ3C] cycloaddition reactions.12 Therefore an effective chiral Au(NHC)Cl complex would be the most promising chiral Au(I) precatalyst for enantioselective inter- and intramolecular [4Cþ3C] cycloaddition reactions. After a survey of the literature, we found that, despite an upsurge of studies on chiral NHC ligands,3,28,29 currently only a few gold catalysts with a chiral NHC ligand are known to be catalytically active.13,15 In this report, we disclose the synthesis, characterization, catalytic reactivity, and thermal stability of two new chiral Au(NHC)Cl complexes. Although almost no enantioselectivity was observed in the cyclopropanation reactions studied using the two new chiral Au(NHC) complexes, important insight into the relationship between structure and reactivity of Au(NHC) complexes has been obtained. (18) Zhang, Z.; Widenhoefer, R. A. Gold(I)-Catalyzed Intramolecular Enantioselective Hydroalkoxylation of Allenes. Angew. Chem., Int. Ed. 2007, 46 (1þ2), 283–285. (19) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. Gold(I)Catalyzed Enantioselective Intramolecular Hydroamination of Allenes. J. Am. Chem. Soc. 2007, 129 (9), 2452–2453. (20) Melhado, A. D.; Luparia, M.; Toste, F. D. Au(I)-Catalyzed Enantioselective 1,3-Dipolar Cycloadditions of Munchnones with Electron-Deficient Alkenes. J. Am. Chem. Soc. 2007, 129 (42), 12638–12639. (21) Liu, C.; Widenhoefer, R. A. Gold(I)-Catalyzed Intramolecular Enantioselective Hydroarylation of Allenes with Indoles. Org. Lett. 2007, 9 (10), 1935–1938. (22) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. Gold(I)Catalyzed Enantioselective Intramolecular Hydroamination of Allenes. J. Am. Chem. Soc. 2007, 129 (9), 2452–2453. (23) Hashmi, A. S. K.; Schaefer, S.; Bats, J. W.; Frey, W.; Rominger, F. Gold Catalysis and Chiral Sulfoxides: Enantioselective Synthesis of Dihydroisoindol-4-ols. Eur. J. Org. Chem. 2008, 29, 4891–4899. (24) Kleinbeck, F.; Toste, F. D. Gold(I)-Catalyzed Enantioselective Ring Expansion of Allenylcyclopropanols. J. Am. Chem. Soc. 2009, 131 (26), 9178. (25) Uemura, M.; Watson, L. D. G.; Katsukawa, M.; Toste, F. D. Gold(I)-Catalyzed Enantioselective Synthesis of Benzopyrans via Rearrangement of Allylic Oxonium Intermediates. J. Am. Chem. Soc. 2009, 131 (10), 3464. (26) Gonzalez, A. Z.; Toste, F. D., Gold(I)-Catalyzed Enantioselective [4þ2]-Cycloaddition of Allene-dienes. Org. Lett. 12, (1), 200-203. (27) Teller, H.; Flugge, S.; Goddard, R.; Furstner, A., Enantioselective Gold Catalysis: Opportunities Provided by Monodentate Phosphoramidite Ligands with an Acyclic TADDOL Backbone. Angew. Chem., Int. Ed. 49, (11), 1949-1953. (28) Herrmann, W. A.; Goossen, L. J.; Kocher, C.; Artus, G. R. J. Chiral Heterocyclic Carbenes in Asymmetric Homogeneous Catalysis. Angew. Chem. Int. Ed. Engl. 1996, 35 (23-24), 2805–2807. (29) Perry, M. C.; Burgess, K. Chiral N-Heterocyclic Carbene-Transition Metal Complexes in Asymmetric Catalysis. Tetrahedron: Asymmetry 2003, 14 (8), 951–961.

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Results and Discussion Our recent success in the gold-catalyzed transannular [4Cþ3C] cycloaddition reactions11 led us to extend the scope of the reaction to the intramolecular version. Initially we screened the gold complexes that have been reported in the literature, i.e, the Au(I) complexes with each of the following ligands: a NHC ligand (I, Au(IPr)Cl),4 a Buchwald o-biphenylphosphine ligand (II),10 and an electron-deficient phosphine ligand (III), 10 or the Au(III) complex (IV)30 (Chart 1). Our initial study on attempted gold-catalyzed intramolecular [4Cþ3C] cycloaddition reactions was more complicated comparing to that on the transannular version.11 The scope and limitation of the study have not been completed for the intramolecular [4þ3] cycloaddition reactions. One surprising outcome was observed for substrate diene-propargyl ester 1. No desired product was obtained with up to 20 mol % of any one of the gold complexes II-IV despite the fact that both complexes II and IV were effective in the transannular version of the [4þ3] cycloaddition.11 A mixture of [4þ3] and formal [2þ2] cycloaddition products 2 and 3 was isolated, although in poor yields, when 10% of Au(IPr)Cl complex I and an equal amount of AgSbF6 were employed, eq 1.

In order to understand the possible reaction pathways and to improve the reaction selectivity and yield, we decided to first simplify the reaction by excluding the [4Cþ3C] cycloaddition pathway with the starting material 4a-c. Instead of the diene moiety in propargyl ester 1, propargyl esters 4a-c contain a terminal alkene; hence they cannot undergo a [4þ3] cycloaddition reaction. They were prepared and studied under the catalysis of Au(IPr)Cl complex I, Scheme 1. Surprisingly, a smooth cyclopropanation reaction was observed. In the presence of complex I and an equal amount of AgSbF6, the propargyl esters 4a-c were converted into bicyclic enol esters 5a-c in high yield at room temperature. The cyclopropanation products (5a-c) were obtained as mixtures of cis/trans double-bond isomers of the enol acetate, which were inseparable by column chromatography. To facilitate the structure identification, the products from the gold-catalyzed cyclopropanation reactions were converted to their corresponding ketones (6a-c), which allowed unambiguous identification by NMR spectroscopy. Several gold-catalyzed tandem [3,3]-rearrangement/cyclopropanation reactions have been reported by the groups of Furstner,31,32 Gagosz,33 and Toste.34 However, there is a marked difference in the present reaction substrates and the (30) Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.; Kurpejovic, E. Gold Catalysis: The Benefits of N and N,O Ligands. Angew. Chem., Int. Ed. 2004, 43 (47), 6545–6547. (31) Furstner, A.; Hannen, P. Carene Terpenoids by Gold-Catalyzed Cycloisomerization Reactions. Chem. Commun. 2004, 22, 2546–2547. (32) Mamane, V.; Gress, T.; Krause, H.; Furstner, A. Platinum- and Gold-Catalyzed Cycloisomerization Reactions of Hydroxylated Enynes. J. Am. Chem. Soc. 2004, 126 (28), 8654–8655.

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Scheme 1. Intramolecular Cyclopropanation Catalyzed by Au(I)IPr Complex I

Scheme 2. Preparation of Au(I) Complexes 9 and 11

products. Previously reported cyclopropanation substrates have the acetate group located in between the alkyne and the alkene bonds and the products contain an endocyclic enol acetate. In the current propargyl esters 4a-c, the ester group is located on the farther side of the triple bond away from the alkene. As a result, the products 5a-c have an exocyclic enol acetate. A recent report of PtCl2-catalyzed cyclopropanation reactions provided similar reaction products,35 but the starting materials were propargyl ethers and the products contained an enol ether moiety rather than an enol ester. High yields of 5a-c were obtained with catalyst I regardless of the characteristics of the substituent R at the propargylic position. On the basis of the study of Furstner,36 this gold-catalyzed cyclopropanation should involve one of two possible pathways: (1) an initial gold-activated 1,2-acetate migration and the formation of a gold carbenoid intermediate followed by cyclopropanation with the terminal alkene, or (2) an initial enyne cyclization with the terminal alkene attacking the gold-activated alkyne, leading to cyclopropanation and a gold carbenoid intermediate, followed by 1,2migration of the acetate and deauration.36 More discussion on possible reaction mechanisms will be presented later. With the results of the cyclopropanation reaction catalyzed by Au(IPr)Cl (I) in hand, our attention turned to the preparation of chiral Au(NHC) complexes. Among the (33) Buzas, A.; Gagosz, F. Gold(I) Catalyzed Isomerization of 5-En-2-yn-1-yl Acetates: An Efficient Access to Acetoxy Bicyclo[3.1.0]hexenes and 2-Cycloalken-1-ones. J. Am. Chem. Soc. 2006, 128 (39), 12614–12615. (34) Watson, L. D. G.; Ritter, S.; Toste, F. D. Asymmetric Synthesis of Medium-Sized Rings by Intramolecular Au(I)-Catalyzed Cyclopropanation. J. Am. Chem. Soc. 2009, 131 (6), 2056. (35) Ye, L.; Chen, Q.; Zhang, J. C.; Michelet, V. PtCl2-Catalyzed Cycloisomerization of 1,6-Enynes for the Synthesis of Substituted Bicyclo[3.1.0]hexanes. J. Org. Chem. 2009, 74 (24), 9550–9553. (36) Furstner, A.; Hannen, P. Platinum- and Gold-Catalyzed Rearrangement Reactions of Propargyl Acetates: Total Syntheses of (-)alpha-Cubebene, (-)-Cubebol, Sesquicarene and Related Terpenes. Chem.;Eur. J. 2006, 12 (11), 3006–3019. (37) Alcarazo, M.; Stork, T.; Anoop, A.; Thiel, W.; F€ urstner, A. Steering the Surprisingly Modular π-Acceptor Properties of N-Heterocyclic Carbenes: Implications for Gold Catalysis. Angew. Chem., Int. Ed. 2010, 49 (14), 2542–2546.

Table 1. Selected Structural Parameters for the New Gold Complexes 9-Cl, 11-Cl, 9-OAc, and 11-OAc complex

Au-C(1) distance (A˚)

δC Au-C(1) (ppm)

νCdO (cm-1)

9-Cl 11-Cl 9-OAc 11-OAc Au(IPr)Cl (I)a

1.998 2.003 na na 1.942

191.0 178.4 185.5 177.3 175.1

na na 1626.7 1627.1 na

a

From ref 4.

widespread interest in the development of better NHC ligands, one of the efforts has been to examine the σ-donor and π-acceptor properties of the ligand.37 We were interested in comparing the catalytic activity of the Au(I) complexes, one with a saturated NHC ligand (9) and another one with an extended conjugation system, the benzimidazolium ligand (11). Preparation of Chiral Au(I) Complexes. The preparation of the chrial Au(I) complexes 9 and 11 is shown in Scheme 2. The preparation of the imidazolium salt 8 and the benzimidazolium salt 10 follows the general protocol of Roland and Alexakis,38 and the conversion from 8 and 10 to the Au(I)Cl complexes 9-Cl and 11-Cl was carried out using the method of Wang and Lin.39 The most widely accepted methodology for the determination of a ligand’s electronic properties is the IR spectroscopic analysis of the CO-stretching frequencies of (L)Ni(CO)3, (L)Rh(CO)2Cl, (L)Ir(CO)2Cl, and related complexes.40-43 The 13C chemical shifts of the carbene carbon have been compared through subtraction of the corresponding (38) Winn, C. L.; Guillen, F.; Pytkowicz, J.; Roland, S.; Mangeney, P.; Alexakis, A. Enantioselective Copper Catalysed 1,4-Conjugate Addition Reactions Using Chiral N-Heterocyclic Carbenes. J. Organomet. Chem. 2005, 690 (24-25), 5672–5695. (39) Wang, H. M. J.; Lin, I. J. B. Facile synthesis of Silver(I)-Carbene Complexes. Useful Carbene Transfer Agents. Organometallics 1998, 17 (5), 972–975. (40) Gusev, D. G. Electronic and Steric Parameters of 76 N-Heterocyclic Carbenes in Ni(CO)(3)(NHC). Organometallics 2009, 28 (22), 6458–6461. (41) Tolman, C. A. Steric Effects of Phosphorus Ligands in Organometallic Chemistry and Homogeneous Catalysis. Chem. Rev. 1977, 77 (3), 313–348.

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Figure 1. ORTEP diagram of chiral NHC-AuCl complexes: 9-Cl and 11-Cl. Hydrogen atoms in complex 9-Cl have been omitted for clarity. Table 2. Catalytic Activities of Au(I) Complexes 9, 11, and I in the Cyclopropanation Reactions of 4a-ca

substrate

LAu(I)Cl

R

time (h)

yield (%)

Z/Eisomeric ratio

4a 4b 4c 4a 4b 4c 4a 4b 4c

9 9 9 11 11 11 I I I

Ph n-propyl isopropyl Ph n-propyl isopropyl Ph n-propyl isopropyl

48 2 2 2 3 1.5 2 1 1

(65% 12a)c 97 95 (56% 12b)c 96 94 90 97 94

NA 2:1 1:1 2:1 2:1 1:1 1:0 3.6:1 2.4:1

b

a Low or near-zero optical rotations were observed for all reaction products. b All yields refer to product 5 except where indicated otherwise. c Product 12 was produced only with the specific combination of the gold complex and substrate 4a.

imidazol-2-ylidene carbene by Nolan and co-workers to study the donor ability of the NHC ligands bound to gold(I).4 In an attempt to identify the difference in the chemical environment surrounding the gold atom in complexes 9 and 11, we hoped to compare the carbonyl stretching frequencies of complexes 9-OAc and 11-OAc. Their preparation is also shown in Scheme 2 following the report of Baker and coworkers.44 Our wish to compare the CdO stretching frequencies of 9-OAc and 11-OAc would turn out to be a bit naı¨ ve because the ester CO groups are not bonded directly to the Au atom (but through an oxygen atom spacer), and (42) Wurtz, S.; Glorius, F. Surveying Sterically Demanding N-Heterocyclic Carbene Ligands with Restricted Flexibility for Palladiumcatalyzed Cross-Coupling Reactions. Acc. Chem. Res. 2008, 41 (11), 1523–1533. (43) Furstner, A.; Alcarazo, M.; Krause, H.; Lehmann, C. W. Effective Modulation of the Donor Properties of N-Heterocyclic Carbene Ligands by “Through-Space” Communication within a Planar Chiral Scaffold. J. Am. Chem. Soc. 2007, 129 (42), 12676. (44) Baker, M. V.; Barnard, P. J.; Brayshaw, S. K.; Hickey, J. L.; Skelton, B. W.; White, A. H. Synthetic, Structural and Spectroscopic Studies of (Pseudo)halo(1,3-di-tert-butylimidazol-2-ylidine) Gold Complexes. Dalton Trans. 2005, 1, 37–43.

consequently its influence diminished. A very small difference in CdO stretching frequencies was observed (Table 1). To characterize the gold complexes and to examine the stereochemical environment of the gold atom, crystals suitable for X-ray structure analysis were grown of complexes 9-Cl and 11-Cl. The ORTEP diagrams of the structures for complexes 9-Cl and 11-Cl are shown in Figure 1. The observed key parameters for the two gold complexes are compiled in Table 1 along with the previously reported data for complex I. The observed 13C NMR chemical shift difference between complexes 9 and complexes 11 are consistent with previous observations of Au(NHC) complexes.4 The differences in Au-C bond distances between 9-Cl and 11-Cl (1.998 vs 2.003 A˚) are too small to be significant. However, the differences in Au-C bond distances between the two new complexes and complex I appear to be real (∼2.00 vs 1.942 A˚). The differences in the CdO stretching frequencies between 9 and 11 are also too small to be significant. However, fortuitously, they appear to parallel the stabilities of the corresponding cationic Au(I) catalyst. The most stable Au(NHC) complex is complex I, which has the shortest bond distance. Later we

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Scheme 3. Assignment of the Relative Configuration of the Diastereomeric Formal [2þ2] Cycloaddition Product 12b and the Corresponding Alcohols 14a and 14b

will show that complex 11, which has the longest Au-C bond length, is the least stable. Catalytic Activity of Gold Complexes 9 and 11.

Interestingly, the reactions of the substrate 4a (R = Ph) provided different products (12a and 12b) when Au(I) complexes 9-Cl and 11-Cl were employed (Table 2). This was especially surprising when considering that a uniformly high yields of the cyclopropanation products 5a-c were obtained when the catalyst Au(IPr) (I) was employed. In the presence of complex 9-Cl/AgSbF6, substrate 4a was converted to allene 12a and no further change was observed even after prolonged stirring at room temperature or heating to reflux in CH2Cl2. On the other hand, with substrates 4b and 4c, the “normal” cyclopropanation products 5b and 5c were obtained in high yield, respectively, as a mixture of double-bond isomers in favor of the Z-isomer. In the presence of complex 11-Cl/AgSbF6, substrate 4a gave yet another product (12b). The formal [2þ2] cycloaddition reaction product 12b was isolated in 56% yield as a 2:1 mixture of double-bond isomers in favor of the Z-isomer from 4a in the presence of complex 11-Cl/AgSbF6, while substrates 4b and 4c produced the “normal” cyclopropanes 5b and 5c in high yield, respectively. Unfortunately no significant optical activity was observed for reactions employing either catalyst system 9-Cl/AgSbF6 or 11-Cl/ AgSbF6. The geometric isomers and the structure of the interesting [2þ2] cycloaddition product 12b were assigned by comparing the chemical shift difference of the vinyl protons and by converting to the bicyclic ketone 13 with ozonolysis, Scheme 3. Furthermore, removal of the acetate group from product 12b allowed the separation of the alcohols 14a and 14b and the determination of the double-bond configuration by a twodimensional NOESY spectrum. The major isomer 14a was determined to have the Z-double bond on the basis of the NOE effect and the unchanged chemical shift of the vinyl proton from its precursor. Possible Pathways Leading to the Observed Products. Plausible pathways for the conversion of the propargyl esters 4a-c in the presence of gold catalysts to different products

are depicted in Scheme 4. Both gold-stabilized carbocations and gold carbenoids have been depicted for intermediates involving Au(I)(NHC) catalysts. The dual characteristics of gold complexes have been discussed extensively.36,45-48 In the presence of catalyst Au(IPr) (I) the formation of the cyclopropanation products 5a-c involves most likely an initial enyne cyclization to form the cyclopropane carbocation intermediate B, which is resonance-stabilized with the gold carbenoid B0 (Scheme 4). A 1,2-acetate migration and deauration from B would give the cyclopropanation product 5. The isolation of product 12a indicates a 1,3-migration of the acetate group in the presence of gold complex 9. According to a computational study of Cavallo and co-workers,48,49 both 1,2- and 1,3-migration of the acetate group are lowbarrier processes and gold-coordinated allenyl ester is 8 kcal/ mol more stable than gold-coordinated propargyl ester. Therefore, it is plausible that 1,3-acetate migration competes with enyne cyclization initially. With substrate 4a, where R = Ph, no cyclopropanation product 5a was observed in the presence of Au(I) catalyst 9 or 11. It is conceivable that a phenyl group stabilizes allene 12a by conjugation, while a propyl or an isopropyl group may destabilize the allene intermediate by making it more prone to electrophilic coordination by the same Au(I) catalyst. With substrate 4a, complex 9 appears to have lost its catalytic activity once 12a was produced. More evidence supporting this hypothesis is presented in the next section. The gold-catalyzed reaction appears to favor the production of the cyclopropanation product 5a with the more stable complex Au(IPr) (I). In order to test this hypothesis, allene (45) Echavarren, A. M. Carbene or Cation? Nat. Chem. 2009, 1 (6), 431–433. (46) Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y. M.; Goddard, W. A.; Toste, F. D. A Bonding Model for Gold(I) Carbene Complexes. Nat. Chem. 2009, 1 (6), 482–486. (47) Amijs, C. H. M.; Lopez-Carrillo, V.; Raducan, M.; Perez-Galan, P.; Ferrer, C.; Echavarren, A. M. Gold(I)-Catalyzed Intermolecular Addition of Carbon Nucleophiles to 1,5- And 1,6-Enynes. J. Org. Chem. 2008, 73 (19), 7721–7730. (48) Marion, N.; Lemiere, G.; Correa, A.; Costabile, C.; Ramon, R. S.; Moreau, X.; de Fremont, P.; Dahmane, R.; Hours, A.; Lesage, D.; Tabet, J. C.; Goddard, J. P.; Gandon, V.; Cavallo, L.; Fensterbank, L.; Malacria, M.; Nolan, S. P. Gold- and Platinum-Catalyzed Cycloisomerization of Enynyl Esters versus Allenenyl Esters: An Experimental and Theoretical Study. Chem.;Eur. J. 2009, 15 (13), 3243–3260. (49) Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.; Nolan, S. P.; Cavallo, L. Golden Carousel in Catalysis: The Cationic Gold/ Propargylic Ester Cycle. Angew. Chem., Int. Ed. 2008, 47 (4), 718–721.

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Scheme 4. Possible Pathways Leading to Observed Products

12a was allowed to stir with complex I under the same conditions, eq 2. Cyclopropanation product 5a was indeed produced with only 2.5% of the catalyst at room temperature.

The formation of the formal [2þ2] cycloaddition product alkylidenecyclobutane 12b with a terminal alkene, to the best of our knowledge, is unprecedented. Previously reported gold-catalyzed intramolecular allene-ene [2þ2] cycloaddition reactions involve either trisubstituted or phenyl-substituted alkenes.50 A stable tertiary or benzylic carbocation is usually proposed as the intermediate in the initial nucleophilic attack on the gold-activated allene moiety by the electron-rich double bond.50,51 For substrate 4a, this mechanism requires the initial formation of 12a, which would be activated by the same Au(I) catalyst and attacked by the terminal alkene. The problem with this pathway is that it invokes a primary carbocation in order to form the cyclobutane, eq 3. Since this is unlikely to happen,

we propose the pathway depicted in Scheme 4 to explain the isolation of the [2þ2] cycloaddition product 12b. Reactive (50) Luzung, M. R.; Mauleon, P.; Toste, F. D. Gold(I)-Catalyzed [2þ2]-Cycloaddition of Allenenes. J. Am. Chem. Soc. 2007, 129 (41), 12402–12403. (51) Zhang, L. M. Tandem Au-catalyzed 3,3-Rearrangement-[2þ2] Cycloadditions of Propargylic Esters: Expeditious Access to Highly Functionalized 2,3-Indoline-Fused Cyclobutanes. J. Am. Chem. Soc. 2005, 127 (48), 16804–16805. (52) Furstner, A.; Morency, L. On the Nature of the Reactive Intermediates in Gold-Catalyzed Cycloisomerization Reactions. Angew. Chem., Int. Ed. 2008, 47 (27), 5030–5033.

intermediates in gold-catalyzed cycloisomerization reactions have been compared to “nonclassical” carbocations.45,52 The delocalization of the electrons in the reactive intermediate can be depicted in three renditions (A, B, and C, Scheme 4). The proposed pathway involves the cyclobutane tertiary carbocation rendition C for the production of 12b.52 A 1,3acetate migration/deauration from C would produce product 12b. The question is why only gold catalyst 11 favors the formation of 12b. A recent study of the π-acceptor property of NHCs in gold catalysis provides a reasonable explanation.37 An electron-rich gold complex tends to stabilize an adjacent carbocation and therefore favor the cyclopropanation pathway via resonance contributors B and B0 ; in contrast, a more electron-deficient gold complex might favor the rendition C, in which the cation center is not directly bound to gold, and therefore produces the alkylidenecyclobutane 12b by a 1,3-acetate migration/deauration process. The proposed pathways in Scheme 4 suggest different catalyst stability for the three Au(I) complexes employed. In order to find corroborative evidence, variable-temperature NMR experiments were performed on the three Au(I) complexes (I, 9, and 11). Each Au(NHC)Cl complex was treated with an equal molar amount of AgSbF6 in CDCl3 and stirred at room temperature for 15 min, eq 4.

The resulting suspension was filtered, the filtrate was loaded into an NMR tube, and the 1H NMR spectra were recorded at 30 min intervals from room temperature to 55 °C. Previously Nolan and co-workers have reported rapid decomposition and generation of colloidal gold upon attempted preparation of the cationic gold(I) complex in dry dichloromethane or dry chloroform with silver salts.5 We were able to record 1H NMR spectra of the cationic Au(I) complexes from rt to 55 °C during a five-hour time period. The CDCl3 we used was purchased and used as received. It contains about 0.1% water, as indicated by its 1H NMR

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Figure 2. Catalyst stability study: ([) catalyst I, (9) catalyst 9, (2) catalyst 11.

Figure 4. 1H NMR spectra of complex 9þ. Complex 9-Cl was stirred with 1 equiv of AgSbF6 for 15 min at rt in CDCl3. After filtering off AgCl, the filtrate was loaded into an NMR tube and the spectra were recorded at 30 min intervals with increasing temperatures. A broadened quartet at 5.6 ppm is observed initially and decreases in intensity as the temperature rises. A second quartet at 5.4 ppm grows from about 5% initially to predominant at 55 °C. At the end of the experiment, gold mirroring was observed for complex 9þ.

catalyst had already decomposed when the first spectrum was recorded (not shown). Thus the variable-temperature NMR experiments carried out with the three gold complexes support the hypothesis that the different results observed with the Au(I) catalysts (I, 9, and 11) are mainly due to the stability difference in the catalyst. Figure 3. 1H NMR spectra of complex I (Au(IPr)þ). Au(IPr)Cl was stirred with 1 equiv of AgSbF6 for 15 min at rt in CDCl3. After filtering off AgCl, the filtrate was loaded into an NMR tube and the spectra were recorded at 30 min intervals with increasing temperatures.

spectrum. It is possible the trace amount of water may have served to stabilize the cationic gold complex in solution. The cationic catalyst I showed no signs of change from room temperature to 55 °C and from the first to the last spectrum taken during the 5 h of time, Figures 2 and 3. The signal for one pair of the isopropyl groups is broadened, but the integrity of the complex remains intact and no gold mirroring was observed. For catalysts 9 and 11, it was convenient to monitor the proton on the stereogenic methine carbon during the NMR study. From the very first NMR spectrum, two sets of signals for the methine proton were recorded, Figures 2 and 4. For catalyst 9, one slightly broadened quartet and one clear quartet were observed at 5.6 and 5.4 ppm, respectively. The broadened quartet was assigned to the cationic catalyst because it gradually disappears and the clear quartet gradually grows as the temperature rises. At the conclusion of the experiments for catalyst 9, a gold mirror was deposited onto the bottom of the NMR tube. For catalyst 11, 50% of the

Conclusions Two new chiral gold complexes have been prepared and their structures determined by X-ray structure analysis. These complexes become catalytically active toward the cyclopropanation reactions of propargyl esters 4a-c upon treatment with a silver salt. However, their thermal stability is inferior compared to the commercially available complex Au(IPr)Cl (I). Future design of other chiral NHC ligands for preparing gold catalysts should take into account the thermal stability of the resulting gold complexes. Work along this line is underway in our laboratories.

Acknowledgment. B.W.G. thanks the CFR of Miami University for a summer stipend. L.N.B. and D.T.C. thank the Department of Chemistry & Biochemistry, Miami University, for a Teaching Award and a Dissertation Scholarship, respectively. Supporting Information Available: Text and figures giving full experimental details for the preparation of all new compounds described in this paper, including copies of 1H and 13C NMR spectra, and crystallographic data and refinement parameters of compounds 9-Cl and 11-Cl. This material is available free of charge via the Internet at http://pubs.acs.org.