Gold(I)-Catalyzed Cycloaddition of 1-(1-Alkynyl)cyclopropyl Ketones

Organometallics 2009, 28, 3129–3139

3129

Gold(I)-Catalyzed Cycloaddition of 1-(1-Alkynyl)cyclopropyl Ketones with Nucleophiles To Yield Substituted Furans: A DFT Study Jinsheng Zhang,†,‡ Wei Shen,† Longqin Li,† and Ming Li*,† School of Chemistry and Chemical Engineering, Southwest UniVersity, Chongqing, 400715, People’s Republic of China and School of Chemistry and Material Science, Guizhou Normal UniVersity, Guiyang, 550001, People’s Republic of China ReceiVed NoVember 23, 2008

By means of density functional theory (DFT), the mechanism for the synthesis of highly substituted furan (2) from 1-(1-alkynyl)-cyclopropyl ketone (1) with nucleophile (MeOH) catalyzed by Au(I) was investigated. As demonstrated, both the intimate ion-pair [AuL]+ · [OTf]- (L ) PPh3, PMe3, and PH3, OTf ) trifluoromethane sulfonate) and the cation [AuL]+ exhibit catalysis, and the former is dominant. Moreover, the bigger the ligand coordinated to gold is, the poorer the catalysis is. The theoretical study reveals that the nucleophiles such as MeOH are important for this reaction, that the reaction between the bicyclo[4.1.0]heptan and the carbinol is a stereospecific addition reaction, and how the proton migration goes through. In the proton migration process, both the anion OTf- and another nucleophile molecule such as MeOH act as a proton shuttle to transport a proton from the nucleophile to the 2-position carbon of alkynyl. The most favorable mechanism includes the activation of the substrate, nucleophile attraction, an addition reaction of the carbonyl triple bond, a stereospecific attack of the nucleophile on the activated cyclopropane, proton migration, and regeneration of the catalyst. The substrate 1 is activated by its combination with Au(I) and a molecule of nucleophile (MeOH), which leads to a decrease in the orbital energy of π*(C1tC2) and σ*(C3-C5) and an increase in the dipole moment of the bent bond σ(C3-C5). On the whole, the solvent effects increase the reaction barriers. 1. Introduction

Scheme 1

Highly substituted furans are key structural elements in many bioactive natural products and important pharmaceuticals.1 They also represent versatile building blocks for the synthesis of more elaborate heterocyclic compounds.2-4 For this reason, the efficient synthesis of functional multisubstituted furans continues to attract interest for synthetic chemists. In recent years, considerable effort has been directed toward the development of new and efficient methodologies for the synthesis of multisubstituted furans. One of the reliable approaches for the synthesis of this class of compounds is the cyclization of allenyl ketones and 3-alkyn-1-ones by use of transition-metal catalysts.5-15 * Corresponding author. Fax: + 86 23 68866796. E-mail: liming@ swu.edu.cn. † Southwest University. ‡ Guizhou Normal University. (1) Mondal, S.; Nogami, T.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2003, 68, 9496–9498. (2) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955–2020. (3) Keay, B. A. Chem. Soc. ReV. 1999, 28, 209–215. (4) Lipshutz, B. H. Chem. ReV. 1986, 86, 795–819. (5) Xiao, Y.; Zhang, J. Angew. Chem., Int. Ed. 2008, 47, 1903–1906. (6) Zhang, J.; Schmalz, H. G. Angew. Chem., Int. Ed. 2006, 45, 6704– 6707. (7) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4531– 4534. (8) Kel’in, A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95–98. (9) Cacchi, S. J. Organomet. Chem. 1999, 576, 42–64. (10) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285–2288. (11) Marshall, J. A.; Bartley, G. S. J. Org. Chem. 1994, 59, 7169–7171. (12) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J. Org. Chem. 1991, 56, 5816–5819.

Among them, the strategy of gold(I)-catalyzed reaction of 1-(1alkynyl)-cyclopropyl ketones with nucleophiles to yield ringexpanded bicyclic furans (Scheme 1), which was developed by Schmalz and co-workers,6 is very interesting. In this strategy, the starting materials contain both an alkyne and a cyclopropane unit and the products contain an expanded ring with a substituted nucleophilic group. Their experiment indicated that [Au(PPh3)]OTf (OTf ) trifluoromethane sulfonate) was a particularly efficient catalyst for this reaction. This reaction tolerates a wide range of nucleophiles including alcohols and phenols and a wide range of alkyl groups on the alkyne in substrate, including (13) Hou, X. L.; Yang, Z.; Wong, H. N. C. In Progress in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon Press: Oxford, U.K., 2002; Vol. 14, pp 139-179. (14) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1991, 56, 960–969. (15) Dudnik, A. S.; Gevorgyan, V. Angew. Chem. 2007, 119, 5287– 5289.

10.1021/om801115a CCC: $40.75  2009 American Chemical Society Publication on Web 05/07/2009

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phenyl, alkyl, and alkenyl substituents, even a cyclopropyl unit. However, no reaction took place if the substrate was subjected to the standard reaction condition (1 mol % of (Ph3P)AuOTf, CH2Cl2, at room temperature) in the absence of a nucleophile. Also, no reaction occurs while Et3SiH, as a potential hydride donor, was used in place of a nucleophile. Herein, Schmalz and co-workers indicated that these facts contradict a mechanism involving a carbocation intermediate, and further studies are necessary to obtain deeper mechanistic insights. It has been reported that (Ph3P)AuX (X ) OTf-, SbF6-) exhibits catalysis in many isomerization reactions including cyclization of monoallylic diols to form tetrahydropyrans,16 benzannulation of hydroxy-enynes to prepare tetrahydronaphthalenes,17 cycloadditions of propargylic esters to produce indoline-fused cyclobutanes,18 cycloisomerization of alleneketones to form bromofurans,19,20 etc. Generally, it is accepted that cation [Au(PPh3)]+ is the efficient ingredient of catalyst, and the anion effect on the activation is always ignored in many theoretical studies.21-25 In spite of this, little is known about the detailed catalyzed mechanisms and functions of the ligand, anion, and nucleophile. Theoretically, the catalyst (Ph3P)AuX (X ) OTf-, SbF6-) most likely exists as an intimate ion-pair [Au(PPh3)]+ · X- in solvent,26 and the anion has some effect on the catalysis. Herein, a theoretical study with the B3LYP density functional was carried out to elucidate the following issues in detail: (a) the reaction mechanism of Au(I)-catalyzed reactions of (1S,6R)-1-(phenylethynyl)bicyclo[4.1.0]heptan-2one (1) with methyl alcohol to result in cyclohepta[b] furan (2), (b) the assistant hydrogen migration functions of OTf- (trifluoromethane sulfonate) and MeOH, (c) why MeOH as the potential hydride source cannot be replaced by Et3SiH, and (d) the effects of ligands (PH3, P(CH3)3, P(Ph)3) coordinated to gold on the Au(I) catalysis.

2. Computational Details All calculations were carried out with the Gaussian 03 programs.27 The geometries of all the species were fully optimized by using density functional theory (DFT)28 of the B3LYP method29,30 with the 6-31G(d) basis set for all atoms except for gold, which (16) Aponick, A.; Li, C.; Biannic, B. Org. Lett. 2008, 10 (4), 669–671. (17) Grise´, C. M.; Rodrigue, E. M.; Barriault, L. Tetrahedron 2008, 64, 797–808. (18) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804–16805. (19) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500–10501. (20) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440–1452. (21) Xia, Y.; Dudnik, A. S.; Gevorgyan, V.; Li, Y. J. Am. Chem. Soc. 2008, 130, 6940–6941. (22) Lemie`re, G.; Gandon, V.; Agenet, N.; Goddard, J. P.; de Kozak, A.; Aubert, C.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2006, 45, 7596–7599. (23) Shi, F.; Li, X.; Xia, Y.; Zhang, L.; Yu, Z. J. Am. Chem. Soc. 2007, 129, 15503–15512. (24) Cheong, P. H.; Morganelli, P.; Luzung, M. R.; Houk, K. N.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 4517–4526. (25) Fang, R.; Su, C.-Y.; Zhao, C.; Phillips, D. L. Organometallics, 2009, 28, 741–748. The main differences between our study and Fang’s study are that in Fang’s study, the effects of the trifluoromethane sulfonate anion (OTf-) and the different ligands of PPh3, PMe3, and PH3 on the overall catalyzed reactions have not been taken into account and the role of two nucleophilic molecules MeOH in the proton migration is not investigated. As demonstrated in our study, the anion OTf- plays a key role in the [AuL]OTf (L ) PPh3, PMe3, PH3, OTf ) trifluoromethane sulfonate) catalyzed reaction. In dynamics, the intimate ion pair [AuL]OTf-catalyzed reaction pathways are more favored than the cation [AuL]+-catalyzed channels. The effect of the different ligands on the reaction is remarkable. The proton migration by two nucleophilic molecules MeOH appears easier. (26) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496–499.

Zhang et al. was described by the LANL2DZ31-33 adding one set of fpolarization function with an exponent of 1.05.34This computational method was successfully applied in the mechanistic studies of transition-metal- or non-transition-metal-catalyzed reactions.23,35-41 Frequency calculations at the same level were performed to confirm each stationary point to be either a minimum or a transition structure (T). The transition states were verified by intrinsic reaction coordinate (IRC)42 calculations and by animating the negative eigenvector coordinates with a visualization program (Molekel 4.3).43,44 The intermediates were characterized by all real frequencies. In addition, the bonding characteristics were analyzed by natural bond orbital (NBO) theory.45-47 Furthermore, based on the gas-phase-optimized geometry for each species, the solvent effects of CH2Cl2 were studied by performing the self-consistent reaction field (SCRF) of polarizable continuum model (PCM)48 approach at the same computational level. The energy components have been computed following the standard protocol. The free energy in solution phase, G(sol), was calculated as follows

G(sol) ) G(gas) + Gsolv G(gas) ) H(gas) + TS(gas) H(gas) ) E(SCE) + ZPE where G(gas) is the free energy in gas phase, Gsolv is the free energy of solvation as computed using the continuum solution model, (27) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision C.02; Gaussian, Inc.: Wallingford, CT, 2004. (28) Parr, R. G.; Yang, W. Density-functional Theory of Atoms and Molecules; Oxford University Press: New York, 1989. (29) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (30) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785–789. (31) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270–283. (32) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284–297. (33) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299–310. (34) Ehlers, A. W.; Bo¨hme, M.; Dapprich, S.; Gobbi, A.; Ho¨llwarth, A.; Jonas, V.; Ko¨hler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G. Chem. Phys. Lett. 1993, 208, 111–114. (35) Faza, O. N.; Lopez, C. S.; Álvarez, R.; de Lera, A. R. J. Am. Chem. Soc. 2006, 128, 2434–2437. (36) Nieto-Oberhuber, C.; Munõz, M. P.; Bun˜uel, E.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem. Int. Ed. 2004, 43, 2402– 2406. (37) Roithova´, J.; Hrusˇa´k, J.; Schro¨der, D.; Schwarz, H. Inorg. Chim. Acta 2005, 358, 4287–4292. (38) Joshi, A. M.; Delgass, W. N.; Thomson, K. T. J. Phys. Chem. B 2006, 110, 2572–2581. (39) Nieto-Oberhuber, C.; Lo´pez, S.; Jimeńez-Nuń˜ez, E.; Echavarren, A. M. Chem. Eur. J. 2006, 12, 5916–5923. (40) Kovaćs, G.; Ujaque, G.; Lledo´s, A. J. Am. Chem. Soc. 2008, 130, 853–864. (41) Zhang, J.; Shen, W.; Li, M. Eur. J. Org. Chem. 2007, 29, 4855– 4866. (42) Gonzalez, C.; Schlegel, H. B. J. Phsy. Chem. 1990, 94, 5523–5527. (43) Flu¨kiger, P.; Lu¨thi, H. P.; Portmann, S.; Weber, J. MOLEKEL 4.3; Swiss Center for Scientific Computing: Manno, Switzerland, 2000/2002. (44) Portmann, S.; Lu¨thi, H. P. Chimia 2000, 54, 766–770. (45) Carpenter, J. E.; Weinhold, F. J. Mol. Struct. (THEOCHEM) 1988, 169, 41–50. (46) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88, 899–926. (47) Foster, J. P.; Weinhold, F. J. Am. Chem. Soc. 1980, 102, 7211– 7218. (48) Miertus, S.; Tomasi, J. Chem. Phys. 1982, 65, 239–245.

Gold(I)-Catalyzed Cycloaddition

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Figure 1. DFT-computed energy surface for the [Au(PMe3)]OTf-catalyzed reaction cycle with OTf--assisted proton migration. H(gas) is the enthalpy in the gas phase, T is the temperature (298.15 K), S(gas) is the entropy in the gas phase, E(SCF) is the self-consistent field energy, and ZPE is the zero-point energy. Molecular orbital compositions and overlap populations were calculated by employing the AOMix program.49,50 The analysis of the MO compositions in terms of occupied and unoccupied fragment molecular orbitals (OFOs and UFOs, respectively), the charge decomposition analysis (CDA), and the construction of orbital interaction diagrams were performed by using AOMix-CDA.51

3. Results and Discussion Because our testing studies demonstrate that the steric and electronic effects of the phenyls in triphenylphosphine have little effect on the reaction mechanism, structures of species, and the trend of potential-energy surface (Tables S1-9 and Figures S1-4 and S9, Supporting Information), unless special emphasis, the following discussion refers to [Au(PMe3)]OTf-catalyzed reactions. In addition, the discussed energies are relative Gibbs free energies, ∆Gsol(298 K), including solvent energies. The relative gas-phase Gibbs free energies ∆G(298 K), enthalpies ∆H(298 K), and ZPE-corrected electronic energies ∆E(0 K) are also provided in Figures 1 and 4 for reference. 3.1. Intimate Ion Pair [AuL]OTf-Catalyzed Process. Four possible reaction channels (1-4) are located in the intimate ionpair [AuL]+ · [OTf]--catalyzed tandem cycloaddition. The DFT(49) Gorelsky, S. I.; Lever, A. B. P. J. Organomet. Chem. 2001, 635, 187–196. (50) Gorelsky, S. I. AOMix: Program for Molecular Orbital Analysis; York University: Toronto, Canada, 1997; http://www.sf-chem.net/. (51) Gorelsky, S. I.; Ghosh, S.; Solomon, E. I. J. Am. Chem. Soc. 2006, 128, 278–290.

computed energy surface for the tandem reaction is given in Figure 1. The optimized structures of key stationary points along the reaction pathways are collected in Figure 2. These reaction pathways begin with coordination of the gold to the substrate 1. In principle, Au(I) can coordinate to either the carbonyl group or the carbon-carbon triple bond of the substrate. Coordination of the catalyst to the C-C triple bond in 1 leads to the formation of the complex Ma. This complex can then enter the subsequent catalytic cycle of the tandem reaction. Alternatively, coordination of the catalyst to the carbonyl group in 1 leads to a deadend path because it would decrease the lone pair orbital energy of carbonyl oxygen, which could make the subsequent addition reaction difficult. Ma is a polarized complex with 2.242 and 2.198 Å distances between Au and two sp-hybridized carbon atoms, respectively. The atoms of Au, OTfO, P, C(1), and C(2) in Ma are nearly coplanar. The high stabilization energy of 102.7 kcal/mol for π(C1-C2) f (6s)Au, which is obtained from the second-order perturbation analysis of donor-acceptor interactions in the NBO basis and used to estimate the strengths of the donor-acceptor interactions of the NBOs, reveals the strong interaction between π(C1-C2) and (6s)Au orbitals and the electron-transfer tendency from π(C1-C2) to (6s)Au. The increase in the ion bond distance d(Au-OTf) (from 2.078 Å in Au(PMe3)OTf to 2.477 Å in Ma) indicates the weakened ion interaction between [Au(PMe3)]+ and OTf-. Moreover, the orbital energies for π*(C1-C2)2 and [2p(LP)O1]2 are decreased by 69.0 and 9.5 kcal/mol, respectively, which leads to the decrease in the energy gap for [π*(C1-C2)]2-[2p(LP)O1]2 by 59.5 kcal/mol. Therefore, the electron transfer from the [2p-(LP)O1]2 occupied orbital to the [π*(C1-C2)]2 empty orbital


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Figure 2. DFT-optimized structures for the species in the [Au(PMe3)]OTf-catalyzed reactions of 1 (bond distances in Angstroms; hydrogen atoms in 1 and catalyst were omitted for clarity).

is easier, and the addition reaction between alkynyl-carbonyl is promoted. In channel 1, Ma captures, by a hydrogen-bond of MeO-H · · · O(OTf), a molecule MeOH to generate the complex

Ma1. This hydrogen-bond energy is 8.5 kcal/mol (in gas phase). Further, the carbonyl oxygen, as an electron donor, attacks on the activated C-C triple bond to lead to an organogold intermediate Ma2. In a carbonyl addition, the


Figure 3. Orbital interaction diagram for Ta2 which is formed by MeOH and cyclopropane fragment (the AOMix-CDA calculation, based on B3LYP/6-31G* results; the net charge donation CT(1f2)CT(2f1) is 0.3 electrons) by gold(I).

carbonyl carbon with a positive charge acts as the electrophilic site to attack the negatively charged site. For the present addition, however, the carbonyl oxygen acts as an electron donor to afford electrons to the antibonding orbital π*(C1tC2). Therefore, the attack of the carbonyl oxygen on the activated C-C triple bond is an unusual addition reaction. This reaction goes through a transition state Ta1 and overcomes only 0.4 kcal/mol of energy reaction barrier. However, Ma2 is lower than Ma1 by 15.8 kcal/mol of free energy. In the σ(O1-C1) bond formation, the distances of d(C1-C2), d(C3-C5), and d(Au-OTf) increase, d(Au-C(2) decreases, and Au shifts to C(2). In Ma2, gold is coordinated with C(2) through the σ(Au-C2) bond. The P-C(3)-C(2) angle is 177.3°, and the distance d(Au-OTf) becomes longer (3.302 Å). Moreover, the bond order indexes of C(1)-C(2), C(2)-C(3), C(3)-C(4), and C(3)-C(5) are 1.675, 1.100,1.255, and 0.628. Clearly, the interaction between C(3) and C(5) is weakened remarkably. In addition, C(3), C(4), and C(5) exhibit -0.422, +0.441, and +0.498 of atomic polar tensors (APT) charges, and the distance d(C3-C5) increases to 1.692 Å. This shows that C(3) and C(5) are most likely a configurationally stable intimate ion pair and that C(5) is an electrophilic property. As illustrated in Figure 2, the hydroxyl group of methanol lies above the plane of C5-C6-C7-H and is opposite to bridgehead carbon C(3). It suggests that the following reaction at the C5 site is apt to stereospecific addition reaction. Noticeably, the NBO orbital energy of σ*(C3-C5) in Ma2 is 94.8 kcal/mol lower than that in 1, and the 2p-(LP)O2 orbital in Ma2 is 12.9 kcal/mol higher than that in MeOH. Thus, the energy gap for σ*(C3-C5)-[2p-(LP)O2] decreases by 107.7 kcal/mol, which promotes the subsequent addition reaction. While MeOH attacks on C(5) from the opposite side of C(3), the addition reaction occurs through the transition state Ta2 (∆Gq ) 2.6 kcal/mol), which gives rise to the intermediate Ma3. In Ta2, C(5) is sp2 hybridized, C(5) and O(2) exhibit +1.008 and -0.957 of APT charges. As shown in Figure 3, the HOMO-0 (included the SN2 orbital interaction between MeOH and cyclopropyl group) for Ta2 is a mixture of 24.9% HOFO-1 (the HOMO-1 of fragment orbitals), 6.4% HOFO-3, and 4.7% HOFO-5 for MeOH · · · OTf (fragment 1) and 47.5% HOFO-5, and 5.8% HOFO-7 for the cyclopropyl fragment (fragment 2). It is clear that the stereospecific addition reaction between MeOH and cyclo-


propane occurs dominantly between HOFO-1 of fragment 1 and HOFO-5 of fragment 2. The net charge donation, which includes both charge donation and electronic polarization contributions, is 0.30 electrons. Clearly, this fact suggests that in this stereospecific addition reaction step, MeOH acts as an electrophile to donate electrons to cyclopropane. In Ma3, C(5) becomes a chiral carbon center with S configuration, and the anion OTf- captures the proton in MeOH to lead to a hydrogen bond of MeO · · · H-OTf (d(O2-H1) ) 1.530 Å, d(O2-OTf) ) 2.565 Å). In addition, the interaction between OTf- and [AuL]+ is weakened remarkably (dAu-OTf ) 3.905 Å). Ma3 isomerizes to result in the furan coordination complex Ma4 through a proton migration from trifluoromethanesulfonic acid to C(2). This process overcomes a tight transition state of Ta3 which lies above Ma3 by 8.6 kcal/ mol of energy. In Ma4, gold coordinates to the C(1)-C(2) double bond. The high stabilization energy of 74.6 kcal/mol for π(C1dC2) f (6s)Au reveals the interaction between π(C1dC2) and (6s)Au. Finally, Ma4 releases cyclohepta[b]furan 2 and regenerates the catalyst. This step is exothermic by 6.4 kcal/ mol. In the second channel (2), the carbonyl oxygen of Ma attacks on the C-C triple bond, leading to an organogold intermediate Ma5 through the transition state Ta4. This reaction is exothermic by 16.5 kcal/mol. Ta1 is higher than Ma by 1.4 kcal/mol of energy. In the σ(O1-C1) bond formation, the distance between C(3) and C(5), d(C3-C5), increases, d(Au-C(2) decreases, and Au shifts to C(1). In Ma5, Au is coordinated with C(2) through the σ(Au-C2) bond. The P-C(3)-C(2) angle is 179.4°, and the distance d(Au-OTf) becomes longer (2.881 Å). Moreover, C(3) and C(5) exhibit -0.390 and +0.382 of atomic polar tensors (APT) charges, and the distance d(C3-C5) increases to 1.687 Å. This shows that C(3) and C(5) are most likely a configurationally stable intimate ion pair, and that C(5) is of electrophilic property. Because Ma5 can form a hydrogen bond of MeO-H · · · O(OTf) with nucleophile MeOH (the hydrogen-bond energy is 5.4 kcal/ mol), Ma5 can capture a MeOH molecule, leading to the complex Ma2, and then, the subsequent reactions go through the first reaction pathway. In the third channel (3), the addition reaction occurs in Ma1 while the captured nucleophile MeOH attacks on C(5) from the opposite side of C(3), via the transition state Ta5 (∆G‡ ) 13.1 kcal/mol), leading to the allene Ma6. In Ta5, C(5) is sp2 hybridized and C(5) and O(2) exhibit +1.029 and -0.928 of APT charges, respectively. Along with the formation of σ(O2-C5), the proton of MeOH is captured by OTf- to form the trifluoromethanesulfonic acid. In Ma6, C(1) and C(3) are sp2 hybridized whereas C(2) is sp hybridized. In addition, Au combines with C(1) to form a σ bond. While the carbonyl oxygen attacks on C(1), Ma6 isomerizes into Ma3 via Ta6, which is a tight transition state with an earlier reaction barrier (∆G‡ ) 27.1 kcal/mol). Along with the ring closure, gold shifts to C(2). As mentioned in channel 1, Ma3 isomerizes to complex Ma4 that decomposes into the furan 2 and the catalyst. In channel 4, Ma6 isomerizes into Ma7 via a proton migration from trifluoromethanesulfonic acid to C(2). This process overcomes 16.0 kcal/mol of energy reaction barrier for transition state Ta7. Because C(1) in Ma7 is sp2 hybridized with +1.018 of atomic polar tensors (APT) charge, intermediate Ma7 can be regarded as a pentadienyl cation, which can undergo a Nazarov-type electrocyclic reaction to give cyclohepta[b]furan Ma8. However, no transition state is found in this reaction process. A loose scan from Ma7 to Ma8 along the σ(O1-C1)


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Figure 4. DFT-computed energy surface for the [Au(PMe3)]+-catalyzed reaction cycle with MeOH-assisted proton migration.

formation is calculated and illustrated in Figure S7, Supporting Information. Obviously, no first saddle point is found in this energy curve, and this fact implies no existence of the transition state in this reaction step. Like for Ma4, Ma8 releases the furan 2 and regenerates the catalyst. This step is exothermic by 7.3 kcal/mol of free energy. On the other hand, the coordinated catalyst of [AuL]Otf in Ma4 is cis to the methoxy group, and this catalyst in Ma7 is trans to the methoxy group. 3.2. [AuL]+-Catalyzed Process. Two possible reaction channels of 5 and 6 are located in the [AuL]+-catalyzed transformation. The DFT-computed energy suface is given in Figure 4. The optimized structures of key stationary points along the reaction pathways are collected in Figure 5. In these two pathways, the cation [AuL]+ first coordinates with the C(1)-C(2) triple bond from the carbonyl group side to form the chelate complex Mb. In Mb, the distance between C(3) and C(5), d(C3-C5), increases to 1.557 Å and C(3) and C(5) exhibit negative and positive APT charges, respectively. Compared with that in 1, the orbital energy of σ*(C3-C5) is lowered by 79.1 kcal/mol. Therefore, the orbital energy gap for σ*(C3-C5)-[2p-LP]O2 decreases by 79.1 kcal/mol. These results demonstrate that the subsequent addition reaction between cyclopropane and MeOH is promoted. The attack of oxygen in MeOH on C(5) in Mb leads to the allene complex Mb1, and the transition state for this addition reaction is Tb1, which is a tight transition state with earlier reaction barrier (∆G‡ ) 13.4 kcal/mol). In Tb1, C(5) is sp3 hybridized, and APT charges for C(5) and O(2) are +1.100 and -0.951, respectively. In Mb1, Au(I) coordinates

with C(1) through the σAu-C(1) bond and C(5) is a chiral carbon center with S configuration. In channel 5, Mb1 isomerizes to form Mb2 via migration of two protons from O(2) to O(3) and from O(3) to C(2). This reaction undergoes the transition state Tb2 with ∆G‡ ) 10.7 kcal/mol. The second MeOH acts as a proton shuttle. C(1), C(2), C(3), and C(4) in Mb2 are sp2 hybridized, and C(1) shows +0.891 of APT charge. The attack of the carbonyl oxygen (-0.564 e) in Mb2 on the positively charged carbon C(1) (+0.891 e) occurs, generating the furan coordination complex Mb3. However, no transition state is found in this ring-closed process. It is shown by a loose scan from Mb2 to Mb3 along the σ(O1-C1) formation that no first saddle point is found (Figure S8, Supporting Information). Finally, Mb3 releases furan 2 and MeOH and regenerates the catalyst. For channel 6, an isomerization reaction in Mb1, passing transition state Tb3, occurs and results in the Au-substituted furan complex Mb4. Tb3 lies above Mb1 by 24.8 kcal/mol and Mb4 below Mb1 by 23.4 kcal/mol. Further, Mb4 transforms into Mb5 via the intramolecular migration of two protons from O(2) to O(3) and from O(3) to C(2). The transition state for this intramolecular proton migration is Tb4. [AuL]+ in Mb5 is nearly vertical to the furan plane, and Au coordinates with π(C1dC2). The high stabilization energy of 117.8 kcal/mol for π(C1-C2) f 6s-(LP)*Au reveals the interaction between π(C1-C2) and (6s)Au orbitals. Finally, Mb5 decomposes into furan 2, MeOH, and the catalyst. 3.3. Stereospecific Addition Reaction. The reaction between the bicyclo[4.1.0]heptan and the methyl alcohol is a stereospecific addition reaction. The bridgehead carbon C(5)



Figure 5. DFT-optimized structures for the species in the [Au(PMe3)]+-catalyzed reactions of 1 (bond distances in Angstroms; hydrogen atoms in 1 and catalyst were omitted for clarity).

of the reaction substrate (1S,6R)-1-(phenylethynyl)bicyclo[4.1.0]heptan-2-one is a chiral carbon with R configuration. In the intimate ion-pair [AuL]+ · (OTf)--catalyzed reactions, because the gold coordinates to the triple bond from the opposite side of carbonyl and the anion trifluoromethane sulfonate forms a hydrogen bond of CF3SO3 · · · H · · · OCH3 with nucleophile MeOH, the methoxyl is controlled to lie above the plane of C5-C6-C7-H and is opposite to bridgehead carbon C(3) (see the structures of Ma2 and Ma5 in Figure 2). Therefore, in the following addition reaction, the methoxyl is apt to attacks the bridgehead carbon C(5) from opposite to carbon C(3) (see the structures of Ta2 and Ta4 in Figure 2), generating a chiral Carbond center C(5) with preserving S-configuration (see the structures of Ma3 and Ma6 in Figure 2). Similarly, in the cation [AuL]+catalyzed reactions, the nucleophile of MeOH mainly attacks on the positively charged C(5) from opposite to carbon C(3), leading to chiral carbon center of C(5) with S-configuration. As illustrated in Figure 6, in the [Au(PH3)]+-catalyzed reaction profile, the solid line and the dashed line represent

the two directions of attack on C(5), respectively, and the transition state Tb1 is 10.3 kcal/mol lower than Tb1′ in the Gibbs free energy. This fact suggests that the attack of MeOH on the chiral carbon center of C(5) from opposite to C(3) is more favorable than that from the C(3) side. Undoubtedly, the addition reaction between the nucleophile MeOH and the substrate 1 is an stereospecific reaction, the opposite attack reaction is favorable, and the product with preserving R-configuration of chiral carbon center C(5) is dominant. 3.4. Functions of Nucleophile MeOH. Nucleophile MeOH plays four roles in the gold(I)-catalyzed reactions. First, it functions as a nucleophile to attack on the bridgehead carbon C(5) of the substrate 1 leading to a stereospecific addition reaction. Second, as a proton donor, it affords hydrogen to the C(2) by proton migration (see the reaction steps of Ma3 f Ma4, Ma6 f Ma7, Mb1 f Mb2, and Mb4 f Mb5). Third, the methyl alcohol can act as a proton shuttle to help proton migration. As illustrated in Figures 4 and 5, by the hydrogen bond of MeO · · · H · · · O(H)-Me, proton migration can occur from MeOH to the 2-position carbon smoothly.


Zhang et al.

Figure 6. Reaction potential-energy suface comparison of the two SN2 attacks of the MeOH on the Mb.

Fourthly, methyl alcohol functions as the solvent in the reaction. Thus, it is not difficult to understand why no reaction was observed when Et3SiH was used in place of a nucleophile because Et3SiH cannot afford these four functions as MeOH has in this reaction. Moreover, the subsequent reactions could not be undergone if no proton-nucleophile takes part in the stereospecific addition reaction. 3.5. Functions of the Anion Otf-. The trifluoromethane sulfonate play three important roles in the reaction. Generally, ionic compounds exist as intimate ion pair in solvent. As illustrated in Scheme 2 and Figures 1 and 4, the ion-pair [AuL]+ · (OTf)--catalyzed reaction mechanism is different from the cation [AuL]+-catalyzed reaction mechanism. The largest differences are the structures and energies of the stationary points. As shown in Figures 2 and 5, because the anion of trifluoromethane sulfonate produces a steric hindrance effect, it controls the coordination direction of the gold to the triple bond from the opposite of the carbonyl (see the structure of Ma). On the contrary, in the cation [AuL]+-catalyzed reactions, the gold coordinates to the triple bond from the same side of the carbonyl. Moreover, as demonstrated, the reactivity of Ma is more favorable than that of Mb. This fact suggests that the anion of OTffunctions to effect the reactivity. Second, because the anion of OTf- can form a hydrogen bond of CF3SO3 · · · H · · · OCH3 with nucleophile MeOH, it can attract the nucleophile outside the catalysis and control the stereospecific addition attack direction. The stereospecific addition reaction between the bicyclo[4.1.0]heptan and the nucleophile MeOH was promoted by the steric help effect of the trifluoromethane sulfonate. Third, in the hydrogen-migration process, the trifluoromethane sulfonate can act as a proton shuttle to assist

the proton migration from the MeOH to the 2-position carbon. As illustrated in Scheme 1, after the addition reaction between the bicyclo[4.1.0]heptan and the methanol, the anion trifluoromethane sulfonate group catches the proton of MeOH to form the trifluoromethanesulfonic acid (see the structures of Ma1, Ma3, and Ma6). Further, the trifluoromethanesulfonic acid affords the proton to the 2-position carbon in place of the cation [AuL]+ (see the structures of Ta3 and Ta7). 3.6. Most Favorable Pathway. As shown in Figure 1, in the four intimate ion-pair [Au(PMe3)]+ · [OTf]--catalyzed channels, Ta1, Ta4, Ta6, and Ta5 are the key transition states with -5.7, 1.4, 15.3, and 7.0 kcal/mol of relative Gibbs free energies in 1, 2, 3, and 4 pathways, respectively. Obviously, channel 1 is the most favorable one. This conclusion is emphasized by the comparison of the intimate ion-pairs [Au(PPh3)]+ · [OTf]-- and [Au(PH3)]+ · [OTf]--catalyzed channels (see Figure S1 and Tables S1 and S5, Supporting Information). As illustrated in Figure 4, in the two cation [Au(PMe3)]+-catalyzed channels, Tb2 and Tb3 are the highest stationary points with 13.7 and 27.8 kcal/mol of relative Gibbs free energies in 5 and 6 pathways, respectively. Evidently, channel 5 is kinetically dominant. In the same way, in the cations [Au(PPh3)]+- or [Au(PH3)]+-catalyzed reactions (see Tables S2 and S6, Supporting Information), channel 5 is more favorable than channel 6. However, in order to evaluate the reactivity of reaction channels 1 and 5, we choose the same Gibbs free energy of 1 + [AuL]Otf + MeOH as energy reference and illustrate the reaction potential-energy sufaces (PES) of 1 and 5 channels in Figure 7. It is indicated that the PES of channel 5 is above that of channel 1. In addition, Ta1, which is the highest transition state in reaction



Scheme 2. Possible Reaction Mechanisms of the Bicyclo[4.1.0]heptan-2-one with Nucleophile MeOH Catalyzed

pathway 1, is lower than Tb1 by 18.1 kcal/mol of Gibbs free energy. In the same way, Ta1 is lower than Tb1 by 15.2 and 20.4 kcal/mol in [Au(PPh3)]OTf- and [Au(PH3)]OTf-catalyzed reactions, respectively (see Figures S3 and S4, Supporting Information). It is clear that reaction channel 1 is more favorable than channel 5 by a long way. Undoubtedly, the 1 pathway is the most dominant one in the overall reaction channels. 3.7. Effect of the Coordinated Ligand. Our calculations indicate that different coordinated ligands (PPh3, PMe3, and PH3) have little effect on the gold(I)-catalyzed reaction potential-energy surface (Tables S1-9 and Figures S1-4, Supporting Information). However, these three catalysts exhibit different catalysis. As illustrated in Figures 8 and 9, the relative free energies of Ta1 (which is the transition state with the highest relative Gibbs free energy in the reaction channel 1 pathway) are 9.0, 3.4, and 1.9 kcal/mol in [Au(PPh3)]+ · OTf--,[Au(PMe3)]+ · OTf--,and[Au(PH3)]+ · OTf-catalyzed reactions, respectively, whereas the relative Gibbs free energies of Tb1 (the highest transition state in reaction channel 5) are 24.2, 21.5, and 22.3 kcal/mol-1 in the [Au(PPh3)]+-, [Au(PMe3)]+-, and [Au(PH3)]+-catalyzed reactions, respectively. These facts suggest that the coordinated ligands (PPh3, PMe3, and PH3) have a great effect on the gold(I) catalysis, and especially in the intimate ion-pair

[AuL]+ · OTf--catalyzed mechanism, the ligand effect is heavier. On the whole, the bigger the coordinated ligand is, the poorer the catalysis is. We obtain insight into the reason from the orbital energy changes. As listed in Tables S10 and S9, Supporting Information, the orbital energies of π*(C1-C2)′ in Ma are decreased by 68.5, 69.0, and 75.3 kcal/mol in PPh3-, PMe3-, and PH3-coordinated situations, respectively, the orbital energies of π*(C1-C2)′ in Ma1 are decreased by 69.2, 69.9, and 75.9 kcal/mol, respectively, whereas the orbital energies of σ*(C3-C5) in Mb are decreased by 70.6, 74.1, and 79.1 kcal/mol in PPh3-, PMe3-, and PH3-coordinated situations, respectively. Theoretically, the lower the accepted orbital energy is, the easier the addition reaction is. Second, we found that the positively charged C(1) in Ta1 exhibits +0.921, +0.955, and +0.977 of APT charges in P(Ph)3-, P(CH3)3-, and PH3-coordinated structures, respectively. Thus, C(1) in Ta1 has the following electrophilic order: P(Ph)3 < P(CH3)3 < PH3. This phenomenon is due to the different electrophilic ability of phenyl, methyl, and hydrogen, because the three phenyl groups, three methyl groups, and three hydrogen atoms in Ta1 have -0.826, -0.475, and +0.448 of APT charges. Third, the steric prohibitive effect likely affects this reaction. As is known well, the steric prohibitive effect order is P(Ph)3 > P(CH3)3 > PH3. Consequently, for the gold(I)-catalyzed reactions of (1S,6R)-1-(phenylethynyl)-


Zhang et al.

Figure 7. Reaction energy surface comparison of 1 and 5 channels (the Gibbs free energies ∆Gsol are relative to 1 + [Au(PMe3)OTf] + 2MeOH).

Figure 8. PES of channel 1 catalyzed by the intimate ion-pair [AuL]+ · (OTf)-.

bicyclo[4.1.0]heptan-2-one with MeOH, the catalysts of [AuL]OTf (L ) PPh3, PMe3, and PH3) have the following catalysis order: PPh3 < PMe3 < PH3. 3.8. Overview of the Reaction Mechanism. As demonstrated above, in the synthesis of furan 2 from gold(I)catalyzed reactions between the bicyclo[4.1.0]heptan-2-one 1 and the nucleophile MeOH, both the intimate ion-pair [AuL]+ · OTf- and the cation [AuL]+ exhibit catalysis, and the former is remarkably favorable. The most favorable reaction pathway begins with coordination of the catalyst [AuL]OTf to the substrate 1, leading to Ma which can further capture a molecule of nucleophile MeOH, and then an addition reaction occurs between the carbonyl and the triple bond. Further, a stereospecific addition reaction of the cyclopropane with the methanol is undergone. The following

proton migration leads to a furan coordination complex, which finally releases the product 2. The addition reaction between the carbonyl and the triple bond is rate controlling for the total reaction. For this addition, the reaction is not a carbocation mechanism because of the attack of the carbonyl oxygen on the antibond orbital π*(C1tC2). Though C(4) in Ma2 and Ma5 are of carbocationic nature, the nucleophile of MeOH does not attack this site. In addition, the reaction between the cyclopropyl unit and MeOH is also not a carbocation mechanism because the carbon C(5) has only a partial positive charge. Because of the differences of the electrophilic ability of the coordinated ligands PPh3, PMe3, and PH3, the gold(I) catalysts coordinated by different ligands have different catalysis. The bigger the coordinated ligand is, the poorer the catalysis is. In the overall reaction, the proton-nucleophile (such as MeOH) is necessary. Because it plays four roles in the reactions, as a nucleophile, proton donor, proton shuttle, and solvent, it cannot be replaced by a hydride donor such as Et3SiH. With regard to the solvent effects of methyl alcohol, nearly all solvation energies of the stationary points in the intimate ion-pair [AuL]+ · [OTf]--catalyzed channels are positive, and those energies in the cation [AuL]+-catalyzed channels are negative. The absolute value of the solvation energies is likely to have a correlation with the molecular dipole moments. The lower the dipole moment is, the higher the absolute value of the solvation energy is. On the whole, the solvent effect increases the reaction energy barriers.

4. Conclusion The intimate ion-pair [AuL]+ · [OTf]- (L ) PPh3, PMe3, and PH3) and the cation [AuL]+ are catalytic for the cycloaddition reaction, and the former is dominant. The



Figure 9. PES of channel 5 catalyzed by the cation [AuL]+.

different coordinating ligand would lead to different catalysis. For the catalyst of [AuL]+ · [OTf]- (L ) PPh3, PMe3, and PH3), the bigger the coordinated ligand is, the poorer the catalysis is. The most favorable reaction channel includes activation of the triple bond of C(1)-C(2), a carbonylstriple bond addition reaction, stereospecific addition reaction of the cyclopropane with MeOH, proton migration, and regeneration of catalyst. The carbonylstriple addition reaction is rate controlling for the total reaction. In the proton migration process, the anion OTf- can act as a proton shuttle to transport a proton from proton-nucleophile to C(2). In the overall reactions, proton-nucleophile MeOH plays four roles: as a nucleophile, proton donor, proton shuttle, and solvent. Thus, it can not be replaced by a hydride donor such as Et3SiH. The essential activation is the decrease of the π*(C1-C2) orbital energy and [π*(C1-C2)]2-[2p-(LP)O1] orbital

energy gap. The solution effect is remarkable and increases the reaction energy barrier.

Acknowledgment. This work was supported by the Key Project of Science and Technology of the Ministry of Education, P. R. (grant no. 104263) and Natural Science Foundation of Chongqing City, P. R. (grant no. CSTC2004BA4024). Supporting Information Available: Computational details about the energies and detailed structures of the stationary points in the reactions. This material is available free of charge via the Internet at http://pubs.acs.org.

OM801115A

Gold(I)-Catalyzed Cycloaddition of 1-(1-Alkynyl)cyclopropyl Ketones

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