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Theoretical Insight into the Mechansim and Origin of Ligand-Controlled Regioselectivity in Homogenous GoldCatalyzed Intramolecular Hydroarylation of Alkynes Yiying Yang, Yanhong Liu, Pingli Lv, Rongxiu Zhu, Chengbu Liu, and Dongju Zhang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03213 • Publication Date (Web): 12 Feb 2018 Downloaded from http://pubs.acs.org on February 13, 2018

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The Journal of Organic Chemistry

Theoretical Insight into the Mechansim and Origin of Ligand-Controlled Regioselectivity in Homogenous Gold-Catalyzed Intramolecular Hydroarylation of Alkynes Yiying Yang,† Yanhong Liu,† Pingli Lv,‡ Rongxiu Zhu,*,† Chengbu Liu,† and Dongju Zhang*,†

†

Key Lab of Colloid and Interface Chemistry, Ministry of Education, Institute of Theoretical Chemistry, Shandong University, Jinan 250100, P. R. China

‡

Faculty of Light Industry, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, P. R. China

Corresponding author: E-mail: [email protected] E-mail: [email protected] Tel: +86-531-88365800 Tel: +86-531-88365833 Fax: +86-531-88564464

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ABSTRACT This work aims at understanding the mechanism and regioselectivity in ligand-controlled gold-catalyzed divergent intramolecular hydroarylation of alkynes reported by Jiang et al. [J. Am. Chem. Soc. 2016, 138, 5218−5221]. Focusing on a representative alkyne, N-propargyl-N-tosyl aniline, we conducted a detailed computational study on the ortho- and para-position hydroarylation of the alkyne catalyzed by gold(I) catalysts with different ligands. Both the ortho- and para-position hydroarylation reactions are found to follow a similar three-stage mechanism: electrophilic cyclization, proton loss, and protiodeauration. The

initial

electrophilic

cyclization

was

identified

as

the

rate-

and

regiochemistry-determining step. With the flexible electron-deficient phosphite ligand, the ortho-position cyclization is identified as the energetically more favorable pathway, while with the rigid electron-abundant phosphine (Xphos) ligand, the dominant pathway turns to the para-position cyclization. The theoretical results are in good agreement with the experimental observations. The π–π interaction between alkynyl phenyl and the directing acylamino group are found to be mainly responsible for the observed ortho-selectivity, while a combination of favorable non-covalent CH···π interaction and steric repulsion between Xphos ligand and alkynyl group contributes to the observed exclusive para-selectivity. The present calculations provide deeper insight into the mechanism and origin of regioselectivity of the title reaction.

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1. INTRODUCTION 1,2-Dihydrogenquinolines are important skeletons of aromatic heterocycles that widely exist in various natural products and medicines.1,2 They also display a broad range of biological functions, such as anti-tumor, anti-viral, anti-inflammatory, and protease-inhibiting activities.3 Effectively building this kind of molecular skeletons has been the hot topic in organic synthetic chemistry. In the past few years, transition metal-catalyzed intramolecular cycloisomerization has emerged as a powerful technique for synthesis of carbo- and heterocycles.4–7 Compared with other transition metal-catalysts, gold catalysts have exhibited exceptional potential to activate C–C unsaturated bonds of alkenes, triggering a variety of intramolecular cyclizations.8,9 Gold(I)-catalyzed intramolecular hydroarylation of alkynes provides one of the most powerful transformations for the construction of fused heteroarenes owing to its mild reaction conditions and highly efficient atom economy.10–14 In recent years, the study for this type of reaction has attracted tremendous attention and made enormous progresses and achievements.15–17 However, two challenging problems still remain: (1) regioselectivity of substituted aromatics, and (2) transformation of electron-deficient aromatics. To solve these two problems, Jiang and co-workers18–21 recently reported a novel gold-catalyzed regiodivergent intramolecular hydroarylation of alkynes via combinedly utilizing the ligand effect and the directing group concept in C–H activation. Scheme 1 shows a representative example of the gold(I)-catalyzed cyclizations carried out by Jiang et al.,18 where using the flexible electron-deficient tris(2,4-di-tert-butylphenyl) phosphite ligand (L1), the alkyne prefers to cyclize at the ortho-position rather than at the para-position, to generate ortho-dihydroquinoline (Pa) in 61% isolated yield, while the rigid, bulky electron-rich Xphos ligand (L2) results in the exclusive formation of the para-position cyclization product, para-dihydroquinoline (Pb) with a high yield of 87%.

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Scheme 1. A Representative Example of Gold(I)-Catalyzed Regiodivergent Intramolecular Hydroarylation of Alkynes Reported by Jiang et al.18

Jiang and co-workers18 have proposed a potential mechanism for these Au(I)-catalyzed hydroarylation reactions, as exhibited in Scheme 2 for the representative reaction (Scheme 1). The reactions were imagined to involve two main substeps: the electrophilic cyclization and the 1,3-H transfer. The observed regiodivergent hydroarylation of alkynes was attributed to both electronic and steric properties of ligands. The flexible electron-deficient phosphite ligand (L1) would favor coordination of the directing group (methoxyl acylamino) to the gold center, which pulls the Au-coordinated π-system to the sterically hindered ortho-position of the directing group. In contrast, the rigid, bulky electron-abundant Xphos ligand (L2) could lower the electrophilicity of the gold center and push the π-system to the para-position of the directing group. However, the mechanism details remain unclear, and the origin of the regioselectivity is still not illuminated well at the molecular level. Here, we present a detailed density functional theory (DFT) study on the representative reaction shown in Scheme 1. The geometrical and energetic details would allow us to “visualize” the reaction and to deeply understand the unique regiodivergent reactivity.

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Scheme 2. Schematically Catalytic Cycle for the Representative Reaction (Scheme 1) of the Gold(I)-Catalyzed Intramolecular Hydroarylation of Alkynes, Proposed by Jiang et al.18

2. COMPUTATIONAL DETAILS To make the theoretical study more efficient, (2,4-tBu2PhO)3P ligand was simplified to (MeO)3P,22–25 and Xphos ligand was mimicked using a model compound (denoted by xphos) in which bulky cyclohexyl and isopropyl groups were replaced by CH3 and H, respectively, as done in previous studies.26 The reasonability of the model ligands has been documented in the key steps by performing benchmark calculations using real phosphite and Xphos ligands. All calculations presented in this work were performed with the Gaussian 09 software package.27 The geometries of all stationary points were optimized using the M06 hybrid functional28,29 with the double-zeta Hay and Wadt ECP basis set (LanL2DZ)30–32 augmented with a f-polarization function (ζf =1.050)33 for Au atom and the 6-31G(d,p)34 basis set for all other atoms. Vibration frequency calculations were carried out at the same level of theory to confirm the optimized structures as minima (no imaginary frequency) or transition states (only one imaginary frequency) and also to obtain the thermodynamic corrections. All transition-state structures were confirmed to connect two relevant minima by performing intrinsic reaction coordinate (IRC) calculations.35,36

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Solvent effects were treated by performing single-point self-consistent reaction field (SCRF)37–39 calculations for gas phase optimized structures with the polarizable continuum model (PCM).40–42 Dichloroethane was used as the solvent and a larger basis set 6-311+G(d,p)34 was used for the main-group elements, while the basis set for Au atom remained unchanged. Unless specifically mentioned, all the energies discussed in the main text refer to solvent-corrected relative free energies. Natural bond orbital (NBO) analyses43,44 for the selected structures were carried out at the M06/6-311+G(d,p)/LAN2DZ level using the NBO 3.1 version45 implemented in the Gaussian 09 to obtain the electronic properties. Non-covalent interactions (NCIs) analyses were performed using the Multiwfn program.46,47 All the NCI isosurfaces were rendered by VMD 1.9.3 program48 and the three-dimensional diagrams of key structures were presented using CYLview visualization softwares.49

3. RESULTS AND DISCUSSION 3.1 Reactions with (MeO)3P Ligand. The experiment carried out by Jiang et al.18 demonstrated that with the flexible electron-deficient (2,4-tBu2PhO)3P ligand, the ortho-position cyclization is much more favorable than the para-position cyclization. To clarify the ligand effects on the regioselectivity, we firstly investigated the detailed mechanism of the (MeO)3PAu(I)-catalyzed intramolecular hydroarylation of alkynes. Figure 1 illustrates our calculated pathways for the formation of both the ortho- and para-position cyclization products. The optimized geometries of key intermediates and transition states are shown in Figure 2. 1a and 1b, two initial complexes between the gold(I)-catalyst [(MeO)3PAu+] and the reactant (R), are the starting points of the ortho- and para-position cyclizations, respectively. The substantial difference of 1a and 1b lies in the dihedral angles of C3–C6–N–C7, 98.5° in 1a vs. 8.0° in 1b (Figure 2). Complex 1a is calculated to be less stable by 6.5 kcal/mol than 1b. Thus the zero energy reference point of the reaction is set as 1b, which lies 7.5 kcal/mol 6


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below the free reactant and the catalyst. It should be emphasized that 1a is identified as a general Au-η2-coordinated π-alkyne complex with the Au(I) close to the oxygen of the sulfonic group in R (Figure 2). The three-coordinated intermediate 1 proposed by Jiang et al.18 (Scheme 2) with the electrophilic gold(I) center trapped by the nitrogen atom on acylamino group was found not to be a true local minimum on the potential energy surface, and it always collapses to structure 1a upon full optimization of structural parameters. Our calculations show that the ortho- and para-position cyclization processes involve intrinsically similar mechanisms, via a three-stage sequence, including electrophilic cyclization, proton loss, and protiodeauration. In Figure 1, the left and right profiles summarize the calculated results for the ortho- and para-position cyclization processes, where intermediates and transition states involved in those processes are marked with subscripts “a” and “b”, respectively. The electrophilic cyclization stage is identified as the rate-determining step of the reaction. In this stage, the Au(I)-induced electrophilic cyclization occurs via transition state TS1a/TS1b to give the Wheland-type intermediate 2a/2b. To cross TS1a from the most stable complex 1b, the overall energy requirement that generally is referred as “the overall energy barrier”50,51 is calculated to be 19.5 kcal/mol, and this process captures an energy of 11.3 kcal/mol. In contrast, to reach TS1b, the energy barrier to be overcome is 20.9 kcal/mol, and the transformation from 1b to 2b is endothermic by 10.8 kcal/mol. The higher stability of TS1a is in agreement with the experimentally observed higher yield of ortho-position cyclization product.

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Figure 1. Calculated free energy profiles for the (MeO)3PAu-catalyzed reaction with schematic structures. The left and right pathways describe the formations of ortho- and para-position cyclization products (Pa and Pb), respectively. The selected bond lengths are given in angstroms.

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Subsequently, the proton loss stage proceeds via TS2a/TS2b with the assistance of more basic triflate (OTf−) counterion. This stage is calculated to be exergonic by 10.1/18.2 kcal/mol with a barrier of 8.6/4.4 kcal/mol for the ortho-/para-position cyclization. The final protiodeauration stage takes place via TS3a/TS3b with a barrier of 1.5/0.2 kcal/mol, and further exergonic by 18.8/19.7 kcal/mol. The proton loss-protiodeauration sequence completes the formal 1,3-H migration and gives the ortho-/para-position cyclization product, Pa/Pb. The exergonic nature of these two stages with low barriers is well consistent with the experimental observation that cleavage of the C–H bond was not the rate-determining step.18 The calculated results above show that the regioselectivity in the Au(I)-catalyzed alkyne hydroarylation reaction with the flexible electron-deficient phosphite ligand is determined in the electrophilic cyclization step. According to Curtin-Hammett principle, the regioselectivity of a reaction is controlled by the competition between the regioselectivity-determining transition states.52–54 Thus the observed regioselectivity for the reaction with (MeO)3P ligand can be rationalized by comparing the relative energies of TS1a and TS1b. The free energy difference between TS1a and TS1b is predicted to be 1.4 kcal/mol, which corresponds to formation of the ortho- and para-cyclization products about in 91:9 ratio (see Table S1 for details). The result is generally in line with the experimentally observed selectivity, 85:15 (5.6:1) for Pa/Pb.18

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Figure 2. Optimized structures of rate-determining transition states and key intermediates for the (MeO)3PAu- and xphosAu-catalyzed reactions. Bond lengths are in angstroms and dihedral angles are in degree. All of the hydrogen atoms are hidden for clarity.

3.2. Reactions with xphos Ligand. Our attention now turns to the Au(I)-catalyzed intramolecular hydroarylation of the same substrate but using the rigid electron-abundant Xphos as the catalyst ligand. Figure 3 shows the calculated free energy profiles of xphosAu-catalyzed hydroarylation along both the ortho- and para-position cyclization pathways. The optimized geometries of the key intermediates and rate-determining transition states are also shown in Figure 2, as indicated by the structures with apostrophe. The involved mechanism details are found to be similar to those using (MeO)3P ligand shown in Figure 1. The reaction involves the same three-stage sequence: electrophilic cyclization, proton loss, and protiodeauration. And again, the electrophilic cyclization is identified as the rate-determining step along both the ortho- and para-position cyclization pathways. Each intermediate and transition state shown in Figure 3 can find its corresponding counterpart in

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Figure 1 and thus is marked similarly with an added apostrophe. Similar to the situation discussed above, the most stable complex between the catalyst and the substrate, 1b′′, is identified as the starting point of the para-position cyclization pathway, and the ortho-position cyclization starts from an energetically less stable structure, 1a′′, which is also identified as a general Au-η2-coordinated π-alkyne complex, rather than the three-coordinated intermediate proposed by Jiang et al.18 (Scheme 2) with the electrophilic gold(I) center trapped by the nitrogen atom on acylamino group. With xphos ligand, the calculated free energy barrier of the rate-determining step along the ortho-position cyclization pathway is 24.2 kcal/mol, while the corresponding one along the para-position cyclization pathway is found to be 21.2 kcal/mol. Clearly, the rigid electron-abundant phosphine ligand favors the para-position cyclization. According to the free energy barrier difference (∆∆G≠ = 3.0 kcal/mol) between these two pathways, the regioselectivity of the reaction is estimated to be

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