C–H Acidity and Arene Nucleophilicity as Orthogonal Control of

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C−H Acidity and Arene Nucleophilicity as Orthogonal Control of Chemoselectivity in Dual C−H Bond Activation Ji-Ren Liu,† Ye-Qing Duan,‡ Shuo-Qing Zhang,† Lu-Jing Zhu,† Yuan-Ye Jiang,*,‡ Siwei Bi,*,‡ and Xin Hong*,† †

Department of Chemistry, Zhejiang University, Hangzhou 310027, China School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China

‡

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S Supporting Information *

ABSTRACT: We discovered a cooperative gold/silver catalysis mechanism in the oxidative cross-coupling reaction between 1,2,4,5-tetrafluorobenzene and N-TIPS-indole, using DFT calculations. A silver(I)catalyzed CMD mechanism is responsible for the C−H activation of 1,2,4,5-tetrafluorobenzene, and C−H acidity determines the chemoselectivity. A gold(III)-catalyzed SE2Ar mechanism is responsible for the C3−H activation of N-TIPS-indole, and arene nucleophilicity determines the chemo- and regioselectivity. The orthogonal chemoselectivity control provides a mechanistic guide for dual C−H activation reactions.

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Scheme 1. Chemo- and Regioselectivities of Gold-Catalyzed Oxidative Cross-Coupling

xidative cross-coupling reaction of arenes via dual C−H bond activation provides an atom- and step-economic approach to functionalize two distinctive C−H bonds in a straightforward fashion.1 This strategy presents remarkable potential for construction of biaryl compounds, due to the low requirement of substrate prefunctionalization. Independent studies from Yu,2 Shi,3 Buchwald,4 Sanford,5 Larrosa,6 Fagnou,7 Miura,8 Zhang,9 and Su10 have realized palladium,2a,c,3−5,7,10 copper,2b,8 gold,6 and cobalt9 catalysis in this transformation and significantly extended the substrate scope. The key challenge of dual C−H bond activation is the programmed cleavages of two distinctive C−H bonds. This requires molecular-level understandings of the bond cleavage process and especially the controlling factors of reactivity and selectivity.11 Recently, Larrosa et al.6 reported a gold-catalyzed oxidative cross-coupling reaction between 1,2,4,5-tetrafluorobenzene and N-TIPS-indole (Scheme 1) with complete chemoselectivity toward cross-coupling products and C3 arylation regioselectivity of substituted indole. This transformation presents intriguing mechanistic questions because of the relatively rare gold catalysis in C−H bond activation of arenes12 as well as the origins of chemo- and regioselectivity. Using density functional theory (DFT) calculations at the M06/6-311+G(d,p)-SDD-SMD(1,4-dioxane)//B3LYP/631G(d)-LANL2DZ level of theory,13,14 we discovered a cooperative silver/gold catalysis mechanism for the dual C− H bond activation. A silver(I)-catalyzed CMD process cleaves the C−H bond of 1,2,4,5-tetrafluorobenzene, in which the C− H acidity determines the chemoselectivity. A subsequent gold(III)-catalyzed SE2Ar-process cleaves the C−H bond of NTIPS-indole, and the arene nucleophilicity controls the chemoand regioselectivity of this step. These mechanistic under© XXXX American Chemical Society

standings of the orthogonal control of dual C−H bond activation will facilitate future designs of related transformations. Based on previous mechanistic studies on silver(I)-catalyzed C−H bond activation and seminal reports of related gold catalysis,12b,f,15 we surmised that a mechanism of cooperative gold/silver catalysis can be operative for this oxidative crosscoupling reaction. A silver(I)-catalyzed C−H bond activation proceeds via a CMD-type mechanism, which cleaves the C−H bond of 1,2,4,5-tetrafluorobenzene. Subsequent transmetalation between AgIAr and AuIX leads to the arylgold(I) species. Received: February 19, 2019

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DOI: 10.1021/acs.orglett.9b00633 Org. Lett. XXXX, XXX, XXX−XXX

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Figure 1. DFT-computed free energy changes of the favorable pathway of gold/silver-catalyzed oxidative cross-coupling reaction.

This arylgold(I) intermediate AuIAr is further oxidized by PBX to the arylgold(III) intermediate X2AuIIIAr. X2AuIIIAr is able to cleave the C−H bond of N-TIPS-indole through an SE2Ar type mechanism to generate the Ar′AuIIIXAr intermediate. Subsequent aryl−aryl reductive elimination produces the biaryl product and regenerates the AuIX catalyst. The DFT-computed free energy changes of the favorable reaction pathway are shown in Figure 1, using the experimental substrates 1,2,4,5-tetrafluorobenzene 1 and N-TIPS-indole 2. From the silver pivalate dimer 5, a CMD-type C−H bond activation occurs via TS6. This step cleaves the C−H bond of 1,2,4,5-tetrafluorobenzene and generates the arylsilver species 7, which is consistent with previous studies from Larrosa,15a Hartwig,15b and Sanford.15c Alternative Ag(I)-catalyzed C−H bond activation transition states, as well as a Ag(I)−Au(I) heterodimer model, are included in the Supporting Information (Figures S1, S2). 7 then undergoes an exergonic ligand exchange with PPh3AuOPiv to form a heterodimer 9, in order to allow an intramolecular transmetalation via TS10. We also considered the direct transmetalation between 7 and 4; details of this unfavorable transmetalation pathway are included in the Supporting Information (Figures S3, S4). The transmetalation via TS10 leads to the arylgold(I) species 11, and subsequent oxidation by PBX generates the arylgold(III) intermediate 13. From 13, the SE2Ar reaction of N-TIPS-indole 2 proceeds via TS15, which cleaves the C3−H bond of N-TIPS-indole and generates intermediate 17. Alternative SE2Ar transition states are included in Figure S5. 17 undergoes an aryl−aryl reductive elimination to produce the cross-coupling product 3 and regenerates the gold catalyst 4. Based on the DFT-computed free energy profile, the rate-determining step is the silver(I)catalyzed C−H bond activation of 1,2,4,5-tetrafluorobenzene via TS6, requiring a barrier of 24.3 kcal/mol.

The oxidation of arylgold(I) species by iodine(III) reagents is experimentally confirmed by Nevado12f and Zhu.15f Larrosa6 and Nevado12f independently showed that the ArFAu(I)PPh3 species is a competent intermediate in the oxidative crosscoupling. Our calculations suggested that the oxidation of Ag(I) by an iodine(III) reagent is highly unfavorable (Scheme S1). Therefore, these experimental and computational results collectively support that the oxidation prior to transmetalation is unlikely. We next studied the chemoselectivity of silver(I)-catalyzed CMD-type C−H bond activation. The free energy changes of the competing C−H bond activations of fluorobenzene 1 and N-TIPS-indole 2 via the same silver(I) pivalate catalysis are shown in Figure 2a. The C−H bond activation of N-TIPSindole via TS19 requires a barrier of 27.0 kcal/mol, which is 2.7 kcal/mol less favorable than that of 1,2,4,5-tetrafluorobenzene via TS6. This indicates a strong chemoselectivity toward the C−H bond cleavage of 1,2,4,5-tetrafluorobenzene, which is consistent with previous experimental observations.6,15a−c,16 Distortion/interaction analysis17 reveals that the C−H acidity determines the chemoselectivity of silver(I)-catalyzed CMD-type C−H bond activation. Distortion energy ΔEdist is the energy penalty associated with the geometric change of catalyst and arene from the ground state to transition state. Interaction energy ΔEint reflects the strength of interaction between the distorted catalyst and substrate in the transition state. From the distortion/interaction analysis (Figure 2b), the distortion energy of arene ΔEdist‑arene is the controlling factor that disfavors the C−H bond activation of N-TIPS-indole via TS19. This arene distortion is mainly caused by the heterolytic dissociation of the arene C−H bond. Therefore, the C−H bond activation selectively occurs on the more acidic C−H bond of 1,2,4,5-tetrafluorobenzene. The computed pKa values B

DOI: 10.1021/acs.orglett.9b00633 Org. Lett. XXXX, XXX, XXX−XXX

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Figure 2. (a) DFT-computed free energy changes of competing silver(I)-catalyzed CMD-type C−H bond activations with 1,2,4,5tetrafluorobenzene 1 and N-TIPS-indole 2. Free energies in kcal/mol are shown in parentheses. (b) Distortion/interaction analysis of the competing transition states TS6 and TS19.

Figure 3. (a) DFT-computed free energy changes of competing gold(III)-catalyzed SE2Ar-type C−H bond activations with 1,2,4,5tetrafluorobenzene 1 and N-TIPS-indole 2. Free energies in kcal/mol are shown in parentheses. (b) Distortion/interaction analysis of the competing transition states TS15 and TS22.

also corroborate the same trend (C−H pKa in DMSO of fluorobenzene 1: 29.5; C3−H pKa in DMSO of N-TIPS-indole 2: 48.2).18 These results suggest that the pKa of the C−H bond can be a useful guide for the substrate reactivity in silver(I)catalyzed CMD-type C−H bond activation. The gold(III)-catalyzed SE2Ar-type C−H bond activation selectively occurs on the C3−H bond of N-TIPS-indole. The free energy changes of the competing C−H bond activations via the gold(III) catalysis are shown in Figure 3a. From the gold(III) intermediate 13, the C−H bond activation of NTIPS-indole is 19.2 kcal/mol more favorable than that of 1,2,4,5-tetrafluorobenzene (TS15 vs TS22, Figure 3a). Distortion/interaction analysis elucidates that the major factor that stabilizes TS15 is the interaction energy ΔEint (Figure 3b). This ΔEint-control is contrast to the ΔEdist‑arene-control in a silver(I)-catalyzed CMD-type mechanism (Figure 2b), which is the molecular basis of orthogonal chemoselectivities of dual C−H bond activation. The interaction between the electrondeficient gold(III) catalyst and arene is determined by arene nucleophilicity. The computed Swain−Scott nucleophilic reactivity parameters confirmed the differences between fluorobenzene and N-TIPS-indole (nCH3−I, 1,2,4,5‑tetrafluorobenzene = −12.76, nCH3−I, C3 of N‑TIPS‑indole = −1.77).19 Therefore, the arene nucleophilicity can serve as a useful guide for substrate reactivity in the gold(III)-catalyzed SE2Ar-type C−H bond activation. Arene nucleophilicity also controls the regioselectivity of NTIPS-indole C−H bond activation. The C3−H bond activation is 12.5 kcal/mol more favorable than the C2−H bond activation (TS15 vs TS24, Figure 4a). This is consistent with the general understanding of indole nucleophilicity (computed Swain−Scott nucleophilic reactivity parameters: nCH3−I, C2 of N‑TIPS‑indole = −4.69; nCH3−I, C3 of N‑TIPS‑indole =

Figure 4. (a) DFT-computed regioselectivity of gold(III)-catalyzed SE2Ar-type C−H bond activation of N-TIPS-indole 2. Free energies in kcal/mol are shown in parentheses. (b) Distortion/interaction analysis of the competing transition states TS15 and TS24.

−1.77).19 Our distortion/interaction analysis found that both the interaction ΔEint and arene distortion ΔEdist‑arene contribute to the strong chemoselectivity of C3−H bond activation C

DOI: 10.1021/acs.orglett.9b00633 Org. Lett. XXXX, XXX, XXX−XXX

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(Figure 4b). This suggests that the steric effects of the bulky TIPS substituent also contribute to the regioselectivity that disfavors the C2−H bond activation. Replacing the TIPS substituent with the H, SiH3, or TMS group still favors the C3−H bond activation, but with a lower degree of regioselectivity (Table S6). The electron-withdrawing CF3 and acetyl groups significantly alter the nucleophilicity of indole, leading to poor regioselectivity (Table S6). In addition, the distortion/interaction analysis can be further interpreted with the transition-state bond energy,20 which provides a consistent trend with the C−H bond activation barriers and can be used as a predictor (Table S7). In summary, we studied the mechanism and origins of selectivities of oxidative cross-coupling reaction between 1,2,4,5-tetrafluorobenzene and N-TIPS-indole with DFT calculations. The reaction proceeds via a cooperative gold/ silver catalysis mechanism. 1,2,4,5-Tetrafluorobenzene first undergoes a silver(I)-catalyzed CMD-type C−H bond activation to generate the arylsilver(I) species. Subsequent transmetalation between the arylsilver(I) and gold(I) catalyst delivers the arylgold(I) intermediate, which is further oxidized by PBX to the corresponding arylgold(III) intermediate. This arylgold(III) intermediate selectively cleaves the C3−H bond of N-TIPS-indole through an SE2Ar-type mechanism, and subsequent aryl−aryl reductive elimination produces the biaryl product and regenerates the active gold(I) catalyst. The silver(I)-catalyzed CMD mechanism and gold(III)catalyzed SE2Ar mechanism rely on distinctive controlling factors to realize the chemoselective C−H bond activation. C− H acidity determines the chemoselectivity of silver(I)catalyzed CMD-type C−H bond activation; thus, the more acidic C−H bond of 1,2,4,5-tetrafluorobenzene is cleaved. Arene nucleophilicity controls the chemo- and regioselectivity of gold(III)-catalyzed SE2Ar-type C−H bond activation, and the C−H bond activation selectively occurs on the C3 position of N-TIPS-indole. We envision that this orthogonal control of chemoselectivity in C−H bond activation should apply to additional transition metals, and further mechanistic studies are ongoing in our laboratories.

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the NSFC (21702182, 21873081 for X. H.; 21873055 for S. B.; 21702119 for Y.-Y. J.), the Chinese “Thousand Youth Talents Plan” (X. H.), “Fundamental Research Funds for the Central Universities” (X. H.), and China Postdoctoral Science Foundation (2018M640546 for S.Q. Z.) is gratefully acknowledged. Calculations were performed on the high-performance computing system at the Department of Chemistry, Zhejiang University.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00633.

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REFERENCES

Computational details, alternative reaction pathways, computational details of pKa and Swain−Scott nucleophilicity parameter, table of energies and Cartesian coordinates (PDF)

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Corresponding Authors

*E-mail: [email protected] (Y.-Y.J.). *E-mail: [email protected] (S.B.). *E-mail: [email protected] (X.H.). ORCID

Shuo-Qing Zhang: 0000-0002-7617-3042 Yuan-Ye Jiang: 0000-0002-4763-9173 Siwei Bi: 0000-0003-3969-7012 Xin Hong: 0000-0003-4717-2814 D

DOI: 10.1021/acs.orglett.9b00633 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b00633 Org. Lett. XXXX, XXX, XXX−XXX