Mechanistic Exploration of the Competition Relationship between a

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Cite This: J. Org. Chem. 2018, 83, 4545−4553

Mechanistic Exploration of the Competition Relationship between a Ketone and CC, CN, or CS Bond in the Rh(III)-Catalyzed Carbocyclization Reactions Yang-Yang Xing, Jian-Biao Liu,* Chuan-Zhi Sun, Fang Huang, and De-Zhan Chen* College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Shandong Normal University, Jinan 250014, P. R. China S Supporting Information *

ABSTRACT: The introduction of a CO, CC, CS, or CN bond has emerged as an effective strategy for carbocycle synthesis. A computational mechanistic study of Rh(III)catalyzed coupling of alkynes with enaminones, sulfoxonium ylides, or α-carbonyl-nitrones was carried out. Our results uncover the roles of dual directing groups in the three substrates and confirm that the ketone acts as the role of the directing group while the CC, CN, or CS bond serves as the cyclization site. By comparing the coordination of the ketone versus the CC, CN, or CS bond, as well as the chemoselectivity concerning the six- versus five-membered formation, a competition relationship is revealed within the dual directing groups. Furthermore, after the alkyne insertion, instead of the originally proposed direct reductive elimination mechanism, the ketone enolization is found to be essential prior to the reductive elimination. The following C(sp2)C(sp2) reductive elimination is more favorable than the C(sp3)C(sp2) formation, which can be explained by the aromaticity difference in the corresponding transition states. The substituent effect on controlling the selectivity was also discussed.

1. INTRODUCTION Transition-metal-catalyzed CH functionalization has served as a powerful tool for the construction of cyclic scaffolds, which enhances the efficiency and scope for the synthesis of diverse heterocyclic and carbocyclic compounds.1 To date, owing to the widely used N-, S-, and P-containing directing groups (DGs), the cyclic products are mainly heterocycles, in which the moiety or whole of the DGs is retained in the target frameworks.2 However, due to the competing heteroatom cyclization reaction, the synthesis of carbocyclic compounds is more challenging, which is noteworthy in view of the fact that carbocycles are carbon skeleton motifs present in various kinds of organics, pharmaceutical molecules, and natural compounds. Therefore, the development of an efficient method to synthesize carbocycles has attracted considerable attention in recent years. Utilization of a weaker coordinating moiety is usually required to promote the carbocycles formation, and the most widely applied synthetic strategy is the introduction of a ketone group that exhibits a high electrophilic reactivity.3 In the pioneering work by Glorius, a method for the comprehensive and selective preparation of diversely functionalized indenol and fulvene derivatives using ketone as a DG was achieved.3a In another key example, in 2011, Cheng et al. developed the Rh(III)-catalyzed carbocyclization of aryl ketones and alkynes (eq 1, Scheme 1).3b Similar reactions involving Rh(III) or Ru(II)-catalyzed CH functionalization by annulation with alkenes or alkynes are also reported.3 Since a ketone group acts © 2018 American Chemical Society

as both directing and cyclization sites in these reactions, only the five-membered carbocyclic ring-containing targets are obtained. Cheng et al. further reported Pd(OAc)2-catalyzed cyclization of allylarenes with alkynes, in which the weaker alkene moiety is used as a DG (eq 2).4 However, the use of an alkene group brings about several known drawbacks such as requiring a strong acidic condition. Recently, Zhu et al. proposed an enaminone-directed CH functionalization method, and a Rh(III)-catalyzed synthesis of naphthalenes via coupling of enaminones with alkynes was realized (eq 3).5 The novel reaction offers an important method for the facile synthesis of six-membered carbocycles. The obtained naphthalene derivatives contain both a nucleophilic aldehyde unit and an electrophilic hydroxyl unit in the same molecule, which makes them interesting synthons in further transformations. Similar reactions for the Cp*Rh(III)-catalyzed coupling of sulfoxonium ylides (eq 4) or α-carbonyl-nitrones (eq 5) with alkynes were reported by Li et al.6 The carbocyclization strategies in eqs 3−5 have similar catalytic cycles. Directing and cyclization sites are separated in the functional groups, and the ketone acts as the role of the directing site, while the CC, CN, or CS bond serves as the cyclization site. Because of the different electronic structures of CC, CN and CS bonds, various naphthalene derivatives were obtained in these reactions. The unit of the aldehyde is incorporated into the Received: January 31, 2018 Published: March 23, 2018 4545

DOI: 10.1021/acs.joc.8b00292 J. Org. Chem. 2018, 83, 4545−4553

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The Journal of Organic Chemistry

work. In addition, the actual sequence of the dimethyl sulfoxide or nitrone group dissociation step and migratory insertion remains unclear. Herein, we performed density functional theory (DFT) calculations on the three representative rhodium(III)-catalyzed carbocyclization reactions to understand the exact cooperative mechanism of the dual directing groups and the underlying factors resulting in the product difference in the three similar catalytic cycles.

Scheme 1. Representative Carbocyclization Reactions Employing Various DGs

2. COMPUTATIONAL METHODS Geometry optimizations and frequency calculations were performed at the B3LYP/BS1 level7 in dichloroethane (DCE) using the SMD solvation model.8 BS1 designates a mixed basis set of ECP28MDF_AVDZ for Rh9 and 6-31G(d,p) for other atoms.10 The results of frequency calculations were further examined to confirm that each structure is a local minimum (no imaginary frequency) or a transition state (only one imaginary frequency). IRC calculations were performed to verify the right connections among a transition state and its forward and reverse minima. Thermodynamic corrections at 353.15 K and 1 atm for all structures in DCE were obtained by harmonic frequency calculations at the B3LYP/BS1 level. To obtain solvation-corrected free energies, we performed single-point energy calculations at the M0611/ECP28MDF_AVDZ/6-311++G(d,p) level in DCE with SMD on the B3LYP/BS1-optimized geometries. All calculations were performed using the Gaussian 09 program package.12 Natural bond order (NBO) calculations were performed by the GenNBO 5.0 program13 using the wave function from the B3LYP/ BS1 level in DCE with the SMD model on the selected systems. The 3D structures were prepared using CYLView14 and VMD.15

3. RESULTS AND DISCUSSION As shown in Scheme 2, the three reactions have similar mechanisms, which are all initiated by the CH activation to form the five-membered rhodacyclic intermediates. Coordination of the substrate 2a to the metal center results in the πcomplexes. The insertion intermediates undergo the O-bound to C-bound tautomerization to generate the seven-membered rings, after which the reactions bifurcate onto two pathways. In

target naphthalenes (eq 3), while the dimethyl sulfoxide or nitrone group dissociates completely from the final products (eqs 4 and 5). Although plausible catalytic cycles were proposed, respectively, for the novel transformations, the detailed mechanisms especially the cooperative pathway of the directing and cyclization sites have not been explored at the outset of this

Scheme 2. Proposed Catalytic Cycle for the Rh(III)-Catalyzed Coupling of Enaminones, Sulfoxonium Ylides, or α-Carbonylnitrones with Alkynes

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similar characters. As revealed by the MO shapes, for the initial CH activation and alkyne insertion steps in the reaction, either the ketone or CC group of substrate 1a can play the role of coordinating. The NPA charges of the O and C atoms in 1a are −0.61 and −0.46, respectively, suggesting that the O atom is more nucleophilic. A similar result was observed in 1c, while the C atom in 1b becomes more electronegative compared to the O atom. For clarity, we only listed the results of CH activation and alkyne insertion steps of substrate 1a in this subsection, and the results of substrate 1b or 1c are given in Figures S2 and S3. It is noteworthy that 1a could rotate around the CC bond to generate a thermodynamically less stable rotamer 1a′ via a barrier of 12.6 kcal/mol (Figure S4). Herein, we chose the more stable substrate 1a as the starting point to compute the overall catalytic cycle. The active species [Cp*RhOAc]+ interacts first with 1a to form the O-coordinated enolate 2 or its C-coordinated isomer 2′.16 The results in Figure 2 show two competitive pathways, that is, 2 to 3 to 4 to 5 versus 2′ to 3′ to 4′ to 5′. In the black path, the CH activation of the enolate 2 proceeds via the concerted metalation−deprotonation (CMD) mechanism, with an energy barrier of 20.4 kcal/mol (TS1 relative to 2). The resulting five-membered rhodacycle 3 subsequently undergoes alkyne insertion to afford 5 via TS2, with an energy barrier of 14.5 kcal/mol (TS2 relative to 4). In the red path, 2′ undergoes CH activation via TS1′ to generate the corresponding rhodacycle 3′, and the energy barrier for this step is calculated to be 22.6 kcal/mol (TS1′ relative to 2′). The subsequent alkyne insertion proceeds via TS2′ with an energy barrier of 16.6 kcal/mol (TS2′ relative to 4′). Thus, in the black path of 2 to 5, the rate-determining step is the CH activation with a barrier of 20.4 kcal/mol, and the rate-determining step is also the CH activation with a barrier of 22.6 kcal/mol in the red path of 2′ to 5′. As a result, the black path is more favorable

one route, the release of the dimethylamino, dimethyl sulfoxide, or nitrone group occurs first; then the CC reductive elimination happens. Alternatively, the reductive elimination might occur first. In the following sections, we will discuss the processes in detail. 3.1. CH Activation and Alkyne Insertion. In addition to the dative bond between the metal center with the oxygen atom of the ketone moiety, the substrate 1a can also coordinate with rhodium through the π electrons of the CC moiety (Figure 1). The frontier MOs of substrates 1b and 1c possess

Figure 1. Highest occupied molecular orbital (HOMO) of substrates 1a and 1b and HOMO−1 of substrate 1c. Numbers in red are NPA charges.

Figure 2. Free energy profiles for CH activation and alkyne insertion of substrate 1a. Energies are relative to [Cp*RhOAc]+ and 1a and are mass balanced (similarly hereinafter). 4547


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Figure 3. Key orbital interactions in 4 and 4′.

than the red one, and the possibility of C-coordination could be ruled out at this stage. On the basis of the calculated free energy profiles of the whole catalytic cycle, CH activation is the ratedetermining step (vide infra), and this is consistent with the large experimental kinetic isotope effects (KIE) (kH/kD = 5.3). Several examples of the similar CH activation and olefin/ alkyne insertion processes have been reported in recent years.17 As shown in Figure 2, the intermediate 4 is lower in energy by 11.5 kcal/mol than 4′. To obtain further insight into the energy difference between intermediates 4 and 4′, we performed NBO analysis. It is known that the π-back-donation exists in the metal−alkyne complexes. The sum of the stabilization energies E(2) arising from the donation from πCC to Rh-5s and the πback-donation are nearly identical in intermediates 4 and 4′ (Figure 3). In 4, the interactions between the lone pair of O and the vacant Rh-5s orbital were also observed and the total stabilization energy is 37.5 kcal/mol. However, in 4′, the stabilization energy arising from the donation from πCC to Rh-5s is relatively small (27.6 kcal/mol). These results reveal that the coordination of the lone pair of electrons on the O atom to Rh brings about a more stable complex, which makes the ketone rather than the alkene group the preferred directing group. Similar results were also observed for substrates 1b and 1c (Figures S2 and S3). Alternatively, the reaction could also proceed via alkyne insertion into the RhO bond to deliver the desired complex 5. (See Figure S5 for details.) However, this path is kinetically unfavorable, with a forbidden high barrier. Additionally, the CH activation happening at the site of the alkene carbon atom adjacent to the dimethylamino group was also excluded in view of the high stationary points along this path. (See Figure S6 for details.) 3.2. Reductive Elimination. Intermediate 5 undergoes isomerization to afford a seven-membered rhodacycle 6. The ensuing reductive elimination leads to the formation of intermediate 9, an RhI species. As shown in Figure 4, the direct C(sp3)C(sp2) reductive elimination via the transition state TS3′ is found to be unfavorable. (See the red path in Figure 4.) This result differs markedly from the previous

Figure 4. Free energy profiles for the reductive elimination of 6. For the optimized structures of TS3 and TS3′, hydrogen atoms are omitted for clarity.

theoretical results, which indicates the pivotal influence of dimethylamino and diphenyl alkenyl groups of 6 on the process of reductive elimination.16 A previous theoretical study by Xu has demonstrated that ketone enolization is necessary before the reductive elimination in the Rh(III)-catalyzed cascade oxidative annulation of benzoylacetonitrile with alkynes.18 However, the underlying reason has not been deeply explored yet. As shown in Figure 4, ketone enolization converts 6 to a less stable complex 7, and the ensuing C(sp2)C(sp2) reductive elimination is relatively facile,19 with a lower free energy transition state TS3. Subsequently, complex 8 undergoes ketone enolization again to reach the intermediate 9. The transition state TS3′ is higher in free energy than TS3 by 14.7 kcal/mol. A comparison of structures of the two transition states indicates two factors may be responsible for the remarkable energy difference. First, TS3 involves a ligand π4548


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The Journal of Organic Chemistry Rh coordination, which is widely present in the π-conjugative structure of the six-membered ring.18,20 In TS3′, the lack of πsystem on the ligand makes the C(sp3)C(sp2) reductive elimination unassisted. Second, the dihedral angle ϕC1−C2−C3‑C4 in TS3′ is 50.0°, which is significantly larger than the value in TS3 (31.1°), implying a stronger distortion within the formation of a six-membered ring. Nucleus-independent chemical shifts (NICS) have been a popular method for the evaluation of magnetic aromaticity. To gain deep insights into the activation energy differences between TS3 and TS3′, the spatial magnetic properties of the two transition states have been calculated by the gaugeinvariant atomic orbitals (GIAO) perturbation method employing the NICS concept.21 The through-space NMR shieldings (TSNMRS) visualized as the iso-chemical-shielding surfaces (ICSSs) of TS3 and TS3′ are given in Figure 5. The obvious π-

oxidant AgOAc to afford [Cp*Rh]2+, which allows further occupation of anion OAc− to regenerate the catalytically active species [Cp*RhOAc]+. In the presence of H2O, the resultant intermediate 10 undergoes stepwise functionalization, including hydrolysis and deamination to generate aldehyde and hydroxyl units. (See the red path in Figure 7.) In TS5, the concerted hydrogen transfer to the oxygen atom and attack of the carbon atom occur, and the process spans an energy barrier of 17.8 kcal/mol (TS5 relative to 11). Subsequently, the HOAcassisted intramolecular hydrogen transfer occurs with a negligible barrier, releasing the byproduct HNMe2. The naphthalene derivative product contains both a nucleophilic aldehyde unit and an electrophilic hydroxyl unit in the same molecule after this stepwise functionalization. The energy profiles for the hydroxyl functionalization of 9b and 9c are shown in Figures S7 and S8. Experimentally, in the absence of H2O, the target product P1 was formed in 25% yield. Our results reveal that the HOAc molecule could also transfer its hydrogen atom to the oxygen atom of carbonyl in intermediate 10. (See the blue path in Figure 7.) This process is found to be facile, with an energy barrier of 7.8 kcal/mol (TS5′ relative to 11′). However, the following deamination with the assistance of HOAc is kinetically less favorable, with a higher energy barrier of 23.9 kcal/mol (TS6′ relative to 13′), indicating the important role of the surrounding water molecules in the hydroxyl/aldehyde functionalization process. Our theoretical results agree well with the experimental fact that water molecules can improve the product yield. Another pathway starting from rhodacycle 6, namely, hydrolysis prior to reductive elimination, was also investigated. (See Figure S9 for details.) Accordingly, there are two possible routes after the formation of hydrate 15: (i) deamination followed by C(sp3)C(sp2) reductive elimination and then βH elimination to afford [Cp*RhH]+ and (ii) direct C(sp3) C(sp2) reductive elimination, followed by deamination and β-H elimination. The results in Figure S9 reveal that both routes are kinetically less favorable, with high barriers. Therefore, the possibility of hydrolysis prior to cyclization can be ruled out. At this stage, intermediate 6b/6c could alternatively undergo elimination of the DMSO/tBuNO before the reductive elimination. (See Figure 8.) For 6b, the release of DMSO is facile, with a barrier of 12.9 kcal/mol. The following C(sp2) C(sp2) reductive elimination also easily occurs, with a low activation energy (9.2 kcal/mol). However, 6c undergoes tBuNO elimination via TS7c with an energy barrier of 29.0 kcal/mol, generating a highly unstable intermediate 15b. This step is thermodynamically unfavorable with ΔG0 = 21.8 kcal/ mol (15b relative to 6c). The differences between the results of 6b/6c are probably due to the intrinsically higher stability of the CN bond than the CS bond. 3.4. Formation of a Six-Membered Ring versus FiveMembered Ring. To understand the competition between ketone and the CC, CN, and CS bonds, we studied the free energy profiles for the formation of six-membered and fivemembered intermediates from the alkyne insertion intermediates 5, 5b, and 5c (Figure 9). The formation of six-membered rings has been discussed above. Alternatively, intermediate 5, 5b, or 5c may undergo direct C(sp2)C(sp2) reductive elimination via TS13, TS7b, or TS8c to generate the corresponding five-membered ring 20, 16b, or 16c. Comparing the two routes from 5, the formation of the six-membered ring via TS3 is 9.4 kcal/mol more accessible than the five-membered

Figure 5. TSNMRS of TS3 and TS3′ visualized as ICSSs. (Blue, red, orange, yellow, and green represent 2, 4, 8, 16, and 32 ppm shielding, respectively. White represents −1 ppm deshielding.)

electron delocalization due to the conjugation of the C1C2 C3C4C5C6 bond in TS3 strengthens the anisotropy effect. As shown in Figure 5, the six-membered ring in TS3 obviously exhibits the tendency to generate paratropic ring currents and therefore aromaticity. In contrast, the classical anisotropy of the corresponding six-membered ring in TS3′ displays deshielding. In summary, our results show that the aromaticity of TS3 is stronger than that of TS3′, which makes the C(sp2)C(sp2) bond formation more favorable. The free energy profiles for the reductive elimination of 6b and 6c are displayed in Figure 6. The CC bond formations of the two intermediates are similar to that of intermediate 6a. The ketone enolization step is again necessary prior to the direct C(sp3)C(sp2) reductive elimination. It is worth noting that, different from 6a and 6c, the reaction for 6b undergoes CS bond cleavage, simultaneously forming a new CC bond. The result indicates that the DMSO dissociation pathway is more favorable, which can be attributed to the lower BDE of the CS bond in 1b compared to that of the CC bond in 1a and CN bond in 1c. The bond strength for the three kinds of double bonds is well revealed by the calculated Wiberg bond index (WBI): 1.6, 1.4, and 1.1 for 1a, 1b, and 1c, respectively. 3.3. Hydroxyl/Aldehyde Functionalization. Upon formation of the Rh(I) complex 9, the ensuing β-H elimination occurs facilely via TS4, only crossing a barrier of 7.0 kcal/mol. The [Cp*RhH]+ released in this step reacts with the external 4549


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Figure 6. Free energy profiles for the reductive elimination of 6b and 6c. Energies are relative to [Cp*RhOAc]+ and 1b as well as [Cp*RhOPiv]+ and 1c, respectively.

Figure 7. Free energy profiles for the hydroxyl/aldehyde functionalization of 9.

formation pathway via TS13 (7 → TS3, 8.4 kcal/mol vs 5 → TS13, 17.8 kcal/mol). In complex 5b or 5c, the formation of a six-membered carbocycle is also kinetically favorable (6b → TS5b, 12.9 kcal/mol vs 5b → TS7b, 24.1 kcal/mol; 7c → TS3c, 3.9 kcal/mol vs 5c → TS8c, 12.8 kcal/mol). Therefore, the possibility for the generation of five-membered products

from 5, 5b, and 5c could be excluded. It should be noted that the five-membered product was formed in the Rh(III)-catalyzed carbocyclization of aryl ketones and alkynes (eq 1 in Scheme 1), in which the external oxidant Cu(OAc)2 helps release the Rh catalyst via transmetalation, and the resulting copper(I) fivemembered ring undergoes protonation to generate the final 4550


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The Journal of Organic Chemistry Scheme 3. Substituent Effect on Reactivity and Regioselectivity of Cyclization of Enaminones to Naphthalenes

Figure 8. Elimination of DMSO/tBuNO prior to reductive elimination in 6b/6c, with energies in kcal/mol.

product. We have also considered the possibility of 20, 16b, and 16c evolving through a ring expansion to 9, 9b, and 9c, respectively. However, all of the three paths are kinetically unfavorable, with high energy barriers. 3.5. Substituent Effect on the Reactivity and Regioselectivity of Cyclization of Enaminones. As seen in Scheme 3, the cyclization of meta-substituted enaminones could principally occur at either the para- or ortho-site. Experimental observations indicated that the methyl at the meta position of substrate 1d generated a single para-coupled product P3 with a yield of 75%, while the possible orthocoupled product P3′ was not observed. Interestingly, a mixture of para- and ortho-coupled products P4 and P4′ was obtained in the cyclization of meta-fluoro-substituted substrate 1e with a high regioisomeric ratio (P4/P4′ = 1:0.15). Figure 10 shows

Figure 10. Free energy profiles of the full catalytic cycle for the cyclization of meta-methyl-substituted and meta-fluoro-substituted enaminones.

Figure 9. Free energy profiles of the competing pathways for the formation of six-membered and five-membered rings from intermediates 5, 5b, and 5c. 4551


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5. CONCLUSIONS In the current study, we have performed a DFT mechanistic study on the Rh(III)-catalyzed coupling of alkynes with enaminones, sulfoxonium ylides, or α-carbonyl-nitrones via dual directing groups. All three reactions begin with CH activation, and the resulting cyclometalated intermediates undergo alkyne insertion to generate the seven-membered rings. It should be noted that the ketone instead of the double bond acts as the directing group in these steps. The O-bound to C-bound tautomerization is crucial prior to the subsequent reductive elimination. C(sp2)C(sp2) reductive elimination is more favorable than the originally proposed direct reductive elimination mechanism in the three reactions. For substrate 1a or 1c, C(sp2)C(sp2) reductive elimination prefers taking place before the elimination of the dimethylamino or nitrone group, whereas substrate 1b prefers undergoing the release of dimethyl sulfoxide prior to the reductive elimination. The mechanistic difference can be explained by the fact that the C C and CN bonds are more stable than the CS bond. The CH activation is the rate-determining step in all three catalytic cycles. Our computational results agree well with experimental kinetic isotope effects (KIE) study. By comparing the coordination of the ketone versus the C C, CN, or CS bond, as well as the chemoselectivity concerning the six-membered versus five-membered formation, the roles of dual directing groups in the three substrates were uncovered. The present results confirm that the ketone acts as the role of the directing group, while the CC, CN, or C S bond serves as the cyclization site. The competition relationship of the dual directing groups is expected to be useful for substrate design in the synthesis of diverse carbocycles.

the free energy profiles of the full catalytic cycle for para- and ortho-coupled with both meta-methyl- and meta-fluoro-substituted enaminones. (See Figures S10 and S11 for the complete results.) According to the energetic span model introduced by Kozuch and Shaik,22 the energetic span (δE) that serves as the apparent activation energy of catalytic cycle is defined by the energy difference between the turnoverfrequency(TOF)-determining transition state (TDTS), the TOF-determining intermediate (TDI), and the reaction driving force. For meta-methyl-substituted enaminones, the TDTSs are the reductive elimination transition states TS 3d and TS 3d′, respectively, and the TDIs are the alkyne insertion species 5d and 5d′, respectively. The apparent activation energy for paracoupled is 27.2 kcal/mol (TS 3d−5d), and the value is 30.1 kcal/mol (TS 3d′−5d′) for ortho-coupled. By comparing the energetic spans of the two free energy surfaces (ΔΔG‡ = 2.9 kcal/mol), the result was in good agreement with the experiment, in which only product P3 was formed. The final apparent activation energies for para- and ortho-coupled with meta-fluoro-substituted enaminones are 27.2 and 28.0 kcal/mol, respectively, indicating the possibility of cyclization at the ortho position. The calculated activation energy also agrees qualitatively well with the experimental value (P4/P4′ = 1:0.15). To gain deep insights into the difference between the two substituents on regioselectivity, the noncovalent interactions in TDTSs are analyzed by the reduced density gradient (RDG) method (Figure 11). In the case of the bulky methyl group, a

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00292. Additional computational results, energies, and Cartesian coordinates of all optimized structures (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jian-Biao Liu: 0000-0002-2550-3355 Fang Huang: 0000-0003-4801-7111 De-Zhan Chen: 0000-0002-2192-4582 Notes

The authors declare no competing financial interest.

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Figure 11. Noncovalent interactions of meta-methyl-substituted and meta-fluoro-substituted enaminones.

ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (NSFC No. 21375082) of China.

weaker repulsion between the phenyl ring and hydrogen atom is observed in TS 3d. The corresponding transition state TS 3d′ suffers a stronger repulsion, which accounts for the energy difference between TS 3d and TS 3d′. In contrast, the less sterically hindered fluoro group could not completely prevent the formation of the ortho-coupled regioisomer due to the nearly identical weaker repulsion existence in both TS3e and TS3e′.

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