Mechanistic Understanding of the Aryl-Dependent Ring Formations in

Jun 11, 2015 - Calculations found that the C–H activation via a CMD mechanism is the most difficult step of the reaction involving phenyl. In contra...
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Mechanistic Understanding of the Aryl-Dependent Ring Formations in Rh(III)-Catalyzed C−H Activation/Cycloaddition of Benzamides and Methylenecyclopropanes by DFT Calculations Wei Guo, Tao Zhou, and Yuanzhi Xia* College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, People’s Republic of China S Supporting Information *

ABSTRACT: The divergence between Rh(III)-catalyzed C− H activation/cycloaddition of phenyl- and 2-furanyl-containing benzamides with methylenecyclopropanes (MCP) was studied by DFT calculations. Calculations found that the C−H activation via a CMD mechanism is the most difficult step of the reaction involving phenyl. In contrast, the C−H activation of the 2-furanyl-containing substrate is kinetically easier but the formed five-membered rhodacycle is relatively unstable, making the following MCP insertion more difficult. Thus, different KIE data was obtained in experiments. The MCP insertion forms a seven-membered-ring rhodacycle intermediate, from which the chemoselectivity of the whole reaction is determined by the competitive pivalate migration (path I) and β-C elimination (path II). While the β-C elimination is lower in energy when a furanylene is contained in the intermediate, a reversed preference of pivalate migration was predicted for the phenylene counterpart. Structural analysis suggested that the unfavorable β-C elimination in the phenylene case should be attributed to the obviously increased ring strain in the corresponding transition state, instead of the difference in electronic properties between the aryl groups. This accounts for why aryl-dependent chemoselectivity was observed. In addition, the results indicated that for both paths I and II the generation of a Rh(V)−nitrenoid intermediate from pivalate migration is crucial for the final C−N bond formation. This explains why no reaction occurred when the N−OPiv moiety was replaced with an N−OMe group, as no Rh(V) intermediate could be formed in this system.

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group was introduced in recent years.7 In this approach the substrate normally contains an N−O or N−N moiety as an internal oxidant,8 which enables greener C−H functionalizations under redox-neutral conditions.9 To make use of the facilely generated rhodacycle intermediate, the reactivity of different coupling partners, such as alkene,10 alkyne,11 allene,12 isocyanate,13 and other unsaturated molecules,14 has been extensively explored. Research in this aspect has led to efficient construction of a variety of benzo-heterocyclic compounds through the Rh(III)catalyzed C−H activation/cyclization strategy. In comparison with the numerous studies on Rh(III)-catalyzed sp2 C−H activation of phenyl-based aromatic compounds, relatively limited attention has been paid to the reactions of heteroaromatic systems,15 despite the fact that such moieties are widely found in numerous molecules of pharmaceutical interests. In addition, novel reactivities may be expected due to the different electronic natures of the heteroarenes.16 Along this line, an interesting Rh(III)-catalyzed C−H activation/cycloaddition of benzamides with methylenecyclopropanes (MCPs) was recently reported by Cui et al. (Scheme 1),17 who found

INTRODUCTION Continuing efforts have been devoted to the development of transition-metal-catalyzed C−H activations in the past decade due to the need for atom- and step-economical strategies for C−C and C−heteroatom bond formations.1 Among different transition-metal catalysts, considerable attention has been paid to the catalysis by Cp*RhIII-based complexes, which are usually derived from the precursor [Cp*RhCl2]2 and are versatile catalysts for sp2 C−H activations of a variety of aromatic compounds.2 Due to the effectiveness of Cp*RhIII-catalyzed C−H activations, many novel methodologies have been developed under relatively mild conditions via formal SN-type reactions.3 To enhance the reactivity and selectivity of C−H activation reactions, one general requirement is that a directing group should be contained in the substrate.4 To this end, amide and imine derivatives are commonly employed in Cp*RhIII catalysis for efficient generation of the rhodacycle intermediate.5 As in most cases the substitution of the C−H bond is an oxidizing process, an oxidant additive is generally required to maintain the catalytic cycle. Thus, an excess amount of Cu(II) or Ag(I) salt is commonly used in typical Rh(III)-catalyzed C−H activations.6 To simplify the reaction conditions and to avoid the use of excess oxidant, a new concept of oxidizing directing © XXXX American Chemical Society

Received: April 15, 2015

A

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process leads to an exo olefin group in the Z configuration in the azepinone product D. Why the Z isomer was favored is unknown. In addition, the N substituent of the amide directing group was found to have a significant effect on the reactions, as no reaction was observed at all when the N−OPiv moiety in A was changed to a N−OMe moiety. The importance of the N− OPiv moiety in the directing group is not yet understood. In addition to the above problems, we proposed that the reductive elimination for C−N bond formations should be more complicated than that given in Scheme 2 in light of our previous mechanistic results.20 DFT study of the Rh(III)catalyzed coupling of benzamide with ethylene revealed that the reductive elimination of Rh(III) intermediate K is very difficult (Scheme 3). Instead, the intermediacy of the Rh(V)−nitrenoid

Scheme 1. Divergent Ring Formations Controlled by the Aryl Group of the Benzamide17

Scheme 3. Insights from Previous DFT Study20 that the reactions of the phenyl-containing substrate A and the 2-furanyl-containing substrate B selectively form the spiro dihydroisoquinolinones C and furan-fused azepinones D, respectively, which are widely found in biologically active natural products and pharmaceuticals.18,19 Thus, one of the most salient features of the above reactions is that the chemoselectivity of the sp2 C−H functionalization is dependent on the aryl group of the benzamide derivatives. The originally proposed mechanism accounting for the observed reactivity is depicted in Scheme 2. Accordingly, the sevenmembered rhodacycle intermediates E and H could be first generated in the reactions of A and B, respectively, from sequential steps of N−H deprotonation, C−H activation, and MCP insertion. Then, a different reactivity of these intermediates was proposed. E is expected to undergo the C−N bond formation reaction to give rise to intermediate F and will finally lead to the spiro dihydroisoquinolinone product C. On the other hand, the reaction of furanylene-containing intermediate H may undergo the β-C elimination more favorably to form the eight-membered rhodacycle I, which will eventually generate the furan-fused azepinone product D. While the above reactions possess a high potential for the facile and controllable synthesis of interesting heterocycles, several interesting mechanistic questions have still not been addressed. First of all, the exact reason for the different ring formations in the reactions of benzamides A and B is not yet understood. Second, in experiments it was found that the C−H activation may be involved in the rate-determining step for reaction of A with a primary KIE value of 2.8, while this value is only 1.1 for the reaction of B. The factors leading to these different kinetic data are unclear. Third, the β-C elimination

M was discovered via a facile pivalate migration, from which the heterocycle could be formed more easily.21 Making clear if Rh(V) species are also involved in the current systems will be useful for understanding the mechanism of C−N formation in related reactions.22 Answering the above mechanistic problems with the furanyland phenyl-involved C−H activations should have implications for the design of novel transformations. Hence, in the current report a comprehensive DFT study was carried out to investigate the mechanisms of the Rh(III)-catalyzed C−H activation/cycloaddition of benzamides and MCPs.23,24 The experimental observations by Cui et al. have been analyzed theoretically, and the origin of the aryl group-dependent chemoselectivity is disclosed.

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COMPUTATIONAL DETAILS

All calculations were carried out by using the Gaussian 09 suite of computational programs.25 All stationary points along the reaction coordinate were fully optimized at the DFT level using the M06 hybrid functional.26 The 6-31+G(d) basis set27 was applied for all atoms

Scheme 2. Proposed Mechanism Accounting for the Divergent Results

B

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Figure 1. Potential energy surface for the sequential N−H deprotonation, C−H activation, and MCP insertion steps. except Rh, which was described by the SDD basis set and effective core potential implemented (BSI).28 Frequencies were analytically computed at the same level of theory to get the thermodynamic corrections and to confirm whether the structures are minima (no imaginary frequency) or transition states (only one imaginary frequency). Intrinsic reaction coordinate (IRC) calculations29 were carried out to confirm that all transition state structures connect the proposed reactants and products. The solvation effect was examined by performing single-point self-consistent reaction field (SCRF) calculations based on the SMD solvation model for gas-phase optimized structures.30 Methanol was used as the solvent, corresponding to the original experimental conditions. Single-point energy calculations were done at the M06 level by using a larger basis set of SDD for Rh and 6-311+G(d,p) for the rest of the elements (BSII). The relative free energies corrected by solvation effects from SMDM06/BSII single point calculations are used for most of the discussion; however, the selectivity-determining steps were also studied by optimizations in MeOH solution at the SMD-M06/BSI level. These energies are given in brackets in Figure 2 and are indicated in context. No change in the conclusions was found when the relative free energies for association/dissociation processes were corrected with the literature method (see the Supporting Information for details). For a species that has more than one conformer, only that having the lowest energy value is used for discussion.

Cp*Rh(OAc)2 are compared in Figure 1. As this sequential process has been previously described for substrate A,20 here we mainly focused on the difference between A and B. Accordingly, the first formations of reactant complexes A-IN1 and B-IN1, by coordination of the amide nitrogen atoms to the Rh center, are endergonic by 3.5 and 4.2 kcal/mol, respectively. Then the N−H deprotonation is realized via TS1, in which one of the acetate anions is the proton acceptor. The A-TS1 has a relative energy of only 4.7 kcal/mol, while B-TS1 has a slightly higher value of 5.2 kcal/mol. This indicated the acidity of the N−H bonds in both A-IN1 and B-IN1 is only marginally influenced by the aryl group. The generated HOAc in intermediate IN2 is still coordinated to the Rh atom, and release of HOAc to the reaction media forms IN3 exergonically. Both A-IN3 and B-IN3 are about 4.0 kcal/mol more stable than the free catalyst and substrates. The following C−H bond activation step via TS2 is a concerted metalation−deprotonation (CMD) process, and the relative energies for the furanyl sp2 C−H activation (via B-TS2) is 17.6 kcal/mol, while that for the phenyl sp2 C−H activation (via A-TS2) is 19.0 kcal/mol. This indicates the Rh(III)-catalyzed C−H activation of 2furanyl is relatively easier than the C−H activation of phenyl, similar to the predicted reactivity of different arenes under Pd catalysis by Gorelsky et al.19c The generation of HOAc-associated intermediate IN4 is endergonic, and the five-membered rhodacycle IN5 is slightly more stable after the dissociation of HOAc. In the following step, the incorporation of MCP forms π complex IN6 endergonically, from which the migratory insertion occurs via TS3. Although the energy gap from B-IN5 to B-TS3 (17.3 kcal/mol) is almost the same as that between A-IN5 and ATS3 (17.0 kcal/mol), B-TS3 has a relative energy of 21.7 kcal/ mol, while that for A-TS3 is only 17.5 kcal/mol. This difference

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RESULTS AND DISCUSSION Sequential Steps of N−H Deprotonation, C−H Activation, and MCP Insertion. According to the mechanism of related reactions,20,22 the Rh(III) monomer Cp*Rh(OAc)2 could be easily formed from the reaction of precatalyst [Cp*RhCl2]2 with excess CsOAc additive. Thus, the Cp*Rh(OAc)2 was regarded as the real catalyst in the current study. The relative energies for the sequential steps of N−H deprotonation, C−H activation, and MCP insertion for the reactions of A and B with MCP under the catalysis of C

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the intermediacy of Rh(V) species (Scheme 3). Thus, the competition between pathways initiated by Rh(V)−nitrenoid formation via pivalate migration (path I) and exo-olefin formation via β-C elimination (path II) from IN8 was studied. As given in Figure 2, the theoretical results are consistent with the experimental observations and aryl-dependent reaction profiles were predicted from IN8. Accordingly, when phenylene is involved in A-IN8, path I initiated by pivalate group migration from N to Rh via A-TS4 requires an activation barrier of only 15.1 kcal/mol, forming Rh(V)−nitrenoid A-IN9 endergonically by 10.7 kcal/mol. This latter intermediate undergoes the reductive elimination very easily, and A-TS5 is even 0.9 kcal/mol lower in energy than A-IN9 (the activation barrier for this step is 2.3 kcal/mol in the gas phase). On the hand, path II initiated by β-C elimination via A-TS6 requires a barrier of 15.9 kcal/mol to form the eight-membered rhodacycle A-IN11. Although the following steps are relatively easy, the energy of A-TS6 is 0.8 kcal/mol higher than that of ATS4, suggesting that the β-C elimination from A-IN8 is less favorable kinetically. When the starting point is B-IN8, which contains a furanylene moiety, a reversed preference for path II was found, as B-TS6 is 2.8 kcal/mol lower in energy than BTS4. The β-C elimination via B-TS6 requires an activation barrier of 10.5 kcal/mol and forms B-IN11 exergonically as a result of a release of the ring strain, and the coordination of the carbonyl oxygen to Rh to form B-IN12 is favorable thermodynamically. Similar to the difficult reductive elimination from IN7 and IN8 (Scheme 4), the direct C−N bond from B-IN12 requires a very high barrier (>50 kcal/mol; see the Supporting Information for details). Instead, the barrier for pivalate migration via B-TS7 is only 14.6 kcal/mol, forming Rh(V)−nitrenoid B-IN13 endergonically by 2.6 kcal/mol. This latter intermediate forms the C−N bond irreversibly via B-TS8 with a barrier of 7.7 kcal/mol, and the final product will be formed by the protonation of cyclic intermediate B-IN14. Thus, one piece of information that could be obtained from the above results is that, for either path I or II, the generation of the Rh(V)−nitrenoid intermediate by pivalate migration is crucial for facile C−N bond formation. The other important information is that the chemoselectivity of the whole reaction is determined by the energy difference between TS4 and TS6, which have the highest relative energies in both paths I and II from IN8.32 The 2.6 kcal/mol energy difference between BTS6 and B-TS4 reproduces well the experimental observation; however, the 0.8 kcal/mol energy difference between A-TS4 and A- TS6 is only in qualitative agreement with the exclusive formation of the spirocycle from A. To make a more clear judgment, these selectivity-determining steps were also optimized in MeOH solution. The energy values in brackets show that the barrier for the pivalate migration via A-TS4 is 13.4 kcal/mol from A-IN8, while the β-C elimination via ATS6 is 16.0 kcal/mol (Figure 2). On the other hand, B-TS6 is 12.4 kcal/mol above B-IN8 and is 2.5 kcal/mol below B-TS4. These further validate the mechanism from standard calculations (SMD-M06/BSII//M06/BSI) and suggest that more precise predictions could be obtained when solvation effects are considered in geometry optimizations. To uncover the underlying causes of the different reactions from IN8, the geometric structures for key species from optimizations in MeOH solution are shown in Figure 3. It was proposed that the electronic nature of the aryl group may be the main reason for the observed divergence and the β-C elimination should be favored when the electron-richer

originates from the fact that B-IN5 is relatively unstable than AIN5 by about 3.9 kcal/mol, probably because the bicyclic 5−5 ring system in the former intermediate is more strained than the 6−5 ring system in the latter species. Consequently, B-TS3 is higher in energy than the CMD via B-TS2, while A-TS3 is slightly lower than A-TS2. Other regioisomeric transition states are higher in energies than TS3, as shown in the Supporting Information. Experiments showed that only MCP is a reactive coupling partner,17 and computations with other olefins found that much higher activation barriers are required for the migratory insertion step (see the Supporting Information for details). The above energetic profile, combined with the lower energy barriers of the following steps as will be presented in the following subsection, explains well why different KIE data were obtained in the reactions of A and B.31 The MCP insertion forms the seven-membered rhodacycle IN7, in which the Rh is coordinated by the π electron of the aryl group, and the isomerization of this intermediate to IN8 is slightly exergonic by coordination of the carbonyl group of the pivalate moiety to the Rh center (geometric structures are given in the Supporting Information). Divergent Ring Formations from IN8. According to the plausible mechanism, two different steps, namely C−N bond formation and β-C elimination, are possible from the sevenmembered rhodacycle IN7 or IN8 (Scheme 2). Consistent with the previous study,20 the reductive eliminations from both Rh(III) species IN7 and IN8 are very difficult (Scheme 4). The Scheme 4. Energies (in kcal/mol) for the Direct C−N Formation from IN7 and IN8

cyclization via TS4′ from IN7 requires activation barriers over 30 kcal/mol, and the barriers are much higher when the Rh atom is coordinated by carbonyl oxygen in TS4″ (from IN8), suggesting that the spiro product could not be formed directly from these intermediates. The energy of TS4′ is much lower than that of TS4″, probably because the Rh atom is coordinated with the phenyl ring in the former case (geometries are given in the Supporting Information). In addition, both processes involving Rh(III)/Rh(I) transformation are unfavorable thermodynamically, as the Rh(I) intermediates IN8′ and IN9′ are higher in energies than the corresponding Rh(III) intermediates. It is implied that the C− N bond formations in the current systems possibly occur via D

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Figure 2. Potential energy surface accounting for the aryl-dependent transformations from IN8. Values in brackets are relative free energies by optimizations in MeOH solution.

Figure 3. Geometries for key TS and intermediates from optimizations in MeOH solution (all hydrogen atoms are omitted for clarity; selected distances and angles are in Å and deg, respectively).

conjugation with the π electrons of the neighboring aryl moiety, as evidenced by the C3−C2−C4−C5 dihedral angles in A-TS6 and B-TS6, which are −59.3 and −63.9°, respectively. Instead, the calculated angles of the substituents on C4 and C5 (C2− C4−C5 and C6−C5−C4) of the arylene groups show that ATS6 is more twisted than B-TS6. In the former TS the C2− C4−C5 and C6−C5−C4 angles are 128.6 and 127.1°, respectively, a total deviation of 15.7° from the unsubstituted benzene. However, the sum of absolute deviation of C2−C4−

furanylene moiety is contained.17 However, natural population analysis indicated that the charge populations on C3 of A-TS6 (0.010e) and B-TS6 (0.012e) are almost the same (numbering of the atoms is shown in Figures 2 and 3). In addition, the key geometric parameters for the breaking C2−C3 and forming C3−Rh distances are also very close in both TSs. These suggest that the electronic nature of the aryl group should only have a marginal influence on the β-C elimination via TS6, probably because the positive charges developed on C2 are not in E

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deprotonation, C−H activation, and MCP insertion steps;20 thus, the seven-membered rhodacycle O-IN1 could be formed exergonically by 7.9 kcal/mol. Different from the reaction of IN8 containing a N−OPiv moiety, the migration of a methoxyl group from O-IN1 to form a Rh(V) intermediate was proved to be very difficult.20 Hence, the competing C−N bond formation and β-C elimination pathways were calculated. As expected, the reductive elimination of Rh(III) intermediate OIN1 via O-TS1 is unfavorable with an activation barrier of 31.6 kcal/mol, while the β-C elimination occurs more facilely via OTS2 with a lower barrier of 15.1 kcal/mol and generates O-IN3 exergonically. However, the following step for C−N bond formation via O-TS3 requires an activation barrier of 53.5 kcal/ mol, hindering the β-C elimination as a productive pathway. Thus, neither the spirocyclic compound nor the exo-olefinic compound could be generated when O was used as a substrate, as a result of the difficult reductive elimination of Rh(III) intermediates. Inspired by the Rh(III)-catalyzed olefination reactions of O,8v we wondered if β-H elimination could occur from O-IN3. Calculations showed that O-TS4 is quite favorable with a barrier of 14.3 kcal/mol to generate the Rh−hydride intermediate O-IN5 endergonically. Then the reductive elimination via O-TS5 will form the Rh(I)-complexed 1,3diene intermediate O-IN16. The energy gap between O-TS5 and O-IN3 is 27.8 kcal/mol, suggesting that such a process is not easy kinetically. In fact, this energy is 30.1 kcal/mol when solvation effects were included in optimization. The possible βH elimination from B-IN11 and B-IN12 was also evaluated, but higher barriers are required in comparison to that for B-TS7 in Figure 2 (details are given in the Supporting Information). Thus, no olefination product was observed in experiments.

C5 and C6−C5−C4 angles in the latter TS from respectively the H2−C3−C2 and H1−C2−C3 angles in unsubstituted furan (Scheme 5) is only 5.0°. Thus, the relatively more difficult β-C elimination from A-IN8 could be attributed to the unfavorable twisting of the phenylene moiety in A-TS6. Scheme 5

The above calculation results showed that the stereochemistry of the exo-olefin moiety in path II is determined by the β-C elimination step. The geometry of B-TS6 suggests that the C1−C2 double bond is almost formed and both C1 and C2 are coordinated to the Rh center, and the Z isomer is generated because the phenyl group on C1 is trans to the cyclopropyl moiety on C2. Calculations showed the energy of the TS would be 4.5 kcal/mol higher than B-TS6 if the phenyl group on C1 is cis to the cyclopropyl moiety on C2, which could be attributed to steric reasons and explains why only the Z isomer of the exo olefin was formed exclusively in the reaction of B. Predicted Reactivity for N−OMe Containing Benzamide Derivative O. Benzamide derivative O was a capable substrate for several C−H functionalization reactions, including Cp*RhIII-catalyzed olefination.8v Interestingly, the experiments by Cui et al. found that this substrate failed to result in any product when using MCP as a coupling partner. This observation can be better understood by the DFT results in Scheme 6, in which the energies for the key steps in reactions of O and MCP are included. It was believed that the N−OMe moiety should only have limited influence on the N−H Scheme 6. DFT Predictions for Substrate O

F

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CONCLUSIONS In summary, the mechanisms for divergent ring formations in Rh(III)-catalyzed C−H activation/cycloaddition of benzamides and methylenecyclopropanes were studied by DFT calculations. The results indicated that the different chemoselectivities observed in phenyl- and furanyl-containing reactions are related more to the steric strain than the electronic effect of the aryl group. After the insertion of MCP into the Rh−C(aryl) bond, the β-C elimination is more favorable both kinetically and thermodynamically than the Rh(V)−nitrenoid formation via pivalate migration when the aryl is a furanyl group, leading finally to a bicyclic product containing an exo-olefin. If the aryl is a phenyl group, however, the β-C elimination is inhibited due to the apparent steric strain in the 1,2-phenylene moiety in the TS. As a result, the pivalate migration becomes kinetically preferred to form a Rh(V)−nitrenoid intermediate, which undergoes reductive elimination easily and generates the spirocyclic product. Except for uncovering the details of the aryl-dependent ring formations, the results also provided insights into the experimentally observed KIE data by comparing the kinetics of the C−H activation and olefin insertion steps, explaining why the N−OMe-containing benzamide is not a competent substrate, and highlighted the importance of Rh(V) intermediates for efficient C−N bond formation. All theoretical results are in good agreement with and provide new insights into the intriguing experimental findings and should have implications for future design.

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ASSOCIATED CONTENT

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AUTHOR INFORMATION

S Supporting Information *

Figures, tables, and an XYZ file giving additional results and discussion, calculated energies, and all computed molecule Cartesian coordinates. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.5b00317. Corresponding Author

*E-mail for Y.X.: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21372178) and the Zhejiang Provincial Natural Science Foundation (LY13B020007) for financial support. W.G. is supported by the Graduate Innovation Foundation of Wenzhou University (3162014042). Facility support from the High Performance Computation Platform of Wenzhou University is acknowledged.

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DOI: 10.1021/acs.organomet.5b00317 Organometallics XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.organomet.5b00317 Organometallics XXXX, XXX, XXX−XXX