Theoretical Study on Ruthenium-Catalyzed Hydrocarbamoylative

Article pubs.acs.org/Organometallics

Theoretical Study on Ruthenium-Catalyzed Hydrocarbamoylative Cyclization of 1,6-Diyne with Dimethylformamide Yoshihiko Yamamoto*

Organometallics 2017.36:1154-1163. Downloaded from pubs.acs.org by HONG KONG UNIV SCIENCE TECHLGY on 01/02/19. For personal use only.

Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan S Supporting Information *

ABSTRACT: The reaction mechanism of ruthenium-catalyzed hydrocarbamoylative cyclization of diynes with dimethylformamide was studied by computation of model complexes using the density functional theory (DFT) method. Based on the DFT calculations, a plausible mechanism is proposed, involving oxidative coupling of a diyne catalyzed by CpRuH (Cp = η5-C5H5), C−H bond-forming reductive elimination, dimethylformamide insertion, and β-H elimination.

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INTRODUCTION Transition-metal (TM)-catalyzed hydrocarbamoylation of substituted alkynes is one of the most straightforward approaches to

Scheme 3. Mechanism Proposed for Hydrocarbamoylative Cyclization

Scheme 1. Hydrocarbamoylation of Substituted Alkynes

Scheme 2. Synthesis of Exocyclic-Diene-Type Dienamides from Enynes or Diynes

It was envisioned that the TM-catalyzed hydrocarbamoylation of two alkynes with a formamide can produce a penta-2,4dienamide derivative, a vinylogous homologue of acrylamide, although such a reaction is yet to be reported. Penta-2,4dienamide is an important structural unit found in various naturally occurring bioactive compounds.4 Moreover, dienamides have been recognized as useful building blocks in organic synthesis.5 Since atom-efficient and short-step approaches are rare, there is a great demand for the development of an effective synthetic method for dienamides.6 D’Souza and Louie reported the synthesis of exocyclic-diene-type dienamides using nickelcatalyzed cyclocoupling of α,ω-enynes with isocyanates (Scheme

substituted acrylamides. To this end, a carbonylative coupling of an alkyne with an amine has been developed (Scheme 1, path A), although the use of harmful carbon monoxide is a major disadvantage of this method.1 Thus, the direct coupling of a substituted alkyne with a formamide is ideal because hydrocarbamoylation proceeds with atom efficiency via cleavage of the formyl C−H bond (Scheme 1, path B). Such inventive acrylamide synthesis was first realized as a rhodium-catalyzed intramolecular reaction by the Takemoto group.2 Later, intermolecular versions were independently developed using nickel and palladium catalysts by the Hiyama group and the Tsuji group, respectively.3 © 2017 American Chemical Society

Received: January 11, 2017 Published: March 3, 2017 1154

DOI: 10.1021/acs.organomet.7b00026 Organometallics 2017, 36, 1154−1163

Organometallics

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2a).7 This method is quite intriguing because enyne cyclization was coupled with amide formation, involving concomitant H transfer. On the other hand, our group developed the novel ruthenium-catalyzed hydrocarbamoylative cyclization of 1,6diynes using formamides, which provides access to exocyclicdiene-type dienamides with complete stereoselectivity (Scheme 2b).8 The above ruthenium-catalyzed hydrocarbamoylative cyclization not only is the first example of TM-catalyzed hydrocarbamoylation involving two alkyne moieties but also is interesting in view of the reaction mechanism. In our previous study, a plausible mechanism (Scheme 3) was postulated based on the following facts: (1) the 1,6-diyne moiety is imperative, (2) direct cleavage of the formyl C−H bond is not involved, and (3) deuterium was incorporated at the vinylic position when the reaction was performed in the presence of D2O.8 According to the proposed mechanism, the reaction starts with the oxidative coupling of the diyne substrate with Cp*RuH species (Cp* = η5C5Me5) to produce ruthenacycle II after dimethylformamide (DMF) coordination; thus, the 1,6-diyne moiety is necessary for this reaction to initiate. The next step is the C−H bond-forming reductive elimination, which converts ruthenacycle II into dienylruthenium III. The subsequent insertion of the CO bond of DMF into the Ru−C bond regioselectively produces alkoxyruthenium IV. Finally, β-H elimination occurs from IV to generate exocyclic-diene-type dienamide V with concomitant regeneration of the Cp*RuH species. On the basis of this mechanism, the experimentally observed incorporation of deuterium from the D2O additive can be explained by the facile H−D exchange with the Cp*RuH species. Other mechanisms could also be proposed, involving oxidative coupling of one of the two alkynes of a diyne substrate with DMF (oxaruthenacycle formation) or oxidative coupling of a diyne with the Cp*Ru+ fragment (cationic ruthenacycle formation) followed by insertion of DMF. However, these pathways are inconsistent with the above-mentioned experimental observations. Therefore, the aim of this study is to suggest which pathway is the most probable one by performing density functional theory (DFT) calculations with model complexes bearing Cp ligands (Cp = η5-C5H5) instead of Cp* ligands.

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RESULTS AND DISCUSSION Oxaruthenacycle Pathway. Oxidative coupling of an alkyne with carbonyl compounds, producing an oxametallacy-

Figure 1. Oxidative coupling of diyne complex 1 leading to oxaruthenacycle 2. Relative Gibbs free energies at 298 K are given in parentheses (kcal/mol).

COMPUTATIONAL METHODS

The Gaussian 09 program package was used for all geometry optimizations.9 The geometries of the stationary points and transition states were fully optimized using Becke’s three-parameter hybrid density functional method (B3LYP),10 with a double-ζ basis set with the relativistic effective core potential of Hay and Wadt (LanL2DZ)11 for Ru and the 6-31G(d)12 basis sets for other elements. The vibrational frequencies, zero-point energy (ZPE), and thermal correction to Gibbs free energy (TCGFE) were calculated at the same level of theory. The obtained structures were characterized by the number of imaginary frequencies (one or zero for the transition or ground states, respectively). The connectivity of each step was also confirmed by intrinsic reaction coordinate (IRC)13 calculation from the transition states, followed by optimization of the resultant geometries. Single-point energies for geometries obtained by the above method were calculated at the same level of theory using a [6s5p3d2f1g] contracted-valence basis set with the Stuttgart−Dresden−Bonn energy-consistent pseudopotential (SDD)14 for Ru and the 6-311++G(d,p)15 basis sets for other elements. To examine the solvent effect, single-point energy calculations were repeated using the polarizable continuum model (PCM)16 with dielectric constants (ε) of 2.2099 for 1,4-dioxane and 37.219 for DMF. The obtained energies, TCGFEs, and imaginary frequencies are summarized in Tables S1−S7 (Supporting Information).

Figure 2. [2 + 2] cycloaddition of ruthenacycle 3 with a DMF ligand. Relative Gibbs free energies at 298 K are given in parentheses (kcal/ mol).

clopentene, has been proposed as the key step in several TMcatalyzed inter- and intramolecular coupling reactions.17 While nickel, rhodium, and iridium complexes of this type are well known, the involvement of oxaruthenacyclopentene is rare.18 1155


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Figure 4. Oxidative coupling of diyne complex 8 leading to planar ruthenacycle 9. Relative Gibbs free energies at 298 K are given in parentheses (kcal/mol).

cally unfavorable; hence, the oxaruthenacycle pathway can be rejected. Cationic Ruthenacycle Pathway. The oxidative coupling of an α,ω-diyne with the Cp′Ru+ fragment produces a cationic ruthenacyclopentatriene. Thus-formed electrophilic cyclic-biscarbene-type intermediates have been proposed as key intermediates in various catalytic transformations.19 In conjunction with such hypothetical cationic ruthenacycle intermediates, several neutral ruthenacyclopentatrienes have been isolated and characterized by X-ray crystallography.20 Therefore, the hydrocarbamoylative cyclization of 1,6-diynes can also proceed via cationic ruthenacyclopentatriene intermediates. To investigate this possibility, the insertion of the CO bond of DMF into the Ru−Cα bond of cationic ruthenacycle 3 with the O-bound DMF ligand was analyzed (Figure 2). Ruthenacycle 3 has a symmetrical and flat metallacyclopentatriene structure. Indeed, the Ru−Cα and Ru−Cα′ distances (1.991 and 1.998 Å, respectively) are similar to those of RuC double bonds, and the Cα−Cβ and Cα′−Cβ′ bonds (1.414 and 1.415 Å, respectively) are slightly longer than the Cβ−Cβ′ bond (1.389 Å). Since 3 has a cyclic biscarbenoid character, one of the RuC double bonds possibly undergoes [2 + 2] cycloaddition with the CO double bond of the DMF ligand via TS3−4. Passing from 3 to TS3−4, the Ru−Cα bond was significantly elongated (2.280 Å), and the carbonyl carbon of DMF moved closer to the carbenoid carbon as the Cα−CDMF distance decreased from 3.565 Å to 1.699 Å. In conjunction with this movement of the DMF ligand, elongation of the carbonyl double bond and decrease of the Ru− ODMF distance were observed. In addition, the Ru−Cα′ bond was slightly elongated and the difference between the Cα′−Cβ′ and Cβ−Cβ′ bond lengths became smaller, showing extensive delocalization. These characteristic geometries are very similar to those observed for product 4, indicating that TS3−4 is a late transition state. In accordance with this fact, a considerably large activation energy of ΔG⧧ = +50.1 kcal/mol was estimated; thus, the formation of 4 is largely endergonic (49.7 kcal/mol).

Figure 3. Oxidative coupling of diyne complex 5 leading to bent ruthenacycle 6 and subsequent reductive elimination leading to monocarbene complex 7. Relative Gibbs free energies at 298 K are given in parentheses (kcal/mol).

Thus, the possibility of oxidative coupling of a 1,6-diyne with DMF was investigated at the outset (Figure 1). Bis(3-phenyl-2propynyl) ether was selected as a diyne substrate because it is not only structurally simple but also experimentally proved to be an efficient diyne substrate. Diyne complex 1 with an O-bound DMF ligand has a symmetrical structure, in which the two alkyne moieties act as η2 ligands. The oxidative cyclization of one of the two alkyne moieties with the DMF ligand proceeds via TS1−2 with an activation energy of ΔG⧧ = +54.1 kcal/mol. In TS1−2, the Ru−Cβ, Ru−ODMF, and CDMF−Cα distances are significantly decreased, while the Ru−Cα, CDMF−ODMF, and Cα−Cβ distances are increased compared to the corresponding distances in 1. The formation of oxaruthenacycle 2 is endergonic by 32.1 kcal/mol. In 2, the back-donation from the Ru center to the remaining alkyne moiety becomes significant in comparison to that in 1: hence, the Ru−Cα′ and Ru−Cβ′ distances were significantly shortened (∼0.2 Å) compared to those in 1. Accordingly, the Cα′−Cβ′ distance also increased from 1.257 Å in 1 to 1.295 Å in 2. Because of the large activation barrier and endergonicity, this process is both kinetically and thermodynami1156


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metallacyclopentadienes has been well established for various transition metals,23 whereas a similar process involving metal hydride species with an intact hydride ligand is rarely proposed, to the best of our knowledge.24 As a starting point, complex 5 was selected, which consists of a CpRuH fragment and a bidentate diyne ligand. Similarly to previously calculated structures of Cp′RuCl diyne complexes,20e 5 has a highly symmetrical threelegged piano stool geometry. The oxidative coupling of 5 proceeded via TS5−6 with a low activation energy of ΔG⧧ = +5.4 kcal/mol. Thus, the transformation of 5 to 6 is kinetically feasible. However, in contrast to previously isolated ruthenacyclopentatrienes derived from Cp′RuX fragments,20 6 is a bent ruthenacyclopentadiene, as evidenced by the dihedral angles of Ru−Cα−Cβ−Cβ′ = 31.1° and Ru−Cα′−Cβ′−Cβ = −31.2°. In addition, the Ru−Cα and Ru−Cα′ bond lengths of 2.035 Å are similar to Ru−C single bonds, and the Cβ−Cβ′ bond (1.491 Å) is significantly longer than the Cα−Cβ and Cα′−Cβ′ bonds (1.358 Å). Accordingly, 6 is expected to be less stable than the corresponding ruthenacyclopentatriene, and the formation of 6 from 5 must be less exergonic (vide inf ra). Attempts to locate a transition state for the isomerization of 6 into a flat ruthenacycle failed; instead, the transition state for C−H bond-forming reductive elimination was located. This transformation occurs via TS6−7 with almost no activation energy (ΔG⧧ = +0.3 kcal/mol) to generate the ring-opening product 7 with a large exergonicity (31.7 kcal/mol from 6). Complex 7 possesses a highly delocalized unsaturated carbene structure. Indeed, the Ru−Cα′ bond is significantly shorter (1.941 Å) and the Cα′−Cβ′, Cβ− Cβ′, and Cα−Cβ bonds have similar lengths (1.413−1.436 Å). Moreover, the Ru−Cα, Ru−Cβ, and Ru−Cβ′ distances are in the range 2.215−2.265 Å, suggesting the existence of bonding interactions. Owing to this interaction, the dienyl moiety is highly distorted, as evidenced by the dihedral angles Ru−Cα′− Cβ′−Cβ = −40.5°, Cα−Cβ−Cβ′−Cα′ = −21.3°, and H−Cα− Cβ−Cβ′ = −33.6°. In the alternative route, the oxidative coupling of diyne complex 8, in which the diyne ligand coordinates backward, proceeded via TS8−9 to generate the planar ruthenacycle 9 with the ring flip of the partially formed metallacycle (Figure 4). For this process, the estimated activation energy was ΔG⧧ = +11.2 kcal/mol. The resultant ruthenacycle 9 has a highly symmetrical and flat metallacyclopentatriene structure. It is evidenced by the RuCα and RuCα′ double bonds (1.947 Å) and the Cα−Cβ and Cα′−Cβ′ bonds (1.444 Å), which are longer than the Cβ− Cβ′ bond (1.366 Å). As expected from its delocalization stability, the formation of 9 is largely exergonic (21.9 kcal/mol). Among the two oxidative cyclization pathways, the one generating bent ruthenacycle 6 is kinetically more favorable than the other leading to planar ruthenol-type complex 9. Moreover, 6 readily undergoes reductive elimination to provide the highly delocalized monocarbene complex 7, which is thermodynamically more favorable than 9. Therefore, further reaction of 7 with DMF was investigated, and the results are shown in Figure 5. A transition state for the insertion of DMF into Ru−Cα′ was located as TS10−11. The staring complex 10, which is derived from 7 and one DMF molecule, is a σ-dienyl complex with the CαCβ double bond coordinated in the η2 fashion. In comparison to 7, the diene moiety of 10 is significantly distorted: the dihedral angle Cα−Cβ−Cβ′−Cα′ is larger in 10 (−54.6°) than in 7 (−21.3°). The insertion of the CO double bond of DMF into the Ru−Cα′ bond proceeded via TS10−11 with an activation energy of ΔG⧧ = +18.3 kcal/mol. Passing from 10 to TS10−11, the Ru−Cα′ and CO bonds lengthened, while the

Figure 5. Reaction of dienyl complex 10 with DMF and subsequent β-H elimination via alkoxy ruthenium complex 12, leading to diene complex 13. Relative Gibbs free energies at 298 K are given in parentheses (kcal/ mol).

Accordingly, this process is both kinetically and thermodynamically inefficient. Ruthenacycle Hydride Pathway. Next, the hydride pathway outlined in Scheme 3 was investigated. Previously, Dixneuf and co-workers reported that cycloisomerization of ether-tethered 1,6-enynes proceeded in the presence of catalytic amounts of Cp*RuCl(cod) in AcOH or EtOH.21 They proposed that catalytically active Cp*RuH(Cl)(OAc) is generated by the oxidative addition of AcOH to Cp*RuCl. In contrast, Cp*RuCl(cod) proved ineffective for our hydrocarbamoylative cyclization: a 1,6-diyne underwent undesired cyclodimerization in a low yield, and no reaction occurred with a 1,6-enyne.8 Thus, a similar Ru(IV) hydride species is unlikely to be involved in our case. In addition, deuterium incorporation was observed when the reaction was performed in the presence of D2O. Accordingly, it was proposed that Cp*RuH is the catalytically active species, even though the detail of its formation is unclear at this stage.22 At the outset, the oxidative coupling of the same diyne substrate with a CpRuH species was evaluated, and the results are shown in Figure 3. The oxidative coupling leading to 1157


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Figure 6. Energy surfaces for conversion of 5 (+ DMF) to 13 in (a) the gas phase and (b) in DMF (blue) or dioxane (red) with relative Gibbs free energies at 298 K.

explore this possibility, the energy surface was scanned by shortening the Ru−ODMF distance (Figure S1, Supporting Information). Because ruthenacycle 6 is a coordinatively unsaturated 16e complex, it was expected that 6 can accommodate a DMF ligand. However, the approach of a DMF molecule to the ruthenium center induced the C−H reductive elimination, generating monocarbene complex 7 with a DMF molecule in close proximity (Pt4), which could be located 22.3 kcal/mol above 7 + DMF. Further shortening of the Ru− ODMF distance ultimately led to 10 with the gradual increase in the Gibbs free energy. The transition state TSPt4−10 could be located for this transformation, and the activation energy was thus estimated to be ΔG⧧ = +8.0 kcal/mol. Therefore, ruthenacycle 6 can be trapped by a DMF molecule to generate DMF-ligated 18e complex 10. Subsequently, the insertion of the DMF carbonyl into the Ru− C bond in 10 occurs with an activation energy of ΔG⧧ = +18.3 kcal/mol to produce the alkoxy complex 11, in which the exocyclic diene moiety coordinates as a η4 ligand. The formation of 11 from 10 is endergonic by 7.9 kcal/mol. The subsequent βH elimination proceeds from the monoalkene complex 12, which is slightly less stable than 11. The highest activation barrier of ΔG⧧ = +19.0 kcal/mol was predicted for β-H elimination, generating the final dienylamide complex 13, and the formation of 13 from 12 is 15.1 kcal/mol exergonic. The activation barriers for the DMF insertion step and the subsequent β-H elimination step are comparable and less than 20 kcal/mol. However, the energy gap between the highest transition state TS11−12 and the lowest intermediate 10 is 30.9 kcal/mol; therefore, heating conditions are required. The overall transformation of 5 to 13 is exergonic by 19.0 kcal/mol and, thus, is thermodynamically favorable. Furthermore, PCM calculations were performed for DMF and 1,4-dioxane, which are used as solvents for the real reactions, to investigate the influence of these solvents (Figure

Ru−ODMF and Cα′−CDMF bonds shortened, and alkoxyruthenium 11 was ultimately formed with an endergonicity of 7.9 kcal/ mol. The diene moiety of 11 behaves as a η4 ligand, as evidenced by similar Ru−Cα, Ru−Cβ, Ru−Cα′, and Ru−Cβ′ distances (2.313, 2.237, 2.284, and 2.238 Å, respectively) and the small dihedral angle (Cα−Cβ−Cβ′−Cα′ = −3.7°). Furthermore, haptotropic isomerization of the η4-diene complex 11 generated the thermodynamically less stable η2alkene complex 12, which has a distorted diene moiety (Cα− Cβ−Cβ′−Cα′ = 24.1°). The Ru−ODMF bond is significantly shorter in 12 (1.968 Å) than in 11 (2.110 Å), implying increasing interaction between the Ru center and the alkoxy oxygen atom. Complex 12 underwent subsequent β-H elimination via TS12−13 with an activation energy of ΔG⧧ = +19.0 kcal/mol. In TS12−13, the Ru−HDMF bond (1.769 Å) is significantly shorter than that in 12 (3.415 Å). In addition, the Ru−ODMF bond elongated and the CDMF−ODMF bond shortened. The formation of the hydride complex 13 from 12 is exergonic by 16.1 kcal/mol. In 13, the CpRuH fragment is bound to the α,β-unsaturated amide moiety; therefore, the distant alkene moiety has no interaction with the ruthenium center. Figure 6a outlines the overall energy profile for the ruthenacycle hydride pathway. The sequence starts with the oxidative coupling of the diyne complex 5 with a small activation energy to generate bent ruthenacycle 6 with the hydride ligand, which is then converted into monocarbene complex 7 via facile reductive elimination with almost no energy barrier. Because of a highly delocalized structure, 7 is much more stable than the other species. Thus, the highly exergonic formation of 7 can be a dead end for this process and should be avoided in the real reaction. Nevertheless, it is assumed that in the presence of excess DMF the post-reductive-elimination species would directly evolve into DMF-ligated dienylruthenium complex 10, which has slightly lower energy than 6, and the reaction can be continued. To 1158


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Figure 9. Energy surfaces for oxidative coupling and reductive elimination steps of p-methoxy (red) and p-formyl (blue) analogues with relative Gibbs free energies in DMF (PCM) at 298 K.

Figure 7. Hydroruthenation from 5 and subsequent alkyne insertion from vinylruthenium complex 15, leading to monocarbene complex 7. Relative Gibbs free energies at 298 K are given in parentheses (kcal/ mol). Figure 10. Energy surfaces for DMF insertion and β-H elimination steps of p-methoxy (red) and p-formyl (blue) analogues with relative Gibbs free energies in DMF (PCM) at 298 K.

6b). Both solvents gave similar energy profiles, although the activation barriers became larger in the insertion step than in the β-H elimination step. In the later part of the reaction, all the intermediates and transition states were of lower energy in 1,4dioxane than in DMF, showing that 1,4-dioxane is superior to DMF as the solvent. Finally, it is worth noting that in the present theoretical study, only one molecule of DMF was considered and the involvement of additional DMF molecules possibly leads to a more accurate mechanistic description. Hydroruthenation/Carboruthenation Pathway. In the relevant palladium-catalyzed hydrocarbamoylation of alkynes with formamides, hydropalladation and subsequent amide insertion followed by β-H elimination were postulated by the Tsuji group.3b Therefore, a similar hydroruthenation pathway might possibly be operative in our hydrocarbamoylative cyclization. Thus, the hydroruthenation from CpRuH diyne complex 5 was investigated, and the results are shown in Figure 7. The hydroruthenation with one of the two alkyne terminals of 5

Figure 8. Energy surfaces for the oxidative cyclization/reductive elimination steps (red) and the hydroruthenation/carboruthenation steps (blue) with relative Gibbs free energies in DMF (PCM) at 298 K.

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Figure 11. Energy surfaces for oxidative coupling and reductive elimination steps of ether (X = O, blue) and malonate (X = C(CO2Me)2, blue) analogues with relative Gibbs free energies in DMF (PCM) at 298 K.

Figure 12. Energy surfaces for DMF insertion and β-H elimination steps of ether (X = O, blue) and malonate (X = C(CO2Me)2, red) analogues with relative Gibbs free energies in DMF (PCM) at 298 K.

proceeded via TS5−14 with a low activation energy of ΔG⧧ = +4.6 kcal/mol, affording alkyne-ligated vinylruthenium complex 14 with an exergonicity (10.0 kcal/mol from 5). Thus, the transformation of 5 to 14 is both kinetically and thermodynamically feasible. In 14, the back-donation from the Ru center to the remaining alkyne moiety becomes significant, forming a ruthenacyclopropene moiety with the Ru−Cα′ and Ru−Cβ′ distances (2.034 and 2.026 Å, respectively) similar to those of Ru−C single bonds. Further computations showed that conformational change precedes the subsequent carboruthenation step: 14 evolves into 15 with slightly lower energy via the flip of the ether tether moiety. Next, the insertion of the coordinated alkyne into the resultant Ru−Cvinyl bond proceeds via TS15−7 with an activation energy of ΔG⧧ = +7.3 kcal/mol to generate the monocarbene complex 7, which is the same intermediate derived from the oxidative cyclization of 5 (Figure 3). Passing from 15 to TS15−7, the Ru−Cβ and Ru−Cβ′ bonds lengthened, while the Cβ−Cβ′ distance significantly shortened. This step is also significantly exergonic (29.8 kcal/mol from 15), owing to the highly delocalized structure of 7.

Figure 13. Structures of malonate analogues 11, 11′, TS11′−13, and 13 with selected bond distances and dihedral angles.

To compare feasibility of oxidative cyclization and hydroruthenation pathways from 5, the energy surfaces of both pathways are shown with relative Gibbs free energies in DMF (PCM) in Figure 8. The energy profiles for both the oxidative cyclization step (5 → TS5−6 → 6) and the hydroruthenation step (5 → TS5−14 → 14) are very similar, although the latter is slightly more feasible from both kinetic and thermodynamic viewpoints. However, subsequent steps are quite different: the C−H bondforming reductive elimination is very facile, as it has almost no activation barrier, while a small but unignorable activation energy of ΔG⧧ = +7.5 kcal/mol was estimated for the alkyne insertion step from 15 to 7. Therefore, it is reasonable to consider that the oxidative cyclization pathway is more feasible than the hydroruthenation/carboruthenation pathaway. Nevertheless, the latter possibility cannot be completely neglected.25 1160


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Organometallics Impact of Aryl Terminal Substituents. In our previous study,8 it was revealed that the reaction efficiency was much lower for substrates bearing p-methoxyphenyl or p-formylphenyl terminals than those bearing phenyl or p-halophenyl terminals. Thus, the effects of electron-donating methoxy and electronwithdrawing formyl substituents on the phenyl terminals were investigated. Figure 9 outlines the initial oxidative coupling and subsequent reductive elimination steps. The activation energy for oxidative coupling was slightly higher and lower for the pmethoxyphenyl and p-formylphenyl analogues, respectively, than the parent phenyl analogue, while the ruthenacycle formation becomes more exergonic for the p-formylphenyl analogue than for others. Although the activation barriers of the reductive elimination step are the same for both p-substituted analogues, the p-methoxy product is slightly more stable than the p-formyl product. Thus, it can be concluded that the early part of the catalytic sequence is kinetically more efficient for the electrondeficient p-formyl system, but thermodynamically more favorable for the electron-donating p-methoxy system. The insertion of DMF and subsequent β-H elimination steps for the p-methoxy and p-formyl analogues are shown in Figure 10. There is no electronic influence of the terminal groups on the activation barrier of the insertion step. In striking contrast, the formation of the alkoxyruthenium intermediate 11 is significantly endergonic for the p-formyl analogue. Moreover, the activation energy of the subsequent β-H elimination step was slightly higher and the final product formation is less exergonic for the p-formyl analogue. Therefore, the strong electron-withdrawing formyl group would hamper the β-H elimination stage. According to these analyses, diynes bearing aryl terminals with significant electron-withdrawing groups should not be used as substrates for ruthenium-catalyzed hydrocarbamoylative cyclization. On the other hand, the low efficiency of the diyne with p-methoxyphenyl terminals in the real catalytic reaction could not be explained based on the present DFT calculations. Impact of Tethers. In addition to aryl terminal groups, tethers connecting two alkynes have great impact on the reaction efficiency: a diyne with a malonate tether was found to be a significantly less efficient substrate than diynes with ether or tosylamide tethers.8 Because diynes bearing a tertiary carbon instead of the malonate moiety in the tethers exhibited higher reactivity, the detrimental effect can be ascribed to the sterically demanding malonate moiety. Nevertheless, there is no information on the most influential step in the proposed catalytic cycle. Therefore, model complexes bearing a malonate tether were computed. Figure 11 outlines the initial oxidative coupling and subsequent C−H bond-forming reductive elimination steps. The activation energy for oxidative coupling was slightly higher for the malonate analogue than the parent ether analogue, and the ruthenacycle formation is less exergonic for the malonate analogue. In addition, no activation barrier was found for the subsequent reductive elimination of the malonate analogue, and the formation of the ring-opening product is ca. 5 kcal/mol less exergonic for the malonate analogue than the ether analogue. Thus, the early part of the catalytic sequence is both kinetically and thermodynamically slightly less efficient for the malonate analogue compared to the ether analogue. The insertion of DMF and subsequent β-H elimination steps for the malonate and ether analogues are shown in Figure 12. The activation barrier of the insertion step is slightly higher for the malonate analogue than for the ether analogue, and the formation of the alkoxyruthenium intermediate 11 is more

endergonic for the malonate analogue. Moreover, the subsequent β-H elimination step of the malonate analogue is different from that of the ether analogue. The alkoxyruthenium η4-diene complex 11 with a malonate moiety isomerizes via the flip of the cyclopentane ring to generate slightly more stable conformer 11′, in which the steric repulsion between the Cp ligand and one of the methoxycarbonyl groups is mitigated (Figure 13). From 11′, the subsequent β-H elimination proceeds via TS11′−13 with a larger activation energy of ΔG⧧ = +26.6 kcal/mol than that for the ether analogue (ΔG⧧ = +18.9 kcal/mol). The formation of enamide complex 13 is less exergonic for the malonate analogue than for the ether analogue. In these transition state and product complexes, one of the methoxycarbonyl groups is in close proximity to the Cp ligand, rendering them energetically less favorable compared to the corresponding ether analogues. Therefore, the inefficiency of the malonate-tethered diyne substrate can be mainly ascribed to the steric repulsion between the Cp ligand and one of the ester groups in the β-H elimination step.

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CONCLUSION To sum up, the DFT calculations suggest that neither the oxaruthenacycle pathway (involving oxidative coupling of the Scheme 4. Plausible Catalytic Cycle for Hydrocarbamoylative Cyclization

one alkyne terminal of a diyne with DMF) nor the cationic ruthenacycle pathway (initiated by oxidative coupling of a diyne with CpRu+) is plausible under experimental conditions. In contrast, the ruthenacycle hydride pathway involving the oxidative coupling of a diyne with CpRuH is predicted as energetically feasible, and the subsequent C−H bond-forming reductive elimination proceeds with almost no activation barrier to afford a monocarbene intermediate. As an alternative possibility, a hydroruthenation/carboruthenation pathway is also operative for the transformation of the diyne with CpRuH into the same monocarbene intermediate, although this process is kinetically less feasible than the oxidative cyclization route. It was also suggested that subsequent DMF insertion from the monocarbene complex and the subsequent β-H elimination of the resultant alkoxo complex are rate-limiting events: both steps 1161


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Organometallics have activation barriers of ∼20 kcal/mol. The overall transformation is thermodynamically feasible because the formation of the final product from the starting diyne complex is exergonic by 19 kcal/mol. On the basis of these analyses, a plausible catalytic cycle for the hydrocarbamoylative cyclization is proposed in Scheme 4. The mechanism for the initial generation of CpRuH remains unclear, and complete elucidation of the entire mechanism requires further investigations.

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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.organomet.7b00026. Tables S1−S9 and Figures S1−2 (PDF) Cartesian coordinates of calculated molecules (XYZ)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yoshihiko Yamamoto: 0000-0001-8544-6324 Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS This research is partially supported by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Information, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science and Japan Agency for Medical Research and Development. Y.Y. is also thankful for JSPS KAKENHI Grant Number JP 16KT0051.

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REFERENCES

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Theoretical Study on Ruthenium-Catalyzed Hydrocarbamoylative

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