Effect of Propargylic Substituents on Enantioselectivity and Reactivity in Ruthenium-Catalyzed Propargylic Substitution Reactions: A DFT Study

We recently proposed a transition-state model for asymmetric propargylic substitution reactions of propargylic alcohols catalyzed by optically active thiolate-bridged diruthenium complexes [Chem. – Asian J.2021, 16, 3760−376634549529]. In the present study, we further examined the effects of propargylic substituents on both enantioselectivity and reactivity in the propargylic substitution reactions via ωB97X-D-level density functional theory (DFT) calculations. When the propargylic alcohol bears a methyl group at the propargylic position, we obtained results that contrast with the result of our previous study on propargylic alcohols without methyl groups. This result indicates that methyl group substitution at the propargylic position reverses the stereoselectivity. Substitution of a trifluoromethyl group for a methyl group was suggested to result in higher enantioselectivity. The obtained results are consistent with the experimental study on enantioselective propargylic phosphinylation reactions reported by our group.


■ INTRODUCTION
The catalytic asymmetric propargylic substitution reaction of propargylic alcohols or their derivatives is an efficient tool for constructing a stereocenter at the propargylic position. 1 Since Nishibayashi et al. reported the asymmetric propargylic alkylation reaction of propargylic alcohols with acetone in the presence of an optically active thiolate-bridged diruthenium complex (1) (Scheme 1), 2 transition metal-and organocatalyzed enantioselective propargylic substitution reactions have been gradually developed. 3−5 In our previous study, we examined the reaction of ruthenium−allenylidene complex 3a, which is generated from an optically active thiolate-bridged diruthenium complex [Cp*RuCl(SR*)] 2 (Cp* = η 5 -C 5 Me 5 , SR* = (R)-SCH(Et)-C 6 H 3 Ph 2 ) (1a) and 1-phenylprop-2-yn-1-ol (2a), with prop-1ene-2-ol, which is the enol isomer of acetone. 6 We used ωB97X-D-level DFT calculations to clarify the origin of the enantioselectivity in the reaction of 2a with acetone catalyzed by 1a or 1b (Scheme 2). By exploring a variety of transitionstate structures for the nucleophilic attack of enol on the γcarbon (C γ ) atom at the ruthenium−allenylidene complex, we revealed that the number of lower-energy structures leading to the major R-product ((R)4a) is larger than that of the structures leading to the minor S-product ((S)4a), which indicates stereoselectivity in the allenylidene moieties.
A variety of nucleophiles, such as N,N-dimethylaniline, furan, indole, 1,5-enyne, and 2-naphthol, were experimentally applied for the enantioselective propargylic substitution reactions catalyzed by 1a or 1b, and the reactions of 2a provided the major products that were obtained by the attack of the nucleophiles from the same direction of the allenylidene ligand (A-face attack in Scheme 3). 1 However, our group recently reported the diruthenium-catalyzed reaction between phosphine oxide and propargylic alcohol bearing a trifluoromethyl group at the propargylic position (2c) (Scheme 4) 7 and found the major product obtained by the attack of the nucleophile from the different direction (B-face attack in Scheme 3).
Thus, the effects of propargylic substituents on the stereoselectivity and reactivity of propargylic substitution reactions catalyzed by the diruthenium complex 1a are next target of our studies. Based on findings obtained in our previous DFT studies, 6,8 we, in the present study, examine model propargylic substitution reactions of propargylic alcohols 2b and 2c (R′ = Me and CF 3 , respectively, in Scheme 2) catalyzed by diruthenium complex 1a.

■ RESULTS AND DISCUSSION
Complexes. The ruthenium−allenylidene complex plays an important role as the key intermediate in the dirutheniumcatalyzed propargylic substitution reactions. 9,10 For 3a, six equilibrium structures with weak intramolecular interactions between the terminal phenyl group in the thiolate ligand and the phenyl group in the allenylidene ligand, I x (x = a−f), were observed in our previous calculations, and the difference in free energy between these structures was relatively small ( Figure  1). 6 For 3b, six structures I Mx (x = a−f) were identified, as was true of 3a (Figures 1 and S1). Structure I Ma , which has an intramolecular CH/π interaction between the meta-C−H bond of the terminal phenyl group of the thiolate ligand and the phenyl group of the allenylidene, corresponds to structure I a observed via X-ray crystallography for 3a ( Figure S2 shows the noncovalent interaction (NCI) plot 11 ). The distance between the hydrogen atom of the terminal phenyl group of the thiolate ligand and the phenyl ring of the allenylidene is 2.75 Å, which is slightly shorter than that in I a , 2.80 Å ( Figure S1). The structure I Mb has a π−π interaction between the terminal phenyl group of the thiolate ligand and the phenyl group of the allenylidene ligand instead of a CH/π interaction. The distance between two phenyl rings is 3.82 Å, which is also shorter than that of I b , 3.84 Å. These results indicate that the electrondonating methyl group enhances CH/π and π−π interactions. 12 I Mb is slightly lower in free energy than I Ma by 1.2 kcal/ mol, showing almost the same energy difference as those in 3a (I b is lower than I a by 1.5 kcal/mol; Figure 1). In the I Mc structure, which corresponds to I c , the methyl group moves away from the terminal phenyl group of the thiolate ligand, while the C γ −H bond in allenylidene interacts with the terminal phenyl group of the thiolate ligand in I c . Thus, the Scheme 2. Examined Reaction Pathway of Ruthenium−Allenylidene Complex 3, Which Is Generated from 1a and Propargyl Alcohol 2, with Prop-1-ene-2-ol Scheme 3. Definition of the Faces at the C γ Position of the Allenylidene Ligand in the Present Study 1 1 energy of I Mc relative to I Mb , 3.2 kcal/mol, is higher than that of I c relative to I b , 2.1 kcal/mol. In the I Md , I Me , and I Mf structures, meanwhile, the allenylidene moiety is rotated, and the ortho-C−H bond in the phenyl group of the allenylidene interacts with the chloride ligand, which coordinates to the ruthenium atom different from the atom attached to the allenylidene ligand. The energies of I Md and I Mf relative to I Mb are 1.4 and 3.4 kcal/mol, respectively, which are slightly higher than the relative energies of 3a (0.5 and 1.5 kcal/mol), while I Me has almost the same relative energy as I Mb (0.2 kcal/mol). The CH/π interactions between one of the methyl C−H bonds in the allenylidene ligand and the terminal phenyl group in the thiolate ligand and the interactions between the ortho-C−H bond of the phenyl group in the allenylidene and the chloride ligand were observed in I Me ( Figure S2 for the NCI plot; the distance between the hydrogen atom and the terminal phenyl group in the thiolate ligand is 2.55 Å). 13 For 3c, seven equilibrium structures I Fx were obtained because two structures corresponding to the structure I Mb , I Fb and I Fb′ , were identified (Figures 1 and S1). 14 Among the seven structures, I Fd and I Fe were found to have lower energies (the energies relative to I Fb are −0.7 and −1.3 kcal/mol, respectively). These structures, in which the trifluoromethyl group is directed to the other side of the chloride ligand, avoid  the repulsive interactions between the fluoride atoms in the trifluoromethyl group and the chloride ligand. In addition, the interactions of the fluoride atom with not only the hydrogen atoms of a pentamethylcyclopentadienyl ligand but also the hydrogen of the ethyl group in the other thiolate ligand were observed ( Figure S2). The NCI plot also indicates the CF/π interaction 15 between a C−F bond and the terminal phenyl group of the thiolate ligand in I Fe . Thus, a trifluoromethyl group undergoes dispersion interactions with the C−H bond and phenyl group in the surrounding ligands.
These results show that methyl or trifluoromethyl substitution certainly affects the structures of ruthenium− allenylidene complexes, but the effects are relatively small from a free energy point of view. The energy differences between the obtained equilibrium structures are within 3.4 and 2.1 kcal/ mol for 3b (I Ma −I Mf ) and 3c (I Fa −I Ff ), respectively (2.1 kcal/ mol for 3a). Thus, further examinations of the transition-state structures for the attack of nucleophiles are required to clarify the enantioselectivity in the catalytic substitution reaction.
Transition-State Structures. In our previous study, 6 we explored 56 transition-state structures for the attacks of the enol isomer on 3a and found that the nucleophile attacks from the direction of the chloride ligand to either the A-face (Siface) or the B-face (Re-face) of the allenylidene moiety. In the A-face attack, two conformations of the terminal phenyl group in the thiolate ligand are possible, while only one conformation leads to the B-face attack. We concluded that the difference leads to the preferential formation of the R-product ((R)4a) over the S-product ((S)4a) in terms of probability distributions (enantiomeric excess was calculated to be 27% ee).
As in the case with 3a, we investigated 56 transition-state structures for attacks of enol to 3b (TS MAnyz and TS MBnyz , in which enol attacks from A-and B-faces, respectively (n = 1−7; y, z = d or u (showing the direction of the ethyl group in thiolate ligands)); Figures S4−S7). Among the calculated transition-state structures, TS MB5dd , which corresponds to the B-face attack, has the lowest Gibbs free energy at 333 K ( Figure 2). The other transition states corresponding to the Bface attack, TS MB3dd and TS MB4dd , have almost the same free energies (the free energies relative to TS MB5dd , ΔΔG 333 K , are 0.2 and 0.5 kcal/mol, respectively.) In contrast, the energies of the transition states where enol attacks from the A-face, TS MA2dd and TS MA4dd , are slightly higher in free energies than TS MB5dd (ΔΔG 333 K are 3.1 and 2.8 kcal/mol, respectively), although TS MA3dd has almost the same free energy (ΔΔG 333 K = 0.1 kcal/mol).
The obtained results indicate that the effect of the methyl group in the transition-state structures for the A-face attack is different from that in the structures for the B-face attack. In the transition states for the A-face attack, the methyl group of the allenylidene ligand faces the terminal phenyl group of the thiolate ligand. The structures with conformation H at the terminal phenyl group of the thiolate ligand (Figure 2), TS MA2dd and TS MA4dd , are sterically more inconvenient than the structures with conformation V, TS MA3dd and TS MA5dd , which increases their relative free energies. In contrast, the steric repulsions caused by the methyl group are relatively smaller in the transition states for the B-face attack because the methyl group is directed in the opposite direction of the terminal phenyl group of the thiolate ligand. Moreover, the dispersion interactions between the phenyl group in the allenylidene and the terminal phenyl group of the thiolate ligand increase slightly upon the introduction of the methyl group. Thus, the methyl moiety located away from the terminal phenyl group of the thiolate ligand lowers the relative energies of these structures compared with those in the transition states corresponding to the A-face attack (Table 1).
Among the transition-state structures with lower free energies, the structures that provide the S-product ((S)4b) through the B-face attack (TS MB5dd , TS MB3dd , and TS MB4dd ) are larger in number than those providing the R-product ((R)4b) through the A-face attack (TS MA3dd ). Thus, (S)4b is preferentially formed over (R)4b based on the probability distributions (Table 1), and the enantiomeric excess is estimated to be 40% ee. This result is in contrast with our previous results that the number of lower-energy structures leading to the R-product ((R)4a) is larger than that of the structures leading to the S-product ((S)4a) in the case of the reaction of 3a. This result suggests that the substitution of a methyl group for a propargylic hydrogen atom in propargylic alcohol makes the stereoselectivity inverse.
We further calculated transition-state structures for the attack of enol to 3c (TS FAnyz for structures giving the S-product through the A-face attack and TS MBnyz for structures giving the R-product through the B-face attack; Figures S4, S8, S9, and S10). Among the structures, TS FB4dd has the lowest free energy, and the structure having the second lowest energy, TS FB3dd , is higher in energy than TS FB4dd by 2.0 kcal/mol (Table 1). Compared to the corresponding transition states TS B4dd 16 and TS MB4dd , the location of enol in TS FB4dd slips slightly from the direction of the chloride ligand to that of the other terminal phenyl group in the thiolate ligand, and the fluoride atom at the trifluoromethyl group interacts with the C(sp 2 )−H bond of the terminal phenyl group in the thiolate  Figure 3a). The other fluoride atom also interacts with not only the hydrogen atom of the ethyl group at the other thiolate ligand (the distance between the hydrogen atom and the fluoride atom is 2.56 Å) but also the hydrogen atoms of the pentamethylcyclopentadienyl ligand (the distance between the hydrogen atoms and the fluoride atom is 2.75 and 2.79 Å. These interactions and the π−π interactions lower the free energy of the transition state compared to those of other structures (Figure 3b for NCI plot). As a result, the B-face attack leading to the R-product ((R)4c) is favorable compared to the A-face attack leading to the S-product ((S)4c), as is the case for the attack of enol on 3b, and the enantiomeric excess was estimated to increase (97% ee). This result indicates that replacing the methyl group at the propargylic position with a trifluoromethyl group leads to a higher enantioselectivity. This result is consistent with the recent experimental results of asymmetric propargylic phosphinylation reactions between propargylic alcohol bearing a trifluoromethyl group at the propargylic position and diphenylphosphine oxide catalyzed by 1a or 1b, where phosphorous acid, a tautomer of phosphine oxide, has been supposed to be a nucleophile (Scheme 4). 7 The computational and experimental results suggest that not the nucleophile but the substituent at the propargylic position of propargylic alcohols controls the enantioselectivity of diruthenium-catalyzed propargylic substitution reactions.
Effects of Substituents on Reactivities. Finally, we examined the effects of substituents on the electrophilicity of the C γ atom in ruthenium−allenylidene complexes 3b and 3c. In the reaction of 3a, the energy of TS A3dd 17 relative to (Ib + acetone), ΔG 333 K , was reported to be 26.7 kcal/mol ( Figure  4a). 6 The corresponding relative energies of TS MB5dd and TS FB4dd were 35.5 and 31.5 kcal/mol, respectively, which are much higher than that of TS A3dd (Figure 4b,c). 18 Although the LUMO of I Fe had the lowest energy level among three ruthenium−allenylidene complexes (−3.93, −3.80, and −4.21 eV for I b , I Mb , and I Fe , respectively; Figure 5), the population of the C γ atom in the LUMO of I Fe was the smallest because of the polarization of π-orbitals in the allenylidene moiety caused by the electronegative trifluoromethyl group (0.320, 0.322 and 0.290 for I b , I Mb , and I Fe , respectively). 19 These two factors determine the order in electrophilicity of the C γ atom. 20 ■ CONCLUSIONS Based on our previous research on the transition-state model for the asymmetric propargylic substitution reactions catalyzed by optically active thiolate-bridged diruthenium complexes, we examined the effects of propargylic substituent (methyl or trifluoromethyl group) on both the enantioselectivity and reactivity of the reactions via ωB97X-D-level DFT calculations. Calculations showed that methyl or trifluoromethyl substitution affected the structures of ruthenium−allenylidene complexes, but the effects were found to be relatively small from a free energy point of view. Thus, transition-state structures for the attack of nucleophiles were explored. In the case of propargylic alcohol bearing a methyl group at the propargylic position, the number of lower-energy structures through the B-face attack was larger than that of the structures through the A-face attack. This result contrasts with the results of our previous work, which studied reactions of a propargylic alcohol without a methyl group, indicating that the methyl group substitution at the propargylic position reverses the enantioselectivity. In the case of trifluoromethyl group substitution, the specific transition-state structure for the Bface attack was found to be much lower in free energy than other structures because of the interactions of fluorine atoms with C−H bonds of other ligands. The evidence suggested that the substitution of a trifluoromethyl group for a methyl group at the propargylic position results in higher enantioselectivity. However, methyl or trifluoromethyl substitution was found to make the electrophilicity of the C γ atom in ruthenium− allenylidene complexes lower.

■ COMPUTATIONAL DETAILS
DFT calculations were carried out with the Gaussian 09 22 program package. Geometry optimization and analytical vibrational frequency analysis were performed via the restricted Kohn−Sham DFT using the long-range corrected (LC) hybrid density functional with empirical dispersion corrections (ωB97X-D). 23, 24 In the numerical integration, a larger grid (superf inegrid) was used. 22 Pople's 6-31G(d) basis set was used for the H, C, N, O, F, S, and Cl atoms, 25 and the SDD basis set with the effective core potential was used for the Ru atom 26 for the Gaussian basis functions (6d type polarization functions). The solvent effects of acetone were estimated by the polarizable continuum model with integral equation formalism (IEF-PCM) 27 for the gas-phase optimized structures. For the IEF-PCM calculations, the SDD basis set was used for the Ru atom and the 6-311++G(d,p) basis set (5d-type polarization functions) was used for other atoms. The Gibbs free energy at 333 K was estimated by the IEF-PCM energy and the gasphase thermal value (ωB97X-D(IEF-PCM)/(SDD,6-311++G-(d,p))//ωB97X-D/(SDD,6-31G(d))). The method used in the present study was the same as that used in our previous study. 6 ■ ASSOCIATED CONTENT