Mechanistic Insights into Solvent and Ligand Dependency in Cu(I

Article Cite This: J. Org. Chem. 2018, 83, 561−570

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Mechanistic Insights into Solvent and Ligand Dependency in Cu(I)Catalyzed Allylic Alkylation with gem-Diborylalkanes Qi Zhang,†,§ Bing Wang,‡ Jia-Qin Liu,*,†,§ Yao Fu,*,‡ and Yu-Cheng Wu†,§ †

Institute of Industry & Equipment Technology, Hefei University of Technology, Hefei 230009, China Department of Chemistry, University of Science and Technology of China, Hefei 230026, China § Key Laboratory of Advanced Functional Materials and Devices of Anhui Province, Hefei 230009, China ‡

S Supporting Information *

ABSTRACT: The recent Cu-catalyzed allylic substitution reaction between gem-diboryalkane and allyl electrophiles shows intriguing solvent and ligand-controlled regioselectivity. The α-alkylation product was obtained in DMF solvent, while γ-alkylation product was obtained in dioxane solvent and the dioxane and NHC ligand situation. In the present study, density functional theory calculations have been used to investigate the reaction mechanism and origin of the regioselectivity. For both dioxane and DMF, γ-alkylation undergoes successive oxidative addition (CH2Bpin trans to leaving group) and direct Cγ−C reductive elimination. The αalkylation is found to undergo oxidative addition (CH2Bpin trans to leaving group), isomerization, and Cα−C reductive elimination rather than the previously proposed oxidative addition (−CH2Bpin cis to the leaving group) and Cα−C reductive elimination. The γ-alkylation and α-alkylation is, respectively, favorable for dioxane and DMF solvent, which is consistent with the γ- and α-selectivity in experiment. The solvent interferes the isomerization step, thereby affects the relative facility of the α- and γ-alkylation. Further investigation shows that η1intermediate formation promoted by solvent is the rate-determining step of the isomerization. The stronger electron-donating ability of DMF than dioxane facilitates the η1-intermediate formation and finally results in the easier isomerization in DMF. For dioxane and NHC situation, in the presence of neutral NHC ligand, the −PO4Et2 group tightly coordinates with the Cu center after the oxidative addition, preventing the isomerization process. The regioselectivity is determined by the relative facility of the oxidative addition step. Therefore, the favorable oxidative addition (in which −CH2Bpin trans to the leaving group) results in the facility of γ-alkylation. bond (Scheme 1c).8 The same reaction was also reported by our group via a Cu-catalyzed system (the allyl electrophile was also tried).9 Recently, using the [NHC]Cu-catalyzed system (NHC refers to N-heterocyclic carbene), Cho10 and our group11 independently reported the coupling between gemdiboryalkane and allyl electrophiles (Scheme 1d). In the allyl electrophile involved alkylation reactions reported by our group (Scheme 1c,d), regioselectivity could be successfully regulated by solvent and ligand.9,11 As shown in Scheme 2a, with CuCl as catalyst and MeOLi as base, the γalkylation products were obtained with dioxane as solvent. The γ-selectivity further increased (from 83:17 to 97:3) when NHC ligand was added. However, when the solvent dioxane was changed to DMF in the absence of NHC, α-alkylation products were surprisingly obtained. The intriguing solvent and ligand-controlled regioselectivity motivates us to investigate the mechanism of the Cu-catalyzed allyl substitution reaction. According to the studies of Nakamura,12 Bäckvall,13

1. INTRODUCTION The Suzuki−Miyaura coupling (SMC) reaction with alkylboron acting as nucleophile provides a mild and efficient method to construct C(sp3)−C bonds in synthesizing complex organic compounds.1 Among these, the gem-diboryalkane is a novel and readily available alkylboron nucleophile containing two boron atoms.2 One gem-boron could assist the transmetalation of another one, and the retaining boron could participate in further coupling reaction to obtain complex multisubstituted compounds.3 For the first time, the Shibata group4 reported the Pd-catalyzed SMC reaction between gem-diboryalkane and aryl halide (Scheme 1a). Through this reaction, various multisubstituted C(sp3)−C(sp2) bonds were successfully constructed.5 Additionally, benzyl and allyl electrophiles could also react with gem-diboryalkane under similar Pdcatalyzed conditions.6 Later, by using chiral phosphine ligand with Pd catalyst, the Morken group accomplished the stereoselective SMC between gem-diboryalkane and aryl7a and alkenyl7b electrophiles (Scheme 1b). They also achieved the noncatalytic reaction between gem-diboryalkane and primary alkyl electrophiles to construct the C(sp3)−C(sp3) © 2017 American Chemical Society

Received: September 7, 2017 Published: December 15, 2017 561

DOI: 10.1021/acs.joc.7b02249 J. Org. Chem. 2018, 83, 561−570

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The Journal of Organic Chemistry Scheme 1. gem-Diboryalkane-Involved Alkylation Reaction

the mechanism proposals. The mechanistic origin for the regulated regioselectivity is worth clarification. To solve these problems, we carried out theoretical analysis on the mechanism of the Cu-catalyzed allyl alkylation reaction (Scheme 2a). Three reaction conditions of solvent dioxane, solvent DMF, and dioxane solvent−NHC ligand were investigated. The calculation results for the mechanism of solvent dioxane and DMF are shown in sections 3.1 and 3.2, and section 3.3 shows the comparison of these two conditions. The calculation results for the mechanism of the dioxane solvent−NHC ligand situation is shown in section 3.4.

2. COMPUTATIONAL METHODS AND MODEL REACTION 2.1. Computational Methods. All calculations in this study were carried out with the Gaussian 09 program.16 The B3LYP17,18/GEN1 method (GEN1:6-31g* for C, H, O, N, P, B, and Li and LANL2DZ for Cu) combined with the SMD model19 were used for geometry optimization in solvent DMF and dioxane (consistent with our experiments9,11). To gain the thermodynamic corrections of Gibbs free energy and verify the stationary points to be local minima or saddle points, we conducted frequency analysis at the same level with optimization (zero imaginary frequency for local minima and one for saddle point). For all transition states, we performed the intrinsic reaction coordinate (IRC) analysis to confirm that they connect the correct reactants and products on the potential energy surface.20 The M0621/GEN2 method (GEN2:6-311++G** for C, H, O, N, P, B, and Li and SDD for Cu) method with the SMD model was used for the solution-phase single-point energy calculations of all of these stationary points. The polarization function was added for Cu(ζ(f) = 3.525).22,23 All energetics involved in this study are calculated by adding the Gibbs free energy correction calculated at B3LYP/GEN1 and the single-point energy calculated with the M06/GEN2 method.24 2.2. Model Reaction. The reaction of allyl electrophile 1a and gem-diboryalkane 2a generating γ-alkylation product 3a and αalkylation product 4a was chosen as the model reaction (Scheme 3). CuCl and MeOLi were used as the catalyst and base, respectively.

Ogle,14 et al., the oxidative addition−reductive elimination mechanism via successive alkene coordination, SN2′-type oxidative addition, and reductive elimination is proposed (Scheme 2b). Meanwhile, the alkene insertion−β-elimination mechanism via successive alkene coordination, alkene insertion, and β-elimination is also possible based on the proposals of Sawamura and Ohmiya.15 Therefore, the mechanism of the Cu-catalyzed allyl substitution reaction is unclear. More importantly, the roles of the solvent and NHC ligand controlling the α/γ-regioselectivity are not reflected in

Scheme 2. (a) Solvent and Ligand-Controlled Regioselectivity; (b) Mechanism Proposal of Cu-Catalyzed Allyl Substitution Reaction

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The Journal of Organic Chemistry Scheme 3. Model Reaction

Figure 1. Different forms of Cu(I) catalyst.

Figure 2. Detailed oxidative addition−reductive elimination mechanism in solvent dioxane (path-α and path-γ).

3. RESULTS AND DISCUSSION 3.1. Mechanism with Solvent Dioxane. The mechanism for the situation of solvent dioxane was first investigated. In this section, both oxidative addition−reductive elimination and alkene insertion−β-elimination mechanisms are examined to determine a favorable mechanism. Before the reaction, the original catalyst CuCl reacted with the base MeOLi and diborylmethane 2a to generate cat1 (Li(BpinCH2CuOMe))

with energy decrease of 50.6 kcal/mol (Figure 1). Ion separation of cat1 generated anionic Cu(I) species cat2 (BpinCH2CuOMe−) with energy increase of 50.5 kcal/mol. Dimerization of cat1 generated cat3 with an energy decrease of 20.9 kcal/mol.25,26 Considering the lower free energy than that of cat1 and cat2, the following steps were investigated from cat3. 563


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Figure 3. Isomerization process from Int5 to Int6.

Oxidative Addition−Reductive Elimination Mechanism. Efforts were first put into examining the oxidative addition− reductive elimination mechanism in which alkene coordination, SN2′-type oxidative addition, and reductive elimination occur successively (Figure 2).12−14 From cat3, the dissociation of one Li−OMe or Li−Bpin interaction is prerequisite to form vacant coordinating site on the Cu(I) center. As shown in Figure 2, a break of one Li−Bpin interaction (i.e., Lia-Bpin) allows the coordination of substrate 1a to the Cu center. The η3-intermediate Int1 is generated with the −CH2Bpin group trans to the leaving −PO4Et2 group. A new interaction forms between Lia and O of the −PO4Et2 group, additionally. The break of one Li−OMe interaction (i.e., Lia−OMe) and 1a coordination generate η3-intermediate Int2 with the −OMe group trans to −PO4Et2. The free energies of Int1 and Int2 are −9.3 and 3.9 kcal/mol, respectively. The SN2′-type oxidative addition then occurs from Int1 and Int2. As shown in Figure 2, Int1 undergoes oxidative addition via transition state TS1, in which CH2Bpin occupies the trans position of the leaving group. Additionally, the Lia+ assists the C−PO4Et2 bond cleavage while the Lib+ cation acts as a bridging between these two BpinCuOMe− moieties. The free energy of TS1 is −2.7 kcal/mol, and the energy barrier is 18.2 kcal/mol (cat3 → TS1). The η3-Cu(III) intermediate Int3 is then generated with a decreased free energy of −26.1 kcal/mol. Similarly, Int2 undergoes oxidative addition via TS2, in which OMe occupies the trans position of the leaving group. The free energy of TS2 is 12.8 kcal/mol, and the energy barrier is 33.7 kcal/mol (cat3 → TS2). Int4 is generated with a free energy of −19.5 kcal/mol. Therefore, the former oxidative addition process is more favorable than the latter, indicating that the CH2Bpin group favorably occupies the trans position of the leaving group. It is understandable because the stronger trans effect of CH2Bpin (than OMe) benefits the C−PO4Et2 bond cleavage. Additionally, we found that the smaller twisting degree of the bridging structure Lia···BpinCH2CuOMe···Lib also contributes to the facility of the former oxidative addition.27 The generated Int3 and Int4 subsequently dissociate the LiCuLi structure to generate the mononuclear intermediate Int5 and Int6.12a,28 With the −CH2Bpin group,

respectively, cis to the Cγ atom and Cα atom in these two intermediates, direct Cγ−C and Cα−C reductive elimination occur from them to yield the γ-alkylation product 3a and αalkylation product 4a. The corresponding transition states are TS3 and TS4, with free energies of −4.6 and −7.0 kcal/mol. Finally, the Cu(I) catalyst CuOMe is regenerated, and the free energy decreases to −29.1 and −32.4 kcal/mol, respectively. As shown in Figure 2, the pathway via TS1 (oxidative addition transition state) and TS3 (reductive elimination transition state) is named path-γ (blue line) for γ-alkylation. Meanwhile, the pathway via TS2 (oxidative addition transition state) and TS4 (reductive elimination transition state) is named path-α (brown line) for α-alkylation. Both path-α and path-γ are irreversible (because the free energies of TS3 and TS4 are lower than that of TS1 and TS2), indicating that the oxidative addition step determines the relative facility of path-α and path-γ. Since the oxidative addition via TS1 is favorable than that via TS2, path-γ is more favorable than path-α, which is consistent with the γ-selectivity for dioxane solvent in experiment. However, the energy barrier difference of these two oxidative addition steps is 15.5 kcal/mol. The large energy barrier difference does not match the experimental phenomenon of small amount of α-product was generated. The inconsistent phenomenon inspires us to find more favorable αalkylation mechanism. Considering the solvent-controlled selectivity and the solvent-coordinated model proposed by Yamanaka et al.,12b we suggest that the solvent might participate in the isomerization of two reductive elimination precursors (Int5 and Int6). The α-product might be generated via isomerization (from Int5 to Int6) and subsequent Cα−C reductive elimination (via TS4), followed by the favorable oxidative addition (via TS1). The process is named as path-α′ (vide infra, see Figure 7). To verify the facility of path-α′, the isomerization from Int5 to Int6 was investigated. Taking into account that the interconversion between η3-intermediates is unlikely in light of the configuration, we tried to obtain the corresponding η1-intermediates. As shown in Figure 3, the solvent coordinates with Int5 to generate the dioxanecoordinated η3-intermediate Int5s with Cu···dioxane distance 564


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Figure 4. Energy profile of alkene insertion step.

Figure 5. Energy profiles of reaction mechanism with DMF as solvent.

from Int5s′ automatically generates η3-intermediate Int6 with energy decrease of 8.7 kcal/mol. Therefore, successive dioxane coordination, η1-intermediate formation, 1,3-conversion and dioxane dissociation constitute a feasible isomerization pathway, with highest energy point of −0.9 kcal/mol. Accordingly, path-α′ and path-γ share the favorable oxidative addition step. After that, isomerization and Cα-C reductive elimination or direct Cγ−C reductive elimination process delivers α or γproduct, with highest energy point of −0.9 kcal/mol and −4.6 kcal/mol, respectively (vide infra, Figure 7). Therefore, the reductive elimination determines the relative facility of the above two processes. Path-γ is more favorable than path-α′, with a free energy barrier difference of 3.7 kcal/mol. Alkene Insertion−β-Elimination Mechanism. Taking the γalkylation process as an example, we further investigated the alkene insertion−β-elimination mechanism. As shown in

of 2.956 Å. Then, in the presence of dioxane, Cu−Cγ bond gradually dissociates and Cu−Cα bond forms to give η1intermediate α-Int5s. Similarly, the gradual Cu−Cα bond cleavage and Cu−Cγ bond formation gives γ-Int5s. The free energies of them are 11.1 and −6.1 kcal/mol, and the isomerization via γ-Int5s was then investigated since the lower free energy. The strong trans effect of CH2Bpin in α-Int5s weakens the Cu−Cα bond, which contributes to its high free energy. The energy scan of the process from Int5s to γ-Int5s shows the highest energy point of −0.9 kcal/mol.29 γ-Int5s then undergoes barrierless 1,3-conversion to generate the Cα-Cu bonded η1-intermediate Int5s′ with decreased free energy of −9.0 kcal/mol.29 This facile conversion might be due to the stability of Int5s′, which is derived from the conjugation of benzene ring and double bond. Next, dioxane dissociation 565


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Figure 6. Isomerization process from Int5DMF to Int6DMF.

Figure 7. Overall mechanism for solvent dioxane.

Figure 4, we first tried to obtain the alkene insertion transition state TSAdd from intermediate Int1. However, all attempts at locating the transition state failed, and the Cu−CH2Bpin bond always reforms and the C−PO4Et2 bond breaks automatically during the geometry optimization. This observation indicates that the Cu−CH2Bpin bond break is difficult and the −PO4Et2 group tends to leave. To estimate the energy demand of the alkene insertion step, we investigated the free energy of the fixed optimization of TSAdd. The energy is calculated to be 12.6 kcal/mol. Therefore, the energy barrier of alkene insertion is about 33.5 kcal/mol (cat3 → TSAdd), which is larger than the overall energy barrier of the overall energy barrier of the oxidative addition−reductive elimination mechanism (21.5 kcal/mol, path-γ). Accordingly, both geometry optimization and energy estimation indicate that the alkene insertion process is difficult. Therefore, the alkene insertion−β-elimination process is unfavorable compared with oxidative addition−reductive

elimination mechanism. In the following sections, we only consider the favorable oxidative addition−reductive elimination mechanism. 3.2. Mechanism with Solvent DMF (Condition 2). Figure 5 shows the energy profiles of path-α (brown line) and path-γ (blue line) in solvent DMF. Similar to the mechanism of solvent dioxane, cat3DMF first coordinates with 1aDMF to give Int1DMF and Int2DMF with increased free energies of −9.5 and 5.0 kcal/mol. Then oxidative addition occurs via TS1DMF and TS2DMF to generate Cu(III) intermediates Int3DMF and Int4DMF, with energy barriers of 22.4 and 37.1 kcal/mol, respectively. Therefore, the former is more favorable, and the CH2Bpin group still occupies the trans position of the leaving group. Then, Int3DMF and Int4DMF dissociate the LiCuLi structure to give Int5DMF and Int6DMF. The Cγ−C and Cα−C reductive elimination subsequently occur from them via TS3 DMF and TS4 DMF with free energies of −0.9 and −10.5 kcal/ mol, respectively. After that, the γ- and α-alkylation product 566


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Figure 8. Favorable mechanism with solvent DMF.

product, with a highest energy point of −0.9 and −4.6 kcal/ mol. Therefore, the reductive elimination determines the relative facility of the above two processes. Path-γ is more favorable than path-α′, which is consistent with the γ-alkylation selectivity in experiment. What’s more important, the smaller energy barrier difference of 3.7 kcal/mol (−0.9 vs −4.6 kcal/ mol) is more reasonable than that of 15.5 kcal/mol (vide supra). Figure 8 shows the overall mechanisms for solvent DMF. Similar to the condition of solvent dioxane, path-γ and path-α′ share the same oxidative addition step. Then, direct Cγ−C reductive elimination and the isomerization and Cα−C reductive elimination occur for path-γ and path-α′ to generate the γ-alkylation and α-alkylation products, respectively. The highest energy points of the direct Cγ−C reductive elimination and isomerization and Cα−C reductive elimination processes are −0.9 and −1.6 kcal/mol. Therefore, the latter is slightly more feasible than the former, indicating path-α′ (rather than path-γ) is favorable for solvent DMF. The calculation is consistent with the α-alkylation selectivity in DMF solvent. Overall, the consistency further verifies the validity of path-α′ for α-alkylation process. In summary, for dioxane solvent, direct Cγ−C reductive elimination is more feasible than isomerization and Cα−C reductive elimination, which leads to γ-alkylation product. For DMF solvent, isomerization and Cα−C reductive elimination is more feasible than direct Cγ−C reductive elimination, which leads to α-alkylation product. Comparison shows that the solvent interferes the isomerization between the two reductive elimination precursors, thereby affects the relative facility of the α- and γ-alkylation. Specifically, the DMF solvent promotes the isomerization (from Int5DMF to Int6DMF) to make the isomerization and Cα−C reductive elimination process feasible. Meanwhile, dioxane could not promote the isomerization (from Int5 to Int6), and thus the direct Cγ−C reduction elimination from Int5 is kinetically favored. In addition, successive solvent coordination, η1-intermediate formation, 1,3-conversion, and solvent dissociation steps constitute a feasible isomerization pathway, among which the η 1 intermediate formation step is rate-determining. The promo-

3aDMF and 4aDMF were yielded. With the regeneration of CuOMe, the free energies decrease to −38.0 and −42.2 kcal/ mol, respectively. Similar to the mechanism of solvent dioxane, both path-γ and path-α are irreversible, and the oxidative addition step determines the relative facility. Since the oxidative addition via TS1DMF is favorable than that via TS2DMF, path-γ is favorable than path-α. However, it is not consistent with the α-selectivity for DMF solvent in experiment, which further indicates a more favorable pathway for α-alkylation. Based on the calculation of section 3.1, we investigated the facility of path-α′ for DMF solvent (successive oxidative addition via TS1DMF, isomerization from Int5 DMF to Int6 DMF, and reductive elimination via TS4 DMF). Figure 6 shows the isomerization from Int5sDMF to Int6sDMF. DMF first coordinates with Int5DMF to generate Int5sDMF with a Cu···DMF distance of 2.664 Å. In the presence of DMF, the η1-intermediates α-Int5sDMF and γInt5sDMF are generated with free energies of 8.6 and −2.5 kcal/ mol. Since the former is already higher than that of TS3DMF (−0.9 kcal/mol, Cγ−C reductive elimination transition state), the isomerization via γ-Int5sDMF was investigated. The energy scan of the process from Int5s to γ-Int5s shows the highest energy point of −2.4 kcal/mol.30 γ-Int5sDMF then undergoes facile 1,3-conversion to generate Int5s′ DMF with decreased free energy of −8.6 kcal/mol.30 Int5s′ then dissociates DMF generating Int6 with energy decrease of 9.5 kcal/mol. Therefore, successive dioxane coordination, η1-intermediate formation, 1,3-conversion, and dioxane dissociation constitute a feasible isomerization pathway with a highest energy point of −2.4 kcal/mol. 3.3. Mechanism Comparison between Dioxane and DMF. According to the calculation results in sections 3.1 and 3.2, favorable mechanisms for γ- and α-alkylation are obtained. This section shows the overall mechanisms and the mechanism comparison of the dioxane and DMF situations. Figure 7 shows the overall mechanisms for solvent dioxane. Path-α′ and path-γ share the favorable oxidative addition step. After that, isomerization and Cα−C reductive elimination or direct Cγ−C reductive elimination process delivers α or γ 567


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Figure 9. Energy profiles of the reaction with dioxane solvent and NHC ligand.

coordinated -PO4Et2 group occupies the coordination site and disables the solvent coordination to Cu center. We tried to remove the -PO4Et2 group and create a coordination site for the solvent. Unfortunately, this process requires the high energy demand of 33.9 kcal/mol. It is understandable because the Cu center and PO4Et2 group are respectively positive and negative in the presence of neutral NHC ligand, the separation of them is difficult in low polarity solvent. In addition, the -PO4Et2 group still coordinates with the Cu center in the following reductive elimination. Therefore, with the coordination of neutral NHC ligand, the leaving group tightly coordinates with the Cu center after the oxidation addition, preventing the solvent coordination, and thereby blocking the isomerization of reductive elimination precursors. Namely, path-α′ is impossible with the NHC ligand coordination. Accordingly, path-γ and path-α are the favorable mechanism for γ- and α-alkylation. Both path-γ and path-α are irreversible, indicating that the oxidative addition step determines the relative facility of them. The energy barrier difference of these two oxidative addition steps is determined by the energy difference between TS1NHC and Int1NHC (7.6 kcal/mol). The energy barrier difference (7.6 kcal/mol) is larger than that of only dioxane situation (3.7 kcal/mol, Section 3.1), which is consistent well with the increased selectivity after the addition of NHC ligand in experiment.

tion effect of DMF originates from its stronger electrondonating ability than dioxane to facilitate the η1-intermediate formation (Int5DMF → γ-Int5sDMF). In conclusion, the solventcontrolled α/γ-selectivity is determined by the different electron-donating ability of the solvent. 3.4. Mechanism with Dioxane and NHC. Similar to the calculations in sections 3.1 and 3.2, path-γ and path-α were also first investigated for the NHC−Cu(I)-catalyzed reaction in dioxane solvent. As shown in Figure 9, active catalyst NHC−Cu−CH2Bpin was generated from NHC−Cu−Cl with a decreased free energy of −8.6 kcal/mol.28,31 The catalyst then coordinated with 1a to give Int1NHC and Int2NHC with a slight energy increase of 2.0 and 1.9 kcal/mol. Inspired by the Li cation assisted −PO4Et2 group leaving in the oxidative addition of sections 3.1 and 3.2, we put LiCl around the −PO4Et2 group of Int1NHC and Int2NHC to generate Int3NHC and Int4NHC with decreased free energies of −25.2 and −22.7 kcal/mol. Then SN2′-type oxidative addition occurs via transition states TS1NHC and TS2NHC with free energies of −14.2 and −9.0 kcal/mol. The former oxidative addition process is always more favorable, and the CH2Bpin group occupies the trans position of the leaving group. After oxidative addition, the Cu(III) intermediates Int5NHC and Int6NHC are generated with decreased free energies of −27.5 and −29.3 kcal/mol. Notably, one oxygen atom of the −PO4Et2 group coordinates tightly with the Cu(III) center in Int5NHC and Int6NHC. The corresponding Cγ−C and Cα−C reductive elimination then occur via transition states TS3NHC and TS4NHC with free energies of −21.4 and −27.3 kcal/mol. They are still lower than that of TS1NHC and TS2NHC (−14.1 and −9.0 kcalmol), indicating the irreversibility of path-γ and pathα. Finally, the γ-alkylation product 3a and α-alkylation 4a are yielded with the regeneration of catalyst NHC−Cu-Cl. We also investigated the isomerization of reductive elimination precursors Int5NHC and Int6NHC. However, the

4. CONCLUSION The Suzuki−Miyaura coupling (SMC) reaction with the novel nucleophile of gem-diboryalkane is a powerful synthetic method to construct C(sp3)−C bonds. Recently, our group accomplished the coupling between gem-diboryalkane and allyl electrophiles by a Cu-catalyzed system. Experimentally, the γalkylation product was obtained in dioxane and the dioxane and NHC ligand combination, while α-alkylation product was obtained in DMF solvent. The DFT calculations were carried 568


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out to illustrate the detailed mechanism and origin of the solvent and NHC ligand controlled α/γ-regioselectivity. For both dioxane and DMF, γ-alkylation undergoes oxidative addition (CH2Bpin trans to leaving group) and direct Cγ−C reductive elimination (path-γ). The α-alkylation is found to undergo oxidative addition, isomerization, and Cα−C reductive elimination (path-α′) rather than oxidative addition (−CH2Bpin cis to the leaving group) and Cα−C reductive elimination (path-α). Path-γ and path-α′ are, respectively, favorable for dioxane and DMF solvent, which is consistent with the γ- and α-selectivity in experiments. The successive solvent coordination, η1-intermediate formation, 1,3-conversion, and solvent dissociation constitute a feasible isomerization pathway. The solvent interferes with the isomerization step, thereby affecting the relative facility of the α- and γalkylation processes. The stronger electron-donating ability of DMF than dioxane promotes the isomerization to facilitate αalkylation. In the presence of NHC ligand, path-γ and path-α are favorable mechanisms for γ-alkylation and α-alkylation. Path-α′ is unfavorable compared with path-α because of the difficult isomerization step, which is derived from the tight coordination of −PO4Et2 group to Cu center. The γregioselectivity is determined by the relative facility of the oxidative addition step (in which −CH2Bpin is trans to the leaving group).

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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.7b02249. Details of different forms of Cu(I) catalyst, complete content for refs 26, 27 29, and30, and Cartesian coordinates, free energies, and thermal corrections (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Qi Zhang: 0000-0001-6340-0130 Yao Fu: 0000-0003-2282-4839 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the 973 Program (2012CB215305), NSFC (21702041,21325208, 21402181, 21572212, 51402078), IPDFHCPST (2014FXCX006), CAS (KFJ-EW-STS-051, YZ201563), FRFCU, PCSIRT, and Young Scholar Enhancement Foundation (Plan B) of Hefei University of Technology (JZ2016HGTB0711). The numerical calculations in this paper have been done on the supercomputing system in the Supercomputing Center of University of Science and Technology of China.

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REFERENCES

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Mechanistic Insights into Solvent and Ligand Dependency in Cu(I

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