A Computational Mechanistic Study of Pd(II)-Catalyzed

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A Computational Mechanistic Study of Pd(II)-Catalyzed Enantioselective C(sp)-H Borylation: Roles of APAO Ligands 3

Yang-Yang Xing, Jian-Biao Liu, Qing-Min Sun, Chuan-Zhi Sun, Fang Huang, and De-Zhan Chen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01227 • Publication Date (Web): 16 Aug 2019 Downloaded from pubs.acs.org on August 16, 2019

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The Journal of Organic Chemistry

A Computational Mechanistic Study of Pd(II)-Catalyzed Enantioselective C(sp3)-H Borylation: Roles of APAO Ligands Yang-Yang Xing,a Jian-Biao Liu,*,a Qing-Min Sun,b Chuan-Zhi Sun,a Fang Huanga and De-Zhan Chen*,a aCollege

of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Shandong Normal University, Jinan 250014, P. R. China bShandong Kaisheng New Materials Co., Ltd, Zibo 255185, P. R. China

Abstract A computational mechanistic study has been performed on the Pd(II)-catalyzed enantioselective reaction involving acetyl-protected aminomethyl oxazolines (APAO) ligands that significantly improved reactivity and selectivity in C(sp3) H borylation. The results support a mechanism including initiation C(sp3) H bond activation generating five-membered palladacycle, ligand exchange, followed by HPO42--promoted transmetalation. These resulting Pd(II) complexes further undergo sequential reductive elimination by coordination of APAO ligands and protonation to afford the enantiomeric products and deliver Pd(0) complexes, which will then proceed by oxidation and deprotonation to regenerate the catalyst. The C(sp3) H activation is found to be the rate- and enantioselectivity-determining step, in which APAO ligand acts as the proton acceptor to form the two enantioselectivity models. The results demonstrate that diverse APAO ligand controls the enantioselectivity by differentiating the distortion and interaction between the major and minor pathways.

1. Introduction Selective functionalization of C H bonds has become an effective and direct approach for synthesizing various useful chiral products.1 Considerable efforts have been made to improve the reactivity and selectivity of C H functionalization via transition metal catalysts.2 As one of the most important fields, the development of chiral ligands with high selectivity and high efficiency has attracted widespread attention to enhance the catalytic effects of transition metals in C H bond functionalization. Among them, enantioselective C H activation has been achieved by a class of environmentally compatible and readily available ligand scaffolds, such as mono-N protected amino acid (MPAA),3 mono-N-protected aminomethyl oxazoline (MPAO) as well as acetyl-protected aminoethyl quinoline (APAQ) ligands with palladium catalysis.4 These versatile and highly efficient ligands have been widely used in a variety of asymmetric reactions, including arylation, alkylation and alkenylation. Despite enormous progress in this area, effective enantioselective C H borylation on ligand-assisted catalysis remains a central challenge.5 This could be attributed to the lack of suitable ligand scaffolds capable of forming carbon-boron bonds. In 2016, Yu s group developed Pd(II)-catalyzed borylation of C(sp3) H bond in various 1

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carboxylic amides assisted by monodentate quinoline ligands.5c However, this method did not provide valuable enantioselective C(sp3) H borylation. In 2019, Sawamura's group proposed borylation of methylene C(sp31A6 bonds with high enantioselectivity, which is caused by the catalyst effectively distinguishing the enantiotopic A6 bonds.6 Very recently, Pd(II)-catalyzed enantioselective -C(sp3) H borylation between carboxylic amides and bis(pinacolato)diboron was elegantly reported by Yu s group shown in Scheme 1. 7 In this reaction, the chiral acetyl-protected aminomethyl oxazolines (APAO) ligands overcame the limitation of the construction of chiral centers for previously described quinoline-based ligands. They revealed that bidentate chiral APAO ligands could achieve a pivotal improvement in Pd(II) catalytic activity in this unprecedented borylation reaction and play a dominant role in determining the selectivity and reactivity. Importantly, this borylation reaction is compatible with a broad range of cyclic carboxylic amides, including cyclohexanes, cyclobutanes as well as cyclopropanes. As shown in Scheme 1, Pd(II) catalysts with several APAO ligands have been used to promote enantioselectivity C(sp3) H borylation. Among them, (S,R)-L1 was identified as the optimal ligand, giving rise to the product P(R,S) in good yield with high enantioselectivity, while (S,S)-L1 and (S)-L7 proved to be far less effective. In addition, Yu et al. proposed asymmetric induction model for this reaction shown in Figure 1. In this model, steric repulsion in the disfavored five-membered palladacycle intermediate B was assumed to be responsible for the enantioselectivity. It could be proposed that different APAO ligand may adjust the steric circumstance around the palladium center, thereby leading to the enantioselectivity difference. Therefore, it is crucial to understand how APAO ligands control the enantioselectivity in this transformation. O

O

H NHArF

+ B2Pin2

H 1a ArF=4-(CF3)C6F4

O

AcHN N

Ligand:

AcHN N

(R)

Me

Me

O

(S)

O

AcHN (S)

N

Me

Me

Me

Me (S,R)-L1 82% yield, 95.6% ee

Bpin P(R,S)

Me

Me

(S)

(S)

NHArF

* *

K2HPO4 (2 equiv) CH3CN/DCE/H2O (16:4:1) 2a (2 equiv) O2, 80 C,15h

Me

Me

Pd(CH3CN)4(OTf)2 (10 mol%) H Ligand (30%)

(S,S)-L1 24% yield, 50.4% ee

(S)-L7 57% yield, 78.8% ee

Scheme 1. Ligand-assisted Pd(II)-catalyzed enantioselective C(sp3) H borylation.

KO

N

PdII H

H

R2 ArF

N

vs H

N

H Ac

KO

O

H

H

R2 ArF

N

PdII H

R1

O

N

H

N

Ac

R1

Intermediate B disfavored

Intermediate A favored

Figure 1. Asymmetric induction model proposed by Yu and coworkers to explain the Pd(II)catalyzed enantioselective C(sp3) H borylation of cyclobutanes.

2


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Figure 2. Free energy profiles for (S,R)-L1-assisted C(sp3)

H activation reactions involve anion N-donor form 1a .

Figure 2 shows the free energy profiles for (S,R)-L1-assisted C(sp3) H activation reactions. In the light of the discrimination between the two methylene C H bonds, major P(R,S) and minor P(S,R) enantiomers are formed accordingly. Analogously with the previous theoretical studies, Pdcatalyzed C(sp3) H activation occurs through a concerted metalation/deprotonation(CMD) mechanism.18 We expect that two pathways would possibly present in corresponding products through the four patterns. For the formation of the major product P(R,S), the active species Cat6 first interacts with 1a with the dissociation of dianionic HPO42- and molecule CH3CN to form the Pd-(S,R)-L1-substrate complex, 3a or 3a , which is endergonic by 19.1 and 20.8 kcal/mol, respectively. The structural difference between these two reaction precursors is the orientation of ArF group in 1a . Our results indicate that the C(sp3) H activation transition state TS1a is about 10 kcal/mol more stable than the corresponding transition state TS1a . The Pd(II) center in TS1a is coordinated with the amide N of the deprotonated substrate, the amide N of the deprotonated ligand and the N of oxazoline. The N-acyl group on the coordinated bidentate ligand could serve as an internal base to aid in cleaving methylene C H bond and promote Pd C bond formation.4a,8e-8i Furthermore, the planar geometry of the bidentate ligand could maintain the quadrangular metal intermediate (Figure 3). The energy barrier for the C H activation via TS1a is 28.1 kcal/mol relative to the separated reactants. After deprotonation of the methylene C(sp3) H bond, intermediate 4a with Pd C and Pd N covalent bonds is formed. There are also two pathways for the C(sp3) H activation to generate the corresponding minor product P(S,R). Formation of the five-membered palladacycle 4b occurs with an energy barrier of 34.1 kcal/mol via TS1b. The overall energy profiles were presented in the following sections. On the basis of the calculated free energy profiles of the whole catalytic cycle, the C(sp3) H activation step was found to be the rate- and enanioselectivitydetermining step (vide infra). The calculated activation free energies of deprotonation model for the formation of P(R,S) and P(S,R) enantiomers are 28.1 and 34.1 kcal/mol, respectively. This result is in agreement with the experimental results that the most favorable product is in RS configuration.

Figure 3. Optimized structures of TS1a and TS1b. To gain deep insights into the origin of enantioselectivity for the deprotonation process, we further analyzed the two optimized structures of TS1a and TS1b presented in Figure 3. In both transition states, Pd(II) center binds with the bidentate ligand APAO and the deprotonated substrate 5




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step. It is worth noting that the reactions reaching the stable intermediate 9a/9b are irreversible (vide infra).Thus, the selectivity is in a kinetically controlled reaction.19 To further understand the role of diverse ligands in controlling the enantioselectivity, we computed the free energy profiles for C(sp3) H activation reactions separately assisted by the APAO ligands (S,S)-L1 and (S)-L7 (see Figures 4 and 5). The rigid skeleton of the transition states could also explain the energy difference as C-N1-Pd-N2 of the transition states shown in Figure 4 and Figure 5. Notably, Yu proposed that the chiral oxazoline ligands lacking a stereocenter on either the side chain or the oxazoline moiety gave poor enantioselectivity,7 which reinforced in our calculations in Figure 5. The calculated ee values are listed in Table 1. Overall, the calculated ee values are in good qualitative agreement with the experimentally observed enantioselectivity among the three APAO ligands.20 Table 1. Experimental and calculated ee values ( ) and corresponding experimental and calculated G‡ values. ligand ee(exp) ee(calc)a G‡ (exp)a G‡ (calc)b (S,R)-L1 (S,S)-L1 (S)-L7

95.6 50.4 78.8

2.7 0.8 1.5

100 21.2 94.6

6.0 0.3 2.5

aComputed b

from exp[ ( G‡)/RT], where T=353.15K. Values are in kcal/mol. G‡(calc) = G[calc (S,R)] G[calc (R,S)]. Values are in kcal/mol. major

minor

G (kcal/mol)

G

(S,R)-L1 (S,S)-L1 (S)-L7

6.0 0.3 2.5

G instrinsic

14.4 11.1 9.2

G instrinsic

9 9.8 8.9 0.6 1.0 2.2

Giso

Figure 6. Free energy profiles for the major and minor pathway based on Curtin-Hammett Principle. Decomposition of the selectivity ( G‡) to the contributions of the isomerization energies ( Giso) between the preceding intermediates and intrinsic C(sp3) H activation barriers G‡intrinsic. The energies are in kcal/mol. On the basis of the Curtin-Hammett Principle,21 the free energies of the determining transition states could be further decomposed to the contributions of the free energies of the preceding intermediates and the intrinsic C(sp3) H activation barriers G‡ intrinsic (Figure 6). Therefore, the selectivity is controlled by the intrinsic barriers of major and minor pathway, as well as the isomerization energies ( Giso) between the preceding intermediates. Among the three kinds of APAO ligands, the intrinsic barriers all also favor the formation of the major product pathway. The use of (S,S)-L1, the diastereomer of the optimal ligand (S,R)-L1, drastically decreased the ee to 50.4%. The comparison between the structure of (S,R)-L1 and (S,S)-L1 highlights that the orientation of isobutyl group in the oxazoline moiety should be the main source of enantioselectivity 7



difference. We next performed distortion-interaction analysis along the reaction coordinate to explore the origins of this difference (Figure 7).22 The nonstationary points along the reaction coordinate as well as the structures of transition state (TS) were separated into two distorted fragments (the distorted substrate and catalyst), then each distorted fragment was performed by single-point energy calculations. The E‡dist-sub is the energy associated with the structural distortion of the substrates that the reactants undergo during the reaction, while E‡dist-cat is the energy associated with the structural distortion of the Pd and its ligands that the reactants undergo during the reaction. The difference between the activation energy E‡act( ) and the total distortion energy is the interaction energy E‡int( ) ( E‡int( )= E‡act( ) E‡dist( )). It is the interplay between the interaction energy E‡int( ) and the distortion energy E‡dist( ) that determines the activation energies E‡act ( ). For the (S,R)-L1-assisted C(sp3) H activation transition states, TS1a and TS1b, E‡dist( ) of TS1b are higher than those of TS1a at any point along the reaction coordinate( ). Although TS1b enhances the stronger stabilizing interaction than TS1a, the activation energies E‡act ( ) of TS1b are still higher than those of TS1a at any point along the reaction coordinate ( ). Furthermore, we also perform analysis at the transition states to accurately reveal the origins of this difference. As shown in Figure 7, for the transition states, TS1a and TS1b, both E‡dist-cat and E‡dist-sub of TS1b are higher than those of TS1a. Particularly, the distortion energy of the catalyst, increases to a striking 21.8 kcal/mol between TS1a and TS1b. These results indicate that the more severe distortion in the disfavored transition state TS1b is the leading cause for the very different energy barrier for the two pathways (28.1 kcal/mol of TS1a vs 34.1 kcal/mol of TS1b). While in the case of (S,S)-L1, similar E‡dist-cat and E‡dist-sub are found in TS1a-SSL1 and TS1b-SSL1. It clearly shows that at any point along the reaction coordinate ( ), both the distortion energy and the interaction energy are almost the same for TS1a-SSL1 and TS1bSSL1. This mitigates the difference of the activation energy, thus the two transition states have almost similar energy barriers (32.7 kcal/mol of TS1a-SSL1 vs 33.0 kcal/mol of TS1b-SSL1). Therefore, the APAO ligand controls the enantioselectivity by differentiating the distortion and interaction between the major and minor C(sp3) H activation step.

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barrier of 12.0 kcal/mol. By dissociating [Bpin-HPO4]- anion, a relative less stable complex 8a is generated. Subsequently, 8a undergoes isomerization to reach the conformation of 9a by releasing the free energy of 26.2 kcal/mol. We can see that intermediate 9a has the least sterically hindered face for the further coordination with APAO ligand to promote the ensuing reductive elimination step. Overall, the transmetalation of 4a with the aid of dianionic HPO42-occurs favorably. We also examined the possibility of the H2PO4--promoted transmetalation (see the blue path in Figure 8 and structures in Figure 9). In fact, the concentration of H2PO4- could be very low in the real system due to the equilibrium between HPO42- and H2PO4- with their counterion, thus the potential energy surface involving [HPO4]2- could be higher if the real concentration of [H2PO4]- was considered. The results of transmetalation of 4b were given in Figure S5. 3.3 Reductive elimination and protonation The free energy profiles for the C B reductive elimination and protonation of 10a leading to the major product P(R,S) are shown in Figure 10. The oxazoline moiety of APAO ligand first coordinates to Pd(II) center in complex 9a to form 10a, which facilitates the succeeding C B reductive elimination step. The formation of C(sp3) B bond within 10a via TS4a has an attainable activation energy of 22.2 kcal/mol and delivers the low valent Pd(0) complex 11a. Subsequently, the hydrogen atom transfer from the APAO ligand to the N atom of the carboxylic acid derived amides takes place easily via TS5a. For complex 12a, the ligand exchange by substitution P(R,S) with O2 could directly occur to the subsequent oxidation step because of the high instability of 13a species. The subsequent reaction results of 9b are shown in Figure S6.

Figure 10. Free energy profiles for the reductive elimination and protonation of 10a. Selected bond distances are given in Å. Irrelevant hydrogen atoms are omitted for clarity.

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3.4 Regeneration of the catalyst As shown in Figure 11, in the presence of molecular oxygen, Pd(II)-peroxo complex 15a could be generated through oxidation, which has been reported experimentally23 and computationally.24 Two molecules of substrate 1a will successively react with Pd(II)-peroxo complex 15a, including stepwise deprotonation to give rise to 19a with the formation of H2O2 as the side product. The hydrogen bond N H O interaction between H of 1a and O of 15a results in intermediate 16a, which then undergoes the first deprotonation step. In TS6a, the hydrogen transfers from N(-ArF) atom to the O atom, and the deprotonated N coordinates to Pd(II) center via the inflow of lone pair electrons of N toward vacant metal orbital. This process is relatively facile, with an energy barrier of 14.2 kcal/mol. Intermediate 17a could be thus formed with a OOH structure. Thereafter, another molecule of substrate 1a reacts with 17a to deliver 18a via the similar hydrogen bond interaction. In TS7a, the hydrogen transfers to the O atom of the OOH, and results in a four-coordinate squareplanar species 19a. The simultaneously resultant H2O2 further decomposes into H2O and O2 as indicated in previous experimental reports.23a By substitution two molecules of substrate 1a with CH3CN, HPO42-, the active species Cat6 could be regenerated.

Figure 11. Free energy profiles for the regeneration of the catalyst. Selected bond distances are given in Å. Irrelevant hydrogen atoms are omitted for clarity.

4. Conclusions Recently, the Yu's group reported Pd(II)-catalyzed enantioselective C(sp3) H borylation of carboxylic acid derived amides. The reaction is characterized by the use of effective and readily available chiral bidentate APAO as crucial ligands, environmentally benign molecular oxygen as an 12


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oxidant. In the present study, the reaction mechanism of borylation of carboxylic acid derived amides was disclosed by DFT calculations, especially the origins of enantioselective. The results show that the whole catalytic cycle consists of six steps: initial C(sp3) H activation involving the N-acyl group on the APAO ligand as a base to deprotonate C(sp3) H bond, ligand exchange, transmetalation, C(sp3) B reductive elimination, protonation to deliver enantiomeric products, and final regeneration of the catalyst by oxidation and deprotonation with ligand exchange at the Pd center. The C(sp3) H activation step is the enantioselectivity- and rate-determining. From the computational results of three APAO ligands: (S,R)-L1, (S,S)-L1, and (S)-L7, towards the enantioselectivity-determining C(sp3) H activation step, the calculated ee values are in good qualitative agreement with the enantioselectivity observed in the experiment. Comparison of two (S,R)-L1- and (S,S)-L1-assisted C(sp3) H activation reactions, the origins of this remarkable different enantioselectivity was revealed by the distortion-interaction analysis along the reaction coordinate. Diverse APAO ligand controls the enantioselectivity by differentiating the distortion and interaction between the major and minor C(sp3) H activation step. Our mechanistic understanding of how APAO ligands control enantioselectivity will provide valuable guidance for the further development and rational design of more efficient ligands towards enantioselective C(sp3) H borylation.

Associated Content Supporting Information The Supporting Information is available free of charge via the Internet at http://pubs.acs.org. Computational results, Cartesian coordinates, and energies of all optimized structures (PDF). Author Information Corresponding Authors *E-mail for D.-Z. C.: [email protected] *E-mail for J.-B. L.: [email protected] Notes The authors declare no competing financial interest. Acknowledgments This work was supported by the National Natural Science Foundation of China (NSFC No. 21375082).

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A Computational Mechanistic Study of Pd(II)-Catalyzed

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