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Mechanism and Origins of Enantioselectivity of IridiumCatalyzed Intramolecular Silylation of Unactivated C(sp3)-H Bonds Mei Zhang, Jiaqi Liang, and Genping Huang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00117 • Publication Date (Web): 22 Jan 2019 Downloaded from http://pubs.acs.org on January 24, 2019

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The Journal of Organic Chemistry

Mechanism and Origins of Enantioselectivity of Iridium-Catalyzed Intramolecular Silylation of Unactivated C(sp3)-H Bonds Mei Zhang, Jiaqi Liang, Genping Huang* Department of Chemistry, School of Science and Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, Tianjin 300072, P. R. China. ABSTRACT: Density functional theory calculations were performed to investigate the iridium-catalyzed intramolecular silylation of unactivated C(sp3)-H bonds. The computations show that the in situ generated iridium(III) silyl dihydride species is the active catalyst, from which the followed migratory insertion and the transmetalation would generate the iridium(III) disilyl hydride species. The reaction was found to take place through an Ir(III)/Ir(V) catalytic cycle, and the C(sp3)-H bond oxidative addition constitutes the rate- and enantioselectivity-determining step. The steric repulsion and C-H---π interaction were found to account for the experimentally observed enantioselectivity.

The organosilicon compounds are widely observed in material science, medicinal science and agroscience.1 The development of the efficient methods for the construction of these complexes is thus of immense importance in organic synthesis.2,3 In this respect, the transition metalcatalyzed silylation of C-H bonds, representing one of the most atom-economical and straightforward strategies, has gained much attention during the past two decades.3-7 However, considerable effort has been devoted to the silylation of aromatic C(sp2)–H bonds,4 whereas the silylation of unactivated C(sp3)–H bonds,5 in particular the enantioselective variants, remains rare and constitutes a key challenge in this field. In this context, Murai, Takai and co-workers in 2015 reported a first example of the asymmetric dehydrogenative silylation of unactivated C(sp3)–H bonds in the presence of a rhodium pre-catalyst and chiral diphosphine ligands (Scheme 1a).6 Nonetheless, the enantioselectivity of the reaction was low, being ≤ 40% ee. Scheme 1. Rhodium(I)- and Iridium(I)-Catalyzed Silylation of Unactivated C(sp3)-H Bonds. (a)

Si (b)

H

[RhCl(cod)]2, (R)-DTBM-Garphos



3,3-dimethyl-1-butene, 50 °C 68.5:31.5 er

Si

R1

R1

[Ir(OMe)(cod)]2, L R 1

Si

H

norbornene, Et2O, 50 °C up to 97% yield & 98:2 er

R Si 2

O N

N L

Very recently, Hartwig and co-workers developed an elegant example of the highly enantioselective intramolecular silylation of unactivated C(sp3)-H bonds under relatively mild reaction conditions (Scheme 1b).7 It was found that with a combination of [Ir(OMe)(cod)]2

and chiral pyridyl oxazoline ligand (L), using the norbornene (nbe) as a hydrogen acceptor, the dimethylaryl-silanes 1 undergo the selective silylation at one of two prochiral methyl groups to afford products 2 in high yields (up to 97%) and excellent enantioselectivity (up to 98:2). To gain some insights into the reaction mechanism, Hartwig et al. conducted the kinetic isotope intermolecular competition experiments and a kinetic isotopic effect (KIE) of 1.9 ± 0.1 was observed, from which the C-H cleavage was suggested to be the ratedetermining step of the reaction. Despite the significant advances in experiments, the mechanistic understanding of these reactions, in particular the origins of the enantioselectivity, remains limited. Hartwig and co-workers have reported the combined experimental and computational studies on the mechanisms of the rhodium(I)-catalyzed silylation.8 However, the iridium-catalyzed silylation remains to be explored. Following our continuous interest in this field,9 we therefore decided to investigate the title reaction by means of density functional theory (DFT) calculations. Very interestingly, the computations show that the in situ generated iridium(III) silyl dihydride species is the active catalyst and the reaction takes place through an Ir(III)/Ir(V) catalytic cycle.10 The presented mechanistic scenario is distinct from that of the rhodium(I)-catalyzed silylation,8 wherein the analog rhodium(III) silyl dihydride species was suggested as the stable off-cycle resting state and the reaction was found to occur via a Rh(I)/Rh(III) catalytic cycle. It should be pointed out here that Sunoj et al. and Li et al. have independently investigated the iridium-catalyzed primary alkyl C-H bond silylation, wherein two reaction mechanisms, namely Ir(I)/Ir(III) and Ir(III)/Ir(V) catalytic cycles, were proposed on the basis of DFT calculations.11

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N Ir H N H [Si] -38.8 TS3

Gsol kcal/mol

Ir

N

N

-56.5 INT5 N N

Ir [Si]

H

migratory insertion

H N Ir Si N H [Si]

H

1

R2

R C H 2C Si N Ir H N [Si] H

R2 1

R C

H2C Si N Ir H -34.7 H N 1 2 [Si] S-TS5 (R =H, R =CH3) TS4 1 2 1 1 2 S-TS7 (R =H, R2=CH3) R-TS5 (R =CH3, R =H) S-TS6 (R =H, R =CH3) R-TS6 (R1=CH3, R2=H) R-TS7 (R1=CH3, R2=H) -49.7 -52.6 S-TS5 -52.9 S-TS7 S-TS6 -56.9 R-TS5 S-INT8 R-TS7 -52.4 -62.8 -54.5 R-TS6 Si S-INT7 -57.3 R-INT8 2 1 R 2 -60.4 R R S-2a R-INT7 R1 C C -64.9 H2C -74.3 H2C (V) Si N (III) [Si] Si N Ir(III) Si INT3 Ir N Ir H -80.9 N H N H H N R-2a Ir INT6 N [Si] H [Si] [Si] H N H 1 2 1 2 [Si] S-INT7 (R =H, R =CH3) S-INT8 (R =H, R =CH3) R-INT7 (R1=CH3, R2=H) R-INT8 (R1=CH3, R2=H)

[Si]

1a

-50.6 nbe -53.3 INT3 INT4 N (III) H Ir N H [Si] N H Ir N H [Si]

R1 R2 H2 C C

[Si] H

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transmetalation

C-H oxidative addition

Si-H oxidative addition

C-Si reductive elimination

Figure 1. Calculated energy profile of iridium-catalyzed intramolecular silylation of unactivated C(sp3)-H bonds. The blue and red pathways lead to products S-2a and R-2a, respectively.

The experimentally used dimethylaryl-silane 1a was selected as the model substrate in the current calculations (Scheme 2). In experiments, the dimer [Ir(OMe)(cod)]2 was used as the pre-catalyst, which could undergo the dissociation and ligand exchange processes to give [LIr(OMe)], from which the formation of INT1 by the coordination of nbe to the Ir center was calculated to be exergonic by 13.1 kcal/mol. Therefore, we set the sum of the free energies of INT1 and 1a to be the zero on the relative free energy scale (Scheme 2). Scheme 2. Formation of Active Catalyst Species.

X [Si]-H Si H 1a

1a

N

N

Ir N (I) OMe

N

Gsol INT1 kcal/mol 0.0

Ir

TS1 1.3

N (III) H Ir OMe N [Si]

1a

N Ir

INT2 -23.2

N

N Ir

N N

H Ir [Si]

[Si] nbe X

INT3a 1.2

[Si] H OMe

TS2 -9.2

O N

C H2C N Ir Si H N MeO H

TS2a 3.3 nbe

H OMe [Si]

H

H H2 C C H N Ir Si N H MeO

N Ir OMe N H

TS2b 1.4

[Si]-OMe 3 N (III) H Ir N H [Si] INT3 -50.6 [Si] N Ir OMe N INT3b -11.6

As shown in Scheme 2, the reaction begins with the SiH oxidative addition of 1a via transition state TS1, with an energy barrier of only 1.3 kcal/mol relative to INT1 + 1a. This step was calculated to be highly exergonic, and the resulted iridium(III) species INT2 is much more stable than INT1 by 23.2 kcal/mol. Another possibility from INT1, namely the C(sp3)-H oxidative addition of 1a, was also considered, which was calculated to be much higher in energy than the Si-H oxidative addition, thereby ruling out this possibility (see the Supporting Information (SI) for details). From iridium(III) complex INT2, several possible pathways can be envisioned (Scheme 2). The C(sp3)-H

oxidative addition via transition state TS2a and the migratory insertion of nbe into the Ir-H bond via transition state TS2b were found to be associated with energy barriers of more than 24 kcal/mol relative to INT2. On the other hand, the transmetalation with 1a via transition state TS2 is much more favorable, with an energy barrier of only 14.0 kcal/mol relative to INT2, leading to the formation of silyl ether 3 and iridium(III) silyl dihydride species INT3. The computations show that this step is highly exergonic and INT3 is more stable than INT2 by as much as 27.4 kcal/mol. Importantly, as will be disclosed below, INT3 turns out to be the active catalyst of the reaction. It should be mentioned here that the analog rhodium(III) silyl dihydride species was also observed in the relevant rhodium(I)-catalyzed silylation, while it was suggested to be the stable off-cycle resting state.8 The calculated energy profile of the most favorable pathway for the reaction catalyzed by active catalyst species INT3 is given in Figure 1. Starting from INT3, the coordination of nbe to the Ir center delivers intermediate INT4, which was calculated to be exergonic by 2.7 kcal/mol. Then, INT4 undergoes the migratory insertion of C-C double bond into the Ir-H via transition state TS3. The resultant intermediate INT5 was found to take place the transmetalation with 1a through transition state TS4 to give iridium(III) disilyl hydride species INT6 and release norbornane. The computations show that the reaction from INT3 to INT6 is favored by as much as 30.3 kcal/mol. To be noted, the other possible options, namely the C(sp3)-H oxidative addition directly from INT3 and CH reductive elimination from INT5, were computed to be much higher in energy than the pathway leading to INT6 (see the SI for details). Upon formation of INT6, the silylation can be realized through an Ir(III)/Ir(V) catalytic cycle via the C(sp3)-H oxidative addition/C-Si reductive elimination. The C(sp3)H oxidative addition can occur in two fashions via


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The Journal of Organic Chemistry transition states R-TS5 and S-TS5, which could eventually lead to products R-2a and S-2a, respectively.12 Very interestingly, the IRC calculations show that these transition states do not lead to the typical oxidative addition products (i.e. iridium(V) complexes). Instead, the intermediates R-INT7 and S-INT7 were generated, wherein 1a was found to be formed concomitantly via the Si-H reductive elimination and the oxidation state of the iridium remains to be +3. The possible reason of this concerted C(sp3)-H oxidative addition/Si-H reductive elimination could be due to that the forming iridium(V) species in this configuration is relatively unstable and the Si-H reductive elimination from the iridium(V) center is facile (vide infra), which consequently results in the formation of the relatively stable iridium(III) complexes spontaneously.

respectively. On the other hand, in R-TS5, the hydrogen atom is at the axial position, and the smaller steric repulsion with the methyl substituent of the silyl group could be expected. Indeed, the C2-C3-C4 and C3-C4-Si angles were found to be 119.9 and 122.1 º , respectively. In addition, the C-H---π interaction between the ligand and the phenyl ring was observed in R-TS5, while no such interaction was observed in S-TS5 probably due to the distortion of the phenyl moiety. The combination of the steric and electronic effects thus leads to the experimentally observed excellent enantioselectivity.

The C-Si reductive elimination directly from iridium(III) intermediates R-INT7 and S-INT7 was calculated to be quite infeasible, with energy barriers of around 48 kcal/mol relative to INT6 (see the SI for details). Alternatively, we found that intermediates R-INT7 and SINT7 first undergo the Si-H oxidative addition via transition states R-TS6 and S-TS6 to form iridium(V) intermediates R-INT8 and S-INT8, respectively. The Si-H oxidative addition was calculated to be endergonic by about 6 kcal/mol, with energy barriers of less than 10 kcal/mol (relative to R-INT7 and S-INT7). The computations show that the C-Si reductive elimination from the iridium(V) center via transition states R-TS7 and S-TS7 is much more favorable than those from the iridium(III) center by at least 18 kcal/mol (see the SI for details), leading to active catalyst INT3 and the final silylation products R-2a and S-2a, respectively.

C2-C3-C4 = 119.9 C3-C4-Si = 122.1

The computations (Figure 1) show that the C(sp3)-H oxidative addition constitutes the rateand enantioselectivity-determining step, being in accordance with the kinetic isotopic experiments.7 The KIE of the rate-determining step (INT6-R-TS5) was calculated, by evaluating the zero-point energies with those of the deuterium-labeled INT6 and R-TS5. The calculated zeropoint energy difference is 0.67 kcal/mol, which corresponds to a calculated KIE of 2.6 at 353.15 K,13 being in agreement with the experimental observed 1.9 ± 0.1.7 The overall energy barriers of the pathways leading to R2a and S-2a are 28.5 and 31.2 kcal/mol, respectively (-52.4 kcal/mol of R-TS5 and -49.7 kcal/mol of S-TS5 relative to 80.9 kcal/mol of INT6). The calculated energy difference of 2.7 kcal/mol corresponds to a calculated enantioselectivity of around 98:2 er at 323.15 K, which is in excellent agreement with the experimentally observed 96:4 er.7 The origins of the enantioselectivity can be explained by a combination of the steric and electronic effects. The optimized geometric structures (Figure 2) show that in STS5, the methyl group is at the axial position, which could have steric repulsion with the methyl substituent of the silyl group. To avoid this steric repulsion, the phenyl moiety was found to be distorted, as evidenced by the C2C3-C4 and C3-C4-Si angles being 124.1 and 126.4 º ,

H2 C C

H H2 C C

H

H N Ir Si N H [Si]

H N Ir Si N H [Si] 2.64

C2-C3-C4 = 124.1 C3-C4-Si = 126.4

2 3 4

1

2

3 4

1

2.08

2.07

Si Ir

Ir

Si

Ir-C1 = 2.34 Ir-H = 1.61 C1-H = 1.68

Ir-C1 = 2.36 Ir-H = 1.61 C1-H = 1.69 R-TS5 (favored)

S-TS5 (disfavored)

Figure 2. Optimized geometric structures of R-TS5 and STS5. The bond distances and angles are given in Å and degrees, respectively. Scheme 3. Overall Catalytic Cycle Based on DFT Calculations.

Si C-Si reductive elimination H C H2C (V) Si N Ir H H N [Si]

N (III) H Ir N H [Si] active catalyst Ir(III)/Ir(V)

Si H nbe norbornane

N (III) [Si] Ir H [Si]

N C-H oxidative addition

To summarize, we have herein presented a mechanistic study on the iridium(I)-catalyzed intramolecular silylation of unactivated C(sp3)-H bonds by means of DFT calculations. The computations show that the in situ generated iridium(III) silyl dihydride species is the active catalyst. The reaction was found to take place through an Ir(III)/Ir(V) catalytic cycle, consisting of three major steps (Scheme 3): (1) the migratory insertion of nbe into the IrH bond followed by the transmetalation with dimethylaryl-silane to generate the iridium(III) disilyl hydride species as the resting state, (2) the C(sp3)-H bond oxidative addition to form the iridium(V) complex, (3) the C-Si reductive elimination to produce the final silylation product and regenerate the active catalyst. The C(sp3)-H bond oxidative addition constitutes the rate- and



enantioselectivity-determining step of the overall reaction. The origins of the enantioselectivity was found to be mainly caused by a combination of the steric repulsion between the methyl group and the methyl substituent of the silyl group in the S-transition state and electronic effect of the additional C-H---π interaction in the Rtransition state, which together enables the experimentally observed enantioselectivity. The present results represent a first example of the mechanistic study on the iridium-catalyzed enantioselective silylation, which should provide important implications for a better understanding of related C-H silylation reactions and the design of new catalytic systems. Computational studies on related reactions are currently ongoing in our laboratory. Computational Details: All of the calculations were performed with the Gaussian 09 package.14 Geometry optimizations were carried out using B3LYP15 functional with a mixed basis set of LANL2DZ16 for Ir and 6-31G(d) for other atoms. Vibrational frequencies were computed analytically at the same level of theory to confirm whether the structures are minima (no imaginary frequencies) or transition states (only one imaginary frequency). Key transition state structures were confirmed to connect corresponding reactants and products by intrinsic reaction coordinate (IRC) calculations.17 Solvation effects (solvent = diethylether, ε = 4.24) were taken into account by performing single-point calculations with the SMD model.18 To obtain better accuracy, energies of the optimized geometries were calculated using B3LYPD3(BJ)19 single-point calculations with a larger basis set, which is SDD for Ir and 6-311+G(d,p) for other atoms. The final free energies reported in the article (ΔGsol) are the large basis set single-point energies with gas-phase Gibbs free energy correction (at 298.15 K) and solvation correction. To further validate our computations, the single-point energies of enantioselectivity-determining transition states (R-TS5 and S-TS5) were re-calculated using M06 functional20, which gives an energy difference of 2.3 kcal/mol. Moreover, R-TS5 and S-TS5 were also reoptimized using B3LYP-D3(BJ) functional, which gives an energy difference of 3.2 kcal/mol. All these results are close to the energy difference reported in the main text (2.7 kcal/mol).

This work was supported by the National Natural Science Foundation of China (No. 21503143) and the Natural Science Foundation of Tianjin (No. 16JCQNJC05600).

REFERENCES 1.

2.

3.

4.

ASSOCIATED CONTENT Supporting Information. Additional computational results, computed energies, and Cartesian coordinates of all optimized structures. This material is available free of charge via the Internet at http://pubs.acs.org. 5.

AUTHOR INFORMATION Corresponding Author * Email: [email protected]; Web: http://genpinghuang.weebly.com

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT

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(a) Jones, R. G.; Ando, W.; Chojnowski, J. Silicon-Containing Polymers; Springer: Berlin, 2000; (b) Cash, G. G. Use of Graph-Theoretical Parameters to Predict Activity of Organosilane Insecticides. Pestic. Sci. 1997, 49, 29; (c) Franz, A. K. The synthesis of biologically active organosilicon small molecules. Curr. Opin. Drug Discovery Dev. 2007, 10, 654; (d) Franz, A. K.; Wilson, S. O. Organosilicon Molecules with Medicinal Applications. J. Med. Chem. 2013, 56, 388. For selected reviews, see: (a) Patai, S.; Rappoport, Z. The Chemistry of Organic Silicon Compounds; Wiley & Sons: New York, 2000; (b) Newton, C. G.; Wang, S.-G.; Oliveira, C. C.; Cramer, N. Catalytic Enantioselective Transformations Involving C–H Bond Cleavage by Transition-Metal Complexes. Chem. Rev. 2017, 117, 8908. For selected reviews, see: (a) Hartwig, J. F. Borylation and Silylation of C–H Bonds: A Platform for Diverse C–H Bond Functionalizations. Acc. Chem. Res. 2012, 45, 864; (b) Cheng, C.; Hartwig, J. F. Catalytic Silylation of Unactivated C-H Bonds. Chem. Rev. 2015, 115, 8946; (c) Yang, Y.; Wang, C. Direct silylation reactions of inert C-H bonds via transition metal catalysis. Sci. China: Chem. 2015, 58, 1266. For selected examples of the silylation of aromatic C(sp2)–H bonds, see: (a) Su, B.; Zhou, T.; Li, X.; Shao, X.; Xu, P.; Wu, W.; Hartwig, J. F.; Shi, Z. A Chiral Nitrogen Ligand for Enantioselective, Iridium-Catalyzed Silylation of Aromatic C-H Bonds. Angew. Chem. Int. Ed. 2017, 56, 1092; (b) Lee, T.; Wilson, T.W.; Berg, R.; Ryberg, P.; Hartwig, J. F. RhodiumCatalyzed Enantioselective Silylation of Arene C-H bonds: Desymmetrization of Diarylmethanols. J. Am. Chem. Soc. 2015, 137, 6742; (c) Ihara, H.; Suginome, M. Easily Attachable and Detachable ortho-Directing Agent for Arylboronic Acids in Ruthenium-Catalyzed Aromatic C-H Silylation. J. Am. Chem. Soc. 2009, 131, 7502; (d) Cheng, C.; Hartwig, J. F. Iridium-Catalyzed Silylation of Aryl C–H Bonds. J. Am. Chem. Soc. 2015, 137, 592; (e) Hua, Y.; Asgari, P.; Avullala, T.; Jeon, J. Catalytic Reductive ortho-C–H Silylation of Phenols with Traceless, Versatile Acetal Directing Groups and Synthetic Applications of Dioxasilines. J. Am. Chem. Soc. 2016, 138, 7982; (f) Ureshino, T.; Yoshida, T.; Kuninobu, Y.; Takai, K. Rhodium-Catalyzed Synthesis of Silafluorene Derivatives via Cleavage of Silicon−Hydrogen and Carbon−Hydrogen Bonds. J. Am. Chem. Soc. 2010, 132, 14324; (g) Zhang, Q.-W.; An, K.; Liu, L.-C.; Yue, Y.; He, W. Rhodium‐Catalyzed Enantioselective Intramolecular C-H Silylation for the Syntheses of PlanarChiral Metallocene Siloles. Angew. Chem., Int. Ed. 2015, 54, 6918; (h) Kuninobu, Y.; Yamauchi, K.; Tamura, N.; Seiki, T.; Takai, K. Rhodium-Catalyzed Asymmetric Synthesis of Spirosilabifluorene Derivatives. Angew. Chem., Int. Ed. 2013, 52, 1520. For selected examples of the silylation of C(sp3)–H bonds, see: (a) Lee, T.; Hartwig, J. F. Rhodium-Catalyzed Enantioselective Silylation of Cyclopropyl C-H Bonds. Angew. Chem. Int. Ed. 2016, 55, 8723; (b) Karmel, C.; Li, B.; Hartwig, J. F. Rhodium-Catalyzed Regioselective Silylation of Alkyl C–H Bonds for the Synthesis of 1,4-Diols. J. Am. Chem. Soc. 2018, 140, 1460; (c) Bunescu, A.; Butcher, T.W.; Hartwig, J. F. Traceless Silylation of β-C(sp3)–H Bonds of Alcohols via Perfluorinated Acetals. J. Am. Chem. Soc. 2018, 140, 1502; (c) Simmons, E. M.; Hartwig, J. F. Catalytic functionalization of unactivated primary C–H bonds


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The Journal of Organic Chemistry

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Si C-Si reductive elimination H C H2C (V) Si N Ir H H N [Si]

N (III) H Ir H [Si] active catalyst N

Ir(III)/Ir(V)

Si H nbe norbornane

N (III) [Si] Ir H [Si]

N C-H oxidative addition


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